Cortical hyperexcitability in amyotrophic lateral sclerosis: from pathogenesis to diagnosis

Abstract

Purpose of review Identification of upper motor neuron involvement remains a critical component of a diagnosis of amyotrophic lateral sclerosis (ALS), although supportive clinical signs are often not easily appreciated, particularly in the early symptomatic stages of the disease. Although diagnostic criteria have been developed to facilitate improved detection of lower motor neuron impairment through electrophysiological features that have improved diagnostic sensitivity, assessment of upper motor neuron involvement remains problematic. Recent findings Recent evidence has emerged about pathophysiological processes, particularly glutamate-mediated excitotoxicity, which has resulted in the development of novel diagnostic investigations and uncovered potential therapeutic targets. Advances in genetics, including the C9orf72 gene, have changed concepts of ALS, from being classified as a neuromuscular disease to a disease that forms a continuum with other primary neurodegenerative disorders, particularly frontotemporal dementia. Transcranial magnetic stimulation has been utilized to provide pathophysiological insights, leading to the development of diagnostic and therapeutic biomarkers, which are now being introduced into the clinical setting. Summary Specifically, the advent of cortical hyperexcitability has been consistently identified as an early and intrinsic feature of ALS. With greater accessibility of TMS techniques promoting clinical utilization, TMS measures of cortical function may develop as a diagnostic biomarker, with further potential utility in the clinical trial setting for monitoring of neuroprotective and genetic-based therapies.

Hyperexcitability of the asymptomatic motor cortex in a case of Mills' syndrome

“…Cortical inexcitability is a well-documented finding in PLS (and late-stage ALS), while cortical hyperexcitability is found in both presymptomatic and early symptomatic ALS, as well as in pure lower motor neurone variants. 7 We note the Newcastle group demonstrated coherence changes in the asymptomatic limb, also supporting subclinical motor cortex dysfunction in the clinically normal hemisphere. 2 Thus, we cannot exclude the possibility that our case, like others previously reported and more classic PLS, will eventually progress to ALS.…”

Intranasal neuropeptide Y1 receptor antagonism improves motor deficits in symptomatic SOD1 ALS mice

“…In ALS, an imbalance between cortical excitation and inhibition has been identified in the motor cortex of animal models, 42 including the SOD1 G93A model, 35,65 and in both sporadic and familial ALS patient cohorts 12,62,66 . This imbalance underlies cortical hyperexcitability and is hypothesised to contribute to the disease pathogenesis through overactivation and excitotoxic damage to motor neurons 13,14,67 . It is therefore plausible that the increased levels of NPY in the ALS motor cortex, influence the electrophysiological properties and function of the cortical motor pathways in ALS.…”

History of ALS and the competing theories on pathogenesis: IFCN handbook chapter

“…Using TMS, to measure the ipsilateral silent period, it has been shown that loss of callosal inhibition is a sensitive and early marker of disease activity in ALS ( Hübers et al, 2021 ). CC hyperexcitability in early stages of disease might explain how TDP-43 aggregation spreads from one hemisphere to another ( Hübers et al, 2021 , Timmins et al, 2023 ). A reduction of transcallosal inhibition is associated with features indicative of cortical hyperexcitability, including reduction of short interval intracortical inhibition and increased in short interval intracortical facilitation.…”

“…A reduction of transcallosal inhibition is associated with features indicative of cortical hyperexcitability, including reduction of short interval intracortical inhibition and increased in short interval intracortical facilitation. Reduction in transcallosal inhibition is also correlated with the rate of disease progression ( Timmins et al, 2023 , van den Bos et al, 2021 ).…”