Traumatic brain injury (TBI) is a major health concern in the United States and worldwide and effective treatment options are limited. Differences in the magnitude and characteristics of the peripheral-derived immune cell response to TBI are key contributors to the secondary cascades of damage following brain trauma, and means of modifying this response to improve clinical outcome are a current area of active research. Our work elucidated the peripheral immune response to TBI by characterizing the transcriptomic profile of juvenile vs adult peripheral immune cells following TBI as well as discovering a novel role for the tyrosine kinase receptor EphA4 in the peripheral-derived immune response to brain trauma. Previous work has demonstrated significant differences in recovery from TBI in young vs adult animals, and some studies have indicated that the immune response contributes to these differences. We utilized next-generation sequencing to compare gene expression profiles of blood cell fraction samples in juvenile and adult mice. Our work demonstrated that juvenile peripheral immune cells show a more dynamic response to TBI than adult and that pattern recognition receptor signaling is a cornerstone of these differences. To assess the specific mechanisms involved in the peripheral response to TBI, we utilized a bone marrow chimeric mouse model lacking EphA4 in the hematopoietic compartment. These studies found decreased lesion infiltration of peripheral immune cells, specifically activated macrophages, in the absence of EphA4. We also showed that EphA4 interacts with the Tie2/Angiopoietin signaling axis to regulate macrophage phenotype on the M1/2 continuum. Overall, our work demonstrated a novel role for EphA4, mediated by Tie2, as a pro-inflammatory regulator of the peripheral-derived immune cell response to TBI. / Traumatic brain injury (TBI) is a major health concern in the United States and worldwide and effective treatment options are limited. While the blood-brain barrier (BBB) excludes immune cells in the blood from entering the healthy brain, brain trauma compromises BBB integrity and allows massive infiltration of peripheral neutrophils, macrophages, and other immune cells. This circulating immune cell response to TBI contributes to damage following brain trauma, and means of modifying this response to improve recovery are a current area of active research. Our work explored the circulating immune cell response to TBI by comparing the gene expression profile of young vs adult circulating immune cells following TBI as well as discovering a novel role for the EphA4 protein in the circulating immune cell response to brain trauma. Previous work has found significant differences in recovery from TBI in young vs adult animals and that the immune response contributes to these differences. To explore this, we compared gene expression profiles of blood immune cells in young and adult mice and found that young immune cells show a more dynamic response to TBI than adult. To assess the specific pathways involved in the circulating immune cell response, we used a mouse model lacking EphA4 in these cells. Our studies found decreased numbers of immune cells, specifically macrophages, entering the injury area in the absence of EphA4. We also showed that EphA4 interacts with the Tie2 protein and its Angiopoietin protein binding partners. Originally studied as an important contributor to blood vessel function, Tie2 has recently been found to play a role in the function of macrophages. Our work demonstrated that EphA4 interacts with Tie2 to regulate pro-recovery vs proinflammatory characteristics in macrophages. Overall, our work demonstrated a novel role for EphA4, mediated by Tie2, as a pro-inflammatory regulator of the circulating immune cell response to TBI.

Between 1.6 and 3.8 million sports-related concussions are sustained by persons living in the United States annually. While sports-related concussion was once considered to only result in immediate neurocognitive impairment and symptoms that are transient in nature, recent research has correlated long-term neurodegenerative effects with a history of sports-related concussion. Increased awareness and current media attention have contributed to concussions becoming a primary health concern. Although much research has been performed investigating the biomechanics of concussion, little is understood about the biomechanics that cause concussion in humans. The research presented in this dissertation investigates human tolerance to head acceleration using methods that pair biomechanical data collected from human volunteers with clinical data. Head impact exposure and injury risk are quantified and presented. In contrast to the publicly available data on the safety of automobiles, consumers have no analytical mechanism to evaluate the protective performance of football helmets. With this in mind, the Summation of Tests for the Analysis of Risk (STAR) evaluation system was developed to evaluate the impact performance of footballs helmets and provide consumers with information about helmet safety. The STAR evaluation system was designed using real world data that relate impact exposure to injury risk. / Ph. D.

