Hyperpolarized 129Xe magnetic resonance imaging (MRI) is a method for studying regionally resolved aspects of pulmonary function. This work presents an end-to-end standardized workflow for hyperpolarized 129Xe MRI of lung ventilation, with specific attention to pulse sequence design, 129Xe dose preparation, scan workflow, and best practices for subject safety monitoring.
Hyperpolarized 129Xe MRI comprises a unique array of structural and functional lung imaging techniques. Technique standardization across sites is increasingly important given the recent FDA approval of 129Xe as an MR contrast agent and as interest in 129Xe MRI increases among research and clinical institutions. Members of the 129Xe MRI Clinical Trials Consortium (Xe MRI CTC) have agreed upon best practices for each of the key aspects of the 129Xe MRI workflow, and these recommendations are summarized in a recent publication. This work provides practical information to develop an end-to-end workflow for collecting 129Xe MR images of lung ventilation according to the Xe MRI CTC recommendations. Preparation and administration of 129Xe for MR studies will be discussed and demonstrated, with specific topics including choice of appropriate gas volumes for entire studies and for individual MR scans, preparation and delivery of individual 129Xe doses, and best practices for monitoring subject safety and 129Xe tolerability during studies. Key MR technical considerations will also be covered, including pulse sequence types and optimized parameters, calibration of 129Xe flip angle and center frequency, and 129Xe MRI ventilation image analysis.
Hyperpolarized 129Xe MRI is an exciting tool for non-invasive, spatially-resolved characterization and quantification of specific aspects of pulmonary function1,2,3. Acquisition and reconstruction approaches similar to those used in anatomical proton MRI yield images of inhaled 129Xe in the lungs, permitting visualization of non-ventilated lung regions and region-resolved quantification of ventilation distribution4,5,6,7,8. More advanced pulse sequence and analysis techniques yield further complementary information, including quantification of gas-exchange efficacy between alveoli and pulmonary capillaries via spectroscopic MRI9,10,11,12,13 and characterization of alveolar microstructure integrity via diffusion-weighted MRI14,15,16.
Inhaled 129Xe has been proven safe and tolerable in adult and pediatric subjects, including those with pulmonary disease17,18. Measurements of lung function derived from 129Xe MRI have shown sensitivity to structural and functional alterations in many pulmonary disease contexts, including chronic obstructive pulmonary disease6,10,19, cystic fibrosis20,21,22, idiopathic pulmonary fibrosis23,24,25, and asthma7,10,26. Given the high safety and tolerability of 129Xe MRI, the lack of ionizing radiation in MRI compared with other common imaging approaches, and the high reproducibility of 129Xe MRI results27,28, 129Xe MRI holds significant promise, in particular for precise serial monitoring of individuals receiving a time course of therapy for chronic pulmonary disease.
The safety and clinical promise of 129Xe MRI have led to its FDA approval in December 2022 for lung ventilation imaging in persons aged 12 years and older29. Given this, it is anticipated that the number of research and clinical sites capable of performing 129Xe MRI (currently ~20 worldwide) will increase significantly over the coming years. As 129Xe MRI spreads to new institutions, it is important that robust methodological resources exist to allow sites to build out clinically relevant 129Xe MRI techniques quickly and to perform scans and generate results that are closely comparable with those of existing sites.
In this work, we will outline the current best practices for human hyperpolarized 129Xe MRI of lung ventilation, as agreed upon by member institutions of the 129Xe MRI Clinical Trials Consortium (Xe MRI CTC) and summarized in a recent position paper30. Topics will include the preparation of tailored pulse sequences ideal for a complete 129Xe MRI workflow, preparation, and administration of hyperpolarized 129Xe gas, an optimized workflow for human 129Xe MRI sessions, and best practices for monitoring subject safety and comfort during MRI sessions.
