Jaime F. Mata

Simultaneous magnetic resonance imaging of ventilation distribution and gas uptake in the human lung using hyperpolarized xenon-129

Despite a myriad of technical advances in medical imaging, as well as the growing need to address the global impact of pulmonary diseases, such as asthma and chronic obstructive pulmonary disease, on health and quality of life, it remains challenging to obtain in vivo regional depiction and quantification of the most basic physiological functions of the lung—gas delivery to the airspaces and gas uptake by the lung parenchyma and blood—in a manner suitable for routine application in humans. We report a method based on MRI of hyperpolarized xenon-129 that permits simultaneous observation of the 3D distributions of ventilation (gas delivery) and gas uptake, as well as quantification of regional gas uptake based on the associated ventilation. Subjects with lung disease showed variations in gas uptake that differed from those in ventilation in many regions, suggesting that gas uptake as measured by this technique reflects such features as underlying pathological alterations of lung tissue or of local blood flow. Furthermore, the ratio of the signal associated with gas uptake to that associated with ventilation was substantially altered in subjects with lung disease compared with healthy subjects. This MRI-based method provides a way to quantify relationships among gas delivery, exchange, and transport, and appears to have significant potential to provide more insight into lung disease.

Exploring lung function with hyperpolarized 129Xe nuclear magnetic resonance

With the use of polarization‐transfer pulse sequences and hyperpolarized 129Xe NMR, gas exchange in the lung can be measured quantitatively. However, harnessing the inherently high sensitivity of this technique as a tool for exploring lung function requires a fundamental understanding of the xenon gas‐exchange and diffusion processes in the lung, and how these may differ between healthy and pathological conditions. Toward this goal, we employed NMR spectroscopy and imaging techniques in animal models to investigate the dependence of the relative xenon gas exchange rate on the inflation level of the lung and the tissue density. The spectroscopic results indicate that gas exchange occurs on a time scale of milliseconds, with an average effective diffusion constant of about 3.3 × 10−6cm2/s in the lung parenchyma. Polarization‐transfer imaging pulse sequences, which were optimized based on the spectroscopic results, detected regionally increased gas‐exchange rates in the lung, indicative of increased tissue density secondary to gravitational compression. By exploiting the gas‐exchange process in the lung to encode physiologic parameters, these methods may be extended to noninvasive regional assessments of lung‐tissue density and the alveolar surface‐to‐volume ratio, and allow lung pathology to be detected at an earlier stage than is currently possible. Magn Reson Med 51:676–687, 2004.

Regional mapping of gas uptake by blood and tissue in the human lung using hyperpolarized xenon-129 MRI

To develop a breathhold acquisition for regional mapping of ventilation and the fractions of hyperpolarized xenon‐129 (Xe129) dissolved in tissue (lung parenchyma and plasma) and red blood cells (RBCs), and to perform an exploratory study to characterize data obtained in human subjects.

Assessment of lung development using hyperpolarized helium-3 diffusion MR imaging.

To determine whether hyperpolarized helium‐3 (HHe) diffusion MR can detect the expected enlargement of alveoli that occurs with lung growth during childhood.

Hyperpolarized Xenon-129 gas-exchange imaging of lung microstructure: First case studies in subjects with obstructive lung disease

To develop and test a method to noninvasively assess the functional lung microstructure.

Assessment of the lung microstructure in patients with asthma using hyperpolarized 3He diffusion MRI at two time scales: comparison with healthy subjects and patients with COPD.

To investigate short‐ and long‐time‐scale 3He diffusion in asthma.

Assessment of lung function in asthma and COPD using hyperpolarized 129Xe chemical shift saturation recovery spectroscopy and dissolved-phase MRI.

Magnetic‐resonance spectroscopy and imaging using hyperpolarized xenon‐129 show great potential for evaluation of the most important function of the human lung ‐‐ gas exchange. In particular, chemical shift saturation recovery (CSSR) xenon‐129 spectroscopy provides important physiological information for the lung as a whole by characterizing the dynamic process of gas exchange, while dissolved‐phase (DP) xenon‐129 imaging captures the time‐averaged regional distribution of gas uptake by lung tissue and blood. Herein, we present recent advances in assessing lung function using CSSR spectroscopy and DP imaging in a total of 45 subjects (23 healthy, 13 chronic obstructive pulmonary disease (COPD) and 9 asthma). From CSSR acquisitions, the COPD subjects showed red blood cell to tissue–plasma (RBC‐to‐TP) ratios below the average for the healthy subjects (p < 0.001), but significantly higher septal wall thicknesses as compared with the healthy subjects (p < 0.005); the RBC‐to‐TP ratios for the asthmatic subjects fell outside two standard deviations (either higher or lower) from the mean of the healthy subjects, although there was no statistically significant difference for the average ratio of the study group as a whole. Similarly, from the 3D DP imaging acquisitions, we found that all the ratios (TP to gas phase (GP), RBC to GP, RBC to TP) measured in the COPD subjects were lower than those from the healthy subjects (p < 0.05 for all ratios), while these ratios in the asthmatic subjects differed considerably between subjects. Despite having been performed at different lung inflation levels, the RBC‐to‐TP ratios measured by CSSR and 3D DP imaging were fairly consistent with each other, with a mean difference of 0.037 (ratios from 3D DP imaging larger). In ten subjects the RBC‐to‐GP ratios obtained from the 3D DP imaging acquisitions were also highly correlated with their diffusing capacity of the lung for carbon monoxide per unit alveolar volume ratios measured by pulmonary function testing (R = 0.91). Copyright

