Improving Hand Movement and Coordination in People With Multiple Sclerosis Using Transcranial Magnetic Stimulation (TMS) and Muscle Electrostimulation (FES) To Support Manual Dexterity and Daily Function

Official title

Restoring Manual Dexterity in Multiple Sclerosis: A Feasibility Study Combining Muscle Electrostimulation and Transcranial Magnetic Stimulation To Enhance Neuroplasticity

Overview

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.

Detailed description

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.

Interventions

• Device TMS and FES- based rehabilitation
  Each 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
• Device FES-based rehabilitation
  Each 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 activit

Primary outcome measures

• 9-Hole Peg Test (9HPT) [Time frame: Before (T0) and after (T1) the rehabilitation treatment (15 sessions of 45 minutes each, 3 times per week for 5 weeks), and at 3 months from T1 (T2).]

Secondary outcome measures (7)

• Box and Block Test (BBT) [Time frame: Before (T0) and after (T1) the rehabilitation treatment (15 sessions of 45 minutes each, 3 times per week for 5 weeks), and at 3 months from T1 (T2).]
• Arm Function in Multiple Sclerosis Questionnaire (AMSQ) [Time frame: Before (T0) and after (T1) the rehabilitation treatment (15 sessions of 45 minutes each, 3 times per week for 5 weeks), and at 3 months from T1 (T2).]
• Symbol Digit Modalities Test (SDMT) [Time frame: Before (T0) and after (T1) the rehabilitation treatment (15 sessions of 45 minutes each, 3 times per week for 5 weeks), and at 3 months from T1 (T2).]
• 12-Item Short Form Survey (SF-12) [Time frame: Before (T0) and after (T1) the rehabilitation treatment (15 sessions of 45 minutes each, 3 times per week for 5 weeks), and at 3 months from T1 (T2).]
• Fatigue Scale of Motor and Cognitive Functions (FSMC) [Time frame: Before (T0) and after (T1) the rehabilitation treatment (15 sessions of 45 minutes each, 3 times per week for 5 weeks), and at 3 months from T1 (T2).]
• Intrinsic Motivation Inventory (IMI) [Time frame: Before (T0) and after (T1) the rehabilitation treatment (15 sessions of 45 minutes each, 3 times per week for 5 weeks), and at 3 months from T1 (T2).]
• System Usability Scale (SUS) [Time frame: After (T1) the rehabilitation treatment (15 sessions of 45 minutes each, 3 times per week for 5 weeks).]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

Italy · 2 centers

• Fondazione Italiana Sclerosi Multipla — Genova
• IRCCS "Santa Maria Nascente" - Fondazione Don Gnocchi — Milan

Publications

• Sirbu CA, Thompson DC, Plesa FC, Vasile TM, Jianu DC, Mitrica M, Anghel D, Stefani C. Neurorehabilitation in Multiple Sclerosis-A Review of Present Approaches and Future Considerations. J Clin Med. 2022 Nov 27;11(23):7003. doi: 10.3390/jcm11237003. PMID 36498578
• Severijns D, Lamers I, Kerkhofs L, Feys P. Hand grip fatigability in persons with multiple sclerosis according to hand dominance and disease progression. J Rehabil Med. 2015 Feb;47(2):154-60. doi: 10.2340/16501977-1897. PMID 25268997
• Sampson P, Freeman C, Coote S, Demain S, Feys P, Meadmore K, Hughes AM. Using Functional Electrical Stimulation Mediated by Iterative Learning Control and Robotics to Improve Arm Movement for People With Multiple Sclerosis. IEEE Trans Neural Syst Rehabil Eng. 2016 Feb;24(2):235-48. doi: 10.1109/TNSRE.2015.2413906. Epub 2015 Mar 24. PMID 25823038
• Reeves BC, Wells GA, Waddington H. Quasi-experimental study designs series-paper 5: a checklist for classifying studies evaluating the effects on health interventions-a taxonomy without labels. J Clin Epidemiol. 2017 Sep;89:30-42. doi: 10.1016/j.jclinepi.2017.02.016. Epub 2017 Mar 27. PMID 28351692
• Neira VE, Niemietz TD, Farrell JW 3rd. THE EFFECTS OF EXERCISE TRAINING ON UPPER EXTREMITY FUNCTION FOR PERSONS WITH MULTIPLE SCLEROSIS: A SYSTEMATIC REVIEW. J Rehabil Med Clin Commun. 2022 Sep 29;5:2306. doi: 10.2340/jrmcc.v5.2306. eCollection 2022. PMID 36249930
• Lo DF, Palhang M, Gawash A, Zia H, Goodwin BJ, Patel K, White CP. Unlocking Therapeutic Potential: The Role of Theta Burst Stimulation in Multiple Sclerosis Management. Prim Care Companion CNS Disord. 2024 Apr 18;26(2):23r03645. doi: 10.4088/PCC.23r03645. PMID 38684013
• Leodori G, Mancuso M, Maccarrone D, Tartaglia M, Ianniello A, Certo F, Baione V, Ferrazzano G, Malimpensa L, Belvisi D, Pozzilli C, Berardelli A, Conte A. Neural bases of motor fatigue in multiple sclerosis: A multimodal approach using neuromuscular assessment and TMS-EEG. Neurobiol Dis. 2023 May;180:106073. doi: 10.1016/j.nbd.2023.106073. Epub 2023 Mar 9. PMID 36906073
• Koch G, Rossi S, Prosperetti C, Codeca C, Monteleone F, Petrosini L, Bernardi G, Centonze D. Improvement of hand dexterity following motor cortex rTMS in multiple sclerosis patients with cerebellar impairment. Mult Scler. 2008 Aug;14(7):995-8. doi: 10.1177/1352458508088710. Epub 2008 Jun 23. PMID 18573820

Identifiers

NCT: NCT07098273 · MANTRAStim-SC · 2024/R-Multi/010

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