Patients with amyotrophic lateral sclerosis (ALS) have been demonstrated to exhibit hyperexcitability in both the motor cortex and peripheral motor axons; however, the link between central and peripheral excitability has not been fully revealed. In a prospective study, 53 ALS patients and 50 healthy subjects underwent threshold tracking transcranial magnetic stimulation (TMS) and motor nerve excitability testing, and the results were analyzed in relation to compound muscle action potential (CMAP) amplitude and the revised ALS Functional Rating Scale. TMS showed decreased short-interval intracortical inhibition (interstimulus interval 1-7 ms; P<0.001) and a shortened silent period (P<0.05) in ALS patients compared with controls, and testing of median nerve excitability showed increased changes in depolarizing threshold electrotonus (TEd) and greater superexcitability (P<0.0001), both of which were indicative of reduced axonal potassium currents. No major associations were discovered between the 2 types of excitability indices (cortical and peripheral). CMAP amplitude was negatively correlated with changes in TEd (90-100 ms) (R=0.33, P=0.03) and superexcitability (R=−0.36, P=0.01), but not with cortical excitability indices. More rapid motor functional decline was associated with only greater TEd (90–100 ms) (β=0.46, P=0.001). Based on these findings, researchers hypothesize that, in ALS, cortical excitability is continually high independent of the extent of the peripheral burden, but peripheral hyperexcitability was connected with the extent of the peripheral burden and the speed of disease evolution. It was possible that changes in ion channel function were central to the pathogenesis of amyotrophic lateral sclerosis.