Numerous studies have reported psychological benefits associated with the practice of values-based self-affirmation. However, there is little evidence regarding their clinical applicability. Many of the purported benefits of values-based self-affirmation are highly relevant to people with bulimia nervosa (BN). This study used a multiple case study design in order to investigate the effectiveness, underlying mechanisms and acceptability of a brief (three week) intervention focussing on the development and practice of values-based self-affirmations with people who have BN. Two participants were recruited from an Eating Disorders (ED) Service waiting list. They completed questionnaires measuring cognitions associated with ED, attitude towards change, self-esteem, self-compassion, body image acceptance, psychological flexibility, cognitive defusion, and SELF repertory grids over four time points. Following appointments qualitative data was collected, and on completion of the intervention participants were interviewed, regarding their experiences. Pre and post intervention behavioural measures of BN were also collected. The use of a personal values-based self-affirmation intervention was associated with reductions in behaviours associated with BN, enhanced attitude towards change and reduced discrepancy between self and ideal self. There was little convincing evidence that the intervention was associated with a reduction in cognitions associated with ED. A very small degree of change in a positive direction was observed in relation to self-esteem, self-compassion, body image acceptance, psychological flexibility and cognitive fusion. However, scores did not reflect Reliable Change in these processes. Overall, results appeared to be slightly better explained by theory underpinning Personal Construct Psychotherapy rather than Acceptance and Commitment Therapy. However, neither theoretical explanation fully accounted for the data. Participants generally found the intervention to be acceptable. The results add novel findings to the literature regarding the use of values-based self-affirmation within the treatment of BN. They suggest that a brief values-based self-affirmation intervention might be a useful adjunct to evidence based treatment of BN. However, the case study design that is utilised in this study limits the degree to which these results may be generalised and future research should explore this further.

Objectives: To study autism spectrum disorder (ASD) in the Faroe Islands, including prevalence, diagnostic stability and environmental factors that are potentially involved in the aetiology of autism. Method: I. The target group was recruited from the entire population sample of participants with ASD during a two-phase screening and diagnostic process of the entire Faroe Islands population in the relevant school age group born between 1985-1994 (7-16 years, n=7,689) in 2002 and again in 2009 (15-24 years, n= 7,128) using an independent clinical diagnosis and standardised tools. II. The diagnostic stability of ASD from childhood to early adulthood over a period of 7 years compared diagnoses in 2002 and 2009. III. A literature search of vitamin D and ASD covering the period from January 1 1995 to October 31 2011 was carried out. IV. A pilot study involved questioning 20 mothers of young individuals from the target group and 13 mothers of healthy comparisons, regarding mothers’ diet habits, health, life-style and well-being during their pregnancy with an index child. V. 25-hydroxyvitamin D3 (25(OH)D3) levels were examined in a population based cross-sectional study that involved 219 individuals: 40 participants with a diagnosis of ASD from the target group (31 males/9 females), their 62 typically developing siblings (29 brothers/33 sisters), their 77 parents (40 mothers/37 fathers), and 40 healthy comparisons (28 males/12 females). Results: I. The rate of ASD rose significantly from 0.56% (n=43) in 2002 to 0.93% (n=66) in 2009. Although these results were still within the range of typical findings from other studies, of the 24 newly discovered cases in 2009 nearly half were females thus altering the male/female ratio from 6/1 to 2.7/1. II. The stability of clinical ASD diagnosis was perfect for AD, good for “atypical autism”/PDD-NOS, and less than perfect for Asperger syndrome (AS). Stability of the diagnoses made by means of research tools were more variable but still good for AD. Both systems showed excellent stability over the seven-year period for “any ASD” diagnosis, although a number of clear cases (especially in females) had been missed in the original screening in 2002. These results support the notion that a single overarching diagnostic category, ‘autism’ or ASD, would better suit clinical realities as outlined in the new DSM-5. III. The systematic review (in 2010) provided some, albeit very limited, support for the possible role of vitamin D deficiency in the pathogenesis of ASD: there are three main areas of involvement of vitamin D in the human body that could potentially have direct impact on the development of ASD: (1) the brain, (2) gene regulation and (3) the immune system. The prevalence of ASD has been suggested to be raised at higher latitudes. IV. Mothers of individuals with ASD had had during their pregnancy significantly less positive “attitude to sun” (p=0.001), consumed fewer vegetables (p=0.026) and also less fruit (p=0.078). V. The ASD case group had significantly lower 25(OH)D3 levels (24.8 nmol/L) than their typically-developing siblings (42.6 nmol/L, p<0.001) and their parents (44.9 nmol/L, p<0.001), and also significantly lower than healthy age and gender matched comparisons (37.6 nmol/L, p=0.002). There was a trend for males having lower 25(OH)D3 levels than females. There was no association between vitamin D and age, month/season of birth, IQ or subcategories of ASD. Among the ASD group, 60% were severely deficient (<30 nmol/L) and 84.2% of the whole study sample (n=219) had deficient/insufficient levels (<50/<75 nmol/L). Conclusions: I. ASD prevalence in the Faroe Islands increased from 0.56% in 2002 to 0.93% in 2009 mainly due to missed cases in 2002, nearly half of them females. II. There was diagnostic stability for the overall category of ASD over time in the group diagnosed in childhood (7—16) years, but considerable variability with regards to diagnostic sub-groupings. Diagnosing females require novel approach. III. Vitamin D deficiency–either during pregnancy or early childhood–may be an environmental trigger for ASD in individuals genetically predisposed to the broad phenotype of autism. IV. There are some interesting differences in the diet and life-style habits between mothers with a child with ASD and mothers with a healthy child. The ASD-group’s negative “attitude to sun” may indicate some life-style/health differences which may play a role in pathogenesis of ASD, especially in combination with other environmental risk factors. V. The present study, demonstrating an association between low levels of 25(OH)D3 and ASD, is the first to be based in a total population and to use siblings, parents and general population control groups. It adds to similar findings from other regions of the world, indicating vitamin D deficiency in the population and especially in individuals with ASD. As all groups were exposed to low levels of sunlight, the very low 25(OH)D3 in the ASD group suggests that some other underlying pathogenic mechanism may be involved.

