Emotional distress is common after stroke and has a negative impact on rehabilitation outcome. The aim of this thesis was to identify factors relating to emotional distress after stroke to inform future interventions. This thesis developed a theoretical framework to guide the study of emotional distress and included stroke and demographic characteristics, background information, disability (personal and extended activities of daily living and aphasia) and psychosocial factors (coping, locus of control and social support). This thesis consisted of three studies. The first study developed and validated the Stroke Cognitions Questionnaire Revised (SCQR), as previous studies used cognitions assessments not appropriate for this population. The SCQR assesses the frequency of positive and negative stroke-related cognitions. The scale was developed from treatment notes of depressed stroke patients. The scale had high internal consistency, inter-rater and test retest reliability, and concurrent validity. Depression (Beck Depression Inventory; BDI) was characterized by a preponderance of negative cognitions and, to a lesser extent, a decrement in positive cognitions. This supports the cognitive model of depression. The second study evaluated factors that predicted the severity of depression in a sample of 112 depressed patients recruited to a randomised controlled trial of cognitive behaviour therapy between one and six months post-stroke. Communication impairment (Sheffield Screening Test for Acquired Language Disorders; SST) at recruitment was predictive of severe depression (BDI) at recruitment. Patients with greater communication impairment (SST) and a more external locus of control (Recovery Locus of Control Scale; RLOC) at recruitment were more likely to remain depressed at six months follow-up. Patients who remained depressed at follow-up were more severely depressed at recruitment. The main study of this thesis evaluated the proposed theoretical framework of emotional distress. In a prospective longitudinal study, 100 patients were recruited from hospital at one month post-stroke and assessed on communication (SST), personal activities of daily living (ADL; Barthel Index), distress (Visual Analogue Mood Scales, Visual Analogue Self-Esteem Scale and Stroke Aphasic Depression Questionnaire). Patients who were not aphasic completed additional assessments of distress (Hospital Anxiety and Depression Scale, Beck Depression Inventory II), recovery locus of control (RLOC), coping (Brief COPE) and cognitions (SCQR). Patients were reassessed on the same measures at six months (n=92), in addition to extended ADL (Extended ADL Index) and social support (Significant Others Scale; SOS). Communication impairment and dependence in personal ADL were predictive of distress at one month. Communication impairment and dependence in extended ADL were predictive of distress at six months. In non aphasic patients, externality of locus of control was also predictive of distress at one months and six months and actual social support was predictive of distress at six months. The relationship between coping and distress was mediated by locus of control. Distress remained persistent at six months post-stroke. The factors found to predict distress (communication impairment, recovery locus of control and activity level) will help identify patients at risk of distress. Also, this demonstrates the need to include aphasic patients. The risk factors are amenable to psychological intervention, such as cognitive behaviour therapy and coping skills training. Future research should evaluate the proposed interventions.

This study provides the result of a doctorate research into the impact of existential psychotherapeutic interventions with people experiencing chronic eating disorders. The results indicate that positive outcomes are correlated to therapeutic interventions which concentrate on the clients own perception of control and choice over their own eating habits. The research aim was to explore both the effects and the effectiveness of existential therapy in altering the individuals subjective interpretation of their Self when they are deeply immersed in the experience of disordered eating. Interventions went beyond the cognitive-behavioural approaches into the implementation of existential psychotherapy which helped individuals to explore the existential concerns of life, choice, hope, social inclusion and love within the context of their own sense of Being. This focus led to an improvement in all study subjects and a reduction in the use of mental health resources. All individuals entered the study following assessment criteria which included chronicity, lengthy use of mental health services and past therapeutic interventions. Three diagnostic criteria were included, Anorexia Nervosa, Bulimia Nervosa and Morbid Obesity. Data presented in the study supported the original premise that all three eating disorders share underlying similarities and justify the inclusion of the diagnostic criteria of morbid obesity within the study. Therapy was either in closed groups or individual and consisted of a fixed number of one-hour sessions. Therapeutic techniques included cognitive-behavioural therapy and person-centred counselling focusing on self-esteem and self-assertion, as well as an existential focus on dualistic perception of the mind/body, the conscious sense of the present and the affective bond with food itself. A series of therapeutic phases were structured to demonstrate the progress from interventions in self-esteem and self-assertion to existential concerns and principles. Taking therapy beyond cognitive-behavioural techniques involved the application of Yaloms' (1980) and Strasser and Strassers' (1997) Existential Therapy and an exploration of Duker and Slades' (1988) concepts of the fragmentation of the sense of Self in individuals experiencing eating disorders. The research demonstrated important differences between the professional perception of appropriate eating and alteration in weight as successful clinical outcomes, and the clients’ dependency on disordered eating as a source of release from interacting with others. Mental health interventions were perceived by clients as attempts to stop such a release without providing a substitute. A clear sense of loss was presented by all study subjects when eating was controlled by others. In most cases disordered eating was habitual and the emotional effects of raised or lowered glucose levels gave a sense of numbness and nothingness which was actively pursued. This was also attained when disordered eating was combined with other self-harm behaviours. Mental health practitioners inadvertently prevented the attainment of a sense of numbness by their focus on eating and body weight. The encouragement of food regimes causes increased anxiety for all clients leading to poor compliance levels. The research results have the potential to impact on mental health education and clinical services as the data indicates that individuals with disordered eating gain more benefit when the therapeutic focus is less on restoring appropriate eating habits and more on the individuals sense of Self; the importance of food intake as a source of escape from others and escape from the internal awareness of Self.

