Eddy current-induced artifact correction in high b-value ex vivo human brain diffusion MRI with dynamic field monitoring.

PURPOSE: To investigate whether spatiotemporal magnetic field monitoring can correct pronounced eddy current-induced artifacts incurred by strong diffusion-sensitizing gradients up to 300 mT/m used in high b-value diffusion-weighted (DW) EPI. METHODS: A dynamic field camera equipped with 16 1 H NMR field probes was first used to characterize field perturbations caused by residual eddy currents from diffusion gradients waveforms in a 3D multi-shot EPI sequence on a 3T Connectom scanner for different gradient strengths (up to 300 mT/m), diffusion directions, and shots. The efficacy of dynamic field monitoring-based image reconstruction was demonstrated on high-gradient strength, submillimeter resolution whole-brain ex vivo diffusion MRI. A 3D multi-shot image reconstruction framework was developed that incorporated the nonlinear phase evolution measured with the dynamic field camera. RESULTS: Phase perturbations in the readout induced by residual eddy currents from strong diffusion gradients are highly nonlinear in space and time, vary among diffusion directions, and interfere significantly with the image encoding gradients, changing the k-space trajectory. During the readout, phase modulations between odd and even EPI echoes become non-static and diffusion encoding direction-dependent. Superior reduction of ghosting and geometric distortion was achieved with dynamic field monitoring compared to ghosting reduction approaches such as navigator- and structured low-rank-based methods or MUSE followed by image-based distortion correction with the FSL tool "eddy." CONCLUSION: Strong eddy current artifacts characteristic of high-gradient strength DW-EPI can be well corrected with dynamic field monitoring-based image reconstruction.

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.

Perivascular space diffusivity and brain microstructural measures are associated with circadian time and sleep quality.

The glymphatic system is centred around brain cerebrospinal fluid flow and is enhanced during sleep, and the synaptic homeostasis hypothesis proposes that sleep acts on brain microstructure by selective synaptic downscaling. While so far primarily studied in animals, we here examine in humans if brain diffusivity and microstructure is related to time of day, sleep quality and cognitive performance. We use diffusion weighted images from 916 young healthy individuals, aged between 22 and 37 years, collected as part of the Human Connectome Project to assess diffusion tensor image analysis along the perivascular space index, white matter fractional anisotropy, intra-neurite volume fraction and extra-neurite mean diffusivity. Next, we examine if these measures are associated with circadian time of acquisition, the Pittsburgh Sleep Quality Index (high scores correspond to low sleep quality) and age-adjusted cognitive function total composite score. Consistent with expectations, we find that diffusion tensor image analysis along the perivascular space index and orbitofrontal grey matter extra-neurite mean diffusivity are negatively and white matter fractional anisotropy positively correlated with circadian time. Further, we find that grey matter intra-neurite volume fraction correlates positively with Pittsburgh Sleep Quality Index, and that this correlation is driven by sleep duration. Finally, we find positive correlations between grey matter intra-neurite volume fraction and cognitive function total composite score, as well as negative interaction effects between cognitive function total composite score and Pittsburgh Sleep Quality Index on grey matter intra-neurite volume fraction. Our findings propose that perivascular flow is under circadian control and that sleep downregulates the intra-neurite volume in healthy adults with positive impact on cognitive function.

High-fidelity, high-spatial-resolution diffusion magnetic resonance imaging of ex vivo whole human brain at ultra-high gradient strength with structured low-rank echo-planar imaging ghost correction.

