Sleep-wake dysfunction in human ischaemic stroke

© 2020 Elie William GottliebSleep-wake dysfunction is increasingly recognised as a key modifiable risk factor and consequence of stroke. Chronic sleep-wake abnormalities, characterised by excessively long sleep duration or sleep disorders, increase the risk of ischaemic stroke. Following stroke, de novo sleep-wake impairment is common and associated with poor recovery. However, the pathogenesis and evolution of sleep-wake disturbances in stroke have been poorly characterised thus far, largely due to methodological limitations. In this thesis, gold-standard sleep measurement tools and advanced MRI methodologies were applied to investigate the impact of chronic stroke on sleep-wake function. There were three primary research questions for this thesis, and each formed the conceptual framework for three major studies: (1) To what extent is sleep-wake dysfunction associated with both stroke risk and post-stroke evolution? (2) What are the neurodegenerative markers of sleep-wake after stroke? (3) What are the sleep architectural and sleep-respiratory characteristics of chronic stroke patients relative to healthy controls? To address the first question, a scoping systematic review of over 5,000 studies was conducted in order to assess the bidirectional relationship between sleep and circadian rhythm dysfunction in human ischaemic stroke. A qualitative synthesis of the extant literature showed that excessively long sleep duration and sleep disorders significantly increase the risk of ischaemic stroke. On the other hand, acute stroke patients exhibit fragmented sleep architecture in the weeks following the incident event – potentially driven by newfound sleep disorders which may also be associated with post-stroke topography and recovery. These findings support a bidirectional relationship between sleep-wake dysfunction and ischaemic stroke with important clinical implications. To expand on limitations of prior studies identified in the aforementioned systematic review, the associations between regional neurodegeneration and objectively measured sleep were investigated in a cohort of mild-to-moderate stroke patients and healthy controls from the Cognition and Neocortical Volume After Stroke (CANVAS) study. Stroke patients with excessively long sleep duration and poor sleep efficiency exhibited volumetric reductions to the thalamus and amygdala relative to healthy controls. Next, a novel method known as a whole brain fixel-based analysis was utilised to investigate fibre-specific white matter degeneration in stroke patients with poor sleep. Stroke patients with excessively long sleep duration exhibited tract-specific neurodegeneration to the cortico-ponto-cerebellar tract. These findings suggest that poor sleep efficiency or long sleep duration may contribute to neurodegeneration following stroke. The final study in this thesis aimed to characterise hemispheric sleep architecture and sleep-respiratory characteristics in stroke patients >4 years after their incident event using gold-standard polysomnography. In a subsample of patients from the CANVAS study, stroke patients and matched controls underwent overnight ambulatory polysomnography and completed an array of sleep and circadian questionnaires. Over half of all stroke patients in this sample exhibited undiagnosed moderate to severe obstructive sleep apnoea. Stroke patients had nearly 40% less restorative slow-wave sleep and potentially compensatory increases in lighter sleep stages relative to healthy controls. Sleep architectural disturbances were not attenuated by obstructive sleep apnoea. There were no sleep architectural differences in the stroke-affected versus healthy-hemisphere. These findings suggest that sleep impairment post-stroke is unlikely to be driven by comorbid obstructive sleep apnoea or the hemispheric distribution of stroke lesions. Furthermore, these results highlight the importance of formal sleep studies in stroke patients in order to identify undiagnosed obstructive sleep apnoea and fragmented sleep architecture. The overall findings from this thesis offer valuable insight into the potential in vivo pathogenesis of sleep-wake dysfunction after stroke and the evolution of sleep abnormalities in the chronic stages of stroke. The clinical-pathogenic implications of sleep-wake dysfunction in stroke are unravelled, and a research agenda for future studies in this emerging field of medicine is outlined