Applied Radiology

Dr. Morrell is a fourth-year Resident in diagnostic radiology at the Hospital of the University of Pennsylvania, Philadelphia, PA. He received both his MD and his PhD in Electrical Engineering from Stanford University, Palo Alto, CA. In 2003, he will begin a fellowship in MRI at the Hospital of the University of Pennsylvania.

Magnetic resonance imaging (MRI) of hyperpolarized helium is a newly developed technique that enables high-resolution imaging of the pulmonary airways and alveolar airspaces. Hyperpolarized xenon can also be used in MRI, and has great promise for spectroscopic imaging in applications such as tumor characterization. This article will explain the rationale for the use of these hyperpolarized gases. Potential clinical applications of hyperpolarized gas MRI are outlined, including the evaluation of asthma, cystic fibrosis, lung transplant rejection, early changes of smoking-induced lung disease, and tumor characterization. Hyperpolarized gas imaging is not yet in widespread clinical use. However, current research will likely lead to clinical applications in these and other conditions in the near future.

Magnetic resonance imaging (MRI) of hyperpolarized helium ( ³ He) and xenon ( ¹²⁹ Xe) is an emerging technique that shows great promise in the evaluation of several important pulmonary diseases. Hyperpolarized ¹²⁹ Xe may also prove to be a valuable agent for imaging other organ systems. Clinical indications for ³ He and ¹²⁹ Xe imaging are still being investigated, and imaging with hyperpolarized gas is not currently in widespread clinical use.

Why hyperpolarized gas?

Although several atomic nuclei are capable of nuclear magnetic resonance, the hydrogen nucleus ( ¹ H) is almost universally used for current clinical MRI and spectroscopy. This is because hydrogen nuclei are abundant within the body in the form of free water and in hydrocarbon molecules, such as fats and proteins. This natural abundance of hydrogen nuclei in the tissues of the body leads to a large magnetic resonance signal. MRI can also be performed with other nuclei, such as isotopes of phosphorus or sodium. However, as these nuclei are scarce within the tissues of the body, their nuclear magnetic resonance signal is weak, and images derived from these signals can be obtained only with very long imaging times.

The signal obtained from ¹ H nuclei during an MRI study is based on the fact that each ¹ H nucleus has a tiny magnetic dipole moment, like a tiny bar magnet with north and south poles. When a patient is placed within the static field created by the large superconducting magnet of an MRI scanner, the individual magnetic dipoles of the ¹ H nuclei can align themselves either with or against the field. Because of thermal energy, each individual nuclear dipole will transition rapidly between states in alignment with or against the external field. A net dipole moment exists within the tissues of the patient because at any instant in time, more dipoles will probably be aligned with the field than against it. This net moment is the source of the magnetic resonance signal. The majority by which the dipoles aligned with the field outnumber the dipoles aligned against the field is the degree of polarization. For instance, if a sample is 50% polarized, this means that 75% of the nuclei are aligned with the field and 25% are not, giving a majority of 50% in alignment with the field. The polarization that occurs when a sample is placed in a magnetic field is termed the thermal equilibrium polarization.

At room temperature in a standard 1.5 T imaging system, the majority of nuclei aligned with the field is only approximately 5 per each million. This corresponds to a polarization of approximately 0.0005%. The vast majority of ¹ H nuclei do not contribute to the magnetic resonance signal; those that are aligned with the field are canceled almost completely by an almost equal number aligned against the field. Fortunately, the low thermal equilibrium polarization of ¹ H nuclei is somewhat offset by their abundance in the human body, and a magnetic resonance signal of useful strength can be obtained.

