Background Previous studies have shown that patients with amyotrophic lateral sclerosis (ALS) have hyperexcitability in both the motor cortex and peripheral motor axons, but the relationship between central and peripheral excitability has not been fully disclosed.
Methods Threshold tracking transcranial magnetic stimulation (TMS) and motor nerve excitability testing were prospectively performed in 53 patients with ALS and 50 healthy subjects, and their relations to compound muscle action potential (CMAP) amplitude and revised ALS Functional Rating Scale were cross-sectionally analysed.
Results Compared with controls, patients with ALS showed both cortical and peripheral hyperexcitability; TMS showed reduced short-interval intracortical inhibition (interstimulus interval 1–7 ms) (p<0.001) and shortened silent period (p<0.05), and median nerve excitability testing revealed greater changes in depolarising threshold electrotonus (TEd) and greater superexcitability (p<0.0001, both), suggesting reduced axonal potassium currents. Significant correlations between cortical and peripheral excitability indices were not found. Greater changes in TEd (90–100 ms) (R=−0.33, p=0.03) and superexcitability (R=0.36, p=0.01) were associated with smaller amplitude of CMAP, whereas cortical excitability indices had no correlation with CMAP amplitude. More rapid motor functional decline was associated with only greater TEd (90–100 ms) (β=0.46, p=0.001).
Conclusions Our results suggest that in ALS, cortical excitability is continuously high regardless of the extent of the peripheral burden, but peripheral hyperexcitability is associated with the extent of the peripheral burden and disease evolution speed. Alterations of ion channel function may play an important role in ALS pathophysiology.
- MOTOR NEURON DISEASE
- MAGNETIC STIMULATION
Data availability statement
All data relevant to the study are included in the article or uploaded as supplemental information.
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Contributors Y-IS, KS and SK designed the study. Y-IS, KS, SM, TS, AT, YK, KN, HK, MP, YA, RO and MM collected clinical and neurophysiological data. KS accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish. Y-IS, KS and SK drafted the manuscript. Y-IS performed statistical analyses. SK supervised this study.
Funding Y-IS (#19K17000), KS (#20K07754), SM (#19K07955) and TS (#20K16594) receive research support from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. SK receives research support from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (#20K07898), and Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, the Ministry of Health, Labour and Welfare of Japan. This work was partially supported by Grants-in Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labour and Welfare Sciences Research Grants, the Ministry of Health, Labour and Welfare, Japan.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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