This three-part thesis focuses on psychological therapy for personality disorders (PDs) and factors that influence both treatment completion and outcome. Part one is a literature review investigating documented mechanisms of change in the cognitive behavioural therapy (CBT) and dialectical behavioural therapy (DBT) treatment for borderline personality disorder (BPD) in current research. Although much research has focussed on improving treatment outcomes for BPD, there is very little research investigating the proposed changes by which these outcomes might occur. Three distinct categories of mechanism of change were found to be consistent across the literature examined. These categories are discussed in detail along with implications for future research and clinical practice. Part two presents a longitudinal empirical study of factors which affect treatment completion and treatment outcome in the CBT or DBT treatment of PD. Data spanning a six year period was collected and analysed for 231 patients. Results showed that therapist expertise was the only variable examined associated with treatment completion: more experienced therapists retained their patients in treatment for longer than less experienced therapists. Therapeutic dose (number of sessions attended), therapist expertise and substance misuse all predicted changes in risk outcome (deliberate self-harm, suicide attempts) and in number of PD diagnoses following treatment. Only therapeutic dose predicted change in other clinical diagnoses following treatment. Implications and strength of these findings are discussed in relation to problems with incomplete data, statistical analyses and non-representative sampling issues. Part three is a critical appraisal of the entire research process reflecting upon its challenges and successes. This section also includes a commentary on the field of PD research in general, and considers issues pertinent to future research.

This thesis investigates the visual deficits associated with developmental dyslexia, particularly that of visual attention. Visual attention has previously been investigated in a wide array of behavioural and psychophysical (amongst others) studies but not many have produced consistent findings. Attention processes are believed to play an integral part in depicting the overall "extent" of reading deficits in dyslexia, so it was of paramount importance to aim at such attention mechanisms in this research. The experiments in this thesis focused on signal enhancement and noise (distractor) exclusion. Given the flexibility of the visual search paradigms employed in this research, factors such as visual crowding and attention distribution was also investigated. The experiments systematically manipulated noise (by increasing distractor count, i.e. set-size), crowding (varying the spacing between distractors), attention allocation (use of peripheral cues to direct attention), and attention distribution (influence of one visual field over the other), all of which were tied to a critical factor, the "location/spatial/decisional uncertainty". Adults with dyslexia were: (i) able to modulate attention appropriately using peripheral pre-cues, (ii) severely affected by crowding, and (iii) unable to counteract increased set-sizes when post or un-cued, the latter signifying poor distractor (noise) suppression. By controlling for location uncertainty, the findings confirmed that adults with dyslexia were yet again affected by crowding and set-size, in addition to an asymmetric attention distribution. Confounding effects of ADHD symptoms did not explain a significant independent variance in performance, suggesting that the difficulty shown by adult dyslexics were not accounted for by co-morbid ADHD. Furthermore, the effects of crowding, set-size and asymmetric attention correlated significantly with literacy, but not ADHD measures. It is believed that a more diffuse and an asymmetric attention system (in dyslexia) to be the limiting factor concerning noise exclusion and attention distribution. The findings from this thesis add to the current understanding of the potential role of deficits in visual attention in dyslexia and in the literacy difficulties experienced by this population.