All research involving human subjects must be approved by an institutional review board (IRB). IRB involvement is not necessary for regulatory-approved clinical use of 129Xe MRI. Before participating in a research study, prospective subjects must be provided with an approved informed consent document. The person obtaining consent must explain the contents of the document, including the purpose, procedures, benefits, and risks of the study, must answer any questions, and must obtain consent from the subject to proceed with the study as documented by the subject's signature on the informed consent document. In the case of pediatric subjects or other special circumstances, approved practices for obtaining consent must be followed. The protocol described below follows the guidelines of the IRB of the University of Virginia, and the example case subjects in this manuscript have signed the University of Virginia IRB-approved consent forms (IRB 13647, 16215, 16885, 19569).
1. Preparation of hardware and pulse sequences for 129Xe MRI
NOTE: The protocol steps under step 1 should be performed before scanning any human subjects. They do not need to be repeated for each subject.
Parameter | Calibration | ||
TR | 15 ms | ||
TE | 0.45 ms (3 T), 0.8 ms (1.5 T) | ||
RF pulse | windowed sinc | ||
RF duration | 0.65-0.69 ms (3 T), 1.15-1.25 ms (1.5 T) | ||
Flip angle | 20° | ||
RF frequency | 218 ppm (dissolved-phase), 0 ppm (gas-phase) | ||
Dwell time | 39 μs | ||
Bandwidth | 25.6 kHz | ||
No. of samples | 256 (not including oversampling, if used) | ||
Readout duration | 10 ms | ||
Number of FIDs | 1 noise (no RF), 499 at dissolved-phase freq., 20 at gas-phase freq. | ||
Gradient spoiling | moment of at least 15 mT/m-ms (each axis, after each FID) | ||
Duration | ~8 s |
Table 1: Recommended pulse sequence parameters for 129Xe calibration. Parameters are given for a non-localized, spectroscopic 129Xe calibration pulse sequence.
Parameter | Ventilation | Anatomical |
Sequence type | RF-spoiled gradient-echo | Single-shot turbo/fast spin-echo |
TR | <10 ms | Infinite |
TE | <5 ms | <50 ms |
Echo spacing | N/A | 3-5 ms |
Excitation flip angle | 8-12° | 90° |
Refocusing flip angle | N/A | ≥90° (highest allowed within SAR limits) |
Slice thickness | 15 mm | 15 mm |
Slice gap | None | None |
Slice orientation | Coronal | Coronal |
Slice order | Sequential (anterior to posterior) | Sequential (anterior to posterior) |
Phase-encoding order | Sequential (left to right) | Sequential (left to right) |
NEX | 1 (up to 7/8 partial Fourier permitted) | Half Fourier |
Asymmetric echo | Allowed | N/A |
Voxel size | 4 x 4 x 15 mm3 | 4 x 4 x 15 mm3 |
Sampling duration per echo | 5-7 ms | 1-1.5 ms |
Scan duration | 8-12 s | ≤16 s |
Table 2: Recommended pulse sequence parameters for 129Xe ventilation and 1H anatomical imaging. Parameters are given for a 2D RF-spoiled fast gradient-echo sequence for 129Xe ventilation imaging (first column) and a 2D single-shot turbo/fast spin-echo sequence for 1H anatomical imaging (second column). Note that the anatomical scan can alternatively be acquired using a 2D RF-spoiled gradient echo sequence. In this case, use the same parameters as the ventilation scan parameters given here, but add phase oversampling as needed to avoid aliasing of the arms into the imaging FOV. Also, note that the particular method for specifying receiver bandwidth varies across scanner manufacturers but that the correct value can be calculated for any scanner manufacturer from the given sampling duration per echo.
2. Screening and preparation of candidates for 129Xe MRI
3. Preparation of hyperpolarized 129Xe doses
NOTE: Detailed 129Xe polarizer and polarization measurement station instructions are proprietary and specific to each vendor. The instructions below comprise a basic summary for general spin-exchange optical pumping 129Xe polarizer operation.
