Comparison of seven modelling algorithms for γ-aminobutyric acid–edited proton magnetic resonance spectroscopy

Edited MRS sequences are widely used for studying γ-aminobutyric acid (GABA) in the human brain. Several algorithms are available for modelling these data, deriving metabolite concentration estimates through peak fitting or a linear combination of basis spectra. The present study compares seven such algorithms, using data obtained in a large multisite study. GABA-edited (GABA+, TE = 68 ms MEGA-PRESS) data from 222 subjects at 20 sites were processed via a standardised pipeline, before modelling with FSL-MRS, Gannet, AMARES, QUEST, LCModel, Osprey and Tarquin, using standardised vendor-specific basis sets (for GE, Philips and Siemens) where appropriate. After referencing metabolite estimates (to water or creatine), systematic differences in scale were observed between datasets acquired on different vendors' hardware, presenting across algorithms. Scale differences across algorithms were also observed. Using the correlation between metabolite estimates and voxel tissue fraction as a benchmark, most algorithms were found to be similarly effective in detecting differences in GABA+. An interclass correlation across all algorithms showed single-rater consistency for GABA+ estimates of around 0.38, indicating moderate agreement. Upon inclusion of a basis set component explicitly modelling the macromolecule signal underlying the observed 3.0 ppm GABA peaks, single-rater consistency improved to 0.44. Correlation between discrete pairs of algorithms varied, and was concerningly weak in some cases. Our findings highlight the need for consensus on appropriate modelling parameters across different algorithms, and for detailed reporting of the parameters adopted in individual studies to ensure reproducibility and meaningful comparison of outcomes between different studies.publishedVersio

Big GABA II: Water-referenced edited MR spectroscopy at 25 research sites

Accurate and reliable quantification of brain metabolites measured in vivo using 1H magnetic resonance spectroscopy (MRS) is a topic of continued interest. Aside from differences in the basic approach to quantification, the quantification of metabolite data acquired at different sites and on different platforms poses an additional methodological challenge. In this study, spectrally edited γ-aminobutyric acid (GABA) MRS data were analyzed and GABA levels were quantified relative to an internal tissue water reference. Data from 284 volunteers scanned across 25 research sites were collected using GABA+ (GABA + co-edited macromolecules (MM)) and MM-suppressed GABA editing. The unsuppressed water signal from the volume of interest was acquired for concentration referencing. Whole-brain T1-weighted structural images were acquired and segmented to determine gray matter, white matter and cerebrospinal fluid voxel tissue fractions. Water-referenced GABA measurements were fully corrected for tissue-dependent signal relaxation and water visibility effects. The cohort-wide coefficient of variation was 17% for the GABA + data and 29% for the MM-suppressed GABA data. The mean within-site coefficient of variation was 10% for the GABA + data and 19% for the MM-suppressed GABA data. Vendor differences contributed 53% to the total variance in the GABA + data, while the remaining variance was attributed to site- (11%) and participant-level (36%) effects. For the MM-suppressed data, 54% of the variance was attributed to site differences, while the remaining 46% was attributed to participant differences. Results from an exploratory analysis suggested that the vendor differences were related to the unsuppressed water signal acquisition. Discounting the observed vendor-specific effects, water-referenced GABA measurements exhibit similar levels of variance to creatine-referenced GABA measurements. It is concluded that quantification using internal tissue water referencing is a viable and reliable method for the quantification of in vivo GABA levels

Anterior cingulate gamma-aminobutyric acid concentrations and electroconvulsive therapy

