INTRODUÇÃO: Os transtornos mentais psicóticos são condições frequentes na população geral e estão associados a grande morbidade e disfuncionalidade. Apesar disso, as bases fisiopatológicas destes transtornos ainda estão em investigação. Estudos neuropatológicos post-mortem e de neuroimagem in vivo sugerem haver comprometimento da microestrutura de substância branca (SB) cerebral nestas condições clínicas, associado a alterações da conectividade cerebral. No entanto, nenhuma investigação prévia de neuroimagem avaliou especificamente se tais anormalidades microestruturais podem ser dependentes do estado clínico do paciente, i.e., se tais alterações podem variar de acordo com a fase da doença. Outra linha de investigação biológica em psicoses aponta para alterações na atividade da fosfolipase A2 (PLA2), uma enzima essencial a diversas funções na homeostase cerebral, incluindo manutenção de membrana celular, mielinização e atividade inflamatória. Estudos prévios sugerem haver relação entre alterações na atividade desta enzima e as fases da esquizofrenia. Entretanto, não há estudos translacionais que tenham avaliado como tais alterações se relacionam com anormalidades microestruturais de SB em pacientes psicóticos. OBJETIVOS: Investigar a hipótese de que alterações de microestrutura de SB presentes em pacientes em fase aguda do primeiro episódio psicótico (PEP) sejam potencialmente reversíveis após estabilização clínica; investigar também possíveis alterações estado-dependentes da atividade de PLA2 no PEP; e examinar interações entre manifestações clínicas, microestrutura de SB cerebral e atividade de PLA2 na fisiopatologia do PEP. METODOLOGIA: Pacientes em PEP não afetivo foram avaliados em dois períodos no tempo: durante a fase aguda da doença (T0); após remissão estável de sintomas (T1). Um grupo controle de voluntários saudáveis (CS) também foi avaliado longitudinalmente. Para investigar alterações de microestrutura de SB estado-dependentes, análises voxel-a-voxel de mapas cerebrais de índices de anisotropia (fractional anisotropy, FA) e difusividade (trace, TR) foram conduzidas, assim como o cálculo de correlações entre tais índices de DTI, variáveis clínicas e atividade de PLA2. A atividade dos três principais subgrupos de PLA2 em plaquetas foi estimada através de um método radioenzimático. RESULTADOS: 25 pacientes PEP e 51 CS foram avaliados em T0, com coleta de dados clínico-demográficos, ressonância magnética (RM) e amostra de sangue. Destes, 21 PEP e 36 CS realizaram a segunda aquisição de RM. No baseline (T0), os pacientes PEP apresentaram redução difusa de FA (p < 0,05, FDR), afetando principalmente SB fronto-límbica e fascículos associativos, projetivos e comissurais. As análises longitudinais demonstraram que a remissão clínica se associou a aumentos de FA em tratos de SB acometidos em T0 (p < 0,001, não corrigido), além de robustas correlações inversas entre aumentos de FA e redução sintomas ao longo do tempo (p < 0,05, FDR). As análises de PLA2 não demostraram efeitos estado-dependentes ou correlações consistentes com os índices de DTI. CONCLUSÃO: Alterações da microestrutura de SB afetando tratos cerebrais essenciais para a integração de informação perceptual, cognição e emoções são detectáveis logo após o início do PEP e podem ser parcialmente revertidas em relação direta com a remissão de sintomas psicóticos agudos. Nossos achados reforçam a visão de que anormalidades de SB de tratos cerebrais são um componente neurobiológico central nos transtornos psicóticos agudos, e que a recuperação de tal patologia de SB pode levar à melhora clínica. Por outro lado, a atividade de PLA2 não parece ter associação direta com o estado de doença ou moderar as alterações microestruturais dinâmicas de SB aqui observadas. Estudos com amostras maiores e com um maior número de avaliações ao longo do tempo são necessários para confirmar e ampliar os resultados aqui apresentados / INTRODUCTION: Psychotic disorders are frequent conditions in the general population and are associated to severe morbidity and functional impairment. Notwithstanding, the pathophysiological basis of such disorders is still under investigation. Post-mortem neuropathologic investigations and in vivo neuroimaging studies have pointed to the occurrence of abnormalities in the microstructure of brain white matter (WM) in such clinical conditions, which are associated to changes in brain connectivity. However, no previous neuroimaging investigation has specifically examined whether such microstructural abnormalities would be state-dependent, i.e., whether such changes could relate to the illness phase. Another field of biological investigation in psychosis points to changes in the activity of phospholipase A2 enzyme (PLA2), which is essential to several functions implicated in brain homeostasis, such as the maintenance of cellular membrane, myelination and inflammatory activity. Previous studies suggest the existence of a relationship between changes on PLA2 activity and schizophrenia phase. Nonetheless, no translational study to date has examined the potential interplay between PLA2 activity and WM microstructural