Examining the development of brain structure in utero with fetal MRI, acquired as part of the Developing Human Connectome Project

The human brain is an incredibly complex organ, and the study of it traverses many scales across space and time. The development of the brain is a protracted process that begins embryonically but continues into adulthood. Although neural circuits have the capacity to adapt and are modulated throughout life, the major structural foundations are laid in utero during the fetal period, through a series of rapid but precisely timed, dynamic processes. These include neuronal proliferation, migration, differentiation, axonal pathfinding, and myelination, to name a few. The fetal origins of disease hypothesis proposed that a variety of non-communicable diseases emerging in childhood and adulthood could be traced back to a series of risk factors effecting neurodevelopment in utero (Barker 1995). Since this publication, many studies have shown that the structural scaffolding of the brain is vulnerable to external environmental influences and the perinatal developmental window is a crucial determinant of neurological health later in life. However, there remain many fundamental gaps in our understanding of it. The study of human brain development is riddled with biophysical, ethical, and technical challenges. The Developing Human Connectome Project (dHCP) was designed to tackle these specific challenges and produce high quality open-access perinatal MRI data, to enable researchers to investigate normal and abnormal neurodevelopment (Edwards et al., 2022). This thesis will focus on investigating the diffusion-weighted and anatomical (T2) imaging data acquired in the fetal period, between the second to third trimester (22 – 37 gestational weeks). The limitations of fetal MR data are ill-defined due to a lack of literature and therefore this thesis aims to explore the data through a series of critical and strategic analysis approaches that are mindful of the biophysical challenges associated with fetal imaging. A variety of analysis approaches are optimised to quantify structural brain development in utero, exploring avenues to relate the changes in MR signal to possible neurobiological correlates. In doing so, the work in this thesis aims to improve mechanistic understanding about how the human brain develops in utero, providing the clinical and medical imaging community with a normative reference point. To this aim, this thesis investigates fetal neurodevelopment with advanced in utero MRI methods, with a particular emphasis on diffusion MRI. Initially, the first chapter outlines a descriptive, average trajectory of diffusion metrics in different white matter fiber bundles across the second to third trimester. This work identified unique polynomial trajectories in diffusion metrics that characterise white matter development (Wilson et al., 2021). Guided by previous literature on the sensitivity of DWI to cellular processes, I formulated a hypothesis about the biophysical correlates of diffusion signal components that might underpin this trend in transitioning microstructure. This hypothesis accounted for the high sensitivity of the diffusion signal to a multitude of simultaneously occurring processes, such as the dissipating radial glial scaffold, commencement of pre-myelination and arborization of dendritic trees. In the next chapter, the methods were adapted to address this hypothesis by introducing another dimension, and charting changes in diffusion properties along developing fiber pathways. With this approach it was possible to identify compartment-specific microstructural maturation, refining the spatial and temporal specificity (Wilson et al., 2023). The results reveal that the dynamic fluctuations in the components of the diffusion signal correlate with observations from previous histological work. Overall, this work allowed me to consolidate my interpretation of the changing diffusion signal from the first chapter. It also serves to improve understanding about how diffusion signal properties are affected by processes in transient compartments of the fetal brain. The third chapter of this thesis addresses the hypothesis that cortical gyrification is influenced by both underlying fiber connectivity and cytoarchitecture. Using the same fetal imaging dataset, I analyse the tissue microstructural change underlying the formation of cortical folds. I investigate correlations between macrostructural surface features (curvature, sulcal depth) and tissue microstructural measures (diffusion tensor metrics, and multi-shell multi-tissue decomposition) in the subplate and cortical plate across gestational age, exploring this relationship both at the population level and within subjects. This study provides empirical evidence to support the hypotheses that microstructural properties in the subplate and cortical plate are altered with the development of sulci. The final chapter explores the data without anatomical priors, using a data-driven method to extract components that represent coordinated structural maturation. This analysis aims to examine if brain regions with coherent patterns of growth over the fetal period converge on neonatal functional networks. I extract spatially independent features from the anatomical imaging data and quantify the spatial overlap with pre-defined neonatal resting state networks. I hypothesised that coherent spatial patterns of anatomical development over the fetal period would map onto the functional networks observed in the neonatal period. Overall, this thesis provides new insight about the developmental contrast over the second to third trimester of human development, and the biophysical correlates affecting T2 and diffusion MR signal. The results highlight the utility of fetal MRI to research critical mechanisms of structural brain maturation in utero, including white matter development and cortical gyrification, bridging scales from neurobiological processes to whole brain macrostructure. their gendered constructions relating to women

