Introduction
Multiple sclerosis (MS) is an immune-mediated neurodegenerative and neuroinflammatory disease characterized by chronic central nervous system (CNS) degeneration with intermittent attacks of inflammatory demyelination and axonal damage ( Reich, Lucchinetti & Calabresi, 2018 ). Mitigation of disease activity, disease progression, and disability accumulation requires early and correct diagnosis ( McNicholas et al., 2018 ). To diagnose MS in a patient with a history suggestive of a demyelinating episode, clinicians must find evidence of lesion dissemination in space and time ( Poser et al., 1983 ). In the 2017 McDonald criteria ( Thompson et al., 2018 ), magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) oligoclonal bands aid the clinical history and exam in finding these features. The 2017 McDonald criteria are highly sensitive; however, their low specificity can lead to misdiagnosis, thus resulting in delayed diagnosis and unnecessary treatment in some individuals ( Filippi et al., 2022 ; Gobbin et al., 2019 ; McNicholas et al., 2018 ). As such, it is desirable to discover biological markers (biomarkers) of disease activity in MS that have the sensitivity to identify subclinical lesions early in the disease course, while possessing high specificity for MS-related disease processes ( Bielekova & Martin, 2004 ).

A biomarker is “an objectively measured indicator of normal biological processes, pathogenic processes, or … responses to a therapeutic intervention” ( Bielekova & Martin, 2004 ). Biomarkers can aid diagnosis, classify the extent of disease, observe natural history, or monitor responses to treatments ( Atkinson et al., 2001 ). The diagnostic utility of a biomarker is based on its performance against a reference standard ( e.g ., clinical-radiologic diagnostic criteria, histopathological diagnosis) ( Adeniyi et al., 2016 ). A sensitive biomarker is one that yields a positive or abnormal result in a high proportion of individuals who have the disease ( Adeniyi et al., 2016 ). A specific biomarker has a normal or negative result in a high proportion of individuals without the disease ( Adeniyi et al., 2016 ). A diagnostic biomarker should ideally have both high sensitivity and high specificity ( Adeniyi et al., 2016 ). Biomarkers are of interest in the broader biomedical literature because they can offer objective, biologically plausible information about a disease process that may go undetected by a patient ( Strimbu & Tavel, 2010 ). In some cases, biomarker-based findings can precede clinical endpoints throughout the disease’s natural history, leading to earlier diagnosis or signifying a change in the disease course ( Andersen et al., 2021 ). In other cases, biomarker results can help distinguish a disease from other entities, leading to the correct diagnosis and targeted management ( Hayes, 2015 ). In MS, a hypothetical diagnostic biomarker could be valuable to narrow the differential diagnosis in a patient with undifferentiated lesions on neuroimaging, or arrive at an earlier diagnosis in a patient with signs and symptoms suggestive of a demyelinating event ( Bielekova & Martin, 2004 ; Paul, Comabella & Gandhi, 2019 ).

Transcranial magnetic stimulation (TMS) measurements are putative biomarkers for MS diagnosis and monitoring ( Alsharidah et al., 2022 ; Simpson & Macdonell, 2015 ). Briefly, TMS uses a time-varying magnetic field to induce an electric field that is parallel to the surface of the brain ( Siebner et al., 2022 ). Depending on TMS coil architecture and orientation, pulse waveform, and stimulation intensity, the TMS-induced electric field can produce an electric current that preferentially depolarizes myelinated axons of superficial presynaptic layer II/III/V cortical pyramidal neurons in the precentral gyrus ( Rossini et al., 2015 ; Siebner et al., 2022 ; Spampinato et al., 2023 ). The cortical pyramidal neuron action potential activates spinal corticospinal tract axons either directly or via mono- or polysynaptic inputs involving both inter- and intracortical connections ( Kesselheim et al., 2023 ; Siebner et al., 2022 ; Spampinato et al., 2023 ). The corticospinal tract volley leads to activation of the spinal nerves, peripheral nerve(s), and motor units corresponding to the target muscle, eliciting a characteristic deflection in the surface electromyography (EMG) trace—the motor evoked potential (MEP) ( Groppa et al., 2012 ; Rossini et al., 2015 ). The amplitude, latency, morphology, and conditioned responses of MEPs ( Figure 1 ) reflect the activity and function of corticospinal pyramidal neurons and CNS interneurons in relation to motor output ( Table 1 ) ( Groppa et al., 2012 ; Rossini et al., 2015 ; Ziemann et al., 2015 ). Various TMS measures can characterize CNS demyelination, axonal damage, and/or excitotoxicity in MS ( Chen et al., 2008 ; Snow et al., 2019 ; Stampanoni Bassi et al., 2020 ; Vucic et al., 2023 ). For example, CNS demyelination, axonal damage, and excitotoxicity can be detected in the MEP waveform as prolonged MEP onset latency or MEP dispersion, reduced MEP amplitude, and shortened post-MEP corticospinal silent period (CSP), respectively ( Fernández et al., 2013 ; Snow et al., 2019 ; Stampanoni Bassi et al., 2020 ) ( Figure 1 ).

Note:

AMPA, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, ionotropic transmembrane glutamate receptor; EMG, electromyography; GABA, gamma-aminobutyric acid; GABA A , ionotropic GABA receptor and ligand-gated ion (chloride, bicarbonate) channel; GABA B , G-protein ( via potassium channels) coupled metabotropic GABA receptor; MSO, maximum stimulator output; VGSC, voltage-gated sodium channel.

To aid diagnosis, a biomarker should balance the probability that a patient has MS and does not have an alternative diagnosis ( Adeniyi et al., 2016 ; Atkinson et al., 2001 ; Richardson & Wilson, 2015 ). This problem is relevant in MS because the differential diagnosis is broad ( Solomon, 2019 ; Solomon et al., 2023 ; Wildner, Stasiolek & Matysiak, 2020 ) and current diagnostic criteria—the 2017 McDonald criteria ( Thompson et al., 2018 )—are sensitive but not specific ( Filippi et al., 2018 , 2022 ; Gobbin et al., 2019 ; van der Vuurst de Vries et al., 2018 ), resulting in a high rate of misdiagnosis ( Dixon & Robertson, 2018 ; Solomon, 2019 ; Solomon, Naismith & Cross, 2019 ). A biomarker should likewise be reliable and valid; biologically plausible and clinically relevant; and practical and cost-effective ( Adeniyi et al., 2016 ; Atkinson et al., 2001 ; Bielekova & Martin, 2004 ). A previous systematic review of TMS biomarker studies in MS, by this research group ( Snow et al., 2019 ), highlighted cross-sectional relationships between various TMS techniques and MS clinical outcomes. However, the previous review did not directly address the role of TMS in MS diagnosis ( Snow et al., 2019 ). Thus, the current critical narrative review aimed to explore the diagnostic accuracy of TMS techniques in MS.