ARTICLES
Cortical Abnormalities Associated With Pediatric
and Adult Obsessive-Compulsive Disorder: Findings
From the ENIGMA Obsessive-Compulsive Disorder
Working Group
Premika S.W. Boedhoe, M.Sc., Lianne Schmaal, Ph.D., Yoshinari Abe, M.D., Pino Alonso, M.D., Ph.D.,
Stephanie H. Ameis, M.D., M.Sc., Alan Anticevic, Ph.D., Paul D. Arnold, M.D., Ph.D., Marcelo C. Batistuzzo, Ph.D.,
Francesco Benedetti, M.D., Jan C. Beucke, Ph.D., Irene Bollettini, Ph.D., Anushree Bose, M.A., Silvia Brem, Ph.D.,
Anna Calvo, M.Sc., Rosa Calvo, M.D., Ph.D., Yuqi Cheng, Ph.D., Kang Ik K. Cho, Ph.D., Valentina Ciullo, Ph.D.,
Sara Dallaspezia, M.D., Damiaan Denys, M.D., Ph.D., Jamie D. Feusner, M.D., Kate D. Fitzgerald, M.D., Jean-Paul Fouche, Ph.D.,
Egill A. Fridgeirsson, M.Sc., Patricia Gruner, Ph.D., Gregory L. Hanna, M.D., Derrek P. Hibar, Ph.D.,
Marcelo Q. Hoexter, M.D., Ph.D., Hao Hu, Ph.D., Chaim Huyser, M.D., Ph.D., Neda Jahanshad, Ph.D., Anthony James, M.D.,
Norbert Kathmann, Ph.D., Christian Kaufmann, Ph.D., Kathrin Koch, Ph.D., Jun Soo Kwon, M.D., Ph.D.,
Luisa Lazaro, M.D., Ph.D., Christine Lochner, Ph.D., Rachel Marsh, Ph.D., Ignacio Martínez-Zalacaín, M.Sc.,
David Mataix-Cols, Ph.D., José M. Menchón, M.D., Ph.D., Luciano Minuzzi, M.D., Ph.D., Astrid Morer, M.D., Ph.D.,
Takashi Nakamae, M.D., Ph.D., Tomohiro Nakao, M.D., Ph.D., Janardhanan C. Narayanaswamy, M.D., Seiji Nishida, M.D., Ph.D.,
Erika Nurmi, M.D., Ph.D., Joseph O’Neill, Ph.D., John Piacentini, Ph.D., Fabrizio Piras, Ph.D., Federica Piras, Ph.D.,
Y.C. Janardhan Reddy, M.D., Tim J. Reess, M.A., Yuki Sakai, M.D., Ph.D., Joao R. Sato, Ph.D., H. Blair Simpson, M.D., Ph.D.,
Noam Soreni, M.D., Carles Soriano-Mas, Ph.D., Gianfranco Spalletta, M.D., Ph.D., Michael C. Stevens, Ph.D.,
Philip R. Szeszko, Ph.D., David F. Tolin, Ph.D., Guido A. van Wingen, Ph.D., Ganesan Venkatasubramanian, M.D., Ph.D.,
Susanne Walitza, M.D., M.Sc., Zhen Wang, M.D., Ph.D., Je-Yeon Yun, M.D., Ph.D., ENIGMA-OCD Working Group,
Paul M. Thompson, Ph.D., Dan J. Stein, M.D., Ph.D., Odile A. van den Heuvel, M.D., Ph.D.
Objective: Brain imaging studies of structural abnormalities
in OCD have yielded inconsistent results, partly because of
limited statistical power, clinical heterogeneity, and methodological differences. The authors conducted meta- and
mega-analyses comprising the largest study of cortical
morphometry in OCD ever undertaken.
Method: T1-weighted MRI scans of 1,905 OCD patients and
1,760 healthy controls from 27 sites worldwide were processed locally using FreeSurfer to assess cortical thickness
and surface area. Effect sizes for differences between patients
and controls, and associations with clinical characteristics,
were calculated using linear regression models controlling
for age, sex, site, and intracranial volume.
Results: In adult OCD patients versus controls, we found a
significantly lower surface area for the transverse temporal
cortex and a thinner inferior parietal cortex. Medicated adult
OCD patients also showed thinner cortices throughout
Disease models of obsessive-compulsive disorder (OCD) propose that abnormalities in the cortico-striato-thalamo-cortical
circuits are key to the pathophysiology of OCD. Recent findings
Am J Psychiatry 175:5, May 2018
the brain. In pediatric OCD patients compared with
controls, we found significantly thinner inferior and superior parietal cortices, but none of the regions analyzed
showed significant differences in surface area. However,
medicated pediatric OCD patients had lower surface area
in frontal regions. Cohen’s d effect sizes varied from 20.10
to 20.33.
Conclusions: The parietal cortex was consistently implicated
in both adults and children with OCD. More widespread cortical
thickness abnormalities were found in medicated adult OCD
patients, and more pronounced surface area deficits (mainly in
frontal regions) were found in medicated pediatric OCD patients.
These cortical measures represent distinct morphological
features and may be differentially affected during different
stages of development and illness, and possibly moderated
by disease profile and medication.
Am J Psychiatry 2018; 175:453–462; doi: 10.1176/appi.ajp.2017.17050485
also implicate the involvement of fronto-limbic and frontoparietal regions in pediatric and adult OCD (1–3). An important
limitation of brain imaging research is the typically small
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CORTICAL ABNORMALITIES ASSOCIATED WITH OCD
samples that limit sensitivity and presumably contribute to
the lack of reproducibility and reliability of findings (4).
This issue may be partially addressed by the use of meta- and
mega-analysis of multiple study samples. We therefore initiated
the OCD working group within the Enhancing Neuro-Imaging
Genetics Through Meta-Analysis (ENIGMA) consortium (5), in
which researchers around the world collaborate to boost
statistical power, with the aim of elucidating brain abnormalities in OCD.
We recently performed meta- and mega-analyses on data
from 3,589 individuals and reported (6) subcortical volume
differences between OCD patients and healthy controls that
were related to clinical characteristics. Distinct subcortical
volume abnormalities were detected in adults and children
with OCD. Adult OCD patients had significantly smaller
hippocampal and larger pallidal volumes. The smaller hippocampal volume seemed to be driven by comorbid depression
and an adult illness onset. The larger pallidal volume was more
pronounced in adult OCD patients who had a childhood
illness onset. Children with OCD had larger thalamic volumes
compared with control children.
With regard to the cortex, previous MRI studies have
consistently shown abnormalities in dorsomedial prefrontal
and anterior cingulate cortices (7–10), findings that are supported by mega-analyses from the OCD Brain Imaging Consortium (OBIC) (11, 12). Abnormalities in the fronto-parietal
and temporo-parietal regions have also been reported (10,
12–14). Findings regarding the orbitofrontal cortex (8, 11, 15)
and the operculum have been inconsistent (8, 10, 11, 13, 16).
