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

Elisa Ruiu; Raffaele Dubbioso; Kristoffer Hougaard Madsen; Olivia Svolgaard; Estelle Raffin; Kasper Winther Andersen; Anke Ninija Karabanov; Hartwig Roman Siebner

doi:10.3389/fneur.2020.00193

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

Front Neurol. 2020 May 5:11:193. doi: 10.3389/fneur.2020.00193. eCollection 2020.

Authors

Elisa Ruiu^{1

2}, Raffaele Dubbioso^{1

3}, Kristoffer Hougaard Madsen^{1

4}, Olivia Svolgaard¹, Estelle Raffin^{1

5}, Kasper Winther Andersen¹, Anke Ninija Karabanov^{1

6}, Hartwig Roman Siebner^{1

7

8}

Affiliations

¹ Danish Research Centre for Magnetic Resonance, Centre for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital Hvidovre, Section 714, Hvidovre, Denmark.
² Department of Neurology, University Hospital of Sassari, Sassari, Italy.
³ Department of Neurosciences, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Naples, Italy.
⁴ Section for Cognitive Systems, Department of Applied Mathematics and Computer Science, Technical University of Denmark, Lyngby, Denmark.
⁵ Brain Mind Institute and Centre of Neuroprosthetics, Swiss Federal Institute of Technology (EPFL), Geneva, Switzerland.
⁶ Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.
⁷ Department of Neurology, Copenhagen University Hospital Bispebjerg, Copenhagen, Denmark.
⁸ Faculty of Medical and Health Sciences, Institute for Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.

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.

Keywords: dorsal premotor cortex; dual-site TMS; fatigue; movement preparation; multiple sclerosis; primary motor cortex.