Showing papers in "NMR in Biomedicine in 2017"

Overview of quantitative susceptibility mapping.

Abstract: Magnetic susceptibility describes the magnetizability of a material to an applied magnetic field and represents an important parameter in the field of MRI. With the recently introduced method of quantitative susceptibility mapping (QSM) and its conceptual extension to susceptibility tensor imaging (STI), the non-invasive assessment of this important physical quantity has become possible with MRI. Both methods solve the ill-posed inverse problem to determine the magnetic susceptibility from local magnetic fields. Whilst QSM allows the extraction of the spatial distribution of the bulk magnetic susceptibility from a single measurement, STI enables the quantification of magnetic susceptibility anisotropy, but requires multiple measurements with different orientations of the object relative to the main static magnetic field. In this review, we briefly recapitulate the fundamental theoretical foundation of QSM and STI, as well as computational strategies for the characterization of magnetic susceptibility with MRI phase data. In the second part, we provide an overview of current methodological and clinical applications of QSM with a focus on brain imaging. Copyright © 2016 John Wiley & Sons, Ltd.

Contributions to magnetic susceptibility of brain tissue

Abstract: This review discusses the major contributors to the subtle magnetic properties of brain tissue and how they affect MRI contrast. With the increased availability of high-field scanners, the use of magnetic susceptibility contrast for the study of human brain anatomy and function has increased dramatically. This has not only led to novel applications, but has also improved our understanding of the complex relationship between MRI contrast and magnetic susceptibility. Chief contributors to the magnetic susceptibility of brain tissue have been found to include myelin as well as iron. In the brain, iron exists in various forms with diverse biological roles, many of which are now only starting to be uncovered. An interesting aspect of magnetic susceptibility contrast is its sensitivity to the microscopic distribution of iron and myelin, which provides opportunities to extract information at spatial scales well below MRI resolution. For example, in white matter, the myelin sheath that surrounds the axons can provide tissue contrast that is dependent on the axonal orientation and reflects the relative size of intra- and extra-axonal water compartments. The extraction of such ultrastructural information, together with quantitative information about iron and myelin concentrations, is an active area of research geared towards the characterization of brain structure and function, and their alteration in disease. Copyright © 2016 John Wiley & Sons, Ltd.

Susceptibility-weighted imaging: current status and future directions.

Abstract: Susceptibility-weighted imaging (SWI) is a method that uses the intrinsic nature of local magnetic fields to enhance image contrast in order to improve the visibility of various susceptibility sources and to facilitate diagnostic interpretation. It is also the precursor to the concept of the use of phase for quantitative susceptibility mapping (QSM). Nowadays, SWI has become a widely used clinical tool to image deoxyhemoglobin in veins, iron deposition in the brain, hemorrhages, microbleeds and calcification. In this article, we review the basics of SWI, including data acquisition, data reconstruction and post-processing. In particular, the source of cusp artifacts in phase images is investigated in detail and an improved multi-channel phase data combination algorithm is provided. In addition, we show a few clinical applications of SWI for the imaging of stroke, traumatic brain injury, carotid vessel wall, siderotic nodules in cirrhotic liver, prostate cancer, prostatic calcification, spinal cord injury and intervertebral disc degeneration. As the clinical applications of SWI continue to expand both in and outside the brain, the improvement of SWI in conjunction with QSM is an important future direction of this technology. Copyright © 2016 John Wiley & Sons, Ltd.

Resolution limit of cylinder diameter estimation by diffusion MRI: The impact of gradient waveform and orientation dispersion

Abstract: Diffusion MRI has been proposed as a non-invasive technique for axonal diameter mapping. However, accurate estimation of small diameters requires strong gradients, which is a challenge for the transition of the technique from preclinical to clinical MRI scanners, since these have weaker gradients. In this work, we develop a framework to estimate the lower bound for accurate diameter estimation, which we refer to as the resolution limit. We analyse only the contribution from the intra-axonal space and assume that axons can be represented by impermeable cylinders. To address the growing interest in using techniques for diffusion encoding that go beyond the conventional single diffusion encoding (SDE) sequence, we present a generalised analysis capable of predicting the resolution limit regardless of the gradient waveform. Using this framework, waveforms were optimised to minimise the resolution limit. The results show that, for parallel cylinders, the SDE experiment is optimal in terms of yielding the lowest possible resolution limit. In the presence of orientation dispersion, diffusion encoding sequences with square-wave oscillating gradients were optimal. The resolution limit for standard clinical MRI scanners (maximum gradient strength 60-80 mT/m) was found to be between 4 and 8 μm, depending on the noise levels and the level of orientation dispersion. For scanners with a maximum gradient strength of 300 mT/m, the limit was reduced to between 2 and 5 μm.

An illustrated comparison of processing methods for phase MRI and QSM: removal of background field contributions from sources outside the region of interest.

Abstract: The elimination of so-called background fields is an essential step in phase MRI and quantitative susceptibility mapping (QSM). Background fields, which are caused by sources outside the region of interest (ROI), are often one to two orders of magnitude stronger than tissue-related field variations from within the ROI, hampering quantitative interpretation of field maps. This paper reviews the current literature on background elimination algorithms for QSM and provides insights into similarities and differences between the many algorithms proposed. We discuss the basic theoretical foundations and derive fundamental limitations of background field elimination. Copyright © 2016 John Wiley & Sons, Ltd.

