Theses - Psychiatry

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Optimizing the neuromodulation of pathological neural circuits: multiparametric approaches and biomarker prediction
Cui, Hailun
Over the last three decades, there has been substantial progress in the development of neurocircuitry models of the brain. These developments have paved the way for hypothesis-driven interventional approaches directly targeting specific brain circuits, offering new possibilities for effective interventions and therapeutic strategies. The modification of brain functioning derived from these devices or surgically based neuromodulations, in turn, has refined and deepened our understanding of the neural and cognitive mechanisms central to the pathophysiology of psychiatric illnesses. This thesis aims to employ this circular structure of knowledge to explore the therapeutic outcomes and underlying mechanisms of two clinically well-established approaches to neuromodulation, namely, the invasive anterior capsulotomy procedure and the non-invasive transcranial magnetic stimulation (TMS) for the management of two common psychiatric disorders that can be clinically intractable: obsessive-compulsive disorder (OCD) and major depressive disorder (MDD). In CHAPTER 1: GENERAL INTRODUCTION, I reviewed the evolution of the understanding regarding the pathophysiology of OCD and MDD, which has led to the emergence and refinement of neurocircuitry models of psychiatric disorders. I included a brief outline of the current therapeutic options available for OCD/MDD, with special highlights on the evolution of modern technologies that have been translated into invasive or non-invasive neuromodulation techniques for managing severe and refractory cases of psychiatric illnesses. This introductory chapter also reviewed how circuit-based disease models can be considered and later examined for both ablative and stimulation-based therapies. It outlined the motivation for the multimodal investigation of therapeutic mechanism underlying the OCD anterior capsulotomy procedure detailed in Chapter 2 and 3, and the MDD TMS protocol detailed in Chapter 4 and 5. In CHAPTER 2: ANTERIOR CAPSULOTOMY FOR OBSESSIVE-COMPULSIVE DISORDER: A COGNITIVE AND NEUROANATOMICAL STUDY, and CHAPTER 3: NEURAL CORRELATES OF ANTERIOR CAPSULOTOMY FOR OBSESSIVE COMPULSIVE DISORDER: NEGATIVE AFFECT PROCESSING, I asked which prefrontal regions and underlying cognitive processes might be implicated in the effects of capsulotomy. I utilized both functional MRI tasks and cognitive tasks selected from the Cambridge Neuropsychological Automated Test Battery (CANTAB) to assess OCD-relevant cognitive mechanisms known to map across prefrontal regions connected to the tracts targeted by capsulotomy, with specific focus on the functional changes at key nodes or connections within the frontostriatal circuitry. Task results showed lower brain activity during the aversive learning phase (anticipation or feedback of aversive events) and during the extinction phase in the nucleus accumbens (NAc), the rostral anterior cingulate cortex (rACC), and the inferior frontal gyrus (IFG) in the post-capsulotomy patients, with attenuated functional connectivity between seed NAc and rACC during aversive versus neutral anticipation. These findings contribute to the literature on the clinical efficacy of anterior capsulotomy, suggesting a neurosurgical effect in downregulating the functional communication along the frontostriatal pathways to be underlying the symptomatic improvement, and highlighted an overlap in neurocircuit-based optimal targeting between deep brain stimulation (DBS) and capsulotomy in OCD neuromodulation. In CHAPTER 4: A DUAL-SITE ACCELERATED rTMS PROTOCOL FOR TREATMENT RESISTANT DEPRESSION, and CHAPTER 5: NEUROIMAGING MECHANISM OF RESPONSE TO DUAL-SITE rTMS, I focused on searching for more effective treatment protocols of TMS for the management of MDD. Considering the cost and time it usually takes for conventional neuronavigation-based TMS protocols to take effect in severe suicidal MDD cases, I tested a novel dual-site accelerated TMS protocol using an EEG 10-20 system-guided approach in a double-blind randomized controlled trial of 20 sessions over five consecutive days comparing (1) the dual-site stimulation group (inhibitory continuous theta burst stimulation of right lateral orbitofrontal cortex (OFC) followed sequentially by excitatory 20 Hz rTMS of left dorsolateral prefrontal cortex (dlPFC)); (2) the active single-site comparator group (sham right lateral OFC followed by excitatory left dlPFC) and (3) the sham TMS group (sham for both