Magn Reson Mater Phy
DOI 10.1007/s10334-013-0411-6
RESEARCH ARTICLE
Association of white matter deficits with clinical symptoms
in antipsychotic-naive first-episode schizophrenia: an optimized
VBM study using 3T
Li Yao • Su Lui • Wei Deng • Min Wu • Lizhou Chen
Yuan Xiao • Sunima Lama • Wenjing Zhang •
Xiaoqi Huang • Tao Li • Qiyong Gong
Received: 24 May 2013 / Revised: 20 September 2013 / Accepted: 24 September 2013
Ó ESMRMB 2013
Abstract
Object To examine the whole brain white matter mor-
phology in antipsychotic-naive patients with first-episode
schizophrenia (FES) and its correlations with symptom
severity.
Materials and methods High-resolution T1-weighted
images of 64 drug-naive FES patients and 64 matched
healthy controls were acquired using a 3 T MR imaging
system. Then, optimized voxel-based morphometry was
performed to compare the group differences. Finally, cor-
relation analyses were conducted between the white matter
volume (WMV) changes and clinical symptoms.
Results The FES showed significantly decreased WMV
in the bilateral posterior limb of the internal capsule (PLIC)
and right subgyral frontal white matter. The volume of the
bilateral PLIC was negatively correlated with the Positive
and Negative Syndrome Scale positive scores. Positive
correlations were observed between all of the changed
WMV measures and the Global Assessment of Functioning
scores.
Conclusion The current findings provide further evidence
to support internal capsule and subgyral frontal white
matter deficits at the early stage of schizophrenia that are
Li Yao and Min Wu have contributed equally to this work.
L. Yao
S. Lui (&)
M. Wu
L. Chen
Y. Xiao
S. Lama

W. Zhang
X. Huang
Q. Gong
Huaxi MR Research Center (HMRRC), Department
of Radiology, West China Hospital of Sichuan University,
No. 37 Guo Xue Alley, Chengdu 610041,
People’s Republic of China
e-mail: 2323008200@qq.com; lusuwcums@tom.com
W. Deng
T. Li
Mental Health Center, West China Hospital of Sichuan
University, Chengdu 610041, People’s Republic of China
•
potentially related to the core pathophysiology of the dis-
ease. Furthermore, these anatomical alterations were rela-
ted to the clinical symptoms but not the untreated illness
duration, suggesting that these deficits are related to aber-
rations in the neurodevelopmental process and may be
relatively stable during the early course of schizophrenia.
Keywords First-episode
Schizophrenia
MRI

White matter
Volume
Introduction
Many morphometry studies have provided evidence for
gray matter deficits in patients with schizophrenia, and
some of them have even found correlations between
regional deficits and clinical symptoms [1–5]. The few
studies that have focused on cerebral white matter have
displayed inconsistent results [6–19]. However, cerebral
white matter is crucial in the understanding of the neuro-
biological substrate of schizophrenia because white matter
abnormalities may play a fundamental role in the neurobe-
havioral manifestations of the disorder [20]. Furthermore,
one of the debated hypotheses of the etiopathogenesis
of schizophrenia is dysfunction in the neural connectivity
(i.e., misconnection) of different cerebral areas or neural
circuitry [21, 22].
Various methods have been used to assess structural
brain changes. Manual methods of delimiting cerebral
anatomic regions include the use of regions of interest,
which represents the greatest anatomic fidelity but the
lowest interrater concordance. In the past few years, voxel-
based morphometry (VBM) [23], an automated method,
has been widely used in psychiatric research. Using this
technique, the images of both the study sample and control
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 Magn Reson Mater Phy

