Discussion
anxiety, traumatic, psychiatric, long-term reduction, PTSD, trauma
EVENTS, BLIND, DISORDERS
In this work, we provided preliminary evidence that a single infusion of 0.5 mg/kg ketamine for 40 min, when combined with exposure and processing of the traumatic memory, lead to alterations in neural circuit functioning, although it did not produce reduction in PTSD symptoms greater than midazolam. These changes were more consistent with modification of the original memory (i.e., post-retrieval extinction) than with enhancement of classic extinction. The ketamine group showed lower amygdala reactivity to recalled subjective traumatic events compared to the midazolam group, with no change in connectivity between the amygdala and vmPFC. Moreover, connectivity between the amygdala and posterior-hippocampus was reduced in the ketamine, but not the midazolam group, at the end of treatment. Last, ketamine, but not midazolam, was also associated with long-term reduction in FA in the UNC. The combined results suggest a potential, larger reduction in the level of neuronal reactivity associated with the original trauma memory in the ketamine group compared to midazolam.The amygdala is a key node in neural networks engaged in extinction and post-retrieval extinction processes [NMDARs are required for the transition of memory from a fixed to a labile state. For example, an NMDAR antagonist, but not an AMPAR antagonist, blocked the reconsolidation process [Studies in animals show that 90 min following acute subanesthetic dose, ketamine causes reduction in synaptic density (PSD-95) due to the blockade of NMDA receptors [It was suggested that ketamine does not simply increase connectivity, rather, it promotes the reorganization of the connections [Our results also show reduced amygdala-hippocampus connectivity following ketamine infusion. This reduction was only apparent 7 days after infusion and not in the follow-up session (30 days), suggesting a transient effect. This finding is consistent with prior research demonstrating a role for amygdala-hippocampus interaction in the acquisition and modification of fear memories [In healthy individuals, higher amygdala-hippocampus connectivity may be associated with enhanced memory under stress, but not neutral, conditions [The facilitation of post-retrieval extinction of trauma memories in this study raises the possibility that behavioral interventions may enhance the reported efficacy of ketamine in the treatment of PTSD [Although neural activity indicated a greater reduction in levels of distress associated with the traumatic memory in the ketamine group, we did not find any differences in PTSD symptoms between the experimental groups. A high level of heterogeneity characterizes PTSD symptomatology and thus presents a challenge for detecting nuances in treatment response, more so, in small samples. In this context, other studies which tested the effectiveness of exposure therapy on PTSD or fear of flying reported similar outcome differences in physiological fear response between the experimental groups at the end of the intervention with no difference in the self-report measure of symptoms [This study has some limitations. First, the number of participants in each group is relatively small, and larger studies will need to replicate the findings. This concern is partially mitigated by the longitudinal aspect of the study, as well as the findings, which are consistent with other animal and human studies. Another potential limitation is the use of an active psychotropic drug, midazolam. We used midazolam as a comparator to control for the subjective effects of ketamine and to preserve the blind conditions. This limits our inferences, however, to the relative effects of similarly tolerable doses of ketamine and midazolam. In order to fully unfold the effect of ketamine, a control group receiving ketamine without recall of trauma is needed. Lastly, it is important to note that since all participants received psychotherapy, it is difficult to determine the specific effect of ketamine alone and the effect of the combination of ketamine and psychotherapy.While preliminary, the present pilot study finds that one-time ketamine infusion might enhance post-retrieval extinction of traumatic memories. This is apparent in the effects found in the ketamine vs. the midazolam group: diminished amygdala reactivity to recall of traumatic events, reduced WMI in the UNC, and attenuation of connectivity between amygdala and hippocampus. These findings complement previous findings in both animal models and humans, on a wider spectrum of psychiatric disorders and both appetitive and aversive memories. As the enhancement of post-retrieval extinction presented here was demonstrated using real-life traumatic events, the applicability of this procedure is high and it might serve as a potential novel future intervention for PTSD and anxiety disorders.