The first part of this thesis discusses developmental influences on the human connectome in relation to autism and attention deficit hyperactivity disorder (ADHD), conditions associated with alterations in brain connectivity and marked by social impairments. It reports an experiment investigating whether the connectomes of individuals with autism or ADHD differ from the connectome of neurotypical individuals, and what the underlying genetic basis could be for any differences in neural architecture. Chapter 2 reports an analysis of networks in children with autism or ADHD, using structural covariance magnetic resonance imaging (scMRI). We found overlapping as well as distinct network features across both conditions. Chapter 3 reports an analysis of how gene expression might be associated with the basic building blocs of these structural covariance networks. We found that synaptic and transcriptionally downregulated genes were replicably associated with cortical thickness differences in children with autism, but not in children with ADHD. In addition, the first part also aims to elucidate the potential modulation effects of sex on autism neurobiology. Chapter 4 reports an analysis of structural covariance networks in male and female adults with and without autism. We found that biological sex is a modulator of neurobiological heterogeneity in autism. Chapter 5 reports pilot data aiming to identify an electrophysiological signature of these network properties using electroencephalography (EEG). We find little evidence for theories about network asymmetry, but indications of altered frontal network integration. The second part of the thesis examines the acute effects of hormones on brain connectomics. Hormones are an integral part of the mechanism of social behaviour. In a series of hormone administration studies, we report experiments to test the acute effects of steroid and peptide hormones on brain functional connectivity (Chapters 6 and 7). Chapter 6 reports an oxytocin administration study that used a novel data-driven approach to assess resting-state fMRI connectivity in women. Although the number of fMRI studies on oxytocin have increased over past years, little is known about its effect on women. We found that oxytocin robustly enhances cortico-subcortical connectivity, and that this effect positively correlates with autistic traits. This is interesting given that oxytocin has been proposed as a potential therapeutic in autism. Chapter 7 reports an experiment testing if testosterone modulates connectivity in a specific social environment (a fear response). This was confirmed during the social task, but not during baseline resting-state, highlighting the role of testosterone in functional connectivity in this specific context. Chapter 8 is the concluding chapter that integrates all the empirical findings in the thesis. We discuss their implications for our understanding of autism and ADHD, and of the role of steroid and peptide hormones in the typically and atypically developing connectome. Chapter 8 also reflects on the limitations of the experiments reported, and sets out future directions for research in this area.

Bibliography: leaves 339-361. / xii, 361 leaves ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Psychiatry, 1993

Background: Anorexia Nervosa is mental health problem which crosses both psychological and physical realms. It is also known to be a difficulty that often arises in adolescence. Unfortunately its prognosis is not favourable with elevated rates of chronicity and a higher mortality rate than any other psychiatric disorder in adolescence. Objectives: This research set out to explore the experiences of young people about the early stages of Anorexia. It was anticipated that this would improve clinicians’ knowledge in this area. Design and Method: This study adopted a qualitative Grounded Theory design for the interviewing and analysing process. Eight participants took part in an interview on their experiences of the early stages of Anorexia. The participants were aged between 13-17 years old. The majority were female with one male participant. Interviews were transcribed verbatim and data were analysed using NVivo software. The process of analysis involved moving between the interviews and generating codes. Through this repeated process the themes emerged from and were validated by the data. Results & Conclusions. Themes developed which illustrated the importance of the interpersonal context. Further analysis and conclusions were drawn from this and presented as this study’s main findings. The main findings were that there is a strong emotional element to the experiences of the early stages of Anorexia; that the level of awareness into Anorexia is something that develops and finally that emotions and awareness impact on responses to interpersonal interactions. The results were considered in reference to literature and clinical recommendations were provided.

There is increasing interest in protective factors for violence risk and it has been proposed that consideration of protective factors in addition to risk factors may lead to more balanced and accurate violence risk assessments. Part 1: A systematic review of the literature was conducted to explore the predictive and incremental validity of protective factors assessed using structured professional judgment (SPJ) violence risk assessment tools. Eighteen studies were identified which reported the predictive validity of protective factors for violent behaviour in adolescent and adult males using five different SPJ risk assessment tools. Overall, most studies found that protective factors were associated with the absence of violence. The evidence to support the incremental validity of protective factors (in addition to risk factors) was however less robust and most studies were identified as having a risk of bias which impacted on the potential accuracy and generalisability of the findings. Part 2: Using a pseudo-prospective design, the predictive and incremental validity of protective factors was explored using the Structured Assessment of Protective Factors (SAPROF) and Historical Clinical Risk Management-20 (HCR-20V3) guidelines in a sample of 75 male patients in a high secure forensic mental health inpatient setting. The SAPROF was associated with the absence of different types of violence within the hospital setting (with AUC values for the total SAPROF score ranging from .69 to .74). The SAPROF did not appear to significantly add to the predictive validity of the dynamic risk factors in the HCR-20V3. The Integrative Final Risk Judgment however demonstrated strong predictive validity (with AUC values for different types of violence ranging from .74 to .81) and incremental validity in the prediction of violent behaviour.

