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Stanford Neuromodulation Therapy (SNT), a high-dose intermittent theta-burst transcranial magnetic stimulation protocol, produces rapid antidepressant effects, but its neurophysiological mechanisms remain unclear. Here, we used longitudinal TMS-EEG to characterize the progressive neurophysiological changes induced by SNT, assess their site-specificity, and explore whether baseline neural markers are associated with clinical response. We conducted a double-blind, randomized, sham-controlled trial at Stanford University (2017\u20132018; analysis August 2024\u2013October 2025) in 24 TMS-na\u00efve participants with TRD (Montgomery-\u00c5sberg Depression Rating Scale \u226520; \u22651 failed antidepressant trial). Participants were randomized to active (n\u2009=\u200912) or sham (n\u2009=\u200912) SNT, consisting of 10 sessions per day over 5 consecutive days targeting the left dorsolateral prefrontal cortex (90,000 pulses). TMS-EEG was acquired at two baseline sessions, before and after each treatment session, and at 1-month follow-up (14 TMS-EEG sessions in total). Active SNT progressively reduced cortical excitability at the treatment site, with significant decreases by day 3 in the early window component (\u221227.9%; P\u2009&lt;\u20090.01), while no changes were observed at the vertex control site. Site-specific comparisons confirmed early window reductions only at the left dorsolateral prefrontal cortex (t\u2082\u2082 = \u22123.82; P\u2009&lt;\u20090.001). SNT also selectively decreased estimated medial prefrontal source activity consistent with the subgenual anterior cingulate cortex (sgACC) across sessions (F\u2081\u2083,\u2082\u2082\u2082 = 4.93; P\u2009&lt;\u20090.001), with effects persisting at 1-month follow-up. In an exploratory analysis in the active group (n\u2009=\u200912), higher baseline estimated sgACC source activity was associated with greater clinical improvement (r = \u22120.67; P\u2009=\u20090.023); although promising, the latter preliminary finding requires replication in larger, adequately powered samples before predictive utility can be established. These findings indicate that SNT induces progressive, site-specific cortical modulation and selective downstream effects on estimated sgACC source activity. Early cortical excitability changes represent candidate neurophysiological markers of SNT response, while the observed association between baseline sgACC activity and clinical outcome, while preliminary, motivates prospective investigation of subcortical source activity as a potential predictor of treatment response in larger trials. ClinicalTrials.gov Identifier: NCT03068715.<\/jats:p>","DOI":"10.1038\/s41380-026-03837-4","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T11:21:40Z","timestamp":1788348100000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurophysiological signatures of Stanford Neuromodulation Therapy in treatment resistant depression"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6048-8296","authenticated-orcid":false,"given":"Davide","family":"Momi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derrick M.","family":"Buchanan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3937-3619","authenticated-orcid":false,"given":"Masataka","family":"Wada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3483-026X","authenticated-orcid":false,"given":"Andrew D.","family":"Geoly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriah J.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleanor J.","family":"Cole","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adi","family":"Maron-Katz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6412-4078","authenticated-orcid":false,"given":"Claudia","family":"Tischler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher C.","family":"Cline","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7772-1143","authenticated-orcid":false,"given":"Diego A.","family":"Pizzagalli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5307-2249","authenticated-orcid":false,"given":"Manish","family":"Saggar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daphne","family":"Voineskos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Griffiths","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camarin E.","family":"Rolle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0529-3490","authenticated-orcid":false,"given":"Corey J.","family":"Keller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4368-3203","authenticated-orcid":false,"given":"Nolan","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"3837_CR1","doi-asserted-by":"publisher","first-page":"20m13699","DOI":"10.4088\/JCP.20m13699","volume":"82","author":"M Zhdanava","year":"2021","unstructured":"Zhdanava M, Pilon D, Ghelerter I, Chow W, Joshi K, Lefebvre P, et al. 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Dr. Williams has served on scientific advisory boards for Otsuka, Jazz Pharmaceuticals, and Janssen. Dr. Keller holds equity in Alto Neuroscience, Inc. and Flow Neuroscience, Inc. Over the past three years, Dr. Pizzagalli has received consulting fees from AbbVie, Boehringer Ingelheim, Circular Genomics, Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, Neurocrine Biosciences, N1 Biocorp., Neuroscience Software, Syntropic Medical,\u00a0Takeda, and Xenon Pharmaceuticals; he has received honoraria from the American Psychological Association, Psychonomic Society and Springer (for editorial work) and from Alkermes; he has received research funding from the Brain and Behavior Research Foundation, Circular Genomics, Dana Foundation, Wellcome Leap, Millennium Pharmaceuticals, and NIMH; he has received stock options from Ceretype Neuromedicine, Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, and Neuroscience Software. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. No other authors report conflicts of interest.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The study was approved by the Stanford University Institutional Review Board and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants prior to enrollment. The trial was registered at ClinicalTrials.gov (NCT03068715) and followed CONSORT guidelines for randomized controlled trials.","order":2,"name":"Ethics","label":"Ethics","group":{"name":"EthicsHeading","label":"Ethics"}}]}}