Epilepsy is one of the most common neurological disorders, a large fraction of which is resistant to pharmacotherapy. In this light, understanding the mechanisms of epilepsy and its intractable forms in particular could create new targets for pharmacotherapeutic intervention. The current project explores the dynamic changes in neuronal network function in the chronic temporal lobe epilepsy (TLE) in rat and human brain in vitro. I focused on the process of establishment of epilepsy (epileptogenesis) in the temporal lobe. Rhythmic behaviour of the hippocampal neuronal networks in healthy animals was explored using spontaneous oscillations in the gamma frequency band (SγO). The use of an improved brain slice preparation technique resulted in the natural occurence (in the absence of pharmacological stimulation) of rhythmic activity, which was then pharmacologically characterised and compared to other models of gamma oscillations (KA- and CCh-induced oscillations) using local field potential recording technique. The results showed that SγO differed from pharmacologically driven models, suggesting higher physiological relevance of SγO. Network activity was also explored in the medial entorhinal cortex (mEC), where spontaneous slow wave oscillations (SWO) were detected. To investigate the course of chronic TLE establishment, a refined Li-pilocarpine-based model of epilepsy (RISE) was developed. The model significantly reduced animal mortality and demonstrated reduced intensity, yet high morbidy with almost 70% mean success rate of developing spontaneous recurrent seizures. We used SγO to characterize changes in the hippocampal neuronal networks throughout the epileptogenesis. The results showed that the network remained largely intact, demonstrating the subtle nature of the RISE model. Despite this, a reduction in network activity was detected during the so-called latent (no seizure) period, which was hypothesized to occur due to network fragmentation and an abnormal function of kainate receptors (KAr). We therefore explored the function of KAr by challenging SγO with kainic acid (KA). The results demonstrated a remarkable decrease in KAr response during the latent period, suggesting KAr dysfunction or altered expression, which will be further investigated using a variety of electrophysiological and immunocytochemical methods. The entorhinal cortex, together with the hippocampus, is known to play an important role in the TLE. Considering this, we investigated neuronal network function of the mEC during epileptogenesis using SWO. The results demonstrated a striking difference in AMPAr function, with possible receptor upregulation or abnormal composition in the early development of epilepsy. Alterations in receptor function inevitably lead to changes in the network function, which may play an important role in the development of epilepsy. Preliminary investigations were made using slices of human brain tissue taken following surgery for intratctable epilepsy. Initial results showed that oscillogenesis could be induced in human brain slices and that such network activity was pharmacologically similar to that observed in rodent brain. Overall, our findings suggest that excitatory glutamatergic transmission is heavily involved in the process of epileptogenesis. Together with other types of receptors, KAr and AMPAr contribute to epilepsy establishment and may be the key to uncovering its mechanism.

Background: Body image disturbances are central to the psychopathology of eating disorders (ED). There is growing recognition that body image is not stable and can be influenced by a variety of factors, however it remains unclear whether perceptual deficits exist in ED individuals. Recent research suggests that experiences of dissociation may undermine the stability of body image and create a vulnerability to body image disturbances. Dissociation is commonly observed in ED and has been linked to body image disturbance. The present study aimed to investigate the relationships between experiences of dissociation, body image disturbance and perceptual body image instability in a group of ED individuals, dieters (DT), and non-dieting healthy controls (HC). Method: 20 individuals diagnosed with an ED, 20 DT, and 20 HC completed experimental and self-report measures of dissociation, body disturbance, body checking and body image instability. Perceptual body image instability was measured using the Rubber Hand Illusion (Botvnik & Cohen, 1998). Results: Findings suggest ED individuals experience higher levels of dissociation, body image disturbance and body checking than HC and DT groups. Contrary to hypotheses, body image instability did not significantly differ between groups. Positive relationships were found between psychological dissociation and body checking cognitions in ED (r(20)=0.52, p<0.01) and in DT (r(20)=0.54, p<0.01). Furthermore, exploratory mediation analysis revealed that body checking cognitions were a significant predictor of the relationship between psychological dissociation and body dissatisfaction (z=-3.28, p<0.01). Conclusions: Body image disturbance in ED is a complex multi-factorial psychopathology. The study did not confirm whether ED individuals experience higher perceptual body image instability than controls; instead findings suggest cognitive-emotional influences impact upon body disturbance in ED to a greater degree. Furthermore, results showed that cognitions surrounding body checking are a significant maintaining factor in the relationship between psychological dissociation and body dissatisfaction. For some individuals, body checking may serve as a method of grounding themselves when experiencing dissociation. Findings have implications for the assessment and treatment of body image in ED.

