This thesis examines the effectiveness of social problem solving programmes and the efficacy of an assessment tool designed for mentally disordered offenders (MDOs) and intellectually disabled (ID) offenders in secure hospital settings. Firstly, a systematic review concluded that all studies reported benefits of the social problem solving programmes with MDOs. Several studies also identified that shorter revised programmes had lower drop-out rates, and were more cost-effective. Methodological limitations were identified and suggested further research is needed. Secondly, Interpretative Phenomenological Analysis (IPA) was utilised to explore the meanings ID offenders in a secure hospital attribute to their experience of the Thinking Skills Offender Programme (TSOP). Five themes emerged and participants’ conveyed a sense of hope in relation to their treatment, discussed challenges they faced, identified the impact the TSOP had on factors contributing to their offending behaviour, and wanted to share their experiences with a wider audience. Further research to develop effective programmes for ID offenders is discussed. Thirdly, an assessment and treatment of an adult male violent offender with ID and Autistic Spectrum Disorder (ASD) who undertook the TSOP in a medium secure unit is examined. The findings highlighted the difficulties in assessing and treating such patients using conventional methods and the need for standardised assessments and interventions for this population is discussed. Finally, the reliability and validity of the Novaco Anger Scale and Provocation Inventory (NAS-PI) is examined with MDOs and ID offenders. Its clinical utility in inpatients settings and limitations are also discussed. This thesis has highlighted the benefits of social problem solving programmes with MDOs and ID offenders, difficulties of conducting research with this population, and the need for further rigorous research into assessments and interventions.

Introduction The number of prescriptions dispensed for opioid medicines has increased in the U.K. in the last two decades and studies have shown patients are receiving opioids for longer periods than in the past. There is a lack of evidence as to the effectiveness of these drugs when used long-term, as efficacy evidence is taken from short clinical trials in populations who do not have the comorbidities commonly seen in chronic pain patients. Large observational studies of patients prescribed opioid medicines outside of clinical trials, have identified that some patients taking long-term opioids are reporting they are still in high levels of pain. There is also a concern that patients are receiving high dosages of opioid medicines without effective pain relief. However, no studies in the U.K. have looked at the proportion of patients who continue to receive opioids (for all conditions) in the long-term or at high dosages so we do not know how opioid use develops in the U.K. Research from other countries has also identified that long-term and high dose use is linked to patient characteristics such as patient demographics and psychological and physical comorbidities. For example, a prior history of depression has been found to increase the risk of long-term and high dose use. This is of concern as this may indicate that patients may be potentially medicating the depression with the opioid. This may not be the case in the U.K. due to key factors such as the structure of the health system, so the aim of this thesis was to see if this phenomenon could potentially be occurring in the U.K. Methods This thesis was a retrospective observational cohort study of patients receiving opioid medicines for non-cancer conditions using data from a U.K. derived primary care database, the clinical practice research datalink (CPRD). Patients were included in the study if they received a prescription for opioid medication at any point in the year 2009 and followed, where possible to January 2015 (though data was collected for baseline variables prior to 2009). This thesis consists of a series of longitudinal analyses that attempt to define and describe the probability of long-term use and proportion of patients who receive high dosages in the U.K and seeks to understand how baseline characteristics (such as having a comorbid condition occurring before opioid use starts) affect the probability of long-term and high dose use. Competing risks methods were used to calculate the probability of continuation of opioid medicines (using death as a competing risk) and to determine long-term use. Cox regression models were used to determine whether baseline factors (such as prior antidepressant use) were associated with discontinuation of long-term use. Calculation of odds ratios were used to predict whether baseline characteristics predicted high dose use. Cox regression was also used to predict time to discontinuation of high dose use. Results In the U.K., 10.58% of patients received opioid medicines to treat non-cancer pain in the year 2009. Of the non-cancer patients included in the study, 41.41% were patients who received opioids in the six months prior to 2009 and the remaining were new users of opioid medicines. In the new user opioid group, 5.75% continued to be prescribed opioids for at least one year. When including new and existing users of opioid medicines, one in thirty people in the U.K. population who started opioids for non-cancer pain in 2009 were continuously prescribed opioids for a full year. Patients who were female, received an antidepressant before opioid use started and were in the youngest age category were more likely to continue opioid use past 2 years. The probability of continuing to take opioid medicines is higher in patients who have been receiving opioids for longer and are on higher dosages; in patients who had received over 10mg OMEQ for over two years, over half of patients continued to receive prescriptions for opioid medicines for the five year period study after 2009. In the U.K. population, one in a hundred opioid medicine users were prescribed a high dose (estimated dosage received >120mg oral morphine equivalents per day for at least 91 days) for non-cancer pain in their first 91 days of use in the year 2009. Patients receiving high dosages were likely to be receiving multiple opioid drug types and to receive preparations with multiple release profiles. In new users of opioid medication, the odds of high dose use were increased in patients who were younger (aged 18-49 years), had 3 or more comorbidities or were in receipt of an antidepressant or benzodiazepine and/or anti-anxiety drug before or after opioid use started. In new and existing users of opioid medicines, patients who were receiving high dosages were more likely to be diagnosed or be recorded with symptoms of depression or anxiety and to have been prescribed an antidepressant or benzodiazepine and/or other anti-anxiety drug in the youngest age group compared to the older age groups. Of the patients that were prescribed high dosages of opioid medicines for at least 91 days, 37.64% of patients did not have a second consecutive high dose quarter due to death or stopping high dose use. Almost one in five patients who had a high dose quarter continued to have a high dose for the next three years (22.98%). Older patients, patients prescribed weak opioids and/or tramadol discontinued high dose use at a faster rate than younger patients. Conclusion Both high dose and long-term use were found to be associated with a prior prescribing of antidepressants before opioid use started, suggesting that in the U.K. psychological comorbidities are associated with continued and high dose opioid use. Further work is required to measure outcomes within these groups and to understand the care that these patients have already received. Most patients who start opioid medicines in the U.K. stop taking them in their first year of use. However, of those who continue use past two years, a large proportion continue for the full five year period. Similarly, only a small proportion of patients receive high dosages of opioid medicines but once this use is established, many patients have a high probability of continuation. Further work should be undertaken to facilitate effective review of these patients in practice.

