MT & ihMT
Guillaume Duhamel1
1CRMBM - CNRS, Aix Marseille University, UMR 7339, France

Synopsis

Keywords: Neuro: White matter, Contrast mechanisms: Microstructure, Contrast mechanisms: CEST & MT

This course provides an outline of the potential of magnetization transfer techniques for myelin imaging. In particular, this presentation will show how inhomogeneous magnetization transfer (ihMT) can overcome limitations of the basic MT contrasts (MTR, MPF) to provide more specific information related to myelin. The potential and scientific/technical challenges of these approaches for clinical applications are discussed.

Course Summary

Microstructure is composed of (macro)molecules other than water that support tissue structure and function. These macromolecules contain an abundance of protons, but their restricted motion makes their T2’s too short for direct detection with conventional MRI imaging. Much of this invisible macromolecular proton pool can be however detected indirectly because it exchanges magnetization with mobile water protons 1. This magnetization exchange occurs by spin diffusion along the molecule to sites exposed to water and then either actual chemical exchange of protons between the water pool and the macromolecular pool or just magnetization transfer through spin-spin interactions (Fig. 1a) 2. Due to their very short T2, the macromolecular protons have a very broad spectrum, which can be selectively saturated using an off-resonance RF irradiation (Fig. 1b). The exchange of magnetization transfers the saturation to the mobile water pool resulting in a net decrease of the free protons magnetization, and therefore in a net decrease of the MR signal. Imaging of this saturation transfer from macromolecules is referred to as Magnetization Transfer (MT) imaging.
In practice, MT effects can be assessed by calculating a metric, MTR (Magnetization Transfer Ratio), defined as the relative variation between a reference image (M0 – image acquired with no MT saturation power applied) and a MT image (MTw – image acquired with MT saturation power applied): MTR=1-MTw/M0 (Fig. 1c). However, the MTR depends on many factors including power and frequency-offset of the MT saturation pulses, pulse sequence details, the tissue relaxation time T1, and B1 inhomogeneities, thus limiting its ability to quantify the MT effects. To overcome limitations of MTR, quantitative approaches of magnetization transfer (qMT) have been developed and solved using a binary spin-bath model, allowing the measurement of several parameters including, the macromolecular proton fraction (MPF), the exchange rate between macromolecular protons and water protons (R) and the transverse relaxation time (T2B) 3 (Figs. 2a-c).
MTR and MPF demonstrated good sensitivity to myelinated tissues and myelin content and provided precious knowledge regarding pathological myelin in both animal models 4,5 and clinical studies on Multiple Sclerosis (MS) (Figs. 2d,e). MS is characterized among other things, by the presence of focal demyelinating lesions in white matter (WM). Demyelination, which causes a breakdown of the macromolecular structure, results in a decreased MTR 6–9 and MPF 3,10–12. Although sensitive to myelin, MTR and MPF are not specific markers since all other macromolecules also contribute to MTR and MPF and pathological processes other than demyelination, such as inflammation, gliosis, also induce MTR or MPF variations 13,14.
RF saturation of the macromolecular pool is more appropriately described by a thermodynamic model 15 based on Provotorov’s theory 16 that has been useful in accounting for the saturation effects occurring in solid spin systems. In this model, the macromolecular pool is divided into a Zeeman order (MZb, relaxation time T1), and a dipolar order (β, relaxation time T1D) that are effectively coupled in the presence of RF irradiation (power, ω12; frequency, ω) (Fig. 3a). Dipolar order effectively distorts the effective instantaneous absorption spectrum, or lineshape, of the motion-restricted Zeeman line, which becomes asymmetric in frequency (as seen in the first line of eqs. 2, Fig. 3a): the lineshape is more saturated on the side where the RF is applied while the opposite side is less saturated. Of note, if power is applied equally at positive and negative frequency (i.e., dual-offset saturation, ±ω) so that their absorption contributions add, the dipolar order effects cancel to the extent that the equilibrium line is symmetric17, usually a good first approximation. Without dipolar order effect, saturation of the Zeeman line is more efficient (eqs. 3, Fig. 3a). Dipolar order effects can thus be highlighted by subtracting an image acquired with dual-offset saturation from a single-offset saturated image (Fig. 3b), an experiment defined as inhomogeneous MT (ihMT) imaging18. IhMT is thus a refinement of MT that provides different contrast between tissues by isolating dipolar order effects within motion-restricted molecules that are weighted by the corresponding dipolar relaxation time, T1D19. Because dipolar order relaxation is slower in myelinated tissues than any other tissue observed, ihMT is highly sensitive to myelin (Fig. 3c).
Dual-offset saturation can be achieved by alternating the frequency of the saturation pulses on a timescale of τswitch 20,21. Varying τswitch allows deriving T1D-filtered ihMT signals with different dependence on T1D relaxation21. High-pass T1D-filtered ihMT signals, obtained by increase of τswitch, isolate long-T1D components (T1D>1ms) and provide very high specificity to myelination, unlike MTR 22 or MPF 23 for which, there is a significant contribution of short-T1D components (T1D<1ms) (Fig. 4a). IhMT is a relatively new technique whose physical concepts and contrast mechanisms were presented in a recent review 24. The very high specificity for myelin, combined with the ease of generating ihMT contrast have made ihMT an attractive method to assess myelin-related information in vivo (Fig. 4b,c), in the preclinical 25,26 and clinical contexts of demyelinating diseases 27–29, or in the context of aging studies 30,31.

Acknowledgements

No acknowledgement found.

References

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Figures

Fig.1: MT imaging. (a) Magnetization transfer exchange between restricted macromolecular protons and free water protons. (b) absorption spectrum of the macromolecular and free water protons and selective saturation of the macromolecular protons by off-resonance RF saturation. (c) M0 and MTR images.

Fig.2: qMT imaging. (a) binary spin-bath MT model and (b) Modified Bloch equations with exchange of longitudinal magnetization between the free protons pool (A) and macromolecular protons pool (B). (c) Parameter images, including the macromolecular proton fraction (F or MPF), derived from fitting eqs. 1 to a series of MT weighted images. (d) Correlation of MPF with myelin density assessed by histology, and (e) application of MPF imaging on MS patients.

Fig.3: Principle of ihMT. (a) Spin-bath model with the macromolecular protons pool divided into Zeeman and dipolar orders, effectively coupled by RF saturation. Equations of the macromolecular pool RF saturation for single-offset (+ω) and dual offset (±ω) saturations. (b) ihMT defined by the subtraction of an image acquired with dual-offset saturation from a single-offset saturated image. (c) representative 3D brain ihMT images obtained at 3T

Fig.4: ihMT imaging. (a) Correlation of ihMT images obtained with different values of τswitch and MPF with myelin density obtained by Green Fluorescence microscopy and Luxol fast blue optical density. Specificity of ihMT T1D-filters and MPF for myelin. (b) Correlation of ihMT with other myelin-sensitive MRI techniques. (c) Application of ihMT on MS patients.


Proc. Intl. Soc. Mag. Reson. Med. 31 (2023)