abnormalities in psychotic patients. OBJECTIVES: To investigate the hypothesis that WM microstructural changes observed in patients during the acute first-episode psychosis (FEP) are potentially reversible following clinical remission; to investigate possible state-dependent changes in PLA2 activity in FEP; and to examine interactions between clinical manifestations, brain WM microstructure and PLA2 activity in the pathophysiology of FEP. METODOLOGY: Patients with non-affective FEP were evaluated in two time points: during the acute phase (T0) and following sustained remission (T1). A control group of healthy volunteers (HC) was also longitudinally studied. In order to investigate state-dependent WM microstructure changes, voxelwise analyses of brain maps of anisotropy (fractional anisotropy, FA) and diffusivity (trace, TR) indexes were conducted, as well as correlations between such DTI metrics, clinical variables and PLA2 activity. The activity of the three main PLA2 subgroups was assessed in platelets using a radioenzymatic method. RESULTS: 25 FEP and 51 HC were evaluated at T0 (clinical and demographic data, MRI scanning, and blood collection). Out of these, 21 FEP and 36 HC also underwent a second MRI acquisition. At baseline (T0), FEP patients presented widespread reduction of FA (p < 0.05, FDR), affecting mainly fronto-limbic WM and associative, projective and commissural fasciculi. Longitudinal analyses showed that clinical remission was associated with FA increase in WM tracts that were affected at T0 (p < 0.001, uncorrected), besides robust inverse correlations between FA increase and symptoms reduction over time (p < 0.05, FDR). PLA2 analyses failed to show state-dependent effects or consistent correlations to DTI indexes. CONCLUSION: WM changes affecting brain tracts critical to the integration of perceptual information, cognition and emotions are detectable soon after the onset of FEP and may partially reverse in direct relation to the remission of acute psychotic symptoms. Our findings reinforce the view that WM abnormalities are a key neurobiological feature of acute psychotic disorders, and that recovery from such WM pathology can lead to amelioration of symptoms. In the other hand, it seems that PLA2 activity has no direct relationship to the disease state or modulatory effects on the dynamic WM changes observed herein. Studies with larger samples and with more time points evaluations are necessary to confirm and expand the findings reported herein

Diffusion-weighted magnetic resonance imaging (MRI) has allowed unprecedented non-invasive mapping of brain neural connectivity in vivo by means of fiber tractography applications. Fiber tractography has emerged as a useful tool for mapping brain white matter connectivity prior to surgery or in an intraoperative setting. The advent of high angular resolution diffusion-weighted imaging (HARDI) techniques in MRI for fiber tractography has allowed mapping of fiber tracts in areas of complex white matter fiber crossings. Raw HARDI images, as a result of elevated diffusion-weighting, suffer from depressed signal-to-noise ratio (SNR) levels. The accuracy of fiber tractography is dependent on the performance of the various methods extracting dominant fiber orientations from the HARDI-measured noisy diffusivity profiles. These methods will be sensitive to and directly affected by the noise. In the first part of the thesis this issue is addressed by applying an objective and adaptive smoothing to the noisy HARDI data via generalized cross-validation (GCV) by means of the smoothing splines on the sphere method for estimating the smooth diffusivity profiles in three dimensional diffusion space. Subsequently, fiber orientation distribution functions (ODFs) that reveal dominant fiber orientations in fiber crossings are then reconstructed from the smoothed diffusivity profiles using the Funk-Radon transform. Previous ODF smoothing techniques have been subjective and non-adaptive to data SNR. The GCV-smoothed ODFs from our method are accurate and are smoothed without external intervention facilitating more precise fiber tractography. Diffusion-weighted MRI studies in amyotrophic lateral sclerosis (ALS) have revealed significant changes in diffusion parameters in ALS patient brains. With the need for early detection of possibly discrete upper motor neuron (UMN) degeneration signs in patients with early ALS, a HARDI study is applied in order to investigate diffusion-sensitive changes reflected in the diffusion tensor imaging (DTI) measures axial and radial diffusivity as well as the more commonly used measures fractional anisotropy (FA) and mean diffusivity (MD). The hypothesis is that there would be added utility in considering axial and radial diffusivities which directly reflect changes in the diffusion tensors in addition to FA and MD to aid in revealing neurodegenerative changes in ALS. In addition, applying adaptive smoothing via GCV to the HARDI data further facilitates the application of fiber tractography by automatically eliminating spurious noisy peaks in reconstructed ODFs that would mislead fiber tracking.

