Abstract
Homo Sapiens consist of trillions of atoms, each inanimate, yet somehow collectively constituting a conscious being. The fundamental question of how organisms are organised to beget consciousness and cognition has largely been approached through independent examination of the structure and function of the nervous system at varying levels of granularity. As neuroscience progresses, it has thus increasingly fragmented into separate streams of research which study the brain at these different scales. This has resulted in the field becoming “data rich, but theory poor”, which is largely attributable to the paucity of methods which bridge these levels of analysis to provide novel trans-hierarchical insights and inform unified theories. The research in this doctoral thesis therefore aims to explore how a specific type of multimodal analysis - Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) – can begin to bridge the theoretic void between molecular level mechanisms and systems levels dynamics to provide novel perspectives on the function and dysfunction of the brain.First, I provide a narrative synthesis of the challenges precluding a meaningful understanding of the human brain utilising conventional functional neuroimaging and outlining how incorporation of molecular information may help overcome these limitations. Specifically, by embedding functional dynamics in the molecular landscape of the brain, we can begin to move from the simple characterisation of “where” cognitive phenomena may be within the brain towards mechanistic accounts of “how” they are produced. Additionally, this offers enticing opportunities to link pharmacological treatments to novel molecular-network based biomarkers.
Second, I explore how networks enriched with the spatial configurations of serotonergic and dopaminergic receptor subtypes are modulated by lysergic acid diethylamide (LSD) as compared to placebo in healthy participants. The results highlight the challenges of disentangling pharmacodynamics of drugs exhibiting rich pharmacology as well as identifying differential relationship between serotonergic and dopaminergic networks and phenomenological sub- components of psychedelic state.
Third, I expand the remit of molecular-enriched network analyses beyond pure psychopharmacology to examine the direct and indirect actions of propofol anaesthesia on inhibitory and modulatory neurotransmission at both rest as well as during a naturalistic listening task. This work demonstrates for the first time that these molecular-networks can capture broader perceptual and cognitive-driven network reconfigurations as well as indirect pharmacological actions on neuromodulatory systems. Moreover, it provides evidence that the effects of propofol on consciousness are enacted through both direct inhibitory as well as indirect neuromodulatory mechanisms.
Finally, I produce normative models of networks enriched with the principal neuromodulatory, excitatory, and inhibitory transmitter systems, testing their capacity to characterise neural dysfunction within and across several neuropsychiatric disorders. This work provides a computational foundation for large scale integration of molecular mechanisms and functional imaging to provide novel individualised biomarkers for neuropsychiatric disorders.
Collectively, this thesis offers methodological and theoretical progress towards a trans-hierarchical characterisation of the human brain, providing insights into the neural correlates of both conscious contents and level as well as the perturbations underlying key neuropsychiatric conditions.
| Date of Award | 1 Dec 2023 |
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| Original language | English |
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| Supervisor | Matthew Howard (Supervisor) & Ottavia Dipasquale (Supervisor) |