SEARCH

SEARCH BY CITATION

Keywords:

  • hyperpolarized 3He;
  • variable flip angles;
  • ventilation;
  • bronchoconstriction

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

A novel imaging method is presented, Flip Angle Variation for Offset of RF and Relaxation (FAVOR), for rapid and efficient measurement of rat lung ventilation using hyperpolarized helium-3 (3He) gas. The FAVOR technique utilizes variable flip angles to remove the cumulative effect of RF pulses and T1 relaxation on the hyperpolarized gas signal and thereby eliminates the need for intervening air wash-out breaths and multiple cycles of 3He wash-in breaths before each image. The former allows an improvement in speed (by a factor of ≈30) while the latter reduces the cost of each measurement (by a factor of ≈5). The FAVOR and conventional ventilation methods were performed on six healthy male Brown Norway rats (190–270 g). Lobar measurements of ventilation, r, obtained with the FAVOR method were not significantly different from those obtained with the conventional method for the right middle and caudal and left lobes (P > 0.05 by a Wilcoxon matched pairs test). A methacholine challenge test was also administered to an animal and reduction and recovery of r was detected by the FAVOR method. The reduced 3He consumption and the improvement in speed provided by FAVOR suggest that it may allow measurement of ventilation in human subjects not previously possible. Magn Reson Med 59:1304–1310, 2008. © 2008 Wiley-Liss, Inc.

MR imaging with hyperpolarized 3He gas has been proposed for measurement of regional ventilation in the rodent lung (1) and has been recently validated with xenon-enhanced CT imaging (2). It is anticipated that 3He MR will provide a favorable approach for measurement of ventilation in animal cohorts to track lung disease over time without the complications associated with accumulated x-ray dose (3). This method measures the dynamic change in lung 3He signal as a function of breath number and extracts the relative refreshment of gas in a given lung voxel per breath. However, the conventional 3He ventilation measurement requires knowledge of the longitudinal relaxation time, T1, of the 3He gas in the ventilator system and in the lung, the latter requiring knowledge of the alveolar oxygen partial pressure (pAO2). Furthermore, without accurate knowledge of the RF pulse history the method requires multiple 3He breathing cycles (i.e., 3He wash-in breaths) with air wash-out breaths between cycles in order to completely clear the lung of 3He gas, which is time-consuming (i.e., several minutes), an inefficient use of hyperpolarized 3He gas (i.e., costly), and can lead to imprecision due to variations in tidal volume from the ventilator.

Perhaps most important, the conventional technique involving multiple 3He and air breathing cycles requires several minutes (≈10 min) for a single ventilation map, which is likely too slow to capture rapid changes in ventilation associated with short-duration bronchoconstriction such as a methacholine (MCh) challenge (<1 min), similar to asthma (4, 5). Previous work has been limited to measurement of pre- and postsensitization effects or post-long-term challenge in part due to the time required to measure ventilation using the conventional method. The ability to detect changes in ventilation over time scales of less than 1 min may provide improved sensitivity to short-term challenge and insight into disease which more closely resembles asthma (6–9). As well, rapid measurement of ventilation may prove critical for evaluation of fast-acting drug therapies for asthma (10, 11).

We propose a novel approach, Flip Angle Variation for Offset of RF and Relaxation (FAVOR), for obtaining regional ventilation in a single set of breathing cycles (i.e., only one set of 3He wash-in breaths and no air wash-out breaths). This approach utilizes variable flip angle (VFA) RF pulses that compensate for the effects of both RF pulse history and lung T1 relaxation on the 3He signal. Furthermore, the speed of the technique (≈15 sec) removes any dependence on T1 relaxation in the ventilator. In this work we describe the implementation of the FAVOR method and the analysis of the results to yield ventilation maps equivalent to the conventional method. Lobar ventilation measurements and ventilation maps and histograms obtained with the two methods are compared experimentally in normal rats. The results indicate that FAVOR provides accurate and precise regional ventilation measurements rapidly and without the need for multiple air wash-out breaths and additional 3He breathing cycles associated with conventional measurement of ventilation. The FAVOR method is demonstrated for the case of short-term MCh challenge in a rat, revealing temporal changes in ventilation during rapid bronchoconstriction (<1 min), not possible with the conventional method.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

