Multislice fractional ventilation imaging in large animals with hyperpolarized gas MRI

The noninvasive assessment of regional lung ventilation is of critical importance in the quantification of the severity of disease and evaluation of response to therapy in many pulmonary diseases. This work presents, for the first time, the implementation of a hyperpolarized (HP) gas MRI technique to measure whole-lung regional fractional ventilation (r) in Yorkshire pigs (n = 5) through the use of a gas mixing and delivery device in the supine position. The proposed technique utilizes a series of back-to-back HP gas breaths with images acquired during short end-inspiratory breath-holds. In order to decouple the radiofrequency pulse decay effect from the ventilatory signal build-up in the airways, the regional distribution of the flip angle (α) was estimated in the imaged slices by acquiring a series of back-to-back images with no interscan time delay during a breath-hold at the tail end of the ventilation sequence. Analysis was performed to assess the sensitivity of the multislice ventilation model to noise, oxygen and the number of flip angle images. The optimal α value was determined on the basis of the minimization of the error in r estimation: α(opt) = 5-6o for the set of acquisition parameters in pigs. The mean r values for the group of pigs were 0.27 ± 0.09, 0.35 ± 0.06 and 0.40 ± 0.04 for the ventral, middle and dorsal slices, respectively (excluding conductive airways r 0.9). A positive gravitational (ventral-dorsal) ventilation gradient effect was present in all animals. The trachea and major conductive airways showed a uniform near-unity r value, with progressively smaller values corresponding to smaller diameter airways, and ultimately leading to lung parenchyma. The results demonstrate the feasibility of the measurement of the fractional ventilation in large species, and provide a platform to address the technical challenges associated with long breathing time scales through the optimization of acquisition parameters in species with a pulmonary physiology very similar to that of humans.     

MRI of stroke using hyperpolarized 129Xe

Because there is no background signal from xenon in biological tissue, and because inhaled xenon is delivered to the brain by blood flow, we would expect a perfusion deficit, such as is seen in stroke, to reduce the xenon concentration in the region of the deficit. Thermal polarization yields negligible xenon signal relative to hyperpolarized xenon; therefore, hyperpolarized xenon can be used as a tracer of cerebral blood flow. Using a rat permanent right middle cerebral artery occlusion model, we demonstrated that hyperpolarized ¹²⁹Xe MRI is able to detect, in vivo, the hypoperfused area of focal cerebral ischemia, that is the ischemic core area of stroke. To the best of our knowledge, this is the first time that hyperpolarized ¹²⁹Xe MRI has been used to explore normal and abnormal cerebral perfusion. Our study shows a novel application of hyperpolarized ¹²⁹Xe MRI for imaging stroke, and further demonstrates its capacity to serve as a complementary tool to proton MRI for the study of the pathophysiology during brain hypoperfusion. Copyright © 2010 John Wiley & Sons, Ltd.     

Quantitative evaluation of pulmonary gas‐exchange function using hyperpolarized 129Xe CEST MRS and MRI

Hyperpolarized ¹²⁹Xe gas MR has been a powerful tool for evaluating pulmonary structure and function due to the extremely high enhancement in spin polarization, the good solubility in the pulmonary parenchyma, and the excellent chemical sensitivity to its surrounding environment. Generally, the quantitative structural and functional information of the lung are evaluated using hyperpolarized ¹²⁹Xe by employing the techniques of chemical shift saturation recovery (CSSR) and xenon polarization transfer contrast (XTC). Hyperpolarized ¹²⁹Xe chemical exchange saturation transfer (Hyper‐CEST) is another method for quantifying the exchange information of hyperpolarized ¹²⁹Xe by using the exchange of xenon signals according to its different chemical shifts, and it has been widely used in biosensor studies in vitro. However, the feasibility of using hyperpolarized ¹²⁹Xe CEST to quantify the pulmonary gas exchange function in vivo is still unclear. In this study, the technique of CEST was used to quantitatively evaluate the gas exchange in the lung globally and regionally via hyperpolarized ¹²⁹Xe MRS and MRI, respectively. A new parameter, the pulmonary apparent gas exchange time constant (T_app), was defined, and it increased from 0.63 s to 0.95 s in chronic obstructive pulmonary disease (COPD) rats (induced by cigarette smoke and lipopolysaccharide exposure) versus the controls with a significant difference (P = 0.001). Additionally, the spatial distribution maps of T_app in COPD rats' pulmonary parenchyma showed a regionally obvious increase compared with healthy rats. These results indicated that hyperpolarized ¹²⁹Xe CEST MR was an effective method for globally and regionally quantifying the pulmonary gas exchange function, which would be helpful in diagnosing lung diseases that are related to gas exchange, such as COPD.     

