Psychiatry - Theses
Permanent URI for this collection
Search Results
1 - 9 of 9
-
ItemThe role of adrenarche in shaping the mind: how adrenarcheal hormones contribute to the development of brain connectivity and internalising symptoms( 2018)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.
-
ItemTau and beta-amyloid deposition, structural integrity, and cognitive function following traumatic brain injury in Australian war veterans( 2018)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.
-
ItemExamining the efficacy of Tuning Relationships with Music™ in helping parents with a history of interpersonal trauma reduce conflict and improve emotional responsiveness with their adolescent( 2018)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.
-
ItemExploring candidate loci, genes, pathways, and evolutionary markers in schizophrenia by re-analyzing candidate gene and genome-wide association studies( 2018)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.
-
ItemIs the epidermal growth factor system a biomarker for clozapine response in schizophrenia?( 2018)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.
-
ItemAn FMRI investigation of emotion regulation in youth depression( 2018)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.
-
ItemConcurrent treatment of mother-child relationship and mood disturbance within the context of postnatal depression( 2018)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.
-
ItemDimensional constructs and methods for their treatment in psychiatry research( 2018)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.
-
ItemPiecing the puzzle together: white, grey and PET imaging across the course of schizophrenia( 2018)Schizophrenia is a severe and debilitating brain disorder, marked by abnormalities in perception, mood and cognition. Despite copious evidence indicating that brain changes are involved in the pathophysiology of schizophrenia, well-replicated neuroimaging markers that track disease progression or reveal therapeutic targets have not been identified. This may be due to regional and unimodal approaches applied in previous neuroimaging studies of schizophrenia, providing limited context to interpret neuropathology; imbedded in a complex multimodal and dynamic system. Furthermore, as neuropathology could evolve over the course of schizophrenia, duration of illness or illness stage reflects a key source of heterogeneity across prior studies. While grey matter deficits are thought to be progressive, it remains unclear whether white matter abnormalities vary as a function of illness stage and whether these changes are regionally linked to structural grey matter loss in anatomically adjacent regions, thus pointing to related aetiological processes. Furthermore, the mechanisms underlying structural grey and white matter deficits remain unknown. Recent evidence points to elevated microglial activation - an inflammatory response in the central nervous system, which might cause secondary neuronal degeneration, decreased neurogenesis and synaptic dysfunction, and may thus underlie structural brain changes in schizophrenia. This thesis applies multimodal imaging to address gaps in our knowledge of brain changes in schizophrenia, through evaluating three primary questions: (i) Do white matter disruptions deteriorate as a function of illness stage over the course of schizophrenia? (ii) Are white matter deficits regionally linked to the well-characterised grey matter deficits in schizophrenia? (iii) Is elevated microglial activation evident and associated with structural brain changes in schizophrenia? Using diffusion-weighted magnetic resonance imaging data, we mapped whole-brain white matter circuitry in patients recently diagnosed with a first-episode psychosis and patients with chronic schizophrenia. We found that white matter pathology in recently diagnosed patients was confined to selective anterior callosal fibres within a more extensive network of white matter disruptions found in chronic illness. These findings may suggest a progressive trajectory of white matter pathology in schizophrenia. Secondly, we applied multimodal imaging techniques to reveal a strong and reproducible relationship between white and anatomically adjacent grey matter deficits in schizophrenia, a relationship that dynamically varied as a function of illness duration. Thirdly, we examined microglial activation, indexed using 11C-(R)-PK11195 positron emission tomography (PET) imaging, as a key mechanism hypothesised to underlie structural deficits in schizophrenia. In contrast to our hypothesis, we found no evidence of microglial activation or a relationship to brain changes in individuals across any stage of illness, including those at ultra-high risk of psychosis, recently diagnosed with a first-episode psychosis and patients with chronic schizophrenia. These findings highlight the need for whole-brain and multimodal approaches to expose patterns of neuropathology in schizophrenia for biomarker and therapeutic detection. Using a whole-brain perspective, our results implicate early grey and white matter abnormalities in schizophrenia, which dynamically evolve over the course of illness. An exciting possibility of these findings is that processes underlying such early deficits could be targeted therapeutically to delay or prevent illness progression or alternatively, as signatures for later illness chronicity.