A new study has analyzed detailed brain imaging data of individuals with chronic PTSD who were treated in a clinical trial with ketamine. Results suggest that improvements in PTSD symptoms that were observed in the trial were related to specific ketamineinduced changes in connectivity between several brain regions. The new results offer clues about how ketamine may alter brain function in PTSD and may also have therapeutic implications.
The imaging data was collected from a subset of participants in a randomized trial led by two-time BBRF grantee Adriana Feder, M.D., of the Icahn School of Medicine at Mount Sinai. The trial was small, involving 30 chronic PTSD patients with moderate to severe symptoms, with half receiving 6 infusions of ketamine over 2 weeks and half receiving 6 infusions of the psychoactive placebo control drug midazolam. Both drugs have been used for years as anesthetics, although in the trial both were given at a subanesthetic doses. The trial was fully blinded, with neither participants nor clinicians knowing which drug the participants were randomly assigned to receive.
In a previous paper, Dr. Feder and colleagues reported that repeated ketamine infusions over a 2-week period did indeed significantly reduce symptom severity in many participants, while also helping to reduce depression symptoms that often accompany PTSD. The control drug used in the trial, which has anti-anxiety effects, also was associated with reductions in PTSD symptoms in some participants, but was markedly less effective compared with ketamine.
In the team’s new paper, first author and 2019 BBRF Young Investigator Agnes Norbury, Ph.D., along with Dr. Feder and colleagues analyzed functional brain imaging data from 21 of the 30 trial participants, drawing upon data from two scanning sessions, one conducted before the trial began and the other after most or all of the infusions of New post ketamine or the control drug were administered. This imaging data enabled the team to look for what they call “neural correlates”—changes in brain activity—of the responses to ketamine and the control drug in trial participants.
Dr. Feder, who is senior author of the paper reporting the new imaging results in the journal Neuropsychopharmacology, is a 2015 BBRF Independent Investigator and 2002 Young Investigator. Other co-authors of the paper included Dennis S. Charney, M.D., an Emeritus member of BBRF’s Scientific Council and 2019 winner of BBRF’s Colvin Prize for Outstanding Research in Mood Disorders; James W. Murrough, M.D., Ph.D., a 2009 BBRF Young Investigator; and Lisa M. Shin, Ph.D., a 1999 BBRF Young Investigator.
The imaging sessions that formed the base of evidence of the new study include scans made while participants were asked to respond to a computer monitor displaying faces depicting various emotions. Each participant also had a scan conducted while “at rest,”with no task being performed.
Regardless of which drug participants received, improvements in PTSD symptom severity were related, the team found, to connectivity changes between regions of the brain previously identified as showing abnormal activity in PTSD. These included two cortical areas: the ventromedial prefrontal cortex (vmPFC) and the dorsal/rostral anterior cingulate cortex (d/rACC), as well as emotion-processing areas including the amygdala and the anterior portion of the insula.
The team postulates a drug-specific mechanism that may induce changes in connectivity between the vmPFC and amygdala following treatment. Improvements in symptoms with both drugs were related to decreased excitation of circuitry leading from the amygdala to the vmPFC during the viewing of the emotional faces. One type of connectivity change, however, was seen only in participants whose symptoms decreased after ketamine treatments: increased “top-down” inhibition of the amygdala, exerted by the vmPFC.
This latter observation leads the team to propose that a decrease in the intensity of the threat response and/or an enhancement of learning to extinguish memory-based fear responses may be responsible for the observed decreases in PTSD symptom severity following treatment with ketamine.
The greater rate of response seen in the trial among participants in the ketamine group compared with those who received the control drug as well as the longer time on Neuropsychopharmacology Blythe Brumleve set the due date to Mon 5:33 am Blythe Brumleve changed status from To Do to Waiting For Tricore 5:33 am 2 more updates Blythe Brumleve created this task 5:31 am Show 1 empty field + Add or edit fields Manual + ADD CHECKLIST compared with those who received the control drug, as well as the longer time, on average, to relapse of symptoms, might be due, the team suggested, to the ability of ketamine to increase neural plasticity in brain circuitry associated with the persistence of symptoms. This has been proposed in other research on ketamine’s mechanism of action.
If less intense responses to threat or an enhancement of fear-extinction learning do in fact contribute to ketamine-related improvement in PTSD symptoms, Dr. Feder suggests, this would point to the potential benefit of combining drug treatment in chronic PTSD with forms of psychotherapy that might work in part via fear-extinction learning.
Such a combined approach might, the team said, “‘open a window’ for the relearning of ingrained cognitive biases or maladaptive fear memories” associated with the persistence of PTSD symptoms.