TMS Combined With Virtual Reality and Multidisciplinary Rehabilitation in Multiple Sclerosis

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

Interventions

DEVICE

Transcranial Magnetic Stimulation

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.

BEHAVIORAL

Physiotherapy

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.

BEHAVIORAL

Non-immersive serious game training

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.

Sponsors & Collaborators

• Federal University of São Paulo

  collaborator OTHER

• University of Sao Paulo

  lead OTHER

Principal Investigators

• Talita D da Silva-Magalhães · University of Exeter

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Model

CROSSOVER

Eligibility

Min Age

20 Years

Max Age

70 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2025-02-03

Primary Completion

2025-10-31

Completion

2026-09-28

Countries

• Brazil

Study Locations