Psychiatry - Theses
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ItemNeural correlates of memory dysfunction across stages of schizophrenia-spectrum disorder( 2020)Schizophrenia-spectrum disorders are severe mental illnesses characterised by hallucinations, delusions, blunted affect and disorganised thought patterns. A core feature of these disorders is cognitive deficits, which are associated with functional disability. Episodic memory, in particular, is one of the most severely impacted areas of cognitive functioning in schizophrenia-spectrum disorder, and memory deficits predict poorer clinical prognosis and increased functional disability. However, the longitudinal course of episodic memory deficits in schizophrenia-spectrum disorders is currently poorly defined, with the focus to date being on areas of functioning that are already impaired in early illness stages, such as verbal memory. In order to better understand trajectories, it may be important to examine areas of functioning that are preserved early in the illness, such as visual associative memory. Furthermore, there is currently a poor understanding of the neural underpinnings of memory impairment in schizophrenia-spectrum disorders, making it difficult to develop targeted interventions aimed at ameliorating these deficits. It is plausible that episodic memory impairments in these disorders is related to underlying dysfunction in the brain regions and networks that underlie this ability – namely, the hippocampus and its connections to the prefrontal cortex. This thesis utilised longitudinal cognitive assessment and cross-sectional multi modal neuroimaging to address three primary research aims: 1. To investigate the longitudinal course of episodic memory ability over a 5-11-year follow-up period in individuals with first-episode psychosis. 2. To investigate relationships between visual associative memory performance and hippocampal subfield volumes in FEP individuals and individuals with chronic schizophrenia-spectrum disorders. 3. to investigate whether visuospatial associative memory ability is related to white matter microstructure in the hippocampal-prefrontal pathway in FEP individuals and individuals with chronic schizophrenia-spectrum disorders. Results showed that visual associative memory ability was preserved in in individuals who had recently experienced a first psychotic episode, but deteriorated over a 5-11 year follow-up period. Conversely, verbal associative memory ability improved over the follow-up period to the same degree in FEP individuals and healthy controls. In a subsequent cross-sectional study, we found that, while hippocampal subfield volume reductions were present only in individuals with chronic schizophrenia-spectrum disorder, poorer episodic memory performance was associated with reduced subfield volumes in the CA4/dentate gyrus (DG) and in the stratum layers in both FEP individuals and those with chronic schizophrenia-spectrum disorder. Finally, we found that abnormal white matter microstructure in a number of memory-related ROIs and hippocampal-prefrontal pathways was present only in individuals with chronic schizophrenia-spectrum disorder. Furthermore, microstructural abnormalities in the fornix and the hippocampal-thalamic pathway were associated with poorer memory performance in individuals with chronic schizophrenia-spectrum disorder, but not FEP individuals. These findings provide new insights into the neural underpinnings of episodic memory impairment across stages of schizophrenia-spectrum disorder, and suggest that hippocampal structure may be more relevant to memory impairment in FEP individuals, with memory-related white matter abnormalities emerging in later illness stages.
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ItemNeuroimaging Biomarkers in Generalised Anxiety Disorder, and Associated Modulations Following an Anxiolytic Intervention( 2020)Introduction and Aims Generalised anxiety disorder (GAD) comprises a debilitating cluster of psychological and physiological symptoms that markedly impairs quality of life. GAD is characterised by hallmark cognitions of persistent worry and anticipatory anxiety. Evidence exists for dysregulation in excitatory/inhibitory neurobiological pathways in prefrontal and limbic brain regions, with the dorsal anterior cingulate cortex an area of particular interest. However, limited research exists assessing regional activations and the role of metabolites such as gamma-aminobutyric acid in these regions, nor modulations as a function of treatment. The aim of the thesis was to investigate the functional and metabolic features of this region, and to assess the role of neuroimaging biomarkers of anxiolytic treatment response. Methods Two investigations were conducted utilising structural features of the region of interest: task-based functional magnetic resonance blood oxygen level-dependant signal activation and GABA levels via magnetic resonance spectroscopy together with relevant psychometric and psychiatric measures. The first study was a cross-sectional investigation undertaken to compare neuroimaging biomarkers in 41 participants with GAD with 35 healthy control participants. The second study was an 8-week RCT sub-study involving 41 participants randomised to either daily 240mg of kavalactones Piper methysticum (Kava) extract or a matching placebo. This proof-of-concept study assessed the aforementioned outcomes and whether these markers signal the plant’s anxiolytic activity. Results The results of the first investigation did not reveal group differences in GABA level (p = .302). The relationship between GABA and anxiety severity was different for each group; a significant positive correlation in GAD (e.g., HAM-A, p = .018) and a negative correlation in healthy controls (e.g., trait anxiety, p = .019). The functional task was successful in eliciting regional BOLD signal differences between valent congruency conditions. Two regions exhibited significant group differences (at p < .05), showing hyperactivation in GAD and reduced activation in healthy controls. In both groups BOLD signal significantly predicted severity of state anxiety (GAD p = .027; HC p = .041). Gender, age, and comorbidity in the GAD group also influenced the biomarker-anxiety relationships. The results of the second study showed that Kava treatment was associated with a reduction to GABA levels at eight weeks (p = .049). The treatment was not associated with anxiety symptom, nor fMRI signal change, measured at eight weeks. Discussion This research investigated regional brain properties in GAD for biomarker utility, before testing them in a ‘proof of concept’ study using the purported anxiolytic agent, Kava. Metabolic and functional data were successful in producing differences in the dorsal ACC that could be (if replicated in a larger study) be utilised as biomarkers to aid in the management of GAD symptoms. Limitations of the studies were small sample sizes, GABA signal quality and equivocal toolbox results. The neurobiological effects of Kava have not been directly studied using MRI imaging in humans. The findings of a reduction to GABA levels after treatment may potentially reflect a normalising of the GABA system similar to healthy control data observed in the first study. GAD is a prevalent psychiatric disorder that is under-diagnosed and under-treated. While a great deal of work is inherent in establishing biomarkers for clinical benefit, this research contributes MRI evidence of biological differences, and insight into the mechanisms of Kava, together with a translational rationale for the study of novel anxiolytics as potential GAD treatments. The outcomes and findings of this research fit well with the current affective disorder literature and exceed contemporary work in the field of GAD biomarker and treatment research.