Escolar Documentos
Profissional Documentos
Cultura Documentos
AN ENCYCLOPEDIC
REFERENCE
Volume 1
Acquisition Methods
Methods and Modeling
BRAIN MAPPING
AN ENCYCLOPEDIC
REFERENCE
Volume 1
Acquisition Methods
Methods and Modeling
EDITOR-IN-CHIEF
ARTHUR W. TOGA
University of Southern California, Los Angeles, CA, USA
SECTION EDITORS
PETER BANDETTINI
National Institute of Mental Health, Bethesda, MD, USA
PAUL THOMPSON
Keck USC School of Medicine, USA
KARL FRISTON
Wellcome Trust Centre for Neuroimaging, London, UK
15 16
17 18 19
10 9 8 7 6 5 4 3 2 1
CONTRIBUTORS
I Aganj
Massachusetts General Hospital, Harvard Medical
School, MA, USA
PA Ciris
Yale University School of Medicine, New Haven,
CT, USA
AL Alexander
University of Wisconsin Madison, Madison, WI, USA
RT Constable
Yale University School of Medicine, New Haven,
CT, USA
DC Alexander
University College London, London, UK
C Allefeld
Universitatsmedizin Berlin, Berlin, Germany
S Arridge
University College London, London, UK
J Ashburner
UCL Institute of Neurology, London, UK
PA Bandettini
National Institute of Mental Health, Bethesda, MD, USA
GR Barnes
University College London, London, UK
DS Barron
University of Texas Health Science Center at San Antonio,
San Antonio, TX, USA
Bharat Biswal
New Jersey Medical School, Rutgers University,
NJ, USA
DA Boas
Harvard Medical School, Charlestown, MA, USA
G Bruce Pike
University of Calgary, Calgary, AB, Canada
RB Buxton
University of California, San Diego, CA, USA
RJ Cooper
University College London, London, UK
P Coutin-Churchman
University of California at Los Angeles, Los Angeles,
CA, USA
O David
Universite Joseph Fourier, Grenoble, France
JA de Zwart
National Institutes of Health, Bethesda, MD, USA
G Deco
Universitat Pompeu Fabra, Barcelona, Spain
JH Duyn
National Institutes of Health, Bethesda, MD, USA
ES Finn
Yale University School of Medicine, New Haven,
CT, USA
C Fischer
CEA, Gif-sur-Yvette, France; CATI Multicenter
Neuroimaging Platform, Paris, France
B Fischl
Charlestown, MA, USA
G Flandin
UCL Institute of Neurology, London, UK
A Cachia
Universite Paris Descartes, Paris, France
PT Fox
University of Texas Health Science Center at San Antonio,
San Antonio, TX, USA; South Texas Veterans Health
Care System, San Antonio, TX, USA
MA Chappell
University of Oxford, Oxford, UK
KJ Friston
UCL Institute of Neurology, London, UK
vi
Contributors
C Gaser
Jena University Hospital, Jena, Germany
RD Hoge
Universite de Montreal, Montreal, QC, Canada
CR Genovese
Carnegie Mellon University, Pittsburgh, PA, USA
AR Hoy
United States Navy, Falls Church, VA, USA; University of
Wisconsin Madison, Madison, WI, USA
G Gerig
University of Utah, Salt Lake City, UT, USA
JH Gilmore
University of North Carolina, Chapel Hill, NC, USA
DR Gitelman
Professor of Neurology, Chicago Medical School at
Rosalind Franklin University, Park Ridge, IL, USA
RN Gunn
Imanova Ltd, London, UK; Imperial College London,
London, UK; University of Oxford, Oxford, UK
Q Guo
Imanova Ltd, London, UK; AbbVie Translational
Sciences, North Chicago, IL, USA; Kings College
London, London, UK; Imperial College London, London,
UK
A Jasanoff
Massachusetts Institute of Technology, Cambridge, MA,
USA
S Jbabdi
Oxford University Centre for Functional MRI of the Brain
(FMRIB), Oxford, UK
P Jezzard
University of Oxford, Oxford, UK
NK Kasabov
Auckland University of Technology, Auckland, New
Zealand
KN Kay
Stanford University, Stanford, CA, USA; Washington
University, St. Louis, MO, USA
A Hahn
Medical University of Vienna, Vienna, Austria
SJ Kiebel
Technische Universitat Dresden, Dresden, Germany
A Hai
Massachusetts Institute of Technology, Cambridge, MA,
USA
G Kindlmann
University of Chicago, Chicago, IL, USA
M Hamalainen
Aalto University, Espoo, Finland; Massachusetts General
Hospital, Charlestown, MA, USA
N Harel
University of Minnesota Medical School, MN, USA
R Hari
Aalto University, Espoo, Finland
J-D Haynes
Universitatsmedizin Berlin, Berlin, Germany; HumboldtUniversitat zu Berlin, Berlin, Germany
S Heldmann
Fraunhofer MEVIS, Lubeck, Germany
G Helms
Medical Radiation Physics, Lund University, Lund,
Sweden
RN Henson
MRC Cognition and Brain Sciences Unit, Cambridge, UK
PJ Koopmans
University of Oxford, Oxford, UK
N Kriegeskorte
Medical Research Council, Cambridge, UK
F Kurth
UCLA School of Medicine, Los Angeles, CA, USA
R Lanzenberger
Medical University of Vienna, Vienna, Austria
F Lecaignard
Lyon Neuroscience Research Center (CRNL), Lyon,
France; University Lyon 1, Lyon, France; Cermep
Imagerie du vivant, Lyon, France
J Lefe`vre
Aix-Marseille Universite, Marseille, France
C Lenglet
University of Minnesota Medical School, Minneapolis,
MN, USA
GT Herman
City University of New York, New York, NY, USA
JP Lerch
The Hospital for Sick Children, Toronto, ON, Canada;
University of Toronto, Toronto, ON, Canada
L Hernandez-Garcia
University of Michigan, Ann Arbor, MI, USA
KK Leung
UCL Institute of Neurology, London, UK
Contributors
Z-P Liang
University of Illinois at Urbana-Champaign, Urbana, IL,
USA
K Mueller
Max Planck Institute for Human Cognitive and Brain
Sciences, Leipzig, Germany
MA Lindquist
Johns Hopkins University, Baltimore, MD, USA
JA Mumford
University of Texas, Austin, TX, USA
TT Liu
University of California, San Diego, CA, USA
G Nedjati-Gilani
University College London, London, UK
JD Lopez
Universidad de Antioquia UDEA, Medelln, Colombia
G Operto
CEA, Gif-sur-Yvette, France; CATI Multicenter
Neuroimaging Platform, Paris, France
E Luders
UCLA School of Medicine, Los Angeles, CA, USA
M Maddah
Cellogy Inc., Menlo Park, CA, USA; SRI International,
Menlo Park, CA, USA
J-F Mangin
CEA, Gif-sur-Yvette, France; CATI Multicenter
Neuroimaging Platform, Paris, France
E Mark Haacke
Wayne State University, Detroit, MI, USA
J Mattout
Lyon Neuroscience Research Center (CRNL), Lyon,
France; University Lyon 1, Lyon, France
vii
X Papademetris
Yale University School of Medicine, New Haven, CT,
USA
N Papenberg
Fraunhofer MEVIS, Lubeck, Germany
L Parkkonen
Aalto University, Espoo, Finland
M Perrot
CEA, Gif-sur-Yvette, France; CATI Multicenter
Neuroimaging Platform, Paris, France
RA Poldrack
Stanford University, Stanford, CA, USA
AR McIntosh
Rotman Research Institute, Toronto, ON, Canada;
University of Toronto, Toronto, ON, Canada
JR Polimeni
Massachusetts General Hospital, Charlestown, MA, USA;
Harvard Medical School, Boston, MA, USA
RS Menon
The University of Western Ontario, London, ON, Canada
J-B Poline
University of California, Berkeley, CA, USA
MI Miller
Johns Hopkins University, Baltimore, MD, USA
A Ponce-Alvarez
Universitat Pompeu Fabra, Barcelona, Spain
D Millett
Hoag Hospital, Newport Beach, CA, USA
V Priesemann
Max Planck Institute for Brain Research, Frankfurt,
Germany
B Misic
Rotman Research Institute, Toronto, ON, Canada;
University of Toronto, Toronto, ON, Canada
J Modersitzki
University of Lubeck, Lubeck, Germany; Fraunhofer
MEVIS, Lubeck, Germany
R Moran
Virginia Tech Carilion Research Institute, Roanoke, VA,
USA; Bradley Department of Electrical and Computer
Engineering, Roanoke, VA, USA
O Puonti
Technical University of Denmark, Lyngby, Denmark
Y Rathi
Harvard Medical School, Boston, MA, USA
JR Reichenbach
Friedrich-Schiller University, Jena, Germany
GR Ridgway
University of Oxford, Headington, UK; UCL Institute of
Neurology, London, UK
S Mori
Johns Hopkins University School of Medicine, Baltimore,
MD, USA
D Rivie`re
CEA, Gif-sur-Yvette, France; CATI Multicenter
Neuroimaging Platform, Paris, France
M Muckley
University of Michigan, Ann Arbor, MI, USA
N Roberts
University of Edinburgh, Edinburgh, UK
viii
Contributors
A Roebroeck
Maastricht University, Maastricht, The Netherlands
J Tohka
Tampere University of Technology, Tampere, Finland
MJ Rosa
University College London, London, UK
X Tomas-Fernandez
Harvard Medical School, Boston MA, USA
N Sadeghi
National Institutes of Health, Bethesda, MD, USA
J-D Tournier
Florey Neuroscience Institutes, Heidelberg West, VIC,
Australia
G Sapiro
Duke University, NC, USA
D Scheinost
Yale University School of Medicine, New Haven, CT,
USA
F Schmitt
Siemens Healthcare, Erlangen, Germany
X Shen
Yale University School of Medicine, New Haven, CT,
USA
J Shi
Arizona State University, Tempe, AZ, USA
AC Silva
National Institutes of Health, Bethesda, MD, USA
JG Sled
Hospital for Sick Children, Toronto, ON, Canada;
University of Toronto, Toronto, ON, Canada
SM Smith
Oxford University Centre for Functional MRI of the Brain
(FMRIB), Oxford, UK
O Sporns
Indiana University, Bloomington, IN, USA
KE Stephan
University of Zurich & Swiss Federal Institute of
Technology (ETH Zurich), Zurich, Switzerland;
University College London, London, UK
JM Stern
University of California at Los Angeles, Los Angeles, CA,
USA
X Tang
Johns Hopkins University, Baltimore, MD, USA
BT Thomas Yeo
National University of Singapore, Singapore, Singapore;
Duke-NUS Graduate Medical School, Singapore,
Singapore; Massachusetts General Hospital, Charlestown,
MA, USA
R Todd Constable
Yale University School of Medicine, New Haven, CT,
USA
NJ Trujillo-Barreto
Institute of Brain, Behaviour and Mental Health, The
University of Manchester, UK
R Turner
Max Planck Institute for Human Cognitive and Brain
Sciences, Leipzig, Germany
D Tward
Johns Hopkins University, Baltimore, MD, USA
K Ugurbil
University of Minnesota, Minneapolis, MN, USA
K Uludag
Maastricht University, Maastricht, The Netherlands
A van der Kouwe
Charlestown, MA, USA
JD Van Horn
University of Southern California, Los Angeles, CA, USA
K Van Leemput
Harvard Medical School, Boston, MA, USA
JF Vargas
Universidad de Antioquia UDEA, Medelln, Colombia
TD Wager
University of Colorado at Boulder, Boulder, CO, USA
LL Wald
Massachusetts General Hospital, Charlestown, MA, USA;
Harvard Medical School, Boston, MA, USA; HarvardMIT Division of Health Sciences and Technology,
Cambridge, MA, USA
BA Wandell
Stanford University, Stanford, CA, USA
Y Wang
Cornell University, New York, NY, USA; Arizona State
University, Tempe, AZ, USA
SK Warfield
Harvard Medical School, Boston MA, USA
C-F Westin
Harvard Medical School, Boston, MA, USA
M Wibral
Goethe University, Frankfurt, Germany
Contributors
J Winawer
New York University, New York, NY, USA
MW Woolrich
University of Oxford, Oxford, UK
E Yacoub
University of Minnesota, Minneapolis, MN, USA
L Ying
State University of New York at Buffalo, Buffalo, NY,
USA
Y Zhang
Johns Hopkins University, Baltimore, MD, USA
ix
xv
Editor-in-Chief
xvii
Section Editors
xix
Acknowledgments
xxiii
29
37
AC Silva
Diffusion MRI
47
Echo-Planar Imaging
53
F Schmitt
75
81
K Uludag
89
High-Field Acquisition
97
RS Menon
103
117
Molecular fMRI
123
131
Myelin Imaging
137
R Turner
xi
xii
143
149
TT Liu
155
161
173
PA Bandettini
183
191
201
203
GT Herman
209
217
223
231
245
C Lenglet
253
257
265
271
M Maddah
277
287
G Helms
295
JG Sled
Rigid-Body Registration
301
J Tohka
307
315
Lesion Segmentation
xiii
323
Manual Morphometry
333
N Roberts
Voxel-Based Morphometry
345
351
JP Lerch
357
BT Thomas Yeo
365
Tissue Classification
373
Tensor-Based Morphometry
383
Surface-Based Morphometry
395
401
417
429
Tract-Based Spatial Statistics and Other Approaches for Cross-Subject Comparison of Local
Diffusion MRI Parameters
437
465
471
477
RN Henson
483
DR Gitelman
Design Efficiency
489
RN Henson
Topological Inference
495
501
CR Genovese
509
517
MJ Rosa
Variational Bayes
MA Chappell and MW Woolrich
523
xiv
535
NJ Trujillo-Barreto
541
RB Buxton
549
557
563
O David
571
581
Bharat Biswal
Effective Connectivity
587
Granger Causality
593
A Roebroeck
599
617
KE Stephan
Dynamic Causal Models for Human Electrophysiology: EEG, MEG, and LFPs
625
R Moran
629
O Sporns
Crossvalidation
635
N Kriegeskorte
641
Reverse Inference
647
RA Poldrack
651
661
667
NK Kasabov
675
Databases
685
JD Van Horn
697
PREFACE
The contributions of brain mapping are self-evident. Perhaps only a few areas of science have been applied as
broadly and deeply as brain mapping. In less than 50 years, it has revolutionized the study of brain structure
and function as well as the practice of clinical neuroscience. The resulting images derived from brain mapping
studies can be found everywhere. They grace the covers of many scientific journals, and even permeate the lay
media. The arresting imagery derived from sophisticated brain mapping methodologies and applied to
previously intractable problems has transformed neuroscience like no other specialty.
Brain mapping is a field that encompasses a wide range of scientific areas from MR physics, molecular
dynamics, and the mathematical modeling of data to the anatomical and physiological measurement of brain
systems and the study of complex cognitive functions. These all have been applied to understand the human
condition in health and disease. Advances have led to new effective treatments in stroke and improved
therapeutic intervention in many diseases affecting the brain. New approaches have enabled measures that
differentiate us as individuals anatomically and functionally. Maps that represent whole populations of people
of a certain age, gender, handedness, suffering from a particular neurological or psychiatric condition or even
genetic cohorts with a particular single nucleotide polymorphism can be created. The utility of these maps as
biomarkers or as guides in clinical trials has become a reality. Brain mapping is as vibrant and dynamic as ever
and increasingly links to other paths of discovery including genetics, proteomics, biologics, and big data.
The creation of this encyclopedia comes at a time that acknowledges the spectacular growth and important
contributions already made and the promise for ever more exciting and significant discoveries. It was just about
20 years ago that the first of the Brain Mapping Trilogy was published with the title, Brain Mapping: The Methods.
At about the same time, a group of brain imaging scientists decided it would be a good idea to form a new
society and the Organization for Human Brain Mapping was born. There are now several journals devoted to
neuroimaging and brain mapping. Other periodicals focused on more general neuroscience invariably include
a considerable number of papers on brain mapping. For the last couple of decades the number of brain
mapping publications grew from around 3200 in 1996 to about 14 000 in 2013, more than a 400% increase!
What a remarkable 20 years it has been. No longer can the breadth of brain mapping be covered in a traditional
text book style. The field has grown just too large.
Given the fact that there are well over 100 000 published papers on brain mapping, an encyclopedic
reference system to navigate these numbers is sorely needed. The three volumes of this encyclopedia fill that
need and consist of a comprehensive collection of thoughtful and informative descriptions of each topic. Well
referenced and written by recognized authorities, each article provides a wealth of information for the novice
and expert alike.
We organized the encyclopedia into seven sections. Volume 1 includes sections entitled Acquisition Methods
edited by Peter Bandettini and another entitled Methods and Modeling edited by Karl Friston and Paul Thompson. Acquisition Methods includes descriptions of magnetic resonance imaging (MRI), functional magnetic
resonance imaging (fMRI), magnetoencephalography (MEG), positron emission tomography (PET), and
near-infrared spectroscopy (NIRS). Most of the articles focus on variations in fMRI acquisition, given the
range and extent of this brain imaging method. However, it is clear that other approaches covered in this section
have lots to offer in the study of brain, each with its own advantages and disadvantages and each method has its
limitations, no one is a panacea. All are highly complementary and benefit from the synergy of multimodal
integration described further in Methods and Modeling. Here, Friston and Thompson selected papers describing advances in analytics built upon novel mathematics for representing and modeling signals, detecting
patterns, and understanding causal effects. These have accelerated the contributions of imaging and brain
xv
xvi
Preface
mapping significantly. Creative applications of random fields to dynamic causal models, graph theory,
networks, and topological measures of connectomes, to chart connections inferred from functional synchrony
or anatomical circuitry. Continuum mechanics fluid flow, differential geometry, and relativity all have been
used to model and manipulate anatomical surfaces in the brain, and to align and compare observations from
whole populations.
Volume 2 includes a section on Anatomy and Physiology edited by Karl Zilles and Katrin Amunts and another
devoted to Systems edited by Marsel Mesulam and Sabine Kastner. In the Anatomy and Physiology section, the
functional, cellular, and molecular basics along with organizational principles of brain structure provide a solid
foundation for models and simulations. This section goes on to provide an overview of brain development
beginning with the evolution of the cerebral cortex as well as embryonic and fetal development of the human
brain. Finally, the last part of this section is dedicated to different brain regions with emphasis focused on
functional systems and a superb lead into Systems. The section on Systems edited by Mesulam and Kastner is
comprised of articles that address the functional anatomy of action, perception, and cognition in multiple
modalities and domains.
Volume 3 contains sections on Cognitive Neuroscience edited by Russ Poldrack and another focused on Social
Cognitive Neuroscience edited by Matthew Lieberman and a third covering Clinical Brain Mapping edited by
Richard Frackowiak. The section on Cognitive Neuroscience covers a broad range of topics on mapping cognitive
functions including attention, learning and memory, decision making, executive function, and language. There
are articles on neuroeconomics, a field that combines neuroscience, psychology, and economics to better
understand the neural mechanisms for decision making. There is also a series of papers on memory, including
episodic memory, familiarity, semantic memory, and nondeclarative forms of learning. Language is covered in
this section as well, with articles on speech perception and production, syntax, semantics, and reading.
Poldrack also included studies of unique populations such as sign language speakers, bilinguals, and individuals with reading disabilities.
The section on Social Cognitive Neuroscience deals with how our brain responds to our social world. There are
papers that chart the different ways in which people respond to the rewards and punishments of social living
such as perceptions of unfair treatment, social rejection, or other negative social influences. There are also
articles describing neural mechanisms for reward and incentive motivation that respond to reinforcers like
money or sexual cues. Another part of this section deals with the concept of self. And another explores the
basic mechanisms of social perception. These articles focus on the perception of faces, bodies, and emotions as
basic cues. Also included are articles about social thinking and attitudinal and evaluative processes that keep
track of what matters to us and who or what we align ourselves with or against. Clinical Brain Mapping provides
numerous examples of the translational value of brain mapping. For example, the time course and cascade of
stroke pathophysiology pointed to the need for hyperacute treatment with thrombolytics. The contribution of
functional imaging first with PET and subsequently with fMRI, forever altered clinical neurology, neurosurgery
and other clinical neuroscience specialties. The ability to perform scans repetitively gave insights into functional
dynamics in the human brain enabling investigations of neurodegenerative disease, psychiatric disorders, and
the efficacy of therapeutic intervention.
Each of these sections stands alone as a comprehensive collection of articles describing the how, why, and
what brain mapping has contributed to these areas. Each article introduces the topic and brings the reader up to
date with the latest in findings and developments. We deliberately structured the encyclopedia so that readers
can peruse the material in any order or concentrate on a particular set of topics from methods to applications.
We kept the articles concise and suggest further reading to those who desire a more extensive review. They are
well referenced and illustrated appropriately.
Together these articles comprise a unique and rich resource for anyone interested in the science of mapping
the brain.
Arthur W. Toga
EDITOR-IN-CHIEF
Arthur W. Toga is the director, Laboratory of Neuro Imaging; director, Institute
of Neuroimaging and Informatics; provost professor, Departments of Ophthalmology, Neurology, Psychiatry, and the Behavioral Sciences, Radiology
and Engineering at the Keck School of Medicine of USC. His research is focused
on neuroimaging, informatics, mapping brain structure and function, and
brain atlasing. He has developed multimodal imaging and data aggregation
strategies and applied them in a variety of neurological diseases and psychiatric
disorders. His work in informatics includes the development and implementation of some of the largest and most widely used databases and data mining
tools linking disparate data from genetics, imaging, clinical and behavior,
supporting global efforts in Alzheimers disease, Huntingtons, and Parkinsons
disease. He was trained in neuroscience and computer science and has written
more than 1000 papers, chapters, and abstracts, including eight books. Recruited to USC in 2013, he directs the
Laboratory of Neuro Imaging. This 110-member laboratory includes graduate students from computer science,
biostatistics, and neuroscience. It is funded with grants from the National Institutes of Health grants as well as
industry partners. He has received numerous awards and honors in computer science, graphics, and neuroscience. Prior to coming to USC he was a distinguished professor of Neurology at UCLA, held the Geffen Chair of
Informatics at the David Geffen School of Medicine at UCLA, associate director of the UCLA Brain Mapping
Division within the Neuropsychiatric Institute, and associate dean, David Geffen School of Medicine at UCLA.
He is the founding editor-in-chief of the journal NeuroImage and holds the chairmanship of numerous
committees within NIH and a variety of international task forces.
xvii
SECTION EDITORS
Peter A. Bandettini is chief of the section on Functional Imaging Methods and
director of the Functional MRI Core Facility at the National Institutes of
Health. He is also editor-in-chief of the journal NeuroImage. He received his
BS from Marquette University in 1989 and his PhD from the Medical College
of Wisconsin in 1994, where he pioneered the development of magnetic
resonance imaging of human brain function using blood oxygenation contrast.
During his postdoctoral fellowship at the Massachusetts General Hospital with
Bruce Rosen, he continued his investigation of methods to increase the interpretability, resolution, and applicability of functional MRI techniques. In
1999, he joined NIMH as an investigator in the Laboratory of Brain and
Cognition and as the director of the NIH Functional MRI Core Facility. In
2001, he was awarded the Scientific Directors Merit Award for his efforts in
establishing the NIH FMRI Core Facility. In 2002, he was conferred the Wiley
Young Investigators Award at the Annual Organization for Human Brain
Mapping meeting. His section on Functional Imaging Methods is currently
developing MRI methods to improve the spatial resolution, temporal resolution, sensitivity, interpretability, and applications of functional MRI. Recently,
his research has focused specifically on improving general methodology for
fMRI applications at 3 and 7 T, investigation of fMRI-based functional connectivity methodology and applications, and investigation of fMRI decoding
methodology and applications. He has published over 120 papers and 20
book chapters and has given over 300 invited presentations. Recently, his
paper Time course EPI of Human Brain Function during Task Activation was
honored by the journal, Magnetic Resonance in Medicine, as one of their 30
papers in the past 30 years that helped shape the field.
Marsel Mesulam is director of Cognitive Neurology and Alzheimers Disease
Center, Northwestern University. He has completed his MD in medicine from
Harvard Medical School in 1972, received his postdoctoral fellow ship from
Harvard University in 1977. He was conferred with Bengt Winblad Lifetime
Achievement Award from Alzheimers Association in 2010 and Lishman Lectureship Award from International Neuropsychiatric Association. His research
interests are neural networks, functional imaging, dementia, cerebral cortex,
and cholinergic pathways. Also he has received Distinguished Career Contribution Award from the Cognitive Neuroscience Society and the Potamkin Prize
from the American Academy of Neurology.
xix
xx
Section Editors
Sabine Kastner is professor at the Princeton Neuroscience Institute and Department of Psychology, Princeton University, Princeton, NJ. She has received her
M.D. from the University of Dusseldorf (Germany) in 1993 and her Ph.D from
the University of Gottingen (Germany) in 1994, and did postdoctoral training at
NIMH. She was conferred with Young Investigator award from the Cognitive
Neuroscience Society (2005), the John Mclean, Jr., Presidential University
Preceptorship from Princeton University (2003), and is a fellow of the American
Psychological Society. Her research interests include the neural basis of visual
perception, attention and awareness, studied in two primate brain models
(monkey and human) with functional brain imaging and electrophysiology.
Richard Frackowiak studied medicine at the University of Cambridge where he
first became interested in the neurosciences. He joined the Medical Research
Councils Cyclotron Unit at Hammersmith Hospital, London, in 1979, under
Professor Terry Jones, who had just installed one of Britains first Positron Emission Tomography (PET) scanners. Richard Frackowiak is director at Department of
Clinical Neuroscience and Head of Service of Neurology, CHUV University Hospital, Lausanne, Switzerland. Frackowiak has won the IPSEN and Wilhelm Feldberg prizes and during the 1990s was the fourth most highly cited British
biomedical scientist. His books include Human Brain Function and Brain Mapping:
The Disorders. He is currently setting up a new Clinical Neuroscience Department
at the University of Lausanne. His research interest has been the functional and
structural architecture of the human brain in health and disease. He has pioneered
the development and introduction of positron emission tomography and magnetic resonance imaging and prosecuted a research programme dedicated to
understanding the organization of human brain functions, but his focus has
been on plasticity and mechanisms for functional recuperation after brain injury
and the patho-physiology of cerebral neurodegenerations. He has become interested in the use of MR-based morphometry especially in the study of genetic
influences on brain disease and in a search for biomarkers and endophenotypes
of neurodegenerative disorders. Most recently he has introduced computerized
image classification for diagnosis and treatment monitoring into clinical science.
Matthew Lieberman received his PhD from Harvard University. Lieberman,
with Kevin Ochsner, coined the term Social Cognitive Neuroscience, an area of
research that integrates questions from the social sciences which the methods
of cognitive neuroscience and has become a thriving area of research.
Lieberman has been a professor at UCLA in the Departments of Psychology,
Psychiatry and Biobehavioral Sciences since 2000. His work uses functional
magnetic resonance imaging (fMRI) to examine the neural bases of social
cognition and social experience. In particular, his work has examined the
neural bases of social cognition, emotion regulation, persuasion, social rejection, self-knowledge, and fairness. His research has been published in top
scientific journals including Science, American Psychologist, and Psychological
Science. His research has been funded by grants from the National Institute of
Mental Health, National Science Foundation, Guggenheim Foundation, and
Defense Advanced Research Projects Agency. His work has received coverage by
HBO, The New York Times, Time magazine, Scientific American, and Discover
Magazine. Lieberman is also the founding editor of the journal Social Cognitive
and Affective Neuroscience and helped create the Social and Affective Neuroscience
Society. Lieberman won the APA Distinguished Scientific Award for Early
Career Contribution to Psychology (2007) and campus wide teaching awards
from both Harvard and UCLA. He is the author of the book Social: Why Our
Brains Are Wired to Connect (finalist for the LA Times Book Prize and winner of
the Society for Personality and Social Psychology Book Prize).
Section Editors
xxi
Karl Zilles, MD, PhD, graduated from the University of Frankfurt, medical
faculty, and received the MD (1971) and the PhD (1977) in anatomy from the
Hannover Medical School, Germany. He was full professor of anatomy and
neuroanatomy at the University of Cologne between 1981 and 1991 and at
the University of Dusseldorf between 1991 and 2012. Additionally, he was
director of the C. & O. Vogt-Brain Research Institute, Dusseldorf, from 1991 to
2012, and of the Institute of Neuroscience and Medicine, Research Center Julich,
Germany, from 1998 to 2012. He is currently JARA senior professor at the
Research Center Julich and at the RWTH Aachen University, Germany. He serves
as editor-in-chief of the journal Brain Structure and Function and was member of
editorial boards of various scientific journals (e.g., NeuroImage). Karl Zilles is
fellow of the German National Academy of Sciences Leopoldina and fellow of
the North-Rhine Westphalia Academy of Science and Arts. His research focus is
on the structural (cyto- and myeloarchitecture), molecular (receptor architecture), and functional (neuroimaging using MRI, fMRI, and PET) organization of
the mouse, rat, nonhuman primate, and human cerebral cortex. He pioneered
brain mapping based on the regional and laminar distribution of transmitter
receptors in the healthy and pathologically impaired human brains and brains
of genetic mouse and models. He recently introduced, together with Katrin
Amunts, Markus Axer, and colleagues, an ultra-high-resolution method for
nerve fiber and fiber tract visualization based on polarized light imaging in the
human, monkey, mouse, and rat brains. He published more than 590 original
articles in nature, science, neuron, brain, and other peer-reviewed journals.
Katrin Amunts, MD, PhD, graduated in 1987 from the Pirogov Medical School
in Moscow, Russia. She received the PhD (1989) in neuroscience, anatomy from
the Institute of Brain Research at the Lumumba University in Moscow, Russia.
After her postdoc at the C. & O. Vogt Institute for Brain Research of the HeinrichHeine-University Dusseldorf, Germany, and at the Institute of Neuroscience and
Medicine, Research Center Julich, she became associate professor for StructuralFunctional Brain Mapping (2004), and full professor at the Department of
Psychiatry, Psychotherapy, and Psychosomatics of the RWTH Aachen University
(2008) as well as director of the Institute of Neuroscience and Medicine (INM-1)
at the Research Centre Julich. Since 2013, she is additionally full professor for
Brain Research and director of the C. & O. Vogt Institute for Brain Research, at the
Heinrich-Heine-University Dusseldorf. She is a member of the editorial board of
Brain Structure and Function. Currently, she is member of the German Ethics
Council and speaker for the programme Decoding the Human Brain of the
Helmholtz Association, Germany. Katrin Amunts is interested in understanding
the relationship between the microstructure of the human brain and functional
systems such as motor control, language, and vision. Although scientists have
been studying brain cytoarchitecture for over 100 years, its importance has
increased rapidly with the advance of modern imaging techniques. This led,
together with Karl Zilles and his team, to the development of a novel, observerindependent and functionally relevant cytoarchitectonic mapping strategy resulting in freely available brain maps comprising approximately 200 areas and
nuclei, as well as the anatomy toolbox software, developed with Simon Eickhoff,
for co-localizing functional activations and cytoarchitectonically defined brain
regions. The Julich atlas JuBrain as a multimodal human brain model will replace
during the next decade the cytoarchitectonic brain atlas, which Korbinian Brodmann published in 1909 (Zilles and Amunts, Nature Reviews Neuroscience,
2010). Recently, the group has provided the first ultra-high resolution model of
the human brain, the BigBrain (Amunts et al., Science, 2013).
xxii
Section Editors
ACKNOWLEDGMENTS
Sometimes, the scope and structure of a book is clear from the outset, other times it evolves as the outlines are
written or because contributors with different perspectives suggest new and different things. This book
occasionally took on a life of its own, morphing into something greater than the original concept. But that
was because of the hundreds (literally) of people who contributed to it. Working independently and together
we created a one-of-a-kind collection of excellent articles on brain mapping, from data generation to knowledge
about the brain. This collaborative effort is one of the greatest joys in working on project of this magnitude. The
end result is a mix of all this expertise into a single product. While such a process could easily produce chaos, in
this case each editor had a clear vision that complemented the other sections of the book. Each contributor
produced a superb article and collectively they cover the field.
One of the most difficult aspects of this project was limiting the scope because its magnitude kept getting
larger the more we all talked about it. There are so many new areas within brain mapping. There are so many
creative ways to apply the ever increasing number of methods to study the structure and function of brain in
health and disease. This scope further motivated us to create an encyclopedia because the field was not only
ready for such a thing, it needed it.
Many of us who worked on this book have known each other for a long time. Others of you are new
acquaintances, but to each of you I owe my sincerest gratitude. You are among the best and brightest minds in
neuroscience and your participation made this book. Your research and writing will be appreciated by the
readers for many years to come.
In addition to all the contributors writing and editing chapters and sections there are many others who
deserve mention. At the Laboratory of Neuro Imaging at the University of Southern California I am privileged
to have a spectacular staff. Grace Liang-Franco manages the lab with an efficiency and deftness that defies limits.
Sandy, Diana, and Catalina all keep things moving smoothly and professionally so I can work on projects like
this encyclopedia. Thanks to you all. The team at Elsevier has been terrific. They have tolerated the fits and starts
associated with a project like this and helped usher into the world an important and substantial work. Thanks
to Mica Haley, Ashlie Jackman, Will Bowden-Green, Erin Hill-Parks, and many others.
Finally, I always express gratitude to my family. They do not help me write or edit or even read the things I
write but somehow they make it possible. I work at home in the evenings and on weekends, just like many of
you reading this book. I guess I could be doing other things but my family tolerates this behavior and has for
decades. Perhaps they are happy I am preoccupied with academic pursuits. It keeps me busy and out of their
hair. But for whatever the real reason, my wife Debbie, and my children Nicholas, Elizabeth, and Rebecca let me
work on these things and I appreciate them more than can be stated here.
Arthur W. Toga
Los Angeles, CA
xxiii
Brain imaging can be thought of as evolving along the parallel paths of applications, methods and modeling,
and acquisition techniques. Each plays a fundamental role in shaping the direction and setting the pace of brain
imaging advancement. The field itself has been defined by the depth and quality of interaction between these
paths, as well as a balance of effort for each. For instance, as new methods for data acquisition are developed,
fundamentally new questions about the brain may be asked perhaps at higher temporal or spatial resolution
or with higher sensitivity and new methods, tailored to the specific acquisition method and with the specific
questions or applications in mind, are developed. From this, new clinical applications or new biomarkers may
emerge.
This section, Acquisition Methods, is an overview of the major acquisition methods that have been
developed over the years each with specific capabilities, costs, limitations, and unique potential. A leader
in the field who has pioneered and advanced their particular acquisition method has written each article.
The acquisition methods described in this section include magnetic resonance imaging (MRI), functional
magnetic resonance imaging (fMRI), magnetoencephalography (MEG), positron emission tomography (PET),
near-infrared spectroscopy (NIRS), and electroencphalography (EEG). The bulk of the articles focus on the many
aspects of fMRI acquisition, as, in the past decade, fMRI has become the predominant brain imaging method.
However, a clear message from these articles is that there is no one best method. All the methods not only are
highly complementary but also can stand to benefit substantially from the synergy of multimodal integration.
The advancement of MRI methods has mostly been driven by technological advancements; however, a surprisingly large number of advancements have been in data processing, resulting in novel applications for neuroscience research and headways into wider clinical use. EEG, MEG and PET have also had something of a resurgence
in recent years as the limits inherent to MRI and fMRI have been more clearly delineated.
A didactic and detailed Anatomical MRI for Human Brain Morphometry article begins this section. A method
invented in the late 1970s and implemented in the early 1980s, MRI provides high spatial resolution and soft
tissue contrast without ionizing radiation, making it the modality of choice for structural brain imaging
applications, including human brain morphometry. This article describes the basics of MRI, some perspective
on the field, and useful details for the sophisticated user. Diffusion MRI, advanced in the late 1980s to early
1990s, is a flourishing field that has grown in sophistication and in relevance to neuroscience as it has shed light
on everything from brain connectivity to localization of lesions associated with trauma to the brain. While
Diffusion Tensor Imaging (DTI) has become an accepted clinical procedure, there is no consensus for best
acquisition and the area itself continues to rapidly evolve. A more recently developed MRI-based method,
susceptibility-weighted imaging (See Susceptibility-Weighted Imaging and Quantitative Susceptibility Mapping), derives its contrast from differences in susceptibility between tissue, thus highlighting, among other things,
iron in the tissue and blood, leading to exciting clinical applications and breathtakingly unique and detailed
images of brain anatomy and venous vasculature. The most recently emergent anatomical MRI technique is
myelin imaging (See Myelin Imaging) or myelography, which, like many MRI acquisition methods, is relatively
easy to implement, yet has taken considerable time to develop as our understanding of how brain anatomy and
physiology influence MRI contrast is even after 30 years still growing.
Since its inception in the early 1990s, functional MRI has grown rapidly in popularity, quickly growing to be
the method of choice for neuroscientists who want to noninvasively map systems-level activity in humans. This
success was due to many factors. First, the ubiquity of fMRI-ready scanners in hospitals around the world from
the decade-earlier insurgence of MRI as a powerful clinical tool was a large factor in the rapidity of the growth of
fMRI. Other aspects of fMRI, including the fidelity and repeatability of the functional signal, the complete
noninvasiveness of the method, and the relatively high spatial and temporal resolution also contributed to its
success. As of 2014, over 2500 papers per year are published using fMRI acquisition. Because of this, and
because fMRI acquisition is still rapidly evolving and diversifying, many articles in this section are devoted to
this area.
Obtaining quantitative information from fMRI/MRI data (See Obtaining Quantitative Information from
fMRI) outlines the current methods for using blood oxygen level-dependent (BOLD) contrast for obtaining
quantitative measures of oxidative metabolism, perfusion, and blood volume changes with activation. Echo
planar imaging (EPI) (See Echo-Planar Imaging) is the method of choice in part because of its speed but
primarily because of its stability. While fMRI acquisition has evolved over the years, the basic method, EPI, has
stayed mostly the same. The hemodynamic signal changes are a source of intense study as they are so neural
information-rich yet so variable and sensitive to other aspects of brain physiology. FMRI dynamics (See
Functional MRI Dynamics) explores all the temporal aspects of the BOLD signal changes. Though BOLD
has been the functional contrast of choice for brain activation, perfusion contrast (See Perfusion Imaging with
Arterial Spin Labeling MRI) has played an important role over the years and has considerable potential for
addressing questions and perhaps slow temporal scales that BOLD cannot. Functional MRI is not limited to
endogenous contrast. In fact, both human and animal studies have benefited substantially from novel
application of contrast agents (See Contrast Agents in Functional Magnetic Resonance Imaging). Article 13
is devoted to the discussion on the development of fMRI contrast agents for molecular imaging (See Molecular
fMRI). Functional MRI fundamentally is based on the acquisition hardware. Article 9 outlines the evolution of
hardware as well as the cutting edge hardware for fMRI (See Evolution of Instrumentation for Functional
Magnetic Resonance Imaging). The most fundamental piece of MRI and fMRI hardware, the main magnetic
field, continues to increase. Two chapters in this section describe the unique challenges and advantages of highfield acquisition (See High-Field Acquisition and fMRI at High Magnetic Field: Spatial Resolution Limits
and Applications).
Several articles describe the limits and potential of fMRI in terms of speed and resolution from a predominantly pulse sequence perspective (See High-Speed, High-Resolution Acquisitions) and a predominantly
hemodynamic perspective (See Temporal Resolution and Spatial Resolution of fMRI). Two other papers
provide comprehensive perspectives of the decision process and variables associated with choosing for the
optimal pulse sequence and acquisition scheme discussing the trade-offs and several applications (See Pulse
Sequence Dependence of the fMRI Signal, MRI and fMRI Optimizations and Applications).
Lastly, the fields of functional near-infrared spectroscopy (See Functional Near-Infrared Spectroscopy),
PET (See Positron Emission Tomography and Neuroreceptor Mapping In Vivo), EEG (See Basic Principles of
Electroencephalography), and MEG (See Basic Principles of Magnetoencephalography) are all well
described by the leaders and pioneers of each. The article on PET also includes the application of neuroreceptor
mapping. The article on MEG also delves into other electrophysiological techniques including EEG.
Overall, the Acquisition Method section provides useful practical knowledge as the articles are highly
readable and didactic. Importantly, this section also provides a history and a broad perspective of the
technology- and acquisition related-issues that have shaped the field of brain imaging.
Peter A. Bandettini
Glossary
Introduction
More than any other imaging modality, MRI provides exquisite
soft tissue contrast that is especially valuable for identifying
anatomy and pathology in the brain. Indeed, one of the earliest
clinical market drivers of MRI, in the early 1980s, was its ability
to definitively and positively diagnose multiple sclerosis (MS).
Before then, MS could only be inferred from the observable
symptoms by eliminating all of the alternative pathologies.
With MRI, the white matter lesions that characterize MS
could be seen directly. With MRI, it also became possible to
collect images of the brain with any slice orientation. Today,
the ability to image with high, isotropic resolution and excellent contrast has enabled reliable and automated brain morphometric analyses.
Fundamental particles such as protons (or hydrogen nuclei
1
H) possess an intrinsic physical property called spin, a quantized form of angular momentum. Like a spinning charged
particle in classical electrodynamics, particles with spin behave
like magnetic dipoles. Groups of particles with spin tend to
align in a static magnetic field, and in the aggregate, they
exhibit classical behavior, like a spinning gyroscope. When
energy is added to the system by an external radio frequency
(RF) pulse with a magnetic component perpendicular to the
static magnetic field, the aggregate magnetic moment is tipped
away from the equilibrium state. MRI derives its signal from
the relaxation of the spins back to their equilibrium state,
during which time they relinquish the absorbed energy and
http://dx.doi.org/10.1016/B978-0-12-397025-1.00001-4
Figure 1 Examples of (top) 5 FLASH (PD-weighted) images, (middle) 30 FLASH (T1-weighted) images, and (bottom) MEMPRAGE (T1-weighted)
images. Note that the amount of weighting depends on the sequence and its associated parameters.
t=T1
Mz t Mz, eq Mz, eq Mz 0 e
[1]
[2]
[3]
Figure 2 Clinical T2-weighted TSE scan with high (0.7 0.7 mm2 interpolated to 0.35 0.35 mm2) in-plane resolution (left) and thick (3 mm)
axial slices evident in sagittal view (right).
Figure 3 SPGR (left) versus MPRAGE. Trading off SNR for CNR.
classes is Gaussian-distributed with different means and variances. The multivariate extension of this measure is the Mahalanobis distance, which is the squared difference between the
class means scaled by the inverse of the covariance matrix (see
Duda and Hart, 1973; for an extensive discussion on this type of
modeling). One further point to note is that it is rarely raw CNR
that we care about, but rather how efficiently we can acquire
images with a given CNR. For example, if one sequence yields a
10% increase in CNR relative to another but requires four times
as long to collect, we would normally consider this a poor tradeoff, as we know that in four times the scan time, we could reduce
the noise by a factor of two and therefore improve our CNR by
two. Thus, the measure we use to assess the quality of an MR
sequence is typically CNR per unit time, which is simply the
CNR divided by the square root of the acquisition time. Thus,
longer acquisitions are penalized as they take up valuable scan
time that could otherwise have been used to acquire multiple
images of a shorter type and average them to increase the CNR.
Finally, it is worth pointing out that because it is CNR per unit
time that we ultimately care about in brain morphometry, we
frequently use MR parameters that increase contrast at the price
of reduced signal or increased noise. A common example of this
will be covered later and is shown in Figure 3, which shows a
fast low-angle shot (FLASH) or spoiled gradient-echo (SPGR)
image on the left compared with a magnetization-prepared rapid
gradient-echo (MPRAGE; Mugler & Brookeman, 1990) image on
the right. As can be seen, the FLASH image has very low withinclass variance and hence high signal-to-noise ratio (SNR). Conversely, the MPRAGE allows more within-class noise to achieve a
significantly larger difference between the class means of gray
matter and white matter, thus resulting in better CNR (or CNR
per unit time) than the FLASH scan despite the reduction of
within-class SNR.
B0
(Direction of main
magnetic field)
Magnetic field without
magnetic field gradients
Figure 4 Schematic of magnetic field before (left) and after (right) the application of the magnetic field gradients used to encode spatial location.
The isocenter is shown in red.
ix 1 i 1
y
[6]
iy 1
[7]
where
readoutx
PEx 1 sample
x
DPEx ix , ix 1 sampleN
ix 2
[8]
h
iNz
90seliz PE iy readoutx
Ny
iz 1 i 1
y
[9]
10
[10]
[11]
Mz TR Mz 0 eTR=T1 Mz, eq 1 eTR=T1
Let E1 eTR=T1 and insert [10] into [11]:
Mz TR Mz 0 cos aE1 Mz, eq 1 E1
[12]
sin a1 E1 TE=T2*
e
1 cos aE1
[13]
where PD Mz,eq, because the equilibrium longitudinal magnetization is proportional to the PD. The flip angle yE that
maximizes the signal for a specific TR and T1 is obtained by
finding the root of the derivative of [13] with respect to a for
which the second derivative is negative:
[14]
yE arccos eTR=T1
This flip angle is called the Ernst angle. For the purposes of
brain morphometry, it is important to note that while the Ernst
angle provides maximum signal, it does not necessarily provide maximum contrast. Generally, signal or time is traded for
contrast.
From eqn [13], it is clear that the FLASH signal is influenced
by parameters that depend on the tissue being imaged (PD, T1,
and T*)
2 and on the sequence parameters (TR, TE, and a). For
all sequence parameters, the FLASH image is linearly weighted
by PD. For small flip angles, eqn [13] reduces to
*
SFLASH PDsinaeTE=T2 , that is, there is no T1 weighting when
the flip angle a approaches zero. As a increases, T1 weighting
increases but overall signal decreases when a > yE. Equation [13]
also shows that T2* weighting increases directly with TE, but this
is accompanied by an overall signal decrease. Clearly, it is
necessary to define SNR and CNR before choosing sequence
parameters for any particular application, and it is also useful to
express these quantities per unit time, as explained in Section
Signal, Noise, and Contrast.
11
Figure 5 (Top) PD values (arbitrary units) and (bottom) T1 values (ms) derived from the combination of the 5 and 30 FLASH acquisitions
shown in Figure 1. Parameters were estimated by fitting the FLASH signal eqn [13].
12
0.3
WM-GM
GM-CSF
0.2
Contrast (AU)
Signal (AU)
0.8
0.6
WM (T1 = 700 ms)
0.4
0.2
0
500
1000
1500
0.1
2000
TR (ms)
-0.1
500
1000
1500
2000
TR (ms)
Figure 6 (Left) Typical FLASH contrast curves (signal vs. TR) for GM (blue), WM (red), and CSF (purple). (Right) Contrast curves for WMGM (blue)
and GMCSF (magenta). The dotted lines indicate the maximum difference in signal between WM and GM (blue dotted) and between GM and
CSF (pink dotted).
Figure 7 (Top) Cortical surface showing FLASH flip angle (with TR 20 ms) required to maximize gray matter/white matter contrast across the
cortex (scale varies from 15 to 20 ) in a healthy young volunteer. (Bottom) Inflated surface showing details in the sulci.
shows how the FLASH signal changes with TR for these tissue
classes, and the optimal value can be calculated for each pair of
classes. This argument has been extended to multiecho FLASH
(MEF) acquisitions (Han et al., 2006) where the multidimensional information is valuable in segregating multiple tissue
classes, especially the subcortical brain regions.
Before starting a study, it is worthwhile to consider the
neuroanatomical question to be answered and the population
group(s) of interest. Tissue parameters (PD, T1, and T2) are
known to vary with age and brain region (Hasan, Walimuni,
Kramer, & Frye, 2010; Saito, Sakai, Ozonoff, & Jara, 2009;
Suzuki, Sakai, & Jara, 2006). In neonates, considerable myelination continues until 1224 months of age, and substantial
brain development continues into the third decade of life
10
9
8
7
6
5
4
3
2
1
0
T2-Weighted Imaging
The basic spin echo experiment consists of a 90 excitation
pulse, followed after a delay TE/2 by a 180 refocusing pulse.
As explained in the introduction, the refocusing pulse reverses
the phase dispersal due to local magnetic field inhomogeneities, resulting in a spin echo at time TE/2 after the refocusing
pulse. The time TE is the spin echo time. The RF pulse refocuses
the T20 component of T2*, leaving only the decay due to spin
spin interactions (T2). This is called the CarrPurcell
experiment, and it has the desirable property that the magnitude of the spin echo is dependent only on T2, a property only
of the sample being examined, independent of the homogeneity of the field:
S PD 1 eTR=T1 eTE=T2 if TR TE
[15]
A sequence structure analogous to multislice 2-D GRE is
used to obtain T2-weighted images. The following is the structure of the 2-D SE sequence that acquires a stack of 2-D slices in
time Ny TR, where the inner loop covers the Nz slices in time
TR and where TR T1 to accommodate T1 recovery between
excitations of the same slice:
h
iNz Ny
90seliz TE=2 180seliz TE=2 PE iy readoutx
iz 1 i 1
y
[16]
8
Transverse magnetization
However, the resulting image contrast is not the same. Moreover, the previous section showed that even with the same
sequence, contrast can be manipulated by adjusting the
sequence parameters. MPRAGE is a variant of the SPGR
sequence specifically designed to enhance T1 contrast between
tissue types. The sequence results in especially good contrast
between the gray matter and white matter, ideal for brain
morphometry.
The MPRAGE sequence is the same as the FLASH sequence
except that a 180 inversion pulse is introduced between slices
and k-space partitions. For example, if there are 176 slices, the
inversion pulse is followed by a gap followed by 176 repetitions of the spoiled GRE sequence kernel (aPEreadout
spoil), which we may refer to as the inner phase encoding
loop, and another gap before the next inversion pulse (sometimes called the delay time). Both gaps are critical to evolve
contrast. The inversion time (TI) is defined as the time between
the middle of the inversion pulse and the partition encoding
step that encodes the centerline of k-space (a gradient echo in
the partition encoding direction). After partition encoding,
there is another gap before the next inversion pulse (as
shown in Figure 8). The TR is redefined as the time between
inversion pulses and therefore includes the gap after the inner
phase encoding loop. The original FLASH TR, or the time
between a pulses, is often called the echo spacing. However,
when there are multiple readouts and therefore multiple gradient echoes between a pulses, as in multiecho MPRAGE
(MEMPRAGE), echo spacing is the time between gradient echoes. Therefore, the time between a pulses may be referred to as
the inter-alpha time.
As the longitudinal magnetization relaxes after the inversion pulse, the signals from different tissue types evolve differentially according to the tissue T1 and the excitation scheme of
the sequence. This process is simulated using the discrete Bloch
equations. Figure 8 shows the excitation structure for a single
TR of the MPRAGE (with typical parameters recommended for
brain morphometry) along with the simulated signal evolution
for white matter, gray matter, and CSF (after a few TRs to
achieve steady state). We choose TI to maximize the separation
between the white matter, gray matter, and CSF. The selection
of TI is critical, but the optimal value is affected by the other
parameters. Although it is tempting to minimize TR to save
time, it is important to note that the steady-state condition
500
13
700
600
500
400
300
200
2
4
100
0
500
0
3
0
1
Pixels
Figure 8 (Left) Excitation structure after inversion pulse for a single TR of a standard MPRAGE protocol. (Middle) Evolution of signal transverse
magnetization across a single TR, estimated using discrete Bloch equations. (Right) Corresponding point spread function. Blue, white matter
(T1 700 ms); red, gray matter (T1 1000 ms); magenta, CSF (T1 3000 ms).
14
0.4
Contrast (AU)
0.8
Signal (AU)
0.5
WM (T2 = 70 ms)
GM (T2 = 100 ms)
CSF (T2 = 300 ms)
0.6
0.4
0.2
0
GM-WM
CSF-GM
0.3
0.2
0.1
50
100
150
200
TE (ms)
0
0
50
100
TE (ms)
150
200
Figure 9 Example T2 decay (left) and contrast (right) curves for white matter (WM, blue), gray matter (GM, red), and cerebrospinal fluid
(CSF, magenta).
Long
Proton
density
T2/T2*
TR
Short
poor!
T1
Short
Long
TE
Figure 10 Summary of common MR contrast types and how to generate
them by varying TR and TE in a basic spin echo sequence (T2) and
gradient-echo sequence (T2*).
15
Figure 11 Example of a T2-weighted image. (Left) TSE with very bright CSF, bright gray matter and dark white matter. (Right) TSE FLAIR with
attenuated CSF.
16
which shows a PD-weighted FLASH scan (top) and a T1weighted FLASH scan (bottom). The echoes are ordered with
the earliest echo at the left (1.85 ms) and the latest echo at the
right (15.85 ms). One can observe T*
2 decay across the echoes,
as the images get darker as one moves from left to right. Further,
these images are minimally distorted, due to their high BW, and
perhaps more important have almost no differential distortion.
That is, any residual distortions remaining in the T1 and PD are
Figure 12 Field maps showing B0 inhomogeneities in the head. Top, susceptibility region affecting the temporal lobes; bottom, susceptibility region
affecting the medial inferior frontal cortex.
Figure 13 Top: PD-weighted multiecho FLASH (flip angle 5 ). Bottom: T1-weighted multiecho FLASH (flip angle 30 ). TR 20 ms, TE 1.85 n.2 ms
(n 0,. . .,7).
17
additional contrasts relative to the single-echo sequences traditionally used in brain morphometry, and these properties are
especially valuable in longitudinal studies.
Multiecho FLASH
MEF is an example of a sequence where the single long
(low-BW) FLASH readout is easily replaced by multiple short
(high-BW) readouts, thus reducing B0-related distortion while
recovering SNR by combining the images resulting from the
multiechoes. Figure 13 shows that MEF can generate a variety
of contrasts. Since the readouts typically alternate in direction
(i.e., the polarity of the readout gradient switches with each
readout, called bipolar gradients), the resulting distortions in
the readout direction alternate. Areas that are compressed in
the images from odd echoes are stretched in the images from
even echoes and vice versa. Algorithms that model this behavior to derive a displacement map and undistort the images
have been described (Andersson, Skare, & Ashburner, 2003;
Holland, Kuperman, & Dale, 2010). These are more typically
applied to EPI-based images with alternating phase encoding
direction where the scale of the distortions is greater. Chemical
shifts also alternate direction. MEF can be collected with all the
readouts in the same direction (monopolar readout gradients), but the additional rewinder gradient required between
readouts increases echo spacing. With very high resolution
and/or high BW, when the systems peak gradient strength is
used, the rewinder gradient may become as long as the readout, in which case a bipolar acquisition with twice the number
of echoes would be time-equivalent to the monopolar acquisition with rewinder gradients. As long as gradient strength is
not limiting, distortions can be reduced sufficiently by increasing BW so that the difference in distortions between alternate
readouts is negligible.
Since the Mahalanobis distance between classes in the 16-D
observation space will necessarily be greater than or equal to a
subset of the same data (single-echo FLASH, or SEF), provided
the SNR loss per echo is fully compensated by the number of
echoes, it is expected that segmentation routines should perform better on MEF data than on SEF data. Indeed, Han et al.
(2006) showed empirically that the multispectral data from
MEF acquisitions can be exploited to provide better segmentation of subcortical structures using FreeSurfer, while cortical
models based on gray matter/white matter segmentation with
the same software performed better with MPRAGE.
As predicted by eqn [13], the images from the low flip angle
(5 ) acquisition are predominantly PD-weighted, with additional T*
2 weighting increasing with TE. The images from the
higher flip angle (30 ) acquisition are also PD- and T2*weighted but are additionally T1-weighted. By fitting eqn
[13], T1, T2, and T*
2 can be estimated for each pixel. MEF
acquisitions were used to obtain the images shown in Figure 1
and the parameter maps (PD and T1) shown in Figure 5.
Figure 14 shows the T2* parameter map. Note that this method
yields noisy T*
2 maps because the TEs for a typical MEF protocol with a practical TR value are short relative to the expected
T2*, and T2* is better modeled with multiple complex exponential components because multiple tissue components typically
contribute to the signal from a single voxel. Nevertheless,
assuming the model (eqn [13]) accurately describes most of
the MEF signal, the 16-D data can be projected onto three
18
Figure 14 T*
2 map (ms) estimated from 5 to 30 MEF acquisitions using the FLASH signal eqn [13].
2.00
0.505
-0.505
-2.00
Figure 15 Displacement (mm) of the outer cortical surface (positive vs. negative readout gradient) with 195 Hz per pixel MPRAGE (left) and 651 Hz
pixel MEMPRAGE (right).
10
9
8
7
6
5
4
3
2
1
0
Transverse magnetization
500
6
5
4
3
2
1
0
1
2
3
4
19
600
TI = 700 ms
TI = 1400 ms
TI = 2100 ms
500
400
300
200
100
0
500
0
3
0
1
Pixels
Figure 16 (Left) Excitation structure after inversion for a single TR of a multiple inversion time (TI 700/1400/2100 ms), MEMPRAGE protocol
(TE 1.69/3.55 ms), flip angle 7 , inter-alpha time 6.5 ms, and TR 2.53 s. (Middle) Evolution of signal transverse magnetization across a single TR,
estimated using discrete Bloch equations. (Right) Corresponding point spread function at each TI for tissue with T1 980 ms. Blue, TI 700 ms;
green, TI 1400 ms; magenta, TI 2100 ms.
20
21
may not be the same as the coil that transmits the RF pulses
into the object to be imaged. In general, there are two rules of
thumb to keep in mind about receive coils. The first is that the
sensitivity of a coil is inversely proportional to its surface area.
The second is that the region of maximum sensitivity extends
to approximately one coil diameter away. Thus, small coils are
extremely sensitive to regions that are close to them but have a
sensitivity profile that decreases rapidly with distance. Conversely, large coils create homogeneous-appearing images as
their sensitivity profiles decrease slowly with distance but have
relatively poor sensitivity over the entire range. Figure 19 gives
examples of the drop-off in sensitivity for different-sized
receive coils, showing that the volume coils have low, but
uniform, sensitivity, while the small coils have very high
sensitivity in proximal regions but a steep drop-off with distance from the coil (Hayes & Axel, 1985; Lawry, Weiner, &
Matson, 1990).
Given that one desires high sensitivity everywhere in the
image, this is another apparent trade-off and one that can also
be avoided, in this case by covering the object to be sampled
with multiple small coils. These multicoil or multichannel
receive coils are known as phased arrays, or sometimes receive
arrays (see Keil and Wald (2013) for a review or Roemer,
Edelstein, Hayes, Souza, and Mueller (1990) for one of the
earliest implementations). Regions that are far from any coil
give rise to noisy image regions, but since there are potentially
many of them (32- and 62-channel arrays for head imaging are
increasingly common), the ensemble of noisy images can be
combined to create a single image that has higher SNR than a
single, large volume coil everywhere in the object (Axel &
Hayes, 1985; Lawry et al., 1990). That is, every coil images
the entire object, and the images are (by construction) as
close to independent as possible. Many techniques have been
devised to optimally combine the images coming from each
channel into a single, high-quality image (De Zwart, van Gelderen, Kellman, & Duyn, 2002; Roemer et al., 1990; Walsh,
Gmitro, & Marcellin, 2000), but they generally rely on a coil
sensitivity map, that is, a spatial map that gives the sensitivity
of each coil at each location in space. The general idea of
the combination is then to weight the images from coils
more strongly in regions in which they have high sensitivity.
As the number of receive coils increases and the coil elements
become smaller, the combined image becomes less uniform,
and the SNR is lowest at the center of the coil, furthest from any
single element. To boost the signal at the center of the coil,
receive array head coils are built to be as tight-fitting to the
head as possible while still accommodating a range of head
sizes. For young children, it is advantageous to use a pediatric
receive array coil.
The fact that receive arrays provide multiple (redundant)
images of the object, even with spatially varying sensitivity,
leads to a second critical advantage of phased arrays over
single-channel coils. The redundancy in the imaging data permits one to accelerate the imaging by skipping part of the
acquisition and then filling in the regions that were not
acquired using the redundancy. As with coil combination,
there are many techniques for accelerated imaging, such as
SENSE, GRAPPA, and SMASH (Griswold et al., 2002; Pruessmann, 2006; Pruessmann et al., 1999; Sodickson, 2000), but
the general idea is the same: some portion, for example, half, of
22
8
a
5
6
4
Relative S/N
b
3
c
10
4
14
2
Head
c
a
0
(a)
10
Depth (cm)
0
0.0
15
(b)
5.0
10.0
15.0
Depth (cm)
Figure 19 (a) SNR profile with distance from coil for single-loop coil elements with various diameters. In (a), the labels ad refer to 8 cm surface coil,
10 cm surface coil, 14 cm surface coil, and head coil, respectively. Reproduced with permission from Hayes, C. E., & Axel, L. (1985) Noise performance
of surface coils for magnetic resonance imaging at 1.5 T. Medical Physics, 12, 604607 and Lawry, T. J., Weiner, M. W., & Matson, G. B. (1990) (b)
Computer modeling of surface coil sensitivity. 8, 10 and 14 refer to the number of array elements. Magnetic Resonance in Medicine, 16, 294302.
23
Figure 21 The effects of accelerations. From left to right, acceleration factors of 3, 4, 5, and 6 (256 256 matrix, normalized, 8 slices,
single-shot SEEPI, 3 T, 32 channels, 0.9 mm in-plane).
Figure 22 Comparison of TSE at 3 T (left) and 7 T (right) (TSE, 11 echoes, 7 min exam, 20 cm FOV, 512 512, 0.4 0.4 mm, 3 mm thick slices).
SNR for 7 T: WM 65; GM 76. SNR for 3 T: WM 26; GM 34.
higher field and T2* gets shorter at higher field. Since T2* represents signal decay, one might think that this implies that lower
field is beneficial for T2* weighting, but in fact the opposite
is true. The shorter T2* can improve contrast, as shown in
Figure 22, which shows penetrating vessels in the cerebral
cortex with excellent clarity and enhanced anatomical detail
in the hippocampus. The size of the human head represents
a substantial fraction of the RF wavelength at 7 T, and constructive interference within the head results in the characteristic center-brightening effect seen in Figure 23 (Collins et al.,
2005; van de Moortele et al., 2005). With parallel receive coils,
7 T images can be especially inhomogeneous. Both B1 (transmit) inhomogeneities and B1 (receive) inhomogeneities contribute. B1 may be corrected with a receive coil sensitivity map,
as described previously (Brey & Narayana, 1988; Murakami,
Hayes, & Weinberger, 1996; Narayana, Brey, Kulkarni, & Sievenpiper, 1988; Wald et al., 1995). Further advances in parallel
transmit technology may facilitate the shaping of B1 by
enabling efficient spatially varying RF pulses that produce
more homogeneous B1 fields (Curtis, Gilbert, Klassen, Gati,
& Menon, 2012; Setsompop et al., 2009).
High-field imaging is especially sensitive to small differences in tissue magnetic susceptibility (Li et al., 2006). Figure 24
24
shows a slice of a FLASH image with considerable T2* (susceptibility) weighting, emphasizing the blood in vessels within the
cortex and subcortical structures.
Motion Correction
The long 3-D encoding scans typically employed for high-quality
brain morphometry are especially sensitive to subject motion
during acquisition. Uncompensated motion during brain imaging degrades the images, introducing a variety of artifacts, including ghosting and blurring, effectively lowering resolution and
image CNR. Even when artifacts are not apparent upon visual
Figure 24 T*-weighted
FLASH collected at 7 T, 0.22 0.22 3 mm3,
2
TR 500 ms, TE 25 ms, BW 30 Hz per pixel, flip angle 35o, acquisition
time 7 min 29 s.
inspection of the images, the derived morphometric measurements are sensitive to the motion. Motion results in spurious and
regionally specific cortical thickness changes, for example, and
this is of particular concern when the control group and patient
group move by a systematically differing amount or in different
ways. Moreover, the pattern of cortical thickness changes introduced by motion may mimic the changes expected in the disorder. Figure 25 shows how cortical thickness measurements are
affected by deliberate subject motion during the scan. These
effects have been shown using various segmentation algorithms
(Reuter, Tisdall, Van Der Kouwe, & Fischl, 2014). Other measurements such as structure volumes may similarly be expected
to be biased by motion during the scan.
Various approaches for correcting head motion in real time
during acquisition have been proposed. Fortunately, if the
nonrigid parts of the head, viz., the lower jaw and neck, are
excluded, the head can be modeled as a single rigid body with
six degrees of freedom. This makes motion detection and correction a far simpler problem in brain imaging, as compared
with nonrigid anatomy such as the heart. Postprocessing
methods may improve image quality, but real-time prospective
methods offer better imaging efficiency and image quality.
Prospective methods may be divided broadly into intrinsic
navigator methods and extrinsic sensor methods. Navigator
methods use the MR signal itself to identify the pose (relative
position and orientation) of the head. Some imaging sequence
types, such as EPI, and some arrangements of radial imaging
can be self-navigating, meaning that the rapidly repeated
images themselves can be used to detect the position of the
head (or other moving anatomy) and correct the next acquisition (Bhat, Ge, Nielles-Vallespin, Zuehlsdorff, & Li, 2011; Thesen, Heid, Mueller, & Schad, 2000). More typically, an
additional short sequence element, or navigator, is interleaved within the main imaging sequence. The navigator represents a snapshot of the head position at regular intervals
throughout the imaging sequence and the position is fed
back to the scanners RF and gradient system to update the
encoded imaging coordinates as the scan proceeds. Navigators
Shake
Free
p = 0.01
p = 0.001
Figure 25 Regions of cortical thinning induced by shaking motion (rotation about the superiorinferior axis) (left) and free motion (including
rotations and translations in a variety of directions) (right). P-values of Wilcoxon signed-rank test are overlaid on the partially inflated cortical surface
model. The figure shows the P-value for a thickness change within each subject, computed for 12 subjects.
25
Figure 26 MEMPRAGE from subject performing deliberate motions during an acquisition without motion correction (left) and with real-time
motion correction, frequency drift correction, and reacquisition of damaged sections of k-space using volumetric navigators (right).
26
Conclusion
In this article, we have tried to give the reader a basic foundation in the fundamentals of MRI acquisition as it relates to
the goal of quantifying brain structure. We have covered the
most common types of MRI acquisitions including T1-, T2-,
PD-, and T2*-weighted imaging. We have shown examples of
each of these image types and also discussed the theoretical
considerations that cause specific configurations of acquisition
parameters to give rise to images with a particular weighting.
The future of anatomical acquisitions will almost certainly
include pushing the useful resolution that can be acquired.
High resolution is challenging in MRI for two fundamental
reasons. The first is the relationship between SNR and resolution that we discussed earlier halving the linear dimensions of
a voxel results in a factor of 8 times reduction in SNR (0.53),
which requires 82 64 times as much acquisition time to
recover. Thus, even with modern large-N phased array coils,
500 mm isotropic scans are close to the limit of what we have
been able to achieve in living humans at 3 T even in dedicated
scan sessions (<1 h of imaging). Higher-resolution scans
have been acquired with special purpose technology such as
ultrahigh-field scanners, dedicated coils, and acquisition
sequences (see Figure 27 (Tisdall, Polimeni, & van der Kouwe,
2013)). The second limitation is that as the voxels in our images
get smaller, other effects that increase the spatial extent of the
PSF begin to become important. Small subject motions that are
irrelevant for 1 mm images become significant sources of blurring at 350 mm. Similarly, physiological processes such as cardiac and respiratory cycles and the concomitant pulsation of
the brain and the flow of CSF can make the effective resolution
of the scans significantly lower than the voxel size. We expect
these issues will be overcome by the continued development of
more sensitive receive coils, the use of multiple transmit coils to
reduce the dielectric effects that plague ultrahigh-field imaging,
and the inclusion of ever-more sophisticated navigator scans
and/or external tracking devices to measure and remove sources
of distortion and blurring that occur during the scan session.
Acknowledgments
Thanks to Lawrence Wald for several of the images used in this
article and for years of teaching the basics of MRI. Thanks also to
John Kirsch for clarification on many questions related to MR
physics. Support was provided in part by the National Center for
Research Resources (P41RR014075, U24RR021382, and
U24RR021992), the National Cancer Institute (R44CA116980
and R01CA137254), the National Institute on Aging
See also: INTRODUCTION TO ACQUISITION METHODS: HighField Acquisition; High-Speed, High-Resolution Acquisitions; MRI and
fMRI Optimizations and Applications; Obtaining Quantitative
Information from fMRI; Susceptibility-Weighted Imaging and
Quantitative Susceptibility Mapping; INTRODUCTION TO
METHODS AND MODELING: Automatic Labeling of the Human
Cerebral Cortex; Computing Brain Change over Time; Cortical
Thickness Mapping; Lesion Segmentation; Manual Morphometry;
Modeling Brain Growth and Development; Sulcus Identification and
Labeling; Surface-Based Morphometry; Tissue Classification; Tissue
Properties from Quantitative MRI; Voxel-Based Morphometry.
References
Alhamud, A., Tisdall, M. D., Hess, A. T., Hasan, K. M., Meintjes, E. M., &
van der Kouwe, A. J. (2012). Volumetric navigators for real-time motion correction
in diffusion tensor imaging. Magnetic Resonance in Medicine, 68, 10971108.
Andersson, J. L., Skare, S., & Ashburner, J. (2003). How to correct susceptibility
distortions in spin-echo echo-planar images: Application to diffusion tensor
imaging. NeuroImage, 20, 870888.
Andrews-Shigaki, B. C., Armstrong, B. S., Zaitsev, M., & Ernst, T. (2011). Prospective
motion correction for magnetic resonance spectroscopy using single camera RetroGrate reflector optical tracking. Journal of Magnetic Resonance Imaging, 33, 498504.
Axel, L., & Hayes, C. (1985). Surface coil magnetic resonance imaging. Archives
Internationales de Physiologie et de Biochimie, 93, 1118.
Bhat, H., Ge, L., Nielles-Vallespin, S., Zuehlsdorff, S., & Li, D. (2011). 3D radial
sampling and 3D affine transform-based respiratory motion correction technique for
free-breathing whole-heart coronary MRA with 100% imaging efficiency. Magnetic
Resonance in Medicine, 65(5), 12691277.
Brass, S. D., Chen, N. K., Mulkern, R. V., & Bakshi, R. (2006). Magnetic resonance
imaging of iron deposition in neurological disorders. Topics in Magnetic
Resonance Imaging, 17, 3140.
Brey, W. W., & Narayana, P. A. (1988). Correction for intensity falloff in surface coil
magnetic resonance imaging. Medical Physics, 15, 241245.
Collins, C. M., Liu, W., Schreiber, W., Yang, Q. X., & Smith, M. B. (2005). Central
brightening due to constructive interference with, without, and despite dielectric
resonance. Journal of Magnetic Resonance Imaging, 21, 192196.
27
Mugler, J. P., 3rd, & Brookeman, J. R. (1990). Three-dimensional magnetizationprepared rapid gradient-echo imaging (3D MP RAGE). Magnetic Resonance in
Medicine, 15, 152157.
Murakami, J. W., Hayes, C. E., & Weinberger, E. (1996). Intensity correction of phasedarray surface coil images. Magnetic Resonance in Medicine, 35, 585590.
Muraskin, J., Ooi, M. B., Goldman, R. I., Krueger, S., Thomas, W. J., Sajda, P., et al.
(2013). Prospective active marker motion correction improves statistical power in
BOLD fMRI. NeuroImage, 68, 154161.
Narayana, P. A., Brey, W. W., Kulkarni, M. V., & Sievenpiper, C. L. (1988).
Compensation for surface coil sensitivity variation in magnetic resonance imaging.
Magnetic Resonance Imaging, 6, 271274.
Norris, D. G., Koopmans, P. J., Boyacioglu, R., & Barth, M. (2011). Power Independent
of Number of Slices (PINS) radiofrequency pulses for low-power simultaneous
multislice excitation. Magnetic Resonance in Medicine, 66, 12341240.
Olesen, O. V., Paulsen, R. R., Hojgaard, L., Roed, B., & Larsen, R. (2012). Motion
tracking for medical imaging: A nonvisible structured light tracking approach. IEEE
Transactions on Medical Imaging, 31, 7987.
Olesen, O. V., Sullivan, J. M., Mulnix, T., Paulsen, R. R., Hojgaard, L., Roed, B., et al.
(2013). List-mode PET motion correction using markerless head tracking: Proof-ofconcept with scans of human subject. IEEE Transactions on Medical Imaging, 32,
200209.
Ooi, M. B., Aksoy, M., Maclaren, J., Watkins, R. D., & Bammer, R. (2013). Prospective
motion correction using inductively coupled wireless RF coils. Magnetic Resonance
in Medicine, 70(3), 639647.
Pouwels, P. J., Kuijer, J. P., Mugler, J. P., 3rd, Guttmann, C. R., & Barkhof, F. (2006).
Human gray matter: Feasibility of single-slab 3D double inversion-recovery highspatial-resolution MR imaging. Radiology, 241, 873879.
Pruessmann, K. P. (2006). Encoding and reconstruction in parallel MRI. NMR in
Biomedicine, 19, 288299.
Pruessmann, K. P., Weiger, M., Scheidegger, M. B., & Boesiger, P. (1999). SENSE:
Sensitivity encoding for fast MRI. Magnetic Resonance in Medicine, 42, 952962.
Redpath, T. W., & Smith, F. W. (1994). Technical note: Use of a double inversion
recovery pulse sequence to image selectively grey or white brain matter. British
Journal of Radiology, 67, 12581263.
Reuter, M., Tisdall, M. D., Van Der Kouwe, A., & Fischl, B. (2014). Head motion in MRI
causes bias in structural brain measurements. In: Annual Meeting of the
Organization for Human Brain Mapping, Hamburg, Germany.
Roemer, P. B., Edelstein, W. A., Hayes, C. E., Souza, O. M., & Mueller, S. P. (1990). The
NMR phased array. Magnetic Resonance in Medicine, 16, 192225.
Saito, N., Sakai, O., Ozonoff, A., & Jara, H. (2009). Relaxo-volumetric multispectral
quantitative magnetic resonance imaging of the brain over the human lifespan:
Global and regional aging patterns. Magnetic Resonance Imaging, 27, 895906.
Salat, D., Lee, S., van der Kouwe, A., Greve, D., Fischl, B., & Rosas, H. (2009). Ageassociated alterations in cortical gray and white matter signal intensity and gray to
white matter contrast. NeuroImage, 48, 2128. http://dx.doi.org/10.1016/j.
neuroimage.2009.06.074.
Schenck, J. F. (1995). Imaging of brain iron by magnetic resonance: T2 relaxation at
different field strengths. Journal of Neurological Sciences, 134, 1018.
Schenker, C., Meier, D., Wichmann, W., Boesiger, P., & Valavanis, A. (1993). Age
distribution and iron dependency of the T2 relaxation time in the globus pallidus and
putamen. Neuroradiology, 35, 119124.
Schulz, J., Siegert, T., Reimer, E., Labadie, C., Maclaren, J., Herbst, M., et al. (2012). An
embedded optical tracking system for motion-corrected magnetic resonance
imaging at 7 T. Magma, 25, 443453.
Segonne, F., Dale, A., Busa, E., Glessner, M., Salvolini, U., Hahn, H., et al. (2004). A
hybrid approach to the skull-stripping problem in MRI. NeuroImage, 22,
11601175.
Setsompop, K., Alagappan, V., Gagoski, B. A., Potthast, A., Hebrank, F., Fontius, U.,
et al. (2009). Broadband slab selection with B1 mitigation at 7 T via parallel
spectral-spatial excitation. Magnetic Resonance in Medicine, 61, 493500.
Setsompop, K., Gagoski, B. A., Polimeni, J. R., Witzel, T., Wedeen, V. J., & Wald, L. L.
(2012). Blipped-controlled aliasing in parallel imaging for simultaneous multislice
echo planar imaging with reduced g-factor penalty. Magnetic Resonance in
Medicine, 67, 12101224.
Sodickson, D. K. (2000). Tailored SMASH image reconstructions for robust in vivo
parallel MR imaging. Magnetic Resonance in Medicine, 44, 243251.
Sodickson, D. K., & Mckenzie, C. A. (2001). A generalized approach to parallel
magnetic resonance imaging. Medical Physics, 28, 16291643.
Souza, S. P., Szumowski, J., Dumoulin, C. L., Plewes, D. P., & Glover, G. (1988). SIMA:
Simultaneous multislice acquisition of MR images by Hadamard-encoded
excitation. Journal of Computer Assisted Tomography, 12, 10261030.
Speck, O., Hennig, J., & Zaitsev, M. (2006). Prospective real-time slice-by-slice motion
correction for fMRI in freely moving subjects. Magma, 19, 5561.
28
Suzuki, S., Sakai, O., & Jara, H. (2006). Combined volumetric T1, T2 and secular-T2
quantitative MRI of the brain: Age-related global changes (preliminary results).
Magnetic Resonance Imaging, 24, 877887.
Thesen, S., Heid, O., Mueller, E., & Schad, L. R. (2000). Prospective acquisition
correction for head motion with image-based tracking for real-time fMRI. Magnetic
Resonance in Medicine, 44, 457465.
Thormer, G., Garnov, N., Moche, M., Haase, J., Kahn, T., & Busse, H. (2012).
Simultaneous 3D localization of multiple MR-visible markers in fully reconstructed
MR images: Proof-of-concept for subsecond position tracking. Magnetic Resonance
Imaging, 30, 371381.
Tisdall, M. D., Hess, A. T., Reuter, M., Meintjes, E. M., Fischl, B., &
Van Der Kouwe, A. J. (2012). Volumetric navigators for prospective motion
correction and selective reacquisition in neuroanatomical MRI. Magnetic Resonance
in Medicine, 68, 389399.
Tisdall, M. D., Polimeni, J. R., & van der Kouwe, A. J. W. (2013). Motion-corrected 350
um isotropic MPRAGE at 3 T using volumetric navigators (vNavs). In: Proceedings of
the International Society for Magnetic Resonance in Medicine, Salt Lake City, UT.
van de Moortele, P. F., Akgun, C., Adriany, G., Moeller, S., Ritter, J., Collins, C. M., et al.
(2005). B(1) destructive interferences and spatial phase patterns at 7 T with a head
transceiver array coil. Magnetic Resonance in Medicine, 54, 15031518.
van der Kouwe, A. J., Benner, T., & Dale, A. M. (2006). Real-time rigid body motion
correction and shimming using cloverleaf navigators. Magnetic Resonance in
Medicine, 56, 10191032.
van der Kouwe, A. J., Benner, T., Salat, D. H., & Fischl, B. (2008). Brain morphometry
with multiecho MPRAGE. NeuroImage, 40, 559569.
van der Kouwe, A. J. W., Tisdall, M. D., Bhat, H., Fischl, B., & Polimeni, J. R. (2014).
Multiple echo and inversion time MPRAGE with inner loop GRAPPA acceleration
and prospective motion correction for minimally distorted multispectral
morphometry. In: 22nd Annual Meeting of the International Society for Magnetic
Resonance in Medicine, Milan, Italy.
Wald, L. L., Carvajal, L., Moyher, S. E., Nelson, S. J., Grant, P. E., Barkovich, A. J., et al.
(1995). Phased array detectors and an automated intensity-correction algorithm for
high-resolution MR imaging of the human brain. Magnetic Resonance in Medicine,
34, 433439.
Walsh, D. O., Gmitro, A. F., & Marcellin, M. W. (2000). Adaptive reconstruction of
phased array MR imagery. Magnetic Resonance in Medicine, 43, 682690.
Weaver, J. B. (1988). Simultaneous multislice acquisition of MR images. Magnetic
Resonance in Medicine, 8, 275284.
Welch, E. B., Manduca, A., Grimm, R. C., Ward, H. A., & Jack, C. R., Jr, (2002).
Spherical navigator echoes for full 3D rigid body motion measurement in MRI.
Magnetic Resonance in Medicine, 47, 3241.
White, N., Roddey, C., Shankaranarayanan, A., Han, E., Rettmann, D., Santos, J., et al.
(2010). PROMO: Real-time prospective motion correction in MRI using imagebased tracking. Magnetic Resonance in Medicine, 63, 91105.
Zaitsev, M., Dold, C., Sakas, G., Hennig, J., & Speck, O. (2006). Magnetic
resonance imaging of freely moving objects: Prospective real-time motion
correction using an external optical motion tracking system. NeuroImage, 31,
10381050.
Zur, Y., Wood, M. L., & Neuringer, L. J. (1991). Spoiling of transverse magnetization in
steady-state sequences. Magnetic Resonance in Medicine, 21, 251263.
Glossary
Introduction
MRIs impact on functional brain mapping during the past
quarter century has been profound, and today, fMRI is the
predominant technique used to image brain activity in
humans. The overwhelming majority of fMRI studies exploit
http://dx.doi.org/10.1016/B978-0-12-397025-1.00002-6
29
30
BOLD Contrast
While the transverse magnetization relaxation time constant
(T2) of blood had been shown to depend upon its oxygenation
in 1982 (Thulborn, Waterton, Matthews, & Radda, 1982), it
was a decade later before it was exploited as a contrast mechanism to image brain activity (Kwong et al., 1992; Ogawa et al.,
1992) and Ogawa coined the term BOLD. A fundamental
underpinning of the technique is the fact that the magnetic
properties of hemoglobin significantly change depending
upon whether it is oxygenated or not (Pauling & Coryell,
1936). While oxyhemoglobin (HbO) is slightly diamagnetic,
similar to other brain tissue, dHb is paramagnetic and thus acts
as an endogenous MRI contrast agent that significantly
increases the transverse relaxation rate (i.e., T2 and T2* relaxation times decrease). Combined with the observation that
blood oxygen saturation changes focally with neuronal activity
(Fox & Raichle, 1986), gradient-echo MR imaging with T2*
contrast weighting provides a mechanism to indirectly map
modulations in neuronal activity. While spin-echo imaging
with T2 contrast weighting can also be used for fMRI, the
greater sensitivity and speed of gradient-echo imaging have
resulted in it being the most widely used technique. The final
key ingredient that made BOLD fMRI so ubiquitous is fast
imaging techniques, such as echo-planar imaging (EPI;
Mansfield, 1977), that permit the acquisition of whole-brain
volumes on a timescale similar to the brains hemodynamic
modulations (a few seconds).
To better understand the BOLD signal, one has to consider
how the amount and distribution of dHb within a voxel alter the
T2* relaxation time. This has largely been achieved using vascular
modeling and simulation of the intravascular and extravascular
MR signal evolution (Boxerman et al., 1995). In such a model,
the key physiological parameters that are expected to change
with neuronal activity are the cerebral blood volume (CBV)
and the oxygen saturation (Y) of each vascular compartment
arterial, capillary, and venous. The oxygen saturation is, in turn,
dependent upon the rate of oxygen delivery (proportional to the
product of arterial oxygen saturation Ya and CBF) and the rate
of utilization (cerebral metabolic rate of oxygen consumption
CMRO2). Since Ya is normally quite stable, one is left with three
fundamental physiological parameters that are expected to vary
with neuronal activity level CBF, CBV, and CMRO2. While
precise knowledge of these parameters does not equate to a direct
Tag
31
Control
Figure 1 Illustration of the arterial spin-labeling (ASL) technique for imaging tissue perfusion. Two sets of images (blue) are acquired, one having an
upstream arterial region labeled (tag e.g., an inversion pulse) and the other not (control). By selecting an appropriate delay between tagging
and imaging, the subtraction of the two datasets produces images where the signal is proportional to perfusion (bottom panel).
arteriolar vascular resistance, and passive, via dilation (constriction) of the venules and veins due to the increase
(decrease) in perfusion pressure (Guyton & Hall, 1996). Volume change at the capillary level is generally thought to be
small with the dominant consequence of upstream regulation
being a change in blood velocity. The active side is driven by a
multitude of neurovascular signaling mechanisms that produce the highly spatially specific response, which is exploited
for functional brain mapping.
While measurement of CBV change was the basis of the first
MRI study to map human brain function (Belliveau et al.,
1991), the technique used was dynamic susceptibility contrast
imaging, which has major shortcomings for functional imaging since it requires bolus injections of gadoliniumDTPA
during rest and stimulation conditions. Steady-state imaging
using long intravascular half-life exogenous contrast agents
(e.g., iron oxide nanoparticle-based agents) alleviates the
requirement for multiple injections and permits dynamic monitoring of CBV changes (Dunn et al., 2004; Kida, Rothman, &
Hyder, 2007; Lu, Soltysik, et al., 2005; Mandeville et al., 1999,
1998; Zhao, Wang, Hendrich, & Kim, 2005; Zhao, Wang,
Hendrich, Ugurbil, & Kim, 2006). However, to date, iron
oxide-based CBV measurements have been limited to animal
studies. Furthermore, this method reflects total blood plasma
32
Stefanovic & Pike, 2004; Thulborn et al., 1982; Wright, Hu, &
Macovski, 1991; Zhao, Clingman, Narvainen, Kauppinen, & van
Zijl, 2007) and is termed venous refocusing for volume
estimation (Stefanovic & Pike, 2005). While this technique can
be used as a standalone method for functional brain mapping, it
is a low SNR method and was developed and used primarily to
enhance our understanding of the CBFvenous CBV relationship for the purpose of BOLD signal modeling and calibration.
CBF, Ya
Input O2 = CBF Ca Ya
Yv
Return O2 = CBF Ca Yv
33
M
CMRO2
BOLD/BOLD0
BOLD/BOLD0
Asymptotic regime
non-linear
regime
CMRO2+
Linear
regime
0
0
(a)
2
3
CBF/CBF0
(b)
2
3
CBF/CBF0
Figure 3 Graphical representation of the dHb dilution model relating BOLD signal, CBF, and CMRO2 (Hoge et al., 1999a). (a) Curve for an iso-metabolic
CBF manipulation such as hypercapnia. (b) Family of curves for different levels of CMRO2 above and below the resting metabolism curve
(dark solid line).
Conclusions
BOLD fMRI has transformed neuroscience research by providing a safe, sensitive, and widely accessible technique to map
brain function. Nonetheless, the BOLD signal is an indirect
measure of neuronal activity with a complex dependence upon
changes in CBF, blood volume, and oxygen consumption. It
has therefore primarily been used as a qualitative technique to
detect where activity occurs. However, MRI methods are now
available to quantitatively measure CBF and volume and when
combined with biophysical models and calibration techniques
can provide quantitative measures of oxygen metabolism.
These techniques are of enormous value in studying the brain
in health and disease because they can provide measures of
both neurovascular and neuroenergetic responses.
Acknowledgments
GBPs work in the area of quantitative fMRI is supported by the
Canadian Institutes of Health Research, the Canadian Foundation for Innovation, Fonds de la recherche en sante du Quebec,
and the Killam Foundation. RDH wishes to acknowledge the
Canadian Institutes for Health Research, the Canadian
34
References
Belliveau, J. W., Kennedy, D. N., McKinstry, R. C., Buchbinder, B. R., Weisskoff, R. M.,
Cohen, M. S., et al. (1991). Functional mapping of the human visual cortex by
magnetic resonance imaging. Science, 254, 716719.
Boxerman, J. L., Bandettini, P. A., Kwong, K. K., Baker, J. R., Davis, T. L., Rosen, B. R.,
et al. (1995). The intravascular contribution to fMRI signal change: Monte Carlo
modeling and diffusion-weighted studies in vivo. Magnetic Resonance in Medicine,
34, 410.
Bulte, D. P., Kelly, M., Germuska, M., Xie, J., Chappell, M. A., Okell, T. W., et al. (2012).
Quantitative measurement of cerebral physiology using respiratory-calibrated MRI.
Neuroimage, 60, 582591.
Buxton, R. B. (2005). Quantifying CBF with arterial spin labeling. Journal of Magnetic
Resonance Imaging, 22, 723726.
Chen, J. J., & Pike, G. B. (2009). Human whole blood T2 relaxometry at 3 Tesla.
Magnetic Resonance in Medicine, 61, 249254.
Chen, J. J., & Pike, G. B. (2010a). Global cerebral oxidative metabolism during
hypercapnia and hypocapnia in humans: Implications for BOLD fMRI. Journal of
Cerebral Blood Flow & Metabolism, 30, 10941099.
Chen, J. J., & Pike, G. B. (2010b). MRI measurement of the BOLD-specific flow-volume
relationship during hypercapnia and hypocapnia in humans. Neuroimage, 53,
383391.
Chen, J. J., Wieckowska, M., Meyer, E., & Pike, G. B. (2008). Cerebral blood flow
measurement using fMRI and PET: A cross-validation study. International Journal of
Biomedical Imaging, 2008, 112.
Chiarelli, P. A., Bulte, D. P., Wise, R., Gallichan, D., & Jezzard, P. (2007). A calibration
method for quantitative BOLD fMRI based on hyperoxia. Neuroimage, 37, 808820.
Christen, T., Lemasson, B., Pannetier, N., Farion, R., Segebarth, C., Remy, C., et al.
(2010). Evaluation of a quantitative blood oxygenation level-dependent (qBOLD)
approach to map local blood oxygen saturation. NMR in Biomedicine, 24, 393403.
Davis, T. L., Kwong, K. K., Weisskoff, R. M., & Rosen, B. R. (1998). Calibrated
functional MRI: Mapping the dynamics of oxidative metabolism. Proceedings
of the National Academy of Sciences of the United States of America, 95,
18341839.
Detre, J. A., Leigh, J. S., Williams, D. S., & Koretsky, A. P. (1992). Perfusion imaging.
Magnetic Resonance in Medicine, 23, 3745.
Detre, J. A., Wang, J., Wang, Z., & Rao, H. (2009). Arterial spin-labeled perfusion MRI
in basic and clinical neuroscience. Current Opinion in Neurology, 22, 348355.
Dickson, J. D., Ash, T. W., Williams, G. B., Harding, S. G., Carpenter, T. A.,
Menon, D. K., et al. (2010). Quantitative BOLD: The effect of diffusion. Journal of
Magnetic Resonance Imaging, 32, 953961.
Donahue, M. J., Hua, J., Pekar, J. J., & van Zijl, P. C. (2009). Effect of inflow of fresh
blood on vascular-space-occupancy (VASO) contrast. Magnetic Resonance in
Medicine, 61, 473480.
Dunn, J. F., Roche, M. A., Springett, R., Abajian, M., Merlis, J., Daghlian, C. P., et al.
(2004). Monitoring angiogenesis in brain using steady-state quantification of
DeltaR2 with MION infusion. Magnetic Resonance in Medicine, 51, 5561.
Ewing, J. R., Cao, Y., Knight, R. A., & Fenstermacher, J. D. (2005). Arterial spin
labeling: Validity testing and comparison studies. Journal of Magnetic Resonance
Imaging, 22, 737740.
Feng, C. M., Narayana, S., Lancaster, J. L., Jerabek, P. A., Arnow, T. L., Zhu, F., et al.
(2004). CBF changes during brain activation: fMRI vs. PET. Neuroimage, 22,
443446.
Fox, P., & Raichle, M. (1986). Focal physiological uncoupling of cerebral blood flow
and oxidative metabolism during somatosensory stimulation in human subjects.
Proceedings of the National Academy of Sciences of the United States of America,
83, 11401144.
Gauthier, C. J., & Hoge, R. D. (2012). Magnetic resonance imaging of resting OEF and
CMRO(2) using a generalized calibration model for hypercapnia and hyperoxia.
Neuroimage, 60, 12121225.
Gauthier, C. J., Madjar, C., Desjardins-Crepeau, L., Bellec, P., Bherer, L., & Hoge, R. D.
(2013). Age dependence of hemodynamic response characteristics in human
functional magnetic resonance imaging. Neurobiology of Aging, 34, 14691485.
Gauthier, C. J., Madjar, C., Tancredi, F. B., Stefanovic, B., & Hoge, R. D. (2011).
Elimination of visually evoked BOLD responses during carbogen inhalation:
Implications for calibrated MRI. Neuroimage, 54, 10011011.
Ge, Y., Zhang, Z., Lu, H., Tang, L., Jaggi, H., Herbert, J., et al. (2012). Characterizing brain
oxygen metabolism in patients with multiple sclerosis with T2-relaxation-underspin-tagging MRI. Journal of Cerebral Blood Flow & Metabolism, 32, 403412.
Grubb, R. L., Phelps, M. E., & Eichling, J. O. (1974). The effects of vascular changes in
PaCO2 on cerebral blood volume, blood flow and vascular mean transit time. Stroke,
5, 630639.
Guyton, A. C., & Hall, J. E. (1996). Textbook of medical physiology. Philadelphia, PA:
W.B. Saunders.
Hall, E. L., Driver, I. D., Croal, P. L., Francis, S. T., Gowland, P. A., Morris, P. G., et al.
(2011). The effect of hypercapnia on resting and stimulus induced MEG signals.
Neuroimage, 58, 10341043.
He, X., & Yablonskiy, D. A. (2007). Quantitative BOLD: Mapping of human cerebral
deoxygenated blood volume and oxygen extraction fraction: Default state. Magnetic
Resonance in Medicine, 57, 115126.
He, X., Zhu, M., & Yablonskiy, D. A. (2008). Validation of oxygen extraction fraction
measurement by qBOLD technique. Magnetic Resonance in Medicine, 60, 882888.
Hoge, R. D., Atkinson, J., Gill, B., Crelier, G. R., Marrett, S., & Pike, G. B. (1999a).
Investigation of BOLD signal dependence on cerebral blood flow and oxygen
consumption: The deoxyhemoglobin dilution model. Magnetic Resonance in
Medicine, 42, 849863.
Hoge, R. D., Atkinson, J., Gill, B., Crelier, G. R., Marrett, S., & Pike, G. B. (1999b).
Linear coupling between cerebral blood flow and oxygen consumption in activated
human cortex. Proceedings of the National Academy of Sciences of the United
States of America, 96, 94039408.
Hyder, F., & Rothman, D. L. (2012). Quantitative fMRI and oxidative neuroenergetics.
Neuroimage, 62, 985994.
Iadecola, C. (2004). Neurovascular regulation in the normal brain and in Alzheimers
disease. Nature Reviews Neuroscience, 5, 347360.
Kety, S. S., & Schmidt, C. F. (1948). The effects of altered arterial tensions of carbon
dioxide and oxygen on cerebral blood flow and cerebral oxygen consumption of
normal young men. Journal of Clinical Investigation, 27, 484492.
Kida, I., Rothman, D. L., & Hyder, F. (2007). Dynamics of changes in blood flow,
volume, and oxygenation: Implications for dynamic functional magnetic resonance
imaging calibration. Journal of Cerebral Blood Flow & Metabolism, 27, 690696.
Kwong, K. K., Belliveau, J. W., Chesler, D. A., Goldberg, I. E., Weisskoff, R. M.,
Poncelet, B. P., et al. (1992). Dynamic magnetic resonance imaging of human brain
activity during primary sensory stimulation. Proceedings of the National Academy of
Sciences of the United States of America, 89, 56755679.
Lu, H., & Ge, Y. (2008). Quantitative evaluation of oxygenation in venous vessels using
T2-Relaxation-Under-Spin-Tagging MRI. Magnetic Resonance in Medicine, 60,
357363.
Lu, H., Golay, X., Pekar, J. J., & Van Zijl, P. C. (2003). Functional magnetic resonance
imaging based on changes in vascular space occupancy. Magnetic Resonance in
Medicine, 50, 263274.
Lu, H., Law, M., Johnson, G., Ge, Y., van Zijl, P. C., & Helpern, J. A. (2005). Novel
approach to the measurement of absolute cerebral blood volume using vascularspace-occupancy magnetic resonance imaging. Magnetic Resonance in Medicine,
54, 14031411.
35
Stefanovic, B., & Pike, G. B. (2005). Venous refocusing for volume estimation: VERVE
functional magnetic resonance imaging. Magnetic Resonance in Medicine, 53,
339347.
Stefanovic, B., Warnking, J. M., Kobayashi, E., Bagshaw, A. P., Hawco, C., Dubeau, F.,
et al. (2005). Hemodynamic and metabolic responses to activation, deactivation and
epileptic discharges. Neuroimage, 28, 205215.
Thulborn, K. R., Waterton, J. C., Matthews, P. M., & Radda, G. K. (1982). Oxygenation
dependence of the transverse relaxation time of water protons in whole blood at high
field. Biochimica et Biophysica Acta, 714, 265270.
Walsh, E. G., Minematsu, K., Leppo, J., & Moore, S. C. (1994). Radioactive
microsphere validation of a volume localized continuous saturation perfusion
measurement. Magnetic Resonance in Medicine, 31, 147153.
Williams, D. S., Detre, J. A., Leigh, J. S., & Koretsky, A. P. (1992). Magnetic
resonance imaging of perfusion using spin inversion of arterial water.
Proceedings of the National Academy of Sciences of the United States of America,
89, 212216.
Wise, R. G., Harris, A. D., Stone, A. J., & Murphy, K. (2013). Measurement of OEF and
absolute CMRO: MRI-based methods using interleaved and combined hypercapnia
and hyperoxia. Neuroimage, 83C, 135147.
Wright, G. A., Hu, B. S., & Macovski, A. (1991). Estimating oxygen saturation of blood
in vivo with MR imaging at 1.5 T. Journal of Magnetic Resonance Imaging, 1,
275283.
Yablonskiy, D. A. (1998). Quantitation of intrinsic magnetic susceptibility-related
effects in a tissue matrix. Phantom study. Magnetic Resonance in Medicine, 39,
417428.
Ye, F. Q., Berman, K. F., Ellmore, T., Esposito, G., van Horn, J. D., Yang, Y., et al.
(2000). H(2)(15)O PET validation of steady-state arterial spin tagging cerebral blood
flow measurements in humans. Magnetic Resonance in Medicine, 44, 450456.
Zappe, A. C., Uludag, K., Oeltermann, A., Ugurbil, K., & Logothetis, N. K. (2008). The
influence of moderate hypercapnia on neural activity in the anesthetized nonhuman
primate. Cerebral Cortex, 18, 26662673.
Zhao, J. M., Clingman, C. S., Narvainen, M. J., Kauppinen, R. A., & van Zijl, P. C.
(2007). Oxygenation and hematocrit dependence of transverse relaxation rates of
blood at 3 T. Magnetic Resonance in Medicine, 58, 592597.
Zhao, F., Wang, P., Hendrich, K., & Kim, S. G. (2005). Spatial specificity of cerebral
blood volume-weighted fMRI responses at columnar resolution. Neuroimage, 27,
416424.
Zhao, F., Wang, P., Hendrich, K., Ugurbil, K., & Kim, S. G. (2006). Cortical layerdependent BOLD and CBV responses measured by spin-echo and gradient-echo
fMRI: Insights into hemodynamic regulation. Neuroimage, 30, 11491160.
Glossary
Introduction
Since its inception in the early 1990s (Belliveau et al., 1991;
Kwong et al., 1992; Menon et al., 1992; Ogawa, Lee, Kay, &
Tank, 1990; Ogawa, Lee, Nayak, & Glynn, 1990; Ogawa et al.,
1992; Turner, 1992), functional magnetic resonance imaging
(fMRI) has had a tremendous impact in our understanding of
the brain. fMRI measures the regional changes in cerebral
blood flow (CBF), cerebral blood volume (CBV), and blood
oxygenation that occur in response to focal changes in neural
activity. What makes fMRI sensitive to the brain hemodynamics is the clever use of both endogenous and exogenous contrast agents, compounds that change the intrinsic relaxation
rates of blood and tissue, to create a functionally specific signal
directly associated with the physiological quantity of interest.
The purpose of this article is to provide the reader with a
glimpse of the main contrast agents used in fMRI today, with
particular emphasis on the mechanism of contrast and on how
the contrast alters the MRI signal in a way to make it sensitive
to the hemodynamic quantity of interest. In the first session,
the endogenous sources of contrast in fMRI, hemoglobin, and
arterial water are described. Hemoglobin is unique in being the
only endogenous contrast that is sensitive to blood
Gadolinium diethylene-triamine-penta-acetate
(Gd-DTPA) An MRI contrast agent used to cause local
changes in the water relaxation properties and useful to
enhance contrast in the vasculature or to detect lesions in
the brain.
Magnetization transfer (MT) Refers to the transfer of
magnetization due to the exchange of free hydrogen ions in
water with hydrogen ions bound to macromolecules in the
tissue.
Mean transit time (MTT) The average time it takes for the
contrast agent to travel from the site of injection to the organ
of interest.
Pulsed ASL (PASL) A form of ASL technique in which
endogenous arterial water is labeled in discrete intervals
interleaved with image acquisition.
Pseudo-continuous ASL (pCASL) A form of ASL technique
in which endogenous arterial water is labeled by a series of
discrete but contiguous labeling pulses prior to image
acquisition.
Superparamagnetic iron oxide nanoparticles
(SPIO) Nanoparticles of iron oxide that have
superparamagnetic properties and that act as an MRI
contrast agent.
VAscular-Space-Occupancy (VASO) An MRI technique
based on measuring the space occupied by the cerebral
vasculature as a way to estimate CBV.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00004-X
37
38
CH2
1
CH3
CH2
H3C
N
N
Fe2+
N
CH3
H3C
2
O
(a)
(b)
OH
OH
100
90
80
SO2 (%)
70
60
50
40
30
20
10
0
(c)
20
40
60
PO2 (mmHg)
80
100
120
Figure 1 (a) 3-D structure of the hemoglobin molecule showing the four subunits in different colors. Within each subunit, the heme molecule is
shown in red. (b) Chemical diagram of the heme molecule showing the iron (Fe2) ion (charged atom) in coordination with four nitrogen atoms in the
center of the porphyrin ring. The iron ion reversibly binds an oxygen molecule. (c) Oxygen dissociation curve for hemoglobin, showing the oxygen
saturation (SO2) of hemoglobin as a function of the partial pressure of oxygen (PO2) in blood. Because of the cooperative binding, the affinity of
hemoglobin for oxygen increases as successive molecules of oxygen bind, until the maximum amount of four oxygen molecules per molecule
of hemoglobin is reached. Thus, the oxygen dissociation curve is relatively flat for PO2 > 80 mmHg. As the PO2 decreases, the affinity of hemoglobin
decreases and oxygen is released to tissue.
[1]
39
10
20
30
40
50
60
70
80
90
100
35%
40%
cblood (ppm)
45%
50%
55%
6
8
10
12
14
16
Figure 2 Plot of the blood susceptibility Dwblood as a function of the blood oxygenation level Y for several different levels of Hct. The susceptibility
of blood is a direct magnetic indicator of the blood oxygenation level. Changes in local susceptibility with blood oxygenation alter the MRI signal,
forming the basis of the BOLD contrast in fMRI.
[2a]
[2b]
[3a]
[3b]
[4]
where R20(*) are the intrinsic relaxation rates and R2,Hb(*) are
the additional relaxation rates induced by deoxyhemoglobin.
Equation [4] implies that the signal decay can be described
by a simple exponential function, and this ignores contributions of water diffusion through inhomogeneous magnetic
fields and multiple compartment sources of signal dephasing
(Yablonskiy & Haacke, 1994; Yablonskiy et al., 2013).
40
[5]
[6]
[7]
dt
Tlm
[8]
where Mt(t) is the tissue longitudinal magnetization (expressed
per g of tissue), M0t is its equilibrium value, Tlt is the longitudinal
Arterial
water
f Ma(t)
(1-E(f))fMa(t)
Capillary water
fMv(t)
41
Venous
water
E(f)fMa(t)
Tissue water
kfor
krev
Macromolecular
water
Brain tissue
Figure 3 Schematic of the use of arterial water as a perfusion tracer. Within a voxel containing brain tissue and its associated vasculature, a fraction E
(f) of the arterial labeled water crosses the bloodbrain barrier and exchanges with tissue water, while the remaining arterial water flows to the
veins. Tissue water is in exchange with macromolecular protons. Tissue water also crosses the BBB to reach the veins.
M0t
M0v
l
[9]
[10]
[11]
42
l
Mcontrol Mlabel
t
t
M0t
2a0 ed=Tla E f Tlapp
[15]
[16]
Sbase
1 Vbase
S
1 Vbase
[17]
where Vbase and Vact are the local blood volumes at rest and
during brain activity, respectively. Note that increases in blood
volume are associated with negative VASO signal changes via
the minus sign in eqn [17].
[18]
where r1 and r2 are the longitudinal and transverse relaxivities of the contrast agent, respectively, and are dependent
43
3T
4.7 T
Trade name
Maker
Short name
r1
r2
r1
r2
r1
r2
Magnevist
Gadovist
ProHance
MultiHance
DOTAREM
OMNISCAN
Schering
Schering
Bracco
Bracco
Guerbet
Amersham
Gd-DTPA
Gd-DO3A-butrol
Gd-HP-DO3A
Gd-BOPTA
Gd-DOTA
Gd-DTPA-BMA
4.1
5.2
4.1
6.3
3.6
4.3
4.6
6.1
5.0
8.7
4.3
5.2
3.7
5.0
3.7
5.5
3.5
4.0
5.2
7.1
5.7
11.0
4.9
5.6
3.8
4.7
3.7
5.2
3.3
3.9
4.8
5.9
5.8
10.8
4.7
5.3
Relaxivities expressed in mmol1 s1. Data obtained in plasma at 37 C (Rohrer et al., 2005).
t
on the magnetic field strength. Table 1 lists r1 and r2 for
gadolinium chelates typically used in clinical practice
(Burtea, Laurent, Vander Elst, & Muller, 2008; Rohrer,
Bauer, Mintorovitch, Requardt, & Weinmann, 2005). In
addition to the effects of relaxivity, the contrast agents
have a high magnetic susceptibility that causes additional
dephasing of water spins due to the compartmentalization
of the agent, further affecting the transverse relaxation rates
R2 and R2* (Rosen et al., 1990; Villringer et al., 1988).
CBV t 1
t
1
Ct tdt
Ca tdt
Ct t
t
1
Ca tRt tdt
1
[21]
St t St 0e
[19]
44
Table 2
3T
4.7 T
Trade name
Maker
Short name
Size (nm)
T1/2 (h)
r1
r2
r1
r2
r1
r2
Endorem
Feridex
Resovist
Sinerem
Combidex
AMAG Pharma
AMI-25
120180
4.5
33
2.7
45
1.2
25
Schering
AMAG Pharma
SHU-555A
AMI-227
60
1530
2.43.6
2436
7.4
9.9
95
65
3.3
160
1.7
118
Half-life in humans (Corot et al., 2006). Relaxivities expressed in mmol1 s1. Data obtained in plasma at 37 C (Rohrer et al., 2005).
Spost
1
ln
Spre
TE
[22]
where Spre and Spost are the MRI signal intensities before and
after the administration of the contrast agent, respectively.
Once DR2* is obtained, CBV can be calculated assuming the
static dephasing regime (Kim et al., 2013; Yablonskiy &
Haacke, 1994):
DR2 *
CBV
4
p1 HctDwUSPIO gB0 rv
3
[23]
*
TEBOLD R*2, BOLD
eTHBOLD R20
DSBOLD
sact Sbase S0 e
*
SBOLD
S0 eTHBOLD R20
Sbase
TEBOLD DR*2, BOLD TEBOLD R*20
TEBOLD R*20
e
e
e
R*
eTEBOLD
20
TEBOLD DR*2, BOLD
e
1 TEBOLD DR*2, BOLD
[24]
where TEBOLD is the echo time of the experiment, usually set at
TEBOLD R1* for maximum sensitivity, and DR*2, BOLD depends
20
linearly on the baseline venous CBV, on the magnetic field
strength, and on changes in oxygenation level (Ogawa et al.,
1993). Following administration of the contrast agent, it is
necessary to reset the echo time of the experiment due to the
effect of the contrast agent to increase R*2 :
R*2, USPIO R*2 DR*2, USPIO R*2 r2* Cv CBV
[25]
DSUSPIO
SUSPIO, act SUSPIO, base
SUSPIO
SUSPIO
*
TEUSPIO R*2, USPIO, act
S0, USPIO e
eTEUSPIO R2, USPIO, base
*
[26]
CBV
DR*2, USPIO
[27]
Conclusions
Endogenous and exogenous contrast agents have a fundamental role in enabling fMRI techniques to probe brain function.
Acknowledgments
This research was supported by the Intramural Research Program of the NINDS, NIH.
References
Alsop, D. C., & Detre, J. A. (1996). Reduced transit-time sensitivity in noninvasive
magnetic resonance imaging of human cerebral blood flow. Journal of Cerebral
Blood Flow and Metabolism, 16, 12361249.
45
Alsop, D. C., Detre, J. A., Golay, X., Gunther, M., Hendrikse, J., Hernandez-Garcia, L.,
et al. (2014). Recommended implementation of arterial spin-labeled perfusion
MRI for clinical applications: A consensus of the ISMRM perfusion study group
and the European consortium for ASL in dementia. Magnetic Resonance in
Medicine. http://dxdoi.org/10.1002/mrm.25197.
Barbier, E. L., Lamalle, L., & Decorps, M. (2001). Methodology of brain perfusion
imaging. Journal of Magnetic Resonance Imaging, 13, 496520.
Belliveau, J. W., Kennedy, D. N., Jr., Mckinstry, R. C., Buchbinder, B. R.,
Weisskoff, R. M., Cohen, M. S., et al. (1991). Functional mapping of the human
visual cortex by magnetic resonance imaging. Science, 254, 716719.
Boxerman, J. L., Bandettini, P. A., Kwong, K. K., Baker, J. R., Davis, T. L., Rosen, B. R., et al.
(1995). The intravascular contribution to fMRI signal change: Monte Carlo modeling
and diffusion-weighted studies in vivo. Magnetic Resonance in Medicine, 34, 410.
Burtea, C., Laurent, S., Vander Elst, L., & Muller, R. N. (2008). Contrast agents:
Magnetic resonance. Handbook of Experimental Pharmacology, 185, 135165.
Calamante, F. (2013). Arterial input function in perfusion MRI: A comprehensive review.
Progress in Nuclear Magnetic Resonance Spectroscopy, 74, 132.
Calamante, F., Thomas, D. L., Pell, G. S., Wiersma, J., & Turner, R. (1999). Measuring
cerebral blood flow using magnetic resonance imaging techniques. Journal of
Cerebral Blood Flow and Metabolism, 19, 701735.
Corot, C., Robert, P., Idee, J. M., & Port, M. (2006). Recent advances in iron oxide
nanocrystal technology for medical imaging. Advanced Drug Delivery Reviews, 58,
14711504.
Dai, W., Garcia, D., De Bazelaire, C., & Alsop, D. C. (2008). Continuous flow-driven
inversion for arterial spin labeling using pulsed radio frequency and gradient fields.
Magnetic Resonance in Medicine, 60, 14881497.
Detre, J. A., Leigh, J. S., Williams, D. S., & Koretsky, A. P. (1992). Perfusion imaging.
Magnetic Resonance in Medicine, 23, 3745.
Detre, J. A., Zhang, W., Roberts, D. A., Silva, A. C., Williams, D. S., Grandis, D. J., et al.
(1994). Tissue specific perfusion imaging using arterial spin labeling. NMR in
Biomedicine, 7, 7582.
Diekhoff, S., Uludag, K., Sparing, R., Tittgemeyer, M., Cavusoglu, M.,
Von Cramon, D. Y., et al. (2011). Functional localization in the human brain:
Gradient-echo, spin-echo, and arterial spin-labeling fMRI compared with
neuronavigated TMS. Human Brain Mapping, 32, 341357.
Dijkhuizen, P., Buursma, A., Fongers, T. M., Gerding, A. M., Oeseburg, B., &
Zijlstra, W. G. (1977). The oxygen binding capacity of human haemoglobin.
Hufners factor redetermined. Pflugers Archiv, 369, 223231.
Duyn, J. (2013). MR susceptibility imaging. Journal of Magnetic Resonance, 229,
198207.
Eichling, J. O., Raichle, M. E., Grubb, R. L., Jr., & Ter-Pogossian, M. M. (1974).
Evidence of the limitations of water as a freely diffusible tracer in brain of the rhesus
monkey. Circulation Research, 35, 358364.
Ferre, J. C., Shiroishi, M. S., & Law, M. (2012). Advanced techniques using contrast
media in neuroimaging. Magnetic Resonance Imaging Clinics of North America, 20,
699713.
Golay, X., Hendrikse, J., & Lim, T. C. (2004). Perfusion imaging using arterial spin
labeling. Topics in Magnetic Resonance Imaging, 15, 1027.
Gunther, M. (2014). Perfusion imaging. Journal of Magnetic Resonance Imaging, 40,
269279.
Herscovitch, P., Raichle, M. E., Kilbourn, M. R., & Welch, M. J. (1987). Positron
emission tomographic measurement of cerebral blood flow and permeabilitysurface area product of water using [15O]water and [11C]butanol. Journal of Cerebral
Blood Flow and Metabolism, 7, 527542.
Hill, R. J., Konigsberg, W., Guidotti, G., & Craig, L. C. (1962). The structure of human
hemoglobin. I. The separation of the alpha and beta chains and their amino acid
composition. The Journal of Biological Chemistry, 237, 15491554.
Jain, V., Abdulmalik, O., Propert, K. J., & Wehrli, F. W. (2012). Investigating the
magnetic susceptibility properties of fresh human blood for noninvasive oxygen
saturation quantification. Magnetic Resonance in Medicine, 68, 863867.
Kim, S. G., Harel, N., Jin, T., Kim, T., Lee, P., & Zhao, F. (2013). Cerebral blood volume
MRI with intravascular superparamagnetic iron oxide nanoparticles. NMR in
Biomedicine, 26, 949962.
Kim, S. G., & Ogawa, S. (2012). Biophysical and physiological origins of blood
oxygenation level-dependent fMRI signals. Journal of Cerebral Blood Flow and
Metabolism, 32, 11881206.
Kwong, K. K., Belliveau, J. W., Chesler, D. A., Goldberg, I. E., Weisskoff, R. M.,
Poncelet, B. P., et al. (1992). Dynamic magnetic resonance imaging of human brain
activity during primary sensory stimulation. Proceedings of the National Academy of
Sciences of the United States of America, 89, 56755679.
Lu, H., Golay, X., Pekar, J. J., & Van Zijl, P. C. (2003). Functional magnetic resonance
imaging based on changes in vascular space occupancy. Magnetic Resonance in
Medicine, 50, 263274.
46
Lu, H., Scholl, C. A., Zuo, Y., Stein, E. A., & Yang, Y. (2007). Quantifying the blood
oxygenation level dependent effect in cerebral blood volume-weighted functional
MRI at 9.4 T. Magnetic Resonance in Medicine, 58, 616621.
Menon, R. S., Ogawa, S., Kim, S. G., Ellermann, J. M., Merkle, H., Tank, D. W., et al.
(1992). Functional brain mapping using magnetic resonance imaging. Signal changes
accompanying visual stimulation. Investigative Radiology, 27(Suppl. 2), S47S53.
Norris, D. G. (2006). Principles of magnetic resonance assessment of brain function.
Journal of Magnetic Resonance Imaging, 23, 794807.
Ogawa, S., Lee, T. M., Kay, A. R., & Tank, D. W. (1990). Brain magnetic
resonance imaging with contrast dependent on blood oxygenation.
Proceedings of the National Academy of Sciences of the United States of
America, 87, 98689872.
Ogawa, S., Lee, T. M., Nayak, A. S., & Glynn, P. (1990). Oxygenation-sensitive contrast
in magnetic resonance image of rodent brain at high magnetic fields. Magnetic
Resonance in Medicine, 14, 6878.
Ogawa, S., Menon, R. S., Kim, S. G., & Ugurbil, K. (1998). On the characteristics of
functional magnetic resonance imaging of the brain. Annual Review of Biophysics
and Biomolecular Structure, 27, 447474.
Ogawa, S., Menon, R. S., Tank, D. W., Kim, S. G., Merkle, H., Ellermann, J. M., et al.
(1993). Functional brain mapping by blood oxygenation level-dependent contrast
magnetic resonance imaging. A comparison of signal characteristics with a
biophysical model. Biophysical Journal, 64, 803812.
Ogawa, S., Tank, D. W., Menon, R., Ellermann, J. M., Kim, S. G., Merkle, H., et al.
(1992). Intrinsic signal changes accompanying sensory stimulation: Functional
brain mapping with magnetic resonance imaging. Proceedings of the National
Academy of Sciences of the United States of America, 89, 59515955.
Ostergaard, L. (2004). Cerebral perfusion imaging by bolus tracking. Topics in
Magnetic Resonance Imaging, 15, 39.
Pauling, L., & Coryell, C. D. (1936). The magnetic properties and structure of
hemoglobin, oxyhemoglobin and carbonmonoxyhemoglobin. Proceedings
of the National Academy of Sciences of the United States of America, 22, 210216.
Raichle, M. E., Eichling, J. O., & Grubb, R. L.,Jr. (1974). Brain permeability of water.
Archives of Neurology, 30, 319321.
Rohrer, M., Bauer, H., Mintorovitch, J., Requardt, M., & Weinmann, H. J. (2005).
Comparison of magnetic properties of MRI contrast media solutions at different
magnetic field strengths. Investigative Radiology, 40, 715724.
Rosen, B. R., Belliveau, J. W., Vevea, J. M., & Brady, T. J. (1990). Perfusion
imaging with NMR contrast agents. Magnetic Resonance in Medicine, 14, 249265.
Silva, A. C., Zhang, W., Williams, D. S., & Koretsky, A. P. (1995). Multi-slice MRI of rat
brain perfusion during amphetamine stimulation using arterial spin labeling.
Magnetic Resonance in Medicine, 33, 209214.
Silva, A. C., Zhang, W., Williams, D. S., & Koretsky, A. P. (1997). Estimation of water
extraction fractions in rat brain using magnetic resonance measurement of perfusion
with arterial spin labeling. Magnetic Resonance in Medicine, 37, 5868.
Silvennoinen, M. J., Clingman, C. S., Golay, X., Kauppinen, R. A., & Van Zijl, P. C.
(2003). Comparison of the dependence of blood R2 and R2* on oxygen saturation at
1.5 and 4.7 Tesla. Magnetic Resonance in Medicine, 49, 4760.
Spees, W. M., Yablonskiy, D. A., Oswood, M. C., & Ackerman, J. J. (2001). Water
proton MR properties of human blood at 1.5 Tesla: Magnetic susceptibility, T(1),
T(2), T*(2), and non-Lorentzian signal behavior. Magnetic Resonance in Medicine,
45, 533542.
Thulborn, K. R., Waterton, J. C., Matthews, P. M., & Radda, G. K. (1982). Oxygenation
dependence of the transverse relaxation time of water protons in whole blood at high
field. Biochimica et Biophysica Acta, 714, 265270.
Diffusion MRI*
AR Hoy, United States Navy, Falls Church, VA, USA; University of Wisconsin Madison, Madison, WI, USA
AL Alexander, University of Wisconsin Madison, Madison, WI, USA
2015 Elsevier Inc. All rights reserved.
Abbreviations
ADC
CHARMED
DBSI
DKI
DSI
Introduction
Magnetic resonance imaging (MRI) contrast is highly sensitive
to the interaction of MRI-visible water with the local environment. As a fluid, pure water is highly mobile and diffuses
through a process called the Brownian motion that describes
the random motion of water particles in space. This diffusion
process causes the water molecules to exhibit increasing spatial
displacements with time. Einstein (1905) derived the equations describing the Brownian motion. These showed that the
spatialtemporal dependence of diffusion was described by a
Gaussian distribution. Additionally, the mean squared displacement from diffusion, Dx2, increases with the product of
the diffusion coefficient, D, and the diffusion time, t:
Dx2 2nDt
where n is dimensionality of the space (n 3 for three dimensions). Water at 37 C (body temperature) has a diffusion
coefficient of roughly 3 103 mm2 s1 but is sensitive to
temperature and pressure and has isotropic directional
dependence.
DTI
EPI
HARDI
HYDI
NODDI
http://dx.doi.org/10.1016/B978-0-12-397025-1.00005-1
47
48
180
90
RF
d
Gss
Gp
Gf
Figure 1 Diffusion weighting can be applied in any arbitrary direction
through modulation of the slice-select (red), phase-encoding (green),
and frequency-encoding (blue) diffusion gradients. D is the time between
diffusion-weighting pulses known as the diffusion time and d is the
duration of the pulse.
DW Pulse Sequences
The most common DW pulse sequence is the pulsed-gradient
spin echo where the diffusion-weighting gradient pulses are
placed on both sides of the 180 refocusing pulse; see Figure 1.
Because DW pulse sequences are highly sensitive to motion at
the microscopic scale, most studies use single-shot rapid image
acquisition methods like echo-planar imaging (EPI). While EPI
is very rapid, the spatial resolution is limited. Also, offresonance effects from static magnetic field inhomogeneities
will lead to significant image distortions. Parallel imaging
methods are commonly applied to reduce the amount of EPI
distortion. Multiple shot acquisition methods that may
improve spatial resolution and reduce distortion have also
been developed. However, these methods require navigator
echoes to correct the phase inconsistencies in the data between
shots. Another issue with DW EPI sequences is the residual
eddy currents from the strong DW gradients. Commercial DW
pulse sequences often include an option for bipolar diffusion
gradients with a dual-refocused spin echo sequence (Reese,
Heid, Weisskoff, & Wedeen, 2003); however, that option significantly increases the echo time, which reduces the measurement signal to noise ratio (SNR). Eddy current-induced
distortions may be corrected using retrospective image registration tools that can also correct for head motion.
DW Encoding
Moseley et al. (1990) and Chenevert, Brunberg, and Pipe (1990)
reported that the brain white matter exhibited anisotropic diffusion properties such that the diffusion was greater in the
direction parallel to the white matter tracts than in the perpendicular direction. Because magnetic field gradients vary the magnetic field in a specific direction, the diffusion sensitivity is
encoded along the direction of the gradient. By applying
diffusion weighting in directions both parallel and perpendicular to white matter fiber tracts, the degree of diffusion anisotropy
may be assessed. Since the local direction of the white matter
49
Figure 2 Signal dependence on gradient direction. All images have the same b-value of 1000 s mm2. From left to right, the gradient directions are
leftright, anteriorposterior, and inferiorsuperior, respectively. The red arrow points out a major WM tract called the corpus callosum. In this slice,
the corpus callosum is oriented primarily leftright and slightly anteriorposterior; thus, there is greater diffusion (hence more attenuation) in the
leftmost image than there is in the rightmost image.
Figure 3 Signal dependence on b-value. All images have the same leftright gradient direction applied. From left to right, the b-values are 0, 500, 1000,
and 1500 s mm2.
rs
2
3 l1 MD l2 MD2 l3 MD2
FA
2
l21 l22 l23
l2 l3
DR
2
D A l1
50
Figure 4 Diffusion metrics shown on an axial slice. These include different displays of FA (a and b) and ADC metrics (c, d, and e). FA can be displayed
as gray scale (a) with intensity determined by the magnitude of anisotropy or as a color-coded image (b) with the primary eigenvalue determining
the displayed color and the brightness determined by FA. In the directional encoding, red is indicative of leftright, green anteriorposterior, and
blue inferiorsuperior. ADCs can be displayed as the MD (c), DA (d), or DR (e). Here, each image is displayed with the same scale.
Gaussian assumption is maintained for any one of the compartments, but any single voxel may contain multiple compartments. This model makes it possible to visualize white matter
pathways, which cross one another while passing through a
single voxel.
Generally, HARDI refers to a class of diffusion methods,
which contain more information than the tensor model. This
includes parametric and nonparametric models. These
methods share a common acquisition with a single b-value
(20004000 s mm2) and many (typically 60100) diffusion directions distributed uniformly over a sphere. The exact
b-value and number of directions are highly dependent on the
chosen model.
quantifying the departure from Gaussian behavior. This deviation is measured as the kurtosis tensor. The link between DTI and
DKI can be readily seen in the signal equation utilized for DKI:
Sb
1
ln
bD b2 DK
S0
6
where K is the kurtosis tensor. Thus, DKI utilizes an additional
second-order term (in b) to measure deviation from Gaussian
behavior. This definition allows for use of the typical DTI
metrics with additional rotationally invariant apparent kurtosis metrics as well. A truly Gaussian diffusion profile results in a
kurtosis value of zero.
Kurtosis provides information that is complimentary to DTI.
Indeed, white matter and gray matter, which have a similar mean
diffusivity, have a markedly different mean kurtosis. While kurtosis is sensitive to tissue microstructure (Hui, Cheung, Qi, &
Wu, 2008), it cannot easily be tied out to a specific biophysical
property. DTI estimates 6 parameters, while DKI fits 15 independent parameters. DKI also requires the use of two different
b-values with a larger b-value of approximately 2000 s mm2.
51
that is, intra- and extra-axonal space, cellularity, CSF contamination, or neurite density, to certain diffusion patterns
or characteristics. Three such techniques will be briefly
introduced.
Assaf, Freidlin, Rohde, and Basser (2004) introduced the
composite hindered and restricted model of diffusion
(CHARMED). This model consists of one extra-axonal compartment and multiple intra-axonal compartments. The extraaxonal compartment is modeled as a diffusion tensor, which is
characteristic of hindered diffusion. Each intra-axonal compartment is characterized by restricted diffusion within a
cylinder.
Neurite orientation dispersion and density imaging
(NODDI) assigns signal to intracellular, extracellular, and
CSF compartments (Zhang, Schneider, Wheeler-Kingshott, &
Alexander, 2012). The intracellular compartment is modeled
as a distribution of highly restricted sticks. A collection of
cylindrically symmetrical tensors models the extracellular compartment. Meanwhile, the CSF compartment is treated as having a fixed isotropic diffusivity.
Diffusion basis spectrum imaging (DBSI) fits a linear combination of a variable number of isotropic and anisotropic
compartments at each voxel (Wang et al., 2011). The anisotropic tensors are considered representative of myelinated and
unmyelinated axons, while the isotropic tensors are hypothesized to be indicative of cells, subcellular structures, and edematous water.
These models are extremely attractive as they provide
meaningful biological explanations for the observed diffusion
phenomena. Typically, these techniques require a higher
b-value, thus, less SNR and a longer acquisition time than
DTI, but less time and greater SNR than q-space techniques.
Improvements in gradient strength and the success of parallel
imaging have made these techniques feasible in a clinical
setting.
Conclusion
Diffusion MR imaging is a flourishing field, which has grown
in complexity and applications since its introduction nearly
52
References
Assaf, Y., Freidlin, R. Z., Rohde, G. K., & Basser, P. J. (2004). New modeling and
experimental framework to characterize hindered and restricted water diffusion in
brain white matter. Magnetic Resonance in Medicine, 52, 965978.
Basser, P. J., Mattiello, J., & Le Bihan, D. (1994). MR diffusion tensor spectroscopy and
imaging. Biophysical Journal, 66, 259267.
Callaghan, P. T. (1991). Principles of nuclear magnetic resonance microscopy. Medical
Physics, 19, 1121.
Chenevert, T. L., Brunberg, J. A., & Pipe, J. G. (1990). Anisotropic diffusion in human
white matter: Demonstration with MR techniques in vivo. Radiology, 177, 401405.
Einstein, A. (1905). On the movement of small particles suspended in stationary
liquids required by the molecular-kinetic theory of heat. Annelan der Physik, 17,
549560.
Hui, E. S., Cheung, M. M., Qi, L., & Wu, E. X. (2008). Towards better MR
characterization of neural tissues using directional diffusion kurtosis analysis.
NeuroImage, 42, 122134.
Jensen, J. H. & Helpern, J. A. (2003). Quantifying non-Gaussian water diffusion by
means of pulsed-field-gradient MRI. In Proceedings of the International Society for
Magnetic Resonance in Medicine, p. 2154.
Jensen, J. H., Helpern, J. A., Ramani, A., Lu, H., & Kaczynski, K. (2005). Diffusional
kurtosis imaging: The quantification of non-gaussian water diffusion by means of
magnetic resonance imaging. Magnetic Resonance in Medicine, 53, 14321440.
Le Bihan, D., Breton, E., Lallemand, D., Grenier, P., Cabanis, E., & Laval-Jeantet, M.
(1986). MR imaging of intravoxel incoherent motions: Application to diffusion and
perfusion in neurologic disorders. Radiology, 161, 401407.
Moseley, M. E., Cohen, Y., Kucharczyk, J., Mintorovitch, J., Asgari, H. S.,
Wendland, M. F., et al. (1990). Diffusion-weighted MR imaging of anisotropic water
diffusion in cat central nervous system. Radiology, 176, 439445.
Reese, T. G., Heid, O., Weisskoff, R. M., & Wedeen, V. J. (2003). Reduction of eddycurrent-induced distortion in diffusion MRI using a twice-refocused spin echo.
Magnetic Resonance in Medicine, 49, 177182.
Stejskal, E. O., & Tanner, J. E. (1965). Spin diffusion measurements: Spin echoes in
the presence of a time-dependent field gradient. Journal of Chemical Physics, 42,
288.
Tuch, D. S., Reese, T. G., Wiegell, M. R., Makris, N., Belliveau, J. W., &
Wedeen, V. J. (2002). High angular resolution diffusion imaging reveals
intravoxel white matter fiber heterogeneity. Magnetic Resonance in Medicine, 48,
577582.
Wang, Y., Wang, Q., Haldar, J. P., Yeh, F.-C., Xie, M., Sun, P., et al. (2011).
Quantification of increased cellularity during inflammatory demyelination. Brain,
134, 35903601.
Wedeen, V., Reese, T., Tuch, D., Weigel, M., Dou, J., Weiskoff, R., et al. (2000).
Mapping fiber orientation spectra in cerebral white matter with Fourier-transform
diffusion MRI. In: Proc. Intl. Sot. Mag. Reson. Med. 8, (p. 5627).
Wu, Y. C., & Alexander, A. L. (2007). Hybrid diffusion imaging. NeuroImage, 36,
617629.
Zhang, H., Schneider, T., Wheeler-Kingshott, C. A., & Alexander, D. C. (2012). NODDI:
Practical in vivo neurite orientation dispersion and density imaging of the human
brain. NeuroImage, 61, 10001016.
Echo-Planar Imaging
F Schmitt, Siemens Healthcare, Erlangen, Germany
2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00006-3
53
54
Pulse Sequences
The MR signal generation and reception is quite complex and will
not be described in this article. Pulse sequences are the essence of
an MRI machine, as it allows acquiring the data required to
calculate images of the organ on scope. For better understanding
MR imaging methods see Mark Haackes book on Physical principles and sequence design of MRI (Haacke et al., 1999a).
Below, a brief walk from the most basic MR pulse sequence,
the GRE sequence, to the various EPI sequences is given. All
common neuroscience and clinical neurology-related single
shot EPI sequences are described.
where G(t) defines the time dependent gradient pulse and g the
gyromagnetic ratio (g 42.578 MHz T1). In graphical terms,
the condition of a gradient echo is achieved when the area
under the (negative polarity) pre-phasing lobe of the RO gradient is balanced by the accumulated area under the (positive
polarity) RO gradient pulse. For clarity reasons these two sections are shown shaded in Figure 1. Usually, this coincides
with the time when the maximum signal is detected and is
called echo time (TE). While the SS and read-out gradient pulse
remain constant during the entire imaging process for a 2D
imaging experiment, conventional MRI employs a so-called
phase encoding step. After each repetition time (TR) one
(k-space) data line is acquired and the PC gradient is changing
a bit, by stepping in incremental steps of dGPC 2GPC/N from
GPC to GPC, where N is the matrix size. Total scan time is
therefore N times TR, while TR is defined application specific.
K-space traversal is line by line as shown in Figure 1. The
image is then calculated by a two dimensional Fourier
Transform (2D FT) of the acquired 2D k-space data (commonly called raw data).
The maximum signal can be expressed as
St TE So eTE=T2*
[2]
[3]
with DBo describing the magnetic flux changes across the voxel
caused by magnetic susceptibility differences of the adjacent
tissue (for fMRI this is the BOLD induced susceptibility effect).
T2* decay is happening asymmetrically across the k-space data
line.
For MR angiographic applications, for example, TE and TR
are kept as short as possible, while for measuring the best
BOLD signal for fMRI one needs to prolong TE quite substantially specific to the field strength of the magnet used. It is
generally established that for 1.5, 3, and 7 T TEs of 40, 30,
and 20 ms are used, respectively, while the repetition time TR is
on the order of seconds to avoid or minimize T1 weighting.
Assuming a matrix size of N 64, which was typically used for
fMRI in the early days, total scan times per image (i.e., slice) are
on the order of 25 min for a stack of slices covering the brain
volume of interest. This takes much too long for performing
useful fMRI experiments. But it can be and was used in the early
times of fMRI as no other faster method like EPI was available
(see above in the history section).
55
a
RF
Raw data
Image data
GSS
2D FT
GPC
GRO
RO
Signal
TE
TR
(a)
PC 1
2
.
.
.
.
.
.
t
.
.
.
.
N
et/T2*
K-space
Image space
1..N
K-space trajectory
Figure 1 (a) GRE sequence. Left column: GRE-2D pulse sequence. Note: Condition for a GRE is highlighted in shaded areas of GRO pulse train.
Middle column: typical magnitude raw-data set (above) and rectilinear k-space trajectory (below). Right column: resulting image. (b) 7 T T2* weighted
high-resolution GRE images (1024 1024 matrix size). Left: magnitude image, right: phase image. Note the contrast variations in the phase image
across the optical radiation fiber bundles (see arrows).
EPI-GRE Sequence
or N/2-ghosting artifact which creates double/ghost images
shifted by half the matrix size N and wrapped around in PC
direction. For further reading on EPI image reconstruction we
suggest (Schmitt et al., 1998).
Figure 2 shows the most basic EPI sequence, that is, the
EPI-GRE type which is used for BOLD imaging. The image
is acquired after a single RF-pulse excitation. Shape and
amplitude of PC and the RO gradient pulses are kept
90
RF
RO
PC 1
2
.
.
.
.
.
.
.
.
.
.
N
PC blips
GPC
EPI Readout
Phase Correction
GRO
et/T2*
Signal
GSS
N....1
N+1 .2N
1..N
K-space trajectory
t
(a)
TE
Figure 2 (a) 2D EPI-GRE sequence. Left column: EPI-GRE sequence. MR signal is T2* weighted as indicated in signal trace. Right column: K-space
trajectory is meander like starting from upper right to lower left. Advance in PC direction is generated by little blips in PC direction. (b) Typical 2D
EPI-GRE images through brain taken on a 3 Thead-only MRI system. Scan parameters: Single shot EPI; TE/TR 3000/50 ms; 128 128 matrix size;
48 slices at 3 mm voxel size.
57
180
90
RF
GSS
RO
PC blips
GPC
1
PC 2
.
.
.
.
.
.
.
.
.
.
N
GRO
t
et/T2
1....N
2N .N+1
K-space trajectory
e|t|/T2*
t
t
TE
(a)
Figure 3 (a) 2D EPI-SE sequence. Left column: EPI-SE sequence. MR signal is T2 weighted as indicated in signal trace. T2* weighting still exists, but is
very minor and occurs only earlier and later to TE. Right column: K-space trajectory is meander like starting from upper left to lower right. Note the
difference in k-space traversal due to 180 HSE refocussing pulse.
(Continued)
58
Figure 3 contd (b-g) Anatomical and functional images from one volunteer taken at 9.4 Tesla. High-resolution anatomical GRE images (b) and (c)
clearly show the veins in both the magnitude and phase representation, respectively. SE-EPI (d) and GRE-EPI (e) have been acquired with 1 mm3
voxel size and show clear activation of the motor and somatosensory cortex (color overlay). Zoomed images of the activation, registered to the
high-resolution anatomical data, are shown in (f) and (g). The locations of the veins are overlaid in blue. The color bar shows the z-score and scaling is
equal in whole brain and zoomed images. Images with permission from MRM and courtesy of Budde, J., Shajan, G., Zaitsev, M., Scheffler, K., &
Pohmann, R. (2014). Functional MRI in human subjects with gradient-echo and spin-echo EPI at 9.4 T. Magnetic Resonance in Medicine, 71, 209218.
Max Planck Institute Tubingen.
[4]
Signal
t
DSt B0 e T1B
[5]
59
[6]
500
450
400
350
300
250
0s
1.5 s
10
3s
4.5 s
20
6s
30
7.5 s
9s
40
Time point
10.5 s 12 s 13.5 s
Figure 4 T2* weighted perfusion time curve. Images shown in insert show the actual time stamps from the bolus arrival until 13.5 s after bolus.
60
HSE-180
Inversion 180
90
t
RF
TI
TE
GSS
GPC
Imaging
slices
Inversion
slab
GRO
Figure 5 2D EPI-ASL sequence. Typically a thick slab in the neck region is inverted and after a wait time of TI an EPI-SE sequence is used to acquire the
flow sensitive MR signal.
In general, the diffusion coefficient is not a scalar quantity but will exhibit a directional dependence. For example,
water molecules can move rather freely along axonal fibers,
but are restricted in their motion perpendicular to fiber axis.
Thus, a tensor model is commonly applied which sets the
stage for advanced processing techniques like fiber tracking.
It requires a modification of the pulse sequence such that
diffusion lobes are applied in all three gradient directions
and vary in amplitude. Diffusion tensor imaging is one
variant of DWI, allowing to track neuronal fibers. It has
one caveat though; crossing fibers in a single voxel are
beyond the scope of the model and thus cannot be resolved
(Tournier et al., 2013). To overcome this uncertainty the
61
180
90
t
RF
TE
GSS
GDiff
GPC
d
d
D
GRO
Figure 7 2D EPI-Diffusion weighted imaging sequence applying the SteijskalTanner diffusion pulsing scheme. The basic sequence is an EPI-SE
sequence with strong diffusion sensitizing gradient lobes (GDiff) between 90 180 pulse and 180 -RO module. These gradient lobes can vary in
amplitude and direction depending on the DTI pulsing scheme. On clinical scanners (Gmax 45 mT m1) with b1000 this pulsing scheme results in
echo-times of about 80100 ms.
b values
s mm2
35
141
318
565
883
EPI-GRE-SE
1271
180
90
t
RF
TE
GSS
GPC
GRO
Figure 9 2D EPI-DSI sequence with diffusion encoding in three directions. Due to the typically very high b-weightings used in DSI long echo-times in
the excess of 100 ms is resulting. This method is therefore better used in very high performing gradient systems (Gmax > 100 mT m1).
b = 10 000 s mm2, 1.5mm isotropic resolution diffusion weighed images (single direction)
Gmax = 40 mT m1
100 mT m1
300 mT m1
10 000 s mm2
10 000 s mm2
15 000 s mm2
Gmax = 40 mT m1
100 mT m1
200 mT m1
300 mT m1
Figure 10 Upper row: Diffusion weighted images (single direction) acquired at Gmax 40 mT m1, 100 mT m1 and 300 mTm1 with
b 10,000 s mm2 and 1.5 mm isotropic resolution. Corresponding TE is 120, 80, 50 ms, respectively. i.e. with increasing available maximum
gradient strength shorter echo times are achieved and hence SNR of the diffusion weighted scans is significantly improved. Data acquired with the 64
channel brain array. Lower row: Effect of gradient strength on diffusion MRI of path crossings. DSI with peak gradients Gmax 40, 100, 200, and
300 mT m1, with mixing time adjusted for constant bmax 10 000 s mm2 are shown in panels 13 (from left to right), and bmax 15 000 in panel 4. As
noted, TEs are minimized for each Gmax. The total number of path solutions identified within the Superior longitudinal fasciculus (SLF; horizontal
green, at center) increases by about 50% from the conventional (40 mT m1) to ultra-high gradient levels. Crossing pathways increase more
dramatically, their count increases by 23x from conventional to intermediate gradient performance (100 mT m1), and an additional 23x gain from
intermediate to the ultra-high gradients (100 vs 300 mT m1). Images courtesy V. Wedeen and L.L. Wald, MGH Martinos Center.
[8]
[9]
DB0
G
[10]
Significant image artifacts arise due to these local inhomogeneities. For further reading we suggest (Ludeke et al., 1985).
For EPI sequences the relevant gradient axis is the very low
strength equivalent PC gradient. Therefore severe distortions
can be seen in regions of strong susceptibility changes, such as
the eye and nasal sinus. Change of the polarity of the PC
gradient is changing the distortion behavior significantly, that
is, it can either stretch or squeeze those regions (see Figure 11).
This leaves room to optimize EPI accordingly to minimize
distortion effects.
Signal voids due to phase cancelation caused by intra-voxel
signal dephasing is also a common susceptibility-related issue
with EPI, described with eqn [11]
DFgDB0 t
[11]
63
64
PC
(a)
Figure 11 (a) Susceptibility artefacts. Distortion in eyes and nasal sinus. Polarity of PC gradient is inverted between left and right image, causing
stretching and squeezing of the eyes and nasal sinus region, respectively. (b) 1 mm resolution diffusion-weighted images showing improvement in
frontal lobe susceptibility distortion as acceleration is increased beyond R 2. Images acquired at 3 T with a 32ch head coil. Data courtesy of L.L. Wald,
MGH Martinos Center. (c) Distortion correction of EPI images via PSF deconvolution. EPI-GRE acquisition taken at 7 T with a 32RX head coil.
Slice thickness 1.4 mm; #slices 10; in plane resolution 1.41.4 mm2; FOV 224224; Matrix 160160; Partial Fourier 6/8; GRAPPA factor 3;
TR/TE 5000/25 ms.
30 ms
40 ms
50 ms
60 ms
Figure 12 (a) Susceptibility artefacts. Through-plane signal void as a function of slice thickness. The thicker the slice the more severe the signal voids. Image courtesy Lawrence L. Wald, MGH. (b) Susceptibility
artefacts. In-plane signal void as a function of echo time TE. The longer TE the more the signal voids are pronounced. Therefore BOLD fMRI is a balance between the desired BOLD signal effect and the
accompanying susceptibility aretfacts. Image courtesy Lawrence L. Wald, MGH.
21 ms
(b)
65
66
Bmax
zS
zL
FOVS
Z-gradient
FOVL
GTh(#pulse)
GTh(TRise)
Figure 13 Peripheral nerve stimulation in relation to short and long gradients illustrated with a z-gradient. PNS occur at location of strongest magnetic
flux exposure.
~30%
TRise
N
Th
#periods
Rise
Figure 14 PNS threshold gradient amplitudes as a function of gradient pulse rise time G fct(T ) for sinusoidal and trapezoidal pulse trains (left).
When increasing the numbers of pulses per pulse train, threshold reduces by about 30% and reach a stable value at about 16 periods.
Accelerated EPI
EPI is the fastest MRI pulse sequence existing. However, acceleration is still advantageous for a variety of reasons. One
reason for accelerating is to minimize susceptibility artefacts,
that is, distortion and signal voids, as described above. Another
reason is data throughput, that is, how many slices per seconds
can be acquired. This is generally achieved by using knowledge
of the spatial extend of the RF coil profiles of multi-channel
receive coils which are common these days. All major vendors
offer head RX coils with up to 32 RX channels for clinical
scanners now. Experimental coils have been proposed and
introduced offering up to 128 RX channels allowing even
further accelerations in MR imaging (Keil and Wald, 2013;
Wiggins et al., 2009).
Acceleration schemes are basically differentiated by
methods which accelerate the scan time per image (i.e., inplane) or by accelerating the scan time per stack of slices (i.e.,
through-plane). Here we briefly describe these two basic
methods, as they are interwoven into the EPI acquisition.
In-Plane Acceleration
The general terminology for accelerated MR imaging is parallel
imaging, abbreviated as pRX. These methods have been
WM
CSF
PH
GM
(a)
1135
1640
Phantom
Mean signal over ROI
1620
1610
1600
1590
1580
50
CSF
1130
1630
100
150
200
Time points
1125
1120
1115
1110
1105
1100
1095
Stability ~ 1.8% peakpeak
1090
250
1085
300
840
250
300
250
300
905
Mean signal over ROI
150
200
Time points
GM
835
830
825
820
815 Stability ~ 0.7% peakpeak
(b)
100
910
WM
810
50
50
100
150
200
Time points
900
895
890
885
250
300
880
50
100
150
200
Time points
Figure 15 (a) Cross sectional EPI-BOLD scan with adjacent phantom to the right taken on a 3T head scanner. Red boxes show 77 pixel
ROIs to be evaluated (see below). Scan parameter are TE 20 ms, TR 2000 ms, matrix size is 6464. (b) Time course evaluation of ROIs
(shown in red in Figure 15 (a)) do reflect MRI scanner noise and physiological noise of an fMRI experiment. Data courtesy of C. Triantafilou
and L. L. Wald, MGH.
67
68
[12]
Through-Plane Acceleration
Through-plane acceleration has been developed over the recent
35 years and is making very promising advances. These
methods are based on a technique called multi band (MB).
While the MB method exists since the early 2000s (Larkman
et al., 2001) it recently has been refined to allow very high
acceleration rates (Feinberg et al., 2010; Moeller et al., 2010).
Simultaneous multi slice (SMS) in combination with EPI is
based on blipped CAIPHRINHA and provides excellent
through-plane acceleration (Setsompop et al., 2012). The real
advantage of not losing SNR with increasing acceleration, as it
happens with the in-plane methods, is very helpful to maintain
high SNR with high accelerations. Through-plane acceleration
allows high temporal resolution resting state fMRI (rsfMRI) as
it shortens the scan time per stack of slices below a second (see
Figure 16).
For high resolution DSI with very long scan times of
30 min or longer are normal if no acceleration is applied.
Combining in-plane and through-plane acceleration helps
to shorten scan time significantly (Setsompop et al., 2013).
Figure 17 shows results of this technique taken at a 7 T
scanner. Fifteen-fold acceleration is achieved by applying
threefold in-plane (using GRAPPA) with fivefold throughplane SMS acceleration.
Appendix
Technology Development of EPI Capable Gradient Systems
The key specifications of a gradient system is shown in
Figure A1 and is characterized by
(a) the maximum achievable gradient amplitude, Gmax,
measured in magnetic flux variation per meter, that is,
mT m1, which is usually expressed as
Gmax SImax
[13]
dG Gmax
dt T Rise
[14]
Gt 2 dt
100%
DCt1 ; t2 2t1
Gref t2 t1
[15]
[16]
U L
dI
RI
dt
[17]
(b)
(c)
(d)
69
Figure 16 Multiband through-plane acceleration applied to resting state fMRI at 3 T by using a 32 channel RX head coil. TE 30 ms and 1.6 mm isotropic voxel resolution. (a) Standard fMRI protocol-no
acceleration, TR 6.7 s, flip angle 90 . (b) MultiBand 6 acceleration, PE3, 6/8 PF, TR 6.7 ms, flip angle <90 . (c) MultiBand 6 acceleration, PE3, 6/8 PF, TR 1.1 ms, flip angle <90 . (d) 2 mm isotropic voxels.
MultiBand 6 acceleration, PE3, 7/8 PF, TR 0.74 ms, flip angle <90 . Images courtesy E. Yacoub, K. Ugurbil, D. Feinberg et al. CMRR, Minneapolis.
(a)
70
Figure 17 In-plane (GRAPPA) and through-plane (SMS) acceleration combined results acquired on a 7 T system by using a 32 channel RX
head coil: In total a R15-fold acceleration is achieved. Rin-plane3, Rthrough-plane5. Images courtesy K. Setsompop & J. Polmeni, MGH Martinos
Center.
G(t)
Gmax
t
I(t)
Gmax= S I max
TRise
Imax
V(t) = I(t)RL
dI ( t)
dt
V(t)
V max
V max = I max R + L
t
I max
TRise
U max LS
Gmax
RImax
T Rise
[18]
Inversion 180
71
90
RF
GSS
GPC
GRO
+Mz
Mz/signal
Magnetization Mz
et/T2*
MR signal
1et/T1
Mz
TNULL
TI
TE
(a)
Inversion 180
180
90
RF
GSS
GPC
GRO
0
+Mz
Mz/signal
Magnetization Mz
et/T2
MR signal
1et/T1
Mz
(b)
TNULL
TI
TE
Figure A2 (a) 2D Inversion recovery with EPI-GRE data acquisition sequence. (b) 2D Inversion recovery with EPI-SE data acquisition sequence.
(Continued)
Figure A2 contd (c) Typical image acquired with a 2D inversion recovery with EPI-GRE data acquisition sequence. Note the different TI causes
different contrast between GM and WM.
180
90
RF
GSS
GPC
GRO
et/T2*
et/T2
e(tTE
HSE)/T2*
t
TEGRE
TEHSE
Figure A3 GRE and SE double acquisition EPI sequence.
Acknowledgments
The author is grateful to T. Feiweier for reading and correcting
the manuscript and to H. Meyer for helping with sequence
diagrams. I also deeply appreciate receiving the imaging data
of K. Ugurbil, L.L. Wald, V. Wedeen, E. Yakoub, C. Triantafyllou, M.-H. In, O. Speck, G. Budde, K. Scheffler, R. Pohmann, K.
Setsompop, J. Polimeni, S. Warach, and R. Edelman.
References
History of EPI
Ordidge, R. (1999). The development of echo-planar imaging (EPI): 19771982.
Magnetic Resonance Materials in Physics, Biology and Medicine, 9, 117121.
Cohen, M. S., & Schmitt, F. (2013). Echo-planar imaging before and after fMRI: A
personal history. NeuroImage, 62, 652659.
Mansfield, P. (2013). The long road to Stockholm The story of MRI An
autobiography. Oxford: Oxford University Press, ISBN: 978-0-19-966454-1.
Cohen, M. S., & Weiskoff, R. M. (1991). Ultra-fast imaging. Magnetic Resonance
Imaging, 9, 137.
Schmitt, F., Fischer, H., & Barfu, H. (1988a). Echo-planar imaging (EPI) erste
Ergebnisse. Siemens Internal Communication.
Schmitt, F., Fischer, H., Bruder, H., et al. (1989). Reconstruction schemes for EPI with
sinusoidal read gradients. Book of abstract SMRI, Los Angeles. Magnetic
Resonance Imaging SMRI, 7(1), P-066.
Schmitt, F., Borth, G., Hagen, U., et al. (1993). A high performance whole body EPIscanner at 1.5 T. Book of abstract SMRI. Magnetic Resonance Imaging Journal, 3,
225.
Muller, M. F., Prasad, P. V., Siewert, B., Nissenbaum, M. A., Raptopoulos, V.,
Lewis, W. D., et al. (1994). Abdominal diffusion mapping using a whole body echo
planar system. Radiology, 190(2), 475478.
Edelman, R. R., Gaa, J., Wedeen, V. J., Loh, E., Hare, J. M., Prasad, P. V., et al. (1994).
In vivo measurement of water diffusion in the human heart. Magnetic Resonance in
Medicine, 32(3), 423428.
Howseman, A. M., Stehling, M. K., Chapman, B., et al. (1988). Improvements in snapshot nuclear magnetic resonance imaging. The British Journal of Radiology, 61,
822828.
Edelman, R. R., Wielopolski, P., & Schmitt, F. (1994). Echo-planar MR imaging.
Radiology, 192, 600612.
Kwong, K. K. (2012). Record of a single fMRI experiment in May of 1991. NeuroImage,
62, 610612.
MR Imaging
Haacke, E. M., Brown, R. W., Thompson, M. R., & Venkatesan, R. (1999a). Magnetic
resonance imaging Physical principles and sequence design. New York: Wiley,
ISBN 0-471-35128-8.
Haacke, E. M., Brown, R. W., Thompson, M. R., & Venkatesan, R. (1999b). The imaging
equation. In Magnetic resonance imaging Physical principles and sequence
design. New York: Wiley, ISBN 0-471-35128-8, Chapter 10.1.1.
Ernst, R. R., & Anderson, W. A. (1966). Application of Fourier transform spectroscopy
to magnetic resonance. Review of Scientific Instruments, 37(1), 93102.
Haase, A., Frahm, J., Matthaei, D., et al. (1986). FLASH imaging. Rapid NMR imaging
using low flip-angle pulses. Journal of Magnetic Resonance, 67, 258266.
Oppelt, A., Graumann, R., Barfuss, H., et al. (1986a). FISP A new fast MRI sequence.
Electromedica, 54, 1518.
Hahn, E. (1950). Spin echoes. Physics Review, 80, 580.
Meyer, C. H. (1998). Spiral echo-planar imaging. In F. Schmitt, M. K. Stehling, & R.
Turner (Eds.), Echo-planar imaging Theory, technique and applications
Magnetic resonance imaging in a fraction of a second. Berlin: Springer3-54063194-1, Chapter 21.
Ahn, C. B., Kim, J. H., & Cho, Z. H. (1986). High speed spiral scan echo planar imaging.
IEEE Transactions on Medical Imaging, 5(1), 25.
Mugler, J. P., & Brookman, J. R. (1991). Rapid three dimensional T1 weighted MR
imaging with the MP-rage sequence. Journal of Magnetic Resonance Imaging, 1,
561567.
73
Echo-Planar Imaging
Mansfield, P. (1977). Multi-planar image formation using NMR spin echoes. Journal of
Physics C: Solid State Physics, 10, L55L58.
Stehling, M. K., Turner, R., & Mansfield, P. (1991). Echo-planar imaging: Magnetic
resonance imaging in a fraction of a second. Science, 254, 4350.
Pykett, I. L., & Rzedzian, R. R. (1987). Instant images of the body by magnetic
resonance. Magnetic Resonance in Medicine, 5, 563571.
Mansfield, P., Harvey, P. R., & Coxon, R. J. (1991). Multi-mode resonant gradient coil
circuit for ultra high speed NMR imaging. Measurement Science and Technology, 2,
10511058.
Wielopolski, P., Schmitt, F., & Stehling, M. K. (1998). Echo-planar imaging pulse
sequences. In F. Schmitt, M. K. Stehling & R. Turner (Eds.), Echo-planar imaging
Theory, technique and applications Magnetic resonance imaging in a fraction of a
second. Berlin: Springer3-540-63194-1 Chapter 4.
Schmitt, F., & Wielopolski, P. (1998). Echo-planar image reconstruction. In F.
Schmitt, M. K. Stehling & R. Turner (Eds.), Echo-planar imaging Theory,
technique and applications Magnetic resonance imaging in a fraction of a second.
Berlin: Springer3-540-63194-1 Chapter 5.
Schmitt, F., Fischer, H., & Ladebeck, R. (1988b). Double acquisition echo-planar
imaging. Book of abstracts SCNMR, Berlin.
Ordidge, R. J., Gibbs, P., Chapman, B., Stehling, M. K., & Mansfield, P. (1990). Highspeed multislice T1 mapping using inversion-recovery echo-planar imaging.
Magnetic Resonance in Medicine, 16, 238245.
fMRI
Thullborn, K. R., Waterton, J. C., Matthews, P. M., et al. (1982). Oxygenation
dependence of the transverse relaxation time of water protons in whole blood at high
field. Biochimica Biophysica Acta, 714, 265270.
Ogawa, S., Lee, T. M., Nayak, A. S., & Tank, D. W. (1990). Brain magnetic resonance
imaging with contrast dependent on blood oxygenation. Proceedings of the National
Academy of Sciences, 87, 98689872.
Ogawa, S., Tank, D. W., Menon, R., et al. (1992). Intrinsic signal changes
accompanying sensory stimulation: Functional brain mapping with magnetic
resonance imaging. Proceedings of the National Academy of Sciences of the United
States of America, 89, 59515955.
Belliveau, J. W., Kennedy, D. N., McKinstry, R. C., et al. (1991). Functional mapping of the
human visual cortex by magnetic resonance imaging. Science, 254(5032), 716719.
Oppelt, A., Graumann, R., Barfuss, H., et al. (1986b). FISP A new fast MRI sequence.
Electromedica, 54, 1518.
Bandettini, P. A. (2011). Sewer pipe, wire, epoxy, and finger tapping: The start of fMRI at
the Medical College of Wisconsin. NeuroImage, 62, 620631.
Bandettini, P. A., Wong, E. C., Hinks, R. S., Tokofksy, R. S., & Hyde, J. S. (1992). Time
course EPI of human brain function during task activation. Magnetic Resonance in
Medicine, 25, 390397.
Turner, R., Jezzard, P., Wen, H., et al. (1993). Functional mapping of the human visualcortex at 4 and 1.5 Tesla using deoxygenation contrast EPI. Magnetic Resonance in
Medicine, 29, 277279.
Blamire, A. M., Ogawa, S., Ugurbil, K., et al. (1992). Dynamic mapping of the human
visual-cortex by high-speed magnetic-resonance-imaging. Proceedings of the
National Academy of Sciences of the United States of America, 89, 1106911073.
Olman, C. A., Inate, S., & Heeger, D. J. (2007). The effect of large veins on spatial localization
with GE BOLD at 3 T: Displacement, not blurring. NeuroImage, 34, 11261135.
Yacoub, E., Van de Moortele, P.-F., Shmuel, A., & Ugurbil, K. (2005). Signal and noise
characteristics of Hahn SE and GE BOLD fMRI at 7 T in humans. NeuroImage, 24,
738750.
Budde, J., Shajan, G., Zaitsev, M., Scheffler, K., & Pohmann, R. (2014). Functional MRI
in human subjects with gradient-echo and spin-echo EPI at 9.4 T. Magnetic
Resonance in Medicine, 71, 209218.
Arterial Spin Labeling
Detre, J. A., Leigh, J. S., Williams, D. S., & Koretsky, A. P. (1992). Perfusion imaging.
Magnetic Resonance in Medicine, 23, 3745.
Edelman, R. R., Siewert, B., Darby, D. G., et al. (1994). Qualitative mapping of
cerebral blood-flow and functional localization with echo-planar MR-imaging
and signal targeting with alternating radio-frequency. Radiology, 192,
513520.
Edelman, R. R., & Chen, Q. (1998). EPISTAR MRI: Multi-slice mapping of cerebral
blood flow. Magnetic Resonance in Medicine, 40, 800805.
Wong, E. C., Buxton, R. B., & Frank, L. R. (1997). Implementation of quantitative
perfusion imaging techniques for functional brain mapping using pulsed arterial
spin labeling. NMR in Biomedicine, 10, 237249.
Wong, E. C., Buxton, R. B., & Frank, L. R. (1998). Quantitative imaging of perfusion
using a single subtraction (QUIPSS and QUIPSS II). Magnetic Resonance in
Medicine, 39, 702708.
74
MR Diffusion Imaging
Stejskal, E. O., & Tanner, J. E. (1965). Spin diffusion measurements: Spin echoes in the
presence of time-dependent field gradient. The Journal of Chemical Physics, 42,
288292.
Le Bihan, D., Breton, E., Lallemand, D., et al. (1986). MR imaging of intravoxel
incoherent motions: Application to diffusion and perfusion in neurologic disorders.
Radiology, 161(2), 401407.
Moseley, M. E., Cohen, Y., Kucharczyk, J., et al. (1990). Diffusion-weighted MR imaging of
anisotropic water diffusion in cat central nervous system. Radiology, 176(2), 439445.
Warach, S., Chien, D., Li, W., Ronthal, M., & Edelman, R. R. (1992). Fast magnetic
resonance diffusion weighted imaging of acute human stroke. Neurology, 42,
17171723.
Tournier, J. D., Mori, S., & Leemans, A. (2013). Diffusion tensor imaging and beyond.
Magnetic Resonance in Medicine, 65(6), 15321556.
Tuch, D. S., Weisskoff, R. M., Belliveau, J. W., & Wedeen V. J. (1999). High angular
resolution diffusion imaging of the human brain, Proceedings of the seventh annual
meeting of the ISMRM, Philadelphia, p. 321.
Kimmlingen, R., Eberlein, E., Dietz, P., Kreher, S., et al. (2012). Concept and realization
of high strength gradients for the human connectome project, Proceedings of the
ISMRM 20th annual meeting in Melbourne, Australia, pp. 0696.
Wedeen, V. J., Wald, L. L., Cohen-Adad, J., et al. (2012). In vivo imaging of fiber pathways
of the human brain with ultra-high gradients. Proceedings of the twentieth annual
meeting of the Society of Magnetic Resonance in medicine, Melbourne, p. 6490.
EPI Limitations
Luedeke, K. M., Roeschmann, P., & Tischler, R. (1985). Susceptibility artefacts in NMR
imaging. Magnetic Resonance Imaging, 3, 329343.
Haacke, E. M., Brown, R. W., Thompson, M. R., & Venkatesan, R. (1999). Permeability
and susceptibility. Magnetic Resonance imaging Physical Principles and
Sequence Design (Chapter 25.2). New York: Wiley, ISBN 0-471-35128-8.
Jezzard, P., & Balaban, R. R. (1995). Correction for geometric distortion in echo-planar
images for B0 field variations. Magnetic Resonance in Medicine, 34, 6573.
Visser, E., Poser, B. A., Bart, M., & Zwiers, M. P. (2012). Reference-free unwarping of
EPI data using dynamic off resonance correction with multi acquisition (DOCMA).
Magnetic Resonance in Medicine, 68, 12471254.
van Gelderen, P., de Zwart, J. A., Stareweicz, P., et al. (2007). Real-time shimming to
compensate for respiratory induced Bo fluctuations. Magnetic Resonance in
Medicine, 57, 363368.
Zaitsev, M., Hennig, J., & Speck, O. (2004). Point spread function mapping with parallel
imaging techniques and high acceleration factors: Fast, robust, and flexible method
for echo-planar imaging distortion correction. Magnetic Resonance in Medicine, 52,
11561166.
Cohen, M. S., Weisskoff, R. M., & Kantor, M. L. (1989). Evidence of peripheral nerve
stimulation by time varying magnetic fields, Proceedings of the Radiological Society
of Northern America (RSNA), 75th annual meeting, p. 1188.
Fischer, H., Hentschel, D., Schmitt, F., et al. (1989). Physiological effects by fats
oscillating magnet field gradients, Proceedings of the Radiological Society of
Northern America (RSNA), 75th annual meeting, p. 1189.
Budinger, T. F., Fischer, H., Hentschel, D., et al. (1991). Physiological effects of fast
oscillating magnetic flux gradients. Journal of Computer Assisted Tomography, 15,
909914.
Schmitt, F., Irnich, W., & Fischer, H. (1998). Physiological side effects of fast gradient
switching. In F. Schmitt, M. K. Stehling & R. Turner (Eds.), Echo-planar imaging
Theory, technique and applications Magnetic resonance imaging in a fraction of a
second. Berlin: Springer, ISBN 3-540-63194-1, Chapter 7.
Irnich, W. (1993). Magnetostimulation in MRI, Proceedings of the seventh annual
meeting of the Society of Magnetic Resonance in medicine, New York, p. 1371.
fMRI Quality Assurance
Weisskoff, R. M. (1996). Simple measurement of scanner stability for functional NMR
imaging of activation in the brain. Magnetic Resonance in Medicine, 36, 643645.
Triantafyllou, C., Hoge, R. D., Krueger, G., et al. (2005). Comparison of physiological
noise at 1.5 T, 3 T and 7 T and optimization of fMRI acquisition parameters.
NeuroImage, 26, 234250.
Triantafyllou, C., Polimeni, J. R., & Wald, L. L. (2011). Physiological noise and signalto-noise ratio in fMRI with multi-channel array coils. NeuroImage, 55(2), 597606.
Accelerated MR Imaging
Margosian, P., Schmitt, F., & Purdy, F. (1986). Faster MR imaging: Imaging with half
the data. Health Care Instruments, 1, 195197.
Haacke, E. M., Lindskop, E.-D., & Lin, W. (1991). Partial-Fourier imaging. A fast,
iterative, POCS technique capable of local phase recovery. Journal of Magnetic
Resonance, 2, 126145.
Pruessmann, K. P., Weiger, M., Scheidegger, M. B., & Boesiger, P. (1999). SENSE:
Sensitivity encoding for fast MRI. Magnetic Resonance in Medicine, 42, 952962.
Further Reading
Perfusion Imaging: Contrast Enhanced Susceptibility Weighted Perfusion
Imaging
Rosen, B. R., Belliveau, J. W., Vevea, J. M., & Brady, T. J. (1990). Perfusion contrast
with NMR contrast agents. Magnetic Resonance in Medicine, 14, 249265.
Arterial Spin Labeling
Detre, J. A., Alsop, D. C., Samuels, O. B., Gonzalez-Atavales, J., & Raps, E. C. (1998).
Cerebrovascular reserve testing using perfusion MRI with arterial spin labeling in
normal subjects and patients with cerebrovascular disease, Proceedings of the
ISMRM sixth annual meeting, p. 243.
MR Diffusion Imaging
Wedeen, V. J., Hagmann, P., Tseng, W. Y., et al. (2005). Mapping complex tissue
architecture with diffusion spectrum magnetic resonance imaging. Magnetic
Resonance in Medicine, 54, 13771386.
Basser, P. J., & Jones, D. K. (2002). Diffusion-tensor MRI: Theory, experimental design
and data analysis A technical review. NMR in Biomedicine, 15, 456467.
Tuch, D. S., Reese, T. G., Wiegell, M. R., et al. (2002). High angular resolution diffusion
imaging reveals intravoxel white matter fiber heterogeneity. Magnetic Resonance in
Medicine, 48, 577582.
EPI Limitations
Schmitt, F., Wielopolski, P., Fischer, H., & Edelman, R. R. (1994). Peripheral
stimulation and their relation to gradient pulse, Proceedings of the seventh annual
meeting of the society of magnetic resonance in medicine, Philadelphia, p. 102.
Reilly, J. P. (1989). Peripheral nerve stimulation by induced electric currents: Exposure
to time varying magnetic fields. Medical & Biological Engineering & Computing,
27, 101110.
Relevant Websites
http://www.loni.usc.edu/ Laboratory of Neuro Imaging.
http://www.nmr.mgh.harvard.edu/martinos/flashHome.php Martinos Center for
Biomedical Imaging at Massachusetts General Hospital, Human Connectome
Project funded by National Institute of Health.
http://www.humanconnectomeproject.org/.
http://www.neuroscienceblueprint.nih.gov/connectome/ NIH Blueprint: The Human
Connectome Project.
http://www.humanconnectome.org/.
Glossary
Introduction
The cellular phenomena that give rise to cerebral electrical activity recorded in the EEG were clarified by a series of microelectrode studies that began with animal studies (Li & Jasper, 1953)
and culminated in a series of micro/macro recordings obtained
from epilepsy patients (Morrell, 1961). Results of these investigations have led to the present understanding that the surface
EEG represents a dynamic spatiotemporal summation of extracellular current flow associated with excitatory and inhibitory
postsynaptic potentials (EPSPs and IPSPs) that occur along the
soma, axon, or dendritic tree of pyramidal neurons. Pyramidal
neurons have cell bodies within layer five of the neocortex with
connections within and beyond the neocortex. As such, EEG is
produced by a population of cells within one cellular layer, but
it depicts a reliable measure of widespread brain activity. EEG
generation depends on populations of EPSPs located along an
apical dendrite producing positive current flow into the cell (a
current sink) with and a corresponding extracellular field that is
negatively charged. Passive current flowing out of the soma (a
current source) maintains electrical neutrality of the system.
Together, an extracellular electrical field is produced with a
dipole in a radial orientation and the negative pole directed
toward the cortical surface. These extracellular dipoles are
more sustained and more spatially synchronized than action
potentials mediated by fast sodium channels because of the
PSP durations, and the summation produces an electrical signal
that can be detected at the distance of the scalp. At the cortical
surface, the polarity of this dipole will depend on whether the
excitatory input to the cortex (i.e., the population of EPSPs) is
located in the superficial or deeper layers of the cortex. Furthermore, both simulation models (Cooper, Winter, Crow, et al.,
1965) and simultaneous intracranial and scalp recordings (Tao,
Ray, Hawes-Ebersole, & Ebersole, 2005) have demonstrated that
approximately 6 cm2 of the synchronously active cortex is necessary to generate an epileptiform discharge recorded from scalp
electrodes, and epileptiform discharges are more often associated with even larger areas of up to 20 cm2. For both endogenous rhythms (reviewed by Hughes and Crunelli, 2005) and
epileptiform discharges (Jasper & Droogleever-Fortuyn, 1947),
http://dx.doi.org/10.1016/B978-0-12-397025-1.00007-5
75
76
NASION
Fp1
Fp2
F7
F8
F3
F4
FS
ylv1
FZ
A1
C3
T3
CZ
P3
land
F Ro
PZ
A2
C4
T4
P4
T5
T6
O2
O1
INION
Figure 1 International system of electrode placement. Reproduced from Klem, G.H., Luders, H.O., Jasper, H.H., et al. (1999). The ten-twenty electrode
system of the International Federation of Clinical Neurophysiology. Electroencephalography and Clinical Neurophysiology: Supplement 52, 36.
Fp1
Fp2
15
19
F7
20
14
13
A1
Fz
F3
T3
F4
F8
16
12
C3
10
11
Cz
C4
77
A2
T4
Intracranial EEG
21
7
T5
17
P3
Pz
P4
T6
18
22
8
O1
O2
Figure 3
Over a half century ago, long before the development of modern neuroimaging methods, depth electrode recordings were
used to locate the source of seizures in patients undergoing
evaluation for surgical treatment of medication-resistant epilepsy. When combined with advanced imaging techniques,
surface EEG now often provides adequate electrophysiological
data to guide surgical therapy, and the use of intracranial EEG
has shifted to increasingly more complicated forms of epilepsy.
Yet, the use of intracranial EEG continues to be an important
Referential montage. Reproduced from Stern, J.M. (2013). Atlas of EEG patterns (2nd ed.). Philadelphia, PA: Lippincott Williams and Wilkins.
78
79
Figure 7 Clustering, quantification, and source localization. The resulting depiction of the dipole region was produced using 2281 epileptiform
discharges from a prolonged EEG recording. Twelve distinct spike clusters with differing morphology, temporal course, and scalp field were estimated.
However, the dipole map shows that all of the clusters are located in the mesiobasal temporal lobes with 72% predominance of the left side.
80
References
Adrian, E. D., & Matthews, B. H. C. (1934). The interpretations of potential waves in the
cortex. Journal of Physiology, 81, 440471.
Alarcon, G., Guy, C. N., Binnie, C. D., et al. (1994). Intracerebral propagation of
interictal activity in partial epilepsy: Implications for source localisation. Journal of
Neurology, Neurosurgery, and Psychiatry, 57, 435449.
Berger, H. (1929). Uber das Elektrenkephalogramm des Menschen. Archiv fur
Psychiatrie und Nervenkrankheiten, 87, 527570.
Cooper, R., Winter, A. L., Crow, H. J., et al. (1965). Comparison of subcortical, cortical
and scalp activity using chronically indwelling electrodes in man.
Electroencephalography and Clinical Neurophysiology, 18, 217228.
Coutin-Churchman, P., Wu, J. Y., Chen, L., et al. (2012). Quantification and localization
of EEG interictal spike activity in patients with surgically removed epileptogenic foci.
Clinical Neurophysiology, 123, 471485.
Dworetzky, B. A., & Reinsberger, C. (2011). The role of the interictal EEG in selecting
candidates for resective epilepsy surgery. Epilepsy and Behavior, 20, 167171.
Ebersole, J. S., & Hawes-Ebersole, S. (2007). Clinical application of dipole models in
the localization of epileptiform activity. Journal of Clinical Neurophysiology, 24,
120129.
Holmes, M. D., Kutsya, R. L., Ojemann, G. A., Wilenskya, A. J., & Ojemann, L. M.
(2000). Interictal, unifocal spikes in refractory extratemporal epilepsy predict ictal
origin and postsurgical outcome. Clinical Neurophysiology, 111, 18021808.
Hughes, S. W., & Crunelli, V. (2005). Thalamic mechanisms of EEG alpha rhythms and
their pathological implications. The Neuroscientist, 11, 357372.
Introduction
In a typical functional neuroimaging experiment, the goal is to
map patterns of neuronal activation while the subject is engaged
in a specific task or is experiencing a sensory stimulus. The fMRI
signal is usually analyzed with the general linear model (GLM)
regressing each voxels time course with the so-called design
matrix (i.e., the experimental design convolved with a hemodynamic response function, HRF; Worsley & Friston, 1995). It is
well known that the hemodynamic response varies between subjects, brain areas, and even neighboring voxels (Handwerker,
Gonzalez-Castillo, DEsposito, & Bandettini, 2012) depending
on basic physiological variables, such as baseline blood oxygenation and volume. To statistically capture various hemodynamic
response shapes, typically two or more basis functions are utilized
(Woolrich, Behrens, & Smith, 2004). For example, an HRF and its
derivative can map hemodynamic responses with different onset
times. The result of this analysis assigns a statistical value to each
voxel indicating activations for positive and deactivations for
negative values. Most fMRI studies do not further examine the
fMRI time course. However, fMRI transients might contain more
valuable information on brain processing (and on nonneuronal
signal sources, such as movement and respiration) than only a
rough indication of the location of the brain area involved in the
task (Buxton, Uludag, Dubowitz, & Liu, 2004).
To appreciate this fact, let us examine the physiological
underpinnings of the fMRI signal: it is directly determined by
the changes in cerebral blood volume (CBV) and blood oxygenation Y, and the latter is determined by cerebral blood flow
(CBF), cerebral metabolic rate of oxygen (CMRO2), and CBV
containing deoxygenated blood (i.e., capillaries and veins;
Uludag et al., 2009). (Note that the fMRI signal, as measured
with standard gradient-echo (GE) or spin-echo (SE) imaging, is
affected not only by the blood oxygenation level-dependent
(BOLD) effect but also directly by the blood volume (Uludag,
Muller-Bierl, & Ugurbil, 2009). Nevertheless, the terms fMRI
and BOLD signals are often used synonymously. Hematocrit
also has a strong influence on the relaxation rate and, hence,
amplitude of the fMRI signal (Silvennoinen, Clingman, Golay,
Kauppinen, & van Zijlv, 2003). However, the change in hematocrit during activation is low. Thus, it is an important variable
for intersubject comparison of the fMRI signal amplitude but
not for assessing the dynamics of the fMRI signal and the
activation patterns within a subject. In Figure 1, the chain of
biophysical events leading to the fMRI signal is illustrated.
Generative models, such as dynamic causal modeling
(Friston, Harrison, & Penny, 2003), might help in disentangling neuronal from vascular effects.
An increase in CMRO2 leads to a decrease in blood oxygenation (hypo-oxygenation) and, hence, in the fMRI signal. In
contrast, an increase in CBF brings oxygenated blood to the
local tissue volume and displaces deoxygenated blood and
therefore leads to hyperoxygenation resulting in an increase
Initial Dip
The initial dip, if detected, only lasts less than 2 s (see Figure 2
for illustration) and is usually not detected or reported
(Buxton, 2001; Ugurbil et al., 2003). Its properties, detectability and even that it is of physiological origin and not a measurement or analysis artifact, have been controversially
discussed in both fMRI and optical imaging. The interest in
the initial dip has been sparked by the expectation that it has a
higher effective spatial resolution than the main positive
hemodynamic response, as the changes in blood oxygenation
Y and CBV during the peak response might not be just localized to the neuronally active tissue volume. This effect has been
poetically phrased as watering the entire garden for the sake of
one thirsty flower (Malonek & Grinvald, 1996).
http://dx.doi.org/10.1016/B978-0-12-397025-1.00008-7
81
82
fMRI signal
Capillary
Blood
flow
Neuronal
response
Energy
75%
Blood
volume
Energy
6%
Synapse
Brain
V
Energy
7%
Neurons
Arriving
spikes
Energy
10%
Deoxy-Hb
content
Astrocyte
CMRO2
Figure 1 The chain of physiological and physical events leading to the fMRI signal. Neuronal activity is associated with the cerebral metabolic rate of
oxygen (CMRO2) and induces changes in cerebral blood flow (CBF). The increase in CBF evokes increases in cerebral blood volume (CBV) and changes
the amount of deoxygenated blood. The blood oxygenation and CBV in a localized brain area are detected by the fMRI signal. Courtesy of Martin Havlicek.
2.0
1.5
1000 ms
250 ms
50 ms
5 ms
1.0
0.5
0.0
0.5
15
10
Time (s)
20
25
30
Poststimulus Undershoot
A more common observation is a dip of the fMRI signal below
baseline after the end of the stimulus, referred to as a poststimulus undershoot (one of the most debated issues in fMRI;
Van Zijl, Hua, & Lu, 2012), which can take a long time to resolve
(>30 s; Sadaghiani, Ugurbil, & Uludag, 2009). In block design
experiments, in which the rest period is not sufficiently long
to allow the undershoot to resolve, the effect appears as an
apparent lowering of the baseline after the first stimulus block.
Therefore, it is recommended that the rest periods should be
approximately twice as long as the stimulus duration to fully
allow recovering of the fMRI signal back to baseline.
Zhao et al. found that the poststimulus undershoot with
laminar resolved GE MRI sequence is localized to the tissue in
contrast to the main positive fMRI response (Zhao, Jin, Wang,
& Kim, 2007). In agreement with this study, Sirotin and colleagues had demonstrated with optical imaging that the spatial
83
84
Flicker
40
Static
2
30
CBF (%)
20
10
0
0
1
10
0
60
120
Time (s)
180
240
60
120
180
Time (s)
240
300
Figure 3 Stimulus dependence of the poststimulus undershoot (Sadaghiani et al., 2009). Static and contrast-reduced flickering checkerboard stimuli
evoke almost the same positive fMRI response in the same voxels (left of the figure). After an initial overshoot, a steady-state value is achieved.
However, the poststimulus undershoot in the fMRI signal is abolished for the static stimulus. In contrast, the CBF for the static stimulus recovers slowly
to baseline, whereas the CBF for the flickering stimulus shows a small deactivation. That is, although the fMRI signal for static stimulus is back to
baseline, the CBF is indicating continuous activation.
BOLD response
Neuronal transients
Neuronal response
0 10 20 30 40 50 60 70
Time (s)
0 10 20 30 40 50 60 70
Time (s)
0 10 20 30 40 50 60 70
Time (s)
BOLD response
0 10 20 30 40 50 60 70
Time (s)
0
0 10 20 30 40 50 60 70
Time (s)
Figure 4 Exemplary theoretical time courses for neuronal and vascular changes. Neuronal signal can exhibit initial overshoot and poststimulus
deactivation. CBF is a smoothed and delayed version of the neuronal response. CBV can be coupled (upper row) or uncoupled (lower row) from CBF.
In the coupled version, the initial overshoot of the neuronal response is almost completely abolished but the neuronal poststimulus deactivation is
reflected. In the uncoupled version, the BOLD response exhibits also an initial overshoot, which however stems from the CBFCBV uncoupling.
The poststimulus undershoot in the BOLD signal is enhanced as compared to the neuronal deactivation. Courtesy of Martin Havlicek.
85
86
See also: INTRODUCTION TO ACQUISITION METHODS: EchoPlanar Imaging; fMRI at High Magnetic Field: Spatial Resolution Limits
and Applications; High-Field Acquisition; High-Speed, HighResolution Acquisitions; Obtaining Quantitative Information from fMRI;
Perfusion Imaging with Arterial Spin Labeling MRI; Pulse Sequence
Dependence of the fMRI Signal; Temporal Resolution and Spatial
Resolution of fMRI; INTRODUCTION TO METHODS AND
MODELING: Convolution Models for FMRI; Dynamic Causal Models
for fMRI; Models of fMRI Signal Changes; The General Linear Model.
References
Bandettini, P. A., Kwong, K. K., Davis, T. L., Tootell, R. B., Wong, E. C., Fox, P. T., et al.
(1997). Characterization of cerebral blood oxygenation and flow changes during
prolonged brain activation. Human Brain Mapping, 5, 93109.
Buxton, R. B. (2001). The elusive initial dip. NeuroImage, 13, 953958.
Buxton, R. B., Uludag, K., Dubowitz, D. J., & Liu, T. T. (2004). Modeling the
hemodynamic response to brain activation. NeuroImage, 23(Suppl. 1), S220S233.
Buxton, R. B., Wong, E. C., & Frank, L. R. (1998). Dynamics of blood flow and
oxygenation changes during brain activation: The balloon model. Magnetic
Resonance in Medicine, 39, 855864.
Chen, J. J., & Pike, G. B. (2009). Origins of the BOLD post-stimulus undershoot.
NeuroImage, 46, 559568.
Cohen, E. R., Ugurbil, K., & Kim, S. G. (2002). Effect of basal conditions on the
magnitude and dynamics of the blood oxygenation level-dependent fMRI response.
Journal of Cerebral Blood Flow and Metabolism, 22, 10421053.
Devor, A., Dunn, A. K., Andermann, M. L., Ulbert, I., Boas, D. A., & Dale, A. M. (2003).
Coupling of total hemoglobin concentration, oxygenation, and neural activity in rat
somatosensory cortex. Neuron, 39, 353359.
Devor, A., Tian, P., Nishimura, N., Teng, I. C., Hillman, E. M., Narayanan, S. N., et al.
(2007). Suppressed neuronal activity and concurrent arteriolar vasoconstriction
may explain negative blood oxygenation level-dependent signal. Journal of
Neuroscience, 27, 44524459.
Duong, T. Q., Kim, D. S., Ugurbil, K., & Kim, S. G. (2000). Spatiotemporal dynamics of
the BOLD fMRI signals: Toward mapping submillimeter cortical columns using the
early negative response. Magnetic Resonance in Medicine, 44, 231242.
Frahm, J., Kruger, G., Merboldt, K. D., & Kleinschmidt, A. (1996). Dynamic uncoupling
and recoupling of perfusion and oxidative metabolism during focal brain activation
in man. Magnetic Resonance in Medicine, 35, 143148.
Friston, K. J., Harrison, L., & Penny, W. (2003). Dynamic causal modelling.
NeuroImage, 19, 12731302.
Gonzalez-Castillo, J., Saad, Z. S., Handwerker, D. A., Inati, S. J., Brenowitz, N., &
Bandettini, P. A. (2012). Whole-brain, time-locked activation with simple tasks
revealed using massive averaging and model-free analysis. Proceedings of the
National Academy of Sciences of the United States of America, 109, 54875492.
Handwerker, D. A., Gonzalez-Castillo, J., DEsposito, M., & Bandettini, P. A. (2012). The
continuing challenge of understanding and modeling hemodynamic variation in
fMRI. NeuroImage, 62, 10171023.
Harms, M. P., & Melcher, J. R. (2002). Sound repetition rate in the human auditory
pathway: Representations in the waveshape and amplitude of fMRI activation.
Journal of Neurophysiology, 88, 14331450.
Harms, M. P., & Melcher, J. R. (2003). Detection and quantification of a wide range of
fMRI temporal responses using a physiologically-motivated basis set. Human Brain
Mapping, 20, 168183.
Hoge, R. D., Atkinson, J., Gill, B., Crelier, G. R., Marrett, S., & Pike, G. B. (1999).
Stimulus-dependent BOLD and perfusion dynamics in human V1. NeuroImage, 9,
573585.
Horiguchi, H., Nakadomari, S., Misaki, M., & Wandell, B. A. (2009). Two temporal
channels in human V1 identified using fMRI. NeuroImage, 47, 273280.
Kim, D. S., Duong, T. Q., & Kim, S. G. (2000). High-resolution mapping of isoorientation columns by fMRI. Nature Neuroscience, 3, 164169.
Kim, T., & Kim, S. G. (2011a). Quantitative MRI of cerebral arterial blood volume. Open
Neuroimaging Journal, 5, 136145.
Kim, T., & Kim, S. G. (2011b). Temporal dynamics and spatial specificity of arterial and
venous blood volume changes during visual stimulation: Implication for BOLD
quantification. Journal of Cerebral Blood Flow and Metabolism, 31, 12111222.
Logothetis, N. (2000). Can current fMRI techniques reveal the micro-architecture of
cortex? Nature Neuroscience, 3, 413414.
Logothetis, N. K., Pauls, J., Augath, M., Trinath, T., & Oeltermann, A. (2001).
Neurophysiological investigation of the basis of the fMRI signal. Nature, 412, 150157.
87
Uludag, K. (2010). To dip or not to dip: Reconciling optical imaging and fMRI data.
Proceedings of the National Academy of Sciences of the United States of America,
107, E23, Author reply E24.
Uludag, K., Dubowitz, D. J., Yoder, E. J., Restom, K., Liu, T. T., & Buxton, R. B. (2004).
Coupling of cerebral blood flow and oxygen consumption during physiological
activation and deactivation measured with fMRI. NeuroImage, 23, 148155.
Uludag, K., Muller-Bierl, B., & Ugurbil, K. (2009). An integrative model for neuronal
activity-induced signal changes for gradient and spin echo functional imaging.
NeuroImage, 48, 150165.
Van Zijl, P. C., Hua, J., & Lu, H. (2012). The BOLD post-stimulus undershoot, one of
the most debated issues in fMRI. NeuroImage, 62, 10921102.
Vanzetta, I. (2006). Hemodynamic responses in cortex investigated with optical imaging
methods. Implications for functional brain mapping. Journal of Physiology Paris,
100, 201211.
Vazquez, A. L., Masamoto, K., Fukuda, M., & Kim, S. G. (2010). Cerebral oxygen delivery
and consumption during evoked neural activity. Frontiers in Neuroenergetics, 2, 11.
Watanabe, M., Bartels, A., Macke, J. H., Murayama, Y., & Logothetis, N. K. (2013).
Temporal jitter of the BOLD signal reveals a reliable initial dip and improved spatial
resolution. Current Biology, 23, 21462150.
Woolrich, M. W., Behrens, T. E., & Smith, S. M. (2004). Constrained linear basis sets
for HRF modelling using Variational Bayes. NeuroImage, 21, 17481761.
Worsley, K. J., & Friston, K. J. (1995). Analysis of fMRI time-series revisitedagain.
NeuroImage, 2, 173181.
Yacoub, E., Ugurbil, K., & Harel, N. (2006). The spatial dependence of the poststimulus
undershoot as revealed by high-resolution BOLD- and CBV-weighted fMRI. Journal
of Cerebral Blood Flow and Metabolism, 26, 634644.
Yesilyurt, B., Ugurbil, K., & Uludag, K. (2008). Dynamics and nonlinearities of the
BOLD response at very short stimulus durations. Magnetic Resonance Imaging, 26,
853862.
Yu, X., Dodd, S. J., Silva, A. C., & Koretsky, A. P. (2014). Mapping the Distinct SingleVessel Vascular Contribution to BOLD and CBV fMRI. Conference Proceedings of
the Annual Meeting of the International Society of magnetic resonance in medicine.
Zhao, F., Jin, T., Wang, P., & Kim, S. G. (2007). Improved spatial localization of poststimulus BOLD undershoot relative to positive BOLD. NeuroImage, 34, 10841092.
Glossary
Introduction
Since the advent of functional MRI (fMRI) in the early 1990s
(Bandettini, Wong, Hinks, Tikofsky, & Hyde, 1992; Kwong,
Belliveau, Chesler, et al., 1992; Ogawa, Lee, Kay, & Tank,
1990), major developments in MRI instrumentation have taken
place that have provided particular benefits for human fMRI and
accelerated its acceptance in the research community. Most notably, improvements in system stability and signal detection hardware, together with increases in gradient switching speed and
magnetic field strength, have significantly increased fMRI spatial
resolution and contrast-to-noise ratio (CNR).
Among the most striking examples of hardware developments that have benefitted fMRI is the gradual transition to
high-magnetic field strength systems. While most human fMRI
was initially performed at systems ranging from 1.5 to 4.0,
7.0 T research systems now have become commonplace in
fMRI research laboratories, and even higher field strengths
(9.4, 10.5, and 11.7 T) are being explored at pioneer sites. At
the same time, gradient switching speeds of clinical MRI systems have improved by more than an order of magnitude,
enabling sophisticated fMRI acquisition techniques, and coil
arrays have improved detection sensitivity severalfold in most
brain regions. Together with improvements in other hardware
and in acquisition and analysis approaches, these developments have led to improved spatial resolution and specificity,
an improved CNR, and a more robust fMRI experiment. In the
following, we will review some of these technological improvements and their specific impact on fMRI research.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00009-9
89
90
INTRODUCTION TO ACQUISITION METHODS | Evolution of Instrumentation for Functional Magnetic Resonance Imaging
10
Field strength (T)
15
20
Gradients
Since the early days of fMRI, it was realized that an important
factor in the performance of an fMRI system is its ability to
perform rapid image acquisition (Bandettini et al., 1992;
Kwong et al., 1992; Turner, 1992). Rapid imaging not only
facilitates capturing the temporal changes in BOLD signal that
occur in response to brain activation but also reduces the
adverse effects of physiological variability and motion on the
temporal stability of the signal. For this reason, fast imaging
sequences like echo-planar imaging (EPI; Mansfield, 1977) are
generally considered the best choice for functional imaging,
since they provide both high temporal resolution and stability.
Fast imaging however requires rapid switching of the magnetic field gradients that are used for encoding the image
information. In the early 1990s, only a handful of research
MRI systems had EPI capability, as conventional (clinical)
systems had gradient switching rates, strengths, and duty cycles
well below those required for EPI. For this reason, EPI alternatives such as FLASH (Frahm, Bruhn, Merboldt, & Hanicke,
1992), FISP (Ogawa, Tank, Menon, et al., 1992), interleaved
EPI (Butts, Riederer, Ehman, Thompson, & Jack, 1994), and
PRESTO (Van Gelderen, Duyn, Ramsey, Liu, & Moonen, 2012)
were used, albeit generally having inferior fMRI performance.
Because of this, and other developing applications in cardiac,
interventional, and neuro-MRI, there was significant interest in
developing faster gradient systems.
Figure 2 The 11.7 T 68 cm bore magnet during installation at the NIH in Bethesda, MD, USA. This is an Agilent (Magnex Scientific) magnet with
Siemens electronics. It weighs approximately 68 metric tons, is 3.5 m long with a 2 m radius, and is filled with 3 m3 of liquid helium that is kept at 2.4 K
by pumping to a pressure of 5 103 Pa.
INTRODUCTION TO ACQUISITION METHODS | Evolution of Instrumentation for Functional Magnetic Resonance Imaging
Some of the problems that needed to be overcome to
develop high-strength, rapidly switching gradients for clinical
systems were eddy currents, acoustic noise, coil heating, and
the lack of high-current high-voltage gradient amplifiers. Over
the course of the development of fMRI, many of these problems have been resolved or mitigated, resulting in vast
improvements in gradient performance (Cohen & Schmitt,
2012; Schmitt, Stehling, & Turner, 1998).
An early and major factor in the improvement of gradient
performance of clinical MRI systems was the use of active
gradient shielding (Chapman, 1999), which prevented detrimental effects of electrical eddy currents in magnet components on the image quality (Bowtell & Mansfield, 1991).
Other factors include improvements in eddy current compensation, gradient coil cooling, and technology for and cooling of
amplifiers.
As a result of these improvements, gradient performance has
evolved to a level at which gradient switching in whole-body
scanners is limited by the peripheral nerve stimulation threshold
(Reilly, 1989), which is on the order of 200 T m1 s1 (Feldman,
Hardy, Aksel, Schenck, & Chronik, 2009). Gradient strength has
increased by two orders of magnitude since human MR imaging
began, from 2.5 mT m1 in the 1980s (Ahn, Lee, Nalcioglu, &
Cho, 1986) to 300 mT m1 for a state-of-the-art gradient set
developed for the human connectome project (Mcnab, Edlow,
Witzel, et al., 2013). The head-only 11.7 T scanner at NIH is
equipped with an AC88 head-only gradient coil allowing
80 mT m1 amplitude and 200 T m1 s1 maximum slew rate.
Currently, commercially available gradient sets in whole-body
3 T scanners from all three major vendors meet or exceed
50 mT m1 at 200 T m1 s1 (http://www.healthcare.philips.
com/main/products/mri/systems; http://www3.gehealthcare.
com/en/Products/Categories/Magnetic_Resonance_Imaging;
http://usa.healthcare.siemens.com/magnetic-resonanceimaging). The availability of such high-performance gradient
systems on commercial clinical systems has lead to EPI
becoming the default imaging technique for fMRI.
91
92
INTRODUCTION TO ACQUISITION METHODS | Evolution of Instrumentation for Functional Magnetic Resonance Imaging
140
Whole brain
Brain center
Average SNR
120
100
80
60
40
Average g factor
2.0
1,3
3,1
1.8
1.6
2,3
3,2
1.4
2,2
1,2
2,1
1.2
1.0
0
10
15
20
Peripheral Hardware
Monitoring of Respiration and Cardiac Cycle
Physiological processes such as heartbeat and respiration affect
the fMRI signals in various ways, resulting in temporal signal
variation that confounds measures of brain activity. Pulsatile
arterial flow related to the heartbeat is directly reflected in the
INTRODUCTION TO ACQUISITION METHODS | Evolution of Instrumentation for Functional Magnetic Resonance Imaging
fMRI signal, as are cerebrospinal fluid flow variations related to
the cardiac (Schroth & Klose, 1992a) and respiratory cycle
(Schroth & Klose, 1992b). The cardiac and respiratory cycles
are also intricately linked with brain perfusion, and changes in
their rates (and also respiration depth) directly affect the BOLD
fMRI signal (Birn, Diamond, Smith, & Bandettini, 2006;
Shmueli, Van Gelderen, de Zwart, et al., 2007). Lastly, respiration also causes magnetic field fluctuations within the brain,
which can similarly result in fMRI signal fluctuations (Raj,
Paley, Anderson, Kennan, & Gore, 2000).
Clinical MRI systems typically come equipped with basic
hardware for monitoring the cardiac and respiratory cycles.
These external signals can be used to correct artifacts, directly
related to either the cardiac and respiratory cycle or changes in
their rate, during postprocessing even if these artifacts are
undersampled in the MRI time-series data, which is the case
in a typical fMRI experiment (Birn et al., 2006; Glover, Li, &
Ress, 2000). Such external physiological monitoring signal can
also be used to adjust magnetic field homogeneity dynamically
to compensate for the effects of respiration (Van Gelderen, de
Zwart, Starewicz, Hinks, & Duyn, 2007), the so-called dynamic
shimming. This requires modification of the scanner hardware
in order to allow dynamic, real-time changes to the scanners
reference frequency and its shim currents.
For fMRI applications, which generally employ single-shot
sequences, both of these approaches mostly serve to improve
temporal stability of the signal, which is the dominant source
of variance in most fMRI experiments, as was discussed in the
preceding text.
Shimming
Magnetic field inhomogeneities (in terms of absolute field
deviations over the object) increase at higher magnetic field
strength. They lead to T2* reduction, as well as geometric image
distortions and signal dropouts, especially in the single-shot
images used in fMRI. At low field strength, first-order (linear
over space) field adjustments through shim adjustments would
93
Real-Time fMRI
The vast increases in computational performance over the
lifetime of fMRI not only have made new MR image reconstruction techniques possible but also have led to the development of real-time fMRI, in which fMRI images are
reconstructed on the fly. Immediate availability of the fMRI
activation maps can be used for quality control or planning
successive runs, as was initially suggested (Cox, Jesmanowicz,
& Hyde, 1995). However, the detected BOLD changes can also
be used to provide feedback to the subject on a subsecond
timescale to yield a braincomputer interface. This real-time
fMRI-based neurofeedback has been used to train selfregulation of the local BOLD response in various different
brain areas and to study resulting behavioral effects, such as
modulation of reaction time, pain, linguistic, or emotional
processing (Weiskopf, 2012).
94
INTRODUCTION TO ACQUISITION METHODS | Evolution of Instrumentation for Functional Magnetic Resonance Imaging
EEG-fMRI
EEG measures the changing electric field produced by the brain
at approximately a millisecond timescale with reasonably high
sensitivity. Its main disadvantages are poor spatial resolution
and poor sensitivity for deep brain areas, which are further
removed from the electrodes. Combining EEG with fMRI can
to some extent alleviate both these issues (Rosenkranz &
Lemieux, 2010) and potentially yield additional information
about the underlying neuronal circuitry (Liu, de Zwart, Chang,
et al., 2014). However, this is not immediately straightforward,
since changes to EEG hardware and processing are required.
This is because MRI introduces two major artifacts in EEG
signal, both of which are based on an electromotive force
that is induced in the conductive loops formed by the scalp
electrodes (Goldman, Stern, Engel, & Cohen, 2000). The two
major artifact sources are the rapid switching of the field gradients in an MRI experiment (gradient artifact) and the pulsatile blood flow through the scalp (ballistocardiographic
artifact). These artifacts can be orders of magnitude lager than
the cerebral signal of interest, requiring EEG amplifiers with a
high dynamic range. To simplify removal of the gradient artifact, as well as to improve its efficacy, the internal clock of the
EEG system is generally linked to the clock of the MRI system to
assure that EEG data collection is synchronous with the timing
of the MR gradients. Finally, the presence of conductive EEG
leads in the MR bore is a potential safety issue. However,
these issues have been reasonably well addressed (Laufs,
Daunizeau, Carmichael, & Kleinschmidt, 2008), leading to it
being regularly used to study epilepsy in humans (Laufs &
Duncan, 2007).
MRIPET
PET allows for the tracking of radiolabeled isotopes in concentrations far below what would be detectable with MRI alone,
below picomolar range (Judenhofer, Wehrl, Newport, et al.,
2008). This makes PET a sensitive tool to monitor brain
function albeit with its own limitations. MRI on the other
hand can provide excellent soft tissue contrast and is noninvasive, allowing high-resolution (functional) imaging and
spectroscopy. The integration of PET and MRI has been challenging since the PET signal detection is conventionally performed with photon-multiplier tubes, which are sensitive to
magnetic fields. Furthermore, the RF coils used in MRI have to
be made PET-transparent. Significant engineering efforts over
the past few years, including the development of solid-state
PET detectors, have in large part resolved these issues
(Judenhofer et al., 2008), and a fully integrated whole-body
clinical MRI/PET system is currently available as a product
from Siemens. The first results of the application of this methodology to fMRI are currently appearing in literature (Sander,
Hooker, Catana, et al., 2013).
Future Developments
Some of the ongoing developments that have not been discussed in the preceding text but are likely to impact fMRI in the
Acknowledgments
We acknowledge the Intramural Research Program of the
National Institute of Neurological Disorders and Stroke for
support.
See also: INTRODUCTION TO ACQUISITION METHODS: EchoPlanar Imaging; fMRI at High Magnetic Field: Spatial Resolution Limits
and Applications; Positron Emission Tomography and Neuroreceptor
Mapping In Vivo.
Bibliography
Ahn, C. B., Lee, S. Y., Nalcioglu, O., & Cho, Z. H. (1986). An improved nuclear
magnetic resonance diffusion coefficient imaging method using an optimized pulse
sequence. Medical Physics, 13, 789793.
Bandettini, P. A., Wong, E. C., Hinks, R. S., Tikofsky, R. S., & Hyde, J. S. (1992). Time
course EPI of human brain function during task activation. Magnetic Resonance in
Medicine, 25, 390397.
Barmet, C., De Zanche, N., & Pruessmann, K. P. (2008). Spatiotemporal magnetic field
monitoring for MR. Magnetic Resonance in Medicine, 60, 187197.
Barry, R. L., Strother, S. C., Gatenby, J. C., & Gore, J. C. (2011). Data-driven
optimization and evaluation of 2D EPI and 3D PRESTO for BOLD fMRI at 7 Tesla: I.
Focal coverage. NeuroImage, 55, 10341043.
Birn, R. M., Diamond, J. B., Smith, M. A., & Bandettini, P. A. (2006). Separating
respiratory-variation-related fluctuations from neuronal-activity-related fluctuations
in fMRI. NeuroImage, 31, 15361548.
Bodurka, J., & Bandettini, P. A. (2002). Toward direct mapping of neuronal activity: MRI
detection of ultraweak, transient magnetic field changes. Magnetic Resonance in
Medicine, 47, 10521058.
Bowtell, R., & Mansfield, P. (1991). Gradient coil design using active magnetic
screening. Magnetic Resonance in Medicine, 17, 1519 discussion 1921.
Butts, K., Riederer, S. J., Ehman, R. L., Thompson, R. M., & Jack, C. R. (1994).
Interleaved echo planar imaging on a standard MRI system. Magnetic Resonance in
Medicine, 31, 6772.
Chapman, B. L. (1999). Shielded gradients. And the general solution to the near field
problem of electromagnet design. MAGMA, 9, 146151.
Chu, R., de Zwart, J. A., van Gelderen, P., et al. (2004). Hunting for neuronal currents:
Absence of rapid MRI signal changes during visual-evoked response. NeuroImage,
23, 10591067.
INTRODUCTION TO ACQUISITION METHODS | Evolution of Instrumentation for Functional Magnetic Resonance Imaging
Cohen, M. S., & Schmitt, F. (2012). Echo planar imaging before and after fMRI: A
personal history. NeuroImage, 62, 652659.
Constable, R. T., & Spencer, D. D. (1999). Composite image formation in z-shimmed
functional MR imaging. Magnetic Resonance in Medicine, 42, 110117.
Cox, R. W., Jesmanowicz, A., & Hyde, J. S. (1995). Real-time functional magneticresonance-imaging. Magnetic Resonance in Medicine, 33, 230236.
de Zwart, J. A., Ledden, P. J., Kellman, P., van Gelderen, P., & Duyn, J. H. (2002).
Design of a SENSE-optimized high-sensitivity MRI receive coil for brain imaging.
Magnetic Resonance in Medicine, 47, 12181227.
de Zwart, J. A., Ledden, P. J., van Gelderen, P., et al. (2004). Signal-to-noise ratio and
parallel imaging performance of a 16-channel receive-only brain coil array at 3.0
Tesla. Magnetic Resonance in Medicine, 51, 2226.
de Zwart, J. A., van Gelderen, P., Kellman, P., & Duyn, J. H. (2002). Application of
sensitivity-encoded echo-planar imaging for blood oxygen level-dependent
functional brain imaging. Magnetic Resonance in Medicine, 48, 10111020.
Derbyshire, J. A., Wright, G. A., Henkelman, R. M., & Hinks, R. S. (1998). Dynamic
scan-plane tracking using MR position monitoring. Journal of Magnetic Resonance
Imaging, 8, 924932.
Donahue, M. J., Hoogduin, H., van Zijl, P. C., et al. (2011). Blood oxygenation leveldependent (BOLD) total and extravascular signal changes and DeltaR2* in human
visual cortex at 1.5, 3.0 and 7.0 T. NMR in Biomedicine, 24, 2534.
Duyn, J. H. (2012). The future of ultra-high field MRI and fMRI for study of the human
brain. NeuroImage, 62, 12411248.
Ehman, R. L., & Felmlee, J. P. (1989). Adaptive technique for high-definition MR
imaging of moving structures. Radiology, 173, 255263.
Feldman, R. E., Hardy, C. J., Aksel, B., Schenck, J., & Chronik, B. A. (2009).
Experimental determination of human peripheral nerve stimulation thresholds in a
3-axis planar gradient system. Magnetic Resonance in Medicine, 62, 763770.
Frahm, J., Bruhn, H., Merboldt, K. D., & Hanicke, W. (1992). Dynamic MR imaging of
human brain oxygenation during rest and photic stimulation. Journal of Magnetic
Resonance Imaging, 2, 501505.
Glover, G. H., Li, T. Q., & Ress, D. (2000). Image-based method for retrospective
correction of physiological motion effects in fMRI: RETROICOR. Magnetic
Resonance in Medicine, 44, 162167.
Goldman, R. I., Stern, J. M., Engel, J., Jr., & Cohen, M. S. (2000). Acquiring
simultaneous EEG and functional MRI. Clinical Neurophysiology, 111, 19741980.
Griswold, M. A., Jakob, P. M., Heidemann, R. M., et al. (2002). Generalized
autocalibrating partially parallel acquisitions (GRAPPA). Magnetic Resonance in
Medicine, 47, 12021210.
Heijtel, D. F. R., de Zwart, J. A., Van Gelderen, P., & Duyn, J. H. (2009). The feasibility of
a generalized passive shimming construct for human brain imaging. In: 17th
scientific meeting and exhibition, April 1824, 2009. Honolulu, HI 3077.
Hennig, J., & Speck, O. (2012). High-field MR imaging. Springer.
Jenkinson, M., Bannister, P., Brady, M., & Smith, S. (2002). Improved optimization for
the robust and accurate linear registration and motion correction of brain images.
NeuroImage, 17, 825841.
Judenhofer, M. S., Wehrl, H. F., Newport, D. F., et al. (2008). Simultaneous PET-MRI:
A new approach for functional and morphological imaging. Nature Medicine, 14,
459465.
Katscher, U., & Bornert, P. (2006). Parallel RF transmission in MRI. NMR in
Biomedicine, 19, 393400.
Keil, B., & Wald, L. L. (2013). Massively parallel MRI detector arrays. Journal of
Magnetic Resonance, 229, 7589.
Koch, K. M., Brown, P. B., Rothman, D. L., & De Graaf, R. A. (2006). Sample-specific
diamagnetic and paramagnetic passive shimming. Journal of Magnetic Resonance,
182, 6674.
Kwong, K. K., Belliveau, J. W., Chesler, D. A., et al. (1992). Dynamic magnetic
resonance imaging of human brain activity during primary sensory stimulation.
Proceedings of the National Academy of Sciences of the United States of America,
89, 56755679.
Larkman, D. J., Hajnal, J. V., Herlihy, A. H., et al. (2001). Use of multicoil arrays for
separation of signal from multiple slices simultaneously excited. Journal of
Magnetic Resonance Imaging, 13, 313317.
Laufs, H., Daunizeau, J., Carmichael, D. W., & Kleinschmidt, A. (2008). Recent
advances in recording electrophysiological data simultaneously with magnetic
resonance imaging. NeuroImage, 40, 515528.
Laufs, H., & Duncan, J. S. (2007). Electroencephalography/functional MRI in human
epilepsy: What it currently can and cannot do. Current Opinion in Neurology, 20,
417423.
Lauterbur, P. C. (1973). Image formation by induced local interactions Examples
employing nuclear magnetic-resonance. Nature, 242, 190191.
Lee, C. C., Jack, C. R., Jr., Grimm, R. C., et al. (1996). Real-time adaptive motion
correction in functional MRI. Magnetic Resonance in Medicine, 36, 436444.
95
Liu, Z., de Zwart, J. A., Chang, C., et al. (2014). Neuroelectrical decomposition of
spontaneous brain activity measured with functional magnetic resonance imaging.
Cerebral Cortex, 24, 30803089.
Mansfield, P. (1977). Multi-planar image-formation using NMR spin echoes. Journal of
Physics C: Solid State Physics, 10, L55L58.
Mcnab, J. A., Edlow, B. L., Witzel, T., et al. (2013). The human connectome project and
beyond: Initial applications of 300 mT/m gradients. NeuroImage, 80, 234245.
Moeller, S., Yacoub, E., Olman, C. A., et al. (2010). Multiband multislice GE-EPI at 7
Tesla, with 16-fold acceleration using partial parallel imaging with application to
high spatial and temporal whole-brain fMRI. Magnetic Resonance in Medicine, 63,
11441153.
Ogawa, S., Lee, T. M., Kay, A. R., & Tank, D. W. (1990). Brain magnetic resonance
imaging with contrast dependent on blood oxygenation. Proceedings of the National
Academy of Sciences of the United States of America, 87, 98689872.
Ogawa, S., Tank, D. W., Menon, R., et al. (1992). Intrinsic signal changes
accompanying sensory stimulation: Functional brain mapping with magnetic
resonance imaging. Proceedings of the National Academy of Sciences of the United
States of America, 89, 59515955.
Osterbauer, R. A., Wilson, J. L., Calvert, G. A., & Jezzard, P. (2006). Physical and
physiological consequences of passive intra-oral shimming. NeuroImage, 29,
245253.
Polimeni, J. R., Fischl, B., Greve, D. N., & Wald, L. L. (2010). Laminar analysis of 7T
BOLD using an imposed spatial activation pattern in human V1. NeuroImage, 52,
13341346.
Pruessmann, K. P., Weiger, M., Scheidegger, M. B., & Boesiger, P. (1999). SENSE:
Sensitivity encoding for fast MRI. Magnetic Resonance in Medicine, 42, 952962.
Qin, L., van Gelderen, P., Derbyshire, J. A., et al. (2009). Prospective head-movement
correction for high-resolution MRI using an in-bore optical tracking system.
Magnetic Resonance in Medicine, 62, 924934.
Ra, J. B., & Rim, C. Y. (1993). Fast imaging using subencoding data sets from multiple
detectors. Magnetic Resonance in Medicine, 30, 142145.
Raj, D., Paley, D. P., Anderson, A. W., Kennan, R. P., & Gore, J. C. (2000). A model for
susceptibility artefacts from respiration in functional echo-planar magnetic
resonance imaging. Physics in Medicine and Biology, 45, 38093820.
Reilly, J. P. (1989). Peripheral nerve stimulation by induced electric currents: Exposure
to time-varying magnetic fields. Medical & Biological Engineering & Computing,
27, 101110.
Roberts, D. C., Marcelli, V., Gillen, J. S., et al. (2011). MRI magnetic field stimulates
rotational sensors of the brain. Current Biology, 21, 16351640.
Roemer, P. B., Edelstein, W. A., Hayes, C. E., Souza, S. P., & Mueller, O. M. (1990). The
NMR phased array. Magnetic Resonance in Medicine, 16, 192225.
Rosenkranz, K., & Lemieux, L. (2010). Present and future of simultaneous EEG-fMRI.
MAGMA, 23, 309316.
Sander, C. Y., Hooker, J. M., Catana, C., et al. (2013). Neurovascular coupling to D2/D3
dopamine receptor occupancy using simultaneous PET/functional MRI.
Proceedings of the National Academy of Sciences of the United States of America,
110, 1116911174.
Schmitt, F., Stehling, M. K., & Turner, R. (1998). Echo-planar imaging: Theory,
technique and application. Springer.
Schroth, G., & Klose, U. (1992a). Cerebrospinal fluid flow. I. Physiology of cardiacrelated pulsation. Neuroradiology, 35, 19.
Schroth, G., & Klose, U. (1992b). Cerebrospinal fluid flow. II. Physiology of respirationrelated pulsations. Neuroradiology, 35, 1015.
Setsompop, K., Gagoski, B. A., Polimeni, J. R., Witzel, T., Wedeen, V. J., & Wald, L. L.
(2012). Blipped-controlled aliasing in parallel imaging for simultaneous multislice
echo planar imaging with reduced g-factor penalty. Magnetic Resonance in
Medicine, 67, 12101224.
Shmueli, K., van Gelderen, P., de Zwart, J. A., et al. (2007). Low-frequency fluctuations
in the cardiac rate as a source of variance in the resting-state fMRI BOLD signal.
NeuroImage, 38, 306320.
Sodickson, D. K., & Manning, W. J. (1997). Simultaneous acquisition of spatial
harmonics (SMASH): Fast imaging with radiofrequency coil arrays. Magnetic
Resonance in Medicine, 38, 591603.
Speck, O., Stadler, J., & Zaitsev, M. (2008). High resolution single-shot EPI at 7T.
MAGMA, 21, 7386.
Triantafyllou, C., Hoge, R. D., Krueger, G., et al. (2005). Comparison of physiological
noise at 1.5 T, 3 T and 7 T and optimization of fMRI acquisition parameters.
NeuroImage, 26, 243250.
Turner, R. (1992). Magnetic resonance imaging of brain function. American Journal of
Physiological Imaging, 7, 136145.
Ugurbil, K., Hu, X. P., Chen, W., et al. (1999). Functional mapping in the human brain
using high magnetic fields. Philosophical Transactions of the Royal Society of
London. Series B, Biological Sciences, 354, 11951213.
96
INTRODUCTION TO ACQUISITION METHODS | Evolution of Instrumentation for Functional Magnetic Resonance Imaging
Uludag, K., Muller-Bierl, B., & Ugurbil, K. (2009). An integrative model for neuronal
activity-induced signal changes for gradient and spin echo functional imaging.
NeuroImage, 48, 150165.
van der Zwaag, W., Francis, S., Head, K., et al. (2009). fMRI at 1.5, 3 and 7 T:
Characterising BOLD signal changes. NeuroImage, 47, 14251434.
van Gelderen, P., de Zwart, J. A., Starewicz, P., Hinks, R. S., & Duyn, J. H. (2007). Realtime shimming to compensate for respiration-induced B0 fluctuations. Magnetic
Resonance in Medicine, 57, 362368.
van Gelderen, P., Duyn, J. H., Ramsey, N. F., Liu, G., & Moonen, C. T. (2012). The
PRESTO technique for fMRI. NeuroImage, 62, 676681.
Vedrine, P., Aubert, G., Beaudet, F., et al. (2010). Iseult/INUMAC whole body 11.7 T
MRI magnet status. IEEE Transactions on Applied Superconductivity, 20,
696701.
Webb, P., & Macovski, A. (1991). Rapid, fully automatic, arbitrary-volume in vivo
shimming. Magnetic Resonance in Medicine, 20, 113122.
Weiskopf, N. (2012). Real-time fMRI and its application to neurofeedback. NeuroImage,
62, 682692.
Wiesinger, F., Boesiger, P., & Pruessmann, K. P. (2004). Electrodynamics and
ultimate SNR in parallel MR imaging. Magnetic Resonance in Medicine, 52,
376390.
Wiesinger, F., Van De Moortele, P. F., Adriany, G., et al. (2004). Parallel imaging
performance as a function of field strength An experimental investigation using
electrodynamic scaling. Magnetic Resonance in Medicine, 52, 953964.
Wiggins, G. C., Polimeni, J. R., Potthast, A., et al. (2009). 96-Channel receive-only head
coil for 3 Tesla: Design optimization and evaluation. Magnetic Resonance in
Medicine, 62, 754762.
Wiggins, G. C., Triantafyllou, C., Potthast, A., et al. (2006). 32-channel 3 Tesla receiveonly phased-array head coil with soccer-ball element geometry. Magnetic
Resonance in Medicine, 56, 216223.
Wilson, J. L., Jenkinson, M., & Jezzard, P. (2002). Optimization of static field
homogeneity in human brain using diamagnetic passive shims. Magnetic
Resonance in Medicine, 48, 906914.
Wright, S. M., & Wald, L. L. (1997). Theory and application of array coils in MR
spectroscopy. NMR in Biomedicine, 10, 394410.
Yacoub, E., Harel, N., & Ugurbil, K. (2008). High-field fMRI unveils orientation columns
in humans. Proceedings of the National Academy of Sciences of the United States of
America, 105, 1060710612.
Zaitsev, M., Dold, C., Sakas, G., Hennig, J., & Speck, O. (2006). Magnetic resonance
imaging of freely moving objects: Prospective real-time motion correction using an
external optical motion tracking system. NeuroImage, 31, 10381050.
High-Field Acquisition
RS Menon, The University of Western Ontario, London, ON, Canada
2015 Elsevier Inc. All rights reserved.
Glossary
Historical Roots
Overview
The explosion in human and animal brain mapping applications over the past 20 years has, in large part, been driven by
advances in high-field (HF) and ultrahigh-field (UHF) MRI
scanners, with each driving advances in the other (Figure 1).
This symbiotic growth represents a confluence of many unanticipated factors. As is so often the case in science, new
technologies motivated by a particular scientific question get
co-opted when the technology proves more adept for something else. For example, the first three human 4T instruments
were obtained by institutions wishing to study cardiac metabolism using MR spectroscopy. One of these became a workhorse for the early demonstration and mechanistic studies of
blood oxygenation level-dependent (BOLD) in humans, but
the pressure on the major manufacturers to provide higherfield MRI scanners to amplify the BOLD effect came only later
as fMRI and multimodality brain mapping laboratories came
into being.
In part, such an evolution has also been driven by the fact
that tremendous challenges have to be met between the first
installation of a higher field strength magnet and its adaptation
for routine use by the clinical and neuroscience communities.
The first installed UHF instruments were the 8T installed at the
Ohio State University in 1998 and the 7T instrument installed
in 1999 at the University of Minnesota, at a time when 3T was
still not in routine use for fMRI. But the routine use of 7T for
neuroscience has been slow, despite the installation of over 60
such systems. It has been very difficult to do whole-brain echo
planar imaging (EPI) for fMRI on UHF scanners, although
recent advances in radio frequency (RF) shimming, multiplexed acquisitions and B0 shimming have reawakened the
desire for doing fMRI at 7T and above. In the mean time,
using less technically demanding sequences, unanticipated
image contrasts in novel anatomical imaging sequences have
become another driving force for the adaptation of these
higher and higher magnetic fields (Lee et al., 2010). As with
BOLD, such contrasts had been predicted (Luo et al., 2010) but
required higher field strengths to be visualized well.
In this article, the rationale for performing fMRI with BOLD
at the highest available magnetic fields is discussed from a
http://dx.doi.org/10.1016/B978-0-12-397025-1.00010-5
97
98
10T
5T
0T
1990
2000
2010
1980
Year of first human images
2020
Figure 1 Progression of magnetic fields used for human MRI since the
first human studies. Using media sources, publications, and press
releases, the dates most closely related to the first human images are
reported.
The results from Thulborn and Ogawa should have immediately argued for the use of higher field strengths for fMRI, but
there was a great deal of controversy about the field dependence of the BOLD effect. Of the three initial demonstrations
of the BOLD effect in humans, two used EPI at 1.5T (Bandettini
et al., 1992; Kwong et al., 1992) and one used conventional
fast low angle shot MRI (FLASH) at 4T (Ogawa et al., 1992).
Comparable signal-to-noise ratio (SNR) and contrast-to-noise
ratio (CNR) were seen at both field strengths on average. The
superiority of EPI for dynamic acquisition and from an SNR/
CNR perspective was clear, as was evident from earlier results
in cats (Turner et al., 1991), but the 4T signals were two to ten
times higher than those at 1.5T, compensating for the reduced
stability of FLASH acquisitions. The first direct field strength
comparison between 1.5T and 4T came from in 1993 (Turner
et al., 1993). It was noted that the 4T result was five times
higher than the 1.5T result, adjusting for different echo times
certainly supralinear. The lower resolution of the EPI techniques of the time precluded the identification of tissue and
vessels in order to separate out the contributions of these two
signal sources. Using a higher-resolution FLASH sequence at
0.5T, 1.5T, and 4T finally demonstrated a power-law dependence for tissue regions where no obvious venous vessels were
located and a linear dependence for large vessels (Gati et al.,
1997). In addition to providing validation of the theory, this
article also demonstrated that the majority of the BOLD signal
at the lower fields was coming from large venous vessels, as the
tissue BOLD signal was simply too small to observe at those
fields. This had been predicted by careful simulation studies
done at the Massachusetts General Hospital (MGH)
(Boxerman et al., 1995). Similar results have been found comparing 4T to 7T, with the added contribution of demonstrating
the improved spatial localization provided by spin-echo (SE)
techniques at the highest fields (Duong et al., 2003).
There are many compelling reasons to perform fMRI acquisitions at higher field strengths. These factors are to a certain
extent interdependent as discussed in the following text.
99
100
Sensitivity
In fMRI, the concept of sensitivity is also important. Ideally,
one wishes to be sensitive to the BOLD signal only from the
capillaries. Sensitivity to capillary BOLD changes is desirable,
because the capillaries are in the closest proximity to the active
neurons and BOLD signal changes in those capillaries presumably best reflect what the neighboring neurons are doing. As
those capillary level changes flow downstream, they pool
together in large veins with changes from other regions and
become easier to detect but further (millimeter to centimeter)
from the neuronal source of activation. Capillary sensitivity is
to be preferred over sensitivity to draining veins, yielding
greater linearity between neural activity and BOLD than the
larger vessels do. This has implications in any kind of graded
paradigm, where BOLD signal is used to explain neural activity.
However, the fractional signal change from the capillaries is
small, as is their volume fraction, and so the BOLD signal in
downstream draining venules and veins dominates, regardless
of field strength. For many of the questions asked by cognitive
neuroscientists, this difference is somewhat moot due to the
blurring that occurs in the preconditioning of the data. Nonetheless, higher resolution has a role to play even when accurate
localization of the neural activity is not warranted. Higher
image resolution dramatically improves the effective point
spread function of fMRI by reducing or eliminating partial
volume effects with the penetrating intracortical and pial
veins (Figure 2). High spatial resolution allows one to spatially
resolve and mask out the pial surface BOLD signal from further
analysis. Intelligent smoothing that avoids the CSF, white
matter, and pial surfaces can be even more beneficial.
The temporal dynamics of the fMRI response to a task also
offer some intriguing opportunities for enhancing spatial resolution as well. As was known from optical imaging for many
years, there appears to be a small transient hypooxygenation of
the blood starting 200 ms after stimulus onset, which switches
within 2 s to the more familiar hyperoxygenation response.
The initial transient (or initial dip in fMRI parlance) is
thought to occur in the capillaries that are in the immediate
vicinity of the active neurons, before the compensatory blood
flow response becomes active. Once the flow increases, a larger
and less spatially precise BOLD increase sweeps into the
Pial surface
Artery
Vein
Grey matter
2 mm
White matter
Future Considerations
Currently, 7T is the next major stepping stone in field strength
for both fMRI and anatomical imaging, representing the cutting edge with over 60 instruments sited around the world.
Bleeding edge could well be considered the less than a handful of 9.4T and higher systems installed or contemplated. As
Figure 1 demonstrates, the development of higher and higher
magnetic fields for human MRI is tapering. With the
101
Movie 1 Time course of task-related activity in a BOLD fMRI experiment from a single voxel assumed to contain the arteries, veins, capillaries, and
neurons and glia. (a) Baseline BOLD signal from a single voxel. Artery provides oxygenated blood to the brain (visually red), and arterioles deliver
this oxygenated blood to the capillaries where oxygen exchange takes place with the neurons (shown as black in their quiescent state). Venules collect
this partially deoxygenated blood and deliver it to veins, both shown as purple, as they appear optically. (b) Continuation of baseline acquisition.
Oscillations in the BOLD signal come from physiological noise sources such as cardiac and respiratory movements, neuronal oscillations (responsible
for resting state fMRI) and thermal noise. (c) Continued baseline acquisition. (d) Task stimulates neurons and glia. (e) Transient deoxygenation occurs in
the capillaries before blood flow-increasing mechanisms step in. Capillaries become more purple and consequently more paramagnetic. (f) Blood flow
increases dramatically, washing in more oxygen than is required for the metabolism. This results in the capillaries becoming hyperoxygenated (redder)
and consequently more diamagnetic. (g) Capillary blood flow, flush with more oxygenated blood flows into venules and veins. (h) Stimulus shuts
off. (i) BOLD signal decreases in a poststimulus undershoot, due to either continuing oxygen consumption in the absence of flow or vasodilation effects,
which increase the volume fraction of paramagnetic perturber. (j) Capillary blood washes into venules and veins, continuing undershoot. (k) BOLD
signal recovers to baseline as capillary and venous oxygenation and volume returns to prestimulus conditions. (l) Homeostasis.
References
Bandettini, P. A., Wong, E. C., Hinks, R. S., Tikofsky, R. S., & Hyde, J. S. (1992). Time
course EPI of human brain function during task activation. Magnetic Resonance in
Medicine, 25, 390397.
Barinaga, M. (1997). What makes brain neurons run? Science, 276, 196198.
Boxerman, J. L., et al. (1995). The intravascular contribution to fMRI signal change:
Monte Carlo modeling and diffusion-weighted studies in vivo. Magnetic Resonance
in Medicine, 34, 410.
Duong, T. Q., Yacoub, E., Adriany, G., Hu, X., Ugurbil, K., & Kim, S. G. (2003).
Microvascular BOLD contribution at 4 and 7T in the human brain: Gradient-echo
and spin-echo fMRI with suppression of blood effects. Magnetic Resonance in
Medicine, 49, 10191027.
Fujita, N. (2001). Extravascular contribution of blood oxygenation level-dependent
signal changes: A numerical analysis based on a vascular network model. Magnetic
Resonance in Medicine, 46, 723734.
Gati, J. S., Menon, R. S., Ugurbil, K., & Rutt, B. K. (1997). Experimental determination
of the BOLD field strength dependence in vessels and tissue. Magnetic Resonance
in Medicine, 38, 296302.
Klassen, L. M., & Menon, R. S. (2007). NMR simulation analysis of statistical effects on
quantifying cerebrovascular parameters. Biophysical Journal, 92, 10141021.
Kwong, K. K., et al. (1992). Dynamic magnetic resonance imaging of human brain
activity during primary sensory stimulation. Proceedings of the National Academy of
Sciences of the United States of America, 89, 56755679.
Lee, J., et al. (2010). Sensitivity of MRI resonance frequency to the orientation of brain
tissue microstructure. Proceedings of the National Academy of Sciences of the
United States of America, 107, 51305135.
Luo, J., He, X., dAvignon, D. A., Ackerman, J. J., & Yablonskiy, D. A. (2010). Proteininduced water 1H MR frequency shifts: Contributions from magnetic susceptibility
and exchange effects. Journal of Magnetic Resonance, 202, 102108.
Malonek, D., & Grinvald, A. (1996). Interactions between electrical activity and cortical
microcirculation revealed by imaging spectroscopy: Implications for functional
brain mapping. Science, 272, 551554.
Ogawa, S., & Lee, T. M. (1990). Magnetic resonance imaging of blood vessels at high
fields: In vivo and in vitro measurements and image simulation. Magnetic
Resonance in Medicine, 16, 918.
Ogawa, S., Lee, T. M., Kay, A. R., & Tank, D. W. (1990a). Brain magnetic
resonance imaging with contrast dependent on blood oxygenation.
Proceedings of the National Academy of Sciences of the United States of
America, 87, 98689872.
Ogawa, S., Lee, T. M., Nayak, A. S., & Glynn, P. (1990b). Oxygenation-sensitive
contrast in magnetic resonance image of rodent brain at high magnetic fields.
Magnetic Resonance in Medicine, 14, 6878.
102
Relevant Websites
http://www.adni-info.org ADNI protocol.
http://www.cis.rit.edu/htbooks/mri/inside.htm Spin-echo and gradient-echo
animations.
http://www.diagnosticimaging.com Varian grows ultra high-field MRI market.
http://www.nasdaq.com/aspx/call-transcript.aspx?StoryId1266171&Titleagilenttechnologies-inc-presents-at-barclays-global-healthcare-conference-mar-122013-08-30-am Agilent bows out of magnet business.
http://en.wikipedia.org/wiki/Paramagnetism Paramagnetism.
http://en.wikipedia.org/wiki/Blood Red blood cells.
http://en.wikipedia.org/wiki/Monte_Carlo_method Monte Carlo method.
Abbreviations
ADC
BOLD
CAIPI
CAIPIRINHA
CBV
CNR
CSF
EPI
EV
fCNR
FLASH
fMRI
FOV
GM
GRAPPA
GRE
HDR
Symbols
B0
D
esp
espeff
M0
PSFbio
Introduction
For the past two decades, the functional imaging community has
measured the BOLD response at essentially the same spatiotemporal resolution. This stagnant situation is driven by difficult
instrumental barriers and the feeling that the community is
already operating near the biological limits, namely, that the
spatiotemporal resolution is limited by the spatial scale at which
blood flow is controlled and the temporal resolution is limited by
the speed of the hemodynamic response. Nonetheless, whenever
someone pushed either domain, additional information about
brain substructure seemed to appear, including columnar
(Cheng, 2012; Fukuda, Moon, Wang, & Kim, 2006; Goodyear,
Nicolle, & Menon, 2002; Kim, Duong, & Kim, 2000; Kim &
Fukuda, 2008; Yacoub, Harel, & Ugurbil, 2008) and laminar
functional architecture (Goense & Logothetis, 2006; Goense,
Merkle, & Logothetis, 2012; Harel, Lin, Moeller, Ugurbil, &
Yacoub, 2006; Lu et al., 2004; Polimeni, Fischl, Greve, & Wald,
HRF
InI
iSNR
MB
MC
MPRAGE
PSF
RBC
RF
SE
SENSE
SH
SMS
SNR
SPM
TE
TR
tSNR
WM
PSFinst
R
R*
2
T1
T2
T*
2
V1
2010; Ress, Glover, Liu, & Wandell, 2007; Silva & Koretsky, 2002;
Tian et al., 2010; Yu, Qian, Chen, Dodd, & Koretsky, 2014) as well
as timing information (Chang et al., 2013; Lin et al., 2013; Silva &
Koretsky, 2002; Yu et al., 2012). These recurring empirical observations have recently been backed up by non-MR-based measures
of hemodynamics suggesting that some degree of blood flow
regulation is present at every level of the vasculature. These findings have eroded the feeling that we are firmly held back by
biological limits and fueled a push to reduce the acquisition
barriers. As a result of advances on many fronts, we have succeeded in reducing spatial and temporal resolutions from the longstanding standard of 3 3 3 mm3 voxels and TR 3 s by a
factor of 10 in either time or space and nearly as impressive factors
in each if applied together. For example, the low-resolution
standard whole-brain protocol on our 7 T scanner is now
1.5 mm isotropic (8 smaller voxel volume) at a TR of 1.2 s
(2.5 faster). Both the spatial and the temporal resolution
improvements have shown benefit beyond what a simple
http://dx.doi.org/10.1016/B978-0-12-397025-1.00011-7
103
104
[1]
The BOLD signal changes stem from small blood oxygenationinduced changes in the transverse relaxation rate (R2* 1/T2*). For
small changes in R*,
2 between the activated and deactivated states,
the fractional signal change DS/S can be shown to be equal to
TE DR2*, where DR2* is the difference in relaxation rates of the
two states. Note that TE is a fixed user-selected parameter and DR*
2
is a biological response to the stimulus that the user has little
control over. Thus, DS/S is a bad metric for assessing most acquisition protocol parameters (except for TE).
Putting the expression for DS/S into the fCNR formula
provides
fCNR TEDR2 *tSNR DR2 *=R2 *tSNR
[2]
105
Figure 1 Left: Automatically generated intermediate cortical surfaces. Right: T2* of the voxels of the middle surface at 7 T. T2* is about 3035 ms
for the frontal and parietal cortex but lower in somatosensory cortex and in problem susceptibility regions. Reproduced from Cohen-Adad, J.,
Polimeni, J. R., Helmer, K. G., Benner, T., McNab, J. A., Wald, L. L., et al. (2012). T2* mapping and B0 orientation-dependence at 7 T reveal cyto- and
myeloarchitecture organization of the human cortex. NeuroImage, 60, 10061014.
106
gG1 s1
espeff sFOV y mm [3]
2p
less than the decrease seen in iSNR when the spatial resolution is
increased. The improved BOLD contrast provided by higherspatial-resolution acquisitions can arise from multiple sources.
First, reduced partial volume averaging within the voxel with
WM and CSF increases BOLD contrast. Both WM and CSF dilute
the BOLD effect since they lack blood. The CSF also adds significant physiological noise to the time series, being the noisiest of
the three brain components (Bianciardi et al., 2009). Secondly,
improving the spatial resolution in the slice direction reduces
through-plane dephasing dropouts above susceptibility areas
such as the sinuses and ear canals. Third, smaller voxels reduce
overall time-series physiological noise, which scales with the
signal strength in the voxel (Triantafyllou et al., 2005). To impact
partial volume dilution problem, the isotropic resolution should
be high enough to resolve the folded cerebral cortex. For typical
cortex (23 mm thick), this requires an isotropic spatial resolution of 1.0 to 1.5 mm. Although well aligned with the goal of
overcoming biological PSF barriers in the BOLD effect, standard
protocols fall short of this goal.
Thus, improving spatial resolution actually mitigates some
problems, and it often surprises people that the resolution of the
fMRI experiment can be pushed beyond what is expected from
looking at the individual images. Finally, improved image resolution improves the localization of the neuronal activation by
allowing the analysis to focus on voxels distant from the pial
surface and its larger veins; thus, improved instrumental resolution can improve biological resolution (Polimeni et al., 2010).
R=2
R=3
R=4
R=5
107
Improved B0 shimming
As discussed earlier, the image distortions from susceptibility
gradients are a major barrier to high-spatial-resolution singleshot EPI. Another way to mitigate this problem is to approach
it at its source and improve brain shimming. This solution strikes
at the heart of the problem and impacts other areas where offresonance effects are problematic. Additionally, gains in shimming are synergistic to the methods outlined earlier aimed at
reducing fMRIs sensitivity to off-resonance; the best results will
be obtained when both strategies are deployed.
In the brain, these field excursions are created by susceptibility differences at tissue/air and tissue/bone interfaces around
Figure 2 Left; One millimeter resolution diffusion-weighted images showing improvement in frontal lobe susceptibility distortion as acceleration is
increased beyond R 2. 3 T 32-ch acquisition. Right: Five averages of a 7 T single-shot GRE-EPI acquired at 0.75 mm isotropic resolution with
R 3 GRAPPA and a 32-ch array.
108
1900
T1 (ms)
3800
Figure 3 Inversion-prepared 7T T1 EPI acquired at 1.1 mm isotropic resolution whole brain in <3 min. The readout parameters of the EPI were
matched to the fMRI data to ensure identical distortions. 26 prep times were used and T1 and M0 were fit to the recovery curve to generate the T1 map.
Then, a T1-weighted image was synthesized to match the graywhite/CSF intensity differences at 3 T, which FreeSurfer expects. Shown to the right
are the resulting surfaces and parcellation obtained on the all-EPI dataset. Courtesy of J. Polimeni and V. Renvall.
128-ch
R=4
R=4
R=4
SNR
64-ch
100
Figure 4 Simulation of the SNR for fourfold accelerated imaging for a 32-ch, 64-ch, and 128-ch brain array on a tight-fitting helmet. The gain over the
32-ch array is 23% and 36% higher in the center for the 64-ch and 128-ch array, respectively. This central SNR boost derives from the improved
g-factor and is not seen in unaccelerated imaging. Simulations courtesy of Boris Keil, MGH.
the sinus cavities and ear canals. The difficulty with improving
B0 shimming has been that the field perturbations are subjectdependent and localized in space (the deviation map DB0(x,y,z)
contains high spatial orders). Conventional shimming with
first-, second-, and perhaps some third-order spherical harmonics is effective at canceling the spatial patterns that resemble spherical harmonics but are unable to cancel the principle
features of DB0(x,y,z) (Spielman, Adalsteinsson, & Lim, 1998)
although some practitioners have advocated for fourth- and
some fifth-order spherical harmonics (Pan, Lo, & Hetherington, 2012). High-order spherical harmonic coils require large
inductances and are notoriously inefficient at producing fields
and difficult to switch rapidly due to the inductance and eddy
currents created. These issues have kept the traditional spherical harmonic shim coil approaches to third order or less.
Local shim methods, such as placing diamagnetic material in
the mouth and ear canals, have met with some success (Wilson,
Jenkinson, & Jezzard, 2002), but a more patient-friendly external
method that requires reasonable currents is to use a matrix of small
loop coils placed on a cylinder around the body. While it is computationally more work to compute the currents due to the nonorthogonality of the field patterns, this is no longer a barrier. It has
recently been shown that most of this higher-order inhomogeneity
can be canceled using such arrays with reasonable currents if the
shim cylinder is brought inside the gradient coil (and thus closer to
the head) (Juchem, Nixon, Diduch, et al., 2010; Juchem, Nixon,
McIntyre, Rothman, & de Graaf, 2010, Juchem et al., 2011). The
interference between shim coils and RF coils then becomes a major
limitation. Optimally, both arrays want to be immediately adjacent to the body to optimize their performance. In the impressive
demonstration at 7 T by Juchem et al., the shim coils needed to be
moved away from the body to suboptimal locations to make room
for the receive array (Juchem, Nixon, Diduch, et al., 2010; Juchem
et al., 2011). This required 100-turn coils (a large amount of copper
near the RF coils). In addition to being moved away to clear a path
for the RF coils, the shim elements were mounted on a cylinder.
It has recently been recognized that the shim loops could be
combined with the RF receive array loops, providing both
128-ch
MC
3rd SH
4th SH
5th SH
6th SH
Slice 1
Slice 2
Slice 3
2nd SH
(at acq.)
109
Figure 5 Simulated effect of higher-order shim sets on 7 T B0 maps for three representative slices. The B0 field maps are acquired in a healthy
subject after conventional second-order SH shimming. Then, higher-order simulation fields are applied to attempt to mitigate the standard susceptibility
issues. Each slice is separately optimized (dynamic shimming). Note that either high-order SH or high-order MC shimming can substantially mitigate
the B0 disturbances. Simulation courtesy of Jason Stockman, MGH.
110
In order to understand the relative contributions of the compartments and how they change with field strength, one must
model the induced field distortions around the complex vessel
architecture, as well as how the water moves randomly among
the different magnetic environments inside and outside the vessels and cells. This has been extensively pursued with Monte
Carlo modeling (Boxerman, Bandettini, et al., 1995; Boxerman,
Hamberg, Rosen, & Weisskoff, 1995; Martindale, Kennerley,
Johnston, Zheng, & Mayhew, 2008; Ogawa et al., 1993; Uludag,
Muller-Bierl, & Ugurbil, 2009). In this picture, the red blood cells
(RBC), making up 40% of the blood volume, are the source of
the paramagnetism modulated by activation and are delivered
fully oxygenated into the brains arteries. While water is seen to
effortlessly move in and out of the RBC, it is trapped either inside
or outside the vasculature for timescales longer than the experiThus, water is described as belonging to either
ment (T2 or T*).
2
an intravascular (IV) or an extravascular (EV) compartment. The
extravascular compartment contains about 20 more water than
the intravascular compartment. Given our interest in spatial
localization, it is also useful to keep track of the relative contributions from various vessel sizes; typically, a distribution of
vessel sizes and orientations are studied. Finally, the motion of
the water within these compartments is studied assuming a
diffusion constant, D, of about 1 mm2 ms1.
At low field strengths (B0 1.5 T), these models show the
gradient recalled echo (GRE) experiment is weighted toward
blood vessels with diameters above 20 mm, while the spin
echo (SE) effect peaks for vessel with 15 mm diameter and
is relatively small for vessels with diameters above 25 mm
(Boxerman, Bandettini, et al., 1995; Martindale et al., 2008).
At 1.5 T, the IV contribution accounts for about 2/3 of the
R2*-based BOLD signal (Boxerman, Bandettini, et al., 1995;
Martindale et al., 2008). In contrast, Martindale and colleagues
suggested that at 3 T, the EV compartment accounts for approximately 2/3 of the signal from small vessels (6 mm diameter)
and 3/4 of the signal from larger vessels (50 mm diameter)
(Martindale et al., 2008). For 7 T, the modeling shows that
nearly all of the GRE-BOLD signal is extravascular (Martindale
et al., 2008; Uludag et al., 2009). For SE, the intravascular
component can be significant for small vessels and like the
GRE experiment is higher at low B0 (Oja, Gillen, Kauppinen,
Kraut, & van Zijl, 1999; Uludag et al., 2009).
A recent Monte Carlo modeling study included relaxation
time information from higher-field-strength measurements and
explicitly studied the fraction of the BOLD signal originating
from the micro- and macrovasculature as a function of TE and
B0 (in addition to the EV and IV components) (Uludag et al.,
2009). In this study, macrovasculature was modeled as a worstcase vessel with 200 mm diameter orientated orthogonal to B0
comprising 5% of the voxel. The microvasculature was modeled
as randomly oriented vessels. The microvascular CBV was taken
to be 2.5% with the fractional contributions from arterioles,
capillaries, and venules of 20%, 40%, and 40%, respectively,
each with a single diameter (16, 6, and 16 mm, respectively).
The SE micro/macro ratio was found to exceed the GRE ratio
for all TEs and B0 values. Additionally, the relative SE microvascular contribution as a function of field strength peaks for
B0 7 T, and a greater microvascular fraction is achieved with
longer TE than the typical choice (TE T2). For GRE acquisitions, the micro/macro ratio can be increased by choosing a
lower field strength, a surprising finding that is likely due to
111
stimulus 1
stimulus 2
Flattened cortex
Cortical surface
5.000
0.500
0.500
5.000
Figure 6 7 T resolution test pattern acquired with 1 mm isotropic voxels analyzed as a function of depth analyzed on the folded cortex. The two
stimuli in the block design consisted of a pattern logarithmically warped to create an M pattern on V1. PSFbio appears to improve for depths more
distant from the pial surface, suggesting that avoiding pial vessels improves BOLD localization and resolution.
112
64-channel commercial headneck array, no in-plane acceleration, a TE 30 ms (for optimal BOLD contrast), and MB 12
for a TR 391 ms. Thus, the scanner was acquiring slices at a
rate of 143 slices per second! At this rate, both cardiac and
respiratory modulations are Nyquist-sampled, which prevents
their nuisance fluctuations from accidentally aliasing into the
frequency band of the BOLD signal (which is typically much
lower for a block design experiment).
113
Figure 8 Subset of slices from a 12-fold accelerated SMS run acquired at 3 T with a 64-ch headneck array. Fifty-six 2.5 mm thick slices were acquired
with TR 391 ms and TE 30 ms (143 slices per second). Courtesy of Kawin Setsompop, MGH.
Canonical HRF
0.5
10
20
30
Cardiac band
1.0
100
105
Respiration band
1010
0
2
3
Frequency (Hz)
Figure 9 Canonical hemodynamic response function (HRF) (from SPM) and its power spectrum with the respiratory, cardiac, and 23 s TR bands
marked. Note that the spectrum has very little power after 1.5 Hz, suggesting little BOLD signal will be captured by capturing BOLD frequencies above
1.5 Hz.
114
intervals at or below 100 ms (albeit with coarse spatial resolution), Lin et al. had shown that the temporal precision of the
BOLD signal is high enough to detect difference in onset time
in cortical responses to visual stimuli presented 100 ms apart
(Chang et al., 2013; Lin et al., 2013). Silva and Koretsky had
shown that onset times in rodents show laminar differences
(Silva & Koretsky, 2002). These specialized studies have clearly
benefited from the high temporal resolutions they have used.
Additionally, ultrafast sampling has proved useful in restingstate connectivity studies (Griffanti et al., 2014; Tong et al.,
2013; Ugurbil et al., 2013).
Given the successes of ultrafast functional imaging, it is worth
revisiting the logic that dismissed it. The basic idea was that the
hemodynamic changes are slow enough that they are adequately
temporally resolved with 3 s temporal resolution. When we
sample a band-limited waveform with maximum frequency present of nmax (sometimes called the Nyquist frequency), we must
sample at the Nyquist rate of twice this bandwidth (2nmax), and
the time period between samples (called the dwell time) is the
inverse of this rate; tdwell 1/(2 nmax). It is possible to oversample
the signal; that is, sample at a rate much higher than the Nyquist
rate (say, a rate 20nmax) and then low-pass filter the resultant
signal back to nmax, but sampling theory tells us that this strategy
will not improve the final SNR. The higher sampling rate lets in
more of the white noise spectrum, but then, the low-pass filtering
simply removes this noise again. So, if the largest frequencies
present in the HRF are about 0.3 Hz (the spectral power is
reduced by a factor of 1000 at this frequency), the Nyquist
sampling rate is 0.6 Hz and the dwell time is 1.7 s. In good
agreement with common perceptions, sampling theory suggests
that sampling faster than this will have little benefit.
The solution to the apparent contradiction comes from asking for a physical interpretation of tdwell and its equivalence in
our imaging experiments. In a conventional voltage signal measurement, the signal recording system connects a sample-andhold device to the signal voltage during the dwell period. During
that time, charge is integrated on the capacitor of the sampleand-hold. This has two purposes. Firstly to hold the signal so
the ADC can go through its comparisons, which is how it
measures the voltage. The second purpose is to integrate noise
fluctuations over the dwell period. This has a filtering effect; the
longer tdwell, the lower the noise variance in a repeated measurement. This aspect of the signal sampling process is critical. In
this view, no matter how you sample, there are no time gaps
where the signal is not being integrated on the capacitor of the
sample-and-hold. You can sample at the minimum rate (the
Nyquist rate) with long dwell times, or you can sample at 10
this rate with 10 shorter dwell times. In both cases, the signal
will be connected to the sample-and-hold capacitor for all the
time available and thus samples at maximum 100% efficiency, a
critical criterion implicit in sampling theory.
How about for imaging sequences? How long does a single
EPI image sample the changing signal intensity? The answer is
it samples it for the duration of the EPI readout, which is about
30 ms for conventional 3 mm EPI. It does not matter whether
the TR is 0.3, 3, or 30 s; the given pixels BOLD signal is sampled
once for an effective integration time of 30 ms in that TR period
and then proceeds, unsampled, until the next TR. The efficiency
is thus 30 ms out of 3 s for conventional studies, about 1%. This
is horribly inefficient and far from the maximally efficient sampling rate demanded by the Nyquist sampling theory. What can
we do to improve the efficiency? Sample faster!
Conclusions
The last decade has seen distinct improvements in the spatial and
temporal resolution of the fMRI acquisition. Acquisition engineering has left the field with considerable gains in sensitivity
from advanced RF array designs and higher field strengths to
considerably cleaner, faster, less distorted single-shot imaging
with improved gradients and parallel imaging acceleration. The
potential benefit of more routine use of the currently exotic
high-end acquisitions is just starting to propagate from specialized studies to more typical studies. Moreover, future needs in
image quality and spatial and temporal resolution are still considerable. Luckily, a long list of technologies at different stages of
development offers considerable promise for future improvements. They attack the problem at the acquisition hardware
level through the coils of MRI, gradient, shim, and transmitter
and receiver, and through improved sampling efficiencies in
volume coverage. The field has also made progress addressing
acquisition problems through postprocessing software such as
nonrigid alignment tools and distortion corrections. Similar
postprocessing steps have helped with variance removal of
motion-induced and biological effects (vein and CSF avoidance). While progress will appear slow, and developments initially only benefits a single laboratory, successful developments
ultimately impact all brain-mapping practitioners.
Acknowledgments
The author gratefully acknowledges the contribution of
Kawin Setsompop and Christina Triantafyllou for their help
in formulating this manuscript. He also acknowledges support
from the National Institutes of Health through grants
U01MH093765, R01EB224334, R01EB006847, K01EB001498,
and P41EB015896.
See also: INTRODUCTION TO ACQUISITION METHODS: EchoPlanar Imaging; Evolution of Instrumentation for Functional Magnetic
Resonance Imaging; fMRI at High Magnetic Field: Spatial Resolution Limits
and Applications; Functional MRI Dynamics; Pulse Sequence Dependence
of the fMRI Signal; Temporal Resolution and Spatial Resolution of fMRI.
References
Bandettini, P. A., Petridou, N., & Bodurka, J. (2005). Direct detection of neuronal activity
with MRI: Fantasy, possibility, or reality? Applied Magnetic Resonance, 29, 6588.
Bandettini, P. A., Wong, E. C., Jesmanowicz, A., Prost, R., Cox, R. W., Hinks, R. S., et al.
(1994). MRI of human brain activation at 0.5 T, 1.5 T and 3.0 T: Comparison of DR*2
115
116
Mitra, P. P., Ogawa, S., Hu, X., & Ugurbil, K. (1997). The nature of spatiotemporal
changes in cerebral hemodynamics as manifested in functional magnetic resonance
imaging. Magnetic Resonance in Medicine, 37, 511518.
Moeller, S., Yacoub, E., Olman, C. A., Auerbach, E., Strupp, J., Harel, N., et al. (2010).
Multiband multislice GE-EPI at 7 tesla, with 16-fold acceleration using partial
parallel imaging with application to high spatial and temporal whole-brain fMRI.
Magnetic Resonance in Medicine, 63, 11441153.
Moon, C. H., Fukuda, M., & Kim, S. G. (2013). Spatiotemporal characteristics and
vascular sources of neural-specific and -nonspecific fMRI signals at submillimeter
columnar resolution. NeuroImage, 64, 91103.
Mulderink, T. A., Gitelman, D. R., Mesulam, M. M., & Parrish, T. B. (2002). On the use
of caffeine as a contrast booster for BOLD fMRI studies. NeuroImage, 15, 3744.
Murphy, D. D., & Wagner, R. C. (1994). Differential contractile response of cultured
microvascular pericytes to vasoactive agents. Microcirculation, 1, 121128.
Nizar, K., Uhlirova, H., Tian, P., Saisan, P. A., Cheng, Q., Reznichenko, L., et al. (2013).
In vivo stimulus-induced vasodilation occurs without IP3 receptor activation and
may precede astrocytic calcium increase. Journal of Neuroscience, 33, 84118422.
Nunes, R. G., Hajnal, J. V., Golay, X., & Larkman, D. J. (2006). Simultaneous slice
excitation and reconstruction for single-shot EPI. In: Proceedings of ISMRM.
OCraven, K. M., Rosen, B. R., Kwong, K. K., Treisman, A., & Savoy, R. L. (1997). Voluntary
attention modulates fMRI activity in human MT-MST. Neuron, 18, 591598.
Ogawa, S., Menon, R. S., Tank, D. W., Kim, S. G., Merkle, H., Ellermann, J. M., et al.
(1993). Functional brain mapping by blood oxygenation level-dependent contrast
magnetic resonance imaging. A comparison of signal characteristics with a
biophysical model. Biophysical Journal, 64, 803812.
Oja, J. M., Gillen, J., Kauppinen, R. A., Kraut, M., & van Zijl, P. C. (1999). Venous blood
effects in spin-echo fMRI of human brain. Magnetic Resonance in Medicine, 42,
617626.
Pan, J. W., Lo, K. M., & Hetherington, H. P. (2012). Role of very high order and degree
B0 shimming for spectroscopic imaging of the human brain at 7 tesla. Magnetic
Resonance in Medicine, 68, 10071017.
Park, J., Ronen, J., Kim, D. S., & Ugurbil, K. (2005). Spatial specificity of high
resolution GE BOLD and Spin Echo (SE) BOLD fMRI in the cat visual cortex at 9.4
Tesla. In: Proceedings of the ISMRM, Miami Beach, FL.
Parkes, L. M., Schwarzbach, J. V., Bouts, A. A., Deckers, R. H., Pullens, P.,
Kerskens, C. M., et al. (2005). Quantifying the spatial resolution of the gradient echo
and spin echo BOLD response at 3 Tesla. Magnetic Resonance in Medicine, 54,
14651472.
Peppiatt, C. M., Howarth, C., Mobbs, P., & Attwell, D. (2006). Bidirectional control of
CNS capillary diameter by pericytes. Nature, 443, 700704.
Petridou, N., Plenz, D., Silva, A. C., Loew, M., Bodurka, J., & Bandettini, P. A. (2006).
Direct magnetic resonance detection of neuronal electrical activity. Proceedings of
the National Academy of Sciences of the United States of America, 103,
1601516020.
Pisauro, M. A., Dhruv, N. T., Carandini, M., & Benucci, A. (2013). Fast hemodynamic
responses in the visual cortex of the awake mouse. Journal of Neuroscience, 33,
1834318351.
Polimeni, J. R., Balasubramanian, M., & Schwartz, E. L. (2006). Multi-area visuotopic
map complexes in macaque striate and extra-striate cortex. Vision Research, 46,
33363359.
Polimeni, J. R., Fischl, B., Greve, D. N., & Wald, L. L. (2010). Laminar analysis of 7 T
BOLD using an imposed spatial activation pattern in human V1. NeuroImage, 52,
13341346.
Renvall, V., Witzel, T., Wald, L. L., & Polimeni, J. R. (2014). Fast variable inversion
recovery time EPI for anatomical reference and quantitative T1 mapping.
In: Proceedings of the ISMRM, Milan, Italy.
Ress, D., Glover, G. H., Liu, J., & Wandell, B. (2007). Laminar profiles of functional
activity in the human brain. NeuroImage, 34, 7484.
Setsompop, K., Cohen-Adad, J., Gagoski, B. A., Raij, T., Yendiki, A., Keil, B., et al.
(2012). Improving diffusion MRI using simultaneous multi-slice echo planar
imaging. NeuroImage, 63, 569580.
Setsompop, K., Gagoski, B. A., Polimeni, J. R., Witzel, T., Wedeen, V. J., & Wald, L. L.
(2012). Blipped-controlled aliasing in parallel imaging for simultaneous multislice
echo planar imaging with reduced g-factor penalty. Magnetic Resonance in
Medicine, 67, 12101224.
Shmuel, A., Yacoub, E., Chaimow, D., Logothetis, N. K., & Ugurbil, K. (2007). Spatiotemporal point-spread function of fMRI signal in human gray matter at 7 Tesla.
NeuroImage, 35, 539552.
Silva, A. C., & Koretsky, A. P. (2002). Laminar specificity of functional MRI onset times
during somatosensory stimulation in rat. Proceedings of the National Academy of
Sciences of the United States of America, 99, 1518215187.
Sirotin, Y. B., Hillman, E. M.C, Bordier, C., & Das, A. (2009). Spatiotemporal precision
and hemodynamic mechanism of optical point spreads in alert primates.
Proceedings of the National Academy of Sciences of the United States of America,
106, 1839018395.
Introduction
Human brain function involves many intermingled timescales.
Sensory percepts, cognitive processes, motor activity, and
social interaction all rely on accurate neuronal timing ranging
from submilliseconds to seconds. Magnetoencephalography
(MEG) is currently routinely available to address brain functions at the required high temporal resolution.
Modern whole-scalp neuromagnetometers comprise
helmet-shaped arrays of more than 300 SQUIDs (superconducting quantum interference devices) and are able to capture
all spatial and temporal information present at the distance of
the sensors. Consequently, the most urgent methodological
challenges today are to interpret the MEG signals properly by
employing sophisticated data analysis methods.
The skull and scalp affect the brains electric potential distributions on the scalp (measured with electroencephalography, EEG) but do not smear the magnetic signals; MEG is thus
able to see cortical events through the skull. Importantly,
MEG and EEG reflect neuronal activity directly rather than
through the associated hemodynamic or metabolic effects.
Therefore, MEG/EEG and hemodynamic methods, e.g. BOLD
fMRI, are set apart not only by their different temporal and
spatial resolutions but also by the physiological origin of the
measured signals.
MEG excels in picking up activity in fissural cortex, poorly
accessible even with intracranial recordings. In contrast, EEG
receives an overwhelming contribution from the activity in the
gyri, and the activity of the fissural cortex is often difficult to
discern from the ongoing, unaveraged EEG signals.
Review articles and textbooks are available on the MEG
technique and its applications (e.g., Aine, 2010; Baillet,
Mosher, & Leahy, 2001; Del Gratta, Pizzella, Torquati, &
Romani, 1999; Hamalainen & Hari, 2002; Hansen, Kringelbach, & Salmelin, 2010; Hari, 2011; Hari, Parkkonen, &
Nangini, 2010; Hari & Salmelin, 2012; Salmelin, 2007).
http://dx.doi.org/10.1016/B978-0-12-397025-1.00012-9
117
118
Subject
119
Experimenter
Frequency (Hz)
40
1.3
Power
1.2
30
1.1
1
20
0.9
0.8
10
0.7
0.08
Frequency (Hz)
40
Coherence
0.06
30
0.04
20
0.02
10
Time
Time (s)
Figure 1 Experimental setup and results of an MEG study implying both activation and stabilization of the primary motor cortex when the subject
observes transient motor acts of another person. Left: Subject is keeping steady isomeric contraction against a force transducer while his brain activity is
recorded with whole-scalp MEG. He observes the experimenter (middle panel) to perform intermittently phasic pinches against a similar force
transducer; only the experimenters hand is visible. Right panels show examples of the results: Group-level (N 9) brain map (top) implicates activation
in the sensorimotor cortex; timefrequency map of relative MEG power (middle) implies activation of the primary motor cortex at frequencies of
up to 18 Hz, whereas the coherence map (bottom) implies a transient stabilization of the motor cortex around 20 Hz. Modified from Hari, R.,
Bourguignon, M., Piitulainen, H., Smeds, E., De Tie`ge, X., & Jousmaki, V. (2014). Human primary motor cortex is both activated and stabilized during
observation of other persons phasic motor actions. Philosophical Transactions of the Royal Society B, 369, 20130171, with permission.
activated the viewers primary motor cortex, evidenced by suppression of MEG power, as demonstrated earlier, but at the
same time as a novel finding cortexmuscle coherence
increased at slightly higher frequencies, around 20 Hz. Thus,
the seen actions both activate and suppress neurons in the
primary motor cortex, but at different frequency bands (Hari
et al., 2014). The stabilization of the motor cortex, as indicated by the transiently increased cortexmuscle coherence,
might reflect prevention of automatic imitation of the
observed movements.
One exciting novel direction is decoding, or multivariate
pattern classification, of brain activity using machine-learning
algorithms; such techniques have successfully been used on
static fMRI activation patterns. Due to its high temporal resolution, MEG readily allows time-resolved decoding, which
can be applied, for example, to estimate when a certain feature
of the stimulus has been analyzed in the brain (Cichy,
Pantazis, & Oliva, 2014; Ramkumar, Jas, Pannasch, Hari, &
Parkkonen, 2013). In addition, similar techniques can be useful in characterizing cortical processing of naturalistic stimuli
(Kauppi, Parkkonen, Hari, & Hyvarinen, 2013; Koskinen
et al., 2013).
Altogether, these new data-driven approaches are changing
the view of how brain imaging can be used to address neuroscientific questions. Decoding results also show that MEG
signals contain much more information than we currently
extract and interpret. In the future, decoding might be applied
Future Prospects
With its good temporal resolution and clear advantages over
EEG, MEG is gaining a well-established role in human neuroscience, bringing the much-needed temporal aspect to brain
imaging: more than 150 centers globally are currently using
whole-scalp MEG. Extremely intensive research focuses on
brain rhythms, their modulations, and functional connectivity,
in both healthy and diseased individuals. Accordingly,
Buzsaki, Logothetis, and Singer (2013) considered the study
of brain rhythms to be among the largest growing fields in
systems neuroscience, mainly because of the crucial importance of accurate timing in brain function. The frequencies
and temporal characteristic of brain rhythms are surprisingly
similar in species with very different brain sizes (Buzsaki et al.,
2013), emphasizing their evolutionary importance.
The established clinical applications of MEG include preoperative localization of eloquent brain areas and epileptic
foci. Emerging clinical applications include follow-up during
stroke recovery. Importantly, the modified vasomotor control
in stroke does not as such affect MEG signals, whereas it alters
the hemodynamic fMRI responses (Forss et al., 2012; Rossini
et al., 2004). Clinical research of chronic pain may benefit
120
Acknowledgments
This work has been supported by the Academy of Finland
(Grant No. 131483 and No. 263800), European Research
Council (Advanced Grant No. 232946), the European Union
Seventh Framework Programme (FP7/20072013) under
grant agreement no. 604102 (Human Brain Project), and the
National Institutes of Health (Grant No. 5P41EB015896 and
No. 2R01EB009048).
References
Aine, C. J. (2010). Highlights of 40 years of SQUID-based brain research and clinical
applications. In: S. Supek & A. Susak (Eds.), Advances in Biomagnetism,
BIOMAG2010. IFMBE Proceedings. (vol. 28, pp. 934). Berlin: Springer. ISBN
978-3-642-12197-5.
Baillet, S., Mosher, J., & Leahy, R. (2001). Electromagnetic brain mapping. IEEE Signal
Processing Magazine, 18, 1430.
Baess, P., Zhdanov, A., Mandel, A., Parkkonen, L., Hirvenkari, L., Makela, J. P., et al.
(2012). MEG dual scanning: A procedure to study interacting humans. Frontiers in
Human Neuroscience, 6, Article 83.
Buzsaki, G., Logothetis, N., & Singer, W. (2013). Scaling brain size, keeping timing:
Evolutionary preservation of brain rhythms. Neuron, 80, 751764.
Cichy, R. M., Pantazis, D., & Oliva, A. (2014). Resolving human object recognition in
space and time. Nature Neuroscience, 17, 455462.
Del Gratta, C., Pizzella, V., Torquati, K., & Romani, G. L. (1999). New trends in
magnetoencephalography. Electroencephalography and Clinical Neurophysiology,
50, 5973.
Forss, N., Mustanoja, S., Roiha, K., Kirveskari, E., Makela, J. P., Salonen, O., et al.
(2012). Activation in parietal operculum parallels motor recovery in stroke. Human
Brain Mapping, 33, 534541.
Hamalainen, M., & Hari, R. (2002). Magnetoencephalographic characterization of
dynamic brain activation: Basic principles, and methods of data collection and
source analysis. In A. Toga, & J. Mazziotta (Eds.), Brain Mapping: The Methods.
(2nd ed.). Amsterdam: Academic Press.
Hansen, P. C., Kringelbach, M. L., & Salmelin, R. (Eds.). (2010). MEG. An Introduction
to Methods. New York: Oxford University Press.
Hari, R. (2011). Magnetoencephalography: Methods and applications. In D. L.
Schomer, & F. H. Lopes Da Silva (Eds.), Niedermeyers Electroencephalography:
Basic Principles, Clinical Applications, and Related Fields, (6th ed.). New York:
Lippincott Williams & Wilkins.
Hari, R., Bourguignon, M., Piitulainen, H., Smeds, E., De Tie`ge, X., & Jousmaki, V.
(2014). Human primary motor cortex is both activated and stabilized during
observation of other persons phasic motor actions. Philosophical Transactions of
the Royal Society B, 369, 20130171.
Hari, R., Parkkonen, L., & Nangini, C. (2010). The brain in time: Insights from
neuromagnetic recordings. Annals of the New York Academy of Science, 1191,
89109.
Hari, R., & Salmelin, R. (2012). Magnetoencephalography: From SQUIDs to
neuroscience. Neuroimage 20th anniversary special edition. NeuroImage, 61,
386396.
121
Ramkumar, P., Jas, M., Pannasch, S., Hari, R., & Parkkonen, L. (2013). Feature-specific
information processing precedes concerted activation in human visual cortex.
Journal of Neuroscience, 33, 76917699.
Rossini, P. M., Altamura, C., Ferretti, A., Vernieri, F., Zappasodi, F., Caulo, M., et al.
(2004). Does cerebrovascular disease affect the coupling between neuronal activity
and local haemodynamics? Brain, 127, 99110.
Salmelin, R. (2007). Clinical neurophysiology of language: The MEG approach. Clinical
Neurophysiology, 118, 237254.
Taulu, S., & Simola, J. (2006). Spatiotemporal signal space separation method for
rejecting nearby interference in MEG measurements. Physics in Medicine and
Biology, 51, 17591768.
Vesanen, P. T., Nieminen, J. O., Zevenhoven, K. C., Dabek, J., Parkkonen, L. T.,
Zhdanov, A. V., et al. (2013). Hybrid ultra-low-field MRI and
magnetoencephalography system based on a commercial whole-head
neuromagnetometer. Magnetic Resonance in Medicine, 69, 17951804.
Molecular fMRI
A Hai and A Jasanoff, Massachusetts Institute of Technology, Cambridge, MA, USA
2015 Elsevier Inc. All rights reserved.
Glossary
Introduction
The realization that the dynamics of cerebral blood flow can be
coupled to contrast in magnetic resonance imaging (MRI) scans
opened the door to using MRI for the noninvasive imaging
of neural activity-dependent blood flow changes in the brain
(Belliveau et al., 1990, 1991; Ogawa, Lee, Kay, & Tank, 1990;
Ogawa et al., 1992). This has transformed the fields of cognitive
neuroscience and clinical neurology and has given rise to what
are now the most prominent techniques to explore brain activation noninvasively, collectively known as functional magnetic resonance imaging (fMRI). Because conventional fMRI
signals arise from cerebral hemodynamic processes, however,
they provide only an indirect readout of neuronal activity
(Logothetis & Wandell, 2004). Hemodynamic changes arise
from a complex interplay of chemical signaling pathways that
originate in both neurons and glia (Iadecola, 2004; Iadecola &
Nedergaard, 2007). Hemodynamic signals therefore do not
permit the discrimination of neural activity components associated with different cell types, neurotransmitters, or intracellular pathways; they also display nonlinear and sometimes
sluggish dynamics with respect to neural signals.
In recent years, there have been growing attempts to combine MRI with molecular probes that allow monitoring of
neurophysiological processes at molecular and cellular levels.
Functional imaging with such probes (molecular fMRI) can
provide far greater specificity than hemodynamic imaging and
also potentially superior spatial and temporal resolution.
Molecular imaging with MRI is far less well developed as an
approach, compared with optical imaging techniques or positron emission tomography (PET). In particular, MRI probes are
less sensitively detected than either optical or PET probes
(Weissleder & Pittet, 2008). Compared with optical imaging,
however, molecular fMRI offers far greater spatial coverage and
depth penetration into the tissue. Compared with PET molecular imaging (reviewed in this volume), MRI offers far better
http://dx.doi.org/10.1016/B978-0-12-397025-1.00013-0
123
124
H O
H
H
O
%
25
N
N
O
O
N
O
Gd
O
O
O
25
H
H
O
H
(a)
% change
2
1
0
1
2
3
20
(b)
30
40
50
Time (min.)
60
70
(c)
Figure 1 T1 and T2 contrast agents for molecular (functional magnetic resonance imaging) fMRI. (a) T1 contrast agents most commonly consist of
paramagnetic atoms such as gadolinium, manganese, or iron, bound to a chelate. A canonical example, Gd3diethylenetriaminepentaacetic acid, is
shown at the left. Such contrast agents interact with water molecules (blue) either directly (dotted line) or through space to promote changes in
water proton T1 magnetic relaxation rate. A shortened T1 results in better recovery of the (magnetic resonance imaging) MRI signal (black traces at the
right) between repetitions of the pulse sequence (gray bars), thereby increasing the observed image intensity. (b) T2 agents, usually in the form of
polymer-coated superparamagnetic nanoparticles (green), induce magnetic field inhomogeneities (yellow) that promote relaxation of nearby diffusing
water protons (blue arrows) and a reduction of the MRI signal observed after each repetition of the pulse sequence (right panel). (c) A proteinbased contrast agent derived from the heme domain of the bacterial cytochrome P450-BM3 binds the neurotransmitter dopamine with an 80% change
in T1 relaxivity in vivo (Shapiro et al., 2010). Shown in the upper left panel is a coronal slice of a rat brain injected with the dopamine-sensing agent
with (orange circle) and without (blue circle) equimolar dopamine. The upper right panel shows color-coded signal change through the injection
of the agent; because the contrast agent turns off in the presence of dopamine, the coinjection region shows little signal change while the sensor-only
region shows a 25% signal increase. The bottom panel shows a molecular fMRI measurement made using the sensor during three pulses of
potassium stimulation (gray bars) in intracranially injected rat striatum. The snapshots above show signal variation in the injected region over one
stimulus cycle. The green trace shows the time course of significantly modulated voxels in the images. Reprinted from Jasanoff, A. (2007). MRI contrast
agents for functional molecular imaging of brain activity. Current Opinion in Neurobiology, 17, 593600, with permission from Elsevier,
Copyright (2007).
125
CEST Agents
A different group of MRI contrast agents makes use of compounds that can exchange protons with surrounding water molecules in what is termed proton CEST (Ward, Aletras, & Balaban,
2000). In this modality, chemicals containing exchangeable protons with resonance frequencies that are well resolved from
protons in bulk water are imaged using a specialized MRI pulse
sequence (Figure 2). In the CEST pulse sequence, strong
saturating radiofrequency irradiation is delivered at the resonance frequency of the exchanging protons; this suppresses their
magnetization and detectability by MRI. Because the saturated
protons are in exchange with water protons that give rise to most
of the MRI contrast, the overall MRI signal in proximity to the
CEST agent is also reduced. The proton exchange rate, frequency
offset between bound and bulk water protons, intensity of
saturation irradiation, and relaxation rates all combine to determine the magnitude of resulting CEST contrast (Woessner,
Zhang, Merritt, & Sherry, 2005; Zhou, Wilson, Sun, Klaus, &
126
O H
H
O
H O
COOH
HO
NH2
(a)
24
14
4
(b)
van Zijl, 2004). Because the selectivity with which CEST effects
can be experimentally manipulated using the MRI pulse
sequence, CEST contrast can be switched on and off. On the
other hand, CEST contrast is typically weaker than relaxationbased MRI contrast, and millimolar concentrations of exchangeable protons are typically required to produce observable effects.
CEST contrast and CEST agents have been applied to detect
a variety of phenomena relevant to functional brain imaging.
Subtle changes in brain pH are associated with neural activity
(Chesler, 2003), and because pH changes relate closely to
proton exchange, they are therefore particularly suitable for
detection by CEST agents. CEST contrast arising from saturation of intrinsic exchanging amide protons has been used to
measure pH in vivo, and pH changes of roughly 0.5 units
associated with ischemic stroke in rat brains could be imaged
Heteronuclear Probes
Molecular imaging agents containing nuclei other than protons, such as carbon (13C) and fluorine (19F), may be imaged
using modified MRI hardware specifically tuned to the resonance frequencies of these nuclei. The MRI signal arising from
such heteronuclear probes is considerably weaker than that of
endogenous water protons because of the much lower abundance of heteronuclear species, compounded by the intrinsically lower sensitivity of MRI techniques to nuclei other than
hydrogen. A long history of magnetic resonance spectroscopy
and spectroscopic imaging has enabled the detection of
13
C-containing metabolites related to brain function. Using
these approaches, it has been possible to perform functional
studies that detect the effect of neural activity on glutamate
metabolism (Rothman et al., 1992; Sibson et al., 1997), albeit
127
adhering astrocytes not only prevents potentially harmful substances in the bloodstream from entering the brain but also
blocks therapeutics and imaging agents. Strategies to transiently
disrupt the BBB include the administration of a hyperosmotic
shock by intravascular injection of a hypertonic substance such
as 25% mannitol (Neuwelt & Rapoport, 1984) and more
recently by the application of focused or unfocused ultrasound,
in which the BBB is disrupted by sonic pressure waves amplified
by intravascular gas-filled microbubbles (Vykhodtseva,
McDannold, & Hynynen, 2008). Both osmotic shock and ultrasound methods have been used to deliver T1 and T2 agents in
sufficient quantities for MRI observation. Other trans-BBB
delivery methods use endogenous transport mechanisms
involving transferrin and insulin receptors (Pardridge, 2012)
and cell-penetrating peptides (Santra et al., 2004) to deliver
agents across the BBB, but these may not be effective enough
for the delivery of MRI contrast agents at useful doses.
The requirement for exogenous delivery of contrast agents is
a substantial drawback of many molecular fMRI approaches,
compared with hemodynamic fMRI. A significant advantage of
molecular techniques is that they can in principle achieve
much higher spatial and temporal resolution, however,
because they are not limited by the spatiotemporal properties
of blood flow changes. The ultimate spatial resolution of MRI
is usually placed in the 110 mm range, limited by the diffusion
of water molecules in the tissue; in practice, this resolution is
rarely achieved, however, because of the long measuring times
required for the buildup of adequate signal-to-noise ratio,
particularly in vivo. Current molecular MRI techniques can
provide spatial resolution on the order of 100 mm and temporal resolution on the order of seconds, but with trade-offs
between the two. Substantial efforts are needed to move
toward millisecond timescales and micrometer spatial features
most relevant to neuronal activity and structure. Gains are
most likely to be made by improving the potency of MRI
contrast agents, going to higher MRI magnetic fields, and optimizing pulse sequences for molecular applications. Molecular
fMRI techniques are still in their infancy, but offer one of few
paths toward truly noninvasive whole-brain analysis of neural
activity at molecular and cellular levels, particularly if technological developments continue along their present course.
References
Allouche-Arnon, H., Lerche, M. H., Karlsson, M., Lenkinski, R. E., & Katz-Brull, R.
(2011). Deuteration of a molecular probe for DNP hyperpolarization A new
approach and validation for choline chloride. Contrast Media & Molecular Imaging,
6, 499506.
Allouche-Arnon, H., et al. (2011). A hyperpolarized choline molecular probe for
monitoring acetylcholine synthesis. Contrast Media & Molecular Imaging, 6,
139147.
Ametamey, S. M., et al. (2007). Human PET studies of metabotropic glutamate receptor
subtype 5 with C-11-ABP688. Journal of Nuclear Medicine, 48, 247252.
Angelovski, G., Fouskova, P., Mamedov, I., Canals, S., Toth, E., & Logothetis, N. K.
(2008). Smart magnetic resonance imaging agents that sense extracellular calcium
fluctuations. Chembiochem, 9, 17291734.
128
Aoki, I., Wu, Y. J.L, Silva, A. C., Lynch, R. M., & Koretsky, A. P. (2004). In vivo detection
of neuroarchitecture in the rodent brain using manganese-enhanced MRI.
NeuroImage, 22, 10461059.
Aptekar, J. W., et al. (2009). Silicon nanoparticles as hyperpolarized magnetic
resonance imaging agents. ACS Nano, 3, 40034008.
Ardenkjaer-Larsen, J. H., et al. (2003). Increase in signal-to-noise ratio of >10,000
times in liquid-state NMR. Proceedings of the National Academy of Sciences of the
United States of America, 100, 1015810163.
Atanasijevic, T., Shusteff, M., Fam, P., & Jasanoff, A. (2006). Calcium-sensitive MRI
contrast agents based on superparamagnetic iron oxide nanoparticles and
calmodulin. Proceedings of the National Academy of Sciences of the United States
of America, 103, 1470714712.
Bar-Shir, A., et al. (2013). Metal ion sensing using ion chemical exchange saturation
transfer (19)F magnetic resonance imaging. Journal of the American Chemical
Society, 135, 1216412167.
Belliveau, J. W., et al. (1990). Functional cerebral imaging by susceptibility-contrast
NMR. Magnetic Resonance in Medicine, 14, 538546.
Belliveau, J. W., et al. (1991). Functional mapping of the human visual-cortex by
magnetic-resonance-imaging. Science, 254, 716719.
Brustad, E. M., et al. (2012). Structure-guided directed evolution of highly selective
p450-based magnetic resonance imaging sensors for dopamine and serotonin.
Journal of Molecular Biology, 422, 245262.
Cai, K. J., et al. (2012). Magnetic resonance imaging of glutamate. Nature Medicine, 18,
302306.
Cai, K., et al. (2013). Mapping glutamate in subcortical brain structures using
high-resolution GluCEST MRI NMR in Biomedicine, .
Caravan, P. (2006). Strategies for increasing the sensitivity of gadolinium based MRI
contrast agents. Chemical Society Reviews, 35, 512523.
Chen, Y. C.I, Mandeville, J. B., Nguyen, T. V., Talele, A., Cavagna, F., & Jenkins, B. G.
(2001). Improved mapping of pharmacologically induced neuronal activation using
the IRON technique with superparamagnetic blood pool agents. Journal of Magnetic
Resonance Imaging, 14, 517524.
Chesler, M. (2003). Regulation and modulation of pH in the brain. Physiological
Reviews, 83, 11831221.
Cohen, B., Dafni, H., Meir, G., Harmelin, A., & Neeman, M. (2005). Ferritin as an
endogenous MRI reporter for noninvasive imaging of gene expression in C6 glioma
tumors. Neoplasia, 7, 109117.
Esqueda, A. C., et al. (2009). A new gadolinium-based MRI zinc sensor. Journal of the
American Chemical Society, 131, 1138711391.
Genove, G., DeMarco, U., Xu, H. Y., Goins, W. F., & Ahrens, E. T. (2005). A new
transgene reporter for in vivo magnetic resonance imaging. Nature Medicine, 11,
450454.
Gilad, A. A., et al. (2007). Artificial reporter gene providing MRI contrast based on
proton exchange. Nature Biotechnology, 25, 217219.
Golman, K., int Zandt, R., & Thaning, M. (2006). Real-time metabolic imaging.
Proceedings of the National Academy of Sciences of the United States of America,
103, 1127011275.
Gruppi, F., Liang, J., Bartelle, B. B., Royzen, M., Turnbull, D. H., & Canary, J. W. (2012).
Supramolecular metal displacement allows on-fluorescence analysis of manganese
(II) in living cells. Chemical Communications, 48, 1077810780.
Hanaoka, K., et al. (2002). Design and synthesis of a novel magnetic resonance imaging
contrast agent for selective sensing of zinc ion. Chemistry & Biology, 9,
10271032.
Higuchi, M., Iwata, N., Matsuba, Y., Sato, K., Sasamoto, K., & Saido, T. C. (2005). F-19
and H-1 MRI detection of amyloid beta plaques in vivo. Nature Neuroscience, 8,
527533.
Hsieh, V., & Jasanoff, A. (2012). Bioengineered probes for molecular magnetic
resonance imaging in the nervous system. ACS Chemical Neuroscience, 3,
593602.
Iadecola, C. (2004). Neurovascular regulation in the normal brain and in Alzheimers
disease. Nature Reviews. Neuroscience, 5, 347360.
Iadecola, C., & Nedergaard, M. (2007). Glial regulation of the cerebral microvasculature.
Nature Neuroscience, 10, 13691376.
Lee, T., Zhang, X.-A., Dhar, S., Faas, H., Lippard, S. J., & Jasanoff, A. (2010). In vivo
imaging with a cell-permeable porphyrin-based MRI contrast agent. Chemistry &
Biology, 17, 665673.
Leite, F. P., et al. (2002). Repeated fMRI using iron oxide contrast agent in awake,
behaving macaques at 3 Tesla. NeuroImage, 16, 283294.
Li, W. H., Fraser, S. E., & Meade, T. J. (1999). A calcium-sensitive magnetic resonance
imaging contrast agent. Journal of the American Chemical Society, 121, 14131414.
Li, A. X., et al. (2011). In vivo detection of MRI-PARACEST agents in mouse brain
tumors at 9.4 T. Magnetic Resonance in Medicine, 66, 6772.
Lin, Y. J., & Koretsky, A. P. (1997). Manganese ion enhances T-1-weighted MRI during
brain activation: An approach to direct imaging of brain function. Magnetic
Resonance in Medicine, 38, 378388.
Logothetis, N. K., & Wandell, B. A. (2004). Interpreting the BOLD signal. Annual Review
of Physiology, 66, 735769.
Louie, A. Y., et al. (2000). In vivo visualization of gene expression using magnetic
resonance imaging. Nature Biotechnology, 18, 321325.
Major, J. L., Parigi, G., Luchinat, C., & Meade, T. J. (2007). The synthesis and in vitro
testing of a zinc-activated MRI contrast agent. Proceedings of the National Academy
of Sciences of the United States of America, 104, 1388113886.
Mandeville, J. B., Jenkins, B. G., Kosofsky, B. E., Moskowitz, M. A., Rosen, B. R., &
Marota, J. J.A (2001). Regional sensitivity and coupling of BOLD and CBV changes
during stimulation of rat brain. Magnetic Resonance in Medicine, 45, 443447.
Matsumoto, Y., & Jasanoff, A. (2013). Metalloprotein-based MRI probes. FEBS Letters,
587, 10211029.
Meiri, U., & Rahamimo, R. (1972). Neuromuscular transmission Inhibition by
manganese ions. Science, 176, 308309.
Merbach, A. S., Helm, L., & Toth, E. (2013). The chemistry of contrast agents in medical
magnetic resonance imaging. Chichester, UK: Wiley.
Mizukami, S., et al. (2008). Paramagnetic relaxation-based F-19 MRI probe to detect
protease activity. Journal of the American Chemical Society, 130, 794795.
Narita, K., Kawasaki, F., & Kita, H. (1990). Mn and Mg influxes through Ca channels of
motor-nerve terminals are prevented by verapamil in frogs. Brain Research, 510,
289295.
Neuwelt, E. A., & Rapoport, S. I. (1984). Modification of the bloodbrain-barrier in the
chemotherapy of malignant brain-tumors. Federation Proceedings, 43, 214219.
Ogawa, S., Lee, T. M., Kay, A. R., & Tank, D. W. (1990). Brain magnetic-resonanceimaging with contrast dependent on blood oxygenation. Proceedings of the National
Academy of Sciences of the United States of America, 87, 98689872.
Ogawa, S., et al. (1992). Intrinsic signal changes accompanying sensory stimulation
Functional brain mapping with magnetic-resonance-imaging. Proceedings of the
National Academy of Sciences of the United States of America, 89, 59515955.
Pardridge, W. M. (2012). Drug transport across the bloodbrain barrier. Journal of
Cerebral Blood Flow and Metabolism, 32, 19591972.
Pautler, R. G., Silva, A. C., & Koretsky, A. P. (1998). In vivo neuronal tract tracing using
manganese-enhanced magnetic resonance imaging. Magnetic Resonance in
Medicine, 40, 740748.
Que, E. L., & Chang, C. J. (2006). A smart magnetic resonance contrast agent for
selective copper sensing. Journal of the American Chemical Society, 128,
1594215943.
Que, E. L., Domaille, D. W., & Chang, C. J. (2008). Metals in neurobiology: Probing
their chemistry and biology with molecular imaging. Chemical Reviews, 108,
15171549.
Raghunand, N., Zhang, S. R., Sherry, A. D., & Gillies, R. J. (2002). In vivo magnetic
resonance imaging of tissue pH using a novel pH-sensitive contrast agent,
GdDOTA-4AmP. Academic Radiology, 9, S481S483.
Rothman, D. L., et al. (1992). H-1 C-13 NMR measurements of 4-C-13 glutamate
turnover in human brain. Proceedings of the National Academy of Sciences of the
United States of America, 89, 96039606.
Santra, S., et al. (2004). TAT conjugated, FITC doped silica nanoparticles for
bioimaging applications. Chemical Communications, 28102811.
Shapiro, M. G., Szablowski, J. O., Langer, R., & Jasanoff, A. (2009). Protein
nanoparticles engineered to sense kinase activity in MRI. Journal of the American
Chemical Society, 131, 24842486.
Shapiro, M. G., et al. (2010). Directed evolution of a magnetic resonance imaging
contrast agent for noninvasive imaging of dopamine. Nature Biotechnology, 28,
264270.
Sibson, N. R., Dhankhar, A., Mason, G. F., Behar, K. L., Rothman, D. L., &
Shulman, R. G. (1997). In vivo C-13 NMR measurements of cerebral glutamine
synthesis as evidence for glutamate-glutamine cycling. Proceedings of the National
Academy of Sciences of the United States of America, 94, 26992704.
Silva, A. C., et al. (2008). Detection of cortical laminar architecture using manganeseenhanced MRI. Journal of Neuroscience Methods, 167, 246257.
Squitti, R., & Polimanti, R. (2013). Copper phenotype in Alzheimers disease: Dissecting
the pathway. American Journal of Neurodegenerative Disease, 2, 4656.
Sumner, J. P., Shapiro, E. M., Maric, D., Conroy, R., & Koretsky, A. P. (2009).
In vivo labeling of adult neural progenitors for MRI with micron sized
particles of iron oxide: Quantification of labeled cell phenotype. NeuroImage, 44,
671678.
Vogl, T. J., et al. (1996). Superparamagnetic iron oxide-enhanced versus gadoliniumenhanced MR imaging for differential diagnosis of focal liver lesions. Radiology,
198, 881887.
129
Zhang, S. R., Merritt, M., Woessner, D. E., Lenkinski, R. E., & Sherry, A. D. (2003).
PARACEST agents: Modulating MRI contrast via water proton exchange. Accounts
of Chemical Research, 36, 783790.
Zhou, J. Y., Payen, J. F., Wilson, D. A., Traystman, R. J., & van Zijl, P. C. M. (2003).
Using the amide proton signals of intracellular proteins and peptides to detect pH
effects in MRI. Nature Medicine, 9, 10851090.
Zhou, J. Y., Wilson, D. A., Sun, P. Z., Klaus, J. A., & van Zijl, P. C. M. (2004).
Quantitative description of proton exchange processes between water and
endogenous and exogenous agents for WEX, CEST, and APT experiments. Magnetic
Resonance in Medicine, 51, 945952.
Zurkiya, O., Chan, A. W.S, & Hu, X. (2008). MagA is sufficient for producing magnetic
nanoparticles in mammalian cells, making it an MRI reporter. Magnetic Resonance
in Medicine, 59, 12251231.
Abbreviation
ASL
BOLD
CBF
CBV
EPI
FLASH
GE
PRESTO
Introduction
By far, the vast majority of functional MRI (fMRI) studies in the
literature have used the blood oxygenation level-dependent
(BOLD) contrast mechanism as their source of fMRI signal
and, by far, the most commonly used MRI pulse sequence
has been the gradient-echo (GE) version of the echo-planar
imaging (EPI) technique. For this reason, a substantial portion
of this article is dedicated to the GE-EPI sequence and its signal
dependency. However, other types of pulse sequence can be
used, and so some of the other flavors of fMRI sequence will
also be discussed. One prominent alternative is to use a spinecho (SE) refocusing pulse within the sequence, which alters
the sensitivity of the fMRI signal to intravascular versus extravascular signal and which also alters the size regime of blood
vessels to which the fMRI signal is most sensitive. However,
radically different types of MRI pulse sequence also exist, such
as those that report more specifically on changes in cerebral
blood volume (CBV) or those that report more explicitly on
cerebral blood flow (CBF). Even more exotic are approaches
that aim to probe changes in the diffusion coefficient of tissue
water as cells swell in response to metabolic activity or
approaches that aim to report more directly on neuronal currents via their associated magnetic field fluctuations.
RF
SE
T1
T2
T2*
TE
TR
VASO
Radio frequency
Spin echo
Longitudinal relaxation time constant
Transverse relaxation time constant
Transverse relaxation time constant, including
the effects of field inhomogeneities
Pulse sequence echo time
Pulse sequence repeat time
Vascular space occupancy (CBV-weighted pulse
sequence)
SE Versus GE
There is, however, a significant difference in the specific sensitivity of GE and SE sequences. The theory to explain this
(Boxerman, Hamberg, Rosen, & Weisskoff, 1995; Boxerman
et al., 1995; Kennan, Zhong, & Gore, 1994) builds on work
done originally to describe the biophysics of injectable exogenous (gadolinium-based) contrast agents to measure blood volume using the method of dynamic susceptibility contrast
imaging. Deoxyhemoglobin represents an analogous endogenous contrast agent to gadolinium, albeit with a lower paramagnetic susceptibility. Figure 1 shows a schematic representation of
the predicted change in relaxivity for the GE and SE signals as a
function of vessel size. It can be seen that at small vessel dimensions (in the range of capillaries), both the GE and SE signals
show a similar increase in relaxivity with increasing vessel size.
However, beyond the size scale of capillaries, the GE relaxivity
change continues to increase and remains sensitive to a wide
range of vessel sizes, whereas the SE signal reaches a peak in
relaxivity sensitivity and then falls off with increasing vessel size.
The origin of this effect lies in the interplay between the
diffusion of tissue water and the extent of the microscopic field
gradients surrounding the blood vessels. In the case of small
vessels (of the size scale of capillaries), the SE sequence does
not refocus the effects of dephasing of the extravascular water
spins that surround the vessels, since the diffusion distance of
water during the echo time (TE) of the pulse sequence is of a
similar scale to the extent of the field gradients. However, for
larger veins, the extent of the field gradients is much larger than
the diffusion distance of water during the TE time. Therefore, a SE
sequence will tend to refocus the signal from magnetic field
http://dx.doi.org/10.1016/B978-0-12-397025-1.00014-2
131
132
4.0
3.0
2.0
1.0
Spin echo
10
Vessel radius (mm)
100
Echo-planar imaging
At the time of writing, the most commonly used pulse
sequence for fMRI is the EPI sequence (Mansfield, 1977).
This sequence reads out a number of lines of k-space following each RF excitation pulse and potentially can acquire all the
required lines of k-space to form an image following a single
RF excitation pulse (the so-called snapshot EPI). The benefit of
the EPI pulse sequence is its speed, since it is capable of
acquiring an entire multislice volume through the brain in
< 2 s. The trade-off with EPI is that it is generally restricted to
low spatial resolutions (typically 2 mm in-plane, although
higher resolutions are possible), and it suffers from geometric
distortion of the images that complicates the registration of EPI
data to high-resolution structural data. Notwithstanding this,
GE-EPI has become the workhorse sequence used in fMRI and
so deserves some further specific discussion.
An important parameter in any fMRI sequence is the TE. For
maximum sensitivity of the pulse sequence, the optimal TE
value will be the one that maximizes the contrast-to-noise
ratio of the phenomenon being studied, in this case the
BOLD fMRI signal. To first approximation, the maximum sensitivity to signal change occurs when the TE value matches the
underlying T2* value for the tissue. This is a field-dependent
and brain region-dependent value, but a useful rule of thumb
(Glover, 2001) is to use a value of 1/T2* 1/T2 c B0 (where
c 4.8 (sT )1 and T2 0.095 s). If the T2* varies locally, then
in some circumstances a shorter TE value than would be the
case normally might actually increase the BOLD sensitivity,
contrary to the expectation that a longer TE time might offer
more BOLD fMRI signal contrast. Poser, Versluis, Hoogduin,
and Norris (2006) proposed the PAID method to deal with
the TE dependency: Parallel imaging acceleration allows the
acquisition of multiple EPI readouts after a single excitation
with different TEs. These are subsequently combined using a
200
160
120
80
40
-400
-300
-200
-100
100
data-driven, weighted approach ensuring optimal BOLD sensitivity in each voxel individually.
Deichmann, Josephs, Hutton, Corfield, and Turner (2002)
had further shown that the presence of any background macroscopic field gradients (poor shim), particularly any that are
in the phase-encoding direction for an EPI sequence, can result
in a significant change to the fMRI experiments BOLD sensitivity from its optimal value. This can be understood by reference to Figure 2 that shows the effect of the presence of a
phase-encoding direction shim gradient on BOLD sensitivity.
Finally, background macroscopic fields in the slice direction
can reduce image SNR due to the top and bottom of a slice
having a different phase at the time of the echo. Many compensation strategies have been proposed including z-shim
gradient blips in the slice direction (Constable & Spencer,
1999; Deichmann, Gottfried, Hutton, & Turner, 2003; Glover,
1999; Yang, Williams, Demeure, Mosher, & Smith, 1998), the
use of thin slices (Merboldt, Finsterbusch, & Frahm, 2000),
and RF pulse manipulations that locally prephase the slice such
that all is in-phase at the time of the echo (Stenger, Boada, &
Noll, 2000).
A specific issue associated with the EPI sequence (mentioned in the preceding text) is its sensitivity to geometric
distortion. This is caused by the low effective bandwidth of
EPI in the phase-encoding direction, which means that any
background macroscopic (shim) field inhomogeneities can
cause misplacement of signal in the resulting image, and consequent distortions. It is possible to ameliorate this problem by
acquiring separate information on the magnetic field distribution (Jezzard & Balaban, 1995) and then using this to relocate
the signal to its correct position or by running two EPI
sequences, one with positive phase-encoding blips and one
with negative phase-encoding blips, and then by using the
133
Spiral
An alternative readout technique to EPI is the spiral imaging
pulse sequence (Ahn, Kim, & Cho, 1986). This sequence is very
similar to EPI, but with a different (spiral) trajectory through
k-space, again potentially allowing data for a full image to be
acquired following a single RF excitation pulse. Spiral imaging
was developed in part to address the gradient hardware
demands of EPI, where severe switching of the gradient amplifiers is necessary. Additionally, it can address the EPI problem
of dead time between the excitation and the readout as the
optimal TE is relatively long (3540 ms at 3 T) compared to
the readout duration. A spiral-in trajectory does not have the
echo at its center but at the end, making TR almost equal to TE
and allowing a speedup similar to the principles of echo shifting with a train of observations (PRESTO) (see succeeding
text). This benefit disappears at high resolution, however, as
the longer readout causes an excessive TE. A drawback of the
spiral sequence is that it requires the k-space trajectory to be
accurately produced in order to avoid missing the echo or to
avoid image reconstruction artifacts that are much harder to
correct than the ones encountered in EPI. Improvements in
hardware in recent years have led to the interesting situation
that artifacts in spiral imaging not only can now be better
controlled but also have allowed EPI to become standard on
modern scanners. Finally, the relatively smooth gradients
reduce sound levels, in turn improving patient comfort. Overall, the spiral imaging method is not widely used, despite its
excellent suitability for low-resolution, low TR scanning.