Background: Asthma now affects up to 10% of pregnant women in high income countries and international prevalence is rising. It is already one of the commonest chronic diseases that can complicate pregnancy and previous studies have raised concern that women with asthma have increased pregnancy risks. Precise estimates of the magnitude of these risks and the extent to which they may differ by asthma severity and asthma exacerbation rates, have not been determined. Aim: The overall aim of this thesis was to investigate the impact of asthma and asthma therapies on pregnancy and perinatal outcomes in the general female population. Methods: The Health Improvement Network primary care database from the United Kingdom was used to develop a dataset of women matched to their liveborn children and all data on these pregnancies and on pregnancies ending in stillbirth, miscarriage or therapeutic abortion, were extracted for analysis. Three separate studies were carried out using the developed dataset. First, a cohort design was used to compare fertility rates of women with and without asthma or other allergic disease. Secondly, a cross-sectional design was used to compare risks of adverse pregnancy outcomes and obstetric complications in women with and without asthma. Thirdly, a case-control design was used to compare the risk of congenital malformation in children born to women with and without asthma, and to assess whether asthma medications are teratogenic. Results: A study population of 1,059,246 women was obtained and pregnancies ending in 268,601 matched live births, 986 stillbirths, 35,272 miscarriages and 37,118 therapeutic abortions were identified. Women with asthma or other allergic disease had similar fertility rates (live births per 1,000 person-years) to women in the general population. Women with asthma also had a similar risk of pregnancy ending in stillbirth (Odds Ratio (OR)=1.04, 95% confidence interval (CI) 0.86-1.24)) or therapeutic abortion (OR=0.95, 95%CI 0.92-0.99), but had a small relative increase in risk of pregnancy ending in miscarriage (OR=1.10, 95%CI 1.06-1.13), compared with women without asthma. Risks of most obstetric complications were similar in women with and without asthma, regardless of asthma severity or acute exacerbations, with the exception of increased risks of antepartum haemorrhage (OR=1.20, 95%CI 1.08-1.34), postpartum haemorrhage (OR=1.38, 95%CI 1.21-1.57), depression in pregnancy (OR=1.52, 95%CI 1.36-1.69), caesarean section delivery (OR=1.11, 95%CI 1.07-1.16), preterm delivery (OR=1.15, 95%CI 1.06-1.24) and low birth weight (OR=1.18, 95%CI 1.05-1.32) in their offspring. Compared with children born to mothers without asthma, children born to mothers with asthma had a small increased risk of major congenital malformation (OR=1.10, 95%CI 1.01-1.20), however, this was not found for mothers with currently treated asthma (OR=1.06, 95%CI 0.94-1.20). Gestational exposure to asthma medications was safe apart from cromones which may increase the risk of musculoskeletal malformation. Conclusions: These findings indicate that women with asthma do not have substantially increased risks associated with pregnancy or with perinatal outcomes. Treatment with asthma medications before pregnancy and during gestation also appear to be safe for the mother and for the unborn child, providing support for the current practice of optimal pharmacological management of asthma in women of childbearing age.

