Congenital heart disease (CHD) is the most common congenital anomaly, with single ventricle (SV) defects accounting for nearly 10% of all CHD. SV defects tend to be the most severe forms of CHD: all patients born with SV require multiple open heart surgeries, often beginning in the neonatal period, ultimately leading to the Fontan procedure. Due to improvements in surgical procedures and medical care, more patients are surviving into adolescence and adulthood. Brain imaging and pathology studies have shown that patients with SV have differences in brain structure and metabolism even before the first surgery, and as early as in utero. Furthermore, a significant number of patients have new or more severe lesions after the initial surgery, and many still have brain abnormalities into early childhood. However, there are no detailed brain structural data of SV patients in adolescence. Our group recruited a large cohort of post-Fontan SV patients aged 10-19 years. Separate analyses of neuropsychological and behavioral outcomes in these patients show deficits in multiple areas of cognition, increased rates of attention deficit-hyperactivity disorder (ADHD), and increased use of remedial and/or special education services compared to a control group. Post-Fontan adolescents have more gross brain abnormalities, including evidence of chronic ischemic stroke. Furthermore, there are widespread reductions in cortical and subcortical gray matter volume and cortical thickness, some of which are associated with medical and surgical variables. Diffusion tensor imaging (DTI) analyses show widespread areas of altered white matter microstructure in deep subcortical and cerebellar white matter. In this dissertation, I use graph theory methods to characterize structural connectivity based on gray matter (cortical thickness covariance) and white matter (DTI tractography), and examine associations between brain structure and neurodevelopment. I found that brain network connectivity differs in post-Fontan patients compared with controls, both at the global and regional level. Additionally, deficits in overall network structure were associated with impaired neurodevelopment in several domains, including general intelligence, executive function, and visuospatial skills. These data suggest that early neuroprotection should be a major focus in the care of SV patients, with the goal of improving long-term neurodevelopmental outcomes.

Communication is the exchange of thoughts and ideas from one person to another, often through the form of narratives. People communicate using speech, gesture, and drawing, or some multimodal combination of the three. Although there has been much research on how we understand and produce speech and pantomimes, there is relatively little on drawing, and even less on cross-modal communication. This dissertation presents novel empirical findings that contribute to a better understanding of the brain areas that mediate narrative communication across speech, pantomime, and drawing. Since the neuroscience of drawing was so understudied, I first used functional magnetic resonance imaging (fMRI) to investigate the existence of a basic drawing network in the human brain (Chapter 2). The drawing network was shown to contain three visual-motion areas that process the emanation of the visual image as drawing occurs. Next, to follow up on the poorly-characterized structural connectivity of these areas in the human dorsal visual stream, I used diffusion imaging to explore how these dorsal stream areas are connected (Chapter 3). The tractography results showed structural connectivity for two of the three predicted branches connecting the three visual-motion areas. Finally, I used fMRI to investigate how the basic drawing network is recruited during the more complex task of narrative drawing, and to find common brain areas among narrative speech, pantomime, and drawing (Chapter 4). Results suggest that people approached narratives in an intrinsically mentalistic fashion in terms of the protagonist, rather than as a mere description of action sequences. Together, these studies advance our understanding of the brain areas that comprise a basic drawing network, how these brain areas are interconnected, and how we communicate stories across three modalities of production. I conclude with a general discussion of my findings (Chapter 5). / Thesis / Doctor of Philosophy (PhD)

