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.
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 (
He) and xenon (
Xe) is an emerging technique that shows great promise in the
evaluation of several important pulmonary diseases. Hyperpolarized
Xe may also prove to be a valuable agent for imaging other organ
systems. Clinical indications for
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 (
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
H nuclei during an MRI study is based on the fact that each
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
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
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
H nuclei is somewhat offset by their abundance in the human body,
and a magnetic resonance signal of useful strength can be
The nuclei of certain isotopes of helium and xenon,
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
He, which is approximately 150,000 times the thermal equilibrium
polarization in a standard 1.5 T imaging magnet. Up to 20%
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
H imaging, despite the low density of nuclei in the gas phase.
Kinetics of hyperpolarized gas
In the familiar case of conventional
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
H MRI, in which the repetition time (TR) is varied to give
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
He and 20 ms for
This rapid T2* decay makes rapid acquisition essential. Fast
gradient-recalled echo (FGRE) or fast low-angle shot (FLASH)
sequences are typically used.
He is a rare isotope of helium that is produced by the breakdown of
radioactive tritium, which is a byproduct of nuclear weapons
He is rare on earth, it is abundant in the crust of the moon, and
moon mining of
He has been proposed (not for MRI use, but as a potential fuel for
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,
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
He is quite rare, it is quite expensive.
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
He imaging is still unclear. Many disease conditions of the lungs
are manifested by heterogeneity of airspace enhancement or frank
ventilation defects on
He imaging. In addition, healthy volunteers have been shown to have
transient ventilation defects that resolve on later imaging,
corresponding to atelectasis.
The ability of
He imaging to depict pulmonary ventilation suggests the possibility
of ventilation/perfusion imaging to evaluate pulmonary embolism.
H perfusion/ angiography and
He ventilation examinations have been performed in rats
and, more recently, in a porcine pulmonary embolism model.
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
He ventilation imaging shows normal ventilation. The usefulness of
this technique in humans has not yet been established.
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.
Good correlation between the net size of static ventilation defects
He imaging and clinical assessment of bronchiolitis obliterans
syndrome, a complication of transplant rejection, has been shown.
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
He imaging in some patients with
clinically suspected or biopsy-proven bronchiolitis obliterans when
chest computed tomography (CT) is negative, suggesting that
He imaging may be more sensitive than CT for early changes of
Figure 3 illustrates a representative
He ventilation image and corresponding axial CT image in a patient
with a right-sided lung transplant affected with bronchiolitis
obliterans, in which
He imaging shows marked abnormality, whereas the CT is essentially
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.
Further investigation may clarify the value of ventilation imaging
for evaluation of cystic fibrosis and monitoring response to
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.
After bronchodilator therapy, ventilation defects have been seen to
diminish or vanish. Figure 4 demonstrates
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).
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 of hyperpolarized helium is possible using a
pulse-sequence design similar to that used for conventional
H diffusion-weighted imaging. Diffusion-weighted
He imaging has been applied primarily to pulmonary emphysema.
Because the alveolar walls create a partial physical barrier to the
He molecules, the breakdown of alveolar structure seen in pulmonary
emphysema is accompanied by an increase in apparent diffusion
coefficient (ADC) on
He diffusion imaging. Recent research has shown a correlation
between measured ADC and alveolar size, as determined by histology.
A theoretical model of
He diffusion, including anisotropy due to the tubular structure of
terminal alveolar units, has been applied with good experimental
Several studies have shown increased ADC in patients with emphysema
when compared with normal controls.
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
) and forced expiratory volume during the first second to forced
expiratory vital capacity ratio (FEV
/ FVC) has also been shown in patients with emphysema.
Static ventilation abnormalities have been seen with higher
frequency in asymptomatic smokers than healthy nonsmoking controls.
Similarly, preliminary results of diffusion-weighted
He imaging show increased mean ADC in smokers versus nonsmokers,
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
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.
The relaxation time constant T1 of
He is dependent on the partial pressure of oxygen (pO
). Higher concentrations of O
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
throughout the lungs. This technique was applied in pigs and
and showed a linear decrease in pO
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
images is complicated because pO
is determined by both ventilation and perfusion. Nevertheless, the
ability to measure the physiologic parameter pO
is intriguing, and may find application to a number of pulmonary
Other applications of
Pulmonary air leaks
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.
Paranasal sinus imaging
He in the paranasal sinuses of pigs has been performed
and may give both static anatomic depiction and dynamic functional
information about the flow of gas in the paranasal sinuses and
He has been prepared in gaseous form within microspheres that have
been injected intravenously in high concentration in rats and in
explanted coronary arteries.
The usefulness of this technique in humans remains to be seen.
Xe is an abundant isotope, composing 26% of atmospheric xenon.
Xe is abundant, it is much less expensive than
He. However, lower levels of hyperpolarization have been acheived
Xe than with
He, with levels of 10% to 20% polarization of
Xe has a lower gyromagnetic ratio than
He. These two factors combine to give much less signal from
Xe than from
He, and ventilation images performed with
Xe have much poorer SNR. Thus,
Xe is not often used for ventilation imaging.
Xe is much more soluble in blood and soft tissue than
He, and detectable levels of
Xe have been seen in the brain, heart, and kidneys in a rat model
after inhalation of
Unfortunately, inhaled xenon acts as a general anesthetic, so the
dose of inhaled xenon must be monitored carefully in an imaging
Xe interacts with its electronic environment to a much greater
He. One manifestation of this is a wide range of chemical shifts in
the resonant frequency of
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
Preliminary research has shown differences in
Xe spectra, measured by single-voxel spectroscopy, in certain tumor
models versus normal tissue. Ex vivo
Xe spectroscopy of a radiation-induced fibrosarcoma (RIF-1) tumor
model showed differences in spectroscopic line shape between tumor
and normal muscle.
In another experiment,
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.
The precise explanation of the
Xe spectra observed from these tumor models remains to be
investigated, but these early results suggest that
Xe spectroscopy may be useful for identification of some
When a PFOB emulsion containing dissolved
Xe is injected intravenously, large PFOB particles remain in the
intravascular compartment, while
Xe diffuses into the extravascular compartments.
Xe dissolved in PFOB has a chemical shift different than
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
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
In the lung, frequency shifts of approximately 200 parts per
million are observed between
Xe in gaseous phase in the pulmonary airspaces and
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
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.
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
Xe can be visualized in the brain, and separate peaks in the
chemical shift spectrum may correspond to gray and white matter.
Although the clinical significance of
Xe brain spectroscopy remains uncertain, low-resolution
Xe images of rodent brain have been obtained,
and chemical shift imaging of
Xe in the human brain has been demonstrated recently.
MRI using hyperpolarized gases is an area of active research,
with many potential clinical applications. Hyperpolarized
He can be used to image the airspaces of the respiratory system.
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
He ventilation imaging may prove to be a useful test for
bronchiolitis obliterans complicating lung transplantation. Other
potential applications of
He imaging include cystic fibrosis and asthma.
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.