Background: Depression is a major health problem worldwide and the majority of patients presenting with depressive symptoms are managed in primary care. Current approaches for assessing depressive symptoms in primary care are not accurate in predicting future clinical outcomes, which may potentially lead to over or under treatment. The Allostatic Load (AL) theory suggests that by measuring multi-system biomarker levels as a proxy of measuring multi-system physiological dysregulation, it is possible to identify individuals at risk of having adverse health outcomes at a prodromal stage. Allostatic Index (AI) score, calculated by applying statistical formulations to different multi-system biomarkers, have been associated with depressive symptoms. Aims and Objectives: To test the hypothesis, that a combination of allostatic load (AL) biomarkers will form a predictive algorithm in defining clinically meaningful outcomes in a population of patients presenting with depressive symptoms. The key objectives were: 1. To explore the relationship between various allostatic load biomarkers and prevalence of depressive symptoms in patients, especially in patients diagnosed with three common cardiometabolic diseases (Coronary Heart Disease (CHD), Diabetes and Stroke). 2 To explore whether allostatic load biomarkers predict clinical outcomes in patients with depressive symptoms, especially in patients with three common cardiometabolic diseases (CHD, Diabetes and Stroke). 3 To develop a predictive tool to identify individuals with depressive symptoms at highest risk of adverse clinical outcomes. Methods: Datasets used: ‘DepChron’ was a dataset of 35,537 patients with existing cardiometabolic disease collected as a part of routine clinical practice. ‘Psobid’ was a research data source containing health related information from 666 participants recruited from the general population. The clinical outcomes for 3 both datasets were studied using electronic data linkage to hospital and mortality health records, undertaken by Information Services Division, Scotland. Cross-sectional associations between allostatic load biomarkers calculated at baseline, with clinical severity of depression assessed by a symptom score, were assessed using logistic and linear regression models in both datasets. Cox’s proportional hazards survival analysis models were used to assess the relationship of allostatic load biomarkers at baseline and the risk of adverse physical health outcomes at follow-up, in patients with depressive symptoms. The possibility of interaction between depressive symptoms and allostatic load biomarkers in risk prediction of adverse clinical outcomes was studied using the analysis of variance (ANOVA) test. Finally, the value of constructing a risk scoring scale using patient demographics and allostatic load biomarkers for predicting adverse outcomes in depressed patients was investigated using clinical risk prediction modelling and Area Under Curve (AUC) statistics. Key Results: Literature Review Findings. The literature review showed that twelve blood based peripheral biomarkers were statistically significant in predicting six different clinical outcomes in participants with depressive symptoms. Outcomes related to both mental health (depressive symptoms) and physical health were statistically associated with pre-treatment levels of peripheral biomarkers; however only two studies investigated outcomes related to physical health. Cross-sectional Analysis Findings: In DepChron, dysregulation of individual allostatic biomarkers (mainly cardiometabolic) were found to have a non-linear association with increased probability of co-morbid depressive symptoms (as assessed by Hospital Anxiety and Depression Score HADS-D≥8). A composite AI score constructed using five biomarkers did not lead to any improvement in the observed strength of the association. In Psobid, BMI was found to have a significant cross-sectional association with the probability of depressive symptoms (assessed by General Health Questionnaire GHQ-28≥5). BMI, triglycerides, highly sensitive C - reactive 4 protein (CRP) and High Density Lipoprotein-HDL cholesterol were found to have a significant cross-sectional relationship with the continuous measure of GHQ-28. A composite AI score constructed using 12 biomarkers did not show a significant association with depressive symptoms among Psobid participants. Longitudinal Analysis Findings: In DepChron, three clinical outcomes were studied over four years: all-cause death, all-cause hospital admissions and composite major adverse cardiovascular outcome-MACE (cardiovascular death or admission due to MI/stroke/HF). Presence of depressive symptoms and composite AI score calculated using mainly peripheral cardiometabolic biomarkers was found to have a significant association with all three clinical outcomes over the following four years in DepChron patients. There was no evidence of an interaction between AI score and presence of depressive symptoms in risk prediction of any of the three clinical outcomes. There was a statistically significant interaction noted between SBP and depressive symptoms in risk prediction of major adverse cardiovascular outcome, and also between HbA1c and depressive symptoms in risk prediction of all-cause mortality for patients with diabetes. In Psobid, depressive symptoms (assessed by GHQ-28≥5) did not have a statistically significant association with any of the four outcomes under study at seven years: all cause death, all cause hospital admission, MACE and incidence of new cancer. A composite AI score at baseline had a significant association with the risk of MACE at seven years, after adjusting for confounders. A continuous measure of IL-6 observed at baseline had a significant association with the risk of three clinical outcomes- all-cause mortality, all-cause hospital admissions and major adverse cardiovascular event. Raised total cholesterol at baseline was associated with lower risk of all-cause death at seven years while raised waist hip ratio- WHR at baseline was associated with higher risk of MACE at seven years among Psobid participants. There was no significant interaction between depressive symptoms and peripheral biomarkers (individual or combined) in risk prediction of any of the four clinical outcomes under consideration. Risk Scoring System Development: In the DepChron cohort, a scoring system was constructed based on eight baseline demographic and clinical variables to predict the risk of MACE over four years. The AUC value for the risk scoring system was modest at 56.7% (95% CI 55.6 to 57.5%). In Psobid, it was not possible to perform this analysis due to the low event rate observed for the clinical outcomes. Conclusion: Individual peripheral biomarkers were found to have a cross-sectional association with depressive symptoms both in patients with cardiometabolic disease and middle-aged participants recruited from the general population. AI score calculated with different statistical formulations was of no greater benefit in predicting concurrent depressive symptoms or clinical outcomes at follow-up, over and above its individual constituent biomarkers, in either patient cohort. SBP had a significant interaction with depressive symptoms in predicting cardiovascular events in patients with cardiometabolic disease; HbA1c had a significant interaction with depressive symptoms in predicting all-cause mortality in patients with diabetes. Peripheral biomarkers may have a role in predicting clinical outcomes in patients with depressive symptoms, especially for those with existing cardiometabolic disease, and this merits further investigation.