The nuclei of certain isotopes of helium and xenon, ³ He and ¹²⁹ Xe, are also capable of magnetic resonance. At 1.5 T and room temperature, these nuclei have thermal equilibrium polarizations of 0.0004% and 0.00014%, respectively. This low polarization combined with the low density of the gas phase at room temperature results in negligible magnetic resonance signal. However, a technique known as optical pumping has been developed recently that allows the polarization of these gases to levels many orders of magnitude greater than their thermal equilibrium. This process is known as hyperpolarization. Optical pumping systems are available commercially. Polarizations of up to 60% have been reported for ³ He, which is approximately 150,000 times the thermal equilibrium polarization in a standard 1.5 T imaging magnet. Up to 20% polarization of ¹²⁹ Xe has been reported, which is more than 140,000 times its thermal equilibrium value. These huge values of polarization make MRI with these hyperpolarized gases feasible, with theoretical signal levels of approximately 100 times the signal obtained by standard ¹ H imaging, despite the low density of nuclei in the gas phase.

Kinetics of hyperpolarized gas

In the familiar case of conventional ¹ H imaging, polarization returns exponentially to its thermal equilibrium value after a radiofrequency (RF) pulse is applied. This exponential regeneration has a time constant of T1. This phenomenon is the basis of T1-weighting in conventional ¹ H MRI, in which the repetition time (TR) is varied to give T1-weighted contrast.

Hyperpolarized gases also return to their thermal equilibrium polarization with a time constant T1. Because this thermal equilibrium polarization is negligible, the hyperpolarization effectively decays from its initial optically pumped state to zero. Thus, after hyperpolarization is achieved by optical pumping, the hyperpolarized gas must be used rapidly in an imaging experiment before the polarization decays to zero. For practical hyperpolarized gas imaging, an optical pumping apparatus must be located near the MRI facility.

Pulse sequence considerations

When an RF pulse is applied in a hyperpolarized gas imaging sequence, a portion of the hyperpolarization is tipped into the transverse plane, where it experiences T2 and T2* decay and is lost. Because hyperpolarized gas experiences no regeneration of hyperpolarization between RF pulses, the amount of polarization that is destroyed by each RF pulse is lost irretrievably, and there is no T1 weighting in the conventional sense. The hyperpolarized gas MRI experiment must be designed in such a way that the polarization is used up incrementally throughout the sequence, typically by a train of low flip angle pulses. The T2* decay time constant in the lung has been measured at approximately 10 ms for ³ He and 20 ms for ¹²⁹ Xe. ¹ This rapid T2* decay makes rapid acquisition essential. Fast gradient-recalled echo (FGRE) or fast low-angle shot (FLASH) sequences are typically used.

Hyperpolarized ³ He

Properties

³ He is a rare isotope of helium that is produced by the breakdown of radioactive tritium, which is a byproduct of nuclear weapons research. Although ³ He is rare on earth, it is abundant in the crust of the moon, and moon mining of ³ He has been proposed (not for MRI use, but as a potential fuel for clean fusion). ³ He is relatively insoluble in blood and soft tissues, and remains in the airspaces of the lung when inhaled. Polarization of up to 60% has been reported by optical pumping. Thus, ³ He gives high signal-to-noise ratio (SNR) images of the airways and alveolar airspaces and is the gas of choice for ventilation imaging. Helium is also harmless to inhale. Unfortunately, because ³ He is quite rare, it is quite expensive.

Ventilation imaging

Because helium does not diffuse quickly into the blood and soft tissues of the lung, it is useful for depicting pulmonary ventilation. Static ventilation images are obtained after the patient has inhaled a few breaths of hyperpolarized helium. Fast imaging techniques have also been developed that allow dynamic ventilation imaging of a single breath of helium, with multiple images closely spaced in time to depict the time course of distribution of the helium in the airways and alveolar spaces. Ventilation can be seen with much greater spatial resolution than is possible with nuclear medicine ventilation scans. Figure 1 presents two coronal slices from a helium ventilation scan in a healthy volunteer. Preliminary results indicate that ventilation imaging may be sensitive for several pulmonary diseases, such as lung transplant rejection, asthma, cystic fibrosis, and emphysema. The specificity of ventilation abnormalities visualized on ³ He imaging is still unclear. Many disease conditions of the lungs are manifested by heterogeneity of airspace enhancement or frank ventilation defects on ³ He imaging. In addition, healthy volunteers have been shown to have transient ventilation defects that resolve on later imaging, corresponding to atelectasis. ²

