O presente trabalho contempla o estudo das principais alterações macroscópicas e anatomopatológicas do sistema nervoso central (SNC) encontradas em animais que morreram em decorrência de traumatismo cranioencefálico (TCE). Além da determinação das lesões de golpe, contragolpe e padrão de lesão axonal difusa encontradas nesse tipo de trauma. Inicialmente realizou-se a necropsia dos animais com devido registro fotográfico, descrição das lesões macroscópicas e coleta de material para processamento histológico de rotina e confecção das lâminas coradas em hematoxilina-eosina (HE) para avaliação histopatológica. A imunohistoquímica foi realizada a partir dos mesmos segmentos utilizados nas lâminas de HE, com os anticorpos anti-proteína precursora do β-amiloide (APP), para determinação da lesão axonal, e anti-GFAP e anti-vimentina para avaliação de respostas do tecido nervoso à injúria, como astrocitose e astrogliose. Macroscopicamente as principais lesões observadas caracterizaram-se por lesões focais decorrentes de traumatismo direto, com fraturas de ossos do crânio, laceração de neuroparênquima e contusões. No exame histopatológico as lesões principais caracterizaram-se por hemorragia subdural e em neuroparênquima, congestão, edema tecidual e necrose em variados graus de intensidade e regiões do encéfalo. A lesão axonal foi confirmada pela imunomarcação do βAPP que revelou marcação multifocal de axônios tumefeitos formando esferoides axonais, bulbos axonais ou axônios varicosos em alguns casos. Astrocitose, astrogliose e neovascularização foram observados na maioria dos casos através dos anticorpos GFAP e vimentina. Conclui-se no presente estudo que cães e gatos com TCE apresentaram lesões histologicamente caracterizadas por hemorragias multifocais em meninge e neuroparênquima em diversas regiões, além de edema, necrose e congestão, principalmente. A lesão axonal caracterizou-se pela formação de esferoides axonais, bulbos axonais e longos axônios varicosos. Esta característica foi observada em apenas 2 animais deste estudo, e destes apenas um animal (caso 6) apresentou um padrão de lesão axonal traumática difusa, confirmada pela presença de acentuada marcação pelo anticorpo βAPP. Adicionalmente, foi observada astrocitose e astrogliose em cinco animais, principalmente das áreas próximas às lesões, avaliadas pelos anticorpos GFAP e vimentina. / The present work contemplates the study of the main macroscopic and anatomopathological changes of the central nervous system (CNS) in animals that died due to traumatic brain injury (TBI). Besides the determination of the coup and countercoup and pattern of diffuse axonal injury in this type of trauma. Initially, the animals were necropsied and photographic recorded and macroscopic lesions were described and collect material for histological processing routine and the preparation of slides in hematoxylin-eosin (HE) staining for histopathological evaluation. Immunohistochemistry was performed from the same segments used in the HE slides, with anti-(β-amyloid precursor protein antibodies (βAPP) for determination of axonal lesion, and anti-GFAP and anti-vimentin for evaluation of tissue responses to injury, such as astrocytosis and astrogliosis. Macroscopically, the main lesions observed were focal lesions due to direct trauma, such as skull fractures, neuroparenchyma laceration and contusions. In the histopathological evaluation, the main lesions were characterized by subdural hemorrhage and in neuroparenchyma, congestion, tissue edema and necrosis in varying degrees of intensity and regions of the encephalon. The axonal injury was confirmed by (βAPP immunostaining that revealed multifocal labeled of swellings axons forming axonal spheroids, axonal bulbs or varicose axons in some cases. Astrocytosis, astrogliosis and neovascularization were observed in most cases through the antibodies GFAP and vimentin. In conclusion the present study demonstrate that dogs and cats with TBI presented histologically lesions characterized by multifocal hemorrhage in meninge and neuroparenchyma in different areas, as well as edema, necrosis and congestion, mainly. Axonal injury was determined by axonal swelling, bulbs and varicosities. This characteristic was observed in only 2 animals in this study, and only one of those (case 6) presented pattern of diffuse traumatic axonal injury, confirmed by accentuated (βAPP labeling. Addiotionally, astrocytosis and astrogliosis was observed in five animals, mainly in areas close to lesions, evaluated by GFAP and vimentin antibodies.

