Phantoms, both numerical (software) and physical (hardware), can serve as a gold standard for the validation of MRI methods probing the brain microstructure. This review aims to provide guidelines on ...how to build, implement, or choose the right phantom for a particular application, along with an overview of the current state-of-the-art of phantoms dedicated to study brain microstructure with MRI. For physical phantoms, we discuss the essential requirements and relevant characteristics of both the (NMR visible) liquid and (NMR invisible) phantom materials that induce relevant microstructural features detectable via MRI, based on diffusion, intra-voxel incoherent motion, magnetization transfer or magnetic susceptibility weighted contrast. In particular, for diffusion MRI, many useful phantoms have been proposed, ranging from simple liquids to advanced biomimetic phantoms consisting of hollow or plain microfibers and capillaries. For numerical phantoms, the focus is on Monte Carlo simulations of random walk, for which the basic principles, along with useful criteria to check and potential pitfalls are reviewed, in addition to a literature overview highlighting recent advances. While many phantoms exist already, the current review aims to stimulate further research in the field and to address remaining needs.
•Microstructural phantoms are imperative for validation of biophysical models.•Guidelines are given to make your own microstructural phantom of interest.•Both NMR visible and invisible materials determine the properties of physical phantoms.•Numerical phantoms offer fully controlled microgeometries and contrast mechanisms.•Overview of current state-of-the-art is given, along with promising new directions.
We introduce and evaluate a post-processing technique for fast denoising of diffusion-weighted MR images. By exploiting the intrinsic redundancy in diffusion MRI using universal properties of the ...eigenspectrum of random covariance matrices, we remove noise-only principal components, thereby enabling signal-to-noise ratio enhancements. This yields parameter maps of improved quality for visual, quantitative, and statistical interpretation. By studying statistics of residuals, we demonstrate that the technique suppresses local signal fluctuations that solely originate from thermal noise rather than from other sources such as anatomical detail. Furthermore, we achieve improved precision in the estimation of diffusion parameters and fiber orientations in the human brain without compromising the accuracy and spatial resolution.
•Denoising enhances the image quality for improved visual, quantitative, and statistical interpretation.•Random matrix theory enables data-driven threshold for PCA denoising.•The Marchenko-Pastur distribution is a universal signature of noise.•The technique suppresses signal fluctuations that solely originate in thermal noise.•Precision of diffusion parameter estimators increases without lowering accuracy.
Axon caliber plays a crucial role in determining conduction velocity and, consequently, in the timing and synchronization of neural activation. Noninvasive measurement of axon radii could have ...significant impact on the understanding of healthy and diseased neural processes. Until now, accurate axon radius mapping has eluded in vivo neuroimaging, mainly due to a lack of sensitivity of the MRI signal to micron-sized axons. Here, we show how – when confounding factors such as extra-axonal water and axonal orientation dispersion are eliminated – heavily diffusion-weighted MRI signals become sensitive to axon radii. However, diffusion MRI is only capable of estimating a single metric, the effective radius, representing the entire axon radius distribution within a voxel that emphasizes the larger axons. Our findings, both in rodents and humans, enable noninvasive mapping of critical information on axon radii, as well as resolve the long-standing debate on whether axon radii can be quantified.
Measuring molecular diffusion is widely used for characterizing materials and living organisms noninvasively. This characterization relies on relations between macroscopic diffusion metrics and ...structure at the mesoscopic scale commensurate with the diffusion length. Establishing such relations remains a fundamental challenge, hindering progress in materials science, porous media, and biomedical imaging. Here we show that the dynamical exponent in the time dependence of the diffusion coefficient distinguishes between the universality classes of the mesoscopic structural complexity. Our approach enables the interpretation of diffusion measurements by objectively selecting and modeling the most relevant structural features. As an example, the specific values of the dynamical exponent allow us to identify the relevant mesoscopic structure affecting MRI-measured water diffusion in muscles and in brain, and to elucidate the structural changes behind the decrease of diffusion coefficient in ischemic stroke.