These inconsistencies may be partially explained by differences in processing protocols, limited statistical power, and
clinical heterogeneity related to variation in disease profile and
developmental stage.
Most of these studies were predominantly based on volumetric measures using voxel-based morphometry (VBM).
Volumetric measures, however, depend on a combination of
changes in gray matter thickness and surface area (17). Fewer
studies have used surface-based methods to generate detailed
maps of cortical thickness and surface area. These measures
represent distinct features of cortical morphometry that are
somewhat genetically independent and are driven by different
neurobiological processes (18). Studying these properties independently will make it easier to interpret the cortical abnormalities reported in OCD in the context of the postulated
neurodevelopmental basis for OCD (19) (see Supplementary
Section S1 in the data supplement that accompanies the online
edition of this article).
Here we performed the largest coordinated worldwide study
to date of cortical measures in patients with OCD compared
with healthy controls. We extracted cortical thickness and
surface area estimates of 1,905 patients with OCD and 1,760
healthy control subjects, using harmonized data processing
and analysis strategies across 27 sites. We also aimed to establish the potential modulating effects of demographic and
clinical characteristics. Based on the literature, we expected
lower cortical thickness in the anterior cingulate cortex,
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orbitofrontal cortex, dorsomedial prefrontal cortex, and parietal regions in OCD patients compared with healthy controls.
In addition, we explored the cortical surface area profile in the
OCD sample.
METHOD
Samples
The ENIGMA-OCD working group includes 38 data sets from
27 international research institutes, with neuroimaging and
clinical data from OCD patients and typically developing healthy
control subjects (i.e., free of psychopathology), including both
children and adults (for a map showing site location, see Figure S1
in the online data supplement). Six of these 38 data sets (the
entire OBIC sample) were identical to those included in the
OBIC mega-analyses using VBM (11) and vertex-based FreeSurfer
(12). We defined adults as individuals age 18 years and older
and children as individuals under age 18 years. The split at
age 18 followed from a natural selection of the age ranges
used in these samples, as most samples used age 18 as a cutoff
for inclusion. The samples’ respective demographic and
clinical characteristics are detailed in Tables S1 and S2 in the
data supplement. In total, we analyzed data from 3,665 subjects, including 1,905 OCD patients (407 children and 1,498
adults) and 1,760 control subjects (324 children and 1,436
adults). All local institutional review boards permitted the
use of measures extracted from the anonymized data for
mega-analyses.
Image Acquisition and Processing
Structural T1-weighted MRI brain scans were acquired and
processed locally. Image acquisition parameters for each site are
listed in Table S3 in the data supplement. All cortical parcellations were performed with the fully automated segmentation
program FreeSurfer, version 5.3 (20), following standardized
ENIGMA protocols to harmonize analyses and quality control
procedures across multiple sites (see http://enigma.usc.edu/
protocols/imaging-protocols/). Segmentation of 68 (34 left and
34 right) cortical gray matter regions based on the DesikanKilliany atlas (21), and two whole-hemisphere measures were
visually inspected and statistically evaluated for outliers. Details
on image exclusion criteria and quality control are presented in
Supplementary Section S1 in the data supplement.
Statistical Analysis
We performed both a meta-analysis (i.e., using group statistics
from the independent studies) and a mega-analysis (i.e., pooling
extracted measures from individual subjects across sites,
while adjusting for site effects) to be consistent with our previous report. In this report, we focus on the mega-analysis;
for methods, results, and discussion of the meta-analysis, see
Supplementary Section S3 in the data supplement.
We examined differences between OCD patients and controls within a mega-analytical framework by pooling the
extracted cortical thickness and surface area measures from
each site. Each of the 70 cortical regions of interest (68 regions
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BOEDHOE ET AL.
and two whole-hemisphere average thickness or total surface
area measures) served as the outcome measure and a binary
indicator of diagnosis as the predictor of interest in multiple
linear regression models. All cortical thickness models were
adjusted for age and sex; cortical surface area models were
corrected for intracranial volume (see Supplementary Section
S1 in the data supplement), age, age-squared, sex, age-by-sex
interaction, and age-squared-by-sex interaction, to account for
any higher-order effects on cortical surface area of age and sex
as well as head size, which do not appear to be detectable for
cortical thickness measures (22). Additionally, all models were
also adjusted for site, coded by using dummy variables. Effect
size estimates were calculated using Cohen’s d, computed from
the t statistic of the diagnosis indicator variable from the
regression models. Similarly, for models testing interactions
(i.e., sex-by-diagnosis interaction and age-by-diagnosis interaction), a multiplicative predictor was the predictor of
interest, with the main effect of each predictor included in
the model. The effect size was calculated using the same
procedure.
To detect potentially different effects of disease with age,
we performed all analyses separately for pediatric and adult
participants. We performed stratified analyses comparing
the medicated and unmedicated groups of OCD patients
separately to controls and to each other. Likewise, stratified
analyses were performed to investigate the effect of comorbid
major depressive disorder, comorbid anxiety disorders, and
OCD symptom dimensions (using the adult and child versions
of the Yale-Brown Obsessive Compulsive Scale [YBOCS]
[23, 24] symptom checklist; see Supplementary Section S2
in the data supplement). To study the neurodevelopmental
aspects of illness within the adult samples, we performed
separate stratified analyses comparing childhood-onset OCD
patients (onset before age 18) and adult-onset OCD patients
(onset at age 18 or later). Furthermore, we examined associations with age at onset, illness duration, and illness severity
(using the total severity score from the YBOCS) as continuous
variables. In these analyses, effect sizes were expressed as
partial-correlation Pearson’s r after removing nuisance
variables (age, sex, site, and intracranial volume). In all
tables (see the data supplement), regions are listed in order of
effect size (strongest to weakest). Throughout, we report
p values corrected for multiple comparisons using the BenjaminiHochberg procedure to ensure a false discovery rate limited
to 5% (q=0.05) for 70 cortical measures.
RESULTS
An overview of the demographic and clinical characteristics
of the pooled samples is provided in Table 1.
Mega-Analysis
Cortical thickness and surface area differences between OCD
patients and controls.
Adults: Lower cortical thickness was observed in adult
OCD patients (N=1,498) compared with controls (N=1,436) in
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the inferior parietal cortex bilaterally (effect size [Cohen’s d]=
20.14) (Figure 1; see also Table S4 in the data supplement). A
lower surface area was observed in the left transverse temporal cortex (Cohen’s d=20.16) (see Table S5 and Figure S2 in
the data supplement). None of the regions showed significant
sex-by-diagnosis or age-by-diagnosis interaction effects.
Children: We found significantly thinner cortices in pediatric OCD patients (N=407) compared with controls (N=324)
in the left and right superior parietal and the left inferior
parietal cortices (Figure 2) and the left lateral occipital cortex
(Cohen’s d values between 20.24 and 20.31) (see Table S6 in
the data supplement). None of the regions analyzed showed
significant differences in cortical surface area or evidence of
sex-by-diagnosis or age-by-diagnosis interaction effects (see
Table S7 in the data supplement).
