Multiple Sclerosis

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system that may cause a broad range of motor and non-motor symptoms. New or worsening neurological symptoms in people with MS are frequently interpreted as a possible relapse. However, relapse-like episodes are not always caused by new inflammatory disease activity and may instead reflect infection, fever, comorbidities, fluctuations of pre-existing symptoms, or an overlapping functional neurological disorder. Functional motor disorders (FMDs) are characterized by altered voluntary motor control and may present with weakness, tremor, gait disturbance, postural instability, abnormal movements, or impaired motor performance. These manifestations may resemble MS-related symptoms and may coexist with established structural neurological disease. In people with MS, functional motor symptoms may therefore be misclassified as relapse or disease progression, potentially leading to unnecessary investigations, corticosteroid treatment, inappropriate escalation of disease-modifying therapy, avoidable healthcare use, and delayed access to appropriate rehabilitation. Despite growing recognition of FMD-MS overlap, its prevalence, clinical characteristics, and optimal management remain insufficiently defined. This multicenter prospective study aims to improve the identification, characterization, and management of FMD-MS overlap in people with MS presenting with acute neurological symptom worsening. The study consists of two sequential and interconnected parts. Part A is an observational, cross-sectional diagnostic and prevalence study. A total of 192 adults with MS according to the 2017 revisions of the McDonald criteria and reporting new or worsening neurological symptoms within the previous 30 days will be enrolled at two tertiary MS centers in Italy. No study-assigned treatment will be administered during Part A. Participants will undergo a standardized multidimensional assessment including demographic and MS-related clinical information, neurological examination, evaluation of positive functional motor signs, disability and functional measures, gait and balance assessments, patient-reported outcome measures, and review of laboratory and magnetic resonance imaging findings obtained as part of routine clinical care when clinically indicated. The primary aim of Part A is to estimate the prevalence of FMD-MS overlap, also referred to in the protocol as functional pseudorelapse, among people with MS presenting with acute symptom worsening. Additional aims are to distinguish FMD-MS overlap from true MS relapse and other causes of symptom worsening and to identify demographic, clinical, functional, gait, balance, psychological, quality-of-life, and routine-care imaging characteristics associated with each diagnostic category. Part B is a pilot randomized, assessor-blinded, active-controlled rehabilitation study. Approximately 26 participants with confirmed FMD-MS overlap identified during Part A and meeting the additional rehabilitation eligibility criteria will enter Part B. These 26 participants are included within the overall cohort of 192 participants and are not an additional study population. Participants entering Part B will be randomized in a 1:1 ratio to either a targeted FMD-specific multidisciplinary rehabilitation programme or conventional MS rehabilitation. The experimental programme will include five consecutive days of in-person rehabilitation focused on education regarding functional symptom mechanisms, movement retraining using attentional-redirection strategies, and development of an individualized self-management plan. This will be followed by a 12-week home-based programme supported by weekly telemedicine sessions. The active comparator will consist of conventional MS rehabilitation addressing mobility, strength, gait, balance, endurance, fatigue management, and functional independence, without protocolized FMD-specific techniques. Part B aims to assess the feasibility, safety, and preliminary efficacy of the FMD-specific rehabilitation programme compared with conventional MS rehabilitation. Outcomes will be assessed at baseline, immediately after the five-day intervention, and at three months. The main efficacy outcome will be change in functional motor symptom severity, with additional evaluation of disability, functional performance, gait, balance, fatigue, pain, emotional functioning, quality of life, healthcare utilization, and costs. Overall, the study is expected to provide prospective evidence on the frequency and clinical profile of FMD-MS overlap and preliminary evidence on whether a mechanism-specific rehabilitation approach may improve outcomes in affected people with MS.

This study is being carried out at Multiple Sclerosis (MS) centers to evaluate whether a full-body stimulation suit at home can help people with Multiple Sclerosis (pwMS) reduce symptoms like spasticity (muscle stiffness) and ataxia (poor coordination), and improve daily functioning. Can pwMS who experience spasticity or ataxia benefit from using a stimulation suit for 6 weeks? Researchers will compare two groups: an intervention group (who will use the suit) and a control group (who will not use the suit). Participants in the intervention group will: * Wear the suit for 6 weeks in total every day or every other day (1 week during their MS center admission and 5 weeks at home). * Receive their usual care in addition to wearing the suit. * Undergo clinical tests at the MS center after 1 week and 6 weeks of stimulation. Participants in the control group will: * Receive their usual care. * Undergo clincial tests at the same time points as the other group.

