Growing interest in the research community has been shown in clinical neuroscience to assess neurotransmitter profiling both in healthy and diseased subjects. A large body of research in this field focuses on schizophrenia to characterise its glutamatergic level according to the most recent hypothesis of NMDA (N-Methyl-D-aspartic acid) receptors hypofunction. Magnetic Resonance Spectroscopy (MRS) is able to detect some of the most common neurotransmitters but a number of issues, such as low signal to noise ratio (SNR), spectra overlapping and line broadening prevents MRS from being clinically relevant for neuropsychiatry. Four important aims were considered relevant for this work. Firstly, we aimed to compare the reliability of conventional and timing-optimized sequences for the detection and measurement of most of the visible metabolites and, in particular, for glutamate (Glu), glutamine (GIn) and gamma-aminobutyric acid (GABA) to assess the best available sequence for a study in schizophrenia. Secondly, we also intended to investigate whether glutamatergic activity might predict the oscillatory activity and how this link might survive or not in schizophrenia. Thirdly, we wanted to study whether the well known animal model of schizophrenia, the rearing in isolation model, exacerbates the effect of ketamine and determines more profound changes on neurotransmitter profile in rats. Fourthly, a further goal focuses on the improved data acquisition and on the data processing to reliably resolve GABA and to be able to quantify a wider range of metabolites. To address those points five studies were performed. The first work (Chapter 3) describes a study of reproducibility on sequences which have been reported in the literature to be capable to detect Glu and GIn. The study was performed on 14 healthy subjects by scanning them twice and repositioning between the two scans. The absolute percentage difference was then computed to assess the accuracy per sequence and metabolite. A good compromise was found in PRESS sequence (TE=80 ms) which was exploited subsequently for the following study on schizophrenic patients (Chapter 4). Twenty-seven early stage schizophrenic patients and twenty-three aged-matched controls were recruited to undergo a protocol including, in two separate sessions, MRS and electroencephalography (EEG). Anterior Cingulate Cortex Glu was found to predict the induced theta activity in healthy controls but not in patients. Furthermore, the NAA values have also been found to be reduced in schizophrenia and linked to N100, an Event Related Potential (ERP) which is well known to be decreased in schizophrenia. Following on from the findings of the study on the early stage of schizophrenia, further investigations were undertaken to study the psychotic state occurring in the disease via a functional MRS, where 25mg/kg of ketamine (NMDA antagonist) injection was administered to two groups of rats. The two groups were group-housed and reared in isolation. This work was able to show increase of prefrontal GIn levels in both groups but showed a selective GABA decrease only in isolated rats. It would have been very interesting to be able to detect GABA changes in the study at 3T but the used protocol did not allow its accurate quantification. Simulations and reliability tests (Chapter 6)were then utilized to optimize a standard sequence to obtain an accurate and reliable GABA concentration. The optimized sequence reproduces the quantification with 12% of accuracy. The preliminary results of the last study (Chapter 7) give an evidence of the potential of combined use of Monte Carlo, Levenberg-Marquardt and NNLS methods embedded in a novel fitting approach for two-dimensional spectra. The three appendices at the end of this work illustrate the details of some of the algorithms and softwares used throughout the studies.