Ventilation/perfusion imaging -- The ability of ³ He imaging to depict pulmonary ventilation suggests the possibility of ventilation/perfusion imaging to evaluate pulmonary embolism. Combined contrast-enhanced ¹ H perfusion/ angiography and ³ He ventilation examinations have been performed in rats ³ and, more recently, in a porcine pulmonary embolism model. ^4,5 Figure 2 shows images from a ventilation/perfusion study performed in a pig. The gadolinium-enhanced angiographic images clearly demonstrate the experimentally induced embolic occlusion of pulmonary arterial branches, whereas the ³ He ventilation imaging shows normal ventilation. The usefulness of this technique in humans has not yet been established.

Transplant evaluation -- Ventilation imaging may be useful in the evaluation of lung transplants. Differences in the time course of various stages of ventilation between diseased native lungs and healthy unilateral transplant lungs have been observed using a rapid imaging sequence for dynamic ventilation imaging. ⁶ Good correlation between the net size of static ventilation defects on ³ He imaging and clinical assessment of bronchiolitis obliterans syndrome, a complication of transplant rejection, has been shown. ⁷ Whether ³ He ventilation imaging will be able to detect stages of bronchiolitis obliterans before it is clinically apparent remains unknown, but static ventilation defects have been seen on ³ He imaging in some patients with
clinically suspected or biopsy-proven bronchiolitis obliterans when chest computed tomography (CT) is negative, suggesting that ³ He imaging may be more sensitive than CT for early changes of rejection. ⁸ Figure 3 illustrates a representative ³ He ventilation image and corresponding axial CT image in a patient with a right-sided lung transplant affected with bronchiolitis obliterans, in which ³ He imaging shows marked abnormality, whereas the CT is essentially normal.

Cystic fibrosis -- Numerous ventilation defects have been reported in patients with cystic fibrosis that were not always accompanied by corresponding abnormalities on proton MRI performed at the same time. ⁹ Further investigation may clarify the value of ventilation imaging for evaluation of cystic fibrosis and monitoring response to therapy.

Asthma -- Ventilation defects have been observed in a small group of patients with asthma, and the size and quantity of the defects may correlate with degree of disease activity. ¹⁰ After bronchodilator therapy, ventilation defects have been seen to diminish or vanish. Figure 4 demonstrates ³ He images of a patient with asthma who has multiple ventilation defects. In the same patient, 3 weeks later, the distribution of the ventilation defects has changed (Figure 4B). Again, in the same patient 30 minutes later, after bronchodilator therapy, the ventilation defects have disappeared (Figure 4C). ³ He MRI may be a means of monitoring the effectiveness of asthma therapy, and may be useful in discriminating asthma from other conditions with similar clinical presentation that do not involve the alveolar airspaces.

