Theses - Psychiatry

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Open Access
Development of a Mobile Health-tracking System for Longitudinal Clinical Assessment of People with Impairments in Brain Functioning
Noh, Jung Min
Individuals with developmental or acquired impairments in brain functioning may present complex needs that affect their quality of life and wellbeing. Clinical assessment in such circumstances would be enhanced if there was a convenient and non-invasive method to collect, integrate, and analyse various health-related measures over time. I propose a novel system that combines electronic observational and self-report data with sensor-based data collected from wearable wrist sensors. The findings focus on people with intellectual disabilities (ID) to illustrate the system’s development, utilisation, and evaluation. The first phase of this thesis provides an overview of the system’s development process. Upon reviewing the relevant literature and web resources, I found that limited attention has been given to the development of integrated assessments encompassing physiological, behavioural, and mental health measures. Mobile applications were created through public and patient involvement (PPI), and various wrist sensors were compared. The final version of the system includes two mobile applications and an external wrist-worn device (Fitbit Versa 2). During the second phase, ten individuals with ID participated in an empirical study. Over the course of two months or more, participants and their informants completed the Daily Assessment Questionnaire at the end of each day, with participants also wearing a wrist sensor on a daily basis. Using the data collected during the empirical phase, the study investigated the feasibility of the system and its inter-rater reliability. Methods of visualising the longitudinal data were explored, and various descriptive and inferential statistical methods were used to examine the relationship between the reported and sensor-based measures. The findings suggest that utilising the proposed method for longitudinal data collection, integration, and analysis could be both acceptable and feasible. The Thesis concludes by discussing the implications of the present work, encompassing ethical and other administrative considerations, and offering suggestions for future research.
Open Access
Development of human functional and structural brain networks in adolescence and its relevance to psychiatric disorders
Dorfschmidt, Anna-Lena; Dorfschmidt, Anna-Lena [0000-0002-0447-1104]
The human brain undergoes various phases of active development during the lifespan. While these neurodevelopmental processes are fundamental to the emergence of new cognitive and social capacities, they also coincide with a period of increased risk of neuropsychiatric disorders, which generally have their highest rates of clinical incidence in the first two decades. Since many neuropsychiatric disorders display sex differences in both prevalence or clinical presentation, this raises the question of whether there are underlying sex differences in processes of adolescent brain development. In this thesis, functional and structural magnetic resonance imaging (MRI) is used to map normative brain development, in adolescence and later life, which might differentially predispose men and women to different levels of risk for adolescent and adult mental illness. First, Chapter 1 reviews relevant research on understanding developmental changes in the brain during adolescence, focusing on prior studies of normative sexual differentiation of neurodevelopmental trajectories, and vulnerabilities associated with developmental changes. Chapter 2 investigates whether there are sex differences in normative adolescent development of *functional* connectivity networks, using an accelerated longitudinal cohort of healthy adolescents aged 14-25 years (N=298), comprising 2 or 3 repeated scans on most participants. Sexually divergent development of functional connectivity was identified in the default mode network, limbic cortex, and subcortical structures. In these regions, females were shown to have a more “disruptive” pattern of development, whereby weak functional connectivity at age 14 became stronger during adolescence, specifically in a cortico-subcortical system including many areas of the default mode network. Using open data on whole genome transcription at multiple sites in adult post mortem brains (provided by the Allen Brain Institute), this fMRI-derived map of sexually divergent brain network development was found to be spatially co-located with brain regions where transcription was enriched for genes on the X chromosome and neurodevelopmentally relevant genes. Chapter 3 starts from the hypothesis that the known sex difference in the prevalence of major depressive disorder (MDD), with increased rates of diagnosis in adolescent females compared to males, could be the psychological or clinical representation of underlying sex differences in adolescent brain network development. To test this hypothesis, the sexually differentiated fMRI network identified in the previous chapter was further contextualized. The fMRI-derived map of sexually divergent brain network development was found to be co- located with prior loci of reward-related brain activation; a map of functional dysconnectivity in major depressive disorder derived from a prior, independent case-control study of adult MDD; and an adult brain gene transcriptional profile enriched for MDD risk genes, as defined by prior genome-wide association studies of MDD. These results collectively suggested that normative sexual divergence in adolescent development of a cortico-subcortical brain functional network was psychologically, anatomically and genetically relevant to depression. Chapter 4 reviews literature on similarity-based *structural* brain networks. Subsequently, Chapter 5 investigates adolescent changes in structural brain network development using morphometric similarity networks derived from the same accelerated longitudinal cohort of healthy adolescents previously used for analysis of functional network development. Morphometric similarity was found to increase during adolescence in insula and limbic regions and to decrease elsewhere in the brain. This profile of decreasing morphometric similarity, or increasing dissimilarity, was associated with the well-known adolescent process of cortical shrinkage, i.e., reduced macro-structural measures of cortical thickness, and with increased magnetization transfer, a micro-structural measure of intra-cortical myelination. Regional nodes of the morphometric similarity networks that became more dissimilar, putatively more differentiated in terms of their cyto- and myelo-architectonics during adolescence, were also found to de-couple from brain functional connectivity, suggesting that increasing morphometric dissimilarity may reflect adolescent development of functional independence. In an effort to move from group level to subject-specific analyses, and acknowledging that brain development is not restricted to adolescence but is a continuous process throughout life, in Chapter 6 a total of 41 prior studies, including a total of 90,000 structural MRI scans, were aggregated to estimate lifespan trajectories of normative subcortical development from 180 days post conception to 100 years of age. This analysis identified novel milestones of subcortical volume development; in particular a set of subcortical regions was defined that reached peak grey matter volume during adolescence. Furthermore, subject-specific deviations from normative, non-linear neurodevelopmental trajectories? were derived and used to estimate case-control differences in subcortical volume across the lifespan in multiple neuropsychiatric disorders, demonstrating the potential clinical applications of these normative subcortical growth charts. In Chapter 7, these new experimental results on adolescent and life-span development of functional and structural brain networks, and subcortical grey matter volume were summarised and drawn together, highlighting how these insights are aligned with each other and with the existing scientific literature on brain development, sexual differentiation and risk of psychiatric disorders.
Open Access
The neurocognitive mechanisms of perceptual inference in autism
Jassim, Nazia; Jassim, Nazia [0000-0001-9761-7784]
Perception is the process by which our brains interpret sensory information. Our brains are constantly evaluating sensory signals in our environments, which shapes how we experience the world and, ultimately, our physical and mental well-being. When this develops differently, it may lead to atypical sensory perception as seen in autism. The addition of sensory symptoms to the most recent diagnostic criteria for autism highlights the need to understand its underlying mechanisms. This thesis used methods from experimental psychology and brain imaging to investigate the neurocognitive mechanisms of perceptual inference in autistic individuals. Chapter 1 introduces the topic of sensory perception, its neurocomputational framework, and its role in autism. It provides an overview of the theories and models of perception in autism and presents the overarching aims of this research. Chapter 2 reports a study of how autistic adults make perceptual decisions on two visual similarity judgment tasks. Signal detection theory analyses indicated that, in both tasks, when compared to typical people, autistic individuals used different decision criteria during conditions of uncertainty. Chapter 3 addresses the limited neuroimaging research on non-social features of autism. Using activation likelihood estimation, findings were condensed from non-social perception task-based functional MRI studies examining differences between autistic and typical participants. Overall, autistic people, compared to typical controls, showed less activity in the prefrontal cortex during perception tasks. More refined analyses revealed that, when compared to typical controls, autistic people showed greater recruitment of the extrastriate cortex during visual processing. Chapters 4 and 5 report findings from a visuomotor probabilistic reversal learning task used to examine how adults with varying levels of autistic traits evaluate sensory information, build, and update sensory expectations. A positive relationship was found between autistic traits and the learning of probable sequences before the reversal. In addition, there were separate main effects of autistic traits and intolerance to uncertainty on the ability to update expectations following the reversal. These findings suggest that, while people with different levels of autistic traits identify statistical regularities at a comparable level to one another, autistic traits play a role in how individuals update their expectations once a change is introduced. Chapter 5 examined how these behavioural findings relate to inhibitory neurotransmitters. In this 7-Tesla MR spectroscopic investigation, γ-Aminobutyric acid (GABA) was measured in the occipital and motor cortices to investigate its role in visuomotor sequential learning and its interactions with autistic traits. Previous findings of a negative relationship between sensorimotor GABA and sequence learning were replicated. At the same time, there were no clear links between autistic traits and occipital and motor GABA. Finally, Chapter 6 ties these findings together and evaluates how they contribute to our understanding of autistic perception. Some of the challenges of cognitive neuroscience research in autism are highlighted alongside clear directions for future work.
