NL1039690C2 - Method of recovering hyperpolarization in hp-mri experiments. - Google Patents

Description

Method of recovering hyperpolarization in HP-MRI experiments The technical field

The invention is in the field of hyperpolarized magnetic resonance imaging (HP-MRI), in 5 which a high degree of the hyperpolarization of the agent is recovered from the experiment.

Background art HP-MRI started in the early 1990s. With increasing degree of polarization, the future for hyperpolarized He-3 and Xe-129 gas for lung imaging is very promising, but there are 10 difficulties. The hyperpolarization of the nuclei decays quickly in the lung, leading to logistical and methodological problems as many MRI methods cannot be efficiently used for the single bolus decaying hyperpolarized gas imaging in a single breath hold of about 20 seconds.

Some aspects of HP-MRI are mentioned. At present a high degree of polarization can be achieved for He-3 and Xe-129 gases, as also for C-13, N-15, F-19, Si-29 and P-31 which are 15 important imaging agents in biomedicine. The He-3 gas is taken as an example. The thermal equilibrium MR signal of He-3 gas is about 0.001 compared to that of proton of water, in the same magnetic field of 1.5 Tesla, room temperature, 1 bar pressure and of same volume. To date the polarization of He-3 gas can be enhanced by more than 100.000 times, so without the need for a high field magnet the hyperpolarized MR signal >100 times that of water in a cryogenic 20 magnet of 1.5 T. More importantly, whereas water is inappropriate for lung imaging, hyperpolarized He-3 gas is most suitable to image lung disease, a major problem in developed nations, presently the third dead cause in the USA and fourth in the EU. Hyperpolarization of the He-3 gas is usually done at specialized sites, transported in a container to the investigation site and can be stored for 4-12 days depending on the type of container, storage temperature 25 and pressure. However, when a single bolus of hyperpolarized He-3 gas is used for in vivo lung imaging, the longitudinal magnetization Mz, which is proportional to the polarization, decays as exp(-t/Ti), with decay time Ti of about 30 seconds. The transverse magnetization M+ decays as exp(-t/T2) with T2 of about 3 seconds. Usually, by natural decay with Ti or T2 during the experiment and procedural destruction, like applying a crusher gradient to destroy the remaining 30 magnetization of one encoding step to avoid aliasing with the magnetization of the next encoding step, at the end of the experiment the hyperpolarized gas is completely depolarized [1]. So it is obvious that hyperpolarization cannot be recovered from such experiments. Therefore no methods exists that recovers the hyperpolarized gas from the experiment. Though the gas may 1039690 2 be recovered, every time it must be returned to the production site to be hyperpolarized again. This fact and the limited availability of He-3 make the hyperpolarized He-3 gas lung imaging complicated and expensive.

5 Disclosure of the invention

The invention is to develop a method of recovering a high degree of the hyperpolarization of the agent, like He-3 gas, from the HP-MRI experiment. It consists of: Starting the experiment with the high speed phase coherent method developed by the author [2], with a slice-selective single shot single sweep 2D encoding, with the acquisition time TaCq much shorter than Ti and 10 T2. The method is most suitable e.g. for hyperpolarized He-3 gas imaging, because of the high

signal to noise ratio available [3]. With present day whole body clinical scanners, Tacq can be a few milliseconds, whereas Ti = 32 - 44 s, T2 = 2 - 10 s, for magnetic fields between 2-0.1 T (the longer times at the lower fields) [4], so that during the experiment the signal decay due to Ti and T2 is negligible. Next, the experiment with method [2] is extended to recover the 15 coherence of the spins, by bringing all the spins all the way back simultaneously to the initial state of the transverse magnetization M+, in such a way that the echo of the rotating gradient coincides with the echo [5] of the main magnet inhomogeneity. In the third step, first a slice-selective flip back 90° rf pulse is applied to return M+ back to Mz, a method known as DEFT

[6]. Then this Mz is stored for each 2D slice. For a multi-slice 3D the sequence, either sequential 20 or interleaved, of 2D slices is continued until the stack is completed. Finally, the hyperpolarized

He-3 gas can be recovered and stored in an appropriate container, which can last for 4 -12 days. The third step is therefore to prolong the decay time Ti of the hyperpolarized He-3 gas from tens of seconds during the experiment, to several days in the storage.