This study was carried out in order to validate the use of EEG mu (μ) suppression as an index of human mirror neuron system (hMNS) related activity. The hMNS is characterized by neuronal activity that responds to both action observation and execution of the same movement. This activity has been directly observed in both macaque monkeys and in humans. There is an abundance of studies using indirect measures of neuronal activity to indicate hMNS-related activity such as TMS, fMRI/PET and EEG/MEG. However, relating indirect indices of neuronal activity to a conceptual group of neurons is controversial because the activity observed could also reflect other neuronal processes. Therefore, the current thesis was designed to establish more direct and causal evidence for the use of EEG in indicating hMNS-related activity through the use of transcranial alternating current stimulation (tACS). This was achieved in six experiments; the first three established an efficient protocol to induce μ-suppression during action observation, and the last three demonstrated by means of tACS that activity in hMNS-related areas is directly related to μ-reactivity during observation of motor movements and in relation to imitation of the movement observed. To this extent, μ-suppression was related to both action observation, and the ability to perform the movement observed. This is interpreted as evidence that EEG μ-suppression is a valid indicator of hMNS-related activity.

The first chapter is a narrative literature review in which key constructs relevant to this thesis are introduced, relevant literature is summarised and critiqued, and areas for future research are identified. Subjective well-being (SWB) is defined and hope (both goal-focused hope and spiritual hope) is identified as important to SWB. It is suggested that two concepts that may help explain the relationship between goal-focused hope and spiritual hope and SWB are flow and mindfulness, which are each examined. It is highlighted that goals are important to both goal-focused hope and flow, and that spirituality is important to both spiritual hope and mindfulness. Based on the literature reviewed, theoretically based hypotheses are proposed. The second chapter is an empirical paper, the intention of which is to build upon the literature review by examining the theoretically derived hypotheses proposed within the review. The aim of the study is to examine the relationships between goal-focused hope, spiritual hope, flow, mindfulness, and SWB, and to explore mechanisms through which hope may affect SWB. The main study variables are examined using a university sample and an online study. The last chapter of the thesis is the concluding section, which has three main sections. This first section is a general overview of the work done, followed by an expanded discussion of possible explanations and interpretations, methodological considerations, and clinical implications. Section two presents a lay summary of the study for dissemination. The summary is presented in a form suitable for publication in a university magazine, with a target audience of university staff and students. The aim of the final section is to explore areas for future research. References are provided at the end of each chapter and appendices are at the end of the thesis.

