Psychiatry - Theses
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A Comparison of an internet-based and face-to-face group intervention to modify body dissatisfaction and disturbed eating in young women
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.
A comparison of homocysteine levels in first episode psychosis patients and age matched controls
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).
A neuroendocrine study of chronic combat-related post-traumatic stress disorder
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.
A population-based study of alcohol use in elderly men: associations with physical and mental health
Considerable attention has been paid to the prevalence and outcomes of alcohol use disorders in both in population-based and clinical samples, and also to the harms associated with alcohol intake in young adults. However less attention has been paid to alcohol consumption in elderly men. The aims of this population-based study were to investigate the patterns of alcohol consumption and the associations between different levels of alcohol intake and demographic, lifestyle, physical and mental health outcomes in a representative sample of elderly men. Five hundred and fifty five participants aged at least 65 years and enrolled in the Geelong Osteoporosis Study reported their usual alcohol consumption for the prior 12-months, had their BMD measured and completed a comprehensive range of medical and lifestyle assessments. Alcohol consumption was common, the majority (48.7%) consumed alcohol moderately (≤2 drinks/day), with a further 19.7% consuming 3-4 drinks and 13.5% consuming ≥5 drinks/day. Almost one in five elderly men in this sample were a non-drinker at the time of assessment. The alcohol consumption groups were compared on demographic and lifestyle variables, and also on key physical and mental health outcomes. The median alcohol consumption increased with increasing socio-economic status. The heaviest alcohol consumption groups were more likely to report current or past cigarette smoking and were also more likely to have low leisure-time physical activity levels in age adjusted models (OR=1.74 95% CI 1.01-3.00), and more likely to have impaired mobility as measured by the Timed Up & Go test (OR=3.01 95% CI 1.41-6.43) when compared to moderate alcohol consumers. Current non-drinkers were more likely to have low leisure-time physical activity levels (OR=1.75 95% CI 1.05-2.91) and were less likely to be current participant in sport (OR=0.52 95% CI 0.29-0.94) than moderate alcohol consumers, independently of age, cigarette smoking and current use of five or more medications. In comparison to non-drinkers, consumers of ≥5 drinks/day had mean differences in adiposity of +4.8% (BMI), +20.1% (FMI), +5.0% (waist circumference), +15.2% (%body fat), +5.3% (% trunk fat) and had a mean difference in lean tissue mass of -5.0%. Furthermore, they had a 2.8-fold increased risk of being classified as obese according to BMI (≥30 kg/m2) and a 3.4-fold increased risk of having a waist circumference of at least 102 cm. While the groups differed in total energy intake, they did not differ in energy intake obtained from food suggesting unregulated supplementation of energy intake from alcohol. Aside from a difference at the mid-forearm site BMD was not associated with alcohol consumption, however bone quality as measured by quantitative ultrasound at the heel decreased with increasing alcohol consumption. Overall, 14.8% of this sample met criteria for a lifetime history of a mental illness, and 3.1% were identified as having a current psychiatric illness, most commonly major depressive disorder. Non-drinkers (OR=2.58 95% CI 1.20-5.56) and consumers of ≥3 drinks/day (OR=1.73 95% CI 0.85-3.51) were more likely to have a lifetime history of any psychiatric illness than moderate alcohol consumers after adjustment for age and mobility. There was a low prevalence of alcohol use disorders in this sample, 2.6% for a lifetime history and 0.8% for a current disorder. One third of elderly men currently drink at a level in excess of the Australian government recommendations for safe alcohol consumption, which in combination with medical comorbidities and high levels of medication use places this group at increased risk of harm. Furthermore, both heavy alcohol consumption and current non-drinking was associated with negative physical and mental health outcomes, this highlights the importance of routinely screening for alcohol consumption within the elderly, and extending the investigation into other important correlates when indicated. Although causality cannot be inferred, these findings provide an insight into the association between alcohol intake, lifestyle and physical and mental health.
A prospective longitudinal study of child development following in-utero exposure to antidepressant medication
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.
A prospective study of the relationship between stress, coping and the onset of psychosis in a high risk group
The experience of stress and associated coping responses are often described as playing an important role in the onset of schizophrenia and other psychotic disorders. Despite widespread acceptance of this model, there is little empirical evidence to support such a relationship. This is partly due to a lack of well-designed prospective studies of the onset of psychotic disorders that incorporate different aspects of the stress and coping process. The relatively recent development of validated and reliable criteria for identifying young people at high-risk (UHR) of developing psychosis has enabled the process of onset of psychotic illnesses to be studied more closely than was previously possible. It has also opened the way to the development and evaluation of preventive interventions. This longitudinal study aimed to compare the experiences of stress and coping between a UHR cohort (N = 143) and a group of young people without mental health concerns (HC group, N = 32). In addition, the contribution of stress and coping in the development of acute psychosis in a subgroup of the UHR cohort (UHR-P, n = 18) was also investigated.
