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Fatigue and activity dependent changes in axonal excitability in amyotrophic lateral sclerosis

Steve Vucic, Arun V Krishnan and Matthew C Kiernan

Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University of New South Wales, Randwick, Australia

Correspondence to:
Associate Professor Matthew C Kiernan, Prince of Wales Medical Research Institute, Barker Street, Randwick, Sydney, NSW 2031, Australia; M.kiernan{at}unsw.edu.au

Background: While patients with amyotrophic lateral sclerosis (ALS) may complain of fatigue, the underlying mechanisms appear complex, with dysfunction of central and peripheral nervous systems independently reported as contributing factors. The aim of the present study was to further delineate the mechanisms underlying increased fatigability in ALS by measuring activity dependent changes in axonal excitability following a maximum voluntary contraction (MVC).

Methods: Nerve excitability changes were recorded before and after an MVC of the abductor pollicis brevis in 16 patients with ALS and 25 controls.

Results: In patients with ALS, there was a greater increase in threshold (36.5 (5.9)%; controls 19.6 (3.5)%; p<0.05) as a result of MVC, with reduction in the amplitude of the compound muscle action potential generated by a submaximal stimulus (ALS 49 (7.6)%; controls 41.0 (5.4)%). These changes were associated with an increase in superexcitability (ALS 65.1 (25.4)%; controls 42.3 (5.7)%) and reduction in strength–duration time constant (ALS 20 (4.9)%; controls 10 (2.5)%; p<0.01), indicative of axonal hyperpolarisation. The increase in threshold was more pronounced in patients with ALS with predominantly lower motor neuronal involvement.

Conclusions: Higher firing rates of surviving motor axons attempting to compensate for neurogenic weakness are likely to explain the greater activity dependent changes in ALS. As such, the present study suggests a further peripheral factor underlying the development of fatigue in ALS.

Abbreviations: ALS, amyotrophic lateral sclerosis; ALSFRS-R, amyotrophic lateral sclerosis functional rating scale-revised; APB, abductor pollicis brevis; CMAP, compound muscle action potential; ECC, excitation contraction coupling; MFI, multidimensional fatigue inventory; MVC, maximum voluntary contraction; _SD, strength duration time constant; UMN, upper motor neurone

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