Tauopathies are a group of neurodegenerative diseases characterized by the abnormal deposition of the protein tau, a microtubule stabilizing protein. Under normal physiological conditions tau is a highly soluble protein that is not prone to aggregation. In disease states alterations to tau lead to enhanced fibril formation and aggregation, eventually forming neurofibrillary tangles (NFTs). The exact cause for NFT deposition is unknown, but increased post-translational modifications and mutations to the tau gene can increase tangle formation. Tauopathic brains are stuck in a detrimental cycle, with cellular dysfunction contributing to the development of tau pathology and the development of tau pathology contributing to cellular dysfunction. The exact mechanisms by which each part of the cycle contributes to the other are still being explored. To investigate the unique contributions of each part of this cycle we utilized two separate models of tauopathy: one chronic and one acute. Overall this project provides novel insight into the role of pathological tau as both a cause, and a consequence, of cellular dysfunction. To understand how development of tau pathology contributes to cellular dysfunction we studied chronic disease models. Using human brain tissue we found that under normal conditions tau associates with ribosomes but that this interaction is enhanced in Alzheimer’s disease brains. We then used in vitro and in vivo models of tauopathy to show that this association causes a decrease in protein synthesis. Finally, we show that wild type tau and mutant tau reduce protein translation to similar levels. To understand how general cellular dysfunction contributes to development of pathology we used an acute model of tauopathy through traumatic brain injury (TBI). We injured rTg4510 tau transgenic mice at different ages to investigate the effect of TBI on tau fibrillization (2 month old) and the effect of TBI on tau already in NFTs (4.5 month old). In 2 month old mice, we found that tau hyperphosphorylation was decreased at 24 hours and increased at 7 days post injury, and that tau oligomerization was decreased at 24 hours post injury. We also found that tau fibrillization was not increased after 24 hours or 7 days post injury. In 4.5 month old mice, we found that TBI did not increase or decrease tangle counts in the brain, but we did qualitatively observe decreased variability within groups. Overall these studies contribute novel understanding of tau’s role in different disease states. We identified a functional consequence of the interaction between tau and ribosomes, and demonstrated that a single head impact did not increase tau fibril formation within 7 days of injury. While human diseases associated with TBI show neurofibrillary tangle deposition, we have yet to recreate that aspect of the disease in research models of TBI. Our findings support the need for further investigation into the nuances of tau in disease, especially following TBI.

Attentional bias effects for threat and emotional words were investigated, using both the emotional Stroop and emotional lexical decision paradigms. Twenty-eight controls and twenty-eight survivors of sexual assault participated in this study, which comprised three key comparisons. First, key predictions of the threat and emotionality hypotheses were compared, in particular specific and general threat effects, and positive and negative emotionality effects. Second, two separate group comparisons were conducted, specifically controls versus survivors of sexual assault overall, and a matched subset of controls versus PTSD positive survivors of sexual assault versus PTSD negative survivors of sexual assault. Third, performance on the emotional Stroop task and emotional lexical decision task paradigms were compared directly. Slowed colour naming responses (i.e. interference) were observed for both threat effects and emotionality effects in the emotional Stroop task. For the emotional lexical decision task, slowed lexical decisions (i.e. interference) were observed for threat effects, whereas speeded lexical decisions (i.e. facilitation) were observed for emotionality effects. The findings of the current study indicate that threat and emotionality effects may co-exist in both control and survivor populations. The relationship between the presence or absence of PTSD symptoms and threat and emotionality effects requires further investigation with larger sample sizes. There may be a relationship between the presence of PTSD symptoms and specific threat effects, however the findings of the current study for general threat information were inconclusive. No relationship was evident between the presence of absence of PTSD symptoms and positive or negative emotionality effects. The current findings suggest that the emotional Stroop task may be better suited to quantifying threat effects but not emotionality effects, whereas the emotional lexical decision task appears to be able to quantify both threat and emotionality effects.

This thesis describes studies assessing the ability of somatosensory evoked potentials (SEPs) to predict outcome following severe brain injury by examining outcome and determining the predictive value of SEPs directly and in comparison to alternative tests in both patients and systematic reviews of the literature. Outcome was assessed using a functional and quality of life measure. It changed over time and was influenced by age, mechanism, timing and the type of outcome measure. When 5 year functional outcome was used, sensitivity and specificity for the initial SEPs were 63.2% and 93.3% with a positive predictive value of 92.3% for favourable outcome and 66.7%, 94.7% and 90.9% for unfavourable outcome prediction. SEPs predictive performance varied and was better in patients with 1 year outcomes, when outcome was measured with the quality of life tool and in patients suffering hypoxicischaemic encephalopathy. Importantly, only twelve false positives were identified in the systematic review of 55 studies from 903 patients with bilaterally absent SEPs. Eight of these false positives suffered focal lesions of the brain stem, large cerebral fluid collections or recent decompressive craniectomy which cause SEPs to be absent because of a mechanical disruption to the electrical signal. Comparisons between SEPs and other tests in the patient cohort and wider literature showed that SEPs were the best overall predictors of outcome but were outperformed by some clinical tests in specific areas. Specificity for unfavourable outcome prediction was better for ICP, CPP and the last pupillary response. In patients with any cause of brain injury, the combination of SEPs and Motor responses provided the best predictions for unfavourable outcome while for favourable outcome the best overall prediction and specificity were achieved with a combination of either SEPs or Motor responses and the best sensitivity with pupillary responses alone or a combination of either SEPs or Pupillary responses. The studies in this thesis provide a detailed evaluation of SEPs and showed that SEPs have a place in the prediction of outcome, alone or in combination with existing tests. Overall, they are superior to clinical tests and can be easily obtained at the bedside and in the presence of pharmacological paralysis and analgesia/sedation.

