In Vivo Absolute Metabolite Quantification Using a Multiplexed ERETIC-RX Array Coil for Whole-Brain MR Spectroscopic Imaging.

BACKGROUND: Absolute quantification of metabolites in MR spectroscopic imaging (MRSI) requires a stable reference signal of known concentration. The Electronic REference To access In vivo Concentrations (ERETIC) has shown great promise but has not been applied in patients and 3D MRSI. ERETIC hardware has not been integrated with receive arrays due to technical challenges, such as coil combination and unwanted coupling between multiple ERETIC and receive channels, for which we developed mitigation strategies. PURPOSE: To develop absolute quantification for whole-brain MRSI in glioma patients. STUDY TYPE: Prospective. POPULATION: Five healthy volunteers and three patients with isocitrate dehydrogenase mutant glioma (27% female). Calibration and coil loading phantoms. FIELD STRENGTH/SEQUENCE: A 3 T; Adiabatic spin-echo spiral 3D MRSI with real-time motion correction, Fluid Attenuated Inversion Recovery (FLAIR), Gradient Recalled Echo (GRE), Multi-echo Magnetization Prepared Rapid Acquisition of Gradient Echo (MEMPRAGE). ASSESSMENT: Absolute quantification was performed for five brain metabolites (total N-acetyl-aspartate [NAA]/creatine/choline, glutamine + glutamate, myo-inositol) and the oncometabolite 2-hydroxyglutarate using a custom-built 4x-ERETIC/8x-receive array coil. Metabolite quantification was performed with both EREIC and internal water reference methods. ERETIC signal was transmitted via optical link and used to correct coil loading. Inductive and radiative coupling between ERETIC and receive channels were measured. STATISTICAL TESTS: ERETIC and internal water methods for metabolite quantification were compared using Bland-Altman (BA) analysis and the nonparametric Mann-Whitney test. P < 0.05 was considered statistically significant. RESULTS: ERETIC could be integrated in receive arrays and inductive coupling dominated (5-886 times) radiative coupling. Phantoms show proportional scaling of the ERETIC signal with coil loading. The BA analysis demonstrated very good agreement (3.3% ± 1.6%) in healthy volunteers, while there was a large difference (36.1% ± 3.8%) in glioma tumors between metabolite concentrations by ERETIC and internal water quantification. CONCLUSION: Our results indicate that ERETIC integrated with receive arrays and whole-brain MRSI is feasible for brain metabolites quantification. Further validation is required to probe that ERETIC provides more accurate metabolite concentration in glioma patients. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

High-speed whole-brain oximetry by golden-angle radial MRI.

PURPOSE: To determine whole-brain cerebral metabolic rate of oxygen (CMRO2 ), an improved imaging approach, based on radial encoding, termed radial OxFlow (rOxFlow), was developed to simultaneously quantify draining vein venous oxygen saturation (SvO2 ) and total cerebral blood flow (tCBF). METHODS: To evaluate the efficiency and precision of the rOxFlow sequence, 10 subjects were studied during a paradigm of repeated breath-holds with both rOxFlow and Cartesian OxFlow (cOxFlow) sequences. CMRO2 was calculated at baseline from OxFlow-measured data assuming an arterial O2 saturation of 97%, and the SvO2 and tCBF breath-hold responses were quantified. RESULTS: Average neurometabolic-vascular parameters across the 10 subjects for cOxFlow and rOxFlow were, respectively: SvO2 (%) baseline: 64.6 ± 8.0 versus 64.2 ± 6.6; SvO2 peak: 70.5 ± 8.5 versus 72.6 ± 5.4; tCBF (mL/min/100 g) baseline: 39.2 ± 3.8 versus 40.6 ± 8.0; tCBF peak: 53.2 ± 5.1 versus 56.1 ± 11.7; CMRO2 (µmol O2 /min/100 g) baseline: 111.5 ± 26.8 versus 120.1 ± 19.6. The above measures were not significantly different between sequences (P > 0.05). CONCLUSION: There was good agreement between the two methods in terms of the physiological responses measured. Comparing the two, rOxFlow provided higher temporal resolution and greater flexibility for reconstruction while maintaining high SNR. Magn Reson Med 79:217-223, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Whole-brain background-suppressed pCASL MRI with 1D-accelerated 3D RARE Stack-Of-Spirals readout.

