Faculty Bibliography

Development of therapies for neurological disorders depends on our ability to non-invasively diagnose and monitor the progression of underlying pathologies at the cellular level. Physics and physiology limit the resolution of human MRI to be orders of magnitude coarser than cell dimensions. Here we identify and quantify the MRI signal coming from within micrometer-thin axons in human white matter tracts in vivo, by utilizing the sensitivity of diffusion MRI to Brownian motion of water molecules restricted by cell walls. We study a specific power-law scaling of the diffusion MRI signal with the diffusion weighting, predicted for water confined to narrow axons, and quantify axonal water fraction and orientation dispersion.

Large-scale consortium efforts such as Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) and other collaborative efforts show that combining statistical data from multiple independent studies can boost statistical power and achieve more accurate estimates of effect sizes, contributing to more reliable and reproducible research. A meta- analysis would pool effects from studies conducted in a similar manner, yet to date, no such harmonized protocol exists for resting state fMRI (rsfMRI) data. Here, we propose an initial pipeline for multi-site rsfMRI analysis to allow research groups around the world to analyze scans in a harmonized way, and to perform coordinated statistical tests. The challenge lies in the fact that resting state fMRI measurements collected by researchers over the last decade vary widely, with variable quality and differing spatial or temporal signal-to-noise ratio (tSNR). An effective harmonization must provide optimal measures for all quality data. Here we used rsfMRI data from twenty-two independent studies with approximately fifty corresponding T1-weighted and rsfMRI datasets each, to (A) review and aggregate the state of existing rsfMRI data, (B) demonstrate utility of principal component analysis (PCA)-based denoising and (C) develop a deformable ENIGMA EPI template based on the representative anatomy that incorporates spatial distortion patterns from various protocols and populations.

PURPOSE:Diffusion kurtosis imaging (DKI) is an advanced magnetic resonance imaging modality that is known to be sensitive to changes in the underlying microstructure of the brain. Image voxels in diffusion weighted images, however, are typically relatively large making them susceptible to partial volume effects, especially when part of the voxel contains cerebrospinal fluid. In this work, we introduce the "Diffusion Kurtosis Imaging with Free Water Elimination" (DKI-FWE) model that separates the signal contributions of free water and tissue, where the latter is modeled using DKI. THEORY AND METHODS:A theoretical study of the DKI-FWE model, including an optimal experiment design and an evaluation of the relative goodness of fit, is carried out. To stabilize the ill-conditioned estimation process, a Bayesian approach with a shrinkage prior (BSP) is proposed. In subsequent steps, the DKI-FWE model and the BSP estimation approach are evaluated in terms of estimation error, both in simulation and real data experiments. RESULTS:Although it is shown that the DKI-FWE model parameter estimation problem is ill-conditioned, DKI-FWE was found to describe the data significantly better compared to the standard DKI model for a large range of free water fractions. The acquisition protocol was optimized in terms of the maximally attainable precision of the DKI-FWE model parameters. The BSP estimator is shown to provide reliable DKI-FWE model parameter estimates. CONCLUSION:The combination of the DKI-FWE model with BSP is shown to be a feasible approach to estimate DKI parameters, while simultaneously eliminating free water partial volume effects. Magn Reson Med 80:802-813, 2018. © 2018 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

For many pathologies, early structural tissue changes occur at the cellular level, on the scale of micrometers or tens of micrometers. Magnetic resonance imaging (MRI) is a powerful non-invasive imaging tool used for medical diagnosis, but its clinical hardware is incapable of reaching the cellular length scale directly. In spite of this limitation, microscopic tissue changes in pathology can potentially be captured indirectly, from macroscopic imaging characteristics, by studying water diffusion. Here we focus on water diffusion and NMR relaxation in the human prostate, a highly heterogeneous organ at the cellular level. We present a physical picture of water diffusion and NMR relaxation in the prostate tissue, that is comprised of a densely-packed cellular compartment (composed of stroma and epithelium), and a luminal compartment with almost unrestricted water diffusion. Transverse NMR relaxation is used to identify fast and slow T