134
SE Sequences
The other main class of BOLD fMRI technique is the SE contrast, which has some advantages over GE contrast. These are
that (i) the macroscopic background field dephasing effects are
refocused (this does not avoid EPI distortion, but does counter
through-slice dephasing); (ii) throughout the brain, T2 varies
considerably <T2* so a single TE is optimal everywhere; and
(iii) at high field strengths, the BOLD signal is more localized
to the capillary bed due to the refocusing of extravascular
dephasing around large vessels (as shown in Figure 1). It
should be noted that SE sequences will still be sensitive to
true T2 changes from the intravascular water in the larger
vessels and so are not immune to large vessel effects, but their
sensitivity to draining veins is greatly reduced due to the short
T2 of venous blood at high field (Duong et al., 2003).
SE sequences have drawbacks, however, which have prevented their widespread use. First and foremost, their loss in
fMRI sensitivity is usually considered too great (Bandettini,
Wong, Jesmanowicz, Hinks, & Hyde, 1994; Thulborn, Chang,
Shen, & Voyvodic, 1997). Most fMRI studies seek to study subtle
effects, and therefore, sensitivity is of utmost importance. Furthermore, research is often focused on group differences where
intersubject anatomical variability is the most limiting factor on
spatial resolution, rather than the sequence resolution. The second main argument against T2-weighted BOLD experiments is
that they are too impractical to perform properly. A purely T2weighted sequence would require the readout to consist of a
string of refocusing pulses as found in turbo spin-echo
sequences, which can quickly lead to prohibitive RF power deposition levels. In practice, therefore, EPI readout modules have
been used instead to measure the SE, but these add a significant
amount of T2* weighting, thereby reintroducing large-vein
effects. Segmented EPI can be used to reduce this contribution,
but Goense and Logothetis (2006) have shown that very large
segmentation factors are needed for it to be effective. This can
increase the volume TR time by an order of magnitude; however,
SE-EPI is already a slow sequence compared with GE-EPI due to
the long TE (6080 ms). Overall, SE-EPI has its niche
applications, but for most fMRI work, the benefits do not generally outweigh the challenges (Norris, 2012).
135
CBF
BOLD
T C T C T C T C T C T C T C T C T C
Figure 3 Interaction of perfusion signal and BOLD signal in the case
of a time course arterial spin labeling experiment that uses a gradientecho readout. The BOLD signal does not cancel during transitions in the
fMRI paradigm, and poor estimation of the CBF signal will also result
from the different acquisition times of the tag image and control image.
These effects require careful analysis to correctly separate the BOLD
and ASL time courses. Inspired by Woolrich et al. 2006.
See also: INTRODUCTION TO ACQUISITION METHODS: EchoPlanar Imaging; fMRI at High Magnetic Field: Spatial Resolution Limits
and Applications; High-Field Acquisition; MRI and fMRI Optimizations
and Applications; Perfusion Imaging with Arterial Spin Labeling MRI;
Susceptibility-Weighted Imaging and Quantitative Susceptibility
Mapping.
References
Ahn, C., Kim, J., & Cho, Z. (1986). High speed spiral scan echo planar NMR imaging.
IEEE Transactions on Medical Imaging, MI-5, 27.
Andersson, J. L., Skare, S., & Ashburner, J. (2003). How to correct susceptibility
distortions in spin-echo echo-planar images: Application to diffusion tensor
imaging. NeuroImage, 20, 870888.
Bandettini, P. A., Wong, E. C., Jesmanowicz, A., Hinks, R. S., & Hyde, J. S. (1994).
Spin-echo EPI of human brain activation using BOLD contrast: A comparative study
at 1.5 T. NMR in Biomedicine, 7, 1220.
Belliveau, J. W., Kennedy, D. N., McKinstry, R. C., et al. (1991). Functional mapping of
the human brain visual cortex by magnetic resonance imaging. Science, 254,
716719.
Bodurka, J., & Bandettini, P. A. (2002). Toward direct mapping of neuronal activity: MRI
detection of ultraweak, transient magnetic field changes. Magnetic Resonance in
Medicine, 47, 10521058.
Bodurka, J., Ye, F., Petridou, N., Murphy, K., & Bandettini, P. A. (2007). Mapping the
MRI voxel volume in which thermal noise matches physiological noise
Implications for fMRI. NeuroImage, 34, 542549.
Boxerman, J. L., Bandettini, P. A., Kwong, K. K., et al. (1995). The intravascular
contribution to fMRI signal change: Mote Carlo modeling and diffusion-weighted
studies in vivo. Magnetic Resonance in Medicine, 34, 410.
Boxerman, J. L., Hamberg, L. M., Rosen, B. R., & Weisskoff, R. M. (1995). MR contrast
due to intravascular magnetic susceptibility perturbations. Magnetic Resonance in
Medicine, 34, 555566.
Breuer, F. A., Blaimer, M., Heidermann, R. M., Mueller, M. F., Griswold, M. A., &
Jakob, P. M. (2005). Controlled aliasing in parallel imaging results in higher
acceleration (CAIPIRIHNA) for multi-slice imaging. Magnetic Resonance in
Medicine, 53, 684691.
Cauley, S. F., Polimeni, J. R., Bhat, H., Wald, L. L., & Setsompop, K. (2013). Interslice
leakage artifact reduction technique for simultaneous multislice acquisitions.
Magnetic Resonance in Medicine, 72(1), 93102.
Constable, R. T., & Spencer, D. D. (1999). Composite image formation in z-shimmed
functional MR imaging. Magnetic Resonance in Medicine, 42, 110117.
Deichmann, R., Gottfried, J. A., Hutton, C., & Turner, R. (2003). Optimized EPI for fMRI
studies of the orbitofrontal cortex. NeuroImage, 19, 430441.
Deichmann, R., Josephs, O., Hutton, C., Corfield, D. R., & Turner, R. (2002).
Compensation of susceptibility-induced BOLD sensitivity losses in echo-planar
fMRI imaging. NeuroImage, 15, 120135.
Duong, T. Q., Yacoub, E., Adriany, G., Hu, X., Ugurbil, K., & Kim, S. G. (2003).
Microvascular BOLD contribution at 4 and 7 T in human brain: Gradient-echo and
spin-echo fMRI with suppression of blood effects. Magnetic Resonance in
Medicine, 49, 10191027.
Duyn, J. H., Moonen, C. T., van Yperen, G. H., de Boer, R. W., & Luyten, P. R. (1994).
Inflow versus deoxyhemoglobin effects in BOLD functional MRI using gradient
echoes at 1.5 T. NMR in Biomedicine, 7, 8388.
Feinberg, D. A., Moeller, S., Smith, S. M., et al. (2010). Multiplexed echo planar
imaging for sub-second whole brain fMRI and fast diffusion imaging. PLoS One, 5,
e15710.
Frahm, J., Haase, A., & Matthaei, D. (1986). Rapid NMR imaging of dynamic processes
using the FLASH technique. Magnetic Resonance in Medicine, 3, 321327.
Gati, J. S., Menon, R. S., Ugurbil, K., & Rutt, B. K. (1997). Experimental determination
of the BOLD field strength dependence in vessels and tissue. Magnetic Resonance
in Medicine, 38, 296302.
Glover, G. H. (1999). 3D z-shim method for reduction of susceptibility effects in BOLD
fMRI. Magnetic Resonance in Medicine, 42, 290299.
136
Qiu, D., Zaharchuk, G., Christen, T., Ni, W. W., & Moseley, M. E. (2012). Contrastenhanced functional blood volume imaging (CE-CBV): Enhanced sensitivity for
brain activation in humans using the ultrasmall superparamagnetic iron oxide agent
ferumoxytol. NeuroImage, 62, 17261731.
Schaller, B., Mekle, R., Xin, L., Kunz, N., & Gruetter, R. (2013). Net increase of lactate
and glutamate concentration in activated human visual cortex detected with
magnetic resonance spectroscopy at 7 Tesla. Journal of Neuroscience Research, 91,
10761083.
Setsompop, K., Gagoski, B. A., Polimeni, J. R., Witzel, T., Wedeen, V. J., & Wald, L. L.
(2012). Blipped-controlled aliasing in parallel imaging for simultaneous multislice
echo planar imaging with reduced g-factor penalty. Magnetic Resonance in
Medicine, 67, 12101224.
Smith, S. M., Beckmann, C. F., Andersson, J., et al. (2013). Resting-state fMRI in the
human connectome project. NeuroImage, 80, 144168.
Song, A. W., & Takahashi, A. M. (2001). Lorentz effect imaging. Magnetic Resonance in
Medicine, 19, 763767.
Stenger, V. A., Boada, F. E., & Noll, D. C. (2000). Three-dimensional tailored RF pulses
for the reduction of susceptibility artifacts in T2*-weighted functional MRI. Magnetic
Resonance in Medicine, 44, 525531.
Thulborn, K. R., Chang, S. Y., Shen, G. X., & Voyvodic, J. T. (1997). High-resolution
echo-planar fMRI of human visual cortex at 3.0 Tesla. NMR in Biomedicine, 10,
183190.
Thulborn, K. R., Waterton, J. C., Matthews, P. M., & Radda, G. K. (1982). Oxygenation
dependence of the transverse relaxation time of water protons in whole blood at high
field. Biochimica et Biophysica Acta, 714, 265270.
Uludag, K., Mueller-Bierl, B., & Ugurbil, K. (2009). An integrative model for activityinduced signal changes for gradient and spin echo functional imaging. NeuroImage,
48, 150165.
Van der Zwaag, W., Francis, S., Head, K., et al. (2009). fMRI at 1.5, 3 and 7 T:
Characterizing BOLD signal changes. NeuroImage, 47, 14251434.
Wang, J., Aguirre, G. K., Kimberg, D. Y., Roc, A. C., Li, L., & Detre, J. A. (2003). Arterial
spin labeling perfusion fMRI with very low task frequency. Magnetic Resonance in
Medicine, 49, 796802.
Wong, E. C., Luh, W. M., & Yu, H. C. (2000). Turbo ASL: Arterial spin labeling with
higher SNR and temporal resolution. Magnetic Resonance in Medicine, 44,
511515.
Woolrich, M. W., Chiarelli, P., Gallichan, D., Perthen, J., & Liu, T. T. (2006). Bayesian
inference of hemodynamic changes in functional arterial spin labeling. Magnetic
Resonance in Medicine, 56, 891906.
Xiong, J., Fox, P. T., & Gao, J. H. (2003). Directly mapping magnetic field effects of
neuronal activity by magnetic resonance imaging. Human Brain Mapping, 20,
4149.
Yang, Q. X., Williams, G. D., Demeure, R. J., Mosher, T. J., & Smith, M. B. (1998).
Removal of local field gradient artifacts in T2*-weighted images at high field by
gradient-echo slice excitation profile imaging. Magnetic Resonance in Medicine, 39,
402409.
Zhu, X. H., Zhang, N., Zhang, Y., Ugurbil, K., & Chen, W. (2009). New insights into
central roles of cerebral oxygen metabolism in the resting and stimulus-evoked
brain. Journal of Cerebral Blood Flow and Metabolism, 29, 1018.
Myelin Imaging
R Turner, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
2015 Elsevier Inc. All rights reserved.
Glossary
Introduction
In human brain, the combination of lipids and proteins known
collectively as myelin comprises about half of the dry weight of
white matter (Siegel, Agranoff, & Gavulic, 1999). The myelin
content of gray matter, which is always lower than in white
matter, varies strikingly between cortical areas, reaching a maximum in the primary motor cortex and a minimum in several
prefrontal regions.
Broadly speaking, the dry-weight composition of myelin is
about 30% protein (including myelin basic protein), about 20%
cholesterol, about 20% galactolipids containing sulfur in their
head groups, and about 30% phospholipids. The nonmyelin
components of white matter are similar, but the proportion of
galactolipids is strikingly lower than that of myelin. Gray matter
contains comparatively more protein and less lipid and has a
higher water content (80%) compared with white matter (70%).
Historically, most of the anatomical research on myelin has
been carried out using histological techniques: brain tissue is
fixed using formalin or other fixatives such as Bodian No. 2,
then sliced with a macrotome into sections about 40 mm thick,
and then finally stained to reveal the presence of myelin. Popular
stains for myelin include the Gallyas silver stain, Luxol fast blue,
and Weigerts method. In addition, immunohistochemical stains
can be used, such as MBP IHC antibody, which selectively stains
myelin basic protein.
It should be noted that some fixatives, such as those containing ethanol or acetic acid, are incompatible with MRI
scanning, because their proton spectra have two closely spaced
http://dx.doi.org/10.1016/B978-0-12-397025-1.00015-4
137
138
Figure 1 Micrograph of human brain tissue stained for myelin using the
Gallyas silver stain technique.
3000
2500
2000
1500
1000
T1
(ms)
Figure 2 Map of T1 in the normal human brain, from the Max Planck
Institute for Human Cognitive and Brain Sciences, Leipzig. The data were
acquired using the MP2RAGE sequence at 7 T, with isotropic spatial
resolution of 0.5 mm. An axial slice is shown, from a whole-brain data set
acquired in 45 min.
intensities can be observed in images that are sensitive to differences in the longitudinal relaxation time T1 (Figure 2). But it has
taken many years to better understand the biophysical origins of
the T1 differences between white matter and gray matter. This
would be surprising if it were not for the fact that myeloarchitecture has itself been sadly neglected in neuroanatomy, neurology, cognitive science, and neuroradiology for close to a century,
since the initial pioneering work of Thudichum (1884), Vogt
and Vogt (1919), and Flechsig (1920). It is only recently that
imaging neuroscientists (Geyer, Weiss, Reimann, Lohmann, &
Turner, 2011; Glasser & Van Essen, 2011; Sereno, Lutti,
Weiskopf, & Dick, 2013) have begun to realize the enormous
Effects of Myelination
What functional benefits and disadvantages does myelination
of axons confer? Exploring this question may lead to rapid
progress in understanding the functional roles of cortical
areas identifiable by their distinctive patterns of myelination
and better understanding of changes in brain structure related
to maturation and learning. There are five important effects,
which may be simply stated:
Myelination of axons
(a) accelerates the conduction speed of action potentials by an
order of magnitude (Waxman, 1980),
(b) greatly decreases energy cost of transmission (Harris &
Attwell, 2012),
139
140
problem appears. Maps of MWF show much greater inhomogeneity throughout the white matter than do T1 maps or MTR
maps. Histograms of T1 and MTR are very sharply peaked at
values corresponding to white matter, with a variance of perhaps
20%, but MWF values can vary systematically by a factor of up to
two from region to region (e.g., Zhang et al., 2014). Clearly,
these methods are measuring different aspects of myelin.
In order to resolve this discrepancy, it is tempting to suggest
that MWF measures all the myelin in a given voxel, while T1 and
MTR maps sample only the myelin that is in close proximity to
relatively free intracellular water, that is, myelin adjacent to the
axonal lumen or surrounding the outer layer of the myelin
sheath. There is already evidence that the exchange time of
water between compartments in white matter is more than
half a second (Kalantari, Laule, Bjarnason, Vavasour, &
MacKay, 2011). This is much longer than the presumed residence time of water molecules at the membranes optimal
relaxing sites (end groups of cholesterol and cerebroside). In
this model, then, the processes resulting in T1 relaxation and
magnetization transfer are localized only to the surface layers of
myelin, the inner layers having insufficiently rapid interchange,
either by spin transfer or chemical exchange, to interact with the
free water. If this model is correct, combining results from MWF
and T1/MTR mapping may offer a simple opportunity to infer
maps of other aspects of white matter myelin, such as the mean
number of wraps and perhaps the mean axonal diameter.
One drawback of MWF mapping is the duration required
for data collection. While this has recently been accelerated
using more efficient acquisition methods such as GRASE
(Prasloski et al., 2012), the time needed is still more than
double that required for an MP2RAGE map of T1 with equivalent spatial resolution. It needs to be mentioned that rapid
acquisition methods such as mcDESPOT that require multivariate fitting of data with prior estimation of several variables
have been shown to provide unrealistic values of MWF
(Lankford & Does, 2013; Zhang et al., 2014).
References
Barbier, E. L., Marrett, S., Danek, A., Vortmeyer, A., van Gelderen, P., Duyn, J., et al.
(2002). Imaging cortical anatomy by high-resolution MR at 3.0 T: Detection of the
stripe of Gennari in visual area 17. Magnetic Resonance in Medicine, 48,
735738.
Bridge, H., Clare, S., Jenkinson, M., Jezzard, P., Parker, A. J., & Matthews, P. M.
(2005). Independent anatomical and functional measures of the V1/V2 boundary in
human visual cortex. Journal of Vision, 5, 93102.
Brody, B. A., Kinney, H. C., Kloman, A. S., & Gilles, F. H. (1987). Sequence of central
nervous system myelination in human infancy. I. An autopsy study of myelination.
Journal of Neuropathology and Experimental Neurology, 46(3), 283301.
Callaghan, M. F., Helms, G., Lutti, A., Mohammadi, S., & Weiskopf, N. (2014). A
general linear relaxometry model of R1 using imaging data. Magnetic Resonance in
Medicine, http://dx.doi.org/10.1002/mrm.25210.
Ceckler, T. L., Wolff, S. D., Yip, V., Simon, S. A., & Balaban, R. S. (1992). Dynamic and
chemical factors affecting water proton relaxation by macromolecules. Journal of
Magnetic Resonance, 98, 637645.
Clark, V. P., Courchesne, E., & Grafe, M. (1992). In vivo myeloarchitectonic analysis of
human striate and extrastriate cortex using magnetic resonance imaging. Cerebral
Cortex, 2, 417424.
Czopka, T., Ffrench-Constant, C., & Lyons, D. A. (2013). Individual oligodendrocytes
have only a few hours in which to generate new myelin sheaths in vivo.
Developmental Cell, 25(6), 599609.
Dortch, R. D., Moore, J., Li, K., Jankiewicz, M., Gochberg, D. F., Hirtle, J. A., et al.
(2013). Quantitative magnetization transfer imaging of human brain at 7 T.
NeuroImage, 64, 640649.
Dubois, J., Dehaene-Lambertz, G., Kulikova, S., Poupon, C., Huppi, P. S., &
Hertz-Pannier, L. (2013). The early development of brain white matter: A review of
imaging studies in fetuses, newborns and infants. Neuroscience, pii: S0306-4522
(13)01069-5.
Flechsig, P. (1920). Anatomie des menschlichen Gehirns und Ruckenmarks auf
myelogenetischer Grundlage. Leipzig: G. Thieme.
Fukunaga, M., Li, T. Q., van Gelderen, P., de Zwart, J. A., Shmueli, K., Yao, B., et al.
(2010). Layer-specific variation of iron content in cerebral cortex as a source of MRI
contrast. Proceedings of the National Academy of Sciences of the United States of
America, 107(8), 38343839.
Geyer, S., & Turner, R. (Eds.). (2013). Microstructural parcellation of the human
cerebral cortex from Brodmanns post-mortem map to in vivo mapping with highfield magnetic resonance imaging. Heidelberg: Springer.
Geyer, S., Weiss, M., Reimann, K., Lohmann, G., & Turner, R. (2011). Microstructural
parcellation of the human cerebral cortex From Brodmanns post-mortem map to
in vivo mapping with high-field magnetic resonance imaging. Frontiers in Human
Neuroscience, 5, 19.
Glasser, M. F., & Van Essen, D. C. (2011). Mapping human cortical areas in vivo based
on myelin content as revealed by T1- and T2-weighted MRI. Journal of
Neuroscience, 31(32), 1159711616.
Grydeland, H., Walhovd, K. B., Tamnes, C. K., Westlye, L. T., & Fjell, A. M. (2013).
Intracortical myelin links with performance variability across the human lifespan:
Results from T1- and T2-weighted MRI myelin mapping and diffusion tensor
imaging. Journal of Neuroscience, 33(47), 1861818630.
Harris, J. J., & Attwell, D. (2012). The energetics of CNS white matter. Journal of
Neuroscience, 32(1), 356371.
Helms, G., Dathe, H., & Dechent, P. (2010). Modeling the influence of TR and excitation
flip angle on the magnetization transfer ratio (MTR) in human brain obtained
from 3D spoiled gradient echo MRI. Magnetic Resonance in Medicine, 64(1),
177185.
141
Jones, D. K., Knosche, T. R., & Turner, R. (2013). White matter integrity, fiber count,
and other fallacies: the dos and donts of diffusion MRI. Neuroimage, 73,
239254.
Kalantari, S., Laule, C., Bjarnason, T. A., Vavasour, I. M., & MacKay, A. L. (2011).
Insight into in vivo magnetization exchange in human white matter regions.
Magnetic Resonance in Medicine, 66(4), 11421151.
Koenig, S. H. (1991). Cholesterol of myelin is the determinant of gray-white contrast in
MRI of brain. Magnetic Resonance in Medicine, 20(2), 285291.
Koenig, S. H., Brown, R. D., 3rd, Spiller, M., & Lundbom, N. (1990). Relaxometry of
brain: Why white matter appears bright in MRI. Magnetic Resonance in Medicine,
14(3), 482495.
Kucharczyk, W., Macdonald, P. M., Stanisz, G. J., & Henkelman, R. M. (1994).
Relaxivity and magnetization transfer of white matter lipids at MR imaging:
Importance of cerebrosides and pH. Radiology, 192(2), 521529.
Lankford, C. L., & Does, M. D. (2013). On the inherent precision of mcDESPOT.
Magnetic Resonance in Medicine, 69(1), 127136.
Lovden, M., Wenger, E., Martensson, J., Lindenberger, U., & Backman, L. (2013).
Structural brain plasticity in adult learning and development. Neuroscience and
Biobehavioral Reviews, 37(9 Pt B), 22962310.
MacKay, A., Whittall, K., Adler, J., Li, D., Paty, D., & Graeb, D. (1994). In vivo
visualization of myelin water in brain by magnetic resonance. Magnetic Resonance
in Medicine, 31(6), 673677.
Marques, J. P., Kober, T., Krueger, G., van der Zwaag, W., Van de Moortele, P. F., &
Gruetter, R. (2010). MP2RAGE, a self bias-field corrected sequence for improved
segmentation and T1-mapping at high field. NeuroImage, 49(2), 12711281.
McGee, A. W., Yang, Y., Fischer, Q. S., Daw, N. W., & Strittmatter, S. M. (2005).
Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor.
Science, 309(5744), 22222226.
Ng, W. P., Cartel, N., Roder, J., Roach, A., & Lozano, A. (1996). Human central nervous
system myelin inhibits neurite outgrowth. Brain Research, 720(12), 1724.
Prasloski, T., Rauscher, A., MacKay, A. L., Hodgson, M., Vavasour, I. M., Laule, C.,
et al. (2012). Rapid whole cerebrum myelin water imaging using a 3D GRASE
sequence. NeuroImage, 63(1), 533539.
Rooney, W. D., Johnson, G., Li, X., Cohen, E. R., Kim, S. G., Ugurbil, K., et al. (2007).
Magnetic field and tissue dependencies of human brain longitudinal 1H2O
relaxation in vivo. Magnetic Resonance in Medicine, 57(2), 308318.
Sanchez-Panchuelo, R. M., Francis, S. T., Schluppeck, D., & Bowtell, R. W. (2012).
Correspondence of human visual areas identified using functional and
anatomical MRI in vivo at 7 T. Journal of Magnetic Resonance Imaging, 35(2),
287299.
Scholz, J., Klein, M. C., Behrens, T. E., & Johansen-Berg, H. (2009). Training
induces changes in white-matter architecture. Nature Neuroscience, 12, 13701371.
Sereno, M. I., Lutti, A., Weiskopf, N., & Dick, F. (2013). Mapping the human cortical
surface by combining quantitative T(1) with retinotopy. Cerebral Cortex, 23(9),
22612268.
Sherman, D. L., & Brophy, P. J. (2005). Mechanisms of axon ensheathment and myelin
growth. Nature Reviews Neuroscience, 6(9), 683690.
Siegel, G. J., Agranoff, B. W., & Gavulic, L. M. (1999). Basic neurochemistry:
Molecular, cellular and medical aspects (6th ed.). Philadelphia: Lippincott-Raven.
Simons, M., & Lyons, D. A. (2013). Axonal selection and myelin sheath generation in
the central nervous system. Current Opinion in Cell Biology, 25(4), 512519.
Snaidero, N., Mobius, W., Czopka, T., Hekking, L. H., Mathisen, C., Verkleij, D., et al.
(2014). Myelin membrane wrapping of CNS axons by PI(3,4,5)P3-dependent
polarized growth at the inner tongue. Cell, 156(12), 277290.
Staal, J. A., & Vickers, J. C. (2011). Selective vulnerability of non-myelinated axons to
stretch injury in an in vitro co-culture system. Journal of Neurotrauma, 28(5),
841847.
Stuber, C., Morawski, M., Schafer, A., Labadie, C., Wahnert, M., Leuze, C., et al. (2014).
Myelin and iron concentration in the human brain: A quantitative study of MRI
contrast. NeuroImage, 93, 95106.
Tardif, C. L., Dinse, J., Schafer, A., Turner, R., & Bazin, P.-L. (2013). Multi-modal
surface-based alignment of cortical areas using intra-cortical T1 contrast. In
Multimodal brain image analysis (pp. 222232). Lecture notes in computer
science8159, (pp. 222232).
Thudichum, J. L.W (1884). A treatise on the chemical constitution of the brain. London:
Baillie`re, Tindall, and Cox.
Turner, R. (2013). Where matters: New approaches to brain analysis. In: S. Geyer & R.
Turner (Eds.), Microstructural parcellation of the human cerebral cortex. Heidelberg:
Springer.
Vogt, C., & Vogt, O. (1919). Allgemeinere Ergebnisse unserer Hirnforschung. Journal
fur Psychologie und Neurologie, 25, 279461.
Wake, H., Lee, P. R., & Fields, R. D. (2011). Control of local protein synthesis and initial
events in myelination by action potentials. Science, 333(6049), 16471651.
142
Young, I. R., Burl, M., Clarke, G. J., Hall, A. S., Pasmore, T., Collins, A. G., et al. (1981).
Magnetic resonance properties of hydrogen: Imaging the posterior fossa. AJR.
American Journal of Roentgenology, 137(5), 895901.
Young, K. M., Psachoulia, K., Tripathi, R. B., Dunn, S. J., Cossell, L., Attwell, D., et al.
(2013). Oligodendrocyte dynamics in the healthy adult CNS: Evidence for myelin
remodeling. Neuron, 77(5), 873885.
Zhang, J., Kolind, S. H., Laule, C., & Mackay, A. L. (2014). Comparison of myelin water
fraction from multiecho T2 decay curve and steady-state methods. Magnetic
Resonance in Medicine, http://dx.doi.org/10.1002/mrm.25125.
Introduction
Using light to noninvasively study the brain is made possible
by the fact that many biological tissues, including human skin
and bone, are relatively transparent to near-infrared light. The
exploitation of this near-infrared window in 1977 resulted in
the first spectroscopic measurements of the brain in vivo, proving that near-infrared light can traverse the human scalp and
skull and return to be measured at the surface (Jobsis, 1977).
The existence of this window is particularly advantageous
because there are a number of physiologically interesting
molecules that exhibit distinct absorption spectra in the
near-infrared range, most notably oxyhemoglobin and deoxyhemoglobin. Near-infrared spectroscopy (NIRS), in its simplest form, is the measurement of changes in the
concentration of these two molecules. Using a single source
location emitting at two wavelengths of near-infrared light and
a single detector (which constitutes one channel), NIRS systems can determine the changes in concentration of both
hemoglobin species in the tissue through which the detected
NIR light has traveled. The ability to measure changes in oxyhemoglobin concentration and deoxyhemoglobin concentration at high temporal resolution allows NIRS to be used to
study the functional response of the brain to external stimuli.
The overcompensation of the cerebral vasculature to the
increased oxygen demand of activated groups of neurons
gives rise to a hemodynamic response, the same physiological
phenomenon that produces the blood oxygen level-dependent
(BOLD) signal of functional magnetic resonance imaging
(fMRI; Logothetis, Pauls, Augath, Trinath, & Oeltermann,
2001). By measuring this hemodynamic response to external
stimuli, NIRS has been used extensively to study healthy brain
function and the impact of cerebral pathology on functional
hemodynamics. This specific use of near-infrared techniques is
now often referred to as functional NIRS, or fNIRS (Boas,
Elwell, Ferrari, & Taga, 2014).
While fNIRS is an effective method of investigating brain
function, the techniques spatial resolution is limited by the
separation between sources and detectors, which is typically
between 20 and 30 cm. However, by extrapolating fNIRS
approaches and applying dense arrays of sources and detectors
that include a range of sourcedetector separations, spatial
information can be obtained in all three dimensions (Boas,
Chen, Grebert, & Franceschini, 2004; Correia, Banga, Everdell,
Gibson, & Hebden, 2009). Although there is a range of nomenclature, this approach is now most commonly referred to as
diffuse optical tomography, or diffuse optical topography
(DOT). While the rarity of absorption interactions allows
near-infrared light to traverse several centimeters of tissue, the
predominance of scattering interactions renders the light field
diffuse, placing a fundamental limit on the resolution of DOT
methods. However, with careful hardware design and the
Theoretical Basis
NIRS relies on an understanding of how light of a given wavelength interacts with tissue. The intensity of light that will pass
through a purely absorbing medium is determined by a simple
exponential relationship, with the intensity decaying exponentially with optical path length. However, biological tissues are
not purely absorbing. At near-infrared wavelengths, scattering
is by far the dominant interaction. In such a medium, the path
traversed by each photon resembles a random walk, increasing
the average optical path length and thus increasing the likelihood of absorption. As a result, the simple exponential relationship must be modified to account for the effect of
scattering. The modified BeerLambert law states that for a
given wavelength of light,
I
exDma G
I0
[1]
where I0 and I are the input and detected intensities, respectively, x is the separation between source and detector, and ma is
the absorption coefficient of the medium. In a medium containing multiple absorbers, the total absorption coefficient is simply
a linear sum of the absorption coefficients of each absorber,
which is proportional to the concentration of that absorber in
the medium. The loss of intensity due to photons being scattered away from the detector are represented by G. The variable
D is the differential path length factor (or DPF). The DPF is
dependent upon the reduced scattering coefficient ms, the
absorption coefficient ma, and the geometry of the source and
detector. The product xD represents the average optical path
length of photons that reach the detector. For a nonzero scattering coefficient, the DPF will always be greater than 1.
Because of the complexities of optically coupling a NIR
source to biological tissue, I0 of eqn [1] is generally unknown.
Similarly, the loss factor G is difficult to calculate. These
unknowns can be eliminated by measuring the changes in
optical intensity between two distinct states, such that
http://dx.doi.org/10.1016/B978-0-12-397025-1.00016-6
143
144
ln
I2
I1
I2
ln
ln
xDDma
I0
I0
I1
[2]
Image Reconstruction
Although the resolution of any diffuse optical system is limited
by the dominance of scattering interactions in biological tissues, all multichannel diffuse optical systems provide significant spatial information. To extract the maximum available
spatial information from diffuse optical data, a detailed modeling and image reconstruction paradigm must be applied. Linear image reconstruction for diffuse optical approaches
assumes that an image of changes in chromophore concentration (DX) can be computed via
DX J 1 DY
[3]
Instrumentation
There are three distinct categories of NIRS systems based on
the type of measurement they obtain. The simplest, least
expensive, and most common are known as continuous
Scalp
HbO
Source
Gray matter
(cortex)
Whiter
matter
Detector
D Concentration (mM)
Cerebrospinal Skull
fluid (CSF)
3 cm
(a)
145
Human brain
14
12
10
8
6
4
2
0
-2
-4
HbT
HbR
-5
(b)
-5
10
Time (s)
15
20
(mM-cm)
0.02
-0.02
(c)
(d)
2.7
0.3
-0.1
-0.8
DHbO
(0.1 mMol)
(e)
(f)
Figure 1 Panel (a) depicts a single sourcedetector pair (channel) at the scalp and illustrates the tissues to which the channel is sensitive (adapted with
permission from Hillman, E. M. C. (2007). Optical brain imaging in vivo: Techniques and applications from animal to man. Journal of Biomedical Optics,
12, 051402). Panel (b) shows a classic hemodynamic response function, as recorded by fNIRS over the primary motor cortex. Time zero marks the
onset of a 2 s duration motor task (adapted with permission from Huppert, T. J., Hoge, R. D., Diamond, S. G., Franceschini, M. A., Boas, D. A., (2006). A
temporal comparison of BOLD, ASL, and NIRS hemodynamic responses to motor stimuli in adult humans. NeuroImage 29, 368382. doi:16/j.
neuroimage.2005.08.065). Panel (c) depicts an imaging array that allows the production of 2-D images of functional activation that can be mapped on
to a model of the cerebral cortex, as shown in panel (d) (adapted with permission from Takeuchi, M., Hori, E., Takamoto, K., Tran, A., Satoru, K.,
Ishikawa, A., et al. (2009). Brain cortical mapping by simultaneous recording of functional near infrared spectroscopy and electroencephalograms
from the whole brain during right median nerve stimulation. Brain Topography, 22, 197214. doi:10.1007/s10548-009-0109-2). Panel (e) shows the
layout of a high-density array used for diffuse optical tomography (DOT), and panel (f) shows corresponding 3-D functional activation maps reconstructed
using a realistic head model (adapted with permission from Hassanpour, M. S., White, B. R., Eggebrecht, A. T., Ferradal, S. L., Snyder, A. Z., Culver, J. P.
(2014). Statistical analysis of high density diffuse optical tomography. NeuroImage, 85 (Part 1), 104116. doi:10.1016/j.neuroimage.2013.05.105).
146
Array Design
The vast majority of fNIRS systems employ an array of optical
fibers that carry light between the instrumentation and the
scalp. The arrangement of source and detector fibers on the
scalp has a significant impact on the utility and accuracy of
the resulting data. The longer the separation between a source
and a detector on the scalp, the deeper into the tissue the average
detected photon will travel. The deeper the average photon
travels, the deeper the regions of tissue to which that channel
will be sensitive (Arridge, 1995). In practice, a balance must be
obtained between the sourcedetector separation and the
amount of light available for detection, which drops by approximately 1 order of magnitude for every 10 mm of separation.
The majority of detectors will not be sensitive enough to detect
light that has traversed more than 4050 mm, which limits the
depths to which fNIRS is typically sensitive. A channel with a
separation of 30 mm will sample the superficial cortex in most
adults, while obtaining a sufficient number of photons to ensure
a high signal quality.
The array of optical fibers can consist of a single channel
(Figure 1(a)) or can be designed to be conducive to the production of images. The simplest form of imaging array consists
of a fixed grid pattern, (Figure 1(c)). Such approaches are
limited to providing two-dimensional information because
any location in the target tissue is only sampled by a single
channel. These approaches are often referred to as DOT.
To produce images that contain information in the third
(depth) dimension, that is, to perform DOT, the array must
provide overlapping measurements (Figure 1(e)). Ideally,
these measurements will include a range of sourcedetector
separations up to 45 mm to ensure cortical sensitivity and
short (<15 mm) separations to allow superficial tissues to be
independently sampled. This is important because for a channel to sample the brain, light must travel through the scalp and
skull to the brain and back again. As a result, diffuse optical
techniques are vulnerable to contamination from scalp hemodynamics. While this interference can often be averaged out,
by sampling it directly with short-separation channels, it can
be directly and efficiently removed (Gagnon, Yucel, Boas, &
Cooper, 2014).
Applications
An excellent survey of the broad range of applications of these
technologies can be found in a recent special issue of Neuroimage, which celebrates 20 years of fNIRS. The issue contains
58 papers, a summary of which is provided in the introductory
article (Boas et al., 2014). The applications described by these
papers can be categorized into five domains: neurodevelopment, perception and cognition, motor control, psychiatric
disorders, and neurology and anesthesia.
Neurodevelopment studies are the largest growth area for
fNIRS as the portability and noninvasive nature of the technique overcome many of the challenges associated with performing neuroimaging studies of infants and children.
Numerous studies are elucidating language development,
visual-working memory, behavioral development, and
resting-state functional connectivity (Cristia et al., 2013;
Homae et al., 2010; Lloyd-Fox, Blasi, & Elwell, 2010). Exciting
recent clinical applications have demonstrated that fNIRS can
help us to better understand the atypical neurodevelopment
associated with attention deficit hyperactivity and autism
spectrum disorders (Fox, Wagner, Shrock, Tager-Flusberg, &
Nelson, 2013; Monden et al., 2012).
The largest clinical application of fNIRS is currently in the
study of psychiatric disorders, including schizophrenia,
affective disorders, and pathological aging. A comprehensive
review by Ehlis et al. describes investigations of the phenomenological characteristics of these psychiatric disorders, treatment effects, and genetic influences (Ehlis, Schneider,
Dresler, & Fallgatter, 2014).
Multimodal Applications
A major advantage of fNIRS is the ease with which it can be
combined with other neuroimaging modalities. Because glass
and plastic optical fibers are used to deliver light to the head of
the subject, fNIRS can be used in combination with magnetoencephalography (MEG) and MRI without producing susceptibility artifacts and in combination with electroencephalography
(EEG) without producing electrical artifacts.
Simultaneous fNIRS and EEG or MEG is appealing because
of the ability to explore neurovascular coupling by obtaining
concurrent measures of the neuronal and hemodynamic
responses to stimuli. Simultaneous fNIRS and MEG has been
used to study neurovascular coupling and habituation effects
in humans using median-nerve stimulation (Ou et al., 2009).
Combining fNIRS with EEG has shown great promise in the
study of epileptic disorders. Epileptic seizures are unpredictably and often in association with excessive motion. Because
fNIRS is relatively insensitive to motion artifacts and can be
applied for long periods in combination with EEG, it has been
shown to have great potential in the study of the neurovascular
coupling of ictal and interictal events (Cooper et al., 2011;
Nguyen et al., 2013; Roche-Labarbe et al., 2008).
The combination of fNIRS with fMRI has been used to cross
validate the two modalities (Eggebrecht et al., 2012; Steinbrink
et al., 2006) and to develop a better understanding of the
physiological processes that underlie both techniques. Early
References
Arridge, S. R. (1995). Photon-measurement density functions. Part I: Analytical forms.
Applied Optics, 34, 73957409. http://dx.doi.org/10.1364/AO.34.007395.
Austin, T., Gibson, A. P., Branco, G., Yusof, R. M., Arridge, S. R., Meek, J. H., et al.
(2006). Three dimensional optical imaging of blood volume and oxygenation in the
neonatal brain. NeuroImage, 31, 14261433. http://dx.doi.org/10.1016/j.
neuroimage.2006.02.038.
Boas, D. A., Chen, K., Grebert, D., & Franceschini, M. A. (2004). Improving the diffuse
optical imaging spatial resolution of the cerebral hemodynamic response to brain
activation in humans. Optics Letters, 29, 15061508.
Boas, D. A., Elwell, C. E., Ferrari, M., & Taga, G. (2014). Twenty years of functional
near-infrared spectroscopy: Introduction for the special issue. NeuroImage, 85(Part
1), 15. http://dx.doi.org/10.1016/j.neuroimage.2013.11.033.
Boas, D. A., Pitris, C., & Ramanujam, N. (2012). Handbook of biomedical optics. Boca
Raton: CRC Press.
Cooper, R. J., Caffini, M., Dubb, J., Custo, A., Tsuzuki, D., Fischl, B., et al. (2012).
Validating atlas-guided DOT: A comparison of diffuse optical tomography informed
by atlas and subject-specific anatomies. NeuroImage, http://dx.doi.org/10.1016/j.
neuroimage.2012.05.031.
Cooper, R. J., Hebden, J. C., OReilly, H., Mitra, S., Michell, A. W., Everdell, N. L., et al.
(2011). Transient haemodynamic events in neurologically compromised infants:
A simultaneous EEG and diffuse optical imaging study. NeuroImage, 55,
16101616, 16/j.neuroimage.2011.01.022.
Cooper, C. E., & Springett, R. (1997). Measurement of cytochrome oxidase and
mitochondrial energetics by nearinfrared spectroscopy. Philosophical
Transactions of the Royal Society of London. Series B: Biological Sciences, 352,
669676. http://dx.doi.org/10.1098/rstb.1997.0048.
Correia, T., Banga, A., Everdell, N. L., Gibson, A. P., & Hebden, J. C. (2009). A
quantitative assessment of the depth sensitivity of an optical topography system
using a solid dynamic tissue-phantom. Physics in Medicine and Biology, 54,
62776286. http://dx.doi.org/10.1088/0031-9155/54/20/016.
147
Cristia, A., Dupoux, E., Hakuno, Y., Lloyd-Fox, S., Schuetze, M., Kivits, J., et al. (2013).
An online database of infant functional near infrared spectroscopy studies: A
community-augmented systematic review. PLoS ONE, 8, e58906. http://dx.doi.org/
10.1371/journal.pone.0058906.
Davis, T. L., Kwong, K. K., Weisskoff, R. M., & Rosen, B. R. (1998). Calibrated
functional MRI: Mapping the dynamics of oxidative metabolism. Proceedings of the
National Academy of Sciences, 95, 18341839, http://dx.doi.org/doi: VL 95.
Eggebrecht, A. T., White, B. R., Ferradal, S. L., Chen, C., Zhan, Y., Snyder, A. Z., et al.
(2012). A quantitative spatial comparison of high-density diffuse optical
tomography and fMRI cortical mapping. NeuroImage, 61, 11201128. http://dx.doi.
org/10.1016/j.neuroimage.2012.01.124.
Ehlis, A.-C., Schneider, S., Dresler, T., & Fallgatter, A. J. (2014). Application of
functional near-infrared spectroscopy in psychiatry. NeuroImage, 85(Part 1),
478488. http://dx.doi.org/10.1016/j.neuroimage.2013.03.067.
Enfield, L., Cantanhede, G., Douek, M., Ramalingam, V., Purushotham, A., Hebden, J.,
et al. (2013). Monitoring the response to neoadjuvant hormone therapy for locally
advanced breast cancer using three-dimensional time-resolved optical
mammography. Journal of Biomedical Optics, 18, 56012. http://dx.doi.org/
10.1117/1.JBO.18.5.056012.
Enfield, L. C., Gibson, A. P., Everdell, N. L., Delpy, D. T., Schweiger, M., Arridge, S. R.,
et al. (2007). Three-dimensional time-resolved optical mammography of the
uncompressed breast. Applied Optics, 46, 36283638. http://dx.doi.org/10.1364/
AO.46.003628.
Ferradal, S. L., Eggebrecht, A. T., Hassanpour, M., Snyder, A. Z., & Culver, J. P. (2013).
Atlas-based head modeling and spatial normalization for high-density diffuse
optical tomography: In vivo validation against fMRI. NeuroImage, 10.1016/j.
neuroimage.2013.03.069.
Fox, P. T., & Raichle, M. E. (1986). Focal physiological uncoupling of cerebral
blood flow and oxidative metabolism during somatosensory stimulation in
human subjects. Proceedings of the National Academy of Sciences, 83,
11401144.
Fox, S. E., Wagner, J. B., Shrock, C. L., Tager-Flusberg, H., & Nelson, C. A. (2013).
Neural processing of facial identity and emotion in infants at high-risk for autism
spectrum disorders. Frontiers in Human Neuroscience, 7, http://dx.doi.org/
10.3389/fnhum.2013.00089.
Franceschini, M. A., Thaker, S., Themelis, G., Krishnamoorthy, K. K., Bortfeld, H.,
Diamond, S. G., et al. (2007). Assessment of infant brain development with
frequency-domain near-infrared spectroscopy. Pediatric Research, 61, 546551.
http://dx.doi.org/10.1203/pdr.0b013e318045be99.
Gagnon, L., Yucel, M. A., Boas, D. A., & Cooper, R. J. (2014). Further improvement in
reducing superficial contamination in NIRS using double short separation
measurements. NeuroImage, 85(Part 1), 127135. http://dx.doi.org/10.1016/j.
neuroimage.2013.01.073.
Gibson, A. P., Austin, T., Everdell, N. L., Schweiger, M., Arridge, S. R., Meek, J. H., et al.
(2006). Three-dimensional whole-head optical tomography of passive motor
evoked responses in the neonate. NeuroImage, 30, 521528.
Gibson, A. P., Hebden, J. C., & Arridge, S. R. (2005). Recent advances in diffuse optical
imaging. Physics in Medicine and Biology, 50, R1R43.
Habermehl, C., Holtze, S., Steinbrink, J., Koch, S. P., Obrig, H., Mehnert, J., et al.
(2012). Somatosensory activation of two fingers can be discriminated with
ultrahigh-density diffuse optical tomography. NeuroImage, 59, 32013211. http://
dx.doi.org/10.1016/j.neuroimage.2011.11.062.
Hebden, J. C., Gibson, A., Yusof, R. M., Everdell, N., Hillman, E. M.C, Delpy, D. T., et al.
(2002). Three-dimensional optical tomography of the premature infant brain.
Physics in Medicine and Biology, 47, 41554166. http://dx.doi.org/10.1088/00319155/47/23/303.
Homae, F., Watanabe, H., Otobe, T., Nakano, T., Go, T., Konishi, Y., et al. (2010).
Development of global cortical networks in early infancy. Journal of Neuroscience,
30, 48774882. http://dx.doi.org/10.1523/JNEUROSCI.5618-09.2010.
Huppert, T. J., Allen, M. S., Diamond, S. G., & Boas, D. A. (2009). Estimating cerebral
oxygen metabolism from fMRI with a dynamic multicompartment Windkessel
model. Human Brain Mapping, 30, 15481567. http://dx.doi.org/10.1002/
hbm.20628.
Huppert, T. J., Hoge, R. D., Diamond, S. G., Franceschini, M. A., & Boas, D. A. (2006).
A temporal comparison of BOLD, ASL, and NIRS hemodynamic responses to motor
stimuli in adult humans. NeuroImage, 29, 368382. doi:16/j.
neuroimage.2005.08.065.
Jobsis, F. F. (1977). Noninvasive, infrared monitoring of cerebral and myocardial
oxygen sufficiency and circulatory parameters. Science, 198, 12641267.
Lloyd-Fox, S., Blasi, A., & Elwell, C. E. (2010). Illuminating the developing brain: The
past, present and future of functional near infrared spectroscopy. Neuroscience and
Biobehavioral Reviews, 34, 269284. http://dx.doi.org/10.1016/j.
neubiorev.2009.07.008.
148
Logothetis, N. K., Pauls, J., Augath, M., Trinath, T., & Oeltermann, A. (2001).
Neurophysiological investigation of the basis of the fMRI signal. Nature, 412,
150157. http://dx.doi.org/10.1038/35084005.
Mintun, M. A., Lundstrom, B. N., Snyder, A. Z., Vlassenko, A. G., Shulman, G. L., &
Raichle, M. E. (2001). Blood flow and oxygen delivery to human brain during
functional activity: Theoretical modeling and experimental data. Proceedings of the
National Academy of Sciences, 98, 68596864. http://dx.doi.org/10.1073/
pnas.111164398.
Monden, Y., Dan, H., Nagashima, M., Dan, I., Tsuzuki, D., Kyutoku, Y., et al. (2012).
Right prefrontal activation as a neuro-functional biomarker for monitoring acute
effects of methylphenidate in ADHD children: An fNIRS study. Neuroimaging
Clinics, 1, 131140. http://dx.doi.org/10.1016/j.nicl.2012.10.001.
Nguyen, D. K., Tremblay, J., Pouliot, P., Vannasing, P., Florea, O., Carmant, L., et al.
(2013). Noninvasive continuous functional near-infrared spectroscopy combined
with electroencephalography recording of frontal lobe seizures. Epilepsia, 54,
331340. http://dx.doi.org/10.1111/epi.12011.
OLeary, M. A., Boas, D. A., Chance, B., & Yodh, A. G. (1995). Experimental images of
heterogeneous turbid media by frequency-domain diffusing-photon tomography.
Optics Letters, 20, 426428. http://dx.doi.org/10.1364/OL.20.000426.
Ou, W., Nissila, I., Radhakrishnan, H., Boas, D. A., Hamalainen, M. S., &
Franceschini, M. A. (2009). Study of neurovascular coupling in humans
via simultaneous magnetoencephalography and diffuse optical imaging
acquisition. NeuroImage, 46, 624632. http://dx.doi.org/10.1016/j.
neuroimage.2009.03.008.
Roche-Labarbe, N., Zaaimi, B., Berquin, P., Nehlig, A., Grebe, R., & Wallois, F. (2008).
NIRS-measured oxy- and deoxyhemoglobin changes associated with EEG spikeand-wave discharges in children. Epilepsia, http://dx.doi.org/10.1111/j.15281167.2008.01711.x.
Scholkmann, F., Kleiser, S., Metz, A. J., Zimmermann, R., Mata Pavia, J., Wolf, U., et al.
(2014). A review on continuous wave functional near-infrared spectroscopy and
imaging instrumentation and methodology. NeuroImage, 85(Pt 1), 627. http://dx.
doi.org/10.1016/j.neuroimage.2013.05.004.
Steinbrink, J., Villringer, A., Kempf, F., Haux, D., Boden, S., & Obrig, H. (2006).
Illuminating the BOLD signal: Combined fMRI-fNIRS studies. Magnetic Resonance
Imaging, 24, 495505. doi:16/j.mri.2005.12.034.
Strangman, G., Culver, J. P., Thompson, J. H., & Boas, D. A. (2002). A quantitative
comparison of simultaneous BOLD fMRI and NIRS recordings during functional
brain activation. NeuroImage, 17, 719731. doi:06/nimg.2002.1227.
Tak, S., Jang, J., Lee, K., & Ye, J. C. (2010). Quantification of CMRO(2) without
hypercapnia using simultaneous near-infrared spectroscopy and fMRI
measurements. Physics in Medicine and Biology, 55, 32493269. http://dx.doi.org/
10.1088/0031-9155/55/11/017.
Tak, S., & Ye, J. C. (2014). Statistical analysis of fNIRS data: A comprehensive review.
NeuroImage, 85(Part 1), 7291. http://dx.doi.org/10.1016/j.
neuroimage.2013.06.016.
Torricelli, A., Contini, D., Pifferi, A., Caffini, M., Re, R., Zucchelli, L., et al. (2014). Time
domain functional NIRS imaging for human brain mapping. NeuroImage, 85(Part 1),
2850. http://dx.doi.org/10.1016/j.neuroimage.2013.05.106.
Yucel, M. A., Huppert, T. J., Boas, D. A., & Gagnon, L. (2012). Calibrating the BOLD
signal during a motor task using an extended fusion model incorporating DOT,
BOLD and ASL data. NeuroImage, 61, 12681276. http://dx.doi.org/10.1016/j.
neuroimage.2012.04.036.
Zeff, B. W., White, B. R., Dehghani, H., Schlaggar, B. L., & Culver, J. P. (2007).
Retinotopic mapping of adult human visual cortex with high-density diffuse optical
tomography. Proceedings of the National Academy of Sciences, 104, 1216912174.
http://dx.doi.org/10.1073/pnas.0611266104.
Introduction
Scientific inquiry into the relationship between brain activity
and blood flow can be traced back to a series of experiments
performed in the late nineteenth century by Angelo Mosso,
showing changes in cerebral blood pulsation during the performance of various mental activities by patients with skull
defects (James, 1890). Later, Roy and Sherrington demonstrated increases in brain blood volume (and presumably
blood flow) in response to nerve stimulation of anesthetized
animals (Roy & Sherrington, 1890). In the 1940s, the ability to
obtain quantitative measures of whole brain blood flow was
demonstrated with the nitrous oxide method of Kety and
Schmidt (Kety & Schmidt, 1948; Small, 2004). Although further advances were made in the 1960s, extending this basic
approach to obtain regional measures of brain perfusion, it
was not until the introduction in the early 1970s of tomographic imaging methods, such as computed tomography
(CT) and positron emission tomography (PET), that the modern era of mapping of brain perfusion would begin (Raichle,
1998). These were followed in the early 1990s by the introduction of regional brain perfusion imaging methods using magnetic resonance imaging (MRI; Rosen, Belliveau, Vevea, &
Brady, 1990; Williams, Detre, Leigh, & Koretsky, 1992).
At present, methods for measuring brain perfusion in
humans include single-photon emission computed tomography,
PET, xenon-enhanced CT, dynamic perfusion CT, dynamic susceptibility contrast (DSC) MRI, and arterial spin labeling (ASL)
MRI (Wintermark et al., 2005). Building upon the basic principles described in the seminal work of Kety and Schmidt (Kety &
Schmidt, 1948), these methods are all based on the measurement of the concentration of a tracer that is delivered to and
cleared from the tissue by blood flow, with additional clearance
due to the natural decay of the tracer. For quantitative measures
of cerebral blood flow (CBF), PET is generally considered
the gold standard, as its accuracy has been validated in nonhuman primate models (Raichle, Martin, Herscovitch, Mintun,
& Markham, 1983). However, its adoption for routine measures
of CBF has been limited by the need for an arterial catheter, the
use of radioactive tracers, and the need for a cyclotron (Carroll
et al., 2002). Both CT and DSC-MRI are widely used to measure
perfusion in clinical settings (Wintermark et al., 2005), but their
application for brain mapping research studies has been limited
by the need to inject contrast agents and, in the case of CT,
concerns about exposure to ionizing radiation. In contrast, ASL
MRI uses arterial water as an endogenous tracer, obviating the
need for the injection of tracers, and the associated MRI image
acquisition process does not involve ionizing radiation. As a
result, ASL can provide measures of regional perfusion with
moderately high spatial resolution in a completely noninvasive
manner, making it amenable to repeated scans and longitudinal
studies. In addition, ASL is well suited to characterizing functional changes in perfusion. Because of these properties, the
ASL Methods
Most ASL methods measure CBF by taking the difference DM of
two sets of images: tag images, in which the magnetization of
arterial blood is inverted or saturated, and control images, in
which the magnetization of arterial blood is fully relaxed. The
difference between the control and tag images yields an image
that is proportional to the blood that has been delivered. To
reduce noise in the CBF estimate, a number of tag and control
images (e.g., 50 tag and 50 control) are typically acquired in an
interleaved fashion, and the average difference is computed.
The time between the acquisition of the tag images and that of
control images is on the order of 24 s, so that an ASL scan
with 100 total images takes 200400 s.
There are a variety of ASL methods that have been developed, and these methods can be divided into three main
classes: (1) pulsed ASL (PASL) in which short radio frequency
(RF) pulses are used to tag the blood over an extended spatial
region that is proximal to the imaging region of interest, (2)
continuous ASL (CASL) in which a long (on the order of several
seconds) RF waveform or train of pulses is used in conjunction
with gradient fields to tag flowing blood spins as they traverse
an irradiated plane (this class also includes pseudocontinuous
ASL or pCASL), and (3) velocity-selective ASL (VS-ASL) in which
an RF pulse train is applied that selectively saturates flowing
spins with no spatial selectivity.
Perfusion Quantification
The ASL difference signal DM not only is proportional to CBF
but also exhibits a complex dependence on a number of physiological parameters. Variations in these physiological parameters can cause systematic errors in the CBF measurements, and
the goal of quantitative ASL methods is to minimize these
http://dx.doi.org/10.1016/B978-0-12-397025-1.00017-8
149
150
INTRODUCTION TO ACQUISITION METHODS | Perfusion Imaging with Arterial Spin Labeling MRI
Signal-to-Noise Ratio
In a typical ASL experiment, about 1 s is allowed for the delivery of blood, corresponding to 1 ml of blood delivered to
100 ml of tissue for the typical CBF value of 60 ml per 100 g
per minute discussed previously. As a result, the overall magnetic resonance (MR) signal due to the delivered blood is only
about 1% of the total signal due to the tissue. This small
percentage contributes to the low intrinsic signal-to-noise
ratio (SNR) of ASL methods. Of the three major classes of
ASL methods, CASL has the highest SNR, followed by PASL,
and then VS-ASL (Chen et al., 2011; Wong, Buxton, & Frank,
1998b; Wong et al., 2006).
20
40
60
80
100
120
Figure 1 Examples of baseline cerebral blood flow (CBF) maps (top row), vascular territory maps (middle row), and functional activation maps (bottom
row). The baseline CBF maps show the spatial distribution of perfusion (with physiological units of milliliter per 100 g per minute) in the brain of a
healthy young volunteer. The vascular territory maps show the territories supplied by the right carotid artery (red), the left carotid artery (green), and the
vertebral arteries (blue). The functional activation maps show those brain regions in which the functional CBF response was significantly correlated
(p < 0.001, corrected for multiple comparisons) with the timing pattern of a visual stimulus (Image Credit: David S. Shin).
INTRODUCTION TO ACQUISITION METHODS | Perfusion Imaging with Arterial Spin Labeling MRI
Cardiac and respiratory fluctuations are a major source of
noise in ASL experiments, especially at higher field strengths.
These can be partially attenuated with physiological noise
reduction methods (Behzadi, Restom, Liau, & Liu, 2007;
Restom, Behzadi, & Liu, 2006) and background suppression
methods that attenuate the static tissue component. However,
background suppression methods can lead to an underestimation of CBF values (Garcia, Duhamel, & Alsop, 2005; Shin, Liu,
Wong, & Liu, 2011).
Image Acquisition
For ASL, the choice of the tagging method (PASL, CASL, and VSASL) is largely independent of the choice of imaging method. As
a result, ASL studies can take advantage of the wide array of 2-D
and 3-D MRI imaging pulse sequences that have been developed. For 2-D imaging, in which the imaging data are acquired
on a slice-by-slice basis, echo planar imaging and spiral
sequences are widely used (Wang et al., 2004). There is an
increasing use of 3-D acquisitions that can offer whole brain
coverage, simultaneous acquisition of all slices, and greater SNR
as compared with 2-D acquisitions (Duhamel & Alsop, 2004;
Fernandez-Seara et al., 2005; Gunther, Oshio, & Feinberg,
2005). With the simultaneous acquisition of slices in a 3-D
acquisition, the longitudinal relaxation of the tagged spins is
the same across slices, leading to a greater consistency in SNR as
compared with 2-D acquisitions, where the superior slices are
acquired at a longer inversion time (with greater relaxation of
the tagged spins) and can exhibit lower SNR as compared to the
inferior slices. There is typically a greater degree of throughplane blurring associated with 3-D acquisitions as compared
to 2-D methods, but these effects can be partly addressed
through the use of variable flip angles in the echo train or robust
multishot acquisitions (Nielsen & Hernandez-Garcia, 2012;
Tan, Hoge, Hamilton, Gunther, & Kraft, 2011).
Typical ASL image acquisition protocols provide CBF values
over the entire brain with a spatial resolution on the order of
35 mm. To improve SNR, the through-plane resolution is
often chosen to be slightly larger than the in-plane resolution
(e.g., 3 3 mm in-plane resolution with a 5 mm slice thickness). With the use of fast imaging sequences and higher
magnetic field strengths, ASL acquisitions with in-plane resolutions of 12 mm (and 58 mm slice thickness) have been
demonstrated (Grossman et al., 2009; Zuo et al., 2013).
151
152
INTRODUCTION TO ACQUISITION METHODS | Perfusion Imaging with Arterial Spin Labeling MRI
the need for methods to reduce physiological noise is especially pronounced. Retrospective image-based correction
methods have been shown to significantly reduce physiological noise for perfusion fMRI studies (Behzadi et al., 2007;
Restom et al., 2006).
Conclusion
ASL MRI offers the ability to image brain perfusion in a
completely noninvasive fashion, without the need for ionizing
radiation or injected tracers. Its accuracy and precision are
comparable or superior to those of alternate methods, such
as PET and CT. ASL MRI can provide measures of both baseline
perfusion and functional changes in perfusion with moderately high temporal and spatial resolution. ASL MRI has been
widely used for research studies, and its adoption for clinical
studies is growing with the increasing availability of this
method on standard MRI systems.
References
Aguirre, G. K., & Detre, J. A. (2012). The development and future of perfusion fMRI for
dynamic imaging of human brain activity. NeuroImage, 62, 12791285.
INTRODUCTION TO ACQUISITION METHODS | Perfusion Imaging with Arterial Spin Labeling MRI
Aguirre, G. K., Detre, J. A., & Wang, J. (2005). Perfusion fMRI for functional
neuroimaging. International Review of Neurobiology, 66, 213236.
Aguirre, G. K., Detre, J. A., Zarahn, E., & Alsop, D. C. (2002). Experimental design and
the relative sensitivity of BOLD and perfusion fMRI. NeuroImage, 15, 488500.
Ances, B., Vaida, F., Ellis, R., & Buxton, R. (2011). Testretest stability of calibrated
BOLD-fMRI in HIV and HIV subjects. NeuroImage, 54, 21562162.
Behzadi, Y., Restom, K., Liau, J., & Liu, T. T. (2007). A component based noise
correction method (CompCor) for BOLD and perfusion based fMRI. NeuroImage,
37, 90101.
Borogovac, A., & Asllani, I. (2012). Arterial Spin Labeling (ASL) fMRI: Advantages,
theoretical constrains, and experimental challenges in neurosciences. International
Journal of Biomedical Imaging, 2012, 818456.
Buxton, R. B. (2005). Quantifying CBF with arterial spin labeling. Journal of Magnetic
Resonance Imaging, 22, 723726.
Carroll, T. J., Teneggi, V., Jobin, M., Squassante, L., Treyer, V., Hany, T. F., et al.
(2002). Absolute quantification of cerebral blood flow with magnetic resonance,
reproducibility of the method, and comparison with H2(15)O positron emission
tomography. Journal of Cerebral Blood Flow and Metabolism, 22, 11491156.
Chen, Y., & Parrish, T. B. (2009). Caffeines effects on cerebrovascular reactivity and
coupling between cerebral blood flow and oxygen metabolism. NeuroImage, 44,
647652.
Chen, Y., Wang, D. J.J, & Detre, J. A. (2011). Testretest reliability of arterial spin
labeling with common labeling strategies. Journal of Magnetic Resonance Imaging,
33, 940949.
Chen, J. J., Wieckowska, M., Meyer, E., & Pike, G. B. (2008). Cerebral blood flow
measurement using fMRI and PET: A cross-validation study. International Journal of
Biomedical Imaging, 2008, 516359.
Chiarelli, P. A., Bulte, D. P., Gallichan, D., Piechnik, S. K., Wise, R., & Jezzard, P.
(2007). Flow-metabolism coupling in human visual, motor, and supplementary
motor areas assessed by magnetic resonance imaging. Magnetic Resonance in
Medicine, 57, 538547.
Dai, W., Robson, P. M., Shankaranarayanan, A., & Alsop, D. C. (2012). Reduced
resolution transit delay prescan for quantitative continuous arterial spin labeling
perfusion imaging. Magnetic Resonance in Medicine, 67, 12521265.
Davis, T. L., Kwong, K. K., Weisskoff, R. M., & Rosen, B. R. (1998). Calibrated
functional MRI: Mapping the dynamics of oxidative metabolism. Proceedings of the
National Academy of Sciences of the United States of America, 95, 18341839.
Donahue, M. J., Lu, H., Jones, C. K., Pekar, J. J., & Van Zijl, P. C.M (2006). An account
of the discrepancy between MRI and PET cerebral blood flow measures. A high-field
MRI investigation. NMR in Biomedicine, 19, 10431054.
Duhamel, G., & Alsop, D. C. (2004). Single-shot susceptibility insensitive whole brain
3D fMRI with ASL. In: 12th ISMRM scientific meeting, Kyoto, p. 518.
Duyn, J. H., Tan, C. X., van Gelderen, P., & Yongbi, M. N. (2001). High-sensitivity
single-shot perfusion-weighted fMRI. Magnetic Resonance in Medicine, 46, 8894.
Feinberg, D. A., Moeller, S., Smith, S. M., Auerbach, E., Ramanna, S., Glasser, M. F.,
et al. (2010). Multiplexed echo planar imaging for sub-second whole brain FMRI
and fast diffusion imaging. PLoS One, 5, e15710.
Feng, C.-M., Narayana, S., Lancaster, J. L., Jerabek, P. A., Arnow, T. L., Zhu, F., et al.
(2004). CBF changes during brain activation: fMRI vs. PET. NeuroImage, 22,
443446.
Fernandez-Seara, M. A., Wang, J., Wang, Z., Rao, H., Guenther, M., Feinberg, D. A.,
et al. (2005). Continuous arterial spin labelling perfusion measurements using
single shot 3D GRASE at 3 T. In: 13th ISMRM scientific meeting, Miami Beach,
p. 1160.
Garcia, D. M., Duhamel, G., & Alsop, D. C. (2005). Efficiency of inversion pulses for
background suppressed arterial spin labeling. Magnetic Resonance in Medicine, 54,
366372.
Gevers, S., van Osch, M. J., Bokkers, R. P., Kies, D. A., Teeuwisse, W. M., Majoie, C. B.,
et al. (2011). Intra- and multicenter reproducibility of pulsed, continuous and
pseudo-continuous arterial spin labeling methods for measuring cerebral perfusion.
Journal of Cerebral Blood Flow and Metabolism, 31(8), 17061715.
Grossman, E. J., Zhang, K., An, J., Voorhees, A., Inglese, M., Ge, Y., et al. (2009).
Measurement of deep gray matter perfusion using a segmented true-fast imaging
with steady-state precession (True-FISP) arterial spin-labeling (ASL) method at 3 T.
Journal of Magnetic Resonance Imaging, 29, 14251431.
Gunther, M. (2006). Efficient visualization of vascular territories in the human brain by
cycled arterial spin labeling MRI. Magnetic Resonance in Medicine, 56, 671675.
Gunther, M., Oshio, K., & Feinberg, D. A. (2005). Single-shot 3D imaging techniques
improve arterial spin labeling perfusion measurements. Magnetic Resonance in
Medicine, 54, 491498.
Helle, M., Rufer, S., van Osch, M. J.P, Jansen, O., & Norris, D. G. (2012). Selective
multivessel labeling approach for perfusion territory imaging in pseudo-continuous
arterial spin labeling. Magnetic Resonance in Medicine, 68, 214219.
153
Hernandez-Garcia, L., Jahanian, H., Greenwald, M. K., Zubieta, J.-K., & Peltier, S. J.
(2011). Real-time functional MRI using pseudo-continuous arterial spin labeling.
Magnetic Resonance in Medicine, 65, 15701577.
Hernandez-Garcia, L., Jahanian, H., & Rowe, D. B. (2010). Quantitative analysis of
arterial spin labeling FMRI data using a general linear model. Magnetic Resonance
Imaging, 28, 919927.
Hernandez-Garcia, L., Lee, G. R., Vazquez, A. L., Yip, C.-Y., & Noll, D. C. (2005).
Quantification of perfusion fMRI using a numerical model of arterial spin labeling
that accounts for dynamic transit time effects. Magnetic Resonance in Medicine, 54,
955964.
Hoge, R. D., Atkinson, J., Gill, B., Crelier, G. R., Marrett, S., & Pike, G. B. (1999). Linear
coupling between cerebral blood flow and oxygen consumption in activated human
cortex. Proceedings of the National Academy of Sciences of the United States of
America, 96, 94039408.
Hutchison, J. L., Shokri-Kojori, E., Lu, H., & Rypma, B. (2013). A BOLD perspective on
age-related neurometabolic-flow coupling and neural efficiency changes in human
visual cortex. Frontiers in Psychology, 4, 244.
Hyder, F. (2004). Neuroimaging with calibrated FMRI. Stroke, 35, 26352641.
Jahng, G. H., Song, E., Zhu, X. P., Matson, G. B., Weiner, M. W., & Schuff, N. (2005).
Human brain: Reliability and reproducibility of pulsed arterial spin-labeling
perfusion MR imaging. Radiology, 234, 909916.
James, W. (1890). The principles of psychology. Cambridge, MA: Harvard.
Jiang, L., Kim, M., Chodkowski, B., Donahue, M. J., Pekar, J. J., Van Zijl, P. C.M, et al.
(2010). Reliability and reproducibility of perfusion MRI in cognitively normal
subjects. Magnetic Resonance Imaging, 28, 12831289.
Kety, S. S., & Schmidt, C. F. (1948). The nitrous oxide method for the quantitative
determination of cerebral blood flow in man: Theory, procedure and normal values.
Journal of Clinical Investigation, 27, 476483.
Kim, S. G., & Duong, T. Q. (2002). Mapping cortical columnar structures using fMRI.
Physiology & Behavior, 77, 641644.
Liau, J., Perthen, J. E., & Liu, T. T. (2008). Caffeine reduces the activation extent and
contrast-to-noise ratio of the functional cerebral blood flow response but not the
BOLD response. NeuroImage, 42, 296305.
Liu, T. T., & Brown, G. G. (2007). Measurement of cerebral perfusion with arterial spin
labeling: Part 1. Methods. Journal of the International Neuropsychological Society,
13, 517525.
Liu, T. T., & Wong, E. C. (2005). A signal processing model for arterial spin labeling
functional MRI. NeuroImage, 24, 207215.
Luh, W. M., Wong, E. C., Bandettini, P. A., & Hyde, J. S. (1999). QUIPSS II with thinslice TI1 periodic saturation: A method for improving accuracy of quantitative
perfusion imaging using pulsed arterial spin labeling. Magnetic Resonance in
Medicine, 41, 12461254.
Luh, W. M., Wong, E. C., Bandettini, P. A., Ward, B. D., & Hyde, J. S. (2000).
Comparison of simultaneously measured perfusion and BOLD signal increases
during brain activation with T(1)-based tissue identification. Magnetic Resonance in
Medicine, 44, 137143.
Miller, K. L., Luh, W. M., Liu, T. T., Martinez, A., Obata, T., Wong, E. C., et al. (2001).
Nonlinear temporal dynamics of the cerebral blood flow response. Human Brain
Mapping, 13, 112.
Mumford, J. A., Hernandez-Garcia, L., Lee, G. R., & Nichols, T. E. (2006). Estimation
efficiency and statistical power in arterial spin labeling fMRI. NeuroImage, 33, 103114.
Nielsen, J.-F., & Hernandez-Garcia, L. (2012). Functional perfusion imaging using
pseudocontinuous arterial spin labeling with low-flip-angle segmented 3D spiral
readouts. Magnetic Resonance in Medicine, 69, 382390.
Perthen, J. E., Bydder, M., Restom, K., & Liu, T. T. (2008). SNR and functional
sensitivity of BOLD and perfusion-based fMRI using arterial spin labeling with spiral
SENSE at 3 T. Magnetic Resonance Imaging, 26, 513522.
Petersen, E. T., Mouridsen, K., & Golay, X. (2010). The QUASAR reproducibility study,
Part II: Results from a multi-center Arterial Spin Labeling testretest study.
NeuroImage, 49, 104113.
Pimentel, M. A.F, Vilela, P., Sousa, I., & Figueiredo, P. (2013). Localization of the hand
motor area by arterial spin labeling and blood oxygen level-dependent functional
magnetic resonance imaging. Human Brain Mapping, 34, 96108.
Raichle, M. E. (1998). Behind the scenes of functional brain imaging: A historical and
physiological perspective. Proceedings of the National Academy of Sciences of the
United States of America, 95, 765772.
Raichle, M. E., Martin, W. R., Herscovitch, P., Mintun, M. A., & Markham, J. (1983).
Brain blood flow measured with intravenous H2(15)O. II. Implementation and
validation. Journal of Nuclear Medicine, 24, 790798.
Raoult, H., Petr, J., Bannier, E., Stamm, A., Gauvrit, J.-Y., Barillot, C., et al. (2011).
Arterial spin labeling for motor activation mapping at 3 T with a 32-channel coil:
Reproducibility and spatial accuracy in comparison with BOLD fMRI. NeuroImage,
58, 157167.
154
INTRODUCTION TO ACQUISITION METHODS | Perfusion Imaging with Arterial Spin Labeling MRI
Restom, K., Bangen, K. J., Bondi, M. W., Perthen, J. E., & Liu, T. T. (2007). Cerebral
blood flow and BOLD responses to a memory encoding task: A comparison between
healthy young and elderly adults. NeuroImage, 37, 430439.
Restom, K., Behzadi, Y., & Liu, T. T. (2006). Physiological noise reduction for arterial
spin labeling functional MRI. NeuroImage, 31, 11041115.
Rosen, B. R., Belliveau, J. W., Vevea, J. M., & Brady, T. J. (1990). Perfusion imaging
with NMR contrast agents. Magnetic Resonance in Medicine, 14, 249265.
Roy, C. S., & Sherrington, C. S. (1890). On the regulation of the blood-supply of the
brain. Journal of Physiology, 11, 85108.
Shin, D. D., Liu, H. L., Wong, E. C., & Liu, T. T. (2011). Effect of background
suppression on CBF quantitation in pseudo continuous arterial spin labeling.
In: 19th annual ISMRM scientific meeting, Montreal, p. 2101.
Small, S. A. (2004). Quantifying cerebral blood flow: Regional regulation with global
implications. Journal of Clinical Investigation, 114, 10461048.
Stefanovic, B., Warnking, J. M., Kobayashi, E., Bagshaw, A. P., Hawco, C., Dubeau, F.,
et al. (2005). Hemodynamic and metabolic responses to activation, deactivation and
epileptic discharges. NeuroImage, 28, 205215.
Tan, H., Hoge, W. S., Hamilton, C. A., Gunther, M., & Kraft, R. A. (2011). 3D GRASE
PROPELLER: Improved image acquisition technique for arterial spin labeling
perfusion imaging. Magnetic Resonance in Medicine, 66, 168173.
Tjandra, T., Brooks, J. C., Figueiredo, P., Wise, R., Matthews, P. M., & Tracey, I. (2005).
Quantitative assessment of the reproducibility of functional activation measured with
BOLD and MR perfusion imaging: Implications for clinical trial design. NeuroImage,
27, 393401.
Wang, J., Aguirre, G. K., Kimberg, D. Y., Roc, A. C., Li, L., & Detre, J. A. (2003). Arterial
spin labeling perfusion fMRI with very low task frequency. Magnetic Resonance in
Medicine, 49, 796802.
Wang, J., Li, L., Roc, A. C., Alsop, D. C., Tang, K., Butler, N. S., et al. (2004). Reduced
susceptibility effects in perfusion fMRI with single-shot spin-echo EPI acquisitions
at 1.5 Tesla. Magnetic Resonance Imaging, 22, 17.
Wang, Y., Saykin, A. J., Pfeuffer, J., Lin, C., Mosier, K. M., Shen, L., et al. (2011).
Regional reproducibility of pulsed arterial spin labeling perfusion imaging at 3 T.
NeuroImage, 54, 11881195.
Williams, D. S., Detre, J. A., Leigh, J. S., & Koretsky, A. P. (1992). Magnetic resonance
imaging of perfusion using spin inversion of arterial water. Proceedings of the
National Academy of Sciences of the United States of America, 89, 212216.
Wintermark, M., Sesay, M., Barbier, E., Borbely, K., Dillon, W. P., Eastwood, J. D., et al.
(2005). Comparative overview of brain perfusion imaging techniques. Stroke, 36,
e83e99.
Wong, E. C. (2005). Quantifying CBF with pulsed ASL: Technical and pulse sequence
factors. Journal of Magnetic Resonance Imaging, 22, 727731.
Wong, E. C. (2007). Vessel-encoded arterial spin-labeling using pseudocontinuous
tagging. Magnetic Resonance in Medicine, 58, 10861091.
Wong, E. C., Buxton, R. B., & Frank, L. R. (1998a). Quantitative imaging of perfusion
using a single subtraction (QUIPSS and QUIPSS II). Magnetic Resonance in
Medicine, 39, 702708.
Wong, E. C., Buxton, R. B., & Frank, L. R. (1998b). A theoretical and experimental
comparison of continuous and pulsed arterial spin labeling techniques for
quantitative perfusion imaging. Magnetic Resonance in Medicine, 40, 348355.
Wong, E. C., Cronin, M., Wu, W. C., Inglis, B., Frank, L. R., & Liu, T. T. (2006).
Velocity-selective arterial spin labeling. Magnetic Resonance in Medicine, 55,
13341341.
Wong, E. C., Luh, W. M., & Liu, T. T. (2000). Turbo ASL: Arterial spin labeling with
higher SNR and temporal resolution. Magnetic Resonance in Medicine, 44,
511515.
Woolrich, M. W., Chiarelli, P., Gallichan, D., Perthen, J., & Liu, T. T. (2006). Inferring
blood volume, blood flow, and blood oxygenation changes from functional ASL
data. In: 14th ISMRM scientific meeting, Seattle, in press.
Xu, G., Rowley, H. A., Wu, G., Alsop, D. C., Shankaranarayanan, A., Dowling, M., et al.
(2010). Reliability and precision of pseudo-continuous arterial spin labeling
perfusion MRI on 3.0 T and comparison with 15O-water PET in elderly subjects at
risk for Alzheimers disease. NMR in Biomedicine, 23, 286293.
Ye, F. Q., Berman, K. F., Ellmore, T., Esposito, G., van Horn, J. D., Yang, Y., et al.
(2000). H(2)(15)O PET validation of steady-state arterial spin tagging cerebral
blood flow measurements in humans. Magnetic Resonance in Medicine, 44,
450456.
Zahneisen, B., Grotz, T., Lee, K. J., Ohlendorf, S., Reisert, M., Zaitsev, M., et al. (2011).
Three-dimensional MR-encephalography: Fast volumetric brain imaging using
rosette trajectories. Magnetic Resonance in Medicine, 65, 12601268.
Zuo, Z., Wang, R., Zhuo, Y., Xue, R., St Lawrence, K. S., & Wang, D. J.J (2013).
Turbo-FLASH based arterial spin labeled perfusion MRI at 7 T. PLoS One, 8,
e66612.
Glossary
Introduction
Positron emission tomography (PET) is an imaging technique
from the field of nuclear medicine. Together with singlephoton emission computed tomography (SPECT), it provides
the unique opportunity to quantify various binding proteins in
the living human brain. This includes, but is not limited to, the
depiction of physiological processes such as perfusion and
metabolism as well as imaging of neurotransmitter systems
by quantitative description of receptors, transporters, and
enzymes. The current article provides a basic introduction
into acquisition principles of PET and different imaging possibilities. The overview of [18F]FDG imaging (2-deoxy-2-[18F]
fluoro-D-glucose), a major PET application, is then followed
by specific implementations regarding the depiction of neurotransmitter systems. This covers the specific characteristics of
reversible radioligands for receptor quantification as well as
advances and challenges in psychiatric and neurological
disorders.
Data Acquisition
The main advantage of PET is that specific functional information is obtained at a molecular level with nano- to picomolar
sensitivity (Wadsak & Mitterhauser, 2010). Hence, only a
minor amount of radioactively labeled substance provides sufficient signal (mostly) without interfering with the biological
system itself. However, the radiation exposure to the patient
also presents the major drawback of PET. For instance, a typical
[18F]FDG scan with an application dosage of 3.6 MBq kg1
already yields an effective dose of 7 mSv for a 70 kg person
(Deloar et al., 1998).
Radioligands
A key component of each PET scan is the radioligand (also
called radiotracer or radiopharmaceutical), which consists of
two parts: the radioactive isotope and the biological tracer
(Wadsak & Mitterhauser, 2010). The first gives a detectable
signal, which in PET is obviously a positron-emitting isotope.
The most common radioactive isotopes are 18F (with a half-life
of 109.8 min), 11C (20.4 min), 13N (10 min), and 15O
(2 min). For the production of these isotopes, a cyclotron
is required and, considering their short half-life, only
[18F]-labeled ligands may be available for transport. The second part of the radioligand is the biological tracer, whose
binding properties define which target molecule will be
imaged. The challenge for the radiochemist/radiopharmacist
is not only to combine the radioactive isotope and the biological tracer into a single molecule but also to develop and
produce a final radioligand that meets specific characteristics
(see succeeding text) in order to allow reliable quantification of
the process or protein of interest.
Measurement Principle
The radioligand is incorporated into the body, mostly by intravenous injection. After the positron is emitted from the radioligand, it travels a short distance until it reacts with a nearby
electron in a process called annihilation. From the annihilation site, two photons are emitted in opposite directions each
with 511 keV. The photons are then perceived simultaneously
by the detector ring within a typical timing window of 814 ns
(Cherry, 2006). This coincidence detection is one of the major
advantages of PET in comparison to SPECT as it provides a
100-fold increase in detection sensitivity, which directly
improves image quality (Rahmim & Zaidi, 2008). Arriving at
the detector ring, the photons then hit the scintillation crystal,
which converts them into visible light. Coupling the crystal to a
photomultiplier tube enables amplification and transformation of light into an electrical signal, which is further processed
by the reconstruction computer.
The main limitations in terms of image resolution are given
by the positron range, photon noncollinearity, and further
detector-related effects (Moses, 2011; Rahmim & Zaidi,
2008). As mentioned, positrons pass a short distance before
an energy level for annihilation is reached. This distance,
known as the positron range, varies for different isotopes
between 0.6 mm for 18F and 2.5 mm for 15O (or reaches values
beyond 6 mm for higher energetic isotopes such as 62Cu and
82
Rb) (Jodal, Le Loirec, & Champion, 2012). Noncollinearity
refers to the observation that the trajectories of the emitted
photons may deviate from 180 due to nonzero energies after
annihilation. The angle varies with a standard deviation of
0.25 , and its effect on image resolution is dependent on the
radius of the detector ring (Moses, 2011; Rahmim & Zaidi,
2008). Both of the earlier mentioned effects cause blurring
of the recorded images in mm range. The third limitation
includes the size of the scintillation crystals as well as
http://dx.doi.org/10.1016/B978-0-12-397025-1.00018-X
155
156
INTRODUCTION TO ACQUISITION METHODS | Positron Emission Tomography and Neuroreceptor Mapping In Vivo
Imaging Applications
T-values
15
(a)
(b)
Figure 1 Patients with unilateral temporal lobe epilepsy undergoing [18F]FDG PET imaging. (a) The axial and coronal slices show a marked reduction in
standard uptake values (SUVs) in the left temporal lobe. (b) In the voxel-wise statistical evaluation, left vs right hemisphere SUV was compared
across an entire patient group with strongest differences in the hippocampus (corrected for multiple comparisons).
INTRODUCTION TO ACQUISITION METHODS | Positron Emission Tomography and Neuroreceptor Mapping In Vivo
Radioligand properties
Although some of the following characteristics may also apply
for other radioligands, the following description highlights
specific properties for quantitative imaging of neuronal receptors. Besides being nontoxic and safe, most radioligands are
assumed to cross the bloodbrain barrier (BBB) via passive
diffusion (except, e.g., [18F]FDG, which uses active glucose
transport). Although practical approaches for BBB imaging
exist (Bauer et al., 2010), it is usually desired to avoid efflux
by transporter proteins such as P-glycoprotein (P-gp) to ensure
that the radioligand reaches its target molecule (Pike, 2009).
Crossing the BBB already implies that the radioligand exhibits
certain characteristics in terms of lipophilicity, size, and
weight. In general, passive brain entry can be obtained by
most radioligands with a log P value (n-octanol/water partition
coefficient as index for lipophilicity) of 23.5 at physiological
pH, low molecular weight (<450 Da), and small crosssectional area (<80 A2) (Laruelle, Slifstein, & Huang, 2003;
Pike, 2009). Although lipophilicity is a major factor for BBB
passage, highly lipophilic tracers will show increases in nonspecific binding in the brain, which, in turn, decreases the
signal-to-noise ratio (Pike, 2009). High lipophilicity also
implies high binding to plasma proteins, hence reducing the
fraction of radioligand that is available for brain uptake.
Another important characteristic of a radioligand is given
by its selectivity. Ideally, it binds to only one target receptor
with appropriate affinity (Pike, 2009). There are, however,
certain examples for radioligands that show high affinity
for several receptor subtypes. For instance, [18F]setoperone
binds to both dopamine D2 and serotonin-2A receptors.
Consideration of the different topological distributions of
these target molecules in the brain gives a striatal signal
corresponding to D2 binding, while radioligand signal in
cortical areas will represent serotonin-2A receptors (Laruelle
et al., 2003). To summarize, the level of selectivity depends
on the affinity for the different receptor subtypes as well as
the distribution of the target proteins within certain regions
of interest.
Though the required affinity of a radioligand is usually in
the range of 10.01 nM, it also depends on the concentration
of the target receptor (Laruelle et al., 2003). High affinity is,
however, often associated with high lipophilicity, which in
turn increases nonspecific binding. Hence, increasing the affinity of a radioligand will only result in better image quality (i.e.,
signal-to-noise ratio) if the nonspecific binding remains constant (Laruelle et al., 2003). Another issue associated with
affinity is the scan duration. Increases in affinity will also lead
to longer scan times since the binding equilibrium required for
quantification is reached later.
As mentioned previously, the radioligand should not interfere with the biological system for most imaging applications,
and it is therefore applied at low doses that lack pharmacological effects (tracer doses). Ideally, the radioligand application
leads to an occupancy of target proteins of < 1%. This also
satisfies the linearity requirements for the kinetic modeling
procedures (Laruelle et al., 2003). On the other hand, this
further implies that radioligands need to be synthesized at a
high specific activity.
Finally, it is desirable that radioligands exhibit limited
peripheral metabolism. This increases the amount of parent
radioligand available for specific receptor binding, which in
157
turn increases the signal-to-noise ratio. Despite high metabolism, most radioligands still represent excellent imaging properties because the radioactive metabolites are more polar
than the parent compound and hence do not cross the BBB.
An elegant example of avoiding radioactive metabolites in
the human brain is given by the serotonin-1A antagonist
WAY-100635 (Pike, 2009). Labeling of this compound at the
O-methyl site leads to high amounts of the radioactive metabolite WAY-100634, which shows high affinity to the same
target receptor. Shifting the labeling position to the carbonyl
site avoids this problem as the main radioactive metabolite
does not cross the BBB (Osman et al., 1998).
Serotonin imaging
The serotonin (5-HT) system is one of the phylogenetically
oldest neurotransmitter systems in the human brain (Saulin,
Savli, & Lanzenberger, 2011). Up to now, 16 receptor subtypes
and one transporter have been identified (Polter & Li, 2010).
These receptors are classified into seven different families by
their pharmacological properties. Except for the 5-HT3 receptor
family, which comprises ionotropic receptors, all other subtypes are G protein-coupled receptors (Bockaert, Claeysen,
Dumuis, & Marin, 2010). Considering that the serotonergic
neurotransmitter system is involved in a variety of psychiatric
disorders (Paterson, Kornum, Nutt, Pike, & Knudsen, 2013;
Savli et al., 2012), in vivo imaging of these receptors provides
novel insight into these pathophysiological mechanisms. The
broad interest in the serotonin system is also reflected by
thorough evaluations of available and upcoming radioligands
(Paterson et al., 2013; Saulin et al., 2011) as well as a recently
established comprehensive database (Savli et al., 2012). Figure 2 shows the different topological distributions of major
serotonin binding proteins.
Among this variety of 5-HT receptors, investigation of the
main inhibitory subtype (5-HT1A) has been of major interest in
several psychiatric disorders due to its high density in the
human brain, excellent pharmacological characterization
(Saulin et al., 2011), and radiotracer availability (Paterson
et al., 2013). For instance, the investigation of patients suffering from panic disorder with PET showed decreases in 5-HT1A
binding (Neumeister et al., 2004), which normalized in cortical areas (postsynaptic) but not in the raphe region (presynaptic) after treatment with selective serotonin reuptake inhibitors
(SSRI) (Nash et al., 2008). Similarly, patients with social anxiety disorder also exhibited reduced pre- and postsynaptic
5-HT1A binding (Lanzenberger et al., 2007). However, after
SSRI therapy, further decreases in receptor binding were
observed in cortical areas but not in the raphe region
(Spindelegger et al., 2009). In addition, SSRI administration
led to a stronger interregional association between the dorsal
raphe nucleus and the amygdalahippocampus complex in
these patients (Hahn et al., 2010). The distinct changes of preand postsynaptic receptor binding may relate, for example, to
differences in internalization processes or G protein coupling
since only postsynaptic but not 5-HT1A autoreceptors in the
raphe nuclei inhibit adenylyl cyclase via the Gia-subunit
(Polter & Li, 2010).
The etiology and treatment effects of major depressive disorder (MDD) have also been linked to the serotonergic system.
However, the results have been more controversial with
decreases (Drevets et al., 1999; Hirvonen et al., 2008; Sargent
158
INTRODUCTION TO ACQUISITION METHODS | Positron Emission Tomography and Neuroreceptor Mapping In Vivo
5-HT1A binding
(a)
5-HT1B binding
1.5
(b)
0
(c)
5-HT2A binding
5-HTT binding
(d)
Figure 2 Topographical distribution of major binding proteins of the serotonin neurotransmitter system in healthy human subjects. These
include the major inhibitory ((a) 5-HT1A and (b) 5-HT1B) and excitatory receptor subtypes ((c) 5-HT2A) as well as the serotonin transporter ((d) 5-HTT
or SERT). The marked difference in binding distributions may relate to the variability of physiological processes and mental disorders where
the serotonergic neurotransmitter system is involved.
Dopamine imaging
Similar to serotonin imaging, the dopaminergic neurotransmitter system has been subject to extensive investigation
using PET (Ito, Takahashi, Arakawa, Takano, & Suhara,
2008). This includes dementias and Parkinsons disease
(Walker & Rodda, 2011), schizophrenia (Howes & Kapur,
2009), and depression (Dunlop & Nemeroff, 2007). In addition to receptor and transporter imaging, a topic of particular
INTRODUCTION TO ACQUISITION METHODS | Positron Emission Tomography and Neuroreceptor Mapping In Vivo
still unchallenged in its binding of the low-affinity receptors,
which decreases signal-to-noise ratio for imaging of endogenous
neurotransmitter release. These theoretical considerations have
also proved useful in practice with higher signal-to-noise
ratio for agonist radioligands (Narendran et al., 2004; Willeit
et al., 2008).
References
Bauer, M., Karch, R., Neumann, F., Wagner, C. C., Kletter, K., Muller, M., et al. (2010).
Assessment of regional differences in tariquidar-induced P-glycoprotein
modulation at the human bloodbrain barrier. Journal of Cerebral Blood Flow and
Metabolism, 30, 510515.
Bockaert, J., Claeysen, S., Dumuis, A., & Marin, P. (2010). Classification and signaling
characteristics of 5-HT receptors. In C. P. Muller & B. L. Jacobs (Eds.), Handbook
of the behavioral neurobiology of serotonin. London: Elsevier.
Chen, W., Silverman, D. H., Delaloye, S., Czernin, J., Kamdar, N., Pope, W., et al.
(2006). 18 F-FDOPA PET imaging of brain tumors: Comparison study with 18 F-FDG
PET and evaluation of diagnostic accuracy. Journal of Nuclear Medicine, 47,
904911.
Cherry, S. R. (2006). The 2006 Henry N. Wagner Lecture: Of mice and men (and
positrons) Advances in PET imaging technology. Journal of Nuclear Medicine, 47,
17351745.
Deloar, H. M., Fujiwara, T., Shidahara, M., Nakamura, T., Watabe, H., Narita, Y., et al.
(1998). Estimation of absorbed dose for 2-[F-18]fluoro-2-deoxy-D-glucose using
whole-body positron emission tomography and magnetic resonance imaging.
European Journal of Nuclear Medicine, 25, 565574.
Devanand, D. P., Mikhno, A., Pelton, G. H., Cuasay, K., Pradhaban, G.,
Dileep Kumar, J. S., et al. (2010). Pittsburgh compound B (11C-PIB) and
159
160
INTRODUCTION TO ACQUISITION METHODS | Positron Emission Tomography and Neuroreceptor Mapping In Vivo
Narendran, R., Hwang, D. R., Slifstein, M., Talbot, P. S., Erritzoe, D., Huang, Y., et al.
(2004). In vivo vulnerability to competition by endogenous dopamine: Comparison
of the D2 receptor agonist radiotracer (-)-N-[11C]propyl-norapomorphine ([11C]
NPA) with the D2 receptor antagonist radiotracer [11C]-raclopride. Synapse, 52,
188208.
Nash, J. R., Sargent, P. A., Rabiner, E. A., Hood, S. D., Argyropoulos, S. V.,
Potokar, J. P., et al. (2008). Serotonin 5-HT1A receptor binding in people with panic
disorder: Positron emission tomography study. British Journal of Psychiatry, 193,
229234.
Neumeister, A., Bain, E., Nugent, A. C., Carson, R. E., Bonne, O., Luckenbaugh, D. A.,
et al. (2004). Reduced serotonin type 1A receptor binding in panic disorder. Journal
of Neuroscience, 24, 589591.
Osman, S., Lundkvist, C., Pike, V. W., Halldin, C., Mccarron, J. A., Swahn, C. G., et al.
(1998). Characterisation of the appearance of radioactive metabolites in monkey and
human plasma from the 5-HT1A receptor radioligand, [carbonyl-11C]WAY-100635
Explanation of high signal contrast in PET and an aid to biomathematical modelling.
Nuclear Medicine and Biology, 25, 215223.
Ossenkoppele, R., Tolboom, N., Foster-Dingley, J. C., Adriaanse, S. F., Boellaard, R.,
Yaqub, M., et al. (2012). Longitudinal imaging of Alzheimer pathology using [11C]
PIB, [18 F]FDDNP and [18 F]FDG PET. European Journal of Nuclear Medicine and
Molecular Imaging, 39, 9901000.
Parsey, R. V., Hastings, R. S., Oquendo, M. A., Huang, Y. Y., Simpson, N., Arcement, J.,
et al. (2006). Lower serotonin transporter binding potential in the human brain
during major depressive episodes. The American Journal of Psychiatry, 163, 5258.
Parsey, R. V., Ogden, R. T., Miller, J. M., Tin, A., Hesselgrave, N., Goldstein, E., et al.
(2010). Higher serotonin 1A binding in a second major depression cohort:
Modeling and reference region considerations. Biological Psychiatry, 68, 170178.
Paterson, L. M., Kornum, B. R., Nutt, D. J., Pike, V. W., & Knudsen, G. M. (2013). 5-HT
radioligands for human brain imaging with PET and SPECT. Medicinal Research
Reviews, 33, 54111.
Paterson, L. M., Tyacke, R. J., Nutt, D. J., & Knudsen, G. M. (2010). Measuring
endogenous 5-HT release by emission tomography: Promises and pitfalls. Journal
of Cerebral Blood Flow and Metabolism, 30, 16821706.
Pike, V. W. (2009). PET radiotracers: Crossing the bloodbrain barrier and surviving
metabolism. Trends in Pharmacological Sciences, 30, 431440.
Polter, A. M., & Li, X. (2010). 5-HT1A receptor-regulated signal transduction pathways
in brain. Cellular Signalling, 22, 14061412.
Price, J. C., Klunk, W. E., Lopresti, B. J., Lu, X., Hoge, J. A., Ziolko, S. K., et al. (2005).
Kinetic modeling of amyloid binding in humans using PET imaging and
Pittsburgh compound-B. Journal of Cerebral Blood Flow and Metabolism, 25,
15281547.
Rahmim, A., & Zaidi, H. (2008). PET versus SPECT: Strengths, limitations and
challenges. Nuclear Medicine Communications, 29, 193207.
Richardson-Jones, J. W., Craige, C. P., Guiard, B. P., Stephen, A., Metzger, K. L.,
Kung, H. F., et al. (2010). 5-HT1A autoreceptor levels determine vulnerability to
stress and response to antidepressants. Neuron, 65, 4052.
Salimpoor, V. N., Benovoy, M., Larcher, K., Dagher, A., & Zatorre, R. J. (2011).
Anatomically distinct dopamine release during anticipation and experience of peak
emotion to music. Nature Neuroscience, 14, 257262.
Sargent, P. A., Kjaer, K. H., Bench, C. J., Rabiner, E. A., Messa, C., Meyer, J., et al.
(2000). Brain serotonin1A receptor binding measured by positron emission
tomography with [11C]WAY-100635: Effects of depression and antidepressant
treatment. Archives of General Psychiatry, 57, 174180.
Saulin, A., Savli, M., & Lanzenberger, R. (2011). Serotonin and molecular imaging in
humans using PET. Amino Acids, 42, 20392057.
Savli, M., Bauer, A., Mitterhauser, M., Ding, Y. S., Hahn, A., Kroll, T., et al. (2012).
Normative database of the serotonergic system in healthy subjects using multitracer PET. NeuroImage, 63, 447459.
Spindelegger, C., Lanzenberger, R., Wadsak, W., Mien, L. K., Stein, P.,
Mitterhauser, M., et al. (2009). Influence of escitalopram treatment on 5-HT(1A)
receptor binding in limbic regions in patients with anxiety disorders. Molecular
Psychiatry, 14, 10401050.
Sun, W., Ginovart, N., Ko, F., Seeman, P., & Kapur, S. (2003). In vivo evidence for
dopamine-mediated internalization of D2-receptors after amphetamine: Differential
findings with [3H]raclopride versus [3H]spiperone. Molecular Pharmacology, 63,
456462.
Varrone, A., Sjoholm, N., Eriksson, L., Gulyas, B., Halldin, C., & Farde, L. (2009).
Advancement in PET quantification using 3D-OP-OSEM point spread function
reconstruction with the HRRT. European Journal of Nuclear Medicine and Molecular
Imaging, 36, 16391650.
Wadsak, W., & Mitterhauser, M. (2010). Basics and principles of radiopharmaceuticals
for PET/CT. European Journal of Radiology, 73, 461469.
Walker, Z., & Rodda, J. (2011). Dopaminergic imaging: Clinical utility now and in the
future. International Psychogeriatrics, 23(Suppl. 2), S32S40.
Willeit, M., Ginovart, N., Graff, A., Rusjan, P., Vitcu, I., Houle, S., et al. (2008). First
human evidence of d-amphetamine induced displacement of a D2/3 agonist
radioligand: A [11C]-()-PHNO positron emission tomography study.
Neuropsychopharmacology, 33, 279289.
Willeit, M., & Praschak-Rieder, N. (2010). Imaging the effects of genetic
polymorphisms on radioligand binding in the living human brain: A review on
genetic neuroreceptor imaging of monoaminergic systems in psychiatry.
NeuroImage, 53, 878892.
Yeung, H. W., Sanches, A., Squire, O. D., Macapinlac, H. A., Larson, S. M., & Erdi, Y. E.
(2002). Standardized uptake value in pediatric patients: An investigation to
determine the optimum measurement parameter. European Journal of Nuclear
Medicine and Molecular Imaging, 29, 6166.
Introduction
Conventional clinical magnetic resonance imaging is, to a large
degree, dominated by anatomical imaging based on spin
density, T1, T2, and T2* contrasts. Gradient echo imaging or
T2* imaging has always played a key role in detecting hemorrhages and the presence of iron because of its sensitivity to
local changes in magnetic field that induce signal loss (a reduction of T2*). About 20 years ago, E Mark Haacke (EMH) began
to focus on phase information as a source of contrast during a
sabbatical in 1993 in Erlangen, Germany, at Siemens Healthcare. This led to two early papers on the role of phase and
susceptibility to study oxygen saturation and validating the
blood oxygen level-dependent mechanism related to the role
of veins (Haacke et al., 1997; Haacke, Lai, Yablonskiy, & Lin,
1995). Already at this time, the concept of high-pass filtering
had been implemented to remove unwanted low spatial frequency information and reveal the interesting anatomical
information shown in phase imaging. Shortly after this, in
1995, Jurgen Reichenbach joined EMHs group in St. Louis
and spent 2 years adding his insight into the role of susceptibility in MR imaging. Later, this filtered phase was used as a
mask (Haacke, Xu, Cheng, & Reichenbach, 2004; Reichenbach
et al., 1998; Reichenbach, Venkatesan, Schillinger, Kido, &
Haacke, 1997) to create susceptibility-weighted images, a technique that is very sensitive to the presence of iron and therefore
small microbleeds as well (Haacke, Raza, Wu, & Kou, 2013;
Tong et al., 2003).
As presented in their 1995 work (Haacke et al., 1995),
phase imaging provides an imaging form of spectroscopy
since it is a frequency-sensitive imaging approach. In this
early paper, it was clearly shown that excellent susceptibility
contrast could be obtained even between the gray matter and
white matter. The problem in dealing with phase images is that
there are a variety of other sources of phase shifts that obscure
the phase from local susceptibility structures. These include
tissue conductivity effects, multiple radio-frequency coil contributions, linear phase shifts (from eddy currents), quadratic
phase shifts (from concomitant gradient fields), partial volume
effects, and insufficient or lack of flow compensation. To further complicate the issue, if the phase exceeds p, then it will
alias and this aliased phase needs to be unwrapped to be
properly processed. To remove most of these other sources of
phase, a high-pass filter was applied leaving effectively the local
fields. From this new phase image, a mask was made to apply
to the original magnitude data to create a susceptibilityweighted image.
However, these phase data, despite its being filtered, still
suffered from the inherent nonlocal characteristics associated
with all surrounding magnetic susceptibilities with the association dependent on orientation, distance, echo time, and field
[1]
1 3 cos 2 y 1
4p
r3
[2]
[4]
http://dx.doi.org/10.1016/B978-0-12-397025-1.00019-1
161
162
Magnitude
Brain mask
Brain
extraction
Original phase
Unwrapped phase
Background
field
removal
Phase
unwrapping
Susceptibility map
Processed phase
Inverse
filtering
Figure 1 QSM data processing steps. *The phase unwrapping step may not be necessary.
CSF
0.7 rad
0.45 ppm
WM
GM
CN
PUT
Veins
TH
-0.06 ppm
Transverse view
Transverse view
-0.7 rad
GP
RN
SN
Coronal view
Coronal view
Saginal view
Sagittal view
Figure 2 Susceptibility model (left) and phase images (right) from a numerical 3-D model of the brain in three orthogonal views (CSF, cerebrospinal
fluid; WM, white matter; GM, gray matter; CN, caudate nucleus; PUT, putamen; TH, thalamus; GP, globus pallidus; SN, substantia nigra; RN, red
nucleus).
[5]
163
G01 k
8
>
>
>
<
1
1 k2
1 k2z
2
, when z2 > t
3 k
3 k
2
2 n
>
1
k
1
k
>
z
z
>
: sgn 2 2 tn1 , n 0 2, when
3 k 3 k
1 k2z
t
3 k2
[7]
[8]
164
[9]
Sources of Noise
The Bayesian approach is quite robust (Liu, Xu, Spincemaille,
Avestimehr, & Wang, 2012d), but noise does propagate into
QSM images. Noise sources include but are not limited to (i)
white noise as transformed from k-space (Fourier domain of
phase images) back to the susceptibility map, (ii) streaking
along the cone of singularity, (iii) streaking within the object
itself, and (iv) other false susceptibility information generated
from phase information that does not correspond to a conventional magnetic field such as linear (echo shifting) and quadratic (concomitant gradient paper) phase offsets, RF coil
phase shifts, chemical shift effects, or phase from flowing
spins that are not properly flow-compensated. This latter
group tends to add systematic noise in the form of artifacts in
the images. The white noise in QSM can be estimated using
simulations (Tang et al., 2013) and we find that
sw
R
ppm
gB0 TESNRmag
[10]
165
Clinical Examples
Currently, the use of QSM is predominantly for measuring iron
in the form of ferritin, hemosiderin, and deoxyhemoglobin.
Quantifying iron offers different and more detailed information than only visualizing the presence of iron with SWI. For
example, measuring iron in the basal ganglia can be used as a
marker for abnormal levels of iron in diseases such as
Parkinsons disease, multiple sclerosis, Huntingtons disease,
and neuroferritinopathies (Haacke et al., 2005; Langkammer
et al., 2013). Iron can also be used to monitor microbleeds in
traumatic brain injury (Liu, Surapaneni, et al., 2012c). Measuring hemosiderin in microbleeds can be used to ascertain if the
bleed changes over time.
A comparison of SWI and QSM is shown in Figures 3 and 4.
Measuring deoxyhemoglobin can be used for monitoring oxygen saturation changes (Haacke et al., 2010) in stroke or intracranial hypertension when there is a perfusion deficit. An
example of the latter is shown in Figure 5 indicating an
increase in deoxyhemoglobin and therefore a region of
reduced perfusion. The ability of using SWI and QSM to visualize and quantify changes in venous oxygen saturation can
also be seen from Figure 6, which shows the changes of image
contrast in SWI and QSM between precaffeine administration
and postcaffeine administration. Note that the improved contrast of the veins in the postcaffeine SWI and QSM is due to the
decreased oxygen saturation (hence increased deoxyhemoglobin or susceptibility) of the veins, caused by caffeine-induced
vaso-constriction (Haacke et al., 2010; Sedlacik et al., 2008).
QSM can provide a reliable measurement of hematoma volume (Figure 7; Shuo et al., 2013). QSM at 3 T provides significantly better data than current standard MRI for depiction of
the deep brain stimulation targets (Figure 8; Liu et al., 2013c).
QSM may provide a new vision into inflammation in multiple
sclerosis by depicting iron in lesions replete with macrophage
activity (Figure 9; Chen et al., 2014). Finally, the geometry and
TE dependence of phase information usually hamper the effectiveness of SWI, especially for high isotropic resolution. These
problems can be overcome by the use of true SWI (tSWI)
generated from susceptibility maps (Figure 10) since the resulting susceptibilities from QSM no longer have either orientation or echo time dependence (at least theoretically) (Gho
et al., 2013; Liu, Neelavalli, Cheng, Tang, & Mark, 2013b).
166
Figure 3 (a) Original magnitude image. (b) Original phase image. (c) Minimum intensity projection of SWI. (d) Maximum intensity projection of the
susceptibility maps.
167
Figure 4 Maximum intensity projection (MIP) of susceptibility maps (a) and minimum intensity projection (mIP) of SWI (b) for a TBI case. Note that
the inhomogeneities show clearly with the minimum intensity since any low intensity signal loss or artifact will show in the mIP even if it occurs
in only a single slice. This will not be a problem when the maximum intensity is used, a major advantage of susceptibility mapping (i.e., that it has
positive contrast).
Figure 5 An example MR angiogram (a), SWI (b), and thresholded susceptibility map (c) for a case of intracranial hypertension. The threshold
in the QSM was set to 200 ppb and those veins that show purple here represent abnormally high levels of deoxyhemoglobin (indicative of perfusion
deficit in the brain). Images courtesy of Jiangtao Liu and Shuang Xia.
168
300
250
200
150
100
50
(a)
(b)
0.2
ppm
0.15
0.1
0.05
(c)
(d)
Figure 6 Minimum intensity projections of SWI (a and b) and maximum intensity projections of susceptibility maps (c and d) for pre- and
postcaffeine administration. Here, (a) and (c) are the projections of SWI and QSM for precaffeine administration, while (b) and (d) are for postcaffeine
administration. The effective slice thickness is 16 mm for all the images.
Figure 7 An example of intracranial hemorrhage: (a) a T2*-weighted gradient echo magnitude image with contrast dependent on TE and other imaging
parameters and (b) QSM demonstrating very strong susceptibility (1 ppm) of blood degeneration products (mostly hemosiderin).
Figure 8 Depiction of deep brain stimulation targets (a) with standard T2-weighted image and (b) with QSM. The zoomed images in (c) and (d) show
the subthalamic nuclei (white arrows) and globus pallidus (black arrows).
Figure 9 Example images from a patient with multiple sclerosis: (a) standard T2-weighted FLAIR and (b) QSM. While T2-weighted FLAIR demonstrates
a relative increase in water in MS lesions, QSM shows the presence of iron in the MS lesions (arrows in b) possibly indicating macrophage activity.
Figure 10 A comparison between minimum intensity projections (mIPs) of conventional SWI and tSWI. (a) Transverse mIP of conventional SWI.
(b) Transverse mIP of tSWI. (c) Sagittal mIP of conventional SWI. (d) Sagittal mIP of tSWI. For transverse mIPs (a and b), the effective slice thickness
is 32 mm, while for the sagittal mIPs, the effective slice thickness is 8 mm. The voxel size of the original dataset is 0.5 0.5 2mm3.
For sagittal mIPs, interpolation was performed to get isotropic resolution, for visualization purposes. Note that the blooming artifact of some of
the major bleeds has been reduced using tSWI (arrows).
References
Abdul-Rahman, H. S., Gdeisat, M. A., Burton, D. R., Lalor, M. J., Lilley, F., &
Moore, C. J. (2007). Fast and robust three-dimensional best path phase
unwrapping algorithm. Applied Optics, 46, 66236635.
Barber, D. (2012). Bayesian reasoning and machine learning. Cambridge: Cambridge
University Press.
Bilgic, B., Pfefferbaum, A., Rohlfing, T., Sullivan, E. V., & Adalsteinsson, E. (2012). MRI
estimates of brain iron concentration in normal aging using quantitative
susceptibility mapping. NeuroImage, 59, 26252635.
Buch, S., Liu, S., Ye, Y., Cheng, Y., Neelavalli, J., & Haacke, E. M. (2014). Susceptibility
mapping of air, bone, and calcium in the head. Magnetic Resonance in Medicine,
http://dx.doi.org/10.1002/mrm.25350.
Chen, W., Gauthier, S., Gupta, A., Comunale, J., Liu, T., Wang, S., et al. (2014).
Quantitative susceptibility mapping of multiple sclerosis lesions at various ages.
Radiology, 271, 183192.
Cheng, Y. C. N., Neelavalli, J., & Haacke, E. M. (2009). Limitations of calculating field
distributions and magnetic susceptibilities in MRI using a Fourier based method.
Physics in Medicine and Biology, 54, 11691189.
De Rochefort, L., Liu, T., Kressler, B., Liu, J., Spincemaille, P., Lebon, V., et al. (2010).
Quantitative susceptibility map reconstruction from MR phase data using bayesian
regularization: Validation and application to brain imaging. Magnetic Resonance in
Medicine, 63, 194206.
Deistung, A., Rauscher, A., Sedlacik, J., Stadler, J., Witoszynskyj, S., &
Reichenbach, J. R. (2008). Susceptibility weighted imaging at ultra high magnetic
field strengths: Theoretical considerations and experimental results. Magnetic
Resonance in Medicine, 60, 11551168.
Deville, G., Bernier, M., & Delrieux, J. M. (1979). NMR multiple echoes observed in
solid He3. Physical Review B, 19, 5666.
Feng, W., Neelavalli, J., & Haacke, E. M. (2013). Catalytic multiecho phase unwrapping
scheme (CAMPUS) in multiecho gradient echo imaging: Removing phase wraps on
a voxel-by-voxel basis. Magnetic Resonance in Medicine, 70, 117126.
Fujima, N., Kudo, K., Terae, S., Ishizaka, K., Yazu, R., Zaitsu, Y., et al. (2011). Noninvasive measurement of oxygen saturation in the spinal vein using SWI:
Quantitative evaluation under conditions of physiological and caffeine load.
NeuroImage, 54, 344349.
171
172
Liu, J., Liu, T., de Rochefort, L., Ledoux, J., Khalidov, I., Chen, W., et al. (2012).
Morphology enabled dipole inversion for quantitative susceptibility mapping using
structural consistency between the magnitude image and the susceptibility map.
NeuroImage, 59, 25602568.
Liu, T., Liu, J., de Rochefort, L., Spincemaille, P., Khalidov, I., Ledoux, J. R., et al.
(2011). Morphology enabled dipole inversion (MEDI) from a single-angle
acquisition: Comparison with COSMOS in human brain imaging. Magnetic
Resonance in Medicine, 66, 777783.
Liu, S., Mok, K., Neelavalli, J., Cheng, Y. C. N., Tang, J., Ye, Y., et al. (2013). Improved
MR venography using quantitative susceptibility-weighted imaging. Journal of
Magnetic Resonance Imaging, http://dx.doi.org/10.1002/jmri.24413.
Liu, S., Neelavalli, J., Cheng, Y.-C. N., Tang, J., & Mark, Haacke E. (2013). Quantitative
susceptibility mapping of small objects using volume constraints. Magnetic
Resonance in Medicine, 69, 716723.
Liu, T., Spincemaille, P., de Rochefort, L., Kressler, B., & Wang, Y. (2009). Calculation
of susceptibility through multiple orientation sampling (COSMOS): A method for
conditioning the inverse problem from measured magnetic field map to
susceptibility source image in MRI. Magnetic Resonance in Medicine, 61, 196204.
Liu, T., Surapaneni, K., Lou, M., Cheng, L., Spincemaille, P., & Wang, Y. (2012).
Cerebral microbleeds: Burden assessment by using quantitative susceptibility
mapping. Radiology, 262, 269278.
Liu, T., Wisnieff, C., Lou, M., Chen, W., Spincemaille, P., & Wang, Y. (2013). Nonlinear
formulation of the magnetic field to source relationship for robust quantitative
susceptibility mapping. Magnetic Resonance in Medicine, 69, 467476.
Liu, T., Xu, W., Spincemaille, P., Avestimehr, A. S., & Wang, Y. (2012). Accuracy of the
morphology enabled dipole inversion (MEDI) algorithm for quantitative
susceptibility mapping in MRI. IEEE Transactions on Medical Imaging, 31, 816824.
Mie, M. B., Nissen, J. C., Zollner, F. G., Heilmann, M., Schoenberg, S. O.,
Michaely, H. J., et al. (2010). Susceptibility weighted imaging (SWI) of the kidney at
3 T Initial results. Zeitschrift fur Medizinische Physik, 20, 143150.
Neelavalli, J., Cheng, Y. N., Jiang, J., & Haacke, E. M. (2009). Removing background
phase variations in susceptibility-weighted imaging using a fast, forward-field
calculation. Journal of Magnetic Resonance Imaging, 29, 937948.
Nocedal, J., & Wright, S. J. (1999). Numerical optimization. Berlin: Springer.
Pruessmann, K. P., Weiger, M., Scheidegger, M. B., & Boesiger, P. (1999). SENSE: Sensitivity
encoding for fast MRI. Magnetic Resonance in Medicine, 42, 952962.
Reichenbach, J. R., Barth, M., Haacke, E. M., Klarhofer, M., Kaiser, W. A., & Moser, E.
(2000). High-resolution MR venography at 3.0 Tesla. Journal of Computer Assisted
Tomography, 24, 949957.
Reichenbach, J. R., Essig, M., Haacke, E. M., Lee, B. C., Przetak, C., Kaiser, W. A., et al.
(1998). High-resolution venography of the brain using magnetic resonance
imaging. Magma, 6, 6269.
Reichenbach, J. R., Venkatesan, R., Schillinger, D. J., Kido, D. K., & Haacke, E. M.
(1997). Small vessels in the human brain: MR venography with deoxyhemoglobin
as an intrinsic contrast agent. Radiology, 204, 272277.
Robinson, S., Grabner, G., Witoszynskyj, S., & Trattnig, S. (2011). Combining phase
images from multi-channel RF coils using 3D phase offset maps derived from a
dual-echo scan. Magnetic Resonance in Medicine, 65, 16381648.
Roemer, P. B., Edelstein, W. A., Hayes, C. E., Souza, S. P., & Mueller, O. M. (1990). The
NMR phased array. Magnetic Resonance in Medicine, 16, 192225.
Salomir, R., de Senneville, B. D., & Moonen, C. T. (2003). A fast calculation method for
magnetic field inhomogeneity due to an arbitrary distribution of bulk susceptibility.
Concepts in Magnetic Resonance Part B: Magnetic Resonance Engineering, 19B,
2634.
Schofield, M. A., & Zhu, Y. (2003). Fast phase unwrapping algorithm for interferometric
applications. Optics Letters, 28, 11941196.
Schweser, F., Deistung, A., Lehr, B. W., & Reichenbach, J. R. (2010). Differentiation
between diamagnetic and paramagnetic cerebral lesions based on magnetic
susceptibility mapping. Medical Physics, 37, 5165.
Schweser, F., Deistung, A., Lehr, B. W., & Reichenbach, J. R. (2011). Quantitative
imaging of intrinsic magnetic tissue properties using MRI signal phase: An
approach to in vivo brain iron metabolism? NeuroImage, 54, 27892807.
Schweser, F., Deistung, A., Sommer, K., & Reichenbach, J. R. (2013). Toward online
reconstruction of quantitative susceptibility maps: Superfast dipole inversion.
Magnetic Resonance in Medicine, 69(6), 15811593.
Schweser, F., Sommer, K., Deistung, A., & Reichenbach, J. R. (2012). Quantitative
susceptibility mapping for investigating subtle susceptibility variations in the human
brain. NeuroImage, 62, 20832100.
Sedlacik, J., Helm, K., Rauscher, A., Stadler, J., Mentzel, H. J., & Reichenbach, J. R. (2008).
Investigations on the effect of caffeine on cerebral venous vessel contrast by using
susceptibility-weighted imaging (SWI) at 1.5, 3 and 7 T. NeuroImage, 40(1), 1118.
Shmueli, K., de Zwart, J. A., van Gelderen, P., Li, T., Dodd, S. J., & Duyn, J. H. (2009).
Magnetic susceptibility mapping of brain tissue in vivo using MRI phase data.
Magnetic Resonance in Medicine, 62, 15101522.
Shuai, Wang, Liu, T., Chen, W., Spincemaille, P., Wisnieff, C., Tsiouris, A. J., et al.
(2013). Noise effects in various quantitative susceptibility mapping methods. IEEE
Transactions on Biomedical Engineering, http://dx.doi.org/10.1109/
TBME.2013.2266795.
Shuo, Wang, Lou, M., Liu, T., Cui, D., Chen, X., & Wang, Y. (2013). Hematoma volume
measurement in gradient echo MRI using quantitative susceptibility mapping.
Stroke: A Journal of Cerebral Circulation, 44, 23152317.
Sun, H., & Wilman, A. H. (2013). Background field removal using spherical mean value
filtering and Tikhonov regularization. Magnetic Resonance in Medicine, http://dx.
doi.org/10.1002/mrm.24765.
Tang, J., Liu, S., Neelavalli, J., Cheng, Y. C. N., Buch, S., & Haacke, E. M. (2013).
Improving susceptibility mapping using a threshold-based K-space/image domain
iterative reconstruction approach. Magnetic Resonance in Medicine, 69,
13961407.
Tao, R., Zhang, J., Dai, Y., You, Z., Fan, Y., Cui, J., et al. (2012). Characterizing
hepatocellular carcinoma using multi-breath-hold two-dimensional susceptibilityweighted imaging: Comparison to conventional liver MRI. Clinical Radiology, 67,
e91e97.
Thulborn, K. R., Waterton, J. C., Matthews, P. M., & Radda, G. K. (1982). Oxygenation
dependence of the transverse relaxation time of water protons in whole blood at high
field. Biochimica et Biophysica Acta, 714, 265270.
Tong, K. A., Ashwal, S., Holshouser, B. A., Shutter, L. A., Herigault, G., Haacke, E. M.,
et al. (2003). Hemorrhagic shearing lesions in children and adolescents with
posttraumatic diffuse axonal injury: Improved detection and initial results.
Radiology, 227, 332339.
Wang, Y. (2012). Principles of magnetic resonance imaging: Physics concepts, pulse
sequences, & biomedical applications. Charleston, SC: CreateSpace Independent
Publishing Platform.
Wang, M., Dai, Y., Han, Y., Haacke, E. M., Dai, J., & Shi, D. (2011). Susceptibility
weighted imaging in detecting hemorrhage in acute cervical spinal cord injury.
Magnetic Resonance Imaging, 29, 365373.
Wharton, S., & Bowtell, R. (2010). Whole-brain susceptibility mapping at high field: A
comparison of multiple- and single-orientation methods. NeuroImage, 53,
515525.
Wharton, S., & Bowtell, R. (2012). Fiber orientation-dependent white matter contrast in
gradient echo MRI. Proceedings of the National Academy of Sciences of the United
States of America, 109, 1855918564.
Wisnieff, C., Liu, T., Spincemaille, P., Wang, S., Zhou, D., & Wang, Y. (2013). Magnetic
susceptibility anisotropy: Cylindrical symmetry from macroscopically ordered
anisotropic molecules and accuracy of MRI measurements using few orientations.
NeuroImage, 70, 363376.
Witoszynskyj, S., Rauscher, A., Reichenbach, J. R., & Barth, M. (2009). Phase
unwrapping of MR images using Phi UN A fast and robust region growing
algorithm. Medical Image Analysis, 13, 257268.
Wu, B., Li, W., Guidon, A., & Liu, C. (2012). Whole brain susceptibility mapping using
compressed sensing. Magnetic Resonance in Medicine, 67, 137147.
Xu, Y., & Haacke, E. M. (2006). The role of voxel aspect ratio in determining apparent
vascular phase behavior in susceptibility weighted imaging. Magnetic Resonance
Imaging, 24, 155160.
Xu, B., Liu, T., Spincemaille, P., Prince, M., & Wang, Y. (2013). Flow compensated
quantitative susceptibility mapping for venous oxygenation imaging. Magnetic
Resonance in Medicine, http://dx.doi.org/10.1002/mrm.24937.
Yablonskiy, D. A., Sukstanskii, A. L., Luo, J., & Wang, X. (2013). Voxel spread
function method for correction of magnetic field inhomogeneity effects in
quantitative gradient-echo-based MRI. Magnetic Resonance in Medicine, 70(5),
12831292.
Yang, Q., Liu, J., Barnes, S. R. S., Wu, Z., Li, K., Neelavalli, J., et al. (2009). Imaging the
vessel wall in major peripheral arteries using susceptibility-weighted imaging.
Journal of Magnetic Resonance Imaging, 30, 357365.
Zheng, W., Haacke, E. M., Webb, S. M., & Nichol, H. (2012). Imaging of stroke: A
comparison between X-ray fluorescence and magnetic resonance imaging methods.
Magnetic Resonance Imaging, 30, 14161423.
Zheng, W., Nichol, H., Liu, S., Cheng, Y.-C. N., & Haacke, E. M. (2013). Measuring iron
in the brain using quantitative susceptibility mapping and X-ray fluorescence
imaging. NeuroImage, 78, 6874.
Zhou, D., Liu, T., Spincemaille, P., & Wang, Y. (2013). Background field removal by
solving the laplacian boundary value problem. NMR in Biomedicine, 27(3),
312319.
Glossary
Nomenclature
GRAPPA
EPI
fMRI
MRI
RF
SENSE
SMASH
SNR
ASL
BOLD
CMRO2
Introduction
The discovery of functional magnetic resonance imaging
(fMRI) in the spring of 1991 started revolution in brain imaging. With fMRI, it was possible to noninvasively map human
brain activation at a temporal resolution on the order of seconds and a spatial resolution on the order of millimeters using
a slightly modified clinical MRI scanner. This was a breakthrough in functional imaging methodology and remains the
method of choice for mapping brain activation in humans.
While the technique has limitations, even after over 20 years,
it continues to improve steadily in sophistication. With these
improvements, applications continue to expand.
Within a very short time after the first fMRI experiments
were reported, researchers around the world were designing
experiments that tested the limits of fMRI. This article looks
closely at the hardware, pulse sequence, and physiological
determinants of the spatial and temporal limits of fMRI.
fMRI benefits from advances coming from a wide range of
areas, including physics, engineering, signal processing, and neuroscience. Figure 1 shows what I like to call the four pillars of
fMRI: hardware and pulse sequences, methodology, interpretation, and applications. Advancement of fMRI fundamentally
requires input and iteration among these four areas. As methods
improve, more sophisticated applications and more in-depth
interpretation are possible. As the technology advances with
higher fields, better coils, and more sophisticated pulse
http://dx.doi.org/10.1016/B978-0-12-397025-1.00020-8
173
174
Technology
Methodology
Coil arrays
High field strength
High resolution
Novel sequences
Paradigm design
Univariate/multivariate
Multi-modal integration
Real-time feedback
Classification
Fluctuations
Dynamics
Functional resolution
Interpretation
Applications
(ASL; Detre, Leigh, Williams, & Koretsky, 1992). ASL is sensitive to blood perfusion and to changes in perfusion with
activation. With ASL, blood is labeled with a radio frequency
(RF) pulse. This RF-labeled inflowing blood alters the signal in
the plane being imaged in proportion to the perfusion in each
voxel. ASL is unique in that maps of baseline and active-state
perfusion may be made, whereas with BOLD contrast, only
maps of changes can be obtained. ASL, while having lower SNR
than BOLD, has a very stable baseline and the potential for
quantification.
Other techniques for noninvasive assessment of brain physiology and physiological changes with activation include the
mapping of blood volume (Lu, Golay, Pekar, & Van zijl, 2003),
cerebral oxidative metabolic rate (Davis, Kwong, Weisskoff, &
Rosen, 1998; Hoge et al., 1999), temperature (Yablonskiy,
Ackerman, & Raichle, 2000), and diffusion coefficient (Le
bihan, Urayama, Aso, Hanakawa, & Fukuyama, 2006). In theory, MRI is sensitive to subtle changes in magnetic fields
induced by neuronal activity (Bandettini, Petridou, & Bodurka,
2005), yet efforts to image this effect in humans have been
largely unsuccessful. Increases in sensitivity and specificity may
allow neuronal current imaging to be feasible in the future.
BOLD fMRI is the brain activation mapping contrast of
choice for almost all neuroscientists because it is the easiest
to implement and is the most sensitive (temporal contrast to
noise ratio ranges from 1 to 10) by a factor of 24 relative to
other MRI-based methods. The need for sensitivity and ease of
use outweighs, most of the time, the advantages in specificity,
quantitation, or baseline information inherent to ASL.
Picking up in 1992, only a handful of laboratories could
perform fMRI because it required not only an MRI scanner but
also the capability of performing high-speed MRI and highly
stable EPI. EPI is a technique by which an entire image (or
plane) is collected with the use of a single RF pulse and a
single subsequent signal echo hence the name EPI. Collecting an entire image in 30 ms (as with EPI) freezes physiological processes that contribute in slower multishot methods to
nonrepeatable artifacts. EPI has significantly higher temporal
stability than multishot techniques, which is critical for fMRI.
Until about 1996, the hardware for performing EPI was not
available on clinical systems. Now, practically every standard
MRI scanner is equipped to perform EPI.
The pulse sequence typically used since about 1993 is
gradient-echo EPI. Typical (or slightly outdated) parameters
are echo time (TE), 40 ms; matrix size, 64 64; field of view,
24 cm; and slice thickness, 4 mm (voxel dimension of about
4 mm 4 mm 4 mm). Today, using accelerated techniques
with local RF coil arrays, voxel dimensions of
1.5 mm 1.5 mm 1.5 mm can be obtained routinely
(Feinberg et al., 2010; Pruessmann, Weiger, Scheidegger, &
Boesiger, 1999; Setsompop et al., 2012). Typically, wholebrain volume coverage using a TR of 2 s is performed. Time
series are collected, lasting on the order of 58 min. A typical
experiment involves the collection of multiple time series per
subject scanning session. The practical upper limit of time to
keep a subject in the scanner is about 2 h allowing for about
an hour of functional time series collection. Regarding hardware, in about the year 2002, the standard field strength
increased from 1.5 to 3 T, improving sensitivity as both MRI
signal and BOLD contrast (Ogawa et al., 1993) increase with
field strength. Up until about 1999, the standard practice was
175
blood volume relative to flow and metabolic rate, (2) a perseveration of metabolic rate relative to flow and volume, and (3) a
postundershoot in flow. Currently, there is no clear consensus
on which mechanism determines the postundershoot as papers
have demonstrated evidence for each of the three.
A transient (<500 ms) preundershoot (Hu, Le, & Ugurbil,
1997) is much more rarely seen in fMRI. In fact, its very
existence has been debated for at least 15 years. The leading
hypothesis for this transient is an increase in oxidative metabolic rate that slightly precedes an increase in flow, leading to a
negative deflection of the BOLD signal.
The BOLD signal change magnitude is sensitive to both
physical (i.e., MRI) and physiological variables. The magnitude
of the BOLD signal change is directly dependent on field
strength and TE. The physiological variables that influence
the BOLD signal can vary on a voxel-wise basis, providing a
challenge for the user who would like to draw neuronal inferences from the signal change. The primary physiological determinant of the magnitude of the BOLD signal is the resting
blood volume per voxel as this can range from 2% to 100%
(large draining vein).
The fMRI signal change latency can vary up to 4 s from
region to region. The latency variation across the brain roughly
follows the signal change magnitude, with the primary determining variable, again, being the baseline blood volume. The
working model is that large draining veins are typically downstream and therefore experience changes in oxygenation at a
later time than venules and capillaries adjacent to the region of
activation.
Methods for looking through the hemodynamics are continually developed. These include task timing modulation
(Menon, Luknowsky, & Gati, 1998), parametric manipulation
of the task intensity or neuronal activity, large vessel masking,
and calibration approaches.
In the following two sections, the spatial and temporal
limits of fMRI as well as the determining factors of these
limits are described in detail.
Spatial Limits
The spatial limits of fMRI are determined by the available SNR,
scanning hardware, pulse sequence, neurovascular coupling
specificity, and brain activation paradigm design. With regard
to spatial limits, it is interesting that the current upper limit of
functional resolution just less than 0.5 mm approximately
matches the smallest functional unit of brain function delineation known that of cortical columns. Neuronal populations at more fine delineations are more homogeneous. If this
remains true, it would be a fortuitous match of fMRI limits to
the limits of cortical unit organization.
176
177
178
advantage of higher contrast and sensitivity and less intravascular signal. BOLD contrast is more selective to capillaries at higher
field for two reasons: First, because of the stronger effect of field
strength on T2* of blood than tissue, there is less intravascular
(and therefore large vessel) signal. Second, small compartment
dephasing effects show a slightly higher Bo dependence than
large compartment; therefore capillary effects, while still small,
will be somewhat greater relative to these effects at low field.
ASL, a method for imaging baseline and changes in perfusion, is known to be minimally sensitive to large vessel effects.
ASL is highly selective to imaging brain activation-related
changes in capillary perfusion. This technique has the added
advantages of high temporal stability, the option for quantitation, and the ability to obtain maps of baseline perfusion. The
disadvantages of this method include a lower functional contrast to noise than BOLD by a factor of about 24, a necessity
for a longer TR to allow for the tagging pulse, and a limit to the
spatial coverage per TR.
Outer volume spin saturation has also been used to eliminate inflow effects and therefore upstream flow changes. Typically, this is not a major problem for multislice acquisition as
most slices have adjacent slices that are naturally saturated.
The upper spatial resolution of fMRI appears to be ultimately determined by the hemodynamics. In humans, individual orientation column activations (<0.5 mm; Yacoub et al.,
2008) and specific cortical layer function have been successfully imaged.
Temporal Limits
Similar to the spatial limits of fMRI, the temporal limits are
also determined by SNR, scanning hardware, pulse sequence,
hemodynamic response, and brain activation paradigm timing. However, in contrast to spatial limits which appear to
fortuitously match the upper limit of the spatial organization
of neurons the sluggish and spatially variable hemodynamic
response is the most significant determinant of the upper limits
of temporal resolution and is much slower than what is known
about the rapidity with which neurons and cortical areas communicate. It is also possible to scan much faster than the limits
imposed by the hemodynamic sluggishness and uncertainty.
The limit imposed by hemodynamics is on the order of seconds, whereas the limit imposed by hardware could be as short
as 100 ms. Neuronal firing occurs on the order of milliseconds.
So, importantly, the upper temporal resolution of fMRI is three
orders of magnitude slower than the neuronal firing rate, yet
the spatial resolution of fMRI is on the same order of magnitude as the spatial distribution and size of functional units.
Before delving further into temporal resolution limits, it is
important to outline what is specifically meant by temporal
resolution limits. Temporal resolution can have the following
definitions: (1) fastest image acquisition rate or fastest volume
acquisition rate, (2) minimum time for the signal to deviate
significantly from baseline, (3) fastest rate at which the brain
can be repeatedly turned on and off and still elicit a signal
change, (4) minimum time that the brain can be turned on and
still elicit a signal change, (5) standard deviation of the baseline signal, (6) standard deviation over time of the hemodynamic response, and (7) standard deviation or simply
179
Latency
-2 s
Magnitude
Venogram
50
2100
40
2080
2060
30
2040
20
2020
10
2000
1980
8 10 12 14 16 18 20
Time (s)
-2
-1.5
-1
-0.5
0
0.5
Delay (s)
1.5
Figure 3 The primary limits on the temporal resolution unpublished data. A simple finger-tapping task was performed for 1 s. Multiple averages were
obtained. The hemodynamic response easily captures the 1 s stimulation; however, a spread in latencies of 2 s occurs within the motor cortex.
This spread is spatially correlated with the magnitude and the venogram shows where large vessels are. Large draining veins receive oxygenated
blood from active tissue. This represents the major obstacle for high-resolution fMRI the spatial heterogeneity of the hemodynamic response.
180
Regions of interest
(a)
(b)
(a)
(b)
Precentral gyrus
(a)
(b)
Conclusion
This article covered some of the history of fMRI and basics of
the hemodynamic response and then delineated the MRI
acquisition parameters and hemodynamic variables associated
with the current limits in the spatial resolution and temporal
resolution of fMRI. With regard to spatial resolution, fMRI is
doing quite well able to resolve down to the smallest known
unit of functional organization in the brain: orientation
columns. With regard to temporal resolution, fMRI can acquire
whole-brain data quite rapidly but cannot with certainty
differentiate relative onset times from different regions of
the brain that occur closer in time than about 2 s. However,
there are still opportunities for calibration and the potential
for increased hemodynamic specificity allowing, assuming
enough SNR, more precise delineation of shorter time differences in the future. Clever paradigms can differentiate onset
modulation down to less than 100 ms and can resolve
See also: INTRODUCTION TO ACQUISITION METHODS: EchoPlanar Imaging; Evolution of Instrumentation for Functional Magnetic
Resonance Imaging; fMRI at High Magnetic Field: Spatial Resolution
Limits and Applications; Functional Near-Infrared Spectroscopy; HighSpeed, High-Resolution Acquisitions; Obtaining Quantitative
Information from fMRI; Obtaining Quantitative Information from fMRI;
Perfusion Imaging with Arterial Spin Labeling MRI; Pulse Sequence
Dependence of the fMRI Signal; Susceptibility-Weighted Imaging and
Quantitative Susceptibility Mapping; INTRODUCTION TO
COGNITIVE NEUROSCIENCE: Reading; INTRODUCTION TO
METHODS AND MODELING: Artifacts in Functional MRI and How to
Mitigate Them; Computing Brain Change over Time; Convolution
Models for FMRI; Design Efficiency; Dynamic Causal Models for fMRI;
Effective Connectivity; Granger Causality; Resting-State Functional
Connectivity; INTRODUCTION TO SYSTEMS: Large-Scale
Functional Brain Organization.
Bibliography
Aguirre, G. K., & Detre, J. A. (2012). The development and future of perfusion fMRI for
dynamic imaging of human brain activity. Neuroimage, 62, 12791285.
Bandettini, P. A. (2012). Sewer pipe, wire, epoxy, and finger tapping: The start of fMRI at
the Medical College of Wisconsin. Neuroimage, 62, 620631.
Bandettini, P. A., Petridou, N., & Bodurka, J. (2005). Direct detection of neuronal
activity with MRI: Fantasy, possibility, or reality? Applied Magnetic Resonance, 29,
6588.
Bandettini, P. A., Wong, E. C., Hinks, R. S., Tikofsky, R. S., & Hyde, J. S. (1992). Time
course EPI of human brain-function during task activation. Magnetic Resonance in
Medicine, 25, 390397.
Bandettini, P. A., Wong, E. C., Jesmanowicz, A., Hinks, R. S., & Hyde, J. S. (1994).
Spin-echo and gradient-echo EPI of human brain activation using bold contrast A
comparative-study at 1.5 T. NMR in Biomedicine, 7, 1220.
Bellgowan, P. S.F, Saad, Z. S., & Bandettini, P. A. (2003). Understanding neural system
dynamics through task modulation and measurement of functional MRI amplitude,
latency, and width. Proceedings of the National Academy of Sciences of the United
States of America, 100, 14151419.
Belliveau, J. W., Kennedy, D. N., Mckinstry, R. C., Buchbinder, B. R., Weisskoff, R. M.,
Cohen, M. S., et al. (1991). Functional mapping of the human visual-cortex by
magnetic-resonance-imaging. Science, 254, 716719.
Birn, R. M., Saad, Z. S., & Bandettini, P. A. (2001). Spatial heterogeneity of the
nonlinear dynamics in the fMRI BOLD response. Neuroimage, 14, 817826.
Blaimer, M., Breuer, F., Mueller, M., Heidemann, R. M., Griswold, M. A., & Jakob, P. M.
(2004). SMASH, SENSE, PILS, GRAPPA: How to choose the optimal method.
Topics in Magnetic Resonance Imaging, 15, 223236.
Bodurka, J., Ye, F., Petridou, N., Murphy, K., & Bandettini, P. A. (2007). Mapping the
MRI voxel volume in which thermal noise matches physiological noise
Implications for fMRI. Neuroimage, 34, 542549.
Boxerman, J. L., Bandettini, P. A., Kwong, K. K., Baker, J. R., Davis, T. L., Rosen, B. R.,
et al. (1995). The intravascular contribution to fMRI signal change Monte-carlo
modeling and diffusion-weighted studies in-vivo. Magnetic Resonance in Medicine,
34, 410.
Buxton, R. B. (2001). The elusive initial dip. Neuroimage, 13, 953958.
181
Buxton, R. B., Wong, E. C., & Frank, L. R. (1998). Dynamics of blood flow and
oxygenation changes during brain activation: The balloon model. Magnetic
Resonance in Medicine, 39, 855864.
Cheng, K., Waggoner, R. A., & Tanaka, K. (2001). Human ocular dominance columns as
revealed by high-field functional magnetic resonance imaging. Neuron, 32,
359374.
Davis, T. L., Kwong, K. K., Weisskoff, R. M., & Rosen, B. R. (1998). Calibrated
functional MRI: Mapping the dynamics of oxidative metabolism. Proceedings of
the National Academy of Sciences of the United States of America, 95,
18341839.
Detre, J. A., Leigh, J. S., Williams, D. S., & Koretsky, A. P. (1992). Perfusion imaging.
Magnetic Resonance in Medicine, 23, 3745.
Feinberg, D. A., Moeller, S., Smith, S. M., Auerbach, E., Ramanna, S., Gunther, M., et al.
(2010). Multiplexed echo planar imaging for sub-second whole brain FMRI and fast
diffusion imaging. PLoS One, 5, e15710.
Formisano, E., & Goebel, R. (2003). Tracking cognitive processes with functional MRI
mental chronometry. Current Opinion in Neurobiology, 13, 174181.
Griswold, M. A., Jakob, P. M., Heidemann, R. M., Nittka, M., Jellus, V., Wang, J., et al.
(2002). Generalized autocalibrating partially parallel acquisitions (GRAPPA).
Magnetic Resonance in Medicine, 47, 12021210.
Hennig, J. (2012). Functional spectroscopy to no-gradient fMRI. Neuroimage, 62,
693698.
Henson, R. N., Price, C. J., Rugg, M. D., Turner, R., & Friston, K. J. (2002).
Detecting latency differences in event-related BOLD responses: Application to words
versus nonwords and initial versus repeated face presentations. Neuroimage, 15,
8397.
Hoge, R. D., Atkinson, J., Gill, B., Crelier, G. R., Marrett, S., & Pike, G. B. (1999).
Investigation of BOLD signal dependence on cerebral blood flow and oxygen
consumption: The deoxyhemoglobin dilution model. Magnetic Resonance in
Medicine, 42, 849863.
Hu, X. P., Le, T. H., & Ugurbil, K. (1997). Evaluation of the early response in fMRI in
individual subjects using short stimulus duration. Magnetic Resonance in Medicine,
37, 877884.
Jones, R. A. (1999). Origin of the signal undershoot in BOLD studies of the visual
cortex. NMR in Biomedicine, 12, 301308.
Kwong, K. K. (2012). Record of a single fMRI experiment in May of 1991. Neuroimage,
62, 610612.
Kwong, K. K., Belliveau, J. W., Chesler, D. A., Goldberg, I. E., Weisskoff, R. M.,
Poncelet, B. P., et al. (1992). Dynamic magnetic-resonance-imaging of human brain
activity during primary sensory stimulation. Proceedings of the National Academy of
Sciences of the United States of America, 89, 56755679.
Le bihan, D., Urayama, S. I., Aso, T., Hanakawa, T., & Fukuyama, H. (2006). Direct and
fast detection of neuronal activation in the human brain with diffusion MRI.
Proceedings of the National Academy of Sciences of the United States of America,
103, 82638268.
Lin, F. H., Tsai, K. W., Chu, Y. H., Witzel, T., Nummenmaa, A., Raij, T., et al. (2012).
Ultrafast inverse imaging techniques for fMRI. Neuroimage, 62, 699705.
Liu, H. L., Pu, Y. L., Nickerson, L. D., Liu, Y. J., Fox, P. T., & Gao, J. H. (2000).
Comparison of the temporal response in perfusion and BOLD-based event-related
functional MRI. Magnetic Resonance in Medicine, 43, 768772.
Logothetis, N. K., Merkle, H., Augath, M., Trinath, T., & Ugurbil, K. (2002).
Ultra high-resolution fMRI in monkeys with implanted RF coils. Neuron, 35,
227242.
Lu, H., Golay, X., Pekar, J. J., & Van zijl, P. C.M (2003). Functional magnetic resonance
imaging based on changes in vascular space occupancy. Magnetic Resonance in
Medicine, 50, 263274.
Lu, H., & Van zijl, P. C. (2012). A review of the development of Vascular-SpaceOccupancy (VASO) fMRI. Neuroimage, 62, 736742.
Mansfield, P., Coxon, R., & Hykin, J. (1995). Echo-volumar imaging (EVI) of the brain
at 3.0 T First normal volunteer and functional imaging results. Journal of
Computer Assisted Tomography, 19, 847852.
Menon, R. S. (2002). Postacquisition suppression of large-vessel BOLD signals in
high-resolution fMRI. Magnetic Resonance in Medicine, 47, 19.
Menon, R. S. (2012). The great brain versus vein debate. Neuroimage, 62, 970974.
Menon, R. S., & Kim, S. G. (1999). Spatial and temporal limits in cognitive
neuroimaging with fMRI. Trends in Cognitive Sciences, 3, 207216.
Menon, R. S., Luknowsky, D. C., & Gati, J. S. (1998). Mental chronometry using
latency-resolved functional MRI. Proceedings of the National Academy of Sciences
of the United States of America, 95, 1090210907.
Menon, R. S., Ogawa, S., Hu, X., Strupp, J. P., Anderson, P., & Ugurbil, K. (1995).
BOLD based functional MRI at 4 Tesla includes a capillary bed contribution: Echoplanar imaging correlates with previous optical imaging using intrinsic signals.
Magnetic Resonance in Medicine, 33, 453459.
182
Menon, R. S., Ogawa, S., Strupp, J. P., & Ugurbil, K. (1997). Ocular dominance in
human V1 demonstrated by functional magnetic resonance imaging. Journal of
Neurophysiology, 77, 27802787.
Ogawa, S., & Lee, T. M. (1990). Magnetic-resonance-imaging of blood-vessels at high
fields In vivo and in vitro measurements and image simulation. Magnetic
Resonance in Medicine, 16, 918.
Ogawa, S., Lee, T. M., Nayak, A. S., & Glynn, P. (1990). Oxygenation-sensitive contrast
in magnetic-resonance image of rodent brain at high magnetic-fields. Magnetic
Resonance in Medicine, 14, 6878.
Ogawa, S., Lee, T. M., Stepnoski, R., Chen, W., Zhuo, X. H., & Ugurbil, K. (2000). An
approach to probe some neural systems interaction by functional MRI at neural time
scale down to milliseconds. Proceedings of the National Academy of Sciences of the
United States of America, 97, 1102611031.
Ogawa, S., Menon, R. S., Tank, D. W., Kim, S. G., Merkle, H., Ellermann, J. M., et al.
(1993). Functional brain mapping by blood oxygenation level-dependent contrast
magnetic-resonance-imaging A comparison of signal characteristics with a
biophysical model. Biophysical Journal, 64, 803812.
Ogawa, S., Tank, D. W., Menon, R., Ellermann, J. M., Kim, S. G., Merkle, H., et al.
(1992). Intrinsic signal changes accompanying sensory stimulation Functional
brain mapping with magnetic-resonance-imaging. Proceedings of the National
Academy of Sciences of the United States of America, 89, 59515955.
Ordidge, R. J., Coxon, R., Howseman, A., Chapman, B., Turner, R., Stehling, M., et al.
(1988). Snapshot head imaging at 0.5 T using the echo planar technique. Magnetic
Resonance in Medicine, 8, 110115.
Ordidge, R. J., Howseman, A., Coxon, R., Turner, R., Chapman, B., Glover, P., et al.
(1989). Snapshot imaging at 0.5 T using echo-planar techniques. Magnetic
Resonance in Medicine, 10, 227240.
Pruessmann, K. P., Weiger, M., Bornert, P., & Boesiger, P. (2001). Advances in
sensitivity encoding with arbitrary k-space trajectories. Magnetic Resonance in
Medicine, 46, 638651.
Pruessmann, K. P., Weiger, M., Scheidegger, M. B., & Boesiger, P. (1999). SENSE:
Sensitivity encoding for fast MRI. Magnetic Resonance in Medicine, 42, 952962.
Setsompop, K., Gagoski, B. A., Polimeni, J. R., Witzel, T., Wedeen, V. J., & Wald, L. L.
(2012). Blipped-controlled aliasing in parallel imaging for simultaneous multislice
echo planar imaging with reduced g-factor penalty. Magnetic Resonance in
Medicine, 67, 12101224.
Setsompop, K., Kimmlingen, R., Eberlein, E., Witzel, T., Cohen-Adad, J., Mcnab, J. A.,
et al. (2013). Pushing the limits of in vivo diffusion MRI for the Human Connectome
Project. Neuroimage, 80, 220233.
Song, A. W., Wong, E. C., & Hyde, J. S. (1994). Echo-volume imaging. Magnetic
Resonance in Medicine, 32, 668671.
Song, A. W., Wong, E. C., Tan, S. G., & Hyde, J. S. (1996). Diffusion weighted fMRI at
1.5 T. Magnetic Resonance in Medicine, 35, 155158.
Turner, R., Lebihan, D., Moonen, C. T.W, Despres, D., & Frank, J. (1991). Echo-planar
time course MRI of cat brain oxygenation changes. Magnetic Resonance in
Medicine, 22, 159166.
Ugurbil, K. (2012). Development of functional imaging in the human brain (fMRI): The
University of Minnesota experience. Neuroimage, 62, 613619.
Wang, J., Aguirre, G. K., Kimberg, D. Y., Roc, A. C., Li, L., & Detre, J. A. (2003). Arterial
spin labeling perfusion fMRI with very low task frequency. Magnetic Resonance in
Medicine, 49, 796802.
Wong, E. C., Luh, W. M., & Liu, T. T. (2000). Turbo ASL: Arterial spin labeling with higher
SNR and temporal resolution. Magnetic Resonance in Medicine, 44, 511515.
Yablonskiy, D. A., Ackerman, J. J.H, & Raichle, M. E. (2000). Coupling between
changes in human brain temperature and oxidative metabolism during prolonged
visual stimulation. Proceedings of the National Academy of Sciences of the United
States of America, 97, 76037608.
Yacoub, E., Harel, N., & Ugurbil, K. (2008). High-field fMRI unveils orientation columns
in humans. Proceedings of the National Academy of Sciences of the United States of
America, 105, 1060710612.
Abbreviations
Introduction
Magnetic resonance imaging (MRI) has revolutionized brain
imaging since the first MR images were collected showing
excellent soft tissue contrast with high spatial resolution. The
contrast characteristics obtainable with MRI were unprecedented compared to existing modalities at the time, and basic
T1 and T2 contrast imaging approaches have since been
extended to depict iron and myelin content, diffusion, perfusion, functional activation, and functional connectivity.
Within each of these realms, there are numerous applications
to understanding the neurophysiology of the brain and the
normal and abnormal distribution of the parameters these
methods measure, as a function of age, gender, genotype, or
disease. In this article, we review some of the more recent
developments in acquisition strategies for different brain imaging applications with emphasis on the information such
methods can provide, and some of their strengths and weaknesses. The article is divided into three sections covering highresolution anatomical imaging (morphometry), microstructural imaging (based on diffusion imaging), and functional
imaging (chiefly blood oxygenation level-dependent (BOLD)
contrast but also considering measures of cerebral blood flow
(CBF) and blood volume (CBV)).
performance, in addition to providing an accurate brain volume for registration of multiple subjects.
Submillimeter anatomical scans are now being obtained at
7 T or higher. At such high field strengths, additional steps are
often needed to account for radio frequency (RF) inhomogeneities on both transmit and receive sides of the equation
(Adriany et al., 2005; Lutti et al., 2012; Van de Moortele
et al., 2005), compensation for susceptibility effects, and the
resultant loss of signal or geometric distortion. High-resolution
acquisitions also benefit from prospective motion correction
(Schulz et al., 2012). T*
2 mapping (Cohen-Adad et al., 2012 at
7 T, Budde, Shajan, Hoffmann, Ugurbil, & Pohmann, 2011 at
9.4 T), susceptibility mapping (Deistung et al., 2013; Schafer
et al., 2012), and frequency difference mapping (Wharton &
Bowtell, 2012) methods have provided exquisite depictions of
neuroanatomy, as well as insights into iron and/or myelin
concentrations and orientations of underlying structures. The
measurement of myelin content in the cortex has recently
garnered great attention, and there is much interest in examining the relationship between functional activity as measured by
functional magnetic resonance imaging (fMRI) and myelin
content (Barazany & Assaf, 2012; Bock et al., 2013; Lutti
et al., 2012).
http://dx.doi.org/10.1016/B978-0-12-397025-1.00021-X
183
184
multislice acquisition and compressive sampling reconstruction with a custom 64-channel brain array at 3 T (Setsompop
et al., 2013). Such developments could enable new insights
into connectional neuroanatomy and the operation of neural
networks, as demonstrated by the ability to probe the distribution of axonal diameters in vivo, as a noninvasive index of
action potential conduction velocity (McNab et al., 2013).
185
186
Additional Considerations
Sinuses and other air-tissue interfaces cause large susceptibility
gradients especially near orbitofrontal and inferior temporal
regions of the brain. EPI acquisitions are associated with
extended readout durations (along the phase encoding direction), exacerbating erroneous phase accumulation in these
regions, leading to severe image artifacts such as geometric
distortions, signal intensity variations, and complete signal
loss. These artifacts can be partially corrected or compensated
for using additional acquisitions, that is, field mapping (Aksit,
Derbyshire, & Prince, 2007; Jezzard & Balaban, 1995), point
spread function mapping (Dragonu et al., 2013; Robson, Gore,
& Constable, 1997; Zaitsev, Hennig, & Speck, 2004; Zeng &
Constable, 2002), and z-shimming (Constable, 1995; Constable & Spencer, 1999) methods (in-plane or through-plane).
Shortening the readout duration (along the phase encoding
direction), by using parallel imaging methods or multishot
acquisitions, is very effective for reducing artifact severity.
Similarly high-bandwidth acquisitions reduce the length of
the readout window and hence geometric distortion, but at
the cost of decreased SNR. Spiral-in/spiral-out (Glover & Law,
Summary
In summary, many advances continue to be made in the development of high spatial and temporal resolution MRI acquisition strategies. In anatomical scanning, the move to higher
field strength has provided unprecedented opportunities for
improving spatial resolution while producing images with very
high SNR. Advances in diffusion imaging have led to extensive
improvements in fiber tracking, and the integration of structural information with functional information is really just
beginning. In functional MRI, advances continue to be made
in the development of sequences that are maximally sensitive
to neuronal activity and minimally sensitive to motion and
other sources of artifacts. The field continues to expand rapidly
and new applications of MRI are constantly invented.
References
Adriany, G., Van de Moortele, P. F., Wiesinger, F., Moeller, S., Strupp, J. P.,
Andersen, P., et al. (2005). Transmit and receive transmission line arrays for 7 Tesla
parallel imaging. Magnetic Resonance in Medicine, 53(2), 434445.
Aguirre, G. K., Detre, J. A., Zarahn, E., & Alsop, D. C. (2002). Experimental design and
the relative sensitivity of BOLD and perfusion fMRI. NeuroImage, 15(3), 488500.
Aksit, P., Derbyshire, J. A., & Prince, J. L. (2007). Three-point method for fast and
robust field mapping for EPI geometric distortion correction. In: 4th IEEE ISBI:
International Symposium on Biomedical Imaging, Washington DC.
Barazany, D., & Assaf, Y. (2012). Visualization of cortical lamination patterns with
magnetic resonance imaging. Cerebral Cortex, 22(9), 8.
Basser, P. J., Mattiello, J., & LeBihan, D. (1994). MR diffusion tensor spectroscopy and
imaging. Biophysical Journal, 66(1), 259267.
Basser, P. J., Pajevic, S., Pierpaoli, C., Duda, J., & Aldroubi, A. (2000). In vivo fiber
tractography using DT-MRI data. Magnetic Resonance in Medicine, 44(4), 625632.
Biswal, B., Yetkin, F. Z., Haughton, V. M., & Hyde, J. S. (1995). Functional connectivity
in the motor cortex of resting human brain using echo-planar MRI. Magnetic
Resonance in Medicine, 34(4), 537541.
Bock, N. A., Hashim, E., Janik, R., Konyer, N. B., Weiss, M., Stanisz, G. J., et al. (2013).
Optimizing T1-weighted imaging of cortical myelin content at 3.0 T. NeuroImage,
65, 112.
Bodurka, J., & Bandettini, P. A. (2002). Toward direct mapping of neuronal activity: MRI
detection of ultraweak, transient magnetic field changes. Magnetic Resonance in
Medicine, 47(6), 10521058.
Brewer, K. D., Rioux, J. A., DArcy, R. C., Bowen, C. V., & Beyea, S. D. (2009).
Asymmetric spin-echo (ASE) spiral improves BOLD fMRI in inhomogeneous
regions. NMR in Biomedicine, 22(6), 654662.
Budde, J., Shajan, G., Hoffmann, J., Ugurbil, K., & Pohmann, R. (2011). Human
imaging at 9.4 T using T(2) *-, phase-, and susceptibility-weighted contrast.
Magnetic Resonance in Medicine, 65(2), 544550.
187
Budde, J., Shajan, G., Zaitsev, M., Scheffler, K., & Functional, Pohmann R. (2013). MRI
in human subjects with gradient-echo and spin-echo EPI at 9.4 T. Magnetic
Resonance in Medicine, 71, 209218.
Buxton, R. B. (2012). Dynamic models of BOLD contrast. NeuroImage, 62, 953961.
Buxton, R. B., Frank, L. R., Wong, E. C., Siewert, B., Warach, S., & Edelman, R. R.
(1998). A general kinetic model for quantitative perfusion imaging with arterial spin
labeling. Magnetic Resonance in Medicine, 40(3), 383396.
Buxton, R. B., Wong, E. C., & Frank, L. R. (1998). Dynamics of blood flow and
oxygenation changes during brain activation: The balloon model. Magnetic
Resonance in Medicine, 39(6), 855864.
Callaghan, P. (1991). Principles of nuclear magnetic resonance microscopy. Oxford,
UK: Oxford Science Publications, Clarendon Press.
Callaghan, P. T., Eccles, C. D., & Xia, Y. (1988). NMR microscopy of dynamic
displacements k-space and q-space imaging. Journal of Physics E: Scientific
Instruments, 21, 820822.
Chen, J. J., & Pike, G. B. (2009). BOLD-specific cerebral blood volume and blood flow
changes during neuronal activation in humans. NMR in Biomedicine, 22(10),
10541062.
Chu, R., de Zwart, J. A., van Gelderen, P., Fukunaga, M., Kellman, P., Holroyd, T., et al.
(2004). Hunting for neuronal currents: Absence of rapid MRI signal changes during
visual-evoked response. NeuroImage, 23(3), 10591067.
Ciris, P. A., Qiu, M., & Constable, R. T. (2014). Noninvasive MRI measurement of
the absolute cerebral blood volume-cerebral blood flow relationship during
visual stimulation in healthy humans. Magnetic Resonance in Medicine, 72(3),
864875.
Ciris, P. A., Qiu, M., & Constable, R. T. (2014). Non-invasive quantification of absolute
cerebral blood volume during functional activation applicable to the whole
human brain. Magnetic Resonance in Medicine, 71, 580590.
Cohen-Adad, J., Polimeni, J. R., Helmer, K. G., Benner, T., McNab, J. A., Wald, L. L.,
et al. (2012). T(2)* mapping and B(0) orientation-dependence at 7 T reveal cytoand myeloarchitecture organization of the human cortex. NeuroImage, 60(2),
10061014.
Constable, R. T. (1995). Functional MR, imaging using gradient-echo echo-planar
imaging in the presence of large static field inhomogeneities. Journal of Magnetic
Resonance Imaging, 5(6), 746752.
Constable, R. T., Kennan, R. P., Puce, A., McCarthy, G., & Functional, Gore J. C.
(1994). NMR imaging using fast spin echo at 1.5 T. Magnetic Resonance in
Medicine, 31(6), 686690.
Constable, R. T., Scheinost, D., Finn, E. S., Shen, X., Hampson, M., Winstanley, F. S.,
et al. (2013). Potential use and challenges of functional connectivity mapping in
intractable epilepsy. Frontiers in Neurology, 4, 39.
Constable, R. T., & Spencer, D. D. (1999). Composite image formation in z-shimmed
functional MR imaging. Magnetic Resonance in Medicine, 42(1), 110117.
Constable, R. T., & Spencer, D. D. (2001). Repetition time in echo planar functional
MRI. Magnetic Resonance in Medicine, 46(4), 748755.
Conturo, T. E., Lori, N. F., Cull, T. S., Akbudak, E., Snyder, A. Z., Shimony, J. S., et al.
(1999). Tracking neuronal fiber pathways in the living human brain. Proceedings of
the National Academy of Sciences of the United States of America, 96(18),
1042210427.
Cory, D. G., & Garroway, A. N. (1990). Measurement of translational displacement
probabilities by NMR: An indicator of compartmentation. Magnetic Resonance in
Medicine, 14(3), 435444.
De Martino, F., Schmitter, S., Moerel, M., Tian, J., Ugurbil, K., Formisano, E., et al.
(2012). Spin echo functional MRI in bilateral auditory cortices at 7 T: An application
of. NeuroImage, 63(3), 13131320.
Deistung, A., Schafer, A., Schweser, F., Biedermann, U., Turner, R., &
Reichenbach, J. R. (2013). Toward in vivo histology: A comparison of quantitative
susceptibility mapping. NeuroImage, 65, 299314.
Donahue, M. J., Sideso, E., MacIntosh, B. J., Kennedy, J., Handa, A., & Jezzard, P.
(2010). Absolute arterial cerebral blood volume quantification using inflow
vascular-space-occupancy with dynamic subtraction magnetic resonance imaging.
Journal of Cerebral Blood Flow and Metabolism, 30(7), 13291342.
Douek, P., Turner, R., Pekar, J., Patronas, N., & Le Bihan, D. (1991). MR color mapping
of myelin fiber orientation. Journal of Computer Assisted Tomography, 15(6),
923929.
Dragonu, I., Lange, T., Baxan, N., Snyder, J., Hennig, J., & Zaitsev, M. (2013).
Accelerated point spread function mapping using signal modeling for accurate
echo-planar imaging geometric distortion correction. Magnetic Resonance in
Medicine, 69(6), 16501656.
Drew, P. J., Shih, A. Y., & Kleinfeld, D. (2011). Fluctuating and sensory-induced
vasodynamics in rodent cortex extend arteriole capacity. Proceedings of the
National Academy of Sciences of the United States of America, 108(20),
84738478.
188
Edelman, R. R., Siewert, B., Adamis, M., Gaa, J., Laub, G., & Wielopolski, P. (1994).
Signal targeting with alternating radiofrequency (STAR) sequences: Application to
MR angiography. Magnetic Resonance in Medicine, 31(2), 233238.
Feinberg, D. A., Moeller, S., Smith, S. M., Auerbach, E., Ramanna, S., Gunther, M., et al.
(2010). Multiplexed echo planar imaging for sub-second whole brain FMRI and fast
diffusion imaging. PloS One, 5(12), e15710.
Feinberg, D. A., Reese, T. G., & Wedeen, V. J. (2002). Simultaneous echo refocusing in
EPI. Magnetic Resonance in Medicine, 48(1), 15.
Feinberg, D. A., & Setsompop, K. (2013). Ultra-fast MRI of the human brain with
simultaneous multi-slice imaging. Journal of Magnetic Resonance, 229, 90100.
Feng, C. M., Narayana, S., Lancaster, J. L., Jerabek, P. A., Arnow, T. L., Zhu, F., et al.
(2004). CBF changes during brain activation: fMRI vs. PET. NeuroImage, 22,
443446.
Gigandet, X. (2009). Global brain connectivity analysis by diffusion MR tractography:
Algorithms, validation and applications. Lausanne: Ecole Polytechnique Federale de
Lausanne.
Glielmi, C. B., Schuchard, R. A., & Hu, X. P. (2009). Estimating cerebral blood volume
with expanded vascular space occupancy slice coverage. Magnetic Resonance in
Medicine, 61(5), 11931200.
Glover, G. H., & Law, C. S. (2001). Spiral-in/out BOLD fMRI for increased SNR
and reduced susceptibility artifacts. Magnetic Resonance in Medicine, 46(3),
515522.
Griffeth, V. E., & Buxton, R. B. (2011). A theoretical framework for estimating cerebral
oxygen metabolism changes using the calibrated-BOLD method: Modeling the
effects of blood volume distribution, hematocrit, oxygen extraction fraction, and
tissue signal properties on the BOLD signal. NeuroImage, 58(1), 198212.
Griswold, M. A., Jakob, P. M., Heidemann, R. M., Nittka, M., Jellus, V., Wang, J., et al.
(2002). Generalized autocalibrating partially parallel acquisitions (GRAPPA).
Magnetic Resonance in Medicine, 47(6), 12021210.
Grubb, R. L., Jr., Raichle, M. E., Eichling, J. O., & Ter-Pogossian, M. M. (1974). The
effects of changes in PaCO2 on cerebral blood volume, blood flow, and vascular
mean transit time. Stroke: A Journal of Cerebral Circulation, 5(5), 630639.
Gu, H., Lu, H., Ye, F. Q., Stein, E. A., & Yang, Y. (2006). Noninvasive quantification of
cerebral blood volume in humans during functional activation. NeuroImage, 30(2),
377387.
Heberlein, K. A., & Hu, X. (2004). Simultaneous acquisition of gradient-echo and
asymmetric spin-echo for single-shot z-shim: Z-SAGA. Magnetic Resonance in
Medicine, 51(1), 212216.
Hennig, J., Welz, A. M., Schultz, G., Korvink, J., Liu, Z., Speck, O., et al. (2008). Parallel
imaging in non-bijective, curvilinear magnetic field gradients: A concept study.
Magma, 21(12), 514.
Hillman, E. M., Devor, A., Bouchard, M. B., Dunn, A. K., Krauss, G. W., Skoch, J., et al.
(2007). Depth-resolved optical imaging and microscopy of vascular compartment
dynamics during somatosensory stimulation. NeuroImage, 35(1), 89104.
Hua, J., Qin, Q., Pekar, J. J., & van Zijl, P. C. (2011). Measurement of absolute arterial
cerebral blood volume in human brain without using a contrast agent. NMR in
Biomedicine, 24(10), 13131325.
Huang, J. (2013). Detecting neuronal currents with MRI: A human study. Magnetic
Resonance in Medicine, 71, 756762.
Ito, H., Ibaraki, M., Kanno, I., Fukuda, H., & Miura, S. (2005). Changes in cerebral blood
flow and cerebral oxygen metabolism during neural activation measured by positron
emission tomography: Comparison with blood oxygenation level-dependent
contrast measured by functional magnetic resonance imaging. Journal of Cerebral
Blood Flow and Metabolism, 25(3), 371377.
Ito, H., Takahashi, K., Hatazawa, J., Kim, S. G., & Kanno, I. (2001). Changes in human
regional cerebral blood flow and cerebral blood volume during visual stimulation
measured by positron emission tomography. Journal of Cerebral Blood Flow and
Metabolism, 21(5), 608612.
Jansons, K. M., & Alexander, D. C. (2003). Persistent angular structure: New insights
from diffusion MRI data. Dummy version. Information Processing in Medical
Imaging, 18, 672683.
Jezzard, P., & Balaban, R. S. (1995). Correction for geometric distortion in echo
planar images from B0 field variations. Magnetic Resonance in Medicine, 34(1), 6573.
Jin, T., & Kim, S. G. (2008). Cortical layer-dependent dynamic blood oxygenation,
cerebral blood flow and cerebral blood volume responses during visual stimulation.
NeuroImage, 43(1), 19.
Jones, M., Berwick, J., & Mayhew, J. (2002). Changes in blood flow, oxygenation, and
volume following extended stimulation of rodent barrel cortex. NeuroImage, 15(3),
474487.
Josephs, O., Turner, R., & Friston, K. (1997). Event-related f MRI. Human Brain
Mapping, 5(4), 243248.
Kida, I., Rothman, D. L., & Hyder, F. (2007). Dynamics of changes in blood flow,
volume, and oxygenation: Implications for dynamic functional magnetic resonance
189
190
Glossary
Biswal, & Jesmanowicz, 2001; Kruger & Glover, 2001; Triantafyllou et al., 2005) result in limited advantages to running lowresolution fMRI studies at high fields. In general, applications
that would otherwise be SNR-starved at 3 T (i.e., higher spatial
and temporal resolution protocols) are ideally suited for higher
fields (i.e., 7 T). While recent work has demonstrated the neuroscience utility of higher temporal resolution fMRI (Feinberg
et al., 2010; Smith et al., 2012), despite the slow hemodynamic
response, historically, pushing the limits of spatial resolution,
while challenging, has proven to be extremely fruitful, opening
opportunities to understand how the living human brain functions at its most fundamental levels.
While high-field gains allow for higher spatial resolution
images, because BOLD fMRI relies on the hemodynamic
response to map brain function, the acquisition of highresolution images alone does not guarantee increases in the
resolution of the functional mapping (Olman & Yacoub,
2011). The spatial resolution and specificity limits of fMRI
depend on both the pulse sequence and parameter choices
and the magnetic field strength used (Uludag, Muller-Bierl, &
Ugurbil, 2009), which can all result in varying sensitivities to
the vascular response and the subsequent functional point
spread function. Conventional fMRI applications are not really
concerned with this because the functional organizations, or
information sought from fMRI signals, are typically segregated
on the order of several millimeters (i.e., hypercolumns and/or
cortical areas; Olman & Yacoub, 2011), conservatively within
the vascular point spread function of the BOLD response at any
field (Engel, Glover, & Wandell, 1997; Shmuel, Yacoub,
Chaimow, Logothetis, & Ugurbil, 2007b). Further, if one is
only interested in the information present in the functional
signals and not the source or spatial organization of the information, it has been shown that some of this information can
be decoded from lower-resolution images (Haynes & Rees,
2005; Kamitani & Tong, 2005). The source of these decoding
signals or how they relate to columnar-level organizations
is, however, controversial (Freeman, Brouwer, Heeger, &
Merriam, 2011; Shmuel et al., 2007a). In any case, even
today, because of the lack of access to higher-field magnets
and the technical challenges associated with higher-resolution
http://dx.doi.org/10.1016/B978-0-12-397025-1.00022-1
191
192
INTRODUCTION TO ACQUISITION METHODS | fMRI at High Magnetic Field: Spatial Resolution Limits and Applications
Spin
echo
Gradient
echo
1 mm
Figure 1 ODC maps from a flat gray matter region along the calcarine
sulcus from the same subject on several different days. On the left is
the overlap of two different scan days using SE at 7 T, while on the right
is the overlap of two different scans using GE. Red or blue pixels
indicate a voxels preference to the right or left eye stimulation. The
expected spatial pattern is an alternating preference (1 mm width,
2 mm cycle) to the right or left eye running along the sulcus. The SE map
retains this pattern throughout the region, while the GE map is
interrupted by extravascular changes around large vessels somewhere
near the region of interest. Reproduced from Figure 5 in Yacoub, E.,
Shmuel, A., Logothetis, N., & Ugurbil, K. (2007). Robust detection of
ocular dominance columns in humans using Hahn Spin Echo BOLD
functional MRI at 7 Tesla. Neuroimage, 37, 116177.
INTRODUCTION TO ACQUISITION METHODS | fMRI at High Magnetic Field: Spatial Resolution Limits and Applications
animal models (i.e., optical imaging of intrinsic signals) as a
guide. However, these data are somewhat limited in the information they have provided about columnar organizations
(Blasdel & Salama, 1986; Bonhoeffer & Grinvald, 1991; Hubel
& Wiesel, 1959, 1962, 1963, 1968, 1977; Mountcastle, 1957;
Shmuel & Grinvald, 1996; Shoham, Hubener, Schulze, Grinvald,
& Bonhoeffer, 1997; Weliky, Bosking, & Fitzpatrick, 1996). Following the demonstrated reliability of high-field SE-based BOLD
signals to map ODCs in humans, the same cortical area was
mapped in the same subjects using an orientation-dependent
paradigm, demonstrating, prior to any other technique, invasive
or otherwise, orientation preference at the columnar level in the
human (Yacoub, Harel, & Ugurbil, 2008). These results did also
closely resemble what had been shown in animal models
(Figure 2). More importantly, this work showed that high-field
high-resolution fMRI could reliably conduct novel explorations
of previously unmapped and potentially unknown columnar
systems in the human brain, suggesting that high-field fMRI
itself could be the ground truth for human brain mapping.
In general, however, to build on this work and/or to
facilitate further mapping of high-resolution functional
architectures in the human requires technical improvements
due to the inefficiencies and limitations of high-resolution
fMRI acquisitions.
Scalebar = 0.5 mm
(a)
193
the many more slices needed to cover the same volume. Longer
acquisition times result in increases in distortions, loss of spatial
resolution, loss of SNR, and increases in susceptibility or other
artifacts ubiquitous to EPI. Nearly all human fMRI studies,
irrespective of spatial resolution, use 2-D SE-based EPI because,
relatively speaking, the sampling time for a single slice, as well as
for an entire volume, is fast. 3-D imaging (i.e., echo-volume
imaging, EVI) (Mansfield, Harvey, & Stehling, 1994), while
having the advantage of higher SNR, can be hampered by physiological noise or motion, which is convolved over the volume
acquisition time. Segmented (2-D or 3-D) EPI can be used to
shorten the readout trains, with a similar caveat of physiological
noise and motion sensitivity. Choosing between 3-D and 2-D
(segmented or single-shot) acquisitions for high-resolution
fMRI might be determined by whether or not physiological
noise limits the functional sensitivity of 3-D acquisitions and
whether or not 2-D acquisitions have sufficient static SNR or
spatial resolution along any specific direction. Cases can be
made to utilize non-EPI-based acquisitions for applications
that require reduced distortions or susceptibility effects; however, the vast majority of fMRI studies cannot afford such a
penalty in efficiency, especially since there are numerous ways
to mitigate artifacts and improve overall image quality in EPI
(Glasser et al., 2013). Spiral sampling trajectories have been
shown to have advantages over EPI for fMRI (Yang et al.,
1998) with associated artifacts manifesting as blurring; however,
the technical requirements of spiral sampling have slowed its
progression into clinical scanners, and thus for the aforementioned reasons, fMRI studies today, be they high- or low-resolution, use 2-D SE-based EPI.
Apart from image segmentation, long acquisition times can
be mitigated using reduced FOV (or zoomed) imaging
0
(b)
Phase
Figure 2 fMRI orientation and ocular dominance maps in a human subject. Ocular dominance and orientation columns in human visual cortex. (a) Red
and blue represent voxels that demonstrated preference to right and left eye stimulation, respectively. (b) Depicts the orientation preference maps
from the same cortical areas as their corresponding ODC maps in (a). ODC borders are marked with solid black lines on both the ODC and
orientation maps. (Color bar for orientation map (b): calculated phase at the stimulus frequency; scale bar: 0.5 mm.) Variant of Figure 2 reproduced
from Yacoub, E., Harel, N., & Ugurbil, K. (2008). High-field fMRI unveils orientation columns in humans. Proceedings of the National Academy of
Sciences of the United States of America, 105, 10 60710 612.
194
INTRODUCTION TO ACQUISITION METHODS | fMRI at High Magnetic Field: Spatial Resolution Limits and Applications
INTRODUCTION TO ACQUISITION METHODS | fMRI at High Magnetic Field: Spatial Resolution Limits and Applications
195
Figure 3 Illustration representing axis of motion columnar mapping approach. (a) Results of MT localization are projected onto the cortical
reconstruction of the subjects left hemisphere (neurological convention). High-resolution cortical grid sampling is performed. Zoomed in view of the
subjects STS with overlaid streamlines at two relative cortical depths (0.5 and 0.8%). In order to not suffer from residual contribution from
superficial blood vessels, sampling was restricted to the midlevel and deeper layers. (b) Results of the high-resolution cortical grid sampling for the
motion direction experiment showing columnar organization of axis of motion features in two sampled layers (scale bar 1 mm, color frames
representing the streamlines in zoomed in view). (c) Representation of the high-resolution cortical grid sampling showing four three-dimensional
vertical slices through the sampled cortical layers depicting the consistency of cortical columns tangential to the surface. Reproduced from Figure 3
in Zimmermann, J., Goebel, R., De Martino, F., Van De Moortele, P. F., Feinberg, D., Adriany, G., Chaimow, D., Shmuel, A., Ugurbil, K., & Yacoub, E.
(2011). Mapping the organization of axis of motion selective features in human area MT using high-field fMRI. PLoS One, 6, E28716.
196
INTRODUCTION TO ACQUISITION METHODS | fMRI at High Magnetic Field: Spatial Resolution Limits and Applications
S1 2.4
S1
3D GRASE
GE
Tuning specificity
2.2
2
1.8
1.6
1.4
1
S2
10 %
90 %
Tuning specificity
1.9
1.8
1.7
1.6
1.5
1.4
1.3
10 %
S3
90 %
1.8
Tuning specificity
1.7
1.6
BOLD% change
1.2
Stimulus probability
1
1
Intact
0.5
Scrambled
0
0.5
1
Distance from WM
1.5
1.4
1.3
1.2
1.1
10 %
WM -> CSF
90 %
INTRODUCTION TO ACQUISITION METHODS | fMRI at High Magnetic Field: Spatial Resolution Limits and Applications
197
Figure 6 Single-shot (single-volume) EPI at 7 T acquired with a 0.9 mm isotropic resolution. In-plane undersampling of 3 and a slice acceleration of 3
were used to acquire the volume (150 slices) in 3.7 s. Data were acquired axially.
Acknowledgments
This project was supported by the WM KECK Foundation under
the NIH grants P41 EB015894, P30 NS076408, R44-NS073417,
R21NS075525 U54MH091657, and S10RR026783. The authors
would like to thank Joseph Vu, Eddie Auerbach, and Steen
Moeller for their data in Figure 6.
References
Adriany, G., Pfeuffer, J., Yacoub, E., Van De Moortele, P.-F., Shmuel, A., Andersen, P.,
et al. (2001). A half-volume transmit/receive coil combination for 7 Tesla
applications. In: Proceedings of the 9th scientific meeting and exhibition, ISMRM,
Glasgow, UK, 1097.
Adriany, G., Schillak, S., Waks, M., Tramm, B., Roebroeck, A., Formisano, E., et al.
(2013). A flexible 4 ch. Transmit/16 ch. Receive auditory cortex array for hires fMRI
at 7 Tesla. In: ISMRM 21st, Salt Lake City 0074.
Blasdel, G. G., & Salama, G. (1986). Voltage-sensitive dyes reveal a modular
organization in monkey striate cortex. Nature, 321, 579585.
Bonhoeffer, T., & Grinvald, A. (1991). Iso-orientation domains in cat visual cortex are
arranged in pinwheel-like patterns. Nature, 353, 429431.
Boxerman, J. L., Bandettini, P. A., Kwong, K. K., Baker, J. R., Davis, T. J., Rosen, B. R.,
et al. (1995). The intravascular contribution to fMRI signal changes: Monte Carlo
modeling and diffusion-weighted studies in vivo. Magnetic Resonance in Medicine,
34, 410.
Chen, L., & Feinberg, D. (2013). Simultaneous multi-volume GRASE imaging.
In: ISMRM 21st annual meeting, Salt Lake City, 2365.
Cheng, K., Waggoner, R. A., & Tanaka, K. (2001). Human ocular dominance columns as
revealed by high-field functional magnetic resonance imaging. Neuron, 32, 359374.
Constable, R., Kennan, R., Puce, A., Mccarthy, G., & Gore, J. (1994). Functional NMR
imaging using fast spin echo at 1.5 T. Magnetic Resonance in Medicine, 31, 686690.
De Martino, F., Zimmermann, J., Muckli, L., Ugurbil, K., Yacoub, E., & Goebel, R.
(2013). Cortical depth dependent functional responses in humans at 7 T: Improved
specificity with 3D GRASE. PLoS One, 8, E60514.
Dechent, P., & Frahm, J. (2000). Direct mapping of ocular dominance columns in
human primary visual cortex. Neuroreport, 11, 32473249.
Duong, T. Q., Yacoub, E., Adriany, G., Hu, X., Ugurbil, K., Vaughan, J. T., et al. (2002).
High-resolution, spin-echo BOLD, and CBF fMRI at 4 and 7 T. Magnetic Resonance
in Medicine, 48, 589593.
Duyn, J. H., Moonen, C. T. W., Yperen, G. H., Boer, R. W., & Luyten, P. R. (1994).
Inflow versus deoxyhemoglobin effects in BOLD functional MRI using gradient
echoes at 1.5 T. NMR in Biomedicine, 7, 8388.
Edelman, R. E., Siewer, B., Darby, D. G., Thangaraj, V., Nobre, A. C., Mesulam, M. M.,
et al. (1994). Quantitative mapping of cerebral blood flow and functional localization
with echo-planar MR imaging and signal targeting with alternating radio frequency.
Radiology, 192, 513520.
Engel, S. A., Glover, G. H., & Wandell, B. A. (1997). Retinotopic organization in human
visual cortex and the spatial precision of functional MRI. Cerebral Cortex, 7,
181192.
198
INTRODUCTION TO ACQUISITION METHODS | fMRI at High Magnetic Field: Spatial Resolution Limits and Applications
Feinberg, D. A., Harel, N., Ramanna, S., Ugurbil, K., & Yacoub, E. (2008). Submillimeter single-shot 3D GRASE with inner volume selection for T2-weighted fMRI
applications at 7 Tesla. In: 16th annual meeting of the international society for
magnetic resonance in medicine, Toronto.
Feinberg, D., Hoenninger, J., Crooks, L., Kaufman, L., Watts, J., & Arakawa, M. (1985).
Inner volume MR imaging: Technical concepts and their application. Radiology,
156, 743747.
Feinberg, D. A., Moeller, S., Smith, S. M., Auerbach, E., Ramanna, S., Gunther, M., et al.
(2010). Multiplexed echo planar imaging for sub-second whole brain fMRI and fast
diffusion imaging. PLoS One, 5, E15710.
Feinberg, D. A., & Oshio, K. (1991). GRASE (gradient- and spin-echo) MR imaging: A
new fast clinical imaging technique. Radiology, 181, 597602.
Frahm, J., Merboldt, K. D., Hanicke, W., Kleinschmidt, A., & Boecker, H. (1994). Brain
or vein-oxygenation or flow? on signal physiology in functional MRI of human brain
activation. NMR in Biomedicine, 7, 4553.
Freeman, J., Brouwer, G. J., Heeger, D. J., & Merriam, E. P. (2011). Orientation
decoding depends on maps, not columns. Journal of Neuroscience: The Official
Journal of the Society for Neuroscience, 31, 47924804.
Gao, J., Xiong, J., Schiff, L. J., Roby, J., Lancaster, J., & Fox, P. (1995). Fast spin-echo
characteristics of visual stimulation-induced signal changes in the human brain.
Journal of Magnetic Resonance Imaging, 5, 709714.
Gardner, J. L., Sun, P., Tanaka, K., Heeger, D. J., & Cheng, K. (2006). Classification
analysis with high spatial resolution fMRI reveals large draining veins with
orientation specific responses. In: Society for neuroscience society for neuroscience
annual meeting 640.14/O7, Atlanta.
Glasser, M. F., Sotiropoulos, S. N., Wilson, J. A., Coalson, T. S., Fischl, B.,
Andersson, J. L., et al. (2013). The minimal preprocessing pipelines for the human
connectome project. NeuroImage, 80, 105124.
Goense, J. B., & Logothetis, N. K. (2006). Laminar specificity in monkey V1 using highresolution SE-fMRI. Magnetic Resonance Imaging, 24, 381392.
Goerke, U., Van De Moortele, P. F., & Ugurbil, K. (2007). Enhanced relative BOLD
signal changes in T(2)-weighted stimulated echoes. Magnetic Resonance in
Medicine, 58, 754762.
Goodyear, B. G., & Menon, R. S. (2001). Brief visual stimulation allows mapping of
ocular dominance in visual cortex using fMRI. Human Brain Mapping, 14, 210217.
Gunther, M., Oshio, K., & Feinberg, D. A. (2005). Single-shot 3D imaging techniques
improve arterial spin labeling perfusion measurements. Magnetic Resonance in
Medicine, 54, 491498.
Harel, N., Lin, J., Moeller, S., Ugurbil, K., & Yacoub, E. (2006). Combined imaginghistological study of cortical laminar specificity of fMRI signals. NeuroImage, 29,
879887.
Haynes, J. D., & Rees, G. (2005). Predicting the orientation of invisible stimuli from
activity in human primary visual cortex. Nature Neuroscience, 8, 686691.
Heidemann, R. M., Anwander, A., Feiweier, T., Knosche, T. R., & Turner, R. (2012). kspace and q-space: Combining ultra-high spatial and angular resolution in diffusion
imaging using ZOOPPA at 7 T. NeuroImage, 60, 967978.
Heidemann, R. M., Ivanov, D., Trampel, R., Fasano, F., Meyer, H., Pfeuffer, J., et al.
(2012). Isotropic submillimeter fMRI in the human brain at 7 T: Combining reduced
field-of-view imaging and partially parallel acquisitions. Magnetic Resonance in
Medicine, 68, 15061516.
Horton, J., & Hedley-Whyte, E. T. (1984). Mapping of cytochrome oxidase patches and
ocular dominance columns in human visual cortex. Philosophical Transactions of
the Royal Society of London. Series B: Biological Sciences, 304, 255272.
Hubel, D. H., & Wiesel, T. N. (1959). Receptive fields of single neurones in the cats
striate cortex. Journal of Physiology, 148, 574591.
Hubel, D. H., & Wiesel, T. N. (1962). Receptive fields, binocular interaction and
functional architecture in the cats visual cortex. Journal of Physiology, 160,
106154.
Hubel, D. H., & Wiesel, T. N. (1963). Shape and arrangement of columns in cats striate
cortex. Journal of Physiology, 165, 559568.
Hubel, D. H., & Wiesel, T. N. (1968). Receptive fields and functional architecture of
monkey striate cortex. Journal of Physiology, 195, 215243.
Hubel, D. H., & Wiesel, T. N. (1977). Functional architecture of macaque monkey visual
cortex. Proceedings of the Royal Society of London [Biological Sciences], 198,
159.
Hyde, J. S., Biswal, B., & Jesmanowicz, A. (2001). High-resolution fMRI using
multislice partial k-space GR-EPI with cubic voxels. Magnetic Resonance in
Medicine, 46, 114125.
Kamitani, Y., & Tong, F. (2005). Decoding the visual and subjective contents of the
human brain. Nature Neuroscience, 8, 679685.
Kim, S.-G. (1995). Quantification of relative cerebral blood flow change by flowsensitive alternating inversion recovery (FAIR) technique: Application to functional
mapping. Magnetic Resonance in Medicine, 34, 293301.
Kim, S.-G., Hendrich, K., Hu, X., Merkle, H., & Ugurbil, K. (1994). Potential pitfalls of
functional MRI using conventional gradient-recalled echo techniques. NMR in
Biomedicine, 7, 6974.
Koopmans, P. J., Boyacioglu, R., Barth, M., & Norris, D. G. (2012). Whole brain, high
resolution spin-echo resting state fMRI using PINS multiplexing at 7 T.
NeuroImage, 62, 19391946.
Kruger, G., & Glover, G. H. (2001). Physiological noise in oxygenation-sensitive
magnetic resonance imaging. Magnetic Resonance in Medicine, 46, 631637.
Kwong, K. K., Belliveau, J. W., Chesler, D. A., Goldberg, I. E., Weisskoff, R. M.,
Poncelet, B. P., et al. (1992). Dynamic magnetic resonance imaging of human brain
activity during primary sensory stimulation. Proceedings of the National Academy of
Sciences of the United States of America, 89, 56755679.
Lai, S., Hopkins, A. L., Haacke, E. M., Li, D., Wasserman, B. A., Buckley, P., et al.
(1993). Identification of vascular structures as a major source of signal contrast in
high resolution 2D and 3D functional activation imaging of the motor cortex at
1.5 T: Preliminary results. Magnetic Resonance in Medicine, 30, 387392.
Lee, A. T., Glover, G. H., & Meyer, G. H. (1995). Discrimination of large venous vessels
in time-course spiral blood-oxygen-level-dependent magnetic resonance functional
neuroimaging. Magnetic Resonance in Medicine, 33, 745754.
Lee, S. P., Silva, A. C., & Kim, S. G. (2002). Comparison of diffusion-weighted highresolution CBF and spin-echo BOLD fMRI at 9.4 T. Magnetic Resonance in
Medicine, 47, 736741.
Lee, S.-P., Silva, A., Ugurbil, K., & Kim, S.-G. (1999). Diffusion-weighted spin-echo
fMRI at 9.4 T: Microvascular/tissue contribution to BOLD signal changes. Magnetic
Resonance in Medicine, 42, 919928.
Lu, H., Golay, X., Pekar, J. J., & Van Zijl, P. C. (2003). Functional magnetic resonance
imaging based on changes in vascular space occupancy. Magnetic Resonance in
Medicine, 50, 263274.
Mandeville, J. B., Marota, J. J., Kosofsky, B. E., Keltner, J. R., Weissleder, R., Rosen, B. R.,
et al. (1998). Dynamic functional imaging of relative cerebral blood volume during Rat
forepaw stimulation. Magnetic Resonance in Medicine, 39, 615624.
Mansfield, P. (1977). Multi-planar image formation using NMR spin echoes. Journal of
Physics C: Solid State Physics, 10, L55L58.
Mansfield, P., Harvey, P. R., & Stehling, M. K. (1994). Echo-volumar imaging. Magma,
2, 291294.
Menon, R. S. (2002). Postacquisition suppression of large-vessel BOLD signals in
high-resolution fMRI. Magnetic Resonance in Medicine, 47, 19.
Menon, R., Ogawa, S., Strupp, J. P., & Ugurbil, K. (1997). Ocular dominance in human
V1 demonstrated by functional magnetic resonance imaging. Journal of
Neurophysiology, 77, 27802787.
Menon, R. S., Ogawa, S., Tank, D. W., & Ugurbil, K. (1993). 4 Tesla gradient recalled
echo characteristics of photic stimulation-induced signal changes in the human
primary visual cortex. Magnetic Resonance in Medicine, 30, 380386.
Miller, K. L., & Jezzard, P. (2008). Modeling SSFP functional MRI contrast in the brain.
Magnetic Resonance in Medicine, 60, 661673.
Moeller, S., Yacoub, E., Olman, C. A., Auerbach, E., Strupp, J., Harel, N., et al. (2010).
Multiband multislice GE-EPI at 7 Tesla, with 16-fold acceleration using partial
parallel imaging with application to high spatial and temporal whole-brain fMRI.
Magnetic Resonance in Medicine, 63, 11441153.
Moon, C. H., Fukuda, M., Park, S. H., & Kim, S. G. (2007). Neural interpretation of
blood oxygenation level-dependent fMRI maps at submillimeter columnar
resolution. Journal of Neuroscience, 27, 68926902.
Mountcastle, V. B. (1957). Modality and topographic properties of single neurons of
cats somatic sensory cortex. Journal of Neurophysiology, 20, 408434.
Norris, D. G., Koopmans, P. J., Boyacioglu, R., & Barth, M. (2011). Power independent
of number of slices (PINS) radiofrequency pulses for low-power simultaneous
multislice excitation. Magnetic Resonance in Medicine, 66, 12341240.
Ogawa, S., Lee, T.-M., Kay, A. R., & Tank, D. W. (1990). Brain magnetic resonance
imaging with contrast dependent on blood oxygenation. Proceedings of the National
Academy of Sciences of the United States of America, 87, 98689872.
Ogawa, S., Tank, D. W., Menon, R., Ellermann, J. M., Kim, S.-G., Merkle, H., et al.
(1992). Intrinsic signal changes accompanying sensory stimulation: Functional
brain mapping with magnetic resonance imaging. Proceedings of the National
Academy of Sciences of the United States of America, 89, 59515955.
Oja, J. M. E., Gillen, J., Kauppinen, R. A., Kraut, M., & Van Zijl, P. C. M. (1999). Venous
blood effects in spin-echo fMRI of human brain. Magnetic Resonance in Medicine,
42, 617626.
Olman, C. A., Harel, N., Feinberg, D. A., He, S., Zhang, P., Ugurbil, K., et al. (2012).
Layer-specific fMRI reflects different neuronal computations at different depths in
human V1. PLoS One, 7, E32536.
Olman, C. A., & Yacoub, E. (2011). High-field fMRI for human applications: An
overview of spatial resolution and signal specificity. The Open Neuroimaging
Journal, 5, 7489.
INTRODUCTION TO ACQUISITION METHODS | fMRI at High Magnetic Field: Spatial Resolution Limits and Applications
Oshio, K., & Feinberg, D. A. (1991). GRASE (gradient- and spin-echo) imaging: A novel
fast MRI technique. Magnetic Resonance in Medicine, 20, 344349.
Pfeuffer, J., Van De Moortele, P. F., Yacoub, E., Adriany, G., Andersen, P., Merkle, H.,
et al. (2002). Zoomed functional imaging in the human brain at 7 Tesla with
simultaneously high spatial and temporal resolution. NeuroImage, 17, 272286.
Polimeni, J. R., Fischl, B., Greve, D. N., & Wald, L. L. (2010). Laminar analysis of 7 T
BOLD using an imposed spatial activation pattern in human V1. NeuroImage, 52,
13341346.
Poser, B. A., Koopmans, P. J., Witzel, T., Wald, L. L., & Barth, M. (2010). Three
dimensional echo-planar imaging at 7 Tesla. NeuroImage, 51, 261266.
Poser, B. A., & Norris, D. G. (2007). Fast spin echo sequences for BOLD functional MRI.
Magma, 20, 1117.
Segebarth, C., Belle, V., Delon, C., Massarelli, R., Decety, J., Le Bas, J.-F., et al. (1994).
Functional MRI of the human brain: Predominance of signals from extracerebral
veins. Neuroreport, 5, 813816.
Setsompop, K., Gagoski, B. A., Polimeni, J. R., Witzel, T., Wedeen, V. J., & Wald, L. L.
(2012). Blipped-controlled aliasing in parallel imaging for simultaneous multislice
echo planar imaging with reduced G-factor penalty. Magnetic Resonance in
Medicine, 67, 12101224.
Shmuel, A., & Grinvald, A. (1996). Functional organization for direction of motion and
its relationship to orientation maps in cat area 18. Journal of Neuroscience: The
Official Journal of the Society for Neuroscience, 16, 69456964.
Shmuel, A., Raddatz, G., Chaimow, D., Logothetis, N., Ugurbil, K., & Yacoub, E. (2007).
Origin of decoding signals in the visual cortex: Gray matter or macroscopic blood
vessels?. Chicago: Human Brain Mapping.
Shmuel, A., Yacoub, E., Chaimow, D., Logothetis, N. K., & Ugurbil, K. (2007). Spatiotemporal point-spread function of fMRI signal in human gray matter at 7 Tesla.
NeuroImage, 35, 539552.
Shoham, D., Hubener, M., Schulze, S., Grinvald, A., & Bonhoeffer, T. (1997). Spatiotemporal frequency domains and their relation to cytochrome oxidase staining in cat
visual cortex. Nature, 385, 529533.
Smith, S. M., Miller, K. L., Moeller, S., Xu, J., Auerbach, E. J., Woolrich, M. W., et al.
(2012). Temporally-independent functional modes of spontaneous brain activity.
Proceedings of the National Academy of Sciences of the United States of America,
109, 31313136.
Song, A. W., Wong, E. C., Tan, S. G., & Hyde, J. S. (1996). Diffusion weighted fMRI at
1.5 T. Magnetic Resonance in Medicine, 35, 155158.
Triantafyllou, C., Hoge, R. D., Krueger, G., Wiggins, C. J., Potthast, A., Wiggins, G. C.,
et al. (2005). Comparison of physiological noise at 1.5 T, 3 T and 7 T and
optimization of fMRI acquisition parameters. NeuroImage, 26, 243250.
Uludag, K., Muller-Bierl, B., & Ugurbil, K. (2009). An integrative model for neuronal
activity-induced signal changes for gradient and spin echo functional imaging.
NeuroImage, 48, 150165.
Vu, A., Feinberg, D., Harel, N., Ugurbil, K., & Yacoub, E. (2013). Diagonal multi-slab
inner volume 3D GRASE imaging for high resolution T2 weighted fMRI. In: ISMRM
21st annual meeting, Salt Lake City, 2364.
199
Weliky, M., Bosking, W. H., & Fitzpatrick, D. (1996). A systematic map of direction
preference in primary visual cortex. Nature, 379, 725728.
Wu, X., Schmitter, S., Auerbach, E. J., Moeller, S., Ugurbil, K., & Van De Moortele, P. F.
(2013). Simultaneous multislice multiband parallel radiofrequency excitation with
independent slice-specific transmit B1 homogenization. Magnetic Resonance in
Medicine, 70, 630638. http://dx.doi.org/10.1002/mrm.24828.
Wu, X., Ugurbil, K., & Van De Moortele, P. F. (2013). Peak RF power constrained pulse
design for multi-band parallel excitation. In: ISMRM 21st meeting, Salt Lake City,
4253.
Yacoub, E., Duong, T. Q., Van De Moortele, P. F., Lindquist, M., Adriany, G., Kim, S. G.,
et al. (2003). Spin-echo fMRI in humans using high spatial resolutions and high
magnetic fields. Magnetic Resonance in Medicine, 49, 655664.
Yacoub, E., Harel, N., & Ugurbil, K. (2008). High-field fMRI unveils orientation columns
in humans. Proceedings of the National Academy of Sciences of the United States of
America, 105, 1060710612.
Yacoub, E., Shmuel, A., Logothetis, N., & Ugurbil, K. (2007). Robust detection of ocular
dominance columns in humans using Hahn Spin Echo BOLD functional MRI at
7 Tesla. NeuroImage, 37, 11611177.
Yacoub, E., Shmuel, A., Pfeuffer, J., Van De Moortele, P. F., Adriany, G., Andersen, P.,
et al. (2001). Imaging brain function in humans at 7 Tesla. Magnetic Resonance in
Medicine, 45, 588594.
Yacoub, E., Ugurbil, K., & Olman, C. (2009). Feasibility of detecting differential layer
specific activations in humans using SE BOLD fMRI at 7 T. In: Proceedings of the
magnetic resonance in medicine, Honolulu.
Yacoub, E., Van De Moortele, P. F., Shmuel, A., & Ugurbil, K. (2005). Signal and noise
characteristics of Hahn SE and GE BOLD fMRI at 7 T in humans. NeuroImage, 24,
738750.
Yang, Y., Glover, G. H., Van Gelderen, P., Patel, A. C., Mattay, V. S., Frank, J. A., et al.
(1998). A comparison of fast MR scan techniques for cerebral activation studies at
1.5 Tesla. Magnetic Resonance in Medicine, 39, 6167.
Ye, Y., Zhuo, Y., Xue, R., & Zhou, X. J. (2010). BOLD fMRI using a modified HASTE
sequence. NeuroImage, 49, 457466.
Zhao, F., Wang, P., Hendrich, K., & Kim, S. G. (2005). Spatial specificity of cerebral
blood volume-weighted fMRI responses at columnar resolution. NeuroImage, 27,
416424.
Zhao, F., Wang, P., Hendrich, K., Ugurbil, K., & Kim, S. G. (2006). Cortical
layer-dependent BOLD and CBV responses measured by spin-echo and
gradient-echo fMRI: Insights into hemodynamic regulation. NeuroImage, 30,
11491160.
Zhao, F., Wang, P., & Kim, S. G. (2004). Cortical depth-dependent
gradient-echo and spin-echo BOLD fMRI at 9.4 T. Magnetic Resonance in
Medicine, 51, 518524.
Zimmermann, J., Goebel, R., De Martino, F., Van De Moortele, P. F., Feinberg, D.,
Adriany, G., et al. (2011). Mapping the organization of axis of motion
selective features in human area MT using high-field fMRI. PLoS One, 6,
E28716.
The complexity and diversity of neuroimaging methods used today have made this one of the most promising
fields for innovation and discovery in all of science, with a host of algorithms and techniques that have had
truly global impact. Novel methods to collect, analyze, and model brain images have revolutionized the fields
of neurology and psychiatry. They continue to open up vast new frontiers for understanding of the brain how
it is organized structurally and functionally, how it develops, and how brain measures relate to cognition,
behavior, and even genetics.
For the last two decades, there has also been a revolution in how brain images are analyzed a deeper
understanding of the statistics of brain signals and images led to powerful new methods for detecting significant
changes in the brain, or features that emerge or change during cognitive tasks, or with a disease process.
To a large degree, these developments were accelerated by novel mathematics for representing and modeling
signals, detecting patterns, and understanding causal effects in time series of signals in the brain. Whole
branches of mathematics have been adapted and extended for studying brain data from the topology of
random fields to dynamic causal models, and a rapidly developing theory of graphs, networks, and topological
measures to study connectomes, patterns of connections inferred from functional synchrony or anatomical
circuitry. Even the mathematics of continuum mechanics fluid flow, differential geometry, and relativity has
been used to model anatomical surfaces in the brain, flatten them, match them, and register them, leading to
sophisticated methods now widely used to align and compare observations from people whose anatomy is
different.
This vast and rich field is surveyed here by experts in its many domains.
The analysis of anatomical MRI was accelerated by the field of computational anatomy, concerned with
modeling aspects of brain structure as statistical fields of static or dynamic signals. One such approach
surface-based modeling employs parametric mesh surfaces that can be graphically visualized, merged, and
combined. Several articles in this section deal with the basic processing and analysis of brain structural data,
from voxel-based and manual morphometry to the broad field of image registration, which enables the
alignment of brain data from different individuals, populations, and imaging methods.
Some of the foremost experts in surface-based analysis of brain data describe how anatomy can be modeled
using 3D meshes, giving rise to the processing of measures on surfaces as complex and variable as the human
cortex. Special attention is given to the modeling brain changes over time, using methods that detect and model
characteristic patterns of development and disease. Clearly, these methods have broad applications in clinical
neuroscience and the understanding of progressive degenerative diseases such as the dementias.
A further broad set of articles survey diffusion-based MRI methods used to collect and analyze the structural
connectivity of the brain, and assess white matter microstructure.
A major shift in the field of brain mapping, which has recently gathered momentum, is to model the
interactions and connectivity among brain regions. This effort has been eased by developments in computational fiber tracking (tractography), network theory, and new methods to model and test hypotheses about the
statistics of fiber pathways in the brain.
The handling of functional images of the brain has evolved rapidly and extensively for over two decades. A
set of articles cover experimental design in fMRI, and the modeling of the hemodynamic response, as well as
causal relationships in time series of functional data. Special considerations arise when modeling data from
MEG and EEG, and several articles cover the development of sophisticated methods for inverse problems and
signal reconstruction, including Bayesian approaches and efforts to fuse information across several complementary modalities. There are several articles covering the modeling and testing of complex hypotheses
regarding functional and effective connectivity, as well as practical considerations in measuring it and interpreting it.
201
202
Finally, a number of articles cover the informatics and databasing of brain data. Neuroinformatics is
evolving to encompass numerous national and global efforts for meta-analysis of results, detection of genetic
and disease-related influences on brain measures, and has led to unprecedented collaborative efforts in
population-based imaging.
Paul Thompson
Karl Friston
x-Ray CT
A possible schematic for CT is shown in Figure 1. The data
collection takes place in M steps. A source and a detector strip
are rotated between two steps of the data collection by a small
angle but are assumed to be stationary while the measurement
is taken. The detector strip consists of 2N 1 detectors, spaced
equally on an arc whose center is the source position. The line
from the source to the center of rotation O goes through the
center of the central detector. As indicated in that figure, any
real-number pair (, y) defines a line and we use [Rf] (, y) to
denote the line integral of f along that line.
A CT scanner does not measure directly such line integrals.
Rather, the detector counts the number of photons that arrive
at it having gone through the head. Such a count by itself is not
sufficient to estimate the integral of f between the source and
the detector; we also need a calibration measurement that
provides an estimate of the number of photons that left the
source. Then, the logarithm of the ratio of the count during
calibration and during the actual measurement with the
patient in the scanner provides an estimate of the line integral
of the x-ray attenuation coefficient, distribution of which is the
f that we wish to reconstruct.
This simple description hides many problems that exist
with the actual data collection. One example is scatter that
arises due to the fact that on the way from the source to the
detector strip, a photon may scatter and get counted by a
detector that is not the one toward which it was heading
originally. Another, example is beam hardening, which is due
to the fact that the x-ray photons generated by the source in a
CT scanner have a range of possible energies and the same
tissue has different x-ray attenuation coefficients for photons
at different energies. Typically, we decide that our f is supposed
to represent the distribution of x-ray attenuation at a particular
energy, but the measurements are unavoidably made using
photons with a whole range of energies and that introduces
an error into our estimate of the line integrals of f. Such
problems necessitate that the raw data collected by the CT
scanner be preprocessed, the result of which is assumed to be
a sufficiently accurate estimate of the line integrals of f.
Reconstruction Algorithms
Basic Concepts of Reconstruction Algorithms
The input to a reconstruction algorithm is estimates, obtained
by a CT scanner (for details, see Herman, 2009), of the values
of [Rf](, y) for the pairs (1, y1),. . ., (I, yI). Let
Ri f Rf li , yi
[1]
http://dx.doi.org/10.1016/B978-0-12-397025-1.00286-4
203
204
Source position
S0
S1
SM1
Angular scan
SM2
Sm
N
nl
m
l
O
Object to be
reconstructed
q
B
1
0 Reading
1
Detector
strip
N
Figure 1 A standard method of CT data collection. Reproduced from Herman, G. T. (2009). Fundamentals of computerized tomography: Image
reconstruction from projections (2nd ed.). New York: Springer.
J
X
xj bj r, f
[3]
j1
where xj isX
the average value of f inside the jth pixel. In shortJ
hand, f^
xb.
j1 j j
Another (and usually preferable) way of choosing the basis
functions is the following. Generalized KaiserBessel window
functions, which are also known by the simpler name blobs,
form a large family of functions that can be defined in a
Euclidean space of any dimension. Here, we restrict ourselves
to 2-D and define
ba, a, d r, f
8
<
:
q
2
2
I2 a 1 ar
Ca, a, d 1 ar
, if 0 r a
0,
otherwise
[4]
J
X
xj Ri bj
[5]
j1
J
X
ri , j x j
[6]
j1
Let R denote the matrix whose (i, j)th element is ri,j. We refer
to this matrix as the projection matrix. Let e be the I-dimensional
205
[8]
[9]
bi ri xk
[10]
ck lk k k 2
ri
k
[7]
The series expansion approach leads us to the discrete reconstruction problem: based on eqn [7], given the data y, estimate the
image vector x. If the solution to this problem is x*, then the
P
estimate f* of f is given by f* Jj1xj*bj.
In eqn [7], the vector e is unknown. The simple approach of
trying to solve eqn [7] by assuming that e is the zero vector is
dangerous: y Rx may have no solutions, or it may have many
solutions with none of them any good for the practical problem at hand. Some criteria have to be developed, indicating
which x ought to be chosen as a solution of eqn [7]. One way of
doing this is by considering both the image vector x and the
yik
J
X
k1
rik , j xj
[11]
j1
[12]
206
[13]
where
ck lk
k
t yik rik , xk uik
2
1 t 2 ri
[14]
Note that both in eqns [9] and [13], the updating of x(k) is
very simple: we just add to x(k) a multiple of the vector rik . This
updating of x(k) can be computationally very inexpensive. Consider, for example, the basis functions associated with a digitization into pixels [2]. Then, ri,j is just the length of intersection
of the ith line with the jth pixel. This has two consequences.
First, most of the components of the vector rik are zero. Second,
the location and size of the nonzero components of rik can be
rapidly calculated from the geometric location of the ikth line
relative to the n n grid using a digital difference analyzer methodology (see Section 4.6 of Herman, 2009).
n X
n
X
u1 v1
jtu, v ru, v j=
n X
n
X
jtu, v j
[15]
u1 v1
Figure 3 A head phantom (a) and its reconstructions from the same projection data using ART with blobs, l(k) 0.05, 5Ith iteration and efficient
ordering (b), ART with blobs, l(k) 0.05, 5Ith iteration and sequential ordering (c), ART with pixels, l(k) 0.05, 5Ith iteration and efficient ordering
(d), ART with blobs, l(k) 1.0 2Ith iteration and efficient ordering (e), and FBP (f). Reproduced from Herman, G. T. (2009). Fundamentals of
computerized tomography: Image reconstruction from projections (2nd ed.). New York: Springer.
207
Table 1
Picture distance measures r and average IROIs for the
various algorithms used in Figure 3
Reconstruction in
IROI
Figure 3(b)
Figure 3(c)
Figure 3(d)
Figure 3(e)
Figure 3(f)
0.0373
0.0391
0.0470
0.0488
0.0423
0.1794
0.1624
0.1592
0.1076
0.1677
<109. Thus, the null hypothesis that the two data access orderings are equally good can be rejected in favor of the alternative
that the efficient ordering is better with extreme confidence.
Next, we emphasize the importance of the basis functions.
In Figure 4, we plot the picture distance measure r against the
number of times ART cycled through all the data. The two cases
that we compare are when the basis functions are based on
pixels [2] and when they are based on blobs [4]. The results are
quite impressive: as measured by r, blob basis functions are
much better. The result of the 5Ith iteration of the blob reconstruction is shown in Figure 3(b), while that of the 5Ith iteration of the pixel reconstruction is shown in Figure 3(d). The
blob reconstructions are clearly superior. By looking at Table 1,
we see a great improvement in the picture distance measure r.
From the point of view of IROI, ART with blobs is found
superior to ART with pixels with the P-value < 1010.
Underrelaxation is also a must when ART is applied to real
data. In the experiments reported so far, l(k) was set equal to
0.05 for all k. If we do not use underrelaxation (i.e., we set l(k)
to 1 for all k), we get from the standard projection data the
unacceptable reconstruction shown in Figure 3(e). Note that
in this case, we used the 2Ith iterate, further iterations gave
worse results. The reason for this is in the nature of ART: After
one iterative step with l(k) 1, the associated measurement is
satisfied exactly as shown in eqn [11], and so, the process
jumps around satisfying the noise in the measurements.
Underrelaxation reduces the influence of the noise. Note in
Table 1 that the figure of merit IROI produced by the taskoriented study for the case without underrelaxation is much
smaller than for the other cases.
Finally, we compare the best of our ART reconstruction
(Figure 3(b)) with one produced by a similarly carefully
selected variant of FBP (Figure 3(f)); for details of the FBP
choices, see Chapter 10 of Herman (2009). Visually, they are
very similar. According to r in Table 1, ART is superior to FBP,
and the same is true according to IROI with extreme significance (the P-value is <1013). This confirms the reports in the
literature that ART with blobs, underrelaxation, and efficient
ordering generally outperforms FBP in numerical evaluations
of the quality of the reconstructions.
Acknowledgments
Much of this article is based on various parts of the book Gabor
T. Herman: Fundamentals of Computerized Tomography: Image
Reconstruction from Projections, 2nd ed., Springer, 2009.
208
Relative error
0.085
0.08
0.075
0.07
0.065
0.06
0.055
0.05
0.045
0.04
0.035
0
10
12
Iteration
14
16
18
20
Figure 4 Values r for ART reconstructions with pixels (light) and blobs (dark), plotted at multiples of I iterations. Reproduced from Herman, G. T.
(2009). Fundamentals of computerized tomography: Image reconstruction from projections (2nd ed.). New York: Springer.
References
Herman, G. T. (2009). Fundamentals of computerized tomography: Image
reconstruction from projections (2nd ed.). New York: Springer.
Herman, G., & Meyer, L. (1993). Algebraic reconstruction techniques can be
made computationally efficient. IEEE Transactions on Medical Imaging, 12,
600609.
Klukowska, J., Davidi, R., & Herman, G. T. (2013). SNARK09 A software package for
the reconstruction of 2D images from ID projections. Computer Methods and
Programs in Biomedicine, 110, 424440.
Relevant Website
http://www.dig.cs.gc.cuny.edu/software/snark09 SNARK09: A Programming System
for the Reconstruction of 2D Images from ID Projections.
Glossary
Introduction
Tomographic detection of radiolabeled molecules in tissues of
interest with positron emission tomography (PET) facilitates the
study of normo-/pathophysiology and therapeutic interventions. Such radiolabeled molecules can be drug candidates or
probes that may bind to and produce readouts from the target
biology of interest. In either case, quantitative information on
specific biological parameters of interest can be derived by applying biomathematical models to the kinetic data that have been
measured with PET. For drugs, this allows estimation of parameters such as the free brain concentration (Gunn et al., 2012) and
target engagement at differing dosing levels (Abanades et al.,
2011; Cunningham, Rabiner, Slifstein, Laruelle, & Gunn, 2009;
Salinas et al., 2013). For specific imaging probes, this allows
measurement of a range of G protein-coupled receptors, transporters, enzymes, or basic physiology such as blood flow
and metabolism (cf. Kety, 1951; Mintun, Raichle, Kilbourn,
Wooten, & Welch, 1984; Sokoloff et al., 1977). In this article,
we will focus on PET pharmacokinetic modeling for receptor
systems, but the modeling and mathematics presented generalize to other target biology.
The purpose of introducing modeling to dynamic PET quantification is to accurately characterize the biological properties of
the system and estimate the intrinsic parameter values free from
confounds. For example, when the total uptake in tissue is taken
as the outcome measure, even if the same dose of radiotracer is
injected to each subject, the uptake value measured at certain time
points after the injection may still differ between subjects. This
could be simply due to the difference in subjects weights rather
than any variation in the target biology. Even when the uptake is
normalized to a standard uptake value (SUV, e.g., by dividing the
uptake by injected dose and multiplying by weight or body
surface area), this still does not account for the differences in
metabolism of radiotracers due to peripheral effects or blood
flow in the target tissue. In order to address these issues properly
in a quantitative manner, it is necessary to measure both the input
and the output data for the system and apply appropriate pharmacokinetic modeling techniques to the dynamic data so that the
biological parameters of interest can be determined independent
of confounds in the peripheral and target tissues.
This article first introduces the PET preprocessing step that
enables derivation of the system input and output data before
Brain Mapping: An Encyclopedic Reference
Data Preprocessing
PET pharmacokinetic modeling is applied to concentration time
profiles in tissues of interest, and these data must first be accurately extracted from the measured emission data themselves.
First, the raw emission data are reconstructed using either analytic
or iterative tomographic reconstruction techniques with the
appropriate corrections for detector normalization, attenuation,
scatter, and detector dead time. Having reconstructed the
dynamic images, it is necessary to correct for any interframe
motion present in the time series this can be achieved using
image registration techniques that typically examine a spatial
similarity metric between image volumes prior to applying a
6-parameter rigid body transformation to correct for motion,
which can be implemented with SPM (Wellcome Trust Center
for Neuroimaging, http://www.fil.ion.ucl.ac.uk/spm) or FSL
(FMRIB Center, http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/).
The concentration time profiles in tissues of interest can
then be derived from individual voxel data to enable parametric image generation from anatomically (or functionally;
Tziortzi et al., 2013) defined regions of interest (ROIs) to
enable regional parameter estimation. While ROIs can be
delineated manually, this is time-consuming, and automated
methods based on the nonlinear deformation of stereotaxic
atlases in conjunction with adjunct structural MRI data are
usually preferred (Hammers et al., 2003; Tziortzi et al., 2011).
PET pharmacokinetic modeling methods also require an input
function that contains information on the concentration of radiotracer that is delivered to the target tissue of interest. This enables
tracer kinetic models to estimate biological parameters specific to
the target tissue of interest rather than being confounded by
peripheral effects. For example, this means that differences in
injected activity, body weight, physiology/metabolism, or other
http://dx.doi.org/10.1016/B978-0-12-397025-1.00287-6
209
210
Reference
tissue
Specific
binding
Non-specific
binding
Free
radioligand
Blood
Target
tissue
Figure 1 Schematic drawing for delivery of a radiolabeled ligand to a tissue from the vasculature and subsequent binding to specific and nonspecific
sites in brain tissue. PET provides concentration time courses in tissue, and associated arterial cannulation and sampling provides a concentration
time course in blood. Adapted from an original drawing by Terry Jones.
n
X
fi eyi t
[1]
i1
Reversible
target system
Plasma input
CT1
Irreversible
target system
CT
CT1
CT
CP
CT
211
CT
CP
CTn
(a)
CT
CT
CTn
CT1
CT
(b)
CT1
CT
CT
CT
CT
CTn
CP
CT
CTn
CR1
CR
CP
CR1
CR
CR
CR
CR
CRm
CR
(c)
CRm
(d)
Figure 2 General plasma input (a, b) and reference tissue input (c, d) compartmental systems for an arbitrary number of compartments. (a) and (c) have
reversible kinetics in the target tissues. (b) and (d) have irreversible kinetics in the target tissue. The reference tissues in (c) and (d) have reversible kinetics.
linear systems (Gunn, Gunn, & Cunningham, 2001) and combined with knowledge of the plasma input function, CP(t),
provides an equation for the tissue time course, CT(t):
CT t
n
X
fi eyi t Cp t
[2]
[5]
fn
[6]
t!1
i1
For tracers that exhibit reversible kinetics, the volume of distribution (VT, or more strictly a partition coefficient that is
defined by the ratio of the total concentration in tissue to the
total concentration in plasma at equilibrium; Innis et al.,
2007) is equal to the integral of the impulse response function:
1
VT
IRFt
[3]
n
X
fi eyi t CP t
[7]
i1
n
X
f
i1
yi
Irreversible kinetics yi6n > 0, yn 0
[4]
212
on anatomy) that is devoid of the target receptor system allowing for measurement of the tracer time course in the absence of
receptor binding. Mathematically, the equations can be again
derived along the principles of linear systems theory, but here,
one derives two sets of equations, one for the reference tissue
time course and one for the target tissue time course. Both of
these equations include the plasma time course, and it is the
substitution for this term that yields a functional equation
describing the target tissue time course as a function of
the reference tissue time course without any dependence
on the plasma concentration (see Figure 2(c) and (d))
(Cunningham et al., 1991; Gunn et al., 2001).
The general equation for a reference tissue input compartmental model is given by
CT t f0 CR t
mn1
X
fi eyi t CR t
[8]
WSSQ
i1
n
X
wi yi f xi , b2
[13]
i1
Model-Driven Methods
Reversible target tissue kinetics yi > 0
IRFt
[9]
VR
0
f0
mn1
X
i1
fi
yi
[10]
For reversible radioligand studies, this parameter allows calculation of the binding potential, BPND VT =VR 1 (Innis
et al., 2007).
Irreversible target tissue kinetics yi6mn1 > 0, ymn1 0
[11]
fmn1
[12]
K1
K1
CF+NS+SP
CP
CT
CP
k2
K1
k3
CF+NS
k2
213
CSP
CT
CF+NS+SP
CT
CF+NS
CR
k2
k4
CP
K1
k2
(a)
(b)
(c)
Figure 3 A range of PET compartmental models commonly used to quantify PET radiotracers. These include models for tracers that exhibit reversible
kinetics and models that use either a plasma or a reference tissue input function: (a) A one-tissue compartment model (1TC), (b) a two-tissue
compartment model (2TC), and (c) a simplified reference tissue model (SRTM). Here, the compartments are depicted in terms of radioligand binding and
constitute either free (F) radioligand, nonspecifically bound (NS) radioligand, specifically bound (SP) radioligand, or some combination of them.
102
1TC
VT
K1
AIC
VT
BRS 6.52
0.08
32.6
8.03
0.15 44.8
THA 5.79
0.10
48.5
7.01
0.19 16.8
STR
0.10
45.2
5.56
0.18 25.1
101
100
2TC
4.59
K1
AIC
101
0
20
(a)
40
60
Time (min)
80
(b)
20
20
15
10
0
(C)
Brain stem
Thalamus
Striatum
Brain stem
Thalamus
Striatum
20
40
60
Time (min)
15
10
80
(d)
20
40
60
Time (min)
80
Figure 4 Compartmental modeling of dynamic PET data acquired in human brain with translocator protein radiotracer [11C]PBR28 with arterial
sampling. (a) Parent plasma concentration; (b) quantification results including estimates for VT, K1, and the Akaike information criteria (AIC) in the brain
stem (BRS), thalamus (THA), and striatum (STR) for 1TC and 2TC model fitting; (c) nonlinear fitting with a 1TC model to the time activity curves
(TACs); and (d) nonlinear fitting with a 2TC model to the TACs. The 2TC is a better model to characterize this tracer than the 1TC as
determined by the AIC.
214
linear regression to be used. One such method involves establishing a set of kinetic basis functions, which can be used for
both specific compartmental models and data-driven
approaches (Gunn, Gunn, Turkheimer, Aston, & Cunningham,
2002). When applied to a simplified reference tissue model
(SRTM, where both the target and the reference regions are
represented by a single compartment (Lammertsma & Hume,
1996)), a spectrum of basis functions are formed, which is the
convolution of the reference curve with a series of single exponentials with different coefficients (Gunn, Lammertsma,
Hume, & Cunningham, 1997). This transforms the problem
into a linear equation and enables the coefficients to be estimated using standard linear least squares. In addition to the
high computational cost, parametric analysis can suffer from
higher levels of noise as compared to ROI-based analysis. To
address this issue, methods such as SRTM2 have been developed that incorporate additional constraints on the model
parameters (Wu & Carson, 2002), and alternative approaches
have also introduced spatial constraints based on the kinetic
information in the neighborhood of a voxel (Zhou, Huang,
Bergsneider, & Wong, 2002). As more constraints are introduced, additional care should be taken to assess bias.
Data-Driven Methods
Compared to model-driven methods, data-driven methods do
not require a priori selection of a specific compartmental
model to describe the data. These methods are often based
on the linearization of the data and thus allow for fast implementation and are particularly useful for parametric analysis to
generate functional images.
One group of these data-driven approaches is the graphical
methods, which employ a transformation of the data such that,
after a certain time, a standard linear regression of the transformed data yields the macrosystem parameter of interest. For
example, the Patlak plot enables the estimation of the irreversible uptake constant KI for an irreversible system (Patlak &
Blasberg, 1985; Patlak, Blasberg, & Fenstermacher, 1983),
and the Logan plot allows for a direct estimation of the volume
of distribution VT for a reversible system (Logan et al., 1990,
1996). As standard linear regression assumes noiseless data on
the x-axis, graphical analyses can lead to noise-induced bias in
parameter estimates when noise is present in both the x- and
the y-variables (Carson, 1993; Cunningham, 1985; Slifstein &
Laruelle, 2000). When bias becomes an issue, other estimation
methods, such as total least squares (Varga & Szabo, 2002)
and likelihood estimation (Ogden, 2003), can be applied.
Alternatively, by rearranging the x- and y-variables of the linear
equation, a multilinear relationship can be established with
reduced noise in the x-variables, and the macroparameters
such that the volume of distribution or the binding potential
can be estimated using multilinear regression with plasma
(MA1, Ichise, Toyama, Innis, & Carson, 2002) or reference
input (MRTM, Ichise et al., 2003), respectively.
In addition to the graphical and multilinear methods, spectral analysis and basis pursuit are basis function methods that
do not assume a particular model to describe the data. Instead,
they are able to return information on the number of tissue
compartments evident in the data and thus are considered as
transparent techniques. The methods characterize the system
as a sum of basis functions (convolution of single exponentials
Study-Level Analyses
PET pharmacokinetic modeling yields quantitative outcome
parameters for individual scans. However, these scans are typically part of larger studies where either subjects are scanned
longitudinally over time or different populations of subjects
are scanned in a cross-sectional manner. Thus, there are further
modeling and statistical analysis techniques that are applied to
these outcome measures at the study level.
For intrasubject longitudinal studies, the reproducibility of
the analysis techniques is often assessed initially in a testretest
design in terms of the variability (%VAR) or the intraclass
correlation coefficient (Koch, 1982). Having demonstrated
good reproducibility, these outcome measures can be used to
determine changes in the target biology following a physiological/psychological or pharmacological intervention. For intersubject studies, standard statistical tests can be applied to
determine differences in the biological parameter of interest
across groups (e.g., in different disease states to identify if a
biological target is altered).
In addition to these statistical analyses at the study level,
there are other dynamic modeling techniques that can be
applied. For instance, in drug occupancy studies, the relationship between cold drug concentrations in plasma and the
target occupancy in the brain as measured with a radioligand
can be evaluated with pharmacokineticreceptor occupancy
models that describe the drugs binding behavior at the target
of interest across subjects over time (Abanades et al., 2011).
This is important for characterizing the target residence time of
the drug and identifying whether there is a simple direct relationship or a more complex indirect relationship between the
plasma concentration and target occupancy (Salinas et al.,
2013). Such techniques also allow the prediction of drug
target interactions under repeat dosing regimes based simply
on single-dose data sets.
References
Abanades, S., van der Aart, J., Barletta, J. A., Marzano, C., Searle, G. E., Salinas, C. A.,
et al. (2011). Prediction of repeat-dose occupancy from single-dose data:
characterisation of the relationship between plasma pharmacokinetics and
brain target occupancy. Journal of Cerebral Blood Flow and Metabolism, 31(3),
944952.
Akaike, H. (1974). A new look at the statistical model identification. IEEE Transactions
on Automatic Control, 19(6), 716723.
Beck, J. V., & Arnold, K. J. (1977). Parameter estimation in engineering and science
(vol. 8). New York: Wiley.
Carson, R. (1986). Parameter estimation in positron emission tomography. Positron
emission tomography and autoradiography: Principles and applications for the
brain and heart. New York: Raven Press, pp. 347390.
Carson, R. (1993). PET parameter estimation using linear integration methods: Bias and
variability considerations. Annals of Nuclear Medicine, 7, S102.
Carson, R. E., Channing, M. A., Blasberg, R. G., Dunn, B. B., Cohen, R. M., Rice, K. C.,
et al. (1993). Comparison of bolus and infusion methods for receptor quantitation:
Application to [18F]cyclofoxy and positron emission tomography. Journal of
Cerebral Blood Flow and Metabolism, 13(1), 2442.
Cunningham, V. (1985). Non-linear regression techniques in data analysis. Informatics
for Health and Social Care, 10(2), 137142.
Cunningham, V. J., Hume, S. P., Price, G. R., Ahier, R. G., Cremer, J. E., & Jones, A. K.
(1991). Compartmental analysis of diprenorphine binding to opiate receptors in the
rat in vivo and its comparison with equilibrium data in vitro. Journal of Cerebral
Blood Flow and Metabolism, 11(1), 19.
Cunningham, V., & Jones, T. (1993). Spectral analysis of dynamic PET studies. Journal
of Cerebral Blood Flow and Metabolism, 13(1), 1523.
Cunningham, V., Rabiner, E., Slifstein, M., Laruelle, M., & Gunn, R. (2009). Measuring
drug occupancy in the absence of a reference region: The Lassen plot re-visited.
Journal of Cerebral Blood Flow and Metabolism, 30(1), 4650.
Gunn, R. N., Gunn, S. R., & Cunningham, V. J. (2001). Positron emission tomography
compartmental models. Journal of Cerebral Blood Flow and Metabolism, 21(6),
635652.
Gunn, R. N., Gunn, S. R., Turkheimer, F. E., Aston, J., & Cunningham, V. (2002).
Positron emission tomography compartmental models a basis pursuit strategy for
kinetic modeling. Journal of Cerebral Blood Flow and Metabolism, 22(12),
14251439.
Gunn, R. N., Lammertsma, A., Hume, S., & Cunningham, V. (1997). Parametric imaging
of ligandreceptor binding in PET using a simplified reference region model.
NeuroImage, 6(4), 279287.
Gunn, R. N., Summerfield, S. G., Salinas, C. A., Read, K. D., Guo, Q., Searle, G. E., et al.
(2012). Combining PET biodistribution and equilibrium dialysis assays to assess
the free brain concentration and BBB transport of CNS drugs. Journal of Cerebral
Blood Flow and Metabolism, 32(5), 874883.
Hammers, A., Allom, R., Koepp, M. J., Free, S. L., Myers, R., Lemieux, L., et al. (2003).
Three-dimensional maximum probability atlas of the human brain, with particular
reference to the temporal lobe. Human Brain Mapping, 19(4), 224247.
Ichise, M., Liow, J., Lu, J., Takano, A., Model, K., Toyama, H., et al. (2003). Linearized
reference tissue parametric imaging methods: Application to [11C]DASB positron
emission tomography studies of the serotonin transporter in human brain. Journal
of Cerebral Blood Flow and Metabolism, 23(9), 10961112.
Ichise, M., Toyama, H., Innis, R. B., & Carson, R. E. (2002). Strategies to improve
neuroreceptor parameter estimation by linear regression analysis. Journal of
Cerebral Blood Flow and Metabolism, 22(10), 12711281.
Innis, R., Cunningham, V., Delforge, J., Fujita, M., Gjedde, A., Gunn, R., et al. (2007).
Consensus nomenclature for in vivo imaging of reversibly binding radioligands.
Journal of Cerebral Blood Flow and Metabolism, 27(9), 15331539.
Jacquez, J. A. (1998). Compartmental analysis in biology and medicine (3rd ed.). Ann
Arbor, MI: Biomedware.
215
Kety, S. S. (1951). The theory and applications of the exchange of inert gas at the lungs
and tissues. Pharmacological Reviews, 3(1), 141.
Koch, G. G. (1982). Intraclass correlation coefficient. Encyclopedia of Statistical
Sciences, 4, 213217.
Lammertsma, A., & Hume, S. (1996). Simplified reference tissue model for PET receptor
studies. NeuroImage, 4(3), 153158.
Landaw, E., & DiStefano, J. (1984). Multiexponential, multicompartmental, and
noncompartmental modeling. II. data analysis and statistical considerations.
American Journal of Physiology, 246(5), R665R677.
Lassen, N., & Perl, W. (1979). Tracer kinetic methods in medical physiology. New York:
Raven Press.
Levenberg, K. (1944). A method for the solution of certain nonlinear problems in least
squares. Quarterly of Applied Mathematics, 2, 164168.
Logan, J., Fowler, J. S., Volkow, N. D., Wang, G. J., Ding, Y. S., & Alexoff, D. L. (1996).
Distribution volume ratios without blood sampling from graphical analysis of PET
data. Journal of Cerebral Blood Flow and Metabolism, 16(5), 834840.
Logan, J., Fowler, J. S., Volkow, N. D., Wolf, A. P., Dewey, S. L., Schlyer, D. J., et al.
(1990). Graphical analysis of reversible radioligand binding from time-activity
measurements applied to [N-11C-methyl]-()-cocaine PET studies in human
subjects. Journal of Cerebral Blood Flow and Metabolism, 10(5), 740747.
Marquardt, D. (1963). An algorithm for least-squares estimation of nonlinear parameters.
Journal of the Society for Industrial and Applied Mathematics, 11(2), 431441.
Mintun, M. A., Raichle, M. E., Kilbourn, M. R., Wooten, G. F., & Welch, M. J. (1984). A
quantitative model for the in vivo assessment of drug binding sites with positron
emission tomography. Annals of Neurology, 15(3), 217227.
Ogden, R. T. (2003). Estimation of kinetic parameters in graphical analysis of PET
imaging data. Statistics in Medicine, 22(22), 35573568.
Patlak, C. S., & Blasberg, R. G. (1985). Graphical evaluation of blood-to-brain transfer
constants from multiple-time uptake data. generalizations. Journal of Cerebral Blood
Flow and Metabolism, 5(4), 584590.
Patlak, C. S., Blasberg, R. G., & Fenstermacher, J. D. (1983). Graphical evaluation of
blood-to-brain transfer constants from multiple-time uptake data. Journal of
Cerebral Blood Flow and Metabolism, 3(1), 17.
Salinas, C., Weinzimmer, D., Searle, G., Labaree, D., Ropchan, J., Huang, Y., et al.
(2013). Kinetic analysis of drugtarget interactions with PET for characterization of
pharmacological hysteresis. Journal of Cerebral Blood Flow and Metabolism, 33(5),
700707.
Schwarz, G. (1978). Estimating the dimension of a model. The Annals of Statistics, 6(2),
461464.
Slifstein, M., & Laruelle, M. (2000). Effects of statistical noise on graphic analysis of
PET neuroreceptor studies. Journal of Nuclear Medicine, 41(12), 20832088.
Sokoloff, L., Reivich, M., Kennedy, C., Des Rosiers, M., Patlak, C. S., Pettigrew, K. D.,
et al. (1977). The [14C] deoxyglucose method for the measurement of local cerebral
glucose utilisation: Theory, procedure, and normal values in the conscious and
anesthetized albino rat. Journal of Neurochemistry, 28(5), 897916.
Tziortzi, A. C., Haber, S. N., Searle, G. E., Tsoumpas, C., Long, C. J., Shotbolt, P., et al.
(2013). Connectivity-based functional analysis of dopamine release in the
striatum using diffusion-weighted MRI and positron emission tomography. Cereb
Cortex, 24(5), 11651177.
Tziortzi, A. C., Searle, G. E., Tzimopoulou, S., Salinas, C., Beaver, J. D., Jenkinson, M.,
et al. (2011). Imaging dopamine receptors in humans with [11C]-()-PHNO:
Dissection of D3 signal and anatomy. NeuroImage, 54(1), 264277.
Varga, J., & Szabo, Z. (2002). Modified regression model for the Logan plot. Journal of
Cerebral Blood Flow and Metabolism, 22(2), 240244.
Wu, Y., & Carson, R. (2002). Noise reduction in the simplified reference tissue model
for neuroreceptor functional imaging. Journal of Cerebral Blood Flow and
Metabolism, 22(12), 14401452.
Zhou, Y., Huang, S. C., Bergsneider, M., & Wong, D. F. (2002). Improved parametric
image generation using spatial-temporal analysis of dynamic PET studies.
NeuroImage, 15(3), 697707.
Introduction
The use of light in the near infrared to investigate functional
activation is increasingly widely spread and is referred to as
functional near-infrared spectroscopy (fNIRS). The interaction
of light with biological tissue is dominated by scattering interactions. As a result, light traveling a distance of more than a few
millimeters into tissue will form a diffuse field. Despite this,
multichannel diffuse optical imaging systems can yield significant spatial information and allow the mapping of changes in
optical properties (and, by proxy, functional activation) in the
cortex with a resolution as good as 510 mm (Habermehl
et al., 2012).
The process of producing an image from multichannel
diffuse optical imaging data has three distinct phases. The
first is to produce a model of how light travels through the
object under investigation given the specific arrangement of
optical sources on the surface. The second is to use this photon
transport model to predict the change in optical measurement
(usually intensity) that would be measured by each channel for
a given change in tissue optical properties. This yields what is
known as a sensitivity matrix. The third and final phase is
image reconstruction, which requires the solution to the
inverse problem in which the sensitivity matrix is inverted.
The fundamental paradigm for mapping the cortex using
diffuse optical imaging involves invoking a hemodynamic
response to a particular cognitive task or external stimulus
and mapping the difference between the pre- and poststimulus
states. In general, the dependence of the optical signal on the
hemodynamic response is nonlinear, which is stated as a nonlinear forward problem
y Ax
[1]
[2]
and constant refractive index (Arridge, 1999). However, solving the radiative transport equation to provide the photon
density at every point in a 3-D volume is computationally
demanding, and more efficient approaches are usually necessary. By assuming that, after a small number of scattering
events, the distribution of directions of propagation of individual photons is nearly isotropic, the radiative transport equation simplifies to what is commonly referred to as the diffusion
equation or diffusion approximation. This equation can be
solved at significantly less computational expense. While the
assumption of diffusivity is valid for most tissues, it can break
down in regions of low scatter (such as in the cerebrospinal
fluid), at boundaries between tissues, and near the locations of
the optical sources.
In simple geometries, it is possible to solve the diffusion
equation (and the radiative transport equation) analytically.
Greens functions can be used to solve the diffusion equation if
each source is modeled as a delta function in both space and
time. By convolving a number of such solutions, the light field
produced by extended sources can also be modeled. While
more sophisticated Greens function techniques have been
developed, such solutions are generally limited to cases where
the target object can be modeled as a slab or semi-infinite
space. Despite this, Greens function approaches have been
used successfully for simple diffuse optical imaging applications (Culver, Siegel, Stott, & Boas, 2003).
For the more complex geometries of multilayered models of
the head and brain, it is necessary to apply numerical techniques to solve the equations governing light propagation. The
most commonly applied to diffuse optical imaging is the finite
element method (FEM) (Arridge, Schweiger, Hiraoka, & Delpy,
1993). The FEM can be used to provide approximate solutions
to the diffusion equation in a 3-D finite element mesh. A
number of other numerical approaches have been devised,
including the finite difference method (Pogue & Patterson,
1994) and the finite volume method (Ren, Abdoulaev, Bal, &
Hielscher, 2004).
The boundary element method (BEM) produces a model of
light propagation by representing a 3-D volume as a set of
closed surfaces, where the tissue within each surface is assumed
to be homogeneous. Greens theorem is used to transform the
diffusion equation to a set of integral equations defined only
on these surfaces. This can significantly simplify the required
meshing procedure and reduce the dimensionality of the forward problem. As a result, BEM can provide a semi-analytic
solution to the forward problem in an efficient manner (Elisee,
Gibson, & Arridge, 2011).
Instead of seeking solutions to the diffusion equation to
calculate photon density in tissue, statistical techniques such as
the Monte Carlo method simulate the trajectories of individual
photons. The 3-D volume is subdivided into elements with
specific values of the absorption (ma) and reduced scattering
(ms0 ) coefficients. Each simulated photon is given a weight on
http://dx.doi.org/10.1016/B978-0-12-397025-1.00288-8
217
218
Sensitivity Matrices
There are several ways that the linearized sensitivity matrix J
can be constructed from a model of photon transport. When
simple analytic models based on the diffusion equation are
employed, then explicit expressions for J can be derived, again
assuming simple geometries such as a semi-infinite space.
When Monte Carlo methods are used, it is possible to calculate
the derivatives of the photon weights at the same time as
calculating the data itself. In general, for complex arbitrary
geometries and inhomogeneous parameters, an explicit perturbation can be made: adding a small variation to the absorption in each voxel and calculating the resulting change in
measurement. This method can be applied to any model
but is computationally expensive, requiring a new forward
solution for each voxel and each source. Instead, most computational techniques exploit the reversibility of photon propagation to show that the sensitivity of a given sourcedetector
pair can be expressed as the product of the fluence resulting
from the source and an adjoint fluence resulting from a
fictitious source placed at the location of the detector. In
Figure 1 are shown several different forms of the sensitivity
function from one source and detector. The differences are to
some extent subtle but are significant in terms of the image
reconstruction because of the severe ill-posedness of the
problem.
model of the object. Monte Carlo simulations can be performed in voxelized or in 3-D mesh-based structural models,
while BEM solutions require a series of surface meshes
(Figure 2).
Studies of diffuse optical imaging and reconstruction
methods have employed a wide range of structural models.
Many image reconstruction simulations and phantom studies
have employed semi-infinite slab and cylindrical geometries.
Early studies of functional activation modeled the brain as a
homogeneous slab, discretized into a regular grid (Everdell
et al., 2005). Such approaches, while crude, are computationally efficient and can provide sufficient spatial information to
address hypotheses relating to the lateralization or gross localization of cognitive processes.
To improve the registration of diffuse optical images to the
brain, realistic head geometries were soon developed. The
simplest consisted of a generic, homogenous head model to
which the source and detector locations were registered
(Gibson et al., 2006).
The optical properties of the fundamental tissues of the
head (i.e., the scalp, skull, cerebrospinal fluid, and gray and
white matter) vary markedly. As a result, the use of multilayered head geometries greatly improves the accuracy of
models of light transport while also helping to constrain the
process of image reconstruction and allowing the resulting
images to be inherently registered to the cortical anatomy.
The production of a finite element mesh is relatively
straightforward for simple homogeneous volumes, but the
efficient production of multilayered meshes of the complex
structure of the brain is a significant challenge and has been
the subject of active research in recent years (Fang & Boas,
2009b; Gibson et al., 2003). A number of software packages
have emerged that allow users to take structural images of the
subjects head and brain (usually via MRI or CT) and produce
accurate, subject-specific, multilayered head meshes (Fang &
Boas, 2009b). The positions of the sources and detectors can be
registered to these multilayered models using 3-D digitization
or photogrammetric techniques.
The resulting multilayered finite element meshes can be
used to solve the forward problem. Using a head model based
on subject-specific structural images constitutes the current
best practice for diffuse optical image reconstruction. However, one of the advantages of optical imaging is that the
systems are portable and can therefore be applied in a wide
range of environments. Requiring a structural MRI for each
subject undermines this advantage. This issue can be overcome by using a generic head model as a substitute for the
subject-specific anatomy. Such generic models are usually produced using an MRI atlas, that is, a spatial average of the head
anatomy of the appropriate population (Custo et al., 2010).
The segmented atlas can be used to generate appropriate
meshes. To employ an atlas model requires careful measurement of the subjects cranial landmarks and scalp surface as
well as accurate measurement of the source and detector
positions relative to the scalp. This information allows the
atlas model to be spatially registered to the subjects external
anatomy. The use of atlas models has been shown to yield
images that, while less accurate than the subject-specific case,
are still accurate enough to localize functional activation to
within 12 cm (Cooper et al., 2012).
219
Figure 1 Examples of sensitivity functions generated by different models. First column: the direct light field produced by the source; second column:
the adjoint field produced by the detector; third column: the resultant sensitivity function. In the first row, the model is the infinite space solution to
the diffusion equation, which has a spherically symmetrical form. In the second row, the boundary conditions for a square domain are introduced.
The third row is the case for a head-shaped mesh, but with homogeneous optical parameters. The fourth row includes realistic optical properties in
each tissue layer. The sensitivity matrix J is formed by compositing all such functions for each sourcedetector pair.
Figure 2 Left: A three-layer BEM model of the scalp and skull and cortical surface. Right: Solution of fluence on the cortical surface for a point source.
220
[3]
1
JT Dy
Dynamic Imaging
An important feature of fNIRS is its dynamic aspect. This is
implicit in eqn [2] because the measurements are typically
-40 -30 -20 -10
10
20
30
40
-40
-30
50
40
-20
30
-10
20
10
10
-10
-20
20
-30
40
30
40
20
20
40
-20
-40
-40
-20
50
Figure 3 Side and top views of a cortical map of a functional activation. An activation of the primary motor and somatosensory regions in response to
arm motion is clearly visible.
[4]
[5]
which describes the time-varying image in terms of a timevarying model Z and a vector of explanatory variables f. A
well-known example is the general linear model that assumes
that eqn [5] is the convolution of a known response function
with a set of experimental designs; Z is then referred to as the
design matrix. However, nonlinear models including higherorder convolution processes and adaptive filters can also be
considered.
Time-series methods have been applied in fNIRS; for a
review, see Huppert, Diamond, Franceschini, and Boas
(2009). In previous work using statistical parametric mapping
(SPM) methodology on fNIRS data, the optical measurement
data have been converted into chromophore concentrations
using the modified BeerLambert law (Koh et al., 2007; Tachtsidis, Koh, Stubbs, & Elwell, 2010; Tachtsidis et al., 2009), and a
model based on homogeneous diffusion and nearest-neighbor
measurements (Ye, Tak, Jang, Jung, & Jang, 2009). Boas, Dale,
and Franceschini (2004) showed that brain activations can be
more accurately localized, and their spatial extent defined, by
performing an image reconstruction rather than merely analyzing individual measurement channels. In Heiskala, Hiltunen, and Nissila (2009), it was shown that accurate modeling
of the optical background can also significantly improve reconstructed images. This suggests that superior results can be
expected by combining the SPM analysis with accurate modeling of the head, using either individual anatomical data or
generic data from an atlas.
Rather than the general linear model, which assumes a
time-invariant HRF, time-series estimation approaches using
adaptive filters have been proposed. This idea was introduced
in Kolehmainen, Prince, Arridge, and Kaipio (2000) for
dynamic imaging without physiological parameter inputs and
extended in Prince et al. (2003), where a linear state-space
model was applied to time-varying image reconstruction. Signal sources such as the heartbeat were modeled by
221
References
Arridge, S. R. (1999). Optical tomography in medical imaging. Inverse Problems, 15(2),
R41.
Arridge, S. R., Schweiger, M., Hiraoka, M., & Delpy, D. T. (1993). A finite element
approach for modeling photon transport in tissue. Medical Physics, 20(2),
299309.
Boas, D. A., Dale, A. M., & Franceschini, M. A. (2004). Diffuse optical imaging of brain
activation: Approaches to optimizing image sensitivity, resolution, and accuracy.
NeuroImage, 23(Suppl. 1), S275S288.
Cooper, R. J., Caffini, M., Dubb, J., Custo, A., Tsuzuki, D., Fischl, B., et al. (2012).
Validating atlas-guided DOT: A comparison of diffuse optical tomography informed
by atlas and subject-specific anatomies. NeuroImage, 62, 19992006.
Correia, T., Gibson, A., Schweiger, M., & Hebden, J. (2009). Selection of
regularization parameter for optical topography. Journal of Biomedical Optics,
14(3), 034044.
Culver, J. P., Siegel, A. M., Stott, J. J., & Boas, D. A. (2003). Volumetric diffuse optical
tomography of brain activity. Optics Letters, 28(21), 20612063.
Custo, A., Boas, D. A., Tsuzuki, D., Dan, I., Mesquita, R., Fischl, B., et al. (2010).
Anatomical atlas-guided diffuse optical tomography of brain activation.
NeuroImage, 49(1), 561567.
Elisee, J., Gibson, A., & Arridge, S. (2011). Diffuse optical cortical mapping using the
boundary element method. Biomedical Optics Express, 2(3), 568578.
Everdell, N. L., Gibson, A. P., Tullis, I. D.C, Vaithianathan, T., Hebden, J. C., &
Delpy, D. T. (2005). A frequency multiplexed near-infrared topography system for
imaging functional activation in the brain. Review of Scientific Instruments, 76(9),
093705.
Fang, Q. (2010). Mesh-based monte carlo method using fast ray-tracing in plucker
coordinates. Biomedical Optics Express, 1(1), 165175.
Fang, Q., & Boas, D. A. (2009a). Monte carlo simulation of photon migration in 3D
turbid media accelerated by graphics processing units. Optics Express, 17(22),
2017820190.
Fang, Q., & Boas, D. A. (2009b). Tetrahedral mesh generation from volumetric binary
and grayscale images. In IEEE international symposium on biomedical imaging:
From nano to macro, 2009. ISBI 09 (pp. 11421145).
Gibson, A. P., Austin, T., Everdell, N. L., Schweiger, M., Arridge, S. R., Meek, J. H., et al.
(2006). Three-dimensional whole-head optical tomography of passive motor
evoked responses in the neonate. NeuroImage, 30(2), 521528.
Gibson, A. P., Riley, J., Schweiger, M., Hebden, J. C., Arridge, S. R., & Delpy, D. T.
(2003). A method for generating patient-specific finite element meshes for head
modelling. Physics in Medicine and Biology, 48(4), 481.
Habermehl, C., Holtze, S., Steinbrink, J., Koch, S. P., Obrig, H., Mehnert, J., et al.
(2012). Somatosensory activation of two fingers can be discriminated with
ultrahigh-density diffuse optical tomography. NeuroImage, 59(4), 32013211.
Heiskala, J., Hiltunen, P., & Nissila, I. (2009). Significance of background optical
properties and time-resolved information in diffuse optical imaging of term
neonates. Physics in Medicine and Biology, 54, 535554.
Hu, X. S., Hong, K. S., Ge, S. S., & Jeong, M. Y. (2010). Kalman estimator and general
linear model-based on-line brain activation mapping by near-infrared spectroscopy.
Biomedical Engineering Online, 9, 82.
Huppert, T. J., Diamond, S. G., Franceschini, M. A., & Boas, D. A. (2009). HomER: A
review of time-series analysis methods for near-infrared spectroscopy of the brain.
Applied Optics, 48(10), 280298.
222
Koh, P. H., Glaser, D. E., Flandin, G., Kiebel, S., Butterworth, B., Maki, A., et al. (2007).
Functional optical signal analysis: A software tool for near-infrared spectroscopy
data processing incorporating statistical parametric mapping. Journal of Biomedical
Optics, 12, 064010.
Kolehmainen, V., Prince, S., Arridge, S. R., & Kaipio, J. P. (2000). A state estimation
approach to non-stationary optical tomography problem. Journal of the Optical
Society of America A, 20, 876884.
Pogue, B. W., & Patterson, M. S. (1994). Forward and inverse calculations for nearinfrared imaging using a multigrid finite difference method. In: R.R. Alfano
(Ed.), Advances in optical imaging and photon migration. Vol. 21 (pp. 176180).
Proc. OSA.
Prince, S., Kolehmainen, V., Kaipio, J. P., Franceschini, M. A., Boas, D., & Arridge, S. R.
(2003). Time series estimation of biological factors in optical diffusion tomography.
Physics in Medicine and Biology, 48(11), 14911504.
Ren, K., Abdoulaev, G. S., Bal, G., & Hielscher, A. H. (2004). Algorithm for solving the
equation of radiative transfer in the frequency domain. Optics Letters, 29(6), 578580.
Tachtsidis, I., Koh, P. C., Stubbs, C., & Elwell, C. E. (2010). Functional optical
topography analysis using statistical parametric mapping (SPM) methodology with
and without physiological confounds. In E. Takahashi & D. F. Bruley (Eds.),
Advances in experimental medicine and biology. Vol. 662. Oxygen transport to
tissue XXXI (pp. 237243). USA: Springer.
Tachtsidis, I., Leung, T. S., Chopra, A., Koh, P. C., Reid, C. B., & Elwell, C. E.
(2009). False positives in functional near-infrared topography. In P. Liss, P.
Hansell, D. F. Bruley, & D. K. Harrison (Eds.), Advances in experimental
medicine and biology: Vol. 645. Oxygen transport to tissue XXX
(pp. 307314). USA: Springer.
Ye, J. C., Tak, S. H., Jang, K. E., Jung, J. W., & Jang, J. D. (2009). NIRSSPM: Statistical
parametric mapping for near-infrared spectroscopy. NeuroImage, 44, 428447.
Glossary
Nomenclature
d(k)
d(k, t)
L
R
s(r)
Imaging Equation
MRI experiments, especially fMRI experiments, often use an
array of receiver coils for data acquisition. The data collected by
an individual coil (after proper simplifications and processing
such as filtering and demodulation) can be expressed as
d k rrs rei2pkr dr
[1]
where r(r) is the desired image function, s(r) denotes the
sensitivity function of the th receiver coil for 1, 2, . . ., L,
and the modulating factor ei2pkr represents phase and frequency encoding effects introduced using magnetic field gradients. If the sensitivity weighting effects are ignored (e.g., for
coils with spatially uniform sensitivity), we have the standard
Fourier transform imaging scheme (known as Fourier encoding). Otherwise, the sensitivity functions of different coils can
r(r)
r(r, t)
r^r
Dk
F
http://dx.doi.org/10.1016/B978-0-12-397025-1.00289-X
Dkx
1
1
, Dky
Wx
Wy
[3]
223
224
ky
ky
kx
(a)
ky
kx
(b)
kx
(c)
Figure 1 Examples of k-space sampling schemes used in MRI experiments: (a) cartesian sampling, (b) polar sampling, and (c) spiral sampling.
Fourier Reconstruction
For Cartesian k-space data sampled uniformly above the
Nyquist rate, image reconstruction is usually done by applying
the FFT (fast Fourier transform) along each dimension. For
simplicity, consider the one-dimensional case (say, along x)
with a single receiver coil. The reconstruction method can be
summarized as
r^x Dkx
N1
X
nN
1
2Dkx
[4]
hx Dkx
[6]
225
R1
X
^ s x m W
^
r x mW
[8]
m0
[9]
where
3
^ s1 x R 1W
^
s1 x s1 x W
6 s2 x s2 x W
^ s2 x R 1W
^ 7
7
S6
4
5
^ sL x R 1W
^
sL x sL x W
2
Rky
Coil 1
Coil 2
Coil 3
Coil 4
ky
(a)
kx
(b)
Figure 3 (a) Cartesian undersampling used in sensitivity encoding (solid lines are acquired and dashed lines are skipped); (b) Fourier reconstructions
from undersampled data acquired by different coils (R 2, L 4).
226
3
2
3
r^1 x
rx
^
6
7
6 r^2 x 7
r xW
7 and r
7
^ 6
r6
4
5
4 5
^
r x R 1W
r^L x
ky
[10]
kx
n0
N1
1
r SH C1 S lI SH C1 r^
[11]
rm1 x 1 2 frm xg
1 frxg jrxjei^x
[12]
[13]
and
Constrained Reconstruction
Conventional methods for image reconstruction are based on a
key mathematical assumption that the desired image function
is support-limited. This assumption enables image reconstruction from discrete measurements. In practice, additional mathematical assumptions can be made about the image function,
such as low-frequency phase variation, sparsity, and lowrankness. These assumptions, formulated as mathematical
constraints, can help improve image reconstruction from limited data. This section describes three representative constrained reconstruction methods.
2 frxg
1
frxg
[14]
227
Figure 5 (a) A brain image and (b) its wavelet transform coefficient map.
ky
(b)
kx
ky
(a)
kx
ky
(c)
kx
Figure 6 (a) Fully acquired k-space; (b) 1-D variable-density undersampling along the phase encoding (ky) direction and the incoherent artifacts in the
reconstructed image; (c) 2-D variable-density Poisson-disk undersampling along both the phase encoding (ky) and frequency encoding (kx)
directions and the aliasing artifacts in the Fourier reconstruction.
228
[16]
[17]
P
X
c r t
[18]
[20]
[21]
Figure 7 An fMRI image sequence reconstructed using conventional Fourier reconstruction method (top) and using the PS model with the same
number of encodings that sparsely sample (k, t)-space (bottom).
Acknowledgments
This work was supported by NSF grant CBET 1265612 and
NIH-R01-EB013695. The authors thank Yihang Zhou for preparing the figures in the article.
See also: INTRODUCTION TO ACQUISITION METHODS: EchoPlanar Imaging; High-Speed, High-Resolution Acquisitions; MRI and
fMRI Optimizations and Applications; Temporal Resolution and Spatial
Resolution of fMRI; INTRODUCTION TO METHODS AND
MODELING: Computerized Tomography Reconstruction Methods.
Further Reading
Bertero, M., & Boccacci, P. (1998). Introduction to inverse problems in imaging.
Bristol, Philadelphia: Institute of Physics Publishing.
229
Cande`s, E. J., Romberg, J. K., & Tao, T. (2006). Robust uncertainty principles: Exact
signal reconstruction from highly incomplete frequency information. IEEE
Transactions on Information Theory, 52, 489509.
Donoho, D. L. (2006). Compressed sensing. IEEE Transactions on Information Theory,
52, 12891306.
Kak, A. C., & Slaney, M. (1988). Principles of computerized tomographic imaging.
Piscataway, NJ: IEEE Press.
Liang, Z.-P. (2007). Spatiotemporal imaging with partially separable functions.
IEEE International Symposium on Biomedical Imaging, Arlington, TX, pp. 988991.
Liang, Z.-P., & Lauterbur, P. C. (1999). Principles of magnetic resonance imaging: A
signal processing perspective. Piscataway, NJ: IEEE Press.
Lustig, M., Donoho, D., & Pauly, J. M. (2007). Sparse MRI: The application of
compressed sensing for rapid MR imaging. Magnetic Resonance in Medicine, 58,
11821195.
Pruessmann, K. P., Weiger, M., Scheidegger, M. B., & Boesiger, P. (1999). SENSE:
Sensitivity encoding for fast MRI. Magnetic Resonance in Medicine, 42, 952962.
Ying, L., & Liang, Z.-P. (2010). Parallel MRI using phased array coils. IEEE Signal
Processing Magazine, 27, 9098.
Glossary
Introduction
This article is devoted to the things that can (and do) go wrong
during acquisition of functional MRI (fMRI) data, particularly
BOLD-weighted time series. For this article, the operational
definition of an artifact is any violation of the assumptions
about the image that results in degradation of the quality of the
data. As such, one has to be mindful of this fact when analyzing
any type of data, because interesting phenomena such as blood
flow effects, cardiac rate, and the BOLD itself could be considered artifacts by this definition. The topic of artifacts in fMRI is
quite broad because of the large number of things that can go
wrong in an image in MRI. There is a vast literature about these
aberrations as they pertain to clinical imaging (see, e.g., Bellon,
Haacke, et al., 1986; Henkelman, 1996; Hornak, 1997), but
providing a comprehensive classification of image artifacts is
not our goal here. Instead, we aim to provide the reader an
understanding of the implicit assumptions made in functional
imaging time series and the most common violations of those
assumptions. Sometimes, these can be prevented or at least
mitigated by careful experimental and pulse sequence design.
Other times, they cannot be prevented but instead must be
corrected or, at least, accounted for during the analysis of
the data.
In order to understand and categorize fMRI artifacts, let us
first take a look at what fMRI time series data consist of.
Although fMRI time series are essentially 3-D movies, in the
http://dx.doi.org/10.1016/B978-0-12-397025-1.00290-6
231
232
INTRODUCTION TO METHODS AND MODELING | Artifacts in Functional MRI and How to Mitigate Them
an autoregressive nature in part because of physiological fluctuations (e.g., heartbeat, respiration, and low-frequency oscillations) and in part because of drifts in the scanners hardware.
Assumption 5: We assume that changes in signal intensity
over the time series are caused by the BOLD responses induced
by the experimental paradigm. Obviously, there are many
other potential sources of signal fluctuation. Some sources
are physiological noise, signal fluctuations due to movement
(partial volume effects), subject noncompliance, etc.
Clearly, there are many violations to the basic assumptions
made by most analysis techniques, but most of them can be
overcome to an acceptable degree through preprocessing techniques and by including the sources of the artifact in the
statistical models. The rest of the article is devoted to describing
the nature of most of these artifacts and the most popular
correction techniques to mitigate them. The level of technical
detail throughout the article is generally not very high, as it is
intended to serve as a general resource to the neuroscientist.
Having said that, some of the concepts are explained in greater
detail than may seem necessary because they are particularly
important and ubiquitous in image analysis, so we feel it is
important that all investigators have a firm grasp of them.
Time points
40
60
80
100
120
140
1
6
7
voxels
10 11
104
Figure 2 As the subjects head moves in the scanner, the contents of the image grid change. Conversely, we can also think of this as moving the
imaging grid for the purpose of realignment. Our mission is to interpolate the contents of the new grid from the neighboring data.
INTRODUCTION TO METHODS AND MODELING | Artifacts in Functional MRI and How to Mitigate Them
The first step in this process is to determine the appropriate
coordinates of that new sampling grid, but before we discuss
that, let us review the concept of rigid body transformations
(i.e., shifting and rotating images without warping them).
Shifting a set of coordinates in space can be easily accomplished by adding the desired shift to each one of their
axes. For example, a point (x1, y1) can be shifted to the right
by adding some shift xs to the x coordinate. In three dimensions, this can be generalized to a simple equation in matrix
notation:
2
3 2 3 2 3
x1
xs
x2
4 y2 5 4 y1 5 4 ys 5
z2
z1
zs
[1]
[2]
y2 x1 sin y y1 cos y
[3]
233
Figure 3 Consider a voxel (in blue) that contains both gray matter and
white matter. When the subject moves, the fraction of gray matter and
white matter in that voxel changes, as depicted in the figure.
234
INTRODUCTION TO METHODS AND MODELING | Artifacts in Functional MRI and How to Mitigate Them
INTRODUCTION TO METHODS AND MODELING | Artifacts in Functional MRI and How to Mitigate Them
235
Raw
290
280
270
260
250
240
50
100
150
200
250
200
250
Global signal
290
280
270
260
250
240
50
100
150
Scan
Figure 5 Data interpolation can propagate noise through the neighboring data points as evidence by the figure. Here, the early settling of the signal due
to T1 relaxation and several instances of movement by the subject introduce spikes or discontinuities in the raw data. The slice timing interpolation
process can propagate those discontinuities as ripples through the neighboring data points. Note that this sort of artifact also occurs when interpolating
data in space.
Original signal
Modulated signal
Time
domain
Frequency
domain
Ghosting artifact from
movement in the
arteries
Figure 6 If a time series signal, like the sinusoid shown in the figure (blue), is modulated by another sinusoid, the frequency content of that
signal (red) becomes split and shifted in frequency. The same thing occurs in two dimensions. In this case, movement in the arteries modulates the
signal coming from the spins inside them. As a result, the reconstructed image shows multiple copies of the arterial spins scattered along the
phase encode direction.
the weights are determined by a sinc function. (The sinc() function is defined as sinc(t) sin(t)/t.)
In practical terms, most fMRI analysis software interpolate
data by a process that is mathematically equivalent to a sinc
interpolation, as follows. It can be shown that the Fourier
transform of a time-shifted function is equal to the Fourier
transform of the original function multiplied by a linear
phase term. In other words, if
F o F ff t g
[6]
[7]
236
INTRODUCTION TO METHODS AND MODELING | Artifacts in Functional MRI and How to Mitigate Them
f t *sinct T F ff t T g
[8]
Image Distortion
Ghosting
Ghosts in MRI are image artifacts where certain parts of the
object become copied and superimposed in the wrong part of
the image. In order to understand why ghosting occurs and
how to correct it, we must recall that MR images are formed by
computing the Fourier transform of raw data. When the raw
data are corrupted, or the assumptions about the raw data are
wrong, the resulting artifact will be a Fourier transform of that
error. In the case of ghosting, it occurs when some parts of the
raw data are modulated by a function of time, like movement
(Bellon et al., 1986; Henkelman, 1996; Stadler, Schima,
et al., 2007).
In order to understand what happens to the image as a
result of this modulation, consider the following. It can be
shown that modulation by a periodic function in the time
domain corresponds to splitting and shifting of the signal in
the frequency domain and vice versa. For example, Figure 6
shows what happens to the Fourier transform of simple sinusoid when it is modulated by another sinusoid. The same is
true in an MRI image. When the signal intensity from a brain
region is modulated by pulsatility during acquisition, as in the
case of an artery, it is Fourier transform (i.e., the reconstructed
image shows multiple copies smeared across the image).
But perhaps ghosting can be most easily understood as a
specific form that occurs in the case of echo-planar imaging
(EPI), the most common fMRI acquisition technique. EPI
10
8
6
4
Ky
2
0
2
4
6
8
10
10
10
Kx
Figure 7 In an echo-planar imaging sequence, the k-space data are collected rapidly line by line, as in the pattern shown in the left panel. If there is a
mismatch between the timing of the odd line and the timing of the even lines, we observe ghosts of the original object superimposed on the image
because of the modulation of the signal along the phase encode direction (ky in this case).
INTRODUCTION TO METHODS AND MODELING | Artifacts in Functional MRI and How to Mitigate Them
Field map
237
Reconstructed image
Figure 8 Sample field map used for inhomogeneity correction during reconstruction of spiral images.
Off-Resonance
You may recall that the resonant frequency of protons is determined by the magnetic field to which they are exposed. This
magnetic field is generated by the MRI scanner, but it is affected
by the chemical environment of the protons. Hence, if the
magnetic field is distorted or if the signal comes from protons
that are not part of a water molecule, but fat instead, which is
also rich in hydrogen atoms, one can expect the signal to be
affected in some way.
In Cartesian imaging (i.e., sequences that collect the k-space
data following a Cartesian grid, like spin warp sequences), the
fat signals frequency shift becomes a spatial shift in the reconstructed image. In other words, the fat components are shifted
238
INTRODUCTION TO METHODS AND MODELING | Artifacts in Functional MRI and How to Mitigate Them
While imaging techniques that use spin echoes can undo these
off-resonance effects, most functional imaging is carried out
using gradient echoes, precisely because the BOLD effect is
caused by distortion of the magnetic field at the microscopic
level (Hornak, Szumowski, et al., 1988). Unfortunately, by
being sensitive to the BOLD effect, the pulse sequences will
also be sensitive to other off-resonance effects. On the right
panel, one can see how a BOLD-weighted image has been
affected by the inhomogeneity around the orbitofrontal lobe
despite using advanced correction techniques during
reconstruction.
In order to mitigate the inhomogeneity effects on the
image, let us first consider the different ways in which it affects
the signal. If the magnetic field varies from top to bottom of the
slice (through-plane), this will cause the spins on the top part
of the slice to precess at a different rate than the ones near the
bottom of the slice. As a result, the magnetization vectors of the
spins will get out of phase with each other, and the net magnetization vector from voxels in that slice will be reduced
because of destructive interference (i.e., cancelation of the
vectors). This generally produces signal voids that cannot be
recovered. Figure 9 shows a very dramatic example of this
phenomenon, in which a subject inadvertently wore a metallic
hairpin in the scanner, which caused major magnetic field
distortion and destroyed the signal in a large part of the image.
The image acquisition parameters can be adjusted to reduce
these effects, though. The most obvious thing to do would be
to reduce the echo time, in order to reduce the time allowed for
the spins to lose phase coherence, but then, we would also lose
sensitivity to the BOLD effect. While one can try to correct for
the magnetic field distortions through careful shimming, even
through additional hardware inserted in the subjects mouth in
order to reshape the field (Constable & Spencer, 1999; Glover,
1999; Wilson & Jezzard, 2003), these approaches tend to be
impractical for most investigators. One can also speed up the
acquisition time, which requires higher performance from the
gradients or using parallel imaging techniques to undersample
the data (Blaimer, Breuer, et al., 2004; Blaimer et al., 2004;
Griswold, Jakob, et al., 2002; Pruessmann, Weiger, et al.,
1999). Finally, one can also reduce the thickness of the slices,
thus allowing a smaller range of precession rates within each
voxel. However, each of these approaches has an associated
cost with it (Glover, Li, et al., 2000; Irarrazabal, Meyer, et al.,
1996; Pandey, 2009). As we will discuss in the next section, the
less time is spent collecting data and the smaller the voxel size,
the lower the signal-to-noise ratio (SNR) of the image.
When the magnetic field is distorted along the slice (inplane distortion), then the effect is that the signal from the
voxels in that region becomes misregistered and the image is
distorted. When the magnetic field is distorted along the slice
(in-plane distortion), then the effect is that the signal from the
voxels in that region becomes misregistered and the image is
distorted, that is, different parts of the brain can appear in the
wrong locations. Fortunately, this type of artifact can be recovered, at least partially. One strategy is to simply undo the
distortions related to the inhomogeneities by processing the
images after reconstruction.
The MRI signal equation is a well-known model of the
observed signal under ideal imaging conditions (Nishimura,
1996). In the presence of field inhomogeneities, it becomes
h
i
st mr ei2pkt r eigBoff r t dr
[9]
Here, the brackets are used to indicate the extra term added
to the original equation in order to account for the magnetic
field inhomogeneity. The Boff(r) term is a spatial map of the
magnetic field deviations from the ideal homogeneous case. If
we want to estimate the distortions from the images themselves, this term needs to be estimated. If an EPI sequence is
used, the data samples in the frequency encode direction are
applied with very small time interval differences (on the order
of a few microseconds). This causes the influence of the field
map to be approximately constant in the frequency encode
direction, and so the only distortion effects occur in the
phase encode direction with an EPI sequence. One can take
advantage of this by modeling the field map itself as being a
sum of cosine functions (Andersson et al., 2001). Using this,
one can estimate the distortions in the phase encode direction
and undo them in a manner similar to motion registration.
However, this method also assumes a rigid body motion
model, and so it will not be able to undo geometric distortion
effects where one signal is on top of another one.
One strategy is to collect a field map, such as the one in
Figure 7, and use it to calculate the deformation field: a map of
the misregistration of each voxel as a result of the field map
distortion. Measuring the field map is a simple procedure that
only requires measuring the phase difference between two
gradient-echo images acquired with different echo times
(Hornak et al., 1988). If we know the field map, we know
that then a pixel will appear shifted as a function of the magnetic field distortion at that pixels true location (Duyn, Yang,
et al., 1998; Jezzard & Balaban, 1995; Jezzard & Clare, 1999).
In the case of an EPI sequence, the shift is predominantly in the
phase encode direction and determined by
Dr r gBoff r N 2tramp NDt
[10]
where r() is the extent of the pixel shift, tramp is the ramp
time of the EPI k-space trajectory, t is the time between
samples, and N is the number of lines in k-space. The correction can then be applied by simply undoing all the shifts in the
image, that is, shifting the pixels back by the calculated
amount. Due to this methods simplicity and the popularity
of EPI sequences for imaging in fMRI, this is the most popular
technique for field inhomogeneity compensation in fMRI.
If a non-EPI sequence is used (such as a spiral), more
sophisticated correction techniques are required. One popular
approach is to approximate the field map as being constant
over voxels and use this assumption to more or less
demodulate the field map effects. This method is also quite
effective and has been used for some time for non-Cartesian
field map distortion correction (Noll, Meyer, et al., 1991).
Both of these methods make approximations to deal with
the physics effects caused by field inhomogeneity. To
completely compensate for these effects in a more general
case, we would instead want to solve an optimization problem
of the following form:
1
x^ argmin ky Axk22
2
x
[11]
INTRODUCTION TO METHODS AND MODELING | Artifacts in Functional MRI and How to Mitigate Them
where A is a system matrix containing the effects of the
sampling trajectory and field map, x is the actual object
(the image), and y is the observed signal. By making more
conservative approximations than those previously discussed, practical algorithms have been developed for solving
this full problem. The strategy is then to solve the inverse
problem by iterating over different objects (i.e., images) and
search for the map that produces the best fit between the
calculated signal from the object and the observed signal.
This is again an optimization problem, where the goal is to
minimize a cost function that describes the discrepancy
between an observed signal and a predicted one. However,
in contrast to the realignment example that we discussed
earlier, the number of unknowns is not limited to a handful
of movement parameters, but it consists of the signal intensity at each voxel. There are a number of strategies that one
can take to facilitate the search, such as imposing smoothness conditions in the data. These iterative methods tend to
be more complex and computationally expensive but they
can be very powerful. These full solvers are generally the best
techniques for removing geometric distortions; however,
they require the most computation time and they are typically not included in standard software packages. The
approximations made by the other methods discussed in
this section generally work quite well and have been in use
in various areas of fMRI for a number of years, so their
properties and performance are well known.
One major aspect of using field inhomogeneity correction
techniques that rely on a field map is the estimation of the
field map itself. Field maps are calculated from the phase
information in the MRI data, which is very susceptible to
noise since it requires dividing one image by another. Since
fMRI is a low SNR regime of MRI to begin with, these noise
effects can be very problematic when implementing field
map-based methods. A number of methods for compensating
for noise effects have been developed over the years. In his
work on correcting field distortions in EPI images, Jezzard
proposed fitting polynomial functions to the field map data
to try to control these noise effects over time (Jezzard &
Balaban, 1995). Another way to control the noise in field
map estimation is to estimate the field map and then smooth
it. Over most of the brain, large changes do not occur in the
field map intensity, the only exception being brain interface
edges around the sinuses. More recently, a number of
methods motivated by statistical estimation techniques have
been proposed, such as the one in Funai, Fessler, et al. (2008).
These methods control the noise effects by assuming some
prior knowledge of what a field map should look like. Since
field maps are usually expected to be smooth, these techniques may penalize large differences between neighboring
voxels in the field map estimation process. Field map estimation techniques are still a topic of research, as it is still an open
problem to find the right balance of smoothing, computation
speed, and robustness.
Ultimately, the best correction technique for each study
will depend on the study. Studies examining the inferior
frontal regions of the brain may want to use more sophisticated field inhomogeneity correction techniques since these
areas of the brain are very susceptible to field distortions.
If the area of the brain being studied is far away from the air
239
10
20
30
40
50
60
10
20
30
40
50
60
sinuses, then more conservative field inhomogeneity correction techniques could be used or possibly no correction
techniques at all.
Noise
Noise is a common term that is used to describe unwanted
signals that are recorded along with the desired signals in any
type of measurement. In general, noise either can be additive or
can modulate (multiplicative) the signal. Noise is generally
thought to be random, but it can also have a deterministic
structure to it. Noise and random processes constitute a field
of study onto itself, but we will only discuss a few practical
aspects that are most relevant to this article. Let us begin by
considering thermal noise in the image, that is, random, independent fluctuations in signal intensity due to the thermal
motion in the sample as well as the scanners electronics.
There is not much that can be done about it, but we can
think about some simple rules that will help minimize it. The
signal observed from a single voxel is directly proportional to
the amount of magnetization available in that voxel and hence
to its volume. The available magnetization of each spin (M0) is
determined by the relaxation constants of the tissue in combination with the choice of echo time and TR. Noise, on the
other hand, is a random process, and the more time one
spends collecting data, the more it cancels itself out. Specifically, we can measure the noise level as the standard deviation
of the signal. It can be shown that for an independent,
Gaussian noise source, the standard deviation decreases with
the square root of the number of averages collected. In MRI,
this boils down to the amount of time spent sampling and
averaging signals (TA/D). The SNR of a measurement is typically
calculated as the signal level divided by its standard deviation
(i.e., the noise level). Putting it all together, we see that
240
INTRODUCTION TO METHODS AND MODELING | Artifacts in Functional MRI and How to Mitigate Them
SNR
p
signal
M0 V T A=D
sn
[12]
INTRODUCTION TO METHODS AND MODELING | Artifacts in Functional MRI and How to Mitigate Them
241
400
600
800
1000
1200
10
12
14
16
18
20
14
16
18
20
14
16
18
20
10
12
10
12
Figure 12 A sample set of basis functions constructed by inserting integer numbers of sinusoids between the start and the end of each respiratory
cycle. The original raw respiratory waveform is shown in the top panel sampled at the plethysmographs sampling rate. Note that the basis
functions, on the other hand, are downsampled to the sampling rate of the scanner.
300
225
150
75
0
Figure 13 This figure shows a sample map of the standard deviation at each voxel in a time series before (left) and after (right) removal of
physiological noise by the RETROICOR method. The reduction in variance is quite noticeable and it is usually observed most dramatically in heavily
vascularized regions.
noise in fMRI (recall that the BOLD signals of interest are only
in the order of less than 2% of the MR signal).
In general, these physiological fluctuations are handled by
filtering them out of MRI signals. While the simplest approach
would be to construct some sort of band-stop frequency filter,
we run into two obstacles. First, the sampling rate of most fMRI
experiments is too low to sample the heartbeat adequately, so
the heartbeats contribution is usually aliased and difficult to
242
INTRODUCTION TO METHODS AND MODELING | Artifacts in Functional MRI and How to Mitigate Them
Acknowledgment
The authors would like to thank Keith Newnham, Ryan Smith,
and Krisanne Litinas for collecting the images used in this
article.
References
Aguirre, G., Detre, J., et al. (2002). Experimental design and the relative sensitivity of
BOLD and perfusion fMRI. NeuroImage, 15(3), 488500.
Andersson, J., Hutton, C., et al. (2001). Modeling geometric deformations in EPI time
series. NeuroImage, 13(5), 903919.
Andersson, J., & Skare, S. (2002). A model-based method for retrospective correction
of geometric distortions in diffusion-weighted EPI. NeuroImage, 16(1), 177199.
Behzadi, Y., Restom, K., et al. (2007). A component based noise correction method
(CompCor) for BOLD and perfusion based fMRI. NeuroImage, 37(1), 90101.
Bellon, E., Haacke, E., et al. (1986). MR artifacts: A review. American Journal of
Roentgenology, 147(6), 12711281, 0361-1803X.
Blaimer, M., Breuer, F., et al. (2004). SMASH, SENSE, PILS, GRAPPA: How to choose
the optimal method. Topics in Magnetic Resonance Imaging, 15(4), 223236.
Boyd, S. P., & Vandenberghe, L. (2004). Convex optimization. Cambridge, UK:
Cambridge University Press.
Bullmore, E., Long, C., et al. (2001). Colored noise and computational inference in
neurophysiological (fMRI) time series analysis: Resampling methods in time and
wavelet domains. Human Brain Mapping, 12(2), 6178.
Buonocore, M. H., & Zhu, D. C. (2001). Image-based ghost correction for interleaved
EPI. Magnetic Resonance in Medicine, 45(1), 96108.
Chan, R. C., Chen, E. Y., et al. (2004). Executive dysfunctions in schizophrenia:
Relationships to clinical manifestation. European Archives of Psychiatry and Clinical
Neuroscience, 254(4), 256262.
INTRODUCTION TO METHODS AND MODELING | Artifacts in Functional MRI and How to Mitigate Them
Constable, R., & Spencer, D. (1999). Composite image formation in z-shimmed
functional MR imaging. Magnetic Resonance in Medicine, 42(1), 110117.
Detre, J., Leigh, J., et al. (1992). Perfusion imaging. Magnetic Resonance in Medicine,
23(1), 3745.
Dietrich, O., Reiser, M. F., et al. (2008). Artifacts in 3-T MRI: Physical background and
reduction strategies. European Journal of Radiology, 65(1), 2935, 0720-0048X.
Duyn, J. H., Yang, Y., et al. (1998). Simple correction method for k-space trajectory
deviations in MRI. Journal of Magnetic Resonance, 132(1), 150153, 1090-7807.
Friston, K. J., Ashburner, J., et al. (1995). Spatial registration and normalization of
images. Human Brain Mapping, 3(3), 165189.
Friston, K. J., Josephs, O., et al. (2000). To smooth or not to smooth? Bias and
efficiency in fMRI time-series analysis. NeuroImage, 12(2), 196208.
Friston, K. J., Williams, S., et al. (1996). Movement-related effects in fMRI time-series.
Magnetic Resonance in Medicine, 35(3), 346355.
Fukunaga, M., Horovitz, S. G., et al. (2006). Large-amplitude, spatially correlated
fluctuations in BOLD fMRI signals during extended rest and early sleep stages.
Magnetic Resonance Imaging, 24(8), 979992.
Funai, A. K., Fessler, J. A., et al. (2008). Regularized field map estimation in MRI. IEEE
Transactions on Medical Imaging, 27(10), 14841494.
Glover, G. H. (1999). 3D z-shim method for reduction of susceptibility effects in BOLD
fMRI. Magnetic Resonance in Medicine, 42(2), 290299, 0740-3194.
Glover, G. H., Li, T. Q., et al. (2000). Image-based method for retrospective correction of
physiological motion effects in fMRI: RETROICOR. Magnetic Resonance in
Medicine, 44(1), 162167.
Grieve, S. M., Blamire, A. M., et al. (2002). Elimination of Nyquist ghosting caused by
read-out to phase-encode gradient cross-terms in EPI. Magnetic Resonance in
Medicine, 47(2), 337343.
Griswold, M., Jakob, P., et al. (2002). Generalized autocalibrating partially parallel
acquisitions (GRAPPA). Magnetic Resonance in Medicine, 47(6), 12021210.
Haacke, E. M., & Lenz, G. W. (1987). Improving MR image quality in the presence of
motion by using rephasing gradients. AJR. American Journal of Roentgenology,
148(6), 12511258.
Henkelman, R. M. (1996). Whole Body Magnetic Resonance Artifacts. eMagRes, John
Wiley & Sons, Ltd.
Hornak, J. P. (1997). Basics of NMR. Rochester Institute of Technology 19962011
(Online book: http://www.cis.rit.edu/htbooks/nmr/nmr-main.htm).
Hornak, J. P., Szumowski, J., et al. (1988). Magnetic field mapping. Magnetic
Resonance in Medicine, 6(2), 158163.
Hu, X., Le, T., et al. (1995). Retrospective estimation and correction of physiological
fluctuation in functional MRI. Magnetic Resonance in Medicine, 34(2), 201212.
Irarrazabal, P., Meyer, C., et al. (1996). Inhomogeneity correction using an estimated
linear field map. Magnetic Resonance in Medicine, 35(2), 278282.
Jenkinson, M., Bannister, P., et al. (2002). Improved optimization for the robust and
accurate linear registration and motion correction of brain images. NeuroImage,
17(2), 825841.
Jezzard, P., & Balaban, R. (1995). Correction for geometric distortion in echo-planar
images from B0 field distortions. Magnetic Resonance in Medicine, 34(1), 6573.
Jezzard, P., & Clare, S. (1999). Sources of distortion in functional MRI data. Human
Brain Mapping, 8(23), 8085.
Johnstone, T., Ores Walsh, K. S., et al. (2006). Motion correction and the use of motion
covariates in multiple-subject fMRI analysis. Human Brain Mapping, 27(10), 779788.
Kim, Y. C., Nielsen, J. F., et al. (2008). Automatic correction of echo-planar imaging
(EPI) ghosting artifacts in real-time interactive cardiac MRI using sensitivity
encoding. Journal of Magnetic Resonance Imaging, 27(1), 239245.
Lenoski, B., Baxter, L. C., et al. (2008). On the performance of autocorrelation
estimation algorithms for fMRI analysis. IEEE Journal of Selected Topics in Signal
Processing, 2(6), 828838.
Lund, T., Madsen, K., et al. (2006). Non-white noise in fMRI: Does modelling have an
impact? NeuroImage, 29(1), 5466.
McKeown, M. J., Hansen, L. K., et al. (2003). Independent component analysis of
functional MRI: What is signal and what is noise? Current Opinion in Neurobiology,
13(5), 620629.
Moeller, S., Auerbach, E., van de Moortele, P.-F., Adriany, G., & Ugurbil, K. (2008).
fMRI with 16 fold reduction using multibanded multislice sampling. In Proceedings
of the 16th Annual Meeting of ISMRM, Toronto, Canada, p. 2366.
243
Moeller, S., Yacoub, E., Olman, C. A., Auerbach, E., Strupp, J., Harel, N., et al. (2010).
Multiband multislice GE-EPI at 7 tesla, with 16-fold acceleration using partial
parallel imaging with application to high spatial and temporal whole-brain fMRI.
Magnetic Resonance in Medicine, 63, 11441153.
Nishimura, D. G. (1996). Principles of magnetic resonance imaging. Stanford, CA:
Stanford University Press.
Noll, D. C., Meyer, C. H., et al. (1991). A homogeneity correction method for magnetic
resonance imaging with time-varying gradients. IEEE Transactions on Medical
Imaging, 10(4), 629637.
Oppenheim, A. V., Schafer, R. W., et al. (1999). Discrete-time signal processing. Upper
Saddle River, NJ: Prentice Hall.
Pandey, K. K. (2009). Mitigation of motion artifacts in functional MRI: A combined
acquisition, reconstruction and post processing approach. (Doctoral dissertation).
Retrieved from ProQuest Dissertations and Theses.
Perlbarg, V., Bellec, P., et al. (2007). CORSICA: Correction of structured noise in fMRI
by automatic identification of ICA components. Magnetic Resonance Imaging,
25(1), 3546.
Pfeuffer, J., Van de Moortele, P., et al. (2002). Correction of physiologically induced
global off-resonance effects in dynamic echo-planar and spiral functional imaging.
Magnetic Resonance in Medicine, 47(2), 344353.
Porter, D. A., Calamante, F., et al. (1999). The effect of residual Nyquist ghost in
quantitative echo-planar diffusion imaging. Magnetic Resonance in Medicine,
42(2), 385392.
Pruessmann, K., Weiger, M., et al. (1999). SENSE: Sensitivity encoding for fast MRI.
Magnetic Resonance in Medicine, 42(5), 952962.
Purdon, P. L., & Weisskoff, R. M. (1998). Effect of temporal autocorrelation due to
physiological noise and stimulus paradigm on voxel-level false-positive rates in
fMRI. Human Brain Mapping, 6(4), 239249.
Sarlls, J. E., Pierpaoli, C., et al. (2011). Robust fat suppression at 3T in high-resolution
diffusion-weighted single-shot echo-planar imaging of human brain. Magnetic
Resonance in Medicine, 66(6), 16581665.
Sladky, R., Friston, K. J., et al. (2011). Slice-timing effects and their correction in
functional MRI. NeuroImage, 58(2), 588594.
Stadler, A., Schima, W., et al. (2007). Artifacts in body MR imaging: Their
appearance and how to eliminate them. European Radiology, 17(5), 12421255,
09387994.
Strang, G. (2006). Linear algebra and its applications. Belmont, CA: Thomson-Brooks/
Cole.
Thomas, C. G., Harshman, R. A., et al. (2002). Noise reduction in BOLD-based fMRI
using component analysis. NeuroImage, 17(3), 15211537.
Totterman, S., Weiss, S. L., et al. (1989). MR fat suppression technique in the evaluation
of normal structures of the knee. Journal of Computer Assisted Tomography, 13(3),
473479, 03638715.
van der Zwaag, W., Francis, S., & Bowtell, R. (2006). Improved echo volumar imaging
(EVI) for functional MRI. Magnetic Resonance in Medicine, 56(6), 13201327.
Wilson, J., & Jezzard, P. (2003). Utilization of an intra-oral diamagnetic passive shim in
functional MRI of the inferior frontal cortex. Magnetic Resonance in Medicine,
50(5), 10891094.
Woolrich, M. W., Ripley, B. D., et al. (2001). Temporal autocorrelation in univariate
linear modeling of FMRI data. NeuroImage, 14(6), 13701386.
Worsley, K. J. (2003). Detecting activation in fMRI data. Statistical Methods in Medical
Research, 12(5), 401418.
Worsley, K. J. (2005). Spatial smoothing of autocorrelations to control the degrees of
freedom in fMRI analysis. NeuroImage, 26(2), 635641.
Wu, X., et al. (2013). Simultaneous multislice multiband parallel radiofrequency
excitation with independent slice-specific transmit B1 homogenization. Magnetic
Resonance in Medicine, 70(3), 630638.
Xiang, Q.A., & Ye, F. Q. (2007). Correction for geometric distortion and N/2 ghosting in
EPI by phase labeling for additional coordinate encoding (PLACE). Magnetic
Resonance in Medicine, 57(4), 731741.
Yang, Y., et al. (1996). Fast 3D functional magnetic resonance imaging at 1.5 T with
spiral acquisition. Magnetic Resonance in Medicine, 36(4), 620626.
Zarahn, E., Aguirre, G. K., et al. (1997). Empirical analyses of BOLD fMRI statistics. I.
Spatially unsmoothed data collected under null-hypothesis conditions. NeuroImage,
5(3), 179197.
Introduction
One of the most popular and widely used (Assaf & Pasternak,
2008; Jellison et al., 2004) mathematical models to describe
the primary orientation of white matter axonal pathways, in a
simple yet powerful way, is called the diffusion tensor (hence the
name diffusion tensor imaging (DTI)). This model was introduced in 1994 (Basser, Mattiello, & Lebihan, 1994a, 1994b),
shortly after the demonstration, in vivo, that tissue organization
affects diffusion-weighted signal obtained using magnetic resonance imaging (MRI) and can therefore be quantified noninvasively (Beaulieu, 2002). This discovery opened, in turn,
new avenues to investigate the integrity and connectivity patterns of the human brain and spinal cord (Dong et al., 2004;
Le Bihan et al., 2001; Mori & Zhang, 2006; White, Nelson, &
Lim, 2008).
Water molecules are under constant translational motion
and can therefore be used as microscopic probes for the
medium in which they diffuse. Free diffusion (i.e., unhindered
and unrestricted) can be characterized by the mean-squared
molecular displacement hrTriover a certain amount of time t
using Einsteins equation (Einstein, 1905) hrTri 6Dt, where
r 2 3 and D, respectively, denote the three-dimensional displacement vector and the self-diffusion coefficient.
In the brain, or any other structured tissue like the heart,
this idealistic situation does not hold in general, as various
intra- and extracellular compartments (e.g., axons and glial
cells) create physical barriers to free-diffusing water molecules,
effectively reducing (Finch, Harmon, & Muller, 1971; Hansen,
1971; Le Bihan et al., 1986) the diffusion coefficient, which is
called apparent diffusion coefficient (ADC) to take this phenomenon into account. In the gray matter, apparent diffusion
remains largely isotropic since, at current imaging spatial resolution (18 mm3), because of their complex microarchitecture, cortical and subcortical areas generally do not exhibit
preferred directions of diffusion. In any other white matter
areas, apparent diffusion is direction-dependent (i.e., anisotropic) due to the underlying organization of axonal fibers. A
single scalar value such as the ADC is therefore insufficient to
fully capture this information, and it was generalized to the
apparent diffusion tensor D, a 3 3 symmetrical and positivedefinite matrix capable of encoding the properties of diffusion
in three dimensions.
Brady, & Rosen, 1990; Doran et al., 1990) further refined this
concept in the human brain, after the demonstration by
Moseley et al. of anisotropic water diffusion in vivo in the cat
brain and spinal cord (Moseley et al., 1990).
To quantify the effect of diffusion on the MR signal in a
given direction q, the StejskalTanner pulsed-gradient spinecho (PGSE) sequence (Stejskal & Tanner, 1965) is widely
used. The general form of the MR signal equation is
Z
T
Sq, t S0
pr, teiq r dr
3
Dg
[1]
where g [gx, gy, gz] is the unit vector defined as g q/|q|. D can
be interpreted as the covariance matrix of the displacement
vector r, such that hrTri 6Dt.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00291-8
245
246
6
7
6
7
4
SqN 5
ln
S0
2 xx 3
D
6 xy 7
6
3
2
D 7
y
y y
y
7
g1x g1x 2g1x g1 2g1x g1z g1 g1 2g1 g1z g1z g1z 6
6 Dxz 7
76
6
7
56 yy 7
b4
[3]
6D 7
y z z z
x x
x y
x z y y
6
gN gN 2gN gN 2gN gN gN gN 2gN gN gN gN 6 yz 7
7
4D 5
zz
D
Equation [3] is of the form Y Bd, with Y the vector of
log-transformed normalized DWI signals. The B-matrix B
(Mattiello, Basser, & Le Bihan, 1994, 1997) encodes the effects
of the imaging and diffusion gradients and describes the interaction between elements of the diffusion tensor to model the
diffusion signal Y.
The most straightforward way to estimate d is to obtain six
measurements, one baseline signal S0, and invert eqn [3], such
that d B1Y. However, this approach has several drawbacks,
as it is highly sensitive to artifacts (Gallichan et al., 2010; Le
Bihan, Poupon, Amadon, & Lethimonnier, 2006) and thermal
noise (Gudbjartsson & Patz, 1995; Henkelman, 1985), which
inevitably affect diffusion-weighted data (Andersson, 2008;
Jones & Basser, 2004). Artifacts arise from physiological
noise, such as subject motion or cardiac pulsation, and are
challenging to deal with since they are, by nature, difficult to
model. Conversely, models of signal variability due to thermal
noise can be used to mitigate its effects on the estimation of the
diffusion tensor. It is not the focus of this article to discuss in
detail the origins of physiological and thermal noise, and we
now summarize computational strategies that have been introduced to deal with them.
N
X
h
i
T
oi Sqi S0 eb:b d
i1
247
LA
l1 l2
l1 l2 l3
PA
2l2 l3
l1 l2 l3
SA
3l3
l1 l2 l3
u3
l3
l1
l2
u2
3
0
0
0
3
0
0
0
3
u1
6
0
0
0
2
0
0
0
2
Figure 1 Graphical representation of the diffusion tensor as a three-dimensional ellipsoid: (Left) Isotropic diffusion tensor characterized by a spherical
ellipsoid. All three eigenvalues are equal and there is no preferred direction of diffusion. (Right) Anisotropic diffusion tensor characterized by an
elongated ellipsoid. The principal eigenvalue is twice that of the left example, while the secondary and tertiary eigenvalues are smaller.
248
MD
FA
Fiber orientation
Figure 2 Diffusion tensor parameters: (Left) Mean diffusivity, (center) fractional anisotropy, (right) color-coded principal direction of diffusion. Fiber
pathways oriented leftright are in red, anteriorposterior are in green, and inferiorsuperior are in blue. Data from the Human Connectome Project
(http://www.humanconnectome.org/) with spatial resolution 1.25 1.25 1.25 mm3.
Applications of DTI
The diffusion tensor and derived quantities such as FA and MD
are sensitive markers of microstructural changes occurring in
the brain (Alexander et al., 2007; Dong et al., 2004; Horsfield &
Jones, 2002; Le Bihan et al., 2001), in the context of
developmental, neurodegenerative, or neuropsychiatric disorders (Sajjadi et al., 2013; White et al., 2008; Yoshida, Oishi,
Faria, & Mori, 2013). Although one must remain cautious
about findings in fiber crossing areas, where the diffusion
tensor model is incomplete (see Properties of the Diffusion
Tensor section) and unable to fully characterize complex white
matter configurations (Lenglet et al., 2009; ODonnell &
Westin, 2011), DTI has demonstrated tremendous potential,
over the past 1520 years, of providing critical insights into
pathological processes affecting the central nervous system.
In multiple sclerosis (Bozzali, Cercignani, Sormani, Comi,
& Filippi, 2002; Werring, Clark, Barker, Thompson, & Miller,
1999), increased MD and decreased FA have been observed,
which may reflect demyelination and axonal loss. In epilepsy,
DTI provides additional information to better identify epileptogenic regions (Arfanakis et al., 2002). In traumatic brain
injury (TBI), DTI seems to help uncover specific white matter
pathways of the frontal and temporal areas, with alterations
shown to correlate with cognitive and behavioral data (Niogi &
Mukherjee, 2010). For brain tumors, which is the second largest clinical application of DTI, tractography has shown to
provide important information about fiber pathways (Lazar,
Alexander, Thottakara, Badie, & Field, 2006; Mori et al., 2002)
near tumors, which can be used for surgical planning purposes.
Acknowledgments
The author is partly supported by NIH grant P41 EB015894.
Data were provided in part by the Human Connectome Project, WU-Minn Consortium (Principal Investigators: David Van
Essen and Kamil Ugurbil; 1U54MH091657), funded by 16
NIH Institutes and Centers that support the NIH Blueprint
for Neuroscience Research, and by the McDonnell Center for
Systems Neuroscience at Washington University.
References
Alexander, D. C., & Barker, G. J. (2005). Optimal imaging parameters for fiberorientation estimation in diffusion MRI. NeuroImage, 27, 357367.
Alexander, A. L., Hasan, K., Kindlmann, G., Parker, D. L., & Tsuruda, J. S. (2000). A
geometric analysis of diffusion tensor measurements of the human brain. Magnetic
Resonance in Medicine, 44, 283291.