Anisotropy Across Fields and Scales

This open access book focuses on processing, modeling, and visualization of anisotropy information, which are often addressed by employing sophisticated mathematical constructs such as tensors and other higher-order descriptors. It also discusses adaptations of such constructs to problems encountered in seemingly dissimilar areas of medical imaging, physical sciences, and engineering. Featuring original research contributions as well as insightful reviews for scientists interested in handling anisotropy information, it covers topics such as pertinent geometric and algebraic properties of tensors and tensor fields, challenges faced in processing and visualizing different types of data, statistical techniques for data processing, and specific applications like mapping white-matter fiber tracts in the brain. The book helps readers grasp the current challenges in the field and provides information on the techniques devised to address them. Further, it facilitates the transfer of knowledge between different disciplines in order to advance the research frontiers in these areas. This multidisciplinary book presents, in part, the outcomes of the seventh in a series of Dagstuhl seminars devoted to visualization and processing of tensor fields and higher-order descriptors, which was held in Dagstuhl, Germany, on October 28–November 2, 2018

Anisotropy Across Fields and Scales

This open access book focuses on processing, modeling, and visualization of anisotropy information, which are often addressed by employing sophisticated mathematical constructs such as tensors and other higher-order descriptors. It also discusses adaptations of such constructs to problems encountered in seemingly dissimilar areas of medical imaging, physical sciences, and engineering. Featuring original research contributions as well as insightful reviews for scientists interested in handling anisotropy information, it covers topics such as pertinent geometric and algebraic properties of tensors and tensor fields, challenges faced in processing and visualizing different types of data, statistical techniques for data processing, and specific applications like mapping white-matter fiber tracts in the brain. The book helps readers grasp the current challenges in the field and provides information on the techniques devised to address them. Further, it facilitates the transfer of knowledge between different disciplines in order to advance the research frontiers in these areas. This multidisciplinary book presents, in part, the outcomes of the seventh in a series of Dagstuhl seminars devoted to visualization and processing of tensor fields and higher-order descriptors, which was held in Dagstuhl, Germany, on October 28–November 2, 2018

Diffusion directions imaging (high resolution reconstruction of white matter fascicles from low angular resolution diffusion MRI)

L'objectif de cette thèse est de fournir une chaine de traitement complète pour la reconstruction des faisceaux de la matière blanche à partir d'images pondérées en diffusion caractérisées par une faible résolution angulaire. Cela implique (i) d'inférer en chaque voxel un modèle de diffusion à partir des images de diffusion et (ii) d'accomplir une ''tractographie", i.e., la reconstruction des faisceaux à partir de ces modèles locaux. Notre contribution en modélisation de la diffusion est une nouvelle distribution statistique dont les propriétés sont étudiées en détail. Nous modélisons le phénomène de diffusion par un mélange de telles distributions incluant un outil de sélection de modèle destiné à estimer le nombre de composantes du mélange. Nous montrons que le modèle peut être correctement estimé à partir d'images de diffusion ''single-shell" à faible résolution angulaire et qu'il fournit des biomarqueurs spécifiques pour l'étude des tumeurs. Notre contribution en tractographie est un algorithme qui approxime la distribution des faisceaux émanant d'un voxel donné. Pour cela, nous élaborons un filtre particulaire mieux adapté aux distributions multi-modales que les filtres traditionnels. Pour démontrer l'applicabilité de nos outils en usage clinique, nous avons participé aux trois éditions du MICCAI DTI Tractography challenge visant à reconstruire le faisceau cortico-spinal à partir d'images de diffusion ''single-shell" à faibles résolutions angulaire et spatiale. Les résultats montrent que nos outils permettent de reconstruire toute l'étendue de ce faisceau.The objective of this thesis is to provide a complete pipeline that achieves an accurate reconstruction of the white matter fascicles using clinical diffusion images characterized by a low angular resolution. This involves (i) a diffusion model inferred in each voxel from the diffusion images and (ii) a tractography algorithm fed with these local models to perform the actual reconstruction of fascicles. Our contribution in diffusion modeling is a new statistical distribution, the properties of which are extensively studied. We model the diffusion as a mixture of such distributions, for which we design a model selection tool that estimates the number of mixture components. We show that the model can be accurately estimated from single shell low angular resolution diffusion images and that it provides specific biomarkers for studying tumors. Our contribution in tractography is an algorithm that approximates the distribution of fascicles emanating from a seed voxel. We achieve that by means of a particle filter better adapted to multi-modal distributions than the traditional filters. To demonstrate the clinical applicability of our tools, we participated to all three editions of the MICCAI DTI Tractography challenge aiming at reconstructing the cortico-spinal tract from single-shell low angular and low spatial resolution diffusion images. Results show that our pipeline provides a reconstruction of the full extent of the CST.RENNES1-Bibl. électronique (352382106) / SudocSudocFranceF

