This work was supported by NIH grants R01HL159898 and R01HL142258.

NOTE: While the hyperpolarized Xenon-129 CSSR MR spectroscopy technique described here is commonly used for animal and human imaging, the protocol below refers to human studies only. All imaging protocols adhered to FDA specific absorption rate (SAR) limitations (4 W/kg) and were approved by the Institutional Review Board at the University of Pennsylvania. Informed consent was obtained from each subject.
1. Pulse sequence design
<ol>
	<li>Decide whether to perform a breath h...

Assessing Lung Function with Hyperpolarized Xenon-129 MRI

<ol>
	<li>Albert, M. S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Biological+magnetic+resonance+imaging+using+laser-polarized+129Xe.">Biological magnetic resonance imaging using laser-polarized 129Xe.</a> Nature. 370 (6486), 199-201 (1994).</li><li>Happer, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Optical+Pumping.">Optical Pumping.</a> Rev Mod Phys. 44 (2), 169-250 (1972).</li><li>Appelt, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Theory+of+spin-exchange+optical+pumping+of+He-3+and+Xe-129.">Theory of spin-exchange optical pumping of He-3 and Xe-129.</a> Phys Rev A. 58 (2), 1412-1439 (1998).</li><li>Hersman, F. W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Large+production+system+for+hyperpolarized+129Xe+for+human+lung+imaging+studies.">Large production system for hyperpolarized 129Xe for human lung imaging studies.</a> Acad Radiol. 15 (6), 683-692 (2008).</li><li>Parnell, S. R., Deppe, M. H., Parra-Robles, J., Wild, J. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Enhancement+of+Xe-129+polarization+by+off-resonant+spin+exchange+optical+pumping.">Enhancement of Xe-129 polarization by off-resonant spin exchange optical pumping.</a> J Appl Phys. 108 (6), 064908 (2010).</li><li>Norquay, G., Collier, G. J., Rao, M., Stewart, N. J., Wild, J. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=^{129}Xe-Rb+spin-exchange+optical+pumping+with+high+photon+efficiency.">^{129}Xe-Rb spin-exchange optical pumping with high photon efficiency.</a> Phys Rev Lett. 121 (15), 153201 (2018).</li><li>Mugler, J. P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=MR+imaging+and+spectroscopy+using+hyperpolarized+129Xe+gas:+preliminary+human+results.">MR imaging and spectroscopy using hyperpolarized 129Xe gas: preliminary human results.</a> Magn Reson Med. 37 (6), 809-815 (1997).</li><li>Ruppert, K., Brookeman, J. R., Hagspiel, K. D., Driehuys, B., Mugler, J. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=NMR+of+hyperpolarized+(129)Xe+in+the+canine+chest:+spectral+dynamics+during+a+breath-hold.">NMR of hyperpolarized (129)Xe in the canine chest: spectral dynamics during a breath-hold.</a> NMR Biomed. 13 (4), 220-228 (2000).</li><li>Butler, J. P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Measuring+surface-area-to-volume+ratios+in+soft+porous+materials+using+laser-polarized+Xenon+interphase+exchange+nuclear+magnetic+resonance.">Measuring surface-area-to-volume ratios in soft porous materials using laser-polarized Xenon interphase exchange nuclear magnetic resonance.</a> J Phys Condens Matter. 14 (13), L297-L304 (2002).</li><li>Mansson, S., Wolber, J., Driehuys, B., Wollmer, P., Golman, K. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Characterization+of+diffusing+capacity+and+perfusion+of+the+rat+lung+in+a+lipopolysaccaride+disease+model+using+hyperpolarized+129Xe.">Characterization of diffusing capacity and perfusion of the rat lung in a lipopolysaccaride disease model using hyperpolarized 129Xe.