Background: Women with epilepsy (WWE) need preconception care to help them weigh the risks of loss of seizure control before and during pregnancy against potential harm to the unborn baby and review medication options. This is most important for those taking the highly teratogenic sodium valproate (VPA). Research shows that the minority of WWE access or remember preconception care, and there is lack of evidence regarding the effectiveness of preconception care and the experience of care and decision making. Aim: to understand the preconception experiences of WWE. Objectives: 1) To understand the communication that occurs between WWE and health care practitioners and the extent to which this enables them to plan and manage their pregnancy; 2) To understand the preconception decision making of WWE regarding their medication options; 3) To identify the preconception interventions that WWE encounter for decision making and preparing for pregnancy and to understand the impact that these have on women's experience. Methods: A qualitative study with descriptive analysis of audio-recorded Preconception Clinic consultations for WWE (n=7), and Interpretative Phenomenological Analysis (IPA) of interviews with the women at home after their consultations and again up to one year later, and interviews with pregnant WWE recruited at a Joint Obstetric Neurology Antenatal Clinic pregnant at time of interview (n=lO, of whom one had previously attended the Preconception Clinic). Purposive sampling included 7 women who had taken VPA before pregnancy, and 10 'non-VPA', and the interviews were analysed in these two groups. Findings were related to attributes of Preconception Care derived from a Concept Analysis. Findings: Preconception Clinic Consultations were 28- 80 minutes, mainly conducted by an Epilepsy Specialist Nurse with a short intervention from the Consultant Neurologist. The consultation covered medication and treatment options, and broader concerns raised by women and their partners/mothers. Women evaluated the clinic positively and described continuing decision making after the clinic - "/ decide". The main theme relating to women who had taken VPA was a "trajectory of balance". Woman moved from "maintaining balance" by using VPA to control seizures, to a "shattering of harmony" at the prospect of changing medication and as a result of the physical and emotional effects of changing medication, to "restoring balance" which could involve "a new self' due to the dramatic changes. They found it difficult to see "who is looking after me?" in the care system, and turned to family and friends for support in the absence of care. For 'Non-VPA' women the main theme was 'the onus is on me', with repeated experience of "care is not consistent" and being "sent off track" by inappropriate advice. In both groups, perception of risk to the future baby was influenced by personal experience (of previous pregnancy or friends), perception of disability, and perception of motherhood. Conclusions: A clear care pathway is needed starting from diagnosis of epilepsy, and offering support for stress. Understanding what influences maternalisation may be helpful in understanding uptake of preconception care.

Aim: The aim of the current research is to gain an understanding of the individual experience of anxiety and worry with a particular focus on spontaneous images. In order to do this, the phenomena of spontaneous images, worry and anxiety require clarification. Some history of these phenomena is provided by describing the more researched worry and anxiety and adding the more recent recognition of the experience of spontaneous images. The current Diagnostic and Statistical Manual of Mental Disorders, (DSM-IV-TR; American Psychiatric Association/APA, 2000) describes a generalised anxiety as a disorder characterized by excessive worry. The new DSM-5 (APA, 2013) also does not acknowledge spontaneous images and their impact on the worrier. The present research is not intended to verify the presence of spontaneous images per se, rather it attempts to explore the lived experience of generalised anxiety and worry and to add another perspective to this age old human characteristic with a specific look at the experience of spontaneous images. In order to do this and allow for these phenomena to unfold, a phenomenological stance on worry, anxiety and spontaneous images is taken. Method: The experience of worry, anxiety and associated spontaneous images was analysed using a qualitative approach namely, Interpretative Phenomenological Analysis (Smith et al, 2009). Data was collected via a semi-structured interview with eight students aged between 18 and 25 years. The interviews took place in a student counselling service and were audio recorded with appropriate consent. The interviews were transcribed verbatim and the participants given pseudonyms to ensure anonymity. Results and Conclusions: Six master themes emerged from participant’s accounts; self- absorption, awareness of worry and anxiety as all-encompassing, trying to cope with anxiety and worry, the past in the present, consumed by the other, and finally, life with spontaneous images. The findings are then discussed in relation to the relevant literature, and implications for therapeutic practice, methodological limitations and directions for future research are presented.