Diffusion magnetic resonance imaging (dMRI) of whole ex vivo human brain specimens enables three-dimensional (3D) mapping of structural connectivity at the mesoscopic scale, providing detailed evaluation of fiber architecture and tissue microstructure at a spatial resolution that is difficult to access in vivo. To account for the short T2 and low diffusivity of fixed tissue, ex vivo dMRI is often acquired using strong diffusion-sensitizing gradients and multishot/segmented 3D echo-planar imaging (EPI) sequences to achieve high spatial resolution. However, the combination of strong diffusion-sensitizing gradients and multishot/segmented EPI readout can result in pronounced ghosting artifacts incurred by nonlinear spatiotemporal variations in the magnetic field produced by eddy currents. Such ghosting artifacts cannot be corrected with conventional correction solutions and pose a significant roadblock to leveraging human MRI scanners with ultrahigh gradients for ex vivo whole-brain dMRI. Here, we show that ghosting-correction approaches that correct for either polarity-related ghosting or shot-to-shot variations in a separate manner are suboptimal for 3D multishot diffusion-weighted EPI experiments in fixed human brain specimens using strong diffusion-sensitizing gradients on the 3-T Connectom MRI scanner, resulting in orientationally biased dMRI estimates. We apply a recently developed advanced k-space reconstruction method based on structured low-rank matrix (SLM) modeling that handles both polarity-related ghosting and shot-to-shot variation simultaneously, to mitigate artifacts in high-angular resolution multishot dMRI data acquired in several fixed human brain specimens at 0.7-0.8-mm isotropic spatial resolution using b-values up to 10,000 s/mm2 and gradient strengths up to 280 mT/m. We demonstrate the improved mapping of diffusion tensor imaging and fiber orientation distribution functions in key neuroanatomical areas distributed across the whole brain using SLM-based EPI ghost correction compared with alternative techniques.

Mapping the human connectome using diffusion MRI at 300 mT/m gradient strength: Methodological advances and scientific impact.

Tremendous efforts have been made in the last decade to advance cutting-edge MRI technology in pursuit of mapping structural connectivity in the living human brain with unprecedented sensitivity and speed. The first Connectom 3T MRI scanner equipped with a 300 mT/m whole-body gradient system was installed at the Massachusetts General Hospital in 2011 and was specifically constructed as part of the Human Connectome Project. Since that time, numerous technological advances have been made to enable the broader use of the Connectom high gradient system for diffusion tractography and tissue microstructure studies and leverage its unique advantages and sensitivity to resolving macroscopic and microscopic structural information in neural tissue for clinical and neuroscientific studies. The goal of this review article is to summarize the technical developments that have emerged in the last decade to support and promote large-scale and scientific studies of the human brain using the Connectom scanner. We provide a brief historical perspective on the development of Connectom gradient technology and the efforts that led to the installation of three other Connectom 3T MRI scanners worldwide - one in the United Kingdom in Cardiff, Wales, another in continental Europe in Leipzig, Germany, and the latest in Asia in Shanghai, China. We summarize the key developments in gradient hardware and image acquisition technology that have formed the backbone of Connectom-related research efforts, including the rich array of high-sensitivity receiver coils, pulse sequences, image artifact correction strategies and data preprocessing methods needed to optimize the quality of high-gradient strength diffusion MRI data for subsequent analyses. Finally, we review the scientific impact of the Connectom MRI scanner, including advances in diffusion tractography, tissue microstructural imaging, ex vivo validation, and clinical investigations that have been enabled by Connectom technology. We conclude with brief insights into the unique value of strong gradients for diffusion MRI and where the field is headed in the coming years.

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.

Removal of partial Fourier-induced Gibbs (RPG) ringing artifacts in MRI.

PURPOSE: To investigate and remove Gibbs-ringing artifacts caused by partial Fourier (PF) acquisition and zero filling interpolation in MRI data. THEORY AND METHODS: Gibbs ringing of fully sampled data, leading to oscillations around tissue boundaries, is caused by the symmetric truncation of k-space. Such ringing can be removed by conventional methods, with the local subvoxel shifts method being the state-of-the-art. However, the asymmetric truncation of k-space in routinely used PF acquisitions leads to additional ringings of wider intervals in the PF sampling dimension that cannot be corrected solely based on magnitude images reconstructed via zero filling. Here, we develop a pipeline for the Removal of PF-induced Gibbs ringing (RPG) to remove ringing patterns of different periods by applying the conventional method twice. The proposed pipeline is validated on numerical phantoms, demonstrated on in vivo diffusion MRI measurements, and compared with the conventional method and neural network-based approach. RESULTS: For PF = 7/8 and 6/8, Gibbs-ringings and subsequent bias in diffusion metrics induced by PF acquisition and zero filling are robustly removed by using the proposed RPG pipeline. For PF = 5/8, however, ringing removal via RPG leads to excessive image blurring due to the interplay of image phase and convolution kernel. CONCLUSIONS: RPG corrects Gibbs-ringing artifacts in magnitude images of PF acquired data and reduces the bias in quantitative MR metrics. Considering the benefit of PF acquisition and the feasibility of ringing removal, we suggest applying PF = 6/8 when PF acquisition is necessary.

