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Subcortical and cortical morphological anomalies as an endophenotype in obsessive-compulsive disorder

Molecular Psychiatry volume 20, pages 224–231 (2015)Cite this article

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Abstract

Endophentoypes, quantifiable traits lying on the causal chain between a clinical phenotype and etiology, can be used to accelerate genomic discovery in obsessive-compulsive disorder (OCD). Here we identify the neuroanatomic changes that are shared by 22 OCD adult and adolescent patients and 25 of their unaffected siblings who are at genetic risk for the disorder. Comparisons were made against 47 age and sex matched healthy controls. We defined the surface morphology of the striatum, globus pallidus and thalamus, and thickness of the cerebral cortex. Patients with OCD show significant surface expansion compared with healthy controls, following adjustment for multiple comparisons, in interconnected regions of the caudate, thalamus and right orbitofrontal cortex. Their unaffected siblings show similar, significant expansion, most marked in the ventromedial caudate bilaterally, the right pulvinar thalamic nucleus and the right orbitofrontal cortex. These regions define a network that has been consistently implicated in OCD. In addition, both patients with OCD and unaffected siblings showed similar increased thickness of the right precuneus, which receives rich input from the thalamic pulvinar nuclei and the left medial temporal cortex. Anatomic change within the orbitofrontostriatal and posterior brain circuitry thus emerges as a promising endophenotype for OCD.

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References

  1. Ruscio A, Stein D, Chiu W, Kessler R . The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Mol Psychiatry 2008; 15: 53–63.

    Article  PubMed  PubMed Central  Google Scholar 

  2. van Grootheest DS, Cath DC, Beekman AT, Boomsma DI . Twin studies on obsessive-compulsive disorder: a review. Twin Res Hum Genet 2005; 8: 450–458.

    Article  PubMed  Google Scholar 

  3. Jonnal AH, Gardner CO, Prescott CA, Kendler KS . Obsessive and compulsive symptoms in a general population sample of female twins. Am J Med Genet 2000; 96: 791–796.

    Article  CAS  PubMed  Google Scholar 

  4. Pauls DL . The genetics of obsessive-compulsive disorder: a review. Dialogues Clin Neurosci 2010; 12: 149.

    PubMed  PubMed Central  Google Scholar 

  5. Mataix-Cols D, Boman M, Monzani B, Ruck C, Serlachius E, Langstrom N et al. Population-based, multigenerational family clustering study of obsessive-compulsive disorder. JAMA Psychiatry 2013; 70: 1–9.

    Article  Google Scholar 

  6. Taylor S . Molecular genetics of obsessive-compulsive disorder: a comprehensive meta-analysis of genetic association studies. Mol Psychiatry 2013; 18: 799–805.

    Article  CAS  PubMed  Google Scholar 

  7. Stewart SE, Yu D, Scharf JM, Neale BM, Fagerness JA, Mathews CA et al. Genome-wide association study of obsessive-compulsive disorder. Mol Psychiatry 2013; 18: 788–798, 843.

    Article  CAS  PubMed  Google Scholar 

  8. Gottesman II, Gould TD . The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003; 160: 636–645.

    Article  PubMed  Google Scholar 

  9. Chamberlain SR, Menzies L, Hampshire A, Suckling J, Fineberg NA, del Campo N et al. Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives. Science 2008; 321: 421–422.

    Article  CAS  PubMed  Google Scholar 

  10. den Braber A, van’t Ent D, Cath DC, Wagner J, Boomsma DI, de Geus EJ . Brain activation during cognitive planning in twins discordant or concordant for obsessive-compulsive symptoms. Brain 2010; 133: 3123–3140.

    Article  PubMed  PubMed Central  Google Scholar 

  11. de Wit SJ, de Vries FE, van der Werf YD, Cath DC, Heslenfeld DJ, Veltman EM et al. Presupplementary motor area hyperactivity during response inhibition: a candidate endophenotype of obsessive-compulsive disorder. Am J Psychiatry 2012; 169: 1100–1108.

    Article  PubMed  Google Scholar 

  12. Riesel A, Endrass T, Kaufmann C, Kathmann N . Overactive error-related brain activity as a candidate endophenotype for obsessive-compulsive disorder: evidence from unaffected first-degree relatives. Am J Psychiatry 2011; 168: 317–324.

    Article  PubMed  Google Scholar 

  13. Menzies L, Achard S, Chamberlain SR, Fineberg N, Chen C-H, Del Campo N et al. Neurocognitive endophenotypes of obsessive-compulsive disorder. Brain 2007; 130: 3223–3236.

    Article  PubMed  Google Scholar 

  14. Menzies L, Chamberlain SR, Laird AR, Thelen SM, Sahakian BJ, Bullmore ET . Integrating evidence from neuroimaging and neuropsychological studies of obsessive-compulsive disorder: the orbitofronto-striatal model revisited. Neurosci Biobehav Rev 2008; 32: 525–549.

