Diffusion Tensor Imaging (DTI) is a well-established magnetic resonance technique that can non-invasively interpret tissue geometry and track neural pathways by sampling the diffusion of water molecules in the brain tissue. However, it is currently limited to tracking large nerve fiber bundles and fails to faithfully resolve thinner fibers. Conventional DTI studies use a diffusion time, t[subscript diff] of 30 ms - 55 ms for diffusion measurements. This work proposes the use of DTI at long t[subscript diff] to enhance the sensitivity of the method towards regions of low diffusion anisotropy and improve tracking of smaller fibers. The Stimulated Echo Acquisition Mode (STEAM) sequence was modified to allow DTI measurements at long t[subscript diff] (approximately 200 ms), while avoiding T2 signal loss. For comparison, DTI data was acquired using STEAM at the shorter value of t[subscript diff] and with the standard Double Spin Echo sequence with matched signal-to-noise ratio. This approach was tested on phantoms and fixed monkey brains and then translated to in vivo studies in rhesus macaques. Qualitative and quantitative comparison of the techniques was based on fractional anisotropy, diffusivity, three-phase plots and directional entropy. Tensor-field maps and probabilistic connectivity fronts were evaluated for all three acquisitions. Comparison of the tracked nerve pathways showed that fibers obtained at long t[subscript diff] were much longer. Further, the optic tract was tracked in ex vivo fixed rhesus brains for cross validation. The optic tract, traced at long t[subscript diff], conformed to the well documented anatomical description, thus confirming the accuracy of tract tracing at long t[subscript diff]. The benefits of DTI at long t[subscript diff] indeed help to realize the potential of tensor based tractography towards studying neural development and diagnosing neuro-pathologies, albeit the improvement is more significant ex vivo than in vivo.

INTRODUÇÃO: Epilepsia do lobo temporal mesial (ELTM) por esclerose hipocampal (EH) é a forma de epilepsia focal mais comum na idade adulta e a causa mais frequente de refratariedade ao tratamento clínico. Apesar de se tratar de uma patologia da substância cinzenta, alguns estudos, por meio da imagem por tensor de difusão (diffusion tensor imaging-DTI), têm demonstrado alteração da substância branca temporal e extratemporal nestes pacientes. O corpo caloso (CC) é a maior comissura cerebral conectando áreas corticais homólogas de ambos os hemisférios cerebrais e tem sido implicado na propagação da atividade epiléptica. O objetivo principal do presente estudo foi avaliar possíveis alterações no CC de pacientes com ELTM-EH pela técnica de DTI e verificar se essas dependem da lateralidade da EH e da concordância entre os exames de ressonância magnética (RM) e os exames de vídeo-eletroencefalograma (EEG). Como objetivo secundário, também avaliou-se se estas alterações se correlacionavam com alguma variável clínica ou com as medidas volumétricas do CC. MÉTODOS: 42 pacientes com ELTM-EH (idades: 20-54 anos) e 30 voluntários saudáveis como grupo controle (idades: 18-53 anos) realizaram exame de RM de crânio, sendo obtidas sequências de DTI com 32 direções de gradiente e imagens volumétricas ponderadas em T1. Os pacientes foram também divididos em subgrupos: EH à direita e EH à esquerda, e em pacientes concordantes e discordantes. Os valores de anisotropia fracionada (AF), difusividade média (DM), difusividade axial (DA), difusividade radial (DR) e os dados volumétricos foram extraídos a partir de cinco segmentos obtidos automaticamente na secção sagital do CC. Foram realizadas comparações dos parâmetros de DTI no CC entre os grupos de pacientes e controles, e entre os subgrupos de pacientes. Foram investigadas correlações entre os parâmetros do tensor de difusão e as variáveis clínicas. As alterações volumétricas no CC dos pacientes com ELTM-EH bem como a correlação dessas alterações com as anormalidades de difusão também foram avaliadas. Considerou-se um valor de p < 0,05 como estatisticamente significativo. RESULTADOS: Nas regiões anterior, médio-posterior e posterior do CC dos pacientes, observaram-se redução da AF e aumento da DM e da DR, em relação aos controles. A DA manteve-se inalterada. Não foram demonstradas diferenças nos padrões de alteração de difusão entre os pacientes com EH à direita e com EH à esquerda, nem entre pacientes concordantes e discordantes. Não foram observadas correlações significativas entre os parâmetros do tensor de difusão com a idade ao evento inicial, idade de início da epilepsia, tempo de doença, tempo de epilepsia, período de latência e frequência de crises. No entanto, pacientes que apresentaram crise febril como evento precipitante inicial exibiram maior intensidade e extensão das alterações de difusão. Observou-se redução volumétrica difusa do CC, sendo demonstrada correlação negativa significativa entre DM e DR, e o volume nos segmentos central, médio-posterior e posterior, e, ainda, entre DA e volume do segmento posterior. Nós observamos, ainda, correlação negativa significativa entre o volume e o tempo de epilepsia, e o tempo de doença. CONCLUSÕES: Houve alteração dos parâmetros de DTI em áreas específicas do CC e redução volumétrica difusa desta estrutura. Tais anormalidades parecem ser secundárias à propagação das crises