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This randomized, double-blind, parallel-group clinical trial aims to assess the effectiveness of a combined intervention consisting of a home-based therapeutic exercise program and transcranial direct current stimulation (tDCS) for the management of fatigue in patients with multiple sclerosis (MS). Fatigue is one of the most disabling and prevalent symptoms in MS, significantly impacting patients' quality of life and functional independence.
Participants diagnosed with MS who meet inclusion criteria will be randomized into two groups:
Group 1: Home-based therapeutic exercise plus sham (placebo) tDCS
Group 2: Home-based therapeutic exercise plus active tDCS
The intervention will span a defined period, with tDCS sessions applied over the dorsolateral prefrontal cortex (DLPFC) using a standard montage and parameters validated in previous studies. The sham stimulation group will follow identical procedures without active current delivery, preserving blinding for participants and evaluators.
The therapeutic exercise program is designed to be feasible for home implementation, targeting key domains affected in MS such as strength, endurance, balance, and mobility. Exercises will be prescribed based on individual patient assessments and progressively adjusted throughout the intervention period.
Primary outcome measures will include functional capacity, evaluated through the Six-Minute Walk Test (6MWT), and fatigue levels, assessed via the Fatigue Severity Scale (FSS) and a Visual Analogue Scale (VAS) for fatigue. Secondary observations may include adherence rates to the exercise program and subjective reports of tolerability and perceived benefits.
This trial seeks to explore whether combining a physical intervention (exercise) with a neuromodulation technique (tDCS) can offer additive benefits in managing fatigue, beyond what exercise alone provides. The ultimate goal is to develop accessible, non-pharmacological treatment strategies to improve daily functioning and quality of life for individuals living with multiple sclerosis.
This study is a randomized, double-blind, controlled clinical trial designed to investigate the efficacy of a combined intervention consisting of a structured home-based therapeutic exercise program and transcranial direct current stimulation (tDCS) for the treatment of fatigue in patients with multiple sclerosis (MS).
Eligible participants will be randomly assigned to one of two parallel groups:
An intervention group receiving a prescribed home-based exercise program in combination with active tDCS.
A control group receiving the same exercise program combined with sham (placebo) tDCS.
The tDCS intervention will target the dorsolateral prefrontal cortex (DLPFC) using a standardized electrode placement, with stimulation parameters based on protocols previously demonstrated to be safe and potentially effective in neurological populations. The sham condition will simulate the sensation of stimulation without delivering an active current, ensuring the integrity of the blinding process for both participants and evaluators.
The therapeutic exercise program will focus on improving muscular strength, cardiovascular endurance, balance, and functional mobility, components known to be affected in individuals with MS. The program will be tailored to individual baseline capabilities and progressively adapted throughout the intervention period to optimize participant engagement and safety.
Primary outcome measures include changes in functional exercise capacity, as assessed by the Six-Minute Walk Test (6MWT), and fatigue severity, evaluated using the Fatigue Severity Scale (FSS) and a Visual Analogue Scale (VAS) for fatigue. Adherence to the intervention and tolerability will also be monitored.
The proposed study addresses a critical need for accessible, non-pharmacological interventions to manage fatigue, one of the most common and disabling symptoms in MS. By combining physical rehabilitation strategies with neuromodulation techniques, the trial aims to determine whether synergistic effects can be achieved, potentially informing future clinical practices aimed at enhancing the quality of life of individuals with multiple sclerosis.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Exercise Plus Active tDCS | Active Comparator | Participants assigned to this arm will complete a home-based therapeutic exercise program combined with active transcranial direct current stimulation (tDCS) targeting the dorsolateral prefrontal cortex (DLPFC). Stimulation parameters will follow validated protocols. Participants and outcomes assessors will be blinded to the assignment. |
