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No / Cortical spreading depression (CSD) is a transient disruption of local ionic homeostasis that may promote migraine attacks and the progression of stroke lesions. We reported previously that the local inhibition of nitric oxide (NO) synthesis with N¿-nitro-L-arginine methyl ester (L-NAME) delayed markedly the initiation of the recovery of ionic homeostasis from CSD. Here we describe a novel method for selective, controlled generation of exogenous NO in a functioning brain region. It is based on microdialysis perfusion of the NO donor, 2-(N,N-diethylamino)-diazenolate-2-oxide (DEA/NO). As DEA/NO does not generate NO at alkaline pH, and as the brain has a strong acid-base buffering capacity, DEA/NO was perfused in a medium adjusted at alkaline (but unbuffered) pH. Without DEA/NO, such a microdialysis perfusion medium did not alter CSD. DEA/NO (1, 10 and 100 ¿M) had little effect on CSD by itself, but it reversed in a concentration-dependent manner the effects of NOS inhibition by 1 mM L-NAME. These data demonstrate that increased formation of endogenous NO associated with CSD is critical for subsequent, rapid recovery of cellular ionic homeostasis. In this case, the molecular targets for NO may be located either on brain cells to suppress mechanisms directly involved in CSD genesis, or on local blood vessels to couple flow to the increased energy demand associated with CSD

Cotutelle entre l’université de Montréal et d’Aix-Marseille / Cette thèse vise à comprendre les fondements et les fonctions des calculs probabilistes impliqués dans les processus visuels. Nous nous appuyons sur une double stratégie, qui implique le développement de modèles dans le cadre du codage prédictif selon le principe de l'énergie libre. Ces modèles servent à définir des hypothèses claires sur la fonction neuronale, qui sont testées à l'aide d'enregistrements extracellulaires du cortex visuel primaire. Cette région du cerveau est principalement impliquée dans les calculs sur les unités élémentaires des entrées visuelles naturelles, sous la forme de distributions d'orientations. Ces distributions probabilistes, par nature, reposent sur le traitement de la moyenne et de la variance d'une entrée visuelle. Alors que les premières ont fait l'objet d'un examen neurobiologique approfondi, les secondes ont été largement négligées. Cette thèse vise à combler cette lacune. Nous avançons l'idée que la connectivité récurrente intracorticale est parfaitement adaptée au traitement d'une telle variance d'entrées, et nos contributions à cette idée sont multiples. (1) Nous fournissons tout d'abord un examen informatique de la structure d'orientation des images naturelles et des stratégies d'encodage neuronal associées. Un modèle empirique clairsemé montre que le code neuronal optimal pour représenter les images naturelles s'appuie sur la variance de l'orientation pour améliorer l'efficacité, la performance et la résilience. (2) Cela ouvre la voie à une étude expérimentale des réponses neurales dans le cortex visuel primaire du chat à des stimuli multivariés. Nous découvrons de nouveaux types de neurones fonctionnels, dépendants de la couche corticale, qui peuvent être liés à la connectivité récurrente. (3) Nous démontrons que ce traitement de la variance peut être compris comme un graphe dynamique pondéré conditionné par la variance sensorielle, en utilisant des enregistrements du cortex visuel primaire du macaque. (4) Enfin, nous soutenons l'existence de calculs de variance (prédictifs) en dehors du cortex visuel primaire, par l'intermédiaire du noyau pulvinar du thalamus. Cela ouvre la voie à des études sur les calculs de variance en tant que calculs neuronaux génériques soutenus par la récurrence dans l'ensemble du cortex. / This thesis aims to understand the foundations and functions of the probabilistic computations involved in visual processes. We leverage a two-fold strategy, which involves the development of models within the framework of predictive