In vivo mapping of cellular resolution neuropathology in brain ischemia with diffusion MRI.

Noninvasive mapping of cellular pathology can provide critical diagnostic and prognostic information. Recent advances in diffusion magnetic resonance imaging enabled in vivo examination of tissue microstructures well beyond the imaging resolution. Here, we proposed to use diffusion time-dependent diffusion kurtosis imaging (tDKI) to simultaneously assess cellular morphology and transmembrane permeability in hypoxic-ischemic (HI) brain injury. Through numerical simulations and organoid imaging, we demonstrated the feasibility of capturing effective size and permeability changes using tDKI. In vivo MRI of HI-injured mouse brains detected a shift of the tDKI peak to longer diffusion times, suggesting swelling of the cellular processes. Furthermore, we observed a faster decrease of the tDKI tail, reflecting increased transmembrane permeability associated with up-regulated water exchange or necrosis. Such information, unavailable from a single diffusion time, can predict salvageable tissues. Preliminary applications of tDKI in patients with ischemic stroke suggested increased transmembrane permeability in stroke regions, illustrating tDKI's potential for detecting pathological changes in the clinics.

Unusual triflic acid-promoted oligomerization of arabinofuranosides during glycosylation.

We discovered an unusual triflic acid-promoted oligomerization of arabinofuranosides during glycosylation of the primary hydroxy group of α-(1 â†’ 5)-linked tetraarabinofuranoside bearing 4-(2-chloroethoxy)phenyl aglycone with α-(1 â†’ 5), ß-(1 â†’ 2)-linked tetraarabinofuranoside containing N-phenyltrifluoroacetimidoyl leaving group, which led to octa-, dodeca- and hexadecaarabinofuranosides. The possible mechanism of triflic acid-promoted oligomerization was proposed. The choice of promoter was found to be a critical factor for the discovered oligomerization of arabinofuranosides. The obtained octa-, dodeca- and hexadecaarabinofuranosides may serve as useful blocks in the synthesis of oligosaccharide fragments of polysaccharides of Mycobacterium tuberculosis.

Callosal Interhemispheric Communication in Mild Traumatic Brain Injury: A Mediation Analysis on WM Microstructure Effects.

BACKGROUND AND PURPOSE: Because the corpus callosum connects the left and right hemispheres and a variety of WM bundles across the brain in complex ways, damage to the neighboring WM microstructure may specifically disrupt interhemispheric communication through the corpus callosum following mild traumatic brain injury. Here we use a mediation framework to investigate how callosal interhemispheric communication is affected by WM microstructure in mild traumatic brain injury. MATERIALS AND METHODS: Multishell diffusion MR imaging was performed on 23 patients with mild traumatic brain injury within 1 month of injury and 17 healthy controls, deriving 11 diffusion metrics, including DTI, diffusional kurtosis imaging, and compartment-specific standard model parameters. Interhemispheric processing speed was assessed using the interhemispheric speed of processing task (IHSPT) by measuring the latency between word presentation to the 2 hemivisual fields and oral word articulation. Mediation analysis was performed to assess the indirect effect of neighboring WM microstructures on the relationship between the corpus callosum and IHSPT performance. In addition, we conducted a univariate correlation analysis to investigate the direct association between callosal microstructures and IHSPT performance as well as a multivariate regression analysis to jointly evaluate both callosal and neighboring WM microstructures in association with IHSPT scores for each group. RESULTS: Several significant mediators in the relationships between callosal microstructure and IHSPT performance were found in healthy controls. However, patients with mild traumatic brain injury appeared to lose such normal associations when microstructural changes occurred compared with healthy controls. CONCLUSIONS: This study investigates the effects of neighboring WM microstructure on callosal interhemispheric communication in healthy controls and patients with mild traumatic brain injury, highlighting that neighboring noncallosal WM microstructures are involved in callosal interhemispheric communication and information transfer. Further longitudinal studies may provide insight into the temporal dynamics of interhemispheric recovery following mild traumatic brain injury.

Signatures of microstructure in gradient-echo and spin-echo signals.

