Schizophrenia Bulletin vol. 45 no. 1 pp.

211–221, 2019
doi:10.1093/schbul/sbx178
Advance Access publication December 20, 2017

Mapping Convergent and Divergent Cortical Thinning Patterns in Patients With

Deficit and Nondeficit Schizophrenia

Teng Xie1–3,10, Xiangrong Zhang4,5,10, Xiaowei Tang6, Hongying Zhang7, Miao Yu5 , Gaolang Gong1–3, Xiang Wang8,

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Alan Evans9, Zhijun Zhang5, and Yong He*,1–3
1
National Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China; 2Beijing Key Laboratory
of Brain Imaging and Connectomics, Beijing Normal University, Beijing, China; 3IDG/McGovern Institute for Brain Research, Beijing
Normal University, Beijing, China; 4Department of Geriatric Psychiatry, Nanjing Brain Hospital Affiliated to Nanjing Medical University,
Nanjing, China; 5Department of Neuropsychiatry, Affiliated ZhongDa Hospital, School of Medicine, Southeast University, Nanjing,
China; 6Department of Psychiatry, Wutaishan Hospital of Yangzhou, Yangzhou, China; 7Department of Radiology, Subei People’s
Hospital of Jiangsu Province, Yangzhou University, Yangzhou, China; 8Medical Psychological Institute of the Second Xiangya Hospital,
Central South University, Changsha, China; 9McConnell Brain Imaging Center, Montreal Neurological Institute, Montreal, Canada
10
These authors contributed equally to this work.
*To whom correspondence should be addressed; National Key Laboratory of Cognitive Neuroscience and Learning, Beijing Key
Laboratory of Brain Imaging and Connectomics, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing
100875, China. E-mail: yong.he@bnu.edu.cn

Deficit schizophrenia (DS) is a homogeneous subtype of Introduction

schizophrenia characterized by primary and enduring neg-
Deficit schizophrenia (DS) is a homogeneous subtype
ative symptoms. However, the underlying neuroanatomical
of schizophrenia, which is characterized by primary and
substrate of DS remains poorly understood. Here, we col-
enduring negative symptoms and impaired social func-
lected high-resolution structural magnetic resonance images
tion and emotional processing.1 Elucidating whether
of 115 participants, including 33 DS patients, 41 nondeficit
neuroanatomical substrates in DS differ from those in
schizophrenia (NDS) patients, and 41 healthy controls (HCs),
nondeficit schizophrenia (NDS) is critical for the facilita-
and calculated the cortical thickness and surface area for
tion of biomarker discovery in this disease.
statistical comparisons among the 3 groups. Relative to the
Structural MRI provides a promising avenue to quan-
control group, both the DS and NDS groups exhibited con-
titatively describe the neuroanatomical features of the
vergent cortical thinning in the bilateral inferior frontal gyri
brain. For example, several cross-sectional studies have
and the left superior temporal gyrus. The cortical thinning
documented that the negative symptoms in schizophre-
in the right inferior frontal cortex in the patient group was
nia are associated with volumetric measures in specific
significantly positively correlated with declines of cognitive
parts of the brain, including the gray matter (GM) in
flexibility and visuospatial memory. Importantly, compared
the entire frontal cortex,2 the ventro-medial prefron-
to the NDS group, the DS group exhibited a more widespread
tal cortex,3 and the temporal lobe4 and the white mat-
cortical thinning pattern, with the most significant differ-
ter in the prefrontal cortex.5 Longitudinal studies have
ences in the left temporo-parietal junction area. For the sur-
revealed that an accelerating reduction in frontal lobe
face area measurement, no significant group differences were
GM and white matter volumes, an increase in the frontal
observed. Collectively, these results highlight the convergent
lobe cerebrospinal fluid (CSF) volume,6,7 and progressive
and divergent cortical thinning patterns between patients with
reduction in temporal lobe GM volume6 are correlated
DS and NDS, which provide critical insights into the neuro-
with greater negative symptom severity. There is also
anatomical substrate of DS and improve our understanding
evidence of a relationship between negative symptoms
of the biological mechanism that contributes to the negative
and the GM thickness of the left orbitofrontal cortex in
symptoms and cognitive impairments in DS.
schizophrenia.8 These findings regarding the relationship
between negative symptoms and morphological measure-
Keywords: deficit schizophrenia/MRI/cortical ments raise the possibility that DS patients who exhibit
thickness/surface area/temporo-parietal junction higher levels of negative symptoms are likely to suffer