coding under the free energy principle. These models serve to define clear hypotheses of neuronal function, which are tested using extracellular recordings of the primary visual cortex. This brain region is predominantly involved in computations on the elementary units of natural visual inputs, in the form of distributions of oriented edges. These probabilistic distributions, by nature, rely on processing both the mean and variance of a visual input. While the former have undergone extensive neurobiological scrutiny, the latter have been largely overlooked. This thesis aims to bridge this knowledge gap. We put forward the notion that intracortical recurrent connectivity is optimally suited for processing such variance of inputs, and our contributions to this idea are multi-faceted. (1) We first provide a computational examination of the orientation structure of natural images and associated neural encoding strategies. An empirical sparse model shows that the optimal neural code for representing natural images relies on orientation variance for increased efficiency, performance, and resilience. (2) This paves the way for an experimental investigation of neural responses in the cat's primary visual cortex to multivariate stimuli. We uncover novel, cortical-layer-dependent, functional neuronal types that can be linked to recurrent connectivity. (3) We demonstrate that this variance processing can be understood as a dynamical weighted graph conditioned on sensory variance, using macaque primary visual cortex recordings. (4) Finally, we argue for the existence of (predictive) variance computations outside the primary visual cortex, through the Pulvinar nucleus of the thalamus. This paves the way for studies on variance computations as generic weighting of neural computations, supported by recurrence throughout the entire cortex.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

INTRODUÇÃO: O surgimento da tomografia computadorizada quantitativa periférica de alta resolução (HR-pQCT) tornou possível medir a densidade mineral óssea (DMO) volumétrica e a microarquitetura óssea tridimensional in vivo, bem como avaliar a resistência óssea através da análise de elemento finito (FE). Como não há na literatura um banco de dados para a população masculina brasileira, o objetivo principal deste estudo transversal e estabelecer valores de referência para os parâmetros ósseos obtidos por HR-pQCT em homens, categorizados por décadas e ajustados por peso e altura, na região distal do rádio e da tíbia. Como objetivo secundário, correlacionar o parâmetro de resistência óssea - rigidez do tecido ósseo (S), com os demais parâmetros medidos por HR-pQCT, e com parâmetros obtidos por absorciometria de raios- X de dupla energia (DXA), incluindo escore de osso trabecular (TBS). METODOS: Homens brasileiros saudáveis (n = 340) entre as idades de 20 e 92 anos foram incluídos neste estudo. O antebraço não dominante e a perna esquerda foram imobilizados, e foram realizados métodos de segmentação padrão e avançado para as análises da região distal do rádio e da tíbia por HRpQCT. A partir das imagens HR-pQCT, a DMO volumétrica e microestrutura do osso trabecular e cortical foram avaliadas, e a resistência óssea foi estimada usando analise de FE. Também foi realizada medição da coluna lombar e fêmur por DXA para obtenção dos valores de DMO e TBS. Os dados foram descritos em mediana e quartis (IQR). Modelos de regressão linear múltipla em função da idade, peso e altura foram desenvolvidos e ilustrados por diagramas de dispersão com intervalos de 95% de normalidade. Foram calculadas as correlações de Pearson entre alguns parâmetros de interesse. RESULTADOS: Tanto na região distal do rádio como na tíbia, os parâmetros de DMO volumétrica, estrutura e de resistência óssea apresentaram relação estatisticamente significativa com a idade (p < 0,05). As correlações entre S com os demais parâmetros de DMO volumétrica e microarquitetura, bem como com DMO areal e TBS, foram mais fortes na região da tíbia, exceto com