Background: In people with multiple sclerosis (MS), brain and cerebrospinal fluid (CSF) biomarkers indicate inflammation or disease. Researchers want to see if 4 drugs given alone or combined affect MS biomarkers. They want to see if a change in biomarker levels can predict which drugs a person with MS might respond to. Objective: To see if signs of inflammation in CSF help predict a person s response to different drugs. Eligibility: People ages 18 and older who: * Are in protocol 09-I-0032 * Have progressive MS * Can stand and walk a few steps * Take an MS drug Design: Participants will be screened in protocol 09-I-0032. Participants will take 1 of the 4 study drugs. Researchers will call after 1 month to see how they are doing. Some will start a second drug. They may take each drug or combination for up to 18 months. Participants will have 2 visits a year for up to 6 years. Visits include: * Medical history * Physical exam * Blood and heart tests * X-rays and scans * Eye exam and tear collection * Lumbar puncture: A needle inserted between back bones removes some CSF. * Lymphocytapheresis: Blood is removed through a needle in one arm and run through a machine. The blood is returned through a needle in the other arm. * A sensor on the forehead records blood flow and oxygen use. * Participants may get a device for testing at home. Participants will stop taking the drugs if they have taken 2 drugs together for 18 months or if they do not do well on the drugs. Participants will be called 3 months later to see how they are doing.

Inflammatory or degenerative diseases of the brain and spinal cord, such as multiple sclerosis, may be related to problems with an individual s immune system. However, more information is needed on the ways in which the cells of the immune system interact with the central nervous system (CNS). This study will compare tests performed on both healthy volunteers and individuals who have signs or symptoms of immune-related damage to their CNS. This study will include two groups of subjects at least 12 years old. Subjects will either have symptoms of immune-related CNS damage, or will be healthy volunteers selected for comparison purposes. Study participants will visit the NIH Clinical Center on an outpatient basis for an initial evaluation visit. During the visit, patients will provide a comprehensive medical history and undergo a neurological examination, and will provide blood samples for research purposes. The healthy volunteers will be asked to schedule a return visit for a magnetic resonance imaging (MRI) procedure, and may be asked to undergo other tests requested by the study researchers on an as-needed basis. The group of patients with symptoms of immune-related CNS damage will be asked to undergo a series of tests, including the following: * MRI procedures, with a minimum of three brain MRIs and one spinal cord MRI taken approximately 4 weeks apart * A diagnostic lumbar puncture, performed on an outpatient basis * Tests of brain and vision activity * Additional blood and tissue samples Patients with symptoms of immune-related CNS damage may be offered the opportunity to participate in additional followup tests with NIH researchers.

This study aims to evaluate the practical and research utility of a new test assessing language and memory in people with MS. To this end, we are administering the test to a group of 100 individuals with MS who are receiving treatment at the National MS Center Melsbroek. These data will allow us to determine whether scores on the new test correlate with those of established cognitive tests. Subsequently, we will administer the new test to 100 individuals without an MS diagnosis who are matched for age, gender, and education level. This will enable us to assess whether there are significant differences in scores between individuals with MS and those without the diagnosis. One year later, we will re-administer the tests to the participants with MS to determine the extent to which changes in scores on the new test correspond to changes in scores on established tests.

This cross-sectional observational study aims to investigate the associations between multiple sclerosis (MS) severity and caregivers' sleep quality, physical activity, body awareness, perceived stress, and caregiver burden. A total of 68 caregivers of patients with MS will be recruited from Başkent University Hospital. MS severity will be assessed using the Expanded Disability Status Scale (EDSS), while caregiver health outcomes will be evaluated using validated questionnaires. The findings are expected to provide insight into the multidimensional impact of MS severity on caregiver health and well-being.

Objectives Objective 1: To determine the effects of a 16-week remotely delivered Pilates intervention on walking endurance, walking speed, balance, fatigue, and pain compared to a waitlist control group in individuals with MS. Objective 2: To examine the impact of a 16-week remotely delivered Pilates intervention on depression \& anxiety, cognitive function, and QOL compared to a waitlist control group in individuals with MS. Aim Aim 1: To assess whether the 16-week remotely delivered Pilates intervention significantly improves walking endurance, walking speed, balance, fatigue, and pain compared to a waitlist control group in individuals with MS Aim 2: To investigate whether the 16-week remotely delivered Pilates intervention significantly improves depression \& anxiety, cognitive function, and QOL compared to a waitlist control group in individuals with MS. Hypothesis Hypothesis 1: The 16-week remotely delivered Pilates intervention will significantly improve walking endurance, walking speed, balance, fatigue, and pain compared to a waitlist control group in individuals with MS. Hypothesis 2: Participants receiving the 16-week remotely delivered Pilates intervention will demonstrate significantly greater improvements in depression \& anxiety, cognitive function, and QOL compared to a waitlist control group in individuals with MS.

