Development of High Angular Resolution Diffusion Imaging Analysis Paradigms for the Investigation of Neuropathology

Diffusion weighted magnetic resonance imaging (DW-MRI), provides unique insight into the microstructure of neural white matter tissue, allowing researchers to more fully investigate white matter disorders. The abundance of clinical research projects incorporating DW-MRI into their acquisition protocols speaks to the value this information lends to the study of neurological disease. However, the most widespread DW-MRI technique, diffusion tensor imaging (DTI), possesses serious limitations which restrict its utility in regions of complex white matter. Fueled by advances in DW-MRI acquisition protocols and technologies, a group of exciting new DW-MRI models, developed to address these concerns, are now becoming available to clinical researchers. The emergence of these new imaging techniques, categorized as high angular resolution diffusion imaging (HARDI), has generated the need for sophisticated computational neuroanatomic techniques able to account for the high dimensionality and structure of HARDI data. The goal of this thesis is the development of such techniques utilizing prominent HARDI data models. Specifically, methodologies for spatial normalization, population atlas building and structural connectivity have been developed and validated. These methods form the core of a comprehensive analysis paradigm allowing the investigation of local white matter microarcitecture, as well as, systemic properties of neuronal connectivity. The application of this framework to the study of schizophrenia and the autism spectrum disorders demonstrate its sensitivity sublte differences in white matter organization, as well as, its applicability to large population DW-MRI studies

A Novel Characterization of Traumatic Brain Injury in White Matter with Diffusion MRI Spherical-Harmonics Rotation Invariants

International audienceThe current DTI-based markers of traumatic brain injury are able to capture affected WM in the brain, but missthe areas of crossing fibers and complex WM due to the simplicity of the model. In this work, we use a novelset of spherical-harmonics rotation invariant indices, recently proposed in the literature. We demonstrate thatthese 12 invariants capture all the information provided by DTI. But in addition, they capture differences incomplex WM, beyond DTI measures. This combined with the clinical feasibility of the method, paves the wayfor them to be used as better markers of brain injury

Rational invariants of even ternary forms under the orthogonal group

In this article we determine a generating set of rational invariants of minimal cardinality for the action of the orthogonal group $\mathrm{O}_3$ on the space $\mathbb{R}[x,y,z]_{2d}$ of ternary forms of even degree $2d$. The construction relies on two key ingredients: On one hand, the Slice Lemma allows us to reduce the problem to dermining the invariants for the action on a subspace of the finite subgroup $\mathrm{B}_3$ of signed permutations. On the other hand, our construction relies in a fundamental way on specific bases of harmonic polynomials. These bases provide maps with prescribed $\mathrm{B}_3$-equivariance properties. Our explicit construction of these bases should be relevant well beyond the scope of this paper. The expression of the $\mathrm{B}_3$-invariants can then be given in a compact form as the composition of two equivariant maps. Instead of providing (cumbersome) explicit expressions for the $\mathrm{O}_3$-invariants, we provide efficient algorithms for their evaluation and rewriting. We also use the constructed $\mathrm{B}_3$-invariants to determine the $\mathrm{O}_3$-orbit locus and provide an algorithm for the inverse problem of finding an element in $\mathbb{R}[x,y,z]_{2d}$ with prescribed values for its invariants. These are the computational issues relevant in brain imaging.Comment: v3 Changes: Reworked presentation of Neuroimaging application, refinement of Definition 3.1. To appear in "Foundations of Computational Mathematics

Computational Brain Connectivity Mapping: A Core Health and Scientific Challenge

International audienceOne third of the burden of all the diseases in Europe is due to problems caused by diseases affecting brain. Although exceptional progress have been obtained for exploring the brain during the past decades, it is still terra-incognita and calls for specific efforts in research to better understand its architecture and functioning. To take up this great challenge of modern science and to solve the limited view of the brain provided just by one imaging modality, this article advocates the idea developed in my research group of a global approach involving new generation of models for brain connectivity mapping and strong interactions between structural and functional connectivities. Capitalizing on the strengths of integrated and complementary non invasive imaging modalities such as diffusion Magnetic Resonance Imaging (dMRI) and Electro & Magneto-Encephalography (EEG & MEG) will contribute to achieve new frontiers for identifying and characterizing structural and functional brain connectivities and to provide a detailed mapping of the brain connectivity, both in space and time. Thus leading to an added clinical value for high impact diseases with new perspectives in computational neuro-imaging and cognitive neuroscience