Hyperpolarized 129Xe MRI using isobutene as a new quenching gas

The use of a quenching gas, isobutene, with a low vapor pressure was investigated to enhance the utility of hyperpolarized ¹²⁹Xe (HP Xe) MRI. Xenon mixed with isobutene was hyperpolarized using a home‐built apparatus for continuously producing HP Xe. The isobutene was then readily liquefied and separated almost totally by continuous condensation at about 173 K, because the vapor pressure of isobutene (0.247 kPa) is much lower than that of Xe (157 kPa). Finally, the neat Xe gas was continuously delivered to mice by spontaneous inhalation. The HP Xe MRI was enhanced twofold in polarization level and threefold in signal intensity when isobutene was adopted as the quenching gas instead of N₂. The usefulness of the HP Xe MRI was verified by application to pulmonary functional imaging of spontaneously breathing mice, where the parameters of fractional ventilation (r_a) and gas exchange (f_D) were evaluated, aiming at future extension to preclinical studies. This is the first application of isobutene as a quenching gas for HP Xe MRI.     

Comparison of hyperpolarized (3)He MRI with Xe-enhanced computed tomography imaging for ventilation mapping of rat lung

Lung ventilation was mapped in five healthy Brown Norway rats (210–377 g) using both hyperpolarized ³He MRI and Xe‐enhanced computed tomography (Xe‐CT) under similar ventilator conditions. Whole‐lung measurements of ventilation r obtained with ³He MRI were not significantly different from those obtained from Xe‐CT (p = 0.1875 by Wilcoxon matched pairs test). The ventilation parameter r is defined as the fraction of refreshed gas per unit volume per breath. Regional ventilation was also measured in four regions of the lung using both methods. A two‐tailed paired t‐test was performed for each region, yielding p > 0.05 for all but the upper portion of the right lung. The distribution of regional ventilation was evaluated by calculating ventilation gradients in the superior/inferior (S/I) direction. The average S/I gradient obtained using the ³He MRI method was found to be 0.17 ± 0.04 cm^?1, whereas the average S/I gradient obtained using the Xe‐CT method was found to be 0.016 ± 0.005 cm^?1. In general, S/I ventilation gradients obtained from both methods were significantly different from each other (p = 0.0019 by two‐tailed paired t‐test). These regional differences in ventilation measurements may be caused by the manner in which the gas contrast agents distribute physiologically and/or by the imaging modality. Copyright © 2011 John Wiley & Sons, Ltd.     

Preclinical hyperpolarized 129Xe MRI: ventilation and T2* mapping in mouse lungs at 7 T using multi‐echo flyback UTE

Fast apparent transverse relaxation (short T₂*) is a common obstacle when attempting to perform quantitative ¹H MRI of the lungs. While T₂* times are longer for pulmonary hyperpolarized (HP) gas functional imaging (in particular for gaseous ¹²⁹Xe), T₂* can still lead to quantitative inaccuracies for sequences requiring longer echo times (such as diffusion weighted images) or longer readout duration (such as spiral sequences). This is especially true in preclinical studies, where high magnetic fields lead to shorter relaxation times than are typically seen in human studies. However, the T₂* of HP ¹²⁹Xe in the most common animal model of human disease (mice) has not been reported. Herein, we present a multi‐echo radial flyback imaging sequence and use it to measure HP ¹²⁹Xe T₂* at 7 T under a variety of respiratory conditions. This sequence mitigates the impact of T₁ relaxation outside the animal by using multiple gradient‐refocused echoes to acquire images at a number of effective echo times for each RF excitation. After validating the sequence using a phantom containing water doped with superparamagnetic iron oxide nanoparticles, we measured the ¹²⁹Xe T₂* in vivo for 10 healthy C57Bl/6 J mice and found T₂* ~ 5 ms in the lung airspaces. Interestingly, T₂* was relatively constant over all experimental conditions, and varied significantly with sex, but not age, mass, or the O₂ content of the inhaled gas mixture. These results are discussed in the context of T₂* relaxation within porous media.     

