{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T18:08:27Z","timestamp":1789063707701,"version":"build-2803163510"},"reference-count":30,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["471191"],"award-info":[{"award-number":["471191"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Conventional treatments for major depressive disorder (MDD) fail to benefit one-third of patients, underscoring the need for therapies with novel mechanisms of action. Bilateral functional electrical stimulation (FES) of the facial muscles uses electrical currents to activate the muscles involved in facial expression and may offer a novel \u201cmind\u2013body\u201d intervention for MDD. Based on preliminary work demonstrating the feasibility of FES for MDD, this proposed study will assess the efficacy, safety, and tolerability of FES in MDD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This single-site, double-blind, randomized, sham-controlled pilot trial will enroll 60 participants to evaluate the therapeutic effects of 20 sessions of bilateral facial FES over four weeks. The study will assess the impact of FES on depressive symptoms, associated anxiety, quality of life, and sleep. Participant dropout and protocol adherence will be monitored to assess tolerability, while adverse events will be monitored to assess safety throughout the trial. Eligible participants will complete 20 on-site intervention visits and 6 online visits, including a screening visit, a baseline visit, and four post-stimulation follow-up visits.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>The findings from this trial will guide the development of a multisite, large-scale randomized controlled trial and inform further refinement of FES treatment parameters for this population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>\n                      This trial was registered at the National Library of Medicine, National Center for Biotechnology Information (ClinicalTrials.gov:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT07629050\" xlink:type=\"simple\">NCT07629050<\/jats:ext-link>\n                      . Date registered: 2026-06-08).\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0357381","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T17:35:01Z","timestamp":1789061701000},"page":"e0357381","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional electrical stimulation for major depressive disorder: Protocol for a pilot randomized controlled trial"],"prefix":"10.1371","volume":"21","author":[{"given":"Fatemeh","family":"Gholamali Nezhad","sequence":"first","affiliation":[{"name":"Interventional Psychiatry Program, St. Michael\u2019s Hospital, Unity Health Toronto","place":["Toronto, Ontario, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haochen","family":"Yu","sequence":"additional","affiliation":[{"name":"Interventional Psychiatry Program, St. Michael\u2019s Hospital, Unity Health Toronto","place":["Toronto, Ontario, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7876-4981","authenticated-orcid":true,"given":"Ilya","family":"Demchenko","sequence":"additional","affiliation":[{"name":"Interventional Psychiatry Program, St. Michael\u2019s Hospital, Unity Health Toronto","place":["Toronto, Ontario, Canada"]},{"name":"Institute of Medical Science","place":["Toronto, Ontario, Canada"],"department":["Temerty Faculty of Medicine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie N.","family":"Iwasa","sequence":"additional","affiliation":[{"name":"The KITE Research Institute, Toronto Rehabilitation Institute, University Health Network","place":["Toronto, Ontario, Canada"]},{"name":"CRANIA, University Health Network and University of Toronto","place":["Toronto, Ontario, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"DiNunzio","sequence":"additional","affiliation":[{"name":"The KITE Research Institute, Toronto Rehabilitation Institute, University Health Network","place":["Toronto, Ontario, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rayna","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering, University of Toronto","place":["Toronto, Ontario, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8842-745X","authenticated-orcid":true,"given":"Jos\u00e9","family":"Zariffa","sequence":"additional","affiliation":[{"name":"The KITE Research Institute, Toronto Rehabilitation Institute, University Health Network","place":["Toronto, Ontario, Canada"]},{"name":"Institute of Biomedical Engineering, University of Toronto","place":["Toronto, Ontario, Canada"]},{"name":"Rehabilitation Sciences Institute, University of Toronto","place":["Toronto, Ontario, Canada"]},{"name":"University of Toronto","place":["Toronto, Ontario, Canada"],"department":["Edward S. Rogers Sr. Department of Electrical and Computer Engineering"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0207-3241","authenticated-orcid":true,"given":"Kei","family":"Masani","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Engineering, University of Toronto","place":["Toronto, Ontario, Canada"]},{"name":"Lyndhurst Centre, KITE Research Institute\u2013University Health Network","place":["Toronto, Ontario, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy","family":"Lou","sequence":"additional","affiliation":[{"name":"Dalla Lana School of Public Health, University of Toronto","place":["Toronto, Canada"],"department":["Division of Biostatistics"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0303-6450","authenticated-orcid":true,"given":"Benoit H.","family":"Mulsant","sequence":"additional","affiliation":[{"name":"Institute of Medical Science","place":["Toronto, Ontario, Canada"],"department":["Temerty Faculty of Medicine"]},{"name":"University of Toronto","place":["Toronto, Ontario, Canada"],"department":["Department of