Psychiatry Research: Neuroimaging 213 (2013) 11–17

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Psychiatry Research: Neuroimaging

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journal homepage: www.elsevier.com/locate/psychresns

Widespread decreased grey and white matter in paediatricobsessive-compulsive disorder (OCD): A voxel-basedmorphometric MRI study

Jian Chen a, Tim Silk a, Marc Seal a, Karen Dally b, Alasdair Vance b,n

a Developmental Imaging, Murdoch Children’s Research Institute, Melbourne, Australiab Academic Child Psychiatry Unit, Department of Paediatrics, University of Melbourne, Royal Children’s Hospital, Murdoch Children’s Research Institute,

Melbourne, Australia

a r t i c l e i n f o

Article history:

Received 11 June 2012

Received in revised form

5 February 2013

Accepted 7 February 2013

Keywords:

Obsessive-compulsive disorder

Voxel-based morphometry (VBM)

Magnetic resonance imaging (MRI)

Childhood psychiatric disorders

27/$ - see front matter Crown Copyright & 2

x.doi.org/10.1016/j.pscychresns.2013.02.003

viations: VBM, voxel-based morphometry;

r; MRI, magnetic resonance imaging; DARTEL

tion using exponentiated lie algebra; ROI, reg

volume; OFC, orbitofrontal cortex; ACC, anter

esponding author. Tel.: þ613 9345 4666; fax

ail address: avance@unimelb.edu.au (A. Vanc

a b s t r a c t

Obsessive-compulsive disorder (OCD) is a chronic, relapsing anxiety disorder. To date, neuroimaging

investigations of OCD have been variable and few studies have examined paediatric populations. Eight

children with OCD and 12 typically developing children matched for age, gender, handedness and

performance IQ underwent a high resolution T1-weighted structural magnetic resonance imaging

(MRI) scan. A voxel-based morphometry (VBM) protocol (using DARTEL) compared the brains of the

paediatric OCD children with those of typically developing children. Overall, children with OCD

demonstrated significantly lower intra-cranial volume (ICV) and grey- and white-matter volumes. ICV

was significantly reduced (�9%) in the OCD group compared with the typically developing group. The

VBM analysis demonstrated lower volumes in widespread grey matter in bilateral frontal, cingulate,

temporal–parietal, occipital–frontal and right precuneus regions for OCD. Lower white matter volume

was found bilaterally in the cingulate and occipital cortex, right frontal and parietal and left temporal

regions, and the corpus callosum. In summary, this study provides further evidence of brain

dysmorphology in paediatric OCD patients. In addition to fronto–striatal–thalamic neural networks,

abnormalities in other brain regions, such as the parietal lobe and corpus callosum, were demonstrated.

These brain regions may play an additional role in the pathophysiology of OCD.

Crown Copyright & 2013 Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction

Obsessive-compulsive disorder (OCD) is one of the most disablinganxiety disorders marked by recurrent, intrusive and distressingthoughts (obsessions) and/or repetitive behaviours (compulsions)(American Psychiatric Association, 2000). It is common in childrenand adolescents with a point prevalence of 2–3% (Rapoport et al.,2000). Further, it has clear continuity into adulthood, with approxi-mately 80% of adult OCD sufferers experiencing the onset of theirOCD symptoms before the age of 18 years McGuire et al. (2012).

The emergence and development of imaging techniques havegreatly contributed to the understanding of neuropsychiatric dis-orders such as OCD. Several excellent reviews of the imagingliterature in adult OCD have appeared (Saxena and Rauch, 2000;Friedlander and Desrocher, 2006; Fontenelle et al., 2009; Kwon

013 Published by Elsevier Ireland

OCD, obsessive-compulsive

, diffeomorphic anatomical

ion of interest; ICV, intra-

ior cingulate cortex

: þ613 9345 6002.

e).

et al., 2009). Most neuroimaging studies in OCD have targeted brainregions identified as abnormal, specifically fronto–striatal–thalamicneural networks, involving the prefrontal regions, together with thecingulate cortex. This is consistent with current aetiological modelsof adult OCD that implicate abnormal feedback loops within large-scale neurocognitive networks, specifically ‘limbic’ or ‘affective’cortico–striato–thalamic circuits, including the orbitofrontal cortex(OFC), that have been hypothesised to play a key role in pathophy-siology in OCD (Graybiel and Rauch, 2000; Saxena et al., 2001).Further, functional neuroimaging studies have implicated a relativeincrease in the activity of key subcortical and cortical brain regionsthat may aid our understanding of OCD. For instance, Insel andWinslow (1992) proposed that there may be increased activity inthe caudate nucleus that inhibits globus pallidus outflow from thebasal ganglia, which in turn increases thalamic activity, orbitofron-tal cortical activity and caudate nucleus activity via thecingulate gyrus.