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| Exercise Plus Sham tDCS | Placebo Comparator | Participants assigned to this arm will complete a home-based therapeutic exercise program combined with sham transcranial direct current stimulation (tDCS). Sham stimulation will mimic the sensation of tDCS without delivering an active current. Participants and outcomes assessors will be blinded to the assignment. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Home-Based Therapeutic Exercise Program | Behavioral | Participants will engage in a structured home-based therapeutic exercise program administered via a smartphone application. The program consists of targeted strength training, stretching routines, and proprioceptive exercises designed to address functional impairments commonly observed in individuals with multiple sclerosis. Each session will have an approximate duration of 20 to 30 minutes. Participants are required to complete a minimum of three sessions per week for the duration of the intervention phase. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Fatigue Severity Measured by the Fatigue Severity Scale (FSS) | Fatigue severity will be assessed using the Fatigue Severity Scale (FSS). The primary endpoint is the percentage reduction in the FSS total score compared to baseline. A clinically meaningful improvement is defined as a reduction greater than 20% in the FSS total score (approximately 13 points). Fatigue assessments will be conducted at baseline (prior to the intervention), at 10 days after the final tDCS session, at 3 months, and at 6 months post-intervention to evaluate both immediate and sustained effects. | Baseline (Day 0), Day 12 (10th and final tDCS session), 3 months from baseline, and 6 months from baseline |
| Change in Fatigue Severity Measured by Visual Analogue Scale (VAS) for Fatigue | Fatigue severity will be assessed using a Visual Analogue Scale (VAS) for fatigue. The primary endpoint is the change in VAS fatigue score compared to baseline. A clinically meaningful improvement is defined as a reduction of at least 2 points on the VAS. Fatigue assessments will be conducted at baseline (prior to the intervention), at 10 days after the final tDCS session, at 3 months, and at 6 months post-intervention to evaluate both immediate and sustained effect | Baseline (Day 0), Day 12 (10th and final tDCS session), 3 months from baseline, and 6 months from baseline |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Functional Capacity Measured by the Six-Minute Walk Test (6MWT) | The Six-Minute Walk Test (6MWT) will be used to assess participants' functional exercise capacity by recording the total distance walked in six minutes. This test reflects submaximal functional endurance and mobility. Changes in distance walked will be compared to baseline measurements to evaluate improvements. | Baseline (Day 0), Day 12 (10th and final tDCS session), 3 months from baseline, and 6 months from baseline |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Handgrip Strength Measured by Hand Dynamometry | Handgrip strength will be measured using a standardized hand dynamometer (Jamar device). The maximal grip strength will be recorded in kilograms with one decimal place of precision. The values obtained will be compared with baseline measurements to assess changes in upper limb strength following the intervention. | Baseline (Day 0), Day 12 (10th and final tDCS session), 3 months from baseline, and 6 months from baseline |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jacobo Formigo, Dr, | Complexo Hospitalario Universitario de A Coruña | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Complexo Hospitalario Universitario de A Coruña | A Coruña | A Coruña | 15009 | Spain | ||
| Complexo Hospitalario Universitario de Santiago de Compostela |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37041183 | Background | Linnhoff S, Haghikia A, Zaehle T. Effects of repetitive twice-weekly transcranial direct current stimulations on fatigue and fatigability in people with multiple sclerosis. Sci Rep. 2023 Apr 11;13(1):5878. doi: 10.1038/s41598-023-32779-y. | |
| 32397748 | Background | Mortezanejad M, Ehsani F, Masoudian N, Zoghi M, Jaberzadeh S. Comparing the effects of multi-session anodal trans-cranial direct current stimulation of primary motor and dorsolateral prefrontal cortices on fatigue and quality of life in patients with multiple sclerosis: a double-blind, randomized, sham-controlled trial. Clin Rehabil. 2020 Aug;34(8):1103-1111. doi: 10.1177/0269215520921506. Epub 2020 May 12. |
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Age, sex, fatigue scoring, treatment, exercise adherence
IPD and supporting information will be available beginning 6 months after publication of the primary results and will remain available for 5 years.
Qualified researchers with an approved proposal may request access to the de-identified IPD and supporting documents. Requests will be reviewed by the study sponsor. Data will be shared through a secure data access platform after signing a data use agreement.
