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Over one million people suffer a traumatic brain injury every year, many of whom are students between the ages of 5 and 18. Using a qualitative case study approach, I wanted to discover the specific factors that both impede and help the school re-entry process for students in grades kindergarten through twelve so that these students can return to school on a full-time basis. The theoretical base behind this problem included motivation theories, memory theories, and emotion theories including self-determination theory, self-efficacy theory, Kübler-Ross Grief Cycle, and Lezak's stage model. Educators, including teachers, school counselors, and administrators, need to provide educational support to children with brain injuries and their families as a result of the Individuals with Disabilities Act of 1990, Public Law 101-476. However, if these individuals do not have a good understanding of what these students need to achieve optimal educational success, then the students will probably not be able to achieve their educational goals. Therefore, I searched for factors that affect the re-entry process. I used a qualitative case study approach in my methodology to complete this study. The sample used in this study included those students associated with the BrainSTEPS team local to my residence who were willing to participate, along with their parents, teachers, counselors, and administrators. Historical data were collected through medical and academic records. The bulk of the data came from interviews and observations I made; I then used the constant comparative method to analyze these data. I had several methods of verification in place to ensure the validity of this study and I did my best to hold the study to the highest ethical standards possible. The factors that were found to enhance the re-entry of students with brain injuries include: education and awareness prior to the injury occurring, the scheduling of frequent breaks during the school day, a gradual transition, providing each student with a brain injury with a non-injured study buddy in the classroom, teaching the student to become a self-advocate, constant communication between all of the key players that begins as early as possible, and support provided by the administration and therapists for the classroom teachers in the form of periodic check-ups. / Educational Administration

Mild traumatic brain injury (mTBI)/ concussion accounts for 70-90% of all reported TBI cases in the United States and can cause long-term neurological outcomes that negatively impact quality of life. Previous studies revealed that increased blood-brain barrier (BBB) leakage is correlated with poor neurological outcomes after mTBI, yet the biological mechanisms linking BBB damage to the onset of neurological deficits after mTBI are not well understood. Previously, we found that astrocytes lose expression of homeostatic proteins after mTBI, characterizing the changes in astrocytic protein expression as an "atypical astrocyte response." Yet, the upstream mechanisms that induce this atypical astrocyte response after mTBI have yet to be elucidated. In models of more severe TBI, exposure to blood-borne factors triggers astrogliosis via upregulation in markers, such as glial fibrillary acidic protein (GFAP), but how exposure to blood-borne factors affects astrocyte protein expression in the context of mTBI is not well understood. Therefore, we hypothesized that mTBI-induced BBB damage causes atypical astrocytes via exposure to blood-borne factors. To test this hypothesis, we use a mTBI mouse model, two-photon microscopy, an endothelial cell-specific genetic ablation model, and serum-free primary astrocyte cultures. Here, we found that mTBI causes BBB damage through the loss of proteins involved in maintaining the BBB's physical and metabolic barriers, and BBB damage is sustained long-term after injury. Also, we demonstrated that leakage of blood-borne factors is sufficient to trigger atypical astrocytes, and plasma exposure triggers a similar response in vitro. Overall, these findings suggest that mTBI induces long-term BBB damage, and exposure to blood-borne factors triggers the loss of key homeostatic astrocytic proteins involved in maintaining healthy neuronal function. / Doctor of Philosophy / Mild traumatic brain injury (mTBI)/ concussion makes up 70-90% of all TBI cases reported in the United States and is commonly observed after car crashes, sports-related tackles, and blast exposure during military combat. People who experience mTBI develop debilitating long-term neurological consequences, such as sleep disturbances, depression, and dementia. Clinical data suggests mTBI causes damage to the barrier between the brain and blood, known as the blood-brain barrier (BBB). This damage has been correlated to the onset of poor neurological deficits, yet how damage to this barrier is causally linked to long-term neurological consequences remains to be fully understood. In our lab, we found that mTBI causes loss of proteins important for maintaining a healthy environment in the brain in specialized cells called astrocytes. However, the biological events that trigger the loss of protein expression in astrocytes after mTBI have yet to be fully investigated. Thus, we hypothesized that mTBI causes loss of these proteins via leakage of blood-borne factors. To test this hypothesis, we used a mTBI mouse model, two-photon microscopy, genetic manipulation, and cell cultures. In our studies, we found that mTBI triggers BBB damage via loss of proteins that make up its protective properties. Also, we demonstrated that leakage of blood-borne factors is sufficient to cause loss of astrocyte-specific proteins both in brain and cell cultures. Altogether, we show that a single mTBI is sufficient to cause loss of astrocyte-specific protein expression via exposure to blood-borne factors. These findings may point to targeting either the blood-borne factor(s) or their corresponding receptor pathways in astrocytes to halt the progression of long-term neurological deficits after mTBI.

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.