Multimodal neuroimaging using a combination of Magnetoencephalography (MEG) and ultra-high-field fMRI are used in order to gain further insight into the neural oscillations and haemodynamic responses in the somatosensory cortex. Single pulse electrical median nerve stimulation (MNS) with regular and jittered intervals is used in MEG. A preliminary study is used to determine acceptable trial number and length, and highlights points to be considered in paradigm optimization. Time-frequency analysis shows that the largest activities are beta event-related desynchronization (ERD) and event-related synchronization (ERS) between 13Hz and 30Hz. No significant difference in both the induced oscillations and evoked responses are found. Paired pulse MNS with varying ISIs are studied using MEG and 7T fMRI. The beta ERD is suggested to have a gating role with a magnitude irrespective of the starting point of stimulus. Non-linearity effects both in beta ERD/ERS and P35m are shown for ISIs of up to 2s, implying that the non-linear neural responses to the stimulus may still contribute to the BOLD non-linearity even when the evoked response has returned to baseline. Multiple pulse MNS with varying pulse train length and frequency are also investigated using MEG and MEG-fMRI. The gating role of beta ERD is further confirmed and the N160m is suggested to be modulated under this role. No accumulative effect is seen in the ERS with increasing pulse number but the amplitude of the ERS is modulated by the frequency. This can be explained by a Cortical Activation Model (CAM). Efforts to spatially separate the beta ERD and ERS are shown for all three studies. Group averaged SAM images suggest a separation of activation areas along the central gyrus. Significant difference are found in the z MNI coordinate between beta ERD and ERS peak locations, suggesting that these two effects could arise from different generators. In the multiple pulse frequency study, by including the temporal signature of beta ERD and ERS as a regressor in BOLD fMRI analysis, delayed BOLD responses are located posterior to the standard BOLD response. However, the exact nature of the relationship between this delayed BOLD response and the ERS effects requires further work.

We can extrapolate a large amount of information about what a person thinks or believes, purely by observing their behaviour. There are separate systems in the brain that decode what action is being performed and why that action is performed. Independently, these systems are reasonably well understood but the way in which they interact is still an open question. In this thesis I investigate how we come to understand others actions, particularly if they are unusual or irrational. Irrational actions provide a special test case for examining this question because full comprehension requires an understanding of what an agent is trying to achieve as well as an understanding of why they are performing the action in an unusual way. I examine this question in a series of experiments with typically developing and autistic participants. First, I demonstrate that dissociable brain networks are engaged during irrational action observation using fMRI. I then use eye tracking to examine the cognitive processes that these neural networks reflect in both typical and autistic adults. I report typical cognitive processing of irrational actions in individuals with autism, despite previous reports of atypical neural activity during the same task. Finally, I aimed to examine the social response to irrational actions in typical and autistic children using an overimitation paradigm. I demonstrate that overimitation in typically developing children is socially driven and dependent upon rationality comprehension. However, my data also indicate that children with autism are immune to this drive. I conclude this thesis with a new model of rationality comprehension which links brain, cognition and behaviour. I also propose that individuals with ASC have the cognitive ability to understand irrational actions but may have difficulty with social modulation of their behaviour.

Aberrant neurotransmitter function promotes cognitive deficits in schizophrenia. These abnormalities in functioning are seen as disruptions in attentional and information processing, as well as disruptions in the consolidation and retrieval of information. Tasks of attentional salience and memory that are used to model these disruptions include the latent inhibition (LI) task of attentional salience, prepulse inhibition (PPI) task of sensorimotor gating and an Episodic memory (EM) task, which is an index of memory for episodes at a particular point in time. Aberrant functioning of candidate genes that are associated with risk for schizophrenia may be seen as behavioural alterations in these tasks of schizophrenia relevant phenotypes. dopaminergic hyperactivity and hypofunction have been implicated in mediating disruptions on these cognitive tasks. Increased transmission in the dopamine system in the striatal region promotes schizophrenia symptoms, and indirect dopamine (DA) agonist Amphetamine worsens these symptoms in patients, and disrupts schizophrenia relevant behaviours on these cognitive tasks. We investigated the effects of deletion of two genes relevant to schizophrenia on cognitive tasks known to be disrupted in the disorder. The effect of deletion of the dopamine D2 receptor (D2R) and trans membrane (TM) domain Neuregulin-1 (Nrg-1) receptor were investigated in mediating disruptions in cognitive processes in an animal model of schizophrenia. The role of the D2R in an attentional model of sensorimotor gating was assessed. PPI was attenuated in D2R knock out (KO), in a one day sensorimotor gating task. In a one day PPI test protocol, amphetamine disruptions on PPI were spared in D2R WT and KO mice. Following on from previous reports of disrupted LI by a single low dose amphetamine injection, separated by 24h interval, we established a single vs. two low dose PPI protocol in order to facilitate a direct comparison of amphetamine induced disruption in LI with PPI. A one injection (prior to test only) vs. two injection (prior to habituation and prior to test) task was established. In the two day protocol, a single low dose of amphetamine disrupted PPI in D2R KO mice and reduced startle reactivity to the 120 dB pulse alone trials. Two low dose injections of amphetamine however, do not disrupt PPI in D2R KO or their WT littermates, and do not mimic low dose amphetamine disruptions in the LI task. These findings demonstrate that prior conclusions about the requirement of the D2R for amphetamine effects in PPI does not generalise to all dose regimens. Episodic memory was also investigated as a measure of cognitive impairment in schizophrenia. D2R KO mice show sex specific dissociations on an EM task. Male D2R WT and KO animals show equal exploration of old vs. recent objects on the what-when component of the EM task, and female KO animals show enhanced memory for old vs. recent objects. Both D2R WT and KO mice show intact memory for displaced objects. These deficits were also investigated in the TM domain Nrg-1 model. Nrg-1 has been implicated as a candidate gene for schizophrenia, and behavioural phenotypes assessing its role in cognitive impairment in schizophrenia were established. Intact LI is seen in both Nrg-1 WT and Het animals. Nrg-1 TM domain Het mutants also show deficits on the schizophrenia relevant PPI task. Nrg-1 Het mutants show attenuated % PPI compared to their WT littermates, which reflects interrupted sensorimotor gating in schizophrenia. Lastly, we found some evidence that reduced function of TM-domain of the Nrg-1 gene disrupted episodic-like memory (what- where-when recognition) in males and improved it in females.

