---
title: "Functional electrical stimulation for major depressive disorder: Pilot randomized sham-controlled"
id: "plos-one-22-functional-electrical-stimulation-for-major-depressive-disorder-protocol-for-a"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-22-functional-electrical-stimulation-for-major-depressive-disorder-protocol-for-a"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357381"
published_at: "2026-09-10T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Functional electrical stimulation for major depressive disorder: Pilot randomized sham-controlled
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-22-functional-electrical-stimulation-for-major-depressive-disorder-protocol-for-a
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0357381)
- **Published At:** 2026-09-10T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This article describes a single-site, double-blind, randomized, sham-controlled pilot trial protocol testing bilateral **functional electrical stimulation (FES)** of facial muscles as a treatment for **major depressive disorder (MDD)**. - The trial will enroll 60 participants to receive 20 on-site FES sessions over four weeks, plus six online visits including screening, baseline, and four follow-up visits. - Primary aims are to evaluate the **efficacy**, **safety**, and **tolerability** of repetitive bilateral facial FES for MDD, and to assess effects on depressive symptoms, anxiety, quality of life, and sleep. - The rationale is grounded in the **facial feedback hypothesis**: activation of facial expression muscles (notably the **zygomaticus major** and **orbicularis oculi**) can influence emotional state via proprioceptive and interoceptive feedback to limbic structures such as the **amygdala**. - Preclinical and small clinical studies support feasibility and possible mood effects: a 2014 pilot in healthy volunteers and an open-label 2019 study in MDD patients showed mood-related changes and reductions in depression rating scales after FES or facial neuromuscular electrical stimulation (fNMES). - The protocol will monitor participant dropout and adherence to assess tolerability, and will record adverse events to evaluate safety throughout the trial. - Results from this pilot are intended to inform a larger multisite randomized controlled trial and to refine FES treatment parameters for this population. - Trial registration is ClinicalTrials.gov NCT07629050, registered 2026-06-08. Funding was provided by the Canadian Institutes of Health Research (CIHR; Grant No. 471191). Some authors hold a related patent; other competing-interest statements are reported in the source. - This article is a study protocol and reports no study data; all relevant information is contained within the paper.
## Clinical Analysis & Structured Key Points
Functional electrical stimulation for major depressive disorder: Protocol for a pilot randomized controlled trial | PLOS One Browse Subject Areas ? Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click here . Article Authors Metrics Comments Media Coverage Peer Review Reader Comments Figures Figures Abstract Background 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 “mind–body” 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. Methods 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. Discussion 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. Trial registration This trial was registered at the National Library of Medicine, National Center for Biotechnology Information (ClinicalTrials.gov: NCT07629050 . Date registered: 2026-06-08). Citation: Gholamali Nezhad F, Yu H, Demchenko I, Iwasa SN, DiNunzio S, Ghosh R, et al. (2026) Functional electrical stimulation for major depressive disorder: Protocol for a pilot randomized controlled trial. PLoS One 21(9): e0357381. https://doi.org/10.1371/journal.pone.0357381 Editor: Avanti Dey, Public Library of Science, UNITED STATES OF AMERICA Received: July 28, 2026; Accepted: August 10, 2026; Published: September 10, 2026 Copyright: © 2026 Gholamali Nezhad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: This article reports a study protocol and does not report any study data. All relevant information is within the paper. Funding: This work was supported by the Canadian Institutes of Health Research (CIHR; Grant No. 471191). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The Principal Investigator has no financial or competing interests to declare. FG holds a Canadian Institutes of Health Research (CIHR) Fellowship award (#531409). M.R.P. & J.Z. are inventors on U.S. Patent No. 9,259,576, titled “Functional electrical stimulation method, use and apparatus for mood alteration,” granted on February 16, 2016. The patent relates to the use of functional electrical stimulation of facial muscles to alter mood or emotional parameters and is assigned to the University Health Network. ID is a Vanier Scholar supported by CIHR (#513715). All other authors declare no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Introduction Major depressive disorder (MDD) is among the leading causes of disability worldwide, with an estimated global prevalence of 185.15 million cases and 274.80 million incident cases in 2019 [ 1 ]. While antidepressants are commonly recommended as first-line treatment