. Human Brain Mapping 2r I ( 1994) .
OVERVIEW
Computational Approaches to Network Analysis
in Functional Brain lmaging
Functional brain mapping iechniques have the po-
iential of revealing not only the activity of brain
regions, but also the rclationships or interactions
between reSrons. UnderstandinS neural interactions
iequires the development of computational ap-
proaches capable of analyzing brain aciiviiy in terms
of funciional networks. Hufldr Brain Mapping has
devoied this special issue io highlighi the significant
advances in developing computational approaches to
neiwork analysis in neuroimaging. The eight articles
in this issue are based on pr€sentations made at the
international symposium on "Computational Ap-
proaches to Neiwork Analysis in Fun.tional Brain
lmaging," h€ld in Austin, Texas on April 25, 1994. It
r€prcs€nts the firsi collection of papers in this area;
and its purpose is to bring together ihe pioneerinS
work done with ihese types of computational meth-
Th€ unifying theme of the various approaches
presented is the focus on analyzing neiwork interac-
tions to reveal the iichness ofbrain imaging data. The
articles also illustrate, with data from animals and
humans, how these methods help to elucidate the
complex funciional interaciions underlying normal
and abnormal brain activities. Computational ap-
proaches aie illmtrated with various applications io
normal sensorimotor and behavioral functjons using
arditory, visual, and motor paradigms. In addiiion,
ihe application of these approaches to investiSaie
brain dystunciion is illustrated in diseases such as
larl inson .. AlTheimer's. HuntinBton-. depre\cron,
schizophrcnia, and othels.
The first ihree articles deal with structural equation
modeling, a method designed to quantify functional
network interactions mediaied by specific neuroana-
tomical connections between brain regions. The a icle
by Mclntosh and Gonzalez-Lima presents the theoreii-
calbasis for boih covariance analysis of neural systems
and neural strucrural equation modeling. ln the follorv-
o l994 Wil€y-liss, Inc.
ing articles, specific applications focus on auditory
learning in rodents (Gonzalez-Lima and Mclniosh)
and chan8es in motor system functional interactions
in Parkinson's Disease before and after surgical inter
vention (Grafton, et al.). The next three articles de-
scdbe several other multivariate statisiical methods for
mpd-urrng funclional inlFrd,lion- rn neuroimdginS
data. The concepts of funciional and effective connec-
tivity aie defined and expressed in relation to brain
imaSingdaia setsin an articleby Fiiston. Th€ pdncipal
components-based scaled subProfile model is Pre-
sented by Alexander and Moeller providint an inte$a-
tion between biain imagnt and neuropsychiatric
measures. clark et al. also use a pincipal comPonents
approach to examine patient variability in HuntinS-
ton's Disease. Poline and Mazoyei piesent a method
to enhance the sensitivity ofactivation analysis throuth
quantification of conti$ous clusters of activated vox-
els. In the 6nal article, Horwitz compares activation
and covariance analyses and suggests ways in which
neural modelint and neuroimaging maybe combined
to yield a beiier undersianding of brain tunction-
Although functional brain imaging techniques such
as positron emissiorl tomography and autoradioSn-
phy have become central to brain research. relatively
few studi€s take full advantage of neuroimadng data
to quantify functional inieractions among brain re-
gions. Therefore, there has been a need to review
siate-olthe art applications of computational ap-
proaches to network analysis to provid€ a basis for
future res€rch in ihis area. It is hoped that this special
issue will fulfill ihis need, and will help to advance the
field of brain mapping into the realm of invesiigating
the complex network interactions underlyinS brain
F. Gonzalez-Lima, PH.D
A.R. Mclntosh, rH.D.
Peter T. Fox, M.D.
 . Human Brain llaDpinS2t2-2211994) .

Structural Equation Modeling and lts Application

to Network Analysis in Functional Brain Imaging

A,R. Mclntosh and F. Gonzalez-Lima

I obonrctu ot Nru,u\ in, Nnt;onnt Ltaittt : on AR,t t. Nntu'trlt tn nu^ lo, Hcntth
Bethc.da. M0tutn d tA R M, ^.
l.t. nnd D, pn, t neat al p.ythotor| an4 ! stitLte to, Ncu,u" in,r.
Unioersity oJ Texas, Austin,Tdns, (F.G.-L.)

Abstracl: The analysis ofbrain imagingdata has recently focused on rhe examination of the covanances
or
etivity among neural regions during differenr behaviors. We present some of rhe rheorerical and
iechnical issues surounding one of rhese covarian.e-based meth;ds: structural equaiion modeling. tn
srruclural equation modelin& conneciions between brain areas are based on known nedroanarom, and
the.inieftegional oaiances of activity are used to calculare path coefficienrs represenring the magdruoe
of the,influence of a.h direltional parh. The togic behind the use of structural eqrarion;odeling stems
rrom ihe sug8e\hon thar bdrn functjon rs rhe resutr ofchanges in the covariances ofactivity amongneural
elements. The te.hnicaifoundations for neural strucrural equaiion modets are p.esenled, emphasizing the
ability to make inlercntial compansons ro evatuaie the experimentat changes in path coefficienrs.
Simulaled data sets were used io tesr the effecrs of omitted regions and orn ted-conn".iio".. rn",".o."
suggested that shuctural modelinS algorithns can give hints as to possible exrernat influences and
missingpaths, but that the finaldecision as ro modelmodifications requires rhe quidance of the .esealcher.
The utilit), ofanatomically based oodels to disringuish between the direct etfecl of one region on anorner,
and indirect effecis mediated through inte ening regions, is demonsrrated in an empin;al daia set that
examined the effects of darkness o! partemed light on rhe metabotic activiry In the rai v,suat sysrem. lhe
anatomical ffamework lor the structural equaiion models rcvealed that rhe rotat impaci of ascending
thalamoco.tical influences was modified by corticocortical inreraciions. Extensions ofsiructural eouation
modeling to human biain imaging erperimenrs are presenred. We con.lude by suggesting rhar neural
covanances may be a more accurare way to examine the dynamic functional ofsanizarion ;f ihe central
nervoussystem. !t9e4wilq.u$,rnc,

K€y words: path analysis, neural parhwav, neural systems, visual sysiem, rat, human, 2_deoxyglucose,
regional cerebral blood flow, positron ehission romography

INTRODUCTION neously the aciivity wiihin the eniire brain of a singl€

Functional neuroimaSing techniques nave pro-
vided a unique opportunity to examine simulta-
Receiv€d forpubli.ationJune 23,1994; revision accepted A!8ust 24,
Addr€ss reprinr requests to A.R. Mclntosh, ar his presenl addiess:
Rotman Research Institute, Baycr€sr Centre for ceriabic Carc, 3560
BathursrSkeet Toronto, Onrano, M6A 2E1 Canada
o 1994 Wiley-tiss, Inc.
subject. New data analysis methods have also taken
ad\dnlaBe oJ ll-is opporlunrt). Imrge averaging a.rosr
subiecls. 5ubird,lion methods, stdlicli.dl pardmetric
maps [Fox et al., 1988; Friston et al., 1991j, and particle
or cluster analysis lPoline and Mazoyer,1993, Roland
et a1.,19931 represent a few of rhe innovarive methods
for increasing the sensitivity of data analyses to locate
chan$s in regonal metabolic activity. The use of
more Eensitive analytic techniques is particulaily im-
 . Stmctural Modelins ofBrai. Inreractions
portant for mappint studies of behavioral funciions
when meiabolic changes are subtle.
Recent trends in the analysis of brain imaging data
have focused on ihe intera.tions amontbrain regions
lFriston et a1.,1993a,b; Horwitz et a1.,1992a,b, Colden
bert et al., 1989; La8rdze, et al., 1993; Mclniosh and
Gonzalez-Lima, 1991r Moeller and Strother, 19911.
They all extract informaiion about neural interactions
lhrouSh decomporrhon of inrerregronrl .ovdndac(-
of activiiy. One of these methods is structural equa-
iion modeling or path analysis. It has proved to be a
powerful way to combine functional neuroimaginB
data with anatomical circuitry io determine the func
tional neuroanatomy underlying a particular iask. We
have applied structural equation modeling to autora-
diographic 2-deoxyglucose (2-DG) and fluorodeoxytlu-
cose (FDG) data obiained from rats in difierent behav-
ioral paradigms lMclntosh and Conza]ez-Lima, 1991,
r992a, 1993, 19941. More recently, siruciural equatiorl
modeling has been applied to human brain imaginS
data obtained from posiiron emission tomographic
(PET) measures of regional cerebral blood flow (rCBF)
lMclntosh et al., 1994a,b1. The toal of ihis paper is to
explain the application of structural equation model
ing to tunctional brain imaging data. The theoretical
and technical issues of siructural equation modeling
in its Seneral use have been extensively researched
le.g-, Bentler,1985; Berrt 1985; Bollen, 1989, Boomsma,
198s, Fr€edman, 1987; HayduK 1987, Jdreskot, 1973;
Jdreskog and Sdrbom, 1979, 1989; Loehlin, 19871, so
ihe focus here is on isslles felated to the application of
structural equation modeling to neural data
Since interegional covariances of activiiy are the
basis of all network analytic techniques, we will begin
by suggesting that the fundamental organization of
rhe cFnlral nervou..)slem mdle. ir ideal ior .ovdri-
ance analysis. From that we will present the basic
iheory underlying structural equation modeling as
applied to the central nervous system. Our application
of structural equation modeling to neural systems
mak€s us€ of the neuroanaiomy to define a network
and io express the interactions among brain re$ons.
Since the method is a modeling iechnique, it often
requires simplifyint assumptions about the anatomy
ihai includes leaving out minor connections and, on
occasion, brain areas. The effects of an incomplete
anatomical model, and the omission of re$ons that
have an impact on other regions included in the
modelwillbe examined usint simulated daia sets. The
utility of anatomically based models in the theoretical
inteipreiation of a neural struciural equation model
will then be presented, followed by recent extensions
of -lruclur"l equdlron modFlinB In hu rdn brdrn inaS
.
in8 expedments. A contrast of daia-driven versus
iheory-driven approaches to modeling is then dis-
cussed. We conclude this paper by suggestinS that
, o\ urid'rce baced melhods, b hich e\plain brain opprd-
tions in the context of funciional interactions, will
provide a more realistic picture of the relationship of
brain activity and behavior.
WHY STUDY COVARIANCES?
The iraditional form ofdata analysis in all neurosci
erce iechnique. h"s been to lool for differen,e. in
Foup or condition means on the measured variable,
whether behavioral (e.9., perlormance on a neuropsy-
chology test) or physiolodcal (e.9., action potentials
per second/ isotop€ incorporation). Brain imaging is
ro e\ceplion lo lhi-. dnd focu5inS on (han8e\ in medn
regional activity has been a successful approach. For
co\ d,idnce-bJ-ed rnd\.e. ro be useful rn neurormaS-
in& th€y must make a significant conidbution to the
understanding of the daia seis beyond what could be
deived from analysis of mean regional activity. Covari-
ance relationships can span many temPoral and sPa-
tial domains, from milliseconds to minutes and from
.in8le npuronr lo neu'al en.emble. and brdin ireJ-.
T\lrdordinrr) in,i8hr. hdve bpen garned by e\dmin-
ing covaiancesat fine spaiialand temporal resolution,
in the case of sintle neuron electrophysioloSy [AeIt-
sen et al., 1987i Opticon and Richmond, 19871 and
across shori temporal intervals but larter spatial ex-
tents using evoked potentials lcevins et al., 1985;
Gevins and Cuiillo, 19931. Wiih brain imaging and
siructural equaiion modeling, the issue is whether
5imilar r'1riShrs . an be gJrned frol.l e\anininS covari
ances based on iime-iniegrated activity measur€s of
ensembles or brain regions.
Expressed in ierms of neural sysiems, a measure of
covaiarce represents the de$ee io which the activi
ties of iwo regions are related to one another, or how
they vary togeiher. Ahigh covaiance between areas A
and B means that if area A increases its activity, so too
will B (in the case of a positive covadance). Covari-
ances are studied in many scientific disciplines, but in
neural systems, covariances of a€tivity have a special
meaning. The dependent variables (regional activity
of brain areas) are anatomically connected to one
another, while in oiher disciplines, such as social
science, there may be no a priori connective relahon-
ships between dependent variables.
More formally, the central nervous sysiem is unique
in that ii is composed ofnumerous interconnected
elements ran8inS from single neurons to entire en-
sembles. These connections range from local intra-
 . Mclblosh and Gonzalez-Lima.

