TMS Combined With Virtual Reality and Multidisciplinary Rehabilitation in Multiple Sclerosis

NCT07593807 | Active Not Recruiting

• 1 other identifier: 84729424.7.0000.5505
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Multiple sclerosis (MS) is a chronic autoimmune central nervous system disease characterized by inflammation, demyelination, and neurodegeneration, resulting in motor, cognitive, speech-language, psychological, and cardiac autonomic impairments. This double-blind, randomized, controlled crossover trial investigates the effects of repetitive transcranial magnetic stimulation (rTMS) applied over the primary motor cortex (Cz) and left dorsolateral prefrontal cortex (F3), combined with virtual reality (VR)-based exercise (MoveHero platform) and conventional physiotherapy, in 30 individuals with MS (EDSS 1.0-6.5). Participants are randomized to Active-then-Sham or Sham-then-Active sequence groups. Each phase consists of 10 consecutive weekday rTMS sessions, followed by at least four weeks washout before crossover. Both targets use a circular coil at 10 Hz. Cz is stimulated at 90% resting motor threshold (30 trains, 50 pulses/train) and F3 at 110% resting motor threshold (40 trains, 50 pulses/train). The sham condition replicates the procedure with the coil inverted at 10% intensity. On six of ten intervention days, rTMS is followed by VR exercise and balance-focused physiotherapy. Outcomes assessed at baseline and post-intervention include cardiac autonomic modulation (heart rate variability), balance, functional mobility, manual dexterity, fatigue, quality of life, depression, attention, executive function, working memory, psychological well-being, verbal fluency, and speech-language function (aphasia, dysphagia, dysarthria, voice quality). Follow-up reassessments are conducted at six months and one year.

Conditions

Multiple Sclerosis

Keywords

Multiple sclerosis; Autonomic nervous system; Transcranial Magnetic Stimulation; Depression; Cognition; Speech Therapy; Psychomotor Performance; Virtual Reality; Memory and Learning Tests

Outcome Measures

Primary Outcomes (1)

• Cardiac autonomic modulation (heart rate variability)

  Heart rate variability (HRV) will be used to assess autonomic nervous system function, including linear and non-linear parameters derived from heart rate recordings.

  Baseline (Day 1) and Day 10 of each intervention phase (active and sham), with a washout period of at least 4 weeks between phases.

Secondary Outcomes (19)

• Systolic and Diastolic Blood Pressure

  Baseline (Day 1) and Day 10 of each intervention phase (active and sham), with a washout period of at least 4 weeks between phases.

• Heart Rate

  Baseline (Day 1) and Day 10 of each intervention phase (active and sham), with a washout period of at least 4 weeks between phases.

• Respiratory Rate

  Baseline (Day 1) and Day 10 of each intervention phase (active and sham), with a washout period of at least 4 weeks between phases.

• Oxygen Saturation

  Baseline (Day 1) and Day 10 of each intervention phase (active and sham), with a washout period of at least 4 weeks between phases.

• Mini-Mental State Examination (MMSE)

  Baseline (Day 1) and Day 10 of each intervention phase (active and sham), with a washout period of at least 4 weeks between phases.

Study Arms (2)

Active TMS

EXPERIMENTAL

Participants receive active transcranial magnetic stimulation.

Device: Transcranial Magnetic Stimulation; Behavioral: Physiotherapy; Behavioral: Non-immersive serious game training

Sham TMS

SHAM COMPARATOR

Participants receive sham transcranial magnetic stimulation.

Device: Transcranial Magnetic Stimulation; Behavioral: Physiotherapy; Behavioral: Non-immersive serious game training

Interventions

Transcranial Magnetic Stimulation DEVICE

Transcranial magnetic stimulation (TMS) will be applied using a circular coil over two cortical targets: the primary motor cortex (Cz) and the left dorsolateral prefrontal cortex (F3). Stimulation will be delivered at 10 Hz, at 90% of the resting motor threshold over Cz (30 trains of 50 pulses) and at 110% over F3 (40 trains of 50 pulses), with 20-second inter-train intervals. Active stimulation will be compared to sham stimulation, delivered using the same coil positioned inversely at 10% of machine output. Sessions will be conducted on 10 consecutive weekdays within each intervention phase.

Also known as: TMS, rTMS, repetitive Transcranial Magnetic Stimulation

Active TMS; Sham TMS

Physiotherapy BEHAVIORAL

Physiotherapy will consist of standardized, task-oriented training focused on balance, mobility, and lower limb function. The intervention will be delivered in a circuit-based format and includes static and dynamic balance exercises, gait training, stair negotiation (ascending and descending), squats on unstable surfaces, and lateral walking. The protocol aims to improve motor performance and functional mobility. Sessions will be conducted three times per week, following transcranial magnetic stimulation.

Also known as: Physical Therapy, Balance Training, Motor Training

Active TMS; Sham TMS

Non-immersive serious game training BEHAVIORAL

Non-immersive serious game training will be conducted using the MoveHero system, based on webcam interaction. Participants will perform lower limb movements in response to visual stimuli, requiring coordination, timing, and motor control. Tasks involve unipodal support and goal-directed movements to interact with virtual targets, promoting motor coordination, dynamic balance, and sensorimotor integration. Sessions will be conducted three times per week, following transcranial magnetic stimulation, in conjunction with physiotherapy.

Also known as: Virtual Reality Training, Serious Game Training, MoveHero

Active TMS; Sham TMS

Eligibility Criteria

• Age: 20 Years - 70 Years
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participants with a confirmed diagnosis of Multiple Sclerosis.
• Ability to understand and follow simple instructions and to participate in the experimental procedures.
• Expanded Disability Status Scale (EDSS) score ≤ 6.5.
• Ability to maintain upright standing position (with or without assistive device) and perform basic static and dynamic balance tasks required for the intervention.

You may not qualify if:

• Presence of metallic implants in the skull, cranial deformities, or absence of cranial vault.
• Cardiac arrhythmias or atrioventricular block.
• Congenital abnormalities, including congenital heart disease or pulmonary malformations.
• History of seizures.
• Use of medications that significantly interfere with autonomic nervous system function, such as antiarrhythmic drugs or insulin.
• Inability to perform the proposed physical and virtual reality-based exercises.
• Inability to tolerate neuromodulation or electrostimulation procedures.
• Non-attendance at baseline or post-intervention assessment sessions, or absence in three or more intervention sessions.
• Incomplete completion of study procedures or withdrawal for any reason.

Sponsors & Collaborators

• University of Sao Paulo: lead
• Federal University of São Paulo: collaborator

Study Sites (1)

ABEM - Associação Brasileira de Esclerose Múltipla

São Paulo, São Paulo, Brazil

Location

MeSH Terms

Conditions

Multiple Sclerosis; Depression; Communication Disorders

Interventions

Transcranial Magnetic Stimulation; Physical Therapy Modalities

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Behavioral Symptoms; Behavior; Neurobehavioral Manifestations; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurodevelopmental Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Magnetic Field Therapy; Therapeutics; Rehabilitation

Study Officials

• Talita D da Silva-Magalhães

  University of Exeter

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Participants, care providers, and outcome assessors will be blinded to group allocation. The researcher responsible for delivering TMS will not be blinded due to the nature of the intervention. Data analysis will be conducted using coded group allocation.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Adjunct Professor

Study Record Dates

• First Submitted: April 23, 2026
• First Posted: May 18, 2026
• Study Start: February 3, 2025
• Primary Completion: October 31, 2025
• Study Completion (Estimated): September 28, 2026
• Last Updated: May 18, 2026

Record last verified: 2026-05

Locations

BR (1)