Psychiatry - Theses

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    Inflammation in psychosis: Impact on brain structure and symptoms in animal models and humans
    Laskaris, Liliana Ellin ( 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.
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    Effects of childhood adversity and glutamatergic polygenic risk score on brain structure and cognition in schizophrenia
    Mohamed 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.
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    Functional brain networks in schizophrenia: mapping connectivity and topology at early and late psychotic illness stages
    Ganella, Eleni ( 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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    Exploration of the NRG-ErbB genetic pathway for biomarkers of Clozapine mediated symptom remission and symptom severity in treatment-resistant schizophrenia
    Mostaid, Md Shaki ( 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.
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    Piecing the puzzle together: white, grey and PET imaging across the course of schizophrenia
    Di Biase, Maria Angelique ( 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.
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    Investigating potential subgroups within the schizophrenias: a study of cholinergic muscarinic receptor density and energy metabolism
    Thomas, Natalie Paige ( 2016)
    Background. A crucial step towards understanding the aetiology of schizophrenia (SCZ), and developing more effective diagnostic methods and treatments is to identify and characterise potential subgroups within the diagnosis. There is growing evidence to support the existence of biologically discrete subgroups; one such demonstration is a subgroup denoted muscarinic receptor deficient schizophrenia (MRDS). Making up 25% of the SCZ population, these subjects are separated due to their marked loss (75%) in [3H] pirenzepine binding (cholinergic muscarinic M1 receptor preferring ligand), measured in the dorsolateral prefrontal cortex (DLPFC) in post-mortem brain tissue. Having established the SCZMRDS subgroup in our laboratory, we have the ability to investigate the pathophysiology that presents within this discrete subgroup. Study 1. Previous reports suggest lower [3H] pirenzepine and [3H] AF-DX 384 (muscarinic M2/ M4 receptor preferring ligand) binding in the caudate putamen (C.Pu) in SCZ subjects. However, it is not known if SCZMRDS subjects drive this decreased binding in the C.Pu, as they do in cortical regions. Therefore, to better understand the changes in muscarinic receptors in the C.Pu from SCZ subjects, and to delineate whether the SCZMRDS subgroup was identifiable in subcortical regions, we measured [3H] pirenzepine and [3H] AF-DX 384, and [3H] 4’DAMP binding in C.Pu from 40 SCZ subjects, 20 of which were SCZMRDS, 20 that were MRDSNON-MRDS, and 20 non-psychiatric controls (CTRL). These measures gave good estimation of muscarinic M1 receptor (CHRM1), CHRM2/4, and CHRM3 receptor levels, respectively. The level of [3H] pirenzepine binding was significantly lower in the C.Pu from subjects with SCZ when compared to CTRL (p < 0.0007). This was driven by the SCZMRDS group (p < 0.0001 relative to CTRL). The levels of [3H] AF-DX 384 binding was significantly lower in the C.Pu from SCZ subjects compared to CTRL (p < 0.0001); this was demonstrated more strongly in SCZMRDS subjects (p < 0.0001) than SCZNON-MRDS subjects (p < 0.001) when compared to CTRL subjects. No significant differences in [3H] 4’DAMP measures were shown. Collectively, the results demonstrated that the SCZMRDS subgroup had significantly different CHRM density profiles within the striatum, when compared to SCZNON-MRDS and CTRLS. These results reinforce the idea that SCZMRDS and SCZNON-MRDS cohorts are biochemically distinct with regards to CHRM biology. Within the cortex, reductions in CHRM density were observed predominately within the SCZMRDS cohort for all binding densities measured. Within the striatum however, reductions of [3H] AF-DX 384 binding were observed in both SCZMRDS and SCZNONMRDS subjects compared to CTRLS. This suggests that in terms of CHRM density, the striatum is more complicated compared to the cortex. As CHRM1/4 agonist therapy represents a promising approach for treatment of both the positive and cognitive symptoms in people with schizophrenia, these results characterising discrete subgroups with regards to CHRM density are extremely relevant to CHRM drug therapy discussions. Study 2. A recent microarray study by our group showed a significant decrease in the expression of Pyruvate dehydrogenase beta subunit (PDHß) in the dorsolateral prefrontal cortex (BA 9) from SCZMRDS subjects compared to SCZNON-MRDS subjects and controls. PDHß is the catalytic component of pyruvate dehydrogenase (PDH) that plays an essential role in its ability to convert pyruvate to acetyl-CoA, a rate-limiting step in the production of energy from glucose. Changes in levels of PDHß within the CNS could therefore have profound effects on energy utilisation in people with SCZ. The potential importance of such changes in PDHß led us to validate the microarray data. Quantitative PCR was used to measure levels of PDHß mRNA whilst Western