129Xe apparent diffusion coefficient (ADC) MRI offers an alternative to 3He ADC MRI, given its greater availability and lower cost. To demonstrate the feasibility of HP 129Xe ADC MRI, we present results from healthy volunteers (HV), chronic obstructive pulmonary disease (COPD) subjects, and age-matched healthy controls (AMC). The mean parenchymal ADC was 0.036±0.003 cm2/s for HV, 0.043±0.006 cm2/s for AMC, and 0.056±0.008 cm2/s for COPD subjects with emphysema. In healthy individuals, but not the COPD group, ADC decreased significantly in the anterior-posterior direction by ~22% (p = 0.006, AMC; 0.0059, HV), likely due to gravity-induced tissue compression. The COPD group exhibited a significantly larger superior-inferior ADC reduction (~28%) than the healthy groups (~24%) (p = 0.00018 HV; p = 3.45×10-5 AMC), consistent with smoking-related tissue destruction in the superior lung. Superior-inferior gradients in healthy subjects may result from regional differences in xenon concentration. ADC was significantly correlated with pulmonary function tests (FEV1, r=-0.77, p=0.0002; FEV1/FVC, r=-0.78, p=0.0002; DLCO/VA, r=-0.77, p=0.0002), and in healthy groups, increased with age by 0.0002 cm2/s/yr (r=0.56, p=0.02). This study shows 129Xe ADC MRI is clinically feasible, sufficiently sensitive to distinguish HV from subjects with emphysema, and detects age and posture-dependent changes.

BackgroundOne of the central physiological functions of the lungs is to transfer inhaled gases from the alveoli to pulmonary capillary blood. However, current measures of alveolar gas uptake provide only global information and thus lack the sensitivity and specificity needed to account for regional variations in gas exchange.Methods and Principal FindingsHere we exploit the solubility, high magnetic resonance (MR) signal intensity, and large chemical shift of hyperpolarized (HP) 129Xe to probe the regional uptake of alveolar gases by directly imaging HP 129Xe dissolved in the gas exchange tissues and pulmonary capillary blood of human subjects. The resulting single breath-hold, three-dimensional MR images are optimized using millisecond repetition times and high flip angle radio-frequency pulses, because the dissolved HP 129Xe magnetization is rapidly replenished by diffusive exchange with alveolar 129Xe. The dissolved HP 129Xe MR images display significant, directional heterogeneity, with increased signal intensity observed from the gravity-dependent portions of the lungs.ConclusionsThe features observed in dissolved-phase 129Xe MR images are consistent with gravity-dependent lung deformation, which produces increased ventilation, reduced alveolar size (i.e., higher surface-to-volume ratios), higher tissue densities, and increased perfusion in the dependent portions of the lungs. Thus, these results suggest that dissolved HP 129Xe imaging reports on pulmonary function at a fundamental level.

Purpose:To evaluate the safety and tolerability of inhaling multiple 1-L volumes of undiluted hyperpolarized xenon 129 ( 129 Xe) followed by up to a 16-second breath hold and magnetic resonance (MR) imaging. Materials and Methods:This study was approved by the institutional review board and was HIPAA compliant. Written informed consent was obtained. Forty-four subjects (19 men, 25 women; mean age, 46.1 years 6 18.8 [standard deviation ]) were enrolled, consisting of 24 healthy volunteers, 10 patients with chronic obstructive pulmonary disease (COPD), and 10 age-matched control subjects. All subjects received three or four 1-L volumes of undiluted hyperpolarized 129 Xe, followed by breath-hold MR imaging. Oxygen saturation, heart rate and rhythm, and blood pressure were continuously monitored. These parameters, along with respiratory rate and subjective symptoms, were assessed after each dose. Subjects' serum biochemistry and hematology were recorded at screening and at 24-hour follow-up. A 12-lead electrocardiogram (ECG) was obtained at these times and also within 2 hours prior to and 1 hour after 129 Xe MR imaging. Xenon-related symptoms were evaluated for relationship to subject group by using a x 2 test and to subject age by using logistic regression. Changes in vital signs were tested for signifi cance across subject group and time by using a repeated-measures multivariate analysis of variance test.

