Project Overview

Rationale: Cortical hyperexcitability has been identified to be a potential driver of ALS pathology leading to excitotoxicity and degeneration of upper motor neurons (UMNs)in the primary motor cortex (M1) and the subsequent degeneration of lower motor neurons (LMNs) in the spinal cord. Transcranial magnetic stimulation (TMS) is a non-invasive neurophysiological technique used to assess cortical function and excitability circuits of the brain. Novel threshold-tracking TMS (TT-TMS) paradigms have provided marked evidence that cortical hyperexcitability in ALS may be due to a combination of increased corticomotor facilitation and inhibitory dysfunction; however, the mechanisms contributing to cortical excitability and its manifestation in ALS clinical phenotypes is poorly understood. Given that TMS as a measurement tool can quantify cortical excitability, associating these neurophysiological parameters with clinical, neuroimaging, and fluid biomarkers of ALS will allow clinicians and researchers to characterize ALS patients via their disease endophenotype for more personalized treatment options and to find more homogenous patient populations to reach clinical trial outcomes.

Objectives & Specific Aims: The over-arching objective of this proposal is to define the phenotypic characteristics of ALS patients with cortical excitability as measured by novel TT-TMS paradigms correlated with clinical measures and multimodal biomarkers, and to identify the optimal parameters in which TT-TMS can be utilized as a neurophysiological biomarker in ALS. This proposal will address the following aims: 1) to establish normative reference values of TT-TMS parameters in a large, multicentre sample for control subjects; 2) to determine the intra-rater and inter-day reliability of TT-TMS parameters in patients with ALS and the patient-specific variability factors contributing to TT-TMS performance as a neurophysiological biomarker in ALS; and 3) to determine the clinical, radiological, and neurofilament profiles associated with cortical hyperexcitability in patients with ALS.

Significance: This project represents the first attempt to comprehensively consolidate threshold-tracking TMS as a validated, neurophysiological biomarker of cortical hyperexcitability in ALS. Not only will this proposal establish the optimal settings and reference values for which to use TT-TMS to assist with the diagnosis of ALS; the unique results will provide the foundation for TT-TMS to be used as a pharmacodynamics biomarker and outcome measure in ALS clinical trials, with validation of neuromodulatory and physiological mechanisms of specific TMS parameters through the addition of MRS neuroimaging correlates. By using TMS paradigms to identify the cortical excitability profile of ALS patients based on disease endophenotype, more homogenous patient populations can be selected for enriched design in ALS clinical trials of promising therapeutics to reduce heterogeneity, optimize the chance to observing a treatment response, and enable TMS to be used as a measurement tool for enhanced brain-directed therapies in ALS paving the way for more diverse and personalized therapies.

Principal Investigator

Liane Phung , Sunnybrook Research Institute

Partners and Donors

ALS Society of Canada