Recent developments in neuroscience have heightened the possibilities to tackle the prodromal stage of dementia. The purpose of this thesis is to identify the relationships between physical health, cognitive function, vascular risk burden and peripheral biomarker candidates in 108 older adults at risk of cognitive decline. The AIBL Active trial participants, aged 60 years and older (32 cases of MCI, 76 cases of SMC) with at least one cardiovascular risk factor present, completed a neuropsychological test battery and provided cross-sectional health data and physical activity information using a validated questionnaire and pedometer recordings. Cardiovascular parameters and blood tests determined if the participants met the clinical definition of metabolic syndrome that referred to a cluster of vascular and metabolic disturbances due to obesity and insulin resistance. This thesis utilised a preferred statistical standardisation of metabolic syndrome factors and obtained continuous variable (z-scores) to indicate the composite cardiovascular risk burden that addressed the progressive nature of the syndrome. Regression models adjusted for covariates examined the associations between the parameters and cognitive function. Almost two-thirds of participants met the national physical activity guidelines for older Australians with MCI or SMC (moderate-to-vigorous physical activity (MVPA) over 150 minutes per week), according to self-report (average 317 minutes/week). The pedometer estimated a mean of 6,926 steps/day for all participants. Participants with lower body mass index (BMI) and higher self-efficacy were 18% and 24% respectively more likely to meet the guideline recommendations. The risk severity of metabolic syndrome was inversely associated with pedometer tracked physical activity and the six-minute walk test, independent of global cognitive performance. The six-minute walk test has a stronger association with metabolic syndrome and may be a preferable assessment tool to evaluate exercise capacity compared to the timed-up-and-go test in participants at risk of cognitive decline. The metabolic syndrome components are traditional vascular and metabolic risk factors, but few cognitive studies have examined the combined risk severity. While cognitive tests scores were similar between the two groups with or without a clinical diagnosis of a metabolic syndrome, the continuous standardised z-scores for metabolic syndrome were associated with lower cognitive performance for global cognition and executive functions. Therefore, the combined risk burden (z-score) was more sensitive to cognitive associations than the presence or absence of the clinical syndrome. Multivariate regression analyses showed separate linear associations between vascular risk factors (fasting homocysteine, glucose and Framingham scores) and lower cognitive functions. The importance and originality of this thesis are that several peripheral biomarkers showed significant associations with cognition, including between increasing plasma tumour necrosis factor (TNF-alpha) and executive dysfunction and between increasing brain-derived neurotrophic factor (BDNF) and better global cognition. A model hypothesising the relationship between physical health, cognition, vascular risk factors and biomarkers is proposed. A higher cardiometabolic risk burden may point to opportunities for cognitive testing and lifestyle modification recommendation in older adults as individuals may experience cognitive changes. The findings in the peripheral biomarker analyses add to the evidence of associations between TNF-alpha, BDNF and cognitive deficits. Future longitudinal research will be needed to establish a direct link between health factors, biomarkers and cognitive decline in older adults at risk of cognitive deterioration.

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.

Background Epidemiological studies have suggested an association between posttraumatic stress disorder (PTSD) and Alzheimer’s dementia in Vietnam veterans. These studies, however, did not use biomarkers of Alzheimer’s disease (AD) to either confirm the diagnosis or assess the relative prevalence of AD pathology when investigating the risk of dementia in PTSD. Aim This study aimed at testing the hypothesis that Vietnam veterans with combat PTSD have an increased risk for Alzheimer’s disease in comparison with veteran controls as measured by biomarkers such as amyloid-beta and tau retention in the brain and regional hypometabolism and atrophy. Method Vietnam veterans with a history of PTSD as defined by the Clinicians-Administered PTSD scale (CAPS) score of 40 or above and veteran control subjects as defined by CAPS score of 30 or below and with no current clinical evidence of dementia participated in the study. Outcome measurements were amyloid-beta and tau deposition and regional brain metabolism and volumetry. Amyloid-beta and tau burden was estimated by the Specific Uptake Value Ratio (SUVR) of 18F-florbetaben, and 18F-AV-1451 respectively. 18F-fluorodeoxyglucose positron emission tomographic (PET) scan measured regional brain metabolism, and 3-Tesla T1 MP-RAGE Magnetic Resonance Imaging (MRI) estimated regional volumetry. Comprehensive neuropsychological battery measured cognitive function. Results Between March 2014 and June 2017, 83 male Vietnam Veterans (controls, n=30, CAPS=4; lifetime PTSD, n=53, CAPS=73.95; lifetime and current PTSD, n=30, CPAS=52.50) completed the assessments. There was no significant difference between the two groups in the uptake of 18F-florbetaben, 18F-AV-1451 or 18F-fluorodeoxyglucose, or regional brain volumetry. The rate of apolipoprotein E e4 allele was not significantly different between the groups. Compared with control veterans, the PTSD participants had a significantly lower level of education, predicted premorbid Intelligent Quotient (IQ), and total intracranial volume and higher depression rating score. The Montreal Cognitive Assessment score was significantly lower in the PTSD group than in controls. The group differences in Montreal Cognitive Assessment did not remain, however, when adjusted for premorbid IQ or depression in a multilinear regression model analysis. Conclusions Posttraumatic stress disorder is not associated with an increased prevalence of biomarkers of Alzheimer’s disease. The proxy measures of cognitive reserve, a factor that may delay the onset of Alzheimer’s dementia, were relatively low in subjects with PTSD, and this may explain the previously reported higher incidence of dementia in subjects with PTSD compared to age-matched controls.

The structure, function and connectivity of the human brain are topographically organized. This topographic organization provides profound insight into cortical information processing, representation of mental states, and accounts for individual variation in behavioral traits and cognition. Whereas classical models of brain topography focus on distinct cortical patches defined by discrete boundaries, contemporary evidence from neuroimaging suggests that topographic variation may be better conceptualized in terms of a set of continuous gradients of gradual change that overlap in space. My work aims to reconcile these two conceptualizations of brain topography, particularly with respect to the insular cortex, a topographically complex and functionally heterogeneous cortical lobe whose organization has remained disputed for centuries. Using modern functional neuroimaging techniques, I showed that the insula’s topography is best conceptualized as a continuum of gradual change oriented along an anterior-posterior axis. I found that individual variation in the insula’s functional topography associates with human cognitive and emotional traits as well as somatosensory functions. Having characterized the functional architecture of the insular cortex in healthy adults, my next aim was to investigate whether neuropsychiatric illness is associated with alterations in the insula’s functional organization. To this end, I compared the insula’s functional connectivity gradients between individuals with schizophrenia and healthy controls. I found evidence suggesting subtle reorganization of the insula’s functional topography in schizophrenia. In particular, the connectivity profile along the anterior-posterior topographic axis of the insular cortex was altered and less differentiated in individuals with schizophrenia. I showed that the extent of reorganization of the insula’s functional topography significantly associates with the severity of clinical symptoms, particularly negative symptoms of psychosis and intellectual impairment. Finally, I applied the new methodology that I developed to map the insula’s topography to study other brain regions, including the entire human subcortex. This unveiled four hierarchical scales of subcortical organization, recapitulating well-known anatomical nuclei at the coarsest scale and delineating 27 new bilateral regions at the finest. Based on this work, I developed a new MRI subcortical atlas to enable holistic connectome mapping and characterization of cortico-subcortical circuits. The new subcortex atlas was personalized to account for connectivity differences across individuals and utilized to uncover a reproducible association between subcortical functional connectivity and tobacco use. Overall, this thesis provides fundamental insight into the functional organization of the human insular cortex and subcortex in health and neuropsychiatric illness, particularly focusing on the distinction between classical models of topographic variation based on discrete regions and contemporary representations involving continuous gradients. The new methodology that I developed is not limited to the insular cortex and the subcortex and can be applied to other cortical and subcortical regions in humans as well as other species.

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.

Communication between neural elements underpins all aspects of brain functioning. Large-scale neural signalling unfolds atop the human connectome, the complex network that describes how gray matter regions are interconnected by white matter projections. The mechanisms governing the propagation and communication of signals across the connectome remain unknown. The main focus of this thesis is the investigation of network communication models aimed at elucidating how the anatomical substrate of nervous systems facilitates and constrains functional interactions between gray matter regions. To date, the vast majority of network neuroscience studies have assumed neural signalling occurs via topological shortest paths. This is reflected by the widespread use of graph measures such as global efficiency, betweenness centrality and the small world coefficient. In recent years, researchers have begun to question this assumption on the basis that communication via shortest paths is contingent on centralized knowledge of connectome topology, and thus may not be a biologically realistic signalling model. This has led to the exploration of decentralized strategies of network propagation. Most efforts in this direction are focused on diffusive communication, which typically models neural signalling from the perspective of random walk processes. While these approaches do not mandate knowledge assumptions about network organization, they fail to promote efficient and energetically frugal neural information transfer. Therefore, the literature on brain network communication models is currently concentrated on the opposing strategies of shortest path routing and diffusive communication. This thesis aims to reconsider this dichotomous state by investigating alternative brain network communication models. In Chapter 3, we explore the concept of navigation in mammalian connectomes. Navigation is a greedy routing strategy in which information is propagated based on the spatial positioning of brain regions. Using human, macaque and mouse brain networks, we provide evidence that connectome organization is conducive to decentralized efficient communication under navigation. Specifically, the combination of empirical connectome topology and geometry was necessary for successful network navigation, with disruptions to either attribute resulting in marked decreases of navigation efficiency. These findings suggest that brain network architecture may have evolved to facilitate efficient decentralized information transfer, and indicate a three-way relationship between topology, geometry and communication in nervous systems. Decentralized network communication models can be asymmetric. This means that the efficiency of signalling paths may vary depending on the direction of information flow. Importantly, this behaviour occurs even in undirected networks. This unexplored facet of network communication provides the opportunity to study directional patterns of signalling in the human structural connectome, in which all connections are considered bidirectional due to the inability of diffusion imaging to resolve axonal directionality. In Chapter 4, we develop the statistical framework of send-receive asymmetry and demonstrate that it contributes novel insight into large-scale neural signalling directionality. Crucially, this chapter provides cross-modal evidence for the utility of decentralized communication models by demonstrating a statistical association between send-receive asymmetry and the directionality of effective connectivity. Lastly, in Chapter 5 we perform a systematic evaluation of the main neural signalling models proposed in the network neuroscience literature. We evaluate models in terms of their (i) predictive utility of interindividual variation in human behaviour and (ii) structure-function coupling strength. We hypothesize that communication models performing better in these criteria may provide more parsimonious characterizations of information transfer mechanisms in the human brain. Importantly, we benchmark communication models against structural connectivity, and provide evidence that accounting for polysynaptic communication improves the behavioural and functional predictions derived from direct anatomical connections alone. Combining behavioral and functional results into a single ranking of communication models positioned navigation as the top model, suggesting that it may more faithfully recapitulate biological neural signalling patterns. The results in this chapter contribute to elucidating the relationship between human behaviour, functional connectivity and connectome communication. Collectively, the findings reported in this thesis further our knowledge of large-scale neural signalling, promoting a unified understanding of brain structure, function and communication.

Adolescent mental health research is a developing area. Existing treatment guidelines for adolescent mental health care in most western countries emphasise the role of inpatient care when needed. Inpatient units are the most widely used acute element of adolescent mental health services internationally. Yet little is known about inpatient units, their therapeutic operations, models of care and perceived helpfulness. Less is known about general adolescent inpatient units from the perspectives of adolescents, caregivers and clinicians. In order to address this gap in understanding an adolescent inpatient model of care in operation, a prospective mixed-methods approach was adopted. Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) were collected, measuring global functioning at T1 (admission) and T2 (discharge). Semi-structured interviews were conducted with 16 adolescents and 12 caregivers at T1, T2 and T3 (six months post discharge). Qualitative data were first analysed thematically followed by a trajectory analysis. One-off semi-structured interviews were conducted with clinicians (n=10) and analysed using thematic analysis. Data collection began in May 2017 and ceased in October 2018. The majority of adolescents (n=72) were 16 years of age (26%), female (82%) and with a primary diagnosis of a mood disorder (57%). HoNOSCA data were completed by clinicians (n=57) and adolescents (n=56). Most adolescents improved at the time of discharge. Self-injury and emotional symptoms had greater reductions according to clinician and adolescent-self-ratings (p<0.01). Mean change (improvement) in HoNOSCA total score was 7.3 (SD 7.5) based on clinician ratings and 7.2 (SD 9.5) for adolescent-self-ratings. The mean length of stay was 28 days (SD 15.8). Interviews with clinicians resulted in the identification of three thematic features of the model of care relating to containment, engagement and therapy. These included; (a) an environment conducive to containment, (b) adolescent engagement through shared experiences and (c) dialectical behaviour therapy embedded culture. Adolescent and caregiver experiences described followed a recovery narrative consisting of three key phases which included, ‘waiting for help’ (T1), ‘help arrived’ (T2) and having ‘returned to regular life’ (T3). The overarching trajectory theme was a ‘winding road to recovery’. Findings revealed the admission was helpful for many young people who were on the winding road to recovery. These findings provide insights into the lived experiences from adolescents who have had an inpatient stay and their caregivers of an adolescent specific inpatient model of care. These findings should be used to improve clinical services and inform research aiming to articulate exemplary adolescent inpatient models of care. Furthermore, the findings provide guidance and practical information to commissioners, clinicians and policy makers implementing models of care. Finally, the detailed findings provide a foundation for planning inpatient care that is valued by clinicians, young people and their families.

