This research was supported in part through computational resources and services provided by Advanced Research Computing at the University of British Columbia, and by a University of British Columbia Department of Radiology AI Grant. RLE was supported by a Michael Smith Health Research BC Trainee Award.

The imaging cases shown here were approved by the University of British Columbia Providence Health Care Research Ethics Board (REB# H21-01237, H21-02149, H22-01264). Participants provided written informed consent prior to completing imaging. The overall pipeline from image acquisition to registration is outlined in Figure 2, and the protocol details here focus on the MR-CT image registration only. Image acquisition and segmentation are dependent on available or preferred imaging hardware, imaging protocols, and image analysis software tools and, therefore, are left to readers&#39; preference. The protocol is designed to be agnostic to those prior steps using single-label masks of the lungs following image segmentation.
1. Software setup
<ol>
	<li>Download and install ANTsPy (see Table of Materials), the Python wrapper for the Advanced Normalization Tools image processing library47,48,49. Tutorials are available at the link under the &#39;tutorials&#39; tab. ANTsPy is also available for Docker installation if desired. 
	NOTE: ANTsPy requires a Linux-based operating system or environment. For the examples here, ANTsPy was installed and used in a virtual high-performance computing environment on a local workstation. The protocol has tended to work better using a virtual computing environment in the authors&#39; experience.</li>
	<li>Download and install segmentation and/or visualization software of choice. 
	NOTE: For the present study, ITK-SNAP was used for visualization (see Table of Materials).</li>
	<li>Download and save the reg.py script (Supplementary File 1).</li>
</ol>
2. Image pre-processing
<ol>
	<li>Click to open images and masks in the desired image visualization software to verify image and mask orientation matches for all CT, 1H, and 129Xe files. Depending on the segmentation method and/or software used, the orientation of some images or masks may need to be adjusted. As needed, we recommend adjusting 1H and 129Xe images and mask orientation to match that of the native CT image.</li>
	<li>Save the image DICOMs and single-label masks (adjusted as in step 2.1 as needed) as Neuroimaging Informatics Technology Initiative files (NIfTI, *.nii; six files total) using the preferred software tool, in the same folder as reg.py that is accessible to the location where ANTsPy is installed and will be run. Follow the naming conventions as mentioned below.
	<ol>
		<li>1H MRI: Proton.nii; 1H MRI mask: Proton_mask.nii. 
		NOTE: Use the 1H image and mask after registration to 129Xe.</li>
		<li>129Xe MRI: Ventilation.nii; 129Xe MRI mask: Ventilation_mask.nii</li>
		<li>CT: CT.nii; CT mask: CT_mask.nii. 
		NOTE: The file names are hard-coded into the registration script and, therefore, must follow the mentioned format, or be revised in the script to match the desired naming convention. These steps can be completed together using any of the recommended software tools listed in step 1.2. With respect to those software tools, some will write the required header information automatically when saving .nii files, whereas others require additional steps to copy and write the header information.</li>
	</ol>
	</li>
</ol>
3. CT-XeMRI registration
<ol>
	<li>Open the reg.py file in the desired Python computing environment setup in step 1.1. 
	NOTE: Script reg.py is based on the built-in ANTs registration tools; additional documentation is available55.</li>
	<li>If using a virtual environment, set the number of central processing units (CPU), number threads, and RAM as desired or available in the computing environment. A virtual computing environment with 16 CPU, 1 thread per CPU, and 186 GB of available RAM was used for the examples herein.</li>
	<li>Set desired transformation and interpolation. The SyNAggro transformation with linear interpolation for images and generic label interpolation for single-label masks, which are default in the provided reg.py script, were&#160;used here. 
	NOTE: SyNAggro is a symmetric normalization transformation, which includes affine + deformable transformation plus more aggressive registration using fine-scale matching and more deformation (compared with plain SyN). Alternative transformation and interpolation algorithms are listed in the ANTs registration documentation link in step 3.155.</li>
	<li>Set the fixed and the moving image. Here, the&#160;CT (single-label mask) was set as the fixed image, and the&#160;1H MRI (single-label mask) was set as the moving image.</li>
	<li>Run reg.py in the Python computing environment. Full registration may take 5-10 min (using our parameters) or longer, depending on computing resources used or available. When complete, warped files will be automatically saved in the same directory as the original image files with the file names as follows: Proton_warped.nii.gz; Ventilation_warped.nii.gz; Ventilation_label_warped.nii.gz. 
	NOTE: NIfTI *.nii.gz files are just zipped versions of *.nii files and can be unzipped or opened as desired. Script reg.py can be modified as desired, for example, using different transformation or interpolation methods or mapping to or creating file directories.</li>
</ol>
4. Evaluation of registration results
<ol>
	<li>Open the CT.nii image as the base image in the desired visualization software.</li>
	<li>Open Ventilation_warped.nii.gz or Ventilation_label_warped.nii.gz as another image and overlay on the CT image with the desired color map.</li>
	<li>Review the overlap of the 129Xe image or mask with the CT image in all image planes (coronal, axial, sagittal), evaluating the visual alignment of landmarks such as the carina and lung boundaries (where available in the 129Xe image).</li>
	<li>Check the results. If satisfied with the results, registration is complete. 
	NOTE: The registered 129Xe image/mask can be multiplied by the CT mask to remove the trachea and main airways (if not removed prior to MRI segmentation) and remove any signal that falls outside of the CT lung boundaries after registration. Further quantification for regional structure-function measurements can be performed as desired.</li>
	<li>If not satisfied with the results, evaluate and optimize alternative types of transformation and associated parameters as needed.</li>
</ol>

