Big GABA: Edited MR spectroscopy at 24 research sites
Introduction
Magnetic resonance spectroscopy (MRS) is unique amongst the neuroimaging modalities in detecting endogenous signals from complex molecules in the brain noninvasively. Of particular interest is the detection and measurement of γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the mammalian brain (McCormick, 1989). Healthy brain function relies on GABAergic inhibitory processes, and understanding GABAergic mechanisms in both healthy and pathological brain function has been one core focus of neuroscience. MRS measurements of GABA have been associated with individual differences in hemodynamic and electrophysiological signals (Donahue et al., 2010, Hu et al., 2013, Kapogiannis et al., 2013, Muthukumaraswamy et al., 2009) and a number of measures of cognition (Fujihara et al., 2015, Shibata et al., 2017, Yoon et al., 2016) and behavior (Boy et al., 2011, Greenhouse et al., 2017, Puts et al., 2011, Silveri et al., 2013). Differential levels of GABA have been observed in a number of neuropsychiatric disorders, such as schizophrenia (Kegeles et al., 2012, Öngür et al., 2010, Rowland et al., 2016, Yoon et al., 2010) and depression (Bhagwagar et al., 2008, Hasler et al., 2007, Price et al., 2009), neurodevelopmental disorders, such as autism spectrum disorder (Drenthen et al., 2016, Gaetz et al., 2014, Puts et al., 2016) and attention deficit hyperactivity disorder (Bollmann et al., 2015, Edden et al., 2012a), and neurological diseases, such as Parkinson's disease (Emir et al., 2012), amyotrophic lateral sclerosis (Foerster et al., 2012, Foerster et al., 2013) and diabetic neuropathy (Petrou et al., 2012).
The most common MRS approach for detecting the GABA signal is the Mescher–Garwood (MEGA) editing sequence (Mescher et al., 1998), a J-difference spectral editing technique that is typically implemented within a point resolved spectroscopy (PRESS) (Bottomley, 1987) acquisition. MEGA-PRESS and other spectral editing techniques exploit the known scalar coupling properties of molecules in order to separate their associated signals from the overlapping signals of other molecules. For lower-concentration metabolites such as GABA, spectral editing differentiates the weak signals of interest from the stronger, overlapping signals of higher-concentration metabolites. 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).
However, despite these positive attributes, the diversity of implementations of MEGA-PRESS across research sites and vendors has meant that comparing data between different studies is difficult. For instance, pulse sequence parameters, and in particular pulse timings, differ between vendor-specific PRESS sequences and lead to subtle but important differences in the resolved GABA signal (Near et al., 2013b). Moreover, spectral editing of GABA is associated with a number of complexities, including TE-dependent J-evolution of the GABA spin system (Edden et al., 2012b), frequency and spatial effects of volume localization (Edden and Barker, 2007, Kaiser et al., 2008), sensitivity to B0 field frequency offsets (Edden et al., 2016, Harris et al., 2014) and contamination from co-edited macromolecules (MM) (Henry et al., 2001, Rothman et al., 1993). It is generally assumed that these factors limit the degree to which a GABA-edited measurement from one site can be compared to another at a different site.
In order to establish the extent to which site-, sequence- and vendor-specific differences impact quantitative MEGA-PRESS measurement outcomes, a multi-vendor, multi-site dataset has been assembled by an international consortium of GABA-edited MRS users. The consortium was formed with the aim of building a normative database of MEGA-PRESS data acquired on the major MRI scanner platforms at a range of imaging centers focused on neuroscience research. This dataset aims to capture some of the diversity of the sequences used, but within the framework of a standardized study design and acquisition protocol that would reflect typical MEGA-PRESS parameters. This approach reduced the number of confounding variables present within the dataset (e.g., standardizing key parameters such as TE, TR and editing pulse bandwidth), while maintaining diversity at the level of pulse sequence implementation (e.g., localization pulse waveforms/bandwidths, pulse timings and crusher gradient schemes).