epilépticas ao longo de vias específicas anatômica ou funcionalmente relacionadas aos lobos temporais promovendo alterações secundárias na substância branca cerebral. O histórico de crise febril está relacionado a maior intensidade e extensão de acometimento do CC / INTRODUCTION: Mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) is the most common form of focal epilepsy in adults and it is frequently associated with refractoriness to medical treatment. Although epilepsy is considered a grey-matter disease, abnormalities in the temporal and extra-temporal white matter have been identified in these patients with diffusion tensor imaging (DTI). The corpus callosum (CC) is the major white matter tract connecting both cerebral hemispheres and has been implicated as an important route of spread of epileptic activity. The first goal of this study was to detect DTI abnormalities in specific areas of the CC in patients with MTLE-HS and to verify if these abnormalities depend on the laterality of the HS and on the concordance between the magnetic resonance imaging (MRI) and video-electroencephalogram (EEG). As a second goal we assessed if DTI results were correlated with any clinical variable or volumetric changes of the CC. METHODS: 42 patients (age: 20-54 years) and 30 healthy controls (age:18-53 years) were submitted to brain MRI. DTI sequences with 32 gradient encoding directions and volumetric T1-weighted images were obtained. Additionally, we grouped the patients in left sided and right sided HS and in concordant and discordant HS. Mean values of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) and volumetric results were extracted from five segments at the midsagittal section of the CC obtained through automatic segmentation. Comparisons of DTI parameters of the CC were performed between patients and controls and between subgroups of patients. Correlations between DTI parameters and clinical findings were calculated. We also evaluated volume abnormalities of the CC in MTLE-HS patients and the correlations between these abnormalities and DTI changes. We considered a value of p <0.05 statistically significant. RESULTS: Our study showed that, when HS patients was compared to controls, the FA was lowest in the anterior, mid-posterior and posterior subregions of the CC. MD and RD were higher in these same segments. No changes were observed in AD. No differences in the CC DTI parameters were detected between right-sided HS and left-sided HS or between concordant and discordant HS patients. Age at initial event, age at epilepsy onset, duration of disease, duration of epilepsy, latency period and seizure frequency were not significantly correlated with the DTI parameters. However, patients who had febrile seizures as initial event exhibited greater intensity and extent of DTI changes. All segments demonstrated volume reduction compared to controls. Significant negative correlation was demonstrated between MD and RD and the volume in the central, midposterior and posterior segments of the CC, and between AD and volume of the posterior segment. We also demonstrated negative correlation between volume and duration of disease and duration of epilepsy. CONCLUSIONS: This study showed diffusion abnormalities in specific areas of the CC and diffuse atrophy in patients with unilateral HS, which may be secondary to seizures propagation along specific pathways leading to secondary changes in brain white matter. The history of febrile seizure is related to greater involvement of the CC

A esquizofrenia é um transtorno mental de alta complexidade e até o presente momento nenhuma teoria conseguiu explicar completamente sua etiologia. Uma dessas teorias acredita que a transferência de informações entre os hemisférios de pacientes com esquizofrenia, que ocorre através do corpo caloso, comissura anterior e posterior, pode estar comprometida. Os objetivos do nosso estudo foram avaliar se existem alterações de conectividade inter-hemisférica (IH) e se essas alterações sofrem influência do gênero, em pacientes portadores de esquizofrenia quando comparados com seus parentes em primeiro grau e controles saudáveis, utilizando-se da imagem de ressonância magnética por tensor de difusão (IRMTD). Participaram do estudo 30 pacientes portadores de esquizofrenia, diagnosticados pelos critérios do Manual diagnóstico e estatístico das doenças mentais em sua quarta edição, os quais foram selecionados entre os pacientes do grupo de medicações atípicas do ambulatório de esquizofrenia e da enfermaria psiquiátrica do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo; 30 parentes em primeiro grau desses pacientes; e 30 voluntários saudáveis. Todos os sujeitos do estudo foram submetidos a um exame de ressonância magnética, realizado no Centro de Ciências das Imagens e Física Médica de nossa instituição, onde foram adquiridas as sequências volumétricas e difusionais utilizadas em nosso estudo. Em posse das imagens de ressonância magnética dos 90 sujeitos do estudo, realizamos o pós-processamento dessas imagens, utilizando o software BrainVoyager QX® versão 2.4, com o intuito de obtermos, por meio dos dados provenientes da IRMTD, os mapas de anisotropia fracional (AF) e difusibilidade média (DM). Com esses mapas em mãos, procedemos à análise estatística do estudo, denominada de análise de covariância voxel a voxel (VANCOVA), no cérebro