Abstract
Multiple sclerosis (MS) is a chronic neurological condition characterised by demyelination and nerve fibre dysregulation. Fatigue, a debilitating symptom affecting over 75% of individuals with MS, remains poorly understood due to its complexity, temporal nature, inconsistent terminology and heterogeneous presentation. This thesis investigated exercise-induced fatigue in people with MS (pwMS) through a comprehensive multi-modal approach combining transcranial magnetic stimulation (TMS), advanced imaging techniques (MRI), neuromuscular and perceptual assessments across four experimental studies. Importantly, perceived fatigue was measured at a trait and state level. The exercise protocol consisted of a 3-min all-out, followed by a submaximal wrist extension.First, this two-bout exercise protocol was found feasible and reliable in healthy controls. The reliability of TMS measures to assess corticospinal integrity was confirmed for motor evoked potential amplitude but voluntary activation demonstrated poor reliability and was not reported in subsequent studies. Three studies compared pwMS (n = 22) to matched controls (n = 22), investigating the exercise protocol's effect on state perceived fatigue, effort, neuromuscular fatigue, corticospinal excitability/inhibition, and anterior cingulate cortex (ACC) metabolite concentrations. Trait and state perceived fatigue were elevated at baseline and muscle strength was reduced at rest in pwMS. The submaximal extension heightened their perceived effort and state fatigue; however, no significant group differences were observed for neuromuscular fatigability. Next, baseline impairments were identified in corticospinal excitability and inhibition among pwMS; however, the exercise-induced changes did not differ significantly from those observed in healthy controls. Finally, magnetic resonance spectroscopy revealed elevated ACC lactate concentrations at rest in pwMS and after the fatiguing exercise, total creatine decreased significantly only in healthy controls.
In conclusion, this research is the first to demonstrate in the same group of pwMS reduced muscle strength, altered corticospinal excitability and metabolic profiles in key brain regions. These mechanisms may increase the observed perception of effort, state and subsequently trait perceived fatigue. These findings support current theories putting disruption in the brain's ability to control bodily states as central in the experience of fatigue. This thesis offers a novel approach to understanding fatigue in pwMS by uniquely combining insights into ACC metabolites, perceptual measures of state fatigue, and assessments of fatigability and corticospinal integrity. This comprehensive profile of MS-related fatigue provides valuable insights into the relationship between subjective fatigue perception and objective fatigability measures, advancing the understanding of this complex symptom and potentially informing the development of more targeted interventions for managing this debilitating condition.
| Date of Award | Jun 2025 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | James Stone (Supervisor), Mara Cercignani (Supervisor) & Jeanne Dekerle (Supervisor) |