Advancing neurophysiological techniques in motor neuron disorders

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that is characterized by progressive loss of central and peripheral motor neurons. Despite extensive efforts, clinical trials have been largely futile, and no effective treatment is available for the overwhelming majority of patients. Developing quantitative biomarkers that support the diagnostic process, that aid prognostic stratification and the detection of target engagement for trials, remains an important aspect of research into motor neuron disorders such as ALS. In this thesis, we aimed to advance our understanding of various neurophysiological techniques’ utility in motor neuron disorders.
Our work demonstrates that a combination of nerve excitability testing and compound muscle action potential (CMAP) scanning based motor unit number estimation (MUNE), may be valuable additions to the arsenal of diagnostic tests for ALS. In multifocal motor neuropathy (MMN), a close mimic of ALS we demonstrated that the CMAP-scan can provide useful measures of motor unit integrity that could improve the monitoring of these patients over time compared to standard clinical and nerve conduction study outcomes. In contrast to these positive results, we found that nerve ultrasound has little utility to differentiate between ALS- and non-ALS patients in a practical clinical setting, with the exception of MMN patients.
An analysis strategy was developed for nerve excitability testing based on pattern-analysis of full recordings. New excitability measurements were based on these patterns, that simplify the interpretation of critical underlying biophysical properties from individual. With this new paradigm, we unveiled a relation between the survival and progression rate of patients and slow-potassium ion-channel gating kinetics. This new measurements also helped to identify a subtle difference in excitability between related asymptomatic carriers and noncarriers of the C9orf72 repeat expansion, the most prevalent ALS-related genetic mutation.
We also explored the role of mathematical modelling tools for improving the utility of neurophysiological recordings. If a priori knowledge on the interaction between a novel drug and neuronal function is available, mathematical nerve models can be fitted on excitability recordings to help to bridge the wide gap between preclinical and clinical studies. This was demonstrated with data from a clinical trial for retigabine (ezogabine). To improve our understanding of the neurodegenerative process in motor neuron disorders, a dynamic muscle model was developed that accurately simulated the electrophysiological effects of neurodegeneration. This model could facilitate the comparison of current- and future MUNE-methods, as an individual’s exact number of motor neurons are not known. Finally, we explored a hybrid neuromechanical-neurophysiological approach relying on a robotic manipulator, that was able to quantify symptoms of upper motor neuron dysfunction.
Developing novel treatments for ALS patients remains a monumental challenge, that will require biomarkers that can aid in various aspects of research, clinical practice and clinical trial design. Altogether, this thesis provides ample insights on how to advance several novel neurophysiological techniques in motor neuron disorders. Especially the nerve excitability test and CMAP-scan, hold promise for assessing the lower motor neuron syndrome in patients with ALS.