Epilepsy affects about 0.8% of individuals [1]. Many treatments are available but more effective and better-tolerated antiepileptic drugs (AEDs) with new mechanisms of actions (MOAs) are needed [2, 3]. Cannabis has been historically used to treat epilepsy [4]. In our laboratory, we have demonstrated anticonvulsant effects of several cannabinoids (e.g. cannabidivarin: CBDV), major cannabis components, in animal models of seizure [5-7]. The aim of this project is to elucidate CBDV's anticonvulsive/ epileptic MOA in order to allow its further clinical development and a further drug discovery for the treatment of epilepsy with a new MOA in the future. To achieve this aim, the effects of CBDV were behaviourally evaluated in several animal models (a rat acute seizure model: pentylenetetrazole (PTZ)-induced acute seizure model, rat chronic epileptic models: pilocarpine-induced spontaneous recurrent seizure (SRS) model and PTZ-kindling model) and subsequently geneiprotein expression analyses were performed using brain tissues from test animals. In an experiment using PTZ-induced acute seizure model, CBOV significantly suppressed seizures. Moreover. suppression of PTZ-induced increases of epilepsy-related gene expressions was seen in CBDV responders. Although CBDV did not show any anti-convulsive effects in PTZ-kindling model, CBDV treatment significantly suppressed disease progression in pilocarpine-induced SRS model.

Social communication is a primary difficulty in autism; however, whilst researchers characterise the communication of children with autism as delayed, deviant and atypical, there is a lack of underpinning evidence for these terms presented in the literature. The current researcher advances understanding of the communicative strategies of people with autism by developing a linguistic framework and highlighting pragmatic and prosodic speech strategies that are linguistically relevant for children with autism. Commonly, research highlights what children with autism are unable to do, for example understand metaphors (see, for example, Rundblad & Annaz, 2010). The researcher's original contribution to knowledge is the identification of both typical and atypical functional linguistic strategies which are adopted and exploited in their communication. The present study offers, therefore; something of a corrective to those studies which focus on the absence rather than presence of targeted language behaviours. The identification of these relevant strategies can provide typical speakers with an insight into how children with autism communicate, and have potential suggestions for clinical intervention. The study's speech data was collected at an autism-specific nursery run by the international charity, 8arnardo's, with the participation of 14 children diagnosed with autism (2;10-4;5 years). Quantitative and qualitative linguistic analyses are performed on segmental and suprasegmental features of the speech data collected. The analytic framework adopted reveals previously undocumented linguistic strategies used by the children with autism, such as prosody-only echolalia, sensory-motivated echolalia, and revelatory aspects to the questions asked and Politeness strategies employed by the children. The researcher suggests that people with autism are communicating, just perhaps not in a way which neurotypicals expect or understand. The overarching principle is that we should aim to find strategies and processes that underlie patterns in their communication; or, in other words, work towards uncovering the dialogue agendas of people with autism.

Identity disturbance has been debated as one of the core features of Borderline Personality Disorder (BPD). The present study availed of biographic narrative interviews to derive life stories of five females with symptoms of borderline personality. Interviews were analysed using thematic analysis. Three themes relating to identity were highlighted from participant transcripts: self to self connection, the distance between us, and hurt and healing. Results provided support for a relational conceptualisation of identity. Participant's identities were impacted upon by family and relationship dysfunction but narratives also illustrated the positive impact of helpful and healing experiences. Findings provided support to theories and interventions that demonstrate a consideration of relational identity and the empowerment of healthy aspects of the self and relationships with others in BPD recovery. Future studies that assess the idiosyncrasies of the association between insight and change may be helpful in providing treatment to this complex population.

This study used the qualitative methodology of Interpretative Phenomenological Analysis (IPA) to examine the experiences of five individuals diagnosed with OCD who underwent a group Cognitive Behavioural Therapy intervention programme to address their symptoms. Three master themes were identified through the analysis process: "Living with OCD prior to the group", "Experiences and process of change" and "Reflections on change". Four of the five participants completed the programme and conveyed their experience of undergoing the group CBT programme to be of great benefit to them in their management of their OCD. For all participants, regardless of whether they completed the group or not, what emerged as being most important in facilitating therapeutic progress across each of their individual narratives ·was whether or not they established a degree of connectedness or relatedness with their fellow group members. It was most resoundingly this commonality that appeared to lay the foundation for subsequent therapeutic change to occur. Key clinical implications arising from the findings are discuss

