Addressing the path-length-dependency confound in white matter tract segmentation

We derive the Iterative Confidence Enhancement of Tractography (ICE-T) framework to address the problem of path-length dependency (PLD), the streamline dispersivity confound inherent to probabilistic tractography methods. We show that PLD can arise as a non-linear effect, compounded by tissue complexity, and therefore cannot be handled using linear correction methods. ICE-T is an easy-to-implement framework that acts as a wrapper around most probabilistic streamline tractography methods, iteratively growing the tractography seed regions. Tract networks segmented with ICE-T can subsequently be delineated with a global threshold, even from a single-voxel seed. We investigated ICE-T performance using ex vivo pig-brain datasets where true positives were known via in vivo tracers, and applied the derived ICE-T parameters to a human in vivo dataset. We examined the parameter space of ICE-T: the number of streamlines emitted per voxel, and a threshold applied at each iteration. As few as 20 streamlines per seed-voxel, and a robust range of ICE-T thresholds, were shown to sufficiently segment the desired tract network. Outside this range, the tract network either approximated the complete white-matter compartment (too low threshold) or failed to propagate through complex regions (too high threshold). The parameters were shown to be generalizable across seed regions. With ICE-T, the degree of both near-seed flare due to false positives, and of distal false negatives, are decreased when compared with thresholded probabilistic tractography without ICE-T. Since ICE-T only addresses PLD, the degree of remaining false-positives and false-negatives will consequently be mainly attributable to the particular tractography method employed. Given the benefits offered by ICE-T, we would suggest that future studies consider this or a similar approach when using tractography to provide tract segmentations for tract based analysis, or for brain network analysis

Characterising population variability in brain structure through models of whole-brain structural connectivity

Models of whole-brain connectivity are valuable for understanding neurological function. This thesis seeks to develop an optimal framework for extracting models of whole-brain connectivity from clinically acquired diffusion data. We propose new approaches for studying these models. The aim is to develop techniques which can take models of brain connectivity and use them to identify biomarkers or phenotypes of disease. The models of connectivity are extracted using a standard probabilistic tractography algorithm, modified to assess the structural integrity of tracts, through estimates of white matter anisotropy. Connections are traced between 77 regions of interest, automatically extracted by label propagation from multiple brain atlases followed by classifier fusion. The estimates of tissue integrity for each tract are input as indices in 77x77 ”connectivity” matrices, extracted for large populations of clinical data. These are compared in subsequent studies. To date, most whole-brain connectivity studies have characterised population differences using graph theory techniques. However these can be limited in their ability to pinpoint the locations of differences in the underlying neural anatomy. Therefore, this thesis proposes new techniques. These include a spectral clustering approach for comparing population differences in the clustering properties of weighted brain networks. In addition, machine learning approaches are suggested for the first time. These are particularly advantageous as they allow classification of subjects and extraction of features which best represent the differences between groups. One limitation of the proposed approach is that errors propagate from segmentation and registration steps prior to tractography. This can cumulate in the assignment of false positive connections, where the contribution of these factors may vary across populations, causing the appearance of population differences where there are none. The final contribution of this thesis is therefore to develop a common co-ordinate space approach. This combines probabilistic models of voxel-wise diffusion for each subject into a single probabilistic model of diffusion for the population. This allows tractography to be performed only once, ensuring that there is one model of connectivity. Cross-subject differences can then be identified by mapping individual subjects’ anisotropy data to this model. The approach is used to compare populations separated by age and gender

High-Resolution Tractography Protocol to Investigate the Pathways between Human Mediodorsal Thalamic Nucleus and Prefrontal Cortex