Open Access
Investigating psychosis in Prader-Willi syndrome: developing cognitive, electrophysiological and neuroimaging approaches
Aman, Lucie; Aman, Lucie [0000-0002-5252-8873]
Prader-Willi syndrome (PWS) is a neurodevelopmental disorder resulting from the absent expression of maternally imprinted, paternally expressed genes located in the chromosomal region 15q11-13. This absence of expression is usually either due to a paternal deletion or maternal uniparental disomy (mUPD). Both genetic subtypes share the same core clinical symptoms, such as developmental delays, intellectual disability, hyperphagia, behavioural and social difficulties, and a heightened risk for anxiety and depression. However, only people with PWS due to mUPD seem to be at particularly high risk for developing psychosis. Research on the causes of this differential risk is very scarce. This PhD study aims to propose potential mechanisms of psychosis in PWS and design and develop a study to test them. I hypothesised that the GABA/glutamate equilibrium is disrupted in PWS due to the absence of paternal expression. In addition, the overexpression of maternal genes on chromosome 15 would cause cholinergic dysfunction in people with mUPD and further disrupt GABAergic, glutamatergic, dopaminergic and cholinergic functions, increasing the probability of psychotic symptoms. In line with the predictive processing model of psychosis, the neurotransmitter disruptions proposed would cause a reduction in the use of priors to formulate predictions, detect and generate prediction errors, and update the prediction system. A case-control study comprising clinical, cognitive, neuroimaging, and remote behavioural testing was designed to investigate the hypotheses. The study was organised into four modules. The EEG module comprised the Global-Local paradigm, a sensory gating paradigm, and resting state. The MRS module measured metabolites in the anterior cingulate cortex, the auditory and visual cortex. The cognitive module contained measures of IQ, processing speed and working memory. The behavioural module was added during the COVID-19 pandemic to enable online data collection and focused on measuring the use of priors in perception. All modules were assessed for use in a PWS population and were feasible, with adjustments. Nineteen participants took part in at least part of the study, demonstrating its feasibility in a PWS population. Because of time constraints, COVID-19, and resources available, not all participants completed all measures. For the same reasons, only the EEG Global-Local data was analysed. The EEG paradigms were collected on 19 participants (11 with deletion, 4 with mUPD), and the global-local paradigm was analysed. Preliminary analysis revealed that people with mUPD have smaller P300 in response to an oddball paradigm than deletion and control participants. Participants with deletion have smaller P300 responses than controls showing impaired attention switching and a flaw in the predicting coding system of people with PWS, particularly in those with mUPD. Contrary to what was expected, the mismatch negativity response to the oddball paradigm was not different between mUPD and controls but was significantly earlier in the deletion group. This could indicate a chronic fight or flight state having the potential to disrupt neurotransmission, interoception and perception further, causing additional disruption of the predictive processing system. A planned analysis of the remaining measures is presented in this thesis and will be applied in the future when sufficient data is analysed.
Open Access
Transcriptomic and proteomic dysregulation in neuropsychiatric disorders
Erady, Chaitanya
The human genome is involved in the development of neuropsychiatric disorders such as schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD), but the causal genomic molecular players remain unclear. Therefore, in this thesis, we evaluated disorder-associated disruptions within different genomic elements – genes, transcripts, novel open reading frames (nORFs: unannotated ORFs in the genome with recent evidence of coding potential), and their proteins – and considered how these elements contributed to disorder development. We used a combination of transcriptomic and proteomic methods, leveraging large RNA-Seq and microarray datasets to circumvent issues with power for the proposed analyses. A literature summary on previously identified transcriptomic and proteomic dysregulations in neuropsychiatric disorders, and motivations for the work presented in the thesis are introduced in Chapter 1. In Chapter 2, we evaluated sex-stratified cell count corrected case-control differences in gene expression and (where possible) transcript expression and transcript usage for five MDD RNA-Seq and microarray datasets derived from peripheral blood mononuclear cells (PBMCs) or whole blood. To improve detection of gene expression signals we used two meta-analytic approaches: a weighted Z-score and a Bayesian framework-based method, to compare 2,375 MDD cases and 3,606 CNT samples (largest meta-analysis to-date). Sex-specific dysregulations in gene and transcript expressions were identified. Pathway enrichment analysis showed that MDD was associated with dysregulations in innate and adaptive immunity, translation, complement cascade and chromatin organisation. Furthermore, theoretically motivated gene lists associated with MDD (e.g., cell cycle genes) were evaluated within each sex, and sex-specific dysregulations in replication-dependent histones, ribosomes, OXPHOS - electron transport chain, and nuclear mitochondrial genes were identified. In Chapter 3, we tested the hypothesis of MDD gene expression heterogeneity by identifying sex-stratified co-expressed clusters of genes present in five different MDD case-control studies and evaluating gene expression profiles in theoretically-motivated MDD subgroups. Weighted gene co-expression network analysis (WGCNA) of these datasets implicated gene modules related to response to wounding, nitrogen catabolism, and protein localisation as different between female MDD and CNT samples. MDD subgroups were identified using a data-driven approach, however, these gene expression-based subgroups did not show significant correlation with MDD associated phenotypic traits. We also evaluated previous evidence of an inflamed subgroup of MDD identified using cell count data and identified enrichments in immune-related pathways in both males and females. Furthermore, using C-reactive protein as a marker of inflammation status, we identified B cell signalling dysregulation in male cases of MDD compared to healthy controls. Therefore, MDD subgroups identified using phenotypic traits have distinct transcriptomic profiles, which should motivate future studies to perform subgroup-based MDD analyses. In Chapter 4, we explored the role of nORF and their protein products in neuropsychiatric disorders. nORFs - present within both protein-coding and noncoding regions of the human genome, represent an unexplored pool of genomic products within previously investigated genomic regions and could prove beneficial in understanding neuropsychiatric disorders. As the functional relevance of nORFs in the human genome is poorly understood, we conducted a systematic analysis to curate nORFs from three online sources, processed them extensively, and evaluated their genomic functions which revealed involvement of nORFs in nucleoside binding, protein-binding, and kinase-related processes. Furthermore, in comparing the genomic sequences of nORFs to canonical ORFs present within genes defined as protein-coding, we identified nORFs as shorter and more exon-rich sequences. Such evidence of noncanonical translations highlight the need to re-evaluate and update long standing binary categorisations of the genome into protein-coding and noncoding. In Chapter 5, a proteogenomic pipeline which combines proteomic and genomic datasets for nORF identification - proteomic data matches against genomic data to identify novel, unannotated peptide sequences such as nORFs, was described. However, proteomic datasets are not always available and some of the largest consortiums like GTEx (The Genotype-Tissue Expression project) and TCGA (The Cancer Genome Atlas) provide only RNA-Seq data. To mitigate this limitation, we developed a transcriptomic pipeline to identify nORFs within transcripts assembled from RNA-Seq data. The proteogenomic and transcriptomic pipelines were validated using datasets isolated from post-mortem human brains and mouse B and T cells and 3,054 transcribed nORFs and 1,658 translated nORFs were identified, respectively. In Chapter 6, the transcriptomic and proteogenomic pipelines we developed were used to identify nORFs in SCZ and BD samples. Commonly available RNA-Seq datasets are prepared using an rRNA depletion or poly(A) selection to remove highly abundant rRNAs which confound detection of transcripts with low abundances, or to select for mRNAs that contain poly(A) tails. As nORFs can be present within non-poly(A)-tailed transcripts, we required RNA-Seq datasets without poly(A) selection which were available for SCZ and BD but not MDD cases. We identified 3,103 transcribed nORFs of which 44 and 61 were differentially expressed in SCZ and BD, respectively. 21 translated nORFs were also identified. nORFs differentially expressed in SCZ and BD were found to be enriched for DHS1 (DNase1 hypersensitive sites) and histone modifications suggesting involvement in gene regulation. Two of the translated nORFs expressed in SCZ and BD but not CNT samples were present near interesting candidate genes: DISC1FP1 and STXBP1. Overlaps between transcribed nORFs, and SCZ- and BD-specific risk genes revealed nORFs to be enriched within SCZ- specific loci on chromosome 2. Functional predictions for the transcribed and translated nORFs revealed potential DNA-binding, enzymatic and cytoskeletal involvement. nORF expression was also found to be different between males and females, and subgroups of schizophrenic cases with and without psychosis. Therefore, nORFs are valuable genomic components that warrant further investigation in neuropsychiatric and other disorder contexts. In Chapter 7, the major findings from this thesis on the transcriptomic and proteomic dysregulations underlying neuropsychiatric disorders and how they add to our understanding of the human genome is discussed. Therefore, this thesis puts into broader clinical perspective what we know about the genetic architecture of neuropsychiatric disorders, including the novel genetic elements described in this thesis, and how this understanding could aid in the development of appropriate diagnostic and therapeutic strategies for these debilitating conditions in the future.