Adenosine Triphosphate (ATP) can be released as a signal between cells in an autocrine and paracrine manner that binds purinergic receptors. Highly conserved, purinergic receptors expressed on the cell surface of neurons and astrocytes are capable of being activated across eight orders of magnitude from hundreds of nanomolar ATP to millimolar. Genetically encoded fluorescent protein biosensors have been used to detect ATP outside the cell, but a high affinity extracellular ATP sensor is required to study the ATP signaling dynamics from nanomolar to micromolar magnitudes. Previously, our lab developed a first generation sensor of extracellular ATP called ECATS1 (Conley et al.). To develop an improved sensor, we caried out site-directed mutagenesis of the sensor's ATP binding site and identified a mutant that exhibited a 4-fold increase in ATP binding affinity in solution. We then optimized the membrane-tethering of the sensor to achieve the 4-fold increase in extracellular ATP binding affinity when measured on live cell.s This second-generation sensor was dubbed ECATS2. As a proof-of-concept application, we sought to detect ATP release from cells using <i>in vitro</i> models of edema. We subjected HEK293A cells to hypo-osmotic shock (HOS), revealing ATP release at micromolar levels. Then we tested HOS in cultured cortical astrocytes, also revealing micromolar ATP release. However, when we tested neuron-astrocyte co-cultures, we no longer observed ATP release in response to HOS. Interestingly, this implies that co-culture either entirely prevented ATP release from astrocytes or dampened it into the nanomolar range below the limit of ECATS2 detection. Thus, we have validated the development of a higher affinity, second-generation sensor and used it to discover that ATP release from astrocytes after HOS can be affected by the presence of neurons. <br>

La cognition sociale, i.e. notre capacité à attribuer des états mentaux à autrui et à identifier ses émotions, est souvent perturbée dans certaines pathologies telles que le traumatisme crânien (TC). Cette capacité est traditionnellement évaluée à l’aide de tâches sous format « papier-crayon » n’impliquant pas le participant dans une situation d’interaction sociale. Pourtant, la cognition sociale est fondamentale dans nos interactions sociales car elle nous permet de comprendre le discours et le comportement d’autrui. Ainsi, dans ce travail de thèse, nous avons évalué les capacités d’attribution d’états mentaux et de reconnaissance émotionnelle de personnes ayant subi un TC à l’aide de tâches les impliquant activement dans une situation de communication (tâche de communication référentielle et tâche EViCog), ce qui n’a jamais été fait dans cette pathologie. La tâche EViCog (Evaluation de la cognition sociale en interaction virtuelle), créée pour cette étude, permet d’avoir des conversations audio-visuelles avec des humains virtuels, qui expriment des émotions et produisent du discours nécessitant d’inférer leurs états mentaux. Les résultats ont montré que les difficultés des personnes TC étaient encore plus importantes pour la tâche en situation d’interaction (tâche EViCog) par rapport à des tâches traditionnelles au format « papier-crayon ». Par ailleurs, en situation d’interaction, les performances de cognition sociale semblent dépendre en partie des capacités mnésiques (mémoire autobiographique et du contexte), ainsi que des fonctions exécutives, alors que pour les tâches traditionnelles, les performances ne seraient expliquées que par certaines capacités exécutives. / Social cognition, i.e. the ability to attribute mental states to others and to identify emotions, is often impaired in various pathologies, such as traumatic brain injury (TBI). This ability is traditionally assessed with “paper-and-pencil” tasks that do not involve the participant in a social interaction situation. However, social cognition is central in our daily social interactions, as it helps us understand others’ speech and behavior. Thus, in this study, we assessed mental state attribution and emotion recognition abilities of TBI participants, using tasks that involve the participant in a communication situation (referential communication task and EViCog task). The EViCog task (social cognition evaluation in virtual interaction), designed for this research, provides audio-visual conversations with virtual humans, which express emotions and produce speech requiring mental state inference. The results showed that the difficulties of the TBI participants were even more important for the task in interaction situation (EViCog task) compared to traditional tasks in paper-and-pencil format. Moreover, in interaction situation, social cognition performance seemed to rely on mnemonic abilities (autobiographical memory and context memory), and on executive functions, while for traditional tasks, performances were only explained by some executive abilities.