A short-breath-hold technique for lung pO2 mapping with 3He MRI.

A pulse‐sequence strategy was developed for generating regional maps of alveolar oxygen partial pressure (pO2) in a single 6‐sec breath hold, for use in human subjects with impaired lung function. Like previously described methods, pO2 values are obtained by measuring the oxygen‐induced T1 relaxation of inhaled hyperpolarized 3He. Unlike other methods, only two 3He images are acquired: one with reverse‐centric and the other with centric phase‐encoding order. This phase‐encoding arrangement minimizes the effects of regional flip‐angle variations, so that an accurate map of instantaneous pO2 can be calculated from two images acquired a few seconds apart. By combining this phase‐encoding strategy with variable flip angles, the vast majority of the hyperpolarized magnetization goes directly into the T1 measurement, minimizing noise in the resulting pO2 map. The short‐breath‐hold pulse sequence was tested in phantoms containing known O2 concentrations. The mean difference between measured and prepared pO2 values was 1 mm Hg. The method was also tested in four healthy volunteers and three lung‐transplant patients. Maps of healthy subjects were largely uniform, whereas focal regions of abnormal pO2 were observed in diseased subjects. Mean pO2 values varied with inhaled O2 concentration. Mean pO2 was consistent with normal steady‐state values in subjects who inhaled 3He diluted only with room air. Magn Reson Med 63:127–136, 2010.

Multiple-exchange-time xenon polarization transfer contrast (MXTC) MRI: initial results in animals and healthy volunteers.

Hyperpolarized xenon‐129 is a noninvasive contrast agent for lung MRI, which upon inhalation dissolves in parenchymal structures, thus mirroring the gas‐exchange process for oxygen in the lung. Multiple‐exchange‐time xenon polarization transfer contrast (MXTC) MRI is an implementation of the XTC MRI technique in four dimensions (three spatial dimensions plus exchange time). The aim of this study was to evaluate the sensitivity of MXTC MRI for the detection of microstructural deformations of the healthy lung in response to gravity‐induced tissue compression and the degree of lung inflation. MXTC MRI was performed in four rabbits and in three healthy human volunteers. Two lung function parameters, one related to tissue‐ to alveolar‐volume ratio and the other to average septal‐wall thickness, were determined regionally. A significant gradient in MXTC MRI parameters, consistent with gravity‐induced lung tissue deformation in the supine imaging position, was found at low lung volumes. At high lung volumes, parameters were generally lower and the gradient in parameter values was less pronounced. Results show that MXTC MRI permits the quantification of subtle changes in healthy lung microstructure. Further, only structures participating in gas exchange are represented in MXTC MRI data, which potentially makes the technique especially sensitive to pathological changes in lung microstructure affecting gas exchange. Magn Reson Med, 2011.

MR grid-tagging using hyperpolarized helium-3 for regional quantitative assessment of pulmonary biomechanics and ventilation.

A new technique is demonstrated in six healthy human subjects that combines grid‐tagging and hyperpolarized helium‐3 MRI to assess regional lung biomechanical function and quantitative ventilation. 2D grid‐tagging, achieved by applying sinc‐modulated RF‐pulse trains along the frequency‐ and phase‐encoding directions, was followed by a multislice fast low‐angle shot (FLASH)‐based acquisition at inspiration and expiration. The displacement vectors, first and second principal strains, and quantitative ventilation were computed, and mean values were calculated for the upper, middle, and lower lung regions. Displacements in the lower region were significantly greater than those in either the middle or upper region (P < 0.005), while there were no significant differences between the three regions for the two principal strains and quantitative ventilation (P = 0.11–0.92). Variations in principal strains and ventilation were greater between subjects than between lung zones within individual subjects. This technique has the potential to provide insight into regional biomechanical alterations of lung function in a variety of lung diseases. Magn Reson Med 58:373–380, 2007.