Alexander, A. L., Lee, J. E., Lazar, M., & Field, A. S. (2007). Diffusion tensor imaging of
the brain. Neurotherapeutics, 4, 316329.
Anderson, A. W. (2001). Theoretical analysis of the effects of noise on diffusion tensor
imaging. Magnetic Resonance in Medicine, 46, 11741188.
Andersson, J. L. (2008). Maximum a posteriori estimation of diffusion tensor
parameters using a Rician noise model: Why, how and but. NeuroImage, 42,
13401356.
Arfanakis, K., Hermann, B. P., Rogers, B. P., Carew, J. D., Seidenberg, M., &
Meyerand, M. E. (2002). Diffusion tensor MRI in temporal lobe epilepsy. Magnetic
Resonance Imaging, 20, 511519.
Arsigny, V., Fillard, P., Pennec, X., & Ayache, N. (2006). Log-Euclidean metrics for fast
and simple calculus on diffusion tensors. Magnetic Resonance in Medicine, 56,
411421.
249
Assaf, Y., & Pasternak, O. (2008). Diffusion tensor imaging (DTI)-based white matter
mapping in brain research: A review. Journal of Molecular Neuroscience, 34,
5161.
Basser, P. J., & Le Bihan, D. (1992). Fiber orientation mapping in an anisotropic
medium with NMR diffusion spectroscopy. In: Eleventh annual meeting of the
society for magnetic resonance in medicine (ISMRM), 1992 Berkeley, CA, Berkeley,
CA: ISMRM (International Society for Magnetic Resonance in Medicine).
Basser, P. J., Mattiello, J., & Lebihan, D. (1994a). Estimation of the effective selfdiffusion tensor from the NMR spin echo. Journal of Magnetic Resonance. Series B,
103, 247254.
Basser, P. J., Mattiello, J., & Lebihan, D. (1994b). MR diffusion tensor spectroscopy
and imaging. Biophysical Journal, 66, 259267.
Basser, P. J., & Pierpaoli, C. (1996). Microstructural and physiological features of
tissues elucidated by quantitative-diffusion-tensor MRI. Journal of Magnetic
Resonance. Series B, 111, 209219.
Batchelor, P. G., Atkinson, D., Hill, D. L., Calamante, F., & Connelly, A. (2003).
Anisotropic noise propagation in diffusion tensor MRI sampling schemes. Magnetic
Resonance in Medicine, 49, 11431151.
Beaulieu, C. (2002). The basis of anisotropic water diffusion in the nervous system A
technical review. NMR in Biomedicine, 15, 435455.
Bozzali, M., Cercignani, M., Sormani, M. P., Comi, G., & Filippi, M. (2002).
Quantification of brain gray matter damage in different MS phenotypes by use of
diffusion tensor MR imaging. AJNR - American Journal of Neuroradiology, 23,
985988.
Chang, L. C., Jones, D. K., & Pierpaoli, C. (2005). RESTORE: Robust estimation of
tensors by outlier rejection. Magnetic Resonance in Medicine, 53, 10881095.
Chenevert, T. L., Brunberg, J. A., & Pipe, J. G. (1990). Anisotropic diffusion in
human white matter: Demonstration with MR techniques in vivo. Radiology, 177,
401405.
Chien, D., Buxton, R. B., Kwong, K. K., Brady, T. J., & Rosen, B. R. (1990). MR diffusion
imaging of the human brain. Journal of Computer Assisted Tomography, 14,
514520.
Conturo, T. E., Lori, N. F., Cull, T. S., Akbudak, E., Snyder, A. Z., Shimony, J. S., et al.
(1999). Tracking neuronal fiber pathways in the living human brain. Proceedings of
the National Academy of Sciences of the United States of America, 96,
1042210427.
Conturo, T. E., Mckinstry, R. C., Akbudak, E., & Robinson, B. H. (1996). Encoding of
anisotropic diffusion with tetrahedral gradients: A general mathematical diffusion
formalism and experimental results. Magnetic Resonance in Medicine, 35, 399412.
Cook, P. A., Symms, M., Boulby, P. A., & Alexander, D. C. (2007). Optimal acquisition
orders of diffusion-weighted MRI measurements. Journal of Magnetic Resonance
Imaging, 25, 10511058.
Deriche, R., Calder, J., & Descoteaux, M. (2009). Optimal real-time Q-ball imaging
using regularized Kalman filtering with incremental orientation sets. Medical Image
Analysis, 13, 564579.
Dong, Q., Welsh, R. C., Chenevert, T. L., Carlos, R. C., Maly-Sundgren, P.,
Gomez-Hassan, D. M., et al. (2004). Clinical applications of diffusion tensor
imaging. Journal of Magnetic Resonance Imaging, 19, 618.
Doran, M., Hajnal, J. V., Van Bruggen, N., King, M. D., Young, I. R., & Bydder, G. M.
(1990). Normal and abnormal white matter tracts shown by MR imaging using
directional diffusion weighted sequences. Journal of Computer Assisted
Tomography, 14, 865873.
Dubois, J., Poupon, C., Lethimonnier, F., & Le Bihan, D. (2006). Optimized diffusion
gradient orientation schemes for corrupted clinical DTI data sets. Magnetic
Resonance Materials in Physics, Biology and Medicine, 19, 134143.
Einstein, A. (1905). Uber die von der molekularkinetischen Theorie der Warme
geforderte Bewegung von in ruhenden Flussigkeiten suspendierten Teilchen.
Annalen der Physik, 322, 549560.
Finch, E. D., Harmon, J. F., & Muller, B. H. (1971). Pulsed NMR measurements of the
diffusion constant of water in muscle. Archives of Biochemistry and Biophysics,
147, 299310.
Gallichan, D., Scholz, J., Bartsch, A., Behrens, T. E., Robson, M. D., & Miller, K. L.
(2010). Addressing a systematic vibration artifact in diffusion-weighted MRI. Human
Brain Mapping, 31, 193202.
Geman, S., & McClure, D. E. (1987). Statistical methods for tomographic image
reconstruction. Bulletin of the International Statistical Institute, 52, 521.
Gudbjartsson, H., & Patz, S. (1995). The Rician distribution of noisy MRI data. Magnetic
Resonance in Medicine, 34, 910914.
Hansen, J. R. (1971). Pulsed NMR study of water mobility in muscle and brain tissue.
Biochimica et Biophysica Acta, 230, 482486.
Hasan, K. M., Basser, P. J., Parker, D. L., & Alexander, A. L. (2001). Analytical
computation of the eigenvalues and eigenvectors in DT-MRI. Journal of Magnetic
Resonance, 152, 4147.
250
Mangin, J. F., Poupon, C., Clark, C., Le Bihan, D., & Bloch, I. (2002). Distortion
correction and robust tensor estimation for MR diffusion imaging. Medical Image
Analysis, 6, 191198.
Mattiello, J., Basser, P. J., & Le Bihan, D. (1994). Analytical expressions for the b matrix
in NMR diffusion imaging and spectroscopy. Journal of Magnetic Resonance,
Series A, 108, 131141.
Mattiello, J., Basser, P. J., & Le Bihan, D. (1997). The b matrix in diffusion tensor
echo-planar imaging. Magnetic Resonance in Medicine, 37, 292300.
Maximov, I. I., Grinberg, F., & Shah, N. J. (2011). Robust tensor estimation in diffusion
tensor imaging. Journal of Magnetic Resonance, 213, 136144.
Mori, S., Crain, B. J., Chacko, V. P., & Van Zijl, P. C. (1999). Three-dimensional
tracking of axonal projections in the brain by magnetic resonance imaging. Annals
of Neurology, 45, 265269.
Mori, S., Frederiksen, K., Van Zijl, P. C., Stieltjes, B., Kraut, M. A., Solaiyappan, M.,
et al. (2002). Brain white matter anatomy of tumor patients evaluated with diffusion
tensor imaging. Annals of Neurology, 51, 377380.
Mori, S., & Zhang, J. (2006). Principles of diffusion tensor imaging and its applications
to basic neuroscience research. Neuron, 51, 527539.
Moseley, M. E., Cohen, Y., Kucharczyk, J., Mintorovitch, J., Asgari, H. S.,
Wendland, M. F., et al. (1990). Diffusion-weighted MR imaging of anisotropic water
diffusion in cat central nervous system. Radiology, 176, 439445.
Mukherjee, P., Bahn, M. M., Mckinstry, R. C., Shimony, J. S., Cull, T. S., Akbudak, E.,
et al. (2000). Differences between gray matter and white matter water diffusion
in stroke: Diffusion-tensor MR imaging in 12 patients. Radiology, 215, 211220.
Niogi, S. N., & Mukherjee, P. (2010). Diffusion tensor imaging of mild traumatic brain
injury. The Journal of Head Trauma Rehabilitation, 25, 241255.
ODdonnell, L. J., & Westin, C. F. (2011). An introduction to diffusion tensor image
analysis. Neurosurgery Clinics of North America, 22, 185196, viii.
Pajevic, S., & Basser, P. J. (2003). Parametric and non-parametric statistical analysis of
DT-MRI data. Journal of Magnetic Resonance, 161, 114.
Pajevic, S., & Pierpaoli, C. (1999). Color schemes to represent the orientation
of anisotropic tissues from diffusion tensor data: Application to white matter
fiber tract mapping in the human brain. Magnetic Resonance in Medicine, 42,
526540.
Papadakis, N. G., Xing, D., Houston, G. C., Smith, J. M., Smith, M. I., James, M. F.,
et al. (1999). A study of rotationally invariant and symmetric indices of diffusion
anisotropy. Magnetic Resonance Imaging, 17, 881892.
Papadakis, N. G., Xing, D., Huang, C. L., Hall, L. D., & Carpenter, T. A. (1999). A
comparative study of acquisition schemes for diffusion tensor imaging using MRI.
Journal of Magnetic Resonance, 137, 6782.
Sajjadi, S. A., Acosta-Cabronero, J., Patterson, K., Diaz-De-Grenu, L. Z.,
Williams, G. B., & Nestor, P. J. (2013). Diffusion tensor magnetic resonance imaging
for single subject diagnosis in neurodegenerative diseases. Brain, 136, 22532261.
Salvador, R., Pena, A., Menon, D. K., Carpenter, T. A., Pickard, J. D., & Bullmore, E. T.
(2005). Formal characterization and extension of the linearized diffusion tensor
model. Human Brain Mapping, 24, 144155.
Schlaug, G., Siewert, B., Benfield, A., Edelman, R. R., & Warach, S. (1997). Time course
of the apparent diffusion coefficient (ADC) abnormality in human stroke. Neurology,
49, 113119.
Skare, S., Hedehus, M., Moseley, M. E., & Li, T. Q. (2000). Condition number as
a measure of noise performance of diffusion tensor data acquisition schemes with
MRI. Journal of Magnetic Resonance, 147, 340352.
Song, S. K., Sun, S. W., Ramsbottom, M. J., Chang, C., Russell, J., & Cross, A. H.
(2002). Dysmyelination revealed through MRI as increased radial (but unchanged
axial) diffusion of water. NeuroImage, 17, 14291436.
Sotiropoulos, S. N., Jbabdi, S., Xu, J., Andersson, J. L., Moeller, S., Auerbach, E. J.,
et al. (2013). Advances in diffusion MRI acquisition and processing in the Human
Connectome Project. NeuroImage, 80, 125143.
Stejskal, E. O. (1965). Use of spin echoes in a pulsed magnetic-field gradient to study
anisotropic, restricted diffusion and flow. The Journal of Chemical Physics, 43,
35973603.
Stejskal, E. O., & Tanner, J. E. (1965). Spin diffusion measurements: Spin echoes in the
presence of a time-dependent field gradient. The Journal of Chemical Physics, 42,
288292.
Thomsen, C., Henriksen, O., & Ring, P. (1987). In vivo measurement of water self diffusion
in the human brain by magnetic resonance imaging. Acta Radiologica, 28, 353361.
Tristan-Vega, A., Aja-Fernandez, S., & Westin, C. F. (2012). Least squares for diffusion
tensor estimation revisited: Propagation of uncertainty with Rician and non-Rician
signals. NeuroImage, 59, 40324043.
Tschumperle, D., & Deriche, R. (2003). Variational frameworks for DT-MRI estimation,
regularization and visualization. In: Proceedings of the ninth IEEE international
conference on computer vision Volume 2. Washington, DC: IEEE Computer
Society. http://www.computer.org/portal/web/guest/contact.
251
Wesbey, G. E., Moseley, M. E., & Ehman, R. L. (1984). Translational molecular selfdiffusion in magnetic resonance imaging. II. Measurement of the self-diffusion
coefficient. Investigative Radiology, 19, 491498.
Westin, C. F., Maier, S. E., Mamata, H., Nabavi, A., Jolesz, F. A., & Kikinis, R. (2002).
Processing and visualization for diffusion tensor MRI. Medical Image Analysis, 6,
93108.
Wheeler-Kingshott, C. A., & Cercignani, M. (2009). About axial and radial
diffusivities. Magnetic Resonance in Medicine, 61, 12551260.
White, T., Nelson, M., & Lim, K. O. (2008). Diffusion tensor imaging in psychiatric
disorders. Topics in Magnetic Resonance Imaging, 19, 97109.
Yoshida, S., Oishi, K., Faria, A. V., & Mori, S. (2013). Diffusion tensor imaging of
normal brain development. Pediatric Radiology, 43, 1527.
Glossary
Eqei2pqr dq;
[1]
P r
3
where E(q) S(q)/S(0) is the normalized diffusion signal measured at the location q in q-space. Note that, the actual signal
with diffusion sensitization in the gradient direction q is represented by S(q), whereas S(0) is the signal without any diffusion
weighting. The average diffusion propagator P(r) gives the
probability (likelihood) of water molecules to undergo a net
displacement r during the diffusion weighting time D of the
diffusion experiment. In other words, the diffusion propagator
P(r) is the Fourier transform of the normalized signal E(q).
Several methods have been proposed to estimate the diffusion propagator P(r) from measurements made in q-space. One
of the first approaches was proposed by Basser, Mattiello, and
LeBihan (1994), which assumed a Gaussian distribution of
water molecules. Under this assumption, the propagator is
completely defined by a diffusion tensor D, and this type of
imaging protocol was aptly named as diffusion tensor imaging
(DTI). Thus, the probability of displacement r in DTI is given by
1
Pr p3=2 jDj 2 exp p2 r T D1 r :
[2]
ODFu
Prur k dr;
[3]
http://dx.doi.org/10.1016/B978-0-12-397025-1.00292-X
253
254
Figure 1 Orientation distribution function (ODF) estimated using (a) Gaussian and (b) generalized inverse multiquadric for the rectangular region
shown on a coronal color-coded FA slice.
the return-to-origin probability (RTOP), given by P(0), is proportional to the inverse of the average pore volume. Similarly,
the return-to-axis probability (RTAP)
RTAP
E? d?
1
hAi
[4]
RTPP
Ejj djj :
[5]
In addition, several other statistical features, such as multivariate kurtosis, mean-squared displacement and higher order
moments can be computed from the diffusion propagator.
These features can provide additional insights on the amount
of restricted diffusion (due to smaller pore sizes) at each voxel.
Thus, measures derived from the diffusion propagator can
provide important structural details regarding the tissue microstructure. Finally, brain connectivity analysis can also be done
using the information obtained from the diffusion propagator.
For example, in Rathi et al. (2013), the authors propose a
unified framework for model estimation (diffusion propagator
estimation) and tractography for tracing neural fiber bundles
in the brain. Subsequently, brain network analysis can be
used to understand network level differences in two populations (e.g. healthy controls and sczhiophrenia) (Hagmann
et al., 2008).
Thus, knowing the diffusion propagator (the probability
distribution function of the diffusion of water molecules)
allows for estimating several biological and statistical properties of the white matter in the brain.
References
Aganj, I., Lenglet, C., Sapiro, G., Yacoub, E., Ugurbil, K., & Harel, N. (2010). Reconstruction
of the orientation distribution function in single-and multiple-shell q-ball imaging within
constant solid angle. Magnetic Resonance in Medicine, 64, 554566.
Assaf, Y., Freidlin, R. Z., Rohde, G. K., & Basser, P. J. (2004). New modeling and
experimental framework to characterize hindered and restricted water diffusion in
brain white matter. Magnetic Resonance in Medicine, 52, 965978.
Assemlal, H.-E., Tschumperle, D., Brun, L., & Siddiqi, K. (2011). Recent advances in
diffusion MRI modeling: Angular and radial reconstruction. Medical Image Analysis,
15, 369396.
Barmpoutis, A., Vemuri, B. C., & Forde, J. R. (2008). Fast displacement probability
profile approximation from hardi using 4th-order tensors. In ISBI (pp. 911914). .
Basser, P. J., Mattiello, J., & LeBihan, D. (1994). MR diffusion tensor spectroscopy and
imaging. Biophysical Journal, 66, 259267.
Callaghan, P. T. (1991). Principles of NMR microscopy. Houston: Tecmag Inc.
Cande`s, E. J., Romberg, J., & Tao, T. (2006). Robust uncertainty principles: Exact signal
reconstruction from highly incomplete frequency information. IEEE Transactions on
Information Theory, 52, 489509.
Cohen, Y., & Assaf, Y. (2002). High b-value q-space analyzed diffusion-weighted MRS
and MRI in neuronal tissuesA technical review. NMR in Biomedicine, 15, 516542.
Descoteaux, M., Deriche, R., Bihan, D. L., Mangin, J. F., & Poupon, C. (2010). Multiple
q-shell diffusion propagator imaging. Medical Image Analysis, 15(4), 603621.
Feinberg, D. A., Moeller, S., Smith, S. M., Auerbach, E., Ramanna, S., Glasser, M. F.,
et al. (2010). Multiplexed echo planar imaging for sub-second whole brain fMRI and
fast diffusion imaging. PLoS One, 5(12), e15710.
Hagmann, P., Cammoun, L., Gigandet, X., Meuli, R., Honey, C. J., Wedeen, V. J., et al.
(2008). Mapping the structural core of human cerebral cortex. PLoS Biology, 6,
159170.
Hosseinbor, A. P., Chung, M. K., Wu, Y. C., & Alexander, A. L. (2012). Bessel Fourier
orientation reconstruction (BFOR): An analytical diffusion propagator reconstruction
for hybrid diffusion imaging and computation of q-space indices. NeuroImage, 64,
650670.
Jensen, J. H., Helpern, J. A., Ramani, A., Lu, H., & Kaczynski, K. (2005). Diffusional
kurtosis imaging: The quantification of non-gaussian water diffusion by means of
magnetic resonance imaging. Magnetic Resonance in Medicine, 53, 14321440.
Jian, B., & Vemuri, B. (2007). A unified computational framework for deconvolution to
reconstruct multiple fibers from diffusion weighted MRI. IEEE Transaction on
Medical Imaging, 26, 14641471.
Merlet, S., Caruyer, E., & Deriche, R. (2012). Parametric dictionary learning for
modeling EAP and ODF in diffusion MRI. In MICCAI.
Merlet, S. L., & Deriche, R. (2013). Continuous diffusion signal, EAP and ODF estimation
via compressive sensing in diffusion MRI. Medical Image Analysis, 17, 556572.
Michailovich, O., Rathi, Y., & Dolui, S. (2011). Spatially regularized compressed
sensing for high angular resolution diffusion imaging. TMI, 30, 11001115.
Mulkern, R. V., Vajapeyam, S., Robertson, R. L., Caruso, P. A., Rivkin, M. J., &
Maier, S. E. (2001). Biexponential apparent diffusion coefficient parametrization in
adult vs newborn brain. Magnetic Resonance Imaging, 19, 659668.
255
Ozarslan, E., Koay, C. G., Shepherd, T. M., Komlosh, M. E., Irfanoglu, M. O.,
Pierpaoli, C., et al. (2013). Mean apparent propagator (map) MRI: A novel
diffusion imaging method for mapping tissue microstructure. NeuroImage, 78,
1632.
Rathi, Y., Gagoski, B., Setsompop, K., Michailovich, O., Ellen Grant, P., & Westin, C.-F.
(2013). Diffusion propagator estimation from sparse measurements in a
tractography framework. In Medical image computing and computer-assisted
interventionMICCAI 2013 (pp. 510517). Berlin Heidelberg: Springer.
Rathi, Y., Michailovich, O., Setsompop, K., Bouix, S., Shenton, M., & Westin, C.-F.
(2011). Sparse multi-shell diffusion imaging. MICCAI, 14, 5865.
Rathi, Y., Niethammer, M., Laun, F., Setsompop, K., Michailovich, O., Ellen Grant, P.,
et al. (2014). Diffusion propagator estimation using radial basis functions. In
Computational diffusion MRI and brain connectivity (pp. 5766). Berlin Heidelberg:
Springer.
Setsompop, K., Borjan, A., Gagoski, J. R., Polimeni, T. W., Wedeen, V. J., & Wald, L. L.
(2011). Blipped-controlled aliasing in parallel imaging for simultaneous multislice
echo planar imaging with reduced g-factor penalty. Magnetic Resonance in
Medicine, 67, 12101224.
Shenton, M. E., Hamoda, H. M., Schneiderman, J. S., Bouix, S., Pasternak, O., Rathi, Y.,
et al. (2012). A review of magnetic resonance imaging and diffusion tensor
imaging findings in mild traumatic brain injury. Brain Imaging and Behavior, 6,
137192.
Thomason, M. E., & Thompson, P. M. (2011). Diffusion imaging, white matter, and
psychopathology. Annual Review of Clinical Psychology, 7, 6385.
Tournier, J.-D., Calamante, F., Gadian, D., & Connelly, A. (2004). Direct estimation of
the fiber orientation density function from diffusion-weighted MRI data using
spherical deconvolution. NeuroImage, 23, 11761185.
Tristan-Vega, A., Westin, C.-F., & Aja-Fernandez, S. (2009). Estimation of fiber
orientation probability density functions in high angular resolution diffusion
imaging. NeuroImage, 47, 638650.
Tuch, D. S. (2004). Q-ball imaging. Magnetic Resonance in Medicine, 52, 13581372.
Tuch, D., Reese, T., Wiegell, M., & Wedeen, V. (2003). Diffusion MRI of complex neural
architecture. Neuron, 40, 885895.
Wedeen, V. J., Hagmann, P., Tseng, W. Y. I, Reese, T. G., & Weisskoff, R. M. (2005).
Mapping complex tissue architecture with diffusion spectrum magnetic resonance
imaging. Magnetic Resonance in Medicine, 54, 13771386.
Wu, Y. C., & Alexander, A. L. (2007). Hybrid diffusion imaging. NeuroImage, 36,
617629.
Ye, W., Portnoy, S., Entezari, A., Blackband, S. J., & Vemuri, B. C. (2012). An efficient
interlaced multi-shell sampling scheme for reconstruction of diffusion propagators.
IEEE Transactions on Medical Imaging, 31, 10431050.
Ye, W., Portnoy, S., Entezari, A., Vemuri, B. C., & Blackband, S. J. (2011). Box spline
based 3d tomographic reconstruction of diffusion propagators from MRI data.
Biomedical imaging: From nano to macro, 2011 IEEE international symposium on,
397400, IEEE.
Zhang, H., Schneider, T., Wheeler-Kingshott, C. A., & Alexander, D. C. (2012). NODDI:
Practical in vivo neurite orientation dispersion and density imaging of the human
brain NeuroImage, 61(4), 10001016.
Glossary
Introduction
Diffusion-weighted imaging (DWI) is a noninvasive imaging
technology that provides valuable information about the
microarchitecture of biological tissue, by measuring the microscopic diffusion of water in three-dimensional (3-D) space.
Through fiber tracking, DWI provides a unique in vivo quantitative measurement of the brains anatomical connectivity. In
this article, we review several DWI signal acquisition strategies.
During the scanning process, diffusion-sensitizing gradient
!
pulses G with the duration d attenuate the image intensity
values. More precisely, parameterizing
the diffusion acquisi!
!
tion with the q-vector q gd G =2p (with g the gyromagnetic
ratio), each volume element
(voxel) of the DW image will have
!
an intensity value S q that is less than S(0), depending on
the amount of local water diffusion at the voxel. Assuming d is
sufficiently small, the 3-D probability density function (PDF)
of the displacement of water molecules after a certain amount
of time t (which depends on the acquisition sequence) has the
following
relationship with the signal attenuation
! !Fourier
E q S q =S0 (Callaghan, 1991):
Z !
!!
!
!
P x
E q e2pix q d3 q
[1]
3
!
where P x , which is also called the ensemble average propagator, carries important structural properties of the underlying
tissue, with applications such as the indication of white matter
anomalies (Assaf et al., 2002). The popularity of DWI in general, however, is largely thanks to its ability to quantify fiber
orientations in vivo. To that end, the diffusion orientation
distribution function (ODF) marginal PDF of diffusion of
water in a given direction u^ is defined as (Tuch, 2002;
Wedeen, Hagmann, Tseng, Reese, & Weisskoff, 2005)
Z 1
ODFu^
P r u^r 2 dr
[2]
0
Since the diffusion of water is hindered in the direction perpendicular to axons, the peaks of the diffusion ODF are often
aligned with the fiber orientations. The diffusion PDF and
subsequently ODF are considered real, positive, and antipodally symmetrical, thereby making real and symmetric spherical
harmonics basis suitable for representation of the orientational
diffusion information (Anderson, 2005; Descoteaux, Angelino,
Fitzgibbons, & Deriche, 2007; Hess, Mukherjee, Han, Xu, &
Vigneron, 2006).
!
!
The frequency spectrum of P x , measured as E q , is
required everywhere in the reciprocal q-space to allow for the
!
!
computation of P x at any point. However, E q is only
available on a finite set of q-vectors corresponding to the
acquired DW images. Therefore, depending on the acquisition
scheme, an interpolation model is needed to estimate the
!
values of E q in the entire q-space from the set of available
discrete data points.
The radial monoexponential model (Stejskal & Tanner,
1965),
Equ^ et2pq
ADCu^
[3]
! !
^ assumes that the diffusion signal decays
where q q , q qu,
2
http://dx.doi.org/10.1016/B978-0-12-397025-1.00293-1
257
258
[4]
DSI
used when these conditions are not satisfied; Canales-Rodrguez, Iturria-Medina, Aleman-Gomez, & Melie-Garca, 2010).
Thus, contrary to DTI and spherical acquisitions, no strong
assumption on the form of the signal is made. In particular,
errors arising from assuming exponential decay for the diffusion signal are not present in this method.
ODFs can be computed from DSI at each voxel by interpo
!
lating the discrete P x and computing eqn [2] numerically
inside a sphere with the radius nmax. Orientational information
obtained from DSI may be used in tractography to track brain
white matter pathways (Schmahmann et al., 2007), identify
crossing fibers (Wedeen et al., 2008), and map the structural
network of the human brain (Hagmann et al., 2008).
A DSI dataset is represented in a 6-D space, which is the
Cartesian product of two 3-D spaces, one representing the
voxel location and the other representing the pattern of diffusion within voxel. As a result, DSI provides us with ample
information about the tissue microstructure, but at the price
of a high acquisition time. The number of DW images to be
acquired in a scan is typically significantly higher for DSI
than for spherical acquisitions, increasing the possibility of
motion artifacts. This, however, may be alleviated through CS
(Bilgic et al., 2012, 2013; Lee, Wilkins, & Singh, 2012; Menzel
et al., 2011; Saint-Amant & Descoteaux, 2011; Setsompop
et al., 2013), as described in the Compressed Sensing section,
and information theoretical approaches (Knutsson & Westin,
2014). Typical parameter values for brain DSI were suggested
by Wedeen et al. (2005) as nmax 5, N 515, with a sampling
interval of a 20 mm1 resulting in a maximum b-value of
17 000 s mm2. A lower practical maximum b-value of
6500 s mm2, however, was later advised by Kuo, Chen,
Wedeen, and Tseng (2008) for the same number of q-space
measurement samples.
Multishell Sampling
DWI is the only available tool that allows to noninvasively
quantify the neural fiber orientation in vivo, primarily through
Single-shell HARDI
Three-shell HARDI
Figure 1 Q-space acquisition schemes of DSI (left), single-shell HARDI (middle), and three-shell HARDI (right), each with a total of 515 sample points.
Later, the monoexponential model, Equ^i Eqs u^i q =qs , initially discussed by Stejskal and Tanner (1965), was used to
zarslan, Shepherd, Vemuri,
compute the diffusion PDF (O
Blackband, & Mareci, 2006) and ODF (Aganj et al., 2010;
Canales-Rodrguez, Melie-Garca, & Iturria-Medina, 2009;
Tristan-Vega, Westin, & Aja-Fernandez, 2010). The exponential
model is particularly consistent with E(0) 1, and is compatible with the free diffusion that is modeled with the diffusion
tensor. Other approaches to reconstruct HARDI data include
spherical deconvolution that computes the fiber ODF
(Anderson & Ding, 2002; Tournier, Calamante, Gadian, &
Connelly, 2004), multitensor models that use a mixture of
Gaussians to represent the diffusion (Alexander, Barker, &
b=1
b=2
b=3
b=4
259
b=5
b=6
b=7
b = 1,2,3
(mono-exp.)
b = 1,2,3
(bi-exp.)
Figure
from a diffusion signal with a cross ()-shaped diffusion profile and radially biexponential decay:
! 2 ODF reconstruction
2
2
E q jsinfjq =2 jcos fjq =2 , where f is the azimuthal angle. From left to right, reconstructions use a single q-shell (b-values of 1, ..., 7 with
monoexponential model) and three q-shells (combined b-values of 1, 2, 3 with mono- and biexponential models). The fiber directions of the ODFs
computed with the monoexponential model depend on the acquisition b-value, and only the biexponential model correctly resolves them from low bvalues. Dark red represents negative values. Reproduced from Aganj, I., Lenglet, C., Sapiro, G., Yacoub, E., Ugurbil, K., & Harel, N. (2010).
Reconstruction of the orientation distribution function in single- and multiple-shell q-ball imaging within constant solid angle. Magnetic Resonance in
Medicine, 64, 554566.
260
Compressed Sensing
Long acquisition time is a major hindrance to the clinical use
of DWI. Acquiring fewer sample points in the k-space and/or qspace reduces the acquisition time, albeit at considerable cost
to the image quality. CS (Candes, Romberg, & Tao, 2006;
Donoho, 2006), aka compressive sampling, improves the
trade-off between the resolution of the reconstructed image
and the acquisition time, through a specific acquisition scheme
that allows the reconstruction artifacts due to the limited sample size to be removed more effectively. Specifically, CS
requires that random undersampling produce incoherent
Acknowledgments
This research was in part supported by a grant from the Massachusetts Alzheimers Disease Research Center (5 P50
AG005134), the MGH Neurology Clinical Trials Unit, and the
Harvard NeuroDiscovery Center, in addition to the NIH 1 R01
NS083534, R01 NS085188, P41 EB015894, P30 NS076408,
and the Human Connectome Project (U54 MH091657) grants.
References
Aboussouan, E., Marinelli, L., & Tan, E. (2011). Non-cartesian compressed sensing for
diffusion spectrum imaging. Proceedings of the International Society for Magnetic
Resonance in Medicine, 19, 1919.
Aganj, I., Lenglet, C., Sapiro, G., Yacoub, E., Ugurbil, K., & Harel, N. (2010).
Reconstruction of the orientation distribution function in single- and multiple-shell
q-ball imaging within constant solid angle. Magnetic Resonance in Medicine, 64,
554566.
Ahrens, C., Nealy, J., Perez, F., & van der Walt, S. (2013). Sparse reproducing
kernels for modeling fiber crossings in diffusion weighted imaging. In IEEE
proceedings of the tenth International Symposium on Biomedical Imaging (ISBI)
(pp. 688691).
Alexander, D. C., Barker, G. J., & Arridge, S. R. (2002). Detection and modeling of nonGaussian apparent diffusion coefficient profiles in human brain data. Magnetic
Resonance in Medicine, 48, 331340.
Anderson, A. W. (2005). Measurement of fiber orientation distributions using high
angular resolution diffusion imaging. Magnetic Resonance in Medicine, 54,
11941206.
Anderson, A., & Ding, Z. (2002). Sub-voxel measurement of fiber orientation using high
angular resolution diffusion tensor imaging. Honolulu, HI: ISMRM.
Assaf, Y., Ben-Bashat, D., Chapman, J., Peled, S., Biton, I. E., Kafri, M., et al. (2002).
High b-value q-space analyzed diffusion-weighted MRI: Application to multiple
sclerosis. Magnetic Resonance in Medicine, 47, 115126.
Assaf, Y., Freidlin, R. Z., Rohde, G. K., & Basser, P. J. (2004). New modeling and
experimental framework to characterize hindered and restricted water diffusion in
brain white matter. Magnetic Resonance in Medicine, 52, 965978.
Assaf, Y., Mayk, A., & Cohen, Y. (2000). Displacement imaging of spinal cord using qspace diffusion-weighted MRI. Magnetic Resonance in Medicine, 44, 713722.
Assemlal, H.-E., Tschumperle, D., & Brun, L. (2009). Efficient and robust computation
of PDF features from diffusion MR signal. Medical Image Analysis, 13, 715729.
Awate, S. P., & DiBella, E. V. R. (2013). Compressed sensing HARDI via rotationinvariant concise dictionaries, flexible K-space undersampling, and multiscale
spatial regularity. In IEEE proceedings of the tenth International Symposium on
Biomedical Imaging (ISBI) (pp. 912).
Basser, P. J., Mattiello, J., & LeBihan, D. (1994). MR diffusion tensor spectroscopy and
imaging. Biophysical Journal, 66, 259267.
Behrens, T. E. J., Woolrich, M. W., Jenkinson, M., Johansen-Berg, H., Nunes, R. G.,
Clare, S., et al. (2003). Characterization and propagation of uncertainty in diffusionweighted MR imaging. Magnetic Resonance in Medicine, 50, 10771088.
Bilgic, B., Chatnuntawech, I., Setsompop, K., Cauley, S. F., Yendiki, A., Wald, L. L.,
et al. (2013). Fast dictionary-based reconstruction for diffusion spectrum imaging.
IEEE Transactions on Medical Imaging, 32, 20222033.
261
Bilgic, B., Setsompop, K., Cohen-Adad, J., Yendiki, A., Wald, L. L., & Adalsteinsson, E.
(2012). Accelerated diffusion spectrum imaging with compressed sensing using
adaptive dictionaries. Magnetic Resonance in Medicine, 68, 17471754.
Callaghan, P. T. (1991). Principles of nuclear magnetic resonance microscopy. Oxford:
Clarendon Press.
Canales-Rodrguez, E. J., Iturria-Medina, Y., Aleman-Gomez, Y., & Melie-Garca, L.
(2010). Deconvolution in diffusion spectrum imaging. NeuroImage, 50, 136149.
Canales-Rodrguez, E. J., Melie-Garca, L., & Iturria-Medina, Y. (2009). Mathematical
description of q-space in spherical coordinates: Exact q-ball imaging. Magnetic
Resonance in Medicine, 61, 13501367.
Candes, E. J., Romberg, J., & Tao, T. (2006). Robust uncertainty principles: Exact signal
reconstruction from highly incomplete frequency information. IEEE Transactions on
Information Theory, 52, 489509.
Caruyer, E., & Deriche, R. (2012). Optimal regularization for MR diffusion signal
reconstruction. In IEEE proceedings of the ninth International Symposium on
Biomedical Imaging (ISBI) (pp. 5053).
Caruyer, E., Lenglet, C., Sapiro, G., & Deriche, R. (2013). Design of multishell sampling
schemes with uniform coverage in diffusion MRI. Magnetic Resonance in Medicine,
69, 15341540.
Chen, Y., Guo, W., Zeng, Q., Yan, X., Rao, M., & Liu, Y. (2005). Apparent diffusion
coefficient approximation and diffusion anisotropy characterization in DWI. In G.
Christensen & M. Sonka (Eds.), Information Processing in Medical Imaging
(Vol. 3565, pp. 246257). Berlin/Heidelberg: Springer.
Cheng J, Shen D, & Yap P-T (2014). Designing Single- and Multiple-Shell Sampling
Schemes for Diffusion MRI Using Spherical Code. In: Golland, P. et al., (Eds.),
Medical Image Computing and Computer-Assisted Intervention MICCAI 2014,
Vol. 8675, (pp. 281288). Boston, MA: Springer International Publishing.
Cheng, J., Deriche, R., Jiang, T., Shen, D., & Yap, P.-T. (2014). Non-negative spherical
deconvolution (NNSD) for estimation of fiber orientation distribution function in
single-/multi-shell diffusion MRI. NeuroImage, 101, 750764.
Cheng, J., Ghosh, A., Deriche, R., & Jiang, T. (2010). Model-free, regularized, fast, and
robust analytical orientation distribution function estimation. In T. Jiang, et al.
(Eds.), Medical Image Computing and Computer-Assisted Intervention MICCAI
2010 Vol. 6361, (pp. 648656). Berlin/Heidelberg: Springer.
Cheng, J., Ghosh, A., Jiang, T., & Deriche, R. (2010). Model-free and analytical EAP
reconstruction via spherical polar fourier diffusion MRI. In T. Jiang, et al. (Eds.),
Medical image computing and computer-assisted intervention MICCAI 2010
Vol. 6361, (pp. 590597). Berlin/Heidelberg: Springer.
Cheng, J., Jiang, T., Deriche, R., Shen, D., & Yap, P.-T. (2013). Regularized spherical
polar fourier diffusion MRI with optimal dictionary learning. In K. Mori, et al. (Eds.),
Medical Image Computing and Computer-Assisted Intervention MICCAI 2013
Vol. 8149, (pp. 639646). Berlin/Heidelberg: Springer.
Daducci, A., Van De Ville, D., Thiran, J.-P., & Wiaux, Y. (2014). Sparse regularization
for fiber ODF reconstruction: From the suboptimality of and priors to. Medical
Image Analysis, 18, 820833.
DeSantis, S., Assaf, Y., Evans, C. J., & Jones, D. K. (2011). Improved precision in the
charmed model of white matter through sampling scheme optimization and model
parsimony testing. Magnetic Resonance in Medicine, 71(2), 661671.
Descoteaux, M., Angelino, E., Fitzgibbons, S., & Deriche, R. (2007). Regularized, fast, and
robust analytical Q-ball imaging. Magnetic Resonance in Medicine, 58, 497510.
Descoteaux, M., Deriche, R., Le Bihan, D., Mangin, J.-F., & Poupon, C. (2011). Multiple
q-shell diffusion propagator imaging. Medical Image Analysis, 15, 603621.
Dolui, S., Kuurstra, A., & Michailovich, O. V. (2012). Rician compressed sensing for
fast and stable signal reconstruction in diffusion MRI. SPIE 8314 Proceedings on
medical imaging 2012: Image processing, Vol. 8314, 83144Q.
Donoho, D. L. (2006). Compressed sensing. IEEE Transactions on Information Theory,
52, 12891306.
Duarte-Carvajalino, J. M., Lenglet, C., Xu, J., Yacoub, E., Ugurbil, K., Moeller, S., et al.
(2013). Estimation of the CSA-ODF using Bayesian compressed sensing of multishell HARDI. Magnetic Resonance in Medicine, 72(5), 14711485.
Freiman, M., Afacan, O., Mulkern, R., & Warfield, S. (2013). Improved multi B-value
diffusion-weighted MRI of the body by simultaneous model estimation and image
reconstruction (SMEIR). In K. Mori, et al. (Eds.), Medical Image Computing and
Computer-Assisted Intervention MICCAI 2013 vol. 8151, (pp. 18). Berlin/
Heidelberg: Springer.
Gao, H., Li, L., Zhang, K., Zhou, W., & Hu, X. (2013). PCLR: Phase-constrained lowrank model for compressive diffusion-weighted MRI. Magnetic Resonance in
Medicine, 72(5), 13301341.
Gramfort, A., Poupon, C., & Descoteaux, M. (2014). Denoising and fast diffusion
imaging with physically constrained sparse dictionary learning. Medical Image
Analysis, 18, 3649.
Hagmann, P., Cammoun, L., Gigandet, X., Meuli, R., Honey, C. J., Wedeen, V. J., et al.
(2008). Mapping the structural core of human cerebral cortex. PLoS Biology, 6, e159.
262
Hess, C. P., Mukherjee, P., Han, E. T., Xu, D., & Vigneron, D. B. (2006). Q-ball
reconstruction of multimodal fiber orientations using the spherical harmonic basis.
Magnetic Resonance in Medicine, 56, 104117.
Hosseinbor, A. P., Chung, M. K., Wu, Y.-C., & Alexander, A. L. (2013). Bessel Fourier
orientation reconstruction (BFOR): An analytical diffusion propagator
reconstruction for hybrid diffusion imaging and computation of q-space indices.
NeuroImage, 64, 650670.
Jansons, K. M., & Alexander, D. C. (2003). Persistent angular structure: New insights from
diffusion magnetic resonance imaging data. Inverse Problems, 19, 1031.
Jarisch, W. R., Ozarslan, E., & Basser, P. J. (2009). Computed tomographic (CT)
reconstruction of the average propagator from diffusion weighted MR data.
Honolulu, HI: ISMRM.
Jbabdi, S., Sotiropoulos, S. N., Savio, A. M., Grana, M., & Behrens, T. E.J (2012).
Model-based analysis of multishell diffusion MR data for tractography: How to get
over fitting problems. Magnetic Resonance in Medicine, 68, 18461855.
Jensen, J. H., Helpern, J. A., Ramani, A., Lu, H., & Kaczynski, K. (2005).
Diffusional kurtosis imaging: The quantification of non-Gaussian water diffusion by
means of magnetic resonance imaging. Magnetic Resonance in Medicine, 53,
14321440.
Kamath, A., Aganj, I., Xu, J., Yacoub, E., Ugurbil, K., Sapiro, G., et al. (2012).
Generalized constant solid angle ODF and optimal acquisition protocol for fiber
orientation mapping. In MICCAI workshop on Computational Diffusion MRI, Nice,
France.
Knutsson, H., & Westin, C-F. (2014). From Expected Propagator Distribution to Optimal
Q-space Sample Metric. In: Golland, P. et al., (Eds.) Medical image computing and
computer-assisted intervention MICCAI 2014, Vol. 8675, (pp. 217224). Boston,
MA: Springer International Publishing.
Khachaturian, M. H., Wisco, J. J., & Tuch, D. S. (2007). Boosting the sampling
efficiency of q-ball imaging using multiple wavevector fusion. Magnetic Resonance
in Medicine, 57, 289296.
Koay, C. G., Ozarslan, E., Johnson, K. M., & Meyerand, M. E. (2012). Sparse and
optimal acquisition design for diffusion MRI and beyond. Medical Physics, 39,
24992511.
Kuo, L.-W., Chen, J.-H., Wedeen, V. J., & Tseng, W.-Y. I. (2008). Optimization of
diffusion spectrum imaging and q-ball imaging on clinical MRI system.
NeuroImage, 41, 718.
Landman, B. A., Bogovic, J. A., Wan, H., ElShahaby, F. E.Z, Bazin, P.-L., & Prince, J. L.
(2012). Resolution of crossing fibers with constrained compressed sensing using
diffusion tensor MRI. NeuroImage, 59, 21752186.
Lee, N., Wilkins, B., & Singh, M. (2012). Accelerated diffusion spectrum imaging via
compressed sensing for the human connectome project. In SPIE 8314 Proceedings
on medical imaging 2012: Image processing (vol. 8314, , p. 83144G). .
Liu, C., Mang, S. C., & Moseley, M. E. (2010). In vivo generalized diffusion tensor
imaging (GDTI) using higher-order tensors (HOT). Magnetic Resonance in
Medicine, 63, 243252.
Ma, H. T., Limin, Z., Rong, R., & Shaohua, W. (2013). Compressed sensing on DTI via
rotating interpolation. In TENCON 20132013 IEEE Region 10 Conference (31194)
(pp. 14).
Mani, M., Jacob, M., Guidon, A., Magnotta, V., & Zhong, J. (2014). Acceleration of high
angular and spatial resolution diffusion imaging using compressed sensing with
multichannel spiral data. Magnetic Resonance in Medicine.
Menzel, M. I., Tan, E. T., Khare, K., Sperl, J. I., King, K. F., Tao, X., et al. (2011).
Accelerated diffusion spectrum imaging in the human brain using compressed
sensing. Magnetic Resonance in Medicine, 66, 12261233.
Merlet, S., Caruyer, E., Ghosh, A., & Deriche, R. (2013). A computational diffusion MRI
and parametric dictionary learning framework for modeling the diffusion signal and
its features. Medical Image Analysis, 17, 830843.
Merlet, S. L., & Deriche, R. (2013). Continuous diffusion signal, EAP and ODF
estimation via compressive sensing in diffusion MRI. Medical Image Analysis, 17,
556572.
Michailovich, O., & Rathi, Y. (2010). On approximation of orientation distributions
by means of spherical ridgelets. IEEE Transactions on Image Processing, 19,
461477.
Michailovich, O., Rathi, Y., & Dolui, S. (2011). Spatially regularized compressed
sensing for high angular resolution diffusion imaging. IEEE Transactions on
Medical Imaging, 30, 11001115.
Niendorf, T., Dijkhuizen, R. M., Norris, D. G., van Lookeren, C. M., & Nicolay, K. (1996).
Biexponential diffusion attenuation in various states of brain tissue: Implications for
diffusion-weighted imaging. Magnetic Resonance in Medicine, 36, 847857.
Ozarslan, E., Koay, C., Shepherd, T. M., Blackband, S. J., & Basser, P. J. (2009). Simple
harmonic oscillator based reconstruction and estimation for three-dimensional qspace MRI. Honolulu, HI: ISMRM.
Ozarslan, E., Koay, C. G., Shepherd, T. M., Komlosh, M. E., Irfanoglu, M. O.,
Pierpaoli, C., et al. (2013). Mean apparent propagator (MAP) MRI: A novel diffusion
imaging method for mapping tissue microstructure. NeuroImage, 78, 1632.
Ozarslan, E., & Mareci, T. H. (2003). Generalized diffusion tensor imaging and analytical
relationships between diffusion tensor imaging and high angular resolution
diffusion imaging. Magnetic Resonance in Medicine, 50, 955965.
Ozarslan, E., Shepherd, T. M., Vemuri, B. C., Blackband, S. J., & Mareci, T. H. (2006).
Resolution of complex tissue microarchitecture using the diffusion orientation
transform (DOT). NeuroImage, 31, 10861103.
Paquette, M., Merlet, S., Gilbert, G., Deriche, R., & Descoteaux, M. (in press).
Comparison of sampling strategies and sparsifying transforms to improve
compressed sensing diffusion spectrum imaging. Magnetic Resonance in Medicine.
Pickalov, V., & Basser, P. J. (2006). 3-D tomographic reconstruction of the average
propagator from MRI data. In IEEE proceedings of third International Symposium on
Biomedical Imaging: Nano to macro (pp. 710713).
Pu, L., Trouard, T. P., Ryan, L., Chuan, H., Altbach, M. I., & Bilgin, A. (2011). Modelbased compressive diffusion tensor imaging. In IEEE International Symposium on
Biomedical Imaging: From nano to macro (pp. 254257).
Rathi, Y., Michailovich, O., Laun, F., Setsompop, K., Grant, P. E., & Westin, C. F.
(2014). Multi-shell diffusion signal recovery from sparse measurements. Medical
Image Analysis, 18, 11431156.
Rathi, Y., Michailovich, O., Setsompop, K., & Westin, C. F. (2014). A dual spherical
model for multi-shell diffusion imaging. Vol. 90340Q. http://dx.doi.org/10.1117/
12.2043493.
Rathi, Y., Niethammer, M., Laun, F., Setsompop, K., Michailovich, O., Grant, P. E., et al.
(2014). Diffusion propagator estimation using radial basis functions. In T. Schultz,
et al. (Eds.), Computational Diffusion MRI and Brain Connectivity (pp. 5766):
Nagoya, Japan: Springer International Publishing.
Ronen, I., Kim, K.-H., Garwood, M., Ugurbil, K., & Kim, D.-S. (2003). Conventional DTI
vs. slow and fast diffusion tensors in cat visual cortex. Magnetic Resonance in
Medicine, 49, 785790.
Saint-Amant, E., & Descoteaux, M. (2011). Sparsity characterisation of the diffusion
propagator. Montreal, Canada: ISMRM.
Scherrer, B., & Warfield, S. K. (2012). Parametric representation of multiple white matter
fascicles from cube and sphere diffusion MRI. PLoS One, 7, e48232.
Schmahmann, J. D., Pandya, D. N., Wang, R., Dai, G., DArceuil, H. E.,
de Crespigny, A. J., et al. (2007). Association fibre pathways of the brain: Parallel
observations from diffusion spectrum imaging and autoradiography. Brain, 130,
630653.
Setsompop, K., Kimmlingen, R., Eberlein, E., Witzel, T., Cohen-Adad, J., McNab, J. A.,
et al. (2013). Pushing the limits of in vivo diffusion MRI for the Human Connectome
Project. NeuroImage, 80, 220233.
Seunarine, K. K., & Alexander, D. C. (2014). Chapter 6 Multiple fibers: Beyond the
diffusion tensor. In H. Johansen-Berg & T. E. J. Behrens (Eds.), Diffusion MRI.
San Diego, CA: Academic Press. (2nd ed., pp. 105123).
Shi, X., Ma, X., Wu, W., Huang, F., Yuan, C., & Guo, H. (in press). Parallel imaging
and compressed sensing combined framework for accelerating high-resolution
diffusion tensor imaging using inter-image correlation. Magnetic Resonance in
Medicine.
Sotiropoulos, S. N., Jbabdi, S., Xu, J., Andersson, J. L., Moeller, S., Auerbach, E. J.,
et al. (2013). Advances in diffusion MRI acquisition and processing in the Human
Connectome Project. NeuroImage, 80, 125143.
Stejskal, E. O., & Tanner, J. E. (1965). Spin diffusion measurements: Spin echoes in the
presence of a time-dependent field gradient. The Journal of Chemical Physics, 42,
288292.
Tournier, J. D., Calamante, F., Gadian, D. G., & Connelly, A. (2004). Direct estimation of
the fiber orientation density function from diffusion-weighted MRI data using
spherical deconvolution. NeuroImage, 23, 11761185.
Tristan-Vega, A., & Westin, C.-F. (2011). Probabilistic ODF estimation from reduced
HARDI data with sparse regularization. In G. Fichtinger, et al. (Eds.), Medical Image
Computing and Computer-Assisted Intervention MICCAI 2011 Vol. 6892,
(pp. 182190). Berlin/Heidelberg: Springer.
Tristan-Vega, A., Westin, C.-F., & Aja-Fernandez, S. (2010). A new methodology for the
estimation of fiber populations in the white matter of the brain with the FunkRadon
transform. NeuroImage, 49, 13011315.
Tuch, D. S. (2002). Diffusion MRI of complex tissue structure. In Division of Health
Science and Technology, Ph.D. Massachusetts Institute of Technology.
Tuch, D. S. (2004). Q-ball imaging. Magnetic Resonance in Medicine, 52,
13581372.
Tuch, D. S., Reese, T. G., Wiegell, M. R., Makris, N., Belliveau, J. W., & Wedeen, V. J.
(2002). High angular resolution diffusion imaging reveals intravoxel white matter
fiber heterogeneity. Magnetic Resonance in Medicine, 48, 577582.
263
Wu, Y., Zhu, Y.-J., Tang, Q.-Y., Zou, C., Liu, W., Dai, R.-B., et al. (2014). Accelerated
MR diffusion tensor imaging using distributed compressed sensing. Magnetic
Resonance in Medicine, 71, 763772.
Yablonskiy, D. A., Bretthorst, G. L., & Ackerman, J. J.H (2003). Statistical model for
diffusion attenuated MR signal. Magnetic Resonance in Medicine, 50, 664669.
Ye, W., Portnoy, S., Entezari, A., Blackband, S. J., & Vemuri, B. C. (2012). An efficient
interlaced multi-shell sampling scheme for reconstruction of diffusion propagators.
IEEE Transactions on Medical Imaging, 31, 10431050.
Ye, W., Vemuri, B. C., & Entezari, A. (2012). An over-complete dictionary based regularized
reconstruction of a field of ensemble average propagators. In IEEE proceedings of ninth
International Symposium on Biomedical Imaging (ISBI) (pp. 940943).
Zhan, L., Leow, A. D., Aganj, I., Lenglet, C., Sapiro, G., Yacoub, E., et al. (2011).
Differential information content in staggered multiple shell hardi measured by the
tensor distribution function. In IEEE International Symposium on Biomedical
Imaging: From nano to macro (pp. 305309).
Zhu, Y., Wu, Y., Zheng, Y., Wu, E. X., Ying, L., & Liang, D. (2012). A model-based method
with joint sparsity constraint for direct diffusion tensor estimation. In IEEE proceedings
of ninth International Symposium on Biomedical Imaging (ISBI) (pp. 510513).
Abbreviations
Other Approaches
Voxel linking
This approach is the earliest form of fiber tracking and is
based on the concept of simply linking one of the adjacent
Global approaches
More recently, advanced algorithms have been proposed to
perform global tractography (e.g., Fillard, Poupon, & Mangin,
2009; Kreher, Mader, & Kiselev, 2008). These methods attempt
to simultaneously estimate the set of all pathways in the brain,
using a process of optimization. The reason this might be
advantageous is that this allows the algorithm to consider
nonlocal effects, for example, the fact that a voxel has a fixed
volume, and therefore, the reconstruction should not allow
more tract volume to exist within each voxel than is physically
possible. These approaches have the potential to provide more
biologically plausible reconstructions but are currently limited
by the typically enormous amount of computation involved in
solving this type of problem.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00294-3
265
266
(a)
Exclusion
(NOT)
region
Inclusion
(AND)
region
Seed
region
(b)
267
(c)
Figure 3 Illustration of tract editing using regions of interest. (a) Using a large seed region leads to the delineation of a number of different
branches. (b) The tract of interest is known to run through the green region; placing an inclusion ROI there removes the most obvious false-positives.
(c) If the tract of interest is known not to project to the red region, an exclusion ROI can be used to remove any spurious trajectories through it.
268
Fiber configuration
DW signal
Fiber ODF
Figure 5 The intrinsic angular resolution of the DW signal itself introduces uncertainty as to the exact fiber configuration. The three configurations on
the left are all predominantly aligned leftright, and consequently, the DW signal intensity is smallest along that axis (middle). The DW signal is
inherently broad, and this essentially blurs the signal. This means that the DW signal for the three configurations shown will be essentially identical, and
consequently, the estimated diffusion or fiber orientation density function (ODF) will be the same in all three cases. The practice of using the peak
orientation of the fiber or diffusion ODF as the best fiber orientation estimate is appealing as it provides much tighter results, but this is only valid
for one of the three configurations shown. It is clear that some ambiguity remains as to what the true fiber orientations are, and this source of uncertainty
should be included in probabilistic algorithms.
Conclusion
Diffusion MRI fiber tracking is clearly a very exciting technology, being the only method that can be used to delineate white
References
Anwander, A., Tittgemeyer, M., von Cramon, D. Y., Friederici, A. D., & Knosche, T. R.
(2007). Connectivity-based parcellation of Brocas area. Cerebral Cortex, 17, 816825.
Behrens, T. E.J, Berg, H. J., Jbabdi, S., Rushworth, M. F. S., & Woolrich, M. W. (2007).
Probabilistic diffusion tractography with multiple fibre orientations: What can we
gain? NeuroImage, 34, 144155.
Behrens, T. E. J., Johansen-Berg, H., Woolrich, M. W., Smith, S. M.,
Wheeler-Kingshott, C. A.M, Boulby, P. A., et al. (2003). Non-invasive mapping of
connections between human thalamus and cortex using diffusion imaging. Nature
Neuroscience, 6, 750757.
Behrens, T. E. J., Woolrich, M. W., Jenkinson, M., Johansen-Berg, H., Nunes, R. G.,
Clare, S., et al. (2003). Characterization and propagation of uncertainty in diffusionweighted MR imaging. Magnetic Resonance in Medicine, 50, 10771088.
Berman, J. I., Chung, S., Mukherjee, P., Hess, C. P., Han, E. T., & Henry, R. G. (2008).
Probabilistic streamline q-ball tractography using the residual bootstrap.
NeuroImage, 39, 215222.
Chao, Y.-P., Chen, J.-H., Cho, K.-H., Yeh, C.-H., Chou, K.-H., & Lin, C.-P. (2008). A
multiple streamline approach to high angular resolution diffusion tractography.
Medical Engineering & Physics, 30, 989996.
Descoteaux, M., Deriche, R., Knosche, T. R., & Anwander, A. (2009). Deterministic and
probabilistic tractography based on complex fibre orientation distributions. IEEE
Transactions on Medical Imaging, 28, 269286.
Fillard, P., Poupon, C., & Mangin, J.-F. (2009). A novel global tractography algorithm
based on an adaptive spin glass model. Medical Image Computing and ComputerAssisted Intervention, 12, 927934.
269
Haroon, H. A., Morris, D. M., Embleton, K. V., Alexander, D. C., & Parker, G. J. M. (2009).
Using the model-based residual bootstrap to quantify uncertainty in fiber orientations
from Q-ball analysis. IEEE Transactions on Medical Imaging, 28, 535550.
Hosey, T. P., Harding, S. G., Carpenter, T. A., Ansorge, R. E., & Williams, G. B. (2008).
Application of a probabilistic double-fibre structure model to diffusion-weighted MR
images of the human brain. Magnetic Resonance Imaging, 26, 236245.
Hosey, T., Williams, G., & Ansorge, R. (2005). Inference of multiple fiber orientations in
high angular resolution diffusion imaging. Magnetic Resonance in Medicine, 54,
14801489.
Jeurissen, B., Leemans, A., Jones, D. K., Tournier, J.-D., & Sijbers, J. (2011).
Probabilistic fiber tracking using the residual bootstrap with constrained spherical
deconvolution. Human Brain Mapping, 32, 461479.
Jeurissen, B., Leemans, A., Tournier, J.-D., Jones, D. K., & Sijbers, J. (2013).
Investigating the prevalence of complex fiber configurations in white matter tissue
with diffusion magnetic resonance imaging. Human Brain Mapping, 34,
27472766.
Jones, D. K. (2003). Determining and visualizing uncertainty in estimates of
fiber orientation from diffusion tensor MRI. Magnetic Resonance in Medicine, 49,
712.
Jones, D. K. (2008). Tractography gone wild: Probabilistic fibre tracking using the wild
bootstrap with diffusion tensor MRI. IEEE Transactions on Medical Imaging, 27,
12681274.
Jones, D. K., Simmons, A., Williams, S. C., & Horsfield, M. A. (1999). Non-invasive
assessment of axonal fiber connectivity in the human brain via diffusion tensor MRI.
Magnetic Resonance in Medicine, 42, 3741.
Koch, M. A., Norris, D. G., & Hund-Georgiadis, M. (2002). An investigation of
functional and anatomical connectivity using magnetic resonance imaging.
NeuroImage, 16, 241250.
Kreher, B. W., Mader, I., & Kiselev, V. G. (2008). Gibbs tracking: A novel approach for
the reconstruction of neuronal pathways. Magnetic Resonance in Medicine, 60,
953963.
Mori, S., Crain, B., Chacko, V., & van Zijl, P. (1999). Three-dimensional tracking of
axonal projections in the brain by magnetic resonance imaging. Annals of
Neurology, 45, 265269.
Parker, G., & Alexander, D. (2005). Probabilistic anatomical connectivity derived from
the microscopic persistent angular structure of cerebral tissue. Philosophical
Transactions of the Royal Society of London, Series B: Biological Sciences, 360,
893902.
Parker, G. J. M., Wheeler-Kingshott, C. A. M., & Barker, G. J. (2002). Estimating
distributed anatomical connectivity using fast marching methods and diffusion
tensor imaging. IEEE Transactions on Medical Imaging, 21, 505512.
Tournier, J., Calamante, F., & Connelly, A. (2012). MRtrix: Diffusion tractography in
crossing fiber regions. International Journal of Imaging Systems and Technology,
22, 5366.
Tournier, J.-D., Mori, S., & Leemans, A. (2011). Diffusion tensor imaging and beyond.
Magnetic Resonance in Medicine, 65, 15321556.
Wedeen, V. J., Wang, R. P., Schmahmann, J. D., Benner, T., Tseng, W. Y.I, Dai, G., et al.
(2008). Diffusion spectrum magnetic resonance imaging (DSI) tractography of
crossing fibers. NeuroImage, 41, 12671277.
Whitcher, B., Tuch, D. S., Wisco, J. J., Sorensen, A. G., & Wang, L. (2008). Using the
wild bootstrap to quantify uncertainty in diffusion tensor imaging. Human Brain
Mapping, 29, 346362.
Abbreviations
MRI
ROI
Region of interest
Introduction
A healthy brain white matter contains millions of myelinated
axons that connect different regions of the gray matter. Bundles
of these axons, often called fiber tracts, ensure proper signal
transfer in the brain and enable its function. Many neuropsychiatric diseases are hypothesized to be associated with disruption and damage to the white matter fiber tracts.
Understanding the pattern of connectivity of fiber tracts, their
properties in healthy subjects, and how they are affected in
each diseased population is of fundamental interest to neuroscientists, neurosurgeons, and the medical community in general. With the advent of diffusion tensor imaging, in vivo study
of the fiber tracts, which was out of reach of other imaging
modalities, became a reality (Basser, Mattiello, & LeBihan,
1994). The presence of a fiber tract that consists of thousands
of microscopic axons running parallel to each other in a given
neighborhood can be detected as reduction in the diffusivity
signal normal to the fiber pathway. A tensor describing the
directional dependence (anisotropy) of the water diffusivity is
most commonly extracted. Trajectories of the fiber bundles are
then reconstructed using a tractography procedure (Mori,
Crain, Chacko, & van Zijl, 1999) usually by following the
major eigenvector of the tensor or similar alternatives (see
Figure 1(a) for an example of tractography output).
Three-dimensional (3-D) visualization of the fiber trajectories is sometimes used to explore the anatomical connectivity
network of the brain, in order to complement functional connectivity maps and to understand how it is affected by aging,
diseases of the brain, or brain lesions. It is also a valuable tool
in surgical planning, risk assessment, and intraoperative
mapping of the tracts (Duncan, 2010). The information conveyed by such visualizations can be greatly improved if the
trajectories are grouped into bundles based on some similarity
measures and labeled based on their correspondence to anatomical fiber tracts (see Figure 1(b) for an example of clustered
trajectories).
Another important application of diffusion tensor magnetic
resonance imaging (MRI) (and other variants of diffusion MRI)
is to quantify differences in the tract connectivity, shape, or
diffusion properties and correlate these differences to the underlying microscopic changes. Clustering and labeling of the trajectories are prerequisites to tract-based quantitative analysis,
where statistics of a parameter of interest are measured over or
along a tract. In multisubject studies, in particular, clustering
and anatomical labeling of trajectories play an important role in
ensuring that the comparison is performed over the same anatomical bundle across all cases.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00295-5
271
272
INTRODUCTION TO METHODS AND MODELING | Tract Clustering, Labeling, and Quantitative Analysis
Figure 1 Sagittal view showing (a) fiber trajectories produced by tractography seeded from the entire white matter and (b) output of a clustering
algorithm that groups these trajectories based on their similarity to each other and to a set of prototype trajectories that represent anatomical bundles.
Reproduced from Maddah, M., Grimson, W. E. L., Warfield, S. K., & Wells, W. M. (2008). A unified framework for clustering and quantitative
analysis of white matter fiber tracts. Medical Image Analysis, 12, 191202.
Table 1
Reference
Model
Ratnarajah, Simmons,
and Hojjatoleslami
(2011)
Liu, Vemuri, and
Deriche (2012)
INTRODUCTION TO METHODS AND MODELING | Tract Clustering, Labeling, and Quantitative Analysis
trajectories and average point distance. Ding, Gore, and
Anderson (2003) used the length ratio and the Euclidean
distance between corresponding segments. However, corresponding segments are calculated with the assumption that
seed points correspond to each other. Brun et al. (2004) used a
9-D shape descriptor including the mean and square root of the
covariance matrix of the points on the trajectories. Leemans,
Sijbers, De Backer, Vandervliet, and Parizel (2006) found the
closest subcurves in the curvature-torsion space and varied the
length of the subcurves to deal with the curve matching problem.
Maddah, Mewes, Haker, Grimson, and Warfield (2005) used the
B-spline representation of 3-D curves to calculate the distance.
Clayden, Bastin, and Storkey (2006) used a combination of
shape and length of the trajectories. Tsai, Westin, Hero, and
Willsky (2007) used dual-rooted graphs to capture both local
and global differences. Maddah, Grimson, Warfield, and Wells
(2008) proposed a distance transform map to efficiently compute
the similarity between the trajectories and cluster centers.
Berkiten and Acar (2010) used pivot points defined as points
on a trajectory that are themselves the closest neighbors of their
closest point on the other trajectory. Mani, Kurtek, Barillot, and
Srivsastana (2010) used a combination of distance, shape,
orientation, and the scale of the trajectories. Other methods
include dynamic time wrapping (Shao et al., 2010) and finding
the longest common subsequences (Bohm et al., 2011).
The choice of clustering has some implications for the
computational efficiency of the algorithm. Similarity-based
methods are often based on pairwise comparisons of the
fiber trajectories, which scale quadratically with the number
of trajectories and thus are computationally demanding,
especially when the distance metric depends on the cluster
assignment. Some approximations to the problem have been
proposed. For example, ODonnell and Westin (2007) used
the Nystrom method to sample and cluster a small subset of
the trajectories and then used these as a reference to cluster the
rest of the trajectories. El Kouby, Cointepas, Poupon, Rivie`re, &
Golestani (2005) divided the space into 3-D cells, clustered
these cells based on their connectivity, and then used these
cells to cluster the trajectories. A similar approach was taken by
Klein et al. (2007). Finally, Bohm et al. (2011) used a lowerbounding distance to reduce the computation time. Alternatively, generative methods are based on comparison of trajectories to parameters of the estimated model (e.g., cluster
centers), which grows linearly with the number of trajectories.
However, they often require iterative processes in parameter
learning to converge (Maddah, Grimson, et al., 2008).
273
Quantitative Analysis
The ultimate goal of processing diffusion MRI data is the
quantitative assessment of spatial and temporal differences in
274
INTRODUCTION TO METHODS AND MODELING | Tract Clustering, Labeling, and Quantitative Analysis
Figure 2 An example of tract-based quantitative analysis. (a) Unclustered trajectories from uncinate fasciculus (UF), inferior fronto-occipital
fasciculus (IFO), and inferior fronto-occipital fasciculus (ILF). (b) Trajectories grouped into anatomically meaningful bundles. (c) Trajectories colored
based on the local variation on fractional anisotropy (FA). The goal of tract-based quantitative analysis is to measure these spatial variations for
each tract. Note that in (b) and (c), clusters are spatially shifted for better visualization.
Acknowledgment
This work is supported by NIAAA Grant AA012388.
References
Abe, O., Takao, H., Gonoi, W., Sasaki, H., Murakami, M., Kabasawa, H., et al. (2010).
Voxel-based analysis of the diffusion tensor. Neuroradiology, 52, 699710.
Basser, P. J., Mattiello, J., & LeBihan, D. (1994). MR diffusion tensor spectroscopy and
imaging. Biophysical Journal, 66, 259267.
Berkiten, S., & Acar, B. (2010). A pointwise correspondence based DT-MRI fiber
similarity measure. IEEE Engineering in Medicine and Biology Society, 2010,
26942697.
Bohm, C., Mai, S. T., Feng, J., Plant, C., He, X., & Shao, J. (2011). A novel similarity
measure for fiber clustering using longest common subsequence. In: Proceedings
of the data mining for medicine and healthcare workshop, pp. 19.
INTRODUCTION TO METHODS AND MODELING | Tract Clustering, Labeling, and Quantitative Analysis
Brun, A., Knutsson, H., Park, H. J., Shenton, M. E., & Westin, C.-F. (2004). Clustering
fiber tracts using normalized cuts. Medical Image Computing and ComputerAssisted Intervention, 3216, 368375.
Catani, M., & Thiebaut de Schotten, M. (2008). A diffusion tensor imaging tractography
atlas for virtual in vivo dissections. Cortex, 44, 11051132.
Clayden, J. D., Bastin, M. E., & Storkey, A. J. (2006). Improved segmentation
reproducibility in group tractography using a quantitative tract similarity measure.
NeuroImage, 33, 482492.
Clayden, J. D., Storkey, A. J., & Bastin, M. E. (2007). A probabilistic model-based
approach to consistent white matter tract segmentation. IEEE Transactions on
Medical Imaging, 26, 15511561.
Colby, J. B., Soderberg, L., Lebel, C., Dinov, I. D., Thompson, P. M., & Sowell, E. R.
(2012). Along-tract statistics allow for enhanced tractography analysis. NeuroImage,
59, 32273242.
Corouge, I., Fletcher, P. T., Joshi, S., Gouttard, S., & Greig, G. (2006). Fiber tractoriented statistics for quantitative diffusion tensor MRI analysis. Medical Image
Analysis, 10, 786798.
Corouge, I., Gerig, G., & Gouttard, S. (2004). Towards a shape model of white matter
fiber bundles using diffusion tensor MRI. ISBI, 1, 344347.
Ding, Z., Gore, J. C., & Anderson, A. W. (2003). Classification and quantification of
neuronal fiber pathways using diffusion tensor MRI. Magnetic Resonance in
Medicine, 49, 716721.
Duncan, J. S. (2010). Imaging in the surgical treatment of epilepsy. Nature Reviews
Neurology, 6, 537550.
El Kouby, V., Cointepas, Y., Poupon, C., Rivie`re, D., Golestani, N., Poline, J. B., et al.
(2005). MR diffusion-based inference of a fiber bundle model from a population of
subjects. Medical Image Computing and Computer-Assisted Intervention, 8,
196204.
Goodlett, C. B., Fletcher, P. T., Gilmore, J. H., & Gerig, G. (2009). Group analysis of DTI fiber
tract statistics with application to neurodevelopment. NeuroImage, 45, S133S142.
Guevara, P., Poupon, C., Rivie`re, D., Cointepas, Y., Descoteaux, M., Thirion, B., et al. (2010).
Robust clustering of massive tractography datasets. NeuroImage, 54, 19751993.
Jiang, H., van Zijl, P. C. M., Kim, J., Pearlson, G. D., & Mori, S. (2006). DtiStudio:
Resource program for diffusion tensor computation and fiber bundle tracking.
Computer Methods and Programs in Biomedicine, 81, 106116.
Jin, Y., Shi, Y., Zhan, L., Li, J., de Zubiacaray, G. I., McMahon, K. L., et al. (2012).
Automatic population HARDI white matter tract clustering by label fusion of multiple
tract atlases. Multimodal Brain Image Analysis, 7509, 147156.
Kanaan, R. A., Shergill, S. S., Barker, G. J., Catani, M., Ng, V. W., Howard, R., et al.
(2006). Tract-specific anisotropy measurement in diffusion tensor imaging.
Psychiatry Research, 146, 7382.
Klein, J., Bittihn, P., Ledochowitsch, P., Hahn, H. K., Konard, O., Rexilius, J., et al.
(2007). Grid-based spectral fiber clustering. Medical imaging: Visualization and
image-guided procedures, 65091E.
Leemans, A., Sijbers, J., De Backer, S., Vandervliet, E., & Parizel, P. (2006). Multiscale
white matter fiber tract coregistration: A new feature-based approach to align
diffusion tensor data. Magnetic Resonance in Medicine, 55, 14141423.
Liu, M., Vemuri, B. C., & Deriche, R. (2012). Unsupervised automatic white matter fiber
clustering using a Gaussian mixture model. Proceedings of the IEEE International
Symposium on Biomedical Imaging, 2012, 522525.
Maddah, M., Grimson, W. E.L, Warfield, S. K., & Wells, W. M. (2008). A unified
framework for clustering and quantitative analysis of white matter fiber tracts.
Medical Image Analysis, 12, 191202.
Maddah, M., Mewes, A. U.J, Haker, S., Grimson, W. E.L, & Warfield, S. K. (2005).
Automated atlas-based clustering of white matter fiber tracts from DTMRI. Medical
Image Computing and Computer-Assisted Intervention, 8, 188195.
Maddah, M., Miller, J. V., Sullivan, E. V., Pfefferbaum, A., & Rohlfing, T. (2011). Sheetlike white matter fiber tracts: Representation, clustering, and quantitative analysis.
Medical Image Computing and Computer-Assisted Intervention, 14, 191199.
Maddah, M., Zollei, L., Grimson, W. E.L, Westin, C.-F., & Wells, W. M. (2008). A
mathematical framework for incorporating anatomical knowledge in DT-MRI analysis.
IEEE International Symposium on Biomedical Imaging, 4543943, 105108.
Mani, M., Kurtek, S., Barillot, C., & Srivsastana, A. (2010). A comprehensive
Riemannian framework for the analysis of white matter fiber tracks. IEEE
International Symposium on Biomedical Imaging.
Merhof, D., Greiner, G., Buchfelder, M., & Nimsky, C. (2010). Fiber selection from
diffusion tensor data based on Boolean operators. Bildverarbeitung fur die Medizin,
147151.
Mori, S., Crain, B., Chacko, V., & van Zijl, P. (1999). Three dimensional tracking of
axonal projections in the brain by magnetic resonance imaging. Annals of
Neurology, 45, 265269.
Mori, S., Oishi, K., Jiang, H., Jiang, L., Li, X., Akhter, K., et al. (2007). Stereotaxic white
matter atlas based on diffusion tensor imaging in an ICBM template. NeuroImage,
40, 570582.
275
ODonnell, L., Golby, A. J., & Westin, C.-F. (2013). Fiber clustering versus the
parcellation-based connectome. NeuroImage, 80, 283289.
ODonnell, L., & Westin, C. F. (2005). White matter tract clustering and correspondence
in populations. Medical Image Computing and Computer-Assisted Intervention, 8,
140147.
ODonnell, L., & Westin, C.-F. (2006). High-dimensional white matter atlas generation
and group analysis. Medical Image Computing and Computer-Assisted
Intervention, 9, 243251.
ODonnell, L., & Westin, C.-F. (2007). Automatic tractography segmentation using a
high-dimensional white matter atlas. IEEE Transactions on Medical Imaging, 26,
15621575.
ODonnell, L., Westin, C.-F., & Golby, A. J. (2009). Tract-based morphometry for white
matter group analysis. NeuroImage, 45, 832844.
Prasad, G., Jahanshad, N., Aganj, I., Lenglet, C., Sapiro, G., Toga, A. W., et al. (2011).
Atlas-based fiber clustering for multi-subject analysis of high angular resolution
diffusion imaging tractography. ISBI, 276280.
Ratnarajah, N., Simmons, A., & Hojjatoleslami, A. (2011). Probabilistic clustering and
shape modelling of white matter fibre bundles using regression mixtures. Medical
Image Computing and Computer-Assisted Intervention, 14, 2532.
Robinson, E. C., Rueckert, D., Hammers, A., & Edwards, A. D. (2010). Probabilistic
white matter and fiber tract atlas construction. ISBI, 11531156.
Schulte, T., Maddah, M., Muller-Oehring, E. M., Rohlfing, T., Pfefferbaum, A., &
Sullivan, E. V. (2013). Fiber tract-driven topographical mapping (FTTM) reveals
microstructural relevance for interhemispheric visuomotor function in the aging
brain. NeuroImage, 77, 195206.
Shao, J., Hahn, K., Yang, Q., Bohm, C., Wohlschlager, A. M., Myers, N., et al. (2010).
Combining time series similarity with density-based clustering to identify fiber
bundles in the human brain. In: IEEE International Conference on Data Mining
Workshops, pp. 747754.
Shimony, J. S., Snyder, A. Z., Lori, N., & Conturo, T. E. (2002). Automated fuzzy
clustering of neuronal pathways in diffusion tensor tracking. ISMRM, p. 10.
Smith, S. M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T. E.,
Mackay, C. E., et al. (2006). Tract-based spatial statistics: Voxelwise analysis of
multi-subject diffusion data. NeuroImage, 31, 14871505.
Suarez, R. O., Commowick, O., Prabhu, S. P., & Warfield, S. K. (2012). Automated
delineation of white matter fiber tracts with a multiple region-of-interest.
NeuroImage, 59, 36903700.
Tsai, A., Westin, C.-F., Hero, A. O., & Willsky, A. S. (2007). Fiber tract clustering on
manifolds with dual rooted-graphs. IEEE Conference on Computer Vision and
Pattern Recognition, pp. 16.
Van Hecke, W., Sijbers, J., De Backer, S., Poot, D., Parizel, P. M., & Leemans, A.
(2009). On the construction of a ground truth framework for evaluating voxel-based
diffusion tensor MRI analysis methods. NeuroImage, 46, 692707.
Wakana, S., Caprihan, A., Panzenboeck, M. M., Fallon, J. H., Perry, M., Gollub, R. L.,
et al. (2007). Reproducibility of quantitative tractography methods applied to
cerebral white matter. NeuroImage, 36, 630644.
Wakana, S., Jiang, H., Nagae-Poetscher, L. M., van Zijl, P. C.M, & Mori, S. (2004).
Fiber tract-based atlas of human white matter anatomy. Radiology, 230, 7787.
Wang, X., Grimson, W. E.L, & Westin, C.-F. (2011). Tractography segmentation using a
hierarchical Dirichlet processes mixture model. NeuroImage, 54, 290302.
Wassermann, D., & Deriche, R. (2008). Simultaneous manifold learning and
clustering: Grouping white matter fiber tracts using a volumetric white matter
atlas. MICCAI workshop Manifolds in medical imaging: Metrics, learning and
beyond.
Wassermann, D., Bloy, L., Kanterakis, E., Verma, R., & Deriche, R. (2010).
Unsupervised white matter fiber clustering and tract probability map generation:
Applications of a Gaussian process framework for white matter fibers. NeuroImage,
51, 228241.
Xia, Y., Turken, A., Whitfield-Gabrieli, S., & Gabrieli, J. (2005). Knowledge-based
classification of neuronal fibers in entire brain. Medical Image Computing and
Computer-Assisted Intervention, 8, 205212.
Yeatman, J. D., Dougherty, R. F., Myall, N. J., Wandell, B. A., & Feldman, H. M. (2012).
Tract profiles of white matter properties: Automating fiber-tract quantification. PLoS
One, 7, e49790.
Ziyan, U., Sabuncu, M. R., Grimson, W. E.L, & Westin, C.-F. (2009). Consistency
clustering: A robust algorithm for group-wise registration, segmentation, and
automatic atlas construction in diffusion MRI. International Journal of Computer
Vision, 85, 279290.
Ziyan, U., Sabuncu, M. R., ODonnell, L., & Westin, C.-F. (2007). Nonlinear registration
of diffusion MR images based on fiber bundles. Medical Image Computing and
Computer-Assisted Intervention, 10, 351358.
Zvitia, O., Mayer, A., Shadmi, R., & Greenspan, H. (2009). Co-registration of white
matter tractographies by adaptive-mean-shift of Gaussian mixture modeling. IEEE
Transactions on Medical Imaging, 29, 132145.
Introduction
Diffusion magnetic resonance imaging (MRI) provides a unique
noninvasive window into the microstructure of biological tissue.
The technique sensitizes the MR signal to the dispersion of water
molecules in tissue from diffusion over timescales from about
1 ms to 1 s. During that time, water molecules at body temperature move average distances of on the order of ones to tens of
micrometers. At this length scale, the cellular architecture of the
tissue restricts and impedes the mobility of the water and so
determines the pattern of dispersion. Diffusion MR measurements are thus sensitive to various histological features of the
tissue, such as size, density, orientation, permeability, and shape
of cells and membranes. Diffusion MR microstructure imaging
aims to provide virtual histology, by estimating these features
from combinations of diffusion MR measurements and mapping them over the brain, as well as other organs or samples.
Standard diffusion MRI techniques, such as apparent diffusion coefficient mapping, diffusion tensor imaging, and diffusion spectrum imaging, provide indices, such as mean diffusivity
(MD) and fractional anisotropy (FA), that are sensitive to various
histological features. However, these indices lack specificity. All
the histological features listed in the preceding text can affect
both MD and FA. While changes in either index arise from
differences in the tissue microstructure, the indices themselves
say little about which specific properties are different.
The general strategy in microstructure imaging is to use a
mathematical model that relates specific properties of the cellular architecture of tissue to the dispersion pattern of water molecules and its evolution over time and thus to diffusion MR
signals. We solve an inverse problem to estimate the tissue
properties by fitting the model to MR measurements. In imaging,
this means acquiring various different diffusion MR images with
different settings on the scanner (diffusion times, b-values, etc.);
this provides a set of measurements in each voxel of the image to
which we fit our model and estimate its parameters. Thus, we can
map the parameters over the image. Figure 1 gives an illustration
of the process for one particular technique.
A general feature of microstructure imaging techniques is that
the parameters they map relate to tissue features much smaller
than the resolution of the image. The example in Figure 1 maps
indices of axon density and diameter; the image voxels represent
blocks of tissue with size of order 1 mm3, whereas the axons
themselves have diameter of order 1 mm. The values in the parameter maps are not measurements of single cells or structures, but
are statistical in nature: a mean axon diameter or average density
over the thousands or millions the voxel contains.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00296-7
277
278
INTRODUCTION TO METHODS AND MODELING | Tissue Microstructure Imaging with Diffusion MRI
Figure 1 An exemplar microstructure imaging technique. The true diffusion MRI signal due to white matter tissue structure (bottom left) is
approximated by a simplified mathematical model using infinitely long parallel cylinders (top left). The model is fit to diffusion-weighted MR images
(center) in order to generate maps of axon diameter and density within the corpus callosum (right).
Fiber Orientation
One class of microstructure imaging technique uses models
designed primarily to estimate fiber orientations for
tractography. Some simple compartment models are useful for
this purpose. The ball-and-stick model (Behrens et al., 2003)
assumes that the white matter MR signal comes from two separate populations of water: one trapped inside axons, which can
move only in the direction of the fiber, and the other outside but
around the axons, which diffuses freely and isotropically. The
parameters of the model are the diffusivity, the orientation of
the stick component, and the ratio of the signals coming from
the two compartments. The signal ratio, or volume fraction,
relates to the density of fibers. Thus, fitting the model provides
INTRODUCTION TO METHODS AND MODELING | Tissue Microstructure Imaging with Diffusion MRI
estimates of two histological parameters: the fiber density and
the fiber orientation. The composite hindered and restricted
model of diffusion (CHARMED) proposed by Assaf, Freidlin,
Rohde, and Basser (2004) similarly separates intra-axonal and
extra-axonal compartments but uses more complex models for
each compartment. Specifically, it models the axons as a collection of straight parallel impermeable cylinders with a distribution of radii typical of the human white matter. The model for
the intra-axonal signal then uses a model of diffusion restricted
within a cylinder; the extra-axonal signal assumes anisotropic
free diffusion with greater hindrance in the directions perpendicular to the fibers than parallel.
A limitation of the basic ball-and-stick model or CHARMED
is the assumption of a single orientation common to all fibers
within each voxel. However, these kinds of model extend easily
to cope with multiple distinct fiber populations, for example, at
fiber crossings, by simply including multiple stick (or more
generally intra-axonal) compartments, as in Hosey, Williams,
and Ansorge (2005), Assaf and Basser (2005), and Behrens,
Johansen-Berg, Jbabdi, Rushworth, and Woolrich (2007). For
more general configurations of fibers, we can consider the signal
as a convolution of signals from a single fiber with an orientation
distribution of fibers (Tournier, Calamante, Gadian, & Connelly,
2004) and deconvolve the signal with a model of the single fiber
signal to estimate the fiber orientation distribution as in Tournier
et al. (2004), Alexander (2005b), Tournier, Calamante, and
Connelly (2007), Sakaie and Lowe (2007), DellAcqua et al.
(2007), and Anderson (2005). Other techniques (Kaden,
Knosche, & Anwander, 2007; Sotiropoulos, Behrens, & Jbabdi,
2012; Zhang, Schneider, Wheeler-Kingshott, & Alexander, 2012)
use simple parametric models for the fiber orientation distribution, such as the Watson and Bingham distributions (Mardia &
Jupp, 1990). Various review articles, for example, Alexander
(2005a), Seunarine and Alexander (2009), and Tournier, Mori,
and Leemans (2011), cover the range of techniques for mapping
fiber orientations in more detail.
Fiber Composition
Other techniques focus on estimating parameters describing
the composition of fiber bundles, such as axon density and
diameter distribution. Stanisz, Wright, Henkelman, and Szafer
(1997) proposed a three-compartment model of nervous tissue: one population of water inside elongated ellipsoidal
axons, another inside spherical glial cells, and a third in the
extracellular space. Each compartment has its own dimensions,
volume fraction, membrane permeability, and internal diffusivity and relaxation constants. Fitting the full model provides
estimates of all these parameters but requires a very rich data
set containing low noise measurements with a wide range of
diffusion times and b-values. The only demonstration of the
technique is on an excised bovine optic nerve using a high-field
small-bore scanner with very high magnetic field gradients.
The AxCaliber technique introduced by Assaf, BlumenfeldKatzir, Yovel, and Basser (2008) uses the CHARMED model but
fits for the axon diameter distribution, modeled as a twoparameter gamma distribution, rather than assuming a fixed
typical distribution. The model is similar to that of Stanisz et al.
(1997), but simpler, because it assumes impermeable membranes and has no glial cell compartment. Experiments on excised
279
280
INTRODUCTION TO METHODS AND MODELING | Tissue Microstructure Imaging with Diffusion MRI
Figure 3 This figure, taken from Assaf et al. (2013), demonstrates several of the techniques discussed in Section Fiber Composition. (a) shows an axon
density map estimated using CHARMED. (b) shows estimates of axon diameter distributions in the rat corpus callosum estimated using AxCaliber (Barazany
et al., 2009), whereas (c) shows estimates of the single axon diameter index using ActiveAx (Dyrby et al., 2013). (d) shows an eccentricity map estimated
using a double-PFG sequence (Shemesh et al., 2012a), which is discussed further in Section Perspectives. Reprinted from Assaf, Y., Alexander, D. C.,
Jones, D. K., Bizzi, A., Behrens, T. E. J., Clark, C. A., Cohen, Y., Dyrby, T. B., Huppi, P. S., Knoesche, T. R., LeBihan, D., Parker, G. J. M., & Poupon, C. (2013).
The CONNECT project: Combining macro- and microstructure. NeuroImage, 80, 273282, Copyright (2013), with permission from Elsevier.
Exchange Imaging
Exchange rate, or membrane permeability, is another important histological property of tissue that affects water mobility
and thus the diffusion MR signal. Permeability is an important
property, because it can highlight tissue damage or disease;
damaged axonal myelin sheaths, for example, can permit
more water to pass through the wall of the axon than healthy
myelin sheaths. Precise mathematical models relating membrane permeability to the signal are not straightforward to
construct, but various approximations are available.
Karger, Pfeifer, and Heink (1988) provided a simple framework for incorporating the effects of exchange on the diffusion
MR measurements by modeling the signals due to intra- and
extra-axonal water as a weakly coupled system. Originally formulated to model exchange between two freely diffusing pools
of protons, the Karger equations have also been modified to
INTRODUCTION TO METHODS AND MODELING | Tissue Microstructure Imaging with Diffusion MRI
model exchange between free and restricted sites (Price, 2009),
and in this formulation, it is one of the most commonly used
methods for modeling axonal exchange (Fieremans, Novikov,
Jensen, & Helpern, 2010; Meier, Dreher, & Leibfritz, 2003;
Nilsson et al., 2009; Stanisz et al., 1997). However, simulation
studies by Nilsson et al. (2010) show that the approximations
used to derive the Karger equations lead to bias in the estimated microstructure parameters.
Lasic, Nilsson, Latt, Stahlberg, and Topgaard (2011)
introduced the apparent exchange rate (AXR) mapping technique, which uses various approximations to find a potentially
practical way to estimate and map an index of exchange rate.
The work uses a specialist pulse sequence that is not widely
available on clinical scanners, although later work by Nilsson
et al. (2013) demonstrates feasibility of the technique on live
human subjects. An example of an in vivo AXR map is shown in
Figure 4.
Perspectives
Microstructure imaging remains an emerging technology.
Although the first clinically feasible techniques are starting to
appear and gain widespread attention from the imaging user
community, considerable refinement of those techniques is
still possible, and a wide range of new possibilities are on the
horizon.
The mathematical models that underpin current microstructure imaging techniques remain a gross simplification of reality,
and refinements are needed to improve the fit to the data and
281
Figure 4 Nilsson et al. (2013) showed maps of the apparent exchange rate (AXR) compared to standard DTI metrics such as fractional anisotropy (FA),
mean diffusivity (MD), and the apparent diffusion coefficient (ADC). Reprinted from Nilsson, M., Latt, J., Wirestam, R., Stahlberg, F., Karlsson, N.,
Johansson, M., Sundgren, P. C., & van Westen, D. (2013). Noninvasive mapping of water diffusional exchange in the human brain using filter-exchange
imaging. Magnetic Resonance in Medicine, 69, 15721580, Copyright (2012), with permission from John Wiley & Sons Ltd.
282
INTRODUCTION TO METHODS AND MODELING | Tissue Microstructure Imaging with Diffusion MRI
90
180
PGSE
Readout(RO)
(a)
90
180
180
dPFG
(b)
90
180
OGSE
(c)
90
180
L-N
(d)
Figure 5 The PGSE sequence (Stejskal & Tanner, 1965) shown in (a) is the standard diffusion MR sequence. However, (c) OGSE (Callaghan &
Komlosh, 2002) improves sensitivity to axon diameter, whereas (b) dPFG (Lawrenz & Finsterbusch, 2011; Shemesh et al., 2012a) and (d) longnarrow
(LN) (Laun et al., 2011) sequences provide sensitivity to pore shape.
orientation distribution, and separates this microscopic anisotropy from the macroscopic anisotropy of pores with coherent
orientation. More general efforts to estimate pore shape offer
future possibilities. Laun, Kuder, Semmler, and Stieltjes (2011)
showed that the shape of any pore is recoverable using combinations of longnarrow pulses, as shown in Figure 6, and later
work by Kuder, Bachert, Windschuh, and Laun (2013) demonstrates the technique experimentally using a physical phantom
and hyperpolarized gas to provide the required signal. Shemesh,
Westin, and Cohen (2012b) proposed a combination of PGSE
and dPFG measurements to recover pore shape and
demonstrated experimentally recovery of a circular pore. As
Kuder and Laun (2013) later pointed out, that technique works
only for shapes with simple symmetries, but they go on to show
how to generalize it for arbitrary pore shapes. Precise pore shape
recovery requires gradient strengths and acquisition time well in
excess of what is available on current human imaging systems,
and these techniques will not become available for brain mapping in the near future. However, apparent eccentricity measurements do translate to human imaging, as shown by Lawrenz and
Finsterbusch (2013), and are the practical face of pore shape
imaging.
A further key area for improvement of microstructure imaging techniques is to extend beyond diffusion MRI and combine
with measurements from other MR or other imaging modalities. Techniques such as T2-spectroscopy potentially provide
information on pore size and shape at much smaller length
scales see, for example, the discussion in Kaden and Alexander (2013) and can also help measurements of exchange
(Dortch, Harkins, Juttukonda, Gore, & Does, 2013). Various
optical techniques are also sensitive to pore shape and may
combine with diffusion MRI to provide better estimates of pore
density and size distribution (Proverbio, Siow, Alexander, &
Gibson, 2013).
Current and future applications of microstructure imaging
offer exciting possibilities in brain mapping. The combination
with tractography is natural and compelling. The idea of tractometry (Bells et al., 2011) is to map microstructural parameters along fiber pathways extracted using tractography. The
technique treats the two steps independently, but combining
estimates of histological parameters and reconstruction of
brain connectivity offers deeper benefits. For example,
Sherbondy, Rowe, and Alexander (2010) showed how knowledge of the composition of individual fiber pathways resolves
long-standing ambiguities for tractography such as kissing versus crossing fibers.
Much of the development work for microstructure imaging
to date concentrates on normal healthy tissue. Recent work
INTRODUCTION TO METHODS AND MODELING | Tissue Microstructure Imaging with Diffusion MRI
283
Figure 6 Laun et al. (2011) showed how the combination of a long and narrow pulse, instead of two equal length pulses, can provide information about
pore shape. With infinitely thin pulses, the pore shape can be recovered almost exactly. Reprinted figure with permission from Laun, F. B., Kuder, T. A.,
Semmler, W., & Stieltjes, B. (2011). Determination of the defining boundary in nuclear magnetic resonance diffusion experiments. Physical Review
Letters, 107, 048102. Copyright (2011), by the American Physical Society.
begins to construct models for tissue affected by specific diseases. Wang et al. (2011) described a model for the diffusion
MR signal from the white matter that aims to separate the
axonal signal from partial volume with CSF, gray matter, and
other cellular compartments, particularly those that arise during inflammation, which is typical of diseases like multiple
sclerosis. The model for the axonal compartment is similar to
the spherical deconvolution model but discretized as originally
proposed by Ramirez-Mananares, Rivera, Vemuri, Carney, and
Mareci (2007), from which Wangs name of diffusion basis
spectrum imaging comes. The model includes an additional
spectrum of isotropically diffusing components. Various
results on animal tissue are promising for future translation
to humans. Figini et al. (2012) tested various mathematical
models to explain diffusion MR signal changes that occur in
prion diseases. These ideas potentially lead to disease-specific
imaging techniques tailored specifically for sensitivity to
particular pathologies. Similar work has been underway
outside the brain, for example, in cancer imaging (Colvin
et al., 2011; Panagiotaki et al., 2013; Xu, Does, & Gore,
2008), for some time.
A final note of caution: As with all model-based techniques,
microstructure imaging relies on the integrity of the underlying
model linking the measured data to tissue features of interest. It
will provide answers whether the model is correct or not, and
the models these techniques use are a gross simplification of
reality.
References
Aboitiz, F., Rodriguez, E., Olivares, R., & Zaidel, E. (1996). Age-related changes in fibre
composition of the human corpus callosum: Sex differences. NeuroReport, 7,
17611764.
Aboitiz, F., Schiebel, A. B., Fisher, R. S., & Zaidel, E. (1992). Fiber composition of the
human corpus callosum. Brain Research, 598, 143153.
Alexander, D. C. (2005a). Multiple-fiber reconstruction algorithms for diffusion MRI.
Annals of the New York Academy of Sciences, 1064, 113133.
Alexander, D. C. (2005b). Maximum entropy spherical deconvolution for diffusion MRI.
Proceedings of Information Processing in Medical Imaging, 19, 7687.
Alexander, D. C. (2008). A general framework for experiment design in diffusion MRI
and its application in measuring direct tissue-microstructure features. Magnetic
Resonance in Medicine, 60, 439448.
Alexander, D. C., Hubbard, P. L., Hall, M. G., Moore, E. A., Ptito, M., Parker, G. J. M.,
et al. (2010). Orientationally invariant indices of axon diameter and density from
diffusion MRI. NeuroImage, 52, 13741389.
Anderson, A. W. (2005). Measurement of fiber orientation distributions using high
angular resolution diffusion imaging. Magnetic Resonance in Medicine, 54,
11941206.
284
INTRODUCTION TO METHODS AND MODELING | Tissue Microstructure Imaging with Diffusion MRI
Assaf, Y., Alexander, D. C., Jones, D. K., Bizzi, A., Behrens, T. E. J., Clark, C. A., et al.
(2013). The CONNECT project: Combining macro- and microstructure.
NeuroImage, 80, 273282.
Assaf, Y., & Basser, P. J. (2005). Composite hindered and restricted model of diffusion
(CHARMED) MR imaging of the human brain. NeuroImage, 27, 4858.
Assaf, Y., Blumenfeld-Katzir, T., Yovel, Y., & Basser, P. J. (2008). AxCaliber: A method
for measuring axon diameter distribution from diffusion MRI. Magnetic Resonance
in Medicine, 59, 13471354.
Assaf, Y., Freidlin, R. Z., Rohde, G. K., & Basser, P. J. (2004). New modeling and
experimental framework to characterize hindered and restricted water diffusion in
brain white matter. Magnetic Resonance in Medicine, 52, 965978.
Barazany, D., Basser, P. J., & Assaf, Y. (2009). In vivo measurement of axon diameter
distribution in the corpus callosum of rat brain. Brain, 132, 12101220.
Bauman, N., & Pham-Dinh, D. (2001). Biology of oligodendrocyte and myelin in the
mammalian central nervous system. Physiological Reviews, 81, 872927.
Bear, M. F., Connor, B. W., & Paradiso, M. A. (2007). Neuroscience: Exploring the brain
(3rd ed.). Baltimore: Lippincott, Williams and Wilkins.
Behrens, T. E.J, Johansen-Berg, H., Jbabdi, S., Rushworth, M. F. S., & Woolrich, M. W.
(2007). Probabilistic tractography with multiple fiber orientations: What can we
gain? NeuroImage, 34, 144155.
Behrens, T. E.J, Johansen-Berg, H., Woolrich, M. W., Smith, S. M.,
Wheeler-Kingshott, C. A.M, Boulby, P. A., et al. (2003). Non-invasive mapping of
connections between human thalamus and cortex using diffusion imaging. Nature
Neuroscience, 6, 750757.
Bells, S., Cercignani, M., Deoni, S. L., Assaf, Y., Pasternak, O., Evans, J., et al. (2011).
Tractometry Comprehensive multi-modal quantitative assessment of white matter
along specific tracts In: Proceedings of the international society for magnetic
resonance in medicine, 678.
Budde, M. D., & Frank, J. A. (2010). Neurite beading is sufficient to decrease the
apparent diffusion coefficient after ischemic stroke. Proceedings of the National
Academy of Sciences, 107, 1447214477.
Bunge, R. P. (1968). Glial cells and the central myelin sheath. Physiological Reviews,
48, 197210.
Callaghan, P. T., & Komlosh, M. E. (2002). Locally anisotropic motion in a
macroscopically isotropic system: Displacement correlations measured using
double pulsed gradient spin-echo NMR. Magnetic Resonance in Chemistry, 40,
S15S19.
Colvin, D. C., Loveless, M. E., Does, M. D., Yue, Z., Yankeelov, T. E., & Gore, J. C.
(2011). Earlier detection of tumor treatment response using magnetic resonance
diffusion imaging with oscillating gradients. Magnetic Resonance Imaging, 29,
315323.
Cory, D. G., Garroway, A. N., & Miller, J. B. (1990). Applications of spin transport as a
probe of local geometry. Polymer Preprints, 31, 149.
DellAcqua, F., Rizzo, G., Scifo, P., Clarke, R. A., Scotti, G., & Fazio, F. (2007). A modelbased deconvolution approach to solve fiber crossing in diffusion-weighted MR
imaging. IEEE Transactions on Medical Imaging, 54, 462472.
Does, M. D., Parsons, E. C., & Gore, J. C. (2003). Oscillating gradient measurements of
water diffusion in normal and globally ischemic rat brain. Magnetic Resonance in
Medicine, 49, 206215.
Dortch, R. D., Harkins, K. D., Juttukonda, M. R., Gore, J. C., & Does, M. D. (2013).
Characterizing inter-compartmental water exchange in myelinated tissue using
relaxation exchange spectroscopy. Magnetic Resonance in Medicine, 70,
14501459.
Drobnjak, I., & Alexander, D. C. (2011). Optimising time-varying gradient orientation for
microstructure sensitivity in diffusion-weighted MRI. Journal of Magnetic
Resonance, 212, 344354.
Drobnjak, I., Siow, B. M., & Alexander, D. C. (2010). Optimizing gradient waveforms for
microstructure sensitivity in diffusion-weighted MR. Journal of Magnetic
Resonance, 206, 4151.
Dyrby, T. B., Sogaard, L. V., Hall, M. G., Ptito, M., & Alexander, D. C. (2013). Contrast
and stability of the axon diameter index from microstructure imaging with diffusion
MRI. Magnetic Resonance in Medicine, 70, 711721.
Ferizi, U., Schneider, T., Tariq, M., Wheeler-Kingshott, C. A. M., Zhang, H., &
Alexander, D. C. (2013). The importance of being dispersed: A ranking of
diffusion MRI models for fibre dispersion using in vivo human brain data.
Proceedings of Medical Image Computing and Computer Assisted Intervention,
16(Part I), 7481.
Fieremans, E., Novikov, D. S., Jensen, J. H., & Helpern, J. A. (2010). Monte Carlo study
of a two-compartment exchange model of diffusion. NMR in Biomedicine, 23,
711724.
Figini, M., Alexander, D. C., Fasano, F., Farina, L., Baselli, G., Tagliavini, F., et al.
(2012). Mathematical models of diffusion in prion disease. In: Proceedings of the
Italian chapter of the international society for magnetic resonance in medicine.
Hosey, T., Williams, G., & Ansorge, R. (2005). Inference of multiple fiber orientations in
high angular resolution diffusion imaging. Magnetic Resonance in Medicine, 54,
14801489.
Ianus, A., Siow, B. M., Drobnjak, I., & Alexander, D. C. (2012). Gaussian phase
distribution approximations for oscillating gradient spin echo diffusion MRI.
Journal of Magnetic Resonance, 227, 2534.
Jacobs, B., Schall, M., & Scheibel, A. B. (1993). A quantitative dendritic analysis of
Wernickes area in humans. II. Gender, hemispheric, and environmental factors.
Journal of Comparative Neurology, 327, 97111.
Jbabdi, S., Sotiropoulos, S. N., Savio, A. M., Grana, M., & Behrens, T. E.J (2012).
Model-based analysis of multishell diffusion MR data for tractography: How to get
over fitting problems. Magnetic Resonance in Medicine, 68, 18461855.
Jespersen, S. N. (2012). Equivalence of double and single wave vector diffusion
contrast at low diffusion weighting. NMR in Biomedicine, 25, 813818.
Jespersen, S. N., Bjarkam, C. R., Nyengaard, J. R., Chakravarty, M. M., Hansen, B.,
Vosegaard, T., et al. (2010). Neurite density from magnetic resonance diffusion
measurements at ultrahigh field: Comparison with light microscopy and electron
microscopy. NeuroImage, 49, 205216.
Jespersen, S. N., Kroenke, C. D., Ostergaard, L., Ackerman, J. J.H, & Yablonskiy, D. A.
(2007). Modeling dendrite density from magnetic resonance diffusion
measurements. NeuroImage, 34, 14731486.
Jespersen, S. N., Leigland, L. A., Cornea, A., & Kroenke, C. D. (2012). Determination of
axonal and dendritic orientation distributions within the developing cerebral cortex
by diffusion tensor imaging. IEEE Transactions on Medical Imaging, 31, 1632.
Kaden, E., & Alexander, D. C. (2013). Can T2-spectroscopy resolve submicrometer
axon diameters? Proceedings of Information Processing in Medical Imaging, 23,
607618.
Kaden, E., Knosche, T. R., & Anwander, A. (2007). Parametric spherical deconvolution:
Inferring anatomical connectivity using diffusion MR imaging. NeuroImage, 37,
474488.
Karger, J., Pfeifer, H., & Heink, W. (1988). Principles and applications of self-diffusion
measurements by nuclear magnetic resonance. Advances in Magnetic Resonance,
12, 189.
Koch, M. A., & Finsterbusch, J. (2011). Towards compartment size estimation in vivo
based on double wave vector diffusion weighting. NMR in Biomedicine, 24,
14221432.
Komlosh, M. E., Ozarslan, E., Lizak, M. J., Horkayne-Szakaly, I., Friedlin, R. Z.,
Horkay, F., et al. (2013). Mapping average axon diameters in porcine spinal cord
white matter and rat corpus callosum using d-PFG MRI. NeuroImage, 78, 210216.
Kuder, T. A., Bachert, P., Windschuh, J. and Laun, F. B. (2013). Diffusion pore imaging
by hyperpolarized Xenon-129 Nuclear Magnetic Resonance. Physical Review
Letters, 111, 028101.
Kuder, T. A., & Laun, F. B. (2013). NMR-based diffusion pore imaging by double wave
vector measurements. Magnetic Resonance in Medicine, 70, 836841.
Lamantia, A.-S., & Rakic, P. (1990). Cytological and quantitative characteristics of four
cerebral commissures in the rhesus monkey. Journal of Comparative Neurology,
291, 520537.
Lasic, S., Nilsson, M., Latt, J., Stahlberg, F., & Topgaard, D. (2011). Apparent
exchange rate mapping with diffusion MRI. Magnetic Resonance in Medicine, 66,
356365.
Latt, J., Nilsson, M., van Westen, D., Wirestam, R., Stahlberg, F., & Brockstedt, S.
(2009). Diffusion-weighted MRI measurements on stroke patients reveal waterexchange mechanisms in sub-acute ischaemic lesions. NMR in Biomedicine, 22,
619628.
Laun, F. B., Kuder, T. A., Semmler, W., & Stieltjes, B. (2011). Determination of the
defining boundary in nuclear magnetic resonance diffusion experiments. Physical
Review Letters, 107, 048102.
Lawrenz, M., & Finsterbusch, J. (2011). Detection of microscopic diffusion anisotropy
on a whole-body MR system with double wave vector imaging. Magnetic Resonance
in Medicine, 66, 14051415.
Lawrenz, M., & Finsterbusch, J. (2013). Double-wave-vector diffusion-weighted
imaging reveals microscopic diffusion anisotropy in the living human brain.
Magnetic Resonance in Medicine, 69, 10721082.
Mardia, K. V., & Jupp, P. E. (1990). Directional statistics: Wiley series in probability and
statistics. Chichester: Wiley.
McNab, J. A., Edlow, B. L., Witel, T., Huang, S. Y., Bhat, H., Heberlein, K., et al. (2013).
The human connectome project and beyond: Initial applications of 300 mT m 1
gradients. NeuroImage, 80, 234245.
Meier, C., Dreher, W., & Leibfritz, D. (2003). Diffusion in compartmental systems. I. A
comparison and an analytical model with simulations. Magnetic Resonance in
Medicine, 50, 500509.
Merboldt, K.-D., Hanicke, W., & Frahm, J. (1985). Self-diffusion NMR imaging using
stimulated echoes. Journal of Magnetic Resonance, 64, 479486.
INTRODUCTION TO METHODS AND MODELING | Tissue Microstructure Imaging with Diffusion MRI
Nilsson, M., Alerstam, E., Wirestam, R., Stahlberg, F., Brockstedt, S., & Latt, J. (2010).
Evaluating the accuracy and precision of a two-compartment Karger model using
Monte Carlo simulations. Journal of Magnetic Resonance, 206, 5967.
Nilsson, M., Latt, J., Nordh, E., Wirestam, R., Stahlberg, F., & Brockstedt, S. (2009). On
the effects of a varied diffusion time in vivo: Is the diffusion in white matter
restricted? Magnetic Resonance Imaging, 27, 176187.
Nilsson, M., Latt, J., Stahlberg, F., van Westen, D., & Hagslatt, H. (2012). The
importance of axonal undulation in diffusion MR measurements: A Monte Carlo
simulation study. NMR in Biomedicine, 25, 795805.
Nilsson, M., Latt, J., Wirestam, R., Stahlberg, F., Karlsson, N., Johansson, M., et al.
(2013). Noninvasive mapping of water diffusional exchange in the human brain
using filter-exchange imaging. Magnetic Resonance in Medicine, 69, 15721580.
Ozarslan, E., & Basser, P. J. (2008). Microscopic anisotropy revealed by NMR double
pulsed field gradient experiments with arbitrary timing parameters. Journal of
Chemical Physics, 128, 154511.
Panagiotaki, E., Schneider, T., Siow, B. M., Hall, M. G., Lythgoe, M. F., &
Alexander, D. C. (2012). Compartment models of the diffusion signal in brain white
matter: A taxonomy and comparison. NeuroImage, 59, 22412254.
Panagiotaki, E., Walker-Samuel, S., Siow, B. M., Johnson, P., Pedley, R. B.,
Lythgoe, M. F., et al. (2013). In vivo characterisation of colorectal tumour
microstructure with DW-MRI. In: Proceedings of the international society for
magnetic resonance in medicine, 2105.
Perry, V. H. (2001). Microglia in the developing and mature central nervous system. In
K. R. Jessen & W. D. Richardson (Eds.), Glial cell development: Oxford: Oxford
University Press.
Portnoy, S., Flint, J. J., Blackband, S. J., & Stanisz, G. J. (2013). Oscillating and pulsed
gradient diffusion magnetic resonance microscopy over an extended b-value range:
Implications for the characterization of tissue microstructure. Magnetic Resonance
in Medicine, 69, 11311145.
Price, W. S. (2009). NMR studies of translational motion: Principles and applications.
Cambridge: Cambridge University Press.
Proverbio, A., Siow, B. M., Alexander, D. C., & Gibson, A. (2013). Multimodality
investigation of microstructures by the combination of diffusion NMR and diffuse
optical spectroscopy. In: Proceedings of the international society for magnetic
resonance in medicine, 3129.
Ramirez-Mananares, A., Rivera, M., Vemuri, B. C., Carney, P., & Mareci, T. (2007).
Diffusion basis functions decomposition for estimating white matter intravoxel fiber
geometry. IEEE Transactions on Medical Imaging, 26, 10911102.
Reichenbach, A., & Wolburg, H. (2005). Astrocytes and ependymal glia. In H.
Kettenmann, & B. R. Ransom (Eds.), Neuroglia: Oxford University Press.
Sakaie, K. E., & Lowe, M. J. (2007). An objective method for regularization of fiber
orientation distributions derived from diffusion-weighted MRI. NeuroImage, 34,
169176.
Scherrer, B., Schwartzman, A., Taquet, M., Prabhu, S. P., Sahin, M., Akhondi-Asl, A.,
et al. (2013). Characterizing the DIstribution of Anisotropic MicrO-structural
eNvironments with Diffusion-weighted imaging (DIAMOND). Proceedings of
Medical Image Computing and Computer-Assisted Intervention, 16, 518526.
Seunarine, K. K., & Alexander, D. C. (2009). Multiple fibers: Beyond the diffusion
tensor. In H. Johansen-Berg & T. E. J. Behrens (Eds.), Diffusion MRI: From
quantitative measurement to in vivo neuroanatomy: London: Academic Press.
Shemesh, N., Barazany, D., Sadan, O., Bar, L., Zur, Y., Barhum, Y., et al. (2012).
Mapping apparent eccentricity and residual ensemble anisotropy in the gray matter
using angular double-pulsed-field-gradient MRI. Magnetic Resonance in Medicine,
68, 794806.
Shemesh, N., Ozarslan, E., Komlosh, M. E., Basser, P. J., & Cohen, Y. (2010). From
single-pulsed field gradient to double-pulsed field gradient MR: Gleaning new
285
Glossary
Nomenclature
APT
B0
CA
Dapp
DT
EES
f0
FA
GE
kA!B and kB!A
MD
MDD
MT
Amide proton transfer
Static magnetic field in tesla (usually 1.5 T
or 3 T)
Contrast agent
Apparent diffusion coefficient/diffusivity
observed in tissue in ml/100 g min1
Diffusion tensor
Extracellular extravascular space
Larmor frequency offset in Hz difference
of local Larmor precession to RF carrier
frequency
Fractional anisotropy, derived from the
diffusion tensor
Gradient echo, without refocusing
radiofrequency pulse
Exchange rates proportionality (firstorder) constants describing an
equilibrium between the numbers in
states A and B (nA/B): kA!BnA kB!AnB
Mean diffusivity, derived from the
diffusion tensor
Main diffusion direction, derived from the
diffusion tensor
Principle of qMRI
In quantitative MRI (qMRI), biophysical properties that govern
the MRI signal are calculated from multiple colocalized MR
images, which have been acquired by varying the corresponding parameter in the pulse sequence. For example, spin echo
(SE) images obtained at different echo times (TE) yield the
PD
R1, R2, and R2*
rCBF
rCBV
rMTT
T1, T2, and T2*
TE
xm
http://dx.doi.org/10.1016/B978-0-12-397025-1.00297-9
287
288
Table 1
Intra- and
intermolecular
Microscopic
Mesoscopic
Macroscopic
Dipoledipole interactions
<1 nm
<10 mm
100 mm
1 mm
[1]
[2]
[3]
where the local rates (R1A and R1B) are weighted by the relative
number of protons (nA and nB). It has been established that the
water permeability of a single phospholipid bilayer (or cell
wall) is too high to allow for compartmentalization of extraand intracellular spaces (Koenig & Brown, 1985). Intermediate
exchange or weakly coupled conditions also lead to biexponential behavior, but other than for compartments
the observed rates and amplitudes deviate from the individual
values. Note that multiple exponential components are rather
difficult to fit reliably.
Diffusion and fast exchange conditions are the reasons why
the observed relaxation is mainly monoexponential. This is
well obeyed by R1, since R1 is smallest and subject to less
variation than R2. Equation [3] can be transformed into a
correlation between R1 and the inverse water content, which
has been confirmed experimentally (Kamman, Go, Brouwer, &
Berendsen, 1988), and in vivo at 3 T (Gelman et al., 2001)
albeit neglecting major ferritin stores.
Magnetization transfer (MT) imaging specifically targets
cross relaxation and exchange between macromolecules and
water. These processes are described by the same mathematics
and cannot be distinguished. MT contrast is evoked by implementing additional off-resonance radiofrequency (RF) pulses
into SE or GE MRI sequences. Such an MT pulse reduces the
Myelin
Bundles of myelinated axons feature a highly ordered microstructure, which is the main source of contrast between GM
and WM. The myelin sheath consists of tightly wrapped multiple phospholipid membranes with embedded proteins. Myelin shortens T1 and decreases PD, because the invisible lipid
protons do strongly interact with water protons (Koenig,
Brown, Spiller, & Lundbom, 1990). Because exchange across
multiple membranes efficiently lowers the permeability, myelin water is trapped inside the sheath and forms a separate
compartment. Cross relaxation shortens T2 to about 15 ms
(MacKay et al., 1994). The myelin water fraction (Figure 1)
can be estimated by constrained inversion of multiple SEs onto
a grid of T2 values (Whittall et al., 1997). Intra- and extraaxonal water cannot be not discerned by T2. Myelin water
strongly contributes to MT, as derived from a four-pool
model (Stanisz, Kecojevic, Bronskill, & Henkelman, 1999),
60
80
100
120
mono-T2 (ms)
140
289
5
10
15
Myelin water fraction, MWF (%)
20
Figure 1 T2 relaxation time and myelin water fraction in a healthy adult. Pseudocolor maps of single exponential T2 (left) and an overlay of myelin water
fraction (MWF, right). The MWF was obtained at 3 T from a constrained inversion of 32 spin echoes; TE being multiples of 10 ms. The mono T2
values in WM are inversely correlated to MWF. The dots are external phantoms. Data courtesy of B. Madler, Bonn, Germany.
290
Table 2
R2*
R2
R1
MT
Iron
Structural
Myelin discernible?
Strong
Medium
Small
None
Small
Medium
Strong
Strong
Anisotropy at high B0
Biexponential in WM
Monoexponential
Monoexponential
Magnitude (a.u)
WM
R2 (sec1)
R1 (sec1)
MT saturation (%)
GM
GM
GM
WM
WM
WM
CSF
[4]
GM
Blood
CSF
High
iron
CSF
Veins
CSF
4000 5000 6000 7000 8000 9000 1e+04 -0.5
(a)
(b)
0.5
1.5
2.5
(c)
0.2
0.4
0.6
0.8
1.2
1.4
10
20
30
40
50
60
(d)
Figure 2 GE-based relaxation parameter maps. Top: Parameter maps of signal magnitude (a), MT saturation (b), R1 (c), and R*2 (d) in a healthy
adult as acquired with 1 mm isotropic resolution at 3 T as in Draganski et al. (2011). Bottom: Histograms show the distribution of values in the
brain and show typical values for CSF, GM, and WM. MT is a structural contrast and insensitive to iron. Low MT reveals the high water content in
large vessels. The offset of WM compared to GM is due to the presence of myelin. R1 is mainly structural and thus similar to MT. The globus pallidus
appears similar to WM (arrow) indicating the influence of tissue iron. R*2 shows little structural contrast between GM and WM. Highly ordered fiber
bundles perpendicular to B0 (optic radiation and callosal fibers) display slightly higher values. The high sensitivity to iron enhances R2* in the
striatum and most prominently in the globus pallidus (arrow). Very high values (R2* > 50 s1) are observed in veins and meninges, enhancing
even smaller vessels, as seen in the genu of the corpus callosum.
291
lc
su
Ce
R1 (sec1)
0.8
Left hemisphere
TE 1.0 (core)
TE 1.1 (lateral)
TE 1.2 (medial)
0.7
ula
Ins
hls
sc
rus
gy
He
0.6
ral
or
ri
pe
0.5
Su
Wallace et
al. (2002)
(a)
Right hemisphere
rus
gy
o
mp
te
erio
Sup
0.70
ulcu
ral s
po
r tem
1 cm
R1
(sec1)
0.675
0.65
(b)
Figure 3 Mapping axonal content of cortical areas by R1. (a) Relaxation rate R1 (in sec1) as function of cortical depth, averaged within
probabilistically defined subdivisions of Brodmanns area 41. (b) Auditory core of Herschels gyrus depicted by a thresholded overlay of R1 at 50%
cortical depth. R1 mapping was performed at 3 T at 0.8 mm isotropic resolution with pertinent processing. Reproduced from Figure 2 of Dick, F.,
Tierney, A.T., Lutti, A., Josephs, O., Sereno, M.I., Weiskopf, N. (2012). In vivo functional and myeloarchitectonic mapping of human primary auditory
areas. Journal of Neuroscience, 32, 1609516105, with permission.
Diffusion-Weighted Imaging
The MRI signal is sensitized to self-diffusion, that is, the random translational motion of water, by an SE preparation with
pulsed field gradients for dephasing and refocusing of transversal magnetization (Johansen-Berg & Behrens, 2009). The
motion component along the direction of the gradient results
in incomplete refocusing and, thus, an attenuation of the
signal S0:
Sb S0 exp Dapp g2 G2 d2 D d=3 S0 exp Dapp b [5]
One commonly speaks of an apparent diffusion coefficient
(Dapp, approx. 0.7 mm2 ms1), because the observed attenuation is influenced by direction, amplitude (G), duration (d) of
the gradient pulses, and the diffusion time lag (D) between the
gradient pulses. The influence of these parameters are combined into the diffusion-weighting parameter b, which typically takes values around 1000 s mm2 1 ms mm2 in a
clinical setting. Equation [5] implicitly assumes consistent
Gaussian distributions of displacements over the experimental
range of D, which implies that the root-mean-square displacement of water molecules increases linearly in time:
2
Ds 2Dapp D
[6]
In an isotropic environment, where Dapp does not depend
on direction, the three-dimensional displacement is obtained
by replacing 2 with 6. In tissue, diffusion is hindered by the
semipermeable cell membranes, which couple the diffusivity
in extra- and intracellular subspaces. Changed tortuosity in EES
and volume shifts between subspaces (vasogenic and cytotoxic
edema) are likely the dominant factors to explain alterations of
292
100
R*2 (s-1)
80
Cortical GM
Deep GM
WM
Internal capsule
60
40
20
-100
100
200
0
Susceptibility difference (ppb)
Figure 4 Gradient echo-derived maps of the deep brain region at 7 T. In deep GM nuclei, R2* and susceptibility are highly correlated, indicating the
dominant influence of ferritin on both parameters (right, red dots). Iron-containing nuclei and WM tracts are sharply depicted on the susceptibility
map (lower left), which is independent on the direction of B0. Outlines in susceptibility appear blurred on frequency and R*2 maps. Mapping was performed
at 7 T at 0.4 mm isotropic resolution. Reproduced from graphical abstract of Deistung, A., Schafer, A, Schweser, F., Biedermann, U., Turner, R., &
Reichenbach, J.R. (2013). Toward in vivo histology: A comparison of quantitative susceptibility mapping (QSM) with magnitude-, phase-, and R2-imaging at
ultra-high magnetic field strength. NeuroImage, 65, 299314, with permission.
CSF
GM
GM
WM
FA
Control
293
MD (mm2 ms1)
Control
WM
CSF
0
0.2
0.4
0.6
0.8
CSF
FA
GM
Lesion X-ALD
0.5
GM
WM
0.2
0.4
2.5
MD (mm2 ms1)
X-ALD
Lesion CSF
WM
1.5
0.6
0.8
0.5
1.5
2.5
Figure 5 Mean diffusivity (MD) and fractional anisotropy (FA) in healthy brain and demyelination. Top: Healthy teenager. Bottom: Boy with bilateral
lesions (arrow) due to X-linked adrenoleukodystrophy, a rapidly progressing inflammatory demyelinating disease. The CSF-like appearance probably
indicates axonal loss following demyelination. Left: Pseudocolor overlays on T1-weighted MRI and whole-brain histograms of FA. Even in isotropic
CSF and GM, nonzero FA is observed due to image noise. The threshold at 0.3 indicates that higher FA is confined to WM. Right: Pseudocolor
overlays and whole-brain histograms of MD. A single peak of WM and GM is observed 0.7 mm2 ms1. MD is strongly increased to 1.6 mm2 ms1 in the
lesion but smaller than in CSF. Diffusion measured at 3 T at 2.2 mm resolution as in Dreha-Kulaczewski et al. (2012).
of amide groups and the exchange rates. From the latter, the
intracellular pH can be derived. APT is a chemically selective
technique and chiefly used to study brain tumors.
References
Alexander, D. C., Hubbard, P. L., Hall, M. G., Moore, E. A., Ptito, M., Parker, G. J., et al.
(2010). Orientationally invariant indices of axon diameter and density from diffusion
MRI. NeuroImage, 52, 13741389.
Boxerman, J. L., Hamberg, L. M., Rosen, B. R., & Weisskoff, R. M. (1995). MR contrast
due to intravascular magnetic susceptibility perturbations. Magnetic Resonance in
Medicine, 34, 555566.
Brooks, R. A., Vymazal, J., Goldfarb, R. B., Bulte, J. W., & Aisen, P. (1998). Relaxometry
and magnetometry of ferritin. Magnetic Resonance in Medicine, 40, 227235.
Callaghan, P. T. (1991). Principles of NMR microscopy. Oxford: Oxford University
Press.
Deistung, A., Schafer, A., Schweser, F., Biedermann, U., Turner, R., &
Reichenbach, J. R. (2013). Toward in vivo histology: A comparison of quantitative
susceptibility mapping (QSM) with magnitude-, phase-, and R2-imaging at ultrahigh magnetic field strength. NeuroImage, 65, 299314.
Deoni, S. C., Rutt, B. K., Arun, T., Pierpaoli, C., & Jones, D. K. (2008). Gleaning multicomponent T1 and T2 information from steady-state imaging data. Magnetic
Resonance in Medicine, 60, 13721387.
Dick, F., Tierney, A. T., Lutti, A., Josephs, O., Sereno, M. I., & Weiskopf, N. (2012).
In vivo functional and myeloarchitectonic mapping of human primary auditory areas.
Journal of Neuroscience, 32, 1609516105.
Draganski, B., Ashburner, J., Hutton, C., Kherif, F., Frackowiak, R. S. J., Helms, G., et al.
(2011). Regional specificity of MR contrast parameters in normal ageing revealed by
voxel-based quantification (VBQ). NeuroImage, 55, 14231434.
Drayer, B., Burger, P., Darwin, R., Riederer, S., Herfkens, R., & Johnson, G. A. (1986).
MRI of brain iron. AJR. American Journal of Roentgenology, 147, 103110.
Dreha-Kulaczewski, S. F., Brockmann, K., Henneke, M., Dechent, P., Gartner, J., &
Helms, G. (2012). Assessment of myelination in hypomyelinating disorders by
quantitative MRI. Journal of Magnetic Resonance Imaging, 36, 13291338.
Edzes, H., & Samulski, E. (1978). The measurement of cross-relaxation effects in the
proton NMR spinlattice relaxation of water in biological systems: Hydrated
collagen and muscle. Journal of Magnetic Resonance, 31, 207229.
Gelman, N., Ewing, J. R., Gorell, J. M., Spickler, E. M., & Solomon, E. G. (2001).
Interregional variation of longitudinal relaxation rates in human brain at 3.0 T:
Relation to estimated iron and water contents. Magnetic Resonance in Medicine, 45,
7179.
294
Gelman, N., Gorell, J. M., Barker, P. B., Savage, R. M., Spickler, E. M., Windham, J. P.,
et al. (1999). MR imaging of human brain at 3.0 T: Preliminary report on transverse
relaxation rates and relation to estimated iron content. Radiology, 210, 759767.
Graham, S. J., & Henkelman, R. M. (1999). Pulsed magnetization transfer imaging:
Evaluation of technique. Radiology, 212, 903910.
Gringel, T., Schulz-Schaeffer, W., Elolf, E., Frolich, A., Dechent, P., & Helms, G. (2009).
Optimized high-resolution mapping of magnetization transfer (MT) at 3 Tesla for
direct visualization of substructures of the human thalamus in clinically feasible
measurement time. Journal of Magnetic Resonance Imaging, 29, 12851292.
Gupta, R. K., Rao, S. B., Jain, R., Pal, L., Kumar, R., Venkatesh, S. K., et al. (2001).
Differentiation of calcification from chronic hemorrhage with corrected gradient
echo phase imaging. Journal of Computer Assisted Tomography, 25, 698704.
Hallgren, B., & Sourander, P. (1958). The effect of age on the non-haemin iron in the
human brain. Journal of Neurochemistry, 3, 4151.
Helms, G., & Piringer, A. (2005). Simultaneous measurement of saturation and
relaxation in human brain by repetitive magnetisation transfer pulses. NMR in
Biomedicine, 18, 4450.
Huppi, P. S., Maier, S. E., Peled, S., Zientara, P. G., Barnes, P. D., Jolesz, F. A., et al.
(1998). Microstructural development of human newborn cerebral white matter
assessed in vivo by diffusion tensor magnetic resonance imaging. Pediatric
Research, 44, 584590.
Johansen-Berg, H., & Behrens, T. E. J. (Eds.). (2009). Diffusion MRI From
quantitative measurement to in-vivo neuroanatomy. London: Academic Press.
Kamman, R. L., Go, K. G., Brouwer, W., & Berendsen, H. J. C. (1988). Nuclear magnetic
relaxation in experimental brain edema: Effects of water concentration, protein
concentration, and temperature. Magnetic Resonance in Medicine, 6, 265274.
Koenig, S. H., & Brown, R. D.III, (1985). The importance of the motion of water for
magnetic resonance imaging. Investigative Radiology, 20, 297305.
Koenig, S. H., Brown, R. D., III, Spiller, M., & Lundbom, N. (1990). Relaxometry of
brain: Why white matter appears bright in MRI. Magnetic Resonance in Medicine,
14, 482495.
MacKay, A., Whittall, K., Adler, J., Li, D., Paty, D., & Graeb, D. (1994). In vivo
visualization of myelin water by magnetic resonance. Magnetic Resonance in
Medicine, 31, 673677.
Morris, C. M., Candy, J. M., Oakley, A. E., Bloxham, C. A., & Edwardson, J. A. (1992).
Histo-chemical distribution of non-haem iron in the human brain. Acta Anatomica,
144, 235257.
Mukherjee, P., Miller, J. H., Shimony, J. S., Conturo, T. E., Lee, B. C. P., Almli, C. R.,
et al. (2001). Normal brain maturation during childhood: Developmental
trends characterized with diffusion-tensor MR imaging. Radiology, 221,
349358.
Neeb, H., Zilles, K., & Shah, N. J. (2006). A new method for fast quantitative mapping of
absolute water content in vivo. NeuroImage, 31, 11561168.
Norris, D. G. (2001). The effects of microscopic tissue parameters on the diffusion
weighted magnetic resonance imaging experiment. NMR in Biomedicine, 14,
7793.
Reichenbach, J. R., Venkatesan, R., Schillinger, D. J., Kido, D. K., & Haacke, E. M.
(1997). Small vessels in the human brain: MR venography with deoxyhemoglobin
as an intrinsic contrast agent. Radiology, 204, 272277.
Sled, J., & Pike, G. B. (2001). Quantitative imaging of magnetization transfer properties
in vivo using MRI. Magnetic Resonance in Medicine, 46, 923931.
Stanisz, G. J., Kecojevic, A., Bronskill, M. J., & Henkelman, R. M. (1999).
Characterizing white matter with magnetization transfer and T2. Magnetic Resonance
in Medicine, 42, 11281136.
Tofts, P. (Ed.). (2003). Quantitative MRI of the brain. Chichester: Wiley.
Whittall, K., MacKay, A., Graeb, D., Nugent, R., Li, D., & Paty, D. (1997). In vivo
measurement of T2 distributions and water contents in normal human brain.
Magnetic Resonance in Medicine, 37, 3443.
Williams, D. S., Detre, J. A., Leigh, J. S., & Koretsky, A. P. (1992). Magnetic
resonance imaging of perfusion using spin inversion of arterial water.
Proceedings of the National Academy of Science of the United States of America, 89,
212216.
Yao, B., Li, T.-Q., van Gelderen, P., Shmueli, K., de Zwaart, J. A., & Duyn, J. H. (2009).
Susceptibility contrast in high field MRI of human brain as a function of tissue iron
content. NeuroImage, 44, 12591266.
Zhou, J., Lal, B., Wilson, D. A., Tryastman, R. J., & van Zijl, P. C. M. (2003). Using the
amide proton signals of intracellular proteins to detect pH effects in MRI. Nature
Medicine, 9, 10851090.
Introduction
Intensity nonuniformity is an image artifact commonly
observed on MRI scans that results in smooth gradations in
signal intensity across the image. Variously referred to as intensity nonuniformity, shading artifact, or bias field, these signal
variations degrade the numerical analysis of neuroimaging
data and in severe cases also interfere with the visual interpretation of images. The artifact arises from a number of scannerrelated sources and, due to the physical interaction between
magnetic fields and tissue, can never be fully eliminated from
the acquired MR signal. It is therefore an essential step in
almost any computational analysis of brain morphology to
first correct for intensity nonuniformity. As an illustration of
this process, Figure 1 shows a typical 3-D T1-weighted MRI
scan corrupted by intensity nonuniformity, an estimate of the
bias field, and the 3-D image after correction. Subtle levels bias,
on the order of 1030%, are typical for clinical images (Sled &
Pike, 1998a) and have little effect on visual assessment; however, at field strengths of 3 T and above (Boyes et al., 2008) or
in combination with multielement coils optimized for superficial sensitivity, the artifact is often plainly visible on the scan.
In this article, we review the causes of intensity nonuniformity, physical models for the artifact, and methods for
correcting the artifact in experimental data.
for B
1 and R that drop rapidly with distance from the coil
element. This leads to severe nonuniformity. However, even
volume coils such as birdcages that are designed for uniform
sensitivity when unloaded will show significant sensitivity variation when a human head is present. This patient-dependent
aspect of intensity nonuniformity defies simple calibrationtype corrections and has led to a significant research effort to
http://dx.doi.org/10.1016/B978-0-12-397025-1.00298-0
295
296
1.25
1.00
(a)
(b)
(c)
0.75
Figure 1 Example of intensity nonuniformity correction. (a) A transverse slice from a T1-weighted 3-D scan acquired at 3 T. (b) An estimate of the
nonuniformity field. (c) A corrected image obtained by dividing the original image by the field estimate.
[1]
297
298
prospective correction techniques based on additional measurements are available, most brain mapping studies rely on
retrospective correction. These retrospective techniques are
easily applied and provide practical benefits by reducing scan
variability and improving the sensitivity of morphological
analyses. However, these methods struggle with a low level of
residual variation that is likely indistinguishable from true
spatial variations in the properties of the tissue. Prospective
correction methods have the potential to remove this residual
variation, but the associated increase in scan time, a factor of
two in the case of ratio methods, has limited their uptake. With
continuing improvements in data acquisition techniques,
signal-to-noise ratio (SNR) has superseded gradient hardware
performance as the limiting factor in high-resolution anatomical scanning. In this regime, an 11% reduction to the three
voxel dimensions corresponds to a doubling of scan time to
maintain equivalent SNR. The future therefore may see a shift
from retrospective to prospective correction methods as more
investigators opt for the advantages of quantitative MRI
acquisition techniques.
References
Ahmed, M. N., Yamany, S. M., Mohamed, N., Farag, A. A., & Moriarty, T. (2002). A
modified fuzzy c-means algorithm for bias field estimation and segmentation of MRI
data. IEEE Transactions on Medical Imaging, 21, 193199. http://dx.doi.org/
10.1109/42.996338.
Alecci, M., Collins, C. M., Smith, M. B., & Jezzard, P. (2001). Radio frequency magnetic
field mapping of a 3 Tesla birdcage coil: Experimental and theoretical dependence
on sample properties. Magnetic Resonance in Medicine, 46, 379385. http://dx.doi.
org/10.1002/mrm.1201.
Arnold, J. B., Liow, J. S., Schaper, K. A., Stern, J. J., Sled, J. G., Shattuck, D. W., et al.
(2001). Qualitative and quantitative evaluation of six algorithms for correcting
intensity nonuniformity effects. NeuroImage, 13, 931943. http://dx.doi.org/
10.1006/nimg.2001.0756.
Ashburner, J., & Friston, K. J. (2005). Unified segmentation. NeuroImage, 26,
839851. http://dx.doi.org/10.1016/j.neuroimage.2005.02.018.
Belaroussi, B., Milles, J., Carme, S., Zhu, Y. M., & Benoit-Cattin, H. (2006). Intensity
non-uniformity correction in MRI: Existing methods and their validation. Medical
Image Analysis, 10, 234246. http://dx.doi.org/10.1016/j.media.2005.09.004.
Boyes, R. G., Gunter, J. L., Frost, C., Janke, J. L., Yeatman, T., Hill, D. L., et al. (2008).
Intensity non-uniformity correction using N3 on 3-T scanners with multichannel
phased array coils. NeuroImage, 39, 17521762. http://dx.doi.org/10.1016/j.
neuroimage.2007.10.026.
Chavez, S., & Stanisz, G. J. (2012). A novel method for simultaneous 3D B(1) and T(1)
mapping: The method of slopes (MoS). NMR in Biomedicine, 25, 10431055.
http://dx.doi.org/10.1002/nbm.2769.
Chen, Y., Zhang, J., & Yang, J. (2012). An anisotropic images segmentation and bias
correction method. Magnetic Resonance Imaging, 30, 8595. http://dx.doi.org/
10.1016/j.mri.2011.09.003.
Chua, Z. Y., Zheng, W., Chee, M. W., & Zagorodnov, V. (2009). Evaluation of
performance metrics for bias field correction in MR brain images. Journal of
Magnetic Resonance Imaging, 29, 12711279. http://dx.doi.org/10.1002/
jmri.21768.
Collins, D. L., Zijdenbos, A. P., Kollokian, V., Sled, J. G., Kabani, N. J., Holmes, C. J.,
et al. (1998). Design and construction of a realistic digital brain phantom. IEEE
Transactions on Medical Imaging, 17, 463468. http://dx.doi.org/10.1109/
42.712135.
Dawant, B. M., Zijdenbos, A. P., & Margolin, R. A. (1993). Correction of intensity
variations in MR images for computer-aided tissue classification. IEEE Transactions
on Medical Imaging, 12, 770781. http://dx.doi.org/10.1109/42.251128.
Glover, G. H., Hayes, C. E., Pelc, N. J., Edelstein, W. A., Mueller, O. M., Hart, H. R., et al.
(1985). Comparison of linear and circular polarization for magnetic resonance
imaging. Journal of Magnetic Resonance, 64, 255270. http://dx.doi.org/10.1016/
0022-2364(85)90349-X.
Goto, M., Abe, O., Miyati, T., Kabasawa, H., Takao, H., Hayashi, N., et al. (2012).
Influence of signal intensity non-uniformity on brain volumetry using an ATLASbased method. Korean Journal of Radiology, 13, 391402. http://dx.doi.org/
10.3348/kjr.2012.13.4.391.
Haselgrove, J., & Prammer, M. (1986). An algorithm for compensation of surface-coil
images for sensitivity of the surface coil. Magnetic Resonance Imaging, 4, 469472.
Ji, Q., Glass, J. O., & Reddick, W. E. (2007). A novel, fast entropy-minimization
algorithm for bias field correction in MR images. Magnetic Resonance Imaging, 25,
259264. http://dx.doi.org/10.1016/j.mri.2006.09.012.
Lee, S. K., & Vannier, M. W. (1996). Post-acquisition correction of MR
inhomogeneities. Magnetic Resonance in Medicine, 36, 275286.
Likar, B., Viergever, M. A., & Pernus, F. (2001). Retrospective correction of MR intensity
inhomogeneity by information minimization. IEEE Transactions on Medical Imaging,
20, 13981410. http://dx.doi.org/10.1109/42.974934.
Mangin, J. F. (2000). Entropy minimization for automatic correction of intensity
nonuniformity. In IEEE workshop on mathematical methods in biomedical image
analysis, proceedings (pp.162169).
Manjon, J. V., Lull, J. J., Carbonell-Caballero, J., Garcia-Marti, G., Marti-Bonmati, L., &
Robles, M. (2007). A nonparametric MRI inhomogeneity correction method.
Medical Image Analysis, 11, 336345. http://dx.doi.org/10.1016/j.
media.2007.03.001.
McVeigh, E. R., Bronskill, M. J., & Henkelman, R. M. (1986). Phase and sensitivity of
receiver coils in magnetic resonance imaging. Medical Physics, 13, 806.
http://dx.doi.org/10.1118/1.595967.
Meyer, C. R., Bland, P. H., & Pipe, J. (1995). Retrospective correction of intensity
inhomogeneities in MRI. IEEE Transactions on Medical Imaging, 14, 3641.
http://dx.doi.org/10.1109/42.370400.
Milchenko, M. V., Pianykh, O. S., & Tyler, J. M. (2006). The fast automatic algorithm for
correction of MR bias field. Journal of Magnetic Resonance Imaging, 24, 891900.
http://dx.doi.org/10.1002/jmri.20695.
Milles, J., Zhu, Y. M., Chen, N. K., Panych, L. P., Gimenez, G., & Guttmann, C. R.
(2006). Computation of transmitted and received B1 fields in magnetic resonance
imaging. IEEE Transactions on Biomedical Engineering, 53, 885895. http://dx.doi.
org/10.1109/TBME.2005.863955.
Moyher, S. E., Vigneron, D. B., & Nelson, S. J. (1995). Surface coil MR imaging of the
human brain with an analytic reception profile correction. Journal of Magnetic
Resonance Imaging, 5, 139144. http://dx.doi.org/10.1002/(ISSN)1522-2586.
Noterdaeme, O., Anderson, M., Gleeson, F., & Brady, S. M. (2009). Intensity correction
with a pair of spoiled gradient recalled echo images. Physics in Medicine and
Biology, 54, 34733489. http://dx.doi.org/10.1088/0031-9155/54/11/013.
Pruessmann, K. P., Weiger, M., Scheidegger, M. B., & Boesiger, P. (1999). SENSE:
Sensitivity encoding for fast MRI. Magnetic Resonance in Medicine, 42, 952962.
http://dx.doi.org/10.1002/(ISSN)1522-2594.
Sled, J. G., Levesque, I., Santos, A. C., Francis, S. J., Narayanan, S., Brass, S. D., et al.
(2004). Regional variations in normal brain shown by quantitative magnetization
transfer imaging. Magnetic Resonance in Medicine, 51, 299303. http://dx.doi.org/
10.1002/mrm.10701.
Sled, J. G., & Pike, G. B. (1998a). Understanding intensity non-uniformity in MRI.
Medical Image Computing and Computer-Assisted Intervention, 1496, 614622.
Sled, J. G., & Pike, G. B. (1998b). Standing-wave and RF penetration artifacts caused by
elliptic geometry: An electrodynamic analysis of MRI. IEEE Transactions on Medical
Imaging, 17, 653662. http://dx.doi.org/10.1109/42.730409.
Sled, J. G., Zijdenbos, A. P., & Evans, A. C. (1998). A nonparametric method for
automatic correction of intensity nonuniformity in MRI data. IEEE Transactions on
Medical Imaging, 17, 8797. http://dx.doi.org/10.1109/42.668698.
Styner, M., Brechbuhler, C., Szekely, G., & Gerig, G. (2000). Parametric estimate of
intensity inhomogeneities applied to MRI. IEEE Transactions on Medical Imaging,
19, 153165. http://dx.doi.org/10.1109/42.845174.
299
Wang, J., Qiu, M., Yang, Q. X., Smith, M. B., & Constable, R. T. (2005). Measurement
and correction of transmitter and receiver induced nonuniformities in vivo. Magnetic
Resonance in Medicine, 53, 408417. http://dx.doi.org/10.1002/mrm.20354.
Wells, W. M., Grimson, W. L., Kikinis, R., & Jolesz, F. A. (1996). Adaptive segmentation
of MRI data. IEEE Transactions on Medical Imaging, 15, 429442. http://dx.doi.org/
10.1109/42.511747.
Wels, M., Zheng, Y., Huber, M., Hornegger, J., & Comaniciu, D. (2011). A
discriminative model-constrained EM approach to 3D MRI brain tissue
classification and intensity non-uniformity correction. Physics in Medicine and
Biology, 56, 32693300. http://dx.doi.org/10.1088/0031-9155/56/11/007.
Yarnykh, V. L. (2007). Actual flip-angle imaging in the pulsed steady state: A method
for rapid three-dimensional mapping of the transmitted radiofrequency field.
Magnetic Resonance in Medicine, 57, 192200. http://dx.doi.org/10.1002/
mrm.21120.
Zhang, Y., Brady, M., & Smith, S. (2001). Segmentation of brain MR images through a
hidden Markov random field model and the expectation-maximization algorithm.
IEEE Transactions on Medical Imaging, 20, 4557. http://dx.doi.org/10.1109/
42.906424.
Zheng, W., Chee, M. W., & Zagorodnov, V. (2009). Improvement of brain segmentation
accuracy by optimizing non-uniformity correction using N3. NeuroImage, 48,
7383. http://dx.doi.org/10.1016/j.neuroimage.2009.06.039.
Rigid-Body Registration
J Tohka, Tampere University of Technology, Tampere, Finland
2015 Elsevier Inc. All rights reserved.
Glossary
Introduction
Image registration aims to geometrically align one image with
another and is a prerequisite for all brain imaging applications
that compare images across subjects, across imaging modalities, or across time (Toga & Thompson, 2001). After the image
registration, the voxels in the two registered images are
assumed to have the same meaning so that the comparison
of the voxel value in one image with the value of the corresponding voxel (with the same coordinates) in the other image
makes sense. In addition to images, registration can analogously be applied to surfaces, contours, or point sets extracted
from the image.
The key issue in the image registration is to find the best
geometric transformation to bring the images into alignment,
that is, to determine a mapping from each voxel position in
one image (called source or floating image) to a corresponding
position in the other image (called target or reference image).
The application of this transformation to actually bring the
images into alignment is an easier process albeit there are
important aspects to consider too such as the choice of the
interpolation method. As Crum et al. (2004), we divide an
image registration method to three components.
First, it is necessary to restrict the set of possible geometric
transformations to find a useful transformation between the
two images that ameliorates irrelevant differences but preserves the important ones. The focus of this article is on
rigid-body and related affine transformations that are the
simplest class of the transformations with the fewest number
of parameters (from 6 to 12). Particularly, a rigid-body transformation is composed of rotations and translations. It does
not alter the shapes or sizes of the objects present in the
image and is therefore used to model different head positions
of the same subject. Thus, rigid-body registrations are used for
within-subject registrations required for the motion correction in functional magnetic resonance imaging (fMRI),
http://dx.doi.org/10.1016/B978-0-12-397025-1.00299-2
301
302
Figure 1 Examples of rigid-body transformations. Clockwise from top left: Original MR image slice, translated image slice with dx,dy 20 voxels,
rotated image with qz 0.2618 radians (15 ), sheared image with kxy 0.3, scaled image with lx,ly 1.3, and rigid-body transformation combining the
aforementioned translation and rotation.
cos
0
cos
qy
x
x 3
y
2
cos qz sin qz 0
4 sin qz cos qz 0 5
0
0
1
2
3
2
3
1 kxy kxz
lx 0 0
L 4 0 ly 0 5, K 4 0 1 kyz 5
0 0 lz
0 0 1
A general affine transformation from a to b is represented as
b Va d, where V is a 3 3 (invertible) matrix and d is a
translation vector. This transformation has 12 parameters. In
addition, affine transform ations with 9 parameters (excluding
shears) and 7 parameters (excluding shears and assuming uniform scalings) can be considered. An affine transformation is
V
d
often represented by 44 matrix T
. This allows
000 1
writing an affine transformation of a vector as a single matrix
multiplication T[ax,ay,az,1]T.
An inverse mapping approach is generally used for applying
an affine transformation to an image. In the inverse mapping,
one takes a voxel of the target image, say, at the coordinates b
[bx,by,bz]T; tracks the corresponding voxel coordinates in the
source image, say a; and chooses the intensity value in the
target image R[b] according to the intensity value S[a] at a in
the source image. Point a is not usually located at the voxel
center, and therefore, an interpolation method has to be used
to find R[b]. There are a variety of interpolation techniques
available, and these have a large practical relevance to the
success of image registration.
Geometric Approaches
The geometric approaches try to match points, contours, or
surfaces, that is, geometric features, found in the images. The
geometric features should have an anatomical interpretation to
be useful for the brain image registration. The easiest case is
when n (noncoplanar) landmarks, each carrying specific anatomical meaning, have been identified in both images. Denote
these landmark sets, extracted from the two images being
registered, as {ai :i 1,. . .,n} and {bi :i 1,. . .,n}. Then, a cost
function for the registration can be written as
CL T 1=n
n
X
jjT ai bi jj2
i1
Intensity-Based Approaches
The intensity-based approaches try to match the intensity patterns over a predefined image region or the entire image
303
X
a2O
T Sa Ra2
p
P
P
CNC T a2O T SaRa p
2
2
a2O
T Sa
a2O
Ra
may provide a more robust alternative for the motion correction within fMRI (Jenkinson, Bannister, Brady, & Smith,
2002).
The most widely used similarity measures for betweenmodality image registration are based on informationtheoretic concepts of mutual information and joint entropy
(Maes, Collignon, Vandermeulen, Marchal, & Suetens, 1997;
Pluim, Maintz, & Viergever, 2003; Wells et al., 1996). The
mutual information of two random variables is a measure of
their mutual dependence that is usually derived via the concept
of entropy. Maximizing the mutual information between the
images leads to an attractive alternative to SSD or correlationbased cost functions, because the assumption is that the images
to be registered show dependent information. This is a more
relaxed assumption than that the images would show the same
(CSSD) or correlated information (CNC). The mutual information is computed based on the joint probability density of
intensity values of images S and R, denoted as PS,R(i,j) and
the related marginal probability densities PS(i) and PR(j),
where i and j run over all possible voxel intensities. In practice,
these probability densities must be approximated by histograms. The joint entropy of the images S and R is then H(S,
P
R) i,jPS,R(i, j)log[PS,R(i, j)] and the marginal entropies as
P
P
H(S) iPS(i)log[PS(i)] and H(R) jPR(j)log[PR(j)].
Now, the negative of mutual information between the
images is
CMI T HS, T R HS HT R
Figure 2 demonstrates the intermodality registration using
CMI as the cost function.
For this and related widely used cost functions, such as
normalized mutual information, (Studholme, Hill, & Hawkes,
1999), it is fundamentally important how the probability densities are estimated and which interpolation method is chosen
(Maes, Vandermeulen, & Suetens, 1999; Tsao, 2003).
Alternative cost functions for between-modality registration
include partitioned image uniformity and ration image uniformity (Woods, Mazziotta, & Cherry, 1993), correlation ratio
(Roche, Malandain, Pennec, & Ayache, 1998), and various
application-specific cost functions, for example, Saad et al.
304
Mutual information
0.2
0.4
0.5
0.6
0.7
20
10
0
Rotation (degrees)
10
20
Final
0.02
0.02
0.015
0.015
Probability
Probability
Initial
0.3
0.01
0.005
0
PET intensity
0.01
0.005
0
MR intensity
PET intensity
MR intensity
Figure 2 MR-PET registration based on minimization of the mutual information cost function CMI. Initially, the fluorodeoxyglucose-PET (FDG-PET)
image is displaced by a rotation around z-axis of 20 . The initial joint histogram of the MR and PET images is shown in the bottom left. After the
minimization of the negative mutual information (CMI; shown here as a function of a single rotation parameter), the PET image is well aligned with the
MR image. The final joint histogram is shown in the bottom right, and it is more sharply peaked than the initial histogram indicating the
improvement in the alignment of the two images. The PET image here is Monte Carlo-simulated based on the MR image (Reilhac et al., 2005), and
therefore, the correct transformation between the images is known.
The cost functions of previous subsection have to be minimized by a numerical algorithm. The choice of the minimization algorithm is important because it can have a substantial
effect on the accuracy of the transformation found by the
algorithm. It is important here to make a difference between
local and global minima. A local minimum of a cost function is
a transformation that has a cost that is lower than the cost of
nearby transformations, and a global minimum is the transformation that has the lowest cost possible. Minimization
algorithms applied in brain image registration are usually
general-purpose numerical optimization algorithms such as
Powells, simplex, or Newtons method. These search for any
local minimum of the cost function, which makes them sensitive to initial conditions of the algorithm. The adverse effects of
this can be greatly reduced by using multiresolution techniques
(Collins, Neelin, Peters, & Evans, 1994; Maes et al., 1999) and
a good interpolation method; the latter is especially important
for the optimization information-theoretic cost functions such
as CMI (Tsao, 2003). Only few works have explicitly adopted
a global optimization approach (Jenkinson et al., 2002;
There is a plethora of freely available software implementations for rigid-body and affine registration of brain images.
Major software packages, such as SPM, FSL, and FreeSurfer,
all implement methods for affine registrations. Widely used
registration-specific software include AIR (Woods et al., 1993,
for the original version of the software) and MNI AutoReg
(Collins et al., 1994). Typically, the methods implemented in
the software tools follow the main lines presented in this
article, but implementation details of these tools differ considerably, and they each can require different preprocessing and
probably provide different results for an individual registration
task, even if using exactly the same cost function to drive the
registration process.
The retrospective evaluations of the affine brain image registration are rare but not nonexistent. West et al. (1997, 1999)
reached the conclusion that the intensity-based based methods
have the upper hand of the surface-based ones. Holden et al.
(2000) concluded that the use of mutual information based cost
functions has advantages over other cost functions when quantifying longitudinal anatomical change. Oakes et al. (2005)
References
Besl, P. J., & McKay, Neil D. (1992). A method for registration of 3-D shapes. IEEE
Transactions on Pattern Analysis and Machine Intelligence, 14(2), 239256.
Collins, D., Neelin, P., Peters, T., & Evans, A. (1994). Automatic 3D intersubject
registration of MR volumetric data in standardized Talairach space. Journal of
Computer Assisted Tomography, 18, 192205.
Crum, W. R., Hartkens, T., & Hill, D. L. (2004). Non-rigid image registration: Theory
and practice. British Institute of Radiology, 77(2), S140153.
Eggert, D. W., Lorusso, A., & Fisher, R. B. (1997). Estimating 3-D rigid body
transformations: A comparison of four major algorithms. Machine Vision and
Applications, 9, 272290.
Evans, A. C., Marrett, S., Torrescorzo, J., Ku, S., & Collins, D. L. (1991). MRI-PET
correlation in three dimensions using a volume-of-interest (VOI) atlas. Journal of
Cerebral Blood Flow and Metabolism, 11, A69A78.
Fitzpatrick, M., Hill, D. L. G., & Maurer, C. R. (2000). Image registration. In M. Sonka &
J. M. Fitzpatrick (Eds.), Medical image processing. Handbook of medical imaging
(vol. 2. Bellingham, WA: SPIE Press.
Freire, L., & Mangin, J.-F. (2001). Motion correction algorithms may create spurious
brain activations in the absence of subject motion. NeuroImage, 14, 709722.
Green, B. F. (1952). The orthogonal approximation of an oblique structure in factor
analysis. Psychometrika, 17, 429440.
Greve, D. N., & Fischl, B. (2009). Accurate and robust brain image alignment using
boundary-based registration. NeuroImage, 48, 6372.
Hill, D. L. G., Batchelor, P. G., Holden, M., & Hawkes, D. J. (2001). Medical image
registration. Physics in Medicine and Biology, 46, R1R45.
Holden, M., Hill, D. L., Denton, E. R., Jarosz, J. M., Cox, T. C., Rohlfing, T., et al.
(2000). Voxel similarity measures for 3-D serial MR brain image registration. IEEE
Transactions on Medical Imaging, 19, 94102.
Jenkinson, M., Bannister, P., Brady, M., & Smith, S. (2002). Improved optimization for
the robust and accurate linear registration and motion correction of brain images.
NeuroImage, 17, 825841.
Jenkinson, M., & Smith, S. (2001). A global optimisation method for robust affine
registration of brain images. Medical Image Analysis, 5, 143156.
305
Maes, F., Collignon, A., Vandermeulen, D., Marchal, G., & Suetens, P. (1997).
Multimodality image registration by maximization of mutual information. IEEE
Transactions on Medical Imaging, 16, 187198.
Maes, F., Vandermeulen, D., & Suetens, P. (1999). Comparative evaluation
of multiresolution optimization strategies for multimodality image
registration by maximization of mutual information. Medical Image Analysis, 3,
373386.
Oakes, T. R., Johnstone, T., Ores Walsh, K. S., Greischar, L. L., Alexander, A. L.,
Fox, A. S., et al. (2005). Comparison of fMRI motion correction software tools.
NeuroImage, 28, 529543.
Pelizzari, C. A., Chen, G. T. Y., Spelbring, D. R., Weichselbaum, R. R., &
Chen, C.-T. (1989). Accurate three-dimensional registration of CT, PET,
and/or MR images of the brain. Journal of Computer Assisted Tomography, 13,
2026.
Pluim, J. P.W, Maintz, J. B.A, & Viergever, M. A. (2003). Mutual-information-based
registration of medical images: A survey. IEEE Transactions on Medical Imaging,
22, 9861004.
Reilhac, A., Batan, G., Michel, C., Grova, C., Tohka, J., Collins, D. L., et al. (2005). PETSORTEO: Validation and development of database of simulated PET volumes. IEEE
Transactions on Nuclear Science, 52, 13211328.
Reuter, M., Rosas, H. D., & Fischl, B. (2010). Highly accurate inverse consistent
registration: A robust approach. NeuroImage, 53, 11811196.
Roche, A., Malandain, G., Pennec, X., & Ayache, N. (1998). The correlation ratio as a
new similarity measure for multimodal image registration. In Medical image
computing and computer-assisted intervention MICCAI98 (pp. 11151124).
Berlin Heidelberg: Springer.
Saad, Z. S., Glen, D. R., Chen, G., Beauchamp, M. S., Desai, R., & Cox, R. W. (2009). A
new method for improving functional-to-structural MRI alignment using local
Pearson correlation. NeuroImage, 44, 839848.
Studholme, C., Hill, D. L. G., & Hawkes, D. J. (1999). An overlap invariant entropy
measure of 3D medical image alignment. Pattern Recognition, 32, 7186.
Toga, A. W., & Thompson, P. M. (2001). The role of image registration in brain
mapping. Image and Vision Computing, 19, 324.
Tsao, J. (2003). Interpolation artifacts in multimodality image registration based on
maximization of mutual information. IEEE Transactions on Medical Imaging, 22,
854864.
Wells, W. M., III, Viola, P., Atsumi, H., Nakajima, S., & Kikinis, R. (1996). Multi-modal
volume registration by maximization of mutual information. Medical Image Analysis,
1, 3551.
West, J., Fitzpatrick, J. M., Wang, M. Y., Dawant, B. M., Maurer, C. R., Jr.,
Kessler, R. M., et al. (1999). Retrospective intermodality registration techniques for
images of the head: Surface-based versus volume-based. IEEE Transactions on
Medical Imaging, 18, 144150.
West, J., Fitzpatrick, J. M., Wang, M. Y., Dawant, B. M., Maurer, C. R., Jr.,
Kessler, R. M., et al. (1997). Comparison and evaluation of retrospective
intermodality brain image registration techniques. Journal of Computer Assisted
Tomography, 21, 554566.
Woods, R. P., Mazziotta, J. C., & Cherry, S. R. (1993). MRI-PET registration
with automated algorithm. Journal of Computer Assisted Tomography, 17,
536546.
Introduction
Image registration, aka warping, fusion, or coregistration, is one
of the key technologies in imaging and an exciting task particularly in medical imaging. As such, it has attracted enormous
attention (see Brown, 1992; Haber, & Modersitzki, 2008; Fischer
& Modersitzki, 2008; Fitzpatrick, Hill, & Maurer, 2000; Glasbey,
1998; Goshtasby, 2005, 2012; Hajnal, Hawkes, & Hill, 2001;
Hill, Batchelor, Holden, & Hawkes, 2001; Holden, 2008; Lester
& Arridge, 1999; Maintz & Viergever, 1998; Modersitzki, 2004,
2009; Scherzer, 2006; Szeliski, 2006; Toga & Mazziotta, 2002;
van den Elsen, Pol, & Viergever, 1993; Yoo, 2004; Zitova &
Flusser, 2003, and references therein). Roughly speaking, the
goal of image registration is to automatically establish correspondences between different images displaying views of objects
or organs. These images may be acquired at different times, from
different devices or perspectives, or reveal even different types of
information. Many applications require nonlinear (i.e., not necessarily linear) alignment strategies and hence nonlinear registration enters into play.
There is a large number of application areas demanding for
image registration, and image registration has impact on basically every imaging technique (see also Modersitzki, 2009).
Specific examples include motion correction (Weickert &
Schnorr, 2001; see also Figure 1), data fusion (Maes,
Collignon, Vandermeulen, Marchal, & Suetens, 1997; see also
Figure 2), spatial normalization of data (Friston et al., 1995),
stitching (Szeliski, 2006) (generating a global picture from
partial views), template matching and identification (Altman
& Bland, 1983) (comparing current images with a data base),
tracking (Acton & Ray, 2006), and optical flow (Horn &
Schunck, 1981). Moreover, particular imaging modalities
such as diffusion tensor imaging rely on image registration
(Stejskal & Tanner, 1965). Therefore, image registration is an
important tool for computational anatomy, computer-aided
diagnosis, fusion of different modalities, intervention and
treatment planning, monitoring of diseases, motion correction, radiation therapy, or treatment verification, to name a
few (see also Alvarez, Weickert, & Sanchez, 1999; Ashburner &
Friston, 1999, 2003); Barron, Fleet, & Beauchemin, 1994;
Christensen, Rabbitt, & Miller, 1996; Craene, Camara, Bijnens,
& Frangi, 2009; Horn & Schunck, 1981; Peshko et al., 2014 and
particularly Modersitzki, 2009 for more examples).
Unfortunately, no unified treatment or general theory for
image registration has yet been established. It appears that each
application area has developed its own approaches and implementations. Depending on the application, the focus can be on
computing time (real-time applications like tracking), image
features, memory requirements (high-resolution histological
or 3-D images), accuracy of results, or others.
This article does not aim for a comprehensive overview on
image registration. The idea here is to provide a framework that
Data Model
The structure of acquired medical data is typically an array of
intensity values associated with a discrete pixel structure, which
makes geometric transformation of images nontrivial. In general, it is not possible to exactly represent transformed versions
of an image on the original pixel structure. Figure 4 illustrates
this difficulty for the example of a 4-by-4 image. The first image
shows the original and the second one a rotated copy. The
problem is that the pixel structure (visualized by the red grid)
is intrinsically present. Already a simple rotation (second
image) changes the image structure, which results in a massive
complication for a comparison of objects (see also section
Distance Measures and the third image). A remedy is to
project the rotated image to the original pixel structure (fourth
image). Note that intensity values have to be invented (e.g.,
top-left pixel), and at the same time, intensity information has
been lost (e.g., top-left corner of the object). Moreover, intensity information that is associated with one pixel (e.g., top-left
white pixel in the original image) has been distributed over
several pixels in the projected image (see also partial volume
effects) and careful considerations are required in order to
resolve these issues. A standard approach is offered by interpolation techniques (Aldroubi & Grochening, 2001; Boor, 1978;
Camion & Younes, 2001; Duchon, 1976; Lehmann, Gonner, &
Spitzer, 1999; Light, 1996; Thevenaz, Blu, & Unser, 2000;
Wahba, 1990). Here, the idea is to generate a continuous
function I that can then be assessed at arbitrary points x:
http://dx.doi.org/10.1016/B978-0-12-397025-1.00300-6
307
308
Figure 1 High-speed echo-planar images with blip-up (left) and blip-down (right) gradients displaying the same tissue with severe distortions due to
inhomogeneous gradient fields: obvious spatial distortions along gradient directions and intensity distortion due to perturbed tissue density. Image
restoration in terms of both spatial position and intensity can be achieved via registration (see also Mohammadi, Nagy, Hutton, Josephs, & Weiskopf,
2011 and Ruthotto et al., 2012).
T1
CT
DBS electrode
CT
T2
T1
DBS electrode
Figure 2 Multimodal image fusion (right) of preoperative T1-weighted (left) and T2-weighted MRI and postoperative CT (middle) after surgical
implantation of an electrode for deep brain stimulation (DBS). DBS has become a well-established therapy for Parkinsons disease, dystonia, and
essential tremor. Accurate intrapatient registration of pre- and postoperative MRI and CT data for surgical planning and therapy control is needed.
High-quality imaging and registration are important for optimal therapy since the target region is small in the range of 23 mm. In addition to intrapatient
registration, registration across patients and to an atlas is used for optimal tuning of stimulation fields based on statistical information in order to
reduce side effects such as speech problems (cf. DHaese et al., 2012; Guo, Parrent, & Peters, 2007; Martens et al., 2011) (see also the IMPACT project,
http://www.impact-fp7.eu, supported by the EU, grant no. 305814 in HEALTH.2012.1.2-1).
Ix interpolatedata, parameters, x
[1]
[2]
Distance Measures
Image similarity or, equivalently, distances provide a way of
emulating the eye of a trained expert. Another important
309
Figure 3 Multiscale representations of an MRI slice: from original and fine-scale (left) to very smooth and coarse-scale (right).
modeling aspect besides run-time and stability is the identification of important features from data. Volumetric image distances are most intuitive and can be formulated in terms of
energies. A simple example is the energy of the difference image
T(y) R:
Regularization
Image registration is an ill-posed problem in the sense of Hadamard (Hadamard, 1902; Modersitzki, 2009). This implies that
the information provided (one intensity value) is insufficient to
determine a solution (a displacement vector). Roughly speaking,
310
Figure 4 Rotated 4-by-4 pixel image, from left to right: original image, rotated image, rotated image with pixel grid, rotated image on pixel grid.
all points sharing the same intensity can be repositioned arbitrarily without changing the image distance. Figure 4 also illustrates a trivial example. Looking only in the one-parametric class
of rotations around the image center, four equivalent solutions
can be found (rotations about 0 , 90 , 180 , and 270 ). Without
further information, it is impossible to determine a particular
solution. In a nonlinear setting, the situation gets considerably
worse, as points with the same intensity can be shuffled around
arbitrarily. However, the problem is deeper and even the existence of solutions is nontrivial.
Regularization is a conceptual way to bypass these difficulties and to remove ambiguity. Tikhonov proposed a general
idea (Tikhonov, 1943) to add an additional term S to the illposed problem and to minimize a modified objective function
J(y),
Jy DT y, R aSy,
[5]
[6]
Sy l mjjryjj2Fro mjdiv yj2 dx
The basic idea in using this linear elasticity model is to decompose the transformation and to penalize rotation and expansion
and contraction by scalars l and m; (see, e.g., Modersitzki, 2004,
2009 for details). This linear elastic model has been a generator
and inspiration for a variety of approaches (Christensen, 1994;
Davatzikos, 1997; Fischer & Modersitzki, 2002a; Freeborough,
1998; Gee & Bajcsy, 1999; Kybic & Unser, 2000; Rueckert et al.,
1999). Note that the same remarks concerning weights as for the
distance measure apply (e.g., spatially dependent l and m (Kabus,
Franz, & Fischer, 2006)).
Particularly in a constrained setting, higher-order regularization is an issue (Burger et al., 2013; Fischer & Modersitzki,
2002a, 2003b, 2004c; Henn, 2006a; Yanovsky, Guyader, Toga,
311
Conclusions
Jy DT y, R aSy bPy
(7)
Here, P can be an indicator function for plausible transformations (hard-constrained, e.g., rigidity: P 0 if y is rigid; P 1
otherwise) or a penalty for unwanted solutions (softconstrained). In the latter case, the penaltyR is typically
formulated in terms of an integral, that is, P(y) p(y)dx (e.g.,
volume changes: p log(det ry)2). Note that in the softconstrained setting, the constraint is in general not satisfied, for
example, P
6 0. Due to the averaging nature of the integral, this is
an issue if the target region is relatively small (measurement of
tumor growth (Haber & Modersitzki, 2004)). Soft constraints
can be advantageous if the information is fuzzy.
Regularization has to be added carefully to ensure the existence of solutions (e.g., for the volume change, hyperelasticity
has to be used as a regularizer to ensure the existence of a
transformation, such that ry exists and det ry is measurable
(Burger et al., 2013)), whereas constraints can be formulated
much more generally.
Though theoretically quite similar, the computational differences between hard and soft constraints are tremendous. Soft
constraints require an additional parameter b, which is not always
easy to be determined and has a negative impact on the condition
of the optimization problem and may lead to numerical instability. Another computational difference relates to the type of constraints: equality (p 0) or inequality (p 0). Constraints can be
formulated globally or locally. For example, volume preservation
can be formulated on the whole image domain or just a subset
such as bones. Depending on the constraints, a Lagrangian framework keeping the spatial setting fixed during transformation can
be computationally advantageous to the more common Eulerian
framework (see also Avants, Schoenemann, & Gee, 2006).
Important constraints in medical imaging include the correspondence of anatomical landmarks (Bookstein, 1989;
Bookstein & Green, 1992; Fischer & Modersitzki, 2003a,2003b,
2004a; Haber et al., 2009b; Hellier & Barillot, 2003; Johnson &
P
Christensen, 2002) (P y l jjy r l t l jj, where t l and r l are
landmarks in reference image and template image, respectively;
possible user interaction via landmark positioning, possible
automatic landmark detection, and good starting guess),
local rigidity of structures Aix bi y(x) 0 for x in Si; superior
results for images containing bones) (Haber, Heldmann, &
Modersitzki, 2009; Keeling & Ring, 2005; Little, Hill, & Hawkes,
1997; Loeckx, Maes, Vandermeulen, & Suetens, 2004; Modersitzki, 2008; Ruthotto, Hodneland, & Modersitzki, 2012; Staring,
Klein, & Pluim, 2006, 2007), and volume change-based constraints (p det ry 1 0 for x 2 S; monitoring tumor growth
and enforcing diffeomorphisms) (Fischer & Modersitzki, 2004a;
Haber, Horesh, & Modersitzki, 2010; Haber & Modersitzki,
2004, 2005, 2006a; Leow et al., 2007; Poschl et al., 2010;
Rohlfing, Maurer, Bluemke, & Jacobs, 2003; Zhu, Haker, & Tannenbaum, 2003).
References
Acton, S. T., & Ray, N. (2006). Biomedical image analysis: Tracking. San Rafael, CA:
Claypool Publisher.
Aldroubi, A., & Grochening, K. (2001). Nonuniform sampling and reconstruction in
shift-invariant spaces. SIAM Review, 43(3), 585620.
Altman, D., & Bland, J. (1983). Measurement in medicine: The analysis of method
comparison studies. The Statistician, 32, 307317.
Alvarez, L., Weickert, J., & Sanchez, J. (1999). A scale-space approach to nonlocal
optical flow calculations. Scale-space theories in computer vision. Berlin: Springer,
235246.
Amit, Y. (1994). A nonlinear variational problem for image matching. SIAM Journal on
Scientific Computing, 15(1), 207224.
Arndt, S., Rajarethinam, R., Cizadlo, T., OLeary, D., Downhill, J., & Andreasen, N. C.
(1996). Landmark-based registration and measurement of magnetic resonance
images: A reliability study. Neuroimaging, 67, 145154.
Arsigny, V., Pennec, X., & Ayache, N. (2003). A novel family of geometrical
transformations: Polyrigid transformations. Application to the registration of
histological slices, Research report 4837, INRIA. http://www.inria.fr/rrrt/rr-4837.
html.
Arsigny, V., Pennec, X., & Ayache, N. (2005). Polyrigid and polyaffine transformations:
A novel geometrical tool to deal with non-rigid deformations Application to the
registration of histological slices. Medical Image Analysis, 9(6), 507523. http://
authors.elsevier.com/sd/article/S1361841505000289, PMID: 15948656.
Ashburner, J. (2007). A fast diffeomorphic image registration algorithm. NeuroImage,
38(1), 95113.
Ashburner, J., & Friston, K. J. (1999). Nonlinear spatial normalization using basis
functions. Human Brain Mapping, 7, 254266.
Ashburner, J., & Friston, K. (2003). Spatial normalization using basis functions. In R.
Frackowiak, K. Friston, C. Frith, R. Dolan, K. Friston, C. Price, S. Zeki, J. Ashburner
& W. Penny (Eds.), Human brain function (2nd ed.). Waltham, MA: Academic Press.
Ashburner, J., & Friston, K. J. (2011). Diffeomorphic registration using geodesic
shooting and gaussnewton optimisation. NeuroImage, 55(3), 954967.
Audette, M. A., Ferrie, F. P., & Peters, T. M. (2000). An algorithmic overview of surface
registration techniques for medical imaging. Medical Image Analysis, 4(3),
201217.
Auzias, G., Colliot, O., Glauns, J. A., et al. (2011). Diffeomorphic brain registration
under exhaustive sulcal constraints. IEEE Transactions on Medical Imaging, 30(6),
12141227.
Avants, B. B., Epstein, C. L., Grossman, M., & Gee, J. C. (2008). Symmetric
diffeomorphic image registration with cross-correlation: Evaluating automated
labeling of elderly and neurodegenerative brain. Medical Image Analysis, 12(1),
2641.
Avants, B. B., Schoenemann, P. T., & Gee, J. C. (2006). Lagrangian frame diffeomorphic
image registration: Morphometric comparison of human and chimpanzee cortex.
Medical Image Analysis, 10(3), 397412.
Bajcsy, R., & Kovacic, S. (1989). Multiresolution elastic matching. Computer Vision,
Graphics, and Image Processing, 46(1), 121.
Banerjee, P. K., & Toga, A. W. (1994). Image alignment by integrated rotational
translational transformation matrix. Physics in Medicine and Biology, 39,
19691988.
Barequet, G., & Sharir, M. (1997). Partial surface and volume matching in three
dimensions. IEEE on Pattern Analysis and Machine Intelligence, 19, 929948.
Barron, J. L., Fleet, D. J., & Beauchemin, S. S. (1994). Performance of optical flow
techniques. International Journal of Computer Vision, 12(1), 4377.
Beg, M. F., Miller, M. I., Trouve, A., & Younes, L. (2005). Computing large deformation
metric mappings via geodesic flows of diffeomorphisms. International Journal of
Computer Vision, 61(2), 139157.
Besl, P. J., & McKay, N. D. (1992). A method for registration of 3-d shapes. IEEE
Transactions on Pattern Analysis and Machine Intelligence, 14(2), 239256.
312
Beuthien B., Kamen A., & Fischer B. (2010). Recursive greens function registration. In:
International conference on medical image computing and computer-assisted
intervention, pp. 546553.
Boes, J. L., & Meyer, C. R. (1999). Multivariate mutual information for registration. In C.
Taylor & A. Colchester (Eds.), Medical image computing and computer assisted
intervention (pp. 606612). Heidelberg: Springer-Verlag.
Boesecke, R., Bruckner, T., & Ende, G. (1990). Landmark based correlation of medical
images. Physics in Medicine and Biology, 35(1), 121126.
Bookstein, F. L. (1984). A statistical method for biological shape comparisons. Journal
of Theoretical Biology, 107, 475520.
Bookstein, F. L. (1989). Principal warps: Thin-plate splines and the decomposition
of deformations. IEEE on Pattern Analysis and Machine Intelligence, 11(6),
567585.
Bookstein, F. L., & Green, D. K. (1992). Edge information at landmarks in medical
images. Visualization in Biomedical Computing, 1808, 242258.
Boor, C. D. (1978). A practical guide to splines. New York: Springer.
Broit, C. (1981). Optimal registration of deformed images, PhD thesis, Computer and
information science, University of Pennsylvania, USA.
Brown, L. G. (1992). A survey of image registration techniques. ACM Computing
Surveys, 24(4), 325376.
Burger, M., Modersitzki, J., & Ruthotto, L. (2013). A hyperelastic regularization energy
for image registration. SIAM Journal on Scientific Computing, 35(1), B132B148.
Cahill, N. D., Noble, J. A., & Hawkes, D. J. (2009). Demons algorithms for fluid and curvature
registration. In: International symposium on biomedical imaging, pp. 730733.
Camion, V., & Younes, L. (2001). Geodesic interpolating splines. In M. Figueiredo, J.
Zerubia & A. K. Jain (Eds.), Proceedings of EMMCVPR 01. LNCS (Vol. 2134,
pp. 513527). Berlin Heidelberg: Springer.
Candes, E. J., Romberg, J. K., & Tao, T. (2006). Stable signal recovery from incomplete
and inaccurate measurements. Communications on Pure and Applied Mathematics,
59(8), 12071223.
Cao Y., Miller M. I., Mori S., Winslow R. L., & Younes L. (2006). Diffeomorphic
matching of diffusion tensor images. In: Computer vision and pattern recognition
workshop, p. 67.
Chef dHotel C., Hermosillo G., & Faugeras O. D. (2002). Flows of diffeomorphisms for
multi-modal image registration. ISBI, IEEE, pp. 753756.
Christensen, G. E. (1994). Deformable shape models for anatomy, PhD thesis, Sever
Institute of Technology, Washington University, USA.
Christensen, G. E. (1999). Consistent linear-elastic transformations for image matching.
Information processing in medical imaging. LCNS (Vol. 1613, pp. 224237).
Heidelberg: Springer-Verlag.
Christensen, G. E., & Johnson, H. J. (2001). Consistent image registration. IEEE
Transactions on Medical Imaging, 20(7), 568582.
Christensen, G. E., Joshi, S. C., & Miller, M. I. (1997). Volumetric transformation of
brain anatomy. IEEE Transactions on Medical Imaging, 16(6), 864877.
Christensen, G. E., Rabbitt, R. D., & Miller, M. I. (1996). Deformable templates using
large deformation kinematics. IEEE Transactions on Image Processing, 5(10),
14351447.
Collignon, A., Vandermeulen, A., Suetens, P., & Marchal, G. (1995). 3d multi-modality
medical image registration based on information theory. Computational Imaging
and Vision, 3, 263274.
Craene, M. D., Camara, O., Bijnens, B. H., & Frangi, A. F. (2009). Large diffeomorphic
FFD registration for motion and strain quantification from 3D-US sequences. In:
International conference on functional imaging and modeling of the heart,
pp. 437446.
Davatzikos, C. (1997). Spatial transformation and registration of brain images using
elastically deformable models. Computer Vision and Image Understanding, 66(2),
207222.
DHaese, P.-F., Pallavaram, S., Li, R., et al. (2012). Cranialvault and its crave tools: A
clinical computer assistance system for deep brain stimulation (dbs) therapy.
Medical Image Analysis, 16(3), 744753.
Droske, M., & Rumpf, M. (2004). A variational approach to non-rigid morphological
registration. SIAM Applied Mathematics, 64(2), 668687.
Duchon, J. (1976). Interpolation des fonctions de deux variables suivant le principle de
la flexion des plaques minces. RAIRO Analyse Numerique, 10, 512.
Durrleman, S., Pennec, X., Trouv, A., Thompson, P., & Ayache, N. (2008). Inferring
brain variability from diffeomorphic deformations of currents: An integrative
approach. Medical Image Analysis, 12(5), 626637.
Fischer, B., & Modersitzki, J. (2002a). Curvature based registration with applications to
MR-mammography. In P. Sloot, C. Tan, J. Dongarra & A. Hoekstra (Eds.),
Computational Science ICCS 2002. LNCS (Vol. 2331, pp. 203206). Heidelberg:
Springer.
Fischer, B., & Modersitzki, J. (2008). Mathematics meets medicine An optimal
alignment. SIAG/OPT Views and News, 19(2), 17.
Fischer, B., & Modersitzki, J. (2002b). Fast diffusion registration. AMS Contemporary
Mathematics, Inverse Problems, Image Analysis, and Medical Imaging, 313,
117129.
Fischer, B., & Modersitzki, J. (2003a). Combining landmark and intensity driven
registrations. PAMM, 3, 3235.
Fischer, B., & Modersitzki, J. (2003b). Curvature based image registration. Journal of
Mathematical Imaging and Vision, 18(1), 8185.
Fischer, B., & Modersitzki, J. (2004a). Intensity based image registration with a
guaranteed one-to-one point match. Methods of Information in Medicine, 43,
327330.
Fischer, B., & Modersitzki, J. (2004b). A unified approach to fast image registration and
a new curvature based registration technique. Linear Algebra and its Applications,
380, 107124.
Fischer, B., & Modersitzki, J. (2006). Image fusion and registration A variational
approach. In E. Krause, Y. Shokin, M. Resch & N. Shokina (Eds.), Computational
science and high performance computing II. Notes on Numerical Fluid Mechanics
and Multidisciplinary Design (Vol. 91, pp. 193205). Heidelberg: Springer.
Fischer, B., & Modersitzki, J. (2008). Ill-posed medicine An introduction to image
registration. Inverse Problems, 24, 119.
Fischler, M. A., & Elschlager, R. A. (1973). The representation and matching of pictorial
structures. IEEE Transactions on Computers, 22(1), 6792.
Fitzpatrick, J. M., Hill, D. L.G, & Maurer, C. R.J (2000). Image registration. In M. Sonka
& J. M. Fitzpatrick (Eds.), Handbook of medical imaging. Medical Image Processing
and Analysis (Vol. 2, pp. 447513). Bellingham, WA: SPIE.
Florack, L., Romeny, B., Koenderink, J., & Viergever, M. (1992). Scale and the
differential structure of images. Image and Vision Computing, 10, 376388.
Fornefett, M., Rohr, K., & Stiehl, H. (2000). Elastic medical image registration using
surface landmarks with automatic finding of correspondences. In T. M. L. Alexander
Horsch (Ed.), Bildverarbeitung fur die Medizin 2000, Algorithmen, Systeme,
Anwendungen (pp. 4852). Informatik Heidelberg: Springer.
Freeborough, P. A. (1998). Modeling brain deformations in alzheimer disease by fluid
registration of serial 3D MR images. Journal of Computer Assisted Tomography,
22(5), 838843.
Friston, K. J., Ashburner, J., Frith, C. D., Poline, J.-B., Heather, J. D., &
Frackowiak, R. S.J (1995). Spatial registration and normalization of images. Human
Brain Mapping, 2, 165189.
Gee, J. C., & Bajcsy, R. (1999). Elastic matching: Continuum mechanical and
probabilistic analysis. Brain Warping, 183197.
Glasbey, C. (1998). A review of image warping methods. Journal of Applied Statistics,
25, 155171.
Glauns, J., Qiu, A., Miller, M. I., & Younes, L. (2008). Large deformation diffeomorphic
metric curve mapping. International Journal of Computer Vision, 80(3), 317336.
Glauns J., Trouve A., & Younes L. (2004). Diffeomorphic matching of distributions: A
new approach for unlabelled point-sets and submanifolds matching. In:
International conference on computer vision and pattern recognition, pp. 712718.
Glauns, J., Vaillant, M., & Miller, M. I. (2004). Landmark matching via large
deformation diffeomorphisms on the sphere. Journal of Mathematical Imaging and
Vision, 20(12), 179200.
Goshtasby, A. A. (2005). 2-D and 3-D image registration. New York: Wiley Press.
Goshtasby, A. A. (2012). Image registration: Principles, tools and methods. New York:
Springer.
Guimond, A., Roche, A., Ayache, N., & Meunier, J. (2001). Three-dimensional
multimodal brain warping using the demons algorithm and adaptive intensity
corrections. IEEE Transactions on Medical Imaging, 20(1), 5869.
Guo, T., Parrent, A. G., & Peters, T. M. (2007). Surgical targeting accuracy analysis of
six methods for subthalamic nucleus deep brain stimulation. Computer Aided
Surgery, 12(6), 325334.
Haber, E., Heldmann, S., & Modersitzki, J. (2009). A framework for image-based
constrained registration with an application to local rigidity. Linear Algebra and its
Applications, 431, 459470.
Haber, E., Horesh, R., & Modersitzki, J. (2010). Numerical methods for
constrained image registration. Numerical Linear Algebra with Applications,
17(23), 343359.
Haber, E., & Modersitzki, J. (2004). Numerical methods for volume preserving image
registration. Inverse Problems, Institute of Physics Publishing, 20(5), 16211638.
Haber E., & Modersitzki J. (2005). A scale space method for volume preserving
image registration. In: Proceedings of the 5th international conference on scale
space and PDE methods in computer vision, pp. 18.
Haber, E., & Modersitzki, J. (2006a). A multilevel method for image registration. SIAM
Journal on Scientific Computing, 27(5), 15941607.
Haber, E., & Modersitzki, J. (2006b). Image registration with a guaranteed displacement
regularity. International Journal of Computer Vision, 1. http://dx.doi.org/10.1007/
s11263-006-8984-4.
313
Lester, H., & Arridge, S. R. (1999). A survey of hierarchical non-linear medical image
registration. Pattern Recognition, 32, 129149.
Light, W. A. (1996). Variational methods for interpolation, particularly by radial basis
functions. In D. Griffiths & G. Watson (Eds.), Numerical analysis 1995
(pp. 94106). London: Longmans.
Lindeberg, T. (1994). Scale-space theory in computer vision. Dordrecht: Kluwer
Academic Publishers.
Little, J., Hill, D., & Hawkes, D. (1997). Deformations incorporating rigid structures.
Computer Vision and Image Understanding, 66(2), 223232.
Loeckx, D., Maes, F., Vandermeulen, D., & Suetens, P. (2004). Nonrigid image
registration using free-form deformations with a local rigidity constraint, MICCAI.
LNCS (Vol. 3216, pp. 639646).
Maes, F., Collignon, A., Vandermeulen, D., Marchal, G., & Suetens, P. (1997).
Multimodality image registration by maximization of mutual information. IEEE
Transactions on Medical Imaging, 16(2), 187198.
Maintz, J. B.A, & Viergever, M. A. (1998). A survey of medical image registration.
Medical Image Analysis, 2(1), 136.
Martens, H. C.F, Toader, E., Decre, M. M.J, et al. (2011). Spatial steering of deep brain
stimulation volumes using a novel lead design. Clinical Neurophysiology, 122(3),
558566.
Miller, M., & Younes, L. (2001). Group actions, homeomorphisms, and matching: A
general framework. International Journal of Computer Vision, 41, 6184.
Modat, M., Vercauteren, T., Ridgway, G. R., Hawkes, D. J., Fox, N. C., & Ourselin, S.
(2010). Diffeomorphic demons using normalized mutual information, evaluation on
multimodal brain MR images. In: Proceedings of the SPIE medical imaging: Image
processing, 76 232K0176 232K8.
Modersitzki, J. (2004). Numerical methods for image registration. New York: Oxford
University Press.
Modersitzki, J. (2008). FLIRT with rigidity Image registration with a local non-rigidity
penalty. International Journal of Computer Vision, 76, 153163. http://dx.doi.org/
10.1007/s11263-007-0079-3.
Modersitzki, J. (2009). FAIR: Flexible algorithms for image registration. Philadelphia:
SIAM.
Modersitzki, J., & Fischer, B. (2003). Optimal image registration with a guaranteed oneto-one point match. In T. Wittenberg et al. (Eds.), Bildverarbeitung fur die Medizin
2003 (pp. 15): Heidelberg: Springer.
Modersitzki, J., & Wirtz, S. (2006). Combining homogenization and registration, In
J. P. Pluim et al. (Eds.), Biomedical image registration: Third international
workshop, WBIR 2006. LNCS (pp. 257263). Springer.
Mohammadi, S., Nagy, Z., Hutton, C., Josephs, O., & Weiskopf, N. (2011). Correction
of vibration artifacts in DTI using phase-encoding reversal (COVIPER). Magnetic
Resonance in Medicine, 68(3), 882889.
Poschl, C., Modersitzki, J., & Scherzer, O. (2010). A variational setting for volume
constrained image registration. Inverse Problems and Imaging, 4(3), 500522.
Pennec X., Stefanescu R., Arsigny V., Fillard P., & Ayache N. (2005). Riemannian
elasticity: A statistical regularization framework for nonlinear registration. In:
International conference on medical image computing and computer-assisted
intervention, pp. 943950.
Peshko, O., Modersitzki, J., Terlaky, T., Menard, C., Craig, T., & Moseley, D. (2010).
Automatic localization and tracking of fiducial markers for organ motion analysis in
image-guided radiation therapy. In: Proceedings of the SPIE 2010, Medical
Imaging, pp. 14.
Pluim, J., Maintz, J., & Viergever, M. (1999). Mutual-information-based registration of
medical images: A survey. IEEE Transactions on Medical Imaging, 22, 9861004.
Pluim, J. P., Maintz, J. B.A, & Viergever, M. A. (2000). Image registration by
maximization of combined mutual information and gradient information. IEEE
Transactions on Medical Imaging, 19(8), 809814.
Roche, A. (2001). Recalage dimages medicales par inference statistique, PhD thesis,
Universite de Nice, Sophia-Antipolis, France.
Roche, A., Malandain, G., Pennec, X., & Ayache, N. (1998). The correlation ratio as a
new similarity measure for multimodal image registration, MICCAI 1998. Lecture
Notes in Computer Science (Vol. 1496, pp. 11151124). Cambridge, MA: Springer
Verlag.
Rohlfing, T., Maurer, C. R., Jr., Bluemke, D. A., & Jacobs, M. A. (2003). Volumepreserving non-rigid registration of MR breast images using free-form deformation
with an incompressibility constraint. IEEE Transactions on Medical Imaging, 22(6),
730741.
Rohr, K. (2001). Landmark-based image analysis. Computational imaging and vision.
Dordrecht: Kluwer Academic Publishers.
Rueckert, D., Hayes, C., Studholme, C., Summers, P., Leach, M., & Hawkes, D. J.
(1998). Non-rigid registration of breast MR images using mutual information. In
A. C. F. Colchester, S. L. Delp & W. M. Wells (Eds.), MICCAI 98: Medical image
computing and computer-assisted intervention (pp. 11441152). Berlin: Springer.
314
Rueckert, D., Sonoda, L., Hayes, C., Hill, D., Leach, M., & Hawkes, D. (1999). Non-rigid
registration using free-form deformations. IEEE Transactions on Medical Imaging,
18(1), 712721.
Ruthotto, L., Gigengack, F., Burger, M., et al. (2012). A simplified pipeline for motion
correction in dual gated cardiac PET. In T. Tolxdorff, T. Deserno, H. Handels, &
H.-P. Meinzer (Eds.), Bildverarbeitung fur die Medizin 2012 (pp. 5156).
Heidelberg: Springer.
Ruthotto, L., Hodneland, E., & Modersitzki, J. (2012). Registration of dynamic contrast
enhanced MRI with local rigidity constraint, In B. Dawant, J. Fitzpatrick, D. Rueckert
& G. Christensen (Eds.), Biomedical image registration, 5th international workshop
WBIR 2012. Heidelberg: Springer, pp. 190198.
Ruthotto, L., Kugel, H., Olesch, J., et al. (2012). Diffeomorphic susceptibility artefact
correction of diffusion-weighted magnetic resonance images. Physics in Medicine
and Biology, 57, 57155731.http://stacks.iop.org/0031-9155/57/5715.
Salden, A. H., Ter Haar Romeny, B. M., & Viergever, M. A. (1998). Linear scale-space theory
from physical principles. Journal of Mathematical Imaging and Vision, 9(2), 103139.
Scherzer, O. (2006). Mathematical models for registration and applications to medical
imaging. New York: Springer.
Staring, M., Klein, S., & Pluim, J. (2006). Nonrigid registration using a rigidity
constraint. In J. Reihnardt, & J. Pluim (Eds.), Proceedings of the SPIE 2006,
medical imaging, 2006, SPIE-6144, 110
Staring, M., Klein, S., & Pluim, J. P.W (2007). A rigidity penalty term for nonrigid
registration. Medical Physics, 34(11), 40984108.
Stejskal, E., & Tanner, J. E. (1965). Spin diffusion measurements: Spin echoes in the
presence of a time-dependent field gradient. Journal of Chemical Physics, 42(1),
288292.
Szeliski, R. (2006). Image alignment and stitching: A tutorial. Foundations and Trends
in Computer Graphics and Vision, 2(1), 1104.http://dx.doi.org/10.1561/
0600000009.
Thevenaz, P., Blu, T., & Unser, M. (2000). Image interpolation and resampling. In I.
Bankman (Ed.), Handbook of medical imaging, processing and analysis
(pp. 393420). San Diego, CA: Academic Press.
Thirion, J.-P. (1995). Fast non-rigid matching of 3D medical images, Technical
report 2547, Institut National de Recherche en Informatique et en Automatique,
France.
Thirion, J.-P. (1996). Non-rigid matching using demons. In IEEE, Conference on
computer vision and pattern recognition, pp. 245251.
Thirion, J.-P. (1998). Image matching as a diffusion process: An analogy with Maxwells
demons. Medical Image Analysis, 2(3), 243260.
Tikhonov, A. N. (1943). On the stability of inverse problems. Doklady Akademii Nauk
SSSR, 39(5), 195198, in Russian.
Toga, A. W., & Mazziotta, J. C. (2002). Brain mapping: The methods (2nd ed.).
Waltham, MA: Academic Press.
Glossary
http://dx.doi.org/10.1016/B978-0-12-397025-1.00301-8
315
316
Introduction
E2 m, f , f
1
mf1 f 2
2s2
E kLvk2
1
km id v f k2
2s2
(a)
(b)
317
2s
where f0 id and dtd ft vt ft . The aim is to optimize the timedependent velocity field, v, where the subscripts denote the
fields at time t (time is a slightly artificial construct for crosssectional registration but makes more intuitive sense for longitudinal growth modeling). The previously mentioned
318
.. . id N1 vN1
f1 id N1 v1 id N1 vN1
N
1
1
1
f1
1 id NvN1 id NvN2 ... id Nv1
Given an initial (f0 id) and final (f1) diffeomorphism,
the regularization component of the objective function essentially finds the trajectory between them that minimizes the
integral of an energy term. This may be conceptualized in
terms of Lagrangian mechanics with only a kinetic energy
term (which links the approach to Riemannian geometry),
where the aim is to determine the trajectory of the evolving
diffeomorphism that satisfies the principle of least (stationary)
action (see, e.g., Marsden & Ratiu, 1999). For this model, the
action is defined as
1
kLvt k2 dt
2 0
v0
f 0,0
f 0,1
f f 0,1
|Df 0,1|
v0.2
f 0.2,0
mf 0.2,0
f 0.2,1
f f 0.2,1
|Df 0,2,1|
v0.4
f 0.4,0
mf 0.4,0
f 0.4,1
f f 0.4,1
|Df 0,4,1|
v0.6
f 0.6,0
mf 0.6,0
f 0.6,1
f f 0.6,1
|Df 0,6,1|
v0.8
f 0.8,0
mf 0.8,0
f 0.8,1
f f 0.8,1
|Df 0,8,1|
v1
f 1,0
mf 1,0
f 1,1
|Df 1,1|
Figure 2 Schematic illustration of velocity fields, diffeomorphisms, and warped images involved in LDDMM.
t, 0
A disadvantage of LDDMM is that it requires a lot of memory to store a number of intermediate diffeomorphisms and
velocity fields. Rather than to determine the trajectory of the
evolving diffeomorphisms from the initial and final configurations (solving a boundary value problem), an alternative
approach would be to compute the trajectory from the initial
(or final) configuration and velocity (Miller, Trouve, & Younes,
2006). This strategy, called geodesic shooting, does not
require so much intermediate information to be stored.
Geodesic Shooting
Closer examination of Algorithm 3 shows that at any time
from
point, bt may
be determined
T
b1 via because mt m1 t, 1
and rmt Dt , 1 rm1 t , 1
bt s12 Dt , 1 mt ft rmt
T
Dt , 1 Dt , 1 b1 t, 1
319
id N1 vn1
1, n1
N
N
T
D
D
u1 Nn , 1
Nn , 1
n
N, 1
vNn KuNn
end for
until convergence
It is relatively straightforward to reformulate the algorithm
to estimate the initial velocity (v0) instead of the final one. In
this case, we obtain the following at the solution:
v0 K s12 D0, 1 m f 0, 1 rm
K s12 a0 rm
where a0 D0, 1 m f 0, 1 . From this, we see that the
diffeomorphic mappings can be reconstructed from a0, m, K,
and s2 (see Figure 3). For a morphometric study, where a
series of images are all registered with the same m, using the
same K and s2, a (sometimes known as the scalar momentum)
provides a useful representation of the deviation of each image
from the template (Singh et al., 2010). Algorithm 5 illustrates
an approach to registration, based on directly optimizing the
initial scalar momentum. A related scheme was used in Vialard,
Risser, Rueckert, and Cotter (2012).
Algorithms 4 and 5 use simple Euler integration approaches
to compute diffeomorphisms from a velocity field. It is possible to use more accurate integrators, but many of these require
320
1 m
2 m
a0 = | Df 0,1 | (m f f 0,1)
u0 horizontal
u0 vertical
v0
v0 horizontal
v0 vertical
Hamiltonian Mechanics
Another framework for diffeomorphic registration involves
parameterizing the dynamical system via particles. Typically,
qi(t) is used to denote the position vector of the ith particle,
and pi(t) is its associated momentum vector at time t. From
these, evolving momentums and velocity fields can be constructed from
X
dx qi t pi t
ut x
i
X
vt x
Kx qi t pi t
i
X
@
pTi rK qi qj pj
@qi
j
@ X
K qi qj pj
@pi
j
Outlook
For many years, most people thought the Earth was flat. While
this was a reasonable working assumption for those who did
not travel far, it fails badly for exploring further afield. Similarly, small deformation approximations to image registration
which assume that displacements can be added and subtracted as if their geometry was Euclidean may be almost
close enough for many current neuroimaging applications.
However, to make real advances in modeling and understanding brain growth, development, aging and pathologies, we may
need to discard Euclids axioms and work within a Riemannian
geometry setting.
This article has focused on simple approaches to pairwise
diffeomorphic image registration. Although progress has been
made, there is much to be done in terms of fully integrating
diffeomorphic deformations into our generative models of brain
image data. Pairwise registration is only the Riemannian geometry equivalent of connecting two points with a straight line.
References
Arsigny, V., Commowick, O., Pennec, X., & Ayache, N. (2006). A log-Euclidean
framework for statistics on diffeomorphisms. Medical image computing and
computer-assisted intervention MICCAI, 924931.
321
Lesion Segmentation
SK Warfield and X Tomas-Fernandez, Harvard Medical School, Boston MA, USA
2015 Elsevier Inc. All rights reserved.
Glossary
Introduction
The development of imaging strategies for the optimal detection and characterization of lesions continues at a rapid pace.
Several modalities are in common use, including magnetic
resonance imaging (MRI), ultrasound, computed technology,
and positron emission tomography (PET). Each modality is
appropriate for certain types of lesions, but MRI is particularly
attractive due to its lack of ionizing radiation and the flexibility
of contrast mechanisms that it provides.
display of contrast and the workspace environment. For example, a laterality bias in visual perception was identified as the
source of leftright asymmetry in some manual segmentations
and was found to be especially prominent in the hippocampus
(Maltbie et al., 2012). If present, this can be managed by
mirroring the images across the leftright plane of symmetry
and segmenting each structure twice, once appearing on the
left hand side and once on the right hand side, and then
averaging (Thompson et al., 2009). This is time-consuming
and therefore expensive and may be avoided by careful management of the experts perception.
The testretest reproducibility of interactive segmentation
has been characterized. In general, it has been found that an
expert rater will be more successful when the boundary of the
structure being delineated is readily observed and with a simple shape. Long and complicated boundaries are more difficult
to segment and lead to a reduction in interrater reliability
(Kikinis et al., 1992). Cortical gray matter, for example, can
be challenging to delineate (Warfield et al., 1995).
http://dx.doi.org/10.1016/B978-0-12-397025-1.00302-X
323
324
An excellent approach that overcomes the inter- and intraexpert reference variability consists in evaluation using synthetic image data (Kwan, Evans, & Pike, 1999). Since the
correct segmentation is known, this allows for direct comparison to the results of automatic segmentation algorithms.
Unfortunately, simulated images may not exhibit the wide
range of anatomy and acquisition artifacts found in clinical
data, and therefore, the conclusions may not generalize to the
broader range found in images of patients.
Given that expert measurements are highly variable, any
validation should always evaluate automatic segmentation
accuracy against a series of repeated measurements by multiple
experts. These multiple expert segmentations can be combined
using STAPLE (Akhondi-Asl & Warfield, 2013; Commowick,
Akhondi-Asl, & Warfield, 2012; Commowick & Warfield,
2010; Warfield, Zou, & Wells, 2004), which provides an optimal weighting of each expert segmentation, based on the comparison of each segmentation to a hidden reference standard
segmentation. The confidence of the expert performance estimates can also be estimated, indicating whether or not sufficient data are available to have high confidence in the reference
standard and the expert performance assessments. Ultimately,
the best automated segmentation algorithms should have an
accuracy similar to that of the best expert segmentations, but
with higher reproducibility.
Validation Metrics
Two main aspects characterize the validation of a segmentation
algorithm: accuracy and reproducibility.
Accuracy
The accuracy of segmentation can be evaluated in many different ways. A sensible evaluation criterion depends on the purpose of the segmentation procedure. If the goal is to estimate
the lesion volume, a measure often referred to as total lesion
load (TLL), the volumetric error would be the criteria of choice
(Garca-Lorenzo, Prima, Arnold, Collins, & Barillot, 2011;
Shiee et al., 2010; Van Leemput, Maes, Vandermeulen,
Colchester, & Suetens, 2001). The main limitation of such
approach is that it does not provide information regarding
the overlap with the reference segmentation. Thus, segmentation with exactly the same volume as the reference can be
completely wrong if a voxel by voxel comparison is made. It
has been demonstrated that high TLL correlation can be
achieved while still achieving a poor degree of precise spatial
correspondence. For example, Van Leemput et al. (2001)
reported a high TLL correlation but considerable disagreement
in spatial overlap between expert segmentations and between
expert and automatic measurements.
Commonly, brain segmentation literature describes the
spatial overlap of segmentations by means of the dice similarity coefficient (DSC) (Dice, 1945). The DSC between the automatic and reference segmentation is defined as the ratio of
twice the overlapping area to the sum of the individual areas.
The value of the index varies between 0 (no overlap) and 1
(complete overlap with the reference). This is an excellent
measure if the detection of every voxel of every lesion is critical.
In practice, evaluation of DSC of MS lesion segmentations is
dependent on the TLL of the patients (Zijdenbos, Dawant,
Reproducibility
High reproducibility, of accurate segmentation, is crucial for
longitudinal trials to ensure that differences in segmentations
obtained over time result from changes in the pathology and
not from the variability of the segmentation approach.
To test interscan variability, MS patients may undergo a
scanrepositionscan experiment. As scans are obtained
within the same imaging session, it is assumed that the disease
has not evolved during this period. Such an approach was used
in Kikinis et al. (1999) and Wei et al. (2002) where reproducibility was measured using the coefficient of variation on
the TLL.
Reproducibility is a necessary but not sufficient part of
validation. One still needs to show that the method is accurate
and sensitive to changes in input data. Measuring accuracy
requires an independent estimate of the ground truth, an
often difficult task when using clinical data.
Validation Datasets
In order to provide objective assessments of segmentation
performance, there is a need for an objective reference standard
with associated MRI scans that exhibit the same major segmentation challenges as that of scans of patients. A database of
clinical MR images, along with their segmentations, may provide the means to measure the performance of an algorithm
by comparing the results against the variability of the expert
segmentations. However, an objective evaluation to systematically compare different segmentation algorithms also needs
an accurate reference standard.
An example of such a reference standard is the synthetic
brain MRI database provided by the Montreal Neurological
Institute that is a common standard for evaluating the segmentations of MS patients. The synthetic MS brain phantom available from the McConnell Brain Imaging Centre consists of
T1w, T2w, and proton density MRI sequences with different
acquisition parameters as well as noise and intensity
325
inhomogeneity levels (Kwan et al., 1999). The MS brain phantom was based on the original BrainWeb healthy phantom,
which had been expanded to capture three different MS lesion
loads: mild (0.4 cm3), moderate (3.5 cm3), and severe
(10.1 cm3). Each MS phantom was provided with its own MS
lesion ground truth.
Although the BrainWeb synthetic dataset provides a reference standard, it presents several limitations. First, the BrainWeb dataset just provides one brain model, which results in a
poor characterization of the anatomical variability present in
the MS population. Also, although the BrainWeb dataset is
based on real MRI data, the final model is not equivalent to
clinical scans in its contrast, and it produces an easier dataset to
segment than real clinical scans.
To overcome these limitations, most of the lesion segmentation algorithms also evaluate their results in a dataset consisting in clinical scans. Such an approach allows for a better
understanding of the performance of the evaluated algorithms
when faced with real data. Unfortunately, because each segmentation algorithm is validated with different datasets, comparison between different methodologies is more difficult.
A recent effort in providing publicly available datasets for
validation of MS lesion segmentation was released at the MS
Segmentation Grand Challenge held during the Medical Imaging Computing and Computer Assisted Intervention (MICCAI
2008) conference (Styne et al., 2008). For this event, the University of North Carolina at Chapel Hill (UNC) and Boston
Childrens Hospital (BCH) released a database of MS MRI
scans that contains anatomical MRI scans from 51 subjects
with MS.
Images were placed into two groups: a 20-subject training
group and a 31-subject testing group, the balance of the original 51 subject cohort. MS lesion manual reference data were
only available for those subjects in the training group. Organizers retained and continue to hold secret the interactively
delineated reference standard lesion segmentations of the testing group. To evaluate the performance of any segmentation
algorithms, researchers may upload their automatic segmentations of the testing data into the challenge website, where a
number of performance metrics are computed and an overall
performance ranking is provided. Since the competitors do not
have access to the reference standard segmentation, this evaluation of publicly available scans allows for a truly objective
comparison.
326
pY i j Zi pZi p@ Zi
j0 pY i j Zi
jpZi jp@ Zi j
327
328
Segmenting the observed image Yis to propose an estimate Z^ of Z on the basis ofY, to this purpose, the parameter c (fZ1, . . ., fZK; fY1, . . ., fYK) needs to be estimated
somehow. If the underlying tissue segmentation Z was
known, estimation of the model parameters would be
straightforward. However, only the image Y is directly
observed, making it natural to tackle this problem as one
involving missing data making the EM algorithm the candidate for model fitting. The EM algorithm finds the
parameter c that maximizes the complete data loglikelihood by iteratively maximizing the expected value of
the log-likelihood log(f(Y, Z|c)) of the complete data (Y,
Z), where the expectation is based on the observed data Y
and the estimated parameters c m obtained in the previous
iteration m:
log LC c log f Y, Zj c
YN X K
log
f Z i ek j fZk f Y i j Z i ek , fYk
i1
k1
XN XK
i1
z log f Z i
k1 ik
ek j fZk
log f Y i Z i ek , fYk
E-step: The E-step requires the computation of the conditional expectation of log(Lc(c)) given Y, using c m for c, which
can be written as
Qc; c m Ecm log LC c Y
As the complete data log-likelihood log LC(c), is linear in
the hidden labels zij, the E-step simply requires the calculation
of the current conditional expectation of Zi given the observed
data Y. Then,
m
f Z i ej j fm
Zj f Y i Z i ej , fYj
Ecm Zi ej j Y PK
f Z i ek j fm f Y i Z i ek , fm
Zk
k1
Yk
that corresponds to the posterior probability that the ith member of the sample belongs to the jth class.
M-step: The M-step on the mth iteration requires the maximization of Q(c; c m) with respect to c over the parameter
space to give the updated estimate c m1. The mixing proportions pk are calculated as follows:
1 XN
m
f
Z
e
,
c
pk f Z i ek j fm1
Y
i
k i
Zk
i1
N
The update of fY on the M-step of the (m 1)th iteration, it
is estimated by maximizing log LC(c) with respect to fY:
XN XK
m @ log f Y i Z i ek , fYk
f
e
j
Y
,c
0
i
i
k
i1
k1
@fY
Consider that f(Yi|Zi ek, fYk) is described by a Gaussian
distribution parameterized by fYk (mk, Sk)
f Y i j Zi ek , fYk
1
m=2
2p
jSk j
1=2
T 1
1
e 2 Y i mk Sk Y i mk
PN
mm1
k
m
i1 Y i f Z i ek Y i , c
PN
m
i1 f Z i ek Y i ,c
m
m T
Y i mm
i1 f Z i ek j Y i , c Y i mk
k
PN
f Zi ek Y i ,c m
PN
Sm1
k
329
log LC c log f Y, P,Z c
XN XK
i1
z log pk f Y i j Z ik ,c k f P ik j Y i ,Z ik , c k
k1 ik
m , S N Y m ,S
z
log
p
p
N
Y
i
i Pik Pik
k Pik
k k
k1 ik
XN XK
i1
i1
P
SPik
jeNR
V ij mPik p Lij ek
jeNR p Lij ek
V ij mPik
P
T
pk pPik N Yi mk , Sk N Yi mPik , SPik
p 0 p 0 N Yi m 0 , S 0 N Yi m 0 , S
k0 1 k
Pik
Pik
Pik0
f
Y
,
P
,Z
vi vi
vi c
i1
Y
h
(N), Zv(N)|c, j N)
330
84.46
84
83
82.12
82.07
82
Score
81
80
80
79.9
79.1
79
78.19
78
77
76
75
ek
be
11
08
tio
20
20
la
zo
04
n
re
20
Lo
a-
10
.,
al
11
20
et
20
le
up
ie
ci
ar
An
Sh
So
ia
08
20
em
er
ic
Br
pu
po
of ct
el bje
od su
M nd
a
Participant team
Figure 1 Comparison of lesion segmentation performance of different algorithms from the MS Lesion Segmentation Grand Challenge (Styne et al.,
2008). The highest score is best.
1 f(Yi, Zi|)
T1w MRI
1.00
0.75
0.50
0.25
0.00
(a)
(c)
T2w MRI
1.00
0.75
0.50
0.25
0.00
(b)
(d)
Conclusion
Lesion segmentation is an important task, regularly carried out
by experts using interactive and semiautomatic segmentation
tools. Automated algorithms for segmentation of lesions have
explored a wide range of techniques and are increasingly effective for a range of types of pathology. Advances in MS lesion
segmentation enable quantitative and accurate detection of
lesions from high-quality MRI.
References
Akhondi-Asl, A., & Warfield, S. K. (2013). Simultaneous truth and performance level
estimation through fusion of probabilistic segmentations. IEEE Transactions on
Medical Imaging, http://dx.doi.org/10.1109/TMI.2013.2266258.
Anbeek, P., Vincken, K. L., van Osch, M. J., Bisschops, R. H. C., & van der Grond, J.
(2004). Automatic segmentation of different-sized white matter lesions by voxel
probability estimation. Medical Image Analysis, 8, 205215. http://dx.doi.org/
10.1016/j.media.2004.06.019.
Ashton, E. A., Takahashi, C., Berg, M. J., Goodman, A., Totterman, S., & Ekholm, S.
(2003). Accuracy and reproducibility of manual and semiautomated quantification of
MS lesions by MRI. Journal of Magnetic Resonance Imaging, 17, 300308. http://
dx.doi.org/10.1002/jmri.10258.
Barkhof, F., Simon, J. H., Fazekas, F., Rovaris, M., Kappos, L., de Stefano, N., et al.
(2012). MRI monitoring of immunomodulation in relapse-onset multiple sclerosis
331
332
Van Leemput, K., Maes, F., Vandermeulen, D., Colchester, A., & Suetens, P. (2001).
Automated segmentation of multiple sclerosis lesions by model outlier detection.
IEEE Transactions on Medical Imaging, 20, 677688.
Van Leemput, K., Maes, F., Vandermeulen, D., & Suetens, P. (1999). Automated
model-based tissue classification of MR images of the brain. IEEE Transactions on
Medical Imaging, 18, 897908. http://dx.doi.org/10.1109/42.811270.
Vannier, M. W., Butterfield, R. L., Jordan, D., Murphy, W. A., Levitt, R. G., & Gado, M.
(1985). Multispectral analysis of magnetic resonance images. Radiology, 154(1),
221224. http://dx.doi.org/10.1148/radiology.154.1.3964938.
Vannier, M. W., Butterfield, R. L., & Jordan, D. (1985). Multispectral analysis of
magnetic, resonance images. Radiology, 154, 221224.
Wack, D. S., Dwyer, M. G., Bergsland, N., Di Perri, C., Ranza, L., Hussein, S., et al.
(2012). Improved assessment of multiple sclerosis lesion segmentation agreement
via detection and outline error estimates. BMC Medical Imaging, 12, 17. http://dx.
doi.org/10.1186/1471-2342-12-17.
Warfield, S. K., Kaus, M., Jolesz, F. A., & Kikinis, R. (2000). Adaptive, template
moderated, spatially varying statistical classification. Medical Image Analysis, 4,
4355.
Warfield, S., Dengler, J., Zaers, J., Guttmann, C. R., Wells, W. M., 3rd., Ettinger, G. J.,
et al. (1995). Automatic identification of gray matter structures from MRI to improve
the segmentation of white matter lesions. Journal of Image Guided Surgery, 1(6),
326338. http://dx.doi.org/10.1002/(SICI)1522-712X.
Warfield, S. K., Zou, K. H., & Wells, W. M. (2004). Simultaneous truth and performance
level estimation (STAPLE): An algorithm for the validation of image segmentation.
IEEE Transactions on Medical Imaging, 23, 903921. http://dx.doi.org/10.1109/
TMI.2004.828354.
Wei, X., Guttmann, C. R., Warfield, S. K., Eliasziw, M., & Mitchell, J. R. (2004). Has your
patients multiple sclerosis lesion burden or brain atrophy actually changed?
Multiple Sclerosis, 10, 402406.
Wei, X., Warfield, S. K., Zou, K. H., Wu, Y., Li, X., Guimond, A., et al. (2002).
Quantitative analysis of MRI signal abnormalities of brain white matter with high
reproducibility and accuracy. Journal of Magnetic Resonance Imaging, 209,
203209. http://dx.doi.org/10.1002/jmri.10053.
Weisenfeld, N. I., & Warfield, S. K. (2009). Automatic segmentation of newborn brain
MRI. NeuroImage, 47, 564572. http://dx.doi.org/10.1016/j.
neuroimage.2009.04.068.
Weisenfeld, N. I., & Warfield, S. K. (2004). Normalization of joint image-intensity
statistics in MRI using the KullbackLeibler divergence. In Proceedings of the 2004
IEEE international symposium on biomedical imaging: From nano to macro,
Arlington, VA, April 1518, 2004.
Wells, W. M., Grimson, W. L., Kikinis, R., & Jolesz, F. A. (1996).
Adaptive segmentation of MRI data. IEEE Transactions on Medical Imaging, 15,
429442.
Wels, M., Huber, M., & Hornegger, J. (2008). Fully automated segmentation of multiple
sclerosis lesions in multispectral MRI. Pattern Recognition and Image Analysis, 18,
347350. http://dx.doi.org/10.1134/S1054661808020235.
Younis, A. A., Soliman, A. T., Kabuka, M. R., & John, N. M. (2007). MS lesions
detection in MRI using grouping artificial immune networks. In IEEE 7th
international symposium on bioinformatics and bioengineering (pp. 11391146).
Zijdenbos, A. P., Dawant, B. M., Margolin, R. A., & Palmer, A. C. (1994). Morphometric
analysis of white matter lesions in MR images: Method and validation. IEEE
Transactions on Medical Imaging, 13, 716724. http://dx.doi.org/10.1109/
42.363096.
Zijdenbos, A. P., Forghani, R., & Evans, A. C. (2002). Automatic pipeline analysis of
3-D MRI data for clinical trials: Application to multiple sclerosis. IEEE Transactions
on Medical Imaging, 21, 12801291.
Relevant Websites
http://brainweb.bic.mni.mcgill.ca/brainweb/selection_ms.html BrainWeb Lesion
Simulator.
http://www.spl.harvard.edu/publications/item/view/1180 Warfield/Kaus database.
http://crl.med.harvard.edu/software STAPLE validation software.
http://martinos.org/qtim/miccai2013/ Multimodal Brain Tumor Segmentation.
http://www.sci.utah.edu/prastawa/software.html Brain Tumor Simulator.
http://www.ia.unc.edu/MSseg/ Multiple Sclerosis Lesion Segmentation Grand
Challenge.
Manual Morphometry
N Roberts, University of Edinburgh, Edinburgh, UK
2015 Elsevier Inc. All rights reserved.
Glossary
Introduction
The aim of this article is to provide a concise description of the
correct methods to be applied for obtaining reliable measurements of the volume and surface area of the living brain and of
its internal compartments and individual brain structures using
medical imaging techniques such as magnetic resonance
imaging (MRI) and X-ray computed tomography (CT) by manual means. The methods in question have been developed
within the discipline of stereology (see Cruz-Orive, 1997;
Howard & Reed, 1998; Mouton, 2011; Roberts, Puddephat, &
McNulty, 2000; West, 2012) and are very convenient to use
when applied in combination with appropriate computer software. Stereology is defined as the statistical inference of geometric parameters from sampled information. The fact that
sampling is involved means that the measurements are estimates rather than exact values. Crucially sampling is performed
according to mathematically rigorous designs that ensure that
the results are unbiased. Furthermore, the use of systematic
sampling strategies means that the methods are highly efficient
and formulae have been developed for predicting the precision
of the estimate from the sampled information.
The ability to obtain a detailed 3D image of the anatomy of
the brain in a living individual is clearly an amazing scientific
achievement with many potential applications including the
prospect of obtaining detailed measurements of brain size.
This is acknowledged in the award of Nobel Prizes to Wilhelm
C. Rontgen (1901) for the discovery of x-rays and to Godfrey
N. Hounsfield and Allan MacLeod Cormack (1979) just under
80 years later for developing the CT technique in which x-rays
are used to produce 3D images of anatomy and pathology to
support clinical diagnosis. Likewise, Nobel Prizes were
awarded to Otto Stern (1943), Isidor I. Rabi (1944), and to
Felix Bloch and Edward M. Purcell (1952) relating to the
discovery of the magnetic moment of the proton and development and refinement of the resonance method for manipulating this magnetization and which paved the way for Paul C.
Lauterbur, USA and Peter Mansfield (2003) to develop the
http://dx.doi.org/10.1016/B978-0-12-397025-1.00303-1
333
334
335
Figure 1 Example of Cavalieri sectioning (a) and area function A(x) which represents the area of the intersection between the object of interest
and a plane at the point of abscissa (continuous curve) (b). The volume is the area under the area function and the volume estimate is the area under
the histogram. Performing Cavalieri sectioning and point counting on every 45th section of the MR image obtained for the cerebral hemisphere
specimen shown in later Figure 2(b) produced a volume estimate of 450 cm3 with a CE of 2.6%. Reproduced with permission from Garcia-Finana, M.,
Cruz-Orive, L. M., Mackay, C. E., Pakkenberg, B., & Roberts, N. (2003). Comparison of MR imaging against physical sectioning to estimate the volume of
human cerebral compartments. NeuroImage, 18, 505516.
extremely efficient procedure. Also, fortunately mathematicians have developed formulae that can be used for predicting
the precision of the estimate from the sampled information. In
particular, the coefficient of error (CE) of the Cavalieri volume
estimate can be simply predicted from a knowledge of the
points recorded on successive sections through the structure
of interest.
The first authors to propose a formula for predicting the CE
of a Cavalieri volume estimate were Gundersen and Jensen
(1987) based on the theory developed by Matheron (1965,
1971). The prediction which is based on modeling the correlation structure of the data via analysis of the covariogram is
model based and therefore is indirect and may potentially be
biased. Gundersen and Jensen (1987) also showed that the
precision of point counting estimates of transect area could
be predicted using theory developed by Matern (1985). The
latter prediction formula required that a so-called dimensionless shape coefficient be computed for the structure of interest.
Fortunately, the value of this shape coefficient can be estimated
at the outset of a study by recording the number of intersections between the boundary of the object transects and a
square grid of test lines overlain on the 2D section images
with random orientation. This value can be used in all future
studies of the same structure.
Cruz-Orive developed an error prediction formula for the
Cavalieri method, which integrated both the sectioning and
point counting contributions described above and again
requiring the input of a value for the dimensionless shape
coefficient. This was tested in studies by Roberts et al. (1993,
1997) which revealed that this so-called general prediction
formula over-estimated the CE in the case of very regular
shaped objects leading to the development of an alternative
formula for so-called quasi-ellipsoidal objects (Roberts et al.,
336
337
Figure 3 (a) Area function obtained with negligible measurement error from a complete set of 274 MR images for the specimen shown in Figure 2(b).
(b) Replicated volume estimates obtained from the complete dataset versus the number of Cavalieri sections (n) and (c) CE versus n. The smooth
line represents the predicted CE and the dashed lines relate to previous so-called general and quasi-ellipsoidal versions. (d) CE of the volume
estimator from the Cavalieri sections analyzed with a square grid of side 9.375 mm for each of the compartments of interest versus number of sections.
(e) Ratio of point counting to section error contributions versus n when grid size is 9.375 mm. (f) Behavior of total CE for n 38 Cavalieri sections
as grid size increases. Reproduced with permission from Garcia-Finana, M., Cruz-Orive, L. M., Mackay, C. E., Pakkenberg, B., & Roberts, N. (2003).
Comparison of MR imaging against physical sectioning to estimate the volume of human cerebral compartments. NeuroImage, 18, 505516.
338
Figure 4 Confidence regions for the regression coefficients (B0, B1) for each technique. The point (B0, B1) (479, 0.96) corresponds to the
postulated model. Reproduced with permission from Garcia-Finana, M., Cruz-Orive, L. M., Mackay, C. E., Pakkenberg, B., & Roberts, N. (2003).
Comparison of MR imaging against physical sectioning to estimate the volume of human cerebral compartments. NeuroImage, 18, 505516.
339
z + 2T
f + 90
z +T
z
O
f
(a)
(b)
1
23
56
6
5
4
3
2
1
(d)
x3
Vertical
2d
Length = 8d
(e)
1
x1
(c)
Series 2, 127
Series 1, 37
x2
2d
5 cm
5 cm
(f)
Figure 5 Sampling of two mutually perpendicular UR directions normal to the corresponding vertical Cavalieri series of sections advocated to use to
estimate brain surface area (a, b). The vertical axis is perpendicular to the paper. Mutually perpendicular UR Cavalieri series normal to the axes
previously sampled at the angles 37 and 127 , respectively, hitting a brain to estimate its surface area. (e) Fundamental tile of the cycloid test grid (f)
containing a fundamental curve consisting of a double cycloid arc. To superimpose the test grid uniformly at random on a vertical section the
associated point of a fundamental curve is brought to coincide with a UR point sampled in the interior of the fundamental tile. The grid must be kept
fixed with the smaller cycloid axes parallel to the vertical direction. Also shown in the upper portions of the center and right sided panels of the figure are
the positions within the brain of the vertical sections corresponding to Series 1 and 2. The actual vertical sections, prepared with the aid of 3DSlicer
software, are shown in the respective lower portions of these panels. The pial and subcortical trace curves shown in red and blue, respectively, were
obtained using FreeSurfer software. The arrow in the first vertical section of Series 1 indicates the vertical direction. Reproduced with permission from
Cruz-Orive, L. M., Gelsvartas, J., & Roberts, N. (2013). Sampling theory and automated simulations, applied to human brain. Journal of Microscopy,
253, 119150.
Sections, and finally a contribution due to intersection counting with a cycloid grid. Up until recently, theory was only
sufficiently developed so as to provide formulae for modeling
the size of the angular sampling (Cruz-Orive & Gual-Arnau,
2002) and systematic sectioning contributions (Garca-Finana
& Cruz-Orive, 2000a, 2000b). In Cruz-Orive et al. (2013),
however, a new error prediction formula relating to the counting of intersections with a cycloid test system is presented and
computer simulations are performed to empirically investigate
its reliability. The relative contribution of all three terms in
estimating the surface area of the brain on Exhaustive Vertical
Sections is also described.
In order to be able to perform the above-mentioned simulations FreeSurfer software was first used to segment the pial
surface and boundary between cortical grey matter and white
matter in a 3D MR image obtained for a living 20-year-old
female subject. The tessellated surface that is produced has a
sub-voxel resolution in that the values that are obtained for
the, for example, percentage of grey matter in each voxel during
the segmentation step is used as the basis for performing an
interpolation to determine where the surface resides within
each voxel. Subsequently, two series of Extended Vertical Sections were reformatted through the tessellated surface, as
shown in Figure 5, and an example of the grey matter boundary for the fifth vertical section in the first series is shown in
Figure 6(a). A software package was written in this laboratory
to enable cycloid tests systems of varying areal density to be
overlain on the vertical sections and the number of intersections between the test system and the cortical boundary to be
automatically recorded, as shown in Figure 6(b).
The left and right columns of Figure 6(b) refer to the first
and second series of Vertical Sections, shown in Figure 5,
respectively, and in each panel the CE due to intersection
counting as predicted using the new formula is plotted against
corresponding empirical values obtained using Monte Carlo
simulations, for three different grid sizes increasing down the
column. Overall there is good agreement between the predicted and empirically determined CE. Thus a reasonably precise and unbiased estimate of the surface area of the cerebral
cortex may be obtained by counting intersections between the
boundary of the surface as it appears on two orthogonal series
of systematic vertical sections obtained with a random starting
angle and random starting position. Furthermore, as described
by Cruz-Orive et al. (2013), all the relevant theory exists to be
able to predict the CE of the surface area estimate. Just as
Garca-Finana and Cruz-Orive (2000a, 2000b) performed simulations to demonstrate the relative efficiency or sectioning
and point counting in estimating volume using the Cavalieri
method, Cruz-Orive et al. (2013) provide a launch point for
designing simulations to investigate the relative efficiency of
angular sampling, sectioning and intersection counting for
estimating surface area using the Extended Vertical Sections
method.
The study by Cruz-Orive et al. (2013) is of a living brain. No
ground truth exists and the main aim of the study is to present
relevant theory and to perform relevant simulations to investigate the reliability of formulae for predicting the precision of
surface area estimates obtained by the Extended Vertical Sections method. However, just as Garca-Finana and Cruz-Orive
(2000a, 2000b) investigated the accuracy of the Cavalieri
340
Figure 6 A vertical section from the vertical Cavalieri series 1 with the pial trace approximated by polygonal curves (in red) with a UR cycloid test
system superimposed and covering it entirely. The relevant intersections with the pial trace curves are marked by white dots. To predict the error
variance component due to intersection counting with the so-called fakir formula, intersection counts have to be scored separately for each fundamental
cycloid curve. To distinguish them, the fundamental curves have been colored alternatively in red and black. The centers of the hit links of the
polygonal chain are represented as red and black circles, respectively. The corresponding counts were collected automatically with the aid of the
StereoTool software. Model predictors of the coefficient of error due to intersection counting (on the pial traces with cycloid test grids), plotted against
the corresponding empirical values obtained by Monte Carlo replications. The checks were performed with grids of three different sizes on each of
the six sections from each of the two vertical Cavalieri series available. Reproduced with permission from Cruz-Orive, L. M., Gelsvartas, J., & Roberts, N.
(2013). Sampling theory and automated simulations, applied to human brain. Journal of Microscopy, 253, 119150.
dots are present at the end of the line in the photograph but are
absent in the MR image. This is because partial voluming artifact that is present in the MR image prevents a sulcus being
seen on MRI that is clearly visible in the photograph. On
average, pial surface area was estimated to be almost half the
extent using MRI compared to physical sectioning (i.e., 45%,
p < 0.05). No such problems exist in applying the Extended
Vertical Sections method to estimate the surface area of the
boundary between grey and white matter. Accurate application
of manual stereological methods for measuring the cortical
surface area, but not the surface area of the boundary between
grey and white matter, thus requires higher resolution MR
imaging than is typically performed at 3 T. Interestingly,
semi-automatic software such as FreeSurfer can provide an
accurate measurement of both pial surface area and the surface
area of the boundary between grey and white matter by first
extracting the latter and then growing a cerebral cortex on top
of this according to appropriate constraints to produce the
latter. Furthermore, 7 T MR imaging systems provide 3D MR
images with isotropic voxels of side 0.5 mm (i.e., resolution of
20 pixels cm1), in which the pial surface can be readily seen in
its entirety, in reasonable imaging times.
Figure 7 A digital color photograph of the upper face of the fourth slice
cut through a postmortem cerebral hemisphere specimen is shown
in (A1), and in (A2) the photograph of (A1) has been converted to a black
and white image, input to EasyMeasure software and overlain by a
cycloid test system with random position and oriented such that the
short axis of the cycloids lies parallel to the vertical direction. In (A3) the
MR image corresponding to the same position in the specimen as the
physical section shown in (A1) and (A2) has also been input to
EasyMeasure software and overlain with a cycloid test system with
random position (in this case, it is the same random position as the one
obtained for the physical section for illustrative purposes) and again
oriented such that the short axis of the cycloids lies parallel to the vertical
direction. Panels (B1), (B2), and (B3) refer to the same images as (A1),
(A2), and (A3), respectively, and in particular show a magnified view
of the region contained within the box outlined in white in (A1).
For further details see text. Reproduced with permission from
Furlong, C., Garca-Finana, M., Sahin, B., Anderson, A., Fabricius, K.,
Eriksen, N., et al. (2013). Application of stereological methods
to estimate postmortem brain surface area using 3 T MRI. Magnetic
Resonance Imaging, 31, 456465.
Discussion
A further interesting advance is the development of the Isotropic Cavalieri method as reported by Cruz-Orive, RamosHerrera, and Artacho-Perula (2010). The advantage of using
the Isotropic Cavalieri method is firstly that explicit, as
opposed to model-based, formula exist for predicting the precision of the estimate, and secondly that an unbiased estimate
of surface area may conveniently also be obtained from the
acquired sections. Whereas in the traditional application of the
Cavalieri method sections may be obtained along an axis at
any arbitrary orientation through an object, in the case of the
Isotropic Cavalieri method the sectioning direction must be
isotropic in 3D. In the case, where for example total brain
volume and surface area is to be compared between two groups
for whom physical specimens have been obtained postmortem
a convenient way of generating Isotropic Cavalieri sections is to
embed each specimen in a sphere of agarose gel and then to
roll the sphere along the bench top until it comes to rest at
which point sectioning each sphere from, say, left to right will
produce Isotropic Cavalieri sections through each specimen
ready for analysis. In the case, where total brain volume and
surface area is to be compared between two groups for whom
341
342
References
Aggleton, J. P., Vann, S. D., Denby, C., Dix, S., Mayes, A. R., Roberts, N., et al. (2005).
Sparing of the familiarity component of recognition memory in a patient with
hippocampal pathology. Neuropsychologia, 43, 18101823.
Alexander, F. M. (1932). The use of the self. New York: E.P. Dutton.
Baddeley, A. J., Gundersen, G. H., & Cruz-Orive, L. M. (1986). Estimation of surface
area from vertical sections. Journal of Microscopy, 142, 259276.
Baker, J. P., & Coffin, C. T. (2013). The importance of an ergonomic workstation to
practicing sonographers. Journal of Ultrasound in Medicine, 32, 13631375.
Barta, P. E., Petty, R. G., McGilchrist, I., Lewis, R. W., Jerram, M., Casanova, M. F., et al.
(1995). Asymmetry of the planum temporale: Methodological considerations and
clinical associations. Psychiatry Research, 61, 137150.
Boucher, J., Cowell, P., Howard, M., Broks, P., Farrant, A., Roberts, N., et al. (2005). A
combined clinical neuropsychological and neuroanatomical study of adults with
high functioning autism. Cognitive Neuropsychiatry, 10, 165213.
Broks, P., Young, A. W., Maratos, E. J., Coffey, P. J., Calder, A. J., Isaac, C., et al.
(1998). Face processing impairments after encephalitis: Amygdala damage and
recognition of fear. Neuropsychologia, 36, 5970.
Brooks, J. C. W., Whitehouse, G. H., Majeed, T., & Roberts, N. (2000). Reduced
neuronal metabolism in hippocampus in chronic fatigue syndrome. The British
Journal of Radiology, 73, 12061208.
Calmon, G., & Roberts, N. (2000). Automatic measurement of changes in brain volume
on consecutive 3D MR images by segmentation propagation. Magnetic Resonance
Imaging, 18, 439453.
Cowell, P. E., Sluming, V. A., Wilkinson, I. D., Cezayirli, E., Romanowski, C. A.,
Webb, J. A., et al. (2007). Effects of sex and age on regional prefrontal brain volume
in two human cohorts. European Journal of Neuroscience, 1, 307318.
Cruz-Orive, L. M. (1997). Stereology of single objects. Journal of Microscopy, 186,
93107.
Cruz-Orive, L. M., Gelsvartas, J., & Roberts, N. (2013). Sampling theory and automated
simulations for vertical sections, applied to human brain. Journal of Microscopy,
253, 119150.
Cruz-Orive, L. M., & Gual-Arnau, X. (2002). Precision of circular systematic sampling.
Journal of Microscopy, 207, 225242.
Cruz-Orive, L. M., Ramos-Herrera, M. L., & Artacho-Perula, E. (2010). Stereology of
isolated objects with the invariator. Journal of Microscopy, 240, 94110.
Denby, C. E., Vann, S. D., Tsivilis, D., Aggleton, J. P., Montaldi, D., Roberts, N., et al.
(2009). The frequency and extent of mammillary body atrophy associated with
surgical removal of a colloid cyst. American Journal of Neuroradiology, 30,
736743.
Edwards, S. G.M, Gong, Q. Y., Liu, C., Zavartau, M. E., Jaspan, T., Roberts, N., et al.
(1999). Infratentorial atrophy on magnetic resonance imaging and disability in
multiple sclerosis. Brain, 122, 291301.
Foster, J. K., Meikle, A., Goodson, G., Mayes, A. R., Howard, M., Suenram, S. I., et al.
(1999). The hippocampus and delayed recall: Bigger is not necessarily better.
Memory, 7, 715732.
Furlong, C., Garca-Finana, M., Sahin, B., Anderson, A., Fabricius, K., Eriksen, N., et al.
(2013). Application of stereological methods to estimate post-mortem brain surface
area using 3 T MRI. Magnetic Resonance Imaging, 31, 456465.
343
Matern, B. (1985). Estimating area of dot counts. In J. Lanke & G. Lindgren (Eds.),
Sampling contributions to probability and statistics in honour of gunnar bloom
(pp. 243257). Lund: University of Lund.
Matheron, G. (1965). Les variables regionalisees et leur estimation (thesis). Paris:
Masson et Cie.
Matheron, G. (1971). The theory of regionalized variables and its applications. In Les
Cahiers du Centre morphologie mathematique de Fontainebleau5. Ecole National
Superieure des Mines de Paris.
McNulty, V., Cruz-Orive, L. M., Roberts, N., Holmes, C. J., & Gual-Arnau, X. (2000).
Estimation of brain compartment volume from MR Cavalieri slices. Journal of
Computer Assisted Tomography, 24, 466477.
Mouton, P. R. (2011). Unbiased stereology: A concise guide. The Johns Hopkins
University Press, Baltimore, MD, USA.
Powell, J. L., Kemp, G. J., Dunbar, R. I.M, Roberts, N., Sluming, V., & Garca-Finana, M.
(2014). Different association between intentionality competence and prefrontal
volume in left and right handers. Cortex, 54, 6376.
Powell, J., Lewis, P., Dunbar, R. I.M, Garca-Finana, M., & Roberts, N. (2010). Orbital
prefrontal cortex volume correlates with social cognitive competence.
Neuropsychologia, 48, 35543562.
Redmond, L. T., Barbosa, S., Blumhardt, L. D., & Roberts, N. (2000). Short-term
ventricular volume changes on serial MRI in multiple sclerosis. Acta Neurologica
Scandinavica, 102, 99105.
Roberts, N., Cruz-Orive, L. M., Reid, N. M., Brodie, D. A., Bourne, M., & Edwards, R. H. T.
(1993). Unbiased estimation of human body composition by the Cavalieri method
using magnetic resonance imaging. Journal of Microscopy, 171, 239253.
Roberts, N., Cruz-Orive, L. M., Bourne, M., Herfkens, R. J., Karowski, R. A., &
Whitehouse, G. H. (1997). Analysis of cardiac function by MRI and stereology.
Journal of Microscopy, 187, 3142.
Roberts, N., Garden, A. S., Cruz-Orive, L. M., Whitehouse, G. H., & Edwards, R. H. T.
(1994). Estimation of fetal volume by magnetic resonance imaging and stereology.
British Journal of Radiology, 67, 10671077.
Roberts, N., Puddephat, M. J., & McNulty, V. (2000). The benefit of stereology for
quantitative radiology. The British Journal of Radiology, 73, 679697.
Ronan, L., Doherty, C. P., Delanty, N., Thornton, J., & Fitzsimons, M. (2006).
Quantitative MRI: A reliable protocol for measurement of cerebral gyrification using
stereology. Magnetic Resonance Imaging, 24, 265272.
Ronan, L., Murphy, K., Delanty, N., Doherty, C., Maguire, S., Scanlon, C., et al. (2007).
Cerebral cortical gyrification: A preliminary investigation in temporal lobe epilepsy.
Epilepsia, 48, 211219.
Sluming, V., Barrick, T. R., Howard, M. A., Mayes, A. R., & Roberts, N. (2002). Voxelbased morphometry reveals increased grey matter density in Brocas area in male
symphony orchestra musicians. NeuroImage, 17, 16131622.
Subsol, G., Roberts, N., Doran, M., Thirion, J.-P., & Whitehouse, G. H. (1997).
Automatic analysis of cerebral atrophy. Magnetic Resonance Imaging, 15, 917927.
Tsivilis, D., Vann, S. D., Denby, C., Roberts, N., Mayes, A. R., Montaldi, D., et al. (2008).
A disproportionate role for the fornix and mammillary bodies in recall versus
recognition memory. Nature Neuroscience, 11, 834842.
West, M. J. (2012). Basic stereology for biologists and neuroscientists. New York: Cold
Spring Harbor Laboratory Press.
Voxel-Based Morphometry
F Kurth and E Luders, UCLA School of Medicine, Los Angeles, CA, USA
C Gaser, Jena University Hospital, Jena, Germany
2015 Elsevier Inc. All rights reserved.
Introduction
The human brain is in a state of constant change and adaptation. This may be driven either by normal developmental or
aging processes or by the effects of learning, training, and new
occurrences in daily life. In addition to these aforementioned
changes, more systematic influences such as gender, disease,
and genes affect the brains structure. Using magnetic resonance imaging, brain changes and differences can be measured
noninvasively and in vivo, making them particularly interesting
for both basic research and clinical research. The easiest way to
assess brain changes (or group differences) is to measure
whole-brain volume. However, assessing the volume of the
entire brain is rather unspecific. So-called region-of-interest
(ROI) analyses are more sensitive to local changes than are
whole-brain assessments but are also subject to several limitations. For example, if one specific region is measured, other
brain structures are ignored, and possible effects remain undetected elsewhere in the brain. Moreover, ROIs are usually
created based on individual protocols and depend on raterspecific judgment calls, thus requiring a clearly definable and
unambiguous structure. For large parts of the brain, however, it
may be difficult to precisely define (or identify) unambiguous
boundaries. Finally, if an ROI is only partially different, this
will lower the sensitivity to detect any effects in this region.
This is where voxel-based morphometry (VBM) comes into
play, as VBM allows for the examination of brain changes
and/or group differences across the entire brain with a high
regional specificity (i.e., voxel by voxel), without requiring the
a priori definition of particular ROIs (Ashburner & Friston,
2000, 2001, 2007).
VBM: An Overview
VBM is an objective approach that enables a voxel-wise estimation of the local amount of a specific tissue. Most
commonly, VBM is directed at examining gray matter but it
can also be used to examine white matter. In the latter case,
however, the sensitivity is limited, for white matter areas are
characterized by large homogeneous regions with only subtle
changes in intensity. The concept of VBM comprises three basic
preprocessing steps: (1) tissue classification, (2) spatial
normalization, and (3) spatial smoothing, which are followed
by the actual statistical analysis. That is, if we know exactly
what tissue can be found at a specific voxel, we can quantify
and analyze it. This can be achieved by tissue classification.
Furthermore, if we know that a specific voxel is at exactly the
same anatomical location across all subjects (e.g., at the tip of
the Sylvian fissure), we can compare voxel values across subjects. This is achieved by spatial normalization. Each brain,
however, is unique; sulcal or gyral patterns, for example, vary
Tissue Classification
Tissue classification is based on intensity values and basically
serves to segment the brain into gray matter, white matter,
and cerebrospinal fluid after removing any nonbrain parts
(Ashburner & Friston, 1997, 2005; Rajapakse, Giedd, & Rapoport, 1997). However, intensity values in structural brain
scans are not exclusively attributable to different tissue
types, as an intensity-based tissue classification would
assume. Rather, inhomogeneities of the magnetic field will
lead to inhomogeneities in image intensity as well. This effect
is even more pronounced with high-field scanners, since it is
more difficult to keep the magnetic field homogeneous for
higher field strengths. As shown in Figure 1 (T1-weighted
image), the intensity inhomogeneity looks like a field of
smoothly varying brightness, which results in different intensities for the same tissue at different locations. Thus, image
intensity inhomogeneities need to be corrected before applying the actual tissue classification. This correction process is
usually referred to as bias correction. The bias-corrected
T1-weighted image can then be classified into any set of tissue
types (usually three different tissue types for the brain plus
one or more background types).
As shown in Figure 2 (left panel), the distributions of
intensities for each tissue class overlap, even after a bias
correction is applied. One reason for this overlap is that at a
common voxel size of 1 1 1 mm3, any given voxel can
contain more than one tissue. This is generally the case at the
border between the brain parenchyma and cerebrospinal fluid,
at boundaries between gray matter and white matter, and in
structures where white matter fibers cross the gray matter.
Thus, even in a bias field-corrected image, signal intensities
for different tissues will vary and result in a considerable
overlap and so-called partial volumes. Partial volumes can be
modeled explicitly in order to more accurately classify the
tissues and calculate local volumes (Tohka, Zijdenbos, &
http://dx.doi.org/10.1016/B978-0-12-397025-1.00304-3
345
346
Original image
(T1-weighted)
Inhomogeneity
correction
Tissue
classification
Nonlinear
normalization
Spatial
smoothing
classification. Since an algorithm that accounts for partial volumes was used, the given segments encode a local volume
estimate of tissue content for every voxel.
Spatial Normalization
In addition to tissue classification, the individual brains or
the native gray matter segments (Figure 3(a)) must be spatially normalized in order to ensure a voxel-wise comparability. Spatial normalization can be divided in linear and
GM
WM
347
CSF
WM
Background
GM
CSF
Figure 2 Tissue classification. Left panel: Whole-brain images can be segmented into background and different tissue classes, such as gray matter
(GM), white matter (WM), and cerebrospinal fluid (CSF) based on their intensity. Note that these tissue-specific intensity distributions overlap, which can
be due to partial volume effects. Right panel: The GM, WM, and CSF segments (top) were obtained using a partial volume estimation, which allows
for more than one tissue per voxel. The partial volume estimation label (bottom) depicts the voxel values as transitions between tissue contents. GM is
shown in yellow, WM in red, and CSF in blue. Voxels containing both GM and WM are shown in varying shades of orange, depending on the mixture
of both tissues at this location. Voxels containing both GM and CSF are shown in varying shades of green, depending on the mixture of both tissues
at this location. As both voxel size and tissue content per voxel are known, proper estimations of local tissue volumes can be made.
Native
gray matter
Normalized
gray matter
Deformation
field
Modulated
gray matter
Subject 1
Subject 2
Figure 3 Spatial normalization. For visualization, two very different examples are depicted. Subject 1 is a 23-year-old male, while subject 2 is a 64year-old female. (a) While local gray matter volumes can be measured in native space in both brains, a voxel-wise comparison is not easily possible.
(b) After spatial normalization, both brains have the same size, shape, and overall pattern of major sulci and gyri. The local amount of gray matter can be
directly compared in voxel-wise statistical tests. (c) The Jacobian determinants derived from the deformation fields that were applied for spatial
normalization indicate different patterns of volume change for both subjects. The deformation forces needed to transform each subjects brain image
to the template and highlight regions that were expanded (blue/cyan) or compressed (red/yellow) to match the respective areas in the template.
Analyzing these deformation fields or the Jacobian determinants constitutes what is known as tensor-based or deformation-based morphometry.
(d) Multiplying these deformation fields (or more precisely, the Jacobian determinants) with the original normalized gray matter segments corrects for
the volume changes that occurred during the spatial normalization and is known as modulation. Voxel-wise statistical testing applied to these
segments will analyze the local gray matter volume as estimated in native space. Note that although both brains are very similar, the second subjects
smaller and probably slightly atrophic brain shows less local volume (evident as darker shades of orange).
348
scaling and shearing (each again in the x-axis, y-axis, and z-axis,
yielding a total of 12 parameters) will alter the size and global
shape of the brain. A 12-parameter transformation (also
known as affine transformation) is frequently used to register
brains to a template space.
While linear transformations can correct for interindividual
differences in brain size, they cannot model local differences in
size and shape as the same transformation is applied to every
voxel. In contrast, nonlinear transformations allow the application of different changes in position, size, and shape locally
and thus correct for interindividual differences on a local scale
(Ashburner, 2007; Ashburner & Friston, 1999, 2005). Still, a
perfect match between any two brains is very unlikely because
brains are highly individual in their local anatomy (e.g., some
sulci and gyri cannot be found in all brains). Nevertheless, in
spite of minor remaining interindividual differences within the
normalized gray matter segments (Figure 3(b)), modern normalization techniques result in brains with a reasonable local
comparability (Ashburner, 2007).
All spatial transformations result in a deformation field
(Figure 3(c)) that describes how local structures were adjusted
to match two brains to each other (i.e., indicating if a part of
the brain had to be enlarged or compressed). The exact voxelwise volume changes can be easily derived from these
deformation fields as Jacobian determinants. Analyzing these
Jacobian determinants or the deformation fields themselves
constitutes what is known as tensor-based morphometry or
deformation-based morphometry. The Jacobian determinant
may also be used to correct resulting gray matter segments for
volume changes that occurred due to the spatial normalization. More specifically, suppose a structure of the brain with a
certain amount of gray matter becomes bigger during normalization. Consequently, this structure will seem to have larger
local gray matter values than are truly present. If the difference
between true gray matter and apparent gray matter can be
quantified which is exactly what the Jacobian determinants
do the measured gray matter can simply be corrected
(i.e., basically undoing the unwanted effects of the normalization). This way, the amount of original gray matter is preserved in the new space and reflected as so-called modulated
gray matter (Figure 3(d)).
Spatial Smoothing
The reason to smooth the images before statistical analysis is
threefold: First of all, parametric tests assume that the residuals
follow a Gaussian distribution. Simple smoothing of the images
satisfies this assumption by the central limit theorem (after
smoothing, the data are more normally distributed) and thus
makes a parametric test a valid choice (Ashburner & Friston,
2000; Nichols & Hayasaka, 2003). Second, as outlined earlier,
the spatial normalization is not perfect and small interindividual
differences remain. Smoothing accounts for these residual small
interindividual differences in local anatomy (Ashburner & Friston, 2000). Finally, according to the matched filter theorem,
smoothing renders the analysis sensitive to effects that approximately match the size of the smoothing kernel (Ashburner &
Friston, 2000). As smoothing kernels usually have a full width at
half maximum of 416 mm, this means that very small differences, which are possibly due to noise, are not picked up by the
analysis. Consequently, after smoothing, each voxel represents a
sphere similar to the smoothing kernel or, in other words, a
weighted mean of its own and its neighbors values.
Statistical Analysis
The smoothed normalized tissue segments can be analyzed in
statistical models using parametric tests, although nonparametric tests are also common. Usually, these tests will be
applied in a mass-univariate approach, which means that the
same test is applied for each voxel simultaneously. As in most
other neuroimaging analyses, this entails a severe multiple
comparison problem and an appropriate correction has to be
applied. In neuroimaging, two major levels of correction are
frequently used that are both based on Gaussian random field
theory (Worsley et al., 1996): a correction on a voxel level and
a correction on a cluster level (though a set-level correction is
also possible) (Friston, Holmes, Poline, Price, & Frith, 1996).
Assume the results are to be corrected controlling the familywise error (FWE) at p 0.05. At the voxel level, an FWE correction will assure that only in 1 out of 20 images a finding will
have reached significance by chance. This is a perfectly legitimate way of correcting the results. To apply an FWE correction
at cluster level, an arbitrary cluster-forming threshold must be
applied, say at p 0.001 uncorrected (Friston et al., 1996).
Given the smoothness of the data, smaller clusters are likely
to occur by chance thus constituting false positives. Larger
clusters, however, are less likely to occur and cluster-forming
thresholds will produce clusters that constitute real effects.
Controlling the FWE at the cluster level therefore means that
only in 1 out of 20 images a cluster of this extent will occur by
chance. This correction will consequently result in a spatial
extent threshold expressed as the minimum number of voxels
comprising the significance cluster.
Unfortunately, statistical parametric maps from structural
analyses vary considerably in local smoothness, meaning that
the appropriate extent threshold varies locally as well. In other
words, within the same image, there might be very smooth
regions where large clusters may occur by chance and relatively
rough regions where true effects may manifest as very small
clusters. Applying one single extent threshold for the whole
image is therefore inappropriate (Ashburner & Friston, 2000;
Hayasaka, Phan, Liberzon, Worsley, & Nichols, 2004). A possible solution is to correct each voxel individually based on the
local smoothness by rendering smoothness isotropic, which
results in locally varying extent thresholds. Another possibility
is to use a correction based on threshold-free cluster enhancement (TFCE) (Smith & Nichols, 2009). This method estimates a
voxel value that represents the accumulative cluster-like local
spatial support at a range of cluster-forming thresholds. TFCE
has a variety of advantages that make it an elegant solution to
correct for multiple comparisons in structural analyses. First of
all, it does not need an arbitrary cluster-forming threshold, making it more objective. Second, it combines statistics based on the
local significance as well as the spatial extent of this effect.
However, because the distribution of the TFCE values is not
known, permutation tests must be used to assess thresholds.
References
Ashburner, J. (2007). A fast diffeomorphic image registration algorithm. NeuroImage,
38, 95113.
Ashburner, J., & Friston, K. (1997). Multimodal image coregistration and
partitioningA unified framework. NeuroImage, 6, 209217.
Ashburner, J., & Friston, K. J. (1999). Nonlinear spatial normalization using basis
functions. Human Brain Mapping, 7, 254266.
Ashburner, J., & Friston, K. J. (2000). Voxel-based morphometryThe methods.
NeuroImage, 11, 805821.
Ashburner, J., & Friston, K. J. (2001). Why voxel-based morphometry should be used.
NeuroImage, 14, 12381243.
Ashburner, J., & Friston, K. J. (2005). Unified segmentation. NeuroImage, 26,
839851.
349
Glossary
Introduction
The advent of high-resolution magnetic resonance imaging
(MRI) combined with advanced image processing algorithms
has given new life to the older neuroanatomical tradition of
mapping the thickness of the cortex. With the now common
availability of acquisitions and algorithms, a multitude of
papers have begun to explore cortical thickness mapping
across development, in health and disease, and in multiple
species.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00305-5
351
352
Molecular layer
(a)
corpus callosum
(b)
(c)
Figure 1 The organization of the cortex. (a, b) The laminal structure of the cortex using immunohistochemical staining of neuronal nuclei (NeuN).
The cell-sparse molecular layer is immediately obvious, and changes in neuronal density and size are visible to the trained eye as one descends toward
the corpus callosum. (c) The radial patterning of the cortex. This slice was obtained by imaging a Thy1YFP fluorescent mouse, featuring Golgi-like
fluorescence in a sparse population of neurons, with a two-photon microscope. The path taken by the apical dendrites toward the molecular layer is
immediately discernible.
efficiently map the thickness of the cortex across a large number of subjects (Figure 2).
The Methods
Algorithms to compute cortical thickness from MRIs follow
one of four strategies. The simplest, and therefore longest
extant, is manual measurements. Here, brain images are
assessed in a viewer and a digital caliper is employed to measure the distance between the white/gray matter boundary and
the pial surface boundary. These types of manual measures are
a direct analogue of cortical thickness measures performed on a
histology slice. The principal drawbacks are their laborious
nature, making them only suitable for a few restricted regions
of interest, and the difficulty associated with accurately estimating the thickness of the complex folded cortex on a 2-D
slice.
The second strategy for estimating cortical thickness determines the boundaries of the cortex through some combination
of tissue classification and automatic parcellation followed
by a boundary value problem approach to estimate the distance between the white matter and the cortical cerebro-spinal
353
Nonuniformity field
Native MRI
Final MRI
Classified MRI
Registration target
Figure 2 Methods for extracting cortical thickness. An illustrative processing flow for extracting cortical thickness metrics, including registration,
nonuniformity correction, tissue classification, and surface fitting.
fluid (CSF). The use of Laplaces equation by Jones, Buchbinder, and Aharon (2000) popularized this approach to mapping
cortical thickness, and it has since been adapted to other species (Leigland et al., 2013; Lerch et al., 2008) by adding additional boundary constraints. The pathlines or streamlines
created between the inside and outside cortical surfaces
through these boundary value equations appear to mimic the
direction taken by cortical columns. This is especially the case
in more recent algorithms explicitly designed to approximate
the cortical column (Waehnert et al., 2013). One downside to
these voxel-based cortical thickness methods is that they lack a
coordinate system for the analysis of thickness across populations. The idiosyncratically folded nature of the cortex makes it
difficult to precisely align 3-D volumes of different subjects;
most voxel-based thickness methods thus rely on the parcellation of the cortex into ROIs and the computation of mean
cortical thickness in those ROIs.
The third, and most common, method of mapping cortical
thickness creates two polyhedral surfaces along the inside and
outside cortical boundaries and then defines cortical thickness
as the distance between these two surfaces. Both FreeSurfer
(Dale, Fischl, & Sereno, 1999; Fischl & Dale, 2000) and
CIVET (Kim et al., 2005; Lerch & Evans, 2005; Lyttelton et al.,
2007) use surface-based cortical thickness techniques. Briefly,
the preprocessing steps include linear alignment to Montreal
Neurological Institute (MNI) space, correction for nonuniformity, and tissue classification. The inside (gray/white)
boundary is then fit, and once complete, that surface is used as
a starting point to expand to the outside (gray/pial) boundary.
Cortical thickness is then defined as the distance between the
inside and outside surfaces. Using surface-based methods to
map cortical thickness has the great advantage of providing a
surface-based coordinate system, allowing for easy vertex-wise
(i.e., point by point) comparison of cortical thickness across
354
Disease
Among the earliest papers to map differences in cortical thickness in a population of subjects were those that dealt with
neurodegenerative diseases, in particular Huntingtons (Rosas
et al., 2002) and Alzheimers disease (Lerch et al., 2005), in each
case finding focal cortical atrophy that spread with disease progression or severity. Since then, most, if not all, mental health
conditions have been examined by studying populations of
affected subjects compared to matched controls. In addition to
detecting atrophy, some conditions, such as congenital amusia,
show focal cortical thickening (Hyde et al., 2007), and others
show altered developmental patterns (Shaw et al., 2007).
Networks
The brain is organized into networks, and the cortical thickness
mapping reflects network properties. For example, as Brocas
area increases or decreases in thickness, Wernickes area changes
in a correlated fashion (Lerch et al., 2006). These correlations in
the language network tighten with age (Lerch et al., 2006) and
can be detected within individual subjects (Raznahan et al.,
2011). The analysis of cortical thickness networks has furthermore been very fruitfully extended into graph theoretical frameworks, showing alterations in the covariance of the anatomy of
the cortex across development, aging, and disease (AlexanderBloch, Giedd, & Bullmore, 2013; Evans, 2013).
References
Alexander-Bloch, A., Giedd, J. N., & Bullmore, E. (2013). Imaging structural co-variance
between human brain regions. Nature Reviews. Neuroscience, 14, 322336.
Amunts, K., et al. (1999). Brocas region revisited: Cytoarchitecture and intersubject
variability. The Journal of Comparative Neurology, 412(2), 319341.
Bock, N. A., et al. (2013). Optimizing T1-weighted imaging of cortical myelin content at
3.0 T. NeuroImage, 65, 112.
Brodmann, K. (1908). Beitrage zur histologischen Lokalisation der Grosshirnrinde.
Clowry, G., Molnar, Z., & Rakic, P. (2010). Renewed focus on the developing human
neocortex. Journal of Anatomy, 217(4), 276288.
Dale, A. M., Fischl, B., & Sereno, M. I. (1999). Cortical surface-based analysis. I.
Segmentation and surface reconstruction. NeuroImage, 9(2), 179194.
Dickerson, B. C., et al. (2008). Detection of cortical thickness correlates of cognitive
performance: Reliability across MRI scan sessions, scanners, and field strengths.
NeuroImage, 39(1), 1018.
Evans, A. C. (2013). Networks of anatomical covariance. NeuroImage, 80, 489504.
Fischl, B., & Dale, A. M. (2000). Measuring the thickness of the human cerebral cortex
from magnetic resonance images. Proceedings of the National Academy of Sciences
of the United States of America, 97(20), 1105011055.
Geyer, S., Weiss, M., Reimann, K., Lohmann, G., & Turner, R. (2011). Microstructural
parcellation of the human cerebral cortex From Brodmanns post-mortem Map to
in vivo mapping with high-field magnetic resonance imaging. Frontiers in Human
Neuroscience, 5, 19.
Gogtay, N., et al. (2004). Dynamic mapping of human cortical development during
childhood through early adulthood. Proceedings of the National Academy of
Sciences of the United States of America, 101(21), 81748179.
GrandMaison, M., et al. (2013). Early cortical thickness changes predict b-amyloid
deposition in a mouse model of Alzheimers disease. Neurobiology of Disease, 54,
5967.
Hebert, F., GrandMaison, M., Ho, M., Lerch, J. P., Hamel, E., & Bedell, B. J. (2013).
Cortical atrophy and hypoperfusion in a transgenic mouse model of Alzheimers
disease. Neurobiology of Aging, 34(6), 16441652.
Hyde, K. L., et al. (2007). Cortical thickness in congenital amusia: When less is better
than more. Journal of Neuroscience, 27(47), 1302813032.
Hyde, K. L., Lerch, J., Norton, A. C., Forgeard, M., Winner, E., Evans, A. C., et al.
(2009). Musical training shapes structural brain development. Journal of
Neuroscience, 29(10), 30193025.
Jones, S. E., Buchbinder, B. R., & Aharon, I. (2000). Three-dimensional mapping of
cortical thickness using Laplaces equation. Human Brain Mapping, 11(1), 1232.
Kabani, N., Legoualher, G., Macdonald, D., & Evans, A. C. (2001). Measurement of
cortical thickness using an automated 3-D algorithm: A validation study.
NeuroImage, 13(2), 375380.
Karama, S., et al. (2013). Childhood cognitive ability accounts for associations between
cognitive ability and brain cortical thickness in old age. Molecular Psychiatry, 19(5),
555559.
Kim, J. S., et al. (2005). Automated 3-D extraction and evaluation of the inner and outer
cortical surfaces using a Laplacian map and partial volume effect classification.
NeuroImage, 27(1), 210221.
Leigland, L. A., Ford, M. M., Lerch, J. P., & Kroenke, C. D. (2013). The influence of fetal
ethanol exposure on subsequent development of the cerebral cortex as revealed by
magnetic resonance imaging. Alcoholism: Clinical and Experimental Research,
37(6), 924932.
355
Glossary
Registration-Based Labeling
Single-Subject Atlas
In the simplest case, the atlas can be the labeled brain of a single
subject. This strategy has been used to transfer labels of cortical
folds or other macroanatomical brain structures from one
labeled subject to another (Lancaster et al., 2000; Sandor &
Leahy, 1997; Shen & Davatzikos, 2002; Tzourio-Mazoyer et al.,
2002). Cortical areas defined using architectonics can be transferred between histological slices and the MRI anatomical scan
of the same subject (Schormann & Zilles, 1998). Van Essen and
colleagues (Van Essen, 2004; Van Essen et al., 2012) had utilized
this strategy to transfer cortical areas derived from visuotopic
functional Magnetic Resonance Imaging (fMRI), task-based
http://dx.doi.org/10.1016/B978-0-12-397025-1.00306-7
357
358
INTRODUCTION TO METHODS AND MODELING | Automatic Labeling of the Human Cerebral Cortex
(a)
(b)
Area 6
7.6
12.5
Area 2
(e)
hOc5
Area 45
(c)
0.2
1.0
(d)
Figure 1 Different types of cortical labels. (a) Cortical labels based on macroanatomy. Gyral-based regions of interest were labeled in a training set of 40
subjects (Desikan et al., 2006), which were then used to train a Markov random field (MRF) classifier for labeling a new subject (Fischl et al., 2004)
from the OASIS (Marcus et al., 2007) dataset. Section Fusion of Registration-Based Labeling and Mixture Models discusses this general approach.
(b) Cortical label based on cortical function. The cortical label was estimated from an automated forward inference meta-analysis of the term MT in MNI
space (Yarkoni, Poldrack, Nichols, Van Essen, & Wager, 2011) and projected to FreeSurfer (Fischl, 2012) fsaverage surface space using
a nonlinear transformation estimated from 1000 subjects (Buckner, Krienen, Castellanos, Diaz, & Yeo, 2011). A high value indicates high likelihood that
studies associated with the motion-sensitive area MT report activations at that spatial location. (c) Cortical labels based on architectonics. Areas 2 (Grefkes,
Geyer, Schormann, Roland, & Zilles, 2001), 6 (Geyer, 2004), 45 (Amunts et al., 1999), and hOc5 (Malikovic et al., 2007) were delineated in ten postmortem
brains based on observer-independent cytoarchitectonic analysis. These areas were mapped onto the FreeSurfer fsaverage space to create prior probability
maps of different cytoarchitectonic areas (Fischl et al., 2008; Yeo et al., 2010b). Area hOc5 may correspond to the region in (b). Section Registration-Based
Labeling discusses this registration-based labeling approach. (d) Cortical labels based on resting-state functional connectivity MRI. Connectivity profiles of
every vertex across both cerebral hemispheres of 1000 subjects were computed and averaged in FreeSurfer fsaverage surface space. The averaged profiles
were modeled with a mixture of von MisesFisher distributions and clustered into networks of regions with similar patterns of connectivity (Yeo et al.,
2011). The resulting parcelation was projected to Caret (Van Essen & Dierker, 2007) PALS-B12 surface space for visualization. Section Mixture Models
discusses this general approach. (e) Cortical labels based on functional topography. Topography of visual areas in a single subject was interrogated using
phase-encoded retinotopic mapping with a rotating angular wedge visual stimuli and spectral analysis (Adapted from Swisher, J.D., Halko, M.A., Merabet,
L.B., McMains, S.A., & Somers, D.C. (2007). Visual topography of human intraparietal sulcus. The Journal of Neuroscience 27, 53265337). Red represents
the upper visual meridian, blue represents the contralateral horizontal meridian, and green represents the lower meridian.
Mixture Models
The registration-based approach (Section Registration-Based
Labeling) assumes the availability of other labeled subjects.
INTRODUCTION TO METHODS AND MODELING | Automatic Labeling of the Human Cerebral Cortex
However, in many situations, an atlas with prior information
might not be available. Therefore, an orthogonal approach is
to directly model the relationship between image features and
cortical labels in the absence of previously labeled training
subjects.
More formally, suppose there are N cortical locations. Let
x {xn} denote the set of cortical locations: n 2 {1, . . ., N}. Let
y {yn} and L {Ln} denote the image features and cortical
labels, respectively, at locations {xn}. We assume there are K
cortical labels of interest, so Ln 2 {1, . . ., K}. Our goal is to
estimate L.
One common approach is to assume the observed features
{yn} are generated from a mixture model. In particular, the
model assumes each cortical label Ln is independently drawn
from a probability distribution, that is, p(L) Pnp(Ln). This is a
key difference with Section Multisubject or Population Atlas,
where the prior came from the training data. Assuming identical distributions across spatial locations, p(Ln) is parameterized
P
by the vector m m1 ; . . . ; mK ; k mk 1.
Conditioned on the cortical label Ln at spatial location xn,
the observed features yn are assumed to be generated from the
distribution p(yn|Ln). We assume that p(yn|Ln) is parameterized
by y {y1, . . ., yK}. For example, if p(yn|Ln) is a Gaussian distribution, then yk might correspond to the mean and variance of
the k-th Gaussian distribution and the entire model is known
as a Gaussian mixture model.
A common way to solve for L is to maximize the likelihood
or posterior probability of the parameters m and y assuming the
observation of the image features y. This can be achieved via
numerical optimization schemes, such as the expectation
maximization (EM) algorithm (Dempster, Laird, & Rubin,
1977). These types of methods essentially perform a datadriven clustering and thus identify clusters of voxels or vertices
that are assigned a label. The well-known k-means clustering
algorithm (MacQueen et al., 1967) can be interpreted as a
special case of this mixture modeling approach.
This clustering (mixture model or k-means) strategy was
used for the segmentation of different tissue types in anatomical MRI data (Kapur, Grimson, Wells, & Kikinis, 1996; Teo,
Sapiro, & Wandell, 1997; Wells, Grimson, Kikinis, & Jolesz,
1996). The same approach has been applied to cortical labels
based on task-based fMRI (Flandin, Kherif, Pennec,
Malandain, et al., 2002; Flandin, Kherif, Pennec, Rivie`re,
et al., 2002; Goutte, Toft, Rostrup, Nielsen, & Hansen, 1999;
Penny & Friston, 2003), connectivity measured by diffusion
MRI (Anwander, Tittgemeyer, von Cramon, Friederici, &
Knosche, 2007; Beckmann, Johansen-Berg, & Rushworth,
2009; Klein et al., 2007; Mars et al., 2011; Nanetti, Cerliani,
Gazzola, Renken, & Keysers, 2009; Tomassini et al., 2007),
connectivity measured by resting-state fMRI (Bellec, RosaNeto, Lyttelton, Benali, & Evans, 2010; Cauda et al., 2011;
Chang, Yarkoni, Khaw, & Sanfey, 2013; Deen, Pitskel, &
Pelphrey, 2011; Golland, Golland, Bentin, & Malach, 2008;
Kahnt, Chang, Park, Heinzle, & Haynes, 2012; Kelly et al.,
2012; Kim et al., 2010; Yeo et al., 2011), and activation coordinates from meta-analysis of functional studies (Cauda et al.,
2012; Kelly et al., 2012).
In the context of cortical labeling, other popular clustering
approaches in the neuroimaging literature include hierarchical
clustering (Bellec et al., 2010; Cauda et al., 2011; Cieslik et al.,
359
2012; Eickhoff et al., 2011; Kelly et al., 2012), spectral clustering (Craddock, James, Holtzheimer, Hu, & Mayberg, 2012;
Thirion et al., 2006; van den Heuvel, Mandl, & Pol, 2008),
and fuzzy clustering (Cauda et al., 2011; Lee et al., 2012).
Unlike mixture modeling, these approaches do not enjoy a
simple generative modeling interpretation.
360
INTRODUCTION TO METHODS AND MODELING | Automatic Labeling of the Human Cerebral Cortex
1
exp U L
ZU
[2]
xn
pL
X
1
exp n W Ln
ZW
X X
1
exp x
V Ln ; Lm
xm 2N xn
n
Z V
Y 1
exp W Ln
nZ
n
X X
1
exp x
V
L
;
L
n
m
xm 2N xn
n
Z V
[4]
[5]
Summary
L
m
(a)
(b)
L
Y
V
(c)
Figure 2 Graphical models summarizing approaches in this article. (a) Model corresponding to the registration-based approach (Section
Registration-Based Labeling). (b) Model corresponding to the mixture modeling approach (Section Mixture Models). (c) Model corresponding
to the MRF approach (Section Fusion of Registration-Based Labeling and Mixture Models). The shaded circles indicate that the features Y are
observed. The arrows indicate conditional dependencies. For example, in (b) and (c), y is conditionally dependent on y and L. L and y are independent.
However, L and y are no longer independent when conditioned on y.
INTRODUCTION TO METHODS AND MODELING | Automatic Labeling of the Human Cerebral Cortex
on the labels L and the likelihood parameters y. Finally, the
MRF approach (Section Fusion of Registration-Based Labeling and Mixture Models) can be represented by the model in
Figure 2(c). Here, the local potentials W replace m and the
labels L also depend on the clique potentials V.
The approaches mentioned earlier have been especially
successful for cortical labeling based on macroanatomy, connectivity (diffusion and resting state), architectonics, and function (meta-analysis of activation coordinates). They are less
popular in task-based fMRI, which generally employs general
linear modeling of the hemodynamic response, and in visuotopic mapping, which generally employs spectral or Fourier
techniques.
Other approaches not covered in this article include independent component analysis; morphological approaches, such
as edge detection (Cohen et al., 2008; Nelson et al., 2010) and
watershed (Lohmann & von Cramon, 2000; Rettmann, Han,
Xu, & Prince, 2002); and machine learning techniques, such
as discriminative models (Tu et al., 2008), neural networks
(Mangin et al., 2004; Riviere et al., 2002), and label fusion
(Heckemann et al., 2006; Sabuncu, Yeo, Van Leemput, Fischl,
& Golland, 2010).
References
Amunts, K., Schleicher, A., Burgel, U., Mohlberg, H., Uylings, H., & Zilles, K. (1999).
Brocas region revisited: Cytoarchitecture and intersubject variability. Journal of
Comparative Neurology, 412, 319341.
Anwander, A., Tittgemeyer, M., von Cramon, D. Y., Friederici, A. D., & Knosche, T. R.
(2007). Connectivity-based parcellation of Brocas area. Cerebral Cortex, 17,
816825.
Beckmann, M., Johansen-Berg, H., & Rushworth, M. F. (2009). Connectivity-based
parcellation of human cingulate cortex and its relation to functional specialization.
The Journal of Neuroscience, 29, 11751190.
Bellec, P., Rosa-Neto, P., Lyttelton, O. C., Benali, H., & Evans, A. C. (2010).
Multi-level bootstrap analysis of stable clusters in resting-state fMRI. NeuroImage,
51, 1126.
361
Buckner, R. L., Krienen, F. M., Castellanos, A., Diaz, J. C., & Yeo, B. T. (2011). The
organization of the human cerebellum estimated by intrinsic functional connectivity.
Journal of Neurophysiology, 106, 23222345.
Cauda, F., Costa, T., Torta, D. M., Sacco, K., DAgata, F., Duca, S., et al. (2012). Metaanalytic clustering of the insular cortex characterizing the meta-analytic connectivity
of the insula when involved in active tasks. NeuroImage, 62(1), 343355.
Cauda, F., DAgata, F., Sacco, K., Duca, S., Geminiani, G., & Vercelli, A. (2011).
Functional connectivity of the insula in the resting brain. NeuroImage, 55, 823.
Chang, L. J., Yarkoni, T., Khaw, M. W., & Sanfey, A. G. (2013). Decoding the role of the
insula in human cognition: Functional parcellation and large-scale reverse
inference. Cerebral Cortex, 23, 739749.
Christensen, G. E., Joshi, S. C., & Miller, M. I. (1997). Volumetric transformation of
brain anatomy. IEEE Transactions on Medical Imaging, 16, 864877.
Cieslik, E. C., Zilles, K., Caspers, S., Roski, C., Kellermann, T. S., Jakobs, O., et al.
(2013). Is there one DLPFC in cognitive action control? Evidence for heterogeneity
from co-activation-based parcellation. Cerebral Cortex, 23(11), 26772689.
Cohen, A. L., Fair, D. A., Dosenbach, N. U., Miezin, F. M., Dierker, D., Van Essen, D. C.,
et al. (2008). Defining functional areas in individual human brains using resting
functional connectivity MRI. NeuroImage, 41, 45.
Collins, D. L., Holmes, C. J., Peters, T. M., & Evans, A. C. (1995). Automatic 3-D
model-based neuroanatomical segmentation. Human Brain Mapping, 3, 190208.
Collins, D. L., Zijdenbos, A. P., Baare, W. F., & Evans, A. C. (1999). Animal Insect:
Improved cortical structure segmentation. In Information processing in medical
imaging (pp. 210223). Berlin: Springer.
Craddock, R. C., James, G. A., Holtzheimer, P. E., Hu, X. P., & Mayberg, H. S. (2012). A
whole brain fMRI atlas generated via spatially constrained spectral clustering.
Human Brain Mapping, 33, 19141928.
Deen, B., Pitskel, N. B., & Pelphrey, K. A. (2011). Three systems of insular functional
connectivity identified with cluster analysis. Cerebral Cortex, 21, 14981506.
Dempster, A. P., Laird, N. M., & Rubin, D. B. (1977). Maximum likelihood from
incomplete data via the EM algorithm. Journal of the Royal Statistical Society: Series
B: Methodological, 39, 138.
Desikan, R. S., Segonne, F., Fischl, B., Quinn, B. T., Dickerson, B. C., Blacker, D., et al.
(2006). An automated labeling system for subdividing the human cerebral cortex on
MRI scans into gyral based regions of interest. NeuroImage, 31, 968980.
Destrieux, C., Fischl, B., Anders, D., & Halgren, E. (2010). Automatic parcellation of
human cortical gyri and sulci using standard anatomical nomenclature.
NeuroImage, 53, 1.
Dobruschin, P. (1968). The description of a random field by means of conditional
probabilities and conditions of its regularity. Theory of Probability and Its
Applications, 13, 197224.
Eickhoff, S. B., Bzdok, D., Laird, A. R., Roski, C., Caspers, S., Zilles, K., et al. (2011).
Co-activation patterns distinguish cortical modules, their connectivity and
functional differentiation. NeuroImage, 57, 938949.
Eickhoff, S. B., Stephan, K. E., Mohlberg, H., Grefkes, C., Fink, G. R., Amunts, K., et al.
(2005). A new SPM toolbox for combining probabilistic cytoarchitectonic maps and
functional imaging data. NeuroImage, 25, 13251335.
Evans, A., Kamber, M., Collins, D., & MacDonald, D. (1994). An MRI-based
probabilistic atlas of neuroanatomy. In Magnetic resonance scanning and epilepsy
(pp. 263274). USA: Springer.
Felleman, D. J., & Van Essen, D. C. (1991). Distributed hierarchical processing in the
primate cerebral cortex. Cerebral Cortex, 1, 147.
Fischl, B. (2012). Freesurfer. NeuroImage, 62, 774781.
Fischl, B., Rajendran, N., Busa, E., Augustinack, J., Hinds, O., Yeo, B. T., et al. (2008).
Cortical folding patterns and predicting cytoarchitecture. Cerebral Cortex, 18,
19731980.
Fischl, B., Salat, D. H., Busa, E., Albert, M., Dieterich, M., Haselgrove, C., et al. (2002).
Whole brain segmentation: Automated labeling of neuroanatomical structures in the
human brain. Neuron, 33, 341355.
Fischl, B., Van Der Kouwe, A., Destrieux, C., Halgren, E., Segonne, F., Salat, D. H., et al.
(2004). Automatically parcellating the human cerebral cortex. Cerebral Cortex, 14,
1122.
Flandin, G., Kherif, F., Pennec, X., Malandain, G., Ayache, N., & Poline, J. B. (2002).
Improved detection sensitivity in functional MRI data using a brain parcelling
technique. In Medical image computing and computer- assisted intervention
(pp. 467474). London: Springer-Verlag.
Flandin, G., Kherif, F., Pennec, X., Rivie`re, D., Ayache, N., & Poline, J. B. (2002).
Parcellation of brain images with anatomical and functional constraints for fMRI data
analysis. In IEEE International Symposium on Biomedical Imaging (pp. 907910).
IEEE.
Fonov, V., Evans, A. C., Botteron, K., Almli, C. R., McKinstry, R. C., & Collins, D. L.
(2011). Unbiased average age-appropriate atlases for pediatric studies.
NeuroImage, 54(1), 313327.
362
INTRODUCTION TO METHODS AND MODELING | Automatic Labeling of the Human Cerebral Cortex
Geyer, S. (2004). The microstructural border between the motor and the cognitive
domain in the human cerebral cortex. Advances in Anatomy, Embryology, and Cell
Biology, 174, 189.
Golland, Y., Golland, P., Bentin, S., & Malach, R. (2008). Data-driven clustering reveals
a fundamental subdivision of the human cortex into two global systems.
Neuropsychologia, 46, 540553.
Goutte, C., Toft, P., Rostrup, E., Nielsen, F.A., & Hansen, L. K. (1999). On clustering
fMRI time series. NeuroImage, 9, 298310.
Grefkes, C., Geyer, S., Schormann, T., Roland, P., & Zilles, K. (2001). Human
somatosensory area 2: Observer-independent cytoarchitectonic mapping,
interindividual variability, and population map. NeuroImage, 14, 617631.
Heckemann, R. A., Hajnal, J. V., Aljabar, P., Rueckert, D., Hammers, A., et al. (2006).
Automatic anatomical brain MRI segmentation combining label propagation and
decision fusion. NeuroImage, 33, 115126.
Held, K., Kops, E. R., Krause, B. J., Wells, W. M., III, Kikinis, R., & Muller-Gartner, H. W.
(1997). Markov random field segmentation of brain MR images. IEEE Transactions
on Medical Imaging, 16, 878886.
van den Heuvel, M., Mandl, R., & Pol, H. H. (2008). Normalized cut group clustering of
resting-state fMRI data. PloS One, 3, e2001.
Hinds, O. P., Rajendran, N., Polimeni, J. R., Augustinack, J. C., Wiggins, G., Wald, L. L.,
et al. (2008). Accurate prediction of V1 location from cortical folds in a surface
coordinate system. NeuroImage, 39, 1585.
Jirousek, R., & Preucil, S. (1995). On the effective implementation of the iterative
proportional fitting procedure. Computational Statistics and Data Analysis, 19,
177189.
Kaas, J. H. (1987). The organization of neocortex in mammals: Implications for theories
of brain function. Annual Review of Psychology, 38, 129151.
Kahnt, T., Chang, L. J., Park, S. Q., Heinzle, J., & Haynes, J. D. (2012). Connectivitybased parcellation of the human orbitofrontal cortex. The Journal of Neuroscience,
32, 62406250.
Kapur, T., Grimson, W. E.L, Wells, W. M., III, & Kikinis, R. (1996). Segmentation of brain
tissue from magnetic resonance images. Medical Image Analysis, 1, 109127.
Kelly, C., Toro, R., Di Martino, A., Cox, C. L., Bellec, P., Castellanos, F. X., et al. (2012).
A convergent functional architecture of the insula emerges across imaging
modalities. NeuroImage, 61, 11291142.
Kim, J. H., Lee, J. M., Jo, H. J., Kim, S. H., Lee, J. H., Kim, S. T., et al. (2010).
Defining functional SMA and pre-SMA subregions in human MFC using resting
state fMRI: Functional connectivity-based parcellation method. NeuroImage, 49,
23752386.
Klein, A., & Tourville, J. (2012). 101 labeled brain images and a consistent human
cortical labeling protocol. Frontiers in Neuroscience, 6, 171. http://dx.doi.org/
10.3389/fnins.2012.00171.
Klein, J. C., Behrens, T. E., Robson, M. D., Mackay, C. E., Higham, D. J., &
Johansen-Berg, H. (2007). Connectivity-based parcellation of human cortex using
diffusion MRI: Establishing reproducibility, validity and observer independence in
BA 44/45 and SMA/pre-SMA. NeuroImage, 34, 204211.
Kolmogorov, V., & Zabin, R. (2004). What energy functions can be minimized via graph
cuts? IEEE Transactions on Pattern Analysis and Machine Intelligence, 26,
147159.
Lancaster, J. L., Woldorff, M. G., Parsons, L. M., Liotti, M., Freitas, C. S., Rainey, L.,
et al. (2000). Automated Talairach atlas labels for functional brain mapping. Human
Brain Mapping, 10, 120131.
Lee, M. H., Hacker, C. D., Snyder, A. Z., Corbetta, M., Zhang, D., Leuthardt, E. C., et al.
(2012). Clustering of resting state networks. PloS One, 7, e40370.
Lohmann, G., & von Cramon, D. Y. (2000). Automatic labelling of the human cortical
surface using sulcal basins. Medical Image Analysis, 4, 179188.
MacQueen, J., et al. (1967). Some methods for classification and analysis of
multivariate observations. In: Proceedings of the Fifth Berkeley Symposium on
Mathematical Statistics and Probability, CA, USA.
Malikovic, A., Amunts, K., Schleicher, A., Mohlberg, H., Eickhoff, S. B., Wilms, M., et al.
(2007). Cytoarchitectonic analysis of the human extrastriate cortex in the region of V5/
MT: A probabilistic, stereotaxic map of area hoc5. Cerebral Cortex, 17, 562574.
Mangin, J. F., Riviere, D., Cachia, A., Duchesnay, E., Cointepas, Y.,
Papadopoulos-Orfanos, D., et al. (2004). Object-based morphometry of the cerebral
cortex. IEEE Transactions on Medical Imaging, 23, 968982.
Marcus, D. S., Wang, T. H., Parker, J., Csernansky, J. G., Morris, J. C., & Buckner, R. L.
(2007). Open access series of imaging studies (oasis): Cross-sectional MRI data in
young, middle aged, nondemented, and demented older adults. Journal of Cognitive
Neuroscience, 19, 14981507.
Mars, R. B., Jbabdi, S., Sallet, J., OReilly, J. X., Croxson, P. L., Olivier, E., et al. (2011).
Diffusion-weighted imaging tractography-based parcellation of the human parietal
cortex and comparison with human and macaque resting-state functional
connectivity. The Journal of Neuroscience, 31, 40874100.
Mazziotta, J. C., Toga, A. W., Evans, A., Fox, P., Lancaster, J., et al. (1995).
A probabilistic atlas of the human brain: theory and rationale for its development.
The international consortium for brain mapping (ICBM). NeuroImage, 2, 89101.
Miller, M. I., Christensen, G. E., Amit, Y., & Grenander, U. (1993). Mathematical
textbook of deformable neuroanatomies. Proceedings of the National Academy of
Sciences, 90, 1194411948.
Nanetti, L., Cerliani, L., Gazzola, V., Renken, R., & Keysers, C. (2009). Group analyses
of connectivity-based cortical parcellation using repeated k-means clustering.
NeuroImage, 47, 16661677.
Nelson, S. M., Cohen, A. L., Power, J. D., Wig, G. S., Miezin, F. M., Wheeler, M. E., et al.
(2010). A parcellation scheme for human left lateral parietal cortex. Neuron, 67, 156.
Ono, M., Kubik, S., Abernathey, C. D., et al. (1990). Atlas of the Cerebral Sulci.
New York: Thieme.
Orban, G. A., Van Essen, D., & Vanduffel, W. (2004). Comparative mapping of higher
visual areas in monkeys and humans. Trends in Cognitive Sciences, 8, 315324.
Penny, W., & Friston, K. (2003). Mixtures of general linear models for functional
neuroimaging. IEEE Transactions on Medical Imaging, 22, 504514.
Rajapakse, J. C., & Piyaratna, J. (2001). Bayesian approach to segmentation of statistical
parametric maps. IEEE Transactions on Biomedical Engineering, 48, 11861194.
Rajkowska, G., & Goldman-Rakic, P. S. (1995). Cytoarchitectonic definition of prefrontal
areas in the normal human cortex: II. Variability in locations of areas 9 and 46 and
relationship to the Talairach coordinate system. Cerebral Cortex, 5, 323337.
Rettmann, M. E., Han, X., Xu, C., & Prince, J. L. (2002). Automated sulcal segmentation
using watersheds on the cortical surface. NeuroImage, 15, 329344.
Riviere, D., Mangin, J. F., Papadopoulos-Orfanos, D., Martinez, J. M., Frouin, V., &
Regis, J. (2002). Automatic recognition of cortical sulci of the human brain using a
congregation of neural networks. Medical Image Analysis, 6, 7792.
Robert, C. P., & Casella, G. (2004). In Monte Carlo Statistical Methods: (vol. 319).
New York: Springer-Verlag.
Ryali, S., Chen, T., Supekar, K., & Menon, V. (2012). A parcellation scheme based on
von MisesFisher distributions and Markov random fields for segmenting brain
regions using resting-state fMRI. NeuroImage, 65, 8396.
Sabuncu, M. R., Yeo, B. T., Van Leemput, K., Fischl, B., & Golland, P. (2010). A
generative model for image segmentation based on label fusion. IEEE Transactions
on Medical Imaging, 29, 17141729.
Sandor, S., & Leahy, R. (1997). Surface-based labeling of cortical anatomy using a
deformable atlas. IEEE Transactions on Medical Imaging, 16, 4154.
Schormann, T., & Zilles, K. (1998). Three-dimensional linear and nonlinear
transformations: An integration of light microscopical and MRI data. Human Brain
Mapping, 6, 339347.
Shattuck, D. W., Mirza, M., Adisetiyo, V., Hojatkashani, C., Salamon, G., Narr, K. L.,
et al. (2008). Construction of a 3D probabilistic atlas of human cortical structures.
NeuroImage, 39, 10641080.
Shen, D., & Davatzikos, C. (2002). Hammer: Hierarchical attribute matching mechanism
for elastic registration. IEEE Transactions on Medical Imaging, 21, 14211439.
Smith, S. M., Jenkinson, M., Woolrich, M. W., Beckmann, C. F., Behrens, T.,
Johansen-Berg, H., et al. (2004). Advances in functional and structural MR image
analysis and implementation as FSL. NeuroImage, 23, S208S219.
Spitzer, F. (1971). Markov random fields and Gibbs ensembles. The American
Mathematical Monthly, 78, 142154.
Steen, R. G., Reddick, W. E., & Ogg, R. J. (2000). More than meets the eye: Significant
regional heterogeneity in human cortical T1. Magnetic Resonance Imaging, 18,
361368.
Svensen, M., Kruggel, F., & von Cramon, D. Y. (2000). Probabilistic modeling of
single-trial fMRI data. IEEE Transactions on Medical Imaging, 19, 2535.
Swisher, J. D., Halko, M. A., Merabet, L. B., McMains, S. A., & Somers, D. C. (2007).
Visual topography of human intraparietal sulcus. The Journal of Neuroscience, 27,
53265337.
Teo, P. C., Sapiro, G., & Wandell, B. A. (1997). Creating connected representations of
cortical gray matter for functional MRI visualization. IEEE Transactions on Medical
Imaging, 16, 852863.
Thirion, B., Flandin, G., Pinel, P., Roche, A., Ciuciu, P., & Poline, J. B. (2006). Dealing
with the shortcomings of spatial normalization: Multi-subject parcellation of fMRI
datasets. Human Brain Mapping, 27, 678693.
Thompson, P., & Toga, A. W. (1996). A surface-based technique for warping threedimensional images of the brain. IEEE Transactions on Medical Imaging, 15, 402417.
Tomassini, V., Jbabdi, S., Klein, J. C., Behrens, T. E., Pozzilli, C., Matthews, P. M., et al.
(2007). Diffusion-weighted imaging tractography-based parcellation of the human
lateral premotor cortex identifies dorsal and ventral subregions with anatomical and
functional specializations. The Journal of Neuroscience, 27, 1025910269.
Tu, Z., Narr, K. L., Dollar, P., Dinov, I., Thompson, P. M., & Toga, A. W. (2008). Brain
anatomical structure segmentation by hybrid discriminative/generative models. IEEE
Transactions on Medical Imaging, 27, 495508.
INTRODUCTION TO METHODS AND MODELING | Automatic Labeling of the Human Cerebral Cortex
Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F., Etard, O.,
Delcroix, N., et al. (2002). Automated anatomical labeling of activations in SPM
using a macroscopic anatomical parcellation of the MNI MRI single-subject brain.
NeuroImage, 15, 273289.
Ungerleider, L. G., & Desimone, R. (1986). Cortical connections of visual area MT in the
macaque. Journal of Comparative Neurology, 248, 190222.
Van Essen, D. C. (2004). Organization of visual areas in macaque and human cerebral
cortex. In L. Chalupa, & J. Werner (Eds.), The visual neurosciences (pp. 507521).
Cambridge, MA: MIT Press.
Van Essen, D. C., & Dierker, D. L. (2007). Surface-based and probabilistic atlases of
primate cerebral cortex. Neuron, 56, 209225.
Van Essen, D. C., Glasser, M. F., Dierker, D. L., Harwell, J., & Coalson, T. (2012).
Parcellations and hemispheric asymmetries of human cerebral cortex analyzed on
surface-based atlases. Cerebral Cortex, 22, 22412262.
Van Leemput, K., Maes, F., Vandermeulen, D., & Suetens, P. (1999). Automated
model-based tissue classification of MR images of the brain. IEEE Transactions on
Medical Imaging, 18, 897908.
Wainwright, M. J., & Jordan, M. I. (2008). Graphical models, exponential families,
and variational inference. Foundations and Trends in Machine Learning, 1, 1305.
Wells, W. M., III, Grimson, W. E. L., Kikinis, R., & Jolesz, F. A. (1996). Adaptive
segmentation of MRI data. IEEE Transactions on Medical Imaging, 15, 429442.
Woolrich, M. W., & Behrens, T. E. (2006). Variational Bayes inference of spatial
mixture models for segmentation. IEEE Transactions on Medical Imaging, 25,
13801391.
363
Yarkoni, T., Poldrack, R.A., Nichols, T.E., Van Essen, D.C., & Wager, T.D. (2011).
NeuroSynth. http://neurosynth.org. Accessed 21.05.13.
Yarkoni, T., Poldrack, R. A., Nichols, T. E., Van Essen, D. C., & Wager, T. D. (2011).
Large-scale automated synthesis of human functional neuroimaging data. Nature
Methods, 8, 665670.
Yeo, B. T., Krienen, F. M., Sepulcre, J., Sabuncu, M. R., Lashkari, D., Hollinshead, M.,
et al. (2011). The organization of the human cerebral cortex estimated by intrinsic
functional connectivity. Journal of Neurophysiology, 106, 11251165.
Yeo, B. T., Sabuncu, M. R., Desikan, R., Fischl, B., & Golland, P. (2008). Effects of
registration regularization and atlas sharpness on segmentation accuracy. Medical
Image Analysis, 12, 603615.
Yeo, B. T., Sabuncu, M. R., Vercauteren, T., Ayache, N., Fischl, B., & Golland, P. (2010).
Spherical demons: Fast diffeomorphic landmark-free surface registration. IEEE
Transactions on Medical Imaging, 29, 650668.
Yeo, B. T., Sabuncu, M. R., Vercauteren, T., Holt, D. J., Amunts, K., Zilles, K., et al.
(2010). Learning task-optimal registration cost functions for localizing
cytoarchitecture and function in the cerebral cortex. IEEE Transactions on Medical
Imaging, 29, 14241441.
Zhang, Y., Brady, M., & Smith, S. (2001). Segmentation of brain MR images through a
hidden Markov random field model and the expectation-maximization algorithm.
IEEE Transactions on Medical Imaging, 20, 4557.
Zilles, K., Armstrong, E., Schleicher, A., & Kretschmann, H. J. (1988). The human
pattern of gyrification in the cerebral cortex. Anatomy and Embryology, 179,
173179.
of the folding global features (Germanaud et al., 2012). Following the footsteps of the neuroanatomists is more ambitious
because it requires the identification of the sulci described in
the literature. Very few experts can perform this difficult and
tedious task for the complete cerebral cortex. With the usual
radiological point of view, namely, a series of slices, even the
largest sulci can be difficult to recognize, which explains the
scarcity of relevant knowledge to overcome the interindividual
variability (see Figure 1). 3-D rendering of the cortical surface is
of great help, but it is often insufficient to deal with unusual
folding patterns that require inspecting the shape of the fold
depths (Regis et al., 2005). Hence, combining 3-D and 2-D
views is often mandatory. Cortical inflation is an attractive
alternative to exhibit the buried cortex (Van Essen, Drury,
Joshi, & Miller, 1998), but the deformations from the actual
folding geometry can be disturbing for sulcus identification.
Whatever the visualization strategy, our ignorance with respect
to the origin of the variability prevents us to decode safely
configurations where the main sulci are split into pieces and
reorganized into unusual patterns. A dedicated atlas describing
the most usual patterns is probably the best guideline for sulcus
identification, but this atlas is not comprehensive because
it stems from the study of only 25 brains (Ono, Kubik, &
Abarnathey, 1990). The reliable identification of secondary
and tertiary folds (Petrides, 2012) is beyond reach with the
current state of knowledge.
The complexity of the cortical folding pattern is overwhelming for human experts. Hence, computational anatomy is now
a key player to help the field to harness the folding variability.
Alignment with a single-subject cortical surface atlas has the
merit to provide the rough localization of primary sulci
(Destrieux, Fischl, Dale, & Halgren, 2010), but is not sufficient
to obtain accurate definition of the sulci for shape analysis. The
idiosyncrasies of the template brain are not a good model for
any other brain. The solution could lie into multisubject atlases
(Heckemann, Hajnal, Aljabar, Rueckert, & Hammers, 2006),
but this approach may not be flexible enough to overcome the
ambiguities hampering a reliable pairwise alignment between
cortical patterns. Hence, the community developed alternatives
with a stronger computer vision flavor. First, bottom-up processing pipelines convert standard MR images into synthetic
representations of individual folding geometries; and second,
pattern recognition techniques match such representations
with a model of the sulci (see Figure 2). Automatic recognition
of the sulci provides a range of opportunities for morphometry
(see Figure 3; Mangin, Jouvent, & Cachia, 2010) or sulcusdriven spatial normalization (Auzias et al., 2011, 2013; Joshi
et al., 2010; Thompson & Toga, 1996).
http://dx.doi.org/10.1016/B978-0-12-397025-1.00307-9
365
S.Pe.C.median.
F.C.L.r.diag.
F.C.L.r.asc.
F.C.L.r.ant.
An artificial neuroanatomis
S.Pe.C.marginal.
S.Pe.C.sup.
S.Pe.C.inter.
S.Pe.C.inf.
S.C.
F.C.L.r.retroC.tr.
F.I.P.Po.C.inf.
S.Po.C.sup.
S.Pa.sup.
S.GSM.
S.F.sup.
F.I.P.r.int.1
S.T.s.ter.asc.ant
F.I.P.r.int.2
S.F.inter.
3-D Retina
Elementary folds
S.F.inf.
F.I.P.
S.T.s.ter.asc.post.
