BACKGROUND:Diffuse axonal injury is a common consequence of traumatic brain injury (TBI) and often co-occurs with hypoxia, resulting in poor neurological outcome for which there is no current therapy. Here, we investigate the ability of the multifunctional compound erythropoietin (EPO) to provide neuroprotection when administered to rats after diffuse TBI alone or with post-traumatic hypoxia.METHODS:Sprague-Dawley rats were subjected to diffuse traumatic axonal injury (TAI) followed by 30minutes of hypoxic (Hx, 12% O2) or normoxic ventilation, and were administered recombinant human EPO-alpha (5000IU/kg) or saline at 1 and 24hours post-injury. The parameters examined included: 1) behavioural and cognitive deficit using the Rotarod, open field and novel object recognition tests / 2) axonal pathology (NF-200) / 3) callosal degradation (hematoxylin and eosin stain) / 3) dendritic loss (MAP2) / 4) expression and localisation of the EPO receptor (EpoR) / 5) activation/infiltration of microglia/macrophages (CD68) and production of IL-1beta.RESULTS:EPO significantly improved sensorimotor and cognitive recovery when administered to TAI rats with hypoxia (TAI+Hx). A single dose of EPO at 1hour reduced axonal damage in the white matter of TAI+Hx rats at 1day by 60% compared to vehicle. MAP2 was decreased in the lateral septal nucleus of TAI+Hx rats / however, EPO prevented this loss, and maintained MAP2 density over time. EPO administration elicited an early enhanced expression of EpoR 1day after TAI+Hx compared with a 7-day peak in vehicle controls. Furthermore, EPO reduced IL-1beta to sham levels 2hours after TAI+Hx, concomitant to a decrease in CD68 positive cells at 7 and 14days.CONCLUSIONS:When administered EPO, TAI+Hx rats had improved behavioural and cognitive performance, attenuated white matter damage, resolution of neuronal damage spanning from the axon to the dendrite, and suppressed neuroinflammation, alongside enhanced expression of EpoR. These data provide compelling evidence of EPO's neuroprotective capability. Few benefits were observed when EPO was administered to TAI rats without hypoxia, indicating that EPO's neuroprotective capacity is bolstered under hypoxic conditions, which may be an important consideration when EPO is employed for neuroprotection in the clinic.

Background and aims: The provenance of post-concussion symptoms (PCS) and post-traumatic stress (PTSD) after mild traumatic brain injury (mTBI) is controversial. This thesis investigated factors influencing these two conditions separately, as well as the interplay between PCS and PTSD, in individuals with mTBI and a control sample without mTBI (orthopaedic injuries). Method: Consecutive adult attendees of an Emergency Department with mTBI or orthopaedic injury were prospectively recruited and completed the Rivermead Post-concussion Questionnaire (RPQ) and Trauma Screening Questionnaire (TSQ) for PTSD at two weeks (T1) and three months (T2) post-injury. The sample at T1 consisted of 34 with complicated mTBI, 76 with uncomplicated mTBI and 47 with orthopaedic injury, and 18 with complicated mTBI, 43 with uncomplicated mTBI and 33 orthopaedic controls at T2. Results: Although there were no differences in overall PCS symptomology between groups, a subset of PCS symptoms (headaches, dizziness and nausea) was found to be specific to mTBI at both time points. These symptoms are proposed to have a neurological basis, as opposed to a psychological basis. PTSD interacted with PCS, particularly in mTBI, such that PTSD was associated with greater “neurogenic” and “psychogenic” symptomology in this group, but only a moderate increase in psychogenic symptoms for controls. A model of the influence of PTSD on PCS is presented. PTSD was influenced by poor memory quality for the traumatic event and attribution of blame to others, but not by mTBI. Discussion and conclusions: Though mTBI may set the scene for at least neurogenic symptoms of PCS to occur, psychological mechanisms, particularly PTSD, have a significant role in the persistence of PCS. Our findings suggest the need for a clear story and sense of meaning for a traumatic event for good recovery from PTSD. Taken together, the results suggest that psychological interventions, particularly aimed at PTSD, may be most effective after mTBI.

