Gary P. Cofer

Spatially resolved measurements of hyperpolarized gas properties in the lung in vivo. Part I: Diffusion coefficient

In imaging of hyperpolarized noble gases, a knowledge of the diffusion coefficient (D) is important both as a contrast mechanism and in the design of pulse sequences. We have made diffusion coefficient maps of both hyperpolarized 3He and 129Xe in guinea pig lungs. Along the length of the trachea, 3He D values were on average 2.4 cm2/sec, closely reproducing calculated values for free gas (2.05 cm2/sec). The 3He D values measured perpendicular to the length of the trachea were approximately a factor of two less, indicating restriction to diffusion. Further evidence of restricted diffusion was seen in the distal pulmonary airspaces as the average 3He D was 0.16 cm2/sec. An additional cause for the smaller 3He D in the lung was due to the presence of air, which is composed of heavier and larger gases. The 129Xe results show similar trends, with the trachea D averaging 0.068 cm2/sec and the lung D averaging 0.021 cm2/sec. Magn Reson Med 42:721–728, 1999.

Imaging alveolar–capillary gas transfer using hyperpolarized 129Xe MRI

Effective pulmonary gas exchange relies on the free diffusion of gases across the thin tissue barrier separating airspace from the capillary red blood cells (RBCs). Pulmonary pathologies, such as inflammation, fibrosis, and edema, which cause an increased blood–gas barrier thickness, impair the efficiency of this exchange. However, definitive assessment of such gas-exchange abnormalities is challenging, because no methods currently exist to directly image the gas transfer process. Here we exploit the solubility and chemical shift of 129Xe, the magnetic resonance signal of which has been enhanced by 105 with hyperpolarization, to differentially image its transfer from the airspaces into the tissue barrier spaces and RBCs in the gas exchange regions of the lung. Based on a simple diffusion model, we estimate that this MR imaging method for measuring 129Xe alveolar-capillary transfer is sensitive to changes in blood–gas barrier thickness of ≈5 μm. We validate the successful separation of tissue barrier and RBC images and show the utility of this method in a rat model of pulmonary fibrosis where 129Xe replenishment of the RBCs is severely impaired in regions of lung injury.

Waxholm Space: An image-based reference for coordinating mouse brain research

We describe an atlas of the C57BL/6 mouse brain based on MRI and conventional Nissl histology. Magnetic resonance microscopy was performed on a total of 14 specimens that were actively stained to enhance tissue contrast. Images were acquired with three different MR protocols yielding contrast dependent on spin lattice relaxation (T1), spin spin relaxation (T2), and magnetic susceptibility (T2*). Spatial resolution was 21.5 mum (isotropic). Conventional histology (Nissl) was performed on a limited set of these same specimens and the Nissl images were registered (3D-to-3D) to the MR data. Probabilistic atlases for 37 structures are provided, along with average atlases. The availability of three different MR protocols, the Nissl data, and the labels provides a rich set of options for registration of other atlases to the same coordinate system, thus facilitating data-sharing. All the data is available for download via the web.

Spatially resolved measurements of hyperpolarized gas properties in the lung in vivo. Part II: T *(2).

The transverse relaxation time, T∗︁2, of hyperpolarized (HP) gas in the lung in vivo is an important parameter for pulse sequence optimization and image contrast. We obtained T∗︁2 maps of HP 3He and 129Xe in guinea pig lungs (n = 17) and in human lungs. Eight different sets of 3He guinea pig studies were acquired, with variation of slice selection, tidal volume, and oxygen level. For example, for a 3He tidal volume of 3 cm3 and no slice selection, the average T∗︁2 in the trachea was 14.7 ms and 8.0 ms in the intrapulmonary airspaces. The equivalent 129Xe experiment yielded an average T∗︁2 of 40.8 ms in the trachea and 18.5 ms in the intrapulmonary airspaces. The average 3He T∗︁2 in the human intrapulmonary airspaces was 9.4 ms. The relaxation behavior was predicted by treating the lung as a porous medium, resulting in good agreement between estimated and measured T∗︁2 values in the intrapulmonary airspaces. Magn Reson Med 42:729–737, 1999.

Magnetic resonance histology for morphologic phenotyping.

