Faculty Bibliography

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

Measuring molecular diffusion is based on the spatial encoding of spin-carrying molecules using external Larmor frequency gradients. Intrinsic variations of the Larmor frequency and of the local relaxation rate, commonly present in structurally complex samples, interfere with the external gradients, confounding the NMR-measured diffusion propagator. Here we consider, analytically and numerically, the effects of the mesoscopic magnetic structure (local susceptibility and transverse relaxation rate) on the NMR-measured "apparent" diffusion coefficient (ADC). We show that in the fast diffusion regime, when molecules spread past the correlation length of the magnetic structure, the deviation of ADC from the genuine diffusion coefficient increases as a power law of diffusion time. The effect of mesoscopically varying transverse relaxation rate is sequence-independent and always leads to the decrease of ADC with time, whereas the effect sign for the mesoscopic Larmor frequency variations depends on the presence of refocussing pulses in the diffusion sequence. We connect this unexpectedly diverging with time ADC discrepancy to the spatial statistics of the mesocopic magnetic structure. Our results establish a novel kind of NMR contrast tied to the microstructural complexity, and can be applied to discern the mesoscopic effects of hindrances to molecular diffusion, susceptibility variations, and varying local relaxation rate, on the measured diffusion propagator. In particular, we numerically show that the susceptibility effect of a microvascular network is sufficient to explain the observed ADC decrease due to superparamagnetic iron-oxide contrast injection in monkeys.

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.

Mapping tissue microstructure with MRI holds great promise as a noninvasive window into tissue organization at the cellular level. Having originated within the realm of diffusion NMR in the late 1970s, this field is experiencing an exponential growth in the number of publications. At the same time, model-based approaches are also increasingly incorporated into advanced MRI acquisition and reconstruction techniques. However, after about two decades of intellectual and financial investment, microstructural mapping has yet to find a single commonly accepted clinical application. Here, we suggest that slow progress in clinical translation may signify unresolved fundamental problems. We outline such problems and related practical pitfalls, as well as review strategies for developing and validating tissue microstructure models, to provoke a discussion on how to bridge the gap between our scientific aspirations and the clinical reality. We argue for recalibrating the efforts of our community toward a more systematic focus on fundamental research aimed at identifying relevant degrees of freedom affecting the measured MR signal. Such a focus is essential for realizing the truly revolutionary potential of noninvasive three-dimensional in vivo microstructural mapping.

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 seek to elucidate the underlying pathophysiology of injury sustained after mild traumatic brain injury (MTBI) using multi-shell diffusion MRI, deriving compartment-specific WM tract integrity (WMTI) metrics. WMTI allows a more biophysical interpretation of WM changes by describing microstructural characteristics in both intra- and extra-axonal environments. Thirty-two patients with MTBI within 30 days of injury and twenty-one age- and sex-matched controls were imaged on a 3T MR scanner. Multi-shell diffusion acquisition was performed with 5 b-values (250 - 2500 s/mm²) along 6 - 60 diffusion encoding directions. Tract-based spatial statistics (TBSS) was used with family-wise error (FWE) correction for multiple comparisons. TBSS results demonstrate focally lower intra-axonal diffusivity (D_axon) in MTBI patients in the splenium of the corpus callosum (sCC) (p < 0.05, FWE-corrected). The Area Under the Curve (AUC)-value for was 0.76 with low sensitivity of 46.9%, but 100% specificity. These results indicate that D_axon may be a useful imaging biomarker highly specific for MTBI-related WM injury. The observed decrease in D_axon suggests restriction of the diffusion along the axons occurring shortly after injury.

Working memory is a complex cognitive process at the intersection of sensory processing, learning, and short-term memory and also has a general executive attention component. Impaired working memory is associated with a range of neurological and psychiatric disorders, but very little is known about how working memory relates to underlying white matter (WM) microstructure. In this study, we investigate the association between WM microstructure and performance on working memory tasks in healthy adults (right-handed, native English speakers). We combine compartment specific WM tract integrity (WMTI) metrics derived from multi-shell diffusion MRI as well as diffusion tensor/kurtosis imaging (DTI/DKI) metrics with Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) subtests tapping auditory working memory. WMTI is a novel tool that helps us describe the microstructural characteristics in both the intra- and extra-axonal environments of WM such as axonal water fraction (AWF), intra-axonal diffusivity, extra-axonal axial and radial diffusivities, allowing a more biophysical interpretation of WM changes. We demonstrate significant positive correlations between AWF and letter-number sequencing (LNS), suggesting that higher AWF with better performance on complex, more demanding auditory working memory tasks goes along with greater axonal volume and greater myelination in specific regions, causing efficient and faster information process.

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.

A novel mega-analytical approach that reduced methodological variance was evaluated using a multisite diffusion tensor imaging (DTI) fractional anisotropy (FA) data by comparing white matter integrity in people with schizophrenia to controls. Methodological variance was reduced through regression of variance captured from quality assurance (QA) and by using Marchenko-Pastur Principal Component Analysis (MP-PCA) denoising. N = 192 (119 patients/73 controls) data sets were collected at three sites equipped with 3T MRI systems: GE MR750, GE HDx, and Siemens Trio. DTI protocol included five b = 0 and 60 diffusion-sensitized gradient directions (b = 1,000 s/mm(2) ). In-house DTI QA protocol data was acquired weekly using a uniform phantom; factor analysis was used to distil into two orthogonal QA factors related to: SNR and FA. They were used as site-specific covariates to perform mega-analytic data aggregation. The effect size of patient-control differences was compared to these reported by the enhancing neuro imaging genetics meta-analysis (ENIGMA) consortium before and after regressing QA variance. Impact of MP-PCA filtering was evaluated likewise. QA-factors explained approximately 3-4% variance in the whole-brain average FA values per site. Regression of QA factors improved the effect size of schizophrenia on whole brain average FA values-from Cohen's d = .53 to .57-and improved the agreement between the regional pattern of FA differences observed in this study versus ENIGMA from r = .54 to .70. Application of MP-PCA-denoising further improved the agreement to r = .81. Regression of methodological variances captured by routine QA and advanced denoising that led to a better agreement with a large mega-analytic study.

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.