Orientadores: Marcondes Cavalcante França Junior, Gabriela Castellano / Texto em português e inglês / Dissertação (mestrado profissional) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T20:36:08Z (GMT). No. of bitstreams: 1 Rezende_ThiagoJunqueiraRibeirode_M.pdf: 1634329 bytes, checksum: 78c3b3cb6bd66174acfe01359a6cb758 (MD5) Previous issue date: 2014 / Resumo: A doença de Machado-Joseph (SCA3/MJD) é a ataxia espinocerebelar mais frequente no mundo, resultante de uma expansão de tripletos CAG no gene MJD1 localizado no cromossomo 14q. Clinicamente ela é caracterizada por danos nos gânglios da base, tronco e cerebelo. Atualmente existem poucos estudos baseados em imagens de ressonância magnética (MRI) que investigam danos no córtex cerebral em pacientes com SCA3/MJD. O objetivo deste estudo foi investigar danos no córtex cerebral na SCA3/MJD usando MRI e correlacionar as possíveis áreas afetadas com dados clínicos, genéticos e neuropsicológicos. Foram recrutados para este estudo 49 pacientes com teste molecular de SCA3/MJD e 49 controles sadios. Os pacientes foram avaliados com a escala de ataxia SARA. Imagens de MR ponderadas em T1 foram adquiridas para todos os voluntários e usadas para a extração das medidas de espessura cortical, realizadas com o software FreeSurfer. O tamanho da expansão CAG médio, SARA e idade de início foram 72,1±4,2, 14,7±7,2 e 37,5±12,5, respectivamente. Os pacientes apresentaram redução de espessura nos córtex precentral e paracentral bem como nos hipocampos e lobos temporal e occipital. Também encontramos redução volumétrica no cerebelo, tálamo, caudado, putamen, globo pálido, tronco e diencéfalo ventral. A gravidade da doença apresentou correlação negativa com a espessura do giro precentral esquerdo (r=-0,302, p=0,035) e com o volume do tronco (r=-0,414, p=0,003). A espessura do giro angular direito apresentou correlação com a duração da doença (r=0,587, p=0,001), mas não com a expansão do tripleto de CAG. O subteste de semelhança de WAIS III apresentou uma correlação com a espessura do sulco central esquerdo (r=0,752, p=0,004) e como o giro occipital superior direito (r=0,704, p=0,016). Estes resultados sugerem que pacientes com SCA3/MJD apresentam dano cortical e subcortical difuso. Os achados estruturais se correlacionaram com as manifestações clínicas da doença, o que apoia a hipótese que a piora nas funções motora e cognitiva e o dano cerebral estão relacionados na SCA3/MJD / Abstract: Machado-Joseph disease (SCA3/MJD) is the most frequent spinocerebellar ataxia worldwide caused by an abnormal expansion of a CAG triplet at the MDJ1 gene located on chromosome 14q. Clinically, it is characterized by brainstem, basal ganglia and cerebellar damage. There are few MRI-based studies that investigated cerebral cortex damage in SCA3/MJD. The objectives of this study are to investigate cerebral cortex damage in SCA3/MJD and to correlate affected areas with clinical, genetics and neuropsychological data. We included 49 patients with molecular confirmation of SCA3/MJD and 49 healthy controls. The scale for assessment and rating of ataxia (SARA) was employed to quantify disease severity. We also performed a comprehensive neuropsychological battery to assess cognitive deficits. Volumetric T1 magnetic resonance images of the brain were acquired for all volunteers and used to calculate cortical thickness measures, performed using the FreeSurfer package. Mean CAG expansion, SARA score and age-at-onset were 72.1±4.2, 14.7±7.2 and 37.5±12.5, respectively. Patients had atrophy at precentral and paracentral cortices as well as the hippocampi, temporal and occipital lobes. We also found volumetric reduction of the cerebellum, thalamus, caudate, putamen, pallidum, brainstem and ventral diencephalon. SARA scores inversely correlated with left precentral gyrus thickness (r=-0.302, p=0.035) and brainstem volume (r=-0.414, p=0.003). Right angular gyrus thickness correlated with disease duration (r=0.587, p=0.001), but not (CAG) expansion. Similarity subscore of WAIS III presented a correlation with thickness of Left central sulcus (r=0.752, p=0.004) and Right superior occipital gyrus (r=0.704, p=0.016). Therefore, patients with MJD/SCA3 have widespread cortical and subcortical atrophy. These structural findings correlate with clinical manifestations of the disease, which support the concept that cognitive/motor impairment and cerebral damage are related in MJD/SCA3 / Mestrado / Fisiopatologia Médica / Mestre em Ciências