regional connections among neurons, io inierregional
connections amongensembles of n€urons across brain
areas. ThouSh perhaps somewhat obvious, it is worth
nohng thai communication beiween neural elements
lneurons or ensembles) is along these interconnec,
tions and these communications underlie brain func-
iion. It iollo$'s from this that a change in the observed
activity of any element results from a change in ihe
communication with one or more connected elements_
In oiher words, an activity change at any central
newous sysiem site must come about throuSh a
change in the influences of one or more affereni
pathways. For peipheral sensory receptors/ activity
changes are the result of environmental stimulation
except where central sites influence the receptors
(olivocochlear bundle). Under physiological condi-
iions, possible exceptions might be found in the
diftuse cent'al ede\1. ot no.1 neurondl ofi8in reg.
peripheral hormonal or hemodynamic changes). Since
one neuml element can influence the activity of arld
therefore th€ vadance of another, the relationship
b€tween neural elemenis can be quantified asa covari-
ance. Therefore, interaciions between neural elements
can be detecied by examinnlg ih€ covariances of
measured activity within the central nervous system.
The Seneral organizational prnrciples of the ner
vous system ouUined above suggest that l7mi, /lr rctrox
is the rcsult af chatlges in the catrrianccs anang neural
clc,rerls. The traditional emphasis on the analysis of
changes in regional activity alone is more in line with
the contrasting view that brain functions are the
responsibility ofspecialized areas IHorwitz and Sporns,
19941. As will be demonstrated laier, covariance analy-
sis can coniribute more to the understanding of brain
operations since it implicitly assumes that the cenrral
nervous system is a collection of parallel funciional
networks rathel than segretated regions. The impor-
ldnce of covdndnce of .1eurdl J.lrvity hai been -e(og-
nized by other researchers dealing with electrophysi-
olo$cal and imagint data lAertsen ei al., 1989, Ahissar
ei al./ 1992 Gersiein ei al., 1978, Horwitz et al., 1992a1
and impliedbysome theories o{brain function lDama-
sio,1989, Luda,1973; Tononi et a1.,19921.
where Y and X are measures of rhe aciivity in two
interconnected bmin regions across a sample. Since
the measures are across a sample, Y and X also
represent the vadance in these two regions. Equation
(1) also contains the Y-intercepi for a line, d, and rhe
slope of the line, B,/., indicarinS ihe size of the
influence of X on y. The final rerm g is rhe residuat
representing the variance in Y that is not determined
b\ X Thi. represenlation i\ \implp line.r regrescion.
The value of B!, is computed directly ftom the covari-
ance of Y and X and when the measures of Y and X
are standardized (transformed to z-scoies), the inter-
cept, o, becomes zero and the slope pu, would be rhe
zero-order correlation between Y and X. Equation (1)
also represents ihe gdreral lineat nodel and forms Ihe
foundation for almost all conventional statistical analy-
ses from simple l-tests to canonical correlations [Har-
ris,19751.
A simple extension of equation (1) can represent
effects of an additional area Z on the regional activity
y=a+Bltx+u.z+,1, (2)
Equation (2) represents the effe€ts of X and Z on y
The p weiShts are the degree to which these two areas
influence ihe variance, or activity, of y. Because of ihe
semi partiallinS of varianc€s sources in the compura-
tion of the P weights, the influences of Z on y and j{
on Y are mathematically independent of each other
lcohen and Cohen, 19831. Equation (2) is a multiple
linear reSression.
Equation (2) shows how the eff€cts from mulriple
influences on .egional activity can be derived from
looking at covariances- The equation can be further
expanded io include more regions and, if expressed as
matrices, can be used io define the interconnections 01
an entire neiwork. The matri)( representation is the
foundation for siructuml equation models.

Mathematical ext€nsion
iil ln, r illil.lll 3

In equation (3), the vaiiances ofall three regions,-X, Y,

The relationship between brain aieas can be de-
\imple linedr mdlhemali.al e\pre$ron
s' ribed u\rn8 a
of the variance of a region as influenced by the
variance ofanother. The equation for this is:
v:@+pv,x+{i
and Z are represented as a vectoi that is determmecl
by the weighted influence of the other regio,rb trnanx
of ll weights) plus the residual influen€es contained in
the vector {r. The zero values in the matrix ll iepresent
connections that do noi exist in the model. Equation
(3) can be represented graphically, as shown in Fig
0)
 . Stroctoral Modelins ofBrain Inleractions.
Fitur€ l.
Graphi< representation of strucrural equarion model from equation
( | ). Cir.les reprBent the meaured variance from re8ions X. Y, ad
Z. Unidirect onal arows represent the path for the inlluence of
these solrces ol vriance on each other, the weightinS of the
influence given by P. CuNed bi-direcrional arrows represent
rsidua infllences whose size is indicated b/{.
Relationship between exp€rimental variance
and covariance
Most of the results obtained from brain imaging
studies have been derived from the analysis of the
differences in regional aciivitybetween task or groups.
It can easily be demonstrated thai this is the same as
evaluating the covaiiance between brain activity and
experimenial manipulation. Using the general linear
model presented in equaiion (1), the activjty in Y is
e\Pres.ed ar beinS partly determrned by an e\perimen-
tal manipulation,4.
Y=d+By"A+{,
ln this equation, y represents a set of measures of
regional activity (variance) ftom two expefmental
condiiions, and A reprcsents a binary vector coding
for an experimental or control condition (e.9., A = 1
for expeiimental condition. ,4 = 0 for conirol condi
tion, this is also referred to as dummy coding [Pedha,
zur, 1982, Cohen and Cohen, 19831). Compuiation of
the influence of,4 on Y, repiesented by Py"/ indicates
whethei thereis a change in the activity ofYrelated io
the iwoconditions, i.e.,whetherthe mean activityof y
ir different rn {he lwo condrhons. Thi\ covarian,e
analysis is identical to a simple f-iest lPedhazur, 1982].
A simple exiension of equation (a) can examne
experimental €ffects on both regional activity and
inierregional covariance.
Y= cr + pr.x + py"A + B!,,,xA + {,
Equation (5) represents the effect of area X on Y, the
experimenial effect of A on y, and the interaction of
the impact ofbrain area X and the experimental effect
A (XA). The interaciion assesses whether the relation-
ship between X and y changes because of the expei-
mental efJect. The B weights represent the deFee to
w\kh rhe-e rhree'acro.s irnuFn,e lhe \dridn.e, or
activity, of Y The influence of area X on Y, indepen-
dent of the experimenial effeci, is evaluaied by the
testint ihe statistical significance of pv.. The signifi-
cdn.e of e\perrmenidll) relaled regional differen.e. rn
the activity of Y, independent of th€ influences of
region X, is assessed by evaluatinS the siFificance of
B!.,. The siSnificance of the slope Py., indicates whether
the influence of region X changes depending on the
experimental condition,i.e., whether the covariance of
Xand ychanges because of ihe experimental manipu-
lation-
Neuroimatint can be used to assess experiment
relat€d functional changes -.ritlrt brain areas by exam-
ining average activity levels and comparing ihese
levels across groups or task. In eqltaiions ( ) and (5),
this is represented by ihe evaluation of ihe eff€ct of A
on Y(p,/"). Funciional changesl,eh,ee, brain areas may
be inferred ftom regional activity, bui some of the
funciional changes may not be obvious fiom regional
mean activity. For example, in eqmtion 5, ii is entirely
possible for the term repr€sentint the experimentally
induced difference in regional aciivity (py.) to be
nonsignificani, bui for the term representing the
change in the relationship between X and ydue to the
experimental effect (pi,") to be siSnificant. This would
be missed if the covariance of X and y was not
(4) evaluated. Civen the inierconn€ctions among neural
elemenis and that re$onal activity in the central
nervous sysiem is mainly determined by ailerent
influences, ihe changes in functional relationships
amongbrain regions can only be quantified by covari-
FOUNDATIONS FOR STRUCTURAL EQUATION
MODELS OF NEURAL SYSTEMS
With the increasing interesi and application of
covariance-based analyses. new terminoloty has also
been introduced. It is useful at ihis point to clarify
some of these terms and define their relation to the
ierms we use to describe neural siructural equaiion
models. The term lunctiollil colinectkns (connectiLrity)
has been used to refer to the correlations of activity
between neural elements in both electrophysiology
{5) lA€rtsen et al., 19871 and brain imaging lFriston et al.,
1993b1. To say that two neural elements (neurons or
brain regions) have a functional connection is to say
that these elemenis show siaiisiically significant corre
 . Mclnlosh and Gonzlle2-Lina.