Animal Preparation

This study was approved by the University of Western Ontario Council on Animal Care. Six male brown Norway rats (225 ± 29 g, Charles River Laboratories, Saint-Constant, Canada) were initially anesthetized with 2.0–5.0% isoflurane (Abbott Laboratories, Saint-Laurent, Canada) using a vaporizer (VetEquip, Pleasanton, CA) followed by intramuscular injections of 0.02 mg/kg glycopyrrolate (Sandoz Canada, Boucherville, Canada) to decrease bronchial secretions and 60 mg/kg ketamine (Bioniche Animal Health, Belleville, Canada) and an intravenous injection of 3.0 mg/kg propofol (Astra Zeneca, Mississauga, Canada). Rats remained anesthetized by intravenous administration of a 10:1 mixture of propofol and ketamine at a rate of ≈45–60 mg/kg/h. LacriLube (Allergan Canada, Markham, Canada) was applied to the eyes to prevent drying. Rats were intubated with a 5-F polypropylene urinary catheter (Sherwood Medical, St. Louis, MO) and ventilated in the supine position with a custom ventilator (GE Healthcare, Malmö, Sweden) compatible with MR imaging of hyperpolarized noble gases (Fig. 1). Following intubation the trachea was exposed by a 2-cm incision to the neck and tied around the intubation catheter using three loops of 0-silk suture (Ethicon, Somerville, NJ) to ensure an airtight seal. The seal was verified under breath-hold conditions by manometry (<5% change in pressure for 3He breath-holds).

thumbnail image

Figure 1. Schematic showing experimental setup. The hyperpolarized 3He gas is provided through a Tedlar bag in an acrylic reservoir externally pressurized by a pump. The nonmetallic, pneumatic valve assembly provides precise and timely breaths of gas from the reservoir system. Pressure is monitored by a transducer at the trachea and calibrated using timing of the flowmeters and adjustment of flow restrictors.

Download figure to PowerPoint

Animals were ventilated with the following settings: respiratory rates of 80 breaths/min for air and 30 breaths/min for 3He, peak inspiratory pressure (PIP) of 12 cm H2O, tidal volume of 8 mL per kg of animal body mass, and inspiratory/expiratory time ratio of 1:1. Inspiratory pressure was monitored during experiments at a rate of 10 samples/sec using a pressure transducer (HCXM050D6V, Sensor Technics, Puchheim, Germany) connected to a pneumatic valve assembly attached to the endotracheal catheter. The valve assembly allowed rapid computer-controlled switching between medical-grade air and the 3He gas within a 350 mL Tedlar plastic bag (Jensen Inert Products, Coral Springs, FL) within a pressured reservoir with minimal depolarization. The ventilator did not allow mixing of O2 and 3He as the gas circuits were straight lines controlled by one valve each. Equal inspiratory pressures and, as a result, application of equal volumes of pure 3He as required during one breathing cycle of each gas were ensured by actively pressurizing the reservoir with a pump and regulating the gas flow from the reservoir with a needle valve (Air Logic, Racine, WI). The respiratory rate of the tracer gas, 3He, was limited to 30 breaths/min by the flow rate of the pump that repressurized the reservoir. The endotracheal tube pressure during each 3He wash-in breath and breath-hold was monitored and gasping by the rat, which would cause irregular tidal volumes and motion artifacts, respectively, was not present. Blood oxygen saturation was not monitored. Tidal volumes and PIPs were calibrated by water displacement and manometry, respectively, and were reproducible in the rat to within 4% for a full bag of 3He. MR imaging experiments using the FAVOR technique were repeated three times on three of the rats to determine measurement precision. Due to limited 3He gas, experiments using the conventional technique were done once on each animal and were repeated two more times on a single representative animal to determine precision.

One of the animals in this study was also given an intravenous (tail vein) injection of 0.25 mg/kg methacholine (Sigma-Aldrich, St. Louis, MO) over a period of 1 min. A measure of whole-lung ventilation using the FAVOR method was started simultaneously with the injection and repeated three times, 48 sec apart, with 40 breaths of air administered to the rat between each repetition. All animals were sacrificed at the end of the experiment by intravenous injection of 540 mg/kg of Euthanyl Forte (Bimeda-MTC, Cambridge, Canada).