The use of the internet over the past decade has played a strong role in several areas of mental health, including the provision of informal peer support forums in which individuals can discuss specific difficulties anonymously. Self-injury is also a topic which has received far greater recognition over the past decade, with research studies reporting prevalence rates of between 4-25% of the adult population and between 22-35% of the college and university population. The current study investigates the use of a self-injury online forum in order to develop a psychological understanding of the functions that this forum provides to its users. This study employed a grounded theory qualitative methodology to analyse the data collected from an online forum across a 5-month period. The results revealed three core categories: i) human contact; ii) battling self-injury; and iii) being helpful – giving advice/ tangible help. The results suggest that a good deal of ‘therapeutic support’ occurs within exchanges on the forum, with possible benefits both for those receiving and for those giving support and advice. The findings highlighted some important considerations for clinical practice and, more specifically, for the role that clinical psychologists can have in developing services specifically to meet the needs of this client group. The findings are reviewed within the context of the current literature, and implications for service development and service delivery are discussed. Suggestions are made for how services might be able to encourage the use of safe and high quality online therapeutic support on a 24 hour basis to supplement live support by health professionals. Keywords: Self-injury, online internet forums, grounded theory, therapeutic support, peer support.

Posttraumatic stress disorder (PTSD) is complex and no one theory can fully explain the development and maintenance of PTSD symptoms. In Scotland, where trauma focused care initiatives are being considered, little is known about the extent of trauma history and associated symptoms presenting in primary care services. Furthermore, subthreshold posttraumatic stress disorder (sPTSD) has recently been associated with clinically significant impairment. With PTSD symptoms often comorbid with other psychopathology such as depression, individuals potentially seek treatment for these symptoms rather than underlying trauma which therefore may go unrecognised. Studies on the effectiveness of psychological treatment for PTSD demonstrate reasonable efficacy for well developed interventions. However, up to half of individuals may not make significant clinical improvements and withdrawal rates are high. This suggests that current treatments are not acceptable to some individuals and may be ineffective for others. In light of such clinical challenges the aim of the thesis was to investigate the incidence and nature of trauma symptoms in an Adult Psychological Therapies Service. Firstly, a systematic review was conducted to appraise the current level of evidence for prevalence and impairment associated with sPTSD. Secondly, an empirical study was undertaken to review the prevalence of trauma history and symptoms in the service. This was followed by an investigation of the relationships between processes posited to underpin many forms psychological distress by a promising new treatment approach called Acceptance and Commitment Therapy (ACT). These include; cognitive fusion, experiential avoidance and valued action. A quantitative cross sectional design collecting self report questionnaire data was used and mixed statistical methodology employed. Results from the systematic review suggest that PTSD was associated with the most impairment, followed by sPTSD, then no PTSD. Subthreshold PTSD was reported to be as, or more prevalent than, PTSD. The results from the empirical study found 89 per cent reported exposure to one or more traumatic events, 51 per cent met PTSD screening criteria, whilst a further 7 per cent reached a sPTSD diagnostic cut-off. Trauma history was positively correlated with increased psychological distress at initial assessment. Cognitive fusion, experiential avoidance and valued action were all correlated with trauma symptom severity. Both cognitive fusion and experiential avoidance mediated the relationship between number of traumatic events and trauma symptom severity in a simple mediation model. However, multiple mediation analysis demonstrated that experiential avoidance, over and above cognitive fusion, explained 33 per cent of the variance. In addition, cognitive fusion and experiential avoidance jointly had a significant indirect effect on the relationship between trauma history and valued action. The implications of the findings and further directions are discussed.

