The Drosophila nervous system undergoes structural synaptic plasticity, however, the mechanisms that govern such event are little understood. Structural synaptic plasticity in mammals is regulated by the neurotrophin brain derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase full length (TrkB-FL). TrkB-FL has a tyrosine kinase domain (TyrK) intracellularly, that is required for its function in structural synaptic plasticity. Trk receptors have long been sought in Drosophila to verify mechanisms of structural synaptic plasticity, but they have not been found. Later, the Kek receptor family was identified as the kinaseless-Trk homologues in flies (Mandai et al., 2009, Bishop, 2013). Here, I validated that Kek-6 is a neurotrophin receptor for DNT2. DNT2 is a novel retrograde factor at the neuromuscular junction (NMJ), and both DNT2 and Kek-6 regulate structural synaptic plasticity. Kek-6 functions in concert with Toll-6. DNT2 and Kek-6 function upstream of CaMKII and Vap33A at the NMJ synapse. Finally, I show that Kek-6 can regulate intracellular levels of calcium in larval motorneurons. In conclusion, I identified a novel mechanism of structural synaptic plasticity in flies that is independent of a TyrK domain. If there are conserved mechanisms, this may also shed light on how truncated Trks function in the adult mammalian brain.

This thesis was submitted in partial fulfillment of the degree of Doctor in Clinical Psychology at the University of Birmingham. The thesis comprises of two volumes. Volume I is concerned with developing a psychological understanding of the psychological impacts and experiences of individuals’ affected by complex grief. It contains three chapters: a meta-ethnography, an empirical paper and a public dissemination document. The meta-ethnography critically reviews qualitative literature of couple’s experiences of a subsequent pregnancy and parenting following a pregnancy loss through miscarriage, stillbirth and/or neonatal death, and provides a higher-level interpretation of these findings. The empirical paper uses Interpretative Phenomenological Analysis (IPA) to conduct an exploration of the lived experience of family members bereaved by heroin overdose. The findings were explored in relation to their applicability to existing models and theories of bereavement. The public dissemination document provides a brief summary using simple language of the first and second chapters, to be accessible to a wider audience. Volume II consists of four clinical practice reports and a summary of an oral presentation describing clinical work undertaken on clinical placements.

The use of cannabis has been found to be prognostic of poorer symptomatic outcome among people with first-episode psychosis. It is therefore important to understand what motivates the use of cannabis in this population. Using a twelve month prospective design this research aimed to quantitatively assess the impact of cannabis use on the symptoms of psychosis, mania, depression and the level of functioning among people with first-episode psychosis. The research also aimed to identify if the motives for cannabis use, such as reasons and expectancy, a person's social network and self-perceived social status may be associated with cannabis use, cessation or abstention. Qualitative methods were also used to explore the factors that the participant perceived to relate to cannabis use and cannabis abstention among people experiencing their first-episode of psychosis. This research found the continued use of cannabis to be associated with increased severity of mania and to impede recovery in psycho-social functioning. The results suggest that similar reasons and expectancies motivate the use of cannabis in young people with and without psychosis. Concern regarding the potential adverse effect of cannabis use on mental health was found to be influential for cannabis cessation and abstention; and abstention from cannabis was also associated with greater negative cannabis expectancy. The sample sizes in this research may have meant that a small number of analyses were underpowered to detect significant differences for some variables. Nevertheless, the results of this research highlight the deleterious effect that continued use of cannabis may have for II people experiencing their first-episode of psychosis. Psycho-education regarding the potentially adverse effects of cannabis use may help to enhance current intervention efforts among this population; however intervention must emphasise "normal" motives for cannabis use rather than psychosis specific motives.

This thesis was submitted in partial fulfilment of a doctorate in Clinical Psychology and is composed to two volumes. Volume One contains the research component which includes a systematic literature review that investigates the role of fathers in the development of eating disorders, and an empirical study which explores the influence of Anorexia Nervosa upon family functioning. The clinical component of the thesis is presented in Volume Two in the form of five clinical practice reports. The first clinical practice report describes the case of a 78 year old woman suffering from agoraphobia and panic attacks that was formulated from Psychodynamic and Cognitive-behavioural approaches. The second report outlines a service evaluation that explored staff’s adherence to new policies within a dementia service. The third report describes a case study of a course of Person-centred Therapy with a 31 year old woman suffering from social anxiety and low mood. The fourth report describes an AB single case experimental design of Schema Therapy with a 17 year old girl diagnosed with Anorexia Nervosa. The fifth report outlines a case study of Psychodynamic assessment and indirect intervention of a 56 year old man diagnosed with a mild learning disability and Bipolar Affective Disorder.