</a> Magn Reson Med. 50 (6), 1170-1179 (2003).</li><li>Abdeen, N., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Measurement+of+Xenon+diffusing+capacity+in+the+rat+lung+by+hyperpolarized+(129)Xe+MRI+and+dynamic+spectroscopy+in+a+single+breath-hold.">Measurement of Xenon diffusing capacity in the rat lung by hyperpolarized (129)Xe MRI and dynamic spectroscopy in a single breath-hold.</a> Magn Reson Med. 56 (2), 255-264 (2006).</li><li>Driehuys, B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Imaging+alveolar-capillary+gas+transfer+using+hyperpolarized+129Xe+MRI.">Imaging alveolar-capillary gas transfer using hyperpolarized 129Xe MRI.</a> Proc Natl Acad Sci U S A. 103 (48), 18278-18283 (2006).</li><li>Patz, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Human+pulmonary+imaging+and+spectroscopy+with+hyperpolarized+129Xe+at+0.2T.">Human pulmonary imaging and spectroscopy with hyperpolarized 129Xe at 0.2T.</a> Acad Radiol. 15 (6), 713-727 (2008).</li><li>Qing, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assessment+of+lung+function+in+asthma+and+COPD+using+hyperpolarized+129Xe+chemical+shift+saturation+recovery+spectroscopy+and+dissolved-phase+MRI.">Assessment of lung function in asthma and COPD using hyperpolarized 129Xe chemical shift saturation recovery spectroscopy and dissolved-phase MRI.</a> NMR Biomed. 27 (12), 1490-1501 (2014).</li><li>Stewart, N. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reproducibility+of+quantitative+indices+of+lung+function+and+microstructure+from+129+Xe+chemical+shift+saturation+recovery+(CSSR)+MR+spectroscopy.">Reproducibility of quantitative indices of lung function and microstructure from 129 Xe chemical shift saturation recovery (CSSR) MR spectroscopy.</a> Magn Reson Med. 77 (6), 2107-2113 (2017).</li><li>Zhong, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Simultaneous+assessment+of+both+lung+morphometry+and+gas+exchange+function+within+a+single+breath-hold+by+hyperpolarized+(129)+Xe+MRI.">Simultaneous assessment of both lung morphometry and gas exchange function within a single breath-hold by hyperpolarized (129) Xe MRI.</a> NMR Biomed. 30 (8), (2017).</li><li>Kern, A. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Regional+investigation+of+lung+function+and+microstructure+parameters+by+localized+(129)+Xe+chemical+shift+saturation+recovery+and+dissolved-phase+imaging:+A+reproducibility+study.">Regional investigation of lung function and microstructure parameters by localized (129) Xe chemical shift saturation recovery and dissolved-phase imaging: A reproducibility study.</a> Magn Reson Med. 81 (1), 13-24 (2018).</li><li>Kern, A. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mapping+of+regional+lung+microstructural+parameters+using+hyperpolarized+(129)+Xe+dissolved-phase+MRI+in+healthy+volunteers+and+patients+with+chronic+obstructive+pulmonary+disease.">Mapping of regional lung microstructural parameters using hyperpolarized (129) Xe dissolved-phase MRI in healthy volunteers and patients with chronic obstructive pulmonary disease.</a> Magn Reson Med. 81 (4), 2360-2373 (2018).</li><li>Xie, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Single+breath-hold+measurement+of+pulmonary+gas+exchange+and+diffusion+in+humans+with+hyperpolarized+(129)+Xe+MR.">Single breath-hold measurement of pulmonary gas exchange and diffusion in humans with hyperpolarized (129) Xe MR.</a> NMR Biomed. 32 (5), e4068 (2019).</li><li>Zanette, B., Santyr, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Accelerated+interleaved+spiral-IDEAL+imaging+of+hyperpolarized+(129)+Xe+for+parametric+gas+exchange+mapping+in+humans.">Accelerated interleaved spiral-IDEAL imaging of hyperpolarized (129) Xe for parametric gas exchange mapping in humans.