MR Imaging

3He MR imaging was performed at 3.0T (Signa EXCITE, GE Healthcare, Waukesha, WI) using a transmit-receive bird cage coil (Morris Instruments, Ottawa, Canada), with a length of 17.15 cm and diameter of 11.8 cm, tuned to the 3He resonance (97.3 MHz) and a high performance insert gradient coil (G = 17 G/cm, slew rate = 1500 mT/m/s) described previously (12). 3He gas was polarized using a spin-exchange optical pumping system (HeliSpin; GE Healthcare, Durham, NC). Optical pumping of the gas was typically performed for 18 hr, resulting in polarizations in excess of 32%. The hyperpolarized 3He gas was transferred to a Tedlar bag previously rinsed three times with medical-grade N2 gas and subsequently vacuumed (100 mtorr) to minimize depolarization of gas caused by 3He interactions with O2. The bag was then placed in the pressurized reservoir attached to the ventilator in the bore of the MR imaging magnet 60 cm from the isocenter. The T1 of the gas in the reservoir within the MR imaging magnet was measured to be ≈43 min.

Single-slice FAVOR images were obtained in the coronal plane using a fast gradient-recalled echo pulse sequence (TE = 1 ms, TR = 3.3 ms, FOV = 4 cm, Nx = 128, Ny = 128) using reverse centric k-space sampling and incorporating VFA pulses triggered by the ventilator following each 3He breath (8 breaths, 2 sec apart) with no air wash-out breaths between 3He breaths. Reverse centric sampling was chosen to allow more time for 3He to diffuse to the periphery of the lungs before acquiring the center of k-space. Each image acquisition was triggered by the ventilator at peak inspiration and required ≈430 ms, during which time respiratory motion was suspended within the 2-sec breathing cycle. For each breath (i.e., image), n, the VFA RF pulse trajectory was calculated using the following equation (13):

  • equation image(1)

where the number of the phase encode step i = 1…128 and the number of RF pulses applied Nn = 1024, 896, 768, …, 128 for breaths n = 1, 2, 3, …, 8, respectively. T1,n = 31, 42, 53, 73, 82, 87, 88.5, 90 sec represent the longitudinal relaxation times due to O2 in the lung previously measured during breath-holds on a representative rat after n successive wash-in 3He breaths (14). However, the speed of the FAVOR technique with respect to T1,O2 means this correction is small (this will be discussed later). The RF pulses were calibrated by adjusting the transmitter gain until no measurable change in signal over 128 pulses over the entire sample (i.e., without phase encoding) was obtained following a single 3He breath. If too much power was applied per RF pulse the received signal from successive pulses decreased; and conversely, if too little power was applied the received signal gradually increased and the response from the last pulse, which had α = 90°, was large (Fig. 2). The slight upward trend at the tail of the uniform response (squares in Fig. 2) is due to a B1 inhomogeneity of 2.47% over a 4 × 4 × 4 cm volume. It was calculated as the coefficient of variation of the flip angle using a balloon phantom with a long T1 compared to the acquisition time such that B1 could be measured. Simulations show that 2% inhomogeneity gives a mean full-width at half-maximum of the point spread function of 1.23 compared to the ideal value of 1.21 for the case of no inhomogeneity. Five to eight single breaths of 3He were usually required for VFA calibration. Figure 3 shows the VFA RF pulse trajectory for an eight-image acquisition. As a further calibration check, the number of pulses was extended to 1024 following a single 3He breath and no significant change in signal was observed, confirming that signal loss due to RF depolarization and T1 relaxation was effectively offset by the FAVOR technique. Two preparatory “dummy” breaths of 3He were supplied by the ventilator prior to data acquisition to bleed the portion of the 3He supply line inside the RF coil containing 3He, which was depolarized during the course of the previous scan.

thumbnail image

Figure 2. VFA calibration curves. When too much power was applied the received signal gradually decreased (triangles); and conversely, if too little power was applied the received signal gradually increased and the response from the last pulse, which has α = 90°, was large (circles). The transmitter gain is adjusted until a uniform response to VFA RF pulses is measured (squares). The slight upward trend at the tail of the uniform response is due to B1 inhomogeneity (2.47%).

