General Anesthesia and Discrete Components of Ketamine Neurophysiology

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. Considering that specific cortical oscillations have been associated with specific therapeutic effects, modulating selective aspects of ketamine neurophysiology could inform efforts to develop more targeted therapies. Objective: To determine whether the neurophysiologic signatures of ketamine are associated with removal of conscious awareness using general anesthesia (GA). Design, Setting, and Participants: This cohort study was a secondary analysis of participant-level data from 3 prospective studies conducted between 2017 and 2023. The primary analysis included data from 2 study cohorts (University of Michigan and Stanford University), and the supplementary analysis included data from a third cohort (University of Auckland). The study cohorts included healthy volunteers, patients undergoing elective surgery, and patients with a diagnosis of depression (all aged ≥18 years). Exposure: Participants received a subanesthetic infusion of ketamine (0.5 mg/kg body weight) over 40 minutes or placebo with or without GA. Main Outcomes and Measures: The primary outcome was change in electroencephalographic (EEG) band power during medication infusion. Changes were computed using nonparametric paired statistical text (Wilcoxon signed-rank test). Results: This study included 52 participants in the primary analysis (mean [SD] age, 43.4 [18.3] years; 34 females [65.4%]) and 27 additional participants in the supplementary analysis (mean [SD] age, 30.2 [8.2] years; 15 females [55.6%]). GA differentially altered EEG features commonly associated with ketamine in all 52 participants (100%) in the primary analysis. Compared with awake administration, ketamine administered during GA preserved its βγ power modulation (mean [SEM] increase from 6.3 [11.3] to 11.6 [2.2] dB for awake administration; increase from 8.5 [2.9] to 11.2 [3.8] dB for administration during GA) but lacked its characteristic θ augmentation (increase from 17.3 [10.5] to 22.9 [3.1] dB during awake administration; nonsignificant decrease from 29.0 [3.0] to 27.8 [3.5] dB for administration during GA). Conclusions and Relevance: In this cohort study, coadministration of ketamine with GA selectively modulated the θ but not the βγ neurophysiologic correlates of ketamine. These findings suggest a potential method to explore the role of these components in the behavioral effects of ketamine.