Diffusion tensor imaging (DTI) enables non-invasive, cyto-architectural mapping of in vivo tissue microarchitecture through voxel-wise mathematical modeling of multiple magnetic resonance imaging (MRI) acquisitions, each differently sensitized to water diffusion. DTI computations are fundamentally estimation processes and are sensitive to noise and artifacts. Despite widespread adoption in the neuroimaging community, maintaining consistent DTI data quality remains challenging given the propensity for patient motion, artifacts associated with fast imaging techniques, and the possibility of hardware changes/failures. Furthermore, the quantity of data acquired per voxel, the non-linear estimation process, and numerous potential use cases complicate traditional visual data inspection approaches. Currently, quality inspection of DTI data has relied on visual inspection and individual processing in DTI analysis software programs (e.g. DTIPrep, DTI-studio). However, recent advances in applied statistical methods have yielded several different metrics to assess noise level, artifact propensity, quality of tensor fit, variance of estimated measures, and bias in estimated measures. To date, these metrics have been largely studied in isolation. Herein, we select complementary metrics for integration into an automatic DTI analysis and quality assurance pipeline. The pipeline completes in 24 hours, stores statistical outputs, and produces a graphical summary quality analysis (QA) report. We assess the utility of this streamlined approach for empirical quality assessment on 608 DTI datasets from pediatric neuroimaging studies. The efficiency and accuracy of quality analysis using the proposed pipeline is compared with quality analysis based on visual inspection. The unified pipeline is found to save a statistically significant amount of time (over 70%) while improving the consistency of QA between a DTI expert and a pool of research associates. Projection of QA metrics to a low dimensional manifold reveal qualitative, but clear, QA-study associations and suggest that automated outlier/anomaly detection would be feasible.

Irreversible white matter (WM) damage, including severe demyelination and axonal loss, is a main determinant of long-term disability in multiple sclerosis (MS). Non-invasive detection of changes in microstructural WM integrity in the disease is challenging since commonly used imaging metrics lack the necessary sensitivity, especially in the early phase of the disease. This study aims at assessing microstructural WM abnormalities in early-stage MS by using ultra-high gradient strength multi-shell diffusion MRI and the restricted signal fraction (FR) from the Composite Hindered and Restricted Model of Diffusion (CHARMED), a metric sensitive to the volume fraction of axons. In 22 early MS subjects (disease duration ≤5 years) and 15 age-matched healthy controls, restricted fraction estimates were obtained through the CHARMED model along with conventional Diffusion Tensor Imaging (DTI) metrics. All imaging parameters were compared cross-sectionally between the MS subjects and controls both in WM lesions and normal-appearing white matter (NAWM). We found a significant reduction in FR focally in WM lesions and widespread in the NAWM in MS patients relative to controls (corrected p < .05). Signal fraction changes in NAWM were not driven by perilesional tissue, nor were they influenced by proximity to the ventricles, challenging the hypothesis of an outside-in pathological process driven by CSF-mediated immune cytotoxic factors. No significant differences were found in conventional DTI parameters. In a cross-validated classification task, FR showed the largest effect size and outperformed all other diffusion imaging metrics in discerning lesions from contralateral NAWM. Taken together, our data provide evidence for the presence of widespread microstructural changes in the NAWM in early MS stages that are, at least in part, unrelated to focal demyelinating lesions. Interestingly, these pathological changes were not yet detectable by conventional diffusion imaging at this early disease stage, highlighting the sensitivity and value of multi-shell diffusion imaging for better characterizing axonal microstructure in MS.

Mesial temporal lobe epilepsy (MTLE) is a network disorder. We aimed to quantify the white matter alterations in the temporal lobe of MTLE patients with hippocampal sclerosis (MTLE-HS) by using magnetic resonance fingerprinting (MRF), a novel imaging technique, which allows simultaneous measurements of multiple parameters with a single acquisition.

