Psychiatry - Theses
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ItemThe role of lifestyle, cardiovascular factors and biomarkers on health status in older adults at risk of cognitive deterioration( 2021)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.
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ItemStriatal morphology, frontostriatal circuits and functional correlates in neurodegenerative disease( 2017)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.
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ItemA Comparison of an internet-based and face-to-face group intervention to modify body dissatisfaction and disturbed eating in young women( 2003-01)Objective: This study compared the effectiveness of a new manual-based group intervention program, The Body Image and Eating Behaviour Program, for women with sub-clinical body dissatisfaction and disturbed eating behaviours, using two delivery modes: a traditional Face-to-Face group intervention and an Internet-based intervention with interactive on-line group sessions in synchronous time. The program was conducted weekly over an 8-session period. Predictors of a good treatment outcome for the intervention program were examined with both delivery modes combined. Methods: Participants (18-30 year old women) were recruited by advertisements on Melbourne university campuses and at community health agencies. They were randomly assigned to group (Face-to-Face group n=19, Internet-based group n=21). Body dissatisfaction, disturbed eating behaviours, psychological status, and stage of change were assessed using standardized instruments prior to and immediately after the intervention, and at two months follow. Results: A 2 (group) X 3 (testing occasions) within subjects repeated measures analysis of variance was used to examine time and between group differences. Significant improvements on all clinical outcome variables were observed at post-test and maintained at follow-up in both groups. However, there were no significant between group differences. Hierarchical multiple regression analyses were used to examine predictors of treatment outcome at follow-up. Milder depression scores predicted greater improvement in binge eating frequency while a greater improvement in bulimic pathology and self-esteem at follow-up was predicted by more severe body dissatisfaction scores. Stage of change before treatment was not a predictor of outcome. Qualitative research demonstrated that the Internet-based delivery mode was a less confronting way of seeking help and a convenient and supportive medium to disclose personal information. However, participants had more difficulty exploring deeper psychological issues in the Internet-based group and forming close bonds with each other due to the speed and flow of the discussion. Discussion: The treatment program was valuable in both delivery modes and was found to be very acceptable by participants. The Internet, with the potential to over-come obstacles of distance and provide a discrete mode of treatment delivery, showed promising results at improving body satisfaction and disturbed eating behaviours in young women. Findings demonstrated inconclusive evidence for predictors of a good treatment outcome.
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ItemUnderstanding the role of frontotemporal brain structures in schizophrenia through magnetic resonance imaging and neuropathological studies( 2012)Section 1: The first two chapters describe my initial hippocampal volumetric work in patients with first-episode psychosis and chronic schizophrenia that identified hippocampal changes early in the course of psychosis. Chapter 3 explores in detail the theoretical basis for hippocampal involvement in schizophrenia and introduces for the first time the concept that the hippocampal volume changes observed in patients with first episode psychosis and chronic schizophrenia may not be present in patients at high risk of psychosis. Chapters 4 to 6 describe a series of cross sectional studies showing that hippocampal volumes are normal in high risk patients who later develop psychosis (Chapter 4 and 6), normal in patients with schizophreniform psychosis (Chapter 6), reduced on the left side in patients with first-episode schizophrenia (Chapter 6) and bilaterally reduced in patients with chronic schizophrenia (Chapter 6). These findings suggest that right hippocampal volume reduction occurs with increased illness duration, a finding supported by a voxel based morphometry study of patients with chronic schizophrenia (Chapter 5). Finally in contrast to our original findings (Chapter 1) that hippocampal volumes were equally reduced in patients with first-episode schizophrenic and non schizophrenic psychoses, our study of a much larger first-episode cohort (Chapter 6) showed that hippocampal volume reduction was specific to schizophrenic psychoses while amygdala enlargement was specific to non schizophrenic first-episode psychoses. These findings suggested either that (i) patients who make the transition from high-risk to first-episode or first-episode to chronic schizophrenia already have hippocampal changes and/or (ii) that hippocampal volume changes occurred progressively over the course of the illness. Section 2: Chapters 7 and 8 describe follow-up longitudinal imaging studies in a first-episode cohort and a high-risk cohort respectively. We did not identify hippocampal volume change over a two-year period (Chapter 7) but observed whole brain changes over time in first-episode and chronic schizophrenia cohorts. We hypothesised that structural changes may have occurred prior to or over the transition