The goal of this interventional study is to test whether combining transcranial magnetic stimulation (TMS) with functional electrical stimulation (FES) can improve hand and upper limb function in adults with Multiple Sclerosis (MS).

The clinical trial aims to determine the following points:

1. Whether TMS combined with FES produces greater effects compared to FES alone.
2. Changes in brain and muscle activity related to hand function after treatment.
3. Specific clinical or neurophysiological factors that predict who will benefit most from the intervention. Researchers will compare the TMS-FES group (receiving brain magnetic stimulation and muscle electrostimulation) with the FES group (receiving only muscle electrostimulation) to assess whether TMS provides additional benefits in improving upper limb function

Participants will:

• Be assigned to a group (TMS-FES group or FES group)
• Attend 15 sessions (45 minutes each, 3 times per week for 5 weeks) of task-based hand and arm exercises, during which FES, or TMS and FES, will be administered to the participant.
• Undergo assessments before, after, and 3 months after training to measure hand function, brain and muscle responses, fatigue, and daily activity performance.

Multiple sclerosis (MS) is a chronic disease of the central nervous system associated with various neurological deficits, including motor impairments that negatively affect autonomy and quality of life. Among these, a significant symptom is reduced manual dexterity, which affects approximately 75% of patients and can interfere with activities of daily living (ADLs), leading to job loss and the need for assistance. This deficit, considered an indicator of disability in progressive MS, stems from altered sensorimotor integration and damage to various neural structures.

In recent years, non-invasive brain stimulation techniques, particularly Transcranial Magnetic Stimulation (TMS), have shown potential in measuring changes in cortical excitability and improving MS symptoms. TMS is a sensitive method for detecting cortical alterations and assessing corticospinal tract function through motor evoked potentials (MEPs), which are reliable biomarkers of disease progression. Moreover, studies and meta-analyses suggest that repetitive TMS (rTMS) may have therapeutic effects on cognitive deficits, spasticity, and fatigue in MS patients. In particular, stimulation of the primary motor cortex (M1) through rTMS has been shown to improve hand movement speed, although the effect dissipates quickly-typically after about 20 minutes.

To prolong these benefits, integrating TMS with Functional Electrical Stimulation (FES) could be an effective strategy. FES stimulates muscles through external surface electrical impulses to counteract the contractile inefficiency typical of MS and may further enhance residual motor function during voluntary exercises by promoting adaptive neuroplasticity. FES is already widely used in gait rehabilitation for MS, with positive effects on muscle strength and quality of life.

However, the application of FES for hand rehabilitation remains less explored, despite recommendations in favor of its investigation.

There is an urgent therapeutic need for non-pharmacological approaches to address upper limb and hand deficits, given their disabling impact on the MS population. Recent guidelines suggest exploring FES as an adjunct to traditional rehabilitation therapy to enhance its effects and improve access to rehabilitation for patients with muscle weakness.

The investigators hypothesize that the combination of TMS and FES may increase cortical excitability, reduce fatigue, and improve motor learning, leading to more effective recovery. The proposed study will assess the feasibility of a rehabilitation protocol based on these technologies, analyzing their effects on manual dexterity and on the central and peripheral neurophysiological correlates of motor recovery.

Furthermore, the investigators aim to identify predictive biomarkers of functional recovery, with the goal of personalizing rehabilitation pathways and optimizing therapeutic interventions for MS.

In this study, 30 individuals with MS are planned to be recruited, divided into the TMS-FES experimental group and the FES group. In the TMS-FES group, the primary motor cortex hand areas will be stimulated with active repetitive TMS before motor execution, while the FES group will receive sham TMS stimulation. Both groups will receive muscular electrical stimulation to assist voluntary movements during task-oriented activities.

The training will consist of three sessions per week, each lasting 45 minutes, for a total of 15 sessions. The investigators will measure variables such as age, gender, clinical status, fatigue, health perception, TMS-based biomarkers, and upper limb muscle synergies in all participants before and after the training. The investigators will investigate long-term effects on motor control, kinematic movement, and daily functional mobility three months after the end of the training through instrumental assessments and self-administered questionnaire.

20 healthy subjects are planned to be recruited, who will serve as the normative reference for the instrumental analysis assessments. The subjects will take part in a single data collection session, during which upper limb kinematics and EMG signals will be recorded while performing instrumented tasks from the Action Research Arm Test (ARAT) used for instrumental evaluation.

Inclusion Criteria:

• age >18;
• diagnosis of MS (according to McDonald criteria);
• stable disease course without a worsening greater than 1 point on the Expanded Disability Status Scale (EDSS) in the past 4 months;
• right-handed;
• score on the Box and Block test lower than the normative value adjusted for sex and age +2 standard deviations;
• score on the cerebellar functional system of the EDSS scale <2;
• ability to provide written informed consent.

Exclusion Criteria:

• score on the Mini-Mental State Examination <24;
• Beck Depression Inventory-II >19;
• other neurological or orthopedic conditions that would interfere with upper limb exercises;
• contraindications to the application of TMS: history of epilepsy or non-febrile seizures; presence of metallic or electronic implants in the cranial or cervical region; presence of pacemakers or implantable defibrillators; severe uncontrolled psychiatric disorders (e.g., psychosis, mania); current or suspected pregnancy;
• contraindications to the application of FES: skin integrity issues at the site of electrode placement; implanted electronic devices.

Shared data will comprise only IPD used in results publication. Data will be available upon reasonable request.

Data will be available after publication with no end date

Request should be addressed to the principal investigator or the corresponding author of the publication.