RLE receives personal consulting fees from VIDA Diagnostics Inc. outside the submitted work. JAL has received an institutional grant from GE Healthcare and honoraria for lectures from Philips and GE Healthcare outside the submitted work.

CT and 129Xe MRI provide complementary information to evaluate regional lung structure and function that is best facilitated using image registration. Multi-modal image registration can be non-trivial to implement, and so the protocol provided here is intended to provide the tools for readers to register 129Xe MRI to CT. The provided protocol uses ANTsPy for easier implementation for users with a broad range of image processing experience using Python rather than C++, as in conventional ANTs. Overal...

Hyperpolarized gas magnetic resonance imaging (MRI) first emerged as a novel functional pulmonary imaging modality to evaluate pulmonary ventilation distribution nearly three decades ago1. Since then, research studies using hyperpolarized gas MRI have revealed numerous insights into the nature of lung function in patients with chronic lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis2,3,4,5,6. Both hyperpolarized 3He and 129Xe gas have been used historically; however, 129Xe is now the primary inhaled agent because of the limited availability of 3He gas. 129Xe also freely diffuses across the alveolar membrane and is absorbed by red blood cells in the pulmonary capillaries; in this so-called &#39;dissolved phase,&#39; 129Xe resonates at unique frequencies that allow for measurement of regional gas exchange in a single breath-hold scan4,7,8. For quantification, volume-matched anatomical 1H MR images are typically contemporaneously acquired for co-registration with 129Xe to delineate boundaries of the thoracic cavity. Conventional 1H MRI, though, does not provide further lung structural information. The impetus for clinical translation of hyperpolarized 129Xe MRI grew in recent years with UK NHS approval in 2015 and US FDA approval in late 20225,9, yet advanced structural characterization is still mostly missing from the pulmonary MRI arsenal.
Chest computed tomography (CT) remains the mainstay of clinical imaging assessment of the lungs, providing three-dimensional high-resolution images of lung structure using conventional imaging protocols. Quantitative approaches have enabled rapid and repeatable measurement of parenchymal integrity, such as emphysema and interstitial lung abnormalities, large airway morphology and pulmonary vasculature, and regional anatomic characterization by identification and segmentation of lung lobes10,11. In the research space, quantitative CT has been widely used to better understand structural alterations and their relationships with patient outcomes in asthma and COPD in large observational studies such as the Severe Asthma Research Program (SARP)12, Genetic Epidemiology of COPD (COPDGene)13, Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS)14, Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE)15, and Canadian Cohort of Obstructive Lung Disease (CanCOLD)16. Alternative CT methods such as expiratory imaging17,18 or computational models19 may derive functional information, but these methods are indirect, and conventional CT does not otherwise provide much for functional characterization of the lungs.
Taken together, CT and 129Xe MRI provide complementary lung structure-function information that can be exploited for regional analysis using image registration. Lung lobes identified on CT have allowed for lobar characterization of MRI ventilation patterns in asthma20,21,22, COPD23,24, bronchiectasis25, and lung cancer26,27. MRI ventilation abnormalities in asthma have also been directly spatially matched to abnormally remodeled large airways28,29,30,31 and air trapping indicative of small airways dysfunction20,32 measured on CT, and to probe regional treatment responses following whole-lung bronchial thermoplasty33. In COPD, MRI ventilation abnormalities have been linked to small airway dysfunction in milder diseases and emphysema in more severe diseases34,35,36. Beyond ventilation imaging in obstructive lung disease, heterogeneous spatial relationships between CT interstitial lung abnormalities and 129Xe MRI gas exchange patterns have also been demonstrated in idiopathic pulmonary fibrosis37. Such studies have provided a deeper understanding of regional lung structure-function in a range of lung diseases that can be used to inform future image-guided interventions.
