title: Brain regions associated with risk and resistance for bipolar I disorder: a voxel-based MRI study of patients with bipolar disorder and their healthy siblings.
abstract: OBJECTIVE
  Bipolar I disorder is a highly heritable disorder but not all siblings manifest with the illness, even though they may share similar genetic and environmental risk factors. Thus, sibling studies may help to identify brain structural endophenotypes associated with risk and resistance for the disorder.
  
  
  METHODS
  Structural magnetic resonance imaging (MRI) scans were acquired for 28 euthymic patients with bipolar disorder, their healthy siblings, and 30 unrelated healthy controls. Statistical Parametric Mapping 8 (SPM8) was used to identify group differences in regional gray matter volume by voxel-based morphometry (VBM).
  
  
  RESULTS
  Using analysis of covariance, gray matter analysis of the groups revealed a group effect indicating that the left orbitofrontal cortex [Brodmann area (BA) 11] was smaller in patients with bipolar disorder than in unrelated healthy controls [F = 14.83, p < 0.05 (family-wise error); 7 mm(3) ]. Paired t-tests indicated that the orbitofrontal cortex of patients with bipolar disorder [t = 5.19, p < 0.05 (family-wise error); 37 mm(3) ] and their healthy siblings [t = 3.89, p < 0.001 (uncorrected); 63 mm(3) ] was smaller than in unrelated healthy controls, and that the left dorsolateral prefrontal cortex was larger in healthy siblings than in patients with bipolar disorder [t = 4.28, p < 0.001 (uncorrected); 323 mm(3) ] and unrelated healthy controls [t = 4.36, p < 0.001 (uncorrected); 245 mm(3) ]. Additional region-of-interest analyses also found volume deficits in the right cerebellum of patients with bipolar disorder [t = 3.92, p < 0.001 (uncorrected); 178 mm(3) ] and their healthy siblings [t = 4.23, p < 0.001 (uncorrected); 489 mm(3) ], and in the left precentral gyrus of patients with bipolar disorder [t = 3.61, p < 0.001 (uncorrected); 115 mm(3) ] compared to unrelated healthy controls.
  
  
  CONCLUSIONS
  The results of this study suggest that a reduction in the volume of the orbitofrontal cortex, which plays a role in the automatic regulation of emotions and is a part of the medial prefrontal network, is associated with the heritability of bipolar disorder. Conversely, increased dorsolateral prefrontal cortex volume may be a neural marker of a resistance factor as it is part of a network of voluntary emotion regulation and balances the effects of the disrupted automatic emotion regulation system.
authors.affiliation: Department of Psychiatry, Ege University School of Medicine, Bornova, Izmir, Turkey; SoCAT Lab and Affective Disorders Unit, Ege University School of Medicine, Bornova, Izmir, Turkey; Department of Neuroscience, Ege University Institute of Health Sciences, Bornova, Izmir, Turkey.
authors.forename: Cagdas
authors.initials: C
authors.lastname: Eker
authors.forename: Fatma
authors.initials: F
authors.lastname: Simsek
authors.forename: Evrim Ebru
authors.initials: EE
authors.lastname: Yılmazer
authors.forename: Omer
authors.initials: O
authors.lastname: Kitis
authors.forename: Cem
authors.initials: C
authors.lastname: Cinar
authors.forename: Ozlem Donat
authors.initials: OD
authors.lastname: Eker
authors.forename: Kerry
authors.initials: K
authors.lastname: Coburn
authors.forename: Ali Saffet
authors.initials: AS
authors.lastname: Gonul
mesh_terms: D000328:Adult; D001714:Bipolar Disorder / Q000235:genetics / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D001931:Brain Mapping; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000473:pathology*; D035781:Siblings
keywords: bipolar disorder; dorsolateral prefrontal cortex; high risk; magnetic resonance imaging; orbitofrontal cortex; relatives; resistance; voxel based morphometry