Quantification of in vivo transverse relaxation of glutamate in the frontal cortex of human brain by radio frequency pulse-driven longitudinal steady state

Abstract

Purpose: The principal excitatory neurotransmitter glutamate plays an important role in many central nervous system disorders. Because glutamate resides predominantly in glutamatergic neurons, its relaxation properties reflect the intracellular environment of glutamatergic neurons. This study developed an improved echo time-independent technique for measuring transverse relaxation time and demonstrated that this radio frequency (RF)-driven longitudinal steady state technique can reliably measure glutamate transverse relaxation in the frontal cortex, where structural and functional abnormalities have been associated with psychiatric symptoms.

Method: Bloch and Monte Carlo simulations were performed to improve and optimize the RF-driven, longitudinal, steady-state (MARzss) technique to significantly shorten scan time and increase measurement precision. Optimized four-flip angle measurements at 0°,12°, 24°, and 36° with matched repetition time were used in nine human subjects (6F, 3M; 27-49 years old) at 7 Tesla. Longitudinal and transverse relaxation rates for glutamate were measured from a 2 x 2 x 2 cm3 voxel placed in three different brain regions: gray matter-dominated medial prefrontal lobe, white matter-dominated left frontal lobe, and gray matter-dominated occipital lobe.

Results: Compared to the original MARzss technique, the scan time per voxel for measuring glutamate transverse relaxation was shortened by more than 50%. In the medial frontal, left frontal, and occipital voxels, the glutamate T2 was found to be 117.5±12.9 ms (mean ± standard deviation, n = 9), 107.3±12.1 (n = 9), and 124.4±16.6 ms (n = 8), respectively.

Conclusions: The improvements described in this study make the MARZSS technique a viable tool for reliably measuring glutamate relaxation from human subjects in a typical clinical setting. It is expected that this improved technique can be applied to characterize the intracellular environment of glutamatergic neurons in a variety of brain disorders.

Fig 1. Diagram of the MARzss method.

The first part is the interleaved RF and gradient pulses (iPFG) train, where FA is the flip angle of each radio frequency (RF) pulse and G is the field gradient inserted between two RF pulses in the train. G is applied in the z direction. Water suppression is applied following the iPFG train. Steady state longitudinal magnetization is measured by a point-resolved spectroscopy (PRESS) sequence optimized for Glu detection at 7 Tesla.

Fig 2. Bloch simulation of Mzss.

Bloch simulation of longitudinal steady state magnetization (Mzss) temporal variation in one repetition time (TR) at different flip angle (FA) (unit: degree). Mzss achieved steady state much more quickly as FA increased. Short recovery of longitudinal magnetization during water suppression was compensated for in Eq 1. RD: recovery delay between PRESS and the interleaved RF and gradient pulses (iPFG) train.

Fig 3. Typical raw in vivo spectra at different flip angles (FAs).

Typical raw in vivo spectra acquired from the medial frontal lobe voxel of a healthy subject using the improved MARzss method at four different FAs.

Fig 4. Monte Carlo simulation at different noise levels.

(A) The mean value of glutamate (Glu) amplitude-to-noise ratio (red cross) from 100 Monte Carlo simulations at 50 different flip angles (FAs). Significant deviations between mean values from Monte Carlo simulations and ground truth values were observed when the Glu amplitude-to-noise ratio was below five. (B) The contour map of Glu amplitude-to-noise ratio as a function of number of signal averages and FA. Values of the ratio are labeled on each contour line. The dashed lines in D indicate that at FA = 36° the Glu amplitude to noise ratio was five when the number of averages = 16.

Fig 5. In vivo spectra fit and signal amplitude ratio fit.

Individual fit of in vivo spectra acquired from the medial frontal lobe region of a healthy subject using the improved MARzss method at four different flip angles (FAs) (A,B,C, and D). All spectra were zero filled eight times and apodized using a combination of Lorentzian and Gaussian functions. Yellow squares were overlaid on the high resolution T₁-weighted MRPAGE images at the right side of the spectra, indicating the position of the MRS voxel in a gray matter (GM)-dominated brain region. The signal amplitude ratio (Rzss) of glutamate (Glu) as a function of FA is plotted as a red circle in subplot E. Linear fitting is shown as a black dashed line.