This study examined police officers' perceptions of self, occupational role and their relation to perceived stress and posttraumatic stress symptomology. Self-report measures for the study variables were completed by 101 police officers. Hypotheses predicted that perception of self and role would be associated with perception of stress and that perception of the stress would mediate PTSD symptomology. Neuroticism, job quality and general job satisfaction were the main predictors of stress. Stress levels mediated between 1) job quality and the symptoms of anxious arousal and impaired self-reference; 2) general job satisfaction and the symptoms of defensive avoidance and dissociation; and 3) neuroticism and the symptom of defensive avoidance. This implies that police officers' job quality, their feelings of general job satisfaction, and low levels of neuroticism are important in alleviating stress and subsequent psychological sequela.

Three recent studies attempted to substantiate Sewell and Cromwell's (1990) theory of Posttraumatic Stress Disorder (PTSD; American Psychiatric Association, 1994) based on personal construct theory (Kelly, 1955). One crucial aspect of the model that was tested in each of the studies is "elaboration," which is the process of bringing more of a person's repertoire of understanding (constructions) to a certain experience to give it meaning. Elaboration is representative of whether or not the individual is using an integrated set of constructs to deal with a traumatic event. A two-part study (1) reanalyzed existing data to assist in understanding discrepancies in past findings, and (2) content analyzed constructs given by subjects in all three studies. Findings concerning elaboration remained somewhat discrepant but suggested possible differences when investigating the emergent versus submerged poles of constructs.

This study examined the relation between level of rape acknowledgement and levels of PTSD symptoms reported in female college students. Subjects were administered the Sexual Experiences Survey (SES), the PTSD Interview, and a demographics questionnaire. Subjects were then grouped into the following categories based on their responses to the SES: reported rape victims, acknowledged rape victims, unacknowledged rape victims, and a control group of non-rape subjects. Small sample analyses did not reveal the expected linear relation between the two variables. Only the acknowledged group showed greater PTSD symptoms. The unacknowledged and control groups did not significantly differ on overall PTSD symptom severity, or on any cluster of PTSD symptoms. Naturalistic selection factors are discussed that could have affected the outcome of the study.

In addition to the acute pathology produced by traumatic brain injury, there are chronic alterations that occur after the trauma, including a depressed state of neuronal activity (Feeney, 1991). This study included a preclinical testing of a novel treatment strategy focusing on increasing neuronal activity during the chronic hypofunctional posttraumatic stage. The present investigation tested the effects of repeated post-injury aniracetam administration on cognitive performance in the Morris water maze (MWM) and on the GluR2 - immunoreactivity and protein expression by Western blot analysis in the hippocampus. The first study examined the optimal dose of aniracetam in the MWM task. Animals received aniracetam (25 mg/kg, 50 mg/kg) or vehicle once daily for fifteen days and on days 11-15 were tested in the MWM. The results indicated that injured aniracetam-treated rats had a significant improvement in MWM performance compared to injured saline-treated animals. When the drug was delayed for 11 days post-injury in the second experiment, its beneficial effects were still present, as injured aniracetam-treated rats performed significantly better that injured saline treated rats on the MWM task. In the third experiment, chronic daily aniracetam administration was terminated after 15 days immediately before MWM testing on days 16-20. The results indicated that termination of aniracetam did not enhance MWM performance as injured terminated aniracetam-treated rats did not have significant improvement over injured saline-treated rats. In the fourth study we investigated the mechanism of aniracetam's effects by examining the expression of the AMPA receptor GluR2 subunit, the only AMPA receptor subunit that is Ca++ impermeable. Using a monoclonal antibody selective for the GluR2 subunit, immunohistochemical results indicated that injured rats treated with aniracetam (50mg/kg for 15 days post-injury) had a slight reduction in the GluR2- IR. The fifth study investigated a change in the GluR2 protein expression in the hippocampus with a Western blot analysis. The results were consistent with the immunohistochemical study outcome as the injured vehicle and injured aniracetam treated animals showed a reduced protein expression in the hippocampus. The changes were not significantly different from the controls. The results of these experiments suggested that chronic aniracetam treatment significantly attenuated injury induced spatial memory deficits when administered continually during the hypofunctional posttraumatic stage and when the treatment was delayed for 11 days, but not when the treatment was terminated before the MWM testing. These effects suggest that the compound does not induce chronic receptor changes and has to be biologically active in an organism for it to exert its beneficial properties. Results from the present studies suggest that aniracetam may become a potential treatment option for brain injury induced cognitive deficits.

