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

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. Theses 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. To examine 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. Experimental findings expand previous observational work on the association between dissociation and fronto-limbic RSFC in individuals with PTSD and call for further research, and potentially, a more differentiated view on the neurobiological underpinning of dissociative phenomena in PTSD.

A pharmacological challenge paradigm to assess neural signatures of script-elicited acute dissociation in women with post-traumatic stress disorder

“…healthy, depressed, post-traumatic samples), ketamine (common dose: 0.5 mg/kg over 40 min) reliably induces dissociative experiences, 60 , 61 which appear psychometrically similar to, but less intense than, 61 naturally occurring dissociation in trauma-exposed samples. A study by Danboeck and colleagues 62 measured alterations in resting-state functional connectivity following ketamine-induced dissociation in PTSD. Opposed to pre-registered hypotheses based on the dissociation model of emotion overmodulation by Lanius and colleagues 12 , experimentally induced dissociation resulted in decreased frontolimbic connectivity in individuals with PTSD receiving ketamine ( n = 12) compared to the control drug ( n = 14).…”

“…Future research needs to determine how ketamine-induced modulation of neurotransmitter systems (possibly mediated by glutamatergic dysfunction) differs from naturally occurring trauma-related dissociation, which has been linked to the opioid system. 62 Here, a comparative fMRI script-driven imagery design (ketamine versus placebo) analysed with event-related independent component analysis may provide new insights into experimentally elicited shifts in neural networks associated with acute post-traumatic dissociation as a reactive shutdown response to trauma reminders.…”