Multiple SclerosisMANTRAStimNCT07098273

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

A study testing TMS and FES- based rehabilitation and FES-based rehabilitation in people with Multiple Sclerosis, run by Fondazione Don Carlo Gnocchi ETS at 2 sites in Italy.

Not yet recruiting

Opening soon. The study is approved but enrolment has not started yet. Sites may already take enquiries.

Sites and contacts

Official record

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Trial summary

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. Read more about this study

Who is it for?: Ages 18 years and olderHealthy volunteers can take part
Conditions the study is for: Multiple Sclerosis
What is being tested?: TMS and FES- based rehabilitation and FES-based rehabilitation
Type of treatment: Medical device
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 50 participants
Where: 2 sitesItaly
Study dates: Oct 2025to May 2027
Phase: Interventional
Are there results?: Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
Healthy volunteers accepted
Adult, Older adult

Who may be able to join

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.

Who cannot join

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.

Trial locations and contacts

2 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Tiziana Lencioni, PhD contact

00390240308547

tlencioni@dongnocchi.it

Italy2 sites

Fondazione Italiana Sclerosi Multipla
Genova, Italy, 16149
Andrea Tacchino, Professor, 00393491403917, andrea.tacchino@aism.it
Andrea Tacchino, Professor
IRCCS "Santa Maria Nascente" - Fondazione Don Gnocchi
Milan, Italy, 20148
Tiziana Lencioni, PhD, 00390240308547, tlencioni@dongnocchi.it
Tiziana Lencioni, PhD

Other trials in Italy

About this study

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

The clinical trial aims to determine the following points:

Whether TMS combined with FES produces greater effects compared to FES alone.
Changes in brain and muscle activity related to hand function after treatment.
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.

Read the 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.

Conditions: Multiple Sclerosis
Being tested: TMS and FES- based rehabilitation, FES-based rehabilitation
Keywords: Multiple Sclerosis, Hand Dexterity, Technology-based Rehabilitation, Functional Electrical Stimulation, Transcranial Magnetic Stimulation
Medical subject headings: Multiple Sclerosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

TMS and FES- based rehabilitationDevice
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 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 rehabilitationDevice
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 activities. The stimulation will be triggered based on the achievement of the electromyographic (EMG) threshold of the selected muscles.

Study groups in NCT07098273
Study group	Role	What they receive
TMS-FES group	Experimental	Before movement execution, the hand area of the primary motor cortex will be stimulated using active repetitive TMS (rTMS). Subsequently, FES will be applied to assist the subject's voluntary movements during task-oriented therapy. Receives: Device: TMS and FES- based rehabilitation
FES group	Active comparator	Before movement execution, the hand area of the primary motor cortex will be stimulated using sham TMS. Subsequently, FES will be applied to assist the subject's voluntary movements during task-oriented therapy. Receives: Device: FES-based rehabilitation

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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 outcomes (7)

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
Measured: 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)
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.
Measured: 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)
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.
Measured: 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)
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.
Measured: 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)
The Fatigue Scale of Motor and Cognitive Functions (FSMC) is a 20-item scale developed as a measure of cognitive and motor fatigue for people with MS. The responses to the items are summed to create separate scores for motor and cognitive fatigue, as well as a total fatigue score. Higher scores generally indicate greater fatigue.
Measured: 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)
The Intrinsic Motivation Inventory (IMI) is a multidimensional measurement device intended to assess participants' subjective experience related to a target activity in laboratory experiments. The instrument yields six subscale scores assessing participants': interest/enjoyment, perceived competence, effort, value/usefulness, felt pressure and tension, and perceived choice while performing a given activity.
Measured: 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)
The System Usability Scale (SUS) is a well-established and reliable tool for assessing the usability of rehabilitation technologies. It consists of 10 statements that evaluate aspects such as ease of use, intuitiveness, and effectiveness. Participants rate each statement on a 5-point scale, ranging from "strongly disagree" to "strongly agree." The responses are then calculated to produce a final usability score out of 100.
Measured: After (T1) the rehabilitation treatment (15 sessions of 45 minutes each, 3 times per week for 5 weeks).