espessura trabecular, que foi melhor na região do rádio. As correlações entre TBS com os parâmetros de densidade (trabecular e cortical), número e espessura trabecular, e espessura cortical nas regiões periféricas, foram significativas (p < 0,05), exceto com espessura cortical na tíbia. Quando o TBS foi avaliado de acordo com a categoria de risco, e correlacionado com a rigidez do tecido na região distal do rádio e da tíbia, e com DMO da coluna lombar, apenas o grupo de baixo risco (TBS ³ 1.310) apresentou correlações significativas (p < 0,05). CONCLUSOES: Este trabalho estabeleceu valores de referência para os parâmetros ósseos obtidos por HR-pQCT, com base em uma população saudável miscigenada do sexo masculino. As correlações entre os parâmetros ajudam a compreender o papel de cada variável em relação ao risco de fratura. Pesquisadores e clínicos poderão utilizar esses dados como uma ferramenta adicional para avaliar a saúde óssea e alterações na qualidade óssea / INTRODUCTION: The availability of high resolution peripheral quantitative computed tomography (HR-pQCT) has made it possible to measure volumetric bone mineral density (BMD) and three-dimensional bone microarchitecture in vivo, as well as to evaluate bone strength through finite element (FE) analysis. As there is no database for Brazilian male population, the main objective of this cross-sectional study was to establish reference values for the bone parameters obtained by HR-pQCT in men, categorized for decades and adjusted for weight and height, of the distal radius and tibia. As a secondary objective, to correlate the bone strength parameter - stiffness (S) and other parameters measured by HR-pQCT and parameters obtained by dual-energy X-ray absorptiometry (DXA), including trabecular bone score (TBS). METHODS: Healthy Brazilian men (n = 340) including ages of 20 to 92 years were included in this study. The non-dominant forearm and left leg were immobilized, and standard and advanced segmentation methods were performed for the distal radius and tibia analyzes by HR-pQCT. From HR-pQCT images, volumetric BMD and bone microstructure of trabecular and cortical were evaluated, and bone strength was estimated using FE analysis. Measurements of the lumbar spine and femur by DXA were also performed to obtain BMD and TBS values. The data were described as median and quartiles (IQR). Multiple linear regression models according to age, weight and height were developed and illustrated by dispersion diagrams with 95% normality intervals. Pearson correlations were calculated between some parameters of interest. RESULTS: Parameters of volumetric BMD, structure and bone strength, at distal radius and tibia, showed a significant association with age (p < 0.05). The correlations between S with the other parameters of volumetric BMD and microarchitecture, as well as with areal BMD and TBS, were stronger in the tibia except for trabecular thickness, which was better in the distal radius. The correlations between TBS and density parameters (trabecular and cortical), number and trabecular thickness, and cortical thickness in the peripheral sites were significant (p < 0.05), except with cortical thickness in the tibia. When TBS was evaluated according to risk category, and correlated with S in the distal radius and tibia, and lumbar spine BMD, only the low risk group (TBS ³ 1.310) had significant correlations (p < 0.05). CONCLUSION: This work developed reference values for the bone parameters obtained by HR-pQCT, based on a healthy population for males. Correlations between the parameters support to understand the role of each variable and the relationship with fracture risk. Researchers and clinicians can use these data as an additional tool to assess male bone health and changes in bone quality