PURPOSE: To determine whether the spatial scale and magnetic susceptibility of microstructure can be evaluated robustly from the decay of gradient-echo and spin-echo signals. THEORY AND METHODS: Gradient-echo and spin-echo images were acquired from suspensions of spherical polystyrene microbeads of 10, 20, and 40 µm nominal diameter. The sizes of the beads and their magnetic susceptibility relative to the medium were estimated from the signal decay curves, using a lookup table generated from Monte Carlo simulations and an analytic model based on the Gaussian phase approximation. RESULTS: Fitting Monte Carlo predictions to spin-echo data yielded acceptable estimates of microstructural parameters for the 20 and 40 µm microbeads. Using gradient-echo data, the Monte Carlo lookup table provided satisfactory parameter estimates for the 20 µm beads but unstable results for the diameter of the largest beads. Neither spin-echo nor gradient-echo data allowed accurate parameter estimation for the smallest beads. The analytic model performed poorly over all bead sizes. CONCLUSIONS: Microstructural sources of magnetic susceptibility produce distinctive non-exponential signatures in the decay of gradient-echo and spin-echo signals. However, inverting the problem to extract microstructural parameters from the signals is nontrivial and, in certain regimes, ill-conditioned. For microstructure with small characteristic length scales, parameter estimation is hampered by the difficulty of acquiring accurate data at very short echo times. For microstructure with large characteristic lengths, the gradient-echo signal approaches the static-dephasing regime, where it becomes insensitive to size. Applicability of the analytic model was further limited by failure of the Gaussian phase approximation for all but the smallest beads.

Assessment of Precision and Accuracy of Brain White Matter Microstructure using Combined Diffusion MRI and Relaxometry.

Joint modeling of diffusion and relaxation has seen growing interest due to its potential to provide complementary information about tissue microstructure. For brain white matter, we designed an optimal diffusion-relaxometry MRI protocol that samples multiple b-values, B-tensor shapes, and echo times (TE). This variable-TE protocol (27 min) has as subsets a fixed-TE protocol (15 min) and a 2-shell dMRI protocol (7 min), both characterizing diffusion only. We assessed the sensitivity, specificity and reproducibility of these protocols with synthetic experiments and in six healthy volunteers. Compared with the fixed-TE protocol, the variable-TE protocol enables estimation of free water fractions while also capturing compartmental T2 relaxation times. Jointly measuring diffusion and relaxation offers increased sensitivity and specificity to microstructure parameters in brain white matter with voxelwise coefficients of variation below 10%.

Volume electron microscopy in injured rat brain validates white matter microstructure metrics from diffusion MRI.

Biophysical modeling of diffusion MRI (dMRI) offers the exciting potential of bridging the gap between the macroscopic MRI resolution and microscopic cellular features, effectively turning the MRI scanner into a noninvasive in vivo microscope. In brain white matter, the Standard Model (SM) interprets the dMRI signal in terms of axon dispersion, intra- and extra-axonal water fractions and diffusivities. However, for SM to be fully applicable and correctly interpreted, it needs to be carefully evaluated using histology. Here, we perform a comprehensive histological validation of the SM parameters, by characterizing WM microstructure in sham and injured rat brains using volume (3d) electron microscopy (EM) and ex vivo dMRI. Sensitivity is evaluated by how close each SM metric is to its histological counterpart, and specificity by how independent it is from other, non-corresponding histological features. This comparison reveals that SM is sensitive and specific to microscopic properties, clearing the way for the clinical adoption of in vivo dMRI derived SM parameters as biomarkers for neurological disorders.

The effects of axonal beading and undulation on axonal diameter estimation from diffusion MRI: Insights from simulations in human axons segmented from three-dimensional electron microscopy.

