To study axonal microstructure with diffusion MRI, axons are typically modeled as straight impermeable cylinders, whereby the transverse diffusion MRI signal can be made sensitive to the cylinder's inner diameter. However, the shape of a real axon varies along the axon direction, which couples the longitudinal and transverse diffusion of the overall axon direction. Here we develop a theory of the intra-axonal diffusion MRI signal based on coarse-graining of the axonal shape by 3d diffusion. We demonstrate how the estimate of the inner diameter is confounded by the diameter variations (beading), and by the local variations in direction (undulations) along the axon. We analytically relate diffusion MRI metrics, such as time-dependent radial diffusivity D(t) and kurtosis K(t), to the axonal shape, and validate our theory using Monte Carlo simulations in synthetic undulating axons with randomly positioned beads, and in realistic axons reconstructed from electron microscopy images of mouse brain white matter. We show that (i) In the narrow pulse limit, the inner diameter from D(t) is overestimated by about twofold due to a combination of axon caliber variations and undulations (each contributing a comparable effect size); (ii) The narrow-pulse kurtosis K$_{t\to\infty}$ deviates from that in an ideal cylinder due to caliber variations; we also numerically calculate the fourth-order cumulant for an ideal cylinder in the wide pulse limit, which is relevant for inner diameter overestimation; (iii) In the wide pulse limit, the axon diameter overestimation is mainly due to undulations at low diffusion weightings b; and (iv) The effect of undulations can be considerably reduced by directional averaging of high-b signals, with the apparent inner diameter given by a combination of the axon caliber (dominated by the thickest axons), caliber variations, and the residual contribution of undulations.
Biophysical modeling is the mediator of evaluating the cellular structure of biological tissues using diffusion-weighted MRI. It is however the bottleneck of microstructural MRI. Beyond the complexity of diffusion, the current development is hindered by the fact that biophysical models heavily rely on diffusion-specific properties of diverse cellular compartments that are still unknown and must be measured in vivo. Obtaining such parameters by straightforward fitting is hindered by the degenerated landscape of the likelihood functions, in particular, the signal obtained for multiple diffusion …
Biophysical modelling of diffusion MRI is necessary to provide specific microstructural tissue properties. However, estimating model parameters from data with limited diffusion gradient strength, such as clinical scanners, has proven unreliable due to a shallow optimization landscape. On the other hand, estimation of diffusion kurtosis (DKI) parameters is more robust as the clinical acquisitions typically probe a regime in which the associated 4th order cumulant expansion is adequate; however, its parameters are not microstructurally specific a priori. Given an appropriate biophysical model, i…
Brownian motion of water molecules provides an essential length scale, the diffusion length, commensurate with cell dimensions in biological tissues. Measuring the diffusion coefficient as a function of diffusion time makes in vivo diffusion MRI uniquely sensitive to the cellular features about three orders of magnitude below imaging resolution. However, there is a longstanding debate, regarding which contribution --- intra- or extra-cellular --- is more relevant in the overall time-dependence of the diffusion metrics. Here we resolve this debate in the human brain white matter. By varying not…
Scattering approach to diffusion quantifies axonal damage in brain injury
Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, NY, USA（纽约大学医学学院放射科生物医学成像中心）；A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland（东部芬兰大学A.I. Virtanen分子科学研究所）；Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA（马萨诸塞州总医院哈佛医学院生物医学成像中心）
We enable the estimation of the per-axon axial diffusivity from single encoding, strongly diffusion-weighted, pulsed gradient spin echo data. Additionally, we improve the estimation of the per-axon radial diffusivity compared to estimates based on spherical averaging. The use of strong diffusion weightings in magnetic resonance imaging (MRI) allows to approximate the signal in white matter as the sum of the contributions from axons. At the same time, spherical averaging leads to a major simplification of the modeling by removing the need to explicitly account for the unknown orientation distri…
Diffusion MRI may enable non-invasive mapping of axonal microstructure. Most approaches infer axon diameters from effects of time-dependent diffusion on the diffusion-weighted MR signal by modelling axons as straight cylinders. Axons do not, however, run in straight trajectories and so far, the impact of the axonal trajectory on diameter estimation has not been systematically investigated. Here, we employ a toy-model of axons, which we refer to as undulating thin-fiber model, to analyze the impact of undulating trajectories on the diffusion-time dependence represented by the diffusion spectrum…
MRI provides a unique non-invasive window into the brain, yet is limited to millimeter resolution, orders of magnitude coarser than cell dimensions. Here we show that diffusion MRI is sensitive to the micrometer-scale variations in axon caliber or pathological beading, by identifying a signature power-law diffusion time-dependence of the along-fiber diffusion coefficient. We observe this signature in human brain white matter, and uncover its origins by Monte Carlo simulations in realistic substrates from 3d electron microscopy of mouse corpus callosum. Simulations reveal that the time-dependen…