This paper presents initial results from this multi-site study, focusing on how variance in creatine-referenced GABA measurements was distributed across research sites and scanner vendors and examining the influence of various acquisition- and participant-related effects. Given the complexity of this dataset, it is not possible to report on all aspects of the project in a single article, so for example, water-referenced quantification (including tissue-dependent correction factors) and site-to-site differences in voxel placement fidelity and segmentation will be presented in a future report.
Section snippets
Data collection
A consortium of 24 research institutions based in nine countries participated in this initiative, with each site contributing 5–12 datasets collected from consenting adult volunteers. Specific guidelines for each site's participant cohort were: 18–35 years old; approximately 50:50 female/male split; no known neurological or psychiatric illness. In total, data from 272 participants were collected. Participant demographics are provided in Table 1. Scanning was conducted in accordance with ethical
Results
GABA-edited MRS data were successfully acquired at all 24 sites. Following quality control analysis, seven GABA+ and 19 MM-suppressed GABA datasets (3% and 7% of the total collected data for either acquisition, respectively) were removed from further analysis. All MM-suppressed GABA data from site G3 were excluded as consistent, excessive center frequency offsets (approximately −0.1 ppm on average) resulted in extremely small or absent GABA signals. Fig. 2 shows the mean ± 1 SD GABA+ and
Discussion
This is the largest multi-site study to date applying GABA-edited MRS in the human brain. The aims at the outset were to establish the extent to which GABA-edited measurements are influenced by site-, sequence- and vendor-specific differences, and to investigate sources of observed variance. Overall, the major findings can be summarized as follows:
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The agreement between GABA+ values was surprisingly good, with whole-dataset CV (12%) not much higher than the mean within-site CV (10%), although
Acknowledgments
This work was supported by NIH grants R01 EB016089, R01 EB023963 and P41 EB015909. Data collection was supported by the Shandong Provincial Key Research and Development Plan of China (2016ZDJS07A16) and the National Natural Science Foundation of China for Young Scholars (no. 81601479). IDW thanks Mrs. J. Bigley of the University of Sheffield MRI Unit for her assistance with data acquisition. JJP was supported by NIAAA grant K23 AA020842. MPS was supported by NIH grant F32 EY025121. NAJP
References (105)
- et al.
Random effects structure for confirmatory hypothesis testing: keep it maximal
J. Mem. Lang.
(2013) - et al.
3D GABA imaging with real-time motion correction, shim update and reacquisition of adiabatic spiral MRSI
Neuroimage
(2014) - et al.
In vivo quantification of intracerebral GABA by single-voxel 1H-MRS—how reproducible are the results?
Eur. J. Radiol.
(2010) - et al.
Absolute metabolite quantification by in vivo NMR spectroscopy: IV. Multicentre trial on MRSI localisation tests
Magn. Reson. Imaging
(1998) - et al.
Dorsolateral prefrontal γ-aminobutyric acid in men predicts individual differences in rash impulsivity
Biol. Psychiatry
(2011) - et al.
A multicenter in vivo proton-MRS study of HIV-associated dementia and its relationship to age
Neuroimage
(2004) - et al.
Absolute metabolite quantification by in vivo NMR spectroscopy: III. Multicentre 1H MRS of the human brain addressed by one and the same data-analysis protocol
Magn. Reson. Imaging
(1998) - et al.
Baseline GABA concentration and fMRI response
Neuroimage
(2010) - et al.
Altered neurotransmitter metabolism in adolescents with high-functioning autism
Psychiatry Res. Neuroimaging
(2016) - et al.
Relationship of γ-aminobutyric acid and glutamate+glutamine concentrations in the perigenual anterior cingulate cortex with performance of Cambridge Gambling Task
Neuroimage
(2015)
GABA estimation in the brains of children on the autism spectrum: measurement precision and regional cortical variation
Neuroimage
Posteromedial cortex glutamate and GABA predict intrinsic functional connectivity of the default mode network
Neuroimage
Absolute metabolite quantification by in vivo NMR spectroscopy: II. A multicentre trial of protocols for in vivo localised proton studies of human brain
Magn. Reson. Imaging
Current practice in the use of MEGA-PRESS spectroscopy for the detection of GABA
Neuroimage
Long-term reproducibility of GABA magnetic resonance spectroscopy
Neuroimage
Elevated gamma-aminobutyric acid levels in chronic schizophrenia
Biol. Psychiatry
Altered excitation-inhibition balance in the brain of patients with diabetic neuropathy
Acad. Radiol.