Magnetic resonance histology (MRH) images of the whole mouse have been acquired at 100‐micron isotropic resolution at 2.0T with image arrays of 256 × 256 × 1024. Higher resolution (50 × 50 × 50 microns) of limited volumes has been acquired at 7.1T with image arrays of 512 × 512 × 512. Even higher resolution images (20 × 20 × 20 microns) of isolated organs have been acquired at 9.4T. The volume resolution represents an increase of 625,000× over conventional clinical MRI. The technological basis is summarized that will allow basic scientists to begin using MRH as a routine method for morphologcic phenotyping of the mouse. MRH promises four unique attributes over conventional histology: 1) MRH is non‐destructive; 2) MRH exploits the unique contrast mechanisms that have made MRI so successful clinically; 3) MRH is 3‐dimensional; and 4) the data are inherently digital. We demonstrate the utility in morphologic phenotyping a whole C57BL/6J mouse. J. Magn. Reson. Imaging 2002;16:423–429. Published 2002 Wiley‐Liss, Inc.

Diffusion-Weighted Hyperpolarized 129Xe MRI in Healthy Volunteers and Subjects with Chronic Obstructive Pulmonary Disease

Given its greater availability and lower cost, 129Xe apparent diffusion coefficient (ADC) MRI offers an alternative to 3He ADC MRI. To demonstrate the feasibility of hyperpolarized 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 sec−1 for HV, 0.043 ± 0.006 cm2 sec−1 for AMC, and 0.056 ± 0.008 cm2 sec−1 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 because of 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 (forced expiratory volume in 1 sec, r = −0.77, P = 0.0002; forced expiratory volume in 1 sec/forced vital capacity, r = −0.77, P = 0.0002; diffusing capacity of carbon monoxide in the lung/alveolar volume (VA), r = −0.77, P = 0.0002). In healthy groups, ADC increased with age by 0.0002 cm2 sec−1 year−1 (r = 0.56, P = 0.02). This study shows that 129Xe ADC MRI is clinically feasible, sufficiently sensitive to distinguish HV from subjects with emphysema, and detects age‐ and posture‐dependent changes. Magn Reson Med, 2010.

Hyperpolarized 129Xe MR Imaging of Alveolar Gas Uptake in Humans

Background One 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 Findings Here 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. Conclusions The 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.

High-throughput morphologic phenotyping of the mouse brain with magnetic resonance histology

The Mouse Biomedical Informatics Research Network (MBIRN) has been established to integrate imaging studies of the mouse brain ranging from three-dimensional (3D) studies of the whole brain to focused regions at a sub-cellular scale. Magnetic resonance (MR) histology provides the entry point for many morphologic comparisons of the whole brain. We describe a standardized protocol that allows acquisition of 3D MR histology (43-microm resolution) images of the fixed, stained mouse brain with acquisition times <30 min. A higher resolution protocol with isotropic spatial resolution of 21.5 microm can be executed in 2 h. A third acquisition protocol provides an alternative image contrast (at 43-microm isotropic resolution), which is exploited in a statistically driven algorithm that segments 33 of the most critical structures in the brain. The entire process, from specimen perfusion, fixation and staining, image acquisition and reconstruction, post-processing, segmentation, archiving, and analysis, is integrated through a structured workflow. This yields a searchable database for archive and query of the very large (1.2 GB) images acquired with this standardized protocol. These methods have been applied to a collection of both male and female adult murine brains ranging over 4 strains and 6 neurologic knockout models. These collection and acquisition methods are now available to the neuroscience community as a standard web-deliverable service.

MR-compatible ventilator for small animals: computer-controlled ventilation for proton and noble gas imaging

We describe an MR-compatible ventilator that is computer controlled to generate a variety of breathing patterns, to minimize image degrading effects of breathing motion, and to support delivery of gas anesthesia and experimental inhalational gases. A key feature of this ventilator is the breathing valve that attaches directly to the endotracheal tube to reduce dead volume and allows independent control of inspiratory and expiratory phases of ventilation. This ventilator has been used in a wide variety of MR and x-ray microscopy studies of small animals, especially for MR imaging the lungs with hyperpolarized gases ((3)He & (129)Xe).

Functional MR microscopy of the lung using hyperpolarized 3He

A new strategy designed to provide functional magnetic resonance images of the lung in small animals at microscopic resolution using hyperpolarized 3He is described. The pulse sequence is based on a combination of radial acquisition (RA) and CINE techniques, referred to as RA‐CINE, and is designed for use with hyperpolarized 3He to explore lung ventilation with high temporal and spatial resolution in small animal models. Ventilation of the live guinea pig is demonstrated with effective temporal resolution of 50 msec and in‐plane spatial resolution of <100 μm using hyperpolarized 3He. The RA‐CINE sequence allows one to follow gas inflow and outflow in the airways as well as in the distal part of the lungs. Regional analysis of signal intensity variations can be performed and can help assess functional lung parameters such as residual gas volume and lung compliance to gas inflow. Magn Reson Med 41:787–792, 1999.