Neural Circuitry Mechanisms of Response to Ketamine in PTSD: Preliminary Findings

Abstract

Patients with chronic PTSD (N=21), who participated in a larger RCT of repeated ketamine (NMDA receptor antagonist) infusions, compared to psychoactive placebo control midazolam, completed fMRI scans before and after repeated infusions to investigate neural circuitry changes associated with PTSD improvement. Participants were randomized to receive six intravenous infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg), three times/week for two consecutive weeks. MRI scans included two emotion-processing tasks and a task-free scan. The CAPS-5 was administered before and after repeated infusions. Leave-one-out cross-validated elastic-net regression analyses were employed to evaluate potential associations between PTSD improvement and changes in a-priori imaging measures. ROIs in pre-registered analyses included dorsal and rostral ACC, vmPFC, anterior hippocampus, anterior insula, and amygdala. PTSD symptom improvement was associated with increased vmPFC-amygdala connectivity during emotional face-viewing (change score retained in the model with minimum predictive error in left-out participants; standardized β=2.90); this association was more pronounced with ketamine than midazolam (interaction β=0.86) and persisted after adjusting for depressive symptoms (β=0.69). PTSD symptom improvement was associated with decreased dACC activation during emotional conflict regulation (Face-Stroop) and increased resting state vmPFC-anterior insula connectivity, only in participants treated with ketamine (βs=-2.82, 0.60). Exploratory dynamic causal modeling analysis revealed that PTSD improvement was associated with increased top-down inhibition of amygdala by vmPFC only following ketamine, but not midazolam infusions. Preliminary results from this study suggest that a course of repeated ketamine infusions might reduce PTSD symptom severity by normalizing hypofrontal control over amygdala in response to social signals of threat.