Our overall objective is to obtain an initial assessment of the potential value of using \[18F\]3F4AP for imaging demyelinating diseases such as multiple sclerosis: * Aim 1) Assess the safety of \[18F\]3F4AP in healthy volunteers and subjects with multiple sclerosis (MS). Hypothesis 1: Administration of \[18F\]3F4AP will result in no changes in vitals or other adverse events. * Aim 2) Assess the pharmacokinetics of a bolus infusion of \[18F\]3F4AP in humans including healthy volunteers and MS patients. Hypothesis 2: the pharmacokinetics of \[18F\]3F4AP at the whole brain level will be similar in controls and MS subjects. The kinetics in demyelinated lesions will be slower than in healthy control areas. * Aim 3) Assess the reproducibility of \[18F\]3F4AP in humans. Hypothesis 3: the test/retest variability of \[18F\]3F4AP within the same subject will be lower than 10%. * Aim 4) Correlate MR brain images with \[18F\]3F4AP PET brain images. Hypothesis 4A: all the lesions seen on the MRI will show increased signal (VT or SUV) on the PET images. Hypothesis 4B: some of the lesions on the MRI will show increased signal (VT or SUV) on the PET but not all. * Aim 5) Correlate \[18F\]3F4AP PET signal with neuropsychological testing in people with MS. Hypothesis 5: increased PET signal (VT or SUV) will correlate with impaired Single Digit Modality Test (SDMT) scores. * Aim 6) Correlate \[18F\]3F4AP PET signal with EDSS score in people with MS. Hypothesis 6: increased PET signal (VT or SUV) will correlate with higher EDSS scores.

Multiple sclerosis (MS) and functional neurological disorders (FND) share clinical features, which may result in FND being overlooked in patients with MS. They also share common comorbidities, including depression and alexithymia. As their management differs, assessing the frequency and determinants of FND in patients with MS is important to improve diagnosis and ensure appropriate management.

To evaluate whether an entire-body positron emission tomography (PET) scanner can be exploited to improve evaluation, monitoring and measurement of both peripheral and central demyelination in multiple sclerosis (MS) patients.

This phase Ib trial studies the side effects of nivolumab and to see how well it works alone and in combination with other treatments, such as ipilimumab, cabozantinib, platinum containing therapy, and fluoropyrimidine, in treating patients with autoimmune disorders and cancer that has spread from where it first started (primary site) to nearby tissue, lymph nodes, or distant parts of the body (advanced), to other places in the body (metastatic) or cannot removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Cabozantinib blocks certain proteins, which may help keep tumor cells from growing. It may also prevent the growth of new blood vessels that tumors need to grow. Cabozantinib is a type of tyrosine kinase inhibitor and a type of angiogenesis inhibitor. Chemotherapy drugs, such as platinum containing therapies and fluoropyrimidine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab alone and in combination with other treatments, including ipilimumab, cabozantinib, platinum containing therapy, or fluoropyrimidine, may be safe, tolerable, and/or effective in treating patients with autoimmune disorders and advanced, metastatic, or unresectable cancer.

Background: Multiple sclerosis (MS) affects the brain, spinal cord, and optic nerves. MS lesions can appear on the MRI (magnetic resonance imaging) scans in many ways. Sometimes they light up from the outer edge and fill inward. This is called ring enhancement. Researchers think this type of lesion may not heal as well as others. Corticosteroids are the standard treatment to reduce symptoms of MS relapse. But there is no standard treatment for people with enhancing MS lesions without signs of MS relapse. Researchers want to see if a short-term high-dose course of corticosteroids helps heal those lesions. Objective: To study the effects of short-term high-dose corticosteroids on ring-enhancing MS. Eligibility: Adults ages 18 and older who: * Have MS and a rim-enhancing lesion on a prior brain MRI * Are enrolled in another NINDS protocol Design: Participants will be screened under another protocol Participants will be randomly assigned to get either no treatment or 3 days of treatment with a corticosteroid. Participants will have: * 1 baseline visit * 3 days of high-dose steroids, intravenous or oral. If IV, participants will receive methylprednisolone by IV each day. Participants will also be prescribed medicine to protect their stomach. * Follow-up visits will be at week 13 and week 25 after randomization to treatment or no treatment. Visits include medical history and physical exam. Participants will have blood and urine tests. Participants will also have neurological exams and MRIs. Participants lie on a table that slides into a cylinder. They are in the scanner 1.5-2 hours. They get a dye through a catheter: A needle guides a thin plastic tube into an arm vein.