to active psychotic illness. Chapter 8 describes parahippocampal and frontal changes in high-risk patients who developed a psychotic illness and not in those who did not develop a psychotic illness. These findings provided support for the concept that some patients with a psychotic illness exhibit progressive structural brain changes. Section 3: Chapters 1 to 8 describe evidence for the presence of structural brain changes in the hippocampi of patients with schizophrenia. Structural MRI cannot determine the neurobiological correlates of such brain changes i.e what is causing the changes or which elements of brain tissue are involved. The neurobiology of diseases that mimic schizophrenia (‘secondary schizophrenias’) has provided insights into schizophrenia. Chapter 9 describes a previously unrecognised association between young onset frontotemporal dementia and schizophrenia-like psychosis and specific hippocampal pathology in these cases. Chapter 10 describes similar pathological abnormalities in the hippocampus of patients with schizophrenia and bipolar disorder, who had never been suspected of having dementia earlier in life. The identification of clinical and neuropathological associations between FTD and schizophrenia / bipolar disorder is of significant clinical relevance and provide new avenues for research into the underlying neurobiology of major mental disorders. Section 4: The concluding section discusses how the work in this thesis can be understood within the context of neuroimaging work that has emanated from this large dataset and the current schizophrenia literature. The association between schizophrenia and FTD identified in Chapters 9 and 10 is explored further in this final section with reference to the literature and some illustrative case reports.
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ItemOutpatient commitment: is it effective?( 1998)Outpatient Commitment (OPC) is a legal procedure that allows for involuntary psychiatric treatment in the community. Legislation for OPC first emerged in the 1970s in the USA in an attempt to provide a legal remedy for the problems posed by ideological reforms to institutional psychiatry and mental health law. OPC in particular attempts to address the difficulties presented by persons with chronic relapsing forms of serious mental illness and poor compliance with outpatient treatment - persons whose disadvantage is now particularly visible in the streets of our large cities. OPC sits awkwardly between the developing and expanding frameworks of community mental health services and mental health law. It potentially overlaps with guardianship laws, enduring medical power of attorney and court orders. Despite the growing provision for OPC and its increasing frequency of use in North America, the Antipodes, and most recently on the boarders of the European continent, there remains little understanding of the conceptual mechanisms involved in its application. Even less is known about the group of patients who might respond best to its implementation. Without taking stock of its potential adverse effects, societies run the risk of enthusiastically embracing this rather crude legal mechanism of persuasion, instead of exploring or supporting the development of potentially more effective and sophisticated clinical interventions to address the problem of non-compliance with outpatient psychiatric treatment. Given the current limitations of clinical interventions for serious mental illness and treatment non-compliance, OPC may provide a very useful role in enhancing the efficacy of these interventions/treatments through its effects on the way a treatment service is provided as well as on the patient's treatment adherence. With this aim in mind, many different forms of OPC have now emerged. However, without adequate research evidence, it is not possible to advocate strongly for the development of one form of OPC legislation over another. Nor is it possible to argue for its use in preference to other legal mechanisms of treatment orders e.g., guardianship orders. The final decision about which form of OPC legislation is chosen appears to have relatively little to do with any empirical evidence of clinical efficacy but more to do with historical and legal concerns. This thesis attempts to go some way to further bridge the gap between evidence based psychiatry and the application of mental health law with respect to Outpatient Commitment. Chapters 1 and 2 describe a brief account of the historical context within which OPC has emerged both internationally and in Australia. Chapter 3 provides a review of clinical outcome studies in the USA and elsewhere, concluding that on simple clinical measures of outcome, OPC appears to be associated with significant benefits. It is of note that all these studies have considerable limitations, and none provide a useful comparison of patients' objective clinical ratings with patients' subjective ratings of the "persuasiveness" or "coerciveness" of OPC. Chapters 4 and 5 of this thesis outline the results of a retrospective controlled study of the clinical outcome of all patients on a form of OPC in a sector of metropolitan Melbourne, Victoria, Australia, between 1987-1992. The characteristics of the patients selected has already been reported in a previous study which describes the sample as being mainly those with chronic relapsing forms of psychotic illness complicated by a history of violence and noncompliance with outpatient treatment. In Chapter 4, the results of an analysis of the clinical outcome of this group of patients suggests that the majority of these patients benefit from the application