An illustrated comparison of processing methods for MR phase imaging and QSM: combining array coil signals and phase unwrapping.

Abstract: Phase imaging benefits from strong susceptibility effects at very high field and the high signal-to-noise ratio (SNR) afforded by multi-channel coils. Combining the information from coils is not trivial, however, as the phase that originates in local field effects (the source of interesting contrast) is modified by the inhomogeneous sensitivity of each coil. This has historically been addressed by referencing individual coil sensitivities to that of a volume coil, but alternative approaches are required for ultra-high field systems in which no such coil is available. An additional challenge in phase imaging is that the phase that develops up to the echo time is " wrapped" into a range of 2p radians. Phase wraps need to be removed in order to reveal the underlying phase distribution of interest. Beginning with a coil combination using a homogeneous reference volume coil -the Roemer approach -which can be applied at 3 T and lower field strengths, we review alternative methods for combining single-echo and multi-echo phase images where no such reference coil is available. These are applied to high-resolution data acquired at 7 T and their effectiveness assessed via an index of agreement between phase values over channels and the contrast-to-noise ratio in combined images. The virtual receiver coil and COMPOSER approaches were both found to be computationally efficient and effective. The main features of spatial and temporal phase unwrapping methods are reviewed, placing particular emphasis on recent developments in temporal phase unwrapping and Laplacian approaches. The features and performance of these are illustrated in application to simulated and high-resolution in vivo data. Temporal unwrapping was the fastest of the methods tested and the Laplacian the most robust in images with low SNR. (C) 2016 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.

Regionally progressive accumulation of iron in Parkinson's disease as measured by quantitative susceptibility mapping

Abstract: The progression of Parkinson's disease (PD) seems to vary according to the disease stage, which greatly influences the management of PD patients. However, the underlying mechanism of progression in PD remains unclear. This study was designed to explore the progressive pattern of iron accumulation at different stages in PD patients. Sixty right-handed PD patients and 40 normal controls were recruited. According to the disease stage, 45 patients with Hoehn–Yahr stage ≤ 2.5 and 15 patients with Hoehn–Yahr stage ≥ 3 were grouped into early-stage PD (EPD) and late-stage PD (LPD) groups, respectively. The iron content in the cardinal subcortical nuclei covering the cerebrum, cerebellum and midbrain was measured using quantitative susceptibility mapping (QSM). The substantia nigra pars compacta (SNc) showed significantly increased QSM values in the EPD patients compared with the controls. In the LPD patients, while the SNc continued to show increased QSM values compared with the controls and EPD patients, the regions showing increased QSM values spread to include the substantia nigra pars reticulata (SNr), red nucleus (RN) and globus pallidus (GP). Our data also indicated that iron deposition was more significant in the GP internal segment (GPi) than in the GP external segment. No other regions showed significant changes in QSM values among the groups. Therefore, we were able to confirm a regionally progressive pattern of iron accumulation in the different stages of PD, indicating that iron deposition in the SNc is affected exclusively in the early stages of the disease, while the SNr, RN and GP, and particularly the GPi segment, become involved in advanced stages of the disease. This is a preliminary study providing objective evidence of the iron-related progression in PD. Copyright © 2016 John Wiley & Sons, Ltd.

Fundamentals of diffusion MRI physics

Abstract: Diffusion MRI is commonly considered the "engine" for probing the cellular structure of living biological tissues. The difficulty of this task is threefold. First, in structurally heterogeneous media, diffusion is related to structure in quite a complicated way. The challenge of finding diffusion metrics for a given structure is equivalent to other problems in physics that have been known for over a century. Second, in most cases the MRI signal is related to diffusion in an indirect way dependent on the measurement technique used. Third, finding the cellular structure given the MRI signal is an ill-posed inverse problem. This paper reviews well-established knowledge that forms the basis for responding to the first two challenges. The inverse problem is briefly discussed and the reader is warned about a number of pitfalls on the way.

Accuracy in the quantification of chemical exchange saturation transfer (CEST) and relayed nuclear Overhauser enhancement (rNOE) saturation transfer effects.

Abstract: Accurate quantification of chemical exchange saturation transfer (CEST) effects, including dipole-dipole mediated relayed nuclear Overhauser enhancement (rNOE) saturation transfer, is important for applications and studies of molecular concentration and transfer rate (and thereby pH or temperature). Although several quantification methods, such as Lorentzian difference (LD) analysis, multiple-pool Lorentzian fits, and the three-point method, have been extensively used in several preclinical and clinical applications, the accuracy of these methods has not been evaluated. Here we simulated multiple-pool Z spectra containing the pools that contribute to the main CEST and rNOE saturation transfer signals in the brain, numerically fit them using the different methods, and then compared their derived CEST metrics with the known solute concentrations and exchange rates. Our results show that the LD analysis overestimates contributions from amide proton transfer (APT) and intermediate exchanging amine protons; the three-point method significantly underestimates both APT and rNOE saturation transfer at -3.5 ppm (NOE(-3.5)). The multiple-pool Lorentzian fit is more accurate than the other two methods, but only at lower irradiation powers (≤1 μT at 9.4 T) within the range of our simulations. At higher irradiation powers, this method is also inaccurate because of the presence of a fast exchanging CEST signal that has a non-Lorentzian lineshape. Quantitative parameters derived from in vivo images of rodent brain tumor obtained using an irradiation power of 1 μT were also compared. Our results demonstrate that all three quantification methods show similar contrasts between tumor and contralateral normal tissue for both APT and the NOE(-3.5). However, the quantified values of the three methods are significantly different. Our work provides insight into the fitting accuracy obtainable in a complex tissue model and provides guidelines for evaluating other newly developed quantification methods.

