The role of the corticomotorneurons in pathogenesis of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative disease of the motor system clinically defined by the presence of upper and lower motor neuron (LMN) signs. The site of onset of pathophysiology within the motor system in ALS remains unresolved and this thesis examines the role of the corticomotor neuron in the pathogenesis of ALS.

The diagnostic utility of the split-hand sign in ALS involving preferential wasting of the ‘thenar’ group of intrinsic hand muscles namely the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) was established by recording the split-hand index (SI) which was noted to reliably differentiate ALS from mimic neuromuscular disorders. The cortical and axonal excitability characteristics of the ‘thenar’ muscles namely the APB and FDI was compared with the hypothenar abductor digiti minimi (ADM) with threshold tracking transcranial magnetic stimulation (TMS) studies revealing cortical hyperexcitability to be a feature of ALS pronounced over the ‘thenar’ muscles while axonal hyperexcitability while a feature of ALS, did not selectively affect the prominently wasted ‘thenar’ muscles. Cortical hyperexcitability was also noted to precede the development of lower motor neuron dysfunction in a clinically and neurophysiologically normal APB muscle. The selective vulnerability of muscles in ALS was further defined by the split hand plus sign with a greater degree of cortical hyperexcitability over the preferentially wasted APB muscle in ALS patients when compared with a similarly innervated and relatively preserved flexor pollicis longus (FPL) muscle.

In summary, corticomotorneuronal hyperexcitability as a marker of corticomotorneuronal dysfunction predominates over the muscles which are preferentially wasted in ALS and precedes evidence of lower motor neuron loss. The findings presented in this thesis support the primacy of the corticomotor neuron in the pathogenesis of the split hand phenomenon and suggest a mechanism for the pathogenesis of ALS.