Axon diameter mapping using high-gradient diffusion MRI has generated great interest as a noninvasive tool for studying trends in axonal size in the human brain. One of the main barriers to mapping axon diameter across the whole brain is accounting for complex white matter fiber configurations (e.g., crossings and fanning), which are prevalent throughout the brain. Here, we present a framework for generalizing axon diameter index estimation to the whole brain independent of the underlying fiber orientation distribution using the spherical mean technique (SMT). This approach is shown to significantly benefit from the use of real-valued diffusion data with Gaussian noise, which reduces the systematic bias in the estimated parameters resulting from the elevation of the noise floor when using magnitude data with Rician noise. We demonstrate the feasibility of obtaining whole-brain orientationally invariant estimates of axon diameter index and relative volume fractions in six healthy human volunteers using real-valued diffusion data acquired on a dedicated high-gradient 3-Tesla human MRI scanner with 300 mT/m maximum gradient strength. The trends in axon diameter index are consistent with known variations in axon diameter from histology and demonstrate the potential of this generalized framework for revealing coherent patterns in axonal structure throughout the living human brain. The use of real-valued diffusion data provides a viable solution for eliminating the Rician noise floor and should be considered for all spherical mean approaches to microstructural parameter estimation.

Strong gradient systems can improve the signal-to-noise ratio of diffusion MRI measurements and enable a wider range of acquisition parameters that are beneficial for microstructural imaging. We present a comprehensive diffusion MRI dataset of 26 healthy participants acquired on the MGH-USC 3 T Connectome scanner equipped with 300 mT/m maximum gradient strength and a custom-built 64-channel head coil. For each participant, the one-hour long acquisition systematically sampled the accessible diffusion measurement space, including two diffusion times (19 and 49 ms), eight gradient strengths linearly spaced between 30 mT/m and 290 mT/m for each diffusion time, and 32 or 64 uniformly distributed directions. The diffusion MRI data were preprocessed to correct for gradient nonlinearity, eddy currents, and susceptibility induced distortions. In addition, scan/rescan data from a subset of seven individuals were also acquired and provided. The MGH Connectome Diffusion Microstructure Dataset (CDMD) may serve as a test bed for the development of new data analysis methods, such as fiber orientation estimation, tractography and microstructural modelling.

The MGH-USC CONNECTOM MRI scanner housed at the Massachusetts General Hospital (MGH) is a major hardware innovation of the Human Connectome Project (HCP). The 3T CONNECTOM scanner is capable of producing a magnetic field gradient of up to 300 mT/m strength for in vivo human brain imaging, which greatly shortens the time spent on diffusion encoding, and decreases the signal loss due to T2 decay. To demonstrate the capability of the novel gradient system, data of healthy adult participants were acquired for this MGH-USC Adult Diffusion Dataset (N=35), minimally preprocessed, and shared through the Laboratory of Neuro Imaging Image Data Archive (LONI IDA) and the WU-Minn Connectome Database (ConnectomeDB). Another purpose of sharing the data is to facilitate methodological studies of diffusion MRI (dMRI) analyses utilizing high diffusion contrast, which perhaps is not easily feasible with standard MR gradient system. In addition, acquisition of the MGH-Harvard-USC Lifespan Dataset is currently underway to include 120 healthy participants ranging from 8 to 90 years old, which will also be shared through LONI IDA and ConnectomeDB. Here we describe the efforts of the MGH-USC HCP consortium in acquiring and sharing the ultra-high b-value diffusion MRI data and provide a report on data preprocessing and access. We conclude with a demonstration of the example data, along with results of standard diffusion analyses, including q-ball Orientation Distribution Function (ODF) reconstruction and tractography.

