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ItemNormative modelling in large-scale multi-site neuroimaging data sets to investigate brain abnormalities in depression( 2023-09)The search for diagnostic biomarkers using cortical thickness alterations in depression has been impeded by a combination factors, including small sample sizes underpowered to detect small effect sizes in cortical thickness differences, clinical and pathogenic between-subject heterogeneity, group average comparisons and brain ageing effects. Sample sizes in clinical neuroimaging can be increased by creating data sets by pooling. However, pooling studies across acquisition sites can create site effects, which stem from differences in during image acquisition and pre-processing. Site effects can induce biases into the estimates of cortical thickness measures and can interact with the effects of additional variables on cortical thickness, which can make their removal difficult. The aim of this thesis is to 1) Provide an educational review of retrospective site effect correction methods, their benefits, drawbacks and use cases, including normative modelling 2) Develop and test a normative model based on the covariates age, sex and site that allows to correct for site effects on cortical thickness measures in a pooled, public normative modelling data set 3) apply the best performing normative model to cortical thickness data of a large pooled depression neuroimaging data set, in order to compare z-score deviations of depressed individuals to those of healthy controls and link those deviations to clinical characteristics. Regarding aim 1) I summarise several retrospective site effect correction methods that have been published. The evaluation of the statistical foundation of each method reveals that each method has different used cases, advantages and disadvantages that the user should be aware of when choosing a method. To address aim 2), linear and non-linear versions of a normative model based on Hierarchical Bayesian Regression were developed and tested against alternative common site-effect correction methods. All models were evaluated based on their interference with making predictions from cortical thickness measures in a test set containing 35 cortical measures (34 bilateral regions and one whole brain average). ComBat 1–3, regressing out site and predictions from raw data led to a shrinkage of variance when predicting cortical thickness measures from the test set, which suggests the removal of both site variance and shared co-variation with other variables, such as age and sex. Normative modelling, in contrast, was able to retain a larger spectrum of variation. 3) Finally, the non-linear version of the normative model was applied to a large, pooled neuroimaging data set in that contained the same 35 cortical thickness measures of 5300 healthy individuals (training set: n = 3181, test set: n = 2119) and 3645 individuals with depression. The results show large between subject variability in cortical thickness alterations within depression and a large overlap of alterations with healthy controls. This thesis highlights the large between -subject variability in brain measures in clinical cohorts, that may be partially due to site effects in pooled neuroimaging studies. The findings of this thesis stress the need for methods and models in clinical neuroimaging that allow for individualised predictions and for site effect correction, stepping beyond the average patient. Last, the large overlap in the distribution of cortical thickness measures between individuals with depression and healthy controls suggests that cortical thickness might not be a suitable marker for the diagnosis of depression.
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ItemPredicting and improving the use of CPAP therapy in individuals with obstructive sleep apnoea( 2023-02)Obstructive sleep apnoea (OSA) is a common chronic sleep disorder characterised by the repetitive narrowing or collapse of the upper airway during sleep. Consequences of untreated OSA include fragmented sleep, intermittent hypoxia, memory deficits, increased risk of cardiovascular events and workplace accidents, and changes in mood, particularly depression. Comorbid depression is highly prevalent in OSA samples, and it is difficult to diagnose one condition in the presence of the other due to symptom overlap. Continuous positive airway pressure (CPAP) is the treatment of choice for moderate to severe OSA. However, CPAP use is suboptimal in many individuals. As such, there remains a significant burden of OSA on the individual and the healthcare system. The work presented in this thesis was part of a larger randomised controlled trial, the CPAP for OSA and Depression (COSAD) trial. The three experimental studies reported herein (Chapters 3-5) stemmed from the COSAD study design. Patients recently diagnosed with OSA and referred to the Austin Health sleep laboratory for CPAP implementation were recruited for this trial. Study 1 examined predictors of CPAP use up to 4 months post CPAP initiation. Predictors included patient and disease characteristics, sex, age, BMI, OSA severity, psychological variables (anxiety and depression), behaviour change variables (decisional balance and processes of change, and self-efficacy, which is comprised of 3 constructs; risk perception, outcome expectancies and CPAP self-efficacy), the first week of CPAP use, and wait time to CPAP initiation. A delay of 95 days to CPAP initiation was not associated with any differences in CPAP use at 1 week, 1 month and 4 months. Female sex, processes of change and self-efficacy were associated with CPAP use at 1 week. Average nightly CPAP use at 1 week was associated with CPAP use at 1 month and 4 months. No other patient or disease characteristics or psychological variables were associated with CPAP use up to 4 months. Study 2 investigated the effect of treating OSA with CPAP therapy on mood and sleepiness. Mood, including depression, anxiety and stress, were measured at baseline and 4 months and were compared between an intervention group (participants underwent 4 months of CPAP therapy for OSA) and a waitlist control group (participants were not treated for OSA). Stress improved in females with 4 months of CPAP therapy compared to females in the control group. Sleepiness, but not mood, improved after 4 months of CPAP therapy compared to control. Study 3 investigated the effect of a multi-dimensional intervention on CPAP use and self-efficacy compared to treatment as usual. CPAP use and self-efficacy improved in the intervention group compared to treatment as usual across the 4-month trial. These findings support previous work that early CPAP use predicts subsequent CPAP use, that CPAP use improves daytime sleepiness and that an intervention can increase CPAP use. Furthermore, this work has advanced the field by demonstrating that a delay to CPAP initiation may not effect subsequent CPAP use. Additionally, there may be sex differences in stress symptoms when treating OSA with CPAP therapy. Implications for future studies include the importance of the early period of CPAP use and the effect of wait time to therapy initiation on subsequent CPAP use.