As imagens de ressonância magnética ponderadas por difusão retratam a difusividade de moléculas de água presentes em tecidos biológicos. Em estruturas biológicas altamente organizadas e compactas como fibras nervosas e musculares, a difusividade é maior na direção paralela às fibras do que perpendicularmente às mesmas. Essa propriedade permite a reconstrução digital das trajetórias das fibras, técnica denominada tractografia, representando uma das poucas formas não invasivas de investigação da conectividade anatômica e organização estrutural do cérebro e do coração. A metodologia de tractografia mais difundida faz uso da integração numérica da direção principal de difusividade para reconstruir essas trajetórias. Porém, esta técnica apresenta problemas como o erro intrínseco a métodos de integração numérica e o erro associado a regiões de incerteza nos dados de difusividade. Uma metodologia considerada mais robusta consiste da modelagem da tractografia como a simulação de um sistema de partículas. No entanto, tal metodologia possui diversos parâmetros que precisam ser otimizados para cada caso e apresenta alta complexidade computacional. Esta dissertação apresenta uma metodologia de tractografia global baseada em sistema de partículas, mas com custo computacional reduzido pois evita passos desnecessários da otimização para reconstrução das trajetórias. Avaliamos sua acurácia em conjuntos de dados com graus de complexidade crescentes utilizando imagens sintéticas de difusão construídas digitalmente e em imagens reais de difusão do miocárdio humano. Nesses testes foram observadas reduções no consumo de tempo e maior acurácia para metodologia global apresentada com relação às descritas na literatura. Essa metodologia possui o potencial de evidenciar a organização e arquitetura de diversos tecidos do corpo humano com maior fidelidade e menor tempo de reconstrução. / The diffusion magnetic resonance imaging portray the diffusivity of water molecules present on biological tissues. High organized and compact biological structures like neuronal fibres and muscles present higher diffusivity parallel to the fibres than perpendicular to those. This property allows the digital reconstruction of fibres trajectories, technique named tractography, being one of the few non invasive ways of investigation of the anatomical connectivity and structural organization of the brain and heart. The most common tractography methodology uses numerical integration following the main diffusion direction in order to reconstruct trajectories. Yet, this technique is prone to intrinsic error to numeric integration and the error associated to uncertainty regions on diffusion data. A methodology considered more robust to such problems consists on modelling tractography as a particle system simulation. However, such methodology has several parameters that require fine tuning for each case and has a high computational complexity. This dissertation presents a global tractography methodology based on particle system but at lower computational cost because of the avoidance of unnecessary optimization steps on trajectory reconstruction. We evaluate its accuracy on synthetic diffusion datasets of increasing complexity and on real human cardiac diffusion images. Theses tests evidence reduced time consumption and increased accuracy for the presented methodology compared to the ones described in the literature. This methodology has the potential to reveal the organization and architecture of several tissues from the human body with higher fidelity and lower reconstruction time.