Direct registration of anatomic CT and functional hyperpolarized gas MRI is challenging,&#160;however, due to fundamentally different imaging contrast between the two methods, the absence of hyperpolarized gas signal in regions of ventilation abnormalities, and potentially different lung volumes. Figure 1 shows four examples of 129Xe and paired anatomical 1H MRI and CT in a healthy volunteer (Figure 1A) and three participants with chronic obstructive pulmonary disease (COPD; Figure 1B-D), highlighting heterogeneous 129Xe ventilation patterns and varying missing lung boundaries in the COPD cases. The key to overcoming these challenges has been using the anatomical 1H MRI acquired contemporaneously with hyperpolarized gas MRI as an intermediate step to register hyperpolarized gas MRI to CT indirectly34,38. Early work employed side-by-side visual comparison and manual segmentation of CT structures, such as lung lobes, onto MRI space20. Advancements in computational resources and open-source image processing tools have enabled three-dimensional registration of CT and hyperpolarized gas MRI, for example, using modality independent neighborhood descriptor (MIND)23,30,34,39,40,41 or Advanced Normalization Toolkit (ANTs) registration21,22,27,31,32,37,38,42,43, both of which were top performers in a pulmonary image registration challenge44. One novel method coupled the two registrations rather than treating them independently45, which has been implemented in a full pulmonary image analysis pipeline designed for phenotyping lung disease46. Overall, hyperpolarized gas MRI to CT registration accuracy was improved using the intermediate 1H step38 and using deformable approaches over affine-only approaches38,45.
The goal here is to build from the existing literature and provide a protocol for 129Xe MR to CT image registration using open-source platforms47,48,49. The protocol is implemented using ANTsPy, and, in line with previous work38, registers a single-label lung mask from 1H MRI to the single-label lung mask from CT; the resulting transformation is subsequently applied to the 129Xe image to map it to the CT image space. The protocol outlined is intended to be appropriate for research or clinical settings, where applicable, and&#160;hyperpolarized 129Xe MRI is available.
For context, image acquisition and analysis for the examples provided herein were performed as follows. Chest CT was acquired at full inspiration (total lung capacity, TLC) according to an established low-dose research protocol50 with parameters: 64 x 0.625 collimation, 120 peak kilovoltage, tube current 100 mA, 0.5 s revolution time, spiral pitch 1.0, 1.25 mm slice thickness, 0.80 mm slice spacing, standard reconstruction kernel, display field-of-view limited to the most lateral extents of the lungs (to maximize spatial resolution). CT segmentation and analysis were performed using commercial software (see Table of Materials).
129Xe and volume-matched 1H MRI were performed according to published guidelines9. For full MRI acquisition details and protocol, readers are directed to another article in this collection51. MRI segmentation and registration were performed using a semi-automated custom pipeline using k-means clustering for 129Xe segmentation, seeded-region growing for 1H segmentation, and landmark-based affine registration to map the 1H image to the 129Xe image52. Affine registration is typically sufficient for 1H-129Xe MR registration to account for most lung inflation or patient position differences between acquisitions; deformable registration is typically not necessary. The 1H-129Xe registration step can be eliminated with simultaneously acquired 129Xe and 1H MRI in the same breath-hold53,54.