    Article  PubMed  Google Scholar 

  15. Saxena S, Brody AL, Schwartz JM, Baxter LR . Neuroimaging and frontal-subcortical circuitry in obsessive-compulsive disorder. Br J Psychiatry 1998; 175 (Suppl 35): 26–37.

    Article  Google Scholar 

  16. Graybiel AM, Rauch SL . Toward a neurobiology review of obsessive-compulsive disorder. Neuron 2000; 28: 343.

    Article  CAS  PubMed  Google Scholar 

  17. Mataix-Cols D, van den Heuvel OA . Common and distinct neural correlates of obsessive-compulsive and related disorders. Psychiatric Clin North Am 2006; 29: 391–410, viii.

    Article  Google Scholar 

  18. Haber SN . The primate basal ganglia: parallel and integrative networks. J Chem Neuroanat 2003; 26: 317–330.

    Article  PubMed  Google Scholar 

  19. Delorme R, Gousse V, Roy I, Trandafir A, Mathieu F, Mouren-Simeoni M-C et al. Shared executive dysfunctions in unaffected relatives of patients with autism and obsessive-compulsive disorder. Eur Psychiatry 2007; 22: 32–38.

    Article  PubMed  Google Scholar 

  20. Viswanath B, Janardhan Reddy Y, Kumar KJ, Kandavel T, Chandrashekar C . Cognitive endophenotypes in OCD: a study of unaffected siblings of probands with familial OCD. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 610–615.

    Article  PubMed  Google Scholar 

  21. Chamberlain SR, Fineberg NA, Menzies LA, Blackwell AD, Bullmore ET, Robbins TW et al. Impaired cognitive flexibility and motor inhibition in unaffected first-degree relatives of patients with obsessive-compulsive disorder. Am J Psychiatry 2007; 164: 335–338.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lennertz L, Rampacher F, Vogeley A, Schulze-Rauschenbach S, Pukrop R, Ruhrmann S et al. Antisaccade performance in patients with obsessive-compulsive disorder and unaffected relatives: further evidence for impaired response inhibition as a candidate endophenotype. Eur Arch Psychiatry Clin Neurosci 2012; 262: 625–634.

    Article  PubMed  Google Scholar 

  23. Grieve KL . The primate pulvinar nuclei: vision and action. Trends Neurosci 2000; 23: 35–39.

    Article  CAS  PubMed  Google Scholar 

  24. Snow JC, Allen HA, Rafal RD, Humphreys GW, Desimone R . Impaired attentional selection following lesions to human pulvinar: evidence for homology between human and monkey. Proc Natl Acad Sci USA 2009; 106: 4054–4059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Cavanna AE, Trimble MR . The precuneus: a review of its functional anatomy and behavioural correlates. Brain 2006; 129: 564–583.

    Article  PubMed  Google Scholar 

  26. Jang JH, Kim J-H, Jung WH, Choi J-S, Jung MH, Lee J-M et al. Functional connectivity in fronto-subcortical circuitry during the resting state in obsessive-compulsive disorder. Neurosci Lett 2010; 474: 158–162.

    Article  CAS  PubMed  Google Scholar 

  27. Stern ER, Fitzgerald KD, Welsh RC, Abelson JL, Taylor SF . Resting-state functional connectivity between fronto-parietal and default mode networks in obsessive-compulsive disorder. PloS One 2012; 7: e36356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Harrison BJ, Soriano-Mas C, Pujol J, Ortiz H, Lopez-Sola M, Hernandez-Ribas R et al. Altered corticostriatal functional connectivity in obsessive-compulsive disorder altered corticostriatal functional connectivity in OCD. Arch Gen Psychiatry 2009; 66: 1189–1200.

    Article  PubMed  Google Scholar 

  29. Milad MR, Rauch SL . Obsessive-compulsive disorder: beyond segregated cortico-striatal pathways. Trends Cogn Sci 2012; 16: 43–51.

    Article  PubMed  Google Scholar 

  30. Rotge J-Y, Guehl D, Dilharreguy B, Tignol J, Bioulac B, Allard M et al. Meta-analysis of brain volume changes in obsessive-compulsive disorder. Biol Psychiatry 2009; 65: 75–83.

    Article  PubMed  Google Scholar 

  31. Radua J, van den Heuvel OA, Surguladze S, Mataix-Cols D . Meta-analytical comparison of voxel-based morphometry studies in obsessive-compulsive disorder vs other anxiety disorders. Arch Gen Psychiatry 2010; 67: 701–711.

    Article  PubMed  Google Scholar 

  32. Zarei M, Mataix-Cols D, Heyman I, Hough M, Doherty J, Burge L et al. Changes in gray matter volume and white matter microstructure in adolescents with obsessive-compulsive disorder. Biol Psychiatry 2011; 70: 1083–1090.

