Abstract
Objective: We employed dual-site TMS to test whether ipsilateral functional premotor-motor connectivity is altered in relapsing-remitting Multiple Sclerosis (RR-MS) and is related to central fatigue.Methods: Twelve patients with RR-MS and 12 healthy controls performed a visually cued Pinch-NoPinch task with their right hand. During the reaction time (RT) period of Pinch and No-Pinch trials, single-site TMS was applied to the left primary motor cortex (M1) or dual-site TMS was applied to the ipsilateral dorsal premotor cortex (PMd) and to M1. We traced context-dependent changes of corticospinal excitability and premotor–motor connectivity by measuring Motor-Evoked Potentials (MEPs) in the right first dorsal interosseus muscle. Central fatigue was evaluated with the Fatigue Scale for Motor and Cognitive Functions (FSMS).Results: In both groups, single-pulse TMS revealed a consistent increase in mean MEP amplitude during the Reaction Time (RT) period relative to a resting condition. Task-related corticospinal facilitation increased toward the end of the RT period in Pinch trials, while it decreased in No-Pinch trials. Again, this modulation of MEP facilitation by trial type was comparable in patients and controls. Dual-site TMS showed no significant effect of a conditioning PMd pulse on ipsilateral corticospinal excitability during the RT period in either group. However, patients showed a trend toward a relative attenuation in functional PMd-M1 connectivity at the end of the RT period in No-Pinch trials, which correlated positively with the severity of motor fatigue (r = 0.69; p = 0.007).Conclusions: Dynamic regulation of corticospinal excitability and ipsilateral PMd-M1 connectivity is preserved in patients with RR-MS. MS-related fatigue scales positively with an attenuation of premotor-to-motor functional connectivity during cued motor inhibition.Significance: The temporal, context-dependent modulation of ipsilateral premotor-motor connectivity, as revealed by dual-site TMS of ipsilateral PMd and M1, constitutes a promising neurophysiological marker of fatigue in MS.
Highlights
Multiple Sclerosis (MS) is the most common autoimmune disorder of the central nervous system (CNS) [1], and its pathology includes both axonal damage and demyelination [2]
Dynamic regulation of corticospinal excitability and ipsilateral dorsal Premotor Cortex (PMd)-Primary Motor Cortex (M1) connectivity is preserved in patients with relapsing-remitting disease course (RR-MS)
- Dynamic modulation of ipsilateral premotor-to-motor cortical drive was probed with Transcranial magnetic stimulation (TMS)
Summary
Multiple Sclerosis (MS) is the most common autoimmune disorder of the central nervous system (CNS) [1], and its pathology includes both axonal damage and demyelination [2]. Paired-pulse TMS, which applies a Abbreviations: CNS, Central Nervous System; CS, Conditioning Stimulus; DMSC, Danish Multiple Sclerosis Centre; dsTMS, dual-site TMS; EDSS, Expanded Disability Status Scale; EMG, Electromyography; FDI, First Dorsal Interosseous; FSMC, Fatigue Scale for Motor and Cognitive Functions; HC, Healthy Controls; ISI, Interstimulus Interval; M1, Primary Motor Cortex; M1HAND, Primary Motor Hand Area; MCV, Maximum Voluntary Contraction; MEP, Motor Evoked Potential; MS, Multiple Sclerosis; PASAT, Paced Auditory Serial Addition Test; PEST, Parameter Estimation in Sequential Test; PMd, dorsal Premotor Cortex; PMd-M1, Premotor-Motor; RMT, Resting Motor Threshold; RR, RelapsingRemitting; RT, Response Time; SD, Standard Error; SDMT, Symbol Digit Modalities Test; SEM, Standard Error of the Mean; SICF, Short Intra Cortical Facilitation; sMRI/fMRI, structural and functional Magnetic Resonance Imaging; TMS, Transcranial Magnetic Stimulation; TS, Test Stimulus
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