Download figure to PowerPoint

thumbnail image

Figure 3. The RF pulse trajectory for FAVOR. In this work, 1024 RF pulses are applied over eight breaths following the VFA scheme in Eq. [1].

Download figure to PowerPoint

For image analysis a lower threshold was set by visual inspection of the last image from a series of breaths, such that all the voxels not adjacent to the lung (i.e., background) were removed. The remaining voxels were used to create a mask which was then applied to all images in the series. Ventilation images were also obtained in the conventional way, i.e., following successively increasing numbers of 3He wash-in breaths (up to eight breaths, tidal volume ≈2.6 mL, PIP = 12 cm H2O) separated by intervals of 80 air wash-out breaths (1). However, a 128 pulse VFA sequence was used to image the last breath in each cycle to avoid any blurring due to nonuniform signal amplitudes from using a constant flip angle sequence. Since the pressurized reservoir used here is known to cause variations in tidal volumes over the large numbers of breaths required by the conventional technique (>50), due to collapse of the Tedlar bag despite the active pressurizing with a pump, a full bag was used for each conventional measurement, resulting in some wasted gas.

Data Analysis

Conventional

Following the method of Deninger et al. (1), the MR signal strength following n breaths of 3He separated by time τ can be expressed as:

  • equation image(2)

where equation image, and Eequation image In Eq. [2], q is the fraction of gas remaining following a breath of fresh gas of fraction r (q + r = 1), T1,ext is the longitudinal relaxation time in the reservoir, NA is the number of wash-out air breaths applied between each group of n3He breaths in order to remove the cumulative effects of RF pulses (1) and restore the blood oxygen levels of the rat, RRHe is the 3He respiratory rate, RRair is the air respiratory rate, p0 is the initial alveolar oxygen partial pressure, and ξ is the proportionality factor between O2-induced relaxation time and alveolar oxygen partial pressure.

Flip Angle Variation for Offset of RF and Relaxation (FAVOR)

In the absence of multiple air wash-out breaths (NA = 0), Eq. [2] can be simplified to exclude reservoir relaxation effects (T1,ext) but must account for the effect of cumulative RF pulses on the depolarization of residual 3He gas in the lung. This leads to an expression for signal which depends explicitly on RF tip angle, α, requiring careful measurement and calibration (15) and subsequent correction in the analysis. However, in the FAVOR method the VFA RF pulse trajectory ensures a signal independent of the cumulative effect of RF pulses during a given breath and with a known variation between breaths given by:

  • equation image(3)

Note in Eq. [3] the effect of subsequent RF pulses on residual gas (q) is described by the summation factor Σsin(αk+1)qk. In Eq. [3] the flip angle, αk+1, used in analyzing the signal at a given breath corresponds to the i = 1 pulse in Eq. [1] since the VFA trajectory ensures all acquired signals are the same for an image.

The ventilation r was estimated for the right cranial, middle, and caudal and left lobes by fitting with Eqs. [2] or [3] (as appropriate) using Scilab 4.1 (INRIA ENPC, France) to yield parametric ventilation “r maps” and histograms and then drawing regions of interest using ImageJ 1.34s (NIMH, Bethesda, MD). Values of T1,ext = 2375 s (measured), p0 = 0.135 bar, and ξ = 2.6 bar · s were used in the conventional equation (Eq. [2]). Statistical tests were performed using GraphPad Prism 5.01 for Windows (GraphPad Software, San Diego, CA).

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

Figure 4 shows representative lung images (anterior/posterior projections) for increasing 3He breath number obtained with both the conventional (Fig. 4a) and FAVOR (Fig. 4b) methods. Although the signal-to-noise ratio (SNR) for the conventional technique was higher than that for the FAVOR technique, the effect of increasing signal due to the 3He wash-in is evident in both methods. The major airways are visible in all images, but have lower signal strength compared to the lungs because they contribute relatively less 3He signal to the projection images. Figure 5 shows whole-lung signals from Fig. 4 as a function of breath number. The measured lobar ventilation r obtained by the conventional and FAVOR methods are summarized in Table 1 and are comparable to the mean whole-lung r value of 0.42 ± 0.12 (mean ± standard deviation, SD) calculated from the known ventilator tidal volume and estimated functional residual capacity based on rat mass (16). A Wilcoxon matched pairs test showed the medians were significantly different for the right cranial lobe (P = 0.03), but not significantly different for the right middle and caudal and left lobes (P = 0.06, P = 0.69, P = 0.09, respectively). Tests for effective pairing, which check for correlation while controlling for systematic errors, indicated significantly effective pairing (P < 0.02) in all cases.

thumbnail image

Figure 4. Typical set of coronal rat lung images for increasing helium breath number obtained with conventional (a) and FAVOR (b) techniques. The FOV of each image is 4 × 4 cm. Successive images were taken 2 sec apart.

