Failure of Facilitation as a Biomarker in ALS - Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressing, neuromotor disease characterized by degeneration of upper (UMN) and lower motor neurons (LMN) affecting ~6/100,000 people in the US. ALS cases are projected to rise 69% globally (∼222K in 2015 to ∼376K in 2040). Most individuals with ALS die within 3-5 years of diagnosis, and as many as one third die within the first year. Yet, the time from onset of ALS symptoms to receive a diagnosis generally ranges from 8-15 months further crippling an individual’s quality of life, ability to plan, and treatment options in the already short time that remains. Finding a robust and reliable biomarker of corticospinal dysfunction in ALS is of paramount importance to improve diagnostic certainty at earlier stages, manage disease heterogeneity, track disease progression, improve patient stratification, and evaluate efficacy in clinical trials. Transcranial magnetic stimulation (TMS) is an effective tool to assess the functional integrity of UMN and LMN by measuring the degree of corticospinal drive – a measure called facilitation. Because the corticospinal system degenerates in ALS, the same tool can be used to quantify the degree of Failure of Facilitation as an indicator of the disease, paving the way for future studies to use this as an early biomarker of disease onset. In Aim 1 of the proposed project, we will test two key hypotheses in healthy individuals about the underlying relationship between facilitation in the corticospinal system and behavior. Then in Aim 2 of the proposed project, we will test whether individuals with ALS exhibit Failure of Facilitation, compared to those who are healthy or have an ALS mimic disorder, and whether the degree of Failure of Facilitation relates to the severity of the disease assessed with standard clinical batteries and neurophysiological tests of UMN dysfunction. This project will have significant scientific and clinical impact by advancing our understanding of the neural mechanisms for motor facilitation for voluntary force generation and providing an initial proof of concept that failure of facilitation is a useful biomarker of UMN dysfunction and disease progression in ALS.