S.F.inf.ant.
S.F.marginal.
Occipital
S.F.orbitaire.
S.Or.
F.C.L.a.
F.C.L.p.
Insula
S.T.pol.
S.T.i.post.
S.O.T.lat.post.
S.O.T.lat.med.
F.C.L.r.sc.post.
S.T.i.ant.
S.C.sylvian.
S.T.s.
F.C.L.r.sc.ant.
Sulcus model
(a)
(d)
(e)
(b)
Bottom-up
processing
Pattern recognition
Sulcus
recognition
(c)
(f)
Figure 2 A computer vision pipeline mimicking a human anatomist. Its 3-D retina is the standard space of the brain mapping community. After
detection of the building blocks of the folding pattern from a negative mold of the brain, the sulci of the standard nomenclature are reassembled
according to a model inferred from a learning database. Reproduced from Perrot, M., Rivie`re, D., and Mangin, J. F. (2011). Cortical sulci recognition and
spatial normalization. Medical Image Analysis, 15(4), 529550.
367
Figure 3 Once identified, a sulcus provides various morphometric features like length (red), depth (yellow), surface area (blue), or average span
between its walls (right).
a graph: The nodes are the elementary folds and the links
represent junctions or the fact that two parallel folds build up
a gyrus.
Some approaches put the focus on the deepest part of the
3-D folding geometry. For this purpose, the representation can
rely on the bottom lines of the folds defined from the 3-D
skeleton using simple topological considerations (Lohmann,
1998; Mangin, Regis, et al., 1995; Mangin, Frouin, Bloch,
Regis, & Lopez-Krahe, 1995). When the key focus is not even
the bottom lines but the deepest points of the folding, an
alternative to the skeleton-based strategy lies in depth-based
processing. For instance, a watershed-based algorithm using
depth as altitude can be used to split the negative mold of
whiter matter in the so-called sulcal basins associated with
depth local maxima (Lohmann & von Cramon, 2000). The
main difficulty is the pruning of the basins in order to keep
only the morphologically meaningful ones.
The end of the nineties coincided with a shift from volumetric processing to surface-based processing, thanks to the
maturity of the pipelines generating spherical cortical surfaces
(Dale, Fischl, & Sereno, 1999). This transition has increased
the trend to focus on the depth of the folding, because the
embedding of the cortical surface into the 3-D space is less
accessible once the cortex is represented as a 2-D mesh. When
dealing with cortical surface meshes, the bottom lines of the
sulci are detected using variants of surface-based skeletonization algorithms acting on buried regions defined from depth or
curvature (Kao et al., 2007; Li, Guo, Nie, & Liu, 2010; Seong
et al., 2010; Shi, Thompson, Dinov, & Toga, 2008). These
methods differ mainly not only in the way they combine
depth and curvature to achieve reliable localization of the
bottom lines but also in their pruning strategy to get rid of
spurious detections. Semiautomatic approaches have been
proposed to delineate the optimal sulcus bottom line from
manually selected extremities (Le Troter, Auzias, & Coulon,
2012; Shattuck et al., 2009). A strong advantage of the
368
(a)
Sulcus Recognition
Most of the graphic representations yielded by the pipelines of
the previous section include oversegmentation of the sulci of
the nomenclature. Indeed, the geometry of a sulcus often
includes subdivisions related to branches or interruptions.
Then, the sulcus recognition requires a reconstruction process
from the set of building blocks listed in the representation,
which amounts to a labeling with the sulcus names of the
nomenclature (see Figures 2 and 4). The number of names
involved in the labeling ranges from 10 to 65 in each hemisphere, according to the richness of the sulcus model. The
labeling can be viewed as a many-to-one matching between
the representation built for a given subject and the model of
the sulci. The model of the sulci can be simply a learning data
set of individual representations labeled by a human expert
(Lyu et al., 2010) or a probabilistic representation of the sulcus
variability inferred from this learning data set: maps of the
spatial variability of each sulcus after optimal alignment across
the data set (Perrot, Rivie`re, & Mangin, 2011) or different kinds
of random graph modeling the joint variability of pairs of sulci
(Mangin, Regis, et al., 1995; Mangin, Frouin, Bloch, Regis, &
(b)
(c)
Figure 4 Standard sulcus nomenclature. (a) Three frontal lobes; (b) the skeleton of the negative brain mold used to detect folds; (1) undetected
dimples; (c) labeling of the folds with the standard sulcus nomenclature (red, central; yellow, precentral; green, superior frontal; cyan, intermediate
frontal; violet, inferior frontal; blue, sylvian valley, etc.).
369
(a)
(b)
(c)
Figure 5 Toward an alphabet of the folding pattern. (a) White matter of the Figure 4 frontal lobes; (2) buried gyri also called plis de passage;
(b, c) labeling of the folds with the sulcal roots nomenclature corresponding to putative indivisible entities. Reproduced from Regis, J., Mangin, J.,
Ochiai, T., Frouin, V., Riviere, D., Cachia, A., Tamura, M., & Samson, Y. (2005). "Sulcal root" generic model: A hypothesis to overcome the
variability of the human cortex folding patterns. Neurologia Medico-Chirurgica, 45(1), 117.
Lopez-Krahe, 1995; Riviere et al., 2002; Shi et al., 2009; Yang &
Kruggel, 2009).
The labeling of the building blocks is driven by an optimization process often casted into a Bayesian framework aiming
at maximizing the similarity between the sulci defined by the
labeling and their model. With this regard, the multiatlas
strategy of Lyu et al. has a specific status since the model is
the set of bottom lines of several instances of each sulcus
efficiently matched with the candidate sulci using a spectral
method. For the other approaches, the global similarity measure to be optimized is a sum of local similarity measures.
These local measures can stem from local registrations between
a fold and probabilistic maps of the sulci (Perrot et al., 2011),
the output of a multilayer perceptron fed with features describing the shape of sulci or pairs of sulci and trained on the
learning database (Riviere et al., 2002), and more standard
potential functions acting on shape features like localization,
orientation, length, moments, or wavelet coefficients (Mangin,
Regis, et al., 1995; Mangin, Frouin, Bloch, Regis, & LopezKrahe, 1995; Shi, Tu, et al., 2009; Yang & Kruggel, 2009). For
all these methods, dealing with graphic representations rather
than images allows the optimization process to rely on sophisticated schemes like simulated annealing (Riviere et al., 2002),
genetic algorithms (Yang & Kruggel, 2009), or belief propagation (Shi, Tu, et al., 2009b).
The lack of gold standard and the fact that only two of these
methods using the same bottom-up pipeline are distributed to
the community prevent simple comparisons (http://brainvisa.
info) (Perrot et al., 2011; Riviere et al., 2002). The leave-oneout validation versus manual labeling of the method of Perrot
et al. has shown an 86% mean recognition rate across the 65
370
the approach of Lyu et al. (2010). This data set would play the
same role as the huge pools of translated documents of institutions like the European Union for automatic language translation. Indeed, todays most advanced translation services rely
on statistical pattern matching rather than on teaching the
rules of human language to the computer. To deal with the
lack of gold standard, the learning dataset could stem from a
consensus-based labeling effort of the community of neuroanatomists in order to generate the body of information
required for the machine to do the job correctly whatever the
brain idiosyncrasies. But with our current understanding of the
variability, would the consensual labeling of unusual patterns
be really reliable? Unlike the field of language translation,
mimicking human behavior is not necessarily the best strategy
for the computer.
It should be noted that the sulcal pits model used to label
individual sulcal pits does not stem from the anatomical literature but from the field of computational anatomy. The pits in
the model are clusters of individual pits detected after nonlinear alignment of a large set of cortical surfaces (Im et al.,
2010). The sulcal pits model is in good agreement with the
sulcal roots model proposed by a human anatomist as an
alphabet of putative indivisible atomic entities supposed to
be stable across individuals because of a developmental origin
(see Figure 5; Regis et al., 2005). The sulcal pits model provides
a good foretaste of the potential of computational anatomy for
paving the way toward new more objective models of the
folding patterns. Advances in the understanding of
the folding dynamics could also largely contribute to this
research program. For instance, the intrinsic geometry of the
cortical surface provided by the first eigenvectors of the
LaplaceBeltrami operator may be intimately associated with
the folding process. The associated coordinate system could be
the ideal alignment between subjects before model inference
or sulcus recognition (Shi, Dinov, & Toga, 2009; Shi, Sun, Lai,
Dinov, & Toga, 2010; Shi, Tu, et al., 2009).
The convoluted shape of the cerebral cortex is a challenge
for human binocular vision. In return, computer vision systems can be endowed with a dedicated architecture including
3-D retina and 3-D higher-level vision areas. Furthermore, this
vision architecture dedicated to the cortical surface can be
duplicated without limit, which overcomes the working memory overload disturbing human experts trying to model the
folding pattern variability. Manifold learning technology
applied on massive databases in the spirit of Ono et al. could
help us to segregate the different folding patterns existing in the
population, in order to trigger a research program aiming at
matching these patterns according to architectural clues provided by other imaging modalities (Ono et al., 1990; Sun,
Perrot, Tucholka, Riviere, & Mangin, 2009). Therefore, computational anatomy should be the perfect assistant to support the
neuroanatomists in their quest for a better model of the
variability.
Acknowledgments
This work was supported by the European FET Flagship project
Human Brain Project (SP2), the French Agence Nationale de
la Recherche (ANR-09-BLAN-0038-01 BrainMorph, ANR-14
References
Ashburner, J. (2007). A fast diffeomorphic image registration algorithm. NeuroImage,
38(1), 95113.
Auzias, G., Colliot, O., Glaune`s, J. A., Perrot, M., Mangin, J. F., Trouve, A., et al. (2011).
Diffeomorphic brain registration under exhaustive sulcal constraints. IEEE
Transactions on Medical Imaging, 30(6), 12141227.
Auzias, G., Lefe`vre, J., Le Troter, A., Fischer, C., Perrot, M., Regis, J., et al. (2013).
Model-driven harmonic parameterization of the cortical surface: HIP-HOP. IEEE
Transactions on Medical Imaging, 32(5), 873887.
Bao, F., Giard, J., Tourville, J., & Klein, A. (2012). Automated extraction of nested
sulcus features from human brain MRI data. In IEEE Engineering in Medicine and
Biology Society (pp. 44294433).
Cachia, A., Borst, G., Vidal, J., Fischer, C., Pineau, A., Mangin, J. F., et al. (2014). The
shape of the ACC contributes to cognitive control efficiency in preschoolers. Journal
of Cognitive Neuroscience, 26(1), 96106.
Cachia, A., Mangin, J., Rivie`re, D., Boddaert, N., Andrade, A., Kherif, F., et al. (2001).
A mean curvature based primal sketch to study the cortical folding process from
antenatal to adult brain. In Medical image computing and computer-assisted
interventionMICCAI 2001 (pp. 897904).
Dale, A. M., Fischl, B., & Sereno, M. I. (1999). Cortical surface-based analysis. I.
Segmentation and surface reconstruction. NeuroImage, 9(2), 179194.
Destrieux, C., Fischl, B., Dale, A., & Halgren, E. (2010). Automatic parcellation of
human cortical gyri and sulci using standard anatomical nomenclature.
NeuroImage, 53(1), 115.
Dubois, J., Benders, M., Borradori-Tolsa, C., Cachia, A., Lazeyras, F.,
Leuchter, R. H.-V., et al. (2008). Primary cortical folding in the human newborn: An
early marker of later functional development. Brain, 131(8), 20282041.
Dubois, J., Benders, M., Cachia, A., Lazeyras, F., Leuchter, R. H.-V., Sizonenko, S. V.,
et al. (2008). Mapping the early cortical folding process in the preterm newborn
brain. Cerebral Cortex, 18(6), 14441454.
Fischl, B., Rajendran, N., Busa, E., Augustinack, J., Hinds, O., Yeo, B. T., et al. (2008).
Cortical folding patterns and predicting cytoarchitecture. Cerebral Cortex, 18(8),
19731980.
Germanaud, D., Lefe`vre, J., Toro, R., Fischer, C., Dubois, J., Hertz-Pannier, L., et al.
(2012). Larger is twistier: Spectral analysis of gyrification (SPANGY) applied to
adult brain size polymorphism. NeuroImage, 63(3), 12571272.
Heckemann, R. A., Hajnal, J. V., Aljabar, P., Rueckert, D., & Hammers, A. (2006).
Automatic anatomical brain MRI segmentation combining label propagation and
decision fusion. NeuroImage, 33(1), 115126.
Im, K., Choi, Y. Y., Yang, J. J., Lee, K. H., Kim, S. I., Grant, P. E., et al. (2011). The
relationship between the presence of sulcal pits and intelligence in human brains.
NeuroImage, 55(4), 14901496.
Im, K., Jo, H. J., Mangin, J.-F., Evans, A. C., Kim, S. I., & Lee, J.-M. (2010). Spatial
distribution of deep sulcal landmarks and hemispherical asymmetry on the cortical
surface. Cerebral Cortex, 20(3), 602611.
Joshi, A. A., Pantazis, D., Li, Q., Damasio, H., Shattuck, D. W., Toga, A. W., et al. (2010).
Sulcal set optimization for cortical surface registration. NeuroImage, 50(3), 950959.
Kao, C. Y., Hofer, M., Sapiro, G., Stem, J., Rehm, K., & Rottenberg, D. A. (2007). A
geometric method for automatic extraction of sulcal fundi. IEEE Transactions on
Medical Imaging, 26(4), 530540.
Le Goualher, G., Procyk, E., Collins, D., Venugopal, R., Barillot, C., & Evans, A. (1999).
Automated extraction and variability analysis of sulcal neuroanatomy. IEEE
Transactions on Medical Imaging, 18(3), 206217.
Le Troter, A., Auzias, G., & Coulon, O. (2012). Automatic sulcal line extraction on
cortical surfaces using geodesic path density maps. NeuroImage, 61(4), 941949.
371
Schaer, M., Cuadra, M. B., Tamarit, L., Lazeyras, F., Eliez, S., & Thiran, J. P. (2008). A
surface-based approach to quantify local cortical gyrification. IEEE Transactions on
Medical Imaging, 27(2), 161170.
Seong, J. K., Im, K., Yoo, S. W., Seo, S. W., Na, D. L., & Lee, J. M. (2010). Automatic
extraction of sulcal lines on cortical surfaces based on anisotropic geodesic
distance. NeuroImage, 49(1), 293302.
Shattuck, D. W., Joshi, A. A., Pantazis, D., Kan, E., Dutton, R. A., Sowell, E. R., et al.
(2009). Semi-automated method for delineation of landmarks on models of the
cerebral cortex. Journal of Neuroscience Methods, 178(2), 385392.
Shi, Y., Dinov, I., & Toga, A. W. (2009). Cortical shape analysis in the Laplace-Beltrami
feature space. Medical Image Computing and Computer-Assisted Intervention,
12(Pt 2), 208215.
Shi, Y., Sun, B., Lai, R., Dinov, I., & Toga, A. W. (2010). Automated sulci identification
via intrinsic modeling of cortical anatomy. Medical Image Computing and
Computer-Assisted Intervention, 13(Pt 3), 4956.
Shi, Y., Thompson, P. M., Dinov, I., & Toga, A. W. (2008). Hamilton-Jacobi skeleton on
cortical surfaces. IEEE Transactions on Medical Imaging, 27(5), 664673.
Shi, Y., Tu, Z., Reiss, A. L., Dutton, R. A., Lee, A. D., Galaburda, A. M., et al. (2009).
Joint sulcal detection on cortical surfaces with graphical models and boosted priors.
IEEE Transactions on Medical Imaging, 28(3), 361373.
Sun, T., & Hevner, R. F. (2014). Growth and folding of the mammalian cerebral cortex:
From molecules to malformations. Nature Reviews Neuroscience, 15(4), 217232.
Sun, Z. Y., Kloppel, S., Rivie`re, D., Perrot, M., Frackowiak, R., Siebner, H., et al. (2012).
The effect of handedness on the shape of the central sulcus. NeuroImage, 60(1),
332339.
Sun, Z., Perrot, M., Tucholka, A., Riviere, D., & Mangin, J. (2009). Constructing a
dictionary of human brain folding patterns. In: MICCAI Proceedings, Berlin,
Hiedelberg: Springer Verlag, LNCS-5762.
Taber, L. A. (2014). Morphomechanics: Transforming tubes into organs. Current
Opinion in Genetics and Development, 27C, 713.
Thompson, P., & Toga, A. W. (1996). A surface-based technique for warping threedimensional images of the brain. IEEE Transactions on Medical Imaging, 15(4),
402417.
Toga, A. W., & Thompson, P. M. (2003). Temporal dynamics of brain anatomy. Annual
Review of Biomedical Engineering, 5, 119145.
Toro, R., & Burnod, Y. (2005). A morphogenetic model for the development of cortical
convolutions. Cerebral Cortex, 15(12), 19001913.
Toro, R., Perron, M., Pike, B., Richer, L., Veillette, S., Pausova, Z., et al. (2008).
Brain size and folding of the human cerebral cortex. Cerebral Cortex, 18(10),
23522357.
Vaillant, M., & Davatzikos, C. (1997). Finding parametric representations of the
cortical sulci using an active contour model. Medical Image Analysis, 1(4),
295315.
Van Essen, D. C. (1997). A tension-based theory of morphogenesis and compact wiring
in the central nervous system. Nature, 385(6614), 313318.
Van Essen, D. C., Drury, H. A., Joshi, S., & Miller, M. I. (1998). Functional and
structural mapping of human cerebral cortex: Solutions are in the surfaces.
Proceedings of the National Academy of Sciences of the United States of America,
95(3), 788795.
Weiner, K. S., Golarai, G., Caspers, J., Chuapoco, M. R., Mohlberg, H., Zilles, K., et al.
(2014). The mid-fusiform sulcus: A landmark identifying both cytoarchitectonic
and functional divisions of human ventral temporal cortex. NeuroImage, 84, 453465.
Yang, F., & Kruggel, F. (2008). Automatic segmentation of human brain sulci. Medical
Image Analysis, 12(4), 442451.
Yang, F., & Kruggel, F. (2009). A graph matching approach for labeling brain sulci
using location, orientation, and shape. Neurocomputing, 73, 179190.
Zilles, K., Palomero-Gallagher, N., & Amunts, K. (2013). Development of cortical
folding during evolution and ontogeny. Trends in Neurosciences, 36(5), 275284.
Tissue Classification
K Van Leemput, Harvard Medical School, Boston, MA, USA
O Puonti, Technical University of Denmark, Lyngby, Denmark
2015 Elsevier Inc. All rights reserved.
Abbreviations
EM
MAP
ML
Expectation-maximization
Computational methods for automatically segmenting magnetic resonance (MR) images of the brain have seen tremendous advances in recent years. So-called tissue classification
techniques, aimed at extracting the three main brain tissue
classes (white matter, gray matter, and cerebrospinal fluid),
are now well established. In their simplest form, these methods
classify voxels independently based on their intensity alone,
although much more sophisticated models are typically used
in practice (Anbeek, Vincken, van Bochove, van Osch, & van der
Grond, 2005; Ashburner & Friston, 1997, 2005; Awate, Tasdizen,
Foster, & Whitaker, 2006; Greenspan, Ruf, & Goldberger, 2006;
Marroquin, Vemuri, Botello, Calderon, & Fernandez-Bouzas,
2002; Pham & Prince, 1999; Rajapakse, Giedd, & Rapoport,
1997; Van Leemput, Maes, Vandermeulen, & Suetens,
1999a,1999b; Warfield, Kaus, Jolesz, & Kikinis, 2000; Wells,
Grimson, Kikinis, & Jolesz, 1996; Zeng, Staib, Schultz, &
Duncan, 1999; Zhang, Brady, & Smith, 2001).
This article aims to give an overview of often-used computational techniques for brain tissue classification. Although
other methods exist, we will concentrate on Bayesian modeling approaches, in which generative image models are constructed and subsequently inverted to obtain automated
segmentations. This general framework encompasses a large
number of segmentation methods, including those implemented in widely used software packages such as SPM, FSL,
and FreeSurfer, as well as techniques for automatically segmenting many more brain structures than merely the three
main brain tissue types only (Ashburner & Friston, 2005;
Fischl et al., 2002; Fischl, Salat et al., 2004; Fischl, van der
Kouwe et al., 2004; Guillemaud & Brady, 1997; Held et al.,
1997; Lorenzo-Valdes, Sanchez-Ortiz, Mohiaddin, & Rueckert,
2004; Marroquin et al., 2002; Menze et al., 2010; Pohl,
Fisher, Grimson, Kikinis, & Wells, 2006; Pohl et al., 2007;
Prastawa, Bullitt, Ho, & Gerig, 2004; Sabuncu, Yeo, Van
Leemput, Fischl, & Golland, 2010; Van Leemput, Maes, Vandermeulen, Colchester, & Suetens, 2001; Van Leemput et al.,
1999b; Wells et al., 1996; Xue et al., 2007; Zhang et al.,
2001).
We first introduce the general modeling framework and the
specific case of the Gaussian mixture model. We then discuss
maximum likelihood (ML) parameter estimation and the
expectationmaximization (EM) algorithm and conclude the
article with further model extensions such as MR bias field
models and probabilistic atlases.
Maximum a posteriori
Maximum likelihood
http://dx.doi.org/10.1016/B978-0-12-397025-1.00308-0
p djl, u^d p lju^l
p ljd, u^
p dju^
[1]
373
374
P
with p dju^ l p djl, u^d p lju^l . For instance, one might
look for the segmentation ^l that has the maximum a posteriori
(MAP) probability
^l arg max p ljd, u^
[2]
l
or estimate the volume of the anatomical structure corresponding to label k by assessing its expected value
X
Vk lp ljd, u^
[3]
pdjl, ud
pdi jli , ud N di jmli , s2li
pljul
pli
[5]
[7]
where
2
N djm, s
[6]
"
#
1
d m2
p exp
2s2
2ps2
[8]
N di jmli , sli
pli
pdi ju
[9]
l
with
pdju
N djmk ,s2k pk
[10]
Equation [10] explains why this model is called the Gaussian mixture model: the intensity distribution in any voxel,
independent of its spatial location, is given by the same linear
superposition of Gaussians. Since no spatial information is
encoded in the model, it can directly be visualized as a way
to approximate the histogram, as shown in Figure 1.
Because of the assumption of statistical independence
between voxels, the segmentation posterior (eqn [1]) reduces
to a simple form that is factorized (i.e., appears as a product)
over the voxels:
Figure 1 In the Gaussian mixture model, the histogram is described as a linear superposition of Gaussian distributions: (a) MR scan of the head, after
removing all non-brain tissue and other pre-processing steps; and (b) corresponding histogram and its representation as a sum of Gaussians.
375
Figure 2 Visualization of the segmentation posterior corresponding to the data and model of figure 1. High and low intensities correspond to
high and low probabilities, respectively.
Q
Q
p djl, u^d p lju^l
^li , s^2li
^li
i N di jm
ip
p ljd, u^
QP
2
^k , s^k p^k
p dju^
i
k N di jm
Y
p li jdi , u^
where
[11]
N di jm^li , s^2li p^li
p li jdi , u^ P
^k , s^2k p^k
k N di jm
[12]
estimate these parameters is to manually click on some representative points in the image to be segmented or in similar
images obtained from other subjects and then collect statistics on the intensity of the selected voxels. In general, however,
such a strategy is cumbersome for such a versatile imaging
modality as MR, where intensities do not directly correspond
to physical properties of the tissue being scanned. By merely
altering the imaging protocol, upgrading the scanner, or collecting images from different scanner models or manufacturers, the values of u^ become inappropriate and need to be
constructed again using manual interaction.
This difficulty can be avoided by estimating appropriate
values for the model parameters automatically from each individual scan. This can be accomplished by estimating the
parameters that maximize the so-called likelihood function
p(d|u), which expresses how probable the observed image d
is for different settings of the parameter vector u:
u^ arg max pdju arg max log pdju
u
[15]
376
log p(d|q )
log p(d|q )
q
~
q
(Current
(a) estimate)
q
(b)
log p(d|q )
~
q
(Current
estimate)
log p(d|q )
(c)
~
q
(Current
estimate)
~
q
(Current
estimate)
q
(d)
log p(d|q )
log p(d|q )
(e)
~
q
(Current
estimate)
q
(f)
~
q q
(Current
estimate)
Figure 3 In the EM algorithm the maximum likelihood parameters are sought by repeatedly constructing a lower bound to the log likelihood function,
in such a way that the lower bound touches the log likelihood function exactly at the current parameter estimate (a). Subsequently the parameter
estimate is updated to the parameter vector that maximizes the lower bound (b). A new lower bound is then constructed at this new location (c) and
maximized again (d), and so forth ((e) and (f)), until convergence. In these plots, the log likelihood function is represented by a full line, and the
successive lower bounds with a broken line.
~u
~ log p dju
~
Q uj
[16]
construct a lower bound for which the parameter vector maximizing it is given directly by analytic expressions. Therefore,
the resulting algorithm effectively breaks up a difficult maximization problem (of the log likelihood function) into many
smaller ones (of the lower bound) that are trivial to solve.
The trick exploited by the EM algorithm to construct its
lower bound is based on the property of the logarithm that it
is a concave function, that is, every chord connecting two
points on its curve lies on or below that curve. Mathematically,
this means that
log wx1 1 wx2 wlog x1 1 wlog x2
[18]
where wk 0 and kwk 1, for any set of points {xk}. This can
now be used to construct a lower bound to the likelihood
log
X
i
log
"
X
di jmk ,s2k
#
pk
"
X N di jmk , s2 pk
"
X X
[21]
wik
#
wik
#
N di jmk , s2k pk
wik
i
k
|{z}
~
Quju
wik log
[22]
[23]
P i
for any set of weights {wik} that satisfy wik 0 and
kwk 1
(the last step
relies
on eqn [19]). We now have a lower bound
~ that satisfies eqn [17], but not eqn [16], so we
function Q uju
are not done yet. Instead of randomly assigning any valid K
weights wik to each voxel i (one weight for each label k), we can
satisfy eqn [16] by choosing the weights so that
wik P
~k
N di j~
m ,s
~2 p
k k
2
0
0N
~
~ k0
d
j~
m
,
s
p
i k
k
k0
[24]
~2k
s
P i
w di
Pi k i
~k
m
w
P i i k
~ 2
i wk di m
P i k
w
P i ik
i wk
~k
p
N
377
[25]
Figure 4 Iterative improvement of the Gaussian mixture model parameters for the MR image of figure 1(a), using the EM algorithm: initialization (a)
and parameter estimate after one (b), 10 (c) and 30 (d) iterations.
378
cm fim
~2k
s
pdj l, ud
Y
i
N di
!
cm fim jmli , s2li
[27]
wik P
di
P
cm fim
m~
i
i wk
[29]
f11
B f2
1
FB
@
N
f1
m1
wi
2
Pi k i
~k
di m ~cm fm m
P i
w
P i ik
i wk
~k
p
N
[26]
fim
i
i wk
~k
m
and
sik
1
f12 ... f1M
2
2 C
f2 ... fM C
A
N
fN
2 ... fM
X
X
~k
sik m
wik
i
~
2 , si
sk , S diag si , di Xk i ,
~k
s
s
k
k k
0
1
~
d1 d1
r@ A
dN d~N
[31]
[32]
Since eqns [29] and [30] depend on one another, one could
in principle try to maximize the lower bound by cycling
through these two equations, one at a time, until some convergence criterion is met. However, the desirable property of
the EM algorithm to never decrease the value of the likelihood
function with each new iteration still holds even when the
lower bound is not maximized but merely improved. Therefore, a more efficient strategy is to construct the lower bound
by computing the weights wik (eqn [28]) and then updating the
Gaussian mixture model parameters (eqn [29]) and subsequently the bias field parameters (eqn [30]) only once to
merely improve it. After that, a new lower bound is constructed
by recomputing the weights, which is again improved by
updating the model parameters, etc., until convergence. Such
an optimization strategy of only partially optimizing the EM
lower bound is known as so-called generalized EM.
The interpretation of the update equations is again very
intuitive (Van Leemput et al., 1999a; Wells et al., 1996), but
outside the scope of this article. Suffice it to say that by extending the Gaussian mixture model with an explicit model for the
bias field artifact this way, it is possible to obtain high-quality
segmentations of MR scans without errors caused by intensity
inhomogeneities, as illustrated in Figure 5.
[28]
Subsequently maximizing the lower bound is more complicated than in the Gaussian mixture model, however,
because setting the derivative with respect to the parameter
vector u to zero no longer yields analytic expressions for the
parameter update rules. If we keep the bias field parameters
fixed at their current values ~cm , and only maximize the lower
bound with respect to the Gaussian mixture model parameters, we obtain
379
Figure 5 Explicit modeling and estimating the bias field artifact in MR scans often improves segmentation results considerably. Shown are a few
sagittal slices from a brain MR scan (a); the posterior probability for white matter using the standard Gaussian mixture model (b); the same when a bias
field model is explicitly taken into account (c); and the automatically estimated bias field model (d). Note the marked improvement in segmentation
accuracy in the upper parts of the brain.
380
Figure 6 Illustration of a probabilistic atlas aligned with an image-to-be-segmented. Top: anatomical scan to be segmented. Bottom: spatially varying
prior probability maps of white matter, gray matter, and cerebrospinal fluid, overlaid on the anatomical scan for illustration purposes. Bright and dark
intensities correspond to high and low probabilities, respectively.
References
Anbeek, P., Vincken, K. L., van Bochove, G. S., van Osch, M. J. P., & van der Grond, J.
(2005). Probabilistic segmentation of brain tissue in MR imaging. NeuroImage,
27(4), 795804.
Ashburner, J., & Friston, K. J. (1997). Multimodal image coregistration and partitioning
A unified framework. NeuroImage, 6(3), 209217.
Ashburner, J., & Friston, K. J. (2005). Unified segmentation. NeuroImage, 26,
839885.
Awate, S. P., Tasdizen, T., Foster, N., & Whitaker, R. T. (2006). Adaptive Markov
modeling for mutual-information-based, unsupervised MRI brain-tissue
classification. Medical Image Analysis, 100(5), 726739.
Fischl, B., Salat, D. H., Busa, E., Albert, M., Dieterich, M., Haselgrove, C., et al. (2002).
Whole brain segmentation: Automated labeling of neuroanatomical structures in the
human brain. Neuron, 33, 341355.
Fischl, B., Salat, D. H., van der Kouwe, A. J. W., Makris, N., Segonne, F., Quinn, B. T.,
et al. (2004). Sequence-independent segmentation of magnetic resonance images.
NeuroImage, 23, S69S84.
Fischl, B., van der Kouwe, A., Destrieux, C., Halgren, E., Segonne, F., Salat, D. H., et al.
(2004). Automatically parcellating the human cerebral cortex. Cerebral Cortex,
140(1), 1122.
Greenspan, H., Ruf, A., & Goldberger, J. (2006). Constrained gaussian mixture model
framework for automatic segmentation of MR brain images. IEEE Transactions on
Medical Imaging, 250(9), 12331245.
Guillemaud, R., & Brady, M. (1997). Estimating the bias field of MR images. IEEE
Transactions on Medical Imaging, 160(3), 238251.
Held, K., Kops, E. R., Krause, B. J., Wells, W. M., III, Kikinis, R., & Muller-Gartner, H. W.
(1997). Markov random field segmentation of brain MR images. IEEE Transactions
on Medical Imaging, 160(6), 878886.
Hunter, D. R., & Lange, K. (2004). A tutorial on MM algorithms. The American
Statistician, 580(1), 3037.
Lorenzo-Valdes, M., Sanchez-Ortiz, G. I., Elkington, A. G., Mohiaddin, R. H., &
Rueckert, D. (2004). Segmentation of 4D cardiac MR images using a probabilistic
atlas and the EM algorithm. Medical Image Analysis, 8(3), 255265.
Marroquin, J. L., Vemuri, B. C., Botello, S., Calderon, F., & Fernandez-Bouzas, A.
(2002). An accurate and efficient Bayesian method for automatic segmentation of
brain MRI. IEEE Transactions on Medical Imaging, 210(8), 934945.
Menze, B., Van Leemput, K., Lashkari, D., Weber, M. A., Ayache, N., & Golland, P.
(2010). A generative model for brain tumor segmentation in multi-modal images.
Medical Image Computing and Computer-Assisted Intervention-MICCAI,
2010(6362), 151159.
Pham, D. L., & Prince, J. L. (1999). Adaptive fuzzy segmentation of magnetic resonance
images. IEEE Transactions on Medical Imaging, 18, 737752.
Pohl, K. M., Bouix, S., Nakamura, M., Rohlfing, T., McCarley, R. W., Kikinis, R., et al.
(2007). A hierarchical algorithm for MR brain image parcellation. IEEE Transactions
on Medical Imaging, 260(9), 12011212.
Pohl, K. M., Fisher, J., Grimson, E. L., Kikinis, R., & Wells, W. M. (2006). A Bayesian
model for joint segmentation and registration. NeuroImage, 31, 228239.
Prastawa, M., Bullitt, E., Ho, S., & Gerig, G. (2004). A brain tumor segmentation
framework based on outlier detection. Medical Image Analysis, 8, 275283.
Puonti, O., Iglesias, J. E., & Van Leemput, K. (2013). Fast, Sequence Adaptive
Parcellation of Brain MR Using Parametric Models. In Medical Image Computing
and Computer-Assisted InterventionMICCAI 2013 (pp. 727734). Berlin/
Heidelberg: Springer.
381
Warfield, S. K., Kaus, M., Jolesz, F. A., & Kikinis, R. (2000). Adaptive, template
moderated, spatially varying statistical classification. Medical Image Analysis, 4,
4355.
Wells, W. M., III, Grimson, W. E.L, Kikinis, R., & Jolesz, F. A. (1996). Adaptive
segmentation of MRI data. IEEE Transactions on Medical Imaging, 150(4),
429442.
Xue, H., Srinivasan, L., Jiang, S., Rutherford, M., Edwards, A. D., Rueckert, D., et al.
(2007). Automatic segmentation and reconstruction of the cortex from neonatal
MRI. NeuroImage, 380(3), 461477.
Zeng, X., Staib, L. H., Schultz, R. T., & Duncan, J. S. (1999). Segmentation and
measurement of the cortex from 3D MR images using coupled surfaces propagation.
IEEE Transactions on Medical Imaging, 180(10), 927937.
Zhang, Y., Brady, M., & Smith, S. (2001). Segmentation of brain MR images through a
hidden Markov random field model and the expectationmaximization algorithm.
IEEE Transactions on Medical Imaging, 20, 4557.
Tensor-Based Morphometry
J Ashburner and GR Ridgway, UCL Institute of Neurology, London, UK
2015 Elsevier Inc. All rights reserved.
Glossary
http://dx.doi.org/10.1016/B978-0-12-397025-1.00309-2
383
384
Introduction
Morphometrics refers to the quantitative analysis of form, which
is a concept that encompasses both the size and shape of an
organism or organ. In neuroimaging, morphometric approaches
are typically used to characterize differences among populations
of subjects or to identify features that correlate with some measurement of interest. These measurements may be clinical scores,
test score results, genetic measurements, or anything else of
interest to the investigator. The usual approaches involve extracting anatomical features or descriptors from MRI data of the
subjects and performing some form of statistical analysis on
them. This article concerns tensor-based morphometric techniques, which involve analyzing features that principally relate
to the relative volumes of structures, as estimated by image
registration. The mathematics involved in morphometrics can
be quite complicated, but we try to keep it relatively simple in
this article.
Morphometrics has a long history throughout many areas
of biology. Most applications do not have the benefit of imaging devices that enable 3-D volumetric scans to be collected,
so generally focus on working with things that can easily be
measured from the organ or organism itself. Traditional
approaches were limited to measures such as lengths, widths,
angles, and distances, which were subjected to statistical analysis. When technological advances made it easier to record
Statistical Analysis
TBM usually involves the framework of statistical parametric
mapping (SPM) (Friston et al., 1995), which localizes statistically significant regional differences. Extensive details of the
procedures involved are described in other articles of this book,
so only a brief summary will be outlined here. Essentially,
image data from a number of subjects are preprocessed by
aligning them to a common anatomical frame of reference,
which gives a feature representation that is more amenable to
voxel-wise statistical testing.
SPMs of voxel-wise univariate measures allow simple questions to be addressed, such as where does the chosen morphometric feature correlate with a particular regressor of interest?
Typically, parametric statistical procedures (t-tests and F-tests)
are used within the frequentist framework. Hypotheses can be
formulated within the framework of a univariate general linear
model (GLM), whereby a vector of observations is modeled by
a linear combination of user-specified regressors (Friston et al.,
1995). The GLM is a flexible framework that allows many
different tests to be applied, ranging from group comparisons
and identification of differences that are related to specified
covariates such as disease severity or age to complex interactions between different effects of interest.
Because the pattern of difference to be determined is not
specified a priori, SPM analyses are a hybrid between statistical
hypothesis testing and exploratory analyses. Rather than test a
single hypothesis, the approach involves testing hypotheses at
each voxel of the preprocessed data. A Bonferroni correction
could be used to correct for the multiple comparisons if
the tests were independent, but this is not normally the case
because of the inherent spatial smoothness of the data. In
practice, a correction for the multitude of tests is usually
obtained via random field theory (Friston, Holmes, Poline,
Price, & Frith, 1996; Worsley et al., 1996), thus allowing a
correction for multiple dependent comparisons that controls
the rate of false-positive results. Alternatively, SPMs may be
corrected for the rate of false discoveries (Chumbley, Worsley,
Flandin, & Friston, 2010; Genovese, Lazar, & Nichols, 2002).
There are also a variety of other statistical analytic methods
that may be applied to the feature data. For example, nonparametric approaches (Nichols & Holmes, 2002) may be
applied in situations where parametric modeling assumptions
do not hold. In recent years, there has been a rediscovery of
Bayesian approaches by the neuroimaging community, leading
385
to various Bayesian inference procedures for localizing differences (Friston & Penny, 2003; Penny & Ridgway, 2013).
y T XX X 0 X 0 y rankX rankX0
=
yT I XX y
rankX
SSH DFH
=
SSE DFE
386
Template
Image
Warped template
Warped image
Feature Representations
There are many ways of characterizing anatomical differences
among populations or finding correlations between anatomy
and, for example, disease severity. Over the years, there has
been a proliferation in the types of features that can be tested,
although most neuroimaging comparisons are made using the
voxel-based morphometric approach. However, a number of
other data representations may also be subjected to statistical
analysis.
One of the challenges for morphometry is to identify shape
modeling features that best differentiate among populations.
Where there are differences between the cortical thickness in
one population and that of another, then cortical thickness
would be the most discriminative shape feature to use. An
analysis of regional gray matter volumes may partially reveal
those differences, but it would not be as accurate as looking at
thickness itself. Similarly, if the difference between groups is
best characterized by cortical surface areas, then an analysis of
cortical thickness is unlikely to show much of interest. In
general, determining the most accurate representations of differences among populations of subjects is something to be
done empirically.
Deformation Fields
Currently, most morphometric studies in neuroimaging are
based on T1-weighted scans. MRI scans contain a variety of
artifacts, many of which will impact on any kind of morphometric analysis. These are especially important for studies that
combine scans from multiple scanners (Jovicich et al., 2009).
Spatial distortions arising from gradient nonlinearities impact
any kind of morphometric analysis, although there are a variety
of correction methods for these (Janke, Zhao, Cowin,
Galloway, & Doddrell, 2004; Jovicich et al., 2006). Further
information about optimizing image acquisition parameters,
artifact correction, etc., for large morphometric studies may be
found in Jack et al. (2008).
TBM requires that the images of all subjects in the study to
be aligned together by some form of spatial normalization.
In neuroimaging, the primary result of spatially normalizing a
series of images is that they all conform to the same space,
enabling region-by-region comparisons to be performed.
However, for TBM, the main objective is to obtain a set of
parameterizations of the spatial transformations required to
Deformation
Horizontal component
387
Vertical component
Identity
Displacements
Figure 2 The components of a 2-D deformation. Top row: The deformation (from Figure 1), with its horizontal and vertical components.
Middle row: An identity transform, with its horizontal and vertical components. Bottom row: Displacements obtained by subtracting the identity
transform from the deformation.
procedures are intended to reduce the bias incurred by selecting a particular individuals image as a template.
In general, one should not expect to obtain exactly the same
findings from morphometric studies using different image registration software. Different algorithms use different models and
assumptions, and in the absence of clear theoretical preferences,
the optimal ones can only be determined empirically. Image
registration algorithms have a number of settings, and changes
to these will generally lead to changes in the findings of a study.
For example, Figure 3 shows a simulated image aligned using a
variety of regularization settings (but the same algorithm), each
giving different maps of relative volumes. The more accurately the
registration model is specified, the more accurately the findings
from a study will reflect real underlying biological differences.
multivariate framework (Ashburner et al., 1998) after appropriate corrections to factor out pose.
Some previous works have applied voxel-wise Hotellings
T2 tests on the displacements at each and every voxel (Gaser,
Volz, Kiebel, Riehemann, & Sauer, 1999; Thompson & Toga,
1999), with statistical significance assessed by random field
corrections (Cao & Worsley, 1999). However, this approach
does not directly localize differences that are intrinsic to the
brains themselves. Rather, it identifies those brain structures
that are in different locations in space, which depends upon
how the poses and possibly sizes of the brains are factored out
of the estimated deformations (Klingenberg, 2013).
The objective of TBM is usually to localize regions of shape
differences among groups of brains, based on deformations
that map points in a template (x1,x2,x3) to equivalent points in
individual source images (y1,y2,y3). In principle, the Jacobian
matrices of the deformations (a second-order tensor field given
by the spatial derivatives of the transformation; see Figure 4)
should be more reliable indicators of local brain shape than
displacements.
388
Figure 3 Effects of different regularization settings on estimates of Jacobian determinants. Left column: Image aligned with different regularization.
Middle column: Estimated deformations. Right column: Estimated Jacobian determinants (all shown on the same color scale).
3
@y1 =@x1 @y1 =@x2 @y1 =@x3
J 4 @y2 =@x1 @y2 =@x2 @y2 =@x3 5
@y3 =@x1 @y3 =@x2 @y3 =@x3
determinants at each point (Davatzikos et al., 1996; Freeborough & Fox, 1998; Machado, Gee, & Campos, 1998;
Studholme et al., 2004). This type of morphometry is useful
for studies that have specific questions about whether growth
or volume loss has occurred. The field obtained by taking the
determinants at each point gives a map of structural volumes
relative to those of a reference image.
There are a number of nonlinearities to consider when analyzing the shapes and sizes of structures. If a structure stays the
same shape but is doubled in length or width, its surface area
will be scaled by a factor of 4 and its volume by a factor of 8.
389
Figure 4 For 2-D deformations, a Jacobian tensor field encodes a 2 2 matrix at each point. Top: Horizontal and vertical gradients of the horizontal
component of the deformation in Figure 2. Bottom: Horizontal and vertical gradients of the vertical component.
smaller displacement fields together. Providing that the constituent deformations are sufficiently small to be one-to-one,
the result from composing them should also be a one-to-one
mapping (Christensen et al., 1995). Even so, the discrete
nature of the actual implementations means that care needs
to be taken when computing Jacobians to ensure that they have
positive determinants.
Some diffeomorphic approaches (Ashburner & Friston,
2011; Beg, Miller, Trouve, & Younes, 2005; Vialard, Risser,
Rueckert, & Cotter, 2012) generate a vector field referred to as
the initial velocity. Rather than analyze the features of the
deformations, it is possible to work instead with features
extracted from this initial velocity field. In particular, the divergence of the initial velocity provides a feature that is numerically similar to the logarithm of the Jacobian determinants.
These divergences encode the volumetric growth rates required
to achieve alignment of the images, according to the diffeomorphic registration model. If they are integrated over some
brain region, this gives the rate at which tissue flows into the
region (this is known as the divergence theorem, or Gausss
theorem). The divergence is computed by summing the diagonal elements of the Jacobian matrices of the velocity field.
One advantage of working with divergences, rather than the
logs of the Jacobian determinants, is that they are linear
390
Folded deformation
Jacobian determinants
Detail of folding
Figure 5 A deformation with folding. Left: Full deformation, generated by doubling the displacement in Figure 2. Center: Jacobian determinants,
containing two regions of negative values. Right: Detail of the folded region.
TBM on Tensors
Allometry
Outside neuroimaging, biologists often consider allometry when
making comparisons. The ideas behind allometry were first
formulated in Sir Julian Huxleys Problems of Relative Growth
d
d
log y k log x
dt
dt
Longitudinal Data
Often, longitudinal data are used for morphometric analyses,
whereby anatomical scans of multiple subjects are collected
at multiple time points. Time differences between scans vary
from a few hours (Tost et al., 2010) to a few decades (Fisniku
et al., 2008) with intervals of a few months being common
for structural plasticity and intervals around a year being
common for neurodegenerative disease. Current applications
include characterizing patterns of atrophy in dementia
(Freeborough & Fox, 1998) or studying brain development
(see Figure 6). Other examples include studies into structural
391
Figure 6 Example of atrophy measured in a single individual via longitudinal registration. Three orthogonal sections of the subjects average image are
shown above the same sections through a map of volume change. Darker regions indicate shrinkage, whereas brighter regions indicate expansion.
392
Outlook
Morphometric approaches used by neuroimagers tend to be
substantially different from those applied in other areas of
biology. Within neuroimaging, there tends to be much more
focus on localizing differences via mass-univariate approaches,
whereas multivariate approaches tend to be favored in other
fields. This difference in viewpoint has drawn criticism in the
past (Bookstein, 2001), although the neuroimaging field has
now begun to embrace multivariate methods rather more.
Currently, most morphometric analyses involve a purely
bottom-up procedure, whereby a pipeline of processing steps is
applied to the data. Although still at the early stages, we are
beginning to see hierarchical generative models emerge, which
combine statistical modeling with registration (Allassonnie`re,
Amit, & Trouve, 2007; Fishbaugh, Durrleman, & Gerig, 2011;
Niethammer, Huang, & Vialard, 2011; Prastawa, Awate, & Gerig,
2012). Instead of statistical analyses that attempt to explain how
the features were generated (ignoring the fact that they came from
nonlinear registration), these developments involve generative
models of the original image data. Such approaches may eventually enable top-down knowledge about disease status, age, etc., to
inform the registration and other image processing components.
As all neuroscientists know, top-down processing is essential for
making sense of the world (Mumford, 1991).
Acknowledgments
Image data used in Figure 6 were part of the OASIS:
longitudinal MRI data in nondemented and demented older
adults dataset (Marcus, Fotenos, Csernansky, Morris, &
Buckner, 2010), funded by grant numbers P50 AG05681,
P01 AG03991, R01 AG021910, P20 MH071616, and U24
RR021382.
References
Adams, D., Rohlf, F., & Slice, D. (2004). Geometric morphometrics: Ten years of
progress following the revolution. Italian Journal of Zoology, 71(1), 516.
Allassonnie`re, S., Amit, Y., & Trouve, A. (2007). Towards a coherent statistical
framework for dense deformable template estimation. Journal of the Royal Statistical
Society, Series B: Statistical Methodology, 69(1), 329.
Arsigny, V., Fillard, P., Pennec, X., & Ayache, N. (2006). Log-Euclidean metrics for fast
and simple calculus on diffusion tensors. Magnetic Resonance in Medicine, 56(2),
411421.
393
Friston, K., & Penny, W. (2003). Posterior probability maps and SPMs. NeuroImage,
19(3), 12401249.
Gaser, C., Volz, H.-P., Kiebel, S., Riehemann, S., & Sauer, H. (1999). Detecting
structural changes in whole brain based on nonlinear deformations Application to
schizophrenia research. NeuroImage, 10, 107113.
Genovese, C. R., Lazar, N. A., & Nichols, T. (2002). Thresholding of statistical maps in
functional neuroimaging using the false discovery rate. NeuroImage, 15(4), 870878.
Hu, X., Erb, M., Ackermann, H., Martin, J. A., Grodd, W., & Reiterer, S. M. (2011).
Voxel-based morphometry studies of personality: Issue of statistical model
specification-effect of nuisance covariates. NeuroImage, 54(3), 19942005.
Hua, X., Gutman, B., Boyle, C., Rajagopalan, P., Leow, A., Yanovsky, I., et al. (2011).
Accurate measurement of brain changes in longitudinal MRI scans using tensorbased morphometry. NeuroImage, 57(1), 514.
Huxley, J. (1932). Problems of relative growth. London: Methuen.
Jack, C. R., Bernstein, M. A., Fox, N. C., Thompson, P., Alexander, G., Harvey, D., et al.
(2008). The Alzheimers disease neuroimaging initiative (ADNI): MRI methods.
Journal of Magnetic Resonance Imaging, 27(4), 685691.
Janke, A., Zhao, H., Cowin, G. J., Galloway, G. J., & Doddrell, D. M. (2004). Use of
spherical harmonic deconvolution methods to compensate for nonlinear
gradient effects on MRI images. Magnetic Resonance in Medicine, 52(1),
115122.
Joshi, S., Davis, B., Jomier, M., & Gerig, G. (2004). Unbiased diffeomorphic atlas
construction for computational anatomy. NeuroImage, 23, 151160.
Jovicich, J., Czanner, S., Greve, D., Haley, E., van der Kouwe, A., Gollub, R., et al.
(2006). Reliability in multi-site structural MRI studies: Effects of gradient nonlinearity correction on phantom and human data. NeuroImage, 30(2), 436443.
Jovicich, J., Czanner, S., Han, X., Salat, D., van der Kouwe, A., Quinn, B., et al. (2009).
MRI-derived measurements of human subcortical, ventricular and intracranial brain
volumes: Reliability effects of scan sessions, acquisition sequences, data analyses,
scanner upgrade, scanner vendors and field strengths. NeuroImage, 46(1),
177192.
Klingenberg, C. P. (2011). MorphoJ: An integrated software package for geometric
morphometrics. Molecular Ecology Resources, 11(2), 353357.
Klingenberg, C. P. (2013). Visualizations in geometric morphometrics: How to read and
how to make graphs showing shape changes. Hystrix, Italian Journal of
Mammalogy, 24(1), 10.
Koikkalainen, J., Lotjonen, J., Thurfjell, L., Rueckert, D., Waldemar, G., & Soininen, H.
(2011). Multi-template tensor-based morphometry: Application to analysis of
Alzheimers disease. NeuroImage, 56(3), 11341144.
Lepore, N., Brun, C. A., Chiang, M.-C., Chou, Y.-Y., Dutton, R. A., Hayashi, K. M., et al.
(2006). Multivariate statistics of the Jacobian matrices in tensor based morphometry
and their application to HIV/AIDS. In Medical image computing and computerassisted interventionMICCAI 2006 (pp. 191198): Springer.
Lepore, N., Brun, C., Chou, Y.-Y., Chiang, M.-C., Dutton, R. A., Hayashi, K. M., et al.
(2008). Generalized tensor-based morphometry of HIV/AIDS using multivariate
statistics on deformation tensors. IEEE Transactions on Medical Imaging, 27(1),
129141.
Lepore, N., Brun, C., Chou, Y.-Y., Lee, A., Barysheva, M., De Zubicaray, G. I., et al.
(2008). Multi-atlas tensor-based morphometry and its application to a genetic study
of 92 twins. In 2nd MICCAI Workshop on Mathematical Foundations of
Computational Anatomy (pp. 4855).
Machado, A. M., Gee, J. C., & Campos, M. (1998). Atlas warping for brain
morphometry. In: SPIE Medical Imaging, Image Processing (pp. 642651),
Citeseer.
Marcus, D., Fotenos, A., Csernansky, J., Morris, J., & Buckner, R. (2010). Open access
series of imaging studies: Longitudinal MRI data in nondemented and demented
older adults. Journal of Cognitive Neuroscience, 22(12), 26772684.
Mitteroecker, P., & Gunz, P. (2009). Advances in geometric morphometrics.
Evolutionary Biology, 36(2), 235247.
Modat, M., Cardoso, M., Daga, P., Cash, D., Fox, N., & Ourselin, S. (2012). Inverseconsistent symmetric free form deformation. In Biomedical image registration
(pp. 7988): Springer.
Mumford, D. (1991). Mathematical theories of shape: Do they model perception?
In: San Diego 91, San Diego, CA: International Society for Optics and Photonics.
Nichols, T. E., & Holmes, A. P. (2002). Nonparametric permutation tests for functional
neuroimaging: A primer with examples. Human Brain Mapping, 15(1), 125.
Niethammer, M., Huang, Y., & Vialard, F. (2011). Geodesic regression for image timeseries. In Medical image computing and computer-assisted interventionMICCAI
2011 (pp. 655662): Berlin, Germany: Springer.
Peelle, J. E., Cusack, R., & Henson, R. N. (2012). Adjusting for global effects in voxelbased morphometry: Gray matter decline in normal aging. NeuroImage, 60(2),
15031516.
394
Thompson, D. W. (1917). On growth and form (1st ed.). Cambridge, UK: Cambridge
University Press.
Thompson, D. W. (1942). On growth and form (2nd ed.). Cambridge, UK: Cambridge
University Press.
Thompson, W., & Holland, D., & Alzheimers Disease Neuroimaging Initiative (2011).
Bias in tensor based morphometry Stat-ROI measures may result in unrealistic
power estimates. NeuroImage, 57(1), 14.
Thompson, P. M., & Toga, A. W. (1999). Brain warping. San Diego, CA: Academic
Press, Chapter 18, pp. 311336.
Tost, H., Braus, D. F., Hakimi, S., Ruf, M., Vollmert, C., Hohn, F., et al. (2010). Acute D2
receptor blockade induces rapid, reversible remodeling in human cortical-striatal
circuits. Nature Neuroscience, 13(8), 920922.
Vialard, F.-X., Risser, L., Rueckert, D., & Cotter, C. J. (2012). Diffeomorphic 3D image
registration via geodesic shooting using an efficient adjoint calculation.
International Journal of Computer Vision, 97(2), 229241.
Whitcher, B., Wisco, J. J., Hadjikhani, N., & Tuch, D. S. (2007). Statistical group
comparison of diffusion tensors via multivariate hypothesis testing. Magnetic
Resonance in Medicine, 57(6), 10651074.
Worsley, K. J., Marrett, S., Neelin, P., Vandal, A. C., Friston, K. J., & Evans, A. C.
(1996). A unified statistical approach for determining significant voxels in images of
cerebral activation. Human Brain Mapping, 4, 5873.
Worsley, K. J., Taylor, J. E., Tomaiuolo, F., & Lerch, J. (2004). Unified univariate and
multivariate random field theory. NeuroImage, 23(Suppl 1), S189S195.
Younes, L., Qiu, A., Winslow, R., & Miller, M. (2008). Transport of relational structures
in groups of diffeomorphisms. Journal of Mathematical Imaging and Vision, 32(1),
4156.
Yushkevich, P., Avants, B., Das, S., Pluta, J., Altinay, M., Craige, C., et al. (2010). Bias
in estimation of hippocampal atrophy using deformation-based morphometry arises
from asymmetric global normalization: An illustration in ADNI 3 T MRI data.
NeuroImage, 50(2), 434445.
Surface-Based Morphometry
J Shi and Y Wang, Arizona State University, Tempe, AZ, USA
2015 Elsevier Inc. All rights reserved.
Glossary
Introduction
registration and morphometry analysis. Brain surface parameterization has been studied extensively. A good surface parameterization preserves the geometric features and facilitates the
following surface signal processing. Some research proposed
quasi-isometric mappings (Schwartz et al., 1989) or areapreserving mappings (Brechbuhler et al., 1995). Another
branch of research used concepts from conformal geometry
to compute brain surface conformal parameterization
(Angenent et al., 1999; Hurdal and Stephenson, 2004). In
addition to angle-preserving property, conformal parameterization provides a rigorous framework for representing, splitting, matching, and measuring brain surface deformations.
According to differential geometry theory, a general surface
can be conformally mapped to one of three canonical spaces,
the unit sphere, the Euclidean plane, and the hyperbolic space.
For a closed genus-zero surface, the spherical conformal mapping method (Gu et al., 2004) can conformally map it to a
sphere by minimizing its harmonic energy (Figure 1(a)). For
brain surface analysis, sometimes, we introduce landmark
curves to annotate important anatomical regions. After surfaces
are cut open along these given landmark curves, one may get a
surface with multiple holes. Euclidean Ricci flow method
(Wang et al., 2012) or holomorphic 1-form method (Wang
et al., 2010) can conformally map them to the Euclidean plane
(Figure 1(b) and 1(c)). To model a topologically complicated
lateral ventricular surface, hyperbolic conformal geometry
emerges naturally as a candidate method because it can induce
hyperbolic conformal parameterizations without any singularities (Shi et al., 2012; Figure 1(d)). Such a set of global brain
surface conformal parameterization methods are technically
sound and numerically stable. They may increase computational accuracy and efficiency when solving partial differential
equations using grid-based or metric-based computations.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00310-9
395
396
Spherical harmonic
mapping
Euclidean
Ricci flow
Conformal slit
mapping
Hyperbolic
Ricci flow
g1
t1
t2
g3
g2
g1
g2
t1
2
t11
t2
g1
t21
(a)
(b)
(c)
(d)
g3
(a)
(e)
Study
surface
(b)
Template
surface
(f)
Feature image
of study surface
Texture
mapping
Texture
mapping
Feature image
of study surface
(c)
Parameter space
visualization
(d)
(g)
Feature image
Parameter space
visualization
(h) of template surface
Forward mapping
Inverse mapping
397
Feature image
of template surface
Figure 2 Hippocampal surface registration with inverse consistent surface fluid registration algorithm. Adapted from Shi, J., Thompson, P. M.,
Gutman, B., et al. (2013). Surface fluid registration of conformal representation: Application to detect disease effect and genetic influence on
hippocampus. NeuroImage, 78, 111134, with permission.
398
(a)
(b)
(c)
References
Angenent, S., Haker, S., Tannenbaum, A., et al. (1999). On the LaplaceBeltrami
operator and brain surface flattening. IEEE Transactions on Medical Imaging, 18(8),
700711.
Arsigny, V., Fillard, P., Pennec, X., et al. (2006). Log-Euclidean metrics for fast and
simple calculus on diffusion tensors. Magnetic Resonance in Medicine, 56(2),
411421.
Bakircioglu, M., Joshi, S., & Miller, M. I. (1999). Landmark matching on brain surfaces
via large deformation diffeomorphisms on the sphere. In: Proceedings of the SPIE
medical imaging, pp. 710715.
Brechbuhler, C., Gerig, G., & Kubler, O. (1995). Parametrization of closed surfaces for
3-D shape description. Computer Vision and Image Understanding, 61(2),
154170.
Christensen, G. E., & Johnson, H. J. (2001). Consistent image registration. IEEE
Transactions on Medical Imaging, 20(7), 568582.
Christensen, G. E., Rabbitt, R. D., & Miller, M. I. (1996). Deformable templates using
large deformation kinematics. IEEE Transactions on Image Processing, 5(10),
14351447.
Chung, M. K., Dalton, K. M., Shen, L., et al. (2007). Weighted fourier series
representation and its application to quantifying the amount of gray matter. IEEE
Transactions on Medical Imaging, 26(4), 566581.
Dale, A. M., Fischl, B., & Sereno, M. I. (1999). Cortical surface-based analysis I:
Segmentation and surface reconstruction. NeuroImage, 9, 179194.
Fischl, B., Sereno, M. I., & Dale, A. M. (1999). Cortical surface-based analysis II:
Inflation, flattening, and a surface-based coordinate system. NeuroImage, 9(2),
195207.
399
Gu, X., Wang, Y., Chan, T. F., et al. (2004). Genus zero surface conformal mapping and
its application to brain surface mapping. IEEE Transactions on Medical Imaging,
23(8), 949958.
Gutman, B., Wang, Y., Morra, J., et al. (2009). Disease classification with hippocampal
shape invariants. Hippocampus, 19(6), 572578.
Hurdal, M. K., & Stephenson, K. (2004). Cortical cartography using the discrete
conformal approach of circle packings. NeuroImage, 23(Suppl. 1), S119S128.
Kurtek, S., Klassen, E., Ding, Z., et al. (2011). Parameterization-invariant shape
comparisons of anatomical surfaces. IEEE Transactions on Medical Imaging, 30(3),
849858.
Lorensen, W. E., & Cline, H. E. (1987). Marching cubes: A high resolution 3D surface
construction algorithm. SIGGRAPH Computer Graphics, 21(4), 163169.
Miller, M. I., Trouve, A., & Younes, L. (2002). On the metrics and Euler-Lagrange
equations of computational anatomy. Annual Review of Biomedical Engineering, 4,
375405.
Panizzon, M. S., Fennema-Notestine, C., Eyler, L. T., et al. (2009). Distinct genetic
influences on cortical surface area and cortical thickness. Cerebral Cortex, 19(11),
27282735.
Pantazis, D., Joshi, A., Jiang, J., et al. (2010). Comparison of landmark-based
and automatic methods for cortical surface registration. NeuroImage, 49(3),
24792493.
Pizer, S., Fritsch, D., Yushkevich, P., et al. (1999). Segmentation, registration, and
measurement of shape variation via image object shape. IEEE Transactions on
Medical Imaging, 18, 851865.
Schwartz, E. L., Shaw, A., & Wolfson, E. (1989). A numerical solution to the generalized
mapmakers problem: Flattening nonconvex polyhedral surfaces. IEEE Transactions
on Pattern Analysis and Machine Intelligence, 11(9), 10051008.
Shi, Y., Lai, R., & Toga, A. W. (2013b). Cortical surface reconstruction via unified Reeb
analysis of geometric and topological outliers in magnetic resonance images. IEEE
Transactions on Medical Imaging, 32(3), 511530.
Shi, J., Thompson, P. M., & Wang, Y. (2012). Hyperbolic Ricci flow and its application
in studying lateral ventricle morphometry. In Multimodal brain image analysis
(pp. 6176). Berlin/Heidelberg: Springer.
Shi, J., Thompson, P. M., Gutman, B., et al. (2013a). Surface fluid registration of
conformal representation: Application to detect disease effect and genetic influence
on hippocampus. NeuroImage, 78, 111134.
Styner, M., Oguz, I., Xu, S., et al. (2006). Framework for the statistical shape
analysis of brain structures using SPHARM-PDM. The Insight Journal, (1071),
242250.
Thompson, P. M., Giedd, J. N., Woods, R. P., et al. (2000). Growth patterns in the
developing human brain detected using continuum-mechanical tensor mapping.
Nature, 404(6774), 190193.
Thompson, P. M., Hayashi, K. M., de Zubicaray, G. I., et al. (2004). Mapping
hippocampal and ventricular change in Alzheimers disease. NeuroImage, 22(4),
17541766.
Thompson, P. M., & Toga, A. W. (2002). A framework for computational anatomy.
Computing and Visualization in Science, 5, 112.
Vaillant, M., & Glaunes, J. (2005). Surface matching via currents. Information
Processing in Medical Imaging, 19, 381392.
Van Essen, D. C., Drury, H. A., Dickson, J., et al. (2001). An integrated software suite for
surface-based analyses of cerebral cortex. Journal of the American Medical
Informatics Association, 8(5), 443459.
Wang, Y., Dai, W., Gu, X., et al. (2009). Teichmuller shape space theory and its
application to brain morphometry. Medical Image Computing and ComputerAssisted Intervention, 12(Pt 2), 133140.
Wang, Y., Shi, J., Yin, X., et al. (2012). Brain surface conformal parameterization with
the Ricci flow. IEEE Transactions on Medical Imaging, 31(2), 251264.
Wang, Y., Song, Y., Rajagopalan, P., et al. (2011). Surface-based TBM boosts power to
detect disease effects on the brain: An N 804 ADNI study. NeuroImage, 56(4),
19932010.
Wang, Y., Zhang, J., Gutman, B., et al. (2010). Multivariate tensor-based morphometry
on surfaces: Application to mapping ventricular abnormalities in HIV/AIDS.
NeuroImage, 49(3), 21412157.
Relevant Websites
http://brainvis.wustl.edu/wiki/index.php/Caret:About CARET.
http://gsl.lab.asu.edu/conformal.htm Subcortical Morphometry System.
http://loni.usc.edu/ BrainSuite.
https://surfer.nmr.mgh.harvard.edu/ FreeSurfer.
Glossary
Introduction
The low-dimensional matrix Lie groups form the core dogma
for the now classic study of the kinematics of rigid bodies in
the field of rigid body mechanics. Their infinite dimensional
analog, the diffeomorphism group, one-to-one smooth transformations (Christensen, Miller, & Rabbit, 1995; Dupuis,
http://dx.doi.org/10.1016/B978-0-12-397025-1.00312-2
401
402
[1]
[2]
Tensor Images: For tensor images which are 3 3 nonnegative symmetric matrices, an action originally defined
by Alexander and Gee (Alexander, Gee, & Bajcsy, 1999)
rotates the eigenfunctions using the previous action on
frames and leaving the eigenvalues unchanged. Another
standard action is
:
IDID*1
[5]
D
Ij mj
Kij E ID
i mi
403
Z
Dxi Dxj
K x, ydxdy:
[8]
[10]
404
Z X
3
3 i1
wi xmi dx
[12]
:
with norm k v k 2V (Lv|v).
When
Lv(dx) m(x)dx has vector
P
R
density m, then Lv
w i 3 mi xwi xdx. We call m Lv
the Eulerian momentum and we choose L to have sufficient
number of derivatives so that the norm being finite implies the
continuous embedding in differentiable functions with at least
1 spatial derivative.
We exploit the parameterization of the diffeomorphism
group by exploiting the geodesic flows from the identity.
We parameterize our group of flows via their initial vector
field vt0 2 V, _ t vt t , for the subset of flows
gtv0 , g_vt 0 vt gtv0 , t 2 0, 1 corresponding to geodesic connections
satisfying conservation (Miller, Trouve, & Younes, 2006)
between coordinate systems so that for all smooth w 2 V, with
g_v00 v0 ;
v v 1
Lvt
dgt 0 w gt 0
Lv0 j w:
[13]
This allows us to induce our distribution on robust deformations by expanding in the tangent space at the identity of the
group and shooting outwards. This initial tangent representation we call geodesic coordinates (Miller et al., 2014).
Our random model is induced by building the distribution
on the initial condition on the vector field at the identity
v0 vt0 determining the geodesic solutions, modeling it as a
zero-mean Gaussian random field with
X
Vi ci , Vi is Gaussian, with variance EVi 2 li : [14]
v0
i
P
We assume the Gaussian process is of trace class
li < 1.
Thus in our prior density we have reparameterized eqn [10]
in v0, and a(n) will correspond to a Gaussian random field
model on the initial tangent vector field which shoots the
geodesics. This is as we did in using the generative model
interpretation for template estimation originally formulated
in Ma et al., 2008. We shall see below that we will solve our
atlas interpretation via integration over the nuisance variables
of unknown deformation using the mode approximation
within this subset of geodesic deformations.
[16]
with the likelihood model for inference being the joint density
X
[17]
pA ap ID , yjIa :
p ID , y
a
[18]
Of course, having observed the measured ID, the conditional probability p(A|ID) changes greatly from the prior
probability p(A). We demonstrate that the solution of the
MAP problem is this conditional probability. Essentially this
is an expectationmaximization (EM) algorithm iteration
(Dempster, Laird, & Rubin, 1977).
Statement 3: For real-valued interior points y 2 Y, the iteration y1, y2, . . . given by
X
p A ajID , yold log pID , yjIa
a
@ pID , y
I
X
y
a
p A ajID , yold
p ID , y
Ia
a
[20]
at fixed points ynew yold y* which gives the necessary interior point maximizer conditions:
old
X p ID , y j Ia
@ pID , yj Ia
pA a y D
pI ,yj Ia
ynew y*
p ID , yold
a
p^ID , yj Ia pa
0 :
p^ A aj ID , y P D
^
0
a0 p I , yj Ia pa
[19]
pID , y*
v:_ v vv
[24]
pA a@y p ID , y*jIa 0
d
Lvt j dgtv0 w gtv0 1 0 8 w 2 V
dt
405
[22]
Ny
X
ay 1
Ny
X
Z
pay j y
GV
ay 1
p ID j Iay , ay , y aj ay ,yd
Ny
X
pay j yp ID , y, g1va j Iay
pay j yp^ ID , yj Iay :
a1
D
ay 1 pyp ay y p I , y Iay
:
p yjI P
0
0
PNy0
0
^ ID , y
Ia 0
0
0
y p
p
a
p
y
a
1
0
y 2Y
y
y
y
We choose the atlas prior uniformly p ay
y N1y .
[28]
406
^ D
ay 1 pyp ay y pI , yj Iay
0
PNy0
^ D 0
0
a1 pyp a y p I , y j Iay0
y 2Y
y^ arg max p^ yj ID P
Vk as in eqn [14], with the variance given by PCA. This gives the
finite dimensional prior in the dimensionality reduced
coordinates.
Two methods for estimating a deformation prior are illustrated in Figure 1, depicted by (e) and (f)(g). Shown in (e) are
given atlases Iay depicted as pointsfor each disease class (blue/
green), along with estimates of separate priors for each disease
type, aay , ay 1, ... , Ny , depicted as the Gaussian ellipsoids.
Shown in (f)(g) is the alternative where we represent the
entire disease via one prior for each disease type with (f)
showing the prior estimated from the group ay(), measured
with respect to a population template Iy (cyan) and (g) showing the preassigned prior to the groups taken from the
population.
407
(a)
Group 1 atlas i
(b)
(c)
(d)
(e)
(f)
(g)
Figure 1 In (a), a set of left hippocampal atlases belonging to two categories (green, blue) are shown along with a target (red). A close up of a given
atlas is shown in (b), which is deformed to match the target as shown in (c). The influence of the deformation prior can be seen by comparing the
atlas to its deformation in (c), and the influence of measurement noise can be seen by comparing the deformed atlas to the target in (d). Two possible
methods for estimating a deformation prior are illustrated in (e) and (f)(g). (e) Shows atlas (points) for each disease class (blue/green), with an
estimated prior via each Gaussian ellipsoid. (f) Shows a set of group specific priors, measured with respect to a population template (cyan). (g) Shows
the same prior assigned to each atlas.
max
log p ID , y :
yW1 , ..., Wn
[31]
Alzheimers disease
Normal
40
Normal
35
AD
30
25
20
15
10
0
15
10
10
15
Figure 2 Top row: Atlases (surfaces) and training data (points) for the Alzheimers disease classification experiment are shown in a 2D coordinate
system. The left/right axis corresponds to the LDA direction, while the up/down axis shows the first principal component. Bottom row: Demonstration of
the disease classification model via eqn [29] approximating the disease cohort distribution ay vay . This model approximates the disease cohort
distribution via LDA coefficients obtained from the PCA LDA classification procedure under the common covariance model. Here it is used in
differentiating 210 normal aging subjects from 175 subjects with AD. The feature space in the classification procedure was obtained from the initial
momentum vectors indexed at each vertex of the bilateral amygdala, hippocampus, as well as ventricle. Sensitivity plus specificity averaged at 86%, as
published in Tang et al. (2014), based on the diffeomorphometry deformation biomarkers.
(Ia5 , W a5)
(Ia6 , Wa6)
(Ia4 , Wa4)
(Ia7 , W a7)
Va ~ GRF (m, K)
7
p(ID | Ia, W)
(Ia1 , Wa1)
(Ia3 , Wa3)
(Ia2 , Wa2)
Figure 3 Figure shows the population of atlases and the target at the center to be segmented. The atlases consist of the idealized image values in the
Gaussian model and the segmentation labels represented via the pairs (Ia, Wa); the target to be segmented is modeled as a random field with
graph structure such that I, , are conditionally independent given W so that p(ID| W, , Ia) p(ID| W, Ia).
Q y; yold E log p ID , y
A
ID , yold
P
a p A aj ID , yold log pID , yj Ia :
Segmentation Classification Algorithm: This gives us the following iterative algorithm based on the mode approximation.
1. For each atlas, initialize the optimal diffeomorphism as
old
a , where a is computed as the optimal diffeomorphism
connecting the global atlas imagery Ia and the observed
old
imagery ID. Initialize yold (Wold
1 , . . ., Wn ).
2. Compute the mode approximation of eqn [23] using
LDDMM algorithm to compute gva matching onto the segmentation labels yold:
p^ID , y W1 , ... , Wn j Ia pID ,y, gva j Ia
pID j y W1 , . .. , Wn ,gva , Ia py, gva j Ia
n
Y
va
p ID
i j Wi , a pW1 , .. ., Wn j g , Ia aa va
ynew arg
max
max
Qgva y; yold
409
[35]
where
X
D old
^
log p ID ,y, gva jIa :
,
y
Qgva y; yold
p
A
ajI
a
5. Update the segmentation yold ynew, go to step 2.
2
kynew yold k
< 1e4 or the number
Stop the iteration if either
old 2
y
k k
of total iterations is > 30.
In the multi-atlas random orbit model, we introduce locality into the global representations of the deformable templates by allowing different atlases to be used to interpret
different voxels or different structures, thereby associate to
the segmentation field the field of atlas labels being used to
interpret it with A (A1, A2, . . .) the field of atlas labels Ai.
To maximize eqn [35], we iterate between fixing the diffeomorphism and maximizing the segmentation, and then
locally maximizing the diffeomorphisms for the fixed segmentation labeling.
The multi-atlas random orbit model of the observable ID
assumes that its mean fields are random deformations of atlascharts arising from perhaps different atlases, each locally indexing different parts in the human brain. The observed image ID
and segmentation field parameters y (W1, . . ., Wn) are linked
to the atlas via the diffeomorphism which transfers the atlas
labeling of the brain into anatomical regions-of-interest of the
target image. This is the explicit term pW1 , ... , Wn j gva , Ia in
eqn [33]. The image ID is modeled as conditionally Gaussian,
conditioned on thesegmentation
labels giving the product law
Q
pID j W, a ni1 p ID
i j Wi , a : We take the mean and variance
of ID
i to be determined by the atlas Aa interpreting the target
image and determined by the segmentation label
ma(Wi), sa(Wi). The different atlases have different mean and
variances for cortical gray, white, and cerebrospinal fluid (CSF)
representing the different substructures of the brain determining the means and standard deviations. For the second term
pW1 , ... , Wn j gva , Ia we use a simple counting probability
given by indicator functions. Given the mapping gva , then
the probability of label Wi is calculated by transferring the label
field Wa from the atlas and using the indicator function
dWa 1 xi Wi ) which for interior voxels is zero when the atlas
label does not agree with the target label, and is 1 otherwise.
On the boundary of structures in which there is fractional
overlap of voxels we use the fraction given by the overlap of
agreement based on nearest neighbor interpolation. For computational efficiency, we use the overlap via set distance calculations to calculate these.
[33]
i1
410
(a)
(b)
(c)
(d)
Figure 4 Panels (a)(d) show the whole brain segmentations of T1weighted images into 136 anatomical regions, including subcortical
structures (e.g., the thalamus, the caudate, and the hippocampus), white
matter (e.g., the cerebellum white matter, the cerebral white matter),
cortex regions (e.g., the anterior cingulated gyrus, the middle frontal
gyrus, and the precentral gyrus), and as well as ventricles (the lateral
ventrical, the third ventricle, and the fourth ventricle), in four
representative cases.
(a)
(b)
Figure 5 Panels (a) and (b) show the segmentation results of two
subjects with Alzheimers disease. For each panel, left to right: input
image, segmentation consisted of air, skull, gray matter, white matter,
CSF, and lateral ventricles, and the input image superimposed by the six
segmentation labels.
Template Generation
Now we examine the atlas generation problem given many
observable ID1 , ID2 , . .. 2 I D the conditionally random field
space, the problem is to estimate the unknown template Ia 2 I .
The unknown template is modeled as an element in the orbit
Single-atlas LDDMM
411
Multi-atlas LDDMM
1
0.9
0.8
0.7
0.6
(a)
1.2
Multi-atlas LDDMM
1
0.8
0.6
le
th
ur
Fo
Th
ird
ve
ve
nt
nt
ric
ric
le
le
ric
nt
ve
L.
ve
nt
ric
pu
oc
pp
R.
am
am
hi
L.
le
s
pu
la
oc
pp
hi
L.
yg
yg
da
da
la
us
am
R.
th
L.
al
al
am
am
us
um
th
R.
pa
llid
um
llid
pa
ca
ud
R.
L.
e
at
e
at
L.
ud
ca
R.
ta
pu
am
R.
(b)
L.
R.
pu
ta
en
en
0.4
Figure 6 Panel (a): A comparison of the segmentation accuracy between single-atlas LDDMM (red) and multi-atlas LDDMM (green), in terms of mean
Dice overlaps. Statistics are computed from 16 subcortical and ventricular structures, including left and right hippocampus, amygdala, caudate,
putamen, globus pallidus, thalamus, lateral ventricles, the third ventricle, and the fourth ventricle, in 35 T1 images from three different clinical groups, 15
diagnosed as Alzheimers disease, 14 age-matched control subjects, and 6 diagnosed as primary progressive aphasia. Panel (b): Boxplots of
the Dice overlaps of 16 different structures for one representative subject, the Dice overlap of which were computed between the manual segmentation
and the automated segmentations obtained from single-atlas LDDMMs using 28 different atlases as well as the one from multi-atlas LDDMM
(blue dotted line).
Figure 7 Results of the whole brain segmentation into 159 structures in three representative cases with large anatomical variability. The segmentation
results are superimposed on color (upper row) and MD (bottom row) images. DTI colormap encoded the fiber orientation by red (left-right),
green (anterior-posterior), and blue (head-foot) colors.
412
[36]
The unknown diffeomorphic change of coordinates determined by the initial vector field and geodesic flow gva , leading
the parameters to be estimated as y va. The observables IDi are
conditional random fields, conditioned on Ii, with density
p(ID|Ii). The Ii are in the orbit and are therefore some unknown
deformation of the unknown template, Ii gvi Ia 2 I , with gvi
the geodesic solution of eqn [21] with ni the initial tangent
vector g_v00i n0i . Of course the gv are not known and form the
latent variables for the EM algorithm. The unknown parameters are y va which determine the template Ia gva I0 .
Statement 6: The MAP estimation of the unknown template
Ia na I0 with ID ID1 , .. ., IDn is given by
[37]
n^a argmax p ID , y va
p IDi
Ii with Ii 2 I . Since Ii is in the orbit, we model it as a
known diffeomorphic change of coordinates of the template
Ii vi Ia with the template a deformation of the hypertemplate Ia va I0 . The conditional Gaussian random field takes
the form (including only terms as a function of the data and
the parameters)
a ~ GRF (m, K)
I D3
I D2
I a = jna I0
I0
I = jn Ia
1
I D1~ GRF (jn Ia, )
1
[40]
na
[39]
bold y E
n
X
jdgvi yj
IDi , vold
a
i1
with
old
Pn
y
i1 E
IDi gvi y
dgvi y
IDi , vold
a
bold y
[41]
q
old
k I I0 gva 1
bold k2 k va k2V :
[42]
vnew
i
Z
argmax
v:_ v vv
kvt k2V dt k IDi
v1
Iold
a 1
vnew
k :
n
X
new
[43]
i1
new
Pn
y
i1 I
Di
new
new
vi y
dvi y
bold y
4. Update parameters ynew argmax yna Q^ y; yold and resulting template given by weighted LDDMM:
Single subject
argmax
d va
va :
va va
dt
new
p
k I I0 va 1 aold k2
new
I0 va
Inew
a
1
1
0
413
k vat k2V dt
[44]
5. Stop the iteration if the number of total iterations is
bigger than N, otherwise update the template
old
ynew vnew
Inew
yold vold
a
a ,Ia
a , go to step 2.
Shown in Figure 9 are atlases generated from T1-weighted MR
images of a normal elderly dataset with the age of 75 /5.9
years old. In this implementation, a set of normal elderly
human brain T1-weighted MR images were used. The template
estimation was applied to estimate the unknown atlas in the
orbit (the image in Figure 9 right column). For comparing
Nonlinear
average
Template
generation
Figure 9 Comparison of brain atlases for normal elderly dataset. The single subject was randomly selected from the elderly human brains and
served as a baseline image of the comparison. The template estimation atlas had preserved the image contrast of the single subject image, and was
sharper than the NGA image.
200%
180%
160%
140%
Dataset (Ref)
SS/Dataset
VTE/Dataset
120%
100%
80%
60%
40%
20%
0%
_R _L _R _L _R _L _R _L _R _L _R _L l_R l_L _R _L _R _L _R r_L _R r_L cle cle
en men ate date GP GP us mus ala dala pus pus nta nta ody ody ium rium rior rio rior rio ntri ntri
d
m a
m
r
d
e
e
e
o
b
t
fe e
te
ta uta au au
yg yg am cam _fro _fr V_b LV_ _at _a ost os _inf _in IV v al V
ala al
C
C
L
Pu P
Th Th Am Am poc po LV LV
LV LV V_p V_p LV LV III- ter
p
p
L
L
La
Hi
Hi
Figure 10 The normalized volumes of 24 subcortical brain structures for normal elderly dataset (blue), the single subject atlas (red) and the
atlas from template generation (purple). The template estimation atlas (purple) approximated the mean volumes of the dataset within 10% range, while
the single subject atlas (red) has severely biased structural volumes from the mean volumes.
414
Acknowledgements
This work was supported by grants R01 MH056584, R24
HL085343, R01 EB000975, P50 MH071616, R01 EB001838,
P41 EB015909, R01 EB008171, R01 MH084803, U01
AG033655, RR025053-01, U01 NS082085-01.
References
Alexander, D. C., Gee, J. C., & Bajcsy, R. (1999). Strategies for data reorientation during
non-rigid warps of diffusion tensor images. Proceedings of Miccai99, 1999,
463472.
Allassonnie`re, S., Amit, Y., & Trouve, A. (2007). Towards a coherent statistical
framework for dense deformable template estimation. Journal of the Royal Statistical
Society: Series B (Statistical Methodology), 69, 329.
Allassonnie`re, S., & Kuhn, E. (2010). Stochastic algorithm for parameter estimation for
dense deformable template mixture model. ESAIM: Probability and Statistics, 14,
382408.
Allassonnie`re, S., Kuhn, E., & Trouve`, A. (2010). Bayesian consistent estimation in
deformable models using stochastic algorithms: Applications to medical images.
Journal De La Societe Francaise De Statistique, 151, 116.
Ashburner, J. (2007). A fast diffeomorphic image registration algorithm. NeuroImage,
38, 95113.
Ashburner, J. (2009). Computational anatomy with the SPM software. Magnetic
Resonance Imaging, 27, 11631174.
Beg, M. F., Miller, M. I., Trouve, A., & Younes, L. (2005). Computing large deformation
metric mappings via geodesic flows of diffeomorphisms. International Journal of
Computer Vision, 61, 139157.
Christensen, G., Miller, M. I., & Rabbit, R. D. (1995). Deformable templates using large
deformation kinematics. IEEE Transactions of Medical Imaging, 5, 14351447.
Dempster, A. P., Laird, N. M., & Rubin, D. B. (1977). Maximum likelihood from
incomplete data via the EM algorithm. Journal of the Royal Statistical Society: Series
B (Methodological), 39, 138.
Dupuis, P., Grenander, U., & Miller, M. I. (1998). Variation problems on flows of
diffeomorphisms for image matching. Quarterly of Applied Mathematics, 56,
617694.
Evans, A. C., Collins, D. L., Mills, S. R., Brown, E. D., Kelly, R. L., & Peters, T. M.
(1993). 3D statistical neuroanatomical models from 305 MRI volumes. Nuclear
Science Symposium and Medical Imaging Conference, 3, 18131817.
Fonov, V., Evans, A. C., Botteron, K., Almli, C. R., Mckinstry, R. C., & Collins, D. L.
(2011). Unbiased average age-appropriate atlases for pediatric studies.
NeuroImage, 54, 313327.
Grenander, U., & Miller, M. I. (1994). Representations of knowledge in complexsystems. Journal of the Royal Statistical Society: Series B (Methodological), 56,
549603.
Grenander, U., & Miller, M. I. (1998). Computational anatomy: An emerging discipline.
Quarterly of Applied Mathematics, 56, 617694.
Grenander, U., & Miller, M. I. (2007). Pattern theory: From representation to inference.
Oxford: Oxford University Press.
Kunsch, H., Geman, S., & Kehagias, A. (1995). Hidden Markov random fields. The
Annals of Applied Probability, 5, 577602.
Ma, J., Miller, M. I., Trouve, A., & Younes, L. (2008). Bayesian template estimation in
computational anatomy. NeuroImage, 42, 252261.
Ma, J., Miller, M. I., & Younes, L. (2010). A Bayesian generative model for surface
template estimation. International Journal of Biomedical Imaging, 2010.
Miller, M. I. (2004). Computational anatomy: Shape, growth, and atrophy comparison
via diffeomorphisms. NeuroImage, 29, 1933.
Miller, M. I., & Qiu, A. (2009). The emerging discipline of computational functional
anatomy. NeuroImage, 45, S16S39.
Miller, M. I., Trouve, A., & Younes, L. (2002). On the metrics and EulerLagrange
equations of computational anatomy. Annual Review of Biomedical Engineering, 4,
375405.
Miller, M. I., Trouve, A., & Younes, L. (2006). Geodesic shooting for computational
anatomy. Journal of Mathematical Imaging and Vision, 24, 209228.
Miller, M. I., & Younes, L. (2001). Group actions, homeomorphisms, and matching: A
general framework. International Journal of Computer Vision, 41, 617694.
Miller, M. I., Younes, L., & Trouve, A. (2014). Diffeomorphometry and geodesic
positioning systems for human anatomy. Technology, 2, 36.
Mori, S., & Crain, B. J. (2005). MRI Atlas of Human White Matter. Amsterdam, Boston:
Elsevier.
Pennec, X. (2011). From Riemannian geometry to computational anatomy. Elements.
Qiu, A., Younes, L., & Miller, M. I. (2012). Principal component based diffeomorphic
surface mapping. IEEE Transactions on Medical Imaging, 31, 302311.
Snyder, D. L., & Miller, M. I. (1991). Random point processes in time and space.
Springer Texts in Electrical Engineering. New York: Springer-Verlag.
Tang, X., Holland, D., Dale, A. M., Younes, L., Miller, M. I., & The Alzheimers Disease
Neuroimaging Initiative. (2014). Shape abnormalities of subcortical and ventricular
structures in mild cognitive impairment and Alzheimers disease: Detecting,
quantifying, and predicting. Human Brain Mapping, 35, 37013725.
Tang, X., Oishi, K., Faria, A. V., Hillis, A. E., Ms, A., & Mori, S. (2013). Bayesian
parameter estimation and segmentation in the multi-atlas random orbit model. PLoS
One, 8.
Thompson, D. A. W. (1942). On growth and form. Cambridge: Cambridge University
Press.
Thompson, P. M., & Toga, A. W. (2002). A framework for computational anatomy.
Computing and Visualization in Science, 5, 1334.
Trouve, A. (1995). An approach of pattern recognition through infinite dimensional
group action. Research Report LMENS, 9599.
415
Zhang, Y., Zhang, J., Ma, J., Oishi, K., Faria, A. V., Miller, M. I., et al. (2011). Creation
of a population-representative brain atlas with clear anatomical definition.
Proceedings of the International Society for Magnetic Resonance in Medicine,
19, 135.
Zhang, Y., Zhang, J., Miller, M. I., & Mori, S. (2012). Population-based human brain
MRI atlas with sharp contrast and its application in image registration. Proceedings
of the International Society for Magnetic Resonance in Medicine, 20, 2570.
Glossary
http://dx.doi.org/10.1016/B978-0-12-397025-1.00313-4
417
418
subtle effects, motivating recent efforts towards standardization (Jack et al., 2011).
Finally, manual (or semiautomated) tracing often provides
an important foundation to evaluate fully automatic methods
(Good et al., 2002) and even to construct new automatic
approaches, such as segmentation propagation, discussed
shortly.
Image Registration
Overview of Methods
Manual Volumetry
Conceptually, the simplest method to compute brain change
over time is to manually trace a region of interest (ROI) in the
images for every time point. The volumes for the ROI can then
be analyzed, and the ROI can also be used to quantify nonvolumetric properties of each image (such as fMRI activity or
diffusion MRI anisotropy). Several software tools enable manual tracing (often including semiautomatic approaches, such
as manual initialization of computational procedures and/or
manual refinement of automated results); a popular free and
open-source package is ITK-SNAP (Yushkevich et al., 2006).
The disadvantages of manual tracing are clear: it requires
expert knowledge, is often very time-consuming, exhibits intraand interrater variability, can be prone to subjective biases, and
often relies on arbitrary conventions to define borders that are
unclear on typical MRI (such as boundaries between cortical
areas). Furthermore, constraints on time and/or expertise limit
the number of regions that can feasibly be considered. While
the regions most affected in a particular disease are often
known a priori, it is typically much less clear which regions
have the greatest differences among clinical or genetic subgroups (Ridgway et al., 2012; Scahill et al., 2013) or which
regions will be most informative for evaluating a candidate
treatment (cf. Fox et al., 2005). The lack of clear boundaries
and multitude of regions of interest are motivations for voxelor vertex-wise analysis (Section Voxel and Tensor-Based
Morphometry). Subjectivity warrants blinding the tracer to
aspects that could bias the study, such as the diagnostic status
of the scans in a clinical study or the hemisphere under consideration in a study of brain asymmetry; however, such blinding is often incomplete, for example, if the expert can easily
distinguish controls and patients from the scans themselves.
However, in relation to more complex methods discussed
next, it is important to recognize that manual tracing sometimes has advantages, such as unambiguous and straightforward interpretation, easily characterized sources of error
(interscan, intrarater, interrater, interscanner, etc.), and
reduced susceptibility to overt failure or bias in the presence
of pathology (see, e.g., Hobbs et al., 2011).
Differences in segmentation protocol can clearly lead to
differences in mean volumes, but they may also lead to differential sensitivity and specificity for example, a subregion
included in some protocols but excluded in others could be
the most affected part of the structure. Protocol differences
complicate the pooling of data from multiple studies, which
is particularly important for the study of rare diseases and/or
Segmentation
Many automatic methods have been developed for segmentation of brain (Leung et al., 2011), tissues (Ashburner & Friston,
2005), and regions (Fischl et al., 2002). Examples of CSF tissue
segments appear in Figure 1(b).
There are also several semiautomated procedures that refine
a rough initial segmentation (from rapid manual initialization
or from automatic approaches) using techniques such as intensity thresholding, region growing, and morphological operations (Freeborough, Fox, & Kitney, 1997) or through the
evolution of deformable surface, active contour, or level-set
models (e.g., Yushkevich et al., 2006).
Image registration allows a region segmented in one image
to be transferred to another image, known as segmentation
propagation (Collins, Holmes, Peters, & Evans, 1995). However, intersubject registration is a challenging problem, due to
the high degree of anatomical variability, which motivates
considering the propagation of segmentations from several
different subjects to the image being segmented, combining
Baseline
12-month repeat
419
24-month repeat
(a)
(b)
(c)
(d)
Figure 1 Example of change over time in Alzheimers disease, using subject 205 from MIRIAD (Malone et al., 2013). Columns correspond to axial
views (and zoomed versions) for three of the available time points. (a) Rigidly aligned images. (b) CSF segments (black denotes 0% tissue probability
and white 100%). (c) Jacobian determinants for transformations of each time point to a within-subject average image (dark colors denote relative
contraction and bright expansion). (d) Voxel-wise products of Jacobian determinants and the tissue segment for the average (white now denotes a value
of 1.4); the voxel-wise sum (integral) of these for each image estimates the same tissue volumes as integrating the individual time-point segments
in row (b). (Related video in Multi-media Annex.)
420
A1
A2
A
f2m
A
f1m
A1
Am
A2
f1T
fmT
f2T
Template
f1T
B
f2T =
A
B
fmT
f2T
B
B1
f2mfmT
Template
B2
(a)
f1m
B1
f2m
Bm
B2
(b)
f2m
fmT
f2m
n2m
f22 = f1
mT
fmT
nmT
n2m
1
f2T = fmT
f2mfmT
(c)
Template
(d)
Template
f2m
Figure 2 (a) Each time point (1, 2, . . .) of each subject (A, B, . . .) can be mapped to a template (T) with direct transformations f. (b) Within-subject
registration is more precise, motivating alignment via within-subject averages, composing between- and within-subject transformations. This enables
analysis of volumes for individual images in the template space; if interested purely in within-subject volume change, one could transform the within-subject
Jacobians (JA2m) without accounting for the between-subject volume changes (JAmT), but this is not mathematically rigorous. (c) Rao et al. (2004)
proposed to determine equivalent longitudinal transformations in template space; this conjugate map can be computed by considering the composition of
transformations around a loop, but only if one assumes there is a single transformation (fmT) mapping from template to subject that holds for all the
time points (and m) so this transformation can be inverted to get from a particular subject-space time point (2) to its template-space equivalent (20 ). (d) The
large-deformation diffeomorphic metric mapping framework characterizes transformations (f) by initial velocity fields (v). The mathematically rigorous
procedure of parallel translation (Younes, Qiu, Winslow, & Miller, 2008) then allows one to transport the within-subject velocity field along the path of the
between-subject transformation, preserving important properties in the process. If needed, equivalent images (e.g., 20 ) can be generated from the
template using the transported velocitys transformation, without any assumption about the direct transformation between 2 and 20 .
421
segmentation of the set of images, often constraining or regularizing the temporal changes (Gilmore et al., 2012; Prastawa,
Awate, & Gerig, 2012; Xue, Shen, & Davatzikos, 2006).
Durrleman et al. (2013) also employed within-subject registration (to the baseline image) but in addition to a relatively
standard combination of within- and between-subject registration applied a novel 1-D time warp to allow for nonlinear (but
monotonic) timing differences between subjects (e.g., developmental delays).
422
(a)
(b)
w
B
(c)
Intensity
Intensity
IWM B
IWM
ICSF
(d)
IWM
ICSF
(e)
ICSF
IWM B
Intensity
Intensity
ICSF
x
Intensity
IWM
ICSF
x
Figure 3 Brain boundary shift integral illustration. (a) Original images for two time points, with brain masks overlaid in blue, and their voxel-wise
difference image. (b) Registered images and difference image. (c) Example of a 1-D transect through the ventricles between points A and B, shown on
each image and the difference; the BSI estimates the 1-D geometric change Dw from the corresponding intensity change. (d) Intensity profiles
along the transect and the shaded area (integral) between them. (e) The area estimated from voxel-wise intensity differences (vertical rectangles)
corresponds to the same area swept out by the horizontal shifts of parts of the intensity profiles; dividing this area by the intensity range gives
the average shift (a length change; a volume change would result from integrating over 3-D space). The final panel is a color-coded difference image
(for brain regions) overlaid on the original illustrating volume change in BSI (red: tissue loss, green: tissue gain).
Statistical Modeling
While cross-sectional image processing of longitudinal data is
typically valid, though suboptimal, statistical analysis must
account for the dependence within-subject; false-positive rates
could be severely inflated if images from multiple time points are
423
compares first-level summaries such as linear slopes or quadratic (acceleration) terms between subjects. This is formally
identical to the standard summary-statistic procedure for hierarchical models used in between-subject fMRI analysis (where
it is commonly known as the random-effects approach). It is
also worth noting that the common practice of comparing
annualized change in studies with just two time points for all
subjects is a special case.
Pattern Analysis
Whenever more than one measure of volume change is available per subject (whether a few regions or millions of voxels),
there is the potential to form a single univariate biomarker
from the multivariate features using machine learning or pattern analysis. Examples of this include the use of a binary
statistical ROI (stat-ROI) defined using univariate significance
testing (Hua et al., 2009) and linear weighted averages, where
the weights can be determined from various techniques, such
as support vector machines (Hobbs et al., 2010) and linear
discriminant analysis (Gutman et al., 2013). It is important to
define the stat-ROI or weight image from independent training
data or to properly cross validate. These references show considerable improvements in power from these novel biomarkers
compared to simpler unweighted averages of volume change
over tissues or anatomically defined regions.
424
1999; Cachier & Rey, 2000; Smith et al., 2001; Thirion, 1998)),
so registering all time points to a single arbitrarily chosen time
point (typically the first or last) is an important source of
potential bias, shown to be of practical importance for both
global (e.g., affine) transformations (Thomas et al., 2009;
Yushkevich et al., 2010) and local (nonlinear) deformations
(Hua et al., 2011). While one source of such bias is the differential interpolation of images that are resampled compared to
the static reference image, it is important to note that even
when affine transformations are used to initialize the search
for nonlinear deformations, such that no explicit interpolation
occurs, the estimation of the nonlinear transformation
includes an internal interpolation process that can still be
biased (Yushkevich et al., 2010).
Related examples of bias from asymmetry include cases
where the registration is symmetrical (or symmetrized), but a
particular time point is segmented, or an average image (used
for segmentation and/or between-subject registration) is created in the space of a particular time point rather than in an
average position and shape. More subtly, initialization and/or
regularization of nonlinear optimization processes that favor a
particular time point can introduce bias, for example, even
symmetrical registration of all time points to baseline could
introduce bias by virtue of the fact that greater changes over
greater time intervals are further from initial values and/or
more heavily affected by regularization terms. This has led
authors to consider registration of each image to every other
image (Leung, Ridgway, Ourselin, Fox, & Alzheimers Disease
Neuroimaging Initiative, 2012) or to a within-subject average
(Ashburner & Ridgway, 2013; Reuter & Fischl, 2011; Reuter
et al., 2012).
While much work has focused on theoretical symmetries in
image registration, it is important to note that more basic
approaches can also be of help. For example, running procedures
with images reordered and averaging results (Holland et al.,
2011; Smith et al., 2001), or even just randomizing the choice
of reference image, can mitigate minor biases. Related to this,
computing effect size (and hence power or sample-size) in relation to a control group will tend to cancel simple additive biases
that are equal in the two groups (Fox, Ridgway, & Schott, 2011).
The presence and magnitude of an additive bias are often
estimated by assuming linearity of brain volume change over
three time points (Thompson, Holland, & Alzheimers Disease
Neuroimaging Initiative, 2011; Yushkevich et al., 2010), with the
assumption that a deceleration is implausible in mildly affected
patients; however, it is important to note that simply fitting a
regression model to all available time points can give a misleading answer in the presence of dropout, since loss of the most
rapidly progressive subjects could lead to an apparent deceleration (Hua et al., 2013). Other means of evaluation, such as
simulations (Camara et al., 2008) scan-re-scan tests, or comparison to less biased but more variable cross-sectionally measured
changes, are therefore complementary (Fox et al., 2011).
Acknowledgments
This work was supported by the Medical Research Council
(grant number MR/J014257/1) and the Wellcome Trust
(grant number 091593/Z/10/Z). The Wellcome Trust Centre
for Neuroimaging is supported by core funding from the
References
Alexander, D., Pierpaoli, C., Basser, P., & Gee, J. (2001). Spatial transformations of
diffusion tensor magnetic resonance images. IEEE Transactions on Medical
Imaging, 20(11), 11311139.
Anderson, V. M., Schott, J. M., Bartlett, J. W., Leung, K. K., Miller, D. H., & Fox, N. C.
(2012). Gray matter atrophy rate as a marker of disease progression in AD.
Neurobiology of Aging, 33(7), 11941202.
Andrews, K. A., Modat, M., Macdonald, K. E., Yeatman, T., Cardoso, M. J., Leung, K. K.,
et al. (2013). Atrophy rates in asymptomatic amyloidosis: Implications for Alzheimer
prevention trials. PLoS One, 8(3), e58816.
Ashburner, J., Andersson, J. L., & Friston, K. J. (2000). Image registration using a
symmetric priorin three dimensions. Human Brain Mapping, 9(4), 212225.
Ashburner, J., & Friston, K. J. (2005). Unified segmentation. NeuroImage, 26(3),
839851.
Ashburner, J., & Friston, K. J. (2011). Diffeomorphic registration using geodesic
shooting and Gauss-Newton optimisation. NeuroImage, 55(3), 954967.
Ashburner, J., & Kloppel, S. (2011). Multivariate models of inter-subject anatomical
variability. NeuroImage, 56(2), 422439.
Ashburner, J., & Ridgway, G. R. (2013). Symmetric diffeomorphic modeling of
longitudinal structural MRI. Frontiers in Neuroscience, 6, 197.
Aubert-Broche, B., Fonov, V. S., Garca-Lorenzo, D., Mouiha, A., Guizard, N., Coupe, P.,
et al. (2012). A new framework for analyzing structural volume changes of
longitudinal brain MRI data. In STIA: Spatio-temporal image analysis for
longitudinal and time-series image data. Lecture Notes in Computer Science
(vol. 7570, pp. 5062). Verlag: Springer.
Avants, B., Anderson, C., Grossman, M., & Gee, J. C. (2007). Spatiotemporal
normalization for longitudinal analysis of gray matter atrophy in frontotemporal
dementia. International Conference on Medical Image Computing and ComputerAssisted Intervention Brisbane, 10, 303310.
Barnes, J., Ridgway, G. R., Bartlett, J., Henley, S. M.D, Lehmann, M., Hobbs, N., et al.
(2010). Head size, age and gender adjustment in MRI studies: A necessary
nuisance? NeuroImage, 53(4), 12441255.
Bernal-Rusiel, J. L., Greve, D. N., Reuter, M., Fischl, B., & Sabuncu, M. R.Alzheimers
Disease Neuroimaging Initiative. (2012). Statistical analysis of longitudinal
neuroimage data with linear mixed effects models. NeuroImage, 66C, 249260.
Bernal-Rusiel, J. L., Reuter, M., Greve, D. N., Fischl, B., & Sabuncu, M. R.Alzheimers
Disease Neuroimaging Initiative. (2013). Spatiotemporal linear mixed effects
modeling for the mass-univariate analysis of longitudinal neuroimage data.
NeuroImage, 81, 358370.
425
Boyes, R. G., Rueckert, D., Aljabar, P., Whitwell, J., Schott, J. M., Hill, D. L.G, et al.
(2006). Cerebral atrophy measurements using Jacobian integration: Comparison
with the boundary shift integral. NeuroImage, 32(1), 159169.
Cachier, P., & Rey, D. (2000). Symmetrization of the non-rigid registration problem
using inversion-invariant energies: Application to multiple sclerosis. In
International conference on medical image computing and computer-assisted
intervention. Lecture Notes in Computer Science (vol. 1935, pp. 472481).
Visegrad: Springer.
Camara, O., Schnabel, J. A., Ridgway, G. R., Crum, W. R., Douiri, A., Scahill, R. I., et al.
(2008). Accuracy assessment of global and local atrophy measurement techniques
with realistic simulated longitudinal Alzheimers disease images. NeuroImage,
42(2), 696709.
Cardoso, M. J., Clarkson, M. J., Modat, M., & Ourselin, S. (2011). Longitudinal cortical
thickness estimation using Khalimskys cubic complex. In International conference
on medical image computing and computer-assisted intervention. Lecture Notes in
Computer Science (vol. 6892, pp. 467475). Berlin: Springer.
Cardoso, M. J., Leung, K., Modat, M., Keihaninejad, S., Cash, D., Barnes, J., et al.
(2013). STEPS: Similarity and truth estimation for propagated segmentations and its
application to hippocampal segmentation and brain parcelation. Medical Image
Analysis, 17(6), 671684.
Chen, R., Resnick, S. M., Davatzikos, C., & Herskovits, E. H. (2012). Dynamic Bayesian
network modeling for longitudinal brain morphometry. NeuroImage, 59(3), 23302338.
Chen, G., Saad, Z. S., Britton, J. C., Pine, D. S., & Cox, R. W. (2013). Linear mixedeffects modeling approach to FMRI group analysis. NeuroImage, 73, 176190.
Christensen, G. E. (1999). Consistent linear-elastic transformations for image matching.
In Information processing in medical imaging. Lecture Notes in Computer Science
(vol. 1613, pp. 224237). Berlin: Springer.
Chung, M. K., Worsley, K. J., Robbins, S., Paus, T., Taylor, J., Giedd, J. N., et al.
(2003). Deformation-based surface morphometry applied to gray matter
deformation. NeuroImage, 18(2), 198213.
Clarkson, M. J., Ourselin, S., Nielsen, C., Leung, K. K., Barnes, J., Whitwell, J. L., et al.
(2009). Comparison of phantom and registration scaling corrections using the ADNI
cohort. NeuroImage, 47(4), 15061513.
Collins, D. L., Holmes, C. J., Peters, T. M., & Evans, A. C. (1995). Automatic 3-D
model-based neuroanatomical segmentation. Human Brain Mapping, 3, 190208.
Cook, N. R., & Ware, J. H. (1983). Design and analysis methods for longitudinal
research. Annual Review of Public Health, 4, 123.http://dx.doi.org/10.1146/
annurev.pu.04.050183.000245.
Crum, W. R., Hartkens, T., & Hill, D. L. G. (2004). Non-rigid image registration: Theory
and practice. British Journal of Radiology, 77, S140S153, Spec No 2.
Daga, P., Winston, G., Modat, M., White, M., Mancini, L., Cardoso, M. J., et al. (2012).
Accurate localization of optic radiation during neurosurgery in an interventional MRI
suite. IEEE Transactions on Medical Imaging, 31(4), 882891.
Das, S. R., Avants, B. B., Pluta, J., Wang, H., Suh, J. W., Weiner, M. W., et al. (2012).
Measuring longitudinal change in the hippocampal formation from in vivo highresolution T2-weighted MRI. NeuroImage, 60(2), 12661279.
Davatzikos, C., Genc, A., Xu, D., & Resnick, S. M. (2001). Voxel-based morphometry
using the RAVENS maps: Methods and validation using simulated longitudinal
atrophy. NeuroImage, 14(6), 13611369.
Douaud, G., Refsum, H., de Jager, C. A., Jacoby, R., Nichols, T. E., Smith, S. M., et al.
(2013). Preventing Alzheimers disease-related gray matter atrophy by B-vitamin
treatment. Proceedings of the National Academy of Sciences of the United States of
America, 110(23), 95239528.
Draganski, B., Ashburner, J., Hutton, C., Kherif, F., Frackowiak, R. S.J, Helms, G.,
et al. (2011). Regional specificity of MRI contrast parameter changes in normal
ageing revealed by voxel-based quantification (VBQ). NeuroImage, 55(4),
14231434.
Draganski, B., Gaser, C., Busch, V., Schuierer, G., Bogdahn, U., & May, A. (2004).
Neuroplasticity: Changes in grey matter induced by training. Nature, 427(6972),
311312.
Durrleman, S., Pennec, X., Trouve, A., Braga, J., Gerig, G., & Ayache, N. (2013).
Toward a comprehensive framework for the spatiotemporal statistical analysis
of longitudinal shape data. International Journal of Computer Vision, 103(1),
2259.
Eshaghi, A., Bodini, B., Ridgway, G. R., Garca-Lorenzo, D., Tozer, D., Sahraian, M. A.,
et al. (2014). Temporal and spatial evolution of grey matter atrophy in primary
progressive multiple sclerosis. Neuroimage, 86, 257264.
Fischl, B., Salat, D. H., Busa, E., Albert, M., Dieterich, M., Haselgrove, C., et al. (2002).
Whole brain segmentation: Automated labeling of neuroanatomical structures in the
human brain. Neuron, 33(3), 341355.
Fitzmaurice, G., Davidian, M., Verbeke, G., & Molenberghs, G. (Eds.), (2008).
Longitudinal data analysis: A handbook of modern statistical methods. Chapman &
Hall.
426
Fjell, A. M., McEvoy, L., Holland, D., Dale, A. M., & Walhovd, K. B., Alzheimers Disease
Neuroimaging Initiative. (2013). Brain changes in older adults at very low risk for
Alzheimers disease. Journal of Neuroscience, 33(19), 82378242.
Focke, N. K., Helms, G., Kaspar, S., Diederich, C., Toth, V., Dechent, P., et al. (2011).
Multi-site voxel-based morphometrynot quite there yet. NeuroImage, 56(3),
11641170.
Fonteijn, H. M., Modat, M., Clarkson, M. J., Barnes, J., Lehmann, M., Hobbs, N. Z.,
et al. (2012). An event-based model for disease progression and its application in
familial Alzheimers disease and Huntingtons disease. NeuroImage, 60(3),
18801889.
Fox, N. C., Black, R. S., Gilman, S., Rossor, M. N., Griffith, S. G., Jenkins, L., et al. (May
2005). Effects of A-beta immunization (AN1792) on MRI measures of cerebral
volume in Alzheimer disease. Neurology, 64(9), 15631572, for the AN1792(QS21)-201 Study Team.
Fox, N. C., Freeborough, P. A., & Rossor, M. N. (1996). Visualisation and quantification
of rates of atrophy in Alzheimers disease. Lancet, 348(9020), 9497.
Fox, N. C., Ridgway, G. R., & Schott, J. M. (2011). Algorithms, atrophy and Alzheimers
disease: Cautionary tales for clinical trials. NeuroImage, 57(1), 1518.
Freeborough, P. A., & Fox, N. C. (1997). The boundary shift integral: An accurate and
robust measure of cerebral volume changes from registered repeat MRI. IEEE
Transactions on Medical Imaging, 16(5), 623629.
Freeborough, P. A., Fox, N. C., & Kitney, R. I. (1997). Interactive algorithms for the
segmentation and quantitation of 3-D MRI brain scans. Computer Methods and
Programs in Biomedicine, 53(1), 1525.
Frost, C., Kenward, M. G., & Fox, N. C. (2004). The analysis of repeated direct
measures of change illustrated with an application in longitudinal imaging.
Statistics in Medicine, 23(21), 32753286.
Giedd, J. N., Blumenthal, J., Jeffries, N. O., Castellanos, F. X., Liu, H., Zijdenbos, A.,
et al. (1999). Brain development during childhood and adolescence: A longitudinal
MRI study. Nature Neuroscience, 2(10), 861863.
Gilmore, J. H., Shi, F., Woolson, S. L., Knickmeyer, R. C., Short, S. J., Lin, W., et al.
(2012). Longitudinal development of cortical and subcortical gray matter from birth
to 2 years. Cerebral Cortex, 22(11), 24782485.
Good, C. D., Scahill, R. I., Fox, N. C., Ashburner, J., Friston, K. J., Chan, D., et al. (2002).
Automatic differentiation of anatomical patterns in the human brain: Validation with
studies of degenerative dementias. NeuroImage, 17(1), 2946.
Grandy, J., (1997). Efficient computation of volume of hexahedral cells. Technical report,
Lawrence Livermore National Laboratory. URL http://doi.org/10.2172/632793.
Guizard, N., Fonov, V. S., Garca-Lorenzo, D., Aubert-Broche, B., Eskildsen, S. F., &
Collins, D. L. (2012). Spatio- temporal regularization for longitudinal registration to
an unbiased 3D individual template. In STIA: Spatio- temporal image analysis for
longitudinal and time-series image data. Nice, Lecture Notes in Computer Science
(vol. 7570, pp. 112). Springer.
Gutman, B. A., Hua, X., Rajagopalan, P., Chou, Y.-Y., Wang, Y., Yanovsky, I., et al.
(2013). Maximizing power to track Alzheimers disease and MCI progression by
LDA-based weighting of longitudinal ventricular surface features. NeuroImage, 70,
386401.
Habas, P. A., Scott, J. A., Roosta, A., Rajagopalan, V., Kim, K., Rousseau, F., et al.
(2012). Early folding patterns and asymmetries of the normal human brain detected
from in utero MRI. Cerebral Cortex, 22(1), 1325.
Hajnal, J. V., Hill, D. L., & Hawkes, D. J. (2001). Medical Image Registration. Boca
Raton, FL: CRC press.
Hobbs, N. Z., Henley, S. M.D, Ridgway, G. R., Wild, E. J., Barker, R. A., Scahill, R. I.,
et al. (2010). The progression of regional atrophy in premanifest and early
Huntingtons disease: A longitudinal voxel-based morphometry study. Journal of
Neurology, Neurosurgery and Psychiatry, 81(7), 756763.
Hobbs, N. Z., Pedrick, A. V., Say, M. J., Frost, C., Dar Santos, R., Coleman, A., et al.
(2011). The structural involvement of the cingulate cortex in premanifest and early
Huntingtons disease. Movement Disorders, 26(9), 16841690.
Holden, M. (2008). A review of geometric transformations for nonrigid body
registration. IEEE Transactions on Medical Imaging, 27(1), 111128.
Holden, M., Hill, D., Denton, E., Jarosz, J., Cox, T., Rohlfing, T., et al. (2000). Voxel
similarity measures for 3-D serial MR brain image registration. IEEE Transactions
on Medical Imaging, 19(2), 94102.
Holland, D., & Dale, A. M.Alzheimers Disease Neuroimaging Initiative. (2011).
Nonlinear registration of longitudinal images and measurement of change in
regions of interest. Medical Image Analysis, 15(4), 489497.
Holland, D., Desikan, R. S., Dale, A. M., & McEvoy, L. K., Alzheimers Disease
Neuroimaging Initiative. (2012). Rates of decline in Alzheimer disease decrease with
age. PLoS One, 7(8), e42325.
Holland, D., McEvoy, L. K., & Dale, A. M., Alzheimers Disease Neuroimaging Initiative.
(2012). Unbiased comparison of sample size estimates from longitudinal structural
measures in ADNI. Human Brain Mapping, 33(11), 25862602.
Horakova, D., Cox, J. L., Havrdova, E., Hussein, S., Dolezal, O., Cookfair, D., et al.
(2008). Evolution of different MRI measures in patients with active relapsingremitting multiple sclerosis over 2 and 5 years: A casecontrol study. Journal of
Neurology, Neurosurgery and Psychiatry, 79(4), 407414.
Hua, X., Gutman, B., Boyle, C. P., Rajagopalan, P., Leow, A. D., Yanovsky, I., et al.
(2011). Accurate measurement of brain changes in longitudinal MRI scans using
tensor-based morphometry. NeuroImage, 57(1), 514.
Hua, X., Hibar, D. P., Ching, C. R.K, Boyle, C. P., Rajagopalan, P., Gutman, B. A., et al.
(2013). Unbiased tensor-based morphometry: Improved robustness and
sample size estimates for Alzheimers disease clinical trials. NeuroImage, 66,
648661.
Hua, X., Lee, S., Yanovsky, I., Leow, A. D., Chou, Y.-Y., Ho, A. J., et al. (2009).
Optimizing power to track brain degeneration in Alzheimers disease and mild
cognitive impairment with tensor-based morphometry: An ADNI study of 515
subjects. NeuroImage, 48(4), 668681.
Huang, J., & Alexander, D. C. (2012). Probabilistic event cascades for Alzheimers
disease. In Advances in neural information processing systems (pp. 31043112). .
http://books.nips.cc/papers/files/nips25/NIPS2012_1428.pdf.
Hutton, C., Draganski, B., Ashburner, J., & Weiskopf, N. (2009). A comparison between
voxel-based cortical thickness and voxel-based morphometry in normal aging.
NeuroImage, 48(2), 371380.
Ishida, S., Sugino, M., Koizumi, N., Shinoda, K., Ohsawa, N., Ohta, T., et al. (1995).
Serial MRI in early Creutzfeldt-Jacob disease with a point mutation of prion protein
at codon 180. Neuroradiology, 37(7), 531534.
Jack, C. R., Jr., Barkhof, F., Bernstein, M. A., Cantillon, M., Cole, P. E., Decarli, C., et al.
(2011). Steps to standardization and validation of hippocampal volumetry as a
biomarker in clinical trials and diagnostic criterion for Alzheimers disease.
Alzheimers Dement, 7(4), 474485, e4.
Jack, C. R., Jr., Lowe, V. J., Weigand, S. D., Wiste, H. J., Senjem, M. L.,
Knopman, D. S., et al. (2009). Serial PIB and MRI in normal, mild cognitive
impairment and Alzheimers disease: Implications for sequence of pathological
events in Alzheimers disease. Brain, 132(Pt 5), 13551365.
Jack, C. R., Jr., Petersen, R. C., Grundman, M., Jin, S., Gamst, A., Ward, C. P., et al.
(2008). Longitudinal MRI findings from the vitamin E and donepezil treatment study
for MCI. Neurobiol Aging, 29(9), 12851295.
Jacobs, D., Sano, M., Marder, K., Bell, K., Bylsma, F., Lafleche, G., et al. (1994). Age at
onset of Alzheimers disease: Relation to pattern of cognitive dysfunction and rate of
decline. Neurology, 44(7), 12151220.
Jernigan, T. L., Gamst, A. C., Fennema-Notestine, C., & Ostergaard, A. L. (2003). More
mapping in brain mapping: statistical comparison of effects. Human Brain
Mapping, 19(2), 9095.
Jovicich, J., Czanner, S., Greve, D., Haley, E., van der Kouwe, A., Gollub, R., et al.
(2006). Reliability in multi-site structural MRI studies: Effects of gradient
non-linearity correction on phantom and human data. NeuroImage, 30(2),
436443.
Jovicich, J., Marizzoni, M., Sala-Llonch, R., Bosch, B., Bartres-Faz, D., Arnold, J., et al.
(2013). Brain morphometry reproducibility in multi-center 3 T MRI studies: A
comparison of cross-sectional and longitudinal segmentations. NeuroImage, 83C,
472484.
Keihaninejad, S., Zhang, H., Ryan, N. S., Malone, I. B., Modat, M., Cardoso, M. J., et al.
(2013). An unbiased longitudinal analysis framework for tracking white matter
changes using diffusion tensor imaging with application to Alzheimers disease.
NeuroImage, 72, 153163.
Kempton, M. J., Ettinger, U., Schmechtig, A., Winter, E. M., Smith, L., McMorris, T.,
et al. (2009). Effects of acute dehydration on brain morphology in healthy humans.
Human Brain Mapping, 30(1), 291298.
Kim, J., Avants, B., Whyte, J., & Gee, J. C. (2013). Methodological considerations in
longitudinal morphometry of traumatic brain injury. Frontiers in Human
Neuroscience, 7, 52.
Lazaro, L., Bargallo, N., Castro-Fornieles, J., Falcon, C., Andres, S., Calvo, R., et al.
(2009). Brain changes in children and adolescents with obsessive-compulsive
disorder before and after treatment: A voxel-based morphometric MRI study.
Psychiatry Research, 172(2), 140146.
Leung, K. K., Barnes, J., Modat, M., Ridgway, G. R., Bartlett, J. W., Fox, N. C., et al.
(2011). Brain MAPS: An automated, accurate and robust brain extraction technique
using a template library. NeuroImage, 55(3), 10911108.
Leung, K. K., Barnes, J., Ridgway, G. R., Bartlett, J. W., Clarkson, M. J., Macdonald, K.,
et al. (2010). Automated cross-sectional and longitudinal hippocampal volume
measurement in mild cognitive impairment and Alzheimers disease. NeuroImage,
51(4), 13451359.
Leung, K. K., Bartlett, J. W., Barnes, J., Manning, E. N., Ourselin, S., Fox, N. C., et al.
(2013). Cerebral atrophy in mild cognitive impairment and Alzheimer disease: Rates
and acceleration. Neurology, 80(7), 648654.
427
Ridgway, G. R., Lehmann, M., Barnes, J., Rohrer, J. D., Warren, J. D., Crutch, S. J., et al.
(2012). Early-onset Alzheimer disease clinical variants: multivariate analyses of
cortical thickness. Neurology, 79(1), 8084.
Ridha, B. H., Anderson, V. M., Barnes, J., Boyes, R. G., Price, S. L., Rossor, M. N., et al.
(2008). Volumetric MRI and cognitive measures in Alzheimer disease: Comparison
of markers of progression. Journal of Neurology, 255(4), 567574.
Rohrer, J. D., Caso, F., Mahoney, C., Henry, M., Rosen, H. J., Rabinovici, G., et al.
(2013). Patterns of longitudinal brain atrophy in the logopenic variant of primary
progressive aphasia. Brain and Language, 127, 121126.
Salat, D. H., Lee, S. Y., van der Kouwe, A. J., Greve, D. N., Fischl, B., & Rosas, H. D.
(2009). Age-associated alterations in cortical gray and white matter signal intensity
and gray to white matter contrast. NeuroImage, 48(1), 2128.
Scahill, R. I., Ridgway, G. R., Bartlett, J. W., Barnes, J., Ryan, N. S., Mead, S., et al.
(2013). Genetic influences on atrophy patterns in familial Alzheimers disease: A
comparison of APP and PSEN1 mutations. Journal of Alzheimers Disease, 35(1),
199212.
Scahill, R. I., Schott, J. M., Stevens, J. M., Rossor, M. N., & Fox, N. C. (2002). Mapping
the evolution of regional atrophy in Alzheimers disease: Unbiased analysis of fluidregistered serial MRI. Proceedings of the National Academy of Sciences of the
United States of America, 99(7), 47034707.
Scholz, J., Klein, M. C., Behrens, T. E.J, & Johansen-Berg, H. (2009). Training induces
changes in white-matter architecture. Nature Neuroscience, 12(11), 13701371.
Schwartzman, A., Dougherty, R. F., & Taylor, J. E. (2005). Cross-subject comparison of
principal diffusion direction maps. Magnetic Resonance in Medicine, 53(6),
14231431.
Skrinjar, O., Bistoquet, A., & Tagare, H. (2008). Symmetric and transitive registration of
image sequences. International Journal of Biomedical Imaging, 2008(686875), 19.
Smith, S. M., Stefano, N. D., Jenkinson, M., & Matthews, P. M. (2001). Normalized
accurate measurement of longitudinal brain change. Journal of Computer Assisted
Tomography, 25(3), 466475.
Smith, S. M., Zhang, Y., Jenkinson, M., Chen, J., Matthews, P. M., Federico, A., et al.
(2002). Accurate, robust, and automated longitudinal and cross-sectional brain
change analysis. NeuroImage, 17(1), 479489.
Sowell, E. R., Thompson, P. M., Leonard, C. M., Welcome, S. E., Kan, E., & Toga, A. W.
(2004). Longitudinal mapping of cortical thickness and brain growth in normal
children. Journal of Neuroscience, 24(38), 82238231.
Studholme, C. (2011). Mapping fetal brain development in utero using magnetic
resonance imaging: The big bang of brain mapping. Annual Review of Biomedical
Engineering, 13, 345368.
Tabrizi, S. J., Scahill, R. I., Durr, A., Roos, R. A., Leavitt, B. R., Jones, R., et al. (2011).
Biological and clinical changes in premanifest and early stage Huntingtons disease
in the TRACK-HD study: The 12-month longitudinal analysis. Lancet Neurology,
10(1), 3142.
Tagare, H., Groisser, D., & Skrinjar, O. (2009). Symmetric non-rigid registration: A
geometric theory and some numerical techniques. Journal of Mathematical Imaging
and Vision, 34(1), 6188.
Thevenaz, P., Blu, T., & Unser, M. (2000). Interpolation revisited. IEEE Transactions on
Medical Imaging, 19(7), 739758.
Thirion, J. P. (1998). Image matching as a diffusion process: An analogy with Maxwells
demons. Medical Image Analysis, 2(3), 243260.
Thomas, C., & Baker, C. I. (2013). Teaching an adult brain new tricks: A critical review
of evidence for training- dependent structural plasticity in humans. NeuroImage, 73,
225236.
Thomas, A. G., Marrett, S., Saad, Z. S., Ruff, D. A., Martin, A., & Bandettini, P. A.
(2009). Functional but not structural changes associated with learning: An
exploration of longitudinal voxel-based morphometry (VBM). NeuroImage, 48(1),
117125.
Thompson, W. K., Hallmayer, J., & OHara, R.Alzheimers Disease Neuroimaging Initiative.
(2011). Design considerations for characterizing psychiatric trajectories across the
lifespan: Application to effects of APOE-e4 on cerebral cortical thickness in Alzheimers
disease. The American Journal of Psychiatry, 168(9), 894903.
Thompson, W. K., & Holland, D.Alzheimers Disease Neuroimaging Initiative. (2011).
Bias in tensor based morphometry Stat-ROI measures may result in unrealistic
power estimates. NeuroImage, 57(1), 14.
Vardhan, A., Prastawa, M., Sharma, A., Piven, J., & Gerig, G. (2013). Modeling
longitudinal MRI changes in populations using a localized, information-theoretic
measure of contrast. In: IEEE International Symposium on Biomedical Imaging
(ISBI) (pp. 13961399).
Walters, R. J., Fox, N. C., Crum, W. R., Taube, D., & Thomas, D. J. (2001).
Haemodialysis and cerebral oedema. Nephron, 87(2), 143147.
Warfield, S. K., Zou, K. H., & Wells, W. M. (2004). Simultaneous truth and performance
level estimation (STAPLE): An algorithm for the validation of image segmentation.
IEEE Transactions on Medical Imaging, 23(7), 903921.
428
Wolz, R., Heckemann, R. A., Aljabar, P., Hajnal, J. V., Hammers, A., Lotjonen, J., et al.
(2010). Measurement of hippocampal atrophy using 4D graph-cut segmentation:
Application to ADNI. NeuroImage, 52(1), 109118.
Xue, Z., Shen, D., & Davatzikos, C. (2006). CLASSIC: Consistent longitudinal
alignment and segmentation for serial image computing. NeuroImage, 30(2),
388399.
Younes, L., Qiu, A., Winslow, R. L., & Miller, M. I. (2008). Transport of relational
structures in groups of diffeomorphisms. Journal of Mathematical Imaging and
Vision, 32(1), 4156.
Yushkevich, P. A., Avants, B. B., Das, S. R., Pluta, J., Altinay, M., Craige, C., et al.
(2010). Bias in estimation of hippocampal atrophy using deformation-based
morphometry arises from asymmetric global normalization: An illustration in ADNI
3 T MRI data. NeuroImage, 50(2), 434445.
Yushkevich, P. A., Piven, J., Hazlett, H. C., Smith, R. G., Ho, S., Gee, J. C., et al. (2006).
User-guided 3D active contour segmentation of anatomical structures: Significantly
improved efficiency and reliability. NeuroImage, 31(3), 11161128.
Zatorre, R. J., Fields, R. D., & Johansen-Berg, H. (2012). Plasticity in gray and white:
Neuroimaging changes in brain structure during learning. Nature Neuroscience,
15(4), 528536.
Relevant Websites
http://www.fil.ion.ucl.ac.uk/spm/ SPM software.
http://fsl.fmrib.ox.ac.uk/ FSL (see SIENA, fsl_anat and FSLVBM, in particular).
http://www.itksnap.org ITK-SNAP software.
http://www.nitrc.org/forum/forum.php?thread_id3881&forum_id2 Longitudinal
MRI data-sets NITRC discussion post.
http://surfer.nmr.mgh.harvard.edu/ FreeSurfer software.
https://surfer.nmr.mgh.harvard.edu/fswiki/LongitudinalData Longitudinal MRI datasets FreeSurfer wiki page.
Glossary
image data using a recently developed framework. Descriptions include the generation of normative models for healthy
singletons and twins and a statistical framework to predict
development at 2 years of age from neonatal data a capability
with excellent potential for preclinical diagnosis and eventual
early therapeutic intervention. As the brain develops, the water
content in the brain tissue decreases while protein content and
http://dx.doi.org/10.1016/B978-0-12-397025-1.00314-6
429
430
Neo
Year 1
Year 2
T1W
T2W
Year 1
Year 2
431
432
Growth Models
Brain growth functions clearly show the nonlinear nature of
changes, starting with rapid changes that flatten off with
increasing age. These characteristics can be observed in measurements of brain volumes, of head circumference, tissue
contrast not only in T1- or T2-weighted anatomical MRI but
also in white matter diffusion obtained from diffusion
weighted MRI (DW-MRI). Linear modeling therefore cannot
capture this structure and has to be replaced by nonlinear
growth modeling. Nonlinear models of growth are generally
based on a differential equation relating growth rate dy/dt to
response variable y (i.e., size and diffusion parameter; Karkach,
2006). This formulation has led to a variety of growth models,
such as exponential, monomolecular, logistic, and Gompertz
functions. We have demonstrated in Sadeghi et al. (2013) that
the parametric Gompertz function best suits the purpose of
modeling early brain development. Moreover, the parameters
of the Gompertz function also provide intuitive parameterization of growth in terms of asymptotic value, delay, and growth
rate: y asymptote exp ( delay exp ( speed t)).
Regional Characterization
Normative Models for White Matter Diffusivities
The nonlinear mixed effects are used to model the longitudinal
changes of diffusion parameters within anatomical regions of
interest. A white matter label map developed and disseminated
by Mori et al. (2008) was used to define regions of interest in
our infant image data set. We select 13 anatomical regions in
the atlas space as shown in Figure 4. In this study, the left and
right regions of anatomical locations are combined, giving a
total of eight regions. The labeling of regions in the atlas space
allows automatic partitioning of each subjects scan into the
different anatomical regions as all the subjects have been
mapped to the atlas space (for details on the image processing
pipeline, please see Sadeghi et al. (2012)). We then estimate
growth trajectories for these regions using the nonlinear mixed
effects (NLME) model of Lindstrom and Bates (1990). Figure 4
illustrates the average FA for each region. In all the regions, FA
increases with age; however, each region has its own distinct
temporal pattern. Most of the regions show a rapid growth in
the first year with continued growth but at a slower rate in the
second year; however, the genu of the corpus callosum shows a
steady growth during the first 2 years. The genu is one of the
regions that develops later and its maturation seems to continue into developmental stages later than the 2-year observation period.
Hypothesis Testing
Mixed effects models provide a powerful and flexible environment for analyzing longitudinal data, properly accounting for
the intercorrelation among observations on each subject
(Diggle et al., 2002). In the mixed effects model, the observed
data are assumed to be a combination of both fixed effects, b,
parameters associated with the entire population (or at least
within a subpopulation), and random effects, b, parameters that
are specific to an individual drawn at random from the population. A mixed effects model distinguishes between a withinsubject source of variability and a between-subject source of
variability. Correlation among repeated scans of an individual
is accounted for by incorporating random effects in the model.
Mixed effects model also results in a group trend (fixed effects)
that better reflects how individuals progress on average compared to a least-square fit as is shown in the Figure 3.
RD
0.007
0.006
0.005
0.004
0
200
400
600
Age (days)
800
200
400
Age (days)
600
800
200
400
Age (days)
600
800
Figure 3 Population growth models, represented as dashed black curves, obtained using nonlinear least-squares (NLS) fit on the left and with
nonlinear mixed effects (NLME) modeling in the middle. Colored points represent data observations, and colored curves represent the
individual growth trajectories. NLME (solid black) better models how individuals progress on average if compared with NLS (dashed black),
with overlay of both shown on the right.
ALIC
PLIC
Genu
0.8
433
BCC
Sp
ExCap
RLIC
PTR
FA
0.6
0.4
0.2
200
400
600
800
Age (days)
Figure 4 Average growth trajectories of the anterior limb of internal capsule (ALIC) and posterior limb of internal capsule (PLIC); the genu, body, and
splenium of the corpus callosum (Genu, BCC, and Sp); external capsule (ExCap) and retrolenticular part of the internal capsule (RLIC); and posterior
thalamic radiation are shown. FA values increase for all these regions during early brain development, but different structures depict a distinct
spatiotemporal pattern.
0.8
FA
0.6
0.4
0.2
0.0
0.5
200
400
600
800
600
800
0.0015
0.0005
0
FA
RD (mm2 s-1)
Age (days)
200
400
Age (days)
Figure 5 Left: Color-coded FA of the corpus callosum at 6, 12, and 24 months (the left side of the image is the posterior region (splenium), whereas the
right side is the anterior region (genu) of cc). Right: Population and individual growth trajectories for the genu (blue) and splenium (red). Thick
curves are the average growth trajectories, whereas dashed curves are the individual trajectories. The following Gompertz parameters were
significantly different (p < 0.05) between these two regions: FA, asymptote and speed; RD, speed.
434
Neo
year 1
RD (mm2 s1)
0.0004
0.0008
0.0012
200
400
Age (days)
600
800
Figure 6 Top: Posterior thalamic radiation is shown as red label on the neonate and year 1 FA scans of one subject. Bottom: Subject 95% prediction
interval compared with the overall prediction for RD of posterior thalamic radiation. Subject-specific interval calculated based on the subjects
scans at neonate and 1 year in addition to population parameters. Subjects year 2 RD value (red square) falls within the predicted range (blue region).
200
400
600
0.0022
800
Singleton
200
Age (days)
600
800
600
800
0.0022
0.0018
Singleton
0.0014
AD (mm2 s-1)
400
Age (days)
0.0010
0.0022
0.0018
Twin
0.0014
0.0010
AD (mm2 s-1)
Singleton
200
400
Age (days)
Twin
0.0018
0.0010
AD (mm2 s-1)
0
0.0014
Twin
0.0018
Singleton
0.0014
0.0010
AD (mm2 s-1)
0.0022
435
200
400
600
800
Age (days)
Figure 7 Comparison of AD growth trajectories of twins and singletons for the ALIC and the anterior corona radiata. The delay parameter (p < 0.05)
was significantly different between twins and singletons in these two regions.
5
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
0
-0.5
-1
-1.5
-2
-2.5
-3
-3.5
-4
-4.5
-5
Figure 8 Differences in axial diffusion (AD) of twins versus singletons ((Twin Singleton)/Singleton)*100. Top: Differences in AD between twins and
singletons at birth. Bottom: Differences at 3 months. The changes from dark blue at birth to light blue at 3 months indicate that differences
between twins and singletons quickly become much smaller and reach the same white matter maturation values.
436
measures between these two groups. These preliminary findings suggest that twins and singletons follow similar growth
trajectories for most white matter regions. This study compared
21 anatomical regions, including projection fibers such as
internal capsule and corona radiata, association fibers including superior longitudinal fasciculus and external capsule, and
commissural fibers such as the genu, body, and splenium of
the corpus callosum. FA and RD did not differ between twins
and singletons in all the regions that were analyzed after correction for multiple comparisons. However, twins and singletons did exhibit differences in AD measures in the ALIC and the
anterior region of the corona radiata. There were significant
differences in the delay parameter of the Gompertz function
for these regions, indicating that twins were delayed compared
with singletons. However, twins appear to have caught up to
singletons by 34 months postterm as though they experience
a period of catch-up growth postbirth (Figures 7 and 8). There
were no significant differences in the asymptote parameter of
the Gompertz function, suggesting that the twinsingleton
differences observed early on in these regions disappear by
early childhood (Figure 7).
Acknowledgments
This research was supported by NIH grants R01 MH070890
(JHG, GG), Conte Center MH064065 (JHG,GG), and National
Alliance for Medical Image Computing (NA-MIC) U54
EB005149 (GG).
References
Alexander, A. L., Lee, J. E., Lazar, M., Boudos, R., DuBray, M. B., Oakes, T. R., et al.
(2007). Diffusion tensor imaging of the corpus callosum in autism. Neuroimage,
34(1), 6173.
Basser, P. J., Mattiello, J., & LeBihan, D. (1994). MR diffusion tensor spectroscopy and
imaging. Biophysical Journal, 66(1), 259267.
Cascio, C. J., Gerig, G., & Piven, J. (2007). Diffusion tensor imaging: Application to the
study of the developing brain. Journal of the American Academy of Child &
Adolescent Psychiatry, 46(2), 213223.
Diggle, P., Heagerty, P., Liang, K., & Zeger, S. (2002). Analysis of longitudinal data
(2nd ed.). New York: Oxford University Press.
Dubois, J., Hertz-Pannier, L., Dehaene-Lambertz, G., Cointepas, Y., & Le Bihan, D.
(2006). Assessment of the early organization and maturation of infants cerebral
white matter fiber bundles: A feasibility study using quantitative diffusion tensor
imaging and tractography. NeuroImage, 30, 11211132.
Fitzmaurice, G. M., Laird, N. M., & Ware, J. H. (2011). Applied longitudinal analysis
(2nd ed.). New Jersey: Wiley.
Geng, X., Gouttard, S., Sharma, A., Gu, H., Styner, M., Lin, W., et al. (2012). Quantitative
tract-based white matter development from birth to age 2 years. NeuroImage, 61(3),
542557.
Gilmore, J., Lin, W., Corouge, I., Vetsa, Y., Smith, J. K., Kang, C., et al. (2007). Early
postnatal development of corpus callosum and corticospinal white matter assessed
with quantitative tractography. American Journal of Neuroradiology, 28(9),
17891795.
Hay, D. A., & OBrien, P. J. (1983). The La Trobe Twin Study: A genetic approach to the
structure and development of cognition in twin children. Child Development, 54(2),
317330.
Hulshoff Pol, H. E., Posthuma, D., Baare, W. F., De Geus, E. J., Schnack, H. G.,
van Haren, N. E., et al. (2002). Twinsingleton differences in brain structure using
structural equation modelling. Brain, 125(Pt 2), 384390.
Huppi, P. (2008). Neuroimaging of brain development - discovering the origins of
neuropsychiatric disorders? Pediatric Research, 64, 325.
Karkach, A. (2006). Trajectories and models of individual growth. Demographic
Research, 15(12), 347400, (URL http://www.demographic-research.org/volumes/
vol15/)12/).
Knickmeyer, R., Gouttard, S., Kang, C., Evans, D., Wilber, K., Smith, J., et al. (Nov
2008). A structural MRI study of human brain development from birth to 2 years.
Journal of Neuroscience, 28, 1217612182.
Knickmeyer, R. C., Kang, C., Woolson, S., Smith, J. K., Hamer, R. M., Lin, W., et al.
(2011). Twinsingleton differences in neonatal brain structure. Twin Research and
Human Genetics, 14(3), 268276.
Lindstrom, M., & Bates, D. (1990). Nonlinear mixed effects models for repeated
measures data. Biometrics, 46, 673687.
Mori, S., Oishi, K., Jiang, H., Jiang, L., Li, X., Akhter, K., et al. (2008). Stereotaxic white
matter atlas based on diffusion tensor imaging in an ICBM template. NeuroImage,
40, 570582.
Mori, S., & Zhang, J. (2006). Principles of diffusion tensor imaging and its applications
to basic neuroscience research. Neuron, 51(5), 527539.
Murgasova, M., Dyet, L., Edwards, D., Rutherford, M., Hajnal, J., & Rueckert, D. (2007).
Segmentation of brain MRI in young children. Academic Radiology, 14.
Pajevic, S., & Pierpaoli, C. (1999). Color schemes to represent the orientation of
anisotropic tissues from diffusion tensor data: Application to white matter fiber
tract mapping in the human brain. Magnetic Resonance in Medicine, 42(3),
526540.
Pfefferbaum, A., Mathalon, D., Sullivan, E., Rawles, J., Zipursky, R., & Lim, K. (1994). A
quantitative magnetic resonance imaging study of changes in brain morphology
from infancy to late adulthood. Archives of Neurology, 51(9), 874887.
Pierpaoli, C., & Basser, P. J. (1996). Toward a quantitative assessment of diffusion
anisotropy. Magnetic resonance in Medicine, 36(6), 893906.
Rutherford, M. (Ed.), (2002). MRI of the neonatal brain: WB Saunders.
Sadeghi, N., Prastawa, M., Gilmore, J., Lin, W., & Gerig, G. (2010). Spatio-temporal
analysis of early brain development. In: Proceedings IEEE asilomar conference on
signals, systems and computers, (pp. 777781).
Sadeghi, N., Prastawa, M., Fletcher, P., Gilmore, J., Lin, W., & Gerig, G. (2012).
Statistical growth modeling of longitudinal DTI-MRI for regional characterization of
early brain development. In: Proceedings of the 2012 IEEE international symposium
on biomedical imaging: From nano to macro, (pp. 15071510).
Sadeghi, N., Prastawa, M., Fletcher, P. T., Wolff, J., Gilmore, J. H., & Gerig, G. (2013).
Regional characterization of longitudinal DT-MRI to study white matter maturation of
the early developing brain. In Neuroimage68, (pp. 236247).
van Gelderen, P., de Vleeschouwer, M. H., DesPres, D., Pekar, J., van Zijl, P., &
Moonen, C. T. (1994). Water diffusion and acute stroke. Magnetic Resonance in
Medicine, 31(2), 154163.
Xue, H., Srinivasan, L., Jiang, S., Rutherford, M., Edwards, A., Rueckert, D., et al.
(2007). Automatic cortical segmentation in the developing brain. IPMI, 257269.
Yakovlev, P., & Lecours, A. (1967). The myelogenetic cycles of regional maturation of
the brain. In A. Minkowski (Ed.), Regional development of the brain in early life
(pp. 370). Oxford: Blackwell Scientific.
Relevant Websites
http://www.ibisnetwork.org/ Brain Development in Autism.
http://www.cidd.unc.edu/piven/ Carolina Institute for Developmental Disabilities.
https://www.cidd.unc.edu/research/default.aspx?id45 Conte Center for
Schizophrenia.
http://www.child-encyclopedia.com/en-ca/child-brain/according-to-experts.html
Encyclopedia on early childhood development: Brain Development.
www.ucnia.org Utah Center for Neuroimage Analysis.
Introduction
As discussed in detail in previous articles, the diffusion of water
in brain tissue is affected by the local tissue microstructure; for
example, water diffuses more easily along the major axis of a
white matter fiber bundle than perpendicular to it. Magnetic
resonance diffusion imaging (sometimes referred to as Diffusion Tensor Imaging (DTI)) is sensitive to these effects, and, in
addition to tractography-based studies of long-range connectivity information (covered in other articles), there has been a
great deal of interest in using voxelwise measures derived from
diffusion data as local markers of the tissue microstructure. The
commonest example is the use of diffusion anisotropy as a
marker for white matter tract integrity, for example, for disease
diagnosis, tracking disease progression, finding disease subcategories, studying normal development/aging, and as complementary information to investigating normal brain function
(Horsfield & Jones, 2002; Lim & Helpern, 2002; Moseley, 2002;
Neil, Miller, Mukherjee, & Huppi, 2002; Pagani, Filippi, Rocca,
& Horsfield, 2005).
Diffusion anisotropy describes how variable the diffusion is
in different directions and is most commonly quantified via a
measure known as fractional anisotropy (FA) (Pierpaoli &
Basser, 1996). It is highest in major white matter tracts (maximum theoretical value 1) and lower in gray matter (GM),
while approaching 0 in cerebro-spinal fluid. As a marker for
tract integrity, FA is a useful quantity to compare across subjects as it is computable voxelwise, and is a scalar value that is
independent of the local fiber orientation (and therefore a
relatively objective and straightforward measure to compare
across subjects). A second common diffusion-derived parameter is the mean diffusivity (MD); this is the apparent diffusion
coefficient averaged over all directions, and therefore provides
complementary information to FA.
Some researchers have simply summarized diffusion characteristics globally (for example, histogram-based summary measures of FA (Cercignani, Inglese, Pagani, Comi, & Filippi, 2001;
Cercignani, Bammer, Sormani, Fazekas, & Filippi, 2003)), in
order to compare different subjects. However, most recent
work has been interested in spatially localizing interesting
diffusion-related changes. In order to achieve comparison of
diffusion parameters across subjects, it is first necessary to solve
the correspondence problem across subjects, for example, by aligning them all into some common space. This is by no means a
trivial problem to solve robustly and accurately, and the majority
of this article is devoted to the variety of methods that have been
proposed to achieve this. Many studies have, to this end, followed similar approaches to voxel-based morphometry (VBM,
originally developed for finding changes in GM density in T1weighted structural brain images; Ashburner & Friston, 2000;
http://dx.doi.org/10.1016/B978-0-12-397025-1.00316-X
437
438
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
Figure 1 Example registrations of three ALS patients (a, c) and three controls (b, d) (Ciccarelli et al., 2009). ROI through the anterior part of the corpus
callosum, in axial view. (a, b) Linear-only registration. (c, d) Linear nonlinear registration. The overlaid red edges are intensity edges from the
target image. Data kindly provided by Olga Ciccarreli.
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
439
(Buchel et al., 2004), testing for L-R asymmetry and handedness, using both 4 and 12 mm FWHM smoothing.
440
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
S0
441
Sn
Anterior
Posterior
AC Point
0.65
0.6
0.65
Left Side
Right Side
PC Point
SD of left
Mean of left
SD of right
Mean of right
0.6
0.55
0.55
0.5
FA-value
FA value
0.5
0.45
0.4
0.4
0.35
0.35
0.3
Anterior
0.25
0.2
-50
0.45
-40
-30
-20
0.3
Posterior
-10
0
10
Arc-angle
20
30
40
50
0.25
-50
Anterior
-40
-30
-20
Posterior
-10
0
10
Arc-angle
20
30
40
50
Figure 2 An example approach of tractography-based FA parameterization, as presented in Gong et al. (2005). Top-left: reconstruction of the upper
cingulum tracts for one subject; red and white denote anterior and posterior parts, respectively. Top-right: illustration of the parameterization
procedure; position along the cingulum is parameterized as a function of angle in the defined coordinate system. Bottom-left: single-subject sampling of
FA along cingulum as a function of angle. Bottom-right: multi-subject combined data, showing cross-subject mean and standard deviation of FA
along cingulum, separately for left and right. Figure material kindly provided by Gaolong Gong and Tianzi Jiang.
442
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
Left cc
Right cc
Left ilf
Right ilf
Left cst
Right cst
Left slf
Left ifo
Right slf
Left unc
Right unc
Right ifo
Figure 3 An example approach of tractography-based medial (skeletonized) representation of tract structure, as presented in Yushkevich et al. (2008).
Top-left: fiber tracking results for the six selected fasciculi. Top-right: skeletons of the models fitted to the six fasciculi. Bottom: the result of
projecting tract-center MD values onto the medial surfaces, and then testing statistically across subjects. T-statistic maps on the medial surfaces show
where MD is significantly different in patients with pediatric chromosome 22q11.2 deletion syndrome, compared with controls. Figure material
kindly provided by Paul Yushkevich and James Gee.
cingulum, arcuate), various methods for automated identification and clustering of white matter bundles are emerging
(Durrleman, Fillard, Pennec, Trouv, & Ayache, 2011; Guevara
et al., 2012, 2011; Li et al., 2010; Yendiki et al., 2011). These
have the potential to aid inter-subject registration, feature
extraction (i.e., bundles) and feature matching across subjects.
Although not yet applied to cross-subject comparisons of diffusion measures, these clustering techniques provide a promising alternative to the skeleton-based methods presented below.
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
An alternative method, termed tract-based spatial statistics
(Smith et al., 2006, 2007), attempts to combine the different
strengths of each of these general approaches. TBSS aims to
solve the alignment and smoothing issues, while being fully
automated and investigating the whole brain not requiring
prespecification of tracts of interest. This is achieved by estimating a group mean FA skeleton, which represents the centers of all fiber bundles (fiber bundle is usually taken to mean a
collection of white matter axons all following a similar anatomical path (at least locally). Tract is sometimes used to
mean individual axons, but more commonly to fiber bundles;
furthermore, tract often implies that the collection of axons
have similar start and end locations. However, in general, and
in this article, the terms tract and fiber bundle are used
interchangeably) that are common across the subjects involved
in a study. Each subjects FA data is then projected onto the
mean FA skeleton in such a way that each skeleton voxel takes
the FA value from the local center of the nearest relevant tract,
thus hopefully resolving issues of alignment and correspondence. To briefly summarize the TBSS approach:
443
Nonlinear Alignment
TBSS starts by registering all subjects FA images into a common space, using linear nonlinear registration (using FLIRT
(Jenkinson & Smith, 2001) and then FNIRT (Andersson,
Jenkinson, & Smith, 2007; Andersson, Smith, & Jenkinson,
2007)). The normal choice of registration target image is the
FMRIB58_FA. However, when a study-specific target is required
(see the registration discussion earlier), the recommended
approach is to identify the most typical subject of the entire
group, that is, to be the target image which minimizes the
amount of warping required for all other subjects to align to it.
To find this most typical subject, one can register every subject to
every other subject and choose the target subject as being the
one with the minimum mean deformation to all other subjects.
Figure 4 Examples of fiber bundles; a thick sheet with a thin surface as its skeleton, and a tube, with a line as its skeleton.
444
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
Figure 5 Example mean FA image (grayscale) underneath the unthresholded (left) and thresholded (right) skeleton. Thresholding was applied at
FA 0.2.
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
445
Note that this approach is effectively achieving fine alignment across subjects in the direction perpendicular to the tract,
not in the direction parallel to the tract. This is what is required;
FA changes very quickly as one moves perpendicular to the
local fiber bundle, so even the smallest misalignments in this
direction have great effect on the final statistics. Parallel to the
tract, FA generally changes relatively slowly, so that the alignment provided by the initial nonlinear registration is sufficient
to align like with like across subjects.
Therefore the skeleton has been filled, for each subject, with
FA values from the centers of the nearest relevant tracts. Note
that the idea of taking a pure FA value from the center of a
tract in a way that claims to be unaffected by partial volume
effects is only strictly true for tracts wider than the relevant
voxel dimension. When this is not the case, that is, for the
thinnest tracts, the center peak FA value will reflect both the
tract width and the true peak FA value, due to partial voluming.
More recently (de Groot et al., 2013), there has been extensive work evaluating whether a more finely detailed nonlinear
warping could replace both stages of the TBSS registration (i.e.,
the initial nonlinear registration and the skeleton projections).
Validation was carried out using the relatively independent
information from tractography, showing that carefully tuned
nonlinear registration can indeed hope to improve on the
alignment accuracy onto the skeleton, as well as providing
better regularization (i.e., consistency of the projection along
the skeleton). Future versions of TBSS will aim to switch to this
approach.
446
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
Figure 8 Anisotropy creases near the corpus callosum: CC; corpus callosum; IC; internal capsule; CR; corona radiata; FX; fornix; CB; cingulum
bundles; EC; external capsule; SLF; superior longitudinal fasciculus.
the search path, since they tend to delimit nearby but distinctly
oriented white matter tracts. Finally, to the extent that the
combination of ridges and valleys delineates the major white
matter pathways, the crease structures extracted from individual scans could guide and constrain nonrigid registration, to
help ensure that distinct tracts (of comparable anisotropy
levels) do not mistakenly overlap.
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
Data
Group 1
(controls)
Group 2
(patients)
Contrasts
447
Regressor 2
(patient group mean)
Regressor 3
Regressor 1
(subject ages, demeaned)
(control group mean)
Subject 1
0.55
-2
Subject 2
0.52
-7
Subject 3
0.48
Subject 4
0.59
Subject 5
0.47
Subject 6
0.51
Subject 7
0.42
-5
Subject 8
0.46
-1
-1
Fitted
model
parameters
noise
Figure 9 Overview of general linear modeling (GLM), also known as multiple regression: data, model and contrasts.
patient group mean. The zero tells this contrast to ignore the
model parameter for the third regressor (age). Independently
of this, Contrast 2 is asking the reverse question: does the
patient group have the higher mean? Finally, Contrast 3
[0 0 1] is asking whether FA correlates with age across all
subjects. The third regressor might either have been included
in the model because the regression with age was of interest, or
simply in order to model out (or remove the effect of) age; in
the latter case, it would be referred to as a confound covariate,
and would not appear in any of the contrasts of interest.
Figure 10 shows several further examples of common
models, along with common contrasts used in conjunction
with such models.
448
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
1 2
1 7
1
4
1
0
1
3
1
4
1 5
1
3
1
1
1
1
1
0
0
0
0
0
0
0
0
1
1
1
0 2
0
0 7
0
0
4
0
0
5
0
1
0
3
1
0
2
1
0
0
1
0 5
1
1
1
1
0
0
0
0
1
1
1
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0
1
1
0
0
0
0
0
0
0
0
1
1
0
0
c1 [ 0 1 ]
c1 [ 1 1 ]
c1 [ 1 1 0 0 ]
c1 [ 1 0 0 0 0 ]
c2 [ 0 1 ]
c2 [ 1 1 ]
c2 [ 1 1 0 0 ]
c2 [ 1 0 0 0 0 ]
0
0
1
1
c3 [ 0 0 1 0 ]
c4 [ 0 0 0 1 ]
c5 [ 0 0 1 1 ]
c6 [ 0 0 1 1 ]
(a)
(b)
(c)
(d)
Figure 10 Several common cross-subject models: (a) group mean and an effect of interest such as age or behavioral score. Note that the latter has
been demeaned (its mean has been subtracted) in order to make the fitting of the two regressors independent of each other. Contrast c1 where
does the data correlate with the effect of interest?; c2 where does the data correlate negatively with the effect of interest? (b) Two group
mean comparison, equivalent to an unpaired t-test. The first five subjects form group 1 and the next three form group 2. c1 where is the first groups
mean greater than the seconds?; c2 where is the second groups mean higher? (c) Two group mean comparison, with an additional separate
age regressor for each group. The age values have been split into the two separate regressors to allow an interaction test, that is, a test of whether the
correlation between the diffusion data and age is different in the two groups. Each set of age values was separately demeaned before being padded
by zeros in the regressors. c1 where is the mean of group 1 higher than that of group 2?; c2 where is the mean of group 2 higher?; c3 where
does the data in group 1 correlate with age?; c4 where does the data in group 2 correlate with age?; c5 where is the correlation with age
higher in group 1 than in group 2?; c6 where is the age correlation higher in group 2? (Note though that the interpretations given for c5 and c6
depend on the correlations being positive; if one or both is negative, the interpretation needs more careful thought, taking into account the results of c3
and c4.) (d) Paired two-group comparison, for example, to test before versus after treatment in subjects. Each pair of rows corresponds to a given
subjects before and after data. The first regressor models the beforeafter comparison; the other regressors model out each subjects mean
separately. This is equivalent to a paired t-test. c1 where is the data higher before than after treatment?; c2 where is the data higher after
treatment?
separate curves for the null and for the signal parts of the
statistic histogram. For a number of practical reasons (such as
the possibility of very large areas of signal), a second approach
is generally more suitable for diffusion data analyses: permutation testing (Nichols & Holmes, 2002). This generates the null
distribution by repeatedly randomizing the order of the subjects in the data (relative to the model). Each of these randomizations produces a resulting statistic image that looks as if the
data contained no signal of interest, and so over thousands of
random permutations, the histogram of the null distribution
can be built up. The statistic image (or set of statistical features)
that was originally estimated can then be compared against
this null distribution, in order to estimate accurate p-values.
The final issue that needs addressing is the problem of
multiple thresholdings across the many voxels or clusters
found in the brain; if one thresholds 10 000 standard-space
voxels for significance at the p < 0.05 level, then purely by
chance about 500 voxels will be (wrongly) reported as containing a significant effect of interest. This is clearly problematic, as
it means that one would find at least 500 false positives in
every study, regardless of whether or not there actually was
something interesting in the data. Researchers typically want to
control the rate of false positives not separately at every voxel
or cluster, but for the image as a whole. This is known as
controlling the family-wise error (FWE) rate, and if done
correctly, the researcher can then make a claim such as the
chance of finding a signal of interest this strong anywhere in
pure noise data is <5%.
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
A simple approach to achieving this multiple comparison
correction is to simply multiply the estimated p-values by the
number of comparisons made before applying the 0.05 threshold. This is known as Bonferroni correction, and is generally
over-conservative, partly because it does not take into account
any spatial smoothness in the data. However, again via the
application of permutation testing, it is straightforward to
carry out accurate multiple comparison correction.
Instead of building up (over random permutations of the
data) the null distribution separately at each point in the brain,
we can, at each permutation, find the maximum test statistic
value across the brain, and build up a null distribution of that.
We therefore know the null of the maximum (across space) test
statistic, and it we test our actual statistic values against that, we
have achieved control of the FWE. Although permutation testing can be slow (as it needs typically several thousand permutations of the data, model refitting and statistic feature
extraction), it is a very sensible approach to inference on diffusion analyses, being accurate and robust.
449
450
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
along tracts. These approaches are flexible and sensitive. Covariates of interest (age and disease) can be used in the regression, and the methods can capture cross-subject variability in
the location of white matter changes.
Figure 11 Relationship between various tensor glyph shapes and tensor FA/mode.
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
451
Figure 12 Examples of color-coded principal tensor eigenvalue (red left-right, green front-back, blue up-down) and mode (colors as
shown in Figure 11), both in native data resolution and in the continuous-space upsampled approximation.
452
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
resampled, more detail is preserved by resampling the raw data
or the full set of tensor parameters, rather than summary scalar
images such as FA. In Figure 13, we illustrate a further important point relating to partial-volume effects and interpolation
in diffusion data. We use very high resolution data in order to
be able to view what we consider the underlying ground-truth
structures, while also downsampling the raw data in order to
simulate how these structures would appear in more normal
resolution data. The data is a complete ex vivo human brain,
acquired at 0.7 0.7 0.7 mm resolution, using a 3D segmented spin-echo sequence on a 3 T Siemens Tim Trio over
99 h (Miller et al., 2011). In Figure 13(a), we see a cortical ROI
of the FA image derived from the original data. We consider
this the ground truth, in the sense that it shows clearly the
delineation of different tissue types. We can see high-FA white
matter, medium-FA cortical GM, and a thin low-FA band
which lies just inside the GM, immediately next to the
white-gray boundary. These delineations were verified by
superimposing and comparing the FA, MD and even higher-
453
Figure 13 Various issues relating to partial volume effects at different image resolutions, as illustrated using high-resolution (0.7 mm) ex vivo
diffusion data (Miller et al., 2011). (a) FA of original ground truth data. (b) FA obtained by blurring the raw data to effectively give 2 mm voxels, and
then recomputing FA. (c) As for (b), but simulating 3.5 mm data. This shows what we expect to see from normal resolution diffusion data; the
tract appears thinner than it actually is, because of partial-volume effects at the white-gray boundary. (d) Principal eigenvectors in the original data,
showing clear anisotropy in the gray matter, oriented perpendicular to the white-gray boundary. Data kindly provided by Jennifer McNab and Karla Miller.
454
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
PVE. (e) This recovery of the true FA, with clearly less bias in
estimated FA in the thinner tracts. Interestingly, when we
attempted to make this correction using nonlinear models
(up to fourth-order polynomials) of just apparent FA or PVE,
we were unable to achieve a reasonable recovery of the true FA.
However, such an approach assumes an accurate estimation
of white matter PVE, and this is not as accessible in reality as it
was here with this ex vivo data. In normal in vivo diffusion data,
the MD does not contain the same high contrast between tissue
types, and the use of structural data (which could provide
accurate PVE) is problematic because the slightest misalignment
between structural and diffusion voxels would probably invalidate the above approach. Furthermore, the assumption of a
correction based on within-voxel PVE and apparent FA does
not take into account the neighboring voxels, and so is likely
missing potentially useful information about variations across
voxels in tensor orientation, related again to the tract thinning
that we have seen. Hence, we proposed that the tensor covariance might be a useful way of indirectly telling us about partial
volume effects and the results of variations across neighboring
voxels of tensor orientation; we hypothesize that both effects
would be encoded in the cross-voxels tensor covariance. An
examples of the (symmetric) covariance is shown in (h), with
the six maps shown being the rotationally invariant tensor
covariance components (corresponding to spatial covariance
of MD, FA and mode). We repeated the above modeling,
attempting to recover true FA via a nonlinear combination of
the six relevant tensor covariance components and the apparent FA. This approach was even more successful in accurately
recovering the true underlying FA. The scatterplots shown in (f)
and (g) show the improvement in correspondence between the
estimated true FA versus the true FA, compared with the greater
spread seen in the apparent FA versus the true FA.
A separate approach has been proposed to deal with partial
volume effects with CSF (Metzler-Baddeley, OSullivan, Bells,
Pasternak, & Jones, 2012; Pasternak, Sochen, Gur, Intrator, &
Assaf, 2009). This is somewhat easier than gray/white PVE, as
the diffusion coefficient of CSF is about three times higher than
that of tissue. Therefore, a partial volume model that includes a
tensor compartment and a free water compartment can be
fitted to diffusion data, providing that CSF diffusivity is
assumed to be known, and constraints are imposed on the
tissue volume fractions (Pasternak et al., 2009). These constraints can be relaxed if one further acquires low b-value data
(e.g., b 300 s mm2), as these will have significant contribution from CSF signal and help fit the PVE model (Jbabdi,
Sotiropoulos, Savio, Grana, & Behrens, 2012).
Such modeling, although reducing bias in estimation of
underlying FA, may ultimately result in an increase in the
uncertainty of the FA estimation, and so may not prove useful
when sensitivity to cross-subject changes is the most important
factor in analysis success. Furthermore, such research is certainly not intended to supplant more experimentally driven
investigations into the relationship between the underlying
biophysical processes and the diffusion MRI acquisition physics, which in the long term may provide better-founded corrections for effects such as the tract-thinning and partial-voluming
in general, as well as better interpretability of changes in diffusion parameters such as FA, MD and the tensor eigenvalues.
30
30
40
R1
R2
R3
R1
True FA
20
20
10
10
(e)
(d)
True FA
(c)
R2
40
50
60
60
50
R3
70
(f)
70
10
20
30
40
Apparent FA
50
60
70
(g)
10
20
30
40
Reconstructed FA
50
60
70
Figure 14 Modeling of FA and partial-volume estimation (PVE) in order to attempt to estimate true underlying FA from normal resolution diffusion data. (a) The original (high) resolution MD image, showing
excellent gray-white contrast. This is fed this into tissue-type segmentation to give white matter PVE, which was blurred to obtain the equivalent PVE that we would obtain in normal resolution data, shown
in (b) (dark blue small white matter partial volume fraction; bright blue pure white matter voxels). We assume that the high resolution FA image (c) represents the true underlying FA; red lowest
FA, yellow highest FA. (d) FA derived by downsampling the raw diffusion data and computing the FA, simulating FA that would be achieved at normal resolution acquisition, and skeletonized in order to only
consider tract-center voxels. Comparing colors with (c), it is clear that FA has been reduced by the downsampling. After modeling apparent FA as a function of true FA and PVE, we can reconstruct an
estimate of true underlying FA, shown in (e). In an alternative approach, we use some components of the tensor covariance (h) instead of PVE in our modeling, and in (f) and (g) show the improved
correspondence between reconstructed FA and true FA with such an approach. Data kindly provided by Jennifer McNab and Karla Miller.
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
(b)
(a)
455
456
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
457
Figure 15 Slices through several MNIl52-space templates and atlases. From top to bottom: MNl152 template image, formed by averaging 152
T1-weighted structural images (nonlinear version of MNI152 kindly provided by Andrew Janke and Louis Collins). FMRlB58_FA, formed by averaging
58 FA images. Julich histological atlas; solid colors show the maximum-probability classification of all current GM and WM structures
(thresholded at 25% probability) and the probability image for the left corticospinal tract (shown in red-yellow, thresholded at 5%). Johns Hopkins
DTI-based white matter labels atlas, created from hand segmentation of an average tensor map from 81 subjects. Johns Hopkins DTI-based probabilistic
tractography atlas, created by averaging tractography results from 28 subjects; shown is the maximum-probability classification of tracts and
the probability image for the left corticospinal tract.
458
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
Repeatability Tests
Cross-session and cross-subject repeatability is also of great
interest. In Smith et al. (2006), we investigated the repeatability of FA values, both across sessions and across subjects. We
analyzed data from eight healthy subjects, each scanned on
three separate occasions. We estimated % coefficient of variation (CoV: 100 standard deviation/mean) across sessions or
subjects as the measure of repeatability.
We first measured CoV at seven voxels placed in the center
of various white matter tracts on the mean FA image; the genu
of the CC, left and right optic radiation, left and right pyramidal tract in the cerebral peduncle, and left and right superior
cingulum bundle. The exact positioning of the points is
described in Heiervang, Behrens, Mackay, Robson, and
Johansen-Berg (2006). As well as estimating CoV for the
Figure 16 Intersession and inter-subject variability results. Eight subjects were scanned three times each. Percentage coefficient of variation (CoV)
variability results are shown at seven white matter positions of interest and also using summary statistics for the whole brain. Data kindly
provided by Einar Heiervang and Heidi Johansen-Berg.
Figure 17 Coronal views through the controls > schizophrenics group comparison of FA. (a) TBSS analysis showing the FA skeleton in blue and
significant group difference in red, in the corpus callosum and fornix. (b) VBM-style analysis, with no spatial smoothing; as well as the corpus callosum
and fornix, a group difference is suggested running along the underside of the ventricles. (The 5 mm and 10 mm FWHM smoothing analyses
showed the same general pattern, though even more diffuse.) (c, d) The mean FA images for the controls and schizophrenics, respectively. It is clear that
while the corpus callosum is well aligned between the two groups, the lower edge of the ventricles is not, due to larger ventricles in the patient
group. This has given rise to a spurious result in the VBM-style analyses. (e) Atlas-based confirmation of structures. The Julich histological probabilistic
atlas shows the cingulum bundles in green, the callosal body in red-yellow, the fornix in light-blue, the corticospinal tract in yellow and the superior
occipito-frontal fascicle in red. The Harvard-Oxford probabilistic subcortical structural atlas shows the thalamus in copper, the ventricles in dark-blue
and the caudate in pink. Data kindly provided by Clare Mackay.
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
generally slightly lower than VBM preprocessing and generally
considerably lower than with hand-placing. Cross-subject variability with TBSS preprocessing is consistently lower than with
VBM preprocessing and lower than hand-placing in four out of
seven positions of interest. The results suggest that TBSS is
successful in aligning equivalent structures across sessions/
459
subjects and that it improves alignment further than pure nonlinear registration has achieved here. With TBSS the intersession CoV is generally between 3% and 5% (mode 3%),
and the inter-subject CoV is generally between 5% and 15%
(mode 12%). These figures should prove useful when carrying
out power calculations for planned DTI studies. For example,
Figure 18 TBSS results from 15 MS patients. (a, b) 3D surface renderings of the mean FA skeleton. Blue shows the group mean lesion probability
distribution, thresholded at 20%. Red shows voxels where FA correlates negatively (across subjects) with subject total lesion volume. (b) is a 3D
stereo pair. (c) Yellow shows where FA correlates negatively with EDSS disability score. (d) Red as above (negative correlation with lesion volume).
In (c) and (d), green shows the mean FA skeleton, blue shows the group mean lesion distribution, and the background image is the MNI152.
Data kindly provided by Heidi Johansen-Berg and Zaheer Cader.
460
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
461
AF
PF
1850
4400
1700
4200
1550
4000
1400
3800
1250
3600
1100
3400
3200
950
CON
AD
800
NS
CON
3000
AD
Figure 20 Top: location of significant increase in MO between controls and MCIs (pink). Superposed is the location of increase in FA (redyellow).
Middle: probabilistic tractography of motor (pinkblue) and association (redyellow) pathways in controls. Bottom: connection probabilities
(unnormalized number of streamlines) from the centrum-semiovale to target ROIs that isolate association (left) and motor (right) pathways. Only the
association pathways are significantly different between controls and AD. Figure kindly provided by Gwenaelle Douaud.
462
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
Conclusions
Localized/voxelwise analysis of multi-subject diffusion MRI
data has a clear role to play in neuroimaging, for example, in
tracking changes in white matter caused by disease. Although
careful tractography-based analyses will increasingly have great
value, whole-brain voxelwise analyses provide a powerful complement to such approaches, by allowing the entire dataset to
be investigated in a straightforward manner. Much has already
been achieved in developing such methodologies, but issues of
References
Alexander, D. C., Pierpaoli, C., Basser, P. J., & Gee, J. C. (2001). Spatial
transformations of diffusion tensor magnetic resonance images. IEEE Transactions
on Medical Imaging, 20(11), 11311139.
Amunts, K., & Zilles, K. (2006). In L. Zaborszky, F. G. Wouterlood & J. L. Lanciego
(Eds.), Neuroanatomical tract-tracing: Molecules, neurons, and systems,
Chapter 18. Berlin: Springer.
Andersson, J., Jenkinson, M., & Smith, S. (2007). Non-linear registration aka spatial
normalisation. Internal technical report TR07JA2, Oxford Centre for Functional
Magnetic Resonance Imaging of the Brain, Department of Clinical Neurology,
Oxford University, Oxford, UK. Available at www.fmrib.ox.ac.uk/analysis/techrep for
downloading.
Andersson, J., Smith, S., & Jenkinson, M. (2007). Non-linear optimisation. Internal
technical report TR07JA1. Oxford Centre for Functional Magnetic Resonance
Imaging of the Brain, Department of Clinical Neurology, Oxford University, Oxford,
UK. Available at www.fmrib.ox.ac.uk/analysis/techrep for downloading.
Ashburner, J., & Friston, K. J. (2000). Voxel-based morphometry The methods.
NeuroImage, 11, 805821.
Ashburner, J., & Friston, K. J. (2001). Why voxel-based morphometry should be used.
NeuroImage, 14(6), 12381243.
Ashburner, J., & Friston, K. J. (2004). Generative and recognition models for
neuroanatomy. NeuroImage, 23(1), 2124.
Barnea-Goraly, N., Eliez, S., Hedeus, M., Menon, V., White, C. D., Moseley, M., et al.
(2003). White matter tract alterations in fragile X syndrome: Preliminary evidence
from diffusion tensor imaging. American Journal of Medical Genetics Part B:
Neuropsychiatric Genetics, 118B, 8188.
Beckmann, C. F., & Smith, S. M. (2004). Probabilistic independent component analysis
for functional magnetic resonance imaging. IEEE Transactions on Medical Imaging,
23(2), 137152.
Behrens, T. E. J., Johansen-Berg, H., Jbabdi, S., Rushworth, M. F. S., &
Woolrich, M. W. (2007). Probabilistic diffusion tractography with multiple fibre
orientations. What can we gain? NeuroImage, 23, 144155.
Behrens, T. E. J., Johansen-Berg, H., Woolrich, M. W., Smith, S. M.,
Wheeler-Kingshott, C. A.M, Boulby, P. A., et al. (2003). Non-invasive mapping of
connections between human thalamus and cortex using diffusion imaging. Nature
Neuroscience, 6(7), 750757.
Bengtsson, S. L., Nagy, Z., Skare, S., Forsman, L., Forssberg, H., & Ullen, F. (2005).
Extensive piano practicing has regionally specific effects on white matter
development. Nature Neuroscience, 8(9), 11481150.
Bookstein, F. L. (2001). Voxel-based morphometry should not be used with
imperfectly registered images. NeuroImage, 14(6), 14541462.
Buchel, C., Raedler, T., Sommer, M., Sach, M., Weiller, C., & Koch, M. A. (2004). White
matter asymmetry in the human brain: A diffusion tensor MRI study. Cerebral
Cortex, 14, 945951.
Cader, S., Johansen-Berg, H., Wylezinska, M., Palace, J., Behrens, T. E., Smith, S., et al.
(2007). Discordant white matter N-acetylasparate and diffusion MRI measures
suggest that chronic metabolic dysfunction contributes to axonal pathology in
multiple sclerosis. NeuroImage, 36(1), 1927.
Cercignani, M., Bammer, R., Sormani, M. P., Fazekas, F., & Filippi, M. (2003). Intersequence and inter-imaging unit variability of diffusion tensor MR imaging
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
histogram-derived metrics of the brain in healthy volunteers. American Journal of
Neuroradiology, 24, 638643.
Cercignani, M., Inglese, M., Pagani, E., Comi, G., & Filippi, M. (2001). Mean diffusivity
and fractional anisotropy histograms of patients with multiple sclerosis. American
Journal of Neuroradiology, 22, 952958.
Ciccarelli, O., Behrens, T. E., Johansen-Berg, H., Talbot, K., Orrell, R. W., Howard, R. S.,
et al. (2009). Investigation of white matter pathology in ALS and PLS using tractbased spatial statistics. Human Brain Mapping, 30(2), 615624.
Conturo, T. E., Lori, N. F., Cull, T. S., Akbudak, E., Snyder, A. Z., Shimony, J. S., et al.
(1999). Tracking neuronal fiber pathways in the living human brain. Proceedings of
the National Academy of Sciences of the United States of America, 96(18),
1042210427.
Corouge, I., Fletcher, P. T., Joshi, S., Gouttard, S., & Gerig, S. (2006). Fiber tractoriented statistics for quantitative diffusion tensor MRI analysis. Medical Image
Analysis, 10, 786798.
Davatzikos, C. (2004). Why voxel-based morphometric analysis should be used
with great caution when characterizing group differences. NeuroImage, 23(1),
1720.
de Groot, M., Vernooij, M. W., Klein, S., Ikram, A., Vos, F. M., Smith, S. M., et al.
(2013). Improving alignment in tract-based spatial statistics: Evaluation and
optimization of image registration. NeuroImage, 76, 400411.
Douaud, G., Mackay, C., Andersson, J., James, S., Quested, D., Kar Ray, M., et al.
(2009). Schizophrenia delays and alters maturation of the brain in adolescence.
Brain, 132, 24372448.
Durrleman, S., Fillard, P., Pennec, X., Trouv, A., & Ayache, N. (2011). Registration, atlas
estimation and variability analysis of white matter fiber bundles modeled as
currents. NeuroImage, 55(3), 10731090.
Eberly, D. (1996). Ridges in image and data analysis. Dordrecht: Kluwer Academic
Publishers.
Eberly, D., Gardner, R., Morse, B., & Pizer, S. (1994). Ridges for image analysis.
Journal of Mathematical Imaging and Vision, 4(4), 353373.
Eickhoff, S. B., Paus, T. P., Evans, A. C., Jenkinson, M., Smith, S., Saad, Z. S., et al.
(2007). The anatomy toolbox for functional neuroimaging - new developments.
In Thirteenth annual meeting of the organization for human brain mapping.
Eickhoff, S. B., Stephan, K. E., Mohlberg, H., Grefkes, C., Fink, G. R., Amunts, K., et al.
(2005). A new SPM toolbox for combining probabilistic cytoarchitectonic maps and
functional imaging data. NeuroImage, 25(4), 13251335.
Ellis, C. M., Simmons, A., Jones, D. K., Bland, J., Dawson, J. M., & Horsfield, M. A.
(1999). Diffusion tensor MRI assesses corticospinal tract damage in ALS.
Neurology, 53, 10511058.
Ennis, D. B., Kindlman, G., Rodriguez, I., Helm, P. A., & McVeigh, E. R. (2005).
Visualization of tensor fields using superquadric glyphs. Magnetic Resonance in
Medicine, 53, 169176.
Ennis, D. B., & Kindlmann, G. (2006). Orthogonal tensor invariants and the analysis of
diffusion tensor magnetic resonance images. Magnetic Resonance in Medicine,
55(1), 136146.
Eriksson, S. H., Rugg-Gunn, F. J., Symms, M. R., Barker, G. J., & Duncan, J. S. (2001).
Diffusion tensor imaging in patients with epilepsy and malformations of cortical
development. Brain, 124, 617626.
Everitt, B. S., & Bullmore, E. T. (1999). Mixture model mapping of brain activation in
functional magnetic resonance images. Human Brain Mapping, 7, 114.
Gong, G., Jiang, T., Zhu, C., Zang, Y., Wang, F., Xie, S., et al. (2005). Asymmetry
analysis of cingulum based on scale-invariant parameterization by diffusion tensor
imaging. Human Brain Mapping, 24, 9298.
Good, C. D., Johnsrude, I. S., Ashburner, J., Henson, R. N., Friston, K. J., &
Frackowiak, R. S. (2001). A voxel-based morphometric study of ageing in 465
normal adult human brains. NeuroImage, 14(1), 2136.
Goodlett, C., Davis, B., Jean, R., Gilmore, J., & Gerig, G. (2006). Improved correspondence
for DTI population studies via unbiased atlas building. In Medical image computing
and computer-assisted intervention (pp. 260267). Berlin: Springer.
Groves, A. R., Beckmann, C. F., Smith, S. M., & Woolrich, M. W. (2011). Linked
independent component analysis for multimodal data fusion. NeuroImage, 54(3),
21982217.
Groves, A. R., Smith, S. M., Fjell, A. M., Tamnes, C. K., Walhovd, K. B., Douaud, G.,
et al. (2012). Benefits of multi-modal fusion analysis on a large-scale dataset: Lifespan patterns of inter-subject variability in cortical morphometry and white matter
microstructure. NeuroImage, 63(1), 365380.
Guevara, P., Duclap, D., Poupon, C., Marrakchi-Kacem, L., Fillard, P., Le Bihan, D.,
et al. (2012). Automatic fiber bundle segmentation in massive tractography datasets
using a multi-subject bundle atlas. NeuroImage, 61(4), 10831099.
Guevara, P., Poupon, C., Rivire, D., Cointepas, Y., Descoteaux, M., Thirion, B., et al.
(2011). Robust clustering of massive tractography datasets. NeuroImage, 54(3),
19751993.
463
Guimond, A., Meunier, J., & Thirion, J.-P. (2000). Average brain models: A
convergence study. Computer Vision and Image Understanding, 77, 192210.
Hayasaka, S., Luan Phan, K., Liberzon, I., Worsley, K. J., & Nichols, T. E. (2004).
Nonstationary cluster-size inference with random field and permutation methods.
NeuroImage, 22(2), 676687.
Heiervang, E., Behrens, T. E. J., Mackay, C. E., Robson, M. D., & Johansen-Berg, H.
(2006). Between session reproducibility and between subject variability of diffusion
MR and tractography measures. NeuroImage, 33(3), 867877.
Horsfield, M. A., & Jones, D. K. (2002). Application of diffusion weighted and diffusion
tensor MRI to white matter diseases. NMR in Biomedicine, 15, 570577.
Hyvarinen, A., Karhunen, J., & Oja, E. (2001). Independent component analysis. New
Jersey: Wiley.
Jbabdi, S., Behrens, T. E., & Smith, S. M. (2010). Crossing fibres in tract-based spatial
statistics. NeuroImage, 49, 249256.
Jbabdi, S., Sotiropoulos, S. N., Savio, A. M., Grana, M., & Behrens, T. E. (2012).
Model-based analysis of multishell diffusion MR data for tractography: How to get
over fitting problems. Magnetic Resonance in Medicine, 68(6), 18461855.
Jenkinson, M., & Smith, S. M. (2001). A global optimisation method for robust affine
registration of brain images. Medical Image Analysis, 5(2), 143156.
Jensen, J. H., Helpern, J. A., Ramani, A., Lu, H., & Kaczynski, K. (2005). Diffusional
kurtosis imaging: The quantification of non-Gaussian water diffusion by
means of magnetic resonance imaging. Magnetic Resonance in Medicine, 53,
14321440.
Jones, D. K., Catani, M., Pierpaoli, C., Reeves, S. J. C., Shergill, S. S., OSullivan, M.,
et al. (2006). Age effects on diffusion tensor magnetic resonance imaging
tractography measures of frontal cortex connections in schizophrenia. Human Brain
Mapping, 27(3), 230238.
Jones, D. K., Griffin, L. D., Alexander, D. C., Catani, M., Horsfield, M. A., Howard, R.,
et al. (2002). Spatial normalisation and averaging of diffusion tensor MRI data sets.
NeuroImage, 17, 592617.
Jones, D. K., Symms, M. R., Cercignani, M., & Howard, R. J. (2005). The effect of filter
size on VBM analyses of DT-MRI data. NeuroImage, 26, 546554.
Kindlmann, G., Ennis, D. B., Whitaker, R. T., & Westin, C.-F. (2007). Diffusion tensor
analysis with invariant gradients and rotation tangents. IEEE Transactions on
Medical Imaging, 26(11), 14831499.
Kindlmann, G. L., San Jose Estepar, R., Smith, S. M., & Westin, C.-F. (2009). Sampling
and visualizing creases with scale-space particles. IEEE Transactions on
Visualization and Computer Graphics, 15(6), 14151424.
Kindlmann, G., Tricoche, X., & Westin, C.-F. (2007). Delineating white matter structure
in diffusion tensor MRI with anisotropy creases. Medical Image Analysis, 11,
492502.
Kubicki, M., Westin, C.-F., Nestor, P. G., Wible, C. G., Frumin, M., Maier, S. E., et al.
(2003). Cingulate fasciculus integrity disruption in schizophrenia: A
magnetic resonance diffusion tensor imaging study. Biological Psychiatry, 54,
11711180.
Lee, J. E., Chung, M. K., Lazar, M., DuBray, M. B., Kim, J., Bigler, E. D., et al. (2009). A
study of diffusion tensor imaging by tissue-specific, smoothing-compensated
voxel-based analysis. NeuroImage, 44(3), 870883.
Li, H., Xue, Z., Guo, L., Liu, T., Hunter, J., & Wong, S. T. C. (2010). A hybrid
approach to automatic clustering of white matter fibers. NeuroImage, 49(2),
12491258.
Li, Y.-O., Yang, F. G., Nguyen, C. T., Cooper, S. R., LaHue, S. C., Venugopal, S., et al.
(2012). Independent component analysis of DTI reveals multivariate microstructural
correlations of white matter in the human brain. Human Brain Mapping, 33(6),
14311451.
Lilliefors, H. (1967). On the KolmogorovSmirnov test for normality with mean and
variance unknown. Journal of the American Statistical Association, 62, 399402.
Lim, K. O., & Helpern, J. A. (2002). Neuropsychiatric applications of DTI A review.
NMR in Biomedicine, 15, 587593.
Lin, F., Yu, C., Jiang, T., Li, K., Li, X., Qin, W., et al. (2006). Quantitative analysis along
the pyramidal tract by length-normalized parameterization based on diffusion tensor
tractography: Application to patients with relapsing neuromyelitis optica.
NeuroImage, 33, 154160.
Metzler-Baddeley, C., OSullivan, M. J., Bells, S., Pasternak, O., & Jones, D. K. (2012).
How and how not to correct for CSF-contamination in diffusion MRI. NeuroImage,
59(2), 13941403.
Miller, K. L., Stagg, C. J., Douaud, G., Jbabdi, S., Smith, S. M., Behrens, T. E., et al.
(2011). Diffusion imaging of whole, post-mortem human brains on a clinical MRI
scanner. NeuroImage, 57(1), 167181.
Mori, S., Wakana, S., van Zijl, P. C. M., & Nagae-Poetscher, L. M. (2005). MRI atlas of
human white matter. Elsevier.
Moseley, M. E. (2002). Diffusion tensor imaging and aging A review. NMR in
Biomedicine, 15, 553560.
464
INTRODUCTION TO METHODS AND MODELING | Tract-Based Spatial Statistics and Other Approaches
Neil, J., Miller, P., Mukherjee, P. S., & Huppi, P. S. (2002). Diffusion tensor imaging of
normal and injured developing human brain A technical review. NMR in
Biomedicine, 15, 543552.
Nichols, T. E., & Holmes, A. P. (2002). Nonparametric permutation tests for functional
neuroimaging: A primer with examples. Human Brain Mapping, 15, 125.
ODonnell, L. J., Westin, C.-F., & Golby, A. J. (2009). Tract-based morphometry for
white matter group analysis. NeuroImage, 45(3), 832844.
Pagani, E., Filippi, M., Rocca, M. A., & Horsfield, M. A. (2005). A method for obtaining
tract-specific diffusion tensor MRI measurements in the presence of disease:
Application to patients with clinically isolated syndromes suggestive of multiple
sclerosis. NeuroImage, 26(1), 258265.
Pajevic, S., & Pierpaoli, C. (1999). Color schemes to represent the orientation of
anisotropic tissues from diffusion tensor data: Application to white matter fiber
tract mapping in the human brain. Magnetic Resonance in Medicine, 42(3),
526540.
Park, H.-J., Kubicki, M., Shenton, M. E., Guimond, A., McCarley, R. W., Maier, S. E.,
et al. (2003). Spatial normalization of diffusion tensor MRI using multiple channels.
NeuroImage, 20, 19952009.
Park, H.-J., Westin, C.-F., Kubicki, M., Maier, S. E., Niznikiewicz, M., Baer, A., et al.
(2004). White matter hemisphere asymmetries in healthy subjects and in
schizophrenia: A diffusion tensor MRI study. NeuroImage, 23, 213223.
Pasternak, O., Sochen, N., Gur, Y., Intrator, N., & Assaf, Y. (2009). Free water
elimination and mapping from diffusion MRI. Magnetic Resonance in Medicine,
62(3), 717730.
Pierpaoli, P., & Basser, P. J. (1996). Toward a quantitative assessment of diffusion
anisotropy. Magnetic Resonance in Medicine, 36, 893906.
Rueckert, D., Sonoda, L. I., Hayes, C., Hill, D. L. G., Leach, M. O., & Hawkes, D. J.
(1999). Nonrigid registration using free-form deformations: Application to breast
MR images. IEEE Transactions on Medical Imaging, 18(8), 712721.
Rugg-Gunn, F. J., Eriksson, S. H., Symms, M. R., Barker, G. J., & Duncan, J. S. (2001).
Diffusion tensor imaging of cryptogenic and acquired partial epilepsies. Brain, 124,
627636.
Salimi-Khorshidi, G., Smith, S. M., & Nichols, T. E. (2011). Adjusting the effect of
nonstationarity in cluster-based and TFCE inference. NeuroImage, 54(3), 20062019.
Simon, T. J., Ding, L., Bish, J. P., McDonald-McGinn, D. M., Zackai, E. H., & Gee, J.
(2005). Volumetric, connective, and morphologic changes in the brains of children
with chromosome 22q11.2 deletion syndrome: An integrative study. NeuroImage,
25, 169180.
Smith, S. M., Jenkinson, M., Johansen-Berg, H., Rueckert, D., Nichols, T. E.,
Mackay, C. E., et al. (2006). Tract-based spatial statistics: Voxelwise analysis of
multi-subject diffusion data. NeuroImage, 31, 14871505.
Smith, S. M., Johansen-Berg, H., Jenkinson, M., Rueckert, D., Nichols, T. E.,
Miller, K. L., et al. (2007). Acquisition and voxelwise analysis of multi-subject
diffusion data with tract-based spatial statistics. Nature Protocols, 2(3), 499503.
Glossary
Introduction
Classical analyses of functional brain signals (EEG/MEG/fMRI/
PET) are based on the general linear model. Model specification,
as an equation, or as a so-called design matrix, is a crucial step
in the analysis of imaging data and precedes parameter estimation. Finally, inferences are made using voxel-wise statistical
tests. This article is based on more extensive presentations in
Kiebel and Holmes (2003, 2007). Newcomers to statistical
methods are directed toward Moulds excellent text Introductory Medical Statistics (Mould, 1998), while the more
mathematically experienced will find Chatfields Statistics for
Technology (Chatfield, 1983) useful. Draper and Smith
(1998) gave a good exposition of matrix methods for the
general linear model and went on to describe regression analysis in general. A rather advanced, but very useful, text on linear
models is Christensen (1996).
Suppose we are to conduct an experiment during which we
will measure a response variable (such as BOLD signal at a
particular voxel) Yj, where j 1, . . ., J indexes the observation.
Yj is a random variable, conventionally denoted by a capital
letter. Suppose also that for each observation, we have a set of L
(L < J) explanatory variables (each measured without error)
denoted by xjl, where l 1, . . ., L indexes the explanatory variables. The explanatory variables may be continuous (or sometimes discrete) covariates, functions of covariates, or dummy
variables indicating the levels of an experimental factor.
A general linear model explains the response variable Yj in
terms of a linear combination of the explanatory variables plus
an error term:
Yj xj1 b1 xjl bl xjL bL ej
[1]
A simple example is linear regression, where only one continuous explanatory variable xj is measured (without error) for
each observation j 1, . . ., J. The model is usually written as
Yj m xj b ej
where the unknown parameters are m, a constant term in the
model, the regression slope b, and ej N 0, s2 . This can be
rewritten as a general linear model by the use of a dummy
variable taking the value xj1 1 for all j:
Yj xj1 m xj2 b2 ej
which is of the form of eqn [1] on replacing b1 with m.
Similarly, the two-sample t-test is a special case of a general
linear model: suppose Yj1 and Yj2 are two independent groups
of random
variables. The two-sample t-test assumes
Yqj N mq , s2 , for q 1, 2, and assesses the null hypothesis
: m1 m2. The index j indexes the data points in both groups.
The standard statistical way of writing the model is
Yqj mq eqj
[2]
Matrix Formulation
Here, we use the general linear model in its matrix formulation, present its least squares parameter estimation, and
http://dx.doi.org/10.1016/B978-0-12-397025-1.00317-1
465
466
Parameter Estimation
Once an experiment has been completed, we have observations of the random variables Yj, which we denote by yj. Usually, the simultaneous equations implied by the general linear
model (eqn [1] with e 0) cannot be solved, because the
number of parameters L is typically chosen to be less than the
number of observations J. Therefore, some method of estimating parameters that best fit the data is required. This is
achieved by the method of ordinary least squares.
Denote a set of parameter estimates by b0 [b10 , . . ., bL0 ]T.
These parameters lead to fitted values y0 [y10 , . . ., yJ0 ]T Xb0 ,
giving residual errors e [e1, . . ., eJ]T y y0 y Xb0 . The residP
ual sum of squares S Jj1 e2 eT e is the sum of the square
differences between the actual and fitted values and thus measures the fit of the model with these parameter estimates. The
least squares estimates are the parameter estimates that minimize the residual sum of squares. In full,
S
J
X
yj xj1 b1 xjL bL
2
j1
J
2
X
0
0
@S
xjl yj xj1 b1 xjL bL 0
0 2
@bl
j1
This equation is the lth row of XTy (XTX)b0 . Thus, the least
^ satisfy the normal equations:
squares estimates, denoted by b,
XT y X T X b^
[3]
For the general linear model, the least squares estimates are
the maximum likelihood estimates and are the best linear unbiased
estimates. That is, of all linear parameter estimates consisting of
linear combinations of the observed data whose expectation is
the true value of the parameters, the least squares estimates
have the minimum variance. If (XTX) is invertible, in which it is
if and only if the design matrix X is of full (column) rank, then
the least squares estimates are
1
b^ XT X XT y
If X has linearly dependent columns, it is rank-deficient,
and (XTX) is singular and has no inverse. In this case, the
model is overparameterized: there are infinitely many parameter sets describing the same model. Correspondingly, there are
infinitely many least squares estimates b^ satisfying the normal
equations (eqn [3]). In this case, a pseudoinverse method can
be used for parameter estimation. Let (XTX) denote the
pseudoinverse of (XTX). Then, we can use (XTX) in place of
(XTX)1. A set of least squares estimates are given by
Statistical Inference
After parameter estimation, t- and F-statistics can be derived,
which are used to test for a linear combination of parameter
estimates. It can be shown that the parameter estimates
are normally
distributed:
if X is full rank, then
1
. From this, it follows that for a column
b^ N b, s2 X T X
vector c containing L weights, then
1
cT b^ N cT b, s2 cT X T X c
For an independent and identical error, the residual variance s^2 is estimated by the residual sum of squares divided by
the appropriate degrees of freedom:
s^2
X 2Jp
eT e
s2
Jp
Jp
467
cT b d
T q
s^2 cT XT X1 c
Sb2 Sb
p p2
F
Fpp2 , Jp
Sb
Jp
1
J1 J2
which is the standard formula for the two-sample t-statistic,
with a Students t-distribution of J1 J2 2 degrees of freedom
under the null hypothesis.
If the model is overparameterized (i.e., X is rank-deficient),
then there are infinitely many parameter sets describing
the same model. Constraints or the use of a pseudoinverse
selects a unique set of parameters. Therefore, when examining
linear compounds cTb of the parameters, it is imperative to
consider only compounds that are invariant over the space
of possible parameters. Such linear compounds are called
contrasts.
F-statistics
The extra sum-of-squares principle provides a method for
assessing general linear hypotheses, where inference is based
on an F-statistic. Here, we will describe the classical F-test based
on the assumption of an independent identically distributed
error. We first present the classical F-test as found in introductory statistical texts. After that, we will derive an equivalent but
more useful implementation of the F-test for typical models in
neuroimaging.
Suppose we have a model with parameter vector b that can
be partitioned into b [bT1, bT2]T, and suppose we wish to test
: b1 0. The corresponding partitioning of the design matrix
is X [X1 X2], and the full model is
2 3
b1
Y X1 X2 4 5 E
b2
which when is true reduces to the reduced model Y X2b2 E.
Denote the residual sum of squares for the full and reduced
models by S(b) and S(b2), respectively. The extra sum of squares
due to b1 after b2 is then defined as S(b1|b2) S(b2) S(b).
Under , S(b1|b2) s2w2p independent of S(b), where the
degrees of freedom are p rank(X) rank(X2). If is not
[4]
MY T MY J p Y T MY J p
T
Fp1 , Jp
Y RY p1
RY T RY p1
b^T X T MX b^ J p
Fp1 , Jp
Y T RY
p1
468
Paired t-Test
Examples
One-Sample t-Test
In this section, we will discuss basic statistical tests as special
cases of the general linear model. The simplest model is the
one-sample t-test used to test the null hypothesis that the mean
of J observations equals zero. In that case, the design matrix
consists of just a constant regressor. The model is
Y x1 b1 e
where x1 is a constant vector of ones and e N 0,s2 IJ . The
null hypothesis is : b1 0 and the alternative hypothesis is
: b1 > 0. Then, the t-value is computed as
b^1
T q
tJ1
s^2 =J
where s^2 yT Ry=J 1, where R is the residual forming matrix
(see above) and yTRy are the sum of squares
J of theresiduals.
X
2
Thiscould also be expressed as yT Ry
yj y^j , where
j1
y^j x1 b^1 b^1 .
j
s^2 =
J1 J2
The difference to the unpaired two-sample t-test lies in the
degrees of freedom J J/2 1. The paired t-test can be a more
appropriate model for a given data set, but more effects are
modeled, that is, there are less error degrees of freedom.
Two-Sample t-Test
As another example, we use the two-sample t-test again (see
above) but in an overparameterized version. The resulting
design matrix consists of three columns: the first two encode
as above the group membership of each observation and the
third models a common constant across all observations of
both groups. Let the number of observations in the first and
second groups be J1 and J2, where J J1 J2. The three regressors consist of ones and zeros, where the first regressor consists
of J1 ones, followed by J2 zeros. The second regressor consists
of J1 zeros, followed by J2 ones. The third regressor contains
ones only. Let the contrast vector be c [1, 1, 0]T, that is, the
alternative hypothesis is : b1 < b2 . Then,
0
1
J1 0 J1
T
@
X X 0 J2 J2 A
J1 J2 J
This model is overparameterized so we use the pseudoinverse (XTX) to compute the t-statistic. We sandwich
J1 J2
and s^2 yT Ry=J 2. We implicitly made the assumption that
we have equal variance in both groups. This assumption may
Analysis of Covariance
A one-way analysis of covariance (ANCOVA) allows one to
model group effects, that is, the mean of each of Q groups.
This model includes the one-sample and two-sample t-tests,
that is, the cases when 1 Q 2. In our example, let the number of groups be Q 3, where there are five scans within each
group, that is, Jq 5 for q 1, . . ., Q. There are a range of different contrasts available. For instance, we could test the null
hypothesis that the group means are all equal using the Fcontrast as described earlier. Here, we wish to test the null
hypothesis, whether the mean of the first two groups is equal
to the mean of the third group, that is, : (b1 b2)/2 b3 0,
and our alternative hypothesis is : b1 b2 =2 <
References
Chatfield, C. (1983). Statistics for technology. London: Chapman & Hall.
Christensen, R. (1996). Plane answers to complex questions: The theory of linear
models. Berlin: Springer-Verlag.
Draper, N., & Smith, H. (1998). Applied regression analysis (3rd ed.). New York: Wiley.
Glaser, D., & Friston, K. (2007). Covariance components. In K. Friston, J. Ashburner,
S. Kiebel, T. Nichols, & W. D. Penny (Eds.), Statistical parametric mapping: The
analysis of functional brain images (1st ed.). London: Elsevier.
469
Kiebel, S., & Holmes, A. (2003). The general linear model. In R. Frackowiak,
K. Friston, C. Frith, R. Dolan, C. Price, S. Zeki, J. Ashburner, & W. Penny (Eds.),
Human brain function (2nd ed.). Amsterdam: Elsevier.
Kiebel, S., & Holmes, A. (2007). The general linear model. In K. Friston,
J. Ashburner, S. Kiebel, T. Nichols, & W. D. Penny (Eds.), Statistical
parametric mapping: The analysis of functional brain images (1st ed.).
London: Elsevier.
Mould, R. (1998). Introductory medical statistics (3rd ed.). London: Institute of Physics
Publishing.
Glossary
Introduction
Understanding how to construct and test a contrast of parameters in a linear model requires understanding what they represent in the model and how they are estimated. This article
presents a few examples of models and contrasts of interest for
these models. It covers issues such as near collinearity and
orthogonalization of regressors. We also discuss how to test
combinations of estimated parameters to form either t- or
F-statistics and how these statistics are related.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00318-3
471
472
Model 2
Model 3
0
40
40
40
80
120
Time (s)
Time (s)
Time (s)
Model 1
0
80
120
160
120
160
X1
80
160
X1
X2
X1
X2
X3
X4
Figure 1 Three different model examples for force data example. In each case, the y-axis is the time in seconds, where the beginning of the run starts
at the top of the axis. The first regressor in each case is the constant regressor, which corresponds to the b0 parameter. Model 1 models all trials
under the assumption that the BOLD response to all forces will be equal. Model 2 assumes a linear relationship between the BOLD response and
force through the modulated regressor, X2. Model 3 models each force using a separate regressor, where forces 14 are modeled in X1X4.
473
Healthy controls
Bipolar
ADHD
X1
X2
X3
Hypothesis
X2
X3
[ 1
[ 1
[ 0
0
0
0
0 ]
1 ]
1 ]
X1
Contrasts
0
0
0
0 ]
1 ]
1 ]
1
0
0
0
1
0
0
0
1
1
1
1
0
1
0
0
0
1
1
0
0
1
1
1
0
0
0
1
1
1
Figure 2 Two parameterizations of a 1-way ANOVA with three levels. The top, left panel is the cell means model approach and models a separate mean
for each group. The top, right panel is an equivalent parameterization that models the controls as the baseline. In the succeeding text, the design
matrices three t-tests and two F-tests are illustrated.
t-Tests
A contrast is most often defined in neuroimaging as a linear
combination of the parameters of the model, quantifying the
effect of interest. As we do not know the true parameters,
contrasts are estimated using the estimates of the parameters,
^ . Since contrasts are used to test hypotheses about linear
the b
i
combinations of the bis, they are created by premultiplying b
by a row vector, lT. This vector, the contrast weights, is also
often called a contrast, by extension. The contrast can also be
thought as a model restriction, which would be expressed as a
linear combination of the columns of the design matrix X.
Recall model 1 in Figure 1, modeling the intercept and the
squeeze task in Y b0 X1b1 E. Since b1 indicates whether the
task activation is greater than baseline, the task effect would be
tested using H0 : b1 0 versus HA : b1 > 0. Rejecting the null
hypothesis concludes that the activation during the task is
greater than baseline. The contrast for this test would be
lT [01], since lTb 0 b0 1 b1 b1.
Model 3 in Figure 1 models each level of force according to
eqn [1], where b1b4 represent the activation of forces 14
versus baseline, respectively. The test of force 1 versus baseline
would use lT [0 1 0 0 0]. To test if the activation for force 4 is
larger than force 1, lT [0 1 0 0 1] would be used. The negative of this contrast, lT [0 1 0 0 1], tests if force 1 has larger
activation than force 4.
For the right-hand side model in Figure 2, constructing the
contrast to test H0 : ADHD 0 versus HA : ADHD > 0 will not be
intuitive, but can be understood by constructing the average of
the model-based values of Y. The predicted value of Y for each of
the ADHD entries (Y(9) to Y(12)) is b1 b3; hence, the average
would be the same and the contrast of interest is lT [1 0 1]. For
models that are not full rank, this procedure gives us a way of
finding the estimable contrasts we need to test the groups means
F-Tests
Using the group 1-way ANOVA with three levels (Figure 2), the
hypothesis may be whether any of the group means differ from
0, corresponding to
H0 : HC 0 and Bipolar 0 and ADHD 0
HA : HC 6 0 or Bipolar 6 0 or ADHD 6 0
There are two important aspects of the F-test. Firstly, rejecting the F-test concludes that at least one of the alternative
474
T h
1 i1 T
^
^ MSEX0 MSEX
DT b
DT X T X D
D b
[3]
0.1
0.0
-0.1
-0.2
-0.3
-0.3
-0.2
-0.1
0.0
b1
0.1
0.2
0.3
1.
2.
3.
4.
5.
X1 T X1 b1 2 X2 T X 2 b2 2 2 X1 T X2 b1 b2 =2s2
[4]
0.2
b2
0.3
Other Considerations
Near Collinearity
Each parameter, or contrast of parameters, from the model is
adjusted for all other effects in the model. Hence, if effect 1 is
very correlated to effect 2, what is tested is only the aspect of
effect 1 not present in effect 2. This can be seen by looking at
the more traditional way of expressing the numerator of the
Orthogonalization
Orthogonalization involves assigning shared variability
between regressors to one of the regressors. For example, in a
model adjusting for height and weight, it would be expected
that these two regressors would be highly correlated.
Orthogonalization assigns the shared variability to one of the
regressors, so orthogonalization of height with respect to
weight would assign shared variability to weight. The height
effect is still adjusted for weight, but the weight effect is no
longer adjusted for height, in this scenario. Since weight is no
longer adjusted for height, the corresponding p-value for the
weight effect will likely decrease. This is often, incorrectly,
viewed as a benefit due to a misinterpretation of the result as
an adjusted effect, when, in fact, the significance of the weight
effect could be due to height.
There are few acceptable uses of orthogonalization. When
parametrically modulated regressors are included, one
475
Conclusion
While the general linear model (GLM) is widely used in neuroimaging for inference with t- and F-tests on the effects of
interest, it is important to realize that the validity of these
inferences will rely on the models assumptions: that the
model is correct the expected Y is Xb and that the noise is
normally distributed. Model checking tools should therefore
be used as much as possible (Luo & Nichols, 2003). For more
details on the flexibility and limitations of the GLM for fMRI,
see Poline and Brett (2012).
References
Birn, R. M., Cox, R. W., & Bandettini, P. A. (2002). Detection versus estimation in eventrelated fMRI: Choosing the optimal stimulus timing. Neuroimage, 15(1), 252264.
Bullmore, E., Brammer, M., Williams, S. C., Rabe-Hesketh, S., Janot, N., David, A., et al.
(1996). Statistical methods of estimation and inference for functional MR image
analysis. Magnetic Resonance in Medicine, 35(2), 261277.
Liu, T. T. (2004). Efficiency, power, and entropy in event-related fMRI with multiple trial
types. Part II: Design of experiments. Neuroimage, 21(1), 401413.
Luo, W. L., & Nichols, T. E. (2003). Diagnosis and exploration of massively univariate
neuroimaging models. Neuroimage, 19(3), 10141032.
Moore, E. (1920). On the reciprocal of the general algebraic matrix. Bulletin of the
American Mathematical Society, 26(9), 394395.
Mumford, J. A., & Nichols, T. (2006). Modeling and inference of multisubject fMRI data.
IEEE Engineering in Medicine and Biology Magazine, 25(2), 4251.
Poline, J. B., & Brett, M. (2012). The general linear model and fMRI: Does love last
forever? Neuroimage, 62(2), 871880.
Woolrich, M. W., Ripley, B. D., Brady, M., & Smith, S. M. (2001). Temporal
autocorrelation in univariate linear modeling of FMRI data. Neuroimage, 14(6),
13701386.
Worsley, K. J., Liao, C. H., Aston, J., Petre, V., Duncan, G. H., Morales, F., et al. (2002).
A general statistical analysis for fMRI data. Neuroimage, 15(1), 115.
Zarahn, E., Aguirre, G. K., & DEsposito, M. (Apr 1997). Empirical analyses of BOLD
fMRI statistics. I. Spatially unsmoothed data collected under null-hypothesis
conditions. Neuroimage, 5(3), 179197.
Abbreviations
ANCOVA
ANOVA
df
Analysis of covariance
Analysis of variance
Degrees of freedom
Introduction
Analysis of variance (ANOVA) is simply an example of the
general linear model (GLM) that is commonly used for factorial
designs. A factorial design is one in which the experimental
conditions can be categorized according to one or more factors,
each with two or more levels (Winer, Brown, & Michels, 1991).
For example, an experiment might present two types of visual
stimuli (e.g., faces and houses), each at three different levels of
eccentricity. This would correspond to a 2 3 ANOVA, in
which the six conditions correspond to unique combinations
of each level of the stimulus-type and eccentricity factors.
In univariate ANOVA, each condition furnishes one measurement (e.g., BOLD response at a given voxel) for each of
multiple replications (e.g., subjects). When each level of one or
more factors is measured on the same thing, for example, the
same subject contributes data to each level, the ANOVA is
called a repeated-measures ANOVA. Such factors are also called
within-subject factors, as distinct from between-subject factors, for
which the levels can be considered independent (ANOVAs that
contain both within-subject and between-subject factors are
sometimes called mixed ANOVAs). A 1 2 repeated-measures
ANOVA corresponds to a paired (or dependent samples) t-test;
1 2 between-subject ANOVA corresponds to an unpaired (or
independent samples) t-test. Repeated-measures ANOVAs
include additional covariates in the GLM to capture variance
across measurements (e.g., between-subject variance), normally reducing the residual error and hence improving statistics for the effects of interest. This is in fact one type of analysis
of covariance, or ANCOVA, in which the data are adjusted for
covariates of no interest (another example covariate might be,
e.g., the order in which conditions were measured). Analysis
of multiple measurements per condition is also possible
(multivariate ANOVA, or MANOVA), though this can be formally reduced to a univariate ANOVA with additional factors
and proper treatment of the error term (see Kiebel, Glaser, &
Friston, 2003), so is not discussed further here. Finally,
ANOVA (and the GLM) can be considered special cases of
linear mixed-effects (LMEs) models (Chen, Saad,
Britton, Pine, & Cox, 2013), though many of the issues to do
with error covariance modeling are generalized later in the text.
What characterizes ANOVA is the focus on a specific set of
statistical tests across the conditions (contrasts), designed to test
the main effects of each factor and interactions between factors.
So in the 2 3 ANOVA example earlier in the text, there would
be three such treatment effects: (1) the main effect of stimulus
GLM
MANOVA
OLS
ReML
type, (2) the main effect of eccentricity, and (3) the interaction
between stimulus type and eccentricity. A significant main
effect of a factor means that the differences between the levels
of that factor are significant (relative to the variability across
replications) when averaging over the levels of all other factors.
So the main effect of stimulus type would correspond to the
difference between faces and houses, regardless of eccentricity.
A significant interaction between two factors means that the
effect of one factor depends on the levels of the other factor. So
an interaction between stimulus type and eccentricity would
mean that the difference between faces and houses depends on
their eccentricity (or equivalently, that the effect of eccentricity
depends on whether the stimulus is a face or house). So, for
example, there might be a large difference between faces and
houses at low eccentricity but less of a difference (or even a
difference in the opposite direction) at high eccentricity
(a result that can be followed up by more focused contrasts
within each level of a factor, sometimes called simple effects). It
is arguably difficult to interpret the main effect of a factor if it
interacts with other factors (or more generally, to interpret an
mth-order interaction if one of the factors is also involved in a
significant (m 1)-th-order interaction). In such cases, a common strategy is to repeat separate ANOVAs on each level of one
of the factors in that interaction, after averaging over the levels
of factors not involved in that interaction. More generally, for a
K-way ANOVA with K factors, there are K main effects, K
(K 1)/2 two-way or second-order interactions, K(K 1)
(K 2)/6 three-way or third-order interactions, etc., and one
highest-order K-way interaction (see Section Generalization
to K-Way ANOVAs).
http://dx.doi.org/10.1016/B978-0-12-397025-1.00319-5
477
478
values are estimated from fitting the model and here correspond to the mean across subjects for that level); and es,a is the
residual error for the sth subject and ath level (again derived
from fitting the model). Sometimes, a fifth regressor would be
added to capture the grand mean across all the data, but this is
not necessary for the F-contrasts considered later in the text.
Fitting the model entails estimating the values of the four
parameters such that the sum of the squares of the residuals
is minimized (the so-called ordinary least squares, or OLS,
estimates).
The same equation can be written in matrix format as
y Xb e
e N 0; Ce
Ce s 2 I
[1]
SSA =df A
SSe =df e
where SS are the sums of squares and df are the degrees of freedom.
In the present example, with L 4 levels of the factor,
dfA L 1 3 (since there are three ways that four things can
differ) and dfe N L 36 (i.e., the df in the data minus the df in
the model). Given those df, the probability of obtaining that
value of F or larger under the null hypothesis, p, can be calculated
from the standard F-distribution and declared significant if p is
less than a certain value, for example, p < 0.05. Note that a
significant main effect could result from any pattern of difference
across the four means (e.g., there is no requirement of an ordinal
relationship across the levels). Note also that F-tests are twotailed, but there is nothing to prohibit a one-tailed (directional)
test of a main effect or interaction if there is only one numerator
df in the contrast.
The F-statistic can also be specified by a contrast matrix, c, or
the so-called F-contrast. For the main effect of A in the present
example, c can be expressed in a number of ways (as long as
rank(c) 3 to reflect dfA), such as three pairwise differences
between the four levels:
2
3
1 1 0 0
c 4 0 1 1 0 5
0 0 1 1
The F-statistic can then be expressed in terms of the param^ full design matrix (X), data y, and contrast c
eter estimates (b),
(see Appendix A of Henson & Penny, 2003). Once the use of
such F-contrasts is understood, more complicated ANOVAs
can be considered, as next.
y1,1,1(s1)
...
y1,1(s1)
...
yA(s1)
yA(s2)
yA(s10)
y10,2,2(s10)
y10,4(s40)
x1(a1) x2(a2) x3(a3) x4(a4)
(a)
...
y1,1,2(s1)
...
y1,2(s11)
...
(b)
s2
...
cA
s10
(c)
Figure 1 GLM design matrices for example ANOVAs, where white 1, gray 0: (a) A 1 4 between-subject ANOVA, (b) a 2 2 within-subject ANOVA
with pooled error, and (c) one of the main effects (or interaction effect) in (b), after premultiplying the data by the contrast for that effect, corresponding
to a partitioned error.
1
1
[2]
1
1
1
1
479
1
Nonsphericity
As mentioned in the preceding text, a second consequence of
ANOVAs with repeated measures is that the IID assumption in
eqn [1] is unlikely to hold, in that the residual for one measurement on one subject is likely to be similar to the residuals
for other measurements on that subject, that is, the residuals
for repeated measurements are likely to be positively correlated
across subjects. This inhomogeneity of covariance is another case
of nonsphericity (in fact, IID is a special case of a spherical Ce; for
more precise definition of nonsphericity, see Appendix C of
Henson & Penny, 2003). Nonsphericity implies that the effective df in the data is less than the number of observations.
Standard approximations exist to estimate the degree of
nonsphericity and associated loss of df, by estimating a proportion 1/df < e < 1 by which the numerator and denominator df of the F-ratio are scaled (e 1 corresponding to
spherical residuals). Common approximations include the
GreenhouseGeisser or HuynhFeldt corrections (Howell,
2002). One problem with these post hoc df corrections however is that they tend to be conservative, since there are rarely
sufficient data to estimate e efficiently (Kiebel et al., 2003).
Q5
Q1
Q2
Q3
Q4
Q6
Q7
Q8
Q9
Q10
480
(K m) !) treatment effects of the mth order (where the firstorder effects are the main effects), and 2K 1 treatment effects
in total. (One should therefore consider correcting the p-values
for the number of treatment effects tested, i.e., to allow for the
multiple comparison problem in classical statistics.)
The F-contrasts for each treatment effect can be built from
two types of component contrast matrix mk and dk for the kth
factor:
0.8
0.8
0.8
0.6
True Pool
True Part
Null Pool
Null Part
0.4
0.2
0.05
0
0.6
True Pool
True Part
Null Pool
Null Part
0.4
0.2
10 12 14 16 18 20 22 24
Number of subjects
0.05
0
dk orthdiff ILk T
mk 1Lk
0.6
True Pool
True Part
Null Pool
Null Part
0.4
0.2
10 12 14 16 18 20 22 24
Number of subjects
0.05
0
10 12 14 16 18 20 22 24
Number of subjects
Figure 3 Sensitivity and bias for various treatments of the error in a 2 2 repeated-measures ANOVA, in which there is a true main effect of A (blue lines),
but no main effect of B (red or green lines). The proportion of 10 000 voxels whose p-values exceed p < 0.05 are plotted against the number of subjects. In
(a), the true error correlation is constant across voxels. The solid lines arise when averaging residual covariances across all voxels and estimating the
nonsphericity of the single pooled-error term (Pool) using ReML and the ten covariance components depicted in Figure 2 (see text for details); the dotted
lines reflect the same effects estimated using a partitioned error (Part). Note the pooled error is more sensitive to the main effect of A while maintaining the
same control of false-positives (at expected chance proportion of 0.05) for the main effect of B. In (b), the error nonsphericity is estimated for each voxel
separately, and the inefficiency of this estimation no longer results in a gain in sensitivity for the pooled relative to partitioned error, and there is now an
increased false-positive rate (red line). In (c), the true error correlation varies across voxels but is still estimated by averaging residuals across voxels. This
also results in a loss of sensitivity and (modest) increase in false-positive rates for pooled relative to partitioned error. The code for these simulations is
available at http://www.mrc-cbu.cam.ac.uk/wp-content/uploads/2013/05/check_pooled_error.m.
1 1
1 1
1
1
1
1 1
1 1
1
1
1
1
Acknowledgments
This work was supported by the UK Medical Research Council
(MC_US_A060_5PR10).
481
References
Chen, G., Saad, Z. S., Britton, J. C., Pine, D. S., & Cox, R. W. (2013). Linear mixedeffects modeling approach to FMRI group analysis. NeuroImage, 73, 176190.
Friston, K. J., Glaser, D. E., Henson, R. N., Kiebel, S., Phillips, C., & Ashburner, J.
(2002). Classical and Bayesian inference in neuroimaging: Applications.
Neuroimage, 16, 484512.
Henson, R. N., & Penny, W. (2003). ANOVAs and SPM. Technical Report, Wellcome
Department of Imaging Neuroscience.
Howell, D. C. (2002). Statistical methods for psychology (5th ed.). Belmont, CA:
Duxbury Press.
Kiebel, S. J., Glaser, D. E., & Friston, K. J. (2003). A heuristic for the degrees of freedom
of statistics based on multiple hyperparameters. NeuroImage, 20, 466478.
Winer, B. J., Brown, D. R., & Michels, K. M. (1991). Statistical principles in
experimental design. McGraw-Hill.
Woolrich, M. W., Jenkinson, M., Brady, J. M., & Smith, S. M. (2004). Fully Bayesian
spatio-temporal modeling of FMRI data. IEEE Transactions on Medical Imaging, 23,
213231.
Relevant Websites
http://afni.nimh.nih.gov/sscc/gangc/ANOVA.html ANOVA in AFNI software, and
extension to LME models: http://afni.nimh.nih.gov/sscc/gangc/lme.html.
https://en.wikipedia.org/wiki/Analysis_of_variance wikipedia, classical perspective.
http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/GLM ANOVA in FSL.
http://www.mrc-cbu.cam.ac.uk/wp-content/uploads/2013/05/check_pooled_error.m
Matlab code used to calculate efficiency in examples here.
http://www.mrc-cbu.cam.ac.uk/personal/rik.henson/personal/
HensonPenny_ANOVA_03.pdf GLM perspective and implementation in SPM.
http://nmr.mgh.harvard.edu/harvardagingbrain/People/AaronSchultz/GLM_Flex.html
software toolbox for partitioned error models in SPM.
http://surfer.nmr.mgh.harvard.edu/fswiki/LinearMixedEffectsModels LME in
Freesurfer.
Glossary
Introduction
LTI Models
LTI systems must by definition have properties of both linearity and time invariance. In order to apply these principles to
fMRI analysis, let us say we have a function f that transforms
neural activation X(t) into BOLD output y(t). Then,
yi t f Xi t
[1]
[2]
http://dx.doi.org/10.1016/B978-0-12-397025-1.00320-1
483
484
Input function
(neural activity)
Impulse response
function (HRF)
Predicted BOLD
timecourse
0
0
20
40
60
Time (s)
80
5 10 15 20 25 30
Peristimulus time (s)
0 10 20 30 40 50 60 70
Time (s)
Figure 1 Convolution example: The stimulus function (a surrogate for neural activity) is combined, using convolution, with the hemodynamic
response function (HRF) to produce a predicted time course of BOLD signal. Notice that convolution acts to blend repeatedly the impulse response
function with the input function. is the symbol for convolution. Adapted from Henson, R., & Friston, K. (2006). Convolution models for fMRI.
In W. D. Penny, K. J. Friston, J. T. Ashburner, S. J. Kiebel, & T. E. Nichols (Eds.), Statistical parametric mapping: The analysis of functional brain images.
London: Academic Press, with permission from Elsevier.
Xt x1 dt 1 x2 dt 2 . .. n9 t 9
d(t t)
t
Time (t)
1
X
xt dt t
[4]
t0
t
X
x4
Xt f dt t
[5]
t0
Xt
0
Xtht t
Xtht tdt
x(t)
x3
x2
x1
5 6
T (TR)
y HX
with H in Toeplitz matrix form.
[6]
485
0
0
(a)
0
(c)
10
15
20
25
Peristimulus time (s)
30
10
15
20
25
Peristimulus time (s)
30
10
15
20
25
Peristimulus time (s)
30
10
15
20
25
Peristimulus time (s)
30
(b)
0
(d)
Figure 4 Temporal basis sets for fMRI analysis. The waveforms or vectors in each graph are convolved with the experimental stimulus function
(i.e., a surrogate for neural activity) to produce a predicted time course. Each time course constitutes a separate column of the design matrix. (a) Three
gamma functions modeling early (blue), middle (red), and late (green) responses. (b) Canonical HRF (blue), temporal derivative (red), and
dispersion derivative (green). (c) Boxcar functions for the FIR model. Each boxcar is generally designed to last for TR seconds. (d) Sine and cosine
waveforms comprise the Fourier basis set. Adapted from Henson, R., & Friston, K. (2006). Convolution models for fMRI. In W. D. Penny, K. J. Friston,
J. T. Ashburner, S. J. Kiebel, & T. E. Nichols (Eds.) Statistical parametric mapping: The analysis of functional brain images. London: Academic
Press, with permission from Elsevier.
486
sine and cosine functions and T is the duration of the HRF. The
number of basis functions is 2N 1. In Figure 4(d), N is 8. The
Fourier basis set may be most appropriate when peristimulus
time sampling, which is the temporal relationship between
event onset times and the MR sampling time (TR), is not
uniform (Henson & Friston, 2006).
Although all of these extended temporal basis sets generally
provide a better fit to the BOLD signal than using a single
waveform to model the HRF, the main disadvantage is the
greater complexity of analyzing the multiple parameter estimates associated with each of the vectors in the temporal basis
set at the second (i.e., multiple subject) level. In some cases,
such as the basis set of three gamma functions, the parameter
estimates associated with each function can be analyzed separately, as each vector has a biologically interpretable meaning,
for example, early versus middle versus late responses. On the
other hand, the parameter estimates for the Fourier or FIR basis
sets must be analyzed as a group using second-level F-tests and
repeated measures ANOVAs. This limits the ability to make
statistical inferences about specific task differences using contrasts and t-tests (Henson & Friston, 2006).
In cases where the HRF may have a significant nonlinear
component, the chosen basis set can be further expanded as a
Volterra series (Friston, Josephs, et al., 1998; Henson & Friston,
2006). Friston et al. noted that a Volterra series is similar to a
Taylor series model that has been extended for dynamic (i.e.,
nonlinear) systems (Friston, Josephs, et al., 1998). In general, a
second-order Volterra model is sufficient for most nonlinear
fMRI analyses (Friston, Josephs, et al., 1998).
Deconvolution
Sometimes, rather than using the convolution equation to
estimate the BOLD response, the goal of the analysis is to
estimate the neural response itself. In such cases, one
must calculate the inverse transform of the convolution operation or deconvolution. Estimates of neural activity are particularly relevant when using fMRI for calculating measures of
effective connectivity or the influences between neural systems. In such analyses, although fMRI signal is measured as
BOLD data, interactions take place at the neuronal level,
hence the need for an estimate of the underlying neural
activity. Mathematically, it is also critical to deconvolve
BOLD to neuronal signal because interactions calculated at
a hemodynamic level are not equivalent to those calculated at
a neuronal level (Gitelman, Penny, Ashburner, & Friston,
2003). For example, let us examine the interaction of neural
activity between two regions, A and B. Note that the interaction term for two vectors is simply their Hadamard product
(i.e., their element-by-element multiplication). If BOLD signals, yAand yB, are measured, then forming the interaction
term at the BOLD level is not equivalent to forming that
term at the neuronal level. Let XA and XB represent the
neuronal activity in each region. Then,
yA yB HXA HXB 6 HXA XB
H is the hemodynamic response function. Therefore, HXA and
HXB represent the BOLD signal from regions A and B, respectively, and H(XA XB) is the BOLD signal resulting from
487
Input signal 1
1
0.5
0
0.5
1
0
0
10
20
30 40
Time (s)
50
60
10 15 20 25 30
Peristimulus time (s)
0.5
0
Input signal 2
2
0.5
1
0
10
20
30
40
50
60
Time (s)
1
2
0
0
10
20
30 40
Time (s)
50
60
10 15 20 25 30
Peristimulus time (s)
Figure 5 Low-pass filter effects of the HRF. Two different neural input signals and their convolution with an HRF are shown. Input signal 1 is sin
(2pt/20). Input signal 2 is sin(2pt/20)sin(2pt/5). Note that the higher frequencies of input signal 2 are filtered out after convolution with the HRF
so that the predicted time courses look nearly identical. Obviously, deconvolution of the predicted time courses would produce results similar to input
signal 1, demonstrating the nonunique mapping between the input signals (i.e., neural signals) and predicted time courses (i.e., simulated BOLD).
Adapted from Zarahn, E. (2000). Testing for neural responses during temporal components of trials with BOLD fMRI. Neuroimage, 11, 783796,
with permission from Elsevier.
488
Conclusions
This article has reviewed techniques for analyzing BOLD fMRI
data using the concepts of LTI systems. The power of this
technique lies in its ability to model a wide variety of experimental designs. Moreover, the use of various basis sets for the
systems impulse response function allows the user to focus on
different temporal aspects of the data and even to analyze
nonlinear responses all within the same flexible framework.
References
Ashby, F. G. (2011). Modeling the BOLD response. Statistical analysis of fMRI data.
Cambridge, MA: MIT Press.
Bandettini, P. A., Jesmanowicz, A., Wong, E. C., & Hyde, J. S. (1993). Processing
strategies for time-course data sets in functional MRI of the human brain. Magnetic
Resonance in Medicine, 30, 161173.
Belliveau, J. W., Kwong, K. K., Kennedy, D. N., Baker, J. R., Stern, C. E., Benson, R.,
et al. (1992). Magnetic resonance imaging mapping of brain function. Investigative
Radiology, 27, S59S65.
Birn, R. M., Saad, Z. S., & Bandettini, P. A. (2001). Spatial heterogeneity of the
nonlinear dynamics in the FMRI BOLD response. NeuroImage, 14, 817826.
Bonakdarpour, B., Parrish, T. B., & Thompson, C. K. (2007). Hemodynamic response
function in patients with stroke-induced aphasia: Implications for fMRI data
analysis. NeuroImage, 36, 322331.
Boynton, G. M., Engel, S. A., Glover, G. H., & Heeger, D. J. (1996). Linear systems
analysis of functional magnetic resonance imaging in human V1. Journal of
Neuroscience, 16, 42074221.
Buxton, R. B., Wong, E. C., & Frank, L. R. (1998). Dynamics of blood flow and
oxygenation changes during brain activation: The balloon model. Magnetic
Resonance in Medicine, 39, 855864.
Cohen, M. S. (1997). Parametric analysis of fMRI data using linear systems methods.
NeuroImage, 6, 93103.
Dale, A. M., & Buckner, R. L. (1997). Selective averaging of rapidly presented individual
trials using fMRI. Human Brain Mapping, 5, 329340.
DEsposito, M., Deouell, L. Y., & Gazzaley, A. (2003). Alterations in the BOLD fMRI
signal with ageing and disease: A challenge for neuroimaging. Nature Reviews.
Neuroscience, 4, 863872.
Friston, K. J., Fletcher, P., Josephs, O., Holmes, A., Rugg, M. D., & Turner, R. (1998).
Event-related fMRI: Characterizing differential responses. NeuroImage, 7, 3040.
Friston, K. J., Frith, C. D., Turner, R., & Frackowiak, R. S.J (1995). Characterizing
evoked hemodynamics with fMRI. NeuroImage, 2, 157165.
Friston, K. J., Harrison, L., & Penny, W. (2003). Dynamic causal modeling.
NeuroImage, 19, 12731302.
Friston, K. J., Holmes, A. P., Worsley, K. J., Poline, J.-B., Frith, C. D., &
Frackowiak, R. S.J (1995). Statistical parametric maps in functional imaging: A
general linear approach. Human Brain Mapping, 2, 189210.
Friston, K. J., Jezzard, P., & Turner, R. (1994). Analysis of functional MRI time-series.
Human Brain Mapping, 1, 153171.
Friston, K. J., Josephs, O., Rees, G., & Turner, R. (1998). Nonlinear event-related
responses in fMRI. Magnetic Resonance in Medicine, 39, 4152.
Gitelman, D. R., Penny, W. D., Ashburner, J., & Friston, K. J. (2003). Modeling regional
and psychophysiologic interactions in fMRI: The importance of hemodynamic
deconvolution. NeuroImage, 19, 200207.
Glover, G. H. (1999). Deconvolution of impulse response in event-related BOLD fMRI.
NeuroImage, 9, 416429.
Henson, R., & Friston, K. (2006). Convolution models for fMRI. In W. D. Penny, K. J.
Friston, J. T. Ashburner, S. J. Kiebel & T. E. Nichols (Eds.), Statistical parametric
mapping: The analysis of functional brain images. London: Academic Press.
Henson, R. N., Price, C. J., Rugg, M. D., Turner, R., & Friston, K. J. (2002). Detecting
latency differences in event-related BOLD responses: Application to words versus
nonwords and initial versus repeated face presentations. NeuroImage, 15, 8397.
Hinrichs, H., Scholz, M., Tempelmann, C., Woldorff, M. G., Dale, A. M., & Heinze, H. J.
(2000). Deconvolution of event-related fMRI responses in fast-rate experimental
designs: Tracking amplitude variations. Journal of Cognitive Neuroscience,
12(Suppl. 2), 7689.
Huettel, S. A., & McCarthy, G. (2000). Evidence for a refractory period in the
hemodynamic response to visual stimuli as measured by MRI. NeuroImage, 11,
547553.
Huettel, S. A., & McCarthy, G. (2001). Regional differences in the refractory period of the
hemodynamic response: An event-related fMRI study. NeuroImage, 14, 967976.
Kwong, K. K., Belliveau, J. W., Chesler, D. A., Goldberg, I. E., Weisskoff, R. M.,
Poncelet, B. P., et al. (1992). Dynamic magnetic resonance imaging of human brain
activity during primary sensory stimulation. Proceedings of the National Academy of
Sciences of the United States of America, 89, 56755679.
Lange, N., & Zeger, S. L. (1997). Non-linear Fourier time series analysis for human
brain mapping by functional magnetic resonance imaging. Journal of the Royal
Statistical Society: Series C: Applied Statistics, 46, 129.
Liao, C. H., Worsley, K. J., Poline, J. B., Aston, J. A., Duncan, G. H., & Evans, A. C.
(2002). Estimating the delay of the fMRI response. NeuroImage, 16, 593606.
Menon, R. S., Luknowsky, D. C., & Gati, J. S. (1998). Mental chronometry using
latency-resolved functional MRI. Proceedings of the National Academy of Sciences
of the United States of America, 95, 1090210907.
Miezin, F. M., Maccotta, L., Ollinger, J. M., Petersen, S. E., & Buckner, R. L. (2000).
Characterizing the hemodynamic response: Effects of presentation rate, sampling
procedure, and the possibility of ordering brain activity based on relative timing.
NeuroImage, 11, 735759.
Ogawa, S., Lee, T. M., Kay, A. R., & Tank, D. W. (1990). Brain magnetic resonance
imaging with contrast dependent on blood oxygenation. Proceedings of the National
Academy of Sciences of the United States of America, 87, 98689872.
Ogawa, S., Lee, T. M., Nayak, A. S., & Glynn, P. (1990). Oxygenation-sensitive contrast
in magnetic resonance image of rodent brain at high magnetic fields. Magnetic
Resonance in Medicine, 14, 6878.
Ogawa, S., Lee, T. M., Stepnoski, R., Chen, W., Zhu, X. H., & Ugurbil, K. (2000). An
approach to probe some neural systems interaction by functional MRI at neural time
scale down to milliseconds. Proceedings of the National Academy of Sciences of the
United States of America, 97, 1102611031.
Ogawa, S., Menon, R. S., Tank, D. W., Kim, S. G., Merkle, H., Ellermann, J. M., et al.
(1993). Functional brain mapping by blood oxygenation level-dependent contrast
magnetic resonance imaging. A comparison of signal characteristics with a
biophysical model. Biophysical Journal, 64, 803812.
Ollinger, J. M., Corbetta, M., & Shulman, G. L. (2001). Separating processes within a
trial in event-related functional MRI: II. Analysis. NeuroImage, 13, 218229.
Ollinger, J. M., Shulman, G. L., & Corbetta, M. (2001). Separating processes within
a trial in event-related functional MRI: I. The method. NeuroImage, 13,
210217.
Puce, A., Allison, T., & McCarthy, G. (1999). Electrophysiological studies of human face
perception. III: Effects of top-down processing on face specific potentials. Cerebral
Cortex, 9, 445458.
Rajapakse, J. C., Kruggel, F., Maisog, J. M., & Von Cramon, D. Y. (1998). Modeling
hemodynamic response for analysis of functional MRI time-series. Human Brain
Mapping, 6, 283300.
Robson, M. D., Dorosz, J. L., & Gore, J. C. (1998). Measurements of the temporal
fMRI response of the human auditory cortex to trains of tones. NeuroImage, 7,
185198.
Sotero, R. C., & Trujillo-Barreto, N. J. (2007). Modelling the role of excitatory and
inhibitory neuronal activity in the generation of the BOLD signal. NeuroImage, 35,
149165.
Vazquez, A. L., & Noll, D. C. (1998). Nonlinear aspects of the BOLD response in
functional MRI. NeuroImage, 7, 108118.
Wink, A. M., Hoogduin, H., & Roerdink, J. B. (2008). Data-driven haemodynamic
response function extraction using Fourier-wavelet regularised deconvolution. BMC
Medical Imaging, 8, 7.
Zarahn, E. (2000). Testing for neural responses during temporal components of trials
with BOLD fMRI. NeuroImage, 11, 783796.
Relevant Websites
http://afni.nimh.nih.gov/afni AFNI software.
http://www.fil.ion.ucl.ac.uk/spm SPM software.
http://fsl.fmrib.ox.ac.uk/fsl FSL software.
Design Efficiency
RN Henson, MRC Cognition and Brain Sciences Unit, Cambridge, UK
2015 Elsevier Inc. All rights reserved.
Abbreviations
AR(p)
BOLD
DCT
FIR
fMRI
GLM
HRF
ReML
SOA
TR
1
e 1= c X T X cT
e N 0, s2 Ce
[1]
T df q
T 1
^2
c X X cT s
[2]
[3]
HRF Convolution
We can start by assuming that stimuli elicit brief bursts of
neural activity, or events, which are modeled by delta functions
every time a stimulus is presented. Then, for the jth of Nj event
types (conditions), the neural activity over time, or neural time
course, uj(t), can be expressed as
uj t
iN
i j
X
d t T ji
i1
kN
Xk
bkj hk t
k1
where bkj are the parameters to be estimated for each HRF and
condition (and voxel).
http://dx.doi.org/10.1016/B978-0-12-397025-1.00321-3
489
490
jN
Xj
uj t bt
j1
jN
i j
Xj kN
Xk iN
X
bkj hk t T ji
[4]
i1
j1 k1
resulting in a linearly separable equation that can be represented by a design matrix X with P NjNk columns.
At one extreme, we can assumed a fixed shape for the BOLD
response by using a single canonical HRF (i.e., Nk 1). At the
other extreme, we can make no assumptions about the shape
of the BOLD response (up to a certain frequency limit) by
using a so-called finite impulse response (FIR) set (see Figure 1;
for multiple basis functions, the contrasts become cINk ,
where c is a contrast across the Nj event types and INk is an
Nk Nk identity matrix for the Nk basis functions). Normally,
one is only interested in the magnitude of a BOLD response,
in which case a single canonical HRF is sufficient to estimate
efficiency a priori (by assuming that a canonical HRF is a
sufficient approximation on average across voxels and individuals). If however one is interested in estimating the shape
Filtering
So far, we have considered definition of the signal, x(t), but the
other factor that affects the T-statistic in eqn [2] is the noise
^2 . fMRI is known to have a preponderance of lowvariance, s
frequency noise, caused, for example, by scanner drift and by
biorhythms (e.g., pulse and respiration) that are aliased by
slower sample rates (1/TR). A common strategy therefore is to
high-pass filter the data. An example matrix, F, for implementing high-pass filtering within the GLM using a discrete cosine
transform (DCT) set is shown in Figure 1. The reduction in
noise will improve sensitivity, as long as the filtering does not
remove excessive signal too. Heuristics suggest that an
Amplitude (a.u.)
Canonical HRF
and
u2 (t)
Transition
table
or
hk(t )
0
0
200
x1 (t)
400 600
Time (s)
5 10 15 20 25 30
Post-stimulus time (s)
800 1000
x2 (t)
u1 (t)
Amplitude (a.u.)
SOAmin
hk(t )
Scans
5 10 15 20 25
Post-stimulus time (s)
F
0
e = 1/(c((KX)T (KX))-1cT )
1
Figure 1 Ingredients for efficiency: the minimal SOA, SOAmin, and stimulus transition table determine the neural time course, uj(t), which is convolved
with HRFs of poststimulus time, hk(t), to create the design matrix, X. This, together with an a priori contrast, c, and any (high-pass) filter matrix,
K (here generated by K IN FF1), then determines the efficiency, e.
1
0:5 0:5
TMp
TMn
2
0:5 0:5
This implies that there is an equal chance of event type 1
being followed by event type 1 as there is for it being followed
by event type 2 and likewise for what follows event type 2.
Specifying a design in terms of probabilistic transition matrices
allows one to treat the design matrix as a random variable and
derive the expected efficiency by averaging over all possible
design matrices (see Friston, Zarahn, Josephs, Henson, &
Dale, 1999, for details). In other words, one can express design
efficiency in terms of the probabilistic contingencies entailed
by the design matrix.
Randomized Designs
For a randomized design with two event types, we can plot the
efficiency against SOAmin for each of 2 contrasts, c 1 1 ,
the differential effect of event types 1 and 2, and c 1 1 , the
common effect of event types 1 and 2 versus the interstimulus
491
Blocked Designs
Events of the same type can be blocked into short sequences,
which can increase the detection power relative to a randomized design. For a blocked design with two event types, there
would be NH events per block; for example, for blocks of three
events,
Time (s)
492
Time (s)
Time (s)
Efficiency (a.u.)
Efficiency (a.u.)
Time (s)
18
14
20
SOA (s)
20
Time (s)
Time (s)
Time (s)
Efficiency (a.u.)
Efficiency (a.u.)
Time (s)
18
14
SOA (s)
(b)
2
(a)
10 18
(c)
30
50
70
(d)
14
20
SOA (s)
Figure 2 Efficiency for various possible contrasts and designs. (a) Efficiency (arbitrary units) as a function of SOAmin in a randomized design using a
canonical HRF for a differential [1 1] contrast between two event types (dashed magenta line) and the common [1 1] contrast versus baseline
(solid cyan line). Insets are sections of corresponding contrasts of regressors (predicted signal) for SOAmin 4 (left) and SOAmin 18 (right). Efficiency
for the differential effect is higher at short SOAs owing to the greater signal variance caused by the random ordering of event types. (b) Similar to (a), but
now including null events with probability 1/3 and an FIR basis set (dashed red differential effect; solid blue common effect). The stochastic
distribution of SOAs caused by null events increases efficiency for common effect versus baseline even at short SOAmin. (c) Efficiency as function of
block length for a differential contrast between two event types in a blocked design (and high-pass filter cutoff of 120 s). The dashed magenta line and
left inset correspond to a canonical HRF; the dashed cyan line and right inset correspond to an FIR basis set. Maximal efficiency with a canonical
HRF arises for a block length of 18 s; for an FIR basis set, blocks shorter than the FIR duration are inefficient, owing to linear dependence between the
basis functions. (d) Efficiency for the unique effect of the second of two event types ([0 1] contrast) using a canonical HRF in a design where the
second event type can only follow the first event type. The dashed blue line and rightmost inset show an alternating design in which the second event
type always follows the first; the solid blue line and left inset show a design in which the second event type follows the first 50% of the time (the
red dashed line in the insets corresponds to the regressor for the first event type). For SOAmin below approximately 10 s (e.g., 6 s), the 50% design is
more efficient (despite fewer events of the second type in total), because it decorrelates the two regressors. In all panels, 2000 scans with TR 2 s
were simulated, with the first 30 s discarded to remove transient effects.
TMp
1
61
6
61
6
62
6
42
2
1
1
2
2
2
1
3
2
1
0
7
60
27
6
6
27
7 TMn 6 0
7
61
27
6
41
15
1
1
3
1
17
7
17
7
07
7
05
0
alternating event types when block length is 1) have low efficiency, for the same reason that the main effect is inefficient at
short SOAs: any variance in neural activity is smoothed out by
the HRF. As in Figure 2(a), efficiency is maximal for block
lengths around 18 s (since 1/18 Hz is close to the highest passband of the canonical HRF filter; Josephs & Henson, 1999), but
for block lengths of 30 s of more, efficiency plummets again
because of the high-pass filter: for such long blocks, most of the
signal variance (particularly that at the fundamental frequency of
the block alternation) is low enough to be removed by the high-
493
example, genetic algorithms (Wager & Nichols, 2003). Additional constraints are often needed however, such as limits on
runs of the same event type; otherwise, an optimization
scheme is likely to converge on a blocked design, which is
always most efficient (for detection power) from the fMRI
perspective, but may not be appropriate from the psychological perspective (e.g., if the presence of structure in the sequence
of events affects brain activity). An interesting class of
pseudorandomized design that has optimal estimation efficiency is an m-sequence (Buracas & Boynton, 2002). This is a
deterministic sequence that presents all combinations of event
histories up to NH m (i.e., has a large, deterministic transition
matrix) but that is nonetheless effectively unpredictable to
participants. Such sequences have been computed for NJ 2,
3, and 5 event types but require a fixed number (NJ NH 1) of
events in total.
Unique Effects
Optimizing Designs
The examples in Figure 2 represent just a subspace of possible
designs, chosen to help illustrate some of the properties of
eqn [5]. Other formal explorations of design space can be
found in, for example, Dale (1999), Josephs and Henson
(1999), Friston et al. (1999), and Hagberg, Zito, Patria, and
Sanes (2001). There are automated ways of maximizing efficiency by searching through possible designs, using, for
Summary
Efficiency is a well-defined mathematical property of the GLM,
and under the linear assumptions of a convolution model for
the BOLD response, efficiency can be optimized for a priori
contrasts of the conditions of an fMRI experiment by selecting
the optimal SOAmin and stimulus transition table.
Acknowledgments
This work was supported by the UK Medical Research Council
(MC_US_A060_5PR10).
494
References
Buracas, G. T., & Boynton, G. M. (2002). Efficient design of event-related fMRI
experiments using M-sequences. NeuroImage, 16, 801813.
Chawla, D., Rees, G., & Friston, K. J. (1999). The physiological basis of attentional
modulation in extrastriate visual areas. Nature Neuroscience, 2, 671676.
Dale, A. M. (1999). Optimal experimental design for event-related fMRI. Human Brain
Mapping, 8, 109114.
Friston, K. J., Josephs, O., Rees, G., & Turner, R. (1998). Non-linear event-related
responses in fMRI. Magnetic Resonance in Medicine, 39, 4152.
Friston, K. J., Zarahn, E., Josephs, O., Henson, R. N., & Dale, A. M. (1999). Stochastic
designs in event-related fMRI. NeuroImage, 10, 607619.
Friston, K. J., Glaser, D. E., Henson, R. N., Kiebel, S., Phillips, C., & Ashburner, J.
(2002). Classical and Bayesian inference in neuroimaging: Applications.
Neuroimage, 16, 484512.
Hagberg, G. E., Zito, G., Patria, F., & Sanes, J. N. (2001). Improved detection of eventrelated functional MRI signals using probability functions. Neuroimage, 14,
11931205.
Josephs, O., & Henson, R. N. (1999). Event-related fMRI: Modelling, inference and
optimisation. Philosophical Transactions of the Royal Society, London, 354,
12151228.
Liu, T. T., Frank, L. R., Wong, E. C., & Buxton, R. B. (2001). Detection power, estimation
efficiency, and predictability in event-related fMRI. Neuroimage, 13, 759773.
Mechelli, A., Price, C. J., Henson, R. N., & Friston, K. J. (2003). Estimating efficiency a
priori: A comparison of blocked and randomised designs. Neuroimage, 18,
798805.
Wager, T. D., & Nichols, T. E. (2003). Optimization of experimental design in fMRI: A
general framework using a genetic algorithm. Neuroimage, 18, 293309.
Relevant Websites
http://www.cabiatl.com/CABI/resources/fmrisim/ Tool for simulating fMRI designs.
http://www.mrc-cbu.cam.ac.uk/wp-content/uploads/2013/09/fMRI_GLM_efficiency.m
Matlab code used to calculate efficiency in examples here.
http://imaging.mrc-cbu.cam.ac.uk/imaging/DesignEfficiency General advice about
how to optimise an fMRI experiment.
http://psych.colorado.edu/tor/Software/genetic_algorithms.html Genetic algorithm
for optimising fMRI designs.
http://surfer.nmr.mgh.harvard.edu/optseq/ Tool for optimising randomised designs.
Topological Inference
G Flandin and KJ Friston, UCL Institute of Neurology, London, UK
2015 Elsevier Inc. All rights reserved.
Glossary
Topological Inference
Conventional whole-brain neuroimaging data analysis uses
some form of statistical parametric mapping (SPM) (Flandin
& Friston, 2008; Friston, 2007). This entails the creation of a
parametric model (usually a general linear model (GLM)) of
data at each point in search space (voxel or vertex) to produce a
SPM: these are fields that are, under the null hypothesis, distributed according to a known probability density function,
usually the Students t- or FisherSnedecor F-distributions
(Friston et al., 1995; Worsley et al., 2002). Topological inference
is then used to test hypotheses about regionally specific effects
attributable to the experimental manipulation (Friston, Frith,
Liddle, & Frackowiak, 1991). By referring to the probabilistic
behavior of random fields, topological features of the SPM are
assigned adjusted p-values, controlling for the implicit multiple
testing problem that occurs when making inference over the
search space (Adler, 1981; Friston, Holmes, Poline, Price, &
Frith, 1996; Friston, Worsley, Frackowiak, Mazziotta, & Evans,
1994; Worsley, Evans, Marrett, & Neelin, 1992; Worsley et al.,
1996).
Multiple Testing
If one knows precisely where to look in the search space,
inference can be based on the value of the statistic at the
specific location in the SPM (sometimes referred to as the
uncorrected p-value). Otherwise, an adjustment for multiple
dependent testing has to be made to the p-values (Hochberg &
Tamhane, 1987). One such adjustment is to control for the
familywise error rate (FWER), that is, the rate of making one or
more false-positive declarations over the search space (Nichols
& Hayasaka, 2003).
A standard approach in the context of discrete statistical
tests is the Bonferroni correction (Shaffer, 1995). There is,
however, a fundamental difference between an SPM and a
collection of discrete statistic values. The data we consider
here are images that can be treated as discrete sampling from
a continuous function of some underlying support. The activation or effect of interest corresponds to some topological
feature of this function. This can be a peak (a local maximum)
or a cluster (a connected component of the excursion set above
some threshold). By doing so, we convert a continuous process
http://dx.doi.org/10.1016/B978-0-12-397025-1.00322-5
495
496
(a)
(b)
(c)
Figure 1 Illustration of the Euler characteristic (EC) heuristic. A two-dimensional Gaussian random field is displayed as a three-dimensional
surface where color is a function of amplitude. The excursion set for increasing thresholds (depicted as a blue plane) is represented underneath.
(a) Intuitively, the EC is counting the number of blobs minus the number of holes; (b) at high threshold, the EC counts the number of blobs; (c) at very
high threshold, the EC is zero or one.
[3]
LD S det Ls1=2 ds 4 log 2D=2 reselD S
497
EC density
rd(u) is the dth EC density of the random field T(s) above u. It
corresponds to the concentration of events (excursion or
peaks) per resel. It depends on the type of statistic and threshold, but not on the geometry and smoothness. Closed-form
expressions for the EC density are available for all univariate
(Adler, 1981; Worsley, 1994; Worsley et al., 1996) and multivariate (Carbonell, Worsley, & Galan, 2008; Worsley et al.,
2004) statistics in common use. An example of the EC densities
for a t-statistic in three dimensions is given in Table 1.
Table 1
Intrinsic volumes of a ball S of radius r and EC densities for a t-statistic random field with n degrees of freedom in three dimensions (D 3).
Ft denotes the cumulative density function for the statistic in question, t here. G is the gamma function
md(S)
d
0
1
2
3
rd(u)
1 Ft(u)
2 n1=2
2p1 1 un
Gn1
2 n1=2
2
2p3=2
u 1 un
n=21=2 Gn=2
n1=2
u2
2
2p2 n1
n u 1 1 n
498
RFT Assumptions
The component (error) fields conform to a reasonable lattice approximation of an underlying random field with a
multivariate Gaussian distribution.
These fields are continuous, with an autocorrelation function twice differentiable at the origin (not necessarily
Gaussian).
Levels of Inference
A General Formulation
Under the assumptions of the Poisson clumping heuristic
(Aldous, 1989), connected components can be viewed as
clumps centered at points of a multidimensional Poisson process. Building on the results presented in the preceding text,
this allows us to construct a general expression for the probability of observing c or more clusters with k or more resels
above a threshold u in an SPM (Friston et al., 1996):
Xc1
u; k; c 1
Poisi, c0 :K u k
[5]
i0
where c0 is the expected number of maxima, approximated by
the expected EC (Eqn [2]), and Pois(.; l) is the Poisson probability density function with mean l. An intuitive interpretation
of Eqn [5] is as follows: consider clusters as rare events that
occur in a volume according to a Poisson distribution with
u; k; 1 1 exp c0 :K u k c0 :K u k
[6]
Peak-level inference: the height of maxima within that cluster. This is a special case of cluster-level inference that
results when the cluster can be small (i.e., k 0):
u; 0; 1 1 exp c0 c0
[7]
499
Chumbley et al., 2010) and therefore still relies on the distributional results from the RFT, as opposed to controlling the
FDR of point tests (e.g., t-tests at each voxel or vertex)
(Genovese, Lazar, & Nichols, 2002).
Topological inference is nowadays a standard practice in
the analysis of imaging modalities such as functional magnetic
resonance imaging (fMRI) and positron emission tomography
(PET) (Nichols, 2012) and electroencephalography (EEG)
and magnetoencephalography (MEG) (Kilner & Friston,
2010; Kilner, Kiebel, & Friston, 2005). Interestingly, thanks
to the generality of the RFT and its suitability to any type
of smooth data lying on a manifold, it has also found applications in numerous fields such as cosmology (Worsley, 1995),
meteorology (Worsley, 2002), and pedobarography (Pataky,
2008).
Final Remarks
RFT can be adopted in any situation in which one would
normally perform parametric statistical tests, such as t- or
F-tests. When these cannot be used, for example, when the
errors are not normally distributed, the requisite null distribution of the maximum statistic can be estimated using nonparametric procedures, such as resampling (Hayasaka & Nichols,
2003; Maris & Oostenveld, 2007; Nichols & Holmes, 2002).
Permutation methods also offer substantial improvements
over the RFT for extreme situations such as low smoothness
or low degrees of freedom (Nichols & Hayasaka, 2003). In such
settings, a Bonferroni correction can be used as a safeguard for
overconservativeness of the RFT.
Note that we have here focused on the use of the RFT for
controlling the FWER of topological features in statistical
maps; similar ideas can also be used to control the false discovery rate (FDR) (Benjamini & Hochberg, 1995). Crucially,
topological FDR controls for the expected FDR of features
(such as peaks or clusters) (Chumbley & Friston, 2009;
References
Adler, R. J. (1981). The geometry of random fields. New York: Wiley.
Adler, R. J., & Hasofer, A. M. (1976). Level crossings for random fields. The Annals of
Probability, 4(1), 112.
Adler, R. J., & Taylor, J. E. (2007). Random fields and geometry. New York: Springer.
Aldous, D. J. (1989). Probability approximations via the Poisson clumping heuristic.
New York: Springer-Verlag.
Ashburner, J., & Friston, K. J. (2000). Voxel-based morphometry The methods.
NeuroImage, 11(6 Pt 1), 805821.
Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: A practical
and powerful approach to multiple testing. Journal of the Royal Statistical Society:
Series B Methodological, 57(1), 289300.
Bullmore, E. T., Suckling, J., Overmeyer, S., Rabe-Hesketh, S., Taylor, E., &
Brammer, M. J. (1999). Global, voxel, and cluster tests, by theory and permutation,
for a difference between two groups of structural MR images of the brain. IEEE
Transactions on Medical Imaging, 18(1), 3242.
Cao, J. (1999). The size of the connected components of excursion sets of w2, t and F
fields. Advances in Applied Probability, 31(3), 579595.
Cao, J., & Worsley, K. J. (2001). Applications of random fields in human brain
mapping. In M. Moore (Ed.), Spatial statistics: Methodological aspects and
applications (pp. 169182). New York: Springer.
Carbonell, F., Worsley, K. J., & Galan, L. (2008). The geometry of the Wilkss L random
field. Annals of the Institute of Statistical Mathematics, 63(1), 127.
Chumbley, J., & Friston, K. J. (2009). False discovery rate revisited: FDR
and topological inference using Gaussian random fields. NeuroImage, 44(1),
6270.
Chumbley, J., Worsley, K. J., Flandin, G., & Friston, K. J. (2010). Topological FDR for
neuroimaging. NeuroImage, 49(4), 30573064.
Flandin, G., & Friston, K. J. (2008). Scholarpedia, 3(4), 6232.
Forman, S. D., Cohen, J. D., Fitzgerald, M., Eddy, W. F., Mintun, M. A., & Noll, D. C.
(1995). Improved assessment of significant activation in functional magnetic
resonance imaging (fMRI): Use of a cluster-size threshold. Magnetic Resonance in
Medicine, 33(5), 636647.
Friston, K. J. (1997). Testing for anatomically specified regional effects. Human Brain
Mapping, 5(2), 133136.
Friston, K. J. (2007). Statistical parametric mapping: The analysis of functional brain
images. Amsterdam/Boston, MA: Elsevier/Academic Press.
Friston, K. J., Frith, C. D., Liddle, P. F., & Frackowiak, R. S.J (1991). Comparing
functional (PET) images: The assessment of significant change. Journal of Cerebral
Blood Flow & Metabolism, 11(4), 690699.
Friston, K. J., Holmes, A., Poline, J. B., Price, C. J., & Frith, C. D. (1996). Detecting
activations in PET and fMRI: Levels of inference and power. NeuroImage, 4(3),
223235.
500
Friston, K. J., Holmes, A. P., Worsley, K. J., Poline, J.-B., Frith, C. D., &
Frackowiak, R. S. J. (1995). Statistical parametric maps in functional imaging: A
general linear approach. Human Brain Mapping, 2(4), 189210.
Friston, K. J., Worsley, K. J., Frackowiak, R. S.J, Mazziotta, J. C., & Evans, A. C. (1994).
Assessing the significance of focal activations using their spatial extent. Human
Brain Mapping, 1(3), 210220.
Genovese, C. R., Lazar, N. A., & Nichols, T. N. (2002). Thresholding of statistical maps
in functional neuroimaging using the false discovery rate. NeuroImage, 15(4),
870878.
Hasofer, A. M. (1978). Upcrossings of random fields. Advances in Applied Probability,
10, 14.
Hayasaka, S., & Nichols, T. E. (2003). Validating cluster size inference: Random field
and permutation methods. NeuroImage, 20(4), 23432356.
Hayasaka, S., Phan, K. L., Liberzon, I., Worsley, K. J., & Nichols, T. E. (2004).
Nonstationary cluster-size inference with random field and permutation methods.
NeuroImage, 22(2), 676687.
Hochberg, Y., & Tamhane, A. C. (1987). Multiple comparison procedures. New York:
Wiley.
Kiebel, S. J., Poline, J. B., Friston, K. J., Holmes, A. P., & Worsley, K. J. (1999). Robust
smoothness estimation in statistical parametric maps using standardized residuals
from the general linear model. NeuroImage, 10(6), 756766.
Kilner, J. M., & Friston, K. J. (2010). Topological inference for EEG and MEG. Annals of
Applied Statistics, 4(3), 12721290.
Kilner, J. M., Kiebel, S. J., & Friston, K. J. (2005). Applications of random field theory to
electrophysiology. Neuroscience Letters, 374(3), 174178.
Maris, E., & Oostenveld, R. (2007). Nonparametric statistical testing of EEG- and MEGdata. Journal of Neuroscience Methods, 164(1), 177190.
Nichols, T. E. (2012). Multiple testing corrections, nonparametric methods, and random
field theory. NeuroImage, 62(2), 811815.
Nichols, T. E., & Hayasaka, S. (2003). Controlling the familywise error rate in functional
neuroimaging: A comparative review. Statistical Methods in Medical Research,
12(5), 419446.
Nichols, T. E., & Holmes, A. P. (2002). Nonparametric permutation tests for functional
neuroimaging: A primer with examples. Human Brain Mapping, 15(1), 125.
Nosko, V. P. (1969). Local structure of Gaussian random fields in the vicinity of high
level shines. Soviet Mathematics Doklady, 10, 14811484.
Pataky, T. C. (2008). Assessing the significance of pedobarographic signals using
random field theory. Journal of Biomechanics, 41(11), 24652473.
Poline, J. B., & Mazoyer, B. M. (1994). Analysis of individual brain activation maps
using hierarchical description and multiscale detection. IEEE Transactions on
Medical Imaging, 13(4), 702710.
Poline, J. B., Worsley, K. J., Evans, A. C., & Friston, K. J. (1997). Combining spatial
extent and peak intensity to test for activations in functional imaging. NeuroImage,
5(2), 8396.
Ridgway, G. R., Henley, S. M.D, Rohrer, J. D., Scahill, R. I., Warren, J. D., & Fox, N. C.
(2008). Ten simple rules for reporting voxel-based morphometry studies.
NeuroImage, 40(4), 14291435.
Roland, P. E., Levin, B., Kawashima, R., & Akerman, S. (1993). Three-dimensional
analysis of clustered voxels in 15O-butanol brain activation images. Human Brain
Mapping, 1(1), 319.
Salmond, C. H., Ashburner, J., Vargha-Khadem, F., Connelly, A., Gadian, D. G., &
Friston, K. J. (2002). Distributional assumptions in voxel-based morphometry.
NeuroImage, 17(2), 10271030.
Relevant Websites
Neuroimaging software implementing topological inference using random
field theory
http://www.math.mcgill.ca/keith/fmristat FMRISTAT.
http://fsl.fmrib.ox.ac.uk FSL.
http://nipy.org NIPY.
http://www.fil.ion.ucl.ac.uk/spm SPM.
http://www.math.mcgill.ca/keith/surfstat SurfStat.
Glossary
http://dx.doi.org/10.1016/B978-0-12-397025-1.00323-7
501
502
Type I
error rate
Type II
error rate
Threshold
from the test statistics, which can be used to perform the test at
any specified level.).
Figure 1 illustrates this trade-off. It shows the sampling
distribution of the test statistic under both a null and alternative model and a choice of significance level, with the probabilities of false discovery (type I error) and false nondiscovery
(type II error) depicted as shaded areas under the corresponding distributions. These probabilities vary with both a and the
difficulty of distinguishing between null and alternative distributions (e.g., the separation between the two distributions in
the figure).
In practice, the problem of performing a single hypothesis
test reduces to a problem of error control. (It should be noted
that the description of hypothesis testing here is based on the
frequentist paradigm. The Bayesian approach to statistics leads
to a different perspective on testing.) It is true that the resolving
power of a hypothesis test can be improved by increasing the
amount of data used, by reducing the intrinsic variability
(noise) in the measurements, and sometimes by choosing
a more effective test statistic. But for a given data set and in a
common situation where good tests have been constructed
(e.g., t-test for comparing group means), a practitioners only
real choice is how to balance the two types of errors, with the
choice of mediating the trade-off between false discoveries
and false nondiscoveries.
However, it is rare for a practitioner to need only a single
hypothesis test, and error control becomes much more complicated when performing many tests simultaneously. Consider, for instance, the case in functional neuroimaging where
we want to test for a treatment effect at each voxel in some
region of interest. A test of the null hypothesis that no voxels
exhibit a treatment effect is of some interest but limited usefulness. There are many interesting alternatives to the null
hypothesis (corresponding to nonzero effects at different combinations of voxels), but a single hypothesis test does not
distinguish among them. Instead, we can perform a test at
each voxel of the null hypothesis that the signal at that voxel
exhibits no treatment effect. Controlling the error rate for each
test in isolation will lead to an effective error rate that scales
with the number of tests performed. So we need an error
control strategy for the individual tests that guarantees control
of some measure of error for the combined inference. Ideally,
this strategy would account for statistical dependence among
the test statistics and structural relations (e.g., spatial contiguity) among the inferences. This is the multiple-testing problem.
As an illustration of the problem, consider m simultaneous
level a tests with test statistics that are statistically independent.
Then, under the null hypothesis for every test, the probability
that there will at least one false discovery among the m tests is
no bigger than 1 (1 a)m, which is approximately ma when a
is small. When a 0.05 and m 1000, the probability of a false
discovery is close to 1 when all the null hypotheses are true,
and the expected number of false discoveries is 50. Setting
a 5.13 105 0.05/1000 reduces the probability of false
discoveries to 0.05. Thus, controlling the combined measure
of error requires a much more stringent threshold for surprise
in the individual tests, with a consequent loss of power for
detecting small deviations from the null hypotheses. Traditional approaches to error control in multiple testing have
centered on maximizing detection power while guaranteeing
control of the probability of making any errors.
Benjamini and Hochberg (BH) (1995) introduced a new
criterion for control the false discovery rate (FDR) which is
the expected portion of rejected null hypotheses that were false
rejected. This allows a multiple-testing strategy to increase
detection power while maintaining principled control of a
combined error measure. BH also introduced a simple method
that guarantees control of FDR under certain assumptions (see
Genovese, Lazar, & Nichols, 2002 for a neuroimaging-focused
review).
Figure 2 illustrates the difference between traditional error
control and FDR error control on the same data. Each panel
shows the results of tests for 20 batches of data. Every batch
contains 1000 points independently drawn from a Gaussian
whose mean increases toward the center of the gray circle and
is zero outside it. The points shown for each batch are those for
which the null hypothesis of zero mean is rejected. The traditional (familywise) control correctly captures points near the
middle of the circle where the signal is highest and, with one
exception, correctly ignores points outside the gray signal
where the signal is truly zero. But it misses most of the points
on the margin of the circle where the signal is weaker but
potentially interesting. In contrast, FDR control not only captures points all the way toward the edges of the circle but also
incorrectly captures a small portion of points outside the circle.
Both the traditional and the BH approaches will be discussed
in detail in the ensuing sections.
503
Figure 2 Tests were performed on 20 batches of data using both a traditional familywise error-controlling procedure and an FDR-controlling
procedure. In each batch, 1000 test statistics are drawn from normal distributions with means corresponding to their location on the plot. Points outside
the gray circle have mean 0 (no signal); points inside the circle have mean rising smoothly as their position moves closer to the center. The points
shown correspond to rejected null hypotheses.
Table 1
Breakdown of m hypothesis tests according to whether the
null hypothesis is true or false and whether the null hypothesis is rejected
or retained
Null hypothesis
true
Null hypothesis
false
Total
Null hypothesis
rejected
Null hypothesis
retained
Total
m0 V
m0
m m0 S
m m0
mR
For any i, let Hi and H(i) denote the null hypothesis corresponding to Pi and P(i), respectively.
The most often considered traditional criteria for error control are
1. familywise error rate (FWER), {V 1}, the probability of
at least one false discovery;
2. per-family error rate (PFER), V , the expected number of
false discoveries; and
3. per-comparison error rate (PCER), V =m, the proportion
of false discoveries relative to the total number of tests.
These rates satisfy PCER FWER PFE. While arguments have
been made for controlling all of these rates, FWER is the most
commonly used and will be the focus here. See Hochberg and
Tamhane (1987) and Shaffer (1995) for a discussion of the
relative merits of the criteria and of the meaning of a family of
tests. See also Nichols and Hayasaka (2003) for a review of
FWER control in neuroimaging.
FWER is a stringent criterion, requiring a small probability
of any false discoveries no matter how many tests are performed. This is a valuable guarantee, but it makes detection
power a primary concern. This has spurred the search for FWERcontrolling procedures that improve power, both for general
504
V
;
min R, 1
[1]
which gives 0 FDR 1 with FDR 0 when no null hypotheses are rejected. Comparing the FWER and FDR criteria shows
how FDR control can achieve more power at the cost of more
type I errors. While a small FWER ensures that V 0 with high
probability, a small FDR allows V to be large as long as (on
average) the number of rejections is substantially larger. Metaphorically, FWER control yields smaller servings of wheat
nearly free of chaff, while FDR control yields a larger serving
of wheat with some but not too much chaff mixed in.
The expectation in the definition [1] makes FDR a population quantity. In particular, knowing that FDR a means that if
one were to repeat the tests every day with new data (but the
same configuration of true and false null hypotheses), the
proportions of false discoveries relative to the number of rejections would average approximately a over many days. For any
specific data set, the proportion could be higher or lower than
the controlled level.
The BH Procedure
Building on the observations of Simes (1986), BH developed a
procedure for controlling FDR at a specified level under some
assumptions about the dependence of the tests. The procedure
is computationally simple: reject all Hi for which Pi TBH,
where
i
TBH max Pi : Pi a , for 0 i m
[2]
m
defining P(0) 0.
BH proved that for independent test statistics, this procedure guarantees
FDR
m0
a
m
[3]
1 at
Gt
[4]
[5]
505
dependence structure and can be extended to tail-control criteria, but the theory behind it is only asymptotic.
Tail control. An alternative to controlling the expectation of
V/min(R,
1) is to
n
o control the probability that this ratio is large,
V
> c for a specified c. Methods for controlling this
min R, 1
measure were introduced by Genovese and Wasserman (2004)
and Dudoit, Van Der Laan, and Pollard (2004), and such
tail control has received substantial attention in the literature
(Genovese & Wasserman, 2004, 2006; Guo, He, & Sarkar,
2014; Guo & Rao, 2010; Guo & Roman, 2007; Hommel &
Hoffmann, 1987; Lehman & Romano, 2005; Romano &
Shaikh, 2006).
False nondiscovery rate. Analogous to type II error, a complement to the FDR is the false nondiscovery rate where
m m0 S=m R is the proportion of incorrectly retained
null hypotheses relative to the total number of retained nulls.
This was introduced in Genovese and Wassermann (2002)
with the goal of choosing a threshold that minimizes this rate
subject to specified control of FDR. The criterion has been the
subject of active study, including Genovese and Wasserman
(2004), Jichun Xie, Cai, Maris, and Li (2011), Sarkar (2002,
2007), and Sun and Cai (2007).
Positive FDR. Storey (2002, 2003) introduced (and developed a method to control) an alternative error criterion called the
positive false discovery rate (pFDR). The pFDR is defined by
V
R > 0
[6]
pFDR
min R, 1
and is related to the FDR by FDR pFDR {R > 0}. The pFDR
has a nice Bayesian interpretation: assuming that all null
hypotheses have the same prior probability of being true, the
pFDR is the posterior probability of an incorrect rejection of a
null hypothesis.
Local FDR. Building on the two-group model for p-values
described earlier, Efron et al. (2001) introduced the local FDR
as an alternative criterion where FDR is based on distribution
functions (recall FDR(t) (1 a)t/G(t)), or equivalently tail
areas, derived from the null and marginal test-statistic density
functions, which are more difficult to estimate. The local FDR
is an empirical Bayesian posterior probability of a true null
given the observed test statistic and thus has the advantage of
ease of interpretation and amenability to theoretical analysis.
Empirical null distributions. Efron (2004, 2007a, 2007b)
pointed out that in many large-scale studies, the theoretical
null distribution of the test statistics is misspecified, due, for
instance, to hidden dependencies, artifacts, and other factors.
This bias can adversely affect the performance of multipletesting methods. These papers describe an empirical Bayesian
approach to multiple testing that involves estimating the null
distribution and using the estimated null distribution for testing. While this necessarily involves some loss of power relative
to the theoretical ideal, it improves performance relative to the
case where the theoretical null is significantly misspecified.
Schwartzman (2008) extended empirical-null procedures to
general exponential-family distributions.
Spatial contiguity and random fields. In many applications,
most notably functional neuroimaging, the unit of testing (e.g.,
the voxel) is not the same as the unit of inference (e.g., the
region). Control of voxelwise error measures such as FDR need
not relate in a simple way to the corresponding regional error
506
Conclusions
Procedures for controlling FDR in multiple testing provide a
principled way to improve detection power and are useful in
large-scale testing regimes like those found in functional neuroimaging. The standard BenjaminiHochberg method is a
computationally simple and broadly applicable procedure
that performs well in variety of realistic situations. Substantial
research has extended this procedure in a variety of ways to
handle alternative dependence structures, increase power with
multistage decisions, and provide alternative error measures
that may be relevant to practitioners. Extensions beyond simple p-value-based rules promise further improvements in statistical efficiency and the ability to target new kinds of
dependence structures in data.
References
Benjamini, Y., & Heller, R. (2007). False discovery rates for spatial signals. Journal of
the Acoustical Society of America, 102, 12721281.
Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: A practical
and powerful approach to multiple testing. Journal of the Royal Statistical Society,
Series B: Statistical Methodology, 57(1), 289300.
Benjamini, Y., & Hochberg, Y. (2000). The adaptive control of the false discovery rate in
multiple comparison problems. Journal of Educational and Behavioral Statistics,
25(1), 6083.
Benjamini, Y., Krieger, A. M., & Yekutieli, D. (2006). Adaptive linear step-up procedures
that control the false discovery rate. Biometrika, 93(3), 491507.
Benjamini, Y., & Yekutieli, D. (2001). The control of the false discovery rate in multiple
testing under dependency. Annals of Statistics, 29, 11651188.
Chumbley, J. R., & Friston, K. J. (2009). False discovery rate revisited: FDR and
topological inference using Gaussian random fields. NeuroImage, 44, 6270.
Donoho, D., & Jin, J. (2008). Higher criticism thresholding: Optimal feature selection
when useful features are rare and weak. Proceedings of the National Academy of
Sciences, 105(32), 1479014795.
Dudoit, S., Van Der Laan, M., & Pollard, K. (2004). Multiple testing. I. Single-step
procedures for the control of general type I error rates. Statistical Applications in
Genetics and Molecular Biology, 3, 1041, Available at www.bepress.com/sagmb/
vol3/iss1/art13.MR2101462.
Efron, B. (2004). Large-scale simultaneous hypothesis testing: The choice of a null
hypothesis. Journal of the Acoustical Society of America, 99(465), 96104.
Efron, B. (2007a). Correlation and large-scale simultaneous significance testing.
Journal of the Acoustical Society of America, 102, 93103.
Efron, B. (2007b). Size, power, and false discovery rates. Annals of Statistics, 35(4),
13511377.
Efron, B., Tibshirani, R., Storey, J., & Tusher, V. (2001). Empirical Bayes analysis of a
microarray experiment. Journal of the Acoustical Society of America, 96,
11511160.
Finner, H., Dickhaus, T., & Roters, M. (2007). Dependency and false discovery rate:
Asymptotics. Annals of Statistics, 35(4), 14321455.
Finner, H., & Roters, M. (2002). Multiple hypotheses testing and expected number of
type I errors. Annals of Statistics, 30, 220238.
Forman, S. D., Cohen, J. D., Fitzgerald, M., Eddy, W. F., Mintun, M. A., & Noll, D. C.
(1995). Improved assessment of significant activation in functional magnetic
resonance imaging (fMRI): Use of a cluster-size threshold. Magnetic Resonance in
Medicine, 33, 636647.
Friedenberg, D. A., & Genovese, C. R. (2013). Straight to the source: Detecting
aggregate objects in astronomical images with proper error control. Journal of the
American Statistical Association, 108(502), 456468.
Genovese, C. R., Lazar, N. A., & Nichols, T. E. (2002). Thresholding of statistical maps
in functional neuroimaging using the false discovery rate. NeuroImage, 15,
870878.
Genovese, C., & Wasserman, L. (2002). Operating characteristics and extensions of the
false discovery rate procedure. Journal of the Royal Statistical Society, Series B:
Statistical Methodology, 64, 499517.
Genovese, C., & Wasserman, L. (2004). A stochastic process approach to false
discovery control. Annals of Statistics, 32, 10351061.
Genovese, C. R., & Wasserman, L. (2006). Exceedance control for the false discovery
proportion. Annals of Statistics, 101(476), 14081417.
Guo, W., He, L., & Sarkar, S. K. (2014). Further results on controlling the false
discovery proportion. Annals of Statistics, 42, 10701101.
Guo, W., & Rao, M. B. (2008). On control of the false discovery rate under no
assumption of dependency. Journal of Statistical Planning and Inference, 138,
31763188.
Guo, W., & Rao, M. (2010). On stepwise control of the generalized familywise error rate.
Electronic Journal of Statistics, 4, 472485.
Guo, W., & Romano, J. (2007). A generalized Sidak-Holm procedure and control of
generalized error rates under independence. Statistical Applications in Genetics and
Molecular Biology, 6(1).
Heller, R., Stanley, D., Yekutieli, D., Rubin, N., & Benjamini, Y. (2006). NeuroImage, 33,
599608.
507
Introduction
What is the unique perspective that Bayes has to offer, when
compared with the widely used classical approaches? As
Kershaw et al. (1999) put it: With [Bayesian] methodology it
is possible to derive a relevant statistical test for activation in an
fMRI time series no matter how complicated the parameters of
the model are. The derivation is usually quite straightforward
and results may be extracted from it without first having to find
estimates for all of the parameters. In other words, Bayes
provides you with a mathematically principled framework, in
which you can probabilistically infer on model parameters no
matter what, or how complicated, the model is.
In this article, we will explore how Bayes provides a framework within which we can attempt to infer on models of
neuroimaging data while allowing us to incorporate our prior
knowledge of the brain and the neuroimaging equipment in
the form of biophysically informed or regularizing priors. It
allows us to extract probabilistic information from the data, for
example, calculate confidence measures for our estimates, and
can be used to combine information from multiple modalities.
Bayes can also be used to compare and select between models.
Bayes Inference
Bayes provides the only generic framework for the adjustment
of belief (in the form of probability density functions (PDFs))
in the presence of new information (Cox, 1946). It gives us a
tool for inferring on any model we choose and guarantees that
uncertainty will be handled correctly.
Bayes rule tells us how (for a model M, with model parameters Y) we should use the data, Y, to update our prior belief in
the values of the parameters, p(Y|M), to get a posterior distribution of the parameter values, p(Y|Y, M):
pYjY, M
Generative Models
In a typical neuroimaging scenario, we are looking to extract
some pertinent information about the brain from noisy data.
Mapping measured data to brain characteristics is generally
difficult to do directly. For example, since fMRI data are
noisy, we cannot directly set up a rule that states, If the fMRI
data look exactly like X, then the brain is definitely active in area
Y. However, it is comparatively easy to turn the problem
around and specify, If the brain is active in area Y, then the
fMRI data should look like X, that is, if we know what the
brain is doing, then we can predict what our neuroimaging
data should look like. This is what we refer to as a generative
model, which sits at the heart of all Bayesian neuroimaging
analysis methods. Figure 1 illustrates an example of a generative model for predicting task fMRI data using linear convolution of a known stimulus time course with a parameterized
hemodynamic response function (HRF).
Generative models are a natural way for us to incorporate
our understanding of the brain and of different neuroimaging
modalities to make predictions about what neuroimaging data
look like. However, in practice, we want to do the opposite. We
want to be able to take acquired data and, using a generative
model, extract pertinent information about the brain (i.e.,
infer on the model and its parameters). The classical approach
to doing this is to fit the generative models to the data, for
example, by minimizing the squared difference between the
data and the generative model to estimate each of the model
parameters. (This approach assumes that the noise is Gaussian,
pYjY, MpYjM
pYjM
[1]
The term p(Y|Y, M) is the likelihood and typically corresponds to the generative model. The numerator in this equation, p(Y|M), is the model evidence, which can be ignored when
inferring on the model parameters, but, as we shall see later,
can come into play when performing model selection.
Often in neuroimaging, data from different voxels are considered to be conditionally independent, that is, conditioned
on the parameters, the data are independent across voxels. This
means that the likelihood can be factorized over voxels:
Y
pY i jYi , M
pYjY, M
i
[2]
pYjM pYjY, MpYjM dY
Y
http://dx.doi.org/10.1016/B978-0-12-397025-1.00325-0
509
510
Generative model
Convolved
with
Gaussian
noise
m
Haemodynamic
response function
m=6s
h=1
Predicited data
Stimulus
time-course
m=9s
h=1
Predicited data
Figure 1 Generative models are at the core of all Bayesian neuroimaging analysis techniques. This figure shows an example of a simple voxelwise
generative model for predicting fMRI data. It consists of an HRF parameterized using the time-to-peak, m, and the height, h. The HRF is convolved
with a time course of the known experimental stimulus (in this case a boxcar stimulus) and then added to Gaussian noise. For the sake of
simplicity, we are assuming that the variance of the Gaussian noise is known. The only unknown parameters in the model are m and h. For
different values for m and h, we can predict what the fMRI data look like in a voxel.
Point Estimation
One approximate method for getting a posterior distribution
on the parameters of interest is by conditioning on the estimates of the other nuisance parameters, YI. This requires
that you have a way of getting point estimates of the nuisance
^ I . Typically, point estimates are obtained using
parameters, Y
techniques such as maximum likelihood, maximum a posteriori, or a maximum marginal likelihood (evidence optimization) approach. The conditional posterior on the parameters of
interest is then given by
^ I , M p YjYI , YI Y
^ I , M
p YI jY, YI Y
^ I
p YI jM, YI Y
[3]
Crucially, these point estimation approaches do not incorporate the uncertainty we have in the nuisance parameters into
the uncertainty we have in the parameters of interest, whereas
marginalization does.
Marginalization
The principled way for getting posteriors on the parameters of
interest is to integrate over the nuisance parameters; this is the
process of marginalization in order to obtain marginal posterior
distributions. This incorporates the uncertainty there is in the
unknown nuisance parameters into the uncertainty we have in
the parameters of interest. This fully Bayesian approach is the
one we will focus on in this article.
The downside of obtaining marginal posterior distributions
is that it involves performing often complicated, highdimensional integrals, that is,
pYI jY, M
pYjY, M dYI
[4]
YI
where YI are the parameters of interest and YI are all other
parameters. As with obtaining the model evidence, these integrals are seldom tractable analytically. But as we shall see later,
this can be handled with approximations and numerical integration techniques.
511
P (h)
P (m)
Priors
3 2 1 0
h (a.u.)
10
12
m (s)
Acquired data, Y
Generative
model
Likelihood P(Y|m,h)
ye
Ba
10
10
2
3
P(mly)
P(hly)
h (a.u.)
m (s)
12
Marginal posterior
12
m (s)
h (a.u.)
Marginal posterior
Figure 2 Schematic of the process of Bayesian inference on the generative model in Figure 3. The ingredients consist of the acquired fMRI data, the
generative model, and the priors. The generative model provides us with the likelihood term in Bayes rule. Bayes combines these ingredients to
give us probabilistic inference on the model parameters in the form of the joint posterior distribution across all parameters in the model. However, we are
often interested in the posterior distribution on a single parameter or a subset of parameters. This can be obtained by integrating (i.e., averaging)
over parameters to obtain the marginal distribution.
parameters. For example, in the example here (fitting a Gaussian), if we integrate over log(b) rather than b, then the Jeffreys
prior, p(log(b)), becomes uniform, but the posterior distribution is unchanged):
pm; b 1=b
[6]
where
1X
Yi
N i
X
S
Y i x2
x
512
[8]
1
0
N
b 2 1 Y
2pN=2
b
exp Y i m2 db
2
This integral can be solved analytically and results in a noncentral t-distribution (see Appendix)
pmjY, M T m; x, S=N 1, n
where n is the degrees of freedom:
nN1
Note that this is an alternative, more accurate reflection of
the posterior distribution over the mean m than can be
obtained using the conditional posterior approach from
eqn [7]. Most notably, the mean is now distributed as a
t-distribution with an increased fatness in its tails (where
lower degrees of freedom results in fatter tails) compared to
a normal distribution; this reflects the extra uncertainty we
have on m given the uncertainty in b. In contrast, the conditional posterior approach from eqn [7] is just a normal distribution, by virtue of not taking the uncertainty in b into
account.
Grid Enumeration
This is a brute force method, only useful for low-dimensional
parameter spaces (i.e., models with low numbers of unknown
parameters). As a rough rule of thumb, it can work up to about
P 6 model parameters (depending on the ease of computation of the generative model), but beyond this, the curse of
dimensionality kicks in, rendering it computationally impractical. In practical neuroimage analysis, it is rarely the case that
this is appropriate. However, we include it here as it is an
excellent toy inference method to play with, and putting the
size of the parameter space aside, it can be used with any
generative model.
The method simply amounts to setting up an appropriate Pdimensional grid for all possible values of your P model
parameters within appropriate ranges. For continuous variables (e.g., the mean of a Gaussian distribution), this requires
the continuous space to be discretized. The unnormalized joint
posterior can then be calculated exhaustively at every point in
the discrete grid.
For example, consider a model with P 2 continuous
parameters, y and l. These can be discretized within appropriate ranges and with appropriate coarseness to give yi and lj,
where i and j index the grid points. We can then compute the
unnormalized joint posterior, Qij, at every grid point using
eqn [8]. Crucially, computing the unnormalized joint posterior
is fairly easy, because it does not require the difficult integration implicit in computing the normalization constant or
model evidence. The normalized joint posterior distribution is
then obtained by
Qij
p y yi , l lj jY X
Q
ij ij
and the marginal posterior distribution for y is given by (with
an analogous expression for l)
X
Q
j ij
py yi jY X
Q
ij ij
513
Accuracy
Speed
Numerical integrat on
Posterior approximation
Conjugate priors?
Yes
Full
evaluation
Rejection
sampling
MCMC
Variational
bayes
No
Variational
laplace
Figure 3 The use of Bayes requires integrations to be performed that are seldom tractable, in which case there are broadly speaking two separate
approaches used: (1) solve the integrals numerically and (2) make approximations to the posterior distribution.
Numerical Integration
Sampling methods draw samples in parameter space from the
joint posterior distribution, implicitly performing the integrals
numerically. For example, we may repetitively choose random
sets of parameter values and choose to accept or reject these
samples according to a criterion based on the value of the
numerator in eqn [1]. Examples of schemes such as this are
rejection sampling and importance sampling (Gamerman,
1997). However, these kinds of sampling schemes tend to be
very slow, particularly in high-dimensional parameter spaces,
as samples are proposed at random, and thus, each has a very
small chance of being accepted.
Markov chain Monte Carlo (MCMC; Gilks, Richardson, &
Spiegelhalter, 1996) is a sampling technique that addresses the
problem of having a large number of parameters by proposing
samples preferentially in areas of high probability. Samples
drawn from the posterior are no longer independent of one
another, but the high probability of accepting samples allows
for many samples to be drawn and, in many cases, for the
posterior PDF to be built in a relatively short period of time
(compared with other numerical integration approaches).
While MCMC is a powerful technique that can be used on a
wide variety of models, it is time-consuming when compared
with posterior approximation approaches.
Priors
Bayesian statistics requires that we specify our prior probabilistic belief about the model parameters. This requirement has
often been a source of criticism of the Bayesian approach.
However, Bayesians support the view that we cannot infer
from data without making assumptions; indeed, the act of
choosing a generative model itself constitutes an assumption
(which the model provides a good description of reality). It
turns out that having a framework within which we can specify
prior assumptions can be a big advantage. As we shall see, this
can serve to augment the assumptions already made in the
generative model with complementary knowledge of the
system.
Posterior Approximations
The intention here is to make approximations such that the
integrals become analytically tractable. These approaches generally optimize the posterior PDF with respect to variational
free energy (an upper bound on the log of the model evidence). This tends to be less accurate, but computationally
faster, than numerical integration and typically requires more
work to be done mathematically rather than computationally.
A key issue is whether or not the model has conjugate
priors. Conjugacy exists for a model if the posteriors have the
same distributional form as the prior. If this is the case, then a
technique known as variational Bayes or ensemble learning can
be employed. Typically, this approximates the true posterior
distribution by estimating it using a posterior factorized over
subsets of the model parameters.
However, models are often not conjugate, for example,
when we have nonlinear generative models with additive
Biophysical Priors
Biophysical priors are priors that encode what we understand
as being biologically plausible. For example, we know that a
value of 1.3 s at 3 T for the T1 of gray matter is plausible,
whereas values of 0.3 s and 2.3 s are not. Within Bayes, we
can encode this information in the form of prior PDFs.
Earlier, in Figures 1 and 2, we saw in a fairly simple example how priors could be used to constrain the HRF shape to
have delays that are biologically plausible. In practice, more
complex and more highly parameterized HRF models can be
used. For example, in Woolrich, Behrens, and Smith (2004a),
priors were placed on the basis function regression parameters
such that the variational Bayes inference is constrained to only
those combinations of parameters that give biophysically plausible HRF shapes; and in Friston (2002), Bayesian inference
514
previous in the chain, with the data at the head of the chain
and the priors at the tail.
In brain mapping, one of the best examples of this is in
multisession/subject modeling. Consider a group analysis of
some functional neuroimaging data, Ys (e.g., task M/EEG,
fMRI), for subject s, for which the within-subject generative
model for Ys (the likelihood) is p(Ys|bs, ys), where bs is the effect
size and ys are some (nuisance) model parameters. In the group
analysis, we want to be able to infer a group average (population
average) effect size. To do this, we assume a group-level generative
model in which the population distribution is normally distributed with group mean, B, and between-subject variance, s2B:
pbs jB, sB N bs ; B; s2B
Regularization Priors
p b, y, B, s2B jY pY s jbs , ys pbs jB, sB p y; B; s2B
where b {bs 8 s} and p(y, B, s2B) are the priors. The conditional
probability distributions sandwiched between the first (likelihood) and last (full prior) terms in hierarchical models are
commonly referred to as empirical priors. These can be thought
of as prior beliefs that are conditioned on other unknown
parameters. Inference on the group mean, B, can then be
obtained via marginalization over all of the other model
parameters:
pBjY p b, y, B, s2B jY dbdyds2B
Inference on any individual subjects effect size, bs, can be
obtained in an analogous way. This approach ensures that the
group mean effect size regularizes the individual subject effect
sizes and vice versa, and inference takes into account the
uncertainty on all of the other model parameters. This kind
of hierarchical model has been used to infer upon task fMRI
group analysis (Ahn, Krawitz, Kim, Busmeyer, & Brown, 2011;
Friston et al., 2002a, 2002b; Sanyal & Ferreira, 2012; Woolrich,
Behrens, Beckmann, Jenkinson, & Smith, 2004), to model the
relationship between local (e.g., voxelwise) and global parameters (Chappell et al., 2010; DuBois Bowman, Caffo, Bassett, &
Kilts, 2008; Groves, Beckmann, Smith, & Woolrich, 2011;
Jbabdi, Woolrich, Andersson, & Behrens, 2007), and has
been proposed as general mechanism of how the brain itself
infers information from the environment (Friston, 2008).
Hierarchical models also offer a route to properly handle
inference of multimodal data, using symmetrical generative
models that simultaneously predict the different data modalities (Daunizeau et al., 2007; Groves et al., 2011; Henson,
Mouchlianitis, & Friston, 2009; Luessi, Babacan, Molina,
Booth, & Katsaggelos, 2011; Valdes-Sosa et al., 2009; Woolrich
& Stephan, 2013).
Hierarchical Bayes
A useful concept when constructing generative models is that
of hierarchical Bayes. This corresponds to the idea that an
overall generative model can be broken down into a chain of
subgenerative models, each conditionally dependent on the
515
1 xc1 x
e b
Gc bc
[A1]
x m2
T x; m; s ; n
n 1
1
s2 n
nps2 2 G 2
!n1
2
References
Ahn, W.-Y., Krawitz, A., Kim, W., Busmeyer, J. R., & Brown, J. W. (2011). A modelbased fMRI analysis with hierarchical Bayesian parameter estimation. Journal of
Neuroscience, Psychology, and Economics, 4, 95110.
Bartsch, A., Homola, G., Biller, A., Solymosi, L., & Bendszus, M. (2006). Diagnostic
functional MRI: Illustrated clinical applications and decision-making. Journal of
Magnetic Resonance Imaging, 23, 921932.
Behrens, T. E. J., Berg, H. J., Jbabdi, S., Rushworth, M. F. S., & Woolrich, M. W.
(2007). Probabilistic diffusion tractography with multiple fibre orientations: What
can we gain? Neuroimage, 34, 144155.
Chappell, M. A., Okell, T. W., Jezzard, P., & Woolrich, M. W. (2010). A general
framework for the analysis of vessel encoded arterial spin labeling for vascular
territory mapping. Magnetic Resonance in Medicine, 64, 15291539.
Ciuciu, P., Poline, J.-B., Marrelec, G., Idier, J., Pallier, C., & Benali, H. (2003).
Unsupervised robust nonparametric estimation of the hemodynamic response
function for any fMRI experiment. IEEE Transactions on Medical Imaging, 22,
12351251.
Cox, R. (1946). Probability, frequency, and reasonable expectation. American Journal of
Physics, 14, 110.
Daunizeau, J., Grova, C., Marrelec, G., Mattout, J., Jbabdi, S., Pelegrini-Issac, M., et al.
(2007). Symmetrical event-related EEG/fMRI information fusion in a variational
Bayesian framework. Neuroimage, 36, 6987.
DuBois Bowman, F., Caffo, B., Bassett, S. S., & Kilts, C. (2008). A Bayesian hierarchical
framework for spatial modeling of fMRI data. Neuroimage, 39, 146156.
Flandin, G., & Penny, W. D. (2007). Bayesian fMRI data analysis with sparse spatial
basis function priors Neuroimage, 34, 11081125.
Friston, K. (2002). Bayesian estimation of dynamical systems: An application to fMRI.
Neuroimage, 16, 513530.
Friston, K. (2008). Hierarchical models in the brain. PLOS Computational Biology, 4,
e1000211.
Friston, K. J., Li, B., Daunizeau, J., & Stephan, K. E. (2011). Network discovery with
DCM. Neuroimage, 56, 12021221.
Friston, K., & Penny, W. (2011). Post hoc Bayesian model selection. Neuroimage, 56,
20892099.
Friston, K. J., Penny, W., Phillips, C., Kiebel, S., Hinton, G., & Ashburner, J. (2002a).
Classical and Bayesian inference in neuroimaging: Theory. Neuroimage, 16,
465483.
Friston, K. J., Penny, W., Phillips, C., Kiebel, S., Hinton, G., & Ashburner, J. (2002b).
Classical and Bayesian inference in neuroimaging: Theory. Neuroimage, 16,
465483.
Gamerman, D. (1997). Markov chain Monte Carlo. London: Chapman and Hall.
Gilks, W., Richardson, S., & Spiegelhalter, D. (1996). Markov chain Monte Carlo in
practice. London: Chapman and Hall.
Gossl, C., Auer, D. P., & Fahrmeir, L. (2001). Bayesian spatiotemporal inference in
functional magnetic resonance imaging. Biometrics, 57, 554562.
Goutte, C., Nielsen, F. A., & Hansen, L. K. (2000). Modeling the haemodynamic
response in fMRI using smooth FIR filters. IEEE Transactions on Medical Imaging,
19, 11881201.
Groves, A. R., Beckmann, C. F., Smith, S. M., & Woolrich, M. W. (2011). Linked
independent component analysis for multimodal data fusion. Neuroimage, 54,
21982217.
516
Groves, A., Chappell, M., & Woolrich, M. (2009). Combined spatial and non-spatial
prior for inference on MRI time-series. Neuroimage, 45, 795809.
Harrison, L. M., Penny, W., Ashburner, J., Trujillo-Barreto, N., & Friston, K. J. (2007).
Diffusion-based spatial priors for imaging. Neuroimage, 38, 677695.
Harrison, L., Penny, W., Daunizeau, J., & Friston, K. (2008). Diffusion-based spatial
priors for functional magnetic resonance images. Neuroimage, 41, 408423.
Hartvig, N. V., & Jensen, J. L. (2000). Spatial mixture modeling of fMRI data human
brain mapping, 11, 233248.
Henson, R. N., Mouchlianitis, E., & Friston, K. J. (2009). MEG and EEG data fusion:
Simultaneous localisation of face-evoked responses. Neuroimage, 47, 581589.
Jbabdi, S., Woolrich, M. W., Andersson, J. L.R, & Behrens, T. E.J (2007). A Bayesian
framework for global tractography. Neuroimage, 37, 116129.
Luessi, M., Babacan, S. D., Molina, R., Booth, J. R., & Katsaggelos, A. K. (2011).
Bayesian symmetrical EEG/fMRI fusion with spatially adaptive priors. Neuroimage,
55, 113132.
Mackay, D. (2005a). Information theory, inference, and learning algorithms. Cambridge
University Press, p. 640.
Marrelec, G., Benali, H., Ciuciu, P., Pelegrini-Issac, M., & Poline, J.-B. (2003). Robust
Bayesian estimation of the hemodynamic response function in event-related BOLD
fMRI using basic physiological information. Human Brain Mapping, 19, 117.
Penny, W. D., Stephan, K. E., Mechelli, A., & Friston, K. J. (2004). Comparing dynamic
causal models. Neuroimage, 22, 11571172.
Penny, W. D., Trujillo-Barreto, N. J., & Friston, K. J. (2005). Bayesian fMRI time series
analysis with spatial priors. Neuroimage, 24, 350362.
Sanyal, N., & Ferreira, M. A.R (2012). Bayesian hierarchical multi-subject multiscale
analysis of functional MRI data. Neuroimage, 63, 15191531.
Smith, S. M., Miller, K. L., Salimi-Khorshidi, G., Webster, M., Beckmann, C. F.,
Nichols, T. E., et al. (2011). Network modelling methods for FMRI. Neuroimage, 54,
875891.
Stephan, K. E., Harrison, L. M., Kiebel, S. J., David, O., Penny, W. D., & Friston, K. J.
(2007). Dynamic causal models of neural system dynamics: Current state and future
extensions. Journal of Biosciences, 32, 129144.
Stephan, K. E., Weiskopf, N., Drysdale, P. M., Robinson, P. A., & Friston, K. J. (2007).
Comparing hemodynamic models with DCM. Neuroimage, 38, 387401.
