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(2021)ThesisMental wellbeing, a state of positive subjective experience and psychological functioning, is a key component of mental health. Despite this, little is known about how mental wellbeing is manifested in the brain, or how such neural associations covary with depression and anxiety symptoms. Thus, the aim of this thesis was to explore potential electrophysiological markers of wellbeing using electroencephalography (EEG) and event-related potentials (ERPs). To facilitate further investigation into the association between electrophysiology and wellbeing, a positive psychology intervention was also developed. Following an introduction to the key topics, Chapter 2 examined the relationship between mental wellbeing and resting EEG power. This study identified a specific profile of resting EEG power that is associated with wellbeing, independent from depression and anxiety symptoms. Twin modelling clarified that this EEG profile shares a genetic correlation with mental wellbeing. Chapters 3 and 4 shift towards using ERPs to investigate how wellbeing and depression and anxiety symptoms are associated with emotional and cognitive processing. Chapter 3 reported that wellbeing was not significantly associated with emotion processing after accounting for depression and anxiety symptoms, which were significantly associated with alterations in emotion processing. In Chapter 4, no evidence was found for an association between wellbeing or depression and anxiety symptoms with cognitive ERPs, although associations with behavioural performance reported in previous studies were replicated. Finally, Chapter 5 reports on the effectiveness of an online positive psychology intervention which was found to significantly improve wellbeing, particularly subjective wellbeing. Although COVID-19 restrictions prevented the evaluation of causal links between wellbeing and EEG using this intervention, it is discussed for purposes of future research. Together, this thesis provides one of the first investigations into the electrophysiological correlates of mental wellbeing. Resting EEG power was identified as the most promising avenue for future research aiming to establish endophenotype markers of mental wellbeing, with the task-related measures assessed here were not associated with wellbeing. A short and effective online intervention was developed that could be used to facilitate future investigations into the use of resting EEG as a predictor and marker of mental wellbeing.
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(2022)ThesisFrom a child interrupting a conversation between her parents to ask "What's for dinner?" to a nurse interrupting a physician in the middle of a complex procedure with an urgent message, interruptions are an inevitable part of our daily lives no matter who we are, where we live, or what we do. Interruptions can have a variety of affects on people's performance and behavior. While interruptions may sometimes facilitate performance, often interruptions have negative consequences. For example, interruptions may result in people making more errors or forgetting to complete a prior task altogether. This thesis examines existing strategies to help mitigate interruption costs and explores the effects of interruptions within different decision environments. Chapter I introduces the topic by discussing a few theoretical frameworks of interruptions and reviewing prior research on what makes interruptions disruptive. One strategy to minimize interruption costs is to use what is called an interruption lag, which can be thought of as taking time to prepare for a pending interruption. Chapter II presents a novel experiment to systematically explore the potential benefits of interruptions lags and an alternative intervention (i.e. providing feedback) when interruption lags are not possible. Chapters III and IV discuss the results from three experiments and a final replication study that all focus on how interruptions affect people's decision making in unique environments. The environments consist of easy problems (i.e. basic arithmetic problems) and trick problems, designed in such a way to lead the reader down an incorrect path. Results from these studies were mixed. While there was some evidence that interruptions may make people more susceptible to falling for the trick answer, this finding was inconsistent across all the experiments. Chapter V applies the findings from the previous chapters to a medical context. This chapter presents novel medical cases that were developed with the help of a medical expert. These cases consisted of easy, hard, and trick cases designed for medical students. The goals of this chapter were to validate the cases and to investigate the effects of interruptions within the different case types. The final chapter (Chapter VI) concludes with a general discussion of the experimental findings, the theoretical implications of the results, and the broader implications of this research for the field of medicine.
