High-order brain interactions during ketamine-induced state changes: A functional marker of response in late-life treatment-resistant depression?

Overview

1. Texas A&M University Naresh K. Vashisht College of Medicine, Department of Psychiatry and Behavioral Sciences,Bryan, TX USA
2. Baylor College of Medicine, Menninger Department of Psychiatry and Behavioral Sciences,Houston, TX USA
3. Department of Psychology, University of the Balearic Islands,Palma de Mallorca, Spain
4. Instituto de Física Interdisciplinar y Sistemas Complejos (IFISC, UIB-CSIC), Campus UIB,Palma de Mallorca, Spain
5. Michael E. DeBakey VA Medical Center,Houston, TX USA

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.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Python codes and GitHub access are available from the research team upon reasonable request.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 2 keywords, 13 MeSH terms, 1 funder, 34 references.

Cite

This paper

Shah, K., Herzog, R., Swann, A. C., O’Brien, B., Balakrishnan, R., Mathew, S. J., & Murphy, N. (2026). High-order brain interactions during ketamine-induced state changes: A functional marker of response in late-life treatment-resistant depression? Translational psychiatry, 16(1), 374. https://doi.org/10.1038/s41398-026-04212-1

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