The necessity of client disclosure was initially emphasised by psychoanalytic theorists and disclosure of experiences, behaviours or emotions continues to be a central aspect of contemporary therapies for a range of difficulties. Empirically a debate has emerged in the literature around potential benefits and negative consequences of client disclosure. Exploration of the process of disclosure and barriers to disclosure in therapy for clients with disordered eating has been limited. The current study explored barriers to disclosure in participants (n=120, 95% women), with experience of therapeutic intervention for current or historical eating distress, utilising thematic analysis. It also explored the language used by this group when describing their experiences of disclosure and treatment utilising metaphor analysis. Barriers to disclosure described were represented by themes around (1) internal processes influencing participants’ decision to disclose in therapy; (2) the impact of treatment context on the decision to disclose; and, (3) the influence of the therapeutic relationship. Metaphorical concepts were identified around disclosure, treatment context and recovery. These concepts further emphasised the challenges clients may experience when considering disclosure in therapy within a treatment system which they perceived to be very powerful. When clients anticipated the impact of disclosure, shame and vulnerability as well as potential reactions of the therapist or treatment system were feared. To support clients in considering whether disclosure is helpful or necessary for them, it may be useful for the process of disclosure and its potential benefits or costs to be explored at the outset of therapy.

Psychotherapies for borderline personality disorder (BPD) utilise a variety of theoretical models and practical approaches to effect changes that ultimately lead to a reduction in BPD symptomatology or related improvements (e.g. quality of life). Different psychotherapies vary in the underlying mechanisms that are theoretically proposed to effect this change. Accordingly, they are composed of differing proposed therapeutic components. This thesis aimed to identify effective therapeutic components in psychotherapies for BPD broadly, and Systems Training for Emotional Predictability and Problem Solving (STEPPS) specifically. Part one of this portfolio presents a review of the empirical literature that specifically examines effective therapeutic components in psychotherapies for BPD. Semantic complexities inherent in conducting this type of process research are considered, and the specific scope of this portfolio within the wider ‘mechanisms of change’ literature is defined. Results synthesise identified effective therapeutic components into four themes that illustrate the broader landscape within which the empirical paper is set. Part two of this portfolio presents an empirical paper that investigated effective therapeutic components in STEPPS, a psychoeducational group treatment for BPD. Results support an association between acquisition of behaviour and emotion regulation skills (the primary treatment component proposed in the STEPPS manual) and improvement in BPD symptoms. Results also support an association between group process (a potential effective therapeutic component related to group alliance) and improvement in BPD symptoms, reflecting results from wider literature. Parts three and four of this portfolio summarise the clinical experience gained on placements throughout the PsychD course, and all other written assignments completed.

Background: Rumination and worry represent two forms of repetitive negative thinking (RNT) common in mood and anxiety disorders. While they have many similarities, it is unclear whether there are fundamental differences in content, mentation style and functions, or whether these are artefacts of different definitions and research focuses, such that both are fundamentally instances of the same process of RNT. This review aimed to determine whether direct comparisons of episodes of rumination and worry suggest fundamental similarities or differences between them. Methods: Studies were included if they were empirical studies comparing characteristics of episodes of rumination and worry, either in the context of depression and/or generalised anxiety, or in a non-clinical context. Only studies published in English in peer-reviewed journals were included. Key exclusion criteria included studies solely of trait rumination and worry as measured by standardised questionnaire. Searches were made of PsycINFO, Scopus, Web of Science and PubMed through to March 2017. Quality was assessed using a specifically developed tool. Results: 9 studies were included, covering both naturally occurring and induced rumination and worry in clinical and non-clinical populations, using experimental and observation methodology. The strongest evidence was for worry being more verbal than rumination, for rumination and worrying containing past-, present- and future-oriented thoughts, and for both leading to a worsening of mood. Rumination and worry are likely to be more abstract than neutral thinking, but the evidence is contradictory as to whether they differ from each other. Rumination emerged as more past-oriented, and worry more future-oriented, but this may be affected by the definitions used. Poorer quality evidence suggested that rumination may be more self-focused, and that there may be greater associations between rumination and sadness, and between worry with anxiety and arousal. Discussion: This review adds further evidence for a small number of similarities and differences between the rumination and worry that align with findings from separate studies of these forms of RNT, and suggests some difference between the two constructs as they are currently defined. Heterogeneous aims and methodology, contradictory findings and some methodological flaws limited the conclusions that could be drawn. Definitions of rumination and worry given to participants may have contaminated findings, particularly in relation to temporal orientation. It is unclear whether all studies were examining the same constructs. Future research would benefit from greater clarity about aspects of RNT are being investigated.