<table><tbody><tr><td>3D Slicer</td><td>Brigham and Women&#039;s Hospital (BWH)</td><td>https://www.slicer.org/</td><td>Image analysis/visualization software; open source</td></tr><tr><td>ANTsPy</td><td>NA</td><td>https://github.com/ANTsX/ANTsPy</td><td>Coding infrastructure; open source</td></tr><tr><td>ITK-SNAP</td><td>NA</td><td>http://www.itksnap.org/pmwiki/pmwiki.php</td><td>Image analysis/visualization software; open source</td></tr><tr><td>MAGNETOM Vida 3.0T MRI</td><td>Siemens Healthineers</td><td>NA</td><td>Can be any 1.5 T or 3.0 T scanner with broadband imaging capability</td></tr><tr><td>MATLAB</td><td>Mathworks</td><td>https://www.mathworks.com/products/matlab.html</td><td>General software, good for image analysis; available by subscription</td></tr><tr><td>reg.py</td><td>NA</td><td>NA</td><td>Registration script (Supplementary File 1)</td></tr><tr><td>Revolution HD CT scanner</td><td>GE Healthcare</td><td>NA</td><td>Can be any CT scanner with &amp;ge;64 detectors</td></tr><tr><td>VIDA Insights</td><td>VIDA Diagnostics Inc.</td><td>NA</td><td>CT analysis software; can be any to generate masks</td></tr></tbody></table>

multi-modal pulmonary imaging: using complementary information from ct and hyperpolarized 129xe mri to evaluate lung structure-function

Hyperpolarized 129Xe gas MRI is an emerging technique to evaluate and measure regional lung function including pulmonary gas distribution and gas exchange. Chest computed tomography (CT) still remains the clinical gold standard for imaging of the lungs, though, in part due to the rapid CT protocols that acquire high-resolution images in seconds and the widespread availability of CT scanners. Quantitative approaches have enabled the extraction of structural lung parenchymal, airway and vascular measurements from chest CT that have been evaluated in many clinical research studies. Together, CT and 129Xe MRI provide complementary information that can be used to evaluate regional lung structure and function, resulting in new insights into lung health and disease. 129Xe MR-CT image registration can be performed to measure regional lung structure-function to better understand lung disease pathophysiology, and to perform image-guided pulmonary interventions. Here, a method for 129Xe MRI-CT registration is outlined to support implementation in research or clinical settings. Registration methods and applications that have been employed to date in the literature are also summarized, and suggestions are provided for future directions that may further overcome technical challenges related to 129Xe MR-CT image registration and facilitate broader implementation of regional lung structure-function evaluation.

This study prospectively acquired paired CT and 129Xe MRI in a research setting for regional lung structure-function characterization and image-guided bronchoscopy across a range of lung diseases and conditions. Figure 3 shows registered 129Xe MRI ventilation and CT in coronal and sagittal planes for four representative participants with a range of MRI ventilation patterns (for the same participants of Figure 1). The registered 129</su...

Read this Scientific Article Protocol about Multi-modal Pulmonary Imaging: Using Complementary Information from CT and Hyperpolarized 129Xe MRI to Evaluate Lung Structure-Function at JoVE.com

Multi-modal Pulmonary Imaging: Using Complementary Information from CT and Hyperpolarized 129Xe MRI to Evaluate Lung Structure-Function

CT and 129Xe MRI provide complementary lung structure-function information that can be exploited for regional analysis using image registration. Here, we provide a protocol that builds from the existing literature for 129Xe MR to CT image registration using open-source platforms.

Multi-modal Pulmonary Imaging: Using Complementary Information from CT and Hyperpolarized 129Xe MRI to Evaluate Lung Structure-Function

Hyperpolarized 129Xe gas MRI is an emerging technique to evaluate and measure regional lung function including pulmonary gas distribution and gas ...

multi-modal-pulmonary-imaging-using-complementary-information-from-ct

Research

JoVE Journal

Medicine

523 Views.  St. Paul’s Hospital. CT and 129Xe MRI provide complementary lung structure-function information that can be exploited for regional analysis using image registration. Here, we provide a protocol that builds from the existing literature for 129Xe MR to CT image registration using open-source platforms.

Video: Multi-modal Pulmonary Imaging: Using Complementary Information from CT and Hyperpolarized 129Xe MRI to Evaluate Lung Structure-Function