group are deformed into a preconstituted template and are Table 1 Demographic characteristics of patients with antipsychotic-
investigated for signal intensity differences [6]. Moreover, naive first-episode schizophrenia (FES) and healthy control subjects
various techniques of magnetic resonance imaging (MRI) FES Healthy P
voxel-based analysis measure white matter structure or (N = 68) comparison
tracts. Previous studies indicated white matter volume (N = 68)
(WMV) reductions particularly in the frontal lobe in Mean SD Mean SD
patients with chronic schizophrenia [9–11]. Such volu-
Age (years) 24.2 8.6 24.7 8.8 0.88
metric reduction could be indicative of abnormal axonal
Education (years) 11.8 3.2 13.0 2.9 0.76
myelination or could represent axonal elimination resulting
Height (cm) 167.3 4.9 166.8 6.4 0.82
from neuronal death. However, confounds associated with
Weight (kg) 59.4 12.8 58.7 10.6 0.85
illness chronicity and prolonged exposure to antipsychotic
medication and possible progressive white matter atrophy Illness duration (months) 8.6 14.3
have contributed to the inconsistent findings across studies Global assessment function 26.2 7.6
[9–11]. Compared to studies that focused on chronic PANSS scores
patients, few attempts have been made to investigate the Total 107.4 15.2
white matter changes of first-episode schizophrenia (FES) Negative 20.6 6.6
patients [7, 8, 15, 16]. The results of these few studies were Positive 26.6 5.4
inconsistent, including decrease [7, 12, 17], increase [7, 18] General 51.8 9.1
and no changes [19]. Furthermore, only one of the studies Thought disturbance 14.4 3.5
examined antipsychotic-naive FES. This study revealed Activation 1.0 2.8
less white matter in the internal capsule, fronto-occipital Paranoid 11.2 2.5
fasciculus and fornices compared with controls [24]. Depression 10.5 4.7
Nevertheless, the investigation of antipsychotic-naive FES Anergia 10.1 4.0
may be important in elucidating the core pathophysiology Impulsive aggression 17.8 5.2
of this illness [4] and may provide significant insight into N % N % P
the nature of the disease, its origins, its clinical course, and
the optimal path for therapeutic intervention. Female 38 55.9 37 54.4 0.91
Thus, the present study was designed to (1) identify regions Male 30 44.1 31 45.6 0.91
with WMV changes using optimized voxel-based morphom-
etry, which is an automated method for the group analysis of
tissue distribution [25] and is more sensitive and convenient through poster advertisement and screened using SCID-NP
than region of interest analysis [26], and (2) investigate the to confirm the lifetime absence of psychiatric and neuro-
association of WMV alterations with clinical symptoms in a logical illness. In addition, the control subjects were
large cohort of antipsychotic-naive FES patients. interviewed to ensure that there was no history of psychi-
atric illness in first-degree relatives. Information about age,
sex, height, weight, handedness (based on the Annett
Materials and methods handedness scale [27]), years of education, duration of
illness and clinical symptom ratings was obtained by two
Participants experienced clinical psychiatrists prior to any treatment
and MR examinations. All patients were evaluated using
A total of 128 right-handed subjects, including 64 anti- the Global Assessment of Functioning (GAF) Scale in
psychotic-naive FES patients and 64 healthy controls, were DSM-IV [28]. Psychopathology associated with FES was
recruited in the present study (Table 1). All patients and evaluated using the Positive and Negative Syndrome Scale
community controls were recruited at the Mental Health (PANSS) [29, 30], which provides a total score, positive,
Center of West China Hospital. This study was approved negative and general symptom score. Age, sex, height,
by the local ethics committee, and all patients and controls weight and years of education were matched between the
provided written informed consent for their participation. schizophrenia and control subjects (Table 1). The follow-
The diagnosis of schizophrenia and duration of illness were ing exclusion criteria applied to all subjects: the existence
determined by the consensus of the attending psychiatrist of neurological disorder, alcohol or drug abuse, pregnancy
and a trained interviewer using the Structured Clinical or any physical illness such as hepatitis, brain tumor,
Interview for DSM-IV (SCID-P), and the diagnoses of all or epilepsy as assessed based on clinical evaluations
patients were confirmed after at least one year of follow- and medical records. The MRI image acquisition was
up. Healthy controls were recruited from the local area performed immediately after the first diagnosis of

