Attention deficit hyperactivity disorder (ADHD) is a common and impairing neurodevelopmental disorder, which frequently co-occurs with autism spectrum disorder (ASD). Both disorders are highly heritable and recent studies report a substantial degree of overlap in genetic risks for ADHD and ASD. The overall objective of this thesis is to examine the clinical co-occurrence and shared genetic susceptibility of these conditions, as well as of related developmental problems. First, the presentation of ASD traits is examined in a clinical sample of children diagnosed with ADHD. This is followed by an assessment of whether the presence of ASD traits in children with ADHD is associated with additional cognitive or developmental difficulties. Lastly, it is investigated whether common genetic risk variants which are associated with clinically-diagnosed ADHD are also associated with ADHD traits, ASD-like social-communication difficulties and neurocognitive abilities (i.e. IQ, working memory, inhibitory control and facial emotion recognition) in children from a general population sample. The results show that ASD traits split into separate, albeit correlated dimensions of social-communication difficulties and restrictive, repetitive behaviours (RRBs) in children with ADHD. They also suggest that there may be some overlap of RRBs and hyperactive-impulsive ADHD symptoms. Increasing levels of ASD traits in children with ADHD are found to index more ADHD symptoms, as well as lower cognitive abilities and a greater likelihood of developmental difficulties. Finally, the results demonstrate that common genetic risk variants relevant to ADHD diagnosis are associated with ADHD and social-communication problems as well as cognitive difficulties (lower IQ and working memory abilities) in children in the general population. This thesis extends our understanding of the clinical importance of assessing ASD in the context of ADHD. Furthermore, the findings demonstrate that common genetic risk variants for childhood ADHD are also relevant to other neurodevelopmental and cognitive outcomes in the general population.

No description available.

This thesis examined the macro-structural and micro-structural changes in Huntington’s disease (HD) in order to improve understanding of the temporal and spatial patterns of neurodegeneration, and the functional relevance of these changes. Translational techniques were employed using genetic mouse models of HD in combination with a patient cohort to examine grey and white matter changes with a particular focus on white matter microstructure. In the patient cohort, the cognitive profile was examined using a cognitive battery not before applied in HD. Specific deficits were found in set-shifting and flexibility, verbal reasoning, working memory and paired associate learning, along with subtle differences in response inhibition that were sensitive to disease burden. A composite cognitive score was produced to examine the relationship between cognitive function and brain structure. A multi-modal examination of white matter tract-specific microstructural measurements revealed abnormalities in the corpus callosum and cingulum bundle that were sensitive to disease burden (chapter 4). In chapter 5, multiple analysis techniques converged to reveal tissue macrostructure abnormalities that were also sensitive to disease burden in HD. Cortical changes were less consistent, and unlike the microstructure findings, white matter macrostructural abnormalities were not related to disease burden. In chapters 6 and 7, genetic mouse models of HD were used to examine changes across the disease course, and to pilot an interventional design. In vivo diffusion MRI and T2-weighted MRI sequences were acquired at 2 different time points in the HdhQ150 knock-in model of HD and imaging data is presented alongside behavioural results and immunohistochemistry. In chapter 7, an environmental modification regime was tested in the YAC128 mouse model using in vivo MRI. Environmental intervention reduced the degree of disease-related atrophy, altered tissue microstructure and improve motor but not cognitive performance in YAC128 mice.

