Hyperpolarized ³He and perfluorocarbon gas diffusion MRI of lungs

A remarkable development at the interface of physics and biomedical science over the past 10 years has been the use of hyperpolarized (HP) noble gases to perform MRI of the lung air space. Such imaging is made possible through laser-optical pumping, which can improve the magnetic resonance sensitivity of certain noble-gas isotopes having non-zero nuclear spin by several orders of magnitude. The two most important isotopes are the spin one-half nuclei ³He and ¹²⁹Xe, because of their long intrinsic T₁ relaxation times. We recall that the conventional thermal polarization P_th in an applied magnetic field B₀ is given by P_th=μB₀/k_BT, where μ is the nuclear magnetic moment, k_B is the Boltzmann constant, and T is the absolute temperature in Kelvins. For fully relaxed protons in a conventional 1.5 T applied field for whole-body MRI, we have P_th=6×10^-6, which suffices for magnetic resonance (MR) imaging of protons in water. Gases delivered at pressures of ≈1 atm are over 2000 times less dense than protons in water with a corresponding decrease in MR sensitivity, but hyperpolarization yields an enhancement of 4 to 5 orders of magnitude (P_hyp=10-50%), more than compensating for the density difference. Indeed, highly polarized ³He can remain sufficiently sensitive to MRI even if it constitutes only a fraction of the inhaled gas mixture. Once introduced in vivo to the lungs, depending on the breathing maneuver and the inhaled mixture, HP gases relax with a time T₁=20-30 s, where the relaxation is dominated by interaction with paramagnetic oxygen. In the glass cell used for hyperpolarization, T₁ values are much longer, ranging from 20 to 40 h. Because the function of the lung is gas exchange, it is hardly surprising that regionally specific information about inspired gas should be at least as relevant to the study of lung physiology and disease as images of the lung-tissue structure (e.g. hydrogen MRI or X-ray CT). Results from several research groups have indeed demonstrated the potential for HP-gas MRI to enhance our understanding of lung function, with further potential impact on disease treatment, surgical planning, and drug development. (Lung diseases such as chronic obstructive pulmonary disease (COPD) and asthma affect tens of millions of people in the US alone [1]). Almost immediately from the time that the first animal- and then human-lung images were demonstrated [2-5], several groups have explored pulse-sequence techniques and contrast mechanisms that go well beyond static spin-density imaging and that make use of the unique physical properties of these gases to address physiologically relevant questions. This article deals largely with one such contrast mechanism: diffusion (i.e. Brownian motion) of gas in the lung. Rapid gas diffusion can cause problems ranging from limited image resolution to signal attenuation due to the presence of bulk susceptibility and/or imaging gradients. However, as with relaxation due to the presence of oxygen (see below), there is a flip side to the story that enables meaningful physiological information to be obtained. Indeed, an early conclusion in HP ³He MRI, based on the fact that diffusion does not limit signal intensity or resolution as much as might be expected, was that airway and alveolar boundaries restrict the diffusive motion of ³He in healthy lung [6,7]. The apparent diffusion coefficient (ADC) of the gas can thus be a powerful indicator of local airway and alveolar architecture, which is itself often profoundly affected by lung disorders, such as COPD [8]. Most of the imaging discussed here involves HP ³He, as it has been most widely used to date in studies of lung ADC. However, we also consider in this regard other gases that may be used as MRI signal sources. Other noble-gas isotopes (principally ¹²⁹Xe) can be hyperpolarized and have been used for lung imaging [9]. Although ¹²⁹Xe has only 1/3 the magnetic moment of ³He and has generally been more technically challenging to polarize in large quantities, it provides unique contrast in that it is taken up by the blood from the lung and exhibits a wide chemical shift range when dissolved in a variety of tissues [10]. The excitement generated by HP-gas MRI has also contributed to a renewed interest in the use of inert fluorinated gases to image the lungs [11,12]; these gases have a number of features that somewhat mitigate the disadvantage of a small (thermally generated) nuclear polarization, and they are technically easier to handle and use, particularly for in vivo studies. Before turning exclusively to diffusion MRI, we will first briefly discuss how hyperpolarized gas is generated