Exploiting Relaxation Along Fictitious Fields
Silvia Mangia1

1CMRR University of Minnesota, United States

Synopsis

The SNR increase of high fields needs to be leveraged with the challenge of maintaining the flexibility of tuning the MRI contrast to the molecular dynamics of interest. Relaxation methods based on frequency-modulated pulses, including T1ρ and T2ρ using adiabatic pulses, and the non-adiabatic method entitled relaxation along a fictitious field (RAFF) in the rotating frame of rank 'n' (RAFFn), offer sensitivity to molecular dynamics in intermediate and slow regimes. The reduced power deposition of RAFFn, along with the opportunity of enhancing sensitivity to exchange by tuning the periodicity of irradiation, are distinct and compelling advantages of the methodology.

TARGET AUDIENCE

Scientists and clinicians who seek to explore innovative MRI methods for enhancing sensitivity to molecular dynamics in the intermediate and slow regime at high magnetic fields, with the ultimate goal of characterizing tissue properties and pathophsyiological processes in vivo.

OUTCOME/OBJECTIVES

Learners will understand how to tune the MRI contrast to the molecular dynamics of interest by using frequency modulated (FM) pulses, particularly those that generate Relaxation Along a Fictitious Field (RAFF) in the rotating frame of rank 'n' (RAFFn).

PURPOSE

Among the large variety of motional regimes that water molecules experience in tissue, those in intermediate and slow regimes are the most sensitive to the intricate nature of tissue microstructure, composition and function [1, 2]. However, at high magnetic fields (3T and above), the rate constant for laboratory frame longitudinal relaxation (R1) mostly reflects molecular fluctuations of magnetic dipolar interactions in fast dynamic regimes, with correlation time τc ~ (γB0)-1 in nanosecond time scale. To sensitize MRI to slower motions, relaxation in an effective field B(n)eff can be exploited in a rotating coordinate system of rank 'n'. The correlation times of motion involved in this case are in the range of τc ~(γB(n)eff)-1 [3-8]. T1ρ relaxation can assess motional regimes with correlation times τc ~ 1/ωeff in microsecond to millisecond time scale, with conventionally used spin-locking [9-13], as well as with adiabatic RF pulses [1, 2, 14, 15]. An interest towards in vivo exploitation of T1ρ MRI has greatly increased due to its sensitivity to different factors related to cell death in several disease models [16, 17]. For example, in rat models of cerebral ischemia, T1ρ is one of the earliest markers that reflect irreversible tissue damage after cessation of blood flow [18] even in those cases where initial diffusion abnormality may transiently recover upon reperfusion [16, 19]. However, high SAR of T1ρ methods severely limit the use of these approaches in clinical settings, thus warranting the exploration of novel methods.

METHODS

To access motions in intermediate and slow regimes (microsecond to millisecond time scale) with lower SAR, one can measure relaxations in higher rotating frames with the rank n ≥ 2. Our group has recently expanded on such concepts by introducing the method RAFFn, which includes components of T1ρ and T2ρ. RAFFn utilizes amplitude and frequency modulated pulses which operate in non-adiabatic regime while producing effective fields in higher rotating frames [20-22].

RESULTS

The benefits of RAFFn in reducing SAR have been demonstrated in earlier work [22]. For instance, a drastic reduction of >90% in SAR can be achieved when comparing RAFF5 with spin-lock T1ρ of similar peak RF amplitude. Another compelling feature of RAFFn involves an enhanced sensitivity to spin coupled systems resulting from the periodic nature of the RF irradiation [23]. The periodic Hamiltonian indeed probes the exchanging spin system, leading to a significant increase of the observed relaxation rate due to the instantaneous flip of the effective (or fictitious) field and the generation of sidebands. There has been considerable interest in utilizing periodic irradiation in MR for various purposes, e.g., inducing magnetization transfer (MT) in MRI [24]. In RAFFn, the periodicity of RF irradiation can easily be tuned to generate sidebands that are positioned optimally off-resonance to induce MT. By tuning the irradiation period to chemical shift differences between exchanging sites, a significant increase in the exchange-induced relaxation rate constants can thus be achieved. Notably, exchange measured with periodic irradiation may have reduced sensitivity to B0 inhomogeneity as compared to other methods providing exchange contrast such as CEST, since it is dependent on the difference in chemical shifts rather than the absolute position of the exchanging spins.

