Psychiatry - Theses
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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.
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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.