Autoimmune neuropathies are a group of conditions resulting from inflammatory attack of the peripheral nervous system (PNS). Guillain-Barré syndrome (GBS), an acute autoimmune neuropathy, presents in both axonal and demyelinating forms. Axonal forms of GBS are caused by autoantibodies which target gangliosides on peripheral nerves. Here, they cause axonal damage via activation of the complement pathway. In ex vivo preparations, anti-ganglioside antibodies have been shown to cause complement-mediated injury to the node of Ranvier and the motor nerve terminal. Of these two vulnerable sites, the motor nerve terminal has recently been shown to be able to internalise anti-ganglioside antibody while the node of Ranvier does not. Rabbit models have demonstrated that immunisation with ganglioside results in a motor axonal neuropathy but no such model currently exists in mice. This is partially due to the fact that wildtype mice respond poorly when immunised with ganglioside and partially due to the requirement of an exogenous complement source to cause injury. This laboratory has recently developed GalNAcT-/--Tg(neuronal) and GalNAcT-/--Tg(glial) mice with complex ganglioside expression restricted to neurons and glia, respectively. This thesis aimed to develop a mouse model of GBS by actively immunising these mice with ganglioside liposomes. Subsequently, the aims were expanded to look at the clearance of the antibodies by membranes which express their ganglioside target. To complete these aims, wildtype, GalNAcT-/-, GalNAcT-/--Tg(neuronal) and GalNAcT-/--Tg(glial) mice were compared. Following immunisation with liposomes containing GD1b, wildtype mice responded poorly as demonstrated by low presence of immunoglobulin in their sera. Conversely, GalNAcT-/- mice, which lack complex gangliosides, showed high presence of immunoglobulin in their sera. GalNAcT-/--Tg(neuronal) and GalNAcT-/--Tg(glial) mice showed intermediate levels. This was assumed to be due to varying levels of tolerance to “self” lipids among the mice. However, when normal human serum was introduced, GalNAcT-/--Tg(neuronal) and GalNAcT-/--Tg(glial) mice did not show any complement-mediated injury. Based upon evidence from ELISpots from the splenocytes of these mice, there did not appear to be any major differences in anti-GD1b antibody-producing cells among genotypes. The possibility that the antibodies produced by these mice were being removed by internalisation was investigated at the NMJ ex vivo and in vivo. Ex vivo, antibodies against complex gangliosides were demonstrated to be cleared in a receptor-dependent and activity-dependent manner. Following passive immunisation with pathogenic monoclonal antibody in vivo, serum levels of the antibody were cleared rapidly in wildtype mice but remain elevated at 7 days in GalNAcT-/- mice. GalNAcT-/--Tg(neuronal) mice cleared antibody at an intermediate rate. Non-pathogenic antibodies were not cleared from the circulation over the 7 days from any of the three genotypes. These results have demonstrated that levels of anti-ganglioside antibody can be regulated by receptor-dependent internalisation, especially at the motor nerve terminal. These studies have highlighted this structure as a novel regulator of anti-ganglioside antibody in vivo. The clearance of antibody is also dependent on the ability of the antibody to bind to living tissue; therefore antibodies detected in patient serum may not represent pathogenic, disease-causing antibodies. These factors may profoundly influence host vulnerability to antibody-mediated disease by affecting circulating levels of pathological antibodies.

