This thesis examined neuropsychological and psychological outcomes following paediatric traumatic brain injury (TBI). The introductory chapter provides an overview of the paediatric TBI literature, giving definitions of key terms and concepts and providing a description of the epidemiology of childhood head injury. Key models relevant to paediatric TBI are introduced, including developmental neurological, cognitive and psychological perspectives. This is followed by a discussion of factors pertinent to outcome after TBI, followed by a description of outcomes relating to cognitive, behavioural, psychological, adaptive and family functioning domains. Existing research demonstrates that poor outcomes are frequently observed in paediatric TBI populations across these domains and difficulties are persistent over time, particularly where children have sustained severe head injury. Thus, research has turned its focus to the prediction of outcomes which can assist clinicians in the identification of those individuals who will require rehabilitation in order to promote their long-term recovery. Whilst the literature has identified injury and demographic factors that can assist in this process, little attention has been given to the potential utility of psychological screening assessment. Given the prevalence of neuropsychological and psychosocial problems after paediatric TBI and lack of empirical data considering factors predictive of difficulty at the post-acute phase, this research aimed to consider the clinical utility of completing a pre-discharge screening assessment in children and adolescents with TBI. Specific areas of consideration included the potential impact of injury severity on neuropsychological functioning, psychosocial impairment and return to full-time schooling. The study design comprised a prospective case series of 11 children and adolescents with TBI (aged 7-15 years), who were assessed both pre- and post-discharge (3-6 month follow-up). Domains of intellectual, emotional, behavioural, and adaptive functioning, health-related quality of life and parenting stress were assessed at both time-points. Clinically significant findings were demonstrated in domains of neuropsychological and psychosocial functioning, particularly for those with a severe TBI. Specifically, ratings of self-reported emotional distress, and parental perceptions of child health-related quality of life were found to be within clinical ranges at pre- and post-discharge for more than half of the participants. The majority of participants with severe injury required further neuropsychological assessment and interventions relating to emotional and/or behavioural management. The post-discharge functioning of this cohort provided preliminary evidence for the clinical utility of cognitive and psychosocial screening after paediatric TBI. The observed level of clinical need, particularly in the severely-injured group indicated that screening was a useful tool for early identification of difficulties, and provided an opportunity for timely intervention. Without screening, children and adolescents with TBI may be discharged to the community without appropriate support in place; raising long-term concerns for the child, family, and the wider social and economic systems. Despite this, further research which explicates these findings within larger samples is required. The discussion chapter reviews these findings in relation to the wider literature, followed by consideration of this study's limitations. The thesis concludes with a description of the clinical implications of the findings and suggested future directions.

The thesis includes three papers: paper 1 is a literature review, paper 2 is an empirical study and paper 3 is a critical reflection. Paper 1 and 2 have been prepared for submission to Clinical Psychology and Psychotherapy. Paper 1 systematically reviews the qualitative literature pertaining to individual experiences of psychotherapy for PTSD. A meta-synthesis of twelve studies was facilitated using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) principles. The meta-synthesis aimed to explore aspects of psychotherapy for PTSD that were deemed helpful or unhelpful. The strengths and limitations of the study are considered, as are their implications for clinical practice. Paper 2 was a qualitative exploration of basic emotions and the affective phenomena of PTSD. Semi-structured interviews were conducted with ten participants and transcripts were analysed using a deductive-inductive thematic analysis. The results highlight the importance of considering a range of basic emotions in the assessment, formulation and psychotherapy relating to PTSD. The strengths and limitations of the study are considered, as are their implications for clinical practice. Paper 3 is not intended for publication and is a critical reflection of the overall study process. It evaluates the strengths and limitations of both paper 1 and paper 2 in more detail, in addition to offering a critical and reflective account of conducting the research.

In the past decade, numerous studies have examined the correlation between repetitive head trauma in athletes who participated in contact sports and the development of various personality, behavioral, and cognitive changes. Autopsy data from these athletes have uncovered unique patterns of neuropathology that are believed to be associated with the observed clinical symptoms, and together characterize a condition known as chronic traumatic encephalopathy (CTE). Historically, the condition was known as “dementia pugilistica” commonly found in boxers; however, recent studies have identified cases of CTE in retired football players, hockey players, soccer players, war veterans, and other non-athletes. CTE is a progressive disease and clinical signs often appear many years after the trauma. These symptoms frequently include depression, aggression, suicidality, short-term memory loss, and executive functioning impairments. Postmortem examinations of individuals with CTE reveal distinct gross and microscopic pathology, including atrophy of the frontal and temporal cortices, sulcal accumulation of hyperphosphorylated tau, -amyloid deposition, and TAR DNA-binding protein 43 abnormalities. Although current hypotheses suggest that repetitive head trauma causes the development of CTE, the lack of prospective studies hinders our ability to definitively determine its etiology. Likewise, the inability to diagnose CTE in vivo has constrained our attempts to systematically examine the disease’s progressive nature. The goal of this paper is to review the past and current literature on CTE in boxers and football players. We also discuss current hypotheses concerning CTE’s clinical presentation and neuropathology, and situate CTE within the context of other neurodegenerative diseases. Finally, we address the current limitations of CTE research and propose key objectives for future studies.

