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.