Neuroimaging has advanced the knowledge of genetic generalised epilepsy via the improvement of methods and technology. The current understanding is that patients with GGE are characterised by abnormalities in the cortical-thalamic network, functionally and also structurally; and in the default mode network, mainly functionally. However, most studies have been performed on treated patients often with poor seizure control. This leaves uncertainty regarding the status of the brain at the onset of the disease and mechanisms that lead to positive and negative treatment outcome. Also, the systematic measurements of epileptic activity during resting fMRI has left questions about the interaction between cognitive status and the brain networks that have been identified as associated with generalised spike waves (GSW). In this thesis I focused on three rarely and/or uniquely explored issues in the field of neuroimaging in GGE to reach a more comprehensive understanding of GGE. First, I undertook a study of brain structure and function free from any effects of anti-epileptic medication. In drug naïve patients, I measured grey matter volume and shape and fMRI BOLD changes related to GSW onset and prior to GSW. I showed that previous findings can be interpreted and confirmed without the potential influence of AEDs. Secondly, I applied a prospective approach via longitudinally following patients from pre-treatment to post-treatment stages to explore treatment response and to identify markers of treatment outcome. I compared grey matter volume and shape between drug naïve pre-treatment patients with good and bad outcomes. I identified a trend of decreased grey matter volume in patients with bad outcome suggesting the existence of differences at baseline between patients with different treatment response. I compared cerebral blood flow (CBF) longitudinally and found a trend of decreased CBF post-treatment. This suggests that BOLD changes post-treatment may be related to CBF differences. Thirdly, I explored the relationship between brain networks associated with GSW and the brain state via measuring BOLD changes associated with GSW recorded during periods of rest and while watching a cartoon. Evidence of different BOLD maps during rest and cartoon is reported suggesting the need to consider initial brain state in defining the GSW related BOLD response. Methodological constraints, clinical applications and future perspectives are discussed.

Autism Spectrum Disorder (ASD) and Obsessive-Compulsive Disorder (OCD) are frequently comorbid and share deficits in executive function, highlighting a need to understand the shared and/or disorder-specific neurofunctional abnormalities underlying these behaviours. First, a comparative, multimodal meta-analysis between ASD and OCD was conducted on whole-brain voxel-based morphometry structural magnetic resonance imaging (MRI) studies and functional MRI studies of cognitive control. Second, functional MRI (fMRI) was used to scan adolescent boys with ASD or OCD, and control boys while they performed tasks measuring sustained attention and reward-based decision-making, including temporal discounting and gambling. Shared abnormalities were observed in the meta-analysis, where both clinical groups had reduced structure and function during cognitive control in medial prefrontal and anterior cingulate regions. During fMRI, shared abnormalities were also observed during executive function tasks of reward-based decision-making, where both clinical groups had reduced activation in ventromedial, inferior frontal and orbitofronto-striatal as well as temporo-parietal regions compared to controls. Disorder-specific abnormalities, on the other hand, were seen predominantly during tasks of non-emotional executive function. OCD patients had disorder-specific increases in striato-insular structure and function, whereas ASD individuals had increased structure but decreased function in dorsolateral prefrontal cortex during cognitive control. Temporo-parietal underactivation during sustained attention was uniquely associated with OCD compared to ASD and controls. These results present novel evidence that neurofunctional abnormalities, including temporo-parietal underactivation and striato-insular overactivation during non-emotional tasks of executive function may be mostly disorder-specific to OCD compared with ASD, whereas abnormalities during emotionally-driven tasks of reward-based decision-making are predominantly shared between ASD and OCD, particularly in ventromedial, inferior and orbitofronto-striatal regions. These studies provide preliminary indication that both shared and disorder-specific neurostructural and neurofunctional biomarkers underpin cognitive dysfunction in these disorders that may have implications for future diagnosis and treatment.

