Genetic liability for bipolar disorder is characterized by excess frontal activation in response to a working memory task

Background: There is evidence that patients with bipolar disorder have working memory deficits even during periods of euthymia. The neural basis of such deficits and its relationship with genetic risk remain unclear. We utilized functional magnetic resonance imaging (fMRI) to investigate neural activity in samples of bipolar disorder patients and their unaffected first-degree relatives while performing working memory tasks of increasing difficulty. Methods: Twenty remitted bipolar I disorder patients, 20 of their unaffected first-degree relatives, and 20 healthy volunteers were recruited and successfully completed scanning. Subjects participated in fMRI scans consisting of an n-back working memory task with three stages of increasing difficulty (1-back, 2-back, and 3-back), alternating with a baseline attention task. Groups were analyzed separately to produce brain activation maps, and a group-by-task analysis of variance (ANOVA) with post hoc comparisons was completed. Results: Patients performed more poorly online than control subjects and relatives on the 2-back and 3-back tasks. The group-by-task ANOVA demonstrated a significantly altered region of neural activity involving a cluster located in the left frontal pole/ventrolateral gyrus. Post hoc analyses demonstrated that this cluster was accounted for by significantly greater activation in relatives compared with control subjects for the 2-back task. Patients demonstrated a trend to significantly greater activation than control subjects in the same cluster during 1-back performance. Conclusions: Left prefrontal hyperactivation during working memory is associated with genetic liability for bipolar disorder and represents a potential neurobiological endophenotype for the illness.