Neurochemical predictors of generalised learning induced by brain stimulation and training.

Methods of cognitive enhancement for humans are most impactful when they generalise across tasks. However, the extent to which such "transfer" is possible via interventions is widely debated. In addition, the contribution of excitatory and inhibitory processes to such transfer is unknown. Here, in a large-scale neuroimaging individual differences study with humans (both sexes), we paired multitasking training and non-invasive brain stimulation (transcranial direct current stimulation; tDCS) over multiple days and assessed performance across a range of paradigms. In addition, we varied tDCS dosage (1.0 mA and 2.0 mA), electrode montage (left or right prefrontal regions), and training task (multitasking versus a control task) and assessed GABA and glutamate concentrations via ultra-high field 7T magnetic resonance spectroscopy. Generalised benefits were observed in spatial attention, indexed by visual search performance, when multitasking training was combined with 1.0 mA stimulation targeting either the left or right prefrontal cortex. This transfer effect persisted for ∼30 days post-intervention. Critically, the transferred benefits associated with right prefrontal tDCS were predicted by pre-training concentrations of glutamate in the prefrontal cortex. Thus, the effects of this combined stimulation and training protocol appears to be linked predominantly to excitatory brain processes.Significance statement Despite the general public's fascination with cognitive training, performance benefits rarely extend beyond the trained task, i.e., 'transfer'. Our study examines the impact of combining executive function training and transcranial direct current stimulation (tDCS) on human cognitive performance and identifies a functional neural metabolite marker (glutamate concentrations in prefrontal cortex assessed via 7 T MR Spectroscopy) that predicts outcomes. In the largest study of its kind to date (178 individuals), we find generalised performance benefits induced by frontal tDCS for an untrained spatial attention task. Further, the degree of transfer correlated with concentrations of glutamate in the frontal cortex. Thus, excitatory neural processes in this region are implicated in the transfer of paired stimulation and training benefits.

Simultaneous Measurement of GABA, Glutathione, and Glutamate-Glutamine in the Thalamus using Edited MR Spectroscopy: Feasibility and Applications in Traumatic Brain Injury.

BACKGROUND: MR spectroscopy (MRS) is a noninvasive tool for evaluating biochemical alterations, such as glutamate (Glu)/gamma-aminobutyric acid (GABA) imbalance and depletion of antioxidative glutathione (GSH) after traumatic brain injury (TBI). Thalamus, a critical and vulnerable region post-TBI, is challenging for MRS acquisitions, necessitating optimization to simultaneously measure GABA/Glu and GSH. PURPOSE: To assess the feasibility and optimize acquisition and processing approaches for simultaneously measuring GABA, Glx (Glu + glutamine (Gln)), and GSH in the thalamus, employing Hadamard encoding and reconstruction of MEscher-GArwood (MEGA)-edited spectroscopy (HERMES). STUDY TYPE: Prospective. SUBJECTS: 28 control subjects (age: 35.9 ± 15.1 years), and 17 mild TBI (mTBI) patients (age: 32.4 ± 11.3 years). FIELD STRENGTH/SEQUENCE: 3T/T1-weighted magnetization-prepared rapid gradient-echo (MP-RAGE), HERMES. ASSESSMENT: We evaluated the impact of acquisition with spatial saturation bands and post-processing with spectral alignment on HERMES performance in the thalamus among controls. Within-subject variability was examined in five controls through repeated scans within a week. The HERMES spectra in the posterior cingulate cortex (PCC) of controls were used as a reference for assessing HERMES performance in a reliable target. Furthermore, we compared metabolite levels and fitting quality in the thalamus between mTBI patients and controls. STATISTICAL TESTS: Unpaired t-tests and within-subject coefficient-of-variation (CV). A P-value <0.05 was deemed significant. RESULTS: HERMES spectra, acquired with saturation bands and processed with spectral alignment, yielded reliable metabolite measurements in the thalamus. The mean within-subject CV for GABA, Glx, and GSH levels were 18%, 10%, and 16% in the thalamus (7%, 9%, and 16% in the PCC). GABA (3.20 ± 0.60 vs 2.51 ± 0.55, P < 0.01) and Glx (8.69 ± 1.23 vs 7.72 ± 1.19, P = 0.03) levels in the thalamus were significantly higher in mTBI patients than in controls, with GSH (1.27 ± 0.35 vs 1.22 ± 0.28, P = 0.65) levels showing no significant difference. DATA CONCLUSION: Simultaneous measuring GABA/Glx and GSH using HERMES is feasible in the thalamus, providing valuable insight into TBI. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Glutamate measurements using edited MRS.

