Addressing the comprehensive needs of individuals with brain injuries is a growing concern in brain injury rehabilitation as well as evaluating the efficacy of these conventional therapeutic modalities: cognitive rehabilitation, and physical, occupational, and speech therapies. Therapeutic dance/movement has not been an integral part of these core services. I have observed its potential, however, during the past thirteen years while providing this intervention to individuals with brain injuries. The focus of this dissertation was to gain a better understanding of the dynamics of a therapeutic dance/movement intervention for individuals with brain injuries by comparing it to conventional physical therapy. Physical therapy, given its longevity in providing rehabilitative services to individuals with brain injuries, afforded a means by which to more systematically explore therapeutic dance/movement. Five individuals with brain injuries were observed and analyzed as they participated in five weekly therapeutic dance/movement sessions and five weekly physical therapy sessions. Laban Movement Analysis (LMA) was used as the observation and analytic tool for the purpose of elucidating similarities and differences between the two interventions in relation to the five case studies. Two questions guided the inquiry: (a) What are the similarities and differences between a physical therapy intervention and a dance/movement intervention? and (b) What are the dynamics of a therapeutic dance/movement intervention? Findings revealed that the physical therapy intervention focused specifically on body level connectivity and single joint action movement from a <i>Body</i> perspective. In comparison, the dance/movement intervention incorporated body level connectivity in addition to the dynamics of <i>Breath/Core Support</i> and <i>Grounding</i>, <i>Effort-Life</i>, <i>Spatial Intent</i>, and Aspects of <i>Shape</i>, providing the spectrum of <i>Body</i>, <i>Effort</i>, <i>Space</i>, and <i>Shape</i> ( <i>BESS</i>) components in harmony with the <i>Movement Themes: Whole/Part, Inner/Outer, Function/Expression, Exertion/Recuperation</i>, and <i>Mobility/Stability</i>.The dance/movement intervention imparted an integrative mind-body approach to learning about one's Inner and Outer self and one's ability to cope with and connect to one's environment. Knowledge was added to the current literature at an opportune time in the brain injury rehabilitation field. Rehabilitation professionals are recognizing the need to transform current assumptions regarding the essential aspects of brain injury rehabilitation and seek additional non-medical model approaches to rehabilitation. This study offers a therapeutic modality along with a viable measurement tool that has the potential for meeting this need. Recommendations for future research are offered. / Ph. D.

The purpose of this linear-analytic exploratory case study is to illustrate the reintegration process from acute care and rehabilitative care to the traditional school setting after one has sustained a Traumatic Brain Injury (TBI). TBI is an unrecognized educational challenge. Few educational professionals are aware of the divarication of TBI. Traumatic Brain Injury is the leading cause of death and disability in children and adolescents in the United States. The review of literature reveals there is a void between the requirements of the law and educator preparedness regarding TBI. There is a need for a proactive means to enhance transition and reintegration of a TBI student from rehabilitation to the traditional school setting. The research study showed the schematic efforts of one school division to integrate a TBI student. This exploratory case study emphasized the importance of a proactive education treatment planning process that facilitates the transition to the school setting. The study is qualitative in design and examined the sequence of subtopics of the problem, a review of relevant literature, methods used, findings of the data collected and analyzed, and conclusions and implications from the findings. This case study is analogous to a single experiment. Data were gathered from archival records, educational records, medical records, teachers and therapists comments, friends' perceptions, family histories, recollections, and interviews with participants in the reintegration process. There were three major domains that have been extracted from the case study. The first domain, the strengths and weakness of the student in the post traumatic brain injury environment were collated, collected, and analyzed. The second domain, the adaptation of Larry involved three general sub sets: (1) Larry's self adaptation, (2) the participants' roles in the student's adaptation, and (3) other influential factors in Larry's adaptation. The third domain centers on the strengths and weaknesses of the strategies used by the school division in the reintegration process. The strengths fell into five general categories; (1) caring professional (2) existing structure for disabled students, (3) cooperation, (4) willingness of general education teachers to make accommodations, and (5) willingness of school-based clinicians to try a variety of approaches. The weaknesses consisted of seven categories; (1) little knowledge of TBI, (2) no in-house pro-active plan,(3) no historical data on TBI, (4) no written records, (5) not central structure (scattered resources), (6) no written plan, and (7) no roster teacher/case manager with authority to direct staff with TBI scenario. The study will enhance the understanding of TBI and will provide a meaningful guide to parents, educators, and school based clinicians. The results illustrated that the data base of this study contained the critical pieces of evidence, this evidence was presented neutrally, and the evidence is valid. A holistic overview of the findings included the major domains and data sources that were explored. Additionally, the integrant building blocks that support this holistic overview are provided. In conclusion this case study discusses implications and recommendations. Of note is the reconciliation of this case study with the literature on TBI. / Ed. D.

