Traumatic brain injury (TBI) is a growing health concern worldwide that affects a broad range of the population. As TBI is the leading cause of disability and mortality in children, several pre-clinical models have been developed using rodents at a variety of different ages; however, key brain maturation events are overlooked that leave some age groups more or less vulnerable to injury. Thus, there has been a large emphasis on producing relevant animal models to elucidate molecular pathways that could be of therapeutic potential to help limit neuronal injury and improve behavioral outcome. TBI involves a host of different biochemical events, including disruption of the cerebral vasculature and breakdown of the blood brain barrier (BBB) that exacerbate secondary injuries. A better of understanding of the mechanism(s) underlying cerebral vascular regulation will aid in establishing more effective treatment strategies aimed at improving cerebral blood flow restoration and preventing further neuronal loss. Our studies reveal an age-at- injury dependence on the Angiopoetin-Tie2 axis, which mediates neuroprotection in a model of juvenile TBI following cortical controlled impact (CCI) that is not seen in adult mice. The protection observed was mediated, in part, by the microvascular response to CCI injury and prompted further detailed analysis of the larger arteriole network across several mouse strains and models of TBI. Our second study revealed both a model and species dependent effect on a specialized network of arteriole vessels, called collaterals after trauma. We demonstrated that a repetitive mild TBI (rmTBI) can induce collateral remodeling in C57BL/6 but not CD1 mice; however, CCI injury had no effect on collateral changes in either strain. Together, these findings demonstrate an age-dependent and species/model dependent effect on vascular remodeling that highlights the importance of individualized therapeutics to TBI. / Ph. D.

The writing of this thesis was guided·by the question "how does one teach English as a second language through theater?" This thesis.contains the pedagogical research basis for teaching English as second language, a script with supporting materials for teaching English as a second language, and a playwright's.journal detailing the writing process for the dramatic work. Within the pedagogical research, there is a comparison between the different founding fathers of modem TESL methodologies, a comparison between the different methodologies, and a practical exploration of teaching English as a second language through Task Based Instruction. The script itself is the lyrical book for a ten day, episodic musical for Spanish speaking 3rd and 4th graders. The dramatic work was written to be performed in a voluntary extracurricular context, such as an ESL summer camp.