Arterial Spin Labeled (ASL) perfusion MRI enables non-invasive, quantitative measurements of tissue perfusion, and has a broad range of applications including brain functional imaging. However, ASL suffers from low signal-to-noise ratio (SNR), limiting image resolution. Acquisitions using 3D readouts are optimal for background-suppression of static signals, but can be SAR intensive and typically suffer from through-plane blurring. In this study, we investigated the use of accelerated 3D readouts to obtain whole-brain, high-SNR ASL perfusion maps and reduce SAR deposition. Parallel imaging was implemented along the partition-encoding direction in a pseudo-continuous ASL sequence with background-suppression and 3D RARE Stack-Of-Spirals readout, and its performance was evaluated in three small cohorts. First, both non-accelerated and two-fold accelerated single-shot versions of the sequence were evaluated in healthy volunteers during a motor-photic task, and the performance was compared in terms of temporal SNR, GM-WM contrast, and statistical significance of the detected activation. Secondly, single-shot 1D-accelerated imaging was compared to a two-shot accelerated version to assess benefits of SNR and spatial resolution for applications in which temporal resolution is not paramount. Third, the efficacy of this approach in clinical populations was assessed by applying the single-shot 1D-accelerated version to a larger cohort of elderly volunteers. Accelerated data demonstrated the ability to detect functional activation at the subject level, including cerebellar activity, without loss in the perfusion signal temporal stability and the statistical power of the activations. The use of acceleration also resulted in increased GM-WM contrast, likely due to reduced through-plane partial volume effects, that were further attenuated with the use of two-shot readouts. In a clinical cohort, image quality remained excellent, and expected effects of age and sex on cerebral blood flow could be detected. The sequence is freely available upon request for academic use and could benefit a broad range of cognitive and clinical neuroscience research.

3D-accelerated, stack-of-spirals acquisitions and reconstruction of arterial spin labeling MRI.

PURPOSE: The goal of this study was to develop a 3D acceleration and reconstruction method to improve image quality and resolution of background-suppressed arterial spin-labeled perfusion MRI. METHODS: Accelerated acquisition was implemented in all three k-space dimensions in a stack-of-spirals readout using variable density spirals and partition undersampling. A single 3D self-consistent parallel imaging (SPIRiT) kernel was calibrated and iteratively applied to reconstruct each imaging volume. Whole-brain (including cerebellum) perfusion imaging was obtained at 3-mm isotropic resolution (nominal) using single- and 2-shot acquisitions and at 2-mm isotropic resolution (nominal) using four-shot acquisitions, achieving effective acceleration factors between 5.5 and 6.6. The signal-to-noise (SNR) performance of 3D SPIRiT was evaluated. The temporal SNR (tSNR) of the cerebral blood flow (CBF) maps and the gray/white matter CBF ratios were quantified. RESULTS: The readout of the arterial spin labeling (ASL) sequence was significantly shortened with acceleration. The CBF values were consistent between accelerated and fully sampled ASL. With shorter spiral interleaves and shorter echo trains, the accelerated images demonstrated reduced blurring and signal dropout in regions with high susceptibility gradients, resulting in improved image quality and increased gray/white matter CBF ratios. The shortened readout was accompanied by a corresponding decrease in tSNR. CONCLUSION: The 3D acceleration and reconstruction allow a rapid whole-brain readout that improved the quality of ASL perfusion imaging. Magn Reson Med 78:1405-1419, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

In vivo lung morphometry with hyperpolarized (3) He diffusion MRI: reproducibility and the role of diffusion-sensitizing gradient direction.

