Language
English
Publication Date
7-4-2026
Journal
Translational Psychiatry
DOI
10.1038/s41398-026-04212-1
PMID
42401545
PMCID
PMC13389161
PubMedCentral® Posted Date
7-4-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Ketamine is a fast-acting intervention for treatment-resistant depression (TRD), yet only a subset of patients show robust clinical response, and the underlying neural mechanisms remain unclear. High-order interactions (HOI) derived from multivariate information theory provide a framework for examining nonlinear dependencies among brain regions beyond pairwise connectivity. One such metric, the O-information, captures the balance between synergistic and redundant interactions across three or more variables. In this secondary analysis of a randomized, double-blind, midazolam-controlled trial (NCT02556606), we examined EEG-derived HOI in 30 late-life veterans with TRD following a single 40-minute intravenous infusion of ketamine (0.1, 0.25, 0.5 mg/kg; n = 18) or midazolam (0.03 mg/kg; n = 12). Resting state and mismatch negativity data were analyzed at baseline, 1 h, 24 h, and 7 d post-infusion. Ketamine induced temporally dynamic alterations in redundancy-dominant O-info, with maximal effects in the alpha-band at 1 h (Cohen's d = 2.57), attenuation at 24 h that shifted toward the theta-band, and partial resurgence in beta and gamma by Day 7. Linear mixed-effects modeling identified significant group effects across most band x metric families, with the strongest effects in alpha, beta, and gamma redundancy. Greater increases in 24-hour alpha-band redundancy were associated with greater improvement in depressive symptoms at Day 7 (β = 69.31, q = 0.05). HOI metrics also tracked acute dissociative states, with several 24-hour alpha and beta features remaining positively associated with symptom severity after correction. These findings extend prior HOI work in healthy samples to a controlled TRD cohort and suggest that ketamine induces temporally structured reorganization of higher-order brain interactions, with exploratory associations to clinical outcomes.
Keywords
Humans, Ketamine, Depressive Disorder, Treatment-Resistant, Male, Double-Blind Method, Electroencephalography, Female, Aged, Brain, Middle Aged, Midazolam, Veterans, Antidepressive Agents, Neuroscience, Human behaviour
Published Open-Access
yes
Recommended Citation
Shah, Krisha; Herzog, Rubén; Swann, Alan C; et al., "High-Order Brain Interactions During Ketamine-Induced State Changes: A Functional Marker of Response in Late-Life Treatment-Resistant Depression?" (2026). Faculty, Staff and Students Publications. 7814.
https://digitalcommons.library.tmc.edu/baylor_docs/7814