Diffusion MRI in the heart

Abstract: Diffusion MRI provides unique information on the structure, organization, and integrity of the myocardium without the need for exogenous contrast agents. Diffusion MRI in the heart, however, has proven technically challenging because of the intrinsic non-rigid deformation during the cardiac cycle, displacement of the myocardium due to respiratory motion, signal inhomogeneity within the thorax, and short transverse relaxation times. Recently developed accelerated diffusion-weighted MR acquisition sequences combined with advanced post-processing techniques have improved the accuracy and efficiency of diffusion MRI in the myocardium. In this review, we describe the solutions and approaches that have been developed to enable diffusion MRI of the heart in vivo, including a dual-gated stimulated echo approach, a velocity- (M1 ) or an acceleration- (M2 ) compensated pulsed gradient spin echo approach, and the use of principal component analysis filtering. The structure of the myocardium and the application of these techniques in ischemic heart disease are also briefly reviewed. The advent of clinical MR systems with stronger gradients will likely facilitate the translation of cardiac diffusion MRI into clinical use. The addition of diffusion MRI to the well-established set of cardiovascular imaging techniques should lead to new and complementary approaches for the diagnosis and evaluation of patients with heart disease. © 2015 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.

The clinical utility of QSM: disease diagnosis, medical management, and surgical planning.

Abstract: Quantitative susceptibility mapping (QSM) is an MR technique that depicts and quantifies magnetic susceptibility sources. Mapping iron, the dominant susceptibility source in the brain, has many important clinical applications. Herein, we review QSM applications in the diagnosis, medical management, and surgical treatment of disease. To assist in early disease diagnosis, QSM can identify elevated iron levels in the motor cortex of amyotrophic lateral sclerosis patients, in the substantia nigra of Parkinson's disease (PD) patients, in the globus pallidus, putamen, and caudate of Huntington's disease patients, and in the basal ganglia of Wilson's disease patients. Additionally, QSM can distinguish between hemorrhage and calcification, which could prove useful in tumor subclassification, and can measure microbleeds in traumatic brain injury patients. In guiding medical management, QSM can be used to monitor iron chelation therapy in PD patients, to monitor smoldering inflammation of multiple sclerosis (MS) lesions after the blood-brain barrier (BBB) seals, to monitor active inflammation of MS lesions before the BBB seals without using gadolinium, and to monitor hematoma volume in intracerebral hemorrhage. QSM can also guide neurosurgical treatment. Neurosurgeons require accurate depiction of the subthalamic nucleus, a tiny deep gray matter nucleus, prior to inserting deep brain stimulation electrodes into the brains of PD patients. QSM is arguably the best imaging tool for depiction of the subthalamic nucleus. Finally, we discuss future directions, including bone QSM, cardiac QSM, and using QSM to map cerebral metabolic rate of oxygen. Copyright © 2016 John Wiley & Sons, Ltd.

Diffusion MRI in early cancer therapeutic response assessment.

Abstract: Imaging biomarkers for the predictive assessment of treatment response in patients with cancer earlier than standard tumor volumetric metrics would provide new opportunities to individualize therapy. Diffusion-weighted MRI (DW-MRI), highly sensitive to microenvironmental alterations at the cellular level, has been evaluated extensively as a technique for the generation of quantitative and early imaging biomarkers of therapeutic response and clinical outcome. First demonstrated in a rodent tumor model, subsequent studies have shown that DW-MRI can be applied to many different solid tumors for the detection of changes in cellularity as measured indirectly by an increase in the apparent diffusion coefficient (ADC) of water molecules within the lesion. The introduction of quantitative DW-MRI into the treatment management of patients with cancer may aid physicians to individualize therapy, thereby minimizing unnecessary systemic toxicity associated with ineffective therapies, saving valuable time, reducing patient care costs and ultimately improving clinical outcome. This review covers the theoretical basis behind the application of DW-MRI to monitor therapeutic response in cancer, the analytical techniques used and the results obtained from various clinical studies that have demonstrated the efficacy of DW-MRI for the prediction of cancer treatment response. Copyright © 2016 John Wiley & Sons, Ltd.

Electric properties tomography: Biochemical, physical and technical background, evaluation and clinical applications

Abstract: Electric properties tomography (EPT) derives the patient's electric properties, i.e. conductivity and permittivity, using standard magnetic resonance (MR) systems and standard MR sequences. Thus, EPT does not apply externally mounted electrodes, currents or radiofrequency (RF) probes, as is the case in competing techniques. EPT is quantitative MR, i.e. it yields absolute values of conductivity and permittivity. This review summarizes the physical equations underlying EPT, the corresponding basic and advanced reconstruction techniques and practical numerical aspects to realize these reconstruction techniques. MR sequences which map the field information required for EPT are outlined, and experiments to validate EPT in phantom and in vivo studies are described. Furthermore, the review describes the clinical findings which have been obtained with EPT so far, and attempts to understand the physiologic background of these findings.