The invention will now be described in more detail. The gyromagnetic ratio of He-3 is 25 32.4 MHz/T. Clinical whole body scanners with magnetic field 1.5-3 T have field of view FOV of 55 cm and maximum magnetic field gradient in the j-direction Gj = 45 mT/m (j = x, y or z) with slew rate of 200 T/m/s, i.e. switch on from zero to maximum in 0.2 ms. As mentioned in [1] Ti = 32 s, T2 = 3 s at 1.5 T and Ti = 44 s, T2 = 10 s at 0.1 T.

The first step, with the method [2]. After a slice-selective 90° rf pulse of duration T90» = 1.2 30 ms, a single sweep 2D spatial encoding of the transverse magnetization M+ with a rotating bipolar magnetic field gradient is completed in a rotation over 180°. The FOV of 55 cm with a gradient of 45 mT/m covers a frequency band width of 800 kHz for He-3. To avoid aliasing, the MR signal is sampled with a sampling frequency fs of at least twice the band width. We take 3 fs = 2 MHz, so the dwell time ta = 0.5 ps. For a 2D imaging matrix of 64x64, the acquisition time Tacq = 4096 x 0.5 ps = 2.0 ms, which is indeed short compared to T2 = 3 - 10 s.

The second step. To recover hyperpolarization, the experiment according to method [2] is extended as follows. During the data acquisition period, M+ can be written as 5 M+ (t) = Mz (0) SG(t) Sinh (t) exp(-t /T2), 0 < t < Tacq (1) where Mz(0) is the magnetization after the slice-selective 90° rf pulse. SG(t) describes the effect of the rotating gradient. Sinh(t) describes the de-phasing effect of the main magnetic field 10 inhomogeneity. The decay exp(-t/T2 ) describes the irreversible loss of coherence, including spin-spin, susceptibility and diffusion effects. The aim is to affect SG(t) and Sinh(t) to refocus simultaneously. It is known that the de-phasing due to the magnetic field inhomogeneity can be refocused by a 180° rf pulse [5]. In general this pulse affects SG(t) also, so its phase and timing are important to achieve the simultaneous echo formation, which will be described for two 15 modalities.

In the first modality the gradient rotation is continued for another 180° rotation to complete a full period, resulting in zero phase change for the transverse magnetization at any point on the selected plane. This complete refocusing over a whole plane occurs for any number of full periods: 20 SG(2nTacq) = SG(0), n =1,2,.. (2)

Eq. (2) is a property of the rotating gradient in 2D-plane, but holds also for refocusing the coherence of the magnetization with periodic magnetic field gradient in mD-plane, m > 1.

25 Thus a suitable time to apply the 180° rf pulse, in quadrature-phase with the slice-selective 90° rf pulse, i.e. with the rf field along M+(0), is at t = 2Tacq, assuming a pulse duration Ti8o° = 2 ms, with the gradient turned off during the pulse. The simultaneous echo will be formed at t = Te: 30 Sg(Te) Si„h(TE) = SG(0) Sinh(0), TE = 4 Tacq + Ti8o° (3)

Data acquisition is continued during gradient rotation, sampling 4 times as was necessary for imaging [2]. The additional data can be used for signal to noise enhancement. The experiment 4 can be extended with more sequences of 180° rf pulse followed by a period of gradient rotation.

In the second modality, which is suitable if Tacq becomes longer, the 180° rf pulse, in quadrature-phase with the 90° rf pulse, is applied at half period of the gradient rotation with the gradient turned off during the pulse, and to continue the gradient rotation in the same direction, 5 but with opposite polarity for the next half period. It follows from the sinogram of each point in the Radon space [7], that the spatial dependent phases of the local magnetizations accrued dining the first half period of the gradient rotation, flipped to the opposite by the above mentioned 180° rf pulse, can be considered as the result of a gradient rotation with opposite polarity, which results in a net phase change of zero by completing the full period, cf. eq. (2).

10 Instead of eq. (3), in this case the echo occurs at

Te = 2 Tacq + Ti8(f (4)

As Te « T2 the transverse magnetization M+ is recovered to a high degree of its original value.

15 Third step, M+ (Te) is returned to Mz with a slice-selective 90° flip back rf pulse [6] in 1.2 ms. So Mz is recovered in a time Tr = Te + 1.2, where Te given by eq. (3) in the first modality and by eq. (4) in the second modality. In hyperpolarized gas the Ti can be prolonged, from tens of seconds in the in vivo experiment, to several days by transferring the gas, e.g. pneumatically, to a suitable container.

