Recruitment of orbitofrontal cortex during unpredictable threat among adults at risk for affective disorders.

Background: Mood and anxiety disorders are characterized by altered prefrontal-amygdala function and increased behavioral inhibition (BI) in response to potential threat. Whether these alterations constitute a vulnerability or a symptom of illness remains unclear. The medial orbitofrontal cortex (mOFC) is thought to play a central role in estimating probability and cost of threat, in turn informing selection of subsequent behaviors. To better understand the behavioral and neural processes that may be associated with risk for psychopathology, we used a virtual reality paradigm to examine behavioral and neural responses of psychiatrically healthy adults with familial history of affective disorders during anticipation of unpredictable threat. Methods: Twenty psychiatrically healthy adults with high familial risk for affective disorders and 20 low-risk matched controls underwent functional magnetic resonance imaging concurrent with a paradigm in which they explored virtual contexts associated with the threat of shock or safety from shock. Subjective anxiety ratings, skin conductance, exploratory behavior, and neural responses were examined for threat versus safe conditions. Results: High-risk adults evidenced greater right mOFC activation, as well as greater BI, compared to low-risk adults. There were no significant group differences in subjective ratings or autonomic responses. Individuals exhibiting greater activity in the right mOFC showed greater BI and decreased skin conductance response. Conclusions: These results suggest that BI and mOFC recruitment during anticipation of aversive outcomes may reflect a vulnerability for affective disorders. However, such a response may also serve as a compensatory response, protecting these high-risk individuals from negative outcomes (i.e., increased physiological arousal). These results suggest that the OFC may play a central role in driving threat-related behaviors and thus may be a target for efforts aimed at early detection or prevention.