lated activity without reference to how that correla-

E
tion is mediated. Efrectile con ectil,itlt is a logcal Vo
Sression from functional connecti\.ity and can be ABC
defined as ihe influence or ef{ect one neural element
has on another lAerisen et al., 1989, Friston et al., B rAB
1993b1. The ierm i/,r.iio,ial ]let-.ro* has been applied to
D
€c-
the pattern of covaiances among evoked potential
rAD rBD rCD

siies [Cevins and Cutillo, 1993], but coul.t also be

applied to a patterrl of covariances obtained through
other measures of neural activity. For our application
/l
Structural Equaiions
n
-
Path Equations
ofstructural equation modeling io neural systems, we
have applied ihe terms r atonidl model and futlctional
model [Mclniosh and Conzalez-Lima, 1993, Mclntosh
et al., 1994a1. The analonicul model simply represents .cD:y2 + vr r vw+ yw +yw
the n€uroanatomical connections beiween brain re-
gions used in ihe structural equation models. The Figure 2.
interreSional corelations ofactivity are used to assign Schematic rep.esentaton of merhods involved in s$uctural eq!a,
numerical weighis to the connections in the anatomi tion modelng of a neural ystem. A: Parh diagrm of a simple
cal model, leading io the funciional model. Afir.tio,rrl ietlvork with four bmin retions (A. B C D) and their anaromical
conne.tions (iidicated by afrowq. Br The infomation about the
,11od.1, therefore, represenis ihe influences of regions
corelations of activties between regions is used ii conjhcrion
within the model on each oiher through the anatomi- with the path diaSram (A) to calculate rhe srengrh of influen.es
cal conneciions.ln some respects, the functionai model
throuth the connections, known uthe path coefcients (v. w, L J/,
is close io ihe notion of effective connectivity since it z). C: Path equations show how rhe correlations between reSions
depicts the influence of one redon on another. The can be decomposed to solve tor the path coefllcients. O: Structu6
difference, as will be illustrated subsequently, is that equations show the Enan.e in acriviry in each region 6 a function
the influences in the functional model are depicted as ol the weighted Erlance of orher b6in reSions and a residual
direct and indirect effects through ihe anatomical influen.e (indi.ated by{) These residuals are iot shown in Aaid
model. Effective connections are typically not ex
Pressed in this manner.
There are many commercially available computer
packages that are specifically designed for structural tions provide a more comprtationally efficient meihod
equation modeling including LISREL Ucjreskog and to solve for the path coeficients as the complexity of
Sctrbom, 19891, EQS [Bentler, 1985] and AMOS IAr- the system increases,
buckle,1992l. The algorithms used in struciural equa
iion modeling have underSone some modifications 0 r +{ (8a)
since ihe initial developmeniby Wright [1920], bui the
procedure remains conceptually unchanged. All struc-
fAl fo o o
turdl equalion nodel- are de.i\ed llon co\i-id1ce
matrices and from a causat structure- Figure 2 illus
?,0
lBl =l' 0 :I;t. lY:t (8b)
trates the basic processes and feaiures of structural lc v o o llc | 1,r,.
equation models. The system, made up of four vali- LDI Lrz0 olLDl Lu"l
ables, has a causal Etructure indicated by the arrows
(Fig. 2A)- The regions and connections define the To construct a model it iE useful to rcfer to equation
analomiml madel lMclntosh and Gonzalez Lima, 1993; (8a and b). The model is expressed in maidx notation
Mclntosh et al., 1994a1. By using this anatomical (8a) and expanded as vectors and matrices in (8b). The
model, the correlation matrix (i.e., standardized cova - equaFon ha- a \ ector, tt, whi.h con rains rhe variancer
ances, Fig.28) canbe decomposed to assign functional of re$onal activity from A ihro!8h D a matfx p,
wFi8hlr or y'tl4,"erf,r,"15 gr\en b) lerrer- .: .ro which defines the network and contains ihe path
each of the arrows. The addition of the path coeffi- coefficients, and a vector of residual efJects, {,. Model
cienis defines Ihe lunctiollal ,iodcl lMclntosh and specification is done through indicating which ele-
Conzalez-Lima, 1993, Mclntosh et a1.,1994a1. The path ments in p and {, are ri"d at zero (indicating no
equations (Fig. 2C) and structural equations (Fit. 2D) anatomical connection), fixed at a non-zero value, or
ar€ mathematically equivalent, but the structural equa- tre io be estimaied. The zero elements ofpjn equation
 . Structural Modelins of B.ain Int€ractions.
(8b) represent fixed coefficienis, while the others
represent coefficienis ihat are free. The vector {, is a
diagonal matrix in the form presented in equation
(8b). It can also be expanded to a full matrix io allow
for correlations amonS iesidual influences.
Solutions to ihe structural equations are typically
obiained through iteraiive estimation. The mosi com-
mon form is maximum-likelihood estimahon, al'
though different leasfsquares methods have been
1lsed lBentler, 1985; l6reskog and Sdrbom, 19891.
Initial estimaies for ihe unknown parameters (paih
coefficients and residuals) in the structural equations
are obtain€d and a set of implied variances and
covariances arc computed llsing derivations similar to
lho.e presented rn Figure 2C. The impliFd covdndnce
mdln\ rs then Lompdred h rlh lhe ofltindl covananLe
matrix. On the basis of the difierences between these
twomatrices, modifications to parameter estimates are
made usinS iierative fitting techniques (e.9., Davidon
Fletcher-Powell method used by LISREL lDavidon,
1959; Fletcher and Powell. 19631, a modified Causs-
Newton method for EQS lBentler, 1985]). This daia
fiiting procedure finishes when the differences be'
tween the observed and implied covariances matrices
are in an acceptabl€ rante. The optimizaiion routines
are surprisingly wellbehaved $ven a reasonable set of
equaiions and initial conditions for iterative estima-
tion, and the methods used for iterative fitting will
typically give the same results in data sets in which fte
covariance matrix is not singr ar l.loreskog and Sor-
bom, 19891. Depariures in th€ final solution are likely
when the numbers of known and unknown param-
eters aie close to being equal or there is singularity in
the data set (one or more regions are perfecily related
to one another). The ultimate ability of the model to
reproduce the daia is given through a X, Soodness-
of-fit statistic (the X,valueis the minimum value of ihe
maximumlikelihood fit function, multiplied by N - 1,
where Nis the total sample size Udresko& 19731).
Eflects decomposition
The representation of the sysiem as a set of path
€quations (Fit. 2C) demonsirates the ability of struc-
iural equation models to determine dir€ct, indirect,
and total eftects. In Figure 2, the effects of region A on
C consist of the direct effect. r,, and the indirect effects
through z, and y. The total of effects of A on C is the
sum of the direct plus indiiect effects. The path
equations depicted in Fi$re 2C do not coniain a
residual term, therefore, the toial effects would be the
zero-ord€r correlation between,4 and C. In rne case rn
which residuals are included, the total effects would
be smaller than the correlation coefficient. Evaluatint
influences within a system as direct, indirect, and iotal
effects is known as effects decomposition and is an
important characteristic of stru€tural equation model-
ing. Ef{ecis decomposition can indicate how the influ-
ence of a region is modified ihrough indirect influ
ences and whether these change d€pending on the
expefm€ntal manipulation. Effective connectivity, as
definedby Aertsen et al. [1992], resembles most closely
total effects in that an ef{ective connection is the
influen.e oi one neural elerrent on .nother irre<pe(-
tive of direct or indirect influences. In structural
equation modelin& effective conneciions, or total
effects. are further decomposed inio direct and indi-
rect effects by use of the anatomical model.
F€edba€k loops
One characteristic of biological neural networks is
that many anatomical connections are reciprocal. Struc-
turai equation models can solve for the functional
weiShts of reciprocal connections between neural
elements and show whether these loops are symmef
ric or asymmetric lBerry, 1984]. Symmetric relation-
ships have equal influences in both diiections of the
loop, while a.yn'nelric reldlion\ willbe l.r8er in one
direction. Such information cannot be dedved from
simple paiNise correlations since coffelations are
symmetric, but can be determined usint structural
The abiliiy to solve these loops is relaied to ihe
complexity of the system- At one extreme, ihere rs th€
two-region model whereby ihe regions are connecied
by a loop. In this case there would be only one known
quantity, the correlation coefficient. and two un-
knowns, the path coefficients. The system is undeter-
mined, as there are more rnknowns than knowns.
Only wiih additional information could this be solved,
so ihe most parsimonious solution would be to assign
each path coefficient the same value equal to half of
the corielation beiween the two regions. On the other
hand, an example ofa determined system is presented
in FiSure 3, and explained below.
ln ihis sysiem, two areas (,4 and B)are connectedby
a loop, with each area receivint an additional proiec-
tion from anoiher area. There are six known correla-
tion coefficients and four unknown path coef{icients
io solve for. The added information provided by ihe
influence ofregions C and D mak€s it possible to solve
the siruciural equation. Moreover, the estimated val-
ues foi the coefficients within the loop are not equal-
 . Mcln(osh and Gonzalez-Lima .