for MDD, they have significant side effects and a therapeutic time lag [ 2 – 4 ]. Around 63% of MDD patients using second-generation antidepressants experienced at least one side effect and around 15% discontinued treatment as a result [ 2 ]. An alternative treatment modality for MDD patients who fail to respond to a course of antidepressants is neurostimulation, including hospital-based methods such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) [ 5 ] along with home-based methods like transcranial direct current stimulation (tDCS) [ 6 ]. However, existing neurostimulation techniques are limited by variable efficacy and practical barriers related to treatment burden, invasiveness, and clinical implementation [ 7 ]. Thus, there is a need to investigate alternative neurostimulation modalities to treat MDD. Functional electrical stimulation (FES) is a therapeutic technique that uses low-energy electrical impulses to activate neuromuscular units, which then stimulate skeletal muscles to contract and perform specific movements [ 8 ]. FES has been actively used in the context of neurorehabilitation and has been shown to be effective in restoring motor function following stroke and spinal cord injury through mechanisms of neuroplasticity [ 8 – 12 ]. Emerging research suggests that FES targeting muscles of facial expression could be a potentially effective modality for the treatment of MDD based on the facial feedback hypothesis, which postulates that facial expressions can influence and modulate an individual’s emotional state through proprioceptive and interoceptive feedback loops [ 13 , 14 ]. A non-Duchenne smile primarily involves activation of the zygomaticus major, whereas a Duchenne smile additionally recruits the orbicularis oculi and has been more consistently associated with positive emotional experience [ 13 ]. These smiles are mediated by different neural pathways. Experimental findings also suggest that combined activation of the zygomaticus major and orbicularis oculi may have a greater positive influence on emotional experience than activation of the zygomaticus major alone, providing a rationale for targeting both muscles with FES. A neural feedback loop has been proposed in which facial muscle activity influences emotional processing through the amygdala, a key structure involved in emotion processing and generation [ 15 ]. Facial motor activity is conveyed to the amygdala, which integrates proprioceptive signals from the trigeminal nerve and interoceptive signals carried through the glossopharyngeal and vagus nerves [ 15 ]. By activating the facial muscles, FES may engage these pathways and contribute to neuroplastic changes involved in emotional regulation. Zariffa et al. (2014) [ 14 ] conducted a pilot study exploring the mood-related effects of a single FES session targeting the Duchenne smile muscles in healthy individuals. Twelve participants receiving FES were compared with 12 controls. Based on the Positive and Negative Affect Schedule-X (PANAS-X), the findings suggested that FES may influence emotional states such as feeling “determined,” “daring,” “scared,” and “concentrating.” Building on this initial study, Kapadia et al. (2019) [ 16 ] conducted an open-label trial with MDD patients and reported significant improvements in depressive symptoms following a treatment course with FES, with participants showing an 8.1-point reduction on the 17-item Hamilton Depression Rating Scale (HAM-D-17) and a 14-point reduction on the Inventory of Depressive Symptomatology after 10 sessions of FES. Moreover, evidence from studies on Facial Neuromuscular Electrical Stimulation (fNMES), which directly activates facial muscles using computer-controlled electrical impulses, also supports an effect of facial muscle activation on emotional experience [ 17 , 18 ]. Participants reported more positive emotions after stronger stimulation of the zygomaticus major (smile muscle) compared to the depressor anguli oris (frown muscle) [ 18 ]. These studies provide promising evidence for the therapeutic potential of FES for MDD, setting the stage for designing a rigorous randomized sham-controlled trial (RCT) examining the efficacy of repetitive FES of facial muscles for MDD. This pilot RCT will assess the efficacy, safety, and tolerability of 20 sessions of FES in 60 participants diagnosed with MDD using a sham-controlled design. Objectives The primary objective of this RCT is to evaluate the efficacy, tolerability, and safety of FES targeting the Duchenne muscles in participants with MDD. We hypothesize that participants receiving active FES will show greater reductions in the HAM-D-17 [ 19 ] total score than participants receiving sham FES with no significant differences in dropout rates, protocol adherence, or the incidence of adverse events (AEs) and serious adverse events (SAEs) between the two groups. A secondary objective of this RCT is to evaluate the impact of FES on MDD response and remission rates, anxiety, quality of life, sleep quality, and the sustainability of these effects over four weeks. We hypothesize that participants receiving active FES will show significantly greater improvements across all these domains compared to those receiving sham FES. A further objective of this RCT is to explore changes