Ce travail de thèse porte sur l’analyse et le traitement des signaux ultrasonores pour la caractérisation de l’os cortical. La première partie est dédiée à l’analyse des signaux acquis par un prototype de sonde de transmission axiale à 1 MHz. Nous montrons qu’une contribution arrivant après le premier signal présente un intérêt pour la caractérisation ultrasonore de l’os cortical. En effet, cette contribution évaluée sur des radius humains in vitro est associée à une onde de flexion propagée dans l’os qui est dépendante de l’épaisseur corticale. L’analyse de cette contribution a nécessité le développement d’une technique de séparation d’ondes. Cette contribution étant plus basse fréquence que le premier signal et associée à un mode de propagation différent, nous montrons ainsi qu’une analyse plus poussée du signal peut permettre une approche multi-modes/multi-fréquences. Dans une seconde partie, nous montrons l’intérêt de l’évaluation de l’atténuation ultrasonore pour la caractérisation de l’os cortical. Lors d’une étude expérimentale in vitro sur des échantillons corticaux bovins, nous montrons la dépendance d’un paramètre d’atténuation aux propriétés osseuses et à la micro-structure. De plus, ce paramètre semble plus sensible aux propriétés osseuses que ne l’est la vitesse de l’onde longitudinale. Ainsi, l’atténuation évaluée en complément de la vitesse pourrait permettre de caractériser de manière plus complète l’os cortical / This work deals with the ultrasonic characterization of cortical bone. In a first part, the signals acquired with a 1-MHz axial transmission device are analyzed. A later contribution occuring after the first arriving signal is studied after the application of a wave separation procedure. This contribution is shown to be of interest for the ultrasonic characterization of cortical bone. Indeed, experiments performed in vitro on human radii show that this contribution is associated with a flexural wave guided which is dependent on the cortical thickness. In addition, this contribution has a lower frequency content than the first arriving signal and is associated with a different propagation mode. Therefore, a more thorough analysis of the ultrasonic signals enables a multi-modal/multi-frequency approach. In a second part, the ultrasonic attenuation is evaluated in an in vitro experimental study on bovine cortical bone samples. Ultrasonic attenuation is shown to be dependent on bone properties and micro-structure. Furthermore, this parameter seems to be more sensitive than the longitudinal wave velocity to bone parameters. Attenuation, in combination with ultrasonic wave velocity, is of interest and may provide a more comprehensive characterization of cortical bone

La navigation et les modes de déplacement intéressent la communauté scientifique depuis maintenant près d'un demi siècle. Cependant, l’augmentation de l’incidence des troubles dégénératifs du système nerveux central chez l’homme rend plus prégnante la nécessité de compréhension de la navigation et de l’influence du temps sur celle-ci. S'il est connu chez l'homme comme chez le rongeur que l'avancée en âge affecte les capacités à se déplacer dans de vastes environnements, peu de données sont disponibles quant aux processus cognitifs impliqués dans ce type de comportement et leurs éventuelles modulations avec l'âge. La définition des stratégies utilisées, l’incidence respective des mécanismes allocentriques et égocentriques, la capacité de mise en œuvre d’une stratégie au moment demandé, lors d’un rappel à court ou à long délai, l’influence du temps qui passe sont autant de questions que nous avons abordées dans ce travail de thèse. Afin d’effectuer ces études, nous avons développé des tâches en environnements virtuels modélisés sur ordinateur et utilisé des tests neuropsychologiques nécessitant la mobilisation des compétences visuo-spatiales. Dans une première étude utilisant une épreuve de localisation spatiale, les résultats obtenus mettent en évidence chez les personnes âgées, une altération des aptitudes lors de la mise en œuvre d’une stratégie allocentrique, sans atteinte des performances égocentriques. La deuxième étude utilisant une version virtuelle du test de la piscine de Morris reconnu comme une tâche allocentrique chez le rongeur, conforte ces données. De façon similaire dans les deux études, les personnes âgées présentent une altération de la sélection et de l’exécution de la stratégie de déplacement qui s’avère optimale pour résoudre la tâche spatiale. Nous avons également mis en évidence une difficulté, chez ces mêmes participants, à utiliser une représentation mentale globale de l’espace, sans toutefois qu’il soit possible de distinguer si l’origine de cette difficulté vient d’une altération de la formation ou de la récupération de cette « carte cognitive ». Le temps pourrait également jouer son rôle de par le délai entre l'acquisition d'une information spatiale et le moment où il est nécessaire de l’utiliser à nouveau. En étudiant l’effet du délai sur la trace mnésique spatiale, nous avons observé que les sujets jeunes utilisant de façon prédominante une stratégie allocentrique voyaient leurs performances diminuer lors d’un rappel après quatre semaines alors que celles des sujets âgés restaient inchangées. Ceci soulève bien entendu la question de la différence d’encodage des informations entre les sujets jeunes et âgés, avec un versant plus détaillé chez les sujets jeunes, mais surtout s’intègre au sein du débat actuel sur l’existence d’une modification de la trace mnésique qui pourrait selon la théorie des traces multiples de la consolidation, évoluer vers un souvenir plus schématisé avec le délai. Les résultats d’une dernière étude dans laquelle nous manipulons le contexte environnemental de la piscine virtuelle de Morris, amène des arguments en faveur d’une « schématisation » du souvenir au cours de la consolidation, en mettant en évidence une absence de discrimination par les participants, d’un changement des repères spatiaux lors d’un rappel de l’information après six semaines de délai. Toutes ces données sont discutées dans le cadre du débat actuel de la consolidation, notamment sur la contribution de l’hippocampe dans le stockage et le rappel des informations anciennes. A la lumière de nos données, nous proposons une vue intégrative du fonctionnement de l’interface hippocampo-corticale