PURPOSE: To demonstrate J-difference coediting of glutamate using Hadamard encoding and reconstruction of Mescher-Garwood-edited spectroscopy (HERMES). METHODS: Density-matrix simulations of HERMES (TE 80 ms) and 1D J-resolved (TE 31-229 ms) of glutamate (Glu), glutamine (Gln), γ-aminobutyric acid (GABA), and glutathione (GSH) were performed. HERMES comprised four sub-experiments with editing pulses applied as follows: (A) 1.9/4.56 ppm simultaneously (ONGABA /ONGSH ); (B) 1.9 ppm only (ONGABA /OFFGSH ); (C) 4.56 ppm only (OFFGABA /ONGSH ); and (D) 7.5 ppm (OFFGABA /OFFGSH ). Phantom HERMES and 1D J-resolved experiments of Glu were performed. Finally, in vivo HERMES (20-ms editing pulses) and 1D J-resolved (TE 31-229 ms) experiments were performed on 137 participants using 3 T MRI scanners. LCModel was used for quantification. RESULTS: HERMES simulation and phantom experiments show a Glu-edited signal at 2.34 ppm in the Hadamard sum combination A+B+C+D with no overlapping Gln signal. The J-resolved simulations and phantom experiments show substantial TE modulation of the Glu and Gln signals across the TEs, whose average yields a well-resolved Glu signal closely matching the Glu-edited signal from the HERMES sum spectrum. In vivo quantification of Glu show that the two methods are highly correlated (p < 0.001) with a bias of ∼10%, along with similar between-subject coefficients of variation (HERMES/TE-averaged: ∼7.3%/∼6.9%). Other Hadamard combinations produce the expected GABA-edited (A+B-C-D) or GSH-edited (A-B+C-D) signal. CONCLUSION: HERMES simulation and phantom experiments show the separation of Glu from Gln. In vivo HERMES experiments yield Glu (without Gln), GABA, and GSH in a single MRS scan.

Neuronal and Glial Metabolite Abnormalities in Participants With Persistent Neuropsychiatric Symptoms After COVID-19: A Brain Proton Magnetic Resonance Spectroscopy Study.

BACKGROUND: The aim of this study was to determine whether neurometabolite abnormalities indicating neuroinflammation and neuronal injury are detectable in individuals post-coronavirus disease 2019 (COVID-19) with persistent neuropsychiatric symptoms. METHODS: All participants were studied with proton magnetic resonance spectroscopy at 3 T to assess neurometabolite concentrations (point-resolved spectroscopy, relaxation time/echo time = 3000/30 ms) in frontal white matter (FWM) and anterior cingulate cortex-gray matter (ACC-GM). Participants also completed the National Institutes of Health Toolbox cognition and motor batteries and selected modules from the Patient-Reported Outcomes Measurement Information System. RESULTS: Fifty-four participants were evaluated: 29 post-COVID-19 (mean ± SD age, 42.4 ± 12.3 years; approximately 8 months from COVID-19 diagnosis; 19 women) and 25 controls (age, 44.1 ± 12.3 years; 14 women). When compared with controls, the post-COVID-19 group had lower total N-acetyl compounds (tNAA; ACC-GM: -5.0%, P = .015; FWM: -4.4%, P = .13), FWM glutamate + glutamine (-9.5%, P = .001), and ACC-GM myo-inositol (-6.2%, P = .024). Additionally, only hospitalized patients post-COVID-19 showed age-related increases in myo-inositol, choline compounds, and total creatine (interaction P = .029 to <.001). Across all participants, lower FWM tNAA and higher ACC-GM myo-inositol predicted poorer performance on several cognitive measures (P = .001-.009), while lower ACC-GM tNAA predicted lower endurance on the 2-minute walk (P = .005). CONCLUSIONS: In participants post-COVID-19 with persistent neuropsychiatric symptoms, the lower-than-normal tNAA and glutamate + glutamine indicate neuronal injury, while the lower-than-normal myo-inositol reflects glial dysfunction, possibly related to mitochondrial dysfunction and oxidative stress in Post-COVID participants with persistent neuropsychiatric symptoms.

Ongoing oxidative stress in individuals with post-acute sequelae of COVID-19.

