Cortical Dysfunction in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a degenerative disease of the human motor system with rapid progression and poor prognosis. It is defined clinically by the presence of concurrent upper and lower motor neurone signs.

While the diagnostic utility of neurophysiological biomarkers of upper and lower motor neurone dysfunction are well established, the understanding of the pathophysiological mechanisms remains incompletely understood.

Specifically, the split hand index offers an accessible and robust diagnostic measure of the prototypical dissociated muscle atrophy pattern of ALS, the split hand sign. However, compound muscle action potential amplitude (CMAP) does not capture the extent of lower motor neurone loss. The diagnostic utility of the split hand index derived from motor unit number index and motor unit number estimation as comparable to CMAP amplitude and enhances the understanding of lower motor neurone dysfunction in ALS. In additional, the recently split elbow phenomenon was quantified, and the novel split elbow index developed. The split elbow index is a specific feature of ALS.

A complex interaction of inhibitory and facilitatory interneuronal processes may underlie development of cortical excitability in the human motor cortex. The direction of transcranial magnetic stimulation (TMS) relative to the motor cortex alters the resultant corticomotoneuronal output and is modulated by recruitment of different interneuronal populations. The dysfunction of distinct inhibitory interneuronal populations, with a posterior-anterior (PA) and latero-medial (LM cortical orientation, contributed to SICI reduction and thereby disinhibition in ALS.

Upregulation of persistent Na+ conductance and reduced K+ currents have been reported in cultured cortical motor neurons mouse models, resulting in neuronal hyperexcitability, and increased neuronal firing frequency. The reduction of cortical stimulation strength duration time constant is prominent in early ALS.