669. Imaging reward circuitry to guide precision ketamine treatment in treatment-resistant depression

Abstract Background Ketamine produces rapid antidepressant and anti-anhedonic effects in treatment-resistant depression, but response is heterogeneous and mechanisms at the circuit level remain incompletely defined. Convergent imaging work implicates anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), and reward-related networks as key loci for ketamine’s therapeutic and abuse-related actions. Aims & Objectives This presentation aims to 1 identify ketamine-sensitive ACC and large-scale networks associated with antidepressant and anti-anhedonic response; 2 relate these changes to glutamatergic and opioid mechanisms in reward circuitry; and 3 outline how multimodal imaging markers could inform precision selection and monitoring of ketamine treatment in mood and substance use disorders.

Method: Findings are synthesized from: (a) a randomized, placebo-controlled, crossover resting-state fMRI study in treatment-resistant depression examining subgenual, perigenual, and dorsal ACC connectivity before and after intravenous ketamine; (b) a functional connectivity network mapping meta-analysis localizing ketamine-responsive regions to distributed large-scale networks; and (c) molecular and functional imaging studies of S-ketamine’s engagement of mu opioid and NMDA receptors in mesocorticolimbic circuits, complemented by electrophysiologic frontocingulate gamma connectivity work.

Results: Resting-state fMRI shows that subgenual ACC connectivity is most strongly modulated by ketamine, with increased coupling to perigenual ACC, ventral striatum, and anterior ventromedial prefrontal cortex, and decreased connectivity with hippocampal formation; these changes track improvements in anhedonia and anticipatory reward rather than overall depression scores. Meta-analytic network mapping reveals that ketamine-responsive loci cluster within a common network spanning default mode, ventral attention, and frontoparietal systems, with prominent DLPFC and insula involvement and only partial overlap with networks implicated in conventional monoaminergic antidepressants. Complementary PET and functional ultrasound data demonstrate that clinically relevant S-ketamine doses occupy and activate mu opioid receptors in anterior cingulate and nucleus accumbens, dynamically altering receptor density and signaling in ways that intersect with its antidepressant efficacy and misuse liability. Discussion & Conclusions Across modalities, ketamine appears to normalize dysregulated ACC-centered circuits and large-scale networks that integrate affective, cognitive control, and reward processing, offering a circuit-level account of its rapid antidepressant and anti-anhedonic effects. When combined with frontocingulate gamma measures and molecular imaging of NMDA–opioid engagement, these findings support development of imaging-based biomarkers to stratify ketamine responders, optimize dosing, and manage risk in both treatment-resistant depression and comorbid substance use disorders.