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ItemPsychological Interventions for Interpersonal Trauma in Young People with symptoms of Posttraumatic Stress, Anxiety and Depression( 2022-08)Worldwide exposure to potentially traumatic events is highly prevalent among young people aged 12 to 25 years, with international data indicating that approximately two-thirds of adolescents experience exposure to a traumatic event before age 16. In addition to interpersonal trauma inflicted by a caregiver, such as abuse (sexual, physical, and emotional), neglect, and maltreatment, young people are often exposed to family violence, physically assaulted or intimidated by siblings or peers, and are bullied. Unfortunately, subsequent exposure to a different interpersonal trauma type is not uncommon, with nearly 65% of young people experiencing multiple exposures once exposed to one interpersonal trauma. Exposure to interpersonal trauma during this developmentally sensitive period is associated with pervasive and long-lasting psychological, physical, behavioural, social, and economic costs accounting for between 28% and 45% of the population attributable risk for the early onset of youth psychological disorders. In addition to posttraumatic stress, anxiety, depression, problematic substance use, emotional dysregulation, lack of impulse control, poor interpersonal relationships, dissociation, as well as attention and cognition, dysfunctions are highly prevalent and associated with increased incidents of self-harming behaviours and suicidal thoughts and behaviours. Although evidence-based interventions and guideline recommendations exist for the treatment of PTSD in children/adolescents and adults, none of the recommended interventions has been developmentally adapted for transitional-aged youth aged 15 to 25 years exposed to interpersonal trauma, and it remains unclear what the most effective and safe treatment is for these young people. This thesis sought to address this significant gap in the literature with the ultimate aim of evaluating the evidence for psychological interventions for posttraumatic stress disorder (PTSD) and comorbidities in young people exposed to interpersonal trauma and understanding if trauma-focused cognitive behavioural therapy ([TF-CBT]; Cohen et al., 2017), specifically are potentially suitable for this group of young people. The research reported in this thesis had three main aims. Aim 1: To collect, interpret and synthesise quantitative research about the efficacy of psychological interventions for treating anxiety, depression, and substance use in addition to posttraumatic stress symptoms in young people exposed to interpersonal trauma. Aim 2: To understand if trauma-focused cognitive behavioural therapy (TF-CBT) is feasible, acceptable, and potentially clinically effective for young people impacted by interpersonal trauma and symptoms of posttraumatic stress disorder (PTSD). Aim 3: To understand if TF-CBT is safe and tolerable, with a specific focus on determining whether the exposure component of TF-CBT (known as trauma narration) is associated with an elevation in distress or an increase in self-harming behaviours or suicidal thoughts and behaviours. Three studies were conducted to address these aims. Study 1: To achieve the first aim, Study 1 used a meta-analytical approach to evaluate the efficacy of psychological interventions in reducing PTSD, anxiety, depression, and substance use symptoms in young people exposed to interpersonal trauma. Until now, the largest meta-analysis of young people is the study conducted by Gutermann et al. (2016). Unfortunately, the results of this study were affected by incomplete age-data (i.e., no mean age or age range) and poorly reported trauma data (i.e., reported mixed types, not specific types). I was interested in overcoming these two issues in order to provide specific evidence of treatment effects for young people (aged 12–25 years) and those exposed to a wide range of interpersonal trauma types (i.e., beyond physical and sexual abuse). Therefore, I conducted a new review, selecting only those studies where participants’ mean age fell between 12 and 25 years, with at least 80% of the sample exposed to one or more interpersonal traumas. Large significant effect sizes were observed for psychological interventions versus controls for outcomes of PTSD, and there were small significant effect sizes for anxiety and small trend-level non-significant effect sizes for depression. TF-CBT outperformed other treatments in the sub-group analysis for PTSD. However, results need to be interpreted within the context of the small sample size and heterogeneity. Study 2: To achieve the second aim, Study 2 employed a single-arm pre vs post study design, with two additional assessment points at the start and end of the trauma narration phase of TF-CBT for transitional-aged young people aged 15- 25. The sample included 20 young people (65% female, n = 13) who participated in up to 20 sessions of TF-CBT over 30 weeks. Two female participants dropped out of treatment (one after the first session and the other before the start of trauma narration. The remaining participants attended a mean of 15 sessions of TF-CBT over 25 weeks. TF-CBT was implemented with fidelity, and young people reported that they would recommend the intervention to a friend experiencing a similar issue. Quantitative data supported the relative clinical efficacy of TF-CBT. At the end of treatment, only one of the 16 participants with a baseline PTSD diagnosis met the diagnostic criteria. Significant improvements were also noted in self-reported PTSD, anxiety, and depression outcomes. Study 3: To achieve the third aim, distress, self-harm and suicide from Study 2 were analysed and interrogated to investigate if TF-CBT was safe and tolerable. The young people enrolled in Study 2 completed the Subjective Units of Distress Scale (SUDS) at the start and end of each session and were also