Cortical excitability threshold can be increased by the AMPA blocker Perampanel in ALS.

Oskarsson, Björn; Mauricio, Elizabeth A; Shah, Jaimin S; Zhuo, Li; Rogawski, Michael A

INTRODUCTION/AIMS Cortical hyperexcitability is a feature of amyotrophic lateral sclerosis (ALS) and cortical excitability can be measured using transcranial magnetic stimulation (TMS). Resting motor threshold (MT) is a measure of cortical excitability, largely driven by glutamate. Perampanel, a glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker, is predicted to increase the cortical excitability threshold. This study aimed to evaluate TMS tp functionally assess target engagement in a study of perampanel in ALS. METHOD We studied the MT of ALS patients randomized to a single dose of perampanel or placebo 5:1 hourly for 4 hours. Twelve patients participated at 4 mg and 7 returned for dosing and retesting at 8 mg. The study was terminated in April 2020 due to COVID-19-related restrictions, after 7 out of 12 planned patients had received the 8mg dose. Serum concentrations were also measured. RESULTS Ten patients received the 4mg dose (2 received placebo) and 5 received the 8mg dose (2 received placebo). Motor Threshold increased at two hours after dosing in the combined treatment group +7% of maximal stimulator output (MSO) (p<0.01). Change could be detected in the larger 4 mg group (p=0.02), but not in the smaller 8 mg dose group (p=0.1). No side effects were reported after single dose exposure. DISCUSSION This study shows that perampanel effects the physiology of upper motor neurons. Studies aiming at gauging the effect of perampanel on ALS disease progression are already ongoing. Motor threshold may serve as a marker of biological target engagement. This article is protected by copyright. All rights reserved.