targets). The results showed more clinical responders (a reduction of at least 50% from baseline in Hamilton Rating Scale of Depression, HRSD-24) by the end of all sessions in the Dual (47.8%) relative to Single (18.2%) and Sham group (4.3%), and a decreased lateral OFC-subcallosal cingulate (SCC) functional connectivity post-treatment in the Dual group. I also found that a greater lateral OFC-thalamic connectivity decrease was associated with better response, with the capacity to predict treatment outcome. Thus, this dual target accelerated TMS protocol showed a rapid onset of antidepressant efficacy, suggesting a non-reward lateral OFC cortico-striatal-thalamic circuit to be implicated in tracking and predicting depression improvement following TMS treatment. This finding also has implications for novel designs of TMS protocols in a real-world clinical setting when neuronavigation is not available. Taken together, these results provided further evidence that the functional restoration of neurocircuit dysfunctions of psychiatric conditions could be achieved via direct modulation of circuit components with either invasive procedures (CHAPTER 2 and 3: anterior capsulotomy) or non-invasive devices (CHAPTER 4 and 5: TMS). Functional imaging studies pre- and post brain modulation provided further support for the existing hypotheses of OCD/MDD circuit based pathophysiology, with room and potential for refinements in precision targeting. Future investigations in neurocircuitry dysfunctions may have the potential to enhance clinical management with novel OCD/MDD treatment targets or nodes that can account for inter individual variability and cater to a wider range of individuals with varied clinical presentations.
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Prediction and Explanation in Disorders of Mood & Anxiety
Roberts, Clark
Among currently classified mental disorders in psychiatry, symptoms of depression and anxiety are among the most reported and prevalent. And yet, a unified consensus of their categorization, predictability, and treatment in psychiatry has remained incomprehensive and controversial. Memes derived from antiquated notions of psychopathology and pop psychology still dominate some public discourse. At the same time, contemporary research psychiatrists struggle in complex and contentious discourse over methodological precision and ontological coherence in diagnosis and classification. Whether rates of anxiety and depression are increasing or an artefact of increased cultural awareness and measurement also remains unknown. Bridging scientific explanations with first-person experiences of depression and anxiety has been perhaps unsurprisingly difficult due to the complexity of internal and external factors, and their interactions. Despite continued resistance, DSM categories of psychopathology still offer pragmatic resources for diagnosis and very often prognosis. Still, they do not answer essential questions regarding variable aetiological trajectories, how specific categories and symptoms interact with each other, or what (if any) adaptive functions such behavioural, emotional, or cognitive features associated with anxiety and low mood in some ranges might ultimately offer. While not universal, interactions between anxiety and low mood are frequent. These will be explored in novel detail and key results from this dissertation will strongly indicate important transdiagnostic mechanisms, potential learning mechanisms, aetiological pathways, cognitive profiles, and specific domains of social feedback which may converge and also separate mood and anxiety dimensions. Several conclusions and outstanding questions for future research are then developed and derived throughout theoretical portions. To progress the understanding of mood and anxiety disorders, this thesis's theoretical and empirical aims are to 1.) Examine the overarching problems in contemporary psychiatry regarding explanation and prediction in mood and anxiety, and offer some potential solutions and novel directions 2.) Analyse some of the central biopsychosocial components within anxiety & mood disorders, their interactions, and how they are frequently exacerbated within self-reinforcing dynamic systems 3.) Investigate the constraints and vulnerabilities of evolved behavioural and cognitive control systems which generate aversive states of mood and anxiety and frequently become inflexible. Several conclusions are drawn in the final chapter which indicate some shifts in assumptions are likely needed to advance explanation and prediction in mood and anxiety disorders across scientific disciplines.