Precision and accuracy of diffusion kurtosis estimation and the influence of b-value selection.

Abstract: Diffusion kurtosis imaging (DKI) is an extension of diffusion tensor imaging that accounts for leading non-Gaussian diffusion effects. In DKI studies, a wide range of different gradient strengths (b-values) is used, which is known to affect the estimated diffusivity and kurtosis parameters. Hence there is a need to assess the accuracy and precision of the estimated parameters as a function of b-value. This work examines the error in the estimation of mean of the kurtosis tensor (MKT) with respect to the ground truth, using simulations based on a biophysical model for both gray (GM) and white (WM) matter. Model parameters are derived from densely sampled experimental data acquired in ex vivo rat brain and in vivo human brain. Additionally, the variability of MKT is studied using the experimental data. Prevalent fitting protocols are implemented and investigated. The results show strong dependence on the maximum b-value of both net relative error and standard deviation of error for all of the employed fitting protocols. The choice of b-values with minimum MKT estimation error and standard deviation of error was found to depend on the protocol type and the tissue. Protocols that utilize two terms of the cumulant expansion (DKI) were found to achieve minimum error in GM at b-values less than 1 ms/μm2 , whereas maximal b-values of about 2.5 ms/μm2 were found to be optimal in WM. Protocols including additional higher order terms of the cumulant expansion were found to provide higher accuracy for the more commonly used b-value regime in GM, but were associated with higher error in WM. Averaged over multiple voxels, a net average error of around 15% for both WM and GM was observed for the optimal b-value choice. These results suggest caution when using DKI generated metrics for microstructural modeling and when comparing results obtained using different fitting techniques and b-values.

Intravoxel incoherent motion MRI as a means to measure in vivo perfusion: A review of the evidence

Abstract: The idea that in vivo intravoxel incoherent motion magnetic resonance signal is influenced by blood motion in the microvasculature is exciting, because it suggests that local and quantitative perfusion information can be obtained in a simple and elegant way from a few diffusion-weighted images, without contrast injection. When the method was proposed in the late 1980s some doubts appeared as to its feasibility, and, probably because the signal to noise and image quality at the time was not sufficient, no obvious experimental evidence could be produced to alleviate them. Helped by the tremendous improvements seen in the last three decades in MR hardware, pulse design, and post-processing capabilities, an increasing number of encouraging reports on the value of intravoxel incoherent motion perfusion imaging have emerged. The aim of this article is to review the current published evidence on the feasibility of in vivo perfusion imaging with intravoxel incoherent motion MRI.

Partitioning k-space for cylindrical three-dimensional rapid acquisition with relaxation enhancement imaging in the mouse brain.

Abstract: Three-dimensional rapid acquisition with relaxation enhancement (RARE) scans require the assignment of each phase encode step in two dimensions to an echo in the echo train. Although this assignment is frequently made across the entire Cartesian grid, collection of only the central cylinder of k-space by eliminating the corners in each phase encode dimension reduces the scan time by ~22% with negligible impact on image quality. The recipe for the assignment of echoes to grid points for such an acquisition is less straightforward than for the simple full Cartesian acquisition case, and has important implications for image quality. We explored several methods of partitioning k-space—exploiting angular symmetry in one extreme or emulating a cropped Cartesian acquisition in the other—and acquired three-dimensional RARE magnetic resonance imaging (MRI) scans of the ex vivo mouse brain. We evaluated each partitioning method for sensitivity to artifacts and then further considered strategies to minimize these through averaging or interleaving of echoes and by empirical phase correction. All scans were collected 16 at a time with multiple-mouse MRI. Although all schemes considered could be used to generate images, the results indicate that the emulation of a standard Cartesian echo assignment, by partitioning preferentially along one dimension within the cylinder, is more robust to artifacts. Samples at the periphery of the bore showed larger phase deviations and higher sensitivity to artifacts, but images of good quality could still be obtained with an optimized acquisition protocol. A protocol for high-resolution (40 μm) ex vivo images using this approach is presented, and has been used routinely with a success rate of 99% in over 1000 images.

Diffusion imaging of the vertebral bone marrow.