Published: November 15, 2023Animal studies have established that the mediodorsal nucleus (MD) of the thalamus is heavily and reciprocally connected with all areas of the prefrontal cortex (PFC). In humans, however, these connections are difficult to investigate. High-resolution imaging protocols capable of reliably tracing the axonal tracts linking the human MD with each of the PFC areas may thus be key to advance our understanding of the variation, development, and plastic changes of these important circuits, in health and disease. Here, we tested in adult female and male humans the reliability of a new reconstruction protocol based on in vivo diffusion MRI to trace, measure, and characterize the fiber tracts interconnecting the MD with 39 human PFC areas per hemisphere. Our protocol comprised the following three components: (1) defining regions of interest; (2) preprocessing diffusion data; and, (3) modeling white matter tracts and tractometry. This analysis revealed largely separate PFC territories of reciprocal MD–PFC tracts bearing striking resemblance with the topographic layout observed in macaque connection-tracing studies. We then examined whether our protocol could reliably reconstruct each of these MD–PFC tracts and their profiles across test and retest sessions. Results revealed that this protocol was able to trace and measure, in both left and right hemispheres, the trajectories of these 39 area-specific axon bundles with good-to-excellent test-retest reproducibility. This protocol, which has been made publicly available, may be relevant for cognitive neuroscience and clinical studies of normal and abnormal PFC function, development, and plasticity.L.M. was supported by Horizon 2020 the European Union’s research and innovation program under Marie Skłodowska-Curie Grant 713673 and from “la Caixa” Foundation (Grants 11660016 and 100010434 under Agreement HR18-00178-DYSTHAL). G.L-U. was supported by the Spanish Ministry of Science and Innovation (Grants IJC2020-042887-I and PID2021-123577NA-I00) and the Basque Government (Grant PIBA-2022-1- 0014). F.C. was supported by the Spanish Ministry of Science and Innovation (Grants MICINN-AEI PCI2019- 111900-2 and PID2020-115780GB-I00). P.M.P-A. was supported by the Spanish Ministry of Science and Innovation (Grant PID2021-123574NB-I00), the Basque Government (Grant PIBA-2021-1-0003), and the Red guipuzcoana de Ciencia, Tecnología e Innovación of the Diputación Foral de Gipuzkoa (Grant FA/OF 422/2022), and “la Caixa” Foundation (Grant 100010434 under Agreement HR18-00178-DYSTHAL). The Basque Center on Cognition, Brain and Language (BCBL) acknowledges funding from the Basque Government through the BERC 2022-2025 program and by the Spanish State Research Agency through BCBL Severo Ochoa Excellence Accreditation CEX2020-001010-S

HARDI Methods: tractography reconstructions and automatic parcellation of brain connectivity