Empirical research on sex therapy appears to be a significant and growing area in the social sciences, with researchers evaluating the use of a variety of different psychotherapy modalities in the treatment of male sexual problems. However, although clinical literature suggests that sex therapists may use psychodynamic techniques in their clinical practice, current empirical research on the place of psychodynamic methods in the sex therapy field is negligible. This research project aims to help fill this gap. The primary aim of this research project is to identify the role of psychodynamic methods in sex therapy. The principal research question underlying this work is: to what extent do psychosexual therapy specialists currently employ psychodynamic therapy techniques in treating men’s sexual dysfunctions? A number of secondary aims also guided this research programme. This work aimed to gather data on: • the ways in which sex therapists conceptualize and use the biopsychosocial model, • the diagnostic and assessment protocols they use with male clients, • the methods they use in establishing clinical goals and developing case formulations, • the ways in which sex therapy specialists conceive of and assess the aetiology of male sexual problems, and • the place that psychodynamic versus cognitive behavioural therapy (CBT) techniques play in the treatment of male sexual dysfunction. The role of psychodynamic theory and technique was considered in relation to all of these factors. Methods: To evaluate these issues, this research project used a combination of: 1) a questionnaire-based survey, administered to practitioners in the sex therapy field, and 2) interviews with sex therapists and subject matter experts. The questionnaire sample 6 consists of specialist sex therapists, and psychotherapy generalists who have experience in treating male sexual dysfunction. By examining the differences in technique reported by these two populations, this research sought to establish what is unique about psychosexual therapy, and what specific role psychodynamic techniques play within this specialization. The qualitative data generated from the interviews were used to clarify the integrative practices by which psychodynamically-based theory and technique are included in the treatment of male sexual dysfunction. Results: The data indicate that both sex therapists and psychotherapy generalists make use of prototypical and distinctive psychodynamic techniques to a significant degree in their work treating male sexual problems. Sex therapists report using psychodynamic and CBT techniques to approximately the same degree. Psychotherapy generalists report a higher level of adherence to psychodynamic techniques than sex therapists. Sex therapists report a high level of endorsement of the biopsychosocial model, and report drawing on a range of psychotherapy frameworks, including psychodynamic methods. A high level of focus on psychosocial and relational factors is reported, and attachment theory is identified as a key clinical factor in sex therapists’ work. The data suggest that sex therapists view insight—including insight into unconscious factors—as an important element of the therapeutic change process. Conclusions: The data indicate that psychodynamic theory and technique are integral to sex therapy practices. Often, however, psychodynamic techniques may be used implicitly and psychosexual therapists may not explicitly recognize their perspective as psychodynamic. Additionally, psychodynamically-informed techniques that focus on the client’s relationships, early life and development, and gaining insight into aetiology, may be of particular importance in the sex therapy field, and represent an area for future research.

Mice lacking functional neurokinin-1 receptors (NK1R-/-) display several behavioural abnormalities that resemble Attention Deficit Hyperactivity Disorder (ADHD), including locomotor hyperactivity (which is alleviated by ADHD medication), impulsivity and inattentiveness. These findings prompted the proposal that NK1R-/- mice offer a novel murine model of ADHD. The first aim of this thesis was to investigate the influence of non-genetic (epigenetic/environmental) factors on the behaviour of NK1R-/- mice by comparing animals from two different breeding protocols. These studies revealed that certain elements of their impulsivity are influenced by non-genetic factors, but other behaviours are not. The second aim was to compare the behaviour of male and female animals, to determine whether there are sex differences in their behaviour. This study revealed that the hyperactivity of NK1R-/- mice is not evident in females, echoing typical sex differences in ADHD patients. Following this, the behavioural effects of several drugs that target the brain renin angiotensin system (BRAS) are reported. This was prompted by preliminary evidence that the BRAS and NK1R interact in the regulation of locomotor activity. The angiotensin converting enzyme (ACE) inhibitor, captopril, abolished the hyperactivity and impulsivity of (male) NK1R-/- mice, suggesting that ACE could provide a novel therapeutic target for the treatment of ADHD. By contrast, angiotensin receptor antagonism either exacerbated or had no effect on these behaviours, suggesting that captopril's therapeutic effect is not due to a reduction in angiotensin II. Finally, the performance of NK1R-/- mice in the 5-Choice Continuous Performance Test was investigated. NK1R-/- mice displayed performance deficits only during certain phases of training, suggesting that detection of the impulsive or inattentive phenotype might require unpredictable test parameters. Overall, these studies further validate/phenotype the NK1R-/- mouse model of ADHD, and point to an interaction between the BRAS and NK1R in the regulation of ADHD-related behaviours, which warrants further investigation.

