Psychiatry - Theses
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ItemUnderstanding the role of frontotemporal brain structures in schizophrenia through magnetic resonance imaging and neuropathological studies( 2012)Section 1: The first two chapters describe my initial hippocampal volumetric work in patients with first-episode psychosis and chronic schizophrenia that identified hippocampal changes early in the course of psychosis. Chapter 3 explores in detail the theoretical basis for hippocampal involvement in schizophrenia and introduces for the first time the concept that the hippocampal volume changes observed in patients with first episode psychosis and chronic schizophrenia may not be present in patients at high risk of psychosis. Chapters 4 to 6 describe a series of cross sectional studies showing that hippocampal volumes are normal in high risk patients who later develop psychosis (Chapter 4 and 6), normal in patients with schizophreniform psychosis (Chapter 6), reduced on the left side in patients with first-episode schizophrenia (Chapter 6) and bilaterally reduced in patients with chronic schizophrenia (Chapter 6). These findings suggest that right hippocampal volume reduction occurs with increased illness duration, a finding supported by a voxel based morphometry study of patients with chronic schizophrenia (Chapter 5). Finally in contrast to our original findings (Chapter 1) that hippocampal volumes were equally reduced in patients with first-episode schizophrenic and non schizophrenic psychoses, our study of a much larger first-episode cohort (Chapter 6) showed that hippocampal volume reduction was specific to schizophrenic psychoses while amygdala enlargement was specific to non schizophrenic first-episode psychoses. These findings suggested either that (i) patients who make the transition from high-risk to first-episode or first-episode to chronic schizophrenia already have hippocampal changes and/or (ii) that hippocampal volume changes occurred progressively over the course of the illness. Section 2: Chapters 7 and 8 describe follow-up longitudinal imaging studies in a first-episode cohort and a high-risk cohort respectively. We did not identify hippocampal volume change over a two-year period (Chapter 7) but observed whole brain changes over time in first-episode and chronic schizophrenia cohorts. We hypothesised that structural changes may have occurred prior to or over the transition to active psychotic illness. Chapter 8 describes parahippocampal and frontal changes in high-risk patients who developed a psychotic illness and not in those who did not develop a psychotic illness. These findings provided support for the concept that some patients with a psychotic illness exhibit progressive structural brain changes. Section 3: Chapters 1 to 8 describe evidence for the presence of structural brain changes in the hippocampi of patients with schizophrenia. Structural MRI cannot determine the neurobiological correlates of such brain changes i.e what is causing the changes or which elements of brain tissue are involved. The neurobiology of diseases that mimic schizophrenia (‘secondary schizophrenias’) has provided insights into schizophrenia. Chapter 9 describes a previously unrecognised association between young onset frontotemporal dementia and schizophrenia-like psychosis and specific hippocampal pathology in these cases. Chapter 10 describes similar pathological abnormalities in the hippocampus of patients with schizophrenia and bipolar disorder, who had never been suspected of having dementia earlier in life. The identification of clinical and neuropathological associations between FTD and schizophrenia / bipolar disorder is of significant clinical relevance and provide new avenues for research into the underlying neurobiology of major mental disorders. Section 4: The concluding section discusses how the work in this thesis can be understood within the context of neuroimaging work that has emanated from this large dataset and the current schizophrenia literature. The association between schizophrenia and FTD identified in Chapters 9 and 10 is explored further in this final section with reference to the literature and some illustrative case reports.
