Transcranial Magnetic Stimulation as a Potential Biomarker in Multiple Sclerosis: A Systematic Review with Recommendations for Future Research

Abstract

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system. Disease progression is variable and unpredictable, warranting the development of biomarkers of disease status. Transcranial magnetic stimulation (TMS) is a noninvasive method used to study the human motor system, which has shown potential in MS research. However, few reviews have summarized the use of TMS combined with clinical measures of MS and no work has comprehensively assessed study quality. This review explored the viability of TMS as a biomarker in studies of MS examining disease severity, cognitive impairment, motor impairment, or fatigue. Methodological quality and risk of bias were evaluated in studies meeting selection criteria. After screening 1603 records, 30 were included for review. All studies showed high risk of bias, attributed largely to issues surrounding sample size justification, experimenter blinding, and failure to account for key potential confounding variables. Central motor conduction time and motor-evoked potentials were the most commonly used TMS techniques and showed relationships with disease severity, motor impairment, and fatigue. Short-latency afferent inhibition was the only outcome related to cognitive impairment. Although there is insufficient evidence for TMS in clinical assessments of MS, this review serves as a template to inform future research.

Probing the Brain–Body Connection Using Transcranial Magnetic Stimulation (TMS): Validating a Promising Tool to Provide Biomarkers of Neuroplasticity and Central Nervous System Function

“…Previous studies confirm that TMS variables derived from upper extremity MEPs are representative of overall CSE [ 67 , 68 ]. Furthermore, the FDI is a commonly studied muscle representation in TMS studies of clinical populations (e.g., stroke [ 2 , 30 ], MS [ 2 , 27 ], amyotrophic lateral sclerosis, Parkinson’s disease, and Huntington’s disease [ 69 , 70 ]). The skin on both hands was prepared at the outset to minimize set-up delays during TMS testing.…”

“…Similar to the eREC, which describes the properties of excitatory (glutamatergic) corticospinal neuron populations, an inhibitory CSP recruitment curve (iREC) can be utilized to index the activity of inhibitory (GABAergic) interneurons [ 26 ] ( Figure 2 ). Additionally, while other TMS protocols such as short-(SICI) and long-interval intracortical inhibition (LICI) and short-interval intracortical facilitation are also thought to be proxies of GABAergic activity in the central nervous system, they are beyond the scope of the current work and are reviewed elsewhere [ 10 , 27 ].…”

“…Another clinically useful TMS-derived variable describes transcallosal inhibition. By applying a suprathreshold (i.e., above motor threshold) TMS stimulus over the target motor representation while the ipsilateral target muscle is contracting, the duration of interruption of the EMG activity in the active muscle captures the ipsilateral silent period (iSP) [ 27 ]. The iSP is thought to be a measure of interhemispheric or transcallosal inhibition [ 28 ], the influence of one cerebral hemisphere’s activity over the other via projections across the corpus callosum [ 25 ].…”

“…However, more research is required to examine its validity in large samples of people with neurological disorders [ 2 ], including MS [ 27 ].…”

“…Thus, variables derived using TMS could help to: (1) provide a better understanding of neuropathophysiological events involved in the onset and sequelae of MS [ 32 ], (2) predict disease severity and progression for prognostication purposes, and (3) investigate whether rehabilitation therapies [ 50 ] and pharmacological treatments [ 5 ] are truly acting on the central nervous system to enhance neuroplasticity and recovery [ 27 ]. Although recent work has recognized the potential role of TMS in providing biomarkers of central nervous system functioning in MS, conclusions were based on small studies that demonstrated a high risk of bias [ 27 ]. Additionally, many TMS procedures require specialized equipment, technical expertise and, in most cases, long testing times.…”