Brain structural response in individuals at familial risk for bipolar disorder: a tale of two outcomes.

t i e B ipolar disorder (BD) is a chronic psychiatric disorder with high morbidity and mortality, deserving of efforts to understand who are at highest risk for developing this disorder. So far, he most reliable risk factor is a family history of BD. Twin and family tudies have reported a 59 – 87% heritability of BD suggesting that rst-degree relatives of probands with BD are at particularly high isk for developing BD themselves (1). Indeed, family members of D probands also have high rates of mood and other psychiatric isorders. However, longitudinal follow-up of offspring of parents ith BD, for example, show variable rates of conversion to full mood yndromes influenced by a variety of factors that have modest redictive power. Researchers are turning to neuroimaging to idenify biologic targets such as aberrant brain structures in individuals ho have a familial risk for developing BD to bridge a clinical assessent of emotion dysregulation with biologically mediated brain bnormalities to advance our understanding of the pathophysiolgy of BD development. In this issue of Biological Psychiatry, Hajek t al. (2) and Mahon et al. (3) present the findings of two studies imed at addressing this important area. Using structural brain magnetic resonance imaging, Hajek et al. 2) found that individuals with BD as well as their affected and naffected relatives had a significantly larger right inferior frontal yrus (IFG) than did healthy control subjects. Although others have ound an enlarged IFG in BD subjects in early stages of the illness (4), his appears to be the first time that enlargement in this region has lso been found in family members of individuals with BD with or ithout the illness. The authors suggest that this finding might be a iomarker for the development of BD, an assertion that makes ense, given what is known about the integral function of the IFG, pecifically Brodmann area 47, in emotional regulation and sociomotional learning. The IFG has been implicated in the pathophysiology of affective isorders. Increased activation in the IFG has been found in youth ith BD in response to emotional tasks (5), and abnormal functional onnectivity of this region with the amygdala was recently reported n adults with BD (6). However, this region has also been implicated n risk for developing other mental disorders such as schizophrenia 7), reducing the potential specificity of this finding. Moreover, the IFG s highly lateralized in function such that the right side mediates proessing of nonverbal material, whereas the left side mainly governs anguage-related function. It is not known which among these funcions of the IFG are most relevant to emotional processing in BD. oreover, it is also unknown whether the structural changes in this egion are caused by abnormal functional demands or by impaired hite matter connections. Additional study of this region in the ontext of bipolar illness development could clarify these issues. Using a similar high-risk design, Mahon et al. (3) examined hite matter integrity (assessed via fractional anisotropy [FA])