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.

Turning around to interact with the environment is a common activity of daily living. The location of a target for interaction may be known or unknown prior to turning and the angle of a turn may vary depending on the task to be carried out. Stroke and Parkinson’s disease could compromise coordination of body movement during turning which may pose a risk for instability and subsequent falls. The sequence of onset latency, peak velocity and timing of peak velocity of body segments (eye, head, shoulder, pelvis and foot) while turning on-the-spot were investigated in people with stroke and age-matched healthy controls (study 1) and in people with Parkinson’s disease and age-matched healthy controls (study 2). The effect of target predictability, turn angle and turn direction on the sequence of the movement of the body segments were also investigated. Participants were asked to stand in front of a light and either turn to a specific light (predictable condition) or locate and turn to a random light (unpredictable condition) placed at 45°, 90° or 135° to the right or left when the light in front extinguished. The results showed that the people with stroke and Parkinson’s disease (PD) initiated the movement of the segments later, had lower peak velocities and attained the peak velocities later than their control counterparts. People with PD showed more simultaneous onset of rotation of body segments as compared to their age-matched control when turning to 135°. The sequence of onset of rotation of the body segments was similar between the people with PD and their age-matched controls for all the other turning tasks. People with stroke also had comparable sequence of onset of rotation of body segments with their age-matched controls for all the turning tasks. While people with stroke presented with consistent pattern of peak velocity of the body segments for all the turning tasks, their control counterparts showed differences in the pattern of the peak velocities when turning to dominant and non-dominant sides. People with PD showed similar peak velocities of pelvis and foot when turning 45° to initially affected side as compared to separate peak velocities of the pelvis and foot in the stroke and control groups. The peak velocities of the segments (head, shoulder, pelvis and foot) occurred at more or less the same time for most of the turning tasks. Impairment of the relative movement of body segments during functional tasks could challenge the balance of an individual. The sequence of movement of body segments in the different tasks could therefore be related to balance during turning to identify which of the strategies of turning could present with risk of falls. Predictability of a target, turn angle and turn direction should be considered when developing interventions to avoid falls during turning and strategies for improving speed of reacting to perturbations should be developed for people with stroke and Parkinson’s disease.

In ammation is recognised as an important contributor to Alzheimer's disease (AD) pathogenesis alongside extracellular deposits of amyloid β protein (Aβ) and intraneuronal deposits of hyper-phosphorylated tau protein. Microglia are the key component of innate immunity within the central nervous system, and the source of in ammation in the brain. The amyloid cascade hypothesis places Aβ at a key point in the pathogenesis of AD. Consequently, immunisation against Aβ is a promising experimental treatment for AD. The current study presents a neuropathological follow-up of a unique cohort of AD patients who took part in the active Aβ42 immunisation clinical trial (AN1792, Elan) and in whom reduction in Aβ load had been observed. The hypothesis of the study is that Aβ42 immunisation affects the microglial activation level and profile associated with the reduction in Aβ. Levels of the microglial markers indicative of specific microglial functions, the microglial receptors involved in antigen recognition and uptake, complement component C1q, IgG, Aβ42 and phospho-tau in the brain tissue (frontal, temporal and parietal lobes) of immunised (n=11) and non-immunised (n=28) AD patients were analysed using immunohistochemistry. In immunised brain, a two-fold reduction in Fc receptor I (P=0.001) and Fc receptor II (P=0.002), a ten-fold reduction in macrophage scavenger receptor A (P <0.001), and a 40% reduction in lysosomal glycoprotein CD68 (P=0.018) compared to non-immunised brain were observed. Similarly, Aβ42 and phospho-tau levels were also decreased by 80% and 40% respectively. No changes in the microglial activation and antigen-presentation receptor HLA-DR, calcium-adapter channel Iba-1, or the levels of IgG and C1q were detected. The load of all microglial markers, IgG and C1q correlated with the phospho-tau load in non-immunised cases. In addition, Iba-1 and Fc RII load inversely correlated with Aβ42 load in the non-immunised group. These correlations no longer held in the immunised group. Instead, a positive correlation between the number of MSR-A positive microglial clusters and Aβ42, and an inverse correlation between C1q and Aβ42 were noted in immunised AD cases. The current study is the first of its kind in presenting a detailed immunohistochemical profile of microglia in human AD and following active Aβ42 immunisation treatment. In addition, a consistent and reproducible method for automated microscopy image analysis was developed as part of this project contributing to research methodologies. The results support the changes in the level and profile of microglial activation implied by the hypothesis. The data also suggest a link between immune system activation and the tau pathology in AD. The ability of microglia to change their profile and switch targets following stimulation by active immunisation is demonstrated in human brain.