Download figure to PowerPoint

thumbnail image

Figure 5. Whole-lung MR signal vs. breath number for images in Fig. 4 for both the conventional (a) and FAVOR (b) techniques. The error bars indicate the SD of three repeated scans and the solid lines are the best fits to the data points based on Eqs. [2] and [3], respectively. Note the fundamental difference in signal dependence vs. breath number for the two methods. The FAVOR signal continues to increase monotonically due to the VFA pulse trajectory which increases the RF pulse flip angle up to π/2 for the final pulse of the final breath.

Download figure to PowerPoint

Table 1. Summary of lobar r values (r ± SD) Obtained For all Rats with Both the Conventional Method and FAVOR
Rat No.Mass (g)Right Cranial LobeRight Middle LobeRight Caudal LobeLeft Lobe
r, Conventionalr, FAVORr, Conventionalr, FAVORr, Conventionalr, FAVORr, Conventionalr, FAVOR
11940.37 ± 0.040.44 ± 0.020.28 ± 0.030.31 ± 0.020.28 ± 0.030.27 ± 0.010.33 ± 0.040.38 ± 0.02
22630.26 ± 0.030.35 ± 0.030.24 ± 0.030.27 ± 0.020.23 ± 0.030.23 ± 0.070.29 ± 0.030.31 ± 0.04
32590.33 ± 0.040.38 ± 0.020.28 ± 0.030.30 ± 0.020.28 ± 0.030.29 ± 0.020.29 ± 0.030.28 ± 0.02
42100.38 ± 0.040.41 ± 0.040.29 ± 0.030.32 ± 0.040.30 ± 0.030.32 ± 0.040.36 ± 0.040.38 ± 0.02
52110.32 ± 0.040.35 ± 0.030.25 ± 0.030.23 ± 0.030.16 ± 0.020.14 ± 0.060.23 ± 0.030.27 ± 0.03
62110.34 ± 0.040.36 ± 0.020.29 ± 0.030.32 ± 0.020.32 ± 0.040.32 ± 0.020.33 ± 0.010.36 ± 0.02

Parametric “r maps” for the conventional and FAVOR methods are shown in Fig. 6. The major airways were identified by the discontinuity in r where they entered the lung lobes and they were masked and histograms were generated (Fig. 7). There are 19% fewer voxels in the map made using the FAVOR technique when the major airways are excluded from both images. In the FAVOR data, 11.3% of the voxels had ventilation values of 0, and 4.4% had values >1, mainly in the basal lung region. The FAVOR histogram was generated after excluding these voxels. There were no excluded voxels from the conventional method data because 0.35% of the voxels had ventilation values of 0, and none had values >1.

thumbnail image

Figure 6. Parametric lung “r map” for rat images in Fig. 4 corresponding to the conventional (a) and FAVOR (b) methods. The regional distribution of r values in the parametric maps follows the expected trend, with larger values of r (0.7–0.8) in the large airways and smaller values in the peripheral lung. Each voxel is 312 × 312 μm.

Download figure to PowerPoint

thumbnail image

Figure 7. Histograms of r values from the maps in Fig. 6 corresponding to the conventional (a) and FAVOR (b) methods, which have (mean ± SD) r values of (0.32 ± 0.07) and (0.36 ± 0.27), respectively. Voxels containing major airways were removed from both graphs and values of r of 0 and >1 were removed in the FAVOR case.

Download figure to PowerPoint

Figure 8 shows a plot of r values at baseline and after MCh injection for one animal revealing ventilation depression during the 1-min injection time and then recovery. The width of each column represents the duration of an eight-breath FAVOR scan. Error values are estimated from repeated FAVOR scans on non-MCh challenge FAVOR scans on this animal. The PIP is also plotted for comparison purposes.

thumbnail image

Figure 8. Plot of r and PIP values at baseline and after methacholine injection (which began at time = 0 and had a duration of 1 min) for one animal showing reduction of r during the first minute and recovery. The width of each column represents the duration of each FAVOR scan. Error bars represent the SD of the baseline r values. The SD of the measured PIP during a breath-hold is smaller than the graphical display of the data points.