Bronchial Thermoplasty:  A Novel Therapeutic Approach to Severe Asthma

Bronchial thermoplasty is a non-drug procedure for severe persistent asthma that delivers thermal energy to the airway wall in a precisely controlled manner to reduce excessive airway smooth muscle. Reducing airway smooth muscle decreases the ability of the airways to constrict, thereby reducing the frequency of asthma attacks. Bronchial thermoplasty is delivered by the Alair System and is performed in three outpatient procedure visits, each scheduled approximately three weeks apart. The first procedure treats the airways of the right lower lobe, the second treats the airways of the left lower lobe and the third and final procedure treats the airways in both upper lobes. After all three procedures are performed the bronchial thermoplasty treatment is complete.
Bronchial thermoplasty is performed during bronchoscopy with the patient under moderate sedation. All accessible airways distal to the mainstem bronchi between 3 and 10 mm in diameter, with the exception of the right middle lobe, are treated under bronchoscopic visualization. Contiguous and non-overlapping activations of the device are used, moving from distal to proximal along the length of the airway, and systematically from airway to airway as described previously. Although conceptually straightforward, the actual execution of bronchial thermoplasty is quite intricate and procedural duration for the treatment of a single lobe is often substantially longer than encountered during routine bronchoscopy. As such, bronchial thermoplasty should be considered a complex interventional bronchoscopy and is intended for the experienced bronchoscopist. Optimal patient management is critical in any such complex and longer duration bronchoscopic procedure. This article discusses the importance of careful patient selection, patient preparation, patient management, procedure duration, postoperative care and follow-up to ensure that bronchial thermoplasty is performed safely.
Bronchial thermoplasty is expected to complement asthma maintenance medications by providing long-lasting asthma control and improving asthma-related quality of life of patients with severe asthma. In addition, bronchial thermoplasty has been demonstrated to reduce severe exacerbations (asthma attacks) emergency rooms visits for respiratory symptoms, and time lost from work, school and other daily activities due to asthma.

Bronchial thermoplasty is a non-drug procedure for severe persistent asthma that delivers thermal energy to the airway wall in a precisely controlled manner to reduce excessive airway smooth muscle. Reducing airway smooth muscle decreases the ability of the airways to constrict, thereby reducing the frequency of asthma attacks.

Bronchial thermoplasty is a non-drug procedure for severe persistent asthma that delivers thermal energy to the airway wall in a precisely controlled ...

Multi-modal Imaging of Angiogenesis in a Nude Rat Model of Breast Cancer Bone Metastasis Using Magnetic Resonance Imaging, Volumetric Computed Tomography and Ultrasound

Angiogenesis is an essential feature of cancer growth and metastasis formation. In bone metastasis, angiogenic factors are pivotal for tumor cell proliferation in the bone marrow cavity as well as for interaction of tumor and bone cells resulting in local bone destruction. Our aim was to develop a model of experimental bone metastasis that allows in vivo assessment of angiogenesis in skeletal lesions using non-invasive imaging techniques.
For this purpose, we injected 105 MDA-MB-231 human breast cancer cells into the superficial epigastric artery, which precludes the growth of metastases in body areas other than the respective hind leg1. Following 25-30 days after tumor cell inoculation, site-specific bone metastases develop, restricted to the distal femur, proximal tibia and proximal fibula1. Morphological and functional aspects of angiogenesis can be investigated longitudinally in bone metastases using magnetic resonance imaging (MRI), volumetric computed tomography (VCT) and ultrasound (US).
MRI displays morphologic information on the soft tissue part of bone metastases that is initially confined to the bone marrow cavity and subsequently exceeds cortical bone while progressing. Using dynamic contrast-enhanced MRI (DCE-MRI) functional data including regional blood volume, perfusion and vessel permeability can be obtained and quantified2-4. Bone destruction is captured in high resolution using morphological VCT imaging. Complementary to MRI findings, osteolytic lesions can be located adjacent to sites of intramedullary tumor growth. After contrast agent application, VCT angiography reveals the macrovessel architecture in bone metastases in high resolution, and DCE-VCT enables insight in the microcirculation of these lesions5,6. US is applicable to assess morphological and functional features from skeletal lesions due to local osteolysis of cortical bone. Using B-mode and Doppler techniques, structure and perfusion of the soft tissue metastases can be evaluated, respectively. DCE-US allows for real-time imaging of vascularization in bone metastases after injection of microbubbles7.
In conclusion, in a model of site-specific breast cancer bone metastases multi-modal imaging techniques including MRI, VCT and US offer complementary information on morphology and functional parameters of angiogenesis in these skeletal lesions.

In the pathogenesis of bone metastasis, angiogenesis is a crucial process and therefore represents a target for imaging and therapy. Here, we present a rat model of site-specific breast cancer bone metastasis and describe strategies to non-invasively image angiogenesis in vivo using magnetic resonance imaging, volumetric computed tomography and ultrasound.

Angiogenesis is an essential feature of cancer growth and metastasis formation. In bone metastasis, angiogenic factors are pivotal for tumor cell ...