This dissertation is about how the concept of harm, damage or wound is applied as a metaphor to a site often called the self or the soul. This is the social space of the individual subject, which is, paradoxically, placed by our language and culture in a person’s interior – a place where we are all said to be vulnerable and endangered by a potentially hostile environment. The thesis consists of a series of studies which are designed to show how the concept of harm to an inner life emerges from different discursive contexts, and how it does so in distinctly variable versions: psychological, emotional, neurological or social, in more or less stable hybrid forms. Using primary sources which are mostly documentary, supported by some interviews, the studies range from a look at the psychiatric history of post traumatic stress disorder (PTSD) and at the story of its rewriting in English tort law; the recent reprised popularity of attachment theory and its marriage to neurology and a look at the career of the concept of the emotional abuse of children as a social problem category in the legal/administrative processes of Child Protection. These are introduced by a first chapter which concentrates on the metaphoric content of invisible wounds or psychic trauma and the way it produces particular forms of the self. The studies which follow this are clustered around the literature and practices of the psychiatric, psychological, psycho-analytic, social work and legal professions, in order to show how the work of these professionals makes the concept of a psychic injury visible, discussible, treatable, administrable and justiciable. Through their efforts, it is argued, the concept moves from being a metaphor, hooked onto the palpable reality of a physical wound, to acquire a ‘facticity’ of its own; it becomes a reality through its achieved status as a social problem category and an ever present risk to self and self regulation at the turn of the 21st century.

This thesis examined the macro-structural and micro-structural changes in Huntington’s disease (HD) in order to improve understanding of the temporal and spatial patterns of neurodegeneration, and the functional relevance of these changes. Translational techniques were employed using genetic mouse models of HD in combination with a patient cohort to examine grey and white matter changes with a particular focus on white matter microstructure. In the patient cohort, the cognitive profile was examined using a cognitive battery not before applied in HD. Specific deficits were found in set-shifting and flexibility, verbal reasoning, working memory and paired associate learning, along with subtle differences in response inhibition that were sensitive to disease burden. A composite cognitive score was produced to examine the relationship between cognitive function and brain structure. A multi-modal examination of white matter tract-specific microstructural measurements revealed abnormalities in the corpus callosum and cingulum bundle that were sensitive to disease burden (chapter 4). In chapter 5, multiple analysis techniques converged to reveal tissue macrostructure abnormalities that were also sensitive to disease burden in HD. Cortical changes were less consistent, and unlike the microstructure findings, white matter macrostructural abnormalities were not related to disease burden. In chapters 6 and 7, genetic mouse models of HD were used to examine changes across the disease course, and to pilot an interventional design. In vivo diffusion MRI and T2-weighted MRI sequences were acquired at 2 different time points in the HdhQ150 knock-in model of HD and imaging data is presented alongside behavioural results and immunohistochemistry. In chapter 7, an environmental modification regime was tested in the YAC128 mouse model using in vivo MRI. Environmental intervention reduced the degree of disease-related atrophy, altered tissue microstructure and improve motor but not cognitive performance in YAC128 mice.