Influence of medication on cortical thickness and surface area.
Adults: Left and right hemisphere cortical thickness was
lower in medicated OCD patients (N=646) compared with
controls (N=1,436). Regionally, we found significantly thinner
cortices in frontal, temporal, parietal, and occipital regions of
adult medicated OCD patients (Cohen’s d values between
20.10 and 20.26) (Figure 3; see also Table S8a in the data
supplement). We did not detect significant differences in
cortical thickness in unmedicated OCD patients (N=831) compared with controls (see Table S8b in the data supplement).
Medicated OCD patients compared with unmedicated patients showed lower cortical thickness in frontal, temporal,
and parietal regions (Cohen’s d values between 20.13 and 20.21)
(see Table S8c and Figure S3 in the data supplement). Similar to
the main group comparison, we found a lower surface area for
the left transverse temporal cortex in medicated OCD patients
compared with controls (Cohen’s d=20.20) (see Table S9a and
Figure S4 in the data supplement). We did not detect differences
in surface area in unmedicated OCD patients compared with
controls and when we compared medicated and unmedicated
patients directly (see Table S9b,c in the data supplement).
Children: Compared with controls (N=324), medicated children with OCD (N=183) showed lower cortical thickness of the
inferior parietal and superior parietal cortices bilaterally and the
left lateral occipital cortex (Cohen’s d20.31) (see Table S10a
and Figure S5 in the data supplement). We did not detect
significant differences in cortical thickness in unmedicated
pediatric OCD patients (N=222) compared with controls or
when we compared medicated with unmedicated patients
(seeTableS10b,c).Morewidespreadsurfaceareadifferenceswere
detected when we compared medicated pediatric OCD patients
and controls, mainly in several frontal regions (Cohen’s d values
between 20.27 and 20.33) (Figure 4; see also Table S11a in
the data supplement). No differences in surface area were
observed when we compared unmedicated patients and
controls (see Table S11b). We did observe a lower surface area
for the right lingual (Cohen’s d=20.34) and pericalcarine
(Cohen’s d=20.40) cortices in medicated compared with unmedicated pediatric OCD patients (see Table S11c and Figure S6
in the data supplement).
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TABLE 1. Demographic and Clinical Characteristics of Patients With Obsessive-Compulsive Disorder (OCD) and Control Subjects in a
Mega-Analysis of Cortical Abnormalities
Characteristic
Age (years)
OCD illness severity scoreb
Age at onset of clinical symptoms (years)
Male
Medication use at time of scan
Current comorbid disorders
Anxiety disorder
Major depression
Tourette’s disorderc
Attention deficit hyperactivity
disorderc
Autism spectrum disorderc
OCD symptom dimensionsd
Aggressive/checking
Contamination/cleaning
Symmetry/ordering
Sexual/religious
Hoarding
Adult OCD Patients
(N=1,498)
Adult Healthy
Controls (N=1,436)
Pediatric OCD
Patients (N=407)
Pediatric Healthy
Controls (N=324)
Mean
SD
Mean
SD
Mean
SD
Mean
SD
32.1a
24.4
19.8
9.7
6.9
9.1
30.5a
9.7
13.8
21.4
10.6
2.5
7.3
3.1
13.6
2.6
N
%
N
%
N
%
N
%
756
646
50.5
43.1
713
49.7
220
183
54.1
45.0
164
50.6
224
167
24
13
15.0
11.1
1.6
0.9
132
29
30
42
32.4
7.1
7.4
10.3
0
0.0
5
1.2
927
791
640
487
379
61.9
52.8
42.7
32.5
25.3
195
172
181
92
92
47.9
42.3
44.5
22.6
22.6
a
Significant difference between groups (t=–4.222, df=2932, p,0.001).
As indicated by total score on the adult and child versions of the Yale-Brown Obsessive Compulsive Scale (YBOCS).
c
Not assessed in all samples.
d
As measured with the YBOCS symptom checklist.
b
Influence of comorbidities on cortical thickness and surface
area. We did not detect any associations between cortical
thickness or surface area and current comorbid depression or anxiety disorder in adults (N=167 and N=224, respectively) or in children (N=29 and N=132, respectively).
These numbers, however, are too small because of the lack
of systematic assessment of comorbidities in some samples, and they reflect an underestimation of comorbidity
because of exclusion of comorbid cases in other samples.
For full details, see Supplementary Section S4 in the data
supplement.
Influence of symptom dimensions on cortical thickness and
surface area.
Adults: Regression analyses on OCD patients’ symptom dimensions (N=1,214) showed no associations between the presence of a particular symptom dimension and cortical thickness
or surface area within any of the regions.
Children: In pediatric OCD patients with ordering and symmetry symptoms (N=181), the surface area of the left cuneus
was higher (Cohen’s d=0.49) (see Table S20 and Figure S7 in
the data supplement). None of the regions analyzed showed
significant differences in cortical thickness or evidence of associations with the other symptom dimensions.
Influence of age at onset and illness duration on cortical
thickness and surface area. Adult OCD patients who had an
adult illness onset (N=775), compared with controls (N=1,436),
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showed thinner cortices in the left and right hemisphere
overall. Regionally, we observed thinner cortices in frontal
and temporal regions of adult-onset patients (Cohen’s d values
between 20.11 and 20.16) (see Table S21a and Figure S8 in the
data supplement). We also found lower surface areas for the
left transverse temporal cortex (Cohen’s d=20.17) and the left
pars opercularis (Cohen’s d=20.14) in OCD patients who had
an adult illness onset (see Table S22a and Figure S9 in the
data supplement). We did not detect significant differences
in cortical thickness or surface area in adult OCD patients who
had a childhood illness onset (N=646) compared with controls, or when we compared adult-onset and childhood-onset
patients directly (see Table S21b,c and Table S22b,c in the
data supplement).
Furthermore, we did not observe any significant linear
(see Tables S23–S26 in the data supplement) or quadratic (see
Tables S37–S40 in the data supplement) associations between age at onset or illness duration as continuous variables
and cortical thickness or surface area changes in the adult
(N=1,419) or pediatric (N=708) OCD groups.
Association between illness severity and cortical thickness and
surface area. We did not detect any significant linear (see
Tables S27 and S28 in the data supplement) or quadratic (see
Tables S41 and S42 in the data supplement) associations in
either the adult (N=1,453) or the pediatric (N=404) OCD patients between illness severity (YBOCS) and cortical thickness or surface area.
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BOEDHOE ET AL.