Diffusion imaging

Diffusion imaging of hyperpolarized helium is possible using a pulse-sequence design similar to that used for conventional ¹ H diffusion-weighted imaging. Diffusion-weighted ³ He imaging has been applied primarily to pulmonary emphysema. Because the alveolar walls create a partial physical barrier to the diffusion of ³ He molecules, the breakdown of alveolar structure seen in pulmonary emphysema is accompanied by an increase in apparent diffusion coefficient (ADC) on ³ He diffusion imaging. Recent research has shown a correlation between measured ADC and alveolar size, as determined by histology. ¹¹ A theoretical model of ³ He diffusion, including anisotropy due to the tubular structure of terminal alveolar units, has been applied with good experimental results. ^12,13 Several studies have shown increased ADC in patients with emphysema when compared with normal controls. ^14,15 Figure 5 shows a coronal slice from ADC maps of a healthy volunteer and of a patient with emphysema. Increased ADC in the emphysematous lungs is particularly pronounced in the apices. Correlation of mean ADC with pulmonary function indices such as forced expiratory volume during the first second (FEV ₁ ) and forced expiratory volume during the first second to forced expiratory vital capacity ratio (FEV ₁ / FVC) has also been shown in patients with emphysema. ¹⁶ Static ventilation abnormalities have been seen with higher frequency in asymptomatic smokers than healthy nonsmoking controls. ¹⁷ Similarly, preliminary results of diffusion-weighted ³ He imaging show increased mean ADC in smokers versus nonsmokers, ¹⁸ even when no abnormality is seen on chest CT. For smokers with changes on CT, focal areas of increased ADC correspond to areas of lucency on chest CT. These findings suggest that ³ He diffusion-weighted imaging may be sensitive for the early subclinical changes of emphysema, and may be valuable for assessing response to therapy in the early stages of the disease. A rapid interleaved spiral diffusion-weighted imaging sequence has recently been developed that allows diffusion imaging of the entire lung in a single helium breathhold. ¹⁹

Oxygenation imaging

The relaxation time constant T1 of ³ He is dependent on the partial pressure of oxygen (pO ₂ ). Higher concentrations of O ₂ lead to lower values of T1, leading to faster decay of the hyperpolarization. Mapping of T1 can be performed with sequences using a train of excitations of variable flip angles or varying time intervals between excitation and readout. Images can then be formed showing the concentration of O ₂ throughout the lungs. This technique was applied in pigs and humans, ²⁰ and showed a linear decrease in pO ₂ with time during a breathhold, reflecting the expected constant rate of transport of oxygen from the lungs to the bloodstream. As implemented, this technique requires two separate acquisitions and is very sensitive to SNR, requiring longer scan times and increased consumption of helium. The interpretation of pO ₂ images is complicated because pO ₂ is determined by both ventilation and perfusion. Nevertheless, the ability to measure the physiologic parameter pO ₂ is intriguing, and may find application to a number of pulmonary disease processes.

Other applications of ³ He imaging

Pulmonary air leaks -- ³ He ventilation imaging has been used to visualize pulmonary air leaks in a porcine model, and could be useful in evaluation of persistent air leaks or bronchopleural fistulae. ²¹

Paranasal sinus imaging -- Imaging of ³ He in the paranasal sinuses of pigs has been performed ²² and may give both static anatomic depiction and dynamic functional information about the flow of gas in the paranasal sinuses and nasal cavity.

Angiography -- Hyperpolarized ³ He has been prepared in gaseous form within microspheres that have been injected intravenously in high concentration in rats and in explanted coronary arteries. ^23,24 The usefulness of this technique in humans remains to be seen.

Hyperpolarized ¹²⁹ Xe

Properties

¹²⁹ Xe is an abundant isotope, composing 26% of atmospheric xenon. Because ¹²⁹ Xe is abundant, it is much less expensive than ³ He. However, lower levels of hyperpolarization have been acheived with ¹²⁹ Xe than with ³ He, with levels of 10% to 20% polarization of ¹²⁹ Xe reported. ^25,26 Additionally, ¹²⁹ Xe has a lower gyromagnetic ratio than ³ He. These two factors combine to give much less signal from ¹²⁹ Xe than from ³ He, and ventilation images performed with ¹²⁹ Xe have much poorer SNR. Thus, ¹²⁹ Xe is not often used for ventilation imaging.

¹²⁹ Xe is much more soluble in blood and soft tissue than ³ He, and detectable levels of ¹²⁹ Xe have been seen in the brain, heart, and kidneys in a rat model after inhalation of ¹²⁹ Xe. ²⁷ Unfortunately, inhaled xenon acts as a general anesthetic, so the dose of inhaled xenon must be monitored carefully in an imaging experiment.

