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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\u2009mg\/kg; n\u2009=\u200918) or midazolam (0.03\u2009mg\/kg; n\u2009=\u200912). Resting state and mismatch negativity data were analyzed at baseline, 1\u2009h, 24\u2009h, and 7\u2009d post-infusion. Ketamine induced temporally dynamic alterations in redundancy-dominant O-info, with maximal effects in the alpha-band at 1\u2009h (Cohen\u2019s d\u2009=\u20092.57), attenuation at 24\u2009h 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 (\u03b2\u2009=\u200969.31, q\u2009=\u20090.05). 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.<\/jats:p>","DOI":"10.1038\/s41398-026-04212-1","type":"journal-article","created":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T09:25:20Z","timestamp":1783157120000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["High-order brain interactions during ketamine-induced state changes: A functional marker of response in late-life treatment-resistant depression?"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-3059-2226","authenticated-orcid":false,"given":"Krisha","family":"Shah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3498-5819","authenticated-orcid":false,"given":"Rub\u00e9n","family":"Herzog","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9879-6198","authenticated-orcid":false,"given":"Alan C.","family":"Swann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany","family":"O\u2019Brien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5162-193X","authenticated-orcid":false,"given":"Rahul","family":"Balakrishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay J.","family":"Mathew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1805-3082","authenticated-orcid":false,"given":"Nicholas","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,4]]},"reference":[{"key":"4212_CR1","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.jpsychires.2022.04.037","volume":"151","author":"Y Alnefeesi","year":"2022","unstructured":"Alnefeesi Y, Chen-Li D, Krane E, Jawad MY, Rodrigues NB, Ceban F, et al. 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Mathew has received consultant fees or research support from Abbott, Almatica Pharma, Autobahn Therapeutics, AtaiBeckley, Boehringer-Ingelheim, Clexio Biosciences, Definium Therapeutics, Douglas Pharmaceuticals, EMA Wellness, Engrail Therapeutics, Freedom Biosciences, Liva Nova, Merck, Motif Neurotech, Neumora, Newleos, Relmada Therapeutics, Sage Therapeutics, Sensorium Biosciences, Signant Health, Sunovion Pharmaceuticals, Supernus, Syndeio Biosciences, and Xenon Pharmaceuticals. N. Murphy has received research funding from Tech Innosphere Eng Ltd, and Syndeio Biosciences (formerly Gate Neuroscience Inc).","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"374"}}