Schizophrenia is highly heritable, indicating that a large proportion of one’s susceptibility to developing the disorder is attributable to genetics. Recent large-scale genomic studies have revealed that genetic variants in patients with schizophrenia affect genes involved in synaptic plasticity processes, which are required for learning and memory, including genes encoding protein complexes associated with the NMDA receptor and the postsynaptic density. Further evidence suggests that associative learning may be particularly affected, although it is unclear which components of this cognitive process are implicated in schizophrenia. The present studies investigated the relationship between particular phases of associative learning, represented by the consolidation, retrieval and extinction of contextual fear memory in rats, with genetic variants, psychoactive drugs and postsynaptic density proteins associated with schizophrenia. I tested associative learning-related gene expression datasets for enrichment in genetic copy number variants from a large cohort of patients with schizophrenia and demonstrated that only genes associated with extinction learning are enriched in patient variants (Chapter 3). I report that fear extinction in rats was impaired by administration of the NMDA antagonist and psychotomimetic, ketamine (Chapter 4). The expression of activity- induced, postsynaptic density products of the Homer1 gene, which has been linked to psychiatric disease, was differentially regulated in specific hippocampal subregions following extinction learning (Chapter 5), and the effect of a partial knockdown of these genes during different phases of associative learning was investigated (Chapter 6). These results build on clinical studies linking abnormalities in associative and, specifically, extinction learning with schizophrenia and support the notion that genetic variants associated with the disorder impact particular cognitive domains. My findings are consistent with the theory that altered inhibitory-type learning processes contribute to the manifestation of schizophrenia.

Do we use one cerebral hemisphere or both to process positive and negative emotions? Is it more physiologically economical for the brain to initiate responses to both types of primary affect from a unilateral locus, or does our readiness to react to emotional stimuli depend on the differential contribution of each hemisphere based on the approach or avoidance behaviours positive and negative affect elicit? This thesis is concerned with these questions that have so far remained unanswered even though they form a key part of emotional perception research. The behavioural literature has provided evidence for both unilaterally (right hemisphere) and bilaterally derived responses to different types of emotional stimuli, with the directionality of response patterns changing depending on stimulus type and task demands. The neuroimaging literature has addressed whether there is a functional need for the lateralised processing of basic emotional stimuli by mapping subcortical and cortical emotional attention networks, specific to different variants of only negative affect (i.e. fear, sadness). How this subcortically originating lateralisation manifests into observable behaviour however still remains to be established. This research therefore posits that hemispheric lateralisation may be a modulated process, and aims to explore how this modulation guides the directionality of our behavioural responses to primary affect. The thesis introduces a novel methodology that provides the first evidence of the modulation of emotional lateralisation by establishing a behavioural paradigm that can effectively investigate hemispheric lateralisation through measures of response efficiency. The thesis further investigates whether subcortically originating lateralisation may be inferred through its resulting behavioural response, by examining visual field asymmetries in responses to positive and negative affect through nasally and temporally viewed stimuli. Additionally, the thesis considers the modulating properties of contextual emotion-enhancing features of facial expressions such as direct vs. averted gaze and the presence of looming sounds on behavioural responses to negative affect, and also investigates whether individual variability in anxiety levels translates into lateralised responses to affect. Findings from the present thesis suggest that lateralisation is not a sustained, static phenomenon, but in fact a dynamic, modulated process that depends on subtle stimulus-contextual elements to subsequently translate into observable response.

No description available.

