New Forms of ALS/MND Defined by Mutations in New Genes

Abstract

Increased cortical excitability, as measured by reduction in short interval intracortical inhibition (SICI), has been reported in amyotrophic lateral sclerosis (ALS). Short interval intracortical inhibition is mediated by GABAA secreting intracortical interneuronal pathways. In ALS, two potential mechanisms have been proposed to underlie this reduction in SICI; reduced intracortical inhibition secondary to degeneration of intracortical neurons; and excessive excitation due to a reduction in threshold of excitatory pathways. If reduced SICI resulted fromreduced inhibition, then the extent of SICI reduction across a range of conditioning stimulus intensities should be similar (and remain significantly different to controls). Alternatively, if reduction in threshold of intracortical excitatory pathways was solely responsible for the reduction of SICI, then inhibition should only be reduced with higher conditioning stimulus intensities. Determining the mechanisms underlying SICI reduction in ALS is of diagnostic and therapeutic significance. Consequently, novel paired-pulse threshold tracking techniques were used to assess the pathophysiological mechanisms underlying SICI reduction in ALS, and specifically, whether the reduction of SICI represented reduced inhibition, or excessive excitation. Cortical excitability studies were undertaken in 12 ALS patients, using a 90mm circular coil, and results were compared to 13 normal controls. Short interval intracortical inhibition was assessed at three different conditioning stimulus (CS) intensities set to 40%, 70% and 90% of resting motor threshold (RMT). Motor evoked potentials were recorded over the abductor pollicis brevis muscle. With the conditioning stimulus set to 70% RMT, SICI was significantly reduced in ALS patients when compared to controls (averaged SICI ALS, 0.3 ± 2.9%; averaged SICI controls 13.0 ± 2.0%, P < 0.001). In addition, SICI was significantly reduced in ALS patients when the conditioning stimulus was set to 40% of resting motor threshold (averaged SICI ALS, -0.7 ± 0.7%; averaged SICI controls1.3 ± 1.8%, P < 0.05) and 90% of restingmotor threshold (averaged SICI ALS, -16.6 ± 4.1%; averaged SICI controls 1.3 ± 5.0%, P < 0.01). The reduction in SICIwas accompaniedbya significant increase in theMEP amplitude (P < 0.05). Together, these findings suggest that the reduction of short interval intracortical inhibition in ALS, and thereby the development of cortical hyperexcitability, representing loss of cortical inhibition, possibly mediated by degeneration of GABAA secreting intracortical interneurons. Neuroprotective treatments preserving the structural and functional integrity ofGABAA secreting intracortical interneurons may provide novel therapeutic targets in ALS.