blotting was used to measure levels of PDHß protein in BA 9 and the caudate in 40 SCZ subjects, 20 of which were SCZMRDS, and 20 non-psychiatric controls. Metabolite levels influenced by the rate of PDH activity were also measured in the caudate (pyruvate and lactate) in the same subjects. PDHß levels were not significantly different between SCZNON-MRDS or SCZMRDS and CTRL in BA9 at the levels of mRNA (p = 0.38), nor protein (p= 0.38). Within the caudate, protein levels were significantly different between the three groups (p < 0.05), where SCZNON-MRDS subjects demonstrated reduced levels compared to SCZMRDS and CTRLS. At the level of the metabolites, both pyruvate and lactate were increased in SCZNON-MRDS subjects compared to SCZMRDS and CTRL (p < 0.05, p < 0.01, respectively). Collectively, these results support the hypothesis that discrete biological subgroups in schizophrenia exist, segregating patients by the presence or absence of energy metabolism dysfunction, specifically PDH protein levels and the concentration of pyruvate and lactate within the caudate. Careful dissection of schizophrenia subgroups is an important step in understanding the aetiology of the syndrome. My data contributes to our understanding of biological subgroups and may ultimately help establish necessary biological markers and appropriate treatments for the diverse patients living with schizophrenia.
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    Hope and recovery in a family treatment for schizophrenia: a program evaluation of a family psychoeducational intervention
    Hayes, Laura ( 2014)
    A focus on recovery is increasingly widespread in practice and policy in services for people with schizophrenia and their families. Recovery principles suggest that hope is integral to recovery, which can occur (and implicitly hope can improve) independent of the symptomatic severity of mental illness. However, there is little research on this or recovery-focused services in general. This is a concern for services wishing to evaluate the provision of recovery-focused practices. Unless the relationship between hope and recovery is investigated broadly, the understanding and evaluation of recovery is compromised. Over 50 RCTs demonstrate the effectiveness of family psychoeducation (FPE) in reducing relapse in consumers and burden in carers. Although not studied previously, FPE appears well suited to improve hope and recovery because it develops purpose and support within families. This study investigated (1) the trajectory of hope, recovery and symptoms across an FPE program; and (2) the usefulness of a hope model which defined hope as the positive expectancy of achieving goals through optimism and self-efficacy. Emergent hope, in contrast, emphasises the beginning of hope as the “tiny fragile spark” in the midst of adversity. Method: The study used a mixed-methods, quasi-experimental design with consumers and relatives selected for FPE suitability, compared to TAU, conducted in community mental health centres in disadvantaged suburbs. Assessments conducted before and after 10 months of FPE or TAU included: hope, consumer functioning and symptoms; and carer distress and burden. Treatment satisfaction was assessed in participants from the treatment cohort. Results: 62 consumers and 63 carers were recruited across treatment and TAU cohorts; most consumers had persistent symptomology and fifty percent had co-morbidities. Average hope in consumers and carers was significantly below community norms. Higher symptoms were correlated with reduced hope. There were no changes over time in outcomes and no significant differences between FPE and TAU groups. Carers expressed some hopes in terms of positive expectancy and self-efficacy, but also discussed hopes without optimism for their attainment. Consumers did not express their hopes in terms of goals, motivation and planning. However, in the absence of objective changes, participants reported high levels of satisfaction with FPE. Conclusion: These results emphasise the lack of hope in consumers with severe and enduring mental illnesses and the need for new ways to address this important problem. The lack of treatment effect for FPE could not be attributed to low statistical power; the findings suggest there are considerable challenges in restoring hope and achieving recovery for this group of consumers. The study demonstrates the difficulties in translating evidence from successful efficacy trials into effective recovery-based programs. Hope was not independent of symptoms, consistent with other research, but not the recovery paradigm. A nuanced reading of recovery narratives suggests that while recovery can occur despite the persistence of symptoms, it is not a given. In the early stages of recovery and low levels of hope, symptoms can dominate positive expectancies. As a mix of optimism and efficacy, expectancy hope showed limited relevance, as it could not account for carer hopes expressed in the face of considerable adversity. Lower hope levels might be better assessed using emergent models of hope. These findings encourage closer attention to the successful implementation of FPE in routine practice, more research into the relationship between hope and recovery, and the need for suitable models and measures of hope to evaluate recovery-focused services.