While PTSD results in various symptomatology, key characteristics concern a sense of being "stuck" on the trauma which keeps the person reliving it through thoughts, feelings and images and a need to avoid anything which reminds them of the trauma. Such avoidance is suggested to prevent the opportunity for processing and integrating the distressing material. One key clinical question is how to help the person work through their trauma without them becoming overwhelmed by trauma symptoms? Eye Movement Desensitisation and Reprocessing (EMDR) is a relatively new technique that has been reported to help PTSD sufferers reduce the intensity and intrusiveness of traumatic thoughts and images. Despite the growing clinical evidence of the effectiveness of EMDR, a strong debate exists within the research literature regarding its empirical and theoretical validity. One aspect of this dissertation is an experimental study looking at the role of eye movements in Eye Movement Desensitisation and Reprocessing and testing a working memory model of "distress reduction". Of course not everyone who experiences a traumatic event will go on to develop PTSD. An often neglected area of trauma investigation is how some individuals experience positive change and personal growth as a result of their traumatic experiences. This is an area that is now beginning to receive some attention and has been termed Posttraumatic Growth (PTG). The move away from looking exclusively at the impact of trauma to consider how people who have experienced trauma might construct a more positive understanding of themselves in the light of the trauma forms the main section of this dissertation. This exploratory study uses personal experience narratives of posttraumatic growth.

This thesis evaluates the ability of (R,S)- and (R,R)-[125I]-QNB, two radioiodinated diastereoisomers of the high affinity muscarinic antagonist quinuclidinyl benzilate (QNB), to image dynamic changes in cholinergic function in the central nervous system using in vivo autoradiography. The regional uptake and retention of (R,S)-[125I]-QNB in the rat brain between 2 and 24 hours after intravenous administration was investigated to assess the utility of this technique to image muscarinic receptors in the central nervous system. Similarly, the uptake and retention of (R,R)-[125I]-QNB was investigated between 30 mins and 6 hours after administration using in vivo autoradiography and was compared to that of (R,S)-[125I]-QNB. Secondly, the sensitivity of (R,S)- and (R,R)-[125I]-QNB to dynamic changes in cholinergic neurotransmission in vivo, was assessed in conscious rats. The uptake and retention of (R,S)- and (R,R)-[125I]-QNB following a cholinergic challenge produced by administration of the long lasting AChE inhibitor heptylphysostigmine, was investigated. Regional brain levels of (R,S)- and (R,R)-[125I]-QNB in heptylphysostigmine treated animals were compared to levels in saline treated animals by in vivo autoradiography. The ability of ACh to displace (R,S)- and (R,R)-[125I]-QNB binding from rat brain sections in vitro in the presence of heptylphysostigmine was also investigated. Finally, the effects of heptylphysostigmine administration on regional cerebral blood flow were investigated using [14C]-IAP autoradiography in conscious rats. Three hypotheses were considered to account for the lack of radioligand displacement observed following heptylphysostigmine administration: 1) Heptylphysostigmine was ineffective in inhibiting AChE and raising synaptic ACh levels at the dosage used in this thesis. 2) A small amount of displacement occurred but was masked by the effects of increased cerebral blood flow. 3) (R,S)- and (R,R)-[125I]-QNB are of too high affinity for mAChRs to be displaced by endogenous neurotransmitter. The third hypothesis is viewed as the most plausible. In conclusion, (R,S)- and (R,R)-[125I]-QNB are unsuitable ligands for the detection of cholinergic function in vivo.