asked question 6 of the C-SSRS, which inquired about their suicidal thoughts and behaviours in the week between therapy sessions. In addition, data from the Deliberate Self Harm Inventory (DSHI) and Adult Suicide Ideation Questionnaire (ASIQ) were also analysed. Across the 279 sessions of TF-CBT (M = 15.5 sessions), there were 16 incidents of elevated distress in seven participants, 15 incidents of self-harming behaviour in seven participants, and one of both elevated distress and suicide ideation. Results indicated there might be a relationship between distress and self-harming behaviours. Conclusion: This thesis used quantitative methods to understand the relative efficacy of psychological interventions for PTSD, anxiety, and depression in transitional-aged young people exposed to interpersonal trauma. The results of the meta-analysis and data from the pilot study demonstrated the potential safety and efficacy of TF-CBT for transitional-aged young people. This new knowledge is timely given the expansion in specialised mental health service delivery and the need to better accommodate the needs of transitional-aged young people with a history of trauma exposure.
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ItemCharacteristics and Predictors of Suicidality in Young People with Depressive Disorders( 2023)Depression is one of the most prevalent and disabling mental health conditions among young people worldwide. Suicidality and depression are closely intertwined, yet the specific factors that contribute to the nature and severity of suicidality, or changes in suicidality over time, are not perfectly understood. Factors other than depressive symptom severity, such as comorbid psychopathology and personality traits, might be important contributors. In order to reduce the burden of suicidality in young people with depression, we need to improve our understanding of its underlying constructs and contributory elements. This has the potential to contribute to improved prevention and early intervention efforts across multiple stages of suicidality, in addition to informing more targeted clinical treatment approaches. Aims and Objectives The broad aim of this research program was to contribute towards an improved understanding of suicidal thoughts and behaviours in young people with clinically diagnosed depressive disorders. More specifically, the aim was to identify modifiable intervention targets, which could inform clinical treatment approaches, and suicide prevention and early intervention efforts more broadly. Methods This research program comprises four studies each addressing different research questions. Study 1 is a comprehensive systematic review of contributors to suicidality in young people with unipolar and bipolar depression. Study 2 is an analysis of the dimensionality of a widely used measure of suicidal ideation, including associations between this measure’s latent factors and actual suicidal behaviour in young people with major depressive disorder (MDD). Study 3 is an investigation of how different dimensions of social support are associated with suicidal ideation in a treatment seeking cohort of young people with MDD; and Study 4 is a longitudinal analysis of associations between a range of psychosocial correlates and suicidal ideation severity in this same cohort of young people MDD, assessed over a 12-week period. Main Results Several key themes can be drawn from the findings of this research program. First, there is a lack of consensus regarding how the construct of suicidality should be defined, highlighting the need for international collaboration in the development of a standardised, validated classification system for suicidal ideation and suicidal behaviours. The second key finding is that suicidality in young people with depressive disorders is multidimensional in nature. That is, the way in which suicidality manifests in an individual is multifaceted. Suicidality is comprised of multiple constructs encompassing both active and passive ideation, intrapersonal cognitions such as hopelessness and lack of self-worth, and interpersonal factors such as perceived burdensomeness. The third key finding is that there are multiple determinants of suicidality in young people with depressive disorders; in addition to depressive symptoms, there are numerous other predictors of the nature and severity of suicidality. Notably, familial support is an important protective factor, while psychopathological features such as state and trait anxiety contribute to suicidality severity. Discussion Outcomes of this research program reinforce the notion that suicidality is complex and multideterminant in nature. Depression symptomatology is an important contributor, suggesting that regular monitoring of depression symptom severity should be a core aspect of the clinical management of suicidality in young people with depressive disorders. Suicidality is not driven by depression symptomatology alone and it is clear that suicide prevention and intervention efforts need to go beyond simply reducing depression severity. Psychiatric comorbidity with depression, particularly comorbid anxiety, is an important determinant of suicidality. Anxiety and depression, in particular, share many clinical features and risk factors. Interventions targeting transdiagnostic features could have clinical utility in reducing the burden of suicide in young people. In addition, methodological assessment of personality features and carefully targeted intervention approaches such as dialectal behaviour therapy, or mentalization-based therapy, could be a beneficial component of the clinical management of depression and suicidality in young people. An important clinical implication of this research program is that there is likely substantial variability underlying the mechanisms for suicidality from one depressed young person to the next. This suggests that there is perhaps a similarly high degree of variability with