todo. Nessa análise, utilizamos a idade como covariável e verificamos a influência do gênero nos resultados encontrados. Nossos resultados 6 evidenciaram que os pacientes portadores de esquizofrenia apresentaram valores de AF e DM alterados em estruturas homólogas ao corpo caloso e áreas frontais adjacentes. Assim, podemos afirmar que descobrimos perda de conectividade IH nesses mesmos pacientes. Por meio de nosso estudo, descobrimos também a influência do gênero nos valores de AF e DM encontrados e então, consequentemente, podemos dizer que a conectividade IH de pacientes portadores de esquizofrenia sofreu influência do sexo. A idade também mostrou influenciar a conectividade IH de nossos pacientes. Com o atual conceito de que alterações de AF e DM podem ser encaradas como indicativos de comprometimento da mielina, e sabendo que a mielina participa diretamente das reações neuroquímicas do sistema glutamatérgico cerebral, também podemos dizer que o sistema glutamatérgico que participa da conectividade IH desses pacientes encontrava-se comprometido. / Schizophrenia is a highly complex mental disorder and no theory to date was able to fully explain the etiology of this disorder. One of the existing theories advocates that interhemispheric communication, which occurs through the corpus callosum and the anterior and posterior commissures, might be impaired in schizophrenia. Our study was designed to investigate whether there are interhemispheric connectivity (IC) alterations in schizophrenia and whether these alterations are influenced by gender through the comparison of schizophrenia patients with their first-degree relatives and healthy controls using diffusion tensor imaging (DTI). We enrolled 30 schizophrenia patients diagnosed according to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders and selected from the Group of Atypical Medications of the Schizophrenia Outpatient Clinic and the psychiatric ward of the Ribeirão Preto Medical School University Hospital, 30 first-degree relatives of these patients and 30 healthy volunteers. All subjects underwent magnetic resonance imaging (MRI) scans for the acquisition of volumetric and diffusion sequences. The images were post-processed using BrainVoyager QX® version 2.4 to create fractional anisotropy (FA) and mean diffusivity (MD) maps from DTI data. The resulting data were analyzed using voxel-to- voxel analysis of covariance (VANCOVA) for the whole brain. In this analysis, we used age as a co-variable and assessed the influence of gender. Our results showed that schizophrenia patients had altered FA and MD values in structures homologous to the corpus callosum and adjacent frontal areas, suggestive of IC loss in the patients. We also found that gender influenced FA and MD values and, therefore, that IC in schizophrenia patients is influenced by gender. Age was also found to influence IC in our patients. Based on the current conception that FA and MD alterations may indicate myelin impairment and knowing that myelin participates directly in neurochemical reactions of the glutamatergic system in the brain, we can infer that the glutamatergic system, which is implicated in IC, is affected in schizophrenia and is influenced by gender.

Die Ursache für das idiopathische Stottern ist bis zum jetzigen Zeitpunkt unbekannt. Typischerweise beginnt die Redeflussstörung im Vorschulalter. Es wird davon ausgegangen, dass 1% der Bevölkerung an Stottern leidet. Bei der Frage nach pathophysiologischen Hintergründen von Sprech- und Sprachstörungen ist der Zusammenhang zwischen einer pathologischen, funktionellen Lateralisierung und einer morphologischen Asymmetrie im Bereich von neuronalen Netzwerken der Sprachbildung bereits seit längerem Gegenstand der Forschung. Im Rahmen der vorliegenden Arbeit wurde die Lateralisierung von Sprache bei 17 stotternden Probanden und 20, im Alter entsprechenden, flüssig sprechenden Probanden untersucht. Hierbei wurde die Sprachlateralisierung mithilfe der fMRT sowohl mit einem Satz- als auch mit einem Wortgenerierungsparadigma ermittelt. Ausgehend von den in der fMRT ermittelten Sprachzentren wurde die angrenzende weiße Substanz unter Verwendung der DTI auf eine Asymmetrie hin untersucht. Im Vergleich zu der Gruppe der Normalprobanden zeigten die schwer stotternden Probanden eine Verschiebung der Indexwerte, deren endgültige Ursache offen bleibt. Gesteigerte funktionelle Aktivierung in Bereichen der rechtshemisphärischen Analoga der Sprachzentren scheint ein möglicher Erklärungsansatz. Vorausgegangene funktionelle Untersuchungen u. a. mittels PET und fMRT bei stotternden Probanden belegten eine Überaktivierung von Teilen des motorischen Kortex sowie eine atypische Lateralisierung bei der Produktion von Sprache mit rechtsseitiger Lateralisierung oder eine bilaterale Aktivität. Darüber hinaus zeigte sich eine morphologische Veränderung, im Sinne einer Abnahme einer linkshemisphärischen Asymmetrie bei den schwer stotternden Probanden, besonders in der an das Wernicke-Areal angrenzenden weißen Substanz. Mithilfe der VBM konnten in mehreren früheren Studien morphologische Unterschiede bei Stotternden gezeigt werden. Gegenüber dem rein morphologischen Untersuchungsansatz vorangegangener Untersuchungen berücksichtigte die Kombination der funktionellen und der diffusionsgewichteten Analyse stärker die intraindividuelle Variabilität der Sprachzentren.

