Abstract

First-degree relatives of persons with bipolar disorders (BDs) carry elevated risk for the illness, and manifest deficits in attention and memory (possible "endophenotypes"). However, there is only one published functional magnetic resonance imaging (fMRI) study of candidate endophenotypes in BD. We used fMRI to examine brain function in BD and in first-degree relatives performing a 2-back working memory (WM) task, and correlated brain activity with mood measures taken at the scanning session. Subjects (age 32-46) were 19 persons with BD, 18 unmedicated, non-psychotic first-degree relatives (RELs) of persons with BD, and 19 matched controls, ascertained from a long-term follow-up of a prenatal cohort study in New England. fMRI signal during 2-back and 0-back WM tasks was measured on a Siemens 1.5T MR scanner. fMRI data were analyzed using SPM-2. Persons with BD and RELs failed to suppress activation in the left anterior insula (BA 13) during WM, whereas controls suppressed activation. Compared to controls, RELs also failed to suppress activation in the orbitofrontal cortex (OFC) and superior parietal cortex. Controls and RELs exhibited greater activation than BD individuals in the left frontopolar cortex (BA 10) during WM. Results remained significant after controlling for confounders except for mild attenuation of OFC findings. Significant correlations between brain activity, mood, and WM suggest that activity in WM circuits is affected by activity in emotion-regulatory circuits. Persons with BD and RELs exhibit altered activity in the frontopolar cortex and insula, which may represent biomarkers of genetic risk for BD.