This thesis examines the neurocognitive biases of body-specific emotional processing in those predisposed to latent biases of depersonalization / derealization (DP/DR) experience. DP/DR is characterised by dissociative feelings of self-consciousness and dulled emotional experience. Emotional arousal was recorded via psychophysiological measures (skin conductance responses: SCRs, and body temperature) in relation to salient, body-related stimuli consisting of aversive simulated body-threats (e.g. injection procedures and fingernail removal). Body-threats were delivered either directly to the participant’s body, observed on a second individual present in the same room, or observed via dynamic movie clips. The principal findings across all empirical studies demonstrated significantly reduced emotional arousal (SCRs) to aversive body-threats in those predisposed to DP/DR experiences. That is, emotional suppression was observed for body-threats delivered to the “self” (participant’s own body), and when observed on “others” in the same room and via movie clips. Crucially, this suppression was specific to aversive body-threat stimuli, and was not observed for baseline (non-body-related) stimuli or measures of baseline / anticipatory arousal. Body-temperature was not mediated by DP/DR experience. Collectively, this work significantly extends previous research and theoretical accounts of DP/DR by utilising aversive body-related stimuli to demonstrate selective biases of emotion regulation in non-clinical instances of DP/DR.

Research indicates that the way in which a clinical diagnosis is delivered impacts on the quality of life post diagnosis. This study explores local and global discursive influences on diagnostic feedback of dementia diagnosis across two NHS memory assessment services. Eight feedback sessions were audio-recorded over a three month period. The recordings were transcribed and analysed using a discourse analytic approach. The transcripts were analysed in terms of their interpersonal and wider discourse features and the ways in which meanings were constructed in the delivery of a dementia diagnosis. The findings suggest that carers, clients and practitioners construct dementia as largely a memory problem, drawing on wider discourses which associates memory with the mind, and that there are interpersonal advantages in downplaying the range of cognitive difficulties that dementia involves. Clinical implications such as post diagnosis procedures and the scope for future research examining the diagnostic delivery methods of different health professionals are presented.

Schizophrenia is a serious psychiatric disorder characterised by a breakdown in thought, emotion and perception, which leads to alterations of normal behaviour and feelings, a withdrawal from reality and an impression of mental defragmentation. Of the positive, negative and cognitive symptoms, the positive symptoms are perhaps the most striking. However, it is the severity of cognitive deficits that are most closely associated with a patients’ functional outcome in the long-term. Despite this, the successful treatment of the cognitive deficits has been met with difficulty, partly due to a lack of suitable animal models. There is an urgent need for animal models with appropriate face, construct and predictive validity for schizophrenia so that improved drug targets can be identified, and new drugs tested. In 2012, Winchester et al. discovered that sequence variations in the Map2k7 gene were associated with increased risk for schizophrenia, and Map2k7 mRNA was decreased in the prefrontal cortex of the post mortem brains of patients. The primary aim of this thesis is to behaviourally and molecularly characterise mice which are heterozygous for Map2k7 (Map2k7+/- mice) as a potential animal model of relevance to schizophrenia. Sequence variants in the Map2k7 gene are moderately common in the population and they almost double the disease risk (OR~1.9); hence, alterations of the Map2k7 gene in mice represent an ideal basis for an animal model with good construct validity. The Map2k7 gene produces the MKK7 protein, a kinase within the stress-activated JNK pathway, and is involved in a diverse range of cellular processes, such as apoptosis, synaptic plasticity and regulation of the immune response. First and foremost, the components of the MKK7/JNK pathway were quantified in Map2k7+/- mice and MKK7γ was found to be significantly decreased in the prefrontal cortex compared to their wildtype (WT) littermates, a highly disrupted brain region in patients with schizophrenia. Map2k7+/- mice also exhibited behavioural phenotypes relevant to schizophrenia: hyperactivity in the open field and attentional dysfunction. Minocycline showed promise in alleviating the attentional deficits and hyperactivity in the open field, but did not influence protein levels of signalling pathway components. Map2k7+/- mice did not show a decrease in sensorimotor gating as many patients do; however, they exhibited signs of altered response to amphetamine administration just prior to testing of sensorimotor gating, compared to WT mice. Decision-making abilities were also investigated: Map2k7+/- mice showed normal learning and performance of the rodent gambling task. Additionally, all mice were able to alter their choice pattern to be more optimal when the task contingencies were subtly switched, which was the first time this has been shown in mice in the touchscreen apparatus. However, when the task demands were altered such that ‘punishment’ no longer featured as prominently, Map2k7+/- mice showed huge difficulty compared to their WT littermates in shifting their choice pattern to be more optimal, suggesting they have a deficit in aspects of cognitive flexibility. Finally, Map2k7+/- mice were investigated as a gene x environment interaction model, by injecting pregnant dams with Poly I:C and examining the resultant immune response in maternal serum and embryonic brain. Map2k7+/- dams exhibited an altered immune response to Poly I:C compared to WT dams; however, future experiments will be required to confirm whether this altered cytokine response is also present in embryonic brain. Overall, Map2k7+/- mice show utility for dissecting the cognitive deficits and some aspects of the positive symptoms of schizophrenia that could be targeted by novel compounds. This would be aimed at restoring the function of the MKK7/JNK pathway. Further molecular and behavioural characterisation will be required, particularly into the potential gene x environment interaction model. Although no mouse model can recapitulate the full symptom spectrum of a human neuropsychiatric disorder, Map2k7+/- mice exhibit an interesting accumulation of phenotypic abnormalities relevant to schizophrenia.

