Cortical hyperexcitability precedes lower motor neuron dysfunction in ALS

•Cortical hyperexcitability appears to develop prior to onset of lower motor neuron dysfunction in amyotrophic lateral sclerosis (ALS).•Cortical hyperexcitability is intrinsic to ALS.•Cortical hyperexcitability may be the primary event in ALS, suggesting a cortical origin of the disease.

ObjectiveTo determine whether cortical hyperexcitability preceded the development of lower motor neuron (LMN) dysfunction in sporadic amyotrophic lateral sclerosis (ALS).MethodsCortical excitability studies were undertaken in 24 ALS patients with motor evoked potential (MEP) recorded over the abductor pollicis brevis (APB) muscle. In the same sitting, LMN function of the target APB muscle was assessed utilising qualitative and quantitative electromyography techniques along with axonal excitability studies.ResultsAt time of assessment, the anatomical and functional integrity of the lower motor neuronal circuits innervating the target APB muscle was preserved in all patients, confirmed by a normal CMAP amplitude (P = 0.37), absence of fasciculations, or features of neurogenic change. Despite this apparent ‘normality’ cortical dysfunction was evident, with significant reduction of short interval intracortical inhibition (P < 0.01), resting motor threshold (P < 0.05) and cortical silent period duration (P < 0.001), along with increases in MEP amplitude (P < 0.05) and intracortical facilitation (P < 0.05).ConclusionThe findings in the present study suggest that cortical hyperexcitability occurs upstream to a seemingly intact lower motor neuronal system.SignificanceCorticomotoneuronal dysfunction appears to be a primary event in ALS, suggesting a cortical origin of the disease.