</a> Magn Reson Med. 82 (3), 1113-1119 (2019).</li><li>Ruppert, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Investigating+biases+in+the+measurement+of+apparent+alveolar+septal+wall+thickness+with+hyperpolarized+129Xe+MRI.">Investigating biases in the measurement of apparent alveolar septal wall thickness with hyperpolarized 129Xe MRI.</a> Magn Reson Med. 84 (6), 3027-3039 (2020).</li><li>Zhang, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantitative+evaluation+of+lung+injury+caused+by+PM(2.5)+using+hyperpolarized+gas+magnetic+resonance.">Quantitative evaluation of lung injury caused by PM(2.5) using hyperpolarized gas magnetic resonance.</a> Magn Reson Med. 84 (2), 569-578 (2020).</li><li>Friedlander, Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hyperpolarized+(129)+Xe+MRI+of+the+rat+brain+with+chemical+shift+saturation+recovery+and+spiral-IDEAL+readout.">Hyperpolarized (129) Xe MRI of the rat brain with chemical shift saturation recovery and spiral-IDEAL readout.</a> Magn Reson Med. 87 (4), 1971-1979 (2022).</li><li>Patz, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Diffusion+of+hyperpolarized+(129)Xe+in+the+lung:+a+simplified+model+of+(129)Xe+septal+uptake+and+experimental+results.">Diffusion of hyperpolarized (129)Xe in the lung: a simplified model of (129)Xe septal uptake and experimental results.</a> New J Phys. 13, 015009 (2011).</li><li>Chang, Y. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=MOXE:+a+model+of+gas+exchange+for+hyperpolarized+129Xe+magnetic+resonance+of+the+lung.">MOXE: a model of gas exchange for hyperpolarized 129Xe magnetic resonance of the lung.</a> Magn Reson Med. 69 (3), 884-890 (2013).</li><li>Stewart, N. J., Parra-Robles, J., Wild, J. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Finite+element+modeling+of+(129)Xe+diffusive+gas+exchange+NMR+in+the+human+alveoli.">Finite element modeling of (129)Xe diffusive gas exchange NMR in the human alveoli.</a> J Magn Reson. 271, 21-33 (2016).</li><li>Ruppert, K., Qing, K., Patrie, J. T., Altes, T. A., Mugler, J. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Using+hyperpolarized+Xenon-129+MRI+to+quantify+early-stage+lung+disease+in+smokers.">Using hyperpolarized Xenon-129 MRI to quantify early-stage lung disease in smokers.</a> Acad Radiol. 26 (3), 355-366 (2019).</li><li>Kern, A. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Investigating+short-time+diffusion+of+hyperpolarized+(129)+Xe+in+lung+air+spaces+and+tissue:+A+feasibility+study+in+chronic+obstructive+pulmonary+disease+patients.">Investigating short-time diffusion of hyperpolarized (129) Xe in lung air spaces and tissue: A feasibility study in chronic obstructive pulmonary disease patients.</a> Magn Reson Med. 84 (4), 2133-2146 (2020).</li><li>Stewart, N. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Experimental+validation+of+the+hyperpolarized+(129)+Xe+chemical+shift+saturation+recovery+technique+in+healthy+volunteers+and+subjects+with+interstitial+lung+disease.">Experimental validation of the hyperpolarized (129) Xe chemical shift saturation recovery technique in healthy volunteers and subjects with interstitial lung disease.</a> Magn Reson Med. 74 (1), 196-207 (2015).</li><li>Fox, M. S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Detection+of+radiation+induced+lung+injury+in+rats+using+dynamic+hyperpolarized+(129)Xe+magnetic+resonance+spectroscopy.">Detection of radiation induced lung injury in rats using dynamic hyperpolarized (129)Xe magnetic resonance spectroscopy.