Artificial synaptic plasticity is a programming approach used in artificial neural simulations to replicate the change in efficacy between two synapses observed in biological neurons. This biological synaptic plasticity is thought to enable neurons to control the connections between them. This control is then thought to lead to complex behaviour such as path integration. This stochastic process of activity dependent biological synaptic plasticity forces groups of neurons to operate together. The operation of large subsets of neurons underlies the cognition and memory formation in animals, without which life could not flourish. The most well studied region in the brain for synaptic plasticity is the hippocampus.This region was the first to display both long term potentiation, as well as long term depression. It has also been implicated in memory retention and has been shown to display spatial tuning. Furthermore, the discovery of place cells, and the more recent discovery of grid cells has created a surge of interest in the region. Entirely plausible models for grid field, place field, and memory formation have been suggested. The hippocampus could very well be the first brain region to be understood which does not represent purely sensory input. This thesis applies the rules of activity dependent synaptic plasticity to the hippocampus by modelling the region in silicon. This model focuses on the head direction cells, grid cells, and place cells. The head direction cells are generated using rotational inputs. The grid cells are then generated using both head direction input and forward motion inputs. Finally, the place cells are created using grid cell inputs. To facilitate the construction of this model, a simulator has also been created.

Spinal cord injury (SCI) leads to severe functional deficits and currently there are no effective treatments. In addition to the initial mechanical damage to axons, neurons and glia, traumatic injury also triggers a complex array of cellular and molecular events. Some of these processes are thought to contribute to mechanisms of progressive damage (secondary mechanisms) whilst others concurrently promote limited repair. Functional outcome depends on the interaction of these two processes. However, the interacting dynamics and time course with which they impact the functional outcome is not fully understood. Secondary processes are studied with molecular and anatomical approaches and loss of axons or neurons are used to infer reduced function. Similarly, recovery of functional outcome is mostly assessed using behavioural approaches. However, these are unable to differentiate recovery due to compensatory plastic changes in the brain which might contribute to recovery. Therefore, the first aim of the thesis was to develop an electrophysiological approach to directly assess functional changes in spinal cord circuits following a contusion SCI. The second aim was to use this protocol combined with behavioural testing in order to investigate the use of human embryonic stem cell derived mesenchymal stem cells (hESC-MSCs) as a potential therapy for spinal cord injury. An electrophysiological approach was used to assess spinal cord function after contusion injuries at the cervical (C6) level of the rat spinal cord. Contusion injuries due to high velocity impact were made using an Infinite Horizon Impactor device. Cord dorsum potentials (CDPs) evoked by supramaximal electrical stimulation of a radial nerve (to activate sensory fibres) or within the pyramids (to activate corticospinal fibres) were used to measure changes in the function of these fibre systems in the vicinity of the injury. Animals were investigated at different time points from acute up to 6 months post injury to characterise the temporal progression of changes in spinal cord function. Contusion injury produced an immediate substantial reduction in sensory circuit function which was highly localized to the site of the impact. However, CDPs continued to be evoked both above and below the injury site. This suggests that the main sensory axons in the dorsal column which carry impulses past the level of the injury are not substantially affected and deterioration of function at the injury centre is a result of damage to the neurons and axon collaterals located at the site of impact. Further worsening occurred over the following 3 days but was more marked above the level of the injury possibly because it is due to demyelination of the main sensory axons. However, CDP mapping at 2 weeks showed almost complete recovery of the potentials above this compared to 3 days reflecting a repair mechanism which is possibly remyelination. The fact that CDP amplitudes at 2 weeks are very close to those recorded immediately after injury suggests that most of the loss of function produced by the contusion is due to primary mechanical trauma and that secondary mechanisms contribute relatively little to the loss of function. CDP amplitudes recorded 4 weeks, 7 weeks and 3 months after injury remained closely similar to 2 weeks suggesting a prolonged period of stability in the sensory system. However, a later phase of deterioration is observed at 6 months below the injury possibly due to extension of the injury cavity causing further neuronal loss. Histology also revealed significantly larger cavities in 6 month survival animals. CDPs evoked by stimulation of the corticospinal tract below the injury level were profoundly depressed immediately following a contusion reflecting extensive damage to the main component of the CST in the dorsal columns while potentials above the injury were not acutely affected. There was a further reduction in CDP amplitudes rostral to the injury at 3 days due to demyelination or die back of CST fibres in the dorsal columns. Substantially this improved at 2 weeks and then remained stable up to 6 months. Below the injury there was a gradual increase in the strength of corticospinal connections evident by an increase in CDP amplitudes at 7 weeks which was maximal by 3 months. This reflects plasticity in the spared corticospinal projection probably those in the lateral component. Mesenchymal stem cells (MSCs) from bone marrow (BM) have been reported to promote repair and some functional improvement in animal models. However, autologous transplantation of BM-MSCs has several disadvantages such as the need for invasive harvesting, variable cell quality and slow proliferation. We have successfully derived MSC-like cells from human embryonic stem cells (hESCs) and have found that these cells show anatomical evidence of repair after transplantation in an animal model of SCI (Mohamad, 2014). Delayed transplants of hESC derived MSCs (hESC-MSCs) were performed in a cervical (C6) contusion (175 kdyn) injury model. These cells were transplanted 3 weeks after injury and immunosuppression was begun two days prior to this and continued for the remainder of the study. Functional outcomes were evaluated behaviourally using grip strength and horizontal ladder walking to assess improvement in forelimb function. In electrophysiology experiments cord dorsum potentials (CDPs) evoked by supra-maximal electrical stimulation of a radial nerve or within the pyramids were used to measure changes in the function of these fibre systems in the vicinity of a spinal cord injury at 7 weeks post-transplant. There was a substantial reduction in the gripping ability immediately after the contusion injury followed by a modest spontaneous recovery. Weekly assessment of the grip strength score before and after transplantation revealed no differences in hESC-MSC transplanted and control groups of animals. Similarly, ladder walk analysis revealed loss of co-ordinated forelimb-hindlimb stepping and increased errors of forepaw placement on the ladder rungs after injury. There was no difference in the recovery of co-ordination or improvement of forelimb function after hESC-MSC transplants compared to control animals. Similarly, terminal electrophysiological experiments showed that the amplitudes of CDPs evoked by radial nerve stimulation were closely similar at all recording locations in both groups of animals. However, corticospinal evoked CDPs showed deterioration of function in the transplanted animals compared to the control group of animals. Histology indicated that hESC-MSCs survived in considerable numbers and were present in all transplanted animals at 7 weeks leading to solid infilling of the injury site and a reduction in injury site extent compared to the medium injected control group of animals. In conclusion, the results in the first part of the thesis suggest that maximum damage after contusion injury occurs at the time of injury and spontaneous recovery of function largely mitigates the small amount of the secondary damage. Therefore, injury due to high velocity impact might not be amenable to neuroprotective therapies. Furthermore, evidence of modest spontaneous plasticity in the spared corticospinal system suggests some compensatory plasticity after the injuries.

