Purpose Macroscopic magnetic field inhomogeneities adversely affect different aspects of MRI images. In quantitative MRI when the goal is to quantify biological tissue parameters, they bias and often corrupt such measurements. The goal of this paper is to develop a method for correction of macroscopic field inhomogeneities that can be applied to a variety of quantitative gradient-echo-based MRI techniques. Methods We have re-analyzed a basic theory of gradient echo (GE) MRI signal formation in the presence of background field inhomogeneities and derived equations that allow for correction of magnetic field inhomogeneity effects based on the phase and magnitude of GE data. We verified our theory by mapping R2* relaxation rate in computer simulated, phantom, and in vivo human data collected with multi-GE sequences. Results The proposed technique takes into account voxel spread function (VSF) effects and allowed obtaining virtually free from artifacts R2* maps for all simulated, phantom and in vivo data except of the edge areas with very steep field gradients. Conclusion The VSF method, allowing quantification of tissue specific R2*-related tissue properties, has a potential to breed new MRI biomarkers serving as surrogates for tissue biological properties similar to R1 and R2 relaxation rate constants widely used in clinical and research MRI.

Phase images obtained with gradient echo MRI provide image contrast distinct from T1-and T2-weighted images. It is commonly assumed that the local contribution to MRI signal phase directly relates to local bulk tissue magnetic susceptibility. Here, we use Maxwell's equations and Monte Carlo simulations to provide theoretical background to the hypothesis that the local contribution to MRI signal phase does not depend on tissue bulk magnetic susceptibility but tissue magnetic architecture-distribution of magnetic susceptibility inclusions (lipids, proteins, iron, etc.) at the cellular and subcellular levels. Specifically, we show that the regular longitudinal structures forming cylindrical axons (myelin sheaths and neurofilaments) can be locally invisible in phase images. Contrary to an expectation that the phase contrast in multiple sclerosis lesions should always increase in degree along with worsening of lesion severity (which happens for all known MR magnitude-based contrast mechanisms), we show that phase contrast can actually disappear with extreme tissue destruction. We also show that the phase contrast in multiple sclerosis lesions could be altered without loss of nervous system tissue, which happens in mild injury to the myelin sheaths or axonal neurofilaments. Moreover, we predict that the sign of phase contrast in multiple sclerosis lesions indicates the predominant type of tissue injury-myelin damage (positive sign) vs. axonal neurofilament damage (negative sign). Therefore, our theoretical and experimental results shed light on understanding the relationship between gradient echo MRI signal phase and multiple sclerosis pathology.RI has played a revolutionary role in enhancing knowledge in biology and medicine. Numerous MRI techniques have been developed over the years to aid physicians and scientists in understanding tissue structure and function in health and disease. One MRI technique that has been of increasing interest in recent years relies on phase images obtained by gradient echo (GE) MRI. It was shown that phase images provide image contrast distinct from T1-weighted (T1W) and T2-weighted (T2W) images (1-6). However, the sources of phase contrast have not been completely understood and are a subject of intense debate. Myelin was proposed as one of the main contributors to MR signal phase in white matter (7), and it was shown that demyelination leads to a loss of phase contrast between white matter (WM) and gray matter (GM) (8,9). This finding could have been explained by the difference in tissue cellular/ molecular content (iron, lipids, and proteins) between GM and WM. However, it was also reported that phase contrast is practically absent between WM and CSF (cerebrospinal fluid) (3, 6), despite substantial differences in their molecular content. Iron was shown to play an important role in formation of phase contrast in iron-rich areas, such as caudate, putamen, and globus pallidus (10-13). However, experimental data on the role of iron in WM is controversial; although a decrease of the phas...

Defining the biophysics underlying the remarkable MRI phase contrast reported in high field MRI studies of human brain would lead to more quantitative image analysis and more informed pulse sequence development. Toward this end, the dependence of water 1H resonance frequency on protein concentration was investigated using bovine serum albumin (BSA) as a model system. Two distinct mechanisms were found to underlie a water 1H resonance frequency shift: (i) a protein-concentration-induced change in bulk magnetic susceptibility, causing a shift to lower frequency, and (ii) exchange of water between chemical-shift distinct environments, i.e., free (bulk water) and protein-associated (“bound”) water, including freely exchangeable 1H sites on proteins, causing a shift to higher frequency. At 37°C the amplitude of the exchange effect is roughly half that of the susceptibility effect.

