Effects of a dissociative drug on fronto-limbic resting-state functional connectivity in individuals with posttraumatic stress disorder: a randomized controlled pilot study
In a randomised controlled pilot study of 26 individuals with PTSD, subanesthetic ketamine (vs midazolam) did not increase resting‑state functional connectivity between the amygdala and medial prefrontal cortex subregions. Instead, ketamine induced a transient decrease in vmPFC–amygdala connectivity, challenging prior correlational links between dissociation and fronto‑limbic overconnectivity.
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.
Research Summary of 'Effects of a dissociative drug on fronto-limbic resting-state functional connectivity in individuals with posttraumatic stress disorder: a randomized controlled pilot study'
Introduction
Dissociation involves disruptions of consciousness, memory, identity and body awareness and can occur acutely after pharmacological challenge or chronically in disorders such as posttraumatic stress disorder (PTSD). Prior observational work has linked a dissociative subtype of PTSD to a pattern of "emotion overmodulation": increased prefrontal activation and reduced limbic engagement during symptom provocation, and elevated resting-state functional connectivity (RSFC) between medial prefrontal cortex (mPFC) regions and the amygdala. However, those findings derive from group comparisons and are therefore limited in establishing causal links between dissociation and fronto-limbic connectivity. Danböck and colleagues set out to test causality by experimentally inducing dissociation with a subanesthetic ketamine infusion and measuring its acute effects on RSFC between the amygdala and mPFC subregions. The trial compared ketamine (0.5 mg/kg over 40 min) to an active control, midazolam (0.045 mg/kg over 40 min), in individuals with PTSD and primarily without chronic dissociative symptoms, with RSFC assessed at baseline and during infusion. The authors hypothesised that ketamine would produce a stronger increase in amygdala–mPFC connectivity than midazolam, consistent with the emotion overmodulation model of dissociation.
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Study Details
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- APA Citation
Danböck, S. K., Duek, O., Ben-Zion, Z., Korem, N., Amen, S. L., Kelmendi, B., Wilhelm, F. H., Levy, I., & Harpaz-Rotem, I. (2024). Effects of a dissociative drug on fronto-limbic resting-state functional connectivity in individuals with posttraumatic stress disorder: a randomized controlled pilot study. Psychopharmacology, 241(2), 243-252. https://doi.org/10.1007/s00213-023-06479-4
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