Made available in DSpace on 2014-06-11T19:29:02Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-12-17Bitstream added on 2014-06-13T18:35:26Z : No. of bitstreams: 1 hoshina_hy_me_assis.pdf: 470475 bytes, checksum: ec500b00f24f41e6bd076492ad0a9075 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A constituição da civilização e da cultura tem sido alvo de estudos e hipotetizações durante muitos anos. A discussão na Psicanálise foi pautada, principalmente, pelo conflito existente entre a liberdade pulsional humana e as restrições que a convivência em conjunto impõem. Este impasse, portanto, marca a principal discussão acerca da angústia social que se observa na civilização. Atualmente, dadas as novas características encontradas na sociedade contemporânea, a discussão alcança um novo patamar. Neste sentido, o desamparo é posto como novo pilar dentro do estudo da angústia social atual. Isto porque o projeto proposto pela modernidade, em que o homem é posto como medida de todas as relações do mundo, lançouo em um movimento de ruptura com todas as tradições e costumes que até então amparavam seus atos. Dessa forma, este trabalho procura compreender a noção de desamparo da Psicanálise, assim como sua influência na estruturação social e cultural da humanidade. Para tanto, após revisão bibliográfica, realiza-se uma análise, tendo como foco o desamparo, de diferentes obras psicanalíticas que retratam épocas diferentes do desenvolvimento civilizatório. Por fim, após estas análises, compreendemos que o desamparo não constitui algo negativo dentro do desenvolvimento da cultura. O desamparo constitui, desse modo, a possibilidade de reconhecimento da falta, da incompletude de sua existência e que, portanto, possibilita ao homem lançar-se em direção à representações que possam preencher o espaço deixado vazio pelo objeto perdido. Assim, o desamparo demonstra sua importância não somente no que tange ao desenvolvimento do instinto gregário, tão essencial para uma civilização, como para a constituição do circuito pulsional. Enfim, concluímos que o desamparo... / The constitution of the civilization and the culture has been issue of studies and hypotheticals for many years. The discussion in Psychoanalysis were ruled, mainly, by the conflict existent between the freedom instinct and the restrictions that the living together imposes. This impasse, therefore, brands the main discussion about the social anguish that can be observed in civilization. Nowadays, because of the new characteristics found in the contemporary society, the discussion gains a new landing. So far, the abandon is placed as the new pillar in the current social anguish study. Since the project proposed by the modernity in which the man is placed as measure of all world’s relations, put him in a rupture movement with all traditions and customs that, so far, sheltered his acts. In this way, this work tries to understand the abandon notion inside the Psychoanalysis as well as its influence in the humankind social and cultural structure. For this, after bibliographic review, we have made an analysis, having as focus the abandon, of different psychoanalytical works that retracts different periods of the civilization development. Finally, after these analyses, we comprehended that the abandon does not constitute something negative in the culture development. The abandon constitutes, in this way, the possibility to recognize the absence, the incompleteness of its existence and thus, enables the man to throw himself in the direction of the representations that can fulfill the empty space left by the lost object. Thus, the abandon demonstrates its importance not only to what regards to the development of the gregarious instinct, so essential to a civilization, but also in the constitution... (Complete abstract click electronic access below)

22q11.2 Deletion Syndrome is a genetic syndrome that occurs in incidence of 1:4000 and is associated with variable phenotypic expression. It is caused by a deletion at chromosome 22q11.2. Individuals with 22q11.2DS have a greatly increased risk of developing neuropsychiatric disorders, in particular schizophrenia in adulthood, and ADHD and ASD in childhood. This thesis sought to investigate the possible molecular mechanisms that underlie the psychiatric variability in 22q11.2DS by studying a well-characterized cohort of 76 children with 22q11.2DS. Four mechanisms were investigated: (a) dosage sensitivity of genes within 22q11.2 region, (b) a disruption of the expression of genes flanking the deletion i.e. positional effect and genome-wide, (c) the presence of additional genetic risk variants within the 22q11.2 region, and (d) the presence of additional CNVs outside of the 22q11.2 deleted region. While this work revealed significant evidence for differential expression of 39 of the genes spanned by the deletion, there was no significant evidence for a positional effect at other genes on chromosome 22. The genome-wide differential gene expression analysis revealed four significantly enriched biological networks (FDR < 0.05) that are involved in: 1) translation, protein synthesis machinery, and post-translation modifications; 2) apoptosis; 3) regulation of the immune system; and 4) intramembrane organelles. The association analyses of genetic variants present on the non-deleted 22q11.2 chromosome did not identify any that were significantly associated with psychiatric phenotypes in 22q11.2DS. The genome-wide screen for additional CNVs identified a non-significant trend that large, rare CNVs were enriched in 22q11.2DS patients with psychiatric phenotypes, however there was no evidence that these additional CNVs were enriched for CNVs that had been previously implicated in developmental delay and neuropsychiatric disease. In addition, in this thesis also investigated the role of deletions at 22q11.2 in a large cohort of individuals with idiopathic Parkinson’s disease. This provided significant evidence that deletions at 22q11.2 increase the risk of Parkinson’s disease, particularly the early-onset form. Taken together,the data presented in this PhD suggested that the mechanism by which haploinsufficiency at 22q11.2 increases risk to psychiatric illness is likely to be complex. To follow up this work, future studies should utilise larger numbers of samples, use neurologically relevant tissue and apply more sophisticated approaches to screen for changes in gene expression and additional genetic variants.