In contrast, few have comprehensively reviewed imaging studiesin paediatric OCD (Huyser et al., 2009). Many brain morphologystudies in paediatric OCD are based on volumetric region-of-interest(ROI) studies. Compared with age-matched typically developingparticipants, paediatric OCD patients have higher grey matter

Ltd. All rights reserved.

J. Chen et al. / Psychiatry Research: Neuroimaging 213 (2013) 11–1712

volumes in the anterior cingulate cortex (ACC) (Rosenberg andKeshavan, 1998; Szeszko et al., 2004, 2008) and in the OFC (Szeszkoet al., 2008; MacMaster et al., 2010). The basal ganglia and thalamushave also been investigated with highly variable results: among thefindings are a lower volume of the putamen but not of the caudatenucleus (Rosenberg et al., 1997b), lower volume of the globus pallidusbut not of the putamen or caudate nucleus (Szeszko et al., 2004), andhigher volume of the thalamus (Gilbert et al., 2000).

Recently, two voxel-based meta-analyses have been conductedexamining grey matter differences in patients with OCD based onvoxel-based morphometry (VBM) (Radua and Mataix-Cols, 2009;Rotge et al., 2010). Due to the limited VBM studies in the OCDliterature, these meta-analyses have employed mixed samplesfrom adult and paediatric studies. Lower grey matter volume hasbeen found in people with OCD in regions such as the frontal eyefields (FEF), dorsolateral prefrontal cortex (DLPFC), medial part ofthe anterior prefrontal cortex (aPFC) (Rotge et al., 2010) andbilateral dorsal medial frontal/anterior circulate gyri (Radua andMataix-Cols, 2009). Higher grey matter volumes have been foundin people with OCD in basal ganglia regions such as the putamenand caudate (Radua and Mataix-Cols, 2009; Rotge et al., 2010),and the lateral part of the orbitofrontal cortex (OFC). One studyfound that there was no significant difference between adults andchildren with OCD (Rotge et al., 2010), while the other did notconduct such an analysis due to too few extant paediatric studies(Radua and Mataix-Cols, 2009).

In these few paediatric VBM studies, the results have beeninconsistent with published ROI-based studies and between thedifferent VBM studies. For example, either no difference (Szeszkoet al., 2008) or lower grey matter volume in the ACC (Carmonaet al., 2007; Gilbert et al., 2008) and lower grey matter volume inbilateral frontal regions (Carmona et al., 2007) have been found inpaediatric OCD patients compared with typically developingparticipants. With regards to the basal ganglia and thalamus,studies have found higher volumes in the caudate nuclei and theright globus pallidus in adolescents with OCD (Zarei et al., 2011),higher volume in the right putamen (Gilbert et al., 2008; Zareiet al., 2011) and bilateral putamen (Szeszko et al., 2008), nothalamic difference (Carmona et al., 2007; Gilbert et al., 2008;Szeszko et al., 2008) or no basal ganglia differences (Carmonaet al., 2007). In addition to those predicted regions, decreasedgrey matter volume bilaterally has been noted in the parietallobes (Lazaro et al., 2009; Zarei et al., 2011).

Far fewer studies have examined differences in white matterin OCD and most findings are from adult samples: for example,significantly lower total white matter volume in female OCDpatients (Jenike et al., 1996) along with decreased bilateralorbitofrontal volume (Szeszko et al., 1999) in OCD patients,although the latter study did not determine if the reduction wasspecific to grey or white matter due to methodological limita-tions. Recent white matter VBM studies in paediatric OCD suggestdecreased white matter volume in bilateral frontal (Carmonaet al., 2007) and right parietal regions (Carmona et al., 2007;Lazaro et al., 2009).

In addition, the corpus callosum has been noted to be larger(except for the isthmus) in paediatric OCD patients (Rosenberg et al.,1997a), and anomalies in signal intensity, width, and length of thecorpus callosum have also been reported in OCD patients in controlledMRI studies [female adult (Jenike et al., 1996); paediatric (Rosenberget al., 1997a); and adult (MacMaster et al., 1999)]. This is consistentwith the corpus callosum being a predicted brain region of interest inOCD, given that primary and association cortices are topographicallymapped in the corpus callosum (Raybaud, 2010).