Tese de mestrado integrado em Engenharia Biomédica e Biofísica (Radiações em Diagnóstico e Terapia), apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2012A neuroanatomia humana tem sido objecto de estudo científico desde que surgiu o interesse na organização do corpo humano e nas suas funções, quer como um todo quer através das partes que o constituem. Para atingir este fim, as autópsias foram a primeira forma de revelar algum conhecimento, o qual tem vindo a ser catalogado e sistematizado à medida que a medicina evolui. Passando por novas técnicas de conservação e tratamento de tecido humano, de que são exemplo as dissecções de Klinger, nas quais se fazem secções de material conservado criogenicamente, bem como por estudos histológicos através da utilização de corantes, conseguiu-se uma forma complementar de realizar estes estudos. Permanecia, no entanto, a impossibilidade de analisar in vivo a estrutura e função dos diferentes sistemas que constitutem o Homem. Com o surgimento das técnicas imagiológicas o diagnóstico e monitorização do corpo humano, bem como das patologias a ele associadas, melhoraram consideravelmente. Mais recentemente, com o aparecimento da ressonância magnética (MRI: do Inglês "Magnetic Resonance Imaging"), tornou-se possível estudar as propriedades magnéticas do tecido, reflectindo as suas características intrínsecas com base na aplicação de impulsos de radiofrequência. Através de ressonância magnética é possível estudar essas propriedades em vários núcleos atómicos, sendo mais comum o estudo do hidrogénio, pois somos maioritariamente consistituídos por água e gordura. Uma vez que só é possível medir variações do campo magnético, aplicam-se impulsos de radiofrequência para perturbar o equilíbrio dos spins e medir os seus mecanismos de relaxação, os quais, indirectamente, reflectem a estrutura do tecido. Contudo, o sinal medido é desprovido de qualquer informação espacial. De facto, para podermos proceder a essa quantificação, é necessária a utilização de gradientes de campo magnético, que permitem modificar localmente a frequência de precessão dos protões, através da alteração local do campo magnético, permitindo assim, adquirir o sinal de forma sequencial. A informação obtida constitui uma função variável no espaço e através da transformação de Fourier pode ser quantificada em frequências espaciais, sendo estes dados armazenados no espaço k. O preencimento deste espaço, caracterizado por frequências espaciais, bem como os gradientes de campo magnético que são aplicados, permitem determinar a resolução da imagem que podemos obter, aplicando uma transformação de Fourier inversa. O estudo da ressonância magnética não se restringe à análise da estrutura mas também ao estudo da função e difusão das moléculas de água. A difusão é um processo aleatório, que se traduz pelo movimento térmico das moléculas de água, e o seu estudo permite inferir sobre o estado do tecido e microestrutura associada, de uma forma não invasiva e in vivo. A técnica de imagiologia de ressonância magnética ponderada por difusão (DWI: do Inglês "Diffusion Weighted Imaging") permite o estudo da direccionalidade das moléculas de água e extracção de índices que reflectem directamente a integridade dos tecidos biológicos. De modo a sensibilizar as moléculas de água à difusão, é necessário aplicar sequências de ressonância magnética modificadas, nas quais se aplicam gradientes de campo magnético de difusão para quantificar o deslocamento das moléculas e a sua relação com o coeficiente de difusão das mesmas. Num ambiente livre e sem barreiras a difusão das moléculas de água é isotrópica, uma vez que se apresenta igual em todas as direcções. Todavia, tal não se verifica no corpo humano. A presença destas barreiras leva a que, na verdade, apenas possa ser medido um coeficiente de difusão aparente. Este, por sua vez, traduz a interacção entre as moléculas de água com a microestrutura e, como tal, uma anisotropia na sua difusão. Como caso particular de difusão anisotrópica a nível cerebral, tem-se a difusão das moléculas de água na matéria branca, uma vez que esta apresenta uma direccionalidade preferencial de acordo com a orientação dos axónios, visto estarem presentes menos restrições à sua propagação, ao contrário do que acontece com a direcção perpendicular (devido à membrana celular e às bainhas de mielina). Por oposição, a matéria cinzenta, constituída pelo aglomerado dos corpos celulares dos neurónios, e o líquido cefalorraquidiano apresentam uma difusão sem direcção preferencial (i.e. aproximadamente isotrópica). A informação obtida através da difusão das moléculas de água encontra-se limitada pelo número de direcções segundo o qual aplicamos os gradientes de difusão. Deste modo, surgiu a imagiologia por tensor de difusão (DTI: do Inglês "Diffusion Tensor Imaging"). Esta técnica permite extrair informação acerca da tridimensionalidade da distribuição da difusão de moléculas de água através da aplicação de seis gradientes de difusão não colineares entre si. A distribuição destas moléculas pode, então, ser vista como um elipsóide, no qual o principal vector próprio do tensor representa a contribuição da difusão das moléculas segundo a direcção do axónio (ou paralela), sendo os dois