The increasing availability of high-performance gradient systems in human MRI scanners has generated great interest in diffusion microstructural imaging applications such as axonal diameter mapping. Practically, sensitivity to axon diameter in diffusion MRI is attained at strong diffusion weightings b , where the deviation from the expected 1 / b scaling in white matter yields a finite transverse diffusivity, which is then translated into an axon diameter estimate. While axons are usually modeled as perfectly straight, impermeable cylinders, local variations in diameter (caliber variation or beading) and direction (undulation) are known to influence axonal diameter estimates and have been observed in microscopy data of human axons. In this study, we performed Monte Carlo simulations of diffusion in axons reconstructed from three-dimensional electron microscopy of a human temporal lobe specimen using simulated sequence parameters matched to the maximal gradient strength of the next-generation Connectome 2.0 human MRI scanner ( ≲ 500 mT/m). We show that axon diameter estimation is accurate for nonbeaded, nonundulating fibers; however, in fibers with caliber variations and undulations, the axon diameter is heavily underestimated due to caliber variations, and this effect overshadows the known overestimation of the axon diameter due to undulations. This unexpected underestimation may originate from variations in the coarse-grained axial diffusivity due to caliber variations. Given that increased axonal beading and undulations have been observed in pathological tissues, such as traumatic brain injury and ischemia, the interpretation of axon diameter alterations in pathology may be significantly confounded.

Optimization and Validation of the DESIGNER dMRI preprocessing pipeline in white matter aging.

Various diffusion MRI (dMRI) preprocessing pipelines are currently available to yield more accurate diffusion parameters. Here, we evaluated accuracy and robustness of the optimized Diffusion parameter EStImation with Gibbs and NoisE Removal (DESIGNER) pipeline in a large clinical dMRI dataset and using ground truth phantoms. DESIGNER has been modified to improve denoising and target Gibbs ringing for partial Fourier acquisitions. We compared the revisited DESIGNER (Dv2) (including denoising, Gibbs removal, correction for motion, EPI distortion, and eddy currents) against the original DESIGNER (Dv1) pipeline, minimal preprocessing (including correction for motion, EPI distortion, and eddy currents only), and no preprocessing on a large clinical dMRI dataset of 524 control subjects with ages between 25 and 75 years old. We evaluated the effect of specific processing steps on age correlations in white matter with DTI and DKI metrics. We also evaluated the added effect of minimal Gaussian smoothing to deal with noise and to reduce outliers in parameter maps compared to DESIGNER (Dv2)'s noise removal method. Moreover, DESIGNER (Dv2)'s updated noise and Gibbs removal methods were assessed using ground truth dMRI phantom to evaluate accuracy. Results show age correlation in white matter with DTI and DKI metrics were affected by the preprocessing pipeline, causing systematic differences in absolute parameter values and loss or gain of statistical significance. Both in clinical dMRI and ground truth phantoms, DESIGNER (Dv2) pipeline resulted in the smallest number of outlier voxels and improved accuracy in DTI and DKI metrics as noise was reduced and Gibbs removal was improved. Thus, DESIGNER (Dv2) provides more accurate and robust DTI and DKI parameter maps as compared to no preprocessing or minimal preprocessing.

Microstructurally Informed Subject-Specific Parcellation of the Corpus Callosum using Axonal Water Fraction.

The corpus callosum (CC) is the most important interhemispheric white matter (WM) structure composed of several anatomically and functionally distinct WM tracts. Resolving these tracts is a challenge since the callosum appears relatively homogenous in conventional structural imaging. Commonly used callosal parcellation methods such as the Hofer/Frahm scheme rely on rigid geometric guidelines to separate the substructures that are limited to consider individual variation. Here we present a novel subject-specific and microstructurally-informed method for callosal parcellation based on axonal water fraction (ƒ) known as a diffusion metric reflective of axon caliber and density. We studied 30 healthy subjects from the Human Connectome Project (HCP) dataset with multi-shell diffusion MRI. The biophysical parameter ƒ was derived from compartment-specific WM modeling. Inflection points were identified where there were concavity changes in ƒ across the CC to delineate callosal subregions. We observed relatively higher ƒ in anterior and posterior areas consisting of a greater number of small diameter fibers and lower ƒ in posterior body areas of the CC consisting of a greater number of large diameter fibers. Based on degree of change in ƒ along the callosum, seven callosal subregions can be consistently delineated for each individual. We observe that ƒ can capture differences in underlying tissue microstructures and seven subregions can be identified across CC. Therefore, this method provides microstructurally informed callosal parcellation in a subject-specific way, allowing for more accurate analysis in the corpus callosum.