The idea that receiving social support in the aftermath of a disaster is beneficial to survivors’ psychological outcomes is widely accepted by both researchers and practitioners. However previous studies assessing the association between received social support and psychological outcomes have produced mixed results. One limitation of these studies is that they only assessed the quantity of support received, but not its quality. However, current evidences suggested that receiving social support is not always beneficial, this can lead to both positive and negative consequences. This research was intended to examine the effects of postdisaster received social support on psychological outcomes, and to explore the determinants of recipients’ perception of social support interactions. In the context of a longitudinal mixed method design, three studies were conducted among survivors of the Lushan earthquake in China: a longitudinal quantitative study examining the impact of post-disaster received social support on posttraumatic stress symptoms and psychological distress; a longitudinal quantitative analysis examining the impact of post-disaster social support on posttraumatic growth; and a qualitative study describing survivors’ experiences of receiving postdisaster social support, and exploring what matters to recipients in their evaluation of these experiences. A convenience sample of Lushan earthquake survivors was invited to complete a questionnaire 7 months after the earthquake (n =199) and was followed up 31 months later (n =161). Face-to-face semi-structured interviews were conducted by the author among a sub-group of participants (n =11) in the follow-up survey. This thesis found that greater quality of social support received 7 months after disaster predicted lower levels of posttraumatic stress symptoms and psychological distress two years later, however quantity of received social support was not significant in predicting these two outcomes. The association between quantity of received social support and PTG was moderated by the quality of received social support. Specifically, for survivors who received high quality of post-disaster social support, greater amounts of support received facilitated their posttraumatic growth. However, for those survivors who received poor quality of post-disaster support, greater quantity of support impeded PTG. Social support recipients cared about features related to outcomes, interaction, provider and management. First, recipients cared about features of the outcomes of social support interactions; that is, whether the support that was received fulfilled their needs, and also whether the distribution of support was equal and fair. Second, they cared about whether the interaction goes smoothly and easily; whether the interaction was initiated by providers; whether the interaction was public and therefore witnessed by others; whether they were treated with dignity in the interaction; and whether they had opportunities to reciprocate. Third, characteristics of help providers, including whether they sincerely wanted to help them, and what they devoted in order to provide assistance, also matter. Lastly, the efficacy and appropriateness regarding the management of disaster relief resources was concerned by recipients.

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.

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.

Aims: This study aimed to investigate the prevalence of the common mental health disorders associated with increased exposure to potentially traumatic events in career and volunteer firefighters, and to identify which individual, acute stressor, operational and organisational factors predict mental health outcomes. Method: Four Australian services participated in a prospective study, with 335 firefighters completing an online survey twice (12-months apart). The survey comprised demographic and fire service information, self-report measures for PTSD, depression, anxiety, alcohol use, exposure to personal trauma and life stressors, number and types of firefighter-related potentially traumatic events experienced in the previous 12-months, job satisfaction related to operational and organisational characteristics of their role, and a measure of the priority their fire service placed on their psychological wellbeing. Structured clinical interviews were conducted with a sample of survey respondents to assess for PTSD, depression, generalised anxiety disorder and alcohol use disorder. Results: From 297 clinical interviews (91 career firefighters and 206 volunteer firefighters), 24% (n = 22) of the career firefighters met diagnosis for any psychiatric disorder. Of these, 3% met criteria for PTSD, 5% for depression, 4% for generalised anxiety disorder, and almost 12% for alcohol use disorder. The primary regression analyses indicated the following findings for the career firefighters. The main variable associated with each of the four disorders was the respective level of symptoms at baseline. In addition, exposure to more potentially traumatic events in the previous 12 months contributed to, and high job satisfaction associated with the operational aspects of their role protected them against the development of PTSD and depression. Finally, the findings indicated that experiencing more recent life events in the previous 12 months and rank (being a firefighter) contributed to more symptoms of Alcohol Use Disorder. From the interviews 17% (n = 35) of the volunteer firefighters met diagnosis for any psychiatric disorder. Of these, 2% met criteria for PTSD, 4% for depression, 5% for generalised anxiety disorder, and 6% for alcohol use disorder. The primary regression analyses indicated that the only predictor of PTSD, generalised anxiety disorder and alcohol use disorder was the respective baseline level for each disorder. The main predictors of depression were baseline level of symptoms of depression and experiencing more recent life events in the previous 12 months. Conclusions: The relatively low prevalence rates for the career and volunteer firefighters in this study indicate their reasonably good mental health across the four disorders. The rates compare favourably with other firefighter studies and are comparable with the rates in the general population for most disorders. An exception to this was volunteer firefighters’ high rate of alcohol dependence and low rate of PTSD. The findings indicate the importance of fire services developing cultures that support and encourage the early identification and management of symptoms and have systems in place to monitor the types of and frequency of firefighters’ exposure to potentially traumatic events. Finally, particularly for the career firefighters, the findings highlight the protective nature of high job satisfaction associated with operational characteristics of their role and reduced mental health symptoms, and the importance for firefighters and managers to recognise and address reductions in job satisfaction.

Background: Greater levels of internalising symptoms during childhood and adolescence increase the risk of developing depression later in life. As such, investigating risk factors for depression in young people is important for understanding the aetiology of the disorder and for informing prevention strategies. Whilst it is known that extreme forms of childhood adversities, such as childhood trauma and abuse, represent a risk factor for depression, less has been done in investigating the effect of parenting behaviour. Emerging research suggests that negative parenting practices (e.g., parental rejection), as well as the lack of positive parental behaviours, increase the risk of internalising symptoms during childhood and adolescence. One of the proposed mechanisms linking poor parenting practices and depression is the effect of parenting behaviour on brain function and brain structure, particularly in regions involved in processing and regulating responses to emotional stimuli, such as the amygdala, prefrontal cortex and hippocampus. Animal studies suggest that parenting may affect the brain via effects on the hypothalamic-pituitary-adrenal (HPA) axis, which has a central role in the response to stress. Genetic factors are also likely to play a role, whereby genetic variants in HPA axis genes may contribute to the regulation/dysregulation of the system. To date, however, there is a lack of research focusing on genes related to HPA axis function, and their interaction with environmental factors (including parenting) in predicting internalising symptoms. Further, no research has investigated the neural mechanisms by which parenting behaviours, HPA genes, and their interaction, exert their influence on internalising symptoms. The aim of this thesis was to investigate a) whether parenting behaviour interacts with HPA genes to influence internalising symptoms in children/adolescents, and b) whether brain structure/function of regions involved in emotion processing (particularly the amygdala and hippocampus) mediates this link. Method: Data from two longitudinal studies were used in this thesis: the Adolescent Development Study (ADS) and the Families and Childhood Transitions Study (FACTS), to explore aims across three experimental chapters. The first study included 98 adolescents from the ADS, for whom hippocampal structural development was measured from magnetic resonance imaging (MRI) scans performed across three waves (W): W1 (mean age =12.6 years), W2 (mean age=16.5 years), W3 (mean age =18.8 years). Maternal negative behaviour was measured at W1 from an observed interaction task. Adolescents’ depressive symptom severity was measured at W1 and W3 with self-reported questionnaires, and genetic risk was calculated using a composite HPA genetic risk score. The second and third studies included 86 (mean age=10.1 years) and 80 (mean age=10.0 years) children, respectively, from FACTS. Observational measures of maternal parenting behaviour were collected during mother-child interactions. Children underwent functional MRI (fMRI) while performing an implicit emotion-processing task. Self-reported and parent-reported measures of child internalising symptoms were also collected. HPA genetic risk was calculated in a similar fashion to the first study. Results: Across both studies, neither HPA genetic risk score nor the interaction between HPA genetic risk score parenting behaviour predicted internalising symptoms in children/adolescents. For study 1, we did not find support for a mediating role of hippocampal structure in the relationship between parenting behaviour and internalising symptoms. Rather, we found a moderation effect such that negative maternal parenting behaviour predicted depressive symptoms longitudinally in adolescents with flattened hippocampal growth and HPA genetic risk. While maternal behaviour was not associated with hippocampal development, in study 2 it was associated with activity/connectivity in brain regions involved in emotion processing. In particular, maternal negative behaviour during a problem-solving interaction was associated with increased amygdala reactivity and connectivity with parietal cortex in children. Maternal negative behaviour during an event-planning interaction was associated with decreased activity in the lingual gyrus in girls. Maternal communicative behaviour was associated with increased medial orbitofrontal cortex activity. These parenting-related neural findings were not associated with child internalising symptoms. In study 3, HPA genetic risk predicted increased amygdala-precuneus connectivity, which in turn was associated with greater internalising symptoms in children. Moreover, HPA genetic risk interacted with negative maternal parenting behaviour to predict increased connectivity between amygdala and superior frontal gyrus, anterior cingulate cortex and parietal cortex. Conclusion: These results suggest that there is a complex interplay between neurobiological, environmental and genetic factors in predicting internalising symptoms in children and adolescents. Neurobiological factors (e.g., hippocampal development) may act as an independent risk factor for depressive symptom severity, but they may also be influenced by environmental and genetic factors. Parenting behaviour, particularly maternal negative and communicative behaviour, may influence brain activity and connectivity in regions involved in emotion processing. The lack of association with internalising symptoms hampers our ability to draw conclusions on the significance of the parenting-related neural findings for children’s mental health. However, given that depression is characterised by impaired emotion processing, including increased sensitivity towards negative stimuli, we speculate that differences associated with negative parenting behaviour, such as amygdala heightened reactivity to negative stimuli, may represent a risk factor for the disorder. HPA genetic variants may moderate the effect of parenting behaviour on these circuits (particularly the frontoamygdala circuitry), such that not all children are sensitive to parenting effects on neurobiology, and may confer risk for depression via altering corticolimbic connectivity. This study highlights the importance of parenting behaviour for children emotional neurocircuitry development and demonstrates the moderating role of genetic factors.

Background Adolescence is widely reported to be a time of increased risk for depression and lower well-being. Importantly, however, outcomes are heterogeneous, and most adolescents do not develop mental health problems. In order to understand how these differences emerge, both environmental and biological factors have been examined in the literature. Evidence indicates that parenting behaviour, socioeconomic status and neurobiology may contribute and, further, that individual differences in brain development may moderate the extent to which contextual factors influence adolescents. That is, individual differences in brain development may confer ‘responsivity’ to context. Several developmental and evolutionary-developmental models provide frameworks with which to interpret such brain-by-environment interactions, and to describe biological responsivity – these are broadly associated with diathesis-stress and differential susceptibility/biological sensitivity frameworks. Broad PhD aim This thesis aims to investigate whether structural brain development moderates adolescent sensitivity to maternal parenting behaviour in the prediction of adolescent depressive symptoms and psychological well-being. Two empirical studies were completed to address this aim. Study 1 examined whether longitudinal change in brain structure modified adolescent vulnerability or susceptibility to aggressive and positive maternal parenting. Effects were assessed to infer evidence in support of either diathesis-stress or differential susceptibility frameworks. Study 2, in light of evidence that positive parenting protects against adversity, considered whether brain development moderated adolescent sensitivity to positive parenting, and whether this association was more pronounced for adolescents with low-socioeconomic status (SES). Methodology During early adolescence (age 13 years), participants completed observed interactions with their mothers, and the frequency of positive maternal behaviour was coded. At three time points (mean ages 13, 17 and 19 years), participants completed structural magnetic resonance imaging (MRI) scans. During late adolescence (age 19 years), participants completed self-report measures of depressive symptoms and psychological well-being. Two separate analyses (studies) were conducted in predicting late adolescent (age 19) outcomes (depressive symptoms and psychological well-being). For both studies, longitudinal brain development was indexed by changes in cortical thickness of structures within the frontal lobe, and volumetric changes of subcortical structures, from early to late adolescence. Study 1: Regression models analysed interactions between maternal behaviour and longitudinal brain development in the prediction of adolescent outcomes. Indices designed to distinguish between diathesis-stress and differential susceptibility effects were employed. Study 2: Regression models were used to investigate interactions between SES (parental occupation), positive maternal behaviour, and longitudinal brain development in the prediction of adolescent outcomes. Results Study 1: Results supported differential susceptibility, whereby less thinning of frontal regions (the left medial orbitofrontal, rostral middle frontal and superior frontal cortices, and the right pars opercularis) was associated with higher well-being in the context of low levels of aggressive maternal behaviour, and lower well-being in the context of high levels of aggressive maternal behaviour. Study 2: Results indicated that individual differences in structural brain development moderated the extent to which positive parenting impacted adolescents dependent on SES. High levels of positive parenting were associated with reduced depressive symptoms for low-SES adolescents with greater volumetric reduction of the right putamen. Further, low positive parenting was associated with reduced psychological well-being for individuals with greater neurobiological sensitivity, however, patterns of brain development that were associated with sensitivity differed by SES. Specifically, low positive parenting was associated with reduced psychological well-being for individuals with more thinning in the context of low-SES, but for individuals with less thinning in the context of high-SES. Significance Results across studies suggested that structural brain development may be associated with individual differences in how sensitive adolescents are to context. Study 1 indicated that reduced frontal cortical thinning during adolescence increased susceptibility to maternal aggressive behaviour in the prediction of well-being, for better and for worse. This finding is significant because it suggests that neither more or less cortical thinning is consistently good or bad for mental health. Results from Study 2 indicated that, although brain change was associated with responsivity to parenting behaviour, patterns of brain development associated with heightened responsivity to parenting were different for high- and low-SES. These results suggested that responsivity functions in a context dependent fashion and highlights the complex interactions that may occur across biological and multilevel environment factors. Results from these studies suggest that structural brain development may be a marker of responsivity to environmental influence. They also emphasise the importance of examining how brain development moderates the impact of multilevel environmental factors on mental health outcomes. Such study designs may better reflect the social settings in which adolescents develop.

