Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system (CNS) of an unknown cause, characterized by demyelinating white matter lesions and neuronal degeneration [1]. The prevalence of MS in the world ranges from 5 to 300 per 100,000 people, and affects women more often [2]. Relapsing–remitting form of the disease (RRMS) is the most common form. The primary progressive form of the disease (PPMS) is significantly less common and occurs in 10% of people with MS (pwMS), while the further progression of the disease indicates the transition from the relapsing–remitting form to the secondary progressive form (SPMS).

The diagnosis of MS is based on laboratory findings (e.g., cerebrospinal fluid-specific bands), oligoclonal bands, and radiologic findings (e.g., magnetic resonance imaging [MRI ≥ 1.5 T or 3T] T2 lesions of the brain and spinal cord, lesions that increase gadolinium), including the application of the 2017 McDonald criteria and the 2021 MAGNIMS-CMSC-NAIMS recommendations [3,4]. The clinical status of disability is expressed through the Expanded Disability Status Scale (EDSS) [5,6], which assesses the status of functional systems including the pyramidal–corticospinal pathway (muscle strength, limb movement), cerebellum (balance, coordination), brainstem (speech, swallowing, nystagmus), sensory pathway (sensation), visual pathway (sight), bladder and bowel function, cognitive functions (memory), and ambulation (walking measured in meters). The key functional components of the EDSS, correlating with sustained disability progression, appear to be mostly pyramidal, followed by cerebellar and sensory functional systems [7].

Various quantitative measures (i.e., the number and volume of contrast-enhancing, the volumes of T2-hyperintense and T1-hypointense lesions, and brain volume changes), derived from conventional and advanced MRI methods, have been proposed as prognostic biomarkers for MS. However, correlations between different MRI indicators and EDSS are not satisfactory, and no specific MRI measure is used as a comprehensive prognostic imaging biomarker for MS [8,9,10].

Evoked potentials (EP) represent neurophysiological measures of signal conduction in the CNS in vivo, and are used to measure the impact of MS pathology on CNS function pathways correlating with clinical status [11]. Multimodal Eps, such as somatosensory evoked potentials (SEPs), visual evoked potentials (VEPs), and motor evoked potentials (MEPs), recorded as baseline (at diagnosis), have been shown to correlate with EDSS [12]. Recent findings suggest the likely application of TMS as a subclinical MEP test that could represent a biomarker of the degree of MS disability [13,14]. Current data suggest a connection between the pathophysiological mechanisms of MS (demyelination and loss of axons) and TMS neurophysiological measures (e.g., lower amplitudes and longer latencies of MEP responses from upper and lower limb muscles, elevated resting motor threshold (RMT), and changes in specific neurophysiological measures of excitation and inhibition) [15]. Furthermore, changes in cortical excitatory and inhibitory processes in MS, assessed with TMS, appear to be evident in early disease progression, during relapse, and later during disease progression [11,15,16]. In addition, changes in neurophysiological TMS measures are associated with the clinical characteristics of MS [14,15]. It has to be noted that MEPs acquired in TMS studies in MS subjects, mainly represent the marker of the integrity of the corticospinal tract (lateral funicle of the cord known as the lateral corticospinal tract) [17] and primary motor cortices (M1). Motor mapping can also demonstrate the presence of the ipsilateral MEP corticospinal tract projections reported in congenital pathologies, including hemiplegic cerebral palsy [18,19,20,21,22] and congenital mirror movements [18,23,24,25]; this is evident in progressive immune-mediated Rasmussen encephalitis, leading to unihemispheric brain atrophy [26] during intraoperative neurosurgical monitoring in patients [27], and in acquired lesions, such as during a cerebral stroke [28,29] or following hemispherectomy [28]. MEPs can also be recorded in the ipsilateral muscles of the upper extremities in healthy subjects [30]. Ipsilateral MEPs are thought to reflect the functional activity of the uncrossed lateral corticospinal tract from the ipsilateral hemisphere [31], may reflect the activation of the cortical–subcortical–spinal pathways [32], or may be due to the activation of the crossed corticospinal tract from the hemisphere contralateral to the target limb; this is due to the proximity of the M1 cortices for lower extremity muscle representation. The functional role of ipsilateral M1 areas in MS has been associated with an adaptive response to chronic CNS injury [33,34,35]. Overall, the TMS investigation of ipsilateral MEPs in MS has not been widely considered, due to the neurophysiological mechanisms still being unknown.

Concerning the clinical use and interpretation of MEPs in diagnosing and monitoring pwMS, TMS guidelines were established by Fernández et al. in 2013 [36], referring to the TMS. This mainly included the magnetic stimulator connected to a standard EMG unit, and was less connected to linenavigated TMS implementations.

2. Assessment of MEPs in Multiple Sclerosis

2.1. Targeting M1 with TMS without Navigation, Line-Navigated TMS and e-Field-Navigated TMS

2.2. Neurophysiological Changes in the Central and Peripheral System in pwMS Investigated with TMS