Woodpeckers can withstand 1200-1400 g of force during repetitive pecking. The forces a woodpecker’s skull and brain are subjected to warrants an in-depth investigation for the possible existence of neuro-trauma. Dr. Philip May and colleagues in 1976 published a paper titled “Woodpeckers and Head Injury” detailing two woodpeckers and one toucan control. The group utilized ferrocyanide staining, a general stain used for detecting iron deposits, on the sections. The results of these stains were not reported in Dr. May’s paper, yet he and his colleagues conclude that “clearly the woodpecker’s brain is protected somehow from impact and vibration injury.” Close to 115 journal articles have cited this one paper as the standard for woodpeckers not incurring brain injury during pecking. Due to limited studies on the woodpecker brain and the fact the woodpecker is a model for advancing helmet technology, we set out to study the woodpecker’s brain for signs of injury. Taking 10 different ethanol preserved woodpeckers from all parts of the world in different climates, and five non-woodpecker, ethanol preserved red-winged black bird experimental controls, paraffin embedded sections were cut and stained. A piece of human Alzheimer’s disease cortex was also used as a positive control. We utilized Gallyas silver stain for the study of neurofibrillary tangles and tauopathies as well as anti-phospho-tau and anti-glial fibrillary acidic protein (GFAP) immunostaining to detect tau protein and GFAP respectively. The results demonstrated perivascular silver-positive deposits in the superficial cortex and axonal tract injury of eight out of the 10 woodpeckers. The anti-phospho-tau immunostaining stained axonal tract injury in two of the three woodpeckers studied. The red-winged back birds demonstrated no positivity for all three stains. The Alzheimer’s positive control showed silver positive and phospho-tau positive staining as expected. This is the first study of this kind to discover and label potential brain injury in the woodpecker model. The negative staining of the red-winged black bird controls contrasted with the positive staining woodpecker sections suggest pecking in the woodpecker may induce brain injury. When addressing the development of safety equipment, the use of the woodpecker model should be approached with caution. Moving forward, research into different immunostaining molecular targets and an age controlled woodpecker and experimental control study should be performed to determine if the brain injury seen with our research is age-dependent.

BACKGROUND: The accumulation of misfolded proteins is a hallmark of many neurodegenerative disorders, including Chronic Traumatic Encephalopathy (CTE). Intracellular protein degradation pathways appear to be insufficient in preventing or halting disease progression. A brain-wide waste clearance pathway mediated by astroglial aquaporin-4 (AQP4) water channels in the perivascular space called the “glymphatic system” has recently been identified. Disruption of this system due to mislocalization of AQP4 away from perivascular astrocytic endfeet (“depolarization”) is linked to reductions in solute clearance and the build up of toxic metabolites in different neurologic conditions associated with aging and traumatic brain injury. Accumulation of aggregated tau protein around blood vessels at the depths of cortical sulci is considered the pathognomonic lesion of CTE, and may reflect impairment of glymphatic pathway function in these perivascular spaces. OBJECTIVES: To investigate whether changes in AQP4 expression or perivascular AQP4 polarization are present in CTE and to assess their relationship with CTE lesions. Additionally, AQP4 expression in CTE will be compared to subjects with a pathological diagnosis of Alzheimer’s disease (AD) and non-pathological controls without a history of head trauma. METHODS: Postmortem frontal cortex samples from neuropatholigcally confirmed cases of CTE, AD, and non-pathological controls were provided by the VA-BU-CLF Brain Bank. Fixed tissue samples were cut at 20 microns from each case and immunofluorescently stained for AQP4, glial fibrillary acidic protein (GFAP), and phosphorylated tau (AT-8). Slides were imaged using a Zeiss 880 Airyscan confocal microscope and analyzed using the HALO image software analysis platform. RESULTS: Increased perivascular AQP4 polarization was significantly associated with lesional vessels compared to non-lesional vessels in CTE (p=0.0187). When assessed between groups, CTE showed less AQP4 polarization surrounding non-lesional vessels compared to controls, and seemingly higher polarization around lesional vessels compared to AD, however these differences were not statistically significant. CONCLUSIONS: Blood brain barrier (BBB) breakdown is a common occurrence following traumatic brain injury (TBI) and has previously been confirmed in postmortem cases of CTE. The findings reported in the current study showing increased, rather than decreased, perivascular AQP4 polarization around lesional vessels compared to non-lesional vessels in CTE may therefore reflect a compensatory mechanism of astrocytes in response to secondary vasogenic edema in the face of chronic inflammation and disrupted BBB integrity, rather than acute cytotoxic edema which is likely the main driver of AQP4 depolarization reported in previous studies.