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Oct 2025May 2027

First posted1 Aug 2025
Study startOct 2025 (estimated)
Primary completionDec 2026 (estimated)
Study completionMay 2027 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (20)Papers the sponsor has linked to this study.
Other trials for Multiple SclerosisStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase N/A
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Model description: Pilot, controlled, multicenter, national, non-profit experimental study with parallel arms, double-blind (evaluator and participant), without the use of drugs or medical devices.
Masking: Double blind
Who is masked: Participant, Outcomes assessor
Enrolment: 50 participants (estimated)

IDs, dates and publications

ClinicalTrials.gov ID: NCT07098273
Sponsor's protocol ID: MANTRAStim-SC
Other IDs: 2024/R-Multi/010
Acronym: MANTRAStim
Status last verified: Apr 2025
First submitted: 25 Jul 2025
Last updated: 12 Aug 2025
Results posted: No
Data monitoring committee: Yes
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: Yes: Shared data will comprise only IPD used in results publication. Data will be available upon reasonable request.

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.
PubMed 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.
PubMed 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.
PubMed 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.
PubMed 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.
PubMed 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.
PubMed 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.
PubMed 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.
PubMed 18573820
Kim Y, Steiner P. Quasi-Experimental Designs for Causal Inference. Educ Psychol. 2016;51(3-4):395-405. doi: 10.1080/00461520.2016.1207177. Epub 2016 Sep 2.
PubMed 30100637
Kamm CP, Uitdehaag BM, Polman CH. Multiple sclerosis: current knowledge and future outlook. Eur Neurol. 2014;72(3-4):132-41. doi: 10.1159/000360528. Epub 2014 Jul 30.
PubMed 25095894
Jonsdottir J, Perini G, Ascolese A, Bowman T, Montesano A, Lawo M, Bertoni R. Unilateral arm rehabilitation for persons with multiple sclerosis using serious games in a virtual reality approach: Bilateral treatment effect? Mult Scler Relat Disord. 2019 Oct;35:76-82. doi: 10.1016/j.msard.2019.07.010. Epub 2019 Jul 20.
PubMed 31352180
Jones S, Man WD, Gao W, Higginson IJ, Wilcock A, Maddocks M. Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease. Cochrane Database Syst Rev. 2016 Oct 17;10(10):CD009419. doi: 10.1002/14651858.CD009419.pub3.
PubMed 27748503
Huertas-Hoyas E, Maximo-Bocanegra N, Diaz-Toro C, Montes-Diez R, Perez-Corrales J, Sanchez-Herrera-Baeza P, Martinez-Piedrola RM, Garcia-Bravo C, Sanchez-Camarero C, Perez-de-Heredia-Torres M. A Descriptive Cross-Sectional Study of Manipulative Dexterity on Different Subtypes of Multiple Sclerosis. Occup Ther Int. 2020 Apr 28;2020:6193938. doi: 10.1155/2020/6193938. eCollection 2020.
PubMed 32425718
Fan J, Fu H, Xie X, Zhong D, Li Y, Liu X, Zhang H, Zhang J, Huang J, Li J, Jin R, Zheng Z. The effectiveness and safety of repetitive transcranial magnetic stimulation on spasticity after upper motor neuron injury: A systematic review and meta-analysis. Front Neural Circuits. 2022 Nov 8;16:973561. doi: 10.3389/fncir.2022.973561. eCollection 2022.
PubMed 36426136
Conradsson D, Ytterberg C, von Koch L, Johansson S. Changes in disability in people with multiple sclerosis: a 10-year prospective study. J Neurol. 2018 Jan;265(1):119-126. doi: 10.1007/s00415-017-8676-8. Epub 2017 Nov 20.
PubMed 29159465

Interested in taking part?

Tiziana Lencioni, PhD

00390240308547

tlencioni@dongnocchi.it

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 12 Aug 2025. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Restoring Manual Dexterity in Multiple Sclerosis: A Feasibility Study Combining Muscle Electrostimulation and Transcranial Magnetic Stimulation To Enhance Neuroplasticity
ClinicalTrials.gov ID: NCT07098273
Acronym / sponsor ID: MANTRAStim / MANTRAStim-SC
Conditions: Multiple Sclerosis
Keywords: Multiple Sclerosis, Hand Dexterity, Technology-based Rehabilitation, Functional Electrical Stimulation, Transcranial Magnetic Stimulation
Study type: Interventional
Recruitment status: Not yet recruiting
Enrolment: 50 participants (estimated)
Lead sponsor: Fondazione Don Carlo Gnocchi ETSUniversity, hospital or other
Collaborators: Fondazione Italiana Sclerosi Multipla
Study start: Oct 2025 (estimated)
Primary completion: Dec 2026 (estimated)
Study completion: May 2027 (estimated)
First posted: 1 Aug 2025 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