/.\ w = 0.6r
l, \ influences in the model, thiswouldequal ihestandard-
(4.].---L=-a.s]l.(8) ized semi partial regression coefJicieni for ihe influ-
il ence of A on B, i.e., ?r. This coefficient will be differeni

y
tl
=,0.6t4 z; -0.553
from r,(8.), which represenis the coefficient of ihc
influence of B on A, i.e., j!-, since the terms that are
tl partialled oui of !8, namely ri. and rsL, have different
ll valu€s. The standardized semipartial regression coct-
{ct
\./ {D)
\-/ ficieni for the influence of,4 on B (zr) is 0.616, and the
standardized semi-pariial regression coeffi.ient for the
ABCD influence of B on,4 (r) is 0.397 (y = 0.552, for C on A,
A 1.00 and: = -0.554 for D on B).'The ability to solve loops
a 0.48 1.00
c 0.52 0.16 1.00 is an important feature of structural equation model
D 0.24 .0.41 0.06 r.00 ing and highlights another important concept. Looped
frlufe r. influences can only be solved when ihe relaiionships
AfouFregion neuralnetwork with re.iproca connections, or loop, among all regions in a model are considered simulta-
between regionsA and I Correations coeffl.ients are siven below neously. The partialhlg procedure thai is used in
the neMoa, a1d tie aJes fo- each arroa a-e lhe m&irJn- structural equation modeling (and regression) reveals
likelihood estimates for the path coencients. Unlike the iitorma relaiionships ihat cannot be deduced from inierre-
tion der ved from the corelaton coemcients. the path.oefrl.ients gional correlaiions.
Ior the influenceswithin the loop are Aymmetnc.
Residual effects

The reason for this is il[rstrated in the structural

equations for regions A and B:
,4=r:B+vC+'lr,r
B= uA+zD+VB
Thoush ,4 and B both influence each other, the
structural equations for each one contain additional
influences that add information, i.e., the influence of
re8ion C on A lequation (9)] and region D on B
iequation (10)1. Since path coefficients are similar to
semi partial regression coefficienis, and since the cor
relations amonS regions are not homoSeneous, the
resulting path coefficients for the influence of A on B
l,u) dnd B on 4 {r) will nor be equJ The l.lJ.imunr
likelihood estimates for the path coefficicnts ir1 Fi8xre
3 illustrate this. The derivatjon of a path coefficieni
relie. nn partiallin8 and \(n'i pirtiallirS or.ovirian.e.
lfor a detailed expianation of pariial and semi-partial
coef{icienis see Cohen and Cohen, 19831. Semi-partial
coef{icienis can be obtained tfuough leasFsquarc eshma-
tion or by using the formula for a semi partial conelahon
as followsl
.,- -:-
ln the formula, r/tsr) represents the semi-parhal corre-
lation coefficient for regions ,4 and B with D held
constant or partialled out. Wiih ihe direction of thc
Structural equation modeling aiso allows for influ-
ence. rol mFa.ured or not med-urdble lo be in\orpo-
raied in the model as residuals [Hayduk,1987; Joreskog
(e)
and Scirbom, 1979, 19891. Residual influences can be
represented in at leasi two forms. One representation
00) ofresiduals is with variable (PSl) in LISREL terminol-
'1,
ogy and is indicaied in equations (3) and (8) and
Figure 2D. These residual inflLrences are besi thought
of as hcludint ihe combhed influences of regjons
outside the model and the influence of a brain region
upon itself [McArdle and McDonald, 198,1, Mclntosh
and Conzalez Lima, 1992ab1. It is important that
residuals be allowed to occur in the model for both
theoreiical and technical reasons. Bmh r€gions that
do not have a residual influence imltv that all ihe
variance in that region is account€d iorb!'the connec-
iions with other regiorls in ih€ mociel This is an
unlikely siiuation in a neurals\.sieln Formodelfittin8,
fixing ihe residuals to zero forces that \ariance attrib
rThe vnl!.s nrr thr -rnn :r(rl resre$ion coetJicients and the
nartinrm lileilhooJ rn!rtr[- i,i rh. path coefficicnb (Fig 3) are
close, but not ideftriil (! rr.ir .lhei This is th€ result of the two
.stin .,,n r.Jhnri!e! +re.ificatly, least'squares for th€
difterent
r€grcsrnrn..ePirne.ri:i.j n1.r\iDum likelihood for thc path .o€fti
(11)
oerG Th. nrf r.:ai. rnr rh€ drrerenc€ is that th€ esliDales for
lean squnrrr \.r( fnirJr;:eF.rilely Ior each coefticientwhile the
narinun lLlelin!a,r .: nrlri \v.r. obtaincd sinrltaneolsly. lt h
usetul to .nrfi.-:2r :::( leinjquar€s €stimates ar€ oflen used as
'r'Ir,L rs im.'.i!n nFrl ud ll m'\imln
 . Structural Modrlin! olBruin lnteractions
uiable io residuals to be expfessed fron a sourcc
within the model, r'hich can seriously impair the
ability to locate an appropriatc soluiion for the modet.
PSI values in LISREL are represenied as variances and
not path coefficients. They can be convertcd b a
coefficient by taking its square root lLoehlin, 19871, but
informaiion aboui the sign of ihe intluence (positive
or negative) is not obtainable unless further model
modifications arc made lHayduk, 19871.
Another representation of residuals is as a variable
hrvrne " drre(l pd.h In.,ne or more .l rhe r,8inr.
within the model. Conceptually, this influence would
represent a region ihat has a stronginfluence on areas
within the model, but could not be included, in other
words, an influence ihat is r-ms.ndrls io the lnodcl ard
is unmeasured. In LISREL, exogenous variables are
rcferred to as t (KSI) variables, rvhose influence can be
represcnted by direct paths to the c,rdo.{?ro,ls variables
(r) in the model (ihc brain regions in ihe systen).
These exogenous paths can be given a lvcighi or path
coefticieni represented b)' I (GAMMA). Path coeffi
cients amongendogenous variables are represented as
B. KSIS can be useful in accounting for influences of
PeriPheril \en-or) urd.rn- .Lch r. ll e relrnr or,o-
chlea [forexamples, seeMclntosh and Gonzalez Lima,
1992a,19931.lt must be emphasized that wllile concep
tually the residuai input reprcsenis a single sorr.e/ the
mathematical reality is ihat other comrnon residual
sources are encompassed in this hnlrcnce. As a resuli,
it is not a "pure" represeniation for the single source.
Esiimaiion of residual eftects wjll depend on the
complexity of the model. Our typicat approach for the
estimation of residuals (KSI and PSI) ls to fix these
vdlue. ir 15 l. t0: of thp roral Iri.r.rce tor r gr\en
brain region depending on its connections within the
rnodel lMclniosh and Conzalez-Lima/ 1991, l992a,bl.
Regions receivnlg more inpnis will have a lorver
residual value and ior areas that do not receive
influences from $'ithh the model, the efteci of residLr-
als is sct b 100%. These residual effects can be
modified if ii significanily improves the fit of the
model. Values for PSI can also be estimaied directlv as
tuce parameters (but\ee simulaiion reslllis below).It is
not advisable to free KSI and PSI in the \ame nodcl
since there is no way to differentiate the solrrce ot the
greaiest residual variance ihat leads to indeterrninacv
in the final solution-
Stacked models for statistical comparison
of structural equation modets
An issue in examinnlg neural interac tions is r\lhether
there is a change dependcrlt on experincntal condi-
.
tions or Sroups ofsubjects (e.9., clini.al popula tion). In
struciuralcquation modelin8, it is possible to conplrte
the functional models wiihin cach condition and then
provide a descriptive compa son of whcre the models
differ [e.9., Mclntosh and Conzalez Lima, 1991]. The
infereniial power of such a sirategy is, howevcr, rather
limited. Most structlrral modeling programs allow for
a ht ltiplt St tp or stackd nadds analysis/ where
instead of estimatinS a functional model for each
condition separatell,, the models are combined in a
single proBram run. The process involves statistically
conparing functional models, using the xr index of
model fit, r4lereby path coefficienis are constrained to
be equal between conditions (null model) with ihose
in whicir the coetficients are allorvcd to diSer (altemn
tivc nrodel). The comparison of mod€ls is mad€ by
subtracting the Xr value for the alternative model from
the Xr value for the null model. If the alternaiive
model, in which the coefficienis were allowed to differ
between groups, had a significantly lower Xr value,
ihcn the coefficienis ihai were allowed to vary be-
tr\een conditions were siaiistically different. This Xj r
is assessed with ihe degrees of freedom equal to ihe
difference in the degrees of freedom for ihe alterna-
tive and null model. The procedure is sinnlar to a
simple i-test for differences in group means in which
ihe null hypoihesis is thai a single esiimate oi the
mean is aclequaie for both groups (i.€., the group
means do not differ). For the stacked mo.lels ap,
proach, th€ null hypoihesis is thai a single estimaie kx
each path coefficient is adequate for both groups (i.e.,
the path coefficienis between groups do not difier).
This fcature of structural equation modeling has the
ben€fit of noi only allowing for inferential evaluaiion
of different models, but also improves the statistical
fiiness of ihe models b), increasing degrees of frcedom
IHayduk, 19871. When models are esiimaied simulta-
neonsly, each covariance matrix operates as a ser of
observed valucs. By constrainint certain parameters
to be equal bet\^,een conditions, the ratio of knowns
(obserued valuet to unknolvns (parameters to be
esinnaied) is increased, making parameter identifica-
tion of the modcls more likely.
Measurement model tor neural systems
As of yet, an undeveloped capacity of neural sttuc
iural equaiion modelhg is the ability to account for
errors of ncasurement in thc model. A complete
struciural equation (Fig. 4) separates the vari,
ance ot the system'noclel
inio iwo main components, a
measurcment mo.iel and a siructural model lloehlin,
19871. The measureneni model is depicied as thc area
 . Mclntosh and Gonzalellima
ey
Fiture4.
Dtision of cohplete strLctun equation model into a mesure-
ment and structural model. The structlral model is dep cted by
e ements conta ned ir shaded Srey box. The medurement modelis
those e ements oltside the box. A meslrement modelimplis that
the activity obseNed in x,, and z (indicato.%riablet is a functioi
or theinfllence of the actual act v ty of the area (X Y. and Z. atent
eriablet plus some eror of medurement (<). The degree that a
meaured variable reflects a atent variable is tiven b/ the valLes
outside the greybox inFigure4 and in matrix notation
is:
[j] [i i :]l?l.l'l
i2
The measurement model represents three vaiables, t
y, and z, that aie directly measured by the researcher.
These variables represent/ or ir,?i.dlc, some latent
variables (X Y, and Z) that cannot be directly ob-
served. The degree to which a lntent I'ntinblc (e.8., X) is
expressed in an irdia?tor 1)l? rirble (e.9., ir) is Siven by ihe
weithtinS, (e.9., I.). Since the relationships of ihe
^ and indicator variables are noi perfect,
latent variabies
part of each indicator variable will be composed of
measurement error (€., €/ and €.). The structural
model for this system was presented in equation (3).
In many senses, this depiction o{a neural structural
equation model tuom brain imagint data ls more
accuraie, as ii implies ihat what is measured, whether
?DC or {BF, is a function of the actual re8ional
d.livil) plu: \ome er-or or ned\u emenl. In mrppinS
data this measurement ellor may represent every-
ihint from errors in quantificaiion of ducose utiliza-
iion or blood flow, machine drift, and recovery coeffi-
cienis, to individual dil{erences in functional and
.
anatomical organization. The measurement model
accounts for the reliability of ihe measudng device.
Such a depiction of a neural structural equation
modelin8 may help to stabilize ihe estimates of the
path coefficients, as it i{ould reduce the potential
amount of vadance to account for. This also cleans up
the sirlrctural motlel since the measurement ellor is
removed from ihe residual term of the struciural
model. lf a measurement model is not used, then pari
of ihe residual term in the siructural model would
include ihis measuremeni error.
The meanins ofa path coefficient
The technical definition of a paih coefficient (ex,
pressed in terms of neural pathways) is the direct
proporiional functional influence one region has on
another region throu Bh iheir direct anatomical connec-
iion, irith all other regions in the model left un-
changed. A paih coedrcieni i, the expected change in
the activitv of one region gnen a unit change in the
reSion influencint it. Ii a path coetficieni for ihe
influeIl:. oI retio r,{ "r B .0.r rh n r r rir incrFd.F rr
the activity of ,4 $'ould l€ad to an increase of half of
that unii in B; assuminS no other regions connecied to
B show any change. For instan.e, ii rCBF in region A
increases by i0 ml/100 I'mnl, ihen rCBF in region B
would increase by 5 lnl 100 g lnin.
The path coefficient indicat€i the a\ erage influence
across the time intefval meaiurecl. If a structural
equation model was con:tru.ted ior nlulti siie single
neuron data, the path coeihcilnis $ ould be ihe influ,
ences on a nillisecond tiIne,cal€. For m€tabolic
mappinS daia, acti\ii\ i. tim€ iniegraied and is the
sum of acti\ii\ h .r rpgion. Path .oefficients, in this
case, sho\! the alefa{e Lniluence across that time
interval. Coing ba.k tu ihe pr€vious example, if we
measure rCBF in 1 dnd 6. th€n the paih coefficient of
0.5 hdicat€\ th.ri a.ross the time inte al measured
(e.9., i min) the influence oi area A accounted for25%
(squar€ of path .oerricieni) of all the innuences on B
(25% of the !arian.e in B).
The ph\siologr.dl interpretation of a nelral path
coefficient, bried on L'rain imaginS data, is somewhat
less ob\iou: in relaiion to cellular electrical events-
Since the ph\ rological inierpretation of a change in a
meiabolic narker r€lated io cellular electrical aciiviiy
depends.n ihe Lrrdin re$on undei consideration
lconzal€z-Lin1.r et al., 19921, tivint a purely physioloti-
cal interpre ia tion io a pathcoefficient is likely mislead-
ing. One i€mf.tation is io interpret a negaiive path
 . Structural Modelinc of Brain Interaclions.
coefficient as an inhibitory influence and a posiiive
path coeficient as excitatory in reference to eleciro
phy{oln8-cal posl<) naphl evenr-. Howe\er, rn in-
crease in metabolism carl result from
either postsynaptic excitation or inhibiiion depending
on the energy demands and cellular geometry of the
region [e-8., Batini et al., 1983; H€il and Scheich, 1986;
Nobrega and Coscina, 1983; Nudo and Masterton,
19861. This does noi allow a direci translation of path
coefficients based on metabolic mappinS data as indi
ces of postsynaptic excitation or inhibiiion. This diffi,
clrlty is not unique io meiabolic mapping. Similar
interyretaiive difficuliies existin evoked or field poten-
tial work, in which a .hange in the electrical activity
cannot be accurately inierpreted as excitaiory or inhibi
tory postsynaptic activity unless additional informa-
iion about the specific cell populaiions recorded fuom
is obtained. The pure physiological interpreiaiion of a
paih coeficient therefore depends on the activiiy
nedsure- from xhi(h lhp interreSio.ldl .orariance*
If covadances between neural elements underlie
brain operation, then path coefficienis may be inter-
preted as an indication of tunctional influences or
how much of lhe ob-erved vdriance in a brdrl reSion i.
due to the direci effect of an interconnected region.
Here the emphasis is on whether ihe path coefficients
show a change across tasks or beiween groups. If,
across tasks, a path coelficient shows a large increase,
or decrease, in absolute magnitude, this suggesis a
quantitative change in funciional influence. If the
absolute matnitude remains the same, but the sign of
a coefiicient changes across iasks (e.t., positive to
negaiive), this may imply a qualitative change across
tasks. Dichotomies such as this are seldom complete,
so it is likely that both magnitude and sign changes
will o€cur. When evaluated in this manner, path
coefficients can indicate whether there are task- or
group-rclated diflerences in functional influences
within ihe same anatomical pathways-
Nonlineariti€s in covariance analysis
A1l models discussed so far have assumed that the
relationship of the m€tabolic activity between brain
ar€as is piedominantly linear. MostbioloFcal systems,
including the central nervous system, have nonlineari-
ties in their r€sponses. The implications of applying a
linear model to a nonlinear sysiem, at a simple level,
would be a loss of information. Ph],siological re-
sponses typically follow a sitmoidal function, which G
essentially a bounded linear function. By assuming a
purely linear response, information about responses at
thebounds of the actual physiological responsewould
be lost, and at woist the degree of linearity would be
overestimated. However, some researchers have sug-
gested that for metabolic mapping data, a linear
approximation to the data is a reasonable one under
most physiological conditions lFriston eI al., 7992,
Nudo and Masterion,1986l. The ability to incoryorate
feedback loops into structural equation models is a
step towards introducing nonlinearities. More formal
nonlinearities can be evaluated before modeling by
examinint the sitnificance of nonlinear trends using
polynomial expansions lPedhazur, 19821, and these
nonlineariiies can be incorporated into the structural
equation models lKenny and ludd, 19841. Ther€ are
currently iwo m€thods by which this can be done. The
first involves modifyint ihe measured activity before
modeling the system. and then addint an extra vari,
able into the model representinS this modification- For
example, if it is suspected thatre8ion yis a function of
both linear effect of X and the square of the effect oft
measures from X would be squared and an additional
variable would be added to the model torepresent the
square of X lfor examples, see Kenny and Judd, 1984
and Hayduk, 19871. The second method involves
constraining the estimate of the influence of one
re$on on another io b€ some nonlinear tunction,
which could have significani utility in modelinS non-
linearoutputin response to alinearinpui. An example
would be constraining the ouiput ofX (its effect on y)
to be the inverse o{ the linear effect of input from
vaiable Z. This feature has been incorporated into
many of the pro$ams for structuial equation model-
ing such as EQS and newer versions of LISREL
(version 8).
SIMULATIONS FOR INCOMPLETE
ANATOMICAL MODELS
One important feature in neural structural equation
modelinS is the use of anaiomical paths to define the
causal structure and assess functional inieractions.
The issue of the accuracy of the anatomical model and
how this affects the utility of the model has not yet
been e)(plored. Moreover, neural structural equation
models are by necessity simplifications of reality since
any given region can be influenced by numerous
oiher areas, some of which may noibe included in the
model. Simulations were car.ied out to provide some
indication of the impact of a missing pathway and of
regions ihat were noi included in the model. These
simulations were Brossly oversimplified and were
meant only to illustrate the behavior of the structural
 . Mclnlosh and Gonzalez-Lina.

