Characterizing brain dynamics during ketamine-induced dissociation and subsequent interactions with propofol using human intracranial neurophysiology
Fangyun Tian, Laura D. Lewis, David W. Zhou, Gustavo Balanza, Angelique C. Paulk, Rina Zelmann, Noam Peled, Daniel J. Soper, Laura A. Santa Cruz Mercado, Robert A. Peterfreund, Linda S. Aglio, Emad N. Eskandar, G. Cosgrove, Ziv M. Williams, R. Richardson, Emery N Brown, Oluwaseun Akeju, Sydney S. Cash, Patrick L. Purdon
Nature Communications March 29, 2023 DOI: 10.1038/s41467-023-37463-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational study with intracranial recordings Peer reviewed |
|---|---|
| Population | Humans |
| Interventions | Ketamine Propofol |
| Topics | Esketamine Ketamine |
| Citations | 63 |
| Key findings | Ketamine produces gamma oscillations in prefrontal cortex and hippocampus and a 3 Hz oscillation in posteromedial cortex, suggesting distinct neural circuit engagement for antidepressant and dissociative effects. |
Abstract
The neural mechanisms underpinning ketamine’s dissociative and antidepressant effects remain poorly understood. Here, the authors analyzed ketamine-induced brain dynamics with intracranial recordings in humans and found that ketamine engages different brain areas in distinct frequency-dependent patterns that may relate to its dissociative and antidepressant effects. Ketamine produces antidepressant effects in patients with treatment-resistant depression, but its usefulness is limited by its psychotropic side effects. Ketamine is thought to act via NMDA receptors and HCN1 channels to produce brain oscillations that are related to these effects. Using human intracranial recordings, we found that ketamine produces gamma oscillations in prefrontal cortex and hippocampus, structures previously implicated in ketamine’s antidepressant effects, and a 3 Hz oscillation in posteromedial cortex, previously proposed as a mechanism for its dissociative effects. We analyzed oscillatory changes after subsequent propofol administration, whose GABAergic activity antagonizes ketamine’s NMDA-mediated disinhibition, alongside a shared HCN1 inhibitory effect, to identify dynamics attributable to NMDA-mediated disinhibition versus HCN1 inhibition. Our results suggest that ketamine engages different neural circuits in distinct frequency-dependent patterns of activity to produce its antidepressant and dissociative sensory effects. These insights may help guide the development of brain dynamic biomarkers and novel therapeutics for depression.
Comparable studies
Other observational and cohort studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Taming the Ketamine Tiger Volunteers from a prison population | 2010 | Observational study | n = 20 |
| Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin Humans | 2017 | Observational study | |
| Disruption of Frontal–Parietal Communication by Ketamine, Propofol, and Sevoflurane Surgical patients undergoing induction of anesthesia with intravenous ketamine | 2013 | Observational cohort | n = 30 |
| Do the dissociative side effects of ketamine mediate its antidepressant effects? Treatment-resistant inpatients with major depressive disorder or bipolar disorder | 2014 | Observational cohort | n = 108 |
| Concomitant BDNF and sleep slow wave changes indicate ketamine-induced plasticity in major depressive disorder Patients with treatment-resistant major depressive disorder | 2012 | Observational cohort | n = 30 |
Citations in the library
Cited by 34
- Randomized trial of ketamine masked by surgical anesthesia in patients with depression Nature Mental Health October 19, 2023
- Ketamine, Esketamine, and Arketamine: Their Mechanisms of Action and Applications in the Treatment of Depression and Alleviation of Depressive Symptoms. Biomedicines October 9, 2024
- Ketamine, an Old–New Drug: Uses and Abuses Pharmaceuticals December 21, 2023
- Ketamine can produce oscillatory dynamics by engaging mechanisms dependent on the kinetics of NMDA receptors. Proceedings of the National Academy of Sciences May 28, 2024
- Randomized Trial of Ketamine Masked by Surgical Anesthesia in Depressed Patients medRxiv Preprint Server April 28, 2023
and 29 more in the library
Cites 18
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Measurement of dissociative states with the Clinician‐Administered Dissociative States Scale (CADSS) Journal of Traumatic Stress 1998
- Are the Neural Correlates of Consciousness in the Front or in the Back of the Cerebral Cortex? Clinical and Neuroimaging Evidence Journal of Neuroscience October 4, 2017
and 13 more in the library