The clinical trial aims to determine the following points:

Whether TMS combined with FES produces greater effects compared to FES alone.
Changes in brain and muscle activity related to hand function after treatment.
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

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

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

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Parallel groups
Masking: Double blind (participant, outcomes assessor)
Number of arms: 2
Model description: Pilot, controlled, multicenter, national, non-profit experimental study with parallel arms, double-blind (evaluator and participant), without the use of drugs or medical devices.

Arm	Type	Receives
TMS-FES group	Experimental	Device: TMS and FES- based rehabilitationBefore movement execution, the hand area of the primary motor cortex will be stimulated using active repetitive TMS (rTMS). Subsequently, FES will be applied to assist the subject's voluntary movements during task-oriented therapy.
FES group	Active comparator	Device: FES-based rehabilitationBefore movement execution, the hand area of the primary motor cortex will be stimulated using sham TMS. Subsequently, FES will be applied to assist the subject's voluntary movements during task-oriented therapy.

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Accepted
Age groups: Adult, Older adult

Key inclusion criteria (7 listed)

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;

Key exclusion criteria (5 listed)

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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
TMS and FES- based rehabilitationEach 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.	Device	TMS-FES group
FES-based rehabilitationEach 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.	Device	FES group

Primary outcome

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).
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.

7 secondary outcomes

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).

Results and safety

This study is still under way. Results are not available in the source record yet.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 12 Aug 2025.
Background: PubMed 36498578Sirbu 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.
Background: PubMed 25268997Severijns 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.
Background: PubMed 25823038Sampson 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.
Background: PubMed 28351692Reeves 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.
Background: PubMed 36249930Neira 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.
Background: PubMed 38684013Lo 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.
Background: PubMed 36906073Leodori 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.
Background: PubMed 18573820Koch 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.
Background: PubMed 30100637Kim Y, Steiner P. Quasi-Experimental Designs for Causal Inference. Educ Psychol. 2016;51(3-4):395-405. doi: 10.1080/00461520.2016.1207177. Epub 2016 Sep 2.
Background: PubMed 25095894Kamm CP, Uitdehaag BM, Polman CH. Multiple sclerosis: current knowledge and future outlook. Eur Neurol. 2014;72(3-4):132-41. doi: 10.1159/000360528. Epub 2014 Jul 30.
Background: PubMed 31352180Jonsdottir J, Perini G, Ascolese A, Bowman T, Montesano A, Lawo M, Bertoni R. Unilateral arm rehabilitation for persons with multiple sclerosis using serious games in a virtual reality approach: Bilateral treatment effect? Mult Scler Relat Disord. 2019 Oct;35:76-82. doi: 10.1016/j.msard.2019.07.010. Epub 2019 Jul 20.
Background: PubMed 27748503Jones S, Man WD, Gao W, Higginson IJ, Wilcock A, Maddocks M. Neuromuscular electrical stimulation for muscle weakness in adults with advanced disease. Cochrane Database Syst Rev. 2016 Oct 17;10(10):CD009419. doi: 10.1002/14651858.CD009419.pub3.
Individual participant dataSharing planned: Yes. Shared data will comprise only IPD used in results publication. Data will be available upon reasonable request.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.

Tiziana Lencioni, PhD contact

00390240308547

tlencioni@dongnocchi.it

Tiziana Lencioni, PhD principal investigator

IRCCS "Santa Maria Nascente" - Fondazione Don Gnocchi

2 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A study testing TMS and FES- based rehabilitation and FES-based rehabilitation in people with Multiple Sclerosis, run by Fondazione Don Carlo Gnocchi ETS at 2 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: opening soon, as of the sponsor's last update on 12 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Tiziana Lencioni, PhD (00390240308547, tlencioni@dongnocchi.it), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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).). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07098273, which also lists 20 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Aug 2025; AzTrials last refreshed its copy on 30 Oct 2026.