Embargo
Revisiting Gender: A Quantitative Study of Self-Injury in Young Adults
Lutz, Nina; Lutz, Nina [0000-0003-4096-0236]
Non-suicidal self-injury is a prevalent and pressing public health concern, especially among young people. In recent decades, psychiatric research has greatly developed our understanding of the aetiology of self-injury and effective avenues for clinical intervention. However, the field has scarcely acknowledged the gender bias which pervades the self-injury literature – research has focused primarily on teenage girls and young women, at the exclusion of men and gender non-conforming people. In this dissertation, I revisit the topic of gender in self-injury research and use cross-sectional statistical analyses to address unanswered questions about gender similarities and differences in the prevalence, clinical severity, and functions of self-injury. I begin by introducing the study of self-injury and current understandings of how psychological distress, emotion dysregulation, and impulsivity contribute to the behaviour. Next, I discuss the gendered origins of our modern knowledge and present some of the gender- based assumptions that pervade the literature. This lays the foundation for subsequent chapters to investigate the aetiology of gender disparities in self-injury prevalence and characterise gender similarities and differences in self-injury presentation. I then present four quantitative studies across two community samples of young adults. The first study uses mediation and moderation analyses to test how self-reported psychological distress, emotion dysregulation, and impulsivity contribute to higher rates of self-injury among women than men. In the second study, these analyses are replicated in a second sample and extended to include gender non-conforming young adults, who report especially high rates of self-injury. The third study investigates whether gender differences in prevalence mirror differences in clinical severity by comparing groups on the reported addictive features of their self-injury, strength and intensity of urges, latency, and age of onset. The fourth study compares gender groups on their endorsement of 24 intrapersonal and social self-injury functions, and tests hypothesized group similarities and differences based on findings from previous chapters. Across the four studies, results are consistent with a priori hypotheses and suggest gender disparities in levels of psychological distress and emotion dysregulation contribute to group differences. Gender non-conforming participants consistently emerge as the highest risk group, highlighting the need for self-injury research to address its neglect of this population. Overall, this dissertation provides novel insights into the aetiology of gender differences in self-injury and reveals key directions for future gender-informed research.
Embargo
Cellular immune mechanisms of psychiatric disorders and the stress response
Lynall, Mary-Ellen; Lynall, Mary-Ellen [0000-0002-1939-7525]
Multiple psychiatric disorders have been associated with abnormalities in the immune system. As I summarise in my opening chapter (Chapter 1), evidence from human and animal studies suggests that the immune system may be implicated in the pathogenesis of these disorders, at least in a subset of patients. However, the direct evidence for a causal role of immune mechanisms is limited. Moreover, there are currently no good biomarkers that allow us to identify which patients with psychiatric disorders have immune dysfunction, and thus might benefit from alternative treatment approaches. I outline the limits of what is known about the causality of immune dysfunction in psychiatric disorders from the existing literature, much of which focuses on soluble biomarkers in peripheral blood in observational case-control studies. This stimulates consideration of more mechanistically refined biomarkers, with a focus on which immune cell subsets, and what cellular mechanisms, might play a causal role in psychiatric symptoms. In this thesis, I use human genetic data, human immunophenotyping and animal models to investigate whether psychiatric disorders and stress are associated with dysfunction in particular immune cell subsets, and the evidence for a causal, pathogenic role of different immune cells. In Chapter 2 I describe an analysis of a flow cytometry study of peripheral immune cell subsets in people with depression and age- and sex-matched controls. I used univariate and multivariate analyses to investigate the immunophenotypes associated with depression and depression severity. I found that depressed cases, compared to controls, had significantly increased immune cell counts, especially neutrophils, CD4+ T cells and monocytes, and increased inflammatory proteins. Depressed cases were partitioned into two subgroups by forced binary clustering of cell counts: the inflamed depression subgroup had increased myeloid and lymphoid cell counts, increased CRP and IL-6, and was more depressed than the uninflamed majority of cases. Relaxing the presumption of a binary classification, data-driven analysis identified four subgroups of depressed cases: two of which were associated with increased inflammatory proteins and more severe depression, but differed in terms of myeloid and lymphoid cell counts, raising the possibility that there may be more than one type of ‘inflamed depression’. Stress is one putative cause of immune dysfunction contributing to the pathogenesis of multiple psychiatric disorders, and recent work has highlighted the potential role of the meningeal compartment of the immune system in behaviour. As described in Chapter 3, I used an animal model to investigate the effects of stress on the peripheral and meningeal immune compartments (the latter being poorly accessible in humans). Using flow cytometry and transcriptomic (including single cell) analyses, I demonstrated dysregulation of both myeloid and lymphoid immune cells in the periphery and meninges, and showed that B cells may influence behaviour by regulating meningeal myeloid cell activation. In Chapter 4, I investigated the implications of genome wide association studies (GWAS) of psychiatric disorders for cellular immunity. I tested for enrichment of GWAS variants associated with multiple psychiatric disorders (cross-disorder or trans-diagnostic risk), and 5 specific disorders (cis-diagnostic risk), in regulatory elements in immune cells. For this analysis, I used three independent epigenetic datasets representing multiple organ systems and immune cell subsets. Trans-diagnostic and cis-diagnostic risk variants (for schizophrenia and depression) were enriched at epigenetically active sites in brain tissues and in lymphoid cells (T, B and NK cells), especially stimulated CD4+ T cells. There was no evidence for enrichment of either trans-risk or cis-risk variants for schizophrenia or depression in myeloid cells. This suggests a model where stimuli, e.g., stress or infection, activate T cells to unmask the effects of psychiatric risk variants, contributing to the pathogenesis of mental health disorders. In summary, the results from the human studies highlight the involvement of both the innate and adaptive immune system in psychiatric disorders. They further suggest that there are likely both shared and distinct contributions of cellular immunity to the pathogenesis of different psychiatric disorders. The results from the mouse model support the role of psychological stress in contributing to immune abnormalities in psychiatric disorders and suggest that the effects of stress may in part be mediated by stress-induced alterations in the meningeal immune system. These results are summarised in a concluding chapter (Chapter 5) which highlights outstanding questions, and priorities for future research, in the current understanding of the role of the immune system in mental health disorders.