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.

L'un des problèmes fondamentaux de l'imagerie cardiaque par résonance magnétique du tenseur de diffusion (IRM-TD) est sa faible résolution spatiale, à cause des limitations matérielles des scanners IRM actuels. L'objectif principal de ce travail de thèse est de développer de nouvelles approches pour améliorer la résolution des données d'IRM-TD afin de mieux représenter l'architecture myocardique du coeur humain et de la comparer avec des résultats issus d'autres techniques d'investigation telles que l'imagerie par lumière polarisée. Dans ce cadre, le travail porte sur trois parties principales. La première concerne le développement d'une nouvelle approche pour l'interpolation des champs de vecteurs propres principaux issus de l'IRM-TD cardiaque humaine. Cette approche consiste d'abord à supprimer les vecteurs corrompus par le bruit au lieu de débruiter de manière uniforme le champ entier de vecteurs, et ensuite à interpoler le champ de vecteurs en utilisant la modèle Thin-Plate-Spline (TPS) afin d'exploiter la corrélation entre les composantes du vecteur. La deuxième partie concerne une nouvelle famille de méthodes d'interpolation pour les champs de tenseurs, basée soit sur les angles d'Euler soit sur le quaternion. Ces méthodes exploitent les caractéristiques du tenseur et préservent les paramètres de tenseurs, tels que le déterminant du tenseur, l'anisotropie fractionnelle (FA) et la diffusivité moyenne (MD). En outre, cette partie compare les principales approches d'interpolation au niveau des images pondérées en diffusion et des champs de tenseurs, et les résultats montrent qu'il serait préférable d'effectuer l'interpolation des données d'IRM-TD au niveau des champs de tenseurs. La troisième partie étudie le changement des paramètres MD et FA après un infarctus du myocarde chez les cochons, et l'influence des méthodes d'interpolation sur ces paramètres dans la zone infarctus et la zone distante. Les résultats montrent que la zone infarctus présente une diminution significative de FA et une augmentation significative de MD, comparée avec la zone distante, et que les méthodes d'interpolations du tenseur ont plus d'influence sur FA que sur MD, ce qui suggère que l'interprétation de ces paramètres cliniques après l'interpolation doive être prise avec précaution. / One of fundamental problems in human cardiac diffusion tensor magnetic resonance imaging (DT-MRI) is its poor spatial resolution, due to the hardware limitations of MRI scanners. The main purpose of this PhD work is to develop new approaches to improving the resolution of cardiac DT-MRI data in order to better understand the myocardial architecture of the heart and compare it with results issues from other investigation techniques such as polarized light imaging. Within this framework, the present work is composed of three main parts. The first part concerns a new approach to interpolating primary eigenvector fields from human cardiac DT-MRI using Thin Plate Spline (TPS) model. This approach removes the noise-corrupted vectors rather than denoising the whole vector field in a uniform manner, and uses TPS model in order to exploit the correlation between vector components during interpolation. The second part is dealt with a new category of feature-based methods for diffusion tensor field interpolation using either Euler angles or quaternion. These feature-based methods well preserve tensor parameters, such as tensor determinant, fractional anisotropy (FA) and mean diffusivity (MD) values. In this part are also compared the main interpolation approaches at the level of diffusion weighted images and tensor fields. The results show that the interpolation of DT-MRI data should be performed at the level of tensor fields. The last part investigates changes in MD and FA after myocardial infarction in porcine hearts, and the influence of diffusion tensor interpolation methods on FA and MD in both infarction and remote region. It is found that the infarction region showed significantly decreased FA and increased MD than the remote region, and that diffusion tensor interpolations have more significant influence on FA than on MD, which suggests that precaution should be taken when performing the clinical analysis based on the parameters after diffusion tensor interpolations.