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Brain Advance Access originally published online on September 13, 2007
Brain 2007 130(12):3223-3236; doi:10.1093/brain/awm205
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Neurocognitive endophenotypes of obsessive-compulsive disorder

Lara Menzies1–3, Sophie Achard1, Samuel R. Chamberlain2–4, Naomi Fineberg2, Chi-Hua Chen1, Natalia del Campo3,4, Barbara J. Sahakian3,4, Trevor W. Robbins3 and Ed Bullmore1,3,5

1Brain Mapping Unit, University of Cambridge, 2Department of Psychiatry, Queen Elizabeth II Hospital, Welwyn Garden City, 3Department of Experimental Psychology, Behavioural and Clinical Neurosciences Institute, University of Cambridge, Cambridge, CB2 3EB, 4Department of Psychiatry, Addenbrooke's Hospital, Cambridge, CB2 2QQ and 5Clinical Unit Cambridge, Addenbrooke's Centre for Clinical Investigations, Clinical Pharmacology & Discovery Medicine, GlaxoSmithKline, Cambridge CB2 2QQ, UK

Correspondence to: Professor Ed Bullmore, Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 2QQ, UK E-mail: etb23{at}cam.ac.uk

Endophenotypes (intermediate phenotypes) are objective, heritable, quantitative traits hypothesized to represent genetic risk for polygenic disorders at more biologically tractable levels than distal behavioural and clinical phenotypes. It is theorized that endophenotype models of disease will help to clarify both diagnostic classification and aetiological understanding of complex brain disorders such as obsessive-compulsive disorder (OCD). To investigate endophenotypes in OCD, we measured brain structure using magnetic resonance imaging (MRI), and behavioural performance on a response inhibition task (Stop-Signal) in 31 OCD patients, 31 of their unaffected first-degree relatives, and 31 unrelated matched controls. Both patients and relatives had delayed response inhibition on the Stop-Signal task compared with healthy controls. We used a multivoxel analysis method (partial least squares) to identify large-scale brain systems in which anatomical variation was associated with variation in performance on the response inhibition task. Behavioural impairment on the Stop-Signal task, occurring predominantly in patients and relatives, was significantly associated with reduced grey matter in orbitofrontal and right inferior frontal regions and increased grey matter in cingulate, parietal and striatal regions. A novel permutation test indicated significant familial effects on variation of the MRI markers of inhibitory processing, supporting the candidacy of these brain structural systems as endophenotypes of OCD. In summary, structural variation in large-scale brain systems related to motor inhibitory control may mediate genetic risk for OCD, representing the first evidence for a neurocognitive endophenotype of OCD.

Key Words: neuroimaging; inhibition; obsessive-compulsive; multivoxel; familial

Abbreviations: ANOVA, analysis of variance; DLPFC, dorsolateral prefrontal cortex; LSD, Least Significant Difference; MADRS, Montgomery Asberg Depression Rating Scale; MNI, Montreal Neurological Institute; MRI, magnetic resonance imaging; NART, National Adult Reading Test; OCD, obsessive-compulsive disorder; OCI-R, Obsessive Compulsive Inventory - Revised; OFC, orbitofrontal cortex; PLS, partial least squares; QTL, quantitative trait locus; RIFG, right inferior frontal gyrus; SPECT, Single Photon Emission Computed Tomography; SSRT, stop-signal reaction time; YBOCS, Yale Brown Obsessive Compulsive Scale

Received April 16, 2007. Revised July 30, 2007. Accepted July 31, 2007.


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