Intermittent Theta-Burst Stimulation for Lower-Limb Spasticity and Pain in Multiple Sclerosis

N/ANot Yet RecruitingNCT07786506

Comenius University40 enrolled

Overview

Spasticity and neuropathic pain are frequent and disabling symptoms of multiple sclerosis. Intermittent theta-burst stimulation (iTBS) is a non-invasive neuromodulation technique that may modulate cortical and corticospinal excitability and thereby improve motor symptoms and pain. This randomized, parallel-group, sham-controlled, assessor-blinded study will evaluate the clinical efficacy of active iTBS compared with sham stimulation in adults with multiple sclerosis and clinically significant lower-limb spasticity and pain. Participants will receive five stimulation sessions over one week. Spasticity, pain, patient-reported outcomes, and the electrophysiological H/M ratio will be assessed at baseline and at Weeks 2 and 4 after the intervention.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system. Lower-limb spasticity and neuropathic pain can substantially impair mobility, daily functioning, and quality of life. Current symptomatic treatments include oral antispastic medication and targeted botulinum toxin type A injections, but their effects may be incomplete or time-limited. Intermittent theta-burst stimulation is a repetitive transcranial magnetic stimulation protocol with the potential to modulate cortical and corticospinal excitability. The study will determine whether active iTBS applied over the primary motor cortex produces a greater reduction in lower-limb spasticity and neuropathic pain than sham iTBS in patients with MS. This is a randomized, two-arm, parallel-group, sham-controlled, assessor-blinded clinical study conducted at the Multiple Sclerosis Centre of the 2nd Department of Neurology, Faculty of Medicine, Comenius University Bratislava and University Hospital Bratislava. Eligible participants will be randomized to active iTBS or sham iTBS. Stimulation will target the primary motor cortex contralateral to the more affected lower limb and the cortical representation of the muscle group corresponding to the dominant spastic pattern, identified using motor-evoked potentials and neuronavigation. Participants will undergo five sessions on consecutive weekdays. The active protocol comprises 1,200 pulses per day, delivered as two 600-pulse blocks separated by a 15-minute inter-block interval. Clinical and neurophysiological assessments will be performed at baseline and at Weeks 2 and 4 after the intervention by an assessor blinded to treatment allocation. Assessments include the Tardieu Scale, pain measures, MS-specific quality-of-life and symptom questionnaires, and the H/M ratio measured by electromyography. Participants with a persistent clinical indication after completion of the four-week follow-up may receive botulinum toxin type A as standard-of-care rescue treatment.

Interventions

Active Intermittent Theta-Burst Stimulation (iTBS)DEVICE

Active iTBS will be delivered using a Neuro-MS/D Advanced Therapeutic magnetic stimulator (Neurosoft) with a figure-of-eight coil. The stimulation target will be the representation of the muscle group corresponding to the dominant spastic pattern of the more affected lower limb in the contralateral primary motor cortex. The target will be identified using motor-evoked potentials and neuronavigation based on the participant's individual MRI. Active motor threshold will be determined from the tibialis anterior muscle. Stimulation intensity will be set at 80% of the active motor threshold. Each burst will consist of 3 pulses at 50 Hz, repeated at 5 Hz. Each 600-pulse block will use a 2-second on/8-second off pattern and last approximately 3 minutes 9 seconds. Two 600-pulse blocks will be delivered per day, separated by a 15-minute interval, for a total of 1,200 pulses per day. Treatment will be administered on five consecutive weekdays, giving 10 stimulation blocks in total.

Sham Intermittent Theta-Burst StimulationDEVICE

In both groups, the TMS coil will be positioned over the primary motor cortex representation of the more affected lower limb and sham electrodes will be attached to the forehead. During sham stimulation, surface electrodes placed on the forehead will deliver low-intensity electrical stimulation at 2 mA to reproduce the somatosensory experience of TMS. The TMS device will simultaneously produce the characteristic clicking sound of coil discharge. The software will conceal the assigned mode from the participant and stimulation operator. The visit schedule, positioning, and total procedural duration will match the active condition.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis of multiple sclerosis according to the 2024 McDonald criteria. * Expanded Disability Status Scale (EDSS) score from 2.5 to 6.0. * Clinically significant spasticity in at least one muscle group of the more affected lower limb, defined as a Modified Tardieu Scale quality of muscle reaction score of at least 2 at velocity V3. * Lower-limb pain intensity of at least 4/10 on a 0-10 Visual Analogue Scale at screening. * Stable pharmacological treatment, including disease-modifying therapy, for at least 3 months before enrolment. * Ability to understand the study procedures and provide written informed consent. Exclusion Criteria: * Epilepsy or another condition associated with an increased risk of seizure. * Metallic implants, implanted electronic devices, or other conditions contraindicating transcranial magnetic stimulation. * Clinical relapse of multiple sclerosis within 30 days before enrolment. * Pregnancy or breastfeeding.

Outcomes

Primary Outcomes

The Modified Tardieu Scale Quality of Muscle Reaction Score

The entire more affected lower limb will be examined using the Modified Tardieu Scale. At baseline, the muscle group corresponding to the dominant spastic pattern will be predefined as the individual target muscle group and the same muscle group will be reassessed at all subsequent visits. The quality of muscle reaction at fast stretch velocity V3 is scored from 0 to 5, where 0 indicates no resistance and higher scores indicate a more pronounced catch or clonus; a lower score indicates less spasticity.