DISCUSSION

Unique and complementary insights into molecular processes linked to tissue function and dysfunction can be gained by characterizing the dynamic properties of protons. The SNR increase achieved at high magnetic fields offers an undeniable advantage which however needs to be leveraged with the challenge of maintaining the flexibility of tuning the MRI contrast to the molecular dynamics of interest. Rotating frame relaxations measured during the application of frequency-modulated pulses offer sensitivity to intermediate and slow molecular dynamics. They offer practical advantages as compared to continuous-wave rotating frame relaxations, including a minimized sensitivity to B1 distributions and a capability to simultaneously tune the contrast to multiple effective frequencies, γBeff(t), due to the time dependence of the modulation functions [25]. MRI relaxation methods based on FM pulses, including T1ρ and T2ρ using adiabatic pulses, and the non-adiabatic method RAFFn provide insights into the pathological processes of multiple brain disorders, such as Parkinson’s disease [26-30], acute ischemia [31], and cell death in rat glioma gene therapy model [32, 33]. They also hold promise for elucidating pathophysiological processes that histology studies suggest are important in MS [34-37]. Although not common yet for clinical studies, overall rotating frame relaxations with FM pulses are robust and sensitive methods for investigations in humans [30, 34, 38, 39].

CONCLUSION

The clinical relevance of rotating frame relaxation contrasts motivates their continued development especially at high fields. The reduced power deposition of the RAFFn acquisitions, along with their flexibility in enhancing sensitivity to exchange by tuning the periodicity of irradiation, are distinct advantages of the methodology as compared to other quantitative MRI methods sensitive to molecular dynamics.

Acknowledgements

Work described in this contribution was supported by the EU H2020 Marie Skłodowska RISE project #691110 (MICROBRADAM) and by the National Institutes of Health (Funding P41 EB015894, P41EB027061, P30 NS076408). The content is solely the responsibility of the author and does not necessarily represent the official views of the funding bodies. The author is also grateful to Shalom Michaeli for helpful discussions and comments.

