Novel pore size-controlled, susceptibility matched, 3D-printed MRI phantoms.

Purpose: We report the design concept and fabrication of MRI phantoms, containing blocks of aligned microcapillaires that can be stacked into larger arrays to construct diameter distribution phantoms or fractured, to create a "powder-averaged" emulsion of randomly oriented blocks for vetting or calibrating advanced MRI methods, that is, diffusion tensor imaging, AxCaliber MRI, MAP-MRI, and multiple pulsed field gradient or double diffusion-encoded microstructure imaging methods. The goal was to create a susceptibility-matched microscopically anisotropic but macroscopically isotropic phantom with a ground truth diameter that could be used to vet advanced diffusion methods for diameter determination in fibrous tissues.

Methods: Two-photon polymerization, a novel three-dimensional printing method is used to fabricate blocks of capillaries.

High-resolution cortical MAP-MRI reveals areal borders and laminar substructures observed with histological staining.

The variations in cellular composition and tissue architecture measured with histology provide the biological basis for partitioning the brain into distinct cytoarchitectonic areas and for characterizing neuropathological tissue alterations. Clearly, there is an urgent need to develop whole-brain neuroradiological methods that can assess cortical cyto- and myeloarchitectonic features non-invasively. Mean apparent propagator (MAP) MRI is a clinically feasible diffusion MRI method that quantifies efficiently and comprehensively the net microscopic displacements of water molecules diffusing in tissues.

High-resolution mapping and digital atlas of subcortical regions in the macaque monkey based on matched MAP-MRI and histology.

Subcortical nuclei and other deep brain structures are known to play an important role in the regulation of the central and peripheral nervous systems. It can be difficult to identify and delineate many of these nuclei and their finer subdivisions in conventional MRI due to their small size, buried location, and often subtle contrast compared to neighboring tissue. To address this problem, we applied a multi-modal approach in ex vivo non-human primate (NHP) brain that includes high-resolution mean apparent propagator (MAP)-MRI and five different histological stains imaged with high-resolution microscopy in the brain of the same subject.

Diffuse axonal injury has a characteristic multidimensional MRI signature in the human brain.

Axonal injury is a major contributor to the clinical symptomatology in patients with traumatic brain injury. Conventional neuroradiological tools, such as CT and MRI, are insensitive to diffuse axonal injury (DAI) caused by trauma. Diffusion tensor MRI parameters may change in DAI lesions; however, the nature of these changes is inconsistent.

Multidimensional MRI for Characterization of Subtle Axonal Injury Accelerated Using an Adaptive Nonlocal Multispectral Filter.

Multidimensional MRI is an emerging approach that simultaneously encodes water relaxation ( and ) and mobility (diffusion) and replaces voxel-averaged values with subvoxel distributions of those MR properties. While conventional (i.e.

Limits to flow detection in phase contrast MRI.

Pulsed gradient spin echo (PGSE) complex signal behavior becomes dominated by attenuation rather than oscillation when displacements due to flow are similar or less than diffusive displacements. In this "slow-flow" regime, the optimal displacement encoding parameter for phase contrast velocimetry depends on the diffusive length scale rather than the velocity encoding parameter = /(Δ). The minimum detectable mean velocity using the difference between the phase at + and - is .

Direct and specific assessment of axonal injury and spinal cord microenvironments using diffusion correlation imaging.

We describe a practical two-dimensional (2D) diffusion MRI framework to deliver specificity and improve sensitivity to axonal injury in the spinal cord. This approach provides intravoxel distributions of correlations of water mobilities in orthogonal directions, revealing sub-voxel diffusion components. Here we use it to investigate water diffusivities along axial and radial orientations within spinal cord specimens with confirmed, tract-specific axonal injury.

Retaining information from multidimensional correlation MRI using a spectral regions of interest generator.

Multidimensional correlation magnetic resonance imaging (MRI) is an emerging imaging modality that is capable of disentangling highly heterogeneous and opaque systems according to chemical and physical interactions of water within them. Using this approach, the conventional three dimensional MR scalar images are replaced with spatially resolved multidimensional spectra. The ensuing abundance in microstructural and chemical information is a blessing that incorporates a real challenge: how does one distill and refine it into images while retaining its significant components? In this paper we introduce a general framework that preserves the spectral information from spatially resolved multidimensional data.

Rapid detection of the presence of diffusion exchange.