Valdes-Sosa, P. A., Sanchez-Bornot, J. M., Sotero, R. C., Iturria-Medina, Y.,
Aleman-Gomez, Y., Bosch-Bayard, J., et al. (2009). Model driven EEG/fMRI fusion
of brain oscillations. Human Brain Mapping, 30, 27012721.
Wipf, D., & Nagarajan, S. (2009). A unified Bayesian framework for MEG/EEG source
imaging. Neuroimage, 44, 947966.
Woolrich, M. W., & Behrens, T. E. (2006). Variational Bayes inference of spatial
mixture models for segmentation. IEEE Transactions on Medical Imaging, 25,
13801391.
Woolrich, M. W., Behrens, T. E. J., Beckmann, C. F., Jenkinson, M., & Smith, S. M.
(2004). Multilevel linear modelling for FMRI group analysis using Bayesian
inference. Neuroimage, 21, 17321747.
Woolrich, M. W., Behrens, T. E. J., Beckmann, C. F., & Smith, S. M. (2005). Mixture
models with adaptive spatial regularization for segmentation with an application to
FMRI data. IEEE Transactions on Medical Imaging, 24, 111.
Woolrich, M. W., Behrens, T. E. J., & Smith, S. M. (2004). Constrained linear basis sets
for HRF modelling using variational Bayes. Neuroimage, 21, 17481761.
Woolrich, M. W., Jenkinson, M., Brady, J. M., & Smith, S. M. (2004). Fully Bayesian
spatio-temporal modeling of FMRI data. IEEE Transactions on Medical Imaging, 23,
213231.
Woolrich, M., & Stephan, K. (2013). Biophysical network models and the human
connectome. Neuroimage, 80, 330338.
Further Reading
Mackay, D. (2005b). Information Theory, Inference, and Learning Algorithms.
Cambridge University Press In particular chapters: 2.02.3, 3, 24, 27, 28; and for
extra fun: 29,33.
Glossary
Introduction
From a historical perspective, brain research has focused on
identifying functional features, such as perceptual or motor processing, that can be anatomically segregated within the cortex.
This perspective, known as functional specialization, suggests
that experimental manipulation leads to activity changes in,
and only in, certain specialized brain areas. Presently, given the
availability of noninvasive imaging techniques, such as functional magnetic resonance imaging (fMRI), functional specialization studies, or functional brain mapping, typically amount
to the production of three-dimensional images of neuronal activation showing which parts of the brain respond to a given
cognitive or sensory challenge. This procedure is traditionally
based on some form of statistical parametric mapping (SPM).
SPM is a modeling framework used to test hypotheses
about regionally specific effects in the brain, also known as
brain activations (Friston et al., 1995). The idea behind this
framework is quite simple: the data from each and every voxel
are analyzed independently using a general linear model
(GLM) and standard univariate (parametric) statistical tests.
The resulting voxel-wise statistics are assembled into an
image and interpreted as continuous statistical processes, by
referring to the probabilistic behavior of random fields, modeled by random field theory (RFT) (Worsley, Evans, Marrett, &
Neelin, 1992; Worsley et al., 1996).
Classical inferences about the GLM parameter estimates are
made using their estimated variance, allowing one to test the
null hypothesis, that all the estimates are zero, using the
F-statistic or that some particular linear combination (e.g., a
subtraction) of the estimates is zero, using a t-test (Poline,
Holmes, Worsley, & Friston, 1997). The t-statistic obtains by
dividing a contrast vector of the ensuing parameter estimates
by the standard error of that contrast (Poline, 2003). However,
in classical inference, without any a priori anatomical hypothesis, a correction for multiple comparisons over the volume
analyzed is necessary to ensure that the probability of rejecting
http://dx.doi.org/10.1016/B978-0-12-397025-1.00326-2
517
518
Bayesian Inference
In Bayesian inference, prior beliefs about parameters, y, of model,
m, are quantified by the prior density, p(y|m). Inference on the
parameters, y, after observing data, y, is based on the posterior
density, p(y|y, m). These densities are related through Bayes rule:
p yy, m p ym
[1]
pyj y,m
p ym
where p(y|y, m) is the probability of the data (likelihood)
conditioned upon the model and its parameters. The normalization factor, p(y|m), is called the model evidence and plays a
central role in model selection. The maximum a posteriori
estimate of the model parameters is simply:
yMAP arg max y pyj y, m
[2]
[3]
likelihood (ReML) or, equivalently, in an Expectationmaximization (EM) algorithm as follows (Friston et al., 2002):
untilconvergence f E step
Ce le V
T 1
1
C X Ce X S1
m CX T C1
e y
M step
1
T 1
U C1
e Ce XCX Ce
1
1 T
g trUV tr U VUyyT
2
2
1
H trUVUV
2
le le H1 g
[7]
y
y X1 , X0 1 e1
y0
[9]
y1 0 e2
where e(1) is the observation error and e(2) the error on the
parameters of interest. By definition, the parameters of interest
sum to zero over all the search volume. Inverting this model for
all voxels at once is computationally infeasible. One efficient
solution is to collapse eqn [9] into the following single-level
model (Friston & Penny, 2003):
y X0 y0 x
x X1 e2 e1
[10]
P
Cx E xxT li Qi
Q X1 Q1 X1T , . .., X1 Qm X1T , V
519
[11]
l l1 , ... , lm , le T
Cx and l in eqn [11] can be estimated using a very similar EM
framework as in eqn [7], where we replace yyT by the sample
mean over voxels, 1n YY T (n is the total number of voxels), Ce by
Cx, and X by X0. See Friston and Penny (2003) for the full
equations. The estimated prior covariance S is then used in eqn
[7], where the error covariance is reestimated to obtain the posterior distribution at each voxel, as described in the preceding text.
More recently, other approaches have been proposed
to estimate the voxel-wise posteriors for PPMs, such as the
variational Bayes approach based on the use of the GLM and
autoregressive error processes. This method is described in
Penny, Kiebel, and Friston (2003).
Motion
[0, 0, 0]
Contrast
PPM
z = 0mm
z = 3mm
Effect size
1
0
Figure 1 Posterior probability map for the effect of motion. The map was created using a threshold of g 0 for the effect size and a threshold of 0.95
for the posterior probability (only for display purposes).
520
the PPM and SPM for the same effect are very similar, allowing
to make very similar spatial inferences about the effect in this
case (this similarity might not be present in other datasets).
However, the SPM tends to be more conservative and identifies
a smaller number of voxels than the PPM (Figures 1 and 2).
This is because, as discussed earlier, the classical approach of
testing the null hypothesis of no activation at each voxel
induces a multiple comparison problem that calls for a procedure to control the rate of false positives. This procedure
depends on the search volume, which means that in large
search volumes, such as in whole-brain analyses, the correction
can be very severe and therefore some of the voxels seen in an
uncorrected SPM disappear when corrected. In contrast, a PPM
that does not label the voxels as activated does not need to be
corrected for multiple comparisons. See Woolrich (2012) for
more discussion.
Conclusions
PPMs correspond to three-dimensional images of the posterior
probability that the effect at a particular voxel exceeds some
specified threshold, given the data. PPMs allow imaging neuroscientists to make Bayesian inferences about regionally specific effects in the brain. As exemplified in this article, using a
single-subject fMRI dataset, they can be similar to SPMs for the
Motion
[0, 0, 0]
Contrast
SPM(T338)
z = 0 mm
z = 3 mm
T-value
7
0
Figure 2 Corresponding statistical parametric map for the same effect of motion (Figure 1). The map has been thresholded at p 0.05
(FWE-corrected).
521
References
Bishop, C. M. (2006). Pattern recognition and machine learning (2nd ed.). New York:
Springer.
Buchel, C., & Friston, K. J. (1997). Modulation of connectivity in visual pathways by
attention: Cortical interactions evaluated with structural equation modelling and
fMRI. Cerebral Cortex, 7(8), 768778.
Friston, K. J., Holmes, A. P., Worsley, K. J., Poline, J. B., Frith, C., &
Frackowiak, R. S. J. (1995). Statistical parametric maps in functional imaging: A
general linear approach. Human Brain Mapping, 2, 189210.
Friston, K. J., Mattout, J., Trujillo-Barreto, N., Ashburner, J., & Penny, W. (2007).
Variational free energy and the Laplace approximation. NeuroImage, 34, 220234.
Friston, K. J., & Penny, W. D. (2003). Posterior probability maps and SPMs.
NeuroImage, 19(3), 12401249.
Friston, K. J., Penny, W. D., Phillips, C., Kiebel, S. J., Hinton, G., & Ashburner, J.
(2002). Classical and Bayesian inference in neuroimaging: Theory. NeuroImage, 16,
465483.
Gelman, A., Carlin, J., Stern, H., & Rubin, D. (Eds.). (1995). Bayesian data analysis.
London: Chapman and Hall.
Penny, W. D., Kiebel, S. J., & Friston, K. J. (2003). Variational Bayesian inference for
fMRI time series. NeuroImage, 19(3), 727741.
Poline, J. B. (2003). Contrasts and classical inference. In R. S. J. Frackowiak, K. J.
Friston, C. Frith, R. Dolan & J. C. Mazziotta (Eds.), Human brain function (2nd ed.).
New York: Academic Press.
Poline, J. B., Holmes, A. P., Worsley, K. J., & Friston, K. J. (1997). Making statistical
inferences. In R. S. J. Frackowiak, K. J. Friston, C. Frith, R. Dolan & J. C. Mazziotta
(Eds.), Human brain function (pp. 85106). USA: Academic Press.
Rosa, M. J., Bestmann, S., Harrison, L., & Penny, W. (2010). Bayesian model selection
maps for group studies. NeuroImage, 49(1), 217224.
Woolrich, M. W. (2012). Bayesian inference in fMRI. NeuroImage, 62(2), 801810.
Woolrich, M. W., Behrens, T. E., Beckmann, C. F., Jenkinson, M., & Smith, S. M.
(2004). Multilevel linear modelling for FMRI group analysis using Bayesian
inference. NeuroImage, 21(4), 17321747.
Worsley, K. J., Evans, A. C., Marrett, S., & Neelin, P. (1992). A three-dimensional
statistical analysis for CBF activation studies in human brain. Journal of Cerebral
Blood Flow & Metabolism, 12, 900918.
Worsley, K. J., Marrett, S., Neelin, P., Vandal, A. C., Friston, K. J., & Evans, A. C.
(1996). A unified statistical approach for determining significant signals in images
of cerebral activation. Human Brain Mapping, 4, 5873.
Relevant Websites
http://www.fil.ion.ucl.ac.uk/spm/ Statistical parametric mapping software.
http://fsl.fmrib.ox.ac.uk/fsl/fslwiki/ FSL software library.
Variational Bayes
MA Chappell and MW Woolrich, University of Oxford, Oxford, UK
2015 Elsevier Inc. All rights reserved.
Glossary
http://dx.doi.org/10.1016/B978-0-12-397025-1.00327-4
523
524
Introduction
Bayesian methods have proved powerful in many applications, including brain mapping, for the inference of model
parameters from data. These methods are based on Bayes
theorem, which itself is deceptively simple. However, in
practice, the computations required are intractable even for
simple cases. While alternative methods for the Bayesian
inference exist, many of these either make too crude an
approximation, for example, point estimation using maximum a posteriori (MAP) estimators, or attempt to estimate
full posterior distributions by sampling from the exact solution that can be computationally prohibitive (e.g., Markov
chain Monte Carlo (MCMC) methods).
However, more recently, the variational Bayes (VB) method
has been proposed (Attias, Leen, & Muller, 2000) that facilitates analytic calculations of the posterior distributions over a
model. The method makes use of the mean field approximation, which approximates the true posterior as the product of
several marginal posteriors. Practical implementations of VB
typically make use of factorized approximate posteriors and
priors that belong to the conjugate-exponential family, making the requisite integrals tractable. The procedure takes an
iterative approach resembling an expectationmaximization
method and whose convergence (albeit to a local minima) is
guaranteed. Since the method is approximate, the computational expense is significantly less than MCMC approaches.
Attias et al. (2000) provided the original derivation of the VB
framework for graphical models (although were not the first to
take such an approach). They introduced the concept of freeform selection of the posterior given the chosen model and
priors, although this is ultimately limited by the need for the
priors and factorized posteriors to belong to the conjugateexponential family (Beal, 2003). A comprehensive example of
the application of VB to a one-dimensional Gaussian mixture
model has been presented in Penny and Roberts (2000). Beal
(2003) has provided a thorough description of VB and its relationship to MAP and maximum likelihood estimation (MLE), as
well as its application to a number of standard inference problems. He has shown that expectationmaximization algorithm
is a special case of VB. In Friston, Mattout, Trujillo-Barreto,
Ashburner, & Penny (2007), they additionally considered the
VB approach and variational free energy in the context of the
Laplace approximation and restricted maximum likelihood
(ReML); this is known as variational Laplace. In this context,
they used a fixed multivariate Gaussian form for the approximate posterior, in contrast to the free-form approach.
This article sets out to provide an introduction to VB starting
from the principles of the Bayesian inference and thus following
on from the previous article in this work on Bayesian model
inversion. The essential principles for constructing a VB inference algorithm are outlined and this is followed by a number of
examples. These include a toy mathematical example for the
inference of the parameters of a Gaussian distribution.
Subsequently, a VB algorithm is developed for inference from
the widely used general linear model (GLM), and a number of
applications and extensions from the brain mapping literature
are highlighted. The VB scheme for the GLM is then used as a
basis for extensions to nonlinear models to provide methods
that can be used relatively widely in various brain mapping
applications, particularly those involving time series data. Examples of its use from the literature are also included. Finally, some
other literature examples are provided demonstrating the application of VB inference in brain mapping.
Variational Bayes
Bayesian Inference
The basic Bayesian inference problem is one where there are a
series of measurements, y, and they are to be used determine
the parameters, w, of the chosen model M. The method is
based on Bayes theorem:
P wjy, M
P yjM
P yjM
[1]
[2]
PyjwP w
F qw log
dw
qw
[3]
[4]
Introduce another (at this stage arbitrary) probability distribution q(w) that is to be compared with (or in this case used
to approximate) P(w|y), to get
P yjwP w
log Py log qw
dw
[5]
qw
Now using Jensens inequality, this can be written as
P yjwP w
dw
log Py qw log
qw
[6]
F f w, qw dw
P y; w
P wjy
[7]
P y; w
dw
qw log
P wjy
2
3
y;
w
5 dw
qw log 4
P wjy qw
[8]
P y; w
qw
dw qw log
dw
qw log
qw
Pwjy
F KL
where KL is the KL distance between q(w) and P(w|y). Since KL
satisfies Gibbs inequality, it is always positive; hence, F is a
lower bound for the log evidence. Thus, to achieve a good
approximation, we either maximize F or minimize KL, only
the former being possible in this case.
[12]
Alternative interpretation
525
PyjwP w
qw
[13]
14
,q
0 [15]
i
i
@qwi wi
dwi @q0wi wi
where the second term is zero, in this case, as g is not dependent upon q0wi wi . Using eqn [14], this can be written as (note
that this
is
equivalent to the form used in (Friston et al., 2007)
@
@F
@qwi @wi 0)
qw (wi)
i
q (w) log
P (y | w) P (w)
dw
i
q (w)
0.
16
Variational Approach
To make the integrals tractable, the variational method chooses
mean field approximation for q(w):
Y
q w i
(9)
qw
i wi
where the parameters in w have been collected into separate
groups wi, each with their own approximate posterior distribution q(wi). This is the key restriction in the VB method, making
q approximate. It assumes that the parameters in the separate
groups are independent, although it does not require complete
factorization of all the individual parameters (Attias et al.,
2000). The computation of q(wi) proceeds by the maximization of q(wi) over F; by application of the calculus of
variations, this gives
log qwi ( wi ) qwi ( wi ) log P (y | w) P (w) dwi
10
17
Hence,
log qwi
18
11
Conjugate-Exponential Restriction
Commonly, the approach referred to by Attias et al. (2000) as
free-form optimization is used, whereby rather than assuming a specific parametric form for the posteriors, we let them
526
[19]
[20]
YN
n1
P yn jm, b
[21]
[22]
Factorized posteriors for both parameters need to be chosen. Restricting this choice to priors that belong to the
conjugate-exponential family, choose prior distributions as
normal for m and gamma for b:
2
1
1
qmjm, n Nm; m; n p e2nmm
2pn
qbjb, c Gab; b; c
1 bc1 b
e b
Gc bc
[23]
[24]
m m2
constfmg
2n
b
log qb c 1 log b constfbg
b
[25]
[26]
Some conjugate priors for typical likelihood for data analysis problems
Likelihood
Model parameters
Bernoulli
Poisson
Normal
with known precision, n
Normal
with known mean, m
Multivariate normal
with known precision matrix, L
1 p
p
x0
x1
Prior parameters
b1
x a1 1 x
Ba; b
a, b
Beta
Gamma
Normal
2
n
n
p e2xm
2p
Gamma
1 nc1 n
e b
Gc bc
b, c
2
L
L
p e 2 xm
2p
Normal
L0 L0 mm0 2
p
e 2
2p
m0, L0
lx l
e
x!
2
n
n
p e2xm
2p
x, is the measured quantity and may be discrete or continuous according to the situation.
1 lc1 l
e b
Gc bc
n0 n0 mm0 2
p
e 2
2p
b, c
m0, n0
[27]
b
c0 1 log b constfbg
b0
[28]
log P m
log P b
[29]
m m0 2
constfm; bg
2n0
XN
s1
527
Xn1
N
yn
y2
n1 n
s2
1 Nn0 bc
m0 n0 bcs1 2
m
Lqb db
1 Nn0 bc
2n0
constfmg
[35]
[36]
[30]
m0 n0 bcs1
1 Nn0 bc
[37]
n0
1 Nn0 bc
[38]
Update on m
From eqn [10],
log qm Lqb db
[31]
Lqb db
8
<
N
bX
b
log b
yn m2 c0 1 log b
:2
2 n
b0
log qb Lqm dm
8
<
N
bX
b
y m2 c0 1 log b
log b
n n
:2
2
b0
m m0 2
2n0
m m0
gGab; b; c db
2n0
[32]
m m0
Lqb db
2n0
2
constfmg
Nm; m; n dm
N
b
log b c0 1 log b
2
b0
b X
y m2 Nm; m; n dm constfbg
n n
2
0
1
0
1
N
1
X
[39]
@ c0 1A log b @ Ab
2
b0 2
m m0 2
Gab; b; c db
2n0
0
1
N
@ c0 1A log bGab; b; c db
2
1
bGab; b; c db
b0
1X
2
bGab; b; c db
y
m
n n
2
Update on b
yn m
[33]
s2 2s1 m N m2 n
[40]
[41]
N
c0
2
[42]
528
These are the updates, informed by the data, for the hyperparameters. Since the update equations for the hyperparameters
for m depend on the hyperparameter values for b and vice versa,
these updates have to proceed as an iterative process.
Numerical Example
Since this example is sufficiently simple, it is possible to plot
the factorized approximation to the posterior against the true
posterior, as is done in Figure 1, where 100 samples were
drawn from a normal distribution with zero mean and unity
variance and where the following relatively uninformative
Free Energy
The expression for the free energy (eqn [13]) for this problem is
given by Penny and Roberts (2000):
F Lav KLqmjjpm KLqbjjpb
(43)
0:5bc s2 N m2 n 2ms1
(44)
0.5
1.5
b
0.5
0.5
0
n0 m2 m20 n 2mm0
0:5
n
2v0
[45]
and c(x) is the digamma function evaluated at x (see
Appendix). The free energy provides a way to monitor the
convergence of the update equations and is an approximation
to the model evidence.
N = 5 approximate
N = 5 true
N = 10 approximate
0.9
N = 10 true
0.8
N = 100 approximate
0.7
N = 100 true
0.6
0.5
0.4
0.3
0.2
0.1
0
1
0
m
0.2
0.4
0.6
0.8
Figure 2 Accuracy of the marginal posterior for m as the size of the data increases. Reproduced with permission from the The FMRIB Variational Bayes
Tutorial, Chappell, M. A., Groves, A. R., & Woolrich, M. W. (2007). A technical report of the Analysis Group, FMRIB Centre, University of Oxford,
TR07MC1.
[46]
e N 0; f1
[47]
Hence,
P yn jf
f
2p
1=2
e1=2e
fe
N
1
log f y yxT fy yx
2
2
[49]
[50]
1
1
1
1
log qyjy yT Ly yT Lm mT Ly constfyg [58]
2
2
2
and the right-hand side of eqn [57] as
Lqfjy df
0
1
1
@ fy yxT y yx y m0 T L0 y m0
2
2
!
constfyg Gaf; s; c df
1
y m0 T L0 y m0
2
1
y yxT y yx fGaf; s; c df constfyg
2
[57]
[48]
529
P y MVN y; m0 ; L0
[51]
Pf Gaf; s0 ; c0
[52]
[53]
qfjy Gaf; s; c
[54]
1
1
y m0 T L0 y m0 scy yxT y yx
2
2
constfyg
[59]
[60]
Lm scx T y L0 m0
[61]
[55]
1
N
L y yx T y yx log f
2
2
1
1
y m0 T L0 y m0 c0 1 log f f
2
s0
constfy; fg
[63]
f
constffg
s
)
1
f constffg qy dy
s0
530
N
1
1
@ c0 1A log f f f y gyT y gy
2
s0
2
MVNy; m; L dy
[64]
N
1
c0 1 log f f
2
s0
o
1 n
f y mxT y mx Trace L-1 xT x
2
[65]
N
co
2
1 1 1
1
y mxT y mx Trace L-1 xT x
s s0 2
2
[66]
[67]
Convergence
The expression for the free energy for this case can be derived
from eqn [13] and is given by
0
1
sc @N
F
c0 1A log s cc
s0
2
o
1n
mm0 T L0 mm0 Tr L-1 L0
2
o
1n
y mxT y mx Tr L-1 xT x s log c
2
0
1
N
log Gc c @ c 1A log s cc
2
1
log det L constant
2
[68]
included an autoregressive noise model making it more applicable to blood oxygenation level-dependent (BOLD) fMRI data.
Penny et al. (2006) included a comparison of the VB solution to
the classical Laplace approximation approach, widely used in
Bayesian inference, of finding the maximum a posteriori solution and locally approximating the posterior distribution using a
Gaussian distribution based on the local curvature. Woolrich,
Behrens, and Smith (2004) extended the framework of Penny
et al. (2003) to include the inference of the hemodynamic
response function via a constrained basis set and spatial priors
on the autoregressive noise parameters. Penny, Trujillo-Barreto,
and Friston (2004) further extended the method to include
spatial priors on the regression coefficients and Penny, Kilner,
and Blankenburg (2007) modeled the noise as a mixture of
Gaussians to derive robust inference scheme. Groves, Chappell,
and Woolrich (2009) implemented a combined spatial and
biophysical prior using a combination of evidence optimization
and a VB solution for inference under the GLM. Makni, Beckmann, Smith, & Woolrich (2008) derived a VB deconvolution
method for fMRI data, permitting the hemodynamic response
function to be inferred from the data, based on the bilinear
dynamic systems model. Chaari, Vincent, Forbes, Dojat, &
Ciuciu (2013) have also taken a variational approach to the
joint detection of hemodynamics and activity in event-related
fMRI.
[69]
where g(y) is the nonlinear forward model for the measurements and e is the additive Gaussian noise with precision f as
in eqn [46]. The specification of the priors and the derivation
of the log likelihood proceed as in the previous section (eqns
[50][56]). Unlike the case for the GLM, L (eqn [56]) may not
produce tractable VB updates for any general nonlinear model.
In this case, tractability will be achieved by considering a linear
approximation of the model. Approximating g(y) by a firstorder Taylor expansion about the mode of the posterior
[70]
d gyx
Jx, y
dyy
N
1
c0 1 log f f
2
s0
1
f kT k Trace L-1 JT J
2
[71]
ym
1 T
y L0 scJT J y yT L0 m0 scJk Jm
2
[73]
[74]
[75]
kk
Trace ( 1JTJ).
76
whereR the indicated terms are zero after the integration (since,
e.g., (y m)MVN(y; m, L) dy m m 0) and the following result has been used:
N
co
2
1 1 1 T
1
k k Tr L-1 JT J
s s0 2
2
[78]
y gy y gm Jy m
k Jy m
531
[79]
[80]
Convergence
The expression for F is given by
0
1
sc @N
F
c0 1A log s cc
s0
2
o
1n
mm0 T L0 mm0 Tr L-1 L0
2
1 T
k k Tr L-1 JT J s log c log Gc
2
0
1
N
1
c @ c 1A log s cc log det L
2
2
constant
(81)
In pure VB the free energy, F should increase at every iteration. However, since the nonlinear version of VB deviates from
an EM approach, the value of F during iteration may pass through
a maximum and actually start to decrease again. The issue of
convergence for this nonlinear inference scheme is discussed
further in Chappell, Groves, Whitcher, & Woolrich (2009).
532
Acknowledgments
A large portion of this work originally appeared as the FMRIB
Variational Bayes Tutorial and the authors are grateful to
Adrian Groves, Saad Jbabdi, and Salima Makni for helpful
comments and advice in preparing that work.
Appendix.
Function Definitions
1 xc1 x
e b
Gc bc
[82]
d
G0 x
ln Gx
Gx
dx
[83]
References
Attias, H., Leen, T., & Muller, K.-L. (2000). A variational Bayesian framework for
graphical models. Advances in Neural Information Processing Systems, 12, 4952.
Beal, M. (2003). Variational algorithms for approximate Bayesian inference. PhD Thesis,
Gatsby Computational Neurosicence Unit.
Chaari, L., Vincent, T., Forbes, F., Dojat, M., & Ciuciu, P. (2013). Fast joint detectionestimation of evoked brain activity in event-related fMRI using a variational
approach. IEEE Transactions on Medical Imaging, 32(5), 821837. http://dx.doi.
org/10.1109/TMI.2012.2225636.
Chappell, M. A., Donahue, M. J., Tee, Y. K., Khrapitchev, A. A., Sibson, N. R.,
Jezzard, P., et al. (2013). Quantitative Bayesian model-based analysis of amide
proton transfer MRI. Magnetic Resonance in Medicine, 70(2), 556567. http://dx.
doi.org/10.1002/mrm.24474.
Chappell, M. A., Groves, A. R., Whitcher, B., & Woolrich, M. W. (2009). Variational
Bayesian inference for a nonlinear forward model. IEEE Transactions on Signal
Processing, 57(1), 223236.
Chappell, M. A., MacIntosh, B. J., Donahue, M. J., Gunther, M., Jezzard, P., &
Woolrich, M. W. (2010). Separation of macrovascular signal in multi-inversion time
arterial spin labelling MRI. Magnetic Resonance in Medicine, 63(5), 13571365.
http://dx.doi.org/10.1002/mrm.22320.
Daunizeau, J., Friston, K. J., & Kiebel, S. J. (2009). Variational Bayesian identification
and prediction of stochastic nonlinear dynamic causal models. Physica D: Nonlinear
Phenomena, 238(21), 20892118. http://dx.doi.org/10.1016/j.physd.2009.08.002.
Friston, K., Harrison, L., & Penny, W. (2003). Dynamic causal modelling. NeuroImage,
19, 12731302.
Friston, K., Mattout, J., Trujillo-Barreto, N., Ashburner, J., & Penny, W. (2007).
Variational free energy and the Laplace approximation. NeuroImage, 34(1),
220234. http://dx.doi.org/10.1016/j.neuroimage.2006.08.035.
Groves, A. R., Chappell, M. A., & Woolrich, M. W. (2009). Combined spatial and nonspatial prior for inference on MRI time-series. NeuroImage, 45(3), 795809. http://
dx.doi.org/10.1016/j.neuroimage.2008.12.027.
Kiebel, S. J., Daunizeau, J., Phillips, C., & Friston, K. J. (2008). Variational Bayesian
inversion of the equivalent current dipole model in EEG/MEG. NeuroImage, 39(2),
728741. http://dx.doi.org/10.1016/j.neuroimage.2007.09.005.
Makni, S., Beckmann, C., Smith, S., & Woolrich, M. (2008). Bayesian deconvolution
fMRI data using bilinear dynamical systems. NeuroImage, 42(4), 13811396. http://
dx.doi.org/10.1016/j.neuroimage.2008.05.052.
Mehndiratta, A., MacIntosh, B. J., Crane, D. E., Payne, S. J., & Chappell, M. A. (2013).
A control point interpolation method for the non-parametric quantification of
cerebral haemodynamics from dynamic susceptibility contrast MRI. NeuroImage,
64, 560570. http://dx.doi.org/10.1016/j.neuroimage.2012.08.083.
Mohseni, H. R., Ghaderi, F., Wilding, E. L., & Sanei, S. (2010). Variational Bayes for
spatiotemporal identification of event-related potential subcomponents. IEEE
Transactions on Biomedical Engineering, 57(10), 24132428.
Nummenmaa, A., Auranen, T., Hamalainen, M. S., Jaaskelainen, I. P., Lampinen, J.,
Sams, M., et al. (2007). Hierarchical Bayesian estimates of distributed MEG
sources: Theoretical aspects and comparison of variational and MCMC methods.
NeuroImage, 35(2), 669685. http://dx.doi.org/10.1016/j.
neuroimage.2006.05.001.
533
Woolrich, M. W., Chiarelli, P., Gallichan, D., Perthen, J., & Liu, T. T. (2006). Bayesian
inference of hemodynamic changes in functional arterial spin labeling data.
Magnetic Resonance in Medicine, 56(4), 891906. http://dx.doi.org/10.1002/
mrm.21039.
Further Reading
Bishop, C. (2006). Pattern recognition and machine learning. New York: Springer http://
research.microsoft.com/cmbishop/PRML.
Mackay, D. (2003). Information theory, inference, and learning algorithms. Cambridge:
Cambridge University Press http://www.inference.phy.cam.ac.uk/mackay/itila/.
Relevant Websites
http://www.fmrib.ox.ac.uk/fsl The FMRIB Software Library incorporating various MR
neuroimaging tools that use VB methods.
http://www.fmrib.ox.ac.uk/fsl/fabber An implementation of the VB technique for the
fitting of a non-linear model to series image data. Includes an application to dualecho functional MRI, but is extendable to other models.
http://www.fmrib.ox.ac.uk/fsl/basil A toolbox for perfusion quantification using
arterial spin labelling MRI incorporating model-based analysis using the VB method
in fabber.
http://www.fmrib.ox.ac.uk/fsl/baycest A tool for the quantification of chemical
exchange saturation transfer MRI using the VB method in fabber.
http://vbmeg.atr.jp A Matlab toolbox for VB MEG analysis.
http://en.wikipedia.org/wiki/Conjugate_prior Contains an extensive table of conjugate
priors.
Introduction
Much of modern neuroscience is concerned with the question of
model choice. A researcher collects data, often in the form of
measurements on many different aspects of the observed units,
and wants to study how these variables affect some outcome of
interest: Which measures are important to the outcome? Which
are not? Are there interactions between the variables that need to
be taken into account? From the statistical point of view, this
enterprise rests on the solution of an inference problem while
accommodating model uncertainty (Clyde & George, 2004). In
many cases, the models (or hypotheses) considered are nonnested or acceptance of the null model is required, which are
unnatural situations in classical hypothesis testing (Kass &
Raftery, 1995). For such setups, the Bayesian approach provides
a natural and general probabilistic framework that simultaneously accommodates both model and parameter
uncertainties.
[3]
[1]
Through conditioning and marginalization, the joint distribution p(y, yk, mk) can be used to obtain posterior summaries of
interest.
K
X
pDjy, mk pmk jy
[4]
k0
where
[2]
Interpretation of BMA
BMA can be thought of as a method for soft model selection.
Equation [4] expresses the probability of observing D given
http://dx.doi.org/10.1016/B978-0-12-397025-1.00328-6
535
536
that the data were generated by exactly one of the models. The
soft weights p(mk|y) only reflect a statistical inability to distinguish the generative model based on limited data. As more data
arrive, the model becomes more distinguishable and BMA will
focus its weight on the most probable model. In this view, the
posterior model probabilities used in BMA account for the
uncertainty on the model selection process. Under complete
certainty about a specific model mi,
1 if k i
pmk jy
[5]
0 if k 6 i
pyjmk
Bk:j
p y mj
which is the Bayes factor (Good, 1958; Kass & Raftery, 1995).
Hence, the Bayes factor Bk:j is the ratio of the posterior odds of
mk versus mj to its prior odds, regardless of the value of its prior
odds. When models are equally probable a priori, the Bayes
factor is equal to the posterior odds. Note that the posterior
model probabilities (eqn [2]) can be expressed entirely in
terms of Bayes factors and prior odds as
Bk:0 ak:0
pmk jy X
Bi:0 ai:0
[6]
[8]
[9]
[10]
where, without losing generality, model m0 is taken as a reference model to which m1, . . ., mK are compared. It is reasonable
to assume that ak:0 1 (all models are equally probable a
priori), but other values may be used to reflect prior information about relative plausibility of competing models.
2 log Bk:j
Bk:j
p(mk|y) (%)
Evidence in favor of mk
(against mj)
02
26
610
10
13
320
20150
150
5075
7595
9599
99
[11]
The accuracy is a measure of data fit (usually the best-fit loglikelihood), and the complexity is interpreted as a penalty term
for the number of parameters used by the model to explain the
data. The log evidence as given by eqn [11] optimizes a tradeoff between accuracy and complexity of the model that can be
understood in the following way: A more complex model can
always fit the data better, but it risks overfitting (it fits signal
and noise), while a too simple model has little flexibility and
therefore has a low goodness-of-fit and generalizes poorly to
new data sets. The optimal model must be accurate and simple.
537
[19]
Laplaces method
By definition, the evidence in eqn [3] is the normalization
constant of the posterior distribution of the parameters. By
conditioning eqn [1] on the data and the model, the Bayes
rule for the parameters is
pyk jy, mk
[20]
where
[12]
py,yk jmk
dyk
Fmk qyk log
qyk
[13]
qyk
dyk
KLqyk kpyk jy, mk qyk log
pyk jy, mk
[14]
[15]
[16]
[17]
[21]
538
[27]
K
X
wk y^k
[28]
k0
where y^k is the maximum likelihood estimator of the parameters under model mk. The Akaikes weights are interpreted as
the probability that model mk is, in fact, the KL best model for
the data. Although the wk values depend on the full models set,
their ratios wk/wj are identical to the original likelihood ratios,
and therefore, they are invariant to the models set.
On the training set, convert the (improper) prior distributions to proper posterior distributions as
pyk jy , mk
[29]
[30]
[31]
[32]
f y, bjmi
, ij, k
Applications to Neuroimaging
The Bayesian treatment of model uncertainty, coupled with
advances in posterior search and computation, has led to an
explosion of research in model selection and model averaging.
In neuroimaging, Bayesian model selection and BMA have been
used to deal with uncertainty about the forward model and/or
References
Akaike, H. (1974). A new look at the statistical model identification. IEEE Transactions
on Automatic Control, 19, 716723.
Akaike, H. (1983). Information measures and model selection. Bulletin of the
International Statistical Institute, 50, 277290.
Attias, H. (2000). A variational Bayesian framework for graphical models. Advances in
Neural Information Processing Systems, 12, 209215.
Berger, J. O., & Pericchi, L. R. (1996). The intrinsic Bayes factor for model selection and
prediction. Journal of the American Statistical Association, 91, 109.
Burnham, K. P. (2004). Multimodel inference: Understanding AIC and BIC in model
selection. Sociological Methods & Research, 33, 261304.
Carlin, B. P., & Chib, S. (1995). Bayesian model choice via Markov chain Monte Carlo
methods. Journal of the Royal Statistical Society: Series B: Methodological, 57,
473484.
Chipman, H. A., George, E. I., Mcculloch, R. E., Clyde, M., Foster, D. P., & Stine, R. A.
(2001). The practical implementation of Bayesian model selection. IMS Lecture
Notes-Monograph Series, 38, 65134.
Clyde, M., & George, E. I. (2004). Model uncertainty. Statistical Science, 19, 8194.
Daunizeau, J., & Friston, K. J. (2007). A mesostate-space model for EEG and MEG.
NeuroImage, 38, 6781.
Friston, K., Harrison, L., Daunizeau, J., Kiebel, S., Phillips, C., Trujillo-Barreto, N. J.,
et al. (2008). Multiple sparse priors for the M/EEG inverse problem. NeuroImage,
39, 11041120.
George, E. I., & McCulloch, R. E. (1993). Variable selection via Gibbs sampling. Journal
of the American Statistical Association, 88, 881889.
539
Godsill, S. J. (2011). On the relationship between Markov Chain Monte Carlo methods
for model uncertainty. Journal of Computational and Graphical Statistics, 10,
230248.
Good, I. J. (1958). Significance tests in parallel and in series. Journal of the American
Statistical Association, 53, 799813.
Green, P. J. (1995). Reversible jump Markov chain Monte Carlo computation and
Bayesian model determination. Biometrika, 82, 711732.
Henson, R. N., Mattout, J., Phillips, C., & Friston, K. J. (2009). Selecting forward
models for MEG source-reconstruction using model-evidence. NeuroImage, 46,
168176.
Hoeting, J. A., Madigan, D., Raftery, A. E., & Volinsky, C. T. (1999). Bayesian model
averaging: A tutorial. Statistical Science, 14, 382417.
Jeffreys, H. (1961). Theory of probability (3rd ed.). Oxford, UK: Oxford University Press.
Kass, R. E., & Raftery, A. E. (1995). Bayes factors. Journal of the American Statistical
Association, 90, 773795.
Madigan, D., & Raftery, A. E. (1994). Model selection and accounting for model
uncertainty in graphical models using Occams window. Journal of the American
Statistical Association, 89, 15351546.
Madigan, D., & York, J. (1995). Bayesian graphical models for discrete data.
International Statistical Review/Revue, 63, 215232.
Mattout, J., Phillips, C., Penny, W. D., Rugg, M. D., & Friston, K. J. (2006). MEG source
localization under multiple constraints: An extended Bayesian framework.
NeuroImage, 30, 753767.
OHagan, A. (1995). Fractional Bayes factors for model comparisons. Journal of the
Royal Statistical Society, Series B, 57, 99138.
Olier, I., Trujillo-Barreto, N. J., & El-Deredy, W. (2013). A switching multi-scale
dynamical network model of EEG/MEG. NeuroImage, 83, 262287.
Penny, W., Kiebel, S., & Friston, K. (2003). Variational Bayesian inference for fMRI time
series. NeuroImage, 19, 727741.
Penny, W. D., Stephan, K. E., Daunizeau, J., Rosa, M. J., Friston, K. J., Schofield, T. M.,
et al. (2010). Comparing families of dynamic causal models. PLoS Computational
Biology, 6, e1000709.
Penny, W. D., Stephan, K. E., Mechelli, A., & Friston, K. J. (2004). Comparing dynamic
causal models. NeuroImage, 22, 11571172.
Rosa, M. J., Kilner, J. M., & Penny, W. D. (2011). Bayesian comparison of
neurovascular coupling models using EEG-fMRI. PLoS Computational Biology,
7, e1002070.
Sato, M., Yoshioka, T., Kajihara, S., Toyama, K., Goda, N., Doya, K., et al. (2004).
Hierarchical Bayesian estimation for MEG inverse problem. NeuroImage, 23,
806826.
Schwarz, G. (1978). Estimating the dimension of a model. The Annals of Statistics, 6,
461464.
Sotero, R. C., Trujillo-Barreto, N. J., Jimenez, J. C., Carbonell, F., &
Rodrguez-Rojas, R. (2009). Identification and comparison of stochastic metabolic/
hemodynamic models (sMHM) for the generation of the BOLD signal. Journal of
Computational Neuroscience, 26, 251269.
Stephan, K. E., Penny, W. D., Daunizeau, J., Moran, R. J., & Friston, K. J. (2009).
Bayesian model selection for group studies. NeuroImage, 46, 10041017.
Sugiura, N. (1978). Further analysis of the data by Akaikes information criterion and the
finite corrections. Communications in Statistics, Theory and Methods, A7, 1326.
Tierney, L., & Kadane, J. B. (1986). Accurate approximations for posterior moments and
marginal densities. Journal of the American Statistical Association, 81, 8286.
Tierney, L., Kass, R. E., & Kadane, J. B. (1989). Fully exponential Laplace
approximations to expectations and variances of nonpositive functions. Journal of
the American Statistical Association, 84, 710716.
Trujillo-Barreto, N. J., Aubert-Vazquez, E., & Valdes-Sosa, P. A. (2004). Bayesian
model averaging in EEG/MEG imaging. NeuroImage, 21, 13001319.
Volinsky, C. T., Madigan, D., Raftery, A. E., & Kronmal, R. A. (1997). Bayesian model
averaging in proportional hazard models: Assessing the risk of a stroke. Journal of
the Royal Statistical Society, Series C, 46, 433448.
Glossary
Abbreviation
ASL
BOLD
CBF
CBVV
CMRO2
EEG
fMRI
HRF
MEG
http://dx.doi.org/10.1016/B978-0-12-397025-1.00329-8
541
542
BOLD response
Stimulus
Change (%)
(a)
40
30
20
10
0
10
20
Change (%)
0.8
0.6
0.4
0.2
0.0
0.2
0.4
10
Time (s)
15
20
CBF response
Stimulus
(c)
10
Time (s)
2.0
1.5
1.0
0.5
0.0
0.5
1.0
BOLD response
Stimulus
20
(b)
Change (%)
Change (%)
15
20
(d)
80
60
40
20
0
20
40
40
Time (s)
60
80
CBF response
Stimulus
20
40
Time (s)
60
80
Figure 1 Stimulus responses. The figures show experimental measurements of the BOLD response in the primary motor cortex to a 2 s finger-tapping
stimulus (a) and in the primary visual cortex to a 20 s flickering checkerboard stimulus (b). The corresponding CBF responses measured with ASL
are shown in (c) and (d). Note the pronounced BOLD poststimulus undershoot for the longer stimulus. Motor cortex data are from Miller, K. L.,
Luh, W. M., Liu, T. T., Martinez, A., Obata, T., Wong E. C., et al. (2001). Nonlinear temporal dynamics of the cerebral blood flow response. Human Brain
Mapping, 13(1), 112 and visual cortex data are from Perthen, J. E., Lansing, A. E., Liau, J., Liu, T. T., & Buxton, R. B. (2008). Caffeine-induced
uncoupling of cerebral blood flow and oxygen metabolism: A calibrated BOLD fMRI study. Neuroimage, 40(1), 23747.
543
E
Neural response
CMRO2
CBV
BOLD
Figure 2 Schematic illustration of the pathway from a stimulus to the BOLD response. A stimulus triggers a neural response, which then drives
changes in blood flow (CBF), oxygen metabolism (CMRO2), and venous blood volume (CBV). The imbalance of changes in flow and metabolism leads to
a change in the oxygen extraction fraction (E), and the combined changes in E and CBV determine the net change in deoxyhemoglobin, resulting in
the measured BOLD response. Curves show possible responses for each physiological variable, including adaptation of the neural response and a slow
recovery of venous CBV leading to a poststimulus undershoot (as in the balloon model). Note that an undershoot of CBF or a slow recovery of
CMRO2 (not shown) also could create a BOLD poststimulus undershoot, and these may be the more dominant effects.
baseline at a rate that depends on the time constant t. A poststimulus undershoot can be included by adding a second
broader gamma-variate function with a negative amplitude. A
standard HRF of this form is illustrated in Figure 3, along with
simulations of the BOLD response for a block stimulus and an
event-related design. The modeled BOLD responses look plausible compared with experimental data, but there is a second
feature of the response that needs to be modeled: the delay from
the beginning of the stimulus to the initial rise of the BOLD
response. The presence of an unknown delay complicates the
analysis with the GLM, because a delay is not easily modeled as
a linear effect. One approach is to add additional functions that
approximate a time shift of the basic HRF. Alternatively, a delay
is simply assumed, or the data are analyzed individually with
different HRFs corresponding to different delays.
The HRF approach is widely used, but these models of the
BOLD response are essentially just mathematical approximations of experimental data and do not attempt to model the
underlying physiological changes nor the physics of how those
changes translate to a change in the magnitude of the BOLD
signal. In addition, the use of a simple linear model for the
BOLD response fails to describe several interesting nonlinear
effects that have been observed.
544
1
0
HRF
0.2
20
(b)
40
Time (s)
60
80
Event-related stimulus
1
0
0
(a)
10
15
20
25
30
Time (s)
0
20
(c)
40
Time (s)
60
80
Figure 3 Typical assumed form of the HRF. In many fMRI analyses, the BOLD response is modeled as a convolution of the HRF (a) with the stimulus
pattern, illustrated here with the resulting BOLD responses for a simple block design (b) and for an event-related design (c). The stimulus pattern
is shown as the lower gray line in (b) and (c). Mathematically, this HRF is a sum of two gamma-variate functions with different signs and widths to model
a primary positive response followed by a weaker negative response, producing a poststimulus undershoot of the BOLD signal. An HRF such as
this is not a physiological model, but simply a convenient mathematical shape that approximates the data.
(a)
Time (s)
Linear
prediction
Actual
(b)
Time (s)
[1]
545
reduction, creating the ceiling on the BOLD signal. The addition of changes in CMRO2 and CBVV further modifies the
amplitude of the BOLD response, with these changes generally
opposing the CBF change. In short, we can think of the BOLD
response as primarily driven by the CBF change, but strongly
modulated by the baseline state (A) (essentially the local concentration of deoxyhemoglobin), the change in CMRO2 (l),
and the change in CBVV (aV).
Equation [1] exhibits a basic nonlinearity due to the BOLD
ceiling effect: if the CBF response is doubled, the BOLD
response is increased by less than a factor of 2. That is, the
fundamental nonlinearity in the way the BOLD response
depends on f in eqn [1] leads to nonlinearities similar to
what have been observed, as illustrated in Figure 4. However,
it is important to note that such nonlinear effects could arise
from other factors in Figure 2 as well. For example, if venous
blood volume increases slowly, then a growing CBVV could
also lead to a reduction of the amplitude of a sustained stimulus compared with a brief stimulus.
Finally, a cautionary note is needed about BOLD signal
models such as eqn [1] or other proposed models currently
in use: They are steady-state models, and their application to
rapid dynamics could produce errors. That is, an abrupt change
in oxygen metabolism will require a few seconds to fully translate into deoxyhemoglobin changes, depending on the time
constants for O2 transport and blood clearance. More detailed
models treating these effects are needed for a full dynamic
BOLD model. Nevertheless, the steady-state assumption is
likely to be reasonably accurate for most applications.
546
References
Aguirre, G. K., Zarahn, E., & DEsposito, M. (1998). The variability of human, BOLD
hemodynamic responses. NeuroImage, 8, 360376.
Attwell, D., & Iadecola, C. (2002). The neural basis of functional brain imaging signals.
Trends in Neurosciences, 25(12), 621625.
Behzadi, Y., & Liu, T. T. (2006). Caffeine reduces the initial dip in the visual BOLD
response at 3 T. NeuroImage, 32(1), 915.
Buxton, R. B. (2010). Interpreting oxygenation-based neuroimaging signals: The
importance and the challenge of understanding brain oxygen metabolism. Frontiers
in Neuroenergetics, 2, 8.
Buxton, R. B. (2012). Dynamic models of BOLD contrast. NeuroImage, 62(2), 953961.
Buxton, R. B. (2013). The physics of functional magnetic resonance imaging (fMRI).
Reports on Progress in Physics, 76, 096601.
Buxton, R. B., Uludag, K., Dubowitz, D. J., & Liu, T. T. (2004). Modeling the
hemodynamic response to brain activation. NeuroImage, 23(Suppl. 1), S220S233.
Buxton, R. B., Wong, E. C., & Frank, L. R. (1998). Dynamics of blood flow and
oxygenation changes during brain activation: The balloon model. Magnetic
Resonance in Medicine, 39, 855864.
Cohen, E. R., Ugurbil, K., & Kim, S. G. (2002). Effect of basal conditions on the
magnitude and dynamics of the blood oxygenation level-dependent fMRI response.
Journal of Cerebral Blood Flow and Metabolism, 22(9), 10421053.
David, O., Guillemain, I., Saillet, S., Reyt, S., Deransart, C., Segebarth, C., et al. (2008).
Identifying neural drivers with functional MRI: An electrophysiological validation.
PLoS Biology, 6(12), 26832697.
Davis, T. L., Kwong, K. K., Weisskoff, R. M., & Rosen, B. R. (1998). Calibrated
functional MRI: Mapping the dynamics of oxidative metabolism. Proceedings of the
National Academy of Sciences of the United States of America, 95, 18341839.
Fox, P. T., & Raichle, M. E. (1986). Focal physiological uncoupling of cerebral blood
flow and oxidative metabolism during somatosensory stimulation in human
subjects. Proceedings of the National Academy of Sciences of the United States of
America, 83, 11401144.
Friston, K. J., & Dolan, R. J. (2010). Computational and dynamic models in
neuroimaging. NeuroImage, 52(3), 752765.
Friston, K. J., Mechelli, A., Turner, R., & Price, C. J. (2000). Nonlinear responses in
fMRI: The balloon model, Volterra kernels, and other hemodynamics. NeuroImage,
12(4), 466477.
Glover, G. H. (1999). Deconvolution of impulse response in event-related fMRI.
NeuroImage, 9, 416429.
Griffeth, V. E., Blockley, N. P., Simon, A. B., & Buxton, R. B. (2013). A new functional
MRI approach for investigating modulations of brain oxygen metabolism. PLoS
One, 8(6), e68122.
Griffeth, V. E., & Buxton, R. B. (2011). A theoretical framework for estimating cerebral
oxygen metabolism changes using the calibrated-BOLD method: Modeling the
effects of blood volume distribution, hematocrit, oxygen extraction fraction, and
tissue signal properties on the BOLD signal. NeuroImage, 58(1), 198212.
Griffeth, V. E., Perthen, J. E., & Buxton, R. B. (2011). Prospects for quantitative fMRI:
Investigating the effects of caffeine on baseline oxygen metabolism and the response
to a visual stimulus in humans. NeuroImage, 57(3), 809816.
547
Handwerker, D. A., Gonzalez-Castillo, J., DEsposito, M., & Bandettini, P. A. (2012). The
continuing challenge of understanding and modeling hemodynamic variation in
fMRI. NeuroImage, 62(2), 10171023.
Handwerker, D. A., Ollinger, J. M., & DEsposito, M. (2004). Variation of BOLD
hemodynamic responses across subjects and brain regions and their effects on
statistical analyses. NeuroImage, 21(4), 16391651.
Kwong, K. K., Belliveau, J. W., Chesler, D. A., Goldberg, I. E., Weisskoff, R. M.,
Poncelet, B. P., et al. (1992). Dynamic magnetic resonance imaging of human brain
activity during primary sensory stimulation. Proceedings of the National Academy of
Sciences of the United States of America, 89(12), 56755679.
Liang, C. L., Ances, B. M., Perthen, J. E., Moradi, F., Liau, J., Buracas, G. T., et al.
(2013). Luminance contrast of a visual stimulus modulates the BOLD response
more than the cerebral blood flow response in the human brain. NeuroImage, 64,
104111.
Mandeville, J. B., Marota, J. J.A, Ayata, C., Zaharchuk, G., Moskowitz, M. A.,
Rosen, B. R., et al. (1999). Evidence of a cerebrovascular post-arteriole Windkessel
with delayed compliance. Journal of Cerebral Blood Flow and Metabolism, 19,
679689.
Miller, K. L., Luh, W. M., Liu, T. T., Martinez, A., Obata, T., Wong, E. C., et al. (2001).
Nonlinear temporal dynamics of the cerebral blood flow response. Human Brain
Mapping, 13(1), 112.
Moradi, F., Buracas, G. T., & Buxton, R. B. (2012). Attention strongly increases oxygen
metabolic response to stimulus in primary visual cortex. NeuroImage, 59(1),
601607.
Moradi, F., & Buxton, R. B. (2013). Adaptation of cerebral oxygen metabolism and
blood flow and modulation of neurovascular coupling with prolonged stimulation in
human visual cortex. NeuroImage, 82, 182189.
Mullinger, K. J., Mayhew, S. D., Bagshaw, A. P., Bowtell, R., & Francis, S. T. (2013).
Poststimulus undershoots in cerebral blood flow and BOLD fMRI responses are
modulated by poststimulus neuronal activity. Proceedings of the National Academy
of Sciences of the United States of America, 110(33), 1363613641.
Obata, T., Liu, T. T., Miller, K. L., Luh, W. M., Wong, E. C., Frank, L. R., et al. (2004).
Discrepancies between BOLD and flow dynamics in primary and supplementary
motor areas: Application of the balloon model to the interpretation of BOLD
transients. NeuroImage, 21(1), 144153.
Ogawa, S., Menon, R. S., Tank, D. W., Kim, S.-G., Merkle, H., Ellerman, J. M., et al.
(1993). Functional brain mapping by blood oxygenation level Dependent contrast
magnetic resonance imaging: A comparison of signal characteristics with a
biophysical model. Biophysical Journal, 64(3), 803812.
Ogawa, S., Tank, D. W., Menon, R., Ellermann, J. M., Kim, S.-G., Merkle, H., et al.
(1992). Intrinsic signal changes accompanying sensory stimulation: Functional
brain mapping with magnetic resonance imaging. Proceedings of the National
Academy of Sciences of the United States of America, 89, 59515955.
Perthen, J. E., Lansing, A. E., Liau, J., Liu, T. T., & Buxton, R. B. (2008). Caffeineinduced uncoupling of cerebral blood flow and oxygen metabolism: A calibrated
BOLD fMRI study. NeuroImage, 40(1), 237247.
Ress, D., Thompson, J. K., Rokers, B., Khan, R. K., & Huk, A. C. (2009). A model for
transient oxygen delivery in cerebral cortex. Frontiers in Neuroenergetics, 1, 3.
Sotero, R. C., & Trujillo-Barreto, N. J. (2007). Modelling the role of excitatory and
inhibitory neuronal activity in the generation of the BOLD signal. NeuroImage,
35(1), 149165.
Stephan, K. E., Weiskopf, N., Drysdale, P. M., Robinson, P. A., & Friston, K. J. (2007).
Comparing hemodynamic models with DCM. NeuroImage, 38(3), 387401.
Storti, S. F., Formaggio, E., Bertoldo, A., Manganotti, P., Fiaschi, A., & Toffolo, G. M.
(2013). Modelling hemodynamic response function in epilepsy. Clinical
Neurophysiology, 124(11), 21082118.
van Zijl, P. C., Hua, J., & Lu, H. (2012). The BOLD post-stimulus undershoot, one of the
most debated issues in fMRI. NeuroImage, 62(2), 10921102.
Yablonskiy, D. A., & Haacke, E. M. (1994). Theory of NMR signal behavior in
magnetically inhomogeneous tissues: The static dephasing regime. Magnetic
Resonance in Medicine, 32, 749763.
! r
!
!
@B
, r B 0,
r E , r E
@t
e
!!
!
!
@E
r B m J e
@t
[1]
http://dx.doi.org/10.1016/B978-0-12-397025-1.00330-4
549
550
Presynaptic
neuron
Neurotransmitters
Presynaptic
membrane
Postsynaptic
neuron
Postsynaptic
membrane
Extracellular
medium
Soma
+ + +
+ + +
Intracellular
medium
ion channel
+
+
ions
(b)
Axon
Nucleus
Extracellular medium
++ ++
++ +
K+
(a)
Basal dendrites
Na+
Apical dendrites
Na+/K+ pump
+ +
+ + + +
+ + +
Extracellular medium
(c)
Figure 1 Schematic view of a neuron. (a) Basic parts of the neuron structure (orange), in connection to other neurons (blue). (b) Neurotransmission at
a chemical synapse. Presynaptic action potential triggers the release of neurotransmitters that bind to receptors on postsynaptic (ligand-gated) ion
channels (blue), hence inducing ionic exchanges across the postsynaptic membrane.(c) Schematic view of the axonal membrane. Sodium-potassium
pumps (red), achieving ionic equilibrium at rest, and (voltage-gated) ion channels (green) involved in the propagation of action potential along the axon, are
represented.
Current
sink
Conduction currents
Current sink
Primary currents Na+
Conduction currents
Na+
(b)
Current lines
Current dipole
(a)
Current sources
Primary currents
Current quadrupole
Figure 2 Schematic view of typical distributions of current sinks and sources (red and black dots respectively). (a) Due to their asymetrical
distribution, postsynaptic currents are fairly approximated by current dipoles. Action potential expresses as two equivalent current dipoles with opposite
directions, leading to a quadrupolar approximation. (b) Illustration of an excitatory synapse. Local sink currents induce primary currents across the
membrane and within the cell. The conducting currents close the loop in the extracellular space, hence creating a distribution of source currents along
the membrane. In the same way, an inhibitory synapse creates a source current.
compared to physiological time constants; hence, scalp measures appear as instantaneous and synchronous, and the quasistatic approximation holds (Plonsey & Heppner, 1967). Under
this regime, Maxwells equations simplify as follows:
!
r E
! !
!
!
!
r
, r E 0 , r B 0, r B m0 J
e0
[2]
[3]
[4]
!
h! 0
0 ! 0 i
!
0
Jp r , t s r grad V r , t r r
m
0
0
Br, t 0
dr
r rj3
4p
[5]
at spatial location r and time t. Electrical and magnetical fields
generated by a single ECD are illustrated in Figure 3(a). In
addition, Figure 3(b,c) shows an example of the difference
between EEG and MEG data generated by the same underlying
sources.
551
Scalp
Skull
B
Cortical ribbon
(b)
J2
s2
J1
s1
Current distorsion
(a)
(c)
Figure 3 (a) Current dipole with electric field lines (red) and magnetic field lines (green). Because of different conductivities in different head tissues,
current lines are distorted when they cross tissue boundaries. (b) Scalp topography of real EEG data (auditory evoked response N100). (c)
Corresponding scalp topography of MEG data (from simultaneously recorded EEG and MEG responses to auditory tones).
552
Sensor Registration
Sensor description relative to the head model is achieved by
means of a spatial transformation based on head landmarks
(least-square fitting) or head surface (surface-matching
methods) or both, identified in both the MRI and the electrophysiological coordinate systems.
Various sources of errors are associated with sensor coregistration, particularly landmark identification on MR images,
electrode and landmark digitization, and head movements
during MEG acquisition. Typically, coregistration errors range
between 5 and 10 mm (Hillebrand & Barnes, 2011; Whalen,
Maclin, Fabiani, & Gratton, 2008), with moderate consequences on EEG inverse solutions (Acar & Makeig, 2013;
Wang & Gotman, 2001) but potentially dramatic effects on
MEG ones (Hillebrand & Barnes, 2003). Interestingly, uncertainty about the forward model, due to coregistration, could be
accounted for in the source reconstruction process thanks to
probabilistic or Bayesian methods (Lopez, Penny, Espinosa, &
Barnes, 2012).
[6]
[7]
553
[8]
where
p(Y| y, M) and p(y| M) are the likelihood and prior distributions, respectively (they fully define the generative
model M),
q(y) is the approximate posterior distribution over model
parameters (the outcome of the inverse inference process),
KL is the KullbackLeibler divergence, which can be interpreted as a statistical distance between two distributions.
Here, it quantifies the distance between the posterior and
the prior distribution over y.
1
1
ln jCy j ln Cy=Y
2
2
T
1
my=Y my
my=Y my C1
y
2
Trace C1
y Cy=Y cst
[9]
where my, Cy and my/Y, Cy/Y are the mean and variance of the
prior and posterior distributions, respectively.
Given those equations, changing the lead-field operator by
moving from a simple spherical head model to a more realistic
one might increase the free energy in two ways:
554
References
Acar, Z. A., & Makeig, S. (2013). Effects of forward mod el errors on EEG source
localization. Brain Topography, 26(3), 378396.
Baillet, S., Riera, J. J., Marin, G., Mangin, J. F., Aubert, J., & Garnero, L. (2001).
Evaluation of inverse methods and head models for EEG source localization using a
human skull phantom. Physics in Medicine and Biology, 46(1), 7796.
Crouzeix, A. (2001). Methodes de localisation des generateurs de lactivite electrique
cerebrale a` partir de signaux electro- et magneto-encephalographiques (pp. 1264).
PhD Thesis, University Lyon 1, France.
Crouzeix, A., Yvert, B., Bertrand, O., & Pernier, J. (1999). An evaluation of dipole
reconstruction accuracy with spherical and realistic head models in MEG. Clinical
Neurophysiology, 110(12), 21762188.
de Munck, J. C., van Dijk, B. W., & Spekreijse, H. (1988). Mathematical dipoles are
adequate to describe realistic generators of human brain activity. IEEE Transactions
on Biomedical Engineering, 35(11), 960966.
Ferree, T. C., Eriksen, K. J., & Tucker, D. M. (2000). Regional head tissue conductivity
estimation for improved EEG analysis. IEEE Transactions on Biomedical
Engineering, 47(12), 15841592.
Gencer, N. G., & Acar, C. E. (2004). Sensitivity of EEG and MEG measurements to tissue
conductivity. Physics in Medicine and Biology, 49(5), 701717.
Goncalves, S., de Munck, J. C., Heethaar, R. M., Lopes da Silva, F. H., & van Dijk, B. W.
(2000). The application of electrical impedance tomography to reduce systematic
errors in the EEG inverse problem A simulation study. Physiological
Measurement, 21(3), 379393.
Gullmar, D., Haueisen, J., & Reichenbach, J. R. (2010). Influence of anisotropic
electrical conductivity in white matter tissue on the EEG/MEG forward and inverse
solution. A high-resolution whole head simulation study. NeuroImage, 51(1),
145163.
Hamalainen, M. S., Hari, R., Ilmoniemi, R. J., Knuutila, J., & Lounasmaa, O. (1993).
Magnetoencephalography Theory, instrumentation, and applications to
noninvasive studies of the working human brain. Reviews of Modern Physics, 65(2),
413497.
Hamalainen, M. S., & Sarvas, J. (1989). Realistic conductivity geometry model of the
human head for interpretation of neuromagnetic data. IEEE Transactions on
Biomedical Engineering, 36(2), 165171.
Henson, R. N., Mattout, J., Phillips, C., & Friston, K. J. (2009). Selecting forward
models for MEG source-reconstruction using model-evidence. NeuroImage, 46(1),
168176.
Hillebrand, A., & Barnes, G. R. (2003). The use of anatomical constraints with MEG
beamformers. NeuroImage, 20(4), 23022313.
555
Wang, Y., & Gotman, J. (2001). The influence of electrode location errors on EEG dipole
source localization with a realistic head model. Clinical Neurophysiology, 112(9),
17771780.
Whalen, C., Maclin, E. L., Fabiani, M., & Gratton, G. (2008). Validation of a method for
coregistering scalp recording locations with 3D structural MR images. Human Brain
Mapping, 29(11), 12881301.
Yvert, B., Bertrand, O., Thevenet, M., Echallier, J. F., & Pernier, J. (1997). A systematic
evaluation of the spherical model accuracy in EEG dipole localization.
Electroencephalography and Clinical Neurophysiology, 102(5), 452459.
Glossary
Abbreviations
BEM
EEG
LORETA
Introduction
Magnetoencephalography (MEG) and electroencephalography
(EEG) give us measures of magnetic field or electric potential
difference at the surface of the head due to neuronal current
flow. Estimating this current flow can give us estimates of brain
function, which update millisecond by millisecond. Figure 1
shows the distribution of magnetic field change outside the
head at a specific time instant. Based on a mathematical model
of the head and its relationship to the MEG sensors, it is
possible to estimate which part of the brain caused this changing field and, if necessary, superimpose this on an anatomical
image or structural MRI.
The estimation of cortical current flow based on MEG/EEG
data is an ill-posed inverse problem, that is, there is an infinity
of possible distributions of current flow that will generate the
same measured data. The accuracy of the solution to this
inverse problem depends both on the accuracy of the forward
model of the head and on the prior information used to reduce
the uncertainty (Baillet & Garnero, 1997).
One form of prior information is to assume that the data
can be explained by a small number of current elements of
dipoles (Supek & Aine, 1993); this is extremely powerful but is
a nonlinear problem that entails the fit of location, orientation,
and dipole magnitude and therefore becomes unstable as the
number of dipoles increases. One popular way to avoid this
problem is to consider that the locations and orientations of
all sources are known and simply estimate their magnitude
(Dale & Sereno, 1993; Grech et al., 2008; Hamalainen & Ilmoniemi, 1984).
There are numerous algorithms each involving different
prior assumption sets and cost functions (see Baillet, Mosher,
and Leahy (2001) for review). They range from the well-known
minimum norm estimation (MNE) algorithm (Hamalainen &
Ilmoniemi, 1984), in which the assumption is that all sources
are active but with minimum energy, to approaches such as
MEG
MSP
PDF
WMNE
Magnetoencephalography
Multiple sparse priors
Probability density function
Weighted minimum norm estimation
http://dx.doi.org/10.1016/B978-0-12-397025-1.00331-6
557
558
Figure 1 The left panel shows the distribution of magnetic field measured outside the head. The middle panel shows the distribution of these
magnetic field measurements relative to the head and cortical surface. The right panel shows an estimate (based on additional prior information) of the
current flow that gave rise to the magnetic field change.
[1]
pYjJpJ
pY
[2]
Smoother-Based Approaches
# dipoles
559
# dipoles
(a)
(b)
# dipoles
Figure 2 (a) The minimum norm assumption is based on an identity matrix. (b) The red circles show the location of the simulated source; the
translucent glass brain shows the frontal, lateral, and superior views of the dipoles with the highest variance during the time windows of interest. Note
that the minimum norm solution tends to be displaced superficially.
(a)
# dipoles
(b)
Figure 3 (a) Gaussian smoothed prior covariance matrix. (b) The smoothed solution (also called LORETA-like) still has a large localization error for
deep sources.
560
Data-Based Approaches
Up until now, the choice of Q has not depended on the data. It
is also possible to use empirical Bayes to estimate these prior
(source noise and sensor noise) covariance matrices from the
data. At the simplest level, one can make an estimate of the
source covariance matrix empirically and use empirical Bayes
to provide the optimal weighting between source and sensor
noise matrices.
For example, beamformer algorithms make a direct estimate of source covariance based on the assumption that there
are no zero-lag correlated sources (Sekihara et al., 1999; van
Veen et al., 1997). The beamforming solution can be introduced into the Bayesian framework as a single covariance
matrix, Q B, where B 2 Nd Nd is a diagonal matrix formed
directly from the data, and it is projected into the source space
with the lead field matrix and normalized (Belardinelli, Ortiz,
Barnes, Noppeney, & Preissl, 2012). Each diagonal element of
B is defined as
1 T T 1 1
Bii
L YY
Li
, 8i 1, . . . , Nd
di i
with Bii the ith main diagonal element of B, and Li the ith
column of L, and the normalization parameters d is defined as
di
1
, 8i 1, . . . , Nd
LTi Li
MSP Algorithm
Nq
X
hi Ci
[4]
i1
# dipoles
covariance
as the
(a)
# dipoles
(b)
Figure 4 (a) Prior covariance matrix formed with the weighted covariance of the data. (b) The beamforming reconstruction is highly smoothed but with
small localization error for single sources of neural activity.
561
# dipoles
# dipoles
(a)
(b)
Figure 5 (a) Set of covariance components that form the matrix Q. (b) The optimization of the MSP can achieve zero localization error if the source of
neural activity coincides with one of the covariance components or a linear mixture of them.
For a given set of covariance components C, the optimization of hyperparameters is performed with an iterative process
called variational Laplace approximation (Friston et al., 2008),
which maximizes the model evidence p(Y), by computing the
gradient and Hessian of the negative variational free energy
(Friston et al., 2007). The free energy is used as the cost function to fit the modeled covariance (determined
by the hyperparameters h) to the data covariance SY 1 Nt YY T . The free
energy can be expressed in words as (Lopez, Litvak et al.,
2013a)
Model
Size of model
Num of data
F
covariance
samples
error
Error in
Error in covariance
hyperparameters
of hyperparameters
The MSP is based on a library of hundreds of covariance
components, each corresponding to a different locally smooth
focal region (or patch) of the cortex (for implementation details
of the MSP algorithm, see Friston et al. (2008), Lopez, Litvak
et al. (2013a), and Belardinelli et al. (2012)). Figure 5(a) shows
how the set of covariance components is formed with diagonal
smoothers representing focal active regions. Figure 5(b)
shows the MSP reconstruction after the optimization process
performed over the hyperparameters; note that zero localization
error may be achieved if the source of neural activity coincides
with one of the active regions in the dictionary of covariance
components C. Finally, the localization error given by each of
the algorithms and their resultant free energy are shown in
Figure 6.
Concluding Remarks
In this article, a brief review of the most widely used Bayesian
distributed inversion approaches for solving the MEG/EEG
inverse problem has been presented. Fundamentally, all
schemes can be put into a common mathematical framework
differing only in the prior assumptions about the source covariance matrix. Here, the mathematical assumptions underlying
30
Localisation error(mm)
Log model evidence
20
10
0
MMN
Loreta
BMF
MSP
Figure 6 Blue bars show the localization error (the distance between
the peak of the estimated current distribution and the simulated source
location) for the four different algorithms used. Red bars show the
relative log model evidence for the four solutions. Note that normally,
localization error is not available but model evidence seems to be a good
proxy with which to judge between prior assumptions.
562
References
Auranen, T., Nummenmaa, A., Hamalainen, M. S., Jaaskelainen, I. P., Lampinen, J.,
Vehtari, A., et al. (2005). Bayesian analysis of the neuromagnetic inverse problem
with Lp-norm priors. Neuroimage, 26, 870884.
Baillet, S., & Garnero, L. (1997). A Bayesian approach to introducing anatomofunctional priors in the EEG/MEG inverse problem. IEEE Transactions on
Biomedical Engineering, 44, 5.
Baillet, S., Mosher, J. C., & Leahy, R. M. (2001). Electromagnetic brain mapping. IEEE
Signal Processing Magazine, 18(6), 1430.
Belardinelli, P., Ortiz, E., Barnes, G., Noppeney, U., & Preissl, H. (2012). Source
reconstruction accuracy of MEG and EEG Bayesian inversion approaches. PLoS
One, 7, 12.
Chowdhury, R. A., Lina, J. M., Kobayashi, E., & Grova, C. (2013). MEG source
localization of spatially extended generators of epileptic activity: Comparing entropic
and hierarchical bayesian approaches. PLoS One, 8(2), e55969.
Dale, A. M., & Sereno, M. I. (1993). Improved localization of cortical activity by
combining EEG and MEG with MRI cortical surface reconstruction: A linear
approach. Journal of Cognitive Neuroscience, 5, 162176.
Daunizeau, J., & Friston, K. J. (2007). A mesostate-space model for EEG and MEG.
NeuroImage, 38(1), 6781.
Friston, K., Harrison, L., Daunizeau, J., Kiebel, S., Phillips, C., Trujillo-Barreto, N., et al.
(2008). Multiple sparse priors for the M/EEG inverse problem. NeuroImage, 39,
11041120.
Friston, K., Mattout, J., Trujillo-Barreto, N., Ashburner, J., & Penny, W. (2007).
Variational free energy and the Laplace approximation. NeuroImage, 34, 220234.
Golub, G. H., Heath, M., & Wahba, G. (1979). Generalized cross-validation as a method
for choosing a good ridge parameter. Technometrics, 21, 215223.
Grech, R., Cassar, T., Muscat, J., Camilleri, K., Fabri, S., Zervakis, M., et al. (2008).
Review on solving the inverse problem in EEG source analysis. Journal of
NeuroEngineering and Rehabilitation, 5, 25.
Hallez, H., Vanrumste, B., Grech, R., Muscat, J., De Clercq, W., Vergult, A., et al. (2007).
Review on solving the forward problem in EEG source analysis. Journal of
NeuroEngineering and Rehabilitation, 4, 46.
Hamalainen, M. S., & Ilmoniemi, R. J. (1984). Interpreting measured magnetic fields of
the brain: Estimates of current distributions. Technical Report, Helsinki University of
Technology.
Hansen, P. C. (2000). Computational inverse problems in electrocardiology: The Lcurve and its use in the numerical treatment of inverse problems. In P. Johnston
(Ed.), Advances in Computational Bioengineering. Computational inverse problems
in electrocardiology (pp. 119142). WIT Press.
Harrison, L., Penny, W., Ashburner, J., Trujillo-Barreto, N., & Friston, K. (2007).
Diffusion-based spatial priors for imaging. NeuroImage, 38, 677695.
Henson, R. N., Wakeman, D. G., Litvak, V., & Friston, K. J. (2011). A parametric
empirical Bayesian framework for the EEG/MEG inverse problem: Generative models
Introduction
Organization of Cortical Microcircuits
The neocortex is commonly described as a six-layered structure
(DeFelipe, Alonso-Nanclares, & Arellano, 2002). Spiny neurons (pyramidal cells and spiny stellate cells) and smooth
neurons are the two major groups of cortical neurons. The
majority of cortical neurons are pyramidal cells that are
found in layers 26. Most spiny stellate cells are interneurons
that are located in the middle cortical layers. Smooth neurons
are essentially GABAergic interneurons distributed in all layers.
In general, cortical neurons are organized into multiple, small
repeating microcircuits. In spite of cortical heterogeneity, a
common basic microcircuit has emerged. Its skeleton is formed
by a pyramidal cell, which receives excitatory inputs that originate from extrinsic afferent systems and spiny cells. Inhibitory
inputs originate mostly from GABAergic interneurons. These
microanatomical characteristics have been found in all cortical
areas and species examined so far, and, therefore, they can be
considered as fundamental aspects of cortical organization
(DeFelipe et al., 2002). These basic microcircuits are commonly referred to as cortical minicolumns (50 mm diameter,
containing about 400 principal cells), which themselves
grouped into cortical macrocolumns (900 mm diameter)
(Jones, 2000). Eventually, a cortical area (12 cm diameter)
is composed of several cortical macrocolumns.
Magnetoencephalographic/Electroencephalographic Signals
Magnetoencephalographic/electroencephalographic
(MEG/
EEG) signals result mainly from primary intracellular (MEG)
and extracellular (EEG) current flow, created by massively
summed postsynaptic potentials in synchronously activated
and vertically oriented neurons, which constitute the dendritic
activity of macrocolumns of pyramidal cells. Spontaneous
MEG/EEG activity is often decomposed into distinct frequency
bands (e.g., delta, 14 Hz; theta, 48 Hz; alpha, 812 Hz; beta,
1230 Hz; and gamma, 3070 Hz; Nunez & Srinivasan, 2005),
which are robust correlates of subjects states and can be readily
used, for example, to define sleep stages. The exact neurophysiological mechanisms, which constrain this synchronization to a
given frequency band, have remained obscure. It is clear though
that the generation of oscillations appears to depend on interactions between large populations of inhibitory and excitatory
neurons, whose kinetics determine their oscillation frequency
(David & Friston, 2003). Event-related fields (ERFs) and potentials (ERPs) are obtained by averaging MEG and EEG signals in
relation to some transient stimulus or task (Coles & Rugg, 1995;
DeFelipe et al., 2002). They have been used for decades as
putative electrophysiological correlates of perceptual and cognitive operations because they last often less than a few seconds
and are correlated with stimulus changes or cognitive set. However, like MEG/EEG oscillations, the exact neurobiological
http://dx.doi.org/10.1016/B978-0-12-397025-1.00333-X
563
564
u1
u1
v1
0
u2
u2
v1
w1
v2
0
w2 v2
MFA
0
w
u, v
un
un
vn
1
0
wn
vn
Figure 1 Mean field approximation (MFA). The left-hand side illustrates a neuronal population composed n neurons. vi, mi, and wi denote the membrane
potential, the normalized firing rate, and the firing threshold of the ith neuron, respectively. The output relations in the graphs show that, in this
example, the neurons fire at 1 or do not fire (0), depending on the threshold of firing, which may exhibit some variation between neurons. On the righthand side, the MFA of the neural mass models stipulates that the dynamics of that neuronal ensemble, or neuronal mass, is sufficiently described by the
mean of the state variables (v and m), using the mean relationship between v and m (the step function is transformed into a sigmoid function by the
averaging). Thus, the effect of the MFA, which is practically very important as n is on the order of a million, is that it reduces a huge system (3*n variables:
wi, vi, mi, i [1,. . .,n]) into a small one (4 variables: w, r, m, and v). The drawback of this approach is that the reconstructed dynamics might not be
accurate, in part because the information about the synchronization among neurons is lost by the averaging step. Adapted with permission from David, O.,
Harrison, L., & Friston, K. (2007). Neuronal models of EEG and MEG. In K. Friston et al. (Eds.), Statistical parametric mapping: The analysis of
functional brain images (pp. 414440). London, Academic Press.
Mean
membrane
potential
Mean
firing
rate
Input
synapses
Mean
firing
rate
Axons
Dendrites
and somas
Figure 2 In neural mass models, a neuronal population is usually
described by its mean membrane potential, which receives incoming
inputs (mean firing rate of all afferent axons) and sends output
signals (mean firing rate of the neurons belonging to the population).
Adapted with permission from David, O., Harrison, L., & Friston, K.
(2007). Neuronal models of EEG and MEG. In K. Friston et al. (Eds.),
Statistical parametric mapping: The analysis of functional brain images
(pp. 414440). London, Academic Press.
Input
synapses
h(t) =
h
t0
t<0
uo
Axons
Dendrites
and somas
t
t
H exp
t
t
uo = S(v)
S(v) =
2e0
1 + exp( rv)
e0
uo
0
0
[3]
v = h ui
[1]
ui
565
Figure 3 Model of a neuronal population that rests on two operators: the first transforms ui, the average density of presynaptic input arriving at the
population, into v, the average postsynaptic membrane potential (PSP). This is modeled by a linear transformation. The kernel h is parameterized by
H and t modeling specific properties of synapses. The parameter H tunes the maximum amplitude of PSPs and t is a lumped representation of the sum
of the rate constants of passive membrane and other spatially distributed delays in the dendritic tree. The second operator transforms the average
membrane potential of the population into an average rate of action potentials fired by the neurons. This transformation is assumed to be instantaneous
and is described by a sigmoid function parameterized with e0 and r. Adapted with permission from David, O., Harrison, L., & Friston, K. (2007).
Neuronal models of EEG and MEG. In K. Friston et al. (Eds.), Statistical parametric mapping: The analysis of functional brain images (pp. 414440).
London, Academic Press.
566
2e0
e0
1 exprv
[4]
C1
x7 = x8
.
H
2x
x
x8 = e (g3S(x0)+ c1u) 8 72
te
te te
Inhibitory
interneurons
Spiny
stellate
cells
g4
g3
.
x1 = x4
2x
x
.
H
x4 = e (g 1S(x0)+ c2u) 4 12
te
te te
g 1 Intrinsic
connections
C2
Extrinsic
connections
u
g2
Pyramidal
cells
[5]
x0 = x5 x6
C3
x2 = x5
.
x
H
2x
x5 = e (g 2S(x1)+ c3u) 5 22
te te
te
.
x3 = x6
2x x
.
H
x6 = i (g 4S(x7) 6 32
ti
ti
ti
Figure 4 State space representation of the Jansen and Rit model of a cortical area. Three neuronal subpopulations are considered to model a cortical
area. Pyramidal cells interact with both excitatory and inhibitory interneurons with the connectivity constants g2 0.8g1, g3 g4 0.25g1. The
parameters He,i and te,i control the expression of postsynaptic potentials as shown in equation. Subscripts e and i denote excitatory and inhibitory,
respectively. Adapted with permission from David, O., Harrison, L., & Friston, K. (2007). Neuronal models of EEG and MEG. In K. Friston et al. (Eds.),
Statistical parametric mapping: The analysis of functional brain images (pp. 414440). London, Academic Press.
Inhibitory
interneurons
567
4
2
Spiny
stellate
cells
0
2
Pyramidal
cells
Inhibitory
interneurons
Spiny
stellate
cells
Pyramidal
cells
100
200
300
400
500
600
Time (ms)
700
800
900
1000
100
200
300
400
500
600
Time (ms)
700
800
900
1000
6
4
2
0
Figure 5 Effect of the shape of extrinsic inputs u on the dynamic of a cortical area (Figure 4). Top: MEG/EEG-like oscillations are obtained when u is
stochastic (Gaussian in this simulation). Bottom: ERP/ERF-like waveforms are obtained when u contains a fast transient (a delta function in this
simulation). This simulation used the model described in Figure 4, with extrinsic inputs entering on spiny stellate cells only, with the following
parameters: He 3.25, Hi 29.3, te 10 ms, ti 15 ms, d d(ij) 10 ms, g1 50, g2 40, g3 g4 12, e0 2.5, v0 0, r 0.56. Adapted
with permission from David, O., Harrison, L., & Friston, K. (2007). Neuronal models of EEG and MEG. In K. Friston et al. (Eds.), Statistical parametric
mapping: The analysis of functional brain images (pp. 414440). London, Academic Press.
x02
c2u(t)
2
x2,q 2
a21S(x01(t d21))
a12S(x0(t d12))
1
c1u(t)
x1,q 1
x10
and 2, y(1) and y(2) are the neuronal parameters of areas 1 and
2, and d(12) and d(21) are the propagation delay from 2 to 1 and
from 1 to 2 (Figure 6). In matrix form and ignoring the
propagation delays for simplicity, eqn [6] is equivalent to
x_ f x, ASx0 Cu,y
[7]
with
"
#
1
1
0 a12
c
x0
x1
x 2 , x0 2 , y y2 , A
, C 1
a
0
c2
x
y
21
x0
568
1
c1
a21
c1
c2
a12
0.6
0.4
0.2
0
0.2
0.4
a12 = 0; a21 = 0
a21
a12
a12 = 0; a21 = 0
6
4
2
0
1.5
1
0.5
0
0.5
1
1.5
a12 = 0; a21 = 60
6
4
2
0
2
200 400 600 800 1000 1200 1400 1600 1800 2000
Time (ms)
100 200 300 400 500 600 700 800 900 1000
Time (ms)
Figure 7 Relationships between effective connectivity (coupling parameters) and functional connectivity (observed correlations between signals). The
model is composed of two areas, asymmetrically coupled. Left: Ongoing activity was simulated using a different stochastic input entering on each area,
which generated synchronous oscillations when increasing neuronal coupling between cortical areas. Right: A fast transient (delta function) was
assumed to occur at the extrinsic input of area 1. When areas are not coupled (left-hand side), the evoked response does not propagate to area 2,
whereas one can observe a late activity in area 2 because of a coupling from area 1 towards area 2 on the right-hand side. Adapted with permission from
David, O., Harrison, L., & Friston, K. (2007). Neuronal models of EEG and MEG. In K. Friston et al. (Eds.), Statistical parametric mapping: The analysis of
functional brain images (pp. 414440). London, Academic Press.
Conclusion
Neural mass models afford a straightforward approach to
modeling the activity of populations of neurons. Their main
References
Almeida, R., & Stetter, M. (2002). Modeling the link between functional imaging and
neuronal activity: Synaptic metabolic demand and spike rates. NeuroImage, 17(2),
10651079.
Babajani-Feremi, A., & Soltanian-Zadeh, H. (2011). Development of a variational
scheme for model inversion of multi-area model of brain. Part I: Simulation
evaluation. Mathematical Biosciences, 229(1), 6475.
Baillet, S., Mosher, J., & Leahy, R. (2001). Electromagnetic brain mapping. IEEE Signal
Processing Magazine, 18(6), 1430.
Blenkinsop, A., et al. (2012). The dynamic evolution of focal-onset epilepsies
Combining theoretical and clinical observations. European Journal of Neuroscience,
36(2), 21882200.
Bojak, I., & Liley, D. T. J. (2010). Axonal velocity distributions in neural field equations.
PLoS Computational Biology, 6(1), e1000653.
Buzsaki, G., Anastassiou, C. A., & Koch, C. (2012). The origin of extracellular fields and
currents EEG, ECoG, LFP and spikes. Nature Reviews Neuroscience, 13(6), 407420.
Coles, M. G. H., & Rugg, M. D. (1995). Event-related brain potentials: An introduction.
In Electrophysiology of mind (pp. 126). Oxford: Oxford University Press.
Coombes, S. (2010). Large-scale neural dynamics: Simple and complex. NeuroImage,
52(3), 731739.
David, O., & Friston, K. J. (2003). A neural mass model for MEG/EEG: Coupling and
neuronal dynamics. NeuroImage, 20(3), 17431755.
David, O., Harrison, L., & Friston, K. J. (2005). Modelling event-related responses in
the brain. NeuroImage, 25(3), 756770.
David, O., Kiebel, S. J., et al. (2006). Dynamic causal modeling of evoked responses in
EEG and MEG. NeuroImage, 30(4), 12551272.
David, O., Kilner, J. M., & Friston, K. J. (2006). Mechanisms of evoked and induced
responses in MEG/EEG. NeuroImage, 31(4), 15801591.
Deco, G., et al. (2008). The dynamic brain: From spiking neurons to neural masses and
cortical fields. PLoS Computational Biology, 4(8), e1000092.
DeFelipe, J., Alonso-Nanclares, L., & Arellano, J. I. (2002). Microstructure of the
neocortex: Comparative aspects. Journal of Neurocytology, 31(35), 299316.
Freeman, W. J. (1978). Models of the dynamics of neural populations.
Electroencephalography and Clinical Neurophysiology, 34(Suppl.), 918.
Friston, K. J., & Dolan, R. J. (2010). Computational and dynamic models in
neuroimaging. NeuroImage, 52(3), 752765.
569
Friston, K., Moran, R., & Seth, A. K. (2013). Analysing connectivity with Granger
causality and dynamic causal modelling. Current Opinion in Neurobiology, 23(2),
172178.
Haskell, E., Nykamp, D. Q., & Tranchina, D. (2001). Population density methods for
large-scale modelling of neuronal networks with realistic synaptic kinetics:
Cutting the dimension down to size. Network (Bristol, England), 12(2),
141174.
Horwitz, B., & Tagamets, M.-A. (1999). Predicting human functional maps with neural
net modeling. Human Brain Mapping, 8(23), 137142.
Jansen, B. H., & Rit, V. G. (1995). Electroencephalogram and visual evoked potential
generation in a mathematical model of coupled cortical columns. Biological
Cybernetics, 73(4), 357366.
Jones, E. G. (2000). Microcolumns in the cerebral cortex. Proceedings of the
National Academy of Sciences of the United States of America, 97(10),
50195021.
Laxminarayan, S., et al. (2012). Modeling habituation in rat EEG-evoked responses via a
neural mass model with feedback. Biological Cybernetics, 105(56), 371397.
Lopes da Silva, F. H. (1974). Model of brain rhythmic activity. The alpha-rhythm of the
thalamus. Kybernetik, 15(1), 2737.
Miller, K. D. (2003). Understanding layer 4 of the cortical circuit: A model based on cat
V1. Cerebral Cortex (New York, NY: 1991), 13(1), 7382.
Moran, R. J., et al. (2008). Bayesian estimation of synaptic physiology from the spectral
responses of neural masses. NeuroImage, 42(1), 272284.
Nguyen Trong, M., Bojak, I., & Knosche, T. R. (2012). Associating spontaneous with
evoked activity in a neural mass model of visual cortex. NeuroImage, 66C, 8087.
Nunez, P. L., & Srinivasan, R. (2005). Electric fields of the brain. New York: Oxford
University Press.
Pinotsis, D. A., & Friston, K. J. (2011). Neural fields, spectral responses and lateral
connections. NeuroImage, 55(1), 3948.
Pons, A. J., et al. (2010). Relating structural and functional anomalous connectivity in
the aging brain via neural mass modeling. NeuroImage, 52(3), 848861.
Rennie, C. J., Robinson, P. A., & Wright, J. J. (2002). Unified neurophysical model of
EEG spectra and evoked potentials. Biological Cybernetics, 86(6), 457471.
Riera, J. J., et al. (2006). Nonlinear local electrovascular coupling. I: A theoretical
model. Human Brain Mapping, 27(11), 896914.
Robinson, P., Rennie, C., & Rowe, D. (2002). Dynamics of large-scale brain activity in
normal arousal states and epileptic seizures. Physical Review E, 65(4), 041924.
Robinson, P., et al. (2001). Prediction of electroencephalographic spectra from
neurophysiology. Physical Review E, 63(2), 021903.
Sotero, R. C., & Trujillo-Barreto, N. J. (2008). Biophysical model for integrating
neuronal activity, EEG, fMRI and metabolism. NeuroImage, 39(1), 290309.
Spiegler, A., et al. (2010). Bifurcation analysis of neural mass models: Impact of
extrinsic inputs and dendritic time constants. NeuroImage, 52(3), 10411058.
Spiegler, A., et al. (2011). Modeling brain resonance phenomena using a neural mass
model. PLoS Computational Biology, 7(12), e1002298.
Stam, C. J., et al. (1999). Dynamics of the human alpha rhythm: Evidence for nonlinearity? Clinical Neurophysiology, 110(10), 18011813.
Suffczynski, P., et al. (2001). Computational model of thalamo-cortical networks:
Dynamical control of alpha rhythms in relation to focal attention. International
Journal of Psychophysiology, 43(1), 2540.
Thomson, A. M., & Deuchars, J. (1997). Synaptic interactions in neocortical local
circuits: Dual intracellular recordings in vitro. Cerebral Cortex (New York, NY:
1991), 7(6), 510522.
Valdes, P. A., et al. (1999). Nonlinear EEG analysis based on a neural mass model.
Biological Cybernetics, 81(56), 415424.
Valdes-Sosa, P. A., et al. (2009). Model driven EEG/fMRI fusion of brain oscillations.
Human Brain Mapping, 30(9), 27012721.
van Rotterdam, A., et al. (1982). A model of the spatialtemporal characteristics of the
alpha rhythm. Bulletin of Mathematical Biology, 44(2), 283305.
Varela, F., et al. (2001). The brainweb: Phase synchronization and large-scale
integration. Nature Reviews Neuroscience, 2(4), 229239.
Voges, N., et al. (2012). Modeling of the neurovascular coupling in epileptic discharges.
Brain Topography, 25(2), 136156.
Wendling, F., et al. (2000). Relevance of nonlinear lumped-parameter models in the
analysis of depth-EEG epileptic signals. Biological Cybernetics, 83(4),
367378.
Wendling, F., et al. (2002). Epileptic fast activity can be explained by a model of
impaired GABAergic dendritic inhibition. The European Journal of Neuroscience,
15(9), 14991508.
Wendling, F., et al. (2012). Interictal spikes, fast ripples and seizures in partial
epilepsies Combining multi-level computational models with experimental data.
European Journal of Neuroscience, 36(2), 21642177.
Wilson, H. R., & Cowan, J. D. (1972). Excitatory and Inhibitory interactions in localized
populations of model neurons. Biophysical Journal, 12(1), 124.
Glossary
http://dx.doi.org/10.1016/B978-0-12-397025-1.00334-1
571
572
INTRODUCTION TO METHODS AND MODELING | Spontaneous and Evoked Functional Connectivity Modeling of the Brain
INTRODUCTION TO METHODS AND MODELING | Spontaneous and Evoked Functional Connectivity Modeling of the Brain
DSI-tractography
573
[1]
[2]
Structural
connectivity
Dynamical
model
Model
FC
Empirical FC
(a)
GABA
(b)
NMDA
AMPA
AMPA
574
INTRODUCTION TO METHODS AND MODELING | Spontaneous and Evoked Functional Connectivity Modeling of the Brain
Table 1
Names and abbreviations of the brain regions considered in
the human connectome from Hagmann et al. (2008) (in alphabetical
order)
Abbreviation
Brain region
BSTS
CAC
CMF
CUN
ENT
FP
FUS
IP
ISTC
IT
LING
LOCC
LOF
MOF
MT
PARC
PARH
PC
PCAL
PCUN
POPE
PORB
PREC
PSTC
PTRI
RAC
RMF
SF
SMAR
SP
ST
TP
TT
Taken from Deco, G., Ponce-Alvarez, A., Mantini, D., Romani, G.L., Hagmann, P., &
Corbetta, M. (2013). Resting-state functional connectivity emerges from structurally and
dynamically shaped slow linear fluctuations. Journal of Neuroscience, 33,
1123911252.
StructureFunction Relation
Given that the linearized version of the DMF model fairly
reproduces the resting global dynamics, we can further simplify
the system of stochastic differential equations by expressing it
in terms of the first- and second-order statistical moments
means and covariances of network activity. In general, the
[3]
where J is the Jacobian matrix evaluated at the steady spontaneous state and Qn is the covariance matrix of the noise.
Equation [3] is solved using the eigendecomposition of the
Jacobian matrix J LDL1, where D is a diagonal matrix containing the eigenvalues of J, noted li, and the columns of
matrix L are the eigenvectors of J. Using the inverse and the
conjugate transpose of L, noted L1 and L{, respectively, we get
Cv LML{
[4]
*
1
{
~ = li l and QL
~
where M is given by Mij Q
Qn L .
ij
j
Equation [4] can be seen as a linear noise propagation
equation: An initial uncertainty or noise (M) is propagated
through the dynamic system and is mapped to its approximated linear output (Cv). It expresses the contribution to the
mapping of the intrinsic noise into the resulting functional
correlations of both the dynamics and the anatomical structure, since the Jacobian matrix is explicitly determined by the
connectivity matrix and the network dynamic state at which
it is evaluated. Hence, eqn [4] gives a direct relation between
the correlation structure, the underlying connectivity, and
dynamics. Finally, using this method, we estimated the
correlation q
structure
between
gating variables, defined as
Qij Cv ij = Cv ii Cv jj .
INTRODUCTION TO METHODS AND MODELING | Spontaneous and Evoked Functional Connectivity Modeling of the Brain
575
100
Single
state
150
Multistability
(with spont.
state)
Multi-stability
(high firing rate)
0
100
0
100
100
0
Spikes .s-1
200
50
10
0
Area #
0
1
(a)
2
3
Coupling strength (G)
Single
state
0
100
100
0
100
0
50
10
0
1
66
Area #
0
1
(b)
100
Multi-stability
Multi(high firing rate)
stability
(with spont.
state)
Spikes .s-1
150
66
2
3
Coupling strength (G)
Figure 2 Mean-field approximation. Bifurcation diagrams of the cortical spiking network (a) and the reduced DMF model (b) as a function of the global
coupling strength. Each point represents the maximum firing rate activity among all nodes. In both cases, depending on the coupling strength (G)
and the initial conditions, the network converges to one of the three possible dynamic regimes: For low values of G, the network settles into a single
stable state of low firing activity (i.e., the spontaneous state); for increasing values of G, new stable states of high activity (blue histograms in the
Insets) coexist together with the spontaneous state (yellow histogram in the Insets); or for even larger values of G, the spontaneous state becomes
unstable. Figure modified from Deco, G., Ponce-Alvarez, A., Mantini, D., Romani, G.L., Hagmann, P., & Corbetta, M. (2013). Resting-state functional
connectivity emerges from structurally and dynamically shaped slow linear fluctuations. Journal of Neuroscience, 33, 1123911252.
576
INTRODUCTION TO METHODS AND MODELING | Spontaneous and Evoked Functional Connectivity Modeling of the Brain
Figure 3 Prediction of the FC. (a) The fitting of empirical data as a function of the global coupling parameter G was calculated for the spiking (red stars)
and for both the reduced DMF models (blue points) and its linearized version around the spontaneous state (gray squares). As a measure of
similarity, we used the Pearson correlation coefficient between the Fisher z-transformed pairwise correlation coefficients of both the empirical and the
simulated FC matrix. In the detailed spiking model, simulated BOLD signals were obtained by transforming the synaptic activity summed over the excitatory
and inhibitory populations in each cortical area by the hemodynamic model, while for the DMF, the synaptic gating variables of each cortical area were
used as input to the hemodynamic model. (b) Similarity between the empirical FC and the correlation structure of gating variable fluctuations obtained using
the moments method. (c) Averaged power spectrum of gating variable fluctuations around the spontaneous state, as a function of the global coupling
and frequency. (d) Comparison between the neuroanatomical and functional connections linking the left posterior cingulate (lPC). Gray bars indicate the
seed. Figure modified from Deco, G., Ponce-Alvarez, A., Mantini, D., Romani, G.L., Hagmann, P., & Corbetta, M. (2013). Resting-state functional
connectivity emerges from structurally and dynamically shaped slow linear fluctuations. Journal of Neuroscience, 33, 1123911252.
INTRODUCTION TO METHODS AND MODELING | Spontaneous and Evoked Functional Connectivity Modeling of the Brain
would change its dynamic state and settle to a new created fixed
point, for which the Jacobian matrix is different, and consequently, the correlations between areas would change. To illustrate this, we applied an arbitrary input to both left and right
lateral occipital cortices and compared the resulting evoked
correlation structure of gating variables with the one obtained
in the spontaneous (or rest) condition (Figure 4(a) and 4(b)).
The stimulus substantially increases or decreases the pairwise
correlations between cortical areas with respect to the spontaneous condition and, therefore, generates a different effective connectivity by changing the network interactions. Effective
connectivity refers to how different cortical areas influence
each other, even in the absence of direct connection between
them (Aertsen et al., 1989; Bullmore & Sporns, 2009; Friston,
2011; Robinson, 2012). Several studies have shown that the
effective connectivity of the brain during cognitive tasks can
change depending on the context (e.g., Friston & Buchel, 2000;
Rowe, Stephan, Friston, Frackowiak, & Passingham, 2005; Toni
et al., 2012). Dynamic changes of effective connectivity are
expected to arise due to activity- and context-dependent brain
dynamics, mediated by synaptic plasticity, neuromodulation, or
even the interplay between excitation and inhibition (Vogels &
Abbott, 2009). The effective connectivity has been efficiently
577
Figure 4 Spontaneous versus evoked correlations. (a) The correlation matrix evoked by an external stimulus (upper triangular part of the matrix) was
compared to the spontaneous correlation matrix (lower triangular part of the matrix); both matrices were calculated using the moments method. In
both conditions, the global coupling was G 2.2, for which the agreement between the spontaneous correlation matrix and the empirical FC was
maximum. In the evoked condition, the right and left lateral occipital cortices (LOCC) received an augmented constant input, equal to I0 dI, with I0 0.3
(nA) and dI 0.05 (nA), while all other cortical areas received the baseline input I0 (see eqn [2]). The stationary states, at which correlations are
calculated, in both spontaneous and evoked conditions, are represented by the histograms. Red bars indicated the stimulated nodes (rLOCC and lLOCC).
(b) Element-by-element difference (Drc) between evoked correlation matrix and spontaneous (rest) correlation matrix. (c) The Fisher information
(FI) was calculated in response to an infinitesimal variation of the stimulus (dI 0.001; black trace). Both the contribution to the FI of the mean response
(FImean; red trace) and the contribution to the FI of the covariance (FIcov; blue trace) present a maximum near the instability. Panels (a) and (b) were
taken from Deco, G., Ponce-Alvarez, A., Mantini, D., Romani, G.L., Hagmann, P., & Corbetta, M. (2013). Resting-state functional connectivity
emerges from structurally and dynamically shaped slow linear fluctuations. Journal of Neuroscience, 33, 1123911252.
578
INTRODUCTION TO METHODS AND MODELING | Spontaneous and Evoked Functional Connectivity Modeling of the Brain
References
Abbott, L. F., & Dayan, P. (1999). The effect of correlated variability on the accuracy of a
population code. Neural Computation, 11, 91101.
Aburn, M. J., Holmes, C. A., Roberts, J. A., Boonstra, T. W., & Breakspear, M. (2012).
Critical fluctuations in cortical models near instability. Frontiers in Fractal
Physiology, 3, 331.
Aertsen, A., Gerstein, G., Habib, M., & Palm, G. (1989). Dynamics of neuronal firing
correlation: modulation of effective connectivity. Journal of Neurophysiology, 61,
900917.
Andreasen, N. C., OLeary, D. S., Cizadlo, T., Arndt, S., Rezai, K., Watkins, G. L., et al.
(1995). Remembering the past: Two facets of episodic memory explored with
positron emission tomography. American Journal of Psychiatry, 152, 15761585.
Biswal, B., Yetkin, F., Haughton, V., & Hyde, J. (1995). Functional connectivity in the
motor cortex of resting human brain using echo-planar MRI. Magnetic Resonance in
Medicine, 34, 537541.
Bullmore, E., & Sporns, O. (2009). Complex brain networks: Graph theoretical
analysis of structural and functional systems. Nature Reviews Neuroscience, 10,
186198.
Burns, N., & Webb, A. (1976). The spontaneous activity of neurons in the cats cerebral
cortex. Proceedings of the Royal Society of London Series B-Biological Sciences,
194, 211223.
Cabral, J., Hugues, E., Sporns, O., & Deco, G. (2011). Role of network oscillations in
resting-state functional connectivity. Neuroimage, 57, 130139.
Daffertshofer, A., & van Wijk, B. C.M (2011). On the influence of amplitude on the
connectivity between phases. Frontiers in Neuroinformatics, 5, 6.
Deco, G., & Corbetta, M. (2011). The dynamical balance of the brain at rest. The
Neuroscientist, 17, 107123.
Deco, G., & Jirsa, V. (2012). Ongoing cortical activity at rest: Criticality, multistability
and ghost attractors. Journal of Neuroscience, 32, 33663375.
Deco, G., Jirsa, V., & McIntosh, A. (2011). Emerging concepts for the dynamical organization
of resting-state activity in the brain. Nature Reviews Neuroscience, 12, 4356.
Deco, G., Jirsa, V., McIntosh, A. R., Sporns, O., & Kotter, R. (2009). Key role of
coupling, delay, and noise in resting brain fluctuations. Proceedings of the National
Academy of Sciences of the United States of America, 106, 1030210307.
Deco, G., Ponce-Alvarez, A., Mantini, D., Romani, G. L., Hagmann, P., & Corbetta, M.
(2013). Resting-state functional connectivity emerges from structurally and dynamically
shaped slow linear fluctuations. Journal of Neuroscience, 33, 1123911252.
Drysdale, P., Huber, J. P., Robinson, P. A., & Aquino, K. M. (2010). Spatiotemporal
BOLD hemodynamics from a poroelastic hemodynamic model. Journal of
Theoretical Biology, 265, 524534.
Eckhoff, P., Wong-Lin, K. F., & Holmes, P. (2011). Dimension reduction and dynamics
of a spiking neuron model for decision making under neuromodulation. Journal on
Applied Dynamical Systems, 10, 148188.
Fox, M., & Raichle, M. (2007). Spontaneous fluctuations in brain activity observed
with functional magnetic resonance imaging. Nature Reviews Neuroscience, 8,
700711.
Fox, M., Snyder, A., Vincent, J., Corbetta, M., Van Essen, D., & Raichle, M. (2005). The
human brain is intrinsically organized into dynamic, anticorrelated functional
networks. Proceedings of the National Academy of Sciences of the United States of
America, 102, 96739678.
Fransson, P. (2005). Spontaneous low-frequency BOLD signal fluctuations: An fMRI
investigation of the resting-state default mode of brain function hypothesis. Human
Brain Mapping, 26, 1529.
Freyer, F., Roberts, J. A., Becker, R., Robinson, P. A., Ritter, P., & Breakspear, M.
(2011). Biophysical mechanisms of multistability in resting-state cortical rhythms.
Journal of Neuroscience, 31, 63536361.
Friston, K. (2011). Functional and effective connectivity: A review. Brain Connectivity, 1,
1336.
Friston, K., & Buchel, C. (2000). Attentional modulation of effective connectivity from
V2 to V5/MT in humans. Proceedings of the National Academy of Sciences of the
United States of America, 97, 75917596.
Friston, K., Harrison, L., & Penny, W. (2003). Dynamic causal modelling. Neuroimage,
19, 12731302.
Ghosh, A., Rho, Y., McIntosh, A., Kotter, R., & Jirsa, V. (2008). Noise during rest
enables the exploration of the brains dynamic repertoire. PLoS Computational
Biology, 4, e1000196.
Greicius, M., Krasnow, B., Reiss, A., & Menon, V. (2003). Functional connectivity
in the resting brain: A network analysis of the default mode hypothesis.
Proceedings of the National Academy of Sciences of the United States of America,
100, 253258.
Hagmann, P., Cammoun, L., Gigandet, X., Meuli, R., Honey, C., Wedeen, V. J., et al.
(2008). Mapping the structural core of human cerebral cortex. PLoS Biology, 6, e159.
INTRODUCTION TO METHODS AND MODELING | Spontaneous and Evoked Functional Connectivity Modeling of the Brain
Hlinka, J., Palus, M., Vejmelka, M., Mantini, D., & Corbetta, M. (2011). Functional
connectivity in resting-state fMRI: Is linear correlation sufficient? Neuroimage, 54,
22182225.
Honey, C., Kotter, R., Breakspear, M., & Sporns, O. (2007). Network structure of
cerebral cortex shapes functional connectivity on multiple time scales. Proceedings
of the National Academy of Sciences of the United States of America, 104,
1024010245.
Honey, C., Sporns, O., Cammoun, L., Gigandet, X., Thiran, J., Meuli, R., et al. (2009).
Predicting human resting-state functional connectivity from structural connectivity.
Proceedings of the National Academy of Sciences of the United States of America,
106, 20352040.
Koch, K., & Fuster, J. (1989). Unit activity in monkey parietal cortex related to
haptic perception and temporary memory. Experimental Brain Research, 76,
292306.
Marreiros, A. C., Kiebel, S. J., Daunizeau, J., Harrison, L. M., & Friston, K. J. (2009).
Population dynamics under the Laplace assumption. Neuroimage, 44,
701714.
Pernice, V., Staude, B., Cardanobile, S., & Rotter, S. (2011). How structure
determines correlations in neuronal networks. PLoS Computational Biology, 7,
e1002059.
Raichle, M. E., MacLeod, A. M., Snyder, A. Z., Powers, W. J., Gusnard, D. A., &
Shulman, G. L. (2001). A default mode of brain function. Proceedings of the
National Academy of Sciences of the United States of America, 98, 676682.
Raichle, M. E., & Mintun, M. A. (2006). Brain work and brain imaging. Annual Review of
Neuroscience, 29, 449476.
Robinson, P. A. (2012). Interrelating anatomical, effective, and functional brain
connectivity using propagators and neural field theory. Physical Review E, 85,
011912.
Robinson, P. A., Drysdale, P. M., Van der Merwe, H., Kyriakou, E., Rigozzi, M. K.,
Germanoska, B., et al. (2006). BOLD responses to stimuli: Dependence on
frequency, stimulus form, amplitude, and repetition rate. Neuroimage, 31, 585599.
579
Introduction
Functional magnetic resonance imaging (fMRI) due to its high
spatial and temporal resolution in addition to its noninvasiveness has become the method of choice for studying
systems-level brain function. MRI in general can generate the
anatomy of different tissue types in the brain; however, it takes
minutes to generate one structural brain image with great
contrast of the different tissue types in the brain. Using
fMRIs, on the other hand, a series of images of the brain are
acquired over time; each individual functional brain image is
acquired within seconds typically with lower spatial resolution.
At its core, fMRI uses the blood oxygen level-dependent
(BOLD) signal, which was discovered by Seiji Ogawa in
1991. It is currently understood that task activation or stimulus
presentation leads to an increase in neuronal firing in the
eloquent regions of the brain. Increased neuronal firing leads
to an increase in oxygen consumption and leads to vasodilation. The activation-induced increase in brain oxygenation
decreases intravascular deoxyhemoglobin and, therefore,
decreases susceptibility-induced intravoxel dephasing. Spin
coherence increases, resulting in increased signal intensity.
Brain activation is observed as localized signal enhancement.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00335-3
581
582
neuronal fields. Such factors would need to be carefully dissected by future efforts. An interesting example of such multifactorial components of the slow fluctuations emerges from
the study of CBV and CYTox during the transition from slowwave sleep to REM sleep in the cat, as will be discussed in the
following sections.
583
584
Biswal and Hyde (), for instance, studied physiological fluctuations in the motor cortex during rest and during a sustained
6 min period of bilateral finger tapping. They observed that the
magnitude of low-frequency physiological fluctuations
observed at rest was enhanced during continuous finger tapping. In addition, maps of these motor cortex-based lowfrequency fluctuations had significantly greater coincidence
with task-activation maps than those in other brain regions.
These results suggest that functionally active networks are
chronically active at rest. Recently, Gao and Fox had hypothesized that ESC represents a subset of the RSC network. Analyzing the sensorimotor cortex, they found a number of
additional regions, including the premotor region, to be connected that are not typically connected during bilateral finger
tapping.
Task-related patterns of BOLD activity may represent acute
activation of the circuits necessary for the task at hand. Such
circuitry may be revealed in ESC analysis models advanced by a
number of researchers (e.g., Buchel & Friston, 2000; Goebel
et al., 2003; McIntosh et al., 1996). ESC analyses have revealed
interconnections between brain regions known to be active during cognitive task performance. In one WM study, for instance,
McIntosh et al. (1999) had observed increases in interactions
among PFC regions and between PFC and corticolimbic regions
with increasing delay intervals. ESC studies comparing younger
and older adults have indicated that older adults show increased
ESC during cognitive task performance. Their results indicated
that, whereas younger adults showed hippocampal interactions
with ventral PFC, during memory encoding, older adults showed
hippocampal interactions with both dorsal and ventral and parietal interactions. At present, the meaning of this age- and diseaserelated increased ESC remains poorly understood. The best evidence suggests that either (1) it may reflect compensatory activity
in the service of optimizing memory performance (Grady et al.,
1999) or (2) it may reflect a decreased inhibition of the default
mode, as Greicius et al. (2004) had suggested. Little leverage
may be gained on these questions because the results come from
different groups of subjects performing different tasks.
In recent years, there has been a renewed interest in lowfrequency spontaneous fluctuations. Using a variety of neuroimaging methodologies in animals (e.g., LDF, reflectance
oximetry, and fMRI), studies have reported spontaneous fluctuations in the 412 cpm range when cerebral perfusion was
challenged by systemic and local manipulations. Hypotension,
hyperventilation, and cerebral artery occlusion substantially
modulate the magnitude of these spontaneous fluctuations.
These studies clearly challenge our current understanding of
CBF autoregulation and demonstrate the dynamic nature of
regional CBF. The work proposed here will contribute to our
understanding of the basic neurophysiology of these phenomena and to our basic understanding of brain function.
The literature reviewed in the preceding text indicates that
RSC and ESC have been used separately to examine differences
between young and old and between old and AD patient
groups.
Neuropsychological and functional neuroimaging studies
indicate that attention is subserved by anatomically overlapping but functionally dissociable networks in the brain (Posner
& Petersen, 1990). A posterior network that includes the superior parietal lobe and its connections to inferior temporal and
585
Effective Connectivity
B Misic and AR McIntosh, Rotman Research Institute, Toronto, ON, Canada; University of Toronto, Toronto, ON, Canada
2015 Elsevier Inc. All rights reserved.
Glossary
The key distinction between functional and effective connectivity lies in the levels of inference they allow. Functional
connectivity, estimated as statistical dependencies between
neural elements, does not allow inference on the directionality
of influence. Effective connectivity is estimated by formulating
an explicit causal model of how neural elements influence one
another, thereby allowing inference about directional influences. This is illustrated in Figure 1, wherein the two anatomical networks differ in one aspect: the presence of a direct
projection from node A to node B (McIntosh & Korostil,
2008). Nodes A and B receive common inputs, and as a result,
they would display functional connectivity in both networks.
Thus, the two networks could not be differentiated in terms of
functional connectivity, but could in terms of effective connectivity. The purpose of effective connectivity is to explicitly
model directionality in the network.
In this article, we give an overview of three techniques for
estimating effective connectivity. Two are confirmatory, in
the sense that an explicit model of element interactions is
formulated and tested to see whether it fits the observed
data and/or whether it fits the observed data better than
alternative models (structural equation modeling, (SEM)
and dynamic causal modeling (DCM)). The third (Granger
causality) is also used to estimate causal influence but is
usually applied in an exploratory fashion to any pair of neural
elements. Indeed, Granger causality can also be thought of as
an assessment of directed functional connectivity, because it
tests for dependencies over time.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00336-5
587
588
Network 1
x1 c x1
x2 px1 cx2
x3 qx1 rx2 cx3
x4 sx2 tx3 cx4
Network 2
C
Model Specification
The path diagram in Figure 2 (left) illustrates how a structural
model is mathematically formulated (McIntosh and Misic,
2013). The activity of each region is treated as a variable.
Effective connectivity between elements is specified by a system
of linear regression equations, termed structural equations, that
define the sources of variance for each region. In the present
example, xi represents the variance of each region, which is
partitioned into variance explained
by other regions, as well as
an error or residual term cxi . Residual terms represent exogenous influences from other regions that could not be included
in the model, as well as the influence of a region on itself. The
regression weights p, q, r, s, and t (also known as path coefficients) represent the strength of each effective connection. The
[1]
[2]
Model Estimation
Path coefficients and residual variances are estimated recursively by fitting the implied covariance matrix to the empirical
covariance matrix. Thus, SEM uses patterns of functional connectivity (covariances) to estimate effective connectivity (path
coefficients).
Path coefficients represent the proportion of activity in one
area that is determined by the activity of other areas that project
to it. For example, in Figure 2, the structural equation for any
given connection (e.g., x1x3) contains terms that represent the
influence of other areas (e.g., the path coefficients for x1x2 and
x2x3), in addition to the path coefficient for that connection.
As a result, a path coefficient can be thought of as a semipartial
correlation, because it reflects the influence of one area on
another, with influences from other areas held constant.
Model Inference
The simplest question that can be addressed with SEM is
whether the model fits the observed data. Here, the discrepancy between the implied and empirical covariance matrices is
assessed using some goodness-of-fit statistic, such as the w2. A
model that is not consistent with the data would yield a large
w2 value, indicating a significant departure from the empirical
(i.e., expected) covariance matrix.
A principal strength of SEM is that it can be extended to
compare multiple models that represent competing hypotheses. For instance, if two regions are reciprocally connected,
SEM can be used to test whether the effective connections
between them are equal (i.e., symmetrical) or unequal
(i.e., asymmetrical). The implied covariance matrices for the
symmetrical and asymmetrical models are compared to the
empirical covariance matrix, generating two separate statistics,
w2symmetric and w2asymmetric, for their respective goodness of fit.
The model fits are then compared directly using the w2 difference test; the difference w2asymmetric w2symmetric is computed and
assessed with respect to the difference in degrees of freedom for
the two models. The test assesses whether the modification of
SEM
DCM
x1
x1
x1
x3
p
r
x3
x4
x2
x4
x1
x2
x3
x4
DCM
x1
x2
x3
x4
0 0 0
p 0 0
r 0
0 s t
0
0
0
0
a12 a13
0 a23
0
0
0
0
x1
x2
x3
x4
0
0
a34
0
a34
x4
X
t
0
0
0
0
x3
a24
u2
X= X+
SEM
a23
b24
u1
a13
x2
c11
a12
x2
589
= AX + uBX + Cu
x1
x2
x3
x4
+ u2
0
0
0
0
0
0
0
0
0
0
0
0
0
b24
0
0
x1
x2
x3
x4
c11
0
0
0
0
0
0
0
u1
u2
Figure 2 Similarities and differences between SEM and DCM. In SEM (left), causal order is specified by a system of linear regression equations with
one set of path coefficients (b) and error terms (c). In DCM (right), causal order is specified by a system of differential equations parameterized
in terms of synaptic couplings (A), as well as exogenous inputs (u) that may influence either the synaptic couplings between regions (B) or intrinsic
activity in individual regions (C). Adapted from McIntosh, A., & Misic, B. (2013). Multivariate statistical analyses for neuroimaging data.
Annual Review of Psychology, 64, 499525.
allowing asymmetrical effects for reciprocal connections significantly improves model fit. A significant difference would
imply that the additional path coefficient improved the overall
model fit, providing evidence that the path coefficients are
different for the two connections. Functional connectivity,
which is symmetrical by definition, could not be used to
make inferences on these competing hypotheses (Mclntosh &
Gonzalez-Lima, 1994).
The hierarchical approach we have just described can also
be used to test whether effective connections differ between
conditions or groups. To test for group differences for specific
connections, several models can be nested in a single multigroup (stacked) run (McIntosh, Cabeza, & Lobaugh, 1998). In
a null model, path coefficients are constrained to be the same
for all groups, yielding the same implied covariance matrix for
each group. The alternative model allows path coefficients for
those connections to vary, yielding a separate implied covariance matrix for each group. If the fit is significantly improved
by allowing path coefficients to vary, then there is a significant
difference in those effective connections between conditions.
So far, we have described how SEM can be used in a confirmatory manner, where the causal structure is predefined
based on known anatomy and the inferential focus is on
whether specific effective connections change between tasks.
Bullmore et al. (2000) proposed a more relativistic approach to
model selection, where only the nodes of the network are
specified a priori, while the connectivity of the model is filled
out in a data-driven manner. The procedure starts with a null
model, in which all path coefficients are set to zero. At each
iteration, the path coefficient with the largest modification
index (the improvement in model fit if that path coefficient
Causal Model
As with SEM, an initial model of causal influence is defined by
specifying a set of regions, which may be chosen based on
hypotheses or analyses. Each region in the model is composed
of neuronal subpopulations intrinsically coupled to each
590
[3]
Forward Model
The underlying causal model describes the temporal evolution
of neuronal activity. To allow comparison between the causal
model and the observed data, a forward model is used to
translate this neural activity into predicted neuroimaging measurements, analogous to the implied covariance matrices in
SEM. The forward model is a mapping (g) from the underlying
neuronal activity (x) to some feature of the data (y):
y g x, yf
[4]
The forward model is chosen according to the imaging
modality used in the experiment. If the data are evoked
responses, such as event-related potentials or fields, the
forward model g is the lead field matrix, modeling the
propagation of electric current or magnetic fields though
the brain, cerebrospinal fluid, skull, and scalp. The location
and orientation of the source dipole are parameterized by yf
(Kiebel, David, & Friston, 2006). If the data are BOLD
contrast, g models the hemodynamic response by mapping
local neuronal activity to changes in blood flow, blood
volume, and deoxygenated hemoglobin (Buxton, Wong, &
Frank, 1998). In that case, parameters yf represent rate
constants of vasodilatory signal decay and autoregulatory
feedback by blood flow (Stephan, Weiskopf, Drysdale,
Robinson, & Friston, 2007).
Figure 2 demonstrates that SEM and DCM have much in
common (McIntosh and Misic, 2013). From the perspective of
SEM, the extrinsic synaptic couplings implemented in DCM
can be thought of as the grand average effective connectivity
across all conditions and the modulatory effects as the changes
in extrinsic connectivity due to experimental manipulation.
From the perspective of DCM, SEM can be thought of as a
special case in which the system is driven by noise rather than
systematic exogenous inputs (Figure 2), while the interactions
are linear and take place at the level of the observations, rather
than at the neural level (McIntosh and Misic, 2013).
Model Inversion
Once the causal model has been translated from neuronal
activity to predicted data (e.g., ERPs and BOLD signal), it can
be compared to the observed data to estimate the unknown
parameters of the model, including the synaptic couplings. In
DCM, the comparison between predicted and observed data is
done within a Bayesian framework. Unknown model parameters are assumed to be random variables. Before the experiment
is performed, these parameters have a prior distribution, which
reflects a priori knowledge about their values. A prior distribution constrains the unknown parameters to an interval or to a
fixed value. For instance, if two regions share no known anatomical connection, their synaptic coupling may be assumed
to be zero. Likewise, prior empirical knowledge may be used to
set the likely range of values of some hemodynamic
parameters.
Following the experiment, the data are used to update the
model (i.e., estimate the parameters), resulting in a posterior
distribution for each parameter, which reflects both prior
beliefs and empirical knowledge. This updating procedure
(Bayesian model inversion) seeks to maximize the model evidence, defined as the probability of the data given the present
model. Model evidence is highest for models that explain the
data accurately and have the fewest parameters.
Inference
DCMs allow statistical inference on models and on parameters
(Stephan et al., 2007, 2010). Two models can be compared
directly by taking either the ratio of their respective evidence
(Kass & Raftery, 1995) or the difference in their respective log
evidence. A model with evidence more than 20 times greater
than another model is considered stronger. This procedure
(Bayesian model selection) can be used to make a wide variety
of comparisons, such as DCMs with different inputs, different
anatomical connections, and different priors. Models with
different numbers of parameters can be compared directly
because evidence takes into account model complexity. Once
the optimal model is selected, specific parameters can be statistically assessed with respect to their posterior densities.
Note that the relative log evidence (or log Bayesian factor)
plays exactly the same role as the difference in w2 goodness-offit statistics in SEM. As we will see in the next section, in
Granger causality, the implicit likelihood of two models is
indexed by the F-statistic. Thus, all of these statistics can be
regarded as comparing the likelihood of models with and
without particular connections or dependencies.
Granger Causality
Autoregressive Models
If the past of signal x1 contains information that can help to
predict the future of another signal x2 above and beyond
information contained in the past of x2 itself, then x1 is said
to have causal influence on x2 (Wiener, 1956). Assuming that it
is purely linear, this causal relationship can be mathematically
represented as a linear regression, where the past values of x1
are used to predict the present value of x2 (Granger, 1969). In
m
X
AiX t i Et
[5]
i1
The ith matrix A(i) has dimensions p p and contains autoregressive coefficients for time lag i, which can be estimated by
ordinary least squares. E(t) is a vector of residuals. The present
value of the jth region xj(n) is a linear combination of m past
values of all other regions, weighted by the elements of the jth
column of matrix A(i). Thus, for an individual effective connection, the influence of all other regions in the network is
accounted for and partialled out. Since the effective connections are formulated as regression equations, their significance
is typically assessed via the F-test. Alternatively, a confidence
interval on the autoregressive coefficients can be constructed
by bootstrapping (Roebroeck, Formisano, & Goebel, 2005).
591
Summary
Effective connectivity describes the distributed network interactions that give rise to mental operations. A diverse repertoire
of techniques has been developed to accommodate different
assumptions, imaging modalities, and experimental questions.
The techniques we have outlined often differ mathematically
and sometimes philosophically, but they all represent specific
and complementary models of how patterns of influence are
established within a network of neural elements and how these
patterns support mental function.
References
Aertsen, A., Gerstein, G., Habib, M., & Palm, G. (1989). Dynamics of neuronal firing
correlation: modulation of effective connectivity. Journal of Neurophysiology,
61(5), 900917.
Baccala, L., & Sameshima, K. (2001). Partial directed coherence: A new concept in
neural structure determination. Biological Cybernetics, 84(6), 463474.
Bollen, K. (1986). Sample size and bentler and bonetts nonnormed fit index.
Psychometrika, 51(3), 375377.
Bressler, S., & McIntosh, A. (2007). The role of neural context in large-scale
neurocognitive network operations. In V. Jirsa & A. McIntosh (Eds.), Handbook of
brain connectivity (pp. 403419). Berlin: Springer.
Bullmore, E., Horwitz, B., Honey, G., Brammer, M., Williams, S., & Sharma, T. (2000).
How good is good enough in path analysis of fmri data? NeuroImage, 11(4),
289301.
592
Buxton, R., Wong, E., & Frank, L. (1998). Dynamics of blood flow and oxygenation
changes during brain activation: The balloon model. Magnetic Resonance in
Medicine, 39(6), 855864.
Ding, M., Chen, Y., & Bressler, S. (2006). Granger causality: Basic theory and
application to neuroscience. In S. Schelter, N. Winterhalder & J. Timmer (Eds.),
Handbook of time series analysis (p. 437). Wiley-VCH.
Friston, K. J. (1994). Functional and effective connectivity in neuroimaging: A
synthesis. Human Brain Mapping, 2(12), 5678.
Friston, K., Harrison, L., & Penny, W. (2003). Dynamic causal modelling. NeuroImage,
19(4), 12731302.
Geweke, J. (1982). Measurement of linear dependence and feedback between multiple
time series. Journal of the American Statistical Association, 77(378), 304313.
Goebel, R., Roebroeck, A., Kim, D., & Formisano, E. (2003). Investigating directed
cortical interactions in time-resolved fmri data using vector autoregressive modeling
and granger causality mapping. Magnetic Resonance Imaging, 21(10), 12511261.
Granger, C. (1969). Investigating causal relations by econometric models and crossspectral methods. Econometrica, 37, 424438.
Joreskog, K., Sorbom, D., Magidson, J., & Cooley, W. (1979). Advances in factor
analysis and structural equation models. Cambridge, MA: Abt Books.
Kaminski, M., Ding, M., Truccolo, W., & Bressler, S. (2001). Evaluating causal relations
in neural systems: Granger causality, directed transfer function and statistical
assessment of significance. Biological Cybernetics, 85(2), 145157.
Kass, R., & Raftery, A. (1995). Bayes factors. Journal of the American Statistical
Association, 90(430), 773795.
Kiebel, S., David, O., & Friston, K. (2006). Dynamic causal modelling of evoked
responses in eeg/meg with lead field parameterization. NeuroImage, 30(4),
12731284.
Loehlin, J. (1987). Latent variable models: An introduction to factor, path, and structural
equation analysis. Hillsdale, NJ: Lawrence Erlbaum.
McArdle, J., & McDonald, R. (1984). Some algebraic properties of the reticular action
model for moment structures. British Journal of Mathematical and Statistical
Psychology, 37(2), 234251.
McIntosh, A. (2000). Towards a network theory of cognition. Neural Networks, 13(89),
861870.
McIntosh, A., Cabeza, R., & Lobaugh, N. (1998). Analysis of neural interactions
explains the activation of occipital cortex by an auditory stimulus. Journal of
Neurophysiology, 80(5), 27902796.
McIntosh, A., & Gonzalez-Lima, F. (1991). Structural modeling of functional neural
pathways mapped with 2-deoxyglucose: Effects of acoustic startle habituation on the
auditory system. Brain Research, 547(2), 295302.
McIntosh, A., Grady, C., Ungerleider, L., Haxby, J., Rapoport, S., & Horwitz, B. (1994).
Network analysis of cortical visual pathways mapped with pet. Journal of
Neuroscience, 14(2), 655666.
McIntosh, A. R., & Korostil, M. (2008). Interpretation of neuroimaging data based on
network concepts. Brain Imaging and Behavior, 2(4), 264269.
McIntosh, A., & Misic, B. (2013). Multivariate statistical analyses for neuroimaging
data. Annual Review of Psychology, 64, 499525.
Mclntosh, A., & Gonzalez-Lima, F. (1994). Structural equation modeling and its
application to network analysis in functional brain imaging. Human Brain Mapping,
2(12), 222.
Roebroeck, A., Formisano, E., & Goebel, R. (2005). Mapping directed influence over the
brain using granger causality and fmri. NeuroImage, 25(1), 230242.
Schreiber, T. (2000). Measuring information transfer. Physical Reviews Letters, 85(2),
461464.
Seth, A. (2007). Granger causality. Scholarpedia, 2(7), 1667.
Stephan, K., Penny, W., Moran, R., den Ouden, H., Daunizeau, J., & Friston, K.
(2010). Ten simple rules for dynamic causal modeling. NeuroImage, 49(4),
30993109.
Stephan, K., Weiskopf, N., Drysdale, P., Robinson, P., & Friston, K. (2007). Comparing
hemodynamic models with dcm. NeuroImage, 38(3), 387401.
Vakorin, V., Krakovska, O., & McIntosh, A. (2009). Confounding effects of
indirect connections on causality estimation. Journal of Neuroscience, 184(1),
152160.
Vicente, R., Wibral, M., Lindner, M., & Pipa, G. (2011). Transfer entropyA model-free
measure of effective connectivity for the neurosciences. Journal of Computational
Neuroscience, 30(1), 4567.
Wiener, N. (1956). The theory of prediction. In E. Beckenbach (Ed.), Modern
mathematics for engineers (pp. 165190). New York: McGraw-Hill.
Granger Causality
A Roebroeck, Maastricht University, Maastricht, The Netherlands
2015 Elsevier Inc. All rights reserved.
Glossary
Abbreviations
AR
Autoregressive
Introduction
Granger causality or G-causality is named after econometrist
Clive Granger and designates a measurable concept of causality
or directed influence for time series data. G-causality is rooted
in econometric and time-series analysis and is defined using
predictability and temporal precedence. Grangers idea
(Granger, 1969) was to give a concrete operational and testable
(in a statistical sense) definition of causality for time series
data, based on earlier ideas of mathematician Wiener (1956).
Specifically, a variable y G-causes another variable x if the
prediction of xs values improves when we use past values of
y, given that all other relevant information z is taken into
account. Here x, y, and z can be multivariate, that is, sets of
variables, such that we can talk about a set of variables jointly
G-causing another set, conditioned on a third set. In the context of neuroimaging, these could be sets of electrodes, sensors,
voxels, or sources. The greater the number of relevant time
series is contained in z, the more strict the test of G-causality
between x and y becomes. This is because our confidence
increases that y contains unique predictive information for xs
future, which we could consider a necessary (but perhaps not
sufficient) condition for a cause of x. Omitting sources of
common influence or intervening variables could lead to spurious causality findings between x and y. A prominent attraction of G-causality over measures of instantaneous (in time)
correlation or statistical dependence is its model-based assessment of direction of influence or causality, independently in
both directions between two time series. The reliance on temporal precedence to define this direction ensures that this
direction is largely derived from information in the data
record, that is, from the dynamics of the time series. Moreover,
G-causality can be formulated in the frequency and the combined timefrequency domain, such that we can talk about, for
http://dx.doi.org/10.1016/B978-0-12-397025-1.00337-7
593
594
n
y 0 n
zn
p
X
T3 Cyz
0
y n
Ay0 iy 0 n i v 0 n varv 0 n CT S
zy
yz
2i1 3
x n
q0 n 4 y n 5
zn
2
3
Cxyz
p
0
X
Y
0
0
0
0
Cyxz 5
q n
Aq0 iq n i w n varw n 4
i1
CTxyz CTyxz Szxy
S C0
Y 0 0T4
C T4
[1]
The measures of total linear dependence between x and y
conditional on z, linear influence from x to y conditional on
z, linear influence from y to x conditional on z, and instantaneous correlation between x and y conditional on z are defined
to be, respectively (Geweke, 1984):
Fx, yjz ln jS3 jjT3 j=Y0
Fx!yjz ln jT3 j=jT4 j
[2]
Fy!xjz ln jS3 j=jS4 j
0
Fxyjz ln jS4 jjT4 j=Y
The completeness in the decomposition of total linear
dependence follows from these definitions:
Fx, yjz- Fx!yjz- Fy!xjz- Fxyjz-
[3]
595
[5]
A second distinction is based on predicting the whole probability distribution (strong influence) or only given moments
(weak influence). Since the most natural formal definition is
one of independence, every influence type amounts to the
negation of an independence statement. The two classifications
give rise to six types of independence and corresponding influence as set out in Table 1.
To illustrate, X1(t) is strongly, conditionally, and globally
independent of X2(t) given X3(t), if
Table 1
Local (immediate
future)
Contemporaneous
[7]
[8]
[6]
Weak (expectation)
Strong and weak conditional global influence (SCGi and WCGi); strong and weak conditional local influence (SCLi and WCLi); strong and weak conditional contemporaneous
influence (SCCi and WCCi).
596
References
Aalen, O. O. (1987). Dynamic modeling and causality. Scandinavian Actuarial Journal,
1987(34), 177190.
Aalen, O. O., & Frigessi, A. (2007). What can statistics contribute to a causal
understanding? Scandinavian Journal of Statistics, 34, 155168.
Akaike, H. (1968). On the use of a linear model for the identification of feedback
systems. Annals of the Institute of Statistical Mathematics, 20, 425439.
Amendola, A., Niglio, M., & Vitale, C. (2010). Temporal aggregation and closure of
VARMA models: Some new results. In M. Greenacre, N. C. Lauro, & F. Palumbo
(Eds.), Data analysis and classification: Studies in classification, data analysis, and
knowledge organization (pp. 435443): Springer.
Astolfi, L., Cincotti, F., Mattia, D., Salinari, S., Babiloni, C., Basilisco, A., et al. (2004).
Estimation of the effective and functional human cortical connectivity with structural
equation modeling and directed transfer function applied to high-resolution EEG.
Magnetic Resonance Imaging, 22, 14571470.
Bergstrom, A. R. (1966). Nonrecursive models as discrete approximations to systems of
stochastic differential equations. Econometrica, 34, 173182.
Bergstrom, A. R. (1984). Continuous time stochastic models and issues of aggregation.
In : Z.Griliches, & M. D. Intriligator (Eds.), Handbook of econometrics: Vol. II.
Amsterdam: Elsevier.
Bernasconi, C., & Konig, P. (1999). On the directionality of cortical interactions studied
by structural analysis of electrophysiological recordings. Biological Cybernetics,
81, 199210.
Chambers, M. J., & Thornton, M. A. (2012). Discrete time representation of continuous
time ARMA processes. Econometric Theory, 28, 219238.
Chen, Y., Bressler, S. L., & Ding, M. (2006). Frequency decomposition of conditional
Granger causality and application to multivariate neural field potential data. Journal
of Neuroscience Methods, 150, 228237.
Deshpande, G., Sathian, K., & Hu, X. (2010). Effect of hemodynamic variability on
Granger causality analysis of fMRI. NeuroImage, 52, 884896.
Dhamala, M., Rangarajan, G., & Ding, M. (2008). Analyzing information flow in brain
networks with nonparametric Granger causality. NeuroImage, 41, 354362.
Ding, M., Bressler, S. L., Yang, W., & Liang, H. (2000). Short-window spectral analysis
of cortical event-related potentials by adaptive multivariate autoregressive modeling:
Data preprocessing, model validation, and variability assessment. Biological
Cybernetics, 83, 3545.
Florens, J. (2003). Some technical issues in defining causality. Journal of
Econometrics, 112, 127128.
Florens, J. P., & Fougere, D. (1996). Noncausality in continuous time. Econometrica,
64, 11951212.
Freiwald, W. A., Valdes, P., Bosch, J., Biscay, R., Jimenez, J. C., Rodriguez, L. M., et al.
(1999). Testing non-linearity and directedness of interactions between neural
groups in the macaque inferotemporal cortex. Journal of Neuroscience Methods,
94, 105119.
Friston, K. J., Harrison, L., & Penny, W. (2003). Dynamic causal modelling.
NeuroImage, 19, 12731302.
Geweke, J. F. (1982). Measurement of linear dependence and feedback
between multiple time series. Journal of the American Statistical Association, 77,
304324.
Geweke, J. F. (1984). Measures of conditional linear dependence and feedback between
time series. Journal of the American Statistical Association, 79, 907915.
Goebel, R., Roebroeck, A., Kim, D. S., & Formisano, E. (2003). Investigating directed
cortical interactions in time-resolved fMRI data using vector autoregressive
modeling and Granger causality mapping. Magnetic Resonance Imaging, 21,
12511261.
Gow, D. W., Jr., Segawa, J. A., Ahlfors, S. P., & Lin, F. H. (2008). Lexical influences on
speech perception: A Granger causality analysis of MEG and EEG source estimates.
NeuroImage, 43, 614623.
Granger, C. W. J. (1969). Investigating causal relations by econometric models and
cross-spectral methods. Econometrica, 37, 424438.
Granger, C. W. J. (1980). Testing for causality: A personal viewpoint. Journal of
Economic Dynamics and Control, 2, 329352.
Havlicek, M., Jan, J., Brazdil, M., & Calhoun, V. D. (2010). Dynamic Granger causality
based on Kalman filter for evaluation of functional network connectivity in fMRI data.
NeuroImage, 53, 6577.
Hesse, W., Moller, E., Arnold, M., & Schack, B. (2003). The use of time-variant EEG
Granger causality for inspecting directed interdependencies of neural assemblies.
Journal of Neuroscience Methods, 124, 2744.
Kaminski, M., Ding, M., Truccolo, W. A., & Bressler, S. L. (2001). Evaluating causal
relations in neural systems: Granger causality, directed transfer function and
statistical assessment of significance. Biological Cybernetics, 85, 145157.
Kujala, J., Pammer, K., Cornelissen, P., Roebroeck, A., Formisano, E., & Salmelin, R.
(2007). Phase coupling in a cerebro-cerebellar network at 8-13 Hz during reading.
Cerebral Cortex, 17, 14761485.
McCrorie, J. R. (2002). The likelihood of the parameters of a continuous time
vector autoregressive model. Statistical Inference for Stochastic Processes, 5,
273286.
Mccrorie, J. R. (2003). The problem of aliasing in identifying finite parameter
continuous time stochastic models. Acta Applicandae Mathematica, 79, 916.
Nalatore, H., Ding, M., & Rangarajan, G. (2007). Mitigating the effects of measurement
noise on Granger causality. Physical Review E: Statistical, Nonlinear, and Soft
Matter Physics, 75, 031123.
Phillips, P. C. B. (1973). The problem of identification in finite parameter continuous
time models. Journal of Econometrics, 1, 351362.
Phillips, P. C. B. (1974). The estimation of some continuous time models.
Econometrica, 42, 803823.
Reinsel, G. C. (1997). Elements of multivariate time series analysis. New York: SpringerVerlag.
Roebroeck, A., Formisano, E., & Goebel, R. (2005). Mapping directed influence over the
brain using Granger causality and fMRI. NeuroImage, 25, 230242.
Roebroeck, A., Formisano, E., & Goebel, R. (2009). The identification of interacting
networks in the brain using fMRI: Model selection, causality and deconvolution.
Neuroimage, 58(2), 296302.
Roebroeck, A., Seth, A. K., & Valdes-Sosa, P. (2011). Causal time series analysis of
functional magnetic resonance imaging data. Journal of Machine Learning
Research: Workshop and Conference Proceedings, 12, 6594.
Ryali, S., Supekar, K., Chen, T., & Menon, V. (2010). Multivariate dynamical
systems models for estimating causal interactions in fMRI. Neuroimage, 54(2),
807823.
Sameshima, K., & Baccala, L. A. (1999). Using partial directed coherence to
describe neuronal ensemble interactions. Journal of Neuroscience Methods, 94,
93103.
Schippers, M. B., Renken, R., & Keysers, C. (2011). The effect of intra- and inter-subject
variability of hemodynamic responses on group level Granger causality analyses.
NeuroImage, 57, 2236.
597
Relevant Websites
http://www.scholarpedia.org/article/Granger_causality.
Nomenclature
d
AXt a1 , . . . aj , . . . aJ
aj
H(X)
H(X|Y)
h(x)
h(x|y)
I(X; Y)
I(X; Y|Z)
i(x, y)
i(x; y|z)
Notes regarding t
http://dx.doi.org/10.1016/B978-0-12-397025-1.00338-9
599
600
1
pai
[1]
601
602
8 t k 2 M, aj
8n 2 , aj 2 AXt
[3]
This condition guarantees that we can estimate the necessary probability distributions pXt of the random variable X(c)
t
(c)
by looking at other random variables XtnT
of the process X(c).
Finally, for stationary processes X(s), we can substitute T in
Eqn [3] by T 1 and
pXt aj pXtn aj 8t, n 2 , aj 2 AXt
[4]
1
log px
px
[5]
px log
x2Ax
1
px
[6]
[2]
hxjy log
1
pxjy
[7]
1
pxjy
y2AY
x2AX
X
1
px; y log
pxjy
x2A , y2A
HXjY
py
pxjy log
[8]
[9]
[10]
px; y
pxpy
[11]
pxjy, z
pxjz
[12]
Hence, mutual information and conditional mutual information are just the expected values of these local quantities.
These quantities are called local, because they allow to quantify
mutual and conditional mutual information between single
realizations. Note however that the probabilities p() that enter
Eqns [11] and [12] are global in the sense that they are representative of all possible outcomes. In this sense, the use of local
information measures is complementary to the evaluation of
probability distributions of single random variables Xt of a
nonstationary process X via an ensemble of realizations. In
other words, a valid probability distribution has to be estimated irrespective of whether we are interested in average or
local information measures.
603
time, then the position xt1 matters for our information about
the next position xt1 of the pendulum at time t 1. Here,
analyzing just xt is not enough to describe the next position.
For example, assume xt 0 and xt1 < 0. In this case, we have a
zero crossing of the pendulum and in the next step xt1 > 0.
Conversely, if xt 0 and xt1 0 as well, the pendulum does
not move at all and the future state of the pendulum is xt1 0.
Clearly, analyzing a single position xt is not enough to inform
us about the next position of the pendulum. In this example,
looking at just one past value together with the present one (xt,
xt1) is sufficient to predict the next position xt1. Therefore,
(xt, xt1) describes the state of the pendulum at time t. In the
next paragraph, we will translate the concept of a state to our
framework of random processes.
In general, if there is any dependence between the Xt, we
have to form the smallest collection of variables
X t Xt ; Xt1 ; Xt2 ; . . . ; Xti ; . . . with ti < t that jointly make Xt1
conditionally independent of all Xtk with tk < min(ti), that is,
pxt1 , xtk jxt pxt jxt pxtk jxt
[13]
604
X
s
psjr log
psjr
ps
[14]
P
[15]
[16]
P
[17]
prjsir S; r
[18]
r2Ar
The resulting measure iSSI(s; R) is called the stimulusspecific information (SSI) (Butts, 2003). Again, it can be
RF1
1
+1
RF3
Receptive fields
RF2
RF3
RF2
(b)
(c)
1
+1
(a)
RF1
605
+1
+1
+1
R1
R3
+1
RF1
RF2
RF3
Stimulus s1
Stimulus s2
1
2
3
RF1
RF1
RF2
RF3
RF2
Stimulus s3
RF3
Stimulus s4
606
X
y2AY
I(Y; X1)
Ird
[19]
Iuq
I(Y; X1X2)
Mutual information
between Y and the set
{X1X2}
I(Y; X1)
Mutual information
between Y and X1
Iuq(Y; {X1}) = ?
Unique information
about Y from X1, which
cannot be obtained
from X2.
Ird(Y; {X1}{X2}) =
Isyn(Y; {X1X2}) = ?
Xi
I(Y;X1X2)
I(Y; X2)
Isyn
Iuq
py min IY y; X i
Redundant information
about Y can be
obtained either from X1
or from X2.
Synergetic information
can only be obtained from
X1 and X2 together (red
area).
Figure 2 Partial information decomposition for three variables: one target Y and two sources X1 and X2. The original partial information decomposition
diagram is a modified version of the one first presented in Williams and Beer (2010).
[20]
{X1}{X2}
{X
1
}{X
2
X3
{X1}
{X1}{X2}{X3}
{X2}
{X2}{X3}
{X1}{X3}
{X
{X3}{X1X2}
2X
3}
}
X2
}
X3
}{X 2
X2
{X 1
}
X3
}{X 1
{X 2
{X1X2}
}
X3
{X 1
{X1X2X3}
}{X
1
xi 2AXi
1
1
log
pxi jy log
py
pyjxi
X3
{X
1
IY y; X i
607
{X3}
{X1X3}{X2X3}
{X
1X2}{X1X3}{X2X3}
608
609
TE estimation
Information Transfer
The analysis of information transfer was formalized initially by
Schreiber using the transfer entropy (TE) functional (Schreiber,
2000) and has seen a rapid surge of interest in neuroscience
(Amblard & Michel, 2011; Barnett, Barrett, & Seth, 2009; Battaglia, Witt, Wolf, & Geisel, 2012; Besserve, Scholkopf, Logothetis,
& Panzeri, 2010; Buehlmann & Deco, 2010; Chavez, Martinerie,
& Le Van Quyen, 2003; Garofalo, Nieus, Massobrio, &
Martinoia, 2009; Gourevitch & Eggermont, 2007; Ito et al.,
2011; Li & Ouyang, 2010; Lindner, Vicente, Priesemann, &
Wibral, 2011; Lizier et al., 2011b; Ludtke et al., 2010; Neymotin,
Jacobs, Fenton, & Lytton, 2011; Palus, Komarek, Hrncr, &
Sterbova, 2001; Staniek & Lehnertz, 2009; Stetter, Battaglia,
Soriano, & Geisel, 2012; Vakorin, Misic, Krakovska, & McIntosh,
2011; Vakorin, Kovacevic, & McIntosh, 2010; Vakorin, Krakovska, & McIntosh, 2009; Vicente et al., 2011; Wibral et al.,
2013; Wibral et al., 2011) and general physiology (Faes & Nollo,
2006; Faes, Nollo, & Porta, 2011; Faes et al., 2012).
Definition
Information transfer from a random process X (the source) to
another random process Y (the target) is measured by the TE
functional (Schreiber, 2000):
TEXtu ! Yt IX tu ; Yt jY t1
or, equivalently:
TEX tu ! Yt
[21]
X
yt 2AYt , yt1 2AY t1 , x tu 2AXtu
[22]
, xtd1t
[23]
dy
dx
yt , yt1 , xtu
d
log
y
x
pyt jyt1
, xdtu
[24]
y
pyt jyt1
y
, has to be constructed
reminder that the past state of Yt, y t1
such that conditioning on the past of the target process is
optimal (see Wibral et al., 2013, for details). Or saying it
y
y
instead of y t1
,
differently, if one would condition on y tu
then the self-prediction for Yt is not optimal and the TE will
be overestimated.
The parameter u is the assumed time that the information
transfer needs to get from process X to Y. It was recently proven
610
[25]
y
y
x
x
TESPO X tu ! Yt Hyt1
; x dtu
Hyt ; y t1
; xdtu
dy
Hyt ; yt1
dy
Hy t1
[26]
dx
t1 x tu
[27]
log
X
yt , yt1 , x tu , v
[28]
611
the approach of Stramaglia and colleagues (2012) by looking at the sign of the contribution of the multiplet.
Unfortunately, there is also the possibility of cancellation
if both types of multivariate information (redundant and
synergistic) are present.
3. As already explained in Section Basic information theory,
nonstationary random processes in principle require that
the necessary estimates of the probabilities in Eqn [21] be
based on physical replications of the systems in question.
Where this is impossible, the experimenter should design
the experiment in such a way that the processes are repeated
in time. If such cyclostationary data are available, then TE
should be estimated using ensemble methods as described
in Wollstadt et al., 2014 and implemented in the TRENTOOL toolbox (Lindner et al., 2011).
y
x
pyt jyt1
, xdtu
y
pyt jyt1
[29]
Information Storage
Before we present explicit measures of information storage, a
few comments may serve to avoid misunderstanding. Since
this article is about the analysis of neural activity, measures of
information storage are concerned with information stored in
this activity rather than in synaptic properties, for example.
As laid out in the preceding text, information storage is
612
k
eXt ixk
t ; xt
[32]
[33]
k!1
[34]
AX lim ix k
t1 t
k!1
[35]
aXt lim ix k
t1 ; xt
[36]
k!1
Excess entropy
Excess entropy is formally defined as
k
EXt lim IX k
t ; Xt
[30]
k!1
k
where Xk
t {Xt, Xt1, . . ., Xtk1} and Xt {Xt1, . . ., Xtk}
indicate collections of the past and future k variables of the
k
process X. These collections of random variables, (Xk
t , Xt ), in
the limit k ! 1 span the semi-infinite past and future,
respectively. In general, the mutual information in Eqn [30]
has to be evaluated over multiple realizations of the process.
For stationary processes, however, EXt is a constant, EX, and
Eqn [30] may be rewritten as an average over time points t and
computed from a single realization of the process (at least in
principle, as we have to take into account that the process must
run for an infinite time to allow the limit lim for all t):
k!1
k
EX lim ix k
[31]
t ; xt
k!1
where i(;) is the local mutual information from Eqn [11], and
k
k
xk
are realizations of Xk
t , xt
t , Xt . Even if the process in
question is nonstationary, we may look at values that are
local in time as long as the probability distributions are derived
appropriately (see Section Basic information theory):
[37]
Information Modification
Langton (1990) described information modification as an interaction between transmitted information and stored information
that results in a modification of one or the other. Attempts to
define information modification more rigorously implemented
this basic idea. First attempts at defining a quantitative measure
of information modification resulted in a heuristic measure
termed local separable information (Lizier et al., 2010), where
X
Zt , i 6X t1
[38]
with Zt , i indicating the past state variables of all processes that
transfer information into the target variable Xt and where the
index t is a reminder that only past state variables are taken
into account, that is, t < t. As shown previously in the text, the
local measures entering the sum are negative if they are misinformative about the future of the target. Eventually, the
overall sum, or separable information, might also be negative,
indicating that neither the pairwise information transfers nor
the history could explain the information contained in the
targets future. This was seen as an indication of a modification
of either stored information or transferred information.
At the same time, the overall information in the future of
the target can of course be explained by looking at the sources
of information and the history of the target jointly, at least up
to the genuinely stochastic part (innovation) in the target, as
shown in Lizier et al. (2010). Even a decomposition of the
overall information into storage, transfer terms, and the innovation is possible for considering the sources jointly (Lizier
et al., 2010). To see why this is possible when considering
the source variables and the history of the target jointly, but
not when we look at pairwise local mutual information terms,
it is instructive to consider a series of subsets formed from the
(ordered) set of all variables Zt , i that can transfer information
into the target, except variables from the targets own history.
Following the derivation in Lizier et al. (2010) (with the exception of adding the variable index t to account for nonstationary
processes), we denote this set as V Xt nX t1 fZt , 1 ; . . . ; Zt , G g,
where G is the number of variables in the set and Xt is the
target. Xt1, the history of the target, is not part of the set. The
bold typeface in Zt , i is a reminder that we work with a state
space representation where necessary. Next,
we create a series
g
g
of subsets V Xt nX t1 such that V Xt nX t1 Zt , 1 ; . . . ; Zt , g1 ,
that is, the gth subset only contains the first g 1 sources. As
the TE is a mutual information, we can decompose the collective TE from all our source variables, TEV Xt nX t1 ! Xt , as a
series of conditional mutual information terms, incrementally
increasing the set that we condition on
TEV Xt nX t1 ! Xt
G
X
g
IXt ; Zt , g jX t1 , V Xt nX t1
[39]
g1
G
X
[40]
g1
G
X
613
[41]
g1
References
Amblard, P.-O., & Michel, O. J. (2011). On directed information theory and Granger
causality graphs. Journal of Computational Neuroscience, 30, 716.
Ay, N., & Polani, D. (2008). Information flows in causal networks. Advances in Complex
Systems, 11, 1741.
614
Barnett, L., Barrett, A. B., & Seth, A. K. (2009). Granger causality and transfer entropy
are equivalent for Gaussian variables. Physical Reviews Letters, 103, 238701.
Battaglia, D., Witt, A., Wolf, F., & Geisel, T. (2012). Dynamic effective connectivity of
inter-areal brain circuits. PLoS Computational Biology, 8, e1002438.
Beggs, J. M., & Plenz, D. (2003). Neuronal avalanches in neocortical circuits. The
Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 23,
1116711177.
Bertschinger, N., Rauh, J., Olbrich, E., & Jost, J. (2013). Shared information-new insights
and problems in decomposing information in complex systems. In Proceedings of the
European Conference on Complex Systems 2012 (pp. 251269). Springer
International Publishing.
Bertschinger, N., Rauh, J., Olbrich, E., Jost, J., & Ay, N. (2014). Quantifying unique
information. Entropy, 16, 21612183.
Besserve, M., Scholkopf, B., Logothetis, N. K., & Panzeri, S. (2010). Causal
relationships between frequency bands of extracellular signals in visual cortex
revealed by an information theoretic analysis. Journal of Computational
Neuroscience, 29, 547566.
Bettencourt, L. M., Gintautas, V., & Ham, M. I. (2008). Identification of functional
information subgraphs in complex networks. Physical Reviews Letters, 100, 238701.
Boedecker, J., Obst, O., Lizier, J. T., Mayer, N. M., & Asada, M. (2012). Information
processing in echo state networks at the edge of chaos. Theory in Biosciences, 131,
205213.
Brenner, N., Strong, S. P., Koberle, R., Bialek, W., & Van Steveninck, R. R. D. R. (2000).
Synergy in a neural code. Neural Computation, 12, 15311552.
Buehlmann, A., & Deco, G. (2010). Optimal information transfer in the cortex through
synchronization. PLoS Computational Biology, 6, e1000934.
Butts, D. A. (2003). How much information is associated with a particular stimulus?
Network: Computation in Neural Systems, 14, 177187.
Butts, D. A., & Goldman, M. S. (2006). Tuning curves, neuronal variability, and sensory
coding. PLoS Biology, 4, e92.
Carandini, M. (2012). From circuits to behavior: A bridge too far? Nature Neuroscience,
15, 507509.
Chavez, M., Martinerie, J., & Le Van Quyen, M. (2003). Statistical assessment of
nonlinear causality: Application to epileptic EEG signals. Journal of Neuroscience
Methods, 124, 113128.
Chicharro, D., & Andrzejak, R. G. (2009). Reliable detection of directional couplings
using rank statistics. Physical Review E, 80, 026217.
Crutchfield, J. P., Ditto, W. L., & Sinha, S. (2010). Introduction to focus issue: intrinsic
and designed computation: Information processing in dynamical systems-beyond
the digital hegemony. Chaos, 20, 037101-1037101-6.
Crutchfield, J. P., & Packard, N. H. (1982). Symbolic dynamics of one-dimensional
maps: Entropies, finite precision, and noise. International Journal of Theoretical
Physics, 21, 433466.
Dewdney, A. K. (1993). The Tinkertoy computer and other machinations. New York:
W.H. Freeman.
DeWeese, M. R., & Meister, M. (1999). How to measure the information gained from
one symbol. Network: Computation in Neural Systems, 10, 325340.
Effenberger, F. (2013). A primer on information theory, with applications to
neuroscience. In Computational biomedicine: Data mining and modeling (135192).
Berlin: Springer-Verlag.
Faes, L., & Nollo, G. (2006). Bivariate nonlinear prediction to quantify the strength of
complex dynamical interactions in short-term cardiovascular variability. Medical
and Biological Engineering and Computing, 44, 383392.
Faes, L., Nollo, G., & Porta, A. (2011). Information-based detection of nonlinear
Granger causality in multivariate processes via a nonuniform embedding technique.
Physical Review E, 83, 051112.
Faes, L., Nollo, G., & Porta, A. (2012). Non-uniform multivariate embedding to assess
the information transfer in cardiovascular and cardiorespiratory variability series.
Computers in Biology and Medicine, 42, 290297.
Fano, R. M. (1961). Transmission of Information: A statistical theory of
communications. Cambridge, MA: Massachusetts Institute of Technology Press.
Gardner, W. A. (1994). An introduction to cyclostationary signals. Cyclostationarity in
Communications and Signal Processing, 190.
Gardner, W. A., Napolitano, A., & Paura, L. (2006). Cyclostationarity: Half a century of
research. Signal Processing, 86, 639697.
Garofalo, M., Nieus, T., Massobrio, P., & Martinoia, S. (2009). Evaluation of the
performance of information theory-based methods and cross-correlation to estimate
the functional connectivity in cortical networks. PloS One, 4, e6482.
Gawne, T. J., & Richmond, B. J. (1993). How independent are the messages carried by
adjacent inferior temporal cortical neurons? Journal of Neuroscience, 13, 27582771.
Gomez, C., Lizier, J. T., Schaum, M., Wollstadt, P., Grutzner, C., Uhlhaas, P., et al.
(2014). Reduced predictable information in brain signals in autism spectrum
disorder. Frontiers in neuroinformatics, 8.
615
dx
dt
f 0; 0
@f
@f
@2f
x u
xu
@x
@u
@x@u
[1]
Setting
A @f =@xju0 , Bi @ 2 f =@x@ui , C @f =@ujx0
leads to the neuronal state equation of DCM for fMRI:
!
m
X
dx
i
f x; u
A
x Cu
ui B
dt
i1
[2]
(3)
Here, the A matrix represents the endogenous (fixed) connectivity (i.e., when the system is not being perturbed), the B
http://dx.doi.org/10.1016/B978-0-12-397025-1.00339-0
617
618
Nonlinear DCM
Bilinear DCM
u2
u2
u1
u2
m
A + ui
i=1
B(i) x + Cu
A + ui
i=1
j=1
B(i) + xj D( j) x + Cu
Figure 1 A summary of the neuronal state equations in bilinear and nonlinear DCMs for fMRI, respectively. This figure is reproduced, with permission,
from Figure 1 in Stephan, K. E., Kasper, L., Harrison, L. M., Daunizeau, J., den Ouden, H. E., Breakspear, M., & Friston, K. J. (2008). Nonlinear
dynamic causal models for fMRI. Neuroimage, 42, 649662.
Model Inversion
Together with parametric assumptions about observation noise
and its serial correlation (Friston et al., 2002), the set of differential equations representing neuronal and hemodynamic processes (with a joint parameter vector y) constitutes a model of
the likelihood of the data y, p(y|y, m). Combined with suitably
chosen priors on the neuronal and hemodynamic parameters,
this results in a full generative model of measured data, that is, a
full probabilistic model specifying the joint probability of all
variables (observations, parameters, and hyperparameters).
Given some measured fMRI data, this model can be inverted
in order to provide posterior estimates of the parameters. In
DCM, this proceeds under Gaussian assumptions about the
posterior (Laplace assumption). However, instead of optimizing
the posterior probabilities directly, for example, through Markov chain Monte Carlo techniques, DCM rests on a variational
Bayesian approach that optimizes the (negative) free energy as a
lower-bound approximation to the log model evidence. This has
the advantage of being computationally efficient and providing
an estimate of the log evidence that serves as the basis for model
comparison, as described later in the text.
The variational Laplace algorithm employed by DCM is
computationally efficient and robust in many situations
(Friston, Mattout, Trujillo-Barreto, Ashburner, & Penny,
2007). However, as it relies on a gradient ascent scheme, it
can be susceptible to local minima; this can become a serious
problem when moving from simple bilinear DCMs for fMRI
data to more complex nonlinear models (Daunizeau, David, &
Stephan, 2011). For this reason, ongoing developments are
concerned with global optimization approaches for DCM
inversion, for example, on the basis of Gaussian processes.
619
Stimulus functions
m
= A + uj B( j ) x + Cu
j=1
dt
dx
Vasodilatory signal
s = x ks g ( -1)
s
s
Flow induction (rCBF)
=s
Hemodynamic
state equations
Balloon model
Changes in volume
t n = - n1/a
Changes in dHb
l (q,n) =
DS
V0 k1(1- q) + k2 1- n + k3(1-n)
S0
k1 = 4.3J0E0TE
k2 = e r0E0TE
k3 = 1-e
BOLD signal
change equation
Figure 2 A graphic summary of the hemodynamic modeling DCM for fMRI. This figure is reproduced, with permission, from Figure 1 in Stephan, K. E.,
Weiskopf, N., Drysdale, P. M., Robinson, P. A., & Friston, K. J. (2007). Comparing hemodynamic models with DCM. Neuroimage, 38, 387401.
620
0.4
0.3
0.2
0.1
0
u2
+++
10
20
30
40
50
60
70
80
90
100
10
20
30
40
50
60
70
80
90
100
10
20
30
40
50
60
70
80
90
100
0.6
0.4
x3
0.2
0
+++
0.3
0.2
0.1
u1
+++
x1
x2
+
1
0
dx
dt
a11
= a21
a12
a22
a32
(3)
a23 + x3 d21
0
a33
0
0
0
0
x1
x +
2
x3
c11
0
u1
0
u
2
c32
0
4
3
2
1
0
-1
10
20
30
40
50
60
70
80
90
100
10
20
30
40
50
60
70
80
90
100
10
20
30
40
50
60
70
80
90
100
3
2
1
0
Figure 3 A simulation of nonlinear gating of connections, as modeled by a nonlinear DCM for fMRI. This figure is reproduced, with permission, from
Figure 2 in Stephan, K. E., Kasper, L., Harrison, L. M., Daunizeau, J., den Ouden, H. E., Breakspear, M., & Friston, K. J. (2008). Nonlinear dynamic
causal models for fMRI. Neuroimage, 42, 649662.
621
Inference on
individual models or model space partition?
Comparison of model
families using
FFX or RFX BMS
Inference on
parameters of an optimal model or parameters of all models?
Yes
Yes
No
No
FFX BMS
FFX BMS
BMA
RFX BMS
FFX analysis of
parameter estimates
(e.g., BPA)
RFX BMS
RFX analysis of
parameter estimates
(e.g., T-test, ANOVA)
Figure 4 A flowchart of the analysis options available in DCM. This figure is reproduced, with permission, from Figure 1 in Stephan, K. E., Penny, W. D.,
Moran, R. J., den Ouden, H. E., Daunizeau, J., & Friston, K. J. (2010). Ten simple rules for dynamic causal modeling. Neuroimage, 49, 30993109.
Model Validation
Careful validation is crucial for any modeling approach, not
just DCM, and requires multiple studies that address different
aspects of validity (e.g., face validity, construct validity, and
predictive validity). Concerning DCM for fMRI, its face validity
has been examined by several simulation studies that tested
whether known parameter estimates or model structure could
be recovered (Daunizeau, 2013; Friston et al., 2003; Friston &
Penny, 2011; Stephan, Friston, et al., 2009; Stephan et al.,
2008; Stephan, Penny, et al., 2009). Construct validity has
also been examined, for example, by testing whether DCMbased estimates of effective connectivity were compatible with
estimates obtained by other methods (e.g., structural equation
modeling; Penny, Stephan, Mechelli, & Friston, 2004b) or with
known neurophysiological effects, such as mutual inhibition
of motor areas via interhemispheric connections (Grefkes,
Eickhoff, Nowak, Dafotakis, & Fink, 2008). Finally, predictive
validity has been established in rodent studies where DCM was
challenged to detect known mechanisms, such as the experimentally induced origin of epileptic seizures (David et al.,
2008) or effects of vagal nerve stimulation (Reyt et al., 2010).
622
(or only to a very limited degree, as in two-state DCMs) distinguish between different types of neurons. Similarly, its inference on synaptic plasticity rests on observing changes in the
effective strength of connections due to experimental factors
known to elicit plasticity (such as learning or pharmacology),
but does not reveal the exact type of plasticity nor the neurotransmitter systems.
Despite this coarse physiological representation, DCM for
fMRI can produce meaningful insights into the pathophysiology of brain diseases. Taking the dysconnection hypothesis
of schizophrenia and (Friston, 1998; Stephan, Baldeweg, &
Friston, 2006) as an example, a recent fMRI study on chronic
schizophrenic patients found that while the degree of prefrontal activation during a working memory task depended on task
performance, the prefrontalparietal connection strength was
uniformly diminished across patients, regardless of task performance, representing a functional dysconnection between
these two areas during working memory (Deserno, Sterzer,
Wustenberg, Heinz, & Schlagenhauf, 2012). In a separate
study (Schmidt et al., 2013), the same connection was found
to be progressively diminished in strength across disease stages
in schizophrenia, with successive reductions from healthy participants via at-risk mental state subjects to untreated firstepisode schizophrenic patients. However, in medicated firstepisode patients, the strength of this connection recovered to
normal levels, indistinguishable from healthy controls
(Schmidt et al., 2013). Other notable work on schizophrenia
examined possible mechanisms why perceptual illusions are
less impaired in schizophrenic patients. Two separate studies,
applying DCM to fMRI and EEG data from the hollow-mask
illusion paradigm, found increased strength of bottom-up but
decreased strength of top-down connections (Dima, Dietrich,
Dillo, & Emrich, 2010; Dima et al., 2009). This replicated
finding nicely agrees with predictions from theories of
impaired perceptual inference in schizophrenia, which posit a
Step 1
model inversion
Step 2
kernel construction
c MQ
B
C
p(q |x,m)
MQ Rd
AB
AC
BB
BC
k : Rd Rd R
Rd
km : MQ MQ R
Measurements from
an individual subject
Subject-specific
inverted generative model
A
Step 3
support vector classification
Step 4
interpretation
B
C
c^ = sgn S ai*k(xi, x) + b*
Jointly discriminative
model parameters
Figure 5 A graphic summary of the idea behind generative embedding. This figure is reproduced, with permission, from Figure 1 in Brodersen, K. H.,
Schofield, T. M., Leff, A. P., Ong, C. S., Lomakina, E. I., Buhmann, J. M., & Stephan, K. E. (2011). Generative embedding for model-based classification
of fMRI data. PLoS Computational Biology, 7, e1002079.
Summary
This article has summarized the conceptual and mathematical
basis of DCM for fMRI and outlined its development over the
past decade. It is probably fair to say that, by highlighting the
importance of forward models and emphasizing the utility of a
Bayesian approach, DCM has introduced some important
changes in the development of fMRI connectivity analyses
(for discussions of different approaches and their interactions,
see Stephan and Roebroeck (2012) and Valdes-Sosa, Roebroeck, Daunizeau, and Friston (2011)). More generally, it has
brought several themes to the attention of the neuroimaging
community that are of critical importance for modeling
approaches in general but had previously been somewhat
neglected, such as the importance of model selection and the
need for validation studies.
Importantly, DCM does not refer to one specific model, but
represents a modeling framework that evolves as new numerical techniques and measurement modalities become available. Model validation is and will remain an important
component in these ongoing developments. In particular,
studies that evaluate the feasibility of model-based predictions,
with respect to independent data, not only provide important
validation but also may establish practical applications that
623
References
Adams, R. A., Stephan, K. E., Brown, H. R., Frith, C. D., & Friston, K. J. (2013). The
computational anatomy of psychosis. Frontiers in Psychiatry, 4, 47.
Bernal-Casas, D., Balaguer-Ballester, E., Gerchen, M. F., Iglesias, S., Walter, H.,
Heinz, A., et al. (2013). Multi-site reproducibility of prefrontalhippocampal
connectivity estimates by stochastic DCM. Neuroimage, 82, 555563.
Brodersen, K. H., Deserno, L., Schlagenhauf, F., Lin, Z., Penny, W. D., Buhmann, J. M.,
et al. (2013). Dissecting psychiatric spectrum disorders by generative embedding.
NeuroImage, 4, 98111.
Brodersen, K. H., Schofield, T. M., Leff, A. P., Ong, C. S., Lomakina, E. I.,
Buhmann, J. M., et al. (2011). Generative embedding for model-based classification
of fMRI data. PLoS Computational Biology, 7, e1002079.
Buxton, R. B., Wong, E. C., & Frank, L. R. (1998). Dynamics of blood flow and
oxygenation changes during brain activation: The balloon model. Magnetic
Resonance in Medicine, 39, 855864.
Daunizeau, J., David, O., & Stephan, K. E. (2011). Dynamic causal modelling: A critical
review of the biophysical and statistical foundations. Neuroimage, 58, 312322.
Daunizeau, J., Friston, K. J., & Kiebel, S. J. (2009). Variational Bayesian identification
and prediction of stochastic nonlinear dynamic causal models. Physica D, 238,
20892118.
Daunizeau, J., Stephan, K. E., & Friston, K. J. (2012). Stochastic dynamic causal modelling
of fMRI data: Should we care about neural noise? Neuroimage, 62, 464481.
Daunizeau, J., Lemieux, L., Vaudano, A. E., Friston, K. J., & Stephan, K. E. (2013). An
electrophysiological validation of stochastic DCM for fMRI. Frontiers in
Computational Neuroscience, 6(103).
David, O., Guillemain, I., Saillet, S., Reyt, S., Deransart, C., Segebarth, C., et al. (2008).
Identifying neural drivers with functional MRI: An electrophysiological validation.
PLoS Biology, 6, 26832697.
Deserno, L., Sterzer, P., Wustenberg, T., Heinz, A., & Schlagenhauf, F. (2012). Reduced
prefrontalparietal effective connectivity and working memory deficits in
schizophrenia. Journal of Neuroscience, 32, 1220.
Di, X., & Biswal, B. B. (2013). Identifying the default mode network structure using
dynamic causal modeling on resting-state functional magnetic resonance imaging.
Neuroimage, 86, 5359.
Dima, D., Dietrich, D. E., Dillo, W., & Emrich, H. M. (2010). Impaired top-down
processes in schizophrenia: A DCM study of ERPs. Neuroimage, 52, 824832.
Dima, D., Roiser, J. P., Dietrich, D. E., Bonnemann, C., Lanfermann, H., Emrich, H. M.,
et al. (2009). Understanding why patients with schizophrenia do not perceive the
hollow-mask illusion using dynamic causal modelling. Neuroimage, 46, 11801186.
Friston, K. J. (1998). The disconnection hypothesis. Schizophrenia Research, 30,
115125.
Friston, K. J. (2008). Variational filtering. Neuroimage, 41, 747766.
Friston, K. J., Frith, C. D., Turner, R., & Frackowiak, R. S. (1995). Characterizing evoked
hemodynamics with fMRI. Neuroimage, 2, 157165.
Friston, K. J., Glaser, D. E., Henson, R. N., Kiebel, S., Phillips, C., & Ashburner, J.
(2002). Classical and Bayesian inference in neuroimaging: Applications.
Neuroimage, 16, 484512.
Friston, K. J., Harrison, L., & Penny, W. (2003). Dynamic causal modelling.
Neuroimage, 19, 12731302.
Friston, K. J., Li, B., Daunizeau, J., & Stephan, K. E. (2010). Network discovery with
DCM. Neuroimage, 56, 12021221.
624
Friston, K., Mattout, J., Trujillo-Barreto, N., Ashburner, J., & Penny, W. (2007).
Variational free energy and the Laplace approximation. Neuroimage, 34, 220234.
Friston, K. J., Mechelli, A., Turner, R., & Price, C. J. (2000). Nonlinear responses in
fMRI: The Balloon model, Volterra kernels, and other hemodynamics. Neuroimage,
12, 466477.
Friston, K., & Penny, W. (2011). Post hoc Bayesian model selection. Neuroimage, 56,
20892099.
Friston, K., Stephan, K. E., Li, B., & Daunizeau, J. (2010). Generalised filtering.
Mathematical Problems in Engineering, 621670, .
Friston, K. J., Trujillo-Barreto, N., & Daunizeau, J. (2008). DEM: A variational treatment
of dynamic systems. Neuroimage, 41, 849885.
Grefkes, C., Eickhoff, S. B., Nowak, D. A., Dafotakis, M., & Fink, G. R. (2008). Dynamic
intra- and interhemispheric interactions during unilateral and bilateral hand
movements assessed with fMRI and DCM. Neuroimage, 41, 13821394.
Hoeting, J. A., Madigan, D., & Raftery, A. E. (1999). Bayesian model averaging: A
tutorial. Statistical Science, 14, 382401.
Kiebel, S. J., Kloppel, S., Weiskopf, N., & Friston, K. J. (2007). Dynamic causal
modeling: A generative model of slice timing in fMRI. Neuroimage, 34, 14871496.
Li, B., Daunizeau, J., Stephan, K. E., Penny, W., Hu, D., & Friston, K. (2011).
Generalised filtering and stochastic DCM for fMRI. Neuroimage, 58, 442457.
Li, B., Wang, X., Yao, S., Hu, D., & Friston, K. (2012). Task-dependent modulation of
effective connectivity within the default mode network. Frontiers in Psychology, 3, 206.
Ma, L., Steinberg, J. L., Hasan, K. M., Narayana, P. A., Kramer, L. A., & Moeller, F. G.
(2012). Stochastic dynamic causal modeling of working memory connections in
cocaine dependence. Human Brain Mapping, 35, 760778.
Mac Kay, D. J.C (1992). A practical bayesian framework for Backpropagation networks.
Neural Computation, 4, 448472.
Marreiros, A. C., Kiebel, S. J., & Friston, K. J. (2008). Dynamic causal modelling for
fMRI: A two-state model. Neuroimage, 39, 269278.
Moran, R. J., Jung, F., Kumagai, T., Endepols, H., Graf, R., Dolan, R. J., et al. (2011).
Dynamic causal models and physiological inference: A validation study using
isoflurane anaesthesia in rodents. PLoS One, 6, e22790.
Moran, R. J., Kiebel, S. J., Stephan, K. E., Reilly, R. B., Daunizeau, J., & Friston, K. J.
(2007). A neural mass model of spectral responses in electrophysiology.
Neuroimage, 37, 706720.
Moran, R. J., Stephan, K. E., Kiebel, S. J., Rombach, N., OConnor, W. T., Murphy, K. J.,
et al. (2008). Bayesian estimation of synaptic physiology from the spectral
responses of neural masses. Neuroimage, 42, 272284.
Moran, R. J., Symmonds, M., Stephan, K. E., Friston, K. J., & Dolan, R. J. (2011). An
in vivo assay of synaptic function mediating human cognition. Current Biology, 21,
13201325.
Penny, W. D., Stephan, K. E., Daunizeau, J., Rosa, M. J., Friston, K. J., Schofield, T. M.,
et al. (2010). Comparing families of dynamic causal models. PLoS Computational
Biology, 6, e1000709.
Penny, W. D., Stephan, K. E., Mechelli, A., & Friston, K. J. (2004a). Comparing dynamic
causal models. Neuroimage, 22, 11571172.
Penny, W. D., Stephan, K. E., Mechelli, A., & Friston, K. J. (2004b). Modelling
functional integration: A comparison of structural equation and dynamic causal
models. Neuroimage, 23(Suppl. 1), S264S274.
Pitt, M. A., & Myung, I. J. (2002). When a good fit can be bad. Trends in Cognitive
Sciences, 6, 421425.
Rehme, A. K., Eickhoff, S. B., & Grefkes, C. (2013). State-dependent differences between
functional and effective connectivity of the human cortical motor system.
Neuroimage, 67, 237246.
Reyt, S., Picq, C., Sinniger, V., Clarencon, D., Bonaz, B., & David, O. (2010). Dynamic
causal modelling and physiological confounds: A functional MRI study of vagus
nerve stimulation. Neuroimage, 52, 14561464.
Rosa, M. J., Friston, K., & Penny, W. (2012). Post-hoc selection of dynamic causal
models. Journal of Neuroscience Methods, 208, 6678.
Rowe, J. B., Hughes, L. E., Barker, R. A., & Owen, A. M. (2010). Dynamic causal
modelling of effective connectivity from fMRI: Are results reproducible and
sensitive to Parkinsons disease and its treatment? Neuroimage, 52,
10151026.
Schmidt, A., Smieskova, R., Aston, J., Simon, A., Allen, P., Fusar-Poli, P., et al. (2013).
Brain connectivity abnormalities predating the onset of psychosis: Correlation with
the effect of medication. JAMA Psychiatry, 70, 903912.
Schuyler, B., Ollinger, J. M., Oakes, T. R., Johnstone, T., & Davidson, R. J. (2010).
Dynamic Causal Modeling applied to fMRI data shows high reliability. Neuroimage,
49, 603611.
Stephan, K. E. (2004). On the role of general system theory for functional neuroimaging.
Journal of Anatomy, 205, 443470.
Stephan, K. E., Baldeweg, T., & Friston, K. J. (2006). Synaptic plasticity and
dysconnection in schizophrenia. Biological Psychiatry, 59, 929939.
Stephan, K. E., Friston, K. J., & Frith, C. D. (2009). Dysconnection in schizophrenia:
From abnormal synaptic plasticity to failures of self-monitoring. Schizophrenia
Bulletin, 35, 509527.
Stephan, K. E., Kasper, L., Harrison, L. M., Daunizeau, J., den Ouden, H. E.,
Breakspear, M., et al. (2008). Nonlinear dynamic causal models for fMRI.
Neuroimage, 42, 649662.
Stephan, K. E., Penny, W. D., Daunizeau, J., Moran, R. J., & Friston, K. J. (2009).
Bayesian model selection for group studies. Neuroimage, 46, 10041017.
Stephan, K. E., Penny, W. D., Moran, R. J., den Ouden, H. E., Daunizeau, J., &
Friston, K. J. (2010). Ten simple rules for dynamic causal modeling. Neuroimage,
49, 30993109.
Stephan, K. E., & Roebroeck, A. (2012). A short history of causal modeling of fMRI data.
Neuroimage, 62, 856863.
Stephan, K. E., Weiskopf, N., Drysdale, P. M., Robinson, P. A., & Friston, K. J. (2007).
Comparing hemodynamic models with DCM. Neuroimage, 38, 387401.
Tricomi, E., Rangel, A., Camerer, C. F., & ODoherty, J. P. (2010). Neural evidence for
inequality-averse social preferences. Nature, 463, 10891091.
Valdes-Sosa, P. A., Roebroeck, A., Daunizeau, J., & Friston, K. (2011). Effective connectivity:
Influence, causality and biophysical modeling. Neuroimage, 58(2), 339361.
Dynamic Causal Models for Human Electrophysiology: EEG, MEG, and LFPs
R Moran, Virginia Tech Carilion Research Institute, Roanoke, VA, USA; Bradley Department of Electrical and Computer
Engineering, Roanoke, VA, USA
2015 Elsevier Inc. All rights reserved.
Glossary
Introduction
Connectivity estimates using dynamic causal modelings (DCMs)
for EEG have been used to inform the mechanisms underlying
Parkinsons disease, epilepsy, the vegetative state, and schizophrenia. Application rests upon a plausible generative model
of neuronal dynamics between connected brain sources and
nodes. These models describe not directly observable mechanisms for example, the strength of synaptic connections along
extrinsic cortico-cortical pathways, using differential equations.
Bayesian inference is then used to map from recorded responses
(electroencephalographic/magnetoencephalographic/local field
potential (EEG/MEG/LFP) data) to their underlying cause.
Hence, the estimates of intrinsic (within-region) and extrinsic
(region-to-region) connections are deemed effective or modelbased assessments. This DCM procedure (Friston, Harrison, &
Penny, 2003) of proposing a generative architecture and then
fitting the model to data can be applied to a range of electrophysiological data features, including event-related potentials
(ERPs), spectral densities, and cross-spectral densities (CSDs),
induced responses (IRs) (timefrequency), and phase coupling
(PHA). DCMs for ERPs and CSDs use neural mass models to
describe active brain sources. In contrast, DCMs for IR and PHA
use phenomenological models to describe interregional effects
using more abstract parameters. This article will first outline the
types of neural mass models used in DCM for ERP/CSDs. The
second section outlines the forward mapping that allows these
models to generate scalp- and sensor-level EEG and MEG data or
invasive LFPs and describes how Bayesian inversion procedures
are used to test competing hypotheses regarding the generative
processes. The following section then demonstrates how these
models and procedures can be applied in the context of either
ERP or CSD data. The final section outlines the phenomenological class of DCMs.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00340-7
625
626
INTRODUCTION TO METHODS AND MODELING | Dynamic Causal Models for Human Electrophysiology: EEG, MEG, and LFPs
Figure 1 This figure shows a neural mass model used in DCM for EEG to represent an active brain source. This 4-subpopulation model uses
MorrisLecar-type differential equations to describe the time evolution of current and conductance states at different cell types. (Cells can possess
AMPA, GABAA, and NMDA receptors with ion-channel time constants (1/k). Layers and sources are connected with strengths parameterized by g.
VREV are reversal potentials for ions through these channels, and VT is the threshold potential.) The neuronal architecture comprises interconnected
neuronal subpopulations, including inhibitory interneurons and pyramidal cells (supragranular and infragranular layers) and spiny stellate cells
(granular layer IV). Pyramidal cells send signals outside of the neural mass. These deliver forward signals (from superficial layer) and backward signals
(from deep layers). The spiny stellate cells, in turn, receive extrinsic forward connections, while the inhibitory cells and superficial pyramidal cells
are in receipt of extrinsic backward connections.
INTRODUCTION TO METHODS AND MODELING | Dynamic Causal Models for Human Electrophysiology: EEG, MEG, and LFPs
627
DCM framework
Parameterized
lead field
Parameterized
interconnected
Neural mass models
Generative model
Bayesian inversion
Empirical data
Figure 2 This figure outlines the elements that comprise the DCM framework. Generative models (physiological for DCM for ERP/CSD and
phenomenological for DCM for IR/PHA) produce a repertoire of empirical recordings. A particular dataset acquired in humans (or animals) can then be
fitted to these models using a variational Bayesian inversion, to reveal the density of model parameters conditional on those particular data.
Both DCM for ERPs (Kiebel, David, & Friston, 2006) and DCM
for CSDs (Moran et al., 2009) use the neural mass models outlined earlier in the text. For ERPs, exogenous inputs, timed
according to experimental stimuli, serve as the input to the
neural masses. This is represented as a thalamic input volley,
with the form of a delayed (by a few tens of milliseconds) narrow
Gaussian impulse function. This can be entered into plausible
cortical nodes. From these sources, dynamics will propagate
throughout connected nodes in the modeled network. The
628
INTRODUCTION TO METHODS AND MODELING | Dynamic Causal Models for Human Electrophysiology: EEG, MEG, and LFPs
Conclusion
The DCM approach to analyzing electrophysiological data
takes advantage of the large and rich prior literature on
References
Friston, K., Harrison, L., & Penny, W. (2003). Dynamic causal modelling. NeuroImage,
19, 12731302.
Kiebel, S., David, O., & Friston, K. (2006). Dynamic causal modelling of evoked
responses in EEG/MEG with lead field parameterization. NeuroImage, 30,
12731284.
Moran, R., et al. (2009). Dynamic causal models of steady-state responses.
NeuroImage, 44, 796811.
Chen, C., Kiebel, S., & Friston, K. (2008). Dynamic causal modelling of induced
responses. NeuroImage, 41, 12931312.
Penny, W., Litvak, V., Fuentemilla, L., Duzel, E., & Friston, K. (2009). Dynamic causal
models for phase coupling. Journal of Neuroscience Methods, 183, 1930.
Relevant Websites
http://www.fil.ion.ucl.ac.uk/spm/software/spm12/ Written by members of the FIL
Methods group at University College London. All the DCM components described
in this article can be implemented using Matlab routines that are available as part of
the academic freeware package SPM.
Glossary
Introduction
The human brain is a complex network of neural elements
(neurons and brain regions) interconnected by a large number
of connections (synaptic links and interregional pathways)
(Bullmore & Sporns, 2009). In recent years, network
approaches to understanding human brain structure and function have been driven by two parallel developments. On one
side, networks have become an object of intensive investigation across many disciplines, from information technology to
the social and biological sciences (Boccaletti, Latora, Moreno,
Chavez, & Hwang, 2006). On the other side, modern brain
imaging techniques have begun to reveal the architecture of
human brain networks in increasing detail. Diffusion imaging
and tractography deliver estimates of anatomical connections
comprising large-scale structural networks (Johansen-Berg &
Rushworth, 2009). Functional magnetic resonance imaging
(fMRI), especially the growing use of resting-state fMRI
(Raichle, 2011), provides neural time series data that can be
processed into a network form, most commonly expressing the
pairwise similarity (cross correlation) of spontaneous signal
fluctuations during rest or coactivation patterns during task
conditions. The confluence of network approaches and neuroimaging technology has catalyzed a new network perspective
on the human brain (Sporns, 2011).
Structural and functional networks can be rendered as connection matrices. Such matrices correspond to graphs comprising sets of network nodes and edges whose configuration
represents the networks topology (Figure 1). In large-scale
human brain networks, nodes generally represent distinct
regions or parcels, while edges express their mutual
http://dx.doi.org/10.1016/B978-0-12-397025-1.00341-9
629
630
Node
Edge
Low degree
Path
High degree
Module 1
Connector hub
Module 2
Provincial hub
Figure 1 Schematic illustration of a graph and some basic graph measures. The graph consists of a set of nodes and edges (top), here represented as
a binary undirected network. Based on the number of edges, nodes can be low-degree or high-degree (middle). Paths connect nodes to each other.
The example shown here is the shortest path (three edges) linking node A to node B (and B to A, since the edges are undirected). The network
can be partitioned into two modules (bottom), and high-degree nodes can be classified as either connector hubs or provincial hubs, based on the pattern
of connections within and between modules.
631
Measures of Centrality
The centrality of a node (or edge) quantifies its importance or
influence within the global network architecture. This definition immediately suggests multiple ways by which centrality
may be captured. Perhaps, the simplest measure of node centrality is the node degree, as it specifies the number of neighbors of each node and hence defines the size of the
neighborhood it can directly influence. Node degree is often
(but not always) highly correlated with betweenness centrality,
defined as the fraction of all shortest paths across the network
that each node (or edge) participates in. A node through which
many short paths must pass is centrally embedded within the
networks topology, potentially acting as a point of convergence or divergence. Another measure of centrality takes into
account how quickly (i.e., in how few steps) a given node can
communicate with all other nodes. This measure, called closeness centrality, is easily computed from the networks distance
matrix. Other topological centrality measures include the
eigenvector centrality (Lohmann et al., 2010) and one of its
variants, the PageRank centrality. According to these measures,
nodes have high centrality if they are connected to other highly
central nodes. Finally, centrality can be measured in relation to
a networks communities or modules, essentially quantifying
the extent to which a given node enables communication
across module boundaries (see the succeeding text).
Another approach for defining centrality is to quantify the
effect on network integrity that results from the removal of a
given node or edge. Computationally, node or edge removal is
easily implemented, and effects on network integrity can be
derived from comparing measures of communication such as
global efficiency before and after node/edge deletion. Generally (but not in all cases), such nodal vulnerability measures
correlate strongly with node degree and/or betweenness. In
addition to providing an indication of centrality for each
node and edge, removal of network elements can reveal important additional information about how networks might
respond to local damage, by rerouting of short communication
paths or readjustments in module boundaries.
Measures of centrality are critical for defining putative network hubs. In brain networks, hubs have been detected in
virtually all anatomical and functional networks, across species
and independent of recording or measuring modality. Despite
the ubiquity of hubs, hub detection does not always lead to
consistent results, in part due to dissociations among multiple
measures of centrality (e.g., degree, betweenness, and closeness). Robust hub detection is best carried out with a combination of measures (Sporns, Honey, & Kotter, 2007), including
nodal degree, path-based betweenness centrality, and measures
that assess vulnerability.
Community Detection
Many networks, including most brain networks, can be partially
decomposed into clusters of nodes that are more densely
632
Conclusion
This article has provided a brief overview of a number of commonly used measures to describe the topology of brain networks.
A number of issues remain for future work, including the careful
Acknowledgment
The authors work was supported by the James S. McDonnell
Foundation.
References
Blondel, V., Guillaume, J. L., Lambiotte, R., & Lefebvre, E. (2008). Fast unfolding of
communities in large networks. Journal of Statistical Mechanics, 2008, P10008.
Blumensath, T., Jbabdi, S., Glaser, M. F., et al. (2013). Spatially constrained
hierarchical parcellation of the brain with resting-state fMRI. NeuroImage, 76,
313324.
Boccaletti, S., Latora, V., Moreno, Y., Chavez, M., & Hwang, D. U. (2006). Complex
networks: Structure and dynamics. Physics Reports, 424, 175308.
Bullmore, E., & Sporns, O. (2009). Complex brain networks: Graph theoretical analysis
of structural and functional systems. Nature Reviews Neuroscience, 10, 186198.
Bullmore, E., & Sporns, O. (2012). The economy of brain network organization. Nature
Reviews Neuroscience, 13, 336349.
Cammoun, L., Gigandet, X., Meskaldji, D., et al. (2012). Mapping the human
connectome at multiple scales with diffusion spectrum MRI. Journal of
Neuroscience Methods, 203, 386397.
Cohen, A. L., Fair, D. A., Dosenbach, N. U. F., et al. (2008). Defining functional areas in
individual human brains using resting state functional connectivity MRI.
NeuroImage, 41, 4557.
de Reus, M. A., & Van den Heuvel, M. P. (2013). The parcellation-based connectome:
Limitations and extensions. NeuroImage, 80, 397404. http://dx.doi.org/10.1016/j.
neuroimage.2013.03.053.
Deco, G., Jirsa, V. K., & McIntosh, A. R. (2011). Emerging concepts for the dynamical
organization of resting-state activity in the brain. Nature Reviews Neuroscience, 12,
4356.
Fornito, A., Zalesky, A., & Breakspear, M. (2013). Graph analysis of the human
connectome: Promise, progress, and pitfalls. NeuroImage, 80, 426444. http://dx.
doi.org/10.1016/j.neuroimage.2013.04.087.
Fortunato, S. (2010). Community detection in graphs. Physics Reports, 486, 75174.
Friston, K. (2009). Causal modeling and brain connectivity in functional magnetic
resonance imaging. PLoS Biology, 7, e1000033.
Friston, K., Moran, R., & Seth, A. K. (2013). Analysing connectivity with Granger causality
and dynamic causal modeling. Current Opinion in Neurobiology, 23, 172178.
Good, B. H., de Montjoye, Y. A., & Clauset, A. (2010). Performance of modularity
maximization in practical contexts. Physical Review E, 81, 046106.
Guimera, R., & Amaral, L. A.N (2005). Functional cartography of complex metabolic
networks. Nature, 433, 895900.
Humphries, M. D., & Gurney, K. (2008). Network small-world-ness: A quantitative
method for determining canonical network equivalence. PLoS One, 3, e0002051.
Johansen-Berg, H., & Rushworth, M. F.S (2009). Using diffusion imaging to study
human connectional anatomy. Annual Reviews in Neuroscience, 32, 7594.
Jones, D. K., Knosche, T. R., & Turner, R. (2013). White matter integrity, fiber count,
and other fallacies: The dos and donts of diffusion MRI. NeuroImage, 73, 239254.
633
Sporns, O., Honey, C. J., & Kotter, R. (2007). Identification and classification of hubs in
brain networks. PLoS ONE, 2, e1049.
Sporns, O., & Kotter, R. (2004). Motifs in brain networks. PLoS Biology, 2, e369.
Telesford, Q. K., Joyce, K. E., Hayasaka, S., Burdette, J. H., & Laurienti, P. J. (2011). The
ubiquity of small-world networks. Brain Connectivity, 1, 367375.
Watts, D. J., & Strogatz, S. H. (1998). Collective dynamics of small-worldnetworks.
Nature, 393, 440442.
Wig, G. S., Laumann, T. O., Cohen, A. L., et al. (2013). Parcellating an individual
subjects cortical and subcortical brain structures using snowball sampling of
resting-state correlations. Cerebral Cortex, http://dx.doi.org/10.1093/cercor/
bht056.
Wig, G. S., Schlaggar, B. L., & Petersen, S. E. (2011). Concepts and principles in the
analysis of brain networks. Annals of the New York Academy of Sciences, 1224,
126146.
Zalesky, A., Fornito, A., Harding, I. H., et al. (2010). Whole-brain anatomical networks:
Does the choice of nodes matter? NeuroImage, 50, 970983.
Relevant Websites
http://www.biological-networks.org/ Biological Networks, with resources and data
sets maintained by Marcus Kaiser.
www.brain-connectivity-toolbox.net Brain Connectivity Toolbox, a matlab graph
analysis toolset maintained by Olaf Sporns and Mika Rubinov.
http://cocomac.g-node.org Cocomac, an online database of macaque anatomical
connectivity.
http://www.humanconnectome.org/ Human Connectome Project website, with
extensive datasets recorded from the human brain.
Crossvalidation
N Kriegeskorte, Medical Research Council, Cambridge, UK
2015 Elsevier Inc. All rights reserved.
Glossary
http://dx.doi.org/10.1016/B978-0-12-397025-1.00344-4
635
636
Figure 1 The division of the data into independent training and test sets
in fivefold crossvalidation.
signals and the noise. Two time points in the same temporal neighborhood therefore must never straddle a division into training and test sets. To avoid this, the data can
be divided into scanner runs (or subruns, with an appropriate hemodynamic safety margin), and two disjoint
sets of runs designated as the training and test data on
each fold.
(2) The folds yield dependent performance estimates. Any inferential procedures must not assume that the performance
estimates obtained on different folds are independent.
For example, when response patterns are classified and
counts of correct and incorrect classifications summed
over folds, a binomial test of the null hypothesis that
performance is at chance level is not appropriate. A good
approach is to obtain a single unbiased performance estimate for each subject, then use a non-parametric test (e.g.,
Wilcoxons signed-rank test) to test whether performance
exceeds chance level. This approach can also be extended
to model comparisons (using performance differences as
the test statistic). It has the additional advantage of treating
the variation across subjects as a random effect, and thus
supports inferences about the population.
(3) Multiple nested levels of crossvalidation might be needed.
Crossvalidation serves the purpose to obtain estimates of
predictive performance that are not biased by overfitting.
In many scenarios, there is more than one level of parameters to be fitted. In a linear pattern classification analysis,
for example, the classifier might have hyperparameters in
addition to the weights associated with each response
channel (e.g., each voxel). If the hyperparameters are to
be chosen so as to maximize the crossvalidation estimate
of performance, the maximum performance estimate will
be biased by overfitting of the hyperparameters. A second
level of crossvalidation is therefore needed. On each fold
of the outer crossvalidation loop, the hyperparameter can
be determined by nested crossvalidation within the training set. The optimal setting is then used to predict the test
set (which has not been used to optimize the
hyperparameter).
637
638
Information Criteria
In certain scenarios, we can avoid both the challenge of a fully
Bayesian approach and the computational demands of crossvalidation. The Akaike information criterion (AIC) and the
Bayesian information criterion (BIC) provide measures of
model performance that account for model complexity. AIC
and BIC combine a term reflecting how well the model fits the
data with a term that penalizes the model in proportion to its
number of parameters. These criteria are easier to compute
than a crossvalidation estimate of predictive performance and
they enable accurate model selection when the assumptions
they are based on hold. The AIC relies on an asymptotic
approximation that may not hold for a given finite data set,
and the BIC relies on the assumption that the model errors are
independent and normally distributed. Both AIC and BIC are
functions of the parameter count and the maximized likelihood, that is, the probability of the data given the maximumlikelihood fit of the model. Counting parameters is not in
general a good method of estimating model complexity. For
example, the effective number of parameters is reduced when
the hypothesis space is regularized using an explicit prior or by
including a penalty on undesirable parameter combinations in
the cost function minimized by the fitting procedure. The
effective number of parameters can be difficult to estimate
accurately. Nevertheless, where applicable, AIC and BIC provide a quick and easy way to compare models.
Concluding Remarks
Statistical inference, whether Bayesian or frequentist, necessarily combines data with (explicit or implicit) prior assumptions.
Prior assumptions can stabilize our estimates and guide our
inferences. In Bayesian inference, an accurate prior will pull our
estimates toward the true value and an inaccurate prior will
pull them away from the true value. In frequentist inference, the
assumption of a particular error distribution lends us power.
Unsurprisingly, nonparametric inference techniques that make
no distributional assumptions tend to have less power. The
classical frequentist statistical approach is to fit and perform
inference on the basis of a single data set. Overfitting can be
accounted for in estimating the error variance. This obviates the
need for checking predictive performance on independent data.
When the inference is performed on a likelihood ratio comparing two point hypotheses, this approach has been shown to be
optimally powerful (Neyman & Pearson, 1933).
Without tests of predictive performance on independent
data, however, the classical statistical approach to inference is
severely limited, for two reasons. First, our assumptions are
usually not exactly true, and therefore our inferences are not
necessarily reliable. Second, the classical statistical approach is
only feasible for a very restricted class of models. This is the
reason why the field that has led the development of the most
complex models, machine learning, heavily relies on crossvalidation. In science our models should mirror the mechanisms
we hypothesize, and not be limited to a small set we happen to
know how to test with a single data set. Our goal is not
mathematical elegance, but learning about nature. Testing
effects and selecting models according to their actual predictive
power on new data puts all assumptions to the test and keeps
us firmly grounded in empirical reality.
In sum, the advantage of crossvalidation over alternative
methods is its generality: It can be applied when other methods
cannot and it does not rely on assumptions or approximations.
For many of the most interesting and well-motivated models in
brain science, a fully Bayesian approach is daunting and the
assumptions required for classical frequentist inference and for
information criteria for model selection may not hold. Crossvalidation enables us to develop our models as motivated by
the science (rather than the statistics) and to employ the familiar procedure of first defining a hypothesis specific enough to
be testable and then testing it empirically within the analysis of
a single data set.
References
Bishop, C. M. (2006). Pattern recognition and machine learning. New York: Springer.
Friston, K. J., Holmes, A. P., Worsley, K. J., Poline, J. P., Frith, C. D., &
Frackowiak, R. S. (1994). Statistical parametric maps in functional imaging: A
general linear approach. Human Brain Mapping, 2(4), 189210.
Genovese, C. R., Lazar, N. A., & Nichols, T. (2002). Thresholding of statistical maps in
functional neuroimaging using the false discovery rate. NeuroImage, 15(4),
870878.
Ghahramani, Z. (2013). Bayesian non-parametrics and the probabilistic approach to
modelling. Philosophical Transactions of the Royal Society A: Mathematical,
Physical and Engineering Sciences, 371(1984). http://rsta.royalsocietypublishing.
org/content/371/1984/20110553.full.
Hastie, T., Tibshirani, R., & Friedman, J. (2002). Elements of statistical learning.
New York: Springer.
Huth, A. G., Nishimoto, S., Vu, A. T., & Gallant, J. L. (2012). A continuous semantic
space describes the representation of thousands of object and action categories
across the human brain. Neuron, 76(6), 12101224.
Kay, K. N., Naselaris, T., Prenger, R. J., & Gallant, J. L. (2008). Identifying natural
images from human brain activity. Nature, 452(7185), 352355.
Kriegeskorte, N. (2011). Pattern-information analysis: From stimulus decoding to
computational-model testing. NeuroImage, 56(2), 411421.
Kriegeskorte, N., Goebel, R., & Bandettini, P. (2006). Information-based functional brain
mapping. Proceedings of the National Academy of Sciences of the United States of
America, 103(10), 38633868.
639
Kriegeskorte, N., Lindquist, M. A., Nichols, T. E., Poldrack, R. A., & Vul, E. (2010).
Everything you never wanted to know about circular analysis, but were afraid to ask.
Journal of Cerebral Blood Flow & Metabolism, 30(9), 15511557.
Kriegeskorte, N., Mur, M., & Bandettini, P. (2008). Representational similarity
analysis Connecting the branches of systems neuroscience. Frontiers in
Systems Neuroscience, 2(4). http://www.ncbi.nlm.nih.gov/pmc/articles/
PMC2605405/.
Kriegeskorte, N., Simmons, W. K., Bellgowan, P. S., & Baker, C. I. (2009). Circular
analysis in systems neuroscience: The dangers of double dipping. Nature
Neuroscience, 12(5), 535540.
Krzanowski, W. J. (1988). Principles of multivariate analysis: A users perspective.
Oxford: Clarendon Press.
MacKay, D. J. (2003). Information theory, inference and learning algorithms. New York:
Cambridge University Press.
Mur, M., Bandettini, P. A., & Kriegeskorte, N. (2009). Revealing representational content
with pattern-information fMRI An introductory guide. Social Cognitive and
Affective Neuroscience, 4(1), 101109.
Neyman, J., & Pearson, E. S. (1933). On the problem of the most efficient
tests of statistical hypotheses. Philosophical Transactions of the Royal
Society A: Mathematical, Physical and Engineering Sciences, 231(694706),
289337.
Nichols, T., & Hayasaka, S. (2003). Controlling the familywise error rate in functional
neuroimaging: A comparative review. Statistical Methods in Medical Research,
12(5), 419446.
Nichols, T. E., & Holmes, A. P. (2002). Nonparametric permutation tests for functional
neuroimaging: A primer with examples. Human Brain Mapping, 15(1), 125.
Vul, E., Harris, C., Winkielman, P., & Pashler, H. (2009). Puzzlingly high correlations in
fMRI studies of emotion, personality, and social cognition. Perspectives on
Psychological Science, 4(3), 274290.
Worsley, K. J., Marrett, S., Neelin, P., Vandal, A. C., Friston, K. J., & Evans, A. C.
(1996). A unified statistical approach for determining significant signals in images
of cerebral activation. Human Brain Mapping, 4(1), 5873.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00345-6
641
Searchlight
Whole
brain
Condition A
Condition B
Voxel 2
642
Region of
interest
Voxel 1
Figure 1 Definition of voxel activation space. Voxelwise data to be used for pattern analysis are extracted from a given area (white outlines), which
can be the whole brain, a region of interest, or a searchlight, that is, a small area that is moved throughout the brain. The extracted data are
concatenated to form voxel activation vectors, which are associated with experimental conditions (blue and orange). The components of vectors can be
interpreted as coordinates into a high-dimensional voxel activation space (only two dimensions shown). In this space, the similarity between
multivariate responses within a condition and the difference between conditions lead to the formation of clusters of data points, which
can be discriminated by pattern analysis.
T
x x1 , x2 , . .., xp comprises values from p different voxels. In
the following, we will denote the vectors for the two conditions
!
!
A and B with x Ai and x Bi , respectively, where i 1 ... n enumerates the data points in each class.
!
These vectors x can then be interpreted as the locations of
points in a p-dimensional voxel activation space. Pattern analysis
algorithms operate on this space trying to identify different
regions where data points belonging to a particular condition
occur more often than those belonging to another condition.
!
centroid distance direction, thereby improving the class separation. As a consequence, the single coefficients of the optimal
!
weight vector w cannot be interpreted as a measure of singlevoxel informativeness.
The weight vector w that defines the discriminant corresponds to a direction in voxel activation space, and the com!
putation of d x is equivalent to a projection of the data onto
this direction.
Figure 2 illustrates how the choice of this direction determines how well data points from the two classes can be sepa!
rated. An alignment of w with one of the two axes, that is, using
only data from one of the voxels, results in not only some
discrimination but also a large overlap of the projected class
distributions. Using the sum of the values from voxels 1 and 2
(corresponding roughly to the univariate analysis of smoothed
data) makes the situation worse because the experimental
manipulation has effects of different signs in the two voxels.
Choosing the direction such that the projected distance
between the two class means (centroids) is maximized gives
an improved result, but there is still overlap. In contrast, the
!
optimal choice w cleanly separates data belonging to the two
classes.
The direction orthogonal to the centroid distance contains
no discriminative information at all (pure noise in Figure 2);
all the variation in this direction is accounted for by the withinclass variance. The reason why the optimally informative direction is still not identical to maxim centroid distance is that the
noise is correlated between voxels 1 and 2. The optimal direction includes part of the pure noise direction to compensate
for that noise which is corrupting information along the
643
pt
im
Pure
nois
Voxel 2
Vo
xe
l1
Vo
xe
l2
al
Max
im.
cen
troid
dist
anc
Voxel 1
Figure 2 Directions in voxel activation space. Data points from two classes (conditions; blue and orange) can be discriminated differently well
depending on the direction that is considered (arrows). If data points are projected onto a direction (gray lines), one-dimensional distributions arise
(colored ticks), which show different degrees of overlap between the classes. The optimal direction is not exclusively determined by the class centroids
(maximizing their projected distance) but also takes the within-class distribution or noise into account.
All data
Fold 1
Fold 2
Fold 3
Fold 4
Fold 5
Figure 3 Cross-validated classification accuracy. To correctly assess a classifiers performance, it has to be tested on data not used for training.
A common way to achieve this with limited data is to partition the data set (leftmost panel) into k subsets. The classification algorithm is then trained on
data from k 1 of the parts (open circles) and tested on the remaining part (filled circles). This is repeated such that each part is once used for
testing (k-fold cross-validation). The classification performance is assessed by the number of test data points correctly classified, the cross-validated
accuracy (here: 7 out of 10 70%).
644
Classification Methods
In the following, we briefly describe three approaches to classification; they are illustrated in Figure 4.
Logistic regression
!
P Bj x 0
1
! !
1 exp w T x b
and
!
!
P Aj x 0 1 P Bj x 0
where
1 ! !
!
!
!
w S1 m B m A and b wT m A m B
2
!
!
!
!
^
^
can be estimated based on m A x A ; m B x B , and
1
^
S 2 SA SB . The optimal classifier under these assumptions
is the one that chooses the class that has the largest posterior
! !
probability, which is equivalent to using wT x b as the decision value.
An important limitation of LDA is that it is necessary
to estimate the within-class covariance matrix, which has
1
2 p1 p free entries, a number that for higher dimensionalities of the voxel activation space can quickly get larger than the
number of data points available to calculate it. In this case,
the estimate becomes singular, which means its inverse cannot
be computed. Even if the number of data points is formally
sufficient, S^1 becomes an unreliable estimator of S1 for
increasing dimensionality, degrading the performance of the
classifier. Two common ways to cope with this problem are
regularization of the model via a shrinkage estimator (Schafer
& Strimmer, 2005) or reduction of dimensionality via principal component analysis (see Jolliffe, 2002).
!
Logistic regression
Another way to circumvent the covariance estimation problem
is to directly fit the equation for the posterior class probabilities
to the data, that is, to treat it as a discriminative model that does
not make an explicit statement about the distribution of the
!
data x . This approach is called logistic regression because
1/(1 exp(s)) is known as the logistic function. It is important to note that despite of its name, logistic regression is not a
form of regression but a classification method.
The advantage of logistic regression over LDA is that it is not
necessary to estimate the within-class covariance but only the
!
p-dimensional weight vector w and scalar bias b. Moreover, the
SVM
Mahalanobis distance
Figure 4 Approaches to pattern analysis. Each panel shows the defining elements of the respective method in black and the resulting posterior class
probabilities or binary classification as a colored background. Linear discriminant analysis assumes multivariate normal distributions for the two
classes and estimates their class means (centroids; dots) and common covariance (ellipses) to compute the posterior probabilities. Logistic regression
directly models the posterior distribution using only a weight vector and bias (arrow with intercept). The support vector machine achieves
classification by searching for a separating area without data points (between colored lines), which is as wide as possible (margin width; double-sided
arrow). This separating area is defined by the data points at the edge, the support vectors (circled). Mahalanobis distance directly quantifies the
distinctness of the two distributions by the distance of the centroids measured in units of the within-class standard deviation (ellipses).
m
X
j1
ai z j and b wT
1 !
!
zA zB
2
645
Acknowledgments
Thanks to Fonov et al. (2009) for the brain template for
Figure 1, rendered with C. Rordens MRIcroGL.
References
Allefeld, C., & Haynes, J.-D. Haynes. (2014). Searchlight-based multi-voxel pattern
analysis of fMRI by cross-validated MANOVA. NeuroImage, 345357. http://dx.doi.
org/10.1016/j.neuroimage.2013.11.043.
Bishop, C. M. (2006). Pattern recognition and machine learning. New York: Springer.
Boser, B. E., Guyon, I., & Vapnik, V. (1992). A training algorithm for optimal margin
classifiers. In Proceedings of the fifth annual workshop of computational learning
theory (pp. 144152). Pittsburgh: Association for Computing Machinery.
Chaimow, D., Yacoub, E., Ugurbil, K., & Shmuel, A. (2011). Modeling and analysis of
mechanisms underlying fMRI-based decoding of information conveyed in cortical
columns. NeuroImage, 56, 627642.
Cortes, C., & Vapnik, V. (1995). Support vector networks. Machine Learning, 20,
273297.
Edelman, S., Grill-Spector, K., Kushnir, T., & Malach, R. (1998). Towards direct
visualization of the internal shape space by fMRI. Psychobiology, 26, 309321.
Fisher, R. A. (1936). The use of multiple measurements in taxonomic problems. Annals
of Eugenics, 7, 179188.
Fonov, V. S., Evans, A. C., McKinstry, R. C., Almli, C. R., & Collins, D. L. (2009).
Unbiased nonlinear average age-appropriate brain templates from birth to
adulthood. NeuroImage, 47, S102.
Freeman, J., Brouwer, G. J., Heeger, D. J., & Merriam, E. P. (2011). Orientation
decoding depends on maps, not columns. Journal of Neuroscience, 31,
47924804.
Friston, K. J., Frith, C. D., Frackowiak, R. S., & Turner, R. (1995). Characterizing
dynamic brain responses with fMRI: A multivariate approach. NeuroImage, 2,
166172.
Friston, K. J., Holmes, A. P., Poline, J. B., Grasby, P. J., Williams, S. C., Frackowiak, R. S.,
et al. (1995). Analysis of fMRI time-series revisited. NeuroImage, 2, 4553.
Fujita, I., Tanaka, K., Ito, M., & Cheng, K. (1992). Columns for visual features of objects
in monkey inferotemporal cortex. Nature, 360, 343346.
Georgopoulos, A. P., Schwartz, A. B., & Kettner, R. E. (1986). Neuronal population
coding of movement direction. Science, 233, 14161419.
Hastie, T., Tibshirani, R., & Friedman, J. (2009). The elements of statistical learning:
Data mining, inference, and prediction (2nd ed.). New York: Springer.
646
McIntosh, A. R., Bookstein, F. L., Haxby, J. V., & Grady, C. L. (1996). Spatial pattern analysis
of functional brain images using partial least squares. NeuroImage, 3, 143157.
Nevado, A., Young, M. P., & Panzeri, S. (2004). Functional imaging and neural
information coding. NeuroImage, 21, 10831095.
Op de Beeck, H. P. (2010). Against hyperacuity in brain reading: Spatial smoothing
does not hurt multivariate fMRI analyses? NeuroImage, 49, 19431948.
Platt, J. C. (2000). Probabilities for SV machines. In A. J. Smola, et al. (Eds.), Advances
in large margin classifiers (pp. 6174). Cambridge: The MIT Press.
Schafer, J., & Strimmer, K. (2005). A shrinkage approach to large-scale covariance
matrix estimation and implications for functional genomics. Statistical Applications
in Genetics and Molecular Biology, 4, 32.
Shmuel, A., Chaimow, D., Raddatz, G., Ugurbil, K., & Yacoub, E. (2010). Mechanisms
underlying decoding at 7 T: Ocular dominance columns, broad structures, and
macroscopic blood vessels in V1 convey information on the stimulated eye.
NeuroImage, 49, 19571964.
Swisher, J. D., Gatenby, J. C., Gore, J. C., Wolfe, B. A., Moon, C. H., Kim, S. G., et al.
(2010). Multiscale pattern analysis of orientation-selective activity in the primary
visual cortex. Journal of Neuroscience, 30, 325330.
Timm, N. H. (2002). Applied multivariate analysis. New York: Springer.
Triantafyllou, C., Hoge, R. D., & Wald, L. L. (2006). Effect of spatial smoothing on
physiological noise in high-resolution fMRI. NeuroImage, 32, 551557.
Vapnik, V. (1982). Estimation of dependences based on empirical data, Addendum 1.
New York: Springer.
Reverse Inference
RA Poldrack, Stanford University, Stanford, CA, USA
2015 Elsevier Inc. All rights reserved.
Glossary
In short, the subjects did not demonstrate the classic brainbased signs of addiction. Instead, they loved their iPhones.
This is a classic example of what has come to be called
reverse inference, which is the use of activation to infer the
presence of a specific cognitive function (in this case, the rather
ill-founded inference that insular activity reflected the fact that
subjects were experiencing feelings of love when viewing the
iPhone).
In this article, I will first outline an analysis of reverse
inference that highlights its problematic logical status and
show how meta-analyses can be used to examine its evidentiary
power. I will also outline how meta-analysis has been formalized using large-scale databases and how the tools of machine
learning provide the potential to perform reverse inference in a
defensible, albeit more limited, manner.
forward inference because it reasons forward from an experimental manipulation to a brain function.
Instead of inferring on the basis of an experimental manipulation, reverse inference proceeds in the opposite direction:
The researcher performs an fMRI study and finds that some
area is activated. Instead of inferring the function of the region
based on the task manipulation, the researcher instead infers
the function of the region via a comparison with other studies
in which the same area was active. For example, given activation in the left inferior frontal region (Brocas area), a
researcher might infer that the subject is engaging language
processes in relation to the manipulation that drove the
activation.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00346-8
647
648
Syntax
Reward
Figure 1 Neurosynth meta-analytic maps for the terms syntax and reward. The voxels shown in red are those for which there was a significant
forward inference association (i.e., the voxel is active when the term appears often in a paper), whereas the voxels in blue are those for which
there was also a significant reverse inference association (i.e., activation in the voxel was predictive of the word appearing in the paper). Note that in both
maps, the anterior cingulate and anterior insula show forward inference activation but no significant reverse inference association, reflecting the fact
that they are activated across a very broad set of tasks.
649
Conclusion
The neuroimaging literature has become increasingly sensitive
to the difficulties of interpreting reverse inferences, with some
arguing that this backlash has actually gone too far (e.g.,
Hutzler, 2013). It is clear that this strategy may be useful in
inspiring novel hypotheses regarding brain function, particularly in new areas of study, but its use must be tempered by the
heavy sensitivity upon base rates of activation. There is great
hope that large-scale databasing, particularly databases of full
datasets such as OpenFMRI, may provide the basis for much
more powerful decoding of mental function from brain activation, providing reverse inferences whose evidence is directly
quantifiable.
References
Aguirre, G. K. (2003). Functional imaging in behavioral neurology and cognitive
neuropsychology. In T. E. Feinberg, & M. J. Farah (Eds.), Behavioral neurology and
cognitive neuropsychology. New York: McGraw-Hill.
Ariely, D., & Berns, G. S. (2010). Neuromarketing: The hope and hype of neuroimaging
in business. Nature Reviews Neuroscience, 11(4), 284292.
Davatzikos, C., Ruparel, K., Fan, Y., Shen, D. G., Acharyya, M., Loughead, J. W., et al.
(2005). Classifying spatial patterns of brain activity with machine learning methods:
Application to lie detection. NeuroImage, 28(3), 663668.
Henson, R. (2006). Forward inference using functional neuroimaging: Dissociations
versus associations. Trends in Cognitive Sciences, 10(2), 6469.
Hutzler, F. (2013). Reverse inference is not a fallacy per se: Cognitive processes can be
inferred from functional imaging data. Neuroimage, 84, 10611069.
Mourao-Miranda, J., Bokde, A. L. W., Born, C., Hampel, H., & Stetter, M. (2005).
Classifying brain states and determining the discriminating activation
patterns: Support vector machine on functional mri data. NeuroImage, 28(4),
980995.
Poldrack, R. A. (2006). Can cognitive processes be inferred from neuroimaging data?
Trends in Cognitive Sciences, 10(2), 5963.
Poldrack, R. A. (2010). Subtraction and beyond: The logic of experimental designs for
neuroimaging. In S. J. Hanson, & M. Bunzl (Eds.), Foundational issues in human
brain mapping (pp. 147160). Cambridge, MA: MIT Press.
Poldrack, R. A., Barch, D. M., Mitchell, J. P., Wager, T. D., Wagner, A. D., Devlin, J. T.,
et al. (2013). Toward open sharing of task-based fMRI data: the openfMRI project.
Frontiers in Neuroinformatics, 7, 12.
650
Poldrack, R. A., Halchenko, Y. O., & Hanson, S. J. (2009). Decoding the large-scale
structure of brain function by classifying mental states across individuals.
Psychological Science, 20, 13641372.
Poldrack, R. A., Mumford, J. A., Schonberg, T., Kalar, D., Barman, B., & Yarkoni, T.
(2012). Discovering relations between mind, brain, and mental disorders using
topic mapping. PLoS Computational Biology, 8(10), e1002707.
Poldrack, R. A., & Wagner, A. D. (2004). What can neuroimaging tell us about the
mind? insights from prefrontal cortex. Current Directions in Psychological Science,
13, 177181.
Shinkareva, S. V., Mason, R. A., Malave, V. L., Wang, W., Mitchell, T. M., & Just, M. A.
(2008). Using fMRI brain activation to identify cognitive states associated with
perception of tools and dwellings. PLoS One, 3(1), e1394.
Yarkoni, T., Poldrack, R. A., Nichols, T. E., Van Essen, D. C., & Wager, T. D. (2011).
Large-scale automated synthesis of human functional neuroimaging data. Nature
Methods, 8, 665670.
Young, L., & Saxe, R. (2009). An fMRI investigation of spontaneous mental state
inference for moral judgment. Journal of Cognitive Neuroscience, 21(7),
13961405.
Glossary
Introduction
Many fields of investigation, spanning medicine, science, and
humanities, have an interest in the spatially localized measurements of human brain activity provided by functional magnetic resonance imaging (fMRI). These fields use a diverse array
of experimental, statistical and computational methods to analyze and interpret fMRI responses, and this diversity reflects the
questions of interest to each field.
The approach in vision science differs substantially from
that taken in most other fields. Most disciplines use neuroimaging designs based on between-group or between-condition
comparisons; the primary aim of these experiments is to find
statistically significant group differences that localize function
by combining weak signals. But the fMRI signals in visual
cortex are relatively strong, so that experiments can be performed in individual subjects using a wide range of stimuli.
Further, the spatial organization and high degree of connectivity across visual cortex is clear, so that localization is not a
driving factor. Instead, the principal goals of neuroimaging in
vision science are (a) to develop computational models that
predict fMRI responses for a wide range of stimuli, and (b) to
integrate neuroimaging measurements with data from other
techniques (psychophysics, intracranial recordings, singleunit physiology, and so forth). To support these goals, neuroimaging designs for vision science use parametric variations of
the stimulus and computational models that compute the
mapping from stimuli to fMRI time series. In vision science,
computational modeling is central and statistical analyses are
secondary.
We illustrate and explain the approach in the following
sections. First, we introduce visual field maps (also called
retinotopic maps). This background section provides the
reader with a sense of the cortical locations where we measure
fMRI responses and the quality of the fMRI time series in visual
cortex. Second, we describe the importance of stimulusreferred measurement in vision science. This approach is critical for integrating different types of measurements. Third, we
describe the current generation of computational models of
the fMRI time series. These models extend conventional visual
field mapping and analyze the time series more fully. Finally,
http://dx.doi.org/10.1016/B978-0-12-397025-1.00347-X
651
652
INTRODUCTION TO METHODS AND MODELING | Computational Modeling of Responses in Human Visual Cortex
Figure 1 Visual field maps in occipital cortex. The small inset at the upper right is a smoothed rendering of the surface boundary between gray
matter and white matter in a right hemisphere, and the dotted rectangle is shown in the magnified and further smoothed images. The dark and light
gray shading indicates sulci and gyri, respectively. The two main images show visual cortex rendered from a point behind the occipital pole. The
underlying anatomy is the same for the two meshes, differing only in the color overlays. The color overlays show the most effective angle (left) or
the most effective eccentricity (right). Colors are shown only for voxels where the data are well fit by a population receptive field model, as explained
below. The solid black lines and labels indicate the positions of ten visual field maps. The view and data were selected to provide a large field of
view spanning most of the occipital lobe. Additional maps have been identified, including some on the intraparietal sulcus (IPS) and anterior ventral
surface (Arcaro, McMains, Singer, & Kastner, 2009; Dechent & Frahm, 2003; Kolster, Peeters, & Orban, 2010; Konen & Kastner, 2008; Sereno,
Pitzalis, & Martinez, 2001). The uncolored region on the ventral surface is close to a large sinus that limits the ability to measure the BOLD signal
(Winawer, Horiguchi, Sayres, Amano, & Wandell, 2010).
INTRODUCTION TO METHODS AND MODELING | Computational Modeling of Responses in Human Visual Cortex
visual maps V1, V2, and V3 is similar to nonhuman
primate. However, research has revealed substantial differences
in the size, spatial layout, and responsiveness between human
and nonhuman primate extrastriate maps (e.g., V3, hV4, V3A/
B, and VO-1). These findings have been reviewed recently, and
we refer the reader to these reviews to learn more about this
work (Silver & Kastner, 2009; Wandell, Dumoulin, & Brewer,
2007; Wandell & Winawer, 2011).
Stimulus-Referred Measurements
It is worthwhile to step back and consider what exactly is measured when a visual field map is defined: the map specifies which
stimulus position most effectively drives the response at each
cortical location. Thus, the map characterizes cortex in terms of
the stimulus. Such stimulus-referred (also called input-referred)
descriptions of neural responses play a key role in vision science.
The great majority of visual neuroscience measurements use a
stimulus-referred approach to characterize neural responses.
Receptive field (RF) measurement is a classic and particularly clear example (Hartline, 1938). Suppose one measures
the response of a V1 neuron to a small spot presented at
different locations in the visual field. The cell will respond
when the spot is within a small region of the visual field, and
this region is called the RF. Note that the RF is a description of
the stimulus properties (locations) that evoke a response.
There is no description of the proximal inputs to the cell
lateral geniculate neurons, other V1 neurons, feedback signals
from extrastriate cortex, and inputs received from the pulvinar.
Stimulus-referred descriptions are a theoretical construct; a V1
neuron lives and dies in the dark, never being directly stimulated by photons. In describing the RF of a cell, the optical
components of the eye and the extensive neural and glial
network that give rise to the RF are not explicitly characterized.
Stimulus-referred descriptions can be applied to many
properties in addition to visual field position, such as orientation, direction, and wavelength (Wandell, 1995). Stimulusreferred measurements summarize neural circuit responses
without requiring the construction of a circuit model. This
capability is important because such circuit models are presently beyond the reach of neuroscience methods.
Perhaps the most valuable aspect of stimulus-referred measurement is that it supports the coordination of insights from
many parts of vision science including optics, retinal processing, cortical circuitry, local field potentials, scalp recordings,
and perception. Integration across these measures is challenging because each samples the nervous system in its own way
and produces outputs with different units. For example, microelectrodes measure voltages or spike rates, calcium imaging
measures photons, fMRI measures modulation in blood oxygenation, and perception measures subject reports. The stimulus is a unifying framework for vision science; the stimulus
representation serves as a common ground where results
from very different measures are compared.
The use of stimulus-referred measurements is very common
in vision science, just as input-referred measurements are very
common in engineering (Wandell, 1995). They are so ubiquitous
that the beauty and value of the approach is rarely taught. One
objective of this article is to make the idea and its value explicit.
653
Population RF Models
The success in the parcellation of visual cortex into maps provides a foundation for a new phase of investigation: building
computational models of fMRI responses to visual stimuli. The
goal of this work is to precisely express and test neural processing principles. Stimulus-referred computational models offer
the best hope for coordinating different types of visual measures into a unified theory. This new phase of modeling could
not take place without the first phase. Response properties
differ across maps; interpreting a set of measurements is difficult unless one knows which map is the source of the
measurements.
In an early step toward theory, Tootell et al. (1997) observed
that reducing the width of a contrast pattern, such as an expanding ring contrast pattern, substantially reduced the duration of
the V1 on-response but had little effect on the V3A on-response.
They explained the difference by the hypothesis that V3A receptive fields cover more of the visual field than V1 receptive fields.
Qualitatively, the on-response in V1 was governed by the stimulus width but in V3A the on-response was governed by the RF
width. Smith, Singh, Williams, and Greenlee (2001) systematically investigated this idea, quantifying the proportion of the
time that the fMRI response is elevated compared to baseline
(the duty cycle) as thin rings or wedges traversed the visual field.
The duty cycle differed substantially between cortical locations,
and they explained these differences in terms of the size of the
RF of neurons in each cortical location.
654
INTRODUCTION TO METHODS AND MODELING | Computational Modeling of Responses in Human Visual Cortex
pRF profile
8
y (deg)
x = 2.5, y = 0.1 ()
8
4
0
x ()
5
0
5
0
24
48
72
96
Time (s)
120
144
168
192
pRF profile
V2
y ()
4
0
r = 3.7, theta= 87
Sigma = 1.2
r = 6.5, theta= 84
Sigma = 5.0
8
15
0
x ()
8
BOLD Signal (%)
8
BOLD Signal (%)
x = 3.7, y = 0.2 ()
10
5
0
5
0
pRF profile
V3A
y (deg)
24
48
72
96
Time (s)
120
144
168
192
0
x ()
48
72
10
0
10
0
24
96
Time (s)
120
144
168
192
Figure 2 A tool to analyze the population receptive field (pRF). The fMRI time series were measured with a 7 Tesla scanner at a resolution of 1 mm3
voxels. The stimulus was a contrast pattern within a slowly translating bar aperture. The aperture swept through the visual field at different angles;
occasionally the contrast pattern was turned off. The three plots show the fMRI signal measured at voxels located in three different locations
(white circles in V1, V2, and V3A; upper right image). The dashed black lines are measurements and the solid blue lines are pRF model fits. The estimated
pRF for each voxel is shown in the image panels. The three time series responses to the same pattern differ in timing and width. This time series
difference is modeled by the center position and size of the pRF. The tool is part of the open source vistasoft package (http://github.com/vistalab). Data
obtained in collaboration with E. Yacoub and K. Ugurbil.
INTRODUCTION TO METHODS AND MODELING | Computational Modeling of Responses in Human Visual Cortex
3 reflects the pooled activity of its inputs and its role in the
neural circuit.
The principal difference between the single-unit RF and the
pRF is that RF measurements tap into circuit activity at a single
point within the neural plexus, while the pRF is a mean-field
measurement of the circuit activity. The key limitation of
mean-field fMRI measurements is obvious spatial resolution.
However, an advantage is that fMRI measurements provide a
much larger field of view and can reveal coordinated activity in
remote sites. The fMRI measurement is also sensitive to signals
that are missed by single unit RF measurements. In some cases
where BOLD and single unit measurements diverge, the BOLD
signal correlates best with perceptual judgments (Maier et al.,
2008). The BOLD signal is also sensitive to glial responses
(Schulz et al., 2012), a cell class often neglected in electrophysiological measurements in animals. Finally, fMRI provides
direct information about human, while single-unit physiology
is carried out in animal models whose circuits may differ.
The pRF framework has been applied usefully in a number
of studies. For example, the framework has been used to clarify
certain visual field maps (Amano, Wandell, & Dumoulin,
2009; Arcaro et al., 2009; Winawer et al., 2010) and to compare pRF sizes between controls and subjects with neurological
conditions (Hoffmann et al., 2012; Levin, Dumoulin, Winawer,
Dougherty, & Wandell, 2010). The method has been applied
to measure plasticity (Brewer, Barton, & Lin, 2012) and the effect
of task-demands (de Haas, Schwarzkopf, Anderson, & Rees,
2013). It has been used in fMRI studies of visual cortex in animal
models (Shao et al., 2013; Smirnakis, Keliris, Shao, Papanikolaou, & Logothetis, 2012) and to elucidate the relationship with
655
Figure 3 Spatial summation of contrast fails to predict the fMRI signal in human visual cortex. The upper bar plots show the measured responses
to a lower field stimulus, an upper field stimulus, and the combination of the two. For the voxel in V1 (upper left) and V3 (upper right), the
response to the full aperture is less than the sum of the responses to the two partial apertures, and hence less than the linear prediction (indicated by
the black lines). The failure of linearity is more severe for V3 than for V1. The lower images show the 2-s circle for the pRF for the two voxels
(dark line V1; light line V3). Reproduced from Kay, K., Winawer, J., Mezer, A., & Wandell, B. A. (2013). Compressive spatial summation in human visual
cortex. Journal of Neurophysiology, 110, 481494.
656
INTRODUCTION TO METHODS AND MODELING | Computational Modeling of Responses in Human Visual Cortex
stimulus that fills both the upper and lower portions of the pRF
should equal the sum of the responses to upper and lower
separately. This spatial summation prediction is somewhat
inaccurate in the posterior maps, V1 and V2, and it misses
substantially in anterior extrastriate maps (Kay et al., 2013a).
Kay et al. showed that incorporating a static nonlinearity into
the standard pRF model remedies the failure of spatial linearity. Furthermore, Kay et al. showed that the specific form of the
nonlinearity fit to the BOLD signal is compatible with existing
models of single neuron spike rates, such as divisive normalization (Carandini & Heeger, 2012).
Connecting these two very different kinds of measurements, fMRI and single unit spiking, is possible because
stimulus-referred models are fit in both domains. It is tempting
to think of divisive normalization as a circuit model rather
than a stimulus-referred model because there has been substantial work trying to explain normalization in terms of circuit
properties such as shunting inhibition, resistance, and capacitance (Ferster, 2010). But in fact divisive normalization model
parameters are specified in the stimulus domain, including
contrast and orientation, and the circuits giving rise to normalization are largely unknown (Carandini & Heeger, 2012). Normalization, like linear filtering, is an application of the
stimulus-referred approach.
In a separate study, Kay, Winawer, Rokem, Mezer, &
Wandell (2013b) further extended the modeling effort by
developing a new pRF model that accounts for measurements
of responses to an even wider range of stimuli. The new model
is also distributed as a full computation (http://kendrickkay.
net/socmodel/). This model is much more complex than the
Dumoulin and Wandell formulation, allowing it to predict the
responses to a much wider range of stimuli.
position and size derived from the ECoG and the fMRI
responses agreed. Third, the spatial summation properties of
broadband, but not stimulus-locked, ECoG signals match the
spatial summation measured in the fMRI signal. From this
stimulus-referred analysis we concluded that the fMRI signal
arises principally from the broadband ECoG component.
Discussion
As computational models of vision increase in accuracy and
power (i.e., account for a larger range of stimuli), they become
more complex. The original Tootell et al. and Smith et al.
papers could reason correctly and informally about RF sizes.
But they accounted for very few stimuli and relied on summary
measures of the response time series. Modern computational
models that account for a much larger range of stimuli and
predict the full time series are significantly more complex
(Figure 5). These models are not captured in a small set of
formulae, and it is necessary to use software implementations
to generate predictions.
Computational modeling is a cumulative process that
expands the domain of application by accounting for an
increasing range of experimental conditions. This differs from
experimental work focused on hypothesis testing. Computational models are built by testing new features while always
checking for the impact of the new features on previous predictions; new data are not viewed as a hypothesis test that
results in accepting or rejecting the model by a statistical test.
Rather, computational model development is a process that
yields increasingly refined predictions from a sustained effort;
we believe this is one of its great benefits.
Finally, we note that even if a computational model is
imperfect, it can still be useful. For example, it is reasonable
to use linear pRF models to estimate RF center positions when
using a single bar width, even though the model does not
generalize to multiple bar widths. The use of a model that is
adequate for a given objective is common in other branches of
science and engineering. After all, we do not calculate local
travel time using relativity and the Earths curvature.
We think it is best to be open to the value of many measurement methods. In fact, we dont think there is a strong
alternative to this approach because it is illusory to think that
even within a measurement domain the signals form a single,
unitary class. For example, in the retina, the same stimulus
produces different responses in different cell types, such as
INTRODUCTION TO METHODS AND MODELING | Computational Modeling of Responses in Human Visual Cortex
657
Figure 4 Stimulus-referred models integrate different measurement modalities. (a) A stimulus-referred pRF model (Kay, Winawer, Mezer, & Wandell,
2013) was applied to V1, V2, and V3 responses from retinotopic stimuli. Measurements were obtained using both ECoG and fMRI, and we further
separated the ECoG signal into two components an asynchronous broadband signal that measured a stimulus-driven increase in response variance,
and a stimulus-locked response that modulated in synchrony with each contrast reversal. The CSS model fit the measured time series of all three
signals. (b) The estimated pRF centers to the two types of ECoG are similar (filled and open symbols; lines connect estimates from a single electrode).
These pRF centers also match the fMRI estimates (not shown). (c) The estimated spatial summation exponent, n, from the pRF model is highly
compressive (n < 1) for fMRI and for ECoG broadband responses. The exponent is close to linear (n 1) for the stimulus-locked response. Hence, fMRI
spatial summation matches broadband ECoG, but not stimulus-locked ECoG. Reproduced from Winawer J., et al. (2013). Asynchronous broadband
signals are the principal source of the BOLD response in human visual cortex. Current Biology, 23, 11451153. See also Harvey et al. (2013) for a
stimulus-referred approach to understanding the relationship between ECoG and fMRI pRF measurements.
Figure 5 A modern computational model of fMRI signals in visual cortex. The model developed by Kay et al. integrates an array of widely used
visual neuroscience computations (energy, divisive normalization, spatial summation, second-order contrast, and compressive nonlinearity). These
operations are organized into two stages of sequential linear, nonlinear, nonlinear (LNN) operations. To develop models of this complexity which are
surely much simpler than what will ultimately be required requires software implementations and the ability to test different forms of the model
on multiple classes of stimuli. Reproduced from Kay, K. N., Winawer, J., Rokem, A., Mezer, A., & Wandell, B.A. (2013). A two-stage cascade model of
BOLD responses in human visual cortex. PLoS Computational Biology, 9(5), e1003079.
658
INTRODUCTION TO METHODS AND MODELING | Computational Modeling of Responses in Human Visual Cortex
Neural measures
Single unit action potentials,
MUA
EcoG, EEG, LFP, MEG
BOLD, Optical imaging
Voltage sensitive dyes
Calcium imaging
Perceptual measures
Sensitivity, discrimination, response time,
similarity, appearance
Figure 6 An integrative view of modeling visual brain function. Computational models of visual neuroscience must take a broad view that spans
the stimulus, brain systems, and perceptual measures. Because visual responses arise from a well-characterized physical stimulus, we can use
stimulus-referred theories to integrate information from many measurement modalities and better understand many aspects of brain circuits.
References
Alvarez, I., De Haas, B., Clark, C. A., Rees, G., & Schwarzkopf, D. S. (2013). Optimal
stimulation for population receptive field mapping in human fMRI. Journal of
Vision, 13(9), 31.
Amano, K., Wandell, B. A., & Dumoulin, S. O. (2009). Visual field maps, population
receptive field sizes, and visual field coverage in the human MT complex. Journal
of Neurophysiology, 102(5), 27042718.
Arcaro, M. J., McMains, S. A., Singer, B. D., & Kastner, S. (2009). Retinotopic
organization of human ventral visual cortex. The Journal of Neuroscience, 29(34),
1063810652.
Benson, N. C., Butt, O. H., Jain, S., Brainard, D. H., & Aguirre, G. K. (2013). Cortical surface
structure predicts extrastriate retinotopic function. Journal of Vision, 13(9), 271.
Binda, P., Thomas, J. M., Boynton, G. M., & Fine, I. (2013). Minimizing biases in
estimating the reorganization of human visual areas with BOLD retinotopic mapping.
Journal of Vision, 13(7), 13.
Box, G., & Draper, N. (1987). Empirical model-building and response surfaces.
New York: Wiley.
Braitenberg, V., & Schuz, A. (1998). Cortex: Statistics and geometry of neuronal
connectivity (2nd ed.). Heidelberg: Springer-Verlag.
Brewer, A. A., Barton, B., & Lin, L. (2012). Functional plasticity in human parietal
visual field map clusters: Adapting to reversed visual input. Journal of Vision,
12(9), 1398.
Bullock, T. H., et al. (2005). Neuroscience. The neuron doctrine, redux. Science,
310(5749), 791793.
Calford, M. B., et al. (2005). Neuroscience: Rewiring the adult brain. Nature, 438(7065),
E3, discussion E34.
Carandini, M., & Heeger, D. J. (2012). Normalization as a canonical neural
computation. Nature Reviews. Neuroscience, 13(1), 5162.
de Haas, B., Schwarzkopf, D. S., Anderson, E. J., & Rees, G. (2013). Effects of
perceptual load on population receptive fields. Journal of Vision, 13(9), 290.
Dechent, P., & Frahm, J. (2003). Characterization of the human visual V6 complex by
functional magnetic resonance imaging. The European Journal of Neuroscience,
17(10), 22012211.
DeYoe, E. A., Bandettini, P., Neitz, J., Miller, D., & Winans, P. (1994). Functional
magnetic resonance imaging (FMRI) of the human brain. Journal of Neuroscience
Methods, 54(2), 171187.
DeYoe, E. A., et al. (1996). Mapping striate and extrastriate visual areas in human
cerebral cortex. Proceedings of the National Academy of Sciences of the United
States of America, 93, 23822386.
INTRODUCTION TO METHODS AND MODELING | Computational Modeling of Responses in Human Visual Cortex
Dumoulin, S. O., & Wandell, B. A. (2008). Population receptive field estimates in human
visual cortex. NeuroImage, 39(2), 647660.
Engel, S. A., Glover, G. H., & Wandell, B. A. (1997). Retinotopic organization in human
visual cortex and the spatial precision of functional MRI. Cerebral Cortex, 7(2),
181192.
Engel, S. A., et al. (1994). fMRI of human visual cortex. Nature, 369(6481), 525.
Felleman, D. J., & Essen, D. C.V (1991). Distributed hierarchical processing in the
primate cerebral cortex. Cerebral Cortex, 1, 147.
Ferster, D. (2010). Diverse mechanisms of contrast normalization in primary visual
cortex. Journal of Vision, 10(15), 29.
Goense, J., & Logothetis, N. K. (2008). Neurophysiology of the BOLD fMRI signal in
awake monkeys. Current Biology, 18(9), 631640.
Grinvald, A., Lieke, E. E., Frostig, R. D., & Hildesheim, R. (1994). Cortical point-spread
function and long-range lateral interactions revealed by real-time optical imaging of
macaque monkey primary visual cortex. The Journal of Neuroscience, 14,
25452568.
Hartline, H. K. (1938). The response of single optic nerve fibers of the vertebrate
eye to illumination of the retina. The American Journal of Physiology, 121,
400415.
Harvey, B. M., et al. (2013). Frequency specific spatial interactions in human
electrocorticography: V1 alpha oscillations reflect surround suppression.
NeuroImage, 65, 424432.
Henschen, S. E. (1893). On the visual path and centre. Brain, 16, 170180.
Hoffmann, M. B., et al. (2012). Plasticity and stability of the visual system in human
achiasma. Neuron, 75(3), 393401.
Holmes, G. (1918). Disturbances of vision by cerebral lesions. British Journal of
Ophthalmology, 2, 353384.
Holmes, G., & Lister, W. T. (1916). Disturbances of vision from cerebral lesions, with
special reference to the cortical representation of thc macula. Brain, 39, 3473.
Horton, J. C., & Hoyt, W. F. (1991a). Quadrantic visual field defects: A hallmark of
lesions in extrastriate (V2/V3) cortex. Brain, 114, 17031718.
Horton, J. C., & Hoyt, W. F. (1991b). The representation of the visual field in human
striate cortex. A revision of the classic Holmes map. Archives of Ophthalmology,
109(6), 816824.
Hubel, D. H., & Wiesel, T. N. (1977). Ferrier lecture. Functional architecture of macaque
monkey visual cortex. Proceedings of the Royal Society of London. Series B:
Biological Sciences, 198(1130), 159.
Inouye, T. (1909). Die Sehstorungen bei Schussverletzungen der kortikalen Sehsphare.
Leipzig, Germany: W. Engelmann.
Kay, K. N., Naselaris, T., Prenger, R. J., & Gallant, J. L. (2008). Identifying natural
images from human brain activity. Nature, 452, 352355.
Kay, K., Winawer, J., Mezer, A., & Wandell, B. A. (2013). Compressive spatial
summation in human visual cortex. Journal of Neurophysiology, 110, 481494.
Kay, K. N., Winawer, J., Rokem, A., Mezer, A., & Wandell, B. A. (2013). A two-stage
cascade model of BOLD responses in human visual cortex. PLoS Computational
Biology, 9(5), e1003079.
Kolster, H., Peeters, R., & Orban, G. A. (2010). The retinotopic organization of the
human middle temporal area MT/V5 and its cortical neighbors. The Journal of
Neuroscience, 30(29), 98019820.
Konen, C. S., & Kastner, S. (2008). Representation of eye movements and stimulus
motion in topographically organized areas of human posterior parietal cortex. The
Journal of Neuroscience, 28(33), 83618375.
Kwong, K. K., et al. (1992). Dynamic magnetic resonance imaging of human brain
activity during primary sensory stimulation. Proceedings of the National Academy of
Sciences of the United States of America, 89(12), 56755679.
Levin, N., Dumoulin, S. O., Winawer, J., Dougherty, R. F., & Wandell, B. A. (2010).
Cortical maps and white matter tracts following long period of visual deprivation and
retinal image restoration. Neuron, 65(1), 2131.
659
Maier, A., et al. (2008). Divergence of fMRI and neural signals in V1 during
perceptual suppression in the awake monkey. Nature Neuroscience, 11(10),
11931200.
Mukamel, R., et al. (2005). Coupling between neuronal firing, field potentials, and FMRI
in human auditory cortex. Science, 309(5736), 951954.
Munk, H. (1881). On the functions of the cortex. In G. Von Bonin (Ed.), The Cerebral
Cortex (pp. 97117). Springfield, Illinois: Charles C. Thomas.
Niessing, J., et al. (2005). Hemodynamic signals correlate tightly with synchronized
gamma oscillations. Science, 309(5736), 948951.
Nishimoto, S., Vu, A. T., Naselaris, T., Benjamini, Y., Yu, B., & Gallant, J. L. (2011).
Reconstructing visual experiences from brain activity evoked by natural movies.
Current Biology, 21, 16411646.
Ogawa, S., et al. (1992). Intrinsic signal changes accompanying sensory stimulation:
Functional brain mapping with magnetic resonance imaging. Proceedings of the
National Academy of Sciences of the United States of America, 89, 5915955.
Phillips, C. G., Zeki, S., & Barlow, H. B. (1984). Localization of function in the cerebral
cortex. Past, present and future. Brain, 107(Pt 1), 327361.
Schulz, K., et al. (2012). Simultaneous BOLD fMRI and fiber-optic calcium recording in
rat neocortex. Nature Methods, 9(6), 597602.
Sereno, M. I., Pitzalis, S., & Martinez, A. (2001). Mapping of contralateral space in
retinotopic coordinates by a parietal cortical area in humans. Science, 294(5545),
13501354.
Sereno, M. I., et al. (1995). Borders of multiple human visual areas in humans revealed
by functional MRI. Science, 268, 889893.
Shao, Y., et al. (2013). Visual cortex organisation in a macaque monkey with macular
degeneration. European Journal of Neuroscience, 38, 34563464.
Silver, M. A., & Kastner, S. (2009). Topographic maps in human frontal and parietal
cortex. Trends in Cognitive Sciences, 13(11), 488495.
Smirnakis, S. M., Keliris, G., Shao, Y., Papanikolaou, A., & Logothetis, N. (2012).
Population receptive field measurements in macaque visual cortex. Journal of
Vision, 12(9), 1397.
Smith, A. T., Singh, K. D., Williams, A. L., & Greenlee, M. W. (2001). Estimating
receptive field size from fMRI data in human striate and extrastriate visual cortex.
Cerebral Cortex, 11(12), 11821190.
Tootell, R. B., et al. (1997). Functional analysis of V3A and related areas in human
visual cortex. The Journal of Neuroscience, 17(18), 70607078.
Victor, J. D., Purpura, K., Katz, E., & Mao, B. (1994). Population encoding of spatial
frequency, orientation, and color in macaque V1. Journal of Neurophysiology,
72(5), 21512166.
Wandell, B. A. (1995). Foundations of vision. Sunderland, MA: Sinauer Press.
Wandell, B. A., Dumoulin, S. O., & Brewer, A. A. (2007). Visual field maps in human
cortex. Neuron, 56(2), 366383.
Wandell, B. A., Dumoulin, S. O., & Brewer, A. A. (2009). Visual cortex in humans. In L.
Squire (Ed.), Encyclopedia of neuroscience. New York: Elsevier.
Wandell, B. A., & Winawer, J. (2011). Imaging retinotopic maps in the human brain.
Vision Research, 51(7), 718737.
Warnking, J., et al. (2002). fMRI retinotopic mapping step by step. NeuroImage,
17(4), 16651683.
Winawer, J., Horiguchi, H., Sayres, R. A., Amano, K., & Wandell, B. A. (2010).
Mapping hV4 and ventral occipital cortex: The venous eclipse. Journal of Vision,
10, 1.
Winawer, J., et al. (2013). Asynchronous broadband signals are the principal
source of the BOLD response in human visual cortex. Current Biology, 23,
11451153.
Zeki, S. (1993). A vision of the brain. London: Blackwell Scientific Publications.
Zuiderbaan, W., Harvey, B. M., & Dumoulin, S. O. (2012). Modeling centersurround configurations in population receptive fields using fMRI. Journal of
Vision, 12(3), 10.
Glossary
Introduction
In recent years, there has been an explosive growth in both the
number and variety of neuroimaging studies being performed
around the world. This is illustrated in Figure 1, which shows
the rapid increase in the yearly number of publications related
to functional magnetic resonance imaging (fMRI) since 1993.
With this growing body of knowledge comes a need to both
integrate and synthesize research findings. Performing metaanalyses has arguably become the primary research tool for
accomplishing this goal (Wager, Lindquist, & Kaplan, 2007;
Wager, Lindquist, Nichols, Kober, & Van Snellenberg, 2009).
They allow for the pooling of multiple separate but similar
studies and can be used to evaluate the consistency of findings
across labs, scanning procedures, and task variants, as well as
the specificity of findings in different brain regions or networks
to particular task types. Meta-analyses have already been used
to study many types of psychological processes, including cognitive control, working memory, decision-making, language,
pain, and emotion (Laird et al., 2005; Phan, Wager, Taylor, &
Liberzon, 2002; Wager, Jonides, & Reading, 2004). They have
also been used to summarize structural and functional brain
correlates of disorders such as attention deficit disorder,
schizophrenia, depression, chronic pain, anxiety disorders,
and obsessivecompulsive disorder (Dickstein, Bannon, Xavier
Castellanos, & Milham, 2006; Etkin & Wager, 2007; Glahn
et al., 2005; Menzies et al., 2008).
To date, the primary goal of meta-analyses has been to
provide summaries of the consistency of regional brain activation for a set of studies of a particular task type, thereby
providing a consensus regarding which regions are likely to
be truly activated by a given task (see Figure 2 for an
illustration). Evaluating consistency across studies is critical
because false-positive rates in neuroimaging are likely to be
significantly higher than in many other fields. In previous
work, we estimated the false-positive rates to lie somewhere
between 10% and 40% (Wager et al., 2009). These inflated
false-positive rates are a by-product of poor control for multiple comparisons combined with the small sample sizes typically used in neuroimaging studies. Though these rates may be
decreasing over time as sample sizes increase and more
Meta-Analytic Data
In an ideal setting, meta-analysis would be performed using
the full statistical maps made available from each study and fit
using a mixed-effects model that aggregates the effect size at
each individual voxel. However, in practice, this information is
not readably available from individual studies. There has been
some movement toward creating such databases, and the
http://dx.doi.org/10.1016/B978-0-12-397025-1.00348-1
661
662
Number of publications
3000
2500
2000
1500
1000
500
0
1995
2000
2005
Publication year
2010
Figure 1 A graph showing the rapid increase in the number of publications that mention the term fMRI in either the title or abstract for the years
19932013 according to PubMed.
Reported peaks
Meta-analysis
results
Meta-Analytic Methods
Kernel-Based Methods
In ALE and KDA, the peak coordinates are the basic units of
analyses. Both methods measure consistency by counting the
number of peak activations in each voxel, convolving the
results with a kernel, and comparing the number of observed
peaks to a null-hypothesis distribution (see Figure 3 for an
illustration). In KDA, the kernel is spherical with radius r, and
the resulting maps are interpreted as the number of peaks
Kernel convolution
Peak density or
ALE map
663
Significant results
Density kernel
1
0
1
1
1 1
OR
ALE kernel
1
0
1
1
1 1
Figure 3 Example of meta-analysis using KDA or ALE on three studies. The three small maps on the left show peaks reported in each study for a
representative axial brain slice. Peaks are combined across studies and the resulting map is smoothed with either a spherical kernel (KDA) or a Gaussian
kernel (ALE). The resulting peak density map or ALE map is thresholded, resulting in a map of significant results.
664
Study-specific Comparison
indicator maps
peaks
Weighted
average
Significant results
Weighted
average
Figure 4 Example of meta-analysis using MKDA on three studies. The three small maps on the left show peaks reported in each study for a
representative axial brain slice. Each map is separately convolved with a spherical kernel, generating indicator maps for each study contrast map. The
weighted average of the indicator maps is computed and thresholded to produce a map of significant results.
Investigating Coactivation
Meta-analysis can also be used to reveal consistent patterns of
coactivation. For example, in MKDA, the data can be organized
as an n v indicator matrix consisting of information about
how the n different study-specific maps activate in the neighborhood of each of the v voxels in the brain. The resulting
connectivity profiles across voxels can be summarized to a
smaller set of structurally or functionally defined regions.
Hypothesis tests can then be performed on connectivity, and
relationships among multiple regions can be summarized and
visualized. There exist several potential measures of association
for bivariate, binomial data that are applicable, including Kruskals gamma, Kendalls tau, and Fishers exact test.
Evaluating Specificity
Meta-analysis provides perhaps the only way to compare neuroimaging results across a wide variety of tasks. For example,
within the kernel-based methods, separate maps can be constructed for each of two task types and subtracted to yield
difference maps. The same procedure can be used in the
Monte Carlo randomization to perform inference. Locations
of contiguous activation blobs (or peaks in ALE/KDA) are
randomized, providing simulated null-hypothesis conditions
that we can use to decide on a threshold for determining
significant differences. These difference maps allow one to
test the relative frequency of activating a given region, compared with the overall frequencies in the rest of the brain. Thus,
a reliable concentration of peaks in a certain brain area for a
specific task type will increase the marginal activation frequencies for that task, which in turn affects the null-hypothesis
difference in the Monte Carlo simulations. A caveat is that for
task types with relatively few peaks, there need not be a greater
absolute probability of activating a region to achieve a significant density for that region relative to other task types.
To test the absolute difference in activation in one condition compared with another, one can alternatively perform a
nonparametric chi-square test (Wager et al., 2007). This allows
one to test whether there is a systematic association between
activation in a particular voxel and a set of tasks.
Software
In recent years, a number of user-friendly software solutions
have been introduced that have simplified the process of performing a meta-analysis. For example, GingerALE is the BrainMap application that is used to perform an ALE meta-analysis
on coordinates in Talairach or MNI space. Neurosynth uses text
mining to automatically harvest peak coordinates from journal
articles and provides a platform for performing large-scale,
automated synthesis of neuroimaging data extracted from published articles. Through a Web interface, simple but useful
analyses of fMRI data can be run on a very large scale. Neurosynth currently contains coordinates from 6000 published
studies, along with words from the full text of the published
papers. Meta-analytic maps of the relationships between brain
activation and use of 10 000 key terms in the papers are available online, as well as online coactivation analyses, topic-based
brain maps, and other features under development. Users can
view lists of papers that activate a given location, create a map
of regions that coactivate with a location, download activation
and coactivation maps for use in studies, and download
feature sets of many commonly used maps (e.g., face,
place, working memory, and reward). Maps for each term
can be forward inference maps, a chi-square test on the likelihood of activation in each brain location given studies that
frequently use a particular term, and reverse inference maps
a chi-square test for independence on the likelihood of a study
involving a term or not, given activation at each location. These
maps can be used for exploration, hypothesis generation, and
inference about activation across domains (e.g., Roy, Shohamy, & Wager, 2012). They can also be used as quantitative
masks for selection of a priori regions of interest (e.g., Wager
et al., 2013). Finally, both KDA and MKDA are available in a
Matlab toolbox.
Future Developments
Meta-analyses have become increasingly popular in recent
years, and there is promise of many interesting developments
References
Dickstein, S. G., Bannon, K., Xavier Castellanos, F., & Milham, M. P. (2006). The neural
correlates of attention deficit hyperactivity disorder: An ALE meta-analysis. Journal
of Child Psychology and Psychiatry, 47(10), 10511062.
Eickhoff, S. B., Laird, A. R., Grefkes, C., Wang, L. E., Zilles, K., & Fox, P. T. (2009).
Coordinate-based activation likelihood estimation meta-analysis of neuroimaging
data: A random-effects approach based on empirical estimates of spatial uncertainty.
Human Brain Mapping, 30(9), 29072926.
Etkin, A., & Wager, T. (2007). Functional neuroimaging of anxiety: A meta-analysis of
emotional processing in PTSD, social anxiety disorder, and specific phobia.
American Journal of Psychiatry, 164(10), 14761488.
Fox, P. T., & Lancaster, J. L. (2002). Mapping context and content: The BrainMap
model. Nature Reviews Neuroscience, 3(4), 319321.
Glahn, D. C., Ragland, J. D., Abramoff, A., Barrett, J., Laird, A. R., Bearden, C. E., et al.
(2005). Beyond hypofrontality: A quantitative meta-analysis of functional neuroimaging
studies of working memory in schizophrenia. Human Brain Mapping, 25(1), 6069.
Kang, J., Johnson, T. D., Nichols, T. E., & Wager, T. D. (2011). Meta analysis of
functional neuroimaging data via Bayesian spatial point processes. Journal of the
American Statistical Association, 106(493), 124134.
665
Kober, H., Barrett, L. F., Joseph, J., Bliss-Moreau, E., Lindquist, K., & Wager, T. D.
(2008). Functional grouping and corticalsubcortical interactions in emotion: A
meta-analysis of neuroimaging studies. NeuroImage, 42, 9981031.
Laird, A. R., McMillan, K. M., Lancaster, J. L., Kochunov, P., Turkeltaub, P. E.,
Pardo, J. V., et al. (2005). A comparison of label-based review and ALE metaanalysis in the Stroop task. Human Brain Mapping, 25(1), 621.
Menzies, L., Chamberlain, S. R., Laird, A. R., Thelen, S. M., Sahakian, B. J., &
Bullmore, E. T. (2008). Integrating evidence from neuroimaging and
neuropsychological studies of obsessivecompulsive disorder: the orbitofrontostriatal model revisited. Neuroscience & Biobehavioral Reviews, 32(3),
525549.
Northoff, G., Heinzel, A., de Greck, M., Bermpohl, F., Dobrowolny, H., & Panksepp, J.
(2006). Self-referential processing in our brain A meta-analysis of imaging
studies on the self. NeuroImage, 31(1), 440457.
Phan, K. L., Wager, T., Taylor, S. F., & Liberzon, I. (2002). Functional neuroanatomy of
emotion: A meta-analysis of emotion activation studies in PET and fMRI.
NeuroImage, 16(2), 331348.
Poldrack, R. A. (2006). Can cognitive processes be inferred from neuroimaging data?
Trends in Cognitive Sciences, 10(2), 5963.
Poldrack, R. A. (2008). The role of fMRI in cognitive neuroscience: Where do we stand?
Current Opinion in Neurobiology, 18(2), 223227.
Roy, M., Shohamy, D., & Wager, T. D. (2012). Ventromedial prefrontalsubcortical
systems and the generation of affective meaning. Trends in Cognitive Sciences,
16(3), 147156.
Turkeltaub, P. E., Eden, G. F., Jones, K. M., & Zeffiro, T. A. (2002). Meta-analysis of the
functional neuroanatomy of single-word reading: Method and validation.
NeuroImage, 16(3), 765780.
Turner, J. A., & Laird, A. R. (2012). The cognitive paradigm ontology: Design and
application. Neuroinformatics, 10(1), 5766.
Van Snellenberg, J. X., Torres, I. J., & Thornton, A. E. (2006). Functional neuroimaging
of working memory in schizophrenia: Task performance as a moderating variable.
Neuropsychology, 20(5), 497.
Wager, T. D., Atlas, L. Y., Lindquist, M. A., Roy, M., Woo, C. W., & Kross, E. (2013). An
fMRI-based neurologic signature of physical pain. New England Journal of
Medicine, 368(15), 13881397.
Wager, T. D., Jonides, J., & Reading, S. (2004). Neuroimaging studies of shifting
attention: A meta-analysis. NeuroImage, 22(4), 16791693.
Wager, T. D., Lindquist, M., & Kaplan, L. (2007). Meta-analysis of functional
neuroimaging data: Current and future directions. Social Cognitive and Affective
Neuroscience, 2, 150158.
Wager, T. D., Lindquist, M. A., Nichols, T. E., Kober, H., & Van Snellenberg, J. (2009).
Evaluating the consistency and specificity of neuroimaging data using metaanalysis. NeuroImage, 45(1), S210S221.
Woo, C. W., Krishnan, A., & Wager, T. D. (2014). Cluster-extent based
thresholding in fMRI analyses: Pitfalls and recommendations. NeuroImage, 91,
412419.
Yarkoni, T., Poldrack, R. A., Nichols, T. E., Van Essen, D. C., & Wager, T. D. (2011).
Large-scale automated synthesis of human functional neuroimaging data. Nature
Methods, 8(8), 665670.
Yue, Y. R., Lindquist, M. A., & Loh, J. M. (2012). Meta-analysis of functional
neuroimaging data using Bayesian nonparametric binary regression. Annals of
Applied Statistics, 6(2), 697718.
Relevant Websites
http://brainmap.org Brainmap.
http://neurosynth.org Neurosynth.
http://sumsdb.wustl.edu/sums/index.jsp Surface Management System Database.
http://wagerlab.colorado.edu/tools Matlab toolbox.
Introduction
The brain is a complex spatio-temporal neurogenetic information processing machine that processes information at different
functional levels (Figure 1). Spatio-temporal activity in the
brain depends on the internal brain structure, on the external
stimuli and also very much on the dynamics at gene-protein
level. Methods for measuring activity of the brain, such as EEG
(electroencephalogram), fMRI (functional magneto resonance
images), MEG (magneto-encephalograms), PET (positron emission technology), and DTI (diffusion tensor imaging), have
been widely used, some of them presented in this encyclopedic
volume. Integrative computational neurogenetic modeling
(CNGM) go one step further integrating these data with
relevant genetic data for a better understanding of the brain.
Genes are both the result of the evolution of species and
the functioning of an individual brain during a life time.
Different genes express as different mRNA, microRNA and
proteins in different areas of the brain and are involved in all
information processes, from spiking activity, to perception,
decision making, and emotions. Functional connectivity
develops in parallel with structural connectivity during brain
maturation where a growth-elimination process (synapses are
created and eliminated) depends on the gene expression and
environment. For example, postsynaptic AMPA-type glutamate
receptors (AMPARs) mediate most fast excitatory synaptic
transmissions and are crucial for many aspects of brain functioning, including learning, memory, and cognition (Henley
et al., 2011). Kang et al. (2011) performed weighted gene
co-expression network analysis to define modules of coexpressed genes and identified 29 such modules, associated
with distinct spatio-temporal expression patterns and biological processes in the brain. The genes in each module form a
gene regulatory network (GRN).
The spiking activity of a neuron may act as a feedback and
affect the expression of genes. As pointed out in Zhdanov
(2011) on a time scale of minutes and hours the function of
neurons may cause changes in the expression of hundreds of
genes transcribed into mRNAs and also in microRNAs. This
links together the short-term, the long-term and the genetic
memories of the neurons representing the global memory of
the whole neuronal system.
The anatomically comprehensive atlas of the adult human
brain trascriptome (www.brain-map.org) is a rich repository of
bran-gene data that will definitely trigger new directions for
research and computational modeling of neurogenetic data
(Hawrylycz et al., 2012; Kasabov, 2014a). Example of a gene
expression brain map is given in Figure 2. Gene expression is
clearly distinguished between structural and functional areas of
the brain. Specific genes define specific functions of different
sections of the brain. Specific genes relate to specific types
of neurons and types of connections. For example, the gene
expression level of genes related to dopamine-signaling (e.g.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00349-3
667
668
__________________________________________________
5. Brain cognitive processes
_________________________________________________
4. System information processing (e.g. neural ensembles)
_________________________________________________
3. Information processing in a cell (neuron)
_________________________________________________
2. Molecular information processing (genes, proteins)
_________________________________________________
1. Quantum information processing
Figure 1 Different levels of information processing in the brain. Reproduced from Kasabov, N. (2007). Evolving connectionist systems: The
knowledge engineering approach. London: Springer (first edition 2002).
Figure 2 From the brain explorer: the expression level of several genes
(on the vertical axis) in different areas of the brain (horizontal axis): ABAT
A_23_P152505, ABAT A_24_P330684, ABAT CUST_52_PI416408490,
ALDH5A1 A_24_P115007, ALDH5A1 A_24_P923353, ALDH5A1
A_24_P3761, AR A_23_P113111, AR CUST_16755_PI416261804, AR
CUST_85_PI416408490, ARC A_23_P365738, ARC
CUST_11672_PI416261804, ARC CUST_86_PI416408490, ARHGEF10
A_23_P216282, ARHGEF10 A_24_P283535, ARHGEF10 CUST_) (from
www.brain-map.org and http://www.alleninstitute.org).
[2]
669
Spikes Stimulus
Integration
+leakage
1.0
Spike
Refractory period
u(t)
0.8
0.4
2
Binary events
0.6
0.2
0.0
4
(a)
(b)
Psij (t)
ni
,Wij (t)
nj
Pcij (t)
Pi (t)
(a)
Pj (t)
A MPA R
NM D A R
GABAAR
GABABR
mGluR
Ion channels SCN, KCN, CLC
(b)
Figure 4 (b) Neuronal action potential parameters and related proteins and ion channels in the computational neuro-genetic model of a spiking
neuron: AMPAR (amino-methylisoxazole- propionic acid) AMPA receptor; NMDR (N-methyl-D-aspartate acid) NMDA receptor; GABAAR (gammaaminobutyric acid) GABAA receptor; GABABR GABAB receptor; SCN sodium voltage-gated channel; KCN kalium (potassium) voltage-gated
channel; CLC chloride channel. Reproduced from Benuskova, L., & Kasabov, N. (2007). Computational neuro-genetic modelling. New York:
Springer, p. 290.
density of the sodium channels in the membrane of the triggering zone. The time decay parameter in a LIFM may be
affected by different genes and proteins depending on the
type of the neuron. Such proteins are transporters in the presynaptic membrane, the glial cells and the enzymes, which
uptake and break down the neurotransmitters in the synaptic
cleft (BAX, BAD, DP5); metabotropic GABAB Receptors; KCNK
family proteins that are responsible for the leak conductance of
the resting membrane potential.
670
0.4
F (%)
PSP
W
0.2
t (ms)
40
20
20
PSPTh
PSPTh
PSP
40
0.2
Output
Input
0.4
(a)
time
Output
(b)
Figure 5 (a) Synaptic change in a STDP learning neuron (Song et al., 2000); (b) rank-order learning neuron.
SNN model
GRN model
Molec. model
M1
M2
Mp
[4]
671
Figure 7 (a) A diagram of the general NeuCube architecture, consisting of input data encoding module, 3D SNNr module, output function module
(e.g. for classification or prediction), gene regulatory networks (GRN) module. (b) Spiking activity in the SNNr during learning of brain data.
(c) Connectivity in the SNNr before training with EEG brain data small world connectivity. (d) Connectivity of the SNNr after training with EEG brain data
using STDP. Reproduced from Kasabov, N. (2014). NeuCube: A spiking neural network architecture for mapping, learning and understanding of
spatio-temporal brain data. Neural Networks, 52, 6276.
672
1000
Neuron
800
600
400
200
1000
2000
3000
4000
5000
Time
Figure 8 A single gene expression level over time can affect the pattern of activity of a whole SNNr of 1000 neurons. The gene controls the t parameter
of all 1000 LIF neurons over a period of 5 s. The top diagram shows the evolution of the t parameter. The response of the 10 000 spiking neurons
is shown as a raster plot of spike activity. A black point in this diagram indicates a spike of a specific neuron at a specific time in the simulation
(the x axis). The bottom diagram presents the evolution of the membrane potential of a single neuron from the network (green curve) along
with its firing continuous noisy threshold (red curve). Output spikes of the neuron are indicated as black vertical lines in the same diagram (from
Kasabov, 2014). Reproduced from Kasabov, N. (Ed.) (2014). Springer handbook of bio-/neuroinformatics. Heidelberg: Springer.
APP
Vascular component
VEGF
trkA
M1/M3-mR; nR
IL-1
NGF
p75NTR
-amyloid
7 nR
AChE
Cholinergic
system
IL-1 TNF
Inflammation/
cytokines
A CNGM would make it possible to model cognitionemotion brain states that could further enable the creation of
human-like cognitive systems. That would require understanding relevant brain processes as different levels of information
processing. For example, it is known that human emotions
depend on the expression and the dynamic interaction of
neuromodulators (serotonin, dopamine, noradrenalin, and
acetylcholine) and some other relevant genes and proteins
(e.g., 5-HTTLRP, DRD4, DAT), that are functionally linked to
the spiking activity of the neurons in certain areas of the brain.
They have wide ranging effects on brain functions. For example, Noradrenaline is important to arousal and attention mechanisms. Acetylcholine has a key role in encoding memory
function. Dopamine is related to aspects of learning and
reward seeking behavior and may signal probable appetitive
outcome, whereas serotonin may affect behavior with probable aversive outcome. Modifying gene and protein expression
levels of genes used in a particular CNGM would affect the
learning and pattern recognition properties of that model. For
example, the modification could cause connections and functional pathways to become stronger or weaker, which could be
observed and further interpreted in terms of cognitive and
emotional states.
Acknowledgements
This work was supported by the Knowledge Engineering and
Discovery Research Institute (KEDRI, http://www.kedri.info)
of the Auckland University of Technology and partially by the
EU FP7 Marie Curie project EvoSpike PIIF-GA-2010-272006,
hosted by the Institute for Neuroinformatics at ETH/UZH
Zurich (http://ncs.ethz.ch/projects/evospike).
673
References
Benuskova, L., & Kasabov, N. (2007). Computational neuro-genetic modelling.
New York: Springer, p. 290.
Bothe, S. M. (2004). The evidence for neural information processing with precise spiketimes: A survey. Natural Computing, 3, .
Delbruck, T. (2007). jAER open source project. http://jaer.wiki.sourceforge.net.
Evans, A. C., Collins, D. L., Mills, S. R., Brown, E. D., Kelly, R. L., & Peters, T. M.
(1993). 3D statistical neuroanatomical models from 305 MRI volumes.
In: IEEE-nuclear science symposium and medical imaging conference. IEEE Press.
Gerstner, W. (2001). Whats different with spiking neurons? In H. Mastebroek & H. Vos
(Eds.), Plausible neural networks for biological modelling (pp. 2348). Dordrecht:
Kluwer Academic Publishers.
Gerstner, W., Sprekeler, H., & Deco, G. (2012). Theory and simulation in neuroscience.
Science, 338, 6065.
Gutig, R., & Sompolinsky, H. (2006). The Tempotron: A neuron that learns spike
timing-based decisions. Nature Neuroscience, 9(3), 420428.
Hawrylycz, M., et al. (2012). An anatomically comprehensive atlas of the adult human
brain transcriptome. Nature, 489, 391399.
Hebb, D. (1949). The organization of behavior. New York: John Wiley and Sons.
Henley, J. M., Barker, E. A., & Glebov, O. O. (2011). Routes, destinations and delays: Recent
advances in AMPA receptor trafficking. Trends in Neuroscience, 34(5), 258268.
Hodgkin, A. L., & Huxley, A. F. (1952). A quantitative description of membrane current
and its application to conduction and excitation in nerve. Journal of Physiology,
117, 500544.
Honey, C. J., Kotter, R., Breakspear, M., & Sporns, O. (2007). Network structure of
cerebral cortex shapes functional connectivity on multiple time scales. Proceedings
of the National Academy of Sciences, 104, 1024010245.
Izhikevich, E. (2006). Polychronization: Computation with spikes. Neural Computation,
18, 245282.
Kang, H. J., et al. (2011). Spatio-temporal transcriptome of the human brain. Nature,
478, 483489.
Kasabov, N. (2007). Evolving connectionist systems: The knowledge engineering
approach. London: Springer (first edition 2002).
Kasabov, N. (2010). To spike or not to spike: A probabilistic spiking neuron model.
Neural Networks, 23(1), 1619.
Kasabov, N. (Ed.), (2014). Springer handbook of bio-/neuroinformatics. Heidelberg:
Springer.
Kasabov, N. (2014b). NeuCube: A spiking neural network architecture for mapping,
learning and understanding of spatio-temporal brain data. Neural Networks, 52,
6276.
Kasabov, N., Benuskova, L., & Wysoski, S. (2005). A computational neurogenetic
model of a spiking neuron. In: Proc. IJCNN, vol. 1, IEEE Press.
Kasabov, N., Dhoble, K., Nuntalid, N., & Indiveri, G. (2013). Dynamic evolving spiking
neural networks for on-line spatio- and spectro-temporal pattern recognition. Neural
Networks, 41, 188201.
Kasabov, N., Schliebs, R., & Kojima, H. (2011). Probabilistic computational
neurogenetic framework: From modelling cognitive systems to Alzheimers disease.
IEEE Transactions of Autonomous Mental Development, 3(4), 3003011.
Koch, C., & Reid, R. (2012). Nature, 483, 397.
674
Maass, W., Natschlaeger, T., & Markram, H. (2002). Real-time computing without stable
states: A new framework for neural computation based on perturbations. Neural
Computation, 14(11), 25312560.
Meng, Y., Jin, Y., Yin, J., & Conforth, M. (2010). Human activity detection using spiking
neural networks regulated by a gene regulatory network. In: Proc. IJCNN, IEEE
Press.
Mohemmed, A., Schliebs, S., Matsuda, S., & Kasabov, N. (2012). SPAN: Spike pattern
association neuron for learning spatio-temporal sequences. Intenational Journal of
Neural Systems, 22(4), 116.
Mohemmed, A., Schliebs, S., Matsuda, S., & Kasabov, N. (2013). Evolving spike pattern
association neurons and neural networks. Neurocomputing, 107, 310.
Morabito, F. C., Labate, D., La Foresta, F., Morabito, G., & Palamara, I. (2012).
Multivariate, multi-scale permutation entropy for complexity analysis of AD EEG.
Entropy, 14(7), 11861202.
Nuntalid, N., Dhoble, K., & Kasabov, N. (2011). EEG classification with BSA spike
encoding algorithm and evolving probabilistic spiking neural network. In LNCS
(vol. 7062, pp. 451460). Springer.
Picard, R. (1997). Affective computing. Cambridge: MIT Press.
Poline, J.-B., & Poldrack, R. A. (2012). Frontiers in brain imaging methods grand
challenge. Frontiers in Neuroscience, 6, 96. http://dx.doi.org/10.3389/
fnins.2012.00096.
Ponulak, F., & Kasinski, A. (2010). Supervised learning in spiking neural networks with
ReSuMe: Sequence learning, classification, and spike shifting. Neural Computation,
22(2), 467510.
Schliebs, R. (2005). Basal forebrain cholinergic dysfunction in Alzheimers disease
Interrelationship with b-amyloid, inflammation and neurotrophin signalling.
Neurochemical Research, 30, 895908.
Schliebs, S., Kasabov, N., & Defoin-Platel, M. (2010). On the probabilistic optimization
of spiking neural networks. International Journal of Neural Systems, 20(6),
481500.
Song, S., Miller, K., Abbott, L., et al. (2000). Competitive Hebbian learning through
spike-timing-dependent synaptic plasticity. Nature Neuroscience, 3, 919926.
Talairach, J., & Tournoux, P. (1988). Co-planar stereotaxic atlas of the human brain: 3dimensional proportional systemAn approach to cerebral imaging. New York:
Thieme Medical Publishers.
Thorpe, S., & Gautrais, J. (1998). Rank order coding. Computational Neuroscience:
Trends in Research, 13, 113119.
Toga, A., Thompson, P., Mori, S., Amunts, K., & Zilles, K. (2006). Towards multimodal
atlases of the human brain. Nature Reviews. Neuroscience, 7, 952966.
VanEssen, et al. (2012). The human connectome project: A data acquisition perspective.
NeuroImage, 62(4), 22222231.
Zilles, K., & Amunts, K. (2010). Centenary of Brodmanns mapConception and fate.
Nature Reviews Neuroscience, 11, 139145.
Zhdanov, V. P. (2011). Kinetic models of gene expression including non-coding RNAs.
Physics Reports, 500, 142.
Relevant Websites
http://www.brain-connectivity-toolbox.net/ Brain Connectivity Toolbox.
http://braincorporation.com BrainCorporation.
http://www.nitrc.org/projects/brainwaver/ BrainwaveR Toolbox.
http://bluebrainproject.epfl.ch The Blue Brain Project.
http://ncs.ethz.ch/projects/EvoSpike EvoSpike Project, EU FP7.
Glossary
Abbreviations
fMRI
ICA
MACM
SPI
SPM
VBM
ALE
CBMA
CBP
functional and structural imaging data; MRI and PET data are
discussed here. Data storage can take place at various stages of
the neuroimaging analysis pipeline: as primary, raw data; as
derived, statistical parametric image (SPI) data; and as reduced,
coordinate data, published in journal articles (see Figure 1).
The advantages and disadvantages of each data type (or even
database) are beyond the scope of this article; we will briefly
discuss primary and derived data archives followed by a deeper
discussion of reduced data archives.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00350-X
675
676
INTRODUCTION TO METHODS AND MODELING | BrainMap Database as a Resource for Computational Modeling
Figure 1 Data types in typical neuroimaging analysis pipeline. Left: Acquisition of primary, raw data as shown by photograph of Sarabeth Pridgen
Fox playing the piano during PET acquisition of primary, raw data; photograph taken by Dr. Stephan Elleringmann. Middle: Example of derived, statistical
parametric data representing statistical differences in primary data image volumes. Right: Table from Petersen et al. (1988) reporting local
maximum of statistical parametric data as reduced, coordinate data.
INTRODUCTION TO METHODS AND MODELING | BrainMap Database as a Resource for Computational Modeling
value from a corresponding SPI; for this reason, coordinate
data are considered a reduced version of a derived SPI. A
number of reduced data repositories exist: BrainMap, SumsDB
(Dickson, Drury, & Van Essen, 2001), Brede, AMAT, and Neurosynth. The former four were reviewed in Derrfuss and Mar
(2009); Neurosynth and BrainMap will be described in the
succeeding text.
Neurosynth was recently created as an online, open-source
resource that uses a parsing engine to automatically extract
reduced, coordinate data from the columns reported in tables
in neuroimaging articles (Yarkoni, Poldrack, Nichols, Van
Essen, & Wager, 2011). Such an automated approach allows
coordinates to be rapidly retrieved. This approach does not
distinguish activations from deactivations, different experimental contrasts, or coordinate space; however, because of
the sheer number of foci gathered, Neurosynth has shown
capable of producing informative brain-wide meta-analyses
(Yarkoni et al., 2011). Neurosynth uses text-mining and
machine-learning techniques to extract metadata and provides
frequency-based weightings for behavioral and cognitive terms
appearing in the coordinate-containing articles. These weightings are used to drive meta-analyses that can be performed
directly from the Neurosynth web interface. At time of writing,
Neurosynth reported 200 000 foci representing 6000 studies (http://neurosynth.org/).
BrainMap (Fox & Lancaster, 1994, 2002; Fox, Mikiten, Davis,
& Lancaster, 1994) was the first online reduced, coordinate
database. From the outset, the BrainMap strategy was to provide
coordinate-based results linked to experimental metadata that
emphasize experimental designs and behavioral conditions (Fox
& Lancaster, 1994). Each neuroimaging experiment is manually
coded and verified by the BrainMap team before being loaded
into the database. It takes a research assistant approximately
3060 min to enter the details of a single publication into
Scribe, the BrainMap data entry application (Laird, 2009).
While this is a time-consuming process, such manual duration
allows a depth and accuracy of coding that provides diverse data
mining opportunities and increases the value of the BrainMap
database; in addition, manual entry is necessary to insure accurate representation of experimental design, coordinate space,
data interpretation, and other aspects per the BrainMap coding
scheme (described in the succeeding text).
BrainMap contains two separate databases: a functional
database (representing fMRI and PET studies) and a voxelbased morphometry (VBM) database (representing structural
data). At time of writing, the BrainMap functional database
contained 90 000 foci representing 2300 papers; the BrainMap VBM database contained 18 000 foci representing 900
papers (http://brainmap.org/).
677
678
INTRODUCTION TO METHODS AND MODELING | BrainMap Database as a Resource for Computational Modeling
Region to region
The concept of coactivation-based, meta-analytic connectivity
model (MACM) was introduced by Koski and Paus (2000). To
identify frontal lobe projections to the anterior cingulate gyrus,
they manually collected and examined data from 107 studies,
reporting differential connection patterns within different subregions of the anterior cingulate. While regarding their new
approach as intrinsically plausible, Koski and Paus (2000)
acknowledged that it lacked formal validation. In view of this
shortcoming, they recommended replications using larger data
sets, the development of statistically more sophisticated
approaches, and validating the approach against alternative
connectivity measure, all of which eventually came to pass.
Note that this application was region to region in that it limited
its scope to connections between the frontal lobe and the
anterior cingulate gyrus; such an analysis can be performed
within Sleuth by searching the BrainMap database with
Sleuths anatomical label AND function (e.g., searching BrainMap for activations within frontal lobe AND anterior
cingulate).
Region-to-whole-brain
The first region-to-whole-brain coactivation meta-analysis was
reported by Postuma and Dagher (2006). Having identified
126 peer-reviewed, whole-brain studies with activations in
caudate or putamen, the authors computed the first wholebrain, meta-analytic functional connectivity images. In these
images, coactivation patterns were observed that were consistent with the concept of spatially segregated corticostriatal
connections as predicted by previous anatomical labeling studies in nonhuman primates. As with Koski and Paus (2000), no
validation other than plausibility was offered.
The region-to-whole-brain analysis strategy was adopted
and extended by Robinson, Laird, Glahn, Lovallo, and Fox
(2010). Using the Harvard/Oxford atlas to define the amygdala, the entire BrainMap database as the data source, and ALE
to compute co-occurrence spatial probabilities, Robinson
mapped the coactivation profile of the left and right amygdalae.
By way of validation of the approach, she termed MACM,
Robinson compared the amygdala MACM results with those
obtained by various tract-tracing methods in rhesus monkeys,
as reported in the CoCoMac database (Stephan et al., 2000),
finding startlingly good correspondence. Robinson et al.
(2012) applied a similar strategy to the caudate nuclei, adding
functional filtering using BrainMap behavioral domain metadata (Figure 2). MACM connectivity profiles have been validated by reference to resting state (Cauda et al., 2011; Cieslik
et al., 2012; Rottschy et al., 2012; Smith et al., 2009), diffusion
tractography (Eickhoff et al., 2010; Robinson et al., 2012), and
electrophysiology (Narayana et al., 2012). MACM analyses are
performed by searching for BrainMap subsets within Sleuth.
Left hemisphere
Right hemisphere
Action specific
Cognition specific
Perception specific
Emotion specific
Figure 2 MACM with behavioral domain filtering. The images illustrate the regional and behavioral specificities of the connections of the caudate
nucleus. Connectivity was computed as coactivations frequency with seed region (caudate nucleus), sampling across the entire BrainMap database.
ALE was used to compute statistical significance of co-occurrences. Behavioral filtering used the top tier of the BrainMap behavioral domain hierarchy.
The projection patterns closely matched those established in the primate literature and were confirmed by DTI tractography. Images are reproduced
with permission from Robinson et al. (2010), the original report of behaviorally filtered MACM connectivity mapping.
INTRODUCTION TO METHODS AND MODELING | BrainMap Database as a Resource for Computational Modeling
Coactivation-based parcellation
679
Cytoarchitectonic
parcellation
Coactivation-based
parcellation
Figure 4 Topological analysis. The comparability of topological networks derived from meta-analysis of the BrainMap database (top row) and
resting-state fMRI in 27 subjects (middle row) is illustrated. In anatomical space (a; upper two rows), the size of the nodes is proportional to their
weighted degree (strength), and their color corresponds to module membership. The relationship between the coactivation metric (Jaccard index; b) and
the connectivity metric for every pair of regions is graphed (b). The degree and distance distributions for both networks are plotted (c and d,
respectively). Reproduced from Crossley, N. A., Mechelli, A., & Vertes, P. E. (2013). Cognitive relevance of the community structure of the human
brain functional coactivation network. Proceedings of the National Academy of Sciences of the United States of America, 110, 1158311588, with
permission.
Figure 5 ICA. The comparability of independent components derived from meta-analysis and resting-state networks is illustrated. Each of the ten
panels shows one well-matched pair of networks from two, 20-component ICA analyses. In each panel, the left-side images are derived from a metaanalysis of the BrainMap database (30 000 subjects); the right-side images are from a 36-subject resting-state fMRI database. Reproduced from
Smith, S. M., Fox, P. T., Miller, K. L., Glahn, D. C., Fox, P. M., Mackay, et al. (2009). Correspondence of the brains functional architecture during
activation and rest. Proceedings of the National Academy of Sciences of the United States of America, 106, 1304013045, with permission.
INTRODUCTION TO METHODS AND MODELING | BrainMap Database as a Resource for Computational Modeling
healthy volunteers. Decompositions were performed into both
20 and 70 components.
Of the 20 components generated separately from the two
datasets, ten maps from each set were unambiguously paired
between datasets, with a minimum correlation r 0.25
(p < 105, corrected for multiple comparisons and for spatial
smoothness). These ten well-matched pairs of networks are
shown in Figure 5. With an ICA dimensionality of 70, the
primary networks split into subnets in similar (but not identical) ways, continuing to show close correspondence between
BrainMap and RSN components. This argues that the full
repertoire of functional networks utilized by the brain in action
(coded in BrainMap) is continuously and dynamically active
even when at rest and, vice versa, that RSNs represent an
intrinsic functional architecture of the brain that is drawn
upon to support task performance.
Behavioral Interpretation
Automated, anatomical labeling machines like the Talairach
Daemon have been widely embraced by the neuroimaging
community (Lancaster et al., 2000). Such a machine returns
an anatomical label for an xyz coordinate location or a 3-D
volume within a standardized space. Automated, behavioral
machines are similar in that they provide behavioral descriptions for locations or volumes and can be produced by referencing the BrainMap metadata. Behavioral descriptions are
681
Figure 6 BrainMap metadata behavioral interpretations. The mapping of BrainMap metadata onto ICA components is shown. Note that behavioral
metadata form discrete groupings that functionally characterize the spatial groupings provided by ICA. In the left panel, 20 behavioral domain
categorizations were correlated with the ten ICA-derived components shown in Figure 5. In the right panel, the metadata analysis has been extended to
include 50 behavioral domain categories and 75 paradigm class categories. Hierarchical clustering was used to group the ICA into spatially and
behaviorally related clusters for all 20 ICA components. (a) Reproduced from Smith, S. M., Fox, P. T., Miller, K. L., Glahn, D. C., Fox, P. M., Mackay, et al.
(2009). Correspondence of the brains functional architecture during activation and rest. Proceedings of the National Academy of Sciences of the
United States of America, 106, 1304013045, with permission; (b) Reproduced from Laird, A. R., Eickhoff, S. B., Fox, P. M., Uecker, A. M., Ray, K. L.,
Saenz, J. J., et al. (2011). The BrainMap strategy for standardization, sharing, and meta-analysis of neuroimaging data. BMC Research Notes, 4,
349; Laird, A. R., Fox, P. M., Eickhoff, S. B., Turner, J. A., Ray, K. L., McKay, D. R., et al. (2011). Behavioral interpretations of intrinsic connectivity
networks. Journal of Cognitive Neuroscience, 23, 40224037, with permission.
682
INTRODUCTION TO METHODS AND MODELING | BrainMap Database as a Resource for Computational Modeling
Conclusion
A closing point of some importance is that databases allow
many rich sources of analysis, as exemplified by the BrainMap
database. Since its inception, BrainMap has evolved with a
family of coordinate-based meta-analysis (CBMA) methods,
described in the preceding text. While these may appear to be
conceptually discrete methods, in practice, they tend to be
applied serially, with simpler forms of meta-analysis providing
input for more advanced forms.
CBMA methods are used as hypothesis generators within
larger-scope studies to define regions of interest for subsequent, extra-BrainMap methods like diffusion tractography
and resting-state fMRI. In addition, rigorous paradigm taxonomy allows BrainMap meta-analysis to offer a versatile, powerful approach for discovering the behavioral significance of
networks mapped using anatomical or functional techniques
that contain no explicit behavioral information.
Acknowledgments
This work was supported by awards from the National Institutes
of Health (MH74457, RR024387, MH084812, NS062254,
AA019691, and EB015314) and the Congressionally Directed
Medical Research Program (W81XWH0820112). Portions of
this article were adapted from Fox and Friston (2012) and
from Fox et al. (2014).
The BrainMap database is an electronic compilation of the
results of peer-reviewed, published neuroimaging studies
(both functional and structural) that utilized standardized
coordinates to analyze and report their results (Fox & Lancaster, 2002). The BrainMap data (as an electronic compilation)
and the coding taxonomy are protected by copyrights held by
the University of Texas Board of Regents (see http://brainmap.
org for the entire BrainMap Database Collaborative-Use
License Agreement).
References
Amunts, K., Kedo, O., Kindler, M., Pieperhoff, P., Mohlberg, H., Shah, N. J., et al.
(2005). Cytoarchitectonic mapping of the human amygdala, hippocampal region
and entorhinal cortex: Intersubject variability and probability maps. Anatomy and
Embryology, 210, 343352.
Barron, D. S., Fox, P. M., Laird, A. R., Robinson, J. L., & Fox, P. T. (2013). Thalamic
medial dorsal nucleus atrophy in medial temporal lobe epilepsy: A VBM metaanalysis. NeuroImage: Clinical, 2, 2532.
Biswal, B., Zerrin Yetkin, F., Haughton, V. M., & Hyde, J. S. (1995). Functional
connectivity in the motor cortex of resting human brain using echo-planar mri.
Magnetic Resonance in Medicine, 34, 537541.
Brown, S., Ingham, R. J., Ingham, J. C., Laird, A. R., & Fox, P. T. (2005). Stuttered and
fluent speech production: An ALE meta-analysis of functional neuroimaging studies.
Human Brain Mapping, 25, 105117.
Bzdok, D., Laird, A. R., Zilles, K., Fox, P. T., & Eickhoff, S. B. (2012). An investigation of
the structural, connectional, and functional subspecialization in the human
amygdala. Human Brain Mapping, 34, 32473266, http://www.ncbi.nlm.nih.gov/
pubmed/22806915.
Cauda, F., Cavanna, A. E., Dagata, F., Sacco, K., Duca, S., & Geminiani, G. C. (2011).
Functional connectivity and coactivation of the nucleus accumbens: A combined
functional connectivity and structure-based meta-analysis. Journal of Cognitive
Neuroscience, 23, 28642877.
Cieslik, E. C., Zilles, K., Caspers, S., Roski, C., Kellermann, T. S., Jakobs, O., et al.
(2012). Is there one DLPFC in cognitive action control? Evidence for heterogeneity
from co-activation-based parcellation. Cerebral Cortex, 23, 26772689, http://www.
ncbi.nlm.nih.gov/pubmed/22918987.
Clos, M., Amunts, K., Laird, A. R., Fox, P. T., & Eickhoff, S. B. (2013). Tackling the
multifunctional nature of Brocas region meta-analytically: Co-activation-based
parcellation of area 44. NeuroImage, 83, 174188, http://www.ncbi.nlm.nih.gov/
pubmed/23791915.
Crossley, N. A., Mechelli, A., & Vertes, P. E. (2013). Cognitive relevance of the
community structure of the human brain functional coactivation network.
Proceedings of the National Academy of Sciences of the United States of America,
110(28), 1158311588.
Derrfuss, Marr (2009). Lost in localization: The need for a universal coordinate
database. Neuroimage, 48, 17.
Dickson, J., Drury, H., & Van Essen, D. C. (2001). The surface management system
(SuMS) database: A surface-based database to aid cortical surface reconstruction,
visualization and analysis. Philosophical Transactions of the Royal Society, B:
Biological Sciences, 356, 12771292.
Dogan, I., Eickhoff, S. B., Schulz, J. B., Shah, N. J., Laird, A. R., Fox, P. T., et al. (2013).
Consistent neurodegeneration and its association with clinical progression in
Huntingtons disease: A coordinate-based meta-analysis. Neurodegenerative
Diseases, 12, 2335.
Eickhoff, S. B., Bzdok, D., Laird, A. R., Roski, C., Caspers, S., Zilles, K., et al. (2011).
Co-activation patterns distinguish cortical modules, their connectivity and
functional differentiation. NeuroImage, 57, 938949.
Eickhoff, S. B., Jbabdi, S., Caspers, S., Laird, A. R., Fox, P. T., Zilles, K., et al. (2010).
Anatomical and functional connectivity of cytoarchitectonic areas within the human
parietal operculum. Journal of Neuroscience, 30, 64096421.
INTRODUCTION TO METHODS AND MODELING | BrainMap Database as a Resource for Computational Modeling
Fitzgerald, P. B., Laird, A. R., Maller, J., & Daskalakis, Z. J. (2008). A meta-analytic
study of changes in brain activation in depression. Human Brain Mapping, 29,
683695.
Fox, P. T., & Friston, K. J. (2012). Distributed processing: Distributed functions?
NeuroImage, 61, 407426.
Fox, P. T., Laird, A. R., Fox, S. P., Fox, P. M., Uecker, A. M., Crank, M., et al. (2005).
Brainmap taxonomy of experimental design: Description and evaluation. Human
Brain Mapping, 25, 185198.
Fox, P., & Lancaster, J. (1994). Neuroscience on the net. Science, 266, 994996.
Fox, P. T., & Lancaster, J. L. (2002). Mapping context and content: The BrainMap
model. Nature Reviews Neuroscience, 3, 319321.
Fox, P. T., Lancaster, J. L., Laird, A. R., & Eickhoff, S. B. (2014). Meta-analysis in
human neuroimaging: Computational modeling of large-scale databases. Annual
Review of Neuroscience, 37, 1.
Fox, P. T., Mikiten, S. A., Davis, G., & Lancaster, J. L. (1994). BrainMap: A database of
human functional brain mapping. In R. W. Thatcher, W. Hallet, T. A. Zeffiro, E. R.
John & M. Huerta (Eds.), Functional neuroimaging. San Diego: Academic Press,
Elsevier.
Fox, P. T., Parsons, L. M., & Lancaster, J. L. (1998). Beyond the single study: Function/
location metanalysis in cognitive neuroimaging. Current Opinion in Neurobiology,
8, 178187.
Fox, M. D., & Raichle, M. E. (2007). Spontaneous fluctuations in brain activity observed
with functional magnetic resonance imaging. Nature Reviews Neuroscience, 8,
700711.
Johansen-Berg, H., Behrens, T. E. J., Robson, M. D., Drobnjak, I.,
Rushworth, M. F. S., Brady, J. M., et al. (2004). Changes in connectivity profiles
define functionally distinct regions in human medial frontal cortex. Proceedings of
the National Academy of Sciences of the United States of America, 101,
1333513340.
Keator, D. B., Grethe, J. S., Marcus, D., Ozyurt, B., Gadde, S., Murphy, S., et al. (2008).
A national human neuroimaging collaboratory enabled by the Biomedical
Informatics Research Network (BIRN). IEEE Transactions on Information Technology
in Biomedicine, 12, 162172.
Koski, L., & Paus, T. (2000). Functional connectivity of the anterior cingulate cortex
within the human frontal lobe: A brain-mapping meta-analysis. Experimental Brain
Research, 133, 5565.
Laird, A. R. (2009). ALE meta-analysis workflows via the BrainMap database:
Progress towards a probabilistic functional brain atlas. Frontiers in
Neuroinformatics, 3, 23, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2715269/.
Laird, A. R., Eickhoff, S. B., Fox, P. M., Uecker, A. M., Ray, K. L., Saenz, J. J., et al.
(2011). The BrainMap strategy for standardization, sharing, and meta-analysis of
neuroimaging data. BMC Research Notes, 4, 349.
Laird, A. R., Eickhoff, S. B., Li, K., Robin, D. A., Glahn, D. C., & Fox, P. T. (2009).
Investigating the functional heterogeneity of the default mode network using
coordinate-based meta-analytic modeling. Journal of Neuroscience, 29,
1449614505.
Laird, A. R., Fox, P. M., Eickhoff, S. B., Turner, J. A., Ray, K. L., McKay, D. R., et al.
(2011). Behavioral interpretations of intrinsic connectivity networks. Journal of
Cognitive Neuroscience, 23, 40224037.
Lambrecq, V., Langbour, N., Guehl, D., Bioulac, B., Burbaud, P., & Rotge, J. Y. (2012).
Evolution of brain gray matter loss in Huntingtons disease: A meta-analysis.
European Journal of Neurology, 20, 315321.