In decerebrate rats, recurrent inhibition between lateral gastrocnemius-soleus (LG-S) and medial gastrocnemius (MG) motor pools was assessed by conditioning monosynaptic reflexes elicited from the cut dorsal roots and recorded either from the LG-S and MG nerves by antidromic volleys delivered to the synergist muscle nerve. The results show that following sciatic nerve crush in both experimental groups there is a significant sustained depression in the level of recurrent inhibition. The reduction in recurrent inhibition observed is less in adult animals when comparisons are made with the results from rats given the nerve injury early in postnatal life. However, following lateral gastrocnemius-soleus nerve crush instead of sciatic nerve crush, which shortened the dennervation time respectively, the reduction of recurrent inhibition was not observed in adult rat group and was much less in 5-day-old rat group. In addition, the different contributions of the recurrent inhibition between LG-S and MG motor pools are dedifferentiated as a result of nerve injury. It is proposed that this reduction of recurrent inhibition occurs due to degeneration of motor axon collaterals following the nerve injury. Such degeneration has been observed in the cat following axotomy (Havton & Kellerth, 1984, 1990a). The maintained reduction of recurrent inhibition may therefore be a consequence of a failure of regenerating axon collaterals to re-establish contact with Renshaw cells and/or alterations in the membrane properties of the injured motoneurones. However, this kind of degeneration may not occur if dennervation is short enough. In conclusion, this observed reduction of recurrent inhibition may contribute to the hyperreflexia reported in young animals following nerve crush (Navarrete et al., 1990) and that the results in this study support the view that peripheral nerve injury induces plastic changes in the behaviour of spinal circuitry.

Apolipoprotein E (apoE denotes protein: APOE denotes gene) is a lipid-transport protein abundantly expressed in the brain and strongly upregulated after acute brain injury. The APOE e4 allele is the major genetic risk factor for Alzheimer’s disease (AD) and has been associated with poorer outcome after various types of acute brain injury, including traumatic brain injury and subarachnoid haemorrhage. However, the role of APOE genotype in focal ischaemic stroke is less clear. The mechanism(s) by which APOE genotype may modulate outcome after acute brain injury are also unclear at present. Accordingly, the studies described in this thesis were undertaken to further address these issues. 1. Endocytic pathway alterations in human temporal lobe after global cerebral ischaemia and association with APOE genotype. 2. Characterisation and validation of the intraluminal filament model of focal cerebral ischaemia in C57BI/6J mice. 3. Association between APOE genotype and differences in outcome and endocytic pathway alterations after focal cerebral ischaemia in mice. 4. Adenovirus-mediated gene transfer of APOE e3 markedly reduces ischaemic brain damage after focal cerebral ischaemia in mice. The data presented in this thesis indicate an important role for APOE genotype in modulating outcome after ischaemic brain injury, further highlighting the favourable effects associated with the APOE e3 allele. APOE genotype-dependent alterations in the endocytic pathway are mechanisms which could contribute to differences in outcome. These data also highlight the neuroprotective effects achieved by manipulating apoE levels to promote the beneficial effects of apoE3. An apoE-based therapeutic strategy may be a potential approach for treatment of ischaemic brain injury in humans.

This thesis presents an exploratory case study evaluation of a dramatherapy intervention in a key stage three and four pupil referral unit for permanently excluded young people. Dramatherapy is a creative arts therapy concerned with the relationship between the therapist and the client using the medium of drama or theatre to make sense of life experiences (Landy, 2006). Existing literature suggests that this is a relatively under-researched topic, and there is a need for evidence-based practice to support the use of dramatherapy (Dokter, Holloway & Seebohm, 2011). Through continued engagement with the literature and subsequently the participants and dramatherapists, the research began to take more of an exploratory path, investigating whether change had occurred in dramatherapy and if so why this could have happened. This change was reflected in the research questions. The research questions focused on the perceived changes that were observed by the participants themselves, their dramatherapists or a member of school staff during the period of the intervention; if changes were perceived what within the intervention could have helped bring the changes about, and what factors external to dramatherapy could have influenced the process of the intervention. A pragmatic, mixed-methods approach was initially adopted for this study. A pilot phase, evaluating the perceived impact of dramatherapy for five participants who were receiving dramatherapy was used to guide the development of quantitative measures in the evaluation phase. Three young people participated in the evaluation phase of the study. A single case experimental design was used to help evaluate perceived changes during dramatherapy and in order to explore whether is was possible to measure change in a dramatherapy intervention. This aimed to support the over-riding qualitative element of the study, involving post-evaluation phase semistructured interviews with the three participants, their dramatherapists and one or more member of school staff. Visual analysis of the single case experimental design graphs suggested that the measures may not have been valid or reliable indicators of the participants' behaviours. This raised questions of the appropriateness of the use of quantitative measures with vulnerable young people who may have social, emotional and behavioural difficulties. Thematic analysis of the qualitative interviews identified that the participants, their dramatherapists and/or a member of staff had observed that the participants were able to make changes within therapy, and within the pupil referral unit. Thematic analysis identified that factors of the therapeutic space, the relationship, and the use of metaphor and projective techniques were seen to have helped the young people make changes. Thematic analysis identified that the process of the dramatherapy intervention was seen to have been influenced by systemic factors. The findings were examined with reference to the relevant literature. Strengths and limitations of the study were discussed. Potential future research and implications for practice are outlined.