Affect on the prestige landscape: the prestige model of spectrum bipolarity
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.
An FMRI investigation of emotion regulation in youth depression
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.
An investigation of the factors that regulate muscarinic receptor expression in schizophrenia
A previous study identified a group of subjects with schizophrenia, who have, on average, a 75% decrease in their cortical cholinergic receptor, muscarinic 1 (CHRM1). To begin to identify the potential factors responsible for the decreased CHRM1 expression, I investigated the DNA methylation level of CpG dinucleotides in the putative CHRM1 promoter region using the bisulphite-based Sequenom MassARRAY EpiTYPER in Brodmann’s area (BA9) from subjects with schizophrenia that have low levels of CHRM1 (SCZ Low [3H]PZP), subjects with schizophrenia that have normal levels of CHRM1 (SCZ Normal [3H]PZP) and control subjects. The levels of methylation were lower in both groups with schizophrenia compared to the control subjects. In addition, DNA methylation showed a strong positive correlation in the SCZ Low [3H]PZP but not those in SCZ Normal [3H]PZP, suggesting that the decreased level of CHRM1 in SCZ Low [3H]PZP was associated with a decrease rather than an increase in promoter DNA methylation, and they did not mediate the change in CHRM1 expression. Another aspect of my studies investigated the CHRMs levels in BA6 from subjects with schizophrenia. CHRM1, 3 and 4 levels were determined using in situ radioligand binding and Quantitative Real-time PCR (qPCR) in BA6 in the same groups. The results showed the levels of CHRM1 were significantly decreased in BA6 in SCZ low [3H]PZP but other CHRMs were not altered in either groups with schizophrenia. In further effort to discover the factors mediating the decreased CHRM1, levels of transcription factors, Sp1 transcription factor (SP1) and SP3 and miRNA-107, known to regulate CHRM1 expression, were determined using Western blot and qPCR. Levels of Sp1, Sp3 and miRNA-107 were not altered in either group of subjects with schizophrenia compared to those in control subjects. Finally, to identify potential regulatory systems, our laboratory conducted a microarray study to identify genes whose expression profile are changed in response to decreased CHRM1 in BA9. The mRNA levels of Ferredoxin 1 (FDX1) were differentially expressed in both groups of schizophrenia according to the microarray, and qPCR was used to validate this finding. FDX1 expression was increased in both groups of schizophrenia, validating the microarray finding. However, the levels of FDX1 were not changed in BA6 or in tissue from subjects with MDD (Major depressive disorder) or BPD (Bipolar disorder). Taken together, this study supports the existence of a subgroup within schizophrenia with dramatically decreased CHRM1 but not CHRM3 and 4 in the pre-frontal cortex. While the level of CHRM1 DNA methylation was changed in schizophrenia, the decreased CHRM1 expression was not simply regulated by local levels of transcription and post-transcription mechanism, such as Sp1, Sp3 and miRNA-107, suggesting that other mechanisms may contribute to the decreased CHRM1 in these subjects. Finally, the microarray validation study found the level of FDX1 mRNA was increased in subjects with schizophrenia. This finding is of particular interest given the metabolic dysfunction associated with the disorder.
Astrocyte neuropathology in autism: role of neuroinflammation & glutamatergic signalling
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.
Brain network communication models
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.
Chinese-Australian families' help-seeking behaviours for mental illness
This thesis includes two studies: a survey of Melbourne's Chinese community and a family interview study. The survey was based on 418 respondents while twenty-eight caregivers participated in the family interview study. The survey explores how depression and schizophrenia are understood and are dealt with in a migrant Chinese community. The purpose of the family interview study was to examine the pathways to care for mental disorders, the social representation of illness and families' experiences of illness. Social knowledge about mental illness, physical illness and the concepts of normal human experiences of distress influenced the labelling of experienced conditions. Disorders were labelled as ‘a mental illness’, ‘a physical illness’, ‘a normal problem’ or ‘an abnormal problem’. Results indicated that schizophrenia was likely to be labelled as a mental illness and psychiatrists were seen as the main form of help. On the other hand, depressive disorder, anxiety disorder and post traumatic stress disorder were likely to be labelled as a ‘normal problem’, an ‘abnormal problem’ or a ‘physical illness’ and were likely to be treated by family members, friends, a traditional Chinese medicine physician or a Western physician. Labels given determined initial responses to the problem but the work also indicates a dynamic relabelling process developed by exposure to the social and professional systems. Pathways to care are intimately related to illness understandings which in themselves are in some respects relatively dynamic. The present study suggests that health professionals and the health institutions need to take into account patients' and family members’ explanations of illness in order to improve access to their services and in order to improve the quality of the services they deliver to the community.