Les données biomécaniques sur les enfants sont rares et difficiles à obtenir lors d'expérimentations. Cette recherche s'intéresse à l'évaluation in vivo du comportement mécanique du tronc et des propriétés mécaniques de l'os cortical des côtes. Le comportement mécanique in vivo du tronc de l'enfant et de l'adulte sous charge pendant des manipulations de kinésithérapie respiratoire ont été étudiées. Trois formes typiques de courbes de force en fonction du déplacement ont été observées. Un plus grand décalage en temps entre les courbes de force en fonction du temps et les courbes de déplacement en fonction du temps ont été observés plus fréquemment chez les enfants que chez les adultes, ce qui conduit à différentes formes de courbes de force en fonction du déplacement entre les enfants et les adultes. Parmi les paramètres qui peuvent affecter le comportement mécanique du tronc, les propriétés mécaniques de l'os cortical des côtes ont été étudiées. Dans un premier temps, il a été constaté ex vivo que les propriétés mécaniques de l'os cortical des côtes des adultes sont liées de façon linéaire à la Densité Minérale Osseuse (DMO) mesurée par la tomodensitométrie quantitative (Quantitative Computed Tomography, QCT) et la tomographie périphérique quantitative à haute résolution (High Resolution Peripheral Quantitative Computed Tomography, HR-pQCT). La DMO peut être mesurée par QCT in vivo. Ensuite, les relations entre la DMO et les propriétés mécaniques pour l'adulte ont été appliquées aux enfants, et les propriétés mécaniques de l'os cortical de l'enfant ont pu être estimées. Les propriétés mécaniques ont été trouvées plus élevées dans la partie latérale des côtes que dans les régions antérieures et postérieures. Il a également été constaté que les propriétés mécaniques augmentent au cours de la croissance. Il s'agite la première étude qui a évalué les propriétés des matériaux de l'os cortical des côtes de l'enfant in vivo. Cette étude peut aider à mieux comprendre la réponse mécanique du tronc de l'enfant et les propriétés mécaniques de l'os cortical costal. À court terme, ces résultats mesurés in vivo seront considérés dans des modèles éléments finis du tronc de l'enfant / Biomechanical data on children, both mechanical behaviors and tissue properties, are rare and difficult to be obtained through biomechanical experiments. This thesis mainly discussed the mechanical behavior of pediatric trunk and mechanical properties of pediatric rib cortical bones in vivo. The mechanical responses of the living and active pediatric and adult trunks during in vivo loading tests were investigated. Three typical shapes of force-displacement curves were observed. Larger time lags between force time histories and displacement time histories were observed more frequently in children than adults, resulting in different shapes of force-displacement curves between children and adults. To better understand the mechanical behavior of pediatric trunk, rib cortical bone mechanical properties were studied. It was found that mechanical properties of adult rib cortical bones were linearly related to Bone Mineral Density (BMD) measured by Quantitative Computed Tomography (QCT) and High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT). The BMD could be measured by QCT in vivo. Then, the mechanical property-BMD relationships were introduced to child population, and the mechanical properties of pediatric rib cortical bones were estimated. The mechanical properties were found higher in the lateral part of the ribs than the anterior and posterior regions. It was also found that the mechanical properties were growing during the growth of children. This is the first study which estimated the material properties of pediatric rib cortical bones in vivo. This study can help to better understand the mechanical response of pediatric trunk and mechanical properties of pediatric rib cortical bones. These results measured in vivo could contribute to improve the biofidelity of pediatric modeling

Pour comprendre comment le cortex cérébral extrait du sens et produit des actions à partir des informations sensorielles, il est nécessaire de comprendre à la fois son architecture et ses états dynamiques. Dans la présente thèse nous avons abordé cette relation structure-fonction au niveau des aires cérébrales, leurs connections et leurs interactions au sein du réseau cortical. Les aires sont connectées entre elles par deux grands types de projections axonales. D'une part, les connections « feedforward » (littéralement « antéroactives ») transmettent l'information des aires sensorielles aux aires de plus haut niveau dans la hiérarchie corticale et dont l'activité sous-tend des représentations plus abstraites. À l'inverse, les connections feedback (rétroactives) relient des aires dans la direction descendante de la hiérarchie corticale, vers les aires sensorielles primaires. Pour explorer les rôles respectifs des connections feedforward et feedback nous avons utilisé une triple approche. Premièrement, nous avons mis en évidence une asymétrie fonctionnelle très nette entre propagation feedforward et feedback grâce à des enregistrements et de la microstimulation électrique dans les aires V1 et V4 de macaques en comportement. D'autre part, nous avons étudié les propriétés globales du réseau cortical grâce