Le traumatisme crânio-cérébral (TCC) précoce (c.-à-d. subi pendant la petite enfance) constitue l’une des blessures les plus énigmatiques, car il touche à un organe complexe et survient lors d’une période sensible du développement. Or, malgré des données épidémiologiques indiquant une incidence particulièrement élevée du TCC en bas âge, et en dépit des préoccupations grandissantes concernant son impact potentiel sur le fonctionnement et le bien-être, le TCC précoce demeure un problème de santé publique peu connu en comparaison à celui subi chez les enfants d’âge scolaire et dans les contextes sportifs. Aussi, plus souvent qu’autrement, les objectifs, hypothèses, construits et théories étudiés chez le jeune enfant sont extrapolés de ceux utilisés chez les individus plus âgés. Ainsi, ils ne sont pas toujours choisis en prenant en considération les enjeux développementaux particuliers de la petite enfance limitant notre compréhension globale et affinée des conséquences suivant un TCC précoce. Alors, qu’en est-il des tout-petits? L’objectif général de la thèse était de recenser la littérature empirique qui documente les conséquences d’un TCC en bas âge et d’étudier les effets d’une telle blessure sur un domaine de fonctionnement clé de la petite enfance, notamment le tempérament. Le premier article de la thèse est une revue systématique de la littérature dont l’objectif était de recenser et synthétiser les trouvailles concernant les conséquences cognitives et comportementales suivant un TCC subi durant la petite enfance. Quatre bases de données ont été examinées de 1990 à 2019 en utilisant des termes clés relatifs au TCC et à la petite enfance. Sur 12 153 articles identifiés lors de la recherche initiale, 43 ont été inclus. Cette revue met en lumière qu’un éventail de difficultés peut survenir à la suite d’un TCC précoce lesquelles sont généralement plus importantes et néfastes lorsque la blessure a été subie à un jeune âge, que sa sévérité est plus grave et que les causes de cette blessure sont non-accidentelles. Le deuxième article est une étude empirique qui visait à explorer l’effet d’un TCC précoce sur le tempérament, lequel représente la tendance comportementale du jeune enfant, c.-à-d. sa façon de réagir et de s’adapter à son environnement. Ce construit constitue un facteur prédictif important du devenir de l’enfant dans plusieurs domaines de fonctionnement et pourrait ainsi être particulièrement approprié afin d’approfondir et de préciser les connaissances quant aux conséquences d’un TCC durant la petite enfance. Les parents de 173 jeunes enfants (âge: 36 ± 12 mois) ayant subi un TCC léger simple (n = 83), un TCC plus sévère (léger complexe, modéré ou sévère, n = 21) ou une blessure orthopédique (n = 69) ont rempli un questionnaire reflétant les profils de tempérament de leur enfant avant la blessure (rétrospectivement) et à 6 et 18 mois suivant la blessure. Les résultats révèlent que les enfants qui ont subi un TCC plus sévère présentent une évolution plus lente de la trajectoire développementale de la dimension Dynamisme du tempérament. En d’autres mots, ces enfants manifestent un niveau d’activité réduit se traduisant par un niveau d’énergie plus faible, une recherche de plaisir à haute intensité diminuée, ainsi qu’une timidité plus importante face à la nouveauté. De façon générale, cette thèse met en évidence que la survenue d’un TCC au cours de la petite enfance, une période sensible pour l'émergence d’habiletés cognitives et sociales de base, peut occasionner un large éventail de conséquences, et ce, même au plan de la trajectoire du tempérament. Étant donné l’importante prévalence du TCC durant la petite enfance, ainsi que le potentiel de conséquences défavorables, il est essentiel que la recherche, la gestion clinique, l’intervention et les efforts de prévention soient davantage développés de manière à tenir compte des caractéristiques uniques de la petite enfance. / Pediatric Traumatic Brain Injury (TBI) constitutes one of the most enigmatic insults, as it affects a complex organ and occurs at a sensitive period in the developmental course. Despite epidemiological data indicating a particularly high incidence of TBI during early childhood and growing concerns regarding its potential impact on child functioning and well-being, early TBI remains a poorly studied public health problem, especially compared to TBI sustained by schooledaged children and in sports settings. Also, all too often, the objectives, hypotheses, constructs and theories studied in young children with TBI are extrapolated from those used in older individuals and therefore rarely chosen in consideration of the developmental concerns specific to early childhood. These issues limit a comprehensive and refined understanding of the consequences of early TBI. So, what about the little ones? The general objective of the thesis was to review the current state of the empirical literature pertaining to children who have sustained TBI during early childhood, and to study the impact of early TBI on a key domain of this developmental period, namely temperament. The first article presented in the thesis is a systematic review of the literature aiming to identify and synthetize the findings concerning cognitive and behavioral consequences following early TBI. Four databases were searched from 1990 to 2019 using key terms related to TBI and early childhood. Of 12,153 articles identified during the initial search, 43 were included. This review of the literature highlights that children who sustain early TBI display a range of difficulties which are generally more pronounced and detrimental when injury is more severe, sustained at a young age, and the cause is non-accidental. The second article constitutes an empirical study aiming to explore temperament after early TBI. Temperament refers to young children’s behavioral tendencies, that is, their way of reacting and adapting to their environment. Besides constituting an important predictor of outcome in several areas of functioning, this construct also takes into account the developmental reality of the young child and could thus be particularly suited to investigate and clarify the consequences of early childhood TBI. Parents of 173 young children (age: 36 ± 12 months) with simple mTBI (n = 83), more severe TBI (mild complicated, moderate or severe, n = 21) or orthopedic injury (n = 69) completed a questionnaire reflecting their child's temperament profile before the injury as well as at 6 and 18 months following the injury. The results reveal that children who sustain more severe TBI experience a slower evolution of the developmental trajectory of the Surgency dimension of temperament. In other words, these children exhibit a reduced activity level which is reflected by less energy, a reduced desire for high-intensity pleasure-seeking, as well as greater shyness in the face of novelty. In general, the thesis highlights that the occurrence of TBI during early childhood, a sensitive period for the emergence of basic cognitive and social skills and a time when environmental influences are particularly salient, can cause a large range of consequences, even affecting the trajectory of temperament. Given the high prevalence of TBI in early childhood and the potential for adverse outcomes, it is essential that research, clinical management, intervention and prevention efforts be further developed based on the empirical literature, and in a manner that takes into account the unique characteristics of early childhood.

TBI stands for Traumatic Brain Injury and refers to damage to the brain resulting from an external physical force, such as a blow, jolt, or penetrating injury to the head. Common causes of TBI include falls, motor vehicle accidents, sports injuries, and violence and has been linked to thousands of deaths and injuries in the US and the EU alike. This thesis was aimed to localise certain TBI to a specific part of the brain by exerting similar loading conditions on an Finite Element Method (FEM) of the rat brain as physical experiments conducted on living rats. By comparing the strain in 7 vital parts of the brain to injury diagnosis conducted in the physical experiments, an effort was made to link localised strain to injury diagnosis. The results indicate that strain in the thalamus and hypothalamus are linked with a loss of consciousness while strain in the hypothalamus coupled with the neocortex correlates greatly with activity-based behaviour changes. Lastly, injury associated with emotional changes are believed to stem from large strains in the neocortex. There is a theory suggesting that the structure of myeline, which provides support in motion and movement patterns of biological systems in humans and animals (known as biomechanical kinematics), could have an impact. However, more studies are needed to confirm and determine the exact cause. / TBI, från engelskans Traumatic Brain Injury, står för Traumatisk Hjärn Skada och syftar på en skada i hjärnan till följd av enyttre fysisk kraft, såsom ett slag, stöt eller genomträngande skada i huvudet. Vanliga orsaker till TBI inkluderar fall, motorfordonsolyckor, sportskador och våld och har kopplats till tusentals dödsfall och skadade i både USA och EU. Denna rapport syftar till att försöka lokalisera viss TBI till en specifik del av hjärnan genom att utöva liknandebelastningsförhållanden på en finit elementmetod (FEM) modell av råtthjärnan som fysiska experimentutförs på levande råttor. Genom att jämföra belastningen i 7 vitala delar av hjärnan med skadediagnos som utfördes i de fysiska experimenten gjordes en ansträngning för att koppla lokaliserad belastning till skadediagnos. Resultaten indikerar att skada i thalamus och hypotalamus är kopplade till en förlust av medvetande medan belastning i hypotalamus i kombination med neocortex korrelerar kraftigtmed aktivitetsbaserade beteendeförändringar. Slutligen är skador i samband med känslomässiga förändringartros härröra från skada i neocortex. Det finns teori som tyder på attstruktur av myelin, som ger stöd i rörelse och rörelsemönster av biologiskasystem hos människor och djur (känd som biomekanisk kinematik), kan ha en inverkan.Det behövs dock fler studier för att bekräfta och fastställa den exakta orsaken.

Head injuries caused by impacts are among the most critical and dangerous types of accidents that can occur while practising sports. Alpine skiing is one of the activities with the highest incidence of head injuries. Over the years, specific regulations have been introduced to protect athletes where possible, but the perception is that the level of protection needed to manage the forces to which they are exposed has yet to be achieved. This thesis project aims to examine video sequences of accidents in alpine ski competitions (Giant Slalom, Super-G, Downhill, Ski Cross) to better understand the translational violence exerted on the head during impacts. After an in-depth analysis, it was shown that, in at least 41% of the videos investigated, the translational impact speeds exceeded the standards adopted in helmet certifications by 44.3% and 52.2%, respectively. Besides, in 60% of these accidents, the blow was located on the upper semicircle of the helmet, which is believed to be due to the ever-increasing use of airbags for the torso. / Huvudskador orsakade av slag är bland den alvarligaste typen av olyckor som kan inträffa vid utövande av idrott. Alpin skidåkning är en av de sporter med den högsta förekomsten av skador på huvudet. Under årens lopp har särskilda regler införts för att skydda atleterna där så är möjligt, men uppfattningen är att den skyddsnivå som krävs för att hantera de krafter åkarna utsätts för ännu inte har uppnåtts. Detta examensarbete syftar göra videoanalys på olyckor vid alpina skidtävlingar (Storslalom, Super-G, Störtlopp, Ski Cross) för att bättre förstå translationsvåldet mot huvudet vid olyckor. Efter en djupgående analys visades att i minst 41% av de undersökta fallen översteg translationshastigheten de hastigheter som används vid hjälmcertifieringar med 44.3% respektive 52.2%. För 60% av olyckorna skedde slaget högt upp på bakre delen av hjälmen, något som tros bero på den ökande användningen av krockkuddar för torso.