Background: Post Traumatic Stress Disorder (PTSD) is frequently linked with substance use disorder (SUD). However, the nature of this association remains unclear. A clearer understanding of the dynamic associations between PTSD and SUD may shed light on the course of these two disorders thereby, identifying areas for intervention, which may potentially reduce some of the associated costly and harmful outcomes. Methods: Firstly, a systematic review was conducted to investigate the evidence base regarding the relationship between PTSD and SUD. Secondly, an empirical project was undertaken to explore functional associations between PTSD and SUD. This was achieved by comparing, motives for substance use, anxiety and depression symptoms, and SUD symptom severity amongst treatmentseeking adults with and without PTSD. Results: Results from the systematic review suggest that individuals with comorbid PTSD and SUD have more severe clinical profiles compared to individuals with a SUD alone. The results from the empirical study indicate that those with PTSD endorse coping-related motives for substance use significantly more than those without PTSD. Furthermore, those with PTSD had significantly elevated SUD severity ratings and higher anxiety and depression scores. Conclusions: Findings suggest that individuals with comorbid PTSD and SUD are motivated to use substances to cope with negative affect. The clinical implications of this are discussed.

Disease (HD) is an autosomal dominant neurodegenerative disease caused by a CAG expansion on the HD gene on chromosome 4, which gives rise to an expanded polyglutamine (polyQ) tract in the huntingtin protein. HD is characterised primarily by motor abnormalities, but is also commonly associated with cognitive impairments and psychiatric disturbances. Huntingtin (HTT) dynamically shuttles between subcellular compartments, however the mutant huntingtin protein (mHTT) is mislocalised to cell nuclei, where it may interfere with nuclear functions, such as transcription. The phosphorylation of HTT has been implicated with the regulation of its subcellular localisation; however the mechanism by which the mislocalisation of mHTT occurs is currently unknown. The localisation of HTT in an immortalised embryonic striatal cell model of HD (StHdhQ111) was identified as being more nuclear with a longer polyQ length. Additionally, stimulation of StHdhQ111 lines with a panel of growth factors alters the apparent subcellular localisation of HTT in a polyQ length-dependent manner. Aberrant kinase responses to growth factor stimulation were identified by ELISA assay. Inhibition of AKT1 and MEK1 phosphorylation indicated that their activation may be involved in mHTT mislocalisation and immediate-early gene expression. Transcriptional dysregulation is a characteristic feature of HD pathogenesis that may be directly influenced by HTT localisation. Microarray analysis of differential gene expression responses to growth factor stimulation uncovered a potential role for SMAD transcription factor activity and the transforming growth factor-β pathway in HD pathogenesis. Primary embryonic striatal cells from the HdhQ111 and HdhQ150 mouse models of HD showed similarities to the StHdhQ111 cell model in terms of HTT localisation, kinase signalling and gene expression. Cellular dysfunction may therefore be an early HD phenotype that is present from embryogenesis, and potentially alters HD development and progression; aberrant control of kinase signalling may regulate mHTT mislocalisation, which in turn modulates transcriptional dysregulation and contributes to HD pathogenesis.

