Binge drinking is characterised by cycles of ethanol intoxication and withdrawal and is thought to be highly deleterious for the normal functioning of the nervous system. The behavioural and neurophysiological consequences of rapid escalation of blood alcohol concentration and subsequent withdrawal, and their effects on learning and memory and underlying neural circuitry can be studied in suitable animal models. Here, spatial and instrumental learning as well as hippocampal LTP were assessed in C57BL/6J mice for the effects of adolescent intermittent ethanol (AIE) and other ethanol treatments. AIE treatment did not impair spatial or non-spatial memory when tested in adulthood. However, if mice were trained whilst intoxicated during AIE treatment, spatial memory was impaired. Post-training injections of ethanol impaired performance in operant conditioning. A rapid rise and fall in ethanol concentration, prior to stimulation, blocked LTP induction in drug naïve hippocampal slices; an effect that was not seen if the ethanol concentration was gradually increased and decreased. Moreover, AIE treatment caused an NMDA receptor-dependent transient increase in hippocampal LTP. The second part of this study used a novel molluscan model Lymnaea stagnalis and demonstrated that high concentrations of ethanol blocked acquisition and retrieval of an associative memory. However, if acquisition occurred in the presence of ethanol then memory could also be retrieved under ethanol, demonstrating ethanol state dependency. By utilising the cerebral giant cells, a modulatory neuron type with known involvement in memory formation, it was found that ethanol reduced the tonic firing frequency as well as the peak-to-trough and half-width parameters of individual action potentials. The development of in vivo and in vitro ethanol treatment and test protocols, and the findings based on their use, open up new avenues for future systematic investigations on ethanol's effects on behaviour and underlying neural circuitry in both vertebrate and invertebrate model systems.

Inherited metabolic diseases (IMD’s) are a large class of heterogeneous genetic disorders caused by dysfunction within a single pathway of intermediary metabolism. In many of these diseases, the dysfunction of metabolic enzymes leads to the accumulation of toxic metabolites which disrupts the normal development of the central nervous system. With the advent of treatments that positively influence neuropsychological outcomes, there is a need for sensitive and objective neuropsychological measures that allow patients to be systematically tracked in order to understand the efficacy of existing treatments. In this thesis, a neuropsychological test battery consisting of attention, language and oculomotor measures was developed to accurately describe individual and developmental differences between IMD patients and healthy developing controls. The functioning of five diseases was examined: Morquio syndrome (\(N\) = 12), Hurler syndrome (\(N\) = 3), Maroteux-Lamy syndrome (\(N\) = 2), Tyrosinemia type I (\(N\) = 13) and Tyrosinemia type III (\(N\) = 5). Findings indicated that disease effects were not homogeneous across tasks, and that performance on the same tasks was not uniform across diseases. The obtained data offers a promising basis for understanding how biological factors influence the severity and timecourse of developmental effects in future research.

This thesis comprises two volumes, representing the research and clinical elements submitted to the University of Birmingham in partial fulfillment of the degree of Doctor of Clinical Psychology (DClinPsy). The first volume is the research component and contains three papers. The first paper is a review of the literature from 1980 to the present day, which has examined intellectual, behavioural and psychological characteristics in participants with Sotos syndrome. The second paper is an empirical study which examines the behavioural phenotype of participants with Sotos syndrome in comparison to 3 other genetic syndromes using standardised, well validated questionnaires. The third paper summarises these in language accessible to the general public. The second volume is the clinical component containing four Clinical Practice Reports and the abstract for an oral examination. These papers represent different aspects of work conducted during clinical placements. They include a paper which formulates from two different psychological perspectives, a service evaluation, a single case experimental design and a case study.

<p>The aim in the study is to search for a deeper understanding of how parents experience a neurological diagnose of the child and how this affects the parenthood. Parenthood was seen in a systemtheoretical perspective as a social construction. The narrative method was used in two lifestory parentinterviews. The analysis was made from parenthood. The result formed stories about parenthood with children having neuropsyciatric functional disability who even came to be a woman’s struggle. Two stories became central, one about righteousness and commonship and one against diagnosis and network. The struggle for support and understanding from the surrounding network was central. There was also a fight between the network and the parent of the authority to decide the child’s normality. The parent and child early experience a segregation in society based on diagnose. Parents experienced insecurity and difficulties regarding dose and sideeffects in medication the child. The networks reception was central for the acceptance of diagnosis and for keeping the parentcompetence. The public debate of inherent or environment created doubt and insecurity. In the stories there was a tendency that the struggle went beside the child and parenthood and instead became a struggle for righteousness against society.</p>

