Psychiatry - Theses
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ItemPiecing the puzzle together: white, grey and PET imaging across the course of schizophrenia( 2018)Schizophrenia is a severe and debilitating brain disorder, marked by abnormalities in perception, mood and cognition. Despite copious evidence indicating that brain changes are involved in the pathophysiology of schizophrenia, well-replicated neuroimaging markers that track disease progression or reveal therapeutic targets have not been identified. This may be due to regional and unimodal approaches applied in previous neuroimaging studies of schizophrenia, providing limited context to interpret neuropathology; imbedded in a complex multimodal and dynamic system. Furthermore, as neuropathology could evolve over the course of schizophrenia, duration of illness or illness stage reflects a key source of heterogeneity across prior studies. While grey matter deficits are thought to be progressive, it remains unclear whether white matter abnormalities vary as a function of illness stage and whether these changes are regionally linked to structural grey matter loss in anatomically adjacent regions, thus pointing to related aetiological processes. Furthermore, the mechanisms underlying structural grey and white matter deficits remain unknown. Recent evidence points to elevated microglial activation - an inflammatory response in the central nervous system, which might cause secondary neuronal degeneration, decreased neurogenesis and synaptic dysfunction, and may thus underlie structural brain changes in schizophrenia. This thesis applies multimodal imaging to address gaps in our knowledge of brain changes in schizophrenia, through evaluating three primary questions: (i) Do white matter disruptions deteriorate as a function of illness stage over the course of schizophrenia? (ii) Are white matter deficits regionally linked to the well-characterised grey matter deficits in schizophrenia? (iii) Is elevated microglial activation evident and associated with structural brain changes in schizophrenia? Using diffusion-weighted magnetic resonance imaging data, we mapped whole-brain white matter circuitry in patients recently diagnosed with a first-episode psychosis and patients with chronic schizophrenia. We found that white matter pathology in recently diagnosed patients was confined to selective anterior callosal fibres within a more extensive network of white matter disruptions found in chronic illness. These findings may suggest a progressive trajectory of white matter pathology in schizophrenia. Secondly, we applied multimodal imaging techniques to reveal a strong and reproducible relationship between white and anatomically adjacent grey matter deficits in schizophrenia, a relationship that dynamically varied as a function of illness duration. Thirdly, we examined microglial activation, indexed using 11C-(R)-PK11195 positron emission tomography (PET) imaging, as a key mechanism hypothesised to underlie structural deficits in schizophrenia. In contrast to our hypothesis, we found no evidence of microglial activation or a relationship to brain changes in individuals across any stage of illness, including those at ultra-high risk of psychosis, recently diagnosed with a first-episode psychosis and patients with chronic schizophrenia. These findings highlight the need for whole-brain and multimodal approaches to expose patterns of neuropathology in schizophrenia for biomarker and therapeutic detection. Using a whole-brain perspective, our results implicate early grey and white matter abnormalities in schizophrenia, which dynamically evolve over the course of illness. An exciting possibility of these findings is that processes underlying such early deficits could be targeted therapeutically to delay or prevent illness progression or alternatively, as signatures for later illness chronicity.