The human brain changes in a complex and heterogeneous way throughout life, the normal aging process is associated to significant alterations in the axonal connections. In this study, we evaluated the age-related changes in physical parameters associated with the brain white and gray matter integrity in healthy subjects, as well as the possible correlation between them in specific tracts. Structural images (1 mm isotropic) and diffusion weighted images (2 mm isotropic, b = 1000 s /mm2) of 158 healthy individuals aged between 18 and 83 years were retrospectively collected at the Clinics Hospital of Ribeirao Preto, after their acquisition in a 3T MR scanner. From the structural images, the cortical thickness was estimated and the age effect was evaluated in several regions based on the Atlas of Destrieux. The diffusion-weighted images were processed to characterize the intravoxel diffusion using two models: diffusion tensor (DT) and constrained spherical deconvolution (CSD). Fractional anisotropy (FA) and apparent density of fiber (AFD) maps were estimated and used in statistical group analysis between the three groups separated by age. The most relevant brain tracts were segmented by three procedures: manually, automatically with a specific tool and based on automatic segmented cortical regions. Physical parameters of diffusion (anisotropy and diffusivities) were evaluated in the segmented tracts to determine the age-related changes. The connectome analysis based on two cortical parcellations was performed to evaluate the age effect on characteristic structural brain network parameters. The tract-cortical relationship was evaluated considering the anisotropy of each tract and the thickness of the cortical areas at the end of the corresponding tract. Further analysis was performed to evaluate a possible association of structural and functional connectivity in the corpus callosum (CC). There was significant cortical thinning in 88.5% of the regions during life (p <0.05, corrected for multiple comparisons); the frontal region was the most affected in the initial aging (after 40 years), and the occipital and temporal regions in the elderly (after 60 years). Similarly, the group analysis demonstrated a global pattern of reduction of FA and AFD in the white matter, with a higher rate of degradation of integrity from the sixth decade of life. The manual selection of tracts from the DT model proved to be the most reliable methodology in the precise definition of the tracts for our data. Following this methodology, analysis of anisotropy and diffusion parameters also indicated degeneration of white matter in normal aging in all studied brain tracts and corroborated to the antero-posterior gradient of degeneration in the CC. Fornix was the most affected tract bilaterally, with a 3.5% reduction and an increase of 4% per decade in these parameters, respectively; followed by CC. In the evaluation of the age effect on the connectome estimates, regardless of diffusion model and cortical atlas, there was a decrease in global efficiency, number of connections and local efficiency with aging, mainly in the prefrontal, temporal and parietal and its connections. In the tract-cortical analysis, cortical regions connected by tracts demonstrated similar thinning patterns for the majority of tracts, and a significant relation between mean cortical thinning rate and FA/MD alteration rates were found. In all evaluated tracts, age was the main effect controlling diffusion parameters alterations; there were no direct correlations with cortical thickness for the majority of tracts. Only for the fornix, the values of FA and MD showed significant correlation with the cortical thickness of the subcallosal gyrus in both hemispheres during aging (p <0.05 corrected). For the other tracts, CC, Inferior Longitudinal Fasciculus, Uncinated Fasciculus, Inferior Fronto-occipital Fasciculus, Corticospinal Tract, Cingulum and Arcuate Fasciculus, age was the main effect controlling alterations in the parameters, but there were no direct correlations between FA and MD and cortical thickness during the aging process. / O cérebro humano muda de forma complexa e heterogênea ao longo da vida, o processo de envelhecimento normal tem associado significativas alterações nas conexões axonais. Neste estudo, avaliamos as mudanças relacionadas à idade em parâmetros físicos associados à integridade das substâncias branca e cinzenta cerebral em sujeitos saudáveis, assim como a possivel correlação entre eles em tratos específicos. Imagens estruturais (1 mm isotrópica) e imagens ponderadas em difusão (2 mm isotrópica e b=1000 s/mm2) de 158 indivíduos saudáveis entre 18 a 83 anos foram coletadas retrospectivamente no Hospital das Clinícas de Ribeirão Preto, após sua aquisição em aparelho de ressonância magnética de 3 Teslas. A partir das imagens estruturais, a espessura cortical foi estimada e o efeito de idade nela foi avaliado em diversas regiões tomando com base o atlas de Destrieux. As imagens ponderadas em difusão foram processadas para caracterizar a difusão intravoxel utilizando dois modelos: tensor de difusão (DT) e deconvolução esférica restrita (CSD). Mapas de anisotropia fracionada (FA) e densidade aparente da fibra (AFD) foram estimados e usados em analise estatistica de três grupos separados por faixa etária. Os tratos cerebrais mais relevantes foram segmentados por tres procedimentos: manualmente, automaticamente com uma ferramenta especifica e com base em regiões corticais automaticante segmentadas. Parâmetros físicos de difusão (anisotropia e difusibilide) foram avaliados nos tratos segmentados para determinar as alterações relacionadas à idade. A análise de conectoma baseada em dois parcelamentos corticais foi realizada para avaliar também o efeito da idade em parâmetros caracteristicos da rede estrutural cerebral. A relação trato-cortical foi avaliada considerando a anisotropia de cada trato e as espessuras das áreas corticais nas extremidades do trato correspondente. Uma análise adicional foi realizada para avaliar uma possivel associação de onetividades estrutural e funcional no corpo caloso (CC). Houve afinamento cortical significativo em 88,5% das regiões durante a vida (p <0,05, corrigido); a região frontal foi a mais afetada no envelhecimento inicial (após 40 anos), e as regiões occipital e temporal nos idosos (após 60 anos). Similarmente, a análise de grupo demonstrou um padrão global de redução de FA e AFD na substância branca, com uma maior taxa de degradação de integridade a partir da sexta década de vida. A seleção manual de tratos baseada no modelo de DT mostrou-se a metodologia mais confiavél na precisa definição dos tratos nos nossos dados. Seguindo essa metodologia, a análise dos parâmetros de anistropia e difusão também indicou degeneração de substância branca no envelhecimento normal em todos os tratos cerebrais estudados e corroborou o gradiente ântero-posterior de degeneração no CC. O fornix foi o trato mais afetado bilatreamente com redução de 3.5% e aumento de 4% por década nesses parâmetros, respectivamente; seguido do CC. Na avaliação do efeito da idade nas estimativas do conectoma, independentemente do modelo de difusão e do atlas cortical usado, houve uma diminuição da eficiência global com o envelhececimento, do número de conexões e da eficiência local, principalmente nas regiões pré-frontal, temporal e parietal e suas conexões. Nas análises trato-corticais, as regiões corticais conectadas por tratos mostraram padrões de afinamento similares para a maioria dos tratos, e uma correlação significativa entre a taxa média de afinamento cortical e as taxas de alteração de FA e difusibilidade média (MD) foram encontradas. Em todos os tratos avaliados, a idade foi o principal efeito controlando das alterações dos parâmetros de difusão; não houve correlações diretas com espessura cortical para a maioria dos tratos. Somente para o fornix, os valores de FA e MD mostraram correlação com a espessura cortical do giro subcalosal (parcelamento de Destrieux) em ambos os hemisférios durante o envelhecimento (p <0,05 corrigido). Para os outros tratos, CC, fascículo longitudinal inferior, fascículo uncinado, fascículo occipitofrontal inferior, trato cortico-espinal, parte cingulada do cíngulo e fascículo arqueado, a idade foi o principal efeito no controle das alterações dos parâmetros, mas não houve correlações diretas entre FA e MD e espessura cortical durante o processo de envelhecimento

