Dawn Wallace Fellowship
Hyperexcitability of motor neurons in Motor Neurone Disease
Dr James Howells
The University of Sydney

Project Summary:

Motor neurone disease (MND) is a universally fatal neurodegenerative disease with no known cure. More than 2000 people in Australia are affected by motor neurone disease with an average life expectancy of 2.5 years.

Classical amyotrophic lateral sclerosis (ALS) accounts for some 80% of MND sufferers, and a clinically definite diagnosis requires progression of symptoms in the upper motor neurons (nerve cells in the motor cortex of the brain) and lower motor neurons (nerve cells in the spinal cord) of several body regions.

Diagnosis of ALS is delayed because there is no good biomarker for the disease and diagnosis requires the exclusion of all other mimics. The time from onset to confirmation of diagnosis has stubbornly remained around 12 months for the last 20 years. This diagnostic delay represents nearly half of the total disease duration and this prevents early intervention.

It has been argued that motor neuron disease begins in the upper motor neuron in the brain, but it can be very difficult to demonstrate early upper motor neuron dysfunction clinically. Over the past decade, we have undertaken research on a non-invasive technique for assessing the excitability of the brain using transcranial magnetic stimulation, and have presented evidence that measurements of cortical excitability may provide a sensitive and specific biomarker of ALS. A robust marker of upper motor neuron dysfunction is also essential for clinical trials of new treatments that are in the pipeline.

The primary objective of this fellowship is to translate this research into a clinical tool for measuring cortical excitability in motor neurone disease. In support of this goal I intend to: further research looking at patterns of progression by correlating cortical excitability to clinical deficits; and quantifying the variability and minimum detectable changes in healthy controls and MND cohorts. I will also examine mechanisms of lower motor neuron degeneration which may be compensatory or secondary to the primary insult, but nonetheless contribute greatly to the patient’s disability.