lors des rappels après un court et long délai, en fonction de l’âge. / While the detrimental effects of human aging on cognitive functions are well documented, how normal aging affects spatial memory processing and the organization of recent and long-term memories remains unclear. What are the cognitive strategies used when confronted to spatial navigation in large environments? How are the selection and use of these strategies affected by aging? How are recent and long-term remote memories organized as a function of aging during systems-level consolidation? These are the questions we sought to address during the course of this Ph.D. thesis by developing a series of virtual environments aimed at assessing spatial navigation and memory performance in young adults and aged participants. In a first series of experiments, participants were tested for object location memory in a virtual environment (a medieval castle) that enabled shifts in spatial viewpoints between study and test. Aged participants exhibited poor performance relative to young adults only in the shifted view conditions, thus providing strong evidence for a decline in allocentric, but not egocentric, spatial memory. In contrast to young adults, aged participants exhibited difficulties in processing efficiently distal cues of the environment and were less prone to adopt allocentric strategies. Manipulations of the spatial layout of the environment led us to the conclusion that aging seems to preferentially interfere with the capacity to form or use mental representations built upon all pieces of the environmental features which typically, are never in full view in real world large-scale environments. In a second set of experiments, participants were tested in an ecologically-relevant virtual version of the Morris water maze which mimics that classically used in rodents. Aged participants performed more poorly compared to middle-aged and young adults and formed a more schematic spatial memory. They favoured a directional single cue-based strategy to locate the hidden platform contrasting with young adults who formed complex geometrical relationships between distal cues of the environment. A neuropsychological test battery confirmed that binding of unrelated items and abilities to mentally manipulate information were two processes involved in solving the water maze task. Thus, upon acquisition, aged participants had difficulties in forming experientially detailed cognitive maps and in binding unrelated features of the environment into a cohesive spatial memory, possibly indicative of altered hippocampal-frontal circuitry. We next proceeded to examine the organization of spatial memory as a function of time. Long-term memory assessed 4 weeks after acquisition revealed that performance decreased more rapidly in young adults compared to elderly participants, suggesting that the passage of time differentially affects the content of spatial memory, richly detailed spatial memories being more vulnerable to decay than schematic ones. This concept of memory transformation (i.e. memories are not stored in the cortex in their original form) was supported by findings of a last experiment in which we provide evidence that participants failed in detecting changes in the spatial layout of the pool as memories matured over time. All these findings are discussed in the context of the current debate about the concept of memory consolidation which opposes the standard model of memory consolidation to the multiple trace theory, two views which make different predictions about the contribution of the hippocampus to remote memory storage and retrieval. In light of our own findings, we attempt to propose an integrative view of the functioning of the hippocampal-cortical interface during recent and remote memory retrieval as a function of normal aging.

Ce travail est une contribution à la caractérisation mécanique de l’os cortical. Dansce cadre, les méthodes ultrasonores sont des outils puissants pour aider à cette caractérisation.Ainsi, les phénomènes de propagation d’ondes mis en jeu lors des mesurespar les techniques ultrasonores de transmission axiale à la fréquence centrale de 1 MHzsont modélisés. Des méthodes numériques basées sur la méthode des éléments finis sontmises en oeuvre pour résoudre les systèmes d’équations aux dérivées partielles associéesaux conditions aux limites et initiales pour des tissus dont le comportement est supposé(visco-)élastique, anisotrope et/ou hétérogène. L’analyse des résultats de simulation permetde discuter l’influence des divers paramètres, non seulement en termes de propriétésmatérielles mais aussi géométriques, sur la nature des ondes qui se propagent dans lestissus. Nous avons ainsi pu analyse l’impact de ces paramètres sur la vitesse du premiersignal laquelle est considérée comme un indice pertinent pour mesurer la qualité du tissuosseux. Toujours dans le but de caractériser le tissu osseux, et en particulier pour obtenirdes valeurs de propriétés matérielles aussi proches que possible de la réalité, nous avonsdéveloppé une nouvelle méthode basée sur les développements asymptotiques, du typehomogénéisation périodique, pour prédire les modules d’élasticité effective de l’os corticaldu tissu hétérogène. / This work provides some contributions to the mechanical characterization of corticalbone by using ultrasound. Thus, the wave propagation phenomena involved during themeasurements by the ultrasound axial transmission techniques at the the central frequencyof 1 MHz are modeled. The finite element method was used to solve the equations ofwaves propagating in bone tissues whose the behavior is assumed to be (visco)elastic,anisotropic and/or heterogeneous. The analysis of simulation results allows us to discusson the influence of various parameters (not only in terms of material properties butalso geometric features), on the nature of waves that propagates through the tissue. Wewere able to analyze the impact of these parameters on the velocity of the first arrivingsignal which is known as an appropriate index to measure the quality of bone tissue.Another aspect in characterizing the bone tissue has also been considered in which wehave developed a new method based on asymptotic expansions, periodic homogenizationtype, for predicting effective properties of elasticity of heterogeneous cortical bone tissue.

