Brain temperature and pH measured by (1)H chemical shift imaging of a thulium agent

Abstract

Temperature and pH are two of the most important physiological parameters and are believed to be tightly regulated because they are intricately related to energy metabolism in living organisms. Temperature and/or pH data in mammalian brain are scarce, however, mainly because of lack of precise and non-invasive methods. At 11.7 T, we demonstrate that a thulium-based macrocyclic complex infused through the bloodstream can be used to obtain temperature and pH maps of rat brain in vivo by (1)H chemical shift imaging (CSI) of the sensor itself in conjunction with a multi-parametric model that depends on several proton resonances of the sensor. Accuracies of temperature and pH determination with the thulium sensor - which has a predominantly extracellular presence - depend on stable signals during the course of the CSI experiment as well as redundancy for temperature and pH sensitivities contained within the observed signals. The thulium-based method compared well with other methods for temperature ((1)H MRS of N-acetylaspartate and water; copper-constantan thermocouple wire) and pH ((31)P MRS of inorganic phosphate and phosphocreatine) assessment, as established by in vitro and in vivo studies. In vitro studies in phantoms with two compartments of different pH value observed under different ambient temperature conditions generated precise temperature and pH distribution maps. In vivo studies in alpha-chloralose-anesthetized and renal-ligated rats revealed temperature (33-34 degrees C) and pH (7.3-7.4) distributions in the cerebral cortex that are in agreement with observations by other methods. These results show that the thulium sensor can be used to measure temperature and pH distributions in rat brain in vivo simultaneously and accurately using Biosensor Imaging of Redundant Deviation in Shifts (BIRDS).

Figure 1

¹H spectrum at 11.7T (500 MHz) of a sample containing 10 mM TmDOTP⁵⁻. The water signal (at 0 ppm) was decreased by three orders of magnitude, while for all the other resonances the vertical scale was the same. Assignment of the six non-exchangeable and non-equivalent proton resonances from the macrocyclic chelate are also shown.

Figure 2

Temperature and pH dependencies of H2, H3 H6 and H1 proton chemical shifts (δ₂, δ₃, δ₆ and δ₁) of TmDOTP⁵⁻ are shown in (A), (B), (C) and (D), respectively, for an in vitro sample (4 mM TmDOTP⁵⁻, 1 mM Ca²⁺, 10% D₂O). The 3D surfaces represent the result of the fits of chemical shift δ as function of temperature T and pH (eq. [1]). The differential and independent “storage” of temperature and pH information by each of these protons is reflected by the non-overlapping 3D surfaces, a fact which can be appreciated by the variable extent of the different color tones.

Figure 3

Effect of spectral SNR on temperature and pH determination. Dependencies of temperature (A) and pH (B) standard deviations using the H2, H3 and H6 proton chemical shifts of TmDOTP⁵⁻. For a typical in vivo SNR value of ∼15, the standard deviations were 0.008 °C for temperature and 0.0013 for pH. The effect of SNR on temperature and pH accuracies was compared with the NAA-water method by ¹H MRS for temperature (C) and Pi-PCr method by ³¹P MRS for pH (D). Under similar in vivo conditions, the SNR values were ∼8 and ∼5, respectively, which corresponded to standard deviations of 0.06 °C for temperature and 0.004 for pH.

Figure 4

Examples of temperature and pH maps of a two compartment phantom containing 4 mM TmDOTP⁵⁻, 3 mM TSP and 1 mM Ca²⁺ in 10% D₂O at two different pH values (7.0 inner and 7.4 outer). (A) ¹H CSI of the phantom obtained in a 32×32 CSI experiment showing the resonances of H2, H3 and H6 protons. The bore temperature was initially maintained at 37.3±0.1 °C. The field of view used was 2.56×2.56 cm and the slice thickness was 4 mm, giving a voxel size of 0.8×0.8×4 mm³. (B) Examples of ¹H spectra from two different voxels (boxed in A) one from the outer compartment at pH of 7.4 (upper spectrum) and the other from the inner compartment at pH of 7.0 (lower spectrum). Temperature and pH maps of the phantom at bore temperatures of 37.3±0.1 °C (C) and 30.1±0.1 °C (D).

Figure 5

Example of temperature and pH maps of rat brain. (A) ¹H CSI of rat brain after TmDOTP⁵⁻ infusion. The signal intensity is much higher in the cortical area mainly due to RF inhomogeneity of the surface coil. (B) Example of ¹H spectra from a 1.6×1.6×4 mm³ voxel (boxed in A) showing the H2, H3 and H6 proton resonances. (C) Temperature and (D) pH maps of rat brain.