Lancaster, J. L., Laird, A. R., Eickhoff, S. B., Martinez, M. J., Fox, P. M., & Fox, P. T.
(2012). Automated regional behavioral analysis for human brain images. Frontiers
in Neuroinformatics, 6, 23.
Lancaster, J. L., Woldorff, M. G., Parsons, L. M., Liotti, M., Freitas, C. S., Rainey, L.,
et al. (2000). Automated Talairach atlas labels for functional brain mapping. Human
Brain Mapping, 10, 120131.
Mazziotta, J. C., Toga, A. W., Evans, A., Fox, P., & Lancaster, J. (1995). A probabilistic
atlas of the human brain: Theory and rationale for its development the international
consortium for brain mapping (ICBM). NeuroImage, 2, 89101.
683
Menzies, L., Chamberlain, S. R., Laird, A. R., Thelen, S. M., Sahakian, B. J., &
Bullmore, E. T. (2008). Integrating evidence from neuroimaging and
neuropsychological studies of obsessivecompulsive disorder: The orbitofrontostriatal model revisited. Neuroscience & Biobehavioral Reviews, 32, 525549.
Narayana, S., Laird, A. R., Tandon, N., Franklin, C., Lancaster, J. L., & Fox, P. T. (2012).
Electrophysiological and functional connectivity of the human supplementary motor
area. NeuroImage, 62, 250265.
Neumann, J., Fox, P. T., Turner, R., & Lohmann, G. (2010). Learning partially directed
functional networks from meta-analysis imaging data. NeuroImage, 49, 13721384.
Nickl-Jockschat, T., Habel, U., Maria Michel, T., Manning, J., Laird, A. R., Fox, P. T.,
et al. (2011). Brain structure anomalies in autism spectrum disorder A metaanalysis of VBM studies using anatomic likelihood estimation. Human Brain
Mapping, 33, 14701489.
Petersen, S. E., Fox, P. T., Posner, M. I., Mintun, M., & Raichle, M. E. (1988). Positron
emission tomographic studies of the cortical anatomy of single-word processing.
Nature, 331(6157), 585589.
Poldrack, R. A. (2006). Can cognitive processes be inferred from neuroimaging data?
Trends in Cognitive Sciences, 10, 5963.
Poldrack, R. A., Barch, D. M., Mitchell, J. P., Wager, T. D., Wagner, A. D., Devlin, J. T.,
et al. (2013). Toward open sharing of task-based fMRI data: The OpenfMRI project.
Frontiers in Neuroinformatics, 7, 12, http://www.ncbi.nlm.nih.gov/pmc/articles/
PMC3703526/.
Poline, J.-B., Breeze, J. L., Ghosh, S., Gorgolewski, K., Halchenko, Y. O., Hanke, M.,
et al. (2012). Data sharing in neuroimaging research. Frontiers in Neuroinformatics,
6, 9, http://www.ncbi.nlm.nih.gov/pubmed/22493576.
Postuma, R. B., & Dagher, A. (2006). Basal ganglia functional connectivity based on a
meta-analysis of 126 positron emission tomography and functional magnetic
resonance imaging publications. Cerebral Cortex, 16, 15081521.
Price, C. J., Devlin, J. T., Moore, C. J., Morton, C., & Laird, A. R. (2005). Meta-analyses
of object naming: Effect of baseline. Human Brain Mapping, 25, 7082.
Robinson, J. L., Laird, A. R., Glahn, D. C., Blangero, J., Sanghera, M. K., Pessoa, L., et al.
(2012). The functional connectivity of the human caudate: An application of metaanalytic connectivity modeling with behavioral filtering. NeuroImage, 60, 117129.
Robinson, J. L., Laird, A. R., Glahn, D. C., Lovallo, W. R., & Fox, P. T. (2010).
Metaanalytic connectivity modeling: Delineating the functional connectivity of the
human amygdala. Human Brain Mapping, 31, 173184.
Rottschy, C., Caspers, S., Roski, C., Reetz, K., Dogan, I., Schulz, J. B., et al. (2012).
Differentiated parietal connectivity of frontal regions for what and where
memory. Brain Structure and Function, 218, 15511567.
Smith, S. M., Fox, P. T., Miller, K. L., Glahn, D. C., Fox, P. M., Mackay, C. E., et al.
(2009). Correspondence of the brains functional architecture during activation and
rest. Proceedings of the National Academy of Sciences of the United States of
America, 106, 1304013045.
Stephan, K. E., Hilgetag, C. C., Burns, G. A. P. C., ONeill, M. A., Young, M. P., &
Kotter, R. (2000). Computational analysis of functional connectivity between areas
of primate cerebral cortex. Philosophical Transactions of the Royal Society, B:
Biological Sciences, 355, 111126.
Titova, O. E., Hjorth, O. C., Schioth, H. B., & Brooks, S. J. (2013). Anorexia nervosa is
linked to reduced brain structure in reward and somatosensory regions: A metaanalysis of VBM studies. BMC Psychiatry, 13, 110.
Toro, R., Fox, P. T., & Paus, T. (2008). Functional coactivation map of the human brain.
Cerebral Cortex, 18, 25532559.
Turner, J. A., & Laird, A. R. (2011). The cognitive paradigm ontology: Design and
application. Neuroinformatics, 10, 5766.
Van Essen, D. C. (2009). Lost in localization But found with foci?!. NeuroImage, 48,
1417.
Van Horn, J. D., & Gazzaniga, M. S. (2013). Why share data? Lessons learned from the
fMRIDC. NeuroImage, 82, 677682.
Yarkoni, T., Poldrack, R. A., Nichols, T. E., Van Essen, D. C., & Wager, T. D. (2011).
Large-scale automated synthesis of human functional neuroimaging data. Nature
Methods, 8, 665670.
Databases
JD Van Horn, University of Southern California, Los Angeles, CA, USA
2015 Elsevier Inc. All rights reserved.
Introduction
Organizing, annotating, archiving, and distributing biomedical data in usable and structured frameworks have become
critical elements across a range of scientific efforts. Driven by
advances in clinical, genetic, and imaging electronic data collection, research data are being gathered at an increasing rate.
The need to store and exchange data in meaningful ways in
support of data analysis, rigorous hypothesis testing, and subsequent analysis is considerable. While a spectrum of infrastructures for neuroimaging databasing exist (Van Horn et al.,
2001), from summary findings to fully curated archives, largescale computing and storage have clear advantages for study
information fidelity (Van Horn & Gazzaniga, 2005), distributed computation (Van Horn et al., 2006), and data reuse (Van
Horn & Ishai, 2007).
There are, however, many challenges to achieving valueadded data sharing, which become more obvious as data are
collected variably, where documentation is insufficient, some
postprocessing and/or data analysis has already occurred, or
the coordination among multiple sites is poor. If processed
versions of data are to be shared, the problem can often be
compounded because knowledge of which version of data was
used for a particular analysis and the order of processing steps
is highly important to the interpretation and reuse of derived
results (Van Horn & Toga, 2009a). Table 1 provides an overview of advantages/drawbacks across the database spectrum.
Nevertheless, advantages of distributed science in the form
of multisite consortia and accompanying databases have
continued to push this approach in many population-level
investigations.
Several noteworthy examples illustrate the breadth of neuroimaging databases. The BrainMap database (Fox & Lancaster,
2002; Fox, Mikiten, Davis, & Lancaster, 1994b; Laird, Eickhoff,
et al., 2011) is among the most well-known and longest-running
brain imaging results database. Recording brain activation focal
statistical results as Talairach/Montreal Neurological Institute
(MNI) space coordinates, BrainMap has systematically evolved
over time (Laird, Lancaster, & Fox, 2005) to incorporate new and
diverse information on study experimental design (Fox et al.,
2005). Now encompassing the results from many thousands of
brain mapping studies, BrainMap is an essential tool for metaanalytic assessments of the neuroimaging literature (Laird, Lancaster, & Fox, 2009; Laird et al., 2009; Laird, Fox, et al., 2011;
Torta & Cauda, 2011).
The fMRI Data Center (fMRIDC) project (Van Horn et al.,
2001) conducted active curation of complete datasets from
functional neuroimaging studies of cognition and behavior
between 2000 and 2007. Despite early misgivings from the
community (Governing Council of the Organization for
Human Brain Mapping, 2001; Toga, 2002b), this database
of functional and structural datasets, accompanied by subject
and paradigm metadata, from over 100 peer-reviewed studies
http://dx.doi.org/10.1016/B978-0-12-397025-1.00351-1
685
686
Table 1
Staffed?
Metadata?
User-side
resources?
Web?
Accessibility?
Log-in?
Provenance?
HIPAA?
QC?
Single
site/multisite?
Published study
datasets?
Robust
infrastructure?
Published
description?
Processing tools?
Upload cost?
Download cost?
Customizable
interface?
CD/DVD/
USB
Anonymous
FTP/SCP
Advertised
metadata
Activation
loci only
Statistical
maps
Personal data
repository
No
Maybe
Yes
Unlikely
Maybe
No
Partially
Maybe
No
Partially
Yes
No
Partially
Study level
No
No
Yes
Yes
Yes
Yes
No
No
One-toone
N/A
Yes
Open
Yes
Open
Yes
Open
Yes
Open
Possibly
Possibly
Yes
Open/partial
No
Unlikely
Yes
Unlikely
Likely
Maybe
Single
Unlikely
Likely
Maybe
Single/multi
Not
required
Unlikely
N/A
N/A
Single
No
Unlikely
Maybe
Unlikely
Single
Software
needed
Unlikely
N/A
N/A
Single
Yes
Possibly
User-driven
Single
Yes
Yes
Curated
Single/multi
Maybe
Maybe
Maybe
Yes
Yes
Possibly
Published/nonpublished
N/A
Maybe
Maybe
Partially
Partially
Maybe
Yes
No
Unlikely
Maybe
Yes
Yes
Maybe
Yes
No
No
Maybe
Workflows
Unlikely
Unlikely
Unlikely
Unlikely
Metaanalytic
None
None
Possibly
None
Only for
media
No
Metaanalytic
None
none
None
None
Possibly
None
No
No
No
No
Possibly
Possibly
Table 2
Participating institutions
Subject population
Alzheimers Disease
Neuroimaging
Initiative (ADNI)
sMRI,
PET
Autism Centers of
Excellent (ACE)
network
Collaborative
Initiative on Fetal
Alcohol Spectrum
Disorder (CIFASD)
MRI, EEG
Normal subjects;
methamphetamine
patients; HIV; children;
and Williams syndrome
International
Consortium for
Brain Mapping
(ICBM)
Functional Imaging
Research in
Schizophrenia
Testbed
(FIRSTBIRN)
Pediatric Brain
Tumor
Consortium
(PBTC)
URL
References
www.adniinfo.org
www.
loni.ucla.
edu/
ADNI/
index.
shtml
ace.loni.
ucla.edu
sMRI,
fMRI,
DTI
www.
cifasd.
org
www.loni.
ucla.edu/
ICBM/
Schizophrenia spectrum
disorders, normal control
subjects
sMRI;
MRS;
MRA;
DTI/
DWI;
PET
sMRI;
fMRI;
DTI
www.
nbirn.
net/
research/
function
sMRI;
PET
www.pbtc.
org
N/A
Multisite trial
687
688
Figure 1 The LONI IDA web interface provides users with the means to both upload, search for, and (in the case of approved users) download
neuroimaging datasets or link to their collections via LONI Pipeline. Archiving data in the IDA is straightforward and secure and requires no specialized
hardware, software, or personnel. All that is required is a computer with Internet access and web browser. The IDA automatically extracts relevant
metadata from the deidentified image files allowing data to be searched within moments of archival. Once archived, data may be downloaded and/or
streamed into the LONI Pipeline processing environment. Integration of the LONI Debabeler file format translation engine (Neu, Valentino, & Toga, 2005)
allows users to download image data in a number of file formats in addition to the original file format.
Databasing Infrastructure
For curated databases, a robust and reliable computational
infrastructure is a necessity for supporting a resource intended
to serve the needs and requirements of a broadly based
research community. The hardware infrastructure behind a
database must provide high performance, security, and reliability at each level being fault-tolerant with no single points
of failure. A firewall appliance would need to protect and
segment network traffic, permitting only authorized ingress
Deidentification
HIPAA
compliance
Data types
Imaging
Biospecimen
Genetic
Clinical
689
Website
Study tracking
Queries
Requests
Downloads
Co
llec
ta
ted
da
Qu
ara
nti
Upload
data
QA and
validation
Acquisition
sites
ta
ne
da
ved
da
Ap
pro
Download
data
ta
Multi-format
downloads
Coriell
Clinical
coordinating
center
De
rive
ta
da
Data
repository
Post
processing
Analysis workflows
Scientific
investigators
and study pls
Figure 2 This figure illustrates a comprehensive model for database deposition and download. Secure uploads from data acquisition sites, data
coordinating centers, or individual investigators are run through deidentification software to remove any sensitive patient information. Data are
compartmentalized into their various data types and subject to quality assurance and validation. Analysis workflows might access the repository directly
for use in processing and novel analyses. Downloads are strictly monitored and data conversions may be performed in multiple file formats.
690
Load
balancing
layer
Security
layer
Online
users
Load balancer
User
authentication
protocol
Request
Website
interface
Authentication server
Authentication key
Writeable
databases
Write request
Web
server
Tomcat servers
Application and
redundancy
layer
Disaster recovery
layer
Sync
Read-only
database
Read request
Backup
Data
Offsite disk
Onsite tapes
Data bunker
Figure 3 The compute infrastructure for a fully curated neuroimaging database might be composed of (a) a load-balancing layer, designed to
ensure limited bottleneck accessibility to compute resources; (b) a rigorous security layer, managing access requests, user authentication, and user
privileges; (c) an application and redundancy layer, for data deposition and database management; and (d) a disaster recovery layer, comprising on-site
tape backup, off-site disk mirroring and archiving, and periodic caching into offsite high-stability data bunkers.
Table 3
Domain
Primary institution
References
University of Kansas
N/A
N/A
Mazziotta et al. (2001)
N/A
Gogtay et al. (2004)
Narr et al. (2007)
Anatomy
Anatomy of the Corpus Callosum
BrainInfo
Brain atlasing
Chinese Digitized Standard Brain Atlas
International Consortium for Brain Mapping
Development
Development
Caring for a child with a serious illness
Mental health
Bipolar Endophenotypes in Population Isolates
Childhood-Onset Schizophrenia
First-Episode Schizophrenia
691
(Continued)
Project utilizing LONI IDA resources
Neurogenomics
ApoE and Alzheimers Disease
Genetic influences on the brain: A twin study
Neurogenomics Investigation of Depression
Neurology
Hippocampal Volume Loss in Multiple
Sclerosis
Human Epileptic Brain: 3D MRI
Huntingtons Disease Neuroimaging Project
Neural Bases of Lexical Processes in H. Stroke
Neuropsychological Progression of New Onset
Epilepsy
Volumetrics in Brain Trauma
Primary institution
References
Cryosection
Mouse BIRN
N/A
MacKenzie-Graham et al. (2007)
N/A
N/A
N/A
Nonhuman
Other
Alzheimers Disease
Neuroimaging Initiative
International Consortium
for Brain Mapping
Huntingtons Disease
Neuroimaging project
Australian Imaging,
Biomarkers and Lifestyle
Multi-center
Estriol Study
North American Prodrome
Longitudinal Study
Bipolar Endophenotypes in
Population Isolates
Multi-Disciplinary Approach
Study of Pelvic Pain
Consortium for
Neuropsychiatric Phenomics
Cardiovascular & HIV/AIDS
Effects on Brain & Cognition
Imaging & Genetic
Biomarkers for AD
Modifiers of Brain Aging &
Alzheimers Disease
Pediatric Thought
Disorder
Neuropsychological Progression
New Onset Epilepsy
00
70
10
00
00
00
10
ill TOTALS
1m
Download
+upload
1 273 730
61 809
23 856
16 458
10 920
10 664
8167
2844
2420
Downloads
Uploads
# of data sets
uploaded and
downloaded
2007-2011
Figure 4 Total transaction activity (uploads and downloads) from the LONI IDA between 2007 and 2011 by differing LONI IDA projects.
1749
1641
1603
1622
1301
11 840
692
Discussion
Though keen interest in databasing neuroimaging results (Fox,
Mikiten, Davis, & Lancaster, 1994a), derived information (Van
Essen, Drury, Joshi, & Miller, 1998), and raw data (Van Horn
et al., 2001) has existed for some time, databases have now
emerged as valid and much sought after resources for access to
brain imaging data. Their increased importance for providing a
comprehensive mechanism to gather, distribute and share
data, results, and information not only between and among
project participants but also to the scientific community has set
the stage for neuroimaging as a big data science. Maturing
informatics models will enable a far more extensive array of
analytic strategies and approaches to interpreting these data.
Successful databasing solutions must build a trust with the
communities they seek to serve and provide dependable
services and open policies to researchers. Several factors
Figure 5 Data processing workflow technologies provide a natural linkage to database resources. For instance, (a) the LONI Pipeline provides
direct connectivity to LONI IDA collections and other web-based data resources, which may be selected to (b) create a Pipeline module group that, at run
time, makes the connection to the database and submits the selected data for processing.
693
Acknowledgments
The work of preparing this article was supported through a P41
(P41EB015922) resource award from the National Institute of
Biomedical Imaging and Bioengineering (NIBIB) of the
National Institutes of Health (NIH) to Dr. Arthur W. Toga.
The LONI Image Data Archive (IDA) featured as an example
herein is expertly supervised by Dr. Scott Neu and Ms. Karen
Crawford. Gratitude is expressed to the faculty and staff of the
Laboratory of Neuro Imaging (LONI) now based at the University of Southern California in Los Angeles, CA.
References
Arzberger, P., Schroeder, P., Beaulieu, A., Bowker, G., Casey, K., Laaksonen, L., et al.
(2004). Science and government: An international framework to promote access to
data. Science, 303(5665), 17771778.
Beaulieu, A. (2001). Voxels in the brain: Neuroscience, informatics and changing
notions of objectivity. Social Studies of Science, 31(5), 635680.
Bischoff-Grethe, A., Ozyurt, I. B., Busa, E., Quinn, B. T., Fennema-Notestine, C.,
Clark, C. P., et al. (2007). A technique for the deidentification of structural brain MR
images. Human Brain Mapping, 28, 892903.
694
Holmes, E., Tsang, T. M., & Tabrizi, S. J. (2006). The application of NMR-based
metabonomics in neurological disorders. NeuroRx, 3(3), 358372.
Hua, X., Leow, A. D., Parikshak, N., Lee, S., Chiang, M. C., Toga, A. W., et al. (2008).
Tensor-based morphometry as a neuroimaging biomarker for Alzheimers
disease: An MRI study of 676 AD, MCI, and normal subjects. NeuroImage, 43,
458469.
Illes, J., & Borgelt, E. (2009). Brain imaging: incidental findings: In practice and in
person. Nature Reviews. Neurology, 5(12), 643644.
Jack, C., Bernstein, M., Fox, N., Thompson, P., Alexander, G., Harvey, D., et al. (2008).
The Alzheimers disease neuroimaging initiative (ADNI): MRI methods. Journal of
Magnetic Resonance Imaging, 27(4), 685691.
Joshi, S. H., Bowman, I., & Van Horn, J. D. (2010). Large-scale neuroanatomical
visualization using a manifold embedding approach. In: Proceedings of the IEEE
Symposium on Visual Analytics Science Technology 2010 (2526 Oct. 2010), (p. 237).
Joshi, S. H., Van Horn, J. D., & Toga, A. W. (2009). Interactive exploration of
neuroanatomical meta-spaces. Frontiers in Neuroinformatics, 3, 38.
Kawas, E., Senger, M., & Wilkinson, M. (2006). BioMoby extensions to the Taverna
workflow management and enactment software. BMC Bioinformatics, 7(1), 523.
Kim, D. I., Mathalon, D. H., Ford, J. M., Mannell, M., Turner, J. A., Brown, G. G., et al.
(2009). Auditory oddball deficits in schizophrenia: An independent component analysis
of the fMRI multisite function BIRN study. Schizophrenia Bulletin, 35(1), 6781.
Laird, A. R., Eickhoff, S. B., Fox, P. M., Uecker, A. M., Ray, K. L., Saenz, J. J., Jr., et al.
(2011). The BrainMap strategy for standardization, sharing, and meta-analysis of
neuroimaging data. BMC Research Notes, 4, 349.
Laird, A. R., Eickhoff, S. B., Kurth, F., Fox, P. M., Uecker, A. M., Turner, J. A., et al.
(2009). ALE meta-analysis workflows via the BrainMap database: Progress towards
a probabilistic functional brain atlas. Frontiers in Neuroinformatics, 3, 23.
Laird, A. R., Fox, P. M., Eickhoff, S. B., Turner, J. A., Ray, K. L., McKay, D. R., et al.
(2011). Behavioral interpretations of intrinsic connectivity networks. Journal of
Cognitive Neuroscience, 23, 40224037.
Laird, A. R., Lancaster, J. L., & Fox, P. T. (2005). BrainMap: The social evolution of a
human brain mapping database. Neuroinformatics, 3(1), 6578.
Laird, A. R., Lancaster, J. L., & Fox, P. T. (2009). Lost in localization? The focus is
meta-analysis. NeuroImage, 48(1), 1820.
Lanctot, K. L., Hussey, D. F., Herrmann, N., Black, S. E., Rusjan, P. M., Wilson, A. A.,
et al. (2007). A positron emission tomography study of 5-hydroxytryptamine-1A
receptors in Alzheimer disease. The American Journal of Geriatric Psychiatry,
15(10), 888898.
Leow, A. D., Klunder, A. D., Jack, C. R., Jr., Toga, A. W., Dale, A. M., Bernstein, M. A.,
et al. (2006). Longitudinal stability of MRI for mapping brain change using tensorbased morphometry. NeuroImage, 31(2), 627640.
Lepore, N., Brun, C. A., Chiang, M. C., Chou, Y. Y., Dutton, R. A., Hayashi, K. M., et al.
(2006). Multivariate statistics of the Jacobian matrices in tensor based morphometry
and their application to HIV/AIDS. Medical Image Computing and ComputerAssisted Intervention, 9(Pt 1), 191198.
Lin, J. J., Salamon, N., Lee, A. D., Dutton, R. A., Geaga, J. A., Hayashi, K. M., et al.
(2007). Reduced neocortical thickness and complexity mapped in mesial temporal
lobe epilepsy with hippocampal sclerosis. Cerebral Cortex, 17(9), 20072018.
Luders, E., Narr, K. L., Thompson, P. M., Rex, D. E., Woods, R. P., DeLuca, H., et al.
(2006). Gender effects on cortical thickness and the influence of scaling. Human
Brain Mapping, 27(4), 314324.
MacKenzie-Graham, A., Lee, E.-F., Dinov, I. D., Yuan, H., Jacobs, R. E., & Toga, A. W.
(2007). Multimodal, multidimensional models of mouse brain. Epilepsia, 48, 7581.
MacKenzie-Graham, A., Payan, A., Dinov, I., Van Horn, J., & Toga, A. (2008).
Neuroimaging data provenance using the LONI pipeline workflow environment.
Provenance and Annotation of Data and Processes, 5272, 208220.
MacKenzie-Graham, A., Tinsley, M., Shah, K., Aguilar, C., Strickland, L., Boline, J.,
et al. (2006). Cerebellar cortical atrophy in experimental autoimmune
encephalomyelitis. NeuroImage, 32, 10161023.
Mackenzie-Graham, A. J., Van Horn, J. D., Woods, R. P., Crawford, K. L., & Toga, A. W.
(2008). Provenance in neuroimaging. NeuroImage, 42(1), 178195.
Marcus, D. S., Olsen, T. R., Ramaratnam, M., & Buckner, R. L. (2007). The extensible
neuroimaging archive toolkit: An informatics platform for managing, exploring, and
sharing neuroimaging data. Neuroinformatics, 5(1), 1134.
Markram, H. (2012). The human brain project. Scientific American, 306(6), 5055.
Mazziotta, J. C., Toga, A. W., Evans, A., Fox, P., & Lancaster, J. (1995). A probabilistic
atlas of the human brain: Theory and rationale for its development. The International
Consortium for Brain Mapping (ICBM). NeuroImage, 2(2), 89101.
Mazziotta, J., Toga, A., Evans, A., Fox, P., Lancaster, J., Zilles, K., et al. (2001).
A probabilistic atlas and reference system for the human brain: International
Consortium for Brain Mapping (ICBM). Philosophical Transactions of the Royal
Society of London. Series B: Biological Sciences, 356(1412), 12931322.
695
Smith, K., Jajodia, S., Swarup, V., Hoyt, J., Hamilton, G., Faatz, D., et al. (2004).
Enabling the sharing of neuroimaging data through well-defined intermediate levels
of visibility. NeuroImage, 22(4), 16461656.
Sowell, E., Peterson, B. S., Kan, E., Woods, R. P., Yoshii, J., Bansal, R., et al. (2007).
Sex differences in cortical thickness mapped in 176 healthy individuals between 7
and 87 years of age. Cerebral Cortex, 17(7), 15501560.
Sowell, E. R., Trauner, D. A., Gamst, A., & Jernigan, T. L. (2002). Development of
cortical and subcortical brain structures in childhood and adolescence: A structural
MRI study. Developmental Medicine and Child Neurology, 44(1), 416.
Taylor, I., Shields, M., Wang, I., & Harrison, A. (2006). Visual grid workflow in Triana.
Journal of Grid Computing, 3, 153169.
Thompson, P., Hayashi, K. M., de Zubicaray, G., Janke, A. L., Rose, S. E., Semple, J.,
et al. (2003). Dynamics of gray matter loss in Alzheimers disease. Journal of
Neuroscience, 23(3), 9941005.
Toga, A. W. (2002a). The Laboratory of Neuro Imaging: What it is, why it is, and how it
came to be. IEEE Transactions on Medical Imaging, 21(11), 13331343.
Toga, A. W. (2002b). Neuroimage databases: The good, the bad and the ugly. Nature
Reviews. Neuroscience, 3(4), 302309.
Toga, A. W., & Crawford, K. L. (2010). The informatics core of the Alzheimers Disease
Neuroimaging Initiative. Alzheimers & Dementia, 6(3), 247256.
Torta, D. M., & Cauda, F. (2011). Different functions in the cingulate cortex, a metaanalytic connectivity modeling study. NeuroImage, 56(4), 21572172.
Van Essen, D. C. (2005). A Population-Average, Landmark- and Surface-based (PALS)
atlas of human cerebral cortex. NeuroImage, 28(3), 635662.
Van Essen, D. C., Drury, H. A., Joshi, S., & Miller, M. I. (1998). Functional and
structural mapping of human cerebral cortex: Solutions are in the surfaces.
Proceedings of the National Academy of Sciences of the United States of America,
95(3), 788795.
Van Horn, J. D., Dobson, J., Woodward, J., Wilde, M., Zhao, Y., Voeckler, J., et al.
(2006). Grid-based computing and the future of neuroscience computation. In C.
Senior, T. Russell, & M. S. Gazzaniga (Eds.), Methods in mind (pp. 141170).
Cambridge, MA: MIT Press.
Van Horn, J. D., & Gazzaniga, M. S. (2005). Maximizing information content in shared
neuroimaging studies of cognitive function. In S. H. Koslow, & A. Subramanian
(Eds.), Databasing the brain: From data to knowledge (pp. 449458). New York:
Wiley.
Van Horn, J. D., & Gazzaniga, M. S. (2012). Why share data? Lessons learned from the
fMRIDC. NeuroImage, 82, 677682.
Van Horn, J. D., Grethe, J. S., Kostelec, P., Woodward, J. B., Aslam, J. A., Rus, D., et al.
(2001). The Functional Magnetic Resonance Imaging Data Center (fMRIDC): The
challenges and rewards of large-scale databasing of neuroimaging studies.
Philosophical Transactions of the Royal Society of London. Series B: Biological
Sciences, 356, 13231339.
Van Horn, J. D., & Ishai, A. (2007). Mapping the human brain: New insights from FMRI
data sharing. Neuroinformatics, 5(3), 146153.
Van Horn, J. D., & Toga, A. W. (2009a). Is it time to re-prioritize neuroimaging
databases and digital repositories? NeuroImage, 47(4), 17201734.
Van Horn, J. D., & Toga, A. W. (2009b). Multisite neuroimaging trials. Current Opinion
in Neurology, 22(4), 370378.
Weiner, M. W., Veitch, D. P., Aisen, P. S., Beckett, L. A., Cairns, N. J., Green, R. C.,
et al. (2012). The Alzheimers Disease Neuroimaging Initiative: A review of
papers published since its inception. Alzheimers & Dementia, 8(1 Suppl),
S1S68.
Wu, H. M., Huang, S. C., Hattori, N., Glenn, T. C., Vespa, P. M., Yu, C. L., et al. (2004).
Selective metabolic reduction in gray matter acutely following human traumatic
brain injury. Journal of Neurotrauma, 21(2), 149161.
Yanovsky, I., Thompson, P. M., Osher, S., Hua, X., Shattuck, D., Toga, A. W., et al.
(2008). Validating unbiased registration on longitudinal MRI scans from
the Alzheimers Disease Neuroimaging Initiative (ADNI). In: 5th IEEE
International Symposium on Biomedical Imaging: From Nano to Macro, Paris,
France: IEEE.
Introduction
Functional connectivity has opened up another dimension for
analysis of fMRI data. Instead of simply examining the magnitude of activation in individual areas, one can now examine the
synchrony of activity between distinct areas in the brain. Particularly powerful are network analyses, which divide the brain
into a set of regions of interest (ROIs), or nodes, and use
temporal similarity in signal fluctuations between pairs of
nodes to determine the strength of the functional connections,
or edges, between them. As functional connectivity is easily
measured while subjects are at rest that is, in the absence of
any externally imposed cognitive task it holds great promise
as a clinical tool as well as a means to basic scientific discovery.
There remain several important methodological concerns
with functional connectivity and network analysis using fMRI
data, and researchers must take caution when conducting and
interpreting such studies. Some of these methodological issues
are the focus of this article, which consists of three parts. In the
section Network Measures and (In)stability Across
Thresholds, we review issues related to the use of graph theory/network measures, in particular the sensitivity of these
measures to the choice of threshold for converting
continuous-valued correlations to a binary connection graph.
In the section Defining Network Nodes, we examine the
issue of defining nodes for network analysis and demonstrate
that using advanced brain parcellation algorithms significantly
improves connectivity results compared to the same analysis
using nodes defined anatomically. Finally, in the section
Motion Confounds for Connectivity Analyses, we describe
motion confounds and related preprocessing concerns. While
functional connectivity and network measures represent a
potentially powerful approach to understanding brain functional architecture, care must be taken in the application of
such analysis techniques to fMRI data in order to accurately
elucidate the large-scale organization of the brain.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00352-3
697
698
INTRODUCTION TO METHODS AND MODELING | fMRI Functional Connectivity and Network Analysis
0.6
0.45
0.4
0.35
0.3
(a)
Females
Males
0.25
0.1
0.2
0.3
0.4
0.5
0.56
1200
0.54
1000
0.52
800
0.5
0.48
600
0.46
400
0.44
0.42
200
0.4
Females
Males
0.38
(b)
0.1
0.2
0.3
0.4
0.5
(c)
4.5
0
0.1
Females
Males
0.2
0.3
0.4
0.5
0.6
0.58
4
0.56
3.5
0.54
0.52
0.5
2.5
0.48
2
(d)
0.46
Females
Males
1.5
0.1
0.2
0.3
0.4
0.5
Females
Males
0.44
(e)
0.1
0.2
0.3
0.4
0.5
Figure 1 Instability of network measures across thresholds. Group differences in network measures for individual nodes may be present only at
certain thresholds (a), that is, only lower thresholds (b) or only higher thresholds (c), or may even reverse across thresholds (d and e). In all graphs, the
x-axis represents correlation threshold, while the y-axis represents the network measure indicated in the graph title. Crosses () indicate a p-value
<0.05 for difference between males and females; asterisks (*) indicate p < 0.01. Location of nodes is provided with sagittal and axial slices to the left of
the respective graph; axial slices are in radiological convention (image-left is subject-right). Char. path length, characteristic path length.
INTRODUCTION TO METHODS AND MODELING | fMRI Functional Connectivity and Network Analysis
Sidebar 1
699
Degree. Perhaps the most fundamental network property, degree is a measure of the number of edges connected to a node. On a node-wise level, it reflects how well
linked the node is to the rest of the network. A networks global degree may be computed by averaging degrees of all individual nodes to give an estimate of overall
network connectivity.
Characteristic path length. A nodes characteristic path length is the average shortest distance between it and all other nodes in the network. Short characteristic path
length is taken to represent a node that is well positioned within the network, able to efficiently exchange information with a variety of other nodes. Characteristic path
length may be computed for the whole network by averaging all of the individual nodes characteristic path lengths.
Clustering coefficient. Clustering coefficient is equal to the fraction of a nodes neighbors that are also connected to each other (Watts & Strogatz, 1998). For
instance, if node A is connected to node B, node B is connected to node C, and node C is connected to node A, these three nodes form a triangle. Clustering coefficient
is calculated by dividing the number of triangles around a node by that nodes total number of connections (degree). A high clustering coefficient therefore reflects the
presence of clustered connectivity around that individual node (Rubinov & Sporns, 2010).
Betweenness centrality. A nodes betweenness centrality is defined as the fraction of all shortest paths in the network that pass through it. Nodes that connect
distinct parts of the network often have a high betweenness centrality (Rubinov & Sporns, 2010).
INTRODUCTION TO METHODS AND MODELING | fMRI Functional Connectivity and Network Analysis
30
AAL
K = 100
700
K = 200
25
K = 300
20
15
10
11
21
31
41
Subjects
51
61
71
INTRODUCTION TO METHODS AND MODELING | fMRI Functional Connectivity and Network Analysis
701
0.6
0.5
(a)
0.4
0.3
0.2
0.1
0
(d) 0.1
0.2
0.3
0.4
0.5
(b)
NI
DYS
0.6
0.5
0.4
0.3
0.2
0.1
(c)
(e) 0.1
0.2
0.3
0.4
0.5
Figure 3 Comparison of connectivity results derived from nodes defined using the AAL atlas versus a data-driven parcellation scheme. Left panels:
(a) Connectivity profile of a seed placed in Brodmann area 19 (green) using data from 15 healthy subjects (showing all voxels correlated with the seed at
r 0.25). Compare (A) to connectivity profiles of two nodes representing functional subdivisions of Brodmann area 19 in a data-driven parcellation
scheme (b, purple seed; c, blue seed). (b and c) Divergent patterns of connectivity that are diluted when the two seed areas are lumped together in (a).
Right panel: (d) Clustering coefficient for a single node using a network of 30 nodes defined based on peaks of task-based activation, compared
between nonimpaired (NI) readers and dyslexic (DYS) readers in a study of brain activity to a reading task; (e) clustering coefficient for a node with
similar coordinates defined using the data-driven whole-brain parcellation scheme described in Shen et al. (2013). As in Figure 1, x-axis represents
correlation threshold, y-axis represents clustering coefficient, crosses () indicate a group difference at p < 0.05, and asterisks (*) indicate p < 0.01.
While group differences are less significant and even switch direction in the task-defined network, the whole-brain data-driven parcellation gives clear
and consistent group differences that are significant across thresholds and do not reverse.
702
INTRODUCTION TO METHODS AND MODELING | fMRI Functional Connectivity and Network Analysis
Figure 4 Areas where BOLD signal is significantly correlated with subject head motion. Areas positively correlated with motion include the
supplementary motor area, primary motor cortex, primary sensory cortex, cerebellum, thalamus, and visual cortex. Areas negatively correlated with
motion include several areas of the medial and lateral frontal lobe and lateral portions of the parietal lobe. Results shown at p < 0.05 corrected for
multiple comparisons.
INTRODUCTION TO METHODS AND MODELING | fMRI Functional Connectivity and Network Analysis
possibly removing subjects/data if necessary, and, second, if
concerns about motion still exist, to perform one or more of
the advanced techniques listed in the preceding text including
censoring, regression of higher-order motion terms, and regression of motion at the group level. New evidence also suggests
that smoothing all images to a uniform degree helps attenuate
the systematic effects of head motion on functional connectivity analyses (Scheinost et al., 2014).
Conclusion
In conclusion, functional connectivity and network analyses
present exciting new opportunities for characterizing the largescale organization of the brain and how this organization
varies with individuals, cognitive states, development, or
disease. While methodological concerns require researchers to
make informed choices about data analysis and preprocessing,
the explosion of interest in these techniques ensures that the
field of brain mapping will continue to refine and optimize
such methods to apply to clinical problems and research goals
in basic neuroscience.
References
Achard, S., Salvador, R., Whitcher, B., Suckling, J., & Bullmore, E. (2006). A resilient,
low-frequency, small-world human brain functional network with highly connected
association cortical hubs. Journal of Neuroscience, 26(1), 6372.
Alexander-Bloch, A., Lambiotte, R., Roberts, B., Giedd, J., Gogtay, N., & Bullmore, E.
(2012). The discovery of population differences in network community structure:
New methods and applications to brain functional networks in schizophrenia.
NeuroImage, 59, 38893900.
Arfanakis, K., Cordes, D., Haughton, V. M., Moritz, C. H., Quigley, M. A., &
Meyerand, M. E. (2000). Combining independent component analysis and
correlation analysis to probe interregional connectivity in fMRI task activation
datasets. Magnetic Resonance Imaging, 18(8), 921930.
Baria, A. T., Baliki, M. N., Parrish, T., & Apkarian, A. V. (2011). Anatomical and
functional assemblies of brain BOLD oscillations. Journal of Neuroscience, 31(21),
79107919.
Beckmann, C., DeLuca, M., Devlin, J., & Smith, S. (2005). Investigations into restingstate connectivity using independent component analysis. Philosophical Transactions
of the Royal Society of London, Series B: Biological Sciences, 360, 10011013.
Biswal, B., Zerrin Yetkin, F., Haughton, V. M., & Hyde, J. S. (1995). Functional
connectivity in the motor cortex of resting human brain using echo-planar mri.
Magnetic Resonance in Medicine, 34(4), 537541.
Buckner, R. L., Sepulcre, J., Talukdar, T., Krienen, F. M., Liu, H., Hedden, T., et al.
(2009). Cortical hubs revealed by intrinsic functional connectivity: Mapping,
assessment of stability, and relation to Alzheimers disease. Journal of
Neuroscience, 29, 18601873.
Carp, J. (2013). Optimizing the order of operations for movement scrubbing: Comment
on Power et al. NeuroImage, 76, 436438.
Chen, S., Ross, T., Zhan, W., Myers, C., Chuang, K.-S., Heishman, S., et al. (2008).
Group independent component analysis reveals consistent resting-state networks
across multiple sessions. Brain Research, 1239, 141151.
703
Cohen, A., Fair, D., Dosenbach, N., Miezin, F., Dierker, D., Essen, D. V., et al. (2008).
Defining functional areas in individual human brains using resting functional
connectivity MRI. NeuroImage, 41, 4557.
Fair, D. A., Dosenbach, N. U. F., Church, J. A., Cohen, A. L., Brahmbhatt, S.,
Miezin, F. M., et al. (2007). Development of distinct control networks through
segregation and integration. Proceedings of the National Academy of Sciences of
the United States of America, 104, 1350713512.
Fornito, A., Zalesky, A., & Breakspear, M. (2013). Graph analysis of the human
connectome: Promise, progress, and pitfalls. NeuroImage, 80, 426444.
Fornito, A., Zalesky, A., & Bullmore, E. T. (2010). Network scaling effects in graph
analytic studies of human resting-state fMRI data. Frontiers in Systems
Neuroscience, 4, 22.
Friston, K. J., Williams, S., Howard, R., Frackowiak, R. S., & Turner, R. (1996).
Movement-related effects in fMRI time-series. Magnetic Resonance in Medicine, 35,
346355.
Hampson, M., Tokoglu, F., Shen, X., Scheinost, D., Papademetris, X., &
Constable, R. T. (2012). Intrinsic brain connectivity related to age in young and
middle aged adults. PLoS One, 7, e44067.
Hoffman, R. E., Fernandez, T., Pittman, B., & Hampson, M. (2011). Elevated functional
connectivity along a corticostriatal loop and the mechanism of auditory/verbal
hallucinations in patients with schizophrenia. Biological Psychiatry, 69(5),
407414.
Lashkari, D., Vul, E., Kanwisher, N., & Golland, P. (2010). Discovering structure in the
space of fMRI selectivity profiles. NeuroImage, 50, 10851098.
Liu, Y., Liang, M., Zhou, Y., He, Y., Hao, Y., Song, M., et al. (2008). Disrupted smallworld networks in schizophrenia. Brain, 131, 945961.
Lynall, M.-E., Bassett, D. S., Kerwin, R., McKenna, P. J., Kitzbichler, M., Muller, U.,
et al. (2010). Functional connectivity and brain networks in schizophrenia. Journal
of Neuroscience, 30, 94779487.
Martuzzi, R., Ramani, R., Qiu, M., Shen, X., Papademetris, X., & Constable, R. T. (2011).
A whole-brain voxel based measure of intrinsic connectivity contrast reveals local
changes in tissue connectivity with anesthetic without a priori assumptions on
thresholds or regions of interest. NeuroImage, 58, 10441050.
Power, J. D., Barnes, K. A., Snyder, A. Z., Schlaggar, B. L., & Petersen, S. E. (2012).
Spurious but systematic correlations in functional connectivity MRI networks arise
from subject motion. NeuroImage, 59, 21422154.
Power, J. D., Fair, D. A., Schlaggar, B. L., & Petersen, S. E. (2010). The development of
human functional brain networks. Neuron, 67(5), 735748.
Rubinov, M., & Sporns, O. (2010). Complex network measures of brain connectivity:
Uses and interpretations. NeuroImage, 52, 10591069.
Satterthwaite, T. D., Elliott, M. A., Gerraty, R. T., Ruparel, K., Loughead, J.,
Calkins, M. E., et al. (2013). An improved framework for confound regression and
filtering for control of motion artifact in the preprocessing of resting-state functional
connectivity data. NeuroImage, 64, 240256.
Satterthwaite, T. D., Wolf, D. H., Loughead, J., Ruparel, K., Elliott, M. A.,
Hakonarson, H., et al. (2012). Impact of in-scanner head motion on multiple
measures of functional connectivity: Relevance for studies of neurodevelopment in
youth. NeuroImage, 60, 623632.
Scheinost, D., Benjamin, J., Lacadie, C. M., Vohr, B., Schneider, K. C., Ment, L. R., et al.
(2012). The intrinsic connectivity distribution: A novel contrast measure reflecting
voxel level functional connectivity. NeuroImage, 62, 15101519.
Scheinost, D., Papademetris, X., & Constable, R. T. (2013). Correlation of head
movement and fMRI temporal signal in motor processing areas: What is artifact?
Seattle, WA: Human Brain Mapping.
Shen, X., Tokoglu, F., Papademetris, X., & Constable, R. T. (2013). Groupwise wholebrain parcellation from resting-state fMRI data for network node identification.
NeuroImage, 82, 403415.
Shi, J., & Malik, J. (2000). Normalized cuts and image segmentation. IEEE Transactions
on Pattern Analysis and Machine Intelligence, 22, 888905.
Stevens, A. A., Tappon, S. C., Garg, A., & Fair, D. A. (2012). Functional brain network
modularity captures inter- and intra-individual variation in working memory
capacity. PLoS One, 7, e30468.
Supekar, K., Menon, V., Rubin, D., Musen, M., & Greicius, M. D. (2008). Network
analysis of intrinsic functional brain connectivity in Alzheimers disease. PLoS
Computational Biology, 4, e1000100.
Tian, L., Jiang, T., Wang, Y., Zang, Y., He, Y., Liang, M., et al. (2006). Altered
resting-state functional connectivity patterns of anterior cingulate cortex in
adolescents with attention deficit hyperactivity disorder. Neuroscience Letters, 400,
3943.
Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F., Etard, O.,
Delcroix, N., et al. (2002). Automated anatomical labeling of activations in SPM
using a macroscopic anatomical parcellation of the MNI MRI single-subject brain.
NeuroImage, 15, 273289.
704
INTRODUCTION TO METHODS AND MODELING | fMRI Functional Connectivity and Network Analysis
van den Heuvel, M. P., Mandl, R. C. W., Kahn, R. S., & Hulshoff Pol, H. E. (2009).
Functionally linked resting-state networks reflect the underlying structural connectivity
architecture of the human brain. Human Brain Mapping, 30, 31273141.
Van Den Heuvel, M., Mandl, R., & Pol, H. H. (2008). Normalized cut group clustering of
resting-state FMRI data. PLoS One, 3(4), e2001.
van den Heuvel, M. P., Mandl, R. C. W., Stam, C. J., Kahn, R. S., & Hulshoff Pol, H. E.
(2010). Aberrant frontal and temporal complex network structure in schizophrenia: A
graph theoretical analysis. Journal of Neuroscience, 30, 1591515926.
Van Dijk, K. R., Sabuncu, M. R., & Buckner, R. L. (2012). The influence of head motion
on intrinsic functional connectivity MRI. NeuroImage, 59, 431438.
Watts, D. J., & Strogatz, S. H. (1998). Collective dynamics of small-world networks.
Nature, 393, 440442.
BRAIN MAPPING
AN ENCYCLOPEDIC
REFERENCE
Volume 2
Anatomy and Physiology
Systems
BRAIN MAPPING
AN ENCYCLOPEDIC
REFERENCE
Volume 2
Anatomy and Physiology
Systems
EDITOR-IN-CHIEF
ARTHUR W. TOGA
University of Southern California, Los Angeles, CA, USA
SECTION EDITORS
KARL ZILLES
Institute of Neuroscience and Medicine (INM-1), Forschungszentrum Julich, Julich, Germany
KATRIN AMUNTS
Institute of Neuroscience and Medicine (INM-1), Forschungszentrum Julich, Julich, Germany
MARSEL MESULAM
Northwestern University, Chicago, IL, USA
SABINE KASTNER
Princeton University, Princeton, NJ, USA
15 16
17 18 19
10 9 8 7 6 5 4 3 2 1
CONTRIBUTORS
K Amunts
Institute of Neuroscience and Medicine (INM-1), Julich,
Germany; JARA Julich-Aachen Research Alliance,
Aachen, Germany; University of Dusseldorf, Dusseldorf,
Germany
E Armstrong
Troy University, Troy, AL, USA
A Aron
Stony Brook University, Stony Brook, NY, USA
G Auzias
Aix-Marseille Universite, Marseille, France
MN Baliki
Northwestern University, Chicago, IL, USA
K-J Bar
Jena University Hospital, Jena, Germany; Psychiatry,
Brighton and Sussex Medical School, Falmer, UK
S Bludau
Institute of Neuroscience and Medicine (INM-1), Julich,
Germany; JARA Julich-Aachen Research Alliance,
Aachen, Germany
D Caplan
Neuropsychology Laboratory, Boston, MA, USA
S Caspers
Institute of Neuroscience and Medicine (INM-1), Julich,
Germany
M Catani
NatBrainLab, Department of Forensic and
Neurodevelopmental Sciences, Institute of Psychiatry
PO50 Kings College London, London, United Kingdom
JL Chan
University of Western Ontario, London, ON, Canada
JT Coull
Aix-Marseille Universite & CNRS, Marseille Cedex 3,
France
O Coulon
Aix-Marseille Universite, Marseille, France
H Critchley
University of Sussex, Falmer, UK
E Borra
Universita` di Parma, Parma, Italy
JC Culham
University of Western Ontario, London, ON, Canada
AD (Bud) Craig
Barrow Neurological Institute, Phoenix, AZ, USA
KR Daffner
Harvard Medical School, Brigham and Womens
Hospital, Boston, MA, USA
A Butt
University of Portsmouth, Portsmouth, UK
C Butti
Icahn School of Medicine at Mount Sinai, New York, NY,
USA
DP Buxhoeveden
University of South Carolina, Columbia, SC, USA
G Dehaene-Lambertz
INSERM-CEA, Cognitive Neuroimaging Unit,
NeuroSpin, Gif-sur-Yvette, France; University Paris Sud,
Orsay, France
JFX DeSouza
York University, Toronto, ON, Canada
D Bzdok
Institut fur Neurowissenschaften und Medizin (INM-1),
Julich, Germany
AS Dick
Florida International University, Miami, FL, USA
K Caeyenberghs
University of Ghent, Ghent, Belgium
M DEsposito
University of California, Berkeley, CA, USA
vi
Contributors
J Dubois
INSERM-CEA, Cognitive NeuroImaging Unit,
NeuroSpin, Gif-sur-Yvette, France; University Paris Sud,
Orsay, France
R Egger
Max Planck Institute for Biological Cybernetics,
Tubingen, Germany
J Gooijers
KU Leuven, Leuven, Belgium
MSA Graziano
Princeton University, Princeton, NJ, USA
MT Herrero
University of Murcia, Murcia, Spain
T Egner
Duke University, Durham, NC, USA
G Hickok
University of California, Irvine, CA, USA
SB Eickhoff
Research Centre Julich, Julich, Germany; HHU
Dusseldorf, Dusseldorf, Germany; Institut fur
Neurowissenschaften und Medizin (INM-1),
Julich, Germany
AB Hillis
Johns Hopkins University School of Medicine, Baltimore,
MD, USA
C Estrada
University of Murcia, Murcia, Spain
PR Hof
Icahn School of Medicine at Mount Sinai, New York, NY,
USA
AC Evans
McGill University, Montreal, QC, Canada
CF Horton
University of California, San Diego, La Jolla, CA, USA
HC Evrard
Center for Integrative Neuroscience and Max Planck
Institute for Biological Cybernetics, Tubingen, Germany
AC Huk
The University of Texas, Austin, TX, USA
L Fadiga
University of Ferrara, Ferrara, Italy; Istituto Italiano di
Tecnologia; Genova, Italy
MA Farmer
Northwestern University, Chicago, IL, USA
D Feldmeyer
Institute of Neuroscience and Medicine, Research Center
Julich, Julich, Germany; RWTH Aachen University,
Aachen, Germany; Julich-Aachen Research Alliance,
Translational Brain Medicine (JARA Brain), Aachen,
Germany
A Flinker
New York University, New York, USA
S Francis
University of Nottingham, Nottingham, UK
I Gauthier
Vanderbilt University, Nashville, TN, USA
M Gerbella
Universita` di Parma, Parma, Italy
R Insausti
University Castilla La Mancha, Albacete, Spain
SJ Joo
The University of Texas, Austin, TX, USA
M Judas
University of Zagreb Croatian Institute for Brain
Research, Zagreb, Croatia; University of Zagreb, Zagreb,
Croatia
JH Kaas
Vanderbilt University, Nashville, TN, USA
RT Knight
University of California, Berkeley, CA, USA
I Kostovic
University of Zagreb Croatian Institute for Brain
Research, Zagreb, Croatia; University of Zagreb, Zagreb,
Croatia
Z Kourtzi
University of Cambridge, Cambridge, UK
CR Gillebert
University of Leuven, Leuven, Belgium; University of
Oxford, Oxford, UK
ML Kringelbach
Aarhus University, Aarhus, Denmark; University of
Oxford, Oxford, UK
R Goebel
Maastricht University, Maastricht, The Netherlands
A Kucyi
University of Toronto, Toronto, ON, Canada
J Goni
Indiana University, Bloomington, IN, USA
KS LaBar
Duke University, Durham, NC, USA
Contributors
C Lopez
Centre National de la Recherche Scientifique (CNRS),
Marseille, France; Aix Marseille Universite, Marseille,
France
JHR Lubke
Institute of Neuroscience and Medicine INM-2, Julich,
Germany; Rheinisch-Westfalische Technische
Hochschule/University Hospital Aachen, Aachen,
Germany; Julich-Aachen Research Alliance Translational
Brain Medicine, Aachen, Germany
G Luppino
Universita` di Parma, Parma, Italy
J-F Mangin
CEA Saclay, Gif-sur-Yvette, France
W Matchin
University of California, Irvine, CA, USA
MM McCarthy
University of Maryland School of Medicine, Baltimore,
MD, USA
V Menon
Stanford University School of Medicine, Stanford, CA,
USA
H Mohlberg
Institute of Neuroscience and Medicine (INM-1), Julich,
Germany; JARA Julich-Aachen Research Alliance,
Aachen, Germany
VI Muller
Research Centre Julich, Julich, Germany; HHU
Dusseldorf, Dusseldorf, Germany
S Nasr
Martinos Center for Biomedical Imaging, Charlestown,
MA, USA; Harvard Medical School, Boston, MA, USA
DE Nee
University of California, Berkeley, CA, USA
M Noda
Kyushu University, Fukuoka, Japan
M Oberlaender
Max Planck Institute for Biological Cybernetics,
Tubingen, Germany; Bernstein Center for Computational
Neuroscience, Tubingen, Germany
N Palomero-Gallagher
Institute of Neuroscience and Medicine (INM-1), Julich,
Germany; JARA Julich-Aachen Research Alliance,
Aachen, Germany
V Parpura
University of Alabama, Birmingham, AL, USA;
University of Rijeka, Rijeka, Croatia
vii
BN Pasley
University of California, Berkeley, CA, USA
M Petrides
McGill University, Montreal, Quebec, Canada
TC Pritchard
The Pennsylvania State University College of Medicine,
Hershey, PA, USA
L Puelles
University of Murcia, Murcia, Spain; Instituto Murciano
de Investigacion Biosanitaria [IMIB], Murcia, Spain
DS Race
Johns Hopkins University School of Medicine, Baltimore,
MD, USA
MA Raghanti
Kent State University, Kent, OH, USA
S Raj
Harvard Medical School, Brigham and Womens
Hospital, Boston, MA, USA
JP Rauschecker
Georgetown University Medical Center, Washington,
DC, USA
PJ Reber
Northwestern University, Evanston, IL, USA
J Regis
CHU La Timone, Marseille, France
D Rivie`re
CEA Saclay, Gif-sur-Yvette, France
G Rizzolatti
University of Parma, Parma, Italy
JJ Rodriguez
IKERBASQUE, Basque Foundation for Science, Bilbao,
Spain; University of the Basque Country UPV/EHU,
Leioa, Spain
A Rollenhagen
Institute of Neuroscience and Medicine, INM-2, Julich,
Germany
ET Rolls
Oxford Centre for Computational Neuroscience, Oxford,
UK
B Rossion
Universite catholique de Louvain, Louvain-la-Neuve,
Belgium
Y Roth
Edith Wolfson Medical Center, Holon, Israel
S Rozzi
Universita` di Parma, Parma, Italy
viii
Contributors
MR Sabuncu
Athinioula A. Martinos Center for Biomedical Imaging,
Charlestown, MA, USA
B Tia
University of Ferrara, Ferrara, Italy; Istituto Italiano di
Tecnologia; Genova, Italy
D Schluppeck
University of Nottingham, Nottingham, UK
R Tootell
Martinos Center for Biomedical Imaging, Charlestown,
MA, USA; Harvard Medical School, Boston, MA, USA
O Schmitt
University Medical Center Rostock, Rostock, Germany
W Schultz
University of Cambridge, Cambridge, UK
K Semendeferi
University of California, San Diego, La Jolla, CA, USA
J Sepulcre
Massachusetts General Hospital and Harvard Medical
School, Boston, MA, USA; Athinioula A. Martinos Center
for Biomedical Imaging, Charlestown, MA, USA
CC Sherwood
The George Washington University, Washington, DC,
USA
S Shushan
Weizmann Institute of Science, Rehovot, Israel; Edith
Wolfson Medical Center, Holon, Israel
HM Sigurdardottir
Brown University, Providence, RI, USA; University of
Iceland, Reykjavk, Iceland
SL Small
University of California, Irvine, CA, USA
N Sobel
Weizmann Institute of Science, Rehovot, Israel
LB Spurlock
Kent State University, Kent, OH, USA
JF Staiger
University Medicine Gottingen, Gottingen, Germany
F Sultan
HIH for Clinical Brain Research, Tuebingen, Germany
ZY Sun
CEA Saclay, Gif-sur-Yvette, France
SP Swinnen
Group Biomedical Sciences, KU Leuven, Belgium; KU
Leuven, Leuven, Belgium
HJ ten Donkelaar
Radboud University Nijmegen Medical Centre,
Nijmegen, The Netherlands
P Tetreault
Northwestern University, Chicago, IL, USA
J Ullmann
University of Queensland, Brisbane, Australia
N Uppal
Icahn School of Medicine at Mount Sinai, New York, NY,
USA
E Vachon-Presseau
Northwestern University, Chicago, IL, USA
TJ van Hartevelt
Aarhus University, Aarhus, Denmark; University of
Oxford, Oxford, UK
R Vandenberghe
University of Leuven, Leuven, Belgium; University
Hospitals Leuven, Leuven, Belgium
W Vanduffel
KU Leuven Medical School, Leuven, Belgium; Harvard
Medical School, Boston, MA, USA; Massachusetts
General Hospital, Charlestown, MA, USA
A Vania Apkarian
Northwestern University, Chicago, IL, USA
L Vasung
University of Zagreb, Zagreb, Croatia; University of
Geneva, Geneva, Switzerland
JH Venezia
University of California, Irvine, CA, USA
A Verkhratsky
The University of Manchester, Manchester, UK;
IKERBASQUE, Basque Foundation for Science, Bilbao,
Spain; University of the Basque Country UPV/EHU,
Leioa, Spain
R Viaro
University of Ferrara, Ferrara, Italy; Istituto Italiano di
Tecnologia; Genova, Italy
BA Vogt
Cingulum NeuroSciences Institute, Manlius, NY, USA;
Institute of Neuroscience and Medicine (INM-1), Julich,
Germany; Boston University School of Medicine, Boston,
MA, USA
C Watson
Curtin University, Perth, Australia; Neuroscience
Research Australia, Sydney, Australia
Contributors
ix
X Weng
Hangzhou Normal University, Hangzhou, China
L Zaborszky
The State University of New Jersey, Newark, NJ, USA
A Wree
University Medical Center Rostock, Rostock, Germany
Q Zhu
KU Leuven Medical School, Leuven, Belgium
X Xu
Idaho State University, Pocatello, ID, USA
K Zilles
Institute of Neuroscience and Medicine (INM-1), Julich,
Germany; JARA Julich-Aachen Research Alliance,
Aachen, Germany; RWTH University Aachen, Aachen,
Germany
D Yilmazer-Hanke
Creighton University, Omaha, NE, USA
xv
Editor-in-Chief
xvii
Section Editors
xix
Acknowledgments
xxiii
11
21
E Armstrong
27
MM McCarthy
37
Sulci as Landmarks
45
53
DP Buxhoeveden
Cell Types in the Cerebral Cortex: An Overview from the Rat Vibrissal Cortex
59
65
D Feldmeyer
69
JF Staiger
81
93
101
109
xi
xii
115
137
157
AC Evans
167
177
Functional Connectivity
187
203
211
L Puelles
Basal Ganglia
217
Thalamus: Anatomy
229
243
F Sultan
251
261
Motor Cortex
277
Somatosensory Cortex
283
JH Kaas
287
R Goebel
293
Auditory Cortex
299
JP Rauschecker
Vestibular Cortex
305
C Lopez
Gustatory System
313
TC Pritchard
317
S Caspers
325
BA Vogt
Amygdala
D Yilmazer-Hanke
341
xiii
347
357
HJ ten Donkelaar
367
377
HJ ten Donkelaar
Insular Cortex
387
395
411
417
M Petrides
423
INTRODUCTION TO SYSTEMS
439
441
449
V Menon
Neural Correlates of Motor Deficits in Young Patients with Traumatic Brain Injury
461
Visuomotor Integration
469
JC Culham
Bimanual Coordination
475
Oculomotor System
483
489
Motion Perception
507
511
Z Kourtzi
Face Perception
515
B Rossion
523
Visuospatial Attention
529
537
xiv
543
Somatosensory Processing
549
553
565
573
ET Rolls
581
T Egner
Working Memory
589
Salience Network
597
V Menon
613
Emotion
619
KS LaBar
Memory
625
PJ Reber
631
Autonomic Control
635
Reward
643
W Schultz
653
Speech Sounds
661
667
D Caplan
Naming
671
Action Understanding
677
G Rizzolatti
683
MSA Graziano
687
PREFACE
The contributions of brain mapping are self-evident. Perhaps only a few areas of science have been applied as
broadly and deeply as brain mapping. In less than 50 years, it has revolutionized the study of brain structure
and function as well as the practice of clinical neuroscience. The resulting images derived from brain mapping
studies can be found everywhere. They grace the covers of many scientific journals, and even permeate the lay
media. The arresting imagery derived from sophisticated brain mapping methodologies and applied to
previously intractable problems has transformed neuroscience like no other specialty.
Brain mapping is a field that encompasses a wide range of scientific areas from MR physics, molecular
dynamics, and the mathematical modeling of data to the anatomical and physiological measurement of brain
systems and the study of complex cognitive functions. These all have been applied to understand the human
condition in health and disease. Advances have led to new effective treatments in stroke and improved
therapeutic intervention in many diseases affecting the brain. New approaches have enabled measures that
differentiate us as individuals anatomically and functionally. Maps that represent whole populations of people
of a certain age, gender, handedness, suffering from a particular neurological or psychiatric condition or even
genetic cohorts with a particular single nucleotide polymorphism can be created. The utility of these maps as
biomarkers or as guides in clinical trials has become a reality. Brain mapping is as vibrant and dynamic as ever
and increasingly links to other paths of discovery including genetics, proteomics, biologics, and big data.
The creation of this encyclopedia comes at a time that acknowledges the spectacular growth and important
contributions already made and the promise for ever more exciting and significant discoveries. It was just about
20 years ago that the first of the Brain Mapping Trilogy was published with the title, Brain Mapping: The Methods.
At about the same time, a group of brain imaging scientists decided it would be a good idea to form a new
society and the Organization for Human Brain Mapping was born. There are now several journals devoted to
neuroimaging and brain mapping. Other periodicals focused on more general neuroscience invariably include
a considerable number of papers on brain mapping. For the last couple of decades the number of brain
mapping publications grew from around 3200 in 1996 to about 14 000 in 2013, more than a 400% increase!
What a remarkable 20 years it has been. No longer can the breadth of brain mapping be covered in a traditional
text book style. The field has grown just too large.
Given the fact that there are well over 100 000 published papers on brain mapping, an encyclopedic
reference system to navigate these numbers is sorely needed. The three volumes of this encyclopedia fill that
need and consist of a comprehensive collection of thoughtful and informative descriptions of each topic. Well
referenced and written by recognized authorities, each article provides a wealth of information for the novice
and expert alike.
We organized the encyclopedia into seven sections. Volume 1 includes sections entitled Acquisition Methods
edited by Peter Bandettini and another entitled Methods and Modeling edited by Karl Friston and Paul Thompson. Acquisition Methods includes descriptions of magnetic resonance imaging (MRI), functional magnetic
resonance imaging (fMRI), magnetoencephalography (MEG), positron emission tomography (PET), and
near-infrared spectroscopy (NIRS). Most of the articles focus on variations in fMRI acquisition, given the
range and extent of this brain imaging method. However, it is clear that other approaches covered in this section
have lots to offer in the study of brain, each with its own advantages and disadvantages and each method has its
limitations, no one is a panacea. All are highly complementary and benefit from the synergy of multimodal
integration described further in Methods and Modeling. Here, Friston and Thompson selected papers describing advances in analytics built upon novel mathematics for representing and modeling signals, detecting
patterns, and understanding causal effects. These have accelerated the contributions of imaging and brain
xv
xvi
Preface
mapping significantly. Creative applications of random fields to dynamic causal models, graph theory,
networks, and topological measures of connectomes, to chart connections inferred from functional synchrony
or anatomical circuitry. Continuum mechanics fluid flow, differential geometry, and relativity all have been
used to model and manipulate anatomical surfaces in the brain, and to align and compare observations from
whole populations.
Volume 2 includes a section on Anatomy and Physiology edited by Karl Zilles and Katrin Amunts and another
devoted to Systems edited by Marsel Mesulam and Sabine Kastner. In the Anatomy and Physiology section, the
functional, cellular, and molecular basics along with organizational principles of brain structure provide a solid
foundation for models and simulations. This section goes on to provide an overview of brain development
beginning with the evolution of the cerebral cortex as well as embryonic and fetal development of the human
brain. Finally, the last part of this section is dedicated to different brain regions with emphasis focused on
functional systems and a superb lead into Systems. The section on Systems edited by Mesulam and Kastner is
comprised of articles that address the functional anatomy of action, perception, and cognition in multiple
modalities and domains.
Volume 3 contains sections on Cognitive Neuroscience edited by Russ Poldrack and another focused on Social
Cognitive Neuroscience edited by Matthew Lieberman and a third covering Clinical Brain Mapping edited by
Richard Frackowiak. The section on Cognitive Neuroscience covers a broad range of topics on mapping cognitive
functions including attention, learning and memory, decision making, executive function, and language. There
are articles on neuroeconomics, a field that combines neuroscience, psychology, and economics to better
understand the neural mechanisms for decision making. There is also a series of papers on memory, including
episodic memory, familiarity, semantic memory, and nondeclarative forms of learning. Language is covered in
this section as well, with articles on speech perception and production, syntax, semantics, and reading.
Poldrack also included studies of unique populations such as sign language speakers, bilinguals, and individuals with reading disabilities.
The section on Social Cognitive Neuroscience deals with how our brain responds to our social world. There are
papers that chart the different ways in which people respond to the rewards and punishments of social living
such as perceptions of unfair treatment, social rejection, or other negative social influences. There are also
articles describing neural mechanisms for reward and incentive motivation that respond to reinforcers like
money or sexual cues. Another part of this section deals with the concept of self. And another explores the
basic mechanisms of social perception. These articles focus on the perception of faces, bodies, and emotions as
basic cues. Also included are articles about social thinking and attitudinal and evaluative processes that keep
track of what matters to us and who or what we align ourselves with or against. Clinical Brain Mapping provides
numerous examples of the translational value of brain mapping. For example, the time course and cascade of
stroke pathophysiology pointed to the need for hyperacute treatment with thrombolytics. The contribution of
functional imaging first with PET and subsequently with fMRI, forever altered clinical neurology, neurosurgery
and other clinical neuroscience specialties. The ability to perform scans repetitively gave insights into functional
dynamics in the human brain enabling investigations of neurodegenerative disease, psychiatric disorders, and
the efficacy of therapeutic intervention.
Each of these sections stands alone as a comprehensive collection of articles describing the how, why, and
what brain mapping has contributed to these areas. Each article introduces the topic and brings the reader up to
date with the latest in findings and developments. We deliberately structured the encyclopedia so that readers
can peruse the material in any order or concentrate on a particular set of topics from methods to applications.
We kept the articles concise and suggest further reading to those who desire a more extensive review. They are
well referenced and illustrated appropriately.
Together these articles comprise a unique and rich resource for anyone interested in the science of mapping
the brain.
Arthur W. Toga
EDITOR-IN-CHIEF
Arthur W. Toga is the director, Laboratory of Neuro Imaging; director, Institute
of Neuroimaging and Informatics; provost professor, Departments of Ophthalmology, Neurology, Psychiatry, and the Behavioral Sciences, Radiology
and Engineering at the Keck School of Medicine of USC. His research is focused
on neuroimaging, informatics, mapping brain structure and function, and
brain atlasing. He has developed multimodal imaging and data aggregation
strategies and applied them in a variety of neurological diseases and psychiatric
disorders. His work in informatics includes the development and implementation of some of the largest and most widely used databases and data mining
tools linking disparate data from genetics, imaging, clinical and behavior,
supporting global efforts in Alzheimers disease, Huntingtons, and Parkinsons
disease. He was trained in neuroscience and computer science and has written
more than 1000 papers, chapters, and abstracts, including eight books. Recruited to USC in 2013, he directs the
Laboratory of Neuro Imaging. This 110-member laboratory includes graduate students from computer science,
biostatistics, and neuroscience. It is funded with grants from the National Institutes of Health grants as well as
industry partners. He has received numerous awards and honors in computer science, graphics, and neuroscience. Prior to coming to USC he was a distinguished professor of Neurology at UCLA, held the Geffen Chair of
Informatics at the David Geffen School of Medicine at UCLA, associate director of the UCLA Brain Mapping
Division within the Neuropsychiatric Institute, and associate dean, David Geffen School of Medicine at UCLA.
He is the founding editor-in-chief of the journal NeuroImage and holds the chairmanship of numerous
committees within NIH and a variety of international task forces.
xvii
SECTION EDITORS
Peter A. Bandettini is chief of the section on Functional Imaging Methods and
director of the Functional MRI Core Facility at the National Institutes of
Health. He is also editor-in-chief of the journal NeuroImage. He received his
BS from Marquette University in 1989 and his PhD from the Medical College
of Wisconsin in 1994, where he pioneered the development of magnetic
resonance imaging of human brain function using blood oxygenation contrast.
During his postdoctoral fellowship at the Massachusetts General Hospital with
Bruce Rosen, he continued his investigation of methods to increase the interpretability, resolution, and applicability of functional MRI techniques. In
1999, he joined NIMH as an investigator in the Laboratory of Brain and
Cognition and as the director of the NIH Functional MRI Core Facility. In
2001, he was awarded the Scientific Directors Merit Award for his efforts in
establishing the NIH FMRI Core Facility. In 2002, he was conferred the Wiley
Young Investigators Award at the Annual Organization for Human Brain
Mapping meeting. His section on Functional Imaging Methods is currently
developing MRI methods to improve the spatial resolution, temporal resolution, sensitivity, interpretability, and applications of functional MRI. Recently,
his research has focused specifically on improving general methodology for
fMRI applications at 3 and 7 T, investigation of fMRI-based functional connectivity methodology and applications, and investigation of fMRI decoding
methodology and applications. He has published over 120 papers and 20
book chapters and has given over 300 invited presentations. Recently, his
paper Time course EPI of Human Brain Function during Task Activation was
honored by the journal, Magnetic Resonance in Medicine, as one of their 30
papers in the past 30 years that helped shape the field.
Marsel Mesulam is director of Cognitive Neurology and Alzheimers Disease
Center, Northwestern University. He has completed his MD in medicine from
Harvard Medical School in 1972, received his postdoctoral fellow ship from
Harvard University in 1977. He was conferred with Bengt Winblad Lifetime
Achievement Award from Alzheimers Association in 2010 and Lishman Lectureship Award from International Neuropsychiatric Association. His research
interests are neural networks, functional imaging, dementia, cerebral cortex,
and cholinergic pathways. Also he has received Distinguished Career Contribution Award from the Cognitive Neuroscience Society and the Potamkin Prize
from the American Academy of Neurology.
xix
xx
Section Editors
Sabine Kastner is professor at the Princeton Neuroscience Institute and Department of Psychology, Princeton University, Princeton, NJ. She has received her
M.D. from the University of Dusseldorf (Germany) in 1993 and her Ph.D from
the University of Gottingen (Germany) in 1994, and did postdoctoral training at
NIMH. She was conferred with Young Investigator award from the Cognitive
Neuroscience Society (2005), the John Mclean, Jr., Presidential University
Preceptorship from Princeton University (2003), and is a fellow of the American
Psychological Society. Her research interests include the neural basis of visual
perception, attention and awareness, studied in two primate brain models
(monkey and human) with functional brain imaging and electrophysiology.
Richard Frackowiak studied medicine at the University of Cambridge where he
first became interested in the neurosciences. He joined the Medical Research
Councils Cyclotron Unit at Hammersmith Hospital, London, in 1979, under
Professor Terry Jones, who had just installed one of Britains first Positron Emission Tomography (PET) scanners. Richard Frackowiak is director at Department of
Clinical Neuroscience and Head of Service of Neurology, CHUV University Hospital, Lausanne, Switzerland. Frackowiak has won the IPSEN and Wilhelm Feldberg prizes and during the 1990s was the fourth most highly cited British
biomedical scientist. His books include Human Brain Function and Brain Mapping:
The Disorders. He is currently setting up a new Clinical Neuroscience Department
at the University of Lausanne. His research interest has been the functional and
structural architecture of the human brain in health and disease. He has pioneered
the development and introduction of positron emission tomography and magnetic resonance imaging and prosecuted a research programme dedicated to
understanding the organization of human brain functions, but his focus has
been on plasticity and mechanisms for functional recuperation after brain injury
and the patho-physiology of cerebral neurodegenerations. He has become interested in the use of MR-based morphometry especially in the study of genetic
influences on brain disease and in a search for biomarkers and endophenotypes
of neurodegenerative disorders. Most recently he has introduced computerized
image classification for diagnosis and treatment monitoring into clinical science.
Matthew Lieberman received his PhD from Harvard University. Lieberman,
with Kevin Ochsner, coined the term Social Cognitive Neuroscience, an area of
research that integrates questions from the social sciences which the methods
of cognitive neuroscience and has become a thriving area of research.
Lieberman has been a professor at UCLA in the Departments of Psychology,
Psychiatry and Biobehavioral Sciences since 2000. His work uses functional
magnetic resonance imaging (fMRI) to examine the neural bases of social
cognition and social experience. In particular, his work has examined the
neural bases of social cognition, emotion regulation, persuasion, social rejection, self-knowledge, and fairness. His research has been published in top
scientific journals including Science, American Psychologist, and Psychological
Science. His research has been funded by grants from the National Institute of
Mental Health, National Science Foundation, Guggenheim Foundation, and
Defense Advanced Research Projects Agency. His work has received coverage by
HBO, The New York Times, Time magazine, Scientific American, and Discover
Magazine. Lieberman is also the founding editor of the journal Social Cognitive
and Affective Neuroscience and helped create the Social and Affective Neuroscience
Society. Lieberman won the APA Distinguished Scientific Award for Early
Career Contribution to Psychology (2007) and campus wide teaching awards
from both Harvard and UCLA. He is the author of the book Social: Why Our
Brains Are Wired to Connect (finalist for the LA Times Book Prize and winner of
the Society for Personality and Social Psychology Book Prize).
Section Editors
xxi
Karl Zilles, MD, PhD, graduated from the University of Frankfurt, medical
faculty, and received the MD (1971) and the PhD (1977) in anatomy from the
Hannover Medical School, Germany. He was full professor of anatomy and
neuroanatomy at the University of Cologne between 1981 and 1991 and at
the University of Dusseldorf between 1991 and 2012. Additionally, he was
director of the C. & O. Vogt-Brain Research Institute, Dusseldorf, from 1991 to
2012, and of the Institute of Neuroscience and Medicine, Research Center Julich,
Germany, from 1998 to 2012. He is currently JARA senior professor at the
Research Center Julich and at the RWTH Aachen University, Germany. He serves
as editor-in-chief of the journal Brain Structure and Function and was member of
editorial boards of various scientific journals (e.g., NeuroImage). Karl Zilles is
fellow of the German National Academy of Sciences Leopoldina and fellow of
the North-Rhine Westphalia Academy of Science and Arts. His research focus is
on the structural (cyto- and myeloarchitecture), molecular (receptor architecture), and functional (neuroimaging using MRI, fMRI, and PET) organization of
the mouse, rat, nonhuman primate, and human cerebral cortex. He pioneered
brain mapping based on the regional and laminar distribution of transmitter
receptors in the healthy and pathologically impaired human brains and brains
of genetic mouse and models. He recently introduced, together with Katrin
Amunts, Markus Axer, and colleagues, an ultra-high-resolution method for
nerve fiber and fiber tract visualization based on polarized light imaging in the
human, monkey, mouse, and rat brains. He published more than 590 original
articles in nature, science, neuron, brain, and other peer-reviewed journals.
Katrin Amunts, MD, PhD, graduated in 1987 from the Pirogov Medical School
in Moscow, Russia. She received the PhD (1989) in neuroscience, anatomy from
the Institute of Brain Research at the Lumumba University in Moscow, Russia.
After her postdoc at the C. & O. Vogt Institute for Brain Research of the HeinrichHeine-University Dusseldorf, Germany, and at the Institute of Neuroscience and
Medicine, Research Center Julich, she became associate professor for StructuralFunctional Brain Mapping (2004), and full professor at the Department of
Psychiatry, Psychotherapy, and Psychosomatics of the RWTH Aachen University
(2008) as well as director of the Institute of Neuroscience and Medicine (INM-1)
at the Research Centre Julich. Since 2013, she is additionally full professor for
Brain Research and director of the C. & O. Vogt Institute for Brain Research, at the
Heinrich-Heine-University Dusseldorf. She is a member of the editorial board of
Brain Structure and Function. Currently, she is member of the German Ethics
Council and speaker for the programme Decoding the Human Brain of the
Helmholtz Association, Germany. Katrin Amunts is interested in understanding
the relationship between the microstructure of the human brain and functional
systems such as motor control, language, and vision. Although scientists have
been studying brain cytoarchitecture for over 100 years, its importance has
increased rapidly with the advance of modern imaging techniques. This led,
together with Karl Zilles and his team, to the development of a novel, observerindependent and functionally relevant cytoarchitectonic mapping strategy resulting in freely available brain maps comprising approximately 200 areas and
nuclei, as well as the anatomy toolbox software, developed with Simon Eickhoff,
for co-localizing functional activations and cytoarchitectonically defined brain
regions. The Julich atlas JuBrain as a multimodal human brain model will replace
during the next decade the cytoarchitectonic brain atlas, which Korbinian Brodmann published in 1909 (Zilles and Amunts, Nature Reviews Neuroscience,
2010). Recently, the group has provided the first ultra-high resolution model of
the human brain, the BigBrain (Amunts et al., Science, 2013).
xxii
Section Editors
ACKNOWLEDGMENTS
Sometimes, the scope and structure of a book is clear from the outset, other times it evolves as the outlines are
written or because contributors with different perspectives suggest new and different things. This book
occasionally took on a life of its own, morphing into something greater than the original concept. But that
was because of the hundreds (literally) of people who contributed to it. Working independently and together
we created a one-of-a-kind collection of excellent articles on brain mapping, from data generation to knowledge
about the brain. This collaborative effort is one of the greatest joys in working on project of this magnitude. The
end result is a mix of all this expertise into a single product. While such a process could easily produce chaos, in
this case each editor had a clear vision that complemented the other sections of the book. Each contributor
produced a superb article and collectively they cover the field.
One of the most difficult aspects of this project was limiting the scope because its magnitude kept getting
larger the more we all talked about it. There are so many new areas within brain mapping. There are so many
creative ways to apply the ever increasing number of methods to study the structure and function of brain in
health and disease. This scope further motivated us to create an encyclopedia because the field was not only
ready for such a thing, it needed it.
Many of us who worked on this book have known each other for a long time. Others of you are new
acquaintances, but to each of you I owe my sincerest gratitude. You are among the best and brightest minds in
neuroscience and your participation made this book. Your research and writing will be appreciated by the
readers for many years to come.
In addition to all the contributors writing and editing chapters and sections there are many others who
deserve mention. At the Laboratory of Neuro Imaging at the University of Southern California I am privileged
to have a spectacular staff. Grace Liang-Franco manages the lab with an efficiency and deftness that defies limits.
Sandy, Diana, and Catalina all keep things moving smoothly and professionally so I can work on projects like
this encyclopedia. Thanks to you all. The team at Elsevier has been terrific. They have tolerated the fits and starts
associated with a project like this and helped usher into the world an important and substantial work. Thanks
to Mica Haley, Ashlie Jackman, Will Bowden-Green, Erin Hill-Parks, and many others.
Finally, I always express gratitude to my family. They do not help me write or edit or even read the things I
write but somehow they make it possible. I work at home in the evenings and on weekends, just like many of
you reading this book. I guess I could be doing other things but my family tolerates this behavior and has for
decades. Perhaps they are happy I am preoccupied with academic pursuits. It keeps me busy and out of their
hair. But for whatever the real reason, my wife Debbie, and my children Nicholas, Elizabeth, and Rebecca let me
work on these things and I appreciate them more than can be stated here.
Arthur W. Toga
Los Angeles, CA
xxiii
With the advent of structural and functional imaging, additional research fields were opened for neurophysiology and particularly neuroanatomy as basic sciences in brain mapping, since solid knowledge of the
underlying structure and function is required for the meaningful interpretation of structural MRI, activation
spots in fMRI, resting-state networks, modeled fiber tracts of diffusion-weighted imaging, and functional
connectivity models. This need has recently become even more acute because the development of highresolution neuroimaging and the modeling and simulation approaches encroach more and more onto the
interface between mesoscopic and microscopic scales. Therefore, detailed data of the functional, cellular, and
molecular basics are necessary to provide solid foundations for models and simulations. We did not intend to
provide a short version of a traditional neuroanatomy textbook, and this section cannot give a comprehensive
review of all necessary details, but aims to build an introduction into the organizational principles of brain
structure.
The first articles in this section provide an overview of brain development beginning with the evolution of
the cerebral cortex and the underlying scaling rules. Variation in cortical microstructure indicates cognitively
significant evolutionary shifts rather than large-scale changes in size (Semendeferi and Horton, Evolution of
the Cerebral Cortex). This is supported by the fact that anthropoids differ from other eutherians in gaining
less mass for every unit increase in isocortical neuron numbers, which probably reflects a relative increase in
the number of interneurons (Armstrong, Quantitative Data and Scaling Rules of the Cerebral Cortex). The
following articles summarize principal aspects of brain morphology. Sex differences in the brain and
the cellular mechanisms of how they are established during development are described (McCarthy, Brain
Sex Differences). Gyrification is a major morphological hallmark of the human cerebral cortex. A detailed
anatomical identification of the sulci and gyri of the probably most frequently used reference brain in
neuroimaging is provided, and two major hypotheses of gyrification mechanisms are discussed (Zilles and
Palomero-Gallagher, Gyrification in the Human Brain). Since sulci are frequently used as landmarks for
anatomical localization of functional neuroimaging data, new computational methods have been designed to
support those activities for improving the role of sulci as landmarks, including models of intersubject variability
of the shape of the sulci (Mangin et al., Sulci as Landmarks). Cortical morphometric methods enable crosssectional and longitudinal studies of large sample sizes of both healthy human subjects and patients. Cortical
thickness, surface and volume are frequently used to analyze anatomical changes. A description of recent
developments and caveats is provided here (Evans, Cortical Surface Morphometry).
The second part of this section deals with the embryonic and fetal development of the human brain. An
obvious feature of the developing human cerebral cortex is the prolonged coexistence of transient fetal and
adultlike circuitry. This enables a considerable plasticity during ontogeny and its surprising reorganization
capacity during brain evolution (Kostovic and Judas, Embryonic and Fetal Development of the Human
Cerebral Cortex). The development of the human cerebral cortex can now be analyzed in-vivo using MRI,
and the impact of the relationships between MRI markers, genetic and environmental factors, and cognitive
development can be studied (Dubois and Dehaene-Lambertz, Fetal and Postnatal Development of
the Cortex: MRI and Genetics). These articles are followed by descriptions of the development of the
basal ganglia and the basal forebrain (ten Donkelaar, Development of the Basal Ganglia and the Basal
Forebrain), the diencephalon (ten Donkelaar and Vasung, Development of the Diencephalon), and the
brain stem and the cerebellum (ten Donkelaar, Development of the Brainstem and the Cerebellum). The
developmental part is concluded by an article on the maturation of structural and functional connectivity,
which starts during the early fetal period and extends until the end of adolescence (Dubois, Kostovic and
Judas, Development of Structural and Functional Connectivity).
A series of articles focus on cell types in the cerebral cortex. The major goal of cell-typing is to understand
functional principles of cortical organization. Some general aspects of somatodendritic cell type classification
are described and how they relate to cell type-specific computations is discussed (Egger and Oberlaender, Cell
Types in the Cerebral Cortex: An Overview from the Rat Whisker System). Since the pyramidal cells are the
most frequent neurons in the cerebral cortex, the correlation between their considerable diversity in function
and structure is important. The enhancement of synaptic response to prior activity enabled by the somatodendritic, axonal, and synaptic organization of these neurons may constitute a mechanism for learning and
memory (Feldmeyer, Functional and Structural Diversity of Pyramidal Neurons). Cortical GABAergic neurons are key players in the organization of intracortical microcircuits. They show a large variety of different cell
types, with differential distribution patterns throughout cortical layers and target specificities. Six of these
GABAergic interneurons are presented here (Staiger, Cortical GABAergic Neurons). The von Economo neurons, which were already described at the beginning of the twentieth century but never analyzed in more detail,
recently raised attention, because of their significance in brain evolution and neurological and psychiatric
illnesses. Their morphology, distribution in the brain, and functional role are described here (Raghanti et al.,
Von Economo Neurons). The elucidation of the synaptic organization in the cerebral cortex is still a work in
progress because of the incredible complexity of synaptic varieties and their involvement in connectivity
(Rollenhagen and Lubke, Synaptic Organization of the Cerebral Cortex). The neurons of the cerebral cortex
are distributed in horizontal (layers) and vertical (columns) structures. The columns can be interpreted as
cortical modules, which are not uniform in composition, but are highly complex and show variations of the
basic columnar concept (Buxhoeveden, Columns of the Mammalian Cortex). The glial cells were interpreted
for a long time as being mere scaffolding elements. This concept is no longer sustainable as shown in the two
articles on the variety of the morphology and functions of macroglial cells and microglia (Verkhratsky et al.,
Astrocytes, Oligodendrocytes and NG2-Cells: Structure and Function; Verkhratsky, Noda, Parpura, Microglia: Structure and Function). Macroglial cells express neurotransmitters and can influence local and remote
neural activity via metabolic and/or signaling pathways. Microglial cells differ from macroglial cells by their
origin from the mesoderm and play various roles during physiological, defensive, and pathological processes
including antigen presentation, phagocytosis, and cytotoxicity.
Brain maps are crucial for the interpretation of the anatomical localization of neuroimaging data. The
pioneering cytoarchitectonic observations of Brodmann are of major importance in this respect; however, the
imaging community unfortunately uses in most cases only his schematic 2-D drawings or the 3-D interpretation
by Talairach and Tournoux. The underlying descriptions by Brodmann and, particularly, the vast cyto- and
myeloarchitectonic literature of the Vogt and von Economo schools published since his pioneering monography
are often neglected or completely forgotten. Brodmanns schematic drawing alone does not provide a sufficient
basis for localization and understanding of the anatomical organization behind the functional imaging data!
Therefore, we have included six articles that describe the often forgotten or recently developed maps of the
human cerebral cortex (Zilles et al., Cytoarchitecture and Maps of the Human Cerebral Cortex), myeloarchitecture (Zilles, Palomero-Gallagher and Amunts, Myeloarchitecture of the Human Cerebral Cortex), receptor
architecture (Palomero-Gallagher, Amunts and Zilles, Transmitter Receptor Distribution in the Human
Brain), and genoarchitecture (Puelles, Genoarchitectonic brain maps). Furthermore, advantages and drawbacks
of different approaches to functional connectivity (Eickhoff and Muller, Functional Connectivity) and the
physiology of the cerebral cortex based on resting-state signal, connectivity, and networks as well as the
dimensions of metabolism (Bzdok and Eickhoff, The Resting-State Physiology of the Human Cerebral Cortex)
are also described.
The last part of this section is dedicated to different brain regions with emphasis on functional systems. It
starts with a article on the brain stem in light of recent gene expression and inducible genetic fate mapping
(Watson and Ullmann, The Brainstem), followed by an article on the anatomy and physiology of the
cerebellum based on connectivity mapping and the cerebellar microcircuitry as well as comparative anatomical
considerations (Sultan, Cerebellum: Anatomy and Physiology). After descriptions of the anatomy, connectivity and function of the basal ganglia (Wree, Basal Ganglia), amygdala (Yilmazer-Hanke, Amygdala), and the
magnocellular structures of the basal forebrain (Zaborszky et al., Basal Forebrain Anatomical Systems in MRI
Space), presentations of various cortical sensory (van Hartevelt and Kringelbach, The Olfactory Cortex; Kaas,
Somatosensory Cortex; Goebel, Functional Organization of the Primary Visual Cortex; Vanduffel and Zhu,
Topographic Layout of Monkey Extrastriate Visual Cortex; Rauschecker, Auditory Cortex; Lopez, Vestibular
Cortex; Pritchard, Gustatory System), motor (Borra et al., Motor Cortex), and higher multimodal systems
(Caspers, Posterior Parietal Cortex; Vogt, Mapping Cingulate Subregions; Evrard and Craig, Insular Cortex;
Fadiga, Tia and Viaro, Anatomy and Physiology of the Mirror Neuron System; Petrides, Lateral and Dorsomedial Prefrontal Cortex and the Control of Cognition; Amunts and Catani, Cytoarchitectonics, Receptorarchitectonics, and Network Topology of Language) conclude this section.
Karl Zilles
Katrin Amunts
Glossary
Derived trait Traits that are newly acquired and did not exist
in the last common ancestor.
Embryonic zone Neural regions present in the developing
embryo which contain progenitor cells and generate cortical
neurons.
GABA-ergic interneuron A neuron that modulates activity
of other neurons using GABA neurotransmitter; typically
inhibitory.
Gyral white matter White matter immediately under the
cortex.
Homoplasy Similar traits in different species that have
evolved independent of ancestral lineage.
Minicolumn Vertically oriented conglomerates of cells that
extend through layers II through VI of the cortex, and serve
http://dx.doi.org/10.1016/B978-0-12-397025-1.00192-5
II
III
Pyramidal cell
Local axon
collateral (local
circuitry)
IV
4
Other
cortical
areas
Thalum
V
Descending axon
(output)
VI
White
matter
(a)
Other cortical
areas, opposite
hemisphere
Subvertical
structures
(e.g., striatum
superior
colliculum)
(b)
Other
cortical
areas
Brainstem
modulatory
systems
(c)
Figure 1 (a) Figure depicting the cytoarchitectonic distinctions of the six layers of the cortex. (b) Figure depicting the input/output specializations of the
cortical layers. (c) Figure depicting the cortical areas (Brodmanns areas) in a human brain. Adapted from Purves, D. (2008). Neuroscience (4th ed.).
Sunderland, MA: Sinaur Associates, Inc. (Figure 26.2 A,B, p. 568; Figure 26.3, p. 269), with permission.
Layers
I
Vertical expansion
Layers
I, V, and VI
IIIII
IV
V
VI
(a)
(b)
domestic cat
E = 30 g; P = 3000 g
Endocast
Endocast
Brain
(a)
(b)
Figure 3 Endocast of a modern (a) and a fossil (b) mammalian brain. E brain weight, P body weight. Reproduced from Jerison, H. (1963).
Interpreting the evolution of the brain. Human Biology, 35(3), 263291, with permission.
Changes in Microanatomy
Changes in brain size had significant effect on neural reorganization in mammalian evolution. Larger brains have more
cortical surface area and more neurons than smaller brains,
but there is little difference in terms of neuronal body size or
axonal length (Bekkers & Stevens, 1970). Brain tissue is
extremely costly, so efficiency is critical with increasing brain
size. One such high cost is long axon lengths, which are both
spatially expensive and metabolically expensive (Swindale,
2001). In larger brains, there is a decrease in the ratio of
soma to axons and a necessary shift in cortical wiring (Zhang
& Sejnowski, 2000), suggesting that network organization may
be different in the scaling of large and small brains. One
reorganizational consequence is that as brain size increases,
each neuron is in contact with a smaller proportion of total
neurons. Therefore, larger brains necessitate more modular
organization through an increase in local processing, a
decrease in long-range connections including interhemispheric
connections through the corpus callosum, and an increase in
hemispheric independence (Kaas, 2000; Ringo, Doty, Demeter,
& Simard, 1994). This also results in larger brains having
relatively more white matter than the cortex in comparison to
smaller brains (Figure 5).
Comparisons across mammalian taxa show that brain size has
a positive correlation with number of cortical areas (Figure 6),
suggesting that size-necessitated modular organization results in
more distinct cortical regions, which may in turn allow more
flexible and refined processing. However, large brain size has a
cost: aside from energetic costs of generating and maintaining
an increasingly large brain (Leonard, Robertson, Snodgrass, &
Kuzawa, 2003), other restraints to brain size are infant head size,
which is constrained by the width of the birth canal (Leutenegger,
30.00
Neocortex (+16)
Striatum (+15)
Diencephalon (+13)
Cerebellum (+10)
20.00
Schizocortex (+10)
Hippocampus (+7)
Septum (+6.5)
Mesencephalon (+3)
10.00
Medulla (+0.5)
Paleocortex (-2)
0.00
4.00
6.05
8.10
10.15
12.20
14.25
Ln white matter
Primates
Carnivores
Others
2
0
-2
-4
-2
2
Ln gray matter
60
Rhesus
50
Number of areas
40
Owl monkey
Marmoset
30
Squirrel monkey
Cat
Galago
20
Squirrel
10
Various shrews, rat
0
0
2000
4000
6000
8000
10 000
12 000
Mouse
V
S
A
Ghost bat
S
S
m
A
r
1mm
across species and cortical regions. The total number of dendritic spines, that is, the number of synaptic inputs onto the
dendrites of a particularity neuron (DeFelipe & Farinas, 1992)
in different cortical regions of the primate cortex, varies significantly. For example, in humans and other primates, spine
density differences between cortical areas can vary by tenfold
(Elston, 2007). These differences have great functional significance and reflect differences in computational capability of a
neuron; for instance, differences in spine number reflect the
amount of excitatory inputs, and differences in length, number
of arborizations, and axonal thickness reflect profound physiological differences in synaptic connectivity (Spruston, 2008).
Species-specific chemical signatures of pyramidal neuron subtypes are another source of pyramidal variation (see Hof &
Sherwood, 2007).
Inhibitory GABAergic interneurons are the second major
class of neurons in the cortex and broadly function to regulate
pyramidal cell activity. Interneurons are difficult to classify
because subtypes are identified by numerous characteristics,
such as size, morphology, calcium-binding proteins (parvalbumin (PV), calbindin (CB), and calretinin (CR)), neuropeptide
content (Andressen, Blumcke, & Celio, 1993; Hendry et al.,
1989; Markram et al., 2004), and other protein expression. The
role of interneuron subtype distribution in cortical evolution is
equally unclear. For example, interneurons expressing the
enzyme tyrosine hydroxylase (TH) are very common in cortical
layers VVI and at the white matter boundary of humans
(Benavides-Piccione & DeFelipe, 2007) and are present in the
same layers of old-world monkeys (Benavides-Piccione &
DeFelipe, 2007; Kohler, Everitt, Pearson, & Goldstein, 1983;
Lewis, Foote, Goldstein, & Morrison, 1988; Raghanti et al.,
2009), but are not present in the great apes (Raghanti et al.,
2009) and have varying abundance and distribution in
nonprimates.
Comparisons of GABAergic interneuron distribution across
species may reflect shifts in cortical evolution. The primate
cortex has a significantly greater proportion of GABAergic
interneurons compared to rodents (Beaulieu, 1993; Beaulieu,
Kisvarday, Somogyi, Cynader, & Cowey, 1992; Hendry,
Schwark, Jones, & Yan, 1987; Meinecke & Peters, 1987). Evidence of different developmental origins of GABAergic interneurons in these mammalian groups (Letinic, Zoncu, & Rakic,
2002; Rakic & Zecevic, 2003) suggests there were a greater
number and a greater variety of newer types of GABAergic
interneurons in primate evolutionary history compared to
rodents or carnivores (DeFelipe, Alonso-Nanclares, & Arellano,
2002). The distribution of interneuron subtypes may also
reflect phylogenetic relationships. For example, the rarity of
PV-immunoreactive interneurons in cetaceans and artiodactyls
may be an ancestrally conserved trait for Laurasiatheria (placental mammals originating from Laurasia) because other laurasiatherians that have many ancestral features also have few
PV-immunoreactive interneurons (Glezer, Jacobs, & Morgane,
1988). Convergent evolution may also be reflected in interneuron subtype distribution. For instance, the calcium-binding
protein interneurons have similar type and distribution in
both Carnivora and Euarchontoglires (rodents, tree shrews,
primates, lagomorphs, and colugos), despite great phylogenetic distance (Ballesteros-Yanez et al., 2005; Glezer, Hof,
Leranth, & Morgane, 1993; Hof et al., 1999). While cell
References
Allman, J. M., Tetreault, N. A., Hakeem, A. Y., Manaye, K. F., Semendeferi, K.,
Erwin, J. M., et al. (2011). The von Economo neurons in the frontoinsular and
anterior cingulate cortex. Annals of the New York Academy of Sciences, 1225,
5971.
Andressen, C. I., Blumcke, I., & Celio, M. R. (1993). Calcium-binding proteins:
Selective markers of nerve cells. Cell and Tissue Research, 271, 181208.
Ballesteros-Yanez, I., Munoz, A., Contreras, J., Gonzalez, J., Rodriguez-Veiga, E., &
DeFelipe, J. (2005). The double bouquet cell in the human cerebral cortex and a
Karten, H. (1969). The organization of the avian telencephalon and some speculations
on the phylogeny of the amniote telencephalon. Annals of the New York Academy of
Sciences, 167, 164180.
Keeler, C. E. (1933). Absence of corpus callosum as mendelizing character in the house
mouse. Proceedings of the National Academy of Sciences of the United States of
America, 19(6), 609611.
Kohler, C., Everitt, B. J., Pearson, J., & Goldstein, M. (1983). Immunohistochemical
evidence for a new group of catecholamine-containing neurons in the basal
forebrain of the monkey. Neuroscience Letters, 37, 161166.
Krubitzer, L., & Kaas, J. H. (2005). The evolution of the neocortex in mammals:
How is phenotypic diversity generated? Current Opinion in Neurobiology, 15,
44453.
Krubitzer, L., & Kahn, D. M. (2003). Nature versus nurture revisited: An old idea with a
new twist. Progress in Neurobiology, 70(1), 3352.
Kwan, K. Y., Sestan, N., & Anton, E. S. (2012). Transcriptional co-regulation of
neuronal migration and laminar identity in the neocortex. Development, 139(9),
15351546.
Leonard, W. R., Robertson, M. L., Snodgrass, J., & Kuzawa, C. W. (2003). Metabolic
correlates of hominid brain evolution. Comparative Biochemistry and Physiology,
Part A: Molecular & Integrative Physiology, 136, 515.
Letinic, K., Zoncu, R., & Rakic, P. (2002). Origin of GABAergic neurons in the human
neocortex. Nature, 417, 645649.
Leutenegger, W. (1982). Encephalization and obstetrics in primates. In E. Armstrong, &
D. Falk (Eds.), Primate brain evolution: Methods and concepts (pp. 4396): New
York: Plenum.
Lewis, D. A., Foote, S. L., Goldstein, M., & Morrison, J. H. (1988). The dopaminergic
innervation of monkey prefrontal cortex: A tyrosine hydroxylase
immunohistochemical study. Brain Research, 449, 225243.
Markram, H., Toledo-Rodriguez, M., Wang, Y., Gupta, A., Silberberg, G., & Wu, C.
(2004). Interneurons of the neocortical inhibitory system. Nature Reviews.
Neuroscience, 5, 793807.
Meinecke, D. L., & Peters, A. (1987). GABA immunoreactive neurons in rat visual
cortex. Journal of Comparative Neurology, 261, 388404.
Mitchison, G. (1991). Neuronal branching patterns and the economy of cortical wiring.
Proceedings of the Royal Society of London B, 245, 151158.
Molnar, Z. (2011). Evolution of cerebral cortical development. Brain, Behavior and
Evolution, 78(1), 94107.
Purves, D. (2008). Neuroscience (4th ed.). Sunderland, MA: Sinaur Associates, Inc.
Raghanti, M. A., Spocter, M. A., Stimpson, C. D., Erwin, J. M., Bonar, C. J.,
Allman, J. M., et al. (2009). Species-specific distributions of tyrosine hydroxylaseimmunoreactive neurons in the prefrontal cortex of anthropoid primates.
Neuroscience, 158, 15511559.
Raghanti, M. A., Stimpson, C. D., Marcinkiewicz, J. L., Erwin, J. M., & Hof, P. R. (2008).
Cholinergic innervation of the frontal cortex: Differences among humans,
chimpanzees, and macaque monkeys. Journal of Comparative Neurology, 506,
409424.
Raghanti, M. A., Stimpson, C. D., Marcinkiewicz, J. L., Erwin, J. M., Hof, P. R., &
Sherwood, C. C. (2008a). Cortical dopaminergic innervation among humans,
chimpanzees, and macaque monkeys: A comparative study. Neuroscience, 155(1),
203220.
Raghanti, M. A., Stimpson, C. D., Marcinkiewicz, J. L., Erwin, J. M., Hof, P. R., &
Sherwood, C. C. (2008b). Differences in cortical serotonergic innervation among
humans, chimpanzees, and macaque monkeys: A comparative study. Cerebral
Cortex, 18(3), 584597.
Rakic, P. (1990). Critical cellular events in cortical evolution: Radial unit hypothesis. In
B. L. Finlay, G. Innocenti, & H. Scheich (Eds.), The neocortex: Ontogeny and
phylogeny (pp. 2132): Plenum.
Rakic, P. (2009). Evolution of the neocortex: A perspective from developmental biology.
Nature Reviews. Neuroscience, 2009, 724735.
Rakic, S., & Zecevic, N. (2003). Emerging complexity of layer I in human cerebral
cortex. Cerebral Cortex, 13, 10721083.
Ringo, J. L., Doty, R. W., Demeter, S., & Simard, P. Y. (1994). Time is of the essence: A
conjecture that hemispheric specialization arises from interhemispheric conduction
delay. Cerebral Cortex, 4, 331343.
Rockel, A. J., Hiorns, R. W., & Powell, T. P. (1980). The basic uniformity in structure of
the neocortex. Brain, 103, 221244.
Schenker, N. M., Buxhoeveden, D. P., Blackmon, W. L., Amunts, K., Zilles, K., &
Semendeferi, K. (2008). A comparative quantitative analysis of cytoarchitecture and
minicolumnar organization in Brocas area in humans and great apes. The Journal of
Comparative Neurology, 510(1), 117128.
Schenker, N. M., Desgouttes, A. M., & Semendeferi, K. (2005). Neural connectivity and
cortical substrates of cognition in hominoids. Journal of Human Evolution, 49(5),
547569.
10
Schenker, N. M., Hopkins, W. D., Spocter, M. A., Garrison, A. R., Stimpson, C. D.,
Erwin, J. M., et al. (2010). Brocas area homologue in chimpanzees (Pan
troglodytes): probabilistic mapping, asymmetry, and comparison to humans.
Cerebral Cortex, 20(3), 730742.
Semendeferi, K., Armstrong, E., Schleicher, A., Zilles, K., & Van Hoesen, G. W. (1998).
Limbic frontal cortex in hominoids: A comparative study of area 13. American
Journal of Physical Anthropology, 106(2), 129155.
Semendeferi, K., Armstrong, E., Schleicher, A., Zilles, K., & Van Hoesen, G. W. (2001).
Prefrontal cortex in humans and apes: A comparative study of area 10. American
Journal of Physical Anthropology, 114(3), 224241.
Semendeferi, K., Damasio, H., Frank, R., & Van Hoesen, G. W. (1997). The evolution of
the frontal lobes: A volumetric analysis based on three-dimensional reconstructions
of magnetic resonance scans of human and ape brains. Journal of Human Evolution,
32, 375388.
Semendeferi, K., Lu, A., Schenker, N., & Damasio, H. (2002). Humans and great apes
share a large frontal cortex. Nature Neuroscience, 5(3), 272276.
Semendeferi, K., Teffer, K., Buxhoeveden, D. P., Park, M. S., Bludau, S., Amunts, K.,
et al. (2011). Spatial organization of neurons in the frontal pole sets humans apart
from great apes. Cerebral Cortex, 21(7), 14851497.
Sherwood, C. C., Stimpson, C. D., Raghanti, R. A., Wildman, D. E., Uddin, M.,
Grossman, L. I., et al. (2006). Evolution of increased glia-neuron ratios in the
Glossary
Nomenclature
DTI
GA
MRI
Introduction
PTA
STS
T1w/T2w images
w GA
Post-term age
Superior temporal sulcus
T1-/T2-weighted images
Weeks of gestational age
Cortical Growth
Because contrasts in T1w and T2w images evolve with maturation (Dubois et al., 2014), the comparison of cortical volume
across ages (Figure 2(a)) should remain cautious. In utero, the
volume of the cortical plate increases from around 10 ml at
21w GA to 70 ml at 31w GA (Scott et al., 2011), and developmental rates differ among brain regions, with higher volume
increases in the parietal and occipital regions than in the
frontal lobe (Rajagopalan et al., 2011). In preterm newborns,
the volume increases from around 25 ml at 29w GA to 250 ml
at 48w GA (Kuklisova-Murgasova et al., 2011). During the first
2 years after term birth, brain growth is mainly due to gray
http://dx.doi.org/10.1016/B978-0-12-397025-1.00194-9
11
12
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Fetal and Postnatal Development of the Cortex: MRI and Genetics
T2w
28w GA
31w GA
35w GA
4w PTA
(a)
DTI-RGB
(b)
(c)
Figure 1 Structural imaging of the developing brain. T2w images (a), DTI-RGB directionality maps (b), and inner cortical surfaces (Dubois, Benders,
Cachia, et al., 2008; Leroy, Mangin, et al., 2011) are presented for three preterm newborns of different ages and an infant aged 4w old
(PTA: postterm age). Note that anisotropy decreases with age in the preterm cortex (b).
Cortical Folding
Concurrently with brain growth, the cortex is getting folded
during the last trimester of pregnancy. Dedicated tools and
morphometric analyses have enabled to map in detail the developing cortical surface and growth patterns in fetuses as young as
20w GA (Habas et al., 2012) and in preterm newborns imaged
shortly after birth (Dubois, Benders, Cachia, et al., 2008; Figure 1
(c)). These in vivo studies confirm earlier postmortem observations (Chi, Dooling, & Gilles, 1977a) and show a precise calendar (with the appearance of primary folds around 20w GA,
secondary folds around 32w GA, and tertiary folds around
term), which can be used as a robust marker of brain maturation.
Gyrification becomes manifest after 24w GA (Rajagopalan et al.,
2011) and greatly heightens during the last weeks before term
(Figure 2(b); Angleys et al., 2014; Dubois, Benders, Cachia,
et al., 2008). Although some variability is observed among individuals, the regional pattern is consistent over the brain surface:
sulcation starts in the central region and proceeds first toward the
parietal, temporal, and occipital lobes and second toward the
frontal lobe (Dubois, Benders, Cachia, et al., 2008; Ruoss, Lovblad, Schroth, Moessinger, & Fusch, 2001).
At term, the cortical surface area is three times smaller
than in adults, but the cortex is roughly similarly folded,
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Fetal and Postnatal Development of the Cortex: MRI and Genetics
13
350
Children
Infants
800
140
Volume (ml)
Cortex
Male
600
250
120
400
150
100
200
50
WM
25
30
(a)
40
35
GA (weeks)
45
50
Female
Parietal lobe
80
0
12
24
Post-natal age (months)
18
10
14
Post-natal age (years)
22
250
200
4.4
Born at term
Area (log)
Area (cm2)
300
Preterm
150
Sulcation index
4.5
4.3
4.2
4.1
4.0
100
3.9
28 30 32 34 36 38 40
(b)
1.7
1.7
1.5
1.5
1.3
1.3
1.1
1.1
GA (weeks)
28 30 32 34 36 38 40
GA (weeks)
40
60
Figure 2 Changes in cortical volume, surface area, and folding during development. Cortical volume (a) increases during the preterm period
(Kuklisova-Murgasova et al., 2011), infancy (Knickmeyer et al., 2008), and childhood, before decreasing during adolescence (Giedd et al., 1999).
The increases in surface area and sulcation (b) are major during the last gestational weeks, going with the growth in brain size (Angleys et al., 2014).
T2w
%
01 year
150
110
(a)
70
Maturation index
Maturation
7w PTA
(b)
Figure 3 Asynchronous development of brain regions. During the first postnatal year, cortical regions demonstrate different rates of volume increase
(a) (Gilmore et al., 2012) and maturation (b) (Leroy, Glasel, et al., 2011): primary sensorimotor regions grow less and appear more mature
(red arrows on T2w images) than associative regions.
14
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Fetal and Postnatal Development of the Cortex: MRI and Genetics
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Fetal and Postnatal Development of the Cortex: MRI and Genetics
15
t=6
Term newborns
Infants 1-year-old
Infants 2-year-old
6
(a)
Right
10
Left
5
0.53
16
0
28 40 mm
Front
Left
Dorsal
STS
Front
5
30 19
0.55
Right
Depth (mm)
20
15
10
Maturation index
STS maturation
24 13 2
Front
0
Ventral
STS
Left
0.51
0.49
20 30 mm
Front
0.55
Right
Right
0.53
Maturation index +
Left
24 13 2
(b)
0.51
0.49
20 30 mm
Figure 4 Interhemispheric asymmetries in cortical development. The cortex folds asymmetrically in perisylvian regions (a), as shown in preterm
newborns (Dubois et al., 2010) and infants (Li, Nie, et al., 2013). Notably, the STS (b) is deeper (Glasel et al., 2011) and more mature (Leroy, Glasel,
et al., 2011) on the right side than on the left.
Sexual Dimorphism
Whereas no difference in folding is detected among fetuses of
the same age (Chi et al., 1977a), males already have larger
cortical volumes than females after preterm (Dubois, Benders,
Cachia, et al., 2008) or term birth (Gilmore et al., 2007).
During childhood and adolescence, this dimorphism
strengthens, with volumes being 10% larger in boys (Giedd
et al., 1999) correlating with body mass index (Brain
Development Cooperative Group, 2012). The age-related
changes in volume peak slightly earlier (12 years) in girls,
but the curve shape does not differ among genders (Giedd
et al., 1999; Lenroot et al., 2007).
Girls tend to have larger gray matter volume relative to
brain size than boys (Groeschel, Vollmer, King, & Connelly,
16
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Fetal and Postnatal Development of the Cortex: MRI and Genetics
2010), and gender differences are more pronounced for volume and surface area than for cortical thickness (Wierenga
et al., 2013), for which sex differences are region-specific
(Sowell et al., 2007). During adolescence, the pattern of differences in cortical thickness between genders accelerates, notably
a wave of maturation sweeps frontal subregions with a delay in
males compared with females (Raznahan et al., 2010) probably related to the earlier female puberty. The acceleration of
cortical thickness changes during this period is different across
regions and is modulated by the level of cerebral androgen
receptor signaling in both males and females (Raznahan et al.,
2010). The effect of gender is strikingly different in the superior
frontal region (accelerated loss in males relatively to females)
and the parietal lobule (reverse pattern), suggesting possible
relationship with gender cognitive differences (e.g., better
social cognition in females versus better visuospatial cognition
in males; Raznahan et al., 2010) despite no direct established
correlation.
Besides hormonal influence, sex chromosome gene expression also directly influences gray matter volume in different
brain regions (parietooccipital and temporoinsular), as demonstrated during the early stages of puberty in normal children
and children with Turner syndrome (females missing one X
chromosome) and Klinefelter syndrome (males having an
additional X chromosome) (Hong et al., 2014). These developmental studies demonstrate the robust influence of hormones and sex chromosome gene dosages on cortical
development and underscore the need to precisely match gender and age when evaluating normal or pathological brain
functioning.
Genetic Influences
To assess how genetics and environment influence cortical
development, most MRI studies have relied on the longitudinal
follow-up of pediatric monozygotic and dizygotic twins. Cortical volume and depth are highly correlated within monozygotic twin pairs, but surface measures are more prone to
environmental influences (White, Andreasen, & Nopoulos,
2002). The volume heritability decreases with age (Wallace
et al., 2006), differently among brain regions (Giedd, Schmitt,
& Neale, 2007). Cortical density is increasingly similar in subjects with increasing genetic affinity, particularly in the frontal,
sensorimotor, and perisylvian language regions (Thompson
et al., 2001). The degree of genetic influence on cortical thickness also differs among brain regions (Van Soelen et al., 2012):
regions that develop earlier show greater genetic effects during
early childhood, while later-developing regions are more heritable in adolescents than children (Lenroot et al., 2009).
So far, the heritability in cortical patterning has not been
studied during development, but in adults, the similarity in
sulcal graphs is higher in twin pairs than in unrelated pairs,
suggesting a genetic influence on cortical folding (Im et al.,
2011). Finally, genetics also influences interhemispheric asymmetries: asymmetries in the planum temporale and sylvian
fissure are slightly heritable during childhood. However, heritability decreases when twins with discordant writing hand or
large birth weight differences are included (Eckert et al., 2002),
suggesting that prenatal and postnatal factors should not be
neglected.
Conclusion
MRI now enables to map and characterize the dynamics of
cortical development and the development of structural and
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Fetal and Postnatal Development of the Cortex: MRI and Genetics
functional connectivity, highlighting the structural bases of
cognitive development. These studies are challenging in healthy
infants and require dedicated methodologies for image acquisition and postprocessing (Dubois et al., 2014), but it is worth the
effort since markers of maturation are required to better understand pathological mechanisms or the deleterious effects of early
disturbances such as prematurity. However, if clear effects of age,
genes, hormonal status, or nutrition are observed on structural
images, the causal relationships between these observations and
cognition are still unknown due to the complex interactions
between these factors and the delicacy of the neural circuitry
still not captured by MR images.
Acknowledgment
The authors thank P. S. Huppi for the images of preterm
newborns (Figure 1) and F. Leroy for images of cortical maturation (Figure 3). The finalization of this work received support from the European Union Seventh Framework Program
(FP7/20072013, grant agreement n 604102), the French
National Agency for Research, the Fyssen Foundation, the
Fondation de France, the Ecole des Neurosciences de Paris,
the Fondation Motrice, and the McDonnell Foundation.
References
Aeby, A., De Tiege, X., Creuzil, M., David, P., Baleriaux, D., Van Overmeire, B., et al.
(2013). Language development at 2 years is correlated to brain microstructure in the
left superior temporal gyrus at term equivalent age: A diffusion tensor imaging
study. NeuroImage, 78, 145151.
Aeby, A., Van Bogaert, P., David, P., Baleriaux, D., Vermeylen, D., Metens, T., et al.
(2012). Nonlinear microstructural changes in the right superior temporal sulcus and
lateral occipitotemporal gyrus between 35 and 43 weeks in the preterm brain.
NeuroImage, 63, 104110.
Aleman-Gomez, Y., Janssen, J., Schnack, H., Balaban, E., Pina-Camacho, L.,
Alfaro-Almagro, F., et al. (2013). The human cerebral cortex flattens during
adolescence. Journal of Neuroscience, 33, 1500415010.
Angleys, H., Germanaud, D., Leroy, F., Hertz-Pannier, L., Mangin, J. F., Lazeyras, F.,
et al., (2014). Successive waves of cortical folding in the developing brain revealed
by spectral analysis of gyrification. Proceedings of OHBM, #4431.
Ball, G., Srinivasan, L., Aljabar, P., Counsell, S. J., Durighel, G., Hajnal, J. V., et al.
(2013). Development of cortical microstructure in the preterm human brain.
Proceedings of the National Academy of Sciences of the United States of America,
110, 95419546.
Brain Development Cooperative Group, (2012). Total and regional brain volumes in a
population-based normative sample from 4 to 18 years: The NIH MRI Study of
Normal Brain Development. Cerebral Cortex, 22, 112.
Chi, J. G., Dooling, E. C., & Gilles, F. H. (1977a). Gyral development of the human
brain. Annals of Neurology, 1, 8693.
17
18
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Fetal and Postnatal Development of the Cortex: MRI and Genetics
Operto, G., Auzias, G., Le Troter, A., Perrot, M., Rivie`re, D., Dubois, J., et al. (2012).
Structural group analysis of cortical curvature and depth patterns in the developing
brain. In: Meeting IEEE ISBI (pp. 422425).
Padilla, N., Alexandrou, G., Blennow, M., Lagercrantz, H., & Aden, U. (in press). Brain
growth gains and losses in extremely preterm infants at term. Cerebral Cortex, Jan 31
Rajagopalan, V., Scott, J., Habas, P. A., Kim, K., Corbett-Detig, J., Rousseau, F., et al.
(2011). Local tissue growth patterns underlying normal fetal human brain
gyrification quantified in utero. Journal of Neuroscience, 31, 28782887.
Raznahan, A., Greenstein, D., Lee, N. R., Clasen, L. S., & Giedd, J. N. (2012). Prenatal
growth in humans and postnatal brain maturation into late adolescence.
Proceedings of the National Academy of Sciences of the United States of America,
109, 1136611371.
Raznahan, A., Lee, Y., Stidd, R., Long, R., Greenstein, D., Clasen, L., et al. (2010).
Longitudinally mapping the influence of sex and androgen signaling on the
dynamics of human cortical maturation in adolescence. Proceedings of the
National Academy of Sciences of the United States of America, 107,
1698816993.
Raznahan, A., Lerch, J. P., Lee, N., Greenstein, D., Wallace, G. L., Stockman, M.,
et al. (2011). Patterns of coordinated anatomical change in human cortical
development: A longitudinal neuroimaging study of maturational coupling.
Neuron, 72, 873884.
Raznahan, A., Shaw, P., Lalonde, F., Stockman, M., Wallace, G. L., Greenstein, D., et al.
(2011). How does your cortex grow? Journal of Neuroscience, 31, 71747177.
Regis, J., Mangin, J. F., Ochiai, T., Frouin, V., Riviere, D., Cachia, A., et al. (2005).
"Sulcal root" generic model: A hypothesis to overcome the variability of the human
cortex folding patterns. Neurologia Medico-Chirurgica (Tokyo), 45, 117.
Ruoss, K., Lovblad, K., Schroth, G., Moessinger, A. C., & Fusch, C. (2001). Brain
development (sulci and gyri) as assessed by early postnatal MR imaging in preterm
and term newborn infants. Neuropediatrics, 32, 6974.
Scott, J. A., Habas, P. A., Kim, K., Rajagopalan, V., Hamzelou, K. S.,
Corbett-Detig, J. M., et al. (2011). Growth trajectories of the human fetal brain
tissues estimated from 3D reconstructed in utero MRI. International Journal of
Developmental Neuroscience, 29, 529536.
Shaw, P., Eckstrand, K., Sharp, W., Blumenthal, J., Lerch, J. P., Greenstein, D., et al.
(2007). Attention-deficit/hyperactivity disorder is characterized by a delay in cortical
maturation. Proceedings of the National Academy of Sciences of the United States of
America, 104, 1964919654.
Shaw, P., Greenstein, D., Lerch, J., Clasen, L., Lenroot, R., Gogtay, N., et al. (2006).
Intellectual ability and cortical development in children and adolescents. Nature,
440, 676679.
Shaw, P., Kabani, N. J., Lerch, J. P., Eckstrand, K., Lenroot, R., Gogtay, N., et al. (2008).
Neurodevelopmental trajectories of the human cerebral cortex. Journal of
Neuroscience, 28, 35863594.
Sowell, E. R., Peterson, B. S., Kan, E., Woods, R. P., Yoshii, J., Bansal, R., et al. (2007).
Sex differences in cortical thickness mapped in 176 healthy individuals between 7
and 87 years of age. Cerebral Cortex, 17, 15501560.
Sowell, E. R., Thompson, P. M., Leonard, C. M., Welcome, S. E., Kan, E., & Toga, A. W.
(2004). Longitudinal mapping of cortical thickness and brain growth in normal
children. Journal of Neuroscience, 24, 82238231.
Sowell, E. R., Thompson, P. M., Rex, D., Kornsand, D., Tessner, K. D., Jernigan, T. L.,
et al. (2002). Mapping sulcal pattern asymmetry and local cortical surface gray
matter distribution in vivo: Maturation in perisylvian cortices. Cerebral Cortex, 12,
1726.
Sun, T., Patoine, C., Abu-Khalil, A., Visvader, J., Sum, E., Cherry, T. J., et al. (2005).
Early asymmetry of gene transcription in embryonic human left and right cerebral
cortex. Science, 308, 17941798.
Thompson, P. M., Cannon, T. D., Narr, K. L., Van Erp, T., Poutanen, V. P., Huttunen, M.,
et al. (2001). Genetic influences on brain structure. Nature Neuroscience, 4,
12531258.
Toro, R., & Burnod, Y. (2005). A morphogenetic model for the development of cortical
convolutions. Cerebral Cortex, 15, 19001913.
Travis, K. E., Curran, M. M., Torres, C., Leonard, M. K., Brown, T. T., Dale, A. M., et al.
(2013). Age-related changes in tissue signal properties within cortical areas
important for word understanding in 12- to 19-month-old infants. Cerebral Cortex,
24(7), 19481955.
Van Essen, D. C. (1997). A tension-based theory of morphogenesis and compact wiring
in the central nervous system. Nature, 385, 313318.
Van Soelen, I. L., Brouwer, R. M., Van Baal, G. C., Schnack, H. G., Peper, J. S.,
Collins, D. L., et al. (2012). Genetic influences on thinning of the cerebral cortex
during development. NeuroImage, 59, 38713880.
Wallace, G. L., Eric Schmitt, J., Lenroot, R., Viding, E., Ordaz, S., Rosenthal, M. A., et al.
(2006). A pediatric twin study of brain morphometry. Journal of Child Psychology
and Psychiatry, 47, 987993.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Fetal and Postnatal Development of the Cortex: MRI and Genetics
Westlye, L. T., Walhovd, K. B., Dale, A. M., Bjornerud, A., Due-Tonnessen, P., Engvig, A.,
et al. (2010). Differentiating maturational and aging-related changes of the cerebral
cortex by use of thickness and signal intensity. NeuroImage, 52, 172185.
White, T., Andreasen, N. C., & Nopoulos, P. (2002). Brain volumes and surface
morphology in monozygotic twins. Cerebral Cortex, 12, 486493.
Wierenga, L. M., Langen, M., Oranje, B., & Durston, S. (2013). Unique developmental
trajectories of cortical thickness and surface area. NeuroImage, 87, 120126.
Wu, M., Lu, L. H., Lowes, A., Yang, S., Passarotti, A. M., Zhou, X. J., et al. (2013).
Development of superficial white matter and its structural interplay with cortical gray
matter in children and adolescents. Human Brain Mapping, 35(6), 28062816.
Xue, H., Srinivasan, L., Jiang, S., Rutherford, M., Edwards, A. D., Rueckert, D., et al.
(2007). Automatic segmentation and reconstruction of the cortex from neonatal
MRI. NeuroImage, 38, 461477.
Further Reading
Dubois, J., Dehaene-Lambertz, G., Soare`s, C., Cointepas, Y., Le Bihan, D., &
Hertz-Pannier, L. (2008). Microstructural correlates of infant functional
development: Example of the visual pathways. Journal of Neuroscience, 28,
19431948.
19
Dubois, J., Dehaene-Lambertz, G., Perrin, M., Mangin, J. F., Cointepas, Y.,
Duchesnay, E., et al. (2008). Asynchrony of the early maturation of white matter
bundles in healthy infants: Quantitative landmarks revealed non-invasively by
diffusion tensor imaging. Human Brain Mapping, 29, 1427.
Kouider, S., Stahlhut, C., Gelskov, S. V., Barbosa, L. S., Dutat, M., De Gardelle, V., et al.
(2013). A neural marker of perceptual consciousness in infants. Science,
340(6130), 376380.
Mahmoudzadeh, M., Dehaene-Lambertz, G., Fournier, M., Kongolo, G., Goudjil, S.,
Dubois, J., et al. (2013). Syllabic discrimination in premature human infants prior to
complete formation of cortical layers. Proceedings of the National Academy of
Sciences of the United States of America, 110(12), 48464851.
Dehaene-Lambertz, G., Hertz-Pannier, L., Dubois, J., Meriaux, S., Roche, A.,
Sigman, M., et al. (2006). Functional organization of perisylvian activation during
presentation of sentences in preverbal infants. Proceedings of the National Academy
of Sciences of the United States of America, 103, 1424014245.
Dehaene-Lambertz, G., Dehaene, S., & Hertz-Pannier, L. (2002). Functional
neuroimaging of speech perception in infants. Science, 298, 20132015.
Dehaene-Lambertz, G., & Dehaene, S. (1994). Speed and cerebral correlates of syllable
discrimination in infants. Nature, 370, 292295.
Glossary
The size of the isocortex is important to its processing information, but like other biological structures, its size is constrained by those of interrelated structures. Consequently,
size is analyzed in association with a reference metric, which
in biology typically uses the bivariate allometric formula
Y bX a
where Y is the metric of some feature, X is the reference metric, b
is the intercept of the derived slope, and a is the coefficient of
allometry (the slope or scaling factor). Because allometry does
not assume an isometric (one-to-one) relationship, it can determine the regularity of associated change even when altered
ratios suggest otherwise. When parallel lines describe different
taxonomic groups, those differences are considered to be grade
shifts of the same type of structure (Barton & Harvey, 2000;
Huxley, 1932). Groups that differ in slopes have altered some
intrinsic factors within the compared structures and alert scientists of the need to investigate the biology in more detail.
Although allometry cannot identify the cause of the relationship, it can eliminate complex explanations by showing that a
simple scaling factor produces the observed size. The sizes of
brain regions with direct interconnections are usually correlated.
Dendritic trees in the cortex are intimately involved with the
cortical microcircuitry. The lengths of dendrites scale at 0.67
with numbers of synapses and branch points in logarithmically
transformed data. The design constraints of dendritic branching
may reflect the function of neurons to both process and distribute information. The dendritic design minimizes the amount of
energy required for recharging synapses and for maintaining
membrane potentials (Cuntz, Mathya, & Haussera, 2012).
Each isocortical neuron may expend the same amount of energy,
but the energy used by the isocortex scales isometrically with
numbers of neurons and not neuronal density (HerculanoHouzel et al., 2011). This can be explained by larger dendritic
and axonal trees having lower energy costs (Karbowski, 2014).
Quantitative data of the isocortex consist mostly of volumetric data and number of neurons. The volumetric data come
from measuring structures identified on histological slides and
the numbers of neurons from the isotropic fractionator.
Both the total volume of the isocortex and its surface area
scale with brain weight among mammals. That is, differences
in absolute volume of the isocortex correlate with that of the
rest of the brain. Despite the coarseness of the measure, some
taxonomic groups differ in relative amounts of cortex after
accounting for brain size; primates have relatively more neocortex than insectivores and within primates, haplorhines have
more neocortex than strepsirhines. The separations appear
robust with parallel slopes and no overlapping values between
taxa (Barton & Harvey, 2000; Stephan, Frahm, & Baron, 1981).
Whereas the total amount of cortex among mammals
ranges by a magnitude of approximately five, cortical thickness, the span of cortex from the pial surface to the white
matter, is relatively stable and differs among extant mammals
by a magnitude of less than one. Constancy in cortical thickness is thought to reflect the conservation of important elements of the microcircuitry of cortical columns, possibly the
lengths of pyramidal apical dendrites (Allman, 1990).
Cortical thickness varies within a brain; in convoluted
mammalian brains, the neocortex is thinnest at the depths of
sulci and widest at the crowns of gyri (Bok, Kip, & Taalman,
1939). Studies using magnetic resonance images have
found that the neocortices of normal adult human and chimpanzee brains have regional, gender, maturational, aging,
neuropathologic, and hemispheric differences in thickness. It
is thickest in association and motor regions and thinnest in
sensory regions (Hopkins & Avants, 2013). The variation is
best known in humans and very little is known how it varies
in smaller-brained and lissencephalic mammals.
Scaling studies of cortical thickness use global or average
values, and these have been determined by dividing the surface
area of a brain by the brains volume. Average isocortical
thicknesses scale with brain weight, but the correlation is rather
low. This may reflect the use of an average value. Small lissencephalic terrestrial mammals have an allometric scaling of
approximately 0.08, whereas mammals with larger brains,
including those with convoluted surfaces, have a higher slope
(0.17). Aquatic mammals have surprisingly thin cortices and
scale separately from other mammals (Haug, 1987; Hofman,
1988). The differences suggest that for every unit increase in
brain weight, small-brained terrestrial mammals increase both
surface area and cortical thickness, whereas mammals with
convoluted brains increase just surface area; that is, add repetitive units (Ventura-Antunes, Mota, & Herculano-Houzel,
2013; Hofman, 1988).
A larger isocortex is also associated with convolutedness
(gyrification) of the cortex. Unlike a grade difference, measurements of gyrification show different allometric exponents
between prosimians and anthropoids and between rodents
http://dx.doi.org/10.1016/B978-0-12-397025-1.00195-0
21
22
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Quantitative Data and Scaling Rules of the Cerebral Cortex
most studied, and most analyses show that their sizes in primates, including humans, are predicted by that of the brain.
Additional complexities arise from lateralization and smaller
regional differences within the prefrontal cortex (Ribeiro et al.,
2013; Semendeferi, Lu, Schenker, & Damasio, 2002; Smaers
et al., 2011). The temporal lobe scales differently with brain
weight between monkeys and apes with the monkey trajectory
being above that of apes (Rilling & Seligman, 2002). Conflict
remains as to whether the ape allometric exponent of temporal
lobe to brain weight predicts human values (Rilling &
Seligman, 2002; Semendeferi and Damasio, 2000). The insula,
with its role in social awareness, has recently been analyzed.
Overall, its size in the human brain is predicted by its hyperallometric scaling in nonhuman primates. Within the hominoid insula the region containing large von Economo neurons
is relatively enlarged when the human brain is compared with
that of the chimpanzee (Bauernfeind et al., 2013).
A few studies have analyzed the sizes of regions within lobes
and most of those have focussed on differences between human
and nonhuman primate brains. A detailed analysis of visual areas
shows that both scaling and changes independent of reference
sizes occur in primates. Motor regions, including the primary
motor cortex (Brodmanns area 4), scale among primates with
human values being predictable from primate scaling. The primate association cortices expand more than the sensorimotor
cortices, but the increases appear predictable by scaling relationships with brain weight (Passingham, 1975; Sanides, 1975).
Except for anthropoid primates, which do not have a statistically significant association, larger cortices have decreased
neuronal densities (Figure 1). The association between neuronal density and cortical mass is much less tight than that found
between number of neurons and cortical mass. The decline in
cortical neuronal densities has overlapping values among
glires, afrotherians, and insectivores, suggesting that they may
2.5
2
Afrotheria
1.5
Anthropoids
Prosimians
0.5
Glires
Insectivores
0.5
Marsupial
Tree shrew
1.5
1.5
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Quantitative Data and Scaling Rules of the Cerebral Cortex
form a single nonanthropoid eutherian group. The marsupial
is quite distinct in its low value.
The findings that anthropoid primates diverge from other
mammals by having smaller differences in cortical mass given
similar changes in neuronal densities (Figure 1) corroborate the
observations of many classical and comparative neuroanatomists, who determined that primate brains have a surprisingly
dense isocortex. Lorent de No (1938) was so impressed by the
difference in densities between mouse and human brains that
he called the mouse organization a skeletal version of humans.
The increase in primate neuronal density occurs primarily
through an increase in small neurons, primarily interneurons
(Golgi II and stellate cells) and small pyramidal cells. The
appearance of very small neurons is more prominent in anthropoid than prosimian brains; the visual cortex suggests that the
difference may be one between haplorhines and strepsirhines.
The anthropoid increase in granularization (small pyramidal
cells and interneurons) is observed primarily in the outer cortical laminae, and while found in various degrees throughout the
isocortex, granularization reaches its apex in the sensory koniocortex (hypergranularized; powdery cortex). Given the small
size of these neurons, their increase in numbers affects the
cortical mass much less than pyramidal cells. Furthermore,
because their axons are often local (intrinsic) or of short range,
their numbers do not increase the white matter mass or cells (see
in the succeeding text). These factors skew the relationship of
neuron numbers to mass and features of the white matter.
At the same time, morphometric analysis of histological
material definitely shows that neuropil expands in primate
cortices often as a function of increased brain size and sometimes independent of it. An automated measure of the proportion of neuropil occupied by stained neuronal cell bodies, glial
and endothelial nuclei compared with the total amount of
tissue, the gray level index (GLI) estimated neuronal density
in the primate posterior cingulate cortex and found that larger
23
4.50
4.00
3.50
3.00
2.50
Anthropoid
2.00
Prosimian
Rodent
1.50
Scandentia
1.00
0.50
0.00
0
0.5
1
1.5
2
2.5
Log number of neurons (g+w)
3.5
Figure 2 The volume of the white matter regressed against number of neurons. Rodents have a strong association. Anthropoids have no statistically
significant association. Data from Ventura-Antunes, L., Mota, B., & Herculano-Houzel, S. (2013). Different scaling of white matter volume, cortical
connectivity, and gyrification across rodent and primate brains. Frontiers in Neuroanatomy, 7, 3.
24
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Quantitative Data and Scaling Rules of the Cerebral Cortex
3.5
3
2.5
2
Anthropoids
Prosimian
1.5
Rodents
Scandentia
1
0.5
0
0
0.5
1.5
2
2.5
Log number of neurons (g+w)
3.5
Figure 3 The number of nonneuronal nuclei (oligodendrocytes and astrocytes) regressed against number of neurons. When rodents are compared
with anthropoids, rodents have more glia for their numbers of neurons, have a steeper slope, and have a tighter association than anthropoids. An
increase in intrinsic neurons moves the anthropoid values away from those of rodents. Data from Ventura-Antunes, L., Mota, B., & Herculano-Houzel, S.
(2013). Different scaling of white matter volume, cortical connectivity, and gyrification across rodent and primate brains. Frontiers in
Neuroanatomy, 7, 3.
References
Allman, J. (1990). Evolution of neocortex. In: E. G. Jones & A. Peters (Eds.), Cerebral
cortex Vol. 8A. New York: Plenum.
Armstrong, E., Curtis, M., Buxhoeveden, D. P., Fregoe, C., Zilles, K., Casanova, M.,
et al. (1991). Cortical gyrification in the rhesus monkey: A test of the mechanical
folding hypothesis. Cerebral Cortex, 1, 426432.
Armstrong, E., Zilles, k., Schlaug, G., & Schleicher, A. (1986). Comparative aspects of the
primate posterior cingulate cortex. Journal of Comparative Neurology, 253, 539548.
Barton, R. A., & Harvey, P. H. (2000). Mosaic evolution of brain structure in mammals.
Nature, 405, 10551058.
Bauernfeind, A. L., de Sousa, A. A., Avasthi, T., Dobson, S. D., Raghanti, M. A.,
Lewandowski, A. H., et al. (2013). A volumetric comparison of the insular cortex and
its subregions in primates. Journal of Human Evolution, 64, 263279.
Bok, S. T., Kip, M. J., & Taalman, V. E. (1939). The size of the body and the size and
number of the nerve cells in the cerebral cortex. Acta Neerlandica Morphologiae
Normalis et Pathologicae, 3, 122.
Cuntz, H., Mathya, A., & Haussera, M. (2012). A scaling law derived from optimal
dendritic wiring. PNAS, 109, 1101411018.
Frahm, H., Stephan, H., & Baron, G. (1982). Comparison of brain structures in
insectivores and primates neocortex. Journal fur Hirnforschung, 23, 375389.
Gabi, M., Collins, C. E., Wong, P., Torres, L. B., Kaas, J. H., & Herculano-Houzel, S.
(2010). Cellular scaling rules for the brains of an extended number of primate
species. Brain, Behavior and Evolution, 76, 3244.
Haug, H. (1987). Brain sizes, surfaces, and neuronal sizes of the cortex cerebri: A
stereological investigation of man and his variability and a comparison with some
mammals (primates, whales, marsupials, insectivores, and one elephant). American
Journal of Anatomy, 180(2), 126142.
Herculano-Houzel, S. (2011). Scaling of brain metabolism with a fixed energy budget
per neuron: Implications for neuronal activity, plasticity, and evolution. PLoS One,
6, e17514.
Herculano-Houzel, S., Collins, C. E., Wong, P., & Kaas, J. H. (2007). Cellular scaling
rules for primate brains. Proceedings of the National academy of Sciences of the
United States of America, 104, 35623567.
Herculano-Houzel, S., Ribeiro, P., Campos, L., Valotta da Silva, A., Torres, L. B.,
Catania, K. C.H, et al. (2011). Updated neuronal scaling rules for the
brains of glires (rodents/lagomorphs). Brain, Behavior and Evolution, 78, 302314.
Hilgetag, C. C., & Barbas, H. (2009). Are there ten times more glia than neurons in the
brain? Brain Structure and Function, 213, 365366.
Hofman, M. A. (1988). Size and shape of the cerebral cortex in mammals II. The cortical
volume. Brain, Behavior and Evolution, 32, 1726.
Hopkins, W. D., & Avants, B. B. (2013). Regional and hemispheric variation in cortical
thickness in chimpanzees (Pan troglodytes). Journal of Neuroscience, 33,
52415248.
Huxley, J. S. (1932). Problems of relative growth. London: Methuen.
Karbowski, J. (2014). Constancy and trade-offs in the neuroanatomical and metabolic
design of the cerebral cortex. Frontiers in Neural Circuits, 9, 116.
Lorente de No, R. (1938). The cerebral cortex: Architecture, intracortical connections
and motor projections. In J. F. Fulton (Ed.), Physiology of the Nervous System
(pp. 291339). London: Oxford University Press.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Quantitative Data and Scaling Rules of the Cerebral Cortex
Neves, K., Ferreira, F. M., Tovar-Moll, F., Gravett, N., Bennett, N. C., Kaswera, C., et al.
(2014). Cellular scaling rules for the brain of afrotherians. Frontiers in
Neuroanatomy, 5, 113.
Passingham, R. E. (1975). Changes in the size and organisation of the brain in man and
his ancestors. Brain, Behavior and Evolution, 11, 7390.
Ribeiro, P. F.M, Ventura-Antunes, L., Gabi, M., Mota, B. M., Grinberg, L. T.,
Farfel, J. M., et al. (2013). The human cerebral cortex is neither one nor many:
Neuronal distribution reveals two quantitatively different zones in the gray matter,
three in the white matter, and explains local variations in cortical folding. Frontiers
in Neuroanatomy, 7, 120.
Rilling, J. K., & Seligman, R. A. (2002). A quantitative morphometric
comparative analysis of the primate temporal lobe. Journal of Human Evolution, 42,
505533.
Sanides, F. (1975). Comparative neurology of the temporal lobe in primates including
man with reference to speech. Brain and Language, 2, 396419.
Sarko, D. K., Catania, K. C., Leitch, D. B., Kaas, J. H., & Herculano-Houzel, S. (2009).
Cellular scaling rules of insectivore brains. Frontiers in Neuroanatomy, 3, 112.
Seelke, A. M., Dooley, J. C., & Krubitzer, L. A. (2014). The cellular composition of the
marsupial neocortex. Journal of Comparative Neurology, 522, 22862298.
25
Semendeferi, K., & Damasio, H. (2000). The brain and its main anatomical subdivisions
in living hominoids using magnetic resonance imaging. Journal of Human
Evolution, 38(2), 317332.
Semendeferi, K., Lu, A., Schenker, N., & Damasio, H. (2002). Humans and great apes
share a large frontal cortex. Nature Neuroscience, 5, 272276.
Smaers, J. B., Steele, J., Case, C. R., Cowper, A., Amunts, K., & Zilles, K. (2011).
Primate prefrontal cortex evolution: Human brains are the extreme of a lateralized
ape trend. Brain, Behavior and Evolution, 77, 6778.
Stephan, H., Frahm, H., & Baron, G. (1981). New and revised data on
volumes of brain structures in insectivores and primates. Folia Primatologica, 35,
129.
Ventura-Antunes, L., Mota, B., & Herculano-Houzel, S. (2013). Different scaling of
white matter volume, cortical connectivity, and gyrification across rodent and
primate brains. Frontiers in Neuroanatomy, 7, 3.
Zilles, K., Armstrong, E., Moser, K. H., Schleicher, A., & Stephan, H. (1989). Gyrification
in the cerebral cortex of primates. Brain, Behavior and Evolution, 34, 143150.
Zilles, K., Armstrong, E., Schlaug, G., & Schleicher, A. (1986). Quantitative
cytoarchitectonics of the posterior cingulate cortex in primates. Journal of
Comparative Neurology, 253, 514524.
Glossary
Introduction
Your gender, whether you are a boy or girl, man or woman, is
one of the most salient and enduring identifying features one
possesses. The term gender is unique to humans as it incorporates both self and societal perceptions of ones sex, which is
either male or female. Thus, studies of animals address sex
differences, whereas studies of humans may involve either or
both gender and sex. Ones sex is determined on several levels
that can be summarized as the three Gs genes, gonads, and
genitalia (Joel, 2012). In the overwhelming majority of cases,
these three variables align such that an XX individual will
develop ovaries and female genitalia whereas an XY individual
will develop testis and male genitalia and this will in turn
inform gender. Thus, sex and gender are internally consistent.
But is this also true for the sex/gender of the brain? That boys
and girls, men and women, behave differently is so self-evident
as to be hardly worth stating. But this easy generality is in
reality highly nuanced and complex in both its origins and
http://dx.doi.org/10.1016/B978-0-12-397025-1.00196-2
27
28
Ovary
Default
Bipotential
gonad
Aromatase
SRY Gene
E2
T
Y Chromosome
Testis
Masculinization
Default
Bipotential
brain
Feminization
Figure 1 Sexual differentiation of the brain. The bipotential gonad is programmed to form an ovary by default but will differentiate into a testis in
response to the activation of the SRY gene on the Y chromosome. The bipotential brain is also programmed towards feminization in the absence of
testosterone (T), which is a precursor to estradiol (E2). In rodents, E2 masculinizes the brain, one manifestation of which is adult male sexual behavior.
In the absence of exposure to high levels of E2 early in development during a sensitive period, often referred to as the organizational phase, the
neural circuits that control sex behavior are feminized. Both male and female adult sex behaviors require activation by the appropriate hormonal milieu.
Via this mechanism of differentiation, a match between gonadal sex and reproductive behavior is assured.
Male
Female
SDN
Healthy cells
E2
Medial preoptic nucleus
29
larger in females (Davis, Shryne, & Gorski, 1996; Gorski, Harlan, Jacobson, Shryne, & Southam, 1980; Simerly, Swanson,
Handa, & Gorski, 1985). Here, estradiol is a cell death signal
and induces both GABAergic and dopaminergic cells to die but
via a distinct cellular cascade for each. In GABAergic neurons,
females have higher levels of TNF-a, which activates NF-kB, a
cell survival protein. Male GABAergic neurons downregulate
this pathway via estradiol-induced expression of TRIP (TNF
receptor-associated factor 2-inhibiting protein). Starved of
NF-kB, the cells die in males (Krishnan, Intlekofer, Aggison,
& Petersen, 2009). In the dopamine neurons, estradiol activates a classic caspase-3 apoptotic cascade (Simerly, Zee, Pendleton, Lubahn, & Korach, 1997; Waters & Simerly, 2009), the
result being that males have fewer GABA and dopamine neurons in the AVPV and thus an overall smaller volume.
30
Microglia
PGE2
ine
Sp
te
AMPA receptors
ri
nd
PGE2
De
yte
oc
tr
As
E2
ER
COX1& 2
Neuron
Figure 3 A sex difference in synaptic patterning involves immune and inflammatory mediators and cell-to-cell communication. Dendrites of POA
neurons in males have twice the density of dendritic spine synapses as females. This sex difference is the result of estradiol (E2) induction of the COX-1
and COX-2 genes that synthesize the prostaglandin PGE2, normally a proinflammatory molecule but here functioning as a regulatory component of
normal brain development. PGE2 released from neurons appears to have multiple functions including induction of increased activation of both
astrocytes and microglia, evidenced by increased stellation and amoeboid-like shape, respectively, and a further production and release of PGE2
from these cell types. This feed-forward mechanism of PGE2 production stimulates glutamate release, presumably from astrocytes, which is in turn
essential for the activation of AMPA receptors and the formation and stabilization of dendritic spine synapses.
Hippocampus
Increased BDNF
Higher
endocannabinoid
tone
Amygdala
= New cells in females
31
32
2011). Thus, steroids may be both the targets and the regulators
of epigenetic changes that allow for organizational modifications
to endure. HDAC activity also contributes to volumetric sex
differences as it is required for steroid-induced masculinization
of the larger BNSTp found in males (Murray, Hien, De Vries, &
Forger, 2009). The importance of DNA methylation is just beginning to emerge with implications for sex differences in social play
behavior (Auger, Jessen, & Edelmann, 2011) and possibly sex
behavior (Edelmann & Auger, 2011; McCarthy et al., 2009;
Nugent & McCarthy, 2011; Nugent, Schwarz, & McCarthy, 2010).
Gliagenesis
Apoptosis
Survival
Synaptic patterning
Migration
Synapse elimination
Synaptogenesis
Epigenetics
Neurochemical phenotype
Growth and differentiation
Histone
acetylation
DNA
Methylation
Dendritic growth
Astrocyte differentiation
Figure 5 Multiple cellular end points are organized by steroids developmentally. As investigation into the biological basis of sex differences in the brain
continues, greater numbers and varieties of cellular end points that are targets of the organizational effects of steroids are emerging. Each of these
variables has been identified to be modulated by steroids and/or different in male versus female brains in rodent animal models. Importantly, the
end points that are modified are region-specific, as are the signal transduction pathways mediating them, yet most are influenced by the same hormones
(predominantly estradiol in rodents) and usually during a common sensitive window. How this high degree of specificity is achieved is unknown but
may involve a convergence between genetic factors, such as sex chromosome compliment, and hormonal action.
33
LH Release
Bnst
AVPV
Arcuate
GnRH Neuron
Sex behavior
Odors
Amygdala
Human connectome
POA
PAG
SNB
Figure 6 Connectomes and networks mediate sex differences in physiology and behavior. While sexual differentiation of specific brain regions may
occur independently, it is the interaction between regions in a network that ultimately influences physiology and behavior. In humans, the recent
findings on the human connectome by Ingalhalikar et al. (2014) using diffusion tensor imaging in almost 1000 subjects revealed that males
predominately make active connections within one cerebral hemisphere whereas females make many more cross hemispheric connections and favor
the frontal cortical areas. In rodents, there are nodes of influence in the neural circuit controlling LH release such that some areas or projections
are larger or smaller in males and females, producing a sex difference in the pattern of gonadotropin secretion. The same is true for the circuit controlling
sex behavior, which involves mostly the same regions in males and females but is differentiated by the sensitivity to specific odors, density of the
synaptic profile, number or type of neurons, etc. In this way, the same region can serve different functions for each sex depending on how it
was organized developmentally and activated in adulthood.
34
stroke are so different in men and women that specific guidelines for the treatment of women have been established
(Bushnell et al., 2014). Modeling these conditions in animals
is difficult and, in some cases, impossible (i.e., stuttering or
Tourettes), but the pervasive impact of sex on biological end
points has persuaded the NIH that all preclinical research
involving animals or humans should incorporate it as an
experimental variable. Guidelines for implementation are
expected in late 2014 and promise to change the perception
of the relevance of sex differences in the brain from narrowly
defined effects on reproduction to a mainstream component of
neural functioning.
References
Abel, K. M., Drake, R., & Goldstein, J. M. (2010). Sex differences in schizophrenia.
International Review of Psychiatry, 22, 417428.
Ahmed, E. I., Zehr, J. L., Schulz, K. M., Lorenz, B. H., Doncarlos, L. L., & Sisk, C. L.
(2008). Pubertal hormones modulate the addition of new cells to sexually dimorphic
brain regions. Nature Neuroscience, 11, 995997.
Amateau, S. K., & McCarthy, M. M. (2002a). A novel mechanism of dendritic spine
plasticity involving estradiol induction of prostglandin-E2. The Journal of
Neuroscience, 22, 85868596.
Amateau, S. K., & McCarthy, M. M. (2002b). Sexual differentiation of astrocyte
morphology in the developing rat preoptic area. Journal of Neuroendocrinology, 14,
904910.
Amateau, S. K., & McCarthy, M. M. (2004). Induction of PGE(2) by estradiol mediates
developmental masculinization of sex behavior. Nature Neuroscience, 7, 643650.
Arnold, A. P. (2004). Sex chromosomes and brain gender. Nature Reviews.
Neuroscience, 5, 701708.
Arnold, A. P., & Burgoyne, P. S. (2004). Are XX and XY brain cells intrinsically
different? Trends in Endocrinology and Metabolism, 15, 611.
Arnold, A. P., & Chen, X. (2009). What does the "four core genotypes" mouse model tell
us about sex differences in the brain and other tissues? Frontiers in
Neuroendocrinology, 30, 19.
Arnold, A. P., Xu, J., Grisham, W., Chen, X., Kim, Y. H., & Itoh, Y. (2004). Minireview:
Sex chromosomes and brain sexual differentiation. Endocrinology, 145, 10571062.
Auger, A. P., Jessen, H. M., & Edelmann, M. N. (2011). Epigenetic organization of brain
sex differences and juvenile social play behavior. Hormones and Behavior, 59,
358363.
Bale, T. L., Baram, T. Z., Brown, A. S., Goldstein, J. M., Insel, T. R., McCarthy, M. M.,
et al. (2010). Early life programming and neurodevelopmental disorders. Biological
Psychiatry, 68, 314319.
Bowers, J. M., Perez Pouchoulen, M., Edwards, N. S., & McCarthy, M. M. (2013).
Foxp2 mediates sex differences in ultrasonic vocalization by rat pups and directs
order of maternal retrieval. The Journal of Neuroscience, 33, 32763283.
Bowers, J. M., Waddell, J., & McCarthy, M. M. (2010). A developmental sex difference
in hippocampal neurogenesis is mediated by endogenous oestradiol. Biology of Sex
Differences, 1, 8.
Bushnell, C., McCullough, L. D., Awad, I. A., Chireau, M. V., Fedder, W. N., Furie, K. L.,
et al. (2014). Guidelines for the prevention of stroke in women: A statement for
healthcare professionals from the american heart association/american stroke
association. Stroke, 45, 15451588.
Clarkson, J., Danglemont De Tassigny, X., Moreno, A. S., Colledge, W. H., &
Herbison, A. E. (2008). Kisspeptin-GPR54 signaling is essential for preovulatory
gonadotropin-releasing hormone neuron activation and the luteinizing hormone
surge. The Journal of Neuroscience, 28, 86918697.
Clarkson, J., & Herbison, A. E. (2006). Postnatal development of kisspeptin neurons in
mouse hypothalamus; sexual dimorphism and projections to gonadotropinreleasing hormone neurons. Endocrinology, 147, 58175825.
Davis, E. C., Popper, P., & Gorski, R. A. (1996). The role of apoptosis in sexual
differentiation of the rat sexually dimorphic nucleus of the preoptic area. Brain
Research, 734, 1018.
Davis, E. C., Shryne, J. E., & Gorski, R. A. (1996). Structural sexual dimorphisms in
the anteroventral periventricular nucleus of the rat hypothalamus are sensitive to
gonadal steroids perinatally, but develop peripubertally. Neuroendocrinology, 63,
142148.
De Vries, G. J., & Simerly, R. B. (2002). Anatomy, development and function of sexually
dimorphic neural circuits in the mammalian brain. In D. W. Pfaff, A. P. Arnold, A. M.
Etgen, S. E. A. Fahrbach, & R. T. Rubin (Eds.), Hormones, brain and behavior (1st
edn.). New York: Academic Press.
Edelmann, M. N., & Auger, A. P. (2011). Epigenetic impact of simulated maternal
grooming on estrogen receptor alpha within the developing amygdala. Brain,
Behavior, and Immunity, 25, 12991304.
Forger, N. G., Rosen, G. J., Waters, E. M., Jacob, D., Simerly, R. B., & De Vries, G. J.
(2004). Deletion of Bax eliminates sex differences in the mouse forebrain.
Proceedings of the National Academy of Sciences of the United States of America,
101, 1366613671.
Gatewood, J. D., Wills, A., Shetty, S., Xu, J., Arnold, A. P., Burgoyne, P. S., et al. (2006).
Sex chromosome complement and gonadal sex influence aggressive and parental
behaviors in mice. The Journal of Neuroscience, 26, 23352342.
Gioiosa, L., Chen, X., Watkins, R., Klanfer, N., Bryant, C. D., Evans, C. J., et al. (2008).
Sex chromosome complement affects nociception in tests of acute and chronic
exposure to morphine in mice. Hormones and Behavior, 53, 124130.
Gioiosa, L., Chen, X., Watkins, R., Umeda, E. A., & Arnold, A. P. (2008). Sex
chromosome complement affects nociception and analgesia in newborn mice. The
Journal of Pain, 9, 962969.
Gorski, R. A., Gordon, J. H., Shryne, J. E., & Southam, A. M. (1978). Evidence for a
morphological sex difference within the medial preoptic area of the rat brain. Brain
Research, 148, 333346.
Gorski, R. A., Harlan, R. E., Jacobson, C. D., Shryne, J. E., & Southam, A. M. (1980).
Evidence for the existence of a sexually dimorphic nucleus in the preoptic area of the
rat. The Journal of Comparative Neurology, 193, 529539.
Gould, E., Woolley, C. S., Frankfurt, M., & Mcewen, B. S. (1990). Gonadal steroids
regulate dendritic spine density in hippocampal pyramidal cells in adulthood.
Neuroscience, 10, 12861291.
Hutton, L. A., Gu, G., & Simerly, R. B. (1998). Development of a sexually dimorphic
projection from the bed nuclei of the stria terminalis to the anteroventral
periventricular nucleus in the rat. The Journal of Neuroscience, 18, 30033013.
Ibanez, M. A., Gu, G., & Simerly, R. B. (2001). Target-dependent sexual differentiation
of a limbic-hypothalamic neural pathway. The Journal of Neuroscience, 21,
56525659.
Ingalhalikar, M., Smith, A., Parker, D., Satterthwaite, T. D., Elliott, M. A., Ruparel, K.,
et al. (2014). Sex differences in the structural connectome of the human brain.
Proceedings of the National Academy of Sciences of the United States of America,
111, 823828.
Joel, D. (2012). Genetic-gonadal-genitals sex (3G-sex) and the misconception of brain
and gender, or, why 3G-males and 3G-females have intersex brain and intersex
gender. Biology of Sex Differences, 3, 27.
Krebs-Kraft, D. L., Hill, M. N., Hillard, C. J., & McCarthy, M. M. (2010). Sex difference
in cell proliferation in developing rat amygdala mediated by endocannabinoids has
implications for social behavior. Proceedings of the National Academy of Sciences
of the United States of America, 107, 2053520540.
Krishnan, S., Intlekofer, K. A., Aggison, L. K., & Petersen, S. L. (2009). Central role of
TRAF-interacting protein in a new model of brain sexual differentiation. Proceedings of
the National Academy of Sciences of the United States of America, 106, 1669216697.
Lenroot, R. K., Gogtay, N., Greenstein, D. K., Wells, E. M., Wallace, G. L., Clasen, L. S.,
et al. (2007). Sexual dimorphism of brain developmental trajectories during
childhood and adolescence. NeuroImage, 36, 10651073.
35
Polston, E. K., Gu, G., & Simerly, R. B. (2004). Neurons in the principal nucleus of the
bed nuclei of the stria terminalis provide a sexually dimorphic gabaergic input to the
anteroventral periventricular nucleus of the hypothalamus. Neuroscience, 123,
793803.
Polston, E. K., & Simerly, R. B. (2003). Sex-specific patterns of galanin,
cholecystokinin, and substance P expression in neurons of the principal bed
nucleus of the stria terminalis are differentially reflected within three efferent
preoptic pathways in the juvenile rat. The Journal of Comparative Neurology, 465,
551559.
Polston, E. K., & Simerly, R. B. (2006). Ontogeny of the projections from the
anteroventral periventricular nucleus of the hypothalamus in the female rat. The
Journal of Comparative Neurology, 495, 122132.
Rhees, R. W., Shryne, J. E., & Gorski, R. A. (1990a). Onset of the hormone-sensitive
perinatal period for sexual differentiation of the sexually dimorphic nucleus of the
preoptic area in female rats. Journal of Neurobiology, 21, 781786.
Rhees, R. W., Shryne, J. E., & Gorski, R. A. (1990b). Termination of the hormonesensitive period for differentiation of the sexually dimorphic nucleus of the preoptic
area in male and female rats. Developmental Brain Research, 52, 1723.
Simerly, R. B. (2002). Wired for reproduction: Organization and development of sexually
dimorphic circuits in the mammalian forebrain. Annual Review of Neuroscience, 25,
507536.
Simerly, R. B., Swanson, L. W., Handa, R. J., & Gorski, R. A. (1985). Influence of
perinatal androgen on the sexually dimorphic distribution of tyrosine hydroxylaseimmunoreactive cells and fibers in the anteroventral periventricular nucleus of the
rat. Neuroendocrinology, 40, 501510.
Simerly, R. B., Zee, M. C., Pendleton, J. W., Lubahn, D. B., & Korach, K. S. (1997).
Estrogen receptor-dependent sexual differentiation of dopaminergic neurons in the
preoptic region of the mouse. Proceedings of the National Academy of Sciences of
the United States of America, 94, 1407714082.
Waddell, J., Bowers, J. M., Edwards, N. S., Jordan, C. L., & McCarthy, M. M. (2013).
Dysregulation of neonatal hippocampal cell genesis in the androgen insensitive Tfm
rat. Hormones and Behavior, 64, 144152.
Wagner, C. K., Xu, J., Pfau, J. L., Quadros, P. S., De Vries, G. J., & Arnold, A. P. (2004).
Neonatal mice possessing an Sry transgene show a masculinized pattern of
progesterone receptor expression in the brain independent of sex chromosome
status. Endocrinology, 145, 10461049.
Waters, E. M., & Simerly, R. B. (2009). Estrogen induces caspase-dependent cell
death during hypothalamic development. The Journal of Neuroscience, 29,
97149718.
Wright, C. L., Burks, S. R., & McCarthy, M. M. (2008). Identification of prostaglandin
E2 receptors mediating perinatal masculinization of adult sex behavior and
neuroanatomical correlates. Developmental Neurobiology, 68, 14061419.
Zhang, J.-M., Konkle, A. T. M., Zup, S. L., & McCarthy, M. M. (2008). Impact of sex and
hormones on new cells in the developing rat hippocampus: A novel source of sex
dimorphism? The European Journal of Neuroscience, 27, 791800.
Zuloaga, D. G., Puts, D. A., Jordan, C. L., & Breedlove, S. M. (2008). The role of
androgen receptors in the masculinization of brain and behavior: What weve learned
from the testicular feminization mutation. Hormones and Behavior, 53, 613626.
Glossary
Ontogeny of the GI
Cortical folding starts at the 16th week of gestation, accelerates conspicuously as from the 28th week, and reaches a
transient maximum between the 66th and 80th weeks
http://dx.doi.org/10.1016/B978-0-12-397025-1.00197-4
37
38
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
Figure 1 Lateral (a, b), medial (c, d), dorsal (e), basal (f), frontal (g), and caudal views (h) of the Montreal Neurological Institute (MNI) single subject
template (Holmes et al., 1998), on which sulci have been identified. 1, Sylvian fissure; 2, posterior subcentral sulcus; 3, horizontal ramus of the Sylvian
fissure; 4, ascending ramus of the Sylvian fissure; 5, diagonal sulcus; 6, central sulcus; 60 , paracentral fossa; 600 , marginal precentral sulcus; 7,
precentral sulcus; 8, medial precentral sulcus; 9, medial frontal sulcus (superior frontal paramidline sulcus); 10, superior frontal sulcus; 11, intermediate
sulcus; 12, inferior frontal sulcus; 13, frontal polar sulcus; 14, frontomarginal sulcus; 15, callosal sulcus; 16, cingulate sulcus; 17, paracingulate sulcus;
18, paracentral sulcus; 19, anterior parolfactory sulcus; 20, superior rostral sulcus; 21, inferior rostral sulcus; 22, olfactory sulcus; 23, sulcus
fragmentosus; 24, medial orbital sulcus; 25, intermediate orbital sulcus; 26, lateral orbital sulcus; 27, transverse orbital sulcus; 28, postcentral sulcus;
29, supramarginal sulcus; 30, intraparietal sulcus; 31, Jensen sulcus (primary intermediate sulcus); 32, superior parietal sulcus; 33, angular sulcus; 34,
subparietal sulcus; 35, precuneal sulcus; 36, transverse temporal sulcus (Heschls sulcus); 37, superior temporal sulcus; 38, inferior temporal sulcus;
39, rhinal sulcus; 40, occipitotemporal sulcus; 41, collateral sulcus; 42, parieto-occipital sulcus; 43, anterior occipital sulcus; 44, calcarine sulcus; 45,
cuneal sulcus (paracalcarine sulcus); 46, lingual sulcus; 47, mid-fusiform sulcus; 48, inferior occipital sulcus; 49, inferior lateral occipital sulcus; 50,
superior lateral occipital sulcus; 51, superior occipital sulcus; 52, transverse occipital sulcus; 53, accessory sulcus. Arrows indicate position of the
occipitotemporal incisure, arrowheads that of the temporolimbic incisure. Circles highlight the anterior and posterior commissures, respectively. For
general aspects concerning anatomical variability, see Ono et al. (1990). For more detailed information concerning sulci, see Amunts et al. (1999),
Caspers et al. (2006), Duvernoy (1999), Malikovic et al. (2012), Tzourio-Mazoyer et al. (2002), Ongur, Ferry, and Price (2003), Petrides (2012), Vogt,
Nimchinsky, Vogt, and Hof (1995), and Weiner et al. (2014).
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h)
39
Figure 2 Lateral (a, b), medial (c, d), dorsal (e), basal (f), frontal (g), and caudal views (h) of the MNI single subject template (Holmes et al., 1998), on
which gyri have been identified. Sulci are color-coded as in Figure 1. fa, precentral gyrus; fb, superior frontal gyrus; fc, medial frontal gyrus; fd, inferior
frontal gyrus; fe, pars triangularis; ff, pars opercularis; fg, cingulate gyrus; fh, superior cingulate gyrus; fi, paraterminal gyrus; fj, subcallosal gyrus;
fk, superior rostral gyrus; fl, inferior rostral gyrus; fm, gyrus rectus; fn, medial orbital gyrus; fo, posterior orbital gyrus; fp, anterior orbital gyrus;
fq, lateral orbital gyrus; fr, frontomarginal gyrus; pa, postcentral gyrus; pb, subcentral gyrus; pc, supramarginal gyrus; pd, angular gyrus; pe, superior
parietal lobule; pf, paracentral lobule; pg, precuneus; ph, cingulate gyrus, parietal part; ta, superior temporal gyrus; tb, intermediate temporal gyrus; tc,
inferior temporal gyrus; td, temporal pole; te, gyrus ambiens; tf, gyrus semilunaris; tg, parahippocampal gyrus; th, fusiform gyrus (lateral
occipitotemporal gyrus); oa, superior occipital gyrus; ob, middle occipital gyrus; oc, inferior occipital gyrus; od, cuneus; oe, lingual gyrus (medial
occipitotemporal gyrus). For further details, see Figure 1.
40
Figure 3 Dorsal view of the MNI single subject template (Holmes et al.,
1998) and photographs of 16 adult human formalin-fixed brains as
examples to visualize intersubject variability in sulcal and gyral patterns.
The gyrification pattern of each human brain appears like an individual
fingerprint.
Multimodal
Multimodal
41
Multimodal
Prefrontal
3.5
3.0
2.5
GI
2.0
1.5
(a)
1.0
(c)
Rostral
Caudal
Variability of
functional
connectivity
GI =
(b)
High variability
Low variability
(d)
Figure 4 (a) Lateral surface of a human left hemisphere. (b) Drawing of the contour of a coronal section through the human brain at the level
highlighted in (a). The lengths of the complete (red line) and outer (blue line) contours were measured and the gyrification index (GI) was calculated for
each section. (c) Course of the band that covers 95% of the single GI values from the frontal pole to the occipital pole in the left hemisphere of 61 human
brains. The approximate extent of multimodal areas is highlighted. Adapted from Zilles, K., Armstrong, E., Schleicher, A., & Kretschmann, H.-J. (1988).
The human pattern of gyrification in the cerebral cortex. Anatomy and Embryology, 179, 173179. (d) Intersubject variability in resting state functional
connectivity. Blue tones code for values below the global mean and orange tones for values above it. Figure in panel (d) was adapted from Mueller, S.,
Wang, D., Fox, M. D., Yeo, B. T., Sepulcre, J., Sabuncu, M. R., et al. (2013). Individual variability in functional connectivity architecture of the human
brain. Neuron, 77, 586595.
3.25
3
2.75
GI
2.5
2.25
66th80th
week
2
1.75
1.5
1.25
1
10
Birth
200
Age (weeks)
4000
Figure. 5 Ontogenetic development of cortical folding in humans from fetal to adult stages. Age in weeks post conception (birth at 40th week). Data
from Armstrong, E., Schleicher, A., Omram, H., Curtis, M., & Zilles, K. (1995). The ontogeny of human gyrification. Cerebral Cortex, 5, 5663;
Zilles, K., Armstrong, E., Schleicher, A., & Kretschmann, H.-J. (1988). The human pattern of gyrification in the cerebral cortex. Anatomy and Embryology,
179, 173179.
42
Acknowledgment
This work was supported by the portfolio theme
Supercomputing and Modeling for the Human Brain of
the Helmholtz Association, Germany.
Competing financial interests: The authors declare that they
have no competing financial interests.
References
Amunts, K., Schleicher, A., Burgel, U., Mohlberg, H., Uylings, H. B.M, & Zilles, K.
(1999). Brocas region revisited: Cytoarchitecture and intersubject variability.
Journal of Comparative Neurology, 412, 319341.
Armstrong, E., Curtis, M., Buxhoeveden, D. P., Fregoe, C., Zilles, K., Casanova, M. F.,
et al. (1991). Cortical gyrification in the rhesus monkey: A test of the mechanical
folding hypothesis. Cerebral Cortex, 1, 426432.
Armstrong, E., Schleicher, A., Omram, H., Curtis, M., & Zilles, K. (1995). The ontogeny
of human gyrification. Cerebral Cortex, 5, 5663.
Bartley, A. J., Jones, D. W., & Weinberger, D. R. (1997). Genetic variability of human
brain size and cortical gyral patterns. Brain, 120(Pt 2), 257269.
Bearden, C. E., van Erp, T. G., Dutton, R. A., Lee, A. D., Simon, T. J., Cannon, T. D., et al.
(2009). Alterations in midline cortical thickness and gyrification patterns mapped in
children with 22q11.2 deletions. Cerebral Cortex, 19, 115126.
Bonneau, D., Toutain, A., Laquerriere, A., Marret, S., Saugier-Veber, P., Barthez, M. A.,
et al. (2002). X-linked lissencephaly with absent corpus callosum and ambiguous
genitalia (XLAG): Clinical, magnetic resonance imaging, and neuropathological
findings. Annals of Neurology, 51, 340349.
Brodmann, K. (1913). Neue Forschungsergebnisse der Grohirnrindenanatomie mit
besonderer Berucksichtigung anthropologischer Fragen. In A. Witting (Ed.),
Verhandlungen der Gesellschaft Deutscher Naturforscher und Arzte (pp. 200240).
Dresden: Vogel.
Caraballo, R. H., Cersosimo, R. O., Mazza, E., & Fejerman, N. (2000). Focal
polymicrogyria in mother and son. Brain and Development, 22, 336339.
Casanova, M. F., Araque, J., Giedd, J., & Rumsey, J. M. (2004). Reduced brain size and
gyrification in the brains of dyslexic patients. Journal of Child Neurology, 19,
275281.
Caspers, S., Geyer, S., Schleicher, A., Mohlberg, H., Amunts, K., & Zilles, K. (2006).
The human inferior parietal cortex: Cytoarchitectonic parcellation and interindividual
variability. NeuroImage, 33, 430448.
Chenn, A., & Walsh, C. A. (2002). Regulation of cerebral cortical size by control of cell
cycle exit in neural precursors. Science, 297, 365369.
43
Chi, J. G., Dooling, E. C., & Gilles, F. H. (1977). Gyral development of the human brain.
Annals of Neurology, 1, 8693.
Davis, S. W., Dennis, N. A., Daselaar, S. M., Fleck, M. S., & Cabeza, R. (2008). Que
PASA? The posterior-anterior shift in aging. Cerebral Cortex, 18, 12011209.
DeFelipe, J. (2011). The evolution of the brain, the human nature of cortical circuits, and
intellectual creativity. Frontiers in Neuroanatomy, 5, 29.
Dennerll, T. J., Lamoureux, P., Buxbaum, R. E., & Heidemann, S. R. (1989). The
cytomechanics of axonal elongation and retraction. Journal of Cell Biology, 109,
30733083.
Dolcos, F., Rice, H. J., & Cabeza, R. (2002). Hemispheric asymmetry and aging: Right
hemisphere decline or asymmetry reduction. Neuroscience & Biobehavioral
Reviews, 26, 819825.
Duvernoy, H. M. (1999). The human brain: Surface, blood supply, and threedimensional sectional anatomy (2nd ed.). Vienna: Springer.
Elias, H., & Schwartz, D. (1969). Surface areas of the cerebral cortex of mammals
determined by stereological methods. Science, 166, 111113.
Fietz, S. A., Kelava, I., Vogt, J., Wilsch-Brauninger, M., Stenzel, D., Fish, J. L., et al.
(2010). OSVZ progenitors of human and ferret neocortex are epithelial-like and
expand by integrin signaling. Nature Neuroscience, 13, 690699.
Francis, F., Meyer, G., Fallet-Bianco, C., Moreno, S., Kappeler, C., Cabrera Socorro, A.,
et al. (2006). Human disorders of cortical development: From past to present.
European Journal of Neuroscience, 23, 877893.
Gaser, C., Luders, E., Thompson, P. M., Lee, A. D., Dutton, R. A., Geaga, J. A., et al.
(2006). Increased local gyrification mapped in Williams syndrome. NeuroImage, 33,
4654.
Gleeson, J. G., Allen, K. M., Fox, J. W., Lamperti, E. D., Berkovic, S., Scheffer, I., et al.
(1998). Doublecortin, a brain-specific gene mutated in human X-linked
lissencephaly and double cortex syndrome, encodes a putative signaling protein.
Cell, 92, 6372.
Hansen, D. V., Lui, J. H., Parker, P. R., & Kriegstein, A. R. (2010). Neurogenic
radial glia in the outer subventricular zone of human neocortex. Nature, 464,
554561.
Hasan, A., McIntosh, A. M., Droese, U. A., Schneider-Axmann, T., Lawrie, S. M.,
Moorhead, T. W., et al. (2011). Prefrontal cortex gyrification index in twins: An
MRI study. European Archives of Psychiatry and Clinical Neuroscience, 261,
459465.
Haydar, T. F., Kuan, C. Y., Flavell, R. A., & Rakic, P. (1999). The role of cell death in
regulating the size and shape of the mammalian forebrain. Cerebral Cortex, 9,
621626.
Herculano-Houzel, S. (2011). Not all brains are made the same: New views on brain
scaling in evolution. Brain, Behavior and Evolution, 78, 2236.
Herculano-Houzel, S., Collins, C. E., Wong, P., Kaas, J. H., & Lent, R. (2008). The basic
nonuniformity of the cerebral cortex. Proceedings of the National Academy of
Sciences of the United States of America, 105, 1259312598.
Hilgetag, C. C., & Barbas, H. (2006). Role of mechanical factors in the morphology of
the primate cerebral cortex. PLoS Computational Biology, 2, e22.
Hogstrom, L. J., Westlye, L. T., Walhovd, K. B., & Fjell, A. M. (2013). The structure of
the cerebral cortex across adult life: Age-related patterns of surface area, thickness,
and gyrification. Cerebral Cortex, 23, 25212530.
Holmes, C. J., Hoge, R., Collins, L., Woods, R., Toga, A. W., & Evans, A. C. (1998).
Enhancement of MR images using registration for signal averaging. Journal of
Computer Assisted Tomography, 22, 324333.
Jockwitz, C., Caspers, S., Lux, S., Jutten, K., Lenzen, S., Moebus, S., et al. (2014).
Gyrification changes in Default Mode Network as correlate of its functional
reorganization with age. Proceedings of the 20th Annual Meeting of the Organization
for Human Brain Mapping.
Jou, R. J., Minshew, N. J., Keshavan, M. S., & Hardan, A. Y. (2010). Cortical gyrification
in autistic and Asperger disorders: A preliminary magnetic resonance imaging
study. Journal of Child Neurology, 25, 14621467.
Judas, M., Sedmak, G., Pletikos, M., & Jovanov-Milosevic, N. (2010). Populations of
subplate and interstitial neurons in fetal and adult human telencephalon. Journal of
Anatomy, 217, 381399.
Kochunov, P., Mangin, J. F., Coyle, T., Lancaster, J., Thompson, P., Riviere, D., et al.
(2005). Age-related morphology trends of cortical sulci. Human Brain Mapping, 26,
210220.
Kostovic, I., & Judas, M. (2010). The development of the subplate and thalamocortical
connections in the human foetal brain. Acta Paediatrica, 99, 11191127.
Kostovic, I., & Rakic, P. (1990). Developmental history of the transient subplate zone in
the visual and somatosensory cortex of the macaque monkey and human brain.
Journal of Comparative Neurology, 297, 441470.
Kriegstein, A., Noctor, S., & Martinez-Cerdeno, V. (2006). Patterns of neural stem and
progenitor cell division may underlie evolutionary cortical expansion. Nature
Reviews. Neuroscience, 7, 883890.
44
Lebed, E., Jacova, C., Wang, L., & Beg, F. (2012). Novel surface-smoothing based local
Gyrification index. IEEE Transactions on Medical Imaging, 32(4), 660669.
Lin, J. J., Salamon, N., Lee, A. D., Dutton, R. A., Geaga, J. A., Hayashi, K. M., et al.
(2007). Reduced neocortical thickness and complexity mapped in mesial temporal
lobe epilepsy with hippocampal sclerosis. Cerebral Cortex, 17, 20072018.
Luders, E., Narr, K. L., Bilder, R. M., Szeszko, P. R., Gurbani, M. N., Hamilton, L., et al.
(2008). Mapping the relationship between cortical convolution and intelligence:
Effects of gender. Cerebral Cortex, 18, 20192026.
Luders, E., Narr, K. L., Thompson, P. M., Rex, D. E., Jancke, L., Steinmetz, H., et al.
(2004). Gender differences in cortical complexity. Nature Neuroscience, 7, 799800.
Lui, J. H., Hansen, D. V., & Kriegstein, A. R. (2011). Development and evolution of the
human neocortex. Cell, 146, 1836.
Magnotta, V. A., Andreasen, N. C., Schultz, S. K., Harris, G., Cizadlo, T., Heckel, D.,
et al. (1999). Quantitative in vivo measurement of gyrification in the human brain:
Changes associated with aging. Cerebral Cortex, 9, 151160.
Malikovic, A., Vucetic, B., Milisavljevic, M., Tosevski, J., Sazdanovic, P., Milojevic, B.,
et al. (2012). Occipital sulci of the human brain: Variability and morphometry.
Anatomical Science International, 87, 6170.
Marino, L., Connor, R. C., Fordyce, R. E., Herman, L. M., Hof, P. R., Lefebvre, L., et al.
(2007). Cetaceans have complex brains for complex cognition. PLoS Biology, 5, e139.
Mazziotta, J. C., Toga, A. W., Evans, A., Fox, P., & Lancaster, J. (1995). A probabilistic
atlas of the human brain: Theory and rationale for its development. The International
Consortium for Brain Mapping (ICBM). NeuroImage, 2, 89101.
Molnar, Z., & Clowry, G. (2012). Cerebral cortical development in rodents and primates.
Progress in Brain Research, 195, 4570.
Mota, B., & Herculano-Houzel, S. (2012). How the cortex gets its folds: An inside-out,
connectivity-driven model for the scaling of mammalian cortical folding. Frontiers in
Neuroanatomy, 6, 3.
Mueller, S., Wang, D., Fox, M. D., Yeo, B. T., Sepulcre, J., Sabuncu, M. R., et al. (2013).
Individual variability in functional connectivity architecture of the human brain.
Neuron, 77, 586595.
Ongur, D., Ferry, A. T., & Price, J. L. (2003). Architectonic subdivision of the human
orbital and medial prefrontal cortex. Journal of Comparative Neurology, 460,
425449.
Ono, M., Kubik, S., & Abernathey, C. D. (1990). Atlas of the cerebral sulci. New York:
Georg Thieme Verlag.
Palaniyappan, L., & Liddle, P. F. (2012). Aberrant cortical gyrification in schizophrenia:
A surface-based morphometry study. Journal of Psychiatry and Neuroscience, 37,
399406.
Pang, T., Atefy, R., & Sheen, V. (2008). Malformations of cortical development.
Neurologist, 14, 181191.
Petrides, M. (2012). The human cerebral cortex: An MRI atlas of the sulci and gyri in
MNI stereotaxic space. Amsterdam: Academic Press.
Piao, X., Basel-Vanagaite, L., Straussberg, R., Grant, P. E., Pugh, E. W., Doheny, K., et al.
(2002). An autosomal recessive form of bilateral frontoparietal polymicrogyria maps to
chromosome 16q12.2-21. American Journal of Human Genetics, 70, 10281033.
Piao, X., Chang, B. S., Bodell, A., Woods, K., Benzeev, B., Topcu, M., et al. (2005).
Genotype-phenotype analysis of human frontoparietal polymicrogyria syndromes.
Annals of Neurology, 58, 680687.
Pienaar, R., Fischl, B., Caviness, V., Makris, N., & Grant, P. E. (2008). A methodology
for analyzing curvature in the developing brain from preterm to adult. International
Journal of Imaging Systems and Technology, 18, 4268.
Pillay, P., & Manger, P. R. (2007). Order-specific quantitative patterns of cortical
gyrification. European Journal of Neuroscience, 25, 27052712.
Rakic, P. (1995). A small step for the cell, a giant leap for mankind: A hypothesis of
neocortical expansion during evolution. Trends in Neurosciences, 18, 383388.
Reillo, I., & Borrell, V. (2012). Germinal zones in the developing cerebral cortex of
ferret: Ontogeny, cell cycle kinetics, and diversity of progenitors. Cerebral Cortex,
22, 20392054.
Reillo, I., de Juan, R. C., Garcia-Cabezas, M. A., & Borrell, V. (2011). A role for
intermediate radial glia in the tangential expansion of the mammalian cerebral
cortex. Cerebral Cortex, 21, 16741694.
Reiner, O., Carrozzo, R., Shen, Y., Wehnert, M., Faustinella, F., Dobyns, W. B., et al.
(1993). Isolation of a Miller-Dieker lissencephaly gene containing G protein betasubunit-like repeats. Nature, 364, 717721.
Richman, D. P., Stewart, R. M., Hutchinson, J. W., & Caviness, V. (1975). Mechanical
model of brain convolutional development. Science, 189, 1821.
Rilling, J. K., & Insel, T. R. (1999). The primate neocortex in comparative
perspective using magnetic resonance imaging. Journal of Human Evolution, 37,
191223.
Robin, N. H., Taylor, C. J., McDonald-McGinn, D. M., Zackai, E. H., Bingham, P.,
Collins, K. J., et al. (2006). Polymicrogyria and deletion 22q11.2 syndrome:
Window to the etiology of a common cortical malformation. American Journal of
Medical Genetics. Part A, 140, 24162425.
Rogers, J., Kochunov, P., Zilles, K., Shelledy, W., Lancaster, J., Thompson, P., et al.
(2010). On the genetic architecture of cortical folding and brain volume in primates.
NeuroImage, 53, 11031108.
Schultz, C. C., Wagner, G., Koch, K., Gaser, C., Roebel, M., Schachtzabel, C., et al.
(2013). The visual cortex in schizophrenia: Alterations of gyrification rather than
cortical thickness-a combined cortical shape analysis. Brain Structure and Function,
218, 5158.
Thompson, P. M., Schwartz, C., Lin, R. T., Khan, A. A., & Toga, A. W. (1996).
Three-dimensional statistical analysis of sulcal variability in the human brain.
Journal of Neuroscience, 16, 42614274.
Toro, R., Perron, M., Pike, B., Richer, L., Veillette, S., Pausova, Z., et al. (2008).
Brain size and folding of the human cerebral cortex. Cerebral Cortex, 18,
23522357.
Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F., Etard, O.,
Delcroix, N., et al. (2002). Automated anatomical labeling of activations in SPM
using a macroscopic anatomical parcellation of the MNI MRI single-subject brain.
NeuroImage, 15, 273289.
van Essen, D. C. (1997). A tension-based theory of morphogenesis and compact wiring
in the central nervous system. Nature, 385, 313318.
van Essen, D. C. (2007). Cerebral cortical folding patterns in primates: Why they vary
and what they signify. In J. H. Kaas (Ed.), Evolution of nervous systems
(pp. 267276). Amsterdam: Elsevier.
Vogt, B. A., Nimchinsky, E. A., Vogt, L., & Hof, P. R. (1995). Human cingulate cortex:
Surface features, flat maps, and cytoarchitecture. Journal of Comparative Neurology,
359, 490506.
Weiner, K. S., Golarai, G., Caspers, J., Chuapoco, M. R., Mohlberg, H., Zilles, K., et al.
(2014). The mid-fusiform sulcus: A landmark identifying both cytoarchitectonic
and functional divisions of human ventral temporal cortex. NeuroImage, 84,
453465.
Welker, W. (1990). Why does cerebral cortex fissure and fold? A review of determinants
of gyri and sulci. In E. G. Jones & A. Peters (Eds.), Comparative structure and
evolution of cerebral cortex (pp. 3136). New York: Plenum Press.
Wolosin, S. M., Richardson, M. E., Hennessey, J. G., Denckla, M. B., & Mostofsky, S. H.
(2009). Abnormal cerebral cortex structure in children with ADHD. Human Brain
Mapping, 30, 175184.
Xu, G., Knutsen, A. K., Dikranian, K., Kroenke, C. D., Bayly, P. V., & Taber, L. A. (2010).
Axons pull on the brain, but tension does not drive cortical folding. Journal of
Biomechanical Engineering, 132, 071013.
Zhang, Y., Zhou, Y., Yu, C., Lin, L., Li, C., & Jiang, T. (2010). Reduced cortical
folding in mental retardation. AJNRAmerican Journal of Neuroradiology, 31,
10631067.
Zilles, K., Armstrong, E., Moser, K. H., Schleicher, A., & Stephan, H. (1989). Gyrification
in the cerebral cortex of primates. Brain, Behavior and Evolution, 34, 143150.
Zilles, K., Armstrong, E., Schleicher, A., & Kretschmann, H.-J. (1988). The human pattern
of gyrification in the cerebral cortex. Anatomy and Embryology, 179, 173179.
Zilles, K., Schleicher, A., Langemann, C., Amunts, K., Morosan, P.,
Palomero-Gallagher, N., et al. (1997). Quantitative analysis of sulci in the human
cerebral cortex: Development, regional heterogeneity, gender difference, asymmetry,
intersubject variability and cortical architecture. Human Brain Mapping, 5,
218221.
Sulci as Landmarks
J-F Mangin, CEA Saclay, Gif-sur-Yvette, France
G Auzias, Aix-Marseille Universite, Marseille, France
O Coulon, Aix-Marseille Universite, Marseille, France
ZY Sun, CEA Saclay, Gif-sur-Yvette, France
D Rivie`re, CEA Saclay, Gif-sur-Yvette, France
J Regis, CHU La Timone, Marseille, France
2015 Elsevier Inc. All rights reserved.
Matching brains is a basic need in neurosciences. Brain architecture provides the guideline for this matching, because architecture stands as the topology of the underlying neural network.
Provided that the brains to be matched come from the same
species, this topology is supposed to be largely invariant across
standard subjects. With regard to the cortical surface, structural
architecture mainly amounts to multiple overlapping parcellations defining homogeneous areas for various microstructural
features (Amunts et al., 2014). Such parcellations can stem, for
instance, from cytoarchitectony, myeloarchitectony, receptor
densities, or structural connectivity profiles. One of the goals
of matching brains is the study of functional architecture, which
is supposed to fit in a way or another structural architecture.
In neuroimaging, matching brains is usually understood as
spatially normalizing images of these brains. Each brain is
warped toward a so-called standard space in which the localization of architectural modules is supposed to be stable across
subjects. Unfortunately, the T1-weighted MR scans classically
used to perform this spatial normalization include very few
architectural features relative to the cerebral cortex. The main
information included in these scans is cortical thickness and
the morphology of cortical folds. Since the link between the
cortical folding pattern and architecture is unclear except in
primary areas (Welker, 1988), the earliest spatial normalization techniques did not strongly focus on aligning cortical
sulci. This situation resulted also from the difficulties raised
by the large variability of the folding pattern across individuals.
The template brains driving the warping to the standard space
were fuzzy brain images obtained by averaging a large number
of normalized brain images without sulcal alignment. Hence,
architectural compliance of spatial normalization was poor at
the onset of the field of neuroimaging.
During the last years, however, impressive advances have
been achieved by spatial normalization technology with regard
to sulcal alignment. While our understanding of the architectural value of sulci is still weak, it did make sense to use them as
a proxy, as long as better architectural clues were missing.
Standard approaches like DARTEL in 3-D (Ashburner, 2007)
or FreeSurfer and CIVET for the cortical surface (Fischl, Sereno,
Tootell, & Dale, 1999; Lyttelton, Boucher, Robbins, & Evans,
2007) are very efficient at aligning automatically primary sulci,
which were shown to improve the alignment of primary architectonic areas (Fischl et al., 2008). Recent advances in neuroimaging will now lead to further improvement in the
architectural compliance of spatial normalization using multimodal data, for instance, myelin maps, or diffusion-based
connectivity information but also functional landmarks that
can be easier to obtain than architectural landmarks in some
http://dx.doi.org/10.1016/B978-0-12-397025-1.00198-6
45
46
Figure 1 Twelve left lateral cortical surfaces with elementary folds manually labeled according to the sulcus atlas of BrainVISA (http://brainvisa.info)
(Perrot, Rivie`re et al. 2011). Reproduced from Perrot, M., Rivie`re, D., & Mangin, J. F. (2011). Cortical sulci recognition and spatial normalization.
Medical Image Analysis, 15(4), 529550.
Figure 2 Twelve left mesial cortical surfaces processed like for Figure 1.
F.C.L.a.
F.C.L.r.ant.
F.C.L.r.diag.
F.C.L.r.sc.ant.
F.C.M.ant.
F.Cal.ant.-Sc.Cal.
F.I.P.Po.C.inf.
F.I.P.r.int.l
F.P.O.
OCCIPITAL
S.C.
S.Call.
S.F.inf.
S.F.int.
S.F.marginal.
S.F.orbitaire.
S.F.sup.
S.Li.ant.
S.O.T.lat.ant.
S.O.T.lat.med.
S.O.p.
S.Or.
S.Pa.sup.
S.Pe.C.inf.
S.Pe.C.marginal.
S.Pe.C.sup.
S.R.inf.
S.T.i.ant.
S.T.pol.
S.T.s.ter.asc.ant.
S.p.C.
ventricle
Paracentral sulcus
Ventricle
F.C.L.p.
F.C.L.r.asc.
F.C.L.r.retroC.tr.
F.C.L.r.sc.post.
F.C.M.post.
F.Coll.
F.I.P.
F.I.P.r.int.2
INSULA
S.C.LPC.
S.C.sylvian.
S.Cu.
S.F.ing.ant.
S.F.inter.
S.F.median.
S.F.polaire.tr.
S.GSM.
S.Li.post.
S.O.T.lat.int.
S.O.T.lat.post.
S.Olf.
S.Pa.int.
S.Pa.t.
S.Pe.C.inter.
S.Pe.C.median.
S.Po.C.sup.
S.Rh.
S.T.i.post.
S.T.s.
S.T.s.ter.asc.post.
S.s.P.
Sub-parietal sulcus
47
48
IT 1
S1
Affine
Dartel
S2
IT 2
...
Disco
Dartel
IT Q
SN
t
Disco
4
(a)
(b)
(c)
Figure 4 Sulcal-driven 3-D spatial normalization. (a) Iterative refinement of a group-based sulcal template aligning individual simplified sulcal imprint.
(b) Detailed illustration in the central sulcal area using five individuals and three alternative alignment procedures. Note that explicit sulcal constraints prevent
mismatch. (c) Group-level activation maps obtained in the left hemisphere for extension of the right wrist for DARTEL (Ashburner, 2007) and DISCO
(Auzias et al., 2011). Maps from ten subjects are superimposed on the corresponding mean structural image computed for each method; t 4.0, p 0.0001
voxel-level uncorrected (Pizzagalli, Auzias, Delon-Martin, & Dojat, 2013). Explicit sulcal constraints improve t values and activation size.
49
Isomap axis
Weights 1:
0.1
0.3
0.06
Weights 2:
Weighted SPAM:
Iso-surface
of the weighted SPAM:
Average 1
Average 2
Hand
motion
Silent reading
Figure 5 Pattern-specific templates. Isomap manifold learning algorithm captures a 1-D approximation of the high-dimensional space spanned by the
central sulcus. Moving averages of the sulcal morphology or of registered individual fMRI maps can be computed along this manifold to get patternspecific templates (Sun, Pinel, et al., 2012). Here, using 252 subjects, the position of the putative hand knob in the pattern-specific template moves
dorsally from one side to the other side of the axis, while a second lower knob appears. The corresponding motor activation template follows the hand
knob, confirming that this well-known functional landmark holds even for extreme configurations. A reading activation template extends toward
premotor areas while the second knob appears, which could provide clues about the architectural value of this second landmark.
50
continuum between the interrupted configuration and the configuration with a very deep pli de passage. Hence, defining the
optimal number of patterns is difficult. As an alternative, it was
proposed to capture a low-dimensional manifold approximation of the high-dimensional space spanned by each sulcus (Sun,
Kloppel, et al., 2012), using Isomap algorithm, a modern version
of multidimensional scaling (Tenenbaum, de Silva, & Langford,
2000). The multitemplate-based strategy mentioned earlier has
been directly extended to this manifold strategy as illustrated in
Figure 5 (Sun, Pinel, et al., 2012). The manifold approach refines
the multitemplate strategy because it provides the transmutation
of the architectural templates along with the transmutation of
morphological patterns, which is a guideline for the second-level
alignment.
(a1)
(a3)
(a2)
(c2)
(b)
(c1)
(d1)
(d2)
Figure 6 Sulcal roots and sulcal pits. (a) Qualitative maps of the pli de passage or annectant gyri leading to propose the concept of sulcal roots, the
atoms of the folding pattern supposed to stem from ontogeny (Regis, 1994). (b) A map of the lateral sulcal roots for a brain oriented according to
Talairach space (Regis et al., 2005). (c) A group map of sulcal pits, the deepest points of the folding pattern in adults (Im et al., 2010). (d) A group map of
sulcal pits in one-year-old infants (Meng, Li, Lin, Gilmore, & Shen, 2014).
51
Figure 7 Meridians and parallels. Top row: Extracting sulcal bottom lines using Morphologist pipeline of BrainVISA. Middle row left: Model of cortical
sulcal organization in meridians and parallels; center: general principle of the Hip-Hop method (Auzias et al., 2013); right: a cortical surface with sulcal
lines, flat harmonic mapping f of the same surface (sulcal lines and mean curvature of the original surface), result of the registration with the model
(mapping g), resulting coordinate system. Bottom row: sulcal lines of 62 subjects in the rectangular domain after harmonic mapping f; same after
registration with the model; same on the average surface of the 62 subjects.
instance, they could slide along the sulcal bottom. Hence, emerging studies with premature babies and infants are of high interest
(Lefe`vre et al., 2009; Meng et al., 2014; Operto & Auzias, 2012).
These mind-opening concepts provide new ways to explore
the links between morphology and architecture. For instance,
sulcal root and sulcal pit maps reveal striking alignments with
the global geometry of the cerebral cortex. This led to design
dedicated coordinate systems mimicking latitude and longitude on Earth (Auzias et al., 2013; Clouchoux et al., 2010;
Toro & Burnod, 2003) (see Figure 7). The meridians and
parallels underlying these systems can be observed in the cortex of a lot of mammals (Welker, 1988) and are supposed to
stem from phylogeny and ontogeny. They could even have an
analog in white matter organization (Wedeen et al., 2012).
Hence, they could have a strong architectural content.
Acknowledgments
Amiez, C., Kostopoulos, P., Champod, A. S., & Petrides, M. (2006). Local morphology
predicts functional organization of the dorsal premotor region in the human brain.
The Journal of Neuroscience, 26(10), 27242731.
Amunts, K., Hawrylycz, M. J., Van Essen, D. C., Van Horn, J. D., Harel, N., Poline, J. B.,
et al. (2014). Interoperable atlases of the human brain. NeuroImage, 99, 525532.
References
52
Plaze, M., Paille`re-Martinot, M.-L., Penttila, J., Januel, D., De Beaurepaire, R.,
Bellivier, F., et al. (2011). Where do auditory hallucinations come from? A brain
morphometry study of schizophrenia patients with inner or outer space
hallucinations. Schizophrenia Bulletin, 37(1), 212.
Regis, J. (1994). Deep sulcal anatomy and functional mapping of the cerebral cortex (in
french), MD Thesis, Universite dAix-Marseille.
Regis, J., Mangin, J., Ochiai, T., Frouin, V., Riviere, D., Cachia, A., et al. (2005). "Sulcal
root" generic model: A hypothesis to overcome the variability of the human cortex
folding patterns. Neurologia Medico-Chirurgica, 45(1), 117.
Regis, J., Tamura, M., Park, M., McGonigal, A., Riviere, D., Coulon, O., et al. (2011).
Subclinical abnormal gyration pattern, a potential anatomic marker of epileptogenic
zone in patients with magnetic resonance imaging-negative frontal lobe epilepsy.
Neurosurgery, 69(1), 8093.
Reillo, I., de Juan Romero, C., Garca-Cabezas, M., & Borrell, V. (2011). A role for
intermediate radial glia in the tangential expansion of the mammalian cerebral
cortex. Cerebral Cortex, 21(7), 16741694.
Robinson, E. C., Jbabdi, S., Glasserlabel, M. F., Andersson, J., Burgess, G. C.,
Harms, M. P., et al. (2014). MSM: A new flexible framework for Multimodal Surface
Matching. NeuroImage, 100, 414426.
Roland, P. E., Geyer, S., Amunts, K., Schormann, T., Schleicher, A., Malikovic, A., et al.
(1997). Cytoarchitectural maps of the human brain in standard anatomical space.
Human Brain Mapping, 5(4), 222227.
Segal, E., & Petrides, M. (2012). The morphology and variability of the caudal rami of
the superior temporal sulcus. The European Journal of Neuroscience, 36(1),
20352053.
Sun, Z. Y., Kloppel, S., Rivie`re, D., Perrot, M., Frackowiak, R., Siebner, H., et al. (2012).
The effect of handedness on the shape of the central sulcus. NeuroImage, 60(1),
332339.
Sun, Z., Perrot, M., Tucholka, A., Rivie`re, D., & Mangin, J.-F. (2009). Constructing a
dictionary of human brain folding patterns. Medical Image Computing and
Computer-Assisted Intervention MICCAI, 12, 117124.
Sun, Z. Y., Pinel, P., Moreno, A., Perrot, M., Rivie`re, D., Dehaene, S., et al. (2012).
Morphological manifold-based spatial normalization for fMRI group analysis.
Beijin: HBM.
Tenenbaum, J., de Silva, V., & Langford, J. (2000). A global geometric framework for
nonlinear dimensionality reduction. Science, 290(5500), 23192323.
Thompson, P., & Toga, A. W. (1996). A surface-based technique for warping threedimensional images of the brain. IEEE Transactions on Medical Imaging, 15(4),
402417.
Toro, R., & Burnod, Y. (2003). Geometric atlas: Modeling the cortex as an organized
surface. NeuroImage, 20(3), 14681484.
Van Essen, D. C. (1997). A tension-based theory of morphogenesis and compact wiring
in the central nervous system. Nature, 385(6614), 313318.
Van Essen, D. C. (2012). Cortical cartography and Caret software. NeuroImage, 62(2),
757764.
Watson, J. D., Myers, R., Frackowiak, R. S., Hajnal, J. V., Woods, R. P., Mazziotta, J. C.,
et al. (1993). Area V5 of the human brain: Evidence from a combined study using
positron emission tomography and magnetic resonance imaging. Cerebral Cortex,
3(2), 7994.
Wedeen, V. J., Rosene, D. L., Wang, R., Dai, G., Mortazavi, F., Hagmann, P., et al.
(2012). The geometric structure of the brain fiber pathways. Science, 335(6076),
16281634.
Weiner, K. S., Golarai, G., Caspers, J., Chuapoco, M. R., Mohlberg, H., Zilles, K., et al.
(2014). The mid-fusiform sulcus: A landmark identifying both cytoarchitectonic
and functional divisions of human ventral temporal cortex. NeuroImage, 84,
453465.
Welker, W. (1988). Why does cerebral cortex fissure and fold? Cerebral Cortex, 8B,
3135.
Yeo, B. T., Sabuncu, M. R., Vercauteren, T., Holt, D. J., Amunts, K., Zilles, K., et al.
(2010). Learning task-optimal registration cost functions for localizing
cytoarchitecture and function in the cerebral cortex. IEEE Transactions on Medical
Imaging, 29(7), 14241441.
Zilles, K., Palomero-Gallagher, N., & Amunts, K. (2013). Development of cortical
folding during evolution and ontogeny. Trends in Neurosciences, 36(5), 275284.
Zlatkina, V., & Petrides, M. (2010). Morphological patterns of the postcentral sulcus in
the human brain. The Journal of Comparative Neurology, 518(18), 37013724.
Glossary
Introduction
http://dx.doi.org/10.1016/B978-0-12-397025-1.00199-8
53
54
Figure 1 Cell arrays or cell columns in layer III. (a) Adult rhesus monkey, (b) adult human cortex, (c) rat brain at 21 days, and (d) cell columns in
1-day-old rat cortex.
55
cortex displays a near-homogeneous vertical arrangement (column) of cells known as ontogenetic or radial cell columns
(Rakic, 1978). The genesis of the cortex occurs in the ventricles
by a series of symmetrical and asymmetrical divisions (Rakic &
Kornack, 2001). In the first phase, cells located in the ventricular zone produce two additional progenitor cells with each
mitotic cell division. This symmetrical division is responsible
for the number of founder cells that controls the total number
of ontogenetic columns that will be produced in the cortex.
According to the radial unit hypothesis, it is the number of
these ontogenetic columns that determines the cortical surface
area (Rakic & Kornack, 2001). At some point, progenitor cells
begin to divide asymmetrically, producing one daughter cell
that becomes a neuron and will move out into the cortical
plate, and which will not undergo further division. The second
phase is responsible for the number of cells within a column
and the thickness of the cortex. Several clones of neurons that
share a common site of origin in the ventricular zone use a
common migratory pathway along the fascicles of the radial
glial cells to settle within the same column in the cortical plate
(Rakic, 2003). Radial glial cells create long fascicles that extend
from the ventricular zone to the top of the cortical plate so that
they span the entire width of the cerebral wall during corticoneurogenesis. New born nerve cells use these to traverse the
cortical plate. Though there are small differences between
radial glial cells among mammals, overall they are very similar
in morphology and chemistry. The neuronalglial unit (consisting of the radial glial cells and migrating neurons) is conserved in a variety of animals including the mouse, rat,
hamster, cat, and human fetus.
Not all cortical interneurons originate from the ventricular
zone and migrate in a radial fashion. In rodents, this is most
notable as the majority of cortical interneurons originate from
the ganglionic eminence of the ventral telencephalon and
migrate tangentially to the cortical plate (Marn & Rubenstein,
2001). In mice, up to 25% of all cortical neurons migrate
nonradially, whereas in human, this percentage is < 10% of
the total (Letinic, Zoncu, & Rakic, 2002). Thus, there are taxonomic specializations associated with this process.
The total amount of radial units that will be present in the
adult cortex are controlled during embryogenesis by a few
regulatory genes, while the final pattern and size of cytoarchitectonic regions is thought to be the work of a different set of
genes (Rakic & Kornack, 2001). The configuration of columns
within an adult cytoarchitectonic area is therefore the result of
the genetic influences described in the preceding text and
epigenetic factors such as interactions of cells, inhibitory neurons, and afferent systems. It is clear that alterations in these
genes or their influences can have profound effects on the
cortex. The increase in founder cell number is exponential so
that a small prolongation of cell division or changes in length
of the cell cycle would result in significant increases in the
number of ontogenetic units produced. The discovery of the
ontogenetic column in the process of encephalization also
elucidates how that process can lead to brain reorganization.
56
Figure 5 (a)(c) Collaterals in the apical dendrite bundles. Note the distinct branching of individual fibers that connect to a neighboring bundle as
highlighted by the yellow arrows. Reprinted with permission from Elsevier Limited.
cells produced per unit affects the cortical depth. Since surface
area has increased a 1000-fold (comparing mouse to human),
while cortical depth has only increased three to four times, the
major impetus for cortical enlargement has been the addition
of new ontogenetic units. The width of minicolumns falls
within a range of 2080 mm, with the typical size being somewhere between 30 and 60. Minicolumn size varies between and
within species as do their internal components and configuration (Buxhoeveden & Casanova, 2002, 2005; HerculanoHouzel, Collins, Wong, Kaas, & Lent, 2008).
There is also no direct correlation between the size of minicolumns and brain size for animals with a diverse evolutionary
history, though it is likely that a correlation does exist for
57
Lamina
I.
II.
49.72
Gray value
III.
IV.
8.60
274.3
0.0
V.
Distance (mm)
(b)
VI.
(a)
Gray value
119.1
Gray value
255
78.8
0
(d)
187
Distance (mm)
0
0
(c)
456
Distance (mm)
Figure 6 (a) Vertical components of minicolumn anatomy. The following include the components that provide the anatomical and physiological basis
for verticality in the cortex. In addition, there are horizontal efferent and afferent fibers as well as local inhibitory connections occurring at different layers.
Modified from Buxhoeveden, D., & Casanova, M. F. (2002). The minicolumn hypothesis in neuroscience. Brain, 125, 935951, p. 938, with permission
from Oxford University Press. Brown: Axons from stellate cells LIV to LIII/II. Green: Apical dendrites from LII to LI that may be a subsystem within
minicolumns. Black: Long apical dendrites LV to LI. Red: Apical dendrites from LVI to LIV. Orange: Apical dendrites from LIII/LII to LI. Magenta:
Myelinated axons from LV. Blue: Myelinated axons from LVI. Purple: Axons of double bouquet cells. Gray: Pyramidal cells. (b)(d) Periodicity. (b)
Columns represent a repeating element of modules in the cortex. Plot made from binary image of pyramidal cells in layer III by running computergenerated horizontal lines across fields of cortex in human brain. Each peak represents the location of a pyramidal cell at the same horizontal level within
the layer. (c) Same analysis plot as in (b) applied to apical dendrite bundles. (d) Plot profile of the same region of interest as (c) but measured in the
horizontal plane. The periodicity is clearly in the vertical dimension only. Similar results occur with cell soma but not always as dramatically.
Unresolved Issues
While the minicolumn is a common feature of cortex, the
anatomical components that constitute a column are not
58
References
Buxhoeveden, D. P. (2012). Minicolumn size and human cortex. In M. A. Hofman & D.
Falk (Eds.), Progress in brain research (Vol. 195, pp. 219235). Elsevier Limited.
Buxhoeveden, D., & Casanova, M. F. (2002). The minicolumn and evolution of the
brain. Brain, Behavior and Evolution, 60, 2551.
Buxhoeveden, D., & Casanova, M. F. (2005). The cell column in comparative anatomy,
chap. 5. Encephalization, minicolumns, and hominid evolution, chap. 6. In M. F.
Cell Types in the Cerebral Cortex: An Overview from the Rat Vibrissal Cortex
R Egger, Max Planck Institute for Biological Cybernetics, Tubingen, Germany
M Oberlaender, Max Planck Institute for Biological Cybernetics, Tubingen, Germany; Bernstein Center for Computational
Neuroscience, Tubingen, Germany
2015 Elsevier Inc. All rights reserved.
Introduction
Historically, neuronal cell types in the cerebral cortex have
been subdivided on the basis of soma location, soma shape,
dendrite, and axon morphologies and the neurotransmitters
released at their synapses (i.e., glutamatergic and GABAergic,
reviewed in Peters and Jones (1984)). These parameters are
related to (i) the input a neuron receives; (ii) the functional
response of the neuron, for example, to sensory input; and (iii)
the neuronal populations targeted by the output of this
neuron. We regard quantitative overlap of input, functional
responses, and output measurements from different neurons
as a minimal prerequisite for assignment to a common cell
type. At the level of single cortical neurons, (i) the input can be
estimated by reconstructing their 3-D soma location in the
cortex and 3-D dendrite branching pattern; (ii) the response
can be measured by electrophysiological recording of, for
example, sensory-evoked sub- and/or suprathreshold activity;
and (iii) the output is determined by reconstructing their 3-D
axon branching pattern.
Classification of neurons with respect to inputoutput relationships has been performed in various systems. Recordings
of sensory-evoked responses and overlap of reconstructed
dendrites and axons have allowed creating a quantitative map
of cell type-specific connectivity in the cat visual cortex
(Binzegger, Douglas, & Martin, 2004). Functional imaging in
combination with electron microscopic reconstruction of neurons in the superficial cortical layers (L2/3) has allowed investigating the role of excitatory and inhibitory inputs in receptive
field formation in the mouse visual cortex (Bock et al., 2011).
Similarly, functional imaging and electron microscopic reconstruction of the mouse retina have revealed the origin of direction selectivity in ganglion cells (Briggman, Helmstaedter, &
Denk, 2011).
Additionally, the relation between input, function, and
output of different cell types has been studied in the vibrissal
part of the primary somatosensory cortex (vS1) of rodents
since its initial description (Woolsey & Van Der Loos, 1970).
Here, the one-to-one correspondence of somatotopically organized, segregated structures in vS1 cortical barrel columns
with individual facial whiskers (Welker, 1976) represents a
reliable reference frame for electrophysiological studies. Additionally, in vivo preparations of the vibrissal system allow correlating structural input and output patterns to sensory inputs
by recovering complete 3-D morphologies of dendrites and
axons of functionally characterized neurons (Brecht &
Sakmann, 2002; De Kock, Bruno, Spors, & Sakmann, 2007).
Combining these 3-D neuron morphologies with distributions
of neuron somata by registration to a standardized 3-D reference frame allows assembling an average model of a barrel
http://dx.doi.org/10.1016/B978-0-12-397025-1.00200-1
59
60
Table 1
Cell
type
Number of
neurons per
barrel column
Soma location
below pia (mm)
Dendrite
length (mm)
Number of
VPM
synapses
Spontaneous spiking
activity (Hz,
anesthetized)
L2
L3
L4ss
L4sp
L4py
L5st
L5tt
L6cc
L6ct
1095 21
1605 18
2752 46
2570 17
459 18
999 25
1613 20
1661 16
2226 9
150400
300550
550900
5001000
600700
10001300
11001400
14001600
15501800
8.58 2.82
6.44 0.95
3.38 1.09
4.23 0.94
7.49 1.18
7.71 1.95
13.84 3.63
5.86 0.77
5.90 0.78
6 12
66 63
246 123
278 159
341 166
165 86
195 82
131 52
139 84
0.47 0.69
0.32 0.53
0.52 0.22
0.32 0.13
0.56 0.42
1.10 0.43
3.53 1.59
0.87 0.35
0.08 0.08
(a)
(b)
Spontaneous spiking
activity (Hz, awake)
0.23 0.19
0.25 0.20
1.16 1.58
1.64 1.26
3.77 3.25
0.38 0.19
1.08 1.91
(c)
L1
L2
0.5
L3
L4
L5A
L5B
1.5
L6A
L6B
Figure 1 Excitatory cell types in the rat vibrissal cortex. (a) Cell types in supragranular layers (shaded region): layer 2 pyramid (L2), L3 pyramid (L3).
(b) Cell types in granular layer (shaded region): L4 pyramid (L4py), L4 star pyramid (L4sp), and L4 spiny stellate (L4ss). (c) Cell types in
infragranular layers (shaded region): L5 slender-tufted pyramid (L5st), L5 thick-tufted pyramid (L5tt), L6 corticocortical pyramid (L6cc), and L6
corticothalamic pyramid (L6ct). Gray bars indicate the range over which somata of the respective cell type are found (mean 1.5 SD).
61
62
Tangential view
ne
Midli
D1
S1
D3
2 mm
500 m
Coronal view
(c)
B3
500 m
B3 C2 D1
500 m
500 m
500 m
500 m
(e)
Midline
(a)
B1
Coronal
plane
S2
S1
VPM
2 mm
(b)
500 m
500 m
(d)
(f)
Figure 2 (a) Tangential view of the rat brain with the barrel field in the vibrissal somatosensory cortex. S1, primary somatosensory cortex; S2,
secondary somatosensory cortex. (b) Coronal view of the rat brain, showing the vertical location of barrels in vS1 and input from the thalamus (ventral
posterior medial nucleus, VPM). (c) VPM core axon in the vibrissal cortex. Left, tangential view; right, coronal view. (d) VPM core/tail axon in the
vibrissal cortex. As in (c). (e) VPM subbarrel/core axon in the vibrissal cortex. As in (c). (f) VPM head axon in the vibrissal cortex. As in (c).
arbor. Figure 3 shows reconstructions of the dendritic and axonal arbors of an L5st pyramid and an L5tt pyramid in vS1. These
spatially intermingling cell types display complementary intracortical axon projection patterns, with the majority of the axon
located outside of the PC. Specifically, L5st pyramids have a
total intracortical axon length of 86.8 5.5 mm, of which
16.4 6.7 mm innervate the PC and 59.9 9.7 mm the surrounding columns and septa in the vibrissal cortex. Vertically,
the innervation profiles differ inside and outside the PC. Within
the PC, axonal innervation in the supragranular, granular, and
infragranular layers is 6.2 3.6 mm, 2.1 1.1 mm, and
8.1 2.7 mm, respectively. In contrast, innervation of supragranular layers outside the PC (43.4 9.7 mm) is much higher than
innervation of granular (7.1 3.6 mm) and infragranular layers
(9.4 3.8 mm). Additionally, L5st pyramids display very specific
projections to the supragranular layers of the dysgranular
zone surrounding the vibrissal cortex (10.6 9.9 mm). L5tt
pyramids have shorter overall axon length (31.6 14.3 mm).
10.1 6.4 mm are confined to the PC and 18.6 7.5 mm to
the surrounding columns and septa of the vibrissal cortex. Vertical innervation of the PC is similar in supragranular and granular
layers (2.1 1.4 mm and 1.4 1.3 mm, respectively) and peaks
in the infragranular layers (6.6 4.1 mm). Outside of the PC, the
supragranular and granular layers show only sparse innervation
(3.0 1.9 mm and 3.3 1.8 mm, respectively), while most of
the axon targets the infragranular layers (12.2 4.4 mm).
Finally, L5tt pyramids have only very sparse innervation of
areas outside the vibrissal cortex (2.9 1.8 mm) and only
target its immediate surroundings (Oberlaender et al., 2011;
Figure 3(a) and 3(b)).
Functionally, these two cell types differ not only in their
spiking response after passive whisker deflection but also when
the animal is awake and moving its whiskers. Specifically, L5tt
pyramidal neurons respond robustly to passive whisker deflection, mediated by input from VPM mostly onto the basal
dendrites (Figure 3(c), left). In contrast, L5st pyramidal neurons increase their firing rate during whisking. The spike timing
of individual L5st pyramidal neurons carries information
63
Pia
E1
E4
D4
D3
D2
D1
Y
White
matter
A4
500 m
A1
500 m
(a)
(b)
Whisking
Passive touch
S1
S1
Active touch
S1
VPM
VPM/POm
VPM/POm
e.g., pons
e.g., striatum
e.g., pons
(c)
Figure 3 (a) Semicoronal view of intracortical projection patterns of an L5 thick-tufted (L5tt, left) and an L5 slender-tufted (L5st, right) pyramidal
neuron. Red, dendrites; blue, axon. (b) Same as in (a), tangential view. (c) L5st and L5tt pyramidal neurons report different signals during
different behavioral states of the animal (t, whisker-touch information; p, whisker-position information). These signals target different subcellular
compartments of L5tt pyramids (red). During simultaneous activation of these sensorymotor pathways, L5tt pyramidal neurons may act as
coincidence detectors and change their spiking output to bursting mode (right panel, thick arrow).
Conclusion
In summary, 3-D reconstruction of soma, dendrites, and axon
of individual cortical neuron morphologies allows objective
classification of excitatory neurons into nine different cell types
in the rat vibrissal cortex. The vertical distribution of the different cell types reveals that laminar locations of the somata do
not predict the neuron cell type. For example, L2 pyramidal
neurons may be found in the upper part of L3, and L5st
and L5tt pyramidal somata intermingle between 1100 and
1300 mm below the pia. Only by reconstructing the entire
dendrite morphology and registration of the neuron to a standardized coordinate system it is possible to unambiguously
identify neuronal cell types. These somatodendritic cell types
predict specific functional properties during different behaviors, as well as cell type-specific innervation by thalamocortical
inputs. Additionally, two cell types in L5 show specific intracortical axon projection patterns, revealing cell type-specific
pathways possibly involved in signaling of different sensory
and behavioral variables.
Thus, the correlation between input, functional responses,
and output pathways of somatodendritic cortical cell types
may provide a basis for quantitative assessment of functional,
structural, and computational studies.
64
References
Binzegger, T., Douglas, R. J., & Martin, K. A. (2004). A quantitative map of the circuit of
cat primary visual cortex. The Journal of Neuroscience, 24, 84418453.
Bock, D. D., Lee, W. C., Kerlin, A. M., Andermann, M. L., Hood, G., Wetzel, A. W., et al.
(2011). Network anatomy and in vivo physiology of visual cortical neurons. Nature,
471, 177182.
Brecht, M., Roth, A., & Sakmann, B. (2003). Dynamic receptive fields of reconstructed
pyramidal cells in layers 3 and 2 of rat somatosensory barrel cortex. The Journal of
Physiology, 553, 243265.
Brecht, M., & Sakmann, B. (2002). Dynamic representation of whisker deflection by
synaptic potentials in spiny stellate and pyramidal cells in the barrels and septa of
layer 4 rat somatosensory cortex. The Journal of Physiology, 543, 4970.
Briggman, K. L., Helmstaedter, M., & Denk, W. (2011). Wiring specificity in the
direction-selectivity circuit of the retina. Nature, 471, 183188.
Bruno, R. M., & Sakmann, B. (2006). Cortex is driven by weak but synchronously active
thalamocortical synapses. Science, 312, 16221627.
Constantinople, C. M., & Bruno, R. M. (2011). Effects and mechanisms of wakefulness
on local cortical networks. Neuron, 69, 10611068.
Constantinople, C. M., & Bruno, R. M. (2013). Deep cortical layers are activated directly
by thalamus. Science, 340, 15911594.
Crochet, S., & Petersen, C. C. (2006). Correlating whisker behavior with membrane
potential in barrel cortex of awake mice. Nature Neuroscience, 9, 608610.
De Kock, C. P., Bruno, R. M., Spors, H., & Sakmann, B. (2007). Layer and cell type
specific suprathreshold stimulus representation in primary somatosensory cortex.
The Journal of Physiology, 581, 139154.
De Kock, C. P., & Sakmann, B. (2009). Spiking in primary somatosensory cortex during
natural whisking in awake head-restrained rats is cell-type specific. Proceedings of
the National Academy of Sciences of the United States of America, 106,
1644616450.
Egger, V., Nevian, T., & Bruno, R. M. (2008). Subcolumnar dendritic and axonal
organization of spiny stellate and star pyramid neurons within a barrel in rat
somatosensory cortex. Cerebral Cortex, 18, 876889.
Feldmeyer, D., Brecht, M., Helmchen, F., Petersen, C. C., Poulet, J. F., Staiger, J. F.,
et al. (2013). Barrel cortex function. Progress in Neurobiology, 103, 327.
Furuta, T., Deschenes, M., & Kaneko, T. (2011). Anisotropic distribution of
thalamocortical boutons in barrels. The Journal of Neuroscience, 31, 64326439.
Hallman, L. E., Schofield, B. R., & Lin, C. S. (1988). Dendritic morphology and axon
collaterals of corticotectal, corticopontine, and callosal neurons in layer V of primary
visual cortex of the hooded rat. The Journal of Comparative Neurology, 272,
149160.
Hay, E., Hill, S., Schurmann, F., Markram, H., & Segev, I. (2011). Models of neocortical
layer 5b pyramidal cells capturing a wide range of dendritic and perisomatic active
properties. PLoS Computational Biology, 7, e1002107.
Helmstaedter, M., Sakmann, B., & Feldmeyer, D. (2009). The relation between dendritic
geometry, electrical excitability, and axonal projections of L2/3 interneurons in rat
barrel cortex. Cerebral Cortex, 19, 938950.
Kumar, P., & Ohana, O. (2008). Inter- and intralaminar subcircuits of excitatory and
inhibitory neurons in layer 6a of the rat barrel cortex. Journal of Neurophysiology,
100, 19091922.
Land, P. W., Buffer, S. A., Jr., & Yaskosky, J. D. (1995). Barreloids in adult rat thalamus:
Three-dimensional architecture and relationship to somatosensory cortical barrels.
The Journal of Comparative Neurology, 355, 573588.
Land, P. W., & Erickson, S. L. (2005). Subbarrel domains in rat somatosensory (S1)
cortex. The Journal of Comparative Neurology, 490, 414426.
Lang, S., Dercksen, V. J., Sakmann, B., & Oberlaender, M. (2011). Simulation of signal
flow in 3D reconstructions of an anatomically realistic neural network in rat vibrissal
cortex. Neural Networks, 24, 9981011.
Larkman, A., & Mason, A. (1990). Correlations between morphology and
electrophysiology of pyramidal neurons in slices of rat visual cortex. I.
Establishment of cell classes. The Journal of Neuroscience, 10, 14071414.
Larkum, M. (2013). A cellular mechanism for cortical associations: An organizing
principle for the cerebral cortex. Trends in Neurosciences, 36, 141151.
Larkum, M. E., Zhu, J. J., & Sakmann, B. (1999). A new cellular mechanism for
coupling inputs arriving at different cortical layers. Nature, 398, 338341.
Manns, I. D., Sakmann, B., & Brecht, M. (2004). Sub- and suprathreshold receptive
field properties of pyramidal neurones in layers 5A and 5B of rat somatosensory
barrel cortex. The Journal of Physiology, 556, 601622.
Meyer, H. S., Egger, R., Guest, J. M., Foerster, R., Reissl, S., & Oberlaender, M. (2013).
Cellular organization of cortical barrel columns is whisker-specific. Proceedings of
the National Academy of Sciences of the United States of America, 110,
1911319118.
Meyer, H. S., Wimmer, V. C., Hemberger, M., Bruno, R. M., De Kock, C. P., Frick, A.,
et al. (2010). Cell type-specific thalamic innervation in a column of rat vibrissal
cortex. Cerebral Cortex, 20, 22872303.
Oberlaender, M., Boudewijns, Z. S., Kleele, T., Mansvelder, H. D., Sakmann, B., &
De Kock, C. P. (2011). Three-dimensional axon morphologies of individual layer 5
neurons indicate cell type-specific intracortical pathways for whisker motion and
touch. Proceedings of the National Academy of Sciences of the United States of
America, 108, 41884193.
Oberlaender, M., De Kock, C. P., Bruno, R. M., Ramirez, A., Meyer, H. S.,
Dercksen, V. J., et al. (2012). Cell type-specific three-dimensional structure of
thalamocortical circuits in a column of rat vibrissal cortex. Cerebral Cortex, 22,
23752391.
Oberlaender, M., Ramirez, A., & Bruno, R. M. (2012). Sensory experience restructures
thalamocortical axons during adulthood. Neuron, 74, 648655.
Peters, A., & Jones, E. G. (Eds.). (1984). Cerebral cortex 1: Cellular components of the
cerebral cortex. London, New York: Plenum Press.
Pierret, T., Lavallee, P., & Deschenes, M. (2000). Parallel streams for the relay of
vibrissal information through thalamic barreloids. The Journal of Neuroscience, 20,
74557462.
Staiger, J. F., Flagmeyer, I., Schubert, D., Zilles, K., Kotter, R., & Luhmann, H. J. (2004).
Functional diversity of layer IV spiny neurons in rat somatosensory cortex:
Quantitative morphology of electrophysiologically characterized and biocytin
labeled cells. Cerebral Cortex, 14, 690701.
Welker, C. (1976). Receptive fields of barrels in the somatosensory neocortex of the rat.
The Journal of Comparative Neurology, 166, 173189.
Wimmer, V. C., Bruno, R. M., De Kock, C. P., Kuner, T., & Sakmann, B. (2010).
Dimensions of a projection column and architecture of VPM and POm axons in rat
vibrissal cortex. Cerebral Cortex, 20, 22652276.
Woolsey, T. A., & Van Der Loos, H. (1970). The structural organization of layer IV in
the somatosensory region (SI) of mouse cerebral cortex. The description of a
cortical field composed of discrete cytoarchitectonic units. Brain Research, 17,
205242.
Xu, N. L., Harnett, M. T., Williams, S. R., Huber, D., Oconnor, D. H., Svoboda, K., et al.
(2012). Nonlinear dendritic integration of sensory and motor input during an active
sensing task. Nature, 492, 247251.
Yu, C., Derdikman, D., Haidarliu, S., & Ahissar, E. (2006). Parallel thalamic pathways
for whisking and touch signals in the rat. PLoS Biology, 4, e124.
Glossary
Dendritic Morphology
Pyramidal cells take their name from their pyramid-shaped
somata and were first described by Ramon y Cajal (1893).
They can be found in vertebrates from fish to humans. Pyramidal cells are the most abundant type of excitatory projection neuron in the neocortex and hippocampus but are also
found in the amygdala (Hall, 1972). A pyramidal cell is
bipolar and has a rather stereotypical morphology: from the
base of its cell body, several, generally short basal dendrites
emerge while an apical dendrite projects from the soma top
toward the pia. However, despite their similarities, there is a
significant degree of diversity, particularly with respect to the
morphology of apical dendrites (Figure 1): some pyramidal
cells, for example, those in the CA1 and CA3 layers of the
Apical
dendrite
Soma
and basal
dendrites
Hippocampus
CA1
CA3
Layer 2/3
Neocortex
Layer 5A
Layer 5B
Layer 6
Figure 1 Dendritic arbor of different pyramidal cell types in rodent hippocampus and neocortex indicating the morphological variability of this neuron
type. Basal and apical dendritic domains in the blue and red shaded area, respectively. Apical dendrites often posses very elaborate and broad tuft
regions; in others, for example, in neocortical layer 5A pyramidal cells, they are slender or even completely absent as in a subgroup of layer 6 pyramidal
cells. Note that the neurons are not drawn to scale.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00201-3
65
66
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Functional and Structural Diversity of Pyramidal Cells
Function
Pyramidal cells play important roles in learning, sensory
perception, and motor control. At the single-cell level, long-
Synaptic Integration
The elaborate dendritic arborizations of pyramidal cells receive
functionally distinct synaptic inputs from different types of
neurons that are targeted to spatially separate region. A prerequisite for the computational power of pyramidal cells is the
integration of these synaptic inputs, a process that occurs
chiefly in the basal and apical dendrites. It has been referred
to as synaptic integration (Spruston, 2008). If dendrites
would behave like passive electric cable structures, synaptic
integration at the soma would be purely linear and proximal
30 mV
20 ms
Ca2+ spike
initiation zone
Na+ spike
initiation zone
(axon hillock)
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Functional and Structural Diversity of Pyramidal Cells
67
Figure 3 Coincidence detection via backpropagation activated Ca2 spike firing. This mechanism is thought to be involved in the shaping of
synaptic integration and its plasticity. (a) Pyramidal cell in neocortical layer 5 with patch electrodes at the soma (blue), the apical dendritic trunk (gray),
and the apical tuft (red). (b) Excitatory postsynaptic potential waveform (Vm, red) evoked by a small dendritic current injection (Istim, red) causes no
dendritic Ca2 spike and has virtually no impact at the cell body (blue). (c) A somatic Na AP (blue) evoked with somatic current injection (Istim,
blue) invades the dendritic tree but still causes no dendritic spike. (d) A combination of current injections at the soma and apical tuft (as in (b) and (c))
reaches threshold for a Ca2 spike in the apical dendrite. In turn, this triggers a burst of Na AP firing. Modified from Larkum, M. E., Zhu, J. J.,
and Sakmann, B. (1999). A new cellular mechanism for coupling inputs arriving at different cortical layers. Nature, 398, 338341, with permission
from Macmillan Publishers Ltd.
It has been proposed that pyramidal cells respond optimally to coincident activation of several dendritic compartments. In neocortical layer 5, the distal apical dendritic tufts
are targeted, for example, by associational axons from other
cortical areas, while the proximal basal dendrites receive input
from other local pyramidal cells or from the thalamus. The
simultaneous activation of these proximal and distal dendrites
results in a burst of APs. These AP bursts are caused when a
dendritic Ca2 spike triggered by distal synaptic inputs is activated simultaneously with a backpropagating AP (Figure 3;
Larkum, 2013; Larkum, Zhu, & Sakmann, 1999); it is therefore
a coincidence detection mechanism. Such an interaction
between the Na AP and the Ca2 spike is involved in many
processes such as associative learning.
68
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Functional and Structural Diversity of Pyramidal Cells
References
Brecht, M., Schneider, M., Sakmann, B., & Margrie, T. W. (2004). Whisker movements
evoked by stimulation of single pyramidal cells in rat motor cortex. Nature, 427,
704710.
Hall, E. (1972). The amygdala of the cat: A Golgi study. Zeitschrift fur Zellforschung und
Mikroskopische Anatomie, 134, 439458.
Houweling, A. R., & Brecht, M. (2008). Behavioural report of single neuron stimulation
in somatosensory cortex. Nature, 451, 6568.
Hubel, D. H., & Wiesel, T. N. (1962). Receptive fields, binocular interaction and
functional architecture in the cats visual cortex. Journal of Physiology, 160,
106154.
Huber, D., Petreanu, L., Ghitani, N., Ranade, S., Hromadka, T., Mainen, Z., et al. (2008).
Sparse optical microstimulation in barrel cortex drives learned behaviour in freely
moving mice. Nature, 451, 6164.
Kampa, B. M., Letzkus, J. J., & Stuart, G. J. (2007). Dendritic mechanisms controlling
spike-timing-dependent synaptic plasticity. Trends in Neurosciences, 30, 456463.
Larkum, M. (2013). A cellular mechanism for cortical associations: An organizing
principle for the cerebral cortex. Trends in Neurosciences, 36, 141151.
Larkum, M. E., Zhu, J. J., & Sakmann, B. (1999). A new cellular mechanism for
coupling inputs arriving at different cortical layers. Nature, 398, 338341.
Markram, H., Lubke, J., Frotscher, M., & Sakmann, B. (1997). Regulation of
synaptic efficacy by coincidence of postsynaptic APs and EPSPs. Science, 275,
213215.
Mountcastle, V. B. (1957). Modality and topographic properties of single
neurons of cats somatic sensory cortex. Journal of Neurophysiology, 20,
408434.
Oberlaender, M., Boudewijns, Z. S., Kleele, T., Mansvelder, H. D., Sakmann, B., &
De Kock, C. P. (2011). Three-dimensional axon morphologies of individual layer 5
neurons indicate cell type-specific intracortical pathways for whisker motion and
touch. Proceedings of the National Academy of Sciences of the United States of
America, 108, 41884193.
Ramon y Cajal, S. (1888). Estructura de los centros nerviosos de las aves. Revista
Trimestral de Histologa normal y patologica, 1, 110.
Ramon y Cajal, S. (1893). Nuevo concepto de la histologia de los centros nerviosos. La
Revista de ciencias medicas de Barcelona, 18, 2140.
Spruston, N. (2008). Pyramidal neurons: Dendritic structure and synaptic integration.
Nature Reviews. Neuroscience, 9, 206221.
Spruston, N. (2009). Pyramidal neuron. Scholarpedia, 4, 6130.
Stuart, G. J., & Sakmann, B. (1994). Active propagation of somatic action potentials into
neocortical pyramidal cell dendrites. Nature, 367, 6972.
Stuart, G., & Sakmann, B. (1995). Amplification of EPSPs by axosomatic sodium
channels in neocortical pyramidal neurons. Neuron, 15, 10651076.
Szentagothai, J. (1975). The module-concept in cerebral cortex architecture. Brain
Research, 95, 475496.
Glossary
The majority of neurons in the neocortex are excitatory principal neurons that basically come in two forms: pyramidal and
nonpyramidal cells. The excitatory nonpyramidal cells are
called spiny stellate neurons (Feldmeyer, Egger, Lubke, &
Sakmann, 1999), and as a transitional form, also, star pyramidal cells are distinguished (Oberlaender et al., 2012; Schubert,
Kotter, Zilles, Luhmann, & Staiger, 2003; Staiger, Flagmeyer,
et al., 2004). These latter cell types, at least in rodents, are
mainly found in layer IV and considered to be excitatory interneurons since they do not project out of their home area and in
most instances also not out of their home column. By contrast,
the pyramidal cells in layers II/III, V, and VI issue long-range
projections to intra- and subcortical target sites (Ahissar &
Staiger, 2010; Feldmeyer, 2012) and are considered to form
the local circuits for information processing with their recurrent axonal collaterals (Douglas & Martin, 2007; Schubert,
Kotter, & Staiger et al. 2007). Interestingly, also, the excitatory
neurons are subject to a debate as to how many types do exist
(Nelson, Sugino, & Hempel, 2006; Sorensen et al., 2013).
Inhibitory GABAergic neurons are a very diverse class of neurons that also show a great deal of regional specificity. For
example, in the archicortex, up to 21 different subtypes have
been classified (Klausberger & Somogyi, 2008), and at an extreme,
it was even concluded that each GABAergic neuron is its own type
(Parra, Gulyas, & Miles, 1998). Here, I would like to focus on the
rodent neocortex, where several groups have studied the properties
of these cells mainly in the motor cortex (or in broader terms often
called frontal cortex; Cauli et al., 1997; Fino, Packer, & Yuste,
Brain Mapping: An Encyclopedic Reference
http://dx.doi.org/10.1016/B978-0-12-397025-1.00202-5
69
70
71
S1BF
I
NGFC
AAC
II/III
BPC
IV
BC
Va
MC
Vb
VI
GPC
wm
Figure 1 Graphical representation of the basic morphological features of the six types of GABAergic neurons. They are exemplified for the primary
somatosensory (barrel) cortex (S1BF). Vertical stippled lines delineate areal borders (to the left being secondary somatosensory cortex and to the
right the hindlimb area), whereas horizontal stippled lines indicate layer borders (Roman numerals indicate cortical layers; wm, white matter).
The different cell types are color-coded and placed into a most typical layer; darker hue is used for the somatodendritic domain and lighter hue for the
axon (AAC, brown; BC, green; MC, yellowish; BPC, red; NGFC, mauve; GPC, blue). Please note the much higher complexity of the arbors in the
photoreconstructions shown in Figure 2(g)2(i).
72
Basket Cells
BCs (Figure 1) are the second and core-contributing cell type for
perisomatic inhibition (Freund & Katona, 2007). In a broad
sense, for this type, three different subtypes were proposed: the
classical (1) small (Figure 2(d)) and (2) large BCs were recently
complemented by the so-called (3) nest BC (Wang et al., 2002),
which as a population can be found in any cortical layer except L
I. Maybe other subtypes exist as well (see succeeding text), and
thus, it is not too surprising that a recent classification attempt
found little agreement on this cell type (De Felipe et al., 2013).
However, parvalbumin seems to be a suitable neurochemical
marker (Figure 2(a)), as is the fast-spiking firing pattern
(Figure 2(g)) at the physiological level (Cauli et al., 1997;
Kawaguchi, 1995). Parvalbumin defines with a proportion of
roughly 40% the largest group of cortical GABAergic neurons
(Pfeffer et al., 2013; Rudy et al., 2011), with a preponderance in
somatic and bouton staining in layers IV and Vb. It should,
however, be noted that also nonparvalbumin, non-fast-spiking
BCs might exist (Kawaguchi & Kubota, 1998).
The main features of small BCs are a very local multipolar
dendritic tree (aspiny and beaded, typical for all axo-axonic
and BCs) and a local (i.e., intralaminar and intracolumnar)
dense axonal plexus, whose boutons form symmetrical synaptic contacts to a large degree on somata and perisomatic dendrites (Alonso-Nanclares et al., 2004; Alonso-Nanclares,
White, Elston, & De Felipe, 2004). At a single cell level, the
formation of pericellular baskets is very subtle, which makes
the morphological identification of these cells more difficult
than expected. So, it is very helpful to have the postsynaptic
target cells labeled, which can be excitatory and inhibitory
Martinotti Cells
Because of their unique axonal ramification in layer I, Martinotti cells (MC; Figure 1) are the second best-recognizable
cell type (in terms of morphology; De Felipe et al., 2013),
and since there are very specific mouse models (Ma, Hu,
Berrebi, Mathers, & Agmon, 2006; Oliva, Jiang, Lam, Smith, &
Swann, 2000; Taniguchi et al., 2011), also, a lot has been
learned about other properties, especially functional ones.
From the present data, it can be stated that Martinotti cells
with a mainly bitufted to multipolar dendritic tree (often
being not so sparsely spiny!) can be found in all cortical layers
(again except L I) and, no matter where they are located, always
send a significant portion of their axon into L I (Figure 2(e))
where it densely ramifies (Wang et al., 2004). However,
although conceptually ignored up to now, the largest portion
of the axon stays outside of L I and has not been studied
functionally so far. Unfortunately, no detailed synaptology for
Martinotti cells does exist in the neocortex. Interestingly, data
from hippocampus strongly suggest that dendritic shafts and
spines of pyramidal cells as well as many types of interneurons
I
II/III
IV
Va
Vb
VI
wm
(a)
(b)
(c)
II/III
IV
Va
Vb
VI
Basket cell
Martinotti cell
Bitufted cell
wm
(d)
(g)
(e)
Fast spiking
(h)
(f)
Adapting
(i)
Irregular-spiking
Figure 2 Basic morphological and electrophysiological properties of the three major neurochemically defined GABAergic neurons in the barrel cortex.
(a) shows a low-magnification image of a PVcre section (pseudocolored green), which makes clear that PV cells (which should be mostly basket
cells in this stain; see Figure 2(d)) have a preferential location in layers IV and Vb. (b) shows a low-magnification image of a SOMcre section
(pseudocolored yellow), which makes clear that SOM cells (which should be mostly Martinotti cells in this stain; see Figure 2(e)) have a preferential
location in layers V and VI. (c) shows a low-magnification image of a VIPcre section (red), which makes clear that VIP cells (which should be
mostly bipolar/bitufted cells in this stain; see Figure 2(f)) have a preferential location in layer II/III. Roman numerals indicate cortical layers; scale bar,
200 mm. (df) show photoreconstructions, all in layer II/III, of a parvalbumin-expressing, fast-spiking basket cell (d), a somatostatin-expressing,
adapting Martinotti cell (e) and a VIP-expressing irregular-spiking bitufted cell (f). Please note the varicosities of the basket cell in L I, which are dendritic
and not axonal. Please also note that the axonal arbor of the Martinotti cell is artificially truncated due to restrictions of figure size but extends over
more than 2 mm tangentially below the pia. (gi) show (one of) the typical action potential firing patterns upon strong depolarizing current injections via
whole cell patch clamp electrodes (g, continuous fast-spiking; h, continuous adapting; i, irregular-spiking).
74
Bipolar/Bitufted Cells
These BPCs (Figure 1), until very recently, were considered to
be enigmatic (Peters & Harriman, 1988) and bear a lot of
further names that are often more ornamental than scientifically helpful, like double-bouquet, arcade, or horsetail cells
(De Felipe et al., 2013; Kawaguchi & Kubota, 1996). In the
primate neocortex, however, the term double-bouquet cell is
reasonably used for a very fascinating calbindin D28kexpressing cell type that possesses a unique axonal feature
(De Felipe, Hendry, Hashikawa, Molinari, & Jones, 1990;
Yanez et al., 2005), namely, a microcolumnar organization.
Here, in rodents, the term BPC is strictly used to describe the
vertically oriented somatodendritic organization; the axon,
however, also being vertically extended, is often spanning
many or even all cortical layers in a narrow, column-restricted
manner (Bayraktar et al., 2000; Kawaguchi & Kubota, 1996).
This suggests that this cell type not only can integrate many
different inputs across all cortical layers but in a momentarily
impossible to elucidate functional logic also feeds back/
forward inhibition to all these same layers (Figure 2(f)). A
useful molecular marker is the ionotropic serotonin receptor
5HT-3 or more specifically vasoactive intestinal polypeptide
(VIP; Figure 2(c)) (Bayraktar et al., 2000; Lee, Hjerling-Leffler,
Zagha, Fishell, & Rudy, 2010; Pfeffer et al., 2013) but also
calretinin or choline acetyltransferase has been detected in
many BPCs (Bayraktar et al., 1997; Caputi, Rozov, Blatow, &
Monyer, 2009; Cauli et al., 2000; von Engelhardt, Eliava, Meyer,
Rozov, & Monyer, 2007). The electrophysiological markers
show a very high input resistance and are predominantly
adapting (previously regular-spiking nonpyramidal) and bursting (burst-spiking, BS), but very often also irregular-spiking
(Figure 2(i)) (Cauli et al., 1997; Karagiannis et al., 2009; Kawaguchi & Kubota, 1996).
We are focussing here on VIP neurons that have been relatively
neglected for a long time but are now in focus of very many
research groups, due to the availability of specific mouse models.
It was estimated that roughly 1217% of all cortical GABAergic
neurons express VIP (Pfeffer et al., 2013; Rudy et al., 2011;
Uematsu et al., 2008), which are highly concentrated in layer II/
III. In the early days, right after their initial description (Morrison,
Magistretti, Benoit, & Bloom, 1984; Sims, Hoffman, Said, &
Zimmerman, 1980), a detailed ultrastructural examination
already suggested that medium-sized smooth dendrites (i.e.,
very likely originating from other inhibitory interneurons) are
their main subcellular target structure (Connor & Peters, 1984;
Peters & Harriman, 1988). Indeed, the VIP neurons are considered
to be of the dendrite-targeting type, although at least small basket
neurons in rat also do seem to express this neuropeptide (Wang
et al., 2002). Also, from the beginning, it had been obvious that
these neurons are predominantly vertically organized, so it was
self-evident to imply them in columnar or even microcolumnar
function (Bayraktar et al., 2000; Magistretti & Morrison, 1988;
Zilles et al., 1993). In functional assays, however, surprisingly, a
net excitatory effect was often found (Haas & Gahwiler, 1992;
Sessler, Grady, Waterhouse, & Moises, 1991). This net excitation is
likely to be one of the many possible outcomes of a behaviorally
specific activation of VIP neurons by (cholinergic) arousal
mechanisms that leads to the inhibition of Martinotti cells as a
preferred target, which in turn results in disinhibition of principal
neurons (Arroyo, Bennett, Aziz, Brown, & Hestrin, 2012; Fu et al.,
2014; Gentet et al., 2012; Lee et al., 2013; Pi et al., 2013; Staiger,
Masanneck, Schleicher, & Zuschratter, 2004).
Neurogliaform Cells
The NGFCs (Figure 1) actually are still very enigmatic, although,
since the landmark papers published by Gabor Tamas group,
the notion is up that they may be an unconventional type of
volume transmission-utilizing interneuron, which not only acts
at a slower timescale via GABA-B-receptors (Olah et al., 2009;
Tamas, Lorincz, Simon, & Szabadics, 2003) but also activates
GABA-A-receptors and is promiscuously connected to other
interneurons by gap junctions (Simon, Olah, Molnar,
Szabadics, & Tamas, 2005). One of the problems of this interneuron type is that there are few specific markers to easily and
reliably identify it. They are characterized by a late-spiking
action potential firing pattern (Miyoshi et al., 2010; Tamas
et al., 2003), alpha-actinin 2, reelin, NPY, or nNOS expression
(Karagiannis et al., 2009; Kubota et al., 2011; Miyoshi et al.,
2010; Olah et al., 2009; Pohlkamp et al., 2013), and also their
unique morphology with many short primary dendrites and
among the thinnest and most densely arborizing axonal arbor
of all neurons (Kubota et al., 2011; Povysheva et al., 2007). This
morphology also led to the names dwarf cell or spiderweb cell
(Jones, 1984). In contrast to all previous cell types described in
this article, it has a frequent occurrence in layer I, which is,
however, not an exclusive location but it can be found in any
layer (Hestrin & Armstrong, 1996; Jiang, Wang, Lee, Stornetta, &
Zhu, 2013; Olah et al., 2009).
75
Acknowledgments
I would like to cordially thank my former mentor, Prof. Karl
Zilles, for setting me on the track of GABAergic interneurons
and for inspiration. Many thanks are due to the members of the
Barrel Cortical Circuits Group and especially Alvar Pronneke
76
Local
cortical input
Long-range
cortical input
Subcortical
neuromodulatory
input
BPC
(VIP)
MC
(SOM)
BC
(PV)
Thalamic input
Figure 3 Circuit diagram depicting some important connectional motifs of VIP-, SOM- and PV-expressing interneurons. This diagram shows that
VIP-expressing BPC can sample input from many local and distant sources and feed forward this integrated input to SOM-expressing MC, PV-expressing
BC, and glutamatergic principal neurons (blue) to cause a complex inhibition (weak, thin line) disinhibition (strong, thick line or weak, in a target
cell type-specific manner) configuration of the local circuit. Long-range cortical input is considered to originate from other cortical areas, local cortical
input from the same area or even the same column; subcortical modulatory inputs are cholinergic from the basal forebrain, serotonergic from the
raphe nuclei, noradrenergic from the locus coeruleus, and potentially dopaminergic from the ventral tegmental area. Especially, cholinergic projections
are powerful activators of VIP neurons. Furthermore, the diagram shows thalamus-generated feedforward inhibition by basket cells. At the same time,
this neuron type is often involved in feedback inhibition, possibly of the very same neurons that excite them, thus forming reciprocal connections.
for the help with the figures. I also would like to thank the
German Research Council (DFG) for supporting this line of
research since 1997. I sincerely apologize to my colleagues
whose great research I could not refer to due to limited space
and the special focus of this book chapter.
References
Abadesco, A. D., Cilluffo, M., Yvone, G. M., Carpenter, E. M., Howell, B. W., &
Phelps, P. E. (2014). Novel disabled-1-expressing neurons identified in adult brain
and spinal cord. European Journal of Neuroscience, 39, 579592.
Adesnik, H., Bruns, W., Taniguchi, H., Huang, Z. J., & Scanziani, M. (2012). A neural
circuit for spatial summation in visual cortex. Nature, 490, 226231.
77
78
Fishell, G., & Tamas, G. (2014). Inhibition: synapses, neurons and circuits. Current
Opinion in Neurobiology, 26, vvii.
Flames, N., & Marin, O. (2005). Developmental mechanisms underlying the generation
of cortical interneuron diversity. Neuron, 46, 377381.
Freund, T. F., & Buzsaki, G. (1996). Interneurons of the hippocampus. Hippocampus, 6,
347470.
Freund, T. F., & Katona, I. (2007). Perisomatic inhibition. Neuron, 56, 3342.
Fu, Y., Tucciarone, J. M., Espinosa, J. S., Sheng, N., Darcy, D. P., Nicoll, R. A., et al.
(2014). A cortical circuit for gain control by behavioral state. Cell, 156, 11391152.
Gentet, L. J. (2012). Functional diversity of supragranular GABAergic neurons in the
barrel cortex. Frontiers in Neural Circuits, 6.
Gentet, L. J., Avermann, M., Matyas, F., Staiger, J. F., & Petersen, C. C. H. (2010).
Membrane potential dynamics of GABAergic neurons in the barrel cortex of
behaving mice. Neuron, 65, 422435.
Gentet, L. J., Kremer, Y., Taniguchi, H., Huang, Z. J., Staiger, J. F., & Petersen, C. C. H.
(2012). Unique functional properties of somatostatin-expressing GABAergic
neurons in mouse barrel cortex. Nature Neuroscience, 15, 607612.
Glickfeld, L. L., Roberts, J. D., Somogyi, P., & Scanziani, M. (2009). Interneurons
hyperpolarize pyramidal cells along their entire somatodendritic axis. Nature
Neuroscience, 12, 2123.
Gonchar, Y., Wang, Q., & Burkhalter, A. (2008). Multiple distinct subtypes of GABAergic
neurons in mouse visual cortex identified by triple immunostaining. Frontiers in
Neuroanatomy, 1, 3.
Gonzalez-Burgos, G., & Lewis, D. A. (2008). GABA neurons and the mechanisms of
network oscillations: Implications for understanding cortical dysfunction in
schizophrenia. Schizophrenia Bulletin, 34, 944961.
Gulledge, A. T., & Stuart, G. J. (2003). Excitatory actions of GABA in the cortex. Neuron,
37, 299309.
Gupta, A., Wang, Y., & Markram, H. (2000). Organizing principles for a diversity of
GABAergic interneurons and synapses in the neocortex. Science, 287, 273278.
Haas, H. L., & Gahwiler, B. H. (1992). Vasoactive intestinal polypeptide modulates
neuronal excitability in hippocampal slices of the rat. Neuroscience, 47, 273277.
Haider, B., Hausser, M., & Carandini, M. (2013). Inhibition dominates sensory
responses in the awake cortex. Nature, 493, 97100.
Hangya, B., Pi, H. J., Kvitsiani, D., Ranade, S. P., & Kepecs, A. (2014). From circuit
motifs to computations: Mapping the behavioral repertoire of cortical interneurons.
Current Opinion in Neurobiology, 26C, 117124.
Helmstaedter, M., Sakmann, B., & Feldmeyer, D. (2009a). L2/3 interneuron groups
defined by multiparameter analysis of axonal projection, dendritic geometry, and
electrical excitability. Cerebral Cortex, 19, 951962.
Helmstaedter, M., Sakmann, B., & Feldmeyer, D. (2009b). Neuronal correlates of local,
lateral, and translaminar inhibition with reference to cortical columns. Cerebral
Cortex, 19, 926937.
Hestrin, S., & Armstrong, W. E. (1996). Morphology and physiology of cortical neurons
in layer I. Journal of Neuroscience, 16, 52905300.
Howard, A., Tamas, G., & Soltesz, I. (2005). Lighting the chandelier: New vistas for axoaxonic cells. Trends in Neurosciences, 28, 310316.
Inan, M., Blazquez-Llorca, L., Merchan-Perez, A., Anderson, S. A., De Felipe, J., &
Yuste, R. (2013). Dense and overlapping innervation of pyramidal neurons by
chandelier cells. Journal of Neuroscience, 33, 19071914.
Inda, M., De Felipe, J., & Munoz, A. (2009). Morphology and distribution of chandelier
cell axon terminals in the mouse cerebral cortex and claustroamygdaloid complex.
Cerebral Cortex, 19, 4154.
Isaacson, J. S., & Scanziani, M. (2011). How inhibition shapes cortical activity. Neuron,
72, 231243.
Jiang, X. L., Wang, G. F., Lee, A. J., Stornetta, R. L., & Zhu, J. J. (2013). The organization
of two new cortical interneuronal circuits. Nature Neuroscience, 16, 210218.
Jones, E. G. (1975). Varieties and distribution of non-pyramidal cells in the somatic sensory
cortex of the squirrel monkey. Journal of Comparative Neurology, 160, 205267.
Jones, E. G. (1984). Neurogliaform or spiderweb cells. In A. Peters & E. G. Jones (Eds.),
Cellular components of the cerebral cortex (pp. 409418). New York: Plenum Press.
Jones, E. G. (1993). GABAergic neurons and their role in cortical plasticity in primates.
Cerebral Cortex, 3, 361372.
Karagiannis, A., Gallopin, T., David, C., Battaglia, D., Geoffroy, H., Rossier, J., et al.
(2009). Classification of NPY-expressing neocortical interneurons. Journal of
Neuroscience, 29, 36423659.
Karnani, M. M., Agetsuma, M., & Yuste, R. (2014). A blanket of inhibition: Functional
inferences from dense inhibitory connectivity. Current Opinion in Neurobiology,
26C, 96102.
Karube, F., Kubota, Y., & Kawaguchi, Y. (2004). Axon branching and synaptic bouton
phenotypes in GABAergic nonpyramidal cell subtypes. Journal of Neuroscience, 24,
28532865.
Katona, I., Acsady, L., & Freund, T. F. (1998). Postsynaptic targets of somatostatinimmunoreactive interneurons in the rat hippocampus. Neuroscience, 88, 3755.
Kawaguchi, Y. (1995). Physiological subgroups of nonpyramidal cells with specific
morphological characteristics in layer II/III of rat frontal cortex. Journal of
Neuroscience, 15, 26382655.
Kawaguchi, Y., & Kondo, S. (2002). Parvalbumin, somatostatin and cholecystokinin as
chemical markers for specific GABAergic interneuron types in the rat frontal cortex.
Journal of Neurocytology, 31, 277287.
Kawaguchi, Y., & Kubota, Y. (1996). Physiological and morphological identification of
somatostatin- or vasoactive intestinal polypeptide-containing cells among
GABAergic cell subtypes in rat frontal cortex. Journal of Neuroscience, 16,
27012715.
Kawaguchi, Y., & Kubota, Y. (1997). GABAergic cell subtypes and their synaptic
connections in rat frontal cortex. Cerebral Cortex, 7, 476486.
Kawaguchi, Y., & Kubota, Y. (1998). Neurochemical features and synaptic connections
of large physiologically-identified GABAergic cells in the rat frontal cortex.
Neuroscience, 85, 677701.
Kepecs, A., & Fishell, G. (2014). Interneuron cell types are fit to function. Nature, 505,
318326.
Kerlin, A. M., Andermann, M. L., Berezovskii, V. K., & Reid, R. C. (2010). Broadly tuned
response properties of diverse inhibitory neuron subtypes in mouse visual cortex.
Neuron, 67, 858871.
Khirug, S., Yamada, J., Afzalov, R., Voipio, J., Khiroug, L., & Kaila, K. (2008).
GABAergic depolarization of the axon initial segment in cortical principal neurons is
caused by the Na-K-2Cl cotransporter NKCC1. Journal of Neuroscience, 28,
46354639.
Kisvarday, Z. F., Martin, K. A., Whitteridge, D., & Somogyi, P. (1985). Synaptic
connections of intracellularly filled clutch cells: A type of small basket cell in the
visual cortex of the cat. Journal of Comparative Neurology, 241, 111137.
Klausberger, T., & Somogyi, P. (2008). Neuronal diversity and temporal dynamics: The
unity of hippocampal circuit operations. Science, 321, 5357.
Krimer, L. S., Zaitsev, A. V., Czanner, G., Kroner, S., Gonzalez-Burgos, G.,
Povysheva, N. V., et al. (2005). Cluster analysis-based physiological classification
and morphological properties of inhibitory neurons in layers 23 of monkey
dorsolateral prefrontal cortex. Journal of Neurophysiology, 94, 30093022.
Kubota, Y., Hatada, S., Kondo, S., Karube, F., & Kawaguchi, Y. (2007). Neocortical
inhibitory terminals innervate dendritic spines targeted by thalamocortical afferents.
Journal of Neuroscience, 27, 11391150.
Kubota, Y., Shigematsu, N., Karube, F., Sekigawa, A., Kato, S., Yamaguchi, N., et al.
(2011). Selective coexpression of multiple chemical markers defines discrete
populations of neocortical GABAergic neurons. Cerebral Cortex, 21, 18031817.
Kullmann, D. M., Moreau, A. W., Bakiri, Y., & Nicholson, E. (2012). Plasticity of
inhibition. Neuron, 75, 951962.
Kvitsiani, D., Ranade, S., Hangya, B., Taniguchi, H., Huang, J. Z., & Kepecs, A. (2013).
Distinct behavioural and network correlates of two interneuron types in prefrontal
cortex. Nature, 498, 363366, U117.
Lecrux, C., Toussay, X., Kocharyan, A., Fernandes, P., Neupane, S., Levesque, M.,
et al. (2011). Pyramidal neurons Are neurogenic hubs in the neurovascular
coupling response to whisker stimulation. Journal of Neuroscience, 31,
98369847.
Lee, S., Hjerling-Leffler, J., Zagha, E., Fishell, G., & Rudy, B. (2010). The largest group
of superficial neocortical GABAergic interneurons expresses ionotropic serotonin
receptors. Journal of Neuroscience, 30, 1679616808.
Lee, S., Kruglikov, I., Huang, Z. J., Fishell, G., & Rudy, B. (2013). A disinhibitory circuit
mediates motor integration in the somatosensory cortex. Nature Neuroscience, 16,
16621670.
Lee, S. H., Kwan, A. C., Zhang, S. Y., Phoumthipphavong, V., Flannery, J. G.,
Masmanidis, S. C., et al. (2012). Activation of specific interneurons improves V1
feature selectivity and visual perception. Nature, 488, 379383.
Lefort, S., Gray, A. C., & Turrigiano, G. G. (2013). Long-term inhibitory plasticity in
visual cortical layer 4 switches sign at the opening of the critical period.
Proceedings of the National Academy of Sciences of the United States of America,
110, E4540E4547.
Letzkus, J. J., Wolff, S. B.E, Meyer, E. M.M, Tovote, P., Courtin, J., Herry, C., et al.
(2011). A disinhibitory microcircuit for associative fear learning in the auditory
cortex. Nature, 480, 331335 U76.
Ma, Y. Y., Hu, H., Berrebi, A. S., Mathers, P. H., & Agmon, A. (2006). Distinct subtypes
of somatostatin-containing neocortical interneurons revealed in transgenic mice.
Journal of Neuroscience, 26, 50695082.
Magistretti, P. J., & Morrison, J. H. (1988). Noradrenaline- and vasoactive intestinal
peptide-containing neuronal systems in neocortex: Functional convergence with
contrasting morphology. Neuroscience, 24, 367378.
79
Sachidhanandam, S., Sreenivasan, V., Kyriakatos, A., Kremer, Y., & Petersen, C. C.
(2013). Membrane potential correlates of sensory perception in mouse barrel
cortex. Nature Neuroscience, 16, 16711677.
Santana, R., McGarry, L. M., Bielza, C., Larranaga, P., & Yuste, R. (2013).
Classification of neocortical interneurons using affinity propagation. Frontiers in
Neural Circuits, 7.
Schubert, D., Kotter, R., & Staiger, J. F. (2007). Mapping functional connectivity in
barrel-related columns reveals layer- and cell type-specific microcircuits. Brain
Structure and Function, 212, 107119.
Schubert, D., Kotter, R., Zilles, K., Luhmann, H. J., & Staiger, J. F. (2003). Cell typespecific circuits of cortical layer IV spiny neurons. Journal of Neuroscience, 23,
29612970.
Sessler, F. M., Grady, S. M., Waterhouse, B. D., & Moises, H. C. (1991).
Electrophysiological actions of VIP in rat somatosensory cortex. Peptides, 12,
715721.
Silberberg, G., & Markram, H. (2007). Disynaptic inhibition between neocortical
pyramidal cells mediated by Martinotti cells. Neuron, 53, 735746.
Simon, A., Olah, S., Molnar, G., Szabadics, J., & Tamas, G. (2005). Gap-junctional
coupling between neurogliaform cells and various interneuron types in the
neocortex. Journal of Neuroscience, 25, 62786285.
Sims, K. B., Hoffman, D. L., Said, S. I., & Zimmerman, E. A. (1980). Vasoactive
intestinal polypeptide (VIP) in mouse and rat brain: an immunocytochemical study.
Brain Research, 186, 165183.
Sohal, V. S., Zhang, F., Yizhar, O., & Deisseroth, K. (2009). Parvalbumin neurons and
gamma rhythms enhance cortical circuit performance. Nature, 459, 698702.
Somogyi, P. (1977). A specific axo-axonal interneuron in the visual cortex of the rat.
Brain Research, 136, 345350.
Somogyi, P., Tamas, G., Lujan, R., & Buhl, E. H. (1998). Salient features of synaptic
organisation in the cerebral cortex. Brain Research Reviews, 26, 113135.
Sorensen, S. A., Bernard, A., Menon, V., Royall, J. J., Glattfelder, K. J., Desta, T., et al.
(2013). Correlated gene expression and target specificity demonstrate excitatory
projection neuron diversity. Cerebral Cortex.
Southwell, D. G., Nicholas, C. R., Basbaum, A. I., Stryker, M. P., Kriegstein, A. R.,
Rubenstein, J. L., et al. (2014). Interneurons from embryonic development to cellbased therapy. Science, 344, 1240622.
Staiger, J. F., Flagmeyer, I., Schubert, D., Zilles, K., Kotter, R., & Luhmann, H. J. (2004).
Functional diversity of layer IV spiny neurons in rat somatosensory cortex:
Quantitative morphology of electrophysiologically characterized and biocytin
labeled cells. Cerebral Cortex, 14, 690701.
Staiger, J. F., Freund, T. F., & Zilles, K. (1997). Interneurons immunoreactive for
vasoactive intestinal polypeptide (VIP) are extensively innervated by parvalbumincontaining boutons in rat primary somatosensory cortex. European Journal of
Neuroscience, 9, 22592268.
Staiger, J. F., Masanneck, C., Schleicher, A., & Zuschratter, W. (2004). Calbindincontaining interneurons are a target for VIP-immunoreactive synapses in rat primary
somatosensory cortex. Journal of Comparative Neurology, 468, 179189.
Staiger, J. F., Zuschratter, W., Luhmann, H. J., & Schubert, D. (2009). Local circuits
targeting parvalbumin-containing interneurons in layer IV of rat barrel cortex. Brain
Structure & Function, 214, 113.
Stark, E., Eichler, R., Roux, L., Fujisawa, S., Rotstein, H. G., & Buzsaki, G. (2013).
Inhibition-induced theta resonance in cortical circuits. Neuron, 80, 12631276.
Suzuki, N., & Bekkers, J. M. (2010a). Distinctive classes of GABAergic interneurons
provide layer-specific phasic inhibition in the anterior piriform cortex. Cerebral
Cortex, 20, 29712984.
Suzuki, N., & Bekkers, J. M. (2010b). Inhibitory neurons in the anterior piriform cortex
of the mouse: Classification using molecular markers. Journal of Comparative
Neurology, 518, 16701687.
Suzuki, N., & Bekkers, J. M. (2012). Microcircuits mediating feedforward and feedback
synaptic inhibition in the piriform cortex. Journal of Neuroscience, 32, 919931.
Szabadics, J., Varga, C., Molnar, G., Olah, S., Barzo, P., & Tamas, G. (2006). Excitatory
effect of GABAergic axo-axonic cells in cortical microcircuits. Science, 311,
233235.
Tamas, G., Lorincz, A., Simon, A., & Szabadics, J. (2003). Identified sources and targets
of slow inhibition in the neocortex. Science, 299, 19021905.
Tamas, G., Somogyi, P., & Buhl, E. H. (1998). Differentially interconnected networks of
GABAergic interneurons in the visual cortex of the cat. Journal of Neuroscience, 18,
42554270.
Taniguchi, H. (2014). Genetic dissection of GABAergic neural circuits in mouse
neocortex. Frontiers in Cellular Neuroscience, 8.
Taniguchi, H., He, M., Wu, P., Kim, S., Paik, R., Sugino, K., et al. (2011). A resource of
Cre driver lines for genetic targeting of GABAergic neurons in cerebral cortex.
Neuron, 71, 9951013.
80
Taniguchi, H., Lu, J. T., & Huang, Z. J. (2013). The spatial and temporal origin of
chandelier cells in mouse neocortex. Science, 339, 7074.
Thomson, A. M., West, D. C., Wang, Y., & Bannister, A. P. (2002). Synaptic connections
and small circuits involving excitatory and inhibitory neurons in layers 25 of adult
rat and cat neocortex: Triple intracellular recordings and biocytin labelling in vitro.
Cerebral Cortex, 12, 936953.
Toledo-Rodriguez, M., Goodman, P., Illic, M., Wu, C. Z., & Markram, H. (2005).
Neuropeptide and calcium-binding protein gene expression profiles predict
neuronal anatomical type in the juvenile rat. Journal of Physiology, 567, 401413.
Tomioka, R., Okamoto, K., Furuta, T., Fujiyama, F., Iwasato, T., Yanagawa, Y., et al.
(2005). Demonstration of long-range GABAergic connections distributed
throughout the mouse neocortex. European Journal of Neuroscience, 21,
15871600.
Uematsu, M., Hirai, Y., Karube, F., Ebihara, S., Kato, M., Abe, K., et al. (2008).
Quantitative chemical composition of cortical GABAergic neurons revealed in
transgenic venus-expressing rats. Cerebral Cortex, 18, 315330.
von Engelhardt, J., Eliava, M., Meyer, A. H., Rozov, A., & Monyer, H. (2007). Functional
characterization of intrinsic cholinergic interneurons in the cortex. Journal of
Neuroscience, 27, 56335642.
Wang, Y., Gupta, A., Toledo-Rodriguez, M., Wu, C. Z., & Markram, H. (2002).
Anatomical, physiological, molecular and circuit properties of nest basket cells in
the developing somatosensory cortex. Cerebral Cortex, 12, 395410.
Wang, Y., Toledo-Rodriguez, M., Gupta, A., Wu, C. Z., Silberberg, G., Luo, J. Y., et al.
(2004). Anatomical, physiological and molecular properties of Martinotti cells in the
somatosensory cortex of the juvenile rat. Journal of Physiology, 561, 6590.
Wilson, N. R., Runyan, C. A., Wang, F. L., & Sur, M. (2012). Division and subtraction by
distinct cortical inhibitory networks in vivo. Nature, 488, 343348.
Woodruff, A. R., McGarry, L. M., Vogels, T. P., Inan, M., Anderson, S. A., & Yuste, R.
(2011). State-dependent function of neocortical chandelier cells. Journal of
Neuroscience, 31, 1787217886.
Wozny, C., & Williams, S. R. (2011). Specificity of synaptic connectivity between layer 1
inhibitory interneurons and layer 2/3 pyramidal neurons in the rat neocortex.
Cerebral Cortex, 21, 18181826.
Xu, X. M., & Callaway, E. M. (2009). Laminar specificity of functional input to distinct
types of inhibitory cortical neurons. Journal of Neuroscience, 29, 7085.
Xu, H., Jeong, H. Y., Tremblay, R., & Rudy, B. (2013). Neocortical somatostatinexpressing GABAergic interneurons disinhibit the thalamorecipient layer 4. Neuron,
77, 155167.
Xu, X. M., Roby, K. D., & Callaway, E. M. (2010). Immunochemical characterization of
inhibitory mouse cortical neurons: Three chemically distinct classes of inhibitory
cells. Journal of Comparative Neurology, 518, 389404.
Yanez, I. B., Munoz, A., Contreras, J., Gonzalez, J., Rodriguez-Veiga, E., & De Felipe, J.
(2005). Double bouquet cell in the human cerebral cortex and a comparison with
other mammals. Journal of Comparative Neurology, 486, 344360.
Yang, W. G., Carrasquillo, Y., Hooks, B. M., Nerbonne, J. M., & Burkhalter, A. (2013).
Distinct balance of excitation and inhibition in an interareal feedforward and
feedback circuit of mouse visual cortex. Journal of Neuroscience, 33,
1737317384.
Yizhar, O., Fenno, L. E., Prigge, M., Schneider, F., Davidson, T. J., OShea, D. J., et al.
(2011). Neocortical excitation/inhibition balance in information processing and
social dysfunction. Nature, 477, 171178.
Young, A., & Sun, Q. Q. (2009). GABAergic inhibitory interneurons in the
posterior piriform cortex of the GAD67-GFP mouse. Cerebral Cortex, 19,
30113029.
Zhu, Y. H., Stornetta, R. L., & Zhu, J. J. (2004). Chandelier cells control excessive cortical
excitation: Characteristics of whisker-evoked synaptic responses of layer 2/3
nonpyramidal and pyramidal neurons. Journal of Neuroscience, 24, 51015108.
Zilles, K., Hajos, F., Csillag, A., Kalman, M., Sotonyi, P., & Schleicher, A. (1993).
Vasoactive intestinal polypeptide immunoreactive structures in the mouse barrel
field. Brain Research, 618, 149154.
Glossary
After these initial descriptions, a few other authors acknowledged the presence of spindle cells in the human cortex
(Braak, 1980; Juba, 1934; Ngowyang, 1932; Rose, 1927,
1928; Syring, 1956). In addition, spindle neurons had been
described in the subicular cortex and entorhinal cortex of the
human hippocampal formation by Ngowyang (1936), indicating that ACC and FI are not the only limbic regions to contain
them. It was only in 1995 that the first modern study of the
morphology, distribution, and apparent numbers of the spindle neurons was performed in the human ACC (Nimchinsky,
Vogt, Morrison, & Hof, 1995), demonstrating their immunoreactivity to dephosphorylated neurofilament proteins and a
rostrocaudal gradient in their density. These authors also provided the first evidence that spindle cells are indeed projection
neurons. These spindle-shaped neurons, generally known until
1999 in the literature as spindle cells, were recently renamed
von Economo neurons (VENs) by Allman, Watson, Tetreault,
and Hakeem (2005) in tribute to Constantin von Economos
first detailed description and to avoid confusion with smaller
fusiform and spindle-shaped interneurons of layer VI.
VENs in Primates
More recently, VENs were reported as a unique neuronal morphology in the ACC of humans and their closest living relatives, the great apes: orangutans (Pongo pygmaeus and Pongo
abelii), gorillas (Gorilla gorilla), bonobos (Pan paniscus), and
chimpanzees (Pan troglodytes) (Nimchinsky et al., 1995, 1999).
Figure 2 shows representative sections in human, chimpanzee,
and gorilla. The incidence of VENs within the ACC was
observed to decrease in a rostral to caudal gradient. In humans
and bonobos, VENs were found in clusters of three to six cells
located in layer Vb of the ACC. In contrast, VENs occurred
singly or in small clusters of only two to three cells in the
http://dx.doi.org/10.1016/B978-0-12-397025-1.00203-7
81
82
83
Figure 2 Images of Nissl-stained sections illustrating von Economo neurons (VENs) in human (a), chimpanzee (Pan troglodytes, b), and gorilla (Gorilla
gorilla, c). Arrows indicate VENs, scale bars 25 mm.
coincident with large brain size and did not negate the prospect
that they were characteristic of socially complex organisms.
Figure 3 shows representative VENs in cetacean species. While
VENs were common in the mysticetes, they were present only in
the two odontocetes with the largest absolute brain sizes. VENs
were found in regions that correspond to the FI and ACC, as well
as the frontal pole of the humpback whale (Megaptera novaeangliae), fin whale (Balaenoptera physalus), sperm whale (Physeter
macrocephalus), and killer whale (Orcinus orca) (Hof & van der
Gucht, 2007). As in primates, VENs were most common in layer
V and occasionally within layer III; there were a rostrocaudal
gradient within the ACC and a tendency for VENs to be more
prevalent in the crowns of gyri. VENs were also observed in
regions of the cetacean cortex that did not correspond to the
hominid distribution and included the inferior temporal cortex,
occipital region of the ecto- and suprasylvian cortex, and paralimbic cortex. More recently, VENs were reported in the ACC, AI,
and frontopolar cortex of smaller odontocetes, including the
bottlenose dolphin (Tursiops truncatus), the Rissos dolphin
(Grampus griseus), and the beluga whale (Delphinapterus leucas)
(Butti, Sherwood, Hakeem, et al., 2009; Hakeem et al., 2009).
Once again, there was a regionally limited neocortical distribution of VENs, with total numbers comparable to those observed
in great ape species.
More recent analyses revealed a ubiquitous and dense distribution of VENs in the cortex of the pygmy hippopotamus
(Hexaprotodon liberiensis), with VENs present in all cortical
regions (Figure 4(a)) (Butti, Fordyce, Raghanti, et al., 2014;
Butti & Hof, 2010; Butti, Raghanti, Sherwood, & Hof, 2011).
Hippopotamids are classified as artiodactyls (i.e., even-toed
ungulates) and represent the closest living relative of cetaceans
(Boisserie, Fisher, Lihoreau, and Weston, 2011); however, they
lack an enlarged brain and, while social, are not categorized as
having complex social behaviors.
To gain a better understanding of the phylogenetic distribution of this morphologically unique neuron type, we examined Nissl-stained sections from the frontopolar cortex of
additional artiodactyl species. This sample included the
domesticated pig (Sus scrofa domesticus), sheep (Ovis aries),
cow (Bos taurus), and white-tailed deer (Odocoileus virginianus).
To this end, the entire circumference of frontopolar coronal
sections was qualitatively analyzed systematically from pia to
white matter.
VENs were present in the frontal pole of each of these
species (Figure 4(b)4(f)), but the distributions and densities
of these cells revealed species-specific properties. Similar to
reports in other taxa, VENs were most numerous in the
crown gyri and absent within sulcal depths. VENs were ubiquitously distributed throughout the frontopolar cortex of the
pig and cow, but with distinctive patterns of distribution for
each species. VENs were restricted to specific regions of the
frontal pole for both deer and sheep. Remarkably, we observed
VENs within layer II of several artiodactyls, of roughly comparable appearance to the layer V VENs, with clusters of layer II
VENs present in the sheep and cow. This is a novel laminar
localization for VENs, which will deserve further investigation
in a larger number of species.
84
Figure 3 Representative images of Nissl-stained sections showing VENs in (a) the minke whale (Balaenoptera acutorostrata), (b) the beluga whale
(Delphinapterus leucas), (c) the humpback whale (Megaptera novaeangliae), (d) the long-finned pilot whale (Globicephala melas), (e) bottlenose dolphin
(Tursiops truncatus), and (f) Rissos dolphin (Grampus griseus). VENs are indicated by arrows. Scale bars 25 mm.
Afrotherians
Following their discovery in cetaceans, VENs were reported to be
present in the brains of the African elephant (Loxodonta africana)
and Indian elephant (Elephas maximus; Figure 6(a)). Because
elephants independently evolved large brains and possess highly
complex social behaviors, this finding provided further opportunity for considering the role of VENs in social interactions. Their
distribution was similar to that observed in hominids and cetaceans, present in the FI, frontal pole, and dorsolateral frontal area
of the African elephant and in the ACC of the Indian elephant
(Hakeem et al., 2009). The estimated number of VENs in the
elephant ACC was less than those of humans and great apes; and
85
Figure 4 VENs are shown in (a) the pygmy hippopotamus (Hexaprotodon liberiensis), in layer II (b) and (c) of the layer V in the frontopolar cortex of
the cow (Bos taurus), (d) in the white matter of the white-tailed deer (Odocoileus virginianus), (e) in layer V of the frontopolar cortex in the domesticated
pig (Sus scrofa domesticus), and (f) sheep (Ovis aries). VENs are indicated by arrows. Scale bars 25 mm.
Figure 5 Nissl-stained sections showing VENs in (a) the common zebra (Equus burchelli), (b) black rhinoceros (Diceros bicornis), (c) horse (Equus
ferus caballus), and (d) walrus (Odobenus rosmarus). VENs are indicated by arrows. Scale bars 25 mm.
86
Figure 6 VENs are shown in (a) the Indian elephant (Elephas maximus)
and (b) the manatee (Trichechus manatus). VENs are indicated by
arrows. Scale bars 25 mm.
hippopotamus and common zebra indicated that a more expansive comparative analysis would be helpful in exploring the evolutionary and functional significance of this neuron type.
Recent evidence indicates that the presence of VENs is not
restricted to large-brained species with complex social organization. Based on these findings, it appears that VENs represent
a phylogenetically ancient neuron type rather than an emergent specialized neuron exclusive to encephalized or socially
complex species. Instead of parallel evolution among multiple
clades, a more parsimonious account would suggest that this
neuron type emerged very early within the mammalian radiation, but their absence in xenarthrans (e.g., anteater and sloths)
and rodents suggests that VENs, as defined by their morphology, were not present in the earliest mammals.
87
Figure 7 Photomicrographs showing morphological alterations of VENs in autism. VEN with surrounding oligodendrocytes (a), corkscrew VEN (b),
and swollen VEN (c). Scale bar 10 mm.
88
89
Cetartiodactyla
Perissodactyla
Carnivora
Laurasiatheria
Pholidota
Chiroptera
Insectivora
Rodentia
Lagomorpha
Dermoptera
Euarchontoglires
Scandentia
Primates
Pilosa
Xenarthra
Cingulata
Afrosoricida
Macroscelidea
Tubulidentata
Afrotheria
Sirenia
Hyracoidea
Proboscidea
Marsupialia
Monotremata
Figure 8 Adaptation of the phylogeny of placental mammals including orders and superorders (derived from Murphy, Eizirik, Johnson, et al., 2001).
Orders that contain at least one species in which VENs have been observed are shown in red.
behavior. This is compatible with Damasios theory of consciousness (Damasio, 1999) in which the anterior insulaACC
network plays a central role in shaping a notion of self from a
representation of integrated body. Finally, our findings of
increased VENs in the FI of children with autism (Santos,
Uppal, Butti, et al., 2011) may well be related to the concept
that such patients have difficulties distinguishing internal and
external stimuli (Haag et al., 2005), leading to increased interoception and overwhelming perceptions.
Phylogenetic Considerations
VEN function remains elusive owing to the impossibility of
performing invasive studies in the species that possess them,
making it difficult, if not impossible, to gain direct evidence on
their actual role in brain circuits and on potential speciesspecific functional differences. Their recent observation in
cercopithecine primates (Evrard et al., 2012) may open possibilities for exploratory tract-tracing investigations that may
shed light on their projections. However, as VENs are found
in an increasing number of species, including artiodactyls,
perissodactyls, sirenians, and carnivores (Figure 8) (Butti
& Hof, 2010; Butti, Santos, Uppal, & Hof, 2013), and exhibit
major differences in their distribution, their evolutionary significance needs to be revisited from early concepts such as the
neurons that make us human to a much broader interpretation, relying on a systems neuroscience-based approach. In this
context, VENs can be envisioned as part of taxon-specific,
functionally specialized networks, depending on their cortical
distribution.
Finally, it must be kept in mind that all available studies of
VENs are based solely on Nissl-stained materials and a few
immunohistochemical observations. As previously emphasized, VENs are not found in species that allow for experimental manipulations, making other approaches impractical. In
the future, the use of transcriptomics with laser capture microscopy and microarray and RNA sequencing, although depending on the availability and quality of frozen autopsy materials
from species in which VENs occur, may become an approach
to analyze VEN-specific gene expression, in a comparative
manner to enhance our understanding of the role of VENs in
brain function.
Acknowledgments
This work is supported by the James S. McDonnell Foundation
(22002078, PRH, CCS), NSF grant BCS-0921079 (MAR),
Autism Speaks (Autism Celloidin Library, PRH), and the Seaver
Foundation (NU). The authors thank Drs. J.M. Allman,
90
References
Allman, J. M., Tetreault, N. A., Hakeem, A. Y., et al. (2010). The von Economo neurons
in frontoinsular and anterior cingulate cortex in great apes and humans. Brain
Structure and Function, 214, 495517.
Allman, J., Watson, K., Tetreault, N., & Hakeem, A. (2005). Intuition and autism: A
possible role for Von Economo neurons. Trends in Cognitive Sciences, 9, 367373.
APA, (2000). Autistic disorder. In APA (Ed.), Diagnostic and statistic manual of mental
disorders (DSM-IV-TR). Washington, DC: APA.
Bauernfeind, A. L., de Sousa, A. A., Avasthi, T., et al. (2013). A volumetric comparison
of the insular cortex and its subregions in primates. Journal of Human Evolution,
64, 263279.
Baumgarten, H., & Gothert, M. (1997). Serotoninergic neurons and 5-HT receptors in
the CNS. Springer.
Betz, W. (1881). Uber die feinere Strukture der Gehirnrinde des Menschen. Centralblatt
fur die medizinischen Wissenschaften, 19, 193195, 209234.
Boisserie, J. R., Fisher, R. E., Lihoreau, F., & Weston, E. M. (2011). Evolving between
land and water: Key questions on the emergence and history of the Hippopotamidae
(Hippopotamoidea, Cetancodonta, Cetartiodactyla). Biological Reviews of the
Cambridge Philosophical Society, 86, 601625.
Borman, R. A., Tilford, N. S., Harmer, D. W., et al. (2002). 5-HT(2B) receptors play a key
role in mediating the excitatory effects of 5-HT in human colon in vitro. British
Journal of Pharmacology, 135, 11441151.
Bouras, C., Kovari, E., Hof, P. R., Riederer, B. A., & Giannakopoulos, P. (2001). Anterior
cingulate cortex pathology in schizophrenia and bipolar disorder. Acta
Neuropathologica, 102, 373379.
Braak, H. (1980). Architectonics of the human telencephalic cortex. Berlin: Springer.
Brodal, P. (1978). The corticopontine projection in the rhesus monkey. Origin and
principles of organization. Brain, 101, 251283.
Brown, W., & Paul, L. (2000). Cognitive and psychosocial deficits in agenesis of the
corpus callosum with normal intelligence. Cognitive Neuropsychiatry, 5, 135157.
Brune, M., Schobel, A., Karau, R., et al. (2010). Von Economo neuron density in the
anterior cingulate cortex is reduced in early onset schizophrenia. Acta
Neuropathologica, 119, 771778.
Brune, M., Schobel, A., Karau, R., et al. (2011). Neuroanatomical correlates of suicide in
psychosis: The possible role of von Economo neurons. PLoS One, 6, e20936.
Bullmore, E., & Sporns, O. (2009). Complex brain networks: Graph theoretical analysis
of structural and functional systems. Nature Reviews. Neuroscience, 10, 186198.
Butti, C., Fordyce, R. E., Raghanti, M. A., et al. (2014). The cerebral cortex of the pygmy
hippopotamus, Hexaprotodon liberiensis (Cetartiodactyla, Hippopotamidae).
Anatomical Record, 297(4), 670700.
Butti, C., & Hof, P. R. (2010). The insular cortex: A comparative perspective. Brain
Structure and Function, 214, 477493.
Butti, C., Raghanti, M. A., Sherwood, C. C., & Hof, P. R. (2011). The neocortex of
cetaceans: Cytoarchitecture and comparison with other aquatic and terrestrial
species. Annals of the New York Academy of Sciences, 1225, 4758.
Butti, C., Santos, M., Uppal, N., & Hof, P. R. (2013). Von Economo neurons: Clinical
and evolutionary perspectives. Cortex, 49, 312326.
Butti, C., Sherwood, C. C., Hakeem, A. Y., Allman, J. M., & Hof, P. R. (2009). The
number and volume of von Economo neurons in the cerebral cortex of cetaceans.
Journal of Comparative Neurology, 515, 243259.
Craig, A. D. (2003). Interoception: The sense of the physiological condition of the body.
Current Opinion in Neurobiology, 13, 500505.
Craig, A. D. (2005). Forebrain emotional asymmetry: A neuroanatomical basis? Trends
in Cognitive Sciences, 912, 566571.
Craig, A. D. (2009). How do you feel now? The anterior insula and human awareness.
Nature Reviews. Neuroscience, 10, 5970.
Craig, A. D., Chen, K., Bandy, D., & Reiman, E. M. (2000). Thermosensory activation of
insular cortex. Nature Neuroscience, 3, 184190.
Critchley, H. D., Mathias, C. J., & Dolan, R. J. (2001). Neural activity in the human brain
relating to uncertainty and arousal during anticipation. Neuron, 29, 537545.
Damasio, A. R. (1999). The feeling of what happens: Body emotion in the making of
consciousness. New York: Harcourt Brace.
Daw, N. D., Kakade, S., & Dayan, P. (2002). Opponent interactions between serotonin
and dopamine. Neural Networks, 15, 603616.
De Crinis, M. (1933). Uber die Spezialzellen in der menschlichen Grohirnrinde.
Journal fur Psychologie und Neurologie, 45, 439449.
Economo, C., & Koskinas, G. N. (1925). Die Cytoarchitektonik der Hirnrinde des
erwachsenen Menschen. Wien und Berlin: J. Springer.
Evrard, H. C., Forro, T., & Logothetis, N. K. (2012). Von Economo neurons in the
anterior insula of the macaque monkey. Neuron, 74, 428429.
Fajardo, C., Escobar, M. I., Butitica, E., Umbarila, J., Casanova, M. F., & Pimienta, H.
(2008). Von Economo neurons are present in the dorsolateral (dysgranular)
prefrontal cortex of humans. Neuroscience Letters, 435, 215218.
Flechsig, P. (1897). Zur anatomie des vorderen Sehhugelsteils, des Cingulum und der
Acusticusbahn. Neurologie Zentralblatt, 16, 290295.
Flechsig, P. (1920). Anatomie des menschlichen Gehirns und Ruckenmarks auf
myelogenetischer Grundlage. Leipzig: G. Thieme.
Fornito, A., Yucel, M., Dean, B., Wood, S. J., & Pantelis, C. (2009). Anatomical
abnormalities of the anterior cingulate cortex in schizophrenia: Bridging the gap
between neuroimaging and neuropathology. Schizophrenia Bulletin, 35, 973993.
Frisoni, G. B., Prestia, A., Adorni, A., et al. (2009). In vivo neuropathology of cortical
changes in elderly persons with schizophrenia. Biological Psychiatry, 66,
578585.
Gallese, V., Keysers, C., & Rizzolatti, G. (2004). A unifying view of the basis of social
cognition. Trends in Cognitive Sciences, 8, 396403.
Glickstein, M., May, J. G., & Mercier, B. E. (1985). Corticopontine projection in the
macaque: The distribution of labelled cortical cells after large injections of
horseradish peroxidase in the pontine nuclei. Journal of Comparative Neurology,
235, 343359.
Glickstein, M., May, J. G., & Mercier, B. E. (1990). Visual corticopontine and
tectopontine projections in the macaque. Archives Italiennes de Biologie, 128,
273293.
Goldstein, M. (1913). Contributiuni la studiul citoarchitectoniei cerebrale (Teza de
Docenta). Bucaresti: Tipografia Cultura Strada Campineana.
Haag, G., Tordjman, S., Duprat, A., et al. (2005). Psychodynamic assessment of
changes in children with autism under psychoanalytic treatment. International
Journal of Psychoanalysis, 86, 335352.
Hakeem, A. Y., Sherwood, C. C., Bonar, C. J., Butti, C., Hof, P. R., & Allman, J. M.
(2009). Von Economo neurons in the elephant brain. The Anatomical Record, 292,
242248.
Hammarberg, C. (1895). Studen uber Klinik und Pathologie der Idiotie nebst
Untersuchungen uber die normale Anatomie des Hirnrinde. Berling: Uppsala.
Hof, P. R., Nimchinsky, E. A., Young, W. G., & Morrison, J. H. (2000). Numbers of
meynert and layer IVB cells in area V1: A stereologic analysis in young and aged
macaque monkeys. Journal of Comparative Neurology, 420, 113126.
Hof, P. R., & Van der Gucht, E. (2007). Structure of the cerebral cortex of the humpback
whale, Megaptera novaeangliae (Cetacea, Mysticeti, Balaenopteridae). Anatomical
Record, 290, 131.
Illingworth, R. (1972). The development of the infant and young child normal and
abnormal (5th ed.). Baltimore: Williams and Wilkins.
91
Santos, M., Uppal, N., Butti, C., et al. (2011). von Economo neurons in autism: A
stereologic study of the frontoinsular cortex in children. Brain Research, 1380,
206217.
Seeley, W. W. (2008). Selective functional, regional, and neuronal vulnerability in
frontotemporal dementia. Current Opinion in Neurology, 21, 701707.
Seeley, W. W., Allman, J., Carlin, D. A., et al. (2007). Divergent social functioning in
behavioral variant frontotemporal dementia and Alzheimer disease: Reciprocal
connections and neuronal evolution. Alzheimers Disease and Associated Disorders,
21, S50S57.
Seeley, W. W., Carlin, D. A., Allman, J., et al. (2006). Early frontotemporal dementia
targets neurons unique to apes and humans. Annals of Neurology, 60,
660667.
Seeley, W. W., Menon, V., Schatzberg, A. F., et al. (2007). Dissociable intrinsic
connectivity networks for salience processing and executive control. Journal of
Neuroscience, 27, 23492356.
Seeley, W. W., Merkle, F. T., Gaus, S. E., Craig, A. D., Allman, J. M., & Hof, P. R.
(2012). Distinctive neurons of the anterior cingulate and frontoinsular cortex: A
historical perspective. Cerebral Cortex, 22, 245250.
Sherwood, C. C., Lee, P. H., Rivara, C.-B., et al. (2003). Evolution of specialized
pyramidal neurons in primate visual and motor cortex. Brain, Behavior and
Evolution, 61, 2844.
Simms, M. L., Kemper, T. L., Timbie, C. M., Bauman, M. L., & Blatt, G. J. (2009). The
anterior cingulate cortex in autism: Heterogeneity of qualitative and quantitative
cytoarchitectonic features suggests possible subgroups. Acta Neuropathologica,
118, 673684.
Sokoloff, P., & Schwartz, J. (2002). The dopamine D3 receptor and its implications in
neuropsychiatric disorders and their treatments. In G. Di Chiara (Ed.), Dopamine in
the CNS: Springer.
Sridharan, D., Levitin, D. J., & Menon, V. (2008). A critical role for the right frontoinsular cortex in switching between central-executive and default-mode networks.
Proceedings of the National Academy of Sciences of the United States of America,
105, 1256912574.
Stimpson, C. D., Tetreault, N. A., Allman, J. M., et al. (2011). Biochemical specificity
of von Economo neurons in hominoids. American Journal of Human Biology, 23,
2228.
Striedter, G. F. (2005). Principles of brain evolution. Sunderland, MA: Sinauer
Associates Inc.
Syring, A. (1956). Die Verbreitung von Spezialzellen in der Grosshirnrinde
verschiedener Saugertiergruppen. Zeitschrift fur Zellforschung und Mikroskopische
Anatomie, 45, 399434.
Taylor, K. S., Seminowicz, D. A., & Davis, K. D. (2009). Two systems of resting state
connectivity between the insula and cingulate cortex. Human Brain Mapping, 30,
27312745.
Tennes, K. H., & Lampl, E. E. (1964). Stranger and separation anxiety in infancy.
Journal of Nervous and Mental Disease, 139, 247254.
Uddin, L. Q., & Menon, V. (2009). The anterior insula in autism: Under-connected and
under-examined. Neuroscience and Biobehavioral Reviews, 33, 11981203.
Vogt, O. (1903). Zur anatomischen Gliederung des Cortex cerebri. Journal fur
Psychologie und Neurologie, 2, 160180.
Vogt, C., & Vogt, O. (1919). Allgemeinere Ergebnisse unserer Hirnforschung. Journal
fur Psychologie und Neurologie, 25, 279461.
von Economo, C. (1926). Eine neue Art Spezialzellen des Lobus cinguli und
Lobus insulae. Zeitschrift fur die Gesamte Neurologie und Psychiatrie, 100,
706712.
Weaver, C. M., & Wearne, S. L. (2008). Neuronal firing sensitivity to morphologic and
active membrane parameters. PLoS Computational Biology, 4, e11.
White, T. P., Joseph, V., Francis, S. T., & Liddle, P. F. (2010). Aberrant salience network
(bilateral insula and anterior cingulate cortex) connectivity during information
processing in schizophrenia. Schizophrenia Research, 123, 105115.
Abbreviations
AMPA
ATP
BDNF
CCK
CNS
GABA
MUNC
NMDA
a-Amino-3-hydroxy-5-methyl-4isoxazolepropionic acid
Adenosine triphosphate
Brain-derived neurotrophic factor
Cholecystokinin
Central nervous system
g-Aminobutyric acid
An acronym for a family of mammalian
uncoordinated proteins located at the presynaptic
density
N-Methyl-D-aspartate
NPY
PSD
RIM
RP
RRP
SNAP
SNARE
VIP
Neuropeptide Y
Postsynaptic density
Family of major active zone proteins
Recycling pool
Readily releasable pool
Soluble N-ethylmaleimide sensitive fusion
attachment protein
Soluble N-ethylmaleimide sensitive fusion
attachment protein receptor, an acronym derived
from SNAP superfamily of active zone proteins
Vasointestinal protein
http://dx.doi.org/10.1016/B978-0-12-397025-1.00204-9
93
94
Figure 1 Structural composition and location of synapses in the neocortex. (a) Electron micrograph showing a synaptic bouton (b1, given in
transparent yellow) establishing a synaptic contact (red arrowheads at b1 and b2) with a dendritic shaft (sh, given in transparent blue). A second bouton
(b2) terminates on a dendritic spine (sp). Note the prominent spine apparatus (framed areas) in the spine neck and head. Scale bar is 1 mm. (b) 3-D
volume reconstruction of a dendritic segment of a neocortical layer 5 pyramidal neuron with three synaptic boutons (transparent yellow) terminating on
different parts of the dendrite (blue). The synaptic boutons were made transparent to visualize important subelements within the synaptic boutons:
active zones are given in red, synaptic vesicles in green, and mitochondria in white. Note that synaptic vesicles are also frequently found in the axon
as indicated by the framed area. (c) Somatic region (so) with numerous synaptic boutons (b1b5). Scale bar is 1 mm. (d) Three synaptic boutons
(b1b3) terminating on an axon initial segment (ais) establishing axoaxonic contacts. The active zones are marked by red arrowheads. Scale bar is
0.5 mm. (e) Two axospinous synapses (b1, sp1 and b2, sp2) isolated by fine astrocytic processes (transparent green). Note that fine astrocytic
processes reach as far as the active zones (marked by red arrowheads). Scale bar is 0.5 mm. Inset: high-power electron micrograph of the active
zone composed of the pre- and postsynaptic densities and the synaptic cleft. Docked vesicles fused with the presynaptic density are marked by
asterisks. Scale bar is 0.1 mm. (f) 3-D volume reconstruction of the synaptic complex (b1 yellow; sp1 blue) in D showing the tight ensheathment
of the bouton and spine by fine astrocytic processes (green). The presynaptic density is marked by red arrowheads.
95
Figure 2 Comparison of two cortical synapses embedded in different microcircuits. (a) Two hippocampal mossy fiber boutons (MFB1 and MFB2,
transparent yellow) terminating on a large proximal dendrite (transparent blue) of a CA3 pyramidal neuron. Here, synaptic contacts are established
exclusively with the spiny excrescences (se, transparent blue), whereas puncta adherentia that are regarded as adhesion complexes (red asterisks) are
only found at the apposition zone between the two boutons and the target dendrite. Scale bar is 0.5 mm. (a1) 3-D volume reconstruction of an en
passant MFB (yellow) and its postsynaptic target dendrite. (b) Electron micrograph of a neocortical axospinous synapse with a perforated postsynaptic
density (red arrowheads). Scale bar is 0.5 mm. (b1) 3-D volume reconstruction of the synaptic complex shown in (b). Note that the mossy fiber
terminal is 20-fold larger than the neocortical bouton as indicated by the white scale bar (5 mm).
The so-called synaptic active zone, that is, the close apposition between the pre- and postsynaptic elements, is the site of
neurotransmitter release. In general, chemical synapses are
composed of three subelements: a pre- and postsynaptic compartment and a cleft between the two elements (Figures 1(e)
inset and 3(a)). The presynaptic element contains a highly
variable pool of synaptic vesicles and several mitochondria
associated with the pool of vesicles (Figure 1(ac) and 1(e)).