Traumatic brain injury (TBI) is the most frequent cause of death in children and young adults in the United States. Besides emergency neurosurgical procedures, there are few medical treatment options to improve recovery in people who have experienced a TBI. Management of patients who survive TBI is complicated by both central nervous system and peripheral systemic effects. The pathophysiology of systemic inflammation and coagulopathy following TBI has been attributed to trauma-induced endothelial cell dysfunction; however, there is little knowledge of the mechanisms by which trauma might impact the functions of the vascular endothelium at sites remote from the injury. The endothelium lining these small vessels normally produces nitric oxide (NO), arachidonic acid metabolites, and endothelial-dependent hyperpolarizing factors to relax the surrounding vascular smooth muscle. For this research study we investigated the effects of fluid-percussion-induced TBI on endothelial-dependent vasodilatory functions in a remote tissue bed (the mesenteric circulation) 24 hours after injury. We hypothesized that TBI causes changes in the mesenteric artery endothelium that result in a loss of endothelial-dependent vasodilation. We found that vasodilations induced by the muscarinic-receptor agonist, acetylcholine, are attenuated following TBI. While the endothelial-derived hyperpolarizing component of vasodilation was preserved, the NO component was severely impaired. Therefore, we tested whether the loss of NO component was due to a decrease in bioavailablity of the NO synthase (NOS) cofactor BH4, the NOS substrate L-arginine, or to changes in expression/activity of the enzyme arginase, which competes with NOS for L-arginine. We found that supplementation of L-arginine and inhibition of the enzyme arginase rescues endothelial-dependent vasodilations in TBI arteries. This study demonstrates that there are pathological systemic effects outside the point of injury following TBI leading to a dysfunctional endothelial vasodilatory pathway. These data provide insight into the pathophysiology of endothelial dysfunction after trauma and may lead to new potential targets for drug therapy.

The mature mammalian brain continually generates new neurons in the subventricular zone and hippocampus throughout life. Adult neurogenesis in the hippocampus is associated with hippocampal-dependent learning and memory function. During aging, this endogenous neurogenic potential is reduced which is accompanied by decreased cognitive function seen in the aging population. We have previously found that the injured adult brain shows heightened levels of endogenous neurogenesis and this response is associated with innate cognitive recovery. We have also found that basic fibroblast growth factor (bFGF), a potent neurotrophic polypeptide, can enhance injury-induced hippocampal neurogenesis and improve cognitive recovery following TBI. In this study, we administered bFGF into the lateral ventricle of aged rats following TBI and assessed the effect of bFGF treatment on hippocampal neurogenesis and cognitive recovery in aged animals. Specifically, male Fisher-344 rats at the age of 20 months received intraventricular infusion of bFGF for 7 days through osmotic mini-pump immediately following a moderate lateral fluid percussion injury. To label cell proliferation, animals received daily single i.p. BrdU injections for 6 days beginning 48 hr after injury. One group of animals was perfused at 1 wk after injury to assess cell proliferation. Another group of animals was first assessed for cognitive performance using the Morris water maze (MWM) at 21-25 days post-injury, then sacrificed at 4 weeks after injury to examine differentiation of newly generated cells. Brain sections were sliced and immunostained for BrdU, early neuronal marker doublecortin (DCX) and other cell type specific markers. Results showed that at 1 week post-injury, injured-aged animals infused with either vehicle or bFGF had a significantly higher number of cell proliferation in the dentate gyrus compared to sham animals. However, cell proliferation in the bFGF-infused animals was not significantly higher than vehicle-treated animals. Nevertheless, the number of DCX-labeled early stage neurons was significantly higher in the injured bFGF-treated animals than in vehicle-treated sham and injured animals. In MWM tests, unlike what we have observed in bFGF-treated younger animals, injured aged rats treated with bFGF did not show improved cognitive function. Furthermore, at 4 weeks post-injury, higher numbers of BrdU-labeled proliferative cells persisted in both injured groups, many of these cells labeled with glial and inflammatory cell markers. Collectively, the current data suggests that bFGF can enhance neurogenesis in the injured-aged hippocampus; however, this effect is not sufficient to improve functional recovery of aged rats following TBI due to the profound injury-induced inflammatory response.