References

  1. Michaeli S, Grohn H, Grohn O, Sorce DJ, Kauppinen R, Springer CS, Jr., Ugurbil K, and Garwood M. Exchange-influenced T2rho contrast in human brain images measured with adiabatic radio frequency pulses. Magn Reson Med, 2005. 53(4):823-9.
  2. Michaeli S, Sorce DJ, Springer CS, Jr., Ugurbil K, and Garwood M. T1rho MRI contrast in the human brain: modulation of the longitudinal rotating frame relaxation shutter-speed during an adiabatic RF pulse. J Magn Reson, 2006. 181(1):135-47.
  3. Abragam A. Principles of Nuclear Magnetism, ed. R Adair, R Elliott, W Marshall, and D Wilkinson. 1991, Oxford: Clarendon Press. Chapter 14.
  4. Atsarkin V and Khazanovich T. Effect of slow molecular motions on nuclear magnetic relaxation under "magic-angle condition". Sov Phys JETP, 1984. 60 (1):162-167.
  5. Blicharski J. Nuclear magnetic relaxation in rotating frame. Acta Phys Pol A, 1972. 41(2):223-236.
  6. Mefed A. Nuclear spin-lattice relaxation in the triply rotating frame and ultraslow molecular motions in solids. Appl Magn Reson, 2001. 21:127-45.
  7. Mefed A. Mechanism of Nuclear Spin-Lattice Relaxation and Its Field Dependence for Ultraslow Atomic Motion. Journal of Experimental and Theoretical Physics, 2008. 107:642-648.
  8. Santyr GE, Fairbanks EJ, Kelcz R, and Sorensen JA. Off-resonance spin locking for MR imaging. Magn Reson Med, 1994. 32:43-51.
  9. Ailion D and Slichter C. Observation of ultra-slow translational diffusion in metallic lithium by magnetic resonance. Phys Rev Lett, 1964. 12:168-171.
  10. Fischer M, Majumdar A, and Zuiderweg E. Protein NMR relaxation: theory, applications and outlook. Progr NMR Spectr, 1998. 33:207-272.
  11. Desvaux H and Berthault P. Study of dynamic processes in liquids using off-resonance RF irradiation. Progr NMR Spectr, 1999. 35:295-340.
  12. Korzhnev D, Billeter M, Arseniev A, and Orekhov V. NMR studies of Brownian tumbling and internal motions in proteins. Prog NMR Spectrosc, 2001. 38:197-266.
  13. Palmer III A, Kroenke C, and Loria J. Nuclear magnetic resonance methods for quantifying microsecond-to-millisecond motions in biological macromolecules. Meth Enzymol, 2001. 339:204-238.
  14. Michaeli S, Sorce DJ, Idiyatullin D, Ugurbil K, and Garwood M. Transverse relaxation in the rotating frame induced by chemical exchange. J Magn Reson, 2004. 169(2):293-9.
  15. Idiyatullin D, Michaeli S, and Garwood M. Product operator analysis of the influence of chemical exchange on relaxation rates. J Magn Reson, 2004. 171(2):330-7.
  16. Grohn OH, Lukkarinen JA, Silvennoinen MJ, Pitkanen A, van Zijl PC, and Kauppinen RA. Quantitative magnetic resonance imaging assessment of cerebral ischemia in rat using on-resonance T(1) in the rotating frame. Magn Reson Med, 1999. 42(2):268-76.
  17. Pitkanen A, Nissinen J, Nairismagi J, Lukasiuk K, Grohn OH, Miettinen R, and Kauppinen R. Progression of neuronal damage after status epilepticus and during spontaneous seizures in a rat model of temporal lobe epilepsy Prog Brain Res, 2002. 135:67-83.
  18. Kettunen MI, Grohn OH, Penttonen M, and Kauppinen R. Cerebral T1r relaxation time increases immediately upon global ischemia in the rat independently of blood glucose and anoxic depelarization. Magn Reson Med, 2001. 46:565-572.
  19. Grohn OHJ, Kettunen MI, Makela HI, Penttonen M, Pitkanen A, Lukkarinen JA, and Kauppinen RA. Early detection of irreversible cerebral ischemia in the rat using dispersion of the magnetic resonance imaging relaxation time, T1rho. J Cereb Blood Flow Metab, 2000. 20(10):1457-66.
  20. Liimatainen T, Sorce DJ, O'Connell R, Garwood M, and Michaeli S. MRI contrast from relaxation along a fictitious field (RAFF). Magn Reson Med, 2010. 64(4):983-94.
  21. Liimatainen T, Mangia S, Ling W, Ellermann J, Sorce DJ, Garwood M, and Michaeli S. Relaxation dispersion in MRI induced by fictitious magnetic fields. J Magn Reson, 2011. 209(2):269-76.