This work evaluates the accuracy and precision of the Diffusion parameter EStImation with Gibbs and NoisE Removal (DESIGNER) pipeline, developed to identify and minimize common sources of methodological variability including: thermal noise, Gibbs ringing artifacts, Rician bias, EPI and eddy current induced spatial distortions, and motion-related artifacts. Following this processing pipeline, iterative parameter estimation techniques were used to derive diffusion parameters of interest based on the diffusion tensor and kurtosis tensor. We evaluated accuracy using a software phantom based on 36 diffusion datasets from the Human Connectome project and tested the precision by analyzing data from 30 healthy volunteers scanned three times within one week. Preprocessing with both DESIGNER or a standard pipeline based on smoothing (instead of noise removal) improved parameter precision by up to a factor of 2 compared to preprocessing with motion correction alone. When evaluating accuracy, we report average decreases in bias (deviation from simulated parameters) over all included regions for fractional anisotropy, mean diffusivity, mean kurtosis, and axonal water fraction of 9.7%, 8.7%, 4.2%, and 7.6% using DESIGNER compared to the standard pipeline, demonstrating that preprocessing with DESIGNER improves accuracy compared to other processing methods.

We measured and compared heritability estimates for measures of functional brain connectivity extracted using the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) rsfMRI analysis pipeline in two cohorts: the genetics of brain structure (GOBS) cohort and the HCP (the Human Connectome Project) cohort. These two cohorts were assessed using conventional (GOBS) and advanced (HCP) rsfMRI protocols, offering a test case for harmonization of rsfMRI phenotypes, and to determine measures that show consistent heritability for in-depth genome-wide analysis. The GOBS cohort consisted of 334 Mexican-American individuals (124M/210F, average age = 47.9 ± 13.2 years) from 29 extended pedigrees (average family size = 9 people; range 5-32). The GOBS rsfMRI data was collected using a 7.5-min acquisition sequence (spatial resolution = 1.72 × 1.72 × 3 mm³ ). The HCP cohort consisted of 518 twins and family members (240M/278F; average age = 28.7 ± 3.7 years). rsfMRI data was collected using 28.8-min sequence (spatial resolution = 2 × 2 × 2 mm³ ). We used the single-modality ENIGMA rsfMRI preprocessing pipeline to estimate heritability values for measures from eight major functional networks, using (1) seed-based connectivity and (2) dual regression approaches. We observed significant heritability (h² = 0.2-0.4, p < .05) for functional connections from seven networks across both cohorts, with a significant positive correlation between heritability estimates across two cohorts. The similarity in heritability estimates for resting state connectivity measurements suggests that the additive genetic contribution to functional connectivity is robustly detectable across populations and imaging acquisition parameters. The overarching genetic influence, and means to consistently detect it, provides an opportunity to define a common genetic search space for future gene discovery studies.

Background: Altered brain connectivity is implicated in the development and clinical burden of schizophrenia. We measured and compared effect sizes (ES) for these phenotypes using Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) rsfMRI and DTI analysis pipeline in three MPRC cohorts with diverse acquisition parameters/protocols. Here, we focused the functional connectivity (FC) between the nodes of common resting state networks (RSNs) and microstructure of white matter tracts using fractional anisotropy (FA) to get more insight into the neural correlates of connectivity deficits in schizophrenia. Methods: Three cohorts of schizophrenia patients (n=261, 161M/100F; age=11-63 years) and controls (n=327, 146M/ 211F; age=10-79 years) were ascertained with three 3T Siemens MRI scanners. We used the single-modality ENIGMA rsfMRI and DTI preprocessing pipeline to extract FC for eight major RSNs using seed-based and dual-regression approaches and FA values for twenty white matter tracts. We tested for case control differences in all cohorts together as well as each cohort independently. We aggregated statistics from the three cohorts and further tested whether ESs were consistent across cohorts. Results: Patients had significantly (p<0.01; multiple correction, ES: 0.2-0.6) lower resting state functional connectivity than controls across cohorts. Patients also showed significantly (p<0.01; multiple correction,ES: 0.2-0.8) reducedFAvalues forwhole-brain and tract-wide measurements. The ESs were similar between FC and FA metrics and varied between 0.2-1.0 for each cohort. Conclusions: This is the first study to show consistency in functional and structural connectivity metrics across diverse cohorts in schizophrenia and demonstrated the impact of lower FC and FA on cognitive and behavioral measurements

