Psychiatry - Theses
Permanent URI for this collection
Search Results
1 - 5 of 5
-
ItemInflammation in psychosis: Impact on brain structure and symptoms in animal models and humans( 2019)Schizophrenia is a severe neuropsychiatric disorder, arising in adolescence and early adulthood and characterised by hallucinations, delusions, blunted affect and disorganised thought patterns. One of the most enduring features of schizophrenia and psychosis are structural brain deficits, whose pathophysiological mechanism is unknown. Accumulating evidence indicates that inflammation both peripherally and centrally in the form of increased activation of the brain’s immune cells, microglia, may be a potential cause of structural deficits in psychosis. The evidence is multi-faceted ranging from mouse models that demonstrate increased numbers of microglia, to clinical studies of patients with schizophrenia showing increased pro- inflammatory molecules within peripheral blood. However, there are still many questions that remain unanswered, including whether inflammation varies across stages of psychosis, whether it is related to structural brain deficits and symptomatology and how inflammation identified in schizophrenia relates to other candidate pathways implicated in psychosis. In this thesis a multi-disciplinary approach was adopted, considered appropriate to tackling the complexity of these questions. Firstly, to determine whether inflammation was associated with other candidate pathways implicated in psychosis, we conducted an animal study, utilising an mGluR5 KO mouse model of psychosis. Glutamate has been shown to influence neuroinflammation, with cellular studies demonstrating that mGluR5 can regulate microglial numbers and activation. At the time of conducting the study, there were no satisfactory mGluR5 PET ligands that enabled in vivo monitoring within the clinical population. The mGluR5 KO mouse had been shown to display neuropsychiatric endophenotypes related to schizophrenia and thereby offered an alternative approach to gaining further insight into the role of mGluR5 in neuroinflammation and how this may impact symptoms associated with psychosis. Our aim was to determine whether neuroinflammation, in the form of increased microglial numbers and activation was present in the mGluR5 KO mouse model thereby giving further insight as to the potential interaction of the glutamatergic system and in particular, mGluR5, with microglial homeostasis. Secondly, we aimed to determine whether peripheral inflammation was related to brain structure and clinical symptomatology. This was executed by conducting two clinical studies, that examined peripheral pro- and anti-inflammatory cytokines and complement proteins in relation to brain regional thickness and volume measurements. We used a multiplex enzyme linked immune-absorbent assays (ELISA) in serum to quantify peripheral cytokines and complement proteins across various stages of psychosis ranging from those at ultra-high risk of psychosis (UHR), to individuals experiencing their first episode (FEP) and subjects with chronic schizophrenia. We sought to determine whether circulating cytokine and complement protein levels were associated with clinical symptomatology and measurements of thickness and brain volume detected using structural magnetic resonance imaging (MRI). This thesis aimed to investigate: 1) whether mGluR5 KO mice, which demonstrate phenotypic features of schizophrenia displayed neuroinflammation in the form of increased microglial numbers when compared to their wildtype littermates 2) whether there was a relationship between cytokine or complement proteins and structural brain measurements across UHR, FEP and chronic schizophrenia 3) whether peripheral inflammatory markers (cytokine or complement proteins) were increased or decreased across stages of psychosis and examine their relationship with clinical symptoms. We found that mGluR5 KO mice have increased microglial numbers compared to WT. This agreed with our hypothesis that animals lacking mGluR5, would show higher rates of inflammation in the brain, in accordance with an anti-inflammatory effect of increased mGluR5 signalling and the psychotic endophenotype of these mice. Our findings indicate that mGluR5 may affect microglial homeostasis in the context of neurodevelopment and may impact on psychosis related behaviours exhibited by mGluR5 KO mice. Secondly, our clinical studies showed that cytokines and complement proteins were related to several brain structures implicated in psychosis, including the frontal cortex and ventricles. We revealed a positive correlation between several anti-inflammatory cytokines such as IL4 and IL13 and increases in frontal cortical thickness, which was absent in patients with psychosis. Conversely, increases in pro-inflammatory cytokine IL5 were associated with decreases in whole brain volume in FEP individuals. Thirdly, we found that while peripheral cytokines did not differ significantly between patients and controls, complement proteins were elevated in UHR and chronic schizophrenia patients. While there were no associations between cytokine proteins and clinical symptoms, we identified a molecular pattern of increased C4 and decreased C3 protein, which was associated with increases in positive and negative symptoms. Taken together, the work of this thesis suggests that inflammation is present in psychosis both in the brain and peripherally but that this depends on the proteins and stage of illness examined. Moreover, we revealed that complement proteins C3 and C4 were associated with alterations in brain structure across the combined cohort; in the case of cytokines however, the positive association between elevated anti-inflammatory cytokines and increased frontal thickness was not preserved or reversed in patient groups, indicating a potential imbalance of pro- and anti- inflammatory cytokines may influence brain structure in psychosis. Finally, we have shown that peripheral inflammation in the form of cytokine and complement proteins, may influence both brain structure and clinical symptomatology, which provides fertile ground for future longitudinal exploration of neuroinflammation in schizophrenia and psychosis.