O desenvolvimento da estimulação magnética transcraniana (EMT) permitiu o estudo de potenciais evocados motores eliciados pela estimulação direta do córtex cerebral de forma não-invasiva. Foi observado que diferentes paradigmas de estimulação cortical por EMT apresentam diferentes padrões de resposta, que posteriormente foram associados ao funcionamento de circuitos corticais GABAérgicos e glutamatérgicos do córtex motor, compondo assim índices de excitabilidade cortical motora (ECM). Ademais, desvios da normalidade de tais índices foram encontrados em diversas condições clínicas, incluindo transtornos mentais como a esquizofrenia. O uso dessas medidas também auxiliou o desenvolvimento da estimulação transcraniana por corrente contínua (ETCC), técnica que se mostrou capaz de produzir efeitos neuromodulatórios no sistema nervoso central de forma segura e com mínimos efeitos adversos. Tal técnica vem apresentando possibilidades terapêuticas promissoras, como por exemplo, tendo sido observado sua eficácia no alívio de alucinações auditivas de indivíduos com esquizofrenia. O uso de ETCC para tratamento de sintomas negativos da esquizofrenia também pode vir a se mostrar uma abordagem eficaz, e a análise da ECM pode auxiliar no entendimento dos seus mecanismos de ação e atuar como possível preditor de resposta terapêutica. O objetivo do presente estudo é avaliar o perfil de ECM em um grupo de indivíduos com esquizofrenia, e as possíveis influências de um protocolo terapêutico utilizando ETCC sobre essas medidas. Com esse objetivo, foi selecionada uma coorte de sujeitos com esquizofrenia que participou em ensaio clínico randomizado e controlado com placebo (estimulação sham), tendo a ETCC como intervenção ativa alvo. A ECM foi mensurada na avaliação inicial dos sujeitos, assim como após a primeira sessão de ETCC, e quando da avaliação de desfecho primário. O protocolo terapêutico de ETCC envolveu a colocação de 2 eletrodos de área 5x7 cm, pólo anódico aplicado sobre região correspondente ao córtex pré-frontal dorsolateral esquerdo e pólo catódico aplicado sobre córtex de transição temporoparietal esquerdo; com intensidade de corrente de 2 mA, aplicada por 20 minutos. Cada sujeito foi submetido a 10 sessões no total. Encontramos que idade se correlacionou com diminuição da inibição intracortical, reproduzindo resultado previamente encontrado em indivíduos saudáveis. Acerca da modulação da ECM após sessão de ETCC, observamos que sujeitos submetidos à intervenção ativa apresentaram aumento da inibição intracortical no hemisfério estimulado, em oposição à ausência de mudança significativa da ECM nos sujeitos que receberam estimulação placebo. Os resultados sugerem que sessão de ETCC, utilizando os parâmetros aplicados neste estudo, levou ao aumento da inibição intracortical. Devido a evidências prévias de déficit de inibição intracortical em pessoas com esquizofrenia, é possível que o fenômeno observado represente mecanismo terapêutico da ETCC. É necessário verificar se tal efeito sobre a ECM acompanha medidas objetivas de resposta clinica. Caso isto se comprove, a ECM pode se tornar um valioso marcador de resposta terapêutica e evolução clinica em pacientes com esquizofrenia / The development of transcranial magnetic stimulation allowed the study of motor evoked potentials by applying direct stimuli to the brain cortex in a non-invasive fashion. Different stimulation protocols were observed to yield different response patterns, which were later associated with the functioning of cortical GABAergic and glutamatergic circuits, assembled as motor cortex excitability indices. Also, deviations from normality of such indices were observed in several clinical conditions, including mental disorders such as schizophrenia. The use of these measurements also helped the development of transcranial direct current stimulation (tDCS), a technique which was shown to promote neuromodulatory effects in central nervous system, with potential treatment applications. This technique has been used with success in the treatment of auditory hallucinations in patients with schizophrenia. The use of tDCS might also be effective in the treatment of negative symptoms of schizophrenia, and motor cortex excitability analysis might be used to clarify its physiological effects and act as a possible treatment response predictor. The aim of the present study is to evaluate the motor cortical excitability profile of individuals with schizophrenia, as well as possible influences of tDCS over these measurements. With this aim, we selected a cohort of subjects with schizophrenia who participated in a randomized placebo controlled clinical trial using transcranial direct current stimulation (and sham stimulation for placebo), and measuring motor cortical excitability during baseline evaluation, after the first stimulation session, and