Effects of a Dissociative Drug on Fronto-Limbic Resting-State Functional Connectivity in Individuals with Posttraumatic Stress Disorder: A Randomized Controlled Pilot Study

A subanesthetic dose of ketamine did not increase resting-state functional connectivity between the medial prefrontal cortex and amygdala in individuals with PTSD, contrary to prior correlational findings. Instead, ketamine produced a stronger transient decrease in vmPFC-amygdala connectivity compared to the control drug midazolam. These preliminary results from a randomized controlled pilot study challenge the view that dissociation involves emotion overmodulation via increased fronto-limbic connectivity, suggesting a more nuanced neurobiological understanding of dissociative phenomena in PTSD is needed.

Study at a glance

Abstract

Rationale. A subanesthetic dose of ketamine, a non-competitive N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist, elicits dissociation in individuals with posttraumatic stress disorder (PTSD), who also often suffer from chronic dissociative symptoms in daily life. These debilitating symptoms have not only been linked to worse PTSD trajectories, but also to increased resting-state functional connectivity (RSFC) between medial prefrontal cortex (mPFC) and amygdala, supporting the conceptualization of dissociation as emotion overmodulation. Yet, as studies were observational, causal evidence is lacking. Objectives. The present randomized controlled pilot study examines the effect of ketamine, a dissociative drug, on RSFC between mPFC subregions and amygdala in individuals with PTSD.Methods. Twenty-six individuals with PTSD received either ketamine (0.5mg/kg; n = 12) or the control drug midazolam (0.045mg/kg; n = 14) during functional magnetic resonance imaging (fMRI). RSFC between amygdala and mPFC subregions, i.e., ventromedial PFC (vmPFC), dorsomedial PFC (dmPFC) and anterior-medial PFC (amPFC), was assessed at baseline and during intravenous drug infusion.Results. Contrary to pre-registered predictions, ketamine did not promote a greater increase in RSFC between amygdala and mPFC subregions from baseline to infusion compared to midazolam. Instead, ketamine elicited a stronger transient decrease in vmPFC-amygdala RSFC compared to midazolam. Conclusions. A dissociative drug did not increase fronto-limbic RSFC in individuals with PTSD. These preliminary experimental findings contrast with prior correlative findings and call for further exploration, and potentially, a more differentiated view on the neurobiological underpinning of dissociative phenomena in PTSD.