-
ItemEffects of childhood adversity and glutamatergic polygenic risk score on brain structure and cognition in schizophrenia( 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.
-
ItemFunctional brain networks in schizophrenia: mapping connectivity and topology at early and late psychotic illness stages( 2017)Schizophrenia is a severe mental disorder that is characterised by symptoms including hallucinations, delusions and disorganized thought. The cause of schizophrenia remains unknown; however, it is thought that a combination of genetics, environment and altered neurobiology play a role in the emergence and perpetuation of the disorder. Accumulating evidence suggests that disrupted brain network connectivity may in part underlie the pathophysiology of psychosis, and that network connectivity is to some extent genetically determined and heritable. However, there is still much to be learned surrounding the nature of network abnormalities and how they differ in early versus late psychosis. Exploring the underlying neurobiology at discrete clinical stages of psychotic illness creates a framework to evaluate the biological factors that may be contributing to the progression from early psychosis, to more advanced chronic stages of the disorder. This thesis used resting-state functional magnetic resonance imaging (fMRI) to characterise network functional connectivity and topology in early and late psychosis, as well as in a group of unaffected family members (UFM) of individuals with schizophrenia. Resting-state fMRI is a well validated and sensitive tool for probing the intrinsic functional integrity of the brain. Specifically, this thesis used a data-driven approach to map the temporal coherence of fMRI time series (functional connectivity) across the whole brain. To complement the resting-state functional connectivity (rs-FC) analysis, this thesis used graph theory to explore functional network topology. Network topology describes that brains ability to maintain a balance between local processing speed and global integration of information. These methodological approaches were used to investigate network abnormalities in three groups relative to healthy controls; a first-episode psychosis (FEP) group, a treatment-resistant schizophrenia (TRS) group and a group of UFM. This thesis aimed to investigate 1) whether rs-FC and network topology was abnormal in the early FEP stage of schizophrenia relative to healthy controls at two time-points (baseline and at 12-months follow-up); 2) whether rs-FC and network topology was impaired in a chronic TRS group relative to healthy controls; 3) whether abnormal rs-FC and network topology was evident in a group of UFM, and whether any network measure could be characterised as a marker of risk or resilience to psychosis in UFM. Firstly, results showed no evidence of abnormal rs-FC or topology in FEP individuals relative to healthy controls at baseline, or at the 12-months follow-up. Further, longitudinal changes in network properties over a 12-month period did not significantly differ between FEP individuals and healthy controls. Secondly, this thesis found widespread reductions in rs-FC in the TRS group that predominantly involved temporal, occipital and frontal brain regions. The TRS group also showed reduced global network efficiency and increased local efficiency relative to controls. Thirdly, TRS and UFM shared frontal and occipital rs-FC deficits, representing a ‘risk’ endophenotype. Additional reductions in frontal and temporal rs-FC appeared to be associated with risk that precipitates psychosis in vulnerable individuals, or may be due to other illness-related effects, such as medication. Functional brain networks were more topologically resilient in UFM compared to TRS, which may protect UFM from psychosis onset despite familial liability. Together, the body of work presented in this thesis provides a number of novel and unique findings that serve to advance the current state of knowledge regarding the pathophysiology and heritability of psychosis. Specifically, the work demonstrated that the latest most severe stage of psychosis, TRS, is associated with widespread reduced rs-FC, and that milder, yet similar patterns of dysconnectivity were observed in UFM, implying a genetic root to some, but not all of the observed network abnormalities. Network topology differed relative to healthy controls in both UFM and TRS patients, suggesting that functional network architecture is also disturbed in late psychosis, and again, results suggest a genetic/shared environmental basis for this characteristic. Our finding of no significant difference in rs-FC or network topology in our FEP sample suggests that there is a differentiation between biological processes occurring in early and late psychosis with a subgroup of individuals’ rs-FC potentially being unaffected in the FEP stage.