This thesis investigates impairments of written sentence comprehension in 14 aphasic adults. The primary purpose of the research was to apply computer technology to the process of assessment, with the aim of improving diagnostic precision and thereby being able to offer better-targeted and more effective treatment. To facilitate the study of sentence processing disorders a microworld was developed, populated solely by animate and inanimate balls, boxes and stars. This medium had two major advantages over natural English. Firstly, the restricted vocabulary and the small set of grammatical structures used permitted finer control of the linguistic environment, and secondly, all the test sentences were fully reversible with equal plausibility. The microworld formed the basis for a suite of patient-controlled computer programs dedicated to the study of two functions: the processing of verbs and the processing of locative prepositions. Computerisation enabled automatic, detailed and objective data collection in assessment mode, freeing the observing clinician to make important complementary observations. In remediation mode the software externalised the subtasks of sentence comprehension for clinical study. The results of an efficacy study are reported in which the aphasic subjects were divided into two groups of seven and subjected to a cross-over design experiment. Group A received verb treatment before preposition treatment and Group B received the treatments in opposite order. Significant treatment effects were obtained which could be attributed confidently to the intervention applied and which included generalisation to 'real world' reading tasks. Many of the subjects maintained benefit of treatment after a non-treatment interval of five months. The thesis presents a range of new data on aphasic performances including details of error patterns, response latencies and susceptibility of the different sentence structures to treatment. In addition the aphasics are compared with 45 normal subjects in their computer interface operation and on a new six-module Syntax Screening Test. Theoretical contributions to knowledge are made in the establishment of the dissociability of verb and preposition processing and in the interpretation of the clinical observations. The microworld and software created have potential application in many other areas of language research.

Myoclonus dystonia (MD) is a neurogenic movement disorder that can be caused by mutations in the SGCE gene encoding ε-sarcoglycan. ε-sarcoglycan belongs to the sarcoglycan family of cell surface-localised, single-pass transmembrane proteins originally identified in muscle where they form a heterotetrameric subcomplex of the dystrophin-associated glycoprotein complex (DGC). Mutations in the SGCA, SGCB, SGCG and SGCD genes encoding α-, β-, γ- and δ-sarcoglycan cause limb-girdle muscular dystrophy (LGMD). There is no phenotypic overlap between MD and LGMD. LGMD-associated sarcoglycan mutations impair trafficking of the entire sarcoglycan complex to the cell surface and destabilise the DGC in muscle, while MD-associated mutations typically result in loss of ε-sarcoglycan from the cell surface. This suggests cell surface ε-sarcoglycan but not other sarcoglycans is required for normal brain function. To gain insight into ε-sarcoglycan’s function(s) in the brain, immunoaffinity purification was used to identify ε-sarcoglycan-interacting proteins. Ubiquitous and brain-specific ε-sarcoglycan isoforms co-purified with three other sarcoglycans including ζ-sarcoglycan (encoded by SGCZ) from the brain. Incorporation of an LGMD-associated β-sarcoglycan mutant into the brain sarcoglycan complex impaired the formation of the βδ-sarcoglycan core but failed to abrogate the association and trafficking of ε- and ζ-sarcoglycan in heterologous cells. Both ε-sarcoglycan isoforms also co-purified with β-dystroglycan, indicating inclusion in DGC-like complexes. Additionally, the brain-specific ε-sarcoglycan isoform co-purified with the perineuronal net component tenascin-R, potentially suggesting a unique function for this isoform in modulating synapses. In common with SGCE, transcripts from the genes encoding α-, β-, δ-, γ- and ζ-sarcoglycans were found to undergo extensive alternative splicing, in some cases producing novel isoforms that affected assembly and trafficking of the sarcoglycan complex. In summary, data presented herein show that alternatively spliced sarcoglycan isoforms are part of the DGC in brain. These data contribute to our understanding of MD pathophysiology and the role of the sarcoglycan protein family.