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    Specialization and integration in brain networks underlying cognitive control in healthy individuals and patients with schizophrenia
    Harding, 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.
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    An investigation of the factors that regulate muscarinic receptor expression in schizophrenia
    Seo, Myoung Suk ( 2013)
    A previous study identified a group of subjects with schizophrenia, who have, on average, a 75% decrease in their cortical cholinergic receptor, muscarinic 1 (CHRM1). To begin to identify the potential factors responsible for the decreased CHRM1 expression, I investigated the DNA methylation level of CpG dinucleotides in the putative CHRM1 promoter region using the bisulphite-based Sequenom MassARRAY EpiTYPER in Brodmann’s area (BA9) from subjects with schizophrenia that have low levels of CHRM1 (SCZ Low [3H]PZP), subjects with schizophrenia that have normal levels of CHRM1 (SCZ Normal [3H]PZP) and control subjects. The levels of methylation were lower in both groups with schizophrenia compared to the control subjects. In addition, DNA methylation showed a strong positive correlation in the SCZ Low [3H]PZP but not those in SCZ Normal [3H]PZP, suggesting that the decreased level of CHRM1 in SCZ Low [3H]PZP was associated with a decrease rather than an increase in promoter DNA methylation, and they did not mediate the change in CHRM1 expression. Another aspect of my studies investigated the CHRMs levels in BA6 from subjects with schizophrenia. CHRM1, 3 and 4 levels were determined using in situ radioligand binding and Quantitative Real-time PCR (qPCR) in BA6 in the same groups. The results showed the levels of CHRM1 were significantly decreased in BA6 in SCZ low [3H]PZP but other CHRMs were not altered in either groups with schizophrenia. In further effort to discover the factors mediating the decreased CHRM1, levels of transcription factors, Sp1 transcription factor (SP1) and SP3 and miRNA-107, known to regulate CHRM1 expression, were determined using Western blot and qPCR. Levels of Sp1, Sp3 and miRNA-107 were not altered in either group of subjects with schizophrenia compared to those in control subjects. Finally, to identify potential regulatory systems, our laboratory conducted a microarray study to identify genes whose expression profile are changed in response to decreased CHRM1 in BA9. The mRNA levels of Ferredoxin 1 (FDX1) were differentially expressed in both groups of schizophrenia according to the microarray, and qPCR was used to validate this finding. FDX1 expression was increased in both groups of schizophrenia, validating the microarray finding. However, the levels of FDX1 were not changed in BA6 or in tissue from subjects with MDD (Major depressive disorder) or BPD (Bipolar disorder). Taken together, this study supports the existence of a subgroup within schizophrenia with dramatically decreased CHRM1 but not CHRM3 and 4 in the pre-frontal cortex. While the level of CHRM1 DNA methylation was changed in schizophrenia, the decreased CHRM1 expression was not simply regulated by local levels of transcription and post-transcription mechanism, such as Sp1, Sp3 and miRNA-107, suggesting that other mechanisms may contribute to the decreased CHRM1 in these subjects. Finally, the microarray validation study found the level of FDX1 mRNA was increased in subjects with schizophrenia. This finding is of particular interest given the metabolic dysfunction associated with the disorder.
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    Understanding the role of frontotemporal brain structures in schizophrenia through magnetic resonance imaging and neuropathological studies
    VELAKOULIS, DENNIS ( 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.