PURPOSE: Lung morphometry with hyperpolarized gas diffusion MRI is a highly sensitive technique for the noninvasive measurement of acinar microstructural parameters traditionally only accessible by histology. The goal of this work is to establish the reproducibility of these measurements in healthy volunteers and their dependence on the direction of the applied diffusion-sensitizing gradient. METHODS: Hyperpolarized helium-3 ((3) He) lung morphometry MRI was performed on a total of five healthy subjects. Two subjects received duplicate imaging on the same day and three subjects received duplicate imaging after a 4-month or 27-month delay to assess reproducibility. Four subjects repeated the measurement during the same session with different diffusion-sensitizing gradient directions to determine the effect on the parameter estimates. RESULTS: The (3) He lung morphometry measurements were reproducible over the short term and long term (e.g., % coefficient of variation [CV] of mean chord length, Lm = 2.1% and 2.9%, respectively) and across different diffusion gradient directions (Lm % CV = 2.6%). Results also show independence of field inhomogeneity effects at 1.5T. CONCLUSION: (3) He lung morphometry is a reproducible technique for measuring acinar microstructure and is effectively independent of the choice of diffusion gradient direction. This provides confidence for the use of this technique to compare populations and treatment efficacy.

In vivo lung morphometry with accelerated hyperpolarized (3) He diffusion MRI: a preliminary study.

PURPOSE: Parallel imaging can be used to reduce imaging time and to increase the spatial coverage in hyperpolarized gas magnetic resonance imaging of the lung. In this proof-of-concept study, we investigate the effects of parallel imaging on the morphometric measurement of lung microstructure using diffusion magnetic resonance imaging with hyperpolarized (3) He. METHODS: Fully sampled and under-sampled multi-b diffusion data were acquired from human subjects using an 8-channel (3) He receive coil. A parallel imaging reconstruction technique (generalized autocalibrating partially parallel acquisitions [GRAPPA]) was used to reconstruct under-sampled k-space data. The morphometric results of the generalized autocalibrating partially parallel acquisitions-reconstructed data were compared with the results of fully sampled data for three types of subjects: healthy volunteers, mild, and moderate chronic obstructive pulmonary disease patients. RESULTS: Morphometric measurements varied only slightly at mild acceleration factors. The results were largely well preserved compared to fully sampled data for different lung conditions. CONCLUSION: Parallel imaging, given sufficient signal-to-noise ratio, provides a reliable means to accelerate hyperpolarized-gas magnetic resonance imaging with no significant difference in the measurement of lung morphometry from the fully sampled images. GRAPPA is a promising technique to significantly reduce imaging time and/or to improve the spatial coverage for the morphometric measurement with hyperpolarized gases.

Quantification of human lung structure and physiology using hyperpolarized 129Xe.

PURPOSE: To present in vivo, human validation of a previously proposed method to measure key pulmonary parameters related to lung microstructure and physiology. Some parameters, such as blood-air barrier thickness, cannot be measured readily by any other noninvasive modality. METHODS: Healthy volunteers (n = 12) were studied in 1.5T and 3T whole body human scanners using hyperpolarized xenon. Xenon uptake by lung parenchyma and blood was measured using a chemical shift saturation recovery sequence. Both dissolved-xenon peaks at 197 ppm and 217-218 ppm were fitted against a model of xenon exchange (MOXE) as functions of exchange time. Parameters related to lung function and structure can be obtained by fitting to this model. RESULTS: The following results were obtained from xenon uptake (averaged over all healthy volunteers): surface-area-to-volume ratio = 210 ± 50 cm(-1) ; total septal wall thickness = 9.2 ± 6.5 µm; blood-air barrier thickness = 1.0 ± 0.3 µm; hematocrit = 27 ± 4%; pulmonary capillary blood transit time = 1.3 ± 0.3 s, in good agreement with literature values from invasive experiments. More detailed fitting results are listed in the text. CONCLUSION: The initial in vivo human results demonstrate that our proposed methods can be used to noninvasively determine lung physiology by simultaneous quantification of a few important pulmonary parameters. This method is highly promising to become a versatile screening method for lung diseases.

MOXE: a model of gas exchange for hyperpolarized 129Xe magnetic resonance of the lung.