Universal Sampling Denoising (USD) for noise mapping and noise removal of non-Cartesian MRI.

Random matrix theory (RMT) combined with principal component analysis has resulted in a widely used MPPCA noise mapping and denoising algorithm, that utilizes the redundancy in multiple acquisitions and in local image patches. RMT-based denoising relies on the uncorrelated identically distributed noise. This assumption breaks down after regridding of non-Cartesian sampling. Here we propose a Universal Sampling Denoising (USD) pipeline to homogenize the noise level and decorrelate the noise in non-Cartesian sampled k-space data after resampling to a Cartesian grid. In this way, the RMT approaches become applicable to MRI of any non-Cartesian k-space sampling. We demonstrate the denoising pipeline on MRI data acquired using radial trajectories, including diffusion MRI of a numerical phantom and ex vivo mouse brains, as well as in vivo $T_2$ MRI of a healthy subject. The proposed pipeline robustly estimates noise level, performs noise removal, and corrects bias in parametric maps, such as diffusivity and kurtosis metrics, and $T_2$ relaxation time. USD stabilizes the variance, decorrelates the noise, and thereby enables the application of RMT-based denoising approaches to MR images reconstructed from any non-Cartesian data. In addition to MRI, USD may also apply to other medical imaging techniques involving non-Cartesian acquisition, such as PET, CT, and SPECT.

In vivo Mapping of Cellular Resolution Neuropathology in Brain Ischemia by Diffusion MRI.

Non-invasive mapping of cellular pathology can provide critical diagnostic and prognostic information. Recent developments in diffusion MRI have produced new tools for examining tissue microstructure at a level well below the imaging resolution. Here, we report the use of diffusion time ( t )-dependent diffusion kurtosis imaging ( t DKI) to simultaneously assess the morphology and transmembrane permeability of cells and their processes in the context of pathological changes in hypoxic-ischemic brain (HI) injury. Through Monte Carlo simulations and cell culture organoid imaging, we demonstrate feasibility in measuring effective size and permeability changes based on the peak and tail of t DKI curves. In a mouse model of HI, in vivo imaging at 11.7T detects a marked shift of the t DKI peak to longer t in brain edema, suggesting swelling and beading associated with the astrocytic processes and neuronal neurites. Furthermore, we observed a faster decrease of the t DKI tail in injured brain regions, reflecting increased membrane permeability that was associated with upregulated water exchange upon astrocyte activation at acute stage as well as necrosis with disrupted membrane integrity at subacute stage. Such information, unavailable with conventional diffusion MRI at a single t, can predict salvageable tissues. For a proof-of-concept, t DKI at 3T on an ischemic stroke patient suggested increased membrane permeability in the stroke region. This work therefore demonstrates the potential of t DKI for in vivo detection of the pathological changes in microstructural morphology and transmembrane permeability after ischemic injury using a clinically translatable protocol.

Mapping tissue microstructure of brain white matter in vivo in health and disease using diffusion MRI.

Diffusion magnetic resonance imaging offers unique in vivo sensitivity to tissue microstructure in brain white matter, which undergoes significant changes during development and is compromised in virtually every neurological disorder. Yet, the challenge is to develop biomarkers that are specific to micrometer-scale cellular features in a human MRI scan of a few minutes. Here we quantify the sensitivity and specificity of a multicompartment diffusion modeling framework to the density, orientation and integrity of axons. We demonstrate that using a machine learning based estimator, our biophysical model captures the morphological changes of axons in early development, acute ischemia and multiple sclerosis (total N=821). The methodology of microstructure mapping is widely applicable in clinical settings and in large imaging consortium data to study development, aging and pathology.

Observation of magnetic structural universality and jamming transition with NMR.