Open Access
The Association Between Cannabis Use and Reward Processing, and the Role of Adolescent Vulnerability
Skumlien, Martine
Cannabis is the third most commonly used controlled substance worldwide, after alcohol and nicotine. With its changing legal profile, a deeper understanding of how cannabis affects the brain and cognition is in urgent need. Cannabis use has historically been linked with the ‘amotivational syndrome’, implying that reward or motivational processes are dysfunctional in cannabis users. Maladapted reward processing, such as anhedonia and apathy, is a cross-diagnostic symptom in psychiatric disorders, including substance use disorders. Finally, adolescents may be particularly vulnerable to adverse effects of cannabis, due to the important socio-emotional, cognitive, and neuromaturation that takes place during this time. The aims of this thesis were twofold. First, to investigate whether acute and chronic cannabis exposure was associated with disrupted reward processing across psychological, behavioural, and neuroimaging outcomes. Second, to assess whether adolescents showed stronger reward processing disruption after acute or chronic cannabis exposure compared with adults. Firstly, a systematic review of the human literature examining the association between cannabis exposure and reward processing was conducted. Results were mixed, with the strongest evidence for a positive relationship between anhedonia and cannabis use in adolescents. A number of caveats prevented the distillation of clear conclusions, including highly variable operationalisation of cannabis use, lack of or only partial control of important confounders, and small, chiefly adult samples, with consequently low power. The subsequent empirical work expanded on previous research by directly comparing large samples of adult and adolescent cannabis users (1-7 days/week) and gender- and age-matched controls on several measures of reward processing, with rigorous assessment of cannabis use and control of important confounders. The primary source of data for this thesis was the CannTeen study, which is a large study of the effects of cannabis in adults and adolescents. The CannTeen study has an acute arm and a non-acute longitudinal arm, and includes both behavioural measures and neuroimaging. First, data from the CannTeen acute study was used to examine whether cannabis exposure was associated with altered neural responses to reward anticipation on the Monetary Incentive Delay task in adults and adolescents. Acute active cannabis attenuated neural reward anticipation responses in key reward regions, including the ventral striatum and insula, relative to placebo. No previous study has shown this effect in healthy participants or adolescents. Subsequently, adult and adolescent cannabis users and controls from the CannTeen non-acute study were compared on neural reward anticipation and feedback, using the same task. There were no significant differences between cannabis users and controls during reward anticipation or in pre-defined regions during feedback. However, cannabis users showed unhypothesised greater feedback activity in the frontopolar and inferior parietal cortex in an exploratory whole-brain analysis. Neither study found differential effects of cannabis exposure in adolescents and adults. Adult and adolescent cannabis users and controls from the CannTeen non-acute study were then compared on two novel, non-neuroimaging reward processing tasks. The Physical Effort task assessed effort-based decision-making for reward and the Real Reward Pleasure task assessed subjective reward wanting and liking. There were no significant differences between cannabis users and controls on any outcomes, and no interactions between user-group and age-group. Finally, two samples of adult and adolescent cannabis users and controls from the CannTeen non-acute study and a separate online survey study, respectively, were compared on anhedonia and apathy. There was tentative evidence of elevated anhedonia in adolescent cannabis users, but not adult users, and no overall differences between users and controls in levels of apathy. This work suggests that cannabis affects the brain’s reward system acutely, but is not associated with lasting disruptions to reward or motivation non-acutely. Adolescents may show greater vulnerability to cannabis-related anhedonia, but not other reward processing outcomes. Thus, reward processes appear to be largely spared in adolescents and adults with moderate cannabis use, and the cannabis-related ‘amotivational syndrome’ is not supported by scientific evidence.
Open Access
Public health approaches for identifying and responding to mental health difficulties amongst children and adolescents
Soneson, Emma; Soneson, Emma [0000-0003-1666-3012]
Summary Public health approaches for identifying and responding to mental health difficulties amongst children and adolescents Emma Soneson Mental health difficulties amongst children and adolescents are a significant societal concern requiring urgent attention and action, and public health approaches may be useful in reducing their incidence, prevalence, and impact. Schools are increasingly featured within UK policy as a key setting for addressing mental health difficulties, yet school staff often do not feel adequately prepared for this role. In this dissertation, I aimed to explore what role schools can play within the public health approach to child and adolescent mental health difficulties; determine whether schools can improve the identification of and response to mental health difficulties; and identify the ‘key ingredients’ of an effective, feasible, and acceptable school-based approach to student mental health. The introductory chapter provides an overview of the scope, aetiology, and impact of mental health difficulties amongst children and adolescents; describes the public health framework that supports the research in this dissertation; and highlights the role of schools within the public health approach to child and adolescent mental health difficulties. The first two empirical chapters present two studies that examined self-report data from the OxWell Student Survey to better understand English school students’ access to and perceptions of school-based and other mental health support. The first of these studies determined whether experience of adversity is related to access to and perceived need for mental health support amongst secondary school students. The second study explored whether various aspects of students’ school experience and their impressions of their wider school culture influence their perceptions of school-based mental health support. The next two chapters describe two studies aimed at improving UK primary schools’ response to pupil mental health difficulties. The first of these chapters describes a consensus study that contributed to the development of a new school-based identification programme. The second presents a feasibility study of an existing low-intensity teacher training programme that aimed to improve identification of and response to pupil mental health difficulties. In the first empirical chapter, I demonstrated that experience of adversity is significantly associated with both prior access to and perceived need for mental health support. This chapter illustrated how many children and adolescents who may benefit from mental health support, and particularly those with experience of adversity, are not accessing it. In the next chapter, I showed how schools may be able to address this care gap through school-based mental health provision, but that students’ perceptions of such support vary according to their school experience and impressions of their wider school culture. This suggested that the provision of mental health support is only one aspect of a broader school-based approach to mental health. In the next chapter, I described the development of the new identification programme guided by stakeholder consensus. The prototype programme features a ‘combined’ approach of staff training, mental health education for pupils, and (potentially) universal screening, and merits further development and evaluation. In the final empirical chapter, I demonstrated how an existing teacher training programme may be a potentially effective, feasible, and acceptable intervention for promoting more accurate identification and facilitating access to support for pupils with mental health difficulties. Taken together and as discussed in my final chapter, these findings provide valuable insight into the role of schools within the public health approach to child and adolescent mental health difficulties. First, the included studies illustrated several ways that schools can be involved in prevention and early intervention. Second, the studies demonstrated that schools do have significant potential to improve both identification of and response to mental health difficulties. Finally, the findings of this dissertation suggested five ‘key ingredients’ for school-based approaches to mental health, including (1) contextualisation of all mental health interventions within a wider school culture that values mental health; (2) identification and management of barriers to intervention implementation and sustainability; (3) support from wider systems; (4) attention to the needs of vulnerable children and adolescents; and (5) partnership working with key stakeholders. It is paramount that schools are supported and empowered to take an increased role in child and adolescent mental health.
Embargo
The role of cerebral small vessel disease in dementia
Low, Audrey; Low, Audrey [0000-0002-2520-454X]
Introduction: Cerebral small vessel disease (SVD) is increasingly recognised as a key factor in dementia and cognitive impairment, although its role in the pathogenesis of Alzheimer’s disease (AD) remains poorly understood. Through the investigation of how SVD relates and interacts with (1) molecular AD pathologies and (2) early midlife risk factors of dementia, this body of work aims to advance our understanding of SVD in relation to AD. Methods: In two separate cohorts, SVD was quantified on 3T MRI through the assessment of white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), cerebral microbleeds (CMB), and lacunes. Regional data on SVD location was used to derive composite scores for global SVD burden, and the SVD subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy. The first objective was investigated in the Neuroimaging of Inflammation in Memory and Other Disorders (NIMROD) study, which consisted of multimodal PET imaging of older adults with varying degrees of clinical severity. Here, we investigated whether SVD was associated and interacted with the hallmark AD pathologies of amyloid, tau, and neuroinflammation (microglial activation) – these were quantified with PET imaging of [11C]PiB, [18F]AV-1451, and [11C]PK11195, respectively. For insights into the pre-clinical stages of AD pathogenesis, we examined cognitively healthy midlife adults from the PREVENT-Dementia study. We investigated whether well-established risk factors of late-life dementia were related to SVD burden much earlier on, at midlife. Results: SVD was associated with PET markers of neuroinflammation and tau, and plasma Aβ. Notably, associations with amyloid and tau markers were largely limited to WMH. In healthy middle-aged adults, inherited predisposition to dementia (APOE4, parental family history of dementia) was related to longitudinal SVD progression, but not baseline SVD severity. On the other hand, modifiable risk factors of late-life dementia were associated with midlife SVD burden. The two SVD subtypes were differentially related to AD pathologies and risk factors – neuroinflammation and modifiable risk factors were more closely associated with hypertensive arteriopathy, while amyloid and tau related more closely to cerebral amyloid angiopathy. Conclusions: Together, our findings implicate SVD in the early pathogenesis of AD and suggest that lifestyle modifications as early as midlife may reduce the vascular-driven component of AD. Findings highlight the need to further inspect the biological underpinnings of WMH and fluid markers of AD pathology.