Gradient Echo Plural Contrast Imaging (GEPCI) is a post processing technique that, based on a widely available multiple gradient echo sequence, allows simultaneous generation of naturally co-registered images with various contrasts: T1 weighted, R2* = 1/T2* maps and frequency (f) maps. Herein, we present results demonstrating the capability of GEPCI technique to generate image sets with additional contrast characteristics obtained by combing the information from these three basic contrast maps. Specifically, we report its ability to generate GEPCI-susceptibility weighted images (GEPCI-SWI) with improved SWI contrast that is free of T1 weighting and RF inhomogeneities; GEPCI-SWI-like images with the contrast similar to original SWI; T1f images that offer superior GM/WM matter contrast obtained by combining the GEPCI T1 and frequency map data; Fluid Suppressed T2* (FST2*) images that utilize GEPCI T1 data to suppress CSF signal in T2* maps and provide contrast similar to FLAIR T2 weighted images; and T2*-SWI images that combine SWI contrast with quantitative T2* map and offer advantages of visualizing venous structure with hyperintense T2* lesions (e.g. MS lesions). To analyze GEPCI images we use an improved algorithm for combining data from multi-channel RF coils and a method for unwrapping phase/frequency maps that takes advantage of the information on phase evolution as a function of gradient echo time in GEPCI echo train.

Purpose The nature of the remarkable phase contrast in high field gradient echo MRI studies of human brain is a subject of intense debates. The Generalized Lorentzian Approach (GLA) (He & Yablonskiy, PNAS 2009;106:13558) provides an explanation for the anisotropy of phase contrast, the near absence of phase contrast between WM and CSF, and changes of phase contrast in multiple sclerosis. In this study we experimentally validate the GLA. Theory and Methods The GLA suggests that the local contribution to frequency shifts in WM does not depend on the average tissue magnetic susceptibility (as suggested by Lorentzian sphere approximation), but on the distribution and symmetry of magnetic susceptibility inclusions at the cellular level. We use ex vivo rat optic nerve as a model system of highly organized cellular structure containing longitudinally arranged myelin and neurofilaments. The nerve's cylindrical shape allowed accurate measurement of its magnetic susceptibility and local frequency shifts. Results We found that the volume magnetic susceptibility difference between nerve and water is −0.116ppm, and the magnetic susceptibilities of longitudinal components are −0.043ppm in fresh nerve, and −0.020ppm in fixed nerve. Conclusion The frequency shift observed in the optic nerve as a representative of WM is consistent with GLA but inconsistent with Lorentzian sphere approximation.

Fetal health is critically dependent on placental function, especially placental transport of oxygen from mother to fetus. When fetal growth is compromised, placental insufficiency must be distinguished from modest genetic growth potential. If placental insufficiency is present, the physician must trade off the risk of prolonged fetal exposure to placental insufficiency against the risks of preterm delivery. Current ultrasound methods to evaluate the placenta are indirect and insensitive. We propose to use Blood-Oxygenation-Level-Dependent (BOLD) MRI with maternal hyperoxia to quantitatively assess mismatch in placental function in seven monozygotic twin pairs naturally matched for genetic growth potential. In-utero BOLD MRI time series were acquired at 29 to 34 weeks gestational age. Maps of oxygen Time-To-Plateau (TTP) were obtained in the placentas by voxel-wise fitting of the time series. Fetal brain and liver volumes were measured based on structural MR images. After delivery, birth weights were obtained and placental pathological evaluations were performed. Mean placental TTP negatively correlated with fetal liver and brain volumes at the time of MRI as well as with birth weights. Mean placental TTP positively correlated with placental pathology. This study demonstrates the potential of BOLD MRI with maternal hyperoxia to quantify regional placental function in vivo.