Simultaneous assessment of both lung morphometry and gas exchange function within a single breath‐hold by hyperpolarized 129Xe MRI

During the measurement of hyperpolarized ¹²⁹Xe magnetic resonance imaging (MRI), the diffusion‐weighted imaging (DWI) technique provides valuable information for the assessment of lung morphometry at the alveolar level, whereas the chemical shift saturation recovery (CSSR) technique can evaluate the gas exchange function of the lungs. To date, the two techniques have only been performed during separate breaths. However, the request for multiple breaths increases the cost and scanning time, limiting clinical application. Moreover, acquisition during separate breath‐holds will increase the measurement error, because of the inconsistent physiological status of the lungs. Here, we present a new method, referred to as diffusion‐weighted chemical shift saturation recovery (DWCSSR), in order to perform both DWI and CSSR within a single breath‐hold. Compared with sequential single‐breath schemes (namely the ‘CSSR + DWI’ scheme and the ‘DWI + CSSR’ scheme), the DWCSSR scheme is able to significantly shorten the breath‐hold time, as well as to obtain high signal‐to‐noise ratio (SNR) signals in both DWI and CSSR data. This scheme enables comprehensive information on lung morphometry and function to be obtained within a single breath‐hold. In vivo experimental results demonstrate that DWCSSR has great potential for the evaluation and diagnosis of pulmonary diseases.     

Hyperpolarized 129Xe lung MRI in spontaneously breathing mice with respiratory gated fast imaging and its application to pulmonary functional imaging

In the present study, a balanced steady-state free precession pulse sequence combined with compressed sensing was applied to hyperpolarized (129) Xe lung imaging in spontaneously breathing mice. With the aid of fast imaging techniques, the temporal resolution was markedly improved in the resulting images. Using these protocols and respiratory gating, (129) Xe lung images in end-inspiratory and end-expiratory phases were obtained successfully. The application of these techniques for pulmonary functional imaging made it possible to simultaneously evaluate regional ventilation and gas exchange in the same animal. A comparative study between healthy and elastase-induced mouse models of emphysema showed abnormal ventilation as well as gas exchange in elastase-treated mice.     

Quantitative analysis of hyperpolarized 129Xe ventilation imaging in healthy volunteers and subjects with chronic obstructive pulmonary disease

In this study, hyperpolarized ¹²⁹Xe MR ventilation and ¹H anatomical images were obtained from three subject groups: young healthy volunteers (HVs), subjects with chronic obstructive pulmonary disease (COPD) and age‐matched controls (AMCs). Ventilation images were quantified by two methods: an expert reader‐based ventilation defect score percentage (VDS%) and a semi‐automated segmentation‐based ventilation defect percentage (VDP). Reader‐based values were assigned by two experienced radiologists and resolved by consensus. In the semi‐automated analysis, ¹H anatomical images and ¹²⁹Xe ventilation images were both segmented following registration to obtain the thoracic cavity volume and ventilated volume, 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 thoracic cavity volume, 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 three groups from one another and correlated significantly with the forced expiratory volume in 1 s (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 (HVs and AMCs), 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 subjects with COPD with similar ventilation defect scores, but visibly different ventilation patterns. Copyright © 2012 John Wiley & Sons, Ltd.     

