TRPMS to Improve Mobility and Depression in Multiple Sclerosis

Study Overview
=================
Brief Summary
-----------------
This study is aimed to test the efficacy of 10 sessions of Transcranial Rotating Permanent Magnetic Stimulation (TRPMS) paired with aerobic exercise or computerized cognitive training (CT) on mobility and depression symptoms in 40 individuals affected by multiple sclerosis (MS). Participants in Arm 1 will complete 10x40 minutes daily sessions of TRPMS+aerobic exercise. Participants in Arm 2 will complete TRPMS+computerized CT. Primary outcomes for both arms will be assessed at baseline, at treatment end and after 4-week from the treatment end (follow-up).

Official Title
-----------------
An Open Label Pilot Study to Investigate the Effect of Transcranial Rotating Permanent Magnetic Stimulation (TRPMS) on Gait, Balance and Depression in People With Multiple Sclerosis (MS)

Conditions
-----------------
Multiple Sclerosis

Intervention / Treatment
-----------------
* Device: TRPMS (Transcranial Rotating Permanent Magnet Stimulation)
* Other: Aerobic Exercise Program
* Other: Computerized CT (Cognitive Training)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: In order to be eligible to participate in Arm 1 of this study, an individual must meet all of the following criteria: Between ages 18 - 70 SDMT z-score ≥ -3.0 Wide Range Achievement Test-4th Edition (WRAT-4) Reading Recognition scaled score ≥ 85 Definite MS diagnosis as assessed by a licensed physician (all subtypes - RRMS, PPMS, SPMS) Expanded Disability Status Scale (EDSS) ≤ 6.5 Clinically stable disease course with absence of relapse within the past 30 days Able to understand the informed consent process and provide consent to participate in the study Complete the TMS screening questionnaire Able to commit to study timeframe Clinically significant gate deviations (T25-FW > 5.0 seconds) Able to walk independently with or without assistive device (i.e. cane, crutches, or walking frames) for medium distance Able to exercise with seated elliptical machine In order to be eligible to participate in Arm 2 of this study, an individual must meet all of the following criteria: Between ages 18 - 70 SDMT z-score ≥ -3.0 Wide Range Achievement Test-4th Edition (WRAT-4) Reading Recognition scaled score ≥ 85 Definite MS diagnosis as assessed by a licensed physician (all subtypes - RRMS, PPMS, SPMS) Expanded Disability Status Scale (EDSS) ≤ 6.5 Clinically stable disease course with absence of relapse within the past 30 days Able to understand the informed consent process and provide consent to participate in the study Complete the TMS screening questionnaire Able to commit to study timeframe Elevated symptoms of depression as determined by BDI of ≥ 4 Exclusion Criteria: Visual, auditory or motor deficits that would influence participant safety as assessed by a licensed physician History of seizure or epileptic history as assessed by licensed physician Medication which significantly lower the seizure threshold as assessed by licensed physician Primary psychiatric disorder that would influence ability to participate Uncontrolled headaches and migraine or recent changes in the rate or severity of head pressure, headache, or migraine in the past two weeks History of stroke or head trauma (e.g., head injury, brain surgery) or medical device implanted in the head (e.g. Deep Brain Stimulator) or in the neck (e.g. Vagus Nerve Stimulator) History of uncontrolled or labile hypertension Other serious uncontrolled medical condition or recent medical traumas Presence of metal or electronic implants in the body contraindicated for TMS Alcohol or other substance use disorder Pregnant or breastfeeding History of clinically significant abnormalities on electrocardiogram (EKG) (Arm 1 only) Presence of chronic medical illness and/or severe ataxia (Arm 1 only) Functional surgery for lower limb in the past 6 months (e.g. hip or knee replacement) (Arm 1 only) Lower limb Botulinum toxin injection within the past 2 months (Arm 1 only)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: TRPMS + Aerobic Physical Activity Program<br> | Device: TRPMS (Transcranial Rotating Permanent Magnet Stimulation)<br>* TRPMS ( is administered through a head cap worn by the participant and controlled by QHTimeStimulate application via computer tablet. Modality: Excitatory stimulation Frequency: 5 Hz Interval between stimulus: 100 ms Duration of each stimulus: 25 ms Duration of stimulation: 40 minutes Position of microstimulators: over primary motor cortex and supplementary motor area for Arm 1; over left and right dorsolateral prefrontal cortex for Arm 2<br>Other: Aerobic Exercise Program<br>* Aerobic exercise consisting of 40 minutes of cycling training with a seated elliptical machine. The daily physical activity program will consist of three 10-minute bouts of aerobic exercise interspersed with two 5-minute bouts of rest. The participants will exercise maintaining their Heart Rate (HR) at least between 60-80% of the maximum age-related HR.<br>|
