Cortical hyperexcitability evolves with disease progression in ALS

Abstract

Objective: Cortical hyperexcitability has been established as an early feature of amyotrophic lateral sclerosis (ALS). The evolution of cortical hyperexcitability with ALS progression remains to be fully elucidated. This study aims to investigate changes in cortical function in ALS with disease progression. Methods: Cortical function assessed by threshold tracking transcranial magnetic stimulation (TMS) along with clinical phenotyping was prospectively undertaken on 444 patients presenting with suspected ALS (345 ALS; 99 neuromuscular mimics). Disease stage was defined as follows: (1) King's clinical staging system and (2) proportion of disease duration statistically categorized into tertials. Results: Cortical hyperexcitability was evident across all ALS stages, being more prominent in later stages of ALS as indicated by increased motor-evoked potential amplitude (P < 0.05), as well as longer disease duration as reflected by reduced short-interval intracortical inhibition (P < 0.05). Prolonged central motor conduction time was evident with disease progression. These changes were accompanied by reduction in neurophysiological index (P < 0.001) and compound muscle action potential amplitude (P < 0.01), progressive muscle weakness (P < 0.001), and decline in the ALS functional rating scale (P < 0.001). Interpretation: This study established an increase in cortical hyperexcitability with increased disease duration in ALS, mediated by cortical disinhibition and direct increase in corticomotoneuronal excitability.

Aging diminishes interlaminar functional connectivity in the mouse cortical V1 and CA1 hippocampal regions

“…More interestingly, in the CA1 subregion, the average inhibitory yield detected was slightly elevated but insignificant across time for both groups, but excitatory yield was significantly higher in aged animals (Figure 2E-F, p < 0.05, likelihood ratio test). This is consistent with the postulation that neuron hyperexcitability without a compensatory increase in inhibitory activity occurs throughout aging and age-related disease states (Burke & Barnes, 2006; Menon et al, 2020; Small et al, 2011; Targa Dias Anastacio et al, 2022; Wilson et al, 2005).…”

Cortical Excitability as a Prognostic and Phenotypic Stratification Biomarker in Amyotrophic Lateral Sclerosis

“…Patients with the selective or predominant LMN impairment (ie, LMN and flail phenotype) show relatively higher MEP:CMAP ratios and a greater percentage of hyperexcitability values, despite the clinical predominance of LMN signs. This suggests that UMN involvement, albeit subtle, is present even in LMN‐predominant forms, with values comparable to the classic ALS phenotypes, as previously reported 13,37 . In line with our findings, Tankisi et al 20 also demonstrated that cortical hyperexcitability, assessed through reduced SICI, was most pronounced in patients with minimal clinical UMN signs, using threshold‐tracking TMS.…”

“…This suggests that UMN involvement, albeit subtle, is present even in LMN-predominant forms, with values comparable to the classic ALS phenotypes, as previously reported. 13,37 In line with our findings, Tankisi et al 20 also demonstrated that cortical hyperexcitability, assessed through reduced SICI, was most pronounced in patients with minimal clinical UMN signs, using threshold-tracking TMS. These results further support the notion that hyperexcitability is a hallmark of LMN-dominant phenotypes, consistent with our observations based on the MEP:CMAP ratio.…”

Effects of mexiletine on hyperexcitability in sporadic amyotrophic lateral sclerosis: Preliminary findings from a small phase II randomized controlled trial

“…Twenty percent of screened subjects in the current study exhibited cortical inexcitability, similar to that reported in previous studies 12,37,38 . Cortical inexcitability has also been attributed to upper motor neuron degeneration 39 .…”