Hyperpolarized Noble Gases Research Articles

SQUID current sensors with an integrated thermally actuated input current limiter

The development of superconducting quantum interference device (SQUID) current sensors with a thermally actuated input current limiter (TCL) integrated into the input circuit of the sensor is presented. The TCL is based on an unshunted Josephson Junction (JJ) series array, around which meanders a galvanically isolated, but tightly, thermally coupled, resistive heater element. By applying a current to the heater, the JJ critical currents can be reduced or completely suppressed, while the other on-chip SQUID circuit elements remain unaffected. The functional parameters of the TCL are determined by direct transport measurements and by static and dynamic flux coupling tests via the input circuit. In liquid helium, a heater power, which reliably suppresses the critical current of the JJ array to zero, of ∼1.5 mW was needed, with the TCL normal state resistance being at 500 Ω. In this configuration, typical TCL switching times of approximately 20 µs were observed in the direct transport measurements. The TCL can be used to temporarily or even permanently disable malfunctioning channels in multichannel SQUID magnetometer systems, when feedback into their otherwise superconducting input circuits is not possible. In doing so, significant signal distortions in neighbouring channels from screening currents in these input circuits are avoided. Furthermore, by completely suppressing and restoring the TCL critical current, dc offset currents in the superconducting input circuits can be prevented. This is relevant, for instance, in SQUID-based spin precession experiments on hyperpolarized noble gases, in which even dc currents of a few µA in the input circuit can lead to significant magnetic field distortions in the adjacent sample region contributing to the transverse spin-spin relaxation rate .

MR imaging of the airways.

The need for airway imaging is defined by the limited sensitivity of common clinical tests like spirometry, lung diffusion (DLCO) and blood gas analysis to early changes of peripheral airways and to inhomogeneous regional distribution of lung function deficits. Therefore, X-ray and computed tomography (CT) are frequently used to complement the standard tests.As an alternative, magnetic resonance imaging (MRI) offers radiation-free lung imaging, but at lower spatial resolution. Non-contrast enhanced MRI shows healthy airways down to the first subsegmental level/4th order (CT: eighth). Bronchiectasis can be identified by wall thickening and fluid accumulation. Smaller airways become visible, when altered by peribronchiolar inflammation or mucus retention (tree-in-bud sign).The strength of MRI is functional imaging. Dynamic, time-resolved MRI directly visualizes expiratory airway collapse down to the lobar level (CT: segmental level). Obstruction of even smaller airways becomes visible as air trapping on the expiratory scans. MRI with hyperpolarized noble gases (3He, 129Xe) directly shows the large airways and peripheral lung ventilation. Dynamic contrast-enhanced MRI (DCE MRI) indirectly shows airway dysfunction as perfusion deficits resulting from hypoxic vasoconstriction of the dependent lung volumes. Further promising scientific approaches such as non-contrast enhanced, ventilation-/perfusion-weighted MRI from periodic signal changes of respiration and blood flow are in development.In summary, MRI of the lungs and airways excels with its unique combination of morphologic and functional imaging capacities for research (e.g., in chronic obstructive lung disease or asthma) as well as for clinical imaging (e.g., in cystic fibrosis).

Hyperpolarized 129Xe MRI at low field: Current status and future directions

Magnetic Resonance Imaging (MRI) is dictated by the magnetization of the sample, and is thus a low-sensitivity imaging method. Inhalation of hyperpolarized (HP) noble gases, such as helium–3 and xenon-129, is a non-invasive, radiation-risk free imaging technique permitting high resolution imaging of the lungs and pulmonary functions, such as the lung microstructure, diffusion, perfusion, gas exchange, and dynamic ventilation. Instead of increasing the magnetic field strength, the higher spin polarization achievable from this method results in significantly higher net MR signal independent of tissue/water concentration. Moreover, the significantly longer apparent transverse relaxation time T2* of these HP gases at low magnetic field strengths results in fewer necessary radiofrequency (RF) pulses, permitting larger flip angles; this allows for high-sensitivity imaging of in vivo animal and human lungs at conventionally low (<0.5 T) field strengths and suggests that the low field regime is optimal for pulmonary MRI using hyperpolarized gases.In this review, theory on the common spin-exchange optical-pumping method of hyperpolarization and the field dependence of the MR signal of HP gases are presented, in the context of human lung imaging. The current state-of-the-art is explored, with emphasis on both MRI hardware (low field scanners, RF coils, and polarizers) and image acquisition techniques (pulse sequences) advancements. Common challenges surrounding imaging of HP gases and possible solutions are discussed, and the future of low field hyperpolarized gas MRI is posed as being a clinically-accessible and versatile imaging method, circumventing the siting restrictions of conventional high field scanners and bringing point-of-care pulmonary imaging to global facilities.

