Functional dysconnection in the prefrontal-amygdala circuitry in unaffected siblings of patients with bipolar I disorder

Objectives Bipolar I disorder (BD) is a highly heritable disorder characterized by mood swings between high-energy and low-energy states. Amygdala hyperactivity and cortical inhibitory hypoactivity [e.g., of the dorsolateral prefrontal cortex (dlPFC)] have been found in patients with BD, as evidenced by their abnormal resting-state functional connectivity (FC) and glucose utilization (GU). However, it has not been determined whether functional abnormalities of the dlPFC–amygdala circuit exist in unaffected, healthy siblings of the patients with BD (BDsib). Methods Twenty euthymic patients with BD, 20 unaffected matching BDsib of the patient group, and 20 well-matched healthy control subjects were recruited. We investigated seed-based FC (seeds: dlPFC) with resting-state functional magnetic resonance imaging and GU in the regions of interest (e.g., dlPFC and amygdala) using 18F-fluorodeoxyglucose positron emission tomography. Results The FC in the dlPFC (right)–amygdala circuit was statistically abnormal in patients with BD and BDsib, but only the patients with BD demonstrated hypoactive GU bilaterally in the dlPFC and hyperactive GU bilaterally in the amygdala. Facilitating differentiation between the BD groups, the altered FC between dlPFC (right) and amygdala (left) was even more prominent in the patients with BD (p