Abstract: Diffusion-weighted MRI (DWI) of the vertebral bone marrow is a clinically important tool for the characterization of bone-marrow pathologies and, in particular, for the differentiation of benign (osteoporotic) and malignant vertebral compression fractures. DWI of the vertebral bone marrow is, however, complicated by some unique MR and tissue properties of vertebral bone marrow. Due to both the spongy microstructure of the trabecular bone and the proximity of the lungs, soft tissue, or large vessels, substantial magnetic susceptibility variations occur, which severely reduce the magnetic field homogeneity as well as the transverse relaxation time T-2(*), and thus complicate MRI in particular with echoplanar imaging (EPI) techniques. Therefore, alternative diffusion-weighting pulse sequence types such as single-shot fast-spin-echo sequences or segmented EPI techniques became important alternatives for quantitative DWI of the vertebral bone marrow. This review first describes pulse sequence types that are particularly important for DWI of the vertebral bone marrow. Then, data from 24 studies that made diffusion measurements of normal vertebral bone marrow are reviewed;summarizing all results, the apparent diffusion coefficient (ADC) of normal vertebral bone marrow is typically found to be between 0.2 and 0.6 x 10(-3)mm(2)/s. Finally, DWI of vertebral compression fractures is discussed. Numerous studies demonstrate significantly greater ADCs in osteoporotic fractures (typically between 1.2 and 2.0 x 10(-3)mm(2)/s) than in malignant fractures or lesions (typically 0.7-1.3 x 10(-3)mm(2)/s). Alternatively, several studies used the (qualitative) image contrast of diffusion-weighted acquisitions for differentiation of lesion etiology: a very good lesion differentiation can be achieved, particularly with diffusion-weighted steady-state free precession sequences, which depict malignant lesions as hyperintense relative to normal-appearing vertebral bone marrow, in contrast to hypointense or isointense osteoporotic lesions. Copyright (C) 2015 John Wiley-Blackwell & Sons, Ltd.

Susceptibility tensor imaging (STI) of the brain

Abstract: Susceptibility tensor imaging (STI) is a recently developed MRI technique that allows quantitative determination of orientation-independent magnetic susceptibility parameters from the dependence of gradient echo signal phase on the orientation of biological tissues with respect to the main magnetic field. By modeling the magnetic susceptibility of each voxel as a symmetric rank-2 tensor, individual magnetic susceptibility tensor elements as well as the mean magnetic susceptibility and magnetic susceptibility anisotropy can be determined for brain tissues that would still show orientation dependence after conventional scalar-based quantitative susceptibility mapping to remove such dependence. Similar to diffusion tensor imaging, STI allows mapping of brain white matter fiber orientations and reconstruction of 3D white matter pathways using the principal eigenvectors of the susceptibility tensor. In contrast to diffusion anisotropy, the main determinant factor of the susceptibility anisotropy in brain white matter is myelin. Another unique feature of the susceptibility anisotropy of white matter is its sensitivity to gadolinium-based contrast agents. Mechanistically, MRI-observed susceptibility anisotropy is mainly attributed to the highly ordered lipid molecules in the myelin sheath. STI provides a consistent interpretation of the dependence of phase and susceptibility on orientation at multiple scales. This article reviews the key experimental findings and physical theories that led to the development of STI, its practical implementations, and its applications for brain research. Copyright © 2016 John Wiley & Sons, Ltd.

Skeletal muscle diffusion tensor-MRI fiber tracking: rationale, data acquisition and analysis methods, applications and future directions.

Abstract: The mechanical functions of muscles involve the generation of force and the actuation of movement by shortening or lengthening under load. These functions are influenced, in part, by the internal arrangement of muscle fibers with respect to the muscle's mechanical line of action. This property is known as muscle architecture. In this review, we describe the use of diffusion tensor (DT)-MRI muscle fiber tracking for the study of muscle architecture. In the first section, the importance of skeletal muscle architecture to function is discussed. In addition, traditional and complementary methods for the assessment of muscle architecture (brightness-mode ultrasound imaging and cadaver analysis) are presented. Next, DT-MRI is introduced and the structural basis for the reduced and anisotropic diffusion of water in muscle is discussed. The third section discusses issues related to the acquisition of skeletal muscle DT-MRI data and presents recommendations for optimal strategies. The fourth section discusses methods for the pre-processing of DT-MRI data, the available approaches for the calculation of the diffusion tensor and the seeding and propagating of fiber tracts, and the analysis of the tracking results to measure structural properties pertinent to muscle biomechanics. Lastly, examples are presented of how DT-MRI fiber tracking has been used to provide new insights into how muscles function, and important future research directions are highlighted. Copyright © 2016 John Wiley & Sons, Ltd.

A comprehensive numerical analysis of background phase correction with V‐SHARP

Abstract: Sophisticated harmonic artifact reduction for phase data (SHARP) is a method to remove background field contributions in MRI phase images, which is an essential processing step for quantitative susceptibility mapping (QSM). To perform SHARP, a spherical kernel radius and a regularization parameter need to be defined. In this study, we carried out an extensive analysis of the effect of these two parameters on the corrected phase images and on the reconstructed susceptibility maps. As a result of the dependence of the parameters on acquisition and processing characteristics, we propose a new SHARP scheme with generalized parameters. The new SHARP scheme uses a high-pass filtering approach to define the regularization parameter. We employed the variable-kernel SHARP (V-SHARP) approach, using different maximum radii (Rm ) between 1 and 15 mm and varying regularization parameters (f) in a numerical brain model. The local root-mean-square error (RMSE) between the ground-truth, background-corrected field map and the results from SHARP decreased towards the center of the brain. RMSE of susceptibility maps calculated with a spatial domain algorithm was smallest for Rm between 6 and 10 mm and f between 0 and 0.01 mm(-1) , and for maps calculated with a Fourier domain algorithm for Rm between 10 and 15 mm and f between 0 and 0.0091 mm(-1) . We demonstrated and confirmed the new parameter scheme in vivo. The novel regularization scheme allows the use of the same regularization parameter irrespective of other imaging parameters, such as image resolution. Copyright © 2016 John Wiley & Sons, Ltd.

