Probing Context-Dependent Modulations of Ipsilateral Premotor-Motor Connectivity in Relapsing-Remitting Multiple Sclerosis

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).Ruiu et al. Ipsilateral Premotor-Motor Connectivity in Multiple SclerosisConclusions: 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 premotormotor connectivity, as revealed by dual-site TMS of ipsilateral PMd and M1, constitutes a promising neurophysiological marker of fatigue in MS.

A comprehensive review of transcranial magnetic stimulation in secondary dementia

“…Moreover, longer cSP duration ( Nantes et al, 2016 ) or triple stimulation technique ( Hofstadt-van Oy et al, 2015 ) did not correlate with cognitive performance in relapsing-remitting MS. However, central mechanisms of fatigue, that can, at least in part, play a role in cognitive performances, appeared related to changes in cortical excitability, especially increased interhemispheric inhibition ( Chalah et al, 2018 ) or SICI ( Chalah et al, 2019 ), as well as attenuation of premotor-motor functional connectivity ( Ruiu et al, 2020 ).…”

Mapping grip-force related brain activity after a fatiguing motor task in multiple sclerosis

“…In the non-fatigue state, the lack of pre-movement facilitation correlated with the amount of self-reported fatigue ( Morgante et al, 2011 ). Furthermore, in a former study including a subgroup of subjects participating in the current study, we applied dual site TMS over the ipsilateral dorsal premotor cortex (PMd) and the M1 and found that the self-experienced fatigue scaled positively with an attenuation of premotor-to-motor functional connectivity ( Ruiu et al, 2020 ).…”

The pathophysiology of motor fatigue and fatigability in multiple sclerosis

“…A transcortical magnetic stimulation study in RRMS–patients found an attenuated connectivity between premotor- and primary motorcortex which was significantly correlated with reported motor fatigue. In contrast, corticospinal connectivity was retained ( 31 ).…”