In summary, although morphometric investigations of OCDhave been variable, the most consistent findings are volumetricabnormalities (either decrease or increase) involving the ventral

prefrontal cortex (which includes the OFC) and the striatum, aswell as white matter abnormalities involving the cingulumbundle and the corpus callosum. The contradictory findings aremost likely due to factors including the data analysis method (ROIor VBM), and/or different OCD sample selection criteria (age,gender, OCD symptom dimensions, comorbidity, length of illness,medication treatment and/or sample size). Despite these metho-dological shortcomings, the published data suggest that theparietal region could be a focus for further exploration, alongwith the ventral prefrontal–striatal regions, if a comprehensivepathophysiology of paediatric OCD is to emerge.

Hence, the current study sought to carefully define medicationnaı̈ve children with similar OCD symptom dimensions and lengths ofillness, without key comorbid conditions such as attention deficithyperactivity disorder, combined type (ADHD-CT), combined type,major depressive disorder and tic disorders. Voxel-based morphome-try was used to compare the brains of the paediatric OCD patientswith those of typically developing participants, matched on age,gender, handedness and performance IQ. We hypothesised thatcompared with typically developing participants, young people withOCD would demonstrate grey and white matter abnormalities in alarge-scale neural network of brain regions, consistent with theore-tical models of OCD, including the ventral prefrontal and cingulatecortices, the corpus callosum and the parietal cortex.

2. Materials and methods

2.1. Participants

Eight young people fulfilling DSM-IV criteria for obsessive-compulsive dis-

order (4 M:4 F) aged 8–15 years (mean 11.772.7 years) were identified at the

Royal Children’s Hospital, Melbourne, Australia. OCD was defined categorically,

using a semi-structured clinical interview with one of both of the participants’

parents and the young people themselves, the Anxiety Disorders Interview

Schedule for Children (A-DISC; Silverman and Albano, 1996), in addition to using

the clinician completed Children’s Yale–Brown Obsessive Compulsive Scale (CY–

BOCS). The CY–BOCS assesses the severity of both obsessions and compulsions

separately, as well as giving an overall score (Scahill et al., 1997); all cases had

similar severity of obsessions and compulsions with a mean CY–BOCS score of

31.174.3. Also, all participants had a recent onset of their OCD symptoms and a

short duration of illness: mean 873.4 months. Participants had a full scale IQ above

70, according to the Wechsler Intelligence Scale for Children (Wechsler, 2004), and

there were no known neurological or endocrine conditions, mood disorders, autistic

disorders, psychotic disorders, ADHD combined type, reading/spelling/arithmetic

learning disorders, developmental coordination disorder or alcohol/substance abuse/

dependence disorders. All participants were medication naive.

Twelve typically developing participants (6 M: 6 F) were matched in age (8–15

years) to the OCD patients. All participants were right-handed based on the scored

developmental neurological examination (Taylor et al., 1986). The typically developing

participants were required to complete the same psychiatric assessment (A-DISC and

CY–BOCS) as the OCD cases to ensure that they did not demonstrate any psychiatric

disorder, neurological disorder or other significant illness. Informed verbal and written

consent was obtained. All procedures were approved by the Human Research Ethics

Committee of the Royal Children’s Hospital, Melbourne, Australia. Participants’ key

clinical measures are listed in Table 1.

2.2. Image acquisition and data analysis

Data were acquired on a 3 T Siemens TIM Trio scanner at the Royal Children’s

Hospital, Melbourne, Australia. High resolution T1-weighted structural MR images

were acquired for each participant (repetition time¼1900 ms, flip angle 901, field of

view¼224�256, slice thickness¼1.0 mm, and in-plane pixels¼0.5�0.5 mm). VBM-

DARTEL analysis, intra-cranial volume (ICV) and tissue volume (grey matter, white

matter) measures were performed using the SPM8 software (Welcome Department of

Imaging Neuroscience, London; http://www.fil.ion.ucl.ac.uk/spm) running on Matlab

2008b (Math-Works, Natick, MA, USA).