Protein aggregations of β-Amyloid (Aβ) and Tau are alone not sufficient to account for all the symptoms and progression of Alzheimer’s Disease (AD), as such there is much emphasis upon the immune component of the disease. The cells of the brain that are capable of initiating an immune response are microglia; these are derivatives of hematopoietic cells and they have the capacity to phagocytose and clear Aβ aggregates or release cytokines such as TNF-a, in a neurotoxic role, promoting apoptosis of the surrounding neurons and hence aiding disease progression. To uncover the precise role of microglia in terms of AD we propose a protocol to enable differentiation of microglia from human embryonic stem cells (hESCs). The protocol we propose is a two-step differentiation procedure i) hESCs to monocytes followed by ii) ES-derived monocytes to microglia. Chapter 3: Exogenous over-expression of PU.1, a transcription factor vital in both the onset of haematopoiesis and the terminal differentiation of monocytes and microglia, was revealed to enable differentiation to a hematopoietic fate. Chapter 4: hESCS were differentiated to monocyte-like cells (CD45+/CD11b+) through culture in the presence of the hematopoietic growth factors; M-CSF and IL-3. Chapter 5: focuses on the differentiation of ES-derived monocytes to microglia. It shows that monocytes cultured in astrocyte conditioned medium give rise to cells that are IBA-1+/Glut5+/CD45low/NG2low/CD80+/CD11c+ and have a ramified microglial phenotype, which upon stimulation with Aβ(1-42) can become activated to the amoeboid phenotype. The development of the protocol for the generation of microglia holds great importance in terms of creating in vitro models for AD research as a whole and can be extended to the differentiation of patient IPSCs that contain mutations in genes associated with innate immunity or SNPs associated with AD risk, disease onset and progression.

AIMS: To investigate self-discrepancies in stroke survivors and explore associations between discrepancies and distress, drawing on Higgins’s (1987) Self-Discrepancy Theory. More specifically, investigate if stroke survivors reported a change in their sense of self following stroke, if this change was related to their reported anxiety and depression, and if this relationship was mediated by their perceived self-esteem. Also, to explore if discrepancies between survivors’ post-stroke self and their ideal and ought self, respectively, were associated with depression and anxiety, respectively. METHOD: A retrospective cross-sectional design was employed. The participants were 67 first-time community-living stroke survivors, with a mean age of 61.6 years and a mean time since stroke of 5.6 years. The measures included the Head Injury Semantic Differential for assessing pre-stroke (retrospectively), post-stroke, ideal and ought selves; the Hospital Anxiety and Depression Scale; the Rosenberg Self-Esteem Scale; the Stroke-Specific Quality of Life Questionnaire (adapted); and the Barthel Index. RESULTS: Stroke survivors perceived themselves significantly more negatively than prior to their stroke. The discrepancy between pre and post-stroke selves was positively associated with affective distress and negatively associated with self-esteem and quality of life, respectively. The discrepancy between post-stroke self and ideal self, and the discrepancy between post-stroke self and ought self were also positively associated with affective distress. However, these relationships were undifferentiated, as the former was not only related to depression but also to anxiety, and the latter was not only related to anxiety but also to depression. Survivors’ perceived self-esteem was a mediator in the relationship between the pre and post-stroke selves discrepancy and affective distress. CONCLUSIONS: This was the first study to show a perceived change in identity in a large sample of stroke survivors, and it contributed to our understanding of how psychological factors may be involved in emotional adjustment after stroke. This highlighted the importance of considering such changes in informing neurorehabilitation; the clinical implications were discussed. It was also the first study to provide support, albeit partial for Higgins’ (1987) self-discrepancy theory in a stroke population. The strengths and limitations of the study were considered and ideas for future research were proposed.