A practical guide to multilevel modeling
J. Sch. Psychol.
In vivo magnetic resonance spectroscopy of GABA: a methodological review
Prog. Nucl. Magn. Reson. Spectrosc.
Amino acid neurotransmitters assessed by proton magnetic resonance spectroscopy: relationship to treatment resistance in major depressive disorder
Biol. Psychiatry
Simultaneous edited MRS of GABA and glutathione
Neuroimage
Frontal lobe γ-aminobutyric acid levels during adolescence: associations with impulsivity and response inhibition
Biol. Psychiatry
Accurate classification of childhood brain tumours by in vivo 1H MRS - a multi-centre study
Eur. J. Cancer
Effect of signal-to-noise ratio and spectral linewidth on metabolite quantification at 4 T
NMR Biomed.
Fitting linear mixed-effects models using lme4
J. Stat. Softw.
Low GABA concentrations in occipital cortex and anterior cingulate cortex in medication-free, recovered depressed patients
Int. J. Neuropsychopharmacol.
1D-spectral editing and 2D multispectral in vivo 1H-MRS and 1H-MRSI - methods and applications
Anal. Biochem.
MR spectroscopy of breast cancer for assessing early treatment response: results from the ACRIN 6657 MRS trial
J. Magn. Reson. Imaging
Developmental changes in gamma-aminobutyric acid levels in attention-deficit/hyperactivity disorder
Transl. Psychiatry
Spatial localization in NMR spectroscopy in vivo
Ann. N. Y. Acad. Sci.
Within- and between-session reproducibility of GABA measurements with MR spectroscopy
J. Magn. Reson. Imaging
Spatial Hadamard encoding of J-edited spectroscopy using slice-selective editing pulses
NMR Biomed.
HERMES: hadamard encoding and reconstruction of MEGA-edited spectroscopy
Magn. Reson. Med.
Simultaneous measurement of Aspartate, NAA, and NAAG using HERMES spectral editing at 3 Tesla
Neuroimage
Two-site reproducibility of cerebellar and brainstem neurochemical profiles with short-echo, single-voxel MRS at 3T
Magn. Reson. Med.
Bootstrap confidence intervals
Stat. Sci.
Spatial effects in the detection of γ-aminobutyric acid: improved sensitivity at high fields using inner volume saturation
Magn. Reson. Med.
Reduced GABA concentration in attention-deficit/hyperactivity disorder
Arch. Gen. Psychiatry
Measuring T2 in vivo with j-difference editing: application to GABA at 3 Tesla
J. Magn. Reson. Imaging
Prospective frequency correction for macromolecule-suppressed GABA editing at 3T
J. Magn. Reson. Imaging
Macromolecule-suppressed GABA-edited magnetic resonance spectroscopy at 3T
Magn. Reson. Med.
Gannet: a batch-processing tool for the quantitative analysis of gamma-aminobutyric acid-edited MR spectroscopy spectra
J. Magn. Reson. Imaging
Elevated pontine and putamenal GABA levels in mild-moderate Parkinson disease detected by 7 Tesla proton MRS
PLoS One
Diurnal stability of γ-aminobutyric acid concentration in visual and sensorimotor cortex
J. Magn. Reson. Imaging
Decreased motor cortex γ-aminobutyric acid in amyotrophic lateral sclerosis
Neurology
An imbalance between excitatory and inhibitory neurotransmitters in amyotrophic lateral sclerosis revealed by use of 3-T proton magnetic resonance spectroscopy
JAMA Neurol.
Multiproject–multicenter evaluation of automatic brain tumor classification by magnetic resonance spectroscopy
Magn. Reson. Mater. Phys. Biol. Med.
Use of tissue water as a concentration reference for proton spectroscopic imaging
Magn. Reson. Med.
Reproducibility of prefrontal γ-aminobutyric acid measurements with J-edited spectroscopy
NMR Biomed.
Partitioning variation in multilevel models
Underst. Stat.
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