in facial expressivity during a semi-structured emotional recall interview using objective facial coding. We hypothesize that participants receiving active FES will demonstrate greater frequency, intensity, and duration of Duchenne smiles than those receiving sham FES during emotional recall interviews, reflecting enhanced emotional expressivity. Methods Study design and setting This study is a single-site, double-blind, pilot RCT conducted at St. Michael’s Hospital, Unity Health Toronto. The study design follows the SPIRIT guidelines ( Fig 1 ) [ 20 ]. Eligible participants will be randomly assigned to receive either 20 sessions of active FES or sham. Both groups will complete a total of 26 visits ( Fig 2 ). Six visits, including a screening visit, a baseline visit, and four follow-up visits, will be conducted remotely via phone or video conferencing using the Zoom platform. The 20 intervention visits will take place on-site, with participants attending one stimulation session per day over 20 consecutive working days. A trained staff member will directly monitor stimulation sessions. AEs and depressive symptoms will be monitored daily. All baseline assessments, except the emotional recall interview, will be repeated at the end of each intervention week and at each follow-up visit. The emotional recall interview will be conducted at baseline and at the end of each intervention week only. The SPIRIT Checklist is available in S1 File . The study protocol (Version 1, dated 10 March 2026; approved by the St. Michael’s Hospital Research Ethics Board, REB No. 24–155) is available as S2 File . Download: PNG larger image TIFF original image Fig 1. SPIRIT figure: schedule of enrollment, interventions, and assessments. Abbreviations: AE = Adverse Event, ATHF = Antidepressant Treatment History Form, CONMED = Concomitant Medication Record, FES = Functional Electrical Stimulation, GAD-7 = Generalized Anxiety Disorder-7, HAMD-17 = 17-Item Hamilton Depression Rating Scale, MADRS = Montgomery–Åsberg Depression Rating Scale, MINI = Mini-International Neuropsychiatric Interview, PSQI = Pittsburgh Sleep Quality Index, QIDS-SR-16 = 16-Item Quick Inventory of Depressive Symptomatology – Short Form, WHO-5 = World Health Organization-Five Well-Being Index. https://doi.org/10.1371/journal.pone.0357381.g001 Download: PNG larger image TIFF original image Fig 2. Study design. FES-Active and FES-Sham groups will complete a total of 26 visits. The 20 intervention visits will take place once per day over 20 days. Created in BioRender: RR29VRAKC1. https://doi.org/10.1371/journal.pone.0357381.g002 Eligibility criteria Recruitment will take place through referrals to the Interventional Psychiatry Program (IPP) at St. Michael’s Hospital, Unity Health Toronto, as well as through approved advertisements and flyers. Sixty participants with unipolar, non-psychotic MDD, as determined by the Mini-International Neuropsychiatric Interview (MINI) [ 21 ], will be recruited. Eligible participants will be males and females aged 18–70 years. They must have a Montgomery–Åsberg Depression Rating Scale (MADRS) [ 22 ] score of ≥7 and no more than two failed treatment trials during the current major depressive episode. Eligible participants will be required to maintain a stable regimen of medication and psychotherapy for at least four weeks before the study, and have no plan to change them throughout the intervention period, and during the follow-up, as reported in the Antidepressant Treatment History Form (ATHF) [ 23 ]. Individuals will be excluded if they have received ECT, magnetic seizure therapy, or intravenous ketamine during the current depressive episode, or rTMS within the previous 28 days. Additional exclusion criteria encompass a diagnosis of fibromyalgia, a history of epilepsy or seizures, oral metallic orthopedic implants, or damaged or dysfunctional facial nerves. Psychiatric comorbidities warranting exclusion consist of past or present symptoms of mania, hypomania, mixed episodes, psychotic disorders, obsessive-compulsive disorder, post-traumatic stress disorder, active substance use or dependence (excluding nicotine and caffeine), neurodegenerative disorders, or dementia. Participants with current suicidal intent or plan (MADRS item 10 score ≥ 4) or inability to generate the Duchenne smile with FES will also be excluded. Additionally, individuals who do not speak English will be excluded from this RCT to ensure clear comprehension of study information, facilitate communication for addressing participant questions, and obtain informed consent effectively. Sample size The sample size calculation is based on a between-group comparison of the mean change in HAM-D-17 scores from baseline to day 20. Analysis of covariance (ANCOVA) will be used, with the change in HAM-D-17 score from baseline to day 20 as the outcome and baseline HAM-D-17 score and sex as covariates. In our previous pilot study [ 16 ], involving 10 participants with moderate to severe MDD who received three FES sessions per week (ranging from a minimum of 10 to a maximum of 40 total sessions), FES demonstrated a moderate to large effect size (d = 0.6–1.2) in MDD. All 10 participants completed the required 10 sessions, and 5 participants completed 40 sessions [ 16 ]. Our RCT will use 20 sessions