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Title: Functional network analysis of human brain systems under pharmacological modulation
Author: Cole, David Michael
ISNI:       0000 0004 2735 3295
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Complex alterations in brain function and neurochemistry underlie pathology and treatment in multiple neuropsychiatric disorders, yet remain incompletely characterised. This thesis outlines possibilities for human neuroimaging techniques sensitive to spontaneous fluctuations in large-scale neurobiological signalling, or ‘resting-state network (RSN) functional connectivity’, to address such knowledge gaps. Novel RSN-sensitive analysis approaches to functional magnetic resonance imaging data are introduced. These techniques are then evaluated experimentally, in contexts relevant for maladaptive cognitive and motivational processing, for their utility to identify and characterise systems-level signatures of individual differences in neurochemistry and psychopharmacological responsiveness. Firstly, RSN functional connectivity measures are investigated in the context of pharmacological intervention with nicotine replacement therapy in habitual smokers. Results identify connectivity between executive control and ‘default mode’ RSNs as a neural signature of pharmacotherapeutic efficacy in treating cognitive symptoms of nicotine withdrawal. Secondly, RSN connectivity is investigated alongside specific neuroreceptor-sensitive measures to investigate the extent to which network connectivity patterns reflect fundamental neurobiology in healthy subjects. Individual differences in dopamine D3 receptor availability - a possible marker for reward-related behaviours -are associated with topographic connectivity signatures within RSNs implicated in cognitive and motivational control. Thirdly, the ability of RSN metrics to characterise distinct neurochemical manipulations is tested in healthy subjects. Dopamine agnostic and antagonistic neuromodulations display differential effects on signalling in cortico-cubcortical and cortico-cortical reward circuitry and interact selectively with subject impulsivity. Finally, RSN cortico-subcortical connectivity metrics are investigated for their sensitivity to clinical-pharmacological effects in Parkinson’s disease. Results reveal evidence for both compensatory large-scale network mechanisms and ‘non-normalising’ dopaminergic medication effects in patients. Overall, findings indicate novel systems-level neuroimaging methodology probing interactions within and between RSNs to provide sensitive, biologically plausible markers for behavioural and neuropharamacological characteristics of neuropsychiatric disorders. Continued developments of functional network analysis approaches may facilitate their direct application to clinical and drug development domains.
Supervisor: Beckmann, Christian Sponsor: Biotechnology and Biological Sciences Research Council ; GlaxoSmithKline
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral