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6 Magnetization Transfer Imaging/2 Magnetization Transfer Ratio/01-Introduction.md

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 Conventional MRI techniques, such as those used for clinical diagnosis, can only directly measure hydrogen bonded to water molecules. Thus, a non-negligible proportion of body mass is not visible with clinical MRIs, such as non-hydrogen atoms (different resonance frequencies) and hydrogen atoms bonded to large molecules which restricts the motion of the atoms (rapid signal decay, T2 ~ μs). The latter, called macromolecules, play an important role in the physiology of the body; for example, myelin in the white matter of the brain plays an important role in signal transmission, and is composed largely of macromolecules (lipids and proteins). Although the images acquired by clinical MRI machines can only be generated from signal from mobile hydrogen, these do interact with nearby molecules and atoms via the electromagnetic fields they mutually generate, and in the 70s and 80s a cross-relaxation mechanism was discovered that sensitizes mobile protons to nearby targeted semi-solid molecules, such as myelin (H. T. Edzes and Samulski 1977; Hommo T. Edzes and Samulski 1978; Wolff and Balaban 1989). With proper experimental design, a higher density of nearby macromolecules in the tissue results in a lower MRI signal. This class of MRI techniques is known as magnetization transfer (MT) imaging.
 In the preceding chapter, we delved into the quantitative aspects of magnetization transfer (qMT) imaging, exploring the Bloch-McConnell model, signal modeling, and fitting techniques using qMRLab. Now, we shift our focus to the more accessible and widely used application of MT: magnetization transfer ratio (MTR). Although less quantitative than qMT, MTR is easier to set up and implement, making it popular choices in the MRI community interested in quantifying myelin loss.
 In the simplest and most used MT imaging method, only two images are acquired (one with MT preparation, and one without), and a normalized difference between the two images is calculated. This quantity is known as the magnetization transfer ratio (MTR), and has been used extensively to infer information on myelin diseases and disorders, such as multiple sclerosis. The proportional relationship between MTR and myelin density has been established using post-mortem immunohistological studies in humans (Schmierer et al. 2004, 2007) and animals (Merkler et al. 2005; Zaaraoui et al. 2008). MTR has also already been used in clinical drug trials for MS (Maguire et al. 2013; Brown et al. 2016). Its widespread use is due to the fact that most scanners are equipped with the necessary software so that it can be added to an imaging protocol with the click of a button, and it is also a very quick measurement with a short acquisition time.

6 Magnetization Transfer Imaging/2 Magnetization Transfer Ratio/02-MTR in theory.md

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 The full mathematical description of the magnetization transfer two-pool exchange model was explained in Chapter 6.1 that focuses on qMT. Although it’s these same equations that explain the signal differences between the two images acquired used to calculate MTR, in this section we’ll present a more conceptual explanation of the MT exchange process.
 
 In its most basic form, MT is modeled as an exchange process between two “pools” of protons, those from “mobile” protons (eg, hydrogen in liquid water) named the “free” pool (those that are directly measured with conventional MRI), and those from “restricted” protons (i.e. macromolecules) named the “restricted” pool (these cannot be measured directly with conventional MRI). Macromolecular hydrogen cannot be measured directly because the restricted movement creates a more static local electromagnetic environment that doesn’t average out, and this results in a transverse relaxation T2r (signal decay) that is too short to provide measurable signal (T2r ~ μs << feasible TE). Another consequence of this short signal decay time is a broadening of the absorption lineshape in the frequency domain (eg. the range of “resonant” frequencies of that pool of protons). This is a known property of the Fourier Transform, and the phenomenon is isomorphic to the quantum mechanics uncertainty principle; as Δx⋅Δp ≥ constant in quantum mechanics means that if Δx increases Δp will decrease, we observe a similar relationship approximated to T2⋅FWHM of the frequencies = constant such that if T2 decreases, the FWHM of the frequencies will increase. If T2 is very very short (such as the case for macromolecules), the range of resonant frequencies will be very wide. MT leverages this property by selectively exciting restricted protons far from the mobile proton resonance frequency (applying a pulse off-resonance), but where the energy will be absorbed by some of the protons in the restricted pool. This is the initial preparation of the MT experiment that triggers the conditions needed for cross-relaxation between the unobservable molecules (restricted pool) and observable protons (free pool).