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more severe neuroanatomical abnormalities than NDS with NDS in neuroanatomical measures of cortical mor-
patients without the predominant features of lasting neg- phology such as surface area and cortical thickness.
ative symptoms. To address this issue, we examined cortical thickness
To date, several structural MRI studies have directly and surface area measures in a large structural MRI data-
examined the neuroanatomical differences between DS set that included 115 participants (33 DS, 41 NDS, and
and NDS, primarily focusing on volumetric analyses and 41 HCs). Given the aforementioned substantial clinical
producing discordant findings. For example, nonsignifi- heterogeneity and morphological differences between
cant differences were observed between the DS and NDS DS and NDS, we hypothesized that patients with the 2
groups in several global measures such as the total brain subtypes of schizophrenia would exhibit convergent and
volume, the total volume of the ventricles,9 the total GM divergent neuroanatomical abnormalities in the frontal
volume, the total white matter volume and the total CSF and temporal regions and that these structural abnormal-

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volume.10 However, significant volumetric differences in ities would correlate with cognitive performance. These
specific GM regions were observed. For example, DS comparisons might help to clarify the commonalities and
patients exhibited significant volumetric reductions in the differences between the neurobiological characteristics of
superior frontal gyrus,11,12 superior and middle temporal DS and NDS patients.
gyrus,11–13 the left anterior cingulate and the right puta-
men11 compared with the volumes in the NDS patients. Methods
Conversely, NDS patients showed a greater volumetric
reduction in the dorsal lateral prefrontal cortex than DS Subjects
patients.14 These conflicting findings could be associated A total of 128 males participated in this study, including
with insensitive GM volumetric measurements, leading 84 clinically stable schizophrenia patients (40 DS and 44
to an imprecise understanding of the neuroanatomical NDS) and 44 HCs. The patients were recruited from the
characteristics of DS and NDS. psychiatric rehabilitation unit of Yangzhou Wutaishan
It is worth noting that the cortical GM volume is the Hospital, Jiangsu Province, China. The patients’ eligibility
product of two morphological indices: cortical thickness criteria included: (1) a diagnosis of schizophrenia accord-
and surface area. Beyond the abovementioned volume- ing to the Diagnostic and Statistical Manual of Mental
based analyses, these 2 surface-based measurements allow Disorders, Fourth Edition (DSM-IV) and confirmed by
us to obtain more detailed information regarding the the Chinese version of the Structured Clinical Interview
alterations of cortical structures observed in schizophre- for DSM-IV (SCID-I)23; (2) right-handed Chinese Han
nia. Specifically, it is assumed that the cortical thickness patients between the ages of 20 and 65 years; and (3) hav-
has greater etiological relevance for schizophrenia than ing stable psychiatric symptoms and treatment with anti-
that of GM volume or density.15 While the cortical thick- psychotic medications for at least 12 months based on their
ness reveals the number, size, and arrangement of the cells medical records. The exclusion criteria for the patients
within a column, the surface area is more related to the included severe comorbid conditions, such as neurological
number of columns within a certain cortical region.16–18 disorders, head trauma, mental retardation, alcoholism or
Previous structural imaging studies have shown that these substance abuse, and a history of previous electroconvul-
2 surface-based characteristics of the brain were associ- sive therapy. The diagnoses of DS and NDS were deter-
ated with schizophrenia19 and negative symptoms.8,20 To mined according to the Chinese version of the schedule
date, only 2 studies have explored the patterns of cortical for the deficit syndrome (SDS).24 The SDS rates the def-
thickness and surface area in DS and NDS patients.21,22 icit syndrome as present if 2 of the following symptoms
Neither of these studies reported significant differences are at least moderately severe, persistent over 12 months
in surface area between 2 patient groups, or between and not attributable to secondary sources (eg, medication
either patient group and the healthy controls (HCs). With side effects, depression, paranoia, and anxiety): restricted
regard to the cortical thickness, Takayanagi et al21 exclu- affect, diminished emotional range, poverty of speech,