Synaesthesia is a cognitive trait in which stimuli of one sensory modality are automatically and consistently experienced in conjunction with perceptions in a separate modality or processing stream. Investigations of synaesthesia may help determine the neural processing required in the generation of a conscious experience. In order to gain the most complete understanding of synaesthesia, we have applied an integrated neurophenomenological approach. In Chapter 2 we present an extended case study of spatial-form synaesthesia (SFS) phenomenology. This investigation goes significantly beyond the rudimentary accounts of provided elsewhere, and provides novel observations on inducer-concurrent relationships, suggesting that guided introspection techniques can provide neurobehaviourally relevant information. In Chapters 3-5 we investigate neural activity in grapheme-colour synaesthesia (GCS). In Chapter 3 we demonstrate that activation in colour selective areas during synaesthetic colour processing is dependent on individual differences in phenomenology, thereby reconciling previous attempts to replicate this key finding in the GCS literature. In Chapter 4 we find no evidence for trait level differences in context specific functional connectivity in GCS, however, we demonstrate that localisation of the synaesthetic concurrents modulate connectivity between colour and low-level visual areas. In 5 we replicate findings of trait level differences in resting state fronto-parietal networks, suggesting that the RFPN may be a significant network in aspects of the synaesthetic experience common to all participants. We demonstrate that localisation of concurrents also modulates resting state visual networks, whilst automaticity of concurrents modulates parietal networks. Both Chapters 4 and 5 support a model of synaesthesia in which localisation of concurrents is modulated by bottom-up connectivity, between colour and early visual areas. This thesis demonstrates that individual differences in synaesthetic phenomenology significantly impact neural activity. We propose that future investigations place emphasis on the phenomenological experience of the participant in the interpretation of neural effects.