On noise, uncertainty and inference for computational diffusion MRI

Diffusion Magnetic Resonance Imaging (dMRI) has revolutionised the way brain microstructure and connectivity can be studied. Despite its unique potential in mapping the whole brain, biophysical properties are inferred from measurements rather than being directly observed. This indirect mapping from noisy data creates challenges and introduces uncertainty in the estimated properties. Hence, dMRI frameworks capable to deal with noise and uncertainty quantification are of great importance and are the topic of this thesis. First, we look into approaches for reducing uncertainty, by de-noising the dMRI signal. Thermal noise can have detrimental effects for modalities where the information resides in the signal attenuation, such as dMRI, that has inherently low-SNR data. We highlight the dual effect of noise, both in increasing variance, but also introducing bias. We then design a framework for evaluating denoising approaches in a principled manner. By setting objective criteria based on what a well-behaved denoising algorithm should offer, we provide a bespoke dataset and a set of evaluations. We demonstrate that common magnitude-based denoising approaches usually reduce noise-related variance from the signal, but do not address the bias effects introduced by the noise floor. Our framework also allows to better characterise scenarios where denoising can be beneficial (e.g. when done in complex domain) and can open new opportunities, such as pushing spatio-temporal resolution boundaries. Subsequently, we look into approaches for mapping uncertainty and design two inference frameworks for dMRI models, one using classical Bayesian methods and another using more recent data-driven algorithms. In the first approach, we build upon the univariate random-walk Metropolis-Hastings MCMC, an extensively used sampling method to sample from the posterior distribution of model parameters given the data. We devise an efficient adaptive multivariate MCMC scheme, relying upon the assumption that groups of model parameters can be jointly estimated if a proper covariance matrix is defined. In doing so, our algorithm increases the sampling efficiency, while preserving accuracy and precision of estimates. We show results using both synthetic and in-vivo dMRI data. In the second approach, we resort to Simulation-Based Inference (SBI), a data-driven approach that avoids the need for iterative model inversions. This is achieved by using neural density estimators to learn the inverse mapping from the forward generative process (simulations) to the parameters of interest that have generated those simulations. By addressing the problem via learning approaches offers the opportunity to achieve inference amortisation, boosting efficiency by avoiding the necessity of repeating the inference process for each new unseen dataset. It also allows inversion of forward processes (i.e. a series of processing steps) rather than only models. We explore different neural network architectures to perform conditional density estimation of the posterior distribution of parameters. Results and comparisons obtained against MCMC suggest speed-ups of 2-3 orders of magnitude in the inference process while keeping the accuracy in the estimates