2.3. Image pre-processing

Each re-orientated image was first segmented into grey matter, white matter

and cerebrospinal fluid (CSF) in native space and then Procrustes aligned grey

matter and white matter images were generated by a rigid transformation. The

resolution of the aligned images was specified as 1.5�1.5�1.5 mm3. The

algorithm is essentially the same as that described by Ashburner and Friston

J. Chen et al. / Psychiatry Research: Neuroimaging 213 (2013) 11–17 13

(2005) with a different treatment of the mixing proportions, an improved

registration model, an extended set of tissue probability maps and a more robust

initial affine registration.

2.4. Customised tissue probability map creation

The study-specific grey matter/white matter templates were then created by the

aligned images from all the patients and controls using the diffeomorphic anatomical

registration using exponentiated lie algebra (DARTEL) registration method (Ashburner,

2007). The procedure began with the generation of an original template computing the

average of all the aligned data, followed by the first iteration of the registration on each

participant in turn. Thus, a new template was created and the second iteration began.

After six iterations, the template was generated, which was the average of the DARTEL

registered data. During iterations, all images were warped to the template, yielding a

series of flow fields that parameterized deformations, which were employed in the

modulation step. Images were then spatially normalised to Montreal Neurological

Institute (MNI) space and were modulated to ensure that the overall amount of each

tissue class was not altered by the spatial normalisation procedure.

2.5. Statistical analyses of images

First, we assessed the volumetric difference between the two groups. Intra-

cranial volume (ICV), grey matter, white matter, and CSF global volumes were

calculated on a modulated segmented image in MNI space. ROIs of the OFC, the

ACC, and the thalamus were defined using the BrainMap database (Nielsen and

Hansen, 2002). The binarised BrianMap ROIs were multiplied by individual

participants (in MNI space) to obtain grey matter and white matter volumes for

each individual in ROIs. Two-sample t-tests were applied to analyse global and ROI

volumetric differences between the groups.

Finally, images were smoothed with an 8-mm full-width at half-maximum

(FWHM) Gaussian kernel for the VBM statistical analysis. The SPM8 parametric

two-sample t-test was used to determine group differences of VBM-generated

grey matter and white matter volumes, both with and without the ICV confound-

ing variable. Clusters that survived a po0.05 FDR (false discovery rate) corrected

at voxel-level threshold, and had an extent threshold of 100 voxels (for grey

matter) or 10 voxels (for white matter), were considered significant. MNI

coordinates of peak voxels in each region were converted to Talairach coordinates

with use of the Talairach atlas anatomical localisation.

To examine if there was a relationship between these regional brain differences

and symptom severity in the OCD group, linear regressions were used to examine

correlations between scores on the CY–BOCS and grey and white matter measures.

Table 2Volumetric results.

Measure: volume (mL) Typically developing participants (M

ICV 1554.77135.3

Total grey matter 739.8763.3

Total white matter 505.9747.2

Total greyþwhite matter 1245.77108.6

ACC (greyþwhite matter) 29.672.8

OFC (greyþwhite matter) 83.578.8

Thalamus (greyþwhite matter) 16.171.3

d.f.¼19.

Table 1Summary of key clinical measures.

Measure: item Typically developingparticipants(Mean7S.D.)

OCD(Mean7S.D.)

Age 11.872.2 11.772.7 t¼0.07, p¼0.94

Sex 6 male 4 male t¼0.21, p¼0.65

6 female 4 female

Full-scale IQ 108.676.0 94.879.8 t¼4.00, p¼0.00

Performance IQ 105.2715.1 92.379.8 t¼2.00, p¼0.06

Verbal IQ 109.077.6 99.1712.6 t¼2.54, p¼0.02

CY–BOCS 31.174.3

d.f.¼18.

3. Results

3.1. Overall brain volume

Overall, young people with OCD demonstrated significantly lowerICV (grey matterþwhite matterþCSF), grey matter and white mattertissue volumes. The ICV was significantly reduced (�9%) in the OCDgroup compared with the typically developing group (p¼0.02 andd.f.¼19). Significant decreases in absolute volumes in the OCD groupwere found in overall white (47 mL; p¼0.03 and d.f.¼19) and greymatter volumes (67 mL; p¼0.02 and d.f.¼19). Regional differences ingrey matter and white matter segmented volumes are shown inTable 2. Young people with OCD also showed significantly lowervolume in the OFC (p¼0.04 and d.f.¼19) and ACC (p¼0.02 andd.f.¼19) and a trend towards lower volume in the thalamus (p¼0.06and d.f.¼19).