We present a model of gas exchange for hyperpolarized (129)Xe in the lung, which we refer to as the Model of Xenon Exchange. The model consists of two expressions and characterizes uptake of dissolved xenon in the lung at two different resonance frequencies. The two expressions are governed by the following five critical pulmonary parameters that characterize both lung function and structure: the surface-area-to-volume ratio, barrier-to-septum ratio (ratio between air-blood barrier thickness and septal thickness), hematocrit, gas-exchange time constant, and pulmonary capillary transit time. The model is first validated by computer simulation. We show that Model of Xenon Exchange can be used to measure the pulmonary parameters mentioned above under various pathological or physiological conditions and is robust against moderate noise. Model of Xenon Exchange is further used to fit an existing data set of xenon uptake, thereby we demonstrate that the data can be well interpreted with Model of Xenon Exchange and reasonable parameters from the fitting routine. The good results obtained in both simulation and fitting to real data indicate that the model is sensitive to various functional and structural changes of the lung, and that it will allow for screening for a variety of pulmonary diseases by using hyperpolarized (129)Xe of the lung.

Spatial and temporal variations of cortical growth during gyrogenesis in the developing ferret brain.

Spatial and temporal variations in cortical growth were studied in the neonatal ferret to illuminate the mechanisms of folding of the cerebral cortex. Cortical surface representations were created from magnetic resonance images acquired between postnatal day 4 and 35. Global measures of shape (e.g., surface area, normalized curvature, and sulcal depth) were calculated. In 2 ferrets, relative cortical growth was calculated between surfaces created from in vivo images acquired at P14, P21, and P28. The isocortical surface area transitions from a slower (12.7 mm(2)/day per hemisphere) to a higher rate of growth (36.7 mm(2)/day per hemisphere) approximately 13 days after birth, which coincides with the time of transition from neuronal proliferation to cellular morphological differentiation. Relative cortical growth increases as a function of relative geodesic distance from the origin of the transverse neurogenetic gradient and is related to the change in fractional diffusion anisotropy over the same time period. The methods presented here can be applied to study cortical growth during development in other animal models or human infants. Our results provide a quantitative spatial and temporal description of folding in cerebral cortex of the developing ferret brain, which will be important to understand the underlying mechanisms that drive folding.

Rapid B1 mapping using orthogonal, equal-amplitude radio-frequency pulses.

We present a new phase-based method for mapping the amplitude of the radio-frequency field (B(1) ) of a transmitter coil in three-dimension. This method exploits the noncommutation relation between rotations about orthogonal axes. Our implementation of this principle in the current work results in a simple relation between the phase of the final magnetization and the flip angle (FA). In this study, we focus on FAs less than 90°. Our method is rapid and easy to implement compared with the existing B(1) mapping schemes. The mapping sequence can be simply obtained by adding to a regular three-dimensional gradient-echo sequence a magnetization preparation radio-frequency pulse of the same FA but orthogonal in phase to the excitation radio-frequency pulse. This method is demonstrated capable of generating reliable maps of the B(1) field within 1 min using FAs no larger than 60°. We show that it is robust against T(1), small chemical shift, and mild background inhomogeneity. This method may especially be suitable for B(1) mapping in situations (e.g., long-T(1) and hyperpolarized-gas imaging) where magnitude-based methods are not readily applicable. A noise calculation of the FA map using this method is also presented.

A new method to measure cortical growth in the developing brain.

Folding of the cerebral cortex is a critical phase of brain development in higher mammals but the biomechanics of folding remain incompletely understood. During folding, the growth of the cortical surface is heterogeneous and anisotropic. We developed and applied a new technique to measure spatial and directional variations in surface growth from longitudinal magnetic resonance imaging (MRI) studies of a single animal or human subject. MRI provides high resolution 3D image volumes of the brain at different stages of development. Surface representations of the cerebral cortex are obtained by segmentation of these volumes. Estimation of local surface growth between two times requires establishment of a point-to-point correspondence ("registration") between surfaces measured at those times. Here we present a novel approach for the registration of two surfaces in which an energy function is minimized by solving a partial differential equation on a spherical surface. The energy function includes a strain-energy term due to distortion and an "error energy" term due to mismatch between surface features. This algorithm, implemented with the finite element method, brings surface features into approximate alignment while minimizing deformation in regions without explicit matching criteria. The method was validated by application to three simulated test cases and applied to characterize growth of the ferret cortex during folding. Cortical surfaces were created from MRI data acquired in vivo at 14 days, 21 days, and 28 days of life. Deformation gradient and Lagrangian strain tensors describe the kinematics of growth over this interval. These quantitative results illuminate the spatial, temporal, and directional patterns of growth during cortical folding.