Diffusion exchange spectroscopy (DEXSY) provides a detailed picture of how fluids in different microenvironments communicate with one another but requires a large amount of data. For DEXSY MRI, a simple measure of apparent exchanging fractions may suffice to characterize and differentiate materials and tissues. Reparameterizing signal intensity from a PGSE-storage-PGSE experiment as a function of the sum, b=b+b, and difference b=b-b of the diffusion encodings separates diffusion weighting from exchange weighting.

Using double pulsed-field gradient MRI to study tissue microstructure in traumatic brain injury (TBI).

Double pulsed-field gradient (dPFG) MRI is proposed as a new sensitive tool to detect and characterize tissue microstructure following diffuse axonal injury. In this study dPFG MRI was used to estimate apparent mean axon diameter in a diffuse axonal injury animal model and in healthy fixed mouse brain. Histological analysis was used to verify the presence of the injury detected by MRI.

Detection and Distinction of Mild Brain Injury Effects in a Ferret Model Using Diffusion Tensor MRI (DTI) and DTI-Driven Tensor-Based Morphometry (D-TBM).

Mild traumatic brain injury (mTBI) is highly prevalent but lacks both research tools with adequate sensitivity to detect cellular alterations that accompany mild injury and pre-clinical models that are able to robustly mimic hallmark features of human TBI. To address these related challenges, high-resolution diffusion tensor MRI (DTI) analysis was performed in a model of mild TBI in the ferret - a species that, unlike rodents, share with humans a gyrencephalic cortex and high white matter (WM) volume. A set of DTI image analysis tools were optimized and implemented to explore key features of DTI alterations in adult male ferret brains ( = 26), evaluated 1 day to 16 weeks after mild controlled cortical impact (CCI).

Generalized Mean Apparent Propagator MRI to Measure and Image Advective and Dispersive Flows in Medicine and Biology.

Water transport in biological systems spans different regimes with distinct physical behaviors: diffusion, advection, and dispersion. Identifying these regimes is of paramount importance in many in vivo applications, among them, measuring microcirculation of blood in capillary networks and cerebrospinal fluid transport in the glymphatic system. Diffusion magnetic resonance imaging (dMRI) can be used to encode water displacements, and a Fourier transform of the acquired signal furnishes a displacement probability density function known as the propagator.

Imaging Local Diffusive Dynamics Using Diffusion Exchange Spectroscopy MRI.

The movement of water between microenvironments presents a central challenge in the physics of soft matter and porous media. Diffusion exchange spectroscopy (DEXSY) is a powerful 2D nuclear magnetic resonance method for measuring such exchange, yet it is rarely used because of its long scan time requirements. Moreover, it has never been combined with magnetic resonance imaging (MRI).

Analysis of the effects of noise, DWI sampling, and value of assumed parameters in diffusion MRI models.

Purpose: This study was a systematic evaluation across different and prominent diffusion MRI models to better understand the ways in which scalar metrics are influenced by experimental factors, including experimental design (diffusion-weighted imaging [DWI] sampling) and noise.

Methods: Four diffusion MRI models-diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), mean apparent propagator MRI (MAP-MRI), and neurite orientation dispersion and density imaging (NODDI)-were evaluated by comparing maps and histogram values of the scalar metrics generated using DWI datasets obtained in fixed mouse brain with different noise levels and DWI sampling complexity. Additionally, models were fit with different input parameters or constraints to examine the consequences of model fitting procedures.

White matter microstructure from nonparametric axon diameter distribution mapping.

We report the development of a double diffusion encoding (DDE) MRI method to estimate and map the axon diameter distribution (ADD) within an imaging volume. A variety of biological processes, ranging from development to disease and trauma, may lead to changes in the ADD in the central and peripheral nervous systems. Unlike previously proposed methods, this ADD experimental design and estimation framework employs a more general, nonparametric approach, without a priori assumptions about the underlying form of the ADD, making it suitable to analyze abnormal tissue.

Detecting compartmental non-Gaussian diffusion with symmetrized double-PFG MRI.

Diffusion in tissue and porous media is known to be non-Gaussian and has been used for clinical indications of stroke and other tissue pathologies. However, when conventional NMR techniques are applied to biological tissues and other heterogeneous materials, the presence of multiple compartments (pores) with different Gaussian diffusivities will also contribute to the measurement of non-Gaussian behavior. Here we present symmetrized double PFG (sd-PFG), which can separate these two contributions to non-Gaussian signal decay as having distinct angular modulation frequencies.

Nonparametric pore size distribution using d-PFG: comparison to s-PFG and migration to MRI.