L’inhalation de monoxyde d’azote (NO) est l’une des thérapies les plus utilisées en réanimation néonatale. Cependant, peu de données sont disponibles sur l’impact de l’inhalation de NO sur le développement cérébral et le devenir des enfants prématurés. Nous avons étudié l’impact du monoxyde d’azote inhalé (iNO) sur le cerveau en développement chez le rongeur. Des portées et leur mère sont placés sous 5 à 20 ppm de NO de la naissance (P0) jusqu’au 7ème jour de vie postnatal (P7). Les animaux exposés au NO présentent une augmentation transitoire de l’angiogenèse et de la myélinisation, sans incidence sur les fonctions cognitives à l’âge adulte. L’exposition au NO est associée à une prolifération d’oligodendrocytes immatures et à une maturation anticipée des formes myélinisantes. Les rôles du NO endogène et du couple VEGF/VEGFR2 dans ces effets ont été évalués via l’injection d’antagonistes : LNAME pour inhiber les NOS, SU-5416 comme antagoniste du VEGFR2. Dans les deux cas, l’inhalation de NO corrige les anomalies de myélinisation et d’angiogenèse induites par ces inhibiteurs. Nous avons soumis des ratons à une agression excitotoxique par injection intracérébrale d’agonistes du glutamate. A P10 les rats exposés au iNO avant l’injection présentent des lésions moins importantes ; ainsi qu’un diminution de densité des microglies activées et des astrocytes. Cet effet neuroprotecteur est associé à une régulation de sous-unités des récepteurs au glutamate dès P5. Cet effet transcriptionnel semble lié à la modulation de la signalisation pCREB/Akt. Les effets à distance du iNO sont liés à un transport réversible endovasculaire du NO. In fine, du NO est delivré à la cellule et les concentrations intracellaires de cGMP augmentent d’un facteur 5. Plusieurs facteurs de transcription sont régulés : PDGFR-α, Sema3F, les sous-unités des récepteurs au glutamate, Thrombospondine-1. Cette dernière est un antagoniste naturel de la signalisation NO-cGMP. L’injection de ABT-510, agoniste de TSP-1, abolit les effets du iNO, confirmant l’hypothèse que les effets à distance reposent sur la signalisation NO-Guanylate Cyclase soluble-cGMP. Au total, nous avons démontré que le iNO est transporté de manière réversible et delivré au cerveau en développement. Il y exerce un effet pro-angiogénique et pro-myélinisant, via une signalisation cGMP, régulée par la thrombospondine-1. Plus encore, l’exposition prophylactique au iNO diminue l’impact d’une agression excitotoxique. Ce qui augure de propriétés neuroprotectrices prometteuses en néonatalogie, et au delà. / Inhaled nitric oxide (iNO) is one of the most promising therapies used in neonates, but littlei known about its effect on the developing brain. We explored the effects of iNO on developing brain in rodent pups, and pathway involved in iNO remote effects. Rat pups and their mothers were placed in a chamber containing 5 to 20 ppm of NO for 7 days after birth. Extensive serum analysis, immunochemistry, RT-PCR analysis, were performed Neonatal exposure to iNO was associated with a transient increase in central nervous system myelination and angiogenesis in rats, without any behavioral consequences in adulthood. Exposure to iNO was associated with a proliferative effect on immature oligodendrocytes and a subsequent promaturational effect. The role of endogenous NO in myelination was investigated in animals treated with the nitric oxides synthase inhibitor N-nitro-L- arginine methyl ester (L-NAME) in the neonatal period ; this led to protracted myelination defects and subsequent behavioral deficits in adulthood. These effects were reversed by rescuing L-NAME-treated animals with iNO. We challenged animals with intracranial injection of glutamate agonists. At P10, rat pups exposed to iNO exhibited a significant decrease of lesion size in both the white matter and cortical plate compared to controls. Microglia activation and astrogliosis were found significantly decreased in NO-exposed animals. This neuroprotective effect was associated with a significantdecrease of several glutamate receptor subunits expression at P5. iNO was associated with an early(P1) downregulation of pCREB/pAkt expression and induced an increase in pAkt proteinconcentration in response to excitotoxic challenge (P7) Those effects were related to a release of NOto the cells, and a rise of cGMP intracellular concentration. Several transcription factor wereregulated, namely PDGFR-α, Sema3F, TSP-1, glutamate receptors subunits, Thrombospondin-1. Thelatter was responsible for NO pathway regulation, and