20 Therefore, by extension of the method [2] with new inventive steps using multi-dimensional refocusing, a high degree of hyperpolarization can be recovered from the experiment, which can also be used for resolution and signal to noise enhancements.

Best mode of carrying out the invention 25 The invention can be carried out for any hyperpolarized element in any field strength provided Tacq and Te are much smaller than T i and T2.

As an example, with the first method for hyperpolarized He-3 gas lung imaging, with Ti = 32 s and T2 = 3 s at magnetic field of 1.5 T [4], Tr = 11.2 ms, exp (-Tr/T2 ) = exp (-0.0037) = 0.996; for the 2D imaging the hyperpolarization can thus be recovered for 99.6% after the 30 experiment. A 3D of 32 sequential multi-slice of 2D imaging takes a time 32x12.4 = 397 ms, including initial slice selection times. During this sequential multi-slice the average wait time is 198 ms and the decay of Mz, with Ti = 32 s, is exp(-0.006) = 0.994, so the average loss of waiting is 0.6%, small indeed. For interleaved multi-slice 3D that might be standard in some 5 clinical scanners the loss would be even less. The hyperpolarization can be recovered for 99.6% for a 2D of 64x64 matrix in 11.2 ms and 99% for a 3D of 64x64x32 matrix in 397 ms He-3 gas lung imaging. With the second method the recovered values are 99.7% for 2D in 7.2 ms and 99.3% for 3D in 267 ms. With ample hyperpolarized gas and time left, further investigation can 5 be done with the single bolus in a single breath hold, offering the opportunity still to save a high degree of hyperpolarized gas, that can be transferred, purified and stored in a suitable container to last for 4 - 12 days. Signal to noise consideration is given at the end.

As another example, for Xe-129 the gyromagnetic ratio is 11.8 MHz/T, Ti = 30 s, T2 = 0.31 s at field 2 - 4.7 T [4]. It is sufficient to take fs = 600 kHz, so td = 1.67 (is, Tacq = 6.8 ms, slice 10 selection 1.2 ms. With the first method Tr = 27.2 + 2 + 1.2 = 30.4 ms. The hyperpolarization can be recovered for 91% in a 2D of 64x64 in 30.4 ms and for 90% in a multi-slice 3D of 64x64x32 in 1 s Xe-129 gas lung imaging. With the second method, the recovered hyperpolarization becomes, for 2D: 95%, instead of 91% and for 3D: 94%, instead of 90%, in about half the time as with the first method. In both cases a high degree of hyperpolarization can 15 be recovered from experiment with Xe-129 gas. The recovered Mz can be transferred and stored in a container, which can last for 1 - 4 days; Ti can be 27 - 99 hours [8] depending on pressure, temperature and magnetic field.

Hyperpolarized contrast agents like dissolved Xe-129 and C-13 labels are used in angiography and metabolic studies. The gyromagnetic ratio of C-13 is 10.7 MHz/T. In 20 angiography Ti = 25 s for Xe-129 dissolved in a lipid emulsion [9], whereas in a solution of C-13 - labelled urea: Ti = 20 s [10] and in a C-13-enriched contrast medium Ti = 40 s, T2 = 2 s [11]; for cardiac metabolism study by hyperpolarized C-13 MRI Ti = 25 s [12]. In all these cases, like in hyperpolarized He-3 and X-129 gas, a high degree of hyperpolarization can be recovered after a 2D or 3D imaging, but it will not be useful or even possible to extract the 25 hyperpolarized agents from the solution. The available hyperpolarization can be used for resolution and signal to noise enhancements or dynamic studies, facilitating clinical application.

Regarding signal to noise, the method can be compared with FLASH (fast low angle shots) mostly used in HP-MRI [1,3], which uses only about 0.1 - 0.2 of the available signal, while hyperpolarization is lost by decay while waiting for a turn and destruction of signal by a crusher 30 gradient to prevent contaminating the next signal in turn. For comparison the case of He-3 is considered, with 99.6% recovered after 4 sets of data sampling in 11.2 ms. Repeating the experiment for 64 times results in signal acquisition of 4(0.996 + (0.996)2 + ....+(0.996)64} ~ 225, against noise of 16 (= V256), in 717 ms, so a gain of factor 14, which is of order 100 times 6 compared to the number for FLASH, while still saving about (0.996)64exp(-0.24), i.e. 60% of hyperpolarized He-3 gas. For subsequent sets the rotating gradient can start at different direction to distribute the strength of the signal differently, to arrive at better distribution of the signal to noise ratio and enhanced resolution across the plane.