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Magn Reson Mater Phy
schizophrenia, and treatment began immediately after the
MRI study. Brain MR images (i.e., T1-weighted and T2-
weighted images) were inspected by an experienced neu-
roradiologist, and no gross abnormalities were observed for
any subject.
Data acquisition
High-resolution T1-weighted images were acquired using a
3 T MR imaging system (EXCITE, General Electric, Mil-
waukee, USA) with a volumetric 3D spoiled gradient-
recalled (SPGR) sequence (TR = 8.5 ms, TE = 3.4 ms, flip
angle = 12°, slice thickness = 1 mm) using an 8-channel
phase array head coil. A field of view (FOV) of
240 9 240 mm2 was used with an acquisition matrix com-
prising 256 readings of 128 phase-encoding steps, producing
156 contiguous coronal slices with a slice thickness of
1.0 mm. The final matrix of T1-weighted images was auto-
matically interpolated in-plane to 512 9 512, yielding an in-
plane resolution of 0.47 9 0.47 mm2.
VBM analysis
Optimized VBM [31] was carried out using the Statistical
Parametric Mapping software (SPM8, Welcome Depart-
ment of Imaging Neuroscience, London; available at http://
www.fil.ion.ucl.ac.uk/spm). The VBM toolbox’s optimized
VBM approach was used for data preprocessing. Opti-
mized VBM consists of a two-step procedure that begins
with the construction of a study-specific, whole brain
template and tissue priors accounting for the magnetic field
properties of the scanner and the anatomical properties of
the study cohorts. In this step, images from all 128 par-
ticipants were normalized to the T1 MNI brain template
in SPM8 using a 12-parameter affine-only procedure,
smoothed (according to SPM specifications) with a 4-mm
isotropic Gaussian kernel, and averaged. In the second step,
the customized template and tissue priors were used for
data segmentation and registration to standard space and
re-segmentation in standard space. Thus, white matter was
automatically segmented from the raw MR images using
tissue signal intensity values and the tissue priors regarding
the distribution of brain tissue type. An automated brain
extraction step was included to eliminate voxels from non-
white matter structures, such as the dural venous sinuses,
scalp, cranial marrow and diplopic space, with similar
signal intensities as white matter. White matter partitions
were spatially normalized (using a 12-parameter affine
transformation and 7 9 8 9 7 non-linear basis functions)
to the created customized white matter template. The
deformation parameters obtained from the normalization
process were applied to the original raw images (in native
space) of all participants to create optimally normalized
whole brain images, which were recursively segmented for
brain tissue measurements. Finally, the segmented images
were modulated with the Jacobian determinants derived
from the spatial normalization. The optimally processed
images were smoothed with an isotropic Gaussian kernel
with full width-half maximum of 8 mm.
Voxel-by-voxel-based comparisons of WMV were per-
formed between groups using two-sample t tests. The sig-
nificance of group differences in each region was estimated
by distributional approximations from the theory of ran-
dom Gaussian fields, and significance levels were set at
P \ 0.05 (corrected for multiple comparisons). To identify
the association between structural abnormalities and clin-
ical symptom severity, the average WMV values of all
voxels in abnormal areas revealed by VBM were extracted
and correlated with PANSS scores, GAF scores, age and
duration of illness.
Results
Compared to the control group, the FES group showed sig-
nificantly decreased WMV in three regions: the left posterior
limb of the internal capsule (Talairach: -20, -26, 9;
6,535 mm3), the right posterior limb of the internal capsule
(Talairach: 15, -25, 20; 3,181 mm3), and right subgyral frontal
white matter near the precentral gyrus (right arcuate fasciculus,
Talairach: 50, -9, 31; 3,085 mm3) (Fig. 1), and the results
were shown using MRIcro (http://www.mccauslandcenter.sc.
edu/mricro/mricro). No significant increase in WMV was
found in the FES group compared to healthy controls.
Significant positive correlations were observed between
the WMV of the three regions where volume reduction was
identified and patients’ general functioning as measured
using the GAF scale (Table 2). Significant negative cor-
relations were found between the WMV of the bilateral
posterior limb of the internal capsule and PANSS positive
scores (Table 2). No correlation was found between the
WMV of the three regions and duration of illness.
Discussion
The present study examined white matter deficits in a large
cohort of antipsychotic-naive FES patients. Reductions in
WMV were observed in three regions, including the
bilateral posterior limbs of the internal capsule (PLIC) and
the right arcuate fasciculus (Fig. 1). Volume reductions in
the three regions were related to the severity of psycho-
pathology (Table 2) but not the duration of illness.
White matter deficits in schizophrenia were usually
reported in previous studies by diffusion tensor imaging
studies and morphometric studies. Compared to healthy
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Fig. 1 Significant group

differences between drug-naive
first episode schizophrenia
patients and healthy comparison
subjects were identified by two
sample t test (P \ 0.05,
corrected for multiple
comparisons with false
discovery rate). The regions in
blue indicate areas with
decreased white matter volume
in first episode schizophrenia,
including bilateral posterior
limb of the internal capsule and
the right subgyral frontal white
matter near the precentral gyrus.
The color bars on the bottom
indicate the t value from two-
sample t test analysis between
the two groups