Angiogenesis in the Ischemic Rat Lung

The adult lung is perfused by both the systemic bronchial artery and the entire venous return flowing through the pulmonary arteries. In most lung pathologies, it is the smaller systemic vasculature that responds to a need for enhanced lung perfusion and shows robust neovascularization. Pulmonary vascular ischemia induced by pulmonary artery obstruction has been shown to result in rapid systemic arterial angiogenesis in man as well as in several animal models. Although the histologic assessment of the time course of bronchial artery proliferation in rats was carefully described by Weibel 1, mechanisms responsible for this organized growth of new vessels are not clear. We provide surgical details of inducing left pulmonary artery ischemia in the rat that leads to bronchial neovascularization. Quantification of the extent of angiogenesis presents an additional challenge due to the presence of the two vascular beds within the lung. Methods to determine functional angiogenesis based on labeled microsphere injections are provided.

The lung is perfused by both the systemic bronchial artery and pulmonary arteries. In most lung pathologies, it is the smaller systemic vasculature that shows robust neovascularization. Cessation of pulmonary blood flow promotes brisk bronchial angiogenesis. We provide surgical details of inducing left pulmonary artery ischemia that promotes bronchial neovascularization.

The  adult lung is perfused by both the systemic bronchial artery and the entire  venous return flowing through the pulmonary arteries. In most lung ...

Obtaining High-Quality Hyperpolarized Xenon-129 Magnetic Resonance Images

Troubleshooting and Quality Assurance in Hyperpolarized Xenon Magnetic Resonance Imaging: Tools for High-Quality Image Acquisition

Hyperpolarized (HP) xenon magnetic resonance imaging (129Xe MRI) is a recently federal drug administration (FDA)-approved imaging modality that produces high-resolution images of an inhaled breath of xenon gas for investigation of lung function. However, implementing 129Xe MRI is uniquely challenging as it requires specialized hardware and equipment for hyperpolarization, procurement of xenon imaging coils and coil software, development and compilation of multinuclear MR imaging sequences, and reconstruction/analysis of acquired data. Without proper expertise, these tasks can be daunting, and failure to acquire high-quality images can be&#160;frustrating, and expensive. Here, we present some quality control (QC) protocols, troubleshooting practices, and helpful tools for129Xe MRI sites, which may aid in the acquisition of optimized, high-quality data and accurate results. The discussion will begin with an overview of the process for implementing HP 129Xe MRI, including requirements for a hyperpolarizer lab, the combination of 129Xe MRI coil hardware/software, data acquisition and sequence considerations, data structures, k-space and image properties, and measured signal and noise characteristics. Within each of these necessary steps lies opportunities for errors, challenges, and unfavorable occurrences leading to poor image quality or failed imaging, and this presentation aims to address some of the more commonly encountered issues. In particular, identification and characterization of anomalous noise patterns in acquired data are necessary to avoid image artifacts and low-quality images; examples will be given, and mitigation strategies will be discussed. We aim to make the 129Xe MRI implementation process easier for new sites while providing some guidelines and strategies for real-time troubleshooting.

Author Spotlight: Using Hyperpolarized Xenon-129 MRI to Study Lung Diseases 

Here, we present a protocol for obtaining high-quality hyperpolarized xenon-129 magnetic resonance images, covering hardware, software, data acquisition, sequence selection, data management, k-space utilization, and noise analysis.

Hyperpolarized (HP) xenon magnetic resonance imaging (129Xe MRI) is a recently federal drug administration (FDA)-approved imaging modality that produces ...

Bioengineering

Hyperpolarized 129Xe Lung MRI and Spectroscopy in Mechanically Ventilated Mice

Hyperpolarized (HP) xenon-129 (129Xe) is an inhaled magnetic resonance imaging (MRI) contrast agent with unique spectral and physical properties that can be exploited to quantify pulmonary physiology, including ventilation, restricted diffusion (alveolar-airspace size), and gas exchange. In humans, it has been used to evaluate disease severity and progression in a variety of pulmonary disorders and is approved for clinical use in the United States and United Kingdom. Beyond its clinical applications, the ability of 129Xe MRI to noninvasively assess pulmonary pathophysiology and provide spatially resolved information is valuable for preclinical research. Among animal models, mice are the most widely used due to the accessibility of genetically modified disease models. Here, 129Xe MRI is promising as a minimally invasive, radiation-free, and sensitive technique to longitudinally monitor lung disease progression and therapy response (e.g., in drug discovery). This technique can extend to preclinical applications by incorporating an MRI-triggered, free-breathing apparatus or mechanical ventilator to deliver gas. Here, we describe the steps and provide checklists to ensure robust data collection and analysis, including creating a thermally polarized xenon gas phantom for quality control, optimizing polarization, animal handling (sedation, intubation, ventilation, and care for mice), and protocols for ventilation, restricted diffusion, and gas exchange data. While preclinical 129Xe MRI can be applied in various animal models (e.g., rats, pigs, sheep), this protocol focuses on mice due to the challenges posed by their small anatomy, which are balanced by their affordability and the availability of many disease models.