3.2. VBM and DARTEL analyses

The VBM analysis demonstrated lower volumes in widespreadgrey matter and white matter regions in participants with OCD.Specifically, lower grey matter volume was found bilaterally infrontal, cingulate, temporal–parietal, occipital–frontal and rightprecuneus regions. Lower white matter volumes were foundbilaterally in the cingulate and occipital cortices, in right frontaland parietal regions, left temporal cortices, and the corpus callo-sum. Regional differences are shown in Table 3 for grey matter andTable 4 for white matter. There were no regions of increased greymatter or white matter volume in the OCD compared with thetypically developing group. Fig. 1 shows the difference in greymatter and white matter volumes between the typically develop-ing and OCD groups. As there was a significant ICV differencebetween the two groups, further analysis was conducted includingICV as a confounding variable in the model. A very similar networkof regions, including frontal, cingulate, and parietal areas in greyand white matter, was still apparent at a lower threshold (uncor-rected po0.001, a threshold equal to or lower than in otherstudies) (Carmona et al., 2007; Szeszko et al., 2008). The resultsare illustrated in supplemental Fig. S1. This suggests that, eventaking into account the fact that OCD patients have smaller brainsize, they still have localised tissue volume abnormality. The OCDgroup had a significantly lower full-scale IQ score (see Table 1)than the typically developing group, so full-scale IQ was includedin the VBM model in addition to ICV. Regions of lower grey matterfor the OCD group still remained in right and left parietal, rightfrontal, left temporal and left cingulate regions (uncorrectedpo0.0001 and d.f.¼16), but not in right cingulate and temporalregions. Regions of lower white matter for the OCD group stillremained in right middle frontal gyrus and left middle occipitalgyrus (uncorrected po0.0001 and d.f.¼16), but not in the corpuscallosum. The current study found no significant correlation ofbrain volume (in either local ROI volume or clusters in whole brain)with symptom severity, as assessed by the CY–BOCS.

ean7S.D.) OCD (Mean7S.D.)

1413.6789.5 t¼2.51, p¼0.019

672.2740.9 t¼2.52, p¼0.016

458.7732.7 t¼2.42, p¼0.025

1131.0772.7 t¼2.51, p¼0.018

26.472.2 t¼2.50, p¼0.017

75.875.2 t¼2.17, p¼0.041

15.670.8 t¼1.57, p¼0.064

Table 3Regions showing significantly higher grey matter volume in typically-developing participants compared to young people with OCD.

Structures Lat. MNI Cluster Voxel Voxel p p (FDR)