We develop a general analytical and numerical framework for estimating intra- and extra-neurite water fractions and diffusion coefficients, as well as neurite orientational dispersion, in each imaging voxel. By employing a set of rotational invariants and their expansion in the powers of diffusion weighting, we analytically uncover the nontrivial topology of the parameter estimation landscape, showing that multiple branches of parameters describe the measurement almost equally well, with only one of them corresponding to the biophysical reality. A comprehensive acquisition shows that the branch choice varies across the brain. Our framework reveals hidden degeneracies in MRI parameter estimation for neuronal tissue, provides microstructural and orientational maps in the whole brain without constraints or priors, and connects modern biophysical modeling with clinical MRI.

Big data initiatives such as the Enhancing NeuroImaging Genetics through Meta-Analysis consortium (ENIGMA), combine data collected by independent studies worldwide to achieve more generalizable estimates of effect sizes and more reliable and reproducible outcomes. Such efforts require harmonized image analyses protocols to extract phenotypes consistently. This harmonization is particularly challenging for resting state fMRI due to the wide variability of acquisition protocols and scanner platforms; this leads to site-to-site variance in quality, resolution and temporal signal-to-noise ratio (tSNR). An effective harmonization should provide optimal measures for data of different qualities. We developed a multi-site rsfMRI analysis pipeline to allow research groups around the world to process rsfMRI scans in a harmonized way, to extract consistent and quantitative measurements of connectivity and to perform coordinated statistical tests. We used the single-modality ENIGMA rsfMRI preprocessing pipeline based on modelfree Marchenko-Pastur PCA based denoising to verify and replicate resting state network heritability estimates. We analyzed two independent cohorts, GOBS (Genetics of Brain Structure) and HCP (the Human Connectome Project), which collected data using conventional and connectomics oriented fMRI protocols, respectively. We used seed-based connectivity and dual-regression approaches to show that the rsfMRI signal is consistently heritable across twenty major functional network measures. Heritability values of 20-40% were observed across both cohorts.

BACKGROUND:Neuroscience research in brain development and disorders can benefit from an in vivo animal model that portrays normal white matter (WM) development trajectories and has a sufficiently large cerebrum for imaging with human MRI scanners and protocols. NEW METHOD/UNASSIGNED:Twelve three-month-old Sinclair™ miniature pigs (Sus scrofa domestica) were longitudinally evaluated during adolescent development using advanced diffusion weighted imaging (DWI) focused on cerebral WM. Animals had three MRI scans every 23.95 ± 3.73 days using a 3-Tesla scanner. The DWI imaging protocol closely modeled advanced human structural protocols and consisted of fifteen b-shells (b = 0-3500 s/mm2) with 32-directions/shell. DWI data were analyzed using diffusion kurtosis and bi-exponential modeling that provided measurements that included fractional anisotropy (FA), radial kurtosis, kurtosis anisotropy (KA), axial kurtosis, tortuosity, and permeability-diffusivity index (PDI). RESULTS:Significant longitudinal effects of brain development were observed for whole-brain average FA, KA, and PDI (all p < 0.001). There were expected regional differences in trends, with corpus callosum fibers showing the highest rate of change. COMPARISON WITH EXISTING METHOD(S)/UNASSIGNED:Pigs have a large, gyrencephalic brain that can be studied using clinical MRI scanners/protocols. Pigs are less complex than non-human primates thus satisfying the "replacement" principle of animal research. CONCLUSIONS:Longitudinal effects were observed for whole-brain and regional diffusion measurements. The changes in diffusion measurements were interepreted as evidence for ongoing myelination and maturation of cerebral WM. Corpus callosum and superficial cortical WM showed the expected higher rates of change, mirroring results in humans.