Mapping Alveolar Oxygen Partial Pressure in COPD Using Hyperpolarized Helium-3: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study.

Chronic obstructive pulmonary disease (COPD) and emphysema are characterized by functional and structural damage which increases the spaces for gaseous diffusion and impairs oxygen exchange. Here we explore the potential for hyperpolarized (HP) 3He MRI to characterize lung structure and function in a large-scale population-based study. Participants (n = 54) from the Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study, a nested case-control study of COPD among participants with 10+ packyears underwent HP 3He MRI measuring pAO2, apparent diffusion coefficient (ADC), and ventilation. HP MRI measures were compared to full-lung CT and pulmonary function testing. High ADC values (>0.4 cm2/s) correlated with emphysema and heterogeneity in pAO2 measurements. Strong correlations were found between the heterogeneity of global pAO2 as summarized by its standard deviation (SD) (p < 0.0002) and non-physiologic pAO2 values (p < 0.0001) with percent emphysema on CT. A regional study revealed a strong association between pAO2 SD and visual emphysema severity (p < 0.003) and an association with the paraseptal emphysema subtype (p < 0.04) after adjustment for demographics and smoking status. HP noble gas pAO2 heterogeneity and the fraction of non-physiological pAO2 results increase in mild to moderate COPD. Measurements of pAO2 are sensitive to regional emphysematous damage detected by CT and may be used to probe pulmonary emphysema subtypes. HP noble gas lung MRI provides non-invasive information about COPD severity and lung function without ionizing radiation.

Free-Breathing Phase-Resolved Oxygen-Enhanced Pulmonary MRI Based on 3D Stack-of-Stars UTE Sequence.

Compared with hyperpolarized noble gas MRI, oxygen-enhanced lung imaging is a cost-effective approach to investigate lung function. In this study, we investigated the feasibility of free-breathing phase-resolved oxygen-enhanced pulmonary MRI based on a 3D stack-of-stars ultra-short echo time (UTE) sequence. We conducted both computer simulation and in vivo experiments and calculated percent signal enhancement maps of four different respiratory phases on four healthy volunteers from the end of expiration to the end of inspiration. The phantom experiment was implemented to verify simulation results. The respiratory phase was segmented based on the extracted respiratory signal and sliding window reconstruction, providing phase-resolved pulmonary MRI. Demons registration algorithm was applied to compensate for respiratory motion. The mean percent signal enhancement of the average phase increases from anterior to posterior region, matching previous literature. More details of pulmonary tissues were observed on post-oxygen inhalation images through the phase-resolved technique. Phase-resolved UTE pulmonary MRI shows the potential as a valuable method for oxygen-enhanced MRI that enables the investigation of lung ventilation on middle states of the respiratory cycle.

Pulmonary functional MRI: Detecting the structure-function pathologies that drive asthma symptoms and quality of life.

Pulmonary functional MRI (PfMRI) using inhaled hyperpolarized, radiation-free gases (such as 3 He and 129 Xe) provides a way to directly visualize inhaled gas distribution and ventilation defects (or ventilation heterogeneity) in real time with high spatial (~mm3 ) resolution. Both gases enable quantitative measurement of terminal airway morphology, while 129 Xe uniquely enables imaging the transfer of inhaled gas across the alveolar-capillary tissue barrier to the red blood cells. In patients with asthma, PfMRI abnormalities have been shown to reflect airway smooth muscle dysfunction, airway inflammation and remodelling, luminal occlusions and airway pruning. The method is rapid (8-15 s), cost-effective (~$300/scan) and very well tolerated in patients, even in those who are very young or very ill, because unlike computed tomography (CT), positron emission tomography and single-photon emission CT, there is no ionizing radiation and the examination takes only a few seconds. However, PfMRI is not without limitations, which include the requirement of complex image analysis, specialized equipment and additional training and quality control. We provide an overview of the three main applications of hyperpolarized noble gas MRI in asthma research including: (1) inhaled gas distribution or ventilation imaging, (2) alveolar microstructure and finally (3) gas transfer into the alveolar-capillary tissue space and from the tissue barrier into red blood cells in the pulmonary microvasculature. We highlight the evidence that supports a deeper understanding of the mechanisms of asthma worsening over time and the pathologies responsible for symptoms and disease control. We conclude with a summary of approaches that have the potential for integration into clinical workflows and that may be used to guide personalized treatment planning.