At the contact zone with the postsynaptic neuron, a dense
accumulation is formed, the presynaptic density (Figure 1(a),
1(c), and 1(e) inset). This density is constituted by a cocktail of
various synaptic proteins including the SNARE and SNAP
complex, various MUNC and RIM proteins, and many others
all involved in the transport, binding, and fusion of synaptic
96
Figure 3 Distribution pattern of AMPA and NMDA receptors at neocortical synapses. (a) Intrasynaptic distribution of the AMPA receptor (subunits
GluR14, black gold grains) at a postsynaptic density (PSD) as revealed by the dense accumulation of so-called intramembranous particles on
a dendritic spine using freeze-fracture replica preparations combined with postimmunogold labeling. Here, the synaptic cleft (as marked by the
arrowheads) separating the pre- (on the left) and PSD (on the right) is clearly visible. (b) Intrasynaptic distribution of the NR1 subunit of the NMDA
receptor (black gold grains) at a PSD at a dendritic shaft. Note the clustered distribution of the NR1 subunit within the PSD. (c) Co-localization of
the AMPA receptor (labeled with 5 nm gold) and the NR1 subunit of the NMDA receptor (labeled with 10 nm gold) at a PSD located at the somatic region
of a neuron. Scale bars in (a)(c) are 100 nm.
97
98
References
Anker, R. L., & Cragg, B. G. (1974). Estimation of the number of synapses in a volume
of nervous tissue from counts in thin sections by electron microscopy. Journal of
Neurocytology, 3, 725735.
Blue, M. E., & Parnavelas, J. G. (1983a). The formation and maturation of synapses in
the visual cortex of the rat. I. Qualitative analysis. Journal of Neurocytology, 12,
599616.
Blue, M. E., & Parnavelas, J. G. (1983b). The formation and maturation of synapses in
the visual cortex of the rat. II. Quantitative analysis. Journal of Neurocytology, 12,
697712.
Bourgeois, J. P., Jastreboff, P. J., & Rakic, P. (1989). Synaptogenesis in visual cortex of
normal and preterm monkeys: Evidence for intrinsic regulation of synaptic
overproduction. Proceedings of the National Academy of Sciences of the United
States of America, 86, 42974301.
Contractor, A., Swanson, G. T., Sailer, A., OGorman, S., & Heinemann, S. F. (2000).
Identification of the kainate receptor subunits underlying modulation of excitatory
synaptic transmission in the CA3 region of the hippocampus. Journal of
Neuroscience, 20, 82698278.
Cowan, W. M., Sudhof, T. C., & Stevens, C. F. (2003). Synapses. Baltimore: John
Hopkins0-8018-7118-2, Paperbacks Edition.
Cragg, B. G. (1972). The development of synapses in cat visual cortex. Investigative
Ophthalmology, 11, 377385.
Cragg, B. G. (1975a). The density of synapses and neurons in normal, mentally
defective ageing human brains. Brain, 98, 8190.
99
Nusser, Z. (2000). AMPA and NMDA receptors: Similarities and differences in their
synaptic distribution. Current Opinion in Neurobiology, 10, 337341.
Oliet, S. H., Piet, R., Poulain, D. A., & Theodosis, D. T. (2004). Glial modulation of
synaptic transmission: Insights from the supraoptic nucleus of the hypothalamus.
Glia, 47, 258267.
Olsen, R. W., & Sieghart, W. (2009). GABA A receptors: Subtypes provide diversity of
function and pharmacology. Neuropharmacology, 56, 141148.
Pozzan, T., Magalhaes, P., & Rizzuto, R. (2000). The comeback of mitochondria to
calcium signalling. Cell Calcium, 28, 279283.
Rakic, P., Bourgeois, J. P., Eckenhoff, M. F., Zecevic, N., & Goldman-Rakic, P. S.
(1986). Concurrent overproduction of synapses in diverse regions of the primate
cerebral cortex. Science, 232, 232235.
Rao, V. R., & Finkbeiner, S. (2007). NMDA and AMPA receptors: Old channels, new
tricks. Trends in Neurosciences, 30, 284291.
Rizzoli, S. O., & Betz, W. J. (2004). The structural organization of the readily releasable
pool of synaptic vesicles. Science, 303, 20372039.
Rizzoli, S. O., & Betz, W. J. (2005). Synaptic vesicle pools. Nature Reviews.
Neuroscience, 6, 5769.
Rizzuto, R., Bernardi, P., & Pozzan, T. (2000). Mitochondria as all-round players of the
calcium game. Journal of Physiology, 529, 3747.
Rollenhagen, A., & Lubke, J. H. (2006). The morphology of excitatory central synapses:
From structure to function. Cell and Tissue Research, 326, 221237.
Rollenhagen, A., Satzler, K., Rodriguez, E. P., Jonas, P., Frotscher, M., & Lubke, J. H.R
(2007). Structural determinants of transmission at large hippocampal mossy fiber
synapses. Journal of Neuroscience, 27, 1043410444.
Schmitz, D., Mellor, J., & Nicoll, R. A. (2001). Presynaptic kainate receptor mediation of
frequency facilitation at hippocampal mossy fiber synapses. Science, 291,
19721976.
Schoch, S., & Gundelfinger, E. D. (2006). Molecular organization of the presynaptic
active zone. Cell and Tissue Research, 326, 379391.
Stanley, E. F. (1997). The calcium channel and the organization of the presynaptic
transmitter release face. Trends in Neuroscience, 20, 404409.
Sudhof, T. C. (2012). The presynaptic active zone. Neuron, 75, 1125.
Ulrich, D., & Bettler, B. (2007). GABA(B) receptors: Synaptic functions and mechanisms
of diversity. Current Opinion in Neurobiology, 17, 298303.
Waites, C. L., Leal-Ortiz, S. A., Okerlund, N., Dalke, H., Fejtova, A., Altrock, W. D., et al.
(2013). Bassoon and Piccolo maintain synapse integrity by regulating protein
ubiquitination and degradation. EMBO Journal, 32, 954969.
Zilles, K., Palomero-Gallagher, N., & Schleicher, A. (2004). Transmitter receptors
and functional anatomy of the cerebral cortex. Journal of Anatomy, 205,
417432.
Glossary
Abbreviations
InsP3R
PNS
TRP
ER
CNS
Endoplasmic reticulum
Central nervous system
1980s by William Stallcup and colleagues as cells of oligodendroglial lineage with certain unique features (for history on
neuroglial research, see Kettenmann & Verkhratsky, 2008).
Definition
The common definition of neuroglia has not been generally
established; conceptually, all cells in the nervous system that
are not neurons or vascular cells are considered to be neuroglia
(Kettenmann & Ransom, 2013; Verkhratsky & Butt, 2013).
These cells are highly heterogeneous in their morphology and
physiology and are different in their origins, microglial cells
being of mesodermal descent and all other cells of ectodermal
descent. Nonetheless, all neuroglia have a common function,
which is preservation of the homeostasis of the nervous system. Therefore, the neuroglia can be broadly defined as cells
that maintain homeostasis of the nervous system, represented by
highly heterogeneous cellular populations of different origin,
structure, and function (Verkhratsky & Butt, 2013).
The homeostatic function of neuroglia is executed at many
levels that include body and organ homeostasis (e.g., astrocytes control the emergence and maintenance of the CNS,
peripheral glia are essential for communication between the
CNS and the body, and enteric glia are essential for every aspect
of gastrointestinal function), cellular homeostasis (e.g., stem
astroglia and NG2 glia are the precursors for adult neuro- and
gliogenesis), morphological homeostasis (radial glia provide
the migratory pathways for neural cells in development, astrocytes form the cytoarchitecture of the gray matter, astrocytes
and microglia control synaptogenesis/synaptic pruning, and
myelinating glia maintain the structural integrity of nerves),
molecular homeostasis (regulation of ion, neurotransmitter,
http://dx.doi.org/10.1016/B978-0-12-397025-1.00205-0
101
102
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Astrocytes, Oligodendrocytes, and NG2 Glia: Structure and Function
Classification
Neuroglial cells in the mammalian nervous system are divided
into PNS glia and CNS glia (Figure 1). The glial cells of the PNS
are represented by (i) myelinating Schwann cells that myelinate
peripheral axons, (ii) nonmyelinating Schwann cells that surround multiple nonmyelinating axons, and (iii) perisynaptic
Schwann cells that enwrap peripheral synapses (e.g., neuromuscular junctions). The PNS glial cells, which surround
neurons in peripheral ganglia, are known as satellite glial cells,
and those in the olfactory system are known as olfactory
ensheathing cells. Finally, the PNS includes enteric glia, which
resides in the enteric nervous system. The glia in the CNS is
represented by astrocytes, oligodendrocytes, NG2 glia, and
microglia.
(iii) radial glia, which are bipolar cells with an ovoid cell body
and elongated processes; radial glia are a common feature of
the developing brain, and after its maturation, they disappear
from most brain regions and transform into stellate astrocytes;
(ivv) radial glia-like cells of the retina (Muller glia) and cerebellum (Bergmann glia); (vi) velate astrocytes of the cerebellum;
(viiviii) interlaminar and polarized astrocytes of the primate
cortex; (ix) varicose projection astrocytes, which exist only in the
human brain; (x) tanycytes localized in the periventricular
organs, the hypophysis, and the raphe part of the spinal cord;
(xi) pituicytes of the neurohypophysis; (xii) perivascular
astrocytes; (xiii) marginal astrocytes; and (xivxvi) cells that
line the ventricles or the subretinal space, represented by
ependymocytes, choroid plexus cells, and retinal pigment epithelial
cells. This remarkable morphological heterogeneity is matched
by physiological differences between astrocytes from different brain regions; astroglial cells show different patterns of
expression of neurotransmitter receptors, various types of
transporters, and enzymes (e.g., monoamine oxidase catabolizing dopamine and serotonin and g-aminobutyric acid
(GABA) transaminase catabolizing GABA).
Physiology
Ion distribution and membrane potential
Astroglia
Heterogeneity
Astroglial cells are highly heterogeneous in the morphological appearance and physiological properties (Matyash &
Kettenmann, 2010; Zhang & Barres, 2010). The main types of
astroglia are as follows: (i) protoplasmic astrocytes of the gray
matter of the brain and in the spinal cord; these astrocytes
usually have 510 primary processes with extremely elaborate
branches to form a complex process arborization; (ii) fibrous
astrocytes localized in the white matter of the brain and in
the spinal cord and in the nerve fiber layer of the retina; they
have long (up to 300 mm) processes that run parallel to axons;
The ion content of astroglia differs from neurons in that astroglial cells have substantially higher cytosolic Na (1517 mM
vs. 8 mM in neurons) and Cl (ranging between 30 and
60 mM vs. 10 mM in mature neurons), whereas the concentration of K (120140 mM) and Ca2 (<0.0001 mM) in
astroglia is generally the same as in neurons. These differences
reflect the high activity of Na/K/2Cl cotransporters that
transport 2Cl into the cell in exchange for 1K and 1Na.
As a result, the reversal potential for Cl is 40 mV and the
activation of Cl permeable channels (e.g., GABAA receptors)
triggers Cl efflux and depolarization of astrocytes. Most
mature astrocytes have a strongly negative resting membrane
potential ( 80 to 90 mV), reflecting the predominant
Neuroglia
Ectodermal origin
Mesodermal origin
Microglia
Astroglia
Schwann cells
Non-myelinating
Myelinating
Oligodendroglia
Perisynaptic
Olfactory
ensheathing
NG2 cells
cells
(polydendrocytes)
Enteric glia
Satellite glial
cells
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Astrocytes, Oligodendrocytes, and NG2 Glia: Structure and Function
resting K conductance, which maintains the membrane
potential close to the potassium equilibrium potential (EK).
103
Ion signaling
Astrocytes are electrically silent but are not nonexcitable cells
they use controlled fluctuations of intracellular ion concentrations as their substrate for excitability (Parpura & Verkhratsky,
2012). Moreover, the gap junctional pathway allows propagating
waves of intracellular messengers and ions, which endow astroglia with an intercellular mechanism for long-range signaling.
The best-characterized mechanism for astroglial excitability
is spatiotemporal fluctuations of cytosolic Ca2 concentration,
generally referred to as Ca2 signaling, which are the
best-characterized mechanisms for astroglial excitability
(Verkhratsky, Rodriguez, & Parpura, 2012). Astroglial Ca2
signals are generated primarily by Ca2 release from the endoplasmic reticulum (ER) that acts as a dynamic intracellular
Ca2 store. The ER is capable of accumulating Ca2 ions
through the activity of specific Ca2 pumps of sarco(endo)
plasmic reticulum ATPase type and release Ca2 through ER
Ca2 channels, which, in astroglia, are primarily inositol 1,4,5trisphosphate receptor (InsP3R) type II. The activity of InsP3Rs
in turn is controlled by the second messenger InsP3, which is
produced following the activation of numerous G proteincoupled metabotropic receptors linked to phospholipase C.
In addition, depletion of the ER Ca2 store triggers plasmalemmal Ca2 entry via store-operated Ca2 channels. Changes in
Ion channel
Molecular identity
Localization
Main function
Inwardly rectifying
potassium
channels
Kir4.1 (predominant)
Kir2.1, 2.2, 2.3
Kir3.1
Kir6.1, 6.2
Kv1.1, Kv1.2, Kv1.5, and
Kv1.6
Ubiquitous
Ubiquitous
Kv1.4
Unknown
KCa3.1
Cortex
Unknown
L- (Cav1.2), N- (Cav2.2),
P/Q- (Cav2.1), R(Cav2.3), and T(Cav3.1)
TRPC1, TRPC4, TRPC5
Regulation of differentiation,
proliferation, and migration(?)
Can be upregulated in pathological
conditions
Unknown
Delayed-rectifier
potassium
channels (KD)
Rapidly inactivating
A-type potassium
currents (KA)
Ca2-dependent K
channels
Sodium channels
Calcium channels
Transient receptor
potential (TRP)
channels
Chloride channels
Aquaporins (water
channels)
Ubiquitous
AQP4 ubiquitous
AQP9 astrocytes in brain stem
and in ependymal cells; tanycytes
in hypothalamus and in subfornical
organ
Water transport
Modified from Verkhratsky, A., & Butt, A. M. (2013). Glial Physiology and Pathophysiology. Chichester: Wiley-Blackwell
104
Table 2
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Astrocytes, Oligodendrocytes, and NG2 Glia: Structure and Function
Astroglial receptors to neurotransmitters and neuromodulators
Receptor type
Ionotropic receptors
Glutamate AMPA
receptors
Glutamate NMDA
receptors
GABAA receptors
P2X (ATP)
purinoreceptors
Glycine receptors
Neuronal nicotinic
cholinoceptors
(nAChRs)
Metabotropic receptors
Metabotropic
glutamate receptors
(mGluRs)
GABAB receptors
Adenosine receptors
A1, A2A, A2B, A3
P2Y (ATP)
purinoreceptors
Adrenergic receptors
a1AR, a2AR
b1AR, b1AR
Muscarinic
cholinoceptors
(mAChRs) M1M5
Oxytocin and
vasopressin
receptors
Serotonin receptors
5-HT1A, 5-HT2A, 5HT5A
Angiotensin receptors
AT1, AT2
Bradykinin receptors
B1, B2
Opioid receptors, m, d,
k
Histamine receptors,
H1, H2
Dopamine receptors
D1D5
Properties/physiological effect
Localization in situ
Ubiquitous
Hippocampus
Hippocampus, cortex
Ubiquitous
Hippocampus
Hippocampus, cerebellum
Substantia nigra, basal ganglia
Modified from Verkhratsky, A., & Butt, A. M. (2013). Glial Physiology and Pathophysiology. Chichester: Wiley-Blackwell
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Astrocytes, Oligodendrocytes, and NG2 Glia: Structure and Function
potential (TRP) channels) or from the activity of Nadependent transporters, most notably glutamate transporters.
Physiological activation of Na fluxes may increase cytosolic
Na concentration by 1020 mM. The transmembrane Na
gradient regulates many homeostatic molecular cascades
expressed in astrocytes, including Na/K ATPase; transporters
for glutamine, glutamate, and GABA; proton and bicarbonate
transporters; and transporters for ascorbic acid, Kir4.1 potassium channels, and glutamine synthetase.
Astroglial Functions
The functions of astrocytes are many and the main functions
are summarized in Table 3. Conceptually, they are responsible
for every possible homeostatic task. In addition, through programs of reactive gliosis, astrocytes act as principal cellular
elements of CNS defense.
Oligodendroglia
Definition
Oligodendrocytes are specialized to form the insulating myelin
sheaths around axons in the CNS (Kettenmann & Ransom, 2013;
Verkhratsky & Butt, 2013). The myelin sheath is a fatty insulating
Table 3
105
Morphology
Oligodendrocytes are classified into four types according to
morphological appearance. Type I oligodendrocytes are mainly
present in the gray matter and have small rounded somata and
a complex process arborization, with fine branching processes
that myelinate 30 or more small diameter axons with short
internodes. Type II oligodendrocytes are most common in the
white matter and have small somata and parallel arrays of
intermediate length internodes (100250 mm). Type III oligodendrocytes myelinate large diameter axons (e.g., in the medulla
oblongata or the spinal cord funiculi); they are characterized
by larger cell bodies and extend one or more thick primary
processes that rarely branch and myelinate a small number of
axons with long internodes (250500 mm). Type IV oligodendrocytes myelinate a single large diameter axon with a very long
internode (up to 1000 mm in length) and are localized at the
entrance of CNS nerve roots.
In addition, a class of perineuronal oligodendrocytes has
been also identified in gray matter areas where these cells are
directly apposed to neuronal cell bodies. The perineuronal
oligodendrocytes are oval or polygonal cells, functions of
Functions of astrocytes
Metabolic support
Synaptic transmission
Neurogenesis
Neural cell migration and formation of the layered gray matter
Synaptogenesis
Parcellation of the gray matter through the process of tiling
Delineation of the pia mater and vessels by perivascular glia
Formation of neurovascular unit
Regulation of the formation and permeability of bloodbrain and cerebrospinal fluid
brain barriers
Formation of glialvascular interface
Control over extracellular K homeostasis through local and spatial buffering
Control over extracellular pH
Regulation of water transport
Removal of neurotransmitters from the extracellular space
Uptake of glucose; deposition of glycogen
Providing energy substrate lactate to neurons in activity-dependent manner
Regulation of synapse maintenance and assisting in synaptic pruning
Providing glutamate for glutamatergic transmission (through de novo synthesis and
glutamateglutamine shuttle)
Regulating synaptic plasticity
Integrating synaptic fields
Providing humoral regulation of neuronal networks through the secretion of
neurotransmitters and neuromodulators
Regulate local blood supply (functional hyperemia) through the secretion of
vasoconstrictors or vasodilators
Chemoreception regulation of body Na homeostasis
Chemoreception regulation of CO2 and ventilatory behavior
Sleep
Memory and learning
Isomorphic and anisomorphic reactive astrogliosis
Scar formation
Catabolizing ammonia in the brain
Immune responses and secretion of proinflammatory factors (cytokines,
chemokines, and immune modulators)
Reproduced with permission from Verkhratsky, A., & Butt, A. M. (2013). Glial Physiology and Pathophysiology. Chichester: Wiley-Blackwell
106
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Astrocytes, Oligodendrocytes, and NG2 Glia: Structure and Function
Physiology
Voltage-gated ion channels
Oligodendroglial cells express several types of voltage-gated
ion channels:
(i) Outwardly rectifying K channels are represented by the
delayed rectifying K channels, transient A-type K channels, and calcium-activated K channels. All these channels
are expressed mostly in oligodendroglial precursor cells
(OPCs) and are markedly downregulated in mature
oligodendrocytes.
(ii) Inwardly rectifying potassium channels (Kir) are expressed in
high densities in mature oligodendrocytes. They set up a
strongly negative (about 80 mV) resting membrane
potential of these cells.
(iii) Voltage-gated sodium channels (TTX-sensitive Nav) have
been identified in OPCs in vitro and in brain slices. The
expression of Nav channels (type Ia, type IIa1, and type
IIIa) is downregulated in mature myelinating oligodendrocytes, although the transcripts for Nav are identifiable.
The Nav channels can contribute to the differentiation
and migration of OPCs.
(iv) Voltage-operated calcium channels (Cav) of L-type (Cav1.2
and 1.3) and T-type (Cav3.1 and 3.2) are expressed in
OPC and possibly in mature oligodendrocytes. They are
important for the early development, contributing to the
regulation of gene expression, cell proliferation, and cell
migration.
(v) Chloride and acid-sensing ion channels (ASICs) have been
identified in OPCs; the expression of ASIC1a, 2a, and 4
was reported to decrease during differentiation.
(iii) Adenosine purinergic receptors. Adenosine purinergic receptors are involved in the regulation of OPC migration,
proliferation, and differentiation.
(iv) P2X ionotropic purinoceptors. P2X ionotropic purinoceptors
are not well mapped in oligodendroglia, but both OPCs
and mature oligodendrocytes express P2X7 receptors activated by high micromolar ATP concentrations.
(v) P2Y metabotropic purinoceptors. Oligodendrocytes express
multiple P2Y subtypes, although the main receptor may
be P2Y1, which mediates Ca2 signaling and, in OPCs,
stimulates cell migration, inhibits the mitogenic response
to platelet-derived growth factor (PDGF), and promotes
differentiation and cell survival.
(vi) Ionotropic GABAAR. The activation of GABAA receptors in
oligodendrocytes leads to Cl efflux and cell depolarization (because of high intracellular Cl concentration).
The stimulation of GABAAR inhibits proliferation of
OPCs. Similar to other neurotransmitter receptors, expression of GABAAR appears to be downregulated in mature
oligodendrocytes.
(vii) Metabotropic GABAB receptors. Metabotropic GABAB
receptors are expressed by OPCs and stimulate proliferation and migration and are downregulated in myelinating oligodendrocytes.
(viii) Glycine receptors (GlyRs).
(ix) Acetylcholine receptors (AChRs), of which both ionotropic
nicotinic and metabotropic muscarinic varieties were
detected in oligodendrocytes.
(x) Dopamine receptors of D2 and D3 subtypes.
(xi) A variety of receptors to neuromodulators, such as bradykinin
receptors, opioid m and k receptors, cannabinoid CB1 and
CB2 receptors, and adrenaline a1 receptors.
NG2 Glia
Definition
Neurotransmitter receptors
Cells of the oligodendroglial lineage express a wide array of
receptors to neurotransmitters, of which those binding glutamate and ATP appear most abundant, and neurohormones:
(i) Ionotropic glutamate receptors (iGluRs). All three types
(AMPA, kainate, and NMDA) are present in the oligodendrocyte lineage. The Ca2-permeable AMPA receptors
(lacking GluA2 subunit) are mainly expressed in OPCs,
whereas mature cells possess Ca2-impermeable receptors
composed of GluA3 and GluA4 subunits. AMPARs mediate
signaling from neurons to OPCs and are proposed to regulate their differentiation and myelination. Kainate receptors are mainly expressed in mature oligodendrocytes.
NMDA receptors are detected in processes of mature oligodendrocytes where they appear to be triheteromers of
GluN1, GluN2C, and GluN3A/B subunits; this combination confers weak Mg2 block at the resting membrane
potential.
(ii) Metabotropic glutamate receptors (mGluRs). All three groups
of mGluRs have been detected in oligodendroglial cells,
with mGluR5-mediated Ca2 signaling being operative in
OPCs. The expression of mGluRs is downregulated in
mature oligodendrocytes.
Morphology
NG2 glia bear several primary processes; the process-delineated
domains have a certain degree of overlap. In the gray matter,
NG2 glial are distributed as a mosaic, whereas in the white
matter, NG2 glia have an elongated appearance, extending
processes along the axonal axis. NG2 glia constitute 89% of
total cells in the white matter and 23% of total cells in
the gray matter. The ratio of NG2 glia to oligodendrocytes
ranges from 1:1 in the rat hippocampus to 1:10 in the cat
spinal cord.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Astrocytes, Oligodendrocytes, and NG2 Glia: Structure and Function
Physiology
Membrane properties
NG2 glia have a resting membrane potential of around 90 mV
and a membrane resistance of 300 MO, reflecting a high resting
K permeability.
107
Neurotransmitter receptors
NG2 glia are characterized by high expression of AMPA-type
glutamate receptors, with predominant expression of the GluA4
subunit. These AMPARs are activated by neuronal synaptic
input and produce inward currents upon stimulation. NG2
glia are also reported to express low amounts of kainate receptors and a subpopulation of NG2 glia express NMDAR with
weak Mg2 block. NG2 glia have functional GABAA receptors;
GABA-mediated currents reverse at 43 mV, indicating that
NG2 glia maintain a high intracellular Cl concentration. In
addition, NG2 glia may express nAChR, mGluR, a1 adrenergic
receptors, and P2 purinergic receptors, although their functional role is enigmatic.
Functions
Apart from acting as OPC, the functional role for NG2 glia is
unknown. In the adult brain, NG2 glia have been reported to
generate neurons in the piriform cortex, although the majority
of cell fate mapping studies indicate that NG2 glia solely
generate oligodendrocytes at all ages. NG2 glia can also be
reactive and respond to CNS insults by increased proliferation
and morphological remodeling, manifested by shortening and
Acknowledgments
Authors research was supported by Alzheimers Research Trust
(UK) Programme Grant (ART/PG2004A/1) to A. Verkhratsky
and by the National Institutes of Health (the Eunice Kennedy
Shriver National Institute of Child Health and Human Development award HS078678).
References
Butt, A. M., Hamilton, N., Hubbard, P., Pugh, M., & Ibrahim, M. (2005). Synantocytes:
The fifth element. Journal of Anatomy, 207, 695706.
Giaume, C., Koulakoff, A., Roux, L., Holcman, D., & Rouach, N. (2010). Astroglial
networks: A step further in neuroglial and gliovascular interactions. Nature Reviews.
Neuroscience, 11, 8799.
Kettenmann, H., & Ransom, B. R. (Eds.), (2013). Neuroglia. Oxford: Oxford University
Press.
Kettenmann, H., & Verkhratsky, A. (2008). Neuroglia: The 150 years after. Trends in
Neurosciences, 31, 653659.
Kirischuk, S., Parpura, V., & Verkhratsky, A. (2012). Sodium dynamics: Another key to
astroglial excitability? Trends in Neurosciences, 35, 497506.
Matyash, V., & Kettenmann, H. (2010). Heterogeneity in astrocyte morphology and
physiology. Brain Research Reviews, 63, 210.
Nishiyama, A., Komitova, M., Suzuki, R., & Zhu, X. (2009). Polydendrocytes (NG2
cells): Multifunctional cells with lineage plasticity. Nature Reviews. Neuroscience,
10, 922.
Parpura, V., & Verkhratsky, A. (2012). Homeostatic function of astrocytes: Ca2 and
Na signalling. Translational Neuroscience, 3, 334344.
Verkhratsky, A., & Butt, A. M. (2013). Glial physiology and pathophysiology.
Chichester: Wiley-Blackwell.
Verkhratsky, A., Rodriguez, J. J., & Parpura, V. (2012). Calcium signalling in astroglia.
Molecular and Cellular Endocrinology, 353, 4556.
Zhang, Y., & Barres, B. A. (2010). Astrocyte heterogeneity: An underappreciated topic in
neurobiology. Current Opinion in Neurobiology, 20, 588594.
Glossary
Abbreviations
CNS
DAMPs
mGluRs
Developmental Origins
Microglial cells do not share their ontogenetic origins with
other neural cells (neurons and macroglia) of the nervous
system; microglia are of mesodermal origin and the microglial
progenitors derive from the extraembryonic yolk sac being the
primitive c-kit erythromyeloid precursors (Kierdorf et al.,
2013). These precursors enter the CNS during early embryonic
development; for example, in mice, this invasion occurs at
embryonic day 10 (Ginhoux et al., 2010). Whether so
NMDA
PAMPs
TLRs
TNF-a
N-Methyl D-aspartate
Pathogen-associated molecular patterns
Toll-like receptors
Tumor necrosis factor-a
Morphology
After entering the CNS, microglial precursors migrate and
disseminate almost homogeneously throughout the parenchyma of the brain and of the spinal cord. In total, microglial
cells account probably for 1015% of all neuroglia, and their
densities are similar in different CNS regions. Migration of
microglial precursors is accompanied by a remarkable morphological and functional metamorphosis: the myeloid
progenitors generally similar to monocytes convert into microglial cells, which acquire neural-like appearance. Differentiated microglial cells have small bodies (45 mm) and several
thin and long processes with characteristic terminal arborization represented by numerous small secondary processes.
This microglial phenotype is generally known as ramified or
resting, although microglial cells are arguably the most restless cells in the nervous system.
Indeed, microglial processes are in continuous motion
(Davalos et al., 2005; Nimmerjahn, Kirchhoff, & Helmchen,
2005), moving through the surrounding CNS tissue at a speed
of 1.5 mm min1. This movement of microglial processes is
accompanied by regular extension/retraction (at 23 mm min1)
of small protrusions. Thus, microglial processes seem to survey
their neighborhood. Microglial processes also define a territorial
domain of a single microglial cell; there is generally little overlap
between microdomains of microglia. Given the speed of
processes movement, the microglial domain could be
completely scanned by these processes within several hours.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00356-0
109
110
Physiology
Microglial cells after entering the CNS environment undergo
profound physiological remodeling and acquire receptive
phenotype compatible with the chemical environment. Arguably, ramified microglia is the most receptive cells of the CNS
because they are in possession of multiple receptors to neurotransmitters and neuromodulators as well as immunological
receptors characteristic for myeloid cells (see Figure 1 and
Kettenmann, Hanisch, Noda, & Verkhratsky, 2011; Pocock &
Kettenmann, 2007; Ransohoff & Perry, 2009); the latter ones
include P2X7 purinoceptors, receptors to chemokines and cytokines, and receptors to various tissue mediators such as platelet
activating factor, thrombin, histamine, or bradykinin, all being
critical for triggering various types of immune responses.
Membrane Potential
Most of electrophysiological experiments were performed on
microglial cells in vitro in culture; these experiments consistently reported resting potential 50 mV. Experiments in situ,
in acute brain slices from rat cortex, striatum, and facial
Ion Channels
Several types of ion channels were described in microglial cells,
especially in culture (see Kettenmann et al., 2011; Noda &
Verkhratsky, 2013 for detailed description and references). It
must be noted that resting microglial cells in situ in brain slices
as a rule have much lower density of voltage-gated currents as
compared with cells in culture. Voltage-gated sodium currents
were described solely on cultured microglial cells from rodents
and humans, although there are numerous contradictory studies that failed to detect any signs of Na channel activity.
Similarly, voltage-gated Ca2 channels were found only in a
single study where small calcium currents were detected
in 30% of cultured cells.
Receptors
Receptors to Neurotransmitters and Neuromodulators
Microglial cells express almost all types of receptors to neurotransmitters and neuromodulators so far found in the nervous
system (Figure 1), including receptors to glutamate, purines,
and GABA. The purinoceptors (adenosine receptors, ionotropic
P2X, and metabotropic P2Y purinoceptors; see Verkhratsky,
Krishtal, & Burnstock, 2009) are, arguably, the most abundant
in microglia. In particular, microglial cells constitutively
express P2X7 receptors that contribute to numerous responses
to neuropathology. The P2X7 receptors are a general feature of
immune cells where they mediate various immune reactions,
including the processing and the release of various cytokines.
Specific properties of P2X7 receptors (which are most likely
associated with their functional relevance) include (i) their
exceptionally low sensitivity to ATP (i.e., receptor needs mM
ATP concentration for activation) and (ii) their ability to form
large transmembrane pores (permeable to molecules with
molecular weight up to 900 Da) upon excessive or long-lasting
stimulation. Thus, the P2X7 receptors are activated in conditions of massive ATP release indicative of neuronal damage
and are linked to immune responses of microglia, being
particular important activators of cytokine release. Incidentally, direct overexpression of P2X7 receptors in microglia is
sufficient to trigger their activation in the in vitro system in the
complete absence of any other exogenous factors (Monif, Reid,
Powell, Smart, & Williams, 2009). Microglia also constitutively
express P2X4 receptors (which are activated by low micromolar
ATP concentrations), which are critically involved in mediating
111
Immunocompetent Receptors
The immune receptors expressed by microglia are represented
by receptors to chemokines and cytokines and pattern recognition. The latter include (i) lectin-type mannose and b-glucan
receptors; (ii) nucleotide-binding and oligomerization
domain-like receptors; (iii) receptors characterized by an RNA
helicase domain and two caspase-recruitment domains, collectively known now as RIG-I-like receptors (RLR); and (iv) the
Toll-like receptors (TLRs). These TLRs of TLR1 to TLR9 types
are particularly important in the initiation and regulation of
microglial activation in pathological conditions (Aravalli,
Peterson, & Lokensgard, 2007).
Functions or Microglia
Microglial functions are remarkably diverse (Table 1); microglial cells are not only involved in mounting CNS defense
but also critically important for normal development, shaping,
112
Table 1
Physiological
CNS development
Neuronal plasticity
Defensive
Recognition of
pathogens
Phagocytosis
Antigen presentation
Immune response
Repair
Pathological
Cytotoxicity
Tumor growth
promotion
Demyelination
Infection
microglial release of TNF-a, which in turn stimulates astrocytes, which subsequently release glutamate and, thus, affect
synaptic activity (Pascual, Ben Achour, Rostaing, Triller, &
Bessis, 2012). Microglial cells can also affect neuronal circuitry
through regulating neurogenesis and through continuous
elimination of redundant neural cells that failed to integrate
into existing networks.
Activation in Pathology
The fundamental function of microglia is to detect the pathology and to produce a defensive response. Microglial activation
forms the backbone for brain immune and defensive responses
to virtually all pathological insults; activated microglia are
indispensable contributors to all neurological diseases (see,
e.g., Perry, Nicoll, & Holmes, 2010).
Molecular signals that trigger microglial activation can be
divided into the ON and OFF signals (see Hanisch & Kettenmann, 2007). Conceptually, the ON signals (which induce
activation) are molecules occurring along with the pathological insult, generally represented by pathogen-associated or
danger-associated molecular patterns (PAMPs or DAMPs,
respectively). The PAMPs are, in essence, pathogens (e.g., fragments of bacteria or viruses), whereas DAMPs are normally
present in the body, but either absent in the brain (e.g., bloodderived factors) or presented by various molecules that appear
in the brain tissue following cellular damage (enzymes) or
appear in an unusually high concentrations (for instance,
ATP massively released following cell damage). The OFF signals (which contain activation) are usually neurotransmitters
(e.g., ACh or adenosine) associated with normal nervous activity of neuroglial circuitry. These molecules are continuously
Conclusions
Microglial cells are fundamental for physiology of the CNS and
are the central elements of nervous tissue defense. Microglial
cells are of myeloid origin; however, after invading the CNS,
they acquire unique morphology and physiology that integrate
them into neural cellular networks. Microglial cells contribute
to normal development of the CNS and are able to influence
synaptic plasticity. In pathology, microglia undergoes complex
program of activation that produces both neuroprotective and
neurotoxic cells, which, by interacting and balancing their
action, define to a large extent the progression and outcome
of neurological diseases.
Acknowledgments
The authors research was supported by the Alzheimers
Research Trust (UK) program grant (ART/PG2004A/1) to AV
and by the National Institutes of Health (The Eunice Kennedy
Shriver National Institute of Child Health and Human Development award HS078678).
113
References
Aravalli, R. N., Peterson, P. K., & Lokensgard, J. R. (2007). Toll-like receptors in
defense and damage of the central nervous system. Journal of Neuroimmune
Pharmacology, 2, 297312.
Davalos, D., Grutzendler, J., Yang, G., Kim, J. V., Zuo, Y., Jung, S., et al. (2005). ATP
mediates rapid microglial response to local brain injury in vivo. Nature
Neuroscience, 2005(8), 752758.
Del Rio-Hortega, P. (1932). Microglia. In W. Penfield (Ed.), Cytology and cellular
pathology of the nervous system (pp. 482534). New York: Hoeber.
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., et al. (2010). Fate
mapping analysis reveals that adult microglia derive from primitive macrophages.
Science, 330, 841845.
Hanisch, U. K., & Kettenmann, H. (2007). Microglia: Active sensor and versatile effector
cells in the normal and pathologic brain. Nature Neuroscience, 10, 13871394.
Inoue, K., & Tsuda, M. (2009). Microglia and neuropathic pain. Glia, 2009(57),
14691479.
Kaindl, A. M., Degos, V., Peineau, S., Gouadon, E., Chhor, V., Loron, G., et al. (2012).
Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and
neuronal cell death in the developing and mature brain. Annals of Neurology, 72,
536549.
Kershman, J. (1939). Genesis of microglia in the human brain. Archives of Neurology
and Psychiatry, 41, 2450.
Kettenmann, H., Hanisch, U. K., Noda, M., & Verkhratsky, A. (2011). Physiology of
microglia. Physiological Reviews, 91, 461553.
Kettenmann, H., Kirchhoff, F., & Verkhratsky, A. (2013). Microglia: New roles for the
synaptic stripper. Neuron, 77, 1018.
Kierdorf, K., Erny, D., Goldmann, T., Sander, V., Schulz, C., Perdiguero, E. G., et al.
(2013). Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8dependent pathways. Nature Neuroscience, 16, 273280.
Monif, M., Reid, C. A., Powell, K. L., Smart, M. L., & Williams, D. A. (2009). The P2X7
receptor drives microglial activation and proliferation: A trophic role for P2X7R pore.
Journal of Neuroscience, 29, 37813791.
Nimmerjahn, A., Kirchhoff, F., & Helmchen, F. (2005). Resting microglial cells are
highly dynamic surveillants of brain parenchyma in vivo. Science, 308, 13141318.
Noda, M., & Verkhratsky, A. (2013). Physiology of microglia. In H. Kettenmann & B. R.
Ransom (Eds.), Neuroglia (pp. 223237) (3rd ed.). Oxford: Oxford University Press.
Pascual, O., Ben Achour, S., Rostaing, P., Triller, A., & Bessis, A. (2012). Microglia
activation triggers astrocyte-mediated modulation of excitatory neurotransmission.
Proceedings of the National Academy of Sciences of the United States of America,
2012(109), E197E205.
Perry, V. H., Nicoll, J. A., & Holmes, C. (2010). Microglia in neurodegenerative disease.
Nature Reviews. Neurology, 6, 193201.
Pocock, J. M., & Kettenmann, H. (2007). Neurotransmitter receptors on microglia.
Trends in Neurosciences, 30, 527535.
Ransohoff, R. M., & Perry, V. H. (2009). Microglial physiology: Unique stimuli,
specialized responses. Annual Review of Immunology, 27, 119145.
Verkhratsky, A., Krishtal, O. A., & Burnstock, G. (2009). Purinoceptors on neuroglia.
Molecular Neurobiology, 39, 190208.
Wake, H., Moorhouse, A. J., Jinno, S., Kohsaka, S., & Nabekura, J. (2009). Resting
microglia directly monitor the functional state of synapses in vivo and determine the
fate of ischemic terminals. Journal of Neuroscience, 29, 39743980.
Glossary
http://dx.doi.org/10.1016/B978-0-12-397025-1.00207-4
115
116
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
Area 4
Area 3
Area 41/42
Area 17
Area 18
IVI
I
II
III
IV
V
VI
3850
200
100
1400
900
1250
1820
220
280
420
280
220
400
2900
260
280
740
450
530
640
1955
246
89
471
653
218
278
2037
272
92
851
148
279
395
Data from von Economo and Koskinas (1925) and Zilles, Armstrong, Schlaug, and
Schleicher (1986).
Paleocortex
Here only a brief survey of the cytoarchitectonic characteristics
is given since a detailed description is given in another article
of this volume.
Olfactory bulb. Its laminar structure justifies classification as
a cortical structure. The human olfactory bulb is smaller and
less differentiated than in other primates (Stephan, 1975), but
displays the same basic laminar organization of six layers
including layer 1 which contains the fibers of the olfactory
nerve. The six layers of the olfactory bulb differ fundamentally
from the six isocortical layers by their cell types, internal circuitry, and inputoutput organization.
Retrobulbar region. Unfortunately, it is frequently called
anterior olfactory nucleus, although it is not a subcortical
nucleus, but has a true cortical structure with two layers
(Stephan, 1975). The retrobulbar region is found where the
olfactory tract merges with the hemispheres.
Olfactory tubercle. It is located within the anterior perforate
substance. Its cortical structure is rudimentary, although a
molecular layer is visible, but cells which belong to the ventral
striatum invade the olfactory tubercule. Islands of Calleja can
occasionally be observed in this brain region.
I
II
IIIa
IIIb
IIIc
I
II
IIIa
IIIb
IIIc
IV
IV
V
VIa
VIb
I
II
IIIa
IIIb
IIIc
IV
Va
Vb
I
II
IIIa
IIIb
IV
IIIc
V
VIa
VIa
VIb
VIa
VIb
VIb
I
II
IIIa
III
I
II
IIIa
I
II
III
IIIb
IIIc
III
IV
IV
V
IV
V
VIa
VIb
I
II
VI
V
VI
IVa
IVb
IVca
IVcb
Va
Vb
VIa
VIb
mol
Pre-a
Pre-b
Pre-g
d
Pri-a
Pri-b
Pri-g
(a)
(Continued)
118
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
Figure 2 Coronal section through the human hippocampus (silver cell body stain). alv alveus, CA1CA4 regions of the Cornu Ammonis; Ent, entorhinal
area; fi, fimbria hippocampi; gr, granular layer of the fascia dentata; LGN, lateral geniculate nucleus; l-m, lacunosum-molecular layer of the Ammons
horn; luc, lucidum layer of the CA3 region; mol, molecular layer of the fascia dentata; mult, multiform layer of the fascia dentata; or, oriens layer of the
Ammons horn; ParS, parasubiculum; ProS, prosubiculum; PrS, presubiculum; pyr, pyramidal layer of the Ammons horn; rad, radiatum layer of the
Ammons horn; Sub, subiculum.
Archicortex
The hippocampal formation consists of the Cornu Ammonis
with the regions CA1CA4, the fascia dentata on the dentate
gyrus, and the subiculum. The fascia dentata is composed of an
outer molecular layer underlaid by the thin and extremely cell
dense granular cell layer followed by a multiform layer. The
molecular layer contains the dendrites of the granular cells,
Figure 1 Cell body stained sections of areas Fp1, Fp2, BA11, BA4, 3b, 5M, BA20, BA17, Ent.med., Ent.lat., BA25, BA33, and auditory cortex (with
subdivisions). BA4 is the primary motor cortex; BA11 is part of the medial orbitofrontal cortex; BA17 is the primary visual cortex; BA20 is a
cytoarchitectonic region on the inferior temporal gyrus; region Ent. med. and Ent. lat., are medial and lateral parts of the entorhinal cortex, respectively;
Fp1 plus Fp2 (Bludau, Eickhoff, Mohlberg, et al., 2014) are comparable to BA10; Te1.0, 1.2, and 1.3 are cytoarchitectonic subdivisions of the primary
auditory cortex (Morosan, Rademacher, Schleicher, et al., 2001); Te2 (Morosan, Schleicher, Amunts, & Zilles, 2005) is part of BA42, TI1, and TI2 are
cytoarchitectonic subdivisions of the medial belt (BA52); 3b (Geyer, Schleicher, & Zilles, 1999) is part of the primary somatosensory cortex (larger part
of BA3); 5M (Scheperjans, Grefkes, Palomero-Gallagher, Schleicher, & Zilles, 2005; Scheperjans, Hermann, Eickhoff, et al., 2008) is a medial subdivision
of BA5. Roman numerals indicate isocortical layers. For the laminar nomenclature of Ent.med. and Ent.lat., see Braak (1980). White arrows in BA4
indicate giant Betz pyramidal cells. Large black arrows indicate the borders between the core and belt regions of the auditory cortex and between the
medial belt and the insular cortex; small black arrows indicate subdivisions within the core and the medial belt regions. sf, Sylvian fissure; STG, superior
temporal gyrus; and TG, temporal gyrus (Heschl gyrus).
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
A more detailed review of the anatomy of the hippocampal
region is found in Insausti and Amaral (2012) and of probability maps in Amunts, Kedo, Kindler, et al. (2005).
The retrosplenial cortex consists of areas BA26, BA29, and
BA30. It is not restricted to the region behind the splenium, but
extends along the caudal third of the corpus callosum in the
callosal sulcus. It can be subdivided into a granular and an
agranular part (Rose, 1927b). There is a transition from primitive allocortical to a differentiated isocortical structure when
moving from the supracommissural hippocampus over areas
119
Table 2
Comparison of various nomenclature systems used in brain maps with the Brodmann (1909, 1914) classification. The nomenclatures of
Brodmann (1909, 1914; BA areas), von Economo and Koskinas (1925), Rose (1927b, 1928), Stephan (1975), Vogt (2009) and the Dusseldorf/Julich
Group (references below) are based on cytoarchitectonic studies. The nomenclature of Vogt (1910) and Vogt and Vogt (1919) is mainly based on
myeloarchitectonic observations, but also includes comparisons with cytoarchitecture. Maps of the Julich/Dusseldorf group are shown in the JuBrain
atlas (www.fz-juelich.de/inm/inm-1/jubrain_cytoviewer) and can be applied by means of the SPM Anatomy Toolbox (www.fz-juelich.de/inm/inm-1/
spm_anatomy_toolbox).
Brodmann
(1909,
1914)
von Economo
and Koskinas
(1925)
Stephan (1975)
Vogt (2009)
Frontal lobe
BA4
BA6
V42, V43
V36V41
FA, FAg
FB
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
Comparability not
clear
Comparability not
clear
V50, V51
V1, V4V9, V10V12
(ventral parts)
Subregio typica
(V17V24, dorsal
part of V12)
FC (?)
n.d.
n.d.
n.d.
4a, 4p
6 (preliminary
delineation)
n.d.
FD (?)
n.d.
n.d.
n.d.
n.d.
FE
FG, FH
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
Fp1, Fp2
n.d.
Rostral parts
of LA1, LA2,
LA3
Area infraradiata
dorsalis (Ird)
Subregio medioradiata
(V25-V32)
Caudal parts of
LA1, LA2, LA3
Subregio
infraradiata
communis
(IRBa-d, IRCa-d)
Regio medioradiata
Area medioradiata
(MR)
a24a, a24b,
24c, p24a,
p24b, 24d
BA25
V13, V14
FL, FM
25
BA32
n.d.
s32, p32, 32
V56, V57
V58, V59 (dorsal part)
V53, V54
V59 (ventral part)
FCBm
FDg
FD
FF
V70
V71, V72 (?)
BA8
BA9
BA10
BA11,
BA12
BA24
BA33
BA44
BA45
BA46
BA47
Parietal lobe
BA1
BA2
BA3
BA5
BA7
V67
V69
V75
V83, V85, V86, V87 (?)
Regio subgenualis
(Sbga, Sbgp)
n.d.
Area infraradiata
ventralis (Irv)
Julich/Dusseldorf
Group
Subregio
infraradiata
ventralis (IRaa-d)
n.d.
n.d.
n.d.
n.d.
33
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
44d, 44v
45a, 45p
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
1
2
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
3a
3b
5L, 5M, 5Ci
7A, 7P, 7PC, hIP3
(Continued)
120
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
Table 2
(Continued)
Brodmann
(1909,
1914)
von Economo
and Koskinas
(1925)
Stephan (1975)
Vogt (2009)
BA23
V77V80, V91V96
LC2, LC3
n.d.
n.d.
BA26
LE2
BA29
Vl3
LE1
29 l, 29 m
29 l, 29 m
BA30
LD
RSag
30
30
BA31
BA39
BA40
n.d.
n.d.
n.d.
d31, v31
n.d.
n.d.
BA43
LC1
PG
Parts of PFop,
PFt, PFcm,
PF, PFm
PFD, parts of
PFop
Area retrosplenialis
granulosa inferior
Area retrosplenialis
granulosa superior
Area retrosplenialis
agranularis
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
31
PGa, PGp
OP 1, OP2, PFop,
PFt, PFcm, PF,
PFm
OP 3, OP 4
OC
OB (OBg,
OBO)
OA (OA1, OA2,
OAm)
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
hOc1
hOc2
n.d.
n.d.
n.d.
hOc3d, hOc3v,
hOc4d, hOc4v,
hOc5 (areas
located within the
region of BA19
and lateral BA37)
and other areas.
Note, that a
homogenous
cytoarchitectonic
or functional area
19 does not exist
Temporal lobe
BA20
n.d.
BA21
n.d.
BA22
n.d.
TE2
TE1
TA1, TA2
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
BA38
BA41
TG, TGA
TC
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
TB
n.d.
n.d.
n.d.
n.d.
n.d.
Te3, Te4 (areas
within BA22)
n.d.
Te1 (Te1.0, Te1.1,
Te1.2)
Te2 (Te2.1, Te2.2)
n.d.
n.d.
n.d.
Regio insularis
agranularis
(Prpy1, ai4, ai5,
ai7, ai10, ai11)
Regio insularis
propeagranularis
(ai1ai3, ai6, ai7a,
ai8, ai9)
Region insularis
granularis (Ief [I1
and I2], Itf [I3I6,
I9], Itc [I13I16],
Iec [I7, I8,
I10I12, I17I24])
Regio
peripalaeocorticalis
claustralis; other
insular regions not
determined
n.d.
Occipital lobe
BA17
Area striata
BA18
Area occipitalis
BA19
BA42
BA37
Insular lobe
Regio
insularis
anterior
and
posterior
Area praeoccipitalis
V38
Area temporalis
transversa interna
Area temporalis
transversa externa
n.d.
Vi1Vi,6 Vai1Vai,4
Vai,6 Vai7
Julich/Dusseldorf
Group
n.d.
(Continued)
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
Table 2
121
(Continued)
Brodmann
(1909,
1914)
von Economo
and Koskinas
(1925)
n.d.
VTb,1 VTb2
TK
n.d.
n.d.
FMt
Stephan (1975)
Vogt (2009)
Julich/Dusseldorf
Group
Tuberculum
olfactorium
Regio retrobulbaris
Tuberculum
olfactorium
Regio retrobulbaris
n.d.
n.d.
n.d.
n.d.
References Dusseldorf/Julich Group: Amunts, Schleicher, Burgel, et al. (1999), Amunts, Lenzen, Friederici, et al. (2010), Amunts, Morosan, Hilbig, and Zilles (2012), Amunts,
Schleicher, and Zilles (2004), Amunts, Malikovic, Mohlberg, Schormann, and Zilles (2000), Bludau, Eickhoff, Mohlberg, et al. (2014), Caspers, Zilles, Eickhoff, et al. (2013), Caspers,
Geyer, Schleicher, et al. (2006), Caspers, Eickhoff, Geyer, et al. (2008), Eickhoff, Amunts, Mohlberg, and Zilles (2006), Eickhoff, Schleicher, Zilles, and Amunts (2006), Geyer,
Ledberg, Schleicher, et al. (1996), Geyer, Schleicher, and Zilles (1999), Geyer (2004), Grefkes, Geyer, Schormann, Roland, and Zilles (2001), Kujovic, Zilles, Malikovic, et al. (2013),
Kurth, Eickhoff, Schleicher, et al. (2010), Malikovic, Amunts, Schleicher, et al. (2007), Morosan, Rademacher, Schleicher, et al. (2001), Morosan, Schleicher, Amunts, and Zilles
(2005), Palomero-Gallagher, Mohlberg, Zilles, and Vogt (2008), Palomero-Gallagher, Zilles, Schleicher, and Vogt (2013), Palomero-Gallagher and Zilles (2009), Rottschy, Eickhoff,
Schleicher, et al. (2007), Scheperjans, Grefkes, Palomero-Gallagher, Schleicher, and Zilles (2005), Scheperjans, Hermann, Eickhoff, et al. (2008), Scheperjans, Eickhoff, Homke, et al.
(2008), Scheperjans, Palomero-Gallagher, Grefkes, Schleicher, and Zilles (2005). n.d., not determined; ?, unclear comparability.
Isocortex
Frontal Lobe
The frontal lobe can be subdivided into three major regions:
122
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
6
8
7a
7b
9
3,1,2
46
40
39
10
18
45
43
44
41 42
47
11
19
17
22
37
38
21
20
3,1,2
6
8
5
7a
24
23
32
33
7b
26
10
12
34
28
38
29
30
18
17
27
35
25
11
19
31
18
37
19
36
20
Figure 3 Cytoarchitectonic map of the human cerebral cortex. Reproduced from Brodmann, K. (1914). Physiologie des Gehirns. In: P. von Bruns (Ed.),
Neue Deutsche Chirurgie (pp. 85426). Stutgart: Verlag von Ferdinand Enke.
A major subdivision of BA6 is the parcellation of the supplementary motor cortex on the mesial surface of the hemisphere
from the premotor cortex on the lateral surface. But also these
two regions must be further subdivided, as shown by observations in human and nonhuman primates (Barbas & Pandya,
1987; Geyer, Matelli, Luppino, et al., 1998; Geyer, Zilles, Luppino, & Matelli, 2000; Luppino, Matelli, Camarda, & Rizzolatti,
1993; Luppino, Murata, Govoni, & Matelli, 1999; Matelli,
Camarda, Glickstein, & Rizzolatti, 1986; Matelli, Govoni, Galletti, Kutz, & Luppino, 1998; Matelli & Luppino, 1996; Matelli,
Luppino, & Rizzolatti, 1991; Penfield & Welck, 1951; Picard &
Strick, 1996; Rizzolatti, Camarda, Fogassi, et al., 1988; Rizzolatti, Luppino, & Matelli, 1998; Rizzolatti, Fadiga, Gallese, &
Fogassi, 1996; Rizzolatti, Fadiga, Matelli, et al., 1996; Rizzolatti,
Luppino, & Matelli, 1996; Roland & Zilles, 1996; Schubotz,
Anwander, Knosche, von Cramon, & Tittgemeyer, 2010; Tanji,
1994; Vorobiev, Govoni, Rizzolatti, Matelli, & Luppino, 1998;
Wise & Strick, 1984; Zilles, Schlaug, Matelli, et al., 1995; Zilles,
Schlaug, Geyer, et al., 1996). The collaboration between the
Vogts and Foerster (Foerster, 1931, 1936; Vogt & Vogt, 1919,
1926) already led to a subdivision of BA6 into several parts by
architectonic and functional criteria. Posterior area 6aa and an
anterior area 6ab extend over the lateral and mesial surface of
BA6. It was shown, that the mesial part of 6aa coincides with the
location of SMA-proper, and the mesial part of 6ab with preSMA (Zilles, Schlaug, Geyer, et al., 1996). Furthermore, a subdivision of SMA-proper into the putative rostral SMAr and caudal SMAc was proposed (Vorobiev, Govoni, Rizzolatti, Matelli,
& Luppino, et al., 1998). SMA-proper may be comparable with
areas 38l, 39l, and 39z and pre-SMA with areas 36l and 37l of
Sanides (1962, Figure 5(b)). The rostral border of BA6 is difficult
to define, since the adjoining areas BA8, BA9, and BA44 are
dysgranular, and thus, although layer IV is present, sharp borders are not easily detected. A recent receptorarchitectonic study
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
36 37
47
38b
123
39b 42
48
44
48a
49
50
44a
39b
45
46
51
54
55
52c
52b
39c
43
58
57 56
40
40
53b
59
55
(a)
53c
41
59
52b 53b
50
49
39c
40
43
40
58 57 56
52c
68
41
65
60
(b)
62
63
5
4
53a
61
?
6 7 8 9
8
6
59
52a
64
53a 61
?
53c
51
52b
51
52a
52c
50
68
7 13 14
(c)
39b 42
34
64
insula
70
38a
39a
48
49
65
13 olf
38b
35
66
60
37
36
47
63
62
53b
69
67
36a 37a
Periarchicortex
33
50
3
51
10
10 11
1
(d)
12
11
14
12 13
Figure 4 Cytoarchitectonic map of the human cerebral cortex. (a) Dorsolateral view; (b) ventrolateral view; (c) orbital view; (d) medial view. Dark red
agranular isocortical area (primary motor cortex BA4), light red agranular isocortical areas (premotor cortex BA6), orange dysgranular isocortical areas,
yellow granular isocortical areas, red dotted agranular allocortical areas; olf, olfactory bulb and tract. A small area on the orbital surface (labeled by a
question mark) was not identified by Ngowyang. Modified from Ngowyang, G. (1934). Die Zytoarchitektonik des menschlichen Stirnhirns. National
Research Institute of Psychology, Academia Sinica, 7, 1.
maps are not directly comparable, particularly in the orbitofrontal region, because here the search for homologies and the modification of Brodmanns system by Walker (1940) introduced
considerable differences. Additionally, Petrides and Pandya
(1994) subdivided BA8 into areas 8Ad, 8Av, and 8B, BA45 into
45A and 45B, and introduced designations like 47/12, 9/46d,
9/46v for areas with transitional cytoarchitectonic features. There
is agreement on the fact that the prefrontal cortex contains a
larger granular than dysgranular part (for more recent work see
Petrides & Pandya, 1999; Preuss & Goldman-Rakic, 1989).
The frontal pole is occupied by BA10 (Bludau, Eickhoff,
Mohlberg, et al., 2014; Brodmann, 1909, 1914; Petrides &
Pandya, 1994). This area and its intersubject variability
38
ce
47
PmZ
48
/48
47
49
44
39/40
45
46
50
40
55/44
51d
FpZ
42
39
37
36
54
Z
FmZ
55
PoZ
43
40/41
53d
52d
56
58
51p
57
52v
41
56/41
59d
59v
53v
65
FoZ
(a)
FmZ
37
36
PmZ
47
39I
FpZ
42dys
Pro/Peri
50z
42
39z
PIZd
47I
50
38I
37I
36I
36I
49 48
ce
39
38
50I
51p
z
2
Pvz
PIZv
Pvl
12
6/1
OmZ
(b)
FpZ
51
2
1
1/
52v
52v 52v/53
PoZ
53v
4
OmZ
61
FoZ
64
60
65
59
62
8
13
olf
63
66
(c)
Figure 5 Cytoarchitectonic map of the human cerebral cortex. (a) Lateral view; (b) medial view; (c) orbital view. Dark red agranular isocortical area
(primary motor cortex BA4), light red agranular isocortical areas (premotor cortex BA6), orange dysgranular isocortical areas, yellow granular isocortical
areas, red dotted agranular allocortical areas. ce, central sulcus; FmZ, frontomotor zone; FoZ, frontopercular zone; FpZ, frontopolar zone; olf, olfactory
bulb and tract; OmZ, orbitomedian zone; PmZ, paramotor zone; PoZ, paropercular zone; Pro/Peri, proiso-periarchicortical region. Modified from
Sanides, F. (1962). Die Architektonik des menschlichen Stirnhirns. Berlin, Gottingen, Heidelberg: Springer Verlag.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
Fp1
Fp2
45
44
44
7A
Te1
Te3
V1
V2
hOc5
Fg1
0%
125
100%
Figure 6 Continuous probability maps of frontopolar areas Fp1 (frontal view) and Fp2 (mesial view, cortical ribbon removed; Bludau, Eickhoff, Mohlberg,
et al., 2014), areas BA45 (lateral view) and BA44 (lateral view of left and right hemispheres for comparison of interhemispheric differences) of Brocas speech
region (Amunts, Schleicher, Burgel, et al., 1999), area 7A (left hemisphere only, dorsolateral view) of the superior parietal lobule (Scheperjans, Eickhoff,
Homke, et al., 2008; Scheperjans, Hermann, Eickhoff, et al., 2008), auditory areas Te1 (rostrolateral inflated view; Morosan, Rademacher, Schleicher,
et al., 2001) and Te3 (lateral view; Morosan, Rademacher, Palomero-Gallagher, & Zilles, 2004), primary and secondary visual areas hOc1 (BA17) and hOc2
(BA18) (occipital views; Amunts, Malikovic, Mohlberg, Schormann, & Zilles, et al., 2000), and extrastriate visual areas hOc5 (lateral view, cortical ribbon
removed; Malikovic, Amunts, Schleicher, et al., 2007) and FG1 (basal view; Caspers, Zilles, Eickhoff, et al., 2013). Scale bar encodes overlap probability.
(Figure 6) was recently analyzed with a quantitative microscopical method leading to a subdivision into a medial (Fp2)
and lateral (Fp1) part, with significantly different cytoarchitecture (Bludau, Eickhoff, Mohlberg, et al., 2014). Fp1 has a wider
layer IV and denser layers II and IIIc than Fp2, whereas layer V
is subdivided into Va and Vb in Fp2 but not in Fp1 (Bludau,
Eickhoff, Mohlberg, et al., 2014).
Rajkowska and Goldman-Rakic (1995a) demonstrated
cytoarchitectonic differences between BA9, which is found on
the middle third of the superior frontal gyrus and adjacent
regions of the middle frontal gyrus, and BA46, which is surrounded by BA9 (or areas 9/46d 9/46v of Petrides & Pandya,
1994 on the middle frontal gyrus). Lamina IV is wider and
contains more densely packed cells in BA46 than in BA9, and
BA46 is less myelinated than BA9. This data argues for a
directed architectonic differentiation from BA9 to BA46 as
already described as a gradation stream by Sanides (1962).
Rajkowska and Goldman-Rakic (1995b) also studied the intersubject variability of the areal borders and found lack of correlation between macroscopical landmarks and areal borders.
BA8 belongs to the dysgranular part of the prefrontal cortex,
the paramotor zone PmZ of Sanides (1962, Figure 5), and area
FC of von Economo and Koskinas (1925). The frontal eye field
126
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
Parietal Lobe
The postcentral region of the parietal lobe belongs to the
somatosensory cortex, whereas the superior and inferior parietal lobules, separated by the intraparietal sulcus, are parts of
the multimodal association cortex. The most posterior part of
the paracentral lobule and the mesial extent of the superior
parietal lobule, bordered by the subparietal and parietooccipital sulci, constitute the mesial part of this brain region.
For further details see the article regarding the inferior parietal
lobule in this volume, and would only focus here on basic
cytoarchitectonic features and forgotten but still relevant brain
maps of the postcentral and superior parietal regions.
The map of the Russian-School (Sarkissov, Filimonoff,
Kononowa, & Preobrachenskaja, 1955) is very similar to that
of Brodmann (see Zilles & Amunts, 2012) and differs only by
minor details. Brodmann (1909, 1914) found three major areas
on the postcentral gyrus, BA3, BA2, and BA1 in a rostral to
caudal sequence. BA3 must be subdivided into the areas 3a
and 3b by myelo-, cyto-, and receptorarchitectonic as well as
functional criteria (Jones & Porter, 1980; Vogt & Vogt, 1919; von
Economo & Koskinas, 1925; Zilles, Palomero-Gallagher,
Grefkes, et al., 2002). Area 3b, which is one of the thinnest
isocortical areas (Table 1), is characterized by an extremely
dense population of small granular cells throughout layers
IIIV (Figure 1), which led to the term koniocortex. It represents
part of the primary somatosensory cortex, where epicritic sensoric functions are processed. BA1 has a typical six-layered isocortex with large pyramidal cells in deeper layer III and a less
conspicuous layer IV than that of area 3b. The border between
BA1 and BA2 was defined by quantitative cyto- and receptorarchitectonic analyses (Geyer, Schleicher, & Zilles, 1997; Geyer,
Schormann, Mohlberg, & Zilles, 2000; Geyer, Schleicher, &
Zilles, 1999; Grefkes, Geyer, Schormann, Roland, & Zilles,
2001). According to von Economo and Koskinas (1925) and
Grefkes, Geyer, Schormann, Roland, & Zilles, et al., (2001), but
in contrast to Brodmann (1909), BA2 does not extend onto the
mesial hemispheric surface. BA 43 is mainly located on the
operculum Rolandi and encroaches onto the most ventral portion of the postcentral gyrus. It can be best compared with the
recent cytoarchitectonically and functionally defined opercular
regions OP 3 and OP 4 (Eickhoff, Amunts, Mohlberg, & Zilles,
2006; Eickhoff, Schleicher, Zilles, & Amunts, 2006). A comparison of the Brodmann areas on the postcentral gyrus with those
of von Economo and Koskinas (1925) and the myeloarchitectonicaly defined areas of Vogt and Vogt (1919) is given in Table 2.
An extremely detailed map of the human parietal isocortex
containing 46 areas, and even more subdivisions, was published by Gerhardt (1940). Since this map is based on combined cyto- and myeloarchitectonic study of only one
hemisphere, it does not seem meaningful to discuss this map
Temporal Lobe
The temporal lobe comprises auditory and visual, as well as
multimodal association areas. The primary and secondary
auditory areas BA41 and BA42 reach a considerable cortical
thickness (Table 1). The dorsal surface of the superior temporal gyrus is subdivided by the transverse gyrus (or gyri), on
which the primary and secondary auditory cortices are found
(Figure 1), into an anterior and a posterior part. The anterior
part is the planum polare, and the posterior part the planum
temporale, which extends to the end of the lateral (Sylvian)
fissure. The latter contains parts of the Wernicke language
region. The lateral and ventral surfaces of the temporal lobe
are occupied by the medial and inferior temporal, fusiform
(lateral occipito-temporal), and rostral part of the lingual
(medial occipito-temporal) gyri. They contain multimodal
association and visual brain regions. The most medial part of
the temporal comprises periallocortical entorhinal, perirhinal,
parasubicular, and presubicular areas, as well as the hippocampus proper and the small cortical part of the amygdala. The
polar zone of the temporal lobe (BA38) is a multimodal iso- to
proisocortical region and has been included by Mesulam
(1998) in the paralimbic belt.
The most detailed architectonic studies of the temporal
cortex are based on myeloarchitectonic observations. A comparison of the cytoarchitectonic parcellation schemes by
Brodmann (1909), von Economo & Koskinas (1925), and
the Julich/Dusseldorf group is given in Table 2.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
Temporopolar region. A recent cytoarchitectonic and immunohistochemical study of the human temporal polar region (Ding,
Van Hoesen, Cassell, & Poremba, 2009) demonstrated that the
agranular perirhinal area BA35 extends into the posterior part of
the polar cortex, and dysgranular area BA36 reaches even more
anteriorly. Granular area TAr and a polysensory granular area
TAp were found anterior to the auditory parabelt area and in the
dorsal bank of the superior temporal sulcus, respectively (Ding,
Van Hoesen, Cassell, & Poremba, 2009). Furthermore, an agranular area TI, which seems to be equivalent to area TI of Beck
(1930), was identified anterior to the limen insulae and the
temporal part of the prepiriform cortex by the presence of olfactory fibers in layer I and the lack of layer IV (Ding, Van Hoesen,
Cassell, & Poremba, 2009). Right at the pole of the polar region,
a dysgranular area TG was observed (Ding, Van Hoesen, Cassell,
& Poremba, 2009). The granular cytoarchitectonic areas TE1 and
TE2 (von Economo & Koskinas, 1925) also reach the temporal
pole region (Ding, Van Hoesen, Cassell, & Poremba, 2009).
A map of the temporopolar region is given in Figure 7.
Auditory cortex. BA41 is found in the lateral fissure
(Figure 6) on the temporal transverse gyrus (Heschl) gyrus,
and has the typical koniocortical structure of primary sensory
areas. It is surrounded caudo-laterally by the secondary auditory BA42, rostrally and laterally by BA22 and BA42, and
medially by BA52. Distinct vertical cell columns (organ
pipes and rain shower formations of von Economo &
Koskinas, 1925) can be seen in BA41 if the section is precisely
vertical to the cortical surface. This is visible in the lateral part
of Te1.0 of Figure 1, whereas the larger medial part has a more
oblique orientation relative to the sectioning plane. The width
of these columns and the intervals between them in auditory
areas are narrower in the right than in the left hemisphere
(Seldon, 1981).
Based on detailed cyto- and receptor architectonic studies, a
parcellation of the human auditory cortex was recently provided
(Clarke & Morosan, 2012; Morosan, Rademacher, Schleicher,
et al., 2001; Morosan, Rademacher, Palomero-Gallagher, &
Zilles, 2004). Notably, the borders of the cytoarchitectonically
defined primary auditory cortex Te1 cannot be defined by macroscopically visible landmarks of the Heschl gyrus, particularly
not at its lateral part (Morosan, Rademacher, Schleicher, et al.,
2001; Rademacher, Morosan, Schormann, et al., 2001). Their
area Te1 (and subdivisions) can be compared with the core
region (BA41), Te2 (and subdivisions) is part of the lateral
belt, and TI (and its subdivisions TI1 and TI2; Figure 1) represents the medial belt, as suggested in a comparison
of anatomical and functional topographies (Moerel, De, & Formisano, 2014). Whereas TI2 is agranular, TI1 shows a transitional appearance between the granular primary auditory cortex
and TI2, with a recognizable layer IV (Figure 1). Therefore, the
TI area of Morosan, Rademacher, Schleicher, et al. (2001) is not
identical with the completely agranular TI area of Beck (1930) as
mentioned above. Subdivisions of a region comparable to TI
were also shown by Rivier and Clarke (1997) and Wallace,
Johnston, and Palmer (2002). For a recent review of the
relation between tonotopic maps and subdivisions of the auditory cortex, see Moerel, De, and Formisano (2014).
BA42 has a less densely packed and narrower layer IV than
BA41. It represents the secondary auditory cortex and the lateral belt. For further details of the cytoarchitecture of the
human auditory cortex, see Amunts, Morosan, Hilbig, and
Zilles (2012).
127
TAr
HG2
TG
HG1
PI
psl GS
TI
GS
psm
In
LI
36 35
U
SG
AG
ss
(a)
7A
TAr
LI
TI
SG
Pir PAC
ss
PACo
Eo
TG
35
rs
Elr EC
cs
36
7A
(b)
rs
35
EC
cs
36
TG
TE
its
(c)
128
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
Occipital Lobe
The occipital lobe houses the visual cortex, but visual areas are
also found in the temporal and parietal lobes. Approximately
half of the human isocortex is occupied by visual areas.
Brodmanns map (1909) shows a tripartition of the occipital lobe into BA17, primary visual area V1, BA18, secondary
visual area V2, andBA19, tertiary visual area (Figure 3).
A similar tripartition was proposed by von Economo and
Koskinas (1925, Table 2), Filimonoff (1932), and Sarkissov
et al. (1955).
The major part of BA17 receives afferents from both eyes
and represents the central part of the visual field at the occipital
pole, whereas the upper visual field is found solely on the
lower bank and the higher visual field on the upper bank of
the calcarine sulcus. The vertical meridian extends along the
border between BA17 and BA18. BA17 shows an extremely
differentiated laminar structure with a prominent, tripartite
layer IV subdivided into sublayers IVac (Figure 1). Layer IVa
receives parvo- and magnocellular afferents and shows a conspicuous immunoreactivity against non-phosphorylated neurofilaments as well as an extracellular proteoglycan distributed
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
matrix protein is also found in the magnocellular layers of the
lateral geniculate body, in layer IVa of Ba17 (see above), and in
area V5/MT (see below). Functional retinotopic studies and
comparisons with the probability maps demonstrated that
hOc2 is comparable with V2 (Abdollahi, Kolster, Glasser,
et al., 2014; Georgieva, Peeters, Kolster, Todd, & Orban,
2009; Wohlschlager, Specht, Lie, et al., 2005).
Whereas Brodmanns (1903b, 1909) identification of BA17
and BA18 is widely accepted and conforms with areas hOc1
and hOc2, respectively (Amunts, Malikovic, Mohlberg, Schormann, & Zilles, 2000), his concept of BA19 has been rendered
untenable based on current structural (Braak, 1980; Caspers,
Palomero-Gallagher, Caspers, et al., 2013; Caspers, Zilles,
Eickhoff, et al., 2013; Eickhoff, Rottschy, Kujovic, PalomeroGallagher, & Zilles, 2008; Eickhoff, Rottschy, & Zilles, 2007;
Weiner, Golarai, Caspers, et al., 2014; Zilles & Clarke, 1997)
and functional data (Abdollahi, Kolster, Glasser, et al., 2014;
Felleman & van Essen, 1991; Georgieva, Peeters, Kolster, Todd,
& Orban, 2009; Grill-Spector, Golarai, & Gabrieli, 2008; GrillSpector, Kourtzi, & Kanwisher, 2001; Kanwisher & Yovel, 2006;
Kolster, Peeters, & Orban, 2010; Sereno, Lutti, Weiskopf, & Dick,
2013; Tootell & Hadjikhani, 2001; van Essen, Lewis, Drury,
et al., 2001; Watson, Myers, Frackwiak, et al., 1993). Thus, the
use of the term area 19 is no longer justified. A comprehensive
description of the functional parcellation of this brain region is,
however, beyond the scope of the present article. Eighteen extrastriate areas were described based on retinotopic mapping and
fMRI in the human brain (Georgieva, Peeters, Kolster, Todd, &
Orban, 2009; Kolster, Peeters, & Orban, 2010). The functional
nomenclature of the visual cortex is used here, whenever the
comparability between functional and architectonical parcellations is demonstrated or highly probable.
The retinotopically defined area V3 is found immediately
rostral to BA18, mainly on the lateral, but also on the mesial
surface of the occipital lobe (Sereno, Dale, Repas, et al., 1995;
Tootell & Taylor, 1995). The border between BA18 and V3 is
the site of the horizontal meridian of the visual field. A distinct
cytoarchitectonic area hOc3v (Rottschy, Eickhoff, Schleicher,
et al., 2007) was found rostral and lateral to hOc2 in the
collateral sulcus. This area does not have large pyramidal neurons in layers III or V and is weakly myelinated without Baillarger stripes. It also differs by its lighter COX staining from
hOc2 and the rostrally adjoining cortex (Clarke, 1994). Topographically, this area seems to be comparable to the functionally defined area V3v/VP. A second cytoarchitectonic area
hOc3d (Kujovic, Zilles, Malikovic, et al., 2013) is located
dorso-lateral to hOc2 in the region of the superior and transverse occipital sulci. Based on its location and topology hOc3d
is thought to be the putative anatomical substrate of functionally defined area V3d. hOc3v and hOc3d together overlap with
the retinotopically defined area V3 to a considerable degree
(Abdollahi, Kolster, Glasser, et al., 2014; Georgieva, Peeters,
Kolster, Todd, & Orban, 2009; Wilms, Eickhoff, Specht, et al.,
2010). Notably, hOc3v has higher GABAA, M1 and M3 receptor
densities than hOc3d (Eickhoff, Rottschy, Kujovic, PalomeroGallagher, & Zilles, 2008). This indicates an additional receptorarchitectonic subdivision in parallel to the cytoarchitectonic
parcellation within the V3 complex. Thus, hOc3d could be a
part of the dorsal visual stream, whereas hOc3v would belong
to the ventral stream (Ungerleider & Haxby, 1994; Ungerleider
& Mishkin, 1982).
129
130
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
(1905) identified four areas (BA13BA16) in the insular cortex
of lower primates, but not in the human brain. Here he only
identified a posterior granular and an anterior agranular region
separated by the central sulcus of the insula. Later studies
demonstrated, that this was an oversimplification, the central
sulcus does not coincide with the cytoarchitectonical subdivision of the human insula into granular and agranular regions.
A detailed cytoarchitectonic analysis of the insula was provided
by Rose (1928, Figure 8). In a later study, this map was further
refined by Brockhaus (1940) and the areas were classified as
iso- meso- and allocortical.
Areas ai4, ai5, ai10, ai11, and Prpy1 of Rose (1928) belong
to the agranular allocortical region. Agranular areas ai10, ai11,
and Prpy1 are not visible in Figure 8. Areas i18i24 represent
the isocortical granular region in the posterior part of the insula,
and areas i1i17 the isocortical dysgranular region (Figure 8).
Areas i13 and i22 of Rose (1928) are located within the central
insular sulcus and therefore not depicted in Figure 8. Area ai8 is
also part of the dysgranular isocortex. The mesocortical region,
which includes areas ai1ai3, ai6, ai7, ai7a and further not
shown in Figure 8, is interposed between the dysgranular isocortical and the agranular allocortical regions.
A principal organization scheme of the insula was proposed
by Mesulam and Mufson (1985). Here the (pre)piriform cortex
and agranular allocortical insular areas are surrounded by three
belts of which the first is the mesocortical dysgranular region
which is characterized by an interrupted and inconspicuous
layer IV. It adjoins the orbitofrontal and temporopolar regions.
The second belt is composed of the isocortical dysgranular
Insular Lobe
The insular cortex is covered by the frontal and parietal opercula as well as by the temporal lobe. The circular sulcus of Reil
circumscribes the outer border of the insular cortex. It is subdivided by a consistently present central sulcus. Brodmann
BS
BP
brac
CA
cis
BPacl
i1 bra
brp
i10
i7
i3
i8
i4
i18
i11
i2
ai8
i6
ai7
bri
i15
i16
cii
i19
i20
i21
cs
i23
i24
CP
i9
ai7
ai3
ai1 ai2
i14
ai6
ai3
i6
i12
i9
i5
BPacll
i17
prci
ai8
ai6
ai5
ai7
T
ai4
Figure 8 Cytoarchitectonic map of the human insula. Red encodes allocortical agranular areas, blue mesocortical areas, orange isocortical dysgranular
areas, and yellow isocortical granular areas. The identification of iso- meso- and allocortical classification follows Brockhaus (1940). bra, short anterior
insular sulcus; brac, short accessory insular sulcus; BP, first short insular gyrus; BPacI, first accessory short insular gyrus; BPacII, second accessory
short insular gyrus; brp, short posterior insular sulcus; BS, second short insular gyrus; CA, precentral insular gyrus; cii, inferior branch of the circular
sulcus; cis, superior branch of the circular sulcus; CP, postcentral insular gyrus; cs, central insular sulcus; cs, central insular sulcus; bri, short
intermediate insular sulcus; prci, precentral insular sulcus; T, temporal cortex. Modified from Rose, M. (1928). Die Inselrinde des menschen und der
Tiere. Journal fur Psychologie und Neurologie, 37, 467624.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
areas and occupies most of the surface of the insular lobe,
extending from anterior parts of the postcentral insular gyrus
over the first and second short insular gyri to the accessory
short insular gyri. The most posterior belt is the granular
region, with a clearly visible layer IV, a subdividable layer III,
and a clear differentiation of layer V from layer VI. The granular
belt is heavily myelinated and has a well discernible outer
stripe of Baillarger. It was recently subdivided using quantitative cytoarchitectonic mapping and functional metaanalysis
into areas Ig1 and Ig2 (Kurth, Eickhoff, Schleicher, et al.,
2010; Kurth, Zilles, Fox, Laird, & Eickhoff, 2010). Ig1 can
probably be compared with the cortical sensory representation
of temperature and pain (Craig, Chen, Bandy, & Reiman, 2000;
Garcia-Larrea, Perchet, Chreach, et al., 2010).
Acknowledgements
This work was supported by the Portfolio Theme Supercomputing and Modeling for the Human Brain of the Helmholtz
Association, Germany.
Competing financial interests: The authors declare that they
have no competing financial interests.
References
Abdollahi, R. O., Kolster, H., Glasser, M. F., Robinson, E. C., Coalson, T. S., Dierker, D.,
et al. (2014). Correspondences between retinotopic areas and myelin maps in
human visual cortex. NeuroImage, 99, 509524.
Amunts, K., Kedo, O., Kindler, M., Pieperhoff, P., Mohlberg, H., Shah, N. J., et al.
(2005). Cytoarchitectonic mapping of the human amygdala, hippocampal region
and entorhinal cortex: Intersubject variability and probability maps. Anatomy and
Embryology, 210, 343352.
Amunts, K., Lenzen, M., Friederici, A. D., Schleicher, A., Morosan, P.,
Palomero-Gallagher, N., et al. (2010). Brocas region: Novel organizational
principles and multiple receptor mapping. PLoS Biology, 8, e1000489.
Amunts, K., Lepage, C., Borgeat, L., Mohlberg, H., Dickscheid, T., Rousseau, M. E.,
et al. (2013). BigBrain: An ultrahigh-resolution 3D human brain model. Science,
340, 14721475.
Amunts, K., Malikovic, A., Mohlberg, H., Schormann, T., & Zilles, K. (2000).
Brodmanns areas 17 and 18 brought into stereotaxic space-where and how
variable? NeuroImage, 11, 6684.
Amunts, K., Morosan, P., Hilbig, H., & Zilles, K. (2012). Auditory system. In J. K. Mai &
G. Paxinos (Eds.), The human nervous system (3rd ed., pp. 12701300).
Amsterdam: Academic Press.
Amunts, K., Schleicher, A., Burgel, U., Mohlberg, H., Uylings, H. B.M, & Zilles, K.
(1999). Brocas region revisited: Cytoarchitecture and intersubject variability.
Journal of Comparative Neurology, 412, 319341.
Amunts, K., Schleicher, A., & Zilles, K. (1997). Persistence of layer IV in the primary
motor cortex (area 4) of children with cerebral palsy. Journal fur Hirnforschung, 38,
247260.
131
132
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
Clarke, S., & Morosan, P. (2012). Architecture, connectivity, and transmitter receptors
of human auditory cortex. In D. Poeppel, T. Overath, A. N. Popper, & R. R. Fay
(Eds.), The human auditory cortex (2nd ed., pp. 1138). New York: Springer.
Cohen, L., Lehericy, S., Chochon, F., Lemer, C., Rivaud, S., & Dehaene, S. (2002).
Language-specific tuning of visual cortex? Functional properties of the Visual Word
Form Area. Brain, 125, 10541069.
Craig, A. D., Chen, K., Bandy, D., & Reiman, E. M. (2000). Thermosensory activation of
insular cortex. Nature Neuroscience, 3, 184190.
Deyoe, E. A., Hockfield, S., Garren, H., & van Essen, D. C. (1990). Antibody labeling of
functional subdivisions in visual cortex: Cat-301 immunoreactivity in striate and
extrastriate cortex of the macaque monkey. Visual Neuroscience, 5, 6781.
Ding, S. L., Van Hoesen, G. W., Cassell, M. D., & Poremba, A. (2009). Parcellation of
human temporal polar cortex: A combined analysis of multiple cytoarchitectonic,
chemoarchitectonic, and pathological markers. Journal of Comparative Neurology,
514, 595623.
Dumoulin, S. O., Bittar, R. G., Kabani, N. J., Baker, C. L., Jr., Le, G. G., Bruce, P. G.,
et al. (2000). A new anatomical landmark for reliable identification of human
area V5/MT: A quantitative analysis of sulcal patterning. Cerebral Cortex, 10,
454463.
Eickhoff, S. B., Amunts, K., Mohlberg, H., & Zilles, K. (2006). The human parietal
operculum. II. Stereotaxic maps and correlation with functional imaging results.
Cerebral Cortex, 16, 268279.
Eickhoff, S. B., Rottschy, C., Kujovic, M., Palomero-Gallagher, N., & Zilles, K. (2008).
Organizational principles of human visual cortex revealed by receptor mapping.
Cerebral Cortex, 18, 26372645.
Eickhoff, S. B., Rottschy, C., & Zilles, K. (2007). Laminar distribution and codistribution of neurotransmitter receptors in early human visual cortex. Brain
Structure & Function, 212, 255267.
Eickhoff, S. B., Schleicher, A., Zilles, K., & Amunts, K. (2006). The human parietal
operculum. I. Cytoarchitectonic mapping of subdivisions. Cerebral Cortex, 16,
254267.
Eickhoff, S. B., Stephan, K. E., Mohlberg, H., Grefkes, C., Fink, G. R., Amunts, K., et al.
(2005). A new SPM toolbox for combining probabilistic cytoarchitectonic maps and
functional imaging data. NeuroImage, 25, 13251335.
Felleman, D. J., & van Essen, D. C. (1991). Distributed hierarchical processing in the
primate cerebral cortex. Cerebral Cortex, 1, 147.
Filimonoff, I. N. (1932). Uber die Variabilitat der Grohirnrindenstruktur. Mitteilung II
Regio occipitalis beim erwachsenen Menschen. Journal fur Psychologie und
Neurologie, 44, 296.
Filimonoff, I. N. (1947). A rational subdivision of the cerebral cortex. Archives of
Neurology and Psychiatry, 58, 296311.
Fischl, B., Rajendran, N., Busa, E., Augustinack, J., Hinds, O., Yeo, B. T., et al. (2008).
Cortical folding patterns and predicting cytoarchitecture. Cerebral Cortex, 18,
19731980.
Flechsig, P. (1920). Anatomie des menschlichen Gehirns und Ruckenmarks auf
myelogenetischer Grundlage. Leipzig: Thieme.
Foerster, O. (1931). The cerebral cortex in man. Lancet, 218, 309312.
Foerster, O. (1936). The motor cortex in man in the light of Hughlings Jacksons
doctrines. Brain, 59, 135159.
Galaburda, A. M., LeMay, M., Kemper, T. L., & Geschwind, N. (1978). Right-left
asymmetrics in the brain. Science, 199, 852856.
Galaburda, A. M., & Sanides, F. (1980). Cytoarchitectonic organization of the human
auditory cortex. Journal of Comparative Neurology, 190, 597610.
Galaburda, A. M., Sanides, F., & Geschwind, N. (1978). Human brain. Cytoarchitectonic
left-right asymmetries in the temporal speech region. Archives of Neurology, 35,
812817.
Garcia-Cabezas, M. A., & Barbas, H. (2014). Area 4 has layer IV in adult primates.
European Journal of Neuroscience, 39, 18241834.
Garcia-Larrea, L., Perchet, C., Creach, C., Convers, P., Peyron, R., Laurent, B., et al.
(2010). Operculo-insular pain (parasylvian pain): A distinct central pain syndrome.
Brain, 133, 25282539.
Georgieva, S., Peeters, R., Kolster, H., Todd, J. T., & Orban, G. A. (2009). The
processing of three-dimensional shape from disparity in the human brain. Journal
of Neuroscience, 29, 727742.
Gerbella, M., Belmalih, A., Borra, E., Rozzi, S., & Luppino, G. (2011). Cortical
connections of the anterior (F5a) subdivision of the macaque ventral premotor area
F5. Brain Structure & Function, 216, 4365.
Gerhardt, E. (1940). Die Cytoarchitektonik des Isocortex parietalis beim Menschen.
Journal fur Psychologie und Neurologie, 49, 367419.
Geschwind, N., & Levitsky, W. (1968). Human brain: Left-right asymmetries in temporal
speech region. Science, 161, 186187.
Geyer, S. (2004). The microstructural border between the motor and the cognitive
domain in the human cerebral cortex. Advances in Anatomy, Embryology, and Cell
Biology, 174, 189.
Geyer, S., Ledberg, A., Schleicher, A., Kinomura, S., Schormann, T., Burgel, U., et al.
(1996). Two different areas within the primary motor cortex of man. Nature, 382,
805807.
Geyer, S., Matelli, M., Luppino, G., Schleicher, A., Jansen, Y., Palomero-Gallagher, N.,
et al. (1998). Receptor autoradiographic mapping of the mesial motor and
premotor cortex of the macaque monkey. Journal of Comparative Neurology, 397,
231250.
Geyer, S., Schleicher, A., & Zilles, K. (1997). The somatosensory cortex of human:
Cytoarchitecture and regional distributions of receptor-binding sites. NeuroImage,
6, 2745.
Geyer, S., Schleicher, A., & Zilles, K. (1999). Areas 3a, 3b, and 1 of human primary
somatosensory cortex. 1. Microstructural organization and interindividual
variability. NeuroImage, 10, 6383.
Geyer, S., Schormann, T., Mohlberg, H., & Zilles, K. (2000). Areas 3a, 3b, and 1 of
human primary somatosensory cortex. 2. Spatial normalization to standard
anatomical space. NeuroImage, 11, 684696.
Geyer, S., Zilles, K., Luppino, G., & Matelli, M. (2000). Neurofilament protein
distribution in the macaque monkey dorsolateral premotor cortex. European Journal
of Neuroscience, 12, 15541566.
Grefkes, C., Geyer, S., Schormann, T., Roland, P., & Zilles, K. (2001). Human
somatosensory area 2: Observer-independent cytoarchitectonic mapping,
interindividual variability, and population map. NeuroImage, 14, 617631.
Grill-Spector, K., Golarai, G., & Gabrieli, J. (2008). Developmental
neuroimaging of the human ventral visual cortex. Trends in Cognitive Sciences, 12,
152162.
Grill-Spector, K., Kourtzi, Z., & Kanwisher, N. (2001). The lateral occipital complex and
its role in object recognition. Vision Research, 41, 14091422.
Hendry, S. H., & Carder, R. K. (1993). Neurochemical compartmentation of monkey and
human visual cortex: Similarities and variations in calbindin immunoreactivity
across species. Visual Neuroscience, 10, 11091120.
Hendry, S. H., Hockfield, S., Jones, E. G., & McKay, R. (1984). Monoclonal antibody
that identifies subsets of neurones in the central visual system of monkey and cat.
Nature, 307, 267269.
Hendry, S. H., Jones, E. G., Hockfield, S., & McKay, R. D. (1988). Neuronal populations
stained with the monoclonal antibody Cat-301 in the mammalian cerebral cortex
and thalamus. Journal of Neuroscience, 8, 518542.
Hockfield, S., Tootell, R. B., & Zaremba, S. (1990). Molecular differences among
neurons reveal an organization of human visual cortex. Proceedings of the National
academy of Sciences of the United States of America, 87, 30273031.
Hof, P. R., & Morrison, J. H. (1995). Neurofilament protein defines regional patterns
of cortical organization in the macaque monkey visual system: A quantitative
immunohistochemical analysis. Journal of Comparative Neurology, 352,
161186.
Homke, L. (2006). A multigrid method for anisotropic PDEs in elastic im age
registration. Numerical Linear Algebra with Applications, 13, 215229.
Huk, A. C., Dougherty, R. F., & Heeger, D. J. (2002). Retinotopy and functional
subdivision of human areas MT and MST. Journal of Neuroscience, 22,
71957205.
Huk, A. C., & Heeger, D. J. (2002). Pattern-motion responses in human visual cortex.
Nature Neuroscience, 5, 7275.
Insausti, R., & Amaral, D. G. (2012). Hippocampal formation. In J. K. Mai & G. Paxinos
(Eds.), The human nervous system (3rd ed., pp. 896942). Amsterdam: Academic
Press.
Jancke, L., & Steinmetz, H. (1993). Auditory lateralization and planum temporale
asymmetry. NeuroReport, 5, 169172.
Jones, E. G., & Porter, R. (1980). What is area 3a? Brain Research Reviews, 2, 143.
Kanwisher, N., & Yovel, G. (2006). The fusiform face area: A cortical region specialized
for the perception of faces. Philosophical Transactions of the Royal Society of
London. Series B: Biological Sciences, 361, 21092128.
Knauer, A. (1909). Die Myeloarchitektonik der Brocaschen Region. Neurologisches
Centralblatt, 28, 12401243.
Kolster, H., Peeters, R., & Orban, G. A. (2010). The retinotopic organization of the
human middle temporal area MT/V5 and its cortical neighbors. Journal of
Neuroscience, 30, 98019820.
Kononowa, E. P. (1935). Structural variability of the cortex cerebri. Inferior frontal gyrus
in adults (Russian). In S. A. Sarkissov & I. N. Filimonoff (Eds.), Annals of the brain
research institute (pp. 49118). Moscow-Leningrad: State Press for Biological and
Medical Literature.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
Kononowa, E. P. (1949). The frontal lobe (Russian). In S. A. Sarkissov, I. N. Filimonoff
& N. S. Preobrashenskaya (Eds.), The cytoarchitecture of the human cortex cerebri
(pp. 309343). Moscow: Medgiz.
Kujovic, M., Zilles, K., Malikovic, A., Schleicher, A., Mohlberg, H., Rottschy, C., et al.
(2013). Cytoarchitectonic mapping of the human dorsal extrastriate cortex. Brain
Structure & Function, 218, 157172.
Kurth, F., Eickhoff, S. B., Schleicher, A., Hoemke, L., Zilles, K., & Amunts, K. (2010).
Cytoarchitecture and probabilistic maps of the human posterior insular cortex.
Cerebral Cortex, 20, 14481461.
Kurth, F., Zilles, K., Fox, P. T., Laird, A. R., & Eickhoff, S. B. (2010). A link between the
systems: Functional differentiation and integration within the human insula revealed
by meta-analysis. Brain Structure & Function, 214, 519534.
Luppino, G., Matelli, M., Camarda, R., & Rizzolatti, G. (1993). Corticocortical
connections of area F3 (SMA-proper) and area F6 (pre-SMA) in the macaque
monkey. Journal of Comparative Neurology, 338, 114140.
Luppino, G., Murata, A., Govoni, P., & Matelli, M. (1999). Largely segregated
parietofrontal connections linking rostral intraparietal cortex (areas AIP and VIP) and
the ventral premotor cortex (areas F5 and F4). Experimental Brain Research, 128,
181187.
Malach, R., Reppas, J. B., Benson, R. R., Kwong, K. K., Jiang, H., Kennedy, W. A., et al.
(1995). Object-related activity revealed by functional magnetic resonance imaging in
human occipital cortex. Proceedings of the National academy of Sciences of the
United States of America, 92, 81358139.
Malikovic, A., Amunts, K., Schleicher, A., Mohlberg, H., Eickhoff, S. B., Wilms, M., et al.
(2007). Cytoarchitectonic analysis of the human extrastriate cortex in the region of
V5/MT : A probabilistic, stereotaxic map of Area hOc5. Cerebral Cortex, 17,
562574.
Matelli, M., Camarda, R., Glickstein, M., & Rizzolatti, G. (1986). Afferent and efferent
projections of the inferior area 6 in the macaque monkey. Journal of Comparative
Neurology, 251, 281298.
Matelli, M., Govoni, P., Galletti, C., Kutz, D. F., & Luppino, G. (1998). Superior area 6
afferents from the superior parietal lobule in the macaque monkey. Journal of
Comparative Neurology, 402, 327352.
Matelli, M., & Luppino, G. (1996). Thalamic input to mesial and superior area 6 in the
macaque monkey. Journal of Comparative Neurology, 372, 5987.
Matelli, M., Luppino, G., & Rizzolatti, G. (1991). Architecture of superior and mesial
area 6 and the adjacent cingulate cortex in the macaque monkey. Journal of
Comparative Neurology, 311, 445462.
Mesulam, M. M. (1998). From sensation to cognition. Brain, 121, 10131052.
Mesulam, M. M., & Mufson, E. J. (1985). The insula of Reil in man and monkey.
Architectonics, connectivity and function. In A. Peters & E. G. Jones (Eds.), Cerebral
cortex (pp. 179226). New York: Plenum.
Mishkin, M., Ungerleider, L. G., & Macko, K. A. (1983). Object and spatial vision: Two
cortical pathways. Trends in Neurosciences, 6, 414417.
Moerel, M., De, M. F., & Formisano, E. (2014). An anatomical and functional
topography of human auditory cortical areas. Frontiers in Neuroscience, 8, 225.
Morosan, P., Rademacher, J., Palomero-Gallagher, N., & Zilles, K. (2004). Anatomical
organization of the human auditory cortex: Cytoarchitecture and transmitter
receptors. In P. Heil, E. Konig, & E. Budinger (Eds.), Auditory cortex Towards a
synthesis of human and animal research (pp. 2750). Mahwah, NJ: Lawrence
Erlbaum.
Morosan, P., Rademacher, J., Schleicher, A., Amunts, K., Schormann, T., & Zilles, K.
(2001). Human primary auditory cortex: Cytoarchitectonic subdivisions and
mapping into a spatial reference system. NeuroImage, 13, 684701.
Morosan, P., Schleicher, A., Amunts, K., & Zilles, K. (2005). Multimodal architectonic
mapping of human superior temporal gyrus. Anatomy and Embryology (Berlin),
210, 401406.
Nakamura, K., Kawashima, R., Sato, N., Nakamura, A., Sugiura, M., Kato, T., et al.
(2000). Functional delineation of the human occipito-temporal areas related to face
and scene processing. A PET study. Brain, 123, 19031912.
Nelissen, K., Luppino, G., Vanduffel, W., Rizzolatti, G., & Orban, G. A. (2005).
Observing others: Multiple action representation in the frontal lobe. Science, 310,
332336.
Ngowyang, G. (1934). Die Zytoarchitektonik des menschlichen Stirnhirns. National
Research Institute of Psychology, Academia Sinica, 7, 1.
Palomero-Gallagher, N., Mohlberg, H., Zilles, K., & Vogt, B. A. (2008). Cytology and
receptor architecture of human anterior cingulate cortex. Journal of Comparative
Neurology, 508, 906926.
Palomero-Gallagher, N., & Zilles, K. (2009). Transmitter receptor systems in cingulate
regions and areas. In B. A. Vogt (Ed.), Cingulate neurobiology & disease, Vol. 1:
Infrastructure, diagnosis, treatment (2nd ed.). Oxford: Oxford University Press.
133
Palomero-Gallagher, N., Zilles, K., Schleicher, A., & Vogt, B. A. (2013). Cyto- and
receptor architecture of area 32 in human and macaque brains. Journal of
Comparative Neurology, 521, 32723286.
Pandya, D. N., Seltzer, B., & Barbas, H. (1988). Input-output organization of the primate
cerebral cortex. In H. D. Steklis & J. Erwin (Eds.), Comparative primate biology
(pp. 3980). New York: Alan R. Liss.
Penfield, W., & Welck, K. (1951). The supplementary motor area of the cerebral cortex; a
clinical and experimental study. AMA Archives of Neurology & Psychiatry, 66,
289317.
Petrides, M., & Pandya, D. N. (1994). Comparative architectonic analysis of the human
and the macaque frontal cortex. In F. Boller, & J. Grafman (Eds.), Handbook of
neuropsychology (pp. 1758). Amsterdam: Elsevier.
Petrides, M., & Pandya, D. N. (1999). Dorsolateral prefrontal cortex: Comparative
cytoarchitectonic analysis in the human and the macaque brain and corticocortical
connection patterns. European Journal of Neuroscience, 11, 10111036.
Petrides, M., & Pandya, D. N. (2009). Distinct parietal and temporal pathways to the
homologues of Brocas area in the monkey. PLoS Biology, 7, e1000170.
Petrides, M., Tomaiuolo, F., Yeterian, E. H., & Pandya, D. N. (2012). The prefrontal
cortex: Comparative architectonic organization in the human and the macaque
monkey brains. Cortex, 48, 4657.
Picard, N., & Strick, P. L. (1996). Motor areas of the medial wall: A review of their
location and functional activation. Cerebral Cortex, 6, 342353.
Pigache, R. M. (1970). The anatomy of "Paleocortex". A critical review. Ergebnisse der
Anatomie und Entwicklungsgeschichte, 43, 62.
Preuss, T. M., & Coleman, G. Q. (2002). Human-specific organization of primary visual
cortex: Alternating compartments of dense cat-301 and calbindin immunoreactivity
in layer 4A. Cerebral Cortex, 12, 671691.
Preuss, T. M., & Goldman-Rakic, P. S. (1989). Connections of the ventral granular
frontal cortex of macaques with perisylvian premotor and somatosensory areas:
Anatomical evidence for somatic representation in primate frontal association
cortex. Journal of Comparative Neurology, 282, 293316.
Preuss, T. M., Qi, H., & Kaas, J. H. (1999). Distinctive compartmental organization of
human primary visual cortex. Proceedings of the National academy of Sciences of
the United States of America, 96, 1160111606.
Rademacher, J., Morosan, P., Schormann, T., Schleicher, A., Werner, C., Freund, H. J.,
et al. (2001). Probabilistic mapping and volume measurement of human primary
auditory cortex. NeuroImage, 13, 669683.
Rajkowska, G., & Goldman-Rakic, P. S. (1995a). Cytoarchitectonic definition of
prefrontal areas in the normal human cortex: I. Remapping of areas 9 and 46 using
quantitative criteria. Cerebral Cortex, 5, 307322.
Rajkowska, G., & Goldman-Rakic, P. S. (1995b). Cytoarchitectonic definition of
prefrontal areas in the normal human cortex: II. Variability in locations of areas 9 and
46 and relationship to the Talairach Coordinate System. Cerebral Cortex, 5,
323337.
Riegele, L. (1931). Die Cytoarchitektonik der Felder der Brocaschen Regionen. Journal
of Physiology & Neurology, 42, 496514.
Rivier, F., & Clarke, S. (1997). Cytochrome oxidase, acetylcholinesterase, and NADPHdiaphorase staining in human supratemporal and insular cortex: Evidence for
multiple auditory areas. NeuroImage, 6, 288304.
Rizzolatti, G., Camarda, R., Fogassi, L., Gentilucci, M., Luppino, G., & Matelli, M.
(1988). Functional organization of inferior area 6 in the macaque monkey. II.
Area F5 and the control of distal movements. Experimental Brain Research, 71,
491507.
Rizzolatti, G., Fadiga, L., Gallese, V., & Fogassi, L. (1996). Premotor cortex and the
recognition of motor actions. Brain Research. Cognitive Brain Research, 3,
131141.
Rizzolatti, G., Fadiga, L., Matelli, M., Bettinardi, V., Paulesu, E., Perani, D., et al. (1996).
Localization of grasp representations in humans by PET: 1. Observation versus
execution. Experimental Brain Research, 111, 246252.
Rizzolatti, G., Luppino, G., & Matelli, M. (1996). The classic supplementary motor area
is formed by two independent areas. Advances in Neurology, 70, 4556.
Rizzolatti, G., Luppino, G., & Matelli, M. (1998). The organization of the cortical motor
system: New concepts. Electroencephalography and Clinical Neurophysiology, 106,
283296.
Roland, P. E., & Zilles, K. (1994). Brain atlasesA new research tool. Trends in
Neurosciences, 17, 458467.
Roland, P. E., & Zilles, K. (1996). Functions and structures of the motor cortices in
humans. Current Opinion in Neurobiology, 6, 773781.
Rose, M. (1927a). Die sog. Riechrinde beim Menschen und beim Affen. II. Teil
Allocortex bei Tier und Mensch. Journal fur Psychologie und Neurologie, 32,
97160.
134
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Cytoarchitecture and Maps of the Human Cerebral Cortex
Zeki, S. M. (1974). Functional organization of a visual area in the posterior bank of the
superior temporal sulcus of the rhesus monkey. Journal of Physiology, 236,
549573.
Zeki, S. (1980). The response properties of cells in the middle temporal area (area MT)
of owl monkey visual cortex. Proceedings of the Royal Society of London B:
Biological Sciences, 207, 239248.
Zilles, K., & Amunts, K. (2010). Centenary of Brodmanns mapconception and fate.
Nature Reviews. Neuroscience, 11, 139145.
Zilles, K., & Amunts, K. (2012). Architecture of the cerebral cortex. In J. K. Mai & G.
Paxinos (Eds.), The human nervous system (3rd ed., pp. 836895). Amsterdam:
Academic Press.
Zilles, K., Armstrong, E., Schlaug, G., & Schleicher, A. (1986). Quantitative
cytoarchitectonics of the posterior cingulate cortex in primates. Journal of
Comparative Neurology, 253, 514524.
135
Zilles, K., & Clarke, S. (1997). Architecture, connectivity, and transmitter receptors of
human extrastriate visual cortex. Comparison with nonhuman primates. Cerebral
Cortex, 12, 673742.
Zilles, K., Palomero-Gallagher, N., Grefkes, C., Scheperjans, F., Boy, C., Amunts, K.,
et al. (2002). Architectonics of the human cerebral cortex and transmitter receptor
fingerprints: Reconciling functional neuroanatomy and neurochemistry. European
Neuropsychopharmacology, 12, 587599.
Zilles, K., Schlaug, G., Geyer, S., Luppino, G., Matelli, M., Qu, M., et al. (1996).
Anatomy and transmitter receptors of the supplementary motor areas in the human
and nonhuman primate brain. In H. O. Luders (Ed.), Supplementary sensorimotor
area (pp. 2943). Philadelphia: Lippincott-Raven.
Zilles, K., Schlaug, G., Matelli, M., Luppino, G., Schleicher, A., Qu, M., et al. (1995).
Mapping of human and macaque sensorimotor areas by integrating architectonic,
transmitter receptor, MRI and PET data. Journal of Anatomy, 187, 515537.
Glossary
Campbell (1905) published a combined cyto- and myeloarchitectonic map of the human brain, in which he described
16 cortical areas. It is the first, though largely incomplete
parcellation scheme. For example, Brocas region is not separated from the premotor cortex, and most of the extrastriate
cortex, the inferior parietal lobule, and medial and inferior
temporal as well as occipito-temporal cortex form one huge
homogeneous conglomerate.
Elliot Smith (1907) examined thin, hand-cut, and
unstained sections through various regions of the human cerebral cortex. He studied the regional variations of the Baillarger
stripes (Figure 1; Baillarger, 1840) caused by the light reflection of the myelinated fibers in those stripes, and proposed a
parcellation of the human cortex into approximately 50 areas
which, he stressed, were sharply delineable. This work can be
seen as a first approach to an exclusively myeloarchitectonic
map of the human cerebral cortex (Figure 2).
Kaes (1907) published an atlas in which he depicted
selected cortical regions from both newborn and adult subjects
using the recently developed Weigert staining technique for
the visualization of myelinated fibers. He defined an outer
http://dx.doi.org/10.1016/B978-0-12-397025-1.00209-8
137
138
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
Cytoarchitecture
I
II
Myeloarchitecture
1
1a
1b
1c
1
2
3a1
3a2
III
Outer
principal
zone
3
3b
4
IV
5a
V
5b
6a1
Inner
principal
zone
VIa
6a2
6
VIb
6b1
6b2
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
prcB
prcA
pocA
pocB
parsB
frsa
frs
frint
frA
pariA
pariC
peristr
frC
parsA
pariB
fri
B
fri
prfr
frB
139
tempsup
parocc
orb
parstr
tempmed
temppol
str
tempinf
partemp
tempocc
prcB
pocA+B
prcA
frs
frsa
frA
frD
callC
parsB
callA
callB
vh
parsA
parspl
peristr
parstr
prfrB
callD
N.A. suh
prfr
str
pyr
partemp
temppol
pardent
peristr
parstr
Figure 2 Myeloarchitectonic map of the human brain. a, visuo-auditory band; b, visuo-sensory band; callA, area callosa A; callB, area callosa B;
callC, area callosa C; callD, area callosa D; frA, area frontalis A; frB, area frontalis B; frC, area frontalis C; frD, area frontalis D; fri, area frontalis inferior;
friB, area frontalis inferior B (posterior inferior frontal); frint, area frontalis intermedia; frs, area frontalis superior; frsa, area frontalis superior
anterior; N.A., ncl. amygdalae; orb, area orbitalis; pardent, area paradentata; pariA, area parietalis inferior A; pariB, area parietalis inferior B; pariC, area
parietalis inferior C ( area parasylvica); parocc, area parieto-occipitalis; parsA, area parietalis superior posterior (A); parsB, area parietalis superior
anterior (B); parspl, area parasplenialis; parstr, area parastriata; partemp, area paratemporalis; peristr, area peristriata; pocA, area postcentralis A; pocB,
area postcentralis B; prcA, area praecentralis A; prcB, area praecentralis B; prfr, area praefrontalis; prfrB, area praefrontalis B; pyr, area pyriformis;
str, area striata; suh, subiculum hippocampi; tempinf, area temporalis inferior; tempmed, area temporalis medialis; tempocc, area temporo-occipitalis;
temppol, area temporalis polaris; tempsup, area temporalis superior; vh, vesticia hippocampi; X, modification of area postcentralis B (lining the
upper lip of the cingulate sulcus); Y, modification of area postcentralis A (surrounding the lower portion of the central sulcus); Z, modification of area
postcentralis A (infringing onto the Sylvian fissure). Modified from Elliot Smith, G. (1907). A new topographical survey of the human cerebral cortex,
being an account of the distribution of the anatomically distinct cortical areas and their relationship to the cerebral sulci. Journal of Anatomy and
Physiology, 41, 237254.
(Brodmann, 1909; Vogt, 1903; Vogt & Vogt, 1919). The transition zone between both is constituted by the mesocortex, which
encompasses the periallocortex and the proisocortex
(Brockhaus, 1940; Stephan, 1975). Isocortical ( neocortical)
areas have a six-layered cytoarchitectonic lamination with the
notable exception of the motor cortex, which lacks a clearly
visible layer IV in adult stages. Allocortical areas ( paleo- and
archicortical areas) have more or less than six layers. The isocortex comprises all cortical regions characterized myeloarchitectonically by an euradiate structure (Vogt & Vogt, 1919). The
140
Table 1
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
Most important terms for myeloarchitectonic descriptions
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
1
2
3a
1
2
3a
3b
3b
3c
1
2
3a
3a
3a
3b
3b
4
3b
5a
5a
5a
5a
1
2
1
2
5b
5b
5b
5a
5b
5b
6
BA4
V42
(a)
6
BA41
Te1
(c)
3b
V69
(b)
1
2
3a
3b
1
2
BA42
Te2
(d)
BA22
Te3
(e)
1
2
1
2
3a
1
2
3
4
3a
3a
4a
3b
3b
4b
3b
5a
4c
5a
5b
5
5b
5
6
6
BA17
hOc1
(f)
BA18
hOc2
(g)
BA38
temp.pol.
(h)
BA24
V19
(i)
BA29
Vl3
(j)
141
the original sections from the Vogt Lab (Figure 5(a)), we can
support the definition of Sanides and Vitzthum (1965b) and
Braak (1980) of BA17 as singulostriate area. The secondary
visual area BA18/hOc2 (Figures 3(g) and 5(b)) shows a conjunctostriate myeloarchitecture with a clearly visible Kaes
Bechterew stripe. The border region between BA17/hOc1 and
BA18/hOc2 found considerable interest in the mapping literature (Amunts et al., 2000; Clarke & Miklossy, 1990; Sanides &
Vitzthum, 1965a, 1965b; von Economo & Koskinas, 1925; Zilles
& Clarke, 1997), because it is an example for gradual changes of
cortical architecture at border regions and their functional relevance for brain mapping. It has been shown, that this border
region is a target site of transcallosal fibers and has a peculiar
myeloarchitecture (Figure 5(c) and 5(d)) consisting of a border
tuft (Grenzbuschel; Sanides & Vitzthum, 1965a) and a fringe
area (Randsaum; Sanides & Vitzthum, 1965a). In cytoarchitectonic studies, von Economo and Koskinas (1925) described an
area OBg, which is part of BA18 adjoining the border region, but
probably larger than the border tuft segment (Amunts et al.,
2000). Fiber tracking studies are necessary to solve the question
how cyto- and myeloarchitectonic features correlate with the
distribution of transcallosal fibers.
Regions of the superior (Figure 4(d)) and inferior
(Figure 4(e)) parietal cortex are shown here as examples for
multimodal association areas. On the dorsolateral surface, the
areas of the superior parietal lobule have a bistriate myeloarchitecture, with a slightly wider and denser external Baillarger
stripe compared to the internal stripe (Batsch, 1956; Hopf,
1969; Vogt, 1911). In contrast to the superior parietal region,
the inferior parietal areas have a propeastriate structure
(Table 1) with finer radial fibers and bundles (Batsch, 1956;
Hopf, 1969; Vogt, 1911). Various subregions within both parietal lobules have been delineated on the basis of detailed
myeloarchitectonic features (see in the succeeding text).
Cortex on the lateral surface of the gyrus rectus (Figure 5(f))
is unistriate and the radial fibers stop within layer 3b. This
is an intermediate feature between the classical infra- and euradiate types, called medioradiate by Strasburger (1937). This
reflects the position of the orbital cortex between the proisocortex and the fully differentiated euradiate isocortex.
Figure 3(i) shows a periallocortical region, the anterior
cingulate area BA24/V19. Here, the radial fibers do not reach
the border between layers 3a and 3b, but stop mainly between
layers 5a and 5b. Only a few fibers ascend to the border between
3b and 4. BA24 is, therefore, an infraradiate and unistriate area
with a well recognizable inner Baillarger stripe (Strasburger,
1937). Periallocortical retrosplenial area BA29/Vl3
(Figure 3(j)) is an example of the supraradiate myeloarchitectonic type with a dense stripe of tangential fibers in layer 4.
Notably, a very dense and rather homogeneous agglomeration
of tangential fibers is found in layer 1 of BA29/Vl3, though
without the usual subdivision into sublayers of different fiber
densities typical of isocortical areas. This appearance of layer 1
is a characteristic feature also found in all allocortical regions.
Because of its periallocortical structure, the laminar terminology cannot be directly compared with that of isocortical areas.
Figure 6 shows examples of allocortical regions in the frontal
lobe. Areas V13 and V14a,b are myeloarchitectonic correlates of
areas BA25. They are characterized by the typical supraradiate
structure of the allocortex (clearly visible in V13 and V14a,b)
142
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
Figure 4 Myelin stained (WeigertKulschitzky method; celloidin embedding) sections through primary motor ((a); BA4), primary somatosensory ((b);
area 3b), primary auditory ((c); Te1), superior (d) and inferior (e) parietal cortex, and gyrus rectus (f) of human brains. Arabic numerals indicate
myeloarchitectonic layers. Original sections form the C & O Vogt Brain Collection, University of Dusseldorf, Germany, are shown. (a), (b), (d), and (e)
come from the right hemisphere of brain A39. (c) is from the right hemisphere of brain A38 and (f) from the left hemisphere of brain A37.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
143
Figure 5 Myelin stained (WeigertKulschitzky method; celloidin embedding) sections through the primary (a) and secondary (b) human visual cortex.
(c) and (d) show the border region between hOc1 (BA17) and hOc2 (BA18). Gb, border tuft (Grenzbuschel; Sanides & Vitzthum, 1965a); Rs,
fringe area (Randsaum; Sanides & Vitzthum, 1965a). Arabic numerals indicate myeloarchitectonic layers. Solid arrowheads indicate the border between
primary and secondary visual cortex. Open arrowheads delineate the fringe area and the border tuft region. Original sections form the C & O Vogt
Brain Collection, University of Dusseldorf, Germany, are shown. (a), (b), and (d) are from the right hemisphere of brain A18, and (c) from the
left hemisphere of brain A38.
V13
1
2
3a
3b
4
5a
5b
V12
V14b
V14a
Figure 6 Drawing of representative periallocortical areas showing myelinated fibers and their lamination pattern in a horizontal section through the
subcallosal region. Arabic numerals indicate myeloarchitectonic layers. Modified from Vogt, C., & Vogt, O. (1919). Allgemeinere Ergebnisse unserer
Hirnforschung. Journal fur Psychologie und Neurologie, 25, 279462.
areas 6aa and 6ab. This finding in the human cortex was further
substantiated by anatomical, connectional, and functional studies in macaque monkeys leading to the concept of a subdivision
of mesial BA6 into a supplementary motor area (SMA proper,
comparable to 6aa) and a presupplementary motor area
144
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
Figure 7 Myeloarchitectonic map of the human frontal lobe. (a) Lateral view, (b) medial view, (c) dorsal view, and (d) ventral view. Prefrontal
areas rostral to areas V36, V39, and V40 are not shown in the dorsal view. Arabic numbers indicate Vogts myeloarchitectonically defined areas. a,
ascending branch of the lateral fissure; ce, central sulcus; cg, cingulate sulcus; d, diagonal sulcus; h, horizontal branch of the lateral fissure; if, inferior
frontal sulcus; tol, olfactory tuberculum. Modified from Vogt, O. (1910). Die myeloarchitektonische Felderung des menschlichen Stirnhirns.
Journal fur Psychologie und Neurologie, 15, 221232.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
Table 2
Comparison of various nomenclature systems used in brain mapping with the Brodmann (1909, 1914) classification
Brodmannn
BA1
BA2
V70
V71, V72 (?)
BA3
BA17
BA18
BA19
V67
V69
V42, V43
V75
V36V41
V83, V85, V86, V87
(?)
Comparability not
clear
Comparability not
clear
V50, V51; S50, S51d,
S51p, S52d, S52v
V1, V4V9, V10V12
(ventral parts)
Area striata
Area occipitalis
Area praeoccipitalis
BA20
BA21
n.d.
n.d.
TE2
TE1
BA22
BA23
BA24
n.d.
V77V80, V91V96
V17V32, V12
(dorsal part)
V13, V14
Vl3
Vl areas except Vl3
V76, V81, V82, V84
V3, V33V35,
V10V11 (dorsal
parts)
V15, V16
n.d.
TA1, TA2
LC2, LC3
LA1, LA2, LA3
BA4
BA5
BA6
BA7
BA8
BA9
BA10
BA11, BA12
BA25
BA29
BA30
BA31
BA32
BA33
BA37
BA38
BA39
BA40
BA41
BA42
BA43
BA44
BA45
BA46
145
V38
V90
Parts of V73 and
V74; V88, V89
Area temporalis
transversa interna
Area temporalis
transversa externa
V68; V73V74
(parts), V72 (?)
V56, V57
V58, V59 (dorsal
part); S58, S59d
V53, V54; S53d, S54,
SZ (above s53d in
Figure 8(d))
Nieuwenhuys et al.
Julich/Dusseldorf Group
70
71, 72 (?)
1
2
67
69
42, 43
75
3641
83, 85, 86, 87 (?)
3a
3b
4a, 4p
5L, 5M, 5Ci
6 (preliminary delineation)
7A, 7P, 7PC, hIP3
n.d.
FD (?)
n.d.
FE
Fp1, Fp2
FG, FH
OC
OB (OBg, OBO)
OA (OA1, OA2,
OAm)
167, 168
162165, comparability
not clear in the
posterior region of
BA21
136139, 158161
7780, 91-96
12, 1732
n.d.
hOc1
hOc2
hOc3d, hOc3v, hOc4d, hOc4v, hOc5 (areas located
within the region of BA19 and lateral BA37) and other
areas. Note, that a homogenous cytoarchitectonic or
functional area 19 does not exist
n.d.
n.d.
FL, FM
LE1
LD
LC1
FCL, FDL, FEL, FHL
13, 14
n.d.
n.d.
76, 81, 82, 84
3, 10, 11 (rostral part),
3335 (ventral parts)
LB1
PH, PHO, PHP,
PHT
TG, TGA
PG
Parts of PFop, PFt,
PFcm, PF, PFm
TC
15, 16
Comparability not clear
33
Fg1, Fg2 (on the fusiform gyrus as parts of medial PH)
120132
90
88, 89
n.d.
PGa, PGp
OP 1, OP2, PFop, PFt, PFcm, PF, PFm
145153
TB
154157
68, 72 (?)
OP 3, OP 4
FCBm
FDg
56, 57
58
44d, 44v
45a, 45p
FD
53 (dorsal part)
n.d.
(Continued)
146
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
Table 2
(Continued)
Brodmannn
BA47
Regio insularis
anterior and
posterior
S53v, S59v
Vi1Vi6, Vai1Vai4,
Vai6, Vai7
FF
IA1, IA2, IAB, IB,
IBT IC, ID
Nieuwenhuys et al.
Julich/Dusseldorf Group
59
97102
n.d.
Ig1 and Ig2 (dorsal part of Vi5), Id1 (Vai6)
The nomenclatures of Brodmann (1909, 1914; BA areas), von Economo and Koskinas (1925), and the Dusseldorf/Julich Group (references below) are based on cyto- and
receptorarchitectonic studies. The maps of the Julich/Dusseldorf group are shown in the JuBrain atlas (www.fz-juelich.de/inm/inm-1/jubrain_cytoviewer) and can be applied by means
of the SPM Anatomy Toolbox (www.fz-juelich.de/inm/inm-1/spm_anatomy_toolbox). The nomenclature of Vogt (1910) and Vogt and Vogt (1919) (V areas) is based on
myeloarchitectonic, that of Sanides (1962) (S areas) on combined cyto- and myeloarchitectonic observations. The Nieuwenhuys et al. (2014) study is a metaanalysis of the
myeloarchitectonic studies of the Vogt-School. n.d. not determined, ? unclear comparability.
References Dusseldorf/Julich Group: Amunts et al. (1999, 2000, 2010), Amunts, Schleicher, and Zilles (2004), Bludau et al. (2014), Caspers, Zilles, et al. (2013), Caspers et al. (2006,
2008), Eickhoff, Schleicher, Zilles, and Amunts (2006), Eickhoff, Amunts, Mohlberg, and Zilles (2006), Geyer et al. (1996), Geyer, Schleicher, and Zilles (1999), Geyer (2004), Grefkes,
Geyer, Schormann, Roland, and Zilles (2001), Kujovic et al. (2013), Kurth et al. (2010), Malikovic et al. (2007), Morosan et al. (2001, 2005), Palomero-Gallagher, Mohlberg, Zilles,
and Vogt (2008), Palomero-Gallagher and Zilles (2009); Rottschy et al. (2007); Scheperjans, Grefkes, Palomero-Gallagher, Schleicher, and Zilles (2005), Scheperjans, PalomeroGallagher, Grefkes, Schleicher, and Zilles (2005), Scheperjans, Hermann, et al. (2008), Scheperjans, Eickhoff, et al. (2008).
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
147
Figure 8 Comparison between the maps of the human frontal lobe modified after Strasburger (Strasburger, E. H. (1937). Die myeloarchitektonische
Gliederung des Stirnhirns beim Menschen und Schimpansen I. Journal fur Psychologie und Neurologie, 47, 460491; (a) lateral view, (e) medial view,
(g) orbital view), Hopf (Hopf, A. (1956). Uber die Verteilung myeloarchitektonischer Merkmale in der Stirnhirnrinde beim Menschen. Journal fur
148
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
Parietal Lobe
The myelin density decreases from the postcentral gyrus to the
more posterior regions of the parietal lobe. Furthermore, the
lowest density of myelinated fibers is found in the inferior
parietal lobule (Hopf & Vitzthum, 1957). This example of a
decrease of myelin density from primary sensory to hierarchically higher multimodal association areas also holds true for
other brain regions like the visual and auditory systems as well
as the prefrontal cortex. Also the density and visibility of the
KaesBechterew stripe as well as the thickness of the radial
fiber bundles decrease considerably from the postcentral
gyrus to the superior and, particularly, the inferior parietal
lobule (Hopf & Vitzthum, 1957).
Two myeloarchitectonic maps of the human parietal cortex
have been published by Vogt (1911) (Figure 9(a)9(c)) and
Batsch (1956) (Figure 9(d)9(f)). The myeloarchitectonic
characteristics of areas V67V73, V75, V79, V81, V83,
V85V87, V89, and V90V92 defined by Batsch (1956), as
well as of several of their subdivisions were confirmed by
photometric measurements (Hopf, 1969, 1970).
Hirnforschung, 2, 311333; (c) lateral view, (d) dorsal view), and Sanides (Sanides, F. (1962). Die Architektonik des menschlichen Stirnhirns. Berlin,
Gottingen, Heidelberg: Springer Verlag; (b) lateral view, (f) medial view, (h) orbital view). The maps of Strasburger and Hopf are based on
myeloarchitectonic, and that of Sanides on combined cyto- and myeloarchitectonic observations. Extensive subdivisions by Strasburger (e.g., areas 48
and 48a, etc.) were merged to one larger area (e.g., 48, etc.). Note that the drawing by Strasburger shows a more dorsal aspect of the lateral surface of
the hemisphere, whereas Hopf and Sanides use a perspectives comparable to that of Vogt (1910) (Figure 7). All areas with same numbers in the maps
have been encoded with the same color. Areas identified by just one or two of the authors have been left in gray. A.a, area adolfactoria; Bol, olfactory
bulb; ce, central sulcus; cg, cingulate sulcus; if, inferior frontal sulcus; Pro/Peri, proiso- periallocortical region (not mapped); Pvz and Pvl fields of the
paralimbic zone of Sanides (1962); tol, olfactory tuberculum.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
149
Figure 9 Comparison between the myeloarchitectonic maps of the human parietal cortex after Vogt (Vogt, O. (1911). Die Myeloarchitektonik des
Isocortex parietalis. Journal fur Psychologie und Neurologie, 18, 379396; (a) dorsal view, (b) lateral view, (c) medial view) and Batsch (Batsch, E.-G.
(1956). Die myeloarchitektonische Untergliederung des Isocortex parietalis beim Menschen. Journal fur Hirnforschung, 2, 225258; (d) dorsal view, (e)
lateral view, (f) medial view). Arabic numerals indicate myeloarchitectonic areas. Continuous lines surround areas, dashed lines indicate their
subdivisions (only in (d)(f)). All areas with same numbers in the maps of both authors have been encoded with the same color. Subregions in the map
of Batsch are labeled with italic letters or roman numerals. calc, calcarine sulcus; cc, corpus callosum; ce, central sulcus; fissl, lateral fissure; ip,
intraparietal sulcus; p-o, parieto-occipital sulcus; poc, postcentral sulcus; temps, superior temporal sulcus.
150
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
Temporal Lobe
The most detailed myeloarchitectonic map of the human temporal lobe presents 60 areas grouped into seven major regions
(Hopf, 1954a, 1955). In a quantitative photometric study
(Hopf, 1968a), the parcellation into these myeloarchitectonic
regions could be confirmed. However, a detailed objective
delineation of the 60 areas was not provided. Thus, we will
here only discuss the mapping of the temporal regions as
shown in Figure 10(a) and 10(c).
Temporopolar region tp (Figure 10(a) and 10(c)), with its
subregions tp.d, tp.l, and tp.m, is characterized by its singulostriate architecture, that is, only one horizontal stripe of
Baillager is visible in layer 4 (Hopf, 1954a). Area tp is comparable to BA38.
The large magnocellular tmag region (Figure 10(b) and
10(c)) with its four subregions is found on the middle and
inferior temporal gyri and is thus comparable to areas BA20
and BA21. Myeloarchitecture of the different subregions and
areas within tmag is uni- to propeastriate and the density of the
inner and outer Baillarger stripes varies from interno- to externodensior depending on the area examined (Hopf, 1954a).
Areas of the tlim region (Figure 10(c)) are found on the
fusiform gyrus. The subregion tlim.o is separated from the
entorhinal area by the collateral sulcus. It has a mixed myeloarchitectonic character depending on the areas, reaching
from singulostriate to propeunistriate and unistriate. The subregion tlim.c is prope- to unistriate, whereas tlim.m is singulostriate. tlim.m is a transition region between the allocortex
and the occipital isocortex (Hopf, 1954a).
The propeunistriate region ttr.1 is found on the (first)
transverse temporal gyrus (Figure 10(a)), and is thus comparable to cytoarchitectonic areas BA41 (Brodmann, 1909) and
Te1 (Morosan et al., 2001). Myeloarchitectonic area ttr.2 has a
similar position as cytoarchitectonic area Te2, and areas tsep
(propeunistriate) and tpartr (propeastriate) on the superior
temporal gyrus as Te3, whereas bistriate area tpari is comparable to TI1 (Morosan et al., 2001).
A myeloarchitectonic map by Beck (1930) with an extreme
parcellation of the supratemporal surface into 79 areas
grouped into seven regions shows, however, a nearly perfect
match with the map of Hopf (1954a) when restricted to the
regional level (Figure 10(a) and 10(d)). The bistriate regions
ttrI, ttrII, ts, and tpar of Beck (1930) resemble areas Te1 (primary auditory), Te2 (secondary auditory), Te3, and TI1, respectively. His singulostriate tp region is comparable to BA38. The
myeloarchitectonic description of ttrIII emphasizes differences
from the typical unimodal sensory structure of ttrI and ttrII,
Occipital Lobe
An early myeloarchitectonic map of the region rostral to BA18
was proposed by Lungwitz (1937). He delineated a total of 17
areas, all of which are euradiate, have a clearly visible Kaes
Bechterew stripe, and are bistriate to conjunctostriate, with a
tendency to a denser external Baillarger stripe (i.e., externodensior). However, a comparison with recent cyto- and receptorarchitectonic maps (Amunts et al., 2000; Caspers, PalomeroGallagher, et al., 2013; Caspers, Zilles, et al., 2013; Eickhoff,
Rottschy, Kujovic, Palomero-Gallagher, & Zilles, 2008; Eickhoff,
Rottschy, & Zilles, 2007; Kujovic et al., 2013; Malikovic et al.,
2007; Rottschy et al., 2007), in vivo magnetic resonance imaging
(MRI) studies of myelin distribution (Glasser & van Essen, 2011)
and functional imaging data (Abdollahi et al., 2014; Ferri,
Kolster, Jastorff, & Orban, 2012; Georgieva, Peeters, Kolster,
Todd, & Orban, 2009; Kolster, Peeters, & Orban, 2010; Sereno,
Lutti, Weiskopf, & Dick, 2013; Wandell, Dumoulin, & Brewer,
2007; Wilms et al., 2010) demonstrates that the parcellation
by Lungwitz (1937) does not match the cyto- or receptorarchitectonic data and cannot be reconciled with functional maps.
Human area MT is the only extrastriate visual area which
can be demonstrated using myelin staining, because of its
extremely high myelin density (Annese, Gazzaniga, & Toga,
2005; Clarke & Miklossy, 1990; Flechsig, 1920; Tootell & Taylor, 1995). It could also be identified by receptor autoradiography in human postmortem brains (Zilles & Clarke, 1997).
The myelin density of distinct retinotopically defined areas
was measured by combining retinotopic and myelin maps
(Abdollahi et al., 2014). It could be demonstrated, that the
myelin density differs significantly between all these retinotopically distinct visual areas. Therefore, a new approach to high
resolution myeloarchitectonic mapping at the microscopic
level seems to be a valuable contribution to fill the gap between
the mesoscopic in vivo studies and cellular observations in the
visual cortex.
Insular Lobe
The most comprehensive myeloarchitectonic study of the insular lobe was published by Brockhaus (1940). He modified an
earlier study by Vogt and Vogt (1911) (Figure 11(a)) and added
own myeloarchitectonic maps of two further brains giving an
impression of intersubject variability (Figure 11(b)11(d)). The
cortex of the insular lobe lies over the claustrum, and is therefore
frequently called claustrocortex. It can be subdivided into isocortical, allocortical, and mesocortical regions.
The isocortical region is the largest part and reaches the
circular sulcus of the insula with the exception of a small
caudodorsal part (T; Figure 11(a), 11(b), and 11(d)), where
the temporal isocortex invades the insular lobe. All areas of the
isocortical part are myeloarchitectonically euradiate. The radial
fiber bundles and the intensity of the Baillarger stripes vary
between the different areas which led to the definition of five
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
151
Figure 10 Myeloarchitectonic map of the human temporal lobe ((a) dorsal view, (b) lateral view, and (c) medial view; modified from Hopf, A. (1954a).
Die Myeloarchitektonik des Isocortex temporalis beim Menschen. Journal fur Hirnforschung, 1, 208279) and of the dorsal surface (d) of the
temporal lobe (modified from Beck, E. (1930). Myeloarchitektonik der dorsalen Schlafenlappenrinde beim Menschen. Journal fur Psychologie und
Neurologie, 41, 129262). Bold letters code names of regions and subregions, italics of areas. Continuous lines surround the regions, dashed lines
indicate subregional borders, and dotted lines areal borders. Orientations of the maps in panels (a) and (d) are indicated (c, caudal direction; m, medial
direction; l, lateral direction; r, rostral direction). Abbreviations for panels (a)(c): CA, Cornu Ammonis region of the hippocampus; ent, entorhinal
area; mt, mesocortex. The regio temporalis limitans (tlim) is subdivided into caudal (c), medial (m), and oral (o) subregions. tlim.c contains two areas
(e, i), tlim.m two areas (e, i), and tlim.o four areas (a, isf, md, p). The regio temporalis magna (tmag) is subdivided into the caudodorsal (cd),
caudoventral (cv), dorsal (d), and ventral (v) subregions. tmag.cd consists of four areas (lim, if, p, s), tmag.cv of two areas (a, p), tmag.d of five
areas (aif, as, md, p, s), and tmag.v of two areas (as, pif). The regio temporopolaris (tp) is subdivided into the dorsal (d), lateral (l), medial (m), and
152
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
Figure 11 Myeloarchitectonic maps of the human insular lobe. (a) Modified from Vogt, C. and Vogt, O. (1911). Nouvelle Contribution a` letude de la
myeloarchitecture de lecorce cerebrale. Communication at the XX Congres des Medicins Alienistes et Neurologistes de France et des pays de langue
francaise, Bruxelles, (pp. 311). (b)(d) Modified from Brockhaus, H. (1940). Die Cyto- und Myeloarchitektonik des Cortex claustralis und des Claustrum
beim Menschen. Journal fur Psychologie und Neurologie, 49, 249348. Area ai2 of Vogt and Vogt (1911) comprises areas aio and aic of Brockhaus
(1940). Continuous lines surround areas, dashed lines indicate their subdivisions (only in (c) and (d)). Note interindividual variability by comparing
reconstruction of insular areas in three different brains by Brockhaus (b)(d). Green encodes isocortical areas, blue mesocortical areas, and red
allocortical areas. Dark green areas are cytoarchitectonically defined as granular areas, light green areas are dysgranular regions (Brockhaus, 1940;
Kurth et al., 2010; Vogt & Vogt, 1911). Area i5 in panel (a) is light green with dark green stripes, because it contains both granular and dysgranular
subareas. ai1ai4, ai6ai7 meso- and allocortical insular or temporal areas after Vogt and Vogt (1911), aic and aio allocortical insular areas after
Brockhaus (1940), BP, first short insular gyrus; BS, second short insular gyrus; CA, precentral insular gyrus; CPP, first postcentral insular gyrus; CPS,
second postcentral insular gyrus; cs, central insular sulcus; i1i6, isocortical insular areas after Vogt and Vogt (1911), i1i6 (and subdivisions),
isocortical insular areas after Brockhaus (1940); ibri and ibrm, iso- and mesocortical insular areas (respectively) adjacent to the orbital cortex after
Brockhaus (1940); mi areas (and subdivisions), mesocortical insular areas after Brockhaus (1940); T, temporal cortex; Tp, temporal lobe.
major areas in front (i1i3, i4a, and i4b, with several subareas)
and of seven areas (i5a, i5b, i5c, i5d, i6a, i6b, and i6li, with
several subareas) behind the central sulcus of the insula
(Brockhaus, 1940). Areas ibri and ibrm (Figure 11(c)) are
transition areas between the insular and orbital cortex.
The isocortical region of the insular cortex is by far its
largest part, followed by the mesocortical region. The latter
is found ventrally to the isocortical part and surrounds the
allocortical part of the insular cortex. Isocortical regions are
ventral (v) subregions. tp.d consists of three areas (e, I, p), tp.l is not further subdivided, tp.m has seven areas (e, i, if, p, pt, Ul, Um), and tp.v two
areas (if, s). The regio temporalis parainsularis (tpari) contains three areas (im, l, m). The regio temporalis paratransversa (tpartr) contains four areas
(a, p, pf, s). The regio temporalis separans (tsep) is subdivided into the lateral (l) and medial (m) subregions. tsep.l contains four areas (a, md, p, pf)
and tsep.m two areas (e, i). The regio temporalis transversa (ttr) is subdivided into the prima caudolateralis (1cl), prima caudomedialis (1cm),
prima orolateralis (1ol), prima oromedialis (1om), and secunda (2) subregions. ttr.1cl is not further subdivided, ttr.1cm has three areas (a, ep, ip),
ttr.1ol three areas (e, I, md), ttr.1om two areas (a, p), and ttr.2 four areas (ae, ai, pe, pi). Abbreviations for panel (d): ent, entorhinal area; Pam,
periamygdalar region; Prpi, prepiriform region; ti, temporal insular region; tp, temporopolar region; tpar, parainsular region; tpt, temporoparietal region;
ttrI, first temporal transversal region; ttrII, second temporal transversal region; ttrIII, third temporal transversal region; ts, supratemporal region.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
153
Acknowledgment
References
Abdollahi, R. O., Kolster, H., Glasser, M. F., Robinson, E. C., Coalson, T. S., Dierker, D.,
et al. (2014). Correspondences between retinotopic areas and myelin maps in
human visual cortex. NeuroImage, 99, 509524.
Allman, J. M., Tetreault, N. A., Hakeem, A. Y., Manaye, K. F., Semendeferi, K.,
Erwin, J. M., et al. (2010). The von Economo neurons in frontoinsular and anterior
cingulate cortex in great apes and humans. Brain Structure and Function, 214,
495517.
Allman, J. M., Watson, K. K., Tetreault, N. A., & Hakeem, A. Y. (2005). Intuition and
autism: A possible role for Von Economo neurons. Trends in Cognitive Sciences, 9,
367373.
Amunts, K., Lenzen, M., Friederici, A. D., Schleicher, A., Morosan, P.,
Palomero-Gallagher, N., et al. (2010). Brocas region: Novel organizational
principles and multiple receptor mapping. PLoS Biology, 8.
Amunts, K., Malikovic, A., Mohlberg, H., Schormann, T., & Zilles, K. (2000).
Brodmanns areas 17 and 18 brought into stereotaxic spaceWhere and how
variable? NeuroImage, 11, 6684.
Amunts, K., Schleicher, A., Burgel, U., Mohlberg, H., Uylings, H. B.M, & Zilles, K.
(1999). Brocas region revisited: Cytoarchitecture and intersubject variability.
Journal of Comparative Neurology, 412, 319341.
Amunts, K., Schleicher, A., & Zilles, K. (2004). Outstanding language competence and
cytoarchitecture in Brocas speech region. Brain and Language, 89, 346353.
Annese, J., Gazzaniga, M. S., & Toga, A. W. (2005). Localization of the human cortical
visual area MT based on computer aided histological analysis. Cerebral Cortex, 15,
10441053.
154
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
Axer, M., Amunts, K., Grassel, D., Palm, C., Dammers, J., Axer, H., et al. (2011). A novel
approach to the human connectome: Ultra-high resolution mapping of fiber tracts in
the brain. NeuroImage, 54, 10911101.
Axer, M., Grassel, D., Kleiner, M., Dammers, J., Dickscheid, T., Reckfort, J., et al.
(2011). High-resolution fiber tract reconstruction in the human brain by means of
three-dimensional polarized light imaging. Frontiers in Neuroinformatics, 5, 34.
Baillarger, J. (1840). Recherches sur la structure de la couche corticale des
circonvolutions du cervau. Memoires de lAcademie royale de Medecine, 8,
149183.
Batsch, E.-G. (1956). Die myeloarchitektonische Untergliederung des Isocortex
parietalis beim Menschen. Journal fur Hirnforschung, 2, 225258.
Beck, E. (1930). Myeloarchitektonik der dorsalen Schlafenlappenrinde beim Menschen.
Journal fur Psychologie und Neurologie, 41, 129262.
Bisley, J. W., & Goldberg, M. E. (2010). Attention, intention, and priority in the parietal
lobe. Annual Review of Neuroscience, 33, 121.
Bludau, S., Eickhoff, S. B., Mohlberg, H., Caspers, S., Laird, A. R., Fox, P. T., et al.
(2014). Cytoarchitecture, probability maps and functions of the human frontal pole.
NeuroImage, 93, 260275.
Braak, H. (1980). Architectonics of the human telencephalic cortex. Berlin: Springer.
Bremmer, F. (2011). Multisensory space: From eye-movements to self-motion. The
Journal of Physiology, 589, 815823.
Brockhaus, H. (1940). Die Cyto- und Myeloarchitektonik des Cortex claustralis und des
Claustrum beim Menschen. Journal fur Psychologie und Neurologie, 49, 249348.
Brodmann, K. (1909). Vergleichende Lokalisationslehre der Grohirnrinde in ihren
Prinzipien dargestellt auf Grund des Zellbaues. Leipzig: Barth.
Brodmann, K. (1914). Physiologie des Gehirns. In P. von Bruns (Ed.), Neue Deutsche
Chirurgie (pp. 85426). Stutgart: Verlag von Ferdinand Enke.
Campbell, A. W. (1905). Histological studies on the localisation of cerebral function.
Cambridge: Cambridge University Press.
Caspers, J., Palomero-Gallagher, N., Caspers, S., Schleicher, A., Amunts, K., &
Zilles, K. (2013). Receptor architecture of visual areas in the face and word-form
recognition region of the posterior fusiform gyrus. Brain Structure and Function,
http://dx.doi.org/10.1007/s00429-013-0646-z.
Caspers, J., Zilles, K., Eickhoff, S. B., Schleicher, A., Mohlberg, H., & Amunts, K.
(2013). Cytoarchitectonical analysis and probabilistic mapping of two extrastriate
areas of the human posterior fusiform gyrus. Brain Structure and Function, 218,
511526.
Caspers, S., Eickhoff, S. B., Geyer, S., Scheperjans, F., Mohlberg, H., Zilles, K., et al.
(2008). The human inferior parietal lobule in stereotaxic space. Brain Structure and
Function, 212, 481495.
Caspers, S., Geyer, S., Schleicher, A., Mohlberg, H., Amunts, K., & Zilles, K. (2006).
The human inferior parietal cortex: Cytoarchitectonic parcellation and interindividual
variability. NeuroImage, 33, 430448.
Caspers, S., Schleicher, A., Bacha-Trams, M., Palomero-Gallagher, N., Amunts, K., &
Zilles, K. (2013). Organization of the human inferior parietal lobule based on
receptor architectonics. Cerebral Cortex, 23, 615628.
Choi, H.-J., Amunts, K., Mohlberg, H., Fink, G. R., Schleicher, A., & Zilles, K. (2006).
Cytoarchitectonic mapping of the anterior ventral bank of the intraparietal sulcus in
humans. Journal of Comparative Neurology, 495, 5369.
Clarke, S., & Miklossy, J. (1990). Occipital cortex in man: Organization of callosal
connections, related myelo- and cytoarchitecture, and putative boundaries of
functional visual areas. Journal of Comparative Neurology, 298, 188214.
Cohen-Adad, J. (2014). What can we learn from T2* maps of the cortex? NeuroImage,
93(Pt 2), 189200.
Cohen-Adad, J., Polimeni, J. R., Helmer, K. G., Benner, T., McNab, J. A., Wald, L. L.,
et al. (2012). T2* mapping and B0 orientation-dependence at 7T reveal cyto- and
myeloarchitecture organization of the human cortex. NeuroImage, 60, 10061014.
De Martino, F., Moerel, M., Xu, J., van de Moortele, P. F., Ugurbil, K., Goebel, R., et al.
(2014). High-resolution mapping of myeloarchitecture in vivo: Localization of
auditory areas in the human brain. Cerebral Cortex.
Deistung, A., Schafer, A., Schweser, F., Biedermann, U., Turner, R., &
Reichenbach, J. R. (2013). Toward in vivo histology: A comparison of quantitative
susceptibility mapping (QSM) with magnitude-, phase-, and R2*-imaging at ultrahigh magnetic field strength. NeuroImage, 65, 299314.
Eickhoff, S., Walters, N. B., Schleicher, A., Kril, J., Egan, G. F., Zilles, K., et al. (2005).
High-resolution MRI reflects myeloarchitecture and cytoarchitecture of human
cerebral cortex. Human Brain Mapping, 24, 206215.
Eickhoff, S. B., Amunts, K., Mohlberg, H., & Zilles, K. (2006). The human parietal
operculum. II. Stereotaxic maps and correlation with functional imaging results.
Cerebral Cortex, 16, 268279.
Eickhoff, S. B., Rottschy, C., Kujovic, M., Palomero-Gallagher, N., & Zilles, K. (2008).
Organizational principles of human visual cortex revealed by receptor mapping.
Cerebral Cortex, 18, 26372645.
Eickhoff, S. B., Rottschy, C., & Zilles, K. (2007). Laminar distribution and codistribution of neurotransmitter receptors in early human visual cortex. Brain
Structure and Function, 212, 255267.
Eickhoff, S. B., Schleicher, A., Zilles, K., & Amunts, K. (2006). The human parietal
operculum. I. Cytoarchitectonic mapping of subdivisions. Cerebral Cortex, 16,
254267.
Elliot Smith, G. (1907). A new topographical survey of the human cerebral cortex,
being an account of the distribution of the anatomically distinct cortical areas and
their relationship to the cerebral sulci. Journal of Anatomy and Physiology, 41,
237254.
Ferri, S., Kolster, H., Jastorff, J., & Orban, G. A. (2012). The overlap of the EBA and the
MT/V5 cluster. NeuroImage, 66C, 412425.
Filimonoff, I. N. (1932). Uber die Variabilitat der Grohirnrindenstruktur. Mitteilung II
Regio occipitalis beim erwachsenen Menschen. Journal fur Psychologie und
Neurologie, 44, 296.
Flechsig, P. (1920). Anatomie des menschlichen Gehirns und Ruckenmarks auf
myelogenetischer Grundlage. Leipzig: Thieme.
Foerster, O. (1931). The cerebral cortex in man. Lancet, 218, 309312.
Foerster, O. (1936). The motor cortex in man in the light of Hughlings Jacksons
doctrines. Brain, 59, 135159.
Gennari, F. (1782). (Translated in Clarke E and OMalley CD (Eds.), (1996). The human
brain and spinal cord: A historical study illustrated by writings from the antiquity to
the twentieth century (2nd ed.). San Francisco: Norman Publ edn.)De peculiari
structura cerebri nonnulisque ejus morbis. Parma: Ex regio typographeo.
Georgieva, S., Peeters, R., Kolster, H., Todd, J. T., & Orban, G. A. (2009). The
processing of three-dimensional shape from disparity in the human brain. Journal
of Neuroscience, 29, 727742.
Geyer, S. (2004). The microstructural border between the motor and the cognitive
domain in the human cerebral cortex. Advances in Anatomy, Embryology, and Cell
Biology, 174, 189.
Geyer, S., Ledberg, A., Schleicher, A., Kinomura, S., Schormann, T., Burgel, U., et al.
(1996). Two different areas within the primary motor cortex of man. Nature, 382,
805807.
Geyer, S., Schleicher, A., & Zilles, K. (1999). Areas 3a, 3b, and 1 of human primary
somatosensory cortex. 1. Microstructural organization and interindividual
variability. NeuroImage, 10, 6383.
Geyer, S., Schormann, T., Mohlberg, H., & Zilles, K. (2000). Areas 3a, 3b, and 1 of
human primary somatosensory cortex. 2. Spatial normalization to standard
anatomical space. NeuroImage, 11, 684696.
Geyer, S., Weiss, M., Reimann, K., Lohmann, G., & Turner, R. (2011). Microstructural
parcellation of the human cerebral cortex From Brodmanns post-mortem map to
in vivo mapping with high-field magnetic resonance imaging. Frontiers in Human
Neuroscience, 5, 19.
Glasser, M. F., Goyal, M. S., Preuss, T. M., Raichle, M. E., & van Essen, D. C. (2014).
Trends and properties of human cerebral cortex: Correlations with cortical myelin
content. NeuroImage, 93(Pt 2), 165175.
Glasser, M. F., & van Essen, D. C. (2011). Mapping human cortical areas in vivo based
on myelin content as revealed by T1- and T2-weighted MRI. Journal of
Neuroscience, 31, 1159711616.
Grefkes, C., & Fink, G. R. (2005). The functional organization of the intraparietal sulcus
in humans and monkeys. Journal of Anatomy, 207, 317.
Grefkes, C., Geyer, S., Schormann, T., Roland, P., & Zilles, K. (2001). Human
somatosensory area 2: Observer-independent cytoarchitectonic mapping,
interindividual variability, and population map. NeuroImage, 14, 617631.
Hopf, A. (1954a). Die Myeloarchitektonik des Isocortex temporalis beim Menschen.
Journal fur Hirnforschung, 1, 208279.
Hopf, A. (1954b). Zur Frage der Konstanz und Abgrenzbarkeit myeloarchitektonischer
Rindenfelder. Deutsche Zeitschrift fur Nervenheilkunde, 172, 188200.
Hopf, A. (1955). Uber die Verteilung myeloarchitektonischer Merkmale in der
isokortikalen Schlafenlappenrinde beim Menschen. Journal fur Hirnforschung, 2,
3654.
Hopf, A. (1956). Uber die Verteilung myeloarchitektonischer Merkmale in der
Stirnhirnrinde beim Menschen. Journal fur Hirnforschung, 2, 311333.
Hopf, A. (1968a). Photometric studies on the myeloarchitecture of the human temporal
lobe. Journal fur Hirnforschung, 10, 285297.
Hopf, A. (1968b). Registration of the myeloarchitecture of the human frontal lobe with an
extinction method. Journal fur Hirnforschung, 10, 259269.
Hopf, A. (1969). Photometric studies on the myeloarchitecture of the human parietal
lobe. I. Parietal region. Journal fur Hirnforschung, 11, 253265.
Hopf, A. (1970). Photometric studies on the myeloarchitecture of the human parietal
lobe. II. Postcentral region. Journal fur Hirnforschung, 12, 135141.
Hopf, A., & Vitzthum, H. (1957). Uber die Verteilung myeloarchitektonische Merkmale
in der Scheitellappenrinde beim Menschen. Journal fur Hirnforschung, 3, 79104.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
Kaes, T. (1907). Die Grosshirnrinde des Menschen in ihren Maen und in ihrem
Fasergehalt. Ein gehirnanatomischer Atlas. Erster Teil: Kurven und Tafeln. Zweiter
Teil: Text. Jena: Fischer.
Kolster, H., Peeters, R., & Orban, G. A. (2010). The retinotopic organization of the
human middle temporal area MT/V5 and its cortical neighbors. Journal of
Neuroscience, 30, 98019820.
Kujovic, M., Zilles, K., Malikovic, A., Schleicher, A., Mohlberg, H., Rottschy, C., et al.
(2013). Cytoarchitectonic mapping of the human dorsal extrastriate cortex. Brain
Structure and Function, 218, 157172.
Kurth, F., Eickhoff, S. B., Schleicher, A., Hoemke, L., Zilles, K., & Amunts, K. (2010).
Cytoarchitecture and probabilistic maps of the human posterior insular cortex.
Cerebral Cortex, 20, 14481461.
Lungwitz, W. (1937). Zur myeloarchitektonischen Untergliederung der menschlichen
Area praeoccipitalis (Area 19 Brodmann). Journal fur Psychologie und Neurologie,
47, 607637.
Luppino, G., Matelli, M., Camarda, R. M., Gallese, V., & Rizzolatti, G. (1991). Multiple
representations of body movements in mesial area 6 and the adjacent cingulate
cortex: An intracortical microstimulation study in the macaque monkey. Journal of
Comparative Neurology, 311, 463482.
Lutti, A., Dick, F., Sereno, M. I., & Weiskopf, N. (2014). Using high-resolution
quantitative mapping of R1 as an index of cortical myelination. NeuroImage,
93(Pt 2), 176188.
Malikovic, A., Amunts, K., Schleicher, A., Mohlberg, H., Eickhoff, S. B., Wilms, M., et al.
(2007). Cytoarchitectonic analysis of the human extrastriate cortex in the region of
V5/MT : A probabilistic, stereotaxic map of area hOc5. Cerebral Cortex, 17(3),
562574.
Matelli, M., Luppino, G., & Rizzolatti, G. (1991). Architecture of superior and mesial
area 6 and the adjacent cingulate cortex in the macaque monkey. Journal of
Comparative Neurology, 311, 445462.
Meynert, T. (1868). Der Bau der Gross-Hirnrinde und seine ortlichen
Verschiedenheiten, nebst einem pathologisch- anatonischem Corollarium.
Vierteljahrsschrift fur Psychiatrie, 88113.
Morosan, P., Rademacher, J., Palomero-Gallagher, N., & Zilles, K. (2004). Anatomical
organization of the human auditory cortex: Cytoarchitecture and transmitter
receptors. In P. Heil, E. Konig & E. Budinger (Eds.), Auditory cortex Towards a
synthesis of human and animal research (pp. 2750). Mahwah, NJ: Lawrence
Erlbaum.
Morosan, P., Rademacher, J., Schleicher, A., Amunts, K., Schormann, T., & Zilles, K.
(2001). Human primary auditory cortex: Cytoarchitectonic subdivisions and
mapping into a spatial reference system. NeuroImage, 13, 684701.
Morosan, P., Schleicher, A., Amunts, K., & Zilles, K. (2005). Multimodal architectonic
mapping of human superior temporal gyrus. Anatomy and Embryology, 210, 401406.
Nieder, A., & Dehaene, S. (2009). Representation of number in the brain. Annual Review
of Neuroscience, 32, 185208.
Nieuwenhuys, R. (2013). The myeloarchitectonic studies on the human cerebral cortex
of the Vogt-Vogt school, and their significance for the interpretation of functional
neuroimaging data. Brain Structure and Function, 218, 303352.
Nieuwenhuys, R., Broere, C. A., & Cerliani, L. (2014). A new myeloarchitectonic map of
the human neocortex based on data from the Vogt-Vogt school. Brain Structure and
Function, http://dx.doi.org/10.1007/s00429-014-0806-9.
Nimchinsky, E. A., Vogt, B. A., Morrison, J. H., & Hof, P. R. (1995). Spindle neurons of
the human anterior cingulate cortex. Journal of Comparative Neurology, 355,
2737.
Palomero-Gallagher, N., Mohlberg, H., Zilles, K., & Vogt, B. A. (2008). Cytology and
receptor architecture of human anterior cingulate cortex. Journal of Comparative
Neurology, 508, 906926.
Palomero-Gallagher, N., Vogt, B. A., Schleicher, A., Mayberg, H. S., Schleicher, A., &
Zilles, K. (2009). Receptor architecture of human cingulate cortex: Evaluation of the
four-region neurobiological model. Human Brain Mapping, 30, 23362355.
Palomero-Gallagher, N., & Zilles, K. (2009). Transmitter receptor systems in cingulate
regions and areas. In B. A. Vogt (Ed.), Cingulate neurobiology & disease. (2nd ed.).
Infrastructure, diagnosis, treatment (Vol. 1. Oxford: Oxford University Press.
Rizzolatti, G., Luppino, G., & Matelli, M. (1996). The classic supplementary motor area
is formed by two independent areas. In H. O. Luders (Ed.), Supplementary
sensorimotor area (pp. 4556). Philadelphia, PA: Lippincott-Raven.
Rottschy, C., Eickhoff, S. B., Schleicher, A., Mohlberg, H., Kujovic, M., Zilles, K., et al.
(2007). Ventral visual cortex in humans: Cytoarchitectonic mapping of two
extrastriate areas. Human Brain Mapping, 28, 10451059.
Sanides, F. (1962). Die Architektonik des menschlichen Stirnhirns. Berlin, Gottingen,
Heidelberg: Springer Verlag.
Sanides, F. (1964). The cyto-myeloarchitecture of the human frontal lobe and its
relation to phylogenetic differentiation of the cerebral cortex. Journal fur
Hirnforschung, 7, 269282.
155
156
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Myeloarchitecture and Maps of the Cerebral Cortex
Wilms, M., Eickhoff, S. B., Homke, L., Rottschy, C., Kujovic, M., Amunts, K., et al.
(2010). Comparison of functional and cytoarchitectonic maps of human visual areas
V1, V2, V3d, V3v, and V4(v). NeuroImage, 49, 11711179.
Zilles, K., & Amunts, A. (2014). Architecture of the cerebral cortex. In J. K. Mai & G.
Paxinos (Eds.), The human nervous system (pp. 836895). (3rd ed.). Amsterdam:
Academis Press.
Zilles, K., & Amunts, K. (2010). Centenary of Brodmanns mapconception and fate.
Nature Reviews. Neuroscience, 11, 139145.
Zilles, K., & Clarke, S. (1997). Architecture, connectivity, and transmitter receptors of
human extrastriate visual cortex. Comparison with nonhuman primates. Cerebral
Cortex, 12, 673742.
Zilles, K., Schlaug, G., Geyer, S., Luppino, G., Matelli, M., Qu, M., et al. (1996).
Anatomy and transmitter receptors of the supplementary motor areas in the human
and nonhuman primate brain. In H. O. Luders (Ed.), Supplementary sensorimotor
area (pp. 2943). Philadelphia, PA: Lippincott-Raven.
Introduction
Methodology
http://dx.doi.org/10.1016/B978-0-12-397025-1.00210-4
157
158
700
600
500
400
300
200
100
1955
1958
1959
1960
1961
1962
1963
1964
1966
1967
1968
1969
1970
1971
1972
1973
1954
1975
1976
1977
1978
1979
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
159
contrast (Van Essen & Glasser, 2014; Figure 2). This lower
intensity gradient has a consequence for surface extraction algorithms, tending to move the GM/WM surface outward and
indicating a thinner cortex. Unless explicitly accounted for in
the cortical thickness algorithm, such spatial variations in myelin content and GM/WM contrast can introduce a spatially
varying cortical thickness where none exists. Such artifacts
force us to consider the underlying architectonic organization
of the human cortex and its relationship to the MRI signal.
T1 maps resemble myelin-stained histology (Geyer, Weiss,
Riemann, Lohmann, & Turner, 2011; Turner & Geyer, 2014),
and myelo- and cytoarchitectural boundaries have been shown
to be similar using a combination of T1-weighted and
Figure 2 Myelin content estimated by taking the voxelwise ratio of T1W (a) to T2W (b) and colorizing (c). (d) Myelin map on the inflated right
hemisphere of the same subject, including heavily myelinated hot spots centered on the area MT (black/white arrow) and in the intraparietal sulcus
(red arrow). Reproduced from Van Essen, D. C., & Glasser, M. F. (2014). In vivo architectonics: A cortico-centric perspective. Neuroimage,
93(Pt 2), 157164.
160
coupling (Raznahan, Lerch, et al., 2011). Frontotemporal association cortices showed the strongest and most widespread maturational coupling with other cortical areas, while lower-order
sensory cortices showed the least. This work was extended
(Alexander-Bloch, Raznahan, Bullmore, & Giedd, 2013) to
reveal substantial overlap between anatomical, maturational,
and functional networks in the developing brain.
He, Chen, and Evans (2007) adopted an ROI-based
approach to generate a full N N correlation matrix of all
possible region pairs, albeit at lower spatial resolution. Graph
analysis was then used to capture topological indices for these
cortical networks. Chen, He, Rosa-Neto, Germann, and Evans
(2008), Chen, He, Rosa-Neto, Gong, and Evans (2011), and
Chen, Panizzon, et al. (2011) took this further to reveal an
underlying modularity that reflected well-known functional
systems in the young, healthy brain and that was reduced in
the normal aging brain.
It is not yet clear what cellular mechanisms give rise to the
macroscopic cortical thickness correlation observed with MRI.
Gong, He, Chen, and Evans (2012) compared cortical thickness correlation and probabilistic tractography and found that
3540% of thickness correlations converged with a tractography connection. Convergence was mostly found for positive
correlations while almost all of the negative correlations
(>90%) had no corresponding tractography connection. Different mechanisms may therefore underlie positive and negative thickness correlations, the latter not being mediated by a
direct fiber pathway. Also, since both methods suffer from
methodological limitations, the two techniques may be revealing complementary characteristics of a more complete description of brain connectivity.
600
1900
2.8
2000
2.9
161
550
1800
2.7
500
1700
10
15
Age
20
10
15
Age
20
10
15
Age
20
Figure 3 Developmental trajectories of cortical thickness, total surface area, and overall cortical volume. Reproduced from Wierenga, L. M., Langen,
M., Oranje, B. & Durston, S. (2014). Unique developmental trajectories of cortical thickness and surface area. NeuroImage, 87, 120126.
http://www.ncbi.nlm.nih.gov/pubmed/24246495.
Applications
There is now a huge literature on clinical and basic applications
of cortical morphometry, in general, and cortical thickness
analysis, in particular, notably in the following areas:
Neurodevelopment: Giedd et al. (1999), Gogtay and
Thompson (2010), Gogtay et al. (2004), Lerch et al. (2006),
Sowell, Thompson, Leonard, et al. (2004), Sowell, Thompson,
and Toga (2004), Thompson et al. (2005), Toga, Thompson,
and Sowell (2006), Raznahan, Lerch, et al. (2011), Raznahan,
Shaw, et al. (2011), Wierenga et al. (2014), Zhou, Lebel, Evans,
and Beaulieu (2013), Lawson, Duda, Avants, Wu, and Farah
(2013), Dennis and Thompson (2013), Khundrakpam et al.
(2013), Alexander-Bloch, Raznahan, et al. (2013), and
Burgaleta, Johnson, Waber, Colom, and Karama (2014).
Gender and aging: Salat et al. (2004), Im et al. (2006, 2008),
Luders, Narr, Thompson, Rex, Jancke, et al. (2006), Luders,
Narr, Thompson, Rex, Woods, et al. (2006), Sowell et al.
(2007), Ecker et al. (2009), Fjell et al. (2009), Lv et al.
(2010), Thambisetty et al. (2010), Chen, Panizzon, et al.
(2011), Chen, He, et al. (2011), Yao, Hu, Liang, Zhao, and
Jackson (2012), Creze et al. (2013), Gautam, Cherbuin,
Sachdev, Wen, and Anstey (2013), and van Velsen et al. (2013).
Cognition and IQ: Giedd et al. (1999), Fjell et al. (2006),
Lerch et al. (2006), Choi et al. (2008), Dickerson et al. (2008),
Andersson, Ystad, Lundervold, and Lundervold (2009),
162
Conclusions
It is apparent that cortical surface morphometry is a booming
industry, with a continuous stream of new methodological
advances and applications in neurology, psychiatry, and developmental neurobiology and cognitive neuroscience. However,
there are also numerous areas where basic assumptions can be
called into question, most notably in the very definition of
cortical thickness, as derived from structural MRI. Such issues
should not be seen as a fundamental flaw in the methodology
but as a caution upon the interpretation of the data. Many
important new insights have arisen from the ability to capture,
noninvasively and automatically, longitudinal and crosssectional measures of cortical morphology at every point on
the brain surface. Some of the concerns regarding the accuracy
of absolute values of cortical thickness are mitigated when one
considers the relative changes inherent in group comparison or
longitudinal studies of cortical morphometry. Of course, such
pragmatic considerations regarding current applications of the
basic techniques do not detract from the drive to improve the
techniques through the use of higher field strength (Fujimoto
et al., 2014; Lusebrink et al., 2013) or novel analytic
approaches to quantify the cortical laminar structures (Tardif
et al., 2013; Turner & Geyer, 2014). The next decade seems
likely to bring a continuing growth of cortical morphometric
methods that are increasingly able to capture the fine structure
of cortical anatomy and revolutionize the painstaking efforts of
the great early twentieth century neuroanatomists.
References
Alexander-Bloch, A., Giedd, J. N., & Bullmore, E. (2013). Imaging structural covariance between human brain regions. Nature Reviews. Neuroscience, 14(5),
322336.
Alexander-Bloch, A., Raznahan, A., Bullmore, E., & Giedd, J. (2013). The convergence
of maturational change and structural covariance in human cortical networks. The
Journal of Neuroscience, 33(7), 28892899. PubMed: 23407947.
Almeida Montes, L. G., Prado Alcantara, H., Martinez Garcia, R. B., De La Torre, L. B.,
Avila Acosta, D., & Duarte, M. G. (2013). Brain cortical thickness in ADHD: Age,
sex, and clinical correlations. Journal of Attention Disorders, 17(8), 641654.
Ameis, S. H., Ducharme, S., Albaugh, M. D., Hudziak, J. J., Botteron, K. N., Lepage, C.,
et al. (2014). Cortical thickness, cortico-amygdalar networks, and externalizing
behaviors in healthy children. Biological Psychiatry, 75(1), 6572.
Andersson, M., Ystad, M., Lundervold, A., & Lundervold, A. J. (2009). Correlations
between measures of executive attention and cortical thickness of left posterior
middle frontal gyrus A dichotic listening study. Behavioral and Brain Functions:
BBF, 5, 41. PubMed: 19796388.
Ashburner, J., & Friston, K. J. (2000). Voxel-based morphometry-the methods.
NeuroImage, 11, 805821.
Ashburner, J., Hutton, C., Frackowiak, R., Johnsrude, I., Price, C., & Friston, K. (1998).
Identifying global anatomical differences: Deformation-based morphometry. Human
Brain Mapping, 6(56), 348357.
Augustinack, J. C., van der Kouwe, A. J., Blackwell, M. L., Salat, D. H., Wiggins, C. J.,
Frosch, M. P., et al. (2005). Detection of entorhinal layer II using 7 Tesla [corrected]
magnetic resonance imaging. Annals of Neurology, 57(4), 489494.
Auzias, G., Colliot, O., Glaune`s, J. A., Perrot, M., Mangin, J.-F., Trouve, A., et al. (2011).
Diffeomorphic brain registration under exhaustive sulcal constraints. IEEE
Transactions on Medical Imaging, 30, 12141227.
Bazin, P. L., Weiss, M., DInse, J., Schaffer, A., Trampel, R., & Turner, R. (2014). A
computational framework for ultra-high resolution cortical segmentation at 7 T.
NeuroImage, 93, 201209.
Benetti, S., Pettersson-Yeo, W., Hutton, C., Catani, M., Williams, S. C., Allen, P., et al.
(2013). Elucidating neuroanatomical alterations in the at risk mental state and first
episode psychosis: A combined voxel-based morphometry and voxel-based cortical
thickness study. Schizophrenia Research, 150(23), 505511. PubMed: 24084578.
Bernhardt, B. C., Chen, Z., He, Y., Evans, A. C., & Bernasconi, N. (2011). Graphtheoretical analysis reveals disrupted small-world organization of cortical thickness
correlation networks in temporal lobe epilepsy. Cerebral Cortex, 21(9), 21472157.
PubMed: 21330467.
Biswal, B. B., Mennes, M., Zuo, X. N., Gohel, S., Kelly, C., & Smith, S. M. (2010).
Toward discovery science of human brain function. PNAS, 107(10), 47344739.
Brodmann, K. (1909). Vergleichende Lokalisationslehre der Grohirnrinde in ihren
Prinzipien dargestellt auf Grund des Zellenbaues. Leipzig: Barth.
Bruhl, A. B., Hanggi, J., Baur, V., Rufer, M., Delsignore, A., & Weidt, S. (2013).
Increased cortical thickness in a frontoparietal network in social anxiety disorder.
Human Brain Mapping, 35, 29662977. PubMed: 24039023.
Buchy, L., Ad-Dabbagh, Y., Lepage, C., Malla, A., Joober, R., Evans, A., et al. (2012).
Symptom attribution in first episode psychosis: A cortical thickness study.
Psychiatry Research, 203(1), 613. PubMed: 22917501.
Burgaleta, M., Johnson, W., Waber, D. P., Colom, R., & Karama, S. (2014). Cognitive
ability changes and dynamics of cortical thickness development in healthy children
and adolescents. NeuroImage, 84, 810819. PubMed: 24071525.
Burzynska, A. Z., Nagel, I. E., Preuschhof, C., Gluth, S., Backman, L., Li, S. C., et al.
(2012). Cortical thickness is linked to executive functioning in adulthood and aging.
Human Brain Mapping, 33(7), 16071620. PubMed: 21739526.
Carman, G. J., Drury, H. A., & Van Essen, D. C. (1995). Computational methods for
reconstructing and unfolding the cerebral cortex. Cerebral Cortex, 5(6), 506517.
Chen, C. H., Fiecas, M., Gutierrez, E. D., Panizzon, M. S., Eyler, L. T., Vuoksimaa, E.,
et al. (2013). Genetic topography of brain morphology. Proceedings of the National
Academy of Sciences of the United States of America, 110(42), 1708917094.
PubMed: 24082094.
Chen, C. H., Gutierrez, E. D., Thompson, W., Panizzon, M. S., Jernigan, T. L.,
Eyler, L. T., et al. (2012). Hierarchical genetic organization of human cortical surface
area. Science, 335(6076), 16341636.
163
Eickhoff, S. B., Paus, T., Caspers, S., Grosbras, M. H., Evans, A. C., Zilles, K., et al.
(2007). Assignment of functional activations to probabilistic cytoarchitectonic areas
revisited. NeuroImage, 36(3), 511521.
Eickhoff, S. B., Stephan, K. E., Mohlberg, H., Grefkes, C., Fink, G. R., & Amunts, K.
(2005). A new SPM toolbox for combining probabilistic cytoarchitectonic maps and
functional imaging data. NeuroImage, 25, 13251335 http://www2.fz-juelich.de/
inm/inm-1/spm_anatomy_toolbox.
Eskildsen, S. F., Coupe, P., Garca-Lorenzo, D., Fonov, V., Pruessner, J. C.,
Collins, D. L., et al. (2013). Prediction of Alzheimers disease in subjects with mild
cognitive impairment from the ADNI cohort using patterns of cortical thinning.
NeuroImage, 65, 511521.
Eskildsen, S. F., & Ostergaard, L. R. (2006). Active surface approach for extraction of
the human cerebral cortex from MRI. Medical Image Computing and ComputerAssisted Intervention, 4191, 823830 Eds: Larsen R, Nielsen M, Sporring J.
Eskildsen, S. F., & Ostergaard, L. R. (2007). Quantitative comparison of two cortical
surface extraction methods using MRI phantoms. Medical Image Computing and
Computer-Assisted Intervention, 4791, 409416 Eds: Ayache N, Ourselin S,
Maeder A.
Evans, A. C. (2013). Networks of anatomical covariance. NeuroImage, 80, 489504.
Eyler, L. T., Chen, C. H., Panizzon, M. S., Fennema-Notestine, C., Neale, M. C., Jak, A.,
et al. (2012). A comparison of heritability maps of cortical surface area and
thickness and the influence of adjustment for whole brain measures: A magnetic
resonance imaging twin study. Twin Research and Human Genetics, 15(3),
304314. PubMed: 22856366.
Fan, Q., Palaniyappan, L., Tan, L., Wang, J., Wang, X., Li, C., et al. (2013). Surface
anatomical profile of the cerebral cortex in obsessive-compulsive disorder: A study
of cortical thickness, folding and surface area. Psychological Medicine, 43(5),
10811091. PubMed: 22935427.
Fischl, B., & Dale, A. M. (2000). Measuring the thickness of the human cerebral cortex
from magnetic resonance images. Proceedings of the National Academy of Sciences
of the United States of America, 97(20), 1105011055. PubMed: 10984517.
Fischl, B., Rajendran, N., Busa, E., Augustinack, J., Hinds, O., Yeo, B. T., et al. (2008).
Cortical folding patterns and predicting cytoarchitecture. Cerebral Cortex, 18(8),
19731980.
Fischl, B., Sereno, M. I., & Dale, A. M. (1999). Cortical surface-based analysis. II:
Inflation, flattening, and a surface-based coordinate system. NeuroImage, 9(2),
195207. PubMed: 9931269.
Fjell, A. M., Walhovd, K. B., Reinvang, I., Lundervold, A., Salat, D., Quinn, B. T., et al.
(2006). Selective increase of cortical thickness in high-performing elderly
Structural indices of optimal cognitive aging. NeuroImage, 29(3), 984994.
PubMed: 16176876.
Fjell, A. M., Westlye, L. T., Amlien, I., Espeseth, T., Reinvang, I., Raz, N., et al. (2009).
High consistency of regional cortical thinning in aging across multiple samples.
Cerebral Cortex, 19(9), 20012012. PubMed: 19150922.
Flechsig, P. (1920). Anatomie des menschlichen Gehirns und Ruckenmarks auf
myelogenetischer Grundlage. Leipzig: Thieme.
Frick, A., Howner, K., Fischer, H., Eskildsen, S. F., Kristiansson, M., & Furmark, T.
(2013). Cortical thickness alterations in social anxiety disorder. Neuroscience
Letters, 536, 5255. PubMed: 23328446.
Fujimoto, K., Polimeni, J. R., van der Kouwe, A. J., Reuter, M., Kober, T., Benner, T.,
et al. (2014). Quantitative comparison of cortical surface reconstructions from
MP2RAGE and multi-echo MPRAGE data at 3 and 7 T. NeuroImage, 90, 6073.
Gautam, P., Cherbuin, N., Sachdev, P. S., Wen, W., & Anstey, K. J. (2013). Sex
differences in cortical thickness in middle aged and early old-aged adults:
Personality and total health through life study. Neuroradiology, 55(6), 697707.
PubMed: 23468177.
Geyer, S., Weiss, M., Riemann, K., Lohmann, G., & Turner, R. (2011). Microstructural
parcellation of the human cerebral cortex From Brodmanns post-mortem map to
in vivo mapping with high-field magnetic resonance imaging. Frontiers in Human
Neuroscience, 5, 19.
Giedd, J. N., Blumenthal, J., Jeffries, N. O., Castellanos, F. X., Liu, H., Zijdenbos, A. P.,
et al. (1999). Brain development during childhood and adolescence: A longitudinal
MRI study. Nature Neuroscience, 2(10), 861863.
Glasser, M. F., Goyal, M. S., Preuss, T. M., Raichle, M. E., & Van Essen, D. C. (2014).
Trends and properties of human cerebral cortex: Correlation with cortical myelin
content. NeuroImage, 93, 165175.
Glasser, M. F., & Van Essen, D. C. (2011). Mapping human cortical areas in vivo based
on myelin content as revealed by T1- and T2-weighted MRI. The Journal of
Neuroscience, 31(32), 1159711616.
Goebel, R. (1996). BrainVoyager: A program for analyzing and visualizing functional
and structural magnetic resonance datasets. NeuroImage, 3, S604.
Goebel, R. (1997). BrainVoyager 2.0: From 2D to 3D fMRI analysis and visualization.
NeuroImage, 5, S635.
164
Joshi, A. A., Lepore, N., Joshi, S. H., Lee, A. D., Barysheva, M., Stein, J. L., et al. (2011).
The contribution of genes to cortical thickness and volume. Neuroreport, 22(3),
101105. PubMed: 21233781.
Julkunen, V., Niskanen, E., Koikkalainen, J., Herukka, S. K., Pihlajamaki, M.,
Hallikainen, M., et al. (2010). Differences in cortical thickness in healthy controls,
subjects with mild cognitive impairment, and Alzheimers disease patients: A
longitudinal study. Journal of Alzheimers disease: JAD, 21(4), 11411151.
PubMed: 21504134.
Kabani, N., Le Goualher, G., MacDonald, D., & Evans, A. C. (2001). Measurement of
cortical thickness using an automated 3-D algorithm: A validation study.
NeuroImage, 13(2), 375380. PubMed: 11162277.
Karama, S., Ad-Dabbagh, Y., Haier, R., Deary, I., Lyttleton, O., Lepage, C., et al. (2009).
Positive association between cognitive ability and cortical thickness in a
representative US sample of healthy 6 to 18 year-olds. Intelligence, 37(2), 145155.
PubMed: 20161325.
Karama, S., Bastin, M. E., Murray, C., Royle, N. A., Penke, L., & Munoz Maniega, S.
(2013). Childhood cognitive ability accounts for associations between
cognitive ability and brain cortical thickness in old age. Molecular Psychiatry, 19,
555559. PubMed: 23732878.
Karama, S., Colom, R., Johnson, W., Deary, I. J., Haier, R., Waber, D. P., et al. (2011).
Cortical thickness correlates of specific cognitive performance accounted for by the
general factor of intelligence in healthy children aged 6 to 18. NeuroImage, 55(4),
14431453. PubMed: 21241809.
Khundrakpam, B. S., Reid, A., Brauer, J., Carbonell, F., Lewis, J., Ameis, S., et al.
(2013). Developmental changes in organization of structural brain networks.
Cerebral Cortex, 23(9), 20722085. PubMed: 22784607.
Kim, G. H., Jeon, S., Seo, S. W., Kim, M. J., Kim, J. H., Roh, J. H., et al. (2012).
Topography of cortical thinning areas associated with hippocampal atrophy (HA) in
patients with Alzheimers disease (AD). Archives of Gerontology and Geriatrics,
54(2), e122e129.
Kim, S. G., Jung, W. H., Kim, S. N., Jang, J. H., & Kwon, J. S. (2013). Disparity
between dorsal and ventral networks in patients with obsessive-compulsive
disorder: Evidence revealed by graph theoretical analysis based on
cortical thickness from MRI. Frontiers in Human Neuroscience, 7, 302. PubMed:
23840184.
Kim, J. S., Singh, V., Lee, J. K., Lerch, J., Ad-Dabbagh, Y., MacDonald, D., et al.
(2005). Automated 3-D extraction and evaluation of the inner and outer cortical
surfaces using a Laplacian map and partial volume effect classification. NeuroImage,
27(1), 210221. PubMed: 15896981.
Kriegeskorte, N., & Goebel, R. (2001). An efficient algorithm for topologically correct
segmentation of the cortical sheet in anatomical MR volumes. NeuroImage, 14(2),
329346.
Kuperberg, G. R., Broome, M. R., McGuire, P. K., David, A. S., Eddy, M., Ozawa, F., et al.
(2003). Regionally localized thinning of the cerebral cortex in schizophrenia.
Archives of General Psychiatry, 60(9), 878888. PubMed: 12963669.
Lawson, G. M., Duda, J. T., Avants, B. B., Wu, J., & Farah, M. J. (2013). Associations
between childrens socioeconomic status and prefrontal cortical thickness.
Developmental Science, 16(5), 641652. PubMed: 24033570.
Lee, J. K., Lee, J. M., Kim, J. S., Kim, I. Y., Evans, A. C., & Kim, S. I. (2006). A novel
quantitative cross-validation of different cortical surface reconstruction algorithms
using MRI phantom. NeuroImage, 31(2), 572584.
Lenroot, R. K., Schmitt, J. E., Ordaz, S. J., Wallace, G. L., Neale, M. C., Lerch, J. P., et al.
(2009). Differences in genetic and environmental influences on the human cerebral
cortex associated with development during childhood and adolescence. Human
Brain Mapping, 30(1), 163174.
Lerch, J. P., & Evans, A. C. (2005). Cortical thickness analysis examined through power
analysis and a population simulation. NeuroImage, 24(1), 163173. PubMed:
15588607.
Lerch, J. P., Pruessner, J., Zijdenbos, A. P., Collins, D. L., Teipel, S. J., Hampel, H.,
et al. (2008). Automated cortical thickness measurements from MRI can accurately
separate Alzheimers patients from normal elderly controls. Neurobiology of Aging,
29(1), 2330. PubMed: 17097767.
Lerch, J. P., Pruessner, J. C., Zijdenbos, A., Hampel, H., Teipel, S. J., & Evans, A. C.
(2005). Focal decline of cortical thickness in Alzheimers disease identified by
computational neuroanatomy. Cerebral Cortex, 15(7), 9951001. PubMed:
15537673.
Lerch, J. P., Worsley, K., Shaw, W. P., Greenstein, D. K., Lenroot, R. K., Giedd, J., et al.
(2006). Mapping anatomical correlations across cerebral cortex (MACACC)
using cortical thickness from MRI. NeuroImage, 31(3), 9931003. PubMed:
16624590.
Luders, E., Narr, K. L., Thompson, P. M., Rex, D. E., Jancke, L., & Toga, A. W. (2006).
Hemispheric asymmetries in cortical thickness. Cerebral Cortex, 16(8), 12321238.
PubMed: 16267139.
165
Rimol, L. M., Hartberg, C. B., Nesvag, R., Fennema-Notestine, C., Hagler, D. J., Jr.,
Pung, C. J., et al. (2010). Cortical thickness and subcortical volumes in
schizophrenia and bipolar disorder. Biological Psychiatry, 68(1), 4150. PubMed:
20609836.
Rimol, L. M., Nesvag, R., Hagler, D. J., Jr., Bergmann, O., Fennema-Notestine, C.,
Hartberg, C. B., et al. (2012). Cortical volume, surface area, and thickness in
schizophrenia and bipolar disorder. Biological Psychiatry, 71(6), 552560.
PubMed: 22281121.
Rimol, L. M., Panizzon, M. S., Fennema-Notestine, C., Eyler, L. T., Fischl, B.,
Franz, C. E., et al. (2010). Cortical thickness is influenced by regionally specific
genetic factors. Biological Psychiatry, 67(5), 493499. PubMed: 19963208.
Sabuncu, M. R., Buckner, R. L., Smoller, J. W., Lee, P. H., Fischl, B., & Sperling, R. A.
(2012). The association between a polygenic Alzheimer score and cortical thickness
in clinically normal subjects. Cerebral Cortex, 22(11), 26532661. PubMed:
22169231.
Salat, D. H., Buckner, R. L., Snyder, A. Z., Greve, D. N., Desikan, R. S., Busa, E., et al.
(2004). Thinning of the cerebral cortex in aging. Cerebral Cortex, 14(7), 721730.
PubMed: 15054051.
Sanabria-Diaz, G., Melie-Garca, L., Iturria-Medina, Y., Aleman-Gomez, Y.,
Hernandez-Gonzalez, G., Valdes-Urrutia, L., et al. (2010). Surface area and cortical
thickness descriptors reveal different attributes of the structural human brain
networks. NeuroImage, 50, 14971510.
Sato, J. R., Hoexter, M. Q., Oliveira, P. P., Jr., Brammer, M. J., Murphy, D., & Ecker, C.
(2013). Inter-regional cortical thickness correlations are associated with autistic
symptoms: A machine-learning approach. Journal of Psychiatric Research, 47(4),
453459. PubMed: 23260170.
Schilling, C., Kuhn, S., Paus, T., Romanowski, A., Banaschewski, T., Barbot, A., et al.
(2013). Cortical thickness of superior frontal cortex predicts impulsiveness and
perceptual reasoning in adolescence. Molecular Psychiatry, 18(5), 624630.
PubMed: 22665261.
Schilling, C., Kuhn, S., Romanowski, A., Schubert, F., Kathmann, N., & Gallinat, J.
(2012). Cortical thickness correlates with impulsiveness in healthy adults.
NeuroImage, 59(1), 824830. PubMed: 21827861.
Schmitt, J. E., Lenroot, R., Ordaz, S. E., Wallace, G. L., Lerch, J. P., Evans, A. C., et al.
(2009). Variance decomposition of MRI-based covariance maps using geneticallyinformative samples and structural equation modeling. NeuroImage, 47(1), 5664.
Schmitt, J. E., Lenroot, R. K., Wallace, G. L., Ordaz, S., Taylor, K. N., Kabani, N., et al.
(2008). Identification of genetically mediated cortical networks: A multivariate study
of pediatric twins and siblings. Cerebral Cortex, 18, 17371747.
Schmitt, J. E., Wallace, G. L., Lenroot, R. K., Ordaz, S. E., Greenstein, D., Clasen, L.,
et al. (2010). A twin study of intracerebral volumetric relationships. Behavior
Genetics, 40, 114124.
Schnack, H. G., van Haren, N. E., Brouwer, R. M., van Baal, G. C., Picchioni, M.,
Weisbrod, M., et al. (2010). Mapping reliability in multicenter MRI: Voxel-based
morphometry and cortical thickness. Human Brain Mapping, 12, 19671982.
Schultz, C. C., Koch, K., Wagner, G., Roebel, M., Nenadic, I., Schachtzabel, C., et al.
(2010). Complex pattern of cortical thinning in schizophrenia: Results from an
automated surface based analysis of cortical thickness. Psychiatry Research, 182(2),
134140. PubMed: 20418074.
Scott, M. L., Bromiley, P. A., Thacker, N. A., Hutchinson, C. E., & Jackson, A. (2009). A
fast, model-independent method for cerebral cortical thickness estimation using
MRI. Medical Image Analysis, 13(2), 269285. PubMed: 19068276.
Shaw, P., Lerch, J., Greenstein, D., Sharp, W., Clasen, L., Evans, A., et al. (2006).
Longitudinal mapping of cortical thickness and clinical outcome in children and
adolescents with attention-deficit/hyperactivity disorder. Archives of General
Psychiatry, 63(5), 540549. PubMed: 16651511.
Sowell, E. R., Peterson, B. S., Kan, E., Woods, R. P., Yoshii, J., Bansal, R., et al. (2007).
Sex differences in cortical thickness mapped in 176 healthy individuals
between 7 and 87 years of age. Cerebral Cortex, 17(7), 15501560. PubMed:
16945978.
Sowell, E. R., Thompson, P. M., Leonard, C. M., Welcome, S. E., Kan, E., & Toga, A. W.
(2004). Longitudinal mapping of cortical thickness and brain growth in normal
children. The Journal of Neuroscience: The Official Journal of the Society for
Neuroscience, 24(38), 82238231.
Sowell, E. R., Thompson, P. M., & Toga, A. W. (2004). Mapping changes in the human
cortex throughout the span of life. The Neuroscientist: A Review Journal Bringing
Neurobiology, Neurology and Psychiatry, 10(4), 372392.
Stam, C., Jones, B., Nolte, G., Breakspear, M., & Scheltens, P. (2007). Small-world
networks and functional connectivity in Alzheimers disease. Cerebral Cortex, 17,
9299.
Tardif, C. L., Dinse, J., Schafer, A., Turner, R., & Pl, B. (2013). Multi-modal surfacebased alignment of cortical areas using intra-cortical T1 contrast. In L. Shen, T.
Liu, P. T. Yap, H. Huang, D. Shen & C. F. Westin (Eds.), Multimodal brain image
166
van Velsen, E. F., Vernooij, M. W., Vrooman, H. A., van der Lugt, A., Breteler, M. M.,
Hofman, A., et al. (2013). Brain cortical thickness in the general elderly population:
The Rotterdam Scan Study. Neuroscience Letters, 550, 189194. PubMed:
23831346.
Vita, A., De Peri, L., Deste, G., & Sacchetti, E. (2012). Progressive loss of cortical gray
matter in schizophrenia: A meta-analysis and meta-regression of longitudinal MRI
studies. Translational Psychiatry, 2, e190. PubMed: 23168990.
Vogt, C., & Vogt, O. (1919). Allgemeinere ergebnisse unserer hirnforschung. Journal
fur Psychologie und Neurologie, 25, 292398.
von Economo, C., & Koskinas, G. N. (1925). Die Cytoarchitektonik der Hirnrinde des
Erwachsenen Menschen. Berlin: Springer.
Waehnert, M. D., Dinse, J., Weiss, M., Streicher, M. N., Waehnert, P., Geyer, S., et al.
(2014). Anatomically-motivated modelling of cortical laminae. NeuroImage, 93,
210220.
Wagner, G., Schultz, C. C., Koch, K., Schachtzabel, C., Sauer, H., & Schlosser, R. G.
(2012). Prefrontal cortical thickness in depressed patients with high-risk for suicidal
behavior. Journal of Psychiatric Research, 46(11), 14491455. PubMed:
22868048.
Walhovd, K. B., Tamnes, C. K., Ostby, Y., Due-Tonnessen, P., & Fjell, A. M. (2012).
Normal variation in behavioral adjustment relates to regional differences in cortical
thickness in children. European Child & Adolescent Psychiatry, 21(3), 133140.
PubMed: 22302474.
Wang, X., Bauer, W., Chiaia, N., Dennis, M., Gerken, M., Hummel, J., et al. (2008).
Longitudinal MRI evaluations of human global cortical thickness over minutes to
weeks. Neuroscience Letters, 441(2), 145148. PubMed: 18603368.
Wang, L., Shi, F., Li, G., & Shen, D. (2013). 4D segmentation of brain MR images with
constrained cortical thickness variation. PLoS One, 8(7), e64207. PubMed:
23843934.
Wierenga, L. M., Langen, M., Oranje, B., & Durston, S. (2014). Unique developmental
trajectories of cortical thickness and surface area. NeuroImage, 87, 120126.
PubMed: 24246495.
Yang, X. R., Carrey, N., Bernier, D., & Macmaster, F. P. (2012). Cortical thickness in
young treatment-naive children with ADHD. Journal of Attention Disorders. http://
dx.doi.org/10.1177/1087054712455501 PubMed: 22912507.
Yang, Y., Joshi, A. A., Joshi, S. H., Baker, L. A., Narr, K. L., Raine, A., et al. (2012).
Genetic and environmental influences on cortical thickness among 14-year-old
twins. Neuroreport, 23(12), 702706. PubMed: 22713927.
Yao, Z., Hu, B., Liang, C., Zhao, L., & Jackson, M. (2012). A longitudinal study of
atrophy in amnestic mild cognitive impairment and normal aging revealed by
cortical thickness. PLoS One, 7(11), e48973. PubMed: 23133666.
Yezzi, A. J., & Prince, J. L. (2003). An Eulerian PDE approach for computing tissue
thickness. IEEE Transactions on Medical Imaging, 22, 10.
Yoon, U., Fahim, C., Perusse, D., & Evans, A. C. (2010). Lateralized genetic and
environmental influences on human brain morphology of 8-year old pediatric twins.
NeuroImage, 53(3), 11171125.
Yoon, U., Perusse, D., & Evans, A. C. (2012). Mapping genetic and environmental
influences on cortical surface area of pediatric twins. Neuroscience, 220, 169178.
Zhou, D., Lebel, C., Evans, A., & Beaulieu, C. (2013). Cortical thickness
asymmetry from childhood to older adulthood. NeuroImage, 83, 6674. PubMed:
23827331.
Ziegler, D. A., Piguet, O., Salat, D. H., Prince, K., Connally, E., & Corkin, S. (2010).
Cognition in healthy aging is related to regional white matter integrity, but
not cortical thickness. Neurobiology of Aging, 31(11), 19121926. PubMed:
19091444.
Zilles, K., & Amunts, K. (2009). Receptor mapping: Architecture of the human cerebral
cortex. Current Opinion in Neurology, 22, 331339.
Glossary
Abbreviations
PP
P-SP
SP
SPr
SVZ
VZ
WM
CP
CX
ECM
IZ
MZ
PCW
Cortical plate
Cerebral cortex
Extracellular matrix
Intermediate zone
Marginal zone
Postconceptional weeks
The cerebral cortex originates from the wall of the prosencephalon, which develops during the fourth postconceptional week
(PCW; His, 1904; ORahilly & Muller, 2006). The first step in
complex morphogenesis and histogenesis of the cerebral cortex
Preplate
Presubplate
Subplate zone
Subplate remnant
Subventricular zone
Ventricular zone
White matter
is the formation of two lateral evaginations of the prosencephalon, that is, the formation of telencephalic (endbrain)
vesicles, which differentiate into dorsal thin neuroepithelial
wall (pallium) and thickened basal portion (subpallium).
http://dx.doi.org/10.1016/B978-0-12-397025-1.00193-7
167
168
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Embryonic and Fetal Development of the Human Cerebral Cortex
fetal period, undergoes a series of transient patterns of organization, and displays plasticity during the entire lifespan
(Figure 1). While all histogenetic events contribute to the formation of transient and/or permanent neuronal circuitry in a
significantly overlapping manner, their intensity varies or may
be even limited to a certain developmental period (Figure 1).
Thus, the functional organization of the brain and the mode of
its interaction with environmental factors and influences also
vary in different developmental periods. Therefore, certain
developmental periods may be described as sensitive/critical
periods characterized by increased vulnerability for adverse
intrinsic and extrinsic pathogenetic influences.
The proper number of cortical neurons is produced by
mitotic divisions (proliferation) of progenitor neuroepithelial
cells within two proliferative zones (ventricular zone (VZ) and
subventricular zone (SVZ)) aptly described as the factories of the
cortex (Bystron, Blakemore, & Rakic, 2008). In the VZ, progenitor cells divide asynchronously; during the DNA replication
phase, their nuclei move away from the VZ surface and then
move back to undergo another mitotic cycle (Rakic, 1988).
During the early embryonic period, progenitor neuroepithelial
cells span the entire thickness of the cerebral wall and undergo
symmetrical divisions, thus doubling the progenitor pool by
each cycle of mitosis. The onset of corticogenesis is marked by
the beginning of asymmetrical progenitor divisions, which give
rise to young postmitotic neurons and glial cells. Radial glial cells
are generated early and serve not only as radial guides for migration of principal (pyramidal) neurons (http://rakiclab.med.yale.
edu/research/index.aspx) but also as neural stem cells (Bystron
et al., 2008; Fishell & Kriegstein, 2003). Neurons are also being
produced in subsequently formed SVZ (Figure 2), which is
Figure 1 Developmental periods of occurrence and intensity of main neurogenetic events in cortical histogenesis. Note the predominance of
proliferation and migration during the first trimester, growth of axons and dendrites during the second and third trimesters, and prolonged postnatal
synaptogenesis, myelination, and neurochemical maturation.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Embryonic and Fetal Development of the Human Cerebral Cortex
169
Figure 2 Sequential development of transient laminar compartments in the neocortical cerebral wall from early embryonic (a) to late fetal period (g)
when six-layered pattern and subplate remnant coexist. Proliferative zones (ventricular zone,VZ and subventricular zone, and SVZ) shown in green; early
synaptic and postmitotic layers with postmigratory neurons (preplate, PP; subplate zone, SP; marginal zone, and MZ) shown in blue; connectivity layer
with postmigratory neurons (cortical plate, CP) shown in gray; axon strata (fetal white matter) shown in red; progenitor cells green, early-differentiating
neurons of MZ and SP blue, CP neurons and migratory neurons black, and glia brown.
Molecular specification of cerebral cortical neurons is commonly divided in two major processes: the areal specification
and the specification of subsets of cortical neurons. According
to the protomap hypothesis (Rakic, 1988, 1995), areal and
laminar position and the cellular phenotype of cortical neurons are specified at the time of their last (asymmetrical) division in proliferative zones. The areal position is specified by
signaling molecules secreted from several patterning centers,
such as the commissural plate and the cortical hem (OLeary,
Chou, & Sahara, 2007). Members of the Fgf family are secreted
from the commissural plate and involved in the specification
of anteriorposterior axis, while members of the Wnt and Bmp
families are secreted from cortical hem and involved in the
specification of posteromedial cortical areas including the hippocampus. Furthermore, the sonic hedgehog is expressed in
the ventral telencephalon and hypothalamus and important
for the specification of the basal telencephalon and subpallium. Other signaling molecules are secreted from the antihem
located between the paleocortical and striatal primordia
(Mallamaci, 2011). These signaling molecules function
through dose-dependent activation of various transcriptional
factors in VZ and SVZ neuronal progenitors, which, combined
with gradient expression of other signaling molecules, creates a
multitude of possible outcomes (Mallamaci, 2011; OLeary
et al., 2007). The specification of subsets of cortical neurons
is regulated by a wealth of recently described genes (Bayatti
et al., 2008; Kwan, Sestan, & Anton, 2012; Mallamaci, 2011;
Molyneaux, Arlotta, Menezes, & Macklis, 2007; Wang
170
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Embryonic and Fetal Development of the Human Cerebral Cortex
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Embryonic and Fetal Development of the Human Cerebral Cortex
endogenous neuronal circuitry, which is nonsensory-driven
and experience-independent. However, it is generally accepted
that such early spontaneous neural activity plays an important
role in the developmental shaping of neuronal circuitry
(Allendoerfer & Shatz, 1994; Kanold & Luhmann, 2010;
Kostovic & Judas, 2010).
Between the 12th and 14th PCW, the deep portion of the
neocortical CP becomes loosely organized and transforms into a
(a)
171
(b)
(c)
(d)
(e)
1 2 3
(f)
(g)
(h)
(i)
Figure 3 Transient midfetal pattern of cerebral wall lamination as revealed by histological (a), histochemical (c), and T1-weighted MRI (b) of the
in vitro human fetal brain. Arrowheads indicate the border between the intermediate zone (fetal white matter) and the subplate (the thickest cortical
compartment). Reproduced with permission from Kostovic, I., Judas, M., Rados, M., & Hrabac, P. (2002). Laminar organization of the human
fetal cerebrum revealed by histochemical markers and magnetic resonance imaging. Cerebral Cortex, 12, 536544.
172
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Embryonic and Fetal Development of the Human Cerebral Cortex
Figure 4 Development of cortical axon pathways in the human fetus. Analysis of sequential development using different histochemical markers and
diffuse tensor MRI techniques can reveal nuclei of origin, pathway selection, waiting with synaptic engagement in the subplate, and ingrowth into
the cortical plate. (a) 10th, 5th PCW, (b) 20th PCW, (c) 23rd PCW, and (d) 28th PCW.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Embryonic and Fetal Development of the Human Cerebral Cortex
173
I
II
FI
III
FII
FI
FIII
FII
IV
FIII
MZ
FIV
FIV
FV
FV
CP
VI
FVI
FVI
MZ
CP
SP
CP
MZ
CP
SPU
SPP
SPL
SP
SP
WM
IZ
IZ
IZ
SP
SP
MZ
IZ
WM
SV
V
10.5 w
13.5 w
17 w
1925 w
2629 w
3234 w
Newborn
Figure 5 Composite drawing of differentiating neurons stained with Golgi method in the human prenatal prefrontal cortex. Note early differentiation of
subplate and marginal zone neurons and acceleration of dendritic development of cortical pyramidal neurons during the last trimester of gestation.
Reproduced with permission from Mrzljak, L., Uylings, H. B. M., Kostovic, I., & Van Eden, C. G. (1988). Prenatal development of neurons in
the human prefrontal cortex: I. A qualitative Golgi study. Journal of Comparative Neurology, 271, 355386.
of prematurely born infants. This phase of cortical development is characterized by several new features: the onset of
gyrification, the peak of subplate development (which receives
new contingents of growing callosal and associative pathways),
the onset of lamination within the CP that reflects the
ingrowth of thalamocortical fibers, and dendritic maturation
of pyramidal neurons (Figure 5). Clinically and functionally,
the most relevant event is the appearance of thalamocortical
synapses within the CP (Kostovic & Judas, 2007, 2010;
Molliver et al., 1973), which are the substrate for early-evoked
potentials and cortical responses to pain stimuli. During establishment of permanent thalamocortical synapses, some thalamic axons retain transient contact with subplate neurons
(Allendoerfer & Shatz, 1994). Thus, there is prolonged coexistence of transient and permanent circuitry in the developing human neocortex (Kostovic & Judas, 2007). In the
hippocampus, there is rapid differentiation of pyramidal neurons with intensive synaptogenesis along their apical dendrites.
During this period, there is a gradual cessation of neuronal
proliferation and migration, with gradual disappearance of the
VZ and SVZ. Both astrocytes and oligodendrocytes are being
produced in large numbers, while initial areal differentiation
enables distinction between primary and associative cortical
areas (Kostovic & Rakic, 1984, 1990).
During the second part of the late fetal period (33rd PCW
onward), three major events are the transformation of fetal
zones, the change in MRI properties (due to gradual reduction
of extracellular matrix and isotropy changes caused by axonal
rearrangements), and expansive growth of the white matter.
Cortical white matter predominantly increases due to abundance and intense growth of corticocortical pathways. Within
the neocortex, a six-layered basic pattern of lamination is
clearly observed, concomitantly with the formation of secondary gyri and sulci and initial development of hemispheric
174
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Embryonic and Fetal Development of the Human Cerebral Cortex
References
Allendoerfer, K. L., & Shatz, C. J. (1994). The subplate, a transient neocortical structure:
Its role in the development of connections between thalamus and cortex. Annual
Review of Neuroscience, 17, 185218.
Bayatti, N., Moss, J. A., Sun, L., Ambrose, P., Ward, J. F., Lindsay, S., et al. (2008). A
molecular neuroanatomical study of the developing human neocortex from 8 to 17
postconceptional weeks revealing the early differentiation of the subplate and
subventricular zone. Cerebral Cortex, 18, 15361548.
Bystron, I., Blakemore, C., & Rakic, P. (2008). Development of human cerebral cortex:
Boulder Committee revisited. Nature Reviews Neuroscience, 9, 110122.
Boulder Committee. (1970). Embryonic vertebrate central nervous system: Revised
terminology. Anatomical Record, 166, 257262.
Fishell, G., & Kriegstein, A. R. (2003). Neurons from radial glia: The
consequences of asymmetric inheritance. Current Opinion in Neurobiology, 13, 3441.
Hevner, R. F., & Kinney, H. C. (1996). Reciprocal entorhinal-hippocampal connections
established by human fetal midgestation. Journal of Comparative Neurology, 372,
384394.
His, W. (1904). Die Entwickelung des menschlichen Gehirns wahrend der ersten
Monate. Leipzig: Hirzel.
Jakovcevski, I., Filipovic, R., Mo, Z., Rakic, S., & Zecevic, N. (2009). Oligodendrocyte
development and the onset of myelination in the human fetal brain. Frontiers in
Neuroanatomy, 3, 115.
Judas, M., Sedmak, G., & Kostovic, I. (2013). The significance of the subplate for
evolution and developmental plasticity of the human brain. Frontiers in Human
Neuroscience, 7, 423.
Judas, M., Sedmak, G., & Pletikos, M. (2010). Early history of subplate and interstitial
neurons: From Theodor Meynert (1867) to the discovery of the subplate zone
(1974). Journal of Anatomy, 217, 344367.
Judas, M., Sedmak, G., Pletikos, M., & Jovanov-Milosevic, N. (2010). Populations of
subplate and interstitial neurons in fetal and adult human telencephalon. Journal of
Anatomy, 217, 381399.
Kanold, P. O., & Luhmann, H. J. (2010). The subplate and early cortical circuits. Annual
Review of Neuroscience, 33, 2348.
Kostovic, I., Jovanov-Milosevic, N., Rados, M., Sedmak, G., Benjak, V.,
Kostovic-Srzentic, M., et al. (2012). Perinatal and early postnatal reorganization of
the subplate and related cellular compartments in the human cerebral wall as
revealed by histological and MRI approaches. Brain Structure and Function. http://
dx.doi.org/10.1007/s00429-012-0496-0490.
Kostovic, I., & Judas, M. (2007). Transient patterns of cortical lamination during
prenatal life: Do they have implications for treatment? Neuroscience and
Biobehavioral Reviews, 31, 11571168.
Kostovic, I., & Judas, M. (2010). The development of the subplate and
thalamocortical connections in the human foetal brain. Acta Paediatrica, 99,
11191127.
Kostovic, I., Judas, M., Rados, M., & Hrabac, P. (2002). Laminar organization of the
human fetal cerebrum revealed by histochemical markers and magnetic resonance
imaging. Cerebral Cortex, 12, 536544.
Kostovic, I., & Molliver, M. E. (1974). A new interpretation of the laminar development
of cerebral cortex: Synaptogenesis in different layers of neopallium in the human
fetus. Anatomical Record, 178, 395.
Kostovic, I., Petanjek, Z., & Judas, M. (1993). Early areal differentiation of the human
cerebral cortex: Entorhinal area. Hippocampus, 3, 447458.
Kostovic, I., & Rakic, P. (1980). Cytology and time of origin of interstitial neurons in the
white matter in infant and adult human and monkey telencephalon. Journal of
Neurocytology, 9, 219242.
Kostovic, I., & Rakic, P. (1984). Development of prestriate visual projections in the
monkey and human fetal cerebrum revealed by transient cholinesterase staining.
Journal of Neuroscience, 4, 2542.
Kostovic, I., & Rakic, P. (1990). Developmental history of the transient subplate zone in
the visual and somatosensory cortex of the macaque monkey and human brain.
Journal of Comparative Neurology, 297, 441470.
Kostovic, I., Seress, L., Mrzljak, L., & Judas, M. (1989). Early onset of synapse
formation in the human hippocampus: A correlation with Nissl-Golgi architectonics
in 15- and 16.5-week-old fetuses. Neuroscience, 30, 105116.
Kwan, K. Y., Sestan, N., & Anton, E. S. (2012). Transcriptional co-regulation of
neuronal migration and laminar identity in the neocortex. Development, 139,
15351546.
Mallamaci, A. (2011). Molecular bases of cortico-cerebral regionalization. Progress in
Brain Research, 189, 3764.
Marin-Padilla, M. (1978). Dual origin of the mammalian neocortex and evolution of the
cortical plate. Anatomy and Embryology, 152, 109126.
Meyer, G. (2007). Genetic control of neuronal migrations in human cortical
development. Advances in Anatomy Embryology and Cell Biology, 189, 1111.
Meyer, G., Schaaps, J. P., Moreau, L., & Goffinet, A. M. (2000). Embryonic and early
fetal development of the human neocortex. Journal of Neuroscience, 20,
18581868.
Molliver, M. E., Kostovic, I., & Van der Loos, H. (1973). The development of synapses
in cerebral cortex of the human fetus. Brain Research, 50, 403407.
Molnar, Z., Metin, C., Stoykova, A., Tarabykin, V., Price, D. J., Francis, F., et al. (2006).
Comparative aspects of cerebral cortical development. European Journal of
Neuroscience, 23, 921934.
Molyneaux, B. J., Arlotta, P., Menezes, J. R. L., & Macklis, J. D. (2007). Neuronal
subtype specification in the cerebral cortex. Nature Reviews Neuroscience, 8,
427437.
Monnier, A., Adle-Biassette, H., Delezoide, A. L., Evrard, P., Gressens, P., & Verney, C.
(2007). Entry and distribution of microglial cells in human embryonic and fetal
cerebral cortex. Journal of Neuropathology and Experimental Neurology, 66,
372382.
Monnier, A., Evrard, P., Gressens, P., & Verney, C. (2006). Distribution and
differentiation of microglia in the human encephalon during the first two trimesters
of gestation. Journal of Comparative Neurology, 499, 565582.
Mrzljak, L., Uylings, H. B. M., Kostovic, I., & Van Eden, C. G. (1988). Prenatal
development of neurons in the human prefrontal cortex: I. A qualitative Golgi study.
Journal of Comparative Neurology, 271, 355386.
OLeary, D. D., Chou, S. J., & Sahara, S. (2007). Area patterning of the mammalian
cortex. Neuron, 56, 252269.
ORahilly, R., & Muller, F. (2006). The embryonic human brain. An atlas of
developmental stages (3rd ed.). New York: Wiley-Liss.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Embryonic and Fetal Development of the Human Cerebral Cortex
Petanjek, Z., Judas, M., Kostovic, I., & Uylings, H. B. M. (2008). Life-span alterations of
basal dendritic trees of pyramidal neurons in the human prefrontal cortex: A layerspecific pattern. Cerebral Cortex, 18, 915929.
Petanjek, Z., Judas, M., Simic, G., Rasin, M. R., Uylings, H. B., Rakic, P., et al. (2011).
Extraordinary neoteny of synaptic spines in the human prefrontal cortex.
Proceedings of the National Academy of Sciences of the United States of America,
108, 1328113286.
Prayer, D., Kasprian, C., Krampl, E., Ulm, B., Witzani, L., Prayer, L., et al. (2006). MRI of
normal fetal brain development. European Journal of Radiology, 57, 199216.
Rakic, P. (1972). Mode of cell migration to the superficial layers of fetal monkey
neocortex. Journal of Comparative Neurology, 145, 6184.
Rakic, P. (1977). Prenatal development of the visual system in the rhesus monkey.
Philosophical Transactions of the Royal Society of London, Series B, 278, 245260.
Rakic, P. (1988). Specification of cerebral cortical areas. Science, 241, 170176.
Rakic, P. (1995). A small step for the cell: A giant leap for mankind A
hypothesis of neocortical expansion during evolution. Trends in Neurosciences, 18,
383388.
175
Rickmann, M., Chronwall, B. M., & Wolff, J. R. (1977). On the development of nonpyramidal neurons and axons outside the cortical plate: The early marginal zone as a
pallial anlage. Anatomy and Embryology, 151, 285307.
Schmechel, D. E., & Rakic, P. (1979). A Golgi study of radial glia cells in developing
monkey telencephalon: Morphogenesis and transformation into astrocytes. Anatomy
and Embryology, 156, 115152.
Verney, C., Monnier, A., Fallet-Bianco, C., & Gressens, P. (2010). Early microglial
colonization of the human forebrain and possible involvement in periventricular
white-matter injury of preterm infants. Journal of Anatomy, 217, 436448.
Volpe, J. J. (1996). Subplate neurons missing link in brain injury of the premature
infant? Pediatrics, 97, 112113.
Wang, W. Z., Hoerder-Suabedissen, A., Oeschger, F. M., Bayatti, N., Ipes, B. K.,
Lindsay, S., et al. (2010). Subplate in the developing cortex of mouse and human.
Journal of Anatomy, 217, 368380.
Zecevic, N., & Verney, C. (1995). Development of catecholamine neurons in human
embryos and fetuses, with special emphasis on the innervation of the cerebral
cortex. Journal of Comparative Neurology, 351, 509535.
Glossary
Language development in humans occurred as a direct consequence of the functional specialization of cortical areas located
in the temporal (i.e., Wernickes region) and frontal lobes (i.e.,
Brocas region) of the left hemisphere. These areas are primarily dedicated to language and for this reason are identified as
core language regions. Other more bilaterally distributed cortical areas connect to these left-lateralized core regions and
form an extended language network. In this article, we aim
to introduce the reader to current approaches used to map the
main language areas as defined by cytoarchitectonics, receptorarchitectonics, and their networks as defined by in vivo diffusion tractography. Although our approach is fundamentally
anatomical, we refer to possible functional correlates and associated symptoms whenever possible.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00211-6
177
178
Figure 1 Cortical mapping of Brocas region based on postmortem cytoarchitectonic and receptorarchitectonic analyses. (a) Top, surface view of the
probabilistic maps for Brodmanns area 44 (BA 44) and Brodmanns area 45 (BA 45) derived from quantitative cytoarchitectonic measurements of
ten individual brains. The probabilistic maps are intended to quantify the interindividual variability of the areas that compose Brocas region, where hot
tones correspond to a high anatomical overlap and cold tones to higher variability. This interindividual variability can be appreciated in the bottom
panel, where the left and right maps for BA 44 (red) and BA 45 (yellow) are reported for two representative brains. Note, for example, the difference in the
leftright asymmetry of BA 44 and BA 45. In addition, the borders of the two areas are not always well identified by the main sulci of this region:
inferior frontal sulcus (IFS), horizontal ramus of the lateral fissure (HRLF), ascending ramus of the lateral fissure (ARLF), precentral sulcus (PrCS),
diagonal sulcus (DS). (The data are from Amunts et al., 2004.) (b) Further segregation of Brocas region based on neurotransmitter receptor distribution.
This analysis can reveal unique characteristics of subregions that may share similar cytoarchitectonic morphology. Areas 44v and op8, for
example, have a similar density of GABAA or alternately GABAA receptors but different density of cholinergic muscarinic receptors M1.
179
Figure 2 The cluster tree illustrates similarities between frontal areas based on their receptor distribution profile. Modified from Amunts, K., Lenzen,
M., Friederici, A. D., Schleicher, A., Morosan, P., Palomero-Gallagher, N., et al. (2010). Brocas region: Novel organizational principles and multiple
receptor mapping. PLoS Biology, 8, e1000489.
#1
#2
#3
#4
#5
#1 #2 #3 #4 #5
Te1
Te2
Te3
Te1.0
(b)
(c)
Te2
Te1.1
Te2
(e)
(d)
Te3
(a)
TI
Te4
(f)
Figure 3 The cytoarchitectonic of the language areas in the superior temporal region. Morosan, P., Schleicher, A., Amunts, K., & Zilles, K. (2005).
Multimodal architectonic mapping of human superior temporal gyrus. Anatomy and Embryology, 210, 401406.
180
Subcortical Structures
Cortical language areas form complex networks with the thalamus, basal ganglia, and cerebellum (Cappa & Vallar, 1992;
Schmahmann & Pandya, 2008; Catani & Thiebaut de Schotten,
2012). Damage to these subcortical structures can manifest with
either isolated aphasia or language deficits that are part of more
complex neurological syndromes. Anatomical and clinical studies suggest that these cortico-subcortical networks are segregated
(Figure 4). Brocas region and the preSMA, for example, receive
their main afferents from the anterior thalamus (i.e., ventral
anterior nucleus). Stuttering and reduced spontaneous speech
have been described in association with damage of the ventral
4
5
3-
1-
6
46
10
44
40
45
11
43
47
38
41
42
21
39
19
22
18
17
37
20
MD
IN
VLp
LD
LP
VA
Mid
VLa
VLm
CM
VPl
Pul
VPm
VPi
LGN
MGN
Figure 4 Thalamocortical connections of the language areas. A: Anterior group; LGN: lateral geniculate nucleus; LP: lateroposterior; MD: mediodorsal;
MGN: medial geniculate nucleus; Mid: midline group; Pul: pulvinar; VA: ventral anterior; VLa: ventral lateral anterior; VPi: ventral posterior
inferior; VPl: ventral posterior lateral; VPm: ventral posterior medial; VLp: ventral lateral posterior. Modified from Catani, M., & Thiebaut de Schotten, M.
(2012). Atlas of human brain connections. Oxford, UK: Oxford University Press.
181
has been studied in humans with postmortem blunt dissections and more extensively with diffusion imaging tractography (Figure 5(a)).
The arcuate fasciculus is a dorsal perisylvian association tract
connecting Wernickes, Geschwinds, and Brocas regions.
Within the arcuate fasciculus, two parallel pathways have been
distinguished: the medial, direct pathway connecting Wernickes
region with Brocas region (i.e., the arcuate fasciculus sensu stricto
or long segment) and the indirect pathway, consisting of an
anterior segment that links Brocas region to Geschwinds region
and a posterior segment between Geschwinds and Wernickes
regions (Catani et al., 2005). Lopez-Barroso et al. (2013) showed
that performance in word learning correlates with microstructural properties and strength of functional connectivity of the
direct connections between Brocas and Wernickes regions. This
study demonstrates that our ability to learn new words relies on
an efficient and fast communication between auditory temporal
and motor frontal regions. Schulze, Vargha-Khadem, and
Mishkin (2012) suggested that the absence of these connections
in nonhuman primates might explain our unique ability to learn
new words. The long segment is also important for syntactic
processing (Tyler et al., 2011; Wilson et al., 2011) and word
repetition (Parker Jones et al., 2014). Within the indirect pathway, the anterior and posterior segments have different roles in
reading (Thiebaut de Schotten, Cohen, Amemiya, Braga, &
Dehaene, 2014), phonological and semantic processing (Binder
et al., 2009; Newhart et al., 2012), verbal working memory
(Jacquemot & Scott, 2006), and pragmatic interpretation
(Hagoort, 2013).
Language areas of the temporal and frontal lobes are also
interconnected by a set of ventral longitudinal tracts (Catani &
Mesulam, 2008). The inferior longitudinal fasciculus carries
visual information from occipital and posterior temporal
Brocas
region
Anterior
temporal
lobe
Uncinate fasciculus
Wernickes
region
Geschwinds
region
Visual word
form area
(a)
(b)
Figure 5 Language networks visualized with diffusion tractography. (a) Association pathways of the left hemisphere connecting the main language
regions. (b) Density of callosal cortical projections based on diffusion imaging. Hot tones indicate higher degree of transcallosal connections.
Note the reduced interhemispheric connectivity for most of the language regions.
182
Conclusion
In this article, we suggest an anatomical language model
encompassing a core and an extended language network. The
core network includes the arcuate fasciculus connecting Brocas
and Wernickes regions. This network is left-lateralized in most
human brains. In addition, an extended network provides
access to social, emotional, and attentional inputs necessary
for successful language performances. One unique feature of
language as cognitive process is the extraordinary ability to
access, process, and bind together information derived from
memory and sensorial perception to create and convey
18
183
85%
Females
Number. of subjects
14
Group 1 (~60%)
Strong left lateralization
Males
10
40%
30%
30%
10%
5%
0
Group 2
Group 3
Group 1
Lateralization pattern
(b)
Group 2 (~20%)
Bilateral, left lateralization
(a)
Group 3 (~20%)
Bilateral, symmetrical
100
90
80
70
10
(c)
5
0
5
10
Right long segment (index size)
Figure 6 The distribution of the pattern of lateralization of the long segment in (a) three groups and (b) differences in lateralization between genders.
Modified from Catani, M., Allin, M. P., Husain, M., Pugliese, L., Mesulam, M. M., Murray, R. M., et al. (2007). Symmetries in human brain
language pathways correlate with verbal recall. Proceedings of the National Academy of Sciences of the United States of America, 104, 1716317168.
(c) Recovery of language 6 months after stroke is correlated with the volume of the right long segment. Reproduced from Forkel, S. J.,
Thiebaut de Schotten, M., DellAcqua, F., Kalra, L., Murphy, D., Williams, S., et al. (2014). Right arcuate fasciculus volume predicts recovery from
left stroke aphasia. Brain (in press).
Acknowledgments
We would like to thank Valentina Bambini, Stephanie Forkel,
and other members of the Neuroanatomy and Tractography
Laboratory (www.natbrainlab.com), the Institute of Neuroscience and Medicine of the Research Center Julich, and C. and O.
Vogt Institute for Brain Research of the Heinrich Heine University Dusseldorf for their helpful comments on the
References
Aboitiz, F., & Garcia, G. L. (1997). The evolutionary origin of language areas in the
human brain. A neuroanatomical perspective. Brain Research Reviews, 25,
381396.
Aboitiz, F., Scheibel, A. B., Fisher, R. S., & Zaidel, E. (1992). Fiber composition of the
human corpus callosum. Brain Research, 598, 143153.
Amunts, K., Lenzen, M., Friederici, A. D., Schleicher, A., Morosan, P.,
Palomero-Gallagher, N., et al. (2010). Brocas region: Novel organizational
principles and multiple receptor mapping. PLoS Biology, 8, e1000489.
Amunts, K., Schleicher, A., Burgel, U., Mohlberg, H., Uylings, H. B. M., & Zilles, K.
(1999). Brocas region revisited: Cytoarchitecture and intersubject variability. The
Journal of Comparative Neurology, 412, 319341.
Amunts, K., Schleicher, A., Ditterich, A., & Zilles, K. (2003). Brocas region:
Cytoarchitectonic asymmetry and developmental changes. The Journal of
Comparative Neurology, 465, 7289.
184
Amunts, K., Weiss, P. H., Mohlberg, H., Pieperhoff, P., Eickhoff, S., Gurd, J., et al.
(2004). Analysis of the neural mechanisms underlying verbal fluency in
cytoarchitectonically defined stereotaxic space The role of Brodmanns areas 44
and 45. NeuroImage, 22, 4256.
Amunts, K., & Zilles, K. (2012). Architecture and organizational principles of Brocas
region. Trends in Cognitive Sciences, 16, 418426.
Binder, J. R., Desai, R. H., Graves, W. W., & Conant, L. L. (2009). Where is the semantic
system? A critical review and meta-analysis of 120 functional neuroimaging studies.
Cerebral Cortex, 19, 27672796.
Binder, J. R., Frost, J. A., Hammeke, T. A., Bellgowan, P. S.F, Springer, J. A.,
Kaufman, J. N., et al. (2000). Human temporal lobe activation by speech and
nonspeech sounds. Cerebral Cortex, 10, 512528.
Buxhoeveden, D. P., Switala, A. E., Litaker, M., Roy, E., & Casanova, M. F. (2001).
Lateralization of minicolumns in human planum temporale is absent in nonhuman
primate cortex. Brain, Behavior and Evolution, 57(6), 349358.
Cappa, S. F., & Vallar, G. (1992). Neuropsychological disorders after subcortical
lesions: Implications for neural models of language and spatial attention. In G.
Valla, S. F. Cappa, & C.-W. Wallesch (Eds.), Neuropsychological disorders
associated with subcortical lesions (pp. 741). New York, NY: Oxford University
Press.
Caspers, S., Geyer, S., Schleicher, A., Mohlberg, H., Amunts, K., & Zilles, K. (2006).
The human inferior parietal cortex: Cytoarchitectonic parcellation and interindividual
variability. NeuroImage, 33, 430448.
Caspers, S., Schleicher, A., Bacha-Trams, M., Palomero-Gallagher, N., Amunts, K., &
Zilles, K. (2013). Organization of the human inferior parietal lobule based on
receptor architectonics. Cerebral Cortex, 23, 615628.
Catani, M., Allin, M. P., Husain, M., Pugliese, L., Mesulam, M. M., Murray, R. M., et al.
(2007). Symmetries in human brain language pathways correlate with verbal recall.
Proceedings of the National Academy of Sciences of the United States of America,
104, 1716317168.
Catani, M., Dellacqua, F., Vergani, F., Malik, F., Hodge, H., Roy, P., et al. (2012). Short
frontal lobe connections of the human brain. Cortex, 48, 273291.
Catani, M., Jones, D. K., Donato, R., & Ffytche, D. H. (2003). Occipito-temporal
connections in the human brain. Brain, 126, 20932107.
Catani, M., Jones, D. K., & Ffytche, D. H. (2005). Perisylvian language networks of the
human brain. Annals of Neurology, 57, 816.
Catani, M., & Mesulam, M. (2008). The arcuate fasciculus and the disconnection theme
in language and aphasia: History and current state. Cortex, 44, 953961.
Catani, M., Mesulam, M. M., Jakobsen, E., Malik, F., Martersteck, A., & Wieneke, C.
(2013). A novel frontal pathway underlies verbal fluency in primary progressive
aphasia. Brain, 37, 17241737.
Catani, M., & Thiebaut de Schotten, M. (2012). Atlas of human brain connections.
Oxford, UK: Oxford University Press.
Cerliani, L., Thomas, R. M., Jbabdi, S., Siero, J. C., Nanetti, L., & Crippa, A. (2012).
Probabilistic tractography recovers a rostrocaudal trajectory of connectivity
variability in the human insular cortex. Human Brain Mapping, 33, 20052034.
Cohen, L., Dehaene, S., Naccache, L., Lehericy, S., Dehaene-Lambertz, G.,
Henaff, M. A., et al. (2000). The visual word form area: Spatial and temporal
characterization of an initial stage of reading in normal subjects and posterior splitbrain patients. Brain, 123, 291307.
Crinion, J., Turner, R., Grogan, A., Hanakawa, T., Noppeney, U., & Devlin, J. T. (2006).
Language control in the bilingual brain. Science, 9, 15371540.
Crosson, B. (1992). Subcortical functions in language: A working model. Brain and
Language, 25, 257292.
Doron, K. W., & Gazzaniga, M. S. (2008). Neuroimaging techniques offer new
perspectives on callosal transfer and interhemispheric communication. Cortex, 44,
10231029.
Dorsaint-Pierre, R., Penhune, V. B., Watkins, K. E., Neelin, P., Lerch, J. P., Bouffard, M.,
et al. (2006). Asymmetries of the planum temporale and Heschls gyrus:
Relationship to language lateralization. Brain, 129(Pt. 5), 11641176.
Dronkers, N. F. (1996). A new brain region for coordinating speech articulation. Nature,
384, 159161.
Duffau, H., Gatignol, P., Mandonnet, E., Peruzzi, P., Tzourio-Mazoyer, N., & Capelle, L.
(2005). New insights into the anatomo-functional connectivity of the
semantic system: A study using cortico-subcortical electrostimulations. Brain, 128,
797810.
Fischl, B., Rajendran, N., Busa, E., Augustinack, J., Hinds, O., & Yeo, B. T. T. (2007).
Cortical folding patterns and predicting cytoarchitecture. Cerebral Cortex, 18,
19731980.
Forkel, S. J., DellAcqua, F., Thiebaut de Schotten, M., Kalra, L., Murphy, D., Williams,
S., & Catani, M. (2014). Right arcuate fasciculus volume predicts recovery from left
stroke aphasia. Brain, 137, 20272039.
Forkel, S. J., Thiebaut de Schotten, M., Kawadler, J. M., Dellacqua, F., Danek, A., &
Catani, M. (2012). The anatomy of fronto-occipital connections from early blunt
dissections to contemporary tractography. Cortex, 56, 7384.
Friederici, A. D., & Kotz, S. A. (2003). The brain basis of syntactic processes: Functional
imaging and lesions studies. NeuroImage, 20(Suppl. 1), S8S17.
Galaburda, A. M., Sanides, F., & Geschwind, N. (1978). Human brain. Cytoarchitectonic
left-right asymmetries in the temporal speech region. Archives of Neurology, 35,
812817.
Geyer, S., Matelli, M., Luppino, G., Schleicher, A., Jansen, Y., Palomero-Gallagher, N.,
et al. (1998). Receptor autoradiographic mapping of the mesial motor and premotor
cortex of the macaque monkey. The Journal of Comparative Neurology, 397, 231250.
Grodzinsky, Y., & Nelken, I. (2014). Neuroscience: The neural code that makes us
human. Science, 343, 978979.
Hagoort, P. (2013). MUC (memory, unification, control) and beyond. Frontiers in
Psychology, 416, 113.
Heim, S., Eickhoff, S. B., & Amunts, K. (2011). Different roles of cytoarchitectonic BA 44
and BA 45 in phonological and semantic verbal fluency as revealed by dynamic
causal modelling. NeuroImage, 48, 616624.
Heim, S., Eickhoff, S. B., Ischebeck, A. K., & Amunts, K. (2007). Modality-independent
involvement of the left BA 44 during lexical decision making. Brain Structure &
Function, 212, 95106.
Hickok, G., & Poeppel, D. (2007). The cortical organization of speech processing.
Nature Reviews. Neuroscience, 8, 393402.
Hutsler, J., & Galuske, R. A. W. (2003). Hemispheric asymmetries in cerebral cortical
networks. Trends in Neurosciences, 26(8), 429435.
Indefrey, P., Brown, C. M., Hellwig, F., Amunts, K., Herzog, H., Seitz, R. J., et al. (2001).
A neural correlate of syntactic encoding during speech production. Proceedings
of the National Academy of Sciences of the United States of America, 98,
59335936.
Jacobs, B., Schall, M., & Scheibel, A. B. (1993). A quantitative dendritic analysis of
Wernickes area in humans. II. Gender, hemispheric, and environmental factors. The
Journal of Comparative Neurology, 327, 97111.
Jacquemot, C., & Scott, S. K. (2006). What is the relationship between phonological
short-term memory and speech processing? Trends in Cognitive Sciences, 10,
480486.
Jeon, H. A., & Friederici, A. D. (2013). Two principles of organization in the prefrontal
cortex are cognitive hierarchy and degree of automaticity. Nature Communications,
4, 2041.
Keller, S. S., Highley, J. R., Garcia Finana, M., Sluming, V., Rezaie, R., & Roberts, N.
(2007). Sulcal variability, stereological measurement and asymmetry of Brocas area
on MR images. Journal of Anatomy, 211, 534555.
Lawes, I. N., Barrick, T. R., Murugam, V., Spierings, N., Evans, D. R., Song, M., et al.
(2008). Atlas-based segmentation of white matter tracts of the human brain using
diffusion tensor tractography and comparison with classical dissection.
NeuroImage, 39, 6279.
Lombardo, M. V., Chakrabarti, B., Bullmore, E. T., Wheelright, S. J., Sadek, S. A.,
Suckling, J., et al. (2010). Shared neural circuits for mentalizing about the self and
others. Journal of Cognitive Neuroscience, 22, 16231635.
Lopez-Barroso, D., Catani, M., Ripollesa, P., DellAcqua, F., Rodrguez-Fornells, A., &
de Diego-Balaguera, R. (2013). Word learning is mediated by the left arcuate
fasciculus. Proceedings of the National Academy of Sciences of the United States of
America, 110, 1316813173.
Mesgarani, N., Cheung, G., Johnson, K., & Chang, E. F. (2014). Phonetic feature
encoding in human superior temporal gyrus. Science, 343, 10061010.
Mesulam, M. M., Wieneke, C., Hurley, R., Rademaker, A., Thompson, C. K.,
Weintraub, S., et al. (2013). Words and objects at the tip of the left temporal lobe in
primary progressive aphasia. Brain, 136, 601618.
Meyer, L., Obleser, J., Anwander, A., & Friederici, A. D. (2012). Linking ordering in
Brocas area to storage in left temporo-parietal regions: The case of sentence
processing. NeuroImage, 62, 19871998.
Morosan, P., Rademacher, J., Schleicher, A., Amunts, K., Schormann, T., & Zilles, K.
(2001). Human primary auditory cortex: Cytoarchitectonic subdivision and mapping
into a spatial reference system. NeuroImage, 13, 684701.
Morosan, P., Schleicher, A., Amunts, K., & Zilles, K. (2005). Multimodal architectonic
mapping of human superior temporal gyrus. Anatomy and Embryology, 210,
401406.
Naeser, M. A., Palumbo, C. L., Helm-Estabrooks, N., Stiassny-Eder, D., & Albert, M.
(1989). Severe nonfluency in aphasia. Role of the medial subcallosal fasciculus and
other white matter pathways in recovery of spontaneous speech. Brain, 112, 138.
Newhart, M., Trupe, L. A., Gomez, Y., Cloutman, J., Molitoris, J. J., & Davis, C. (2012).
Asyntactic comprehension, working memory, and acute ischemia in Brocas area
versus angular gyrus. Cortex, 48, 12881297.
185
Thiebaut de Schotten, M., Cohen, L., Amemiya, E., Braga, L. W., & Dehaene, S. (2014).
Learning to read improves the structure of the arcuate fasciculus. Cerebral Cortex,
24, 989995.
Tyler, L. K., Marslen-Wilson, W. D., Randall, B., Wright, P., Devereux, B. J., Zhuang, J.,
et al. (2011). Left inferior frontal cortex and syntax: Function, structure and
behaviour in patients with left hemisphere damage. Brain, 134, 415431.
Uylings, H. B. M., Jacobsen, A. M., Zilles, K., & Amunts, K. (2006). Left-right
asymmetry in volume and number of neurons in adult Brocas area. Cortex, 42,
652658.
Vilberg, K. L., & Rugg, M. D. (2008). Memory retrieval and the parietal cortex: A
review of evidence from a dual-process perspective. Neuropsychologia, 46,
17871799.
Wallace, M. N., Johnston, P. W., & Palmer, A. R. (2002). Histochemical identification of
cortical areas in the auditory region of the human brain. Experimental Brain
Research, 143, 499508.
Watkins, K. E., Smith, S. M., Davis, S., & Howell, P. (2008). Structural and
functional abnormalities of the motor system in developmental stuttering. Brain,
131, 5059.
Wilson, S. M., Galantucci, S., Tartaglia, M. C., Rising, K., Patterson, D. K., &
Henry, M. L. (2011). Syntactic processing depends on dorsal language tracts.
Neuron, 72, 397403.
Yoshida, K., Saito, N., Iriki, A., & Isoda, M. (2011). Representation of others action by
neurons in monkey medial frontal cortex. Current Biology, 21, 249253.
Zilles, K., & Amunts, K. (2009). Receptor mapping: Architecture of the human cerebral
cortex. Current Opinion in Neurology, 22, 331339.
Functional Connectivity
SB Eickhoff and VI Muller, Research Centre Julich, Julich, Germany; HHU Dusseldorf, Dusseldorf, Germany
2015 Elsevier Inc. All rights reserved.
Glossary
http://dx.doi.org/10.1016/B978-0-12-397025-1.00212-8
187
188
aspects. The other aspect in the description of functional interactions in the brain networks that is also the most widely
employed approach to the investigation of brain connectivity
at the moment is functional connectivity in the more confined
sense.
189
190
191
192
193
194
(a) Resting-state FC
(b) Task-based FC
Figure 1 Example of seed-based functional connectivity analyses: based on a functionally defined seed in the hand area of the left primary motor
cortex (blue), functional connectivity was delineated by resting-state (a) and task-based functional connectivity analyses (b). Both analyses are
thresholded at the same level of significance (p < 0.05, corrected for multiple comparisons). Note that using of the same seed region and threshold, both
approaches to functional connectivity show a fundamentally similar motor-related network. Yet, several divergences between both approaches are
also apparent, indicating that resting-state and task-based functional connectivity analyses provide complementary information.
univariate approach became significant. Moreover, seedbased analyses may also be used to localize regions showing
significant differences in functional connectivity with the
regions of interest. In the context of resting-state functional
connectivity, such contrasts may, for example, be used to identify regions, which show a significant difference in functional
connectivity with the seed between patients and controls, that
is, regions that show a disease-dependent dys-connectivity with
that seed. In task-based functional connectivity analyses, coactivation patterns with a seed between different tasks and
behavioral domains may be compared. That is, additional
contextual filters may be applied when identifying those experiments in the database that feature activation within the seed
and the ensuing whole-brain coactivation patterns may then be
compared. This allows, for example, identifying those regions,
which show significantly more consistent coactivation with the
seed in cognitive tasks as compared with motor tasks.
Thus, there are various applications for seed-based functional connectivity analyses based on resting-state fMRI or
analyses of coactivations, which may be applied independently
but can also be combined. In particular, when performed for
more several, conceptually related, seed regions of interest,
such analyses may represent a powerful approach to the delineation of functional networks interacting (differentially) with a
set of a priori defined regions. In this case, the seed regions
would in turn provide the functional context for the interpretation of the observed connectivity patterns.
On the downside, it must be acknowledged that the results
of seed-based functional connectivity analyses strongly depend
on the precise localization of the seed. Consequently, the
quantitative definition of the seed, that is, the operationalization of the scientific question by a binary mask, is crucial to the
entire endeavor. As an example, suppose one wants to investigate the functional connectivity of the hand area within the
195
196
Resting-state FC
Functional connectivity
(a)
Action_Execution
Action_Execution_
Speech
0.4
0.3
0.2
0.1
0
2
3
4
Likelihood ratio
Finger tapping
-0.1
Recitation/repetition
-0.2
Flexion/extension
-0.3
(b)
Task-based FC
35
40
45
50 55 60 65 70
Finger tapping score
75
80
85
0
(c)
4
6
Likelihood ratio
Figure 2 Example of network-based functional connectivity analyses investigating a specific network: In this case, functional connectivity was
investigated in a motor network identified in a previous fMRI study (a). By using resting-state functional connectivity analyses, the connectivity strength
between each pair of nodes was computed and then subsequently related to behavioral measurements. This analysis revealed a significant positive
correlation between functional connectivity between the left cerebellum and right basal ganglia and the interindividual variability of performance in a
finger-tapping test (b). In contrast, by using task-based coactivation analysis and functional decoding using the BrainMap database, it could be shown
that coactivation of the left cerebellum with the right basal ganglia was significantly associated to experiments related to action execution and to tasks
like finger tapping, recitation/repetition, and flexion/extension (c). The integration of task-based and resting-state functional connectivity analyses thus
allows both functional decoding of mental operations associated with a particular connection and its relation to interindividual differences in phenotype.
In particular, in larger networks covering multiple individual regions, this approach may likewise become localizing by
testing which connections within the examined network show
a relationship to a neurocognitive measure of interest or a
difference between patients and controls. These kinds of
analyses may thus be seen as an extension of the localizing
framework for seed-based functional connectivity analyses or
brainbehavior correlations using other imaging modalities to
the network level. Finally, the properties of individual nodes or
the entire network may be summarized using network measures derived from graph theory such as the average degree, the
average shortest path length, and the presence of hubs. These
graph theoretical analyses, although outside the scope of this
overview, have the appeal that they allow the characterization
of complex networks or the role of individual nodes within
these by a few characteristic numbers. They come, however,
with the downside that these measures are usually fairly
abstract, making them at time difficult to interpret in a neurobiological sense. Moreover, they also represent a highly
reduced characterization of usually complex connectivity
patterns.
Similarly, as in seed-based analyses, how to set up the regions
of interest, that is, the nodes making up the investigated network,
has an important influence on the ensuing functional connectivity measures and any follow-up analyses. Evidently, these
regions of interest may be assembled in many different ways,
reflecting different ideas and goals for the functional connectivity
197
200
400
600
800
1000
1200
1400
1600
(a)
(b)
Figure 3 Example of a network-based, connectome-style functional connectivity analysis covering the entire brain. The whole brain was subdivided
into 1600 equally sized regions of interests (a). Resting-state functional connectivity was then determined by correlating all 1600 nodes with each
other resulting in a full connectivity matrix for the entire brain (b).
of those interactions that, for example, differ between two populations or that relate to a particular phenotype. This advantage,
however, comes with a potentially severe multiple comparison
problem. For example, at a granularity of 1000 regions of interest
(which would be equivalent to each cortical region covering
roughly 23 cm2 of cortex, i.e., probably more than an individual functional module), any statistical inference on the ensuing
functional connectome would need to deal correcting for almost
half a million parallel tests. Increasing the granularity in order to
arrive at more specific coverage of functional units substantially
worsens the problem as the number of parallel tests increases to
the second degree with the number of regions. Conversely,
reducing the number of regions ameliorates the multiple comparison problem but in turn dramatically reduces the specificity
of any findings. In particular, it may be argued that these larger
regions, which would result from a parcellation of lower granularity, would contain multiple functional modules, each showing a potentially specific pattern of functional connectivity.
Averaging across these may thus obscure relevant features in
the functional connectome. In other words, choosing a finegrained parcellation with the extreme case of considering
each voxel individually will allow a more specific analysis
and localization of effects but comes at a rapidly increasing
multiple comparison problem. In turn, choosing a broader parcellation will lead to less problems in statistical inference but
entails lower specificity and probably also validity of the findings. This predicament has more recently started an interest in
the use of multivariate pattern-analysis approaches for the investigation of connectome data (e.g., Sripada et al., 2013). These
avoid the problem of multiple independent tests but rather use
the entire pattern of functional connectivity measures, that is, the
strengths along all edges of the whole-brain network, to identify
patterns that are predictive of, for example, clinical classifications
(health vs. disease) or phenotypic variables such as cognitive
performance. Referring the reader to the respective section on
pattern analyses for further details, we would thus summarize
that network-based analyses in which the regions of interest
cover the entire brain have the intriguing potential of characterizing the entire functional connectome but are still faced with
198
199
Figure 4 Example of a component derived by independent component analyses using resting-state fMRI data. Here, the color scale indicates how
strongly each voxel is associated with this particular component (thresholded at p > .5 for displaying purposes). Using dual regression, subject-specific
versions of this group-level spatial map and their associated time series may be computed and subsequently subjected to statistical inference
testing for differences across subjects or groups in the expression of that particular component at each voxel.
200
factors, that is, aspects other than the effects of interest, which
affect the correlation structure in the data. Keeping these
caveats in mind, however, functional connectivity analyses
have a unique role in multimodal brain mapping that is complementary to functional and structural mapping and anatomical connectivity analyses.
It must also be noted that functional connectivity represents
a very broad concept that comprises multiple different possible
analysis approaches. These range from hypothesis-driven
investigations of interregional coupling among a set of predefined regions, usually from a particular functional system; to
seed-based analyses testing for regions showing significant
functional connectivity with that particular seed; to connectome analyses investigating the full functional connectivity
pattern between a large set of regions covering the entire
brain; to finally ICAs decomposing the signal in a completely
data-driven fashion. Moreover, functional connectivity estimated on resting-state fMRI time series represents not only
the most widely used approach but also the probably most
feasible method to obtain functional network information in
larger or less compliant cohorts of subjects. In the spectrum of
functional connectivity modalities, however, it only represents
one possible aspect. In turn, investigation of task-based coactivation patterns and cross correlation analyses of MEG/
EEG time series may provide valuable and most important
complementary information in functional interactions during
a different mental state, that is, the performance of externally
structured tasks, and at a higher temporal resolution, respectively. In this context, one important question for further
research is the relationship between different aspects of functional connectivity and their relation to measures of structural
connectivity and functional specialization.
References
Aertsen, A., Erb, B., & Palm, G. (1994). Dynamics of functional coupling in the cerebral
cortex: An attempt at a model-based interpretation. Physica D, 75, 103128.
Behrens, T. E., & Sporns, O. (2012). Human connectomics. Current Opinion in
Neurobiology, 22, 144153.
Birn, R. M. (2012). The role of physiological noise in resting-state functional
connectivity. NeuroImage, 62, 864870.
Biswal, B., Yetkin, F. Z., Haughton, V. M., & Hyde, J. S. (1995). Functional connectivity
in the motor cortex of resting human brain using echo-planar MRI. Magnetic
Resonance in Medicine, 34, 537541.
Buckner, R. L., & Vincent, J. L. (2007). Unrest at rest: Default activity and spontaneous
network correlations. NeuroImage, 37, 10911096 discussion 10971099.
Dagli, M. S., Ingeholm, J. E., & Haxby, J. V. (1999). Localization of cardiac-induced
signal change in fMRI. NeuroImage, 9, 407415.
Duncan, N. W., & Northoff, G. (2013). Overview of potential procedural and participantrelated confounds for neuroimaging of the resting state. Journal of Psychiatry and
Neuroscience, 38, 8496.
Ebisch, S. J., Mantini, D., Romanelli, R., Tommasi, M., Perrucci, M. G., Romani, G. L.,
et al. (2013). Long-range functional interactions of anterior insula and medial frontal
cortex are differently modulated by visuospatial and inductive reasoning tasks.
NeuroImage, 78, 426438.
Eickhoff, S. B., & Grefkes, C. (2011). Approaches for the integrated analysis of structure,
function and connectivity of the human brain. Clinical EEG and Neuroscience, 42,
107121.
Eickhoff, S. B., Jbabdi, S., Caspers, S., Laird, A. R., Fox, P. T., Zilles, K., et al. (2010).
Anatomical and functional connectivity of cytoarchitectonic areas within the human
parietal operculum. Journal of Neuroscience, 30, 64096421.
Fox, M. D., & Raichle, M. E. (2007). Spontaneous fluctuations in brain activity observed
with functional magnetic resonance imaging. Nature Reviews. Neuroscience, 8,
700711.
Friston, K. (1994). Functional and effective connectivity in neuroimaging: A synthesis.
Human Brain Mapping, 2, 5678.
Friston, K. (2002). Beyond phrenology: What can neuroimaging tell us about distributed
circuitry? Annual Review of Neuroscience, 25, 221250.
Friston, K. J. (2011). Functional and effective connectivity: A review. Brain Connectivity,
1, 1336.
Gerstein, G. L., & Perkel, D. H. (1969). Simultaneously recorded trains of action
potentials: Analysis and functional interpretation. Science, 164, 828830.
Goebel, R., Roebroeck, A., Kim, D. S., & Formisano, E. (2003). Investigating directed
cortical interactions in time-resolved fMRI data using vector autoregressive
modeling and Granger causality mapping. Magnetic Resonance Imaging, 21,
12511261.
Greicius, M. D., Krasnow, B., Reiss, A. L., & Menon, V. (2003). Functional connectivity
in the resting brain: A network analysis of the default mode hypothesis.
Proceedings of the National Academy of Sciences of the United States of America,
100, 253258.
Hohlefeld, F. U., Huchzermeyer, C., Huebl, J., Schneider, G. H., Nolte, G., Brucke, C.,
et al. (2013). Functional and effective connectivity in subthalamic local field
potential recordings of patients with Parkinsons disease. Neuroscience, 250C,
320332.
Honey, C. J., Kotter, R., Breakspear, M., & Sporns, O. (2007). Network structure of
cerebral cortex shapes functional connectivity on multiple time scales. Proceedings
of the National Academy of Sciences of the United States of America, 104,
1024010245.
Horwitz, B., Duara, R., & Rapoport, S. I. (1984). Intercorrelations of glucose
metabolic rates between brain regions: Application to healthy males in a state of
reduced sensory input. Journal of Cerebral Blood Flow and Metabolism, 4,
484499.
Jakobs, O., Langner, R., Caspers, S., Roski, C., Cieslik, E. C., Zilles, K., et al. (2012).
Across-study and within-subject functional connectivity of a right temporo-parietal
junction subregion involved in stimulus-context integration. NeuroImage, 60,
23892398.
Lourens, M. A., Meijer, H. G., Contarino, M. F., Van Den Munckhof, P.,
Schuurman, P. R., Van Gils, S. A., et al. (2013). Functional neuronal activity and
connectivity within the subthalamic nucleus in Parkinsons disease. Clinical
Neurophysiology, 124, 967981.
Moeller, J. R., Strother, S. C., Sidtis, J. J., & Rottenberg, D. A. (1987). Scaled subprofile
model: A statistical approach to the analysis of functional patterns in positron
emission tomographic data. Journal of Cerebral Blood Flow and Metabolism, 7,
649658.
Muller, V. I., Cieslik, E. C., Laird, A. R., Fox, P. T., & Eickhoff, S. B. (2013). Dysregulated
left inferior parietal activity in schizophrenia and depression: Functional connectivity
and characterization. Frontiers in Human Neuroscience, 7, 268.
Murphy, K., Birn, R. M., & Bandettini, P. A. (2013). Resting-state fMRI confounds and
cleanup. NeuroImage, 80, 349359.
Murphy, K., Birn, R. M., Handwerker, D. A., Jones, T. B., & Bandettini, P. A. (2009). The
impact of global signal regression on resting state correlations: Are anti-correlated
networks introduced? NeuroImage, 44, 893905.
Roland, P., Svensson, G., Lindeberg, T., Risch, T., Baumann, P., Dehmel, A., et al.
(2001). A database generator for human brain imaging. Trends in Neurosciences,
24, 562564.
Ruchkin, D. (2005). EEG coherence. International Journal of Psychophysiology, 57,
8385.
Satterthwaite, T. D., Elliott, M. A., Gerraty, R. T., Ruparel, K., Loughead, J., Calkins, M. E.,
et al. (2013). An improved framework for confound regression and filtering for control
of motion artifact in the preprocessing of resting-state functional connectivity data.
NeuroImage, 64, 240256.
Schilbach, L., Bzdok, D., Timmermans, B., Fox, P. T., Laird, A. R., Vogeley, K., et al.
(2012). Introspective minds: Using ALE meta-analyses to study commonalities in
the neural correlates of emotional processing, social and unconstrained cognition.
PLoS One, 7, e30920.
201
Van Horn, J. D., Grethe, J. S., Kostelec, P., Woodward, J. B., Aslam, J. A., Rus, D., et al.
(2001). The functional magnetic resonance imaging data center (fMRIDC): The
challenges and rewards of large-scale databasing of neuroimaging studies.
Philosophical Transactions of the Royal Society of London. Series B: Biological
Sciences, 356, 13231339.
Zuo, X. N., Kelly, C., Adelstein, J. S., Klein, D. F., Castellanos, F. X., & Milham, M. P.
(2010). Reliable intrinsic connectivity networks: Testretest evaluation using ICA
and dual regression approach. NeuroImage, 49, 21632177.
Glossary
Introduction
Without focus on an explicit task, the brain is not at rest. Rather,
the brain is continuously metabolizing large quantities of oxygen
and glucose energy from the cerebral blood vessels to fuel general
maintenance and ongoing neural communication. The baseline
brain metabolism is subject to surprisingly little modulations due
to the cognitive load necessary to process environmental challenges. Such basic properties of oxygen and glucose consumption
will be introduced in the first half of this article and discussed
with respect to their relation to vasculature and neural activity. In
the second half of this article, we will detail three metabolismrelated aspects of brain physiology that are frequently intermingled but clearly distinct. These are the functional connectivity
(i.e., a class of methodological approaches), resting-state (RS)
correlations (i.e., a particular methodological approach), and
default-mode network (DMN; i.e., a neural network with coherent RS fluctuations). In particular, functional connectivity can be
defined as temporal correlations between spatially distant neurophysiological events (Friston, Frith, Fletcher, Liddle, &
Frackowiak, 1996). It is believed to quantify the statistical relationship of the functional interaction between brain regions.
One example of functional connectivity is RS connectivity. RS
connectivity measures functional coupling between distant
brain regions by correlation between time series of the metabolic
fluctuations outside of an experimental context. RS connectivity,
in turn, led to the discovery of several robust resting-state
networks (RSNs), including the DMN. The latter is widely held
to reflect ongoing random thought in the absence of structured
environmental challenges. We will elaborate these aspects of
brain physiology along the lines of metabolism, the RS signal,
ensuing RS connectivity and thus derivable neural networks.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00213-X
203
204
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | The Resting-State Physiology of the Human Cerebral Cortex
Neurovascular Coupling
The neuroscientist is typically interested in neural activity,
which was suggested to induce regional blood flow changes
already in the nineteenth century (Roy & Sherrington, 1890).
Physiologically, neurovascular coupling describes the brain
vasculatures time-lagged dilation response to locally increasing metabolic products. This is directly observable using water
or butanol positron emission tomography and indirectly using
functional magnetic resonance imaging (fMRI) as the BOLD
(blood oxygen level-dependent) signal (Figure 1). The BOLD
signal is caused by local changes in blood oxygenation, that is,
the oxyhemoglobin to deoxyhemoglobin ratio (red blood cells
carrying vs. not carrying oxygen) (Logothetis & Wandell, 2004;
Ogawa, Lee, Kay, & Tank, 1990). It exhibits an initial dip after
the onset of neural activity increase that is attributed to the fast
local increase in deoxyhemoglobin. The ensuing hyperperfusion and the thus generated (relative) hyperoxygenation (cf.
next paragraph) then dictate the BOLD signal shape (hemodynamic response function). It is variable across the brain regions
of an identical organism, across organisms, and probably
across different tasks. Neural activation is finally followed by
reinhibition of blood flow observable as an undershoot at the
end of the BOLD signal (Logothetis, Pauls, Augath, Trinath, &
Oeltermann, 2001).
Comparing neural activity and corresponding BOLD signals, the BOLD signal is at least one order of magnitude noisier, scales roughly linearly with neural activity, and is better
predicted by local field potentials than multiunit spiking activity. The BOLD signal is possibly more associated with input to
and processing in a local neuronal population rather than its
output. There is thus no clear-cut quantitative relation between
the spike rate of neuronal populations and the ensuing BOLD
response. Rather, the BOLD signal reflects a mixture of transient spikes and continuous membrane potentials (Logothetis
& Wandell, 2004).
3.0
Open
Closed
Open
Closed
Open
Closed
Energy Consumption
The baseline energy demand of the human brain is very high
and almost exclusively covered by the consumption of glucose.
Glucose metabolism in turn is tightly coupled with oxygen
metabolism. However, 10% of the overall glucose is consumed
in anaerobic pathways.
On a microscale, as much as 50% of baseline energy consumption is explained by the physiology of ongoing synaptic
transmission, including neurotransmitter recycling, as well as
maintenance and restoration of electrochemical membrane
potentials (Attwell & Laughlin, 2001). Such synaptic activity
is closely coupled with glucose uptake and oxygen consumption. The metabolic increase due to neural activity is primarily
located in the nerve terminals rather than cell bodies of neurons. This implies intra- and interneuronal housekeeping functions as particularly important in the human brains resting
functionality. In contrast to this baseline consumption, environmental events evoke increased energy costs of only less than
5%. Importantly, however, most neuroimaging investigations
focus on these (minor) metabolic changes due to external
Open
Closed
% BOLD change
2.5
2.0
1.5
Open
Closed
0.5
0
0.5
1
0
50
100
150
200
250
Times (s)
Figure 1 Left: Depicts the unaveraged blood oxygen level-dependent (BOLD) time course (in magenta) in a part of the primary visual cortex. BOLD
time series were recorded during a task that asked participants to open and close their eyes. The blue lines indicate this paradigm. Right: Result of
contrast analysis between trials with open and closed eyes by subtraction between both conditions. Taken from Fox, D. F., & Raichle, M.E., (2007).
Spontaneous fluctuations in brain activity observed with functional magnetic resonance imaging. Nature Reviews. Neuroscience, 8, 700711, Figure 1.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | The Resting-State Physiology of the Human Cerebral Cortex
205
Activation
CBF
CBV
CMRO2
OEF
Hgb-O2
BOLD
()
0
(+) ()
0
Percentage change from baseline
(+)
Figure 2 The relationship between metabolic and circulatory changes in brain areas with increasing (activation) or decreasing (deactivation) neural
activity. CBF cerebral blood flow, CBV cerebral blood volume, CMRO2 cerebral metabolic rate for oxygen, OEF oxygen extraction function,
HgbO2 hemoglobin carrying oxygen, BOLD blood oxygen level-dependent signal. Taken from Raichle, M. E., MacLeod, A. M., Snyder, A. Z., Powers,
W. J., Gusnard, D. A., & Shulman, G. L., (2001). A default mode of brain function. Proceedings of the National Academy of Sciences of the United
States of America, 98, 676682, Figure 3.
RS Signals
In the absence of task (i.e., during mind wandering), interneuronal communication continues. This is suggested by physiological fluctuations in resting brains that contribute to the
fluctuations of the BOLD signal as measured by fMRI. More
specifically, the RS signal follows a 1/f distribution with
increasing power at lower frequencies. Such signal properties
were also consistently observed in EEG (electroencephalogram), magnetoencephalography, local field potentials, and
human behavioral measurements (Fox & Raichle, 2007).
Low-frequency fluctuations resembling the (fMRI) RS signal
have furthermore been observed in a number of physiological
measurements, including oxygen availability, cytochrome oxidase activity, and blood flow and volume. Physiologically
interrelated mechanisms might thus contribute to ongoing
neural computation reflected by the RS (BOLD) signal.
Importantly, the (small) amplitude of the RS signal is modulated by transient psychological states (e.g., arousal, attention,
RS Connectivity
Correlation analysis can detect temporal coincidence in spontaneous, slow fluctuations (0.010.1 Hz) in fMRI signals. This is
taken as a measure of RS connectivity between topographically
distant parts of the brain. Faster frequencies, not apparent in
(intrinsically low-pass-filtered) BOLD signals, in turn are predominantly associated with cardiac and respiratory sources. RS
connectivity is task-unconstrained by probing participants that
lie in the scanner without following a defined experimental task.
206
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | The Resting-State Physiology of the Human Cerebral Cortex
Instead, participants are instructed to think of nothing in particular, let their minds go, and leave their eyes open/closed or
look at a fixation cross. During mind wandering, humans mentally shift between various heterogeneous types of thoughts,
memories, and predictions. This is why RS connectivity is
believed to reflect the repertoire of cognitive operations that
the human brain can perform (Smith et al., 2009; but see
Mennes, Kelly, Colcombe, Castellanos, & Milham, 2013).
The most commonly used methodological approach to
measure RS connectivity is seed correlation with a predefined
region of interest. In fact, the feasibility of exploiting BOLD
signals to investigate spatially distributed networks was first
demonstrated by seeding from the primary motor cortex
(Biswal, Yetkin, Haughton, & Hyde, 1995). Time series of a
motor seed, obtained from a finger-tapping task, were temporally correlated with the rest of the brain. This yielded a distributed network of motor-related brain regions within and
across hemispheres (Figure 3). As the BOLD signal contains
both neuronal and nonneuronal components (cf. the preceding text), several nonneuronal contributions are typically
removed from the correlation maps (Satterthwaite et al.,
2013). This hypothesis-driven approach has successfully recovered many robust neural networks related to visual, auditory,
episodic memory, language, and dorsal attention systems.
Independent component analysis (ICA) is the other most
common form of RS analysis. ICA decomposes multivariate
neuroimaging data into a set of discrete fluctuation patterns
coherently correlated across time and space. It is a more datadriven approach than seed correlation. Without a priori region,
ICA can simultaneously extract several networks while separating out nonneuronal variance from movements, ventricles,
white matter, and respiratory and cardiac cycles (Beckmann,
DeLuca, Devlin, & Smith, 2005). Despite their differences, ICA
and seed correlation generate functional networks that are
highly comparable.
RS connectivity is modulated by age, experience, and disease
as well as conscious, cognitive, and emotional states. A comprehensive testretest reliability study on RS connectivity (Shehzad
et al., 2009) concluded that (i) statistically significant
correlations at group level were more reliable than nonsignificant ones, (ii) significant positive correlations were more
reliable than significant negative ones, and (iii) regions within a
neural networks were more reliably correlated with each other
than with other brain regions. Moreover, the more reliably a
voxel is positively correlated with a given network, the more
reliably it is negatively correlated with voxels from other networks. A comprehensive description of RS connectivity should
therefore comprise positive and negative correlations. Despite
initial skepticism, RS connectivity results were repeatedly shown
to be consistent across participants, brain scans, time points,
and other factors (e.g., eyes open vs. closed).
In sum, seed correlation and ICA studies thus showed that
RS connectivity reflects robust functional relationships
between brain regions.
Resting-State Networks
Observed RS connectivity patterns led to the discovery of the
coherent spatiotemporal fluctuations termed resting-state networks (RSNs). Notably, there are probably not a deterministic
number of RSNs in the brain as they are decomposable up to
single-region networks. The individual RSNs exhibit BOLD
signal variability that typically revolves around 23%
(Damoiseaux et al., 2006). High BOLD signal variability even
tends to coincide with high spatiotemporal consistency of
RSN. Structural connectivity by fiber bundles does constrain
but not exhaustively determine functional connectivity in RSN,
as evidenced by empirical measurements and computational
modeling (Honey et al., 2009).
Figure 3 Left: Task-evoked BOLD response during left and right finger movement in functional magnetic resonance imaging. Right: Resting-state
connectivity of a seed region in the motor cortex. a/b bilateral primary motor cortex, c Brodmanns area 6, d extension of the primary sensorimotor
cortex, e premotor area. Taken from Biswal, B., Yetkin, F. Z., Haughton, V. M., & Hyde, J. S., (1995). Functional connectivity in the motor cortex
of resting human brain using echo-planar MRI. Magnetic Resonance in Medicine, 34, 537541, Figure 3.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | The Resting-State Physiology of the Human Cerebral Cortex
coupling between regions of a particular network often also
allows prediction of the extent of neural response during corresponding behavioral performance. Indeed, several authors
speculate that the continuous fluctuations in known networks
might reflect the brains tracking and prediction of environmental events to adaptively optimize future behavioral
responses (Binder et al., 1999). Within and outside of experimental settings, activity in RSN thus seems to relate to psychological processes. Interestingly, experimentally imposed
cognitive sets modulate connectivity within RSN such that
negative RS correlations are more strongly modulated than
positive RS correlations. This continuation and modulation
of RS fluctuations during experimentally controlled brain
states complicates the interpretation of neuroimaging findings.
In a seminal study (Smith et al., 2009), ICA was applied
individually to large quantities of task-constrained and taskunconstrained fMRI data to maximize intranetwork homogeneity and between-network heterogeneity. These two separate
decompositions of brain signals into networks yielded largely
homologues network pairs, including sensorimotor, visual,
auditory, executive control, saliency, and dorsal attention networks (Figure 4). The authors concluded that an identical
repertoire of neural networks is underlying functional brain
architecture in active and resting brain states. These were hence
more generally called intrinsic connectivity networks.
Brain regions simultaneously increasing neural activity
in response to a given external stimulus or task increase correlation between each other and decrease correlation with
207
Figure 4 Ten matched pairs of networks independently derived from independent component analysis of task-unrelated resting-state data from
36 subjects (resting-state network, RSN) and task-related coordinates from neuroimaging contrasts from the BrainMap database (BM). The networks
were paired automatically using spatial cross correlation. Taken from Smith, S. M., Fox, P. T., Miller, K. L., Glahn, D. C., Fox, P. M., Mackay, C. E.,
et al. (2009). Correspondence of the brains functional architecture during activation and rest. Proceedings of the National Academy of Sciences
of the United States of America, 106, 1304013045, Figure 1.
208
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | The Resting-State Physiology of the Human Cerebral Cortex
Computational Studies
Theoretical studies based on computational modeling of RSN
dynamics also contributed several implications (Deco, Jirsa, &
McIntosh, 2011): (i) Different models of fast and slow oscillations can explain empirically observed spatiotemporal RSN
behavior, without being mutually exclusive. That is, there are
different conceivable ways for RSN nodes to functionally cooperate. (ii) The configuration of RSN is a function of assessed time
window over which network dynamics are measured. Assessment of long time windows yields strong similarity with
known anatomical connectivity patterns. Assessment of short
time windows yields nodes of RSN that transiently form new
functional networks. (iii) Incorporation of stochastic (i.e., noisy)
and deterministic (i.e., constant) elements into RSN dynamics
yields transient oscillatory features provided that the deterministic framework is critical (i.e., instable). That is, an optimal
amount of randomness appears necessary to drive RSN dynamics
in the absence of external stimulation (Faisal, Selen, & Wolpert,
2008). Computational modeling approaches thus highlight correspondence between measures of time and space, anatomical
connectivity between nodes, and sources of randomness as key
factors that orchestrate the physiology of RSN.
Conclusion
A set of fluctuating yet robust brain networks that span several
spatial and temporal scales determine functional brain architecture across rest and task. These brain networks are tightly
coupled with brain oxygen and glucose metabolism as well as
continuous mental operations. Neuroimaging studies using
seed correlation and ICA recovered well-known neural networks and evidenced their relation to behavioral performance.
They might be the physiological instantiation of a human
beings mental repertoire.
References
Attwell, D., & Laughlin, S. B. (2001). An energy budget for signaling in the grey matter
of the brain. Journal of Cerebral Blood Flow and Metabolism, 21, 11331145.
Beckmann, C. F., DeLuca, M., Devlin, J. T., & Smith, S. M. (2005). Investigations into
resting-state connectivity using independent component analysis. Philosophical
Transactions of the Royal Society of London. Series B: Biological Sciences, 360,
10011013.
Binder, J. R., Frost, J. A., Hammeke, T. A., Bellgowan, P. S., Rao, S. M., & Cox, R. W.
(1999). Conceptual processing during the conscious resting state: A functional MRI
study. Journal of Cognitive Neuroscience, 11, 8093.
Birn, R. M., Diamond, J. B., Smith, M. A., & Bandettini, P. A. (2006). Separating
respiratory-variation-related fluctuations from neuronal-activity-related fluctuations
in fMRI. NeuroImage, 31, 15361548.
Biswal, B., Yetkin, F. Z., Haughton, V. M., & Hyde, J. S. (1995). Functional connectivity
in the motor cortex of resting human brain using echo-planar MRI. Magnetic
Resonance in Medicine, 34, 537541.
Buckner, R. L., Andrews-Hanna, J. R., & Schacter, D. L. (2008). The brains default
network: Anatomy, function, and relevance to disease. The Annals of the New York
Academy of Sciences, 1124, 138.
Bzdok, D., Langner, R., Schilbach, L., Jakobs, O., Roski, C., Caspers, S., et al. (2013).
Characterization of the temporo-parietal junction by combining data-driven
parcellation, complementary connectivity analyses, and functional decoding.
NeuroImage, 81, 381392.
Clark, D. D., & Sokoloff, L. (1999). Basic neurochemistry. In G. J. Siegel, B. W.
Agranoff, R. W. Albers, S. K. Fisher, & M. D. Uhler (Eds.), Molecular, cellular and
medical aspects (pp. 637670). Philadelphia, PA: Lippincott-Raven.
Cox, S. B., Woolsey, T. A., & Rovainen, C. M. (1993). Localized dynamic changes in
cortical blood flow with whisker stimulation corresponds to matched vascular and
neuronal architecture of rat barrels. Journal of Cerebral Blood Flow and Metabolism,
13, 899913.
Damoiseaux, J. S., Rombouts, S. A., Barkhof, F., Scheltens, P., Stam, C. J.,
Smith, S. M., et al. (2006). Consistent resting-state networks across healthy
subjects. Proceedings of the National Academy of Sciences of the United States of
America, 103, 1384813853.
Deco, G., Jirsa, V. K., & McIntosh, A. R. (2011). Emerging concepts for the dynamical
organization of resting-state activity in the brain. Nature Reviews. Neuroscience, 12,
4356.
Faisal, A. A., Selen, L. P., & Wolpert, D. M. (2008). Noise in the nervous system. Nature
Reviews. Neuroscience, 9, 292303.
Fox, P. T., & Raichle, M. E. (1986). Focal physiological uncoupling of cerebral blood
flow and oxidative metabolism during somatosensory stimulation in human
subjects. Proceedings of the National Academy of Sciences of the United States of
America, 83, 11401144.
Fox, D. F., & Raichle, M. E. (2007). Spontaneous fluctuations in brain activity observed
with functional magnetic resonance imaging. Nature Reviews. Neuroscience, 8,
700711.
Fox, M. D., Snyder, A. Z., Vincent, J. L., Corbetta, M., Van Essen, D. C., & Raichle, M. E.
(2005). The human brain is intrinsically organized into dynamic, anticorrelated
functional networks. Proceedings of the National Academy of Sciences of the United
States of America, 102, 96739678.
Friston, K. J., Frith, C. D., Fletcher, P., Liddle, P. F., & Frackowiak, R. S. (1996).
Functional topography: Multidimensional scaling and functional connectivity in the
brain. Cerebral Cortex, 6, 156164.
Fukunaga, M., Horovitz, S. G., van Gelderen, P., de Zwart, J., Jansma, J.,
Ikonomidou, V., et al. (2006). Large-amplitude, spatially correlated fluctuations in
BOLD fMRI signals during extended rest and early sleep stages. Magnetic
Resonance Imaging, 24, 979992.
Goldman, R. I., Stern, J. M., Engel, J., Jr., & Cohen, M. S. (2002). Simultaneous EEG
and fMRI of the alpha rhythm. Neuroreport, 13, 24872492.
Gusnard, D. A., Akbudak, E., Shulman, G. L., & Raichle, M. E. (2001). Medial prefrontal
cortex and self-referential mental activity: Relation to a default mode of brain
function. Proceedings of the National Academy of Sciences of the United States of
America, 98, 42594264.
Gusnard, D. A., & Raichle, M. E. (2001). Searching for a baseline: Functional imaging
and the resting human brain. Nature Reviews. Neuroscience, 2, 685694.
Harrison, R. V., Harel, N., Panesar, J., & Mount, R. J. (2002). Blood capillary
distribution correlates with hemodynamic-based functional imaging in cerebral
cortex. Cerebral Cortex, 12, 225233.
Honey, C. J., Sporns, O., Cammoun, L., Gigandet, X., Thiran, J. P., Meuli, R., et al.
(2009). Predicting human resting-state functional connectivity from structural
connectivity. Proceedings of the National Academy of Sciences of the United States
of America, 106, 20352040.
Logothetis, N. K., Pauls, J., Augath, M., Trinath, T., & Oeltermann, A. (2001).
Neurophysiological investigation of the basis of the fMRI signal. Nature, 412,
150157.
Logothetis, N. K., & Wandell, B. A. (2004). Interpreting the BOLD signal. Annual Review
of Physiology, 66, 735769.
Mennes, M., Kelly, C., Colcombe, S., Castellanos, F. X., & Milham, M. P. (2013). The
extrinsic and intrinsic functional architectures of the human brain are not equivalent.
Cerebral Cortex, 23, 223229.
Obrig, H., Neufang, M., Wenzel, R., Kohl, M., Steinbrink, J., Einhaupl, K., et al. (2000).
Spontaneous low frequency oscillations of cerebral hemodynamics and metabolism
in human adults. NeuroImage, 12, 623639.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | The Resting-State Physiology of the Human Cerebral Cortex
Ogawa, S., Lee, T. M., Kay, A. R., & Tank, D. W. (1990). Brain magnetic resonance
imaging with contrast dependent on blood oxygenation. Proceedings of the National
Academy of Sciences of the United States of America, 87, 98689872.
Raichle, M. E. (2008). Loss of resting interhemispheric functional connectivity
after complete section of the corpus callosum. Journal of Neuroscience, 28,
64536458.
Raichle, M. E., MacLeod, A. M., Snyder, A. Z., Powers, W. J., Gusnard, D. A., &
Shulman, G. L. (2001). A default mode of brain function. Proceedings of
the National Academy of Sciences of the United States of America, 98,
676682.
Reivich, M., Kuhl, D., Wolf, A., Greenberg, J., Phelps, M., Ido, T., et al. (1979). The
[18F]fluorodeoxyglucose method for the measurement of local cerebral glucose
utilization in man. Circulation Research, 44, 127137.
Roy, C. S., & Sherrington, C. S. (1890). On the regulation of the blood supply of the
brain. Journal of Physiology, 11, 85108.
Satterthwaite, T. D., Elliott, M. A., Gerraty, R. T., Ruparel, K., Loughead, J.,
Calkins, M. E., et al. (2013). An improved framework for confound regression and
filtering for control of motion artifact in the preprocessing of resting-state functional
connectivity data. NeuroImage, 64, 240256.
209
Schacter, D. L., Addis, D. R., & Buckner, R. L. (2007). Remembering the past to imagine
the future: The prospective brain. Nature Reviews. Neuroscience, 8, 657661.
Schilbach, L., Eickhoff, S. B., Rotarska-Jagiela, A., Fink, G. R., & Vogeley, K. (2008).
Minds at rest? Social cognition as the default mode of cognizing and its putative
relationship to the "default system" of the brain. Consciousness and Cognition, 17,
457467.
Shehzad, Z., Kelly, A. M., Reiss, P. T., Gee, D. G., Gotimer, K., Uddin, L. Q., et al.
(2009). The resting brain: Unconstrained yet reliable. Cerebral Cortex, 19,
22092229.
Smith, S. M., Fox, P. T., Miller, K. L., Glahn, D. C., Fox, P. M., Mackay, C. E., et al.
(2009). Correspondence of the brains functional architecture during activation and
rest. Proceedings of the National Academy of Sciences of the United States of
America, 106, 1304013045.
Spreng, R. N., Mar, R. A., & Kim, A. S. (2009). The common neural basis of
autobiographical memory, prospection, navigation, theory of mind, and the default
mode: A quantitative meta-analysis. Journal of Cognitive Neuroscience, 21, 489510.
Wise, R. G., Ide, K., Poulin, M. J., & Tracey, I. (2004). Resting fluctuations in arterial
carbon dioxide induce significant low frequency variations in BOLD signal.
NeuroImage, 21, 16521664.
Introduction
Adult and developing brain structure has been variously studied
in the past, giving rise to cytoarchitectonic, myeloarchitectonic,
glioarchitectonic, and chemoarchitectonic brain maps. A powerful variant of chemical neuroanatomy recently named
genoarchitectony (Ferran et al., 2009; Puelles & Ferran, 2012)
resulted from the possibility to map gene expression in terms of
specific cytoplasmic mRNA content with in situ hybridization
(ISH) procedures. In the standard case, an mRNA probe is
produced whose nucleotide sequence is complementary to a
targeted sector of mRNA transcript sequence; the target sequence
is selected to be highly characteristic of a specific gene, using
in silico genomic sequence analysis. The probe is tagged with an
epitope that allows subsequent visualization and is applied to
fixed tissue (sections or whole mounts) under reaction conditions that favor its specific hybridization to the target mRNA
molecules in the cellular cytoplasm. The protocol ensures by
diverse washing steps that the reaction product remains
restricted to those cells that expressed the gene of interest at
the moment of fixation. Various degrees of signal intensity are
obtained, depending on the number of copies of the specific
mRNA transcript and the reaction conditions. The expression of
a gene may be stable over time, eventually providing a molecular marker for the cell type, if the expression is selective (at least
regionally), or may be transient, when associated to a transient
developmental stage or a mature nonconstitutive (occasional)
cell function. It is possible to perform double or triple ISH
reaction against different gene sequences (Lauter, Soll, &
Hauptman, 2011), as well as complementing the ISH with an
immunochemical reaction.
Since translation of mRNA into protein largely occurs in the
cell body, the ISH reaction mainly visualizes neuronal or glial
somata. Exceptionally, some neurons with large quantities of
transcripts may transport them into their axons, leading to
axonal labeling (this applies likewise for radial glial cell processes). A needed note of caution is that the presence of a
specific mRNA transcript in the cytoplasm of a cell does not
necessarily imply that the corresponding protein is being produced, though that is often the case (in critical cases, appropriate controls are required). On the other hand, ISH may allow
us to identify the cellular sources of transported or secreted
proteins that accumulate in a particular neuropile, but are not
detectable in cell bodies, due to low concentration.
ISH reaction provides a very discriminative dissection tool
for the study of brain structure and function, due to the existence of thousands of genes in the genome and their variable
expression patterns in specific cells at particular periods of
prenatal or postnatal life. This approach provides direct access
to the molecular phenotype of even previously unknown cell
types as it evolves dynamically over ontogenetic time. Genes
coding for transcription factors are crucial for the understanding of differentiative developmental processes and related
http://dx.doi.org/10.1016/B978-0-12-397025-1.00214-1
211
212
Early
Intermediate
Later (fixed)
pros
Otx2
Otx2
Otx2
mes
Gbx2
hb
Gbx2
sc
Gbx2
Dynamic
Dynamic
Equilibrium
Figure 1 Three schemata illustrate early dynamic changes in the respective expression domains of the transcriptor factor genes Otx2 and Gbx2 at
the neural plate stages. Antagonistic interaction at the boundary of these two territories is transiently won by Gbx2, so that its domain results
expanded and that of Otx2 simultaneously contracts. Eventually, an equilibrium is reached at the midbrainhindbrain boundary. This is a common early
mechanism for establishing regional boundaries but seems limited to stages in which the distances are small. pros, prosencephalon; mes,
mesencephalon; hb, hindbrain; sc, spinal cord.
r2
Alar
Basal
SC
TG
IC
InC
Plsth
Isthmus
CbVermis
r1
CbHem
r2
Flocculus
Alar
Basal
Figure 2 Schematic illustration of the gradiental field mechanism
generated by the isthmic organizer (IOrg), a typical example of a
secondary organizer. The upper panel shows that initially, the morphogen
FGF8 is secreted by the IOrg and spreads gradientally both rostrally
and caudally, within a given spatial range, the signal becoming less
abundant the more distant from the source (red line). The bottom
panel illustrates the reaction of the relevant midbrain and hindbrain
territories. They become regionalized in a steplike fashion into diverse
anteroposterior subdivisions characterized by differential molecular
identities and correlative structural differences. The general fates are
identified. The dashed line in r1 marks its internal subdivision into
rostral and caudal parts. CbVermis, vermis of cerebellum; CbHem,
hemisphere of cerebellum; IC, inferior colliculus; InC, intercollicular area;
IOrg, isthmic organizer; r1, rhombomere 1; r2, rhombomere 2; SC,
superior colliculus; TG, tectal gray.
213
214
(a)
Tbr1
Otp/Sim1
Dl5
Gb2
Pa3/Pa7
Pallium
E
ch
Hb
Pallial A
Subpall. A
St
ALON
EPH
NC TH
IE
p2
ZL
PTh p3 ZI
Pa
Subpallium
Septal
roofplate
PRM
PB
RTu
hp1
SPa
POA hp2
ac
VMH
AH
AB
(b)
m2
RP
alarbasal limit
FP
Cephalic
STh
Rt
Dg
m1
ita nigra
tan
bs
Su
PThE
Pal
MES
PT
p1
PHy flexure
THy
RM
Mam
PM
Tu
Arc
Limit of median
acroterminal
region
NHy
Eye SCH
Figure 3 Panel (a) illustrates an example of a developmental genoarchitectonic ISH mapping (the gen Enc1; blue signal), which is counterstained by
immunohistochemistry of calbindin (brown signal); note that both labels complement each other in regional distribution, emphasizing various
anteroposterior and dorsoventral limits. The sagittal section is of an E12,5 mouse embryo, and the forebrain (the telencephalon, hypothalamus, and
diencephalon, as defined in the prosomeric model; see (b)), midbrain, and rostral hindbrain enter into the frame. The major anatomical regions are
identified, aiming for comparison with the bottom panel. Panel (b) shows the prosomeric model for this area of the brain, illustrating the length axis as
revealed by the roof and floor plates (both in gray) and the alarbasal boundary (red line); the zona limitans interthalamica singularity (ZL; zli
marked by Enc1 in (a)) represents another secondary organizer the middiencephalic one which is important for prethalamic and thalamic patterning.
Note also the dorsoventral continuity of the telencephalon and the hypothalamus and the more caudally placed diencephalon (extending between
thicker black borders marked by arrows) and mesencephalon. Various gene expression patterns appear color-coded (see upper right corner); obviously,
the Enc1 pattern shown in (a) does not underline all details contemplated on the model, but is visibly consistent with it on the whole.
or neuromeres (5 prosomeres, 2 mesomeres, and 12 rhombomeres, respectively). This subdivision into transverse units is
fundamentally metameric, insofar as neuromeres share their
primary DV structure (floor, basal, alar, and roof plates).
215
Figure 4 This image corresponds to one of the sections used for the P56 reference atlas of the Allen Developing Mouse Brain Atlas and illustrates how
a sagittal section through the adult mouse brain would start to be interpreted using the prosomeric model (only the alarbasal border and the
interprosomeric limits are delineated), in order to map any gene expression studied in this database at this section level.
in the developing and/or adult mouse brain (also other species, including man and some nonmammals). These important
data sets are often correlated with anatomical reference atlases
(caution needs to be recommended in their use, due to the
persistence of the obsolete columnar brain model; so far, only
the Allen Institute for Brain Science offers the prosomeric
model in its developmental atlas (Figure 4), though not consistently in all its atlases; it is important that the user develops
his or her own interpretive criteria, preferably keeping in mind
relevant developmental data, and does not blindly confide in
the authority of experts that leave developmental advances
aside). There is also very useful data-mining software associated to these repositories, which allow searching the databases
in various ways, including relative position, coexpression, and
time dynamics. In this way, it has been possible to identify
layer-specific gene markers in the cerebral cortex and investigate fine molecular subdivisions in many regions of the brain.
Unfortunately, some of the early developmental expression
patterns fade out during the postnatal period. Specific studies
are then needed to determine which are the new relevant
genoarchitectonic markers at these sites, in order to retrace
the cryptic boundary. These are normally represented by differentiation markers of the boundary-related neurons or glia or
by genes that control differential aspects of the local adult
functional molecular phenotype. Fate-mapping results and
transgenic analysis of the progeny of given molecularly defined
progenitor domains serve to corroborate such analyses.
Genes coding for neurotransmitter- and peptide-characteristic
markers can be efficiently mapped genoarchitectonically, as well
as those coding for the rich variety of transporters, channels, and
receptors, plus the cascades of intermediate messengers and regulators of biochemical events at the cell membrane, cytoplasmic
matrix and organelles, or the cell nucleus. Markers associated to
connective cells, meninges, blood vessels and blood-derived cells,
melanocytes, glial cell types, tanycytes, and various circumventricular organs can be used as well in genoarchitectonic mappings.
Finally, genoarchitectonic maps allow nowadays the development of transgenic tools by which injected substances can be
precisely targeted to molecularly defined brain areas, so that the
projections of given neurons can be specifically studied. These
are just some examples of many other technical breakthroughs
that are emerging as genoarchitectonic maps develop their scientific potential. Application of these maps to clinical issues is still
in its infancy, though some correlations are starting to appear.
For instance, interventional radiological neurosurgeons are finding that sectors of the cerebral cortex that were originally delimited genoarchitectonically in embryos seem relevant to
understand the characteristic spatial distributions of arteriovenous malformations they need to treat surgically in their patients.
References
Ferran, J. L., Dutra de Oliveira, E., Sanchez-Arrones, L., Sandoval, J. E.,
Martnez-de-la-Torre, M., & Puelles, L. (2009). Genoarchitectonic analysis of
regional histogenesis in the chicken pretectum. The Journal of Comparative
Neurology, 517, 405451.
Hawrylycz, M., Baldock, R. A., Burger, A., Hashikawa, T., Johnson, G. A., Martone, M.,
et al. (2011). Digital atlasing and standardization in the mouse brain. PLoS
Computational Biology, 7(2), e1001065.
216
In G. Paxinos (Ed.), The rat nervous system (3rd ed., pp.325). San Diego, CA:
Academic Press.
Puelles, L., Martinez-de-la-Torre, M., Bardet, S., & Rubenstein, J. L. R. (2012).
Hypothalamus. In C. Watson, G. Paxinos & L. Puelles (Eds.), The mouse nervous
system (pp. 221312). London: Academic Press/Elsevier, Chapter 8.
Puelles, L., Martnez-de-la-Torre, M., Paxinos, G., Watson, C., & Martnez, S. (2007). The
chick brain in stereotaxic coordinates: An Atlas featuring neuromeric subdivisions and
mammalian homologies. San Diego, CA: Elsevier/Academic Press.
Puelles, L., & Rubenstein, J. L. R. (1993). Expression patterns of homeobox and other
putative regulatory genes in the embryonic mouse forebrain suggest a neuromeric
organization. Trends in Neurosciences, 16, 472479.
Puelles, L., & Rubenstein, J. L. R. (2003). Forebrain gene expression domains and the
evolving prosomeric model. Trends in Neurosciences, 26, 469476.
Swanson, L. W. (2012). Brain architecture: Understanding the basic plan (2nd ed.).
Oxford: Oxford University Press.
Thompson, C. L., Ng, L., Menon, V., Martinez, S., Lee, C.-K., Glattfelder, K., et al.
(2015). A high resolution spatiotemporal atlas of gene expression of the C57Bl/6J
developing mouse brain. Neuron, 83, 309323.
Waddington, C. H. (1940). Organisers and genes. Cambridge: Cambridge University
Press.
Waddington, C. H. (1975). The evolution of an evolutionist. Edinburgh: Edinburgh
University Press, pp. 99102.
Basal Ganglia
A Wree, University Medical Center Rostock, Rostock, Germany
O Schmitt, University Medical Center Rostock, Rostock, Germany
2015 Elsevier Inc. All rights reserved.
Glossary
Abbreviations
AChE
ChAT
DARPP-32
DR1
DR2
GPe
GPi
MSN
nc
Acetylcholine esterase
Choline acetyl transferase
DA- and cAMP-regulated phosphoprotein
32 kDa
D1 dopamine receptor
D2 dopamine receptor
Globus pallidus pars externa (external
segment)
Globus pallidus pars interna (internal
segment)
Medium spiny neuron of Str
Nucleus
Introduction
As early as 1664, the anatomist Thomas Willis separated a
subcortical region from the lateral ventricle and thalamus and
named it the corpus striatum (Willis, 1664, p. 167; Figure 1).
Later on, Parent (1986) introduced the term basal ganglia
for the corpus striatum and further subcortical nuclear regions.
According to structural, functional, chemoarchitectonic, and
hodologic properties, the basal ganglia include the corpus
striatum (the caudate nucleus and putamen, often also termed
as the neostriatum), nucleus accumbens (part of the ventral
striatum), globus pallidus (external and internal segments),
nucleus subthalamicus, and substantia nigra pars compacta
(SNc) and pars reticulata (some publications also include the
amygdaloid body and the claustrum). The basal ganglia, which
are massively influenced by widespread cortical afferents,
process and modulate motivated and goal-directed behaviors,
as their circuits project back primarily to the motor cortex
(Alexander & Crutscher, 1990; Alexander, DeLong, & Strick,
1986). With regard to the processing of motor signals, the
NC
NOS
P
PAN
PD
PPN
PV
Str
SNc
SNr
STN
TAN
VTA
Caudate nucleus
Nitric oxide synthase
Putamen
Phasically active neuron
Parkinsons disease
Pedunculopontine nucleus
Parvalbumin
Striatum
Substnatia nigra pars compacta
Substnatia nigra pars reticulata
Subthalamic nucleus
Tonically active neuron
Ventral tegmental area
http://dx.doi.org/10.1016/B978-0-12-397025-1.00215-3
217
218
Figure 1 Cover page of the book Cerebri Anatome of Thomas Willis and the first published illustration of the corpus striatum (A) on page 167. The
legend to A says the following: Corpus striatum in medio discissum, ut illius stria medullares appareant.
219
Figure 2 The basal ganglia are shown in histological sections of a human brain dataset of Amunts et al. (2013) in neuroVIISAS (Schmitt & Eipert, 2012)
(http://neuroviisas.med.uni-rostock.de/neuroviisas.html). (a) A frontal section through the human brain depicting the rostral part of the striatum
with NCc and P, both incompletely separated by the internal capsule leaving caudolenticular gray bridges. Further details of the basal ganglia more
rostral than the level of (a) are given in (b) and details of the basal ganglia more caudal in (ce). ACb, accumbens nucleus; CGB, caudolenticular gray
bridges; GPe, globus pallidus pars externa; GPi, globus pallidus pars interna; IC, internal capsule; NCc, caput nuclei caudati (head); NCcp, corpus
nuclei caudati (body); NCcd, cauda nuclei caudati (tail); P, putamen; SN, substantia nigra pars compacta and pars reticulata; STN, subthalamic nucleus;
VL, ventrolateral thalamic nucleus; MD, mediodorsal thalamic nucleus.
220
Striatum
SNr
Primary
motoric
cortex
Thalamus
Ventral nuclei
Ventrolateral nc.
Ventromedial nc.
SNc
STN
Secondary
motoric
cortex
Intralaminary nuclei
Parafascicular nc.
Central medial nc.
Central lateral nc.
Direct pathway
GPi
Motoric
corticostriatal
output
221
Indirect pathway
GPe
Inhibitory
D2 receptors
Hyperdirect pathway
Figure 3 Summary of the so-called motor basal ganglia pathways in a simplified block diagram of the principal connections. The nuclei of the basal
ganglia, the striatum, the external segment of the globus pallidus (GPe), the internal segment of the globus pallidus (GPi), the substantia nigra pars
reticulata (SNr), the substantia nigra pars compacta (SNc), and the subthalamic nucleus (STN) are shown in their main connections with the motor
cortex and thalamus. The two major inputs to the striatum come from the cortex and the thalamus (intralaminar nuclei and ventral nuclei). The SNr
and GPi built up the output nuclei of the basal ganglia, projecting as part of the loop to thalamic nuclei. Dopaminergic neurons of the SNc are reciprocally
connected to the striatum (other SNc efferents are not depicted in this scheme) and modulate cortical and thalamic information flow through the
striatum. In the direct pathway, the information flow leads to a disinhibition of thalamus. The indirect pathway from the striatum through the GPe and
STN to GPi/SNr results in a reduced disinhibition and a reduced thalamic stimulation of the motor cortex and the striatum. The STN also receives
cortical input, forming the hyperdirect pathway. The arrows indicate the direction of the projection and the principal transmitters used by the respective
projection neurons: green, glutamatergic; red, GABAergic; yellow, dopaminergic. GPe, globus pallidus pars externa; GPi, globus pallidus pars
interna; nc, nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus.
222
AGI
GPe
Str
GPi
STN
SNc
SNr
Figure 4 Much of the intrinsic connectivity of the basal ganglia has been
revealed in the laboratory rat as shown in the wiring diagram. Many
reciprocal connections are described in publications applying anterograde
and retrograde tract tracing methods. These data were collected and
represented in this overview diagram using neuroVIISAS (Schmitt &
Eipert, 2012). AGl, agranular lateral cortex (M1); GPe, globus pallidus pars
externa; GPi, globus pallidus pars interna; SNc, substantia nigra pars
compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus;
Str, striatum; T, thalamus.
223
Glut
AGI
DPW
GABA
DR1
ACh
Str
DR2
GABA
IPW
DR2
Glut
GABA
DA
GABA
Thalamus
GPi/SNr
SNc
GPe
Glut
STN
Figure 5 Neurotransmitters and dopamine receptors of the main projection neurons forming the direct (DPW) and indirect (IPW) pathways through
the basal ganglia. The arrows indicate the direction of the projection and the principal transmitters used by the respective projection neurons: green,
glutamatergic; red, GABAergic; yellow, dopaminergic; blue, cholinergic. ACh, acetylcholine; AGl, agranular lateral cortex (the primary motor cortex); DA,
dopamine; DR1, dopamine receptor 1; DR2, dopamine receptor 2; GABA, g-aminobutyric acid; Glut, glutamate; GPe, globus pallidus pars externa;
GPi, globus pallidus pars interna; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus; Str, striatum.
oriented ventrally and horizontally and occupy major portions of the pars reticulata. Furthermore, they express high
levels of dopamine transporter and D2 receptor mRNAs.
The relatively large multipolar SNc neurons (diameter
about 2545 mm) not only have long and spine-poor dendrites
mainly situated in the SNc but also extend into the SNr (Yelnik,
Francois, Percheron, & Heyner, 1987). They receive dense synaptic input from the striatal MSNs (GABA), the GPe (GABA),
the STN (glutamate), the PPN (acetylcholine), and dorsal
raphe nuclei (serotonin) (Figures 3 and 5). Axons leave the
SNc and mainly project to the striatum and via collaterals also
to GPe and STN and colliculus superior (Hedreen & DeLong,
1991). However, a dendritic release of dopamine is shown to
influence via D2 autoreceptors neighboring dopaminergic SNc
neurons. In the striatum, the axons of the SNc neurons ramify
massively giving rise to about 300 000 symmetrical synapses
that are located predominantly at the neck of various spines of
many MSNs in a topographic fashion.
224
movements, mastication, vocalization, and habits); (2) learning, acquisition, and adjustment of new behaviors; and (3)
development of habits depending on reinforcement. The
basal ganglia can act in a very efficient way to select an appropriate action in a particular context (Hikosaka, 2009). Moreover, the basal ganglia also contribute to a wide range of
cognitive functions that drive behaviors. These functions
include learning, memory, skill, planning, switching, sequencing, timing, and the processing of rewards and other feedback.
The basal ganglia are parts of circuits or loops involved in
the chain cortexbasal gangliathalamuscortex; the basal
ganglia can be functionally grouped into four categories: (1)
input nuclei, the striatum and STN receiving cortical inputs;
(2) output nuclei, GPi and SNr projecting to the thalamus and
the brain stem; (3) connecting nucleus, GPe connecting the
input nuclei to the output nuclei; and (4) modulatory nucleus,
SNc modulating the activity of the basal ganglia (Figure 6).
Generally, the striatum as the input nucleus receives excitatory glutamatergic input from the cerebral cortex. Striatal projection neurons innervate the output nuclei, GPi/SNr, via two
different pathways: (1) the direct pathway (MSN with GABA,
substance P, and dynorphin project directly to the GPi/SNr) and
(2) the indirect pathway (MSN with GABA and enkephalin
project indirectly and polysynaptically to the GPi/SNr via the
Motoric, sensorimotoric
GPe and STN) (Albin, Young, & Penney, 1989; Anderson, 2009;
Baev et al., 2002; Kravitz, Tye, & Kreitzer, 2012).
Excitation of striatal neurons through the direct
monosynaptic pathway has inhibitory effects on GPi/SNr neurons. As GPi/SNr neurons are inhibited by the MSNs GABA,
they themselves release fewer GABA at their thalamic
terminals, thus allowing the thalamic nuclei project to cortical
areas and thereby increasing the excitatory influence on the
cortex. The behavioral results of this direct chain are locomotor
activation and movements. Excitatory signals of the striatal
neurons through the indirect pathway have excitatory effects
on GPi/SNr neurons because both striato-GPe and GPe-STN
projections are inhibitory (net effect is in a disinhibition of
GPi/SNr neurons) and STNGPi/SNr projections are excitatory. Subsequently, increased activity of GPi/SNr neurons
leads to increased GABA release in thalamic nuclei, the latter
leading to decreased thalamocortical excitatory projections. At
the end, this effect results in a reduction of locomotor activity
and movement.
Excitation from the cerebral cortex, additional to the basal
ganglia circuitry, is forwarded directly and with fast conduction
velocity to the STN in a somatotopically organized manner.
The STN can therefore also be considered an input nucleus of
the basal ganglia, forming a third pathway, the hyperdirect
Associative, cognitive
Limbic
Motor cortex
Oculomotor
cortex
Dorsolateral
prefrontal cortex
Orbital + medial
prefrontal cortex
Anterior
cingular cortex
Putamen
Central lateral
caput and corpus
nc. caudati
Dorsolateral
caput nc. caudati
Ventromedial
caput nc. caudati
Ventral striatum
vl GPi
cdm GPi
Idm GPi
mdm GPi
cl SNR
vl SNR
rl SNR
rm SNR
rd SNR
pm MDmc
rl GPi
VP
VLo
I VAmc
VApc
m VAmc
VLm
MDpl
MDpc
MDmc
CMm
CMm
PFc
PFc
PFa
Eye movements
Working memory,
strategic planing
Reward based
behaviors,
motivation
Emotions,
drug addiction
Execution of wanted
motor behavior,
habits
Figure 6 Functional segregation of direct pathways through the basal ganglia (modified after Alexander et al., 1986). The circuit motor/sensorimotor,
associative/cognitive, or limbic territories of specific regions of the cerebral cortex, the striatum, the pallidum pars interna, the substantia nigra pars
reticulata, and the specific and intralaminar nuclei are involved. cdm GPi, caudal dorsomedial globus pallidus pars interna; cl GPi, caudolateral globus
pallidus pars interna; cl SNr, caudolateral substantia nigra pars reticulata; CMl, central median nucleus lateral part; CMm, central median nucleus
medial part; ldm GPi, lateral dorsomedial globus pallidus pars interna; MDmc, mediodorsal thalamic nucleus magnocellular part; MDpc, mediodorsal
thalamic nucleus parvocellular part; MDpl, mediodorsal thalamic nucleus paralaminar part; mdm GPi, medial dorsomedial globus pallidus pars
interna; nc, nucleus; PFa, parafascicular nucleus anterior part; PFc, parafascicular nucleus caudal part; pm MDmc posteromedial mediodorsal thalamic
nucleus magnocellular part; rd SNr: rostrodorsal substantia nigra pars reticulata; rm SNr, rostromedial substantia nigra pars reticulata; rl GPi,
rostrolateral globus pallidus pars interna; l VAmc, lateral ventroanterior thalamic nucleus magnocellular part; m VAmc medial ventroanterior thalamic
nucleus magnocellular part; VApc, ventroanterior thalamic nucleus parvocellular part; vl GPi, ventrolateral globus pallidus pars interna; VLm,
ventrolateral thalamic nucleus medial part; VLo, ventrolateral thalamic nucleus oral part; vl SNr, ventrolateral substantia nigra pars reticulata; VP, ventral
pallidum. http://neuroviisas.med.uni-rostock.de/neuroviisas.html.