The impact of realistic axonal shape on axon diameter estimation using diffusion MRI.

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 3-dimensional 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→∞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.

In vivo observation and biophysical interpretation of time-dependent diffusion in human cortical gray matter.

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 â€‹gray matter sub-regions, in 10 healthy subjects. Significant diffusivity and kurtosis time-dependence is observed for t=21.2-100 â€‹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.

Effects of COVID-19 Prevention Measures on Other Common Infections, Taiwan.

To determine whether policies to limit transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hinder spread of other infectious diseases, we analyzed the National Health Insurance database in Taiwan. Rates of other infections were significantly lower after SARS-CoV-2 prevention measures were announced. This finding can be applied to cost-effectiveness of SARS-CoV-2 prevention.

Physical and numerical phantoms for the validation of brain microstructural MRI: A cookbook.

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.

What dominates the time dependence of diffusion transverse to axons: Intra- or extra-axonal water?

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 MRI-derived diffusion metrics. Here we resolve this debate in the human brain white matter. By varying not just the diffusion time, but also the gradient pulse duration of a standard diffusion MRI sequence, we identify a functional form of the measured time-dependent diffusion coefficient transverse to white matter tracts in 10 healthy volunteers. This specific functional form is shown to originate from the extra-axonal space, and provides estimates of the fiber packing correlation length for axons in a bundle. Our results offer a metric for the outer axonal diameter, a promising candidate marker for demyelination in neurodegenerative diseases. From the methodological perspective, our analysis demonstrates how competing models, which describe different physics yet interpolate standard measurements equally well, can be distinguished based on their prediction for an independent "orthogonal" measurement.

An analytic expression for the ultimate intrinsic SNR in a uniform sphere.

PURPOSE: The ultimate intrinsic signal-to-noise ratio (UISNR) is normally calculated using electrodynamic simulations with a complete basis of modes. Here, we provide an exact solution for the UISNR at the center of a dielectric sphere and assess how accurately this solution approximates UISNR away from the center. METHODS: We performed a mode analysis to determine which modes contribute to central UISNR - ζ(r→0). We then derived an analytic expression to calculate ζ(r→0) and analyzed its dependence on main magnetic field strength, sample geometry, and electrical properties. We validated the proposed solution against an established method based on dyadic Green's function simulations. RESULTS: Only one divergence-free mode contributes to ζ(r→0). The UISNR given by the exact solution matched the full simulation results for various parameter settings, whereas calculation speed was approximately 1000 times faster. We showed that the analytic expression can approximate the UISNR with <5% error at positions as much as 10-20% of the radius away from the center. CONCLUSION: The proposed formula enables rapid and direct calculation of UISNR in the central region of a sphere. The resulting UISNR value may be used, for example, as an absolute reference to assess the performance of head coils with spherical phantoms.

In vivo observation and biophysical interpretation of time-dependent diffusion in human white matter.

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 600 ms, 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.

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.

DIMOND: DIffusion Model OptimizatioN with Deep Learning.