of FES, which was well tolerated in research on rTMS for MDD and FES for stroke and spinal cord injury rehabilitation. A total of 60 participants (30 in the active arm and 30 in the sham arm) is planned to detect a clinically meaningful between-group difference in HAM-D-17 scores, assuming a moderate effect size of 0.5 (Cohen’s d), a two-tailed significance level of 0.05, and 80% power. Accounting for a 15% attrition rate, approximately 51 participants are expected to complete the study, exceeding the recommended minimum sample size (24–50 participants) needed to generate reliable estimates of the standard deviation and correlation of HAM-D-17 scores for future sample size calculations in a definitive trial. Furthermore, a sample size of 60 will allow the anticipated 15% dropout rate to be estimated with an approximate 95% confidence interval margin of error of ±8.4. As the first proof-of-concept RCT of its kind, this trial is designed primarily to detect a signal for the primary outcome, change in HAM-D-17 over time. We recognize that the proposed sample size may not provide high statistical power for some secondary and exploratory outcomes. Recruitment Participants referred to the IPP will be contacted to receive an overview of the study, have their questions addressed, and provide verbal consent for participation. Interested participants will then complete a pre-screening survey via Research Electronic Data Capture (REDCap) to determine preliminary eligibility. Individuals responding to social media advertisements or flyers will be directed to REDCap via the link provided in the advertisements to complete the same pre-screening survey. For those who meet initial eligibility criteria, a screening visit over the phone will be scheduled to assess full eligibility. The screening visit will include an eligibility review, collection of demographic data, medical history, confirmation of MDD diagnosis, and completion of an FES safety questionnaire. Verbal informed consent will be obtained before screening, and written informed consent will be obtained on the first day of on-site intervention sessions. While there are no known risks of FES stimulation to ova or fetuses during pregnancy, the possibility of unknown risks cannot be entirely ruled out. Thus, female participants will be asked to confirm they are not pregnant or planning a pregnancy during the study. Upon meeting all requirements, a baseline visit will be scheduled. Randomization and masking Participants will be randomly assigned in a 1:1 ratio to receive either active FES or sham using a randomization schedule generated through a secure REDCap module. Block randomization, stratified by sex, will account for potential differences in response and tolerability. Personnel conducting outcome assessments and other blinded study procedures will not have access to the fixed block size or treatment assignments. Randomization will be conducted by the intervention staff, who will have access to group assignments as required to deliver and monitor the stimulation sessions. In an emergency, the study doctor may be informed of the participant’s group assignment if this information is necessary for clinical management. Moreover, to preserve blinding, sensory and non-Duchenne-patterned sham stimulation will be utilized. Participants will be instructed to avoid interaction with one another throughout the study. Blinding effectiveness will be assessed after each session by asking participants and raters to indicate whether they believe the participant received active or sham FES. Intervention Participants will receive transcutaneous FES targeting the bilateral zygomaticus major and orbicularis oculi muscles with self-adhesive surface electrodes placed on all four muscles ( Fig 3 ). Each FES session, whether active or sham, will last for 60 minutes, comprising 15 minutes of preparation and 45 minutes of stimulation. FES will be administered using the Twin Stim® Plus Digital TENS/EMS FES device (Health Canada License name: TWIN STIM SERIES), providing 300 μs charge-balanced biphasic pulses at 40 Hz. During the intervention sessions, participants will watch a comedy video designed to elicit genuine Duchenne smiles while being instructed to intentionally produce a Duchenne smile at least once per minute. All intervention visits will be video recorded. Download: PNG larger image TIFF original image Fig 3. Surface electrode placement. FES of bilateral zygomaticus major and orbicularis oculi muscles. https://doi.org/10.1371/journal.pone.0357381.g003 For the active group, a synchronized stimulation of four muscles (i.e., the bilateral zygomaticus major and bilateral orbicularis oculi) will be delivered. The current amplitude will range from 8 to 15 mA, which is sufficient to induce contractions in the desired target muscles, with alternating 15-second periods of stimulation and rest. These parameters align with previous FES studies for muscle activation [ 24 ]. If participants experience discomfort, the stimulation intensity may be adjusted within permitted parameters, and all adjustments will be documented. Participants in the sham arm will receive FES with identical parameters, except that the stimulation will be limited to sensory
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