Project Summary/Abstract Binge eating disorder is the most common eating disorder afflicting up to 10% of US adults. It is characterized by recurring episodes of eating large sums with a sense of loss of control. Preclinical studies have implicated dysregulation of the nucleus accumbens (NAc) in loss of control eating. To provide a deeper understanding as to how the NAc underlies LOC eating in humans, we leverage data from an early feasibility trial entitled Responsive Neurostimulation for Loss of Control Eating (NCT03868670). This UH3 study aims to examine the safety, feasibility, and preliminary efficacy of responsive neurostimulation of the NAc for LOC eating. Two subjects are currently enrolled and successfully underwent bilateral surgical implantation of the responsive neurostimulation system (NeuroPace, Inc.) into the NAc. Both subjects are undergoing responsive DBS guided by NAc delta (2-4Hz) oscillations (i.e. “delta-responsive DBS”) and have exhibited less LOC (primary endpoint). A supplement to enroll the 4 additional subjects is under FDA review. Here, we intend to characterize the role of NAc delta signaling in human LOC eating behaviors. Preliminary data suggests that ventral NAc delta power and bilateral connectivity elevate during anticipatory and LOC-like cravings states, specific to palatable foods. Futhermore, delta power and ventral bilateral NAc connectivity are reduced following delta-responsive DBS, and that this effect is sensitive to stimulation parameter optimization. Our central hypothesis suggests the NAc as a key region in LOC eating, and that aberrant delta signaling underlies LOC eating. As such, we predict that delta-responsive DBS acts on LOC behaviors through a rescue of the NAc’s aberrant delta signaling. Our aims are to determine how NAc delta power and connectivity can differentiate LOC eating from normal eating, and identify neural underpinnings of behavioral response to NAc delta-responsive DBS. As LOC is common to all binges and is a transdiagnostic feature of many mental health disorders, this work will provide invaluable insight relevant to much of Psychiatry.