4. Pre-scan preparation and coaching of subject
NOTE: It is recommended that if the subject receives a full exam that includes a six-minute walk test, the walk should not take place until after 129Xe MRI is completed to avoid fatiguing the subject in a manner that could potentially impact 129Xe MRI results. This is particularly relevant for patients with cardiopulmonary disease.
5. Preparation of MRI scanner room and positioning of subject on scanner patient table
6. Scanning procedure
7. Post-scan procedures
8. Analysis of 129Xe MRI ventilation data
NOTE: The acquired 129Xe ventilation and 1H anatomical images should automatically be reconstructed on the MRI scanner computer using the vendor's default image reconstruction pipeline.
Figure 1 shows representative ventilation and three-plane localizer images from a healthy individual. High 129Xe signal can be observed throughout the lungs in the ventilation images, and no ventilation impairment is evident in this individual.
Figure 2, Figure 3, and Figure 4 show representative ventilation and anatomical images from diseased individuals. Figure 2 depicts an individual with alpha-1 antitrypsin deficiency, in which severe ventilation impairment can be easily detected by observing the patchy appearance of the 129Xe images. Similarly, severe ventilation impairment can be seen in Figure 3, depicting an individual with severe cystic fibrosis. Figure 4 depicts an individual with chronic obstructive pulmonary disease, in which more subtle ventilation defects can be noted using the 129Xe images.
Figure 5 shows ventilation images from a study that was unknowingly performed using a 129Xe vest coil with a damaged cable. One of the two lungs displays a far lower SNR than the other and an intensity roll, with both of these phenomena particularly prominent in the posterior slices. Figure 6 shows ventilation images from a study that was performed with the 129Xe vest coil placed too far toward the subject's feet. Artificially low 129Xe signal is observed in both lung apices due to the lack of receiver sensitivity there.
Figure 7 shows representative ventilation and anatomical images from an individual with diagnosed COPD, along with binarized ventilation maps calculated using the simple method described in step 8 of the protocol. Widespread ventilation defects are apparent in this individual, including nearly complete loss of ventilation in the upper lobe of the left lung, and the calculated VDP for this individual is 52%. While the analysis procedure appropriately categorizes regions of clearly high or low 129Xe signal, partially ventilated image regions (or regions of partial volume effect, in which a given slice spans both ventilated and nonventilated regions along the slice-select direction) are more difficult to characterize. In this instance, the analysis procedure tends toward characterizing these regions as non-ventilated. This example underscores the utility of analysis procedures that categorize ventilation into more than two categories. Development, testing, and comparison of such analysis procedures is an important ongoing effort in the field of 129Xe MRI30,33.
Figure 1: Representative images from a healthy individual. (A) Ventilation and (B) three-plane localizer images from a 22-year-old 117 lb healthy female. No ventilation impairments can be readily detected in this individual. Please click here to view a larger version of this figure.
Figure 2: Representative images from an individual with alpha-1 antitrypsin deficiency. (A) Ventilation and (B) anatomical images from a 60-year-old 144 lb female with diagnosed alpha-1 antitrypsin deficiency. Severe ventilation impairments are evident in this individual. Please click here to view a larger version of this figure.
Figure 3: Representative images from an individual with severe cystic fibrosis. (A) Ventilation and (B) anatomical images from an 18-year-old 132 lb male with diagnosed severe cystic fibrosis. Severe ventilation impairments are evident in this individual. Please click here to view a larger version of this figure.
Figure 4: Representative images from an individual with chronic obstructive pulmonary disease. (A) Ventilation and (B) anatomical images from a 56-year-old 110 lb female with diagnosed chronic obstructive pulmonary disease. Mild ventilation defects can be detected in this individual. Please click here to view a larger version of this figure.
