Stephen Kadlecek

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.

Optimal transfer of spin-order between a singlet nuclear pair and a heteronucleus

Intramolecular spin-order transfer is a useful technique for signal enhancement of insensitive and low-concentration molecular species. We present a closed-form, optimized pulse sequence which maximizes the efficiency of transfer between a singlet (para) nuclear pair and a vicinal heteronucleus. Neglecting the decay of coherences while the nuclei are in the transverse plane, the scheme is unity efficient for all combinations of internuclear scalar couplings. Efficiency loss due to T2-like decay is also minimized by keeping the sequence as short as possible. We expect this result to be useful for hyperpolarization experiments in which the spin-order originates in parahydrogen, as well as studies of singlet state decay aimed at longer-term storage of spin-order in hyperpolarized Magnetic Resonance Imaging.

Hyperpolarized 13C MRI of the pulmonary vasculature and parenchyma

The study of lung perfusion in normal and diseased subjects is of great interest to physiologists and physicians. In this work we demonstrate the application of a liquid‐phase hyperpolarized (HP) carbon‐13 (13C) tracer to magnetic resonance imaging (MRI) of the pulmonary vasculature and pulmonary perfusion in a porcine model. Our results show that high spatial and temporal resolution images of pulmonary perfusion can be obtained with this contrast technique. Traditionally, pulmonary perfusion measurement techniques have been challenging because of insufficient signal for quantitative functional assessments. The use of polarized 13C in MRI overcomes this limitation and may lead to a viable clinical method for studying the pulmonary vasculature and perfusion. Magn Reson Med 57:459–463, 2007.

Imaging the interaction of atelectasis and overdistension in surfactant-depleted lungs.

Objective:Atelectasis and surfactant depletion may contribute to greater distension—and thereby injury—of aerated lung regions; recruitment of atelectatic lung may protect these regions by attenuating such overdistension. However, the effects of atelectasis (and recruitment) on aerated airspaces remain elusive. We tested the hypothesis that during mechanical ventilation, surfactant depletion increases the dimensions of aerated airspaces and that lung recruitment reverses these changes. Design:Prospective imaging study in an animal model. Setting:Research imaging facility. Subjects:Twenty-seven healthy Sprague Dawley rats. InterventionsSurfactant depletion was obtained by saline lavage in anesthetized, ventilated rats. Alveolar recruitment was accomplished using positive end-expiratory pressure and exogenous surfactant administration. Measurements and Main Results:Airspace dimensions were estimated by measuring the apparent diffusion coefficient of 3He, using diffusion-weighted hyperpolarized gas magnetic resonance imaging. Atelectasis was demonstrated using computerized tomography and by measuring oxygenation. Saline lavage increased atelectasis (increase in nonaerated tissue from 1.2% to 13.8% of imaged area, p < 0.001), and produced a concomitant increase in mean apparent diffusion coefficient (~33%, p < 0.001) vs. baseline; the heterogeneity of the computerized tomography signal and the variance of apparent diffusion coefficient were also increased. Application of positive end-expiratory pressure and surfactant reduced the mean apparent diffusion coefficient (~23%, p < 0.001), and its variance, in parallel to alveolar recruitment (i.e., less computerized tomography densities and heterogeneity, increased oxygenation). Conclusions:Overdistension of aerated lung occurs during atelectasis is detectable using clinically relevant magnetic resonance imaging technology, and could be a key factor in the generation of lung injury during mechanical ventilation. Lung recruitment by higher positive end-expiratory pressure and surfactant administration reduces airspace distension.

A simple and low-cost device for generating hyperpolarized contrast agents using parahydrogen.