Table 2 Correlation of white matter volume with clinical symptoms

myelin gene expression or white matter structure are a
in antipsychotic-naive first-episode schizophrenia patients
direct cause of the psychiatric disorder or a secondary
Area of white matter reduction (r) consequence of medications or illness chronicity. Exam-
Right Left Right AF ining a large cohort of drug-naive FES, the current study
PLIC PLIC confirmed white matter deficits in schizophrenia at an early
stage. The result suggests that disrupted cortical white
Global assessment function 0.423## 0.428## 0.370##
scores matter in schizophrenia is not a secondary effect of chro-
PANSS scores nicity, medication or psychopathology, but it may be
Total -0.224 -0.310# -0.152 related to the core pathophysiology of the disease.
Positive -0.325 ##
-0.355## -0.148 Previous studies have found reduced internal capsule
Negative 0.024 -0.075 -0.018 size and DTI changes in FES; these changes are associated
General -0.197 -0.219 -0.145 with clinical features and poor outcome [34, 35]. A
Thought disturbance -0.390## -0.474## -0.209
decreased volume of the posterior limb of the internal
Activation -0.171 -0.231 -0.129
capsule was observed in early-onset schizophrenia [36]. In
Paranoid -0.233 -0.208 -0.079
addition, independent studies using diffusion tensor imag-
ing (DTI) and meta-analysis have found fractional anisot-
Depression -0.048 0.002 -0.032
ropy (FA) deficits in the PLIC [37–39]. Decreased FA in
Anergia 0.009 -0.074 -0.019
the left PLIC was found in FES [37]. Similarly, lower FA
PLIC posterior limb of internal capsule, AF arcuate fasciculus in the white matter in the vicinity of the left caudate
# ##
P \ 0.05, P \ 0.01 nucleus was found among minimally treated schizophrenia
patients [8]. These findings suggest that the white matter
controls, white matter loss was observed in the frontal and deficits of PLIC are involved in the early course of
temporal regions and the internal capsule using region of schizophrenia. The internal capsule abuts onto the basal
interest or VBM [7, 8, 15, 16]. In these studies, abnormal ganglia, and the PLIC comprised of pyramidal tract inter-
myelin genes were found through postmortem examination mingles with fibers of the superior thalamic peduncle and
of brain tissue from patients suffering from schizophrenia the parieto-occipito-pontine tract [40]. These thalamocor-
[32, 33]. Such volumetric reduction could be indicative of tical fibers constitute projections from the lateral thalamic
abnormal axonal myelination or could represent axonal nuclei to the precentral and postcentral gyri [38]. The
elimination resulting from neuronal death. However, an present findings lend further evidence for the hypothesis
important issue in these studies is whether these changes in of thalamocortical disconnectivity in schizophrenia. The