Background: Post-traumatic stress and exposure to early traumatic events are often characterised by negative self-cognitions and experiences of shame, guilt or blame. These symptoms are theoretically linked to the concept of self-compassion which is an important factor in affect regulation, and is predictive of mental wellbeing and psychological distress. Interventions aimed at increasing acceptance, non-judgement and self-compassion such as mindfulness may be useful in the treatment of post-traumatic stress symptoms. Methods: The first part of this portfolio presents a systematic review which aimed to collate and evaluate the existing research for the use of mindfulness based interventions to treat post-traumatic stress symptoms. The search process involved a systematic search of relevant research databases, hand search of relevant journals, and relevant authors were contacted. The second part of this portfolio presents a quantitative research study which explored the relationship between the experience of childhood trauma and self-compassion; and whether self-compassion was predictive of post-traumatic stress and growth in an adult clinical sample. Data were collected through postal survey and analysed using correlation and hierarchical regression analysis. Systematic Review Results: The systematic review resulted in 12 studies which met eligibility criteria, the majority of studies indicated positive outcomes with improvements in post-traumatic stress symptoms, particularly in reducing avoidance. Many of these studies lacked methodological rigour and further studies with more robust research design are required. Research Study Results: The quantitative study showed that greater experience of childhood emotional abuse, neglect, punishment and sexual abuse were significantly correlated with lower self-compassion in adulthood. Hierarchical regression showed that self-compassion was predictive of total post-traumatic stress symptoms, post-traumatic avoidance and intrusion when age, gender, exposure to traumatic events and childhood trauma were controlled. The experience of post-traumatic growth showed no significant relationship with self-compassion. Conclusions: Studies indicate that mindfulness interventions show promise for the treatment of PTSD symptoms, although further research with more robust methodology is needed. Greater experience of childhood abuse is related to lower self-compassion in adulthood and lower self-compassion is predictive of higher PTSD avoidance and intrusion symptoms. This suggests that future research investigating self-compassion interventions may be beneficial in treating PTSD.

Traumatic brain injury (TBI) is a common event that can lead to profound consequences for the individual involved, and a considerable socio-economic cost. The initial injury event triggers a series of secondary brain injury mechanisms that lead to further mortality and contribute to morbidity. One classical injury pathology is termed traumatic axonal injury (TAI), which in clinical settings produces the picture of diffuse axonal injury. TAI occurs both as a primary insult, and as a consequence of secondary mechanisms. One secondary injury mechanism that worsens TAI may be Wallerian degeneration (WD), a cell-autonomous axonal death pathway. The relationship between traumatic axonal injury and WD is poorly characterised. This thesis explores the basic mechanisms by which a physical axonal trauma can lead to WD, and how modulation of the WD pathway can affect the cellular responses to a traumatic injury. This involves the development and characterisation of in vitro and in vivo models of traumatic axonal injury. These models are then used to explore the response of cellular cultures to injury when treated with pharmacological and genetic modulators of WD. Using a primary neuronal stretch-injury system we demonstrate that rates of neurite degeneration are altered by modulators of the WD pathway but that a purported neuroprotective compound ‘P7C3-A20’ did not protect primary cultures in vivo and did not act via a WD dependent mechanism. An organotypic hippocampal slice stretch injury model was then used to demonstrate genetic rescue of cellular death, and used to assess amyloidogenic responses to injury. Next we established a TBI model using Drosophila Melanogaster, and demonstrated that a loss of function mutation in a key WD gene ‘highwire’ which controls NMNAT levels, was capable of rescuing premature death and a range of behavioral deficits after a high impact trauma. The injury caused dopaminergic neuronal loss and this was rescued by highwire mutation. Furthermore, this dopaminergic neuronal protection extended to a genetic PINK1 model of Parkinsonism. Together these results help establish WD as an important secondary injury mechanism in TBI, and provide evidence that modulation of the WD pathways can improve outcomes in various model systems. This provides a foundation for future translational research into the fields of WD and TBI.