Epileptic seizures, characterised by paroxysmal disturbance of brain electrical activity, are recognisable by temporary change in clinical state (for example motor signs, behavioural modification or altered conscious level), temporally associated with the cerebral discharge. While analysis of such clinical seizure signs (“semiology”) formed the main basis of epilepsy study from the late 19th century onwards, understanding of the neural basis of semiological expression has advanced relatively little, in comparison to other aspects of epilepsy research. Analysis of ictal clinical signs is today considered essential for diagnosis of epilepsy, offering clues to underlying anatomical localisation and pathophysiology; however, paradoxically, the cerebral substrate of semiological signs remains incompletely understood in many cases and its localising value is therefore debated. Characterising the anatomo-pathophysiological basis of seizure semiology is especially important in the context of epilepsy pre-surgical evaluation, even more so when no radiologically visible lesion is present, since semiological analysis, if validated for a given seizure type, offers crucial localising information. For pharmacoresistant focal epilepsies in which surgical treatment might be possible, a number of cases require intracranial EEG recording. The method of stereoelectroencephalography (SEEG) is particularly useful as this allows simultaneous exploration of multiple, distant brain structures using stereotaxically placed multi-lead electrodes with concurrent video recording. The data thus acquired help form a three dimensional view of spatio-temporal seizure dynamics. Using SEEG it is therefore possible to undertake detailed analysis of semiological patterns and to study their temporal relation to the abnormal electrical cerebral activity occurring in brain networks during seizures. Epileptic seizures characterised clinically by transient cognitive dysfunction, behavioral change and complex motor signs are particularly challenging to analyse and categorise semiologically; indeed any paroxysmal behavioral disturbance must also be analysed with regards to whether it is actually caused by an epileptic discharge or not, since other forms of pathology, particularly psychogenic nonepileptic seizures (PNES), may be difficult to distinguish from epileptic seizures on a purely clinical basis, and require video-EEG recording for confirmation. This issue is particularly pertinent for prefrontal and parietal lobe seizures, which pose specific challenges for electroclinical analysis. PNES have a different and as yet poorly defined neurobiological basis compared to epileptic seizures. However growing understanding of the brain networks underlying emotional dysfunction, complex motor behaviour and altered consciousness, in particular data derived from intracranial studies of epileptic seizures, can help to further knowledge of how altered activity within these neural networks might interact with psychological and other factors in the pathophysiology of PNES. Through detailed observation of multiple epileptic seizures across a large population of patients, it can be appreciated that similarities exist in both clinical pattern and anatomical organisation of seizures. The existence of semiological patterns is in favour of the hypothesis that specific neural circuits underlie some forms of behavioural expression, and thus reinforces the validity of pursuing this line of investigation in epileptic seizures.

Objective: Cognitive Estimation Tests (CETs) are used to assess decision-making. Previous versions include culturally- biased questions likely to disadvantage certain sections of the population. This study aimed to develop a new culture fair questionnaire and assess its reliability and validity. Method: A 30-item questionnaire was developed and assessed for culture fairness. A normative range of answers was gathered, and a scale developed to define level of deviation from typical responses. Performance in a group of people with brain injury was compared to a matched group of healthy controls. Those with brain injury deemed able to make significant life decisions were compared with a group considered to lack this capacity, to determine whether this test may be useful when assessing decision-making capacity. Correlational analyses were conducted to determine whether there was a relationship between the test and performance on the Dysexecutive Questionnaire (DEX), a measure of everyday executive functioning. Test-retest reliability was examined with 30 of the normative sample. Results: Results confirm previous literature showing that those with brain injury perform significantly worse than healthy controls. The test did not discriminate between patients with and without capacity to make important decisions, did not significantly correlate with the total score on the DEX and demonstrated relatively poor consistency. Conclusions: Based on these results, CETs do not appear to be reliable or valid enough for use in clinical assessments. A sub-set of the most sensitive items may prove useful, but further work is required to examine the reliability and validity of this item subset in new samples.

Cysteine Dioxygenase is an enzyme that catalyses the reaction of cysteine to cysteinesulfinic acid and is thought to regulate the intracellular concentrations of its substrate. The enzyme may also be involved in the oxidation of exposed sulfidrils of protein and by implication, involved in cell signalling or regulation. Substrate and products of cysteine dioxygenase are known to be disrupted in a number of neurodegenerative diseases making the protein an important target for medical research. To date, the structure of the protein has not been solved. An understanding of its structure and reaction mechanism will further the understanding of the aetiology of a number of different pathologies. Its structure may also further the development of novel pharmacological drugs.

Mental retardation is the most common brain disease. One of the first genes identified in X-linked mental retardation (XLMR) was the OPHN-1 gene. Mutation of this gene has been described in patients with moderate to severe cognitive impairments. MR is characterized by reduced cognitive function with or without other clinical features, thus providing a direct approach to study the neurobiology of cognition and pathogenesis of MR. I propose in this thesis to clarify the underlying mechanisms responsible for the learning impairments. My first approach was to investigate the functioning of a neuronal population using extracellular recording of fast oscillations which are thought to underlie higher cognitive performance. I showed that \(Ophn-1\) null mice displayed weaker gamma oscillations. Thereafter, Investigation of the synaptic properties of CA3 pyramidal neurons using the patch-clamp technique has been undertaken. I have shown reduced inputs of excitatory and inhibitory neurotransmission to CA3 pyramidal neurons accompanied with reduced frequency dependent facilitation of the inhibitory neurotransmission at 33Hz. Finally, a reduction in readily releasable pool size in inhibitory synapses of CA3 area was unravelled. This defect explained the reduction of frequency of sIPSCs and consequently the reduction in gamma oscillations power in Ophn-1\(^{-/y}\) slices.