Globally, preterm birth (defined as birth at < 37 weeks of gestation) affects around 11% of deliveries and it is closely associated with cerebral palsy, cognitive impairments and neuropsychiatric diseases in later life. Magnetic Resonance Imaging (MRI) has utility for measuring different properties of the brain during the lifespan. Specially, diffusion MRI has been used in the neonatal period to quantify the effect of preterm birth on white matter structure, which enables inference about brain development and injury. By combining information from both structural and diffusion MRI, is it possible to calculate structural connectivity of the brain. This involves calculating a model of the brain as a network to extract features of interest. The process starts by defining a series of nodes (anatomical regions) and edges (connections between two anatomical regions). Once the network is created, different types of analysis can be performed to find features of interest, thereby allowing group wise comparisons. The main frameworks/tools designed to construct the brain connectome have been developed and tested in the adult human brain. There are several differences between the adult and the neonatal brain: marked variation in head size and shape, maturational processes leading to changes in signal intensity profiles, relatively lower spatial resolution, and lower contrast between tissue classes in the T1 weighted image. All of these issues make the standard processes to construct the brain connectome very challenging to apply in the neonatal population. Several groups have studied the neonatal structural connectivity proposing several alternatives to overcome these limitations. The aim of this thesis was to optimise the different steps involved in connectome analysis for neonatal data. First, to provide accurate parcellation of the cortex a new atlas was created based on a control population of term infants; this was achieved by propagating the atlas from an adult atlas through intermediate childhood spatio-temporal atlases using image registration. After this the advanced anatomically-constrained tractography framework was adapted for the neonatal population, refined using software tools for skull-stripping, tissue segmentation and parcellation specially designed and tested for the neonatal brain. Finally, the method was used to test the effect of early nutrition, specifically breast milk exposure, on structural connectivity in preterm infants. We found that infants with higher exposure to breastmilk in the weeks after preterm birth had improved structural connectivity of developing networks and greater fractional anisotropy in major white matter fasciculi. These data also show that the benefits are dose dependent with higher exposure correlating with increased white matter connectivity. In conclusion, structural connectivity is a robust method to investigate the developing human brain. We propose an optimised framework for the neonatal brain, designed for our data and using tools developed for the neonatal brain, and apply it to test the effect of breastmilk exposure on preterm infants.

Paediatric posterior fossa tumors are often effectively controlled with a combination of radiation, chemotherapy and surgery. However, therapeutic craniospinal radiation has been associated with widespread cognitive late effects. Working memory is one such cognitive ability that has yet to be fully examined in this clinical population. Bilateral tracts connecting the cerebellum with the DLPFC were delineated using DTI tractography in all participants, replicating the cerebrocerebellar pathway outlined in an animal model. There were observable differences in white matter integrity (quantified by DTI measures of anisotropy, and mean, axial, and radial diffusivity) of the cerebellum-DLPFC pathway in patients versus controls. Additionally, working memory deficits that were found in patients were correlated with DTI indices pertaining to the cerebellum-DLPFC pathway. Therefore, this thesis is the first to explore the possible relations between white matter integrity of this pathway following treatment for paediatric posterior fossa tumors and working memory function.