Transcranial direct current stimulation (tDCS) is a popular non-invasive brain stimulation technique, which has the potential to modulate cortical excitability. The effects of tDCS are known to outlast the stimulation period, and in some cases, repeated applications have been found to produce long lasting clinically relevant effects. The primary aim of this thesis was to explore the reliability and therapeutic potential of this technique. In Chapters 3 and 4 transcranial magnetic stimulation (TMS) was used to measure tDCS effects. These experiments revealed substantial variability regarding the way in which healthy adults responded to stimulation. Notably, there were differences between participants regarding the direction and magnitude of change in cortical excitability. Furthermore, even when group level effects were found reliably, there was substantial intra-subject variability across repeated testing sessions. Subsequent experiments in Chapters 5 and 6, explored the biological and behavioural effects of tDCS in individuals with Gille de la Tourette’s syndrome (GTS). GTS is a neurodevelopmental disorder characterised by motor and phonic tics which have been linked to hyper excitability within motor-cortical regions. Therefore, these experiments aimed to reduce cortical excitability of targeted regions in the hope that this would impact on tics. Disappointingly, no such effects were found immediately after a single session of tDCS (Chapter 5). Consequently, it was hypothesised that repeated applications may be necessary for significant reductions in tics to occur. This was investigated in Chapter 6 using an in-depth case study. The results were encouraging, in particular there was a substantial drop in tics following 10 days of tDCS at 1.5mA intensity. The stimulation was well tolerated and the treatment regimens were closely adhered to, despite tDCS being delivered in the participants own home with remote supervision. A weaker stimulation intensity was not as effective. The findings of Chapters 3-6 highlight that the optimal stimulation parameters may vary from person to person, and that exploration of individual data is critical in therapeutic contexts. The results also suggest that tDCS may be helpful as a treatment for GTS and furthermore highlight the feasibility of home use stimulation.