Oxygen‐dependent hyperpolarized 129Xe brain MR

Hyperpolarized (HP) ¹²⁹Xe MR offers unique advantages for brain functional imaging (fMRI) because of its extremely high sensitivity to different chemical environments and the total absence of background noise in biological tissues. However, its advancement and applications are currently plagued by issues of signal strength. Generally, xenon atoms found in the brain after inhalation are transferred from the lung via the bloodstream. The longitudinal relaxation time (T₁) of HP ¹²⁹Xe is inversely proportional to the pulmonary oxygen concentration in the lung because oxygen molecules are paramagnetic. However, the T₁ of ¹²⁹Xe is proportional to the pulmonary oxygen concentration in the blood, because the higher pulmonary oxygen concentration will result in a higher concentration of diamagnetic oxyhemoglobin. Accordingly, there should be an optimal pulmonary oxygen concentration for a given quantity of HP ¹²⁹Xe in the brain. In this study, the relationship between pulmonary oxygen concentration and HP ¹²⁹Xe signal in the brain was analyzed using a theoretical model and measured through in vivo experiments. The results from the theoretical model and experiments in rats are found to be in good agreement with each other. The optimal pulmonary oxygen concentration predicted by the theoretical model was 21%, and the in vivo experiments confirmed the presence of such an optimal ratio by reporting measurements between 25% and 35%. These findings are helpful for improving the ¹²⁹Xe signal in the brain and make the most of the limited spin polarization available for brain experiments. Copyright © 2016 John Wiley & Sons, Ltd.     

Retrospective cine 3He ventilation imaging under spontaneous breathing conditions: a non-invasive protocol for small-animal lung function imaging

A non-invasive and free-breathing hyperpolarized (HP) (3)He imaging protocol for small animals was implemented and validated on rats for lung function imaging. Animals were allowed to breathe a mixture of air and (3)He from a mask and a gas reservoir fitted to their heads. Radial imaging sequences were used, and MRI signal intensity changes were monitored for retrospective cine image reconstruction. The ventilation cycle of the animals was imaged with a 100 ms temporal resolution. The sliding window imaging technique was applied to reconstruct 5 ms time-shifted image series covering the complete breathing cycle. Image series were processed to extract quantitative ventilation parameters such as the gas arrival time. The reproducibility and the non-invasiveness of this ventilation imaging protocol were evaluated by multiple acquisitions on the same animals.     

Fractional ventilation mapping using inert fluorinated gas MRI in rat models of inflammation and fibrosis

The purpose of this study was to extend established methods for fractional ventilation mapping using ¹⁹F MRI of inert fluorinated gases to rat models of pulmonary inflammation and fibrosis. In this study, five rats were instilled with lipopolysaccharide (LPS) in the lungs two days prior to imaging, six rats were instilled with bleomycin in the lungs two weeks prior to imaging and an additional four rats were used as controls. ¹⁹F MR lung imaging was performed at 3 T with rats continuously breathing a mixture of sulfur hexafluoride and O₂. Fractional ventilation maps were obtained using a wash‐out approach, by switching the breathing mixture to pure O₂, and acquiring images following each successive wash‐out breath. The mean fractional ventilation (r) was 0.29 ± 0.05 for control rats, 0.23 ± 0.10 for LPS‐instilled rats and 0.19 ± 0.03 for bleomycin‐instilled rats. Bleomycin‐instilled rats had a significantly decreased mean r value compared with controls (P = 0.010). Although LPS‐instilled rats had a slightly reduced mean r value, this trend was not statistically significant (P = 0.556). Fractional ventilation gradients were calculated in the anterior/posterior (A/P) direction, and the mean A/P gradient was ?0.005 ± 0.008 cm^?1 for control rats, 0.013 ± 0.005 cm^?1 for LPS‐instilled rats and 0.009 ± 0.018 cm^?1 for bleomycin‐instilled rats. Fractional ventilation gradients were significantly different for control rats compared with LPS‐instilled rats only (P = 0.016). The ventilation gradients calculated from control rats showed the expected gravitational relationship, while ventilation gradients calculated from LPS‐ and bleomycin‐instilled rats showed the opposite trend. Histology confirmed that LPS‐instilled rats had a significantly elevated alveolar wall thickness, while bleomycin‐instilled rats showed signs of substantial fibrosis. Overall, ¹⁹F MRI may be able to detect the effects of pulmonary inflammation and fibrosis using a simple and inexpensive imaging approach that can potentially be translated to humans. Copyright © 2016 John Wiley & Sons, Ltd.     

