Pulmonary acinar structure and function assessed by hyperpolarized 129Xe stimulated echo NMR
Agilo Luitger Kern1,2, Marcel Gutberlet1,2, Frank Wacker1,2, Jens Hohlfeld2,3,4, and Jens Vogel-Claussen1,2
1Institute of Diagnostic and Interventional Radiology, Hannover Medical School, Hannover, Germany, 2Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), Hannover, Germany, 3Department of Clinical Airway Research, Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany, 4Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany


A pulse sequence for hyperpolarized 129Xe NMR based on accumulated stimulated echoes has been implemented. Pairs of 90° pulses are repeatedly irradiated at the frequency of 129Xe in tissue-plasma and the decaying signal transferred to the gas phase is subsequently acquired. A study with healthy volunteers and patients of chronic obstructive pulmonary disease (COPD) has been performed to assess the method’s sensitivity for disease. A significant reduction of initial stimulated echo signal and trend for faster decay are observed in COPD. The proposed method has been demonstrated to be highly sensitive for emphysema and hyperinflation and shows promising diagnostic potential.


Gas transport in the lung is driven by two mechanisms–convection and diffusion. Since diffusional transport in acinar airways is slow, the lung’s efficiency is reduced, an effect known as acinar screening.1 The situation changes in exercise and disease: Early emphysema leads to reduced alveolar surface area but only mildly diminished gas uptake at rest since the effect of acinar screening is reduced.2 This protective mechanism of the lung may be a reason why early emphysematous lung disease frequently remains unnoticed. 3He MRI has been used for measurements of diffusion in the long regime using stimulated echo-techniques, which are thought to be particularly sensitive to alterations of acinar microstructure and airway connectivity.3,4 The gas uptake process itself, however, remains inaccessible for 3He MRI. Xenon, by contrast to other MR-visible gases, has the unique property of being soluble in biological tissues, opening new avenues for assessing both gas uptake and lung structure noninvasively by hyperpolarized 129Xe MRI.5–7 Purpose of this work was to develop a pulse sequence particularly sensitive for early emphysematous changes in the acinus by creating stimulated echoes (STE) in gas phase 129Xe transferred from accumulated excitations of dissolved-phase 129Xe and to test its sensitivity in a clinical study with patients of chronic obstructive pulmonary disease (COPD) and healthy volunteers.


A pulse sequence according to the diagram in Figure 1 was implemented. A 90° Fermi-shaped pulse of width 2300µs centered on the tissue/plasma resonance at Δf=3485Hz is irradiated followed by a dephasing gradient and another 90° pulse of same frequency and phase. To accumulate spatially modulated magnetization, this first module was repeated N1=20 times with TR1=21.8ms. Subsequently, a train of N2=50 excitation and readout elements was played out with TR2=12.3ms to obtain both FID and STE signals. As a control acquisition, the pulse sequence was repeated with off-resonance frequency Δf=–3485Hz and orthogonal orientation of the de-/rephasing gradients.
The performed study was approved by the institutional review board and written informed consent was obtained from all subjects. 12 patients of COPD and 8 healthy volunteers (HV) were included in the study, see Table 1 for subject demographics. 129Xe imaging was performed at 1.5T (Avanto, Siemens, Erlangen, Germany) using a custom-made coil (Rapid Biomedical, Rimpar, Germany). A repeated MRI scan was performed in HV1. All subjects underwent conventional lung function testing.
Data were corrected for off-resonance apparent in FID signals and Fourier-transformed for visual inspection. Signals in the STE pathway were subsequently phase corrected using averaged data from the first three acquisitions. The real parts of both signals were integrated and the ratio Q of phase-corrected STE and FID signal was computed for each acquisition. Since the total diffusion-weighting b caused by the STE dephasing gradients increases linearly with acquisition number, an approximately exponential decay of the STE signal due to diffusion attenuation is expected and the following function was fit to the data,

with N the acquisition number.