respect to potentially effective treatment targets for suicidality. It raises the question of how useful it is to consider a diagnosis of depression as a specific risk factor for suicidality in young people. Alternative approaches to identifying aetiological mechanisms of suicidality, such as a specific symptom approach, could be warranted. It is crucial to develop and employ early intervention approaches for suicidality in young people which focus on the earliest stage of suicidality. Potential targets for early intervention, such as increasing adaptive social support to reduce severity of suicidal ideation, are likely to be beneficial in preventing transition to suicidal behaviour. This highlights the need to assess and monitor suicidality early in young people presenting with mental health symptoms, irrespective of the specific diagnosis. This requires the use of age-appropriate suicidality assessment tools designed for use in young people. Given the fluctuating nature of suicidality, real-time symptom monitoring could perhaps be implemented as part of routine clinical care. The use of transdiagnostic interventions aimed at modifying common cognitive processes underlying depression, anxiety, and suicidality could be an effective treatment approach. Although suicidality is a complex phenomenon and no single approach to prevention or intervention is likely to be universally effective, the findings of this research program do have the potential to help reduce the suicidality-related health burden in this particularly vulnerable population.
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ItemExploring the Bi-directional Association between Depression and Diabetes: A Real-world Electronic Medical Records Based Study( 2022)Depression and type 2 diabetes are leading causes of disability and major contributors to the global disease burden. Clinical studies have suggested a bidirectional association between diabetes and depression: Individuals with type 2 diabetes have a higher risk of developing depression than individuals without diabetes, while individuals with depression have a significantly higher risk of developing type 2 diabetes than those without depression. The bidirectional nature of this comorbidity is often associated with adverse health outcomes in both diseases including reduced quality of life and increased risk of other complications and death. Identifying individuals and factors associated with the onset of both diseases may help clinicians to provide alternative management and preventive strategies, which will eventually have long-term positive effects on both mood and glycemic control. As of date, the temporal trends in the burden and risks of both diseases in people of different age groups, gender, and ethnicities are underreported. In addition, the role of related complications in the bidirectional association between the two diseases has not been addressed at the population level. This thesis used nationally representative electronic medical records from the UK (The Health Improvement Network database, THIN) and the US (General Electric Centricity Electronic Medical Record, GE CEMR) to examine the dynamism in the bidirectional association between type 2 diabetes and depression, and the interplay of cardiometabolic diseases and prognostic factors. To add to what is already known in the literature, emphases were laid on three main objectives: (i) Evaluation of risk factor distribution and long-term depression and cardiovascular risks in people with young-onset diabetes (diagnosed with type 2 diabetes at age less than 40 years) and usual-onset diabetes (diagnosis at age of 40 years or more); (ii) Evaluation of risk factor distribution, and the risk of type 2 diabetes in people with depression, and (iii) The real-world therapeutic management of people with depression. Chapter 1 introduces the key concepts of the mechanisms for the bidirectional link between depression and diabetes and presents the aims, research questions, and outline of the thesis. The second part of this thesis describes the database used and evaluates the representativeness of the US database with respect to the number of visits and the distribution of demographics, major cardiometabolic, and mental illnesses. The number of visits (designed to meet the need for objective and reliable information about the use of ambulatory medical care services) and the distribution of major cardiometabolic and mental illnesses (designed to assess the health and nutritional status) were compared with those from the US national surveys. Results from this section demonstrated the comparable distribution of office visits and major diseases including diabetes, obesity, and depression. Potential differences in gender and age distribution were observed and adjusted for in all downstream analyses. The results reaffirm the usability of the Centricity electronic medical records for conducting epidemiological studies while acknowledging major weaknesses inherent to all electronic medical records. Chapter 3 examines the trends in the bidirectional association between depression and type diabetes in different sociodemographic groups using the US database. Several key findings emerged. First, the prevalence of depression in people with type 2 diabetes increased significantly, especially among African Americans. Second, African Americans diagnosed with depression above the age of 50 years are the most likely to have type 2 diabetes, while white women with diabetes below 50 years had the highest probability of depression. The observed trend and sociodemographic disparity in both diseases imply a growing number of high-risk individuals with poorly managed depression and type 2 diabetes. This paved the way for further research pertaining to the real-world management of depression (chapter 4), and the understanding of factors that are contributing to the increase in depression and type 2 diabetes, including factors specific to demographic