at the time of the primary outcome evaluation. The transcranial direct current stimulation protocol used in the present study involved the use of 2 electrodes of area 5x7 cm, anode placed over the region corresponding to the left dorsolateral prefrontal cortex, and cathode over the left cortical temporoparietal juntion. A current of 2 mA intensity was applied for 20 minutes. Each subject underwent a total of 10 sessions. We found that age was correlated to reduced intracortical inhibition, as has been previously found in healthy subjects. Regarding changes of motor cortical excitability following a transcranial direct current stimulation session, we observed that subjects that received the active stimulation displayed an increase in intracortical inhibition, as opposed to those who received sham stimulation, which did not present with any significant change. Results suggest that transcranial direct current stimulation session, using the parameters described in this study, led to an increase in intracortical inhibition. Given previous evidence of intracortical inhibition deficit in individuals with schizophrenia, it is possible that the observed phenomenon corresponds to a treatment mechanism of the electrical stimulation in this population. This need to be confirmed by comparing such changes in cortical excitability to objective measurements of clinical improvement. In case that is confirmed, measurement of motor cortical excitability may have a valuable application as a marker of treatment response and clinical outcome for patients with schizophrenia

Der Schlaganfall steht hinter den Herz- und Tumor-Erkrankungen an dritter Stelle aller Todesursachen. Der wichtigste Faktor für die Vermeidung dauerhafter Invalidität und die Wiederherstellung maximaler Lebensqualität ist die Verhinderung von sekundären Komplikationen. Dabei stellt die Infarktprogression eine der schwerwiegendsten Komplikationen dar. Im Rahmen dieser Arbeit konnte bei insgesamt 45 Patienten mit einem malignen Schlaganfall mittels serieller MRT-Aufnahmen bestimmt werden, ob eine Infarktprogression vorlag. Ein Schwerpunkt der Arbeit war es, die hämodynamische Antwort und die zeitliche und räumliche Ausbreitung von Spreading Depolarizationen (CSD) im Periinfarktgewebe von Patienten mit malignem Schlaganfall zu untersuchen. In dieser Studie konnte zum ersten Mal die zeitliche und räumliche Ausbreitung von CSDs und deren hämodynamische Kopplung am humanen Kortex gezeigt werden. In einer zweiten Substudie wurden mit Hilfe der zerebralen Mikrodialyse die Konzentrationen von Glutamat, Glukose, Laktat und Pyruvat im Periinfarktgewebe bestimmt. Damit sollte im Besonderen geklärt werden, ob es Unterschiede in den Konzentrationen bei Patienten mit Infarktprogression zu Patienten ohne Infarktprogression gibt. Zusammenfassend war ein bemerkenswerter Anteil von verzögerter Infarktprogression nach Dekompression bei Patienten mit malignem Schlaganfall assoziiert mit veränderten biochemischen Markern innerhalb der Periinfarktregion. Des Weiteren wurde untersucht, inwiefern CSDs mit einer veränderten Konzentration von Glutamat, Glukose, Laktat und Pyruvat einhergeht. Hierzu wurde eine Korrelation zwischen CSDs und den Mikrodialysekonzentrationen von Glutamat, Glukose, Laktat und Pyruvat erstellt. / Stroke is the third leading cause of death. The most important factor in preventing permanent disability and recovering quality of life is the prevention of secondary complications. Infarct progression is one of the most serious complications after stroke. In the present study we determined by volumetric analysis from serial magnetic resonance imaging in 45 patients with malignant hemispheric stroke whether an infarct progression was present or not. The next aim was to investigate the hemodynamic response pattern and spatiotemporal propagation of cortical spreading depolarization (CSD) in the peri-infarct region of malignant hemispheric stroke. For the first time, intraoperatively the spatiotemporal propagation of CSDs and their hemodynamic coupling in the human cerebral cortex was visualized. In a second study, the levels of glutamate, glucose, lactate and pyruvate in the peri-infarct region using cerebral microdialysis in patients with malignant stroke were investigated. In particular, it was necessary to clarify whether there are differences in the metabolic changes are associated with delayed infarct progression. In summary, we observed a notable proportion of delayed infarct progression after decompressive surgery in patients with malignant hemispheric stroke associated with a disarrangement of biochemical markers within the peri-infarct region. Furthermore I investigated how CSDs are associated with metabolic changes. For this, a correlation between CSD and the concentrations of glutamate, glucose, lactate and pyruvate was prepared.