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Randomized, double-blind, parallel assignment trial
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| Transcranial Direct Current Stimulation | Device | Transcranial direct current stimulation (tDCS) targeting the left dorsolateral prefrontal cortex (DLPFC). Stimulation will be delivered using a standard electrode montage, with the anode positioned over the left DLPFC and the cathode over the contralateral supraorbital area. The stimulation parameters will include a current intensity of 1.5 mA applied for 20 minutes per session, with a ramp-up and ramp-down phase of 10 seconds each at the beginning and end of stimulation, respectively. Sessions will be conducted five days per week over a two-week period, for a total of 10 sessions. |
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| Sham tDCS | Device | Participants assigned to the sham tDCS condition will receive identical electrode placement to the active tDCS group, with the anode over the left dorsolateral prefrontal cortex (DLPFC) and the cathode over the contralateral supraorbital area. The stimulation device will deliver an initial ramp-up phase of 10 seconds of actual stimulation after which no current will be delivered for 1180 seconds, and ending by a ramp-down phase of 10 seconds, The total session duration will match that of the active group (20 minutes), ensuring participant blinding. Sessions will occur five days per week over a two-week period, for a total of 10 sessions. |
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| Change in Quality of Life Measured by EuroQol 5D (EQ-5D) | Participants' self-perceived health status and quality of life will be evaluated using the EuroQol 5D questionnaire (EQ-5D). Changes from baseline in the EQ-5D score will be analyzed to determine whether the intervention has an impact on the participant's perception of overall health and quality of life. | Baseline (Day 0), Day 12 (10th and final tDCS session), 3 months from baseline, and 6 months from baseline |
| Change in Exercise Tolerance Measured by Distance Walked in the 6-Minute Walk Test (6MWT) | Exercise tolerance will be assessed using the 6-Minute Walk Test (6MWT). The total distance walked (in meters) during the test will be recorded. Changes from baseline in the distance walked will be analyzed to evaluate the effect of the intervention on exercise tolerance. | Baseline (Day 0), Day 12 (10th and final tDCS session), 3 months from baseline, and 6 months from baseline |
| Change in Perceived Exertion After 6-Minute Walk Test Measured by Borg Rating of Perceived Exertion (RPE) Scale | Participants' perception of exertion after the 6-Minute Walk Test (6MWT) will be assessed using the Borg Rating of Perceived Exertion (RPE) Scale (0-10). Changes from baseline in Borg RPE scores will be analyzed to evaluate the effect of the intervention on perceived exertion during exercise. | Baseline (Day 0), Day 12 (10th and final tDCS session), 3 months from baseline, and 6 months from baseline |
| Tolerance to tDCS Measured by Visual Analogue Scale (VAS) | Tolerance to tDCS will be evaluated through a specific VAS (0 to 10) | Immediately after each stimulation session |
| Adverse Events Associated With tDCS Application | The frequency, intensity, and duration of adverse events related to tDCS (e.g., itching, tingling, headache) will be monitored through structured questionnaires completed after each session. | Throughout the Intervention Period (during each session) |
| Change in Self-Perceived Health Status Measured by EuroQol Visual Analogue Scale (EQ-VAS, EuroQol Thermometer) | Participants' self-perceived health status will be evaluated using the EuroQol Visual Analogue Scale (EQ-VAS, EuroQol Thermometer), a visual analogue scale ranging from 0 to 100. Changes from baseline in the EQ-VAS score will be analyzed to determine whether the intervention has an impact on the participant's perception of overall health statu | Baseline (Day 0), Day 12 (10th and final tDCS session), 3 months from baseline, and 6 months from baseline |
| Participant Satisfaction Assessed by a 5-Point Nominal Satisfaction Scale | Participants will evaluate their satisfaction with the intervention using a nominal 5-point satisfaction scale ranging from much worse to much better than expected. | Baseline (Day 0), Day 12 (10th and final tDCS session), 3 months from baseline, and 6 months from baseline |
| Program Adherence Measured Through the ReHub Platform | Adherence to the exercise program will be monitored via the ReHub platform, recording the percentage of completed sessions over the total prescribed. | Throughout the 12-Week Exercise Program |
| Santiago de Compostela |
| A Coruña |
| 15706 |
| Spain |
| Complexo Hospitalario Universitario de Vigo | Vigo | Pontevedra | 36214 | Spain |
| 37190539 | Background | Bertoli M, Tataranni A, Porziani S, Pasqualetti P, Gianni E, Grifoni J, L'Abbate T, Armonaite K, Conti L, Cancelli A, Cottone C, Marinozzi F, Bini F, Cecconi F, Tecchio F. Effects on Corticospinal Tract Homology of Faremus Personalized Neuromodulation Relieving Fatigue in Multiple Sclerosis: A Proof-of-Concept Study. Brain Sci. 2023 Mar 29;13(4):574. doi: 10.3390/brainsci13040574. |
| 36528976 | Background | Xian C, Barbi C, Goldsworthy MR, Venturelli M, Sidhu SK. The interaction between metaplastic neuromodulation and fatigue in multiple sclerosis. J Neurol Sci. 2023 Jan 15;444:120521. doi: 10.1016/j.jns.2022.120521. Epub 2022 Dec 11. |
| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| D005221 | Fatigue |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D065908 | Transcranial Direct Current Stimulation |
| ID | Term |
|---|---|
| D004599 | Electric Stimulation Therapy |
| D013812 | Therapeutics |
| D003295 | Convulsive Therapy |
| D013000 | Psychiatric Somatic Therapies |
| D004191 | Behavioral Disciplines and Activities |
| D004597 | Electroshock |
| D011580 | Psychological Techniques |
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