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 stored in an altered form. This concept might have significant clinical implications in treating PTSD. 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) to enhance post-retrieval extinction of PTSD trauma memories. Post-extinction, ketamine recipients (vs midazolam) showed a lower amygdala and hippocampus reactivation to trauma memories. Post-retrieval ketamine administration was also associated with decreased connectivity between the amygdala and hippocampus, with no change in amygdala-vmPFC connectivity, which suggests that ketamine may enhance post-retrieval extinction of PTSD trauma memory in humans. These findings demonstrate the capacity to rewrite human traumatic memories and to modulate the fear response for at least 30 days post-extinction.
Competing Interest Statement
J.K. registered patents 20180318288 GLUTAMATE AGENTS IN THE TREATMENT OF MENTAL DISORDERS and 20200253894 INTRANASAL ADMINISTRATION OF KETAMINE TO TREAT DEPRESSION
Clinical Trial
NCT02727998
Funding Statement
The main source of funding for this work was provided by: Independent Investigator Grant from the Brain and Behavior Research Foundation (IHR); by the Clinical Neurosciences Division of the National Center for PTSD (IHR);a donation from the American Brain Society (IHR), and the Yale Center for Clinical Investigation(YCCI) supported by CTSA Grant from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH). The contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
The study was approved by the Yale IRB, study number 1509016530
All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.
Yes
Footnotes
Removed the low-resolution figures and replaced them with high resolution + caption.
Data Availability
Data and analysis can be found in the github repository. All raw data are available from the corresponding author upon reasonable request. Code availability: All analysis scripts can be found here https://github.com/orduek/KPE.