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.

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.

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.

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.

abstract: Approximately 2.8 million Americans seek medical care for traumatic brain injury (TBI) each year. Of this population, the majority are sufferers of diffuse TBI, or concussion. It is unknown how many more individuals decline to seek medical care following mild TBI. This likely sizeable population of un- or self-treated individuals combined with a lack of definitive biomarkers or objective post-injury diagnostics creates a unique need for practical therapies among diffuse TBI sufferers. Practical therapies stand to decrease the burden of TBI among those who would otherwise not seek treatment or do not meet clinical diagnostic criteria upon examination. For this unique treatment niche, practical therapies for TBI are defined as having one or more of the following qualities: common availability, easy administration, excellent safety profile, and cost-effectiveness. This dissertation identifies and critically examines the efficacy of four classes of practical treatments in improving rodent outcome from experimental diffuse traumatic brain injury. Over-the-counter (OTC) analgesics, omega-3 fatty acids, specialized pro-resolving mediators (SPMs), and remote ischemic conditioning (RIC) were administered before or following midline fluid percussion injury. Behavioral, histological, and molecular analyses were used to assess treatment effects on functional outcome and secondary injury progression. Acute administration of common OTC analgesics had little effect on post-injury outcome in mice. Dietary supplementation with omega-3 fatty acid docosahexaenoic acid (DHA) prior to or following diffuse TBI significantly reduced injury-induced sensory sensitivity and markers of neuroinflammation with no effect on spatial learning. Intraperitoneal administration of omega-3 fatty acid-derived SPM resolvin E1 significantly increased post-injury sleep and suppressed microglial activation. Aspirin-triggered (AT) resolvin D1 administration improved both motor and cognitive outcome following diffuse TBI. RIC treatment in mice demonstrated little effect on functional outcome from diffuse TBI. Untargeted proteomic analysis of plasma samples from RIC-treated mice was used to identify candidate molecular correlates of RIC. Identification of these candidates represents a vital first step in elucidating the neuroprotective mechanisms underlying RIC. The overall findings suggest that omega-3 fatty acid supplementation, SPM administration, and RIC may serve as effective practical therapies to reduce the somatic, cognitive, and neurological burden of diffuse TBI felt by millions of Americans. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2017

There is increasing evidence that repeat mild traumatic brain injury (rmTBI) may result in cumulative and long-term symptoms, more pronounced behavioural deficits, and neurodegeneration. Children have a greater susceptibility to head injury and represent a significant at risk population for rmTBI, especially those that participate in contact sports. Despite this, there is a paucity of data on rmTBI pathophysiology in the juvenile brain. The current study utilizes a novel awake closed head injury (ACHI) model to deliver repeat injuries to fully conscious juvenile rats. The ACHI model avoids the potential confounds of anaesthesia, and facilitates the assessment of neurological function immediately after each impact. Results indicate that the ACHI model produces acute neurological deficits after each impact, and that repeat injury worsens outcomes. Behavioural testing identified transient anxiety-like behaviour and motor impairment in response to rmTBI. The functional impairments and affective behaviour were in the absence of tau protein pathology. This study represents the first investigation of the consequences of rmTBI on the juvenile brain using an awake model of brain injury. / Graduate

