The puzzling case of hyperexcitability in amyotrophic lateral sclerosis

Abstract

The development of hyperexcitability in amyotrophic lateral sclerosis (ALS) is a well-known phenomenon. Despite controversy as to the underlying mechanisms, cortical hyperexcitability appears to be closely related to the interplay between excitatory corticomotoneurons and inhibitory interneurons. Hyperexcitability is not a static phenomenon but rather shows a pattern of progression in a spatiotemporal aspect. Cortical hyperexcitability may serve as a trigger to the development of anterior horn cell degeneration through a 'dying forward' process. Hyperexcitability appears to develop during the early disease stages and gradually disappears in the advanced stages of the disease, linked to the destruction of corticomotorneuronal pathways. As such, a more precise interpretation of these unique processes may provide new insight regarding the pathophysiology of ALS and its clinical features. Recently developed technologies such as threshold tracking transcranial magnetic stimulation and automated nerve excitability tests have provided some clues about underlying pathophysiological processes linked to hyperexcitability. Additionally, these novel techniques have enabled clinicians to use the specific finding of hyperexcitability as a useful diagnostic biomarker, enabling clarification of various ALS-mimic syndromes, and the prediction of disease development in pre-symptomatic carriers of familial ALS. In terms of nerve excitability tests for peripheral nerves, an increase in persistent Na(+) conductances has been identified as a major determinant of peripheral hyperexcitability in ALS, inversely correlated with the survival in ALS. As such, the present Review will focus primarily on the puzzling theory of hyperexcitability in ALS and summarize clinical and pathophysiological implications for current and future ALS research.

Keywords: amyotrophic lateral sclerosis; corticomotoneuron; gamma-aminobutyric acid; hyperexcitability; interneuron.

Fig. 1

Threshold tracking transcranial magnetic stimulation (TT-TMS) protocol to identify the cortical excitability. The dashed horizontal line represents the target output of 0.2 mV (peak to peak) which was "tracked". The circles (clear and filled) represent the magnitude of the motor evoked potential (MEP) amplitude with each stimulus (A). Illustrated three MEP responses of different amplitude track are tracked. The MEP response is initially larger (a), then smaller (b), and again larger (c) than the target output of 0.2 mV in three consecutive stimuli (B) (permission from John Wiley and Sons).

Fig. 2

Short interval intracortical inhibition in fALS and sALS. SICI is decreased in patients who are clinically affected with fALS, who express a mutation in SOD1, and in patients with sALS in comparison to healthy controls. Modified from Vucic et al. (permission from Oxford University Press). fALS: familial amyotrophic lateral sclerosis, sALS: sporadic amyotrophic lateral sclerosis, SICI: short-inhibitory cortical interval, SOD1: superoxide dismutase type 1.

Fig. 3

Grand-averaged data of multiple excitability measurements in patients with ALS (n=58; filled circle) and in age-matched normal subjects (n=25; open circle). In Stimulus-Response Curve, left curves were obtained by stimulus duration=1.0 ms; right curves were obtained by stimulus duration=0.2 ms. Each plot denotes various parameters of axonal excitability: stimulation-response curve (A), strength-duration time constant (B), threshold electrotonus (C), current/threshold relationship (D), recovery cycle (E). Error bars indicate SEM (permission from Oxford University Press). ALS: amyotrophic lateral sclerosis, SEM: standard error mean.