Eating disorders are common mental health concerns that affect over 700,000 individuals in the UK. A common issue across eating disorder diagnoses is the engagement in compulsive exercise and this has been associated with the development and maintenance of eating disorders. Compulsive exercise can be one of the first symptoms to present and has been noted to impact negatively on treatment outcome. To try and explain this, researchers have focused on exploring the psychological factors, beliefs and motivations that might be associated with compulsive exercise, however, these studies have tended to rely on self-report measures. The literature review aimed to explore the psychological factors that are associated with compulsive exercise in clinical (eating disorders) and non-clinical adolescents. Four electronic databases were searched and 16 studies met the inclusion criteria. The findings were not always consistent, however, there was evidence to suggest that compulsive exercise was associated with increased eating disorder symptomology, depression, anxiety, affect regulation, obsessionality, perfectionism and self-esteem across both clinical and non-clinical groups. However, due to the various methodologies used, further research is required to reliably establish the psychological factors associated to compulsive exercise in adolescents. The empirical study aimed to explore the experiences of compulsive exercise in adult individuals diagnosed with an eating disorder. Semi-structured interviews were conducted with seven females diagnosed with anorexia nervosa and these were analysed using Interpretative Phenomenological Analysis. The analysis generated four superordinate themes and 13 corresponding sub-themes. The themes were discussed in relation to relevant psychological theory and previous research and the clinical implications and recommendations for future research also discussed. The critical appraisal provides a reflection on the research process and includes the professional and personal development of the researcher from undertaking the study.

In this thesis I have determined the effects of seizures on AMPA receptors and examined the effects of AMPA receptor modulation, by medium chain triglycerides and derivatives, on seizures. AMPA receptors play a central role in synaptic transmission in the brain and are critical for the generation of seizure activity. Recent work has indicated that prolonged seizures alter AMPA receptor transmission. Here I determined whether these changes occur in an acute in vitro seizure model, to aid exploration of the underlying mechanisms of these alterations. I demonstrated that, as observed in vivo, seizure activity changes the kinetics of AMPA receptor-mediated currents by increasing the proportion of GluA2-lacking, calcium permeable AMPA receptors. I next showed that this subunit switch is dependent on the activation of NMDA receptors and calcineurin. In a separate set of experiments I determined the effects of a range of novel AMPA receptor antagonists on synaptic transmission and seizure activity. Decanoic acid, a key component of the medium chain triglyceride ketogenic diet used in refractory epilepsy, has recently been shown to act as a non-competitive AMPA receptor antagonist. Here I showed that a range of structurally related compounds which also act as AMPA receptor antagonists are effective in in vitro models of seizure-like activity. I have further explored the mechanisms underlying decanoic acid's action. Decanoic acid is synergistic with the AMPA receptor antagonist, perampanel, and is not use-dependent. Moreover, I have shown that decanoic acid has an action at voltage-gated sodium channels to decrease the intrinsic excitability of neurons. Decanoic acid reduces the persistent sodium current, without altering the transient sodium current. Surprisingly, decanoic acid has minimal effect on in vivo status epilepticus (prolonged seizure activity) possibly because of rapid and extensive metabolism by the liver. Lastly, I undertook preliminary experiments in human neurons. Decanoic acid effectively reduces induced seizure-like activity in slices from surgically-resected human neocortical tissue. It inhibits AMPA receptor-mediated currents but does not alter intrinsic excitability, as in rat CA1, possibly due to regional differences in neuronal properties. My findings indicate that seizure activity rapidly changes the AMPA receptors expressed in the synapse and identify a range of compounds that target AMPA receptors, which are effective against seizure activity.

Huntington's disease (HD) is caused by the expansion of a CAG repeat in the huntingtin (HTT) gene The R6/2 transgenic mouse model exhibits a rapid onset of Huntington's disease-like phenotypes including neurodegeneration and aggregation of mutant huntingtin protein (mHTT). Neural progenitor cells (NPCs) are a pool of cells with stem cell-like properties and are responsible for self-renewal and differentiation into the cells of the central nervous system and mature brain. In this thesis, NPC lines were established from cells extracted from foetal R6/2 and wildtype mouse embryos and cultured in optimised culture media. NPCs were successfully maintained in a mitotic state as monolayer cultures for multiple passages without effects to karyotype or CAG repeat length. Cultures were differentiated by removal of growth factors, into mixed neurons and glia populations that expressed proteins indicative of mature cell types; neurons showed evidence of synaptophysin expression at junctions between cell neurites, suggesting synaptic functionality and formation of rudimentary neural networks. After differentiation, mHTT aggregation was detectable using immunohistochemistry from 14 days of differentiation in 5% of R6/2 cell nuclei, rising to 20% by 28 days, recapitulating an HD-like phenotype found in vivo. Detection of detergent insoluble mHTT-aggregated protein was also validated via western blotting. Super high resolution cell imaging showed aggregation of mHTT is also present in the cytoplasm. High-content imaging analysis system was performed using the Operetta system to explore morphological differences between WT and R6/2 cultures, as well as within the subset of cells with detectable aggregation. R6/2 nuclei were found to be larger than those of WT cells. Novel compounds known to affect protein aggregation were applied to the cell lines to assess their potential use in screening for approaches to modulation mHTT aggregation. The cells developed in this thesis are a novel and useful complement to the R6/2 mouse; phenotypes observed in vivo can be interrogated at the molecular level in terms of how mHTT protein misfolding and aggregation occur and how this affects cellular function.

