Neuromodulatory Systems in Neurodegenerative Diseases of Ageing and in Sleep

Abstract

Neuromodulatory systems facilitate changes to many brain and behavioural states. These ascending arousal systems undergo profound alterations across ageing and in the face of neurodegenerative diseases. Understanding the complex impact of these alterations is pivotal to improving therapeutic treatment. This thesis examines the role of several neuromodulators in neurodegenerative disease and health, drawing on insights from neuroimaging, electrophysiology, pharmacology, cognition, and sleep. Specifically, Part I of this thesis focuses on neuromodulatory systems in neurodegenerative diseases of ageing. We review the neurobiology of the cholinergic and noradrenergic systems in neuropsychiatric diseases of ageing, calling for new symptomatic treatments, within a more personalised framework. We demonstrate how noradrenergic modulation can alter oculomotor function and cognitive control in Parkinson’s disease, and highlight the utility of measuring the effects of noradrenergic pharmacotherapy via oculomotor tasks. We offer a novel perspective on dopaminergic mechanisms underlying large-scale, functional brain organisation in Parkinson’s disease. Part II of this thesis focuses on neuromodulatory systems in sleep. We reveal specific measures of sleep spindle architecture associated with clinical phenotypes of prodromal dementia. Lastly, we substantiate spectral, haemodynamic and network topological signatures of the immediate periods surrounding sleep spindles in human non-rapid eye movement sleep, linking this with underlying neuromodulatory involvement. This thesis reinforces the value of these systems for understanding the processes that arise in neurodegenerative diseases and sleep, and their promise as therapeutic targets. Ultimately, the multimodal framework by which we investigate neuromodulatory systems in this thesis underscores the powerful influence they have upon human brain states and behaviour.