Single breath‐hold measurement of pulmonary gas exchange and diffusion in humans with hyperpolarized 129Xe MR

Pulmonary diseases usually result in changes of the blood‐gas exchange function in the early stages. Gas exchange across the respiratory membrane and gas diffusion in the alveoli can be quantified using hyperpolarized ¹²⁹Xe MR via chemical shift saturation recovery (CSSR) and diffusion‐weighted imaging (DWI), respectively. Generally, CSSR and DWI data have been collected in separate breaths in humans. Unfortunately, the lung inflation level cannot be the exactly same in different breaths, which causes fluctuations in blood‐gas exchange and pulmonary microstructure. Here we combine CSSR and DWI obtained with compressed sensing, to evaluate the gas diffusion and exchange function within a single breath‐hold in humans. A new parameter, namely the perfusion factor of the respiratory membrane (SVR_d/g), is proposed to evaluate the gas exchange function. Hyperpolarized ¹²⁹Xe MR data are compared with pulmonary function tests and computed tomography examinations in healthy young, age‐matched control, and chronic obstructive pulmonary disease human cohorts. SVR_d/g decreases as the ventilation impairment and emphysema index increase. Our results indicate that the proposed method has the potential to detect the extent of lung parenchyma destruction caused by age and pulmonary diseases, and it would be useful in the early diagnosis of pulmonary diseases in clinical practice.     

Development of a fast method for quantitative measurement of hyperpolarized 129Xe dynamics in mouse brain

A fast method has been established for the precise measurement and quantification of the dynamics of hyperpolarized (HP) xenon‐129 (¹²⁹Xe) in the mouse brain. The key technique is based on repeatedly applying radio frequency (RF) pulses and measuring the decrease of HP ¹²⁹Xe magnetization after the brain Xe concentration has reached a steady state due to continuous HP ¹²⁹Xe ventilation. The signal decrease of the ¹²⁹Xe nuclear magnetic resonance (NMR) signal was well described by a simple theoretical model. The technique made it possible to rapidly evaluate the rate constant α, which is composed of cerebral blood flow (CBF), the partition coefficient of Xe between the tissue and blood (λ_i), and the longitudinal relaxation time (T_1i) of HP ¹²⁹Xe in the brain tissue, without any effect of depolarization by RF pulses and the dynamics in the lung. The technique enabled the precise determination of α as 0.103 ± 0.018 s^‐1 (± SD, n = 5) on healthy mice. To investigate the potential of this method for detecting physiological changes in the brain of a kainic acid (KA) ‐induced mouse model of epilepsy, an attempt was made to follow the time course of α after KA injection. It was found that the α value changes characteristically with time, reflecting the change in the physiological state of the brain induced by KA injection. By measuring CBF using ¹H MRI and ¹²⁹Xe dynamics simultaneously and comparing these results, it was suggested that the reduction of T_1i, in addition to the increase of CBF due to KA‐induced epilepsy, are possible causes of the change in ¹²⁹Xe dynamics. Thus, the present method would be useful to detect a pathophysiological state in the brain and provide a novel tool for future brain study. Copyright © 2011 John Wiley & Sons, Ltd.     

Reinvestigating hyperpolarized (129)Xe longitudinal relaxation time in the rat brain with noise considerations

The longitudinal relaxation time of hyperpolarized (HP) (129)Xe in the brain is a critical parameter for developing HP (129)Xe brain imaging and spectroscopy and optimizing the pulse sequences, especially in the case of cerebral blood flow measurements. Various studies have produced widely varying estimates of HP (129)Xe T(1) in the rat brain. To make improved measurements of HP (129)Xe T(1) in the rat brain and investigate how low signal-to-noise ratio (SNR) contributes to these discrepancies, we developed a multi-pulse protocol during the washout of (129)Xe from the brain. Afterwards, we applied an SNR threshold theory to both the multi-pulse protocol and an existing two-pulse protocol. The two protocols yielded mean +/- SD HP (129)Xe T(1) values in the rat brain of 15.3 +/- 1.2 and 16.2 +/- 0.9 s, suggesting that the low SNR might be a key reason for the wide range of T(1) values published in the literature, a problem that might be easily alleviated by taking SNR levels into account.     