Aggressive behaviour in people with intellectual disability is a far reaching problem, estimated to be expressed by 7% of the population of people with intellectual disability. People with intellectual disability who are aggressive often experience an inequality in service provision. Carers who work in aggressive environments can find the management of aggression an overwhelming challenge and may suffer burnout. At a service level, providing suitable care for people who may be aggressive, whilst also providing a comprehensive care package, is very difficult. Aggression in people with intellectual disability is more prevalent than in equivalent cared for groups, but there is little research to date on the sequential nature of that aggression. Like all behaviour, aggression occurs as part of a sequence, and a crucial part of understanding violent behaviour in people with intellectual disability is to understand the nature of their aggression, and especially the (temporal) structure of these episodes, as well as the potential factors involved. Current research in aggression in people with intellectual disability focuses on the nature of static risk factors, mental health issues and the function that aggressive behaviour provides for the individual expressing it. The main aim of this thesis is to document the patterns of aggressive behaviour in people with intellectual disability in order to examine what factors may be involved in increasing the risk of aggression in this population. Guidance as to what those factors may be was taken from research into aggression in the general and intellectual disability population. The first phase of this study involved creating a database of violent incidents from the health care records of 18 participants, drawn from three National Health Service units for Intellectual Disability. These were collated into an aggressive incident database that brought together information from different sources about individual incidents. The patterns in the incidents were used to construct a typology of aggression. The second phase of the study formed the main focus of the research, and involved analysing the aggressive incident database using Sequence Analysis methods. The pattern of these results indicated that reports focused mainly on aggression that involved staff, and found visits, outings and denial of requests by participants were significant factors in the sequence of an aggressive incident. The third phase focused on data drawn from a risk management system called Sentinel, and examined all aggressive incidents occurring across three units for people with intellectual disability over four and a half years to investigate temporal patterns of aggression using time interval analysis. This was used to identify distinct temporal patterns of aggression for each of the three units involved in the study. The results indicated that visits and outings, meal times and requests were part of the sequence of aggression behaviour in people with intellectual disability. The possible implications of this were discussed, and these findings related to the wider literature.

The aim of the present study was to further understand psychological well-being (PWB) and future-directed thinking in individuals with a diagnosis of Borderline Personality Disorder (BPD). A cross-sectional mixed design was used with 24 individuals with a diagnosis of BPD and 24 community participants (Controls). Participants were measured on PWB and a measure of future-directed thinking. Future-thoughts provided by participants were also content analysed, and it was hypothesised the BPD Group would have particularly marked deficits within interpersonal future thoughts. Consistent with previous findings (MacLeod et al., 2004), BPD participants had fewer positive future-directed thoughts compared to Controls, in the absence of any differences in negative future-directed thoughts. The BPD Group had significantly lower PWB scores on all six of the Ryff Psychological Well-being dimensions. The Control Group generated significantly more positive future-directed thoughts related to Relations with Others and Recreational activities, as well as more thoughts related to Having/Raising Children than the BPD Group. The findings extend the understanding of BPD individuals by profiling their well-being and describing in more detail their future-directed thinking.

ZNF804A was (at the time this work started) one of only a few robustly implicated schizophrenia susceptibility genes, due to replicated genome-wide significant evidence for association between a polymorphism in the gene and schizophrenia. Determining the function of the ZNF804A protein, which is currently unknown, may provide a way of elucidating the pathophysiology of this relatively common, complex disorder. Based on the hypothesis that the ZNF804A protein regulates gene expression or splicing, the aim of this thesis was to identify genes that exhibit altered expression or splicing in brain tissue from mice in which the orthologue Zfp804a carries a nonsense mutation. No robust evidence was obtained that showed the effects of the mutation on differential expression in individual genes. Although this finding does not support the hypothesis that ZNF804A acts directly to regulate gene expression, the results may reflect the possibility that effects on gene expression may be too subtle to be detected using the methods applied. Evidence was obtained to show the mutation affected the alternative splicing of a number of individual genes, which could suggest a role for ZNF804A in the direct or indirect regulation of alternative splicing. Through RNA sequencing, I identified a novel transcript in Zfp804a with an alternative exon upstream of the Refseq exon 1. I also showed that a proportion of the significant splicing differences identified in mutants were artefacts of strain differences in gene sequences that are likely to affect the efficiency of hybridisation on the exon array. Genes identified as differentially spliced between mutants and wildtypes were enriched in axon guidance and cell adhesion pathways, both thought to be important during development. The findings of this thesis suggest the novel hypothesis that ZNF804A effects risk for schizophrenia via aberrant splicing in the above pathways that are critical to normal brain development. Further studies with increased power are required to understand the effects on gene expression.

