My research interests are in the understanding of the pathophysiological mechanisms underlying neurodegeneration in amyotrophic lateral sclerosis (ALS). While upper and lower motor neuron signs typical co-exist in ALS, the precise site of onset of ALS and the mechanisms governing the relationship of upper and lower motor neuronal involvement, and thereby neurodegeneration remains an important issue. Clarification of the site of ALS onset has implications for future nerve regeneration projects (e.g. stem cells) that may be considered for ALS. At present, if such therapy were available, there is no consensus as to which level the therapy should be directed – brain, spinal cord or peripheral nerve.
Employing the novel threshold tracking transcranial magnetic stimulation (TMS) technique for assessing cortical excitability that I developed during my PhD thesis at University of New South Wales, we established that cortical hyperexcitability is an early feature in sporadic ALS correlating with axonal degeneration. Separately, I established that the development of cortical hyperexcitability precedes the clinical onset of familial forms of ALS, thereby strongly suggesting that ALS begins in the motor cortex and that the ensuing anterior horn cell degeneration was mediated by glutamate excitotoxicity. The series of manuscript detailing these findings were published in Brain, one of the highest ranking neurology journals and on the back of these studies a clinical drug trial is currently being conducted through the Neuroscience Research Australia (NEURA), on which I am an investigator. Of further relevance, my research has established normal cortical function in asymptomatic superoxide dismutase-1 gene mutation carriers, using a combination of threshold tracking TMS and diffusion tensor imaging techniques, thereby arguing against the need for prophylactic therapy in this group. I have recently been awarded the prestigious W.A.B Brazier award by the International Federation of Clinical Neurophysiology.
In addition to these pathophysiological studies in ALS, my research has also focused on better defining the varied clinical phenotypes of ALS. Utilizing the threshold tracking TMS technique, I established sub-clinical cortical involvement in the flail-arm-variant ALS, thereby suggesting that the flail-arm-variant ALS was unusual phenotype of ALS with prolonged survival. Further, a pure bulbar palsy phenotype of ALS was also identified that was distinguishable form bulbar onset ALS by a relatively normal cortical excitability. Phenotyping these unusual ALS variants will result in better prognostication and more equitable recruitment into different arms of clinical drug trials.
In parallel to studies on ALS patients, I investigated the specificity of cortical hyperexcitability in neuromuscular disorders by assessing a cohort of patients with Kennedy’s disease, a sensorimotor neuronopathy that mimics ALS. I established that cortical hyperexcitability was specific to ALS, thereby providing further support for the excitotoxic theory in ALS and resolving a controversy that cortical dysfunction was evident in Kennedy’s disease. In addition to providing support for the excitotoxic theory, this study suggested that the threshold tracking transcranial magnetic stimulation (TMS) technique was a useful diagnostic technique in the clinical setting. A manuscript detailing these findings was published in Clinical Neurophysiology, the official journal of the International Federation of Clinical Neurophysiology. In addition, the manuscript was the subject of an editorial by Professor Andrew Eisen, one of the world experts and opinion leaders on ALS. Further, I was awarded the prestigious Golseth Young Investigator Award, by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) in October 2007, and the threshold tracking TMS technique was recently short-listed for a “Prize for Life” (March 2009), submitted by NSW innovations.
Of further relevance, I have also investigated the specificity of cortical hyperexcitability in neuromuscular disorders other than Kennedy’s disease, including acquired neuromyotonia and distal hereditary motor neuronopathy with pyramidal features, a disorder previously labeled as ALS type 4. My research established normal cortical excitability in these two disorders, clearly distinguishing ALS from the mimic disorders. In addition to indicating that the threshold tracking TMS technique is of diagnostic utility, these studies lend further support for the excitotoxic theory of ALS.
Currently, I am heading a multicenter study in Australia which aims to further clarify the site of ALS disease onset. Specifically, this project combines diffusion tensor imaging, volumetric MRI studies for determining cortical thickness and sodium coil imaging, along with Bayesian MUNE techniques and quantitative EMG to help clarify site of disease onset.