Impairments of Neuro-muscular Communication in Motor-Neuron Disease: A Bio-Marker for Early and Personalised Diagnosis

Amyotrophic Laterals Sclerosis (ALS) or Motor Neuron Disease (MND) is a terminal neurodegenerative disease, that leads to progressive loss of motor function. Treatment of ALS remains an unresolved challenge and despite intensive research, diagnosis and therapy are not yet adequately personalised . New therapeutics and the quality of care after diagnosis can be enhanced by early diagnosis at the individual patient level, enabling tailored care and individualised treatment.

To personalise the diagnosis, there is a need for reliable quantitative biomarkers, for early detection of disease onset and to distinguish the different sub-types of the disease. Specifically, several biomarkers have been investigated for use in ALS, including Motor Unit Number Estimation (MUNE), Motor Unit Number Index (MUNIX), Cortical Excitability in Transcranial Magnetic Stimulation (TMS), EMG Inter-muscular Coherence, Magnetic Resonance (MR) and other imaging techniques, and EEG signatures. However, the diagnostic utility of these techniques, especially the inexpensive non-invasive recordings of electrical muscle activity - bipolar or high-density surface electromyography (sEMG), and electrical brain activity -surface electroencephalography (sEEG)-, is limited: the biomarkers are not strongly linked to the neurophysiological mechanisms affected in ALS.

The human motor system encompasses 2 sub-systems: the α motor system directly innervates the motor neurons and spinal interneurons and the γ system that modulates the sensors of the muscles' feedback reflex loops to indirectly contribute to muscle activations. These 2 systems form a neuromuscular communication and control network, through which neural signals are communicated to and from muscles for coordinated movement. In ALS, there is a disruption of the function of both upper and lower motor neurons. In the lower motor neurons, the degeneration of the α-motor system starts prior to the γ-system, thus changing the relative contribution of the α and γ system which distorts the patterns of neuromuscular communication in movements. It is therefore of interest to distinguish and dissociate the electrophysiological signatures that reflect sensorimotor network communication patterns pertaining to each sub-system in function and dysfunction, which in turn can act as biomarkers. In specific subgroups of ALS, i.e. Primary Lateral Sclerosis (PLS) and Progressive Muscle Atrophy (PMA) - there is selective degeneration of the upper or lower motor neurons respectively. Therefore, more specific changes in network communication patterns are to be expected.

To analyse the cybernetic characteristics (communication, control, and information transfer), electrophysiological signals need to be analysed from several points of the neuromuscular system as an interconnected network. This can be achieved by joint recording and advanced analysis of co-variability of patterns in the EMG/EEG, e.g. (directional) cortico-muscular coherence and directional network influences, during functional motor tasks. It is hypothesised that neuromuscular communication measures based on both EEG and EMG (indicators of pathophysiological change, measured as a network) better reflect ALS onset and subtypes than measures based on either EEG or EMG in isolation (indicators of structural change, measured at nodes).

Successful discrimination of the electrophysiological signatures can be used to diagnose ALS which may be also useful in terms of better patient care and the development of novel neuro-motor rehabilitation.