The human brain can be divided into multiple areas, each responsible for different aspects of behaviour. For a century we have been developing techniques to non-invasively map these areas and their associated functions, a discipline now known as neuroimaging. In recent years the field has undergone a paradigm shift to investigate how the brain communicates with itself; it is widely regarded that healthy brain function relies upon efficient connectivity between different functional areas, and the neuroimaging field has been revolutionised by our ability to estimate this connectivity. Studies into communication between spatially separate locations in the brain have revealed a series of robust functional networks which govern mental processes. However these studies have been based on the temporal averaging of minutes or even hours of data to give us a generalised ’snapshot’ of connectivity. Increasing evidence shows us that these connections are dynamic in space, time and frequency and so the next generation of of neuroimaging methods, which capture this 5-dimensional connectivity will prove to be key tools in the investigation of brain networks and ultimately their breakdown in disease. In this thesis we introduce novel methods to capture non-stationarity using magnetoencephalography (MEG), an imaging modality which measures the changes in extracranial magnetic fields associated with neuronal current flow. MEG is a direct measurement of neural activity and has an excellent temporal resolution, which makes it attractive for non-invasively tracking dynamic functional connections. However there are many technical limitations which can confound assessment of functional connectivity which have to be addressed. In Chapters 2 and 3 we introduce the theory behind MEG; specifically how it is possible to measure the femtoTelsa changes in magnetic field generated by the brain and how to project these data to generate a 3-dimensional picture of current in the brain. Chapter 4 reviews some of popular methods of assessing functional connectivity and how to control for the influence of artefactual functional connections erroneously produced during source projection. Chapter 5 introduces a pipeline to assess functional connections across time, space and frequency and in Chapter 6 we apply this pipeline to show that resting state networks, measured using ’static’ metrics are in fact comprised of a series of rapidly forming and dissolving subnetwork connections. Finally, Chapter 7 introduces a pipeline to track dynamic network behaviour simultaneously across the entire brain volume and shows that networks can be characterised by their temporal signatures of connectivity.

Since its discovery over a decade ago, DISC1 has become one of the most promising candidate genes for Schizophrenia and associated chronic mental disorders. This notion has been supported by a wealth of evidence from genetic and biochemical studies. With multiple interacting partners, DISC1 acts as a scaffold protein, orchestrating vital signalling pathways that underpin neurodevelopment and signalling. While the aetiology of Schizophrenia is poorly understood, loss of DISC1 protein function remains one of the proposed disease mechanisms. Furthermore, its tendency to form aggregates is reminiscent of neurodegenerative illnesses such as Alzheimer’s and Parkinson’s disease. C-terminal truncation of DISC1 (TrDISC1) is known to decrease neurite outgrowth and number in the PC12 cell line, abolish protein interaction with proteins such as Ndel1 and also disrupt vital physiological process such as mitochondrial transport. However, very little is known about the underlying disease mechanism at the molecular level. In order to gain insight in to the role of DISC1 pathway in Schizophrenia and associated mental illnesses, I studied novel post translational modifications of DISC1. The main conclusion of my thesis is that these modifications affect DISC1 turnover and its scaffold function. The work described in this thesis has uncovered 2 novel post translational modifications and identified the E3 ligase involved in regulating DISC1 turn over. My work has also laid the foundation for the design and discovery of both peptide and non-peptide, small molecule inhibitors of the DISC1 and its cognate E3 ligase interaction. These inhibitors can serve as both pharmacological tools and for further investigation of the role of this novel interaction in DISC1 pathway and the vital physiological functions it is involved in. Furthermore, this work also indicates the feasibility of controlled and directed differentiation of patient specific iPS cells in to neurons, which act as a useful tool for disease modelling.