Can increased spatial resolution solve the crossing fiber problem for diffusion MRI

Abstract: It is now widely recognized that voxels with crossing fibers or complex geometrical configurations present a challenge for diffusion MRI (dMRI) reconstruction and fiber tracking, as well as microstructural modeling of brain tissues. This "crossing fiber" problem has been estimated to affect anywhere from 30% to as many as 90% of white matter voxels, and it is often assumed that increasing spatial resolution will decrease the prevalence of voxels containing multiple fiber populations. The aim of this study is to estimate the extent of the crossing fiber problem as we progressively increase the spatial resolution, with the goal of determining whether it is possible to mitigate this problem with higher resolution spatial sampling. This is accomplished using ex vivo MRI data of the macaque brain, followed by histological analysis of the same specimen to validate these measurements, as well as to extend this analysis to resolutions not yet achievable in practice with MRI. In both dMRI and histology, we find unexpected results: the prevalence of crossing fibers increases as we increase spatial resolution. The problem of crossing fibers appears to be a fundamental limitation of dMRI associated with the complexity of brain tissue, rather than a technical problem that can be overcome with advances such as higher fields and stronger gradients.

Single-step quantitative susceptibility mapping with variational penalties

Abstract: Quantitative susceptibility mapping (QSM) estimates the underlying tissue magnetic susceptibility from the gradient echo (GRE) phase signal through background phase removal and dipole inversion steps. Each of these steps typically requires the solution of an ill-posed inverse problem and thus necessitates additional regularization. Recently developed single-step QSM algorithms directly relate the unprocessed GRE phase to the unknown susceptibility distribution, thereby requiring the solution of a single inverse problem. In this work, we show that such a holistic approach provides susceptibility estimation with artifact mitigation and develop efficient algorithms that involve simple analytical solutions for all of the optimization steps. Our methods employ total variation (TV) and total generalized variation (TGV) to jointly perform the background removal and dipole inversion in a single step. Using multiple spherical mean value (SMV) kernels of varying radii permits high-fidelity background removal whilst retaining the phase information in the cortex. Using numerical simulations, we demonstrate that the proposed single-step methods reduce the reconstruction error by up to 66% relative to the multi-step methods that involve SMV background filtering with the same number of SMV kernels, followed by TV- or TGV-regularized dipole inversion. In vivo single-step experiments demonstrate a dramatic reduction in dipole streaking artifacts and improved homogeneity of image contrast. These acquisitions employ the rapid three-dimensional echo planar imaging (3D EPI) and Wave-CAIPI (controlled aliasing in parallel imaging) trajectories for signal-to-noise ratio-efficient whole-brain imaging. Herein, we also demonstrate the multi-echo capability of the Wave-CAIPI sequence for the first time, and introduce an automated, phase-sensitive coil sensitivity estimation scheme based on a 4-s calibration acquisition. Copyright © 2016 John Wiley & Sons, Ltd.

Reproducibility of R2 * and quantitative susceptibility mapping (QSM) reconstruction methods in the basal ganglia of healthy subjects.

Abstract: The basal ganglia are key structures for motor, cognitive and behavioral functions. They undergo several changes with aging and disease, such as Parkinson's or Huntington's disease, for example. Iron accumulation in basal ganglia is often related to these diseases, which is conventionally monitored by the transverse relaxation rate (R2*). Quantitative susceptibility mapping (QSM) is a novel contrast mechanism in MRI produced by adding information taken from the phase of the MR signal to its magnitude. It has been shown to be more sensitive to subtle changes in Parkinson's disease. In order to be applied widely to various pathologies, its reproducibility must be evaluated in order to assess intra-subject variability and to disseminate into clinical and pharmaceutical studies. In this work, we studied the reproducibility and sensitivity of several QSM techniques. Fourteen subjects were scanned four times, and QSM and R2* images were reconstructed and registered. An atlas of the basal ganglia was used to automatically define regions of interest. We found that QSM measurements are indeed reproducible in the basal ganglia of healthy subjects and can be widely used as a replacement for R2* mapping in iron-rich regions. This reproducibility study could lead to several lines of research in relaxometry and susceptibility measurements, in vivo iron load evaluation as well as pharmacological assessment and biomarker development. Copyright © 2016 John Wiley & Sons, Ltd.

Diffusion parameter mapping with the combined intravoxel incoherent motion and kurtosis model using artificial neural networks at 3 T.