subgroups (chapters 5 and 6). The study in Chapter 4 explores the real-world population-based patterns and intensifications of specific antidepressant prescriptions targeting major depressive disorder, and the factors driving treatment intensifications after depression diagnosis. Findings from this research suggest more than a third of adults in the UK and the US diagnosed with depression are between the ages of 18-39 years with consistent increasing trends among men. It was also concluded that age, socioeconomic status, ethnicity, and cardiometabolic multimorbidity are the major sociodemographic and non-psychiatric risk factors for antidepressant prescription changes among adults with depression in the real world. In Chapter 5, two research studies were conducted involving cohorts of individuals newly diagnosed with type 2 diabetes. The first study found increasing trends in young-onset diabetes and the prevalence of cardiometabolic multimorbidity and depression in people with type 2 diabetes between 2012 and 2017. Importantly, this study also concludes that African Americans have significantly higher risks of cardiovascular diseases compared to White Caucasians (especially among young adults recording 42 – 88% higher risks). Findings from the second research work indicate a significant increase in the burden and risk of mental illnesses including depression in people with type 2 diabetes between 2006 and 2017. After adjusting for major confounders, the study also found younger adults with type 2 diabetes had 5 – 57% significantly increasing risks of depression onset irrespective of gender and baseline diabetic complications (cardiovascular diseases, cancer, retinopathy, neuropathy, chronic kidney diseases, obesity). Finally, Chapter 6 evaluates the role of cardiometabolic multimorbidity and obesity in the development of type 2 diabetes among African Americans and White Caucasians newly diagnosed with depression. Results from this chapter indicate a higher prevalence of cardiometabolic multimorbidity among African Americans and an increasing prevalence of obesity between 2006 and 2017 in both African Americans and White Caucasians with significantly higher values among African Americans. Compared with their white counterparts, African Americans had significantly higher risks of type 2 diabetes across all age groups with 17 – 35% of the increase attributed to differences in multimorbidity and 15 – 31% via the obesity pathway. To conclude, this dissertation provides a detailed exploration and valuable insights into the current burdens and rates of type 2 diabetes and depression in real-life settings. It also provides an updated algorithm for the identification and estimation of both diseases in the population to overcome the underestimation of the diseases from national surveys. This is of particular importance to public health considering the increasing prevalence of both diseases over the past decades. The thesis also identifies cohorts of individuals and risk factors associated with significant and/or greater increases in depression and type 2 diabetes over time, which could serve as a guide for allocating resources toward these cohorts in the management of the diseases in the population. With the increasing prevalence of diabetes coupled with longevity, especially in developed countries, the findings from this thesis could be recommended as part of a strategy to reduce the incidence of, and morbidity and mortality from, diabetes and its associated complications. For example, the Australian National Diabetes Strategy 2021 - 2030 has set aside 7 high-level goals in reducing diabetes in the community spanning prevention and awareness strategy; early detection and management; identification of high-risk individuals; and research agenda. The strategy identifies the most effective and appropriate interventions to reduce the impact of diabetes in the community and lead the way internationally in diabetes prevention, management, and research. Overall, this thesis advances current approaches to understanding the complexity of the bidirectional association between depression and type 2 diabetes.
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ItemNo Preview AvailableUsing Machine Learning to Disentangle Heterogeneity Within and Between Psychosis and Depression: Improving Pathways for Precision Medicine in Psychiatry( 2022)The aim of this PhD was to examine the clinical and biological -primarily structural brain- heterogeneity within and between depression and psychosis and provide tools for the improvement of diagnosis and targeted treatment. In chapter 3, a systematic review of structural neuroimaging studies in depression and psychosis identified potential transdiagnostic patterns of gray matter volume (GMV) and white matter volume (WMV) reductions in areas including the middle frontal gyrus, hippocampus, and left-sided posterior subgenual prefrontal cortex. In chapter 4, clinical/neurocognitive and neuroanatomical support vector machine (SVM) learning models demonstrated separability of prototypic depression from psychosis. Psychosis patients with affective comorbidity aligned more strongly to depressive rather than psychotic disease processes. In chapter 5, we identified two transdiagnostic neuroanatomically informed clusters which are clinically and biologically distinct, challenging current diagnostic boundaries in recent onset mental health disorders. In chapter 6, five clusters of schizophrenia with distinct immune signatures, associated with differing GMV and neurocognitive function were identified, with potential to inform the development of novel, targeted treatments. Overall, machine learning was utilised to elucidate and reduce heterogeneity within and between psychosis and depression, and identify biologically relevant and transdiagnostic subtypes that could become potential candidates for targeted treatment. The results are promising and challenge the current nosological system.