Dans ce manuscrit nous proposons une architecture neuronale d'inspiration corticale, capable de développer un traitement émergent de type auto-organisation. Afin d'implémenter cette architecture neuronale de manière distribuée, nous utilisons le modèle de champs neuronaux dynamiques, un formalisme mathématique générique conçu pour modéliser la compétition des activités neuronales au niveau cortical mésoscopique. Pour analyser en détail les propriétés dynamiques des modèles de référence de ce formalisme, nous proposons un critère formel et un instrument d'évaluation, capable d'examiner et de quantifier le comportement dynamique d'un champ neuronal quelconque dans différents contextes de stimulation. Si cet instrument nous permet de mettre en évidence les avantages pratiques de ces modèles, il nous révèle aussi l'incapacité de ces modèles à conduire l'implantation des processus d'auto-organisation (implémenté par l'architecture décrite) vers des résultats satisfaisants. Ces résultats nous amènent à proposer une alternative aux modèles classiques de champs, basée sur un mécanisme de rétro-inhibition, qui implémente un processus local de régulation neuronale. Grâce à ce mécanisme, le nouveau modèle de champ réussit à implémenter avec succès le processus d'auto-organisation décrit par l'architecture proposée d'inspiration corticale. De plus, une analyse détaillée confirme que ce formalisme garde les caractéristiques dynamiques exhibées par les modèles classiques de champs neuronaux. Ces résultats ouvrent la perspective de développement des architectures de calcul neuronal de traitement d'information pour la conception des solutions logicielles ou robotiques bio-inspirées / In this work we propose a cortically inspired neural architecture capable of developping an emergent process of self-organization. In order to implement this neural architecture in a distributed manner, we use the dynamic neural fields paradigm, a generic mathematical formalism aimed at modeling the competition between the neural activities at a mesoscopic level of the cortical structure. In order to examine in detail the dynamic properties of classical models, we design a formal criterion and an evaluation instrument, capable of analysing and quantifying the dynamic behavior of the any neural field, in specific contexts of stimulation. While this instrument highlights the practical advantages of the usage of such models, it also reveals the inability of these models to help implementing the self-organization process (implemented by the described architecture) with satisfactory results. These results lead us to suggest an alternative to the classical neural field models, based on a back-inhibition model which implements a local process of neural activity regulation. Thanks to this mechanism, the new neural field model is capable of achieving successful results in the implementation of the self-organization process described by our cortically inspired neural architecture. Moreover, a detailed analysis confirms that this new neural field maintains the features of the classical field models. The results described in this thesis open the perspectives for developping neuro-computational architectures for the design of software solutions or biologically-inspired robot applications

Die Pathogenese der verzögerten ischämischen Defizite (VIND) nach Subarachnoidalblutung wird mit Produkten der Hämolyse in Zusammenhang gebracht. Topische Hirnsuperfusion mit einer artifiziellen cerebrospinalen Flüssigkeit (ACSF), die L-NA, einen NOS-Inhibitor, in Kombination mit einer erhöhten Kaliumkonzentration erhielt, hat bei der Ratte zu Ischämien geführt. Dieses Phänomen wurde als Cortical spreading ischemia (CSI) bezeichnet. Dabei scheint es während der neuronalen Depolarisation zu einer gestörten Kopplung zwischen cerebralem Metabolismus und Blutfluß zu kommen, die zu einer Vasokonstriktion und schließlich zur Ischämie führt. Die vorliegenden Arbeit beschäfftigte sich zum einen mit der Frage, ob Hämoglobin und hoch Kalium (35 mmol/l) auch zu CSIs führt,und ob es in Folge der CSIs zu cerebralen Parenchymschäden kommt. Methode: 24 Tieren wurde eine ACSF in den künstlich geschaffenen Subarachnoidalraum perfundiert. Diese ACSF enthielt eine erhöhte Kaliumkonzentration (K+ ) von 35 mmol/l und 2 mmol/l freies Hämoglobin (Hb). Unter dieser Versuchsanordnung kam es, als Antwort auf die neuronale Depolarisation, zu einem langandauernden massiven Abfall des rCBF in ischämische Bereiche, der sogenannten cortical spreading ischaemia (CSI). Zum Nachweis eines möglichen cerebralen Parenchymschadens durch die CSI wurden die Gehirne von 11 Versuchstieren histologisch untersucht. Von den 11 histologisch sowie immunhistochemisch gefärbten Hirnpräparaten wiesen 9 Hirne eine ausgeprägte cortikale Zellnekrose auf. Bei den Kontrolltieren, denen entweder nur die erhöhte K+ oder Hämoglobin in der ACSF superfundiert wurde, kam es nicht zum Auftreten