No description available.

A lesão do plexo braquial é considerada a alteração neural mais grave das extremidades. A principal causa é o trauma de alta energia, especialmente acidentes envolvendo veículos a motor. Por este motivo, as lesões traumáticas do plexo braquial são cada vez mais frequentes. O presente estudo avaliou a acurácia da ressonância magnética (RM) no diagnóstico das lesões traumáticas do plexo braquial no adulto, utilizando o achado intraoperatório como padrão-ouro. Também foi avaliada a acurácia da neurografia pesada em difusão (neurografia DW) em relação à RM convencional e a capacidade de diferenciação dos três tipos de lesão: avulsão, ruptura e lesão em continuidade. Trinta e três pacientes com história e diagnóstico clínico de lesão traumática do plexo braquial foram prospectivamente estudados por RM. Os achados obtidos pela RM sem e com o uso da neurografia DW, e os achados de exame clínico foram comparados com os achados intraoperatórios. A análise estatística foi feita com associação de significância de 5%. Observou-se alta correlação entre a RM com neurografia DW e a cirurgia (rs=0,79), e baixa correlação entre a RM convencional e a cirurgia (rs=0,41). A correlação interobservador foi maior para a RM com neurografia DW (rs = 0,94) do que para a RM sem neurografia DW (rs = 0,75). Os resultados de sensibilidade, acurácia e valor preditivo positivo foram acima de 95% para as RM com e sem neurografia DW no estudo de todo o plexo. As especificidades foram, em geral, maiores para a neurografia DW (p < 0,05). Em relação à diferenciação dos tipos de lesão, a RM com neurografia DW apresentou altas acurácias e sensibilidades no diagnóstico da avulsão/rotura, e alta especificidade no diagnóstico da lesão em continuidade. A acurácia da RM (93,9%) foi significativamente maior que a do exame clínico (76,5%) no diagnóstico das lesões de todo o plexo braquial (p < 0,05). / Brachial plexus injury is considered the most severe neural disorder in the extremities and in general resulting from high-energy trauma in young patients, usually involving motor vehicles. For this reason, traumatic brachial plexus injuries are becoming more frequent. This study evaluated the accuracy of magnetic resonance imaging (MRI) in the diagnosis of traumatic brachial plexus injuries in adults, using surgical findings as the gold standard method. We also evaluated the accuracy of diffusion weighted image neurography (DW neurography) compared to conventional MRI and the ability to differentiate the three types of injuries by MRI: avulsion, rupture and lesion-in-continuity. Thirty-three patients with clinical history and diagnosis of traumatic brachial plexus injury were prospectively studied by MRI. MRI findings (obtained with and without use of DW neurography) and clinical examination were compared with intraoperative findings. The statistical analysis was performed with 5% significance association. There was high correlation between MRI with DW neurography and surgery (rs = 0.79) and low correlation between conventional MRI and surgery (rs = 0.41). The interobserver correlation was higher for MRI with DW neurography (rs = 0.94) than for regular MRI (rs = 0.75). The sensitivities, accuracies and positive predictive values were above 95% for MRI (with and without DW neurography) in the evaluation of the entire plexus. The specificities were generally higher for DW neurography (p < 0.05). Regarding the differentiation between types of lesions, MRI with DW neurography demonstrated high accuracies and sensitivities in the diagnosis of avulsion / rupture and high specificity in the diagnosis of lesion-in-continuity. MRI accuracy (93.9%) was significantly higher than clinical examination (76.5%) in diagnosis of brachial plexus traumatic lesions (p < 0.05).