Background: Epilepsy is a serious chronic neurological disorder that has a higher incidence in children and young people (CYP) than in adults. Epilepsy negatively impacts physical and psychosocial quality of life of CYP. Good outcomes of epilepsy are associated with optimal choice of drug treatment and adequate adherence to the prescribed medicines. Research on the patterns of medication use and adherence to prescribed medicines in CYP remains limited. The long-term clinical outcomes and costs of treating epilepsy have not been extensively studied in CYP in the UK. Aim of the study: This thesis aimed to investigate the pattern of antiepileptic drug (AED) prescribing and the dynamic of medication adherence in CYP with epilepsy. The long-term clinical outcomes and direct costs of treating epilepsy in CYP were estimated at population level. Methods: This study is an observational cohort study of CYP, age 0-17 years, identified from The Health Improvement Network (THIN) primary care database from the UK between January 1988 and December 2004. Four different analyses were carried out on this cohort. First, a cross-sectional design repeated annually was employed to estimate the incidence and prevalence of epilepsy and the pattern of AED prescribing in this population. Secondly, the long-term adherence to prescribed AEDs was calculated using the medication possession ratio (MPR) method. Applying panel data analysis and the Generalised Estimating Equation (GEE) multivariate regression, factors that may have been associated with adherence to the prescribed AEDs were examined. Thirdly, seizure outcomes in terms of seizure frequency and remission of seizures and potential associated factors were assessed using the method of multiple failure survival analysis. Finally, the direct costs of treating epilepsy in CYP in primary care were estimated and stratified by the number of years after the first recording of epilepsy in THIN data. Results: Of total 528,760 CYP born on or after 1st January 1988 and registered in general practices contributed to THIN until 31st December 2004, 2020 CYP were identified who had a diagnosis of epilepsy, from under 1 up to 16.3 years of age (mean=5.6; SD=4.1). The annual incidence of epilepsy in CYP stratified by calendar years ranged from 44.4 (95% CI=31.9-61.8) to 61.2 (95% CI=50.6 -74.1) per 100,000 person-years. Incidence of epilepsy was significantly higher in children with greater socioeconomic deprivation than those with lower deprivation. Around 60% of CYP with epilepsy were prescribed monotherapy each year. Old AEDs such as carbamazepine and sodium valproate were the most frequently prescribed drugs and often prescribed as monotherapy to control epilepsy throughout 1990-2003. Prescribing of lamotrigine, a new AED, increased from 0.07 per person-years in 1992 to 2 per person-years in 2003. The calculated annual adherence to AEDs showed that around 50% of CYP adhered to at least 80% of the prescribed medications each year. Demographic characteristics of CYP were of little significance to affect adherence levels. The incidence of seizures was 0.73 (95% CI=0.71-0.75) per person-years. Incidence of seizures was higher in younger children up to 2 years and decreased with increasing age. A proportion of 94% (95% CI=93%, 96%) of CYP achieved 1 year remission of seizures, 80% (95% CI= 78%, 83%) achieved 2 years and 47% (95% CI=43%, 50%) achieved 5 years remission of seizures. The mean total direct cost associated with treating epilepsy in CYP, according to information in the general practice records that also indicated specialist and hospital care, was estimated at £ 1,153 (SD=1,808) per child in the first year following epilepsy diagnosis and at £459 (SD=1,633) per child for subsequent years. The costs of hospital care and AEDs represented the highest contribution to the total direct costs of epilepsy. The annual direct cost was significantly higher in younger children up to 2 years old. No significant difference in the annual costs was observed between CYP who adhered to at least 80% of medications and those who adhered to less than 80%. Conclusions: The incidence of epilepsy was highest in young children and CYP of higher socioeconomic deprivation. Old AEDs were most often prescribed as first-line drugs and as monotherapy to control epilepsy. Of newer AEDs, there was an increasing trend of prescribing lamotrigine and topiramate as add-on therapy. Long-term adherence to prescribed AEDs was suboptimal in one-half of CYP and positively associated with higher seizure frequency. Inpatient hospital care and drugs were the major contributors to the direct costs of treating epilepsy in CYP. Non-adherence to prescribed medicines was associated with higher hospital care costs but not with total direct costs as the medicines themselves made large contribution to the direct costs

