Reliability and Uncertainty in Diffusion MRI Modelling

Current Diffusion MRI studies often utilise more complex models beyond the single exponential decay model used in clinical standards. As this thesis shows, however, two of these models, biexponential and kurtosis, experience mathematical, ill-conditioning issues that can arise when used with regression algorithms, causing extreme bias and/or variance in the parameter estimates. Using simulated noisy data measurements from known truth, the magnitude of the bias and variance was shown to vary based on signal parameters as well as SNR, and increasing the SNR did not reduce this uncertainty for all data. Parameter estimate reliability could not be assessed from a single regression fit in all cases unless bootstrap resampling was performed, in which case measurements with high parameter estimate uncertainty were successfully identified. Prior to data analysis, current studies may use information criteria or cross-validation model selection methods to establish the best model to assess a specific tissue condition. While the best selection method to use is currently unclear in the literature, when testing simulated data in this thesis, no model selection method performed more reliably than the others and these methods were merely biased toward either simpler or more complex models. When a specific model was used to generate simulated noisy data, no model selection method selected this true model for all signals, and the ability of these methods to select the true model also varied depending on the true signal parameters. The results from these simulated data analyses were applied to ex vivo data from excised prostate tissue, and both information criteria measures and bootstrap sample distributions were able to identify image voxels whose parameter estimates had likely reliability issues. Removing these voxels from analysis improved sample variance of the parameter estimates

Multi-parametric quantification of white matter microstructure in the human brain

To date the majority of MRI studies of white matter (WM) microstructure have used diffusion tensor MRI (DT-MRI), comparing groups on a voxel-by-voxel basis. There are limitations to this approach. Firstly, the analysis approach treats each voxel independently, ignoring the fact that adjacent voxels may come from the same tract (or may come from completely separate tracts). Secondly, DT-MRI is sensitive to both interesting properties of WM (e.g., myelination, axon density), and less interesting properties (e.g., intra-voxel orientational dispersion). In contrast, other imaging approaches, based on different contrast mechanisms, can provide increased specificity and therefore sensitivity to differences in one particular attribute of tissue microstructure (e.g., myelin content or axonal density). Both quantitative magnetization transfer (qMT) imaging and multicomponent relaxometry provide proxy estimates of myelin content while the combined hindered and restricted model of diffusion (CHARMED) provides a proxy estimate of axon density. We present a novel imaging method called tractometry, which permits simultaneous quantitative assessment of these different microstructural attributes along specific pathways.Crucially, the metrics were only weakly correlated, suggesting that tractometry provides complementary WM microstructural information to DT-MRI. In developing the tractometry pipeline, we also performed a detailed examination of the qMT pipeline, identifying and reducing sources of variance to provide optimized results. We also identify a number of issues with the current state-of-the art, including the stability of tract based spatial statistics (TBSS). We show that conducting a structure-function correlation TBSS study may lead to vastly different conclusions, based simply on the participants recruited into the study. We also address microstructural asymmetry, including the degree of partial-volume effects (PVEs) from free water, which impact on WM metrics. The observed spatial heterogeneity of PVEs can potentially confound interpretation in studies where contralateral hemispheres are used as internal controls, and could either exacerbate or possibly negate tissue difference

The Role of Arterial Spin Labelling (ASL) in Classification of Primary Adult Gliomas

Currently, the histological biopsy is the gold standard for classifying gliomas using the most recent histomolecular features. However, this process is both invasive and challenging, mainly when the lesion is in eloquent brain regions. Considering the complex interaction between the presence of the isocitrate dehydrogenase (IDH)-mutation, the upregulation of the hypoxia-induced factor (HIF), the neo-angiogenesis and the increased cellularity, perfusion MRI may be used indirectly for gliomas staging and further to predict the presence of key mutations, such as IDH. Recently, several studies have reported the subsidiary role of perfusion MRI in the prediction of gliomas histomolecular class. The three most common perfusion MRI methods are dynamic susceptibility contrast (DSC), dynamic contrast enhancement (DCE) and arterial spin labelling (ASL). Both DSC and DCE use exogenous contrast agent (CA) while ASL uses magnetically labelled blood water as an inherently diffusible tracer. ASL has begun to feature more prominently in clinical settings, as this method eliminates the need for CA and facilitates quantification of absolute cerebral blood flow (CBF). As a non-invasive, CA-free test, it can also be performed repeatedly where necessary. This makes it ideal for vulnerable patients, e.g. post-treatment oncological patients, who have reduced tolerance for high rate contrast injections and those suffering from renal insufficiency. This thesis performed a systematic review and critical appraisal of the existing ASL techniques for brain perfusion estimation, followed by a further systematic review and meta-analysis of the published studies, which have quantitatively assessed the diagnostic performance of ASL for grading preoperative adult gliomas. The repeatability of absolute tumour blood flow (aTBF) and relative TBF (rTBF) ASL-derived measurements were estimated to investigate the reliability of these ASL biomarkers in the clinical routine. Finally, utilising the radiomics pipeline analysis, the added diagnostic performance of ASL compared with CA-based MRI perfusion techniques, including DSC and DCE, and diffusion-weighted imaging (DWI) was investigated for glioma class prediction according to the WHO-2016 classification

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 MRI analysis:robust and efficient microstructure modeling

Diffusion MRI (dMRI) allows for investigating the structure of the human brain. This is useful for both scientific brain research as well as medical diagnosis. Since the raw dMRI data is not directly interpretable by humans, we use mathematical models to convert the raw dMRI data into something interpretable. These models can be computed using multiple different computational methods, each having a different trade-off in accuracy, robustness and efficiency. In this thesis we studied multiple different computational models for their usability and efficiency for dMRI modeling. In the end we provide the reader with methodological recommendations for dMRI modeling and provide a high performance GPU enabled dMRI computing platform containing all recommendations