General anesthesia dissociates discrete components of ketamine neurophysiology
Ben Deverett, Duan Li, Theresa R. Lii, Phillip E. Vlisides, Vijay Tarnal, Anna Forsyth, Rachael L. Sumner, Pilleriin Sikka, Alan F. Schatzberg, Suresh Muthukumaraswamy, George A. Mashour, Boris D. Heifets
medRxiv August 7, 2025 preprint DOI: 10.1101/2025.08.05.25333019 via OpenAlex
Summary
Ketamine's neurophysiologic effects can be selectively modulated by the use of general anesthesia (GA). In a study involving 52 participants receiving ketamine or placebo, it was found that while GA preserves high-frequency EEG power modulation during ketamine administration, it does not enhance low-frequency power as seen when ketamine is given while awake. This suggests a potential method to better understand how different aspects of ketamine's effects contribute to its therapeutic benefits.
Study at a glance
| Design | observational cohort study |
|---|---|
| Sample size | 79 |
| Population | healthy volunteers, patients undergoing elective surgery, and patients with a diagnosis of depression |
| Key finding | Co-administration of ketamine with general anesthesia selectively modulates the high- and low-frequency neurophysiological correlates of ketamine. |
Abstract
Structured Abstract Importance Ketamine has well known dissociative, analgesic, and antidepressant properties, but it is unknown whether the neurophysiologic effects that are associated with these properties can be modulated separately from one another. Given prior studies that link specific cortical oscillations with specific therapeutic effects, it is likely that modulating selective aspects of ketamine neurophysiology can inform efforts to develop more targeted therapies. Objective To determine how the neurophysiologic signatures of ketamine are influenced by removal of conscious awareness using general anesthesia. Design Observational cohort study from trials spanning 2017 to 2023. Setting Multicenter study using data from two study cohorts (U-Michigan and Stanford) and supplementary analysis of a third cohort (U-Auckland). Participants 52 participants in primary analysis and 27 additional participants in supplementary analyses. Study cohorts included healthy volunteers, patients undergoing elective surgery, and patients with a diagnosis of depression. Intervention Participants received a subanesthetic infusion of ketamine (0.5 mg/kg) or placebo with or without general anesthesia (GA). Main Outcome and Measure Changes in electroencephalographic (EEG) band power during medication infusion. Results GA differentially alters EEG features commonly associated with ketamine. In comparison to awake administration, ketamine during GA preserves its high-frequency power modulation but lacks its characteristic low-frequency augmentation. Conclusions and Relevance Co-administration of ketamine with GA selectively modulates the high- and low-frequency neurophysiological correlates of ketamine, suggesting a method to explore these components’ role in ketamine’s behavioral effects.