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Quantifying the myelin sheath radius of myelinated axons in vivo is important for understanding, diagnosing, and monitoring various neurological disorders. Despite advancements in diffusion MRI (dMRI) microstructure techniques, models specifically designed to estimate myelin sheath radii remain unavailable. In this proof-of-concept theoretical study, we present two novel dMRI models that characterize the signal from water diffusion confined to cylindrical surfaces, approximating myelin water diffusion. We derive their spherical mean signals, which conveniently eliminate fiber orientation and dispersion effects. These models are further extended to account for multiple concentric cylinders, mimicking the layered structure of myelin. Additionally, we introduce a method to convert histological distributions of axonal inner radii from the literature into myelin sheath radius distributions and derive analytical expressions to estimate the effective myelin sheath radius expected from these distributions. Monte Carlo (MC) simulations conducted in cylindrical and spiral geometries validate the models, demonstrating agreement with analytical predictions across various diffusion regimes and significant correlations between the effective radii estimated from the histological distributions and the effective radius obtained by fitting the resulting dMRI signal to a single-cylinder model. These models may be integrated into existing multi-compartment dMRI techniques, opening the door to non-invasive, in vivo assessments of myelin sheath radii in MRI scanners equipped with strong diffusion gradients that enable measurements with short echo times. Further work is required to validate the technique with real dMRI data., Comment: 55 pages, 7 figures, 1 table, manuscript under review

Purpose: This study aims to evaluate two distinct approaches for fibre radius estimation using diffusion-relaxation MRI data acquired in biomimetic microfibre phantoms that mimic hollow axons. The methods considered are the spherical mean power-law approach and a T2-based pore size estimation technique. Theory and Methods: A general diffusion-relaxation theoretical model for the spherical mean signal from water molecules within a distribution of cylinders with varying radii was introduced, encompassing the evaluated models as particular cases. Additionally, a new numerical approach was presented for estimating effective radii (i.e., MRI-visible mean radii) from the ground truth radii distributions, not reliant on previous theoretical approximations and adaptable to various acquisition sequences. The ground truth radii were obtained from Scanning Electron Microscope images. Results: Both methods show a linear relationship between effective radii estimated from MRI data and ground-truth radii distributions, though some discrepancies were observed. The spherical mean power-law method overestimated fibre radii. Conversely, the T2-based method exhibited higher sensitivity to smaller fibre radii but faced limitations in accurately estimating the radius in one particular phantom, possibly due to material-specific relaxation changes. Conclusion: The study demonstrates the feasibility of both techniques to predict pore sizes of hollow microfibres. The T2-based technique, unlike the spherical mean power-law method, does not demand ultra-high diffusion gradients but requires calibration with known radius distributions. This research contributes to the ongoing development and evaluation of neuroimaging techniques for fibre radius estimation, highlights the advantages and limitations of both methods and provides datasets for reproducible research., Comment: 37 pages, 8 figures. Accepted in Magnetic Resonance in Medicine, Dec, 2023

Monte-Carlo diffusion simulations are a powerful tool for validating tissue microstructure models by generating synthetic diffusion-weighted magnetic resonance images (DW-MRI) in controlled environments. This is fundamental for understanding the link between micrometre-scale tissue properties and DW-MRI signals measured at the millimetre-scale, optimising acquisition protocols to target microstructure properties of interest, and exploring the robustness and accuracy of estimation methods. However, accurate simulations require substrates that reflect the main microstructural features of the studied tissue. To address this challenge, we introduce a novel computational workflow, CACTUS (Computational Axonal Configurator for Tailored and Ultradense Substrates), for generating synthetic white matter substrates. Our approach allows constructing substrates with higher packing density than existing methods, up to 95 % intra-axonal volume fraction, and larger voxel sizes of up to (500um) 3 with rich fibre complexity. CACTUS generates bundles with angular dispersion, bundle crossings, and variations along the fibres of their inner and outer radii and g-ratio. We achieve this by introducing a novel global cost function and a fibre radial growth approach that allows substrates to match predefined targeted characteristics and mirror those reported in histological studies. CACTUS improves the development of complex synthetic substrates, paving the way for future applications in microstructure imaging., Comment: 21 pages, 7 figures

