Several methods of functional MRI (fMRI) have been described for imaging of pulmonary perfusion and ventilation. The authors review the physical basis of these methods, including examples of potential clinical applications. Functional pulmonary MRI methods continue to evolve, and are likely in the future to become an important clinical tool in the evaluation of patients with pulmonary disease.
Dr. Roberts, Dr. Rizi,
are Assistant Professors, Department of Radiology, University of
Pennsylvania, Philadelphia, PA;
is an Assistant Professor, Department of Radiology, Evanston
Northwestern Healthcare and Feinberg School of Medicine at
Northwestern University, Evanston, IL; and
is a Medical Student, Department of Radiology, University of
Virginia, School of Medicine, Charlottesville, VA.
Noninvasive imaging of human pulmonary function is an important
step in the clinical evaluation of patients with various pulmonary
diseases, including pulmonary embolism (PE), emphysema,
interstitial lung disease, and asthma. Under normal circumstances,
regional pulmonary ventilation (V) and perfusion (Q) are usually
highly matched processes. Various disease states alter this normal
relationship, causing V/Q mismatch. Noninvasive assessment of
regional V/Q relationships is important in the diagnosis,
evaluation, and treatment of patients with pulmonary disease.
There are several limitations of the clinical studies that are
currently used to assess pulmonary function. Standard pulmonary
function tests (PFTs) provide invaluable information about global
lung function; however, they do not allow for determination of the
spatial distribution of pulmonary function. Currently, nuclear
medicine techniques based on the introduction of radioactive
tracers are considered the gold standard for noninvasive functional
imaging of the lung. However, these methods suffer from several
significant limitations, including relatively poor spatial
resolution, limitations on the acquisition of three-dimensional
data, and the costs and risks associated with the radioactive
Magnetic resonance imaging (MRI) of the lung is challenging due
to the effects of respiratory movement and the short transverse
relaxation time (T2*) that results from the microscopic
heterogeneity in the magnetic field. However, the recent
development of high-speed gradient systems, coupled with the
subsequent implementation of short echo-time acquisition has
allowed for imaging of the lung parenchyma.
As a result, several methods of functional MRI (fMRI) have recently
been described to perform imaging of pulmonary perfusion and
ventilation. The physical basis of these methods will be reviewed,
including examples of potential clinical applications.
Extravascular-space gadolinium (Gd) chelates have been used for
perfusion imaging in the central nervous system for more than a
In this approach, the tissue magnetization is observed dynamically
using a rapid pulse sequence during the passage of a Gd compound
following intravenous injection. The Gd causes shortening of both
the longitudinal (T1) and transverse (T2*) relaxation time of the
tissue; therefore the observed tissue signal intensity changes are
a function of the weighting of the pulse sequence used for
observation. For applications in the pulmonary circulation,
T1-weighted rapid gradient-echo pulse sequences have been used,
leading to signal enhancement during Gd passage.
These methods offer the possibility of quantification of perfusion
and have been validated in animal models.
Advantages of the Gd-based perfusion methods include a
relatively high contrast-to-noise ratio and spatial resolution,
which offers high sensitivity for the detection of small perfusion
defects (Figures 1 and 2). However, the injection of Gd inevitably
results in some degree of background enhancement. This may degrade
the quality of subsequent MR angiographic (MRA) or perfusion
studies. Specifically, serial studies of perfusion to characterize
dynamic processes are not feasible by this approach due to
cumulative background enhancement. In addition, Gd-based techniques
involve the risks and expenses of exogenous contrast
administration. Nevertheless, Gd-enhanced MRI is a validated and
robust method for pulmonary perfusion imaging.
Magnetically labeled arterial water may be used as an endogenous
contrast agent for perfusion MRI, which forms the basis for the
so-called arterial spin-labeling (ASL) methods.
Magnetic labeling may be achieved using a variety of methods,
including spatial saturation,
or adiabatic inversion.
Images acquired under conditions of arterial labeling are
subtracted from images acquired under appropriate control
conditions to generate a perfusion image, as shown in Figure 3.
Solution of the modified Bloch equations may be performed to
generate absolute values of perfusion.
The ASL perfusion pulse sequences may be divided into continuous
and pulsed ASL (PASL) methods.