This study presents an evaluation of the FRIENDS for Life program (Barrett, 2010) with an autism spectrum (AS) population. FRIENDS for Life is an intervention program underpinned by the principles of cognitive behavioural therapy (CBT) with a primary aim of reducing participant anxiety levels (Barrett, 2010). Existing research suggests it is an effective intervention in reducing participant anxiety levels (Briesch, Hagermoser Sanetti and Briesch, 2010) and it has been recognised by the World Health Organisation (2004) as the only evidence based program effective in reducing anxiety as a universal and targeted intervention. In recent years an evidence base for the application of CBT with children with AS has emerged, though primarily this research has been conducted in a clinical setting. Therefore this study aims to contribute to both evidence bases through implementing the FRIENDS for Life program within a new population as well as contributing to the broader evidence base evaluating the effectiveness of CBT with children with AS. The study adopted a post positivist epistemology and used a single case experimental design (SCED) to evaluate the effectiveness of the intervention in reducing the anxiety of four participants, aged nine to eleven, accessing special school provision. Anxiety was measured during a baseline, intervention and follow up phase using two weekly measures: the Paediatric Index of Emotional Distress (PI-ED;O'Connor et al, 2010); a short pupil questionnaire, and a weekly observation of participant behaviour. These measures were also triangulated with pre and post measures of anxiety using the Spence Child Anxiety Scale, child (Spence, 1997) and parent (Spence, 1999) version, and the School Anxiety Scale- Teacher Form (Lyneham, Street, Abbott and Rapee, 2008). Outcomes from the SCED showed that for all four pupils there was a significant decrease in anxiety from baseline to follow up on at least one weekly measure of anxiety, indicating a delayed effect on anxiety. The parent, child and teacher report triangulation measures suggested there was no significant change in anxiety post intervention. When considering outcomes, several key limitations to the study's design and implementation were taken into account including threats to construct validity and missing data in the intervention phase for two participants. The study concludes with support for the positive impact on participant anxiety as a result of the FRIENDS for Life intervention and recommendations are made for further investigation of the use of CBT interventions in schools with an AS population.