The aim in the study is to search for a deeper understanding of how parents experience a neurological diagnose of the child and how this affects the parenthood. Parenthood was seen in a systemtheoretical perspective as a social construction. The narrative method was used in two lifestory parentinterviews. The analysis was made from parenthood. The result formed stories about parenthood with children having neuropsyciatric functional disability who even came to be a woman’s struggle. Two stories became central, one about righteousness and commonship and one against diagnosis and network. The struggle for support and understanding from the surrounding network was central. There was also a fight between the network and the parent of the authority to decide the child’s normality. The parent and child early experience a segregation in society based on diagnose. Parents experienced insecurity and difficulties regarding dose and sideeffects in medication the child. The networks reception was central for the acceptance of diagnosis and for keeping the parentcompetence. The public debate of inherent or environment created doubt and insecurity. In the stories there was a tendency that the struggle went beside the child and parenthood and instead became a struggle for righteousness against society.

This thesis examines how Soviet psychiatry took the particular form that it did and how it had a historically specific relationship to the state. Psychiatry in the USSR was used by the state against those who opposed the regime. In particular it was used after the death of Stalin against a dissident intelligentsia. Chapter One examines the position of the Soviet psychiatric patient with relation to the political economy of the USSR. The legal position of the psychiatric patient was a precarious one because the absence of private property meant there was no basis for law. It was possible to co-opt doctors as repressive agents of the state because they were dependent on it in a way which their counterparts in the West were not. Chapter Two examines the historical development of Russian and Soviet psychiatry and assesses the importance of its development under tsarism. The point at which Soviet psychiatry became differentiated from world psychiatry is located in the Stalin period. Chapter Three examines the role played by Soviet psychology and the supposed influence of Marxism-Leninism in shaping psychiatry in the USSR. It is argued that Soviet psychology owed nothing to Marxism but that it was distorted in a similar way to other branches of science. Chapter Four discusses the defective nature of Soviet psychiatry and shows how Soviet political economy led to archaic practice in psychiatry. All Soviet medicine was similarly defective and this had serious consequences for the Soviet population as a whole. Chapter Five examines the role that psychiatry played in repressing the dissident movement in the 1960s and 70s. Psychiatry was used as an ameliorated form of the labour camp at a time when mass killings and labour camps were less useful to the elite. Psychiatry played this role from about 1953 until 1988 and was used mostly against the intelligentsia.