Novel Thoracic MRI Approaches for the Assessment of Pulmonary Physiology and Inflammation.

Excessive pulmonary inflammation can lead to damage of lung tissue, airway remodelling and established structural lung disease. Novel therapeutics that specifically target inflammatory pathways are becoming increasingly common in clinical practice, but there is yet to be a similar stepwise change in pulmonary diagnostic tools. A variety of thoracic magnetic resonance imaging (MRI) tools are currently in development, which may soon fulfil this emerging clinical need for highly sensitive assessments of lung structure and function. Given conventional MRI techniques are poorly suited to lung imaging, alternate strategies have been developed, including the use of inhaled contrast agents, intravenous contrast and specialized lung MR sequences. In this chapter, we discuss technical challenges of performing MRI of the lungs and how they may be overcome. Key thoracic MRI modalities are reviewed, namely, hyperpolarized noble gas MRI, oxygen-enhanced MRI (OE-MRI), ultrashort echo time (UTE) MRI and dynamic contrast-enhanced (DCE) MRI. Finally, we consider potential clinical applications of these techniques including phenotyping of lung disease, evaluation of novel pulmonary therapeutic efficacy and longitudinal assessment of specific patient groups.

A Novel System for Patient Ventilation and Dosing of Hyperpolarized 3He for Magnetic Resonance Imaging of Human Lungs

A versatile ventilator for controlling a patient’s breath cycle and dosing 3He gas has been designed and constructed. It is compatible with a medical magnetic resonance imaging scanner and can be incorporated into routine human lungs imaging procedure that employs hyperpolarized noble gas as a contrast agent. The system adapts to the patient’s lung volume and their breath cycle rhythm, providing maximum achievable comfort during the medical examination. Good quality magnetic resonance lung images of healthy volunteers were obtained. The system has the capability of recycling the exhaled gas to recover the expensive 3He isotope, and can be also adapted to human lung imaging with hyperpolarized 129Xe.

Nanoparticle-Based Contrast Agents for 129Xe HyperCEST NMR and MRI Applications.

Spin hyperpolarization techniques have enabled important advancements in preclinical and clinical MRI applications to overcome the intrinsic low sensitivity of nuclear magnetic resonance. Functionalized xenon biosensors represent one of these approaches. They combine two amplification strategies, namely, spin exchange optical pumping (SEOP) and chemical exchange saturation transfer (CEST). The latter one requires host structures that reversibly bind the hyperpolarized noble gas. Different nanoparticle approaches have been implemented and have enabled molecular MRI with 129Xe at unprecedented sensitivity. This review gives an overview of the Xe biosensor concept, particularly how different nanoparticles address various critical aspects of gas binding and exchange, spectral dispersion for multiplexing, and targeted reporter delivery. As this concept is emerging into preclinical applications, comprehensive sensor design will be indispensable in translating the outstanding sensitivity potential into biomedical molecular imaging applications.

$k$ -Space-Based Enhancement of Pulmonary Hyperpolarized 129Xe Ventilation Images

