**7. Outlook of hyperpolarized 129Xe brain MRI**

This subsection will summarize the current progress as previously described, and comment the future research directions and applications in the brain imaging. Conventional MRI focuses mainly on the nuclear spin of the proton because it is ubiquitous in most parts of the human body. However, certain organs have a low proton spin density attributable to the large volume of air dispersed throughout the tissue. The low sensitivity of traditional magnetic resonance has motivated the development of techniques using hyperpolarized noble gases for NMR and MRI. Xenon has the unique characteristic of being soluble in many fluids and biological tissues, such as water, blood, lung tissue, and white and gray matter. Being a trace element in the atmosphere, xenon has no natural background signal in the human body. Therefore, dissolved-phase xenon MRI and molecular imaging could provide rich information related to biological and physiological changes beyond void space lung imaging. Efforts have demonstrated the value of dissolved xenon MRI in the study of lung gas exchange (Swanson et.al, 1999), and brain perfusion (Swanson et al., 1997; Kilian et al., 2004; Zhou et al., 2008, 2011a, 2011b) and function (Mazzanti et al., 2011). Recently, xenonbased molecular imaging has been demonstrated by using cryptophane-containing biosensors (Hilty et al., 2006). Sensitivity enhancement using a chemical amplification technique, hyperpolarized xenon chemical exchange saturation transfer (Hyper-CEST) (Schröder et al., 2006), allows imaging at low concentrations; however, for *in vivo* applications the small filling factor of a region of interest in the body relative to the NMR coil is a significant factor limiting sensitivity. In such cases remote detection methods (Hilty et.al, 2005) can provide dramatic improvements in sensitivity. In remote detection, the normal NMR coil that contains the full region of interest is used to encode spectroscopic and spatial information, then stores it as longitudinal magnetization. These encoded spins then flow into a second coil with an optimized filling factor for detection.

Remote detection can overcome the filling factor issue of dissolved xenon MRI, although a low concentration of xenon in solution can be another significant impediment to highly sensitive detection. It has been shown that the solvated xenon signal can be amplified by xenon polarization transfer contrast, in which the dissolved-phase xenon from either lungs or brains is selectively saturated, and through exchange, the gas-phase signal is attenuated.

Hyperpolarized Xenon Brain MRI 141

Bock C, et al. (1998). Functional MRI of somatosensory activation in rat: effect of

Blümich B, et al. (2008). Mobile single-sided NMR. *Prog. Nucl. Magn. Reson. Spectr.*, Vol.52,

Cherubini A & Bifone A. (2003). Hyperpolarized xenon in biology. *Prog. Nucl. Magn. Reson.* 

Choquet P, et al. (2003) Method to determine *in vivo* the relaxation time T1 of hyperpolarized xenon in rat brain. *Magn. Reson. Med.,* Vol. 49, pp.(1014–1018).

Duhamel G, et al. (2002). Global and regional cerebral blood flow measurements using NMR of injected hyperpolarized xenon-129. *Acad. Radiol.*, Vol. suppl 2, pp.(S498-S500). Goodson BM. (2002). Nuclear magnetic resonance of laser-polarized noble gases in molecules, materials, and organisms. *J. Magn. Reson.*, Vol.155, pp.(157–216). Gur D & Good WF.(1982). *In vivo* mapping of local cerebral blood flow by xenon-enhanced

Hilty C, et al. (2006). Spectrally resolved magnetic resonance imaging of a xenon biosensor.

Hilty C, et al. (2005). Microfluidic gas-flow profiling using remote-detection NMR. *Proc.* 

Kilian W, et al. (2004). Dynamic NMR spectroscopy of hyperpolarized 129Xe in human brain analyzed by an uptake model. *Magn. Reson. Med.,* Vol. 51, pp.(843–847). Mandeville JB, et al. (1999). MRI measurement of the temporal evolution of relative CMRO2 during rat forepaw stimulation. *Magn. Reson. Med.,* Vol. 42, pp.(944–951). Martin CC, et al. (1997). The pharmacokinetics of hyperpolarized xenon: implications for

Mazzanti M, et al. (2011). Distribution of hyperpolarized xenon in the brain following sensory stimulation: preliminary MRI findings. *PLoS ONE*, Vol. 6, pp.(e21607). Meng X, et al. (2004). Characterizing the diffusion/perfusion mismatch in experimental focal

Navon et al. (1996). Enhancement of solution NMR and MRI with laser-polarized xenon.