The parameter selection for diffusion MRI experiments is dominated by the "k-q tradeoff" whereby the Signal to Noise Ratio (SNR) of the images is traded for either high spatial resolution (determined by the maximum k-value collected) or high diffusion sensitivity (effected by b-value or the q vector) but usually not both. Furthermore, different brain regions (such as gray matter and white matter) likely require different tradeoffs between these parameters due to the size of the structures to be visualized or the length-scale of the microstructure being probed. In this case, it might be advantageous to combine information from two scans - a scan with high q but low k (high angular resolution in diffusion but low spatial resolution in the image domain) to provide maximal information about white matter fiber crossing, and one low q but high k (low angular resolution but high spatial resolution) for probing the cortex. In this study, we propose a method, termed HIgh b-value and high Resolution Integrated Diffusion (HIBRID) imaging, for acquiring and combining the information from these two complementary types of scan with the goal of studying diffusion in the cortex without compromising white matter fiber information. The white-gray boundary and pial surface obtained from anatomical scans are incorporated as prior information to guide the fusion. We study the complementary advantages of the fused datasets, and assess the quality of the HIBRID data compared to either alone.

Quantitative assessment of brain myelination has gained attention for both research and diagnosis of neurological diseases. However, conventional pulse sequences cannot directly acquire the myelin-proton signals due to its extremely short T2 and T2* values. To obtain the myelin-proton signals, dedicated short T2 acquisition techniques, such as ultrashort echo time (UTE) imaging, have been introduced. However, it remains challenging to isolate the myelin-proton signals from tissues with longer T2. In this article, we extended our previous two-dimensional ultrashort echo time magnetic resonance fingerprinting (UTE-MRF) with dual-echo acquisition to three dimensional (3D). Given a relatively low proton density (PD) of myelin-proton, we utilized Cramér-Rao Lower Bound to encode myelin-proton with the maximal SNR efficiency for optimizing the MR fingerprinting design, in order to improve the sensitivity of the sequence to myelin-proton. In addition, with a second echo of approximately 3 ms, myelin-water component can be also captured. A myelin-tissue (myelin-proton and myelin-water) fraction mapping can be thus calculated. The optimized 3D UTE-MRF with dual-echo acquisition is tested in simulations, physical phantom and in vivo studies of both healthy subjects and multiple sclerosis patients. The results suggest that the rapidly decayed myelin-proton and myelin-water signal can be depicted with UTE signals of our method at clinically relevant resolution (1.8 mm isotropic) in 15 min. With its good sensitivity to myelin loss in multiple sclerosis patients demonstrated, our method for the whole brain myelin-tissue fraction mapping in clinical friendly scan time has the potential for routine clinical imaging.

Automatic cerebral cortical surface reconstruction is a useful tool for cortical anatomy quantification, analysis and visualization. Recently, the Human Connectome Project and several studies have shown the advantages of using T1-weighted magnetic resonance (MR) images with sub-millimeter isotropic spatial resolution instead of the standard 1-mm isotropic resolution for improved accuracy of cortical surface positioning and thickness estimation. Nonetheless, sub-millimeter resolution images are noisy by nature and require averaging multiple repetitions to increase the signal-to-noise ratio for precisely delineating the cortical boundary. The prolonged acquisition time and potential motion artifacts pose significant barriers to the wide adoption of cortical surface reconstruction at sub-millimeter resolution for a broad range of neuroscientific and clinical applications. We address this challenge by evaluating the cortical surface reconstruction resulting from denoised single-repetition sub-millimeter T1-weighted images. We systematically characterized the effects of image denoising on empirical data acquired at 0.6 mm isotropic resolution using three classical denoising methods, including denoising convolutional neural network (DnCNN), block-matching and 4-dimensional filtering (BM4D) and adaptive optimized non-local means (AONLM). The denoised single-repetition images were found to be highly similar to 6-repetition averaged images, with a low whole-brain averaged mean absolute difference of ~0.016, high whole-brain averaged peak signal-to-noise ratio of ~33.5 dB and structural similarity index of ~0.92, and minimal gray matter-white matter contrast loss (2% to 9%). The whole-brain mean absolute discrepancies in gray matter-white matter surface placement, gray matter-cerebrospinal fluid surface placement and cortical thickness estimation were lower than 165 μm, 155 μm and 145 μm-sufficiently accurate for most applications. These discrepancies were approximately one third to half of those from 1-mm isotropic resolution data. The denoising performance was equivalent to averaging ~2.5 repetitions of the data in terms of image similarity, and 1.6-2.2 repetitions in terms of the cortical surface placement accuracy. The scan-rescan variability of the cortical surface positioning and thickness estimation was lower than 170 μm. Our unique dataset and systematic characterization support the use of denoising methods for improved cortical surface reconstruction at sub-millimeter resolution.

