Suppression of Endogenous Alpha Power Predicts Clinical Response to 10 Hz tACS in Major Depressive Disorder: A Double-Blind Randomized Controlled Trial

Suppression of Endogenous Alpha Power Predicts Clinical Response to 10 Hz tACS in Major Depressive Disorder: A Double-Blind Randomized Controlled Trial | medRxiv Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Suppression of Endogenous Alpha Power Predicts Clinical Response to 10 Hz tACS in Major Depressive Disorder: A Double-Blind Randomized Controlled Trial View ORCID Profile Tobias Schwippel , View ORCID Profile Francesca Pupillo , Hadden LaGarde , View ORCID Profile Athena Stein , View ORCID Profile Mengsen Zhang , View ORCID Profile David Rubinow , Flavio Frohlich doi: https://doi.org/10.64898/2026.03.17.26348625 Tobias Schwippel 1 Department of Psychiatry, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599, USA 2 Carolina Center for Neurostimulation, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Tobias Schwippel Francesca Pupillo 1 Department of Psychiatry, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599, USA 2 Carolina Center for Neurostimulation, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Francesca Pupillo Hadden LaGarde 1 Department of Psychiatry, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599, USA 2 Carolina Center for Neurostimulation, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Athena Stein 1 Department of Psychiatry, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599, USA 2 Carolina Center for Neurostimulation, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Athena Stein Mengsen Zhang 1 Department of Psychiatry, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599, USA 2 Carolina Center for Neurostimulation, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Mengsen Zhang David Rubinow 1 Department of Psychiatry, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for David Rubinow Flavio Frohlich 1 Department of Psychiatry, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599, USA 2 Carolina Center for Neurostimulation, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599, USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: flavio_frohlich{at}med.unc.edu Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Background Transcranial alternating current stimulation (tACS) is a promising non-pharmacological intervention for major depressive disorder (MDD), but its effects on endogenous alpha oscillatory dynamics and their relationship to clinical improvement remain unclear. Methods In this double-blind, sham-controlled randomized clinical trial, 20 adults with MDD received five consecutive days of prefrontal 10 Hz tACS or sham. Resting 128-channel EEG was acquired before stimulation on Day 1 (D1), Day 5 (D5), and two-week follow-up. Changes in alpha power spectral density were quantified at the stimulation frequency (10 Hz) and at each participant’s individual alpha frequency (IAF), using prefrontal regions of interest and whole-head topographical analyses. Depression severity was assessed using the Hamilton Depression Rating Scale (HDRS-17). Results Between-group comparisons revealed no significant differences in prefrontal alpha power changes at either 10 Hz or IAF during the intervention week or at follow-up, although right prefrontal 10 Hz power showed a trend-level reduction with tACS. In contrast, within the tACS group, greater reductions in prefrontal IAF power were associated with greater HDRS-17 improvement from D1 to follow-up, and early IAF power suppression during the intervention week predicted later symptom improvement. Whole-head analyses identified a posterior cluster of reduced 10 Hz power at follow-up in the tACS group relative to sham, whereas clinically relevant correlations were specific to IAF power and distributed across frontal-central and parietal electrodes. Depression scores improved over time in both groups, with greater reductions in HDRS-17 scores observed in the tACS group. Conclusions Findings suggest that five days of 10 Hz tACS engages depression-relevant alpha mechanisms, with symptom improvement linked specifically to modulation of alpha power at IAF. Results support personalization of tACS in future trials. Competing Interest Statement Conflict of Interest Disclosures. Tobias Schwippel, Francesca Pupillo, Hadden LaGarde, Athena Stein and Mengsen Zhang do not report a conflict of interest. F.F. holds equity in and serves as a consultant for Electromedical Products International (EPI). F.F. is the lead inventor of non-invasive brain stimulation technology and receives royalty payments from the University of North Carolina at Chapel Hill. F.F. is the founder and sole owner of Flavio Labs LLC, a coaching and consulting firm, and co-founder and equity holder of Qortical Clinical Partners Inc. F.F. holds an adjunct professorship at Inselspital, Bern University Hospital (University of Bern, Switzerland) and serves as a consultant to that institution. F.F. receives royalty payments from Academic Press for the textbook Network Neuroscience. David Rubinow receives research funding from the NIH, the Baszucki Foundation, and Sage Therapeutics. He serves on the Scientific Advisory Boards of Sage Therapeutics and Sensorium Therapeutics. He serves on the Clinical Advisory Boards of Felicitypharma and Embarkneuro. He serves as a consultant to Brii Biosciences, GH Research-Ireland, and Aldeyra Therapeutics. Clinical Trial NCT03994081 Funding Statement This study was funded by the Foundation of Hope. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Office of Human Research Ethics of the University of North Carolina at Chapel Hill gave ethical approval for this work (IRB # 20-1822). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as https://ClinicalTrials.gov . I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability De-identified data produced in the present study are available from the authors upon reasonable request. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Back to top Previous Next Posted March 19, 2026. Download PDF Supplementary Material Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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