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The Nature and Mechanisms of Psychotic Experiences in Borderline Personality Disorder
Peitzmeier, Charlotte
Borderline personality disorder (BPD) is a diagnostic label ascribed to a markedly heterogenous psychiatric phenotype, with symptoms ranging from intense emotions to disturbed relatedness, from impulsivity and self-harm to chronic feelings of guilt, shame, and emptiness. While often regarded as an affective disorder, psychotic symptoms such as hallucinations and delusional convictions are also frequently experienced by people with BPD but are habitually dismissed in both research and clinical practice. Their aetiology and the mechanisms underlying them remain poorly understood, largely due to historical and prevailing stigma towards the disorder. By building on recurring findings of psychotic symptom correlates, and by drawing on causal and cognitive models of psychosis in other mental health conditions it is possible to explore potential risk factors and create a preliminary aetiological framework to better inform and direct future research. This dissertation aims to expand the currently sparse literature on psychotic experiences in BPD, by providing a detailed assessment of the prevalence (Chapter 4), type, and range of hallucinations and delusions (Chapter 5), as well as investigating key factors hypothesised to influence their occurrence or severity (Chapter 6 and 7) with two empirical studies – an online experiment recruiting BPD participants identified by self-report, and a laboratory study of people with a confirmed clinical diagnosis. Both hallucinatory and delusional experiences were significantly more common in people with BPD, presenting on a broad spectrum of frequency and severity – ranging from non-pathological to comparable with psychotic disorders. Dissociation was the strongest predictor for psychotic symptom prevalence and severity for both, perceptual and delusional experiences. Several other factors (including trauma and adversity, disorder severity, psychiatric comorbidities, and common mental distress) were found to generally correlate with (but have limited predictive value for) psychotic experiences. Additionally, current stress levels appeared to influence dissociative and psychotic state symptoms. Results did not support a causal role of aberrant prediction error signalling (as postulated by predictive processing theories) for psychosis proneness in people with borderline personality disorder. In summary, this thesis furthers our understanding of the prevalence and nature of psychotic symptoms in BPD and provides novel insights into the possible cognitive and aetiological mechanisms underlying these experiences.
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The Effects of Concussion on Cognition and the Use of MRI as a Disease Biomarker
Macedo, Debora
[Restricted]
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Elucidating the Principles of Brain Network Organisation through Neurosurgery
Poologaindran, Anujan
Recently, leaders in human brain mapping and the clinical neurosciences outlined the need for prospective trials in neurosurgery to establish the clinical relevance of connectomics. This doctoral dissertation addresses this challenge by using diffuse gliomas as a model to study the principles of brain network organisation through neurosurgery. Specifically, I combined insight from a normative cohort of healthy individuals across the lifespan with a highly rare neurosurgical cohort of diffuse glioma patients who underwent longitudinal connectomic and cognitive testing throughout their clinical care. By understanding how gliomas infiltrate eloquent cortex with little to no cognitive deficits, we may be able to better understand the brain and cancer and ultimately devise new treatment approaches. Overall, the twin scientific and clinical aims were to i) understand how gliomas embed themselves within circuits governing higher-order cognition and ii) determine the utility of connectomics in mapping higher-order cognitive functions for presurgical planning and postsurgical rehabilitation. In the first set of investigations, I deployed structural connectomics to demonstrate that the structural integrity of the Multiple Demand (MD) system for domain-general cognition uniquely predicts interindividual differences in executive functioning across the lifespan. I then demonstrated that diffuse gliomas primarily co-localise to the MD system’s core frontoparietal network, with connectomic, transcriptomic, and neurochemical analyses revealing that connector hubs, oligodendrocyte precursor cells (OPCs), and proto-oncogenes are uniquely enriched in the MD system making it vulnerable to oncogenesis. When investigating the cognitive impact of gliomas infiltrating the MD system, the data reveals long-term cognitive improvements, indicating the brain underwent structural changes to accommodate the tumour and consequently minimize its impact. Presurgical structural analyses of glioma patients’ brains revealed decreases in cortical thickness in the MD system and homotopic areas compared to age- and sex-matched controls. Remarking, normative modelling revealed that the presence of gliomas induced cortical thinning and accelerated ‘brain ageing’, which was partially normalised following surgery and more consistent with healthy adults. In the second set of investigations, I complemented the structural investigation with functional connectomics to demonstrate that gliomas strategically embed themselves within hierarchical gradients and that long-term cognitive deficits result from increased cortical gradient dispersion. Given that meningiomas exert their deleterious effects by compressing brain tissue whereas gliomas infiltrate the tissue, contrasting both patient groups with healthy controls, gliomas decreased global gradient dispersion whereas meningiomas did not. More regionally, to assess mesoscale cortical dynamics, resecting more presurgical connector hubs leads to long-term cognitive deficits whereas resecting provincial hubs did not cause long-term deficits. In addition, changes in perioperative modularity differentiated patients with long-term cognitive deficits from those with long-term improvements. Finally, in the last section of this dissertation, I deployed interventional connectomics to demonstrate how non-invasive brain stimulation is safe and can be utilised in the perioperative setting to promote functional recovery and potentially accelerate long-term cognitive outcomes. Specifically, transcranial magnetic stimulation can be safely applied without causing seizures to improve deficits in motor or language function. In summary, this dissertation presents new evidence on how gliomas embed themselves within the connectome and the clinical utility of connectomics for neurosurgery. Based on connectomic data, the stage is set for future studies to carry this work forward with prospective randomized clinical trials (RCTs) on modulating the presurgical connectome and/or accelerating postsurgical cognitive rehabilitation. Finally, I conclude with providing future directions on how systems neuroscience and functional neurosurgery can be strategically combined to advance the emerging field of cancer neuroscience.
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Understanding the Dynamics of Depressive Symptoms Over Time: A Developmental Perspective
Schlechter, Pascal; Schlechter, Pascal [0000-0002-5916-3694]
Depression is a complex condition which changes over development. The focus of this PhD is on the developmental period from adolescence to emerging adulthood, but I also examined symptom development during a major population stressor in adulthood (i.e., COVID-19 pandemic) and during older adulthood. The overarching aim of this thesis was to understand the development of depressive symptoms from different perspectives. Across different developmental periods, I therefore aimed to (1) test measurement invariance (MI) of depression scales to ensure valid interpretation of the depression construct over time, (2) disentangle time-invariant and time-varying variance components (latent trait state occasion analysis) of the depression construct, (3) unravel symptom level associations and dynamics using network analysis, and (4) investigate differences in symptom reports of adolescents and their mothers. In Chapter 1, I outline complex developmental processes involved in depression. Chapter 2 addresses MI of depression scales from childhood to emerging adulthood. My systematic review of available evidence for gender, age, and longitudinal MI of child and adolescent depression scales revealed that MI is understudied in this age range. I then tested MI of the Short Mood and Feelings Questionnaire (SMFQ) in the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based study in South-West England (N = 7,364; ages 11-26). Longitudinal MI was not fully supported in models that included ages 11 and 13, but the highest level of MI (strict) was established from ages 14-26. At each wave, (partial) strict MI across gender was established. In Next Steps, a UK national cohort study (N = 13,539), MI of the General Health Questionnaire-12 (GHQ-12) was established from age 15 to 25 and across gender. Longitudinal and gender MI were also established for the eight-item Center for Epidemiological Studies Depression Scale (CES-D-8) in the English Longitudinal Study of Ageing (ELSA), a nine-wave representative study of the English population above 50 years of age (N = 11,391). These empirical results increase confidence in the interpretation of findings using total scores from SMFQ, GHQ-12, or CES-D-8 across these age ranges. Chapter 3 examines how much variance in symptoms of depression or psychological distress are attributable to stable time-invariant variance compared to transient time-varying variance. In ALSPAC, time-invariant variance in depressive symptoms increased from 8.1% at age 11 to 57.0% at age 26. Time-varying variance ranged from 91.9% at age 11 to 36.4% at age 26. Small proportions of the variance were explained by autoregressive pathways. Maternal depression, relationship with parents, stressful life events, school enjoyment, and previous mental and general health problems predicted time-varying variance at different ages. In Understanding Society, a UK probability- based longitudinal study of adults, using pre-pandemic (2015-2020) and pandemic data (N = 17,761, April 2020 to March 2021), time-varying variance in psychological