To estimate microstructure-related parameters from diffusion MRI data, biophysical models make strong, simplifying assumptions about the underlying tissue. The extent to which many of these assumptions are valid remains an open research question. This study was inspired by the disparity between the estimated intra-axonal axial diffusivity from literature and that typically assumed by the Neurite Orientation Dispersion and Density Imaging (NODDI) model (d∥=1.7μm2/ms). We first demonstrate how changing the assumed axial diffusivity results in considerably different NODDI parameter estimates. Second, we illustrate the ability to estimate axial diffusivity as a free parameter of the model using high b-value data and an adapted NODDI framework. Using both simulated and in vivo data we investigate the impact of fitting to either real-valued or magnitude data, with Gaussian and Rician noise characteristics respectively, and what happens if we get the noise assumptions wrong in this high b-value and thus low SNR regime. Our results from real-valued human data estimate intra-axonal axial diffusivities of ∼2-2.5μm2/ms, in line with current literature. Crucially, our results demonstrate the importance of accounting for both a rectified noise floor and/or a signal offset to avoid biased parameter estimates when dealing with low SNR data.

Axon diameter mapping using diffusion MRI in the living human brain has attracted growing interests with the increasing availability of high gradient strength MRI systems. A systematic assessment of the consistency of axon diameter estimates within and between individuals is needed to gain a comprehensive understanding of how such methods extend to quantifying differences in axon diameter index between groups and facilitate the design of neurobiological studies using such measures. We examined the scan-rescan repeatability of axon diameter index estimation based on the spherical mean technique (SMT) approach using diffusion MRI data acquired with gradient strengths up to 300 mT/m on a 3T Connectom system in 7 healthy volunteers. We performed statistical power analyses using data acquired with the same protocol in a larger cohort consisting of 15 healthy adults to investigate the implications for study design. Results revealed a high degree of repeatability in voxel-wise restricted volume fraction estimates and tract-wise estimates of axon diameter index derived from high-gradient diffusion MRI data. On the region of interest (ROI) level, across white matter tracts in the whole brain, the Pearson's correlation coefficient of the axon diameter index estimated between scan and rescan experiments was r = 0.72 with an absolute deviation of 0.18 μm. For an anticipated 10% effect size in studies of axon diameter index, most white matter regions required a sample size of less than 15 people to observe a measurable difference between groups using an ROI-based approach. To facilitate the use of high-gradient strength diffusion MRI data for neuroscientific studies of axonal microstructure, the comprehensive multi-gradient strength, multi-diffusion time data used in this work will be made publicly available, in support of open science and increasing the accessibility of such data to the greater scientific community.

We present a whole-brain in vivo diffusion MRI (dMRI) dataset acquired at 760 μm isotropic resolution and sampled at 1260 q-space points across 9 two-hour sessions on a single healthy participant. The creation of this benchmark dataset is possible through the synergistic use of advanced acquisition hardware and software including the high-gradient-strength Connectom scanner, a custom-built 64-channel phased-array coil, a personalized motion-robust head stabilizer, a recently developed SNR-efficient dMRI acquisition method, and parallel imaging reconstruction with advanced ghost reduction algorithm. With its unprecedented resolution, SNR and image quality, we envision that this dataset will have a broad range of investigational, educational, and clinical applications that will advance the understanding of human brain structures and connectivity. This comprehensive dataset can also be used as a test bed for new modeling, sub-sampling strategies, denoising and processing algorithms, potentially providing a common testing platform for further development of in vivo high resolution dMRI techniques. Whole brain anatomical T1-weighted and T2-weighted images at submillimeter scale along with field maps are also made available.