injection of TSP-1 agonist (AbT-510) abolishediNO remote effects. iNO remote effects are not associated VEGF concentration increase nor VEGFRstimulation, as VEGF-R antagonist SU54-16 failed to abolish iNO effects on angiogenesis andmyelination. Moreover iNO reverses severe myelination and angiogenesis defects induced by this SU-5416. Thus, we demonstrate transport and considerable remote effect of iNO on angiogenesis andmyelination in rodents. Those effects are related to an enhancement of cGMP pathway, regulated byTSP-1, and transcriptional effects. Moreover we described and investigated the neuroprotectiveeffect of iNO in neonatal excitotoxic-induced brain damage. These data point to potential newavenues for neuroprotection in human perinatal brain damage.

Le traumatisme crânien (TC) est la première cause de visite aux urgences pour la population pédiatrique. Indépendamment du niveau de sévérité du TC, les patients pédiatriques souffrent sur le long-terme de troubles cognitifs et émotionnels, cependant les mécanismes moléculaires et cellulaires sous-jacents sont encore peu connus, et il n’existe pas de traitement efficace disponible à ce jour. L’unité neurovasculaire est composée de vaisseaux sanguins, neurones et astrocytes. Les astrocytes sont essentiels à une variété de fonctions physiologiques assurées par cette unité tels que l’homéostasie cérébrale et le couplage neurovasculaire. Suite à une lésion, les astrocytes deviennent « réactifs », et cette « astrocytopatie » peut impacter leur rôle physiologique et empirer les conséquences de la lésion.Nous avons étudié le rôle de l’astrocytopatie dans le TC juvénile et fait l’hypothèse que : (1) les astrocytes réactifs contribuent à la propagation de l’œdème via les jonctions serrées connexines après un TC juvénile modéré ; (2) l’astrocytopatie se développe également après un TC juvénile léger avec des changements calciques qui pourraient contribuer à (3) une altération de la réactivité vasculaire, tout cela impactant sur les conséquences comportementales qui font suite à la lésion.Nous avons montré que :(1) Réduire l’astrocythopatie en sous-régulant la connexine 43 permettait d’améliorer les conséquences comportementales après un TC modéré juvénile, mais n’impactait pas la propagation de l’œdème.(2) Les astrocytes devenaient réactifs et subissaient des changements morphologiques après un TC juvénile léger avec des perturbations dans les signaux purinergiques-calciques liés à des changements dans l’expression du canal aqueux aquaporine 4 (AQP4).(3) Une dysfonction vasculaire majeure s’était développée après le TC juvénile léger avec des changements fonctionnels et morphologiques des vaisseaux intraparenchymaux parallèles aux altérations comportementales et précédant les dommages axonaux après la lésion.Ce travail apporte un nouvel aperçu de la pathophysiologie du TC juvénile et ouvre des possibilités pour développer des thérapies ciblant l’astrocytopatie après une lésion. / Traumatic brain injury (TBI) is the first cause for emergency department visits in the pediatric population. Regardless of the severity of TBI, pediatric patients suffer long-term cognitive and emotional impairments but the underlying cellular and molecular mechanisms are still poorly understood and there are no effective treatments available. The neurovascular unit is composed by blood vessels, neurons and astrocytes. Astrocytes are crucial for various physiological functions of this unit such as brain homeostasis and neurovascular coupling. In injuries astrocytes become “reactive”, and this “astrocytopathy” can impact their physiological roles and worsen the outcome after injury.We investigated astrocytopathy in juvenile TBI and hypothesized that: (1) reactive astrocytes contribute to spread of edema through connexin gap junctions after juvenile moderate TBI; and that (2) astrocytopathy also develops after juvenile mild TBI with calcium changes that could contribute to (3) impaired vascular reactivity, all of which impacts the behavioral outcome after injury.We have shown that:(1) Reducing astrocytopathy by downregulating the gap junction protein connexin 43 improved the behavioral outcome after juvenile moderate TBI, but did not impact the spread of edema.(2) Astrocytes became reactive and underwent morphological changes after juvenile mild TBI with disturbances in purinergic-calcium signaling related to expression changes of the water channel aquaporin 4 (AQP4).(3) Major vascular dysfunction developed after juvenile mild TBI with functional and morphological changes of the intraparenchymal vessels that paralleled behavioral impairments and preceded axonal damage after injury.This work brings new insights in the pathophysiology of juvenile TBI and opens prospects for developing therapeutics targeting astrocytopathy after injury.