The presence of micrometer-level restrictions leads to a decrease of diffusion coefficient with diffusion time. Here we investigate this effect in human white matter in vivo. We focus on a broad ...range of diffusion times, up to 600ms, covering diffusion length scales up to about 30 μm. We perform stimulated echo diffusion tensor imaging on 5 healthy volunteers and observe a relatively weak time-dependence in diffusion transverse to major fiber tracts. Remarkably, we also find notable time-dependence in the longitudinal direction. Comparing models of diffusion in ordered, confined and disordered media, we argue that the time-dependence in both directions can arise due to structural disorder, such as axonal beads in the longitudinal direction, and the random packing geometry of fibers within a bundle in the transverse direction. These time-dependent effects extend beyond a simple picture of Gaussian compartments, and may lead to novel markers that are specific to neuronal fiber geometry at the micrometer scale.
•We measure time-dependent DTI (55 ms – 600 ms) in vivo in human white matter.•Pronounced longitudinal and weaker transverse time-dependent diffusion is observed.•Longitudinal time-dependence is attributed to axonal varicosities.•Transverse time-dependence is attributed to the random axon packing geometry.•Varying diffusion time may provide a novel microstructural contrast.
White matter microstructural changes during the first three years of healthy brain development are characterized using two different models developed for limited clinical diffusion data: White Matter ...Tract Integrity (WMTI) metrics from Diffusional Kurtosis Imaging (DKI) and Neurite Orientation Dispersion and Density Imaging (NODDI). Both models reveal a non-linear increase in intra-axonal water fraction and in tortuosity of the extra-axonal space as a function of age, in the genu and splenium of the corpus callosum and the posterior limb of the internal capsule. The changes are consistent with expected behavior related to myelination and asynchrony of fiber development. The intra- and extracellular axial diffusivities as estimated with WMTI do not change appreciably in normal brain development. The quantitative differences in parameter estimates between models are examined and explained in the light of each model's assumptions and consequent biases, as highlighted in simulations. Finally, we discuss the feasibility of a model with fewer assumptions.
The dependence of the diffusion MRI signal on the diffusion time t is a hallmark of tissue microstructure at the scale of the diffusion length. Here we measure the time-dependence of the mean ...diffusivity D(t) and mean kurtosis K(t) in cortical gray matter and in 25 gray matter sub-regions, in 10 healthy subjects. Significant diffusivity and kurtosis time-dependence is observed for t=21.2-100 ms, and is characterized by a power-law tail ∼t−ϑ with dynamical exponent ϑ. To interpret our measurements, we systematize the relevant scenarios and mechanisms for diffusion time-dependence in the brain. Using the effective medium theory formalism, we derive an exact relation between the power-law tails in D(t) and K(t). The estimated dynamical exponent ϑ≃1/2 in both D(t) and K(t) is consistent with one-dimensional diffusion in the presence of randomly positioned restrictions along neurites. We analyze the short-range disordered statistics of synapses on axon collaterals in the cortex, and perform one-dimensional Monte Carlo simulations of diffusion restricted by permeable barriers with a similar randomness in their placement, to confirm the ϑ=1/2 exponent. In contrast, the Kärger model of exchange is less consistent with the data since it does not capture the diffusivity time-dependence, and the estimated exchange time from K(t) falls below our measured t-range. Although we cannot exclude exchange as a contributing factor, we argue that structural disorder along neurites is mainly responsible for the observed time-dependence of diffusivity and kurtosis. Our observation and theoretical interpretation of the t−1/2 tail in D(t) and K(t) altogether establish the sensitivity of a macroscopic MRI signal to micrometer-scale structural heterogeneities along neurites in human gray matter in vivo.
Myelin insulates neuronal axons and enables fast signal transmission, constituting a key component of brain development, aging and disease. Yet, myelin-specific imaging of macroscopic samples remains ...a challenge. Here, we exploit myelin's nanostructural periodicity, and use small-angle X-ray scattering tensor tomography (SAXS-TT) to simultaneously quantify myelin levels, nanostructural integrity and axon orientations in nervous tissue. Proof-of-principle is demonstrated in whole mouse brain, mouse spinal cord and human white and gray matter samples. Outcomes are validated by 2D/3D histology and compared to MRI measurements sensitive to myelin and axon orientations. Specificity to nanostructure is exemplified by concomitantly imaging different myelin types with distinct periodicities. Finally, we illustrate the method's sensitivity towards myelin-related diseases by quantifying myelin alterations in dysmyelinated mouse brain. This non-destructive, stain-free molecular imaging approach enables quantitative studies of myelination within and across samples during development, aging, disease and treatment, and is applicable to other ordered biomolecules or nanostructures.
PDF