Psychiatry"]},{"name":"Centre for Addiction and Mental Health","place":["Toronto, Ontario, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hani E.","family":"Naguib","sequence":"additional","affiliation":[{"name":"University of Toronto","place":["Toronto, Ontario, Canada"],"department":["Department of Mechanical and Industrial Engineering"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milos R.","family":"Popovic","sequence":"additional","affiliation":[{"name":"The KITE Research Institute, Toronto Rehabilitation Institute, University Health Network","place":["Toronto, Ontario, Canada"]},{"name":"CRANIA, University Health Network and University of Toronto","place":["Toronto, Ontario, Canada"]},{"name":"Institute of Biomedical Engineering, University of Toronto","place":["Toronto, Ontario, Canada"]},{"name":"University of Toronto","place":["Toronto, Ontario, Canada"],"department":["Department of Mechanical and Industrial Engineering"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8768-1173","authenticated-orcid":true,"given":"Venkat","family":"Bhat","sequence":"additional","affiliation":[{"name":"Interventional Psychiatry Program, St. Michael\u2019s Hospital, Unity Health Toronto","place":["Toronto, Ontario, Canada"]},{"name":"Institute of Medical Science","place":["Toronto, Ontario, Canada"],"department":["Temerty Faculty of Medicine"]},{"name":"University of Toronto","place":["Toronto, Ontario, Canada"],"department":["Department of Psychiatry"]},{"name":"Li Ka Shing Knowledge Institute, St. Michael\u2019s Hospital","place":["Toronto, Ontario, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"pone.0357381.ref001","doi-asserted-by":"crossref","first-page":"115958","DOI":"10.1016\/j.psychres.2024.115958","article-title":"Global, regional, and national temporal trend in burden of major depressive disorder from 1990 to 2019: an analysis of the global burden of disease study","volume":"337","author":"G Yan","year":"2024","journal-title":"Psychiatry Res"},{"issue":"10","key":"pone.0357381.ref002","doi-asserted-by":"crossref","first-page":"851","DOI":"10.2165\/00002018-200831100-00004","article-title":"Comparative risk for harms of second-generation antidepressants","volume":"31","author":"G Gartlehner","year":"2008","journal-title":"Drug Safety"},{"key":"pone.0357381.ref003","unstructured":"Pharmacological and non-pharmacological treatments for major depressive disorder: review of systematic reviews. BMJ Open."},{"issue":"1","key":"pone.0357381.ref004","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1002\/hup.180","article-title":"Limitations to enhancing the speed of onset of antidepressants \u2014 are rapid action antidepressants possible?","volume":"16","author":"F Artigas","year":"2001","journal-title":"Hum Psychopharmacol Clin Exp"},{"key":"pone.0357381.ref005","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.cpr.2014.10.006","article-title":"Neurostimulation as an intervention for treatment resistant depression: from research on mechanisms towards targeted neurocognitive strategies","volume":"41","author":"R De Raedt","year":"2015","journal-title":"Clin Psychol Rev"},{"issue":"1","key":"pone.0357381.ref006","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/s41591-024-03305-y","article-title":"Home-based transcranial direct current stimulation treatment for major depressive disorder: a fully remote phase 2 randomized sham-controlled trial","volume":"31","author":"RD Woodham","year":"2025","journal-title":"Nat Med"},{"key":"pone.0357381.ref007","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.l1079","article-title":"Comparative efficacy and acceptability of non-surgical brain stimulation for the acute treatment of major depressive episodes in adults: systematic review and network meta-analysis","author":"J Mutz","year":"2019"},{"key":"pone.0357381.ref008","first-page":"401","article-title":"Functional Electrical Stimulation Therapy: Mechanisms for Recovery of Function Following Spinal Cord Injury and Stroke.","author":"MR Popovic","year":"2022","journal-title":"Reinkensmeyer DJ, Marchal-Crespo L, Dietz V, editors. Neurorehabilitation Technology. Cham: Springer International Publishing"},{"issue":"1","key":"pone.0357381.ref009","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1186\/s12938-020-00773-4","article-title":"Functional electrical stimulation therapy for restoration of motor function after spinal cord injury and stroke: a review","volume":"19","author":"C Marquez-Chin","year":"2020","journal-title":"Biomed Eng Online"},{"issue":"5","key":"pone.0357381.ref010","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1109\/TNSRE.2018.2816238","article-title":"Automated FES for upper limb rehabilitation following stroke and spinal cord injury","volume":"26","author":"EF Hodkin","year":"2018","journal-title":"IEEE Transac Neural Syst Rehabilit Eng"},{"issue":"5","key":"pone.0357381.ref011","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/j.apmr.2015.01.013","article-title":"Functional electrical stimulation improves activity after stroke: a systematic review with meta-analysis","volume":"96","author":"OA Howlett","year":"2015","journal-title":"Arch Phys Med Rehabil"},{"issue":"10","key":"pone.0357381.ref012","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/sj.sc.3102101","article-title":"Benefits of FES gait in a spinal cord injured population","volume":"45","author":"EJ Nightingale","year":"2007","journal-title":"Spinal Cord"},{"issue":"1","key":"pone.0357381.ref013","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1037\/1528-3542.2.1.52","article-title":"Duchenne smile, emotional experience, and autonomic reactivity: a test of the facial feedback hypothesis","volume":"2","author":"R