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Effects of Fraction of Inhaled Oxygen on Hyperpolarized 129Xe MR Signals Acquired from the Rat Brain In Vivo

Yonni Friedlander^1,2, Marcus Couch^1,2, Andrea Kassner^1,3, and Giles Santyr^1,2

¹Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada, ²Medical Biophysics, University of Toronto, Toronto, ON, Canada, ³Medical Imaging, University of Toronto, Toronto, ON, Canada

Synopsis

A theoretical model was developed to describe the dependence of the signal strength of ¹²⁹Xe dissolved in the rat brain on the fraction of inhaled oxygen (F_iO₂). To validate the model, ¹²⁹Xe MR signals were measured in the rat brain in vivo for four different values of F_iO₂ using a continuous ventilation scheme. The measured ¹²⁹Xe RBC signal showed a strong dependence on F_iO₂ in good agreement with the trends predicted by the theoretical model. These results underscore the need to optimize and control F_iO₂ when using ¹²⁹Xe signals to probe brain function.

Introduction

¹²⁹Xe MRI has gained interest as a tool to probe for brain function such as cerebral blood flow (CBF)^1,2. The purpose of this work was to develop a theoretical model for the dependence of hyperpolarized ¹²⁹Xe signal from red blood cells (RBCs) in the brain on the fraction of inhaled oxygen (F_iO₂). The model is validated using ¹²⁹Xe RBC signals acquired in vivo from rat brain following inhalation breathing paradigms which vary F_iO₂.

Method

Theoretical Model

We incorporated previously presented equations for the relationships between oxygen concentration and T₁ of ¹²⁹Xe in the lungs³ and T₁ of ¹²⁹Xe in the blood⁴ with a time-dependent theoretical signal model for ¹²⁹Xe in the brain based on the Kety-Schmidt equations⁵. In addition, we modeled the effects of oxygen saturation on the T₂^* of RBCs in the brain⁶ to develop a comprehensive model for the dependence of ¹²⁹Xe signal in the brain on F_iO₂.

MR Spectroscopy

Alternating 3ml breaths of xenon (~86% ¹²⁹Xe, ~15% polarization) and air or O₂ were delivered to five mechanically-ventilated rats using four different breathing paradigms (Fig. 1) to vary the F_iO₂. Using a 3T MRI Scanner (Siemens, Germany) and quadrature transmit/receive birdcage coils (inner radii of 1.7cm or 6cm, Morris Instruments, Canada), ¹²⁹Xe spectra were acquired following an excitation pulse delivered every 1s during ventilation (30° flip angle, 3-lobe sinc, pulse of length 1280μs, transmit frequency at 200ppm from gas, slice thickness of 4cm, centered on the rat brain). Once steady ¹²⁹Xe signal was reached in the brain, the spectra were averaged and decomposed in the time domain into six additive exponential components (five dissolved components and one gas component) using spectral analysis code provided by the Duke Center for In Vivo Microscopy NIH/NIBIB (P41 EB015897)⁷. The signal of each dissolved component was calculated as the area under each Lorentzian curve in the spectral domain, normalized to the gas signal.

Results

A representative ¹²⁹Xe signal time-course is shown in Fig. 2 where a steady-state signal is reached at approximately 20s after initiation of the paradigms shown in Fig. 1. A representative ¹²⁹Xe spectrum is shown in Fig. 3a. The chemical shift of each spectral component agrees with previously reported values^8–10. Fig. 3b shows a comparison of two spectra acquired in the same rat but at different F_iO₂. The measured and predicted signal values as a function of F_iO₂ are shown in Fig. 4 and summarized in Table 1.

Discussion

The ¹²⁹Xe RBC signal measured in rat brain in vivo shows a strong dependence on F_iO₂ which agrees with the trends predicted by the theoretical model (Fig. 4). The measured ¹²⁹Xe RBC signal reduction at F_iO₂ of 10.5% was 55%±19% relative to the signal at F_iO₂ of 50%. The drop in signal was statistically significant (t-test, P<0.0001). The maximum RBC signal, as predicted by the model, occurs at F_iO₂ = 61%. By fitting a model of ¹²⁹Xe uptake in the brain⁵ to the time-course signal, the transit time for ¹²⁹Xe to reach the brain from the lungs was measured to be 2.5s. Previous studies predicted a transit time of 4–5s in humans^5,11. It is reasonable to expect the transit time in rats to be less than that in humans.