equation modeling aLsorithms uncler the two co'1cli- TABIE ll. Results from simulations*
tions indicated above. VI v2 V3 V5

Methods
V1
The model was construcied using EQS version 4 V2
"regions"
lBeniler and Weeks, i980; Beniler,l9ssl Six v3
(variables V1 to V6) were simulated from a L'nii o.ror
normal distribution with a samPle size of 100 (io avoid V5 0..153 0.712 0.515 .,194
0.563 0.848
confounds due to sampl€ size issues lBoomsma, 19851).
ln the population siruciural equaiion model, regions PSI 1.00 1.00 0.382 0.211 0.24a 0.322
receiving influences from within the model had re- Tesi model ironission ofpath from v4 to V5
V1
sidual variances equal io 0.25, and those not receivin8
VZ
input from wiihin the model had r€sidual variances V3 -.505
sei at 1.0. The samPle .ovaiance matrix used for the o.+or 10.18
analysis is presented in TabLe L Thc sPecific values tor V5 0.692 0.726
-
21.67 -.5rt4
the Dath coefficients and residuals arc siven in Table 0.601
-
0.9,10
tl. itre Uase model was essentially a feectforward -
neiworkwith one looP between V3 and V6 A graPhic
PSI 1.00 1.00 0.382 0.211 0.248 0.322
Test model2: omission of Vl
depiciion of the base model and the simlllation results V1
is presented in FiSure 5. V2
Three simulations were conducted to deiennine ihe V3
effect of region or path elimination The first test 45.31 20.13
0.664
-
moclel was an elimination of the Path from V'l to V5,
0.601 0.940
the second was an elimination of V1 from the model,
and the final was an elimination of the feedback from PSt 1.00 0.382 0.211 0.248 0.322
V6 io V3. The e(ects of these omissions lvere assessed 45 31 7.61

by examination of changes in path coefficients from Test odel3: omission of path from V6 to V3
the base model and by evaluation at nlotliftoturtt V1
11.46
V2
n?dlccs [J6reskog and Sdrbom, 1989; HayduK 1987] 11.46 4.07 ,u.ot
Modification indices are comPuted from th€ firsi- and v4 O..ter
second-order pariial dedvatives for each possible pa- V5 0.453 a_v2 0.515 , .494
rameter in the model Path coefficicnts and residuals 0.489 0.374 4.28
They suSSesi Parameters thai should be freed to fsl 1.00 1.00 0.382 0.211 0.248 0.322
improve ihe fit of the model A high modification 1.07 4.26
index suggesis ihai allowing the estimate of the
pdrdmerer l. chdngL ru-udll) fInmzeror sould 'i8nih- " Each s€clion conttins Path coeffici.nts Rows lnt variables
being
."ntl1 'nprove llre iil ol rhc m'd.l They cdn bL afi..ted ind collnnslist sourcc ot e6€ct Th. t]{o 6nal rows (PSl)
show th. residual influ.n.€s oneach vari.ble.ltems lort€stmodek
evaluated as a xr value with l degree of freedom
(PSl) 1 :l rhorln in bold italics are thc modificatnrn indic€s roi ihe
Udreskog and Scirbom, lgS9l Residual influences crpecled improvement in th. model fit (cv.luated as itr with 1
were fixed at the values obtained from ihe basc model d€gree oi ireedon) if cstimate Ior thrt Parameter !{ere changed
to determine whether the most promising rmProve- Valucs are 8r!cn for all pahncte6 lthose modification 'ndex
.xc€eds n probability of 005 (381). Cells..nranrinS a dash ( )
indic.t. padr coeffici.nts lhal sere sct to zero
TABI-E L Covariance maftix used lor data simurations