restantes componentes responsáveis pela contribuição transversal. Além da difusividade média (MD: do Inglês "Mean Diffusivity") e das contribuições da difusão paralela (MD//) e perpendicular (MD ) às fibras, é também possível extrair outros índices, como a anisotropia fraccional (FA: do Inglês "Fractional Anisotropy"), que fornece informação acerca da percentagem de difusão anisotrópica num determinado voxel. Para a matéria branca, tal como já foi referido, existe difusão preferencial e, portanto, a anisotropia fraccional será elevada. Por outro lado, para a matéria cinzenta e para o líquido cefalorraquidiano, verificar-se-á uma FA reduzida, devido à ausência de anisotropia. Todavia, regiões com reduzida anisotropia fraccional podem camuflar regiões de conformação de cruzamento de fibras, ou fibras muito anguladas, que a imagiologia por tensor de difusão não consegue resolver. A razão para esta limitação reside no número reduzido de diferentes direcções de difusão que são exploradas, assim como o pressuposto de que a distribuição das moléculas de água é Gaussiana em todo o cérebro, o que não é necessariamente verdade. A fim de se ultrapassar estas limitações, novas técnicas surgiram, nomeadamente as de elevada resolução angular (HARDI: do Inglês "High Angular Resolution Diffusion Imaging"). Estas fazem uso de uma aquisição em função de múltiplas direcções de gradiente e de uma diferente modelação dos dados obtidos, dividindo-se em dois tipos. As técnicas livres de modelos permitem extrair uma função de distribuição da orientação das fibras num determinado voxel directamente do sinal e/ou transformações da função densidade de probabilidade do deslocamento das moléculas de água. Contrariamente, as técnicas baseadas em modelos admitem existir determinados constrangimentos anatómicos e que o sinal proveniente de um determinado voxel é originado por um conjunto de sinais individuais de fibras, caracterizados por uma distribuição preferencial das direcções das fibras. Todos estes métodos têm como objectivo principal recuperar a direcção preferencial da difusão das moléculas de água e reconstruir um trajecto tridimensional que represente a organização das fibras neuronais, pelo que se designam métodos de tractografia. Esta representa a única ferramenta não invasiva de visualização in vivo da matéria branca cerebral e o seu estudo tem revelado uma grande expansão associada ao estabelecimento de marcador biológico para diversas patologias. Adicionalmente, esta técnica tem vindo a tornar-se uma modalidade clínica de rotina e de diversos protocolos de investigação, sendo inclusivamente utilizada para complementar o planeamento em cirurgia, devido à natureza dos dados que gera. Particularmente no caso de dissecções manuais, nas quais os dados de tractografia são manuseados por pessoal especializado, com vista a realizar a parcelização de diferentes tractos de interesse, o processo é moroso e dependente do utilizador, revelando-se necessária a automatização do mesmo. Na realidade, já existem técnicas automáticas que fazem uso de algoritmos de agregação1, nos quais fibras são analisadas e agrupadas segundo características semelhantes, assim como técnicas baseadas em regiões de interesse, em que se extraem apenas os tractos seleccionados entre as regiões escolhidas. O objectivo principal desta dissertação prende-se com a análise automática de dados de tractografia, bem como a parcelização personalizada de tractos de interesse, também esta automática. Em primeiro lugar, foi desenvolvido um algoritmo capaz de lidar automaticamente com funções básicas de carregamento dos ficheiros de tractografia, o seu armazenamento em variáveis fáceis de manusear e a sua filtragem básica de acordo com regiões de interesse de teste. Neste processo de filtragem é feita a avaliação das fibras que atravessam a região de interesse considerada. Assim, após a localização das fibras entre as regiões de interesse os tractos resultantes podem ser guardados de duas formas, as quais têm, necessariamente, que ser especificadas antes de utilizar o software: um ficheiro que contém todas as fibras resultantes da parcelização e outro que contém o mapa de densidade associado, isto é, o número de fibras que se encontra em cada voxel. Após esta fase inicial, a flexibilidade e complexidade do software foi aumentando, uma vez que foram implementados novos filtros e a possibilidade de utilizar regiões de interesse de diferentes espaços anatómicos padrão. Fazendo uma análise a esta última melhoria, pode referir-se que, através de um procedimento de registo não linear da imagem anatómica do espaço padrão ao espaço individual de cada sujeito, foi possível, de forma automática, guardar o campo de deformações que caracteriza a transformação e, assim, gerar regiões de interesse personalizadas ao espaço do sujeito. Estas regiões de interesse serviram depois para a parcelização básica e para seleccionar tractos, mas também para filtragens adicionais, como a exclusão de fibras artefactuosas2 e um filtro especial, no qual apenas os pontos que ligam directamente as diferentes regiões são mantidos. Além do que já foi referido, recorreu-se também à aplicação de planos de interesse que actuam como constrangimentos neuroanatómicos, o que não permite, por