Ketamine normalizes subgenual cingulate cortex hyper-activity in depression

Mounting evidence supports the rapid anti-depressant efficacy of the N-methyl-d-aspartate receptor antagonist, ketamine, for treating major depressive disorder (MDD); however, its neural mechanism of action remains poorly understood. Subgenual anterior cingulate cortex (sgACC) hyper-activity during rest has been consistently implicated in the pathophysiology of MDD, potentially driven by excessive hippocampal gluatmatergic efferents to sgACC. Reduction of sgACC activity has been associated with successful anti-depressant treatment. This study aimed to examine whether task-based sgACC activity was also higher in MDD patients compared to controls and to determine whether this activity was altered by single-dose ketamine. In Study 1, patients with MDD (N = 28) and healthy controls (N = 20) completed task-based functional magnetic resonance imaging using an established incentive-processing task. In Study 2, a second cohort of patients with MDD (N = 14) completed the same scanning protocol pre and post intravenous infusion of 40 min (0.5 mg/kg) ketamine treatment. Task-based activation of sgACC was examined with a seed-driven analysis assessing group differences and changes from pre to post treatment. Patients with MDD showed higher sgACC activation to positive and negative monetary incentives compared to controls, associated with anhedonia and anxiety, respectively. In addition, patients with MDD also had higher resting-state functional connectivity between hippocampus and sgACC, associated with sgACC hyper-activation to positive incentives, but not negative incentives. Finally, ketamine reduced sgACC hyper-activation to positive incentives, but not negative incentives. These findings suggest a neural mechanism by which ketamine exerts its anti-depressant efficacy, via rapid blunting of aberrant sgACC hyper-reactivity to positive incentives.