Paediatric posterior fossa tumors are often effectively controlled with a combination of radiation, chemotherapy and surgery. However, therapeutic craniospinal radiation has been associated with widespread cognitive late effects. Working memory is one such cognitive ability that has yet to be fully examined in this clinical population. Bilateral tracts connecting the cerebellum with the DLPFC were delineated using DTI tractography in all participants, replicating the cerebrocerebellar pathway outlined in an animal model. There were observable differences in white matter integrity (quantified by DTI measures of anisotropy, and mean, axial, and radial diffusivity) of the cerebellum-DLPFC pathway in patients versus controls. Additionally, working memory deficits that were found in patients were correlated with DTI indices pertaining to the cerebellum-DLPFC pathway. Therefore, this thesis is the first to explore the possible relations between white matter integrity of this pathway following treatment for paediatric posterior fossa tumors and working memory function.

Computer vision encompasses a host of computational techniques to process visual information. Medical imagery is one particular area of application where data comes in various forms: X-rays, ultrasound probes, MRI volumes, EEG recordings, NMR spectroscopy, etc. This dissertation is concerned with techniques for accurate reconstruction of neural pathways from diffusion magnetic resonance imagery (dMRI). This dissertation describes a filtered approach to neural tractography. Existing methods independently estimate the diffusion model at each voxel so there is no running knowledge of confidence in the estimation process. We propose using tractography to drive estimation of the local diffusion model. Toward this end, we formulate fiber tracking as recursive estimation: at each step of tracing the fiber, the current estimate is guided by those previous. We argue that this approach is more accurate than conventional techniques. Experiments demonstrate that this filtered approach significantly improves the angular resolution at crossings and branchings. Further, we confirm its ability to trace through regions known to contain such crossing and branching while providing inherent path regularization. We also argue that this approach is flexible. Experiments demonstrate using various models in the estimation process, specifically combinations of Watson directional functions and rank-2 tensors. Further, this dissertation includes an extension of the technique to weighted mixtures using a constrained filter.

Background: Gliomas are neuroepithelial tumours classified by cell type and grade. In adults, low-grade gliomas are comprised mainly of astrocytomas and oligodendrogliomas grade II. The aim was to non-invasively characterise suspected low-grade gliomas through use of 11C-methionine-PET and physiological MRI in order to facilitate treatment decisions. Materials and methods: Patients with suspected low-grade glioma were prospectively and consecutively included after referral to the Neurosurgical Department, Uppsala University Hospital, between February 2010 and February 2014. All patients underwent morphological MRI, perfusion MRI, diffusion MRI and 11C-methionine PET. The institutional review board approved the study, and written informed consent was obtained prior to participation from each patient. Results: 11C-methionine PET hot spot regions corresponded spatially with regions of maximum relative cerebral blood volume in dynamic susceptibility contrast (DSC) perfusion MRI. The skewness of the transfer constantin dynamic contrast-enhanced (DCE) perfusion MRI, and the standard deviation of relative cerebral blood flow in DSC perfusion MRI could most efficiently discriminate between glioma grades II and III. In diffusion MRI, tumour fractional anisotropy differed between suspected low-grade gliomas of different neuropathological types. Quantitative diffusion tensor tractography was applicable for the evaluation of tract segment infiltration. Conclusion: PET and physiological MRI are able to characterise low-grade gliomas and are promising tools for guiding therapy and clinical decisions before neuropathological diagnosis has been obtained.

Geodesic Tractography Segmentation is the two component approach presented in this thesis for the analysis of imagery in oriented domains, with emphasis on the application to diffusion-weighted magnetic resonance imagery (DW-MRI). The computeraided analysis of DW-MRI data presents a new set of problems and opportunities for the application of mathematical and computer vision techniques. The goal is to develop a set of tools that enable clinicians to better understand DW-MRI data and ultimately shed new light on biological processes. This thesis presents a few techniques and tools which may be used to automatically find and segment major neural fiber bundles from DW-MRI data. For each technique, we provide a brief overview of the advantages and limitations of our approach relative to other available approaches. / Acknowledgements page removed per author's request, 01/06/2014.