Figure 5: Representative images performed using a defective 129Xe vest coil. (A) Ventilation and (B) anatomical images from a 20-year-old 136 lb female with diagnosed cystic fibrosis from a scan that was unknowingly performed using a 129Xe vest coil with a damaged cable. The right lung (left as the images appear on the page) displays a lower signal-to-noise ratio (SNR) than the left lung (right as the images appear on the page), and the right lung also displays a notable intensity roll, with higher SNR in the anterior slices than in the posterior slices, and higher SNR toward the medial edge of the lung than toward the lateral edge. Please click here to view a larger version of this figure.
Figure 6: Representative images in which the coil was placed too far in the inferior direction. (A) Ventilation and (B) anatomical images from a 6-year-old 46 lb male with diagnosed mild cystic fibrosis, scanned with the 129Xe vest coil placed too far in the inferior direction. The measured signal in the lung apices is artificially low due to the resulting lack of receiver sensitivity in the lung apices. Please click here to view a larger version of this figure.
Figure 7: Representative ventilation analysis using 129Xe MR images. (A) Anatomical and (B) ventilation images from an 84-year-old 188 lb male with diagnosed chronic obstructive pulmonary disease, with (C) ventilation maps calculated using the simple binarized analysis procedure described in step 8 of the protocol. Ventilated areas of the lung are shown in cyan, while unventilated areas of the lung are shown in magenta. Severe ventilation defects can be detected in this individual, including nearly complete loss of ventilation in the upper lobe of the left lung. Please click here to view a larger version of this figure.
Supplementary File 1: Example MR safety form. This form is used at the University of Virginia to assess subject MR safety. Please click here to download this File.
The ventilation and anatomical MRI approaches outlined above are designed to maximize image quality and SNR while maintaining simplicity of implementation – these sequence protocols can in general be adapted from vendor product pulse sequences, provided multinuclear operation is enabled, and images will automatically reconstruct on the scanner computer. One disadvantage of the 2D approaches described here is the use of slice-selective excitation RF pulses, which introduces signal differences between slices collected earlier in the 129Xe ventilation acquisition than later due to T1 relaxation of the inhaled hyperpolarized 129Xe during the scan. Another disadvantage of the procedure described here is that the 129Xe ventilation scan and its corresponding 1H anatomical scan are acquired in different breath holds, possibly introducing variations in lung inflation level or position between ventilation and anatomical scans.
Approaches for 3D ventilation imaging and for single-breath-hold imaging of both 129Xe and 1H have become increasingly common. 3D imaging approaches allow reconstruction of isotropic voxels (as opposed to the non-isotropic voxels with coarser resolution along the slice direction necessitated by slice-selective 2D imaging) and avoid potential T1-driven 129Xe signal variation from one slice to the next35,36. When using Cartesian k-space trajectories, 3D imaging with isotropic resolution requires longer scan times than 2D imaging of the same volume. Therefore, more time-efficient non-Cartesian k-space sampling is often used for 3D imaging. The much greater time efficiency afforded by non-Cartesian sampling can also permit the acquisition of the 129Xe and 1H images in the same breath hold37. These advanced approaches remain more difficult to implement and standardize across sites due to the required pulse sequence programming and advanced reconstruction techniques. However, as vendor support for pulse sequences with non-Cartesian readout becomes available, these more advanced approaches may become commonplace and standardized across sites.
The ventilation analysis procedure presented in step 8 of the protocol is a simple method that can be easily implemented and interpreted, as it returns a binary defect/no-defect answer for each segmented lung voxel and compiles these results into a single VDP number for the scanned individual. While this approach is a reasonable starting point for ventilation analysis, voxel-wise binarization cannot fully characterize ventilation heterogeneity. More complex approaches to ventilation categorization have been developed and tested and are currently in use at some research institutions33. In general, these approaches seek to characterize voxel-wise ventilation beyond simply ventilated and non-ventilated by including other categories, such as hyperventilated and partially ventilated, with an eye toward producing more descriptive and meaningful readouts than binary VDP. Specific categorization methods include linear binning of normalized voxel intensities using histograms4; voxel intensity classification using k-means38, fuzzy c-means39,40, and Gaussian mixture modeling41; and deep convolutional neural networks training on existing hyperpolarized-gas ventilation images33,34. Ventilation quantification using 129Xe MRI remains an area of active development and discussion, with no consensus best-practice method identified as of this writing.