</a> Med Phys. 41 (7), 072302 (2014).</li><li>Li, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantitative+evaluation+of+radiation-induced+lung+injury+with+hyperpolarized+Xenon+magnetic+resonance.">Quantitative evaluation of radiation-induced lung injury with hyperpolarized Xenon magnetic resonance.</a> Magn Reson Med. 76 (2), 408-416 (2016).</li><li>Ruppert, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Detecting+pulmonary+capillary+blood+pulsations+using+hyperpolarized+Xenon-129+chemical+shift+saturation+recovery+(CSSR)+MR+spectroscopy.">Detecting pulmonary capillary blood pulsations using hyperpolarized Xenon-129 chemical shift saturation recovery (CSSR) MR spectroscopy.</a> Magn Reson Med. 75 (4), 1771-1780 (2016).</li><li>Walkup, L. L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Feasibility,+tolerability+and+safety+of+pediatric+hyperpolarized+129Xe+magnetic+resonance+imaging+in+healthy+volunteers+and+children+with+cystic+fibrosis.">Feasibility, tolerability and safety of pediatric hyperpolarized 129Xe magnetic resonance imaging in healthy volunteers and children with cystic fibrosis.</a> Pediatr Radiol. 46 (12), 1651-1662 (2016).</li><li>Willmering, M. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pediatric+(129)+Xe+gas-transfer+MRI-feasibility+and+applicability.">Pediatric (129) Xe gas-transfer MRI-feasibility and applicability.</a> J Magn Reson Imaging. 56 (4), 1207-1219 (2022).</li><li>Amzajerdian, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Simultaneous+quantification+of+hyperpolarized+Xenon-129+ventilation+and+gas+exchange+with+multi-breath+Xenon-polarization+transfer+contrast+(XTC)+MRI.">Simultaneous quantification of hyperpolarized Xenon-129 ventilation and gas exchange with multi-breath Xenon-polarization transfer contrast (XTC) MRI.</a> Magn Reson Med. 90 (6), 2334-2347 (2023).</li><li>Niedbalski, P. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Utilizing+flip+angle/TR+equivalence+to+reduce+breath+hold+duration+in+hyperpolarized+(129)+Xe+1-point+Dixon+gas+exchange+imaging.">Utilizing flip angle/TR equivalence to reduce breath hold duration in hyperpolarized (129) Xe 1-point Dixon gas exchange imaging.</a> Magn Reson Med. 87 (3), 1490-1499 (2022).</li><li>Chang, Y. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Toward+a+quantitative+understanding+of+gas+exchange+in+the+lung.">Toward a quantitative understanding of gas exchange in the lung.</a> arXiv. , (2010).</li><li>Chang, Y. V., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantification+of+human+lung+structure+and+physiology+using+hyperpolarized+129Xe.">Quantification of human lung structure and physiology using hyperpolarized 129Xe.</a> Magn Reson Med. 71 (1), 339-344 (2014).</li><li>Collier, G. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Observation+of+cardiogenic+flow+oscillations+in+healthy+subjects+with+hyperpolarized+3He+MRI.">Observation of cardiogenic flow oscillations in healthy subjects with hyperpolarized 3He MRI.</a> J Appl Physiol. 119 (9), 1007-1014 (2015).</li><li>Niedbalski, P. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Protocols+for+multi-site+trials+using+hyperpolarized+(129)+Xe+MRI+for+imaging+of+ventilation,+alveolar-airspace+size,+and+gas+exchange:+A+position+paper+from+the+(129)+Xe+MRI+clinical+trials+consortium.">Protocols for multi-site trials using hyperpolarized (129) Xe MRI for imaging of ventilation, alveolar-airspace size, and gas exchange: A position paper from the (129) Xe MRI clinical trials consortium.</a> Magn Reson Med. 86 (6), 2966-2986 (2021).</li></ol>