As many as 3.8 million sports-related traumatic brain injuries (TBIs) occur each year, nearly all of which are mild or concussive. These injuries are especially concerning given recent evidence that repeated concussions can lead to long-term neurodegenerative processes. One way of reducing the number of injuries is through improvements in protective equipment design. Safety standards and relative performance ratings have led to advancements in helmet design that have reduced severe injuries and fatalities in sports as well as concussive injuries. These standards and evaluation methods frequently use laboratory methods and brain injury criteria that have been developed through decades of research dedicated to determining the human tolerance to brain injury. It is necessary to determine which methods are the most appropriate for evaluating the performance of helmets and other protective equipment. Therefore, the aims of this research were to evaluate the use of different brain injury criteria and apply them to laboratory evaluation of helmets. These aims were achieved through evaluating the predictive capability of different brain injury criteria and comparing laboratory impact systems commonly used to evaluate helmet performance. Laboratory methods were developed to evaluate the relative performance of hockey helmets given the high rate of concussions associated with the sport. The implementation of these methods provided previously unavailable data on the relative risk of concussion associated with different hockey helmet models. / Ph. D.

The research presented herein is a combination of work done in two distinct subcategories of sport related head injury research. The body of work is aimed at increasing the understanding of head impact biomechanics across a broad spectrum of impact scenarios as well as the ability of helmets to affect head impact biomechanics over time. The first study utilizes in situ testing of controlled impacts of an instrumented head form to more fully characterize head accelerations resulting from impacts to the ice, board, and glass surfaces present in an ice hockey rink. The full characterization of head impacts across a spectrum of loading conditions and impact surfaces gives researchers insight into head impact tolerance and head protection capabilities and limitations in ice hockey. The second study details the development of a method to impact helmet pads for repeated loading studies based on published head impact exposure data. The third study uses this newly developed methodology to test the effects of a season of impacts on the energy absorbing properties of three different helmet padding technologies. The body of work is aimed at increasing understanding of head impact and concussion and the ability of existing helmet technologies to prevent these injuries with a goal of reducing the occurrence of injury. / Master of Science

Fit is often pointed to as the most important factor to consider when selecting a helmet. However, there is no published biomechanical evidence suggesting that of helmet fit effects concussion risk. The objectives of this study were to quantify helmet fit on a headform and to determine the effect fit has on helmet performance. An impact pendulum was used to strike a helmeted NOCSAE headform mounted on a Hybrid III neck. Helmets were impacted at 4 locations at 3 energies representing a range of concussive to sub-concussive impacts. The fit conditions evaluated in this study represent fitting scenarios in which an athlete is provided a helmet that is properly or improperly sized and cases in which a properly sized helmet is too loose, too tight, or properly adjusted. A custom pressure sensor was developed and used to characterize helmet fit in each condition with a quantitative fit metric representative of a variation from zero pressure on the headform. All helmets produced significant differences in both peak linear and peak angular acceleration due to fit. Differences were generally small with some exceptions. Furthermore, air bladder inflation generated significant differences in both peak linear and peak angular acceleration, but these were generally small in magnitude. While fit associated with size and air bladder inflation significantly affected linear and rotational head acceleration for most impact conditions, the best fit condition did not always generate the lowest accelerations. Differences can be attributed to varying helmet characteristics between and within helmet models. / Master of Science

Yes / Klüver-Bucy syndrome (KBS) is a rare clinical presentation following traumatic brain injury (TBI). Symptoms include visual agnosia, placidity, hyperorality, sexual hyperactivity, changes in dietary behavior, and hypermetamorphosis. The purpose of this article was to identify and synthesize the available evidence from case reports and case series on the treatment profile of KBS among adolescents and adults after TBI. Four bibliographic databases (MEDLINE OVID, EMBASE, PsycINFO, and SCOPUS) were searched for relevant literature. No date or language restrictions were applied. All case reports containing original data on KBS following TBI among adolescents and adults were included. Articles were evaluated, and data were extracted according to predefined criteria. The literature search identified 24 case reports of KBS post-TBI published between 1968 and 2017. Most case subjects were male (70.1%), and the mean age at injury was 25.1 years (range, 13–67 years). Injury to one or both temporal lobes occurred in most cases. Inappropriate sexual hyperactivity was the most common KBS symptom, followed by a change in dietary behavior and hyperorality. Visual agnosia was the least reported. In 50% of cases, the patient fully recovered from KBS. One-half of all participants described pharmacological management; the most common medication prescribed was carbamazepine. Overall, there was a lack of data available on pharmacotherapy initiation and duration. The complex presentation of KBS presents challenges in terms of treatment options. Although overall individuals who were prescribed carbamazepine had positive outcomes, given the reliance on case reports, it is difficult to make a definitive recommendation to guide clinical practice. / Institute for Safety, Compensation and Recovery Research, Monash University, Bionomics,Eli Lilly, Lundbeck, Novartis, Servier

