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First-recruited motor units adopt a faster phenotype in amyotrophic lateral sclerosis

Research output: Contribution to journalArticlepeer-review

James Bashford, Thomas Weddell, Aidan Wickham, Raquel Iniesta, Maoqi Chen, Ping Zhou, Emmanuel Drakakis, Martyn Boutelle, Kerry Mills, Christopher Shaw

Original languageEnglish
Pages (from-to)4117-4130
Number of pages14
JournalJournal of Physiology
Volume599
Issue number17
DOIs
Accepted/In press4 Jul 2021
Published1 Sep 2021

Bibliographical note

Funding Information: T. Weddell carried out the work as part of a clinical academic foundation programme. J. Bashford was supported for 14?months by the Sattaripour Charitable Foundation and the Motor Neurone Disease Association (Shaw/Jul15/932-794). Funding for 36?months was provided through the MRC/MNDA Lady Edith Wolfson Clinical Research Training Fellowship (MR/P000983/1). A. Wickham was funded by a PhD studentship in the Engineering and Physical Sciences Research Council's Centre for Doctoral Training in Neurotechnology for Life and Health. R. Iniesta's input represents independent research supported by the NIHR BioResource Centre Maudsley at South London and Maudsley NHS Foundation Trust (SLaM) & Institute?of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London. The views expressed are those of the authors and not necessarily those of the NHS, NIHR, Department of Health or King's College London. We would like to thank all the patients involved in this study for their willingness and determination to participate. We thank TMSi for supplying the amplifier and sensors. Funding Information: T. Weddell carried out the work as part of a clinical academic foundation programme. J. Bashford was supported for 14 months by the Sattaripour Charitable Foundation and the Motor Neurone Disease Association (Shaw/Jul15/932‐794). Funding for 36 months was provided through the MRC/MNDA Lady Edith Wolfson Clinical Research Training Fellowship (MR/P000983/1). A. Wickham was funded by a PhD studentship in the Engineering and Physical Sciences Research Council's Centre for Doctoral Training in Neurotechnology for Life and Health. R. Iniesta's input represents independent research supported by the NIHR BioResource Centre Maudsley at South London and Maudsley NHS Foundation Trust (SLaM) & Institute of Psychiatry, Psychology and Neuroscience (IoPPN), King's College London. The views expressed are those of the authors and not necessarily those of the NHS, NIHR, Department of Health or King's College London. Publisher Copyright: © 2021 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

King's Authors

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with a median survival of three years. We employed serial high-density surface EMG (HDSEMG) to characterise voluntary and ectopic patterns of motor unit (MU) firing at different stages of disease. By distinguishing MU subtypes with variable vulnerability to disease, we aimed to evaluate compensatory neuronal adaptations that accompany disease progression. Twenty patients with ALS and five patients with benign fasciculation syndrome (BFS) underwent 1-7 assessments each. HDSEMG measurements comprised 30 minutes of resting muscle and 1 minute of light voluntary activity from biceps brachii bilaterally. MU decomposition was performed by the progressive FastICA peel-off technique. Inter-spike interval, firing pattern, MU potential area, afterhyperpolarisation duration and muscle fibre conduction velocity were determined. In total, 373 MUs (ALS=287; BFS=86) were identified from 182 recordings. Weak ALS muscles demonstrated a lower mean inter-spike interval (82.7ms) than strong ALS muscles (96.0ms; p=0.00919) and BFS muscles (95.3ms; p=0.0039). Mean MU potential area (area-under-the-curve: 487.5 vs. 98.7μV ms; p<0.0001) and muscle fibre conduction velocity (6.2 vs. 5.1m/s; p=0.0292) were greater in weak ALS muscles than in BFS muscles. Purely fasciculating MUs had a greater mean MU potential area than MUs also under voluntary command (area-under-the-curve: 679.6 vs. 232.4μV ms; p=0.00144). These results suggest that first-recruited MUs develop a faster phenotype in latter stages of ALS, likely driven by the preferential loss of vulnerable fast-twitch motor units. Inhibition of this potentially maladaptive phenotypic drift may protect the longevity of the motor unit pool, stimulating a novel therapeutic avenue.

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