sively examined the mean thickness of the anterior cin- curbing of interests, diminished sense of purpose, and
gulate gyrus using a region of interest (ROI) approach diminished social drive. The SDS scale is also organized
and observed significant thinning in this region in the into 2 factors (factor 1, avolition and factor 2, poor emo-
DS group as compared with that in the NDS groups. tional expression) based on previous studies.25,26 The HCs
Voineskos and colleagues22 reported that compared with were matched for age and handedness with the patients,
HCs, both DS and NDS patients showed cortical thin- were recruited from the local community, and met the fol-
ning in the several frontal and temporal regions, but no lowing criteria: (1) no lifetime history of psychotic, mood,
significant differences between the 2 patient groups. They or substance abuse or dependence, as ascertained by the
speculated that cortical thinning might serve as a common Structured Clinical Interview for DSM-IV Non-Patient
neuroanatomical feature in patient with schizophrenia, version (SCID-NP) 27; (2) no history of organic brain dis-
regardless of the 2 clinical subtypes. Thus, it remains to be orders, mental retardation, or severe head trauma; and
elucidated whether patients with DS differ from patients (3) no family history of psychiatric disorders. The data
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from 13 subjects were excluded due to head motion dur- into 4 rationally motivated domains: sustained vigilance/
ing the scan (7 DS, 2 NDS, and 1 HC) and imaging proc- attention (hereinafter labeled sustained attention with 4
essing failures (1 NDS and 2 HC). Lastly, the data from tests: DVT, TMT-A, Stroop colors, and Stroop words),
the remaining 115 participants (33 DS, 41 NDS, and 41 cognitive flexibility (2 tests: TMT-B and Stroop interfer-
HCs) were included in the final analysis. The study was ence), ideation fluency (2 tests: ANT and COWAT), and
approved by the Institutional Ethical Committee for clin- visuospatial memory (2 tests: Spatial Processing, Block
ical research of Zhongda Hospital Affiliated to Southeast Design and WAIS-RC). For each cognitive domain, a
University. Written informed consent was obtained from composite score analysis was conducted as follows.30,34,35
each participant. Briefly, for each patient the standardized Z score of each
cognitive test was calculated based on the corresponding
neurocognitive data of the control group. The composite

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Clinical Evaluation
scores in the cognitive domain were then calculated by
The severity of the schizophrenic symptoms was evalu- summing the Z-transformed scores of all of the neuro-
ated by the Brief Psychiatric Rating Scale (BPRS), the psychological tests within the domain. The data reduc-
Scale for the Assessment of Negative Symptoms (SANS), tion of the neurocognitive measures avoids multiple
and the Scale for the Assessment of Positive Symptoms comparisons and corrects the interdependency between
(SAPS). The BPRS scale is organized into positive, neg- the neuropsychological measures.30,34,35 Notably, some
ative, disorganized, and affect syndromes based on the variables (eg, TMT), in which low values indicated good
findings of the most comprehensive factor analysis of the performance, were adjusted for sign to ensure that higher
18-item BPRS.28,29 Table 1 illustrates the clinical and dem- Z-scores represented better performance for all variables.
ographic data of all participants. Thus, for each patient, we obtained 4 composite scores
representing performance in the 4 cognitive domains.
Neurocognitive Assessments Finally, Cronbach’s alpha and Cohen’s d effect sizes36,37
were computed for each cognitive domain. Table 2 pre-
For each participant, we performed a battery of classical sented the neurocognitive data of the 3 groups.
neuropsychological tests, including the Digit Vigilance
Test (DVT), the Animal Naming Test (ANT), the
Controlled Oral Word Association Test (COWAT), the Image Acquisition and Processing
Block Design Test in Wechsler Adult Intelligence Scale- Structural MRI data were acquired with a high-resolution
Chinese Revision (WAIS-RC), the Trail Making Test-A, 3D magnetization prepared rapid acquisition gradient echo
B (TMT-A,B), the Stroop Color-Word Test (SCWT), and sequences (for details, see supplementary information). We
the Spatial Processing Test (Block Design). Based on pre- used the CIVET pipeline (version 1.1.9.38) to measure the
vious reports regarding the cognitive processes assessed cortical thickness and surface area in the brain. Briefly,
by each test,30–34 these variables were further grouped the native MR images were first registered into stereotaxic