The authors have no conflicts of interest to disclose.

HXe CSSR MR spectroscopy is a powerful technique for assessing several pulmonary function metrics that would be difficult or impossible to quantify in vivo using any other existing diagnostic modality24. Nevertheless, the acquisition and subsequent data analysis are based on certain assumptions about physiological conditions and technical parameters that are never entirely achievable in living subjects. These limitations and their impact on the interpretation of the extracted metrics will...

Hyperpolarized Xenon-129 (HXe) magnetic resonance imaging (MRI)1 is a technique that offers unique insights into lung structure, function, and gas exchange processes. By dramatically amplifying the magnetization of Xenon gas through spin-exchange optical pumping, HXe MRI achieves an order-of-magnitude improvement in signal-to-noise ratio compared to thermally polarized Xenon MRI2,3,4,5,6. This hyperpolarization enables the direct visualization and quantification of Xenon gas uptake into lung tissue and blood, which would otherwise be undetectable with conventional thermally polarized MRI7.
Chemical shift saturation recovery (CSSR) MR spectroscopy8,9,10,11,12,13 has proven to be one of the most valuable HXe MRI techniques. CSSR involves selectively saturating the magnetization of Xenon dissolved in lung tissue and blood using frequency-specific radiofrequency (RF) pulses. The subsequent recovery of the dissolved-phase (DP) signal as it exchanges with fresh hyperpolarized Xenon gas in the airspaces on a timescale of ms offers important functional information about the lung parenchyma.
Since its development in the early 2000s, the techniques behind CSSR spectroscopy have been progressively refined14,15,16,17,18,19,20,21,22,23. Further, advances in modeling Xenon uptake curves have enabled the extraction of specific physiological parameters, such as alveolar wall thickness and pulmonary transit times10,24,25,26. Studies have shown CSSR&#39;s sensitivity to subtle changes in lung microstructure and gas exchange efficiency in the form of pulmonary abnormalities found in clinically healthy smokers27, as well as in a range of lung diseases, including chronic obstructive pulmonary disease (COPD)18,27,28, fibrosis29, and radiation-induced lung injury30,31. CSSR spectroscopy has also been demonstrated to be sensitive to detect oscillations in the DP signal corresponding to pulsatile blood flow during the cardiac cycle32.
While significant progress has been made, practical challenges remain in implementing CSSR spectroscopy on clinical MRI systems. Scan times requiring single-dose breath holds approaching 10 s may be too long for pediatric subjects33,34 or patients with severe lung disease35,36. Additionally, the technique is susceptible to measurement biases if acquisition parameters such as the order of the saturation delay times or the efficacy of the dissolved-phase saturation are not properly optimized21. To address these limitations and make CSSR more accessible to the broader research community, clear, step-by-step protocols for both conventional breath hold and free-breathing acquisitions, currently under development, are needed.
The objective of this paper is to present a detailed methodology for performing optimized CSSR MR spectroscopy using HXe gas. The protocol will cover polarization and delivery of the Xenon gas, RF pulse calibration, sequence parameter selection, subject preparation, data acquisition, and key steps in data analysis. Examples of experimental results will be provided. It is hoped that this comprehensive guide will serve as a foundation for CSSR implementations across sites and help realize the full potential of this technique for quantifying lung microstructural changes in a range of pulmonary diseases.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Bi-directional Pneumotach&#160;</td>
			<td>B&#38;B Medical AccutachTM</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Chest Vest Coil</td>
			<td>Clinical MR Solutions</td>
			<td></td>
			<td>Adult Size</td>
		</tr>
		<tr>
			<td>Face Mask</td>
			<td>Hans Rudolph</td>
			<td>7450</td>
			<td></td>
		</tr>
		<tr>
			<td>Matlab</td>
			<td>Mathworks</td>
			<td>Release 2018a</td>
			<td>Optimization Toolbox required</td>
		</tr>
		<tr>
			<td>Physiological Monitoring System&#160;</td>
			<td>BIOPAC Systems Inc</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Tedlar Bag</td>
			<td>Jensen Inert Products</td>
			<td></td>
			<td>250-mL and 500-mL; specialised PVF bag</td>
		</tr>
		<tr>
			<td>Xenon Polarizer</td>
			<td>Xemed LLC</td>
			<td>X-box E10&#160;</td>
			<td></td>
		</tr>
		<tr>
			<td>Whole-body MRI Scanner</td>
			<td>Siemens</td>
			<td>1.5 T Avanto</td>
			<td></td>
		</tr>
	</tbody>
</table>

quantitative measure of lung structure and function obtained from hyperpolarized xenon spectroscopy

