Cognitive impairment is a major cause of disability for a large number of working-age adults living with chronic psychiatric and neurological conditions. Although well recognised in schizophrenia spectrum disorders and in neurological diseases such as multiple sclerosis (MS), cognitive impairment has historically received less attention in mood disorders. The relative prevalence of cognitive impairment in bipolar disorder (BD) and major depression compared with other conditions has not been clearly established, and the risk factors that drive cognitive variation within and across conditions are not well understood. The primary focus of this thesis was on BD, and the objectives were: (1) to investigate the prevalence of cognitive impairment in BD, compared with major depression, schizophrenia, MS and Parkinson’s disease (PD); and (2) to develop causal models to quantify and explain variation in cognitive function in BD and in other conditions. The methods encompassed a systematic literature review, a prevalence study using cross-sectional data from the UK Biobank cohort, and a series of multivariable analyses of UK Biobank data using graphical methods, regression- and matching-based estimation, and mediation models. The systematic review indicated that between 5% and 58% of adults with euthymic BD showed cognitive impairment. Prevalence was lower in the mania/BD group identified within the UK Biobank cohort, at around 7-10%, which was similar to rates seen in the MS and PD groups within the cohort. When causal models of cognitive performance in the mania/BD group took account of multiple potential confounders, performance on a short-term visuospatial memory test showed a small but reliable decrement. Mediation models provided evidence of indirect negative effects on cognitive performance via psychotropic medication, but not via cardiometabolic disease. A similar pattern of results was seen in the major depression group, though with smaller effect sizes. This thesis emphasises the importance of cognitive function as a fundamental phenotype in psychiatric and epidemiological research. There is scope to build on this work in future follow-up waves in UK Biobank, as well as in other UK and international cohort studies and through linkage with routine healthcare data.

Homeostatic synaptic scaling mechanisms, which normally balance potentiation during learning, may direct the progression of the disease throughout the brain as cells scale up their sensitivity to compensate for lost activation. Such a mechanism would be likely to target those cells with the lowest contribution of information to the network in early stages of the disease, resulting in delayed onset of cognitive symptoms and making timely intervention and treatment of the disease more difficult. These predictions were investigated in a Hopfield-type neural network. Lesioning according to the scaling-driven progression hypothesis of AD showed that the pathology is capable of targeting neurons with lowest information contribution to the network at early stages of the disease. Additional experiments revealed a positive-feedback loop by which noisy compensatory synaptic scaling mechanisms caused the accelerated degradation of recent memories, which were themselves preferentially used as drivers of the compensatory mechanism. The hypothesis was then tested in a biologically-realistic spiking model of neocortex. Cell death, modelled as an abstract excitotoxicity mechanism based on scaling factor values, confirmed the earlier results and showed that low-information neurons (and neurons from cortical layers with the lowest information contribution) were again the first to die in scaling-driven AD pathology.

This thesis is an investigation of how written words are processed and represented for output. A single case study of an acquired dysgraphic patient is presented who produced a serial position effect in spelling tasks characterised by an increase in error rate from word beginning of word end. This pattern is assumed to reflect a deficit in the retrieval of stored orthographic representations. It is suggested that the order of output of letters may be encoded by an ordering of activation values. The nature of the deficit in terms of distinctions between input and output and access and storage are considered. The findings are discussed in relation to an existing connectionist model of spelling which was implemented and lesioned in an attempt to reproduce certain aspects of the patients data. Furthermore, a detailed analysis of the patients spelling errors suggests that orthographic representations consist of representational units other than the single letter and whole word. Finally, the role of the semantic system in lexical retrieval was investigated with regards to the distinction between proper names and common nouns. The ability of two patients to write/read proper names semantically was studied. Differences in the representational properties of proper names may result in them being selectively spared or impaired.

