Distinct neuronal circuits mediate cortical hyperexcitability in amyotrophic lateral sclerosis.

Abstract

Cortical hyperexcitability is an important pathophysiological mechanism in amyotrophic lateral sclerosis (ALS), reflecting a complex interaction of inhibitory and facilitatory interneuronal processes that evolves in the degenerating brain. The advances in physiological techniques have made it possible to interrogate progressive changes in the motor cortex. Specifically, the direction of transcranial magnetic stimulation (TMS) stimulus within the primary motor cortex can be utilised to influence descending corticospinal volleys and to thereby provide information about distinct interneuronal circuits. Cortical motor function and cognition was assessed in 29 ALS patients with results compared to healthy volunteers. Cortical dysfunction was assessed using threshold-tracking TMS to explore alterations in short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), the index of excitation (IE), and stimulus response (SR) curves using a figure-of-eight coil with the coil oriented relative to the primary motor cortex in a posterior-anterior (PA), lateral-medial (LM), and anterior-posterior (AP) direction. Mean SICI, between interstimulus interval (ISI) of 1-to-7 ms, was significantly reduced in ALS patients compared to healthy controls when assessed with the coil oriented in PA (P = 0.044) and LM (P = 0.005) but not the AP (P = 0.08) directions. A significant correlation between mean SICI oriented in a PA direction and the total Edinburgh Cognitive and Behavioural ALS Screen score (Rho = 0.389, P = 0.037) was evident. In addition, the mean SICF, between ISI 1-to-5 ms, was significantly increased in ALS patients when recorded with TMS coil oriented in PA (P = 0.035) and LM (P < 0.001) directions. In contrast, SICF recorded with TMS coil oriented in the AP direction was comparable between ALS and controls (P = 0.482). The IE was significantly increased in ALS patients when recorded with the TMS coil oriented in PA (P = 0.041) and LM (P = 0.003) directions. In ALS patients, a significant increase in the SR curve gradient was evident compared to controls when recorded with TMS coil oriented in PA (P < 0.001), LM (P < 0.001) and AP (P = 0.002) directions. The present study has established that dysfunction of distinct interneuronal circuits mediates the development of cortical hyperexcitability in ALS. Specifically, complex interplay between inhibitory circuits and facilitatory interneuronal populations, that are preferentially activated by stimulation in posterior-to-anterior or lateral-to-medial directions, promotes cortical hyperexcitability in ALS. Mechanisms that underlie dysfunction of these specific cortical neuronal circuits will enhance understanding of the pathophysiological processes in ALS, with the potential to uncover focussed therapeutic targets.