The Salkovskis (1999) model of obsessive-compulsive disorder (QGD) provides a clinically useful aid to formulation and treatment of OCD (Fenger et al., 2007). Despite fragmented evidence for several of the components and processes in the model, to date there has been no complete empirical evaluation of the model as a whole, and as such, the model represents an untested clinical theory. The present thesis aimed to test and amend this clinical theory by a) reviewing the literature for the individual components and processes of the model; b) operationalizing the components of the model (and additional relevant phenomena) and using structural equation modelling to assess the proposed structure; c) experimentally testing the core emphasis placed by the model on misinterpretation of intrusions, by using a provocation of an obsession-like thought; and d) investigating the proposed central role for misinterpretation of intrusive thoughts in the model, by assessing the relationship between intrusions and creativity. Results indicated that whilst the Salkovskis model was empirically plausible and parsimonious, the focus on responsibility beliefs and appraisals was not sufficient to account for the full range of obsessive-compulsive phenomena. Responsibility appraisals were particularly important in eliciting neutralising behaviour, but obsessional anxiety was more closely linked with morality appraisals. The importance of/need to control thoughts and perfectionism/intolerance of uncertainty belief domains explained additional variance in the tendency to misinterpret intrusions. Disgust sensitivity was also a stronger predictor of obsessional anxiety than any obsessive belief domain, and this relationship was mediated by misinterpretations, supporting a disgust appraisal model. Additional results indicated a relationship between intrusive thoughts and creativity, and a negative relationship between misinterpretation of intrusions and creativity, providing further support for the proposed destructive role of misinterpretation of otherwise innocuous intrusive thoughts in OCD. Theoretical and clinical implications were discussed throughout.

Autism spectrum disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD) are both defined on the basis of behavioural impairments and there is no informative biological test available for the diagnosis of the two disorders yet. The current diagnostic criteria adopt hierarchical approach and preclude the diagnoses of ADHD and ASD in an individual. The thesis investigated whether ASD and ADHD could be discriminated based on their neuropsychological profiles. Moreover, the study explored the cognitive profile of the comorbid ASD-ADHD group. Finally, the thesis assessed whether the biomarkers represent putative endophenotype. The findings suggested that even though the core diagnostic criteria of ADHD and ASD are entirely different, they can co-occur possibly due to shared risk. The neuropsychological data revealed that the poor inhibitory control and premature style of responding appeared to be candidate biomarkers that showed some differentiation between ADHD and ASD. Whereas, weak central coherence style as observed by a disregard for sentence context and impairment in response monitoring were in common to both disorders. Comorbidity was not associated with a more impaired cognitive profile than the pure groups. The comorbid ASD-ADHD group showed a response inhibition deficit and a premature style of responding similar to the ADHD group; and relatively poor understanding of the stories with social content similar to the ASD group. In addition, similar to both groups, they showed impairments of response monitoring and the weak coherence style in verbal domain, which suggests similar neuropsychological correlates. The study opened up an avenue for future endophenotype research by showing antisaccade correction rate and saccade amplitude to meet the co-familiarity criterion for a broad endophenotype that is shared across ASD and ADHD. The study has implication for diagnosis and treatment of the two disorders and their comorbidity, and suggests that the comorbid ASD-ADHD could be a fruitful candidate for future research.

Eating behaviour is an important aspect of social behaviour, and illnesses like eating disorders thus have a profound impact on quality of life. Family and twin studies provide compelling evidence for the heritability of eating disorders; it is estimated that roughly half of the phenotypic variance is accounted for by genetic factors. The presumed genetic architecture of eating disorders constitutes multiple genetic variants, each with a small effect size. This thesis aimed to replicate findings from the most extensive genetic studies of eating disorders done thus far, in a sample of 700 anorexia nervosa cases and 700 controls from the United Kingdom, the Netherlands, and Austria. The results are non-significant, which is in line with genetic studies of other psychiatric disorders, as well as complex traits such as human intelligence, height, and body mass index. Power to detect genetic risk variants with small effect sizes could be increased by larger samples sizes, and by focussing on disease related quantitative traits rather than diagnoses. Candidate quantitative traits for eating disorders include drive for thinness, bulimia, and body dissatisfaction as measured by the Eating Disorders Inventory (EDI) questionnaire. Chapter 3 of this thesis presents the distribution of these traits in a general population sample from the United Kingdom (n = 3,624 females), and Chapter 4 presents the results of genome-wide association gene (GWAG) analyses of these traits. No gene p values passed a multiple gene testing correction, but among the top genes were several previously implicated in the aetiology of eating disorders. Larger sample sizes would be needed to verify these results. The results of this thesis underscore the phenotypic and aetiologic complexity of eating disorders, but demonstrate that a general population approach using quantitative trait measurements combined with genome-wide hypothesis-free gene analyses can be fruitful.