Hyperpolarized Xenon-129 (HXe) magnetic resonance imaging (MRI) provides tools for obtaining 2- or 3-dimensional maps of lung ventilation patterns, gas diffusion, Xenon uptake by lung parenchyma, and other lung function metrics. However, by trading spatial for temporal resolution, it also enables tracing of pulmonary Xenon gas exchange on a ms timescale. This article describes one such technique, chemical shift saturation recovery (CSSR) MR spectroscopy. It illustrates how it can be used to assess capillary blood volume, septal wall thickness, and the surface-to-volume ratio in the alveoli. The flip angle of the applied radiofrequency pulses (RF) was carefully calibrated. Single-dose breath-hold and multi-dose free-breathing protocols were employed for administering the gas to the subject. Once the inhaled Xenon gas reached the alveoli, a series of 90&#176; RF pulses was applied to ensure maximum saturation of the accumulated Xenon magnetization in the lung parenchyma. Following a variable delay time, spectra were acquired to quantify the regrowth of the Xenon signal due to gas exchange between the alveolar gas volume and the tissue compartments of the lung. These spectra were then analyzed by fitting complex pseudo-Voigt functions to the three dominant peaks. Finally, the delay time-dependent peak amplitudes were fitted to a one-dimensional analytical gas-exchange model to extract physiological parameters.

Author Spotlight: Advancing Lung Disease Research with Free-Breathing Hyperpolarized Xenon-129 MRI

Quantitative Measure of Lung Structure and Function Obtained from Hyperpolarized Xenon Spectroscopy

Our research focuses on using hyperpolarizing on 129 MRI technology to assess pulmonary function and to investigate lung diseases. The main objective is to see how this imaging technique can lead to better detection, understanding, and tracking of different lung conditions. Most hyperpolarized lung MR imaging is performed during a breath hold.We believe that pulmonary function quantified under such an artificial condition, may not fully reflect gas exchange during regular respiration, and we are testing new free breathing measurements that do not require any breath hold. Current challenges include the optimization of the CSSR acquisition technique for consistency and accuracy in the face of physiological variation and patient compliance. Severely ill or pediatric patients struggle with maintaining lengthy breath holds.The CSSR heart technique appears particularly sensitive to changes in alveolar septal wall thickness. As we and others in the field of demonstrated, alveolar wall thickening can indicate the presence of interstitial edema, inflammation, or pulmonary fibrosis. All metrics derived from CSSR spectroscopy acquisitions are currently based on the temporal dynamics of the signal amplitudes.In the future though, we hope to include changes in peak shape and center frequency in the analysis to obtain a more complete picture of the ongoing gas exchange processes.

Figure 2&#160;illustrates a typical Xenon spectrum observed in the human lung during a breath hold, subsequent to the inhalation of 500 mL of Xenon dose. The spectrum displays two distinct regions, the GP resonance around 0 ppm, and the DP region, which consists of the membrane peak at approximately 197 ppm and the red blood cell peak at approximately 217 ppm. The relative peak amplitudes depend on a number of factors including the shape, duration, and center frequency of the RF excitation p...

Watch this Scientific Journal Video about Author Spotlight: Advancing Lung Disease Research with Free-Breathing Hyperpolarized Xenon-129 MRI at JoVE.com

The manuscript presents a detailed protocol for using hyperpolarized Xenon-129 chemical shift saturation recovery (CSSR) to trace pulmonary gas exchange, assess the apparent alveolar septal wall thickness, and measure the surface-to-volume ratio. The method has the potential to diagnose and monitor lung diseases.

Hyperpolarized Xenon-129 (HXe) magnetic resonance imaging (MRI) provides tools for obtaining 2- or 3-dimensional maps of lung ventilation patterns, gas ...

