1. To investigate the relationship between corticospinal inhibition and clinical, psychological, and cognitive features in MS patients.
2. To examine the association between corticospinal inhibition and radiological findings, including MRI lesions and white matter damage

Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system (CNS), characterized by demyelinating white matter lesions and diffuse neurodegeneration. These pathological changes lead to variable and unpredictable clinical presentations and disease progression. Beyond motor and sensory deficits, MS is frequently associated with cognitive and emotional disturbances. Cognitive impairment affects 40-70% of patients, particularly in domains such as attention, processing speed, executive functions, and working memory-significantly impacting daily life and quality of care.

Alexithymia, a condition involving difficulty in identifying and describing emotions, externally oriented thinking, and limited imaginative ability, has been reported in a substantial proportion of patients, especially in progressive forms of the disease. It is frequently associated with sleep disturbances, anxiety, and depression.

Fatigue is one of the most burdensome and common symptoms in MS. It may present at any stage and is defined as a persistent lack of physical or mental energy that interferes with daily function. Fatigue may be classified as primary-linked directly to MS pathophysiology-or secondary, due to comorbid conditions, medication effects, or inactivity. Unlike general fatigue, MS-related fatigue is not relieved by rest and has a distinctly disabling nature.

Depression is another prevalent comorbidity, with lifetime prevalence in MS ranging widely. Its development reflects both the psychological burden of chronic disease and neurobiological mechanisms, such as inflammation and demyelination affecting mood circuits.

Given this wide spectrum of motor, cognitive, and emotional manifestations, comprehensive and multidimensional tools are essential for assessing the functional impact of MS. The Multiple Sclerosis Functional Composite (MSFC) is one such standardized, performance-based assessment. It captures core aspects of MS-related disability across three domains: ambulation (Timed 25-Foot Walk, T25FW), upper limb coordination (9-Hole Peg Test, 9HPT), and cognition (Paced Auditory Serial Addition Test, PASAT-3).

Magnetic resonance imaging (MRI) plays a pivotal role in both diagnosis and disease monitoring. Beyond identifying dissemination in time and space, advanced MRI techniques have linked symptom burden-particularly fatigue and cognitive deficits-to microstructural damage in normal-appearing white matter. This suggests that functional disconnection, rather than lesion volume alone, contributes to clinical manifestations.

Transcranial magnetic stimulation (TMS) provides a non-invasive, neurophysiological method to assess corticospinal excitability. When applied to the primary motor cortex, TMS elicits motor-evoked potentials (MEPs) that reflect both direct and trans-synaptic activation of motor pathways, offering insights into cortical inhibition and conduction properties in MS.

Despite advances in neuroimaging and functional assessments, the relationship between corticospinal inhibition and the heterogeneous symptomatology of multiple sclerosis-including fatigue, cognitive dysfunction, and emotional dysregulation-remains underexplored. Few studies have integrated transcranial magnetic stimulation (TMS) with clinical, cognitive, and radiological metrics in a multidimensional framework. This gap limits understanding of the neurophysiological substrates underlying these complex and disabling symptoms.

The present study aims to investigate the relationship between corticospinal inhibition, as assessed by TMS, and the clinical, psychological, cognitive, and radiological profiles of patients with multiple sclerosis. The hypothesis is that altered corticospinal inhibition will correlate with increased fatigue, cognitive dysfunction, alexithymia, and specific MRI abnormalities, reflecting the integrated neurophysiological basis of multiple sclerosis-related symptoms.

Inclusion Criteria:

1. Age 18 years or older.
2. Diagnosis of RRMS based on the 2017 McDonald Criteria.
3. Expanded Disability Status Scale (EDSS) score ≤ 6.5.
4. On a stable dose of disease-modifying therapy (DMT) for at least 3 months or naeive patients not use DMT before
5. Free of relapses or steroids treatment (at least 3 months after a relapse or corticosteroid therapy)
6. Ability to give informed consent and complete neuropsychological assessments.

Exclusion Criteria:

1. Presence of other neurological or psychiatric disorders (e.g., major depression, bipolar disorder, schizophrenia).
2. History of alcohol or substance abuse.
3. Contraindications to MRI (e.g., pacemakers, metallic implants) and TMS (i.e., history of seizures, presence of ferromagnetic implants in the head area).
4. Medications known to alter the corticospinal excitability.
5. Severe visual deficit, motor weakness, or intellectual impairment (as per the Mini-Mental State Exam score < 24).

the sample size calculation was performed using EpI-Info 2002 software statistical package designed by World Health Organization (WHO) and by Centers for Disease Control and Prevention (CDC). The sample size was calculated based on the following considerations: 95% confidence level and according to a previous study (Chaves, A. R.,2024). Therefore, resulting sample size of 82 thus sample size increased to 90

Chaves, A. R., Tremblay, S., Pilutti, L., & Ploughman, M. (2024). Lowered ratio of corticospinal excitation to inhibition predicts greater disability, poorer motor and cognitive function in multiple sclerosis. Heliyon, 10(15).