Synopsis

Keywords: Contrast mechanisms: Thermometry, Physics & Engineering: Interventional, Neuro: Brain

Different levels of techniques and accuracy should be adopted for MR thermometry. Proton resonance frequency (PRF) shift with phase mapping technique is suitable for monitoring brain thermal therapy using laser or high intensity focused ultrasound. For monitoring hypothermia therapy or for detecting ischemia and traumatic brain injury, PRF shift detected spectroscopically with internal reference such as NAA, chorine and creatine may help. However, careful consideration regarding variation of bulk susceptibility, distributions of electrolyte and macromolecules as well as status of pH should be made. The purpose of this lecture is to discuss thermometry techniques and the factors influencing temperature quantification.

Introduction

Most proton (1H) magnetic resonance (MR) parameters are temperature dependent(1). These include the proton resonance frequency (PRF) or chemical shift (CS) of hydroxyl or other groups with hydrogen bonding, spin-lattice relaxation time, T1 (2-5); spin-spin relaxation time, T2 (3, 6, 7); proton density or thermal equilibrium magnetization, M0 (8, 9); and the diffusion coefficient, D (10, 11). Among these parameters, PRF can be measured independently from the other parameters, which are determined using signal amplitudes and are thus affected by each other within a limited measurement time. Moreover, the thermal coefficient of PRF in water molecules is almost tissue insensitive. Thus, water PRF is thought to be the most reasonable and practical indicator for temperature measurement. There are two major approaches, MR spectroscopy (MRS) (12-17) and phase mapping (18, 19) to measure the water PRF. Although the phase mapping techniques have been widely accepted (20-22) for monitoring thermal therapies (23-26), they yield only relative temperature change with reference to a baseline temperature. On the other hand, MRS techniques have potential to be used for monitoring hypothermia therapy or for detecting ischemia and traumatic brain injury(27) as shown in Figure 1. To make MRS technique to be practical for those applications, some factors affecting on temperature quantifications has to be considered.

Principle of temperature dependence of water PRF

Hydrogen bonds between the protons in the hydroxyl groups and other more electronegative atoms are primarily responsible for inducing the temperature dependence of the chemical shift of protons(28). Briefly, the electrical currents from the electronic orbitals surrounding the MR nuclei produce a weak magnetic field that opposes the external applied field (B0) producing a shielding effect(29). Consequently, the resonance frequency of the water proton decreases with the rate around -0.01ppm/oC(30). A schematic diagram of this temperature dependence including effect of volume susceptibility is depicted in Figure 2(31).

Factors for temperature dependence of water PRF

Electrolytes
We can also observe the downward shift of the MR frequency in water when univalent electrolytes are added. This phenomenon is referred to as “bond-breaking processes”(32) . When sodium or potassium ions are dissolved in water, their positive charges attract oxygen atoms in the hydroxyl group, which increases the likelihood of breaking the hydrogen bonds between other water molecules(32). Interestingly, the temperature coefficient of water PRF slightly increase with ionic concentrations up to 1 M applied(33).
Bulk susceptibility
When a group of nuclei are in a isotropic region at temperature T, the nuclei experience a local magnetic field, ,described elsewhere (34, 35). The rate of volume susceptibility change with temperature in an aqueous medium is negative, and is several-fold smaller (~ -0.002 ppm/oC)(34, 35) than that of the screening constant of water protons. However, it is also known that the blood oxygenation dependent susceptibility during functional activation reaches as large as 0.02 ppm(36), which corresponds to the PRF shift equivalent to 2 oC temperature change. Moreover, the susceptibility difference between completely deoxygenated and completely oxygenated red blood cells can be 0.264 ppm(37).
pH
The effect of the pH on the PRF of an aqueous hydroxyl group is presently unresolved. Some of the published results are summarized in Table 1 (15, 17, 38, 39). If the pH is constant during the period temperature is being monitored and only relative temperature change is of interest, the effect of pH can generally be neglected. Meanwhile, we do need to consider pH effects when attempting absolute temperature measurements.
Macromolecules
Generally, water molecules tend to cluster around large protein molecules due to hydrogen bonding, and there is exchange between these molecules and freer water in the cytosol. Averaged over the time period of observation, the hydrogen bonding causes a small increase in the water PRF as compared to that of pure water. Some representative results of temperature dependence of the proton chemical shifts in tissues obtained with internal references are summarized in Table 1 based on the previous studies (15, 16, 38-43). The possible factors described above are depicted in Figure 3 together with variation of the chemical shift between water and the methyl resonance of N-acetylaspartate (NAA) in a normal volunteer.

Acquisition Strategies for brain temperature measurement

MRS techniques with internal reference are focused here. Figure 4 shows the basic idea of using MRS technique for temperature measurement. By using an internal reference signal, temperature change of bulk susceptibility can be cancelled, and thus only the change in the shielding constant is detected. Single voxel spectroscopy using conventional Point Resolved Spectroscopy (PRESS) has been extensively explored the temperature dependence of the water PRF, and to measure temperature at various spatially localized sites in tissue.(15, 42, 44, 45) As an internal reference in brain, a temperature-insensitive reference metabolite such as NAA (~1.98 ppm) has been preferred because of its prominence and relatively isolated chemical shift position in cerebral spectra(15, 16, 38-41, 45). The resonances from choline-containing metabolites (Cho; ~3.2 ppm) and total creatine (Cr; ~3.0 ppm) have also been used(41, 42).
Signal averaging is essential for detecting reference signals from relatively low concentration (~10 mM) of these metabolites. Multivariate analysis in conjunction with spectral processing techniques is one of the key techniques for improving both inter-subject reproducibility, resilience, and the quantification of the thermal change of water-metabolite chemical shifts(41).
2D- and 3D- Magnetic Resonance Spectroscopic Imaging (MRSI) have been explored for imaging temperature.(43, 46-48). Recent technique with adiabatic selective refocusing pulse such as sLASER (semi localized adiabatic selective refocusing)(49) in conjunction with sophisticated shimming techniques such as FASTESTMAP and GRESHIM(50) has greatly improved the spectral quality good for thermometry(27).
To overcome the low temporal resolution of the phase-encoding-based SI approach, echo-planar spectroscopic imaging (EPSI) (51, 52) and line-scan EPSI (LSEPSI) (40, 48, 53) have been introduced for thermometry. The latter is a combination of the echo-planar technique with column scanning that accelerates multi-voxel MRS, while avoiding spectral degradation due to eddy currents from the phase-encoding process. It should be noted that the EPSI and LSEPSI approaches are substantially similar to the multiple gradient-echo phase mapping technique(54).

Other possible means

Other than the PRF approach, there has been a few attempts to use diffusion coefficient of cerebrospinal fluid (CSF) to measure brain temperature(55). Indeed, there is clear temperature dependence in diffusion coefficient in pure water(56), we cannot deny the effect of macromolecules or other factors in the diffusivity of the water molecules in CSF.
Some nuclei other than protons such as 13C (57), 31P (58, 59), or 59Co (60) also demonstrate properties that may be suitable for thermometry. However, it is difficult to justify their use in the practical consequences of their lower abundance and sensitivity, and the hardware/software limitations of MR scanners.
Hyperpolarized 129Xe in a cryptophane-A cage has a temperature dependent chemical shift of 0.29 ppm/oC (61). Although this temperature coefficient is more than 10 times larger than that of water protons and this phenomenon is interesting as basic science, the hyperpolarization process is laborious, and clinical translation has not yet to be seen. Refer to table 2 for reviewing some non-PRF or non-proton parameters for temperature measurement.

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