The papers included in the thesis, and summarized in this covering document, were selected, in discussion with my supervisor, Dr. Roessler, from papers I have published in the philosophy of psychiatry. In parallel to this philosophical work, I have worked clinically as a psychiatrist and academically as a research psychiatrist. My clinical work has largely been working with Early Intervention Services, both in South London and in Coventry and Warwickshire, and this work has been acting as a psychiatrist in clinical teams who work with young people who may either be at risk of developing a psychotic illness, or are in the earliest stages of such an illness. My empirical work has been in the same clinical group and has used functional neuroimaging and cognitive neuropsychology to characterize those at risk of psychosis and to chart the onset of psychosis and the formation of delusions. As required by the university guidelines, a full list of publications, both empirical and philosophical, is detailed in appendix 1. The papers included in the thesis hence parallel many of these clinical and empirical interests: papers 2 and 4, in particular, examine the role neuroimaging may play in studying delusions and relate the prodromal phase of psychosis to both the neurodevelopmental and continuum models of psychosis. Paper 3 is one of two papers written with Lisa Bortolotti drawing on Richard Moran’s work and examining delusions. Paper 1 is perhaps the paper least connected to my empirical and clinical work as has a wider focus and tries to examine what mental illnesses are and to begin to describe a position Lisa Bortolotti and I later expanded on and referred to as ‘psychological realism’, with Paper 2 being a case example of this account being applied to a particular area of psychopathology, namely delusions. The papers form a progression with Paper 1 outlining a general conception of mental disorder, Paper 2 being a case study of this approach specifically in the area of delusion. Paper 3 takes the example of thought insertion and develops ideas from Paper 2 that reason giving is a crucial feature that helps highlight what is pathological about certain experiences. Paper 4 brings together the philosophical concerns regarding a wholly neuroscientific conception of psychopathology, and how this is of clinical and scientific relevance when we use psychopathology to demarcate the various stages of psychotic experience and illness.

This study presents a mixed methods investigation into the efficacy of an indicated CBT-based intervention for addressing anxiety in a sample of secondary school students within the UK. Phase One of the study employs a quasi-experimental evaluation of a CBT-based intervention. 18 participants (7 male, 11 female, mean age: 12 years 6 months) were allocated to intervention (n=8) or wait-list comparison (n=10) conditions using a matched pairs process. The intervention comprised six sessions of a CBT-based programme, delivered by teaching assistants trained in the principles of CBT; wait-list participants attended their usual lessons. Phase One investigated the effects of intervention participation upon students’ self-reported anxiety and parent-reported perceptions of student anxiety, using the respective versions of the Spence Children’s Anxiety Scale (SCAS and SCAS-P). Results demonstrated that there were no statistically significant effects upon student-reported anxiety or parent-reported perceptions of student anxiety. Parents of participants within the wait-list condition reported increased student anxiety during the intervention phase, albeit this trend did not reach statistical significance. Phase Two represents a qualitative exploration of participants’ perceptions of their post-intervention anxiety regulation abilities and their insight into the programme mechanisms. This phase incorporated Focus Group and Nominal Group Technique approaches, with data reviewed through Thematic Analysis. Findings suggested that participants perceived intervention attendance to have developed their knowledge and understanding of strategies which may either a) actively address the causes of their anxiety or b) enable them to manage the physiological, emotional, cognitive and behavioural implications of anxiety. Participants indicated that intervention participation had increased their understanding of the importance of seeking social support for managing anxieties. Key methodological reflections for this two-phase design are discussed. Findings are compared to the wider literature regarding anxiety and CBT approaches in children and young people. The implications of these findings for future research and the practice of Educational Psychologists are considered.

This project aimed to prove the existence of fine subdural veins hypothesised to be the source of intracranial bleeding seen in cases of accidental and non-accidental traumatic head injuries, and consequently illustrate their anatomical structure. This was important in contributing towards establishing the causal mechanism for traumatic intracranial bleeding, and was particularly applicable in unexplained traumatic head injuries in cases of possible child abuse. These issues are on-going, worldwide concerns that have been of public as well as scientific concern for many years. To illustrate the fine cerebral vessels, a unique modelling technique was recently developed involving polyurethane resin casting of the brain vasculature. Rat, marmoset, rhesus macaque and human brain tissue were all used. Tissue surrounding the resin perfused vessels were then either macerated to reveal the whole cast, or dissected to illustrate the cast as it would appear in situ. To allow analysis of these fine subdural vessels, various imaging techniques including fluorescence microscopy, light microscopy, confocal microscopy, scanning electron microscopy, transmission electron microscopy, magnetic resonance imaging, micro-computed tomography and 3D X-ray microscopy were used. The existence of subdural vessels was clearly illustrated via gross dissection of both primate and cadaveric material. Fluorescence imaging of resin-filled rat brain histological sections also showed orientation of fine vessels within the subdural space. Magnetic resonance imaging of the human head in vivo, as well as cadaveric material have shown signs of small calibre vessels that have never been previously documented, that are too fine to be bridging veins, yet seem to drain into the superior sagittal sinus. These results prove the existence of subdural vessels, present in a range of different species. Future work will further illustrate the exact morphological structure of these vessels, and biomechanical modelling will be applied to determine the exact forces required to cause them to rupture.