Abstract: Artificial neural networks (ANNs) were used for voxel-wise parameter estimation with the combined intravoxel incoherent motion (IVIM) and kurtosis model facilitating robust diffusion parameter mapping in the human brain. The proposed ANN approach was compared with conventional least-squares regression (LSR) and state-of-the-art multi-step fitting (LSR-MS) in Monte-Carlo simulations and in vivo in terms of estimation accuracy and precision, number of outliers and sensitivity in the distinction between grey (GM) and white (WM) matter. Both the proposed ANN approach and LSR-MS yielded visually increased parameter map quality. Estimations of all parameters (perfusion fraction f, diffusion coefficient D, pseudo-diffusion coefficient D*, kurtosis K) were in good agreement with the literature using ANN, whereas LSR-MS resulted in D* overestimation and LSR yielded increased values for f and D*, as well as decreased values for K. Using ANN, outliers were reduced for the parameters f (ANN, 1%; LSR-MS, 19%; LSR, 8%), D* (ANN, 21%; LSR-MS, 25%; LSR, 23%) and K (ANN, 0%; LSR-MS, 0%; LSR, 15%). Moreover, ANN enabled significant distinction between GM and WM based on all parameters, whereas LSR facilitated this distinction only based on D and LSR-MS on f, D and K. Overall, the proposed ANN approach was found to be superior to conventional LSR, posing a powerful alternative to the state-of-the-art method LSR-MS with several advantages in the estimation of IVIM-kurtosis parameters, which might facilitate increased applicability of enhanced diffusion models at clinical scan times.

Investigation of the contribution of total creatine to the CEST Z-spectrum of brain using a knockout mouse model

Abstract: The current study aims to assign and estimate the total creatine (tCr) signal contribution to the Z-spectrum in mouse brain at 11.7 T. Creatine (Cr), phosphocreatine (PCr) and protein phantoms were used to confirm the presence of a guanidinium resonance at this field strength. Wild-type (WT) and knockout mice with guanidinoacetate N-methyltransferase deficiency (GAMT−/−), which have low Cr and PCr concentrations in the brain, were used to assign the tCr contribution to the Z-spectrum. To estimate the total guanidinium concentrations, two pools for the Z-spectrum around 2 ppm were assumed: (i) a Lorentzian function representing the guanidinium chemical exchange saturation transfer (CEST) at 1.95 ppm in the 11.7-T Z-spectrum; and (ii) a background signal that can be fitted by a polynomial function. Comparison between the WT and GAMT−/− mice provided strong evidence for three types of contribution to the peak in the Z-spectrum at 1.95 ppm, namely proteins, Cr and PCr, the latter fitted as tCr. A ratio of 20 ± 7% (protein) and 80 ± 7% tCr was found in brain at 2 μT and 2 s saturation. Based on phantom experiments, the tCr peak was estimated to consist of about 83 ± 5% Cr and 17 ± 5% PCr. Maps for tCr of mouse brain were generated based on the peak at 1.95 ppm after concentration calibration with in vivo magnetic resonance spectroscopy.

In vivo measurement of membrane permeability and myofiber size in human muscle using time-dependent diffusion tensor imaging and the random permeable barrier model.

Abstract: The time dependence of the diffusion coefficient is a hallmark of tissue complexity at the micrometer level. Here we demonstrate how biophysical modeling, combined with a specifically tailored diffusion MRI acquisition performing diffusion tensor imaging (DTI) for varying diffusion times, can be used to determine fiber size and membrane permeability of muscle fibers in vivo. We describe the random permeable barrier model (RPBM) and its assumptions, as well as the details of stimulated echo DTI acquisition, signal processing steps, and potential pitfalls. We illustrate the RPBM method on a few pilot examples involving human subjects (previously published as well as new), such as revealing myofiber size derived from RPBM increase after training in a calf muscle, and size decrease with atrophy in shoulder rotator cuff muscle. Finally, we comment on the potential clinical relevance of our results. Copyright © 2016 John Wiley & Sons, Ltd.

Elevated phosphodiester and T2 levels can be measured in the absence of fat infiltration in Duchenne muscular dystrophy patients

Abstract: Quantitative MRI and MRS are increasingly important as non-invasive outcome measures in therapy development for Duchenne muscular dystrophy (DMD). Many studies have focussed on individual measures such as fat fraction and metabolite levels in relation to age and functionality, but much less attention has been given to how these indices relate to each other. Here, we assessed spatially resolved metabolic changes in leg muscles of DMD patients, and classified muscles according to the degree of fat replacement compared with healthy controls. Quantitative MRI (three-point Dixon and multi-spin echo without fat suppression and a tri-exponential fit) and 2D–CSI 31P MRS scans were obtained from 18 DMD patients and 12 healthy controls using a 3 T and a 7 T MR scanner. Metabolite levels, T2 values and fat fraction were individually assessed for five lower leg muscles. In muscles with extensive fat replacement, phosphodiester over adenosine triphosphate (PDE/ATP), inorganic phosphate over phosphocreatine, intracellular tissue pH and T2 were significantly increased compared with healthy controls. In contrast, in muscles without extensive fat replacement, only PDE/ATP and T2 values were significantly elevated. Overall, our results show that PDE levels and T2 values increase prior to the occurrence of fat replacement and remain elevated in later stages of the disease. This suggests that these individual measures could not only function as early markers for muscle damage but also reflect potentially reversible pathology in the more advanced stages.