In this study, hyperpolarized (HP) 129Xe MR ventilation and 1H anatomical images were obtained from 3 subject groups: young healthy volunteers (HV), subjects with chronic obstructive pulmonary disease (COPD), and age-matched control subjects (AMC). Ventilation images were quantified by 2 methods: an expert reader-based ventilation defect score percentage (VDS%) and a semi-automatic segmentation-based ventilation defect percentage (VDP). Reader-based values were assigned by two experienced radiologists and resolved by consensus. In the semi-automatic analysis, 1H anatomical images and 129Xe ventilation images were both segmented following registration, to obtain the thoracic cavity volume (TCV) and ventilated volume (VV), respectively, which were then expressed as a ratio to obtain the VDP. Ventilation images were also characterized by generating signal intensity histograms from voxels within the TCV, and heterogeneity was analyzed using the coefficient of variation (CV). The reader-based VDS% correlated strongly with the semi-automatically generated VDP (r = 0.97, p < 0.0001), and with CV (r = 0.82, p < 0.0001). Both 129Xe ventilation defect scoring metrics readily separated the 3 groups from one another and correlated significantly with FEV1 (VDS%: r = -0.78, p = 0.0002; VDP: r = -0.79, p = 0.0003; CV: r = -0.66, p = 0.0059) and other pulmonary function tests. In the healthy subject groups (HV and AMC), the prevalence of ventilation defects also increased with age (VDS%: r = 0.61, p = 0.0002; VDP: r = 0.63, p = 0.0002). Moreover, ventilation histograms and their associated CVs distinguished between COPD subjects with similar ventilation defect scores but visibly different ventilation patterns.

BackgroundAs an increasing number of patients exhibit concomitant cardiac and pulmonary disease, limitations of standard diagnostic criteria are more frequently encountered. Here, we apply noninvasive 129Xe magnetic resonance imaging (MRI) and spectroscopy to identify patterns of regional gas transfer impairment and haemodynamics that are uniquely associated with chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), left heart failure (LHF) and pulmonary arterial hypertension (PAH).MethodsHealthy volunteers (n=23) and patients with COPD (n=8), IPF (n=12), LHF (n=6) and PAH (n=10) underwent 129Xe gas transfer imaging and dynamic spectroscopy. For each patient, three-dimensional maps were generated to depict ventilation, barrier uptake (129Xe dissolved in interstitial tissue) and red blood cell (RBC) transfer (129Xe dissolved in RBCs). Dynamic 129Xe spectroscopy was used to quantify cardiogenic oscillations in the RBC signal amplitude and frequency shift.ResultsCompared with healthy volunteers, all patient groups exhibited decreased ventilation and RBC transfer (both p≤0.01). Patients with COPD demonstrated more ventilation and barrier defects compared with all other groups (both p≤0.02). In contrast, IPF patients demonstrated elevated barrier uptake compared with all other groups (p≤0.007), and increased RBC amplitude and shift oscillations compared with healthy volunteers (p=0.007 and p≤0.01, respectively). Patients with COPD and PAH both exhibited decreased RBC amplitude oscillations (p=0.02 and p=0.005, respectively) compared with healthy volunteers. LHF was distinguishable from PAH by enhanced RBC amplitude oscillations (p=0.01).ConclusionCOPD, IPF, LHF and PAH each exhibit unique 129Xe MRI and dynamic spectroscopy signatures. These metrics may help with diagnostic challenges in cardiopulmonary disease and increase understanding of regional lung function and haemodynamics at the alveolar–capillary level.