Here we present the successful translation of a pore size distribution (PSD) estimation method from NMR to MRI. This approach is validated using a well-characterized MRI phantom consisting of stacked glass capillary arrays (GCA) having different diameters. By employing a double pulsed-field gradient (d-PFG) MRI sequence, this method overcomes several important theoretical and experimental limitations of previous single-PFG (s-PFG) based MRI methods by allowing the relative diffusion gradients' direction to vary.

Mean apparent propagator (MAP) MRI: a novel diffusion imaging method for mapping tissue microstructure.

Diffusion-weighted magnetic resonance (MR) signals reflect information about underlying tissue microstructure and cytoarchitecture. We propose a quantitative, efficient, and robust mathematical and physical framework for representing diffusion-weighted MR imaging (MRI) data obtained in "q-space," and the corresponding "mean apparent propagator (MAP)" describing molecular displacements in "r-space." We also define and map novel quantitative descriptors of diffusion that can be computed robustly using this MAP-MRI framework.

Collagen composition and content-dependent contrast in porcine annulus fibrosus achieved by using double quantum and magnetization transfer filtered UTE MRI.

Purpose: To test the potential of combining double quantum and magnetization transfer filtered ultra-short echo time (DQF-MT-UTE) MRI to obtain information about the macromolecular composition and characteristics of connective tissues.

Methods: A DQF-MT-UTE pulse sequence was implemented on a 14.1 T AVANCE III Bruker spectrometer equipped with a Bruker micro2.

Characterization and mapping of dipolar interactions within macromolecules in tissues using a combination of DQF, MT and UTE MRI.

This study shows that by combining a double-quantum filtered magnetization transfer (DQF-MT) with an ultra-short TE (UTE) MRI that it is possible to obtain contrast between tissue compartments based on the following characteristics: (a) the residual dipolar coupling interaction within the biomacromolecules, which depends on their structure, (b) residual dipolar interactions within water molecules, and (c) the magnetization exchange rate between biomacromolecules and water. The technique is demonstrated in rat-tail specimens, where the collagenous tissue such as tendons and the annulus pulposus of the disc are highlighted in these images, and their macromolecular properties along with those of bones and muscles can be characterized. DQF-MT UTE MRI also holds promise because collagenous tissues that are typically invisible in conventional MRI experiments produce significant signal intensities using this approach.

Pore diameter mapping using double pulsed-field gradient MRI and its validation using a novel glass capillary array phantom.

Double pulsed-field gradient (d-PFG) MRI can provide quantitative maps of microstructural quantities and features within porous media and tissues. We propose and describe a novel MRI phantom, consisting of wafers of highly ordered glass capillary arrays (GCA), and its use to validate and calibrate a d-PFG MRI method to measure and map the local pore diameter. Specifically, we employ d-PFG Spin-Echo Filtered MRI in conjunction with a recently introduced theoretical framework, to estimate a mean pore diameter in each voxel within the imaging volume.

A system and mathematical framework to model shear flow effects in biomedical DW-imaging and spectroscopy.

The pulsed-field gradient (PFG) MR experiment enables one to measure particle displacements, velocities, and even higher moments of complex fluid motions. In diffusion-weighted MRI (DWI) in living tissue, where the PFG MRI experiment is used to measure diffusion, Brownian motion is assumed to dominate the displacements causing the observed signal loss. However, motions of water molecules caused by various active biological processes occurring at different length and time scales may also cause additional dephasing of magnetization and signal loss.

From single-pulsed field gradient to double-pulsed field gradient MR: gleaning new microstructural information and developing new forms of contrast in MRI.

One of the hallmarks of diffusion NMR and MRI is its ability to utilize restricted diffusion to probe compartments much smaller than the excited volume or the MRI voxel, respectively, and to extract microstructural information from them. Single-pulsed field gradient (s-PFG) MR methodologies have been employed with great success to probe microstructures in various disciplines, ranging from chemistry to neuroscience. However, s-PFG MR also suffers from inherent shortcomings, especially when specimens are characterized by orientation or size distributions: in such cases, the microstructural information available from s-PFG experiments is limited or lost.

A multivariate hypothesis testing framework for tissue clustering and classification of DTI data.

The primary aim of this work is to propose and investigate the effectiveness of a novel unsupervised tissue clustering and classification algorithm for diffusion tensor MRI (DTI) data. The proposed algorithm utilizes information about the degree of homogeneity of the distribution of diffusion tensors within voxels. We adapt frameworks proposed by Hext and Snedecor, where the null hypothesis of diffusion tensors belonging to the same distribution is assessed by an F-test.