Figure 2 shows exemplary FID and STE spectra from a healthy volunteer and a COPD patient for both off-resonance frequencies. Only small contamination possibly from parasitic excitation is apparent in the control acquisition. A clear decay of the ratio Q with increasing acquisition number was observed in all subjects as apparent in Figure 3. Fitting results are shown in Table 1. The phase of the STE signal is mostly close to, but significantly different from π in a Wilcoxon signed-rank test in COPD patients, P=0.0024. Plots comparing fitting results of Q0 and N0 are shown in Figure 4. In a Wilcoxon rank-sum test Q0 is significantly reduced in COPD, P=2.5e–4, while there is also a trend for reduced N0, P=0.0698. Q0 is significantly correlated with FEV1/FVC in the study population, Spearman-ρ=0.81, P=1.5e–5.


We developed a new hyperpolarized 129Xe MR pulse sequence for assessment of pulmonary acinar structure and function, which has been shown to be particularly sensitive for emphysema and/or hyperinflation. In order to improve the SNR, we implemented a train of 90° pulse pairs for accumulating STE signal as motivated by work from Gutjahr et al.8 Compared to existing methods probing hyperpolarized 129Xe exchange like XTC,9 the proposed method does not necessitate control acquisitions in principle. The method probes gas diffusion on the time scale of ~1s corresponding roughly to the acinar length scale and thus suggesting sensitivity to acinar structure, which still needs to be validated by histological comparison. One limitation of the proposed approach is the more qualitative assessment of emphysema by the quantities Q0 and N0, which are expected to depend on sequence parameters. Further, in some COPD patients the obtained signal Q0 was apparently too small to allow accurate quantification of N0. The method is also suspected to be susceptible to motion. This could possibly be reduced by adding 1D readouts for resolving the spatially modulated magnetization in the STE pathway. This may require parameter optimization or use of higher 129Xe doses and polarization levels to achieve higher SNR.


A new pulse sequence for assessment of pulmonary acinar structure and function has been developed which has been shown to be highly sensitive for emphysema and hyperinflation and thus shows promising diagnostic potential.


This work was funded by the German Center for Lung Research (DZL).


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Figure 1. Pulse sequence diagram. The phase difference of the two 90° pulses was chosen to be 0 at the given off-resonance frequency Δf. Fermi-shaped pulses are used for selectively creating spatially modulated magnetization in the 129Xe dissolved phase while providing a sufficient amplitude integral to achieve 90° flip angles within the dissolved phase T2*. The whole sequence is repeated as a control acquisition with inverted off-resonance frequency and STEAM de- and rephasing gradients rotated by 90°.

Figure 2. Exemplary line-broadened spectra after off-resonance correction and phasing for the FID signal from a) a healthy volunteer and b) a COPD patient after excitation at +3485 Hz. Real part of FID signal shown in orange, STE signal in blue and rescaled by factor 100. In a) as expected for pure TP excitation, an approximate phase difference of π is found. In b) at later times a noticeable phase change is observed, possibly due to signal contamination or motion. Control acquisitions are shown for the HV in c) and the COPD patient in d). Only small signals are observed in the STE pathway.

Figure 3. Decaying ratios Q of STE signal with increasing readout number, corresponding to increased diffusion-weighting, for a) a healthy volunteer and b) a COPD patient. Clearly reduced initial amplitude and a trend towards faster decay are apparent in the case of COPD.

Figure 4. Box plots of fitting results for a) Q0 and b) N0 in healthy volunteers (HV) and COPD patients. The parameter Q0 separates both groups without overlap. In b) there are outlying data points for HV 1 and COPD 10 outside the plotting range, see Table 1. c) Scatter plot of Q0 and Tiffeneau index.

Table 1. Subject demographics, results from lung function tests and fitting results. *Repeated MRI scan, not included in statistical analysis.

Proc. Intl. Soc. Mag. Reson. Med. 29 (2021)