Long term structural and functional neural changes following a single infusion of Ketamine in PTSD

Abstract

NMDA receptor antagonists have a vital role in extinction, learning, and reconsolidation processes. During the reconsolidation window, memories are activated into a labile state and can be reconsolidated in an altered form. This concept might have significant clinical implications in treating PTSD. In this pilot study we tested the potential of a single infusion of ketamine, followed by brief exposure therapy, to enhance post-retrieval extinction of PTSD trauma memories. 27 individuals diagnosed with PTSD were randomly assigned to receive either ketamine (0.5 mg/kg 40 min; N = 14) or midazolam (0.045 mg/kg; N = 13) after retrieval of the traumatic memory. 24 h following infusion, participants received a four-day trauma-focused psychotherapy. Symptoms and brain activity were assessed before treatment, at the end of treatment, and at 30-day follow-up. Amygdala activation to trauma scripts (a major biomarker of fear response) served as the main study outcome. Although PTSD symptoms improved equally in both groups, 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 = 0.11, 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]). Taken together it is possible that ketamine may enhance post-retrieval extinction of the original 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. When combined with psychotherapy for PTSD, further investigation of ketamine dose, timing of administration, and frequency of administration, is warranted.

Fig. 1. Illustration of the procedure.

Days 3–6 = days 3,4,5 and 6 in which the PE sessions were conducted. Recall procedure inside the magnet included 3 rounds of each audio recall script (traumatic, sad, and relax, 120 seconds each).

Fig. 2. Amygdala Reactivity.

A Differences between the ketamine and midazolam groups in amygdala reactivity to trauma vs. relax scripts across the three-time points. Each dot is a participant, the horizontal line in the middle of the boxplot represents median. On the right of each panel is the posterior distribution of the difference between the groups. The black line is the 95% HDI. B Average amygdala reactivity to trauma vs. relax in the ketamine group (blue) and the midazolam group (orange) in the three-time points. Error bars represent standard error of the mean. Brain image depicts the mask of the amygdala ROI (center: MNI [−22,0,−20], [22,0,−20]).

Fig. 3. Hippocampus Reactivity.

A Differences between the ketamine and midazolam groups in hippocampus reactivity to trauma vs. relax scripts across the three time points. Each dot is a participant, the horizontal line in the middle of the boxplot represents median. On the right of each panel is the posterior distribution of the difference between the groups. The black line is the 95% HDI. B Average hippocampus reactivity to trauma vs. relax in the ketamine group (blue) and the midazolam group (orange) in the three time points. Error bars represent standard error of the mean. Brain image depicts the mask of the hippocampus ROI (center: MNI [−28,−18,−16], [28,−18,−16]).

Fig. 4. Diffusion Tensor Imaging analysis (DTI).

Differences between the ketamine and midazolam groups in the (A) right and (B) left UNC FA adjusted for age, gender, motion and baseline corrected. Each dot is a participant, boxplots include the median, two hinges and two whiskers, and the density distribution of participants. C An illustration of the UNC.