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(2022)ThesisWellbeing, a key aspect of mental health, is defined as a state of positive subjective experience and optimal psychological functioning. This thesis presents a series of studies devised to comprehensively explore phenotypic, genetic, and neural correlates of wellbeing. The first study (Chapter 2) aimed to compare the heritability and stability of different wellbeing measures in the TWIN-E dataset (N~1600) to discern the most suitable approach for measuring wellbeing for subsequent gene discovery efforts. This twin-based study concluded that multi-item measures of wellbeing such as the COMPAS-W scale, were more heritable and stable than single-item measures. Wellbeing-associated variants were identified via genome-wide association studies (GWAS) and highlighted the need for larger sample size. The subsequent studies were conducted using population-scale data from the UK Biobank comprising ~130,000 participants with phenotypic and genetic data. Thus, in Chapter 3, I constructed a multi-item “wellbeing index” measure using UK Biobank data to investigate its relationship phenotypically and genetically (using GWAS, polygenic scores and LD score regression) with negative mental health indicators (e.g., neuroticism and loneliness), childhood maltreatment and psychiatric illness. I confirmed that SNP-heritability of wellbeing index was higher than both single-item measures and estimates previously reported (SNP-h2 = 8.6%). Moreover, I provide an overview of phenotypic and genetic correlations between wellbeing index and negative mental health indicators. In addition, childhood maltreatment and psychiatric illnesses were associated with reduced wellbeing, with evidence that genetic factors may influence their correlations. In Chapter 4, I investigated the genetic and phenotypic associations between wellbeing index and brain structure, using magnetic resonance image-derived phenotypes from the UK Biobank. This study found associations between wellbeing and volumes of brainstem, cerebellum and subcortical regions, and structural morphology of various cortical regions. Thus, wellbeing is associated with complex structural variations, each with a small effect. Together, this thesis explores the multifaceted nature of wellbeing, elucidating its phenotypic and genetic relationships with related phenotypes, childhood maltreatment, and psychiatric outcomes, and provides novel insights into the associations between wellbeing, its genetic signatures and brain structure.
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(2022)ThesisThis thesis focuses on the development and applications of magnetic resonance electrical properties tomography (MREPT), which is an emerging imaging modality to noninvasively obtain the electrical properties of tissues, such as conductivity and permittivity. Chapter 2 describes the general information about human research ethics, MRI scanner, MR sequence and the method of phase-based MREPT implemented in this thesis. Chapter 3 examines the repeatability of phase-based MREPT in the brain conductivity measurement using balanced fast field echo (bFFE) and turbo spin echo (TSE) sequences, and investigate the effects of compressed SENSE, whole-head B_1 shimming and video watching during scan on the measurement precision. Chapter 4 investigates the conductivity signal in response to short-duration visual stimulus, compares the signal and functional activation pathway with that of BOLD, and tests the consistency of functional conductivity imaging (funCI) with visual stimulation across participants. Chapter 5 extends the use of functional conductivity imaging to somatosensory stimulation and trigeminal nerve stimulation to evaluate the consistency of functional conductivity activation across different types of stimuli. In addition, visual adaptation experiment is performed to test if the repetition suppression effect can be observed using funCI. Chapter 6 explores if resting state conductivity networks can be reliably constructed using resting state funCI, evaluates the consistency of persistent homology architectures, and compares the links between nodes in the whole brain. Chapter 7 investigates the feasibility of prostate conductivity imaging using MREPT, and distinctive features in the conductivity distribution between healthy participants and participants with suspected abnormalities.
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(2022)ThesisRodents learn to fear a stimulus (e.g., a light) that signals the imminent arrival of an innate source of danger (typically an aversive foot shock). They also learn to fear a stimulus (e.g., a noise) that signals a learned source of danger (e.g., the already conditioned fear-eliciting light). Following Pavlov (1927), the former type of fear is termed first-order conditioned fear, because the stimulus is paired with an aversive unconditioned stimulus (US). The latter is termed second-order conditioned fear, because the stimulus is paired, not with a US, but with an already conditioned stimulus. There are both commonalities and differences in the neural substrates underlying these two forms of fear. Both require neuronal activity in the basolateral amygdala complex (BLA), including activation of NMDA receptors, for their encoding, and both require CaMK signalling, gene expression and DNA methylation for their consolidation. However, de novo protein synthesis is required for consolidation of first-order fear but not for consolidation of second-order fear.