This research explores the links between bipolar disorder and work. It focuses on the factors that impact an individual’s ability to work and explores whether a simple intervention to support all the key stakeholders (employees with bipolar disorder, line managers and occupational health professionals) involved in the process can be effective. This thesis involved three distinct parts. In the first part a qualitative focus group study explored the views and experiences of the employee, line manager and occupational health professional (OH) participants with respect to the management of bipolar disorder and work. Consensus was reached across the three groups on the main challenges to managing work and bipolar disorder and the solutions to overcome these. The three groups were in agreement on the key areas to be addressed in the intervention to meet the needs of each stakeholder group. In the second part, a qualitative questionnaire study explored the employment patterns and the impact of clinical and demographic variables on the employment outcome across a large sample of participants with a diagnosis of bipolar disorder. This study identified that individuals with bipolar disorder can obtain and sustain employment for prolonged periods, with some reporting sickness absence levels that match those without a mood disorder. It also identified the key clinical and demographical variablesbest associated with employment outcome, which included educational attainment, age of onset of contact with psychiatric services and length of longest psychiatric hospital admission. In the third part, informed by the literature review and focus group findings, the intervention 'Working With Bipolar' was developed that aimed to improve the interactions and conversations between the three key stakeholders in regard to the management of bipolar disorder and work. This intervention was well regarded among the target users and allowed positive and constructive ideas for change.

The striatal neuronal populations comprise medium spiny projection neurons (MSNs) and GABAergic and cholinergic interneurons. Huntington’s disease (HD) involves massive degeneration of striatal neurons. The derivation of MSNs and interneurons from human pluripotent stem cells (hPSCs) would allow modelling of striatal function and HD in vitro, as well as provide a viable source of tissue for cell replacement therapy. Our lab has previously demonstrated that Activin A can induce MSN fate in hPSCs, and that these cells can survive and differentiate in vitro and in vivo. In this study, it was found that this effect occurs via the Activin receptor, independently of SHH signalling. Furthermore, blockade of BMP signalling accelerated MSN differentiation. Electrophysiological analysis demonstrated their potential to acquire functional membrane properties and synaptic activity in vitro. Wnt inhibition and SHH activation have been shown to pattern hPSCs into medial ganglionic eminence (MGE) progenitors and cortical interneurons. Both cortical and striatal interneurons are born in the MGE. This thesis presents the first account of generating MGE progenitors for the purpose of producing striatal interneurons in vitro. They expressed subtype markers such as parvalbumin, somatostatin, calretinin and choline acetyltransferase. When transplanted into neonatal rat striatum, hPSC-derived MGE progenitors migrated to the septum and hippocampus within 6 weeks. The majority of differentiated neurons became calretinin GABAergic interneurons, and a few in the striatum acquired cholinergic interneuron fate. Patch clamp analysis both in vitro and in vivo revealed functional neuronal characteristics and synaptic connectivity, although a more mature neuronal phenotype was achieved in vivo. In conclusion, functional striatal MSNs and interneurons can be generated using hPSCs, which will be invaluable for research into striatal function and dysfunction in HD and other striatum relevant disorders. They may also serve as a desperately needed therapy for HD, pending further preclinical studies in HD animal models.

Creative ideas are those that are both novel and useful. Creativity is considered to be a valuable social resource, which has supported the development of society in myriad domains. It has been suggested that behavioural indicators of creativity overlap with symptoms of Attention Deficit Hyperactivity Disorder (ADHD). Indeed, there is some preliminary evidence to suggest that individuals with ADHD may be more creative than individuals without ADHD. The first chapter of this thesis outlines the relevant research and theory and presents the ‘creative advantage hypothesis’. Specifically it is argued that defocused attention in individuals with ADHD increases the likelihood of unusual associations forming, thus increasing the likelihood of creative responses. The potential mediating roles of inhibition and delay aversion are also discussed. The second chapter of this thesis describes a study designed to test predictions of the creative advantage hypothesis. Parents of pupils in Year 8 were asked to rate their child’s level of inattentiveness and hyperactivity. Sixty six pupils completed a measure of figural creativity, inhibition and delay aversion in school. ADHD symptoms predicted creativity scores on one aspect of creativity, originality, and this effect was found in boys only. Inhibition and delay aversion were not found to mediate the relationship between ADHD symptomology and creativity in boys. Limitations and implications for Educational Psychologists and teachers are also discussed.