Magister Artium - MA / Traumatic brain injury (TBI) has enjoyed extensive research and several therapeutic modalities, approaches and models have been developed where the main outcomes are focused on the successful return to work of individuals with brain injury. Research into women with TBI has, however, been negligible compared to research into the young adult male population. Gaining insight into how women with traumatic brain injury participate in their work environment would contribute valuable feedback to clinicians utilising return to work approaches and models. The study aimed to explore the challenges women who sustained TBI experience in the work environment after vocational rehabilitation. A qualitative research design was used to explore these experiences and perceptions from ten female participants. The method of data collection used to access the experiences and perceptions of the participants was in-depth semi-structured interviews. Furthermore semi-structured interviews were conducted with two occupational therapist, who were selected as key informants. The data from the study was analysed using thematic analysis. The study further aimed to obtain the participants` perceptions and experiences of barriers and facilitators as well as adaptation processes that influenced their ability to resume their work roles. Four themes originated from the findings of this study. Theme one describes the barriers experienced by women with TBI while returning to work in the form of barriers to work participation for women with TBI, loss of functional capacity hindering return to work, experiences of negative stigma and exploitation in the workplace, and contextual hindrances in the form of parental roles as well as public transportation systems. Theme two describes the factors that facilitated the resumption of the work role for women with TBI. Reestablishing a worker identity by means of vocational rehabilitation, utilising the Model of Occupational Self-Efficacy (MOOSE) as an approach, enabled the women with TBI to overcome their barriers and return to work. Theme three describes an inherent adaptation process where participants could come to terms with their losses, accept the present self and aspire towards a future self, by utilising personalised response approaches to overcome demands and challenges in the work context as well as experiencing success at work by adapting to the work environment. Theme four describes the participants’ views of changes needed in the rehabilitation program and services as well as policies that would aid in the quick return of women with TBI to productive roles. These suggestions are discussed as attainable through developing a multi-dimensional rehabilitation program for women with TBI as well as partnering with relevant stakeholders in the promotion of work opportunities for women with disabilities. The Model of Occupational Adaptation (MOA) was used as a framework to interpret the findings of this study; the barriers, facilitators and adaptation process were assessed as they impact on the experiences of the women with TBIs return to work. The return to work of the women with TBI was not observed only to be influenced by the personal characteristics but also by the environmental context within which the return to work process took place.

Abstract Traumatic Brain Injury (TBI) is a global epidemic (Schwarzbold et al., 2008). According to Brey (2006), a brain injury occurs every 21 second in the United States, which results in 1.5 million head injuries annually. The purpose of this project was to educate psychiatric personnel regarding the needs of the TBI population and to measure learning and retention. This is a quality improvement project that utilized a pretest and posttest design with an educational intervention. The intervention was administered electronically via Microsoft PowerPoint. Results were measured with the Wilcoxon Signed Rank Test. A total of 17 participants completed the pretest and posttest, and 11 completed the second posttest; the second posttest administered six weeks after the initial posttest. The results show that knowledge increased from pretest to posttest, (p < 0.05), however, retention of the material did not occur per test results, (p ≥ 0.05). There is no other research to compare to these results. Therefore, more research and educational intervention are needed to educate psychiatric personnel regarding the needs of the TBI patient.

Traumatic brain injury (TBI) is one of the leading causes of death and disability in children. The prefrontal cortex (PFC) is most susceptible to injury which leads to deficits in executive function, sociability, and cognitive flexibility. The oxytocin (OT) system plays a significant role in the modulation of species-typical social behaviors, such as social recognition and memory. Intranasal OT (IN-OT) has been shown to be neuroprotective against neuronal insults and social deficits through various mechanisms. Due to this and OT’s role in the modulation of social behaviors, it is possible that IN-OT could improve the social deficits caused by a PFC injury. The primary goal of this study was to determine the effects of a TBI on the development of the OT system. The secondary goal was to address the efficacy of IN-OT as a treatment for the social deficits observed following a TBI. For these studies, animals received a single cortical contusion injury bilaterally damaging the medial pre-frontal cortex. Immediately following injury (1-2 minutes), animals were given a single dose of IN-OT (20 μg, 1 μg/1 μl Ringer’s solution), placebo, or no treatment and sacrificed at days 1, 14, and 30 post-injury. Animals were assessed using behavioral and histological measures. It was predicted that animals that received IN-OT would demonstrate fewer social deficits on the behavioral measures and a smaller lesion size. Additionally, it was expected that a TBI would increase inflammation levels and decrease the levels of OT and OT receptors compared to sham animals. The results indicate that OT treatment did not significantly improve histopathological outcomes. However, the vehicle that was utilized impaired outcomes. Additionally, there was minimal changes to the OT system at the injury site, in the anterior olfactory nucleus, and in the caudate putamen due to injury. But vehicle treatment altered the expression levels of the OT peptide and receptors. Behaviorally, OT treatment improved performance in the Morris water maze in TBI animals compared to vehicle-treated and untreated TBI animals, but not other behaviors. However, vehicle-treated, and OT-treated animals were more likely to be aggressive than expected and untreated sham animals were less likely to be aggressive than expected. Taken together, it was observed that administration of a hypotonic saline solution following TBI significantly increases pathophysiology after TBI, and these effects translate into increased aggression levels. Although, learning and memory remained unaffected by the vehicle. Thus, further studies are needed to examine the effects of OT on TBI for behavioral and pathophysiological improvements.