Characterizing ketamine-induced dissociation using human intracranial neurophysiology: brain dynamics, network activity, and interactions with propofol
Fangyun Tian, Laura D. Lewis, David W. Zhou, Gustavo A Balanza Villegas, 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 Rees Cosgrove, Ziv M. Williams, Robert M. Richardson, Emery N Brown, Oluwaseun Akeju, Sydney S. Cash, Patrick L. Purdon
bioRxiv Preprint Server May 2, 2022 preprint DOI: 10.1101/2022.05.02.490333 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with intracranial recordings |
|---|---|
| Population | Humans |
| Interventions | Ketamine Propofol |
| Dose | subanesthetic dose |
| Topics | Esketamine Ketamine |
| Keywords | Ketamine research Ketamine studies Ketamine neurobiology Ketamine effects Ketamine mechanisms Ketamine action Antidepressant development Depression treatment Drug discovery Therapeutic development Mental health therapeutics Novel antidepressants Brain activity Neurophysiology Brain waves Neural circuits Brain oscillations Brain research Dissociative effects Anesthetic effects Ketamine dissociation Propofol effects |
| Key findings | Ketamine increases gamma oscillations in prefrontal cortex and hippocampus and induces a 3 Hz oscillation in posteromedial cortex, linking distinct frequency patterns to its antidepressant and dissociative effects. |
Abstract
Subanesthetic doses of ketamine produce rapid and sustained anti-depressant effects in patients with treatment-resistant depression. Unfortunately, the usefulness of ketamine as a treatment is limited by its potential for abuse because of psychotropic side effects such as dissociation. Understanding the brain dynamics and the neural circuits involved in ketamine’s effects could lend insight into improved therapies for depression with fewer adverse effects. It is believed that ketamine acts via NMDA receptor and hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels to produce changes in oscillatory brain dynamics. Here we show, in humans, a detailed description of the principal oscillatory changes in cortical and subcortical structures by administration of a subanesthetic dose of ketamine. Using recordings from intracranial electrodes, we found that ketamine increased gamma oscillations within prefrontal cortical areas and the hippocampus--structures previously implicated in ketamine’s antidepressant effects. Furthermore, our studies provide direct evidence of a ketamine-induced 3 Hz oscillation in posteromedial cortex that has been proposed as a mechanism for its dissociative effects. By analyzing changes in neural oscillations after the addition of propofol, whose GABAergic activity antagonizes ketamine’s NMDA-mediated disinhibition alongside a shared HCN1 inhibitory effect, we identified brain dynamics that could be attributed to NMDA-mediated disinhibition versus HCN1 inhibition. Overall, our results imply 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 novel brain dynamic biomarkers and therapeutics for depression.
Comparable studies
Other experimental studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Ketamine activates psychosis and alters limbic blood flow in schizophrenia Schizophrenic individuals | 1995 | Experimental study | |
| The spectral exponent of the resting EEG indexes the presence of consciousness during unresponsiveness induced by propofol, xenon, and ketamine Healthy participants | 2019 | Controlled experimental study | n = 15 |
| Ketamine Increases Human Motor Cortex Excitability to Transcranial Magnetic Stimulation Normal human subjects | 2003 | Experimental study | n = 7 |
| Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans Human participants | 2015 | Experimental study | |
| Simultaneous population pharmacokinetic modelling of ketamine and three major metabolites in patients with treatment‐resistant bipolar depression Patients with treatment-resistant bipolar depression | 2012 | Population pharmacokinetic analysis | n = 9 |
Citations in the library
Cites 10
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- 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
- Deep posteromedial cortical rhythm in dissociation Nature September 16, 2020
- Ketamine Has Distinct Electrophysiological and Behavioral Effects in Depressed and Healthy Subjects Molecular Psychiatry February 27, 2018
and 5 more in the library