Embargo
Development of a Smartphone Intervention for Cognitive Bias Modification in Alcohol Abuse and Alcohol Dependence
Peerenboom, Nele
Abstract Objective: Heavy alcohol use and alcohol dependence are major public health issues, and in-person treatment has been impaired by the restrictions necessary during the Covid-19 pandemic. This thesis follows the development of a smartphone-based cognitive bias modification training, which heavy drinkers and patients treated for alcohol dependence can access for at-home use. Method: Several versions of a smartphone-based alcohol approach avoidance training (AAT) were developed and tested through three pilot experiments (n = 26, n = 25, n = 13). The newly developed AAT web-app was then validated in two short online studies on heavy drinkers with one-day (n = 62) and one-week follow-ups (n = 107). Finally, the web-app was used for a three-months randomized control clinical trial in patients leaving clinic treatment for alcohol dependence (n = 598). Results: Heavy drinkers showed a reduction in craving scores and problem alcohol use at follow-up after only 20 – 30 minutes of training on the AAT web-app. Alcohol dependent patients exhibited high adherence to the web-app, accessing it for over 50 training sessions on average. Feedback for the web-app was positive, and suggestions for improvement were collected and addressed through updates of the web-app. While an intention to treat analysis showed no significant differences between training and control groups, secondary subgroup analyses of participants who accessed the app for regular training point to efficacy of the active training when used for at least five to fifteen sessions. Participants who used the active version of the AAT web-app for at least five sessions showed reduced craving. An analysis of preliminary data points to lower relapse rates at one-year follow-up in patients who used the active training web-app for at least fifteen sessions. Conclusions: The web-app was developed and piloted from a basic prototype to a three-months intervention with gamification elements. Effects on craving and problem alcohol use were assessed through several studies with concurrent measures. A preliminary analysis with relapse data points to an effect of active training on abstinence in alcohol-dependent participants who accessed the app for at least 15 training sessions. The web-app was well liked, and participants showed high adherence. This new web-app is now in use as part of standard care in an in-patient treatment centre for alcohol dependence in Germany.
Open Access
Functional neuroimaging studies of peripheral inflammation-related depression
Aruldass, Athina; Aruldass, Athina [0000-0002-6553-659X]
Depression is recognized as a leading cause of disability worldwide although it lacks one of the typical characteristics of a disorder, disease or disability in the traditional sense, i.e., biological markers. Depression is difficult to characterize in that it is highly heterogeneous epidemiologically and symptomatically. Depression is often a comorbidity, associated with other physical or mental health disorders, and depressive symptoms occur on a spectrum of severity ranging from mild dysphoria to major depressive disorder (MDD). Comorbid depression is associated with an array of neurological disorders with neuroimmunological or neuroinflammatory mechanisms, as well as peripheral systemic inflammatory disorders such as rheumatoid arthritis, psoriasis, and cancers. Recent research on the immune mechanisms of depression has reproducibly demonstrated a robust association between biological markers of peripheral inflammation, e.g., blood levels of C-reactive protein, and depressive symptoms. However, there have been fewer brain imaging studies of inflammation-related depression, which are important for bridging the explanatory gap between peripheral immune states, like inflammation, and mental states, like depression, in humans. Chapter 1 introduces a dichotomy in thinking about depression, discussing briefly historical concepts that on one hand supported a monolithic view of the disorder, and on the other hand, alluded to greater complexity based on how the body might interact with the brain and mind. On this basis, I highlight areas of contemporary immunopsychiatric research that both support and challenge the hypothesis central to this thesis, that is, peripheral (bodily) inflammation may elicit depressive symptoms via brain functional abnormalities. In Chapter 2 I present a more focused discussion in the form of a literature review of current brain functional neuroimaging studies on inflammation-linked depression. I noted through this endeavor that the body of knowledge addressing fMRI abnormalities in inflammation-linked depression is presently limited, and it is further complicated by considerable variability in study setting, methodology, sample and analytic approaches. Peripheral inflammation has often been measured simply by blood concentration of C-reactive protein (CRP) and brain phenotypes have often been measured in a few, selected regions of interest (ROIs) rather than across the whole brain. Nonetheless, the extant literature very broadly converged to suggest the concept that dysregulation of the peripheral immune system could indeed be associated with brain functional abnormalities in depression. In Chapter 3, I describe the design and assessments used in an observational case-control study (BioDep) of three groups of participants, i.e., healthy controls (HC), low-CRP depression cases (CRP ≤ 3 mg/L), and high-CRP depression cases (CRP > 3 mg/L). All participants completed assessments of peripheral blood immune markers, behavioral questionnaires, resting-state fMRI, and a probabilistic reinforcement-learning task-based fMRI paradigm. On this basis, I tested the following key hypotheses which were the focus of subsequent chapters: (i) increased concentrations of innate and adaptive immune markers is characteristic of inflammation-linked depression, (ii) inflammation-linked depression is associated with diffuse functional connectivity abnormalities, (iii) increased peripheral inflammation attenuates functional connectivity in depression, and (iv) peripheral inflammation reorients response to affective experience in depression. In Chapter 4, I first investigated sociodemographic, clinical, behavioral and immune variability in the analyzable cohort (N = 129; Ndepression = 83). BMI and sex differed significantly between the low CRP (N = 50) and high CRP depression cases (N = 33), with both BMI and proportion of females being greater in the high CRP depression cases. Sex and BMI were therefore noted as potentially confounding variables that would require careful consideration in subsequent analyses. With regards to immune markers, I first performed a simple pair-wise correlational analysis on CRP and 16 other inflammatory proteins, i.e., cytokines and chemokines. Weighted network visualization, coupled with a literature search-based functional assignment of each biomarker, indicated that functionally-related inflammatory proteins were more strongly positively correlated with each other. Thus, concentrations of these clusters of immune markers were similarly increased or decreased in the blood. Next, I reduced the dimensionality of this multivariate biomarker dataset using principal component analysis (PCA) on 15 inflammatory proteins (excluding IL-6). This resulted in 5 selected principal components. I interpreted the first principal component (PC1) to be a weighted average of all inflammatory proteins or a global index of immune state. PC1 score was also positively correlated with neutrophil count. Chapter 5 marks the start of my investigation of the links between peripheral inflammation and the brain, using whole-brain functional connectivity (FC) measures derived from resting-state functional magnetic resonance imaging (fMRI) data. I conducted a two-fold exploratory analysis: (i) multi-granular decomposition of the functional connectome at coarse- and fine- grained anatomical resolutions, and (ii) a data-driven subnetwork-level decomposition of the functional connectome using network-based statistics (NBS). This non-parametric method of significance testing for high CRP depression case-control differences yielded a set of interconnected brain regions - in other words, a network - that showed progressively increased abnormalities, denoted by weaker and more negative functional connections, in high CRP depression cases, followed by low CRP cases, compared to controls. The attenuated functional connections were mainly anatomically located between the left insula/frontal operculum and posterior cingulate cortices. Meta-analytic search of an independent fMRI database suggested that this network was functionally specialised for interoception, i.e., brain sensing of internal bodily states for emotion modulation. In Chapter 6, the putative interoceptive network discovered by the case-control analysis of high CRP depression cases versus controls in Chapter 5 was used as a 'mask' to test the continuous association between brain functional connectivity and peripheral inflammation in all depression cases (including low CRP cases but excluding controls). There was robust negative scaling between average network connectivity (or 'within-network' connectivity) and CRP (N = 83), IL-6 (N = 72), and PC1 scores (N = 72) from the principal component analysis of 15 cytokines and chemokines in Chapter 4. Corroborating this association between functional connectivity and inflammatory proteins, neutrophil count (N = 36) also showed significant negative scaling with average network connectivity. These results are interpreted as evidence suggesting that inflammation-linked depression could be underpinned by abnormalities of interoceptive processing of afferent peripheral immune signals, and/or signaling in other motivational or reward-related circuits, which could be clinically manifest as dysregulation or misrepresentation of emotional states, i.e., feelings of depression. In Chapter 7, I investigated abnormalities of affective traits, e.g., anhedonia and pessimism, using task-based fMRI in inflammation-linked depression. Through a probabilistic reinforcement learning paradigm, I tested for evidence of hyposensitivity to reward, and hypersensitivity to punishment, with increasing inflammation. Voxel-wise activation was observed in key brain regions sensitive to monetary reward (ventromedial prefrontal cortex, vmPFC; nucleus accumbens, NAc) and punishment (insula) outcomes in all three groups (HC, low CRP depression and high CRP depression). However, there was no significant difference in activation between any two groups. Within depression cases, increasing CRP scaled negatively with activation in the right vmPFC and left NAc. However, there was no significant association between regional activation and severity of anhedonic or negative attitudes measured by Beck’s Depression Inventory (version II). Finally, in Chapter 8, I conclude by reviewing the initially proposed central hypothesis, noting that whilst the novel evidence generated by these studies provide some support for the hypothesis that peripheral inflammation is associated with functional abnormalities in depression-related brain networks, these data also prompt further refinement and evolution of this model. In particular, these results indicate that the brain circuits most sensitive to inflammatory states in depression may be functionally specialised for interoceptive sensing and processing of peripheral immune signals. These results have also shown that immune dysregulation in inflammation-linked depression is at the level of the 'immune interactome' - as opposed to a single immune marker in the periphery - warranting particular look into chemokines and immune cells, beyond CRP and IL-6. In view of these findings, I finally highlight the need for future work focused on interoceptive representation of peripheral immune signals within the brain, and CNS vascular physiology, that can together better delineate mechanisms of interaction between the brain and the body as demonstrated here in inflammation-related depression.