x (mm) y (mm) z (mm) size k T equiv Z

Precuneus and cingulate 14 �62 47 21,826 6.23 4.49 0.000 0.042

�9 �2 47 4.99 3.90 0.000 0.042

2 13 54 4.94 3.88 0.000 0.042

Orbitofrontal cortex L �15 52 �22 1096 4.03 3.36 0.000 0.043

�32 33 �6 3.78 3.20 0.001 0.044

�27 28 �12 3.53 3.04 0.001 0.044

R 27 28 �9 294 3.75 3.18 0.001 0.044

21 38 �12 3.02 2.68 0.004 0.046

Inferior frontal gyrus L �50 22 20 143 3.47 3.00 0.001 0.044

Precentral gyrus R 45 �9 57 1694 5.52 4.17 0.000 0.042

46 �2 39 3.82 3.26 0.001 0.044

Temporal pole/uncus L �48 12 �40 3567 5.46 4.17 0.000 0.042

�32 �2 �36 4.44 3.60 0.000 0.042

�51 �6 �12 3.1 2.74 0.003 0.045

R 33 21 �37 293 3.47 2.99 0.001 0.044

28 0 �37 582 3.64 3.11 0.001 0.044

21 �2 49 3.13 2.76 0.003 0.045

36 �5 �51 2.96 2.64 0.004 0.047

0.5

Insula (postcentral) R 49 �8 20 4500 5.28 4.05 0.000 0.042

42 10 �6 3.77 3.20 0.0010. 0.044

66 �3 3.29 2.87 0.001 0.044

L �38 4 5 715 3.66 3.13 0.001 0.044

Hippocampus L �14 �17 �21 116 3.16 2.78 0.003 0.045

0.5

Inferior temporal gyrus R 50 �23 �30 279 3.91 3.29 0.001 0.044

50 �33 �16 535 3.77 3.19 0.001 0.044

52 �44 �18 3.32 2.89 0.002 0.044

Middle temporal gyrus L �46 �54 �1 353 4.15 3.43 0.000 0.043

�51 �50 5 3.46 2.99 0.001 0.044

�48 �51 �9 3.23 2.83 0.002 0.045

Superior temporal gyrus R 51 0 �18 1370 4.37 3.56 0.000 0.042

Temporo-parietal junction L �57 �32 29 2007 4.37 3.56 0.000 0.042

�34 �30 47 4.69 3.74 0.000 0.042

�48 �41 15 3.38 2.94 0.002 0.044

Inferior parietal lobule R 51 �26 35 418 3.69 3.14 0.001 0.044

Superior parietal lobule L �36 �56 60 209 3.37 2.93 0.002 0.044

�24 �50 62 3.28 2.86 0.002 0.044

Inferior occipital gyrus L �29 �90 �1 745 4.95 3.88 0.000 0.042

�34 �81 3 4.88 3.85 0.000 0.042

0.5

Middle occipital gyrus L �28 �80 20 933 5.63 4.22 0.000 0.042

Lingual gyrus L �6 �96 �9 1138 4.31 3.52 0.000 0.042

R 14 �84 2 3.64 3.11 0.001 0.044

3 �90 0 3.54 3.04 0.001 0.044

L �14 �77 0 152 3.52 3.03 0.001 0.044

�20 �68 2 3.16 2.78 0.003 0.045

Cerebellar inferior semi-lunar Lobule L �10 �69 �39 287 3.71 3.16 0.001 0.044

R 12 �84�45 648 3.41 2.95 0.002 0.044

9 �72 �40 3.2 2.81 0.002 0.045

po0.05 (FDR corrected), 4100 voxels, d.f.¼19. Cluster peaks shown underlined, followed by secondary and tertiary significant local maxima.

J. Chen et al. / Psychiatry Research: Neuroimaging 213 (2013) 11–1714

4. Discussion

The VBM approach used in this carefully defined group ofchildren and adolescents with OCD and matched typically devel-oping participants yielded the following important findings: theexpected brain volume differences were evident in grey matterventral prefrontal cortex and the striatum, as well as white matterabnormalities involving the cingulum bundle and the corpuscallosum. Further, as hypothesised, the parietal region wasanomalous in the OCD group. Specifically, relative to typicallydeveloping participants, young people with OCD showed reducedoverall ICV, as well as total grey and white matter volumes. Withregards to region-specific differences, young people with OCD hadlower grey matter volumes in bilateral frontal, parietal and

temporal cortices, the left cingulate and occipital cortices, as wellas the right limbic regions. Young people with OCD also had lowerwhite matter in bilateral limbic–cingulate and occipital cortices,the right frontal, parietal and insula cortices, and the left temporalregions. Importantly, this is the first study to report significantlylower volume reduction in posterior parts of the corpus callosumin young people with OCD.

After taking into account ICV differences between the twogroups, the similar network of regions, including frontal, cingu-late, and parietal areas in grey and white matter was stillapparent at a lower threshold. Further analysis controlling full-scale IQ revealed differences in most of these regions, except inthe corpus callosum, right cingulate and temporal regions, whichsuggests their relatively greater association with full-scale IQ.

Table 4Regions showing significantly higher white matter volume in typically-developing participants compared to young people with OCD.

Structures Lat. MNI Cluster Voxel Voxel p p (FDR)

x (mm) y (mm) z (mm) size k T equiv Z

Corpus callosum R 3 �27 27 1000 5.62 4.22 0.000 0.047

4 �39 24 4.86 3.84 0.000 0.047

L �6 �26 24 4.74 3.77 0.000 0.047

Middle frontal gyrus R 27 7 47 314 5.33 4.08 0.000 0.047

Insula R 46 �12 20 46 4.44 3.60 0.000 0.047

Middle occipital gyrus L �27 �87 11 133 5.17 4.00 0.000 0.047

�26 �83 5 4.74 3.77 0.000 0.047

Middle temporal gyrus L �36 �68 21 62 4.97 3.89 0.000 0.047

Superior temporal gyrus L �44 3 �28 295 4.97 3.89 0.000 0.047

Precuneus R 27 �51 47 105 4.83 3.82 0.000 0.047

14 �62 33 72 4.75 3.77 0.000 0.047

12 �48 50 15 4.20 3.46 0.000 0.047

Fusiform gyrus L �36 �51 �12 12 4.31 3.53 0.000 0.047

Cingulate gyrus L �8 �35 36 44 4.30 3.52 0.000 0.047

po0.05 (FDR corrected), 410 voxels, degrees of freedom¼19. Cluster peaks shown underlined, followed by secondary and tertiary significant local maxima.

