Improved detection limits of J-coupled neurometabolites in the human brain at 7 T with a J-refocused sLASER sequence

Abstract

In a standard spin echo, the time evolution due to homonuclear couplings is not reversed, leading to echo time (TE)-dependent modulation of the signal amplitude and signal loss in the case of overlapping multiplet resonances. This has an adverse effect on quantification of several important metabolites such as glutamate and glutamine. Here, we propose a J-refocused variant of the sLASER sequence (J-sLASER) to improve quantification of J-coupled metabolites at ultrahigh field (UHF). The use of the sLASER sequence is particularly advantageous at UHF as it minimizes chemical shift displacement error and results in relatively homogenous refocusing. We simulated the MRS signal from brain metabolites over a broad range of TE values with sLASER and J-sLASER, and showed that the signal of J-coupled metabolites was increased with J-sLASER with TE values up to ~80 ms. We further simulated "brain-like" spectra with both sequences at the shortest TE available on our scanner. We showed that, despite the slightly longer TE, the J-sLASER sequence results in significantly lower Cramer-Rao lower bounds (CRLBs) for J-coupled metabolites compared with those obtained with sLASER. Following phantom validation, we acquired spectra from two brain regions in 10 healthy volunteers (age 38 ± 15 years) using both sequences. We showed that using J-sLASER results in a decrease of CRLBs for J-coupled metabolites. In particular, we measured a robust ~38% decrease in the mean CRLB (glutamine) in parietal white matter and posterior cingulate cortex (PCC). We further showed, in 10 additional healthy volunteers (age 34 ± 15 years), that metabolite quantification following two separate acquisitions with J-sLASER in the PCC was repeatable. The improvement in quantification of glutamine may in turn improve the independent quantification of glutamate, the main excitatory neurotransmitter in the brain, and will simultaneously help to track possible modulations of glutamine, which is a key player in the glutamatergic cycle in astrocytes.

Keywords: 7 T; J-coupled metabolites; J-refocused sLASER; aspartate; detection limits; glutamate; glutamine; human brain.

FIGURE 1

Diagrams of the (A) sLASER and (B) J‐sLASER sequences. Slice selection gradients are represented in black and refocusing/spoiler gradients are shown in gray. The crusher gradient scheme for the J‐sLASER sequence was modified from its original form to ensure fully refocused transverse magnetization at the time of the π/2 pulse. All π pulses are adiabatic slice‐selective FOCI RF pulses. The additional π/2 square RF pulse with concomitant slice selection and refocusing gradients in the J‐sLASER sequence are highlighted with a dotted blue rectangle.

FIGURE 2

Simulated spectra (S/S) of the (A) ³CH₃ lactate and (B) ⁴CH₂ glutamate resonances as a function of TE for the sLASER and J‐sLASER sequences including T₂ relaxation; (C) Signal of J‐coupled proton groups of eight brain metabolites over a range of TE values (normalized to the signal at TE = 10 ms) as measured for sLASER (black solid line) and J‐sLASER (blue line), and the signal difference (J‐sLASER – sLASER; light gray dotted line). The superscript number indicated for each metabolite corresponds to the carbon group of the molecule. GABA, gamma‐aminobutyric acid; GSH, glutathione; NAA, N‐acetyl‐aspartate

FIGURE 3

Example of brain‐like simulated spectra with sLASER and J‐sLASER sequences used for the Monte Carlo simulations. (A) sLASER spectrum at TE = 29 ms (black); (B) J‐sLASER spectrum at TE = 38 ms (blue). The sLASER spectrum at TE = 38 ms is also displayed (gray) to illustrate the increase in signal of J‐coupled resonances with J‐sLASER at this TE value. Asp, aspartate; GABA, gamma‐aminobutyric acid; Gln, glutamine; Glu, glutamate; GSH, glutathione; Ins, myo‐inositol; Lac, lactate; MM, macromolecule; PE, phosphoethanolamine; Tau, taurine

FIGURE 4

Whisker plots representing the distributions of the LCModel Cramer–Rao lower bound (CRLB) values (%) over 20 repetitions (left) and of the coefficient of variation (CoV) (%) of CRLBs measured over the 20 repetitions for the 50 subgroups (right) for both sLASER at TE = 29 ms (black) and J‐sLASER at TE = 38 ms (blue). Statistical significance was evaluated using an unpaired t test with equal variance with *p < 0.05 and ****p ≤ 0.0001. Asp, aspartate; GABA, gamma‐aminobutyric acid; Gln, glutamine; Glu, glutamate; GSH, glutathione; Ins, myo‐inositol; Lac, lactate; PE, phosphoethanolamine; Tau, taurine

FIGURE 5

Representative spectra acquired from the BRAINO phantom with the (A) sLASER and (B) J‐sLASER sequences with a range of TE values between 38 and 148 ms. The spectra have been zero‐filled and a line‐broadening of 12 Hz has been applied. (C) Quantification of J‐coupled and non–J‐coupled resonances from data acquired with sLASER (black solid line, triangle) and J‐sLASER (blue solid line, diamond). Subtraction of the signal obtained for both sequences is shown in light gray (circle). Glu, glutamate; Ins, myo‐inositol; Lac, lactate; NAA, N‐acetyl‐aspartate

FIGURE 6

(A) Representative placement of the volume of interest in the PWM region (dashed line) and in the PCC region (solid line). (B) Representative spectra acquired in vivo with the two sequences in both regions. (C) The spectral region between 2.0 and 2.8 ppm shown for sLASER (TE = 29 ms and TE = 38 ms) and J‐sLASER (TE = 38 ms), illustrating the signal gain for J‐coupled CH_n groups. PCC, posterior cingulate cortex; PWM, parietal white matter

FIGURE 7

CRLB values estimated for several J‐coupled metabolites from sLASER acquisition at shortest TE and J‐sLASER acquisitions in both brain regions. Whisker plots (min‐max) and individual data are shown. The black triangle represents the sLASER individual data and the blue diamond represents the J‐sLASER individual data. The black line connects data obtained from the same subject. Statistical significance of the differences between sLASER and J‐sLASER was evaluated using a Wilcoxon signed‐rank paired test with *p < 0.05 and **p < 0.005. Asp, aspartate; CRLB, Cramer–Rao lower bound; GABA, gamma‐aminobutyric acid; Gln, glutamine; Glu, glutamate; GSH, glutathione; Ins, myo‐inositol; PCC, posterior cingulate cortex; PWM, parietal white matter

FIGURE 8

Results of the test–retest analysis for three J‐coupled metabolites are shown: Bland–Altman plots for all three metabolites from data acquired with (A) sLASER at shortest TE (black triangles) and (B) J‐sLASER (blue diamonds). Dotted lines indicate the 95% limits of agreements. (C) Scatterplots for all three metabolites for both sLASER at shortest TE (black triangles) and J‐sLASER (blue diamonds). The dotted line indicates the identity line. (D) Cramer–Rao lower bound (CRLB) values estimated from sLASER acquisition at shortest TE and J‐sLASER acquisitions. Whisker plots (min‐max) and individual data are shown. The black triangles represent the sLASER individual data and the blue diamonds represent the J‐sLASER individual data. The black line connects data obtained from the same subject. Statistical significance of the differences between sLASER and J‐sLASER was evaluated using a Wilcoxon signed‐rank paired test with *p < 0.05. Asp, aspartate; Gln, glutamine; Glu, glutamate; tCr, total creatine