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ItemEmpathy during childhood; an investigation of associations with anxiety and depressive symptoms, and brain structure and function( 2021)This thesis investigated the associations between empathy and internalising (i.e., depressive and anxiety) symptoms, and the underlying structural, and functional connectivity neural correlates of empathy in late childhood. Background: Empathy refers to the understanding and sharing of others’ emotions, is a multidimensional construct, and includes cognitive and affective components. Empathy is important for social functioning, and alterations in empathy have been demonstrated in many developmental/psychiatric disorders. Studies in adults have demonstrated that both cognitive and affective empathy are associated with internalising symptoms. Studies in adults have also examined the neural underpinnings of empathy, implicating two major functional brain networks: the Default Mode Network (DMN) has been implicated in cognitive empathy, while the Salience Network (SN) has been implicated in affective empathy. These findings have mostly resulted from investigating brain activity during empathy tasks (i.e., in functional Magnetic Resonance Imaging [fMRI] studies). Less research has examined the associations between trait empathy, and brain structure or intrinsic functional connectivity. Few studies have investigated these associations between empathy and either internalising symptoms or the neural correlates in young people, particularly children. Investigating associations between empathy, mental health, and brain structure and function during childhood is beneficial to begin to build a comprehensive picture of the development of empathy components and the neural correlates of empathy across the lifespan. Based on previous research in adults and preliminary work in children, we hypothesised that higher levels of empathic distress and lower levels of cognitive empathy would be associated with higher depressive and anxiety symptoms (particularly social anxiety symptoms). We also hypothesised that children’s cognitive and affective empathy would be associated with individual differences in brain structure and function within areas related to the DMN and the SN, respectively. Methods: Participants were 9- and 10-year-old children, a subset from the second wave of the Families and Childhood Transitions Study (FACTS), a longitudinal, community-based cohort study. Sample size across the empirical chapters of the thesis differed depending on measures completed and quality of brain images (study 1 n =127, study 2 n = 125, study 3 n = 112). Self-report measures of empathy (cognitive empathy, affective empathy: affective sharing, empathic concern, empathic distress) and internalising (anxiety and depressive) symptoms were administered, as well as a task-based measure of cognitive empathy. To investigate associations between empathy and internalising symptoms (study 1), canonical correlation analysis (CCA), a multivariate technique, was employed. Participants underwent MRI of the brain where T1-weighted structural images and resting-state functional sequences were collected. Grey matter volume, cortical thickness (study 2), seed-to-whole-brain and dual regression resting-state functional connectivity (study 3) were examined. Results: Study 1: CCA demonstrated that components of affective empathy, specifically affective sharing and empathic distress, were associated with internalising (particularly social anxiety) symptoms. Cognitive empathy was not associated with internalising symptoms. Study 2: In region of interest analyses, individual differences in affective and cognitive empathy were related to grey matter volume in the insula and the precuneus. Although these associations were of similar strength to those found in previous research, they did not survive correction for multiple comparisons. While no associations were detected between grey matter volume and empathy in exploratory whole-brain analysis, associations were found between empathic concern and cortical thickness in the right precentral gyrus. Study 3: Seed-to-whole-brain resting-state functional connectivity analyses demonstrated that both affective sharing and empathic distress were associated with decreased connectivity between key hubs of the DMN (precuneus and temporal parietal junction) and other widespread areas in the brain. Analyses of resting-state networks demonstrated that cognitive empathy was associated with both increased and decreased connectivity between dorsal and lateral regions of the DMN and regions outside of the DMN, including the pre- and postcentral gyrus, and the cerebellum. Affective empathy was associated with increased connectivity between the anterior SN and the pre- and postcentral gyrus. These relationships did not survive strict correction for multiple comparisons. Conclusions: Findings suggested that children who share others’ emotions strongly are more likely to experience anxiety, particularly of a social nature. This study also provided preliminary evidence that individual differences in self-reported empathy in children may be related to certain aspects of brain structure and functional connectivity. Overall, we observed less clear dissociations between the neural correlates of affective versus cognitive empathy, and more widely spread involvement from other brain areas. This potentially indicates reduced maturation and specialisation of the systems underlying affective versus cognitive empathy in this age group. However, more research is required to demonstrate reproducibility of the findings. More research investigating the mental health associations and neurobiological correlates of empathy in children is needed, particularly of a longitudinal nature, to track these changes across development. One limitation of our study is that the majority of our findings were based around self-report measures of empathy, which may not accurately reflect empathic ability.
