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Multicenter Voxel-Based Morphometry Mega-Analysis of Structural Brain Scans in Obsessive-Compulsive Disorder
Stella J. de Wit, M.D.; Pino Alonso, M.D., Ph.D.; Lizanne Schweren, M.Sc.; David Mataix-Cols, Ph.D.; Christine Lochner, Ph.D.; José M. Menchón, M.D., Ph.D.; Dan J. Stein, M.D., Ph.D.; Jean-Paul Fouche, M.Sc.; Carles Soriano-Mas, Ph.D.; Joao R. Sato, Ph.D.; Marcelo Q. Hoexter, M.D., Ph.D.; Damiaan Denys, M.D., Ph.D.; Takashi Nakamae, M.D., Ph.D.; Seiji Nishida, M.D., Ph.D.; Jun Soo Kwon, M.D., Ph.D.; Joon Hwan Jang, M.D., Ph.D.; Geraldo F. Busatto, M.D., Ph.D.; Narcís Cardoner, M.D., Ph.D.; Danielle C. Cath, M.D., Ph.D.; Kenji Fukui, M.D., Ph.D.; Wi Hoon Jung, Ph.D.; Sung Nyun Kim, M.D.; Euripides C. Miguel, M.D., Ph.D.; Jin Narumoto, M.D., Ph.D.; Mary L. Phillips, M.D., Ph.D.; Jesus Pujol, M.D., Ph.D.; Peter L. Remijnse, M.D., Ph.D.; Yuki Sakai, M.D., Ph.D.; Na Young Shin, M.A.; Kei Yamada, M.D., Ph.D.; Dick J. Veltman, M.D., Ph.D.; Odile A. van den Heuvel, M.D., Ph.D.
Am J Psychiatry 2014;171:340-349. doi:10.1176/appi.ajp.2013.13040574
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The authors report no financial relationships with commercial interests.

Supported by the Dutch Organization for Scientific Research (NWO) (grants 912-02-050, 907-00-012, 940-37-018, and 916.86.038); the Carlos III Health Institute (PI09/01331, PI10/01753, PI10/01003, CP10/00604, and CIBER-CB06/03/0034); the Agency for Administration of University and Research (AGAUR, Barcelona; 2009SGR1554); a “Miguel Servet” contract from the Carlos III Health Institute (CP10/00604) to Dr. Soriano-Mas; Ministry of Education, Culture, Sports, Science, and Technology (Japan) Grants-in-Aid for Young Scientists to Dr. Narumoto (23591724) and to Dr. Nakamae (24791223); Wellcome Trust project grant 064846; a grant from the Foundation for the Support of Research in the State of São Paulo (FAPESP) to Dr. Miguel (2005/55628-8); a FAPESP scholarship to Dr. Hoexter (2005/04206-6); and a National Research Foundation of Korea grant funded by the Korean government (Ministry of Education, Science, and Technology, 2012-0005150).

From the Departments of Psychiatry and of Anatomy and Neurosciences, VU University Medical Center, Amsterdam; Department of Psychiatry, Bellvitge University Hospital-Bellvitge Institute for Biomedical Research (IDIBELL), University of Barcelona, Barcelona, Spain; Carlos III Health Institute, Center for Biomedical Research Network on Mental Health (CIBERSAM), Barcelona; Institute of Psychiatry, King’s College London, London; MRC Unit on Anxiety and Stress Disorders, Department of Psychiatry, University of Stellenbosch, Stellenbosch, South Africa; Departments of Human Biology and of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa; Center of Mathematics, Computation, and Cognition, Federal University of ABC, Santo André, Brazil; Department and Institute of Psychiatry, University of São Paulo Medical School, São Paulo, Brazil; Department of Psychiatry, Academic Medical Center, Amsterdam; Departments of Psychiatry and Radiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh; and CRC-Hospital del Mar, Barcelona.

Address correspondence to Dr. van den Heuvel (oa.vandenheuvel@vumc.nl).

Copyright © 2014 by the American Psychiatric Association

Received April 29, 2013; Revised August 28, 2013; Accepted September 12, 2013.

Abstract

Objective  Results from structural neuroimaging studies of obsessive-compulsive disorder (OCD) have been only partially consistent. The authors sought to assess regional gray and white matter volume differences between large samples of OCD patients and healthy comparison subjects and their relation with demographic and clinical variables.

Method  A multicenter voxel-based morphometry mega-analysis was performed on 1.5-T structural T1-weighted MRI scans derived from the International OCD Brain Imaging Consortium. Regional gray and white matter brain volumes were compared between 412 adult OCD patients and 368 healthy subjects.