Hyperpolarized (HP) noble gas (e.g., 3He/129Xe) MR images are susceptible to noise and artifacts due to the rapid attenuation of nonrenewable HP magnetization along with the scan time. However, a little attention is paid to this issue through postprocessing techniques. Here, a $k$ -space-based analysis method is proposed to improve the overall signal-to-noise ratio (SNR) and lessen the blurring of pulmonary HP 129Xe ventilation images. This method performs $k$ -space weighting using low-frequency boost and a high-frequency modulation which offsets the magnetization loss per excitation, and then integrates two outputs in image domain through a convex combination model. Furthermore, a nonreference quality metric, called second-derivative measure of improvement by entropy (SMIE), is introduced to assess the image quality of HP gas MRI. The simulation results demonstrate that the enhanced images are statistically significantly different to the original ones regarding the SNR, peak SNR, structural similarity, and SMIE (each $P$ -value is less than 0.0001). In vivo results indicate that the proposed method significantly upsets the SNR and SMIE in human pulmonary HP 129Xe ventilation images (all $P$ -values are less than 0.05), while maintaining the appearance of ventilation defects or fine structures. In this case, the proposed scheme has potential for improving the understandability and/or differentiation of regions of interest in the lung.

Advanced pulmonary MRI to quantify alveolar and acinar duct abnormalities: Current status and future clinical applications.

There are serious clinical gaps in our understanding of chronic lung disease that require novel, sensitive, and noninvasive in vivo measurements of the lung parenchyma to measure disease pathogenesis and progressive changes over time as well as response to treatment. Until recently, our knowledge and appreciation of the tissue changes that accompany lung disease has depended on ex vivo biopsy and concomitant histological and stereological measurements. These measurements have revealed the underlying pathologies that drive lung disease and have provided important observations about airway occlusion, obliteration of the terminal bronchioles and airspace enlargement, or fibrosis and their roles in disease initiation and progression. ex vivo tissue stereology and histology are the established gold standards and, more recently, micro-computed tomography (CT) measurements of ex vivo tissue samples has also been employed to reveal new mechanistic findings about the progression of obstructive lung disease in patients. While these approaches have provided important understandings using ex vivo analysis of excised samples, recently developed hyperpolarized noble gas MRI methods provide an opportunity to noninvasively measure acinar duct and terminal airway dimensions and geometry in vivo, and, without radiation burden. Therefore, in this review we summarize emerging pulmonary MRI morphometry methods that provide noninvasive in vivo measurements of the lung in patients with bronchopulmonary dysplasia and chronic obstructive pulmonary disease, among others. We discuss new findings, future research directions, as well as clinical opportunities to address current gaps in patient care and for testing of new therapies. Level of Evidence: 5 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2019;50:28-40.

Ultra-Sensitive Atomic Magnetometers for Studying Spin Precessions of Hyperpolarized Noble Gases Based on System Identification

We reported an efficient approach to analyze spin precessions of different hyperpolarized noble gases with atomic magnetometers based on system identification. Spin evolution of the magnetometer can be robustly approximated as the second order system by referring to the Bloch equation under the negligible self-interaction and its transfer function model can be deduced. We measured the dynamic responses of different atomic pairs, such as cesium magnetometer with a partner of xenon-129, potassium magnetometer with a partner of helium-3, and hybrid of cesium and rubidium magnetometer with a partner of neon-21. By referring to the experimental results, corresponding systematic parameters for the transfer function models have been identified based on least-square method, whose outputs were consistent with experimental results. Based on the models, the system stabilities and their variations with different gains have been analyzed with control theory, both of which are described here. Applying control theory to analyze dynamic responses of spin ensembles plays an important role for the future applications.

Heterogeneous Parahydrogen Pairwise Addition to Cyclopropane.

Hyperpolarized gases revolutionize functional pulmonary imaging. Hyperpolarized propane is a promising emerging contrast agent for pulmonary MRI. Unlike hyperpolarized noble gases, proton-hyperpolarized propane gas can be imaged using conventional MRI scanners with proton imaging capability. Moreover, it is non-toxic odorless anesthetic. Furthermore, propane hyperpolarization can be accomplished by pairwise addition of parahydrogen to propylene. Here, we demonstrate the feasibility of propane hyperpolarization via hydrogenation of cyclopropane with parahydrogen. 1 H propane polarization up to 2.4 % is demonstrated here using 82 % parahydrogen enrichment and heterogeneous Rh/TiO2 hydrogenation catalyst. This level of polarization is several times greater than that obtained with propylene as a precursor under the same conditions despite the fact that direct pairwise addition of parahydrogen to cyclopropane may also lead to formation of propane with NMR-invisible hyperpolarization due to magnetic equivalence of nascent parahydrogen protons in two CH3 groups. NMR-visible hyperpolarized propane demonstrated here can be formed only via a reaction pathway involving cleavage of at least one C-H bond in the reactant molecule. The resulting NMR signal enhancement of hyperpolarized propane was sufficient for 2D gradient echo MRI of ∼5.5 mL phantom with 1×1 mm2 spatial resolution and 64×64 imaging matrix despite relatively low chemical conversion of cyclopropane substrate.