Das posttraumatische Hirnödem trägt zur erhöhten Morbidität und Mortalität Schädel-Hirn-traumatisierter Patienten bei. Das vasodilatierende Bradykinin führt als ein Bestandteil des Kallikrein-Kinin-Systems über Bradykinin-2 (B2)-Rezeptoren zu einer Öffnung der Blut-Hirn-Schranke und trägt damit zur Entstehung und Aufrechterhaltung des vasogenen bzw. zytotoxischen Hirnödems bei. Eine selektive Hemmung der B2-Rezeptoren konnte bereits die Ausbreitung des posttraumatischen vasogenen Hirnödems erfolgreich vermindern. Im ersten Teil der vorliegenden Arbeit wurde zunächst die Entwicklung des vasogenen Hirnödems, der hemisphäralen Schwellung und der Integrität der Blut-Hirn-Schranke im zeitlichen Verlauf bis 7 Tage nach Controlled Cortical Impact Injury (CCII) an Ratten anhand T2- und T1-gewichteter MRT-Bildgebung charakterisiert. Im zweiten Teil wurde eine mögliche therapeutische Wirkung des spezifischen B2-Antagonisten LF 16.0687 Ms auf das posttraumatische Ödem und der Blut-Hirn-Schrankenöffnung durch Anwendung von MRT- und gravimetrischer Methoden untersucht. In den T2-gewichteten Sequenzen kam es innerhalb von 90 Minuten nach CCII zum prozentual stärksten Anstieg der hemisphäralen Schwellung, ein Maximum lag zwischen 24 und 48 Stunden vor gefolgt von einer Abnahme bis 7 Tage danach. T1-gewichtete Aufnahmen zeigten ein durch die Extravasation von Gadolinium-DTPA erzeugtes Maximum der Kontrastverstärkung innerhalb des Läsionszentrums bereits 6 Stunden nach CCII, während die Kontrastverstärkung in der Ödemperipherie erst nach 48 Stunden Maximalwerte erreichte. Bei einer frühzeitigen Gabe des Kontrastmittels 90 Minuten nach CCII kam es im Verlauf zu einer signifikant höheren Kontrastverstärkung innerhalb der traumatisierten Hemisphäre, vermutlich durch eine Retention des extravasierten Kontrastmittels. Dies könnte für eine frühe Restitution der Blut-Hirn-Schranken Integrität innerhalb der Kontusion sprechen, während der Verschluß perikontusionell erst später erfolgt. LF 16.0687 Ms führte bei frühzeitiger Gabe nach CCII zu einer signifikanten Reduktion der gravimetrisch bestimmten posttraumatischen hemisphäralen Schwellung um 27%. Hierbei korrelierte die im MRT ermittelte hemisphärale Schwellung signifkant mit den gravimetrisch gemessenen Werten. / Posttraumatic brain edema contributes to a higher morbidity and mortality in severe head-injured patients. Vasodilatating bradykinin, part of the kallikrein-kinin-system, mediates over bradykinin 2 (B2) receptors an blood-brain-barrier (BBB) disfunction and causes the formation and maintenance of vasogenic and cytotoxic brain edema. A selective blocking of the B2 receptors has been shown to successfully reduce brain edema formation. One objective of this study was to analize the development of vasogenic brain edema, lesion-size, hemispheric swelling and BBB-integrity after controlled cortical impact injury (CCII) in rats over a period of 7 days using magnetic resonance imaging (MRI) techniques (T2- and T1-weighted MRI, Gadolinium-DTPA (Gd-DTPA)). The other purpose was to investigate the protective effect of the novel nonpeptide B2 receptor antagonist LF 16-0687 Ms on posttraumatic edema and BBB-opening using MRI- and gravimetric methods. T2-weighted imaging showed the highest percentual increase of hemispheric swelling during the first 90 minutes after CCII, a maximum between 24 and 48 hours after CCII and and a decrease after 7 days. T1-weighted imaging revealed a maximum of contrast enhancement caused by extravasation of Gd-DTPA in the lesion-center 6 hours after CCII, while contrast enhancement in the lesion periphery reached its maximum at 48 hours.After an early administration of Gd-DTPA (90 minutes after CCII) contrast enhancement in the traumatized hemisphere was significantly higher compared to the non-traumatized hemisphere. This could be explained by a retention of Gd-DTPA caused by an early closure of the BBB in the lesion-center, while BBB-integrity in the lesion-periphery re-establishes later. The novel nonpeptide B2 receptor antagonist LF 16-0687Ms significantly reduced brain swelling by 27% after single administration measured by gravimetric wet-dry-weighting. Gravimetric and T2-weighted MRI-measurements of hemispheric swelling correlated significantly.