In recent years evidence has emerged that the endocannabinoid system (ECS) may have a significant role in metabolism and energy homeostasis. Several studies have identified upregulation of the peripheral ECS in obesity and type 2 diabetes, but the mechanisms behind this and the consequences of upregulation are unclear. The aim of this thesis was to further elucidate the role of the ECS in mature adipocytes, and its activity in obesity and related metabolic dysfunction. Three adipose tissue depots were dissected from lean, obese and obese diabetic Zucker rats (n=6-8). In human studies, written informed consent was obtained from healthy volunteers within the University of Nottingham and obese surgical patients at the Royal Derby Hospital. Anthropometric measurements and venous blood samples were obtained. In these studies, subcutaneous abdominal adipose tissue was taken from all subjects (n=28 healthy study; n=27 surgical study), and visceral adipose tissue was obtained from some of the surgical patients (n=14). In all studies, collagenase was used to isolate mature adipocytes from the adipose tissue, and FAAH and MGL activities in the adipocytes were assayed using tritium labelled substrates. Human subcutaneous preadipocytes (Promocell, Germany) were cultured and differentiated. Adipocytes were cultured with high concentrations of glucose (15 mM) and/or insulin (1 μM) for 24 hours, in combination with anandamide or 2-AG for 2 or 24 hours. Adiponectin, leptin and resistin in the cell culture media were then measured using sandwich ELISAs. In another study, anandamide and 2-AG uptake were measured in differentiated adipocytes after 2 or 24 hours’ stimulation with glucose and/or insulin. FAAH and MGL activities in the cultured adipocytes were also measured in this study. In rats, FAAH and MGL activities correlated with body mass. In healthy humans, FAAH activity in subcutaneous adipocytes correlated with BMI and waist circumference, but not with other anthropometric measurements, serum glycaemic markers or adipokines. In obese patients, the enzyme activities had no relationships with any of the anthropometric or metabolic markers investigated. Furthermore, there were no differences in activity between patients with metabolic syndrome or diabetes and those without. In both rats and humans, there were no significant differences in FAAH and MGL activities between subcutaneous and visceral adipocytes. In the cell culture studies, anandamide and 2-AG did not alter adipokine secretion under normal, high glucose or high insulin conditions. Chronic insulin exposure increased anandamide uptake, but none of the other acute or chronic treatments with glucose and/or insulin affected anandamide or 2-AG uptake. Glucose and insulin were found to reduce MGL activity. These studies suggest that the rate of anandamide hydrolysis in mature adipocytes is increased in obesity. This relationship was not apparent in a morbidly obese sample. MGL activity in humans does not have relationships with adiposity or metabolic markers, and this may reflect its role as a major component of lipid metabolism, particularly lipolysis. Anandamide and 2-AG are unlikely to be direct mediators of adipokine secretion, at least in cell culture. Insulin may affect endocannabinoid signalling in adipocytes by increasing anandamide uptake and suppressing MGL activity. Overall, these results support the notion that the ECS in adipocytes is dysregulated in obesity, but this is not driven by specific factors associated with obesity.

Multisystemic Therapy (MST) provides intensive short-term interventions for young people with antisocial behaviour and the systems that surround them. A wealth of research over the past 30 years has demonstrated the efficacy of MST. Its success has led to it being transported to many countries and this prompted investigations into the need for cultural adaptation. Despite these investigations highlighting the importance of tailoring MST to new countries, when MST was transported to England in 2001, it did not undergo a formal process of cultural tailoring. This study employed a qualitative approach using a Grounded Theory methodology to explore the assumption that all transported programmes require a level of adaptation and aimed to identify the processes and rationale behind informal ‘cultural tailoring' undertaken by therapists. It aimed to explore areas in MST that might benefit from ‘cultural tailoring' to improve the effectiveness of its implementation in England. Eight MST therapists from across three MST teams in England participated in semi-structured interviews. Analysis of the data generated a theoretical model of adherence: the Post Implementation Model of Adherence (PIMA). The PIMA model seeks to explain how therapists in England experience and manage adhering to MST. It proposes that MST therapists strive to adhere to all aspects of the MST model whilst ensuring that it is acceptable and workable for the families and systems they work with. The PIMA model comprised four theoretical codes: Facilitators to therapists staying faithful to the MST model; barriers to therapists implementing MST, overcoming barriers to implementing MST; and the therapist holding the tension. The findings highlight important cultural adjustments to improve MST's ‘fit' in England. Findings also extend Schoenwald's (2008) recommendations for successful transportation of MST, by drawing attention to how a lack of cultural tailoring can be overcome or experienced as stressful by therapists.