à une riche base de données de connectivité basée sur des injections de traceurs fluorescents, et décrit une propriété générale et fondamentale de l'organisation corticale. Enfin, nous avons combiné des propriétés anatomiques des aires corticales et les données de connectivité dans un modèle dynamique à grande échelle du cortex / To understand how the cerebral cortex does what it does, it is necessary to elucidate both how its dynamic states are correlated with the functions it performs, and how it is organised. Many functional and anatomical gradients have been described that reflect the hierarchical abstraction at the heart of cortical computation. It was showed that two flavours of cortical connections exist, and that in the visual cortex they happen to transport information in opposite directions along this gradient. It was also hypothesised that other modalities exhibit the same type of gradient in their respective domains. However, studying requires knowledge of the architecture at different levels (such as the cortical column) and a causal understanding of the functional properties of these types of connections. First, we have studied the dynamics of both feedforward and feedback propagation in the visual system of awake, behaving macaque monkeys. Using the causal method of electrical microstimulation and recording, we have found a dynamic signature of each type of projections and an asymmetry in the way each type of input interacts with ongoing activity in a given visual area. Secondly, thanks to a rich and systematic data set in the macaque, we have found a fundamental organisational principle of the embedded and weighted cortical network that holds also in the more detailed level of neuronal connections inside an area. Finally, we have combined known anatomical gradients with actual inter-areal connectivity into a dynamic model, and here we show how it relates to both the ordering of areas along a hierarchical gradient and the wiring diagram of the cortical network

Dans ce travail, la nanoindentation et la Microscopie à Force Atomique ont été utilisées pour déterminer les caractéristiques mécaniques et morphologiques de l'os cortical aux échelles micro et nanoscopique. Les propriétés mécaniques qui dépendent du temps, élastique et plastique ont été quantifiées par nanoindentation en utilisant une méthode spécifique. Les essais ont été réalisés sur trois différentes espèces d'os cortical. Dans un premier temps, l'os du rat fut utilisé pour quantifier l"évolution des propriétés mécaniques de la croissance à la sénescence. La variation des propriétés mécaniques avec l'âge fut démontrée et sa corrélation avec les propriétés physico-chimiques établie. Les équations de prédiction ont été proposées afin de décrire le comportement mécanique puis pour quantifier un âge de maturation apparent pour chaque propriété. Dans un deuxième temps, le comportement mécanique qui dépend du temps a été examiné sur l'os humain. Les systèmes Haversiens avec différents contenus du minéral furent identifiés à partir d'images ESEM. Les résultats démontrent l'hétérogénéité mécanique des systèmes Haversiens et l'influence des propriétés mécaniques qui dépendent du temps sur l'anisotropie de l'os. Enfin, l'os bovin fut utilisé pour quantifier les effets mécaniques et morphologiques du processus de déminéralisation. Le résidu organique de l'os déminéralisé présente un comportement mécanique quasi-isotrope. Les images AFM montrent que les fibres de collagène sont orientées dans une direction privilégiée. Les données obtenues pourront servir à développer des matériaux biomimétiques et à établir des lois de comportement multi-échelles de l'os cortical. / Bone is a dynamical, anisotropic, hierarchical, inhomogeneous and time-dependent biological material. At the micro and nano scales, their mechanical and structural characterizations are still being a challenging topic. Nanoindentation and Atomic Force Microscopy are used to assess the mechanical and morphological characteristics of cortical bones. Time-dependent, elastic and plastic mechanical properties were computed using the nanoindentation method proposed by (Mazeran et al., 2012). Experiments were performed on different species of bones for different conditions. Wistar rat femoral cortical bone was used to assess the evolution of the mechanical properties in a life span model (from growth to senescence). The variation of the mechanical properties with age was evidenced and their correlation with physico-chemical properties was established. Then, prediction equations were proposed to describe these behaviours. From these equations, it is possible to estimate an apparent maturation age for each mechanical property. Our findings suggest maturation age is earlier and growth rate are higher for elastic properties than for time-dependent mechanical properties. Time-dependent mechanical behaviour of Human femoral