On noise, uncertainty and inference for computational diffusion MRI

Diffusion Magnetic Resonance Imaging (dMRI) has revolutionised the way brain microstructure and connectivity can be studied. Despite its unique potential in mapping the whole brain, biophysical properties are inferred from measurements rather than being directly observed. This indirect mapping from noisy data creates challenges and introduces uncertainty in the estimated properties. Hence, dMRI frameworks capable to deal with noise and uncertainty quantification are of great importance and are the topic of this thesis. First, we look into approaches for reducing uncertainty, by de-noising the dMRI signal. Thermal noise can have detrimental effects for modalities where the information resides in the signal attenuation, such as dMRI, that has inherently low-SNR data. We highlight the dual effect of noise, both in increasing variance, but also introducing bias. We then design a framework for evaluating denoising approaches in a principled manner. By setting objective criteria based on what a well-behaved denoising algorithm should offer, we provide a bespoke dataset and a set of evaluations. We demonstrate that common magnitude-based denoising approaches usually reduce noise-related variance from the signal, but do not address the bias effects introduced by the noise floor. Our framework also allows to better characterise scenarios where denoising can be beneficial (e.g. when done in complex domain) and can open new opportunities, such as pushing spatio-temporal resolution boundaries. Subsequently, we look into approaches for mapping uncertainty and design two inference frameworks for dMRI models, one using classical Bayesian methods and another using more recent data-driven algorithms. In the first approach, we build upon the univariate random-walk Metropolis-Hastings MCMC, an extensively used sampling method to sample from the posterior distribution of model parameters given the data. We devise an efficient adaptive multivariate MCMC scheme, relying upon the assumption that groups of model parameters can be jointly estimated if a proper covariance matrix is defined. In doing so, our algorithm increases the sampling efficiency, while preserving accuracy and precision of estimates. We show results using both synthetic and in-vivo dMRI data. In the second approach, we resort to Simulation-Based Inference (SBI), a data-driven approach that avoids the need for iterative model inversions. This is achieved by using neural density estimators to learn the inverse mapping from the forward generative process (simulations) to the parameters of interest that have generated those simulations. By addressing the problem via learning approaches offers the opportunity to achieve inference amortisation, boosting efficiency by avoiding the necessity of repeating the inference process for each new unseen dataset. It also allows inversion of forward processes (i.e. a series of processing steps) rather than only models. We explore different neural network architectures to perform conditional density estimation of the posterior distribution of parameters. Results and comparisons obtained against MCMC suggest speed-ups of 2-3 orders of magnitude in the inference process while keeping the accuracy in the estimates

Translating Data from the Laboratory into Simulation: A Computational Framework for Subject-Specific Finite Element Musculoskeletal Simulation

Computational modeling is a powerful tool which has been used to inform decisions made by engineers, scientists, and clinicians for decades. Musculoskeletal modeling has emerged as a computational modeling technique used to understand the interaction between the body and its surroundings. There are several common approaches used for musculoskeletal modeling which take advantage of different model formulations to obtain information of interest. Unfortunately, models with different joint formulations inherit disparities in representations of ligament, muscle, and cartilage at joints of interest. These differences affect the way the joint functions and limit the insight it provides through computational analysis. Musculoskeletal models with high fidelity joint representations in a finite element framework have become increasingly viable in recent years, but three challenges limit progression: model personalization, modeling infrastructure, and computational efficiency. The goal of musculoskeletal modeling is almost entirely to understand the motion of the body, the mechanics of the joints, and the strain on the tissues in subjects performing various activities. These interests require models that act as the subject’s body would – a very complex task. Improving on methods in model personalization for calibrating joint strength, soft tissue response, and modeling geometry will continue to drive this work toward true subject specificity. Previously, software has been released which provides a modeling infrastructure for musculoskeletal modeling using rigid body dynamics. No such framework exists to build and perform musculoskeletal modeling with high fidelity joint representations in a finite element environment. A computational framework which provides methods to scale models and estimate joint kinematics and muscle forces directly from laboratory data would improve the accessibility and usability of these complex techniques. Developing tools which promote computational efficiency and manage effective parallelization of simulation and optimization will help improve the usability of musculoskeletal finite element modeling. The purpose of this work was to improve upon methods in musculoskeletal finite element modeling by developing novel techniques to evolve the current state-of-the-art in this area of research. Specifically, the first study calibrated the knee strength response of a musculoskeletal model of the lower limb to healthy data collected from subjects. The model was then used in the second study to perform concurrent estimation of muscle forces and tissue strain in subjects performing two activities. The third study considered markerbased motion and compared it to kinematics obtained from stereo radiography-based bone tracking. As part of this study a new set of polynomial splines describing the motion in 5 degrees of freedom at the knee were provided. Lastly, a computational framework was developed which served to scale a generic musculoskeletal finite element model and perform estimations of joint kinematics and muscle forces directly from laboratory data. The goal of this dissertation was to increase the accessibility of a powerful modeling approach to researchers around the globe by developing and advancing techniques which improve the usability of these methods