Characterising the role of the ascending arousal system in facilitating global brain dynamics in health and neurodegeneration

Abstract

The inherent complexity of the brain can be attributed to countless interacting parts, from microcircuit detail scaled to large oscillatory fluctuations of macroscopic activity. One such structure that has previously been shown to influence dynamic macroscopic fluctuations in brain activity is the ascending arousal system. The ascending arousal system is comprised of multiple nuclei that send diffuse and broad-reaching neuromodulatory inputs across the brain – a function proposed to facilitate global brain activity changes. However, little is known about the exact mechanisms or extent of the influence of the ascending arousal system in facilitating large-scale brain dynamics. Hence, this thesis attempts to reveal the role of the underlying ascending arousal system in facilitating global brain dynamics that are critical for brain function. Specifically, this thesis unpacks the importance of considering the interactions between the cholinergic and noradrenergic system in facilitating global brain state dynamics.

We reveal that the structural connections between the noradrenergic and cholinergic systems are critical in constraining global brain-state dynamics. We show a causal role of the cholinergic system in facilitating global brain-state dynamics and demonstrate a microcircuit mechanism of global brain-state dynamics. Next, we discuss the importance of viewing the brain through the lens of a complex system to understand both its function and dysfunction across neurodegenerative diseases. Then, we establish a maladaptive mechanism of the noradrenergic system in the manifestation of freezing of gait in Parkinson’s disease. Lastly, we examine the role of the noradrenergic system in other symptom manifestations in Parkinson’s disease.

Ultimately, this thesis characterises the interactions of the cholinergic and noradrenergic systems in facilitating global brain-state dynamics in both healthy and diseased brains.