The transition from childhood to adolescence is a particularly vulnerable period for the development of internalising symptoms and disorders. Hormonal changes as well as changes in brain structure and function may play a role in this increased vulnerability. Most of the research to date has focused on the hormonal and brain changes during gonadarche, whereas the literature is much more limited for adrenarche, an earlier pubertal phase that takes place prior to gonadarche. Therefore, this thesis aimed to examine how (changes in) adrenarcheal hormones relate to the development of brain structural and functional connectivity, and how that in turn affects internalising symptoms in late childhood to early adolescence. Data were used from two longitudinal community-based samples with two time points each (sample 1 M ages 9.5 and 12.2 years; sample 2 M ages 8.5 and 10 years). At each time point in each study, levels of dehydroepiandrosterone (DHEA), its sulfate (DHEAS) and testosterone were measured and averaged from morning saliva samples collected across several days. Participants also underwent Magnetic Resonance Imaging (MRI) scans, and completed self-report questionnaires, at both time points. Diffusion-weighted imaging scans were analysed to examine white matter structural connectivity. Functional Magnetic Resonance Imaging (fMRI) scans during an affective face processing paradigm were analysed to examine functional connectivity. Levels of internalising symptoms were based on self-report questionnaires: the Spence Children’s Anxiety Scale, the Children’s Depression Inventory, and the Positive And Negative Affect scale. Analyses were conducted to investigate associations between hormone levels (initial levels and changes in levels over time) and brain structural and functional connectivity (baseline and change over time). Analyses were also conducted to investigate whether hormone-related changes in structural/functional connectivity were associated with symptoms. The results showed that children with high DHEA levels at age 9 had higher mean diffusivity (cross-sectionally) in a wide range of white matter tracts, suggesting that relatively early exposure to DHEA might be negatively associated with white matter microstructure. Changes in testosterone from age 8.5 to 10 years were negatively associated with the development of white matter structure as quantified by fibre cross-section in posterior white matter tracts. Higher levels of testosterone at age 8.5 years, however, were related to stronger development of fibre cross-section from age 8.5 to age 10 years. These hormone-related changes in white matter structure were not significantly associated with levels of internalising symptoms. Analyses of functional connectivity during affective face processing focused on connectivity of the amygdala to the rest of the brain, because of the crucial role of the amygdala in emotion processing and consistent findings of its involvement in internalising disorders. Indirect effects were found of adrenarcheal hormone levels (controlled for age, potentially indicating a timing effect, i.e. maturation relative to same-age peers) on anxiety symptoms at age 9 years, mediated by amygdala connectivity to visual and limbic areas. Timing of adrenarcheal hormone exposure was also found to have indirect effects on anxiety symptoms longitudinally. Specifically, higher DHEA at age 9 years was indirectly related to more anxiety symptoms at age 12 years, controlling for symptoms at age 9 years, via more positive amygdala to inferior frontal gyrus connectivity. Thus, the findings in this thesis have demonstrated that elevated adrenarceal hormone levels (potentially reflecting early timing of adrenarche) are both cross-sectionally and longitudinally associated with anxiety symptoms through an effect on amygdala functional connectivity. We also showed that the hormonal processes of adrenarche have an impact on white matter microstructure development. These findings have implications for the understanding of how individual variation in adrenarcheal processes can impact children’s brain development and mental health. Future studies should examine whether effects of variation in adrenarcheal processes on brain development and mental health are persistent, as well as establish whether predictors found in the current thesis are also relevant in clinical samples.

Background: Traumatic brain injury (TBI), has been diagnosed in over 355,000 US military service personnel since 2000. Epidemiological research indicates that veterans with TBI are two-to-four times more likely to develop dementia than controls; however, mechanisms contributing to this relationship are poorly understood. The aim of this study was to investigate if Vietnam war veterans with a TBI show evidence of Alzheimer’s disease (AD) pathological markers, as assessed by A-amyloid, tau and glucose metabolism using PET, as well as structural MRI, including diffusion tensor imaging, and neuropsychological testing. Methods: Sixty-nine male veterans - 40 with TBI (aged 68.0±2.5 years) and 29 controls (aged 70.1±5.3 years) - underwent A-amyloid (18F-Florbetaben), tau (18F-AV1451) and 18F-FDG PET, MRI, psychiatric and neuropsychological assessment. The TBI cohort included 15 participants with mild, 16 with moderate, and 9 with severe injury. Fractional Anisotropy (FA) was employed as a measure of white matter tissue integrity. PET Standardized Uptake Value Ratios (SUVR) were calculated using the cerebellar cortex as reference region. Analyses were adjusted for IQ, age, ApoE status and psychiatric comorbidities. Results: Veterans with moderate-to-severe TBI performed significantly worse than controls on composite measures of memory and learning (M = -0.55  0.69, t(67) = 2.86, p=0.006, d=0.70) and attention and processing speed (M = -0.71  1.08, t(52) = 2.53, p=0.014, d=0.69). The moderate-to-severe TBI group had significantly lower FA than controls in the genu (F(3,36)=8.81, p<0.05, partial 2 = 0.17), and body (F(3,36)=4.39, p <0.05, partial 2=0.14) of the corpus callosum, as well as in global white matter (F(3,36)=5.35, p <0.05, partial 2=0.13). There were no significant differences in 18F-Florbetaben or 18F-AV1451 uptake amongst the groups, however the moderate-to-severe TBI group had significantly lower 18F-FDG retention than controls in the mesial temporal region (F(8,44) = 2.21, p <0.05, partial 2 = 0.13). No differences were found between the mTBI group and controls on any of the outcome measures. Conclusions: These findings indicate that moderate-to-severe TBI, but not mTBI, is associated with later-life cognitive deficits, and diminished global white matter integrity, specifically in the corpus callosum. However, these deficits are not associated with AD pathology. These results are consistent with current evidence of white matter axonal damage as the primary source of cognitive impairment in TBI, and are not reflective of a neurodegenerative process.

Parents who have experienced interpersonal trauma in childhood often struggle with relational functioning including difficulties with nonverbal communication (NVC), which may influence their ability to remain regulated during parent-child interaction. The challenges of parenting an adolescent may trigger memories of maltreatment, intensifying conflict, resulting in negative cycles of relating and poorer responsiveness to emotions when parenting. The thesis first explored existing knowledge about NVC in parent-child relationships. Then, the efficacy of Tuning Relationships with Music™ (TRM), an intervention developed by the author for parent- adolescent dyads experiencing heightened conflict where the parent has an interpersonal trauma history, was examined. TRM was expected to reduce conflict and adolescent mental health difficulties and improve parent responsiveness and emotion coaching. A randomised control (RCT) design was used where 26 parent-adolescent dyads were recruited from community services. Dyads were randomly allocated into intervention or wait-list control, completing self-report and observational measures at baseline, and again four months later. The thesis includes three studies. Study 1 reviews the literature about how nonverbal communication (NVC) is assessed and intervened with in parent-child relationships, in order to inform TRM development. Results showed that reliable and validated NVC assessment tools are not routinely used to inform intervention development or measure effectiveness, and that very few interventions directly target parent-child NVC. Study 2 reports on outcomes from the RCT of TRM, which found dyads that participated in TRM reported significantly reduced conflict, and parents were clinically observed to be less reactive and more responsive compared with dyads in the control condition. Although parents reported they were less dismissive and punitive, and more encouraging of their adolescent’s emotions, and both parents and adolescents reported improvements in the young person’s mental health, these were not statistically significant. Study 3 examined dyads as a single dynamic system during nonverbal conflict interaction, and aimed to examine relationships between parents’ trauma history, parent-adolescent conflict, parents’ reactivity and non-responsiveness, and dyads’ emotion regulation, consistency and predictability. A second aim was to discover whether TRM’s focus on NVC and emotion regulation would have an impact on post-intervention dyads’ nonverbal conflict interaction compared with controls. State space grid analyses showed that where parents reported higher levels of parent conflict this was correlated with predictable NVC sequences while dyads were emotionally dysregulated, and parents’ reactivity was correlated with dyads’ inconsistent NVC. Post-intervention dyads were more emotionally regulated, consistent and predictable during their nonverbal conflict interaction. Findings have important implications for intervention with parent-adolescent dyads where a parent has a childhood interpersonal trauma history, suggesting that a systemic focus on NVC and emotion regulation may assist dyads to reduce conflict and increase responsive interaction. This thesis makes a contribution to existing understandings of the systemic dynamics of parent-adolescent conflict where a parent has experienced interpersonal trauma, suggesting that using music to improve emotion regulation and NVC may reduce conflict and improve parents’ responsiveness in parent-adolescent relationships. Further research of TRM with a larger sample will be useful, to determine whether a focus on nonverbal processes may improve relational functioning.

In the last decade, consistent efforts have been made by psychiatric geneticists to elucidate the genetic mechanisms of schizophrenia, especially after the rise of genome-wide association studies (GWAS). However, the genetic etiology of schizophrenia has not been fully discovered, and enormous genetic datasets have been produced, allowing for additional investigation. In my PhD study, I have systematically identified candidate gene and GWAS in schizophrenia. Furthermore, I have re-analyzed these genetic datasets using meta-analyses, pathway analyses and evolutionary-based analyses. The results of these studies revealed new and supported current candidate loci, genes and pathways associated with increased risk of schizophrenia. I also provided evidence supporting a novel evolutionary mechanism for schizophrenia that extended the current conceptualizations of how schizophrenia emerged. In Chapter 1, I introduced the progress of genetic studies already achieved in schizophrenia, including family and twin studies, linkage studies, candidate gene association studies, genome-wide association studies, copy number variation studies and wholeexome/genome sequencing studies. A literature review of GWAS in schizophrenia and the aims of the thesis are included in this Chapter. Chapter 2 of this thesis provides a systematic review of genetic association studies in schizophrenia. In this study, I have reviewed more than 3000 association studies and merged them with the data from the existing schizophrenia knowledgebase (SzGene). Two rounds of meta-analyses, i.e. candidate-gene-only meta-analyses and expanded meta-analyses combined with samples from GWAS, have been conducted. In total, I have identified 21 Bonferroni significant single nucleotide polymorphisms (SNPs) in 14 Linkage disequilibrium (LD)-independent loci associated with schizophrenia susceptibility. Three of these loci, including methylenetetrahydrofolate reductase (MTHFR), D-amino acid oxidase activator (DAOA) and ARVCF, delta catenin family member (ARVCF), had never been implicated by a schizophrenia GWAS. Chapter 3 aimed to test the notion that schizophrenia is a pathway disorder. In this study, I conducted a pathway-wide association study, testing the association between schizophrenia and 255 biological pathways. Five independent GWAS datasets across three distinct ethnic populations were collected for pathway analyses. Almost half of biological pathways were associated with schizophrenia in each of three populations, and five of them (serotonergic synapse, ubiquitin mediated proteolysis, hedgehog signaling, adipocytokine signaling and renin secretion) were shared across three populations. These findings suggest schizophrenia is a poly-pathway disorder, and provide empirical support for that notion. In Chapter 4, I attempted to address the evolutionary paradox of schizophrenia: why negative genetic selection has not eliminated the deleterious alleles associated to schizophrenia susceptibility from the modern human genome? Using evolutionary markers in the genome, I showed that modern humans carried more protective SNPs for schizophrenia compared with our collateral ancestors: Neanderthals and Denisovans. Based on these findings, I proposed a novel framework to explain the evolutionary paradox and genetic origin of schizophrenia. In Chapter 5, the main findings and conclusion of my thesis are summarized. In addition, an expanded discussion of the meta-analyses of genetic association studies, the pathway-wide association study, and the evolutionary analysis are provided along with limitations and future directions.