-
ItemExploration of the NRG-ErbB genetic pathway for biomarkers of Clozapine mediated symptom remission and symptom severity in treatment-resistant schizophrenia( 2017)Schizophrenia is a disabling mental health disorder that is characterized by positive symptoms (delusions, hallucinations etc.), negative symptoms (apathy, social withdrawal, emotional blunting etc.) and cognitive deficits (impaired memory, lack of attention etc.). Current pharmacological treatment includes typical and atypical antipsychotics but 20-30% of patients do not adequately respond to these treatments and are thus defined as treatment-resistant. Clozapine is indicated for the treatment of treatment-resistant schizophrenia (TRS). However, biomarkers of clozapine mediated symptom remission and symptom severity in TRS have yet to be identified. One promising biomarker is neuregulin 1 (NRG1), a growth factors that activates ErbB receptor tyrosine kinases and initiates the NRG-ErbB signalling pathway, which plays a key role in neurodevelopment. Genomic, transcriptomic, and proteomic abnormalities in NRG-ErbB pathway have been linked to schizophrenia and clozapine has been shown to modulate NRG1 gene and protein expression. Thus, NRG-ErbB pathway gene and protein expression profiles, as well as genetic variation, may serve as biomarkers for clozapine mediated symptom remission and symptom severity. In this thesis, we will present our investigation of the peripheral gene and protein expression levels of NRG-ErbB pathway genes in TRS patients and healthy controls and how they relate to clozapine mediated symptom remission as well as symptom severity. In addition, we will discuss the role genetic polymorphisms in NRG1 play in regulating its gene and protein expression. Finally, we will present results from healthy peripheral blood mononuclear cells exposed in vitro to clozapine for 24 hours and seven days and discuss the effects of clozapine on NRG-ErbB pathway gene and protein expression. Chapter 1 contains systematic review of scientific literatures and justifies the main 3 goals of the thesis. Chapter 2 of this thesis aimed at investigation of the candidate SNPs and microsatellites within the NRG1 gene among 16,720 patients, 20,449 controls, and 2,157 family trios via a meta-analytic procedure. We found significant association for three polymorphisms at the 5’ end (rs62510682, rs35753505, and 478B14-848) and two (rs2954041 and rs10503929) at the 3’ end of the NRG1 with schizophrenia. We could not find association for haplotypes. Chapter 3 aimed to assess the peripheral expression pattern of major NRG1 mRNA isoforms in whole blood and NRG1-β1 protein in serum in patients with TRS to find clinically useful biomarkers of clozapine mediated symptom severity and symptom remission. Using RT-qPCR we found upregulation of three NRG1 mRNA isoforms (NRG1 EGFα, NRG1 EGFβ, NRG1 typeI(Ig2)) in whole blood in TRS patients. However, protein assay via ELISA showed lower level of serum NRG1-β1 in TRS patients but it was confounded by smoking. Expression of NRG1 EGFα, NRG1 EGFβ was also negatively correlated with age of illness onset. In Chapter 4, we continued to examine the peripheral mRNA expression pattern of the major NRG-ErbB pathway downstream signaling genes in TRS patients and controls to see if increased expression in ligands leads to overexpression of receptors and subsequent upregulation of the full pathway in treatment-resistant schizophrenia. We found that five mRNA transcripts (ErbB3, PIK3CD, AKT1, P70S6K, eIF4EBP1) were upregulated in TRS patients, although only one (P70S6K) survived after correction for multiple comparisons. Moreover, investigation of the clinical factors revealed that expression of ErbB2, PIK3CD, PIK3R3, AKT1, mTOR, and P70S6K were negatively correlated with duration of illness. Chapter 5 summarises the main findings of the thesis, its relevance to previous literature, advancement of knowledge, implications and future steps in investigation of the NRG-ErbB genetic pathway for suitable biomarkers in schizophrenia, more specifically treatment-resistant schizophrenia.
-
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.