Objective The anticonvulsant hypothesis posits that ECT’s mechanism of action is related to enhancement of endogenous anticonvulsant brain mechanisms. Results of prior studies investigating the role of the inhibitory neurotransmitter gamma‐aminobutyric acid (“GABA+”, GABA and coedited macromolecules) in the pathophysiology and treatment of depression remain inconclusive. The aim of our study was to investigate treatment‐responsive changes of GABA+ in subjects with a depressive episode receiving electroconvulsive therapy (ECT). Methods In total, 41 depressed subjects (DEP) and 35 healthy controls (HC) were recruited at two independent sites in Norway and the USA. MEGA‐PRESS was used for investigation of GABA+ in the anterior cingulate cortex. We assessed longitudinal and cross‐sectional differences between DEP and HC, as well as the relationship between GABA+ change and change in depression severity and number of ECTs. We also assessed longitudinal differences in cognitive performance and GABA+ levels. Results Depressive episode did not show a difference in GABA+ relative to HC (t71 = −0.36, p = .72) or in longitudinal analysis (t36 = 0.97, p = .34). Remitters and nonremitters did not show longitudinal (t36 = 1.12, p = .27) or cross‐sectional differences in GABA+. GABA+ levels were not related to changes in antidepressant response (t35 = 1.12, p = .27) or treatment number (t36 = 0.05, p = .96). An association between cognitive performance and GABA+ levels was found in DEP that completed cognitive effortful testing (t18 = 2.4, p = .03). Conclusion Our results failed to support GABA as a marker for depression and abnormal mood state and provide no support for the anticonvulsant hypothesis of ECT. ECT‐induced change in GABA concentrations may be related to change in cognitive function.publishedVersio

Real-time motion and magnetic field correction for GABA editing using EPI volumetric navigated MEGA-SPECIAL sequence: Reproducibility and Gender effects

γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter and is of great interest to the magnetic resonance spectroscopy (MRS) community due to its role in several neurological diseases and disorders. Since GABA acquisition without macromolecule contamination requires long scan times and strongly depends on magnetic field (B0) stability, it is highly susceptible to motion and B0 inhomogeneity. In this work, a pair of three-dimensional (3D) echo planar imaging (EPI) volumetric navigators (vNav) with different echo times, were inserted in MEGA-SPECIAL to perform prospective correction for changes in the subject's head position and orientation, as well as changes in B0. The navigators do not increase acquisition time and have negligible effect on the GABA signal. The motion estimates are obtained by registering the first of the pairs of successive vNav volume images to the first volume image. The 3D field maps are calculated through complex division of the pair of vNav contrasts and are used for estimating zero- and first-order shim changes in the volume of interest (VOI). The efficacy of the vNav MEGA-SPECIAL sequence was demonstrated in-vitro and in vivo. Without motion and shim correction, spectral distortions and increases in spectral fitting error, linewidth and GABA concentration relative to creatine were observed in the presence of motion. The navigated sequence yielded high spectral quality despite significant subject motion. Using the volumetric navigated MEGA-SPECIAL sequence, the reproducibility of GABA measurements over a 40 minute period was investigated in two regions, the anterior cingulate (ACC) and medial parietal (PAR) cortices, and compared for different analysis packages, namely LCModel, jMRUI and GANNET. LCModel analysis yielded the most reproducible results, followed by jMRUI and GANNET. GABA levels in ACC were unchanged over time, while GABA levels in PAR were significantly lower for the second measurement. In ACC, GABA levels did not differ between males and females. In contrast, males had higher GABA levels in PAR. This gender difference was, however, only present in the first acquisition. Only in males did GABA levels in PAR decrease over time. These results demonstrate that gender differences are regional, and that GABA levels may fluctuate differently in different regions and sexes

No evidence for changes in GABA concentration, functional connectivity, or working memory following continuous theta burst stimulation over dorsolateral prefrontal cortex