Aims: To fully characterise the RGC-5 cell line and determine whether it would be a suitable substitute for primary RGC cell culture. To optimise a CNTF Nogo-P4 inhibitory assay and establish whether (a) CNTF alone is capable of stimulating RGC neurite outgrowth and survival, or (b) an increase in intracellular cAMP is required for CNTF to be effective. To determine whether recombinant AAV2 viral constructs were capable of producing detectable levels of CNTF in HEK-293 transfected conditioned media. To optimise AAV2-eGFP delivery and establish whether AAV2-CNTF-hrGFP and AAV2-CNTF-shRhoA-hrGFP could promote RGC survival and regeneration after optic nerve crush surgery. Methods: The RGC-5 cell line was characterised using semi-quantitative PCR, sequencing and immunocytochemistry. RGC-5 cells were screened for a selection of neuronal, glial, progenitor, oligodendroglial lineages and cone photoreceptor cell markers to identify the cells origin. Retinal cultures were treated with recombinant CNTF and/or Forskolin to promote RGC neurite outgrowth and survival - this was quantified after 3 d. Retinal wholemounts were prepared to assess GFP transduction and survival after intravitreal delivery of AAV2-eGFP. Axonal regeneration and RGC survival were assessed through histological examination of optic nerves and retinal sections. Results: The RGC-5 cell line predominantly expressed oligodendroglial lineage markers and only weakly expressed \(\beta\)III-Tubulin mRNA. RGC-5 cells did not express mRNA for many of the phenotypic markers of RGC. CNTF was effective at stimulating RGC neurite outgrowth without the need for cAMP elevation - furthermore recombinant CNTF could disinhibit Nogo-P4 treated RGC in vitro. GFP transduction was low when injected alone, however, when administered with Pronase-E there was a significant increase in GFP expression. AAV2-CNTF-hrGFP and AAV2-CNTF-shRhoA-hrGFP did not promote RGC survival or regeneration 23 d post optic nerve crush. Conclusions: RGC-5 cells are not an appropriate substitute for primary retinal cell culture in vitro as they express many of the same markers as oligodendrocyte progenitors. CNTF is capable of stimulating RGC neurite outgrowth without an additional elevation of cAMP. AAV2-mediated GFP expression could be enhanced through the partial digestion of the inner limiting membrane - this seems to be the major obstacle in achieving optimal AAV2 transduction.

Growing numbers of children are being diagnosed with autism in the UK and, against a backdrop of increased legislative and administrative provisions for educational inclusion, more autistic children are being educated in mainstream primary school settings. However, while there is evidence of the continued exclusion of autistic children, their performance in school tests seems poor, and their longer-term outcomes impoverished. Meanwhile, debates continue about the nature of autism itself. My project, informed by the social model of disability, theories of language and interpretation, inclusion, difference and aspects of feminism, aims to uncover the reasons behind the difficulties autistic children are experiencing in schools, by considering if, and how they are accessing the curriculum and tests. Employing a predominantly interpretative paradigm and a case study design, and based in five mainstream primary schools in England, the views of school staff, autistic children and their parents, as well as a sample of autistic adults, are incorporated. My findings show that by setting aside the association of autism with impairments, listening to autistic children, engaging with them meaningfully and enabling their own learning styles and particular dispositions to be manifest, educational inclusion, and positive outcomes for all, are much more likely to occur.

How do we know where objects are in the environment and how do we use this information to guide our actions? Recovering the three-dimensional (3D) structure of our surroundings from the two-dimensional retinal input received from the eyes is a computationally challenging task and depends on the brain processing and combining ambiguous sources of sensory information (cues) to depth. This thesis combines psychophysical and computational techniques to gain further insight into (i) which cues the brain uses for perceptual judgments of depth and motion-in-depth; and (ii) the processes underlying the combination of the information from these cues into a single percept of depth. The first chapter deals with the question which sources of information the visual system uses to estimate the time remaining until an approaching object will hit us; a problem that is complicated by the fact that the variable of interest (time) is highly correlated to other perceptual variables that may be used (e.g. distance). Despite these high correlations we show that the visual system recovers a temporal estimate, rather than using one or more of its covariates. In the second chapter I ask how extra-retinal signals (changes in the convergence angles of the eyes) contribute to estimates of 3D speed. Traditionally, extra-retinal signals are reputed to be a poor indicator of 3D motion. Using techniques to isolate extra-retinal signals to changes in vergence, we show that judgments of 3D speed are best explained on the basis that the visual system computes a weighted average of retinal and extra-retinal signals. The third and fourth chapters investigate how the visual system combines binocular and monocular cues to depth in judgments of relative depth and the speed of 3D motion. In chapter three I show that differences in retinal size systematically affect the perceived disparityde defined depth between two unfamiliar targets, so that a target with a larger retinal size is seen as closer than a target with a smaller retinal size at the same disparity-defined distance. This perceptual bias increases as the retinal size ratio between the targets is increased but remains constant as the absolute sizes of the targets change concurrently while keeping the retinal size ratio constant. In addition, bias increases as the absolute distance to both targets increases. I propose that these findings can be explained on the basis that the visual system attempts to optimally combine disparity with retinal size cues (or in the case of 3D motion: changing disparity information with looming cues), but assumes that both objects are of equal size while they are not. In chapter 4 these findings are extended to 3D motion: physically larger unfamiliar targets are reported to approach faster than a smaller target moving at the same speed at the same distance. These findings cannot be explained on the basis of observers' use of a biased perceived distance, caused by differences in the retinal size (as found in chapter 3). I conclude that, in line with contemporary theories of visual perception, the brain solves the puzzle of 3D perception by combining all available sources of visual information in an optimal manner, even though this may lead to inaccuracies in the final estimate of depth.

