Regulation of emotion and cholinergic system connectivity in bipolar disorder
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Background: The human brain comprises distributed cortico-subcortical regions that are structurally and functionally connected into a network that is known as the human connectome. Understanding how connections between regions are arranged with regards to other functionally specialised cortico-subcortical networks, and how independent functional subsystems integrate globally and relate back to anatomical networks, is key to understanding how the human brain’s architecture underpins abnormalities of mood and emotions. Structural and functional abnormalities, mostly involving prefrontal and limbic systems, alongside changes in the neuromodulatory muscarinic-cholinergic system, have been associated with disorders of emotion regulation such as bipolar disorder (BD); however, the neurobiological and molecular basis of this illness are currently poorly understood. Current pharmacological intervention of BD includes predominantly mood stabilisers and antipsychotics. However, BD treatment remains suboptimal resulting in a considerable proportion of patients remaining refractory to treatment. The search of new agents that are specific to BD may be eased by emphasising the interface between human brain organisation, preferential patterns of dysconnectivity and neuromodulatory systems influence. To date, the paucity of structural and functional graph analysis investigations in BD have yielded inconsistent findings. Thus, the present thesis avails of graph analyses to examine features of structural and functional brain network organisation and to investigate the contribution of the neuromodulatory muscarinic-cholinergic system to core emotional symptoms of BD in a predominantly euthymic sample of individuals presenting with BD relative to psychiatrically-healthy controls. Methods: Individual structural and functional connectivity matrices were constructed using a subject-specific 34-cortical and 9-subcortical bilateral nodes (Desikan-Killiany atlas). Structural edges weighted by fractional anisotropy and streamline count were derived from deterministic tractography using constrained spherical deconvolution, and functional edges were weighted by Pearson’s’ and partial correlation coefficients representing the association between averaged nodal resting-state time-series. Wholebrain connectivity measures and a permutation-based statistical approach were employed in the structural and functional connectivity analyses alongside rich-club connectivity and structure-function coupling; all to investigate topological variance in BD relative to healthy volunteers. To examine the role of the muscarinic-cholinergic system in BD, participants underwent a functional scan and performed an emotioninhibition task with intravenous physostigmine cholinergic system challenge (1 mg) or placebo between fMRI runs to assess functional activation, changes across mood (Profile of Mood States) and behavioural performance (accuracy and reaction time). Results: Subjects with BD, relative to controls, demonstrated impairments across whole-brain topological arrangements (density, degree, and efficiency) but preserved whole-brain structural and functional connectivity strength. A dysconnected structural subnetwork involving limbic and basal ganglia connections was observed in BD relative to controls. Increased betweenness centrality scores were observed generally in females and increased rich-club connectivity most evident in females with BD, with fronto-limbic and parieto-occipital nodes not members of BD rich-club. A dysconnected functional subnetwork encompassing fronto-limbic fronto-temporal and posterior-occipital connections was observed in BD relative to controls. Further, a comparable structuralfunctional relationship was observed for whole-brain and within edge-class connections. When processing emotional stimuli, under-activation of the anterior cingulate cortex and impaired behavioural performance were observed in BD relative to controls. However, cholinergic system challenge physostigmine affected behavioural performance without significantly altering mood and was associated with overactivation of the posterior cingulate cortex in BD compared to controls during the inhibition of the negative salience of the emotional stimuli. Discussion: These findings suggest BD dysconnectivity is present, it is not diffuse but rather localised to involve communication within and between structural and functional networks generally underpinning emotion, reward and salience. The structural and functional abnormalities observed in BD largely overlap with networks involved in ventromedial and ventrolateral routes to emotional control which support processes of interoception and visceromotor control. Disturbances in these neurocircuitries may modulate and thus explain maladaptive internal representations of external stimuli occurring in BD and consequent aberrant perception of emotional negative stimuli as increasingly salient. Considering that the examined subjects were predominantly euthymic at the time of scanning, the detected structural and functional abnormalities may underpin a compensatory mechanism of neural rewiring or activity that may be necessary to sustain a remitted clinical state of the illness; and provide flexibility in the ability to switch between segregated and integrated states. This thesis supports the application of graph theory to diffusion tensor and functional imaging data to identify abnormalities of subnetworks associated with BD and elucidates the underlying neurobiology of this illness highlighting the contribution of the neuromodulatory muscarinic-cholinergic system to core emotional symptoms of BD. This thesis may inform future studies aimed at incorporating neuroimaging techniques into studies of treatment mechanism and prediction of treatment response, looking at neuromodulatory systems and connectomics as a therapeutic avenue of BD.