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(2022)ThesisWith widespread access to combination anti-retroviral therapy (cART) and HIV suppression, life expectancy among people living with HIV (PLHIV) is increasing more than ever. According to UNAIDS, there were 8.1 million older PLHIV (i.e., 50 years of age and over) in 2020 globally. Although HIV-associated dementia has become rare in the cART era, mild neurocognitive impairments remain prevalent among PLHIV (~30% in virally suppressed). With aging, there is an increasing concern that HIV may precipitate neurocognitive abnormal aging because HIV is associated with increased markers of aging (e.g., immunosenescence and hyper-coagulopathy) and multiple age and HIV-related comorbidities (e.g., cardiovascular diseases). Importantly, these comorbidities occur at an earlier age and at a higher rate among PLHIV compared to age-matched HIV-negative persons. Earlier, more severe and more rapidly progressing neurocognitive impairment would have major public health consequences for the millions of PLHIV and the healthcare system. The overarching aim of this PhD thesis is to determine whether having chronic stable HIV infection and suppressive ART is associated with abnormal cognitive aging including premature cognitive aging (HIV and age synergistically/addictively lead to much lower cognitive performance at a younger age compared to controls), accentuated cognitive aging (HIV and age synergistically/addictively lead to much greater prevalence and severity of neurocognitive impairment), and/or accelerated cognitive aging (HIV and age synergistically/ addictively lead to much more rapid progression of neurocognitive impairment). To address these questions, we used a range of scientific methodologies including a systematic review, and several types of advanced statistical analyses using national and international longitudinal cohort data. First, to contextualise the potential public health consequences of cognitive aging in PLHIV, we conducted a narrative review of the burden of established dementia risk factors among PLHIV. We identified that the burden of several major dementia risk factors is much greater among PLHIV than in the general population. Second, we conducted the first-ever systematic review evaluating the current evidence for premature, accentuated and accelerated cognitive aging among PLHIV. We determined moderate evidence for premature cognitive aging and strong evidence for accelerated cognitive aging, while accentuated cognitive aging had not been optimally assessed. Lastly, addressing the previous literature major limitations (low sample size, cross-sectional study design, low proportion of older PLHIV, and inadequate controls/norms), we quantified the profiles of cognitive aging in four longitudinal studies of PLHIV. We demonstrated robust trends for premature cognitive aging among PLHIV compared to age-matched HIV-negative persons. We also demonstrated that older PLHIV had a higher risk for both neurocognitive impairment and neurocognitive decline compared to younger PLHIV, while controlling for normative age effect. These results are indicative of both accentuated and accelerated aging, although our research identified the need for longer-term studies using very large sample size to assess these trends especially in PLHIV older than 70+. Based on these findings, we discussed implications for clinical practice and future research directions.
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(2022)ThesisTargeting and reducing the processes underlying the development and maintenance of depression and anxiety disorders, such as repetitive negative thinking (RNT), is a promising approach suggested to improve the efficacy and durability of psychological treatment. Delivering treatment online overcomes many of the barriers to accessing mental health treatment and improves treatment coverage. This thesis therefore involved the development and evaluation of a novel internet-delivered treatment targeting RNT. Study 1 involved an online qualitative survey to gain insight into how individuals define, experience, and understand rumination and worry. The findings from Study 1 were used to inform the development of the online intervention evaluated in subsequent chapters. Study 2 outlines the pilot evaluation of the online intervention. The results of Study 2 demonstrated the preliminary efficacy and acceptability of the intervention in adults, with significant reductions in participants self-reported levels of RNT, rumination, and worry, as well as symptoms of depression and generalised anxiety. Treatment effects were maintained at 1-month follow-up. Study 3 aimed to extend these preliminary findings using a randomised controlled trial design and compared the intervention when it was delivered with and without clinician guidance to a treatment-as-usual (TAU) control group. Participants in both the clinician guided and self-help groups had significantly lower levels of RNT, rumination, and worry, as well as symptoms of depression and anxiety compared to TAU at both post-treatment and 3-month follow-up. Treatment effects were significantly larger in the clinician guided group compared to self-help. This thesis provided the first evidence that targeting rumination and worry, both types of RNT, using an online intervention is efficacious, feasible, and acceptable in adults. This thesis also provided the first direct comparison of treatment outcomes and adherence between guided and self-help intervention formats and, in doing so, is the first to demonstrate the superiority of the clinician guided format. These findings add to the growing body of literature suggesting that internet-delivered interventions can successfully simultaneously target rumination and worry and that doing so is associated with significant improvements in depression and anxiety symptoms.
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(2021)ThesisTalking about dying can be distressing, but for young people with incurable diseases like cancer, talking about their needs and wishes at end-of-life is critical for achieving the best possible outcomes for patients and their families. There is a gap in the literature on factors influencing individual differences in how young people talk about death. To address this gap, this thesis examines the relevance of attachment theory in this context. Across five experiments using explicit and implicit measures, this research manipulated awareness of attachment figures prior to imagining end-of-life scenarios in order to examine the impacts of attachments on how end-of-life conversations are approached. Experiment 1 examined whether a mortality salience induction influenced how young people felt when talking about end-of-life. Experiment 2 assessed whether an attachment induction influenced how young people felt when talking about death. Experiment 3 replicated the design of Experiment 2, with the addition of measures to determine whether the attachment induction influenced what young participants chose to talk about. Experiment 4 examined whether young people who are avoidantly attached experienced a simulated end-of-life conversation differently to securely attached individuals, and whether there were differences between these groups on the topics mentioned in these end-of-life conversations. Experiment 5 used the same design as Experiments 2 and 3 but tested whether the attachment induction influenced how young people talk about the death of a close person. Across experiments, priming attachment awareness appeared to play a role in young people’s engagement with end-of-life conversations, with this relationship appearing to be moderated by individual attachment style. Further, attachment style seemed to influence the content of these simulated end-of-life conversations among young people. Individual differences in openness to discussing difficult topics such as death based on individual attachment style should be expected. These results suggest that consideration of attachment theory may have an important role to play in outcomes around end-of-life for young people and their families.
