Brain structural signature of familial predisposition for bipolar disorder: Replicable evidence for involvement of the right inferior frontal gyrus

Background: To translate our knowledge about neuroanatomy of bipolar disorder (BD) into a diagnostic tool, it is necessary to identify the neural signature of predisposition for BD and separate it from effects of long-standing illness and treatment. Thus, we examined the associations among genetic risk, illness burden, lithium treatment, and brain structure in BD. Methods: This is a two-center, replication-design, structural magnetic resonance imaging study. First, we investigated neuroanatomic markers of familial predisposition by comparing 50 unaffected and 36 affected relatives of BD probands as well as 49 control subjects using modulated voxel-based morphometry. Second, we investigated effects of long-standing illness and treatment on the identified markers in 19 young participants early in the course of BD, 29 subjects with substantial burden of long-lasting BD and either minimal lifetime (n = 12), or long-term ongoing (n = 17) lithium treatment. Results: Five groups, including the unaffected and affected relatives of BD probands from each center as well as participants early in the course of BD showed larger right inferior frontal gyrus (rIFG) volumes than control subjects (corrected p <.001). The rIFG volume correlated negatively with illness duration (corrected p <.01) and, relative to the controls, was smaller among BD individuals with long-term illness burden and minimal lifetime lithium exposure (corrected p <.001). Li-treated subjects had normal rIFG volumes despite substantial illness burden. Conclusions: Brain structural changes in BD may result from interplay between illness burden and compensatory processes, which may be enhanced by lithium treatment. The rIFG volume could aid in identification of subjects at risk for BD even before any behavioral manifestations.