of OPC. In Chapter 5, the results of the control group comparison also indicate that though these OPC patients have evidence of higher levels of morbidity than other involuntary patients discharged directly into the community, OPC patients improve relatively better while on OPC orders. However, a minority of OPC patients do not seem to benefit or even deteriorate with the application of OPC. The study attempts to identify the characteristics that might predict better or worse clinical outcomes associated with OPC. It is important to note that the study, because of its retrospective design, suffers from limitations similar to those evident in other studies and, in particular, it does not account for influence of patients' subjective experiences of OPC. Finally in Chapters 6 & 7, based on the experience of this study and on a review of the literature, a conceptual model is proposed in order to assist with an understanding of how OPC might work. This model focuses on the nature of the impact of OPC on treatment adherence, through its effect on the patient and on the system within which the patient is being treated. It suggests that a balance needs to be struck between the persuasiveness versus the coerciveness of the Outpatient Commitment procedure. An ineffectual mechanism may discredit the procedure as a persuasive aid to treatment adherence. Conversely, an overly coercive mechanism may actually deter patients from accepting any form of assistance for their illness. This model forms the basis of recommendations for future research to test the effectiveness of OPC and to compare or contrast different forms of OPC with each other and with other less formal mechanisms of coerced community psychiatric treatment. Australia, given its relatively uniform structure and administration of mental health services, is in a good position to compare the benefits or otherwise of the rather disparate forms of OPC being introduced into each of its various states and territories. With a multi-centre randomised controlled trial of OPC in this setting, it may then be possible to make recommendations about which form of OPC most effectively and collaboratively assists in the improvement of poor treatment compliance, and which group of patients with serious mental illness are likely to benefit most from its application. It may also assist with determining OPC's relative clinical merit when compared with other less formal coercive/persuasive clinical interventions for treatment non-compliance. Without attempts to study and confirm the empirical evidence for the 'clinical efficacy' of OPC, this increasingly internationally accepted model of OPC oriented community psychiatric care runs the risk of being prematurely challenged in some future wave of mental health reform. As in the example of de-institutionalisation, the ultimate future of OPC may, however, rest not with the law but with the advent of better and more effective treatments for psychotic disorders.
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ItemA neuroendocrine study of chronic combat-related post-traumatic stress disorder( 1997)Descriptions of the development of psychiatric symptoms in response to traumatic experience can be found in literature dating back to some of the earliest writings found. Amongst these symptoms there have always been descriptions consistent with what we would now term Post Traumatic Stress Disorder (PTSD). Tomb (1994) describes how such symptoms historically have been most frequently described in relation to combat experience and are contained in such classical texts as Homer’s Iliad. Recognition that such symptoms also occur in association with non combat related trauma is a relatively recent event. This can be seen in description of response to traumas such as The Boston Coconut Grove Fire (Adler 1943) and the Buffalo Creek Dam collapse (Gleser et al 1981). Combined with the massive number of combat veterans with combat experience related to psychiatric disability following the World Wars, significant impetus appears to have developed for separate classification and understanding of trauma related psychiatric symptoms. Together, these forces led to the creation of the diagnostic category of PTSD for the first time in the American Psychiatric Associations DSMIII (APA 1980). In this series of studies, we are thus aiming to further the understanding of the neurobiology of Post Traumatic Stress Disorder by specifically examining a group of male Australian Vietnam veterans with current PTSD, comparing them to two control Vietnam veteran populations, one group of those veterans who previously met criteria for a diagnosis of PTSD and a third group who never have met criteria for a diagnosis of PTSD. We examined these three groups in a number of ways. Firstly, to further understand aspects of central noradrenergic receptor function we utilised a clonidine growth hormone challenge test. Consistent with previous literature on the HPA axis in PTSD from North American we utilised a modified dexamethasone suppression test to investigate feedback within the HPA axis. Finally, we investigated serotonergic receptor function peripherally with a further study of platelet paroxetine binding and performed the first large study examining central serotonergic receptor function using the d-fenfluamine prolactin challenge test. Before describing the methodology and results of these studies I will review relevant findings to these three systems from studies of animal and human models of stress, clinical populations with PTSD and their treatment and previous experimental analysis of relevant biological variables in subjects with PTSD.