Tourette Syndrome (TS) is a developmental neurological disorder characterised by vocal and motor tics and is associated with cortical-striatal-thalamic-cortical circuit dysfunction and hyper-excitability within cortical motor areas. TS symptoms often become more controlled throughout adolescence until the individual is largely tic-free by early adulthood. It is likely that adaptive changes occur in the development of brain structure and function throughout the critical developmental period of adolescence in people with TS, which leads to tic remission in some individuals. To investigate this I used multiple brain-imaging approaches including diffusion tensor imaging to look at white matter microstructure, T1-weighted anatomical MR imaging to measure cortical grey matter thickness and MR-Spectroscopy (MRS) to measure neurotransmitters of interest (GABA and glutamate) in a group of young people with TS and a typically developing matched control group. Brain function (measures of excitation and inhibition in M1) was also considered by using transcranial magnetic stimulation. A significant positive relationship was found between white matter structural integrity (FA) measured from the body of the corpus callosum that contained projections to M1 or the SMA and motor tic severity. The TS group had increased levels of GABA in the SMA, as measured by MRS, compared to the control group. SMA- GABA levels had a significant positive relationship with FA from the SMA ROI but a negative relationship with TMS measures of cortical excitability during movement preparation. This suggests that those individuals with the least severe tic symptoms also have reduced callosal white matter from the SMA (an area implicated in the production and suppression of tics) in adolescents with TS, which relates to a reduction in task based cortical excitability and a reduction in SMA-GABA compared to those with more severe tics. The results from this thesis suggest that tic-suppression may occur through decreasing excitatory inputs to M1, either through increasing the inhibition (GABA levels) of the SMA, or by decreasing the number of excitatory interhemispheric inputs to sensorimotor regions.

Lysosomal storage disorders (LSDs) are rare diseases caused by inherited mutations in genes coding for proteins of the endolysosomal system. The lysosome is an organelle responsible for the degradation of dysfunctional organelles and for the catabolism, and subsequent recycling, of macromolecules within the cell. When this process becomes defective the substrates of lysosomal catabolism accumulate; these can include lipids, proteins, polysaccharides, nucleotides and diverse combinations of all three. The phenotypic spectrum of these diseases in isolation, and even more so as a group, is extremely broad but an almost universal consequence of lysosomal dysfunction is severe, early onset neurodegeneration. Neurodegenerative diseases of ageing such as Alzheimer’s disease, Parkinson’s disease and Huntington’s disease represent a major challenge to the provision of human healthcare in light of an ageing global population. Whilst some commonalities exist between these three diseases a myriad of hypotheses for the onset of pathology has been proposed. There is growing evidence for involvement of the lysosome in all three of these diseases. We have been looking at specific lysosomal pathologies such as lipid storage, endocytosis and Ca2+ dysregulation in forms of these three neurodegenerative diseases of ageing whilst using LSDs as models to inform our study. We have found that lysosomal alkalisation in familial models of Alzheimer’s disease results in changes to lipid and Ca2+ homeostasis in this compartment and identified a lysosomal ion channel, transient receptor potential cation channel, mucolipin subfamily, member 1 (TRPML1), as a key constituent of this process. Our study of models of Huntington’s disease have implicated the Niemann-Pick type C1 protein (NPC1) in the pathogenesis of this disease and identified ways in which this could be therapeutically targeted. Finally, we have found evidence of Ca2+ dyshomeostasis throughout the cell in genetic models of Parkinson’s disease which have defects in lysosomal proteins. Taken together, these studies strengthen the evidence for lysosomal involvement in neurodegenerative diseases of ageing, albeit with different mechanisms in each case, whilst expanding on the molecular basis for these processes. Accordingly, our understanding of the mechanisms underlying the pathogenesis of these diseases has improved and new therapeutic targets have been identified by these studies.

This thesis explores parenthood in the context of anxiety. Chapter One presents a systematic literature review exploring parenting behaviours in parents with anxiety disorders. This aims to critically review studies which consider the association between parental anxiety disorder and parenting behaviour towards school-aged children, specifically those that independently observe parent-child interactions. Fifteen such studies of parents diagnosed with anxiety disorders were reviewed. The majority of studies presented comparative data of anxious and non-anxious parents, frequently finding no differences between groups. Inconsistencies in the findings are highlighted and discussed. Methodological and theoretical limitations, implications for clinical practice and theory, and recommendations for future research are discussed. The review concludes that evidence does not consistently demonstrate a relationship between parental anxiety disorder and parenting, which supports findings of other reviews in the area. However, numerous methodological limitations associated with the use of independent observation must be considered. Chapter Two is an empirical paper regarding mothers’ experiences of obsessive-compulsive disorder (OCD). Nine mothers who associated their OCD onset or exacerbation with a pregnancy or child’s birth were interviewed. Interpretative Phenomenological Analysis was used to explore their experiences, with particular consideration to motherhood in the context of OCD. Two superordinate themes of ‘changing identity’ and ‘disconnection’ were interpreted. Consideration is given to how these findings relate to existing research into obsessive-compulsive disorder, maternal mental health and motherhood. Methodological limitations, clinical implications and potential future directions for research are discussed. Chapter Three provides reflections on the research journey. Specifically, the paper considers the researcher’s selection of the research area and explores reflections on areas where the researcher’s experience of the research converged with experiences of the mothers with OCD who participated in the research project.