Diffusion tensor magnetic resonance imaging (DTI) is unsurpassed in its ability to map tissue microstructure and structural connectivity in the living human brain. Nonetheless, the angular sampling requirement for DTI leads to long scan times and poses a critical barrier to performing high-quality DTI in routine clinical practice and large-scale research studies. In this work we present a new processing framework for DTI entitled DeepDTI that minimizes the data requirement of DTI to six diffusion-weighted images (DWIs) required by conventional voxel-wise fitting methods for deriving the six unique unknowns in a diffusion tensor using data-driven supervised deep learning. DeepDTI maps the input non-diffusion-weighted (b ​= ​0) image and six DWI volumes sampled along optimized diffusion-encoding directions, along with T1-weighted and T2-weighted image volumes, to the residuals between the input and high-quality output b = 0 image and DWI volumes using a 10-layer three-dimensional convolutional neural network (CNN). The inputs and outputs of DeepDTI are uniquely formulated, which not only enables residual learning to boost CNN performance but also enables tensor fitting of resultant high-quality DWIs to generate orientational DTI metrics for tractography. The very deep CNN used by DeepDTI leverages the redundancy in local and non-local spatial information and across diffusion-encoding directions and image contrasts in the data. The performance of DeepDTI was systematically quantified in terms of the quality of the output images, DTI metrics, DTI-based tractography and tract-specific analysis results. We demonstrate rotationally-invariant and robust estimation of DTI metrics from DeepDTI that are comparable to those obtained with two b ​= ​0 images and 21 DWIs for the primary eigenvector derived from DTI and two b ​= ​0 images and 26-30 DWIs for various scalar metrics derived from DTI, achieving 3.3-4.6 × ​acceleration, and twice as good as those of a state-of-the-art denoising algorithm at the group level. The twenty major white-matter tracts can be accurately identified from the tractography of DeepDTI results. The mean distance between the core of the major white-matter tracts identified from DeepDTI results and those from the ground-truth results using 18 ​b ​= ​0 images and 90 DWIs measures around 1-1.5 ​mm. DeepDTI leverages domain knowledge of diffusion MRI physics and power of deep learning to render DTI, DTI-based tractography, major white-matter tracts identification and tract-specific analysis more feasible for a wider range of neuroscientific and clinical studies.

Spatio-temporal MRI methods enable whole-brain multi-parametric mapping at ultra-fast acquisition times through efficient k-space encoding, but can have very long reconstruction times, which limit their integration into clinical practice. Deep learning (DL) is a promising approach to accelerate reconstruction, but can be computationally intensive to train and deploy due to the large dimensionality of spatio-temporal MRI. DL methods also need large training data sets and can produce results that don't match the acquired data if data consistency is not enforced. The aim of this project is to reduce reconstruction time using DL whilst simultaneously limiting the risk of deep learning induced hallucinations, all with modest hardware requirements.

To propose a virtual coil (VC) acquisition/reconstruction framework to improve highly accelerated single-shot EPI (SS-EPI) and generalized slice dithered enhanced resolution (gSlider) acquisition in high-resolution diffusion imaging (DI).

To evaluate alterations in apparent axon diameter and axon density obtained by high-gradient diffusion MRI in the corpus callosum of MS patients and the relationship of these advanced diffusion MRI metrics to neurologic disability and cognitive impairment in MS.

White matter damage in the visual pathway is common in multiple sclerosis (MS) and is associated with retinal thinning, although the underlying mechanism of association remains unclear. The goal of this work was to evaluate the presence and extent of white matter tract integrity (WMTI) alterations in the optic radiation (OR) in people with MS and to investigate the association between WMTI metrics and retinal thinning in the eyes of MS patients without a history of optic neuritis (ON) as measured by optical coherence tomography (OCT). We hypothesized that WMTI metrics would reflect axonal damage that occurs in the OR in MS, and that axonal alterations revealed by WMTI would be associated with retinal thinning.