V1 v2 V] V5 V6 ment to the fit of the model woutd come from

increasing a residual, or adding a Path lt has been
v] 0.9,t9 noied by other researchers that there is a iendency for
v2 .093 1.060 unaccounted variance to be expressed in ihe residual
v3 -.032 -.210 0.272 term if the estimate for that term is unconstrarned
v.1 0.438 -.057 -.005 0.413 because it is usually the fastesi way to minimize ihe fit
v5 0.585 0.466 .146 0.386 1.013
function lHayduk, 19871. Fixhg the residual influ-
va, 0.009 0.440 .001 .032 0.061 0..184
encesin the testmodels avoided this Possible Problem.
 . StructuralModelinsof Brain Inreractions.
9=a*
X>'l;>e
\Jj/+.-\-/
Figure 5.
Ghphic depiction of results from datasimu ations to test rhe ef{ecrs
of omitted paths or regions. A: 86e modelirom which the data set
ws tenented. A-D: Results from three tesr hodes in which a
part of the bse model wB omined. Elements that are shown by
segmented lina are omissions trom rhe model, while elements
hi8hllshted by a g€y box ue suggsted chantes to rhe test mode s
derived trom moditication indices (see text). Vaues for rhe path
.oeficients. residuas, and modifi.ation indices are presented in
Results
Test model I : elimination of po.h from V4 to Vs
In the first test model (Fi8. 5B), the estimates for the
path coefficients did noi appear to change substan-
tially. The larSest modification index was for the path
from V4 to V5 and the second largest was for ihe path
from V5 to V4- For test model 1, ihe modification
indices accurately identified ihe missing path.
Test model 2: omission of V I
There was a large change in the path coefficient for
the influence of V4 on V5 (from 0.515 in the base
model to 0.995 in test model 2). This is likely a
rene,lion of lhe diiempr ro jclounr Jor the !arar.e
attribuiable to the missing variable (i.e., to 6t the
original covariance matrix better). The larSesr modifi-
cation ;ndices were for the residual influence on V,l
(PSl and influence of V4 on itself) path from V5 ro V4,
and the residual influence on V5 (PSl and influence of
V5 on iiself) (Fig.5C). Exarnination of the modification
indice\\u8ge\red hir aI e\tern"l innuen,e wd.mi,-
in8, since ihe indices for the residual influences were
high. However, the modification index for ihe path
from V5 to V4 was higher than ihe modification index
for the residual innuence on V5. In ihis simulation,
only one missing element \\'ould have been accurat€ly
identi6ed, the residual iniluence on V4. The residual
influence on V5 would likelv have been missed since
ihe modification nrder for this was lower than that of
ihe path from V5 to V,1.
Test model 3: elimination of Path ftom V5 to V3
There was a reduction in the path coeficient for the
infiuence of V3 on V6 (0.848 in the base model to 0.374
in test model 3) as a result of the removal of the
negative feedback paih. The largest modification indi-
ces were for V6 to V3, a reciprocal pathbetween V2 to
V3, and the residuals of V3 and V6 (Fig. sD). The
reciprocal path likely represents an alternative way to
account for the variance in V3 when ihe innuence of
V6 is omitted. Though the modification indices identi-
fied the omiited path, the differences between indices
were noi as $eat as in test models 1 and 2.
Conclusions from simulations
It appears ihat ihe modification tudices obtained
from struciural equation modelinS algorithms are able
to indicate possible omissions from the anaiomical
model, and where regions are omitted. Consistent
with iniuition lMclntosh and Gonzalez-Lima, 1992b],
omitted regions will result in increased residuals.
However, the modification indices alone were noi
completely accurate. In test model2, only one missing
component was accurately identified, and in test
model 3 the differences among indices were not as
greai as in models 1 and 2. Therefore, modification
indices can provide clues as to possible omissions, but
the final decision ofwhether to add a path or mcrease
a residual should be made by ihe researcher. Usually
the regions thatare included in the modelare selected
beforehand using either sia iistical criteda or a theoreti-
cal guide (see section on data-driven versus iheory-
driven modeling presented below). There was some
indeterminacy in the simplistic mo.iels used in these
-rmuldlron.. -o therL Bill Ikply be even more in
complicated neural based models. In social science
applicaiions of structural equaiion modelhg, one of
the main concerns is the vatidiiy of data-driven modi-
fications ofmodels, in which it is unclearhow much of
the data-driven causal struciure results from siatistical
noise [Freedman, 1987, Maccallum et al., 1992]. The
uniqueness of neural structurai equaiion models is
less of a problem because the causal structure is
estabtished by neuroanatomy. However, if modifica-
 . MclDtosb aDd Gonzalez-Lima
tions to the anaiomical modelare made from the data,
the simulation results presented here sugsest that the
same concerns as in social sciercc applications should
extend to the neural applications.
ANATOMICAL CONSTRAINTS
ln the central nervous systcm there are numerous
ways one area can have a functional impact on
another. Many neuralsystems havca parall!'l anatomi-
cal ortanization by which connections between areas
can be both direct (hierarchical) and indirect. Effects
decomposition of anatomically based structural equa-
tion models allows for the evaluation of whether the
influence of one reSion on another is through a direct
ef{ect or is mediaied through one or more indirect
routes. Moreov€r, when €valuatinS experimental dif-
ferences, it is entirely possible for the total effects of
two regions to be th€ same while direct and indir€ct
effects differ, or for total effects to differ when direct
ef{ects do not.
An empirical examplecomes from a 2-DC siudy thai
examined the effects of footshock on visual system
metabolic activity in patterned liShi and darkness
IMclniosh et al., 1992, Mcintosh and Gonzalez-Lima,
1992a1. A 2-by-2 design was employed havinS a pat-
terned light footshock condition, patterned liSht no
shock condition, darkness-footshock condition, and
darkness no shock condition. For full details of the
study and resulis, the interested reader is referred to
the primary papers. To illustrate the informaiion
obtained by constraining the expression of the covari-
ances by the neuroanatomy, portions of the functional
models from patterned lighi-no shock and dark-
ness no shockconditions will be presented.
Fiture 6 shows the direct and total effects for the
Seniculocortical portion of the rat visual systcm stluc-
tural equation models. The full model contained ihe
lateral posterior thalamic nucleus and thc superficial
and intermediate layers of ihe superior colliculus. The
Seniculocortical portion was selected to illustrate the
difference between total and direct effects and how
the anatomical model helps io interpret these effects.
The upper poriion of the 6gure shows tirat the
ascending thalamocortical direct effecis from the dor-
sal lateral geniculate nucleus (LGNd) to primary vi-
sual cortex (VCl) were stronSer in the patterned liSht
model. Descending corticothalamic direct effecis from
secondary visual cortex (VC2) were weaker in the
patterned light mod€l,and all other direct eftects were
not statistically difterent between models. Evaluation
of the total effects within this iri-nodal loop (bottom of
Fig.6) provided additional information about the
.
influenc€ of indirect effects- The darkness model
showed skong corticofugal effects from both VC1 and
VC2,bui in the patt€rned lightmodel, the corticofugal
effects were zcro and the thalamocortical ef{ects w€re
relatively stronger.
The differences between direct and total effects in
Figure 6 suggested thai ihe indireci effects throlgh
corticocortical connections and thalamocortical loops
acted to chan8e the nature of thalamocortical interac-
tions. For €xample, the sign of the direct ef{ect from
LCNd to VC2 was netative for the pattemed liSht
model. The indirect effect of ihe LGNd would be
through thc positive ascending path to VCl and the
positive loop between VC1 and VC2. A positive loop
tends to amplify eafects transmitted through it and
therefore the indirect effeci of LCNd was large and
posiiive (conversely, negative loops tend io dampen
total effects). This, added to the relatively smaller
neSative direct effect of LCNd on VC2, resulted in a
larSe posiiiv€ total eftects from LCNd. Corticocortical
inieractions may have acted to modify the ascending
thalamic siSnal in the patterned light model. Corticai
modulation of ascending signals has been docu-
mented in electrophysiological studies IMolot€hnikotr
ei al., 1984; Wickelgrcen and Sterling, 19691. Though
much of this modulaiion is likely from descendin8
corticofugal influences, the functional models shown
here suggest that corticocortical interactions, espe-
cially feedback from secondary cortices, may also play
an important role. Reversible lesiol experiments with
cortical cooling have suggested that feedback effects
ar€ an important determinant of prinury cortical
responses [Sandell and Schiller,198]1. lvithout the use
of the anaiomy as thc foundatilrn to express the
interregional covariance relationships, it would noi
have bcen po'srble 1,, JelermDrg ri the drfference* in
the ascending efiects behleen patterned liSht and
darkness models here simpl\'because of direct tha-
lamic influences or if the\' r€sulted from mediaiion
through indirect efi€cis. The abiliiy to distinguish
between direct .1nd indirect ellccts is an important
quality ot structural equ.ltion modeling that sets it
,)pdrl from nlhF- L.\nr.rn(L' br\ed melhodc.
The example presenied above shows that the ana-
tomi€al founddtion is ihe key feature for neural struc
tural equation moLiels. An immediate concern with
the use ol the anaionrical constraint is the degr€e to
which ihe anaiomic.rl model reflects realiiy. Any
system of c'quations in which there are unknowns to
be solved L'enc'fit lronl constraints to possible so[r-
tions. Usint d1e connective anatomy of the svstem
helps to consirain soluiions. However, ifall m.rjor and
minor paths \!€re included, most models $olrlli con
 Gen icu locortica I Circuits
Direct Effects
Darkness Patterned Light