Continuous theta burst stimulation (cTBS) is thought to reduce cortical excitability and modulate functional connectivity, possibly by altering cortical inhibition at the site of stimulation. However, most evidence comes from the motor cortex and it remains unclear whether similar effects occur following stimulation over other brain regions. We assessed whether cTBS over left dorsolateral prefrontal cortex altered gamma aminobutyric acid (GABA) concentration, functional connectivity and brain dynamics at rest, and brain activation and memory performance during a working memory task. Seventeen healthy individuals participated in a randomised, sham-controlled, cross-over experiment. Before and after either real or sham cTBS, magnetic resonance spectroscopy was obtained at rest to measure GABA concentrations. Functional magnetic resonance imaging (fMRI) was also recorded at rest and during an n-back working memory task to measure functional connectivity, regional brain activity (low-frequency fluctuations), and task-related patterns of brain activity. We could not find evidence for changes in GABA concentration (P = 0.66, Bayes factor [BF10] = 0.07), resting-state functional connectivity (P(FWE) > 0.05), resting-state low-frequency fluctuations (P = 0.88, BF10 = 0.04), blood-oxygen level dependent activity during the n-back task (P(FWE) > 0.05), or working memory performance (P = 0.13, BF10 = 0.05) following real or sham cTBS. Our findings add to a growing body of literature suggesting the effects of cTBS are highly variable between individuals and question the notion that cTBS is a universal ‘inhibitory’ paradigm

Establishing reliable MR spectroscopy techniques for measuring GABA and Glutathione in the human brain

Background: Proton MR spectroscopy (MRS) is a well-established method for measuring the relative concentration of a wide range of metabolites in the human brain noninvasively. Lately, more advanced spectroscopic techniques, such as MEGAPRESS, have emerged enabling us to measure low concentrated metabolites with complex peak splitting patterns. Examples of such metabolites are the main inhibitory brain neurotransmitter, g-aminobutyric acid (GABA), and the main brain antioxidant, glutathione (GSH). Impairment of both GABA and GSH have been implicated in the pathophysiology of several psychiatric and neurodegenerative disorders, including schizophrenia, bipolar disorder, autism spectrum disorder (ASD), multiple sclerosis, Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson disease. An accurate and reliable quantification of these metabolites in vivo is therefore of utmost interest and clinical relevance. The PhD started with an ASD focus, setting out to examine brain MRS measurable differences between boys with ASD and controls. The focus, however, soon shifted to the methodological aspect of MRS, with a desire to contribute in establishing reliable MRS techniques for measuring GABA and GSH in the human brain. Aims: The aim of the ASD study was to explore the excitatory/inhibitory hypothesis in children with ASD by looking for imbalances in brain metabolites in boys with ASD compared with typically developing controls with standard and advanced MRS techniques. Validating GABA and GSH edited MEGA-PRESS, and comparing these sequences to the standard single voxel measurements; short TE STEAM and PRESS sequence. Methods: Four different studies were performed, all on a 3.0 T GE MRI scanner. The ASD study: 14 boys with ASD and 24 age-matched controls were examined with both the GABA edited MEGA-PRESS and PRESS sequence. Autism symptom severity were reported by the Autism Spectrum Screening Questionnaire (ASSQ). The GABA reprod study: Two 20 min long GABA edited MEGA-PRESS acquisition were performed in 21 healthy young male volunteers. The participants were scanned twice with identical protocols. By applying a timewindowing approach, within-and between-session reproducibility was calculated. The “Christmas phantom” study: 122 GSH edited MEGA-PRESS and PRESS spectra of a phantom containing GSH were acquired over a time period of 11 days. The resulting decaying GSH curve (GSH oxidizes to GSSG) were modelled. A 1-year-after follow-up acquisition for both sequences was also performed. The GSH reprod study: GSH edited MEGA-PRESS and short TE STEAM and PRESS acquisitions were performed in 36 healthy volunteers. The participants were scanned twice with identical protocols, one week apart. The timewindowing approach was applied for within- and between-session reproducibility for GSH edited MEGA-PRESS. Differences between quantified GSH levels between males and females were examined, and the three different methods of measuring GSH were evaluated. Main Results: There was a significant negative correlation in the ASD group between ASSQ and GABA levels, however there was no significant difference between the ASD group and the control group in MEGA-PRESS measured GABA levels. Increasing the number of repetitions in GABA edited MEGA-PRESS showed improvements for within- and between-session reproducibility up to about 218 paired repetitions (scan length ~ 13 min). Gannet combined with LCModel proved the best method processing the GABA data. Both GSH edited MEGA-PRESS and PRESS were able to measure the degradation of GSH in the phantom, however the modelled GSH edited MEGA-PRESS degradation curve was more accurate than PRESS. Between-session variability of GSH edited MEGA-PRESS stabilised at around 128 paired repetitions (~8 min). There were no significant correlations between GSH measured with MEGA-PRESS, STEAM and PRESS, and no differences in measured GSH levels between males and females. Conclusion: In line with other studies, the ASD participants have GABA values that seem to change with their clinical severity although there was no group difference with healthy controls. For both GABA and GSH, it is possible to acquire reproducible MEGA-PRESS measurements. GSH edited MEGA-PRESS measurements have somewhat higher coefficient of variation (meaning lower reproducibility), but stabilises at a shorter scan length than GABA edited MEGA-PRESS. MEGA-PRESS is more accurate that both PRESS and STEAM in measuring GSH for in vivo measurements. This is also reflected in its in vitro quantification, where the PRESS measurements fit of GSH seem to include oxidised GSH