Fig. 1. Lower grey matter and white mater tissue volume in young people with OCD. (a) Regions of significantly lower grey matter volume in young people with OCD and

(b) regions of significantly lower white matter volume in young people with OCD. (po0.05 and d.f.¼19, FDR multiple comparison corrected). Images are displayed in

Neurological Orientation (Left¼Left). Colours indicate the t-score. (For interpretation of the references to color in this figure legend, the reader is referred to the web

version of this article.)

J. Chen et al. / Psychiatry Research: Neuroimaging 213 (2013) 11–17 15

Decreased tissue volumes in frontal and occipital (extendinginto parietal) regions are concordant with previous findings inpaediatric OCD VBM studies (Carmona et al., 2007; Szeszko et al.,2008; Lazaro et al., 2009) as well as the meta-analyses (Radua andMataix-Cols, 2009; Rotge et al., 2010). Also, decreased cingulatevolume is consistent with VBM studies of paediatric (Carmonaet al., 2007) and adult OCD sufferers (Kim et al., 2001; Pujol et al.,2004; Valente et al., 2005) as well as the meta-analysis byRadua and Mataix-Cols (2009). Lower frontal and cingulatevolumes have important implications for our understanding ofOCD pathophysiology: neuropsychological studies have showndeficits in executive functioning and cognitive-behavioral flex-ibility, known to be subserved by neural networks involving thesebrain regions (Friedlander and Desrocher, 2006). Task-specificfMRI studies in adult (Maltby et al., 2005) and paediatric OCD(Lazaro et al., 2008; Woolley et al., 2008) have also showndysfunction in many of these key brain regions, which may relateto underlying structural abnormalities. Further, these brain regionsare consistent with known neuroanatomical models of OCD suchas shown by Insel and Winslow (1992). However, our findings

differ from those reported in a previous manual tracing study(MacMaster et al., 2010) and VBM study (Szeszko et al., 2008) inpaediatric OCD, even though lower volumes in frontal regions werereported in adult OCD patients (Szeszko et al., 1999; Pujol et al.,2004), paediatric OCD patients (Carmona et al., 2007) and themeta-analysis of OFC ROI volume study (Rotge et al., 2009). Todate, structural neuroimaging studies have partially confirmed theOFC to be a critical brain region in fronto–striatal–thalamic models,even if extant findings are currently heterogeneous. Future studiesare necessary to clarify this point.

Consistent with Carmona et al. (2007), no significant basalganglia differences were found in the current study. This seems tocontradict the majority of adult OCD findings. The basal ganglia,especially the caudate nucleus and putamen (striatum), havebeen extensively linked with routine task performance and taskreinforcement. Indeed, these regions, together with their OFCconnections, have been of central interest in models of OCDpathophysiology (Canales and Graybiel, 2000; Graybiel andRauch, 2000; Haruno and Kawato, 2006; Williams and Eskandar,2006). For instance, Pujol et al. (2004) found a positive correlation

J. Chen et al. / Psychiatry Research: Neuroimaging 213 (2013) 11–1716

between age and striatal abnormalities, implying enduring stria-tal dysfunction. However, the absence of any striatal differencehas been reported in many OCD populations (Luxenberg et al.,1988; Szeszko et al., 2004; Gilbert et al., 2008). These contrary,variable results may arise from the following factors: first, thevariable developmental nature and trajectory of OCD, along withexcessive OCD compulsive habits, such as the repetition ofroutines, may alter the structural and/or functional developmen-tal trajectory of the basal ganglia (Carmona et al., 2007). Second,regional brain developmental differences, for example, phylogen-etically older regions maturing earlier than newer ones andhigher order association cortices maturing later; both in a non-linear fashion (Gogtay et al., 2004) and the ‘inverted U’ develop-mental course of key brain regions (Lenroot and Giedd, 2006) mayinfluence findings arising from children and adolescents com-pared to adults and even other groups of children and adoles-cents. Third, gender brain developmental differences, for example,the basal ganglia volumes peaking at 7.5 years in girls comparedto 10.0 years in boys and frontal lobe volumes peaking at 11.0years in girls compared to 12.0 years in boys (Lenroot and Giedd,2006), may again influence our findings.