Table 1. Demographics and Clinical Characteristics for DS, NDS, and HC Groups

F/χ /t
2
DS （n = 33） NDS (n = 41) HC (n = 41) P-Value

Age (years) 49.03 ± 7.67 45.71 ± 6.64 45.78 ± 9.48 1.97 .145
Education (years) 8.82 ± 2.02△ 9.12 ± 1.82△ 10.54 ± 2.72 6.51 .002
Age at onset (years) 22.03 ± 2.81 22.39 ± 2.66 −0.56 .575
Duration of illness (years) 27.00 ± 6.92* 23.32 ± 6.88 2.28 .025
BPRS total 31.67 ± 2.97** 27.56 ± 2.65 6.29 <.001
Positive syndrome 6.00 ± 1.06 6.41 ± 1.05 −1.68 .097
Negative syndrome 12.33 ± 1.67** 7.46 ± 1.00 14.74 <.001
Disorganized syndrome 6.55 ± 1.37 6.46 ± 0.84 0.32 .752
Affect 6.79 ± 1.19 7.22 ± 1.31 −1.46 .148
SANS total 56.97 ± 8.47** 31.98 ± 6.11 14.73 <.001
SAPS total 8.67 ± 3.76 10.17 ± 4.24 −1.60 .115
SDS total score 11.06 ± 2.52** 4.07 ± 2.42 12.11 <.001
Avolition 5.94 ± 1.56** 2.54 ± 1.52 9.47 <.001
Poor emotional expression 5.12 ± 1.27** 1.54 ± 1.12 12.90 <.001
Smoking ratio (%) 63.60 75.60 1.26 .263
CPZ-equivalent daily dosage (mg/day) 467.73 ± 234.98 527.80 ± 208.14 −1.17 .248

Note: DS, deficit schizophrenia; NDS, nondeficit schizophrenia; HC, healthy controls; BPRS, Brief Psychiatric Rating Scale; SANS, the
Scale for the Assessment of Negative Symptoms; SAPS, the Scale for the Assessment of Positive Symptoms; SDS: the Schedule for the
Deficit Syndrome; CPZ, chlorpromazine; *Vs NDS, P < .05; **Vs NDS, P < .001; △Vs HC, P < .05.

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Table 2. Comparisons of Neurocognitive Domains and Raw Neuropsychological Performance Among DS, NDS, and HC Groups

DS (n = 33) NDS (n = 41) HC (n = 41) F P-Value Cronbach’s Alpha

Sustained vigilance/ −11.02 ± 6.86 −4.04 ± 3.28 — — — 0.789

attention
Digit vigilance test (s) 312.36 ± 161.02**△△ 178.31 ± 66.76 137.82 ± 42.34 24.54 <.001 —
TMT-A (seconds) 132.95 ± 67.68**△△ 81.80 ± 30.95△ 49.31 ± 22.87 27.52 <.001 —
Stroop words only 42.70 ± 18.93**△△ 59.07 ± 16.09△△ 79.15 ± 16.79 33.66 <.001 —
Stroop colors only 26.79 ± 12.63*△△ 35.20 ± 11.14△△ 49.32 ± 13.26 22.92 <0.001 —
Ideation fluency −3.44 ± 1.82 −2.03 ± 2.09 — — — 0.669
COWAT 4.88 ± 3.16*△△ 6.76 ± 3.51△ 9.17 ± 2.33 14.20 <.001 —