Neuropsychiatric disorders commonly co-exist with focal epilepsy. Despite intense investigation there remains significant limitations to our current understanding of the aetiological relationship between these conditions, as well as the clinical and radiological factors that are associated with the development of mental illness in epileptic patients. To address these questions I assembled a large cohort of consecutive focal epilepsy patients reviewed at a large tertiary referral centre over an 11-year period, and analysed relevant clinical, radiological and demographic findings using both cross-sectional (baseline evaluation) and longitudinal (serial assessments) study designs. For cross-sectional analyses, psychiatric and epilepsy comorbidity were comprehensively identified and compared to baseline MRI-determined Deep Brain Structure (DSB) volumes. In the prospective study, standardised psychiatric and quality of life assessments were obtained in a subset of patients and the development of mental illness compared to interval changes in DSB volumes. I focus on depression and psychosis, as they represent the two most prevalent psychiatric disorders identified, and classify focal epilepsy patients according to the site of seizure origin and presence of a lesion. Contrary to the common medical belief, I found that the rates of neuropsychiatric disorders in temporal lobe epilepsy were equivalent to those in extratemporal lobe epilepsy. There were no differences between those with and without psychiatric disorder by age, gender, and laterality of seizure, epilepsy severity or duration. Patients with non-lesional epilepsy, both temporal and extratemporal, have double the rate of depression compared to those with lesional focal epilepsy. There were high rates of quality of life difficulties in people with epilepsy and comorbid psychiatric disorders but the pattern of subjective concerns does not match objective clinician ratings. The hippocampal and amygdalae volumes of epilepsy patients were reduced compared to normal controls. People with co-existing epilepsy and depression had a trend towards smaller reductions in temporal lobe structures, which may represent differential expressions of progression through inflammation, trauma or emotional processing needs with either relative sparing or volumetric increases. People with psychosis and epilepsy have bilaterally reduced hippocampi compared to those with epilepsy, where reductions are predominantly ipsilateral to seizure focus. There is less evidence for amygdala change in psychosis, but a small relative increased volume was observed compared to those with epilepsy alone. There was no evidence of progression over time at a population level over 3.9 years, although there was greater variability in size in all epilepsy subjects compared to normal controls. These results convincingly argue against assumptions about the primary role of temporal lobe foci in the pathogenesis of psychiatric comorbidities in patients with epilepsy, whilst allowing for the possibility that disruption to frontotemporal networks may be a component in the development of psychiatric disorders. Progression is not an inevitable part of the natural history, at least over a 4 year period but it is possible that individuals may exhibit marked changes. They highlight the as yet unexplored possibility that the absence of a lesion as an epileptic site may be associated with greater risks of neuropsychiatric illness and allow for speculation that this may be related to inhibitory surround impacts, more extensive underlying diffuse abnormalities and disruption to frontotemporal connectivity.

Schizophrenia is a severe neuropsychiatric disorder associated with significant disability. The antipsychotic drugs, the mainstay of treatment, are only effective in a proportion of patients. For those who do not respond, so-called treatment refractory schizophrenia (TRS) patients, the only available treatment is the atypical antipsychotic drug, clozapine. Although it has singular efficacy in treating TRS patients its use is restricted and delayed due to rare and potentially fatal side effects. Ability to predict response can help identify potential responders and introduce treatment early, but studies have so far not been able to identify any clinically useful biomarkers of response. A system that has been implicated in both schizophrenia and mechanism of action of clozapine is the epidermal growth factor (EGF) system. This study sought to examine the EGF system for potential predictors of response and did so by measuring peripheral EGF and betacellulin (BTC) levels in a prospective cohort of TRS patients commencing clozapine treatment. It also examined a larger cross-sectional sample of long-term clozapine treated patients for potential associations with EGF system single nucleotide polymorphisms (SNPs). The prospective sample of TRS patients were followed up over twenty-six weeks and clinical data and blood samples were collected at set time points. Symptom severity was measured using the Positive and Negative Syndrome Scale (PANSS). Additional clinical information was gathered using the Clinical Global Impression – Severity (CGI-S) scale, Global Assessment of Functioning (GAF) scale, Simpson Angus Scale (SAS) and the Calgary Depression Scale (CDS). Both EGF and BTC levels were determined using commercially available enzyme linked immuno-sorbent assay (ELISA) kits. Of the sixty-four patients who consented for the prospective study sixty entered the study and forty-nine completed the twenty-six weeks of clozapine treatment. Socio-demography of the patients revealed the significant disadvantages suffered by TRS patients. While 78.3% of the patients had completed more than ten years of education and 93.3% had been previously employed, at the time of the study 83.3% were dependent on the disability support pension. The average duration of illness of 11.2 years reflected the general reluctance and delay in introducing clozapine treatment. Although the response rate of 51.9% reiterated the unique efficacy of clozapine in treating TRS, the absence of any effect on negative symptoms highlighted this major gap in the treatment of schizophrenia. Significant improvement in both CGI-S and GAF scales in both responders and non-responders, while justifying continuation of treatment in the non-responders, also questions the current definition of response that is based solely on symptom improvement. Trends in smoking and psycho-active substance use, even though statistically not significant suggested possible additional advantages of clozapine. The low peripheral EGF and BTC levels in this study provide further support for an EGF system dysfunction in schizophrenia. Although clozapine treatment increased the EGF levels they still remained significantly lower than the healthy controls, implying that regardless of the duration of treatment, clozapine does not normalize EGF levels. Peripheral BTC levels were not affected by clozapine, but the correlation with positive symptoms suggest they could be a state marker. Neither EGF nor BTC levels predicted response to clozapine. The genetic analyses did not show any significant associations. Being an observational study, there was no provision to control for possible confounding factors, and having exclusively TRS patients limits its generalizability. Nevertheless, the findings of this study further implicate the EGF system both in schizophrenia and the mechanism of action of clozapine. Further exploration of this system would help better understand the pathogenesis of schizophrenia at the same time inform future development of antipsychotic medications.

The ability to regulate emotions plays an important role in social development during adolescence and young adulthood. Further, impaired ability to regulate emotions using cognitive strategies is a hallmark feature of major depressive disorder. Currently, there is a limited understanding of the neural underpinnings of emotion regulation in young people and how cognitive forms of emotion regulation (like cognitive reappraisal) develop. This issue is particularly pertinent to improving our understanding of depression in young people, given that the period from adolescence to young adulthood is associated with substantial brain maturational changes in regions associated with emotion–regulation and it is a time when most first episodes of depression occur. In the present study, a cognitive reappraisal paradigm containing social–stimuli was designed to probe the neural correlates of emotion regulation in depressed youth: in particular, to determine whether there were differences in the way that depressed and control participants regulated social–affective material, as well as developmental effects observed within the two groups. tudy participants—a large group of 15– to 25–year–old depressed participants and a matched control group—underwent fMRI where they used cognitive strategies to reinterpret negative social imagery. As expected, this cognitive reappraisal paradigm robustly activated regions involved in cognitive control and social–affective processing in both groups. Among healthy 15– to 25–year–olds (Study One), younger participants exhibited greater activation of temporal and occipital brain regions during reappraisal—implicated in processing social material—in combination with weaker suppression of amygdala reactivity. Further analyses demonstrated that these age–related influences on amygdala reactivity were specifically mediated by activation of the fusiform face area. Study Two revealed that depressed youth were significantly less able to reduce negative affect during reappraisal (compared to healthy individuals), which corresponded to blunted modulation of amygdala activity. Depressed youth also showed heightened activation of the ventromedial prefrontal cortex (vmPFC) and reduced activation of the dorsal midline cortex. Further, as distinct from the healthy youth, there was no relationship between development and modulation of amygdala activation in the depressed group. As the largest study of reappraisal in a young sample to date, our results in healthy controls highlight the importance of activation changes in social–processing and emotion processing networks, as being crucial to potential differences in the ability for adolescents to regulate their emotions. Enhanced neural sensitivity to social stimuli (e.g., facial stimuli) in younger individuals suggests a sensitivity to emotions of others during reappraisal that may be both adaptive in facilitating learning, but might also suggest difficulty disengaging from aversive social–cues. Findings in depressed youth are consistent with those in adults which suggest depression–related disturbances in both extended medial prefrontal (‘generative’) as well as dorsal (‘regulatory’) systems that contribute to adaptive emotional processing. Excessive engagement of the vmPFC—a region emphasised in contemporary neural systems models of MDD— may, in particular, be central to understanding how the process of assigning a new meaning to negative emotional material may be altered in depressed youth, with implications for treatment.

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.

Aims. The aim of this study was to investigate the effect of the addition of an attachment-focussed mother and baby component to a standard group interpersonal therapy (IPT) treatment of postnatal depression. Specifically, the research looked at whether an intervention was capable of addressing both the mood disturbance and the relationship between the mother and baby concurrently. Methods. The research involved designing a new IPT protocol, which built on an existing model shown to address mood disturbance in new mothers. Elements of attachment theory and elaboration of the theoretical approach of IPT were used to guide the development of the new IPT-MC protocol. This therapy was then used with a group of mothers who were identified by a Maternal and Child Health Nurse (MCHN) as meeting criteria for major depressive disorder (post-natal onset) and requiring support. The group was compared with a group of mothers who received treatment-as-usual from their MCHN, including referral for GP, psychiatric, or psychological review and treatment as considered necessary. The mood disturbance and relationship changes were measured using a number of maternal self-report and observercoded variables. Results. The results indicated that the amendment of an evidence-based therapy for postnatal depression to include a mother-child focus did not affect the ability of the treatment to address mood disturbance. That is, there were no negative effects demonstrated that reduced its effectiveness, and it appeared to compare with the results of routine trials of IPT for postnatal depression. Due to the lack of exclusion criteria this study did not have the ability to determine whether the IPT-MC itself treated the mood disturbance. Results also indicated that IPT-MC has potential to address mother-child relational issues to a similar extent to existing treatments, and that these benefits can be shown at a moderate follow-up length (three months). IPT-MC improved the mother-child relationship significantly more than the treatment-as-usual condition. Conclusions. Clinical implications and limitations of the study are addressed. Further research extending the numbers and demographic of women involved would be warranted to confirm the findings.

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.

This thesis comprises five major sections, based on research work that I have led via an international network of collaborators that I established. The studies in this thesis are targeted at characterising quantitative measures of the structural integrity of recurrent fronto-striato-pallido-thalamo-cortical neural circuits and the relationship of such measures to clinical manifestations of neurodegenerative disease. Section 1 presents the foundational basis of my conceptualisation of quantitative measurement of human brain neuroanatomical structures (shape and volume – morphology), specifically, the striatum, as a means of developing in vivo biomarkers that correlate to clinical intermediate phenotypic manifestations (endophenotypes) of neurodegenerative disease. I describe here the international collaborative research network I established to conduct the research program embodied in this thesis. Section 2 involves the results of studies of the in vivo morphology of the striatum in neurodegenerative diseases in which neuropathology of the striatum has been implicated, comparing relative differences in striatal morphology between disease groups. In Section 3, I extend the work in Section 2 by examining whether quantitative morphology (morphometry) of the striatum correlates to endophenotypic cognitive, emotional, behavioural and motoric manifestations of the specific neurodegenerative diseases. In Section 4, the theoretical underpinning of the conceptualisation of the thalamus as another target for quantitative morphology and correlation to endophenotype, as well as the development of an innovative quantitative manual measurement method for the thalamus, is described. Through the works in Sections 1-4, I had come to conceptualise a subcortical connectome (Section 5): a quantitative mapping of the hubs and spokes of recurrent neuroanatomical circuits, as well as potentially the spaces between the structures underlying and connecting to the cortex. In Section 5, I also describe the development of a further vision for my collaborative research program. Section 1: The first two chapters describe the theory and hypotheses underpinning my research on the quantitative morphometry (measurement of shape and volume) of fronto-striato-pallido-thalamo-cortical (frontostriatal) circuit hubs in neurodegenerative disease. Chapter 1 describes the conceptual background for the study of striatal morphology, a key hub of frontostriatal circuits, as a potential biomarker in neurodegenerative disease. Chapter 2 extends the striatal morphology biomarker model to the frontotemporal dementias towards establishing potential intermediate phenotypes (endophenotypes). Chapter 3 describes the Australian, US, Scandinavian Imaging Exchange (AUSSIE) research network I established to conduct the research program and to expand our knowledge of the role of the subcortical connectome as a potential biomarker in neurodegenerative disease. Section 2: Chapters 4-7 describe the application of the theory and methods outlined in section 1, initially in differentiating between neurodegenerative disease groups that have striatal morphologic change implicated as part of disease progression. Chapters 3 and 4 describe cross-sectional studies of differential striatal morphometry in frontotemporal dementia subtypes and Alzheimer’s disease (AD). Chapter 5 describes the application of striatal morphometry to progressive supranuclear palsy (PSP), whilst Chapter 6 describes cross-sectional studies of differential striatal morphometry in Huntington’s disease (HD), frontotemporal dementia (FTD) and Alzheimer’s disease. Section 3: Chapters 8-10 describe the extension of the striatal morphometric work to investigate functional correlations of morphology with clinical manifestations of the cognitive, emotional and motor circuits subserved by frontostriatal circuits, i.e. towards establishing an endophenotype. Chapters 7 and 8 describe correlations of striatal morphometry with executive dysfunction and gait disturbance in a cohort of persons with age-related white matter change respectively. Chapter 9 describes correlations of striatal morphometry with measures of behavioural change in frontotemporal dementia. Section 4: Chapters 11-12 describe development of methods for further research into another hub in fronto-striatal circuits (Chapter 10). Chapter 10 describes the characterisation of another crucial hub in frontostriatal circuits, the thalamus, and the rationale for further investigation. Chapter 11 describes the development of a method for manual neuroanatomical measurement of the thalamus for quantification of its shape and volume, i.e. morphology, in neurodegenerative disease. Section 5: Chapter 13 describes the conceptualisation of the overarching concept of the subcortical connectome to direct further research extending to other key subcortical structures and spaces in neurodegenerative disease. This thesis describes the development of quantitative measures of the shape and volume of crucial brain neurocircuit hubs (quantified morphology = morphometry) in human neurodegenerative disease that correlate to clinical cognitive, emotional, behavioural and motoric manifestations of disease aimed towards developing endophenotypes.  