Le traumatisme crânien (TC) représente un des problèmes majeurs de santé publique, pour lequel à l’heure actuelle il n’existe aucun traitement. Le TC induit une neuro-inflammation délétère qui pourrait contribuer à l’apparition des lésions de la substance blanche (SB). Ces dernières sont à l’origine de lourdes conséquences neurologiques chez les patients victimes de TC. Néanmoins, très peu d’études se sont intéressées à ces lésions bien que plus sévères que les lésions de la substance grise. Ainsi une meilleure connaissance de leur évolution et des causes devient indispensable. L’hyperactivation de la poly(ADP ribose)polymérase (PARP) joue un rôle délétère dans les conséquences post-traumatiques, notamment sur la neuro-inflammation. Ainsi son inhibition pourrait être bénéfique le développement des lésions de la SB. Dans ce contexte, l’objectif de notre travail a été d’évaluer le rôle de la PARP dans les lésions de la SB dans un modèle expérimental de TC induit par impact cortical contrôlé chez la souris. Dans une première partie, nous avons étudié l’évolution de la démyélinisation dans le corps calleux, une structure riche en SB, entre 6 heures et 3 mois post-TC. Parallèlement, les évolutions de la lésion cérébrale, des déficits sensorimoteurs, de la neuro-inflammation et de l’œdème cérébral ont été étudiées. Le TC induit (1) une démyélinisation dès 7 jours et au moins jusqu’à 3 mois post-TC, précédée par (2) une lésion cérébrale entre 24 et 72 heures suivie par une cicatrisation, (3) une neuro-inflammation entre 6 heures et 7 jours et (4) un œdème cérébral entre 6 et 72 heures post-TC. De plus, le TC induit des déficits sensorimoteurs à 6 heures et 3 mois. Ces résultats montrent que ce modèle est adapté pour étudier les lésions de la SB post-TC, et que la neuro-inflammation et l’œdème cérébral pourrait être impliqués dans la démyélinisation. Dans une deuxième partie, nous avons étudié le rôle de la PARP dans les lésions de la SB suite à TC à l’aide de souris knockout (KO) et wild-type (WT) pour le gène de la PARP. Nous avons mis en évidence que les souris KO ne présentent pas de démyélinisation bilatérale du corps calleux après un TC par rapport aux souris WT à 7 jours post-TC, démontrant pour la première fois l’implication de cette enzyme dans les lésions de la SB consécutives à un TC. De plus, nous avons constaté que les souris KO non traumatisées présentent une diminution de myélinisation comparativement aux souris WT non traumatisées, suggérant un rôle de la PARP dans le processus physiologique de la myélinisation.En conclusion, l’ensemble de ce travail expérimental a permis (1) une meilleure caractérisation de la démyélinisation post-TC et des mécanismes potentiellement impliqués dans cette dernière, et (2) de démontrer pour la première fois le rôle délétère de la PARP dans la démyélinisation induite par un TC. Nos travaux suggèrent le potentiel de l’inhibition de la PARP comme stratégie thérapeutique pour la prévention des lésions de la SB post-traumatiques. / Traumatic brain injury (TBI) is a leading cause of death and disability for which there is no neuroprotective treatment up to date. It results in neuroinflammation that may participate in lasting motor and cognitive impairments accompanied by changes in white matter (WM) tracts. WM lesions, evidenced by demyelination, are associated with neurological disorders and in clinical studies are common consequences in patients with chronic TBI. Several studies suggest a contribution of an overactivation of the poly(ADP-ribose) polymerase (PARP) to the neuroinflammatory response which may lead to demyelination. The first part of this study was dedicated to a detailed in vivo assessment of the evolution over time of neurological disorders, cerebral lesion and edema, neuroinflammation and white matter injury induced by controlled cortical impact (CCI) between 6 hours and 12 weeks post-TBI. Notably in the corpus callosum, a significant demyelination starting at 7 days appeared to be a major consequence to post-traumatic neuroinflammation associated with motor dysfunctions. The second part of this study was dedicated to the evaluation of PARP’s role in WM lesions post-TBI, using PARP knockout (KO) mice. Our main findings reveal a diminished demyelination in the corpus callosum of TBI PARP KO as opposed to TBI PARP wildtype specimens. Hence, these data suggest for the first time PARP’s deleterious role in post-traumatic demyelination. In conclusion, taken together these data give an overall view of motor/sensorimotor deficits, neuroinflammation and demyelination in a CCI model of TBI that could help to validate pharmacological strategy for preventing post-traumatic WM injury. Notably, PARP’s inhibition seems to be a valid candidate as this enzyme participates in the establishment of a demyelinating process.