von CSIs. und Anzeichen von nekrotischem Zelluntergang waren nicht zu sehen. Schlussfolge: Subarachnoidales Hb kombiniert mit hoch K+ fürt zur cortical spreading ischemia und in weiterer Folge zu ausgedehnten corticalen Infarkten. / The pathogenesis of delayed ischemic neurological deficits after subarachnoid hemorrhage has been related to products of hemolysis. Topical brain superfusion of artificial cerebrospinal fluid (ACSF) containing L-NA a NOS-inhibitor and high concentration of K+ has shown to induce ischemia in rats. Superimposed on a slow vasospastic reaction, the ischemic events represent spreading depolarisation of the neuronal-glial network that trigger acute vasoconstriction. The purpose of the present study was to investigate whether such spreading ischemias in the cortex could be caused also by the hemolysis products hemoglobin and K+ and whether such spreading cortical ischemias lead to brain damage. Methods: A cranial window was implanted in 24 rats. Cerebral blood flow (CBF) was measured using laser Doppler flowmetry, and direct current(DC)potentials were recorded. The ACSF was superfused topically over the brain. Rats were assigned to three groups representing ACSF composition. Analysis included classical histochemical and immunhistochemical studies. Superfusion of ACSF containing Hb combined with high concentration of K+ (35 mmol/L) reduced CBF gradually. Spreading ischemia in the cortex appeared when CBF reached 40 to 70% compared to baseline (which was 100%). This cortical spreading ischemia was characterized by sharp negative shift in DC, which preceded a steep CBF decrease that was followed by a slow recovery. In 9 of the surviving animals widespread cortical infarction was observed at the site of the cranial window and neighbouring areas in contrast to the findings in the two control groups. Conclusion: Subarachnoid Hb combined with high K+ causes cortical spreading ischemia and leads to widespread necrosis of the cortex.

Die Kopplung zwischen neuronaler Aktivität und cerebralem Blutfluss ist ein fundamentaler Prozess, der alle cerebralen Funktionen begleitet. Das Thema meiner Habilitation ist die Entdeckung einer neuen Ischämievariante, bei der neuronale Aktivierung eine cerebrale Ischämie auslöst, indem sich die Kopplung zwischen neuronaler Aktivierung und cerebralem Blutfluss umkehrt. Diese Umkehrung wird durch Produkte roter Blutkörperchen im Subarachnoidalraum hervorgerufen. Die eigentümlichste Eigenschaft dieser Ischämievariante ist ihre Wanderung im cerebralen Cortex gemeinsam mit der Welle neuronaler Aktivierung. Deshalb habe ich das Phänomen cortical spreading ischaemia genannt. Das vorgestellte tierexperimentelle Modell könnte für die verzögerten ischämischen neurologischen Defizite nach Subarachnoidalblutung Implikationen besitzen. Die Verbindung mit diesem klinischen Syndrom basiert auf: (a) der Induktion der cortical spreading ischaemia durch Produkte roter Blutkörperchen im Subarachnoidalraum, (b) der Übereinstimmung im Läsionsmuster mit corticalen ischämischen Infarkten, und (c) den therapeutischen Effekten von Nimodipin und mässiger hypervolämischer Hämodilution im klinischen Syndrom und im Tiermodell. Mit Hilfe dieses Modells ist es zum ersten Mal gelungen, experimentell die Hypothese zu bestätigen, dass Produkte roter Blutkörperchen eine cerebrale Ischämie induzieren können. Ich hoffe, dass das Modell dazu beitragen wird, neue Strategien bei der Behandlung von Patienten mit Subarachnoidalblutung zu entwickeln. / The coupling between neuronal activity and cerebral blood flow is a fundamental process, which underpins all cerebral functions. The topic of my Habilitation is the discovery of a new variant of ischaemia in which neuronal activation triggers a cerebral ischaemic event through the inversion of the coupling between neuronal activation and cerebral blood flow. This inversion occurs when red blood cell products are present in the subarachnoid space. The most distinct feature of this variant of ischaemia is its propagation in the cerebral cortex together with the wave of neuronal activation. Therefore, I named the phenomenon cortical spreading ischaemia . The presented animal model may have implications for the delayed ischaemic neurological deficits after subarachnoid haemorrhage. The link with this clinical syndrome has been based: (a) on the induction of cortical spreading ischaemia by red blood cell products in the subarachnoid space, (b) the correspondence between the characteristic patterns of the cortical ischaemic lesions, and (c) the therapeutic effects of nimodipine and moderate hypervolaemic haemodilution in clinical syndrome and animal model. With the aid of this model, it was possible to experimentally confirm the hypothesis that red blood cell products can induce cerebral ischaemia. I hope that the model will contribute to develop new strategies for the treatment of patients with subarachnoid haemorrhage.