Hyperpolarized xenon MRI can quantify regional lung microstructure (air-space dimensions) and physiology (ventilation and gas exchange) in translational research and clinical care. Although challenging, it can provide comparable pulmonary insights in preclinical studies. This protocol describes the infrastructure and procedures needed to perform routine xenon lung MRI in mice.

Hyperpolarized (HP) xenon-129 (129Xe) is an inhaled magnetic resonance imaging (MRI) contrast agent with unique spectral and physical properties that can ...

Assessing Lung Function with Hyperpolarized Xenon-129 MRI

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

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 ...

A Standardized Workflow for Hyperpolarized 129Xe MRI to Study Pulmonary Function

Acquiring Hyperpolarized 129Xe Magnetic Resonance Images of Lung Ventilation

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&#160;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.

Author Spotlight: Standardization and Best Practices for Advancing Lung Imaging Using 129Xe MRI

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 ...

Dynamic Lung Ventilation Assessment with 3D Phase Resolved Functional Lung MRI

Three-Dimensional Phase Resolved Functional Lung Magnetic Resonance Imaging

Pulmonary magnetic resonance imaging (MRI) offers a variety of radiation-free techniques tailored to assess regional lung ventilation or its surrogates. These techniques encompass direct measurements, exemplified by hyperpolarized gas MRI and fluorinated gas MRI, as well as indirect measurements facilitated by oxygen-enhanced MRI and proton-based Fourier decomposition (FD) MRI. In recent times, there has been substantial progress in the field of FD MRI, which involved improving spatial/temporal resolution, refining sequence design and postprocessing, and developing a comprehensive whole-lung approach.
The two-dimensional (2D) phase-resolved functional lung (PREFUL) MRI stands out as an FD-based approach developed for the comprehensive assessment of regional ventilation and perfusion dynamics, all within a single MR acquisition. Recently, a new advancement has been made with the development of 3D PREFUL to assess dynamic ventilation of the entire lung using 8 min exam with a self-gated sequence.
The 3D PREFUL acquisition involves employing a stack-of-stars spoiled-gradient-echo sequence with a golden angle increment. Following the compressed sensing image reconstruction of approximately 40 breathing phases, all the reconstructed respiratory-resolved images undergo registration onto a fixed breathing phase. Subsequently, the ventilation parameters are extracted from the registered images.
In a study cohort comprising healthy volunteers and patients with chronic obstructive pulmonary disease, the 3D PREFUL ventilation parameters demonstrated strong correlations with measurements obtained from pulmonary function tests. Additionally, the interscan repeatability of the 3D PREFUL technique was deemed to be acceptable, indicating its reliability for repeated assessments of the same individuals.
In summary, 3D PREFUL ventilation MRI provides a whole lung coverage and captures ventilation dynamics with enhanced spatial resolution compared to 2D PREFUL. 3D PREFUL technique offers a cost-effective alternative to hyperpolarized 129Xe MRI, making it an attractive option for patient-friendly evaluation of pulmonary ventilation.

Three-dimensional (3D) phase-resolved functional lung (PREFUL) is a functional magnetic resonance imaging (MRI) technique that allows for quantification of regional ventilation of the whole human lung volume, using tidal breathing and contrast-agent free acquisition for 8 min. Here, we present an MR protocol to collect and analyze 3D PREFUL imaging data.

Pulmonary magnetic resonance imaging (MRI) offers a variety of radiation-free techniques tailored to assess regional lung ventilation or its surrogates. ...