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Animal naming test 9.73 ± 3.47*△△ 12.46 ± 4.46△△ 18.41 ± 4.60 33.15 <.001 —
Cognitive flexibility −4.12 ± 2.59 −2.08 ± 1.37 — — — 0.725
TMT-B (s) 304.05 ± 119.44**△△ 199.09 ± 53.33△△ 123.57 ± 63.47 35.97 <.001 —
Stroop interference 17.42 ± 11.08△△ 21.34 ± 8.81△△ 32.32 ± 10.58 15.92 <.001 —
Visuospatial memory −3.72 ± 2.00 −2.11 ± 1.42 — — — 0.681
Spatial processing 11.24 ± 4.39*△△ 13.41 ± 3.35 △△ 18.02 ± 3.46 24.16 <.001 —
(block design)
WAIS-RC (block 13.55 ± 8.87**△△ 21.41 ± 6.55△ 27.73 ± 8.27 21.98 <.001 —
design)

Note: Patients’ neuropsychological test scores were standardized using the healthy control (HC) group data. Sustained vigilance/attention
domain includes Stroop words only and colors only, Trail making test part A and Digit vigilance test. Ideation fluency domain includes
Controlled Oral Word Association test and Animal Naming Test. Cognitive flexibility includes Stroop color/word interference test and
Trail making test part B. Visuospatial memory domain includes Spatial processing test and Wechsler adult intelligence scale (Block
Design, Chinese version). DS, deficit schizophrenia; NDS, non-deficit schizophrenia.*Vs NDS, P < .05;**Vs NDS, P < .001; △Vs HC,
P < .05; △△Vs HC, P < .001.

space39 using a 9-parameter linear transformation.40 each cognitive domain between the 2 patient subgroups
Simultaneously, the images were corrected for nonuniform- were evaluated using effect size estimation (Cohen’s d).
ity artifacts using the N3 algorithms.41 The registered and For all analyses, the significance level was set to P < .05.
corrected images were further segmented into GM, white To detect cortical thickness differences among the 3
matter, CSF, and background using an advanced neural groups, we performed the GLM analysis with age and
net classifier.38 The inner and outer GM surfaces were then education as covariates at 3 scales: the mean thickness,
automatically extracted from each MR volume using the vertex-based, and an ROI-based thickness analysis based
constrained Laplacian-based automated segmentation with on the automated anatomical labeling atlas. For the group
proximities algorithm42,43 and the cortical thickness was main effects from either the vertex-based or ROI-based
measured in native space using the linked distance between GLM analyses, a false discovery rate (FDR) correction
the 2 surfaces at 81 924 vertices (40 962 on each hemisphere) was implemented to correct for multiple comparisons.49
throughout the cortex. The measurement in native space Three contrast tests (DS vs HC, NDS vs HC, and DS vs
provided an unadjusted estimate of the absolute cortical NDS) based on the same model were performed to deter-
thickness.44 Smoothing with 20 mm kernel was then applied mine between-group differences. An FDR correction was
to improve sensitivity.45 The cortical thickness algorithm applied in which the P-values from all 3 comparisons were
was validated using both manual measurements46 and sim- pooled together. The q-value was set to .05. A cluster
ulation approaches.47,48 The surface area was evaluated on size threshold of 30 vertices was then applied to further
a mid-surface, represented as a polyhedral mesh lying right reduce false positive clusters. To remove the effects of ill-
in the middle of the inner and outer GM surfaces. The sur- ness duration and medication dose in the patient groups,
face area on each vertex was defined as a third of the total we applied another GLM to the DS and NDS groups with
area of all the triangles adjoining to it, then smoothed with illness duration and medication dose as additional covari-
a 20 mm kernel. The surface area of a brain region was the ates, followed with an FDR correction at q-value = .05.
sum of all the vertices belonging to it. All the cortical thickness comparisons were conducted
using SurfStat toolbox (http://www.math.mcgill.ca/keith/
surfstat/, Accessed November 12, 2017) and the results
Statistics were visualized using the BrainNet Viewer toolbox.50 For
The continuous and categorical variables were analyzed the surface area measurements, the statistical comparisons
using the general linear model (GLM) and the chi-square were the same as those for the cortical thickness analysis.
test, respectively. Comparisons of clinical symptoms To determine brain-cognitive/clinical relationship,
between the DS and NDS groups were conducted using we performed the GLM analyses using the GRETNA
2 sample t-tests. The differences of composite scores of toolbox.51 For the overlapping regions with significant
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 Cortical Thinning in Deficit Schizophrenia

