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

PURPOSE: To determine whether hyperpolarized helium-3 (HHe) diffusion MR can detect the expected enlargement of alveoli that occurs with lung growth during childhood. MATERIALS AND METHODS: A total of 29 normal subjects aged four to 30 years underwent HHe diffusion MR imaging with the b-value pair 0, 1.6 second/cm(2). A second acquisition during a separate breathhold was performed using the b-value pair 0, 4 second/cm(2) to evaluate the dependence on b-value. The mean apparent diffusion coefficient (ADC) and lung volume for each acquisition and each subject was determined. RESULTS: Subjects as young as four years of age were able to cooperate with the imaging procedure. The mean ADC increased with increasing subject age (r = 0.8; P < 0.001), with a 55% increase in mean ADC from the youngest to oldest subject. Lung volumes measured on MR were highly repeatable for the two HHe MR acquisitions (r = 0.980, P < 0.001). The mean ADC values measured with the two different b-value pairs were highly correlated (r = 0.975; P < 0.001), but the higher b-value pair resulted in slightly lower mean ADCs (P < 0.001). CONCLUSION: HHe diffusion MR appears to detect the expected increase in alveolar size during childhood, and thus HHe MR may be a noninvasive method to assess development of the lung microstructure.     

MR microscopy of lung airways with hyperpolarized 3He

A technique using hyperpolarized (HP) ³He to image the small airways of the lung by using moderate flip angles and a short scanning period during early inspiration is demonstrated. Flip angles (α) ranging from 10–90° were used in guinea pig experiments with scanning during the entire inspiration period. A second series acquired data throughout a short window of the ventilatory cycle with α= 45°. The success of the animal studies has motivated implementation of similar imaging techniques in the clinical arena. Human studies involved imaging over the total inspiration period with α ≈? 10°. The first series of guinea pig experiments demonstrated that larger flip angles (50-90°) destroy the magnetization before it reaches the smaller airways. At moderate flip angles (20-40°), airway branching down to the fourth generation was apparent. Fifth-order branchings were seen in the images of the second series. The trachea down to fourth generation pulmonary airway branching, along with some distal air spaces, was seen in the human lung images.     

Quantitative assessment of emphysema using hyperpolarized 3He magnetic resonance imaging.

In this experiment, Sprague-Dawley rats with elastase-induced emphysema were imaged using hyperpolarized (3)He MRI. Regional fractional ventilation r, the fraction of gas replaced with a single tidal breath, was calculated from a series of images in a wash-in study of hyperpolarized gas. We compared the regional fractional ventilation in these emphysematous rats to the regional fractional ventilations we calculated from a previous baseline study in healthy Sprague-Dawley rats. We found that there were differences in the maps of fractional ventilation and its associated frequency distribution between the healthy and emphysematous rat lungs. Fractional ventilation tended to be much lower in emphysematous rats than in normal rats. With this information, we can use data on fractional ventilation to regionally distinguish between healthy and emphysematous portions of the lung. The successful implementation of such a technique on a rat model could lead to work toward the future implementation of this technique in human patients.     

Diffusion-weighted MRI of the lung with hyperpolarized helium-3: a study of reproducibility

PURPOSE: To determine the reproducibility of several parameters of the ADC measurement by calculating the scan-to-scan intrasubject variability. MATERIALS AND METHODS: Measurements were performed using a gradient-echo sequence with a bipolar gradient for diffusion weighting (b=3.89 sec/cm2). Five patients with pulmonary emphysema, and six healthy-lung volunteers were included in the study. Images were acquired after inspiration of 3He during a single inspiratory breath-hold. To assess the reproducibility, the measurement was performed twice (time between measurements=20 minutes) without repositioning the subjects. Analysis was performed on the basis of region-of-interest (ROI) analysis and global lung ADC histograms. RESULTS: The mean ADC of a ROI varied by 5.1% between two measurements for volunteers and by 6.1% for patients. In the global evaluation, the 75th percentile demonstrated the best reproducibility (2%), while other parameters showed variations up to 12%. Only the variation of the standard deviation (SD) and the measure of homogeneity of the ADC map showed a significant difference between patients and volunteers. CONCLUSION: Diffusion-weighted imaging (DWI) is a well-reproducible method for assessing the lung microstructure.     

