Mehdi A J Van den Bos1, Mana Higashihara1, Nimeshan Geevasinga1, Parvathi Menon1, Matthew C Kiernan1, Steve Vucic2. 1. From the Westmead Clinical School (M.A.J.V.d.B., M.H., N.G., P.M., S.V.) and Brain and Mind Center (M.C.K.), University of Sydney, Australia; and Department of Neurology (M.H.), Tokyo Metropolitan Geriatric Hospital, Japan. 2. From the Westmead Clinical School (M.A.J.V.d.B., M.H., N.G., P.M., S.V.) and Brain and Mind Center (M.C.K.), University of Sydney, Australia; and Department of Neurology (M.H.), Tokyo Metropolitan Geriatric Hospital, Japan. steve.vucic@sydney.edu.au.
Abstract
OBJECTIVE: To determine the relative contribution of inhibitory and facilitatory circuits in the development of cortical hyperexcitability in amyotrophic lateral sclerosis (ALS). METHODS: In this cross-sectional study, cortical excitability was assessed in 27 patients with ALS, and results compared to 25 healthy controls. In addition, a novel neurophysiologic measure of cortical function, short-interval intracortical facilitation (SICF), was assessed reflecting activity of the facilitatory circuits. RESULTS: There was a significant increase in SICF (ALS -18.51 ± 1.56%, controls -8.52 ± 1.21%, p < 0.001) in patients with ALS that was accompanied by a reduction of short-interval intracortical inhibition (ALS 3.94 ± 1.29%, controls 14.23 ± 1.18%, p < 0.001) and cortical silent period duration (p = 0.034). The index of excitation, a biomarker reflecting the contribution of inhibitory and facilitatory circuit activity, was significantly increased in patients with ALS (82.79 ± 6.01%) compared to controls (36.15 ± 3.44, p < 0.001), suggesting a shift toward cortical excitation. Increased excitation correlated with upper motor neuron signs (R 2 = 0.235, p = 0.016) and greater functional disability as reflected by a correlation with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score (R 2 = 0.335, p = 0.002). CONCLUSIONS: The present study established that cortical hyperexcitability is a key contributor to ALS pathophysiology, mediated through dysfunction of inhibitory and facilitatory intracortical circuits. Therapies aimed at restoring the cortical inhibitory imbalance provide novel avenues for future therapeutic targets.
OBJECTIVE: To determine the relative contribution of inhibitory and facilitatory circuits in the development of cortical hyperexcitability in amyotrophic lateral sclerosis (ALS). METHODS: In this cross-sectional study, cortical excitability was assessed in 27 patients with ALS, and results compared to 25 healthy controls. In addition, a novel neurophysiologic measure of cortical function, short-interval intracortical facilitation (SICF), was assessed reflecting activity of the facilitatory circuits. RESULTS: There was a significant increase in SICF (ALS -18.51 ± 1.56%, controls -8.52 ± 1.21%, p < 0.001) in patients with ALS that was accompanied by a reduction of short-interval intracortical inhibition (ALS 3.94 ± 1.29%, controls 14.23 ± 1.18%, p < 0.001) and cortical silent period duration (p = 0.034). The index of excitation, a biomarker reflecting the contribution of inhibitory and facilitatory circuit activity, was significantly increased in patients with ALS (82.79 ± 6.01%) compared to controls (36.15 ± 3.44, p < 0.001), suggesting a shift toward cortical excitation. Increased excitation correlated with upper motor neuron signs (R 2 = 0.235, p = 0.016) and greater functional disability as reflected by a correlation with the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score (R 2 = 0.335, p = 0.002). CONCLUSIONS: The present study established that cortical hyperexcitability is a key contributor to ALS pathophysiology, mediated through dysfunction of inhibitory and facilitatory intracortical circuits. Therapies aimed at restoring the cortical inhibitory imbalance provide novel avenues for future therapeutic targets.
Authors: Clara M Bacmeister; Helena J Barr; Crystal R McClain; Michael A Thornton; Dailey Nettles; Cristin G Welle; Ethan G Hughes Journal: Nat Neurosci Date: 2020-05-18 Impact factor: 24.884
Authors: Mehdi A J van den Bos; Nimeshan Geevasinga; Mana Higashihara; Parvathi Menon; Steve Vucic Journal: Int J Mol Sci Date: 2019-06-10 Impact factor: 5.923
Authors: Parvathi Menon; Mana Higashihara; Mehdi van den Bos; Nimeshan Geevasinga; Matthew C Kiernan; Steve Vucic Journal: Ann Clin Transl Neurol Date: 2020-04-18 Impact factor: 4.511