Die Höhe des optimalen zerebralen Perfusionsdruckes nach schwerem Schädel-Hirn-Trauma wird kontrovers diskutiert. Während im sogenannten Lund-Konzept ein niedriger Perfusionsdruck angestrebt und die Gabe von Katecholaminen aufgrund potentieller zerebraler vasokonstringierender und weiterer Nebeneffekte vermieden wird, befürwortet das CPP-Konzept nach Rosner eine Anhebung des zerebralen Perfusionsdruckes, wenn notwendig unter intravenöser Gabe von Katecholaminen. Vor diesem Hintergrund galt es, in einem experimentellen Schädel-Hirn-Trauma- Modell der Ratte (Controlled Cortical Impact Injury) den Bereich des optimalen zerebralen Perfusionsdruckes nach traumatischer Hirnkontusion zu ermitteln und den Effekt von Katecholaminen auf den posttraumatischen zerebralen Blutfluss und die Entwicklung des sekundären Hirnschadens zu untersuchen. Die wesentlichen Ergebnisse dieser Arbeit lassen sich wie folgt zusammenfassen: In der Akutphase nach Hirnkontusion liegt der Bereich des zerebralen Perfusionsdruckes, welcher die Entwicklung des Kontusionsvolumens nicht beeinflusst, zwischen 70 und 105 mm Hg. Eine Senkung des Perfusionsdruckes unterhalb bzw. Anhebung oberhalb dieser Schwellenwerte vergrößert das Kontusionsvolumen. Die Anhebung des Blutdruckes mittels intravenöser Infusion von Dopamin oder Noradrenalin führt sowohl in der Frühphase als auch in der Spätphase nach Trauma (4 Stunden bzw. 24 Stunden nach kortikaler Kontusion) zu einem signifikanten Anstieg im kortikalen perikontusionellen Blutfluss und in der Hirngewebe-Oxygenierung. Die durch Anhebung des zerebralen Perfusionsdruckes auf über 70 mm Hg induzierte Verbesserung des posttraumatischen zerebralen Blutflusses bewirkte jedoch keine Reduzierung der Hirnschwellung. Für eine Katecholamin-induzierte zerebrale Vasokonstriktion nach kortikaler Kontusion gibt es keinen Anhalt. Um die Entwicklung des sekundären Hirnschadens nach kortikaler Kontusion zu minimieren, sollte der zerebrale Perfusionsdruck nach traumatischem Hirnschaden nicht unterhalb 70 mm Hg liegen. Eine Anhebung des Perfusionsdruckes auf über 70 mm Hg erscheint nicht notwendig oder vorteilhaft zu sein. Wenn notwendig, kann sowohl in der Früh- als auch Spätphase nach Trauma der zerebrale Perfusionsdruck mittels intravenöser Gabe von Katecholaminen angehoben werden. / The optimum cerebral perfusion pressure after severe traumatic brain injury remains to be controversial. In the Lund concept a relatively low cerebral perfusion pressure is preferred, and administration of catecholamines is avoided due to potential catecholamine-mediated cerebral vasoconstriction and other side effects. In contrast, the CPP concept of Rosner recommends elevation of cerebral perfusion pressure, if needed by intravenous administration of catecholamines. Based on this, in an experimental model of traumatic brain injury of the rat (Controlled Cortical Impact Injury) the optimum range of cerebral perfusion pressure after traumatic brain contusion and the effects of catecholamines on posttraumatic cerebral perfusion and development of secondary brain injury were investigated. The most significant results can be summarized as follows: In the acute phase after brain contusion the range of cerebral perfusion pressure that does not affect the development of posttraumatic contusion volume was found to be between 70 and 105 mm Hg. Reduction of the cerebral perfusion pressure below or elevation above these thresholds increases contusion volume. Elevation of blood pressure by intravenous infusion of dopamine or norepinephrine during the early (4 hours) as well as late (24 hours) phase after trauma results in a significant increase in pericontusional blood flow and brain tissue oxygenation. The increase in cerebral blood flow by elevating cerebral perfusion pressure above 70 mm Hg did not decrease cerebral edema formation. There was no evidence of a catecholamine-induced cerebral vasoconstriction after cortical contusion. In order to minimize secondary brain injury after cortical contusion, cerebral perfusion pressure should not fall bellow 70 mm Hg. However, a further active elevation of cerebral perfusion pressure does not appear necessary or beneficial. If needed cerebral perfusion pressure can be elevated by administration of catecholamines in the early as well late phase after trauma.