Reduced beta bursting underpins loss of corticomuscular coherence in amyotrophic lateral sclerosis.

Abstract

Biomarkers of disease activity that holistically capture motor system dysfunction are needed to accelerate drug discovery in amyotrophic lateral sclerosis. Magnetoencephalography is a sensitive, non-invasive measure of cortical neurophysiology. Corticomuscular coherence reflects the functional coupling of cortical oscillations with downstream muscle activity recorded by electromyography. Cortical beta frequency bursting is known to represent a core feature of the neurophysiology underpinning movement. This study aimed to characterize disruption of beta frequency activity in both cortex and muscle to refine the understanding of corticomuscular coherence loss in amyotrophic lateral sclerosis. The study analysed 42 people living with amyotrophic lateral sclerosis and 33 healthy age-matched controls. Participants undertook an isometric hand gripping task during magnetoencephalography. Muscle contraction was measured using bipolar surface electromyography recordings at both forearms. All participants performed 120 trials of the gripper task bilaterally, and 60 trials unilaterally on each side. For each trial type, the mean corticomuscular coherence over trials was calculated for each participant and the groups were compared via cluster-based permutations tests. Beta burst metrics were calculated for the motor cortex (magnetoencephalography) and flexor forearm muscles (surface electromyography) including burst fractional occupancy, burst duration and amplitude. During muscular contraction, beta frequency corticomuscular coherence from the motor cortices contralateral to the gripper task was markedly reduced in amyotrophic lateral sclerosis patients, despite no significant difference in grip strength compared with controls. Source localization analysis showed globally reduced corticomuscular coherence in amyotrophic lateral sclerosis with significant differences in the motor regions contralateral to the engaged hand. There were no significant beta frequency activity changes in the engaged-hand electromyography signal in amyotrophic lateral sclerosis compared with controls. In contrast, analysis of the cortical motor regions revealed reduced rate of beta bursting and higher amplitude during the contraction phase of the task in amyotrophic lateral sclerosis. The corticomuscular coherence disruption in amyotrophic lateral sclerosis appears driven more by cerebral pathology than by muscle denervation. Equal grip strength during the task implies compensatory pathways in disease that are not captured by corticomuscular coherence. Interneuronal dysfunction may underlie the disruption to motor cortex beta bursting. Motor cortical beta frequency metrics have potential as secondary outcome measures in therapeutic trials and need exploration as prodromal markers in asymptomatic individuals genetically predisposed to amyotrophic lateral sclerosis.