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Cortical and Spinal Connectivity of Motor Units as a novel biomarker of Amyotrophic Lateral Sclerosis pathology

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative condition characterised by motor neuron death and a progressive loss of muscle control. One of the most important steps in confirming ALS is the detection of abnormal firing patterns in motor units (MUs) within a muscle. These recordings, however, are an insensitive, semi-quantitative sign of neuronal degeneration and as much as 50-80% of motor units may be lost before weakness is clinically apparent. This study will use high density surface electromyography (HD-sEMG) technology to develop methodology that can sensitively monitor MU degeneration and detect early abnormalities in the connections between the brain and motor units. Concurrent recordings of HD-sEMG and electroencephalography (EEG) will be used to examine both spinal (MU-MU) and corticospinal (EEG-MU) functional connectivity. Abnormal brain connectivity in ALS has been previously established in a large-scale EEG study, and the proposed study will provide a novel layer of information on the connection between the brain and individual MUs. This combined assessment of upper and lower motor neuron function will increase the likelihood of detecting early degenerative changes within the motor network. MU connectivity patterns will present a more complete profile of cortico-spinal network connectivity than is available using existing methods and will reveal new insights into the heterogeneous degenerative process affecting different MU categories. The study will assess whether these quantitative measures of brain-muscle connection can provide markers to identify the earliest point of disease onset (diagnostic biomarkers). It will also determine whether ALS subgroups can be separated based on individual connectivity patterns (stratification biomarkers). The final aim is to evaluate these measures as biomarkers of disease progression. With the advent of new ALS clinical trials, there is an urgent need for biomarkers that can rapidly establish a diagnosis and provide quantitative outcome measures to objectively assess therapeutic effects.