This thesis examines factors associated with length of hospital stay for mentally disordered offenders, detained within the medium secure psychiatric estate. Following an introduction, Chapter two presents a systematic literature review examining the current literature on factors that predict length of stay for patients detained in medium secure hospitals. Mixed results were found. There was limited convergence across clinical and forensic variables investigated, but greater consensus on what is not associated with length of stay. The limited research available and inconsistencies found indicates the need for further research. Chapter three comprises an empirical research study, investigating which variables within a population of male mentally disordered offenders predict length of stay within a regional, medium secure psychiatric hospital. Preliminary analyses revealed statistically significant relationships between length of stay and nine variables. Effect sizes were small to medium. Logistic regression revealed a statistically significant relationship between length of stay of two years or more and having a diagnosis of schizophrenic disorder. Chapter four presents a critical review of the Historical, Clinical, Risk–20 Violence Risk Assessment (HCR-20) (Version 2), a widely adopted risk assessment framework utilised within forensic psychiatry and the standardised measure used within the empirical study. The review explores the literature on the reliability and validity of the HCR-20, and considers its strengths and limitations. A discussion of the work presented concludes the thesis.

This thesis considers Borderline Personality Disorder (BPD), its diagnosis in adolescence and apparent gender differences in diagnosis and treatment. Although often considered within a clinical mental health context, the gap between clinical and forensic practice is rarely closer than when considering BPD and its close association with an increased risk of criminal behaviour and the forensic population. This coupled with Dialectical Behaviour Therapy (DBT) as a treatment of choice for BPD and its development in a variety of settings including the forensic population means that BPD, adolescence and DBT research is at an interesting juncture. In this controversial area fraught with complications from diagnosis to treatment, it is argued that this thesis could provide a useful collaboration between the available research to date and an exploration of future research developments, which are desperately needed.

Since the 1970s the number of people suffering from functional somatic syndromes such as fibromyalgia has increased dramatically. These syndromes are characterised by higher levels of incapacity and disability than can be accounted for by objective medical testing. Here the possibility that socially derived labels and health information are contributing to the incapacity experienced by these patients was investigated. Investigations conducted with healthy people found that the way people perceive themselves as behaving, and whether that behaviour is labelled as healthy, influences how satisfied people are with their own health, and their health in comparison to others. It was also found that people who are labelled as unhealthy are evaluated as having less moral worth than those who are not. Further investigations found that the labels used to understand a painful sensation alter the way people respond to that sensation. Investigations with fibromyalgia patients found that the diagnostic label of fibromyalgia changes the information patients have access to, and therefore the information available to interpret their experiences. It was concluded that incapacity in functional syndromes may be partly driven by people being encouraged by to interpret their experiences in a particularly anxiety-provoking way through information in the environment.

The role of excitatory processes in human visual learning has been well characterised through the use of technologies such as functional magnetic resonance imaging (fMRI). However, established imaging modalities do not distinguish excitatory processes from the inhibitory ones that are also involved. Here we investigate inhibitory processes using magnetic resonance spectroscopy (MRS) and the MEGA-PRESS pulse sequence. We measure concentrations of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in different brain regions as functional markers of inhibitory potential. We then investigate the correlations between GABA concentrations and psychophysical learning metrics. We detail a full analysis pipeline that improves the accuracy of in vivo GABA quantification and introduce new scaling methods to resolve the grey matter contribution to metabolite measurements. We develop visual learning experiments that are mediated by training difficulty, which we link to inhibitory processes across different time scales. We also present novel evidence for GABAergic inhibitory mechanisms across multiple brain areas using fine and coarse discrimination tasks. Our results support a cooperative top-down and bottom-up model of visual learning in occipital and frontal cortical regions. Our findings reveal chemical interactions with cognition to contribute to our understanding of inhibitory processes in the human learning brain.