Background: The International Classification of Diseases (ICD)-11 that is due for release in 2018 will introduce revised Posttraumatic Stress Disorder (PTSD) criteria as well as a new diagnosis of Complex PTSD. Criteria for this diagnosis of Complex PTSD has been under development, with considerable debate and revision of proposed criteria to this point. This study aimed to test the proposed ICD-11 criteria for PTSD and Complex PTSD in a sample of people who have experienced homelessness. Objective: This study investigated the fit of the ICD-11 Complex PTSD construct with mental health symptoms as reported by a sample of people who have experienced homelessness. This population was chosen to investigate the construct based on previous literature and clinical experience, suggesting that the experience of homelessness is largely synonymous with significant histories of trauma and associated mental health difficulties. Method: Two studies were conducted. First, a pilot study of semi-structured interviews were completed with individuals (N = 20) known to have a history of homelessness and trauma exposure. Findings were used to inform the second study: a cross-sectional empirical investigation of trauma exposure, related symptoms and comorbid mental disorders. Participants (N = 206) were service users who attended homeless support agencies in Melbourne, Australia. Latent Class Analysis (LCA) was used to investigate ICD-11 diagnostic groups in the sample. Results: The sample experienced very high levels of trauma exposure with the majority experiencing childhood abuse and neglect. Four distinct classes of participants emerged in relation to the potential to meet the proposed diagnosis: Class 1, ‘LCA Complex PTSD’ (n=119, 58%), Class 2, ‘LCA no diagnosis’ (n= 34, 16%); Class 3, ‘LCA PTSD’ (n=23, 11%) and finally Class 4, ‘LCA affect, social and self difficulties’ (n= 28, 14%). While those with an ICD-11 Complex PTSD diagnoses fell into the LCA Complex PTSD class, so also did those with an ICD-11 PTSD diagnosis. Conclusions: Our findings provide support for the proposed distinction between Complex PTSD and PTSD. The sample used in this study, of people experiencing homelessness, may have impacted on our findings given they were a highly exposed trauma sample.

Psychiatry has lagged behind other fields within the cognitive sciences regarding the analysis of dimensional constructs. This has surely improved recently by diagnostic classifications’ organisation of communication around mental disorders, however it has not kept up with developments in psychology in recent decades. Statistical methods developed for the study of intelligence could have been incorporated in psychiatry, as they may improve the field by permitting objective evaluation of dimensional constructs. For several reasons, this path has not been taken. This project aims to ameliorate this issue, by trying to do just that. It first applies a familiar method in psychology called structural equation modelling (SEM) to specify latent variables in data sets with information from subjects suffering from mental disorders. Genetic and neuroimaging (fractional anisotropy and volumetric segmentation) data is used and incorporated into structural equation models. Secondly, the project analyses what this approach can offer psychiatry, and what limitations of these techniques one should expect. It was found that these methods may help in specifying relations between psychometric scores and neurological features that are not reductive, or at least are not radically so. These methods are more parsimonious when comparing data from neuroimaging and data from cognitive abilities. When variables representing cognitive scores are involved in multiple comparisons, they may overestimate significant correlations, because of the shared variability that these types of cognitive variables present. SEM helps to improve that. Furthermore, factor analysis may be a good method of defining latent constructs that should fit appropriately with new proposals for classification like the recent Research Domain Criteria. Finally, psychiatry may benefit from a picture of science that accepts modelling as a viable approach for describing and understanding psychiatric conditions.

Alterations in excitatory glutamatergic signalling together with increased astrocytic activation and neuroinflammation have been observed in the brain of individuals with autism. Astrocytes play important roles in developmental corticogenesis and neurogenesis, as well as regulating glutamate receptor signalling and intercellular glutamate levels at the glutamatergic tripartite synapse. The overall aim of my PhD was to investigate astrocytic neuropathology in autism and its potential interaction with disruptions in mGluR5 signalling. I conducted a post-mortem stereological investigation within the white matter of the dorsolateral prefrontal cortex (DLPFC) to assess density of astrocyte and other glia utilising the optical fractionator. In addition, astrocytic somal size was assessed via the nucleator and total astrocyte process length estimated utilising the spaceballs probe. Using an in-vitro approach I then explored the effect of Poly I:C mediated astrocyte activation on mGluR5 glutamatergic signalling. This included assessing levels of the pro-inflammatory markers IL-6 and Rantes using ELISA, gene expression of astrocytic and glutamatergic genes via qPCR, as well as mGluR5 activity using a radioligand binding assay. Finally, I characterised the gene and protein expression of astrocyte markers of human pluriporent stem cells (hPSC) derived astrocytes using qPCR and immunohistochemistry, as well as cytokines levels using ELISA. The current study revealed no change in astrocyte density or activation morphology within the white matter of the DLPFC in autism versus age matched controls. There was also no alteration in astrocyte cell somal size and total process length. In-vitro Poly I:C induced astrocyte activation demonstrated reduced mGluR5 binding and mRNA expression, with disruption to other astrocytic glutamatergic elements. A novel protocol for differentiating. human pluripotent stem cells into astrocytes was developed, with hPSC-derived astrocytes displaying morphology similar to that of primary human foetal astrocytes and expressing mature astrocyte markers at the gene and protein level, as well as having the ability to be activated upon exposure to Poly I:C. My findings suggest that astrocyte activation within the brain in autism may be less severe than previously appreciated, with the absence of severe astrocytic hypertrophy and increased proliferation not observed. Results from the mechanistic in-vitro studies suggest that mGluR5 and glutamatergic signalling dysregulation can occur as a result of astrocyte activation, and that modulation of mGluR5 through positive allosteric modulation may have potential benefits in reversing some of these astrocyte activation mediated glutamatergic disruptions. Finally, our improved protocol for hPSC astrocyte differentiation provides a simple and efficient method to derive mature and functional astrocytes as an in-vitro model for autism and other neurological disorders.

Schizophrenia is a severe neuropsychiatric disorder characterised by positive symptoms such as delusions and hallucinations, negative symptoms such as amotivation and asociality and cognitive symptoms such as working memory and processing speed deficits. It is also accompanied by consequential clinical features and paradigms such as suicidality and treatment resistance. Clozapine, an atypical antipsychotic medication, mitigates suicidality and is efficacious in treatment resistance. The unique actions of clozapine may be due to its ability, but not other anti-psychotic medications, to recruit the Epidermal Growth Factor (EGF)/EGF Receptor (EGFR) signalling system. In this thesis, we used post mortem brain samples from the dorsolateral prefrontal cortex (DLPFC) of 37 individuals with schizophrenia and 37 without the disorder, who were a matched cohort. We utilized quantitative PCR to examine the EGF receptor. Then, to establish the distribution and localisation of EGFR in schizophrenia, we supplemented our quantitative studies with protein assays for the EGFR protein and in situ hybridization followed by autoradiography for EGFR mRNA. In order to then examine the relationship of cognitive functioning in schizophrenia and the EGF/EGFR signalling molecules, we examined the cognitive profile of 449 persons with schizophrenia and 637 control participants from the Australian Schizophrenia Research Bank database. We also examined if the cognitive performance in schizophrenia cluster to inform disorder sub typing and subsequently explored the relationship of cognition in schizophrenia to EGF/EGFR genomic signals by way of a candidate gene approach. In our studies, we found that EGFR protein levels are significantly increased in the DLPFC of persons with schizophrenia, although, there were no mRNA expression differences. The older neopallidal layers of the cortex showed that participants who had died of non-suicide had lower EGFR mRNA expression. Similarly, those without a history of suicide attempts showed a decreased mRNA expression more widely in the neopallidal layers. We also showed layer specific changes in relation to a number of clinical features in schizophrenia. In comparison to all other previous studies, we showed a case control difference without the need for stratification that persons who carry the AA genotype of the EGF A61G single nucleotide polymorphism (SNP), are more likely to have schizophrenia. We also showed that there are three clusters of cognitive performance within schizophrenia and treatment resistance and 2 NRG1 SNPs associate with various cluster memberships significantly. Our results show evidence to support the role of EGF/EGFR signalling in mediating and moderating several clinical parameters in schizophrenia such as treatment resistance, suicidality and cognitive functioning. We also have identified a relationship between EGF/EGFR signalling system hypofunction and schizophrenia and propose that clozapine may augment this signalling thereby mitigating this hypofunctional state. Together, these results may offer further insights into the relationship between the EGF signalling system, cognition and clinical features of schizophrenia and allow for development of novel biomarker strategies to identify early at-risk patients.

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.

Objective: Burn injuries are common and debilitating traumatic injuries that are associated with a range of post-injury maladjustments. Burn patients experience high rates of psychiatric morbidity, have low rates of return to work and experience reductions in quality of life in the months and years after discharge. Despite this, very limited longitudinal research has evaluated these outcomes in less severe burns, and has examined what early psychosocial risk factors may contribute to these outcomes. Further, common limitations across burns psychological research include variation in sample characteristics, limited reporting of findings, simplistic methodologies and small sample sizes. Aims: In light of the limitations in the burns literature, this research study aimed to investigate what pre-burn, acute and 3-month early psychosocial risk factors contribute to psychopathology, quality of life and return to work outcomes 6-months after burn injury. Method: Consecutive admissions to the burns unit in Melbourne, Victoria with a Total Burned Surface Area of 20% or less were recruited for the study. 109 burn patients provided consent to participate, and 74 completed the 3 and 6-month follow-up assessments. Participants completed structured clinical interviews to measure psychiatric history and post-trauma symptomatology, and a battery of self-report questionnaires assessing factors such as pain, sleep quality, appearance dissatisfaction, anger and social support. Bayesian Structural Equation Modeling was conducted for each outcome (psychopathology, quality of life, return to work) to identify early psychosocial contributors to these outcomes. Results: At 6-months, 28.4% of participants met criteria for an Axis I psychiatric disorder, and while only 3.0% met criteria for PTSD, 7.5% met criteria for subsyndromal PTSD. Quality of life was most affected in relation to taking care of the burn and skin sensitivity. 14% reported not having returned to work at 6-months as a result of the burn, and many participants reported at least moderate difficulty with performing work tasks. Symptoms of PTSD at 6-months were predicted by 3-month mental health symptoms, higher 3-month pain and social support. Symptoms of depression were predicted by higher age and more mental health symptoms at 3-months. Symptoms of anxiety were predicted by 3-month mental health symptoms only. Quality of life, as indicated by the domains of Affect and Relations, Skin Involvement and Functioning, were significantly predicted by various earlier risk factors, but they differed by domain outcome. Specifically, Affect and Relations, meaning problems related to affect, interpersonal relationships and sexuality, was predicted by 3-month mental health symptoms and higher pain. Skin involvement, meaning problems related to skin sensitivity and taking care of the burn, was predicted by burn severity (TBSA) and 3-month mental health symptoms. Functioning at 6-months was only significantly predicted by higher age. Problems returning to work at 6-months was significantly predicted by 3-month greater pain and more mental health symptoms. Conclusions: The findings from this study suggest that even in minor burn injuries, maladjustment is common in the months following the burn. Specifically, these burns experience elevated rates of psychiatric disorders, reduced quality of life and problems returning to work. While these outcomes are related, the findings further demonstrate that different risk factors are important to predicting each of these outcomes. Overall this study highlights the need for early, although not acute, psychosocial screening of even minor burns in order to improve psychosocial services available to minor burns.