Animal models of depression have provided invaluable insight into the disease neurobiology, yet when it comes to novel antidepressant targets, the research progress in this area struggled to keep up with the growing prevalence of the disease. Thus this thesis is dedicated to improvement and optimisation of two frequently used models in mice, the unpredictable chronic mild stress (UCMS) with its good construct and predictive validity, and lipopolysaccharide (LPS) exposure relevant for the inflammatory theory of depression. The experiments described in this thesis show that following optimisation, UCMS can be a reliable model to induce some of the depression-like behaviours, as well as alterations in adult hippocampal neurogenesis (AHN) in mice. However, it appeared that the prefrontal cortex (PFC) but not the hippocampus responds to UCMS with profound gene expression changes and microglial activation. Importantly, UCMS was not associated with a strong profile of systemic inflammatory changes seen in depressed patients. Therefore, the need for an intervention specifically targeting the immune system became apparent. For this, LPS exposure, which induces a depression-like phenotype by activating the immune system, was employed. Results suggested that repeated LPS injections rather than frequently used single LPS exposure might be a suitable model to induce chronic immune changes relevant for depression, as well as some alteration of AHN. However, measures such as dose increment and sufficient recovery time between injections should be taken to avoid development of tolerance towards LPS, although they were not successful in sustaining the long-term behavioural depressive-like phenotype. In conclusion, this research showed that both UCMS and LPS-based interventions induce some endophenotypes relevant for depression, yet neither is sufficient to fully model behavioural changes and neurobiology of the disease in mice. It is suggested that future work combining the two treatments might be more suitable for uncovering and testing novel antidepressant targets.

Myoclonic astatic epilepsy (MAE) is a rare generalised childhood epilepsy with variable but poorly described neurodevelopmental outcome. Family studies suggest a major genetic influence as up to two thirds of relatives have seizures, or electroencephalographic (EEG) abnormalities. MAE is associated with 10 different genes, yet these genes account for less than 20% of the genetic aetiology of MAE leaving the majority unexplained. The aims of this thesis were (1) describe the epilepsy and neurodevelopmental phenotype of MAE cases, (2) perform EEG studies on first degree family members for familial EEG abnormalities and compare occurrence of epileptiform features to population prevalence and (3) to collect DNA and identify MAE causative genetic variants through exome sequencing. I assembled the largest MAE cohort (n=123) to date. The epilepsy phenotype is remarkably similar to previously published cohorts. I identified a severe neurodevelopmental phenotype: intellectual disability was reported in 64.9%, autism spectrum disorder in 21.3% and attention deficit hyperactivity symptoms in 41.0%. Additionally, extremely low adaptive behavioural scores were identified in 69.4% of cases. I performed EEG studies on 38 first-degree relatives of 13 MAE families, and found an excess of epileptiform EEG features in adults (>16 years), compared to controls (P=0.05, RR 6.82). I identified likely pathogenic or candidate variants in 11 of 109 cases. This comprised known genes associated with MAE: CHD2 n=1, SYNGAP1 n=2, SLC6A1 n=1, KIAA2022 n=1; epilepsy associated genes novel for MAE: KCNB1 n=1, MECP2 n=1, KCNH5 n=1, and three new candidate genes; SMARCA2 n=1, ASH1L n=1 and CHD4 n=1. Lastly, I highlight phenotypic features which help correlate with known and novel specific gene associations, discuss that MAE is a phenotypic and genetic nosological bridge between genetic generalised epilepsy and epileptic encephalopathy, and discussion applications and future directions leading on from this project.