This thesis compared the effect on weight loss of either replacing diet beverages (DBs) with water or continuing to consume DBs (study 1 in healthy overweight and obese, n=89 and study 2 in patients with type 2 diabetes, n=81) adults during a 24-wk weight-loss program (for study1 and 2) and 18 month weight loss and weight maintenance plan (for study3, n=89). In study 1, compared with the DB group, the water group had a greater decrease in weight (1.2kg more weight loss in the water group compared with the DBs Group ,P=0.015), BMI (0.5 kg/m² more BMI reduction in the water compared with the DBs Group ,P=0.002), fasting insulin (1 mU/l more Fasting insulin reduction in the water compared with the DBs Group,P < 0.001), homeostasis model assessment of insulin resistance (HOMA-IR)(0.2 more HOMA-IR reduction in the water compared with the DBs Group, P < 0.001) and 2-h postprandial glucose(0.305 mmol/l more 2hpp reduction in the water compared with the DBs Group,P < 0.001). In study 2, weight (2.5 kg more weight loss in the water compared with the DBs Group, P=0.005) and BMI (0.9 kg/m² more BMI reduction in the water group compared with the DBs Group, P=0.005) decrease after 18 months in the water group compared with the DBs group was significant. There was also a greater reduction in fasting insulin levels (1.8 mU/l more Fasting insulin reduction in the water group compared with the DBs Group,P < 0.001), better improvement in HOMA-IR (0.5 more HOMA-IR reduction in the water group compared with the DBs Group, P < 0.001), a greater decrease in 2-h postprandial plasma glucose (0.5 mmol/l more 2hpp reduction in the water group compared with the DBs Group, P < 0.001) and glycated hemoglobin (0.2 more HbA1c reduction in the water group compared with the DBs Group, P=0.030) in the water group compared with the DBs over 18 months. In study 3, obese participants with Type 2 diabetes in the water group of study 2 had more weight loss (1.16 kg more weight loss in the water group compared with the DBs Group, P=0.006) and BMI (0.5 kg/m² more BMI reduction in the water group compared with the DBs Group, P=0.006). Also reduction of fasting insulin (1.6 mU/l more Fasting insulin reduction in water group compared with DBs Group,P < 0.001), fasting plasma glucose (0.3mmol/l more Fasting plasma glucose reduction in the water group compared with the DBs Group, P=0.003), HOMA-IR (0.7 more HOMA-IR reduction in the water group compared with the DBs Group, P=0.003) and 2 hour postprandial glucose (0.3 mmol/l more 2hpp reduction in the water group compared with the DBs Group, P=0.027) was greater in the water group. By contrast, changes in waist circumference and lipid profiles were not significantly different between the two groups in these three studies. Replacement of DBs with water after the main meal in obese and overweight healthy and type 2 diabetic women who were regular users of DBs may cause greater weight reduction during 24 weeks and also in the longer period of an 18 month weight management program. In addition, replacement of DBs with water offers clinical benefits to improve insulin resistance. Generally, better improvements in energy and carbohydrate metabolism may occur when water rather than DBs is consumed over a weight loss program.

In this thesis I explored cognition, psychopathology and the role of Catechol-O-Methyltransferase (COMT) in children at increased risk of schizophrenia with the aim of making a contribution to our understanding of the processes that take place early in the development of psychosis. Two samples were studied. The first sample came from the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) where I examined the relationships between a priori selected cognitive domains and psychotic experiences (PEs). The results indicated that impaired processing speed and attention were related to greater risk of PEs in children, with processing speed being a key cognitive feature. Moreover, the relationships between cognition and later occurrence of PEs were similar to those that have previously been reported between cognition and schizophrenia. I also examined whether genetic variation in COMT was associated with PEs indirectly through cognition and anxiety disorders. The findings showed that COMT was indirectly associated with PEs through processing speed, IQ and attention. The second sample comprised children with 22q11.2 Deletion Syndrome (22q11.2DS). I examined the nature and prevalence of psychopathology and cognitive dysfunction in the sample and their siblings and to what extent the children’s intellectual impairment indirectly influences the risk of psychopathology associated with the deletion. There were high rates of psychopathology and cognitive impairments in children with 22q11.2DS. However, I found no evidence for an indirect association between the deletion and the risk of psychopathology through cognition. Finally, there was no evidence that COMT is related to the susceptibility of children with 22q11.2DS to cognitive and psychiatric problems. These findings have potentially important implications for our understanding of the development of psychosis during childhood and they also show that using different research designs to investigate specific aims in samples at increased risk enables the researcher to widen their scope of interpretation.