5

So, the invented method is claimed, which recovers a high degree of hyperpolarization from hyperpolarized He-3 and Xe-129 gas lung imaging experiments and comparable situations of hyperpolarized MRI. The method using periodic magnetic field gradient for multi-dimensional spatial encoding and refocusing of the coherence of the magnetization is also claimed.

10

References [1] Fumito Imai et al: Hyperpolarized 129Xe MR imaging with balanced steady-state free precession in spontaneously breathing mouse lungs, Magn Reson Med Sci 10 (2011) 33-40.

[2] EP 1995604 Bl, S. Emid, High speed, high resolution, silent, real-time MRI method, 15 date 04-11-2009.

[3] S. B. Fain, F. R. Korosec, J. H. Holmes et al, Review article: Functional lung imaging using hyperpolarized gas MRI, J. Magn. Reson. Imaging 25 (2007) 910-923.

[4] L. L. Tsai, R. W. Mair, et al, An open-access, very low field MRI system for posture-dependent He-3 human lung imaging, J. Magn. Reson. 193 (2008) 274-285.

20 [5] E. L. Hahn, Spin Echoes, Physical Review 80 (1950) 580-594.

[6] R. R. Shoup, E. D. Becker and T. C. Farrar, The driven equilibrium Fourier transform NMR technique: An experimental study, J. Magn. Reson. 8 (1972) 298-310.

[7] EP 2306402 Al, S. Emid, Exact image reconstruction method, date 07-04-2011.

[8] B. J. Anger, Polarization and Relaxation in hyperpolarized He-3 and Xe-129, 25 PhD thesis, University of Utah, 2008.

[9] H. E. Möller, et al, Magnetic resonance angiography with hyperpolarized Xe-129 dissolved in a lipid emulsion, Magn. Reson. Med. 41 (1999) 1058-1064.

[10] K. Golman, J. H. Ardenkjaer-Larsen, et al, Molecular Imaging with endogenous substances, Proc. Natl. Acad. Sci USA 100 (2003) 10435-1039.

30 [11] J. Svensson, S. Mansson, etal, Hyperpolarized C-13 MR angiography using trueFISP, Magn. Reson. Med. 50 (2003) 256-262.

[12] K. Golman, J. S. Petersson, et al, Cardiac metabolism measured noninvasively by hyperpolarized C-13 MRI, Magn. Reson. Med. 59 (2008) 1005-1013.

1039690

Claims (3)

Method for MRI imaging with hyperpolarized gases or contrast media, characterized in that a high degree of hyperpolarization is recovered from the experiment by location coding in the plane selected by the plane-selective 90 ° rf pulse in the plane rotating bipolar magnetic field gradient, by causing the magnetic field gradient to rotate a full period in one embodiment and a half period in the other embodiment in a time that is short with respect to the decay times of the magnetizations in that plane, after which the dephasing of the magnetization due to the inhomogeneity of the main magnetic field is reversed by a square selective 180 ° rf pulse in quadrature phase with the selective 90 ° rf pulse, with the magnetic field gradient turned off, the magnetic field gradient after the 180 ° rf pulse, with one embodiment with the same strength and rotation speed as for the pulse rotates again a whole period, so that at the end of this period the transversal magnetization in an echo, and in the other embodiment, the magnetic field gradient rotates with the same rotation speed and direction, but with opposite polarity, the second half of the period, so that at the end of this half period the transversal magnetization ends in an echo. In both cases, the transversal magnetization is recovered with a high degree of hyperpolarization, which is converted into longitudinal magnetization with a selective 90 ° rf pulse. 2. Method for location coding in MRI, characterized by performing phase coding and refocusing of the coherence of the magnetization in a multi-dimensional plane with a periodically variable magnetic field gradient in that plane. 3. Method of MRI imaging according to claims 1 and 2, characterized in that the phase of the rotating magnetic field gradient is changed step by step for the successive refocusing in order to achieve a better distribution of the resolution and signal-to-noise ratio across the plane. 1039690