Low back pain is a common condition that will affect 80% of the population at some point in their lives. For the majority of people the pain and associated disability will be resolved and they will resume normal activities. For a small proportion of this group however, the condition will remain unresolved with associated long-term pain and disability; this is termed chronic low back pain (CLBP). The costs associated with CLBP are high both physically and emotionally for the individual, and in terms of the economic burden placed on society pertaining to healthcare costs and lost productivity. CLBP is a multifaceted condition. Whilst a biopsychosocial model of care, as opposed to the traditional biomedical model, is advocated as the best approach for its management it has been suggested that the impact on the self-concept and identity of individuals with this condition has not been fully explored or addressed. This study employed a biographical approach with the aim of understanding the impact on the lives and identities of men living with CLBP. Five men were recruited and in-depth interviews were undertaken which were audio-recorded, transcribed verbatim and analysed thematically. The identity of all the participants in the study had been affected by CLBP. Clear themes emerged that included feeling defined by their CLBP, experiencing feelings of frustration and anger, the inability to retain their masculine role, the impact on fatherhood, public and private identities, physicality and feeling a liability or burden to others. The support received from significant others was also highlighted. The participants detailed how exercise and education were major aspects in the management of their condition whilst resilience and the use of humour were also very apparent in their narratives as mechanisms to enable them to cope with CLBP.

No description available.

Organophosphate compounds have been widely developed as pesticides (e.g. paraoxon) and also as chemical warfare agents (nerve agents, e.g. sarin). These compounds rapidly inhibit the enzyme acetylcholinesterase (AChE), causing overstimulation within the cholinergic nervous system. If left untreated, this can be fatal. Current medical countermeasures to nerve agent poisoning consist of pretreatment with pyridostigmine and an emergency therapy comprising atropine, diazepam and pralidoxime. As well as a replacement pretreatment for pyridostigmine, physostigmine has been proposed as a component of a next generation of therapy to nerve agent poisoning, along with scopolamine and HI6. In animal studies, this therapy has been shown to lessen the level of incapacitation and increase survivability post poisoning with nerve agent. The exact mechanism of action of physostigmine in this combination is as yet unclear. The primary aim of this study was to test the hypothesis that the beneficial effect of physostigmine in the proposed therapy is due to reversible inhibition of AChE, thereby protecting it from irreversible inhibition by nerve agent. To test this, extracellular field potentials were recorded from the molecular layer of the dentate gyrus in an in vitro slice model developed from the guinea pig. This response was shown to be modulated by the application of physostigmine and the nerve agent sarin and interactions between the two inhibitors were characterised. The results provided evidence for protection of ChE by physostigmine. The functional response (field potential) was related to cholinesterase activity measured in slices exposed to sarin. This is the first evidence of the mechanism of action of physostigmine protection against nerve agent in the CNS. Not only will these results support the use of physostigmine as a pre-treatment, it also supports its use as a possible immediate therapy.

This dissertation considers coping and psychological well-being in informal carers of stroke survivors with aphasia. Firstly, a literature review examines the main problems reported by this group of carers, the coping strategies they use to manage these problems, and the links between coping and psychological well-being. This is followed by an empirical paper which reports on a study investigating how informal carers of stroke survivors with aphasia cope with communication problems, and examining the links between coping and an aspect of psychological well-being - depressive symptoms. Further, this study also explores the question of how best to measure how carers cope with communication problems, by including questions specifically developed for this topic alongside a traditional coping inventory. As expected, the results demonstrated a relationship between coping strategies and depressive symptoms in this group of carers. The use of avoidant coping strategies was associated with increased symptoms of depression. No links were found between problem-focused coping strategies and depressive symptoms, however it was shown that coping by ‘positive reframing’ was linked with reduced levels of depressive symptoms. The study also found that a traditional style coping inventory gives a useful assessment of the pertinent coping strategies used by informal carers of stroke survivors with aphasia to manage communication problems. However this is usefully supplemented by more specific questioning about the use of avoidance and withdrawal. The study concludes with a discussion of the clinical implications of the results and where future research in this area would be beneficially directed.