D. Ed. / Trauma can be described as the emotional shock response to a physical or emotional injury that is overwhelming and has a lasting effect on a person. Based on this definition, trauma can be considered an integral part of life in South Africa. The consequences and effects of trauma are severe, both on individual and society levels. Nobody escapes the effects of trauma, but women and children are particularly vulnerable. Unfortunately the vast majority of South Africans have little or no access to mental health services. Some people, however, seem to be resilient in response to trauma and hardship. Although various definitions of resilience can be found in the literature, resilience is defined in this thesis as the ability and characteristics that enable a person to endure, recover from, and be strengthened to grow personally, regardless of exposure to traumatic life events. Women are generally the primary educators of children in the South African society, whether it be their own children, grandchildren or others. If South African women were equipped with skills that could enable them to deal more effectively with trauma, they would – as primary educators – naturally transfer their skills and knowledge to the children in their care. There exists a need for preventative interventions that may equip women to cope effectively with trauma. Certain educational interventions may provide avenues through which this may be achieved. Educational drama is one such avenue through which women of diverse educational, socio-economical, and cultural backgrounds may be reached in a comprehensible, accessible and non-discriminatory way. In this study a number of issues pertaining to the prevalence of resilience in South African women have been explored and described. The purpose of this study was to create an interactive educational play aimed at facilitating mental health in women exposed to traumatic life events.

Football safety has increased over time, in part due to improvements in equipment and body mechanics, but there are still inherent risks involved, including exposure to repetitive head impacts (RHI). Significant head impacts can result in a constellation of symptoms including nausea, vomiting, headache, dizziness, and amnesia, which typically assist in the diagnosis of concussion. However, it has been shown that subconcussive impacts may result in microstructural changes and physiological alterations in the brain. This is particularly concerning because athletes may be undergoing changes in the brain in the absence of outwardly visible symptoms. Poorer neurologic outcomes later in life have been associated with cumulative exposure rather than number of diagnosed concussions. Accelerometers installed in helmets have shown that college football players may receive up to 1,850 head impacts throughout the course of one season. The concussion rate is obviously much lower, indicating there are a high number of head impacts per diagnosed concussion. Axons are especially susceptible to damage from RHI because of their extension throughout the nervous system. The subtle changes thought to result from RHI are not easy to measure, but several modalities have been proposed. These include diffusion tensor imaging (DTI), plasma tau protein, and King-Devick testing. The proposed study will look to quantify cumulative head impact exposure in college football players prior to the start of a season and see if this has any impact on the variables. They will then participate in one season of football wearing helmet accelerometers to measure the number of head impacts sustained. Changes in the variables will be compared to non-contact sport college athletes. Data will be analyzed to determine if number of head impacts correlates with changes in variables and if prior head impact exposure has any effect on these changes. Data obtained from this study will have significant implications in the field of head injury. It may strengthen the use of several markers of brain injury that could be utilized in the future. Additionally, the effects of cumulative head impact exposure and one season of head impacts will be thoroughly examined. This information can be provided to trainers, coaches, and athletes to further improve football safety.