0.15
0.10
0.05
FIGURE 2. Mega-Analysis Effect Sizes for Regions That Showed a
Significant (q<0.05) difference in Cortical Thickness Between
Pediatric OCD Patients and Healthy Controlsa
0.15
Left Hemisphere
Left Hemisphere
FIGURE 1. Mega-Analysis Effect Sizes for Regions That Showed a
Significant (q<0.05) difference in Cortical Thickness Between Adult
OCD Patients and Healthy Controlsa
0.10
0.05
–0.05
–0.10
–0.15
0.00
Right Hemisphere
Right Hemisphere
0.00
Negative effect sizes (shown in red) indicate thinner cortices in OCD
patients compared with controls.
Meta-Analysis
Decreased cortical thickness of the inferior parietal cortex was
present in adult patients with OCD compared with healthy
controls, but at a less stringent significance threshold (Cohen’s
d20.14; p,0.01, uncorrected). The meta-analysis did show
significant widespread effects of medication on cortical thickness and a lower surface area for the transverse temporal
cortex in adult OCD patients. The pediatric meta-analysis, also
at a less stringent significance threshold (Cohen’s d20.31;
p,0.05, uncorrected), showed decreased cortical thickness of
the inferior and superior parietal cortex in children with OCD.
In addition, scanner field strength did not significantly explain
the effect size estimates of cortical thickness or surface area
differences in adult and pediatric OCD patients compared
with controls (see Supplementary Section S3 in the data
supplement).
DISCUSSION
Cortical Thickness
This is the largest neuroimaging study conducted on cortical
measures in OCD to date. We found that the parietal cortex was
consistently implicated in both adult and pediatric OCD, which
is consistent with previous VBM and FreeSurfer studies (12,
25). Lower cortical thickness of the inferior parietal cortex in
adult OCD patients compared with controls is in accordance
with results reported by Kühn et al. (10) and the OBIC consortium (12). Lower cortical thickness of the inferior and superior parietal cortex in children with OCD is a novel finding.
The only other study of cortical thickness in pediatric OCD
that we are aware of found lower cortical thickness for another parietal region, the supramarginal gyrus (26). Other
imaging studies have reported lower gray matter volume in
the parietal lobe, especially in the angular gyrus of the inferior
parietal lobe, in children and adults with OCD (25, 27).
In contrast with previous mega-analyses from the OBIC
consortium, we did not find cortical thickness abnormalities
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–0.10
–0.15
Cohen's d
Cohen's d
a
–0.05
a
Negative effect sizes (shown in red) indicate thinner cortices in OCD
patients compared with controls.
in the orbitofrontal cortex, anterior cingulate cortex, or
dorsomedial prefrontal cortex. Six of our 38 data sets (the
entire OBIC sample) were identical to those included in the
OBIC mega-analysis. Apart from a much larger sample size
and the inclusion of samples from more countries, no discrepancies between demographic and clinical characteristics
could be found between this sample and the OBIC sample.
Thus, these inconsistencies likely reflect differences in analytical methods and the overall sample size. While FreeSurfer
measures thickness and surface area separately, it segments
whole structures based on probabilistic information from a
predefined atlas (20), compared with VBM’s voxel-wise registration (28). It is mainly global or regional differences in
structure that can be inferred from these atlas-based FreeSurfer analyses, as opposed to local morphology, as with VBM.
Moreover, the OBIC consortium’s FreeSurfer mega-analysis
(12) was conducted using vertex-based analyses rather than the
atlas-based approach we used in the present study. It is thus
possible that certain abnormalities on the vertex level are not
detectable when data are averaged across whole regions (29).
Notably, the OBIC sample included only 1.5-T scans and was
processed using an earlier version of FreeSurfer (version 4.5).
Further research using higher-resolution parcellation (such as
that described in reference 30) is necessary to validate our
results.
In this study, we had sufficient statistical power to detect
subtle cortical abnormalities in OCD (Cohen’s d values, 20.15
to 20.31) (see Supplemental Section S5 in the data supplement). Large-scale studies such as ours are well powered to
distinguish consistent, generalizable findings from false positives. Structural MRI provides a crude and indirect measure of
putative alterations at the molecular level, but these subtle
abnormalities in the parietal cortex may still be relevant from
a pathophysiological perspective (31). These results provide
insight into what systems are affected, which can promote further research to evaluate specific pathways implicated in the
pathophysiology of OCD.
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CORTICAL ABNORMALITIES ASSOCIATED WITH OCD
Left Hemisphere
0.15
0.10
0.05
FIGURE 4. Mega-Analysis Effect Sizes for Regions That Showed a
Significant (q<0.05) Difference in Cortical Surface Area Between
Medicated Pediatric OCD Patients and Healthy Controlsa
Left Hemisphere
FIGURE 3. Mega-Analysis Effect Sizes for Regions That Showed a
Significant (q<0.05) Difference in Cortical Thickness Between
Medicated Adult OCD Patients and Healthy Controlsa
–0.15
Cohen's d
Negative effect sizes (shown in red, orange, and yellow) indicate thinner
cortices in OCD patients compared with controls.
Neuroimaging studies of normal brain maturation demonstrate a continuous increase in parietal thickness, reaching
peak values around age 12, followed by a steady decrease over
subsequent decades (32). In terms of neurodevelopmental
abnormalities, our results may be cautiously interpreted as
evidence for a relationship between the expression of OCD
and disturbances in factors influencing radial cortical expansion, which influences gray matter thickness, rather than
factors influencing the tangential expansion that determines
the overall surface area (33). In this context, our results could
indicate an altered cortical maturation in OCD resulting in a
thinner parietal cortex in early childhood that persists into
adulthood, although further confirmatory work using longitudinal samples is needed.
Cognitive studies in OCD suggest that the parietal cortex
plays a significant role in accounting for the cognitive deficits
seen in OCD patients. Parietal lobe activation may be related
to attention, set shifting, planning, and response inhibition,
which are also reported to be impaired in OCD patients (34)
and reflect a lack of cognitive flexibility that may be related to
the repetitive nature of OCD symptoms and behaviors. The
inferior parietal cortex is an important node in both the frontoparietal network and the default mode network. Several studies
have reported altered connectivity within these networks in patients with OCD (35–37). The phenomenology of the disorder is
consistent with the idea of a disrupted relationship between
ongoing internal thought and external information, in that
patients often focus excessively on internally generated fears
that are inconsistent with evidence present in the external
environment (38).
We reported lower cortical thickness of numerous regions
throughout the brain in medicated adult OCD patients. These
medication effects partially overlap with those reported in
previous research (12). Although these findings need to be
interpreted with caution, it has been suggested that antidepressants may modulate plasticity in the brain (39). Additionally, post hoc analyses suggest that these medication
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Right Hemisphere
Right Hemisphere
a
–0.10
0.10
0.05
0.00
0.00
–0.05
0.15
–0.05
–0.10
–0.15
Cohen's d
a
Negative effect sizes (shown in red) indicate reduced cortical surface
area in OCD patients compared with controls.
effects are strongest in those patients taking antidepressants
with adjuvant antipsychotics (see Table S36a–c and Supplementary Section S4 in the data supplement). Alternatively,
those patients taking medication could represent a more clinically severe cohort that manifests these morphometric abnormalities. The results may have been confounded by a higher
illness severity and a higher percentage of comorbid depression in the medicated adult OCD group (see Table S35 in
the data supplement). However, results of post hoc analyses
comparing the most severe (YBOCS score .30) unmedicated
OCD patients with controls did not show the same pattern of
medication effects. Nevertheless, the cortical abnormalities in
currently medicated OCD patients could reflect persistent
abnormalities related to greater OCD severity before treatment. In addition, medication effects persisted after adding a
covariate correcting for illness severity (data not shown).