Nuclear magnetic resonance (NMR) has been instrumental in deciphering the structure of proteins. Here we show that transverse NMR relaxation, through its time-dependent relaxation rate, is distinctly sensitive to the structure of complex materials or biological tissues at the mesoscopic scale, from micrometers to tens of micrometers. Based on the ideas of universality, we show analytically and numerically that the time-dependent transverse relaxation rate approaches its long-time limit in a power-law fashion, with the dynamical exponent reflecting the universality class of mesoscopic magnetic structure. The spectral line shape acquires the corresponding non-analytic power law singularity at zero frequency. We experimentally detect the change in the dynamical exponent as a result of the transition into maximally random jammed state characterized by hyperuniform correlations. The relation between relaxational dynamics and magnetic structure opens the way for noninvasive characterization of porous media, complex materials and biological tissues.

Feasibility of Accelerated Prostate Diffusion-Weighted Imaging on 0.55 T MRI Enabled With Random Matrix Theory Denoising.

INTRODUCTION: Prostate cancer diffusion weighted imaging (DWI) MRI is typically performed at high-field strength (3.0 T) in order to overcome low signal-to-noise ratio (SNR). In this study, we demonstrate the feasibility of prostate DWI at low field enabled by random matrix theory (RMT)-based denoising, relying on the MP-PCA algorithm applied during image reconstruction from multiple coils. METHODS: Twenty-one volunteers and 2 prostate cancer patients were imaged with a 6-channel pelvic surface array coil and an 18-channel spine array on a prototype 0.55 T system created by ramping down a commercial magnetic resonance imaging system (1.5 T MAGNETOM Aera Siemens Healthcare) with 45 mT/m gradients and 200 T/m/s slew rate. Diffusion-weighted images were acquired with 4 non-collinear directions, for which b = 50 s/mm 2 was used with 8 averages and b = 1000 s/mm 2 with 40 averages; 2 extra b = 50 s/mm 2 were used as part of the dynamic field correction. Standard and RMT-based reconstructions were applied on DWI over different ranges of averages. Accuracy/precision was evaluated using the apparent diffusion coefficient (ADC), and image quality was evaluated over 5 separate reconstructions by 3 radiologists with a 5-point Likert scale. For the 2 patients, we compare image quality and lesion visibility of the RMT reconstruction versus the standard one on 0.55 T and on clinical 3.0 T. RESULTS: The RMT-based reconstruction in this study reduces the noise floor by a factor of 5.8, thereby alleviating the bias on prostate ADC. Moreover, the precision of the ADC in prostate tissue after RMT increases over a range of 30%-130%, with the increase in both signal-to-noise ratio and precision being more prominent for a low number of averages. Raters found that the images were consistently of moderate to good overall quality (3-4 on the Likert scale). Moreover, they determined that b = 1000 s/mm 2 images from a 1:55-minute scan with the RMT-based reconstruction were on par with the corresponding images from a 14:20-minute scan with standard reconstruction. Prostate cancer was visible on ADC and calculated b = 1500 images even with the abbreviated 1:55-minute scan reconstructed with RMT. CONCLUSIONS: Prostate imaging using DWI is feasible at low field and can be performed more rapidly with noninferior image quality compared with standard reconstruction.

Identifying relevant diffusion MRI microstructure biomarkers relating to exposure to repeated head impacts in contact sport athletes.

PURPOSE: Repeated head impacts (RHI) without concussion may cause long-term sequelae. A growing array of diffusion MRI metrics exist, both empiric and modeled and it is hard to know which are potentially important biomarkers. Common conventional statistical methods fail to consider interactions between metrics and rely on group-level comparisons. This study uses a classification pipeline as a means towards identifying important diffusion metrics associated with subconcussive RHI. METHODS: 36 collegiate contact sport athletes and 45 non-contact sport controls from FITBIR CARE were included. Regional/whole brain WM statistics were computed from 7 diffusion metrics. Wrapper-based feature selection was applied to 5 classifiers representing a range of learning capacities. Best 2 classifiers were interpreted to identify the most RHI-related diffusion metrics. RESULTS: Mean diffusivity (MD) and mean kurtosis (MK) are found to be the most important metrics for discriminating between athletes with and without RHI exposure history. Regional features outperformed global statistics. Linear approaches outperformed non-linear approaches with good generalizability (test AUC 0.80-0.81). CONCLUSION: Feature selection and classification identifies diffusion metrics that characterize subconcussive RHI. Linear classifiers yield the best performance and mean diffusion, tissue microstructure complexity, and radial extra-axonal compartment diffusion (MD, MK, De,⊥) are found to be the most influential metrics. This work provides proof of concept that applying such approach to small, multidimensional dataset can be successful given attention to optimizing learning capacity without overfitting and serves an example of methods that lead to better understanding of the myriad of diffusion metrics as they relate to injury and disease.