Effects of ozone exposure in rat lungs investigated with hyperpolarized 3 He MRI

PURPOSE: To investigate the effects of subchronic ozone exposure on rat lung ventilation using hyperpolarized (HP) (3)He MRI. MATERIALS AND METHODS: A total of 24 Sprague-Dawley rats, distributed in one control group and four groups exposed to 0.5 ppm ozone concentration for two days or six days, either continuously (22 hours/day) or alternatingly (12 hours/day). A three-step MRI protocol was designed and applied to each animal, including: 1) (3)He gas distribution images acquired at inspiratory capacity, 2) measurements of intrapulmonary (3)He diffusion coefficients, and 3) dynamic ventilation acquisitions performed during lung filling with (3)He. RESULTS: No differentiation between animals exposed to ozone and control animals was observed from the ventilation images obtained at inspiratory capacity. The (3)He diffusion coefficients were not statistically different from one group to another. Ventilation defects, appearing as delayed lung filling regions and heterogeneous lung filling, were observed in the dynamic lung ventilation image series. The percentage of animals with ventilation defects in the control, two-day, and six-day exposed groups were equal to 20%, 43% and 75%, respectively. In the subgroup of the animals exposed six days for 12 hours per day, the percentage of animals exhibiting ventilation defects was equal to 85%. CONCLUSION: Heterogeneous obstructive patterns in an experimental animal model of subchronic ozone exposure were observed using HP (3)He MRI.     

Functional lung imaging using hyperpolarized gas MRI

The noninvasive assessment of lung function using imaging is increasingly of interest for the study of lung diseases, including chronic obstructive pulmonary disease (COPD) and asthma. Hyperpolarized gas MRI (HP MRI) has demonstrated the ability to detect changes in ventilation, perfusion, and lung microstructure that appear to be associated with both normal lung development and disease progression. The physical characteristics of HP gases and their application to MRI are presented with an emphasis on current applications. Clinical investigations using HP MRI to study asthma, COPD, cystic fibrosis, pediatric chronic lung disease, and lung transplant are reviewed. Recent advances in polarization, pulse sequence development for imaging with Xe-129, and prototype low magnetic field systems dedicated to lung imaging are highlighted as areas of future development for this rapidly evolving technology.     

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.     

Imaging of lung function using hyperpolarized helium-3 magnetic resonance imaging: Review of current and emerging translational methods and applications

During the past several years there has been extensive development and application of hyperpolarized helium-3 (HP (3)He) magnetic resonance imaging (MRI) in clinical respiratory indications such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, radiation-induced lung injury, and transplantation. This review focuses on the state-of-the-art of HP (3)He MRI and its application to clinical pulmonary research. This is not an overview of the physics of the method, as this topic has been covered previously. We focus here on the potential of this imaging method and its challenges in demonstrating new types of information that has the potential to influence clinical research and decision making in pulmonary medicine. Particular attention is given to functional imaging approaches related to ventilation and diffusion-weighted imaging with applications in chronic obstructive pulmonary disease, cystic fibrosis, asthma, and radiation-induced lung injury. The strengths and challenges of the application of (3)He MRI in these indications are discussed along with a comparison to established and emerging imaging techniques.     

Improved technique for measurement of regional fractional ventilation by hyperpolarized 3He MRI

Quantitative measurement of regional lung ventilation is of great significance in assessment of lung function in many obstructive and restrictive pulmonary diseases. A new technique for regional measurement of fractional ventilation using hyperpolarized ³He MRI is proposed, addressing the shortcomings of an earlier approach that limited its use to small animals. The new approach allows for the acquisition of similar quantitative maps over a shortened period and requires substantially less ³He gas. This technique is therefore a better platform for implementation in large species, including humans. The measurements using the two approaches were comparable to a great degree, as verified in a healthy rat lung, and are very reproducible. Preliminary validation is performed in a lung phantom system. Volume dependency of measurements was assessed both in vivo and in vitro. A scheme for selecting an optimum flip angle is proposed. In addition, a dead space modeling approach is proposed to yield more accurate measurements of regional fractional ventilation using either method. Finally, sensitivity of the new technique to model parameters, noise, and number of included images were assessed numerically. As a prelude to application in humans, the technique was implemented in a large animal study successfully. Magn Reson Med, 2010. © 2009 Wiley‐Liss, Inc.     