Download figure to PowerPoint

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

The FAVOR method offers an accurate, precise, and efficient approach to the measurement of regional ventilation using hyperpolarized 3He. Regional ventilation on a lobar basis measured with this method compared well with the conventional method involving multiple air wash-out breaths between 3He wash-in cycles. Regionally, the ventilation maps obtained with the two methods were similar (Fig. 6) and showed the expected regional variation (i.e., larger airways had high r values compared to peripheral lung). However, the fitting of the ventilation model to the basal area of the lungs failed to converge using the FAVOR method data, possibly due to a lower SNR; the thresholding technique did not remove a significant number of basal voxels. The histograms (Fig. 7) show good agreement in mean r values as well, but the data using the FAVOR method had a larger (SD). Despite the lower SNR in the FAVOR images, due to the much smaller amount of remaining polarization, the mean coefficient of variation of FAVOR measurements is still reasonable (4.4% for conventional vs. 9.5% for FAVOR using the left lobe region of interest).

The FAVOR technique as implemented in this work uses 10 breaths (eight imaged 3He breaths and two “bleeding” dummy breaths) and therefore would be expected to provide precise tidal volumes over the course of the ventilation measurement, independent of bag collapse. Indeed, a decrease in PIP of 8.1% after 41 3He breaths was observed, confirming bag collapse. Therefore, each bag was always replaced after ≈45 3He breaths (depending on tidal volume). Additionally, FAVOR is insensitive to change in the reservoir T1, T1,ext, which has been demonstrated to affect r in conventional ventilation measurements (1) where T1,ext needs to be measured precisely because it is affected by the local magnetic field gradient (17). Further analysis of the robustness of the FAVOR technique as a function of number of 3He breaths, the variation of flip angle throughout the lung, and the SNR for a given polarization is warranted.

Correction of the cumulative effects of RF pulses on the dynamic hyperpolarized 3He signal can also be accomplished by direct measurement of the flip angle α and subsequent postprocessing of the data (14). The method proposed here eliminates the need for precise knowledge of α provided the VFA flip angle trajectory is adjusted to provide a constant signal over all images as described in the method by ensuring that the signal follows Eq. [3] exactly for subsequent use of Eq. [1] with i = 1 during postprocessing. We have found the calibration of the VFA trajectory to be very straightforward in practice, requiring only several short-duration 3He breaths to optimize the transmitter gain to two significant figures. It should be kept in mind that B1 field (i.e., α) inhomogeneities can potentially corrupt the VFA acquisition and analysis, but this would be apparent in the calibration step. In this study, a birdcage coil of diameter approximately three times the rat size ensured that the RF field was reasonably uniform across the rat lung (2.47%). Other coil/sample geometries may require more attention to ensure homogeneity. In situations where the B1 field is more inhomogeneous, such as in clinical transceiver RF coils, further investigation will be required.

Ideally, the implementation of FAVOR requires measurement of the appropriate T1,O2 following each breath a priori to calculate the corresponding VFA flip angles (Eq. [1]) and also assumes that T1 is constant throughout the lung. However, it can be demonstrated that ignoring T1,O2 leads to errors in r of less than ≈10% (presumably due to the speed of the method with respect to T1,O2), which is on the order of the coefficient of variation for measuring r using the FAVOR technique and should therefore provide acceptable results even if T1,O2 maps are not available.

The FAVOR implementation described here uses a single-slice 2D acquisition approach to provide rapid imaging with a brief (430 ms) suspension of breathing. If longer breath-holding is performed the method is completely extendable to a multislice or 3D implementation, provided that the VFA trajectory (Eq. [1]) accounts for the increased number of pulses and phase encode steps. In this study, hyperpolarized 3He signal decay due to both RF and T1 depolarization is effectively removed between breaths (i.e., images) to measure dynamic changes in gas density due to ventilation. In principle, FAVOR could be used to advantage in other forms of hyperpolarized 3He imaging where measurement of relative changes in signal from one image to the next is desired (e.g., apparent diffusion coefficient or relaxation time measurement). A further feature of FAVOR is that signal decay is eliminated during image acquisition, thereby minimizing potential blurring due to modulation of k-space.