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internal capsule abuts onto the basal ganglia, which are rich
in dopamine receptors involved in the antipsychotic
response [37]. Thus, damage to the internal capsule fiber
tracts could lead to a ‘‘functional disconnection’’ of the
feedback loops resulting in the behavioral and intellectual
symptoms observed in patients with schizophrenia [41].
Furthermore, the present study found that the positive
symptom scores of schizophrenia patients were negatively
associated with the volume of the bilateral PLIC. Metel-
man et al., reported that the negative syndrome subscale
scores are inversely correlated with white matter deficits in
the PLIC. To our knowledge, the current study is the first to
demonstrate a relationship between positive symptoms and
decreased white matter volume of the bilateral posterior
limb of the internal capsule.
The second cluster was located in the right subgyral
frontal white matter near the precentral gyrus. A loss in
precentral gyrus gray matter volume has been found in
schizophrenia using both advanced VBM method and ROI
study [42, 43]. Furthermore, the precentral gyrus is a key
target of the dopamine system, which is involved in the
pathology of schizophrenia [44]. As the substrate of gray
matter, white matter volume increases in a roughly linear
pattern throughout development and into adulthood [45]. As
one of the last brain regions to mature, the frontal lobe
shows this pattern more prominently. These changes most
likely reflect ongoing myelination of axons by oligoden-
drocytes enhancing neuronal conduction and communica-
tion [46]. Several studies have shown a significant reduction
in oligodendroglial cells and ultrastructural alterations of
myelin sheaths in schizophrenia. Previous studies that
focused on chronic schizophrenia indicated volumetric
white matter reductions, particularly in the frontal lobe [9–
11]. Consistent with this finding, an FES study found
decreased frontal white matter and demonstrated that the
reduction is partly progressive [47]. Numerous DTI studies
have found reductions in the anatomical integrity of arcuate
fasciculus (AF) [48–50]. The AF passing through the frontal
and temporo-parietal language areas is the most prominent
bundle connecting the superior longitudinal fasciculus and
the precentral gyrus [49]. Therefore, reductions in the
frontal AF may suggest disruption of the fronto-temporal
communication. A previous gray matter morphometric
study also confirmed reduced fronto-temporal volumes
[51]. Furthermore, such abnormalities in the premotor and
supplementary motor cortices may disrupt the top-down
inhibitory control process needed to distinguish the source
of hallucinations as inner thought rather than an external
source [49]. Taken together, these abnormalities may affect
the auditory and speech production areas during overt and
inner speech, which can underlie psychotic experiences
such as auditory hallucinations. Previous studies have
shown that AF deficits are associated with psychotic
symptoms in schizophrenia [49, 52]. In line with this result,
the current study found positive correlations between the
WMV of AF and GAF scores, which suggest that the
abnormalities may account for the social dysfunction.
No significant correlations were observed between the
altered WMV and the untreated illness duration. This result
seems contradictory to the hypothesis that schizophrenia is
a progressive disease with a deteriorating effect on the
cerebral structures [53]. Previous longitudinal studies have
shown progressive clinical symptoms and further decrease
in brain tissue [54–57]. However, the results were con-
founded by the effects of antipsychotic medication, sub-
stance abuse and prolonged course of illness. In fact,
evidence from some clinical studies was contradictory to
the hypothesis that schizophrenia is a progressive disease.
For example, cognitive functioning does not appear to
become worse over time [58, 59]. The result that some
experience cognitive deterioration may reflect poor access
or adherence to treatment, the effects of comorbidities,
poverty and lack of social support. The current findings
further suggest that the anatomical alterations may be rel-
atively stable or slowly evolving in the early stage of
schizophrenia and, thus, could be a relatively objective
biomarker for early diagnosis of the disease. However, it
should also be considered that there exists a different
neuropathologic mechanism, which is associated with the
progressive alteration in the later course of illness. Because
the longitudinal study of drug-naive schizophrenia is
unethical, a cross-sectional design that includes relatively
longer illness course may be an optimal way to detect and
confirm the relationship between the structural alteration
and illness course and reveal the nature of the pathophys-
iologic process.
Limitations
Several issues should be addressed when explaining the
current findings. First, we aimed to investigate the white
matter changes of unmedicated patients with schizophrenia
and their illness duration for months to years; however, the
duration was primarily limited to within 36 months. Sam-
ples of patients with longer illness course are quite small.
Thus, the present study revealed an anatomic alteration
specific to the early stage of schizophrenia. Second, we
must bear in mind that the findings of MRI studies that
report structural changes cannot be interpreted as final
evidence of the neuropathogenesis of schizophrenia [60].
Conclusion
In summary, the present study confirmed the abnormal
white matter volume in the bilateral posterior limb of the
123

internal capsule and right subgyral frontal white matter
near the precentral gyrus (right arcuate fasciculus) in
antipsychotic-naive first-episode schizophrenia. Further-
more, these anatomical alterations were related to the
clinical symptoms but not the untreated illness duration.
These alterations suggest that these anatomical deficits are
related to aberrations in the neurodevelopmental process
and may be relatively stable during early course of the
disease. Future studies that include antipsychotic-naive
patients with longer untreated illness course may help to
clarify the effects of illness course on the brain in the later
stages of the disease and the natural dynamic process of
schizophrenia.
Acknowledgments This work was supported by the National Nat-
ural Science Foundation (Grants 81222018, 81030027, 81227002, and
81220108013); the Programs for New Century Excellent Talents in
University (Grant no. NCET-10-0596); Young Scholars of Sichuan
(Grant no. 2011JQ0005); the Distinguished Professorship awarded to
Dr. Qiyong Gong by the China Medical Board administered by the
Institute of International Education, Washington, DC; the Program for
Changjiang Scholars and Innovative Research Team in University of
China; and the National Key Technologies R&D Program of China
(Program 2012BAI01B03).
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