Production and Applications of Spin-Polarized Isotopes of Noble Gases

The development of a new direction of research on the production and application of spin-polarized isotopes of noble gases, 3He and 129Xe, is overviewed. Methods of laser hyperpolarization, problems of enhancing the efficiency of laser energy input, and methods of storing hyperpolarized (HP) isotopes are described. Examples and advantages of using HP isotopes in fundamental physics, engineering, medicine, and biology, as well as the progress in the creation of biosensors on hyperpolarized noble gases, are discussed. It has been shown that the study of protein structures and host–guest molecular complexes can prove useful in searching for means of the targeted delivery of radioactive isotopes (radiopharmaceuticals) in nuclear medicine. It is concluded that the progress in modern technologies for producing miniature electronic devices is suggestive of an imminent emergence of small-size scanners for human brain research. At the same time, a high sensitivity of the method is expected to provide the possibility of studying not only the structure of tissues and bloodstream, but also the response of the brain to various stimuli, and even cognitive functions.

Airway Inflammation and Inflammatory Biomarkers.

Severe asthma is a complex disease consisting of different endotypes with different inflammatory and clinicopathological characteristics due to the heterogeneity of immune responses and smooth muscle dysfunction. There is an unmet clinical need to develop and to validate biomarkers that can differentiate between the asthma endotypes and guide clinical management, particularly since the availability of biologicals directed against T2 cytokines. The presence of a "Th2 endotype" is currently assessed in clinical practice using markers, such as eosinophil count in sputum or blood, fraction of exhaled nitric oxide, and immunoglobulin E. Individually or in combination, they may help to identify, for example, if the dominant effector protein is interleukin (IL) 5, IL13, or IgE. There is no reliable marker of a "non-Th2 endotype" although sputum neutrophil may provide some indication. The unbiased systems biology approach to severe asthma endotyping which integrates omics signatures and clinical data using large cohort studies may provide more comprehensive information than simple cellular measurements. Novel imaging techniques, such as hyperpolarized noble gas magnetic resonance imaging and computed tomography parametric response maps and metabolomics profiling in breath and other body fluids are also being evaluated as potential biomarkers to guide therapy and to assess prognosis.

A novel switched frequency 3He/1H high‐pass birdcage coil for imaging at 1.5 tesla

ABSTRACTThe ability to produce hyperpolarized noble gases 3He and 129Xe has opened up exciting possibilities for pulmonary magnetic resonance imaging (MRI). We have recently built a hyperpolarizer with the goal of using hyperpolarized 3He gas for MRI in neonatal lungs in a dedicated small foot‐print 1.5 T MR scanner developed at our institution and sited in our Neonatal Intensive Care Unit. Although hyperpolarized gas imaging can provide unique insights into lung ventilation, acinar microstructure, and gas‐exchange dynamics, there is an undiminished need for 1H MRI of the lung to provide anatomic references, B1 and B0 maps, and 1H images of lung parenchyma. To address this need, we designed, built and tested a novel radiofrequency body coil that provides a high‐pass birdcage coil that can be used for both 3He and 1H frequencies (48.65 and 63.86 MHz, respectively, at 1.5 T). To switch between frequencies, the birdcage coil has a large mechanical actuator that simultaneously changes the capacitance between every rung of the birdcage. Advantages of this coil design include: 1) quadrature excitation and reception at the 3He and 1H frequencies, 2) identical B1 field maps for 3He and 1H imaging, 3) excellent signal‐to‐noise ratio and B1 homogeneity at both frequencies, and 4) rapid (10–20 s) switching times between 3He and 1H operation. This report provides details of the coil's design and fabrication. Images of hyperpolarized 3He and 1H in phantoms and ex vivo rabbit lungs demonstrate the image quality obtained with the coil. © 2015 Wiley Periodicals, Inc. Concepts Magn Reson Part B (Magn Reson Engineering) 45B: 174–182, 2015