Total Effects
Darkness Patterned Light

Legeno
Positive Negative
r0.7to1.0
-At^-6
0.1 to 0.3
-0.41o06 -
- Orrr.a
Schemati. of geniculocon@l luncnona mode s obiained for rars other regons. The s ze oI the dtrect or tota effect is ind <ared bI
presented wth pafterned light or darkness. Modek..e presented the relative width oI the arow. Values for the width tradient are
on a corona section ol the rar bran with rhe inreracling retions given in the etend the bottom ofthe f8!re Positive influences
shown n whte (top s do6al and r€ht s latera). The top vo are shown d solid afows. wheres nesative ones are shown 4
models represenr rhe dlrect efiects of the source region on the setmeited arows. LGNd, doroal late€ geni.uate nu<lelsr VCl,
target reSion. The boftom Mo models repretent the total effects, prima./ visual conexi VC2, s4ondarf vislalcodex-
which are rhe slms of d rect etrects and lndirect effe.B thfough
 . Mclntosh and Gon?rle2-Llma.
tain reciprocal loops at nearlv every level, with somc
interconnections beiween levcls, both feedforwarci
and feedback. Whcn all possible anaionlical connec-
tionsare includlrd, it is likclt, ihai an und('rdetermined
svsten of equations would result, in which there are
either the same number of known and unknown
clcnr€nis or morc unknown elements. In either casc,
urliclue soluti(nrs are noi obtainable. A hierarchical
model building strateg]' could be used whereby a
smaller part of the model is estimated 6rst, th€ param-
eters fixed at those estimates, and then more pathsanci
regions ad.led to complete the model [Mclntosh and
Conzalez-Lima, l992al. In most cases, hor\'ever, some
conrpromise between anatomical accuracy .lnd inter-
pretability may be needecl. Any mocleling efiort,
whcther ba-ed on -irnularion. ,'r ddlr-filhnt i. nece*
.arly ,r rinpl6i,rliUn. and (.prc.p rl- rn dppro\im.r-
tion of .ealit),. It is the de8r!'e of simplification that
determines th€ utility of th€ model.
STRUCTURAL EQUATION MODELING
IN HUMAN PET STUDIES
Siructural equation modeling of animal 2-DC stud-
re- h-tve provideJ rmpunanr in-iBhl. Inlo br.in opern-
tion. Recent extensions of structural equation model-
in8 kr PET rCBF studi€s in humans havc also provided
important information beyond what was concluded
from examinaiion of regional activiiy changes [Mcln-
tosh et al., 1994a1. The nlitial application was to a
visual perception study comparint cortical inier,tc-
tions during match-to-sample tasks ior obiect visiorl
(face matchinS) versus spatial vision (doClocation
matching). The object visnrn task showell relativelv
grcrl('r dcri\ rry rn ! enlrrl occiprtoremp.r,rl hrain drer.
while the spatial vision task showed relntively greater
activity in dorsaloccipital and parietal cortices lHaxby
et al., 19911. Thcse results suggested a functional
segre8ation of visual proccssing strearrs into dorsal
and ventral patlrrvays similar to that observed in
nonhuman prinrates IUnserleidcrand Mishkin, 19821.
Using a principal components analysis, we were abl€
to identify temporal and prefronial r{rgions showing
task-relaied covariance patterns. Structural equatiol
models from anatomical models of dorsal and ventral
processing streams were constructed for both obicct
ancl spaiiat vision tasks. The brain regions includcd
striaie and extrastriate area 17 and ]U, dorsal and
veniral areas 19 (19d and l9v), occipibtpmporal area
37, temporal area 21, parietal area 7, and frontal area
46. The ventral stream consisted of the connections
from areas 17llil, through area 19v, then into area 37
and area 21, and terminat!'d in area ,16. The dorsal
stream started in areas 17l18, thcn went throu8h area
19d and parietal arca 7 and ended in toontal area 46.
lnteractknls between the two streams were included
as the an.lbmical connections be,tween areas 37 and 7,
and are.1s 7 and 21. There was also a feedb.lck path
inclu.led from area 46 to area 19v. The flrnctional
models for the right hemisphere were consisient with
the differences in nrcan iCBF. Arcas alonS the ventral
stream showed stronS interactions in the object vision
task, relltive to spatial vision, while spatial vision
funciional models showed stronSer interactions along
the dorsal strean. Structural equation modeling ex-
tendcd the results by showinS how processing fol-
lo$'ed into temporal and lrontal cortices. The models
added to the results by showinS ihat these iwo
sireans were not functionally independent as there
rvere strong inieractions beiween them in both condi-
tions. Also, the el{ects of ftontal lobe fe€dback were
task d€pcndent, where feedback was present only
in the spatial visior model.
Within the same anatomical Drodel, the left hemi-
sphere tunctional nrodels did not show the separation
ofprocessing streams present in the riSht hcmispher€.
This seemed contrary to the activation results, which
showed equal activation in boih hemispheres. It was
hypothcsized that the bilat€ral activation may have
arisen from transcallosal influences of the risht hemi
sphere on the left lHorwiiz et al., l992al. Interhemi'
spheric siructural equation models showed that this
hypothesis was tenable. As illustrated schemaiically in
Fiture 7, ventral arcas in the riSht hemisph€re had
strongtr contralateral influences than did the lcft
hemisphere areas. In thc spatial vision models, dorsal
areas showed sinilar asymmeiric inflLlences. These
aslrmmetries could only have bepn deduced from the
covaflance analyses,
Wc have recently extended ihe obj€ct vision models
to look at changes in this basic functional neiworkin a
delayed maich-to-sample iask in which th€ delay
interval was paramctrically increased. In this study,
we werlr able to rcplicate the oriSinal obiect vis'on
network, and we showed chan8es in both right hemi-
sphere and left heDlisphere interaciions as a function
ofincreasing delay IMclntosh ct al., l994bl. Across the
delay interval, the functional models showed a dc'
crease in ihe right hemisphere inieractions along the
veniral stream with strongef interactions among dor-
sal areas into cingulate cortcx, and bilateral increased
interactions arnong frontal, temporal, and cingulate
areas. Collectirelv, the resrlts from th€se stLrdies show
that the aPplication of struciura I equatior nodelinB to
brain ilnaging in hnmans will Sreatl), aid in thc
 . Stru.lur.l Modelire ofBraitr Interacdons.

Object Vision Spatial Vision

as<- 46 46

aa

19vi 19v

17 t18

Inte.hemspherlc ilnctona mod€s for obiect vGion and spatal nte.hem spher c nteractions n both rsks. The magnitlde ol the
vison taks (see tex9. Brodmann ares are shown on a schematc d rect efiect s iidcated by the relat ve wdth of rhe atrow. The
ora hor zonta sect on ofthe human bm n Gop is anteror. afd rert is va ues for the width gradient are $ shown in Fisure 6. Posir ve
eft within each section). More doEally ocated are6 7 and l9d are nf uences are shown s solid arrows. wheres neSative ones are
separated by gay boxes. The fi8ure llsrates the dymmet.c shown 6 segmented arrows.