Emphysema quantification in inflation-fixed lungs using low-dose computed tomography and 3He magnetic resonance imaging.

OBJECTIVE: To evaluate the use of inflation-fixed lung tissue for emphysema quantification with computed tomography (CT) and He magnetic resonance (MR) diffusion imaging. METHODS: Fourteen subjects representing a range of chronic obstructive pulmonary disease severity who underwent complete or lobar lung resection were studied. Computed tomographic measurements of lung attenuation and MR measurements of the hyperpolarized 3He apparent diffusion coefficient (ADC) in resected specimens fixed in inflation with heated formalin vapor were compared with measurements obtained before fixation. RESULTS: The mean (SD) CT emphysema indices were 56% (17%) before and 58% (19%) after fixation (P = 0.77; R = 0.76). Index differences correlated with differences in lung volume (R = 0.47). The mean (SD) 3He ADCs were 0.40 (0.15) cm/s before and 0.39 (0.14) cm/s after fixation (P = 0.03, R = 0.98). The CT emphysema index and the 3He ADC were correlated before (R = 0.89) and after fixation (R = 0.79). CONCLUSIONS: Concordance of CT and 3He MR imaging measurements in unfixed and inflation-fixed lungs supports the use of inflation-fixed lungs for quantitative imaging studies in emphysema.

Effects of diffusion time on short-range hyperpolarized (3)He diffusivity measurements in emphysema.

PURPOSE: To characterize the effect of diffusion time on short-range hyperpolarized (3)He magnetic resonance imaging (MRI) diffusion measurements across a wide range of emphysema severity. MATERIALS AND METHODS: (3)He diffusion MRI was performed on 19 lungs or lobes resected from 18 subjects with varying degrees of emphysema using three diffusion times (1.6 msec, 5 msec, and 10 msec) at constant b value. Emphysema severity was quantified as the mean apparent diffusion coefficient (ADC) and as the percentage of pixels with ADC higher than multiple thresholds from 0.30-0.55 cm(2)/sec (ADC index). Quantitative histology (mean linear intercept) was obtained in 10 of the lung specimens from 10 of the subjects. RESULTS: The mean ADCs with diffusion times of 1.6, 5.0, and 10.0 msec were 0.46, 0.40, and 0.37 cm(2)/sec, respectively (P < 0.0001, analysis of variance [ANOVA]). There was no relationship between the ADC magnitude and the effect of diffusion time on ADC values. The mean linear intercept correlated with ADC (r = 0.91-0.94, P < 0.001) and ADC index (r = 0.78-0.92, P < 0.01) at all diffusion times. CONCLUSION: Decreases in ADC with longer diffusion time were unrelated to emphysema severity. The strong correlations between the ADC at all diffusion times tested and quantitative histology demonstrate that ADC is a robust measure of emphysema.

Role of collateral paths in long-range diffusion in lungs.

The long-range apparent diffusion coefficient (LRADC) of (3)He gas in lungs, measured over times of several seconds and distances of 1-3 cm, probes the connections between the airways. Previous work has shown the LRADC to be small in health and substantially elevated in emphysema, reflecting tissue destruction, which is known to create collateral pathways. To better understand what controls LRADC, we report computer simulations and measurements of (3)He gas diffusion in healthy lungs. The lung is generated with a random algorithm using well-defined rules, yielding a three-dimensional set of nodes or junctions, each connected by airways to one parent node and two daughters; airway dimensions are taken from published values. Spin magnetization in the simulated lung is modulated sinusoidally, and the diffusion equation is solved to 1,000 s. The modulated magnetization decays with a time constant corresponding to an LRADC of approximately 0.001 cm(2)/s, which is smaller by a factor of approximately 20 than the values in healthy lungs measured here and previously in vivo and in explanted lungs. It appears that collateral gas pathways, not present in the simulations, are functional in healthy lungs; they provide additional and more direct routes for long-range motion than the canonical airway tree. This is surprising, inasmuch as collateral ventilation is believed to be physiologically insignificant in healthy lungs. We discuss the effect on LRADC of small collateral connections through airway walls and rule out other possible mechanisms. The role of collateral paths is supported by measurements of smaller LRADC in pigs, where collateral ventilation is known to be smaller.

