The original contribution of this thesis is providing evidence that the basal ganglia may mitigate the effect of fatiguability on cognition in multiple sclerosis (MS). Fatigue is one of the most commonly reported symptoms of MS, but studies are inconsistent in establishing its impact on cognition. Moreover, the underlying mechanisms remain poorly understood. This may be due to the subjective nature of self-report measures and difficulty in assessing fatigue objectively. This thesis set out to use an alertness-motor paradigm and MRI to establish how mental fatigue affects cognition in MS. To determine whether this alertness-motor paradigm provides an objective measure of fatiguability and the underlying neural substrates. 40 MS participants and 40 age-matched healthy controls (HC) performed baseline and post-scan neuropsychological attention tests. Participants completed an alertness-motor paradigm, designed to enhance fatiguability, whilst undergoing magnetic resonance imaging (MRI) in a 3 Tesla scanner. Performance on the neuropsychological tests determined whether induced fatigue impacted cognitive performance. Voxel-based morphometry evaluated structural atrophy and neuroanatomical correlates of fatigue and fatiguability. The alertness-motor paradigm assessed the influence of fatiguability on behavioural performance over time. fMRI established the neuronal substrates that underlie this process. A neural connectivity approach investigated whether whole-brain network topology and basal ganglia functional connectivity were altered by fatiguability. The principle findings showed significant atrophy in the basal ganglia and prefrontal cortex of MS group compared to HC. Grey and white matter volume was not significantly correlated with fatigue or fatiguability scores, but the functional activations demonstrated that the basal ganglia (associative loop) may mitigate the impact fatiguability has on cognition. This was supported by consistent increased functional connectivity of the basal ganglia in groups demonstrating no fatiguability. MS was traditionally viewed as a white matter disease, however, the grey matter function may provide a better understanding of disease symptomology.
|Date of Award||7 May 2019|
- The University of Bristol
|Supervisor||Naoki Masuda (Supervisor) & Jade Thai (Supervisor)|