Quantitative measurements of regional lung ventilation using helium-3 MRI in a methacholine-induced bronchoconstriction model

PURPOSE: To demonstrate ventilation changes in an animal model of methacholine-induced bronchoconstriction using hyperpolarized (HP) helium-3 (He-3) MRI. MATERIALS AND METHODS: Bronchoconstriction was induced in 11 healthy rats using an intravenous injection of methacholine. The He-3 was laser-polarized using a custom-built system. MRI studies were performed on a 2-Tesla bore magnet. Coronal dynamic ventilation images were obtained using a single inhalation of the laser-polarized He-3 gas before and after methacholine injection. Ventilation image series were processed on a pixel-by-pixel basis to generate three regional ventilation parameters: gas flow rate, filling time, and maximum gas volume. Student's paired t-test was used for analysis. RESULTS: Ventilation image series with a temporal resolution of 5 msec were obtained before and after methacholine challenge. Quantitative regional gas dynamic information demonstrated statistically significant differences between the baseline and constricted states. Following methacholine injection, the mean flow values were significantly lower for the right lung (RL) (P = 0.006) and left lung (LL) (P = 0.024), while the mean filling time was found to be greater (RL: P = 0.08, LL: P = 0.021). Gas volume values at maximum inspiration were found to be significantly lower after methacholine (RL: P = 0.002; LL: P = 0.036). CONCLUSION: He-3 MRI demonstrated and quantified regional ventilation changes in bronchoconstriction conditions in rats.     

Advantages of parallel imaging in conjunction with hyperpolarized helium--a new approach to MRI of the lung.

Hyperpolarized helium (3He) gas MRI has the potential to assess pulmonary function. The non-equilibrium state of hyperpolarized 3He results in the continual depletion of the signal level over the course of excitations. Under non-equilibrium conditions the relationship between the signal-to-noise ratio (SNR) and the number of excitations significantly deviates from that established in the equilibrium state. In many circumstances the SNR increases or remains the same when the number of data acquisitions decreases. This provides a unique opportunity for performing parallel MRI in such a way that both the temporal and spatial resolution will increase without the conventional decrease in the SNR. In this study an analytical relationship between the SNR and the number of excitations for any flip angle was developed. Second, the point-spread function (PSF) was utilized to quantitatively demonstrate the unconventional SNR behavior for parallel imaging in hyperpolarized gas MRI. Third, a 24-channel (24ch) receive and two-channel (2ch) transmit phased-array system was developed to experimentally prove the theoretical predictions with 3He MRI. The in vivo experimental results prove that significant temporal resolution can be gained without the usual SNR loss in an equilibrium system, and that the entire lung can be scanned within one breath-hold (approximately 13 s) by applying parallel imaging to 3D data acquisition.     

Pulmonary ventilation and perfusion scanning using hyperpolarized helium-3 MRI and arterial spin tagging in healthy normal subjects and in pulmonary embolism and orthotopic lung transplant patients.

Conventional nuclear ventilation/perfusion (V/Q) scanning is limited in spatial resolution and requires exposure to radioactivity. The acquisition of pulmonary V/Q images using MRI overcomes these difficulties. When inhaled, hyperpolarized helium-3 ((3)He) permits MRI of gas distribution. Magnetic labeling of blood (arterial spin-tagging (AST)) provides images of pulmonary perfusion. Three normal subjects, two patients who had undergone single lung transplantation for emphysema, and one subject with pulmonary embolism (PE), were imaged. (3)He distribution and blood perfusion appeared uniform in the normal subjects and throughout the lung allografts. Gas distribution and perfusion in the emphysematous lungs were non-uniform and paralleled radiographic abnormalities. AST imaging alone revealed a lower-lobe wedge-shaped perfusion defect in the patient with PE that corresponded to computed tomography (CT) imaging. Hyperpolarized (3)He gas is demonstrated to provide ventilation images of the lung. Blood perfusion information may be obtained during the same examination using the AST technique. The sequential application of these imaging methods provides a novel tool for studying V/Q relationships.     

Parallel imaging of hyperpolarized helium-3 with simultaneous slice excitation.

Hyperpolarized (HP) gas imaging of the lungs is an ideal potential application for parallel imaging. This is due to the fact that there is limited scan time (breath hold of 20 s) and limited non-renewable polarization. Reduced phase encode parallel imaging is demanding on hardware in that it requires multiple receivers. In this work, simultaneous parallel acquisition of hyperpolarized (HP) 3He images from multiple slices was demonstrated in phantoms and in vivo using a simultaneous slice excitation method, at a field strength of 1.5 T. The pulse sequence allows simultaneous acquisition of n slices per RF excitation, thus reducing the number of RF pulses needed to fully cover a given volume with multi-slicing. Unlike conventional parallel imaging, this method does not require prior reference scan information, which would consume some of the finite longitudinal polarization in lung ventilation studies with HP gas.     