cortical bones were assessed considering its heterogeneity. Haversian systems with different apparent mineral content were identified by means of their apparent grey levels obtained from ESEM images. Results prove the mechanical heterogeneity of the Haversian systems and highlight the influence of the time-dependent mechanical properties in the anisotropic behaviour of bone. Bovine femoral cortical bone was used to quantify the mechanical and morphological effects of the demineralization process. Bone seems to have a quasi-isotropic mechanical behaviour after mineral loss. AFM images of the remaining organic components show that collagen fibrils are oriented in a possible privileged direction. According to our knowledge, few investigations have been performed simultaneously on mechanical, morphological and physico-chemical properties of bone. All these results provide a better understanding of the interactions of the collagen-mineral matrix, bone remodelling and their influence especially in the time-dependent mechanical response. Data reported in this work could be useful to develop and to improve multi-scale bone models and multi-scale constitutive laws for cortical bone.

Children with focal intractable epilepsy caused by MCD, FCD and TSC are in a high risk of development of cognitive delay, as a result of both drug resistant epilepsy and genetically determined abnormal structure of the neuronal networks. Epilepsy surgery represents an established and safe treatment method of focal drug resistant epilepsy, and increases the chances for these patients to be rid of epileptic seizures, anti-epileptic medication and cognitive comorbidities. Current data on genetic background of focal MCD and FCD and their comorbidities provide space to expand the diagnostic process in epilepsy surgery candidates. However, available information on genetic causes of MCD and FCD do not allow us to infer prognostic estimates on chances of seizure freedom and optimal cognitive development. Future studies should elucidate these uncertainties.

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The main goal of the dissertation was to determine task-dependent modulation of corticospinal descending output. From this main goal, I conducted three different studies to determine how corticospinal output to muscles of the upper arm and hand changed as a function of the task demands. In study 1, I examined how a somatosensory-motor circuit changes when a muscle needs to be active in a task and found that this circuit may be dependent on the movement phase, type of afferent input, and the task demands. In study 2, I examined how this same somatosensory-motor circuit acts to both allow and prevent muscle activity before movement. I revealed that this somatosensory-motor circuit may function to prevent muscle activity when a muscle is not needed in a task and creates facilitation of corticospinal output when it needs to be active in a task. These effects, however, are dependent on the movement phase and the digit the muscle is controlling. Study 3 determined how corticospinal output is modulated to upper arm muscles when performing movements that required different combinations of segmental interactions to achieve the task successfully. Corticospinal output was increased when inertia and the BBC moment at a joint resisted the intended joint rotation and these effects were dependent on the muscle and movement phase. I propose a model of the connectivity between the primary motor and somatosensory cortices that would increase, modulate, or decrease corticospinal output to a muscle depending on its role in the task. The findings from this work provides information to guide future neural rehabilitative interventions for individuals who have movement disorders arising from altered somatosensory-motor processing such as Cerebellar Ataxia, Developmental Coordination Disorder, Focal Hand Dystonia, Parkinson’s disease, and stroke. / Dissertation / Doctor of Philosophy (PhD) / On a day to day basis, we perform a variety of movements without giving much thought to how complicated it is for our nervous system to perform said movements. There are many different areas of the brain that are responsible for controlling movement. This dissertation focuses on two key areas that are critical for movement performance, namely the primary motor and somatosensory cortices. The primary motor cortex is largely responsible for sending signals to the muscles to control movement, while the primary somatosensory cortex plays a crucial role in receiving and understanding sensory input from our body. The studies in this dissertation describe how these two areas of the brain communicate during finger and arm movements to produce or prevent muscle activity. This work has implications for individuals with disorders that impact their everyday movements.

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