# An Overview of Transcranial Magnetic Stimulation and Its Application in Multiple Sclerosis
## 5 TMS Measures in the Diagnosis and Evaluation of MS
### TMS Measures and the Association with MRI Markers  
MRI imaging sequences are routinely used to assess the presence and distribution of lesions that characterize MS [1,62]. Highlighting the importance of these measures in research and clinically, T2-weighted sequences and T1-weighted sequences post gadolinium contrast administration form a central part of current diagnostic criteria to establish dissemination in space and time. Given the importance of MRI as a Gold Standard surrogate of MS lesion structural pathology, it is important to explore and understand the association of MRI measures with TMS measures (a putative functional correlate) to clearly establish structure-function relationships which implicitly underpin the promise of TMS measures as useful biomarkers. [PERSON] et al. [41] monitored a group of 19 MS patients (original n = 20, minus 1 withdrawal) over 12 months, with CMCT measured at the beginning and end of the study, and clinical and MRI examinations conducted at monthly intervals. They reported an increase in CMCT to upper limb muscles correlated with MRI lesion load and the presence of atrophy in the cervical cord. Additionally, while clinical deterioration measured via worsened EDSS scores was observed in 15 of 19 patients, only 4 saw an increase in motor response latencies, all of whom had developed new cord lesions. A more recent study by [PERSON] et al. [50] examined a cohort of 52 MS patients and found that T1- and T2-weighted brain lesion volume and the number of spinal cord lesions had moderate positive correlations with CMCT to all limbs (upper/lower, right/left) and a correlation with EDSS results. The paper noted that the number of lesions did not differ significantly between the MS subtype groups. A study by [PERSON] et al. [31] also found that CMCT was correlated with the T2 brain lesion load. However, a study by [PERSON] et al. [30] examined 30 MS patients and reported that EDSS scores were correlated significantly with TMS measures (CMCT, MEP amplitude, MT, ICI) but not with MRI lesion load. Considering all of this, the association between TMS measures and MRI measures needs clarification: some studies report an association between CMCT and lesion load, while others do not. [PERSON] et al. [41], in their longitudinal assessment, reported deterioration that was both associated with and independent of changes in CMCT/MRI measures. Furthermore, the spatial distribution of MRI lesions, which focally involve the corticospinal tracts as they course through the frontal lobes, deep white matter tracts, brainstem, and spinal cord, is an important consideration that has not been extensively evaluated. Larger scale, longitudinal studies that collect both TMS and MRI data at varying intervals are necessary to clarify the association between these variables and their clinical utility when combined.  
Beyond'standard' MRI measures, a host of new MRI biomarkers have been recently developed in the context of MS. Myelin water fraction (MWF) and the magnetization transfer ratio (MTR) have been proposed as possible structural measures of the myelination state in MS, which may plausibly be associated with TMS measures as functional correlates. In one such study, corpus callosum MWF was correlated with TMS-derived transcallosal inhibition (TCI; a brief suppression of voluntary activity in the primary motor cortex elicited by contralateral stimulation via the corpus callosum), which may suggest an association between structure and function in the context of MS demyelination [63]. Additional novel MRI measures of interest include the central vein sign, a specific feature of MS lesions that may have a diagnostic role, as well as slowly expanding lesions (SELs) and paramagnetic rim lesions (PRLs), which are thought to be evidence of chronic ongoing inflammation at the rim of previously enhancing lesions via MRI as a substrate of progressive injury. Currently, the association of these measures with TMS measures as structural correlates has not been extensively explored.