Soussignan","year":"2002","journal-title":"Emotion"},{"issue":"1","key":"pone.0357381.ref014","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1111\/ner.12056","article-title":"Neuromodulation of emotion using functional electrical stimulation applied to facial muscles","volume":"17","author":"J Zariffa","year":"2014","journal-title":"Neuromodulation"},{"issue":"1","key":"pone.0357381.ref015","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s12984-023-01187-8","article-title":"Manipulating facial musculature with functional electrical stimulation as an intervention for major depressive disorder: a focused search of literature for a proposal","volume":"20","author":"I Demchenko","year":"2023","journal-title":"J Neuroeng Rehabil"},{"issue":"1","key":"pone.0357381.ref016","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1186\/s12938-019-0730-6","article-title":"Functional electrical stimulation of the facial muscles to improve symptoms in individuals with major depressive disorder: pilot feasibility study","volume":"18","author":"N Kapadia","year":"2019","journal-title":"Biomed Eng Online"},{"key":"pone.0357381.ref017","doi-asserted-by":"crossref","first-page":"109877","DOI":"10.1016\/j.jneumeth.2023.109877","article-title":"Measurement of the N170 during facial neuromuscular electrical stimulation (fNMES)","volume":"393","author":"J Baker","year":"2023","journal-title":"J Neurosci Methods"},{"issue":"1","key":"pone.0357381.ref018","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1037\/emo0001408","article-title":"Smiling and frowning induced by facial neuromuscular electrical stimulation (fNMES) modulate felt emotion and physiology","volume":"25","author":"TN Efthimiou","year":"2025","journal-title":"Emotion"},{"issue":"1","key":"pone.0357381.ref019","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1136\/jnnp.23.1.56","article-title":"A rating scale for depression","volume":"23","author":"M Hamilton","year":"1960","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"3","key":"pone.0357381.ref020","doi-asserted-by":"crossref","first-page":"200","DOI":"10.7326\/0003-4819-158-3-201302050-00583","article-title":"SPIRIT 2013 statement: defining standard protocol items for clinical trials","volume":"158","author":"A-W Chan","year":"2013","journal-title":"Ann Intern Med"},{"key":"pone.0357381.ref021","unstructured":"Sheehan DV. The Mini-International Neuropsychiatric Interview (M.I.N.I.): The development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10."},{"key":"pone.0357381.ref022","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1192\/bjp.134.4.382","article-title":"A new depression scale designed to be sensitive to change","volume":"134","author":"SA Montgomery","year":"1979","journal-title":"Br J Psychiatry"},{"key":"pone.0357381.ref023","unstructured":"Ovid. The impact of medication resistance and. J Clin Psychopharm. Accessed 2026 July 15."},{"issue":"5","key":"pone.0357381.ref024","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1177\/1545968310392924","article-title":"Functional electrical stimulation therapy of voluntary grasping versus only conventional rehabilitation for patients with subacute incomplete tetraplegia: a randomized clinical trial","volume":"25","author":"MR Popovic","year":"2011","journal-title":"Neurorehabil Neural Repair"},{"issue":"5","key":"pone.0357381.ref025","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1016\/S0006-3223(02)01866-8","article-title":"The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression","volume":"54","author":"AJ Rush","year":"2003","journal-title":"Biol Psychiatry"},{"issue":"10","key":"pone.0357381.ref026","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1001\/archinte.166.10.1092","article-title":"A brief measure for assessing generalized anxiety disorder: the GAD-7","volume":"166","author":"RL Spitzer","year":"2006","journal-title":"Arch Intern Med"},{"issue":"3","key":"pone.0357381.ref027","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1159\/000376585","article-title":"The WHO-5 well-being index: a systematic review of the literature","volume":"84","author":"CW Topp","year":"2015","journal-title":"Psychother Psychosom"},{"issue":"2","key":"pone.0357381.ref028","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/0165-1781(89)90047-4","article-title":"The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research","volume":"28","author":"DJ Buysse","year":"1989","journal-title":"Psychiatry Res"},{"issue":"4","key":"pone.0357381.ref029","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.3758\/s13428-023-02262-7","article-title":"Application of facial neuromuscular electrical stimulation (fNMES) in psychophysiological research: Practical recommendations based on a systematic review of the literature","volume":"56","author":"TN Efthimiou","year":"2024","journal-title":"Behav Res Methods"},{"issue":"1","key":"pone.0357381.ref030","doi-asserted-by":"crossref","DOI":"10.1093\/scan\/nsae013","article-title":"Zygomaticus activation through facial neuromuscular electrical stimulation (fNMES) induces happiness perception in ambiguous facial expressions and affects neural correlates of face processing","volume":"19","author":"TN Efthimiou","year":"2024","journal-title":"Soc Cogn Affect Neurosci"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0357381","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T17:35:08Z","timestamp":1789061708000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0357381"}},"subtitle":[],"editor":[{"given":"Avanti","family":"Dey","sequence":"first","affiliation":[{"name":"Public Library of Science","place":["UNITED STATES OF AMERICA"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,9,10]]},"references-count":30,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0357381","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,10]]}}}