The purpose of this study is to assess and compare how well multiple sclerosis (MS) patients tolerate cetirizine versus diphenhydramine as a pre-medication before receiving anti-CD20 infusion therapy of ocrelizumab, ublituximab or rituximab. The study will also compare the safety of cetirizine versus diphenhydramine as a pre-medication for preventing infusion reactions in MS patients receiving anti-CD20 infusion therapy.

Approximately 2.8 million people worldwide suffer from multiple sclerosis (MS). In 40 to 70% of cases, individuals with MS experience cognitive impairments that significantly interfere with their personal lives, careers, and quality of life. Current pharmacological and neurorehabilitation treatment options do not adequately reduce cognitive deficits. The absence of standards of care in Switzerland or internationally regarding cognitive neurorehabilitation in MS highlights the need for effective interventions with lasting effects. To address this need, we are exploring different approaches to support and improve cognitive impairments through training exercises using computerized tools. Traditionally, these exercises are in paper-and-pencil format, consisting of tests, puzzles, and memory tasks. While this approach is useful, computerized tools now allow us to offer more playful, interactive, and engaging approaches. In this study, we are examining the effect of serious video games (a medical device) on cognitive deficits related to MS. The serious video games we are testing have already been evaluated at CHUV in individuals with MS and cognitive impairments. This recent study demonstrated the feasibility and safety of using these games in people with MS. With the current study, we aim to test these tools on a larger scale in order to better understand their effects on cognitive functions. More specifically, we seek to determine which of the two proposed interventions provides the greatest cognitive benefits.

ETOTUR is a research project comprising two complementary stages. The first is an observational study in approximately 50 healthy adults to develop and validate a mobile tool for quantitative assessment of muscle tone using the pendulum test. Measurements obtained with the mobile tool will be compared with laboratory reference systems, and preliminary reference values will be established. The second stage, which is the focus of this clinical trial registration, is a pilot controlled study involving approximately 30 adults with multiple sclerosis and altered muscle tone and standing postural control. Participants will receive either Inductive Therapeutic Exercise (ETI, from the Spanish "Ejercicio Terapéutico Inductivo") or Sham Inductive Therapeutic Exercise (sham-ETI), a simulated intervention, with one individual session of approximately 40 minutes per week for 8 weeks. ETI combines specific active movements and breathing patterns intended to elicit involuntary neuromuscular responses in other body regions. Sham-ETI uses similar movements while omitting the principal movement and breathing components intended to produce induction. Participants will be assigned using a nonrandom sequential balancing procedure based on relevant baseline characteristics. Outcome assessment will be performed by a physiotherapist blinded to group allocation. Outcomes will be assessed at baseline, immediately after the 8-week intervention, and approximately one month later. The main outcomes are lower-limb muscle tone assessed using the pendulum test, standing postural control measured with a pressure platform, and health-related quality of life assessed with the Multiple Sclerosis Quality of Life-54 questionnaire (MSQoL-54). Adherence, tolerability, and intervention-related clinical incidents will also be recorded. The study will explore whether changes following ETI differ from those observed after sham-ETI and will provide preliminary information to support the design of subsequent confirmatory research.

The purpose of this study is to assess the imaging biomarkers, patient outcomes, safety, tolerability, and treatment satisfaction of ocrelizumab (OCR) combined with recombinant human hyaluronidase (rHuPH20) administered subcutaneously (SC) in participants with relapsing multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS) after switching from another anti-cluster of differentiation 20 (aCD20) therapy approved for RMS (ofatumumab SC, ublituximab-xiiy intravenous \[IV\], ocrelizumab IV) or PPMS (ocrelizumab IV).