6 Magnetization Transfer Imaging/2 Magnetization Transfer Ratio/03-MTR in practice.md

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 Typically, MTR imaging protocols are implemented on the scanner by adding a relatively long (~5-10 ms) high amplitude off-resonance (~2kHz) preparation RF pulse prior to each TR of an existing imaging sequence. In the early days of MT, the MT pulse was a very long pulse (~10 seconds) prior to one imaging readout of saturation-recovery sequences, but this results in impractically long acquisition times and is very SAR prohibitive. Alternative approaches were explored (eg. 1-2-1 pulses), however now most MT-weighted sequences are done using steady-state sequences (eg SPGR) with a shorter preparation pulse (~10 milliseconds). Figure 1 illustrated this using a spoiled-gradient recalled echo (SPGR) sequence, with a Gaussian-shaped MT preparation pulse prior to the excitation pulse.
 
 ```{figure} img/sequence.png

6 Magnetization Transfer Imaging/2 Magnetization Transfer Ratio/04-Parting Thoughts.md

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 To sum up, our exploration of Magnetization Transfer Ratio (MTR) has highlighted its widespread utility within the field of MRI, in particular for myelin quantification applications. However, it's essential to emphasize that MTR, while immensely valuable, is not a truly quantitative metric. This point underscores the need for caution when comparing MTR values or conducting longitudinal studies, as various factors, including scanner upgrades (both in hardware and software), can potentially result in variations in MTR values for the same subject or samples.
 
 In our next segment, we'll shift our focus to MTsat, which is a promising semi-quantitative metric that rivals MTR for its ease of use and rapid acquisition times. MTsat aims to address some of the challenges associated with MTR, while still offering robust sensitivity to macromolecular content.

6 Magnetization Transfer Imaging/2 Magnetization Transfer Ratio/A1- Appendix A.md

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 In reality, what *is* conserved and transferred during an MT experiment, is energy, and this energy is exhibited as non-zero magnetization under the correct conditions. Figure 7 illustrates this. As is known from MR theory, the net magnetization of a population of spins at thermal equilibrium is a result of an excess (on the order of 10 ppm at 3T) of spins in the low energy level (spins aligned with the magnetic field) relative to the high energy level (spins anti-parallel to the magnetic field), with the energy level splitting (a) being due the nuclear Zeeman effect and for the free pool, has an difference E of γhB0 (i.e. the energy corresponding to the resonance frequency, h being the Planck constant). By applying an off-resonance frequency RF pulse (Δ), we can selectively transfer energy from the electromagnetic field to the restricted pool system such that some spins will jump from the low energy level to the high energy level (RF pumping, b), leaving the free pool undisturbed. This excess in energy that is now in the restricted pool spin population will then redistribute itself through several physical processes to reach a new system-wide equilibrium, such as energy transfer into heat through collisions, or spin exchange free pool spins through dipolar coupling or chemical exchange (Figure 7c). This energy transferred to the free pool is represented by a slight reduction in the net magnetization of the free pool, which manifests as a decrease in the observed MR signal. This signal reduction occurs because the energy absorbed by the restricted pool (via the off-resonance RF pulse) results in fewer spins in the low-energy state in the free pool, thus reducing its longitudinal magnetization. Over time, the system will reach a new equilibrium state, where the magnetization of both the restricted and free pools reflects this redistributed energy.
 
 In Figure 7c (right), the new equilibrium state of the magnetization is shown, highlighting how the energy transfer process affects the magnetization of the free pool and, consequently, the overall MR signal. This phenomenon is central to magnetization transfer (MT) imaging, where the contrast in images is derived from the differences in energy transfer between different tissue types. The degree of MT contrast is influenced by factors such as the efficiency of energy transfer processes and the specific properties of the tissue, including the concentration and exchange rates of the restricted pool.