Traumatic brain injury (TBI) is the leading cause of death and disability in the industrialized world. This pilot study investigated demographic, clinical and environmental factors associated with return to work (RTW) among workers who sustained a mild to moderate work-related TBI (WrTBI). Using a retrospective cohort design, participants were recruited through an outpatient clinic dedicated to evaluating injured workers after a WrTBI. A mailed survey and medical record abstraction tool were used for data collection. Of the 40 injured workers who participated in this study, 19 reported working at time of follow-up. Those who were unable to RTW scored significantly lower on measures of emotional well-being; there were no significant between-group differences in cognitive or physical impairments. Gradual RTW and workplace accommodations were reported as key factors facilitating RTW. Our findings provide information that addresses improved rehabilitation and management of WrTBI as well as better education and support for employers.

Traumatic brain injury (TBI) is the leading cause of death and disability in the industrialized world. This pilot study investigated demographic, clinical and environmental factors associated with return to work (RTW) among workers who sustained a mild to moderate work-related TBI (WrTBI). Using a retrospective cohort design, participants were recruited through an outpatient clinic dedicated to evaluating injured workers after a WrTBI. A mailed survey and medical record abstraction tool were used for data collection. Of the 40 injured workers who participated in this study, 19 reported working at time of follow-up. Those who were unable to RTW scored significantly lower on measures of emotional well-being; there were no significant between-group differences in cognitive or physical impairments. Gradual RTW and workplace accommodations were reported as key factors facilitating RTW. Our findings provide information that addresses improved rehabilitation and management of WrTBI as well as better education and support for employers.

With an estimated incidence of 1.5 million each year, traumatic brain injury (TBI) is a major cause of mortality and morbidity in the United States. Opening of the mitochondrial permeability transition pore (mPTP) is a key event contributing to TBI pathology. Cyclophilin D (CypD), a matrix peptidyl-prolyl cis-trans isomerase, is believed to be the regulating component of the mPTP. Cyclosporin A, an immunosuppressant drug, inhibits CypD and blocks mPTP formation and has been shown to be neuroprotective following TBI. However, it is unclear if CsA’s neuroprotective mechanism is due to inhibition of CypD and/or immuno-suppression. Therefore to directly assess the contribution of CypD to TBI pathology, CypD knockout mice were subjected to a controlled cortical impact model of TBI. CypD ablation resulted in increased tissue sparing, hippocampal protection, and improved mitochondrial complex I driven respiration. Next a dose-response study of the Cyclophilin D inhibitor, NIM811, was performed. NIM811 administration following TBI resulted in improved cognition, increased tissue sparing, and improved mitochondrial function. These results suggest a major role for CypD in TBI pathology and validate CypD as a potential therapeutic target for TBI. TBI has been proposed to be the signature injury of the current Middle Eastern conflicts with an estimated prevalence of 15-60 % among combat soldiers. Although the brain does appear to be vulnerable to blast, the exact mechanisms underlying the injury remain unclear. Adult male Sprague-Dawley rats were exposed to a moderate level of blast overpressure. Following blast, blood brain barrier disruption was evident at 3 and 24 h post-exposure, oxidative damage increased at 3 h post-exposure, and microglia were activated in the hippocampus at 5 and 10 days post-exposure. This may widen future neuroprotective avenues for blast since blast brain injury appears to share similar mechanisms of injury with other TBI models.

Current studies in peace-building suggest that effective peace-building approaches comprise of intervention strategies that value the interconnectedness of trauma and peace-building processes. However current research reports suggest that there is limited evidence supporting this notion. In addition, there is little information as to how to effectively integrate the two themes to achieve lasting peace. The research study aims to articulate the role of an integrated approach to peace-building to inform current practice and it serves to encourage the donor community to support initiatives which recognise the link between trauma and peace building. The research took a close look at experiences of participants who attended trauma recovery workshops conducted by Sinani (an isiZulu word meaning “we are with you”), the KwaZulu-Natal Programme for Survivors of Violence, the name of the Non-Governmental Organisation (NGO) for which the researcher works. In particular, it explored how participants who had attended these workshops could serve as catalysts to peace by examining their experiences of violence in relation to trauma and peace-building. In addition it attempted to explore experiences of participants who did not attend Sinani trauma recovery workshops and the possible implication this would have for trauma and peace-building. Furthermore it analysed recent research papers and reports which addressed trauma and peace-building from a psycho-social perspective. The proposed hypothesis is that if trauma support work is ignored in post conflict peace-building processes, certain survivors of past violence are at risk of becoming perpetrators of future violence. Integrating trauma support work in peace-building interventions will yield lasting peace. The emerging findings suggest several factors contribute to violence and peace-building. Children’s exposure to violence, the extent of trauma and certain aspects of the criminal justice system have been described by participants as factors that contribute to violence. Equally participants suggested a competent leadership collective, functioning safety and security structures as valuable contributions to peace. Other valuable insights were shared by participants on the role of spirituality as well as indigenous cultural rituals valuable in the trauma and peace-building field. / Thesis (M.A.)-University of KwaZulu-Natal, Durban, 2013.

Thesis (MPsy(Clinical))--University of South Australia, 2001.

Thesis (MA (Counselling Psychology))--University of Pretoria, 2006. / Includes bibliographical references. Available on the Internet via the World Wide Web.

Thesis (Ph.D.)--Kent State University, 2007. / Title from PDF t.p. (viewed Mar. 11, 2009). Advisor: Douglas Delahanty. Includes bibliographical references (p. 55-71).