distress was higher at the first COVID-19 lockdown (April 2020, 61.2%) compared to before the pandemic (~50%), suggesting increased fluctuations in distress at the start of the pandemic. Loneliness most strongly predicted time-varying variance during the first lockdown. These studies highlight the presence of fluctuations in mental health symptoms during adolescence and a major population stressor, but also indicate time-sensitive periods for intervention. In Chapter 4, I apply network modelling to understand dynamics of depressive symptoms across development beyond a common pathogenic pathway perspective. Across adolescent and emerging adult population-based samples, central symptoms encompassed negative self-evaluations and self-worth, both cross-sectionally (Sample 1: the Mental Health of Children and Young People in Great Britain 1999 survey [N = 4,235, ages 11-15]; Sample 2: the Millennium Cohort Study in the UK 2015 [N = 11,176, age 14]; Sample 3: the mental health of young people looked after by local authorities in England 2002 survey [N = 643, ages 11-17] and over time [ALSPAC]). In looked-after children, I was a bad person constituted a central symptom, while this was among the least central symptoms in the other two cross-sectional datasets. In an older representative population (ELSA), everything was an effort, could not get going and loneliness emerged as consistent central symptoms across time. Nosological core symptoms such as not enjoying anything were not central in the examined data sets. These findings point to clinically relevant symptoms in the development and persistence of depression, which may also challenge nosological views of depression. Chapter 5 focuses on informant discrepancies between mothers and their children in ALSPAC between the ages of 10-17. Latent-Trait-Occasion analysis indicated that mothers conceptualized their children’s depressive symptoms as more stable (time-invariant) compared with adolescents who conceptualized their own symptoms as more fluctuating (time-varying). Response surface analyses indicated that especially incongruent ratings (adolescent rating > mother rating) led to increased subsequent depression in adolescents. These studies highlight the importance of parental educational efforts to increase awareness and monitoring of children’s depressive symptoms in adolescence. Chapter 6 synthesizes the results by discussing differences and similarities across the examined developmental periods, what the different statistical approaches offer, as well as nosological considerations and resulting research questions arising from the findings. Overall, this work has significant implications for prevention and intervention initiatives in depression in sensitive developmental periods.
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Predictive Processing Alterations in Psychosis Across Illness Stage, Hierarchical Level and Thematic Domain
Griffin, Juliet
Predictive processing is a domain-general account of the brain as a hierarchical, dynamically evolving Bayesian predictive model: of a volatile, stochastic world whose nested hidden states interactively and probabilistically generate sensory inputs. The brain infers the hidden causes of ambiguous, noisy neural activity at each level by predicting that level’s most probable state a priori, and integrating this with its estimate of the most likely state given the observed data. Discrepancies between expectations and observations – prediction errors – influence the posterior estimate in proportion to their precision, which itself must be inferred (from the estimated reliability of the data, relative to the confidence in the prior). A subtle, pervasive perturbation to the precision-weighting of prediction error signalling is theorized to explain the formation of psychotic symptoms. However, how predictive processing alterations at different levels manifest, across different phases of illness, and how these relate to phenomenological changes (such as the form of delusions’ relationship to evidence, confidence, and motivation) is not yet well understood. Hypothetical predictive processing alterations, suggested by simulation and pharmacological models of the development of psychotic illness, were tested in participants with at-risk mental state (ARMS), first episode psychosis (FEP), or healthy cognition (HC) (Chapter 2). The use of low-level perceptual priors in visual discrimination (Chapter 3); the use of performance (sub)optimality to monitor meta-level confidence (Chapter 4) and neural signatures of confidence-modulated learning rate and choice temperature (Chapter 5); and the effect of beliefs about an external cue’s source on bias and sensitivity to it (Chapter 6) were investigated. A separate behavioural study investigated the perceptual inference and hierarchical reinforcement learning tasks (Chapters 3 and 4) in treatment-resistant chronic schizophrenia (CSZ) (Chapter 7). “Weak priors” accounts of trait-like vulnerability, previously challenged by empirical findings that ARMS participants made better use of priors to improve the sensitivity of visual discrimination than did controls, were tested on a modified version of that visual inference task whose demands more specifically probed lower-level