Neste trabalho é proposto um modelo mecanobiológico de remodelagem óssea para a estimativa de variações, provocadas por perturbações mecânicas ou biológicas, na matriz de rigidez estrutural da escala macroscópica e na densidade mineral em uma região do osso. Na cooperação entre as áreas da saúde e da engenharia, como nos estudos estruturais de biomecânica no sistema esquelético, as propriedades mecânicas dos materiais devem ser conhecidas, entretanto os ossos possuem uma constituição material altamente complexa, dinâmica e variante entre indivíduos. Sua dinâmica decorre dos ciclos de absorção e deposição de matriz óssea na remodelagem óssea, a qual ocorre para manter a integridade estrutural do esqueleto e adaptá-lo aos estímulos do ambiente, sejam eles biológicos, químicos ou mecânicos. Como a remodelagem óssea pode provocar alterações no material do osso, espera-se que suas propriedades mecânicas também sejam alteradas. Na literatura científica há modelos matemáticos que preveem a variação da matriz de rigidez estrutural a partir do estímulo mecânico, porém somente os modelos mais recentes incluíram explicitamente processos biológicos e químicos da remodelagem óssea. A densidade mineral óssea é um importante parâmetro utilizado no diagnóstico de doenças ósseas na área médica. Desse modo, para a obtenção da variação da rigidez estrutural e da densidade mineral óssea, propõe-se um modelo numérico mecanobiológico composto por cinco submodelos: da dinâmica da população de células ósseas, da resposta das células ao estímulo mecânico, da porosidade óssea, da densidade mineral óssea e, baseado na Lei de Voigt para materiais compósitos, da rigidez estrutural. Os valores das constantes das equações dos submodelos foram obtidos de literatura. Para a solução das equações do modelo, propõe-se uma implementação numérica e computacional escrita em linguagem C. O método de Runge-Kutta-Dorman-Prince, cuja vantagem consiste no uso de um passo de solução variável, é utilizado no modelo para controlar o erro numérico do resultado do sistema de equações diferenciais. Foi realizada uma avaliação comparativa entre os resultados obtidos com o modelo proposto e os da literatura dos modelos de remodelagem óssea recentes. Conclui-se que o modelo e a implementação propostos são capazes de obter variações da matriz de rigidez estrutural macroscópica e da densidade mineral óssea decorrentes da perturbação nos parâmetros mecânicos ou biológicos do processo de remodelagem óssea. / This Master thesis addresses a mechanobiological model that estimates variations in the bone macroscopic stiffness matrix and mineral density caused by mechanical or biological disturbances in a bone site undergoing the bone remodeling phenomenon. In interdisciplinary studies in health and engineering sciences, as structural biomechanical studies of the skeleton, the mechanical properties of the materials must be known. However, the bone material is highly complex, displays a dynamic behavior and its characteristics vary among individuals. Its dynamic behavior results from the bone matrix deposition and resorption cycles of the bone remodeling phenomenon for the maintenance of the skeletal structural integrity and its adaptation to environmental stimuli, which can be biological, chemical or mechanical. As bone remodeling can change the quantities of the bone material, deviations in the bone mechanical properties are also expected. The literature reports mathematical models that can predict changes in the bone structural stiffness matrix promoted by mechanical stimuli, however, only the newest ones have explicitly included the biochemical processes from bone remodeling. Bone mineral density is an important parameter for the diagnosis of bone diseases, therefore, a mechanobiological numerical model of the bone remodeling phenomenon is proposed for the determination of changes in bone stiffness and mineral density. The method is composed of five modules, namely, bone cells population dynamics, response of bone cells to mechanical stimuli, bone porosity, bone mineral density and bone stiffness calculated by Voigt\'s Law for composite materials. The values of the constants for the equations of the modules were obtained from the literature. A numerical computational code written in C language was implemented, so that the equations of the model could be solved automatically. The Runge-Kutta-Dorman-Prince method, whose advantage is its variable solution step, solved the differential equations ensuring numerically controlled errors for the solutions. A benchmark analysis was conducted using the solutions of the proposed model and the latest bone remodeling models. The model, the numerical method and the code implementation estimated changes in the macroscopic structural stiffness matrix and mineral density of the bone caused by induced disturbances in the mechanical or biological parameters of the bone remodeling process.