Axon radius is a potential biomarker for brain diseases and a crucial tissue microstructure parameter that determines the speed of action potentials. Diffusion MRI (dMRI) allows non-invasive estimation of axon radius, but accurately estimating the radius of axons in the human brain is challenging. Most axons in the brain have a radius below one micrometer, which falls below the sensitivity limit of dMRI signals even when using the most advanced human MRI scanners. Therefore, new MRI methods that are sensitive to small axon radii are needed. In this proof-of-concept investigation, we examine whether a surface-based axonal relaxation process could mediate a relationship between intra-axonal T2 and T1 times and inner axon radius, as measured using postmortem histology. A unique in vivo human diffusion-T1-T2 relaxation dataset was acquired on a 3T MRI scanner with ultra-strong diffusion gradients, using a strong diffusion-weighting (i.e., b = 6,000 s/mm$^2$) and multiple inversion and echo times. A second reduced diffusion-T2 dataset was collected at various echo times to evaluate the model further. The intra-axonal relaxation times were estimated by fitting a diffusion-relaxation model to the orientation-averaged spherical mean signals. Our analysis revealed that the proposed surface-based relaxation model effectively explains the relationship between the estimated relaxation times and the histological axon radius measured in various corpus callosum regions. Using these histological values, we developed a novel calibration approach to predict axon radius in other areas of the corpus callosum. Notably, the predicted radii and those determined from histological measurements were in close agreement., Comment: 47 pages, 10 figures

Purpose: Biophysical models of diffusion MRI have been developed to characterize microstructure in various tissues, but existing models are not suitable for tissue composed of permeable spherical cells. In this study we introduce Cellular Exchange Imaging (CEXI), a model tailored for permeable spherical cells, and compares its performance to a related Ball \& Sphere (BS) model that neglects permeability. Methods: We generated DW-MRI signals using Monte-Carlo simulations with a PGSE sequence in numerical substrates made of spherical cells and their extracellular space for a range of membrane permeability. From these signals, the properties of the substrates were inferred using both BS and CEXI models. Results: CEXI outperformed the impermeable model by providing more stable estimates cell size and intracellular volume fraction that were diffusion time-independent. Notably, CEXI accurately estimated the exchange time for low to moderate permeability levels previously reported in other studies ($\kappa<25\mu m/s$). However, in highly permeable substrates ($\kappa=50\mu m/s$), the estimated parameters were less stable, particularly the diffusion coefficients. Conclusion: This study highlights the importance of modeling the exchange time to accurately quantify microstructure properties in permeable cellular substrates. Future studies should evaluate CEXI in clinical applications such as lymph nodes, investigate exchange time as a potential biomarker of tumor severity, and develop more appropriate tissue models that account for anisotropic diffusion and highly permeable membranes., Comment: 7 figures, 2 tables, 21 pages, under review

Diffusion-weighted magnetic resonance imaging (DW-MRI) is used to characterize brain tissue microstructure employing tissue-specific biophysical models. A current limitation, however, is that most of the proposed models are based on the assumption of negligible water exchange between the intra- and extracellular compartments, which might not be valid in various brain tissues, including unmyelinated axons, gray matter, and tumors. The purpose of this work is to quantify the effect of membrane permeability on the estimates of two popular models neglecting exchange, and compare their performance with a model including exchange. To this aim, DW-MRI experiments were performed in controlled environments with Monte-Carlo simulations. The DW-MRI signals were generated in numerical substrates mimicking biological tissue made of spherical cells with permeable membranes like cancerous tissue or the brain gray matter. From these signals, the substrates properties were estimated using SANDI and VERDICT, the two compartment-based models neglecting exchange, and CEXI, a new model which includes exchange. Our results show that, in cellular permeable tissue, the model with exchange outperformed models without exchange in the estimation of the tissue properties by providing more stable estimates of cell size, intracellular volume fraction and extracellular diffusion coefficient. Moreover, the model with exchange estimated accurately the exchange time in the range of permeability reported for cellular tissue. Finally, the simulations performed in this work showed that the exchange between the intracellular and the extracellular space cannot be neglected in permeable tissue with a conventional PGSE sequence, to obtain accurate estimates. Consequently, existing compartmentalized models of impermeable tissue cannot be used for microstructure estimation of cellular permeable tissue., Comment: 29 pages, 8 figures, 3 tables, submitted

