Brain γ-aminobutyric acid (GABA) detectionin vivowith theJ-editing¹H MRS technique: a comprehensive methodological evaluation of sensitivity enhancement, macromolecule contamination and test-retest reliability

Abstract

Abnormalities in brain γ-aminobutyric acid (GABA) have been implicated in various neuropsychiatric and neurological disorders. However, in vivo GABA detection by proton magnetic resonance spectroscopy (1H MRS) presents significant challenges arising from low brain concentration, overlap by much stronger resonances, and contamination by mobile macromolecule (MM) signals. This study addresses these impediments to reliable brain GABA detection with the J-editing difference technique on a 3T MR system in healthy human subjects by (a) assessing the sensitivity gains attainable with an 8-channel phased-array head coil, (b) determining the magnitude and anatomic variation of the contamination of GABA by MM, and (c) estimating the test-retest reliability of measuring GABA with this method. Sensitivity gains and test-retest reliability were examined in the dorsolateral prefrontal cortex (DLPFC), while MM levels were compared across three cortical regions: the DLPFC, the medial prefrontal cortex (MPFC) and the occipital cortex (OCC). A 3-fold higher GABA detection sensitivity was attained with the 8-channel head coil compared to the standard single-channel head coil in DLPFC. Despite significant anatomic variation in GABA+MM and MM across the three brain regions (p < 0.05), the contribution of MM to GABA+MM was relatively stable across the three voxels, ranging from 41% to 49%, a non-significant regional variation (p = 0.58). The test-retest reliability of GABA measurement, expressed either as ratios to voxel tissue water (W) or total creatine, was found to be very high for both the single-channel coil and the 8-channel phased-array coil. For the 8-channel coil, for example, Pearson’s correlation coefficient of test vs. retest for GABA/W was 0.98 (R2 = 0.96, p = 0.0007), the percent coefficient of variation (CV) was 1.25%, and the intraclass correlation coefficient (ICC) was 0.98. Similar reliability was also found for the co-edited resonance of combined glutamate and glutamine (Glx) for both coils.

Big GABA: Edited MR spectroscopy at 24 research sites

“…The ratio between MM-suppressed GABA and GABA+ measurements (0.38) is lower than expected. Typically, it is assumed that ~50% of the GABA+ signal is GABA (Harris et al, 2015a; Mikkelsen et al, 2016a; Shungu et al, 2016). This is largely explained by differential T 2 relaxation between GABA signal at TE = 68 ms and TE = 80 ms (13% edited signal loss based on a T 2 of 88 ms (Edden et al, 2012b)) and artificially reduced “MM-suppressed GABA” values due to negative MM co-editing (~5% edited signal loss due to mean $\overline{\mathrm{normal\Delta }{\delta }_0}$ of −0.005 ppm (see Edden et al, 2016)).…”

“…Difference editing techniques in particular use frequency-selective inversion pulses to achieve this (for methodological reviews, see Harris et al, 2017; Puts and Edden, 2012). The popularity of MEGA-PRESS is attributed to a number of factors, including the wide availability of the basic PRESS sequence across scanner platforms, its relatively straightforward implementation (Mullins et al, 2014), its reproducibility (Bogner et al, 2010; Brix et al, 2017; Geramita et al, 2011; Mikkelsen et al, 2016a; Near et al, 2014; O’Gorman et al, 2011; Shungu et al, 2016) and continued development of acquisition methodology and data processing tools (Chan et al, 2016; Edden et al, 2014). …”

Assessment of Anterior Cingulate Cortex (ACC) and Left Cerebellar Metabolism in Asperger's Syndrome with Proton Magnetic Resonance Spectroscopy (MRS)

“…First, conventional short echo time (TE) spectra were obtained using the Stimulated Echo Acquisition Mode (STEAM) sequence with repetition time (TR) = 5000 ms, echo time (TE) = 15 ms and 48 signal averages to record spectra from a 1.5×2.0×2.0-cm 3 voxel prescribed in the ACC and in the left cerebellum (Fig 1). Next, without moving the subjects spectra were again obtained from a 3x3x3-cm 3 voxel, but using the standard Point RESolved Spectroscopy (PRESS) sequence, which had been modified to enable the detection of γ-aminobutyric acid (GABA) by J-edited spin echo difference technique [16], as fully described recently [17,18]. Briefly, to implement the J-editing technique, a pair of a frequency-selective inversion pulses was inserted into the standard PRESS method, and then applied on the GABA C-3 resonance at 1.9 ppm on alternate scans, using TE/TR 68/2500ms.…”

Normalizing data from GABA-edited MEGA-PRESS implementations at 3 Tesla

“…Finally measurement reproducibility will influence these results but is not accounted for in the κ,μ-correction. Most recently, Shungu et al [42] showed excellent test-retest GABA repeatability for both water-referenced and Cr-referenced data. In the literature, reproducibility of measurements is variable with test-retest studies presenting CVs from as low as 5%, as per Shungu et al, intermediate values of 8–15% as seen by Evans et al [14] and O’Gorman et al [43], to larger values 13–20%, as seen by Bogner et al [35].…”