The noradrenaline system is extensively innervated throughout the brain, implicated in the aetiology of a wide range of psychiatric conditions, and the pharmacological modulation of the noradrenaline system has had a positive influence upon the alleviation of symptoms for those suffering psychiatric or neurological disease. Clinical imaging of the brain with technologies such as Single Photon Emission Computed Tomography (SPECT) can provide clinicians and researchers with valuable information for elucidating disease aetiology, monitoring patient condition, and also confirming the mechanism of action for drug development through occupancy studies. However, to date, there is no SPECT brain imaging tracer for the noradrenaline transporter in regular clinical use. This thesis is a body of work to develop a novel SPECT brain imaging tracer for the noradrenaline transporter with compounds that are iodinated forms of reboxetine, the selective noradrenergic reuptake inhibitor and clinically used antidepressant. From the compounds synthesised and tested, the one which demonstrated the best pharmacological affinity and selectivity for the noradrenaline transporter was NKJ-64. This same compound also displayed many of the HPLC-derived properties predicting in vivo molecular behaviour that are associated with successful brain imaging tracers. Therefore, NKJ-64 was recommended for radiolabelling and further study. PCP MODEL OF THE METABOLIC HYPOFRONTALITY OBSERVED IN SCHIZOPHRENIA: The metabolic hypofunction observed in the prefrontal cortex of schizophrenic patients is mimicked in a rat model via repeated, low-dose phencyclidine administration. The neural mechanisms underlying this hypofrontality are unclear. Whilst dopaminergic transmission is classically associated with aberrant activity in schizophrenia, modulation of noradrenergic neurotransmission is correlated with the alleviation of negative symptoms. Furthermore, the noradrenaline transporter rather than the dopamine transporter functions as the dominant dopaminergic reuptake mechanism in the prefrontal cortex. It was hypothesised that repeated phencyclidine administration in the rat would induce a down-regulation of the NAT. Ligands labelled with [3H] were used for autoradiographic imaging of the noradrenaline, dopamine, and serotonin transporters in phencyclidine-treated and control groups, and [35S]-labelled oligonucleotide probes specific for the mRNA of each transporter were used for in situ hybridisation. The binding densities of the noradrenaline and dopamine transporters were unaltered in the model, however significant selective reductions of serotonin transporter binding sites were measured. The densities of mRNA for all three monoamine transporters were unaltered, so the unaltered densities of noradrenaline and dopamine transporter binding sites and the changes in serotonin transporter binding densities were not the result of altered gene expression. Although the noradrenaline transporter was not directly affected in this model of one particular aspect of schizophrenia and the model is not ideal for demonstrating the capability of a SPECT tracer for the NAT, this does not imply that the noradrenaline transporter is uninvolved in the disease aetiology of schizophrenia or of diminished importance to future schizophrenia studies. The aforementioned correlation of noradrenaline transporter modulation to the alleviation of negative symptoms emphasises the importance of acquiring the clinical ability to assess the density and/or occupancy of the noradrenaline transporter by developing a useful SPECT brain imaging tracer for this site. PHARMACOLOGICAL CHARACTERISATION OF POTENTIAL SPECT BRAIN IMAGING TRACERS FOR THE NORADRENALINE TRANSPORTER: In vivo imaging of the noradrenaline transporter was previously limited to peripheral tracers such as metaiodobenzylguanidine (MIBG), which does not cross the blood-brain barrier, and neuroligands such as radiolabelled desiprimine, which demonstrated problematically high nonspecific binding. Recent efforts in the literature have focused upon modified reboxetine analogues, and some progress was made with the S,S-isomer of iodophenoxy-ring reboxetine, referred to as both INER and IPBM in publication (Tamagnan et al. 2007; Kanegawa et al. 2006). Synthesised iodophenyl-ring compounds in S,S-, R,R-, S,R-, and R,S-isomers were evaluated for their affinity for the NAT. The R,S-isomer demonstrated a very similar level of binding to the S,S-isomer and so this was explored in an iodophenoxy isomer to determine if improvement upon the characteristics of lead iodinated reboxetine compounds in the literature was possible. The R,S-isomer iodophenoxy reboxetine analogues were synthesised with the iodine in the ortho, meta, and para positions of the phenoxy ring and assigned the designations NKJ-64, NKJ-67, and NKJ-68, respectively. NKJ-64 has strong affinity and selectivity for the noradrenaline transporter, with a KD of 8.4 ± 1.7 nM, a 6-fold selectivity for the noradrenaline transporter over the serotonin transporter, and a 63-fold selectivity for the noradrenaline transporter over the dopamine transporter. From the compounds synthesised and tested, NKJ-64 has the most suitable pharmacology to be developed further as a SPECT brain imaging tracer for the noradrenaline transporter and has an affinity in the same order of magnitude as iodinated compounds in the literature, such as the aforementioned INER/IPBM. USING HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC) TO PREDICT IN VIVO CHARACTERISTICS OF TRACER CANDIDATES: The development of any candidate tracer compound must include an evaluation of its in vivo properties. To streamline this process and select only the most viable compounds for further testing, predictors of in vivo molecular characteristics are used to conserve research effort. Measures such as lipophilicity, phospholipophilicity, and plasma protein binding, used to estimate the potential for blood-brain barrier penetration, nonspecific binding, and the likelihood of serum availability would be very time-intensive to determine via traditional bench-top methodologies. High-performance liquid chromatography (HPLC) is a quick, precise, and reliable technique that is a rapid and high-throughput automatable process with exceptional precision that does not rely on the bench-top proficiency of an individual experimenter. The optimisation of gradient elution protocols and formulae to interpret sample retention times on commercially available columns into reproducible standardised units has allowed for the efficient evaluation of tracer candidate compounds. The iodinated reboxetine compounds were compared to examples of both successful and failed neuroimaging tracers. Generally, the evaluations of the successful and failed neuroimaging tracers validated the combined methodologies of the HPLC-derived predictors of in vivo molecular behaviour. In applying these methodologies to the synthesised iodoreboxetine compounds, NKJ-64 displayed many of the HPLC-determined properties that are consistent with successful tracers.