Huntington’s disease (HD) is a late-onset, autosomal, dominant and progressive neurodegenerative disorder for which there is no disease-modifying therapy. An abnormal trinucleotide CAG repeats expansion (>36 CAG repeats) in exon 1 of the gene coding for the Huntingtin (HTT) protein is the causative mutation for the disease. Animal models of HD, such as the R6/2 mouse model, already exist. Yet, in order to understand the disease at a molecular level, cellular models of HD are also needed. At the beginning of this project, existing models had been developed from tumour cell lines using genome-integrating lentiviral delivery system carrying a mutated HTT exon 1. This model was not optimal, as the cells will always have noninnate extra copies of HTT, which expression is driven by exogenous promoter. In order to circumvent this, we were aiming to develop two human stem cell models of HD and use them as tools in drug discovery and further understanding of molecular mechanisms of the disease. The first model is human embryonic stem cells (hESCs) isolated from clinically unsuitable embryos, donated by consenting couples. The embryos carrying a mutation in HTT gene, as determined by Preimplantation Genetic Diagnosis (PGD), were used to derive HD-specific mutation-carrying hESC lines (HD-hESC). Seven HD- hESCs lines were derived at the Assisted Conception Unit (ACU) at Guy’s Hospital, King’s College London (KCL). The second model is induced pluripotent stem cells (iPSCs) that I would derive from keratinocytes obtained from plucked hairs of consenting HD patients. Their greater availability means that we would be able to derive lines representing a larger spectrum of HD phenotype due to variations in CAG repeats expansion. Reprogramming will be done using a combination of modified mRNAs and/or a lentiviral vector encoding the transcription factors needed for reprogramming. The overall goal of the project was to optimize culture conditions for the HD-hESC and HD-iPS cell lines, fully characterise them, and differentiate them in vitro. Epidemiology studies suggest that cardiac failure is the second cause of death in HD patients. For this reasons, HD-ESCs were differentiated into cardiac cells (cardiomyocytes) in order to define and characterize the cardiac HD phenotype. Here, I am describing thorough characterization of normal and HD-hESC lines and their differentiation into cardiomyocytes. I am also presenting my data on reprogramming of human fibroblasts into iPSC using synthetic modified mRNA. Due to time limit and several technical issues outlined in the text, I was unable to successfully reprogram cells from keratinocytes obtained from plucked hairs of consenting HD patients.

Anorexia nervosa is a serious and complex mental illness, where little is known of factors implicated in its maintenance. Current effective treatments for adolescent anorexia nervosa have shown promising outcomes, however a significant group of patients still remain unwell. One factor that contributes to a poor treatment outcome is comorbid anxiety. However, there is a lack of knowledge of anxiety related vulnerability factors in individuals with anorexia nervosa. A potentially useful anxiety related factor is intolerance of uncertainty (IU). Theoretically and clinically IU could be associated with eating disorder psychopathology and the need for control, often found in individuals with anorexia nervosa. This thesis comprises of a conceptual model of IU in anorexia nervosa, four studies that empirically examine IU and associated factors in relation to anorexia nervosa and a proposed future study. The first quantitative study investigates anxiety related factors in adults with anorexia nervosa and healthy controls. The two subsequent qualitative studies explore the meaning of uncertainty for adolescents with anorexia nervosa and their parents. The fourth study examines anxiety related factors in adolescents with anorexia nervosa, similar to study 1, and further investigates whether such factors along with beliefs about having an eating disorder and parental distress moderate/mediate response to treatment. Findings, suggest that IU and anxiety related factors are elevated in adults and adolescents with anorexia nervosa compared to the normal population and are positively associated with eating disorder psychopathology. Personal accounts from adolescents further reveal that IU is predominately a negative experience, while parents find uncertainty in relation to their child’s illness excessive and a source of distress. Results from the fourth study indicate that ambivalence in adolescents at the beginning of therapy predicts response to treatment. This thesis has brought to the forefront the construct of IU as a possible maintenance factor of anorexia nervosa. Data are discussed in relation to the proposed model of IU in anorexia nervosa and both theoretical and clinical implications are discussed.