The goal of this clinical trial is to learn whether the Lexical Association Technique (LAT) can improve well-being in people recently diagnosed with multiple sclerosis (MS), either relapsing-remitting (RRMS) or secondary progressive (SPMS). The main questions it aims to answer are: * Does the LAT increase well-being more than a placebo technique ? * Does this technique help reduce psychological distress and improve quality of life ? Participants will: * Be randomly assigned to either the LAT group or the active control group * Complete short visualization exercises at home using a personal computer * Fill out questionnaires about self-esteem, stress, anxiety, depression, quality of life, and adjustment to illness * Take part in the study over several weeks, with assessments before, after, and 14 days after the intervention Researchers will compare results between the two groups (LAT group vs. Control group) to test the immediate and lasting effects of the LAT.

This study will assess the impact of a MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet on brain health and MS symptoms. Participants will be randomly assigned to one of two arms: the diet intervention arm or the "continue current diet"/control arm. Participants randomized to the dietary intervention arm will change their diet to follow a MIND dietary pattern for one year; diet-related education and programming is provided to support this change. Participants randomized to the continue/control arm will be asked to continue their current dietary habits, without major change for one year; multiple sclerosis (MS) MS-related related education and programming (unrelated to diet) is provided. All participants will be asked to provide blood \& stool samples and to complete online questionnaires \& three in-person assessments.

This cross-sectional study aims to assess the pattern of gait in patients with multiple sclerosis and to evaluate its relation to cognitive function, visual evoked potentials, and radiological findings.

The goal of this clinical trial is to shed light on the use of cooling during intensive active training sessions during a three-week multidisciplinary inpatient rehabilitation stay in persons with Multiple Sclerosis. The objectives of this study are: * to investigate the effects of one week of using a cooling vest during intensive active training sessions compared with one week of not using a cooling vest during inpatient rehabilitation on the state fatigue in persons with Multiple Sclerosis. * to investigate the effects of one week of using a cooling vest during intensive active training sessions compared with one week of not using a cooling vest during inpatient rehabilitation on the walking capacity, functional lower limb muscle strength, balance and cognition in persons with Multiple Sclerosis. * to investigate the effects of the three-week inpatient rehabilitation on the cardiorespiratory fitness, muscle strength and trait fatigue in persons with Multiple Sclerosis. Researchers will compare the effects of one week of using a cooling vest during intensive active training sessions with one week of not using a cooling vest during intensive active training sessions during three weeks of inpatient rehabilitation. Participants will * Wear a cooling vest during intensive active training sessions for one week * Attend the assessment appointments during study participation * Keep a diary recording their use of a cooling vest during intensive active training sessions

Phase 1 will test single oral doses of PRO-1562 in healthy adult subjects to characterize the safety and the amount of drug that is absorbed into the body. Some subjects will have lumbar punctures performed to measure the amount of drug that crosses the blood-brain barrier since that is the site of drug activity. Phase 2a will be a 6-month trial to test the ability of once monthly dosing of PRO-1562 to promote remyelination of the CNS and provide clinical benefit to adult patients with relapsing multiple sclerosis (RMS) who also have long-term vision problems diagnosed as chronic optic neuropathy. The benefits of remyelination will be measured using tests of visual acuity, speed of optic nerve conduction signals, and clinical assessments of cognitive and motor function. PRO-1562 will be added on to a stable regimen of MS disease modifying therapy.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system that causes variable degrees of neurological disability. Epstein-Barr virus (EBV) has been identified as an important environmental factor implicated in the pathogenesis and progression of MS. However, the serological profile, antibody titers, and clinical relevance of EBV infection among Egyptian individuals with MS remain limited. The primary purpose of this hospital-based observational study is to evaluate the frequency and titers of EBV-specific antibodies, specifically anti-viral capsid antigen (anti-VCA) IgG and anti-Epstein-Barr virus nuclear antigen 1 (anti-EBNA1) IgG, in Egyptian patients diagnosed with MS compared with age- and sex-matched healthy controls. The study also aims to assess whether EBV antibody levels correlate with MS disease activity, degree of neurological disability, relapse frequency, clinical subtype, brain MRI lesion burden, and response to disease-modifying therapies (DMTs). A total of 140 participants will be enrolled at the Department of Neurology and Psychiatry, Assiut University Hospital, comprising 70 adult patients with MS diagnosed according to the 2024 McDonald criteria and 70 matched healthy controls. Participants will undergo clinical and demographic assessment, neurological disability evaluation using the Expanded Disability Status Scale (EDSS) for MS patients, and review of existing brain MRI scans. A single venous blood sample will be collected from all participants to measure anti-VCA IgG and anti-EBNA1 IgG levels using enzyme-linked immunosorbent assay (ELISA).