A significant component of diffuse brain injury (DBI) is diffuse axonal injury (DAI) which is responsible for the morbidity and mortality associated with this condition. DAI and its experimental counterpart traumatic axonal injury (TAI) result in scattered microscopic pathology characterized by focal impairment of axonal transport leading to progressive swelling and delayed axotomy. DBI-mediated perisomatic axotomy does not result in acute neuronal death suggesting that delayed axotomy was responsible for this unanticipated response. To evaluate this hypothesis, we examined the spatiotemporal progression of DBI-mediated perisomatic TAI. LM / TEM identified impaired axonal transport within 15 - 30 min post-injury. Perisomatic TAI revealed somata and related proximal / distal axonal segments with normal ultrastructural detail continuous with axonal swellings. In other cases, axotomy was confirmed by loss of axonal continuity distal to the swelling. By 60 - 180 min post-injury, somatic, proximal segment, and swelling ultrastructure were comparable to earlier time points although swelling diameter increased. Distal segment ultrastructure revealed the initial stages of Wallerian degeneration. Axotomy sites did not internalize pre-injury administered dextran suggesting pathogenesis independent of altered axolemmal permeability. Given the rapidity of perisomatic axotomy, absence of axolemmal permeability may constitute the more significant finding in terms of somatic protection.DBI-mediated neuroinflammatory reactions were then examined to see if this non-lethal neuronal pathology evoked responses comparable to those following focal injury. Microglia / macrophage responses within diffusely injured loci uncomplicated by focal pathology were explored using LM, TEM, and confocal evaluations as was albumin immunoreactivity to assess injury-induced blood-brain barrier (BBB) alterations. Initially, microglial activation was observed within injured loci while microglia within adjoining regions maintained resting phenotypes. Scattered activated microglia were observed among injured axons though no clear associations were seen. Later, activated microglia contained myelin debris while only limited microglial aggregations were recognized. Macrophages also localized to injured loci with select cells approximating somata of axotomized neurons. Immune cell observations correlated with altered BBB permeability. These data indicated rapid, yet initially uncoordinated, and persistent immune cell reactivity to DBI pathology. Taken together, these responses suggest that histopathological evaluation following DBI may include non-lethal neuronal injury with unique neuroinflammatory findings.