The influence of axonal beading and undulation on axonal diameter mapping.

We consider the effect of non-cylindrical axonal shape on axonal diameter mapping with diffusion MRI. Practical sensitivity to axon diameter is attained at strong diffusion weightings b, where the deviation from the 1/b scaling yields the finite transverse diffusivity, which is then translated into axon diameter. While axons are usually modeled as perfectly straight, impermeable cylinders, the local variations in diameter (caliber variation or beading) and direction (undulation) have been observed in microscopy data of human axons. Here we quantify the influence of cellular-level features such as caliber variation and undulation on axon diameter estimation. For that, we simulate the diffusion MRI signal in realistic axons segmented from 3-dimensional electron microscopy of a human brain sample. We then create artificial fibers with the same features and tune the amplitude of their caliber variations and undulations. Numerical simulations of diffusion in fibers with such tunable features show that caliber variations and undulations result in under- and over-estimation of axon diameters, correspondingly; this bias can be as large as 100%. Given that increased axonal beading and undulations have been observed in pathological tissues, such as traumatic brain injury and ischemia, the interpretation of axon diameter alterations in pathology may be significantly confounded.

Measuring water exchange on a preclinical MRI system using filter exchange and diffusion time dependent kurtosis imaging.

PURPOSE: Filter exchange imaging (FEXI) and diffusion time (t)-dependent diffusion kurtosis imaging (DKI(t)) are both sensitive to water exchange between tissue compartments. The restrictive effects of tissue microstructure, however, introduce bias to the exchange rate obtained by these two methods, as their interpretation conventionally rely on the Kärger model of barrier limited exchange between Gaussian compartments. Here, we investigated whether FEXI and DKI(t) can provide comparable exchange rates in ex vivo mouse brains. THEORY AND METHODS: FEXI and DKI(t) data were acquired from ex vivo mouse brains on a preclinical MRI system. Phase cycling and negative slice prewinder gradients were used to minimize the interferences from imaging gradients. RESULTS: In the corpus callosum, apparent exchange rate (AXR) from FEXI correlated with the exchange rate (the inverse of exchange time, 1/τex ) from DKI(t) along the radial direction. In comparison, discrepancies between FEXI and DKI(t) were found in the cortex due to low filter efficiency and confounding effects from tissue microstructure. CONCLUSION: The results suggest that FEXI and DKI(t) are sensitive to the same exchange processes in white matter when separated from restrictive effects of microstructure. The complex microstructure in gray matter, with potential exchange among multiple compartments and confounding effects of microstructure, still pose a challenge for FEXI and DKI(t).

Neurite Exchange Imaging (NEXI): A minimal model of diffusion in gray matter with inter-compartment water exchange.

Biophysical models of diffusion in white matter have been center-stage over the past two decades and are essentially based on what is now commonly referred to as the "Standard Model" (SM) of non-exchanging anisotropic compartments with Gaussian diffusion. In this work, we focus on diffusion MRI in gray matter, which requires rethinking basic microstructure modeling blocks. In particular, at least three contributions beyond the SM need to be considered for gray matter: water exchange across the cell membrane - between neurites and the extracellular space; non-Gaussian diffusion along neuronal and glial processes - resulting from structural disorder; and signal contribution from soma. For the first contribution, we propose Neurite Exchange Imaging (NEXI) as an extension of the SM of diffusion, which builds on the anisotropic Kärger model of two exchanging compartments. Using datasets acquired at multiple diffusion weightings (b) and diffusion times (t) in the rat brain in vivo, we investigate the suitability of NEXI to describe the diffusion signal in the gray matter, compared to the other two possible contributions. Our results for the diffusion time window 20-45 ms show minimal diffusivity time-dependence and more pronounced kurtosis decay with time, which is well fit by the exchange model. Moreover, we observe lower signal for longer diffusion times at high b. In light of these observations, we identify exchange as the mechanism that best explains these signal signatures in both low-b and high-b regime, and thereby propose NEXI as the minimal model for gray matter microstructure mapping. We finally highlight multi-b multi-t acquisition protocols as being best suited to estimate NEXI model parameters reliably. Using this approach, we estimate the inter-compartment water exchange time to be 15 - 60 ms in the rat cortex and hippocampus in vivo, which is of the same order or shorter than the diffusion time in typical diffusion MRI acquisitions. This suggests water exchange as an essential component for interpreting diffusion MRI measurements in gray matter.