A substantial body of research has been conducted examining depressive symptom prevalence in the early stages of reproductive ageing, yet few studies have examined prevalence into the early and late postmenopause. Much of what is known about the relationship between mood and reproductive ageing is drawn from longitudinal, epidemiological studies of varying durations. This thesis aims to extend this research by utilising data from an Australian longitudinal study, the Women’s Healthy Ageing Project (WHAP), which is of adequate duration to assess mood changes from the late reproductive stage through to late postmenopause. The Women’s Healthy Ageing Project is an ongoing longitudinal, epidemiological study examining factors that contribute to women’s healthy ageing in a sample of community dwelling Australian women. At baseline, in 1992, women were aged between 45 and 55 years, with a mean age of 50 years. In 2012, the last assessment point utilised in this work, women were aged between 65 and 75 years. This project utilises data drawn from the first twenty years of the study, providing an assessment of mood factors spanning two decades. Measures used included the Negative Mood scale from the Affectometer 2 , the Centre for Epidemiological Studies Depression Scale – Short Form (CESD-SF) administered between 2002 and 2012, and the Geriatric Depression Scale – Short Form (GDS-SF) administered in 2012. The thesis is comprised of two main studies, each with two sub-studies. Study 1 explored prevalence rates of negative mood and depressive symptoms in regards to chronological ageing (Study 1.1). In the second sub-study negative mood scores (Affectometer-2) and depressive symptoms (CESD-SF) were examined in relation to the stages of reproductive ageing (Study 1.2). Within this thesis particular emphasis was placed on examining mood scores in the context of early postmenopause and late postmenopause, based on the STRAW+10 criteria, rather than the broader category of ‘postmenopause’ employed by numerous studies. The findings from Study 1 demonstrated that both negative mood and depressive symptoms decreased significantly as women transitioned from mid-life to late life. Scores of negative mood and depressive symptoms were significantly higher in the early postmenopause than the late postmenopause, suggesting the need to distinguish between these two stages in any future research relating to mood and reproductive ageing. While there were significant reductions for both mood measures between the stages of reproductive ageing, age was found to have a stronger association with score. In exploring mood and reproductive ageing, chronological ageing should always be considered. The second part of the thesis, Study 2, determined the extent to which the prevalence of depressive symptoms was consistent between the WHAP cohort and an age matched cross-cultural sample, in this case a sample of community dwelling Japanese women. With the increasing number of women migrating to Western populations, the effects of cross-cultural influence on item selection and score on depressive symptom measures needs to be evaluated to test the generalisability of findings. The first sub-study, Study 2.1, compared the prevalence rates of depressive symptoms in the WHAP cohort and an age matched sample of Japanese women from the Kumamoto prefecture in Southern Japan. Of the Japanese cohort 33% scored within the mild/moderate range on the GDS-SF, compared to 9% of the Australian women. This prompted an examination of cultural influences on item selection and possible inflation of scores to determine if the depressive symptom prevalence reported was a true phenomenon or impacted by the type of measure being used to assess the depressive symptoms (Study 2.2.). Culture specific profiles of item endorsement were found, and it was determined that the GDS-SF was a good fit for assessing the Australian cohort but not for the Japanese cohort. These findings suggest that the GDS picks up on distinctive aspects of depressive symptomatology in different cultural samples, despite the measure being well established to assess symptoms across populations. Any cross-cultural examination of depressive symptoms should use caution when interpreting results and further work in this area is needed to examine culture specific presentations of symptoms.

Background: Shame and guilt are negative moral emotions that are usually experienced when rules, norms or social agreements are broken. These emotions are associated with punishing feelings of self-blame relating to behaviour and character and are crucial for social development during adolescence. However, there is currently a poor understanding of the neurobiological underpinnings of these emotions. The importance of understanding the neural correlates of these emotions lies in a better understanding of human social functioning and the role they play in particular mental disorders such as depression. Depression is a mood disorder that affects a large number of adolescents. A key component of depression is emotional dysfunction, and it has been recognised that moral emotions such as shame and guilt play an important role in the development and maintenance of depression. Despite extensive knowledge of the neural mechanisms underlying deficits in basic emotional processes in adolescent depression, there is no research to date that has investigated the neural correlates of shame and guilt in a depressed adolescent population. Broad Aim of PhD study: To investigate the common and distinct neural correlates of the experience of negative self-conscious emotions (i.e., shame and guilt) in healthy and depressed adolescents using a novel social moral dilemma paradigm. Methodology: A novel shame and guilt induction paradigm was developed for use with functional Magnetic Resonance Imaging (fMRI). A total of 44 female teenager-relevant social moral dilemmas were created and validated via an online survey. Twenty-two female adolescents with major depressive disorder (MDD) (mean age = 20.19) and 47 healthy female controls (mean age = 18.89) aged 15-24 were recruited from the Melbourne area. Patients were recruited from Orygen Youth Health and Headspace Centres in Melbourne. During fMRI, the adolescents were presented with dilemmas one at a time and were requested to a) make a decision about what they would do if in that situation, and b) reflect upon how they would feel. Ratings of emotional experience were collected post-scan. Analyses were conducted to investigate the neural correlates of self-reported shame and guilt experiences in both depressed and healthy adolescents, and to examine whether the groups differed in their neural response associated with these negative self-blaming emotions. Results: Findings showed marked individual variations in shame and guilt responses to the different dilemmas in both the healthy control and MDD participants. The common experience of shame and guilt in healthy individuals was associated with significant activation in lateral and medial parts of the prefrontal cortex (including the medial and dorsomedial PFC extending to the supplementary motor cortex, the dorsal anterior cingulate cortex and mid-cingulate, the lateral superior, middle and inferior frontal gyri, and the ventrolateral PFC extending to the anterior insula), temporal area (superior temporal sulcus), parietal regions (supramarginal and angular gyri), as well as some subcortical regions (thalamus and caudate nucleus). Adolescents with major depressive disorder showed similar associations between shame and guilt and brain activity compared with healthy participants, but with a lesser extent of activation. In terms of differences between healthy and depressed individuals, the anterior middle temporal cortex was associated with guilt to a greater extent for the control group compared to the patient group. Additionally, results showed activity in the superior parietal cortex extending to the inferior parietal cortex and the precuneus to be associated with shame to a greater extent in patients compared to controls. Significance: The proposed project will advance the understanding of the neural correlates of shame and guilt in healthy individuals as well as the neural basis of these same emotions in depressed adolescents. The information gained from this will be of significant value for the development of prevention and treatment efforts for depression as well as other mental disorders for which these self-conscious emotions play a significant role.

Bipolar disorder is a chronic illness characterised by extreme mood swings. The efficacy limitations of medication alone have flagged a role for adjunctive psychosocial treatments. Despite strong evidence for these interventions, accessing such specialised programs is problematic. Online psychosocial interventions have been found to be effective for a range of mental illness, and some burgeoning work that has evaluated online bipolar programs is encouraging. This current study seeks to further contribute to this embryonic work. Two studies are described within this thesis. Study one, aimed to test the efficacy of a self-guided online intervention (MoodSwings) for bipolar disorder. In a head to head trial of an international sample, 156 participants with bipolar disorder were randomised to receive either a psychoeducation (PE) based program, or the same PE program plus additional interactive Cognitive Behavioural Therapy elements. A mixed model repeated measure (MMRM) analysis found a significant (p = 0.02) difference between the two groups at 12 months on mania scores. Both groups also demonstrated significant within group differences. An exploratory analysis based on effect sizes >.8 found the following potential factors suggestive of having an impact on outcomes: demographic factors associated with functionality, time on site, locus of control and medication adherence. Study two utilised the same participant sample and reports on the use of MoodSwingssmall group discussion boards. It aimed to explore their role in enhancing social support and identifying the types of supportive exchanges. Contrary to the hypotheses, no significant differences (p = .271) were found on social support levels between high and low posting groups. In addition, those on higher posting boards did not demonstrate greater program engagement (p = .298). There was a significantly higher number of posts by those in the PE condition in comparison to the CBT group (p <.000). Qualitatively the posts contained many supportive comments, the most frequent demonstrated emotional support. This current study was limited by only using self-report assessments, a moderate sample size, and a high attrition rate in the completion of follow up assessments. The head-to-head study design did not allow for a determination of whether MoodSwings was superior to a control condition or treatment as usual. Further studies could explore this using an attention control condition. A guided intervention model would also provide an interesting contrast to the current studies self-guided approach in terms of additional costs and benefits. There is also a great opportunity to further explore the use of online discussion boards both as a tool of engagement and as having its own therapeutic elements. MoodSwings is one of the first online programs for BD. Its findings are encouraging and pave the way for future studies to build on this work.

Human pluripotent stem cells (hPSC) constitute a valuable resource for establishing in vitro models of nervous system development, function and dysfunction. This is particularly needed for complex developmental brain disorders whereby animal models and access to postmortem human brain tissue may be limited. A major prerequisite step to developing suitable in vitro models of the human nervous system is to establish hPSC induction protocols to derive regionally specific neuronal populations. The first major aim of this thesis was to characterize the phenotype and maturation stage of neural progenitor cell types derived from the following induction protocols: the dual SMAD inhibition protocol (DS), sonic hedgehog pathway agonist protocol (SAG), and SMAD/GSK3b inhibition protocol (CHIR). Our studies show that the dual SMAD inhibition protocol results predominantly in cortical progenitors representative of deep and intermediate cortical layer neurons, while combined early treatment of sonic hedgehog agonist during neural induction give rise to progenitors of ventral cortical identity. Using an induction protocol involving inhibition of the SMAD and GSK3b pathways, followed by later exposure to BMP2/4, hPSC are directed towards neural crest lineages, which upon further differentiation give rise to peripheral sensory neurons. Another essential component for in vitro modelling of the human nervous system using hPSC is to demonstrate neuronal activity and connectivity as measures of functionality. Whilst intercellular activity and characteristics of hPSC-derived neurons are well documented, reports on their potential to form functional network is scarce. This feature is critical for using hPSC to model psychiatric disorders such as Autism spectrum disorder (ASD) in which abnormal connectivity is one of the major characteristics of the disease. Using microelectrode arrays (MEA), the second major aim of this thesis was to assess the functional maturation rate and neuronal network activities of hPSC-derived cortical and peripheral sensory neuronal populations. Our data demonstrate that functional maturation of hPSC-derived cortical neurons occurs at a slower rate relative to hPSC-derived sensory neurons with no evidence of network activities detected over 8 weeks of differentiation. In contrast, hPSC-derived sensory neurons show faster maturation and form functional networks in vitro by week 6-7 post differentiation. Further functional characterization on MEA reveals the capability of sensory neuronal subtypes to respond to appropriate stimuli including heat, capsaicin and hypoosmotic induced stretch. The final major objective of the thesis was to employ our in vitro model of corticogenesis to interrogate neurodevelopmental disorders, specifically microcephaly and ASD. Accordingly, one aim was to investigate the function of WD Repeat Domain 62 (WDR62) in neurogenesis, a major candidate gene of autosomal recessive primary microcephaly. Studies of WDR62 utilizing human based in vitro models are lacking. Our studies show that WDR62 expression coincides with SOX2 and PAX6 expression during hPSC neural induction, the prime period of neurogenesis. Furthermore, knockdown of WDR62 expression in hPSC impacted on neurogenic and gliogenic differentiation, as shown by a reduction in TBR2 (EOMES) and S100b+ progenitor populations, respectively. The final aim was to characterize idiopathic ASD induced pluripotent stem cell (iPSC)-derived cortical neurons, focusing on the expression of genes associated with corticogenesis, glia specification, synaptic function, cell proliferation and cell death. Our data suggests higher expression of TBR1 and lower expression of MAP2AB, GFAP and GRM5 in ASD neurons compared to controls. These results implicate processes related to deep cortical layer neuronal differentiation, dendritic formation, glial differentiation and synaptic function in ASD core pathophysiology, paving the way for future studies utilizing these ASD iPSC lines. In summary, these studies provide key information for utilizing hPSC to model neural circuitry systems and demonstrate hPSC robustness as a complementary in vitro model system to investigate developmental brain disorders.

The primary aim of this PhD research programme was to explore the neurophysiological correlates of temporal disintegration. This phenomenon is typified by disturbing anomalies in the normal flow and experience of time, and is a significant co-morbidity in a variety psychiatric illnesses. The research focused on the application of sub-second and supra-second psychophysical methods as well as neuroimaging to explore neural correlates of temporal disintegration. Experiments were conducted with two cohorts: patients with bipolar disorder, and healthy participants who were administered the dissociative agent ketamine. The bipolar disorder study utilised a longitudinal, repeated measures design. The ketamine experiments were randomised, double blind studies with placebo controls. Three main types of measurements were used in the studies. Firstly, questionnaires were administered which measured mood states, dissociative states and temporal disintegration. Secondly, behavioural responses to visual stimuli were measured in two temporal domains: sub-second perceptual ordering, and supra-second perceived duration judgement. Thirdly, during performance of the sub-second task, neuroimaging was conducted: fMRI for participants given ketamine and EEG for patients with bipolar disorder. The sub-second method was adapted from the temporal order judgement task of Morrone et al. [2005]. Participants reported the order of two briefly flashed stimuli presented close to the time that they made an eye movement. In this task, the stimuli may appear to be inverted in temporal order, especially when eye movements coincide with the flashed stimuli. The supra-second method was adapted from the colour-time task of Coull et al. [2004]. It involved judging the relative duration of two successive stimuli that cycled through a range of colours over time. In the bipolar disorder patients, a strong association was found between measures of mood, dissociative symptoms and the phenomenon of temporal dissociation. For the supra-second task, we found lower mood scores (measured by the Bipolar Depression Rating Scale) were associated with a greater number of errors in the time condition than the colour condition. For the sub-second psychophysical tests, the proportion of inverted temporal judgements increased in association with manic symptoms (11% increase for each point increase in Young Mania Rating Scale, p<0.05). Manual reaction times in 2AFC responses to temporal judgements were lengthened by ketamine and in inverted judgements. The fMRI results showed increased BOLD signal for inverted trials bilaterally in the insular/claustral regions and in the anterior cingulate cortex (p<0.001). In inverted trials, temporal disintegration as measured by the Temporal Integration Inventory was correlated with the activity of the left temporoparietal junction (Kendall’s τ = 0.48, p < 0.01). Together, these findings indicate that there is a significant linkage between mood and dissociative states and the phenomenon of temporal disintegration. They also reveal that both sub-second and supra- second timing performance are altered by ketamine induced dissociation and with mood changes in bipolar disorder. The findings provide support for an integrated functional network involved in sub-second temporal processing which includes the claustrum and temporoparietal junctions. These insights are important in that they can inform our understanding of the determinants of temporal disintegration and may also provide insights into the underlying pathology of bipolar disorder.