This thesis examines perspectives on gender in eating disorders. Chapter one critically reviews research into psychosocial influences on adolescent boys' concerns about eating and body shape. [...] Chapter two is an empirical study of therapists' experiences of working with men with eating disorders. [...] Chapter three provides a reflective account of the author's experiences of being a Trainee Clinical Psychologist working with female patients in an eating disorder service.

In this thesis, we develop some novel models and methods for the analysis of both structural and functional brain images, and their joint analysis with genetic data. In the first project, we present a suite of methods to increase the power of whole-brain genome-wide association studies. We introduce a kernel-based multilocus model to capture the interactions between single nucleotide polymorphisms (SNPs) and model their joint effect on the imaging traits. We provide a fast implementation of voxel- and cluster-wise inferences based on random field theory to take full use of the 3D spatial information in images and account for multiple comparison problems. We also propose a fast permutation procedure to increase the efficiency of standard permutation methods and provide accurate small p-value estimates based on parametric tail approximation. We explore the relationship between 448,294 SNPs and 18,043 genes in 31,662 voxels of the entire brain across 740 elderly subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI), and show boosted power of our approach by making head-to-head comparisons with previous voxel-wise genome-wide association studies. The various advantages of our methods over existing approaches indicate a great potential offered by this novel framework to detect genetic in uences on human brains. In the second project, we present a Bayesian spatial model of multiple sclerosis binary lesion maps based on a spatial generalized linear mixed model with spatially varying coefficients. Our model fully respects the binary nature of the data and the spatial structure of the lesion maps, as opposed to existing massive univariate methods, and produces regularized (smoothed) estimates of lesion incidence without an arbitrary smoothing parameter. Our model also allows for explicit modeling of the spatially varying effects of subject specific covariates such as age, gender, disease duration and disabilities scores, producing spatial maps of these effects and their significance, as well as the (scalar) effect of spatially varying covariates such as the fraction of white matter in each voxel. We apply our model to binary lesion maps derived from T2-weighted MRI images from 250 multiple sclerosis patients classified into five clinical subtypes, and determine the spatial dependence between lesion location and subject specific covariates. We also demonstrate dramatically improved predictive capabilities of our model over existing methods.

Myoclonus Dystonia Syndrome is a childhood onset hyperkinetic movement disorder characterised by alcohol responsive upper body myoclonus and dystonia. A proportion of cases are due to mutations in the maternally imprinted SGCE gene, which encodes the transmembrane epsilon-sarcoglycan protein. Previous studies suggest an increased rate of psychiatric disorders in those with SGCE mutations. This study aimed to establish a cohort of myoclonus dystonia syndrome patients, identify the rate and type of SGCE mutations, determine differences in motor characteristics between mutation positive and negative cases and whether psychiatric disorders form part of the disease phenotype. Eighty-nine probands with clinically suspected MDS were recruited. Information regarding onset and distribution of motor symptoms was collected via systematic questionnaires and video taped examination. SGCE was analysed using direct sequencing and for copy number variants. Psychiatric symptoms were assessed using systematic and standardised questionnaires and compared to a disability-matched, alcohol responsive tremor control group. Nineteen (21%) probands had an SGCE mutation. All had evidence of upper body predominant myoclonus and dystonia during their disease course. Five had contiguous gene deletions ranging from 0.7 to 2.3Mb in size with distinctive clinical features. Recruitment of family members increased the affected SGCE mutation positive group to 27 of whom 21 (77%) had psychiatric symptoms. Obsessive-Compulsive Disorder was eight times more likely (p<0.001) in mutation positive cases, compulsivity being the predominant feature (p<0.001). Generalized Anxiety Disorder (p=0.003) and alcohol dependence (p=0.02) were five times more likely in cases than tremor controls. Overall, SGCE mutations are associated with a narrow clinical and specific psychiatric phenotype. The presence of myoclonus, dystonia, age at onset ≤10 years and a positive family history of the disorder are the strongest predictors of an SGCE mutation. SGCE mutations are likely to have a pleiotropic effect in causing both motor and specific psychiatric symptoms.