Open Access
Sex differences in human perinatal development and autism
Tsompanidis, Alexandros; Tsompanidis, Alex [0000-0002-7338-6536]
Autism is a neurodevelopmental condition that is more frequently diagnosed in males than females. To explain this, in 2014, the prenatal sex steroid theory was proposed. This extended the fetal testosterone theory, published in 2004. The prenatal sex steroid theory proposes that exposure to higher levels of prenatal sex steroids (e.g., prenatal androgens and estrogens) that are on average higher in male fetuses are associated with higher likelihood for autism and elevated autistic traits. This background literature is reported in Chapter 1. In this thesis, eight novel studies are reported that test and extend the prenatal sex steroid theory by investigating perinatal factors related to sex differences in physiology. Study 1 (described in Chapter 2) reports a case-control analysis of steroid levels in the amniotic fluid of males who were later diagnosed as autistic, linked with the Danish Biobank (n = 98 cases, n = 177 controls). This included univariate analyses of both prenatal androgens and estrogens, as well as the aromatisation ratio. All estrogens, but not testosterone, on average were elevated in autistic males. Study 2 (described in Chapter 3) reports a prospective cohort study (the Cambridge Ultrasound and Pregnancy [CUSP] study) of pregnant women and their infants in Cambridge (n=219), who were assessed for their autistic traits during pregnancy and late infancy. Steroid hormone levels were assessed in maternal serum. Estradiol levels correlated with both maternal autistic traits and the male infants’ autistic traits, but there was no correlation with female infants’ autistic traits. Study 3 (described in Chapter 4) reports a large prospective cohort study in Rotterdam (Generation-R) that studied the levels of placental function markers in maternal serum (n=3469), their sex differences in the general population, their association with both autistic traits in childhood (assessed using the Social Responsiveness Scale - SRS), and with likelihood for autism in males. Male-like patterns in placental angiogenic markers, high placental growth factor (PlGF) and low soluble fms-like tyrosine kinase-1 (sFlt-1) levels, respectively correlated with higher autistic traits in females and an autism diagnosis in males. Chapter 5 describes Studies 4, 5, and 6, all based on a longitudinal cohort, the Cambridge Human Infant Longitudinal Development [CHILD] Study. This included prenatal (n=41) and postnatal (n=27) brain MRI imaging and salivary testosterone measurements during mini-puberty. Study 4 found that both male and female infants experienced transient increases in testosterone postnatally (2 to 6 months), but this did not correlate to their autistic traits at 18 months. Study 5 focused on total brain volume and surface area in infancy, as well as rate of brain growth perinatally, all of which correlated negatively with the infant’s autistic traits. Study 6 found that this was driven by low volume in regions that show sex differences and are involved in face recognition. Chapter 6 describes two genetic studies, which found that autism-related genetic variance (rare and common variance respectively) overlaps with X-linked genes that show sex differences in the placenta (Study 7) and correlates with the genetics for early age of menarche (Study 8). Chapter 7 brings all of the findings from Studies 1 to 8 together to draw conclusions and consider limitations and future directions. Based on these analyses, I then propose a new theory on the role of the placenta in mediating sex differences in human perinatal development and autism.
Open Access
The Physical Health and Healthcare of Autistic Adults
Weir, Elizabeth; Weir, Elizabeth [0000-0001-5434-9193]
Autism spectrum conditions (henceforth autism) are a set of lifelong, neurodevelopmental conditions characterized by social and communication difficulties; markedly restricted, repetitive interests and behavior; and differences in cognitive profile including atypical sensory perception and information processing, motor abilities, and intellectual ability. Existing evidence suggests that autistic individuals may be at higher risk of premature mortality, and that increased likelihood of comorbid physical health conditions may be contributing to this risk; however, most of the existing research focuses heavily on the experiences of young adults. This thesis aims to broadly describe the experience of autistic individuals across the adult lifespan, including the areas of chronic disease comorbidity, lifestyle behaviors, identity, and healthcare. In Chapter 1, I discuss the challenges that autistic individuals (and particularly adults and females) currently face, and how these areas can affect both length and quality of life. Chapter 2 provides an outline of all the methodologies utilized throughout the thesis. Chapters 3-6 utilize data from the Autism and Physical Health Survey to compare the experiences of autistic and non-autistic adults regarding risks of cancers, cardiovascular conditions, respiratory conditions, and diabetic conditions (Chapter 3); diet, exercise, and sleep, as well as their relationships to body mass index (BMI) and chronic disease risk (Chapter 4); sexual health and sexual orientation (Chapter 5); and smoking, alcohol use, and recreational drug use (Chapter 6). Chapter 3 confirms previous findings in samples of primarily younger adults to suggest that autistic individuals across the adult lifespan have greater risks of cardiovascular, respiratory, and diabetic conditions (which persist even after accounting for BMI, smoking, and alcohol use), and that these risks may vary based on biological sex. Chapter 4 provides the results of the first study to broadly describe the diet, exercise, and sleep patterns of autistic adults, and the first to consider their relationships to BMI, cardiovascular and health outcomes. The findings suggest that autistic individuals (and particularly autistic females) are more likely to exhibit unhealthy patterns, including restricted diets, insufficient nutrition, limited exercise, diminished sleep duration, and sleep disturbances; there is also some preliminary evidence that these patterns may relate to risk of cardiovascular conditions. Chapter 5 suggests that autistic individuals are far more likely to identify as asexual or ‘other’ sexual orientations (and less likely to identify as heterosexual); less likely to have ever engaged in sexual activity; and that they are equally likely as non-autistic individuals to contract sexually transmitted infections (STIs). In Chapter 6, I employ a mixed methods approach to illustrate that, despite relatively limited quantitative differences in frequency of substance use, autistic individuals are far more likely to report qualitative differences in motivations for using or abstaining from substances alongside vulnerability associated with substance use. In Chapters 7 and 8, I investigate the risk of cancer overall, as well as for hormone-associated cancers among autistic individuals and non-autistic mothers of autistic individuals (NMAI), respectively. These studies use large samples of General Practitioner (GP) records, provided by the Clinical Practice Research Datalink (CPRD), as well as cancer records from the National Cancer Registry and Analysis Service (NCRAS) from Public Health England (PHE). Chapter 9 utilizes the Autism and Healthcare Experiences Survey to identify differences in the healthcare experiences of autistic and non-autistic individuals in the areas of access and advocacy, sensory processing, communication, stress, system problems, and shutdowns and meltdowns. Finally, in Chapter 10, I summarize and integrate the empirical findings across Chapters 3-9. I discuss their implications for understanding of the experience of autistic adults facing increased risk of chronic health conditions and limited support. I also discuss the strengths and limitations of each of the studies, future directions of research, and implications for healthcare providers working with autistic patients.