A recuperação motora da mão é importante para a independência funcional de pacientes com acidente vascular cerebral (AVC). A estimulação magnética transcraniana (EMT) é uma técnica não invasiva que pode ser usada para avaliar a excitabilidade do córtex motor. O objetivo principal deste estudo foi avaliar a correlação entre as medidas de EMT (inibição intracortical, IIC; facilitação intracortical, FIC; período silente ipsilateral, Psil) e o desempenho motor em atividades relevantes para as atividades de vida diária, em indivíduos com AVC (grupo AVC) e boa recuperação motora, assim como em sujeitos sem AVC (grupo controle). As medidas foram realizadas no hemisfério afetado (HA) dos indivíduos com AVC e no hemisfério homólogo dos sujeitos do grupo controle. Os objetivos secundários foram: confirmar que a as medidas de EMT do grupo AVC seriam comparáveis às do grupo controle; investigar a relação entre as medidas de IIC ou FIC e o Psil nos dois grupos. Após avaliação de elegibilidade de 2298 sujeitos, 12 pacientes (seis homens) foram incluídos no grupo AVC com média (+- desvio-padrão) de idade 52,9 (+- 11,8) anos, pontuações na escala de AVC do National Institutes of Health de 2,6 (+- 1,8) e na subescala de avaliação do membro superior de Fugl-Meyer de 57,5 (+- 4,6). No grupo controle foram incluídos 10 indivíduos (seis homens) com média de idade 53,3 (+- 12,0) anos. Nos dois grupos, foram avaliados: desempenho no teste de Jebsen Taylor, força de preensão, limiar motor, IIC, FIC e Psil. O coeficiente de correlação de Spearman foi utilizado para avaliar a correlação entre medidas de desempenho motor e medidas de EMT, assim como para associações entre medidas de excitabilidade intracortical e Psil. Para comparação das medidas entre o grupo AVC e o grupo controle, foi utilizado o teste de Mann-Whitney. Foi encontrada uma correlação significativa (r = 0,68; p = 0,014) entre a força de preensão e a IIC no Grupo AVC, mas não no grupo controle (r= 0,16; p= 0,47). Não foram encontradas correlações estatisticamente significativas entre o desempenho no teste de Jebsen-Taylor e qualquer outra medida de excitabilidade nos dois grupos. Não houve diferenças estatisticamente significativas entre as medidas de EMT nos dois grupos (p > 0,05). Não houve correlação significativa entre as medidas de excitabilidade intracortical e o Psil no grupo AVC, mas houve correlação significativa entre aumento da IIC e maior duração do Psil no grupo controle (r=-0,8; p= 0,008). A FIC não teve correlação significativa com o Psil em quaisquer dos grupos. Esses resultados sugerem que a atividade gabaérgica no córtex motor primário do HA seja relevante para a força da mão parética em indivíduos com AVC. Além disso, confirmam a hipótese de que pacientes com boa recuperação motora apresentem padrões de excitabilidade cortical semelhante aos de indivíduos saudáveis. Finalmente, os resultados não corroboram a hipótese de que um mesmo grupo de interneurônios medeie a IIC do HA e a inibição inter hemisférica do hemisfério afetado para o hemisfério não afetado em indivíduos com AVC e bom desempenho motor, na fase crônica / Recovery of hand motor function is important for the functional independence of patients with stroke. Transcranial magnetic stimulation (TMS) is a non-invasive technique for assessment of motor cortex excitability. The main objective of this study was to evaluate the correlation between TMS measures (short-interval intracortical inhibition, SICI; intracortical facilitation, ICF and ipsilateral silent period, ISP) and motor performance in subjects with stroke and good motor recovery (stroke group) as well as in subjects without stroke (control group). Measurements were performed in the affected hemisphere of stroke subjects and in the homologous hemisphere of subjects in the control group. The secondary objectives were: to confirm that the SICI, ICF and ISP of the stroke group would be comparable to those of the control group; to investigate the relation between SICI or ICF and the ISP in the two groups. After assessment of eligibility in 2298 subjects, 12 patients (six men) were included in the stroke group. Mean (+- standard deviation) age was 52.9 (+- 11.8) years, National Institutes of Health Stroke Scale score was 2.6 (+- 1.8) and Fugl-Meyer upper limb subscale score was 57.5 (+- 4.6) in the stroke group. In the control group, 10 subjects (six men) were included with a mean age of 53.3 (+- 12.0) years. In the two groups, the Jebsen-Taylor test, grip strength, motor threshold, SICI or ICF and ISP were evaluated. The Spearman\'s correlation coefficient was used to assess the correlation between motor performance measures and TMS measures, as well as the associations between intracortical excitability measures and the ISP. The Mann-Whitney test was used to compare the measures between the stroke group and the control group. A significant correlation (r = 0.68, p = 0.014) was found between grip strength and SICI in the stroke group, but not in the control group (r = 0.16, p = 0.47). No statistically significant correlations were found between performance in the Jebsen-Taylor test and any other measures of excitability in the two groups. There were no statistically significant differences between the TMS measurements between the two groups (p > 0.05). There was no significant correlation between the SICI measures and the ISP in the stroke group, but there was a significant correlation between increased SICI and longer duration of the ISP in the control group (r=-0.8; p=0.008). ICF had no significant correlation with the ISP in any of the groups. These results suggest that increased gabergic activity in the motor cortex of the affected hemisphere is relevant for strength of the paretic hand in patients with stroke. Also, they confirm the hypothesis that patients with good motor recovery present patterns of cortical excitability similar to those of healthy subjects. Finally, the results do not support the hypothesis that the same group of interneurons mediate intracortical inhibition and interhemispheric inhibition of the unaffected hemisphere by the affected hemisphere in subjects with stroke and good motor performance in the chronic phase