Background: Evidence suggests that oxidative stress may be related to the aetiology of autism. This is supported by studies showing deficiencies in glutathione and other antioxidants, mitochondrial dysfunction and genetic links between autism and abnormalities in redox biology. Glutathione, an important cellular antioxidant, is therefore proposed as a potential treatment target in autism. N-acetyl cysteine (NAC), a glutathione precursor, may be an effective method of supplementing glutathione levels, and thus improving behavioural symptoms and functioning, in children with autism. Method: This study was a mixed-methods, double-blind, randomised, placebo-controlled clinical trial of 500 mg daily NAC, in addition to treatment as usual, for 6 months in children with autistic disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, revised. The primary outcomes were the core symptoms of autistic disorder: social interaction, as measured by the Social Responsiveness Scale; communication, as measured by the Children’s Communication Checklist – Second Edition; and restricted and repetitive behaviours and interests, as measured by the Repetitive Behavior Scale – Revised. Secondary outcomes were problem behaviours, as measured by the Developmental Behaviour Checklist – Primary Carer Version; adaptive functioning, as measured by the Vineland Adaptive Behavior Scales – Second Edition; and parent and clinician global impression scales. In addition, qualitative analysis of parent/guardian reports and clinicians’ observations was carried out to supplement the main efficacy study. Results: A total of 98 children (79 male, 19 female; age range = 3.1-10.1 years) were enrolled into the study, of whom 48 were randomised to receive NAC and 50 were randomised to receive placebo. The NAC and placebo groups did not differ on any demographic or baseline symptom severity measure. Seventy-one participants (34 from NAC group, 37 from placebo group) completed the 6-month trial. NAC did not differ from placebo on safety and tolerability. There were no differences between the NAC and placebo groups on any primary or secondary outcome measures. In contrast, the qualitative analysis found that NAC was associated with more frequent reports of improved calmness and verbal communication than placebo. Conclusions: This study found that NAC was not effective in improving core symptoms or functioning in children with autism, as assessed by a range of comprehensive quantitative measures. However, this study did demonstrate the potential utility of mixed-methods approaches in autism treatment trials. Overall, this study does not support the widespread use of NAC for autism, although questions remain regarding dosage, and effects on specific symptoms within the broader clinical picture.

With the rapidly ageing global population, there will be increased demand on informal older carers, who provide important roles in supporting older adults to live longer in their own homes. Depression in older carers is a well-known adverse outcome, however there is lack of consistent knowledge concerning factors associated with this outcome. The research reported in this thesis therefore investigated factors associated with depressive symptoms in a sample of older carers living at home with the older adults with whom they were caring for (the care-recipient, CR). This study differs from previous work in that a variety of different, but clinically relevant factors have been investigated. A convenience sample of 202 older carers were assessed cross-sectionally on their demographic characteristics, health measures, depressive symptoms, personality, attitudes to ageing, and CR factors (CR diagnosis and the hours spent caring). The cut-off score on the Geriatric Depression Scale (GDS-15) of ≥5 was used to delineate “depressed” and “non-depressed” carers, and a comparison of these characteristics was made between the 87 depressed, and 115 non-depressed carers. Female gender, but no other demographic factors were associated with a higher number of depressive symptoms. The CR diagnosis was not an independent factor associated with depressive symptoms. Higher levels of Neuroticism and more negative attitudes to ageing in the carers were associated with depressive symptoms. Depressed carers had worse physical health, participated in increased amounts of domestic physical activity (PA), but similar amounts of leisure-PA, compared to non-depressed carers. The regression analyses demonstrated that higher levels of Neuroticism, increased hours spent caring, and possibly increased amounts of domestic-PA, were independent factors associated with depressive symptoms. The findings of this study highlight the importance of carer-related factors when identifying risk factors for depressive symptoms in older carers. The clinical implications of this study, particularly that increased hours of care are a risk factor for depressive symptoms, suggest that in order to potentially reduce the risk of developing depression, older carers should be encouraged to “share the care” – that is the support of the CR should be preferably spread among more than one person, whether this be among other family members, and/or formal care services. Thus, being able to access support services such as “Home Help”, and respite is important. This approach may not be supported by the principles behind the current Victorian Active Services Model, which encourages self-reliance and enablement. Clinicians have an important role to encourage older carers to accept help, but this needs to be individually tailored, taking into account the carers’ personality structure.

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.

This research investigated the role of imagery as a mechanism underlying anger’s relationship to posttraumatic stress disorder (PTSD). Previous research has demonstrated that anger is a strong predictor of PTSD severity and comprehensive reviews have argued for the development of nuanced explanatory models describing the psychological mechanisms underlying this relationship. Research has shown that visual imagery is linked to a range of psychological phenomena and psychopathologies, the clearest case being anxiety disorders. Imagery may also have a strong role in eliciting anger. Exemplifying this is research demonstrating that imagery with angry content has a profound psycho-physiological effect. Dysregulated imagery is the hallmark of PTSD and research has shown that anger in PTSD is directly related to intrusion prevalence. PTSD sufferers with high imagery control have fewer intrusions and less anger, compared to those with low imagery control. The current research program investigated these issues in three separate cross-sectional and longitudinal studies. It aimed to explore the potential moderating and mediating roles of imagery and negative thought as twin dimensions of cognition in anger in PTSD, compared to their roles in anxiety and depression. Participants in Studies One and Three comprised treatment seeking past and present police and military personnel with PTSD (n = 123 and 462 respectively). Study Two explored these issues in an analogue population of university students (n = 197). It was predicted that anger would be more strongly associated with PTSD than anxiety and depression and that imagery and thought would be differentially associated with anger compared to anxiety and depression. It was further hypothesised that the magnitude of imagery and thought and their impact on affect would increase in the context of PTSD via direct and interactive effects and that patterns of effect would vary by PTSD population and the nature of the trauma experienced. Results demonstrated that: (a) anger was strongly predictive of PTSD, (b) different facets of imagery were linked to different negative affects, (c) imagery and thought were linked to anger and mediated its relationship to PTSD, (d) thought mediated the effect of imagery in anger in PTSD and (e) the potency of imagery and thought were increased in PTSD and were reflective of the nature of the trauma involved. These findings demonstrated the powerful role played by imagery and thought in the genesis and maintenance of anger in PTSD. They provide a basis for developing a fuller description and theoretical account of the aetiology and maintenance of anger in PTSD and offer new possibilities for improvements in its treatment.

Background: Bipolar spectrum conditions arose during the Pleistocene epoch, where social inclusion was maintained through prestige – the investment of the group in the individual. This thesis seeks to investigate the interplay between bipolarity and prestige. Methods: A case control study categorised 228 adult participants into a seven node bipolar spectrum. (1) Structural differences in prestige approach motivation (MSPaM) between the nodes were assayed. (2) A dynamic model of bipolar pathogenesis was tested by means of correlation and path analysis. (3) Binary logistic regression was utilised to examine the relationships between MSPaM, bipolar family history, perceived childhood relational trauma (PCRT)and bipolar disorder. (4) Contour plots of affective change on the plot of MSPaM versus prestige were drawn. (5) An exploratory analysis was undertaken. Results: (1) After controlling for mood variables, bipolar I (S1), bipolar II (S2) and (bipolar family history-positive) pseudounipolar (S3) groups were found to have higher mean MSPaM scores than controls (S7). (2) There was good evidence to support the modelling for the dynamic model stem and depressive (withdrawal) branch, while support for the approach arm was ambiguous; the relationship for tension and prestige only being evident in moderate mood elevation. In hypomania MSPaM correlated strongly with prestige (r = 0.51). While the bipolar depressed cohort demonstrated a raised MSPaM, the unipolar depressed cohort did not. The pseudounipolar (S3) node had both elevated MSPaM and prestige when compared with the unipolar (S6) node. (3) MSPaM predicted BD (OR 6.8), but only in the absence of bipolar family history, and the converse trend was evident. (4) The contour maps showed three affective zones – depressive, elevated and euthymic. Conclusions: Developmental, genetic, and social-prestige variables relate dynamically to the bipolar spectrum, where those with bipolar disorder have a greater drive to social inclusion. Mood disorders may have arisen in evolutionary time through prestige competition in the context of relative social marginality; bipolar depression being a means of ostracism avoidance and hypomania serving to raise social value (prestige) through mood elevation and prestige approach motivation. The contour plots provide us with a landscape of bipolar mood states, promoting the view that they may be evolutionarily stable strategies in the ancestral competition for prestige. There was a complex interaction of MSPaM and bipolar family history with respect to bipolar causation, suggestive of at least two pathways to bipolar disorder. Childhood relational trauma (PCRT) appeared to be a further aetiological factor. The prestige model offers a new conceptualisation of affective disorders and has received preliminary support.

Objective: Comorbidity between psychiatric disorders is the rule rather than the exception, with some patterns of comorbidity more common than others. The tendency for disorders to cluster together in predictable patterns can be accounted for by the existence of higher order internalising and externalising dimensions. These dimensions, in turn, are underpinned by personality traits. The relationship between personality and psychopathology has been a particular focus of researchers interested in explaining the diverse range of psychopathology experienced by survivors of traumatic events. However, extant research in this field has been limited to cross-sectional investigations of PTSD comorbidity, despite the fact that PTSD patients represent only a small minority of trauma survivors. In addition, the relationship between personality and posttraumatic functioning outside of the mental health domain has received minimal attention. Perhaps most importantly, the influence of personality on the longitudinal trajectory of posttraumatic disorders has not been examined. Therefore it is not known whether personality profiles varying on the internalising and externalising dimensions respond differently to trauma exposure over time. Aims: In light of the limitations of the extant literature, this study aimed to 1) investigate whether and how pre-trauma personality influences the trajectory of a range of common posttraumatic disorders, and 2) establish the relationship between personality and non-psychiatric maladaptive responses to trauma. Method: During hospitalisation for serious physical injury, 323 Australian adults completed a retrospective assessment of pre-injury personality and psychiatric history. Post-injury psychiatric diagnoses were assessed 3 and 12 months later using a structured clinical interview. A range of non-psychiatric outcomes were also assessed at 12 months post-injury (e.g., disability, quality of life, anger, risk of re-injury, exposure to trauma and life stress). Latent profile analysis conducted on initial personality scores identified subgroups of participants, while latent change modelling examined differences in disorder trajectories controlling for psychiatric history. Regression analyses were used to investigate the influence of personality on non-psychiatric outcomes. Results: Three personality-based classes of trauma survivors were identified, corresponding to internalising, externalising, and normal personality profiles. After controlling for psychiatric history, the internalising class showed a high risk of developing all disorders. Unexpectedly, however, the normal personality class was not always at lowest risk of disorder. Rather, the externalising class, while more likely than the normal personality class to develop substance use disorders, were less likely to develop PTSD and depression. In terms of non-psychiatric outcomes, internalisers reported poorer health and higher levels of life stress and trauma exposure in the year after injury, while externalisers were more likely to engage in activities that put them at risk of re-injury. These relationships, however, were largely accounted for by gender and the experience of pain at 12 months post-injury. Conclusions: Results suggest that personality is an important mechanism in influencing the development and form of psychopathology and related outcomes after trauma. These findings suggest that screening and early intervention using a personality-based approach may be an effective method of predicting and subsequently preventing much of the burden of posttraumatic problems across both mental health and related domains.

Objective: Anorexia nervosa (AN) is a serious psychiatric condition characterised by significantly low body weight, a fear of weight gain and a disturbance in the experience of one’s own body weight or shape. The 12-month prevalence of AN is approximately 0.4% among females, and approximately one-tenth of that among males. AN is associated with exceptionally high morbidity rates, and a mortality rate among the highest of any psychiatric illness. AN is also associated with exceptionally high relapse rates. A major contributing factor for the high rates of morbidity and mortality experienced by these individuals is that the factors involved in the genesis and maintenance of the illness remain unclear, resulting in a hindrance in the improvement of current treatments or the development of new and more effective treatments. Though a number of treatment modalities have emerging evidence for efficacy, many patients remain under- or unresponsive. Thus, gaining a better understanding of the factors involved in the illness has the potential to lead to the development of more effective treatments in the future. Therefore, the aim of this thesis was to investigate the neurobiological and cognitive features of AN through a range of cognitive assessments, eyetracking tasks and functional neuroimaging measures. Method: Twenty-six right-handed female participants with AN and 27 healthy controls, matched for age, gender and premorbid intelligence participated in the study. Participants were required to attend three test sessions within a one week period that involved the completion of a variety of tasks. Included among these tasks were a cognitive battery, basic saccade tasks (prosaccade/antisaccade/no-go, memory-guided and self-paced saccade tasks), an emotional face processing task, a body size estimation task, a resting state functional magnetic resonance imaging (fMRI) scan, and a fixation task. Results: Participants with AN were found to demonstrate differences in performance on a variety of measures, relative to controls. AN participants showed a trend for poorer performance on a working memory task component of the cognitive battery which required the manipulation of visuospatial information. AN participants also displayed shorter prosaccade latencies and an increased rate of inhibitory errors on the memory-guided saccade task, but no significant difference in antisaccade, no-go or self-paced saccade performance. AN participants also demonstrated intact emotion identification of others, and relatedly, no significant difference in blood oxygen level dependent (BOLD) activity to face stimuli depicting different emotions. BOLD activity was however found to significantly differ to participants’ own faces, with AN participants displaying increased activity in the right inferior and middle temporal gyri, and right lingual gyrus. AN participants also avoided fixating on salient features of their own face and showed hyperscanning behaviours to images of their own face, emotional face stimuli and biological motion stimuli. The estimation of body size of biological motion stimuli was, however, not found to differ between groups. Findings of the resting state analysis indicated reduced functional connectivity within the sensorimotor and visual network in AN, but no significant group difference in default mode network connectivity. Finally, AN participants were found to make saccadic intrusions, specifically square wave jerks (SWJs), at a greater rate than healthy controls during fixation. The rate of SWJs also negatively correlated with state anxiety in AN, but not in controls. Discussion: The findings of the study indicate distinctive eye movement differences and visuospatial processing deficits in individuals with AN. The findings are discussed in terms of their overlap with reported findings in anxiety disorders, and the potential brain areas contributing to these results. Specifically, the potential role of the superior colliculus and gamma-aminobutyric acid (GABA) in AN are implicated through a number of findings. Furthermore, the negative correlation between SWJ rate and state anxiety classified groups with very high accuracy and was identified as a distinctive biomarker for AN. The clinical implications of these findings are discussed, as are the potential directions for treatment focus.

