Axonal Excitability in Amyotrophic Lateral Sclerosis

Abstract

Axonal excitability testing provides in vivo assessment of axonal ion channel function and membrane potential. Excitability techniques have provided insights into the pathophysiological mechanisms underlying the development of neurodegeneration and clinical features of amyotrophic lateral sclerosis (ALS) and related neuromuscular disorders. Specifically, abnormalities of Na and K conductances contribute to development of membrane hyperexcitability in ALS, thereby leading to symptom generation of muscle cramps and fasciculations, in addition to promoting a neurodegenerative cascade via Ca-mediated processes. Modulation of axonal ion channel function in ALS has resulted in significant symptomatic improvement that has been accompanied by stabilization of axonal excitability parameters. Separately, axonal ion channel dysfunction evolves with disease progression and correlates with survival, thereby serving as a potential therapeutic biomarker in ALS. The present review provides an overview of axonal excitability techniques and the physiological mechanisms underlying membrane excitability, with a focus on the role of axonal ion channel dysfunction in motor neuron disease and related neuromuscular diseases.

Acute Effects of Riluzole and Retigabine on Axonal Excitability in Patients With Amyotrophic Lateral Sclerosis: A Randomized, Double‐Blind, Placebo‐Controlled, Crossover Trial

“…In ALS, it showed evidence of increased persistent sodium-conductance and reduced potassium-conductance, both of which may contribute to axonal hyperexcitability and fasciculation. [2][3][4][5][6] Furthermore, the presence of increased persistent sodium-conductance was shown to be correlated with more rapid functional decline and shorter survival, 7,8 and the presence of fasciculation with shorter survival. 9 Because increased membrane excitability in ALS may be a relevant step in the cascade leading to structural damage of motor neurons, 10 early identification of hyperexcitable motor neurons may provide an argument for initiating neuroprotective intervention.…”

“…Excitability testing is a neurophysiological tool that allows noninvasive assessment of axolemmal voltage‐gated ion‐channel activity in motor axons of a peripheral nerve. In ALS, it showed evidence of increased persistent sodium‐conductance and reduced potassium‐conductance, both of which may contribute to axonal hyperexcitability and fasciculation . Furthermore, the presence of increased persistent sodium‐conductance was shown to be correlated with more rapid functional decline and shorter survival, and the presence of fasciculation with shorter survival .…”

In vivo evidence for reduced ion channel expression in motor axons of patients with amyotrophic lateral sclerosis

“…; Park et al . ). Using axonal excitability, an early study found evidence for a reduction in K + conductances in patients with ALS, and this was reproduced in the rat in vitro using the K + channel blockers tetraethylammonium and 4‐aminopyridine (Bostock et al .…”

“…These studies put a focus on axonal ion channels as a source of abnormality, clinical features and potentially novel therapies (Park et al . , ).…”

An Appraisal of Novel Biomarkers for Evaluating and Monitoring Neurologic Diseases: Editorial Introduction

“…Intramembrane processes such as ionconductance channels can be studied using a technique developed for use in humans as an extension of the threshold electrotonus technique developed by Hugh Bostock. These methods can specifically evaluate axonal excitability changes owing to alterations in slow and fast conductance channels specific to a variety of ions, and have shown abnormalities in ALS, diabetic neuropathy, and other peripheral nerve processes [11]. Given that abnormal excitability in axons and cell bodies has been suggested to be important in ALS, these techniques are currently being utilized in several clinical trials studying drugs expected to affect ion channels.…”