The CASL methods establish a steady state of arterial labeling,
while the PASL methods do not. The CASL methods may be acquired in
a steady state, thereby allowing for respiratory-triggered
The PASL methods do not seek to establish a steady state and,
therefore, generally require breath-holding and cardiac gating. The
PASL methods have also been applied successfully to the pulmonary
In both approaches, blood is typically labeled either at the level
of the mediastinum or the right/left pulmonary arteries. The ASL
methods have been used with success to obtain high-resolution
perfusion maps of the pulmonary circulation in many disease states.
Due to their inherent sensitivity to changes in both perfusion and
blood volume, these methods are expected to have high sensitivity
to the detection of pulmonary embolism (Figures 4 and 5).
The ASL methods have several distinct advantages over Gd-based
methods of perfusion imaging. As an entirely noninvasive method,
ASL avoids the risks and expenses of an exogenous contrast agent.
The ASL methods offer the possibility of quantification and may,
therefore, be used to follow patients during therapy. Finally, ASL
methods may be used repeatedly over time to study dynamic
processes, as there is no degradation in the perfusion image as is
seen with Gd-enhanced methods.
Laser-polarized noble gases
The laser-polarized noble gases helium (
He, a rare isotope of
He) and xenon (
Xe) are inhaled contrast agents capable of creating high-resolution
images of the gas distribution within the lung during a single
Polarization is performed in a high-power laser apparatus under
conditions of high temperature and pressure. The laser-polarized
magnetization is five orders of magnitude larger than the
thermal-equilibrium magnetization of protons in the lung, and this
explains why the gases are visible in MRI despite their low
density. However, the magnetization is in a nonequilibrium state
and is therefore nonrenewable. Thus, the total available
magnetization is fixed, and must be managed appropriately during
the application of the MR pulse sequence. In addition to a magnet
system capable of multinuclear broadband acquisition, a dedicated
coil and transmit/receive switch tuned to the helium frequency
(48.66 MHz at 1.5 T) must be available for
As a result of the large, nonequilibrium polarization, the
signal-to-noise ratio of ventilation MRI using hyperpolarized
He is very high. The resulting ventilation images show with superb
clarity the anatomic structure of the lungs, outlining the major
and minor airways, pulmonary fissures, and vascular structures with
exceptional detail (Figure 6). High spatial resolution has allowed
for new capabilities in ventilation MRI, such as the noninvasive
localization of air leaks that cause pneumothorax.
He MRI has been used to measure pulmonary volumes with high
accuracy, showing excellent agreement with pulmonary function
In addition to imaging the static distribution of gas within the
lung, the unique properties of these gases provide additional
contrast mechanisms for structural and functional imaging of the
He does not cross the alveolar membrane readily and has a high
diffusion coefficient, it can be used to probe airspace morphology.
He MRI has been used to detect early changes in chronic obstructive
pulmonary disease (COPD) (Figure 7).
The T1 relaxation rate of
He, which increases significantly in the presence of oxygen, has
been exploited to measure regional intrapulmonary oxygen
Images of the T1 relaxation rate of the gas may be used to map
intrapulmonary oxygen concentration (Figure 8). The gas flow
He in the lung during inspiration and expiration can be measured
with high temporal and spatial resolution using echoplanar imaging
or interleaved spiral pulse sequences (Figure 9).
The rapid exchange of
Xe across alveolar membrane enables the integrity of the pulmonary
diffusion barrier to be probed.
Preliminary studies of laser-polarized
He imaging have shown potential for detecting ventilation defects
in a variety of lung pathologies including COPD,
and obliterative bronchiolitis (OB), a form of chronic lung
Ventilation defects appear as areas of the lung that do not
completely fill with
He during a single inspiratory breath-hold. These ventilation
defects represent regions of the lung distal to restrictions in the
airway due to airway hyperactivity, mucous plugging, or altered
alveolar oxygen content.
He diffusion MRI has shown promise for detecting emphysematous
changes in the lung (Figure 7), and has been shown to correlate
with pulmonary function tests.
As the lung parenchyma is destroyed, the changes in airspace
morphology cause a decrease in the restriction of the gas's motion,
resulting in an increase in the apparent diffusion coefficient of
An alternative to MR ventilation imaging with laser-polarized
noble gas uses inhaled oxygen (O
) as a paramagnetic agent.
Though oxygen is weakly paramagnetic, its overall effect on the
lung is considerable given the large surface area of the lung and
the large difference in partial pressures between room air (21%
oxygen) and 100% oxygen. MR signal modulation between inhaling room
air and 100% oxygen results from the shortening of the longitudinal
relaxation time (T1) of the lung caused by the increased
concentration of dissolved oxygen in pulmonary tissues and blood
after breathing 100% oxygen. An average oxygen-induced shortening
to T1 of approximately 150 msec has been reported, leading to
signal changes of 20% to 30%.