¹²⁹ Xe interacts with its electronic environment to a much greater extent than ³ He. One manifestation of this is a wide range of chemical shifts in the resonant frequency of ¹²⁹ Xe in response to its local chemical environment. The value of xenon in MRI may be in its tissue solubility and its wide range of chemical shifts, which have been exploited in several different ways.

Tumor characterization

Preliminary research has shown differences in ¹²⁹ Xe spectra, measured by single-voxel spectroscopy, in certain tumor models versus normal tissue. Ex vivo ¹²⁹ Xe spectroscopy of a radiation-induced fibrosarcoma (RIF-1) tumor model showed differences in spectroscopic line shape between tumor and normal muscle. ²⁸ In another experiment, ¹²⁹ Xe dissolved in a perflouro octyl bromide (PFOB) emulsion was injected into RIF-1 and prolactinoma tumors in living mice, and characteristic differences in the nuclear magnetic resonance spectra were observed. ²⁵ The precise explanation of the ¹²⁹ Xe spectra observed from these tumor models remains to be investigated, but these early results suggest that ¹²⁹ Xe spectroscopy may be useful for identification of some tumors.

When a PFOB emulsion containing dissolved ¹²⁹ Xe is injected intravenously, large PFOB particles remain in the intravascular compartment, while ¹²⁹ Xe diffuses into the extravascular compartments. ¹²⁹ Xe dissolved in PFOB has a chemical shift different than ¹²⁹ Xe that has diffused out of the PFOB into the surrounding tissues. Because of this chemical shift, the intravascular and extravascular components of the injected ¹²⁹ Xe can be detected and imaged separately. Preliminary in vitro experiments suggest that this property may be exploited to measure the arterial input function and tissue residual function, two significant tumor blood flow characteristics, in tumors such as breast cancer. ²⁹

Polarization transfer

In the lung, frequency shifts of approximately 200 parts per million are observed between ¹²⁹ Xe in gaseous phase in the pulmonary airspaces and ¹²⁹ Xe dissolved in the pulmonary parenchyma and blood. This difference in resonant frequency allows the independent selective excitation of the gaseous or dissolved phases. In a technique that has been labeled xenon polarization transfer contrast, the tissue-dissolved compartment of inhaled ¹²⁹ Xe is inverted selectively and allowed to exchange by diffusion with the gaseous phase compartment in the pulmonary airspaces. This results in a decrease in signal from the gaseous phase compartment on subsequent imaging. ^30,31 The degree of signal decrease after selective inversion of the tissue-dissolved phase indicates the relative volume occupied by lung parenchyma versus pulmonary air space. Potential clinical implications of this information remain to be explored.

Brain imaging and spectroscopy

Inhaled ¹²⁹ Xe can be visualized in the brain, and separate peaks in the chemical shift spectrum may correspond to gray and white matter. ²⁶ Although the clinical significance of ¹²⁹ Xe brain spectroscopy remains uncertain, low-resolution ¹²⁹ Xe images of rodent brain have been obtained, ³² and chemical shift imaging of ¹²⁹ Xe in the human brain has been demonstrated recently. ³³

Conclusion

MRI using hyperpolarized gases is an area of active research, with many potential clinical applications. Hyperpolarized ³ He can be used to image the airspaces of the respiratory system. ³ He diffusion imaging shows promise as a sensitive early indicator of smoking-related lung disease and may be useful for the evaluation of therapies targeted to early subclinical stages of emphysema. ³ He ventilation imaging may prove to be a useful test for bronchiolitis obliterans complicating lung transplantation. Other potential applications of ³ He imaging include cystic fibrosis and asthma. ¹²⁹ Xe is less well suited for imaging pulmonary air spaces, but has unique properties that may be useful for tumor characterization and for selective imaging of air- and tissue-dissolved phases in the pulmonary air spaces and lung parenchyma. As further research in hyperpolarized gas MRI is conducted, these and other applications will likely reach clinical practice.