Young people with Autism Spectrum (AS) are a population at risk of experiencing Mental Health Problems (MHPs); with anxiety being the most commonly reported internalising MHP for this population (Skokauskas & Gallagher, 2012). Schools have been identified as well placed to support pupils experiencing MHPs (DoH & DfE, 2017). The primary aim of the present research was to evaluate the Homunculi Approach (Greig & MacKay, 2013b) as an intervention for secondary aged pupils with AS experiencing anxiety. The secondary aim of the research was to explore factors affecting implementation of the Homunculi Approach. An embedded mixed methods design was utilised where the primary research aim (Phase 1) was supplemented by the secondary research aim (Phase 2). Phase 1 consisted of an A-B single case experimental design (SCED) with four participants across four different secondary schools. Anxiety was measured through: repeated behavioural observations and a weekly anxiety questionnaire (PI-ED); pre and post intervention measures, completed by the young people, parents and teachers (SCAS, SAS-TF and SDQ); and measures which occur organically within the Homunculi Approach intervention. Phase 2 of the research explored the factors which affected implementation of the intervention in schools by interviewing the school staff who delivered the Homunculi Approach. The data was collected using an activity theory framework. The findings from the research indicated the intervention was effective in reducing anxiety for two participants, and ineffective in reducing anxiety for the other two participants. Several implementation factors were identified which may have impacted on the effectiveness of the Homunculi Approach when delivered by members of school staff in secondary schools. The findings are discussed in relation to the literature. Limitations of the research, such as the small sample size and possible impact of external factors, are acknowledged. Possible implications and ideas for future research are presented.

