ihMT Principles & Applications
Olivier M. Girard1
1Aix Marseille Univ, CNRS, CRMBM UMR 7339, Marseille, France

Synopsis

This lecture will cover the basic principles and applications of the recently developed inhomogeneous Magnetization Transfer (ihMT) MRI technique. IhMT is a promising myelin imaging technique and it offers an exciting opportunity to exploit a new endogenous contrast mechanism in vivo using MRI, by discriminating biological tissues based on their dipolar relaxation time (T1D). This presentation will review the basics of the dipolar order concept and associated thermodynamic models. The lecture will also cover typical ihMT experiments and describe up to date MRI sequence optimization. Promising MRI applications will be presented, as well as future research directions.

Target audience

MRI scientists and engineers interested in new contrast mechanisms, Magnetization Transfer techniques, dipolar order imaging, and more specifically inhomogeneous Magnetization Transfer (ihMT). Clinicians interested in myelin imaging techniques.

Learning objectives

This lecture will cover the basic principles and applications of the recently developed inhomogeneous Magnetization Transfer (ihMT) MRI technique.
Following this lecture, the attendees should:
  • understand the origin of dipolar order within spin systems.
  • understand how ihMT measure dipolar order effects and how it is weighted by the dipolar order relaxation time (T1D).
  • know several kinds of RF pulse sequences used for ihMT imaging and their potential for myelin imaging.

Introduction

IhMT imaging is a recent MRI modality that allows indirect observation of dipolar order effects occurring within motion-restricted (semi-solid) macromolecules. It is based on conventional MT, hence requiring magnetization exchange between macromolecules and free water, and the ihMT signal is obtained by combining datasets acquired with specific RF irradiation patterns to isolate the dipolar order contribution to the RF saturation effects occurring within the macromolecular pool. Following the first observations of the ihMT signal (1,2), the contrast mechanism has been elucidated and attributed to dipolar order (3–5), and optimized for various sequence implementations (6–12).

IhMT brings a new contrast mechanism to MRI and is intrinsically weighted by the dipolar relaxation time (T1D) (5,9,13), which provides a new way to generate MRI contrast within biological tissues in vivo. While myelin, which has a relatively long T1D component (in the 5-10 ms range (13)) and is readily observable with ihMT, has been the primary application to date (14–20), ihMT may also be adapted to probe shorter T1D components (on the order of or lower than 1 ms) found is other tissues such as skeletal muscle, myocardium, tendon, kidney or liver (9,11,19,21).

This presentation will review the basics of the dipolar order concept and associated thermodynamic models. The lecture will also cover typical ihMT experiments and describe up to date MRI sequence optimization. Promising MRI applications will be presented, as well as future research directions.

Dipolar order and the spin temperature concept

Motional restrictions occurring in macromolecules lead to broad NRM spectrum due to partial averaging of dipolar couplings and result in additional degrees of freedom within the quantum energy level description. Under the high field, high temperature approximation and following the thermodynamic approach, the spin system may then be described by two independent quasi-equilibrium states corresponding to the usual (Zeeman) longitudinal magnetization MZ, and the inverse (dipolar) spin temperature β (22,23). These states are related to the degree of polarization, or order, of the spins aligned within the static magnetic field B0 (Zeeman order), and with the local dipolar fields ωD (dipolar order). These two independent thermal reservoirs are coupled under RF irradiation according to the Provotorov theory of RF saturation in solids (24,22), which describes thermal mixing for the case of weak RF fields (ω1 << ωD). Combining Bloch equations, to describe the free water pool, and the Provotorov theory to describe the macromolecular pool, one can build a model to interpret and analyze ihMT imaging (3).

The ihMT MRI experiment

The typical ihMT MRI experiment combines single- and dual-frequency offset RF irradiation to generate a composite image that reflects the intensity of the dipolar order effects occurring within macromolecules. Whereas the single-offset MT experiment is sensitive to dipolar order, the dual-offset experiment is free from dipolar order contribution by symmetry property (3), leading to a signal difference between the two MT experiments that represents the dipolar order contribution to the RF saturation effects.