Implementation of Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) for quantification of ɣ-aminobutyric acid (GABA) and glutathione (GSH)

The present study aimed to accelerate and improve accuracy of ɣ-aminobutyric acid (GABA) and glutathione (GSH) quantification. These metabolites, present at low concentrations in the brain, are challenging to detect using MR spectroscopy due to the fact that their resonance frequencies overlap with those of other more abundant metabolites. The advanced spectral editing techniques involving J-difference editing that are required to resolve the overlapping signals of these low concentration metabolites are not routinely available on clinical MRI scanners. In this work we implemented on a 3T Siemens Skyra MRI a novel MRS technique called Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) to simultaneously detect GABA and GSH, developed a novel postprocessing technique that simultaneously models the sum and various difference spectra, and evaluated the performance of the sequence and processing method both in phantoms and in vivo. HERMES was implemented by modifying the Siemens GABA-edited MEGA-PRESS WIP sequence to include two additional sub-experiments – one editing GSH with a single lobe pulse and one editing both GABA and GSH using a dual lobe pulse, and replacing the Siemens pulses with ‘universal' pulses similar to those used in a previous implementation of HERMES on a Philips platform. Performance was assessed in a phantom and 22 healthy adults, 15 of whom provided usable data (7 male, mean age 25.6 ± 2.7 yr). Three of the subjects were scanned 3 times to assess reproducibility. Data were processed and compared using a set of custom scripts in MATLAB. Following frequency and phase correction of individual averages with GANNET, we applied our custom simultaneous linear combination model that iteratively fit the concatenated sum and difference spectra using a least squares routine. SPM was used for tissue segmentation of structural images and FID-A to simulate high-resolution basis sets. The simultaneous modelling technique provided absolute quantification results for 15 metabolite moieties using internal unsuppressed water as a reference. The performance of the simultaneous fitting approach was compared to multiple independent fittings for HERCULES (Hadamard Editing Resolves Chemicals Using Linear-combination Estimation of Spectra) data that had been previously acquired on a 3T Philips Achieva MRI. Although the HERMES sequence implemented on the Siemens platform as part of this project was able to successfully edit both GABA and GSH, and generate line shapes consistent with the work by Saleh et al. (2016), quantification accuracy was disappointing. In the phantom data, GSH and GABA concentrations were both roughly 50% of known levels. Since the actual concentrations in vivo were not known, we were not able to establish accuracy, but quantification agreement between the MEGA-PRESS and HERMES sequences was poor for most metabolites. Specifically, GABA levels were two to three times higher than expected values using both HERMES and GABA-edited MEGA-PRESS. Despite poor absolute agreement, concentrations from HERMES and MEGA-PRESS data were moderately correlated, and HERMES data showed lower coefficients of variation across subjects, suggesting that it may be more reliable. HERMES was also more reproducible across scanning sessions and participants for more metabolites than GABA- or GSH-edited MEGA-PRESS. Our findings also showed that simultaneous fitting using the sum and difference spectra produces lower coefficients of variation for most metabolites than fittings to sum and difference spectra separately