Since the identification of a widespread transcriptional dysregulation that occurs in Huntington's disease (HD), histone deacetylase (HDAC) inhibition has been explored as a possible therapeutic strategy for this devastating disease. Studies using broadrange acting HDAC inhibitors have shown great promise in HD mouse models. Concomitantly, effects of inhibition of individual HDACs have been investigated, however, these experiments have been most frequently performed in worm, fly, and cell and less so in mouse models of HD. Previous reports have demonstrated disease modifying potential for both HDAC6 and SIRT2, which are the only tubulin deacetylases known in mammals. Nevertheless, the therapeutic value of these enzymes has not yet been explored in a complex mammalian system. This work addressed the question of what is the effect of genetically depleting either HDAC6 or SIRT2 in the R6/2 mouse model of HD on disease progression. After thorough characterisation of both Hdac6KO and Sirt2KO mice and expression of either mutation in the R6/2 mouse, a battery of physiological, behavioural and molecular readouts has clearly demonstrated that previous studies performed in invertebrate or cell culture systems do not translate to the mouse and that, therefore, HDAC6 and SIRT2 inhibition would not be of therapeutic value and should not be prioritised as a therapeutic strategy in HD.

The thesis examined the evidence base for psychological interventions for the treatment and prevention of adolescents with callous-unemotional characteristics exhibiting aggression and self-harm behaviours. The research process has three sections. Self-Contained Literature Review: Within the adult literature Dialectical Behavioural Therapy (DBT) is recognised as an effective treatment with adults presenting with suicidal ideation and self-harm. Clinicians have adapted the adult DBT programme for adolescents (DBT-A) and the review paper considered the literature base for the effectiveness of the adapted intervention for adolescents who exhibited suicidal ideation and self-harm behaviours. The review critically appraised ten quantitative studies that employed either comparison groups (4 studies) or a pre-post design (6 studies). The results suggested DBT was effective in reducing symptoms of suicidal ideation and self-harm behaviours, in additional to ameliorating other mental health problems. There were issues with confounding variables and the delivery of the DBT-A programmes were varied across studies. Future research needs to be of a higher quality. Research Report: The empirical study was conducted within medium secure facilities with 76 in-patient adolescents to explore the associations of aggression (proactive and reactive) and non-suicidal self-injury (NSSI) with callous-unemotional (CU) traits. CU traits consisted of three dimensions of behaviour, callousness, uncaring, and unemotional that might designate a subgroup of inpatient adolescents. A number of significant associations were identified between the components of CU traits and proactive aggression and reactive aggression. The findings suggested that adolescents characterised by higher levels of CU traits were more than likely to exhibit combined proactive and reactive aggression. Those young people who exhibited NSSI scored higher on the unemotional dimension of CU traits. The findings were discussed in the context of existing research. Critical Appraisal: A personal account of the researcher’s reflections on the research process was provided in the critical appraisal.

The first aim of the research was to extend the work of Gelfond (1991) to consider how far the symptoms of agoraphobia were present in a non-clinical sample of males and females. This was achieved using both statistical and qualitative (Interpretative Phenomenological Analysis) methods. The results indicated that both male and female participants' experience discomfort when alone in public places on a continuum with clinical descriptions of agoraphobia. Two differences between clinical and non-clinical accounts were identified. The first being that differences appeared to be dimensional (e. g. intensity, preoccupation). Secondly, non-clinical participants' accounts did not describe 'catastrophic misinterpretations' of physiological arousal as seen in clinical accounts. The second aim of the research related to how a gender analysis of male and female participants' accounts of their use of public places alone would contribute to our understanding of agoraphobia. Statistical results suggested that only female participants were significantly avoidant of public places alone compared to when they were accompanied. In addition, three qualitative tools of analysis (Interpretative Phenomenological Analysis, Rhetorical Discourse Analysis and Foucauldian Analysis) were adopted. These analyses highlighted social processes by which lone women may experience greater discomfort than lone men in public places, as well as exploring how such processes predispose males and females to react to discomfort in different ways. It is argued that these social processes 'prepare' women, in particular, for anxiety and avoidance on a continuum with symptoms of agoraphobia. This in turn provides an explanation as to why the majority of those diagnosed with agoraphobia are women. This poses questions for the assertion in DSM IV (American Psychiatric Association, 1994) that social practices that restrict women's use of public places should be distinguished from agoraphobia. Clinical and research implications are discussed.