T1-weighted MR sequences such as inversion recovery (IR) or
multiple inversion recovery (MIR) have been applied to detect the
signal difference in the lung as the subject alternatively inhales
room air and 100% oxygen.
To minimize misregistration artifacts, images with matched
respiratory phases should be selected and subsequently averaged.
The difference between the average images acquired during room air
and 100% oxygen yields a qualitative oxygen-enhanced ventilation
map. Additionally, a qualitative oxygen-enhanced ventilation map
can be obtained using statistical analysis, an approach widely used
in fMRI analysis to detect brain activation.
This approach exploits the box-car pattern of the signal modulation
of the lung between periods of inhalation of room air and 100%
Oxygen-enhanced ventilation imaging has been successful in
detecting regional ventilation defects in animal models and in
patients with emphysema (Figure 10).
Oxygen-enhanced MRI provides a means to study oxygen transfer from
the pulmonary alveoli to the pulmonary vasculature because oxygen
is a principal component in the functional gas exchange.
Additionally, oxygen is readily available as part of the emergency
equipment in most MR suites and is safe and inexpensive. By
coupling oxygen ventilation MRI with ASL perfusion, a completely
safe and noninvasive evaluation of regional V/Q may be performed
Pulmonary physiologists have used sulfur hexaflouride (SF
) to study gas distribution in the lung by taking advantage of its
low blood solubility and high density.
Additionally, high-resolution computed tomography (HRCT) imaging
using helium and SF
has been shown to be useful in predicting acinar gas distribution
abnormalities in patients with pulmonary disease.
has been described as a contrast agent for ventilation MRI.
The most abundant isotope of fluorine is
F, whose nucleus possesses a spin
/2 and is therefore potentially visible in an MRI system. The
resonance frequency and gyromagnetic ratio of
F are close to those of the proton nucleus. In contrast to
He, the fluorine signal from SF
gas is generated from an equilibrium magnetization, just as for
routine proton imaging. This is advantageous because the gas is
less sensitive to the surrounding environment and there is no loss
of magnetization with successive radiofrequency pulses. Imaging may
therefore be performed during relatively long periods of time.
Figure 12 shows a coronal image of SF
gas obtained in rat lung at 4.7 T.
Functional pulmonary MRI ventilation and perfusion imaging
methods have several distinct advantages over those that employ
radioactive tracers. In general, the resolution of ventilation and
perfusion MRI techniques is superior to that of nuclear medicine
techniques. In addition, the MRI system offers the capability to
acquire spatially co-registered three-dimensional images of
ventilation and perfusion and therefore makes feasible imaging of
the V/Q ratio. The absence of ionizing radiation makes this a safe
method for use in children.
There are many clinical areas in which the V/Q MRI methods may
have an impact. They may be useful in improving the noninvasive
diagnosis of pulmonary embolism, where the improved resolution may
reduce the number of indeterminate functional scans. Due to its
intrinsically high sensitivity, helium MRI may become useful as a
means for early detection of rejection following lung
or for following patients with asthma during therapy.
He MRI has been shown to be sensitive to early functional changes
occurring in smokers.
He MRI has been shown useful in the early detection of emphysema.
As such, the fMRI methods may become an important tool in the
evaluation of patients who undergo lung volume reduction surgery
(LVRS), both to predict response preoperatively, and to evaluate
Functional pulmonary MRI methods continue to evolve, and they
are likely to improve in both spatial and temporal resolution as
improvements in hardware occur. They have broad applicability to
many important disease states, including emphysema, pulmonary
embolism, and asthma. Given their accuracy and safety, these
methods are likely to become an important clinical tool in the
evaluation of patients with pulmonary disease in the future.
The authors thank Norman Butler, RT, Tanya Kurtz, RT, and Doris
Cain, RT, Jaime F. Mata, John M. Christopher, RT (R)(MR), and Doris
A. Harding, RN for valuable assistance.
Dr. Roberts is supported by an RSNA Scholar 2000 grant. Dr.
Roberts and Dr. Rizi are supported by NIH grants RR02305 and
RO1-HL64741. Dr. Mai is supported by a grant from the American
Heart Association. Dr. Lipson is supported by NIH grant K23 HL
04486. Dr. Salerno is supported by NIH grants R44-HL059022 and
RO1HL66479, and by the University of Virginia School of Medicine,
Amersham Health, and Siemens Medical Systems.