The lack of association between severity according to the
YBOCS and cortical measures could be due to medication reducing the symptom severity. Additionally, current symptom
severity may not be an optimal measure for capturing the longterm disease severity.
With regard to retrospectively ascertained age at onset in
adult patients, the lack of inferior parietal abnormalities in
the adult sample with childhood onset might be explained by
insufficient power. When looking at the effect sizes, decreased
cortical thickness of the inferior parietal cortex was present in
adult patients with a childhood onset compared with healthy
controls, but at a less stringent significance threshold. The
effect size was even slightly larger than that of the main group
comparison, suggesting a power issue rather than a lack of
inferior parietal abnormalities. In contrast, adult illness onset
was associated with widespread thinner cortices. The adultonset group is older than the childhood-onset group but also
has a higher percentage of medicated patients. Post hoc analyses showed that these effects mostly disappear when medication status is corrected for, suggesting that these findings
are driven mainly by medication.
Am J Psychiatry 175:5, May 2018
BOEDHOE ET AL.
Cortical structural deficits were not associated with
comorbid depression or anxiety. The effect sizes of these small
subgroups with comorbid anxiety or depression indicate insufficient statistical power to address this issue with certainty.
From a clinical point of view, comorbid Tourette’s syndrome
and attention deficit hyperactivity disorder are more relevant to study in children with OCD. Because of the lack of
systematic clinical investigation of comorbidities, we were
unable to investigate this. Common comorbidities may be
more aptly termed interacting variables, as they interact in
complex ways. Therefore, excluding comorbid conditions
will ignore complex interactions that are often integral to the
disorder.
Surface Area
The transverse temporal cortex surface area deficit was consistent across analyses in adult OCD. This region belongs
to the primary auditory cortex and has not been implicated
in OCD pathophysiology before. Lower cortical thickness
and lower volume of this region have been associated with
auditory hallucinations in schizophrenia (40). Previous attempts to detect structural alteration in this region may have
been hampered by small samples or the modest sensitivity
of conventional volumetric approaches. The advantage of
high statistical power allows us to examine abnormalities
throughout the brain without the need to prespecify regions
of interest and thus to identify new regions putatively associated with the disorder. Further research is necessary to
understand the involvement of the transverse temporal
cortex in OCD.
Medicated children with OCD had smaller left and right
hemisphere total surface area, reflecting a diffuse pattern
of frontal surface area deficits. These findings cannot be
explained by differences in illness severity, comorbidity, or
age at onset (see Table S35 in the data supplement). This
may indicate delayed cortical maturation, although longitudinal studies are needed to prove that. The surface area
of these frontal regions matures over a more prolonged interval during adolescence (41) and may be especially prone to a
maturational delay in pediatric OCD, possibly affected by
medication status. Such delayed maturation may alter functional connections with other regions through decreases in
growth and branching of dendritic trees and the number of
synapses associated with gray matter volume (42), which
may persist into adult OCD even if surface area measures
normalize after the transition to adulthood. The absence of
cortical surface area abnormalities in the adult OCD patients
who had a childhood onset could indicate such normalization.
Limitations
We used existing data across samples worldwide, and the data
collection protocols were not prospectively harmonized.
Imaging acquisition protocols and clinical assessments therefore differed across studies, which limits analysis of sources
of heterogeneity. We note also that the T1-weighted scans
were not collected with direct measures of head motion, which
Am J Psychiatry 175:5, May 2018
may have introduced potential motion-induced bias in cortical measures (43).
In addition, FreeSurfer measurements may benefit from
manual edits if they are made consistently across all scans.
Although we had an extensive standardized protocol for
quality checking, the individual sites did not perform manual
editing, as this could have resulted in increased variation in
the data across sites because of the high number of sites
involved.
We reported widespread medication effects in both adults
and children with OCD. However, the present study did not
allow a reliable investigation of medication effects because of
its cross-sectional design and a lack of detailed information on
history, type, dosage, and duration of psychotropic medication treatment. Our results must therefore be interpreted
with caution, and we cannot make any conclusions about the
effect of anti-OCD medication. Further efforts, such as intervention studies with comparisons before and after medication, are required to draw valid conclusions on the impact of
medication use on cortical structure.
Several studies using a symptom dimensional approach
suggest that symptom dimensions may be mediated by partially distinct neural systems (44, 45). Except for the association between a higher surface area of the left cuneus and
ordering/symmetry dimension in children, we did not detect
thickness or surface area effects of the other symptom dimensions in children and adults. An explanation may be that
symptom subtype differences are more focal and remain
undetected in this atlas-based analysis. On the other hand,
variance in use of instruments across the participating sites
may have led to suboptimal harmonization of the symptom
dimension scores, which in turn may explain the absence of
associations with symptom dimensions in our study. During
harmonization, we defined symptom dimensions in a binary
manner as absent or present for each participant based on the
YBOCS symptom checklist, whereas previous studies have
correlated the dimension scores with cortical measures.
As a minor limitation, we note that we followed the
pediatric-adult age cutoff of the study samples to split the
data into adult (age 18 or over) and pediatric (age under 18)
groups, a cut-off that may not be an optimally related to the
onset and evolution of OCD (46, 47). In addition, the pediatric sample represents a wide age range, including puberty. We did not have enough data on pubertal stage to take
pubertal development into account. Given the role of hormonal influence on cortical structures, this will be useful to
pursue in future research.
CONCLUSIONS
The parietal cortex was implicated in both adult and pediatric
OCD. These results support the hypothesis that the pathophysiology of OCD cannot be explained solely by alterations
of the classical cortico-striato-thalamo-cortical regions and
emphasize the importance of parietal regions. Widespread
cortical thickness abnormalities were found in medicated
ajp.psychiatryonline.org
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CORTICAL ABNORMALITIES ASSOCIATED WITH OCD
adult OCD patients, while more pronounced surface area
deficits were found in medicated pediatric OCD patients.
Cortical thickness and surface area represent distinct features of the cortex and may be differentially affected by OCD
and possibly moderated by medication status. Further work
using longitudinal designs and incorporating genetic and
environmental variables will be useful in understanding the
precise mechanisms underlying the structural abnormalities
preceding the onset of the illness and occurring during the
course of the illness.