Background: The recognition of the importance of treatment for depression in pregnancy to optimise both maternal and child outcomes parallels the increasing use of antidepressants in pregnancy across many countries in the world. However, there is also research to suggest that women are often reluctant to commence treatment or they abruptly cease antidepressant treatment on becoming pregnant due to concerns about long term safety of exposure for their unborn child. This thesis examines child developmental outcomes following in utero exposure to antidepressant medication using two data sets. These two data sets are distinct in methodology allowing a comparison of both methods and results when examining child outcomes following exposure in pregnancy. Methods: The first study is the Victorian Psychotropic Registry (VPR), a purpose designed, prospective, longitudinal study established by the candidate and where children have been followed from in utero to 5 years of age. The second study is the Longitudinal Study of Australian Children (LSAC), a large, normative, population based cohort across early childhood established by the Commonwealth Government of Australia. Both studies had an antidepressant exposed group of children and a control group and both studies had measures of maternal depression in pregnancy, postpartum and into childhood as well as measures of other exposures in pregnancy, such as alcohol and smoking. The VPR collected all data prospectively whereas the pregnancy measures for LSAC were retrospectively collected in the postpartum. The three areas of child development of focus in this thesis are: cognitive development, motor development and child adjustment and emotional development. Where possible, measures were chosen in LSAC, which closely matched those in age and domain to the VPR. Children were assessed at 4-7 years of age across the two studies. Results: This thesis found that in both data sets there was no evidence of an effect on cognitive development from antidepressant exposure in pregnancy. The results for both motor development and emotional development were more complex. For motor development there was a trend to lower scores in the VPR study on a specific neuropsychological measure of motor development: Movement ABC, without reaching a statistically significant difference but small effect sizes. There was no observational or task measures of motor development in LSAC. Both the VPR study and LSAC found a difference on a screening measure, Peds QL Physical Health Score, with exposed children having a lower score. However, when this was adjusted for the covariate of maternal depression this was no longer significant. Child adjustment and emotional development was examined in two areas. The first was internalizing and externalizing scores, within the VPR on the CBCL and within LSAC on SDQ, the second area was parenting and parent-child relational stress measured in VPR with PSI total stress score and within LSAC with the Parenting Efficacy Scale. VPR found there was no statistically significant difference on either measure for exposed children. Whereas, LSAC found both internalizing and externalizing scores and Parenting Efficacy Scale scores did show statistically significant differences, with higher externalizing and internalizing scores and lower Parenting Efficacy scores in exposed children. However, again when adjusted for the covariate of maternal depression these differences became non significant. Conclusions: Using two independent samples to examine antidepressant exposure in pregnancy on child developmental outcomes, no statistically significant difference was found between children exposed and controls on a range of cognitive, motor, child emotional and adjust outcomes at 4-6 years of age. There was also no difference in mothers who took antidepressants in pregnancy on parenting stress and efficacy at 4-6 years postpartum. However, the secondary findings within LSAC study was that maternal depression in the postpartum, as measured by the K6, was associated with poorer cognitive, language, emotional and parenting outcomes This suggests the very important role of maternal depression in examining longitudinal child outcomes. This thesis has contributed both original data to the limited information available on child developmental outcomes following antidepressant exposure across two distinct studies. By using two studies this thesis has also allowed a comparison of findings using different methodologies. This thesis has also been able to contribute data on the effects of maternal depression on child development. These findings support clinical recommendations and practices, which highlight the importance of detection and appropriate treatment of maternal depression in pregnancy.  

Variation in cholinergic muscarinic receptor (CHRM) levels is thought to be involved in the pathophysiology of bipolar disorder (BPD) and major depressive disorder (MDD). Lower levels of CHRM2/CHRM4 protein in the human dorsolateral frontal cortex (Brodmann’s area (BA) 46) from subjects with BPD and MDD, and CHRM3 in the human orbitofrontal cortex (BA 10) from subjects with BPD have previously been reported by my laboratory. I sought to confirm those findings in BA 10 and 46 in a larger cohort from subjects with BPD (n = 15), MDD (n = 15) and controls (n = 20) as well as see whether these changes occur in other cortical regions by examining BA 17, 24 and 47, which are also thought to be affected in mood disorders. I investigated whether the binding densities of the CHRM selective radioligands [3H]4-DAMP, [3H]pirenzepine and [3H]AF-DX 384 are altered in mood disorders. Findings from the binding data were confirmed using Western blot and quantitative Real-Time PCR (qPCR), and oxotremorine M stimulated-[35S]GTPγS binding was used to see whether changes in protein levels affected the receptor activity. I also investigated whether muscarinic receptor levels, using [3H]AF-DX 384 and [3H]pirenzepine binding, are altered in the rat brain regions 24 hours after the last acute or chronic treatment with mood stabilisers or antidepressant drugs (n = 20 per group) as part of potential confounding factors. Previous protocols used to measure [3H]4-DAMP binding measured both CHRM3 and CHRM1. I adapted this protocol to make the [3H]4-DAMP binding assay more selective to CHRM3. Contrasting previous findings, there was no difference in levels of CHRM3 protein in any cortical region from subjects with BPD and MDD compared to controls. [3H]pirenzepine binding was lower in the outer layer of BA 17 and BA 24 in BPD and MDD, and in BA 47 from subjects with MDD, but not BPD. [3H]AF-DX 384 binding was lower in the outer layer of BA 17 and BA 24 from subjects with BPD and MDD, and in the inner layer of BA 17 and BA 46 from subjects with BPD, but not MDD, compared to controls. I subsequently examined levels of CHRM2 and CHRM3 protein using Western blotting. Two CHRM2-specific immunogenic bands were detected on the western blots. CHRM2 protein levels were significantly lower in the upper band (71 kDa), but not the lower band (67 kDa), in BA 24 in BPD only compared to controls. By contrast, there was no change in BA 46 from subjects with BPD and MDD. Moreover, levels of CHRM3 protein were not changed in BA 10 from subjects with BPD and MDD compared to control subjects. Similarly, the levels of CHRM3 mRNA using qPCR in BA 10 were also not altered. Levels of specific [35S]GTPγS binding stimulated by oxotremorine M were significantly lower in BA 24 from subjects with BPD, but not MDD, compared to controls. However, there was no change in oxotremorine M stimulated-[35S]GTPγS binding in BA 46. In neuropsychopharmacological studies, there were widespread regions-specific increases in levels of [3H]AF-DX 384 and [3H]pirenzepine binding in rats following chronic treatment lithium and sodium valproate. Chronic lithium administration resulted in a significant increase in the densities of [3H]AF-DX 384 binding in the cingulate, parietal cortices, caudate putamen, nucleus accumbens and olfactory tubercle, but not the frontal cortex. Interestingly, there were significantly higher levels of [3H]pirenzepine binding in all rat brain regions examined after treatment with lithium. Moreover, treatment with sodium valproate for 28 days caused an increase in levels of [3H]AF-DX 384 binding in the caudate putamen, nucleus accumbens and olfactory tubercle of rats and an increase in [3H]pirenzepine binding densities in the cingulate cortex, caudate putamen and nucleus accumbens. By contrast, acute and chronic antidepressant drugs, fluoxetine and imipramine, administration resulted in no change in the levels of [3H]AF-DX 384 binding in any brain region of rats. No change in [3H]pirenzepine binding was found in any rat brain region following acute and chronic administration of antidepressant drugs. These findings suggest that regionally specific decreases in the level of cortical muscarinic receptors are involved in the pathophysiology of mood disorders.

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.

Elevated serum homocysteine concentrations are neurotoxic and are strongly implicated as a risk factor for neuropsychiatric disease (Fabender, Mielke, Bertsch, & Hennerici, 1999; Kim & Pae, 1996; Kruman et al., 2000; Reutens & Sachdev, 2002). This study compares homocysteine levels in early stages psychosis patients and healthy controls. Data from 48 healthy controls were compared with 50 previously diagnosed psychosis patients, 15-25 years, and with a gender ratio males: females 7:3. Patients were outpatients or inpatients at ORYGEN Youth Health, with a diagnosis of first episode of psychosis defined as daily psychotic symptoms lasting longer than a week that could not be explained by other means such as “drug-induced” or “organic”. All subjects were interviewed to collect information relating to family psychotic history. A possible history of psychotic disease in control subjects was tested using the SCID Psych Screening Module, drug use recorded using Alcohol Use Disorders Identification Test (AUDIT) (for alcohol use), The Modified Fagerström Tolerance Questionnaire (mFTQ) (for smoking), Opiate Treatment Index (OTI) (for opiate-type drugs). Dietary and medication histories were also taken. Blood tests were performed to determine serum homocysteine, serum folate, red blood cell folate and serum vitamin B12 levels. An independent sample t test to compare homocysteine levels in patients and controls was performed. Serum homocysteine levels were significantly higher for patients (M = 12.9, S.D. = 3.6) than controls (M = 11.1, S.D. = 2.7) (t(96) = 2.7, p = 0.007, two-tailed). After General Linear Model (GLM) analysis it was found that group (patients or controls), and not serum folate, vitamin B12 and the T allele of MTHFR C677 polymorphism had significant effect on homocysteine levels. Thus a number of factors that may increase homocysteine levels were ruled out. Although it was not possible to obtain a complete data set for some factors (alcohol, smoking and caffeine consumption) (a weakness of the study), strengths included consecutive recruitment, minimisation of selection bias, good matching for age and gender between patients and controls, and the consideration of (serum) folate and (serum) vitamin B12 as potential confounding variables. A number of other studies have found significantly increased homocysteine levels in young patients compared with controls, particularly males. Most related studies favoured the homocysteine-psychosis link. The probability of symptomatic recovery is very high (80-90%) after treatment for first episode psychosis (Robinson et al., 1999) and delayed treatment, but prolonged duration of treatment is associated with poorer response in treatment and worse outcome (Malla & Norman, 2002). This justifies studying homocysteine levels and cognitive function in that first period of psychosis. This research offers evidence for the importance of serum homocysteine levels as showing involvement in the etiology of psychosis. Lowering homocysteine may have a beneficial effect on symptoms and cognitive dysfunction in psychotic illness. Two randomised controlled trials have demonstrated benefit in psychotic illness of giving folate and consequently reducing homocysteine.(Godfrey & Toone, 1990; Levine et al., 2006b). Benefits of taking folate were found in both trials for both cognition and psychotic symptoms. By reducing homocysteine levels early in the illness, some of the excess cardiovascular mortality may be prevented. Secondary prevention of CVD does not appear to influence outcome (Hermann, Herrmann, & Obeid, 2007), so the right time to intervene and reduce risk would appear to be early in the course of psychosis. Additionally, by lowering homocysteine cognitive functioning and psychotic symptoms may be improved (Levine et al., 2006b).

The thesis develops models for social phenomena based on two primitive concepts: individual and relation. The models - based on the p* class of models for social networks - are designed to examine the inter-dependence of individual characteristics together with the social relations that exist among those individuals. The goal of constructing such models is to extend the capacity to develop rich descriptions of social processes. Relations among individuals are represented by a network or networks of interpersonal ties. The first part of the thesis describes models solely for such sets of relational ties. Techniques to represent data dependencies, approaches to model interpretation, and methods for valued attribute and relational data, are developed. (For complete abstract open document)

Psychiatric terminology has undergone a number of significant shifts over time. These have reflected broader social circumstances surrounding mental illness. One of the biggest upheavals was publication of the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III) in 1980, which created a strictly defined categorical system of diagnostic labels. A framework from historical sociolinguistics, proposed by Weinreich, Labov and Herzog (1968), has been used to investigate this change. Three terms were analysed in detail – Schizophrenia, Bipolar Disorder and Panic Disorder – and were found to have very different histories leading up to DSM-III. The Weinreich et al. framework is evaluated for its utility in this type of complex semantic change, and is found to be effective with some minor modifications. Broader effects of language on shaping perceptions of mental illness are also briefly sketched.