Medicine & Health

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Now showing 1 - 10 of 14
  • (2021) Chilver, Miranda
    Thesis
    Mental 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.

  • (2022) Sloane, Jennifer
    Thesis
    From 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.

  • (2022) Jamshidi, Javad
    Thesis
    Wellbeing, 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.

  • (2022) Shvetcov, Artur
    Thesis
    Rodents 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.

  • (2022) Aung, Htein Linn
    Thesis
    With 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.

  • (2022) Joubert, Amy
    Thesis
    Targeting 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.

  • (2021) Evans, Holly
    Thesis
    Talking 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.

  • (2023) Rossi Nogueira Rizzo, Rodrigo
    Thesis
    Low back pain is the leading cause of years lived with disability and is associated with personal suffering and societal and economic burden. The burden of low back pain has not improved since 1990, partially because most current interventions are ineffective, and patients do not have access to many adequate treatments. The findings of this thesis have provided new evidence on the effects of a promising pharmacological intervention, the effects of contemporary nonpharmacological interventions, and the mechanisms and acceptability of novel interventions with new treatment targets for low back pain. This thesis has six chapters. Chapter One introduced problems and evidence gaps in the literature on low back pain addressed in the following thesis chapters. Chapter Two provided evidence that the most promising and advanced pharmacological intervention in the development pipeline for chronic pain, anti-NGF, does not provide clinically meaningful improvements in pain and function and is associated with an increased risk of experiencing an adverse event in adults with low back pain. Chapter Three summarised the findings from all Cochrane systematic reviews that investigated the effects of nonpharmacological interventions for low back pain, providing an accessible synthesis for consumers of the high-quality evidence of current treatments for low back pain. Chapter Four investigated the importance of targeting pain catastrophising to reduce pain intensity for chronic low back pain. Chapter Five presented the facilitators and barriers for the acceptability of an effective nonpharmacological intervention involving new treatment targets to treat chronic low back pain. Chapter Six summarised the main findings and provided the clinical and research implications for the management of low back pain. This doctoral thesis provides new evidence to optimise the management of low back pain. It is unlikely that a new and effective pharmacological intervention will be available for the management of low back pain in the following years. There are nonpharmacological options that probably provide benefits for chronic low back pain. Higher-quality randomised controlled trials are necessary to clarify the effects of nonpharmacological interventions on acute low back pain. Treatment optimisation for chronic low back pain depends on identifying new treatment targets and interventions. The identification of effective treatment targets requires high-quality mediation studies. The successful implementation of interventions with new treatment targets will depend on strategies to address common barriers to the acceptability of the treatment.

  • (2023) Chen, Wenting
    Thesis
    Hoarding disorder (HD) is associated with social impairment, including isolation, loneliness, and reduced social support. Social factors also play a role in the maintenance of hoarding symptoms. However, current treatments for HD do not include an interpersonal component. One potential treatment target for hoarding is empathy. Empathy is fundamental to the development of successful social bonds, and disrupted empathy has been implicated in the social difficulties in other disorders. As such, the aim of this current thesis is to explore the relationship between hoarding and empathy and examine whether empathy could be an interpersonal target in hoarding treatment. In Study 1, I investigated the relationship between hoarding and empathy in an unselected sample. Hoarding was positively associated with emotional contagion, a core component of emotional empathy, and negatively related to cognitive empathy. Self-reported emotional empathy and a behavioural measure of cognitive empathy predicted hoarding beyond depression, and a clinical subgroup of participants showed mild-to-moderate impairments in the behavioural cognitive empathy task. Studies 2-4 expanded upon these findings to investigate empathy-related concepts in relation to hoarding. In Study 2, I examined the relationship between hoarding with social motivation and social support, two variables that represent a predecessor and consequence of normal empathy development, respectively. Hoarding was associated with greater social anhedonia, enjoyment of both positive and negative social rewards, and reduced social support. In Study 3, I aimed to investigate if those with high and low hoarding symptoms differ in prosocial behaviour, a common behavioural component of empathy. No significant differences were found between groups. In Study 4, I aimed to clarify if hoarding was associated with experiences and expressions of anger. Dysregulations in emotional and cognitive empathy may reflect in unhelpful emotional and cognitive experiences of anger. Moreover, aggression is a common behavioural consequence of dysregulated empathy, so was potentially relevant to hoarding. Hoarding was positively associated with angry feelings, hostility, and direct aggression, as well as related concepts of angry rumination and displaced aggression. Lastly, Study 5 was a pilot intervention investigating a social cognition intervention for individuals diagnosed with HD. Participants showed improvements in primary outcomes of cognitive empathy and hostility bias and secondary outcomes of hoarding symptoms and loneliness from pre- to post-treatment. This dissertation provides preliminary evidence that empathy may represent a promising construct to improve the understanding and treatment of psychosocial difficulties in hoarding.

  • (2020) Rowlands, Benjamin
    Thesis
    Sirtuins (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.