Huntington’s disease (HD) is an inherited neurodegenerative condition characterised by progressive motor, cognitive and psychiatric symptoms. The most frequent cause of death is respiratory failure, yet little is known about respiratory function through the progression of the disease or the underlying causes of respiratory failure. A thorough exploration of the relevant literature led to the development of a conceptual framework for respiratory failure in people with HD. Within this framework respiratory failure was characterised as type 1 hypoxaemic and type2 hypercapnic failure and further evaluated through (i) an observational study to investigate respiratory function in people with HD, and (ii) the benefit and feasibility of inspiratory muscle training in people with HD. In order to develop understanding of potential underlying causes of type 1 hypoxaemic and type 2 hypercapnic respiratory failure, the observation study aimed to investigate if there was a difference in respiratory function between healthy controls and people with HD at different stages of the disease, and to explore factors that may influence or be influenced by respiratory function. The framework was further evaluated through the intervention study which investigated the feasibility and benefit of inspiratory muscle training in people with HD as a method of increasing capacity of the respiratory system. Method In the observation study 67 people with HD and 39 healthy control participants underwent a series of measurements of respiratory function based on underlying causes of type 1 hypoxaemic respiratory failure and type 2 hypercapnic respiratory failure. These included measurement of lung volume, respiratory muscle strength and endurance. Exercise capacity, physical activity, swallow and posture as potential influencing factors were also measured in people with HD. In the intervention study 20 people with HD were randomly allocated either to inspiratory muscle training at 50% of maximal inspiratory pressure, or to training against a load suggested to have no effect, completed in the home. The training protocol was 30 breaths, twice daily for six weeks, which was preceded by a habituation period of one week. Sniff nasal inspiratory pressure, peak cough flow and 30 second sit to stand were measured before and after the intervention. The programme was supported by alternate weekly phone calls and home visits. Results All measures of respiratory function, except FEV1/FVC were significantly decreased (p <0.001) in people with manifest HD compared to healthy control participants and people with pre-manifest HD. There was no difference between healthy control participants and people with pre-manifest HD. Respiratory function demonstrated a significant linear decline with disease progression measured by the total functional capacity scale (p<0.001). In particular, peak cough flow was abnormal at the middle stage of the disease. Exercise capacity, physical activity, swallow and posture were significantly related to respiratory function in people with manifest HD (p range 0.016-0.001). In people with manifest HD, exercise capacity was 27.73% ±26.29 predicted and swallow capacity was abnormal in 84.80% of participants. In the intervention study, five participants completed the intervention arm and 7 completed the sham arm. Adherence to the inspiratory muscle training programme ranged from 37-100% across both groups, with mean adherence rates of 70.67% ±26.35 and 74.53% ±21.03 for intervention and sham groups respectively. There was no difference in inspiratory muscle strength, peak cough flow or 30 second sit to stand as a result of the intervention. Participants and their carers identified carer support as a key enabler and life events as a barrier for carrying out the exercises. Conclusion The findings from this study indicate that people with HD are susceptible to type 1 hypoxaemic respiratory failure and predisposed to type 2 hypercapnic respiratory failure due to increased elastic and resistive loads and decreased capacity of respiratory muscles. The risk of type 1 hypoxaemic respiratory failure is high due to decreased swallow capacity and concomitant decreased cough efficacy. Decreased lung volume leading to hypoventilation may be impact on both type 1 hypoxaemic respiratory failure and lead on to type 2 hypercapnic respiratory failure. The predisposition to type 2 hypercapnic respiratory failure is due to decreased respiratory muscle capacity and increased elastic and resistive load. The study also highlighted the complex relationship between respiratory function, exercise capacity and physical activity. Although inspiratory muscle strength, cough efficacy and functional activity remained unchanged in this small sample, the results of the intervention study suggest that inspiratory muscle training is feasible in people with HD. Further studies should use protocols that are directly related to the primary outcome measure e.g. a power based protocol to improve cough efficacy or an endurance based protocol to improve physical activity. A model of respiratory failure in people with HD incorporating both type 1 hypoxaemic and type 2 hypercapnic respiratory failure can be proposed based from the findings of the studies that informs future research and clinical management of people with HD.

Absence seizures (ASs) are the predominant form of seizure featuring in the idiopathic generalised epilepsies, and are the only seizure type of childhood absence epilepsy. They are characterised by behavioural arrest, impairment of consciousness and an electrographic signature of spike-and-wave discharges (SWDs) and are associated with psychosocial and cognitive impairment of development. The seizures are known to arise in the thalamocortical network, but the firing dynamics of thalamic neurones during seizure is not known. In vivo and in vitro studies have yielded contradictory results, suggesting predominant silence and regular burst firing respectively, but no studies have previously recorded from intact, single thalamic neurones in a freely moving model of absence epilepsy. In this thesis it has been shown that, in Genetic Absence Epilepsy Rats from Strasbourg, thalamocortical (TC) neurones are mostly either silent or fire single spikes irregularly but synchronously during AS. T-type calcium channel-mediated bursts in neurones of the reticular thalamic nucleus (nRT) were frequently observed during full seizure expression. These cells expressed varied firing patterns ranging from regular burst firing to predominant silence, with similarly varying degrees of synchrony. It is also suggested that the nRT burst firing observed may be required for seizure generation. T-type calcium channel-mediated burst firing of TC neurones is neither necessary for, nor commonly observed in, the full generation or propagation of absence seizures These results suggest that TC neurones are predominantly silent during AS. This is compatible with the idea of a cortical seizure initiator and driver, as suggested by the cortical initiation site and cortical abnormalities observed in multiple experimental AS models. The observations herein also confirm that the temporal relationship between thalamic firing and SWDs previously observed in anaesthetised animals is maintained in the freely moving condition, but suggest that there is a greater incidence of asynchronous thalamic activity during AS (particularly of nRT neurones) than previously suggested. The firing dynamics of thalamic neurones observed are a crucial step towards understanding TC network activity during AS, and provide a significant insight into the role of the thalamus in alterations of sensation, movement, and consciousness associated with these seizures.