quantitative-measure-lung-structure-function-obtained-from

Research

JoVE Journal

Medicine

Patient Preparation and Subject Training for Hyperpolarized Xenon MRI

To begin, set up the physiological monitoring system to record breathing curves and real-time gas analysis during imaging. Connect and test the MRI room headphones with the audio signal that guides the subject using an inhale-exhale audio recording. Adjust the playback speed of the audio track.Inhale.Exhale.Based on the normal breathing rate of each subject.Inhale.Exhale. Next, prepare the scanner bed with a clean headrest, leg support pillow and blanket. Place the unfastened Xenon 129 chest vest coil on the table of the MRI scanner and insert the connector plug of the coil.For a free breathing study, introduce the subject to the inhale-exhale voice recording for synchronized breathing during imaging. Lead the subject into the MRI room and position them on the scanner bed, lying on top of the open xenon vest coil. Once the subject is positioned, fasten the Velcro straps so that the vest coil is closed, but does not constrict the subject's chest.For a free breathing study, place a face mask with a pneumatac over the patient's face. Tighten the straps so the mask fits snugly over the nose and mouth without being too tight. After fitting, remove the mask and set it aside for later, leaving the straps behind the subject's head.Then place two pulse oximeters on both index fingers to continuously monitor heart rate and blood oxygen saturation during the study. Place MRI compatible headphones over the subject's ears. Move the MRI scanner table into the magnet bore so the subject's lungs are positioned in the center of the field of view.

Polarizing Xenon-129 for Hyperpolarized Xenon Spectroscopy

To begin, heat up the xenon polarizer approximately 2.5 hours before the study starts. Thread the connector two of a 250 milliliter specialized polyvinyl fluoride or PVF bag through a ceiling clip. Attach the bag to one of the four available polarizer dispense ports.On the polarizer touchscreen, select the enriched xenon tank. Set the flow rate to medium and the polarization volume to 250 milliliters. Then press the start button to initiate the polarization process.Once the polarized xenon gas has been dispensed, the polarizer's touchscreen will display a message to remove the bag. Pinch the connector tube of the specialized PVF bag shut with the ceiling clip, and then disconnect the bag to place it inside the bore of the MRI scanner.

Performing Hyperpolarized Xenon-129 Inhalation for Chemical Shift Saturation Recovery (CSSR) Measurement

To perform xenon inhalation using the breath hold method, place a nose clip on the nose of the subject to facilitate breathing through the mouth. At the end of a normal exhalation to functional residual capacity, insert the mouthpiece of the xenon bag into the subject's mouth. Allow the subject to inhale 500 milliliters of xenon gas from the xenon bag.Then remove the mouthpiece and instruct the subject to continue inhaling room air until the lungs are full. At the end of inhalation, ask the subject to raise their thumb. Request the nurse coordinator to verbally convey this information to the scanner operator to start the pulse sequence.After the data acquisition period, instruct the subject to return to normal breathing. Move the subject out of the MRI scanner. Place a face mask over their nose and mouth.Connect the hoses to the mask, and then connect the pre-fitted straps from behind the head to the mask and secure it in place. Move the subject to its original position inside the MRI scanner. Once the subject follows the breathing protocol, ask the nurse coordinator to inform the MRI operator to initiate data acquisition.The nurse coordinator then opens the valves on the gas delivery system and the subject inhales 50 milliliters of hyperpolarized xenon 1-29 mixed with the airflow inside the breathing mask. Instruct the subject to continue breathing for approximately 10 breaths until the volume of xenon gas has been used up for the imaging protocol. Load the CSSR pulse sequence for free breathing.Set the acquisition frequency according to the hyperpolarized xenon gas phase frequency determined during the calibration scan. Adjust the reference voltage to match the value obtained from the calibration scan. Select the wait for user option, or its equivalent, for sequence execution, following the system vendor's operating instructions.Start the MRI scanner sequence. The scanner will pause for user input before data acquisition. Once the nurse coordinator switches the hyperpolarized xenon gas or air mixture, start data acquisition.Ensure the sequence is already running before the subject inhales the first dose of xenon gas. After the three minute data acquisition, or exhaustion of hyperpolarized xenon gas, remove the subject from the MRI scanner. In the young, healthy female, the membrane signal increases rapidly due to the quick filling of thin walls.In the older, lung transplant recipient, the membrane signal rises more gradually reflecting the longer time required to fill the thicker septal walls.

357 Views.  University of Pennsylvania.  The manuscript presents a detailed protocol for using hyperpolarized Xenon-129 chemical shift saturation recovery (CSSR) to trace pulmonary gas exchange, assess the apparent alveolar septal wall thickness, and measure the surface-to-volume ratio. The method has the potential to diagnose and monitor lung diseases.

Assessing Lung Function with Hyperpolarized Xenon-129 MRI

Summary