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease characterized by diffuse and focal areas of tissue loss. Conventional MRI techniques such as T1-weighted and T2-weighted scans are generally used in the diagnosis and prognosis of the disease. Yet, these methods are limited by the lack of specificity between lesions, their perilesional area and non-lesional tissue. Alternative MRI techniques exhibit a higher level of sensitivity to focal and diffuse MS pathology than conventional MRI acquisitions. However, they still suffer from limited specificity when considered alone. In this work, we have combined tissue microstructure information derived from multicompartment diffusion MRI and T2 relaxometry models to explore the voxel-based prediction power of a machine learning model in a cohort of MS patients and healthy controls. Our results show that the combination of multi-modal features, together with a boosting enhanced decision-tree based classifier, which combines a set of weak classifiers to form a strong classifier via a voting mechanism, is able to utilise the complementary information for the classification of abnormal tissue., Comment: Accepted at ISBI2021

This paper presents novel single and multi-shell sampling schemes for diffusion MRI. In diffusion MRI, it is paramount that the number of samples is as small as possible in order that scan times are practical in a clinical setting. The proposed schemes use an efficient number of measurements in that the number of samples is equal to the degrees of freedom in the orthonormal bases used for reconstruction. Novel reconstruction algorithms based on smaller subsystems of linear equations, as compared to the standard regularized least-squares method, are developed for both single and multi-shells sampling schemes. The smaller matrices used in these novel reconstruction algorithms are designed to be well-conditioned, leading to improved reconstruction accuracy. Accurate and robust reconstruction is also achieved through incorporation of regularization into the novel reconstruction algorithms and using a Rician or non-central Chi noise model. We quantitatively validate our single and multi-shell schemes against standard least-squares reconstruction methods to show that they enable more accurate reconstruction when the number of samples is equal to the degrees of freedom in the basis. Human brain data is also used to qualitatively evaluate reconstruction, Comment: 19 pages, with 6 pages supplementary material attached at the end, submitted to PLOS ONE

Spherical deconvolution (SD) methods are widely used to estimate the intra-voxel white-matter fiber orientations from diffusion MRI data. However, while some of these methods assume a zero-mean Gaussian distribution for the underlying noise, its real distribution is known to be non-Gaussian and to depend on the methodology used to combine multichannel signals. Indeed, the two prevailing methods for multichannel signal combination lead to Rician and noncentral Chi noise distributions. Here we develop a Robust and Unbiased Model-BAsed Spherical Deconvolution (RUMBA-SD) technique, intended to deal with realistic MRI noise, based on a Richardson-Lucy (RL) algorithm adapted to Rician and noncentral Chi likelihood models. To quantify the benefits of using proper noise models, RUMBA-SD was compared with dRL-SD, a well-established method based on the RL algorithm for Gaussian noise. Another aim of the study was to quantify the impact of including a total variation (TV) spatial regularization term in the estimation framework. To do this, we developed TV spatially-regularized versions of both RUMBA-SD and dRL-SD algorithms. The evaluation was performed by comparing various quality metrics on 132 three-dimensional synthetic phantoms involving different inter-fiber angles and volume fractions, which were contaminated with noise mimicking patterns generated by data processing in multichannel scanners. The results demonstrate that the inclusion of proper likelihood models leads to an increased ability to resolve fiber crossings with smaller inter-fiber angles and to better detect non-dominant fibers. The inclusion of TV regularization dramatically improved the resolution power of both techniques. The above findings were also verified in brain data.