exemplo, no caso da radiação óptica, que as fibras se propaguem para o lobo frontal. Esta ferramenta foi utilizada com sucesso para a parcelização automática do Fascículo Arcuado, Corpo Caloso e Radiação Óptica, tendo sido feita a comparação com a dissecção manual, em todos os casos. O estudo do Fasciculo Arcuado demonstrou ser o teste ideal para a ferramenta desenvolvida na medida que permitiu identificar o segmento longo, assim como descrito na literatura. O método automático de duas regiões de interesse deu a origem aos mesmos resultados obtidos manualmente e permitiu confirmar a necessidade de estudos mais aprofundados. Aumentando a complexidade do estudo, realizou-se a parcelização do Corpo Caloso de acordo com conectividade estrutural, isto é, com diferentes regiões envolvidas em funções distintas. Procedeu-se deste modo, e não com base em informação acerca de divisões geométricas, uma vez que estas já demonstraram incongruências quando correlacionadas com subdivisões funcionais. O uso adicional de regiões de interesse para a exclusão de fibras demonstrou-se benéfico na obtenção dos mapas finais. Finalmente, incluiu-se a utilização de um novo filtro para realizar a parcelização da Radiação Óptica, comparando os resultados para DTI e SD(do Inglês "Spherical Deconvolution"). Foi possível determinar limitações na primeira técnica que foram, no entanto, ultrapassadas pela utilização de SD. O atlas final gerado apresenta-se como uma mais-valia para o planeamento cirúrgico num ambiente clínico. O desenvolvimento desta ferramenta resultou em duas apresentações orais em conferências internacionais e encontra-se, de momento, a ser melhorada, a fim de se submeter um artigo de investigação original. Embora se tenha chegado a um resultado final positivo, tendo em conta a meta previamente estabelecida, está aberto o caminho para o seu aperfeiçoamento. Como exemplo disso, poder-se-á recorrer ao uso combinado das duas abordagens de parcelização automática e à utilização de índices específicos dos tractos, o que poderá trazer uma nova força à delineação dos tractos de interesse. Adicionalmente, é também possível melhorar os algoritmos de registo de imagem, tendo em conta a elevada variabilidade anatómica que alguns sujeitos apresentam. Como nota final, gostaria apenas de salientar que a imagiologia por difusão e, em particular, a tractografia, têm ainda muito espaço para progredir. A veracidade desta afirmação traduz-se pela existência de uma grande variedade de modelos e algoritmos implementados, sem que, no entanto, exista consenso na comunidade científica acerca da melhor abordagem a seguir.Diffusion weighted imaging (DWI) has provided us a non-invasive technique to determine physiological information and infer about tissue microstructure. The human body is filled with barriers affecting the mobility of molecules and preventing it from being constant in different directions (anisotropic diffusion). In the brain, the sources for this anisotropy arise from dense packing axons and from the myelin sheath that surrounds them. Only with Diffusion Tensor Imaging (DTI) it was possible to fully characterize anisotropy by offering estimations for average diffusivities in each voxel. However, these methods were limited, not being able to reflect the index of anisotropic diffusion in regions with complex fibre conformations. It was possible to reduce those problems through the acquisition of many gradient directions with High Angular Resolution Diffusion Imaging (HARDI). There are model-free approaches such as Diffusion Spectrum Imaging (DSI) and Q-ball Imaging (QBI) which retrieve an orientation distribution function (ODF) directly from the water molecular displacement. Another method is Spherical Deconvolution, which is a model-based approach based on the computation of a fibre orientation distribution (FOD) from the deconvolution of the diffusion signal and a chosen fibre response function. Reconstructing the fibre orientations from the diffusion profile, generates a three-dimensional reconstruction of neuronal fibres (Tractography) whether in a deterministic, probabilistic or global way. Tractography has two main purposes: non-invasive and in vivo mapping of human white matter and neurosurgical planning. In order to achieve those purposes it is common to apply parcellation techniques which can be subdivided into ROI-based or Clustering base. The aim of this project is to develop an automated method of tract-based parcellation of different brain regions. This tool is essential to retrieve information about the architecture and connectivity of the brain, overcoming time consuming and expertise related issues derived from manual dissections. Firstly we investigated basic functions to handle diffusion and tractography data. In particular, we focused on how to load track files, filter them according to regions of interest and save the output in different formats. Results were always compared with manual dissection. The developed tool increased complexity by introduction a new filtering and the use of regions of interest from different standard spaces, created trough non-linear registrations. Three major tracts of interest were analysed: Arcuate Fasciculus, Corpus Callosum and Optic Radiation