The scope of this protocol is confined to 129Xe ventilation MRI, and to date, this remains the only 129Xe MRI technique approved for clinical use by the FDA. However, an interesting advantage of the 129Xe MRI suite of techniques is its potential for regional characterization of numerous different aspects of pulmonary function. In particular, the recent position paper30 from the Xe MRI CTC provides current recommended practices for imaging of pulmonary gas exchange using dissolved-phase 129Xe MRI and quantification of alveolar-airspace size using 129Xe diffusion MRI. These protocols generally cannot be adapted from vendor-supplied protocols and, therefore, require significant pulse sequence programming. Once pulse sequences are developed, the associated protocols can be readily integrated into the workflow for 129Xe ventilation MRI described here, as best practices for xenon polarization, xenon dosing, and subject safety monitoring are common across the various 129Xe MRI methods. When numerous 129Xe MRI scan types are expected to be performed in a single subject, it is advisable to perform 129Xe scans that represent the primary study endpoint first after performing 129Xe calibration, in case the resulting images are not acceptable, and the primary endpoint scan must be repeated using a 129Xe dose that was originally intended for a subsequent secondary-endpoint scan.
The protocol described here is intended for imaging of adults and older adolescents, and 129Xe ventilation MRI is currently only approved for clinical use by the FDA in individuals aged at least 12 years. However, 129Xe MRI is of increasing interest as a tool for pediatric pulmonary disease research17,22,42,43, and FDA approval for 129Xe MRI in pediatric populations will be sought in short order. Difficulty maintaining breath-hold and/or executing breathing instructions is more likely in pediatric subjects, and thus, pre-scan coaching is especially important. The test bag practice procedure described in step 4 of the protocol also assumes a more crucial role, as it can help decide whether to proceed to 129Xe imaging. Additionally, protocols for pediatric 129Xe MRI should strive to shorten scan times (and thus breath-hold times) where possible. Smaller lungs in pediatric subjects may necessitate different 129Xe dosing considerations and resolution and/or FOV settings than those used for older individuals.
The authors have nothing to disclose.
This work was funded by the National Institutes of Health (grant numbers R01-CA172595-01, R01-HL132177, R01-HL167202, S10-OD018079, and UL1-TR003015) and by Siemens Medical Solutions.
1.5T or 3T human MRI scanner | Siemens | MAGNETOM Symphony (1.5T) or Vida (3T); older models fine, as long as multinuclear option is/can be installed; scanners also available from GE and Philips | |
129Xe hyperpolarizer | Polarean | 9820 | |
129Xe MRI phantom | |||
129Xe MRI vest coil | Clinical MR Solutions | Also available from other vendors | |
129Xe polarization measurement station | Polarean | 2881 | |
1H MRI phantom | |||
Coil file for 129Xe MRI vest coil | Also available from other vendors for their respective coils | ||
ECG machine | |||
Helium buffer gas | |||
Interface box from coil to scanner | May be built into coil, but needs to be included separately if not | ||
Liquid nitrogen | |||
MRI-safe pulse oximeter | Philips | Expression MR200 | |
Nitrogen buffer gas | |||
PFT machine | |||
Programming/image analysis software | MATLAB | R2023a | Various other options available |
Pulse sequence design software | Siemens | IDEA software package; also available from GE and Philips for their respective scanners | |
Scanner multinuclear option | Siemens | Scanner integrated hardware/software package; also available from GE and Philips for their respective scanners | |
Tedlar gas sampling bags (500, 750, 1000, 1250, 1500 mL) | |||
Xenon gas (129Xe isotopically enriched) |