The aim of this final thesis is to apply Feuerstein's instrumental enrichment program (FIE) to a person with traumatic brain injury (TBI). The theoretical part deals with the problematic of traumatic brain injury and Feuerstein's approach to the development of cognitive functions. The empirical part focuse on qualitative research to find out whether there has been an improvement in cognitive functions with three respondents with TBI after five months of intervention using the FIE program, or not. Respondents are young men aged between 23 and 32, about 10 years after the accident, who regularly rehabilitate and undergo reeducation at the Jedlička Institute and Schools (JÚŠ). The aim of the research is to compare whether the influence of the FIE program has improved cognitive functions. The comparison is achieved by objective assessment of cognitive functions using Klecanská opakovatelná neuropsychologická baterie (KONB; Klecany Repeatable Neuropsychological Battery). The results of the research are presented in structured case studies. These in addition to the results of the KONB examination and the description of several months of intervention, follows the respondents throughout their past from life before the accident, through the rehabilitation of the consequences of the accident to the present...

Les objectifs de cette thèse étaient de caractériser les corrélats neuronaux fonctionnels et structurels de l'abolition de la conscience observés pendant le coma et d'identifier les signatures neuronales précoces de la récupération neurologique à partir de cet état. Pour atteindre ce but, nous avons étudié des patients cérébrolésés, recrutés au stade aigu du coma, à l'aide de l'IRM fonctionnelle au repos et IRM structurale. Nos résultats indiquent une réorganisation topologique globale du cerveau des patients, reflétée par une dédifférenciation et une réduction de la résilience des réseaux fonctionnels au repos d'ordre élevé. Ces anomalies sont accompagnées d'une perte de connexions fronto-pariétales à longue distance. Au niveau régional, nous avons observé un schéma complexe de diminution et d'augmentation de la densité de connexion fonctionnelle entre le cortex postéromédial et le cortex préfrontal médial : régions précédemment décrites pour avoir un rôle critique dans la conscience. De manière intéressante, ces modifications de densité de connexion étaient significativement liées à la récupération des patients trois mois après le coma. Enfin, l'analyse multimodale a permis de démontrer une association significative entre la connectivité fonctionnelle et l'intégrité structurelle cérébrales antéro-postérieure, fournissant des informations importantes sur le lien structure/fonction au décours de ces troubles acquis de la conscience. / The aim of the present thesis was to characterize the functional and structural neural correlates of acute consciousness abolition induced by severe brain injury and identify early neural signatures of long-term neurological recovery. To do so, we studied brain-injured patients, recruited in the acute stage of coma, using resting-state functional and structural MRI. Our findings indicated a global topological brain reorganization in coma patients, reflected in dedifferentiated and less resilient high-order resting-state functional networks, paralleled with a loss of long-range fronto-parietal connections. On a regional level, we found a complex pattern of voxel-wise decrease and increase in functional connection density between the posteromedial cortex and the medial prefrontal cortex, regions previously described to have a critical role in conscious processing. These connection density patterns seemed to permit outcome prediction in patients, assessed three months post-coma. Furthermore, the multi-modal MRI analysis demonstrated a significant association between antero-posterior functional connectivity and structural integrity, providing further insights into the pathological underpinning of conscious processing.