Several ihMT pulse sequences have been developed and may be classified according to the properties of their 1/ MT irradiation pattern (RF power, offset frequencies, timings, simultaneous vs. sequential dual-frequency irradiation, RF duty cycle…), and 2/ associated readout module (2D vs. 3D, single-shot vs. steady state, spoiled GRE vs. SSFP…), or whether these two modules are interleaved or separated in time, such as in magnetization prepared experiments.

As a rule of thumb a given T1D component may be observed with ihMT according to WRFT1D > 0.01 (5) (where WRF represents the RF absorption rate of the macromolecular lineshape), assuming a simultaneous dual-offset saturation is used (i.e. a multiband pulse using a cosine-modulated RF envelope). The frequency alternated approach provides an extra degree of freedom to filter out short-T1D components from the generated signal (9,13). Overall these two mechanisms are driving the T1D-weighting of the sequence and associated specificity for given tissue components such as myelin.

In terms of sensitivity, while the average RF power (constraint by SAR regulatory limitations) and offset frequency are important parameters, it has also been found that low duty cycle RF irradiations, consisting of high intensity RF irradiation phases interleaved with long recovery and mixing periods, provide strong sensitivity enhancement as compared to more distributed RF irradiation patterns (10,11). Of interest low duty cycle experiments also reveal higher signal from short-T1D components, as expected from the higher RF absorption rate, but they may also be associated with short-T1D filtering strategy to recover specificity for long T1Ds, hence leading to a compromise between sensitivity and specificity. The readout module on the other hand contributes to the signal-to-noise ratio and time-efficiency of the technique as for any other MRI application.

In practice, ihMT MRI relies on simple post-processing and has shown good test-retest and multi-site reproducibility (10,25).

Current ihMT applications

IhMT has been mostly applied in human for central nervous system applications. Several studies have focused on brain or spinal cord examinations in healthy volunteers (e.g. to study brain maturation (20) or cortical myelination (26)) and patients (e.g. MS (16) and ALS (15)), and compared with other myelin sensitive techniques such as conventional MT, myelin water imaging or diffusion MRI (6,14–18,20). Noteworthy rodent applications have also allowed validating the sensitivity of ihMT for myelin by comparison with histology (19).

Future research directions

It is naturally expected that more studies will focus on myelin in order to evaluate the added value of ihMT for clinical and neuroscience applications. While other studies will likely focus on other biological targets using ihMT sequences designed to probe shorter T1D components (21), other research directions should aim at a deeper understanding of the ihMT signal and of the contrast mechanisms driving T1D relaxation in biological tissues (e.g. molecular composition, mobility, water accessibility, structural anisotropy…). As illustrative examples, ihMT has been shown sensitive to the white matter fiber orientation (27) and T1D measurements can provide information related to molecular composition and dynamics (28,29).

Acknowledgements

I thank all my colleagues, collaborators and other researchers with whom I have had highly stimulating and helpful scientific discussions along this exciting ihMT project.

References

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Figures

A) Distribution of the spins over the energy levels of a spin system accounting for Zeeman and dipolar interactions. Under the high-field, high-temperature approximation the system may be described by two independent quasi-equilibrium states corresponding to the inverse Zeeman spin temperature α and the inverse spin temperature β. B) Dipolar and Zeeman orders are coupled under off-resonance RF irradiation according to the Provotorov theory. Dipolar order may be viewed as an extra degree of freedom within the spin system which acts against RF saturation of the Zeeman order.

The ihMT MRI experiment. Whereas the single-offset MT experiment is sensitive to dipolar order and leads to spectrally non-uniform, or inhomogeneous, RF saturation of the macromolecular pool, the dual-offset MT experiment is free from dipolar order contribution by symmetry property, providing more efficient RF saturation of the macromolecular pool. This results in a signal difference between the two MT experiments that represents the dipolar order contribution to the RF saturation effects.

Example of brain ihMT acquisitions. A) In vivo human brain images acquired using a 3D ihMT-GRE sequence @ 3T. B) In vivo mouse brain images acquired using a 2D ihMT-RARE sequence @ 11.75T. The high apparent specify for myelinated tissues can be explained by their relatively long T1D as compared to other tissues.

Proc. Intl. Soc. Mag. Reson. Med. 28 (2020)