The speed of the FAVOR sequence used here is about 15 sec, compared to 8 min for the conventional method. This is important for capturing rapid airway bronchoconstriction/dilation responses (<1 min) associated with the MCh challenge in rodents and humans (6, 7, 18, 19). Alternate means for capturing fast bronchoconstriction include the sliding pulmonary imaging for respiratory overview (SPIRO) technique (4, 20). This technique is capable of making images with 5 ms temporal spacing over 5 sec and regional measurements of average inflation rate, filling time, and maximum volume. Our ventilator is capable of making repeated 16-sec ventilation maps spaced 15 sec apart to allow an animal time to breathe air. As the Tedlar bag empties, there is a tendency for the PIP to decrease due to bag collapse. The baseline PIP measurements in Fig. 8 confirm that an effect due to bag collapse is measured even in the absence of MCh. A full bag of 3He was put in the ventilator reservoir immediately before the last baseline scan, causing the increase in PIP. In order to increase the number of FAVOR scans during a MCh challenge, a larger bag may be used within the reservoir of the ventilator. With a specialized gas mixing system, 3He and O2 could be mixed immediately before delivery to a human subject for clinical measurement of lung ventilation with a minimal number of breathing cycles. This could provide human ventilation maps similar to those shown in Fig. 6, previously not possible. We have done pulse amplitude calibration with doses as small as 100 mL of 3He (with N2 as the balance of the inhaled gas) in humans. If a real-time gas mixing system is unavailable, to ensure delivery of identical volumes of gas a 3He-N2 mixture can be premeasured into separate gas delivery bags with O2 added to each bag immediately before scanning. However, the depolarizing effect of O2 will have to be taken into account as an external effect on T1, T1,ext, as shown previously (1).

CONCLUSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

The FAVOR method provides precise and accurate 3He ventilation measurements with minimal effect due to RF pulses and T1 in the lung and the ventilator. This approach eliminates the need for multiple 3He wash-in and air wash-out breaths resulting in savings of a factor of 4.5 in hyperpolarized 3He gas volume and a factor of ≈30 in time. The elimination of multiple ventilation cycles should also reduce errors due to variability in ventilator performance. The method can capture dynamic ventilation changes (<1 min) in the rat lung during short-term methacholine challenge.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES

The helium polarizer was made available by Merck and GE Healthcare. We thank Heather-Anne Cadieux and Tracy Hill for assistance with animal care, M. Reza Akhavan Sharif for assistance with MR imaging, and Ben Chen and Laura Gee for assistance with the methacholine challenge. We also thank Sean Fain for providing the fast gradient-recalled echo pulse sequence.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. CONCLUSION
  7. Acknowledgements
  8. REFERENCES
  • 1
    Deninger AJ, Månsson S, Petersson JS, Pettersson G, Magnusson P, Svensson J, Fridlund B, Hansson G, Erjefeldt I, Wollmer P, Golman K. Quantitative measurement of regional lung ventilation using 3He MRI. Magn Reson Med 2002; 48: 223232.
  • 2
    Santyr G, Lam W, Ouriadov A, Drangova M, McCormack D, Holdsworth D. Comparison of Hyperpolarized Helium MR imaging of Regional Ventilation with Xenon-enhanced CT in Rodents. In: Proc 14th Annual Meeting ISMRM, Seattle, Washington; 2006: 1334.
  • 3
    Greschus S, Savai R, Wolf JC, Rose F, Seeger W, Fitzgerald P, Traupe H. Non-invasive screening of lung nodules in mice comparing a novel volumetric computed tomography with a clinical multislice CT. Oncol Rep 2007; 17: 707712.
  • 4
    Mosbah K, Crémillieux Y, Adeleine P, Dupuich D, Stupar V, Nemoz C, Canet E, Berthezène Y. Quantitative measurements of regional lung ventilation using helium-3 MRI in a methacholine-induced bronchoconstriction model. J Magn Reson Imaging 2006; 24: 611616.
  • 5
    Haczku A, Emami K, Fischer MC, Kadlecek S, Ishii M, Panettieri RA, Rizi RR. Hyperpolarized He-3 MRI in asthma: measurements of regional ventilation following allergic sensitization and challenge in mice — preliminary results. Acad Radiol 2005; 12: 13621370.
  • 6
    Lundblad LKA, Thompson-Figueroa J, Allen GB, Rinaldi L, Norton RJ, Irvin CG, Bates JHT. Airway hyperresponsiveness in allergically inflamed mice — the role of airway closure. Am J Respir Crit Care Med 2007; 175: 768774.
  • 7
    Chen BT, Johnson GA. Dynamic lung morphology of methacholine-induced heterogeneous bronchoconstriction. Magn Reson Med 2004; 52: 10801086.
  • 8
    Amirav I, Kramer SS, Grunstein MM. Methacholine-induced temporal changes in airway geometry and lung density by CT. Chest 2001; 119: 18781885.
  • 9
    Driehuys B, Walker J, Pollaro J, Cofer G, Mistry N, Schwartz D, Johnson GA. 3He MRI in mouse models of asthma. Magn Reson Med 2007; 58: 893900.
  • 10
    Derom EY, Pauwels RA. Time course of bronchodilating effect of inhaled formoterol, a potent and long-acting sympathomimetic. Thorax 1992; 47: 3033.
  • 11
    Wallin A, Sandstrom T, Rosenhall L, Melander B. Time-course and duration of bronchodilatation with formoterol dry powder in patients with stable asthma. Thorax 1993; 48: 611614.
  • 12
    Mayer D, Zahr NM, Adalsteinsson E, Rutt B, Sullivan EV, Pfefferbaum A. In vivo fiber tracking in the rat brain on a clinical 3T MRI system using a high strength insert gradient coil. Neuroimage 2007; 35: 10771085.
  • 13
    Zhao L, Mulkern R, Tseng CH, Williamson D, Patz S, Kraft R, Walsworth RL, Jolesz FA, Albert MS. Gradient-echo imaging considerations for hyperpolarized 129Xe MR. J Magn Reson Ser B 1996; 113: 179183.
  • 14
    Ouriadov AV, Evans A, Lam W, Etemad-Rezai R, Parraga G, McCormack D, Santyr G. Variable Flip Angle MR Imaging of 3He Spin Lattice Relaxation Times for Measurement of Alveolar Oxygen Partial Pressure. In: Proc 15th Annual Meeting ISMRM, Berlin, Germany; 2007: 2790.
  • 15
    Emami K, Guyer R, Kadlecek S, Woodburn JM, Zhu J, Vahdat V, Yu J, Ishii M, Cadman R, Rajaei S, Cox C, Law M, Stephen M, Shrager J, Lipson DA, Gefter W, Rizi R. A Novel Approach to Measure Regional Lung Ventilation Using Hyperpolarized 3He MRI –Potential in Clinical Studies. In: Proc 15th Annual Meeting ISMRM, Berlin, Germany; 2007: 946.
  • 16
    Schulz H, Muhle H. Respiration. In: KrinkeGJ, editor. The laboratory rat. San Diego: Academic Press; 2000. p 323344.
  • 17
    Schearer LD, Walters GK. Nuclear spin-lattice relaxation in the presence of magnetic-field gradients. Phys Rev 1965; 139: A1398A1402.
  • 18
    Goldin JG, McNitt-Gray MF, Sorenson SM, Johnson TD, Dauphinee B, Kleerup EC, Tashkin DP, Aberle DR. Airway hyperreactivity: assessment with helical thin-section CT. Radiology 1998; 208: 321329.
  • 19
    Samee S, Altes T, Powers P, de Lange EE, Knight-Scott J, Rakes G, Mugler JP, Ciambotti JM, Alford BA, Brookeman JR, Platts-Mills TAE. Imaging the lungs in asthmatic patients by using hyperpolarized helium-3 magnetic resonance: assessment of response to methacholine and exercise challenge. J Allergy Clin Immunol 2003; 111: 12051211.
  • 20
    Dupuich D, Berthezène Y, Clouet P-L, Stupar V, Canet E, Crémillieux Y. Dynamic 3He imaging for quantification of regional lung ventilation parameters. Magn Reson Med 2003; 50: 777.