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(2020)ThesisSirtuins (SIRTs) comprise a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, capable of affecting health-span and DNA expression. In cell-culture and peripheral-tissue models, researchers have identified that SIRT1 and SIRT2 are also capable of changing enzymatic activity in glycolysis and Krebs cycle. In brain, the impact of SIRT1 and SIRT2 deacetylase activity on metabolism is poorly understood. The aim of this project was to determine if metabolic pathways in brain could be regulated by SIRT1 and SIRT2-mediated deacetylation in mammalian systems. An established ex vivo reductionist model of brain metabolism was used to test the hypothesis that direct inhibition, activation or ablation of SIRT1 or SIRT2 deacetylase activity would result in significant changes in brain metabolism. Alterations in brain metabolism were assessed by examining changes in 13C-enriched substrates, and metabolite pools with 13C and 1H nuclear magnetic resonance spectroscopy. Chapter three provides evidence that approximately 30% of the GABA synthesized from [1,2-13C]acetate was made directly in neurons. Activation of neuronal specific SIRT1 caused an increase in the incorporation of [1,2-13C]acetate into brain, while activation of astrocytes with potassium depolarization caused a decrease in [1,2-13C]acetate incorporation. These results indicate that acetate is not a reliable marker, nor exclusively metabolised in astrocytes. Further, brain metabolism of acetate is modulated through enzyme acetylation regulated by SIRT1 deacetylase activity. Results in chapter four posit that activation of SIRT1 with SRT 1720 directly stimulated incorporation of 13C into Krebs cycle intermediates and reduced incorporation into lactate. Several off-target effects were observed for SIRT1 activator resveratrol and SIRT1 inhibitory EX-527 that questions their suitability for study of SIRT1 activity. Chapter five concludes that inhibition of SIRT deacetylase activity by AGK2 produced an effect consistent with glutamatergic AMPA receptor activation, in keeping with known SIRT2 targets. Potent SIRT2 inhibitor C64 increased 13C label incorporation into GABA from [1-13C]D-glucose in guinea pigs, and glutamine from [1,2-13C]acetate in WT mice, an effect that was also observed in SIRT2 KO mice. These results indicate that SIRT2 deacetylase activity may impact neurotransmitter systems. This thesis supports the theory that SIRT1 and SIRT2 deacetylase activity can influence brain metabolism in mammalian systems.
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(2021)ThesisConcern about falling is a common and serious health concern for older people. However, older people's participation in proven interventions for reducing concern about falling remains low. Health literacy could be influential to older people’s long-term participation in health programs for concern about falling. This thesis aimed to understand the relationship between health literacy and concern about falling in community-living older people. Six studies were conducted: (i) proposed a multicomponent theoretical model on health literacy and concern about falling; (ii) conducted a systematic review and meta-analysis exploring the relationship between health literacy and physical activity; (iii) developed and validated the Falls Health Literacy Scale (FHLS), a health literacy instrument specific to falls; (iv) developed cut-points for the 30-item and 10-item Iconographical Falls Efficacy Scales (IconFES) and evaluated their construct and predictive validity to falls and reduced physical activity; (v) assessed the effectiveness of a six-week online cognitive behavioural therapy (CBT) program for reducing concern about falling; (vi) explored how health literacy affects adherence to a home-based exercise program. The main findings were: (i) health literacy is closely related to many determinants of concern about falling and greater efforts are needed to clarify the impact of health literacy on intervention adherence and decision-making of older people with concern about falling; (ii) older people with inadequate health literacy are less likely to engage in physical activity on ≥5 days per week than those with adequate health literacy; (iii) the FHLS is sensitive to levels of fall-related health literacy, with good validity in an older population; (iv) the developed IconFES cut-points were sensitive to variables associated with concern about falling and predicted fall incidence and physical activity restriction after one year; (v) online CBT is a feasible treatment method for older people, and a targeted program with a well-integrated psychoeducation module on concern about falling seems warranted to boost the therapeutic effects; (vi) education, history of falls, anxiety and neuroticism moderate the relationship between health literacy and adherence of older people to a home-based exercise program. The thesis findings elucidate key aspects of the relationship between health literacy and concern about falling in older people.