L’imagerie par résonance magnétique de diffusion (l’IRMd) est actuellement la seule technique non-invasive pour étudier l’architecture tridimensionnelle des fibres myocardiques du cœur humain à la fois ex vivo et in vivo. Cependant, il est difficile de savoir comment les caractéristiques de diffusion calculées à partir des images de diffusion reflètent les propriétés des microstructures du myocarde à cause de l’absence de la vérité-terrain sans parler de l’influence de divers facteurs tels que la résolution spatiale, le bruit et les artéfacts. L'objectif principal de cette thèse est donc de développer des simulateurs de l’IRM de diffusion basés sur des modèles réalistes afin de simuler, en intégrant différentes modalités d'imagerie, les images pondérées en diffusion des fibres myocardiques à la fois ex vivo et in vivo, et de proposer un outil générique permettant d’évaluer la qualité de l’imagerie et les algorithmes de traitement d’images. Pour atteindre cet objectif, le présent travail se focalise sur quatre parties principales. La première partie concerne la formulation de la théorie de simulation IRMd pour la génération d’images de diffusion et pour les applications sur les modèles simples de fibres cardiaques chez l’homme, et essaie de comprendre la relation sous-jacente entre les propriétés mesurées de la diffusion et les caractéristiques à la fois physiques et structurelles des fibres cardiaques. La seconde partie porte sur la simulation des images de résonance magnétique de diffusion à différentes échelles en s’appuyant sur des données du cœur humain issues de l'imagerie par lumière polarisée. En comparant les propriétés de diffusion à différentes échelles, la relation entre la variation de la microstructure et les propriétés de diffusion observée à l'échelle macroscopique est étudiée. La troisième partie consacre à l’analyse de l'influence des paramètres d'imagerie sur les propriétés de diffusion en utilisant une théorie de simulation améliorée. La dernière partie a pour objectif de modéliser la structure des fibres cardiaques in vivo et de simuler les images de diffusion correspondantes en combinant la structure des fibres cardiaques et le mouvement cardiaque connu a priori. Les simulateurs proposés nous fournissent un outil générique pour générer des images de diffusion simulées qui peuvent être utilisées pour évaluer les algorithmes de traitement d’images, pour optimiser le choix des paramètres d’IRM pour les fibres cardiaque aussi bien ex vivo que in vivo, et pour étudier la relation entre la structure de fibres microscopique et les propriétés de diffusion macroscopiques. / Diffusion magnetic resonance imaging (dMRI) appears currently as the unique imaging modality to investigate noninvasively both ex vivo and in vivo three-dimensional fiber architectures of the human heart. However, it is difficult to know how well the diffusion characteristics calculated from diffusion images reflect the microstructure properties of the myocardium since there is no ground-truth information available and add to that the influence of various factors such as spatial resolution, noise and artifacts, etc. The main objective of this thesis is then to develop realistic model-based dMRI simulators to simulate diffusion-weighted images for both ex vivo and in vivo cardiac fibers by integrating different imaging modalities, and propose a generic tool for the evaluation of imaging quality and image processing algorithms. To achieve this, the present work focuses on four parts. The first part concerns the formulation of basic dMRI simulation theory for diffusion image generation and subsequent applications on simple cardiac fiber models, and tries to elucidate the underlying relationship between the measured diffusion anisotropic properties and the cardiac fiber characteristics, including both physical and structural ones. The second part addresses the simulation of diffusion magnetic resonance images at multiple scales based on the polarized light imaging data of the human heart. Through both qualitative and quantitative comparison between diffusion properties at different simulation scales, the relationship between the microstructure variation and the diffusion properties observed at macroscopic scales is investigated. The third part deals with studying the influence of imaging parameters on diffusion image properties by means of the improved simulation theory. The last part puts the emphasis on the modeling of in vivo cardiac fiber structures and the simulation of the corresponding diffusion images by combining the cardiac fiber structure and the a priori known heart motion. The proposed simulators provide us a generic tool for generating the simulated diffusion images that can be used for evaluating image processing algorithms, optimizing the choice of MRI parameters in both ex vivo and in vivo cardiac fiber imaging, and investigating the relationship between microscopic fiber structure and macroscopic diffusion properties.