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ItemThe specificity of morphological changes of the corpus callosum in schizophrenia and related major mental disorders( 2010)Schizophrenia is a disabling major mental illness associated with marked impairments in reality testing, organization of speech and behaviour and cognition. Significant evidence points to functional dysconnectivity between cortical and subcortical regions as the major pathophysiological underpinning of the symptoms and disability associated with schizophrenia. Modern neuroimaging techniques have suggested that this dysconnectivity is driven, at least partially, by neuroanatomical changes to connectivity in the brain at the level of white matter tracts, the main connecting “organs” in the brain. This thesis describes the analysis of the structure of the corpus callosum, the brain’s largest white matter fibre tract, with the aim of determining if changes to anatomical connectivity in schizophrenia are associated with a unique callosal shape “signature”. This was undertaken by using a shape analysis methodology that examined regional callosal thickness, using a non-parametric permutation method to determine between-group differences and the relationship between illness variables and callosal shape. This methodology was applied to multiple illness stages: established illness, first-episode psychosis and pre-psychotic patients. It was then applied to other major mental disorders, including multiple cohorts of patients with bipolar disorder and patients with major depression, to determine if any changes seen in schizophrenia patients were specific to schizophrenia-spectrum illness or were more general markers of major mental illness. The results suggest that patients with schizophrenia-illness show specific thickness reductions at the level of the anterior callosum, connecting frontal cortical regions, that are present during the pre-psychotic phase and with first-episode illness. Furthermore, with established illness, these changes are accompanied by additional changes in the callosum connecting cingulate, temporal and parietal regions. Changes seen in healthy individuals as part of the normal ageing process appeared to be disrupted in schizophrenia patients. In bipolar patients, a very different pattern of results emerged, with more global thickness reductions and disproportionate thinning at the level of the posterior callosum. Depressed patients, by contrast, showed state-specific posterior expansions, which bore some homology to changes seen in patients with depressed first-episode psychotic patients and patients with schizoaffective disorder. Furthermore, in the schizophrenia-spectrum group, changes at the level of the genu were strongly predictive of transition to psychosis in those individuals at high-risk for psychosis, and in first-episode individuals were highly predictive of long-term outcome of their psychotic illness. These changes suggest that there are schizophrenia-specific changes at the level of the callosum, marking a unique callosal “signature” for schizophrenia-spectrum illness. These changes show predictive validity for outcome at the earliest stages of illness, and are distinct from changes seen in major affective disorders. These findings suggest that shape changes to white matter structures may be a useful marker to aid diagnosis, in the identification of individuals who may develop a psychotic illness, and in defining the nature of their future illness course.
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ItemFace processing in schizophrenia: an investigation of configural processing and the relationship with facial emotion processing and neurocognition( 2010)Cognitive impairment is a key characteristic of schizophrenia and is a clear predictor of functional outcome. This thesis explores the relationship between cognitive ability relating to social and non-social processing. Schizophrenia patients demonstrate an impaired ability to recognise, label and discriminate emotional expression within the face. The underlying mechanisms behind this social cognitive impairment are not yet fully understood. This thesis explores the notion that a basic perceptual impairment in processing facial information adversely impacts on the perception of more complex information derived from faces, such as emotional expression. Face perception relies on processing the featural characteristics of a face as well as the relationship between these features. Information pertaining to the spatial distances between features is referred to as configural information. A group of schizophrenia patients and healthy control participants completed a battery of tasks that assessed basic neurocognition, facial emotion processing and configural face processing. A model of face processing was proposed and used to systematically pinpoint specific deficits that may contribute to impaired face processing in schizophrenia. The results indicated that schizophrenia patients show impairments on three broad constructs; basic neurocognition, facial emotion processing, and most pertinently, deficits in configural processing. It was revealed that although neurocognitive and face processing both explained a significant proportion of the variance in facial emotion processing, the effect of neurocognition was indirect and mediated by face processing. To investigate the diagnostic specificity of these findings, a group of bipolar disorder patients was also tested on the task battery. The results indicated that bipolar disorder patients also show social and non-social cognitive impairments, however, not as severe as that demonstrated by the schizophrenia patients. Furthermore, the effect of neurocognitive performance on facial emotion processing appeared more direct for bipolar disorder patients compared to schizophrenia patients. Although deficits in face processing were observable in bipolar, they were not specific to configural processing. Thus, deficits in emotion processing were more associated to neurocognitive ability in bipolar disorder patients, and more associated to configural face processing in schizophrenia patients. The configural processing deficits in schizophrenia are discussed as a lower-order perception problem. In conclusion, the results of this thesis are discussed in terms of their implication for treatment.