¹²⁹Xe MRI of the brain has traditionally used the time-course of the ¹²⁹Xe signal magnitude in the brain as a measure of CBF^{1,2,8,12–15}. An important implication of this study is that the ¹²⁹Xe signal depends on oxygen-induced relaxation effects, in addition to hemodynamic effects, thereby confounding measurements of CBF. For example, increased T₁ relaxation in the blood during transit to the brain would reduce the ¹²⁹Xe signal in the brain up to 40% by the end of a 30s breath hold¹⁶. ¹²⁹Xe signal from RBCs in the brain would be further reduced by 20% due to T₂^* relaxation for the excitation pulse used in our study. This effect is further exemplified by the brain tissue spectra in Fig. 3b. An increased brain tissue signal is expected for the hypoxic paradigm due to an increase in CBF. However, the signal does not increase, suggesting a possible masking of the increased CBF by the increased relaxation rates.

Conclusion

A dependence of¹²⁹Xe RBC signal on F_iO₂ is observed in the rat brain, in qualitative agreement with a theoretical model based on changes in oxygen-induced T₁ and T₂^* relaxation of ¹²⁹Xe gas in the lung, dissolved ¹²⁹Xe signal in the blood, and ¹²⁹Xe uptake in the brain. These results underscore the need to optimize and control F_iO₂ when using ¹²⁹Xe signals to probe brain function.

Acknowledgements

Thanks to E. Stirrat, N. Kanhere, A. Lindenmaier, B. Zanette, and F. Morgado for their assistance with imaging experiments. This work was supported by grant funding from NSERC Discovery Grant (RGPIN-2015-03832). Y.F. was financially supported by a Queen Elizabeth II Graduate Scholarship in Science and Technology.

References

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Figures

Figure 1 – Four different ventilation paradigms used to vary F_iO₂ in the rats. A total of 28 MR spectroscopy acquisitions were performed for four different ventilation patterns: (i) N_FiO2=50% = 13, (ii) N_FiO2=33.3% = 3, (iii) N_FiO2=14% = 3, (iv) N_FiO2=10.5%= 9. All five rats were ventilated with patterns (i) and (iv) and two of the rats were ventilated with patterns (ii) and (iii).

Figure 2 – Representative time-course for ¹²⁹Xe signal acquired from the brain RBCs and the rest of the brain respectively from the rat in vivo. The x-axis shows time after the start of the ventilation paradigms shown in Fig. 1.

Figure 3 – (a) Representative spectrum of ¹²⁹Xe dissolved in the rat brain. The thin blue line is the magnitude of the acquired spectrum and the thick coloured lines are the magnitude of the fitted spectrum showing the identification of the various peaks. A linear phase correction has been applied to each component. (b) Example ¹²⁹Xe spectrum demonstrating the effects of changing F_iO₂ on the acquired signals. Note the increase in ¹²⁹Xe RBC signal at higher values of F_iO₂. The figure shows the fitted spectrum with the raw data shown in the inset.

Figure 4 – Signal as a function of fraction of inhaled oxygen (F_iO₂). The black circles shows the mean experimental measurements and the error bars represent one standard deviation of error calculated over all rats at each F_iO₂. The asterisks show the theoretical predictions corresponding to the two measurements (F_iO₂ = 10.5% and 14% respectively), corrected for an expected hypoxia-induced increase in CBF^17,18.

Table 1 - Summary of effect of oxygen on ¹²⁹Xe RBC signal. Value for 1 standard deviation is shown in parenthesis. Predicted values are corrected for a 50% increase in CBF during hypoxia.

Proc. Intl. Soc. Mag. Reson. Med. 26 (2018)

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