Mild traumatic brain injury (mTBI) accounts for approximately 73-83% of all traumatic brain injuries (TBI) and continues to be a serious clinical challenge [1]. The role of injury mechanism in TBI has been widely debated, and it is believed that although there are differences between diffuse and focal TBI, the resulting injury is not influenced by the way in which it was acquired [1], [2]. It is known that TBIs can cause cognitive impairments that are often due to injury experienced in the hippocampus [2]. In response to insult, quiescent neural stem cell (NSC) populations within the dentate gyrus region of the hippocampus become activated. Stem cell differentiation following injury is hypothesized to be unique for diffuse and impact TBIs, primarily due to the differences in mechanotransduction pathways triggered by each respective injury. By quantifying the lineage of stem cells through immunohistochemistry, this study examined the dentate gyrus following mTBI in a rodent model, and the contribution that injury mechanism plays in mTBI outcomes. Additionally, the behavioral effects of mTBI were assessed through open field testing at 72 hours and four weeks following injury. Overall, these findings indicated that after four weeks following mTBI, there are not significant differences between impact and blast both from an immunohistochemical and behavioral standpoint. Despite there being few differences between injury groups, these findings help clarify the role of injury mechanism not only in the context of neurogenesis, but they also inform future studies addressing preventative and treatment strategies for mTBI. / Master of Science / Mild traumatic brain injury (mTBI) accounts for approximately 73-83% of all traumatic brain injuries (TBI) [1]. There are two main ways in which a mTBI can occur: through diffuse or focal injury. A diffuse injury is due to the brain experiencing a force that does not physically come into contact with the head, such as a shockwave from an explosion. These types of injuries typically affect the entire head. Impact injuries on the other hand, are caused by the head encountering an object at a force that causes injury to the brain. These injuries tend to be focal, as the entire head rarely comes into contact with an object. Both diffuse and focal injuries can cause mTBI, and there is a current debate questioning if the mode of injury has an impact on the damage experienced by the brain [1], [2]. However, it is also known that mTBI can cause cognitive impairments such as changes in behavior, memory, and even mental health, which can occur in the hippocampus of the brain [2]. Within the hippocampus, there is a small subset of cells referred to as neural stem cells (NSC) that become active following injury. The activation of these cells is believed to be in response to injury in the brain. Furthermore, NSCs have the ability to differentiate into various cell types within the brain, including astrocytes, oligodendrocytes, and neurons. Each of these cell types perform an integral role in the function of the brain. It is hypothesized that the response of NSCs in the hippocampus is unique depending on if an injury was acquired through diffuse or impact mechanisms. To investigate this, the lineage of NSCs was quantified within the hippocampus following blast and impact mTBI in a rodent model. Additionally, the behavioral effects of diffuse and impact injury were investigated at 72 hours and four weeks following injury. Despite there being no significant differences in outcomes between injury groups, these findings help clarify the role of injury mechanism not only in the context of NSC response, but they also inform future studies addressing preventative and treatment strategies for mTBI.