The current study found significantly lower white matter volumesin the isthmus and splenium regions of the corpus callosum in OCD.Lower white matter volume in the corpus callosum has not beenreported in previous OCD-VBM studies; however, there is increasingevidence for corpus callosum abnormalities in patients with OCD:signal intensity, width, and length of the corpus callosum have beenfound to be abnormal in OCD patients (Jenike et al., 1996; Rosenberget al., 1997a; MacMaster et al., 1999). The corpus callosum has beenfound to be significantly larger in paediatric OCD patients (notincluding the isthmus), and the corpus callosum volume was sig-nificantly correlated with OCD symptom severity, but not with illnessduration (Rosenberg et al., 1997a). Also, diffusion tensor imaging(DTI) studies have revealed corpus callosum anomalies of FA anddiffusivity in adult and paediatric OCD patients compared withhealthy control participants (Saito et al., 2008; Bora et al., 2011;Nakamae et al., 2011; Zarei et al., 2011; Silk et al., under review). Thecorpus callosum is the largest inter-hemispheric white matter com-missure connecting homologous areas of the cerebral hemispheres. Inaddition, the splenium region of the corpus callosum contains inter-hemispheric fibres connecting associative regions in parietal–occipitallobes of both sides of the brain and the genu region of the corpuscallosum contains fibres connecting to the medial frontal region(Raybaud, 2010). Thus, deficits in the corpus callosum may beassociated with the tissue volume abnormalities in frontal andparietal regions.

Lower volumes of both white and grey matter were detected inparietal–occipital regions. Despite not being part of traditional OCDnetworks, parietal lobe abnormalities have been reported in paedia-tric OCD and OCD patients with right parietal multiple sclerosis(Carmona et al., 2007; Douzenis et al., 2009; Lazaro et al., 2009).Indeed, the possibility that parietal lobe white matter might play arole in mediating obsessions and compulsions through disruptions ofthe functional connectivity between cortical–cortical and/or cortical–subcortical brain regions implicated in the pathophysiology of OCDhas been previously discussed by Douzenis et al. (2009).

The current study also found regional volume differences inthe insula. The insular cortex forms part of the limbic regionneural network, and abnormalities in this region have beenconfirmed for OCD in grey matter volume (Pujol et al., 2004;Yoo et al., 2008), functional activation (Gilbert et al., 2009),diffusivity matrices (Nakamae et al., 2008, 2011; Fan et al.,2012), and cortical thickness (Nakamae et al., 2012). As a hubthat is located between the anterior and posterior cerebral hemi-spheres, the insula is a region with many functions linked to itsstructure. The key role of the insula may involve orchestrating the

balance between those brain structures that deal with adaptationto the environment, monitoring body state, and working togetherwith other limbic cortical structures to integrate thoughts andfeelings (Shelley and Trimble, 2004). Therefore, dysfunction ofinsula-linked neural networks may involve restriction of effectiveintegration of body state, emotion and higher cognitive function.

The current study found no significant correlation of brainvolume with symptom severity, as assessed by the CY–BOCS.While adult studies and meta-analyses have found correlations(Yoo et al., 2008; Radua and Mataix-Cols, 2009), studies assessingpaediatric populations have not reported an association with brainstructure at a corrected level (Carmona et al., 2007; Jayarajan et al.,2012; Silk et al., under review). The lack of this association may bedue to the developmental differences between paediatric and adultpopulations. The other possibility may be that the limited samplesize and the small range of CY–BOCS scores may not be sufficient tomake statistical inferences.

In summary, this study provides further evidence of braindysmorphology in paediatric OCD patients. In addition to fronto–striatal–thalamic neural networks, abnormalities in other brainregions, such as the parietal lobe and corpus callosum, weredemonstrated. These brain regions may play an additional role inthe pathophysiology of OCD. Future studies with larger samplesizes to replicate these findings, the power to examine specificOCD symptom dimensions and the power to investigate keycomorbid conditions commonly occurring with OCD will bevaluable extensions to the current work.

Acknowledgements

This work was supported by the Eric Ormond Baker Trust, bythe National Health and Medical Research Council, by the Victor-ian Government’s Operational Infrastructure Support Programand by the Royal Children’s Hospital staff and patients. T.S. wassupported by a NHMRC Career Development Award.

Appendix A. Supporting information

Supplementary data associated with this article can be foundin the online version at http://dx.doi.org/10.1016/j.pscychresns.2013.02.003.

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