Open Access
On the origins of glioma: insights from brain network mapping
Mandal, Ayan
Glioma tumours are among the most lethal brain disorders, claiming the lives of thousands of people in the United Kingdom each year. Despite the severity and prevalence of the condition, remarkably little is understood about the origins of gliomas, or the mechanisms that guide their spread within the brain. The aim of this thesis is to invoke a relatively new approach – brain network mapping – to provide insights into the origins of gliomas and their pathological spread along neural circuits. First, I provide a historical overview of both brain network mapping and glioma neurobiology, along with the recent advances and techniques popular in each field. In particular, I highlight preclinical research implying that gliomas originate from neural stem cells in the subventricular zone, as well as other work in mouse models demonstrating that gliomas infiltrate previously healthy brain networks. This thesis contributes three studies of clinical datasets which evaluate the hypothesis that glioma initiation and progression are guided by brain networks. In the first study, I describe convergent evidence from both intracranial electrocorticography recordings and resting-state functional imaging of four patients with low-grade gliomas that tumour-infiltrated cortex can participate in large-scale cognitive circuits responsive to executive function. These findings imply that gliomas integrate into neural circuits, suggesting that their development and maintenance could be sustained by functional brain networks. In support of this idea, I next demonstrate that the spatial distribution of gliomas in the brain follows the distribution of functional network hubs, as well as cellular and genomic factors related to gliomagenesis. These results suggest two possibilities regarding the origins of glioma: the predilection of gliomas to hub locations could be a result of the vulnerability of hubs to oncogenesis, or the result of tumours arriving at central network locations while spreading through brain networks. To help disambiguate between these possibilities, I developed a novel approach termed “lesion covariance network mapping” to identify networks of brain regions co-lesioned in glioma, which indicate areas along which tumours are inferred to spread. This method revealed that gliomas cluster around horns of the lateral ventricles, consistent with the hypothesis that these tumours originate from neurogenic niches within subventricular zone. The lesion covariance network method also demonstrated that glioma localisation patterns follow specific structural and functional connectivity networks disseminating from periventricular grey matter. Cumulatively, the findings of the thesis support a model wherein periventricular brain connectivity guides glioma development from the subventricular zone into distributed regions of the cortex. In the conclusion, I discuss potential clinical applications of the presented research, such as in supporting predictive modelling approaches to forecast glioma progression, for the purpose of planning pre-emptive radiation and surgical treatments of glioma.
Open Access
The Deconstruction of Reinforcement Learning in Human Substance Use Disorder
Lim, Tsen Vei; Lim, Tsen Vei [0000-0002-6565-4326]
Individuals diagnosed with substance use disorder (SUD) often behave in ways detrimental to their own interest and well-being. The mechanisms behind such maladaptive behaviour in human SUD remain unclear, but can be explained by disruptions to reinforcement learning processes that under normal circumstances shape behaviour adaptively. This perspective has led to two different, but not mutually exclusive, hypotheses: (1) reinforcement learning is impaired in drug-addicted individuals, as they are unable to learn from the consequences of their actions, and (2) learned behaviour in drug-addicted individuals reflects an imbalance between two regulatory systems: the goal-directed and the habit system. Recently, trial-by-trial computational modelling lends itself as a promising tool to deconstruct latent cognitive processes that underpin learning, which can provide mechanistic insights into these impairments. Thus, with multiple learning paradigms, the objectives of this thesis are two-fold: (1) to characterise the cognitive profile related to impaired reinforcement learning and its supporting processes in SUD with computational modelling; (2) to clarify the relationship between impaired reinforcement learning and habit learning in SUD. The first part of the thesis describes the computational analyses of task performance in probabilistic reinforcement learning. These analyses identified in two independent cohorts of stimulant-addicted individuals a selectively reduced learning rate from punishment, suggesting that their behaviour may be less amenable to negative feedback. In one of these cohorts, participants underwent pharmacological manipulations with dopamine D2/3 receptor agents, which found that both dopamine D2/3 receptor antagonist (400mg amisulpride) and agonist (0.5 mg pramipexole) differentially modulated behaviour in stimulant-addicted individuals: while both dopamine agents impaired performance in control participants, they ameliorated learning from negative feedback in stimulant-addicted individuals – confirming the link between aberrant learning and dopamine dysfunction in SUD. Next, I investigated the integrity of declarative and non-declarative memory systems in cocaine use disorder patients with a category learning task, as these systems are thought to complement reinforcement learning. I found that cocaine use disorder patients showed clear deficits in both declarative and non-declarative memory. Analyses of their response strategies revealed that these patients were more likely than control participants to adopt a simple but suboptimal memorisation strategy during learning, as opposed to a more complex integrative strategy, which supports the notion of an aberrant engagement of memory systems during reinforcement learning. Given that SUD is associated with enhanced habit formation, I then tested the hypothesis that reinforcement learning impairments exacerbate subsequent habit formation in cocaine use disorder, by reanalysing prior data on an appetitive instrumental learning task with computational methods. Contrary to the hypothesis, I found that impaired reinforcement learning in cocaine use disorder, in the form of a reduced learning rate, is insufficient to account for enhanced habit formation in these patients, suggesting other modulatory factors at play. I subsequently addressed the question of whether patients with cocaine use disorder have insight into their behavioural tendencies by using self-report questionnaires. These data revealed evidence for a predilection for automatic habits and reduced goal-directed actions in their daily lives. Finally, I expanded my work by measuring instrumental learning in a community sample of individuals recruited online who consume alcohol hazardously (as measured with the Alcohol Use Disorder Identification Test questionnaire) – but not formally diagnosed with alcohol use disorder. I tested this with a novel task paradigm which measures goal-directed and habitual responses in a conflict situation, but did not find any evidence for an impaired goal-directed or augmented habitual control associated with harmful alcohol use. Jointly, the study of reinforcement learning with multiple paradigms refined our understanding of maladaptive behaviours in severe SUD, which may be characterised by the attenuated effects of negative feedback on behaviour, as well as aberrant non-declarative and declarative memory systems. Impaired reinforcement learning, however, cannot fully account for habit predominance associated with SUD. Instead, this predominance might be modulated differentially by different drugs of abuse, drug use severity and individual differences in habitual tendencies.
Open Access
Effects of oxytocin on the social brain in autistic and typical women
Procyshyn, Tanya; Procyshyn, Tanya [0000-0003-1266-6697]
Chapter 1 of this work introduces the neurohormone oxytocin, its roles in social behaviour and cognition, and its associations with autism. Oxytocin is then discussed as one of the few compounds to have shown effects for the core social challenges of autism, and the gaps in knowledge that have hindered therapeutic applications of oxytocin are described. Specifically, uncertainty regarding the neural mechanisms through which oxytocin influences social behaviour and the inconsistent patterns of oxytocin’s effects across studies are noted. Chapter 2 presents a systematic review of the oxytocin administration literature to identify variables shown to influence individual differences in response to oxytocin, including biological sex, oxytocin-related genotype, and broader autism phenotype. Chapters 3 to 6 report the findings of a double-blind, placebo-controlled oxytocin administration experiment involving 42 adult women, 16 of whom have an autism diagnosis. Chapter 3 reports pre- to-post administration changes in participants’ salivary hormone levels and tests relationships between baseline hormone levels and psychological traits. An increase in salivary testosterone after oxytocin administration was observed in autistic women, but not in non-autistic women, and autistic-like traits correlated positively with greater testosterone relative to oestradiol. In Chapter 4, fMRI is used to assess the effects of oxytocin on resting-state connectivity. In the placebo condition, autistic women showed lower resting-state connectivity among social brain areas compared to non-autistic women. At the group level, oxytocin enhanced connectivity among autistic women, but decreased connectivity among non-autistic women, such that average connectivity in autistic women in the oxytocin condition resembled that in non-autistic women in the placebo condition. Chapter 5 reports the effects of oxytocin on activation of the amygdala, a brain region implicated in autism and emotional response, while matching images of negatively-valenced face stimuli (Hariri task). Matching faces (relative to matching shapes) robustly activated bilateral amygdala in both groups. Oxytocin was found to increase amygdala activation to face stimuli in autistic women and to enhance amygdala functional connectivity in the combined sample. Chapter 6 presents the effects of oxytocin on neural reward processing during two variants of an incentive delay task: one involving a social reward (a smiling face) and one involving a non-social reward (money). Autistic women showed lower activation of brain areas associated with reward anticipation relative to non-autistic women. Oxytocin increased activation of the same regions, with variation by group, task phase (anticipation vs outcome), and reward type. The discussion in Chapter 7 ties the findings of the multiple neuroimaging studies together, suggesting that oxytocin influences several neural pathways expected to influence social behaviour and cognition. The general patterns of how individual differences, including autism phenotype and social traits, influenced the effects of oxytocin on brain activation and the implications for therapeutic applications of oxytocin are also discussed. Finally, the limitations of these studies and directions for future research in this area are addressed.