intcrprctation of the distributecl ictiYity ch.lnges un,
derlving cognitive opcrations.
DATA.DRIVEN VERSUS THEORY-DRIVEN
MODELING
A concern with image based analyses is (41etheL an
objcctivc or clata-driven mcthod is superior to a
purcly thcoretic.l approach. Thi\ h.s been an rssue rn
the anal],ris of l'ET daia and is demonsh.atcd by ihc
drhFrpr"p.n p\ts1-b,\.., ,bi,, .p. r. -' - .,n.,i
intcreslbased (theoretical) approaches Ie.9., ',. fox €t al.,
19i18 verslrs Peiit ct al., 19931. A snnilir clisiinclnrn can
be nade in covariancc analyris and is oilcn disiin,
guisheclasexploratory (objcctive) \'eLsLrsconfirnaiorY
'rh,1',ur('l Jr.,l\-,. fr r,ipal .,rrrpor err.-acah-i.
(IrCA) and fack,r analvsis arc e\reniiailv exploratory
techniques since no constrainis afe placcd up hou'
the variance in the sysicnr is €xpresse.l. Shuctural
equation modeling is t),picallv thought of as a confir-
mabD'.pproach (confirmaiory factor anaLysis) sin ce a
causal modcl is uslrally bcing confirmed or discul
timed lLoehlin,1987l.
A purely data-driven appronch requi.cs adclitional
staiistical methods to construct a structural mod€I.
Thcsc nrcthods arc used to select regions that apPear
to be operating as n functiolal Lrnii. Some examPlcs
in.lude the use ol univariate analyses of reSnrnal
actiYity beir{e€n condition, (e.8., t iesis, ANOVA), or.
oihcr multivariate methods such as l'CA (and deriva,
ti!e5) nncl discriminani analysis. Univariate ditfer,
ences in reSional activity can provide clues for somc
regions that need to be includcd h a struciural
cquati.rn nodel. PCA based on ihe covariances b€-
tseen brain arcas sunrnrarize the potentinlly large
covariance nairices from the comrnon patierns oi
relauonlhips amont brain regions and suSsesi re-
gi(nls that mat, be part oi ditferent functional systems.
 . clnro\h and Gonzalez-Limn
This approach has been used in PET iCBF stndies of
visual perception to select retions for a structural
equaiion model lMclntosh et al., 1994a,b]. A further
extension of this, discriminant analysis, selects
weighted combinations of retions that differcntiate
experimental conditions and serves as an indication of
the functional systems that distinguish cond;tions.
Discriminant analysis has been used for the selection
of relevant reSions for inclusion in a model in a brain
mapping study of associative learnint [Mclntosh and
Conzalez-Lima, 19941. Other groups have also used
principal componenis analyses, but not in the context
of build ing structura I equation models IGoldenberg et
al., 1989, Lagrize et al., 1993, Moeller and Strother,
1991; se€ also papers by Friston and Alexander and
Moeller in this issuel.
Daia-driven approaches can be confounded by
sample-specific conditions that limit the generalizabil-
ity of the results. Forexample, heterogeneou s samples,
outlier observations, and measurement error can all
influence covariances within a sample. All analysis
algorithms cannoi distinglish these sources of vari-
ance and therefore they may be expressed in what
appears to be strong changes in covariance. Principal
components anaLysis may be especially vulnerable
since it simply summarizes the covariance matrix and
therefore if some of the observed covariance patterns
are a result of noise, they will be reflected in the
principalcomponents IWidaman, 1993].
Theory-driven approaches usually eniail ihe selec-
tion of a "system of interest" befor€ the experiment.
This was the approach used in our initial application
ofstructural equation modeling to functional neuroim-
aSint studies of the rai auditory and visual systems
lMclntosh and Gonzalez-Lina, 1991, 1992a1. The
theory-driven approach is used when specific hypoth-
eses are being tested about the nature of a Particular
neural system. For example, the choice of the auditory
system was ddven by ihe hypothesis that functional
interactions in the auditory system could code for the
behavioral significance of acoustic stimuli as well as
the pure physical characteristics IMclntosh andConza-
lez-Lima, 199L, 1993l.'N hile the same potential statisti-
cal prcblems with sample-specific chaiacteristics can
affect theory-driven models, a maior concern with
theory-driven approa(hes is whether the actual func-
tional models for a given iask are ideniified. It is
possible that the system of interest does not show a
chanSe in the o(periment and that the functional
model is actually composed of anotherset of regions.
As with most dichotomies, distinctions such as
da ta-d riven versus theory driven are uselulin discuss-
ing seemingly opposinS views or approaches but are
.
seldom useful in practice. Therefore, rather than assum-
in8 a posture ateither end of the continuum, it is more
productive to amalgamate qualities of both objective
and theoretical approaches in to covariance-based mod-
eling efforts. This represe^$ a data-dtutn bttt hypothcsis-
co,.5trniill,r] ltpproach to modeling. For experimental
conditions in which the functional systems involved
are noi obvious, a data-driven approach can be adopted
to select brain areas usinS such methods as a PCA or
discriminant analysis alonS with univariate regional
analyses- Structural equation modelinS can provide
cllres as to possibLe functional influences (i.e., paths)
thatshould be added to the model toimprove explana-
tory power. The data-ddven approach should be
constrained by whether the functional influence can
theoretically exist whether there is an anatomical
conneclion belwFen reSrons. For e\ample. cuppo:e in
modeling the cortical visual system there is a large
modification index fora €onnection from striatecortex
to prefrontal cortex. Since there have been no reports
of direci striatofrontal connections, this path would
noi be included. This may be taken as a case in which
theinfluenceismediatedbyindirectconnections(e.9.,
occipito-temporal frontal) and suSgests that another
region should be added to the model. E)amples ofthe
data driven theory-constrained approach are in FDG
experiments dealing with Pavlovian conditioning in
rats lMclntosh and Conzalez-Lima, 19941 and in hu-
man PET rCBF studies of visual perception and
memory [Mclntosh et a1.,1994a,b].
This combined approach has an additional benefit
in developing theodes of brain operation. Because
each structural equation model combines empirical
data with researcher intuition it forces ihe models to
be explicitly descibed. Each anatomical connection
needs to be confirmed. Any connections that are
included without specific reference to neuroanatomy
(e.9., effective connections) need concrete theoretical
explanation as io whether the effective conneciion is
mediated through brain areas not included in the
structural equation model. Neural structural equation
models add a degree of exactness that is not often
present i)l brain imaginS siudies. With the ability of
brain imaging to measure activity through ihe entire
brain it is often the case that numerous areas show
increases or decreases in activity in an experiment.
Brain imaginS researchers will often discuss the re-
sults in terms of "functional neiworks" without spe-
cific references to how these network are form€d. By
requi'in8 that the nelworki be e\pressed In a covari
ance-based model, the assumptions of the researcher
as to the organization of the neiwork are more easily
 . Structural Modeling ofAmin Inte.rctions.
The relative exactness of neural siructural equaiion
models also allows for the generation of testable
hypotheses. The functional models obtained from
struciural equation models of the human cofiical
visual system showed that feedback tuom prefronial
cortex was present in a match{o-sample task involv-
ing spatial locatior! but not in ihe matching of faces
lMclntosh ei a1.,1994a1. This led to the hypothesis that
the involvement of feedback from the prefrontal
cortex depends on the task difficulty. Moreover, rn.ne
face-matching task there was a stronger influence of
the right hemisphere on left hemisphere than the left
h€misphere on the ritht. This led to the hypothesis
that the right hemisphere was ensaged in most of ihe
taskand ihatleft hemisphere involvementwas through
callosal influences. Our research on associaove redrrr
in8 involvint Pavlovian condiiioning of auditory
stimuli in the rai lMclniosh and Gonzalez-Lima, 19941
has suggesied ihai the sign (positive versus netativ€)
of the influences within a basal forebrain loop involv-
ingthe septalregions and the nucleus accumbens may
refl€ct ihe moiivational or affective property of the
acoustic stimulus. The associative value, on the other
hand, may have been refle.ted by interactions within
a limbic thalamocortical circuit of retrosplenial, perirhi
nal, and insular cortices and the antedor thalamus.
The value of structuial equation modeling as a data
analytic tool for brain ima8in8, and as a hypothesis-
generating hypothesis-testint tool has been discmsed.
There is anoiher potential role for neural structural
equation models as a bridge between €xpedmental
data and n€ural networkmodelingboth at the sysiems
and neuronal level Isee Horwitz and Spoms, 1994, for
a full discussion of these issuesl. Here, the functional
models can act as constraints for computational mod-
els based on reSional interactions lotto ei al., 1992] or
neuronal interactions lTononi et a1.,1992]. This poten-
tial will greatly expand the theoretical utility of siruc
tural equation modeling in neuroscience.
WHAT IS THE BENEFIT OF ANALYTIC
APPROACHES TOWARD THE STUDY OF
NEURAL INTERACTIONS IN NEUROSCIENCE?
Many contemporary cognitive neuioscience theo
ries are based mainly on evidence obtained concern-
ing the role a particular structure plays in a particular
behavior. For example, researh on memoryhas dif{er-
entiated between those memory piocesses thai are
"hippocampal dependent" and "hippocampal inde
pendent" IEichenbaum et al., 1992, Squire et al., 19931.
These theoies incoryorate data from animal lesion
studies, human clinical studies, and studies tna! monr,
tor reSiondl dclivr.y Junng tdsks of inlerest (e.9..
electrophysiology). On ihe other hand, if the covari-
ance among neural elements is criiical to brain opera-
tion, the role of any $ven region in a particular
behavior must b€ viewed in ihe contexi of its interac-
tions wiih other regions. Network analytic approaches
have supported the idea that brain function involves
the cooperative interaction among many neural re
gions, and though it may be that a particular area is
citical for a certain function, the performance of any
task is a result of the funciional interactions of many
regions llohn and Schwartz, 1978; Conzalez-Lima,
1992, Mclntosh and Gon zalez Lirna, 79931.
The study of neural interactions will be important
for relating cognitjve theodes with brain operations. It
is highly unlikely that ihe functional organization of
rhe brain follow. lhe rndependeni moduldr orgdni./d-
tion of psycholo$cal construcis. Therefore, it is also
unlikely that a single brain re8ion has only one
co$itive function. lnstead, fhnctionally specialized
anatomical networks within the brain mav be more
easily related io cognitive constructs. There may not
be a single brain area that represents "aitention" for
instance, but there are more likely numerous brain
areas whose int€ractions represeni atteniion opera-
tions. The imporiant point is that it may be possible for
parts of the same anatomical network to be involved
in anoiher function when the interactions change. For
example/ numerous behavioral brain studies have
su8gested that primary auditory areas show activity
related both to ihe pereptual components of a stimu-
lus and its learned behavioral relevance lconzalez-
Lima, 1992, Mclniosh and Gonzalez-Lima, 1993,
Scheich ei a1.,1992; Weinberger et al., 19901. Thus, the
same anatomical network can code, in parallel, the
perceptual and behavioral properties of stimuli de-
pendingon the nature of the interactions between the
parts of the network. The hippocampus has a well-
established role in declarative memory piocesses
lsquire et al., 1993], but its activity has also been
related to voluntary moior behavior and sensory
processing in high states of arousal lBland, 1986,
Sainsbur), et al., 19871 and habituation or motivation
Icray and McNaughton, 1983; lanard, 19931. These
examples sutgesi ihat different brain areas can play
important roles in multipl€ functions beyond their
classical distinctions, and ihis may be a teneial prop-
eriv of the ceniral nervous system rather than specific
ro orl\ d few brdin retion.. Indeed. lhFse viesr dre
consistent with ihe adaptive characieristics of the
.L rtrcl nervous -v-rem. in whrch tun,lionrl orSanird-
 . Mclnlosh and Gonzalez-Lima.
tion is viewed as dynamically related to the Particular
environmenial demands rather than a static proPerty
Uohn and Schwartz, 1978; Mclntosh and Conzalcz
Lima, 1993, 1994; Merzenich and Sameshima, 1993,
Pascaul-Leone et al., 1994; Recanzone ei al., 1992,
S€heich ei al., 1992, Wolpaw and Lee, 1989t Zohary et
al., 19941. Brain imaginS iechniques will make an
important contribuiion to the understanding of this
propefiy/ given their ability to assess activity across
many neural regions. Covariance analyses like strx.-
iural equation modeling will contribuie to th1s under-
standing by determining the functional relahons
among these areas and showing how they are modr-
fied JeppndinB on lhe behd\io al coqnrtr\e requirF-
ACKNOWLEDGMENTS
The authors thankDr. Barry Horwitz and Dr' Nancy
l. Lobaugh for their insishtful discussions rn the
preparation of ihis manuscriPt. We acknowledge suP-
port for this work toom NIMH grant R01MH43353 and
NSF grant IBN9222075. A.R.M. was supported by ihe
Natural Sciences and Engineering Research Council of
Canada.
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