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ItemBugs and Brains: The Gut and Mental Health Study Characterising the gut microbiota in anxiety, depression, irritable bowel syndrome, and their comorbidity( 2021)Background: The community of microorganisms inhabiting the gastrointestinal tract, collectively known as the gut microbiota, is intimately involved in the maintenance of host health. Comprehensive characterisation of the gut microbiota may enable us to better understand conditions whose pathophysiologies remain poorly understood, including internalising mental health disorders (anxiety and depressive disorders) and irritable bowel syndrome (IBS). While existing research has sought to characterise the gut microbiota in these conditions, the two systematic reviews included within this thesis reveal that studies have failed to consider essential confounders, including age, dietary intake, medication use, biological sex, and body mass index. The inadequate consideration of IBS and internalising disorder co-occurrence was also highlighted. Accordingly, this thesis aimed to investigate the gut microbiota in medication-free females with either IBS or an internalising disorder, as well as females with comorbid IBS and anxiety/depression, whilst controlling for key covariates (age, dietary intake, body mass index). Study 1 aimed to compare the gut microbiota of females with IBS relative to controls, as well as compare microbial composition between the three major IBS subtypes (IBS-diarrhoea, IBS-constipation, IBS-mixed). Study 2 aimed to characterise the gut microbiota of females with an internalising mental health disorder relative to controls. Study 3 aimed to compare and contrast the gut microbiota of females with comorbid IBS and an internalising disorder to controls, as well as to participants with IBS or an internalising disorder separately. Method: This thesis includes 162 females, recruited as part of the Bugs and Brains Study, who belonged to one of four groups: i) 42 controls; ii) 36 participants with an internalising disorder (depressive/anxiety disorder), but no IBS; iii) 42 participants with IBS, but no internalising disorder and iv) 42 participants with both an internalising disorder and IBS. Participants completed comprehensive questionnaires, attended a clinical mental health interview, collected a stool sample, and had their anthropometrics measured within a 1-month period. The gut microbiota was estimated using 16S rRNA gene sequencing on an Illumina MiSeq platform (V4 hypervariable region). Sequences were pre-processed using QIIME2 and following the DADA2 denoising pipeline to produce amplicon sequence variants (ASVs). ASVs were taxonomically assigned against the SILVA database (v.138). Data analysis was performed using R (v.1.3.1073), with the packages phyloseq and picante (alpha diversity), vegan (beta diversity), ANCOM-BC and MaAsLin2 (differential abundance), and randomForest (random forests). Results: Comprehensive multivariate analyses revealed key similarities with regards to the gut microbiota in IBS and anxiety/depression relative to controls. Females with IBS or an internalising disorder tended to be enriched in bacterial species associated with inflammation (e.g., Proteobacteria, Parabacteroides, Alistipes), and participants with either condition harboured a lower relative abundance of immunoregulatory SCFA-producing bacteria relative to controls (e.g., Barnesiella, Bacteroides eggerthii, Lachnospira, Faecalibacterium). Moreover, both the anxiety/depression and IBS groups had higher relative abundances of species known to degrade the essential amino acid tryptophan (i.e., Alistipes). While similar findings were observed in participants with comorbid anxiety/depression and IBS, the gut microbiota composition in this group was heterogeneous, and alterations were not more pronounced than those observed in participants with either disorder separately. Of note, higher abundances of mucin-degrading bacterial taxa were observed in IBS-C and IBS-M relative to controls and the IBS-D group (e.g., Akkermansia muciniphila), suggesting this alteration may be a unique to constipation. Conclusion: This thesis presents a comprehensive characterisation of the gut microbiota in females with IBS, an internalising mental health disorder, and their comorbidity. Similar alterations in the gut microbiota composition relative to controls were identified in these conditions and were not driven by their comorbidity, as participants in the IBS group had no lifetime history of a mental health disorder, and participants in the anxiety/depression group had no lifetime history of IBS. The included studies have great strength in highlighting these findings independent of key confounding factors, including age, dietary intake, BMI, and host sex. Participants in this study were also medication-free and without relevant medical comorbidities. While these studies are well placed to examine the cross-sectional associations between gut bacteria with IBS and internalising disorders, future research should seek to integrate functional analyses and examine other microbial members of the gut microbiota. Longitudinal research designs that combine taxonomic and functional investigations will elucidate the true complexity of gut microbe interactions with host mental health and gastrointestinal functioning.