AUTHOR AND ARTICLE INFORMATION
From the Department of Psychiatry and the Department of Anatomy and
Neurosciences, VU University Medical Center, Amsterdam; Amsterdam
Neuroscience, Amsterdam; Orygen, National Centre of Excellence in
Youth Mental Health, Melbourne; the Centre for Youth Mental Health,
University of Melbourne, Melbourne; the Department of Psychiatry,
Graduate School of Medical Science, Kyoto Prefectural University of
Medicine, Kyoto, Japan; the Department of Psychiatry, Bellvitge University
Hospital, Bellvitge Biomedical Research Institute–IDIBELL, L’Hospitalet de
Llobregat, Barcelona, Spain; Centro de Investigación Biomèdica en Red de
Salud Mental (CIBERSAM), Barcelona; the Department of Clinical Sciences,
University of Barcelona, Barcelona; the Margaret and Wallace McCain
Centre for Child, Youth, and Family Mental Health, Campbell Family Mental
Health Research Institute, Centre for Addiction and Mental Health, Department of Psychiatry, Faculty of Medicine, University of Toronto,
Toronto; the Centre for Brain and Mental Health, Hospital for Sick Children, Toronto; the Department of Psychiatry, Yale University School of
Medicine, New Haven, Conn.; the Mathison Centre for Mental Health
Research and Education, Hotchkiss Brain Institute and Department of
Psychiatry, Cumming School of Medicine, University of Calgary, Calgary,
Canada; the Department of Psychiatry, Institute of Psychiatry, University of
São Paulo School of Medicine, São Paulo, Brazil; Psychiatry and Clinical
Psychobiology, Division of Neuroscience, Scientific Institute Ospedale
San Raffaele, Milan, Italy; the Department of Psychology, HumboldtUniversität zu Berlin, Berlin; the Obsessive-Compulsive Disorder (OCD)
Clinic, Department of Psychiatry, National Institute of Mental Health and
Neurosciences, Bangalore, India; the Department of Child and Adolescent
Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich,
Zurich; the Magnetic Resonance Image Core Facility, IDIBAPS (Institut
d’Investigacions Biomèdiques August Pi i Sunyer), Barcelona; the Department of Child and Adolescent Psychiatry and Psychology, Institute of
Neurosciences, Hospital Clínic Universitari, Barcelona; the Department
of Psychiatry, First Affiliated Hospital of Kunming Medical University,
Kunming, China; the Institute of Human Behavioral Medicine, SNU-MRC,
Seoul, Republic of Korea; the Laboratory of Neuropsychiatry, Department
of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation,
Rome; the Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam; the Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam;
the Department of Psychiatry and Biobehavioral Sciences, University of
California, Los Angeles; the Department of Psychiatry, University of
Michigan, Ann Arbor; the Department of Psychiatry, University of Cape
Town, Cape Town, South Africa; Yeongeon Student Support Center, Seoul
National University College of Medicine, Seoul, Republic of Korea; Imaging
Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics
Institute, Keck School of Medicine, University of Southern California,
Marina del Rey; Shanghai Mental Health Center, Shanghai Jiao Tong
University School of Medicine, Shanghai, China; the Bascule, Academic
Center for Child and Adolescent Psychiatry, Amsterdam; the Department
of Child and Adolescent Psychiatry, Academic Medical Center, University
of Amsterdam, Amsterdam; the Department of Psychiatry, Oxford University, Oxford, U.K.; the Department of Neuroradiology and the TUMNeuroimaging Center (TUM-NIC), Klinikum rechts der Isar, Technische
460
ajp.psychiatryonline.org
Universität München, Munich; the Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea; the Department of Brain and Cognitive Sciences, Seoul National University
College of Natural Sciences, Seoul, Republic of Korea; Institut d’Investigacions Biomèdiques, August Pi i Sunyer (IDIBAPS), Barcelona; the Department of Medicine, University of Barcelona, Barcelona; the SU/UCT
MRC Unit on Anxiety and Stress Disorders, Department of Psychiatry,
University of Stellenbosch, Stellenbosch, South Africa; the Department
of Psychiatry, Columbia University Medical College, and New York State
Psychiatric Institute, New York; the Department of Clinical Neuroscience, Center for Psychiatry Research, Karolinska Institutet, Stockholm; the Mood Disorders Clinic and the Anxiety Treatment and
Research Center, St. Joseph’s HealthCare, Hamilton, Ontario; the
Department of Neuropsychiatry, Graduate School of Medical Sciences,
Kyushu University, Fukuoka, Japan; Centro Fermi–Enrico Fermi Historical Museum of Physics and Study and Research Center, Rome; ATR
Brain Information Communication Research Laboratory Group, Kyoto,
Japan; the Center for Mathematics, Computing, and Cognition,
Universidade Federal do ABC, Santo Andre, Brazil; the Center for OCD
and Related Disorders, New York State Psychiatric Institute, New York;
the Department of Psychobiology and Methodology of Health
Sciences, Universitat Autònoma de Barcelona; the Beth K. and Stuart C.
Yudofsky Division of Neuropsychiatry, Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston; the Clinical Neuroscience and Development Laboratory, Olin Neuropsychiatry Research
Center, Hartford, Conn.; the Department of Psychiatry, Icahn School of
Medicine at Mount Sinai, New York; the James J. Peters VA Medical Center,
Bronx, N.Y.; the Institute of Living, Hartford Hospital, Hartford, Conn.; the
Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China; and the
Department of Psychiatry, Seoul National University Hospital, Seoul, Republic
of Korea.
Address correspondence to Ms. Boedhoe (p.boedhoe@vumc.nl).
See the online data supplement for the complete list of ENIGMA OCD
Working Group members.
The ENIGMA OCD Working Group gratefully acknowledges support from
NIH BD2K award U54 EB020403-02 (principal investigator, Dr. Thompson)
and Neuroscience Amsterdam, IPB grant to Dr. Schmaal and Dr. van den
Heuvel. Supported by the Hartmann Muller Foundation (grant 1460 to
Dr. Brem); the International Obsessive-Compulsive Disorder Foundation
Research Award to Dr. Gruner; the Dutch Organization for Scientific
Research (NWO) (grants 912-02-050, 907-00-012, 940-37-018, and
916-86-038); the Netherlands Society for Scientific Research (NWOZonMw VENI grant 916-86-036 to Dr. van den Heuvel; NWO-ZonMw
AGIKO stipend 920-03-542 to Dr. de Vries); a NARSAD Young Investigator
Award to Dr. van den Heuvel; the Netherlands Brain Foundation (2010(1)50 to Dr. van den Heuvel); the Oxfordshire Health Services Research
Committee (Dr. Anthony James); the Deutsche Forschungsgemeinschaft
(KO 3744/2-1 to Dr. Koch); the Marató TV3 Foundation (grants 01/2010
and 091710 to Dr. Lazaro); the Wellcome Trust and a pump priming grant
from the South London and Maudsley Trust, London (project grant
064846 to Dr. Mataix-Cols); the Japanese Ministry of Education, Culture,
Sports, Science, and Technology (MEXT KAKENHI grant 26461753 to Dr.