Small animal magnetic resonance microscopy (MRM) has evolved significantly from testing the boundaries of imaging physics to its expanding use today as a tool in noninvasive biomedical investigations. MRM now increasingly provides functional information about living animals, with images of the beating heart, breathing lung, and functioning brain. Unlike clinical MRI, where the focus is on diagnosis, MRM is used to reveal fundamental biology or to noninvasively measure subtle changes in the structure or function of organs during disease progression or in response to experimental therapies. High-resolution anatomical imaging reveals increasingly exquisite detail in healthy animals and subtle architectural aberrations that occur in genetically altered models. Resolution of 100 mum in all dimensions is now routinely attained in living animals, and (10 mum)(3) is feasible in fixed specimens. Such images almost rival conventional histology while allowing the object to be viewed interactively in any plane. In this review we describe the state of the art in MRM for scientists who may be unfamiliar with this modality but who want to apply its capabilities to their research. We include a brief review of MR concepts and methods of animal handling and support, before covering a range of MRM applications-including the heart, lung, and brain-and the emerging field of MR histology. The ability of MRM to provide a detailed functional and anatomical picture in rats and mice, and to track this picture over time, makes it a promising platform with broad applications in biomedical research.

We present a ventilator that enables high‐resolution proton and hyperpolarized gas MR imaging of mice and rats. The design differs from previous approaches by eliminating the need for a custom pneumatic valve located near the trachea. This permits the system to be constructed from off‐the‐shelf components and reduces dead volumes sufficiently to make HP gas MRI feasible in the mouse. The constant‐volume ventilator routinely ventilates mice and rats for period of time up to 6 hrs and maintains reproducible tidal volumes over extended image acquisition periods, as we demonstrate with high‐resolution 3D lung images in the mouse using 1H, 3He and 129Xe. The ventilator is designed to deliver a constant tidal volume regardless of changes in airway resistance, which we demonstrate with 3He MR images acquired during severe broncho‐constriction. While the images reveal clear airway narrowing, the 3He signal intensity remained within ±10% of baseline level. Finally, given the paucity of 3He and the high cost of enriched 129Xe, the ventilator has been designed to enable the recapture of these rare gases and we demonstrate a compact system to compress and store them for subsequent reprocessing. We expect that this constant‐volume ventilator will be readily reproducible by other laboratories, which we facilitate by providing extensive parts lists, detailed wiring diagrams and complete plumbing schematics. © 2011 Wiley Periodicals, Inc. Concepts Magn Reson Part B (Magn Reson Engineering) 39B: 78–88, 2011

While many neuroscience questions aim to understand the human brain, much current knowledge has been gained using animal models, which replicate genetic, structural, and connectivity aspects of the human brain. While voxel-based analysis (VBA) of preclinical magnetic resonance images is widely-used, a thorough examination of the statistical robustness, stability, and error rates is hindered by high computational demands of processing large arrays, and the many parameters involved therein. Thus, workflows are often based on intuition or experience, while preclinical validation studies remain scarce. To increase throughput and reproducibility of quantitative small animal brain studies, we have developed a publicly shared, high throughput VBA pipeline in a high-performance computing environment, called SAMBA. The increased computational efficiency allowed large multidimensional arrays to be processed in 1–3 days—a task that previously took ~1 month. To quantify the variability and reliability of preclinical VBA in rodent models, we propose a validation framework consisting of morphological phantoms, and four metrics. This addresses several sources that impact VBA results, including registration and template construction strategies. We have used this framework to inform the VBA workflow parameters in a VBA study for a mouse model of epilepsy. We also present initial efforts towards standardizing small animal neuroimaging data in a similar fashion with human neuroimaging. We conclude that verifying the accuracy of VBA merits attention, and should be the focus of a broader effort within the community. The proposed framework promotes consistent quality assurance of VBA in preclinical neuroimaging, thus facilitating the creation and communication of robust results. Electronic supplementary material The online version of this article (10.1007/s12021-018-9410-0) contains supplementary material, which is available to authorized users.