Made available in DSpace on 2016-04-28T20:56:20Z (GMT). No. of bitstreams: 1 Silvia Cristina de Freitas Feldberg.pdf: 8472150 bytes, checksum: d1b62a4823332d0da7e9ca29e7af441c (MD5) Previous issue date: 2010-10-25 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / This study evaluated the mathematical performance of children and adolescents with congenital or acquired brain injuries, trying to identify whether (and how) the neuropsychological profile reflects in this performance. Since math learning is central to a successful school experience, it is important to identify whether the brain lesions necessarily promote, as claimed by teachers, learning difficulties, or whether, instead, the plasticity of the brain, combined with a good school, discredits that statement. The theoretical approach is based on the neuropsychology and the socio-historical conception of human development, considering the importance of the biological basis and, moreover, of the social world in which the process of learning and human development occurs. The study investigated 5 male adolescents diagnosed with brain damage. The boys were 12 to 15 years old and were attending series 6th to 9th in private schools in the state of Sao Paulo (BR). They answered a battery of tests, which included verification of their IQs, their performance in Math and also a neuropsychological evaluation. The procedures were applied individually, lasting three to four sessions of 90 minutes in average. The results were analyzed according to the standards required by each instrument. For performance in mathematics, qualitative and quantitative analyses of the tests were made. The results showed that, among the neuropsychological functions, the visual constructive and the executive one showed more pronounced problems. Regarding Math performance, the greatest difficulties were detected in skills related to Space and Form, Information Processing, Multiplication and Problems Resolution. However, since the participants are similar to the average Brazilian students in terms of IQ and mathematical performance, the inadequate functioning of their psychological functions seems to be due not to the brain damage but to the precarious teaching of that school discipline. Thus, the research findings defy simplistic analysis, which establish a causal relationship between learning difficulties and brain damage. The recommendation, once again, is to invest efforts in promoting teachers professional development so that they can offer to any student the necessary incentive, motivation, help and guidance to conquer what society expects and schools must deliver / O presente trabalho avaliou o desempenho matemático de crianças e adolescentes com lesões cerebrais congênitas ou adquiridas, tentando identificar se (e como) o perfil neuropsicológico se reflete neste desempenho. Como a aprendizagem da matemática é central para uma trajetória escolar bem-sucedida, convém identificar se as lesões encefálicas concorrem, como alegam os professores, para a presença de dificuldades de aprendizagem ou se, ao contrário, a plasticidade do cérebro, aliada a uma escola de boa qualidade, desacredita essa afirmação. O referencial teórico adotado apoia-se na neuropsicologia e na concepção sócio-histórica do desenvolvimento humano, considerando tanto a importância da base biológica como a do mundo social no processo de aprendizagem e desenvolvimento humano. Foram pesquisados cinco adolescentes com idades entre 12 e 15 anos, do sexo masculino, diagnosticados com lesão cerebral, cursando entre o sexto e o nono ano do ensino fundamental, em escolas privadas localizadas no Estado de São Paulo. Foi-lhes aplicada uma bateria de testes, que incluíam a verificação do coeficiente intelectual, o desempenho matemático e, ainda, uma avaliação neuropsicológica. Os procedimentos foram aplicados individualmente e levaram cerca de três ou quatro sessões, de duração média de 90 minutos. Os resultados