Reproducibility of the Standard Model of diffusion in white matter on clinical MRI systems.

Estimating intra- and extra-axonal microstructure parameters, such as volume fractions and diffusivities, has been one of the major efforts in brain microstructure imaging with MRI. The Standard Model (SM) of diffusion in white matter has unified various modeling approaches based on impermeable narrow cylinders embedded in locally anisotropic extra-axonal space. However, estimating the SM parameters from a set of conventional diffusion MRI (dMRI) measurements is ill-conditioned. Multidimensional dMRI helps resolve the estimation degeneracies, but there remains a need for clinically feasible acquisitions that yield robust parameter maps. Here we find optimal multidimensional protocols by minimizing the mean-squared error of machine learning-based SM parameter estimates for two 3T scanners with corresponding gradient strengths of 40and80mT/m. We assess intra-scanner and inter-scanner repeatability for 15-minute optimal protocols by scanning 20 healthy volunteers twice on both scanners. The coefficients of variation all SM parameters except free water fraction are ≲10% voxelwise and 1-4% for their region-averaged values. As the achieved SM reproducibility outcomes are similar to those of conventional diffusion tensor imaging, our results enable robust in vivo mapping of white matter microstructure in neuroscience research and in the clinic.

Connectome 2.0: Developing the next-generation ultra-high gradient strength human MRI scanner for bridging studies of the micro-, meso- and macro-connectome.

The first phase of the Human Connectome Project pioneered advances in MRI technology for mapping the macroscopic structural connections of the living human brain through the engineering of a whole-body human MRI scanner equipped with maximum gradient strength of 300 mT/m, the highest ever achieved for human imaging. While this instrument has made important contributions to the understanding of macroscale connectional topology, it has also demonstrated the potential of dedicated high-gradient performance scanners to provide unparalleled in vivo assessment of neural tissue microstructure. Building on the initial groundwork laid by the original Connectome scanner, we have now embarked on an international, multi-site effort to build the next-generation human 3T Connectome scanner (Connectome 2.0) optimized for the study of neural tissue microstructure and connectional anatomy across multiple length scales. In order to maximize the resolution of this in vivo microscope for studies of the living human brain, we will push the diffusion resolution limit to unprecedented levels by (1) nearly doubling the current maximum gradient strength from 300 mT/m to 500 mT/m and tripling the maximum slew rate from 200 T/m/s to 600 T/m/s through the design of a one-of-a-kind head gradient coil optimized to minimize peripheral nerve stimulation; (2) developing high-sensitivity multi-channel radiofrequency receive coils for in vivo and ex vivo human brain imaging; (3) incorporating dynamic field monitoring to minimize image distortions and artifacts; (4) developing new pulse sequences to integrate the strongest diffusion encoding and highest spatial resolution ever achieved in the living human brain; and (5) calibrating the measurements obtained from this next-generation instrument through systematic validation of diffusion microstructural metrics in high-fidelity phantoms and ex vivo brain tissue at progressively finer scales with accompanying diffusion simulations in histology-based micro-geometries. We envision creating the ultimate diffusion MRI instrument capable of capturing the complex multi-scale organization of the living human brain - from the microscopic scale needed to probe cellular geometry, heterogeneity and plasticity, to the mesoscopic scale for quantifying the distinctions in cortical structure and connectivity that define cyto- and myeloarchitectonic boundaries, to improvements in estimates of macroscopic connectivity.