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.
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 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;
Parallel
TMS and FES- based rehabilitation
DeviceEach subject will receive 15 individual sessions (45 minutes each, 3 times per week for 5 weeks) of task-based hand and arm exercises. Before movement execution, the hand area of the primary motor cortex will be stimulated using active rTMS. The rTMS protocol will use intermittent theta burst stimulation (iTBS), which delivers bursts of 3 pulses at 50 Hz every 200 ms (5 Hz) for 2 seconds, followed by 8 seconds of rest, totaling 600 pulses in \~3 minutes. The hand area will be identified as the optimal site for eliciting a motor evoked potential (MEP) in the abductor digiti minimi (ADM) muscle, contralateral to the dominant limb, with the lowest possible stimulation intensity. Subsequently, FES will be applied to assist the subject's voluntary movements during the task-oriented activities. The stimulation will be triggered based on the achievement of the electromyographic (EMG) threshold of the selected muscles.
FES-based rehabilitation
DeviceEach subject will receive 15 individual sessions (45 minutes each, 3 times per week for 5 weeks) of task-based hand and arm exercises. Before movement execution, the TMS coil will be positioned over the hand areas of the primary motor cortex, but tilted away from the scalp so as to produce a sound similar to the real intervention, but at a low intensity, without inducing current in the cortex. FES will then be applied to assist the patient's voluntary movements during the task-oriented activities. The stimulation will be triggered based on the achievement of the electromyographic (EMG) threshold of the selected muscles.
9-Hole Peg Test (9HPT)
The 9-Hole Peg Test evaluates manual dexterity and fine motor function of the upper limb. The test consists in taking pegs from a container, one by one, and place them into the holes on the board, as quickly as possible, using only the hand being evaluated. Pegs then have to be removed from the holes, one by one, and be placed back into the container. Score is given according to the number of seconds it takes for the patient to complete the test or alternatively, the number of pegs placed in 50 or 100 seconds.
Box and Block Test (BBT)
The Box and Block Test (BBT) measures unilateral gross manual dexterity. The BBT goal is to move, one by one, the maximum number of blocks from one compartment of a box to another of equal size, within 60 seconds. The score is determined by counting the number of blocks carried over the partition from one compartment to the other during the one-minute trial period. Higher scores on the test indicate better gross manual dexterity
Arm Function in Multiple Sclerosis Questionnaire (AMSQ)
The Arm Function in Multiple Sclerosis Questionnaire (AMSQ) is a unidimensional 31-item questionnaire for measuring arm function in Multiple Sclerosis. Each item asks about the extent to which MS has limited the individual's ability to perform specific daily activities in the past two weeks and is rated on a scale, from 1 (not at all) to 6 (unable to perform this activity). The total score is calculated by summing the scores for all items, and higher scores indicate greater limitations.
Symbol Digit Modalities Test (SDMT)
The Symbol Digit Modalities Test (SDMT) examines processing speed and sustained attention by primarily assessing complex visual scanning and tracking. Using a reference key, the test taker has 90 seconds to pair specific numbers with given geometric figures. Responses can be written or given orally, and administration time is just five minutes for either response mode.
12-Item Short Form Survey (SF-12)
The 12-Item Short Form Survey (SF-12) is a self-reported outcome measure assessing the impact of health on an individual's everyday life. Patients fill out a 12-question survey covering physical and mental health domain, which is then scored by a clinician or researcher. The responses are scored using a standardized algorithm to calculate two summary scores: the Physical Component Summary (PCS-12) and the Mental Component Summary (MCS-12). These scores are interpreted using a norm-based scoring system, with a mean of 50 and a standard deviation of 10 in the general population. Higher scores generally indicate better health.
Surface Electromyography (EMGs)
Surface Electromyography (EMGs) is a non-invasive tool able to assess muscular electrical activity during the execution of active movements using electrodes applied on the skin surface. Muscular contraction amplitude will be recorded from 24 sensors placed on upper limbs (12 sensors/limb), during the execution of motor acts. Then, the difference between patient's and observed model's temporal dynamic of muscular contraction will be chosen as EMG outcome.
Body Kinematics
Kinematics of the upper limb and trunk will be recorded using a 9-camera optoelectronic system during 3D motor acts. The system will measure the 3D coordinates of spherical markers attached to body landmarks to compute trunk, shoulder, elbow, wrist, and finger angles. Data processing will provide measures of deviations from physiological movement.
Motor Evoked Potential (MEP)
In order to detect changes in corticospinal function and neural plasticity induced by the intervention, the neurophysiological protocol consists of recording motor evoked potentials (MEPs) from the abductor digiti minimi (ADM) muscle of the upper limb, using a focused coil with neuronavigated positioning on the scalp.
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Fondazione Don Carlo Gnocchi Onlus
Lead sponsor
Fondazione Italiana Sclerosi Multipla
Collaborator
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