Huntington’s disease (HD) is a primary example of a basal ganglia disorder, from which, medium spiny neurons in the striatum degenerate. As this causes a breakdown in basal ganglia cortico-thalamic circuitry, this leads to a range of symptoms including motor, cognitive and behavioural deficits. One therapeutic option is to replace medium spiny neurons with precursor striatal cells and reconnect the lost circuitry. However, the lack of performance based functional outcome measures for people with HD have made it difficult to assess how the graft affects standards of daily living. Although neuroimaging techniques can be used to quantify the morphological and molecular effects that the intervention has on that brain region, and associated circuitry, an important question still remains, namely whether there has been any effect on functional ability. Using assessments that have high ecological validity, such as dual tasks could be a valuable measure, especially as previous studies suggest that the striatum is required for optimal performance in such tasks. Therefore the focus of this thesis was to design, develop and assess performance based functional tasks that involve the neurocircuity affected in HD; namely the basal ganglia. The aim of the study in Chapter 2 was to select, develop and evaluate motor-cognitive dual task paradigms for use in people with HD. The findings revealed that the Step and Stroop which targeted lower limb function, best distinguished disease stage in HD compared to the other lower limb assessments tested. During this experiment, it became apparent that upper limb assessments for people with HD were particularly limited. Therefore, in Part 2, a new upper limb dual task assessment was developed and called the Clinch token transfer test (C3t). The findings revealed that this was sensitive to disease stage and could provide a useful outcome measure for people with HD in the future. To take the findings from Chapter 2 further, a new, standardised C3t was developed. This version was evaluated, optimised, and then validated in a large group of people gene positive for HD, and in heathy controls. The findings revealed that the C3t significantly correlated with all the Unified Huntington Disease Rating Scale measures, successfully distinguished between all disease stages, and revealed that the performance in this task was also sensitive to the subtle disease symptoms in the early stages of HD. As the Stroop task is commonly used in people with HD, the aim of Chapter 3 was to use immediate early gene expression to identify if the striatum was activated during a rodent analogue of the Stroop task. The findings revealed what could be the first in a series of experiments in that, striatal activation significantly correlated with performance in the congruent and the incongruent versions of this test when compared to cage controls. The findings presented in this thesis support that dual task assessments could have an important role in assessing function in HD, which could translate to performance in tasks that affect the standards of daily living. Importantly, as different dual tasks can result in different levels of dual task interference, this suggests that practice effects could affect how sensitive some dual task paradigms are over others. In addition, selecting outcome measures that are specific to the regions affected in HD, in both clinic and in pre-clinical models, will permit sensitive tracking of neurodegeneration, and could also be used to assess the outcomes of therapies that target this specific neural region.

While mood disorders rank within the top ten disabilities worldwide, there has been limited research done on cognitive schemas and the role they play in the development of mood disorders in South Africa. Cognitive conceptualisations of depression typically emphasize the schema-based automatic processing of information. Beck (1967, 1976 & 1987) suggested that schematically driven automatic thinking is a key element in depressive disorders. Research in the field of depression has identified cognitive schemas as a factor which increases an individual’s diathesis to depression. The primary aim of this research is to explore and describe maladaptive cognitive schemas, hopelessness and levels of depression amongst individuals diagnosed with Unipolar Mood Disorder. A further aim of the research has been to explore the relationship between maladaptive cognitive schemas and hopelessness as a diathesis to depression. In order to achieve the objectives, data was collected from a sample of 50 inpatients diagnosed with Unipolar Mood Disorder. The following measures were used: Young’s Schema Questionnaire, Beck's Depression Inventory – 2nd edition and Beck’s Hopelessness Scale. The research is quantitative in nature and takes the form of an exploratory-descriptive study. Data has been analysed by means of descriptive statistics in order to identify the mean, ranges and standard deviation of the measures used. Cross-tabulations have been used to further explore the relationship between the variables mentioned above. It was found that a statistically significant correlation exists between the BDI, BHS and YSQ. Maladaptive cognitive schemas were found to have a strong positive correlation 4 to depression, whereas hopelessness was found to have a less significant role in Unipolar Mood Disorder. The most significant schemas found in relation to hopelessness, were the Social Isolation, Unrelenting Standards and Pessimism schemas. With regards to depression, the most significant schemas were found to be Mistrust, Practical Incompetence, Vulnerability, Subjugation, Self-Sacrifice, Emotional Inhibition, Unrelenting Standards, Entitlement, Insufficient Self-Control, Admiration, Pessimism and Self-Punitiveness. All the above mentioned variables proved to have a statistically significant relationship. The findings of this research study are for the most part consistent with the literature on depression, hopelessness and cognitive vulnerabilities, and all of the above mentioned concepts have been found to be related.

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.