| Active Comparator: Arm 2: TRPMS + Adaptive Cognitive Training<br> | Device: TRPMS (Transcranial Rotating Permanent Magnet Stimulation)<br>* TRPMS ( is administered through a head cap worn by the participant and controlled by QHTimeStimulate application via computer tablet. Modality: Excitatory stimulation Frequency: 5 Hz Interval between stimulus: 100 ms Duration of each stimulus: 25 ms Duration of stimulation: 40 minutes Position of microstimulators: over primary motor cortex and supplementary motor area for Arm 1; over left and right dorsolateral prefrontal cortex for Arm 2<br>Other: Computerized CT (Cognitive Training)<br>* Computerized cognitive training (CT) consisting of 40 minutes Brain-HQ training. The adaptive cognitive training games also serve to engage them during the stimulation session, and to keep them seated at the computer for the entire duration of the session.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Sessions Completed | Feasibility of at-home usage of TRPMS device measured by percent of sessions completed (80%) | Day 10 | 
| Change in Gait Velocity | To determine the primary efficacy of the TRPMS intervention paired with aerobic exercise, gait velocity will be assessed during the instrumented 10-meter walking test. Gait velocity will be measured using a wearable inertial sensor (G-Sensor). | Baseline (Day 0), Day 10 | 
| Change in PROMIS Depression Score | Arm 2: To determine the primary efficacy of the TRPMS intervention paired with computerized CT, changes in PROMIS Depression from baseline to treatment-end will be measured. The PROMIS Depression questionnaire consists of 8 items. Each item on the measure is rated on a 5-point scale (1=never; 2=rarely; 3=sometimes; 4=often; and 5=always) with a range in score from 8 to 40 with higher scores indicating greater severity of depression. | Baseline (Day 0), Day 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Gait Velocity | Arm 1: To assess sustained improvements, gait velocity will be assessed during the instrumented 10-meter walking test. Gait velocity will be measured using a wearable inertial sensor (G-Sensor). | Baseline (Day 0), Week 4 | 
| Change in Distance Traveled During 2-Minute Walking Test | Arm 1 | Baseline (Day 0), Day 10 | 
| Change in the Total Time for Completing the Timed Up and Go (TUG) test | Arm 1: The test requires the subject to rise from a chair, walk 3.0 m at a comfortable pace to a mark placed on the floor, turn around at the 3.0 m mark, walk back to the starting point, and return to sitting in the chair. | Baseline (Day 0), Day 10 | 
| Change in Modified Fatigue Impact Scale (MFIS) Score | MFIS consists of 21 statements that describe the effects of fatigue. Each statement is scored on a scale of 0-4 (0 = never, 1 = rarely, 2 = sometimes, 3 = often, 4 = almost always). The total MFIS score can range from 0-84; the higher the score, the stronger the feelings of fatigue. | Baseline (Day 0), Day 10 | 
| Change in Short Form (SF)-36 Score | The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. | Baseline (Day 0), Day 10 | 
| Change in PROMIS Depression Score | Arm 2: To determine the primary efficacy of the TRPMS intervention paired with computerized CT, changes in PROMIS Depression from baseline to treatment-end will be measured. The PROMIS Depression questionnaire consists of 8 items. Each item on the measure is rated on a 5-point scale (1=never; 2=rarely; 3=sometimes; 4=often; and 5=always) with a range in score from 8 to 40 with higher scores indicating greater severity of depression. | Baseline (Day 0), Week 4 | 
| Change in Center for Epidemiological Studies-Depression short form (CESD-10) Score | Arm 2: CESD-10 10-item Likert scale questionnaire assessing depressive symptoms in the past week. It includes three items on depressed affect, five items on somatic symptoms, and two on positive affect. Options for each item range from rarely or none of the time (score of 0) to all of the time (score of 3). The total range of score is 0-30; higher scores indicate the presence of significant depressive symptoms. | Baseline (Day 0), Day 10 | 
| Change in Patient Health Questionnaire 9 (PHQ-9) Score | Arm 2: The PHQ-9 is the depression module, which scores each of the nine DSM-IV criteria as 0 (not at all) to 3 (nearly every day). A PHQ-9 score ≥10 had a sensitivity of 88% and a specificity of 88% for major depression. PHQ-9 scores of 5, 10, 15, and 20 represented mild, moderate, moderately severe, and severe depression, respectively. | Baseline (Day 0), Day 10 | 
| Change in Inventory of Depressive Symptomatology Self-Report (IDS-SR) Score | Arm 2: Each of the 28 items is scored on a 1 to 3 scale (0-the absence of pathology; 3-severe pathology). The total scores range from 0 to 84. The higher the score, the more severe the pathology. | Baseline (Day 0), Day 10 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Transcranial Rotating Permanent Magnetic Stimulation