Measurement is the foundation of epidemiologic thought and practice. The appropriate measurement of exposures and outcomes of interest is the underlying assumption to all causal investigations. Poor quality measurement, be it through inappropriate data collection methods or changing diagnostic criteria, which can result in erroneous estimates, has a deleterious impact on scientists, policy makers, and the public. Mental health disorders particularly suffer from a lack of diagnostic clarity as diagnosis is often based on self-report of overlapping symptoms with no clear measureable biomarkers. The release of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) in May of 2013 is the most recent attempt to codify existing diagnostic criteria for psychiatric disorders. Posttraumatic stress disorder (PTSD) diagnostic criteria shifted from a three-cluster approach of avoidance, hyper-arousal, and re- experiencing to a four-cluster approach of avoidance, arousal, negative cognitions and mood, and re- experiencing. The very existence of multiple diagnostic frameworks for the same psychiatric disorder is proof that accurate diagnosis is a complex and unresolved issue that warrants investigation. This complexity in posttraumatic stress disorder (PTSD) symptom presentation, limits our ability to develop appropriate responses. In this dissertation I conducted four independent but related studies to explore the construct validity of PTSD. In Chapter 1 I systematically reviewed the extant empiric literature from PubMed and PsychINFO on PTSD symptom structure to identify a universal PTSD factor structure. I found 40 (3%) of 1,302 citations published between 1980-2014 provided empiric PTSD factor structure estimates forming the basis of my review. While consensus exists with respect to the general multifactorial make-up of PTSD, a universal understanding of the specific operationalization of this structure, supported by the empiric literature, is absent. In Chapter 2, I used population-based, cross-sectional data from adult survivors of the 2010 earthquake in Haiti, to assesses model fit of six theoretical factor structures of PTSD: one-factor Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV; three-factor DSM-IV-TR (arousal, avoidance, and intrusion); three-main factor (arousal, avoidance, and intrusion) and one-hierarchical factor DSM-IV-TR; four-factor King 1998 (avoidance, hypervigilance, emotional numbing, re-experiencing); four-factor Simms 2002 (avoidance, dysphoria, hyperarousal, intrusion); and four-factor DSM-5 (arousal, avoidance, intrusion, negative mood and cognition) models through confirmatory factor analyses (CFA). While all models adequately fit the data, the three-factor DSM-IV-TR (arousal, avoidance, and intrusion) model best fit the sample (χ2=593.257, 116 degrees of freedom; RMSEA=0.056; CFI=0.927; TLI=0.915, WRMR=1.769; AIC=24,760.459; and BIC=24,952.178). Again drawing on the cross-sectional, population data from Haitian earthquake survivors, in Chapter 3 I used multiple linear regressions to model pre-, peri-, and post-earthquake factor associations with mean PTSD symptom cluster (arousal, intrusion, and avoidance, validated in Chapter 2) endorsement. I found that mean PTSD symptom factor endorsement is heterogeneously associated with pre-, peri-, and post- earthquake factors, consistent with dimensional theoretical foundations: arousal endorsement more likely to be associated with pre-earthquake factors, intrusion endorsement more likely to be associated with factors across the temporal field, and avoidance endorsement more likely to be associated with post- earthquake factors. In Chapter 4, I used exploratory factor analysis (EFA) to assess the factor stability of the DSM-IV-TR (arousal, intrusion, avoidance) defined PTSD structure when major depressive disorder (MDD) items are introduced, in the same Haitian post-earthquake population-based study. A six-factor, 25-item model was estimated and fit the data (χ2=253.427, 165 degrees of freedom, p<0.001; RMSEA=0.021, 90% CI:0.016, 0.026; CFI=0.987; TLI=0.976) better than the PTSD-only model specified in Chapter 2. PTSD-specific items did not load on the original PTSD factors or with the original factor items (new factors included items from 0-3 different original PTSD factors), in the presence of MDD items. PTSD dimensionality was not stable in the presence of MDD items, thus challenging the discriminant validity of PTSD. This exploration into PTSD construct validity found that while consensus exists with respect to the general multifactorial make-up of PTSD, a universal understanding of the specific operationalization of this structure, supported by the empiric literature, is absent. The tight range in model fit statistics documented in the CFA provides additional evidence of this, suggesting that empirical-based model selection is insufficient to universally characterize PTSD. Given the overall consensus of general factors, the significant and heterogeneous pre-, peri-, and post-earthquake factor associations with the unique PTSD symptom clusters provides additional evidence of the multidimensional theoretical mechanisms behind PTSD psychopathology. PTSD model stability, an indication of discriminant validity, failed to hold when challenged by MDD items, further challenging PTSD construct validity. There are several important implications of this work. First, based on the systematic review and CFA findings, adjudication of PTSD model selection based on empiric findings is insufficient and should be theoretically driven. Future investigations should always include the most commonly supported models as they develop and refine additional models, thus enabling rigorous cross-context, cross-potentially traumatic event, and cross-study comparisons that are currently not possible. Second, the multidimensional modeling of PTSD factors provided valuable insight into the psychopathology of PTSD without additional data collection burden and should be widely adopted. Researchers should look to model PTSD both as a dichotomous variable and on a continuous scale, both as a complete construct and by each dimensional component. Third, while the exploration into discriminant validity builds on another study that found PTSD factor structure unstable in the presence of MDD item challenges, more research is needed here to understand the theoretic and empiric utility of the specified six-factor model across settings and diagnostic criteria. Fourth, while endeavoring to explore construct validity, exploratory qualitative methods with populations beyond the highly studied U.S. military populations are needed to propose additional items that could, provide valuable missing empiric evidence for PTSD factor dimensionality.

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.