Helium-3 diffusion MR imaging of the human lung over multiple time scales

RATIONALE AND OBJECTIVES: Diffusion magnetic resonance imaging (MRI) with hyperpolarized (3)He gas is a powerful technique for probing the characteristics of the lung microstructure. A key parameter for this technique is the diffusion time, which is the period during which the atoms are allowed to diffuse within the lung for measurement of the signal attenuation. The relationship between diffusion time and the length scales that can be explored is discussed, and representative, preliminary results are presented from ongoing studies of the human lung for diffusion times ranging from milliseconds to several seconds. MATERIALS AND METHODS: (3)He diffusion MRI of the human lung was performed on a 1.5T Siemens Sonata scanner. Using gradient echo-based and stimulated echo-based techniques for short and medium-to-long diffusion times, respectively, measurements were performed for times ranging from 2 milliseconds to 6.5 seconds in two healthy subjects, a subject with subclinical chronic obstructive pulmonary disease and a subject with bronchopulmonary dysplasia. RESULTS: In healthy subjects, the apparent diffusion coefficient decreased by about 10-fold, from approximately 0.2 to 0.02 cm(2)/second, as the diffusion time increased from approximately 1 millisecond to 1 second. Results in subjects with disease suggest that measurements made at diffusion times substantially longer than 1 millisecond may provide improved sensitivity for detecting certain pathologic changes in the lung microstructure. CONCLUSIONS: With appropriately designed pulse sequences it is possible to explore the diffusion of hyperpolarized (3)He in the human lung over more than a 1,000-fold variation of the diffusion time. Such measurements provide a new opportunity for exploring and characterizing the microstructure of the healthy and diseased lung.     

1H and hyperpolarized 3He MR imaging of mouse with LPS‐induced inflammation

Purpose

To evaluate the lipopolysaccharide (LPS) model of chronic obstructive pulmonary disease (COPD) in mouse with ¹H and hyperpolarized (HP) ³He MR imaging.

Materials and Methods

Axial slices of the lung volume were acquired with HP ³He and ¹H MRI at 4, 24, and 48 h after LPS exposure. A quantitative ventilation index was calculated from two HP ³He acquisitions. A bronchoalveolar lavage (BAL) for a cell count was performed following magnetic resonance imaging (MRI).

Results

The LPS exposure resulted in a significant increase of cells in BAL, with maximum at 48 h. Lesions on ³He images were characterized by ventilation defects, whereas lesions on ¹H images were hyperintense and were attributed to edema. The number of lesions was at maximum at 48 h. At this time point, and for both ³He and ¹H MRI, the volume of the lesions was significantly higher for LPS‐exposed mice compared to controls. At 4, 24, and 48 h the ventilation index from the ³He data was significantly smaller for the LPS‐exposed animals compared to controls.

Conclusion

The time point 48 h after LPS exposure was advantageous for MRI evaluation. Functional read‐out with ³He MRI seems to be more sensitive than conventional ¹H MRI. J. Magn. Reson. Imaging 2009;29:977–981. © 2009 Wiley‐Liss, Inc.     

Probing lung microstructure with hyperpolarized noble gas diffusion MRI: theoretical models and experimental results

The introduction of hyperpolarized gases (³He and ¹²⁹Xe) has opened the door to applications for which gaseous agents are uniquely suited—lung MRI. One of the pulmonary applications, diffusion MRI, relies on measuring Brownian motion of inhaled hyperpolarized gas atoms diffusing in lung airspaces. In this article we provide an overview of the theoretical ideas behind hyperpolarized gas diffusion MRI and the results obtained over the decade‐long research. We describe a simple technique based on measuring gas apparent diffusion coefficient (ADC) and an advanced technique, in vivo lung morphometry, that quantifies lung microstructure both in terms of Weibel parameters (acinar airways radii and alveolar depth) and standard metrics (mean linear intercept, surface‐to‐volume ratio, and alveolar density) that are widely used by lung researchers but were previously available only from invasive lung biopsy. This technique has the ability to provide unique three‐dimensional tomographic information on lung microstructure from a less than 15 s MRI scan with results that are in good agreement with direct histological measurements. These safe and sensitive diffusion measurements improve our understanding of lung structure and functioning in health and disease, providing a platform for monitoring the efficacy of therapeutic interventions in clinical trials. Magn Reson Med 71:486–505, 2014. © 2013 Wiley Periodicals, Inc.     

Functional MRI of the lung using hyperpolarized 3-helium gas

Lung imaging has traditionally relied on x-ray methods, since proton MRI is limited to some extent by low proton density in the lung parenchyma and static field inhomogeneities in the chest. The relatively recent introduction of MRI of hyperpolarized noble gases has led to a rapidly evolving field of pulmonary MRI, revealing functional information of the lungs, which were hitherto unattainable. This review article briefly describes the physical background of the technology, and subsequently focuses on its clinical applications. Four different techniques that have been used in various human investigations are discussed: ventilation distribution, ventilation dynamics, and small airway evaluation using diffusion imaging and oxygen uptake assessment.