Researchers return again and again to the therapeutic relationship as it is such a fundamental part of any type of therapeutic work. However, developing relationships with individuals diagnosed as having a `personality disorder' has been considered to be difficult. Those thought to be particularly difficult to engage in relationships are those within the forensic population who have attracted a diagnosis of `personality disorder' and who have histories of reoffending. This study attempts to understand the experiences of therapeutic relationships of these individuals in a community-based forensic personality disorder service. As much of the current research points out problems and negative experiences of relationships, this study aims to explore positive examples of relationships as well. Six male service users from a community-based forensic personality disorder service were interviewed using semi-structured interviews. An interpretative phenomenological analysis (IPA) was used to develop four themes from the interview data. The analysis revealed that relationships between participants and staff were complicated by their own concerns about engaging in close relationships ('stopping myself from getting close'). Difficulties also arose due to how staff were experienced ('other people stop me from getting close'). However, more positive experiences of relationships were talked about ('working the relationship out together') and participants found themselves to be active in their own rehabilitation when they felt empowered by relationships ('now I can make it happen'). The findings are discussed in relation to other research with this client group and theoretical understandings of relationships. Recommendations are made for how clinical psychologists can work directly with these clients and support others working with them. It is suggested that future research into relationships could focus on positive as well as more problematic experiences of relationships.

In this thesis, a cellular automaton model of wave motion is developed with the goal of creating a model of seizure progression. We create a cellular automaton model of seizure progression based upon the model of wave motion. This is compared to existing models from the literature of both seizure progression and neuronal dynamics: good correspondence is found. The model is then used to assist in determining the location of epileptic foci from which seizures originate based on data obtained from intra-operative optical coherence tomography data. A tool based on the cellular automaton model is created, which predicts the location of an epileptic focus based on optical coherence tomography data obtained during surgery. Together, these results suggest that the incorporation of geometrical techniques into mathematical models of seizure activity can provide new insights into underlying pathophysiology.

Spontaneous facial mimicry is a biological marker of affective empathy. Individuals with Autistic Spectrum Conditions (AS C), known to be weak empathisers, show reduced spontaneous facial mimicry compared with typically developed individuals. However, evidence that deliberate facial mimicry in ASC is intact refutes the notion of a deficit in the ASC mimicry system per se, and instead raises two interesting questions; (I) What drives spontaneous facial mimicry in the general population? (2) Why do individuals with ASC not engage in spontaneous facial mimicry to the same extent as typically developed individuals? In this thesis I test the hypothesis that a connection exists between the brain's reward and mimicry systems and that this reward-mimicry link is dysfunctional in individuals diagnosed with ASC. In addressing the first question, this thesis integrates findings from two techniques; electromyography (chapter 3) and fMRI (chapter 4 and 5). Furthermore, a meta-analysis of previous imaging studies explores whether overlap exists between the neural correlates reported III fMRI studies of reward and empathy (chapter 2). The results described in chapters 3, 4, and 5 confirm the hypothesis of a reward-mimicry link in the general population, whilst the meta-analysis indicates that the link might extend beyond mimicry to other components of empathy. In addressing the second question, the autism quotient (AQ) was used to measure autistic traits in participants in the EMG and fMRI studies. In each case there was evidence that the reward-mimicry link was weaker in individuals with high autistic traits compared to those with low autistic traits. In the final study (chapter 6) EMG was used to examine the reward mimicry link in individuals diagnosed with ASC. Partial evidence of a dysfunctional reward mimicry link was found in individuals diagnosed with ASC who possessed AQ scores at the extreme high end of the spectrum. However, based on the current evidence, the possibility that this finding resulted from a regionally specific deficit in the ASC mimicry system - and not from a deficit in the reward-mimicry link - cannot be ruled out.

Transgenic and knockout mouse models of disease and gene function have revolutionised the field of biomedical research and the targeted mutations of genes expressed in the brain are revealing the mechanisms underlying normal behaviour and behavioural abnormalities which has led to the development of behavioural neuroscience. However, it is also clear that the phenomena know as "redundancy" can limit the effectiveness of traditional knockout models by the effects of compensatory mechanisms. This thesis utilises transgenic and knockout mouse models to explore the role of the tachykinins in the pathogenesis of anxiety, depression and epilepsy focusing on the TACl gene products and their functionality via the TACRl (NKl) receptor. The generation of a novel double knockout line via the cross breeding of single knockout models relevant for the tachykinin signalling pathways circumnavigates the problems associated with redundancy and also reveals that this phenomena is contributing to the data generated using the single knockouts. The use of these animals in a variety of experimental models to compare their function with the original "parental" knockouts and their corresponding wildtype controls reveals novel models for the action of the tachykinins in epilepsy and suggests a correlation with serotonin levels with an ultimate effect on the behavioural responses observed.