There has been a rapid development and implementation of Crisis Resolution Home Treatment Teams (CRHT) in the United Kingdom over the past decade. The available research studies of this service provision to date have largely focussed on issues related to the ‘outputs’ of CRHT, for example cost efficacy and the impact on admission rates. There is no available research on the experiences of clinical psychologists within CRHT. This is despite the fact that it would seem that research exploring the experiences of clinical psychologists in CRHT is important, as working in a new area of service provision may present specific challenges. An understanding of the nature of these challenges is considered important in order to support clinical psychologists in these settings, and to sustain and improve service delivery. This study presents a qualitative exploration of clinical psychologists’ experiences of working in a CRHT. Eleven clinical psychologists were interviewed about their perceptions of working within CRHT, their relationships with other professionals and their experiences of working with service users in ‘crisis’. The Grounded Theory approach was employed to analyse participants’ accounts. Three broad themes relating to ‘Psychological and Clinical Work’, ‘Teamwork’ and ‘Positive and Negative Aspects of CRHT Working’ were identified in the study. The emergent themes are compared to the wider literature on clinical psychologists’ experiences of working in teams, and working with service users in crisis. The findings have a range of implications for clinical practice in CRHT, service development and future research.

The hippocampus has been implicated in the learning and memory of arrays of spatial cues. Certain theories of the function of the hippocampus have stressed the importance of the hippocampus in learning about configurations of stimuli that have non-linear associations. Recent evince has suggested that the hippocampus may not be responsible for learning about unique configurations but rather the unique spatial relationships formed by a configuration of visual cues. This thesis examines the effects of hippocampal lesions on visual configural discriminations, in which the solution relies on learning the features that are necessary for configural learning, and also discriminations in which the solution of the task relies on learning the spatial structure of the features that form the configurations. It was found that hippocampal lesions made after acquisition impaired performance of a structural discrimination. Hippocampal lesions did not impair performance of previously acquired configural discriminations. A probe test revealed that although hippocampal lesioned and control rats do not differ on performance of a configural discrimination that does not require learning structural information, control rats learn the structural features of the configurations to a greater extent than hippocampal lesioned rats. Hippocampal lesioned rats were impaired at learning structural information when a task explicitly demanded, and when the structural features were incidental to the requirements of a task. The results are discussed with regards to a configural account of hippocampal dependent allocentric spatial learning, and also theories of hippocampal dependent stimulus representation

The present study investigated the possible involvement of nine candidate genes in NF1 tumours by assessing loss of heterozygosity, promoter hypermethylation, and expression in NF1-related tumours. The CDKN2A/p16INK4a , RB1, TP53</italic> and MGMT genes have previously been found to be altered in NF1 tumours, and this was confirmed in this study. However, new candidate genes were also found to be involved in NF1 MPNSTs and rare malignancies (RARB, MLH1 and RASSF1A).

There is increasing recognition that recovery from heroin addiction is possible but there is limited understanding of the recovery process and of how services can support people in that process. At present, most of the research concerning recovery from heroin addiction comes from the United States where the treatment system is very different to that in the UK. This study aimed to gain a better understanding of the recovery process from the perspective of people who are in recovery from heroin addiction, with the aim of informing service development and delivery in the South Wales area. This study employed a grounded theory qualitative methodology to analyse data collected from ten interviews with people in recovery from heroin addiction in the South Wales area. The results revealed four core categories: i) initiating recovery, including the triggers for recovery and what helps; ii) maintaining recovery, consisting of thought changes, lifestyle changes and the role of supportive networks; iii) the reality of recovery, encompassing the process of recovery and obstacles faced; and iv) service provision, encompassing current problems, how support needs can be met and how wider needs can be addressed. The findings highlighted some important considerations for the development of services specifically designed to meet the needs of this client group, thus facilitating long term stable recovery. The findings are reviewed in relation to the wider literature regarding recovery from heroin addiction. Implications for clinical practice and service delivery are also reviewed, and suggestions provided for how services can incorporate recovery-orientated principles. Suggestions for future research are also considered.