Abstract
Background Novel biomarker discovery and validation are essential to the development and appraisal of emerging therapies for the devastating cerebral neurodegenerative disorder motor neuron disease (MND), the commonest phenotype of which is amyotrophic lateral sclerosis (ALS). MND pathology (and strong genetic risk of MND prior to symptoms) was hypothesised to be manifested by changes in movement-related cortical neuronal β-oscillations. Methods We used magnetoencephalography (MEG) to investigate both symptomatic patients and asymptomatic mutation carriers at risk of developing ALS. MEG data were acquired during a visually cued lateralised motor preparation task that included infrequent movement inhibition trials. Data from 11 patients with ALS, ten with the upper motor neuron-only phenotype primary lateral sclerosis (PLS), and 12 asymptomatic mutation carriers were age-matched against healthy controls. Source-space MEG analysis used a combination of functionally defined voxels of interest and whole brain data to measure β-power before, during, and after movement execution or inhibition. Findings Patients with PLS were slower to respond to targets relative to controls (663 ms [SD 189]vs440 [124], p=0·008), but the task was otherwise comparably performed across groups. Source reconstructed MEG data revealed excessive β-desynchronisation relative to controls in the motor cortices of both patients with ALS (p=0·012) and in asymptomatic mutation carriers (p=0·043). In only those patients with PLS, β-desynchronisation was inadequately lateralised to the contralateral motor cortex during response preparation. Transition to β-rebound was slowed in patients with ALS relative to controls (p=0·028). During successfully performed inhibition trials asymptomatic mutation carrier (p=0·046) groups demonstrated reduced inhibitory β-power relative to controls immediately before their expected response time to GO trials. Interpretation MEG is sensitive to cortical dysfunction in MND through changes in neural β-oscillations related to motor pathology. These abnormalities differ by phenotype, yet may be detectable before the development of overt symptoms in those at genetic risk. Funding Wellcome Trust, Medical Research Council.