Blast-induced traumatic brain injury (bTBI) remains a significant problem among military populations. When an explosion occurs, a high magnitude positive pressure rapidly propagates away from the detonation source. Upon contact, biological tissues throughout the body undergo deformation at high strain rates and then return to equilibrium following a brief negative pressure phase. This mechanical disruption of the tissue is known to cause oxidative stress and neuroinflammation in the brain, which can lead to neurodegeneration and consequently poor cognitive and behavioral outcomes. Further, these clinical outcomes, which can include chronic headaches, problems with balance, light and noise sensitivity, anxiety, and depression, may be sustained years following blast exposure and there are currently no effective treatments. Thus, there is a need to investigate the acute molecular responses following bTBI in order to motivate the development of effective therapeutic strategies and ultimately improve or prevent long-term patient outcomes. It is important to not only understand the acute molecular response, but how the brain tissue mechanics drive these metabolic changes. The objective of this work was to identify the interplay between the tissue-level biomechanics and the acute bTBI pathophysiology. In a rodent bTBI model, using adult rats, intracranial pressure was mapped throughout the brain during blast exposure where frequency contributions from skull flexure and wave dynamics were significantly altered between brain regions and were largely dependent on blast magnitude. These findings informed the subsequent spatial and temporal changes in neurometabolism. Amino acid molecular precursor concentrations decreased at four hours post-blast in the cortex and hippocampus regions. This motivates further investigation of amino acids as therapeutic targets aimed to reduce oxidative stress and prevent prolonged injury cascades. However, neurochemical changes were not consistent across blast magnitudes, which may be explained by the disparities in biomechanics at lower blast pressures. Lastly, we investigated the acute changes in metabolic regulators influencing excitotoxicity where it was found that astrocytes maintained normal clearance of excitatory and inhibitory neurotransmitters prior to astrocyte reactivity. Outcomes of this work provide improved understanding of blast mechanics and associated acute pathophysiology and inform future therapeutic and diagnostic approaches following bTBI. / Doctor of Philosophy / Blast-induced traumatic brain injury (bTBI) remains a significant problem among military populations. When an explosion occurs, a high magnitude positive pressure wave rapidly propagates away from the detonation source. Upon contact, biological tissues throughout the body undergo deformation that can cause injury. This mechanical disruption of the tissue is known to trigger negative biological processes that lead to persistent cognitive and behavioral deficits. Further, these clinical outcomes, which can include chronic headaches, problems with balance, light and noise sensitivity, anxiety, and depression, may be sustained years following blast exposure. There are currently no effective treatments that can help those afflicted, and biomarkers for injury diagnostics are limited. Thus, there is a great need to investigate the early biological responses following bTBI in order to motivate the development of effective therapeutic strategies and ultimately improve or prevent long-term patient outcomes. It is important to not only understand the immediate responses, but also how the brain tissue mechanics drive these metabolic changes. The objective of this work was to identify the interplay between the brain biomechanics and the acute bTBI pathophysiology. Using a translational animal model, pressure inside the brain was measured with pressure sensors during blast exposure. Subsequent spatial and temporal changes in neurochemical concentrations were quantified. The results showed (1) significant disparities in the pressure dynamics inside the brain and it varied across brain regions, (2) neurochemical precursors may have therapeutic potential post-injury, and (3) biomechanical and neurochemical responses were dependent on blast severity. Outcomes of this work provide improved understanding of blast mechanics and associated pathophysiology and inform future therapeutic and diagnostic approaches to prevent prolonged injury cascades.

Across almost all types of neurological pathophysiology, inflammation and corresponding breakdown of the Blood Brain Barrier (BBB) are hallmarks of injury/disease progression. In fact, BBB disruption can occur early during neuropathophysiological development, in many cases even before neurological and cognitive impairments become apparent. Whether as an early causative factor, a side effect, or both as it pertains to neurological injury/disease, BBB breakdown and dysfunction represents a novel and under investigated target for therapeutic development, especially for neurological pathologies with unmet therapeutic needs. Toward this goal, the endocannabinoid system (ECS) has emerged as a promising biological target for drug discovery efforts. Particularly, the Cannabinoid 2 Receptor (CB2R) has been proposed as a druggable target due to its anti-inflammatory effects and since it is not associated with the neurological side effect profile representative of Cannabinoid 1 Receptor (CB1R) drugs. Interestingly, neuroinflammatory conditions promote upregulation of CB2R on brain microvascular endothelial cells (BMVECs) suggesting a possible role toward resolution of inflammation in this cell type. Moreover, previous research has shown promising effects of CB2R agonists on cerebrovascular function, although these effects cannot be directly attributed to endothelial CB2R. The central hypothesis of this research is that endothelial CB2R activation confers effects which are vascular protective and that promote BBB repair, (irrespective of the effects