• bipolar disorder;
  • dorsolateral prefrontal cortex;
  • high risk;
  • magnetic resonance imaging;
  • orbitofrontal cortex;
  • relatives;
  • resistance;
  • voxel based morphometry


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.


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).


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 [= 14.83, p < 0.05 (family-wise error); 7 mm3]. Paired t-tests indicated that the orbitofrontal cortex of patients with bipolar disorder [= 5.19, p < 0.05 (family-wise error); 37 mm3] and their healthy siblings [= 3.89, p < 0.001 (uncorrected); 63 mm3] 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 [= 4.28, p < 0.001 (uncorrected); 323 mm3] and unrelated healthy controls [= 4.36, p < 0.001 (uncorrected); 245 mm3]. Additional region-of-interest analyses also found volume deficits in the right cerebellum of patients with bipolar disorder [= 3.92, p < 0.001 (uncorrected); 178 mm3] and their healthy siblings [= 4.23, p < 0.001 (uncorrected); 489 mm3], and in the left precentral gyrus of patients with bipolar disorder [= 3.61, p < 0.001 (uncorrected); 115 mm3] compared to unrelated healthy controls.


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.