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ItemThe hyper-ordinary depression hypothesis, and mechanisms of cognitive rigidity in depression (or zen and art of reducing depressive cycle maintenance)( 2017)This thesis is comprised of two related parts: a theoretical inquiry into the antidepressant mechanisms of a range of Non-ordinary States of Consciousness (NSCs), alongside the development of a novel mechanistic account of depression; and a set of four empirical studies that investigated aspects of cognitive rigidity in depression that relate to this novel account. In Chapter 1, I show that various disparate induction procedures (e.g., mindfulness practice, psychedelics, brain entrainment, and endurance exercise) are associated with both the production of NSCs and the reduction of depressive symptoms. Interestingly, these NSCs have in common many core neurological, psychological, and phenomenological features that are antithetical to core features of depression. I suggest that these features of NSCs represent potential therapeutic mechanisms, and that the production of certain NSCs mediates the reduction in depressive symptoms. I argue that two related superordinate features underlie these changes – enhanced Receptivity (e.g., perceptual, particular, absorbed, suggestible, flexible, open) and enhanced Projectivity (e.g., self-efficacious, intimate, relational, self-transcendent), that together represent elevated Interdependence between the individual and the world. In contrast, I argue that numerous features of depression appear to represent a fundamental deficiency in Interdependent processing, and that this deficiency extends into the most basic level of minimal subjectivity, representing a global qualitative change that satisfies criteria for an altered state of consciousness. Consequently, I argue that depression is associated with a ‘Hyper-ordinary’ state of consciousness. I suggest that the degree to which an NSC can reduce depression is a function of the degree to which Interdependent processing occurs within the state, and endures thereafter. Chapters 2, 3, and 4 report on a set of four empirical studies that investigated cognitive abnormalities in depression associated with the Receptivity aspect of the Hyper-ordinary account of depression. These tasks explored the link between depressive symptoms and three related processes that fall under the rubric of ‘cognitive flexibility’ – the ability for unexpected information to gain access to awareness; the ability to generate divergent representations for that information; and the ability to abandon extant representations in favour of those that are more compatible with unexpected information. As depression is associated with various forms of cognitive rigidity, including biased beliefs and interpretations that resist change, these studies investigated processing abnormalities in depression that might account for such rigidities. Additionally, as cognitive rigidity in depression is typically confined to specific forms of information processing, the tasks all employed stimuli that are highly relevant to the level of construal, the thematic content, and the rhetorical mode of depressotypic thinking, thereby increasing their sensitivity to detect differences, and their ability to reveal potential therapeutic targets. Results showed that depressive symptoms were related to slower access to awareness for unexpected positive information (Chapter 4), deficits in producing diverse categories of response, with no relation to the total number of responses generated (Chapter 3), and deficits in updating interpretations, regardless of whether updating resulted in a more positive or negative interpretation (Chapter 2). Together, this thesis offers a novel account of the depression experience, argues for a set of plausible therapeutic candidates for the antidepressant effects of certain NSCs, and reports on three novel tasks that probe ecologically relevant features of cognitive rigidity in depression, thereby revealing novel therapeutic targets. The picture of depression that emerges from the theoretical account is of a profoundly isolated state characterised by a fundamental deficit in the individual’s susceptibility to be affected by their context, and the perception that one’s context cannot be affected by the individual. The empirical studies show how this deficiency relates to the diminished influence of contextual factors over interpretations and expectations in depression. The hope is that this work can improve and extend the current understanding of depression and its causes, and lead to new methods of recovery.
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ItemSubjective and objective sleep outcomes in young adults who sustained traumatic brain injury in childhood: relationship with fatigue, depression, and quality of life( 2019)Background: Traumatic Brain Injury (TBI) is highly prevalent in children and often associated with impairments in several functional domains including sleep. Sleep-wake disturbances (SWD) are common in children with TBI and are associated with functional impairments in several domains. While some children may recover from SWD in the short-term postinjury, others may experience persistent symptoms, until late adolescence. Although not explored in children with TBI, studies involving adults with TBI have associated SWD with fatigue and depression symptoms, with these symptoms often co-occurring and impacting quality of life (QoL). In addition, no study has investigated sleep-wake outcomes in adulthood following childhood TBI. This thesis is aimed at evaluating outcomes of subjective and objective sleep, fatigue, depression, and QoL, and the relationship between these outcomes in a sample of young adults with a history of childhood TBI. Also examined were the relationships between sleep outcomes and injury-related factors, socio-demographic factors, mental health, lifestyle factors, and medication use. Methods: The study used a longitudinal prospective design with a cross-sectional assessment of sleep outcomes. Participants included 54 young adults with childhood TBI (mild, moderate, and severe) and 13 typically developing control (TDC) participants matched to the TBI group on age, sex, and socioeconomic status at the time of recruitment. SWD were assessed subjectively with questionnaires and objectively using 14 days actigraphy recording, and all other evaluations were subjective. Results: At 20 years postinjury, subjective sleep outcomes were generally favorable in young adults who sustained TBI in childhood, although moderate TBI was associated with poorer subjective sleep quality compared to severe TBI. With the exception of objective sleep duration, no other objective sleep parameter was significantly associated with history of childhood TBI or TBI severity. Fatigue, depression, and QoL outcomes were also similar between study groups. Nonetheless, poor subjective sleep quality was significantly associated with evening chronotype, increased use of tobacco and psychotropic medications, greater symptoms of anxiety and pain, as well as increased symptoms of fatigue and depression, and reduced health status in the TBI group. Conclusions: Evidence from this first evaluation of SWD in young adulthood following childhood TBI revealed favorable outcomes in SWD, fatigue, depression, and QoL at this developmental stage postinjury, although a subgroup of this TBI sample presented with problems in these domains. Poor subjective sleep quality in the TBI group was associated with less severe TBI, mental health and physiological factors, behavioural factors, and QoL. These findings provide preliminary insight into these outcomes at this stage postinjury and highlight the important influence of sleep in these related domains, particularly, fatigue, depression, and QoL. Clinicians are encouraged to routinely assess sleep and these related outcomes in young adults who have sustained TBI in childhood to identify those at risk of poor outcomes and improve very-long-term outcomes in this TBI population.