Fatigue and activity dependent changes in axonal excitability in ALS

Abstract

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 a MVC of abductor pollicis brevis in 16 ALS patients and 25 controls.

Results: In ALS patients, 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 compound muscle action potential amplitude 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 hyperpolarization. The increase in threshold was more pronounced in ALS patients 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.