priors. Having thereby prevented higher-level gist-based priors from being useful to performance on the visual discrimination required, I found that priors were underweighted (relative to controls) in ARMS and especially in FEP (Chapter 3), and also in CSZ (Chapter 7), consistent with the theoretical role of low-level priors in trait vulnerability to psychosis. Chapter 4’s task and hierarchical reinforcement learning model had previously been used to demonstrate reduced confidence-modulation of learning and choice under ketamine. Surprisingly, this was not replicated in ARMS (a clinical model of the same prodromal construct for which ketamine is a pharmacological one): ARMS and HC did not differ from one another behaviourally or computationally (Chapter 4). FEP participants’ behavioural impairments superficially resembled those demonstrated under ketamine, but what characterized FEP at the computational level was their elevated baseline choice temperature relative to controls. This introduced “agentic uncertainty” into the (sub)optimality teaching signal used to monitor confidence, such that it less reliably related to the validity of lower-level beliefs – yet this epistemically-degraded metacognitive estimate, in FEP, modulated learning and behaviour to the same extent as observed in the other groups: with viciously circular ramifications for FEP participants’ ability to robustly maintain an adaptive model in the face of environmental stochasticity. Functional neural correlates of behaviour on this task, though broadly replicated in my larger sample, were not similarly affected in patients as they had been under ketamine. Instead of ketamine’s broad disengagement of the large dorsoparietal choice temperature network, in both FEP and ARMS there was suggestive evidence of a more circumspect disruption to (right) anterior insula, whose negative relationship with learning rate was replicated (Chapter 5). Interestingly, the behavioural case-control study of this task in Chapter 7 found reduced confidence-modulation of choice temperature in CSZ – in the absence of any performance impairment (though choices were on average riskier in CSZ than matched controls). The overall pattern across these studies resonates with classic and contemporary accounts of the adaptations acquired over time in the progression from acute psychosis to chronic schizophrenia. Irresolvable, uninformative uncertainty resulting from disorganization of response selection (in acute psychosis) gradually comes to be assigned less weight (in accordance with its newly degraded epistemic value). Learning to reduce the influence of metacognitive (un)certainty over the degree to which prepotent lower-level inferences constrain behaviour may permit some habitual engagement with salient aspects of non-delusional reality and weaken the motivational grip of firm delusional convictions. Predictive processing’s domain-general, hierarchical, and dynamic Bayesian understanding of the brain as an evolving model of its environment (including the reliability of its own estimates thereof) fares well in explaining delusions’ psychological form and its temporal evolution. However, an adequate theory must also explain delusions’ content. The domain-specificity with which delusions usually centre around social themes has been the basis of challenges to predictive processing’s explanatory feasibility. The particularly taxing computational challenges inherent in social inferences may partially explain their especial vulnerability (Chapter 1), but this Bayesian account faces further problems in reckoning with the bizarre content of many more severe delusions (which may be less social, but whose implausible propositions are still thematically specific: typically involving fundamentally altered relations between mind, body, and world). Chapter 6 manipulated a cue’s source (social/non-social), independently from its predictive validity. Controls were more biased towards the cue, and FEP participants were less biased towards it, when it was perceived to be social. In HC, sensitivity to the cue’s value was blunted in the Social condition – perhaps reflecting healthy developmental priors tuned to ecological statistics of the environment. Patients’ sensitivity was not affected by Condition. Though rational within the task, this suggests ARMS and FEP are both associated with a tendency to overestimate how reliably others’ mental states can be inferred from physical, observable ones. Chapter 4’s findings suggest that in FEP, this may extend also to one’s own mental states. Delusions’ domain-specific content may reflect disruptions to the domain-general statistical learning mechanisms by which agentic causal processes can be distinguished from mechanical or natural law-like ones. Failure to thus differentiate social from non-social sources may be computationally, as well as phenomenologically, core to understanding the content of delusions across the psychosis spectrum.
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.
Open Access
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.
Open Access
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.
Open Access
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.

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