  22. Liimatainen T, Hakkarainen H, Mangia S, Huttunen JM, Storino C, Idiyatullin D, Sorce D, Garwood M, and Michaeli S. MRI contrasts in high rank rotating frames. Magn Reson Med, 2015. 73:254-262.
  23. Liimatainen T, Laakso H, Idiyatullin D, Mangia S, and Michaeli S. Capturing exchange using periodic radiofrequency irradiation. J Magn Reson, 2018. 296:79-84.
  24. Portnoy S and Stanisz GJ. Modeling pulsed magnetization transfer. Magn Reson Med, 2007. 58(1):144-55.
  25. Mangia S, Liimatainen T, Garwood M, and Michaeli S. Rotating frame relaxation during adiabatic pulses vs. conventional spin lock: simulations and experimental results at 4 T. Magn Reson Imaging, 2009. 27(8):1074-87.
  26. Michaeli S, Oz G, Sorce DJ, Garwood M, Ugurbil K, Majestic S, and Tuite P. Assessment of brain iron and neuronal integrity in patients with Parkinson's disease using novel MRI contrasts. Mov Disord, 2007. 22(3):334-40.
  27. Michaeli S, Burns TC, Kudishevich E, Harel N, Hanson T, Sorce DJ, Garwood M, and Low WC. Detection of neuronal loss using T(1rho) MRI assessment of (1)H(2)O spin dynamics in the aphakia mouse. J Neurosci Methods, 2009. 177(1):160-7.
  28. Nestrasil I, Michaeli S, Liimatainen T, Rydeen CE, Kotz CM, Nixon JP, Hanson T, and Tuite PJ. T1rho and T2rho MRI in the evaluation of Parkinson's disease. J Neurol, 2010. 257(6):964-8.
  29. Tuite PJ, Mangia S, Tyan AE, Lee MK, Garwood M, and Michaeli S. Magnetization transfer and adiabatic R1rho MRI in the brainstem of Parkinson's disease. Parkinsonism Relat Disord, 2012. 18(5):623-5.
  30. Mangia S, Svatkova A, Mascali D, Nissi MJ, Burton PC, Bednarik P, Auerbach EJ, Giove F, Eberly LE, Howell MJ, Nestrasil I, Tuite PJ, and Michaeli S. Multi-modal Brain MRI in Subjects with PD and iRBD. Front Neurosci, 2017. 11:709.
  31. Jokivarsi KT, Niskanen JP, Michaeli S, Grohn HI, Garwood M, Kauppinen RA, and Grohn OH. Quantitative assessment of water pools by T1rho and T2rho MRI in acute cerebral ischemia of the rat. J Cereb Blood Flow Metab, 2009. 29(1):206-16.
  32. Sierra A, Michaeli S, Niskanen JP, Valonen PK, Grohn HI, Yla-Herttuala S, Garwood M, and Grohn OH. Water spin dynamics during apoptotic cell death in glioma gene therapy probed by T1rho and T2rho. Magn Reson Med, 2008. 59(6):1311-9.
  33. Liimatainen T, Sierra A, Hanson T, Sorce DJ, Yla-Herttuala S, Garwood M, Michaeli S, and Grohn O. Glioma cell density in a rat gene therapy model gauged by water relaxation rate along a fictitious magnetic field. Magn Reson Med, 2012. 67(1):269-77.
  34. Mangia S, Carpenter AF, Tyan AE, Eberly LE, Garwood M, and Michaeli S. Magnetization transfer and adiabatic T1rho MRI reveal abnormalities in normal-appearing white matter of subjects with multiple sclerosis. Mult Scler, 2013. 20(8):1066-1073.
  35. Mangia S, Svatkova A, Bednarik P, Nestrasil I, Eberly LE, Capenter A, and Michaeli S. Rotating frame MRI in human subjects with Multiple Sclerosis. 24th Scientific Meeting and Exhibition of the International Society for Magnetic Resonance in Medicine (ISMRM), Singapore, 2016. 24:5673.
  36. Hakkarainen H, Sierra A, Mangia S, Garwood M, Michaeli S, Grohn O, and Liimatainen T. MRI relaxation in the presence of fictitious fields correlates with myelin content in normal rat brain. Magn Reson Med, 2016. 75(1):161-8.
  37. Satzer D, DiBartolomeo C, Ritchie MM, Storino C, Liimatainen T, Hakkarainen H, Idiyatullin D, Mangia S, Michaeli S, Parr AM, and Low WC. Assessment of dysmyelination with RAFFn MRI: application to murine MPS I. Plos One, 2015. 10(2):e0116788.
  38. Andronesi OC, Bhat H, Reuter M, Mukherjee S, Caravan P, and Rosen BR. Whole brain mapping of water pools and molecular dynamics with rotating frame MR relaxation using gradient modulated low-power adiabatic pulses. Neuroimage, 2014. 89:92-109.
  39. Casula V, Autio J, Nissi MJ, Auerbach EJ, Ellermann J, Lammentausta E, and Nieminen MT. Validation and optimization of adiabatic T1rho and T2rho for quantitative imaging of articular cartilage at 3 T. Magn Reson Med, 2017. 77(3):1265-1275.
Proc. Intl. Soc. Mag. Reson. Med. 27 (2019)