Susceptibility‐based time‐resolved whole‐organ and regional tissue oximetry

Abstract: The magnetism of hemoglobin - being paramagnetic in its deoxy and diamagnetic in its oxy state - offers unique opportunities to probe oxygen metabolism in blood and tissues. The magnetic susceptibility χ of blood scales linearly with blood oxygen saturation, which can be obtained by measuring the magnetic field ΔB of the intravascular MR signal relative to tissue. In contrast to χ, the induced field ΔB is non-local. Therefore, to obtain the intravascular susceptibility Δχ relative to adjoining tissue from the measured ΔB demands solution of an inverse problem. Fortunately, for ellipsoidal structures, to which a straight, cylindrically shaped blood vessel segment conforms, the solution is trivial. The article reviews the principle of MR susceptometry-based blood oximetry. It then discusses applications for quantification of whole-brain oxygen extraction - typically on the basis of a measurement in the superior sagittal sinus - and, in conjunction with total cerebral blood flow, the cerebral metabolic rate of oxygen (CMRO2 ). By simultaneously measuring flow and venous oxygen saturation (SvO2 ) a temporal resolution of a few seconds can be achieved, allowing the study of the response to non-steady-state challenges such as volitional apnea. Extensions to regional measurements in smaller cerebral veins are also possible, as well as voxelwise quantification of venous blood saturation in cerebral veins accomplished by quantitative susceptibility mapping (QSM) techniques. Applications of susceptometry-based oximetry to studies of metabolic and degenerative disorders of the brain are reviewed. Lastly, the technique is shown to be applicable to other organ systems such as the extremities using SvO2 as a dynamic tracer to monitor the kinetics of the microvascular response to induced ischemia. Copyright © 2016 John Wiley & Sons, Ltd.

Cerebral hemodynamics and pseudo‐continuous arterial spin labeling considerations in adults with sickle cell anemia

Abstract: Sickle cell anemia (SCA) is a genetic disorder resulting in reduced oxygen carrying capacity and elevated stroke risk. Pseudo-continuous arterial spin labeling (pCASL) measures of cerebral blood flow (CBF) may have relevance for stroke risk assessment; however, the effects of elevated flow velocity and reduced bolus arrival time (BAT) on CBF quantification in SCA patients have not been thoroughly characterized, and pCASL model parameters used in healthy adults are often applied to patients with SCA. Here, cervical arterial flow velocities and pCASL labeling efficiencies were computed in adults with SCA (n = 19) and age- and race-matched controls without sickle trait (n = 7) using pCASL in sequence with phase contrast MR angiography (MRA). Controls (n = 7) and a subgroup of patients (n = 8) also underwent multi-post-labeling-delay pCASL for BAT assessment. Mean flow velocities were elevated in SCA adults (velocity = 28.3 ± 4.1 cm/s) compared with controls (velocity = 24.5 ± 3.8 cm/s), and mean pCASL labeling efficiency (α) was reduced in SCA adults (α = 0.72) relative to controls (α = 0.91). In patients, mean whole-brain CBF from phase contrast MRA was 91.8 ± 18.1 ml/100 g/min, while mean pCASL CBF when assuming a constant labeling efficiency of 0.86 was 75.2 ± 17.3 ml/100 g/min (p < 0.01), resulting in a mean absolute quantification error of 23% when a labeling efficiency appropriate for controls was assumed. This difference cannot be accounted for by BAT (whole-brain BAT: control, 1.13 ± 0.06 s; SCA, 1.02 ± 0.09 s) or tissue T1 variation. In conclusion, BAT variation influences pCASL quantification less than elevated cervical arterial velocity and labeling efficiency variation in SCA adults; thus, a lower labeling efficiency (α = 0.72) or subject-specific labeling efficiency should be incorporated for SCA patients.

Detection of metabolite changes in response to a varying visual stimulation paradigm using short‐TE 1H MRS at 7 T

Abstract: The two-fold benefit of 1 H magnetic resonance spectroscopy (MRS) at high B0 fields - enhanced sensitivity and increased spectral dispersion - has been used previously to study dynamic changes in metabolite concentrations in the human brain in response to visual stimulation. In these studies, a strong visual on/off stimulus was combined with MRS data acquisition in a voxel location in the occipital cortex determined by an initial functional magnetic resonance imaging experiment. However, 1) to exclude the possibility of systemic effects (heartbeat, blood flow, etc.), which tend to be different for on/off conditions, a modified stimulation condition not affecting the target voxel needs to be employed, and 2) to assess important neurotransmitters of low concentration, in particular γ-aminobutyric acid (GABA), it may be advantageous to analyze steady-state, rather than dynamic, conditions. Thus, the aim of this study was to use short-TE 1 H MRS methodology at 7 T to detect differences in steady-state metabolite levels in response to a varying stimulation paradigm in the human visual cortex. The two different stimulation conditions were termed voxel and control activation. Localized MR spectra were acquired using the SPECIAL (spin-echo full-intensity acquired localized) sequence. Data were analyzed using LCModel. Fifteen individual metabolites were reliably quantified. On comparison of steady-state concentrations for voxel versus control activation, a decrease in GABA of 0.05 mmol/L (5%) and an increase in lactate of 0.04 mmol/L (7%) were found to be the only significant effects. The observed reduction in GABA can be interpreted as reduced neuronal inhibition during voxel activation, whereas the increase in lactate hints at an intensification of anaerobic glycolysis. Differences from previous studies, notably the absence of any changes in glutamate, are attributed to the modified experimental conditions. This study demonstrates that the use of advanced 1 H MRS methodology at 7 T allows the detection of subtle changes in metabolite concentrations involved in neuronal activation and inhibition.