A detailed description of the construction and use of a device for hyperpolarization of select contrast agents is presented. The device is based on molecular incorporation of the spin‐order inherent to parahydrogen, followed by order transfer to a metastable heteronuclear alignment. Design considerations and experimental results relating to catalyst/solvent choice and handling, solvent heating, efficient gas entrainment and spin‐order transfer are described. The resulting degree of hyperpolarization is shown to be substantial, ranging from a few to over 50%, depending on the choice of target molecule. Finally, the use of the hyperpolarized agent is demonstrated in a series of in vivo images. Copyright

Quantitative imaging of alveolar recruitment with hyperpolarized gas MRI during mechanical ventilation

The aim of this study was to assess the utility of (3)He MRI to noninvasively probe the effects of positive end-expiratory pressure (PEEP) maneuvers on alveolar recruitment and atelectasis buildup in mechanically ventilated animals. Sprague-Dawley rats (n = 13) were anesthetized, intubated, and ventilated in the supine position ((4)He-to-O(2) ratio: 4:1; tidal volume: 10 ml/kg, 60 breaths/min, and inspiration-to-expiration ratio: 1:2). Recruitment maneuvers consisted of either a stepwise increase of PEEP to 9 cmH(2)O and back to zero end-expiratory pressure or alternating between these two PEEP levels. Diffusion MRI was performed to image (3)He apparent diffusion coefficient (ADC) maps in the middle coronal slices of lungs (n = 10). ADC was measured immediately before and after two recruitment maneuvers, which were separated from each other with a wait period (8-44 min). We detected a statistically significant decrease in mean ADC after each recruitment maneuver. The relative ADC change was -21.2 ± 4.1 % after the first maneuver and -9.7 ± 5.8 % after the second maneuver. A significant relative increase in mean ADC was observed over the wait period between the two recruitment maneuvers. The extent of this ADC buildup was time dependent, as it was significantly related to the duration of the wait period. The two postrecruitment ADC measurements were similar, suggesting that the lungs returned to the same state after the recruitment maneuvers were applied. No significant intrasubject differences in ADC were observed between the corresponding PEEP levels in two rats that underwent three repeat maneuvers. Airway pressure tracings were recorded in separate rats undergoing one PEEP maneuver (n = 3) and showed a significant relative difference in peak inspiratory pressure between pre- and poststates. These observations support the hypothesis of redistribution of alveolar gas due to recruitment of collapsed alveoli in presence of atelectasis, which was also supported by the decrease in peak inspiratory pressure after recruitment maneuvers.

A multislice single breath-hold scheme for imaging alveolar oxygen tension in humans

Reliable, noninvasive, and high‐resolution imaging of alveolar partial pressure of oxygen (pAO2) is a potentially valuable tool in the early diagnosis of pulmonary diseases. Several techniques have been proposed for regional measurement of pAO2 based on the increased depolarization rate of hyperpolarized 3He. In this study, we explore one such technique by applying a multislice pAO2‐imaging scheme that uses interleaved‐slice ordering to utilize interslice time‐delays more efficiently. This approach addresses the low spatial resolution and long breath‐hold requirements of earlier techniques, allowing pAO2 measurements to be made over the entire human lung in 10–15 s with a typical resolution of 8.3 × 8.3 × 15.6 mm3. PO2 measurements in a glass syringe phantom were in agreement with independent gas analysis within 4.7 ± 4.1% (R = 0.9993). The technique is demonstrated in four human subjects (healthy nonsmoker, healthy former smoker, healthy smoker, and patient with COPD), each imaged six times on 3 different days during a 2‐week span. Two independent measurements were performed in each session, consisting of 12 coronal slices. The overall pAO2 mean across all subjects was 95.9 ± 12.2 Torr and correlated well with end‐tidal O2 (R = 0.805, P < 0.0001). The alveolar O2 uptake rate was consistent with the expected range of 1–2 Torr/s. Repeatable visual features were observed in pAO2 maps over different days, as were characteristic differences among the subjects and gravity‐dependent effects. Magn Reson Med, 2012.

Simultaneous measurement of pulmonary partial pressure of oxygen and apparent diffusion coefficient by hyperpolarized 3He MRI

Hyperpolarized 3He (HP 3He) MRI shows promise to assess structural and functional pulmonary parameters in a sensitive, regional, and noninvasive way. Structural HP 3He MRI has applied the apparent diffusion coefficient (ADC) for the detection of disease‐induced lung microstructure changes at the alveolar level, and HP 3He pulmonary partial pressure of oxygen (pO2) imaging measures the oxygen transfer efficiency between the lung and blood stream. Although both parameters are affected in chronic obstructive pulmonary disease (COPD), a quantitative assessment of the regional correlation of the two parameters has not been reported in the literature. In this work, a single acquisition technique for the simultaneous measurement of ADC and pO2 is presented. This technique is based on the multiple regression method, in which a general linear estimator is used to retrieve the values of ADC and pO2 from a series of measurements. The measurement uncertainties are also analytically derived and used to find an optimal measurement scheme. The technique was first tested on a phantom model, and then on an in vivo normal pig experiment. A case study was performed on a COPD patient, which showed that in a region of interest ADC was 29% higher while oxygen depletion rate was 61% lower than the corresponding global average values. Magn Reson Med, 2009.