Previously, we have demonstrated that nicotinamide (NAm), a neuroprotective soluble B-group vitamin, improves recovery of function following traumatic brain injury (TBI). However, no prior studies have examined whether NAm is beneficial following continuous infusions over seven days post-TBI. The purpose of this study was to investigate the preclinical efficacy of NAm treatment as it might be delivered clinically; over several days by slow infusion. Rats were prepared with either unilateral controlled cortical impact (CCI) injuries over the somatosensory cortex (SMC) or sham procedures and divided into three groups: CCI-NAm, CCI-vehicle, and sham. Thirty minutes following CCI, Alzet osmotic mini-pumps were implanted subcutaneously. NAm was delivered at a rate of 50 mg/kg/day for seven days immediately post-CCI. On day seven following injury, the pumps were removed and blood draws were collected for serum NAm and nicotinamide adenine dinucleotide (NAD+) analyses. Starting on day two post-CCI, animals were tested on a battery of sensorimotor tests (bilateral tactile adhesive removal, locomotor placing, and limb-use asymmetry). Statistical analyses of the tactile removal and locomotor placing data revealed that continuous administration of NAm significantly reduced the initial magnitude of the injury deficit and improved overall recovery compared to the vehicle-treated animals. NAm treatment also significantly decreased limb-use asymmetry compared to vehicle-treated animals. Continuous infusion of NAm resulted in a significant serum elevation in NAm, but not NAD+, as well as significantly attenuated cortex tissue loss than un-treated animals. The NAm-treated group also had the lowest number of glial fibrillary acidic protein (GFAP) positive cells. No detrimental effects were seen following continuous infusion. The present results suggest that NAm delivered via a clinically relevant therapeutic regimen may truncate behavioral damage following TBI. Thus our results offer strong support for translation into the clinical population.

Research related to positive psychological reactions following exposure to traumatic events, also known as post-traumatic growth (PTG), has suggested that support from others can facilitate such outcomes. The current study focused on whether people's perceptions of PTG differed based on the gender of a hypothetical survivor and nature of the trauma. Characterological differences amongst those who perceive growth as being more, or less, likely was also of interest. Perceptions of growth were measured in relation to three possible traumatic scenarios (vignettes) that were randomly assigned to participants. Following the vignette, participants completed a variety of self-report measures. Contrary to previous PTG literature, there were no consistent characterological differences among participants who did, and who did not, perceive growth as a possible outcome following trauma exposure. PTG was not related to nature of the trauma or gender of the survivor. Implications for clinical practice and future directions for research are discussed.

AN ABSTRACT OF THE THESIS OF AIDAN CHRISTIE SMITH, for the MASTER OF ARTS degree in PSYCHOLOGY, presented on OCTOBER 27th, 2017, at Southern Illinois University Carbondale. TITLE: EFFECTS OF NICOTINAMIDE ON MICROGLIAL RESPONSE IN JUVENILE RATS AFTER CONTROLLED CORTICAL IMPACT MAJOR PROFESSOR: Dr. Michael J. Hylin Traumatic brain injury (TBI) is a leading cause of death, cognitive and behavioral disability in children in industrialized nations. Preclinical trials of nicotinamide (NAM) treatment provide neuroprotection and reduced inflammatory responses in adult models of TBI. The primary goal of this study was to address the neuroprotective effects of NAM in the developing brain, specifically, the microglial response that occurs following injury. Animals received a bilateral craniotomy with a single cortical contusion injury over the parietal lobe and were treated with either 500mg/kg of nicotinamide or 0.9% saline via intraperitoneal injection. Animals received three injections, 15 minutes, 24 hours, and 48 hours after injury, and were sacrificed at 4 time points, 3 hours, 72 hours, 1 week, or 1 month following injury. Brains were then used for histological assessment for microglial activity. The results show that NAM attenuates the activation of microglia after CCI. Over the course of time, saline treated animals had a marked increase in microglia at 72 hours and remained elevated after 1 week. In NAM treated animals however, there was no significant increase in the number of microglia at any time point. It is suggested here that NAM has a great effect on the inflammatory response. Further studies are needed to examine NAM’s effects on behavior and functional recovery.