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

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.

• 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 Stimulation (Device): 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.

Primary outcomes

• The Modified Tardieu Scale Quality of Muscle Reaction Score [Baseline, Week 2, and Week 4 after the final stimulation session]: 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.
• Worst Lower-Limb Pain Intensity on the Numeric Rating Scale [Baseline, Week 2, and Week 4 after the final stimulation session]: Participants will rate the worst pain intensity experienced in the affected lower limb during the preceding 14 days on an 11-point Numeric Rating Scale from 0 (no pain) to 10 (worst imaginable pain). Lower scores indicate less pain.

Secondary outcomes

• Neuropathic Pain Features Measured by the Douleur Neuropathique 4 Questionnaire [Baseline, Week 2, and Week 4 after the final stimulation session]: The Douleur Neuropathique 4 (DN4) questionnaire will be scored from 0 to 10. Higher scores indicate more neuropathic pain features; a score of 4 or more supports the presence of neuropathic pain.
• Multiple Sclerosis Impact Scale - Physical Impact Score [Baseline, Week 2, and Week 4 after the final stimulation session]: The physical-impact subscale of the Multiple Sclerosis Impact Scale version 2 will be transformed to a 0-100 score. Higher scores indicate a greater physical impact of MS.
• Multiple Sclerosis Impact Scale - Psychological Impact Score [Baseline, Week 2, and Week 4 after the final stimulation session]: The psychological-impact subscale of the Multiple Sclerosis Impact Scale version 2 will be transformed to a 0-100 score. Higher scores indicate a greater psychological impact of MS.
• Multiple Sclerosis Quality of Life-54 - Physical Health Composite Score [Baseline, Week 2, and Week 4 after the final stimulation session]: The Physical Health Composite of the Multiple Sclerosis Quality of Life-54 will be scored from 0 to 100. Higher scores indicate better health-related quality of life.
• Multiple Sclerosis Quality of Life-54 - Mental Health Composite Score [Baseline, Week 2, and Week 4 after the final stimulation session]: The Mental Health Composite of the MSQOL-54 will be scored from 0 to 100. Higher scores indicate better health-related quality of life.
• Fatigue Scale for Motor and Cognitive Functions Total Score [Baseline, Week 2, and Week 4 after the final stimulation session]: The Fatigue Scale for Motor and Cognitive Functions total score ranges from 20 to 100. Higher scores indicate more severe fatigue.
• Hospital Anxiety and Depression Scale - Anxiety Subscale Score [Baseline, Week 2, and Week 4 after the final stimulation session]: The Hospital Anxiety and Depression Scale Anxiety subscale ranges from 0 to 21. Higher scores indicate more severe anxiety symptoms.
• Hospital Anxiety and Depression Scale - Depression Subscale Score [Baseline, Week 2, and Week 4 after the final stimulation session]: The Hospital Anxiety and Depression Scale Depression subscale ranges from 0 to 21. Higher scores indicate more severe depressive symptoms.
• Multiple Sclerosis Neuropsychological Screening Questionnaire Score [Baseline, Week 2, and Week 4 after the final stimulation session]: The patient-report Multiple Sclerosis Neuropsychological Screening Questionnaire total score ranges from 0 to 60. Higher scores indicate greater perceived neuropsychological impairment.
• Patient-Determined Disease Steps Score [Baseline, Week 2, and Week 4 after the final stimulation session]: The Patient-Determined Disease Steps score ranges from 0 (normal) to 8 (bedridden). Higher scores indicate greater walking disability.
• H/M Ratio as a Neurophysiological Marker of Spinal Excitability [Baseline, Week 2, and Week 4 after the final stimulation session]: The H-reflex will be elicited by stimulation of the tibial nerve and recorded from the soleus muscle. The maximal H-reflex amplitude will be divided by the maximal M-wave amplitude and expressed as Hmax/Mmax × 100%. The same limb, electrode placement, and acquisition protocol will be used at all visits.
• Treatment-Emergent Adverse Events [From the first stimulation session through Week 4 after the final stimulation session]: Number and proportion of participants experiencing any treatment-emergent adverse event during the stimulation week and follow-up. Events will be recorded by type, severity, seriousness, and relationship to the stimulation procedure.

Sex: All, ages: 18 Years to any

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.

• Peter Valkovič, prof. MD PhD., Principal investigator, Faculty of Medicine, Comenius University Bratislava