Unsupervised deep learning of human brain diffusion magnetic resonance imaging tractography data

L'imagerie par résonance magnétique de diffusion est une technique non invasive permettant de connaître la microstructure organisationnelle des tissus biologiques. Les méthodes computationnelles qui exploitent la préférence orientationnelle de la diffusion dans des structures restreintes pour révéler les voies axonales de la matière blanche du cerveau sont appelées tractographie. Ces dernières années, diverses méthodes de tractographie ont été utilisées avec succès pour découvrir l'architecture de la matière blanche du cerveau. Pourtant, ces techniques de reconstruction souffrent d'un certain nombre de défauts dérivés d'ambiguïtés fondamentales liées à l'information orientationnelle. Cela a des conséquences dramatiques, puisque les cartes de connectivité de la matière blanche basées sur la tractographie sont dominées par des faux positifs. Ainsi, la grande proportion de voies invalides récupérées demeure un des principaux défis à résoudre par la tractographie pour obtenir une description anatomique fiable de la matière blanche. Des approches méthodologiques innovantes sont nécessaires pour aider à résoudre ces questions. Les progrès récents en termes de puissance de calcul et de disponibilité des données ont rendu possible l'application réussie des approches modernes d'apprentissage automatique à une variété de problèmes, y compris les tâches de vision par ordinateur et d'analyse d'images. Ces méthodes modélisent et trouvent les motifs sous-jacents dans les données, et permettent de faire des prédictions sur de nouvelles données. De même, elles peuvent permettre d'obtenir des représentations compactes des caractéristiques intrinsèques des données d'intérêt. Les approches modernes basées sur les données, regroupées sous la famille des méthodes d'apprentissage profond, sont adoptées pour résoudre des tâches d'analyse de données d'imagerie médicale, y compris la tractographie. Dans ce contexte, les méthodes deviennent moins dépendantes des contraintes imposées par les approches classiques utilisées en tractographie. Par conséquent, les méthodes inspirées de l'apprentissage profond conviennent au changement de paradigme requis, et peuvent ouvrir de nouvelles possibilités de modélisation, en améliorant ainsi l'état de l'art en tractographie. Dans cette thèse, un nouveau paradigme basé sur les techniques d'apprentissage de représentation est proposé pour générer et analyser des données de tractographie. En exploitant les architectures d'autoencodeurs, ce travail tente d'explorer leur capacité à trouver un code optimal pour représenter les caractéristiques des fibres de la matière blanche. Les contributions proposées exploitent ces représentations pour une variété de tâches liées à la tractographie, y compris (i) le filtrage et (ii) le regroupement efficace sur les résultats générés par d'autres méthodes, ainsi que (iii) la reconstruction proprement dite des fibres de la matière blanche en utilisant une méthode générative. Ainsi, les méthodes issues de cette thèse ont été nommées (i) FINTA (Filtering in Tractography using Autoencoders), (ii) CINTA (Clustering in Tractography using Autoencoders), et (iii) GESTA (Generative Sampling in Bundle Tractography using Autoencoders), respectivement. Les performances des méthodes proposées sont évaluées par rapport aux méthodes de l'état de l'art sur des données de diffusion synthétiques et des données de cerveaux humains chez l'adulte sain in vivo. Les résultats montrent que (i) la méthode de filtrage proposée offre une sensibilité et spécificité supérieures par rapport à d'autres méthodes de l'état de l'art; (ii) le regroupement des tractes dans des faisceaux est fait de manière consistante; et (iii) l'approche générative échantillonnant des tractes comble mieux l'espace de la matière blanche dans des régions difficiles à reconstruire. Enfin, cette thèse révèle les possibilités des autoencodeurs pour l'analyse des données des fibres de la matière blanche, et ouvre la voie à fournir des données de tractographie plus fiables.Abstract : Diffusion magnetic resonance imaging is a non-invasive technique providing insights into the organizational microstructure of biological tissues. The computational methods that exploit the orientational preference of the diffusion in restricted structures to reveal the brain's white matter axonal pathways are called tractography. In recent years, a variety of tractography methods have been successfully used to uncover the brain's white matter architecture. Yet, these reconstruction techniques suffer from a number of shortcomings derived from fundamental ambiguities inherent to the orientation information. This has dramatic consequences, since current tractography-based white matter connectivity maps are dominated by false positive connections. Thus, the large proportion of invalid pathways recovered remains one of the main challenges to be solved by tractography to obtain a reliable anatomical description of the white matter. Methodological innovative approaches are required to help solving these questions. Recent advances in computational power and data availability have made it possible to successfully apply modern machine learning approaches to a variety of problems, including computer vision and image analysis tasks. These methods model and learn the underlying patterns in the data, and allow making accurate predictions on new data. Similarly, they may enable to obtain compact representations of the intrinsic features of the data of interest. Modern data-driven approaches, grouped under the family of deep learning methods, are being adopted to solve medical imaging data analysis tasks, including tractography. In this context, the proposed methods are less dependent on the constraints imposed by current tractography approaches. Hence, deep learning-inspired methods are suit for the required paradigm shift, may open new modeling possibilities, and thus improve the state of the art in tractography. In this thesis, a new paradigm based on representation learning techniques is proposed to generate and to analyze tractography data. By harnessing autoencoder architectures, this work explores their ability to find an optimal code to represent the features of the white matter fiber pathways. The contributions exploit such representations for a variety of tractography-related tasks, including efficient (i) filtering and (ii) clustering on results generated by other methods, and (iii) the white matter pathway reconstruction itself using a generative method. The methods issued from this thesis have been named (i) FINTA (Filtering in Tractography using Autoencoders), (ii) CINTA (Clustering in Tractography using Autoencoders), and (iii) GESTA (Generative Sampling in Bundle Tractography using Autoencoders), respectively. The proposed methods' performance is assessed against current state-of-the-art methods on synthetic data and healthy adult human brain in vivo data. Results show that the (i) introduced filtering method has superior sensitivity and specificity over other state-of-the-art methods; (ii) the clustering method groups streamlines into anatomically coherent bundles with a high degree of consistency; and (iii) the generative streamline sampling technique successfully improves the white matter coverage in hard-to-track bundles. In summary, this thesis unlocks the potential of deep autoencoder-based models for white matter data analysis, and paves the way towards delivering more reliable tractography data