Aggressive behaviour in people with intellectual disability is a far reaching problem, estimated to be expressed by 7% of the population of people with intellectual disability. People with intellectual disability who are aggressive often experience an inequality in service provision. Carers who work in aggressive environments can find the management of aggression an overwhelming challenge and may suffer burnout. At a service level, providing suitable care for people who may be aggressive, whilst also providing a comprehensive care package, is very difficult. Aggression in people with intellectual disability is more prevalent than in equivalent cared for groups, but there is little research to date on the sequential nature of that aggression. Like all behaviour, aggression occurs as part of a sequence, and a crucial part of understanding violent behaviour in people with intellectual disability is to understand the nature of their aggression, and especially the (temporal) structure of these episodes, as well as the potential factors involved. Current research in aggression in people with intellectual disability focuses on the nature of static risk factors, mental health issues and the function that aggressive behaviour provides for the individual expressing it. The main aim of this thesis is to document the patterns of aggressive behaviour in people with intellectual disability in order to examine what factors may be involved in increasing the risk of aggression in this population. Guidance as to what those factors may be was taken from research into aggression in the general and intellectual disability population. The first phase of this study involved creating a database of violent incidents from the health care records of 18 participants, drawn from three National Health Service units for Intellectual Disability. These were collated into an aggressive incident database that brought together information from different sources about individual incidents. The patterns in the incidents were used to construct a typology of aggression. The second phase of the study formed the main focus of the research, and involved analysing the aggressive incident database using Sequence Analysis methods. The pattern of these results indicated that reports focused mainly on aggression that involved staff, and found visits, outings and denial of requests by participants were significant factors in the sequence of an aggressive incident. The third phase focused on data drawn from a risk management system called Sentinel, and examined all aggressive incidents occurring across three units for people with intellectual disability over four and a half years to investigate temporal patterns of aggression using time interval analysis. This was used to identify distinct temporal patterns of aggression for each of the three units involved in the study. The results indicated that visits and outings, meal times and requests were part of the sequence of aggression behaviour in people with intellectual disability. The possible implications of this were discussed, and these findings related to the wider literature.

ZNF804A was (at the time this work started) one of only a few robustly implicated schizophrenia susceptibility genes, due to replicated genome-wide significant evidence for association between a polymorphism in the gene and schizophrenia. Determining the function of the ZNF804A protein, which is currently unknown, may provide a way of elucidating the pathophysiology of this relatively common, complex disorder. Based on the hypothesis that the ZNF804A protein regulates gene expression or splicing, the aim of this thesis was to identify genes that exhibit altered expression or splicing in brain tissue from mice in which the orthologue Zfp804a carries a nonsense mutation. No robust evidence was obtained that showed the effects of the mutation on differential expression in individual genes. Although this finding does not support the hypothesis that ZNF804A acts directly to regulate gene expression, the results may reflect the possibility that effects on gene expression may be too subtle to be detected using the methods applied. Evidence was obtained to show the mutation affected the alternative splicing of a number of individual genes, which could suggest a role for ZNF804A in the direct or indirect regulation of alternative splicing. Through RNA sequencing, I identified a novel transcript in Zfp804a with an alternative exon upstream of the Refseq exon 1. I also showed that a proportion of the significant splicing differences identified in mutants were artefacts of strain differences in gene sequences that are likely to affect the efficiency of hybridisation on the exon array. Genes identified as differentially spliced between mutants and wildtypes were enriched in axon guidance and cell adhesion pathways, both thought to be important during development. The findings of this thesis suggest the novel hypothesis that ZNF804A effects risk for schizophrenia via aberrant splicing in the above pathways that are critical to normal brain development. Further studies with increased power are required to understand the effects on gene expression.