Introduction: Patients with idiopathic generalised epilepsy (IGE) show generalised discharges, which are assumed to occur synchronously over the entire cortex. We hypothesis that (1) Generalised discharges are propagated and this can be shown by latency differences between EEG spikes recorded over homologous sites at discharge onset, and (2) Discharge synchronicity may predict treatment response. Methods: Eighty-five patients EEGs, containing generalised discharges were analysed to identify latency differences between spikes recorded at homologous regions between hemispheres at discharge onset. The discharges were either synchronous or non-synchronous generalised spike-and-waves (GSW), polyspike-and-waves (PSW) or GSW+PSW. Results: At onset, discharges were synchronous (with no latency differences between hemispheres) in 29 patients (34 %), were led by the left hemisphere in 17 patients (20%) and by the right hemisphere in 16 patients (19 %). In 23 patients (27%), discharges were a mixture of synchronous and non-synchronous discharges at onset. In non-synchronous discharges, the range of latency differences at discharge onset was 6-45 ms (mean latency 19.2ms). Interictal focal abnormalities were seen in 59 patients (69 %) in addition to the generalised discharges. There was an association between presence of synchronous discharges and one seizure type, and between presence of non-synchronous discharges and multiple seizure types (P =0.01). In addition, there was an association between presence of synchronous generalised discharges and good response to prescribed antiepileptic drugs (AED), and between non-synchronous discharges and poor response to AEDs (p=0.0001). The proportion of patients who responded favourably to medical treatment was significantly higher among those with synchronous discharges (>80 %) compared to those where one hemisphere led (<25 %). Conclusion: In IGE, generalised discharges are not always synchronous. EEG latency analysis could be used to identify non-synchronous discharges, which may be predictors for multiple seizure types and poor response to AEDs.

In recent years Autism Spectrum Disorders (ASD) have been considered as resulting from altered connectivity between regions, which may explain characteristic manifestations in socio-emotional function, communication and repetitive behaviour observed clinically. This thesis aims to provide evidence for altered anatomy of networks in ASD. The first step consisted in the creation of a diffusion tensor tractography atlas of the normal human brain derived from 40 healthy adults. The atlas was then used to localise the findings from a metaanalysis of published voxel-based morphometry studies investigating white matter abnormalities in ASD. This analysis showed that patients with ASD display abnormalities in long white matter association tracts, such as the arcuate and uncinate fasciculus, known to be important for language and social cognition. A second step consisted in the tractography analysis of limbic and cerebellar tracts in a small pilot study. Our findings confirmed differences in the the uncinate tract in ASD and in addition we found differences in the cingulum and major intracecebellar and cerebellar output tract. Finally, Tract-Based Spatial Statistics (TBSS) and tractography analysis of a multi-centre, case-control study was performed on 61 individuals with ASD and 61 controls. Differences in the frontal connections of the arcuate fasciculus, uncinate fasciculus, cingulum and corpus callosum were found. Tract specific measurements in the arcuate and uncinate were associated with a history of delayed echolalia and impaired used of face expression in childhood, respectively. In conclusion these series of studies show that ASD are associated with specific structural abnormalities of the limbic, language and interhemispheric white matter fibres. Differences in white matter anatomy were localised in major connections to the frontal lobe and associated with specific autistic features and traits in chilldhood. These results are compatible with the concept of ASD as a developmental frontal connectivity syndrome.

Interferon-alpha (IFN-α) therapy for chronic hepatitis C virus (HCV) infection is associated with the development of depression and other neuropsychiatric adverse effects. However, well-defined predictors of this depression are still lacking. Several interlinked biological systems as well as cognitive and psychosocial factors may predispose individuals to the development of IFN-α-induced depression. The aim of this study was to identify such predictive factors as well as prospectively monitor the impact of IFN-α on a variety of clinical and biological outcomes. Forty-eight patients with chronic HCV infection were recruited and assessed at baseline and after 4, 8, 12, 16, 20 and 24 weeks of IFN-α treatment. At each assessment, patients were evaluated with a number of questionnaires as well as the structured Mini International Neuropsychiatric Interview (MINI) for a diagnosis of major depressive disorder. Blood samples were also collected at all time points as well as salivary cortisol at baseline and end of treatment. IFN-α-induced depression developed in 40% of patients. Patients who developed IFN-α-induced depression had more negative illness perceptions, lower baseline levels of cortisol during the day, and lower baseline levels of kynurenic acid. Patients who developed IFN-α-induced depression also had altered gene expression in a number of pathways relevant for depression such as inflammation and neuroplasticity. Finally, detection and management of depression in this population is shown to be a complex process, reliant on the availability of clinical experts and good communication within a multidisciplinary team. In conclusion, the findings of this study provide evidence for a number of cognitive, psychosocial and biological predictors of IFN-α-induced depression. These findings provide a rationale to test the effect of preventative cognitive interventions in these patients. However, future studies are needed to confirm some of these novel clinical and biological predictors, as well as to look at the interplay between these factors.