abnormalities shared by the 2 patient groups, we esti- the NDS and HC groups or between the DS and NDS
mated the relationship across all patients. For the regions groups (P = .16 and .10, respectively). The total sur-
that differed between the DS and NDS groups, we sepa- face area did not differ significantly among the 3 groups
rately estimated the brain-cognition/clinical (including 2 (P = .26).
factors of the SANS: diminished expression and social The vertex-based analyses revealed the main effects of
amotivation) relationships in each group. Age, educa- group (q = .05, FDR-corrected, figure 1A), which was
tion, illness duration, and medication dose were taken as primarily distributed in the bilateral superior temporal
covariates. For details, see supplementary materials. gyri, the bilateral middle temporal gyri, the bilateral infe-
rior frontal gyri, the left Heschl gyrus, the left supramar-
Results ginal gyrus, and the left angular gyrus. Further post hoc
analyses revealed that, compared with the HC group, the

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Demographic and Clinical Characteristics
DS group exhibited widespread cortical thinning, with
Among the 3 groups, the differences in education patterns similar to those observed for the main effects of
(P = .002), but not age (P = .145), were significant group and the NDS patients had thinner cortices in the
(Table 1). Least-significant difference post hoc com- bilateral inferior frontal gyri and the left superior tem-
parisons revealed lower education levels in both the poral areas (supplementary figure S1). Thus, compared
DS (P = .001) and NDS (P = .005) patients relative to to the HC group, the 2 schizophrenia subgroups exhib-
the HCs, whereas the 2 patient subgroups did not dif- ited shared cortical thinning in the bilateral inferior fron-
fer significantly (P = .562). The DS patients exhibited a tal gyrus and the left anterior superior temporal gyrus
longer illness duration (P = .025) and more severe psy- (figure 2, middle row). Notably, the DS group showed
chopathological total symptoms and negative symptoms significant cortical thinning in the left temporo-parietal
(all P < .001) than the NDS patients. For the types of junction (TPJ) (including the angular gyrus, the supra-
antipsychotic drugs, there was no significant difference marginal gyrus, and the posterior superior temporal
between the DS and NDS groups (χ2[2] = 1.163, P = .559) gyrus52) as compared to the NDS group (Figure 3). The
(conventional antipsychotics: 48.5% [n = 16] and 36.6% differences of the TPJ area remained significant after
[n = 15]; novel antipsychotics: 30.3% [n = 10] and 34.1% removing the effects of 4 cognitive domain scores and
[n = 14]; combination: 21.2% [n = 7] and 29.3% [n = 12], clinical evaluations (SAPS, BPRS total score or the pos-
respectively). The mean age of onset, smoking, antipsy- itive syndrome, disorganized syndrome, and affect sub-
chotic medication dose (chlorpromazine equivalents), the scales of BPRS). Finally, the ROI-based analyses results
positive, affect, and disorganized syndromes did not dif- were approximately the same as the vertex-analyses
fer significantly between the 2 patient subgroups. results (Figure 1B; supplementary figure S2 and table S1).

