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

Date Published: April 17, 2019

Publisher: Public Library of Science

Author(s): Ningzhi Li, Linqing Li, Yan Zhang, Maria Ferraris Araneta, Christopher Johnson, Jun Shen, Jessica Dubois.


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.

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.

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.

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.

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Glutamate (Glu) has several fundamentally important functions in the central nervous system (CNS). It is the principal excitatory neurotransmitter as well as a key metabolite linking carbon and nitrogen metabolism [1]. The dual roles of Glu as a neurotransmitter and as a by-product of the citric acid cycle are intricately connected. Because of Glu’s crucial role in the glutamatergic process and energy metabolism, in vivo magnetic resonance spectroscopy (MRS) has been widely used to study the function of Glu in basic neuroscience as well as in various brain disorders [2–7]. Indeed, altered Glu concentrations have been linked to many pathologies, including head trauma, pain, aging, and many neurodegenerative diseases [2–5]. In addition, abnormal glutamatergic activity has been associated with psychiatric disorders such as schizophrenia and depression, and the glutamatergic system is currently a key focus of developing novel treatments for those disorders [6, 7].

Fig 2 displays the Bloch simulation of temporal variation of longitudinal magnetization at different FAs during one TR. As expected, the signal attenuated more from thermal equilibrium signal intensity as FA increased. The time needed for longitudinal magnetization to achieve steady state also varied for each FA. For example, only 4.5 secs of TR were required when the FA was at 36°. Overall, the time required for magnetization to achieve RF-driven steady state gradually decreased as FA increased. This indicates that a shorter TR can be used for a larger FA and, commensurately, that the total scan time can be significantly reduced by using different TRmin for different FAs; here, TRmin is defined as the minimum time required for magnetization to achieve RF-driven steady state (when the amplitude change of magnetization is less than 0.1%) in a single scan.

The present study made significant improvements to the previously developed MARzss method and applied it to characterize Glu relaxation in the frontal cortex. Bloch simulation suggested that both recovery delay time and RF pulse train duration could be shortened when the FA of the RF pulse train increased. However, when the FA is too large, the relatively weak signal intensity of Glu may become too small to be reliably determined. This study also determined experimental parameters for Glu T2 measurements based on Monte Carlo analysis and achievable SNR. The overall data acquisition time in this study was significantly shortened by using TRmin for each FA determined by Bloch simulation. Notably, the original MARzss method [12] used an iPFG train with fixed length and a long recycle delay and required more than 15 minutes to obtain enough data to conduct a T2 calculation if the number of averages was set to 16 for each FA. In contrast, the improved MARzss method used here significantly reduced the total scan time per voxel for the same SNR.

In this work we significantly improved the MARzss method as evidenced by the shortened total scan times per voxel and significantly reduced standard deviations of Glu T2 values in vivo. In particular, we demonstrated that this improved MARzss method can be used in a typical clinical setting to reliably measure Glu T2 from multiple anatomical locations, including the technically more challenging frontal cortex.




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