This study was undertaken with people who have a learning disability and dementia and their carers. The overall aim of this research was to gain insight into the perspective of the person with a learning disability who had developed dementia, alongside that of their carer, with the anticipation that this would influence the development of practice and service delivery accordingly. People with a learning disability are two to three times more likely to develop dementia than the general population, but historically, dementia care policy has rarely made specific reference to this group of people. In order to ensure that the needs of people with a learning disability and dementia are met, their voices need to be heard regarding their views and perceptions on what their needs are and what health and social care support services are required in order to meet those needs. Very few studies relating to this group of people can be found, one of the main reasons appearing to be the ethical and methodological challenges involved in carrying out research with people who have a learning disability. This qualitative study involved 11 people who had a learning disability and dementia, along side a nominated carer participant for each person. Semi-structured interviews were used and the transcriptions were analysed using Interpretative Phenomenological Analysis, whereby themes were identified. The findings illustrated that services experienced difficulties in providing person centred care, particularly the poor communication between service providers working with each individual, and the general lack of person centred approaches to care. The data indicated that people with a learning disability and dementia wanted improved communication between service providers; improved understanding of dementia by those with the illness, and by family, paid and professional carers; to stay as well as possible; continue living in their home; and to have good access to a range of activities, services and support as deemed necessary. In conclusion, this research goes someway to exploring and overcoming the barriers to including people with a learning disability and dementia in research studies. It found ways of listening to and interpreting the views of people with a learning disability and dementia about their lives and circumstances and has made it possible to produce recommendations in relation to practice and policy development. These include ways of ensuring person centred approaches to care, and suggestions on the effective implementation of policy documents key to this group of people.

Cerebral autoregulation is the process by which blood flow to the brain is maintained despite changes in arterial blood pressure. Experiments using transcranial Doppler ultrasonography allow rapid measurements of blood flow velocity in the middle cerebral artery. Measurements of this velocity and a subject's arterial blood pressure are used in the assessment of the dynamic cerebral autoregulatory response. Two mathematical models representing the dynamic cerebral autoregulation response as a feedback mechanism, dependent on pressure and flow respectively, are derived. For each model two parameters are introduced, a rate of restoration and a time delay. Solutions for both flow between fixed plates and flow in a rigid pipe are obtained using Laplace transform methods. In both cases solutions for the velocity are found for a general arterial blood pressure, allowing the model to be applied to any experiment that uses changes in arterial blood pressure to assess dynamic cerebral autoregulation. Velocity profiles are determined for the thigh cuff and vacuum box experiments, modelled as a step change and sinusoidal variation in pressure gradient in the middle cerebral artery respectively. The influence of the underlying heart and breathing cycles on measurements obtained from the vacuum box experiments is assessed, before results derived using the mathematical model with a flow dependent feedback mechanism are compared with data from the two experiments. The comparisons yield similar estimates for the rate of restoration and time delay suggesting that these parameters could be independent of the pressure change stimulus and depend only on the main features of the dynamic cerebral autoregulation process. The modelling also indicates that for imposed oscillatory variations in arterial blood pressure a small phase difference between the pressure and velocity waveforms does not necessarily imply impaired autoregulation. The ratio between the percentage variation in maximum velocity and pressure can be used, along with the phase difference, to indicate more accurately the nature of the autoregulatory response. Finally, the relationship between arterial blood pressure and pressure gradient in the middle cerebral artery is modelled using electrical analogue theory. The influence of this relationship on the autoregulation model for flow in a rigid pipe is investigated.