How accurately can the parameters from a model of anisotropic 3He gas diffusion in lung acinar airways be estimated? Bayesian view.

In the framework of a recently proposed method for in vivo lung morphometry, acinar lung airways are considered as a set of randomly oriented cylinders covered by alveolar sleeves. Diffusion of (3)He in each airway is anisotropic and can be described by distinct longitudinal and transverse diffusion coefficients. This macroscopically isotropic but microscopically anisotropic model allows estimation of these diffusion coefficients from multi b-value MR experiments despite the airways being too small to be resolved by direct imaging. Herein a Bayesian approach is used for analyzing the uncertainties in the model parameter estimates. The approach allows evaluation of relative errors of the parameter estimates as functions of the "true" values of the parameters, the signal-to-noise ratio, the maximum b-value and the total number of b-values used in the experiment. For a given set of the "true" diffusion parameters, the uncertainty in the estimated diffusion coefficients has a minimum as a function of maximum b-value and total number of data points. Choosing the MR pulse sequence parameters corresponding to this minimum optimizes the diffusion MR experiment and gives the best possible estimates of the diffusion coefficients. The mathematical approach presented can be generalized for models containing arbitrary numbers of estimated parameters.

Relaxation and diffusion of perfluorocarbon gas mixtures with oxygen for lung MRI.

We report measurements of free diffusivity D(0) and relaxation times T(1) and T(2) for pure C(2)F(6) and C(3)F(8) and their mixtures with oxygen. A simplified relaxation theory is presented and used to fit the data. The results enable spatially localized relaxation time measurements to determine the local gas concentration in lung MR images, so the free diffusivity D(0) is then known. Comparison of the measured diffusion to D(0) will express the extent of diffusion restriction and allow the local surface-to-volume ratio to be found.

3He diffusion MRI of the lung.

RATIONALE AND OBJECTIVES: MR imaging of the restricted diffusion of laser-polarized 3He gas provides unique insights into the changes in lung microstructure in emphysema. RESULTS: We discuss measurements of ventilation (spin density), mean diffusivity, and the anisotropy of diffusion, which yields the mean acinar airway radius. In addition, the use of spatially modulated longitudinal magnetization allows diffusion to be measured over longer distances and times, with sensitivity to collateral ventilation paths. Early results are also presented for spin density and diffusivity maps made with a perfluorinated inert gas, C3F8. METHODS: Techniques for purging and imaging excised lungs are discussed.

19F MR imaging of ventilation and diffusion in excised lungs.

Perfluorinated gases, particularly C2F6, are potentially suitable alternatives to hyperpolarized noble gases for pulmonary airspace spin density and diffusion MRI. This work focuses mainly on 19F imaging of C2F6 gas in healthy and emphysematous explanted lungs, avoiding regulatory issues of human in vivo measurements. Three-dimensional gradient echo and spin echo spin density images of human lungs can be made in 10 s with adequate signal-to-noise, demonstrating the feasibility for breathing dynamics to be captured during a succession of short breath holds. As expected, the spin echo images have much smaller susceptibility artifacts than the gradient echo images. 19F and 3He images of the same lungs are compared. The apparent diffusion coefficient (ADC) of C2F6 is sensitive to restrictions imposed by the lung microstructure: the average ADC is measured to be 0.018 cm2/s in healthy lungs versus 0.031 cm2/s in emphysematous lungs at a diffusion time Delta=2.2 ms. The low free diffusivity of pure C2F6 (D0=0.033 cm2/s) places it in a regime where the ADC measurement allows the surface-to-volume ratio to be determined in each voxel, a potentially valuable quantitative characterization of regional lung tissue destruction in emphysema.