and imaged. We will also highlight (though by no means exhaustively), some of the developments in the last 10 years across the field of lung imaging with HP gases. More complete reviews of the field may be found in Refs. [13,14]. The subsequent sections on diffusion MRI are based largely on research done by the group at Washington University, where it has been a major effort for the past 8 years. We will start with how simple measurements of ³He ADC can be used to gauge the regional severity of tissue destruction due to emphysema. We then discuss a more detailed model of airway architecture that can be tested by investigating ³He diffusion anisotropy. The fact that gases diffuse so rapidly affords the opportunity to explore lung structure on many different length scales, and the next section discusses experiments to measure long-range ³He diffusion in the lung. Finally, we present some recent work involving ¹⁹F diffusion MRI. Hyperpolarization of ³He: ³He is a stable non-radioactive isotope of helium with nuclear spin 1/2 and a gyromagnetic ratio about 25% smaller than the proton; it has ≈1 ppm natural abundance but is available in pure form as the result of collection from tritium decay. The nucleus can be polarized to values approaching unity by transfer of angular momentum from circularly polarized laser light. There are two basic schemes for this transfer: metastability-exchange optical pumping (MEOP) [15,16] and spin-exchange optical pumping (SEOP) [17]. In both schemes, the ³He gas typically resides in a glass vessel (cell) through which the laser light is directed. In MEOP, a radio-frequency discharge is ignited in the cell to create a population of ³He atoms in the triplet-2S metastable electron state. Optical pumping with 1083 nm laser light, corresponding to transitions from the triplet-2S to certain triplet-2P states, leads to a large electron polarization in the metastable state, which is immediately transferred to the nucleus via hyperfine coupling. Rapid electron-exchange collisions then produce nuclear polarized ³He atoms in the ground state. In SEOP, an alkali metal (usually rubidium) serves as an intermediary in the angular momentum-transfer process. Laser light is absorbed by the Rb vapor at a wavelength of 795 nm, corresponding to the first principal dipole transition (5S_1/2-5P_1/2), causing the Rb valence electron to become highly polarized. A density of Rb vapor appropriate to the amount of available laser light is produced in the cell by heating it to 160-200 °C. The angular momentum is then transferred to the ³He nucleus via a hyperfine interaction (zero-quantum transition) that takes place during Rb-³He binary collisions. In both methods, the mechanism for polarization transfer is easily turned off (in MEOP by terminating the discharge and in SEOP by cooling down the cell and condensing the Rb vapor), leaving the angular momentum stored in the form of polarized ³He nuclei. The longitudinal relaxation time of the gas (usually dominated by collisions with the cell walls) can, with some attention given to how the cell is fabricated, be many 10 s of hours, allowing sufficient time for storage and transport of the hyperpolarized gas to an MRI scanner. We note that the SEOP method can also be used to hyperpolarize the other stable and abundant spin-1/2 noble-gas isotope, ¹²⁹Xe. Generally speaking, MEOP has historically had the advantage of an intrinsically faster production rate and largest maximum ³He polarization, routinely producing quantities ∼1 STP-liter/hour at >60% polarization [18]. However, the RF discharge requires that the gas be polarized at pressures ∼1 Torr and then compressed to atmospheric pressures without causing significant polarization loss [19]. In addition, the lasers used in MEOP have been somewhat more expensive and more difficult to maintain. Initial large-scale polarization systems have been large and expensive, but much more portable and inexpensive MEOP systems have been recently demonstrated [20]. By contrast, SEOP systems have the advantage of cheap powerful portable lasers and the ability to operate at helium pressures between 1 and 10 atm but a slower intrinsic production rate; a typical system requires many hours to produce 1 STP-liter of HP ³He [21]. SEOP is a photon-limited process, and the introduction in the 1990s of compact inexpensive diode-laser arrays, capable of several tens of watts at 795 nm, was a crucial technological advance that allowed the production of quantities of HP ³He sufficient for human-lung MRI. Recently, the simultaneous use of both rubidium and potassium metals in a SEOP cell has been shown to improve the HP ³He production rate by an order of magnitude [22]. ...