SAMMANFATTNING Bakgrund Traumatisk skallskada drabbar relativt många och leder till personligt lidande och finansiell belastning för individ och samhälle då majoriteten får en svår till medelsvår funktionsnedsättning efter vårdtiden. På 1970-talet påvisades ett signifikant samband mellan högt ICP och sekundära hjärnskador. I studier där ICP >20 mmHg har förekommit kunde signifikant sämre utfall ses. Syfte Syftet med studien var att med hjälp av omvårdnadsprocessen observera intensivvårdssjuksköterskans identifiering och vidtagande av omvårdnadsåtgärder vid ett högt ICP samt utvärdera de utförda omvårdnadsåtgärderna.  Metod Prospektiv tvärsnittsundersökning, där sju intensivvårdssjuksköterskor och fem patienter observerades med hjälp av ett observationsformulär. Resultat 51(73 %) av de höga ICP normaliserades inom en minut och intensivvårdssjuksköterskan uppskattades ha observerat högt ICP i 50(71 %) av tillfällena inom en minut. 19(27 %) tillfällen observerades inte och 11(65 %) av omvårdnadsåtgärderna skedde inom en minut. Omvårdnadsåtgärder som utfördes var administrering av bolusdos med läkemedel (35 %) eller dränera likvor (35 %). Efter utförd omvårdnadsåtgärd normaliserades högt ICP inom en till två minuter, 7(41 %), och 4(24 %) normaliserades inom två till tre minuter. Slutsats Majoriteten av tillfällena med högt ICP uppmärksammades inom en minut och vanligast förkommande omvårdnadsåtgärderna var administrering av bolusdos sederande läkemedel eller dränera likvor. Av de tillfällen med intrakraniell hypertension som inte blev observerade var enbart ett par tillfällen ihållande i längre än en minut och samtliga normaliserades spontant inom två minuter. Intensivvårdssjuksköterskorna identifierade och effektivt åtgärdade intrakraniell hypertension snabbt, vilket kan bidra till ett bättre utfall för patienterna. / ABSTRACT Background Due to traumatic brain injury a financial burden is placed on the individual as well as the society and personal suffering also occurs. A significant correlation between elevated ICP and secondary injury was found in the 1970s. Significantly worse outcome was found in a numerous of studies where ICP >20mmHg occurred. Objective The aim of this study was to observe intensive care nurses nursing interventions and its efficiency to decrease ICP by using Orem’s Self-care deficit theory. Methods A prospective observational study. Seven intensive care nurses and five patients were observed. Results 51(73%) of the observed ICP >20mmHg were normalized within the minute. The intensive care nurses were estimated to have observed an on-going intracranial hypertension in 50(71 %) within the minute. 19(27 %) went unnoticed and 11(65 %) of the nursing interventions were executed within the minute. Nursing interventions executed were administration of a sedative (35 %), drainage of cerebrospinal fluid (35 %). Elevated ICP was normalized in 7(41 %) within two minutes and 4(24 %) within three minutes due to the nursing intervention. Conclusion Intensive care nurses noticed the majority of occasions with elevated ICP within one minute. The most commonly used nursing intervention was to administrate a sedative or to drain cerebrospinal fluid. All of the elevated ICP that went unnoticed normalized spontaneously within two minutes. The fast identification of and treated intracranial hypertension are likely to have contributed positively in the patient’s outcome.

<p><bold>Abstract</bold></p><p>More than 300,000 soldiers have returned from Southwest Asia (i.e., Iraq and Afghanistan) with combat-related mild traumatic brain injuries (mTBIs) associated with exposure to improvised explosive devices (IEDs). Despite less visible physical injuries, these soldiers demonstrate varying levels of physical and cognitive symptoms that impact their post-mTBI family reintegration. The existing literature acknowledges post-mTBI changes in the injured individual affect family functioning; however, post-injury family functioning, such as coping and adaptation, has not been explored. The intent of this dissertation is to explore the problems and challenges of military family reintegration following mTBI.</p><p>Nine soldiers with mTBI and their spouses participated for a total of 27 interviews. Both joint and separate individual interviews were conducted to explore their post-mTBI family reintegration experiences. Participants included active duty soldiers with mTBI who were between 2 and 24 months post-deployment and their civilian spouses. Strauss and Corbin's grounded theory methodology was used to collect and analyze the data. This dissertation study consists of three papers, each of which explored experiences that surround family reintegration following mTBI.</p><p>The first paper is a comprehensive literature review, examining commonly reported mTBI signs/symptoms, and the impact of these symptoms on the injured individuals and their families. The findings also suggest that psychological distress symptoms such as depression and anxiety are common in injured individuals and their</p><p>families after mTBI. The second paper explores the family reintegration processes of post-mTBI soldiers and their spouses. The majority of participants interviewed, both soldiers and their spouses, indicated that symptoms such as irritability, memory loss, and cognitive deficit affected their family reintegration. Some participants reported they had accepted the changes and were working toward a new normal, whereas others indicated these changes were unacceptable and continued their efforts to resume pre-injury functioning.</p><p>The third paper examined the experiences of soldiers and their spouses about seeking treatment for mTBI-related symptoms. The majority of interviewed soldiers and their spouses indicated that a delayed diagnosis, difficulty accessing mental health care, and having to navigate an unfamiliar military healthcare system were their biggest challenges. Post-mTBI soldiers experienced significant disruption due to mismatched expectations among themselves and other family members concerning their post-injury capabilities. More research is needed in order to develop effective post-injury rehabilitation programs for soldiers with mTBI and their families.</p> / Dissertation

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