Dimensionality reduction of diffusion MRI measures for improved tractometry of the human brain

Various diffusion MRI (dMRI) measures have been proposed for characterising tissue microstructure over the last 15 years. Despite the growing number of experiments using different dMRI measures in assessments of white matter, there has been limited work on: 1) examining their covariance along specific pathways; and on 2) combining these different measures to study tissue microstructure. Indeed, it quickly becomes intractable for existing analysis pipelines to process multiple measurements at each voxel and at each vertex forming a streamline, highlighting the need for new ways to visualise or analyse such high-dimensional data. In a sample of 36 typically developing children aged 8–18 years, we profiled various commonly used dMRI measures across 22 brain pathways. Using a data-reduction approach, we identified two biologically-interpretable components that capture 80% of the variance in these dMRI measures. The first derived component captures properties related to hindrance and restriction in tissue microstructure, while the second component reflects characteristics related to tissue complexity and orientational dispersion. We then demonstrate that the components generated by this approach preserve the biological relevance of the original measurements by showing age-related effects across developmentally sensitive pathways. In summary, our findings demonstrate that dMRI analyses can benefit from dimensionality reduction techniques, to help disentangling the neurobiological underpinnings of white matter organisation

Dimensionality reduction of diffusion MRI measures for improved tractometry of the human brain

Various diffusion MRI (dMRI) measures have been proposed for characterising tissue microstructure over the last 15 years. Despite the growing number of experiments using different dMRI measures in assessments of white matter, there has been limited work on: 1) examining their covariance along specific pathways; and on 2) combining these different measures to study tissue microstructure. Indeed, it quickly becomes intractable for existing analysis pipelines to process multiple measurements at each voxel and at each vertex forming a streamline, highlighting the need for new ways to visualise or analyse such high-dimensional data. In a sample of 36 typically developing children aged 8–18 years, we profiled various commonly used dMRI measures across 22 brain pathways. Using a data-reduction approach, we identified two biologically-interpretable components that capture 80% of the variance in these dMRI measures. The first derived component captures properties related to hindrance and restriction in tissue microstructure, while the second component reflects characteristics related to tissue complexity and orientational dispersion. We then demonstrate that the components generated by this approach preserve the biological relevance of the original measurements by showing age-related effects across developmentally sensitive pathways. In summary, our findings demonstrate that dMRI analyses can benefit from dimensionality reduction techniques, to help disentangling the neurobiological underpinnings of white matter organisation

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

Robust processing of diffusion weighted image data

The work presented in this thesis comprises a proposed robust diffusion weighted magnetic resonance imaging (DW-MRI) pipeline, each chapter detailing a step designed to ultimately transform raw DW-MRI data into segmented bundles of coherent fibre ready for more complex analysis or manipulation. In addition to this pipeline we will also demonstrate, where appropriate, ways in which each step could be optimized for the maxillofacial region, setting the groundwork for a wider maxillofacial modelling project intended to aid surgical planning. Our contribution begins with RESDORE, an algorithm designed to automatically identify corrupt DW-MRI signal elements. While slower than the closest alternative, RESDORE is also far more robust to localised changes in SNR and pervasive image corruptions. The second step in the pipeline concerns the retrieval of accurate fibre orientation distribution functions (fODFs) from the DW-MRI signal. Chapter 4 comprises a simulation study exploring the application of spherical deconvolution methods to `generic' fibre; finding that the commonly used constrained spherical harmonic deconvolution (CSHD) is extremely sensitive to calibration but, if handled correctly, might be able to resolve muscle fODFs in vivo. Building upon this information, Chapter 5 conducts further simulations and in vivo image experimentation demonstrating that this is indeed the case, allowing us to demonstrate, for the first time, anatomically plausible reconstructions of several maxillofacial muscles. To complete the proposed pipeline, Chapter 6 then introduces a method for segmenting whole volume streamline tractographies into anatomically valid bundles. In addition to providing an accurate segmentation, this shape-based method does not require computationally expensive inter-streamline comparisons employed by other approaches, allowing the algorithm to scale linearly with respect to the number of streamlines within the dataset. This is not often true for comparison based methods which in the best case scale in higher linear time but more often by O(N2) complexity

A comparison of methods for the registration of tractographic fibre images

Diffusion tensor imaging (DTI) and tractography have opened up new avenues in neuroscience and are allowing previously unexplored areas of neuroanatomy and function to be researched