MEMORY RELATED STRUCTURAL AND FUNCTIONAL NEURAL CHANGES FOLLOWING A SINGLE INFUSION OF KETAMINE IN PTSD

Abstract Background NMDA receptor antagonists play a vital role in new fear memory learning and extinction. Crucial to post-retrieval extinction processes is the reconsolidation window, where memories are activated into a labile state and then reconsolidated in an altered form into the hippocampus. This concept might have significant clinical implications for the treatment of PTSD. Aims & Objectives we tested the potential of a single subanesthetic intravenous infusion of ketamine (NMDA receptor antagonist) after recall, to enhance post-retrieval extinction of PTSD trauma memories. Method 28 participants suffering from PTSD were randomly assigned to receive either ketamine (0.5mg/kg 40 minutes; N=14) or midazolam (0.045mg/kg; N=14) after retrieval of the traumatic memory. 24 hours following infusion, participants received a four-day retrieval and processing trauma-focused psychotherapy. They were assessed before treatment, at the end of treatment, and at 30-day follow-up. Using amygdala activity as a major biomarker of fear response, we tested the potential of a single subanesthetic intravenous infusion of ketamine (NMDA receptor antagonist) after recall, to enhance post-retrieval extinction of PTSD trauma memories. We also tested changes in white matters pre-post treatment. Results Post-treatment, ketamine recipients showed a lower amygdala (-0.33, sd=0.13, 95%HDI [-0.56,-0.04])and hippocampus (-0.3 (sd=0.19), 95%HDI [-0.65, 0.04]; marginal effect) reactivation to trauma memories, compared to midazolam recipients. Post-retrieval ketamine administration was also associated with decreased connectivity between the amygdala and hippocampus (-0.28, sd=.11, 95%HDI [-0.46, -0.11]), with no change in amygdala-vmPFC connectivity. Moreover, reduction in fractional anisotropy in bi-lateral uncinate fasciculus was seen in the Ketamine recipients compared with the midazolam recipients (right: post-treatment: -0.01108, 95% HDI [-0.0184,-0.003]; follow-up: -0.0183, 95% HDI [-0.02719,-0.0107]; left: post-treatment: -0.019, 95% HDI [-0.028,-0.011]; follow-up: -0.017, 95% HDI [-0.026,-0.007]) Discussion & Conclusion Taken together it is possible that ketamine may enhance post-retrieval extinction of trauma memories in humans. These preliminary findings show promising direction toward the capacity to rewrite human traumatic memories and modulate the fear response for at least 30 days post-extinction. The naturalistic stimuli used here promote an ecological measurement of the brain’ s response to traumatic memories.