This paper presents Contextual Fibre Growth (ConFiG), an approach to generate white matter numerical phantoms by mimicking natural fibre genesis. ConFiG grows fibres one-by-one, following simple rules motivated by real axonal guidance mechanisms. These simple rules enable ConFiG to generate phantoms with tuneable microstructural features by growing fibres while attempting to meet morphological targets such as user-specified density and orientation distribution. We compare ConFiG to the state-of-the-art approach based on packing fibres together by generating phantoms in a range of fibre configu…
Mapping tissue microstructure accurately and noninvasively is one of the frontiers of biomedical imaging. Diffusion Magnetic Resonance Imaging (MRI) is at the forefront of such efforts, as it is capable of reporting on microscopic structures orders of magnitude smaller than the voxel size by probing restricted diffusion. Double Diffusion Encoding (DDE) and Double Oscillating Diffusion Encoding (DODE) in particular, are highly promising for their ability to report on microscopic fractional anisotropy (μFA), a measure of the pore anisotropy in its own eigenframe, irrespective of orientation dist…
Development of successful therapies for neurological disorders depends on our ability to diagnose and monitor the progression of underlying pathologies at the cellular level. Physics and physiology limit the resolution of human MRI to millimeters, three orders of magnitude coarser than the cell dimensions of microns. A promising way to access cellular structure is provided by diffusion-weighted MRI (dMRI), a modality which exploits the sensitivity of the MRI signal to micron-level Brownian motion of water molecules strongly hindered by cell walls. By analyzing diffusion of water molecules in h…
Monte-Carlo Diffusion Simulations (MCDS) have been used extensively as a ground truth tool for the validation of microstructure models for Diffusion-Weighted MRI. However, methodological pitfalls in the design of the biomimicking geometrical configurations and the simulation parameters can lead to approximation biases. Such pitfalls affect the reliability of the estimated signal, as well as its validity and reproducibility as ground truth data. In this work, we first present a set of experiments in order to study three critical pitfalls encountered in the design of MCDS in the literature, name…
Microscopic Propagator Imaging (MPI) with Diffusion MRI
University of Verona（维罗纳大学）；Technical University of Denmark（丹麦技术大学）；Copenhagen University Hospital - Amager and Hvidovre（哥本哈根大学医院阿马格和维杜夫雷院区）；Danish Research Centre for Magnetic Resonance（丹麦磁共振研究中心）
In vivo mapping of the neurite density with diffusion MRI (dMRI) is a high but challenging aim. First, it is unknown whether all neurites exhibit completely anisotropic ('stick-like') diffusion. Second, the 'density' of tissue components may be confounded by non-diffusion properties such as T2 relaxation. Third, the domain of validity for the estimated parameters to serve as indices of neurite density is incompletely explored. We investigated these challenges by acquiring data with 'b-tensor encoding' and multiple echo times in both healthy brain and white matter lesions. Results showed that m…
The fiber g-ratio is the ratio of the inner to the outer diameter of the myelin sheath of a myelinated axon. It has a limited dynamic range in healthy white matter, as it is optimized for speed of signal conduction, cellular energetics, and spatial constraints. In vivo imaging of the g-ratio in health and disease would greatly increase our knowledge of the nervous system and our ability to diagnose, monitor, and treat disease. MRI based g-ratio imaging was first conceived in 2011, and expanded to be feasible in full brain with preliminary results in 2013. This manuscript reviews the growing g-…
Axons in white matter have been shown to have varying geometries within a bundle using ex vivo imaging techniques, but what does this mean for diffusion MRI (dMRI) based spherical deconvolution (SD)? SD attempts to estimate the fibre orientation distribution function (fODF) by assuming a single dMRI fibre response function (FRF) for all white matter populations and deconvolving this FRF from the dMRI signal at each voxel to estimate the fODF. Variable fibre geometry within a bundle however suggests the FRF might not be constant even within a single voxel. We test what impact realistic fibre ge…
Unveiling neuronal microstructure in the human brain in vivo with time-dependent radial diffusivity in MRI
GE HealthCare（通用医疗）；The University of Iowa（爱荷华大学）；Uniformed Services University（联邦服务大学）；Walter Reed National Military Medical Center（沃尔特·里德国家军事医疗中心）；Mass General Brigham, Harvard Medical School（麻省总医院布里格姆医院，哈佛医学院）；King's College London（伦敦国王学院）；University of Wisconsin-Madison（威斯康星大学麦迪逊分校）
This work introduces a compartment-based model for apparent soma and neurite density imaging (SANDI) using non-invasive diffusion-weighted MRI (DW-MRI). The existing conjecture in brain microstructure imaging trough DW-MRI presents water diffusion in white (WM) and grey (GM) matter as restricted diffusion in neurites, modelled by infinite cylinders of null radius embedded in the hindered extra-neurite water. The extra-neurite pool in WM corresponds to water in the extra-axonal space, but in GM it combines water in the extra-cellular space with water in soma. While several studies showed that t…
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 …
Diffusion-weighted MRI (DW-MRI) has recently seen a rising interest in planar, spherical and general B-tensor encodings. Some of these sequences have aided traditional linear encoding in the estimation of white matter microstructural features, generally by making DW-MRI less sensitive to the orientation of axon fascicles in a voxel. However, less is known about their potential to make the signal more sensitive to fascicle orientation, especially in crossing-fascicle voxels. Although planar encoding has been commended for the resemblance of its signal with the voxel's orientation distribution f…
ReMiDi: Reconstruction of Microstructure Using a Differentiable Diffusion MRI Simulator
University of California Santa Cruz（加州大学圣克鲁兹分校）；Indian Institute of Technology Madras（印度马德拉斯理工学院）；King's College London（伦敦国王学院）；Inria-Saclay（法国国家信息与自动化研究所萨克雷分部）