Oros A-M & Shah NJ. (2004). Hyperpolarized xenon in NMR and MRI. *Phys. Med. Biol.*, Vol.

Paulsen JL, et al. (2008). Volume-selective magnetic resonance imaging using an adjustable, single-sided, portable sensor. *Proc. Natl. Acad. Sci. USA*, Vol.105, pp.(20601–20604). Peled S, et al. (1996). Determinants of tissue delivery for 129Xe magnetic resonance in

Ruppert K, et al. (2000). Probing lung physiology with xenon polarization transfer contrast

Swanson SD & Rosen MS. (1997). Brain MRI with laser-polarized 129Xe. *Magn. Reson. Med.,*

Cook GE. (1961). Argon, Helium and the Rare Gases, Interscience Publishers, New York Duhamel G, et al. (2000). *In vivo* 129Xe NMR in rat brain during intra-arterial injections of

computed tomography. *Science,* Vol.215, pp.(1267–1268).

cerebral MRI. *J. Magn. Reson. Imag.*, Vol. 7, pp.(848–854).

cerebral ischemia. *Ann. Neurol.*, Vol. 55, pp.(207-212).

humans. *Magn. Reson. Med.*, Vol. 36, pp.(340–344).

(XTC). *Magn. Reson. Med.*, Vol. 44, pp.(349–357).

*Science*, Vol. 271, pp.(1848-1851).

49, pp.(R105–R153).

Vol.38, pp.695–698,

*Angew. Chem. Int. Ed*. Vol.45, pp.(70–73).

*Natl. Acad. Sci. USA,* Vol.102, pp.(14960–14963).

Vol. 39, pp.(457–461).

*Spectr.*, Vol. 42, pp.(1–30).

pp.(197–269).

(529-536).

hypercapnic upregulation on perfusion- and BOLD-imaging. *Magn. Reson. Med.*,

hyperpolarized 129Xe dissolved in a lipid emulsion. *C.R. Acad. Sci. III*, Vol. 323, pp.

This method is able to indirectly image dissolved-phase xenon, but is limited to tissue in direct exchange with the air in the lungs. The gas exchange process could be similarly exploited for direct signal amplification of dissolved xenon with the remote detection technique, which extends the study area from lung to brain. Xenon gas can be extracted from the dissolved solutions and concentrated in the gas phase for detection. Furthermore, with the long longitudinal relaxation time of gas-phase xenon, extracted xenon gas from solution can be compressed or liquefied while preserving the encoded information. The xenon density in the liquid state is approximately four orders of magnitude higher than in aqueous solutions, which in principle could result in up to 10,000 times enhancement of spin density, thus allowing substantial signal amplification

We have demonstrated the hyperpolarized xenon signal amplification by gas extraction (Hyper-SAGE) method (Zhou et al., 2009b) with enhanced NMR spectra and time-of-flight (TOF) images by using recently commercialized membrane technology for high-efficiency xenon dissolution (Baumer et.al, 2006). The Hyper-SAGE technique relies on physical amplification by exploiting a phase change and is completely distinct from chemical amplification. In combination with additional amplification techniques such as Hyper-CEST, this method promises to dramatically decrease the detection threshold of MRI and has the potential to benefit molecular imaging applications and brain imaging.

Recent innovations in the production of highly polarized 129Xe and novel method of signal enhancement should make feasible the emergence of hyperpolarized 129Xe MRI as a viable adjunct method to conventional MRI for the study of brain function and disease. The high sensitivity of hyperpolarized noble gas signal and non-background noise in biological tissue offer xenon as an important and promising contrast agent to study the brain. Because the polarization of hyperpolarized xenon does not depend on the magnetic field strength, the technique for brain imaging could also be applied for use with low field portable MRI devices (Appelt, 2007; Blümich, 2008; Paulsen, 2008).
