Daily EEG reveals stage-specific alpha power and functional connectivity modulation across five days of tACS in major depressive disorder

Daily EEG reveals stage-specific alpha power and functional connectivity modulation across five days of tACS in major depressive disorder | medRxiv Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Daily EEG reveals stage-specific alpha power and functional connectivity modulation across five days of tACS in major depressive disorder View ORCID Profile Athena Stein , View ORCID Profile Tobias Schwippel , Francesca Pupillo , Hadden LaGarde , View ORCID Profile Mengsen Zhang , David Rubinow , View ORCID Profile Flavio Frohlich doi: https://doi.org/10.64898/2026.03.17.26348546 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 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 4 Department of Psychiatry, Psychotherapy and Psychosomatics, Goethe University , Frankfurt, Germany 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 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 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 3 Department of Computational Mathematics, Science and Engineering, Michigan State University , East Lansing, MI 48824 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 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 ORCID record for Flavio Frohlich For correspondence: flavio_frohlich{at}med.unc.edu Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Background Major depressive disorder (MDD) is characterized by altered frontal alpha oscillations. Transcranial alternating current stimulation (tACS) can normalize aberrant oscillations in MDD, yet the daily dynamics of tACS target engagement of alpha oscillations in depression remain unclear. Methods In a double-blind randomized controlled trial ( NCT03994081 ), 20 participants with MDD received verum or sham 10 Hz tACS (40 min/day, 5 days) targeted to left and right dorsolateral prefrontal cortex (F3/F4). High-density EEG was collected pre/post-stimulation each day to quantify within-session and cumulative changes in alpha power and functional connectivity (wPLI). Results Verum stimulation produced late-emerging, session-specific alpha power decreases compared to sham, with robust day (D)4 post-pre reductions at both IAF and 10 Hz across frontal and parietal regions (t=-2.42 to -3.82, p<0.05; parietal t=-3.82, pFDR<0.05). Whole-brain topographical analysis confirmed a distinct condition x D4 effect at left prefrontal cortex (t=2.9, pFWE<0.05, cluster permutation). Connectivity changes emerged earlier and more transiently, with D2 bilateral frontal wPLI reductions (t=-2.53, p<0.05). Cumulative analyses (change from D1) showed significant wPLI decreases on D2 and D3 (t=-2.65 and t=-2.46; p<0.05). Exploratory clinical correlations showed that the D4 IAF power decrease was associated with increased reward sensitivity (spearman rho= -0.6, p<0.05, cluster-corrected). Conclusions Alpha-tACS produced a temporally distinct neural response: an early, transient decrease in functional connectivity on D2, which may have driven a later suppression of left prefrontal alpha power on D4, correlated with clinical and behavioral improvements. These results delineate target engagement and validation mechanisms in a multi-day tACS trial, supporting optimized dosing in future tACS interventions. Competing Interest Statement This work was supported by The Foundation of Hope. Tobias Schwippel, Francesca Pupillo, Hadden LaGarde, and Mengsen Zhang do not report a conflict of interest. A.S. is supported by the American Australian Association Graduate Education Scholarship. 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. DR receives research funding from the NIH, the Baszucki Foundation, and Sage Therapeutics. DR serves on the Scientific Advisory Boards of Sage Therapeutics and Sensorium Therapeutics. DR serves on the Clinical Advisory Boards of Felicitypharma and Embarkneuro. DR serves as a consultant to Brii Biosciences, GH Research-Ireland, and Aldeyra Therapeutics. Clinical Trial NCT03994081 Funding Statement This work was supported 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 University of North Carolina at Chapel Hill Institutional Review Board and Office of Human Research Ethics provided ethical approval for this study. 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 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 All data produced in the present study are available upon reasonable request to the authors 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 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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Share Daily EEG reveals stage-specific alpha power and functional connectivity modulation across five days of tACS in major depressive disorder Athena Stein , Tobias Schwippel , Francesca Pupillo , Hadden LaGarde , Mengsen Zhang , David Rubinow , Flavio Frohlich medRxiv 2026.03.17.26348546; doi: https://doi.org/10.64898/2026.03.17.26348546 Share This Article: Copy Citation Tools Daily EEG reveals stage-specific alpha power and functional connectivity modulation across five days of tACS in major depressive disorder Athena Stein , Tobias Schwippel , Francesca Pupillo , Hadden LaGarde , Mengsen Zhang , David Rubinow , Flavio Frohlich medRxiv 2026.03.17.26348546; doi: https://doi.org/10.64898/2026.03.17.26348546 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Psychiatry and Clinical Psychology Subject Areas All Articles Addiction Medicine (638) Allergy and Immunology (918) Anesthesia (351) Cardiovascular Medicine (5011) Dentistry and Oral Medicine (496) Dermatology (428) Emergency Medicine (677) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1695) Epidemiology (16273) Forensic Medicine (36) Gastroenterology (1241) Genetic and Genomic Medicine (7286) Geriatric Medicine (753) Health Economics (1093) Health Informatics (5298) Health Policy (1469) Health Systems and Quality Improvement (1834) Hematology (599) HIV/AIDS (1383) Infectious Diseases (except HIV/AIDS) (16498) Intensive Care and Critical Care Medicine (1203) Medical Education (700) Medical Ethics (156) Nephrology (752) Neurology (7606) Nursing (379) Nutrition (1130) Obstetrics and Gynecology (1296) Occupational and Environmental Health (1041) Oncology (3749) Ophthalmology (1093) Orthopedics (410) Otolaryngology (466) Pain Medicine (502) Palliative Medicine (143) Pathology (721) Pediatrics (1861) Pharmacology and Therapeutics (756) Primary Care Research (786) Psychiatry and Clinical Psychology (6139) Public and Global Health (9997) Radiology and Imaging (2534) Rehabilitation Medicine and Physical Therapy (1521) Respiratory Medicine (1271) Rheumatology (662) Sexual and Reproductive Health (804) Sports Medicine (598) Surgery (804) Toxicology (109) Transplantation (320) Urology (308)

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