Probing the brain’s white matter with diffusion MRI and a tissue dependent diffusion model

While diffusion MRI promises an insight into white matter microstructure in vivo, the axonal pathways that connect different brain regions together can only partially be segmented using current methods. Here we present a novel method for estimating the tissue composition of each voxel in the brain from diffusion MRI data, thereby providing a foundation for computing the volume of different pathways in both health and disease. With the tissue dependent diffusion model described in this thesis, white matter is segmented by removing the ambiguity caused by the isotropic partial volumes: both grey matter and cerebrospinal fluid. Apart from the volume fractions of all three tissue types, we also obtain estimates of fibre orientations for tractography as well as diffusivity and anisotropy parameters which serve as proxy indices of pathway coherence. We assume Gaussian diffusion of water molecules for each tissue type. The resulting three-tensor model comprises one anisotropic (white matter) compartment modelled by a cylindrical tensor and two isotropic compartments (grey matter and cerebrospinal fluid). We model the measurement noise using a Rice distribution. Markov chain Monte Carlo sampling techniques are used to estimate posterior distributions over the model’s parameters. In particular, we employ a Metropolis Hastings sampler with a custom burn-in and proposal adaptation to ensure good mixing and efficient exploration of the high-probability region. This way we obtain not only point estimates of quantities of interest, but also a measure of their uncertainty (posterior variance). The model is evaluated on synthetic data and brain images: we observe that the volume maps produced with our method show plausible and well delineated structures for all three tissue types. Estimated white matter fibre orientations also agree with known anatomy and align well with those obtained using current methods. Importantly, we are able to disambiguate the volume and anisotropy information thus alleviating partial volume effects and providing measures superior to the currently ubiquitous fractional anisotropy. These improved measures are then applied to study brain differences in a cohort of healthy volunteers aged 25-65 years. Lastly, we explore the possibility of using prior knowledge of the spatial variability of our parameters in the brain to further improve the estimation by pooling information among neighbouring voxels