Conventional MRI based on weighted spin-echo (SE) images aids in the diagnosis of multiple sclerosis (MS); however, MRI markers derived from SE sequences provide limited information about lesion severity and correlate poorly with patient disability assessed with clinical tests. In this study, we introduced a novel method [based on quantitative R2* (1/T2*) histograms] for estimating the severity of brain tissue damage in MS lesions. We applied at 1.5 T an advanced, multi-gradient-echo MRI technique [gradient echo plural contrast imaging (GEPCI)] to obtain images of the brains of healthy control subjects and subjects with MS. GEPCI is a simple yet robust technique allowing simultaneous acquisition of inherently co-registered quantitative T2* and FLAIR-like maps, along with T1-weighted images within a clinically acceptable time frame. Images obtained with GEPCI appear highly similar to standard scans; hence, they can be used in a reliable and conventional way for a clinical evaluation of the disease. Yet, the main advantage of GEPCI approach is its quantitative nature. Analysis of R2* histograms of white matter revealed a difference in the distribution between healthy subjects and subjects with MS. Based on this difference, we developed a new method for grading the severity of tissue damage [tissue-damage score (TDS)] in MS lesions. This method also provides a tissue damage load (TDL) assessing both lesion load and lesion severity, and a mean tissue damage score (MTDS) estimating the average MS lesion damage. We found promising correlations between the results derived from this method and the standard measure of clinical disability.

Background Alzheimer disease (AD) affects at least 5 million individuals in the USA alone stimulating an intense search for disease prevention and treatment therapies as well as for diagnostic techniques allowing early identification of AD during a long pre-symptomatic period that can be used for the initiation of prevention trials of disease-modifying therapies in asymptomatic individuals. Methods Our approach to developing such techniques is based on the Gradient Echo Plural Contrast Imaging (GEPCI) technique that provides quantitative in vivo measurements of several brain-tissue-specific characteristics of the gradient echo MRI signal (GEPCI metrics) that depend on the integrity of brain tissue cellular structure. Preliminary data were obtained from 34 participants selected from the studies of aging and dementia at the Knight Alzheimer’s Disease Research Center at Washington University in St. Louis. Cognitive status was operationalized with the Clinical Dementia Rating (CDR) scale. The participants, assessed as cognitively normal (CDR = 0; n = 23) or with mild AD dementia (CDR = 0.5 or 1; n = 11) underwent GEPCI MRI, a collection of cognitive performance tests and CSF amyloid (Aβ) biomarker Aβ42. A subset of 19 participants also underwent PET PiB studies to assess their brain Aβ burden. According to the Aβ status, cognitively normal participants were divided into normal (Aβ negative; n = 13) and preclinical (Aβ positive; n = 10) groups. Results GEPCI quantitative measurements demonstrated significant differences between all the groups: normal and preclinical, normal and mild AD, and preclinical and mild AD. GEPCI quantitative metrics characterizing tissue cellular integrity in the hippocampus demonstrated much stronger correlations with psychometric tests than the hippocampal atrophy. Importantly, GEPCI-determined changes in the hippocampal tissue cellular integrity were detected even in the hippocampal areas not affected by the atrophy. Our studies also uncovered strong correlations between GEPCI brain tissue metrics and beta-amyloid (Aβ) burden defined by positron emission tomography (PET) - the current in vivo gold standard for detection of cortical Aβ, thus supporting GEPCI as a potential surrogate marker for Aβ imaging – a known biomarker of early AD. Remarkably, the data show significant correlations not only in the areas of high Aβ accumulation (e.g. precuneus) but also in some areas of medial temporal lobe (e.g. parahippocampal cortex), where Aβ accumulation is relatively low. Conclusion We have demonstrated that GEPCI provides a new approach for the in vivo evaluation of AD-related tissue pathology in the preclinical and early symptomatic stages of AD. Since MRI is a widely available technology, the GEPCI surrogate markers of AD pathology have a potential for improving the quality of AD diagnostic, and the evaluation of new disease-modifying therapies.