Activity‐dependent conduction failure: molecular insights

Weakness and fatigue are commonly encountered symptoms in neurological disorders and significantly impair quality of life. In the case of motor axons, conduction block contributes to weakness and fatigue and may be associated with aberrant nerve activity including fasciculations and cramp. These symptoms result from dysfunction of the constituent channels and pumps of the axonal membrane. In critically conducting axons, impulse conduction can be impaired by the effects of activity or by other mechanisms that produce a significant shift in membrane potential. Conduction failure may be accentuated or relieved by maneuvers that manipulate the time course of the driving current, including the administration of agents that interfere with Na+ channel function. In patients with inflammatory neuropathies, normal activity may be sufficient to precipitate conduction failure at sites of impaired function in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). From a clinical perspective, these features are not assessed adequately by conventional neurophysiological techniques. As weakness and fatigue may only develop following activity or exertion, it is useful to assess the effects of impulse trains to determine the extent of conduction failure and the resulting symptoms in neurological patients. These techniques and the physiological mechanisms underlying the development of activity‐dependent hyperpolarization will be critically appraised in this review, with a focus on demyelinating neuropathies, MMN and the neurodegenerative disease, and amyotrophic lateral sclerosis (ALS).