    Article  PubMed  Google Scholar 

  33. Choi J-S, Kim SH, Yoo SY, Kang D-H, Kim C-W, Lee J-M et al. Shape deformity of the corpus striatum in obsessive-compulsive disorder. Psychiatry Res 2007; 155: 257–264.

    Article  PubMed  Google Scholar 

  34. Kang D-H, Kim SH, Kim C-W, Choi J-S, Jang JH, Jung MH et al. Thalamus surface shape deformity in obsessive-compulsive disorder and schizophrenia. Neuroreport 2008; 19: 609–613.

    Article  PubMed  Google Scholar 

  35. Rotge J-Y, Langbour N, Guehl D, Bioulac B, Jaafari N, Allard M et al. Gray matter alterations in obsessive-compulsive disorder: an anatomic likelihood estimation meta-analysis. Neuropsychopharmacology 2009; 35: 686–691.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Narayan VM, Narr KL, Phillips OR, Thompson PM, Toga AW, Szeszko PR . Greater regional cortical gray matter thickness in obsessive-compulsive disorder. Neuroreport 2008; 19: 1551–1555.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Fallucca E, MacMaster FP, Haddad J, Easter P, Dick R, May G 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.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Shin YW, Yoo SY, Lee JK, Ha TH, Lee KJ, Lee JM et al. Cortical thinning in obsessive compulsive disorder. Hum Brain Mapp 2007; 28: 1128–1135.

    Article  PubMed  PubMed Central  Google Scholar 

  39. DuPaul GJ Power JD Anastopouls AA Reid R . (1998). ADHD Rating Scale-IV: Checklists, Norms and Clinical Interpretation. The Guilford Press: New York, NY, USA.

    Google Scholar 

  40. Reich W . Diagnostic interview for children and adolescents (DICA). J Am Acad Child Adolesc Psychiatry 2000; 39: 59–66.

    Article  CAS  PubMed  Google Scholar 

  41. Chakravarty M, Steadman P, van Eede MC, Calcott RD, Gu V, Shaw P et al. Performing label-fusion-based segmentation using multiple automatically generated templates. Hum Brain Mapp 2013; 34: 2635–2654.

    Article  PubMed  Google Scholar 

  42. Chakravarty MM, Bertrand G, Hodge CP, Sadikot AF, Collins DL . The creation of a brain atlas for image guided neurosurgery using serial histological data. Neuroimage 2006; 30: 359–376.

    Article  PubMed  Google Scholar 

  43. Chakravarty MM, Sadikot AF, Germann J, Bertrand G, Collins DL . Towards a validation of atlas warping techniques. Med Image Anal 2008; 12: 713–726.

    Article  PubMed  Google Scholar 

  44. Collins DL, Pruessner JC . Towards accurate, automatic segmentation of the hippocampus and amygdala from MRI by augmenting ANIMAL with a template library and label fusion. Neuroimage 2010; 52: 1355–1366.

    Article  PubMed  Google Scholar 

  45. Lorensen WE, Cline HE . Marching cubes: a high resolution 3D surface construction algorithm. Proceedings of the 14th Annual Conference on Computer Graphics and Interactive Techniques. New York, NY, USA. 1987.

    Google Scholar 

  46. Borghammer P, Ostergaard K, Cumming P, Gjedde A, Rodell A, Hall N et al. A deformation-based morphometry study of patients with early-stage Parkinson’s disease. Eur J Neurol 2010; 17: 314–320.

    Article  CAS  PubMed  Google Scholar 

  47. Lyttelton OC, Karama S, Ad-Dab’bagh Y, Zatorre RJ, Carbonell F, Worsley K et al. Positional and surface area asymmetry of the human cerebral cortex. Neuroimage 2009; 46: 895–903.

    Article  PubMed  Google Scholar 

  48. Kim JS, Singh V, Lee JK, Lerch J, Ad-Dab’bagh Y, MacDonald D et al. Automated 3-D extraction and evaluation of the inner and outer cortical surfaces using a Laplacian map and partial volume effect classification. Neuroimage 2005; 27: 210–221.

    Article  PubMed  Google Scholar 

  49. Lerch JP, Evans AC . Cortical thickness analysis examined through power analysis and a population simulation. Neuroimage 2005; 24: 163–173.

    Article  PubMed  Google Scholar 

  50. Lyttelton O, Boucher M, Robbins S, Evans A . An unbiased iterative group registration template for cortical surface analysis. Neuroimage 2007; 34: 1535–1544.

    Article  PubMed  Google Scholar 

  51. Rapoport JL . Childhood obsessive-compulsive disorder. In: Shaffer D, Ehrhardt A, Greenhill L (eds). The Clinical Guide to Child Psychiatry. The Free Press: New York, NY, 1985, pp 208–218.

