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ItemEffects of childhood adversity and glutamatergic polygenic risk score on brain structure and cognition in schizophreniaMohamed Saini, Suriati ( 2019)Schizophrenia is a chronic disabling disorder with complex multifactorial aetiology. It is associated with childhood adversity and glutamatergic genes, both of which contribute to brain development and cognition. However, the relationships between these factors are not fully understood and must still be elucidated. This thesis addresses gaps in understanding of this complex link. These findings will be informative for early identification and treatment of those with schizophrenia. Chapter one provides a conceptual framework for the models used in this thesis. A literature review on schizophrenia, childhood adversity, glutamatergic genes, brain development, and cognition is included. The links between these factors are described and the aims of the thesis are justified. Chapter two aimed to identify the association between metabotropic glutamate receptor 3 genetic variation and schizophrenia and explored potential population stratification. This meta-analysis study consisted of 14 single nucleotide polymorphisms of metabotropic glutamate receptor 3 from a total of 11318 schizophrenia cases, 13820 controls, and 486 parent proband trios. We found significant associations for three single nucleotide polymorphisms. We also found evidence for population stratification in that the risk allele was dependent on the population under study. These findings support the genome wide-implicated link between metabotropic glutamate receptor 3 genetic variation and schizophrenia risk, and further support the notion that alleles conferring this risk may be population specific. Chapter three aimed to examine the extent to which the association between childhood adversity and cognition is mediated by structural brain volumes and moderated by glutamatergic polygenic risk score in the context of brain volumes as a mediator. A total of 176 schizophrenia patients and 118 healthy controls participants were assessed for a history of childhood adversity and underwent cognitive testing and structural neuroimaging. Six glutamatergic genes were genotyped, and a weighted glutamatergic polygenic risk score was calculated. Mediation and moderated-mediation models were tested. We found that that there were significant mediation effects of intracranial and total brain volumes on the association between childhood adversity and delayed memory in the overall sample, as well as in the schizophrenia patients. There was also a significant mediation effect of subcortical volume on the association between childhood adversity and working memory in the schizophrenia patients, but not healthy controls. However, there was no significant moderation effect of glutamatergic polygenic risk score on the association between childhood adversity and cognition in the context of brain volume as a mediator. This study demonstrated that childhood adversity exerts a negative impact on intracranial, total brain, and subcortical volumes in schizophrenia. Adversity encountered during childhood may pre-program the brain for subsequent memory performance in adulthood. The effect of glutamatergic polygenic on the association between childhood adversity, brain volume, and cognition in schizophrenia could be related to illness stage or severity. Chapter four aimed to examine interrelationships between childhood adversity, glutamatergic polygenic risk score, frontal lobe volume, and spatial working memory in 51 treatment-resistant schizophrenia patients and 40 healthy controls from the Cooperative Research Centre for Mental Health psychosis study cohort. We found that treatment-resistant schizophrenia patients displayed impairment in spatial working memory between search errors, spatial working memory strategy, and spatial span relative to healthy controls. A significant moderation effect of glutamatergic polygenic risk score was found on the association between childhood adversity and the spatial working memory factor which comprising spatial working memory between search errors, spatial working memory strategy, and spatial span in the treatment-resistant schizophrenia group, but not in the healthy controls. The conditional effects on the association between childhood adversity and spatial working memory indicated that, in the presence of higher childhood adversity, treatment-resistant schizophrenia patients with higher glutamatergic polygenic risk score demonstrated poorer spatial working memory, while those with lower glutamatergic polygenic risk score showed better spatial working memory. Synergistic effects between childhood adversity and glutamatergic polygenic risk score on spatial working memory performance in treatment-resistant schizophrenia patients suggests that lower glutamatergic polygenic risk score may, in part, protect patients from the detrimental effects of childhood adversity on spatial working memory performance, while higher glutamatergic polygenic risk score increases the risk. Chapter five summarises the main findings of each study and highlights the clinical implications and future directions of this critical research area so as to improve mental health for children subjected to adversity.
ItemSpecialization and integration in brain networks underlying cognitive control in healthy individuals and patients with schizophreniaHarding, Ian Herbert ( 2013)Cognitive control lies at the foundation of dynamic and adaptive human behaviour. Through the flexible top-down regulation of lower-order processes, cognitive control operations serve to direct the perceptual, motor, and other cognitive resources of the brain in response to ever changing environmental demands and behavioural goals. These abilities, including cognitive interference resolution and working memory operations, rely on a common set of brain regions located within the prefrontal and parietal association cortices, together forming the frontoparietal control network. The component regions of this network are variously responsible for encoding and updating goal and context representations, signalling motivational salience, monitoring action-outcomes, and discriminating amongst ambiguous perceptual information and behavioural contingencies. Meaningful and coherent behaviour is dependent both on information processing within each of these regions (specialization) and the amalgamation of function across the network (integration). Although the frontoparietal control network is well defined and has been widely investigated, little is yet known about how it operates when faced with multiple concurrent control demands, as would be expected in real-world environments. Moreover, the shared and unique nature of connectivity patterns within this common brain network across different cognitive control processes is currently unknown. In schizophrenia patients, dysfunction in cognitive control abilities is endemic and is thought to lie at the core of the significant disability faced by patients suffering from the illness. Current theories variously propose that abnormalities in the integrity and efficiency of neural functioning, as well as in the normal integration of activity within the frontoparietal control network may underlie these deficits. This thesis presents a series of experiments exploring the activation and connectivity patterns defining the frontoparietal network as a function of distinct cognitive control demands. Functional magnetic resonance imaging (fMRI) data was acquired during performance of a novel cognitive paradigm in which cognitive interference and working memory demands were manipulated in a factorial manner. Functional activations and effective connectivity were assessed using statistical parametric mapping (SPM) and dynamic causal modelling (DCM) techniques, respectively. Investigations were first undertaken in a group of healthy adults, and followed thereafter by a characterization of differences evident in a cohort of patients suffering from schizophrenia. Taken together, the frontoparietal system was found to be highly adaptable, widely interconnected, and characterized by both common and unique dynamics in response to different cognitive control demands. These characteristics were generally shared in patients with schizophrenia, although distinct decrements in inter-regional interactions within the prefrontal cortex were observed. The outcomes of this work serve to build upon, and in some cases challenge, current mechanistic models of cognitive functioning and pathophysiological processes, and inform compelling future research directions in the fields of cognitive neuroscience and psychiatry.