Inter-temporal choice refers to a situation where a decision has to be made between two or more rewards of different sizes that are available after different delays. There is evidence that abnormalities of inter-temporal choice behaviour (biased selection of smaller immediate rewards in preference to larger delayed rewards) may be associated with some clinical conditions, such as attention deficit hyperactivity disorder (ADHD), which are characterised by deficient impulse control. Evidence suggests that abnormal inter-temporal choice behaviour and occurrence of ADHD may develop from dysfunction of cortico-striato-thalamo-cortical (CSTC) circuits in the brain. Three experiments described in this thesis examined. the effects of a systematic disruption of CSTC circuits on inter-temporal choice performance in rats. The results of these experiments generated hypotheses about the roles of some components of the CSTC circuits in regulating the efficacy or 'instantaneous valueof reinforcers, which were tested in two further experiments that employed quantitative analyses of performance on a single-operandum progressive ratio (PR) schedule of reinforcement. Chapter 1 reviews the literature dealing with key theoretical concepts and experimental findings pertaining to inter-temporal choice and single-operandum schedules. Section 1. J is a preamble that offers a general background to the work that was carried out as well as the aims and brief outline of the experiments that were conducted. Section 1.2 reviews the history of the concept of inter-temporal choice and the way it has been accounted for from economic as well as behavioural perspectives. It examines the empirical data from the experimental analysis of behaviour in inter-temporal choice tasks and gives an account of the putative neurobiology that underlies this behaviour. Section 1.3 reviews the theoretical as well as practical notions of the use of PR schedules and their potential for dissociating behavioural mechanisms involved in inter-temporal choice behaviour. Chapters 2~ describe a series of five experiments that examined the effects on inter-temporal choice and PR performance following damage inflicted to the CSTC circuits in the rat brain. Experiment I sought to elaborate on previous findings that lesions of the core of the nucleus accumbens (Acbe) promote preference for smaller earlier reinforcers over larger delayed reinforcers in inter-temporal choice paradigms by clarifying whether this reflects an effect of the lesion on the rate of delay discounting, on sensitivity to reinforcer magnitude, or both. A quantitative method that allows effects on delay discounting to be distinguished from effects on sensitivity to reinforcer size showed that lesions to the Acbe promote preference for smaller, earlier reinforcers, and suggested that this reflects an effect of the lesion on the rate of delay discounting. Experiment II examined the effect of disconnecting the orbital prefrontal cortex (OPFC) from the Ache on inter-temporal choice performance. Rats were given excitotoxin-induced contralateral lesions of the OPFC and Acbe (disconnection), severing of the anterior corpus callosum (callosotomy), a combined lesion (disconnection+ca11osotomy) or sham lesions. Using the same behavioural training and quantitative method as in Experiment L the disconnection+callosotomy group showed a lower intercept of the indifference function than the sham-lesioned group; the disconnection group showed a similar but less robust effect, whereas tbe callosotomy group did not differ significantly from the sbam-lesioned group. The results suggest that OPFC-AcbC connections are involved in delay discounting of food reinforcers. Tbe subthalamic nucleus (STN) is a major relay in the indirect striatofugal pathway and plays an important role in extrapyramidal motor control. Recent findings indicate that it may also play a role in modulating the efficacy of food reinforcers. The objective of Experiment ill was to examine the effect of lesions of the STN on inter-temporal choice performance. Following bilateral excitotoxin-induced or sham lesions of the STN and behavioural training and methodology as Experiments I and IT, STN-lesioned rats showed a flatter slope of the indifference function (implying higher instantaneous reinforcer values) compared to sham-lesioned rats; there was no difference in intercepts between the two groups. The results agree with recent findings that indicate a function of the STN in incentive value. However, in contrast to some previous studies, these results do not indicate a role of the STN in delay discounting. Experiment N investigated the effect of AcbC lesions on performance on a PR schedule using a quantitative model that discriminates between effects of interventions on motor and motivational processes. Following bilateral excitotoxin-induced and sham lesions of the AcbC, rats were trained to respond for food reinforcers under a PR schedule. The motor parameter, d, was significantly higher in the AcbC-Iesioned than the sham-Iesioned group, reflecting lower overall response rates in the lesioned group. The motivational parameter, a, was sensitive to changes in reinforcer magnitude, but showed no significant difference between the two groups. The AcbC-lesioned group showed longer post-reinforcement pauses and lower running response rates than the sham-lesioned group. The results suggest that destruction of the Ache impairs response capacity but does not alter the efficacy of food reinforcers. The results are consistent with the findings in Experiment I that Ache lesions do not alter sensitivity to reinforcer size in inter-temporal choice schedules. The objective of Experiment V was to examine the effect of lesions of the STN on performance on a PR schedule using the same quantitative model as in Experiment IV. After bilateral excitotoxin-induced and sham lesions of the STN, rats were given the same behavioural training under the same protocol as in Experiment N . Parameter t5 was significantly higher in the STN-lesioned than the sham-lesioned group. indicating lower overall response rates in the lesioned group. Parameter a was significantly higher in the STN-lesioned group than in the sham-Iesioned group, consistent with the results from Experiment ill which suggested enhanced instantaneous reinforcer value in the STN-lesioned group compared to the sham-lesioned group. The results suggest that destruction of the STN impairs response capacity and enhances the incentive value of food reinforcers. In conclusion, chapter 7 recapitulates the findings from all the experiments that were carried out and discusses the emerging implications about the role of CSIC circuits in regulating inter-temporal choice behaviour, and the behavioural processes that may underline this role.