Cognitive Characteristics Surface Area Comparisons

For each neuropsychological test, we observed significant The surface area analysis did not reveal any significant
differences among the 3 groups with age and education difference among the 3 groups after FDR correction.
as covariates (all P < .001, table 2). Least-significant dif-
ference post hoc comparisons indicated that both of the
Correlation Between Cognitive/Clinical Variables and
patient groups performed significantly worse than the
the Morphological Measurements
control group on most of the neuropsychological tests
(all P < .05, except the DVT for NDS vs HC, P = .129). We observed that the mean cortical thickness of the larg-
Moreover, the DS group performed significantly worse est overlapping cluster, which was located in the right
than the NDS group on most neuropsychological meas- inferior frontal gyrus, was positively correlated with cog-
ures (all P < .05, except the Stroop interference for DS vs nitive flexibility (P = .0018) and visuospatial memory
NDS, P = .346). Cronbach’s alpha ranged from 0.669 to performance (P = .00006) (figure 2, bottom row). For the
0.789 in the 4 cognitive domains, indicating relatively high SANS, we only found a trend toward negative correlation
internal consistency among the measures. The Cohen’s d between the TPJ thickness and the social amotivation
effect size ranged from 0.720 to 1.298 in the 4 cognitive factor (P = .09) in the DS group.
domains, indicating that the DS–NDS differences in cog-
nitive performance achieved moderate to large effect sizes. Discussion
The present study explored the cortical abnormalities
Cortical Thickness Comparisons of patients with DS and NDS as well as the relationship
The mean cortical thickness in the whole cortex differed between cortical thickness and cognitive performance.
significantly among the 3 groups (P = .02), with signif- Relative to HCs, both patient groups demonstrated com-
icantly thinner cortices in the DS group than the HC mon cortical thinning in the bilateral inferior frontal and
group (P < .005) and nonsignificant differences between the left superior temporal regions. We also provided the
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Fig. 1. Main effects of group on the cortical thickness (FDR corrected, q < .05). (A) Regions differed among the 3 groups on the vertex
level. (B) Regions differed among the 3 groups on the region of interest level.

first evidence illustrating that the cortical thinning in the revealing the structural changes related to the disease. In
left TPJ is a salient feature in DS as compared with NDS. this study, the thickness in the right orbital frontal region
We observed that the bilateral inferior frontal and left positively correlated with cognitive flexibility and visuo-
superior temporal areas were overlapped regions showing spatial memory performance. Intriguingly, a previous
significant cortical thinning in both of the DS and NDS study found correlation between the GM density in the
subgroups relative to the HC subjects. Our findings are right inferior frontal region and the cognitive flexibility.71
in agreement with previous morphological studies reveal- Another study demonstrated an activation in the right
ing cortical thinning in the orbitofrontal, inferior fron- orbitofrontal area in the process of memory formation.72
tal,8,53–61 and the superior temporal regions17,53,56–58,62–64 in Our findings implied that the cortical thinning in the infe-
schizophrenia. A previous study of cortical thickness in rior frontal and the superior temporal regions are a com-
DS and NDS found that the patient groups shared nearly mon feature of the clinical syndrome of schizophrenia
the same cortical thinning pattern, involving the bilateral and may contribute to the cognitive impairments, regard-
temporal and inferior frontal areas, which is similar to less of different subtypes of the disease.
our results.22 Volumetric studies of DS and NDS patients Importantly, we showed distinct cortical thinning
also identified the frontal and temporal lobes as regions patterns in the left TPJ between DS and NDS patients.
preferentially affected by the 2 subtypes of schizophre- Different from our findings, Voineskos et al22 did not
nia.10–14,65 Considering that the current study and other report significant differences when they directly compared
surface-based studies comparing patients with DS and the cortical thickness between DS and NDS patients. This
NDS and HCs21,22 did not find any significant difference result discrepancy between the previous work and our
in surface area, cortical thickness measurement may play study might be due to several methodological differences:
a vital role in describing neuroanatomical signatures the magnetic field strength of the MRI scanning (1.5T
in schizophrenia of different subtypes. Rimol and col- vs 3.0T), the criteria classifying DS/NDS patients (PDS
leagues also demonstrated that cortical thinning rather [the proxy for the deficit syndrome] vs SDS) and the com-
than surface contraction mainly drives the volume reduc- position of subjects (gender [14 males and 4 females for
tions in schizophrenia.19 Cortical thickness and surface each group vs all male participants] and ethnicities [both
area reveal different neurophysiological information,16–18 Caucasians and non-Caucasians vs Chinese]). Although
have distinct genetic origins66,67 and different develop- still controversial, it has been previously reported that
mental trajectories.68–70 These 2 relatively independent DS patients exhibit decreased temporal GM volumes11,12
structural features of the cortex may respond differently and an increased left temporal CSF volume,4 compared
to the undergoing pathological process of schizophrenia, with NDS patients. Previous studies also demonstrated
which might account for their different capabilities in that schizophrenia patients with more severe negative
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Fig. 2. Regions showing common cortical thinning in the 2 patient groups comparing with the healthy control on the vertex level (false
discovery rate corrected, q < .05). Box-plots on the top showed the distribution of mean thickness within corresponding cluster. The
bottom shows the correlation between the mean thickness of the right inferior frontal region and cognitive flexibility and visuospatial
memory scores. Red circles and blue triangles referred to deficit schizophrenia and nondeficit schizophrenia patients, respectively.