Open Access
The role of Synaptic Genes NRXN1 and SHANK3 in Autism: an induced pluripotent stem cell study
Paul, Arloprovo
Autism is a complex neurodevelopmental condition with hundreds of genes associated with its pathophysiology. A number of autism related genes have been reported to be strongly associated with the structural or functional aspects of neuronal connections or synapses. However, it is poorly understood how the loss of function of these synaptic genes contribute to the neuronal morphology, network physiology and atypical communication between brain cells. This thesis aims to first establish and characterise an induced pluripotent cell (iPSC) derived neuronal model suitable for studying autism related synaptic genes. Secondly, it aims to study the effect of pre-synaptic NRXN1 and post-synaptic SHANK3 deletions on neuronal morphology and synaptic network activity. The first hypothesis of this thesis is that iNeurons derived by NGN2 forward programming approach would express autism related genes, post synaptic density molecules, synaptic receptors and demonstrate mature electrophysiological activity relevant for studying autism related functional phenotypes, within four weeks of neuronal induction. The second hypothesis is that iNeurons with deletions in NRXN1 or SHANK3 derived from individuals with autism would show altered morphological and electrophysiological cellular phenotypes. This study proposes a novel in vitro model for generating more homogenous and functional neurons compared to the existing methods adopted in the field of autism research. It has been exemplified that the effect mutations in synaptic genes such as NRXN1 and SHANK3 on mature cellular phenotypes can be studied using iNeurons. Further research is needed for technological fine-tuning to establish a robust scalable cell-based platform that would potentially be useful to investigate cellular phenotypes caused by anomalies in any autism risk gene and better understand the pathophysiology of neurodevelopmental conditions.
Open Access
A neuroimaging study to characterise adolescent major depressive disorder, the effects of cognitive behavioural therapy, and potential subtypes based on familial loading
Villa, Luca; Villa, Luca [0000-0001-5091-6410]
Adolescent major depressive disorder (MDD) can have devastating consequences that remain into adulthood. Although the severe effects on those that suffer from MDD are well understood, the neural mechanisms underpinning the illness are still unclear, as the past literature exploring adolescent MDD has suffered greatly from a lack of consistency. In particular, it is still unclear as to what deviations of brain structure and function actually occur in adolescent MDD. Furthermore, though much of the past literature has claimed that cognitive behavioural therapy (CBT) has a normalising effect on disrupted brain function in adolescent MDD, this has not been directly tested. Additionally, past literature has found that adult MDD patients with a high familial loading for MDD, defined as having at least one first degree relative with MDD, show different symptom profiles to MDD patients with a low familial loading for the illness. However, it is not yet clear whether these symptom differences also occur in adolescent MDD patients with differing familial loadings, nor is it clear whether these two patient groups also differ with respect to brain structure and function. If so, familial loading for MDD could potentially be used to subtype adolescent MDD patients. This thesis aimed to further elucidate the neural processes that may be unfolding within the depressed adolescent brain by investigating pre-treatment differences in cortical thickness, white matter volume, and resting-state functional connectivity, using the largest studied sample of adolescent MDD patients under the age of 18 years. This thesis further aimed to investigate CBT’s effects on brain function, and whether adolescent MDD patients could be subtyped based on familial loading for MDD. Before receiving treatment, adolescent MDD patients showed structural deviations in the form of greater cortical thickness and white matter volume within frontal and limbic regions of the brain. Furthermore, adolescent MDD patients also showed extensive pre-treatment overconnectivity within multiple functional brain networks, being the fronto-limbic, default mode, central executive, and salience networks. Moreover, when investigating the CBT-related changes to resting-state functional connectivity, in adolescent MDD patients, and how they relate to regions showing pre-treatment functional disruption, it was found that regions showing the greatest pre-treatment functional disruption actually showed the weakest CBT-related changes in resting-state functional connectivity. This suggests that CBT does not have a normalising effect on brain function in adolescent MDD but instead may have a rehabilitative effect on resting-state functional connectivity. Finally, when separating adolescent MDD patients into those with a high or low familial loading for MDD, the two patient groups differed with respect to the structure and function of the default mode network, as well as differing in rumination symptoms. Together, this work demonstrates the need for larger sample sizes to be used when investigating an illness as heterogenous as adolescent MDD, as well as direct investigations into the potential mechanisms of CBT. Moreover, it appears that some of this heterogeneity found in adolescent MDD may be partly addressed by subtyping patients, which may have implications for how the illness is viewed and treated in the future.
Open Access
Risk of depression and cardiovascular disease across the lifespan: the role of systemic inflammation.
Chaplin, Anna; Chaplin, Anna [0000-0002-7655-2093]
Both depression and cardiovascular disease (CVD) affect millions of people worldwide and account for considerable mortality. In adults, comorbidity between these conditions is common, suggesting that shared pathophysiological mechanisms, such as systemic inflammation, may be involved. However, the direction of association between depression and CVD risk in young people remains unclear. Gaps also remain in our understanding of the role of different immune components in these relationships across the lifespan. The purpose of this thesis was two-fold. First, to investigate the association between CVD risk (as defined by systolic blood pressure, total cholesterol, low-density lipoprotein, high-density lipoprotein, high body mass index, and smoking status) and depressive symptoms in young people. Second, to test the convergence of evidence for systemic inflammation as a shared mechanism for depression and CVD across the lifespan. I conducted a systematic review and meta-analysis of longitudinal studies of CVD risk factors and subsequent depressive symptoms in young people. Then I used data from two contrasting observational studies: the Avon Longitudinal Study of Parents and Children (ALSPAC) and the United Kingdom (UK) Biobank to study associations between inflammation, depression, and CVD risk in different age groups. ALSPAC is a prospective birth cohort of 15,000 individuals born in and around Bristol in 1990/91. In contrast, UK Biobank is a long-term UK-based study of over 500,000 individuals aged 40 years old and over. I used several measures of systemic inflammation including interleukin-6 (IL-6), C-reactive protein (CRP), white blood cell count (WCC), and number of childhood infections. Through the systematic review and meta-analysis, I highlighted that obesity and cigarette smoking are strongly associated with depressive symptoms in individuals up to age 24 years. Few longitudinal studies of young people have considered the effect of other CVD risk factors such as systolic blood pressure, total cholesterol, low-density lipoprotein, or high-density lipoprotein. I followed PRISMA guidelines when reporting these findings. Using ALSPAC data, I revealed that CVD risk is associated with subsequent depressive symptoms but not the other way around. Obesity and cigarette smoking in particular appear to drive this association. These findings suggest that targeting smoking and obesity in young people may be important for the prevention of both depression and CVD in adults. I also used ALSPAC to study the effects of inflammatory markers on health outcomes in young people. Specifically, I investigated the associations of childhood infections, IL-6, and CRP with depressive symptoms and psychotic experiences. I showed that a higher burden of common childhood infections is associated with depressive symptoms and psychotic experiences in early and mid-adolescence. In contrast, I discovered that childhood IL-6 and CRP were more strongly associated with subsequent CVD risk than depressive symptoms. CVD risk in adolescence appeared to mediate the relationship between childhood IL-6 or CRP and depressive symptoms in late-adolescence. These results suggest that markers of systemic inflammation in early life have differing associations with depression and CVD risk in young people. I used the UK Biobank to investigate the potential effects of inflammatory markers on comorbid and monomorbid depression and CVD outcomes in middle-aged and older adults. I used both CRP concentration and WCC as exposures. I discovered that CRP and WCC are both associated with depression and ischaemic heart disease (IHD), as well as comorbid depression and IHD. I also showed evidence of specific association between WCC and IHD. These findings suggest that systemic inflammation is likely to be a shared mechanism for depression and IHD, but the risk of each outcome may be underpinned by distinct inflammatory pathways. Taken together, these results indicate that the bidirectional association between CVD and depression is not present until adulthood. While the association between systemic inflammation and depression/CVD appears to be robust, pathophysiological mechanisms for depression and CVD may differ across the lifespan.