Introduction
trauma, PTSD, traumatic
SHOCKS, BLIND, CORTEX
Reactivation of a stored memory (i.e., bringing the previously encoded memory back into consciousness), might change its state from consolidated into a labile, in which its content or meaning may be altered. In a process known as reconsolidation, the memory is then stored again in this altered form [In the laboratory, fear learning is typically modeled using a paradigm in which neutral cues are paired with aversive outcomes (e.g, electric shocks) and acquire aversive value [Functional connectivity between the amygdala and hippocampus may also play an important role in the processing of aversive memories [Anatomical connectivity was also found to play a role in fear conditioning. In vivo magnetic resonance diffusion tensor imaging (DTI) in rodents showed alterations in fractional anisotropy (FA) in the amygdala and hippocampus following fear conditioning. In humans, the uncinate fasciculus (UNC), a white matter bundle connecting the orbito-frontal cortex with limbic structures within the anterior temporal lobe (i.e., amygdala and hippocampus) [Extinction may be further enhanced with the use of ketamine, a non-competitive N-methyl-D-aspartate glutamate receptor (NMDAR) antagonist. The NMDAR has a key role in learning, extinction, and reconsolidation in both animals and humans [Recent studies have demonstrated the potential of post-retrieval extinction - using behavioral and pharmacological agents - to reduce fear responses. In spider phobia, repeated exposure to a spider image after fear reactivation attenuated amygdala response to that image 24 h later [In this initial investigation, we explored the ability of a single subanesthetic intravenous infusion of ketamine (0.5 mg/kg over 40 min) to enhance post-retrieval extinction of real traumatic memories. To control for the subjective effects of ketamine, we randomized individuals with PTSD to receive an infusion of either ketamine or the benzodiazepine midazolam. We have used active control in order to keep the participants blind. The use of midazolam in such studies and reasoning was reported and discussed in previous published work [The aim of this novel pilot exploration was to identify neural biomarkers for post-retrieval extinction of the original traumatic memory for a potential translational clinical trial. Our main hypothesis focused on the amygdala; we predicted a greater reduction in amygdala reactivity to trauma cues in individuals with PTSD who received ketamine, compared to those who were administered midazolam. As the target-engagement mechanism was of reconsolidation-based extinction (and not classic extinction), we expected no change in vmPFC activation or its functional coupling with the amygdala. Moreover, we hypothesized that if ketamine produces greater post-retrieval extinction than midazolam, this effect will also be associated with a reduction in functional connectivity between the amygdala and the hippocampus. We also hypothesized that ketamine will induce alterations on white matter bundles connecting the frontal and temporal lobes. Lastly, we hypothesized that ketamine will be associated with greater reduction in PTSD symptoms than midazolam when combined with exposure treatment.