symptoms suffered more severe brain atrophy in the left persons’ mental states.”73 It has been shown previously
temporal lobe,4,6 which provided further support for our that compared to HCs, activation in left TPJ is abnormal
result. One particularly interesting finding here was that in schizophrenia patients during various ToM tasks.74–83
the cortical reduction was apparent predominantly in the Previous studies have also demonstrated an association
left TPJ. Notably, the TPJ is a critical region of the theory between performance in ToM tasks and the severity of
of mind (ToM), a social cognitive construct referring to negative symptoms.84–89 These findings implied that the
“the ability to make inference upon one’s own and other dysfunction of the left TPJ may be more related to the
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patients.22,94 These findings indicate that DS patients with

the primary negative symptoms might show abnormal
brain connectivity, which needs to be explored in the
future. Finally, the current study lacked social cognitive
tests. Future studies with more comprehensive cognitive
evaluations would help understanding the brain–cogni-
tion relationship in patients with DS and NDS.

Supplementary Material
Supplementary data are available at Schizophrenia

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Fig. 3. Regions showing cortical thinning in deficit schizophrenia Bulletin online.
than nondeficit schizophrenia groups on the vertex level (false
discovery rate corrected, q < .05).
Funding
deficit type of schizophrenia. There are also evidences
This study was supported by the National Natural
showing the involvement of the left TPJ in various pro-
Science Foundation of China (81620108016, 91432115,
cesses such as eye gaze perception and representation90
81571314, and 81371474), the National Key Research
and affective prosody perception.91 Cortical thickness
and Development Program (2016YFC1307000), the
abnormalities in the left TPJ might interfere these func-
Beijing Natural Science Foundation (Z161100004916027,
tions and result in difficulties in social activities, which
Z161100000216152, and Z151100003915082), the
was supported by our finding of a negative association
Fundamental Research Funds for the Central Universities
trend between the TPJ thickness and the social amotiva-
(2015KJJCA13 and 2017XTCX04), Nanjing Technology
tion factor of SANS in the DS group. Furthermore, a
Development Foundation (201505001), and the Six Talent
more severe TPJ (the angular gyrus and the supramar-
Peaks Project in Jiangsu Province (2015-WSN-071).
ginal gyrus) hypometabolism was also observed in DS
than in NDS patients.92 Finally, transcranial magnetic
stimulation on the left TPJ area could alleviate negative Acknowledgment
symptoms of schizophrenia patients.93 In summary, our
results suggest that the cortical thickness abnormalities The authors declared no conflicts of interest.
in TPJ were related to the negative symptoms but not to
the cognitive impairments in DS patients. The biological
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