The overall goal of this study is to elucidate a mechanism by which vancomycin modulates the gut-brain axis in multiple sclerosis (MS). The gut microbiome plays an important role in autoimmunity, including MS. However, the identity of gut microbes modulating neuroinflammation in MS and their mechanisms of action remain obscure. Hence, here the research team proposes to investigate the effects of vancomycin on the gut microbiota composition, peripheral immune function, and brain MRI lesions in MS patients.

The goal of this clinical trial is to learn if the time an individual eats each day impacts neurological health in people with multiple sclerosis. The main questions the investigators are asking are: 1. Does meal timing affect biomarkers of neuronal health (neurofilament light chain \[NfL\] and BDNF) and inflammation (IL-6, IL-17, TNF-ɑ) in adults with MS. 2. Does meal timing affect expression of circadian clock genes and genes associated with autophagy in adults with MS. Participants will be instructed to start and stop eating at specific times each day based on their group assignment and their personal schedule. They will respond to prompts sent to them on their smartphone to record the times they start and stop eating each day. As a secondary goal, the study will also explore the feasibility of including translocator protein (TSPO)-PET imaging of neuroinflammation in future clinical trials of TRE in people with MS. To accomplish this, imaging will be completed in a subset of 8 participants at the beginning and end of the study.

Multiple Sclerosis (MS) is a chronic neurological disease impacting 2.8 million individuals globally, with fatigue being its most debilitating symptom, reported by 75% of patients. Despite its prevalence, the pathophysiology of MS-related fatigue remains poorly understood, and current pharmacological treatments have limited effectiveness. This research addresses this critical gap by investigating two non-invasive brain stimulation (NIBS) techniquestranscranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS)as innovative, effective and scalable therapeutic approaches for MS fatigue. The study employs a parallel, randomized, triple-blind, multicentric, sham-controlled design to assess and compare the short- and long-term efficacy of TMS and tDCS in addressing MS-related fatigue. 80 participants will be recruited from multiple centers in Spain and randomly assigned to one of four experimental groups: TMS, tDCS, Sham-TMS, Sham-tDCS. Each intervention will consist of 20 sessions, conducted daily from Monday to Friday, over 4 weeks. The left dorsolateral prefrontal cortex (DLPFC, F3 following the 10/20 system for EEG) was selected as the stimulation site based on its involvement in MS-related self-reported fatigue and in cognitive fatigability. For TMS experimental groups, intermittent theta-burst protocol (iTBS) will be used to increase the cortical excitability of the stimulated area. iTBS delivers a total of 600 pulses, organised into 50 Hz triplets repeated at 5 Hz, with 2second blocks of pulses, interleaved with 8 seconds of rest, repeated 20 times (total duration: 190s). The intensity of stimulation will be individually tailored based on the active motor threshold (aMT), setting it at 80% of the aMT. The sham stimulation will follow the same protocol, but using a sham coil (placebo). For tDCS experimental groups anodal tDCS will be applied (increasing cortical excitability) with the anode over the left DLPFC (F3), and the cathode over the contralateral supraorbital area. The intensity will be 2mA, and the duration of the stimulation will be 20min per session. For tDCS placebo condition, the sham option available on the device will be selected. Primary outcomes include changes in fatigue levels measured through MS validated self-report scales (Modified Fatigue Impact Scale-MFIS; Fatigue Scale for Motor and Cognitive Functions-FSMC); secondary outcomes include depression (Beck Depression Inventory-II, BDI-II), quality of life (Multiple Sclerosis Quality of Life, MSQOL-54), functional independence (Functional Independence Measure, FIM), and cognitive fatigability (Symbol Digit Modalities Test, SDMT). All the outcomes will be assessed at baseline, at the end of the intervention, and six months after the end of the treatment (6 months follow-up). This project promotes personalized precision medicine and innovative new treatment methods. This research is expected to expand scientific knowledge on NIBS efficacy in MS, establish evidence-based clinical practices, and set the foundation for cost-effective, patient-centered therapies. The study also addresses gender-specific responses to treatment, ensuring inclusive therapeutic strategies. Furthermore, it has the potential to benefit other neurological conditions characterized by fatigue, such as stroke, chronic fatigue syndrome or Parkinsons disease, showing significant social, clinical, and economic impact.