    Google Scholar 

  52. Spreng RN, Grady CL . Patterns of brain activity supporting autobiographical memory, prospection, and theory of mind, and their relationship to the default mode network. J Cogn Neurosci 2010; 22: 1112–1123.

    Article  PubMed  Google Scholar 

  53. Greicius MD, Srivastava G, Reiss AL, Menon V . Default-mode network activity distinguishes Alzheimer’s disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci USA 2004; 101: 4637–4642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cavedini P, Zorzi C, Piccinni M, Cavallini MC, Bellodi L . Executive dysfunctions in obsessive-compulsive patients and unaffected relatives: searching for a new intermediate phenotype. Biol Psychiatry 2010; 67: 1178–1184.

    Article  PubMed  Google Scholar 

  55. Rauch SL, Savage CR, Alpert NM, Dougherty D, Kendrick A, Curran T et al. Probing striatal function in obsessive-compulsive disorder: a PET study of implicit sequence learning. J Neuropsychiatry Clin Neurosci 1997; 9: 568–573.

    Article  CAS  PubMed  Google Scholar 

  56. Rauch SL, Wedig MM, Wright CI, Martis B, McMullin KG, Shin LM et al. Functional magnetic resonance imaging study of regional brain activation during implicit sequence learning in obsessive-compulsive disorder. Biol Psychiatry 2007; 61: 330–336.

    Article  PubMed  Google Scholar 

  57. Peper JS, Brouwer RM, Boomsma DI, Kahn RS, Pol H, Hilleke E . Genetic influences on human brain structure: a review of brain imaging studies in twins. Hum Brain Mapp 2007; 28: 464–473.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Stein JL, Hibar DP, Madsen SK, Khamis M, McMahon KL, de Zubicaray GI et al Discovery and replication of dopamine-related gene effects on caudate volume in young and elderly populations (N= 1198) using genome-wide search. Mol Psychiatry 2011; 16: 927–937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lenroot RK, Schmitt JE, Ordaz SJ, Wallace GL, Neale MC, Lerch JP et al. Differences in genetic and environmental influences on the human cerebral cortex associated with development during childhood and adolescence. Hum Brain Mapp 2009; 30: 163–174.

    Article  PubMed  Google Scholar 

  60. Welch JM, Lu J, Rodriguiz RM, Trotta NC, Peca J, Ding J-D et al. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 2007; 448: 894–900.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Burguilere E, Monteiro P, Feng G, Graybiel AM . Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors. Science 2013; 340: 1243–1246.

    Article  Google Scholar 

  62. Bienvenu O, Wang Y, Shugart Y, Welch J, Grados M, Fyer A et al. Sapap3 and pathological grooming in humans: results from the OCD collaborative genetics study. Am J Med Genet B 2009; 150: 710–720.

    Article  Google Scholar 

  63. Ciliax BJ, Heilman C, Demchyshyn LL, Pristupa ZB, Ince E, Hersch SM et al. The dopamine transporter: immunochemical characterization and localization in brain. J Neurosci 1995; 15: 1714–1723.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ivanov I . Morphological abnormalities of the thalamus in youths with attention deficit hyperactivity disorder. Am J Psychiatry 2010; 167: 397–408.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Nakao T, Radua J, Rubia K, Mataix-Cols D . Gray matter volume abnormalities in ADHD: voxel-based meta-analysis exploring the effects of age and stimulant medication. Am J Psychiatry 2011; 168: 1154–1163.

    Article  PubMed  Google Scholar 

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Acknowledgements

The study was funded by the Intramural Programs of the National Human Genome Research Institute and the National Institute of Mental Health.

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Authors and Affiliations

  1. Section on Neurobehavioral Clinical Research, Social and Behavioral Research Branch, National Human Genome Research Institute,, Bethesda, MD, USA

    P Shaw, G Sudre & A Wharton

  2. Intramural Program of the National Institute of Mental Health,, Bethesda, MD, USA

    P Shaw, W Sharp, D Greenstein, A Raznahan & J Rapoport

  3. Brain Imaging Centre, Montreal Neuroimaging Institute and Hospital, McGill University, Montreal, QC, Canada,

    A Evans

  4. Kimel Family Imaging-Genetics Research Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada

    M M Chakravarty

  5. Department of Psychiatry and Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada

    M M Chakravarty

  6. Program in Neuroscience and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada,

    J P Lerch

  7. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    J P Lerch

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  1. P Shaw
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Shaw, P., Sharp, W., Sudre, G. et al. Subcortical and cortical morphological anomalies as an endophenotype in obsessive-compulsive disorder. Mol Psychiatry 20, 224–231 (2015). https://doi.org/10.1038/mp.2014.3

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