225
References
Albin, R. L., Young, A. B., & Penney, J. B. (1989). The functional anatomy of basal
ganglia disorders. Trends in Neurosciences, 12(10), 366375.
226
Haber, S. N., & Gdowki, M. J. (2004). The basal ganglia. In G. Paxinos & J. K. Mai
(Eds.), The human nervous system (pp. 676738). (2nd ed.). Amsterdam: Elsevier.
Haber, S. N., Lynd-Balta, E., & Mitchell, S. J. (1993). The organization of the
descending ventral pallidal projections in the monkey. Journal of Comparative
Neurology, 329, 111129.
Haber, S. N., & Watson, S. J. (1985). The comparative distribution of enkephalin,
dynorphin and substance P in the human globus pallidus and basal forebrain. The
Journal of Neuroscience, 4, 10111024.
Hardman, C. D., Henderson, J. M., Finkelstein, D. I., Horne, M. K., Paxinos, G., &
Halliday, G. M. (2002). Comparison of the basal ganglia in rats, marmosets,
macaques, baboons, and humans: Volume and neuronal number for the output,
internal relay, and striatal modulating nuclei. Journal of Comparative Neurology,
445, 238255.
Hedreen, J. C., & DeLong, M. R. (1991). Organization of striatopallidal, striatonigral,
and nigrostriatal projections in the Macaque. Journal of Comparative Neurology,
304, 569595.
Heimer, L., De Olmos, J. S., Alheid, G. F., Person, J., Sakamoto, N., Shinoda, K., et al.
(1999). The human basal forebrain. Part II. In F. E. Bloom, A. Bjorklund & T. Hokfelt
(Eds.), Handbook of chemical neuroanatomy (pp. 57226). Amsterdam: Elsevier.
Hikosaka, O. (2009). Basal ganglia and oculomotor control. In M. D. Binder, N.
Hirokawa & U. Windhorst (Eds.), Encyclopedia of neuroscience (pp. 5361). Berlin:
Springer.
Hikosaka, O., Nakamura, K., & Nakahara, H. (2006). Basal ganglia orient eyes to reward.
Journal of Neurophysiology, 95, 567584.
Hikosaka, O., & Wurtz, R. H. (1983). Visual and oculomotor functions of monkey
substantia nigra pars reticulata. IV. Relation of substantia nigra to superior
colliculus. Journal of Neurophysiology, 49, 12851301.
Holt, D. J., Graybiel, A. M., & Saper, C. B. (1997). Neurochemical architecture of the
human striatum. Journal of Comparative Neurology, 384, 125.
Holt, D. J., Hersh, L. B., & Saper, C. B. (1996). Cholinergic innervation in the human
striatum: A three-compartment model. The Journal of Neuroscience, 74, 6787.
Kawaguchi, Y. (1997). Neostriatal cell subtypes and their functional roles. Neuroscience
Research, 27, 18.
Kawaguchi, Y., Wilson, C. J., Augood, S. J., & Emson, P. C. (1995). Striatal
interneurones: Chemical, physiological and morphological characterization. Trends
in Neurosciences, 18, 527535.
Kliem, M. A., & Wichmann, T. (2009). Basal ganglia: Functional models of normal and
disease states. In M. D. Binder, N. Hirokawa & U. Windhorst (Eds.), Encyclopedia of
neuroscience (pp. 8792). Berlin: Springer.
Koob, G. F., & Nestler, E. J. (1997). The neurobiology of drug addiction. The Journal of
Neuropsychiatry and Clinical Neurosciences, 9, 482497.
Kravitz, A. V., Tye, L. D., & Kreitzer, A. C. (2012). Distinct roles for direct and indirect
pathway striatal neurons in reinforcement. Nature Neuroscience, 15, 816818.
Lange, H., Thorner, G., & Hopf, A. (1976). Morphometric-statistical structure analysis of
human striatum, pallidum and nucleus subthalamicus. III. Nucleus subthalamicus.
Journal fur Hirnforschung, 17, 3141 (Article in German).
Mai, J., Paxinos, G., & Voss, T. (2008). Atlas of the human brain (3rd ed.). San Diego:
Academic Press.
Marsden, C. D. (1984). Function of the basal ganglia as revealed by cognitive and motor
disorders in Parkinsons disease. Canadian Journal of Neurological Sciences, 11,
129135.
McFarland, N. R., & Haber, S. N. (2000). Convergent inputs from thalamic motor nuclei
and frontal cortical areas to the dorsal striatum in the primate. The Journal of
Neuroscience, 20, 37983813.
Nambu, A. (2009). Basal ganglia: Physiological circuits. In M. D. Binder, N. Hirokawa &
U. Windhorst (Eds.), Encyclopedia of neuroscience (pp. 111117). Berlin: Springer.
Nambu, A., Tokuno, H., Hamada, I., Kita, H., Imanishi, M., Akazawa, T., et al. (2000).
Excitatory cortical inputs to pallidal neurons via the subthalamic nucleus in the
monkey. Journal of Neurophysiology, 84, 289300.
Nambu, A., Tokuno, H., & Takada, M. (2002). Functional significance of the
cortico-subthalamo-pallidal hyperdirect pathway. Neuroscience Research, 43,
111117.
Nelson, A. B., & Kreitzer, A. C. (2014). Reassessing models of basal ganglia function
and dysfunction. Annual Review of Neuroscience, 37, 117135.
Nieuwenhuys, R., Voogd, J., & van Huijzen, C. (2008). The human central nervous
system (4th ed.). Berlin: Springer.
Olszewski, J., & Baxter, D. (1982). Cytoarchitecture of the human brain stem (2nd ed.).
Basel: Karger.
Parent, A. (1986). Comparative neurobiology of the basal ganglia. New York: Wiley.
Parent, A. (1990). Extrinsic connections of the basal ganglia. Trends in Neurosciences,
13, 254258.
Parent, A., & Hazrati, L. N. (1993). Anatomical aspects of information processing in
primate basal ganglia. Trends in Neurosciences, 16, 111115.
227
Thorner, G., Lange, H., & Hopf, A. (1975). Morphometrical-statistical structure analysis
of human striatum, pallidus and subthalamic nucleus. II. Globus pallidus. Journal
fur Hirnforschung, 16, 401413 (Article in German).
Wichmann, T., Bergman, H., & DeLong, M. R. (1994). The primate subthalamic
nucleus. I. Functional properties in intact animals. Journal of Neurophysiology, 72,
494506.
Wiesendanger, R., & Wiesendanger, M. (1985). The thalamic connections with medial
area 6 (supplementary motor cortex) in the monkey (Macaca fascicularis).
Experimental Brain Research, 59, 91104.
Willis, T. (1664). Cerebri anatome: cui accessit nervorum descriptio et usus. Amsterdam.
Wilson, C. J. (2004). Basal ganglia. In G. M. Shepherd (Ed.), The synaptic organization
of the brain (pp. 361413). (5th ed.). New York: Oxford University Press.
Yelnik, J., Francois, C., Percheron, G., & Heyner, S. (1987). Golgi study of the primate
substantia nigra. I. Quantitative morphology and typology of nigral neurons. Journal
of Comparative Neurology, 265, 455472.
Yeterian, E. H., & Pandya, D. N. (1998). Corticostriatal connections of the superior
temporal region in rhesus monkeys. Journal of Comparative Neurology, 399,
384402.
Relevant Websites
http://bigbrain.cbrain.mcgill.ca The BigBrain LORIS Database of the Montreal
Neurological Institute and the Forschungszentrum Julich.
http://www.thehumanbrain.info/about_us.php The human brain info is a web based
interactive knowledge and atlas system of the Atlas of the human brain from Mai,
Voss and Paxinos.
http://www.loni.usc.edu/ The Laboratory of Neuro Imaging (LONI) offers challenging
tools for brain atlases and differents sets of imaging data.
http://de.slideshare.net/ananthatiger/anatomy-of-basal-ganglia This extensice slide
show provides a good overview of the basalganglia.
http://neuroscience.uth.tmc.edu/s3/chapter04.html The electronic textbook for
neurosciences contains a chapter of the Basal Ganglia with many structural and
functional details.
http://neuroviisas.med.uni-rostock.de/neuroviisas.html NeuroVIISAS is generic
framework for the integration of digital atlases, connectomes and population
simulations. It has a database on its webpage for querying all known connections of
the rat nervous system.
http://homepage.psy.utexas.edu/HomePage/Class/Psy394U/Hayhoe/
IntroSensoryMotorSystems/week7/Ch43.pdf This very informative web resource
about the basal ganglia has been build by Mahlon De Long.
Thalamus: Anatomy
MT Herrero, University of Murcia, Murcia, Spain
R Insausti, University Castilla La Mancha, Albacete, Spain
C Estrada, University of Murcia, Murcia, Spain
2015 Elsevier Inc. All rights reserved.
Glossary
Abbreviations
Anterior nuclear complex
Medialmidline group
Pt
PV
Re
AD
MDmc
MDpc
Lateral group
LP
VA
VL
VM
VP
VPL
VPM
VPpo
VPI
http://dx.doi.org/10.1016/B978-0-12-397025-1.00216-5
229
230
Intralaminar group
CL
CM
PCn
Pf
Posterior group
PM
Metathalamus
Pul
LGN
The Thalamus
The diencephalon, which forms the central core of the brain, is
at the dorsal end of the brain stem. Inside the diencephalon,
the dorsal thalamus (just called the thalamus) is its largest
component; however, the human thalamus is small when
compared to the rest of the encephalon (Tuohy et al., 2004).
The thalamus is a midline bilateral structure with two symmetrical halves separated by the third ventricle but connected by
the interthalamic adhesion (massa intermedia), a flattened gray
band (Morel, 2007). Then, the medial surface of the thalamus
corresponds to the upper part of the lateral wall of the third
ventricle. From a radiological point of view, thalamic segmentation defines the anterior boundary of the thalamus as the first
slice caudal to the anterior commissure: at rostral slices, the
thalamus starts behind the columnae fornicis and the mammillary bodies, and at the caudal slices, the thalamus is the region
below the fornix. The geniculate nuclei (both medial and
lateral) were included in the outline at levels where the lateral
geniculate nucleus (LGN) was attached to the corpus of the
thalamus and not separated from it by a white matter tract.
Ventrally, the thalamus is located close to the hypothalamus
and the mesencephalon. The hypothalamus lies ventral to the
thalamus and is more anteriorly situated relative to the
thalamus; therefore, in coronal sections, the mammillary bodies (the caudal part of the hypothalamus) are at the same plane
of section compared with the anterior complex of the thalamus. At all levels, the thalamus is bordered medially by the
third ventricle, dorsally by the lateral ventricles, and laterally
by the internal capsule on both sides (Figure 1(a) and 1(b)).
The thalamus has an average volume of around 9 cm3 in males
and 8 cm3 in females being around 5.7 cm in length, 2.5 cm in
height, and about 2 cm in width. It has been estimated that
there are about 10 million thalamic neurons in each
hemisphere.
The thalamus, the major relay to the cerebral cortex, is not
only the part of the nervous system where sensory inputs
(except olfaction) can be modulated but also the relay for
limbic pathways and cerebellar and basal ganglia inputs to
the cerebral cortex (Zhang et al., 2010). Moreover, the
thalamus is also implicated in numerous systems and functions as in alertness, arousal, memory, and the ability to
accomplish tasks of fast information processing. The thalamus dispenses specific alerting or engagement response to the
different domains of function to which it contributes. With
the exception of the reticular nucleus (RN), the other nuclei
of the thalamus project to the cerebral cortex and receive
reciprocal connections from the same cortical areas that in
turn can modulate the thalamic functions filtering its thalamic inputs.
231
(a)
(b)
(c)
Figure 1 The thalamus is an oval-shaped region located in the center of the brain. (a) Coronal cross section of the brain showing the thalamic medial
surface that forms part of the lateral wall of the third ventricle (III) and is usually connected to the opposite thalamus by the gray matter
interthalamic connection (interthalamic adhesion) and the thalamic lateral limits, the internal capsule, and the caudate nucleus; please note the lateral
border of the superior surface of the thalamus is limited by the stria terminalis (gray) and overlying thalamostriate vein (blue), which separate
thalamic nuclei from the body of the caudate nucleus. Additionally, the external medullary lamina, white matter, separates the main body of the thalamus
Continued
232
Figure 1 Contd from the reticular nucleus. (b) Sagittal section showing the rostral limits, the anterior commissure (AC), and the caudal limits, the
posterior commissure (PC). It can be noted that dorsally, the thalamus is bounded by the fornix (and subarachnoid space in the form of the transverse
cerebral fissure) and ventrally is limited by the hypothalamic sulcus (HS, sulcus of Monro) of the third ventricle (this sulcus in the lateral wall of third
ventricle extends from the upper end of midbrain aqueduct posteriorly to the interventricular foramen anteriorly). (c) Cartoon of the prosomeric
model showing the three prosomeres part of the caudal forebrain, being P2 (in gray) the segment origin of the thalamus (modified from Epstein, 2012).
AC, anterior commissure; CC, corpus callosum; Cd, caudate nucleus; cDi, caudal diencephalon; CM, centromedian nucleus; HS, hypothalamic
sulcus; Hyp, hypothalamus; IA, interthalamic adhesion; IC, internal capsule; LP, lateral posterior nucleus; LV, lateral ventricle; MD, mediodorsal nucleus;
Mes, mesencephalon; Met, metencephalon; PC, posterior commissure; Pf, parafascicular nucleus; RN, reticular nucleus; ST, stria terminalis; Tel,
telencephalon; Th, thalamus; TSV, thalamostriate vein; VPL, ventral posterior lateral nucleus; VPM, ventral posteromedial nucleus; III, third ventricle.
Note: The interthalamic adhesion (mediodorsal neurons) is found in 7080% of humans and its anteroposterior diameter is about 1 cm in length.
233
Comments
234
Table 1
Abbreviations
Comments
LIM
LIMm
LIMd
LIMps
pIl
LCL
LCM
LArc
G
Gm
Gl
Lemniscal thalamus
N. ventral posterolateral, VPL
N. ventral posteromedial, VPM
Gustatory thalamus
Spinothalamic thalamus
N. ventral posterior inferior, VPI
N. ventral posterior, VPpo
Auditory thalamus, MGN
Visual thalamus, LGN
The dorsal thalamus (II) is divided into allo- (II.A) and isothalamus (II.B).
a
There is no polar subdivision without lower afferents in front of the pallidal and nigral territories and thus no reason for isolating a nucleus lateralis polaris or a polar VA (Percheron
et al., 1996).
b
Nucleus lateralis oralis, situs ventralis (LOv) nucleus ventralis oralis posterior, Vop (Hassler, 1959) nucleus ventral lateral ventral (Hirai & Jones, 1989). Pallidal connections.
c
Nucleus lateralis intermedius mediodorsalis, situs ventralis medialis (LIMm) N. ventralis intermedius (Vim) (Hassler, 1959) nucleus ventral lateral posterior (ventral part) (Hirai &
Jones, 1989). Cerebellar connections.
Source: Modified with permission from Herrero, M. T., Barcia, C., Navarro, & J. M. (2002). Functional anatomy of thalamus and basal ganglia. Childs Nervous System, 18, 386404;
previously modified from Percheron, G., Francois, C., Talbi. B., Yelnik, J., & Fenelon, G. (1996). The primate motor thalamus. Brain Research Reviews, 22, 93181.
nuclei and with different functions (arousal, hearing, emotional, movement, sight or touch). The RN is the only
thalamic nucleus that does not project to the cerebral cortex but in this nucleus blend afferents from cortical areas,
from the globus pallidus, and from dorsal thalamic nuclei.
In fact, most inputs to other thalamic nuclei are collaterals
of fibers passing through this nucleus modulating the flow
of information from other nuclei to the cortex. Its neurons
are GABAergic (inhibitory) and contribute to the synchrony and rhythms of thalamic activity with a relevant
importance in consciousness, sleep, and epilepsy. These
GABAergic cells are innervated by collateral branches of
thalamocortical and corticothalamic fibers (with connectivity with both the thalamic nuclei and its associated
cortical area) (Jones, 2002a, 2002b).
(ii) The specific sensory thalamic nuclei include the ventroposterior nuclei (lateral, medial, and inferior; VPL, VPM, and
VPI, respectively) and the geniculate nuclei (medial and
lateral; MGN and LGN, respectively). The topographical
organization of the afferents to the somatosensory thalamic nuclei is contralateral (however, some nuclei have
both contralateral and ipsilateral connections (as the gustatory system, Iannilli, Singh, Schuster, Gerber, &
Hummel, 2012)). The ventroposterior nuclei receive topographically organized projections from the dorsal column
(medial lemniscus) and the spinothalamic and the trigeminothalamic tracts: VPL nucleus controls body and
limbs, and VPM nucleus the head, neck, and gustatory
relays. VPL and VPM nuclei are somatotopically interconnected with primary unimodal somatosensory parietal
cortices (Figures 2 and 3, Table 2). The gustatory
235
L
V
AN
RN
MD
IM
VA
IA
LD
LP
VL
Pu
l
VP
EM
LGN
Rostral
MGN
Middle
Caudal
LP
LD
A (R)
P (C)
Coronal plane
AD
RN
RN
RN
VPL
CL
VA
CL
MD
Pt
Pul
MD
PV PCn
CM
VL
CM
VM
Re
Pf
VPM
Pf
MTT
VL
MGN
LGN
Middle
Ventral
Dorsal
VA
Axial plane
RN
MD
VL
Sagittal plane
Pt
VP
CM
VA
VL
LP
PV
VP
VPM
CL
MD
VP
Pf
CM
MG Pul
N
LGN
RN
LD
VL
CL
Pv
Medial
RN
VA
MD
VPM
AD
AV
Re
D
Pul
Pul
Middle
Lateral
LD
LP
AD
MD
AV
Pt
VA
Re
VA
Pul
VL
Pf
VP
Pul
VL
MG
CM
VP
LG
Figure 2 At the top: Divisions of the thalamus. Nuclei: yellow, anterior group; blue, lateral group; purple, posterior group; green, midline group; orange,
intralaminar group. Underneath: anatomy and subdivisions of the thalamus nuclei analyzed by means of coronal, axial, and sagittal planes.
Continued
236
MC
C
PMC
SS
PC
PFC
POC
AC
VC
TC
A
L
M
P
V
AN
RN
IA
M
IM
VA
SMA
MC
LD
SSC
LP
VL
CC
PFC
Pu
l
VP
RS
EM
POC
LGN
MGN
VC
TC
Figure 3 Topography of projections of the thalamic nuclei. (a) Cerebral cortex, lateral view of the right hemisphere; (b) cerebral cortex, sagittal view of
the left hemisphere; (c) thalamic nuclei. Please see the code of colors similar in the left thalamic nuclei and its corresponding cortical areas (Behrens
et al., 2003). A, anterior; AC, auditory cortex; AN, anterior nuclear complex; CC, cingulate cortex; D, dorsal; EML, external medullary lamina; IA,
interthalamic adhesion; IML, internal medullary lamina; L, lateral; LD, laterodorsal nucleus; LGN, lateral geniculate nucleus; LP, lateral posterior nucleus;
M, medial; MC, motor cortex; MD, mediodorsal nucleus; MGN, medial geniculate nucleus; PC, parietal cortex; PFC, prefrontal cortex; PMC, premotor
cortex; P, posterior; POC, parieto-occipital cortex; Pul, pulvinar complex; RN, reticular nucleus; RS, retrospenial cortex; SMA, supplementary motor
area; SSC, somatosensory cortex; TC, temporal cortex; V, ventral; VA, ventral anterior nucleus; VC, visual cortex; VL, ventral lateral nucleus; VP, ventral
posterior nucleus.
thalamus is made up of three topographically distinct territories: nigral, pallidal, and cerebellar. The thalamic cerebellar territory is located caudally in front of the somesthetic
ventral posterior nucleus. These nuclei are implicated in the
control of movement because they are strategically located
between motor areas of the cerebral cortex and motorrelated subcortical structures, such as the cerebellum and
basal ganglia; in fact, these nuclei are a part of the segregated
but integrated cortico striatalthalamocortical loops (the
functional entities for motor and sensory processes as well
as for higher cognitive functions like cognitive and emotional processes, which also include the dorsomedial,
intralaminar, and anterior thalamic nuclei) (Figure 3;
Metzger et al., 2013).
Figure 2 Contd A, anterior; AD, anterodorsal nucleus; AV, anteroventral nucleus; C, caudal; CL, central lateral nucleus; CM, centromedian nucleus;
D, dorsal; EML, external medullary lamina; IA, interthalamic adhesion; IML, internal medullary lamina; L, lateral; LD, laterodorsal nucleus; LGN, lateral
geniculate nucleus; LP, lateral posterior nucleus; M, medial; MD, mediodorsal nucleus; MGN, medial geniculate nucleus; MTT, mammillothalamic tract;
P, posterior; PCn, paracentral nucleus; Pf, parafascicular nucleus; Pt, paratenial nucleus; Pul, pulvinar complex; PV, paraventricular nucleus; R, rostral;
Re, nucleus reuniens; RN, reticular nucleus; V, ventral; VA, ventral anterior nucleus; VL, ventral lateral nucleus; VM, ventral medial nucleus; VP, ventral
posterior nucleus; VPL, ventral posterior lateral nucleus; VPM, ventral posteromedial nucleus.
237
Nucleus
Anterior nuclear complex
Anterodorsal, anteromedial, and
anteroventral nuclei
Laterodorsal nucleus
Medialmidline group
Lateral group
Lateral posterior nucleus
Ventral anterior nucleus
Ventral lateral nucleus
Ventral posterior nucleus
Ventral posterolateral nucleus
Ventral posteromedial nucleus
Ventral posterior nucleus
Intralaminar nuclei
Metathalamus
Medial geniculate nucleus
Lateral geniculate nucleus
Reticular nucleus
Afferents
Efferents
Cingulate cortex
Prefrontal cortex
Amygdala, olfactory cortex
Basal ganglia
Somatosensory cortex
Somatosensory cortex
Superior colliculus
Secondary somatosensory cortices
Inferior colliculus
Retina (optic tract)
Thalamocortical projections
Corticothalamic projections
Globus pallidus
Dorsal thalamic nuclei
Thalamic nuclei
Somatosensory cortex
238
surgery target for treating tremor (Hyam, Owen, Kringelbach, et al., 2012; Schatelbrand & Bailey, 1959).
(iv) The thalamic limbic nuclei (Although nowadays the concept
of limbic system (related to emotion and memory) is
diffuse and variable, it was initially related to the cortex
that surrounds the thalamus, the grand lobe limbique of
Broca and the Papezs circuit. This circuit starts in the subiculum of the hippocampal formation projecting (fimbriafornix system) to the hypothalamic mammillary
complex that projects (mammillothalamic tract) to the
AN complex of the thalamus that sends its projections to
the cingulate cortex.) related to the limbic system (limbic
system used in its broadest sense) are located at the anterior
half part of the thalamus: the rostral pole with the AN
complex, the LD nucleus, and the magnocellular part of
the dorsomedial nucleus. Its function in general is related
with memory, learning, mood, emotional experiences, and
motivation (Child & Benarroch, 2012). The anterior complex is made up of the AD, AM, and AV nuclei and the LD
nucleus, which is considered a caudal extension of the
anterior complex. This group receives the projection from
the mammillary complex, being the AD nucleus the
nucleus that receives bilateral projections, while the projections to the AM and AV nuclei are only ipsilateral. It has
been established that it is only the posterior cingulate
cortex that receives afferents from the AN complex and
the LD of the thalamus, while anterior cingulate cortex
does receive afferents from the midline thalamic nuclei.
The anterior complex is reciprocally connected with the
hippocampal formation (memory-related functions)
through the mammillary nuclei. The mammillary nuclei
receive the postcommissural fornix and project to the AN
complex through the mammillothalamic tract. Other functional activities of the AN complex are related to the prefrontal cortex, with which it has extensive connections, as
well with parts of the cingulate cortex (The anterior cingulate cortex receives afferents as well from the MD thalamic
nucleus. In fact, there are two functional components
in the cingulate cortex: an anterior cingulate cortex territory under the dependence of the magnocellular part of
the MD nucleus and a posterior cingulate cortex dependent on the thalamic AN complex.) (Figures 2 and 3,
Table 2).
(v) The intralaminar thalamic nuclei can be classified into an
anterior and a posterior group. The anterior includes the
PCn and CL nuclei. The posterior group is integrated by
the CM and the Pf nuclei. The last two nuclei are the most
representative of the group and are related mainly to the
striatum and basal ganglia being the CM nucleus implicated in motor functions and the Pf nucleus in emotional
and cognitive circuits/loops. The intralaminar nuclei
have reciprocal connections with cortical areas and
receive afferents from the spinal cord, the brain stem,
and the cerebellum. In fact, the midline nuclei receive
nonspecific projections from the periaqueductal gray matter processing the motivational and affective components
of pain. Moreover, due to its cortical connections, the
intralaminar nuclei can form important hubs in frontal,
parietal, and temporal networks (Saalman, 2014; Figures 2 and 3, Table 2): (a) The anterior intralaminar
nuclei (PCn and CL nuclei) are part of the oculomotor
239
The presence of specific and diffuse corticothalamic projections may serve to promote coherent activity of large populations of cortical and thalamic neurons in perception, attention,
and conscious awareness (Jones, 2002a). Additionally, thalamic nuclei receive inhibitory projections from the RN. The
interactions between RN cells and relay cells are mediated by
GABAergic inhibitory receptors (GABA-A and GABA-B). There
are intrinsic thalamic circuitries (generated and maintained by
corticothalamic projections) that interact with GABAergic cells
of the RN and glutamatergic relay cells. These intrinsic circuits
underlie rhythmic activities of neurons in the thalamo
corticothalamic network (associated with changes in the conscious state). Electrical synapses are a major feature of the
inhibitory circuitry in the thalamocortical system, mainly in
the RN. The interaction between inhibitory neurons can induce
rhythmic action potentials that are synchronized within a millisecond precision, being the substrate of temporal and spatial
coordination of the complex neural activity in the thalamocortical projections (The electrical synapses are active in the inhibitory circuitry of the thalamocortical system. Electrical synapses
have gap junction channels interconnecting neurons. Gap
junction channels (made of specific proteins connexins)
allow ionic current and small organic molecules to pass
directly between cells, usually with symmetrical ease
(Cruikshank, Landisman, Mancilla, & Connors, 2005).
Cholinergic afferents
Cholinergic systems have been broadly involved in state regulation (sleepwake cycle and attention) and may contribute to
state-dependent changes in information routing in the neocortex; brain stem cholinergic inputs can modulate cortical activity through the thalamus. Cholinergic neurons projecting to
the thalamus have collaterals to more than one thalamic
nucleus as well as to other nonthalamic regions. The main
sources of cholinergic innervation are the laterodorsal tegmental nucleus (LDTN) and the pedunculopontine tegmental
nucleus (PPN). The MD, LP, VA, ventral lateral, LD, and posterior nuclei receive fibers from the LDTN and the intralaminar
nuclei, and the CL nuclei receive afferent fibers bilaterally from
the PPN. The CM nucleus receives from both cholinergic areas.
Additionally, the PPN projects both to the LGN and to the
superior colliculus.
Serotonin innervation
Serotonergic projections from medial and lateral divisions of
the midbrain are implicated in the control of the sleepwake
cycle as well as in emotional disorders like depression. In the
thalamus, serotonergic afferents target preferentially the midline, anterior, and intralaminar nuclei (which are strongly
interconnected with cortical executive areas), where they have
heterogeneous effects on membrane potential and could evoke
changes in firing mode throughout the sleepwake cycle.
240
Dopaminergic modulation
The thalamus does not receive strong dopaminergic innervation from the substantia nigra, but it gets dopamine afferents from the ventral tegmental area, the hypothalamus, the
zona incerta, the periaqueductal gray, and the lateral parabrachial nucleus. The densest projections are to the midline
thalamus, and the lowest densities are found in sensory firstorder nuclei. Dopaminergic terminals are often near thalamic terminals at their targets (e.g., the neocortex and
striatum); this means that at least some of the thalamic
dopaminergic modulation may occur at the terminal site
rather than at the soma.
Histamine
The histaminergic projection arises from the hypothalamic
tuberomammillary neurons (which are only active during
wakefulness and their degree of activation correlates with alertness levels). This modulator can be involved in attentional
levels and in the regulation of general changes of activity across
states of vigilance through the sleepwake cycle. Histaminergic
presynaptic receptors (H3 and H4) could be important in the
modulation of thalamostriatal terminals.
AN
IA
RN
D
IM
VA
MD
LD
VA
One of the main sources of information about thalamic functions is due to diseases of the cerebrovascular system, comparing the clinical symptoms with the location of the lesion on
in vivo neuroimaging or on pathological examination of the
brain (Schmahmann, 2003). The symptoms can reveal the
functional and behavioral roles of different thalamic nuclei,
but it is exceptional to have clean lesions (the infarcts usually
affect to vascular territories, which are not specific of single
nuclei) (Schmahmann & Pandya, 2008). In fact, vascular
lesions involve larger regions implicating few anatomical
nuclei; however, the functions of one (or more) region(s)
depending on the personal variation of the vascular anatomy
of each individual frequently prevail. The thalamic arteries vary
between individuals (the number of arteries and its position,
the origin, or the nuclei supplied by each branch). For instance,
the tuberothalamic artery is absent in approximately one-third
of the population (its territory is supplied by the paramedian
artery). Thalamic infarction or hemorrhage of each of the
different arterial territories develop the main four thalamic
vascular syndromes: (i) the tuberothalamic artery, which is a
branch of the carotid artery; (ii) the paramedian artery, which
is branch of the basilar artery; (iii) the inferolateral artery,
which is a branch of the posterior cerebral artery; and (iv) the
posterior choroidal artery, which is a branch of the mesencephalic artery (the mesencephalic artery is the P1 region of the
posterior cerebral artery) (Figure 4). For more details about the
vascular supply of thalamic nuclei and the main clinical features after focal thalamic infarctions, please see Tables 3 and 4
(modified from Schmahmann & Pandya, 2008).
P
V
VL
LP
VL
MD
Pu
VP
VP
EM
LGN
MGN
9
2
Pul
2
4
6 Tuberothalamic artery
7 Paramedian artery
9 Inferolateral artery
Figure 4 Thalamic vascularization. A, anterior; AN, anterior nuclear complex; D, dorsal; EML, external medullary lamina; IA, interthalamic adhesion;
IML, internal medullary lamina; L, lateral; LD, laterodorsal nucleus; LGN, lateral geniculate nucleus; LP, lateral posterior nucleus; M, medial; MD,
mediodorsal nucleus; MGN, medial geniculate nucleus; P, posterior; Pul, pulvinar complex; V, ventral; VA, ventral anterior nucleus; VL, ventral lateral
nucleus; VP, ventral posterior nucleus. The tuberothalamic artery (6, in yellow) is a branch of the carotid artery (1); the paramedian artery (7, in green) is
a branch of the basilar artery (2); the posterior choroidal artery (8, in purple) is a branch of the mesencephalic artery (3) (the P1 region of the posterior
cerebral artery); the inferolateral artery (9, in blue) is a branch of the posterior cerebral artery (4). The posterior communicant artery (5) is located
between the carotid and the basilar arteries. Modified from Schmahmann, J. D., & Pandya, D. N. (2008). Disconnection syndromes of basal ganglia,
thalamus, and cerebrocerebellar systems. Cortex, 44, 10371066.
Table 3
Four major
thalamic arteries
Tuberothalamic
artery
Paramedian
artery
Nuclei irrigated
RN
AD, AM, AV
MD (ventral
pole)
IL
VA, VL
(rostral pole)
IML (ventral)
VAP
MTT
MD, PV
CL, CM, Pf
VPM
LD
Pul
(ventromedial)
Tracts irrigated
VP
VL (ventral part)
Medial
branch
Inferolateral
pulvinar branches
Lateral
branches
Medial
branches
MGN
LD
Pul (rostral and
lateral)
LGN
LD
LP
Pul
(inferolateral)
MGN
CM, Pf
Pul
IML (dorsal)
AD, anterodorsal nucleus; AM, anteromedial nucleus; AV, anteroventral nucleus; CL, central lateral nucleus; CM, centromedian nucleus; IL, intralaminar nuclei; IML, internal medullary
lamina; LD, laterodorsal nucleus; LGN, lateral geniculate nucleus; LP, lateral posterior nucleus; MD, mediodorsal nucleus; MGN, medial geniculate nucleus; MTT, mammillothalamic
tract; Pf, parafascicular nucleus; Pul, pulvinar complex; PV, paraventricular nucleus; RN, reticular nucleus; VA, ventral anterior nucleus; VAP, ventral amygdalofugal pathway; VL,
ventral lateral nucleus; VP, ventral posterior nucleus; VPM, ventral posteromedial nucleus. The tuberothalamic artery is a branch of the carotid artery; the paramedian artery is a branch
of the basilar artery; the inferolateral artery is a branch of the posterior cerebral artery; the posterior choroidal artery is a branch of the mesencephalic artery (the P1 region of the
posterior cerebral artery).
Source: Modified from Schmahmann, J. D., & Pandya, D. N. (2008). Disconnection syndromes of basal ganglia, thalamus, and cerebrocerebellar systems. Cortex, 44, 10371066.
Table 4
Paramedian artery
Inferolateral artery
MD, PV
CL, CM, Pf
VPM
LD
Pul (ventromedial)
Tracts irrigated
Principal inferolateral
branch
IML
VAP
MTT
IML
VP complex
VA, VL, VM
Medial branch
Inferolateral pulvinar
branches
Posterior choroidal
artery
Lateral branches
Medial branches
MGN
Pul (rostral and
lateral)
LD
Pul (inferolateral),
LGN
LD, LP
Pul, MGN
CM, Pf
Aphasia
Memory impairment
Variable sensory loss
Weakness
AD, anterodorsal nucleus; AM, anteromedial nucleus; AV, anteroventral nucleus; CL, central lateral nucleus; CM, centromedian nucleus; IL, intralaminar nuclei; IML, internal medullary
lamina; LD, laterodorsal nucleus; LGN, lateral geniculate nucleus; LP, lateral posterior nucleus; MD, mediodorsal nucleus; MGN, medial geniculate nucleus; MTT, mamilothalamic
tract; Pf, parafascicular nucleus; Pul, pulvinar complex; PV, paraventricular nucleus; RN, reticular nucleus; VA, ventral anterior nucleus; VAP, ventral amygdalofugal pathway; VL,
ventral lateral nucleus; VP, ventral posterior nucleus; VPM, ventral posteromedial nucleus.
Source: Modified from Schmahmann, J. D., & Pandya, D. N. (2008). Disconnection syndromes of basal ganglia, thalamus, and cerebrocerebellar systems. Cortex, 44, 10371066.
242
Acknowledgments
This article is supported by the University of Murcia (Campus
Mare Nostrum) and Spanish Center for Networked Biomedical
Research on Neurodegenerative Diseases (CIBERNED) (CB05/
05/505) to MTH and by grant BFU 2009-14705 of the Ministry
of Economy and Competitiveness and Junta de Comunidades
de Castilla-La Mancha to RI. The invaluable assistance of Juani
Alegra (Maqueta2, Murcia) to MTH through her drawings is
gratefully acknowledged.
References
Apkarian, A. V., Shi, T., Bruggemann, J., & Airapetian, L. R. (2000). Segregation of
nociceptive and non-nociceptive networks in the squirrel monkey somatosensory
thalamus. Journal of Neurophysiology, 84, 484494.
Bartlett, E. L. (2013). The organization and physiology of the auditory thalamus and its
role in processing acoustic features important for speech perception. Brain and
Language, 126, 2948.
Behrens, T. E.J, Johansen-Berg, H., Woolrich, M. W., et al. (2003). Non-invasive
mapping of connections between human thalamus and cortex using diffusion
imaging. Nature Neuroscience, 6, 750757.
Chen, W., Zhu, X. H., Thulborn, K. R., & Ugurbil, K. (1999). Retinotopic mapping of
lateral geniculate nucleus in humans using functional magnetic resonance imaging.
Proceedings of the National Academy of Sciences of the United States of America,
96, 24302434.
Child, N. D., & Benarroch, E. E. (2013). Anterior nucleus of the thalamus: Functional
organization and clinical implications. Neurology, 81, 18691876.
Craig, A. D. (2003). Pain mechanisms: Labelled lines versus convergence in central
processing. Annual Review of Neuroscience, 26, 130.
Cruikshank, S. J., Landisman, C. E., Mancilla, J. G., & Connors, B. W. (2005).
Connexon connexions in the thalamocortical system. Progress in Brain Research,
149, 4157.
Epstein, D. J. (2012). Regulation of thalamic development by sonic hedgehog. Frontiers in
Neuroscience, 6, 57. http://dx.doi.org/10.3389/fnins.2012.00057 (eCollection 2012).
Haber, S., & Calzavara, R. (2009). The cortico-basal ganglia integrative network: The
role of the thalamus. Brain Research Bulletin, 78, 6974.
Hassler, R. (1959). Anatomy of the thalamus. In G. Schaltenbrand, & P. Bailey (Eds.),
Introduction to stereotaxis with an atlas of the human brain. Stuttgart: Thieme.
Herrero, M. T., Barcia, C., & Navarro, J. M. (2002). Functional anatomy of thalamus and
basal ganglia. Childs Nervous System, 18, 386404.
Hirai, T., & Jones, E. G. (1989). A new parcellation of the human thalamus on the basis
of histochemical staining. Brain Research Reviews, 14, 134.
Hyam, J. A., Owen, S. L., Kringelbach, M. L., et al. (2012). Contrasting connectivity of
the ventralis intermedius and ventralis oralis posterior nuclei of the motor thalamus
demonstrated by probabilistic tractography. Neurosurgery, 70, 162169.
Iannilli, E., Singh, P. B., Schuster, B., Gerber, J., & Hummel, T. (2012). Taste laterality
studied by means of umami and salt stimuli: An fMRI study. NeuroImage, 60,
426435.
Jones, E. G. (2002a). Progress thalamic organization and function after Cajal. Progress
in Brain Research, 136, 333357.
Jones, E. G. (2002b). Thalamic circuitry and thalamocortical synchrony. Philosophical
Transactions of the Royal Society of London. Series B: Biological Sciences, 357,
16591673.
Jones, E. G. (2007). The thalamus (2nd ed.). Cambridge, UK: Cambridge University
Press.
Jones, E. G. (2009). Synchrony in the interconnected circuitry of the thalamus and
cerebral cortex. Annals of the New York Academy of Sciences, 1157, 1023.
Kolliker, A. (1896). (6th ed.). Handbuch der Gewebelehre des Menschen.
Nervensysteme des Menschen und der Thiere (Vol. 2, p. 95). Leipzig: Engelman.
Krauth, A., Blanc, R., Poveda, A., et al., (2010). A mean three-dimensional atlas of the human
thalamus: Generation from multiple histological data. NeuroImage, 49, 20532062.
Metzger, C. D., van der Werf, Y. D., & Walter, M. (2013). Functional mapping of
thalamic nuclei and their integration into cortico-striatal-thalamo-cortical loops via
ultra-high resolution imaging-from animal anatomy to in vivo imaging in humans.
Frontiers in Neuroscience, 7, 24.
Mitchell, A. S., & Chakraborty, S. (2013). What does the mediodorsal thalamus do?
Frontiers in Systems Neuroscience, 7, 37.
Morel, A. (2007). Stereotactic atlas of the human thalamus and basal ganglia. New York:
Informa Healthcare Inc.
Percheron, G., Francois, C., Talbi, B., Yelnik, J., & Fenelon, G. (1996). The primate
motor thalamus. Brain Research Reviews, 22, 93181.
Puelles, L., & Rubinstein, J. L. (1993). Expression patterns of homeobox and other
putative regulatory genes in the embryonic mouse forebrain suggest a neuromeric
organization. Trends in Neurosciences, 16, 472479.
Ramon y Cajal, S. (1903). Plan de estructura del talamo optico. Madrid: Congreso
Medico Internacional.
Ramon y Cajal, S. (1900). Cajal: Contribucion al estudio de la va sensitiva central y de
la estructura del talamo optico. (Con cuatro grabados.) Revista trimestral
micrografica, tomo V.
Saalman, Y. B. (2014). Intralaminar and medial thalamic influence on cortical
synchrony, information transmission and cognition. Frontiers in Systems
Neuroscience, 8, 18.
Schatelbrand, G., & Bailey, P. (1959). Introduction to stereotaxis with an atlas of the
human brain. Stuttgart: Thieme.
Schmahmann, J. D. (2003). Vascular syndromes of the thalamus. Stroke, 34,
22642278.
Schmahmann, J. D., & Pandya, D. N. (2008). Disconnection syndromes of basal
ganglia, thalamus, and cerebrocerebellar systems. Cortex, 44, 10371066.
Schneider, K. A., Richter, M. C., & Kastner, S. (2004). Retinotopic organization and
functional subdivisions of the human lateral geniculate nucleus: A high-resolution
functional magnetic resonance imaging study. Journal of Neuroscience, 24,
89758985.
Tuohy, E., Leahy, C., Dockery, P., et al. (2004). P1: An anatomical and MRI study of the
human thalamus. Journal of Anatomy, 205, 527.
Varela, C. (2014). Thalamic neuromodulation and its implications for executive
networks. Frontiers in Neural Circuits, 8, 69. http://dx.doi.org/10.3389/
fncir.2014.00069.
Vue, T. Y., Aaker, J., Taniguchi, A., et al. (2007). Characterization of progenitor domains
in the developing mouse thalamus. Journal of Comparative Neurology, 505, 7391.
Zhang, D., Snyder, A. Z., Shimony, J. S., et al. (2010). Non-invasive functional and
structural connectivity mapping of the human thalamocortical system. Cerebral
Cortex, 20, 11871194.
Relevant Websites
http://blog.susannereiterer.eu/wp-content/uploads/2013/01/06Mang_et-al-ThalamusSeg_MRM2011.pdf Thalamus Segmentation Based on the Local Diffusion
Direction: A Group Study.
http://www.princeton.edu/~napl/research.htm University of Princeton NAPL.
http://users.umassmed.edu/charlene.baron/pdfs/AxialMRI_Atlas08oe.pdf UMass
Medical School Mind Brain Behavior 1.
Abbreviations
CF
DCN
IO
MF
PC
PF
Climbing fiber
Deep cerebellar nuclei
Inferior olive
Anatomy
Cerebellum: Basic Structural Organization
The cerebellum is present in nearly all vertebrates and
undergoes a remarkable expansion in the mammalian and
avian orders. The cerebellum of mammals is composed of a
strongly folded cerebellar cortex that covers the white matter
and the deep cerebellar nuclei (DCN). The cerebellar cortex
consists of three layers: the granule cell layer, the molecular
layer, and, in between these two, the Purkinje cells (PCs)
arranged in a two-dimensional array. The cerebellar cortex
receives two kinds of afferents, the mossy fiber (MF) and
climbing fiber (CF), which mediate a wide variety of vestibular,
somatosensory, visual, and auditory sensory modalities, as
well as tectal and cerebral cortical afferents. MFs contact the
granule cells that send their axons to the molecular layer where
they make T-shaped ramifications, the so-called parallel fibers
(PFs). These PFs are very thin and unmyelinated and form
excitatory synapses on their postsynaptic targets. They contact
the dendritic trees of the PCs and of the inhibitory interneurons of the molecular layer (the so-called basket and stellate
cells) up to a distance of 23 mm from the site of bifurcation.
The myelinated CFs, all of which have their origin in the
inferior olive (IO), contact the PCs directly. The PCs mediate
the sole output of the cerebellar cortex by projecting to the
DCN and to the vestibular nuclei.
Unlike in the cerebral cortex, there are few obvious structural differences among different regions of the cerebellar
cortex. Moreover, in comparison with the cerebral cortex,
the cerebellar cortex stands out through its well-defined geometric texture. The parallel arrangement of the folds of the
cerebellum, with the folds all running in a laterolateral
direction, is readily apparent macroscopically. The PFs all
run along the folds. They constitute one-half of the orthogonal cerebellar lattice, while the dendritic trees of the PCs and
the dendrites and axons of the basket and stellate cells provide
the other. The latter all ramify only in the direction perpendicular to the folds.
The majority of the cell types in the cerebellum are inhibitory. However, the granule cells with their PF axons are the
most numerous cells in the cerebellum and are excitatory. The
excitatory pyramidal cells in the cerebral cortex form contacts
with each other, whereas the granule cells do not. In fact, the
division of the cerebellar cortex into two major layers (the
granular and molecular layers) appears to have the important
consequence of keeping the granule cell dendrites and their
Mossy fiber
Purkinje cell
Parallel fiber
http://dx.doi.org/10.1016/B978-0-12-397025-1.00218-9
243
244
Anterior lobe
Anterior lob.
A X B C 1 C 2 C3 D 1 Y D 2
I
II/III
Crus I
IV/V
VI
Lob. simplex
Lob. simplex
VIIA
Crus II
VIIB
Dorsal parafloc.
XI
Ventral parafloc.
Crus I
X
Flocculus
(b)
(c)
Vent.
Floc. parafloc.
Paramed.
Dors.
parafloc. lob.
Crus II
(a)
(d)
Figure 1 Introduction to the cerebellar anatomy. (a) Drawing of the dorsal view of the human cerebellum. Modified from Riley, H. A. (1928).
The mammalian cerebellum. Archives of Neurology & Psychiatry, 20, 8951034. The cerebellum is slightly stretched to enable the different lobules to
be more easily distinguished. In (b), the correspondence of the human lobes and lobules to that of the cats cerebellum is shown. Modified
from Glickstein, M., Sultan, F., & Voogd, J. (2009). Functional localization in the cerebellum. Cortex, 47, 5980. The cats cerebellum is now
stretched semiquantitatively. The right-hand side of (b) shows the longitudinal zones (A, X, B, C13, D12, and Y) according to Voogd and Bigare (1980).
(b) Within the vermis (middle folial chain), the lobule numbering IX according to Larsell (1948) is shown. The quantitative extent of the
unfolded cat (c) and the human cerebellum (d) is shown. The silhouette-like maps were obtained by connecting the ends of the most prominent folia.
The scale in between corresponds to 10 cm for the cat and 30 cm for the human cerebellum. Modified from Sultan, F., & Braitenberg, V. (1993).
Shapes and sizes of different mammalian cerebella. A study in quantitative comparative neuroanatomy. Journal fur Hirnforschung, 34, 7992.
Cerebellar modules
The cerebellar cortex shows no obvious differences between its
various areas. Analysis of its connections and chemoarchitecture reveal, however, that the PCs are arranged in a series of
precisely organized zones (Voogd, 1969) with different histochemical properties (Hawkes & Leclerc, 1987). The zonal organization of the cerebellar output system is the basis of the
modular organization of the cerebellum. The zones are a series
of stripes oriented perpendicularly to the folia and fissures. The
functional nature of the zones is determined by the output of
their target nuclei (for a review, see Glickstein et al., 2011).
The longitudinal or parasagittal zones were originally
defined by mapping both the anatomical connectivity
(Voogd, 1969) and the electrophysiological receptive field
responses (Oscarsson, 1969) following somatosensory stimulation. Oscarsson and colleagues showed that the longitudinal
zones in the cat were 1 mm wide (along the PF axis) and
100 mm long. An even finer parcellation into microzones
with 200 mm width was also shown (Oscarsson, 1979). PCs
within such a zone project to a defined region of the cerebellar
output structures, the DCN and vestibular nuclei. Neurons
within the IO nucleus are organized in subgroups that project
245
their axons as CFs to PCs that are restricted within a longitudinal zone. The IO neurons also innervate subgroups of the DCN
and vestibular nuclei via axon collaterals. These subgroups
then receive input from the same PCs. These connected subgroups of neurons in the IOPCDCN and IODCN paths
join to constitute a module. Oscarsson proposed that these
modules are the operational units of the cerebellum
(Oscarsson, 1979). The importance of these zones was reinforced by the fact that they were found in a number of animals.
In various animal species (birds and mammals), very similar pattern can be observed in several regions within the
cerebellum (notably the regions at the rostral and caudal
ends, that is, the lobus anterior and the floccularnodular
parts). Careful mapping of the sensory receptive fields divulged
that longitudinal zones can be divided even further into what
are known as microzones.
Based on the molecular gene expression found in PCs, it
was possible to unveil a concept similar to that of longitudinal/
sagittal zones. The first molecule to be studied in depth was
Zebrin II (metabolic aldolase C), which was discovered by
Hawkes and Leclerc (1987) in PCs and surrounding glia. Subsets of PC positive for the epitope alternate with negative
stripes. Like the zones, the stripes are distributed symmetrically
across the midline. Later studies showed that the Zebrin stripes
do not show the full complexity of heterogeneous molecular
markers in PCs, since even finer bands can be detected within
Zebrin bands (see Apps & Hawkes, 2009 for review). The way
in which the strips are organized is reminiscent of the microzonal organization. They are similar in both size
(100300 mm wide) and number (several hundred stripes
in mice and rats). Each stripe is estimated to have several
hundred PCs (total number of PCs in rats 3 105).
246
cluster, the interstitial cell groups, is located between the fastigial and posterior interposed nuclei.
The differentiation of subregions within the DCN is intimately linked to the parcellation of the connected cerebellar
cortex and IO. Using aldolase C labeling, the DCN can be
further distinguished into ten regions. In an elaborate study,
multiple small tracer injections into the IO revealed clustering
of the IODCN collaterals (collaterals of the CF), demarking
well-delineated subregions in the DCN (Figure 2). The extent
of the IO collaterals in the DCN was limited to a radius of
about 100150 mm. A careful analysis by Sugihara and
Shinoda (2007) showed that these numerous clusters could
be classified into five classes on the basis of the origin of the
Group
Cerebellar
cortex
aldolase C
Cerebellar
cortex zones
I
(green)
Mesodiencephalic
IIa
(cyan and blue)
Vestibular
IIa
(cyan and blue)
Collicular
III
(yellow and orange)
Somatosensory,
Vestibular,
Mesodiencephalic
IV
(pink and red)
Somatosensory
V (gray)
Visual
Caudodorsal view
(b)
(a)
(c)
Figure 2 Cerebellar zones. Mapping of the topography of the olivocortical and olivonuclear projections together with aldolase C immunostaining. In the
work by Sugihara and Shinoda (2007), five groups were distinguished and mapped onto the unfolded cerebellar cortex of a rat (a). (b) and (c) show
the 3-D scheme and two views of the left DCN (b: ventral portions; c: dorsocaudal view). The zones defined by aldolase C are marked by numerals
with / signs, denoting aldolase C-positive and aldolase C-negative stained regions. The convention is that the numbering ascends from the most
medial stripe. This plot is the summary of a large number of experiments, tracing the olivocerebellar, olivonuclear, and corticonuclear projections. The
correspondence of this nomenclature with Voogds zones (Figure 1(b)) is shown in the table. The table also denotes the afferent types received by
the corresponding olivary regions and the color coding. The arrows represent a finer topographic correspondence within each group between the areas
in the cortex and the nuclei. Reproduced from Sugihara, I., Fujita, H., Na, J., Quy, P. N., Li, B.-Y., & Ikeda, D. (2009). Projection of reconstructed
single purkinje cell axons in relation to the cortical and nuclear aldolase C compartments of the rat cerebellum. The Journal of Comparative Neurology,
512, 282304, with permission of John Wiley & Sons, Inc.
247
Elephant
Chimpanzee
Manatee
Kangaroo
Rhesus
Flying fox
Rabbit
Porpoise
Rat
Cat
Bear
Cow
248
Prosimian-type
Simian-type
Hominoid-type
103
Human
Baboon
Gibbon
Spider monkey
Rhesus monkey
102
101
100
100
101
(a)
102
Log brain weigth (g)
103
dors
ant
post
vent
(b)
(d)
lat
med
5 mm
(c)
1
0.5
0
(e)
5 mm
Figure 4 Comparative DCN. Regularities and irregularities are evident in the scaling of the cerebellar dentate nucleus. In (a), data from the study of
Macleod, Zilles, Schleicher, Rilling, and Gibson (2003) are shown (Glickstein et al., 2011). Plotted is the dentate volume versus brain volume for
primates on a double-logarithmic plot. A proportional increase in the volume of both can be observed (slope of regression line of 1.04). Different primate
suborders are denoted with different symbols. The gibbon is the first ape that shows a highly folded dentate, although the volume of its dentate is
comparable to other monkeys of similar size. (be) Surface reconstructions of the dentate nucleus of the macaque (b and c) and of the human (d and e).
Overlaid on the surfaces is the thickness of the lamina at the respective site color-coded with white depicting thicker regions (see color bar). Clearly, a
thicker macrogyric part can be discerned in the ventrolateral region of the macaque. This is not the case in the human dentate. Scale bars: 5 mm.
shown that the human dentate nucleus is activated in manipulative tasks (Dimitrova et al., 2006; Gao et al., 1996).
The specialization of the primate cerebellum becomes particularly evident when compared to marine mammals (see
Figure 4). In cetaceans (whales and dolphins) and pinnipeds
(seals), the second loop containing the dorsal and ventral
paraflocculus is much larger. The huge size of the paraflocculus
is due to an expanded (width and length) C2 zone and an
extremely expanded nucleus interpositus posterior, as opposed
to the primate D2-dentate expansion in width and length. This
differential expansion in these very encephalized animals is an
excellent example of specialized brain architecture and refutes
the theory that regular brain scaling underlays large brains. In
References
Angaut, P., & Sotelo, C. (1987). The dentato-olivary projection in the rat as a
presumptive gabaergic link in the olivocerebelloolivary loop An ultrastructuralstudy. Neuroscience Letters, 83, 227231.
Apps, R., & Hawkes, R. (2009). Cerebellar cortical organization: A one-map hypothesis.
Nature Reviews. Neuroscience, 10, 670681.
Batini, C., Compoint, C., Buisseret-Delmas, C., Daniel, H., & Guegan, M. (1992).
Cerebellar nuclei and the nucleocortical projections in the rat: Retrograde tracing
coupled to GABA and glutamate immunohistochemistry. Journal of Comparative
Neurology, 315, 7484.
Bolk, L. (1906). Das Cerebellum der Saugetiere. Jena: Gustav Fischer Verlag.
Braitenberg, V. (2001). Brain size and number of neurons: An exercise in synthetic
neuroanatomy. Journal of Computational Neuroscience, 10, 7177.
Chen, S., & Hillman, D. E. (1993). Colocalization of neurotransmitters in the deep
cerebellar nuclei. Journal of Neurocytology, 22, 8191.
Dimitrova, A., De Greiff, A., Schoch, B., Gerwig, M., Frings, M., Gizewski, E. R., et al.
(2006). Activation of cerebellar nuclei comparing finger, foot and tongue
movements as revealed by fMRI. Brain Research Bulletin, 71, 233241.
Dow, R. S. (1942). The evolution and anatomy of the cerebellum. Biological Reviews of
the Cambridge Philosophical Society, 17, 179220.
Dum, R. P., Li, C., & Strick, P. L. (2002). Motor and nonmotor domains in the monkey
dentate. Annals of the New York Academy of Sciences, 978, 289301.
Eccles, J. C., Ito, M., & Szentagothai, J. (1967). The cerebellum as a neuronal machine.
Berlin: Springer-Verlag.
Gao, J. H., Parsons, L. M., Bower, J. M., Xiong, J., Li, J., & Fox, P. T. (1996).
Cerebellum implicated in sensory acquisition and discrimination rather than motor
control. Science, 272, 545547.
Gebo, D. L. (1996). Climbing, brachiation, and terrestrial quadrupedalism: Historical
precursors of hominid bipedalism. American Journal of Physical Anthropology,
101, 5592.
Gellman, R., Gibson, A. R., & Houk, J. C. (1985). Inferior olivary neurons in the awake
cat: Detection of contact and passive body displacement. Journal of
Neurophysiology, 54, 4060.
Gibson, A. R., Horn, K. M., & Pong, M. (2004). Activation of climbing fibers.
Cerebellum, 3, 212221.
Glickstein, M., Sultan, F., & Voogd, J. (2009). Functional localization in the cerebellum.
Cortex, 47, 5980.
Glickstein, M., Sultan, F., & Voogd, J. (2011). Functional localization in the cerebellum.
Cortex, 47, 5980.
Hawkes, R., & Leclerc, N. (1987). Antigenic map of the rat cerebellar cortex: The
distribution of parasagittal bands as revealed by monoclonal anti-Purkinje cell
antibody mabQ113. Journal of Comparative Neurology, 256, 2941.
Horn, K. M., Pong, M., & Gibson, A. R. (2010). Functional relations of cerebellar
modules of the cat. Journal of Neuroscience, 30, 94119423.
Kennedy, P. R., Gibson, A. R., & Houk, J. C. (1986). Functional and anatomic
differentiation between parvicellular and magnocellular regions of red nucleus in the
monkey. Brain Research, 364, 124136.
Larsell, O. (1948). The development and subdivisions of the cerebellum of birds.
Journal of Comparative Neurology, 89, 123189.
249
Leiner, H. C., Leiner, A. L., & Dow, R. S. (1993). Cognitive and language functions of
the human cerebellum. Trends in Neurosciences, 16, 444447.
Macleod, C. E., Zilles, K., Schleicher, A., Rilling, J. K., & Gibson, K. R. (2003).
Expansion of the neocerebellum in Hominoidea. Journal of Human Evolution, 44,
401429.
Matano, S., & Hirasaki, E. (1997). Volumetric comparisons in the cerebellar complex of
anthropoids, with special reference to locomotor types. American Journal of
Physical Anthropology, 103, 173183.
Murphy, J. T., & Sabah, N. H. (1971). Cerebellar Purkinje cell responses to afferent
inputs. I. Climbing fiber activation. Brain Research, 25, 449467.
Oelschlager, H. H.A (2008). The dolphin brainA challenge for synthetic
neurobiology. Brain Research Bulletin, 75, 450459.
Oscarsson, O. (1969). The sagittal organization of the cerebellar anterior lobe as
revealed by the projection patterns of the climbing fiber system. In S. R. Llin (Ed.),
Neurobiology of cerebellar evolution and development. Chicago, IL: American
Medical Association.
Oscarsson, O. (1979). Functional units of the cerebellum Sagittal zones and
microzones. Trends in Neurosciences, 2, 143145.
Palkovits, M., Magyar, P., & Szentagothai, J. (1972). Quantitative histological analysis
of the cerebellar cortex in the cat. IV. Mossy fiber-Purkinje cell numerical transfer.
Brain Research, 45, 1529.
Riley, H. A. (1928). The mammalian cerebellum. Archives of Neurology & Psychiatry,
20, 8951034.
Rossi, F., Wiklund, L., Van Der Want, J. J. L., & Strata, P. (1989). Climbing fibre
plasticity in the cerebellum of the adult rat. European Journal of Neuroscience, 1,
543547.
Sakai, S. T., Inase, M., & Tanji, J. (1996). Comparison of cerebellothalamic
and pallidothalamic projections in the monkey (macaca-fuscata) A
double anterograde labeling study. Journal of Comparative Neurology, 368,
215228.
Schmahmann, J. D., & Caplan, D. (2006). Cognition, emotion and the cerebellum.
Brain, 129, 290292.
Schuz, A., & Sultan, F. (2009). Brain connectivity and brain size. In In: L. R. Squire
(Ed.), New Encyclopedia of neuroscience (vol. 2. Oxford: Academic Press.
Shinoda, Y., Sugihara, I., Wu, H. S., & Sugiuchi, Y. (2000). The entire trajectory of
single climbing and mossy fibers in the cerebellar nuclei and cortex. Progress in
Brain Research, 124, 173186.
Sugihara, I., Fujita, H., Na, J., Quy, P. N., Li, B.-Y., & Ikeda, D. (2009). Projection of
reconstructed single purkinje cell axons in relation to the cortical and nuclear
aldolase C compartments of the rat cerebellum. The Journal of Comparative
Neurology, 512, 282304.
Sugihara, I., & Shinoda, Y. (2007). Molecular, topographic, and functional organization
of the cerebellar nuclei: Analysis by three-dimensional mapping of the
olivonuclear projection and aldolase C labeling. Journal of Neuroscience, 27,
96969710.
Sultan, F. (2002). Analysis of mammalian brain architecture. Nature, 415,
133134.
Sultan, F., & Braitenberg, V. (1993). Shapes and sizes of different mammalian cerebella.
A study in quantitative comparative neuroanatomy. Journal fur Hirnforschung, 34,
7992.
Voogd, J. (1969). The importance of fiber connections in the comparative anatomy of
the mammalian cerebellum. In S. R. Llin (Ed.), Neurobiology of cerebellar evolution
and development. Chicago, IL: American Medical Association.
Voogd, J. (2004). Cerebellum and precerebellar nuclei. In G. Paxinos & J. K. May
(Eds.), The human nervous system. Amsterdam: Elsevier.
Voogd, J., & Bigare, F. (1980). Topographical distribution of olivary and corticonuclear fibers in the cerebellum: A review. In J. Courville (Ed.), The inferior olivary
nucleus: Anatomy and physiology. New York: Raven Press.
Voogd, J., & Glickstein, M. (1998). The anatomy of the cerebellum. Trends in
Neurosciences, 21, 370375.
Walberg, F., Pompeiano, O., Brodal, A., & Jansen, J. (1962). The fastigiovestibular
projection in the cat. An experimental study with silver impregnation methods.
Journal of Comparative Neurology, 118, 4976.
Glossary
Introduction
The brain stem joins the forebrain to the spinal cord. It consists
of the midbrain and the hindbrain. The cerebellum is an
outgrowth of the rostral hindbrain and technically should be
included as part of the hindbrain. However, it is not considered
in most texts to be an integral part of the brain stem, and in this
book, it will be dealt with in a separate article. We have found
that the best way to deal with this semantic problem is to use
the term axial hindbrain to distinguish the cylindrical parts of
the hindbrain from the cerebellar outgrowth.
The discovery of gene targeting in mice (Capecchi, 1989,
2005) has opened a new era of brain anatomy, in which
patterns of developmental gene expression can be used to
define the true relationships and subdivisions of parts of the
brain. These new revelations have had a major impact on
concepts relating to the midbrain and hindbrain. The most
important of these changes are
http://dx.doi.org/10.1016/B978-0-12-397025-1.00219-0
251
252
& Ashwell, 2009; Watson & Paxinos, 2010) and atlases of the
developing brain of rat and mouse (Ashwell & Paxinos, 2008;
Paxinos, Halliday, Watson, Koutcherov, & Wang, 2007). A
notable feature of the Paxinos family of atlases is that they all
use the same nomenclature and abbreviations, mutatis
mutandis.
Outside of this family of atlases, some other notable works
have appeared the rat brain atlases of Swanson (2003) and
Kruger, Saporta, and Swanson (1995); the Allen Mouse Brain
Atlas (Dong, 2008); and the hamster brain atlas of Morin and
Wood (2001). Of these, the first three use the nomenclature of
Swanson (2003), but the Morin and Wood atlas uses the
nomenclature of Paxinos and Watson (1982).
The Isthmus
The Midbrain
The midbrain (mesencephalon) joins the diencephalon to the
hindbrain. During development, the neuraxis undergoes a
sharp bend in the region of the midbrain, which distorts the
adult anatomy of the midbrain (Puelles, Puelles, & Watson,
2012). This bend, called the cephalic flexure, causes the midbrain to assume a pronounced wedge shape in the sagittal
plane in all vertebrate brains (Figure 1). The result of this
distortion is that the ventral surface is very compressed, and
the dorsal surface is expanded, the latter forming the four
colliculi in the mammalian brain. The significance of the compression of the ventral surface is not generally appreciated, but
it has important implications for understanding the anatomy
of the midbrain in all mammals. The only reliable mark of true
Pallium
Roof
plate
Pretectum
Diencephalon
Telencephalon
p1
p2
Striatum
Substantia
nigra
STh
Terminal
hypothalamus
Eye
Basilar
pons
r1
r2
r3
r4
in
Preoptic
area
Cerebellum
is
a
br
nd
Peduncular
hypothalamus
Dg
m2
Hi
Cephalic
flexure
p3
Pallidum
Midbrain
m1
Cervical
flexure
r11
Spinal
cord
Figure 1 A diagram of a sagittal view of a developing brain showing the subdivisions of the brain stem and the adjacent forebrain. The diagram shows
the boundaries of the diencephalic prosomeres (p3, p2, and p1), the mesomeres of the midbrain (m1 and m2), and the isthmus (is) and
rhombomeres of the hindbrain (only r1, r2, r3, r4, and r11 are labeled). The subthalamic nucleus (STh) and the mammillary area of the
hypothalamus (MB) are labeled, as are the subdivisions of the telencephalon (Dg, diagonal domain). The diagram is based on an original prepared
by Professor Luis Puelles (Puelles et al., 2012). Note the fact that the pontine nuclei (basilar pons) are restricted to the ventral parts of r3 and r4.
253
Pineal
gland
Cerebral cortex
um Hippocampus
3V
u mac
ST
Preoptic
area
och
Fourth ventricle
4N
Fourth ventricle
3N
p3
Pa
Olfactory
tubercle
m (p1)
a lli
Diencephalon
Pretectu
Su
bp
Thalamus (p2)
ix
Septum
For n
Olfactory
bulb
Cerebellum
Periaqueductal
gray
Mesenceph
alon
pus
Cor
Inferior
colliculus
(auditory)
Superior
colliculus
(visual)
os
call
hm
Ist
scp
r1
r2
Hypothalamus
r3
VMH
Pituitary
gland
Basilar
pontine
nuclei
Rhombencephalon
r4
r5
r6
r7
Pyramidal tract
r8
r9
r10
r11
Pyramidal
decussation
Figure 2 This shows a sagittal section of an adult rat brain accompanied by a diagram that identifies some major features of the midbrain
(mesencephalon) and hindbrain (isthmus and rhombencephalon). Note the severe restriction of the ventral surface of the midbrain, due to the cephalic
flexure. The boundary between the oculomotor nucleus (3N) and the trochlear nucleus (4N) represents the junction of midbrain and isthmus. The
superior cerebellar peduncle (scp) and the 11 rhombomeres (r1r11) are labeled. In noting that the pontine nuclei are ventral components of
rhombomeres 3 and 4, it must be remembered that the rostral interrhombomeric boundaries are very oblique, sloping from dorsal to ventral at about 45
to the vertical. The prosomeres of the diencephalon (p1p3) are labeled. Other structures labeled include the paraventricular and ventromedial nuclei of
the hypothalamus (Pa and VMH), the optic chiasm (och), the anterior commissure (ac), and the bed nucleus of the stria terminalis (ST).
254
The Rhombomeres
The rhombomeres are transverse developmental units of the
embryonic hindbrain (Figure 1). The rostral rhombomeres
(r1r6) are initially marked by transverse constrictions in the
neural tube wall in the early embryo (Nieuwenhuys, 1998;
Orr, 1887; Vaage, 1973; von Kupffer, 1906), but these constrictions disappear after the early embryonic period. The caudal
rhombomeres (r8r11) are not separated by overt constrictions
in the developing hindbrain (Cambronero & Puelles, 2000). The
boundaries and contents of the rhombomeres in the avian brain
have been delineated by fate mapping and by studies of hox gene
expression (Cambronero & Puelles, 2000; Marin, Aroca, &
Puelles, 2008; Marn & Puelles, 1995). A detailed presentation
of the boundaries and contents of rhombomeres is found in the
atlas of the chicken brain of Puelles, Martinez-de-la-Torre,
Paxinos, Watson, and Martinez (2007). A number of studies
have now shown that the rhombomeric boundaries and rhombomere contents in the mouse are essentially the same as found
in the chick (Aroca & Puelles, 2005; Farago et al., 2006; Jensen
et al., 2008; Pasqualetti, Diaz, Renaud, Rijlii, & Glover, 2007).
However, Lumsden and Krumlauf, who are pioneers in the field
of gene expression in the rhombomeres (Krumlauf, 1994; Lumsden & Keynes, 1989; Lumsden & Krumlauf, 1996), have in recent
publications consistently ignored Puelles contention that there
are 11 rhombomeres and not 8 as previously thought. In recent
review articles, Lumsden, Krumlauf, and their colleagues did not
discuss or even cite any of the relevant Puelles hindbrain studies
of the past 20 years (Kiecker & Lumsden, 2005; Tumpel,
Wiedemann, & Krumlauf, 2009). Even if Puelles is subsequently
proven to be wrong, his work has appeared in major journals
and deserves consideration. In our opinion, this type of covert
censorship has no place in modern science.
landmarks by which these segmental structures can be recognized. Our knowledge of the segmental position of these structures is based chiefly on extensive studies in the chick
(Cambronero & Puelles, 2000; Marin et al., 2008; Marin &
Puelles, 1995; Puelles et al., 2007), but the same segmental
pattern is clearly present in the mouse (Farago et al., 2006;
Jensen et al., 2008; Watson, 2010):
255
reference atlas (Dong, 2008) and a number of very sophisticated (and robust) search engines. One example is the AGEA
tool, which can be used to pick out a single brain region (such
as the inferior olive) and ask what genes are selectively
expressed there. The availability of the Allen gene expression
atlas means that any scientist can access ISH data at no cost. In
addition to the adult brain gene expression atlas, the Allen site
also offers a series of atlases of the developing mouse brain
(Allen Developing Mouse Brain Atlas: http://mouse.brainmap.org) showing the expression of a subset of genes with
ISH at different developmental stages. An example of such a
preparation is seen in Figure 3, in which the raphe serotonergic
DR
mes
mes
is
PMnR
ROb
r4
RMg
RPa
DR
mes
MnR
is
PnR
r4
ROb
RPa
Figure 3 Photographs of two sagittal sections of an E18.5 mouse brain showing the expression of the serotonin solute carrier 6a4 (Slc6a4) in the
raphe nuclei as revealed by in situ hybridization. The upper image is from a midline section, and the lower image is from a section just lateral to the
midline. The location of serotoninergic (5HT) neurons in the raphe nuclei is clearly shown (DR, dorsal raphe; PMnR, paramedian raphe; RMg,
raphe magnus; RPa, raphe pallidus; ROb, raphe obscures). Note that 5HT neurons are confined to the hindbrain, with the exception of a few that
migrate into the caudal midbrain (mes) from the isthmus (is). Note also that rhombomere 4 (r4) does not contain any 5HT neurons. These images
are taken with permission from the Allen Developing Mouse Brain Atlas created by the Allen Institute for Brain Science (Allen Mouse Brain Atlas
(Internet). Seattle (WA): Allen Institute for Brain Science) 2009. Available from http://mouse.brain-map.org.
256
4b
Cb
pc
3N
4N
Sol
5N
Sol
IP
Amb
7N
r2
Pn
(a)
(b)
Figure 4 (a) An image of a thick sagittal slice about 1.5 mm from the midline of the brain stem of a mouse from a Phox2b-cre-LacZ lineage, stained to
show the presence of LacZ. Phox2b is chiefly expressed in the brachial motor, visceral motor, and visceral sensory neurons. The neurons of
branchial motor nuclei (motor trigeminal, 5N; facial, 7N; and ambiguus, Amb) are clearly labeled, whereas the hypoglossal motor neurons are not. The
rostral part of the solitary nucleus complex is also strongly labeled. (b) A thick sagittal slice from the same brain as shown in (a), but very close to
the midline. As anticipated, the visceral sensory nucleus (the solitary nucleus, Sol) is strongly labeled. The ventral border of the staining in Sol contains a
line of vagal motor neurons, but they are hard to distinguish at this magnification. Two interesting features can be noted: Firstly, the oculomotor
(3N) and trochlear (4N) motor neurons are labeled; secondly, a band of neuropil staining nicely marks out the territory of the second rhombomere (r2).
The expression in 3N and 4N is at first surprising, since they are traditionally classified as somatic motor, but the expression of Phox2b confirms a
long-standing suspicion by evolutionary biologists that these two nuclei were originally branchial motor supplying the most rostral gill muscles in
very early vertebrates. The significance of Phox2b expression in r2 is not clear, but it provides a fortuitous demonstration of the extent of the r2
segment. It shows incidentally that r2 is interposed between the pontine nuclei (Pn), which are in r3 and r4, and the interpeduncular nuclei (IP), which
are in r1 and the isthmus. The cerebellum (Cb) and the posterior commissure (pc) are labeled for reference. The images in (a) and (b) were kindly
supplied by Dr. Petr Tvrdik of the Mario Capecchi Laboratory at the University of Utah.
0.00 mm
-1.88 mm
V1
SuG
257
SuVe
PDTg
6N
IP
7n
6n
ml
RIP
Pn
ml
-2.92 mm
-1.40 mm
Crus1
Crus2
Med
4n
me5
PM
scp
Cop
SpVe
Pr
mlf
5N
Pr5
RtTg
VCA
Sp5I
ROb
LSO
Sol
Amb
Tz
Figure 6 A group of four coronal MR images of the brain stem from an image set derived from an average of MR of the brains of 18 C57BL/6J mice.
Each section is identified in the top left of the image with the distance from the interaural plane of the corresponding section in the mouse brain atlas of
Paxinos and Franklin (2013). A number of different fiber bundles, nuclei, and cortical areas are identified. The contrast in the images is very favorable and
the averaging of 18 brains has reduced noise to a very low level. Some small nuclei (such as the abducens nucleus (6N), the nucleus of the trapezoid
body (Tz), the reticulotegmental nucleus, the posterodorsal tegmental nucleus, the nucleus raphe interpositus (RIP), the nucleus raphes obscurus
(ROb), and the nucleus ambiguus (Amb)) and small fiber bundles (such as the mesencephalic trigeminal tract (me5), the trochlear nerve (4n), and the
abducens nerve (6n)) are relatively easy to distinguish. Some larger nuclei, such as the interpeduncular nucleus (IP), the lateral superior olive (LSO), the
pontine nuclei (Pn), the medial cerebellar nucleus (Med), the superior vestibular nucleus (SuVe), the principal trigeminal sensory nucleus (Pr5), the
trigeminal motor nucleus (5N), the ventral cochlear nucleus anterior part (VCA), the nucleus prepositus (Pr), the solitary nucleus (Sol), the spinal
vestibular nucleus (SpVe), and the spinal trigeminal nucleus interpolar part (Sp5I), display characteristic contrast areas with sharp borders. Major fiber
bundles (such as the medial lemniscus (ml), superior cerebellar peduncle (scp), the facial nerve (7n), and the medial longitudinal fasciculus (mlf)) stand
out well against their surrounds. The primary visual cortex (V1), the superficial gray layer of the superior colliculus (SuG), and a number of cerebellar
lobules (Crus 1, Crus 2, the paramedian lobule (PM), and the copula (Cop)) are labeled for reference.
258
dimensional data sets, can be used with live animals, and can
repeat scans over time in order to track the development of
changes in the brain. The first reports of the use of these methods
in the 1990s defined the boundaries of only a limited number
of structures in the brain, but since 2005, much more detailed
MR atlases of rodent brains have been published (Johnson,
Calabrese, Badea, Paxinos, & Watson, 2012; Ullmann et al.,
2012).
The enhanced characterization of brain anatomy with MRI is
the result of advances in three different areas. First, improvements in MRI scanners, coils, and acquisition sequences have
resulted in the acquisition of very high-resolution and highcontrast data sets. Numerous facilities around the world now
work with magnets with field strengths greater than 16 T, and
when combined with specially built solenoid or cryogen-cooled
coils, data sets can be acquired with resolutions of 30 mm3 or
better (Ullmann et al., 2012; Ullmann, Cowin, Kurniawan, &
Collin, 2010). Additionally, a multitude of acquisition
sequences (such as T1, T2, proton density, and diffusion tensor
imaging) can be derived from a single data set, and this has led
to the creation of detailed multidimensional atlases of the central nervous system (Johnson et al., 2010).
Second, the development of contrast agents for both
in vivo and ex vivo imaging has facilitated the identification
of a greater number of structures. Gadolinium-based compounds, which transiently bind to the hydrogen protons in
water, reduce relaxation times (Weinmann, Brasch, Press, &
Wesbey, 1984) and produce contrast that closely parallels the
cell density found in the brains. Areas with high cell density
appear hyperintense while regions with low cell density
appear hypointense. More recently, additional contrast agents
have also shown great promise; these include Luxol fast
blue (Blackwell, Farrar, Fischl, & Rosen, 2009), chromium
(Watanabe, Tammer, Boretius, Frahm, & Michaelis, 2006),
and manganese, a calcium analog that can be transported
along voltage-gated calcium channels to assess neuronal function and highlight specific brain areas that are active (Pautler
& Koretsky, 2002).
Third, improvements in registration algorithms, in combination with greater access to powerful computer clusters,
enable registration of an ever-increasing number of data sets
and the creation of more detailed probabilistic atlases. While
initial rodent atlases were based on an individual animal,
todays modern brain atlas can be made up of data sets
from a large number of brains, which greatly improves the
contrast-to-noise ratio. Moreover, the registration can now be
based on a recursive nonlinear hierarchical fitting strategy
with a robust averaging process that places a lower weight
on data that are greater than two standard deviations from
the current model (Fonov et al., 2011). This iterative process
requires the use of powerful computer clusters that were
previously not available. The result is the production of digital brain atlas that represents the average normalized intensity and shape of a population, a high contrast-to-noise ratio,
and a very high level of anatomical structural detail.
The combination of these three developments has produced very detailed MRI-based atlases of the rodent brain.
The Australian Mouse Brain Mapping Consortium, based in
the University of Queensland, has made use of a 16.4 T scanner
and averaging techniques to produce very high-resolution
images of mouse brains. The images of the brain stem shown
References
Aitken, A. R., & Tork, I. (1988). Early development of serotonin-containing neurons and
pathways as seen in wholemount preparations of the fetal rat brain. Journal of
Comparative Neurology, 274, 3247.
Aroca, P., & Puelles, L. (2005). Postulated boundaries and differential fate in the
developing rostral hindbrain. Brain Research Reviews, 49, 179190.
Ashwell, K. W.S, & Paxinos, G. (2008). Atlas of the developing rat nervous system (3rd
ed.). San Diego: Elsevier Academic Press.
Awatramani, R., Soriano, P., Rodriguez, C., Mai, J. J., & Dymecki, S. M. (2006). Cryptic
boundaries in roof plate and choroid plexus identified by intersectional gene
activation. Nature Genetics, 35, 7075.
Badea, A., Ali-Sharief, A. A., & Johnson, G. A. (2007). Morphometric analysis of the
C57BL/6J mouse brain. NeuroImage, 37, 683693.
Blackwell, M. L., Farrar, C. T., Fischl, B., & Rosen, B. R. (2009). Target-specific contrast
agents for magnetic resonance microscopy. NeuroImage, 46, 382393.
Branda, C. S., & Dymecki, S. M. (2004). Talking about a revolution: The impact of
site-specific recombinases on genetic analyses in mice. Developmental Cell, 6,
728.
Brodal, P. (2010). The central nervous system (4th ed.). New York: Oxford University
Press.
Cambronero, F., & Puelles, L. (2000). Rostrocaudal nuclear relationships in the avian
medulla oblongata: Fate-map with quail-chick chimeras. Journal of Comparative
Neurology, 427, 522545.
Capecchi, M. R. (1989). The new mouse genetics: Altering the genome by gene
targeting. Trends in Genetics, 5, 7076.
Capecchi, M. R. (2005). Essay: gene targeting in mice: Functional analysis of the
mammalian genome for the twenty-first century. Nature Reviews. Genetics, 6, 507512.
Dong, H. W. (2008). The Allen reference atlas: A digital color brain atlas of the C57BL/
6J mouse. Hobeken, NJ: John Wiley and Sons Inc.
Dymecki, S. M. (1996). Flp recombinase promotes site-specific DNA recombination in
embryonic stem cells and transgenic mice. Proceedings of the National Academy of
Science, 93, 61916196.
Dymecki, S. M., & Kim, J. C. (2007). Molecular neuroanatomys "Three Gs": A primer.
Neuron, 54, 1734.
Dymecki, S. M., & Tomasiewicz, H. (1998). Using Flp-recombinase to characterize
expansion of Wnt1-expressing neural progenitors in the mouse. Developmental
Biology, 201, 5765.
Eddison, M., Toole, L., Bell, E., & Wingate, R. J.T (2004). Segmental identity and
cerebellar granule cell induction in rhombomere 1. BMC Biology, 2, 14. http://dx.
doi.org/10.1186/1741-7007-2-14.
Farago, A. F., Awatramani, R. B., & Dymecki, S. M. (2006). Assembly of the brainstem
cochlear nuclear complex is revealed by intersectional and subtractive genetic fate
maps. Neuron, 50, 205218.
Fonov, V., Evans, A. C., Botteron, K., Almli, C. R., McKinstry, R. C., & Collins, D. L.
(2011). Unbiased average age-appropriate atlases for pediatric studies.
NeuroImage, 54, 313327.
259
Paxinos, G., Halliday, G., Watson, C., Koutcherov, Y., & Wang, H. Q. (2007). Atlas of the
developing mouse brain at E17.5, P0, and P6. San Diego: Elsevier Academic Press.
Paxinos, G., & Huang, X. F. (1995). Atlas of the human brainstem. San Diego: Academic
Press.
Paxinos, G., Huang, X.-F., Petrides, M., & Toga, A. W. (2009). The rhesus monkey brain
in stereotaxic coordinates (2nd ed.). San Diego: Elsevier Academic Press.
Paxinos, G., Huang, X.-F., Sengul, G., & Watson, C. (2012). Organization of human
brainstem. In J. K. Mai & G. Paxinos (Eds.), The human nervous system (3rd ed.).
San Diego: Elsevier Academic Press.
Paxinos, G., & Watson, C. (1982). The rat brain in stereotaxic coordinates. Sydney:
Academic Press.
Paxinos, G., & Watson, C. (1986). The rat brain in stereotaxic coordinates (2nd ed.).
Sydney: Academic Press.
Paxinos, G., & Watson, C. (1997). The rat brain in stereotaxic coordinates (3rd ed.). San
Diego: Academic Press.
Paxinos, G., & Watson, C. (1998). The rat brain in stereotaxic coordinates
Comprehensive (4th ed.). San Diego: Academic Press.
Paxinos, G., & Watson, C. (2005). The rat brain in stereotaxic coordinates: The new
coronal set (5th ed.). San Diego: Elsevier Academic Press.
Paxinos, G., & Watson, C. (2007). The rat brain in stereotaxic coordinates (6th ed.). San
Diego: Elsevier Academic Press.
Paxinos, G., Watson, C., Carrive, P., Kirkcaldie, M., & Ashwell, K. (2009).
Chemoarchitectonic atlas of the rat brain (2nd ed.). San Diego: Elsevier Academic Press.
Paxinos, G., Watson, C., Petrides, M., Rosa, M., & Tokuno, H. (2012). The marmoset
brain in stereotaxic coordinates. San Diego: Elsevier Academic Press.
Puelles, L., Martinez-de-la-Torre, M., Paxinos, G., Watson, C., & Martinez, S. (2007).
The chick brain in stereotaxic coordinates: An atlas featuring neuromeres and
mammalian homologies. San Diego: Elsevier Academic Press.
Puelles, E., Puelles, L., & Watson, C. (2012). Midbrain. In C. Watson, G. Paxinos & L.
Puelles (Eds.), The mouse nervous system (pp. 337359). San Diego: Elsevier
Academic Press (Chapter 10).
Puelles, L., & Watson, C. (2012). Diencephalon. In C. Watson, G. Paxinos & L. Puelles
(Eds.), The mouse nervous system (pp. 331336). San Diego: Elsevier Academic
Press (Chapter 9).
Soriano, P. (1999). Generalized lacZ expression with the ROSA26 Cre reporter strain.
Nature Genetics, 21, 7071.
Swanson, L. W. (2003). Brain maps III: The structure of the rat brain (3rd ed.). San
Diego: Elsevier Academic Press.
Tumpel, S., Wiedemann, L. M., & Krumlauf, R. (2009). Hox genes and segmentation of
the vertebrate hindbrain. In: O. Pourquie (Ed.), Hox genes. Current topics in
developmental biologyvol. 88. San Diego: Academic Press.
Tvrdik, P., & Capecchi, M. R. (2012). Gene targeting. In C. Watson, G. Paxinos & L.
Puelles (Eds.), The mouse nervous system. San Diego: Elsevier Academic Press.
Ullmann, J. F.P, Cowin, G., Kurniawan, N. D., & Collin, S. P. (2010). A threedimensional digital atlas of the zebrafish brain. NeuroImage, 51, 7682.
Ullmann, J. F., Keller, M. D., Watson, C., Janke, A. L., Kurniawan, N. D., Yang, Z., et al.
(2012). Segmentation of the C57BL/6J mouse cerebellum in magnetic resonance
images. NeuroImage, 62, 14081414.
Vaage, S. (1973). The histogenesis of the isthmic nuclei in chick embryos (Gallus
domesticus). 1. A morphological study. Zeitschrift fur Anatomie und
Entwicklungsgeschichte, 142, 283314.
von Kupffer, C. (1906). Die Morphogenie des Central Nervensystems. In O. Hertwig
(Ed.), Handbuch der vergleichenden Entwicklungslehre der Wirbeltiere. Jena:
Gustav Fischer Bd 2 Teil 3.
Watanabe, T., Tammer, R., Boretius, S., Frahm, J., & Michaelis, T. (2006). Chromium
(VI) as a novel MRI contrast agent for cerebral white matter: Preliminary results in
mouse brain in vivo. Magnetic Resonance in Medicine, 56, 16.
Watson, C. (2010). The presumptive isthmic region in a mouse as defined by fgf8
expression. Brain, Behavior and Evolution, 75, 315.
Watson, C. (2012). Hindbrain. In C. Watson, G. Paxinos & L. Puelles (Eds.), The mouse
nervous system (pp. 397422). San Diego: Elsevier Academic Press (Chapter 12).
Watson, C., & Paxinos, G. (2010). Chemoarchitectonic atlas of the mouse brain. San
Diego: Elsevier Academic Press.
Weinmann, H.-J., Brasch, R. C., Press, W.-R., & Wesbey, G. E. (1984). Characteristics
of gadolinium-DTPA complex: A potential NMR contrast agent. American Journal of
Roentgenology, 142, 619624.
Zinyk, D., Mercer, E. H., Harris, E., Anderson, D. J., & Joyner, A. L. (1998). Fate
mapping of the mouse midbrainhindbrain constriction using a site-specific
recombination system. Current Biology, 8, 665668.
Glossary
Abbreviations
ChAT
DG
GABA
GAD
Ncl
NMDA
QNB
5-HT
AMPA
BA
BZ
CA
Serotonin
a-Amino-3-hydroxy-5-methyl-4isoxazolepropionic acid
Brodmanns area
Benzodiazepine binding site of the GABAA
receptor
Cornu ammonis
Choline acetyltransferase
Dentate gyrus
g-Amino-butyric acid
Glutamate decarboxylase
Nucleus
N-Methyl-D-aspartate
Quinuclidinyl benzilate
http://dx.doi.org/10.1016/B978-0-12-397025-1.00221-9
261
262
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Transmitter Receptor Distribution in the Human Brain
Glutamate Receptors
AMPA receptors reach highest densities in BA47, posterior part
of BA39, BA24, and BA25. Lowest values are found in the
motor, visual, auditory, somatosensory, and parahippocampal
cortices. In the hippocampus, AMPA receptors reach highest
densities in the pyramidal layer of the CA1 region of the cornu
ammonis (CA) and the molecular layer of the dentate gyrus
(DG), intermediate levels in CA2 and CA3, and lowest values
in the subiculum.
NMDA receptors show a rather homogeneous distribution
throughout the cortex, with somewhat higher densities in BA9,
BA45, BA47, and BA25. Lowest densities were described in
BA4, area 3b, BA41, BA42, BA24, and BA32. The frontal cortex
only reaches 50% of the NMDA receptor density of CA1 and
the DG of the hippocampus. NMDA receptors are found at
highest densities in CA1 and the DG, at intermediate levels in
the entorhinal cortex, and at lower levels in CA2/3 and the
subiculum.
Kainate receptors present highest densities in BA9, BA46,
BA47, BA7, the middle and inferior temporal gyri, BA24, and
the parahippocampal cortex. Lowest densities are found in
primary sensory areas 3b, BA17, and BA41, as well as in BA42
and the primary motor cortex. In the hippocampus, by far,
highest kainate receptor densities are found in CA3 (the stratum lucidum and pyramidal layer) and the hilus of the DG,
whereas densities in CA1, the subiculum, the presubiculum,
and the entorhinal cortex are lower.
Comparison between receptor subtypes. In all neocortical
areas, NMDA receptors occur at much higher densities than
kainate receptors (Amunts et al., 2010; Caspers et al., 2013;
Dean et al., 2001; Jansen, Faull, & Dragunow, 1989;
Palomero-Gallagher et al., 2009; Zavitsanou, Ward, & Huang,
2002; Zilles, Bacha-Trams, Palomero-Gallagher, Amunts, &
Friederici, 2014). The primary motor, somatosensory, auditory,
and visual cortices, as well as the anterior cingulate and superior
parietal association cortices, show higher absolute AMPA than
kainate densities, whereas both receptors have comparable
densities in the middle frontal gyrus (Jansen et al., 1989; Zavitsanou et al., 2002).
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Transmitter Receptor Distribution in the Human Brain
AMPA
NMDA
Kainate
GABAA
M1
M2
Nicotinic 4/2
263
5-HT1A
5-HT2
D1
D2
8
3,2,1
4
5
9
46
40
10 45 44 43 41 42
47
22
11
21
38
20
Map
8
9
39
18
19
17
37
10 32
12
11
3,2,1
5
24
23 31
19
AB C
18
D EFG RSP
17
25 27
19
18
34 35
28 36
37
38
20
FG1, FG2
Figure 1 Schematic maps of the regional distribution of glutamatergic AMPA (3H-AMPA or 3H-CNQX), NMDA (3H-MK801) and kainate (3H-kainate),
GABAergic GABAA (3H-muscimol, 3H-flunitrazepam, or 3H-flumazenil), cholinergic M1 (3H-pirenzepine), M2 (3H-oxotremorine-M or 3H-AF-DX384) and
a4/b2 (3H-epibatidine, 3H-nicotine, or 5-[125I]-A-85380), adrenergic a1 (3H-prazosin) and a2 (3H-UK 14,304, 3H-RX 821002, or 125I-iodoclonidine),
serotonergic 5-HT1A (3H-8-OH-DPAT or 3H-WAY-100635) and 5-HT2 (3H-ketanserin), and dopaminergic D1 (3H-SCH 23390) and D2 (125I-epidepride,
3
H-spiroperidol, 3H-raclopride, or 125I-NCQ 298 in the presence of raclopride) receptor binding sites in the human brain. The densities are given as
relative values for each receptor type. Red codes high density; green, intermediate density; and blue, low density. Gray indicates regions for which no
data are available. Dotted blue regions in the temporal lobe indicate minimally higher D2 receptor densities. The anatomical localization is based on
Brodmanns map (Brodmann, 1909) in most of the papers and shown in the lower right part of the figure. Arabic numbers, Brodmanns areas; A,
caudateputamen; B, globus pallidus; C, diencephalon; D, amygdala; E, CA1 region of the hippocampus; F, CA2/3 region of the hippocampus; G, the
dentate gyrus; RSP, retrosplenial areas. References for glutamate receptors: Ball et al. (1994), Caspers, Schleicher, et al. (2013), Caspers,
Palomero-Gallagher, et al. (2013), Court et al. (1993), Dean et al. (2001), Dewar, Graham, and McCulloch (1990), Dure et al. (1991), Eickhoff et al.
(2007), Gao et al. (2000), Ibrahim et al. (2000), Jansen et al. (1989), Kornhuber et al. (1989), Kravitz, Gaisler-Salomon, and Biegon (2013),
Meador-Woodruff, Davis, and Haroutunian (2001), Meoni et al. (1998), Morosan, Rademacher, Palomero-Gallagher, and Zilles (2004), Noga and Wang
(2002), Palomero-Gallagher et al. (2009), Palomero-Gallagher and Zilles (2009), Perry et al. (1993), Scarr, Pavey, Sundram, MacKinnon, and Dean
(2003), Scheperjans, Palomero-Gallagher, Grefkes, Schleicher, and Zilles (2005), Tremblay, Represa, and Ben-Ari (1985), Villares and Stavale (2001),
(Continued)
264
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Transmitter Receptor Distribution in the Human Brain
AMPA
NMDA
Kainate
mGlu2/3
GABAA
700
950
800
6200
2000
40
50
60
200
150
M1
M2
M3
Nicotinic 4/2
1000
350
1500
200
100
15
500
5-HT1A
5-HT2
D1
450
1250
700
600
120
30
50
100
Figure 2 Coronal sections showing the absolute densities of AMPA (3H-AMPA), NMDA (3H-MK801), kainate (3H-kainate), mGlu2/3 (3H-LY 341,495),
GABAA (3H-muscimol), muscarinic M1 (3H-pirenzepine), muscarinic M2 (3H-oxotremorine-M), muscarinic M3 (3H-4-DAMP), nicotinic a4/b2
(3H-epibatidine), a1 (3H-prazosin), a2 (3H-UK 14,304), 5-HT1A (3H-8-OH-DPAT), 5-HT2 (3H-ketanserin), and D1 (3H-SCH 23390) receptor binding sites in
the human occipital lobe. Distribution of nicotinic a4/b2 receptors in the primary visual cortex is shown at a higher magnification. Arrow points at
the nicotinic a4/b2 receptor-rich layer IVc; arrowheads mark the borders between BA17 and BA18.
Figure 1Contd Villegas, Estruch, Mengod, and Cortes (2011), Zavitsanou et al. (2002), Zilles (2005), Zilles and Amunts (2009), Zilles et al. (2014),
and Zilles, Schleicher, Palomero-Gallagher, and Amunts (2002). References for GABA receptors: Caspers, Palomero-Gallagher, et al. (2013), Caspers,
Schleicher, et al. (2013), Dean et al. (2001), Eickhoff et al. (2007), Morosan et al. (2004), Nishino et al. (1988), Palomero-Gallagher et al. (2009),
Palomero-Gallagher and Zilles (2009), Perry et al. (1993), Scheperjans, Palomero-Gallagher, Grefkes, Schleicher, and Zilles (2005), Zezula et al. (1988),
Zilles (2005), and Zilles et al. (2014). References for acetylcholine receptors: Araujo et al. (1988), Caspers, Palomero-Gallagher, et al. (2013), Caspers,
Schleicher, et al. (2013), Cortes et al. (1986), Cortes, Probst, and Palacios (1987), Cortes and Palacios (1986), Court et al. (1993), Court et al. (1997),
Crook, Tomaskovic-Crook, Copolov, and Dean (2000), Crook, Tomaskovic-Crook, Copolov, and Dean (2001), Eickhoff et al. (2007), Lin et al. (1986),
Lowenstein et al. (1990), Marutle et al. (2001), Matsumoto et al. (2005), Morosan et al. (2004), Nastuk and Graybiel (1988), Palomero-Gallagher et al.
(2009), Palomero-Gallagher and Zilles (2009), Perry, Court, Johnson, Piggott, and Perry (1992), Perry et al. (1993), Piggott et al. (2002), Piggott
et al. (2003), Pimlott et al. (2004), Rodriguez-Puertas et al. (1997), Scheperjans, Palomero-Gallagher, Grefkes, Schleicher, and Zilles (2005), Sihver,
Gillberg, and Nordberg (1998), Vanderheyden et al. (1990), Zilles (2005), and Zilles et al. (2014). References for noradrenalin receptors: Aldrich et al.
(1994), Caspers, Palomero-Gallagher, et al. (2013), Caspers, Schleicher, et al. (2013), De Vos, Vauquelin, De, De Backer, and Van (1992), Eickhoff
et al. (2007), Gross-Isseroff, Dillon, Fieldust, and Biegon (1990), Gross-Isseroff et al. (2000), Morosan et al. (2004), Palomero-Gallagher et al.
(2009), Palomero-Gallagher and Zilles (2009), Pazos et al. (1988), Scheperjans, Palomero-Gallagher, Grefkes, Schleicher, and Zilles (2005), Zilles,
Schleicher, Palomero-Gallagher, and Amunts (2002), and Zilles et al. (2014). References for serotonin receptors: Burnet et al. (1997), Caspers,
Palomero-Gallagher, et al. (2013), Caspers, Schleicher, et al. (2013), Cross and Slater (1989), Dean et al. (2001), Eickhoff et al. (2007), Gross-Isseroff,
Salama, Israeli, and Biegon (1990a), Hall et al. (1997), Hoyer et al. (1986a); Hoyer, Pazos, Probst, and Palacios (1986b), Matsumoto et al. (2005),
Morosan et al. (2004), Palacios et al. (1988), Palomero-Gallagher et al. (2009), Palomero-Gallagher and Zilles (2009); Pazos et al. (1987a,1987b),
Perry et al. (1993), Scheperjans, Palomero-Gallagher, Grefkes, Schleicher, and Zilles (2005), and Zilles et al. (2014). References for dopamine receptors:
Caspers, Palomero-Gallagher, et al. (2013), Caspers, Schleicher, et al. (2013), De Keyser et al. (1988), Eickhoff et al. (2007), Joyce et al. (1991),
Kessler et al. (1993), Kohler et al. (1991), Palacios et al. (1988), Palomero-Gallagher et al. (2009), Palomero-Gallagher and Zilles (2009), Rieck, Ansari,
Whetsell, Deutch, and Kessler (2004), Scheperjans, Palomero-Gallagher, Grefkes, Schleicher, and Zilles (2005), Sun et al. (2012), and Zilles
et al. (2014).
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Transmitter Receptor Distribution in the Human Brain
GABAA
cs
1
Te1
2
3a
3b
M2
cs
1
Te1
3a
3b
cs
1
Te1
3a
2
3b
Low
High
GABA Receptors
The GABAA receptor shows a relatively homogeneous distribution throughout the cortex, with highest densities in BA17 and
fusiform areas FG1 and FG2 (Caspers, Zilles, et al., 2013) and
lowest densities in BA46, BA4, BA41, and BA42. The primary
auditory and somatosensory cortices also have slightly higher
GABAA receptor densities than the surrounding secondary
areas, but their values do not reach the high density of the
primary visual cortex. The latter value is due to the exceptionally high density in layers IIIVcb (Zezula, Cortes, Probst, &
Palacios, 1988; Zilles, Palomero-Gallagher, & Schleicher, 2004;
Zilles & Schleicher, 1993). In the hippocampus, GABAA receptor binding sites reach highest densities in the CA1 pyramidal
and lacunosum molecular layers, in the molecular layer of the
DG, and in the presubiculum and lowest concentrations in the
hilus, CA3, and subiculum.
265
Noradrenaline Receptors
Acetylcholine Receptors
Although earlier studies reported M1 receptor data from hemispheric lobes (Araujo, Lapchak, Robitaille, Gauthier, &
Quirion, 1988; Rodriguez-Puertas, Pascual, Vilaro, & Pazos,
1997), this gross parcellation does not provide sufficient
266
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Transmitter Receptor Distribution in the Human Brain
Serotonin Receptors
The 5-HT1A receptor densities in BA6, BA9, BA10, BA11, BA46,
BA24, and BA32 are comparable to those of most other cortical
areas. The primary motor, visual, and somatosensory areas and
the primary and secondary auditory areas, the language areas
BA44 and BA45, and BA47 and retrosplenial areas present
lower 5-HT1A receptor densities. BA25 stands out by a considerably higher 5-HT1A receptor density. Notably, the hippocampus and the entorhinal cortex present, together with BA25, the
highest 5-HT1A receptor densities. In the hippocampus, they
reach the highest value in CA1 and much lower densities in
CA3. The density is slightly lower in the subiculum than in
CA1, but higher than in the entorhinal cortex when averaged
over all cortical layers. Notably, the anterior part of the entorhinal cortex can be clearly delineated from the medial and
posterior parts by a conspicuous decrease of 5-HT1A receptor
densities in the deeper layers from a very high level in the
anterior part to a low level in the medial and posterior parts,
whereas the density remains comparable in the more superficial layers of all parts of the entorhinal cortex (Pazos, Probst, &
Palacios, 1987a).
Highest 5-HT2 densities are found in BA9, BA10, BA11,
BA44, BA45, BA46, BA24, BA25, BA31, BA32, retrosplenial
areas, and the entorhinal cortex. The primary motor cortex
has the lowest density of all areas in the frontal lobe. Low
densities were also found in the extrastriate visual areas; in
the superior, middle, and inferior temporal gyri; and in the
parahippocampal gyrus. The primary visual, primary and secondary auditory, and primary somatosensory cortices present
Dopamine Receptors
The D1 receptors occur with low density throughout all neocortical areas. Slightly higher densities are found in BA7, BA17,
BA24, BA25, BA39, BA40, BA46, FG1, and FG2. The overall D1
receptor density is very low in the hippocampus. The relatively
highest density is found in the pyramidal layer of CA1, with
very low values in the DG.
The D2 receptors are around the limit of detection. In the
temporal cortex, minimally higher D2 values were reported.
The overall D2 receptor density is low in the hippocampus.
Highest values are found in the radiatum layer of CA3 and the
hilus of the DG; intermediate densities, in the subiculum and
presubiculum; and lowest densities, in the entorhinal cortex,
parasubiculum, and other regions and layers of the hippocampus (Joyce, Janowsky, & Neve, 1991; Kohler et al., 1991).
Comparison between receptor subtypes. D2 receptors occur
by 25 times lower values than D1 receptors in the cerebral
cortex; in the hippocampus, this difference is not so conspicuous (De Keyser et al., 1988; Palacios, Camps, Cortes, &
Probst, 1988).
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Transmitter Receptor Distribution in the Human Brain
but also regarding the regional density of a given receptor subtype. To the best of our knowledge, a comprehensive study of
the subregional receptor expression is presently not available.
The mean AMPA, NMDA, and kainate receptor densities are
below the level of values reported for the hippocampus. The
lateral and basal nuclei contain comparable AMPA and kainate
receptor densities (Graebenitz et al., 2011; Noga & Wang,
2002). Within the lateral nucleus, NMDA receptors show the
highest densities, followed by kainate and AMPA receptors
(Graebenitz et al., 2011).
Mean GABAA receptor densities in the amygdala are comparable to those found in CA1. Highest densities are found in
the lateral nucleus and much lower densities in the basal and
basolateral nuclei (Graebenitz et al., 2011; Zezula et al., 1988).
The M1 receptor density of the amygdala is similar to that
of CA1 and the dentate. It differs only slightly between the
basal, basolateral, and lateral nuclei (Cortes, Probst, Tobler, &
Palacios, 1986; Graebenitz et al., 2011). The M2 receptor density in the lateral nucleus reaches an intermediate level between
the total hippocampal region and the neocortex. However,
the basolateral nucleus shows a clearly higher density than the
lateral nucleus (Graebenitz et al., 2011). Nicotinic a4/b2 receptor
densities are very low and are similar between the lateral and
basolateral nuclei (Graebenitz et al., 2011; Zilles, Schleicher,
Palomero-Gallagher, & Amunts, 2002).
The overall a1 adrenoceptor density in the amygdala is
comparable to that of the cerebral cortex. Slightly lower values
are found in the basal and basolateral nuclei than in the lateral
nucleus (Aldrich et al., 1994; Graebenitz et al., 2011). The a1
adrenoceptor density of the amygdala is considerably higher
than the a2 density. The a2 adrenoceptors are considerably
lower in the amygdala compared to the cerebral cortex and
reach slightly higher values in the basal and basolateral nuclei
than in the lateral nucleus (Aldrich et al., 1994; Graebenitz
et al., 2011). The b1 adrenoceptor density is considerably lower
than in the basal ganglia and slightly lower compared to the
neocortex (De Paermentier et al., 1989).
The amygdala contains a very low mean 5-HT1A receptor
density. Lowest values are found in the lateral, basolateral, and
basal accessory nuclei. The granular and cortical nuclei as well
as the transitory zone exhibit higher densities (Graebenitz
et al., 2011; Hall et al., 1997; Pazos et al., 1987a). The 5-HT2
receptor densities are also very low in the amygdala but higher
than the 5-HT1A receptor densities, with highest values in the
lateral and basolateral nuclei (Graebenitz et al., 2011; Pazos
et al., 1987b). 5-HT3 receptors reach intermediate densities in
the amygdala, slightly higher than in the hippocampus, but
clearly lower compared to the striatum (Marazziti et al., 2001).
The D1 receptor of the amygdala reaches the level of the
anterior cingulate and posterior parietal cortices and a five
times higher density than D2 receptors in the amygdala. The
D1 receptor density is slightly higher in the basolateral than in
the lateral nucleus (Graebenitz et al., 2011). The D2 receptor
density is very low but approximately three times higher than
in the neocortex.
Basal Ganglia
The basal ganglia comprise various subcortical nuclei, each of
which has a distinct cytological and neurochemical organization
(Haber & Gdowski, 2004). They are strongly interconnected
267
with the cortex and thalamus and are associated with motor,
cognitive, and emotional functions (Figure 1).
AMPA receptor densities in the caudateputamen are
comparable to those measured in the frontal cortex, whereas
NMDA and kainate receptor densities only reach approximately half of the cortical values. The densities of all three
receptor types are considerably higher in the caudateputamen
than in the globus pallidus or the subthalamic nucleus (Ball,
Shaw, Ince, & Johnson, 1994; Meoni, Mugnaini, Bunnemann,
Trist, & Bowery, 1998; Villares & Stavale, 2001). Slightly lower
AMPA and NMDA values are found in the caudateputamen
than in the ncl. accumbens; they do not differ in their kainate
receptor densities (Meador-Woodruff, Hogg, & Smith, 2001).
AMPA and NMDA receptors seem to be higher concentrated in
the matrix than in the striosomes, whereas kainate receptors
show the reverse distribution (Dure, Young, & Penney, 1991).
GABAA receptor densities in the caudateputamen only
reach 40% of the values measured in the motor cortex but are
approximately 50% higher than in the globus pallidus, particularly its medial part, or the subthalamic nucleus (Nishino,
Fujiwara, Noguchi-Kuno, & Tanaka, 1988; Zezula et al., 1988).
Interestingly, an increasing rostrocaudal gradient in GABAA
receptor density was found in the caudateputamen, though
not in the globus pallidus.
The density of cholinergic muscarinic M1 receptors in the
caudateputamen is approximately twice that of the frontal,
inferior parietal, and extrastriate visual cortices and considerably higher than in the globus pallidus and subthalamic
nucleus, but slightly lower than in the ncl. accumbens. Within
the caudateputamen, contradictory results have been
reported regarding the association of M1 receptors with the
striosomematrix segregation. Whereas Lowenstein, Joyce,
Coyle, and Marshall (1990) reported higher M1 receptor density in the matrix, Nastuk and Graybiel (1988) assigned higher
M1 receptor densities to the striosome compartment.
M2 receptor densities in the caudateputamen are approximately twice those of BA20, BA21, BA22, and BA36 and four
times higher than in BA24. They are also significantly higher in
the caudateputamen than in the globus pallidus (Piggott
et al., 2002, 2003). M2 receptors are homogeneously distributed
throughout the matrix and striosomes (Nastuk & Graybiel,
1988). A comparison between the densities of M1 and M2
receptors shows a more than two times higher density of M1
receptors in the caudateputamen (Rodriguez-Puertas et al.,
1997). Nicotinic a4/b2 receptor densities are very low in the
caudateputamen and comparable to those of the hippocampus
and neocortex (Lange et al., 1993). Nevertheless, they are by
three times higher in the caudateputamen than in the globus
pallidus (Nordberg, Alafuzoff, & Winblad, 1992).
The a1 adrenoceptor density in the caudateputamen is
approximately a third of that in the middle temporal gyrus.
In the medial part of the globus pallidus, a1 densities are
similar to those of the caudateputamen; in the lateral part,
lower densities are found (Aldrich et al., 1994). The a2 adrenoceptor density in the caudateputamen is approximately
half of that measured in the superior, middle, or temporal
gyri and only reaches 25% of values found in the superior
frontal gyrus. In the globus pallidus, a2 adrenoceptors only
reach one-third of the density of the caudateputamen
(Aldrich et al., 1994). Considerably higher b adrenoceptor
densities are found in the caudateputamen (with highest
268
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Transmitter Receptor Distribution in the Human Brain
Diencephalon
The diencephalon consists of numerous nuclei with different
cellular structures and connectivities (Jones, 2007). It relays
sensory and motor information between brain regions and
controls many autonomic and limbic functions (Percheron,
2004; Saper, 2004; Figure 1). A detailed description of the
receptor expression in the different nuclei is far beyond the
scope of this article. Therefore, we focus here on mean values of
the thalamus, with some examples of selected nuclei.
On average, the densities of AMPA, NMDA, and kainate
receptors are low compared to the hippocampus and some
cortical regions. Only the NMDA receptors reach intermediate
densities, as most cortical areas. The limbic anterior thalamic
nucleus presents intermediate to high NMDA and low kainate
receptor densities (Ball et al., 1994). The AMPA and NMDA
receptors reach lowest values in the reticular nucleus (Ibrahim
et al., 2000), which receives input from the whole cortex and
projects to numerous thalamic nuclei. Somewhat higher
NMDA receptor densities are found in the medial geniculate
Cerebellum
The AMPA receptor density of the cerebellar cortex is similar to
that of the occipital neocortex, but the NMDA and kainate
values are higher (compare Figures 2 and 4). Within the cerebellar cortex, AMPA densities are higher in the molecular than
in the granular layer, and the opposite holds true for kainate
and NMDA receptors (Dewar, Chalmers, Shand, Graham, &
McCulloch, 1990; Jansen, Dragunow, Faull, & Leslie, 1991;
Jansen, Faull, & Dragunow, 1990; Makowiec, Albin, Cha,
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Transmitter Receptor Distribution in the Human Brain
AMPA
1500
GABAA
250
7000
NMDA
500
Kainate
3500
250
2200
mGlu2/3
10000
GABAB
500
5500
M3
200
750
150
1000
D1
200
400
269
Map
M2
50
250
nic 4/2
15
500
25
1200
5-HT2
5-HT1A
30
400
50
300
1000
150
Figure 4 Sections showing AMPA, NMDA, kainate, mGlu2/3, GABAA, GABAB, muscarinic M2, muscarinic M3, nicotinic a4/b2, a1, a2, 5-HT1A, 5-HT2,
and D1 receptor binding sites in the human cerebellum. 1: Molecular layer of the cerebellar cortex; 2: granular layer of the cerebellar cortex; 3: ncl.
dentatus; 4: white matter of the cerebellum. Muscarinic M1 receptors are not shown because their density in the cerebellum is below the detection level.
layers is found for the GABAB receptor (Albin & Gilman, 1990,
also see Figure 4). In the case of the GABAB receptor, the
dentate nucleus can be detected, though at a low density.
The cholinergic muscarinic M1 receptor density is around
the detection level of receptor autoradiography (Lin, Olson,
Okazaki, & Richelson, 1986; Piggott et al., 2002) and, therefore, not shown in Figure 4. The M2 receptor density is much
lower in the cerebellar than in the cerebral cortex, with slightly
higher values in the molecular than in the granular layer of the
cerebellum (Piggott et al., 2002). The dentate nucleus is not
detectable. The M3 receptors of the cerebellar cortex and dentate nucleus show similar densities but lower values than in the
occipital lobe (compare Figures 2 and 4). Nicotinic a4/b2
receptor densities are higher in cerebellar than in the cerebral
cortex and higher in the molecular than in the granular cell
layer of the cerebellum. The dentate nucleus takes an intermediate position between the values of both layers (Court et al.,
1997; Pimlott et al., 2004).
270
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Transmitter Receptor Distribution in the Human Brain
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Transmitter Receptor Distribution in the Human Brain
AMPA
I
II
III
IV
V
VI
NMDA
I
II
III
IV
V
VI
M2
I PF 44d
II
III
IV
V
VI
1
I
II
III
IV
V
VI
5-HT2
I
II
III
IV
V
VI
I
II
III
IV
V
VI
I
II
III
IV
V
VI
1
5-HT1A
D1
I
II
III
IV
V
VI
32
I
II
III
IV
V
VI
I
II
III
IV
V
VI
5-HT7
I
II
III
IV
V
VI
4/2
M3
2
I
II
III
IV
V
VI
GABAA
I
II
III
IV
V
VI
I
II
III
IV
V
VI
I
II
III
IV
V
VI
M1
Kainate
D2
I
II
III
IV
V
VI
271
Palomero-Gallagher, et al. (2002), Zilles, Schleicher, PalomeroGallagher, and Amunts (2002), Zilles et al. (2004), Zilles et al. (2014), and
Zilles and Amunts (2009). Receptors for acetylcholine: Amunts et al.
(2010), Caspers, Palomero-Gallagher, et al. (2013), Caspers, Schleicher,
et al. (2013), Cortes and Palacios (1986), Eickhoff et al. (2007), Morosan
et al. (2004), Palomero-Gallagher and Zilles (2009), Rodriguez-Puertas
et al. (1997), Scheperjans, Grefkes, Palomero-Gallagher, Schleicher, and
Zilles (2005), Scheperjans, Palomero-Gallagher, Grefkes, Schleicher, and
Zilles (2005), Sihver et al. (1998), Vogt et al. (1990), Vogt, Crino, and
Volicer (1991), Zilles, Palomero-Gallagher, et al. (2002), Zilles,
Schleicher, Palomero-Gallagher, and Amunts (2002), Zilles, Eickhoff, and
Palomero-Gallagher (2003), Zilles et al. (2004), Zilles et al. (2014), Zilles
and Amunts (2009), and Zilles and Amunts (2010). Receptors for
noradrenaline: Amunts et al. (2010), Caspers, Palomero-Gallagher, et al.
(2013), Caspers, Schleicher, et al. (2013), Eickhoff et al. (2007), Morosan
et al. (2004), Palomero-Gallagher and Zilles (2009), Pazos et al. (1988),
Scheperjans, Grefkes, Palomero-Gallagher, Schleicher, and Zilles (2005),
Scheperjans, Palomero-Gallagher, Grefkes, Schleicher, and Zilles (2005),
Vogt et al. (1991), Zilles, Palomero-Gallagher, et al. (2002), Zilles,
Schleicher, Palomero-Gallagher, and Amunts (2002), Zilles et al. (2014),
and Zilles and Amunts (2010). Receptors for serotonin: Caspers,
Palomero-Gallagher, et al. (2013), Caspers, Schleicher, et al. (2013),
Dean et al. (2001), Dewar, Graham, and McCulloch (1990), Dillon, GrossIsseroff, Israeli, and Biegon (1991), Eickhoff et al. (2007), Hall et al.
(1997), Hoyer et al. (1986b), Martin-Cora and Pazos (2004), Morosan
et al. (2004), Palomero-Gallagher and Zilles (2009), Pazos et al.
(1987a,1987b), Scheperjans, Grefkes, Palomero-Gallagher, Schleicher,
and Zilles (2005), Scheperjans, Palomero-Gallagher, Grefkes, Schleicher,
and Zilles (2005), Vogt et al. (1990), Zilles, Schleicher, PalomeroGallagher, and Amunts (2002), Zilles et al. (2004), and Zilles et al. (2014).
Receptors for dopamine: Caspers, Palomero-Gallagher, et al. (2013),
Caspers, Schleicher, et al. (2013), Dawson, McCabe, Stensaas, and
Wamsley (1987), Eickhoff et al. (2007), Joyce et al. (1991), PalomeroGallagher and Zilles (2009), Scheperjans, Grefkes, Palomero-Gallagher,
Schleicher, and Zilles (2005), Zilles, Schleicher, Palomero-Gallagher, and
Amunts (2002), and Zilles et al. (2014).
272
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Transmitter Receptor Distribution in the Human Brain
a complex system of language-related areas in the left hemisphere that consists of the four subdivisions of BA44 and BA45,
BA47, an hitherto unidentified area in the inferior frontal
sulcus close to its junction with the precentral sulcus, the
secondary auditory area BA42, and a region in the posterior
part of the superior temporal gyrus and sulcus (Zilles et al.,
2014). The fingerprints of the areas in this functional system
clearly differ from those of primary sensory cortical areas,
multimodal areas of the inferior and superior parietal lobules,
higher extrastriate visual areas, BA32, and the primary motor
cortex. A separate analysis of the fingerprints of the right and
left hemispheres revealed a notable interhemispheric
difference.
A fingerprint analysis of the different areas of the inferior
parietal lobule in comparison with motor, auditory, somatosensory, and visual areas and BA44 demonstrated a very close
relation between BA39 and the extrastriate area V3v (Caspers,
Schleicher, et al., 2013), thus supporting the notion that at
least the posterior part of BA39 (i.e., area PGp) is a hub in the
ventrodorsal visual stream (Pisella, Binkofski, Lasek, Toni, &
Rossetti, 2006).
The hierarchical cluster analysis of the receptor fingerprints
of fusiform areas FG1 and FG2 (Caspers, Palomero-Gallagher,
et al., 2013) argues for their position between the ventral visual
stream (Ungerleider & Haxby, 1994) and multimodal association areas of the inferior parietal lobule (Caspers et al., 2006;
Wu et al., 2009). FG1 and FG2 are involved in the processing of
visual objects (Grill-Spector, Kourtzi, & Kanwisher, 2001;
Malach, Levy, & Hasson, 2002) but differ from the early visual
areas of the ventral stream (Orban, van Essen, & Vanduffel,
2004; Sereno et al., 1995; Wilms et al., 2010). A principal
component analysis shows that all visual areas are separated
from nearly all other cortical areas studied, but FG1 and FG2
segregate from early visual areas, thus indicating their close
association with multimodal association areas of the inferior
parietal lobule (Caspers, Palomero-Gallagher, et al., 2013).
Therefore, the mapping using multiple receptor expressions
(receptor fingerprints) not only is an excellent approach to
cortical parcellation on the basis of its neurochemical
organization but also provides insight into principles of
structural and functional connectivities as well as systemic
organization.
Acknowledgments
This work was supported by the portfolio theme Supercomputing and Modeling for the Human Brain of the Helmholtz
Association, Germany.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Transmitter Receptor Distribution in the Human Brain
References
Albin, R. L., & Gilman, S. (1990). Autoradiographic localization of inhibitory and
excitatory amino acid neurotransmitter receptors in human normal and
olivopontocerebellar atrophy cerebellar cortex. Brain Research, 522, 3745.
Albin, R. L., Price, R. H., Sakurai, S. Y., Penney, J. B., & Young, A. B. (1991). Excitatory
and inhibitory amino acid binding sites in human dentate nucleus. Brain Research,
560, 350353.
Aldrich, M. S., Prokopowicz, G., Ockert, K., Hollingsworth, Z., Penney, J. B., & Albin, R. L.
(1994). Neurochemical studies of human narcolepsy: Alpha-adrenergic receptor
autoradiography of human narcoleptic brain and brainstem. Sleep, 17, 598608.
Amunts, K., Kedo, O., Kindler, M., Pieperhoff, P., Mohlberg, H., Shah, N. J., et al.
(2005). Cytoarchitectonic mapping of the human amygdala, hippocampal region
and entorhinal cortex: Intersubject variability and probability maps. Anatomy and
Embryology, 210, 343352.
Amunts, K., Lenzen, M., Friederici, A. D., Schleicher, A., Morosan, P.,
Palomero-Gallagher, N., et al. (2010). Brocas region: Novel organizational
principles and multiple receptor mapping. PLoS Biology, 8, .
Araujo, D. M., Lapchak, P. A., Robitaille, Y., Gauthier, S., & Quirion, R. (1988).
Differential alteration of various cholinergic markers in cortical and subcortical
regions of human brain in Alzheimers disease. Journal of Neurochemistry, 50,
19141923.
Ball, E. F., Shaw, P. J., Ince, P. G., & Johnson, M. (1994). The distribution of excitatory
amino acid receptors in the normal human midbrain and basal ganglia with
implications for Parkinsons disease: A quantitative autoradiographic study using [3H]
MK-801, [3H]glycine, [3H]CNQX and [3H]kainate. Brain Research, 658, 209218.
Bar-Peled, O., Gross-Isseroff, R., Ben-Hur, H., Hoskins, I., Groner, Y., & Biegon, A.
(1991). Fetal human brain exhibits a prenatal peak in the density of serotonin 5HT1A receptors. Neuroscience Letters, 127, 173176.
Bar-Peled, O., Israeli, M., Ben-Hur, H., Hoskins, I., Groner, Y., & Biegon, A. (1991).
Developmental pattern of muscarinic receptors in normal and Downs syndrome
fetal brain An autoradiographic study. Neuroscience Letters, 133, 154158.
Brodmann, K. (1909). Vergleichende Lokalisationslehre der Grohirnrinde in ihren
Prinzipien dargestellt auf Grund des Zellbaues. Leipzig: Barth.
Brooksbank, B. W., Atkinson, D. J., & Balazs, R. (1981). Biochemical development of
the human brain. II. Some parameters of the GABA-ergic system. Developmental
Neurosciences, 4, 188200.
Brooksbank, B. W., Atkinson, D. J., & Balazs, R. (1982). Biochemical development of
the human brain. III. Benzodiazepine receptors, free gamma-aminobutyrate (GABA)
and other amino acids. Journal of Neuroscience Research, 8, 581594.
Burnet, P. W., Eastwood, S. L., & Harrison, P. J. (1997). [3H]WAY-100635 for 5-HT1A
receptor autoradiography in human brain: A comparison with [3H]8-OH-DPAT and
demonstration of increased binding in the frontal cortex in schizophrenia.
Neurochemistry International, 30, 565574.
Carlson, M. D., Penney, J. B., Jr., & Young, A. B. (1993). NMDA, AMPA, and
benzodiazepine binding site changes in Alzheimers disease visual cortex.
Neurobiology of Aging, 14, 343352.
Caspers, S., Geyer, S., Schleicher, A., Mohlberg, H., Amunts, K., & Zilles, K. (2006).
The human inferior parietal cortex: Cytoarchitectonic parcellation and interindividual
variability. NeuroImage, 33, 430448.
Caspers, J., Palomero-Gallagher, N., Caspers, S., Schleicher, A., Amunts, K., &
Zilles, K. (2013). Receptor architecture of visual areas in the face and word-form
recognition region of the posterior fusiform gyrus. Brain Structure and Function.
http://dx.doi.org/10.1007/s00429-013-0646-z.
Caspers, S., Schleicher, A., Bacha-Trams, M., Palomero-Gallagher, N., Amunts, K., &
Zilles, K. (2013). Organization of the human inferior parietal lobule based on
receptor architectonics. Cerebral Cortex, 23, 615628.
Caspers, J., Zilles, K., Eickhoff, S. B., Schleicher, A., Mohlberg, H., & Amunts, K.
(2013). Cytoarchitectonical analysis and probabilistic mapping of two extrastriate
areas of the human posterior fusiform gyrus. Brain Structure and Function, 218,
511526.
Cortes, R., & Palacios, J. M. (1986). Muscarinic cholinergic receptor subtypes in
the rat brain. I. Quantitative autoradiographic studies. Brain Research, 362,
227238.
Cortes, R., Probst, A., & Palacios, J. M. (1987). Quantitative light microscopic
autoradiographic localization of cholinergic muscarinic receptors in the human
brain: Forebrain. Neuroscience, 20, 65107.
Cortes, R., Probst, A., Tobler, H. J., & Palacios, J. M. (1986). Muscarinic cholinergic
receptor subtypes in the human brain. II. Quantitative autoradiographic studies.
Brain Research, 362, 239253.
Court, J. A., Lloyd, S., Johnson, M., Griffiths, M., Birdsall, N. J., Piggott, M. A., et al.
(1997). Nicotinic and muscarinic cholinergic receptor binding in the human
273
274
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Transmitter Receptor Distribution in the Human Brain
Marazziti, D., Betti, L., Giannaccini, G., Rossi, A., Masala, I., Baroni, S., et al. (2001).
Distribution of [3H]GR65630 binding in human brain postmortem. Neurochemical
Research, 26, 187190.
Marcusson, J. O., Morgan, D. G., Winblad, B., & Finch, C. E. (1984). Serotonin-2
binding sites in human frontal cortex and hippocampus. Selective loss of S-2A sites
with age. Brain Research, 311, 5156.
Martin-Cora, F. J., & Pazos, A. (2004). Autoradiographic distribution of 5-HT7
receptors in the human brain using [3H]mesulergine: Comparison to other
mammalian species. British Journal of Pharmacology, 141, 92104.
Marutle, A., Zhang, X., Court, J., Piggott, M., Johnson, M., Perry, R., Perry, E., &
Nordberg, A. (2001). Laminar distribution of nicotinic receptor subtypes in cortical
regions in schizophrenia. Journal of Chemical Neuroanatomy, 22, 115126.
Matsumoto, I., Inoue, Y., Iwazaki, T., Pavey, G., & Dean, B. (2005). 5-HT2A and
muscarinic receptors in schizophrenia: A postmortem study. Neuroscience Letters,
379, 164168.
Meador-Woodruff, J. H., Davis, K. L., & Haroutunian, V. (2001). Abnormal kainate
receptor expression in prefrontal cortex in schizophrenia.
Neuropsychopharmacology, 24, 545552.
Meador-Woodruff, J. H., Hogg, A. J., Jr., & Smith, R. E. (2001). Striatal ionotropic
glutamate receptor expression in schizophrenia, bipolar disorder, and major
depressive disorder. Brain Research Bulletin, 55, 631640.
Meoni, P., Mugnaini, M., Bunnemann, B. H., Trist, D. G., & Bowery, N. G. (1998). [3H]
MK-801 binding and the mRNA for the NMDAR1 subunit of the NMDA receptor are
differentially distributed in human and rat forebrain. Brain Research. Molecular
Brain Research, 54, 1323.
Montague, D. M., Lawler, C. P., Mailman, R. B., & Gilmore, J. H. (1999). Developmental
regulation of the dopamine D1 receptor in human caudate and putamen.
Neuropsychopharmacology, 21, 641649.
Morgan, D. G., Marcusson, J. O., Nyberg, P., Wester, P., Winblad, B., Gordon, M. N.,
et al. (1987). Divergent changes in D-1 and D-2 dopamine binding sites in human
brain during aging. Neurobiology of Aging, 8, 195201.
Morosan, P., Rademacher, J., Palomero-Gallagher, N., & Zilles, K. (2004). Anatomical
organization of the human auditory cortex: Cytoarchitecture and transmitter receptors.
In P. Heil, E. Konig & E. Budinger (Eds.), Auditory cortex Towards a synthesis of
human and animal research (pp. 2750). Mahwah, NJ: Lawrence Erlbaum.
Nastuk, M. A., & Graybiel, A. M. (1988). Autoradiographic localization and biochemical
characteristics of M1 and M2 muscarinic binding sites in the striatum of the cat,
monkey, and human. Journal of Neuroscience, 8, 10521062.
Nishino, N., Fujiwara, H., Noguchi-Kuno, S. A., & Tanaka, C. (1988). GABAA receptor
but not muscarinic receptor density was decreased in the brain of patients with
Parkinsons disease. Japanese Journal of Pharmacology, 48, 331339.
Noga, J. T., & Wang, H. (2002). Further postmortem autoradiographic studies of AMPA
receptor binding in schizophrenia. Synapse, 45, 250258.
Nordberg, A., Alafuzoff, I., & Winblad, B. (1992). Nicotinic and muscarinic subtypes in
the human brain: Changes with aging and dementia. Journal of Neuroscience
Research, 31, 103111.
Nusser, Z., Lujan, R., Laube, G., Roberts, J. D., Molnar, E., & Somogyi, P. (1998). Cell
type and pathway dependence of synaptic AMPA receptor number and variability in
the hippocampus. Neuron, 21, 545559.
Orban, G. A., van Essen, D. C., & Vanduffel, W. (2004). Comparative mapping of higher
visual areas in monkeys and humans. Trends in Cognitive Sciences, 8, 315324.
Palacios, J. M., Camps, M., Cortes, R., & Probst, A. (1988). Mapping dopamine receptors
in the human brain. Journal of Neural Transmission, Supplement, 27, 227235.
Palacios, J. M., Probst, A., & Mengod, G. (1992). Receptor localization in the human
hypothalamus. Progress in Brain Research, 93, 5768.
Palomero-Gallagher, N., Vogt, B. A., Schleicher, A., Mayberg, H. S., Schleicher, A., &
Zilles, K. (2009). Receptor architecture of human cingulate cortex: Evaluation of the
four-region neurobiological model. Human Brain Mapping, 30, 23362355.
Palomero-Gallagher, N., & Zilles, K. (2009). Transmitter receptor systems in cingulate
regions and areas. In B. A. Vogt (Ed.), Infrastructure, diagnosis, treatment (2nd ed.).
Cingulate neurobiology and disease (vol. 1). Oxford: Oxford University Press.
Palomero-Gallagher, N., Zilles, K., Schleicher, A., & Vogt, B. A. (2013). Cyto- and
receptor architecture of area 32 in human and macaque brains. Journal of
Comparative Neurology, 521, 32723286.
Pazos, A., Gonzalez, A. M., Pascual, J., Meana, J. J., Barturen, F., & Garca-Sevilla, J. A.
(1988). a2-adrenoceptors in human forebrain: Autoradiographic visualization and
biochemical parameters using the agonist [3H]UK-14304. Brain Research, 475,
361365.
Pazos, A., Probst, A., & Palacios, J. M. (1985). Beta-adrenoceptor subtypes in the
human brain: Autoradiographic localization. Brain Research, 358, 324328.
Pazos, A., Probst, A., & Palacios, J. M. (1987a). Serotonin receptors in the human brain.
III. Autoradiographic mapping of serotonin-1 receptors. Neuroscience, 21, 97122.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Transmitter Receptor Distribution in the Human Brain
Pazos, A., Probst, A., & Palacios, J. M. (1987b). Serotonin receptors in the human
brain. IV. Autoradiographic mapping of serotonin-2 receptors. Neuroscience, 21,
123139.
Percheron, G. (2004). Thalamus. In G. Paxinos & J. K. Mai (Eds.), The human nervous
system (2nd ed., pp. 592675). Amsterdam: Elsevier.
Perry, E. K., Court, J. A., Johnson, M., Piggott, M. A., & Perry, R. H. (1992).
Autoradiographic distribution of [3H]nicotine binding in human cortex: Relative
abundance in subicular complex. Journal of Chemical Neuroanatomy, 5, 399405.
Perry, E. K., Court, J. A., Johnson, M., Smith, C. J., James, V., Cheng, A. V., et al.
(1993). Autoradiographic comparison of cholinergic and other transmitter receptors
in the normal human hippocampus. Hippocampus, 3, 307315.
Piggott, M. A., Ballard, C. G., Dickinson, H. O., McKeith, I. G., Perry, R. H., &
Perry, E. K. (2007). Thalamic D2 receptors in dementia with Lewy bodies,
Parkinsons disease, and Parkinsons disease dementia. International Journal of
Neuropsychopharmacology, 10, 231244.
Piggott, M. A., Owens, J., OBrien, J., Colloby, S., Fenwick, J., Wyper, D., Jaros, E., et al.
(2003). Muscarinic receptors in basal ganglia in dementia with Lewy bodies,
Parkinsons disease and Alzheimers disease. Journal of Chemical Neuroanatomy,
25, 161173.
Piggott, M., Owens, J., OBrien, J., Paling, S., Wyper, D., Fenwick, J., et al. (2002).
Comparative distribution of binding of the muscarinic receptor ligands pirenzepine,
AF-DX 384, (R, R)-I-QNB and (R, S)-I-QNB to human brain. Journal of Chemical
Neuroanatomy, 24, 211223.
Pimlott, S. L., Piggott, M., Owens, J., Greally, E., Court, J. A., Jaros, E., et al. (2004).
Nicotinic acetylcholine receptor distribution in Alzheimers disease, dementia with
Lewy bodies, Parkinsons disease, and vascular dementia: In vitro binding study
using 5-[125I]-A-85380. Neuropsychopharmacology, 29, 108116.
Pisella, L., Binkofski, F., Lasek, K., Toni, I., & Rossetti, Y. (2006). No doubledissociation between optic ataxia and visual agnosia: Multiple sub-streams for
multiple visuo-manual integrations. Neuropsychologia, 44, 27342748.
Represa, A., Tremblay, E., Schoevart, D., & Ben-Ari, Y. (1986). Development of high affinity
kainate binding sites in human and rat hippocampi. Brain Research, 384, 170174.
Reynolds, G. P., Mason, S. L., Meldrum, A., De, K. S., Parnes, H., Eglen, R. M., et al.
(1995). 5-Hydroxytryptamine (5-HT)4 receptors in post mortem human brain tissue:
Distribution, pharmacology and effects of neurodegenerative diseases. British
Journal of Pharmacology, 114, 993998.
Rieck, R. W., Ansari, M. S., Whetsell, W. O., Jr., Deutch, A. Y., & Kessler, R. M. (2004).
Distribution of dopamine D2-like receptors in the human thalamus:
Autoradiographic and PET studies. Neuropsychopharmacology, 29, 362372.
Rinne, J. O. (1987). Muscarinic and dopaminergic receptors in the aging human brain.
Brain Research, 404, 162168.
Rodriguez-Puertas, R., Pascual, J., Vilaro, M. T., & Pazos, A. (1997). Autoradiographic
distribution of M1, M2, M3, and M4 muscarinic receptor subtypes in Alzheimers
disease. Synapse, 26, 341350.
Saper, C. B. (2004). Hypothalamus. In G. Paxinos & J. K. Mai (Eds.), The human
nervous system (2nd ed., pp. 513550). Amsterdam: Elsevier.
Sastre, M., Guimon, J., & Garcia-Sevilla, J. A. (2001). Relationships between beta- and
alpha2-adrenoceptors and G coupling proteins in the human brain: Effects of age
and suicide. Brain Research, 898, 242255.
Scarr, E., Pavey, G., Sundram, S., MacKinnon, A., & Dean, B. (2003). Decreased
hippocampal NMDA, but not kainate or AMPA receptors in bipolar disorder. Bipolar
Disorders, 5, 257264.
Scheperjans, F., Grefkes, C., Palomero-Gallagher, N., Schleicher, A., & Zilles, K.
(2005). Subdivisions of human parietal area 5 revealed by quantitative receptor
autoradiography: A parietal region between motor, somatosensory and cingulate
cortical areas. NeuroImage, 25, 975992.
Scheperjans, F., Palomero-Gallagher, N., Grefkes, C., Schleicher, A., & Zilles, K.
(2005). Transmitter receptors reveal segregation of cortical areas in the human
superior parietal cortex: Relations to visual and somatosensory regions.
NeuroImage, 28, 362379.
Schmitz, E., Reichelt, R., Walkowiak, W., Richards, J. G., & Hebebrand, J. (1988). A
comparative phylogenetic study of the distribution of cerebellar GABAA/benzodiazepine
receptors using radioligands and monoclonal antibodies. Brain Research, 473, 314320.
Sereno, M. I., Dale, A. M., Reppas, J. B., Kwong, K. K., Belliveau, J. W., Brady, T. J.,
et al. (1995). Borders of multiple visual areas in humans revealed by functional
magnetic resonance imaging. Science, 268, 889893.
Shaw, P. J., & Ince, P. G. (1994). A quantitative autoradiographic study of [3H]kainate
binding sites in the normal human spinal cord, brainstem and motor cortex. Brain
Research, 641, 3945.
Sihver, W., Gillberg, P. G., & Nordberg, A. (1998). Laminar distribution of nicotinic
receptor subtypes in human cerebral cortex as determined by [3H](-)nicotine, [3H]
cytisine and [3H]epibatidine in vitro autoradiography. Neuroscience, 85, 11211133.
275
Sun, J., Xu, J., Cairns, N. J., Perlmutter, J. S., & Mach, R. H. (2012). Dopamine D1, D2,
D3 receptors, vesicular monoamine transporter type-2 (VMAT2) and dopamine
transporter (DAT) densities in aged human brain. PLoS One, 7, e49483.
Tohgi, H., Utsugisawa, K., Yoshimura, M., Nagane, Y., & Mihara, M. (1998a). Agerelated changes in nicotinic acetylcholine receptor subunits a4 and b2 messenger
RNA expression in postmortem human frontal cortex and hippocampus.
Neuroscience Letters, 245, 139142.
Tohgi, H., Utsugisawa, K., Yoshimura, M., Nagane, Y., & Mihara, M. (1998b).
Alterations with aging and ischemia in nicotinic acetylcholine receptor subunits a4
and b2 messenger RNA expression in postmortem human putamen. Implications for
susceptibility to parkinsonism. Brain Research, 791, 186190.
Tremblay, E., Represa, A., & Ben-Ari, Y. (1985). Autoradiographic localization of kainic
acid binding sites in the human hippocampus. Brain Research, 343, 378382.
Ungerleider, L. G., & Haxby, J. V. (1994). What and where in the human brain. Current
Opinion in Neurobiology, 4, 157165.
Vanderheyden, P., Gies, J. P., Ebinger, G., De, K. J., Landry, Y., & Vauquelin, G. (1990).
Human M1-, M2- and M3-muscarinic cholinergic receptors: Binding characteristics
of agonists and antagonists. Journal of Neurological Sciences, 97, 6780.
Villares, J. C., & Stavale, J. N. (2001). Age-related changes in the N-methyl-D-aspartate
receptor binding sites within the human basal ganglia. Experimental Neurology,
171, 391404.
Villegas, E., Estruch, R., Mengod, G., & Cortes, R. (2011). NMDA receptors in frontal
cortex and hippocampus of alcohol consumers. Addiction Biology, 16, 163165.
Vogt, B. A., Crino, P. B., & Volicer, L. (1991). Laminar alterations in g-aminobutyric
acidA, muscarinic, and b adrenoceptors and neuron degeneration in cingulate cortex
in Alzheimers disease. Journal of Neurochemistry, 57, 282290.
Vogt, B. A., Sikes, R. W., & Vogt, L. J. (1990). Anterior cingulate cortex and the medial
pain system. In B. Kolb & R. C. Tees (Eds.), The cerebral cortex of the rat
(pp. 313344). Cambridge, MA: MIT.
Whitehouse, P. J., Muramoto, O., Troncoso, J. C., & Kanazawa, I. (1986).
Neurotransmitter receptors in olivopontocerebellar atrophy: An autoradiographic
study. Neurology, 36, 193197.
Wilms, M., Eickhoff, S. B., Homke, L., Rottschy, C., Kujovic, M., Amunts, K., et al.
(2010). Comparison of functional and cytoarchitectonic maps of human visual areas
V1, V2, V3d, V3v, and V4(v). NeuroImage, 49, 11711179.
Wu, S. S., Chang, T. T., Majid, A., Caspers, S., Eickhoff, S. B., & Menon, V. (2009).
Functional heterogeneity of inferior parietal cortex during mathematical cognition
assessed with cytoarchitectonic probability maps. Cerebral Cortex, 19, 29302945.
Zavitsanou, K., Ward, P. B., & Huang, X. F. (2002). Selective alterations in ionotropic
glutamate receptors in the anterior cingulate cortex in schizophrenia.
Neuropsychopharmacology, 27, 826833.
Zelnik, N., Angel, I., Paul, S. M., & Kleinman, J. E. (1986). Decreased density of human
striatal dopamine uptake sites with age. European Journal of Pharmacology, 126,
175176.
Zezula, J., Cortes, R., Probst, A., & Palacios, J. M. (1988). Benzodiazepine receptor
sites in the human brain: Autoradiographic mapping. Neuroscience, 25, 771795.
Zilles, K. (2005). Evolution of the human brain and comparative cyto- and receptor
architecture. In S. Dehaene, J. R. Duhamel, M. D. Hauser & G. Rizzolatti (Eds.),
From monkey brain to human brain (pp. 4156). Cambridge: MIT Press.
Zilles, K., & Amunts, K. (2009). Receptor mapping: Architecture of the human cerebral
cortex. Current Opinion in Neurology, 22, 331339.
Zilles, K., & Amunts, K. (2010). Centenary of Brodmanns map Conception and fate.
Nature Reviews Neuroscience, 11, 139145.
Zilles, K., Bacha-Trams, M., Palomero-Gallagher, N., Amunts, K., & Friederici, A. D.
(2014). Common molecular basis of the sentence comprehension network revealed
by neurotransmitter receptor fingerprints. Cortex, 63, 7989.
Zilles, K., Eickhoff, S. B., & Palomero-Gallagher, N. (2003). The human parietal cortex: A
novel approach to its architectonic mapping. Advances in Neurology, 93, 121.
Zilles, K., Palomero-Gallagher, N., Grefkes, C., Scheperjans, F., Boy, C., Amunts, K., &
Schleicher, A. (2002). Architectonics of the human cerebral cortex and transmitter
receptor fingerprints: Reconciling functional neuroanatomy and neurochemistry.
European Neuropsychopharmacology, 12, 587599.
Zilles, K., Palomero-Gallagher, N., & Schleicher, A. (2004). Transmitter receptors
and functional anatomy of the cerebral cortex. Journal of Anatomy, 205, 417432.
Zilles, K., & Schleicher, A. (1993). Cyto- and myeloarchitecture of human visual cortex
and the periodical GABAA receptor distribution. In B. Gulyas, D. Ottoson & P. E.
Roland (Eds.), Functional organisation of the human visual cortex (pp. 111121).
Oxford: Pergamon Press.
Zilles, K., Schleicher, A., Palomero-Gallagher, N., & Amunts, K. (2002). Quantitative
analysis of cyto- and receptor architecture of the human brain. In A. W. Toga & J. C.
Mazziotta (Eds.), Brain mapping the methods (2nd ed., pp. 573602). Amsterdam:
Elsevier.
Motor Cortex
E Borra, M Gerbella, S Rozzi, and G Luppino, Universita` di Parma, Parma, Italy
2015 Elsevier Inc. All rights reserved.
Abbreviations
CB
DLPF
Introduction
The primate frontal lobe hosts two large regions: a rostral one
involved in cognitive functions, designated as prefrontal cortex,
and a caudal one the motor cortex mostly devoted to motor
functions. This article will be mostly focused on the description
of the main anatomical and functional organizational principles of the motor cortex. Specifically, we will show that the
primate motor cortex hosts a multiplicity of architectonically
distinct areas displaying specific cortical and subcortical connections underpinning a parallel processing of different aspects
of motor control. Though most of the available information
presented here derives from studies in nonhuman primates,
state-of-the-art anatomical and functional mapping techniques
suggest that similar organizational principles also exist in
humans.
IPL
SPL
VLPF
http://dx.doi.org/10.1016/B978-0-12-397025-1.00222-0
277
278
Figure 1 Three-dimensional reconstructions of an illustrative monkey cerebral hemisphere, showing a map of the architectonic areas of the motor
cortex and the multiplicity of body representations. The reconstruction on the right is shown from a rostrolateral view in which the posterior bank
of the arcuate sulcus was exposed with dissection along its fundus. The small hemisphere below shows with a darker color, the brain sector removed
to expose the postarcuate bank. CgS, cingulate sulcus; CS, central sulcus; IAS, inferior arcuate sulcus; IPS, intraparietal sulcus; LF, lateral fissure;
LuS, lunate sulcus; PS, principal sulcus; SAS, superior arcuate sulcus.
Over the years, the proposed map shown in Figure 1 has been
validated by converging evidence showing that each of these
architectonic subdivisions is functionally and connectionally
distinct, thus fulfilling all the criteria generally accepted for the
definition of a cortical area (see Van Essen, 1985).
Accordingly, the organization of the macaque motor cortex
is much more complex than previously thought and appears as
a mosaic of several distinct areas that contains a multiplicity of
body movement representations (Figure 1). There is clear evidence for a similar general organization also in the human
motor cortex (Fink, Frackowiak, Pietrzyk, & Passingham,
1997). This complex organizational picture raised the question
of which could be the possible role played in motor control by
each area.
A crucial contribution in addressing this issue has been
provided by hodological studies. Specifically, tract tracing
experiments unraveling each motor areas anatomical connections with other cortical areas or subcortical structures showed
up to be crucial for the functional interpretation of each areas
role in motor control. Taken together, this body of evidence first
showed that each frontal motor area has a specific pattern of
anatomical connections. Furthermore, based on their general
pattern of cortical and subcortical connectivity, the various
premotor areas can be grouped into two major groups
(Rizzolatti & Luppino, 2001) corresponding to the areas of
the caudal and the rostral premotor domains, respectively.
279
d
CS
SAS PS
IPS
CS
IAS
1 mm
F1
F2
F7
8b
(a)
CS
F1
F2
F7
8b
(b)
CS
SAS
IPS
PS
IAS
F5c
CS
PS
IAS
F4
F1
F5p
F5a
(c)
F1
CS
F4
F5c
IAS
PS
F5p
(d)
F5a
Figure 2 Chemoarchitectonic features of the different rostrocaudal motor domains and the transition between the agranular and the granular
frontal cortices. (a) and (c): Low-power photomicrographs of two SMI-32-immunostained parasagittal sections shown in a medial to lateral order,
respectively. (b) and (d): Low-power photomicrographs of two CB immunostained parasagittal sections shown in a medial to lateral order,
respectively. The top view of the hemispheres in (a) and (c) shows approximately the dorsolateral level where the pair of sections in (a) and (b) and that
in (c) and (d) were taken, respectively. Arrows on the photomicrographs indicate the location of cytoarchitectonic borders reported from adjacent
Nissl-stained sections. Scale bar in (a) applies to all the photomicrographs. Abbreviations as in Figure 1.
280
showing that (a) the dorsal visual stream inputs to the SPL and
the IPL mostly originate from distinct extrastriate visual areas,
that is, area V6 and MT, respectively, and (b) the IPL, but not
the SPL, is connected also to temporal polymodal areas or
inferotemporal areas located at the highest levels of the ventral
visual stream. It has been then proposed that while the dorsodorsal stream is involved in visuomotor transformation for
online control of movement, the ventrodorsal stream is
involved in motor control based also on perceptual processes
and is crucial in mediating motor cognitive functions. A similar
organizational model has been proposed by Jeannerod and
Jacob (2005) for the human parietal cortex.
A further major source of input to the motor cortex is the
lateral prefrontal cortex. This cortex is a functionally heterogeneous region essential for different aspects of executive functions, that is, optimizing behavioral performance when
cognitive processes are required (Tanji & Hoshi, 2008). Prefrontal projections to the motor cortex are primarily directed to the
rostral premotor areas (see Gerbella, Belmalih, Borra, Rozzi, &
Luppino, 2011, and Rizzolatti & Luppino, 2001). Specifically,
the dorsal part of the lateral prefrontal cortex (DLPF) projects to
F7, the ventral (VLPF) part projects to F5a, whereas both DLPF
and VLPF project to F6. These projections could play a role in
the selection of the appropriate potential actions, generated as
the result of sensorimotor transformations, based on abstract
rules, memorized information, and behavioral goals. This process could be at the basis of the transformation of potential
actions into actual actions.
281
References
IPS
SAS
F1
AIP
PS
PFG
CS
F5p
IAS
F5a
46vc
12r
SII
LF
STS
(see Fogassi & Luppino, 2005), and SII contributes with information related to haptic coding of objects (Fitzgerald, Lane,
Thakur, & Hsiao, 2004). In the prefrontal component of the
network, area 12r contributes to the exploitation of nonspatial
memory-based or working memory information related to
object properties (e.g., weight, center of mass, fragility, and
texture) or identity, for controlling object-oriented actions
(Borra, Gerbella, Rozzi, & Luppino, 2011). Finally, area 46vc
contributes to selecting and monitoring hand actions based on
behavioral goals and behavioral guiding rules, in order to organize motor acts in intentional action sequences (Gerbella,
Borra, Tonelli, Rozzi, & Luppino, 2013).
Concluding Remarks
The data reviewed in the preceding text show that a multidisciplinary approach based on multimodal architectonic,
functional, and connectional techniques has been crucial for
obtaining a modern view of the organizational principles of
the nonhuman primate motor cortex. The much lower resolution of the connectional and functional techniques currently
available for studies in humans still preclude a detailed
description of the organization of the human motor cortex.
However, tractographic studies showing general connectional
features of different premotor regions similar to those observed
in macaques (e.g., Schubotz, Anwander, Knosche, Von
Cramon, & Tittgemeyer, 2010) and functional imaging studies
showing topographical and functional homologies (e.g.,
Bremmer et al., 2001; Cavina-Pratesi et al., 2010) in the organization of the nonhuman primate and human motor and
parietal cortex confirm the eminent role of monkey studies
for the investigation of human cortical functions.
Belmalih, A., Borra, E., Contini, M., Gerbella, M., Rozzi, S., & Luppino, G. (2007).
A multiarchitectonic approach for the definition of functionally distinct areas and
domains in the monkey frontal lobe. Journal of Anatomy, 211, 199211.
Borra, E., Belmalih, A., Calzavara, R., Gerbella, M., Murata, A., Rozzi, S., et al. (2008).
Cortical connections of the macaque anterior intraparietal (AIP) area. Cerebral
Cortex, 18, 10941111.
Borra, E., Belmalih, A., Gerbella, M., Rozzi, S., & Luppino, G. (2010). Projections of the
hand field of the macaque ventral premotor area F5 to the brainstem and spinal cord.
Journal of Comparative Neurology, 518, 25702591.
Borra, E., Gerbella, M., Rozzi, S., & Luppino, G. (2011). Anatomical evidence for the
involvement of the macaque ventrolateral prefrontal area 12r in controlling goaldirected actions. Journal of Neuroscience, 31, 1235112363.
Borra, E., Gerbella, M., Rozzi, S., Tonelli, S., & Luppino, G. (2014). Projections to the
superior colliculus from inferior parietal, ventral premotor, and ventrolateral
prefrontal areas involved in controlling goal-directed hand actions in the macaque.
Cerebral Cortex, 24, 10541065.
Bremmer, F., Schlack, A., Shah, N. J., Zafiris, O., Kubischik, M., Hoffmann, K.-P., et al.
(2001). Polymodal motion processing in posterior parietal and premotor cortex: A
human fMRI study strongly implies equivalencies between humans and monkeys.
Neuron, 29, 287296.
Brodmann, K. (1909). Vergleichende Lokalisationslehre der Groshirnrinde. Leipzig:
Barth (Reprinted 1925).
Cavina-Pratesi, C., Monaco, S., Fattori, P., Galletti, C., Mcadam, T. D., Quinlan, D. J.,
et al. (2010). Functional magnetic resonance imaging reveals the neural substrates
of arm transport and grip formation in reach-to-grasp actions in humans. The
Journal of Neuroscience, 30, 1030610323.
Dancause, N., Barbay, S., Frost, S. B., Zoubina, E. V., Plautz, E. J., Mahnken, J. D., et al.
(2006). Effects of small ischemic lesions in the primary motor cortex on
neurophysiological organization in ventral premotor cortex. Journal of
Neurophysiology, 96, 35063511.
Fink, G. R., Frackowiak, R. S. J., Pietrzyk, U., & Passingham, R. E. (1997). Multiple
nonprimary motor areas in the human cortex. Journal of Neurophysiology, 77,
21642174.
Fitzgerald, P. J., Lane, J. W., Thakur, P. H., & Hsiao, S. S. (2004). Receptive field
properties of the macaque second somatosensory cortex: Evidence for multiple
functional representations. Journal of Neuroscience, 24, 1119311204.
Fogassi, L., & Luppino, G. (2005). Motor functions of the parietal lobe. Current Opinion
in Neurobiology, 15, 626631.
Gerbella, M., Belmalih, A., Borra, E., Rozzi, S., & Luppino, G. (2011). Cortical
connections of the anterior (F5a) subdivision of the macaque ventral premotor area
F5. Brain Structure and Function, 216, 4365.
Gerbella, M., Borra, E., Tonelli, S., Rozzi, S., & Luppino, G. (2013). Connectional
heterogeneity of the ventral part of the macaque area 46. Cerebral Cortex, 23, 967987.
Geyer, S., Matelli, M., Luppino, G., & Zilles, K. (2000). Functional neuroanatomy of the
primate isocortical motor system. Anatomy and Embryology, 202, 443474.
He, S. Q., Dum, R. P., & Strick, P. L. (1993). Topographic organization of corticospinal
projections from the frontal lobe: Motor areas on the lateral surface of the
hemisphere. Journal of Neuroscience, 13, 952980.
He, S. Q., Dum, R. P., & Strick, P. L. (1995). Topographic organization of corticospinal
projections from the frontal lobe: Motor areas on the medial surface of the
hemisphere. Journal of Neuroscience, 15, 32843306.
Hof, P. R., Glezer, I. I., Conde, F., Flagg, R. A., Rubin, M. B., Nimchinsky, E. A., et al.
(1999). Cellular distribution of the calcium-binding proteins parvalbumin,
calbindin, and calretinin in the neocortex of mammals: Phylogenetic and
developmental patterns. Journal of Chemical Neuroanatomy, 16, 77.
Hof, P. R., & Morrison, J. H. (1995). Neurofilament protein defines regional patterns of
cortical organization in the macaque monkey visual system: A quantitative
immunohistochemical analysis. Journal of Comparative Neurology, 352, 161186.
Jeannerod, M., & Jacob, P. (2005). Visual cognition: A new look at the two-visual
system model. Neuropsychologia, 43, 301312.
Keizer, K., & Kuypers, H. G. J. M. (1989). Distribution of corticospinal neurons with
collaterals to the lower brain stem reticular formation in monkey (Macaca
fascicularis). Experimental Brain Research, 74, 311318.
Lemon, R. N. (2008). Descending pathways in motor control. Annual Review of
Neuroscience, 31, 195218.
Morecraft, R. J., Louie, J. L., Herrick, J. L., & Stilwell-Morecraft, K. S. (2001). Cortical
innervation of the facial nucleus in the non-human primate: A new interpretation of
the effects of stroke and related subtotal brain trauma on the muscles of facial
expression. Brain, 124, 176208.
282
Murata, Y., Higo, N., Oishi, T., Yamashita, A., Matsuda, K., Hayashi, M., et al. (2008).
Effects of motor training on the recovery of manual dexterity after primary motor
cortex lesion in macaque monkeys. Journal of Neurophysiology, 99, 773786.
Nishimura, Y., Onoe, H., Morichika, Y., Perfiliev, S., Tsukada, H., & Isa, T. (2007).
Time-dependent central compensatory mechanisms of finger dexterity after spinal
cord injury. Science, 318, 11501155.
Rizzolatti, G., & Luppino, G. (2001). The cortical motor system. Neuron, 31, 889901.
Rizzolatti, G., Luppino, G., & Matelli, M. (1998). The organization of the cortical motor
system: New concepts. Electroencephalography and Clinical Neurophysiology, 106,
283296.
Rizzolatti, G., & Matelli, M. (2003). Two different streams form the dorsal visual system:
Anatomy and functions. Experimental Brain Research, 153, 146157.
Schubotz, R. I., Anwander, A., Knosche, T. R., Von Cramon, D. Y., & Tittgemeyer, M.
(2010). Anatomical and functional parcellation of the human lateral premotor cortex.
NeuroImage, 50, 396408.
Tanji, J., & Hoshi, E. (2008). Role of the lateral prefrontal cortex in executive behavioral
control. Physiological Reviews, 88, 3757.
Van Essen, D. C. (1985). Functional organization of primate visual cortex. In E. G.
Jones, & A. Peters (Eds.), Cerebral cortex. New York: Plenum Press.
Somatosensory Cortex
JH Kaas, Vanderbilt University, Nashville, TN, USA
2015 Elsevier Inc. All rights reserved.
Glossary
Introduction
http://dx.doi.org/10.1016/B978-0-12-397025-1.00223-2
283
284
ot
Foo
M2
M1
CS
Visual
Dys.
Pa
w
Olfactory
bulb
V1
S1
Pa
Fo
Face and
S1
vibrissae
Face
p
Li
5 mm
Upper
lip
Face
Face
PV
Li m b s
S2
Li m b s
R hin a l s
Aud
ulcu
Figure 1 A dorsolateral view of a rat brain showing the locations of somatosensory areas. These areas include the primary area, S1 of granular cortex,
which contains a representation of the touch receptors of the contralateral body surface. S1 is disrupted rostrally by dysgranular (Dys) cortex that
forms another representation of the contralateral body but of deep receptors in muscles and joints. Two smaller representations lateral to S1 are
somatotopically organized and respond to touch: the second somatosensory area (S2) and the parietal ventral somatosensory area (PV). A narrow
band of cortex caudal to S1, the caudal somatosensory area (CS), gets inputs from S1. Somatosensory areas provide inputs to primary motor
cortex (M1) and secondary motor cortex (M2, premotor cortex). Primary visual cortex (V1) and auditory cortex (Aud) are shown for reference.
(SA-II) are deeper in the skin and are very sensitive to vibration.
SA-II afferents might, for example, detect the vibrations that
travel through the ground that are made by an approaching
predator. Other afferents signal tissue damage (pain), temperature, and poorly localized touch.
limb) to lateral (teeth and tongue) in the nucleus. As a complication, neurons from the representation of teeth and tongue also
project ipsilaterally to VPM in most mammals. Thus, VPM has
separate representations of contralateral and ipsilateral teeth and
tongue. This may be important since the teeth and tongue on
both sides of the mouth function closely together. In some
rodents, especially in rats and mice, isolated groups of neurons
in VP are best activated by the movement of a single mystacial
vibrissa. Each cell group, called a barreloid in VP (van der Loos,
1976), projects to a matching cortical barrel in S1.
Afferents from muscles and joints that provide position
sense (proprioception) terminate in other nuclei in the upper
spinal cord and brain stem and activate neurons that also
project to the contralateral somatosensory thalamus. These
proprioceptive inputs terminate dorsal to VP in the ventroposterior superior (VPS) nucleus in primates and rostrodorsal cap
to VP in rats, cats, and probably most mammals (Francis, Xu, &
Chapin, 2008; Kaas, 2008). Other afferents related to pain,
temperature, and touch activate spinal cord and brain stem
neurons that cross to the opposite side of the spinal cord
ascend to the somatosensory thalamus in the spinothalamic
tract and its equivalent in the brain stem. Some of these
spinothalamic axons terminate in the ventroposterior inferior
(VPI) nucleus just under VP in primates or a similar region
capping caudoventral VP in other mammals. Other spinothalamic axons terminate in other parts of the somatosensory
thalamus, including a nucleus, that is part of a pain network,
and parts of the posterior nuclear complex. All these thalamic
nuclei receive other inputs, including feedback connections
from somatosensory cortex, and they generally contain a
mixture of about 75% excitatory neurons that project to cortex
and 25% inhibitory neurons that suppress ongoing activity in
the nucleus and help constrict the receptive fields of thalamic
neurons. However, in VP, rats and mice replace inhibitory
neurons in VP with inhibitory inputs from the thalamic reticular nucleus.
285
286
References
Abraira, V. E., & Ginty, D. D. (2013). The sensory neurons of touch. Neuron, 79,
618639.
Brecht, M., Preilowski, B., & Merzenich, M. M. (1997). Functional architecture of the
mystacial vibrissae. Behavioural Brain Research, 84, 8197.
Dawson, D. R., & Killackey, H. P. (1987). The organization and mutability of the forepaw
and hindpaw representations in the somatosensory cortex of the neonatal rat.
Journal of Comparative Neurology, 256, 246257.
Francis, J. T., Xu, S., & Chapin, J. K. (2008). Proprioceptive and cutaneous
representations in the rat ventral posterolateral thalamus. Journal of
Neurophysiology, 99, 22912304.
Kaas, J. H. (1983). What, if anything, is SI? The organization of first somatosensory
area of cortex. Physiological Reviews, 63, 206231.
Kaas, J.H. (2008). The somatosensory thalamus and associated pathways. The senses:
A comprehensive reference London: Elsevier.
Kaas, J. H. (2012). Somatosensory system. In J. K. Mai & G. Paxinos (Eds.), In The
human nervous system (3rd ed.). London: Elsevier.
Kaas, J. H., Gharbawie, O. A., & Stepniewska, I. (2011). The organization and evolution
of dorsal stream multisensory motor pathways in primates. Frontiers in
Neuroanatomy, 5, 17.
Kim, U., & Ebner, F. F. (1999). Barrels and septa: Separate circuits in rat barrel field
cortex. Journal of Comparative Neurology, 408, 489505.
Krubitzer, L., Campi, K. L., & Cooke, D. F. (2011). All rodents are not the same: A
modern synthesis of cortical organization. Brain, Behavior and Evolution, 78,
5193.
Reed, J. L., Qi, H. X., & Kaas, J. H. (2011). Spatiotemporal properties of neuron
response suppression in owl monkey primary somatosensory cortex when stimuli
are presented to both hands. Journal of Neuroscience, 31, 35893601.
Remple, M. S., Henry, E. C., & Catania, K. C. (2003). Organization of
somatosensory cortex in the laboratory rat (Rattus norvegicus): Evidence for two
lateral areas joined at the representation of the teeth. Journal of Comparative
Neurology, 467, 105118.
van der Loos, H. (1976). Barreloids in mouse somatosensory thalamus. Neuroscience
Letters, 2, 16.
Introduction
The primary visual cortex is commonly known as area V1, or
area 17 according to Brodmann (Brodmann, 1909), or area OC
according to von Economo (von Economo & Koskinas, 1925).
The primary visual cortex is the first cortical area in which the
visual information converge after their initial separate processing in the retina and subcortical nuclei, in particular lateral
geniculate nucleus (LGN) and superior colliculus. It is believed
that the unity of the information needed for a complete reconstruction for the visual world is still preserved in this first
cortical processing stage of the visual pathway. Beyond area
V1, different features of the visual world are processed in
separate cortical areas in a massively parallel manner
(Felleman & Van Essen, 1991; Ungerleider & Haxby, 1994).
While most of our knowledge about the structure and function
of V1 originate from studies in nonhuman primates, in particular that of old-world monkeys (Felleman & Van Essen, 1991),
the basic scaffold of the functional architecture in humans is
generally assumed to be homologous to that of other primates.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00224-4
287
288
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Functional Organization of the Primary Visual Cortex
xx0
yy0
2s2
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Functional Organization of the Primary Visual Cortex
Calcarine sulcus
289
Fitted pRF
model
Calcarine sulcus
x = 4.9
y = 1.4
s = 0.8
Occipital lobe
V2d
(a)
V1
Calcarine sulcus
V2v
VP
10.0
hV4
HM
x = 0.3
y = 0.9
s = 0.4
0.0
(b)
Eccentricity
(c)
Polar angle
(d)
Fitted pRF
model
Figure 1 Topography of primary visual cortex and surrounding areas in a single subject revealed by retinotopic mapping analysis based on the
population receptive field (pRF) method. (a) Eccentricity values in the range from 0 to 10 of visual angle (see color bar in (b)) were calculated from the
estimated pRF x and y location of visually responsive voxels and visualized on a selected mid-sagittal (left) and coronal slice (right). (b) The same
eccentricity map visualized on a view of the medial bank of a folded cortex mesh of the right hemisphere (anterior is to the left, posterior is to the right).
(c) While a 3D rendering of a folded 3D mesh as in (b) better reveals the topographic layout of the eccentricity map than 2D slices as in (a), the full
topographic layout of V1 is only revealed on inflated (or fully flattened) cortex meshes. (d) Polar angle values, calculated from the same estimated
pRF location values, can be used to demarcate the extent of V1 and surrounding areas by identifying the horizontal and vertical (half-)meridians. The
lower left visual field quadrant is mapped to the upper bank of the calcarine sulcus demarcated by the left horizontal meridian (dotted line labeled
HM) and the vertical half-meridian of the lower visual field. The upper left visual field quadrant is mapped to the lower bank of the calcarine sulcus
demarcated again by the left horizontal meridian and the vertical meridian of the upper visual field. Fitted pRF models are shown in insets for two
exemplary locations within V1 (for details see text).
290
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Functional Organization of the Primary Visual Cortex
Scalebar = 0.5 mm
(a)
2p
0
(b)
Phase
This neuroimaging data is compatible with the predictive coding theory that assumes that early sensory areas are prepared
with a predictive model for the external incoming information
through cortical feedback from higher cognitive areas (Bastos
et al., 2012; Mumford, 1992; Rao & Ballard, 1999). More
specifically, top-down predictions are generated and sent
downwards to early visual areas in order to enable comparison
of sensory hypotheses (reflecting the expected state of the
world) with incoming bottom-up sensory information. This
comparison results in a prediction error that is used to update
the higher-level representations reducing prediction error at
lower levels in the next round. With its possibility to separate
responses in cortical layers, UHF fMRI will likely play an
important role in the future to link processing in different
layers of the canonical microcircuit to the predictive coding
theory (Bastos et al., 2012). More generally, fMRI at the mesoscopic level of cortical columns and layers will further elucidate
the role of V1 in perception, attention, and visual awareness
(Lamme, Super, Landman, Roelfsema, & Spekreijse, 2000;
Tong, 2003).
Acknowledgments
Supported by the European Research Council (ERC) under
European Unions Seventh Framework Program FP7/
20072013/ERC Grant Agreement Number 269853.
References
Bannert, M. M., & Bartels, A. (2013). Decoding the yellow of a gray banana. Current
Biology, 23, 22682272.
Bastos, A. M., Usrey, W. M., Adams, R. A., Mangun, G. R., Fries, P., & Friston, K. J.
(2012). Canonical microcircuits for predictive coding. Neuron, 76, 695711.
Bonhoeffer, T., & Grinvald, A. (1991). Iso-orientation domains in cat visual cortex are
arranged in pinwheel-like patterns. Nature, 353, 429431.
Brodmann, K. (1909). Vergleichende Lokalisationslehre der Grosshirnrinde. Leipzip:
Johann Ambrosius Barth.
Cheng, K., Waggoner, R. A., & Tanaka, K. (2001). Human ocular dominance columns as
revealed by high-field functional magnetic resonance imaging. Neuron, 32,
359374.
Daniel, P. M., & Whitteridge, D. (1961). The representation of the visual field on the
cerebral cortex in monkeys. Journal of Physiology, 159, 203221.
De Martino, F., Zimmermann, J., Muckli, L., Ugurbil, K., Yacoub, E., & Goebel, R.
(2013). Cortical depth dependent functional responses in humans at 7 T: improved
specificity with 3D GRASE. PloS One, 8, e60514.
Douglas, R. J., & Martin, K. A.C (2007). Mapping the matrix: The ways of neocortex.
Neuron, 56, 226238.
Douglas, R. J., Martin, K. A. C., & Whitteridge, D. (1989). A canonical microcircuit for
neocortex. Neural Computation, 1, 480488.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Functional Organization of the Primary Visual Cortex
Dumoulin, S. O., & Wandell, B. A. (2008). Population receptive field estimates in human
visual cortex. NeuroImage, 39, 647660.
Feinberg, D., Harel, N., Ramanna, S., Ugurbil, K., & Yacoub, E. (2008). Submillimeter
single-shot 3D GRASE with inner volume selection for T2-weighted fMRI
applications at 7 Tesla. Proceedings of the International Society for Magnetic
Resonance in Medicine, 16, 2373.
Felleman, D. J., & Van Essen, D. C. (1991). Distributed hierarchical processing in the
primate cerebral cortex. Cerebral Cortex, 1, 147.
Gennari, F. (1782). De peculiari structura cerebri nonnulisque ejus morbis. Parma
(Italy): Ex Regio.
Goebel, R., Khorram-Sefat, D., Muckli, L., Hacker, H., & Singer, W. (1998). The
constructive nature of vision: Direct evidence from functional magnetic resonance
imaging studies of apparent motion and motion imagery. The European Journal of
Neuroscience, 10, 15631573.
Goebel, R., Muckli, L., Zanella, F. E., Singer, W., & Stoerig, P. (2001). Sustained
extrastriate cortical activation without visual awareness revealed by fMRI studies of
hemianopic patients. Vision Research, 41, 14591474.
Haak, K. V., Langers, D. R., Renken, R., van Dijk, P., Borgstein, J., & Cornelissen, F. W.
(2013). Abnormal visual field maps in human cortex: A mini-review and a case
report. Cortex, 56C, 1425.
Hubel, D. H., & Wiesel, T. N. (1968). Receptive fields and functional architecture of
monkey striate cortex. The Journal of Physiology, 195, 215243.
Hubel, D. H., & Wiesel, T. N. (1969). Anatomical demonstration of columns in the
monkey striate cortex. Nature, 221, 747750.
Hubel, D. H., & Wiesel, T. N. (1972). Laminar and columnar distribution of geniculocortical fibers in the macaque monkey. The Journal of Comparative Neurology, 146,
421450.
Hubel, D. H., & Wiesel, T. N. (1977). Ferrier lecture. Functional architecture of macaque
monkey visual cortex. Proceedings of the Royal Society of London. Series B:
Biological Sciences, 198, 159.
Kok, P., & de Lange, F. P. (2014). Shape perception simultaneously up- and
downregulates neural activity in the primary visual cortex. Current Biology, 24,
15311535.
Koopmans, P. J., Barth, M., Orzada, S., & Norris, D. G. (2011). Multi-echo fMRI of the
cortical laminae in humans at 7 T. NeuroImage, 56, 12761285.
Lamme, V. A. F., Super, H., Landman, R., Roelfsema, P. R., & Spekreijse, H. (2000). The
role of primary visual cortex (V1) in visual awareness. Vision Research, 40,
15071521.
Lee, S., Papanikolaou, A., Logothetis, N. K., Smirnakis, S. M., & Keliris, G. A. (2013). A
new method for estimating population receptive field topography in visual cortex.
NeuroImage, 81, 144157.
Leuba, G., & Kraftsik, R. (1994). Changes in volume, surface estimate,
three-dimentional shape and total number of neurons of the human primary
visual cortex from midgestation until old age. Anatomy and Embryology, 190,
351366.
Logothetis, N. K. (2008). What we can do and what we cannot do with fMRI. Nature,
453, 869878.
Lund, J. S. (1988). Anatomical organization of macaque striate visual cortex. Annual
Review of Neuroscience, 11, 253288.
Malonek, D., & Grinvald, A. (1996). Interactions between electrical activity and cortical
microcirculation revealed by imaging spectroscopy: Implications for functional
brain mapping. Science, 272, 551554.
Mumford, D. (1992). On the computational architecture of the neocortex. II. The role of
cortico-cortical loops. Biological Cybernetics, 66, 241251.
Norris, D. G. (2012). Spin-echo fMRI: The poor relation? NeuroImage, 62,
11091115.
291
OKusky, J., & Colonnier, M. (1982). A laminar analysis of the number of neurons, glia,
and synapses in the visual cortex (area 17) of adult macaque monkeys. The Journal
of Comparative Neurology, 210, 278290.
Olman, C., Harel, N., Feinberg, D. A., He, S., Zhang, P., et al. (2012). Layer-specific
fMRI reflect different neuronal computations at different depths in human V1. PloS
One, 7, e32536.
Peters, A., & Jones, E. G. (1984). Classification of cortical neurons. In A. Peters, & E. G.
Jones (Eds.), Cerebral cortex (pp. 107121). New York: Plenum.
Rao, R. P., & Ballard, D. H. (1999). Predictive coding in the visual cortex: A functional
interpretation of some extra-classical receptive-field effects. Nature Neuroscience, 2,
7987.
Rockel, A. J., Hiorns, R. W., & Powell, T. P.S (1980). The basic uniformity in structure
of the neocortex. Brain, 103, 221244.
Roebroeck, A., & Goebel, R. (2014). Computational causal modeling of high-resolution
functional MRI data. In M. S. Gazzaniga (Ed.), The cognitive neurosciences V.
Cambridge, MA: MIT Press.
Senden, M., Reithler, J., Gijsen, S., & Goebel, R. (2014). Evaluating population
receptive field estimation frameworks in terms of robustness and reproducibility.
PLoS One, 9, e114054.
Sereno, M. I., Dale, A. M., Reppas, J. B., Kwong, K. K., Belliveau, J. W., Brady, T. J.,
et al. (1995). Borders of multiple visual areas in humans revealed by functional
magnetic resonance imaging. Science, 268, 889893.
Smith, F. W., & Muckli, L. (2010). Nonstimulated early visual areas carry information
about surrounding context. Proceedings of the National Academy of Sciences of the
United States of America, 107, 2009920103.
Tong, F. (2003). Primary visual cortex and visual awareness. Nature Reviews.
Neuroscience, 4, 219229.
Tootell, R. B., Dale, A. M., Sereno, M. I., & Malach, R. (1996). New images from human
visual cortex. Trends in Neurosciences, 19, 481489.
Trampel, R., Ott, D. V. M., & Turner, R. (2011). Do the congenitally blind have a stria of
Gennari? First intracortical insights in vivo. Cerebral Cortex, 21, 20752081.
Ungerleider, L. G., & Haxby, J. V. (1994). What and where in the human brain. Current
Opinion in Neurobiology, 4, 157165.
Vetter, P., Smith, F. W., & Muckli, L. (2014). Decoding sound and imagery content in
early visual cortex. Current Biology, 24, 12561262.
von Economo, C., & Koskinas, G. N. (1925). Die Cytoarchitektonik der Hirnrinde des
erwachsenen Menschen. Vienna: Springer Verlag.
Waehnert, M. D., Dinse, J., Weiss, M., Streicher, M. N., Waehnert, P., Geyer, S., et al.
(2014). Anatomically motivated modeling of cortical laminae. NeuroImage, 93,
210220.
Wandell, B. A., Dumoulin, S. O., & Brewer, A. A. (2007). Visual field maps in human
cortex. Neuron, 56, 366383.
Yacoub, E., Harel, N., & Ugurbil, K. (2008). High-field fMRI unveils orientation columns
in humans. Proceedings of the National Academy of Sciences of the United States of
America, 105, 1060710612.
Yacoub, E., Shmuel, A., Logothetis, N., & Ugurbil, K. (2007). Robust detection of ocular
dominance columns in humans using Hahn Spin Echo BOLD functional MRI at 7
Tesla. NeuroImage, 37, 11611177.
Zilles, K. (1990). Cortex. In G. Paxinos (Ed.), The human nervous system
(pp. 757802). San Diego, CA: Academic Press.
Zimmermann, J., Goebel, R., De Martino, F., van de Moortele, P. F., Feinberg, D.,
Adriany, G., et al. (2011). Mapping the organization of axis of motion selective
features in human area MT using high-field fMRI. PloS One, 6, e28716.
Zimmermann, J., Senden, M., De Martino, F., & Goebel, R. (2014). Cortical depth
dependent connective population receptive fields at sub-millimeter resolution.
Submitted.
Abbreviations
AD
AF
AL
AM
antSTS
DP
fMRI
FST
HM
IT
LPP
LVF
LVM
MF
midSTS
ML
mPPA
mRSC
MSTv
Anterior dorsal face patch
Anterior fundus face patch
Anterior lateral face patch
Anterior medial face patch
Anterior STS body patch
Dorsal prelunate area
Functional magnetic resonance
imaging
Fundus of superior temporal area
Horizontal meridian
Inferior temporal cortex
Lateral place patch
Lower visual field
Lower vertical meridian
Middle fundus face patch
Middle STS body patch
Middle lateral face patch
Monkey homologue of PPA
Monkey homologue of RSC
contralateral hemifield, with segregated upper and lower quadrants (the so-called split-field representations) in ventral and
dorsal portions of the occipital cortex, respectively. Besides a
foveal and lower field representation in the ventral cortex,
possibly corresponding to architectonic area TEO, these original fMRI mapping studies yielded little evidence for visual field
maps anterior to ventral V4.
Within the visual hierarchy, area V3A is the first region
located exclusively in the dorsal visual cortex containing a
representation of both the upper and lower quadrants surrounded by a VM (complete hemifield). This area is located
on the anectant gyrus and its foveal representation is separated
from the central foveal confluence of areas V1V4. However,
unlike these latter areas, area V3A remains difficult to identify
consistently in all subjects.
A more recent high-resolution retinotopic mapping study
(Kolster et al., 2009) revealed that MT and its immediate
neighbors are organized as a visual field map cluster with a
shared foveal representation surrounded by a semicircular
array of isoeccentricity contours (Figure 1). The existence of
such field map clusters was first described by Wandell, Brewer,
and Dougherty (2005) who proposed it as a general organizational principle with which the extrastriate cortex groups areas
sharing similar functionalities. The shared foveal representation is distinct from the central foveal confluence of V1V4 and
is located in the posterior bank of the STS. Areas MT, MSTv,
and FST each contains a complete contralateral visual field,
while in the original study, only the upper quadrant was
http://dx.doi.org/10.1016/B978-0-12-397025-1.00225-6
293
294
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Topographic Layout of Monkey Extrastriate Visual Cortex
Figure 1 Biologically relevant phase-encoded stimuli and retinotopic organization of the macaque occipitotemporal cortex. Color code and line
conventions: see insets. Stars indicate the positions of the central visual field representations. Green line indicates the eccentricity ridge around the MT
cluster. A, anterior; D, dorsal; RH, right hemisphere. Modified from Janssens, T., Zhu, Q., Popivanov, I. D., & Vanduffel, W. (2014). Probabilistic
and single-subject retinotopic maps reveal the topographic organization of face patches in the macaque cortex. The Journal of Neuroscience,
with permission.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Topographic Layout of Monkey Extrastriate Visual Cortex
et al. (2014) study showed that V4A, PITd, PITv, and OTd
shared a common foveal representation, distinct from the central foveal confluence (of V1V4) or the MT cluster (V4t, MT,
MSTv, and FST) (Figure 1). Hence, in the monkey occipitotemporal cortex, at least three separate visual field map clusters
can be identified, indicating an evolutionarily preserved and
fundamental organizational principle of the primate visual
cortex (Kolster et al., 2009). As Wandell et al. (2005) proposed,
such clustering may be the most efficient manner of minimizing neural distances between processing modules that require
strong functional interactions. The Janssens et al. (2014) study
also hinted at other regions anterior to the MT and PIT clusters
showing foveal biases. These regions, located in the anterior
bank of the STS (corresponding to STP) and in the middle
temporal gyrus, do not necessarily overlap with regions showing face selectivity, as postulated for the human visual cortex
(Hasson, Levy, Behrmann, Hendler, & Malach, 2002).
Faces
Several groups have shown a set of cortical regions that are
preferentially activated by faces compared to nonface objects
(Pinsk et al., 2009; Popivanov, Jastorff, Vanduffel, & Vogels,
2012; Tsao, Freiwald, Tootell, & Livingstone, 2006). Initial
reports defined six such patches: PL, ML, MF, AL, AF, and AD
(with P posterior, M medial, A anterior, L lateral,
F fundus, and D dorsal) (Figure 2). The AF described by
Tsao et al. (2008) likely corresponds to a combination of AF
and AD (Pinsk et al., 2009).
In addition, using concurrent microstimulation and fMRI,
Tsaos group showed that the face patches in the monkey
extrastriate cortex formed an interconnected functional network (Moeller, Freiwald, & Tsao, 2008). Quite surprisingly,
when using dynamic facial expressions, Zhu et al. (2012)
observed an additional face-responsive region lateral to the
face patches (Figure 2).
Although significant progress has been made in understanding the neuronal response characteristics of monkey
face patches (Freiwald & Tsao, 2010; Freiwald et al., 2009;
Hadj-Bouziane et al., 2008; Issa & DiCarlo, 2012; Pinsk et al.,
2009; Tsao et al., 2006), little is known about their topographic
organizations. Relating face patches to retinotopic areas, however, has implications for the neural computations they
295
Bodies
A number of imaging studies have also shown occipitotemporal areas responding more strongly to images of bodies
and body parts than to faces and other object categories (Bell,
Hadj-Bouziane, Frihauf, Tootell, & Ungerleider, 2009; Bell
et al., 2011; Pinsk et al., 2009; Pinsk, Moore, Richter, Gross,
& Kastner, 2005; Popivanov et al., 2012; Popivanov, Jastorff,
Vanduffel, & Vogels, 2014; Tsao, Freiwald, Knutsen, Mandeville, & Tootell, 2003). These body-selective patches are located
adjacent to the middle and anterior face patches (Popivanov
et al., 2012): The midSTS patch lies between the ML and MF
face patches, while parts of the antSTS patch abut AL medially
and AF more laterally (Figure 2). As with most face patches, the
body patches are located within the nonretinotopic cortex,
except for the most posterior part of the midSTS patch. Interestingly, within the body patches, multivoxel pattern analysis
(MVPA) primarily differentiated between faces and other
object classes (including bodies) instead of the expected distinction between animate and inanimate objects (Popivanov
et al., 2012).
Scenes
Alongside face and body patches, fMRI has also revealed evidence for three specialized scene-processing modules in the
human visual cortex: the parahippocampal place area (PPA),
transverse occipital sulcus (TOS), and retrosplenial cortex
(RSC). In the monkey, Tootells group described sceneselective regions in the dorsal occipital cortex: mTOS in a
region partially overlapping V3A, V4d, or DP; mRSC on the
medial wall near peripheral V1; and mPPA lying lateral to the
ML face patch (Nasr et al., 2011). Kornblith et al. (2013) also
described a scene patch located more lateroventrally within the
OTS, which they call the lateral place patch (LPP) and which
may correspond to mPPA (Figure 2).
Other recent monkey fMRI studies revealed an interesting
pattern of color-selective patches that were paired with the face
296
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Topographic Layout of Monkey Extrastriate Visual Cortex
Figure 2 Clustering of object-category selectivity in the macaque occipitotemporal cortex. Regions (colored area) and coordinates (filled circle)
are displayed on F99 right hemisphere flattened surface. Face, body, and place patches. Modified with permission from Janssens, T., Zhu, Q., Popivanov,
I. D., & Vanduffel, W. (2014). Probabilistic and single-subject retinotopic maps reveal the topographic organization of face patches in the macaque
cortex. The Journal of Neuroscience; Popivanov, I. D., Jastorff, J., Vanduffel, W., & Vogels, R. (2012). Stimulus representations in body-selective
regions of the macaque cortex assessed with event-related fMRI. Neuroimage, 63(2), 723741; Nasr, S., Liu, N., Devaney, K. J., Yue, X., Rajimehr, R.,
Ungerleider, L. G., et al. (2011). Scene-selective cortical regions in human and nonhuman primates. Journal of Neuroscience, 31(39), 1377113785.
AM, mRSC, and LPP: coordinates from Tsao, Schweers, Moeller, and Freiwald (2008); Nasr et al. (2011); and Kornblith, Cheng, Ohayon, and Tsao
(2013). Regions sensitive to motion (beyond the MT cluster) and emotional expressions: from Nelissen, Vanduffel, and Orban (2006) and Zhu et al.
(2012). Coordinates of color-sensitive regions, from Lafer-Sousa and Conway (2013). Retinotopic areas: probabilistic map from Janssens et al. (2014).
Line and symbol (star) conventions as Figure 1. LuS, lunate sulcus; IOS, inferior occipital sulcus; STS, superior temporal sulcus; OTS, occipitotemporal
sulcus; IPS, intraparietal sulcus.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Topographic Layout of Monkey Extrastriate Visual Cortex
evidence, such as combined retinotopic, functional, connectional, and possibly detailed anatomical (e.g., myelin density)
information, in formulating conclusions about specific parcellation schemes (Janssens, Arsenault, Polimeni, & Vanduffel, 2013)
or homologies across species. Hence, in vivo imaging technology
in concert with ex vivo histological tools will further advance our
view concerning the topographic layout of the monkey visual
cortex, providing vital clues to the organizational principles that
triggered its onto- and phylogenetic development. All this information will prove critical to our understanding of the workings
of the human brain.
Acknowledgments
This work received support from Inter-University Attraction
Pole 7/21, Programme Financing PFV/10/008, Impulsfinanciering Zware Apparatuur and Hercules funding of the KU
Leuven, and Fonds Wetenschappelijk OnderzoekVlaanderen
G0A5613N, G043912N, G062208N10, G059309N10,
G083111N10, and K714811N. QZ is postdoctoral fellow of
FWO Vlaanderen. The Martinos Center for Biomedical Imaging
is supported by the National Center for Research Resources
grant P41RR14075. The authors declare that they have no
competing financial interests.
References
Bell, A. H., Hadj-Bouziane, F., Frihauf, J. B., Tootell, R. B., & Ungerleider, L. G. (2009).
Object representations in the temporal cortex of monkeys and humans as revealed
by functional magnetic resonance imaging. Journal of Neurophysiology, 101(2),
688700.
Bell, A. H., Malecek, N. J., Morin, E. L., Hadj-Bouziane, F., Tootell, R. B., &
Ungerleider, L. G. (2011). Relationship between functional magnetic resonance
imaging-identified regions and neuronal category selectivity. Journal of
Neuroscience, 31(34), 1222912240.
Brewer, A. A., Press, W. A., Logothetis, N. K., & Wandell, B. A. (2002). Visual areas in
macaque cortex measured using functional magnetic resonance imaging. Journal of
Neuroscience, 22(23), 1041610426.
Epstein, R., & Kanwisher, N. (1998). A cortical representation of the local visual
environment. Nature, 392(6676), 598601.
Felleman, D. J., & Van Essen, D. C. (1991). Distributed hierarchical processing in the
primate cerebral cortex. Cerebral Cortex, 1, 147.
Fize, D., Vanduffel, W., Nelissen, K., Denys, K., Chef dHotel, C., Faugeras, O., et al.
(2003). The retinotopic organization of primate dorsal V4 and surrounding areas: A
functional magnetic resonance imaging study in awake monkeys. Journal of
Neuroscience, 23(19), 73957406.
Freiwald, W. A., & Tsao, D. Y. (2010). Functional compartmentalization and viewpoint
generalization within the macaque face-processing system. Science, 330, 845851.
Freiwald, W. A., Tsao, D. Y., & Livingstone, M. S. (2009). A face feature space in the
macaque temporal lobe. Nature Neuroscience, 12, 11871196.
Hadj-Bouziane, F., Bell, A. H., Knusten, T. A., Ungerleider, L. G., & Tootell, R. B. (2008).
Perception of emotional expressions is independent of face selectivity in monkey
297
298
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Topographic Layout of Monkey Extrastriate Visual Cortex
Tsao, D. Y., Schweers, N., Moeller, S., & Freiwald, W. A. (2008). Patches of faceselective cortex in the macaque frontal lobe. Nature Neuroscience, 11(8), 877879.
Vanduffel, W., Fize, D., Mandeville, J. B., Nelissen, K., Van Hecke, P., Rosen, B. R., et al.
(2001). Visual motion processing investigated using contrast agent-enhanced fMRI
in awake behaving monkeys. Neuron, 32(4), 565577.
Vanduffel, W., Fize, D., Peuskens, H., Denys, K., Sunaert, S., Todd, J. T., et al. (2002).
Extracting the third dimension from motion: Differences in human and monkey
intraparietal cortex. Science, 298, 413415.
Wandell, B. A., Brewer, A. A., & Dougherty, R. F. (2005). Visual field map clusters in
human cortex. Philosophical Transactions of the Royal Society of London, Series B:
Biological Sciences, 360(1456), 693707.
Zeki, S. M. (1971). Convergent input from the striate cortex (area 17) to the cortex of the
superior temporal sulcus in the rhesus monkey. Brain Research, 28(2), 338340.
Zhu, Q., Nelissen, K., Van den Stock, J. V., De Winter, F. L., Pauwels, K., de Gelder, B.,
et al. (2012). Dissimilar processing of emotional facial expressions in human and
monkey temporal cortex. NeuroImage, 66C, 402411.
Auditory Cortex
JP Rauschecker, Georgetown University, Washington, DC, USA
2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00226-8
299
10
+2
ce
ip
ip
ai
ip
la
la
orm
tmp
oi
PG
LC
la
TA
ts
OA
ip
ci
PG
ts
as
TA
ts
tma
TE
oi
10
Auditory
ts
ca
ca
tmp
TH
OB
TE
TF
+2
ot
Visual
FC
FD
as
ce
ci
ci
LA
ip
ce
PF
IB
(a)
TF
ts
rh
TG
tma
TE
FD
p
ci
la
FD
p
ai
FDv
la
TA
A
FD
p
FCD
IB
+14
as
ci
LA
ai
la
TE
TH
FD
FBA
TA
ts
+8
ci
LA
+20
rh
TGv
TGd
FF
FL
orm
+26
FDv
FL
+32
FDv
FL
+38
ts
(b)
Figure 1 Auditory cortex defined by functional mapping with 2-deoxyglucose (2-DG) and by histochemical markers in the rhesus monkey. (a)
Schematic summary of cortical areas related to the processing of auditory, auditory plus visual, and visual stimuli (red, pink, and gray areas,
respectively), based on a comparison of the present results with those obtained in an earlier 2-DG visual experiment. Standard coronal sections through
the right hemisphere are at levels indicated by the vertical lines on the lateral surface view (upper left). Numerals refer to number of millimeters
anterior () or posterior () to the interaural plane. Boundaries were determined by visual inspection followed by quantitative examination of the
autoradiographs for the individual cases, and the boundary positions were averaged across the cases within each study. Cortical abbreviations are the
cytoarchitectonic designations of Bonin and Bailey. Sulcal abbreviations: ai, inferior limb of arcuate; as, superior limb of arcuate; ca, calcarine; ce,
central; ci, cingulate; ip, intraparietal; l, lunate; la, lateral; oi, inferior occipital; orm, medial orbital; ot, occipitotemporal; p, principal; rh, rhinal; tma,
anterior middle temporal; tmp, posterior middle temporal; and ts, superior temporal. (Reproduced from Poremba, A., Saunders, R. C., Crane, A. M.,
Cook, M., Sokoloff, L., & Mishkin, M. (2003). Functional mapping of the primate auditory system. Science, 299, 568572.) (b) Brain sections were cut
parallel to the surface of artificially flattened cortex and processed for parvalbumin. A large, dark oval corresponding to the core auditory area I (AI) is
apparent. The rostral core area (R) is also apparent as a dark oval, whereas the rostrotemporal area (RT) is most visible in (b). In (b), note also
slight differences in the darkness of the caudomedial (CM), caudolateral (CL), middle lateral (ML), and anterolateral (AL) areas of the auditory belt. Dots
outline these areas, as well as the lip of the lateral sulcus (LS). An arrowhead marks the diamidino yellow injection site. Scale bar 5 mm.
Reproduced from Hackett, T. A., Stepniewska, I., & Kaas, J. H. (1998). Subdivisions of auditory cortex and ipsilateral cortical connections of the parabelt
auditory cortex in macaque monkeys. Journal of Comparative Neurology, 394, 475495.
1/3 octave
1/2 octave
1 octave
10
5
0
2 octaves
Frequency (kHz)
301
500
300
200
100
70
AL (n = 31)
ML (n = 89)
CL (n = 16)
p < 0.0001
50
30
20
20 30
A (V) 0
0 100 200 300 400
(a)
50 70 100
Time (ms)
CS
Is
sts
NCR
8
0.4
6.5
0.35
20
12.5
CL
0.6
10
2
3
1.2
ML
0.35
11
0.8
M
AL
(c)
C
L
Figure 2 Lateral belt areas of the rhesus monkey auditory cortex. The use of band-passed noise bursts (a) leads to significant enhancement of the
response in lateral belt areas (b). This allows mapping of LB areas and reveals a cochleotopic map with two reversals. The three areas were
termed anterolateral (AL), middle lateral (ML), and caudolateral (CL) areas. Reproduced from Rauschecker, J. P., Tian, B., & Hauser, M. (1995).
Processing of complex sounds in the macaque nonprimary auditory cortex. Science, 268, 111114.
302
PFC
8a,46
PP
LIP VIP
10,12
Where
Tpt, TPJ
CPB
PP
46d 8a
46v
CL
CM
MGd
CPB
ML
AL
A1
RPB
Ts1/Ts2
MGv
RPB
What
Parabelt
AL
Belt
Core
Cortex
Thalamus
Ts1/Ts2
Figure 3 Schematic diagram of dual auditory cortical pathways in primates representing auditory object/pattern (what) processing in an anteroventral
projection and auditory space (where) processing in a posterodorsal projection (modified and expanded from Rauschecker, J. P. & Tian, B. (2000).
Mechanisms and streams for processing of what and where in auditory cortex. Proceedings of the National Academy of Sciences of the United States of
America, 97, 1180011806). The projections of the posterodorsal stream are highlighted in solid lines; participating cortical areas are marked with oblique
lines. The anteroventral pathway is shown in dashed lines. Areas that are not uniquely participating in either pathway are shown in dark blocks (primary auditory
cortex, A1) or stippled (middle lateral belt area, ML). Prefrontal connections of the LB are also shown directly on a lateral view of a rhesus monkey brain.
(Reproduced from Romanski, L. M., Tian, B., Fritz, J., Mishkin, M., Goldman-Rakic, P. S., & Rauschecker, J. P. (1999). Dual streams of auditory afferents target
multiple domains in the primate prefrontal cortex. Nature Neuroscience, 2, 11311136.) Abbreviations: MGd, medial geniculate nucleus; dorsal division; MGv,
medial geniculate nucleus, ventral division; CM, caudomedial area; R, rostral area; CL, caudolateral area; CPB, caudal parabelt area; RPB, rostral parabelt area;
Tpt, temporoparietal area; TPJ, temporoparietal junction; PP, posterior parietal cortex; LIP, lateral intraparietal area; VIP, ventral intraparietal area; Ts1, Ts2,
rostral temporal areas of Pandya & Sanides (1972); PFC, prefrontal cortex. Brodmann areas are abbreviated with their respective numbers.
(a)
0.03
0.00
(b)
(c)
Figure 4 Meta-analysis of speech sound representations in the human brain. Results of neuroimaging studies are shown with foci meeting inclusion criteria
for ALE-statistic maps for regions of significant concordance (p < 103). Analyses show an anterior progression with phoneme-length studies showing the
greatest concordance in the left mid-STG ((a); nexp 14), word-length studies showing the greatest concordance in the left anterior STG ((b); nexp 16), and
phrase-length analyses showing the greatest concordance in the left anterior STS ((c); nexp 19). nexp denotes the number of experiments (i.e., the number of
contrasts from independent samples) contributing to each analysis. Reproduced from DeWitt, I. & Rauschecker, J. P. (2012). Phoneme and word recognition
in the auditory ventral stream. Proceedings of the National Academy of Sciences of the United States of America, 109, E505E514.
303
IFG / vPMC
dPMC
Pre-SMA
z = 61
z = 47
z = 16
z = 3
neuroimaging studies of phoneme, word, and phrase recognition confirms an anterior rather than posterior location of the
Wernickes area (DeWitt & Rauschecker, 2012) (Figure 4).
Given the role of the posterior ST in auditory spatial processing mentioned in the preceding text, the question arises what
if any role this region is playing in speech processing. An
answer is provided by human imaging data that implicate the
auditory dorsal stream in audiomotor integration and control,
including the processing of sequences (Figure 5) (Leaver et al.,
2009; Rauschecker, 2011; Rauschecker & Scott, 2009). It
appears that the dorsal stream creates an interface between
sensory and motor networks and performs a matching operation between predicted outcomes and actual events. While the
computational algorithms in the brain are far from clear, they
must resemble the internal forward models that have revolutionized thinking in motor control and robotics (Kawato,
1999; Wolpert, Ghahramani, & Jordan, 1995).
304
References
Alain, C., Arnott, S. R., Hevenor, S., Graham, S., & Grady, C. L. (2001). What and
where in the human auditory system. Proceedings of the National Academy of
Sciences of the United States of America, 98, 1230112306.
Binder, J. R., Frost, J. A., Hammeke, T. A., Bellgowan, P. S., Springer, J. A.,
Kaufman, J. N., et al. (2000). Human temporal lobe activation by speech and
nonspeech sounds. Cerebral Cortex, 10, 512528.
Binder, J. R., Liebenthal, E., Possing, E. T., Medler, D. A., & Ward, B. D. (2004). Neural
correlates of sensory and decision processes in auditory object identification.
Nature Neuroscience, 7, 295301.
Chevillet, M., Riesenhuber, M., & Rauschecker, J. P. (2011). Functional correlates of
the anterolateral processing hierarchy in human auditory cortex. Journal of
Neuroscience, 31, 93459352.
Cohen, Y. E., Russ, B. E., Davis, S. J., Baker, A. E., Ackelson, A. L., & Nitecki, R. (2009).
A functional role for the ventrolateral prefrontal cortex in non-spatial auditory
cognition. Proceedings of the National Academy of Sciences of the United States of
America, 106, 2004520050.
Desimone, R., & Schein, S. J. (1987). Visual properties of neurons in area V4 of the
macaque: Sensitivity to stimulus form. Journal of Neurophysiology, 57, 835868.
DeWitt, I., & Rauschecker, J. P. (2012). Phoneme and word recognition in the auditory
ventral stream. Proceedings of the National Academy of Sciences of the United
States of America, 109, E505E514.
DeWitt, I., & Rauschecker, J. P. (2013). Wernickes area revisited: Parallel streams and
word processing. Brain and Language, 127, 181191.
Galaburda, A. M., Sanides, F., & Geschwind, N. (1978). Human brain. Cytoarchitectonic leftright asymmetries in the temporal speech region. Archives of Neurology, 35, 812817.
Goldman-Rakic, P. S. (1996). The prefrontal landscape: Implications of functional
architecture for understanding human mentation and the central executive.
Philosophical Transactions of the Royal Society of London, Series B: Biological
Sciences, 351, 14451453.
Hackett, T. A. (2011). Information flow in the auditory cortical network. Hearing
Research, 271, 133146.
Hackett, T. A., Stepniewska, I., & Kaas, J. H. (1998). Subdivisions of auditory cortex and
ipsilateral cortical connections of the parabelt auditory cortex in macaque monkeys.
Journal of Comparative Neurology, 394, 475495.
Jones, E. G., Dellanna, M. E., Molinari, M., Rausell, E., & Hashikawa, T. (1995).
Subdivisions of macaque monkey auditory cortex revealed by calcium-binding
protein immunoreactivity. Journal of Comparative Neurology, 362, 153170.
Kaas, J. H., & Hackett, T. A. (2000). Subdivisions of auditory cortex and processing
streams in primates. Proceedings of the National Academy of Sciences of the United
States of America, 97, 1179311799.
Kawato, M. (1999). Internal models for motor control and trajectory planning. Current
Opinion in Neurobiology, 9, 718727.
Kikuchi, Y., Horwitz, B., & Mishkin, M. (2010). Hierarchical auditory processing
directed rostrally along the monkeys supratemporal plane. Journal of Neuroscience,
30, 1302113030.
Kikuchi, Y., Horwitz, B., Mishkin, M., & Rauschecker, J. P. (2014). Processing of
harmonics in the lateral belt of macaque auditory cortex. Frontiers in Neuroscience,
8, 204.
Kusmierek, P., Ortiz, M., & Rauschecker, J. P. (2012). Sound-identity processing in
early areas of the auditory ventral stream in the macaque. Journal of
Neurophysiology, 107, 11231141.
Kusmierek, P., & Rauschecker, J. P. (2009). Functional specialization of medial auditory
belt cortex in the alert rhesus monkey. Journal of Neurophysiology, 102,
16061622.
Leaver, A. M., & Rauschecker, J. P. (2010). Cortical representation of natural complex
sounds: Effects of acoustic features and auditory object category. Journal of
Neuroscience, 30, 76047612.
Leaver, A., Van Lare, J. E., Zielinski, B. A., Halpern, A., & Rauschecker, J. P. (2009).
Brain activation during anticipation of sound sequences. Journal of Neuroscience,
29, 24772485.
Maeder, P. P., Meuli, R. A., Adriani, M., Bellmann, A., Fornari, E., Thiran, J. P., et al.
(2001). Distinct pathways involved in sound recognition and localization: A human
fMRI study. NeuroImage, 14, 802816.
Morel, A., Garraghty, P. E., & Kaas, J. H. (1993). Tonotopic organization, architectonic
fields, and connections of auditory cortex in macaque monkeys. Journal of
Comparative Neurology, 335, 437459.
Morosan, P., Rademacher, J., Schleicher, A., Amunts, K., Schormann, T., & Zilles, K.
(2001). Human primary auditory cortex: Cytoarchitectonic subdivisions and
mapping into a spatial reference system. NeuroImage, 13, 684701.
Pandya, D. N., & Sanides, F. (1972). Architectonic parcellation of the temporal
operculum in rhesus monkey and its projection pattern. Zeitschrift fur Anatomie und
Entwicklungsgeschichte, 139, 127161.
Petkov, C. I., Kayser, C., Augath, M., & Logothetis, N. K. (2006). Functional imaging
reveals numerous fields in the monkey auditory cortex. PLoS Biology, 4, e215.
Poremba, A., Malloy, M., Saunders, R. C., Carson, R. E., Herscovitch, P., & Mishkin, M.
(2004). Species-specific calls evoke asymmetric activity in the monkeys temporal
poles. Nature, 427, 448451.
Poremba, A., Saunders, R. C., Crane, A. M., Cook, M., Sokoloff, L., & Mishkin, M.
(2003). Functional mapping of the primate auditory system. Science, 299,
568572.
Rauschecker, J. P. (2011). An expanded role for the dorsal auditory pathway in
sensorimotor integration and control. Hearing Research, 271, 1625.
Rauschecker, J. P., & Scott, S. K. (2009). Maps and streams in the auditory cortex:
Nonhuman primates illuminate human speech processing. Nature Neuroscience,
12, 718724.
Rauschecker, J. P., & Tian, B. (2000). Mechanisms and streams for processing of what
and where in auditory cortex. Proceedings of the National Academy of Sciences of
the United States of America, 97, 1180011806.
Rauschecker, J. P., & Tian, B. (2004). Processing of band-passed noise in the lateral
auditory belt cortex of the rhesus monkey. Journal of Neurophysiology, 91,
25782589.
Rauschecker, J. P., Tian, B., & Hauser, M. (1995). Processing of complex sounds in the
macaque nonprimary auditory cortex. Science, 268, 111114.
Rauschecker, J. P., Tian, B., Pons, T., & Mishkin, M. (1997). Serial and parallel
processing in rhesus monkey auditory cortex. Journal of Comparative Neurology,
382, 89103.
Romanski, L. M., & Goldman-Rakic, P. S. (2002). An auditory domain in primate
prefrontal cortex. Nature Neuroscience, 5, 1516.
Romanski, L. M., Tian, B., Fritz, J., Mishkin, M., Goldman-Rakic, P. S., &
Rauschecker, J. P. (1999). Dual streams of auditory afferents target multiple
domains in the primate prefrontal cortex. Nature Neuroscience, 2, 11311136.
Scott, S. K., Blank, C. C., Rosen, S., & Wise, R. J. S. (2000). Identification of a pathway
for intelligible speech in the left temporal lobe. Brain, 123, 24002406.
Tian, B., & Rauschecker, J. P. (2004). Processing of frequency-modulated sounds in
the lateral auditory belt cortex of the rhesus monkey. Journal of Neurophysiology,
92, 29933013.
Tian, B., Reser, D., Durham, A., Kustov, A., & Rauschecker, J. P. (2001). Functional
specialization in rhesus monkey auditory cortex. Science, 292, 290293.
Wang, X. (2000). On cortical coding of vocal communication sounds in primates.
Proceedings of the National Academy of Sciences of the United States of America,
97, 1184311849.
Wessinger, C. M., Vanmeter, J., Tian, B., Van Lare, J., Pekar, J., & Rauschecker, J. P.
(2001). Hierarchical organization of the human auditory cortex revealed by
functional magnetic resonance imaging. Journal of Cognitive Neuroscience, 13, 17.
Wolpert, D. M., Ghahramani, Z., & Jordan, M. I. (1995). An internal model for
sensorimotor integration. Science, 269, 18801882.
Zatorre, R. J., Bouffard, M., & Belin, P. (2004). Sensitivity to auditory object features in
human temporal neocortex. Journal of Neuroscience, 24, 36373642.
Vestibular Cortex
C Lopez, Centre National de la Recherche Scientifique (CNRS), Marseille, France; Aix Marseille Universite, Marseille, France
2015 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00227-X
305
306
Caloric vestibular
stimulation (CVS)
Galvanic vestibular
stimulation (GVS)
Application of a percutaneous
current through an anode and a
cathode placed on the opposite
mastoid processes.
P
VN
A
H
VN
A
H
U
S
U
S
Air-conducted sounds
preferentially activate saccular
receptors.
VN
Sounds
(saccular stimulation)
(c)
Figure 1 Methods to stimulate the vestibular receptors in neuroimaging studies. (a) Caloric vestibular stimulation, (b) galvanic vestibular
stimulation, and (c) auditory stimulation are the three main methods used to artificially stimulate the peripheral vestibular organs without physical
head movements. A, H, P: anterior, horizontal, and posterior semicircular canals; S: saccule; U: utricle; VN: vestibular nerve. Reprinted from Lopez, C.,
Blanke, O., & Mast, F. W. (2012). The vestibular cortex in the human brain revealed by coordinate-based activation likelihood estimation metaanalysis. Neuroscience, 212, page 161, Copyright (2012), with permission from Elsevier.
3aNv
3aHv
2v
VIP MIP
307
6
Periarcuate cortex
7
Intra.
VPS
PIVC
te
al
p.
ter
La
tem
p.
Su
ua
Arc
al
nt r
Ce
MST
Hippocampus
(a)
Posterior insula,
parietal operculum,
and temporoparietal junction
PIVC
Somatosensory cortex
areas 2v, 3av
213
4
40
Premotor cortex
area 6v, FEF
39
9
22
19
42
44
46
41
18
45
22
10
17
47
37
11
38
21
20
MT/MST
Anterior insula
312
6
Cingulate gyrus
Vestibular
cingulate
9
region
10
Precuneus
31
23
24
GVS
23
19
30
29
33
18
32
11
12
35
17
18
38
36
28
CVS
Bottini et al., 1994
Vitte et al., 1996
Suzuki et al., 2001
Fasold et al., 2002
et al., 2002
Dieterich et al., 2003
Emri et al., 2003
Hegemann et al., 2003
Indovina et al., 2005
Wang et al., 2008
Marcelli et al., 2009
zu Eulenburg et al., 2013
37
19
Sounds
Hippocampus and
parahippocampal gyrus
20
(b)
Figure 2 Main vestibular areas identified in the monkey and human cerebral cortex. (a) Vestibular areas identified in monkeys include areas 2v, 6v, 7,
and 3av. 3aHv, 3a-hand-vestibular region; 3aNv, 3a-neck-vestibular region; MIP, medial intraparietal area; MST, medial superior temporal area; PIVC,
parietoinsular vestibular cortex; VIP, ventral intraparietal area; VPS, visual posterior sylvian area. Major sulci shown are the arcuate sulcus (arcuate),
central sulcus (central), lateral sulcus (lateral), intraparietal sulcus (intra.), and superior temporal sulcus (sup. temp.). (b) Schematic representation
of vestibular activations revealed by human neuroimaging studies during caloric vestibular stimulation (CVS, red symbols), galvanic vestibular
stimulation (GVS, green symbols), and auditory stimulation (blue symbols). Vestibular areas assumed to be homologous to vestibular areas identified
in animals are indicated in bold letters. FEF, frontal eye fields. Adapted from Lopez, C., & Blanke, O. (2011). The thalamocortical vestibular system
in animals and humans. Brain Research Reviews, 67, page 129, Copyright (2011), with permission from Elsevier.
308
CVS
GVS
Sounds
III
Ri
II
III IV OP2
Ri
IV
OP2
III
309
II
I
cis
(a)
(b)
Figure 4 Human parietoinsular vestibular cortex. (a) Core vestibular cortex in the posterior end of the lateral sulcus identified with coordinate-based
activation likelihood estimation meta-analysis. Spatial overlap between activations related to CVS, GVS, and sounds. Regions in yellow, magenta,
and cyan show spatial overlap between two techniques to stimulate the peripheral vestibular organs. The white area shows the spatial overlap
between three techniques of vestibular stimulation (i.e., caloric vestibular stimulation (CVS), galvanic vestibular stimulation (GVS), and auditory
stimulation). I, II, III: short insular gyri (anterior insula); IV and V: long insular gyri (posterior insula); cis: central insular sulcus; H: Heschls gyrus; Ri:
retroinsular cortex; OP: parietal operculum. Reprinted from Lopez, C., Blanke, O., & Mast, F. W. (2012). The vestibular cortex in the human brain
revealed by coordinate-based activation likelihood estimation meta-analysis. Neuroscience, 212, Page 168, Copyright (2012), with permission from
Elsevier. (b) Functional connectivity of the PIVC. Cytoarchitectonic area OP2 was used as a seeding point to analyze the PIVC functional
connectivity (resting state). The PIVC is functionally connected with the bilateral perisylvian cortex, inferior parietal cortex, primary motor and
somatosensory cortex, area 6, and V5. Reprinted from zu Eulenburg, P., Caspers, S., Roski, C., & Eickhoff, S. B. (2012). Meta-analytical definition and
functional connectivity of the human vestibular cortex. NeuroImage, 60(1), 166, with permission from Elsevier.
Frontal Cortex
Neuroimaging data showed that both CVS and GVS activate
several regions of the lateral and medial frontal lobes (Figure 2
(b)). Vestibular activations were mainly found in the primary
310
Cingulate Cortex
Vestibular activations have often been reported in the cingulate
cortex, in both its anterior part (Brodmann areas 24/32) and
posterior part (area 23) (Bense et al., 2001; Bottini et al., 1994;
Della-Justina et al., 2014; Dieterich et al., 2003; Fasold et al.,
2002; Miyamoto et al., 2007). Activations of the caudal part of
the anterior cingulate cortex were also evident from a metaanalysis of vestibular activations (Lopez et al., 2012). This
portion of the anterior cingulate cortex has been involved in
motor control (i.e., cingulate motor area) and attention. Cingulate activations reported in humans may be located in a
region homologue to the vestibular cingulate region described
in monkeys (Guldin & Grusser, 1998). Tracer studies showed
that the vestibular cingulate region is connected with the PIVC
and somatosensory area 3a, but there is so far no direct recording of vestibular-responsive neurons in this region.
Hippocampus
Functional MRI studies revealed that CVS activates the hippocampus, the subiculum, and the parahippocampal gyrus (BA
36) (Suzuki et al., 2001; Vitte et al., 1996). These data suggest
vestibular processing in the human hippocampus in relation
with spatial navigation and memory (Brandt et al., 2005). This
finding is in agreement with electrophysiological recordings in
macaque monkeys showing that hippocampal neurons
respond to passive whole-body displacements (OMara et al.,
1994). Further studies demonstrated that the activity of place
cells and head direction cells is strongly dependent on vestibular signals (Smith, 1997) since, for example, experimental
inactivation of the peripheral vestibular system deteriorates
the place and direction selectivity of hippocampal neurons
(Stackman et al., 2002).
Conclusions
Neuroimaging data obtained over the last two decades have
identified a highly distributed vestibular cortical network centered on the PIVC and perisylvian cortex. Yet, neuroimaging
studies used only artificial vestibular stimulations (CVS, GVS,
and auditory stimulation) that have no physiological
Acknowledgments
The research leading to these results has received funding from
the People Programme (Marie Curie Actions) of the European
Unions Seventh Framework Programme (FP7/20072013)
under REA grant agreement number 333607 (BODILYSELF,
vestibular and multisensory investigations of bodily self-consciousness). We thank Steven Gale for correcting this paper.
References
Akbarian, S., Grusser, O. J., & Guldin, W. O. (1993). Corticofugal projections to the
vestibular nuclei in squirrel monkeys: Further evidence of multiple cortical
vestibular fields. The Journal of Comparative Neurology, 332, 89104.
Akbarian, S., Grusser, O. J., & Guldin, W. O. (1994). Corticofugal connections between
the cerebral cortex and brainstem vestibular nuclei in the macaque monkey. The
Journal of Comparative Neurology, 339, 421437.
Barra, J., et al. (2010). Humans use internal models to construct and update a sense of
verticality. Brain, 133, 35523563.
Baumgartner, U., et al. (2010). Multiple somatotopic representations of heat and
mechanical pain in the operculo-insular cortex: A high-resolution fMRI study.
Journal of Neurophysiology, 104, 28632872.
Bense, S., et al. (2001). Multisensory cortical signal increases and decreases during
vestibular galvanic stimulation (fMRI). Journal of Neurophysiology, 85, 886899.
Berthoz, A. (1996). How does the cerebral cortex process and utilize vestibular signals?
In R. H. Baloh & G. M. Halmagyi (Eds.), Disorders of the vestibular system
(pp. 113125). New York: Oxford University Press.
Blanke, O. (2012). Multisensory brain mechanisms of bodily self-consciousness.
Nature Reviews. Neuroscience, 13(8), 556571.
Bottini, G., et al. (1994). Identification of the central vestibular projections in man: A
positron emission tomography activation study. Experimental Brain Research, 99,
164169.
Bottini, G., et al. (2001). Cerebral representations for egocentric space: Functionalanatomical evidence from caloric vestibular stimulation and neck vibration. Brain,
124, 11821196.
Brandt, T., & Dieterich, M. (1999). The vestibular cortex. Its locations, functions, and
disorders. Annals of the New York Academy of Sciences, 871, 293312.
Brandt, T., Dieterich, M., & Danek, A. (1994). Vestibular cortex lesions affect the
perception of verticality. Annals of Neurology, 35, 403412.
Brandt, T., et al. (2005). Vestibular loss causes hippocampal atrophy and impaired
spatial memory in humans. Brain, 128, 27322741.
Bremmer, F., et al. (1999). Linear vestibular self-motion signals in monkey medial
superior temporal area. Annals of the New York Academy of Sciences, 871,
272281.
Bremmer, F., et al. (2002). Visual-vestibular interactive responses in the macaque
ventral intraparietal area (VIP). The European Journal of Neuroscience, 16,
15691586.
Bucher, S. F., et al. (1998). Cerebral functional magnetic resonance imaging of
vestibular, auditory, and nociceptive areas during galvanic stimulation. Annals of
Neurology, 44, 120125.
311
312
Suzuki, M., et al. (2001). Cortical and subcortical vestibular response to caloric
stimulation detected by functional magnetic resonance imaging. Brain Research.
Cognitive Brain Research, 12, 441449.
Takahashi, K., et al. (2007). Multimodal coding of three-dimensional rotation and
translation in area MSTd: Comparison of visual and vestibular selectivity. The
Journal of Neuroscience, 27, 97429756.
Tuohimaa, P., et al. (1983). Studies of vestibular cortical areas with short-living 15O2
isotopes. ORL: Journal for Oto-Rhino-Laryngology and Its Related Specialties, 45,
315321.
Vitte, E., et al. (1996). Activation of the hippocampal formation by vestibular stimulation:
A functional magnetic resonance imaging study. Experimental Brain Research, 112,
523526.
Wang, Z., et al. (2008). Why cold water delays the onset of vestibular vertigo An
functional MRI study. European Journal of Radiology, 67(3), 459465.
Zu Eulenburg, P., et al. (2012). Meta-analytical definition and functional connectivity of
the human vestibular cortex. NeuroImage, 60(1), 162169.
Zu Eulenburg, P., et al. (2013). Interoceptive and multimodal functions of the operculoinsular cortex: Tactile, nociceptive and vestibular representations. NeuroImage, 83,
7586.
Gustatory System
TC Pritchard, The Pennsylvania State University College of Medicine, Hershey, PA, USA
2015 Elsevier Inc. All rights reserved.
Introduction
Animals meet their energy needs for healthy development and
growth by ingesting food. In the wild, where the line between
food and nonfood items is often blurred and survival hangs in
the balance, animals must distinguish safe and nutritious
foods from toxic and potentially lethal substances. The gustatory system plays a key role in this process. The elaborate
process of taste perception begins when chemicals released
from foods and beverages bind to taste buds receptors that
line the oral cavity. After this information is transmitted to
the brain, neural circuitry located in the caudal hindbrain
makes a swift decision to either accept (swallow) or reject
(expectorate) the substance. Reflexive orofacial movements
complete the task of acceptance or rejection. Other brainstem
circuits manage autonomic reflexes that release saliva, gastric
enzymes, and insulin during ingestion. The forebrain completes the sensory analysis of taste quality and then uses this
highly processed gustatory information to support more complex taste-guided behaviors. These motivated behaviors are
shaped by multisensory input, including feedback from the
internal milieu regarding the long- and short-term nutritional
needs of the animal. This article describes the organization of
the gustatory system from its humble beginning as an array of
chemoreceptors in the mouth to its participation in sophisticated reward-based behaviors in the cerebral cortex. This article
emphasizes the gustatory system of nonhuman primates,
which represents the best model available for the taste system
of humans.
http://dx.doi.org/10.1016/B978-0-12-397025-1.00228-1
313
314
in the ipsilateral PBN. Electrophysiological studies have confirmed that PBN neurons respond to visceral and nociceptive
stimulation. Although the ascending projections from the rostral, gustatory pole of the NST also ascend through the CTT,
they bypass the PBN and terminate in the ipsilateral thalamic
relay, VPMpc (Beckstead, Morse, & Norgren, 1980). Consistent
with the anatomical data, there is no electrophysiological evidence that PBN neurons respond to gustatory stimulation, but
this issue should be investigated more thoroughly. Given its
role as a visceral relay, it is not surprising that neurons in the
PBN project to limbic/autonomic nuclei such as the hypothalamus, the amygdala, and the bed nucleus of the stria terminalis
rather than VPMpc. In summary, the NST and VPMpc both
have gustatory and visceral subdivisions in subprimate species,
but in nonhuman primates and presumably humans, the PBN
is strictly a visceral relay. The presence of a direct NST-VPMpc
projection in nonhuman primates represents a significant species difference, the implication of which is not understood.
The projection from the NST to VPMpc in nonhuman primates ascends ipsilaterally. A number of studies have examined
the brainstem taste pathways in patients who have had cardiovascular accidents or sustained focal damage from multiple
sclerosis. Lesion variability and the close proximity of the
PBN, the CTT, and the medial lemniscus have compromised
many of these studies and made interpretation of these data
difficult. The challenge for these investigators has been to
determine whether the damaged area includes the PBN itself,
the afferent or efferent projections of the PBN, or the ascending
axons from NST neurons that bypass the PBN en route to the
thalamus. At present, the weight of evidence supports an ipsilateral trajectory for the ascending taste pathway in humans.
Thalamus
Rodent
Primate
OFC
As described earlier, anatomical tract-tracing and electrophysiological experiments have demonstrated that the mammalian
relay for taste in the thalamus is located immediately medial to
the representation of oral touch and temperature. The significant interspecies differences in the ascending taste pathway
between primate and non-primate species in the caudal brainstem have had no impact on the location of the thalamic taste
area. Although the same nucleus serves as the thalamic relay in
all mammalian species, there is no universally accepted name.
In nonhuman primates, it is called VPMpc. The clinical literature places the thalamic taste relay in the homologous region
in humans.
Insula
VPMpc
Ventral forebrain
PBN
Facial
Glossopharyngeal
Vagus
NST
Figure 2 Schematic diagram of the taste circuitry of the rodent and
primate.
Cortex
Investigators using anatomical techniques have shown that
neurons in the thalamic gustatory relay, VPMpc, project to a
small crescent of cortex in the rostral insula and adjacent inner
operculum (Pritchard, Hamilton, Morse, & Norgren, 1986).
Electrophysiological experiments in several species have
confirmed that the insularopercular cortex contains tasteresponsive neurons. Although several older studies placed
primary taste cortex in humans near the cortical somatosensory
representation of the oral cavity at the foot of the postcentral
gyrus, these findings have been refuted by more recent reports.
The most authoritative study, to date, describes a series of
315
316
Summary
The multistep process of gustatory perception begins when
sapid stimuli bind to taste receptors located on the microvilli
of the taste buds that protrude into the oral cavity. Primary
afferent fibers that synapse on the taste receptor cells project to
neurons located in the rostral half of the NST in the medulla. In
rodents, taste information is relayed from the NST to the PBN,
which in turn, projects to VPMpc. In nonhuman primates and
presumably humans, the ascending projections from the NST
bypass the PBN. Gustatory neurons in VPMpc project to the
rostrodorsal insula and inner operculum, which serves as primary taste cortex. Neurons in primary taste cortex project to
secondary cortical areas in the ventral and agranular insulae.
Projections arising from these secondary taste areas to the OFC
may provide the anatomical basis for perception of flavor as
well as the role that taste information plays in reward evaluation and goal-seeking behavior.
References
Beckstead, R. M., Morse, J. R., & Norgren, R. (1980). The nucleus of the solitary tract in
the monkey: Projections to the thalamus and brain stem nuclei. Journal of
Comparative Neurology, 190, 259282.
Hosokawa, T., Kato, K., Inoue, M., & Mikami, A. (2007). Neurons in the macaque
orbitofrontal cortex code relative preference of both rewarding and aversive
outcomes. Neuroscience Research, 57, 434445.
Motta, G. (1959). I centri corticali del gusto. Bulletino delle Scienze Mediche, 131,
480493.
Pritchard, T. C. (2012). Gustatory system. In G. Paxinos & J. Mai (Eds.), The human
nervous system (pp. 11871218). (3rd ed.). New York: Elsevier.
Pritchard, T. C., Hamilton, R. B., Morse, J. R., & Norgren, R. (1986). Projections from
thalamic gustatory and lingual areas in the monkey, Macaca fascicularis. Journal of
Comparative Neurology, 244, 213228.
Glossary
Abbreviations
hIP2
hIP3
IPL
IPS
PPC
SLF
SPL
V3d
V5
5-HT1A
5-HT2
AF
AMPA
BA
CBP
GABA
hIP1
http://dx.doi.org/10.1016/B978-0-12-397025-1.00229-3
317
318
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Posterior Parietal Cortex: Structural and Functional Diversity
was parcellated into the two major areas PA2 and PE with the
subfields PEm, PEp, and PEg. Furthermore, von Economo and
Koskinas (1925) provided a separate area within the IPS and the
adjacent postcentral sulcus, termed PED. Gerhardt (1940) identified several subdivisions within the IPL (74, 88, 89, 90)
and the SPL (75, 75scm, 83, 84, 85, 86, 87), which mainly
follow the myeloarchitectonic subdivisions found by Vogt
and Vogt (1919).
Recent studies provided new 3D maps of PPC areas within
a common reference space (Figure 1) as part of the JuBrain
Cytoarchitectonic Atlas (Zilles & Amunts, 2010), which is
Figure 1 Cytoarchitectonic maps of the human PPC. (a) Map of Brodmann (1914) and (b) map of von Economo and Koskinas (1925) (SPL highlighted
in green, IPL highlighted in blue). (c) Maps of the JuBrain Cytoarchitectonic Atlas, according to: IPL Caspers et al. (2006, 2008); SPL Scheperjans,
Eickhoff, et al. (2008), Scheperjans, Hermann, et al. (2008); IPS Choi et al. (2006), Scheperjans, Eickhoff, et al. (2008), Scheperjans, Hermann,
et al. (2008). Top row: left, right, and dorsal views on PPC (pial surface reconstruction); bottom row: left dorsal and right dorsal view (white matter
interface reconstruction for visualization of IPS areas). Color coding according to legend within the figure. IPL, inferior parietal lobule; IPS,
intraparietal sulcus; SPL, superior parietal lobule.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Posterior Parietal Cortex: Structural and Functional Diversity
Hermann, et al., 2008). For the IPS, three cytoarchitectonic maps
are available up till now that cover the anterior portion: areas
hIP1, hIP2 (Choi et al., 2006), and hIP3 (Scheperjans, Eickhoff,
et al., 2008; Scheperjans, Hermann, et al., 2008), which are
assumed to be the human homologues of macaque areas
anterior intraparietal area (AIP), ventral intraparietal area (VIP),
and medial intraparietal area (MIP), respectively (Grefkes &
Fink, 2005).
All these areas differ in their cytoarchitectonic characteristics, making each area a distinct microstructurally defined
entity (for overview: Caspers, Amunts, & Zilles, 2012). Overall,
all PPC areas have a generally well-developed layer IV and a
pronounced layer III. But the areas within each part of PPC,
that is, IPL, SPL, and IPS, share some common features which
distinguish them from areas of the other parts. The areas of the
SPL have much bigger pyramidal cells in lower layer III and
layer V as compared to the IPS and the IPL. While in the SPL
and the IPL, the major part of the cortex is covered by supragranular layers, pushing the infragranular layers to the lower
third, they are more equally proportioned in the IPS areas.
Layer III is cell denser and the layering is less pronounced in
the SPL and the IPL as compared to the IPS.
Myeloarchitecture
Myeloarchitectonical studies revealed a similar variety of PPC
parcellations (for a recent review: Nieuwenhuys, 2013).
Flechsig (1920) mainly corroborated the cytoarchitectonic parcellation of Brodmann (1909) by defining two areas (22, 29)
in the SPL but three areas (26, 37, 42) in the IPL. The most
detailed myeloarchitectonic map of the PPC was provided by
Vogt (1911) and Vogt and Vogt (1919). They identified four
areas in the IPL (74, 88, 89, 90) and six in the SPL (75, 83, 84,
85, 86, 87). This parcellation was later largely corroborated by
Batsch (1956) who additionally added some subdivisions, for
example, of area 75 into areas 75inf and 75sup. The extent of
some areas differed slightly from that of Vogt and Vogt (1919).
Hopf and Vitzthum (1957) and Hopf (1969) found similar
minor deviations from these maps, but in general postulated a
comparably complex myeloarchitecture within PPC.
Receptorarchitecture
The receptor architecture of the PPC areas reflects the neurochemical architecture as the basis for their involvement in different functional systems (Zilles & Amunts, 2009). Based on the
receptor architecture, the same seven IPL areas as identified
cytoarchitectonically were found (Caspers et al., 2013). Additionally, similarity analyses of the receptor distributions in these
areas revealed a functionally meaningful tripartition of the IPL,
consisting of a rostral (areas PFop, PFt, PFcm), a middle (areas
PF, PFm), and a caudal group (areas PGa, PGp). Within the SPL,
differences in receptor distribution were found according to the
seven SPL areas (Scheperjans, Grefkes, Palomero-Gallagher,
Schleicher, & Zilles, 2005; Scheperjans, Palomero-Gallagher,
Grefkes, Schleicher, & Zilles, 2005). Further analyses showed
that the rostral areas of the BA 5 region were more similar to
each other than to the areas of the caudal BA 7 region.
While there are distinct differences between the PPC areas,
there are also some similarities in receptor distribution. The
319
rostral PPC areas (both the IPL and the SPL) have a similar
receptor distribution as somatosensory cortex, whereas the
caudal PPC areas are more similar to extrastriate visual areas.
At the protein level, this difference between the rostral and
the caudal PPC is accompanied by an increase in receptor
concentration of the glutamatergic AMPA, the GABAergic
GABAA, and the cholinergic nicotinic receptors and a mirrored
decrease in concentration of the serotoninergic 5-HT1A and
5-HT2 receptors.
Connectivity Patterns
In order to understand the role of the PPC areas within the
brain, their connections to other brain areas and their involvement in different functional brain networks need to be considered. Based on detailed anatomical maps of the PPC areas, the
structural and functional connectivity patterns provide information about the basis for their functional integration.
Structural Connectivity
With the advent of diffusion MR imaging to study structural
connectivity in humans in vivo (Le Bihan & Johansen-Berg,
2011), novel insight into the human brains fiber architecture
was gained, so far mainly deduced from tracer studies in
macaques.
Using connectivity-based parcellation (CBP) based on the
structural connectivity information to other areas of the brain,
different parts of the PPC were parcellated into areas with
distinct structural connectivity. CBP of the IPL revealed five
subregions with distinct connectivity profiles (Mars et al.,
2011; Wang et al., 2012), which were in good agreement with
the cytoarchitectonically delineated areas PFop, PFt, PFm, PGa,
and PGp (see Section Microstructural Parcellation and Features). Another study identified three subregions within the
IPL, a rostral, a middle, and a caudal one (Ruschel et al.,
2013), which is in line with the three main areas of the macaque
IPL (Gregoriou, Borra, Matelli, & Luppino, 2006) as well as with
insights from receptorarchitecture which demonstrated such a
functionally relevant tripartition of the human IPL (see Section
Microstructural Parcellation and Features). CBP of the lateral
SPL and the adjacent IPS distinguished five regions with distinct
connectivity profiles (Mars et al., 2011), which corresponded
to cytoarchitectonic areas 7A, 7PC, 5L, and hIP3 (see Section
Microstructural Parcellation and Features). Another study
identified three subregions on the mesial part of the SPL
(Zhang et al., 2013), which corresponded to cytoarchitectonic
areas 5L/5M, 7A, and 7M/7P (see Section Microstructural Parcellation and Features).
The fiber architecture of the PPC is dominated by two major
fiber bundles. The arcuate fasciculus (AF) is the main connection pathway of the IPL to the inferior frontal gyrus, mainly to
Brocas area, and the adjacent premotor cortex, and to the
posterior temporal cortex (Catani, Jones, & ffytche, 2005).
The superior longitudinal fasciculus (SLF) with its three parts
(I, II, III) connects all aspects of the PPC with areas of the
frontal lobe (Thiebaut de Schotten et al., 2011). The AF is
often deemed part of the SLF III (Martino et al., 2013). But
there is evidence that the AF is lateralized to the left, while the
320
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Posterior Parietal Cortex: Structural and Functional Diversity
Functional Connectivity
Besides the efforts to functionally decode the role of different
PPC areas or their involvement in specific functional brain
networks (see Section Functional Segregation), studying
the resting-state functional connectivity allows identifying
frequently occurring functional correlations between different
brain areas in a task-free state of the brain (Fox &
Raichle, 2007).
In a whole-brain CBP study based on resting-state data, the
PPC was involved in four different networks (Yeo et al., 2011):
a rostral IPL network interacting with caudal inferior frontal
cortex, frontal operculum, supplementary motor, and posterior temporal cortex; a caudal IPL network interacting with
rostral inferior frontal, medial prefrontal, posterior cingulate,
and anterior temporal cortex, which correlates with the default
mode network; an IPS network interacting with lateral prefrontal and posterior inferior temporal cortex; and an SPL network
interacting with dorsal premotor and lateral temporo-occipital
cortex. In a more fine-grained parcellation of the cortex into 17
networks, the parcellation of the PPC followed the main line of
the coarser segregation, adding subparcellations particularly
within the IPL.
Functional Segregation
Action Processing and Apraxia
Different PPC areas contribute, together with motor, premotor,
and prefrontal areas, to the planning and control of actions,
including the choice of the appropriate action set as well as
distinguishing between different goals or targets of an action
(Rowe & Siebner, 2012). Rostral IPL and adjacent IPS are
involved in the perception of observed actions and play a
role in imitating an action (Caspers, Zilles, Laird & Eickhoff,
2010; Molenberghs, Cunnington & Mattingley, 2012), being
responsible for mapping an observed action onto ones own
motor system and thus providing the parietal nodes of the
human mirror neuron system (Cattaneo & Rizzolatti, 2009;
Iacoboni & Mazziotta, 2007). Taken together, this ability helps
to interpret observed actions, which is essential in everyday
social interactions (Ocampo & Kritikos, 2011).
Areas of the lateral aspect of the superior parietal cortex and
adjacent IPS, on the other hand, are mainly involved in visuomotor coordination regarding planning and choosing the
appropriate action for reaching a given target. These areas
also enable the identification of the relevant objects needed
for the action (Culham & Valyear, 2006; Iacoboni, 2006; Lindner, Iyer, Kagan, & Andersen, 2010).
Lesions to these rostral PPC areas particularly within the left
hemisphere, for example, due to stroke of the middle cerebral
artery, typically lead to different forms of apraxia, such as
motor or tactile, keeping subjects from knowing the correct
program for performing an action or using a tool (Freund,
2003; Goldenberg, 2009; Rushworth, Johansen-Berg, Gobel, &
Devlin, 2003).
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Posterior Parietal Cortex: Structural and Functional Diversity
(Krawitz, Saleem, Baker, & Mishkin, 2011). Hereby, a dorsal
system involving the middle IPS and the adjacent SPL maintains attention, while a ventral system involving the middle
aspect of the IPL and the temporo-parietal junction contributes
to attention reorientation (Corbetta, Patel, & Shulman, 2008).
The functional right hemispheric lateralization is supported by
respective structural connectivity, that is, the lateralization of
the SLF II is associated with visuospatial performance
(Thiebaut de Schotten et al., 2011).
Disruption of these frontoparietal attention networks is
largely associated with neglect, that is, the missing attention
to one part of space or to certain features, particularly after
right hemisphere lesions since attention to both hemispaces
largely depends on the right hemisphere (Mesulam, 1999). In
accordance with the two main attention systems, spatial
neglect mainly occurs after lesions to the PPC areas of the
dorsal attention network, while lesions to the ventral system
mainly accompany nonspatial neglect (Corbetta & Shulman,
2011; Ptak & Schnider, 2011).
321
References
Ardila, A. (2010). A review of conduction aphasia. Current Neurology and Neuroscience
Reports, 10(6), 499503.
Arsalidou, M., & Taylor, M. J. (2011). Is 2 2 4? Meta-analyses of brain areas
needed for numbers and calculations. NeuroImage, 54(3), 23822393.
322
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Posterior Parietal Cortex: Structural and Functional Diversity
Greenberg, A. S., Verstynen, T., Chiu, Y. C., Yantis, S., Schneider, W., & Behrmann, M.
(2012). Visuotopic cortical connectivity underlying attention revealed with whitematter tractography. Journal of Neuroscience, 32, 27732782.
Grefkes, C., & Fink, G. R. (2005). The functional organization of the intraparietal sulcus
in humans and monkeys. Journal of Anatomy, 207(1), 317.
Gregoriou, G. G., Borra, E., Matelli, M., & Luppino, G. (2006). Architectonic
organization of the inferior parietal convexity of the macaque monkey. Journal of
Comparative Neurology, 496, 422451.
Hopf, A. (1969). Photometric studies on the myeloarchitecture of the human parietal
lobe. I. Parietal region. Journal fur Hirnforschung, 11(4), 253265.
Hopf, A., & Vitzthum, H. G. (1957). Uber die Verteilung myeloarchitektonischer
Merkmale in der Scheitellappenrinde beim Menschen. Journal fur Hirnforschung,
3(23), 79104.
Iacoboni, M. (2006). Visuo-motor integration and control in the human posterior cortex:
Evidence from TMS and fMRI. Neuropsychologia, 44(13), 26912699.
Iacoboni, M., & Mazziotta, J. C. (2007). Mirror neuron system: Basic findings and
clinical applications. Annals of Neurology, 62(3), 213218.
Krawitz, D. J., Saleem, K. S., Baker, C. I., & Mishkin, M. (2011). A new neural framework
for visuospatial processing. Nature Reviews Neuroscience, 12(4), 217230.
Le Bihan, D., & Johansen-Berg, H. (2011). Diffusion MRI at 25: Exploring brain tissue
structure and function. NeuroImage, 61(2), 324341.
Lindner, A., Iyer, A., Kagan, I., & Andersen, R. A. (2010). Human posterior parietal
cortex plans where to reach and what to avoid. Journal of Neuroscience, 30(35),
1171511725.
Mars, R. B., Jbabdi, S., Sallet, J., OReilly, J. X., Croxson, P. L., Olivier, E., et al. (2011).
Diffusion-weighted imaging tractography-based parcellation of the human parietal
cortex and comparison with human and macaque resting-state functional
connectivity. Journal of Neuroscience, 31(11), 40874100.
Martino, J., De Witt Hamer, P. C., Berger, M. S., Lawton, M. T., Arnold, C. M.,
de Lucas, E. M., et al. (2013). Analysis of the subcomponents and
cortical terminations of the perisylvian superior longitudinal fasciculus: A fiber
dissection and DTI tractography study. Brain Structure and Function, 218,
105121.
Mesulam, M. M. (1999). Spatial attention and neglect: Parietal, frontal and cingulate
contributions to the mental representation and attentional targeting of salient
extrapersonal events. Philosophical Transactions of the Royal Society, B: Biological
Sciences, 354(1387), 13251346.
Molenberghs, P., Cunnington, R., & Mattingley, J. B. (2012). Brain regions with mirror
properties: a meta-analysis of 125 human fMRI studies. Neuroscience &
Biobehavioral Reviews, 36, 341349.
Nieder, A., & Dehaene, S. (2009). Representation of number in the brain. Annual Review
of Neuroscience, 32, 185208.
Nieuwenhuys, R. (2013). The myeloarchitectonic studies on the human cerebral cortex
of the Vogt-Vogt school, and their significance for the interpretation of functional
neuroimaging data. Brain Structure and Function, 218, 303352.
Ocampo, B., & Kritikos, A. (2011). Interpreting actions: The goal behind mirror neuron
function. Brain Research Reviews, 67(12), 260267.
Ono, M., Kubik, S., & Abernathey, C. D. (1990). Atlas of the cerebral sulci. Stuttgart:
Thieme.
Parker, G. J. M., Luzzi, S., Alexander, D. C., Wheeler-Kingshott, C. A. M.,
Ciccarelli, O., & Ralph, M. A. L. (2005). Lateralization of ventral and dorsal auditorylanguage pathways in the human brain. NeuroImage, 24, 656666.
Petrides, M., & Pandya, D. N. (2009). Distinct parietal and temporal pathways to the
homologues of Brocas area in the monkey. PLoS Biology, 7(8), e1000170.
Powell, H. W., Parker, G. J., Alexander, D. C., Symms, M. R., Boulby, P. A.,
Wheeler-Kingshott, C. A., et al. (2006). Hemispheric asymmetries in languagerelated pathways: A combined functional MRI and tractography study. NeuroImage,
32(1), 388399.
Price, C. J. (2000). The anatomy of language: Contributions from functional
neuroimaging. Journal of Anatomy, 197(3), 335359.
Price, C. J. (2012). A review and synthesis of the first 20 years of PET and fMRI studies
of heard speech, spoken language and reading. NeuroImage, 62(2), 816847.
Ptak, R., & Schnider, A. (2011). The attention network of the human brain: Relating
structural damage associated with spatial neglect to functional imaging correlates of
spatial attention. Neuropsychologia, 49(11), 30633070.
Rademacher, J., Caviness, J., Steinmetz, H., & Galaburda, A. M. (1993). Topographical
variation of the human primary cortices: Implications for neuroimaging, brain
mapping, and neurobiology. Cerebral Cortex, 3, 313329.
Raine, A., & Yang, Y. (2006). Neural foundations to moral reasoning and antisocial
behavior. Social Cognitive and Affective Neuroscience, 1(3), 203213.
Rowe, J. B., & Siebner, H. R. (2012). The motor system and its disorders. NeuroImage,
61(2), 464477.
INTRODUCTION TO ANATOMY AND PHYSIOLOGY | Posterior Parietal Cortex: Structural and Functional Diversity
Ruschel, M., Knosche, T. R., Friederici, A. D., Turner, R., Geyer, S., & Anwander, A.
(2013). Connectivity architecture and subdivisions of the human inferior parietal
cortex revealed by diffusion MRI. Cerebral Cortex, 24(9), 24362448. http://dx.doi.
org/10.1093/cercor/bht098.
Rushworth, M. F. S., Behrens, T. E. J., & Johansen-Berg, H. (2006). Connection
patterns distinguish 3 regions of human parietal cortex. Cerebral Cortex, 16,
14181430.
Rushworth, M. F., Johansen-Berg, H., Gobel, S. M., & Devlin, J. T. (2003). The left
parietal and premotor cortices: Motor attention and selection. NeuroImage,
20(Suppl. 1), S89S100.
Scheperjans, F., Eickhoff, S. B., Homke, L., Mohlberg, H., Hermann, K., Amunts, K.,
et al. (2008). Probabilistic maps, morphometry, and variability of
cytoarchitectonic areas in the human superior parietal cortex. Cerebral Cortex,
18(9), 21412157.
Scheperjans, F., Grefkes, C., Palomero-Gallagher, N., Schleicher, A., & Zilles, K.
(2005). Subdivisions of human parietal area 5 revealed by quantitative receptor
autoradiography: A parietal region between motor, somatosensory, and cingulate
cortical areas. NeuroImage, 25(3), 975992.
Scheperjans, F., Hermann, K., Eickhoff, S. B., Amunts, K., Schleicher, A., & Zilles, K.
(2008). Observer-independent cytoarchitectonic mapping of the human superior
parietal cortex. Cerebral Cortex, 18(4), 846867.
Scheperjans, F., Palomero-Gallagher, N., Grefkes, C., Schleicher, A., & Zilles, K.
(2005). Transmitter receptors reveal segregation of cortical areas in the human
superior parietal cortex: Relations to visual and somatosensory regions.
NeuroImage, 28(2), 362379.
Schleicher, A., Palomero-Gallagher, N., Morosan, P., Eickhoff, S. B., Kowalski, T.,
de Vos, K., et al. (2005). Quantitative architectural analysis: A new approach to
cortical mapping. Anatomy and Embryology, 210(56), 373386.
Seghier, M. L. (2013). The angular gyrus: Multiple functions and multiple subdivisions.
The Neuroscientist, 19(1), 4361.
Shalom, D. B., & Poeppel, D. (2008). Functional anatomic models of language:
Assembling the pieces. The Neuroscientist, 14, 119127.
Smallwood, J., Brown, K., Baird, B., & Schooler, J. W. (2012). Cooperation between the
default mode network and the fronto-parietal network in the production of an internal
train of thought. Brain Research, 1428, 6070.
323
Smith, G. E. (1907). A new topographical survey of the human cerebral cortex, being an
account of the distribution of the anatomically distinct cortical areas and their
relationship to the cerebral sulci. Journal of Anatomy, 41, 237254.
Thiebaut de Schotten, M., DellAcqua, F., Forkel, S. J., Simmons, A., Vergani, F.,
Murphy, D. G. M., et al. (2011). A lateralized brain network for visuospatial attention.
Nature Neuroscience, 14(10), 12451246.
Tononi, G., Sporns, O., & Edelman, G. M. (1994). A measure for brain complexity:
Relating functional segregation and integration in the nervous system. Proceedings
of the National Academy of Sciences of the United States of America, 91(11),
50335037.
Uddin, L. Q., Supekar, K., Amin, H., Rykhlevskaia, E., Nguyen, D. A., Greicius, M. D.,
et al. (2010). Dissociable connectivity within human angular gyrus and intraparietal
sulcus: Evidence from functional and structural connectivity. Cerebral Cortex, 20,
26362646.
Vigneau, M., Beaucousin, V., Herve, P. Y., Duffau, H., Crivello, F., Houde, O., et al.
(2006). Meta-analyzing left hemisphere language areas: Phonology, semantics, and
sentence processing. NeuroImage, 30(4), 14141432.
Vogt, O. (1911). Die Myeloarchitektonik des Isocortex parietalis. Journal fur
Psychologie und Neurologie, 18, 107118.
Vogt, C., & Vogt, O. (1919). Allgemeinere Ergebnisse unserer Hirnforschung. Journal
fur Psychologie und Neurologie, 25, 279461.
von Economo, K., & Koskinas, G. (1925). Die Cytoarchitektonik der Hirnrinde des
erwachsenen Menschen. Wien: Springer.
Wang, J., Fan, L., Zhang, Y., Liu, Y., Jiang, D., Zhang, Y., et al. (2012). Tractography-based
parcellation of the human left inferior parietal lobule. NeuroImage, 63(2), 641652.
Yeo, B. T., Krienen, F. M., Sepulcre, J., Sabuncu, M. R., Lashkari, D., Hollinshead, M.,
et al. (2011). The organization of the human cerebral cortex estimated by intrinsic
functional connectivity. Journal of Neurophysiology, 106, 11251165.
Zhang, Y., Fan, L., Zhang, Y., Wang, J., Zhu, M., Zhang, Y., et al. (2013). Connectivitybased parcellation of the human posteromedial cortex. Cerebral Cortex, 24(3),
719727. http://dx.doi.org/10.1093/cercor/bhs353.
Zilles, K., & Amunts, K. (2009). Receptor mapping: Architecture of the human cerebral
cortex. Current Opinion in Neurology, 22(4), 331339.
Zilles, K., & Amunts, K. (2010). Centenary of Brodmanns map Conception and fate.
Nature Reviews. Neuroscience, 11(2), 139145.
Glossary
Abbreviations
pMCC
RSC
sACC
Spls
vPCC
Nomenclature
aMCC
CG
cgs
dPCC
pACC
http://dx.doi.org/10.1016/B978-0-12-397025-1.00230-X
325
326
67 69
71
38
47
67
42
37
36
35
70
69
39
71
48
mr
ECG
cgs
34
49
30
24
20
23
19
18
50
29
22
2.
4.
3.
71
39 I
79
96
93
83 I
83
75
75 112
80
77
96 78
75
71
5.
28
27
CG
26
33
32
31
82
spls
6. 95
92
85
7.
81
91
85 I
cas
25
84
8.
21 17
pcgs
51
15
94
76
14
1
10
11
12
13
1.
10.
9.
Figure 1 Vogt and Vogts (1919) map of areas on the medial surface (two images in their Figure 51 merged). The red highlights were added as an aid
to interpreting this work in the context of recent findings. The most important are the horizontal divisions within the cingulate gyrus (2), the border
between ACC and MCC (3), the nine divisions of area 32 (asterisks), the two parts of MCC (4), the border between aMCC and pMCC (parenthesis marking
pMCC), and an extension of motor cortex into the cingulate sulcus (5). cas, callosal sulcus; CG, cingulate gyrus; cgs, cingulate sulcus; ECG,
external cingulate gyrus; mr, marginal ramus of the cgs; spls, splenial sulci.
Figure 2 shows his ACC divided into anterior and posterior parts
(at pointer) (arrows show coronal section positions). Sections in
Figure 2(b) are autoradiographs for two of the 15 receptors that
were chosen because an asymmetry index showed them to be
statistically different (Palomero-Gallagher et al., 2009). Clearly,
GABAA receptors are quite low in anterior area 24, while they are
extremely high in layers IIII of posterior area 24. In contrast,
-amino-3-hydroxy-5-methyl-4 isoxazole-proprionic acid receptors are very high in layers IV in anterior area 24 but extremely
low in posterior area 24. A polar plot of 15 receptors (Figure
2(c)) is of binding throughout the entire area, and receptors that
are significantly different in each subregion are noted with asterisks. Eight of the 15 neurotransmitter receptors differed significantly in the two divisions. Thus, the anterior and posterior parts
of Brodmanns ACC are qualitatively different in their neurochemistry and connections.
Although the midcingulate concept arose from a cytoarchitectural study (Vogt Nimchinsky, Vogt, & Hof, 1995), this and
other neurobiological differences have emerged including
functional imaging (Palomero-Gallagher et al., 2008, 2009;
Vogt, 2009a, 2009b; Vogt & Palomero-Gallagher, 2012; Vogt,
Vogt, & Laureys, 2006; Yu et al., 2011) to support the hypothesis that MCC differs qualitatively from ACC. Thus, MCC is not
a division of ACC, and studies that subdivide ACC into dorsal,
rostral, ventral, or caudal are employing Brodmanns centuryold view without reference to substantial recent observations.
They also overlook the predictive nature of the eight-subregion
model. Following on this issue, it is often said that the name
for a subregion is simply a matter of consensus. Ernst Mach
Brodmanns
anterior
cingulate cortex
24
32
BA24
2923
25
(a)
GABAA
427
2105
AMPA
345
Anterior
(b)
Polar plot
Posterior
AMPA
2500
D1
Kainate
2000
5-HT2
NMDA
1500
1000
5-HT1A
GABAA
500
0
a2
GABA
a1
BZ
N
M1
M
(c)
M2
Figure 2 Assessment of 15 neurotransmitter receptors in the anterior and posterior parts of Brodmanns area 24. (a) Map of his anterior cingulate
region with a pointer separating its two parts used in the analysis. (b) Coronal sections for two receptors through each part show a radical difference
in the laminar patterns of binding. (c) Polar plots for anterior (red line SD) and posterior (green line SD) with asterisks emphasizing the
receptors that are statistically significant. The null hypothesis was rejected, and these findings validate the midcingulate concept; that is, caudal ACC is
not a part of ACC. Modified from Palomero-Gallagher et al. (2009) Receptor architecture of human cingulate cortex: insights into the four-region
neurobiological model. Human Brain Mapping 30: 23362355.
70
70
60
50
40
30
20
10
Cognitive
task
Emotional
task
60
50
pMCC
40
Cognitive
division
30
aMCC
100
20
10
pACC
cc
50
0
10
20
Affective
division
sACC
30
(a)
(b)
Figure 3 (a) Meta-analysis of Bush et al. (2000) showing activity in the affective and cognitive divisions of cingulate cortex. The black arrow marks the
border between pACC and aMCC. (b) Correlations of resting glucose metabolism seeded in area s32 showing the functional independence and
border between ACC and MCC.
328
Subregional Cytoarchitecture
Cingulate Flat Map
(d)
(a)
4
5
X
Apex
3
4
cgs
Apex
X
Fundus
Fundus
Apex
(b)
X
1
cc
(c)
1
X
Figure 4 (a) Flat map of cingulate areas with the coordinates from Talairach and Tournoux (1988). The flattening orientations are shown with double
arrows over the genu and behind the splenium of the corpus callosum. As the splenium was rotated ventrally to expose the ventral bank of the cgs
to show areas 29 and 30, the actual length of the corpus callosum is shown with the red double arrow. (b) A histological section with the midcortical
layer marked. (c) The latter line is broken into segments and measured. (d) The segments are flattened and used to derive the flat map.
329
p24b
p24a
(c)
a24b
(b)
(a)
(d)
(e)
25
(f)
24b
Figure 5 Cytoarchitecture of the gyral surface in ACC and MCC including sampling sites for pairs of NeuN and SMI32 images (a). The blue dashed
arrow emphasizes the substantial expression of intermediate neurofilament proteins in layer III of area p24b0 compared with those in area p24a0 .
Scale bar, 1 mm.
330
Area 32:
location and
architecture
area 320 . There is also a progressive reduction in neuron densities in layers Va and Vb. The fingerprints of ligand binding for
the mean of all layers (Figure 6(b)) and the laminar binding
patterns for benzodiazepine (BZ) (Figure 6(c)) and GABAB
(Figure 6(d)) receptors are shown. The BZ binding is most
dense in layers IIIIV of area s32, and it is progressively lower
in areas p32, d32, and 320 . Although a similar trend occurs
for GABAB binding, that for area d32 is higher than that for
area p32.
III ab
III c
IV
Va
Vb
200 mm
(a)
s32
BZ
IIIc
IV
Va
Vb
NMDA
VI
GABA A
(c)
727
1409
2091
2773
GABAB
M3 M2 M1
BZ
I/II
s32
(b)
32
I/II
AMPA Kainate
5HT1A
a2b
a1
N
d32
IIIab
Fingerprint
layer III
3000
2500
D1 2000
5HT2 1500
1000
p32
IIIab
p32
IIIc
d32
IV
Va
32
Vb
VI
GABA
436
1145
1855
2564
(d)
Figure 6 (a) Location of each sample site and associated cytoarchitecture of four divisions of area 32. The red arrows draw attention to the progressive
shift in the largest neurons in layer IIIab of area s32 to layer IIIc in area 320 . (b) Fingerprint of binding for 15 receptors in layer III with arrows
emphasizing significant differences in GABAB and benzodiazepine (BZ) binding. (c) Laminar profiles in binding showing the highest BZ mainly in layers III
and IV and progressive reduction in binding from area s32 to area 320 . GABAB binding is more concentrated in layers II and IIIab and undergoes
significant changes with area s32 having the broadest distribution of receptors and area 320 the fewest. The laminar differences in binding confirm
cytoarchitectural findings of four divisions of area 32. Reproduced from Vogt, B. A., & Palomero-Gallagher, N. (2012). Cingulate cortex. In: G. Paxinos &
J. K. Mai (Eds.), The human nervous system (3rd ed.). (pp. 943987). Academic Press, Chapter 25.
331
332
(a)
(b)
p24c
(f)
p24b
(e)
area 24d
p33
p24a
(c) p24a
p24b
p24c
(d) X1.5
Figure 7 The cingulate premotor areas and adjacent areas on the gyral surface. (a) Sampling sites (different orientations due to a change in the
plane of section). (b) Section through area p240 . (c) Higher magnification of three p240 areas and (d) magnification of sections in (c) by 1.5. The red
asterisks in layer Vb emphasize the largest neurons in area p24c0 compared with those in area p24b0 . (e) Section through area 24d. (f) Three
preparations of area 24d including pigment architecture (PA) originally used by Heiko Braak to identify this area. These three photographs provide a
means of extrapolating from the PA to NeuN and SMI32 preparations. Scale bar, 100 mm.
Kainate
AMPA
NMDA
GABAA
333
D1
24c
a24c
24d
23c
Figure 8 Sulcal area cytology with matched receptor binding from Palomero-Gallagher and Zilles (2009): area 24c in ACC, areas a24c0 and 24d in MCC,
and area 23c in dPCC. The lines on each cytoarchitectural area mark the border between layers IIIc and Va, and on the left magnified sections, it is
between layers Va and Vb. Of particular note is that layer Vb neurons are largest in areas a24c0 and 24d, kainate binding is highest in layer V of area 24c
and progressively decreases in caudal areas, AMPA receptors are mainly in superficial layers and decrease caudally, and dopamine-1 receptors are
at highest levels in area a24c0 and quite low in other areas. Scale bars, 500 mm; autoradiograph scale for relative comparisons.
334
NeuN
SMI32
d23b
d23b
d23a
(a)
Area d23b
23c
23c
d23a
CML
(b)
v31
(c)
(d)
Area v23b
Area 30
v23b
v23a
36
(e)
(f)
(g)
Figure 9 Histology of posterior cingulate and retrosplenial cortices. (a) Medial surface with section orientations. The asterisk marks a splenial sulcus
(spls) branch that extends to the callosal sulcus (cas). (b) dPCC just caudal to dysgranular area 23d. The asterisk emphasizes the layer Va border
between areas d23b and 23c, and the square is the position of area 30 enlargement in (g) and (c) matched SMI32 section to (b), with the border of layer
III marked with an asterisk between areas d23b and 23c and an arrow showing area d23b enlarged in (d). (e) Caudomedial lobule (CML; NeuN) with
a box for the cortex enlarged for (f) v23b. (f, g) show the cytoarchitecture of the surface cortex on the CML and area 30 in the callosal sulcus. The key
point is that area 30 does not extend onto the caudal surface of the cingulate gyrus as shown in the Talairach and Tournoux (1988) atlas. Instead,
areas 29 and 30 are buried in the caudal end of the cas around the splenium of the corpus callosum (sCC). CG, cingulate gyrus; cgs, cingulate sulcus;
ECG, external cingulate gyrus; IG, indusium griseum; mr, marginal ramus of the cgs; pcgs, paracingulate sulcus; pos, parieto-occipital sulcus; Sub,
dorsal subicular rudiment. All scale bars are 1 mm.
RSC but also involves area 23 and part of area 31; white matter
damage assures that the resulting symptoms are not solely due
to damage to areas 29 and 30. This literature also blurs the
relationship between the retrosplenial location around the
splenium and RSC defined cytoarchitecturally. To avoid this
ongoing confusion, we suggest the term perisplenial when
referring to a general location around the splenium and reserving the word retrosplenial for cytoarchitectonically defined
areas 29 and 30. In the few instances where there is adequate
spatial resolution to locate RSC (Sugiura et al., 2005),
retrosplenial is a valid term.
Area 30 (Figure 9(g)) has a wide layer II from which layer
IIIab pyramids are poorly differentiated compared with that in
area v23b. Layer IIIc is clearly present but layer IV is dysgranular; that is, it is variable in thickness and pyramids in layers IIIc
and Va often intermingle. Layer Va is not as broad and neuron
dense as layer VI in area v23b and is substantially more elaborated than in area 30. These many differences assert the claim
that area 30 is not present on the caudal cingulate gyral surface.
Area 30, however, is also located in the cas around the splenium (Figure 9(e), sCC) where it is flanked by area 29m.
335
Figure 10 Medial surfaces from MRI studies. In all instances, the subregional borders are marked with arrows, and the external edge of the cingulate
cortex is marked with red dots. Red arrows in (b) and (d) emphasize mismatches between the boundary of cingulate cortex and the maps, and red
parentheses emphasize where area 32 should be located in the maps. (a) Beckmann et al. (2009), (b) Destrieux, Fischl, Dale, and Halgren (2010), (c, d)
Craddock, James, Holtzheimer, Hu, and Mayberg (2012) for 50 and 1000 specified ROIs, respectively, (e) left and (f) right hemispheres from Yeo,
Krienen, Sepulcre, et al. (2011).
336
Amygdala
CS
M
AB
LB
RS
Lat
Hippocampal cortex
CS
CC
RS
RS
RhS
Ventral striatum
CS
CS
CC
CC
Dorsal striatum
CS
CS
CC
CC
Parietal cortex
IPS
CS
CC
STS
Figure 11 Comparison of human connections shown by Beckmann et al. (2009) and those for monkey; striatal monkey connections from Kunishio and
Haber (1994) and all others from Vogt and Pandya (1987).
dPCC, and ten in vPCC. Area 32 on the ECG was not part of
pACC or aMCC (red brackets), and part of dPCC was not
included with ROI 9 (red arrow). Thus, this cingulate model
is close in many ways to the cytoarchitectural observations and
could be modified to accommodate these few shortcomings.
Local Connections
Craddock et al. (2012) used a data-driven method to generate
an ROI atlas by parceling whole-brain resting-state functional
MRI (fMRI) data into spatially coherent regions of homogeneous functional connectivity. ROI size and hence the number
of ROIs in a parcellation had the greatest impact on their
Network Connections
Yeo et al. (2011) published a study of resting-state
functional connectivity using surface-based alignment, and
Figure 11(e) and 11(f) shows their results. The most striking
correspondences of these connections with the cytoarchitectural
map are in sACC, pACC, and dPCC, which were uniquely identified, and the differentiation of aMCC and pMCC. Sites of
discordance include the failure to identify area 32, the premotor
areas in aMCC, RSC is combined with PCC and heterogeneity in
vPCC. Of course, these are functional networks that do not
necessarily require concordance with cytoarchitectural observations, although it is a concern that area 32 does not stand out as
having unique connectivities.
Yu et al. (2011) evaluated resting-state functional connectivity of each cingulate subregion from a network perspective;
each subregion was integrated in predescribed functional networks and showed anticorrelated resting-state fluctuations.
The sACC and pACC were involved in an affective network
and anticorrelated with the sensorimotor and cognitive networks, while the pACC also correlated with the default-mode
network and anticorrelated with the visual network. The aMCC
was correlated with the cognitive and sensorimotor networks
and anticorrelated with the visual, affective, and default-mode
networks, whereas the pMCC correlated with the sensorimotor
network and anticorrelated with the cognitive and visual networks. The dPCC and vPCC involved in the default-mode
network and anticorrelated with the sensorimotor, cognitive,
337
and visual networks, and RSC was mainly correlated with the
PCC and thalamus. Based on this hypothesis-driven approach,
they confirmed the subregional analysis in terms of functional
neuroanatomy.
(a)
24b
24c
24b
32
24a
24c
(c) 1
24b
24a
32
10 m
(b)
25
25
(c) 2
Figure 12 (a) Topographic projections to the periaqueductal gray (Dujardin & Jrgens, 2005; labeled neurons observed in all cases). Distribution
of PAG projection neurons in layer V of ACC (An, Bandler, Ongur, & Price, 1998). (c1) Correlations of fMRI voxels with PAG resting state in healthy
controls and (c2) PAG correlations in migraineurs (Mainero et al., 2011). The vast majority of PAG correlations in the migraine state do not represent
PAG connections.
338
References
Amunts, K., Malikovic, A., Mohlberg, H., Schormann, T., & Zilles, K. (2000).
Brodmanns areas 17 and 18 brought into stereotaxic space Where and how
variable? NeuroImage, 11, 6684.
An, X., Bandler, R., Ongur, D., & Price, J. L. (1998). Prefrontal cortical projections to
longitudinal columns in the midbrain periaqueductal gray in macaque monkeys.
Journal of Comparative Neurology, 401, 455479.
Bancaud, J., & Talairach, J. (1992). Clinical semiology of frontal lobe seizures.
Advances in Neurology, 57, 358.
Beckmann, M., Johansen-Berg, H., & Rushworth, M. F. S. (2009). Connectivity-based
parcellation of human cingulate cortex and its relation to functional specialization.
Journal of Neuroscience, 29, 11751190.
Berthoz, A. (1997). Parietal and hippocampal contribution to topokinetic and
topographic memory. Philosophical Transactions of the Royal Society, B: Biological
Sciences, 352, 14371448.
Biber, M. P., Kneisley, L. W., & LaVail, J. H. (1978). Cortical neurons projecting to the
cervical and lumbar enlargements of the spinal cord in young and adult rhesus
monkeys. Experimental Neurology, 59, 492508.
Braak, H. (1976). A primitive gigantopyramidal field buried in the depth of the cingulate
sulcus of the human brain. Brain Research, 109, 219233.
Brodmann, K. (1909). Vergleichende lokalisationslehre der grosshirnrinde in ihren
prinzipien dargestellt auf grund des zellenbaues. Leipzig: Barth.
Buckwalter, J. A., Schumann, C. M., & Van Hoesen, G. W. (2008). Evidence for direct
projections from the basal nucleus of the amygdala to retrosplenial cortex in the
Macaque monkey. Experimental Brain Research, 186, 4757.
Bush, G. (2009). Dorsal anterior midcingulate cortex: Roles in normal cognition and
disruption in attention-deficit/hyperactivity disorder. In B. A. Vogt (Ed.), Cingulate
neurobiology and disease (pp. 245274). London: Oxford University Press.
Bush, G., Luu, P., & Posner, M. I. (2000). Cognitive and emotional influences in
anterior cingulate cortex. Trends in Cognitive Sciences, 4, 215222.
Cajal, R. Y. (1999). Advice for a young investigator. Cambridge, MA: MIT Press,
translated by Swanson, N. and Swanson, L. W.
Chiba, T., Kayahara, T., & Nakano, K. (2001). Efferent projections of infralimbic and
prelimbic areas of the medial prefrontal cortex in the Japanese monkey, Macaca
fuscata. Brain Research, 888, 83101.
Craddock, R. C., James, G. A., Holtzheimer, P. E., III, Hu, X. P., & Mayberg, H. S.
(2012). A whole brain fMRI atlas generated via spatially constrained spectral
clustering. Human Brain Mapping, 33, 19141928.
Destrieux, C., Fischl, B., Dale, A., & Halgren, E. (2010). Automatic parcellation of
human cortical gyri and sulci using standard anatomical nomenclature.
NeuroImage, 53, 115. http://dx.doi.org/10.1016/j.neuroimage.2010.06.010.
Dujardin, E., & Jrgens, U. (2005). Afferents of vocalization-controlling periaqueductal
regions in the squirrel monkey. Brain Research, 1034, 114131.
Enriquez-Geppert, S., Eichele, T., Specht, K., Kugel, H., Pantev, C., & Huster, R. J.
(2013). Functional parcellation of the inferior frontal and midcingulate
cortices in a Flanker-stop-change paradigm. Human Brain Mapping, 34(7),
15011514.
Escobedo, F., Fernandez-Guardiola, A., & Solis, G. (1973). Chronic stimulation of the
cingulum in humans with behavior disorders. In L.V. Laitinen & K. E. Livingston
(Eds.), Surgical approaches in psychiatry (pp. 6568). Lancaster (UK), Baltimore:
MTP.
George, M. S., Ketter, T. A., Gill, D. S., Haxby, J., Ungerleider, L. G., Herscovitch, P.,
et al. (1993). Brain regions involved in recognizing facial emotion or identity: An
oxygen-15 PET study. Journal of Neuropsychiatry and Clinical Neurosciences, 5,
384394.
George, M. S., Ketter, T. A., Parekh, P. I., Horwitz, B., Herscovitch, P., & Post, R. M.
(1995). Brain activity during transient sadness and happiness in healthy women.
The American Journal of Psychiatry, 152, 341351.
Ghaem, O., Mellet, E., Crivello, F., Tzourio, N., Mazoyer, B., Berthoz, A., et al. (1997).
Mental navigation along memorized routes activates the hippocampus, precuneus,
and insula. NeuroReport, 8, 739744.
Goldman-Rakic, P. S., Selemon, L. D., & Schwartz, M. L. (1984). Dual pathways
connecting the dorsolateral prefrontal cortex with the hippocampal
formation and parahippocampal cortex in the rhesus monkey. Neuroscience, 12,
719743.
Grachev, I. D., Berdichevsky, D., Rauch, S. L., Heckers, S., Kennedy, D. N.,
Caviness, V. S., et al. (1999). A method for assessing the accuracy of intersubject
registration of the human brain using anatomic landmarks. NeuroImage, 9,
250268.
Granzieraa, C., Hadjikhanif, N., Arzyc, S., Seeckd, M., Meulib, R., & Kruegere, G.
(2011). In-vivo magnetic resonance imaging of the structural core of the Papez
circuit in humans. NeuroReport, 22, 227231.
339
Shibata, H., & Yukie, M. (2003). Differential thalamic connections of the posteroventral
and dorsal posterior cingulate gyrus in the monkey. European Journal of
Neuroscience, 18, 16151626.
Shibata, H., & Yukie, M. (2009). Temporocingulate interactions in the monkey. In B. A.
Vogt (Ed.), Cingulate neurobiology and disease (pp. 145162). London: Oxford
University Press.
Shima, K., Aya, K., Mushiake, H., Inase, M., Aizawa, H., & Tanji, J. (1991). Two
movement-related foci in the primate cingulate cortex observed in signal-triggered
and self-paced forelimb movements. Journal of Neurophysiology, 65, 188202.
Shima, K., & Tanji, J. (1998). Role for cingulate motor area cells in voluntary movement
selection based on reward. Science, 282, 13351338.
Shin, L. M., Lasko, N. B., Macklin, M. L., Karpf, R. D., Milad, M. R., Orr, S. P., et al.
(2009). Resting metabolic activity in the cingulate cortex and vulnerability to
posttraumatic stress disorder. Archives of General Psychiatry, 66, 10991107.
Sugiura, M., Shah, N. J., Zilles, K., & Fink, G. R. (2005). Cortical representations of
personally familiar objects and places: Functional organization of the human
posterior cingulate cortex. Journal of Cognitive Neuroscience, 17, 116.
Takahashi, N., Kawamura, M., Shiota, J., Kasahata, N., & Hirayama, K. (1997). Pure
topographic disorientation due to right retrosplenial lesion. Neurology, 49,
464469.
Talairach, J., Bancaud, J., Geier, S., Bordas-Ferrer, M., Bonis, A., & Szikla, G. (1973).
The cingulate gyrus and human behavior. Electroencephalography and Clinical
Neurophysiology, 34, 4552.
Talairach, J., & Tournoux, P. (1988). Co-planar stereotaxic atlas of the human brain.
Stuttgart and New York: Georg Thieme.
Torta, D. M., & Cauda, F. (2011). Different functions in the cingulate cortex, a metaanalytic connectivity modeling study. NeuroImage, 56, 21572172.
Vogt, B. A. (2009a). Regions and subregions of the cingulate cortex. In B. A. Vogt (Ed.),
Cingulate neurobiology and disease (pp. 330). London: Oxford University Press.
Vogt, B. A. (2009b). Architecture, neurocytology and comparative organization of
monkey and human cingulate cortices. In B. A. Vogt (Ed.), Cingulate neurobiology
and disease (pp. 6593). London: Oxford University Press.
Vogt, B. A., & Palomero-Gallagher, N. (2012). Cingulate cortex. In G. Paxinos & J. K.
Mai (Eds.), The human nervous system (pp. 943987) (3rd ed.). Amsterdam:
Academic Press (Chapter 25).
Vogt, B. A., & Pandya, D. N. (1987). Cingulate cortex of rhesus monkey. II. Cortical
afferents. Journal of Comparative Neurology, 262, 271289.
Vogt, B. A., & Paxinos, G. (2014). Cytoarchitecture of mouse and rat cingulate cortex
with human homologies. Brain Structure and Function, 219, 185192. http://dx.
doi.org/10.1007/s00429-012-0493-3.
Vogt, B. A., & Sikes, R. W. (2009). Cingulate nociceptive circuitry and roles in pain
processing: The cingulate premotor pain model. In B. A. Vogt (Ed.), Cingulate
neurobiology and disease (pp. 312338). London: Oxford University Press.
Vogt, C., & Vogts, O. (1919). Allegemeine ergebnisse unserer hirnforschung. Journal
fur Psychologie und Neurologie, 25, 279462.
Vogt, B. A., & Vogt, L. J. (2009). Opioids, placebos and descending control of pain and
stress systems. In B. A. Vogt (Ed.), Cingulate neurobiology and disease (pp. 339
364). London: Oxford University Press.
Vogt, B. A., Berger, G. R., & Derbyshire, S. W. J. (2003). Structural and functional
dichotomy of human midcingulate cortex. European Journal of Neuroscience, 18,
31343144.
Vogt, B. A., Vogt, L. J., & Laureys, S. (2006). Cytology and functionally correlated
circuits of posterior cingulate areas. NeuroImage, 29, 452466.
Vogt, B. A., Nimchinsky, E. A., Vogt, L. J., & Hof, P. R. (1995). Human cingulate cortex:
Surface features, flat maps, and cytoarchitecture. Journal of Comparative Neurology,
359, 490506.
Vogt, B. A., Vogt, L., Farber, N. B., & Bush, G. (2005). Architecture and
neurocytology of the monkey cingulate gyrus. Journal of Comparative Neurology,
485, 218239.
Vogt, B. A., Vogt, L. J., Perl, D. P., & Hof, P. R. (2001). Cytology of human caudomedial
cingulate, retrosplenial, and caudal parahippocampal cortices. Journal of
Comparative Neurology, 438, 353376.
Yeo, B. T.T, Krienen, F. M., Sepulcre, J., Sabuncu, M. R., Lashkari, D., Hollinshead, M.,
et al. (2011). The organization of the human cerebral cortex estimated by intrinsic
functional connectivity. Journal of Neurophysiology, 106, 11251165.
Yu, C., Zhou, Y., Liu, Y., Jiang, T., Dong, H., Zhang, Y., et al. (2011). Functional
segregation of the human cingulate cortex is confirmed by functional connectivity
based neuroanatomical parcellation. NeuroImage, 54, 25712581.
Amygdala
D Yilmazer-Hanke, Creighton University, Omaha, NE, USA
2015 Elsevier Inc. All rights reserved.
Glossary
comprehensive delineation of individual nuclei of the mammalian amygdala. Johnston (1923) included observations in
marsupials, reptiles, and amphibians into his considerations
and adapted the delineation of amygdalar nuclei to the modern nomenclature, which is still used today with some
variation.
Recent classifications of the amygdala often distinguish
three major nuclear groups that are anatomically, functionally,
developmentally, and evolutionarily distinct: (i) the deeply
located basolateral group, which develops from the claustroamygdaloid complex and shows coordinated expansion along
with the evolutionarily newer neocortical sensory association
http://dx.doi.org/10.1016/B978-0-12-397025-1.00232-3
341
342
Figure 1 Oblique view to the brain showing ventral (basal) and medial
parts of the temporal and frontal lobes and midline structures. The
amygdala expands laterally where it is deeply hidden in the medial
temporal lobe. It reaches the surface of the medial temporal lobe at the
semilunar gyrus (SLG), which is separated from the parahippocampal
gyrus (PHG) by the semiannular sulcus (sas). AS, anterior perforating
substance; CrC, crus cerebri; cs, collateral sulcus; FuG, fusiform
gyrus; III. V, the 3rd ventricle; IRc, infundibular recess; MB, mammillary
body; OCh, optic chiasm; Olf, olfactory; OT, optic tract; PHG,
parahippocampal gyrus; rs, rhinal sulcus; sas, semiannular sulcus; SLG,
semilunar gyrus; SN, substantia nigra; SRc, supraoptic recess; TPol,
pole of the temporal lobe. Black pin fixes the OCh at the base of the frontal
lobe. Bar 1 cm.
Topography
In mammals, large portions of the amygdala proper are surrounded by temporal cortical areas. In primates, the amygdala
is encircled anteriorly by the piriform cortex and ventrally by
the entorhinal cortex. This is in marked contrast to rodents, in
which the piriform cortex lies ventrally and the entorhinal
cortex is localized posteriorly, indicating an anterior rotation
of primate mesiotemporal structures. In many mammalian
species, the hippocampus head is interposed between the
amygdala and the respective cortex at caudal levels. Laterally,
the inferior limb of the external capsule separates the basolateral group of the amygdala from the claustrum and endopiriform nucleus. The superficial cortex-like region and the medial
nucleus (Me) assigned to the centromedial group occupy the
medial surface of the amygdala. The central nucleus (Ce), also
located in the latter group, lies in the angle between the Me and
basolateral group. Dorsally, the Me and Ce are surrounded by
various basal forebrain structures. The cortical fiber systems
connecting the amygdala with other brain areas run in the
external capsule and subamygdaloid white matter. The ventral
Architecture
The cell types found in the basolateral group are comparable to
the cerebral cortex, but nuclei in this group do not occupy the
brain surface. Instead, they form a subcortical nuclear mass
similar to the claustrum. Like in the cortex, approximately
7090% of neurons in the basolateral group constitute glutamatergic spiny modified pyramidal and stellate projection
neurons. These neurons do not show a recognizable pattern
in their orientation within individual amygdalar nuclei, compatible with a nuclear rather than cortical organization. The
remaining neurons consist of a heterogeneous population of
nonpyramidal spine-sparse interneurons with various sizes
and shapes that are mostly GABAergic and classically coexpress
a variety of neuropeptides such as neuropeptide Y, somatostatin, vasoactive intestinal peptide, and cholecystokinin.
Projection neurons and interneurons have common electrophysiological properties with their cortical counterparts.
343
Figure 2 Coronal myelin sections through the middle third of the main body of the amygdala at the z-coordinate 5.4 mm. Acp, anterior commissure
posterior limb; AG, ambient gyrus; al, ansa lenticularis; BC, basal nucleus of Meynert; BL, basolateral amygdaloid nucleus (also basal nucleus); i,
intermediate part; mg, magnocellular part; pvl, lateral parvicellular part; pvm, medial parvicellular part; BM, basomedial amygdaloid nucleus (also
accessory basal nucleus); mg, magnocellular part; pv, parvicellular part; vm, ventromedial part; CeL, central amygdaloid nucleus lateral part; CeM,
central amygdaloid nucleus medial part; Cl, claustrum; en, entorhinal sulcus; Ent, entorhinal cortex; Epn, endopiriform nucleus; icm, intermediate
caudomedial fiber masses; ICN, intercalated nuclei; ilf, inferior longitudinal fasciculus (also inferior limb of the external capsule); La, lateral amygdaloid
nucleus; DM, dorsomedial part; L, lateral part; VM, ventromedial part; li, intermediate amygdalar medullary lamina; ll, lateral amygdalar medullary
lamina; lm, medial amygdalar medullary lamina; MeP, medial amygdaloid nucleus posterior part; ot, optic tract; PHA, parahippocampalamygdaloid
area; PL, paralaminar amygdaloid nucleus; Pu, putamen; sas, semiannular sulcus (also semiannular fissure or amygdaloid fissure); SLEA, sublenticular
extended amygdala; SLG, semilunar gyrus; SO, supraoptic nucleus; unc, uncinate fasciculus; unn, uncal notch; VCo, ventral cortical nucleus; Ri,
rostral inferior part; Rs, rostral superior part. Adapted from Yilmazer-Hanke et al. (2012a) and the Atlas of the Human Brain, Plate 26 in Mai et al. (2007),
with permission from Academic Press.
Development
The cortex-like cytoarchitecture in the basolateral nuclear
group and superficial cortex-like amygdala suggests a common
origin of neuronal cell types in both regions. Developmental
studies show that neurons in these two regions are derived
from specific pools of telencephalic progenitor neurons. Both
amygdalar regions are populated by excitatory pyramidal neurons displaying various pallial markers during development
(e.g., Emx2 and Tbr1) and by interneurons migrating from
the medial or caudal ganglionic eminences.
The centromedial nuclei located in the amygdala proper
contain neurons that originate mostly from subpallial telencephalic regions. Because neurons in the extended amygdala
show morphological, histochemical, neurochemical, and connectional similarities to neurons in the centromedial group,
344
neurons in corresponding parts may have a similar developmental origin. Indeed, the majority of neurons that migrate to
the Me and medial nuclei of the BST and SLEA originate from
the telencephalic anterior peduncular and preoptic areas. Furthermore, the Ce, ICN, lateral BST, and lateral SLEA all contain
neurons expressing markers of the lateral ganglionic eminence
(striatal primordium). Yet, the lateral BST may have a different
developmental origin than the rest of this group, because
in-wandering cells predominantly originate from the medial
ganglionic eminence (pallidal primordium) rather than the
striatum, at least at early developmental stages.
Connections
The basolateral group and cortex-like superficial region are the
sensory input stations of the amygdala. Olfactory inputs predominate in the Co and NLOT, but intra-amygdalar and insular afferents are other significant sources of information. In
contrast, the basolateral group receives converging multimodal
cortical and subcortical sensory afferents, which is the basis for
associative learning. These afferents arise from high-order
visual, acoustic, somatosensory, gustatory, and viscerosensory
cortical areas and the posterior thalamus. Both regions also
have extensive connections with fronto-temporo-insular cortical areas. Connections to the entorhinalhippocampal system
contribute to the integration of emotional and contextual/
cognitive information, whereas direct and indirect projections
(through ventral striato-pallidal regions and mediodorsal thalamic nuclei) to medial prefrontal areas are important for
motivation, goal-directed behavior, and decision-making.
The centromedial nuclei are characterized by prominent
downstream projections. The Me is a heterogeneous and sexually dimorphic nucleus that is mainly driven by olfactory stimuli and modulates food intake, sexual behavior, and defensive
responses through projections to hypothalamic areas. The Ce
controls fear responses and autonomic reactions through projections to various hypothalamic and brain stem regions. Both
nuclei are also involved in the regulation of hormonal homeostasis. Evolutionarily, the superficially located Me is often
regarded as an anatomical and functional continuum with
the Co, a primitive layered superficial amygdalar region associated with the olfactory system, because the two regions coevolved independently in various species known to
communicate with olfactory signals. This is in stark contrast
to the Ce that serves as a striatal-like viscero- and somatomotor
output center of the basolateral group, which is driven by
multimodal but nonolfactory stimuli. Nevertheless, a considerable portion of the Me and Co lack connections with olfactory areas in primates, suggesting an adaptation to more
complex social behaviors. Recent behavioral data in rodents
further indicate that distinct subregions of the BST are involved
in similar behaviors and functions like the Ce and Me.
MEDIAL PREFRONTAL
CORTEX
MEDIAL PREFRONTAL
CORTEX
tion
tinc
r ex
Fea
CS+US
La
ICN
BL
HIPPOCAMPAL
FORMATION
CA1
CA3
GP/SNr, Th
dStr
vP, mdTh
Acb
vStr
DG Sub
Stimuli La
ith
kw
ac tual
b
n
ed ex
Fe Cont matio
r
o
Inf
Motor
Output
STRIATUM
Complex
Ce
FRONTAL ASSOCIATION
AND MOTOR AREAS
dIFron
M1
IL
AC
ENTORHINAL
CORTEX
345
ICN
Ce
BL
AMYGDALA
AMYGDALA
SNc
Conditioned
Fear
(a)
VTA
DOPAMINERGIC NUCLEI
(b)
Figure 3 Brain circuits involved in two commonly studied forms of behavioral conditioning. (a) In Pavlovian (classical) fear-conditioning, the
conditioned stimulus (CS) and unconditioned stimulus (US) that are paired in time converge on the lateral amygdala (La) leading to associative learning.
The information processed within the La is relayed through indirect intra-amygdalar pathways (via BL, BM and ICN) to the central nucleus (Ce), which
induces a reflexive fear response through its projections to hypothalamic and brain stem regions, for example, cessation of behavior (freezing), increase
in startle response, and autonomic changes in heart rate, blood pressure, body temperature, sweating, and electric skin resistance. Feedback from
hippocampal circuits to the amygdala provides contextual information, and the medial prefrontal cortex can inhibit the fear response. (b) In instrumental
conditioning, the stimuli reaching the amygdala are more complex and the individual is required to make a choice (decision-making) that results in a
complex motor behavior like pressing a lever. The activation of the ventral striato-pallidal system directed towards the medial prefrontal cortex and the
coactivation of frontal association areas are needed to eventually generate the motor response together with dorsal striatal loops and cerebellar loops
(not shown). AC, anterior cingulate cortex; Acb, accumbens nucleus; BL, basolateral (basal) amygdaloid nucleus; Ce, central amygdaloid nucleus;
dlFron, dorsolateral frontal cortex; dStr, dorsal striatum; GP, globus pallidus; ICN, intercalated nuclei; IL, infralimbic cortex; La, lateral amygdaloid
nucleus; M1, primary motor cortex; mdTh, mediodorsal thalamic nucleus; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata;
Th, thalamus; VP, ventral pallidum; vStr, ventral striatum; VTA, ventral tegmental area.
References
Aggleton, J. P. (1992). The amygdala: Neurobiological aspects of emotion, memory and
mental dysfunction. New York: Wiley-Liss.
Aggleton, J. P. (2000). The amygdala: A functional analysis. New York: Oxford
University Press.
de Olmos, J. (2004). Amygdala. In G. Paxinos & J. Mai (Eds.), The human nervous
system (pp. 739868). (2nd ed.). San Diego, CA: Academic Press.
346
Mai, J. K., Paxinos, G., & Voss, T. (2007). Atlas of the Human Brain. San Diego, CA:
Academic Press.
Shinnick-Gallagher, P., Pitkanen, A., Shekhar, A., & Cahill, L. (2009). The amygdala in
brain function: Basic and clinical approaches. New York: New York Academy of
Sciences.
Whalen, P. J., & Phelps, E. A. (2008). The human amygdala. New York: Guilford
Publications.
Yilmazer-Hanke, D. (2012a). Amygdala. In J. K. Mai & G. Paxinos (Eds.), The human
nervous system (pp. 759834). (3rd ed.). London: Academic Press (Elsevier Ltd).
Relevant Websites
www.alz.org ALZ.
www.nimh.nih.gov/health/topics/anxiety-disorders NIH.
www.parkinson.org Parkinson.
Introduction
Olfaction, or as it is more commonly known, the sense of
smell, is of great importance for species survival in terms of
both reproduction and food selection, especially when taken
together with the sense of taste (gustation). Taste and smell are
so closely linked that when people talk about, for example, the
flavor of food, they in fact talk about this multimodal experience. Studies on, among others, single-cell organisms indicate
that the combined chemical sense of taste and smell is possibly
the oldest of the senses and the most universally employed
(Hoover, 2010; Kovacs, 2004).
Humans and other animals rely strongly on olfaction to
locate and identify food sources. Most animals also rely heavily
on olfaction for mate selection and to identify their offspring.
Further evidence for the importance of olfaction can be found
in the size of the olfactory organ and system in a vast majority
of species. For example, dogs have about 100 times more
olfactory receptor cells compared to humans.
It has been argued that compared to other animals, humans
depend less on olfactory functions and more on other senses
such as vision and hearing (Jacobs, 2009). Evidence does exist
however for how we rely heavily on our sense of smell to
identify spoiled or toxic food, or our ability to identify sources
of potential danger. The function of olfaction with regard to
food selection is not limited to identifying potential dangerous
food sources. Deficits in olfactory function can sometimes lead
to malnutrition (Warner, Peabody, Flattery, & Tinklenberg,
1986). The lack of olfaction is a strong predictor of anhedonia,
the lack of pleasure in eating or smelling and tasting food, and
as such may contribute to the malnutrition.
In addition to the function of smell in food selection,
olfaction is also important in sex. Although humans do not
use olfaction for mate selection to the extent other animals do,
olfaction is still related to sex drive. Studies using smell for
attractiveness ratings show that men and women are susceptible to pheromones and rate the opposite sex as more or less
attractive depending on their hormonal state and the hormonal state of the opposite sex (Mostafa, Khouly, & Hassan,
2012). Smells from family members are readily identified as
such (and generally rated as less attractive), which may indicate
a mechanism to select genetically different partners and avoid
inbreeding. Mothers are able to recognize the smell of their
newborn babies (and vice versa) after prior exposure of as little
as 1 h (Porter, 1998).
Furthermore, olfactory dysfunction is associated with apathy, depression, and a lower quality of life (Cramer, Friedman,
& Amick, 2010; Smeets et al., 2009). These observations combined with the fact that olfactory neurons project directly to the
amygdala and hippocampus without a thalamic relay suggests
a prominent role for olfaction in mediating hedonic experience. Taken together, the weight of the evidence shows that
olfaction is a very important sensory system in humans which
http://dx.doi.org/10.1016/B978-0-12-397025-1.00235-9
347
348
Olfactory Bulb
In most primates, including humans, the olfactory bulb is pulled
forward from its point of attachment to the cerebral hemisphere,
remaining connected by a relatively long olfactory stalk or
peduncle. The olfactory bulb in young adult humans is
5060 mm3 (per side) (Turetsky et al., 2000). The intrinsic structural features of the human olfactory bulb are similar to those in
other species, but they are somewhat less sharply defined. The
olfactory bulb has a concentric laminar structure with distinct
neuronal somata and synaptic neuropil separated into layers.
Although our understanding of the synaptic organization of the
olfactory bulb depends on observations made in rats and other
animals (Mori, Nagao, & Yoshihara, 1999), it is very likely that
the human bulb has the same basic organization (see Figure 1).
In humans, 8000 glomeruli and 40 000 mitral cells have
been counted in young adults (Meisami, Mikhail, Baim, &
Bhatnagar, 1998). There is a progressive decrease with age in
(a)
(b)
Figure 1 Olfactory epithelium and olfactory bulb. (a) The location of the olfactory epithelium inside the nasal cavity, the connections to the olfactory
bulb, and the location of and connections from the olfactory bulb to primary olfactory cortices. (b) The connections from the olfactory epithelium
entering the olfactory bulb through the cribriform plate. The organization of the glomerular and mitral layer is clearly indicated. Reproduced from
van Hartevelt, T. J., Kringelbach, M. L. (2012). The olfactory system. In: Mai, J. K., Paxinos, G. (Eds.), The human nervous system (pp. 12191238).
3rd ed. San Diego: Academic Press.
349
(a)
(b)
Figure 2 The olfactory bulb, lateral olfactory tract, and primary olfactory cortices. (a) The cut line along the temporal lobe to make the
underlying olfactory areas visible. (b) The olfactory bulb (OB), projecting through the lateral olfactory tract (LOT) to the anterior olfactory nucleus (AON),
the olfactory tubercle (OTUB), both anterior and posterior piriform cortices (APC and PPC, respectively), and the entorhinal cortex (EC). Reproduced
from Gottfried, J. A. (2010). Central mechanisms of odour object perception. Nature Review Neuroscience, 11, 628641.
Olfactory Tubercle
More caudally on the ventral surface of the frontal lobe, the LOT
runs at the junction of the olfactory tubercle (OTUB), medially,
and the piriform cortex, dorsal and laterally (Figure 3). The
OTUB is a prominent structure in rodents and birds with a
well-developed laminar structure similar to that in other olfactory cortical areas. It is much less distinct in primates, but still
has a laminar arrangement of cell bodies and afferent fibers.
Both in humans and nonhuman primates the OTUB is less
readily identifiable due to the small size of the basal forebrain
bulge, which houses the OTUB (Wesson & Wilson, 2011). In
human imaging studies the OTUB has been identified between
the uncus and the medial forebrain bundle. Furthermore,
besides the direct inputs from the olfactory bulb, the OTUB
Piriform Cortex
The piriform cortex is the largest and most distinctive primary
olfactory cortical area. The piriform cortex is situated deep and
lateral to the LOT, from the caudolateral aspect of the frontal
lobe, around the limen insulae, to the rostral dorsomedial
aspect of the temporal lobe (Figure 2). The piriform cortex is
characterized by a densely packed layer II composed of moderately large pyramidal cell somata, and a less dense layer III of
slightly larger pyramidal cells and other neurons. Layer II is
found throughout the piriform cortex but layer III is only well
developed in the caudal part of the cortex.
Evidence from anatomical, physiological, and functional
differences suggests that the piriform cortex can actually be
divided into two different sections, the anterior piriform cortex
(APC) and the posterior piriform cortex (PPC) (Gottfried,
2010). However, input from the olfactory bulb does not
appear to exhibit spatial patterning across the piriform cortex.
Additionally, contrary to the olfactory bulb, the piriform cortex
has not been shown to have a spatial organization.
350
0.8
0.4
0
0.4
0
APC
(a)
8 12 16 20 24 26
Time (s)
8 12 16 20 24 26
Time (s)
PPC
0.8
0.4
0
0.4
0.8
0
8 12 16 20 24 26
Time (s)
Different group
Same group
(b)
8 12 16 20 24 26
Time (s)
Different quality
Similar quality
0.8
0.6
0.4
0.2
0
0.2
(c)
1
0
1
2
Subjective pleasantness of smell
Figure 3 Olfactory processing in humans measured with neuroimaging. A dissociation has been found between the anterior and posterior parts of
the piriform cortex with the anterior part encoding the difference between group of odors but not their perceptual quality, while the posterior part encodes
perceptual quality but not between group of odors (Gottfried, 2010). (a) Specifically, the presentation of odorants from the same functional group leads
to significantly reduced activity in the APC (circled in red), as shown in the leftmost plot, while the rightmost graph shows no significant differences
for perceptual quality. (b) This is different from the presentation of odorants containing similar perceptual qualities which leads to reduced activity in the
posterior piriform cortex (circled in red). Here, the leftmost plot shows no effect for functional group, while the rightmost graph shows a significant
difference between perceptual qualities. Following this perceptual processing, the affective valence is processed in the orbitofrontal cortex. (c) Region of
the medial orbitofrontal (circled in white) and medial prefrontal cortices correlate significantly with the subjective pleasantness ratings of odors, as
demonstrated by the correlation between signal change and pleasantness ratings (shown on the right). Reproduced from Rolls, E. T., Kringelbach, M. L. &
De Araujo, I. E. T. (2003). Different representations of pleasant and unpleasant odours in the human brain. European Journal of Neuroscience, 18, 695703.
All of the olfactory cortical areas except the OTUB send fibers
back to the olfactory bulb (Carmichael et al., 1994). These
351
352