Intermediate Physics for Medicine and Biology: Hyperpolarized 129Xe MRI of the Human Lung

Chapter 18 of the 4th edition of Intermediate Physics for Medicine and Biology is devoted to magnetic resonance imaging. Russ Hobbie and I discuss many aspects of MRI, including functional MRI and diffusion tensor imaging. One topic we do not cover is using hyperpolarized spins to study lung function. Fortunately, a clearly written review article, “Hyperpolarized ¹²⁹Xe MRI of the Human Lung,” by John Mugler and Talissa Altes, appeared recently in the Journal of Magnetic Resonance Imaging (Volume 37, Pages 313–331, 2013). Below I reproduce excerpts from their introduction, with citations removed.

CLINICAL MAGNETIC RESONANCE IMAGING (MRI) of the lung is challenging due to the lung’s low proton density, which is roughly one-third that of muscle, and the inhomogeneous magnetic environment within the lung created by numerous air–tissue interfaces, which lead to a T2* value on the order of 1 msec at 1.5 T. Although advances continue with techniques such as ultrashort echo time (UTE) imaging of the lung parenchyma, conventional proton-based MRI is at a fundamental disadvantage for pulmonary applications because it cannot directly image the lung airspaces. This disadvantage of proton MRI can be overcome by turning to a gaseous contrast agent, such as the noble gas helium-3 (³He) or xenon-129 (¹²⁹Xe), which upon inhalation permits direct visualization of lung airspaces in an MR image. With these agents, the low density of gas compared to that of solid tissue can be compensated by using a standalone, laser-based polarization device to increase the nuclear polarization to be roughly five orders of magnitude (10,000 times) higher than the corresponding thermal equilibrium polarization would be in the magnet of a clinical MR scanner. As a result, the MR signal from these hyperpolarized noble gases is increased by a proportionate amount and is easily detected using an MR scanner tuned to the appropriate resonance frequency. MRI using hyperpolarized gases has led to the development of numerous unique strategies for evaluating the structure and function of the human lung that provide advantages relative to current clinically available methods. For example, as compared with nuclear-medicine ventilation scintigraphy scans using ¹³³Xe or aerosolized technetium-99m DTPA, hyperpolarized-gas ventilation MR images provide improved temporal and spatial resolution, expose the patient to no ionizing radiation, and can be repeated multiple times in a single day if desired. Although inhaled xenon has also been used as a contrast agent with computed tomography (CT), which can provide high spatial and temporal resolution, the high radiation dose and low contrast on the resulting ventilation images has dampened enthusiasm for the CT-based technique.

Although the first hyperpolarized-gas MR images were obtained using hyperpolarized ¹²⁹Xe, and images of the human lung were acquired with hyperpolarized ¹²⁹Xe only a few years later, the vast majority of work in humans has been performed using hyperpolarized ³He instead. This occurred primarily because ³He provided a stronger MR signal, due to its larger nuclear magnetic moment (and hence larger gyromagnetic ratio) compared to ¹²⁹Xe and historically high levels of polarization (greater than 30%) achieved for ³He, and because there are no significant safety concerns associated with inhaled helium. However, in the years following the terrorist attacks of 9/11 there was a surge in demand for ³He for use in neutron detectors for port and border security, and this demand far exceeded the replenishment rate from the primary source, the decay of tritium used in nuclear warheads. As a result, ³He prices skyrocketed and availability plummeted. Currently, the U.S. government is regulating the supply of ³He, allocating this precious resource among users whose research or applications depend on ³He’s unique physical properties. This includes an annual allocation for medical imaging, which allows research on hyperpolarized ³He MRI of the lung to continue. Nonetheless, unless a new source for ³He is found it is clear that insufficient ³He is available to permit hyperpolarized ³He MRI of the lung to translate from the research community to a clinical tool.

In contrast to ³He, ¹²⁹Xe is naturally abundant on Earth and its cost is relatively low. Thus, ¹²⁹Xe is the obvious potential alternative to ³He as an inhaled contrast agent for MRI of the lung. While the ³He availability crisis has accelerated efforts to develop and evaluate hyperpolarized ¹²⁹Xe for human applications, it is important to understand that ¹²⁹Xe is not just a lower-signal alternative to ³He, forced upon us by practical necessity. In particular, the relatively high solubility of xenon in biological tissues and an exquisite sensitivity to its environment, which results in an enormous range of chemical shifts upon solution, make hyperpolarized ¹²⁹Xe particularly attractive for exploring certain characteristics of lung function, such as gas exchange and uptake, that cannot be accessed using hyperpolarized ³He. The quantitative characteristics of gas exchange and uptake are determined by parameters of physiologic relevance, including the thickness of the blood–gas barrier, and thus measurements that quantify this process offer a potential wealth of information on the functional status of the healthy and diseased lung.

Historically, polarization levels for liter-quantities of hyperpolarized ¹²⁹Xe have been roughly 10%, while those for similar quantities of hyperpolarized ³He have been greater than 30%. (Recall that the thermal equilibrium polarization of water protons at 1.5T is 0.0005%—four to five orders of magnitude lower.) Given ¹²⁹Xe’s lower nuclear magnetic moment, this situation has put hyperpolarized ¹²⁹Xe at a distinct disadvantage relative to ³He. A recent, key advance for ¹²⁹Xe is the development of systems that can deliver liter quantities of hyperpolarized ¹²⁹Xe with polarization on the order 50%. This now puts ¹²⁹Xe on a competitive footing with ³He, positioning MRI of the human lung using hyperpolarized ¹²⁹Xe to advance quickly in the immediate future, and making hyperpolarized ¹²⁹Xe MRI of interest to the broader radiology and medical-imaging communities.

This idea of gas hyperpolarization is fascinating. How does one hyperpolarize the gas? Mugler and Altes explain:

Although it is possible to image either ¹²⁹Xe or ³He by simply placing the gas (in a suitable container) in the magnet of an MR scanner, the low density of gas compared to that of solid tissue results in a signal that is too low to be of practical use for imaging the human lung… Nonetheless, the nuclear polarization can be increased dramatically compared to that produced by the magnet of the MR scanner by using a method called opticalpumping and spin exchange (OPSE), which was originally developed for nuclear-physics experiments many years before being applied to medical imaging.

As its name implies, OPSE is, in concept, a two-step process. The first step, optical pumping, involves using a laser to generate electron-spin polarization in a vapor of an alkali metal. This process takes place within a glass container, called an optical cell…positioned within a magnetic field... A small amount of the alkali metal, typically rubidium, is placed in the cell, which is heated…during the polarization process to create rubidium vapor. The optical cell is illuminated with circularly polarized laser light…at a specific wavelength (795 nm) to optically pump the rubidium atoms. This pumping preferentially populates one of the two spin states for the valence electron, thereby polarizing the associated electron spins and resulting in electron-spin polarization approaching 100%. In the second step of OPSE, collisions between spin-polarized rubidium atoms and noble-gas (¹²⁹Xe or ³He) atoms within the cell result in spin exchange—the transfer of polarization from rubidium electrons to noble-gas nuclei...