Results  Relative to healthy comparison subjects, OCD patients had significantly smaller volumes of frontal gray and white matter bilaterally, including the dorsomedial prefrontal cortex, the anterior cingulate cortex, and the inferior frontal gyrus extending to the anterior insula. Patients also showed greater cerebellar gray matter volume bilaterally compared with healthy subjects. Group differences in frontal gray and white matter volume were significant after correction for multiple comparisons. Additionally, group-by-age interactions were observed in the putamen, insula, and orbitofrontal cortex (indicating relative preservation of volume in patients compared with healthy subjects with increasing age) and in the temporal cortex bilaterally (indicating a relative loss of volume in patients compared with healthy subjects with increasing age).

Conclusions  These findings partially support the prevailing fronto-striatal models of OCD and offer additional insights into the neuroanatomy of the disorder that were not apparent from previous smaller studies. The group-by-age interaction effects in orbitofrontal-striatal and (para)limbic brain regions may be the result of altered neuroplasticity associated with chronic compulsive behaviors, anxiety, or compensatory processes related to cognitive dysfunction.

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FIGURE 1. Regional Gray and White Matter Volume Differences Between OCD Patients (N=412) and Healthy Comparison Subjects (N=368)a

a Compared with healthy subjects, OCD patients exhibit smaller (blue/green) regional medial and inferior frontal gray (panel A) and white (panel B) matter volume and greater (red/yellow) regional cerebellar gray matter volume (panel C). Brain slices in panels A–C are in coronal (left), sagittal (middle), and axial (right) direction; left side of brain is on the left. MNI coordinates (x, y, z) of panel A, –1, 18, 0; of panel B, –11, 23, 12; of panel C, 6, –55, –40. All presented imaging results are T-statistic images overlain over the SPM8 single-subject T1 standard brain with MRIcron (www.mccauslandcenter.sc.edu/mricro/mricron) and thresholded at p<0.001 uncorrected with a minimum cluster extent of 100 voxels. T values are displayed from red/blue (T=3.1) to yellow/green (T≥4.0).

FIGURE 2. Group-by-Age Interactions in the Putamen and Orbitofrontal Cortex in OCD Patients (N=412) and Healthy Comparison Subjects (N=368)a

a The left-hand panel shows relative preservation of putamen/insular (circle in upper image) and orbitofrontal (circle in lower image) gray matter volume with increasing age in OCD patients compared with healthy subjects. T-statistic images are from linear and nonlinear age-by-group analyses and are thresholded at p<0.001 uncorrected with a minimum cluster extent of 98 voxels for illustration purposes. In the right-hand panel, the line plots show mean peak voxel values of the right putamen/insula cluster (upper plot; linear age scale) and left orbitofrontal frontal cortex (lower plot; quadratic age scale) in patients and healthy subjects. Displayed values are the mean parameter estimate (which relates to relative gray matter volume) per time bin (1 year) per group in arbitrary units (aU). L=left.

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TABLE 1.Demographic and Clinical Characteristics of OCD Patients and Healthy Comparison Subjects
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a Missing data for characteristics ranged from N=0 to N=40.

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b As measured with the Yale-Brown Obsessive Compulsive Scale (YBOCS) total score. Mean score on the obsessions subscale, 12.6 (SD=3.4); mean score on the compulsions subscale, 12.3 (SD=3.8).

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c As measured with the YBOCS symptom checklist.

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TABLE 2.Number of Scans Provided and Included for OCD Patients and Healthy Comparison Subjects at Each Center
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a Poor quality is an umbrella term referring to scans being either nonsegmentable or having artifacts related to motion, poor contrast, or imaging.

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TABLE 3.Regional Brain Volume Differences Between OCD Patients (N=412) and Healthy Comparison Subjects (N=368)a
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a Analysis of covariance thresholded at p<0.001 uncorrected and a minimum cluster extent (ke) of 100 voxels. Table shows local maxima more than 8.0 mm apart. Results are corrected for age, gender, education level, total gray matter or white matter volume, and scan sequence. BA=Brodmann’s area; MNI=Montreal Neurological Institute; L=left; R=right; ns=not significant.

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b Whole-brain cluster family-wise error corrected and nonstationarity corrected p value.

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TABLE 4.Group-by-Age Interactions on Regional Brain Volume in OCD Patients (N=412) and Healthy Comparison Subjects (N=368)a
Table Footer Note

a Linear (age) and nonlinear (age squared) group-by-age interaction analysis thresholded at p<0.001 uncorrected and a minimum cluster extent (ke) of 100 voxels. Table shows local maxima more than 8.0 mm apart. Results are corrected for gender, education level, total gray matter or white matter volume, and scan sequence. BA=Brodmann’s area; MNI=Montreal Neurological Institute; L=left; R=right; ns=not significant.

Table Footer Note

b Whole-brain cluster family-wise error corrected and nonstationarity corrected p value.

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