New insights into lung diseases using hyperpolarized gas MRI

Hyperpolarized (HP) gases are a new class of contrast agents that permit to obtain high temporal and spatial resolution magnetic resonance images (MRIs) of the lung airspaces. HP gas MRI has become an important research tool not only for morphological and functional evaluation of normal pulmonary physiology but also for regional quantification of pathologic changes occurring in several lung diseases. The purpose of this work is to provide an introduction to MRI using HP noble gases, describing both the basic principles of the technique and the new information about lung disease provided by clinical studies with this method. The applications of the technique in normal subjects, smoking related lung disease, asthma, and cystic fibrosis are reviewed.

RM con gases hiperpolarizados: Nuevas perspectivas en el estudio de enfermedades pulmonares

Hyperpolarized (HP) gases are a new class of contrast agents that permit to obtain high temporal and spatial resolution magnetic resonance images (MRI) of the lung airspaces. HP gas MRI has become important research tool not only for morphological and functional evaluation of normal pulmonary physiology but also for regional quantification of pathologic changes occurring in several lung diseases. The purpose of this work is to provide an introduction to MRI using HP noble gases, describing both the basic principles of the technique and the new information about lung disease provided by clinical studies with this method. The applications of the technique in normal subjects, smoking related lung disease, asthma, and cystic fibrosis are reviewed.

Inert fluorinated gas MRI: a new pulmonary imaging modality.

Fluorine-19 ((19)F) MRI of the lungs using inhaled inert fluorinated gases can potentially provide high quality images of the lungs that are similar in quality to those from hyperpolarized (HP) noble gas MRI. Inert fluorinated gases have the advantages of being nontoxic, abundant, and inexpensive compared with HP gases. Due to the high gyromagnetic ratio of (19)F, there is sufficient thermally polarized signal for imaging, and averaging within a single breath-hold is possible due to short longitudinal relaxation times. Therefore, the gases do not need to be hyperpolarized prior to their use in MRI. This eliminates the need for an expensive polarizer and expensive isotopes. Inert fluorinated gas MRI of the lungs has been previously demonstrated in animals, and more recently in healthy volunteers and patients with lung diseases. The ongoing improvements in image quality demonstrate the potential of (19)F MRI for visualizing the distribution of ventilation in human lungs and detecting functional biomarkers. In this brief review, the development of inert fluorinated gas MRI, current progress, and future prospects are discussed. The current state of HP noble gas MRI is also briefly discussed in order to provide context to the development of this new imaging modality. Overall, this may be a viable clinical imaging modality that can provide useful information for the diagnosis and management of chronic respiratory diseases.

Using pulmonary imaging to move chronic obstructive pulmonary disease beyond FEV1.

FEV1, measured using spirometry, provides a straightforward, widely available, and inexpensive global measurement of airflow limitation and lung function. For decades, FEV1 has remained the main intermediate endpoint used in research studies and for the development of new chronic obstructive pulmonary disease (COPD) therapies. Not surprisingly, treatments that acutely improve FEV1 dominate as COPD therapies. However, in patients with COPD, the relationship of FEV1 with symptoms and outcomes such as exacerbations and mortality is weak, and, importantly, FEV1 does not take into account the heterogeneity of COPD or its different phenotypes. Thoracic imaging provides a way to quantify airway remodeling, emphysematous destruction, regional ventilation abnormalities (ventilation defects), and gas trapping in ex-smokers in whom FEV1 may be normal and in patients with COPD with very modest lung function deterioration. In individual patients and in COPD cohort studies, thoracic imaging using X-ray computed tomography, and magnetic resonance imaging (conventional (1)H as well as hyperpolarized noble gases such as (129)Xe, (3)He, and inhaled O2 and (19)F) can be used to directly visualize the structural and functional consequences of COPD and thus provide a clearer picture of COPD mechanisms, disease progression, and response to therapy. We briefly describe pulmonary imaging methods that provide a way to visualize and quantify, with high spatial and temporal resolution, regional ventilation abnormalities, gas trapping, emphysema, and airway remodeling in COPD. Finally, we discuss the implications of recent imaging findings and their impact on future biomarker and therapy research aimed at improving COPD outcomes.