Traumatic Brain Injury (TBI) is one of the leading causes of death and disability among young adults and has been a significant field in medical research over the past decades. Intensive studies focusing on how to repair tissue damage resulting from head injuries have discovered that the central nervous system (CNS) retains a regenerative capacity throughout life due to the persistent presence of neural stem/progenitor cells (NS/NPCs) in the neurogenic regions. In the normal brain, cells generated in the subventricular zone (SVZ) migrate along the rostral migratory stream (RMS) to the olfactory bulb and cells in the subgranular zone (SGZ) migrate laterally into the granule cell layer of the dentate gyrus. Directed movement of these NS/NPCs is controlled by a variety of factors, and among them the chemoattractant SDF-1 is of particular importance. Studies have identified that the chemokine SDF-1α and its receptor CXCR4 play an important role in guiding cell migration in many types of cells including NS/NPCs. The current study tested if SDF-1 could be delivered through alginate to attract and guide migration of NS/NPCs and its progeny both in vitro and in vivo. Using a Boyden chamber migration assay, we found SDF-1α either added directly in the medium or incorporated into alginate threads was capable of influencing migration of cultured NS/NPCs in a dose-dependent manner. In the in vivo study, when injected directly into the cerebral cortex, SDF-1  showed limited capability in inducing neuroblasts migration off the normal tract to the site of SDF-1 injection. When SDF-1 was delivered via alginate thread to the focal injury site at 2 days post TBI, significantly increased number of migrating neuroblasts derived from the SVZ was observed around the injury site. Increased expression of SDF-1 receptor CXCR4 was observed in the NS/NPCs in the SVZ and around the injury site following TBI. These data suggest that bioactive SDF-1α can be delivered via alginate thread and exogenous delivery of SDF-1α and its interaction with receptor CXCR4 mediates migration of newly generated neurons from the SVZ to the site of injury following TBI. Collectively, our study indicates that SDF-1α could be utilized as a guidance cue for tissue repair following brain injury.

Epidemiological data indicate that patients who experience a traumatic brain injury (TBI) have an elevated risk of developing a substance use disorder (SUD), but the underlying neurobiological connections remain unclear. To further understand the relationship between TBI and SUD, we investigated the effects of TBI on the abuse-related effects of oxycodone in preclinical models. Our evaluation utilized a lateral fluid percussion injury of moderate severity in adult male Sprague-Dawley rats. In the first aim, we tested the hypothesis that moderate TBI increases the risk for relapse to an opioid use disorder as measured by reinstatement of lever-pressing behavior following extinction in an intravenous oxycodone self-administration procedure. In the second aim, we tested the hypothesis that moderate TBI increases physiological dependence to oxycodone as measured by decreases in food-reinforced lever-pressing behavior and increases in other withdrawal behaviors in both precipitated withdrawal and spontaneous withdrawal. In tests for self-administration, brain-injured subjects, relative to non-injured subjects, showed no significant differences in the number of oxycodone-reinforced sessions required to meet stable maintenance criteria for lever-pressing behavior. Likewise, brain-injured subjects showed no significant differences in the number of non-reinforced sessions to meet extinction criteria for lever-pressing behavior relative to non-injured subjects. In tests for reinstatement, non-injured subjects reinstated responding under oxycodone-associated cue- and oxycodone prime-induced conditions, however, brain-injured subjects did not reinstate lever-pressing behavior under any conditions. In tests for physical dependence, brain-injured subjects showed no significant differences from non-injured subjects with regards to their mean withdrawal scores or food-reinforced lever-pressing behavior. Overall, these data suggest that brain-injured patients no significant pre-morbid history of opioid abuse are at a lesser risk of relapse to opioid use disorders. Moreover, the characteristic withdrawal syndrome in opioid-dependent patients may not contribute to continued opioid abuse to a greater degree in brain-injured patients than compared to non-injured patients.

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