of CB2R in other central nervous system (CNS) cell types). To address this hypothesis, endothelial CB2R expression dynamics were assessed following experimental Traumatic Brain Injury (TBI) followed by a series of assays to assess the therapeutic potential of a novel chromenopyrazole based CB2R agonist, PM289. Results of these experiments demonstrated upregulation of CNR2, the gene which encodes CB2R, following in vivo experimental TBI and in vitro cytokine induced inflammation. Moreover, PM289 exhibited robust CB2R-dependent therapeutic potential by partially restoring TNFa-induced physical barrier disruption, attenuating TNFa-induced ICAM1 upregulation, and promoting rapid monolayer repair following electrolytic wound. Mechanistically, these effects may be explained via CB2R-dependent inhibition of NFkB/P65 signaling. Overall, these results are supportive of the notion that CB2R in BMVECs could aid in vascular protection and promote BBB function in the context of neuroinflammation. Future studies are warranted to understand the in vivo therapeutic efficacy of PM289 in a variety of injury/disease models. Additionally, alternative cell signaling mechanisms should be considered including a comprehensive examination of potential interplay between ECS components and candidates that fall under the umbrella of the endocannabionoidome (ECBome). / Biomedical Sciences

Millions of people sustain a mild traumatic brain injury (concussion) each year. While most clinical signs and symptoms resolve within 7-10 days for the majority of typical concussions, some gait and balance tasks have shown abnormalities lasting beyond the resolution of clinical symptoms. These abnormalities can persist after athletes have been medically cleared for competition, yet the implications of such changes are unclear. Most prior research has examined straight gait and standard measures of balance, yet there is a lack of knowledge regarding potential persistent effects on non-straight maneuvers or on indicators of motor control variability or complexity. To expand the knowledge of post-concussion locomotor and postural changes, this investigation examined the recovery of recently concussed athletes longitudinally, over the course of one year, in three domains: 1) path selection and body kinematics during turning gait, 2) non-linear local dynamic stability during straight gait, and 3) postural control complexity during quiet standing. Compared to matched health controls, concussed athletes exhibited significant and persistent differences in turning kinematics, local dynamic stability, and postural complexity over the initial six weeks following injury. These motor differences may increase the risk of injury to concussed athletes who are cleared to return to play. Given the persistent nature of these effects, future clinical tests may benefit from incorporating gait assessments before returning athletes to competition. Future research should prospectively and longitudinally monitor locomotor and postural control in conjunction with structural and functional changes within the brain to better understand the pathophysiology of concussions and potential rehabilitation strategies. / Ph. D.

Traumatic brain injury (TBI) continues to be a widespread problem in the United States with approximately 1.7 million occurrences annually [1]. Current automotive crash test standards use the Head Injury Criterion (HIC) [2] to assess head injury potential, but this metric does not relate an impact to underlying damage. For an injury metric to effectively predict TBI, it is crucial to relate level of impact to resulting injury. The research presented in this dissertation explains the development and repeatability of two novel injury devices, impact response characterization over the course of 24 hours in the Gottingen minipig and the relationships between metabolite changes, underlying disruption, and impact kinematics, and the characterization of impact response over the course of 72 hours. The translation-input and combined translation and rotation-input injury devices were shown to be repeatable, minimizing the number of animals needed for testing. Impact response over the course of 24 hours showed axonal disruption through immunostaining and proton magnetic resonance spectroscopy. The translation-input injury group metabolite analyses revealed the initial stages of glutamate excitotoxicity while the combined-input injury group showed a clear pathway for glutamate excitotoxicity. Numerous correlative relationships and potential underlying disruption predictors were found between metabolites, immunostaining, and kinematics. The most promising predictor combination for the translation-input injury device was N-acetylaspartylglutamate/Scyllo at 24 hours compared to 1 hour and linear speed for predicting underlying light neurofilament disruption. For the combined-input injury device, the strongest predictor combination was Glutamine/N-acetylaspartylglutamate at 24 hours compared to baseline and angular acceleration for predicting underlying light neurofilament disruption. Statistically significant predictors were found between Glutamate+Glutamine/Total Creatine at 24 hours compared to baseline and all kinematics and injury metrics with an angular component for predicting heavy neurofilament disruption. Analyses over the course of 72 hours revealed persistent axonal disruption and metabolite perturbations. Overall, this dissertation and the complementary parts of this project have many societal implications. Due to the high incidence of traumatic brain injury, there is a need for prevention, mitigation, and treatment strategies. Developing a new injury metric will help improve prevention strategies, especially in the automotive, sporting, and military environments. 1 Faul, M., Xu, L., Wald, M. M., and Coronado, V. G. (2010). Traumatic Brain Injury in the United States. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. 2 Versace, J. (1971). A Review of the Severity Index. SAE Technical Paper. No. 710881 / Ph. D.