The pathogenesis of affective disorders is not clearly understood and the diagnostic validity of psychiatric disorders remains unclear. The aim of this thesis was to identify sub-phenotypes in affective disorders that may be biologically validated by future molecular genetic studies. The dataset comprised over 1000 subjects meeting diagnostic criteria (DSM-IV) for bipolar I disorder (BPI) or major recurrent depression (MDDR) who were previously recruited as part of ongoing molecular genetic studies. Subjects had been assessed in detail using Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and case-note reviews. I undertook hypotheses testing and exploratory analyses in this dataset using a range of univariate and multivariate statistical tests. I found that a depressive episode at illness onset in BPI subjects was associated with a more depressive course of illness. I also found clinical characteristics of depression that were associated with a bipolar, rather than unipolar, course of illness. Using the HCL-32, I identified a substantial number of MDDR subjects (17%) who reported bipolar symptoms at a level similar to that reported by BPI subjects. I found significant differences in the clinical course of illness of MDDR and BPI subjects according to the lifetime presence of recurrent panic attacks, as well as clinical characteristics that appeared to be associated with the presence of panic attacks only in BPI subjects. In the unipolar sample, I found that within subjects psychotic episodes tended to be more severe than non-psychotic episodes. However, between subjects there was wide variation in severity in both those that did, and did not, experience psychotic episodes. In MDDR subjects, I found that episodes of postpartum depression clustered in families (p=0.015). I found no significant evidence for the familiality of reporting of life events in the MDDR sample. These studies identify sub-phenotypes that may be of use in future genetic studies.

ADHD and schizophrenia are neurodevelopmental disorders that are more prevalent in males and show sex differences in age of onset or severity. The Y chromosome is potentially an important influence on male susceptibility to neuropsychiatric disorders. The way the Y chromosome could increase risk to neuropsychiatric disorders is directly or indirectly by interacting with autosomal genes expressed in the brain. In addition, it could modify the disease phenotype. However, due to difficulties arising from the lack of recombination and widely accepted nomenclature, the Y chromosome has been largely excluded from genetic and genomic studies of neuropsychiatric disorders. To overcome this lack of knowledge, 9 Y chromosome markers were selected to represent the main Y chromosome haplogroups that are present in the U.K. and they were genotyped in a sample of 210 cases with ADHD, 313 cases with schizophrenia and 637 U.K. controls. Statistical analysis of Y chromosome haplogroups revealed that although there was no significantly increased representation of any haplogroup in cases with ADHD or schizophrenia compared to controls, there was evidence of a possible modifying effect on the phenotype of ADHD and schizophrenia. Y chromosome haplogroup 3 was associated with higher performance and full scale IQ within the sample of patients with ADHD. Haplogroup 1 was associated with better outcome and higher educational level within the sample of patients with schizophrenia. There was no association of Y chromosome haplogroups with IQ in a population sample of 3,749 individuals. Y chromosome haplogroups were also tested for interaction with tyrosine hydroxylase SNPs because animal studies suggest this is biologically plausible. Although there was no evidence of interaction, three tyrosine hydroxylase SNPs showed nominally significant association in the sample of male patients with schizophrenia. This study is one of the largest Y chromosome studies in the UK. It suggests that although Y chromosome variation does not appear to be associated with ADHD or schizophrenia, it may modify cognitive performance and clinical features.