Effects of Transcranial Magnetic Stimulation Combined With Virtual Reality, Multidisciplinary Rehabilitation, and Cardiac Autonomic Modulation in Multiple Sclerosis: A Clinical Trial
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 入组人数
- 30
- 试验地点
- 1
研究概览
简要总结
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.
详细描述
**Background and Rationale** Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by inflammation, demyelination, gliosis, and neuronal loss. Lesions are restricted to the central nervous system, sparing the peripheral nervous system. Pathological mechanisms include perivascular lymphocytic infiltration and macrophage-mediated myelin degradation, predominantly during relapses, as well as gliosis and neurodegeneration associated with disease progression. MS typically manifests between ages 20 and 50 and is twice as common in women.
Neurological symptoms vary according to lesion location and include visual impairment, sensory disturbances, focal weakness, urinary and bowel dysfunction, and cognitive impairment, all of which impact gait, balance, and functional mobility. Although no cure exists, therapeutic strategies targeting post-relapse recovery, relapse prevention, and disability reduction have been developed. With disease progression, individuals become increasingly dependent for activities of daily living.
Beyond motor and cognitive impairment, autonomic nervous system (ANS) dysfunction has been documented in MS, manifesting as orthostatic intolerance, postural tachycardia syndrome, and reduced heart rate variability (HRV). These conditions are related to brainstem lesions and reflect dysregulation between sympathetic and parasympathetic activity at the sinoatrial node. HRV, a non-invasive index of cardiac autonomic modulation, captures beat-to-beat variation in RR intervals and provides prognostic information regarding cardiovascular and autonomic health.
Virtual reality (VR)-based rehabilitation has demonstrated benefits for sensorimotor learning, balance, strength, cognition, and attention in neurological populations, including MS. The MoveHero platform, developed by the Research and Technological Application in Rehabilitation Group (PATER) at the University of São Paulo, is a task-oriented VR game requiring timed upper or lower limb movements to targets presented on screen, with visual and auditory feedback.
Non-invasive brain stimulation, particularly repetitive transcranial magnetic stimulation (rTMS), has emerged as a promising neuromodulatory approach in neurological and neuropsychiatric conditions. rTMS modulates neural excitability through time-varying magnetic fields that induce electrical currents in cortical tissue, promoting neuroplasticity. Evidence supports its efficacy for depression, aphasia, spasticity, fatigue, and cognitive impairment in MS. However, no study to date has examined the combination of rTMS with VR exercise and conventional physiotherapy targeting motor, cognitive, speech-language, psychological, and cardiac autonomic outcomes concurrently in individuals with MS.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 20 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
- •Ability to maintain upright standing position (with or without assistive device) and perform basic static and dynamic balance tasks required for the intervention.
排除标准
- •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.
研究者
Talita Dias da Silva-Magalhães
Adjunct Professor
University of Sao Paulo