Nakamae); International OCD Foundation Research Award 20153694 and
a UCLA Clinical and Translational Science Institute Award (to Dr. Nurmi);
NIMH grant R01MH081864 (to Drs. O’Neill and Piacentini) and grant
R01MH085900 (to Drs. O’Neill and Feusner); Government of India grants
to Prof. Y.C. Janardhan Reddy (SR/S0/HS/0016/2011) and Dr. Janardhanan
C. Narayanaswamy (DST INSPIRE faculty grant IFA12-LSBM-26) of the
Department of Science and Technology; Government of India grants to
Prof. Y.C. Janardhan Reddy (BT/PR13334/Med/30/259/2009) and Dr.
Janardhanan C. Narayanaswamy (BT/06/IYBA/2012) of the Department of
Biotechnology; the Wellcome-DBT India Alliance grant to Dr. Ganesan
Venkatasubramanian (500236/Z/11/Z); the Carlos III Health Institute (CP10/
00604, PI13/00918, PI13/01958, PI14/00413/PI040829); FEDER funds/
European Regional Development Fund, AGAUR (2014 SGR 1672 and
2014 SGR 489); a “Miguel Servet” contract (CP10/00604) from the Carlos III
Am J Psychiatry 175:5, May 2018
BOEDHOE ET AL.
Health Institute to Dr. Soriano-Mas; the Italian Ministry of Health (grant
RC10-11-12-13-14-15A to Dr. Spalletta); the Swiss National Science Foundation (grant 320030_130237 to Dr. Walitza); and the Netherlands Organization for Scientific Research (NWO VIDI 917-15-318 to Dr. van Wingen).
The authors acknowledge Nerisa Banaj, Ph.D., Silvio Conte, Sergio
Hernandez B.A., Yu Jin Ressal, and Alice Quinton.
Dr. Anticevic has served as a consultant and a scientific advisory board
member for BlackThorn Therapeutics. Dr. Lochner was funded by the
South African Medical Research Council. Dr. Minuzzi has received grant or
research support from an Alternative Funding Plan Innovations Award, the
Brain and Behavioral Foundation, the Canadian Institutes of Health Research, the Hamilton Health Sciences Foundation, the Ontario Brain Institute, and the Ontario Mental Health Foundation, and he has served on
speakers bureaus or received honoraria from Allergan, Bristol-Myers
Squibb, the Canadian Psychiatric Association, CANMAT, Lundbeck,
and Sunovion. Dr. Piacentini has received grant or research support
from NIMH, the TLC Foundation for Body-Focused Repetitive Behaviors, the Tourette Association of America, the Pettit Family Foundation, and Pfizer Pharmaceuticals through the Duke University Clinical
Research Institute Network; he has served on the speakers bureau of the
Tourette Association of America, the International Obsessive Compulsive
Disorder Foundation, and the TLC Foundation for Body-Focused Repetitive
Behaviors; and he receives royalties from Guilford Press and Oxford
University Press. Dr. Simpson has received royalties from Cambridge
University Press and UpToDate. Dr. Tolin has served as a consultant for
Mindyra, he has received research grants from Palo Alto Health Sciences and Pfizer. Prof. Walitza has received lecture honoraria from
AstraZeneca, Eli Lilly, Janssen-Cilag, Opopharma, and Shire; she
has received support from the Swiss National Science Foundation,
the German Research Foundation, different EU FP7 projects, the
Hochspezialisierte Medizin of the Canton of Zurich (Switzerland), the
Zurich Program for Sustainable Development of Mental Health Services,
the Hartmann Müller Foundation, the Olga Mayenfisch Foundation,
the NOMIS Foundation, the University Medical Center Utrecht, and
Germany’s Federal Ministry of Education and Research. Dr. Stein has
received research grants and/or consultancy honoraria from Biocodex,
Lundbeck, Servier, and Sun. The other authors report no financial
relationships with commercial interests.
Received May 2, 2017; revisions received Aug. 4 and Sept. 20, 2017;
accepted Sept. 25, 2017; published online Dec. 15, 2017.
REFERENCES
1. van den Heuvel OA, van Wingen G, Soriano-Mas C, et al: Brain
circuitry of compulsivity. Eur Neuropsychopharmacol 2016; 26:
810–827
2. Milad MR, Rauch SL: Obsessive-compulsive disorder: beyond
segregated cortico-striatal pathways. Trends Cogn Sci 2012; 16:43–51
3. Piras F, Piras F, Chiapponi C, et al: Widespread structural brain
changes in OCD: a systematic review of voxel-based morphometry
studies. Cortex 2015; 62:89–108
4. Button KS, Ioannidis JP, Mokrysz C, et al: Power failure: why small
sample size undermines the reliability of neuroscience. Nat Rev
Neurosci 2013; 14:365–376
5. Thompson PM, Andreassen OA, Arias-Vasquez A, et al: ENIGMA
and the individual: predicting factors that affect the brain in 35
countries worldwide. Neuroimage 2017; 145(Pt B):389–408
6. Boedhoe PSW, Schmaal L, Abe Y, et al: Distinct subcortical volume
alterations in pediatric and adult OCD: a worldwide meta- and megaanalysis. Am J Psychiatry 2017; 174:60–69
7. Radua J, Mataix-Cols D: Voxel-wise meta-analysis of grey matter
changes in obsessive-compulsive disorder. Br J Psychiatry 2009; 195:
393–402
8. Rotge J-Y, Langbour N, Guehl D, et al: Gray matter alterations in
obsessive-compulsive disorder: an anatomic likelihood estimation
meta-analysis. Neuropsychopharmacology 2010; 35:686–691
Am J Psychiatry 175:5, May 2018
9. Venkatasubramanian G, Zutshi A, Jindal S, et al: Comprehensive
evaluation of cortical structure abnormalities in drug-naïve adult
patients with obsessive-compulsive disorder: a surface-based morphometry study. J Psychiatr Res 2012; 46:1161–1168
10. Kühn S, Kaufmann C, Simon D, et al: Reduced thickness of anterior
cingulate cortex in obsessive-compulsive disorder. Cortex 2013; 49:
2178–2185
11. de Wit SJ, Alonso P, Schweren L, et al: Multicenter voxel-based
morphometry mega-analysis of structural brain scans in obsessivecompulsive disorder. Am J Psychiatry 2014; 171:340–349
12. Fouche J-P, du Plessis S, Hattingh C, et al: Cortical thickness in
obsessive-compulsive disorder: multisite mega-analysis of 780 brain
scans from six centres. Br J Psychiatry 2017; 210:67–74
13. Nakamae T, Narumoto J, Sakai Y, et al: Reduced cortical thickness in
non-medicated patients with obsessive-compulsive disorder. Prog
Neuropsychopharmacol Biol Psychiatry 2012; 37:90–95
14. Fan Q, Palaniyappan L, Tan L, et al: Surface anatomical profile of the
cerebral cortex in obsessive-compulsive disorder: a study of cortical
thickness, folding, and surface area. Psychol Med 2013; 43:1081–1091
15. Radua J, van den Heuvel OA, Surguladze S, et al: Meta-analytical
comparison of voxel-based morphometry studies in obsessivecompulsive disorder vs other anxiety disorders. Arch Gen Psychiatry 2010; 67:701–711
16. Narayan VM, Narr KL, Phillips OR, et al: Greater regional cortical
gray matter thickness in obsessive-compulsive disorder. Neuroreport 2008; 19:1551–1555
17. Hutton C, Draganski B, Ashburner J, et al: A comparison between
voxel-based cortical thickness and voxel-based morphometry in normal aging. Neuroimage 2009; 48:371–380
18. Winkler AM, Kochunov P, Fox PT, et al: Heritability of volume,
surface area, and thickness for anatomically defined cortical brain
regions estimated in a large extended pedigree. Neuroimage 2009;
47:S162
19. Rosenberg DR, Keshavan MS: AE Bennett Research Award: Toward
a neurodevelopmental model of of obsessive-compulsive disorder.