Diffusion magnetic resonance imaging is an important tool for mapping tissue microstructure and structural connectivity non-invasively in the in vivo human brain. Numerous diffusion signal models are proposed to quantify microstructural properties. Nonetheless, accurate estimation of model parameters is computationally expensive and impeded by image noise. Supervised deep learning-based estimation approaches exhibit efficiency and superior performance but require additional training data and may be not generalizable. A new DIffusion Model OptimizatioN framework using physics-informed and self-supervised Deep learning entitled "DIMOND" is proposed to address this problem. DIMOND employs a neural network to map input image data to model parameters and optimizes the network by minimizing the difference between the input acquired data and synthetic data generated via the diffusion model parametrized by network outputs. DIMOND produces accurate diffusion tensor imaging results and is generalizable across subjects and datasets. Moreover, DIMOND outperforms conventional methods for fitting sophisticated microstructural models including the kurtosis and NODDI model. Importantly, DIMOND reduces NODDI model fitting time from hours to minutes, or seconds by leveraging transfer learning. In summary, the self-supervised manner, high efficacy, and efficiency of DIMOND increase the practical feasibility and adoption of microstructure and connectivity mapping in clinical and neuroscientific applications.

Interplay between MRI-based axon diameter and myelination estimates in macaque and human brain.

Axon diameter and myelin thickness are closely related microstructural tissue properties that affect the conduction velocity of action potentials in the nervous system. Imaging them non-invasively with MRI-based methods is thus valuable for studying brain microstructure and function. However, the relationship between MRI-based axon diameter and myelination measures has not been investigated across the brain, mainly due to methodological limitations in estimating axon diameters. In recent years, studies using ultra-high gradient strength diffusion MRI (dMRI) have demonstrated improved estimation of axon diameter across white-matter (WM) tracts in the human brain, making such investigations feasible. In this study, we aim to investigate relationships between tissue microstructure properties with MRI-based methods and compare the imaging findings to histological evidence from the literature. We collected dMRI with ultra-high gradient strength and multi-echo spin-echo MRI on ex vivo macaque and human brain samples on a preclinical scanner. From these data, we estimated axon diameter, intra-axonal signal fraction, myelin water fraction (MWF) and aggregate g-ratio and investigated their correlations. We found that the microstructural imaging parameters exhibited consistent patterns across WM tracts and species. Overall, the findings suggest that MRI-based axon geometry and myelination measures can provide complementary information about fiber morphology, and the relationships between these measures agree with prior histological evidence.

Romer-EPTI: rotating-view motion-robust super-resolution EPTI for SNR-efficient distortion-free in-vivo mesoscale dMRI and microstructure imaging.

Purpose: To overcome the major challenges in dMRI acquisition, including low SNR, distortion/blurring, and motion vulnerability. Methods: A novel Romer-EPTI technique is developed to provide distortion-free dMRI with significant SNR gain, high motion-robustness, sharp spatial resolution, and simultaneous multi-TE imaging. It introduces a ROtating-view Motion-robust supEr-Resolution technique (Romer) combined with a distortion/blurring-free EPTI encoding. Romer enhances SNR by a simultaneous multi-thick-slice acquisition with rotating-view encoding, while providing high motion-robustness through a motion-aware super-resolution reconstruction, which also incorporates slice-profile and real-value diffusion, to resolve high-isotropic-resolution volumes. The in-plane encoding is performed using distortion/blurring-free EPTI, which further improves effective spatial resolution and motion robustness by preventing not only T2/T2*-blurring but also additional blurring resulting from combining encoded volumes with inconsistent geometries caused by dynamic distortions. Self-navigation was incorporated to enable efficient phase correction. Additional developments include strategies to address slab-boundary artifacts, achieve minimal TE for SNR gain at 7T, and achieve high robustness to strong phase variations at high b-values. Results: Using Romer-EPTI, we demonstrate distortion-free whole-brain mesoscale in-vivo dMRI at both 3T (500-µm-iso) and 7T (485-µm-iso) for the first time, with high SNR efficiency (e.g., 25×), and high image quality free from distortion and slab-boundary artifacts with minimal blurring. Motion experiments demonstrate Romer-EPTI's high motion-robustness and ability to recover sharp images in the presence of motion. Romer-EPTI also demonstrates significant SNR gain and robustness in high b-value (b=5000s/mm2) and time-dependent dMRI. Conclusion: Romer-EPTI significantly improves SNR, motion-robustness, and image quality, providing a highly efficient acquisition for high-resolution dMRI and microstructure imaging.