Advanced Lung Imaging for Disease Detection and Monitoring

Phase-Resolved Functional Lung MRI for Pulmonary Ventilation and Perfusion (V/Q) Assessment

Fourier decomposition is a contrast agent-free 1H MRI method for lung perfusion (Q) and ventilation (V) assessment. After image registration, the time series of each voxel is analyzed with regard to the cardiac and breathing frequency components.
Using a standard 2D spoiled gradient-echo sequence with a temporal resolution of ~300 ms, an image-sorting algorithm was developed to produce phase-resolved functional lung imaging (PREFUL) with an increased temporal resolution. Thus, it is feasible to evaluate regional flow volume loops (FVL) during tidal volume breathing and depict the propagation of the pulse wave during the cardiac cycle. This method can be applied at 1.5T or 3T with standard MR hardware without the necessity for sequence programming, as the described protocol can be implemented with the default SPGRE sequence on most systems.
PREFUL ventilation MRI has been validated using 129Xe and 19F gas imaging with good regional agreement. Perfusion-weighted PREFUL MRI has been validated using SPECT as well as dynamic contrast enhanced (DCE) MRI. PREFUL has been tested in a dual center dual vendor setting and is currently applied in several ongoing multicenter trials. Furthermore, it is feasible across a range of field strengths (0.55T-3T) and different age groups, including newborns.
Quantitative V/Q PREFUL MRI has been used in patients with cystic fibrosis, chronic obstructive pulmonary disease, chronic thromboembolic pulmonary hypertension, and corona virus disease-2019 to quantify disease and monitor treatment change after therapy. Furthermore, PREFUL V/Q imaging has been shown to predict transplant loss due to chronic lung allograft dysfunction in patients after lung transplantation. In summary, PREFUL MRI is a validated technique for quantitative ventilation and pulmonary pulse wave/perfusion imaging for regional pulmonary disease detection, quantification, and treatment monitoring with potential added value to the current clinical routine.

Author Spotlight: Enhancing Diagnostic Strategies and Biomarker Development for Comprehensive Lung Function Analysis

Here, we describe the implementation of phase-resolved functional lung MRI as a contrast-agent-free proton MR technique for the assessment of pulmonary ventilation and perfusion dynamics. Validated and applicable across different field strengths and age groups, it could enhance clinical decision-making in the future by aiding in disease quantification and therapy monitoring.

Fourier decomposition is a contrast agent-free 1H MRI method for lung perfusion (Q) and ventilation (V) assessment. After image registration, the time ...

Protocol for High-Resolution Lung Imaging Using 3T UTE MRI with Self-Gating

Pulmonary Structural MRI using Free-Breathing, Self-Gated Ultra-short Echo Time Imaging

High quality MRI of the lungs is challenged by low tissue density, fast MRI signal relaxation, and respiratory and cardiac motion. For these reasons, structural imaging of the lungs is performed almost exclusively using Computed Tomography (CT). However, CT imaging delivers ionizing radiation, and thus is less well suited for certain vulnerable populations (e.g., pediatrics) or for research applications. As an alternative, MRI using ultra-short echo times (UTE) is attracting interest. This technique can be performed during free-breathing over the course of a ~5-10 min scan. Respiratory motion information is encoded alongside images; this information can be used to "self-gate" images. Self-gating thus removes the requirement of advanced MRI pulse sequence programming or the use of respiratory bellows, which simplifies image acquisition. In this protocol, simple, robust, and computationally efficient acquisition and reconstruction methods for acquiring high quality UTE MRI of the lungs are presented. This protocol was developed for use on a 3T MRI scanner, but the same principles can be implemented at lower magnetic field strength. The protocol includes recommended parameter settings for 3D radial UTE image acquisition as well as directions for self-gated image reconstruction to generate images at distinct respiratory phases. Through the implementation of this protocol, users can generate high-resolution UTE images of the lungs with minimal to minimal-to-no motion artifacts. These images can be used to evaluate pulmonary structure, which can be implemented for research use in a variety of pulmonary conditions.

Author Spotlight: Optimized Lung MRI Protocol with Computationally Efficient Reconstruction Methods

A protocol is described for generating high-resolution structural images of the lungs using ultra-short-echo time (UTE) Magnetic Resonance Imaging (MRI). This protocol allows for images to be acquired using a simple MRI pulse sequence during free-breathing.

High quality MRI of the lungs is challenged by low tissue density, fast MRI signal relaxation, and respiratory and cardiac motion. For these reasons, ...

Multi-modal Pulmonary Imaging: Using Complementary Information from CT and Hyperpolarized ¹²⁹Xe MRI to Evaluate Lung Structure-Function

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