Biol Psychiatry 1998; 43:623–640
20. Fischl B, Salat DH, Busa E, et al: Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain.
Neuron 2002; 33:341–355
21. Desikan RS, Ségonne F, Fischl B, et al: An automated labeling system
for subdividing the human cerebral cortex on MRI scans into gyral
based regions of interest. Neuroimage 2006; 31:968–980
22. Westlye LT, Walhovd KB, Dale AM, et al: Differentiating maturational and aging-related changes of the cerebral cortex by use of
thickness and signal intensity. Neuroimage 2010; 52:172–185
23. Goodman WK, Price LH, Rasmussen SA, et al: The Yale-Brown
Obsessive Compulsive Scale, I: development, use, and reliability.
Arch Gen Psychiatry 1989; 46:1006–1011
24. Scahill L, Riddle MA, McSwiggin-Hardin M, et al: Children’s YaleBrown Obsessive Compulsive Scale: reliability and validity. J Am
Acad Child Adolesc Psychiatry 1997; 36:844–852
25. Lázaro L, Bargalló N, Castro-Fornieles J, et al: Brain changes in
children and adolescents with obsessive-compulsive disorder before
and after treatment: a voxel-based morphometric MRI study. Psychiatry Res 2009; 172:140–146
26. Fallucca E, MacMaster FP, Haddad J, et al: Distinguishing between
major depressive disorder and obsessive-compulsive disorder in
children by measuring regional cortical thickness. Arch Gen Psychiatry 2011; 68:527–533
27. Koprivová J, Horácek J, Tintera J, et al: Medial frontal and dorsal
cortical morphometric abnormalities are related to obsessivecompulsive disorder. Neurosci Lett 2009; 464:62–66
28. Ashburner J, Friston KJ: Voxel-based morphometry: the methods.
Neuroimage 2000; 11:805–821
29. Clarkson MJ, Cardoso MJ, Ridgway GR, et al: A comparison of voxel
and surface based cortical thickness estimation methods. Neuroimage 2011; 57:856–865
ajp.psychiatryonline.org
461
CORTICAL ABNORMALITIES ASSOCIATED WITH OCD
30. Glasser MF, Coalson TS, Robinson EC, et al: A multi-modal parcellation of human cerebral cortex. Nature 2016; 536:171–178
31. Boedhoe PSW, Schmaal L, Mataix-Cols D, et al: Association and
causation in brain imaging in the case of OCD: response to McKay
et al. Am J Psychiatry 2017; 174:597–599
32. Gogtay N, Giedd JN, Lusk L, et al: Dynamic mapping of human
cortical development during childhood through early adulthood.
Proc Natl Acad Sci USA 2004; 101:8174–8179
33. Rakic P: Specification of cerebral cortical areas. Science 1988; 241:
170–176
34. Graybiel AM, Rauch SL: Toward a neurobiology of obsessivecompulsive disorder. Neuron 2000; 28:343–347
35. Stern ER, Fitzgerald KD, Welsh RC, et al: Resting-state functional
connectivity between fronto-parietal and default mode networks
in obsessive-compulsive disorder. PLoS One 2012; 7:e36356
36. Posner J, Song I, Lee S, et al: Increased functional connectivity
between the default mode and salience networks in unmedicated
adults with obsessive-compulsive disorder. Hum Brain Mapp 2017;
38:678–687
37. Zhang T, Wang J, Yang Y, et al: Abnormal small-world architecture
of top-down control networks in obsessive-compulsive disorder.
J Psychiatry Neurosci 2011; 36:23–31
38. O’Connor K, Aardema F: Fusion or confusion in obsessive compulsive disorder. Psychol Rep 2003; 93:227–232
39. Hoexter MQ, de Souza Duran FL, D’Alcante CC, et al: Gray matter
volumes in obsessive-compulsive disorder before and after fluoxetine or cognitive-behavior therapy: a randomized clinical trial.
Neuropsychopharmacology 2012; 37:734–745
462
ajp.psychiatryonline.org
40. Chen X, Liang S, Pu W, et al: Reduced cortical thickness in
right Heschl’s gyrus associated with auditory verbal hallucinations severity in first-episode schizophrenia. BMC Psychiatry 2015;
15:152
41. Wierenga LM, Langen M, Oranje B, et al: Unique developmental
trajectories of cortical thickness and surface area. Neuroimage 2014;
87:120–126
42. Anderson BJ: Plasticity of gray matter volume: the cellular and
synaptic plasticity that underlies volumetric change. Dev Psychobiol
2011; 53:456–465
43. Savalia NK, Agres PF, Chan MY, et al: Motion-related artifacts in
structural brain images revealed with independent estimates of inscanner head motion. Hum Brain Mapp 2017; 38:472–492
44. van den Heuvel OA, Remijnse PL, Mataix-Cols D, et al: The
major symptom dimensions of obsessive-compulsive disorder
are mediated by partially distinct neural systems. Brain 2009; 132:
853–868
45. Mataix-Cols D, Wooderson S, Lawrence N, et al: Distinct neural
correlates of washing, checking, and hoarding symptom dimensions
in obsessive-compulsive disorder. Arch Gen Psychiatry 2004; 61:
564–576
46. Leckman JF, Denys D, Simpson HB, et al: Obsessive-compulsive
disorder: a review of the diagnostic criteria and possible subtypes
and dimensional specifiers for DSM-V. Depress Anxiety 2010; 27:
507–527
47. Anholt GE, Aderka IM, van Balkom AJLM, et al: Age of onset in
obsessive-compulsive disorder: admixture analysis with a large sample.
Psychol Med 2014; 44:185–194
Am J Psychiatry 175:5, May 2018