An increasing evidence base is evolving which attempts to understand the consequences of the deployment of military troops to war zones and what may mediate these. Chapter one critically appraises the literature examining the link between secure attachment style classification, the dimensions of attachment anxiety and avoidance and operational stress injury. The results indicate that the reviewed articles used a variety of attachment measures, including discourse and self-report measures, which produce different results about the relationship between adult attachment and operational stress injury. The methodological limitations of the studies and implications of these findings for psychological therapies are discussed. Suggestions for future research are made, including longitudinal studies which measure attachment and mental health prior to deployment, and whether certain personality variables mediate the relationship between attachment and operational stress injury. Chapter two presents a qualitative analysis of the experiences of and roles played by the partners of military personnel receiving care for operationally-attributed mental health difficulties. Similar research has been carried out internationally, but as far as the author is aware British military partners had not been investigated. Grounded theory analysis of semi-structured interviews led to the development of a theoretical model, which explains the effect of operational events on service members and their partners, and the ways adopted to manage these. It is suggested that enhanced understanding of this process, aided by communication and services, helps to dissipate the couples’ distress, although barriers to communication and services were identified. Results are discussed in accordance with existing literature. Implications for service provision to deliver information and support for partners, and ideas for future research which tests the effects of partners receiving these, are made. Chapter three is a reflective paper based upon the thoughts, opinions and experiences the author had whilst carrying out the literature review and empirical research.

This thesis is concerned with the relationships between physiological changes and subjective and behavioural responses to stress. The effects of noise stress were examined under laboratory conditions, and retrospective studies of stress induced by life events were also carried out. Changes in blood glucose levels were of particular significance under stressful conditions and interesting relationships were found between changes in blood glucose levels and performance at experimental tasks under stressful conditions. Performance and the experience of stress were shown to be affected by the experimental manipulations of blood glucose levels. The effects of stressful conditions on diabetic subjects with impaired control of blood glucose levels were of particular interest. The poor control of blood glucose levels in the 'high glucose diabetics' was exaggerated when working under noise stress. Studies of life events demonstrated that diabetic subjects' experience of life events was associated with physiological disturbance of diabetic control. Diabetics' subjective experiences of stressful conditions were also examined and compared with the experiences of control subjects. Previous research showed considerable evidence to suggest that stress was a promoting factor in ischaemic heart disease (IHD). Subjects with IHD and controls were included in the present research. Experiments similar to those with diabetic subjects were carried out. The IHD subjects had enhanced physiological responses to noise stress which were associated with significantly low levels of reported stress. Subjective experiences of stress were further examined with investigations of the degree of stress associated with life events by Myocardial infarction patients. Differences in subjective experience of stress by patient groups and their controls were discussed in relation to the concept of alexithymia. Experiments with healthy subjects were carried out in order to examine the mechanisms involved in the relationships found between glucose, performance and the perception and experience of stress. The effects of glucose preloading were shown to be primarily of physiological rather than of psychological origin, and a vagal-insulin model was proposed to account for the relationship between glucose preloading and performance efficiency. Experimenter effects were examined in the studies of healthy subjects and the implications of such effects discussed in relation to the results of the experiments with hospital subjects in this work and with reference to other psychophysiological research. The experimental findings were evaluated and suggestions made for further research. In particular research directed towards the possibility of developing a more flexible, individual approach to diabetic management, taking account of unavoidable sources of stress, was outlined.

The aim of this thesis was to examine linguistic and social processing in autism and Asperger syndrome (AS), through computer-mediated communication. The first investigation used conversational analysis, on a corpus of computer-mediated dialogue, generated by two adults with AS. The results revealed that one of the two individuals had problems asking questions. Hence, an inability to ask questions may be one aspect of AS communication, though it may be not universal in this population. The second study used a computer program called Bubble Dialogue (Gray, Creighton, McMahon & Cunningham, 1991) to investigate the working understanding of nonliteral language and responses to inappropriate requests in individuals with AS and high-functioning autism (HFA). The AS/HFA group showed poorer understanding of a figure of speech and were more likely to consent to socially inappropriate requests compared to their typically developing peers. In contrast, understanding of sarcasm was predicted neither by verbal ability, executive ability nor clinical diagnosis. The results suggest that having AS/HFA does not, a priori, dispose someone to having problems with communication and socialisation, and that verbal ability protects the individual to a certain extent. Additionally, executive ability also seems important in mediating socialisation and communication ability. The third experiment tested the hypothesis that an autistic preference for internet-based communication may be due to the absence of verbal and non verbal cues, physical distance, and slower rate of information exchange through that medium. To test this, participants worked out predetermined map routes by asking the experimenter closed questions either via text chat, or through telephone conversations. An initial examination of the results suggested that AS performance may in fact have been better via the telephone. However, a detailed look at the strategies employed by some individuals with AS suggests that their executive problems may have resulted in their use of a less than systematic way to solve the task in both media. The results of this study also indicate a relation between executive and mentalising ability because both are required to solve the task. Interestingly, many of the participants with AS could generate novel closed questions to successfully solve the map task in both media, though they were slower than controls. Using computer mediated communication has therefore given us greater detail into the nature of, and the factors that influence, communication in autism.