Traumatic brain injury (TBI) elicits an immediate neuroinflammatory response that involves resident glia and infiltrating peripheral immune cells that coordinate tissue damage and functional deficits. The activation of resident microglial has been associated with a change in their morphology from a branched-like ramified cell to an ameboid state. This activation is thought to initiate a pro-inflammatory response leading to the release of neurotoxic, immune chemoattractant, and antigen-presenting signals. Subsequently, peripheral-derived immune cells (PICs), such as neutrophils and monocytes, travel to the site of injury and help coordinate this response. However, little is known regarding whether PICs influence the progressive activation state of microglia in the acute and chronic phases of injury. Overactivation of microglia can lead to neuroinflammation-mediated tissue damage and death or dysfunction of healthy neurons. Therefore, understanding how microenvironmental cues may regulate the microglial response may aid in strategies to retool their activation state in the brain. EphA4 receptor tyrosine kinase has been identified as a potential cell-to-cell contact protein on PICs that could be involved in the inflammatory changes following TBI. While microglial activation changes have been described in TBI models, the mechanistic role of infiltrating peripheral-derived immune cell (PIC) recruitment on microglial fate and function is not well understood. The purpose of my project is to gain a better understating of the temporospatial influence that EphA4-expressing PICs, specifically monocyte/macrophages, have on microglial proliferation, survival, activation phenotype, and debris clean-up using bone marrow GFP chimeric mice and the cortical contusion injury TBI model. / Doctor of Philosophy / Traumatic brain injury (TBI) triggers an immediate response from the brain's immune system, involving both local glial cells and immune cells from outside the brain. These cells work together to mediate the initial injury but, in some cases, cause development of a secondary injury. Microglia, the brain's resident immune cell, change their shape and behavior when activated by a TBI, becoming more aggressive and releasing inflammatory proteins. At the same time, immune cells from the bloodstream, like neutrophils and monocytes, rush to the injury site to assist. Yet, it's unclear how these immune cells affect microglia over time during the injury's acute and chronic phases. If microglia become too active, they can cause further damage to brain tissue and harm healthy neurons. Therefore, understanding the signals that control microglial activity could help us develop therapies to manage brain inflammation. One protein of interest in this process is the EphA4 receptor found on immune cells, which might play a crucial role in inflammation following TBI. While we know that microglia change post-TBI, we don't fully understand how the recruitment of immune cells from outside the brain affects them. My research aims to clarify how EphA4-expressing immune cells, especially monocytes/macrophages, influence microglia in terms of growth, behavior, and their ability to mediate a TBI.

While there has been ample research examining the relationship between an acute concussion on immediate neuropsychological performance, very little research has examined the relationship between lifetime concussion history with current neuropsychological performance. We collected preseason neuropsychological test performance (ImPACT) and a detailed lifetime concussion history questionnaire from 71 UCF football players. Stepwise linear regressions were conducted for each of the five ImPACT domain scores for the 18 participants that reported at least one lifetime concussion. The regressions used the following four concussion history predictors: total number of lifetime concussions, length of time between last concussion and lmPACT testing, severity of worst concussion, and severity of most recent concussion. Results revealed that only one ImpACT domain score had at least one predictor enter the model. For the domain of visual memory, the predictor of length of time between last concussion and ImPACT testing entered the model (and only that predictor),P = 4.07, t(l7) = 2.78,p = .01, R1 = .33, as a shorter length of time between the last concussion and the preseason testing related to lower performance on the visual memory tests. Many athletes and clinicians assume that the cognitive effects of a concussion are relatively brief in duration. However, the results of this study suggest that, at least for visual memory, these effects may last for several years following a concussion. The correlational design of this study precludes drawing conclusions about the causal direction of this relationship, but future longitudinal research may be able to clarify this important preliminary finding.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality among young children and adults. This primary injury initiates an inflammatory response that may lead to a secondary brain injury. Nursing care in the critical care setting supports prevention or reduction of secondary injury through control of intracranial pressure (ICP), mean arterial pressure (MAP), and the subsequent cerebral perfusion pressure (CPP). While secondary injury may be preventable, some nursing interventions may contribute to increased ICP and decreased CPP. Patients with increased ICP or decreased CPP are at risk for poor clinical outcomes. This literature review examined the effort of routine nursing care interventions on outcomes of TBI patients in the critical care setting. Eleven research articles studying head of bed elevation, head and neck positioning, turning, and spacing of patient care activities were the focus of the analysis. Results typically showed positive outcomes by elevating the head of the bed to thirty degrees. CPP was also maintained at thirty degrees, but showed varied results. ICP and CPP are best controlled with the head and neck in a neutral position. Turning patients is a routine nursing intervention that contributes to increased ICP in some positions in some patients. Most studies suggest ICP is lowest in the supine position and highest in the left lateral position, but differences in findings were noted. Providing basic nursing care interventions in close succession also may contribute to increases in ICP in some patients. Results from this review provide evidence to support the importance of assessing and planning care for each TBI patient individually. It is hoped that findings from this review will provide guidance for bedside nurses to improve clinical practice and drive future research to support best practices for care of patients who suffer TBI.