Background Many randomised controlled trials (RCTs) are available to support using different pharmacotherapy agents in the management of various neuropathic pain conditions. However, choosing these pharmacotherapy agents for neuropathic pain is challenging, due to the limited evidence-based knowledge to support the use of different pharmacotherapy agents in different neuropathic pain conditions. Aims The aim of this PhD is to evaluate the efficacy and safety of oral and topical pharmacotherapies for managing neuropathic pain by deriving placebo and active comparative efficacy and safety evidence from RCTs. Methods This research used three approaches to summarise and synthesise evidence from randomised controlled studies including: a systematic review of placebo and active control RCTs to summarise and criticise the current evidence in neuropathic pain; a meta-analysis and sequential analysis of eligible studies to provide a more precise estimate of the overall treatment effects; and a network meta-analysis to estimate the relative effectiveness of the most commonly used interventions in neuropathic pain. Results Systematic review Two hundred placebo and active-controlled trials met the inclusion criteria. A wide range of different treatments were studied in these trials, including anticonvulsants, antidepressants, opioids and topical capsaicin and lidocaine. Most of the included studies were parallel placebo-controlled trials and commonly lasted for 3 to 12 weeks. In addition, the vast majority of the included RCTs were conducted in participants with painful diabetic neuropathy and post-herpetic neuralgia, while only a few trials were conducted in participants with central neuropathic pain conditions. Pairwise meta-analysis Sixty seven trials were eligible for the pairwise meta analysis of efficacy outcomes. Of the anticonvulsants group pregabalin and gabapentin compared with placebo demonstrated efficacy for 50% and 30% pain reduction and global improvement in patients with neuropathic pain. The efficacy of anticonvulsants varied in different types of neuropathic pain. Gabapentin when compared against a placebo was better than a placebo in PHN and PDN, while pregabalin was significantly effective in patients with post-herpetic neuralgia (PHN) and painful diabetic neuropathy (PDN) but not in patients with HIV associated neuropathic pain. Others anticonvulsant agents, such as lamotrigine, valproic acid, topiramate, levetiracetam and oxcarbazepine, were tested in a small number of trials. These did not provide useful benefits compared with a placebo for a 50% and 30% pain reduction. Of the antidepressant group, duloxetine when compared to a placebo demonstrated efficacy for 50% and 30% pain reduction in diabetic neuropathic pain. A few active comparison trials failed to demonstrate superior efficacy of one drug over another for a 50% and 30% reduction in neuropathic pain. Trial sequential analysis To examine the reliability and conclusiveness of the available evidence, trialsequential analysis has been applied in this study. The results show convincing evidence of the efficacy of some interventions (e.g. pregabalin, gabapentin and duloxetine) to reduce pain by 50% in some neuropathic pain conditions (e.g. diabetic neuropathic pain and post-herpetic neuralgia). The continuation of RCTs of pregabalin and duloxetine in diabetic neuropathy and gabapentin in post-herpetic neuralgia is not necessary as there appears to be sufficient evidence of the efficacy of these treatments in the management diabetic neuropathic pain and post herpetic neuralgia. Further RCTs of duloxetine, pregabalin and gabapentin are however required for central neuropathic pain. In contrast, the analysis failed to provide evidence that opioids and high concentration capsaicin demonstrate a 50% pain reduction. Network meta-analysis Twenty-eight trials were eligible for the network meta-analysis. The results incorporating both direct-comparison and indirect-comparison evidence suggested that there is no superiority of duloxetine over amitriptyline, pregabalin and gabapentin in achieving at least a 30% and 50% pain reduction with a treatment duration of 7 to 12 weeks in patients with neuropathic pain conditions, such as diabetic neuropathic pain, postherpetic neuralgia and spinal cord injury. Conclusions In summary, this research has found that some good quality trials provide good evidence regarding the efficacy of duloxetine, pregabalin and gabapentin in a minority of patients with neuropathic pain. Until advancements in developing mechanism-based approaches and improved clinical trial design become available, the routine use of these medications is unlikely to be changed. This may support the hypothesis that traditional RCTs might not be a suitable method of choice to address provisional health questions in routine clinical practice.

Magnetic Resonance Imaging allows electromagnetic properties of the brain to be measured in vivo, providing new markers of structure at a microscopic level. Evaluation of the local complex signal evolution observed using a multi-echo gradient-echo (MEGE) sequence can allow the electromagnetic and relaxivity properties of individual tissue compartments to be accessed. The phase evolution carries valuable information about the different compartments, but is dominated by non-local, large-length-scale field variations which present the main challenge in processing complex MEGE data. In this work 2-compartment and 3-pool models are used to describe signal evolution from a mixed tissue and venous compartment and from white matter, respectively. A new method for removing the effects of non-local field variations without corrupting local non-mono-exponential phase evolution is proposed. The 2-compartment model of venous blood complex signal has been used to access the vascular dependence on orientation and oxygenation levels, and has been validated against existing methods on large distinguishable veins. A phantom consisting of capillary tubes filled with ferritin solution immersed in a water bath has been used to validate the 2-compartment model and the estimated frequency offsets between the ferritin and water compartments at multiple orientations to B⃗0 shown to agree with predictions of theory. White matter in the corpus callosum has been investigated using a saturation-recovery MEGE sequence with variable flip angles with the aim of revealing differences in the T1-relaxation properties of the myelin, the external and the intra-axonal water compartments. The results show that the relative saturation of the myelin water compartment decreases with increasing flip angle and is consistent with there being a short-T1 component associated with myelin water. However, the observed signal behaviour shows less contrast than expected based on the findings from the previous studies. This could be related to differences in exchange rates between compartments. Finally, diffusion-weighted, asymmetric spin-echo imaging was used to simultaneously investigate the diffusivity and electromagnetic properties of the external and intra-axonal compartments of white matter. This approach could provide additional information about white matter microstructure. Asymmetry of the spin echo sequence was achieved by delaying the acquisition by ∆t. The preliminary results show an increase in the scaled magnitude with echo delay at a constant b-value in some regions of the corpus callosum. The preliminary results are promising, but further investigation and method development are required. This thesis has investigated a number of novel methods of studying white matter structure and cerebral microvasculature.