Quantitative Assessment of Lung Ventilation and Microstructure in an Animal Model of Idiopathic Pulmonary Fibrosis Using Hyperpolarized Gas MRI

RATIONALE AND OBJECTIVES The use of hyperpolarized (3)He magnetic resonance imaging as a quantitative lung imaging tool has progressed rapidly in the past decade, mostly in the assessment of the airway diseases chronic obstructive pulmonary disease and asthma. This technique has shown potential to assess both structural and functional information in healthy and diseased lungs. In this study, the regional measurements of structure and function were applied to a bleomycin rat model of interstitial lung disease. MATERIALS AND METHODS Male Sprague-Dawley rats (weight, 300-350 g) were administered intratracheal bleomycin. After 3 weeks, apparent diffusion coefficient and fractional ventilation were measured by (3)He magnetic resonance imaging and pulmonary function testing using a rodent-specific plethysmography chamber. Sensitized and healthy animals were then compared using threshold analysis to assess the potential sensitivity of these techniques to pulmonary abnormalities. RESULTS No significant changes were observed in total lung volume and compliance between the two groups. Airway resistance elevated and forced expiratory volume significantly declined in the 3-week bleomycin rats, and fractional ventilation was significantly decreased compared to control animals (P < .0004). The apparent diffusion coefficient of (3)He showed a smaller change but still a significant decrease in 3-week bleomycin animals (P < .05). CONCLUSIONS Preliminary results suggest that quantitative (3)He magnetic resonance imaging can be a sensitive and noninvasive tool to assess changes in an animal interstitial lung disease model. This technique may be useful for longitudinal animal studies and also in the investigation of human interstitial lung diseases.

Measurement of Pulmonary Partial Pressure of Oxygen and Oxygen Depletion Rate with Hyperpolarized Helium-3 MRI: A Preliminary Reproducibility Study on Pig Model

RATIONAL AND OBJECTIVES Pulmonary partial pressure of oxygen (pO(2)) and oxygen depletion rate (R) are two important parameters of lung function. The dependence of hyperpolarized (3)He (HP (3)He) T(1) on local oxygen concentration provides the basis for high-resolution mapping of the regional distributions of pO(2) and R in the lung. Although the oxygen-sensitive HP (3)He magnetic resonance imaging technique has been applied in human subjects and several animal species, reproducibility studies are rarely reported in the literature. This work presents a preliminary reproducibility study on a pig model. In this study, important scan parameters, such as measurement timing and flip angle, are optimized to minimize the noise-induced measurement uncertainty. MATERIALS AND METHODS In the in vivo study, five normal pigs and one diseased pig with simulated pulmonary emboli were scanned with a small flip angle gradient echo sequence. The pulmonary oxygen measurement was repeated two to four times in each pig. In each measurement, a series of six images were acquired with optimal timing and flip angle. The parametric maps were generated using a bin-based data processing procedure that applied the multiple regression fitting method to extract the pO(2) and R. Variations of global mean, percentiles, and regions of interest were calculated from the maps to analyze reproducibility. RESULTS The global statistical analyses show that average variation of global mean is 10.7% for pO(2) and 23.8% for R, and that the average variation of percentiles (10th, 25th, 50th, 75th, and 90th) and interquartile range is 14.8% for pO(2) and 30.4% for R. The region-of-interest analysis on the manually selected regions shows that the average variation of mean is 12.6% for pO(2) and 21.9% for R. CONCLUSION In this work, a preliminary study on the reproducibility of measuring pO(2) and R with HP (3)He magnetic resonance imaging on a pig model is presented.