da avaliação foram analisados conforme as normas requeridas em cada instrumento utilizado. Para o desempenho em matemática, foram feitas análises qualitativas e quantitativas dos testes empregados. Os resultados mostraram que, no âmbito neuropsicológico, as habilidades visoconstrutivas e funções executivas apresentavam os problemas mais acentuados. Em relação ao desempenho em matemática, maiores dificuldades foram detectadas nas competências relacionadas aos domínios Espaço e Forma e Tratamento da Informação, Multiplicação e Resolução de Problemas. No entanto, como os participantes não discrepavam da média dos alunos brasileiros em termos de QI e, inclusive, de desempenho matemático, as funções psicológicas deficitárias parecem ser devidas não às lesões cerebrais, e sim, à precariedade do ensino dessa disciplina. Dessa forma, os achados da pesquisa desafiam análises simplistas, que estabelecem uma relação causal entre dificuldades de aprendizagem e lesões cerebrais. A recomendação, mais uma vez, é a de se investir na formação profissional dos docentes, para que possam oferecer a todo e qualquer aluno ainda que mais a uns do que a outros, para cumprir o preceito da equidade estímulos, motivação, auxílio e guia para dominarem aquilo que a sociedade espera deles e que a escola tem por meta lhes ensinar

This thesis explores physiological changes occurring after acute brain injury. The first two chapters focus on traumatic brain injury (TBI), a significant cause of disability and death worldwide. I discuss the evidence behind current management of secondary brain injury with emphasis on partial brain oxygen tension (PbtO2) and intracranial pressure (ICP). The second chapter describes a subgroup analysis of the effect of hypothermia on ICP and PbtO2 in 17 patients enrolled to the Eurotherm3235 trial. There was a mean decrease in ICP of 4.1 mmHg (n=9, p < 0.02) and a mean decrease in PbtO2 (7.8 ± 3.1 mmHg (p < 0.05)) in the hypothermia group that was not present in controls. The findings support previous studies in demonstrating a decrease in ICP with hypothermia. Decreased PbtO2 could partially explain worse outcomes seen in the hypothermia group in the Eurotherm3235 trial. Further analysis of PbtO2 and ICP guided treatment is needed. The third chapter focuses on delayed cerebral ischaemia (DCI) after aneurysmal subarachnoid haemorrhage (aSAH), another form of acute brain injury that causes significant morbidity and mortality. I include a background of alpha-calcitonin gene-related peptide (αCGRP), a potential treatment of DCI, along with results from a systematic review and meta-analysis of nine experimental models investigating αCGRP. The meta-analysis demonstrates a 40.8 ± 8.2% increase in cerebral vessel diameter in those animals treated with αCGRP compared with controls (p < 0.0005, 95% CI 23.7 to 57.9). Neurobehavioural scores were reported in four publications and showed a Physiological responses to brain tissue hypoxia and blood flow after acute brain injury standardised mean difference of 1.31 in favour of αCGRP (CI -0.49 to 3.12). I conclude that αCGRP reduces cerebral vessel narrowing seen after SAH in animal studies but note that there is insufficient evidence to determine its effect on functional outcomes. A review of previous trials of αCGRP administration in humans is included, in addition to an original retrospective analysis of CSF concentrations of αCGRP in humans. Enzyme-linked immunosorbent assay of CSF (n = 22) was unable to detect αCGRP in any sample, which contrasts with previous studies and was likely secondary to study methodology. Finally, I summarise by discussing a protocol I designed for a dose-toxicity study involving the intraventricular administration of αCGRP to patients with aSAH and provide some recommendations for future research. This protocol was based upon the systematic review and was submitted to the Medical Research Council's DPFS funding stream during the PhD.