A protocol for quantifying cardiogenic oscillations in dynamic 129Xe gas exchange spectroscopy: The effects of idiopathic pulmonary fibrosis

The spectral parameters of hyperpolarized ¹²⁹Xe exchanging between airspaces, interstitial barrier, and red blood cells (RBCs) are sensitive to pulmonary pathophysiology. This study sought to evaluate whether the dynamics of ¹²⁹Xe spectroscopy provide additional insight, with particular focus on quantifying cardiogenic oscillations in the RBC resonance. ¹²⁹Xe spectra were dynamically acquired in eight healthy volunteers and nine subjects with idiopathic pulmonary fibrosis (IPF). ¹²⁹Xe FIDs were collected every 20 ms (T_E = 0.932 ms, 512 points, dwell time = 32 μs, flip angle ≈ 20°) during a 16 s breathing maneuver. The FIDs were pre‐processed using the spectral improvement by Fourier thresholding technique (SIFT) and fit in the time domain to determine the airspace, interstitial barrier, and RBC spectral parameters. The RBC and gas resonances were fit to a Lorentzian lineshape, while the barrier was fit to a Voigt lineshape to account for its greater structural heterogeneity. For each complex resonance the amplitude, chemical shift, linewidth(s), and phase were calculated. The time‐averaged spectra confirmed that the RBC to barrier amplitude ratio (RBC:barrier ratio) and RBC chemical shift are both reduced in IPF subjects. Their temporal dynamics showed that all three ¹²⁹Xe resonances are affected by the breathing maneuver. Most notably, several RBC spectral parameters exhibited prominent oscillations at the cardiac frequency, and their peak‐to‐peak variation differed between IPF subjects and healthy volunteers. In the IPF cohort, oscillations were more prominent in the RBC amplitude (16.8 ± 5.2 versus 9.7 ± 2.9%; P = 0.008), chemical shift (0.43 ± 0.33 versus 0.083 ± 0.05 ppm; P < 0.001), and phase (7.7 ± 5.6 versus 1.4 ± 0.8°; P < 0.001). Dynamic ¹²⁹Xe spectroscopy is a simple and sensitive tool that probes the temporal variability of gas exchange and may prove useful in discerning the underlying causes of its impairment.     

A robust protocol for regional evaluation of methacholine challenge in mouse models of allergic asthma using hyperpolarized 3He MRI

Hyperpolarized (HP) ³He magnetic resonance imaging has been recently used to produce high‐resolution images of pulmonary ventilation after methacholine (MCh) challenge in mouse models of allergic inflammation. This capability presents an opportunity to gain new insights about these models and to more sensitively evaluate new drug treatments in the pre‐clinical setting. In the current study, we present our initial experience using two‐dimensional (2D), time‐resolved ³He MRI of MCh challenge‐induced airways hyperreactivity (AHR) to compare ovalbumin‐sensitized and challenged (N = 8) mice to controls (N = 8). Imaging demonstrated that ovalbumin‐sensitized and challenged animals exhibited many large ventilation defects even prior to MCh challenge (four out of eight) compared to no defects in the control animals. Additionally, the ovalbumin‐sensitized and challenged animals experienced a greater number of ventilation defects (4.5 ± 0.4) following MCh infusion than did controls (3.3 ± 0.6). However, due to variability in MCh delivery that was specific to the small animal MRI environment, the difference in mean defect number was not statistically significant. These findings are reviewed in detail and a comprehensive solution to the variability problem is presented that has greatly enhanced the magnitude and reproducibility of the MCh response. This has permitted us to develop a new imaging protocol consisting of a baseline 3D image, a time‐resolved 2D series during MCh challenge, and a post‐MCh 3D image that reveals persistent ventilation defects. Copyright © 2009 John Wiley & Sons, Ltd.