Investigating white matter changes underlying overactive bladder in multiple sclerosis with diffusion MRI

Lower urinary tract symptoms (LUTS) are presented in more than 80% of multiple sclerosis (MS) patients. Current understanding of LUT control is based on studies exploring activities in grey matter (GM) and investigating functional correlations with LUTS. The relationship between white matter (WM) changes and overactive bladder (OAB) symptoms are limited to findings in small vessel disease, and the nature of the association between WM changes and OAB symptoms is poorly understood. Advanced diffusion-weighted magnetic resonance imaging (MRI) techniques provide non-invasive techniques to study WM abnormalities and correlates to clinical observations. The overarching objectives of this work are to explore WM abnormalities subtending OAB symptoms in MS, and to reconstruct the structural network underpinning the working model of lower urinary tract (LUT) control. Using Tract-Based Spatial Statistics (TBSS), OAB symptoms related WM abnormalities in MS can be identified, and a structural network subtending OAB symptoms in MS can be subsequently created. The findings of this work illustrate the correlation between OAB symptoms severity and WM abnormalities in MS. These were observed in regions in frontal lobes and non-dominant hemisphere, including corpus callosum, anterior corona radiata bilaterally, right anterior thalamic radiation, superior longitudinal fasciculus bilaterally, and right inferior longitudinal fasciculus. The structural network created for OAB symptoms in MS connected regions known to be involved in the working model of LUT control, and the network identified connectivity between insula and frontal lobe, which is the key circuit for perception of bladder fullness. Moreover, structural connectivity between insula-temporal lobe and insula-occipital lobe were observed, which may underpin changes seen in functional MRI (fMRI) studies. The novel findings of this study present WM abnormalities and structural connectivity subtending LUTS in MS with diffusion-weighted imaging (DWI). The techniques used in this work can be applied to other patterns of LUTS and other neurological diseases

Myelination of Preterm Brain Networks at Adolescence

Prematurity and preterm stressors severely affect the development of infants born before 37 weeks of gestation, with increasing effects seen at earlier gestations. Although preterm mortality rates have declined due to the advances in neonatal care, disability rates, especially in middle-income settings, continue to grow. With the advances in MRI imaging technology, there has been a focus on safely imaging the preterm brain to better understand its development and discover the brain regions and networks affected by prematurity. Such studies aim to support interventions and improve the neurodevelopment of preterm infants and deliver accurate prognoses. Few studies, however, have focused on the fully developed brain of preterm born infants, especially in extremely preterm subjects. To assess the long-term effect of prematurity on the adult brain, myelin related biomarkers such as myelin water fraction and g-ratio are measured for a cohort of 19-year-old extremely preterm subjects. Using multi-modal imaging techniques that combine T2 relaxometry and neurite density information, the results show that specific regions of the brain associated with white matter injuries due to preterm birth, such as the Posterior Limb of the Internal Capsule and Corpus Callosum, are still less myelinated in adulthood. Such findings might imply reduced connectivity in the adult preterm brain and explain the poor cognitive outcome

Effect of perinatal adversity on structural connectivity of the developing brain

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

From Diffusion MRI to Brain Connectomics

International audienceDiffusion MRI (dMRI) is a unique modality of MRI which allows one to indirectly examine the microstructure and integrity of the cerebral white matter in vivo and non-invasively. Its success lies in its capacity to reconstruct the axonal connectivity of the neurons, albeit at a coarser resolution, without having to operate on the patient, which can cause radical alterations to the patient's cognition. Thus dMRI is beginning to assume a central role in studying and diagnosing important pathologies of the cerebral white matter, such as Alzheimer's and Parkinson's diseases, as well as in studying its physical structure in vivo. In this chapter we present an overview of the mathematical tools that form the framework of dMRI - from modelling the MRI signal and measuring diffusion properties, to reconstructing the axonal connectivity of the cerebral white matter, i.e., from Diffusion Weighted Images (DWIs) to the human connectome