Quantifying the neural pathways of amyotrophic lateral sclerosis: a structural and functional approach

Abstract

The development of amyotrophic lateral sclerosis (ALS) represents a singularly human, progressive neurodegenerative process that mainly affects upper (corticomotor) and lower (spinal cord) motor neurones. The considerable heterogeneity within this motor syndrome has rendered disease mechanisms unclear, and the initial site of disease onset and patterns of spread still remain unanswered. As such, this requires contemporary re-investigation using sensitive measures of disease burden. The aim of the work presented in this thesis was to utilise functional and structural techniques to explore the motor cortex in sporadic ALS patients, and to characterise patterns of central change across each ALS motor phenotypes, linking these findings to clinical and prognostic outcomes. New approaches were developed using threshold tracking transcranial magnetic stimulation (TT-TMS) techniques to probe cortical dysfunction. Both the hand and leg motor regions were analysed, in a novel ‘all-four-limbs’ protocol. A global presence of cortical hyperexcitability was demonstrated across the ALS cohort, which was apparent from both motor regions across each hemisphere. Paralleling these findings, widespread changes of microstructural integrity were also demonstrated using diffusion tensor imaging (DTI), which extended along the length of the CST bilaterally. In addition to the global cortical changes across the ALS brain, focality of cortical dysfunction was also seen in very early disease stages, supporting a discrete point of onset from which progressive motor degeneration may evolve, and rationalising the clinical asymmetrical disease onset site. ‘Inexcitability’ to TMS was also defined for the first time, which revealed a unique clinical profile and reduced survival when present early in disease. These central disease patterns remained relevant across the ALS motor phenotypes, suggesting that these subgroups all exist within one disease continuum, but were significantly worse in the bulbar-onset phenotype. Taken together, the patterns of corticomotoneuronal dysfunction provide cogent neurophysiological grounding for the early presence of cortical dysfunction in the ALS brain, and suggest that differences in cortical disease patterns may be linked to clinical and prognostic outcomes.