To increase granularity in human neuroimaging science, we designed and built a next-generation 7 Tesla magnetic resonance imaging scanner to reach ultra-high resolution by implementing several advances in hardware. To improve spatial encoding and increase the image signal-to-noise ratio, we developed a head-only asymmetric gradient coil (200 mT m-1, 900 T m-1s-1) with an additional third layer of windings. We integrated a 128-channel receiver system with 64- and 96-channel receiver coil arrays to boost signal in the cerebral cortex while reducing g-factor noise to enable higher accelerations. A 16-channel transmit system reduced power deposition and improved image uniformity. The scanner routinely performs functional imaging studies at 0.35-0.45 mm isotropic spatial resolution to reveal cortical layer functional activity, achieves high angular resolution in diffusion imaging and reduces acquisition time for both functional and structural imaging.

Diffusion-weighted magnetic resonance imaging (DW-MRI) has evolved to provide increasingly sophisticated investigations of the human brain's structural connectome in vivo. Restriction spectrum imaging (RSI) is a method that reconstructs the orientation distribution of diffusion within tissues over a range of length scales. In its original formulation, RSI represented the signal as consisting of a spectrum of Gaussian diffusion response functions. Recent technological advances have enabled the use of ultra-high b-values on human MRI scanners, providing higher sensitivity to intracellular water diffusion in the living human brain. To capture the complex diffusion time dependence of the signal within restricted water compartments, we expand upon the RSI approach to represent restricted water compartments with non-Gaussian response functions, in an extended analysis framework called linear multi-scale modeling (LMM). The LMM approach is designed to resolve length scale and orientation-specific information with greater specificity to tissue microstructure in the restricted and hindered compartments, while retaining the advantages of the RSI approach in its implementation as a linear inverse problem. Using multi-shell, multi-diffusion time DW-MRI data acquired with a state-of-the-art 3 T MRI scanner equipped with 300 mT/m gradients, we demonstrate the ability of the LMM approach to distinguish different anatomical structures in the human brain and the potential to advance mapping of the human connectome through joint estimation of the fiber orientation distributions and compartment size characteristics.

Cerebral white matter exhibits age-related degenerative changes during the course of normal aging, including decreases in axon density and alterations in axonal structure. Noninvasive approaches to measure these microstructural alterations throughout the lifespan would be invaluable for understanding the substrate and regional variability of age-related white matter degeneration. Recent advances in diffusion magnetic resonance imaging (MRI) have leveraged high gradient strengths to increase sensitivity toward axonal size and density in the living human brain. Here, we examined the relationship between age and indices of axon diameter and packing density using high-gradient strength diffusion MRI in 36 healthy adults (aged 22-72) in well-defined central white matter tracts in the brain. A recently validated method for inferring the effective axonal compartment size and packing density from diffusion MRI measurements acquired with 300 mT/m maximum gradient strength was applied to the in vivo human brain to obtain indices of axon diameter and density in the corpus callosum, its sub-regions, and adjacent anterior and posterior fibers in the forceps minor and forceps major. The relationships between the axonal metrics, corpus callosum area and regional gray matter volume were also explored. Results revealed a significant increase in axon diameter index with advancing age in the whole corpus callosum. Similar analyses in sub-regions of the corpus callosum showed that age-related alterations in axon diameter index and axon density were most pronounced in the genu of the corpus callosum and relatively absent in the splenium, in keeping with findings from previous histological studies. The significance of these correlations was mirrored in the forceps minor and forceps major, consistent with previously reported decreases in FA in the forceps minor but not in the forceps major with age. Alterations in the axonal imaging metrics paralleled decreases in corpus callosum area and regional gray matter volume with age. Among older adults, results from cognitive testing suggested an association between larger effective compartment size in the corpus callosum, particularly within the genu of the corpus callosum, and lower scores on the Montreal Cognitive Assessment, largely driven by deficits in short-term memory. The current study suggests that high-gradient diffusion MRI may be sensitive to the axonal substrate of age-related white matter degeneration reflected in traditional DTI metrics and provides further evidence for regionally selective alterations in white matter microstructure with advancing age.