Objectives: Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with lower plasma glutathione (GSH) levels due to oxidative stress. However, plasma levels may not reflect brain GSH levels. Individuals with post-acute sequelae of COVID-19 (PASC) have a higher prevalence of cognitive fatigue, which might be related to altered brain γ-aminobutyric-acid (GABA) levels. Hence, our study aims to measure the brain GSH and GABA levels in PASC. Methods: 29 PASC participants and 24 uninfected controls were recruited for this study. Each was evaluated with detailed neuropsychiatric assessments and an edited proton MRS (Hadamard Encoding and Reconstruction of Mega-Edited Spectroscopy, HERMES) method to measure GABA and GSH concentrations in predominantly grey matter (GM) and predominantly white matter (WM) brain frontal voxels. Results: PASC participants were 219 ± 137 days since their COVID-19 diagnosis. Nine individuals with PASC were hospitalized. Compared to controls, individuals with PASC had similar levels of GABA in both brain regions, but lower GSH and greater age-related GSH decline in the frontal GM region. Conclusions: The lower-than-normal frontal GM GSH level in participants with PASC suggest that they have ongoing oxidative stress in the brain, and that older individuals may be even more vulnerable to oxidative stress.

Excitatory/Inhibitory Imbalance Underlies Hippocampal Atrophy in Individuals With 22q11.2 Deletion Syndrome With Psychotic Symptoms.

BACKGROUND: Abnormal neurotransmitter levels have been reported in individuals at high risk for schizophrenia, leading to a shift in the excitatory/inhibitory balance. However, it is unclear whether these alterations predate the onset of clinically relevant symptoms. Our aim was to explore in vivo measures of excitatory/inhibitory balance in 22q11.2 deletion carriers, a population at genetic risk for psychosis. METHODS: Glx (glutamate+glutamine) and GABA+ (gamma-aminobutyric acid with macromolecules and homocarnosine) concentrations were estimated in the anterior cingulate cortex, superior temporal cortex, and hippocampus using the Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence and the Gannet toolbox in 52 deletion carriers and 42 control participants. T1-weighted images were acquired longitudinally and processed with FreeSurfer version 6 to extract hippocampal volume. Subgroup analyses were conducted in deletion carriers with psychotic symptoms. RESULTS: While no differences were found in the anterior cingulate cortex, deletion carriers had higher levels of Glx in the hippocampus and superior temporal cortex and lower levels of GABA+ in the hippocampus than control participants. We additionally found a higher Glx concentration in the hippocampus of deletion carriers with psychotic symptoms. Finally, more pronounced hippocampal atrophy was significantly associated with increased Glx levels in deletion carriers. CONCLUSIONS: We provide evidence for an excitatory/inhibitory imbalance in temporal brain structures of deletion carriers, with a further hippocampal Glx increase in individuals with psychotic symptoms that was associated with hippocampal atrophy. These results are in line with theories proposing abnormally enhanced glutamate levels as a mechanistic explanation for hippocampal atrophy via excitotoxicity. Our results highlight a central role of glutamate in the hippocampus of individuals at genetic risk for schizophrenia.

MRSCloud: A cloud-based MRS tool for basis set simulation.

PURPOSE: The purpose of this study is to present a cloud-based spectral simulation tool "MRSCloud," which allows MRS users to simulate a vendor-specific and sequence-specific basis set online in a convenient and time-efficient manner. This tool can simulate basis sets for GE, Philips, and Siemens MR scanners, including conventional acquisitions and spectral editing schemes with PRESS and semi-LASER localization at 3 T. METHODS: The MRSCloud tool was built on the spectral simulation functionality in the FID-A software package. We added three extensions to accelerate computation (ie, one-dimensional projection method, coherence pathways filters, and precalculation of propagators). The RF waveforms were generated based on vendors' generic pulse shapes and timings. Simulations were compared within MRSCloud using different numbers of spatial resolution (21 × 21, 41 × 41, and 101 × 101). Simulated metabolite basis functions from MRSCloud were compared with those generated by the generic FID-A and MARSS, and a phantom-acquired basis set from LCModel. Intraclass correlation coefficients were calculated to measure the agreement between individual metabolite basis functions. Statistical analysis was performed using R in RStudio. RESULTS: Simulation time for a full PRESS basis set is approximately 11 min on the server. The interclass correlation coefficients ICCs were at least 0.98 between MRSCloud and FID-A and were at least 0.96 between MRSCloud and MARSS. The interclass correlation coefficients between simulated MRSCloud basis spectra and acquired LCModel basis spectra were lowest for glutamine at 0.68 and highest for N-acetylaspartate at 0.96. CONCLUSIONS: Substantial reductions in runtime have been achieved. High ICC values indicated that the accelerating features are running correctly and produce comparable and accurate basis sets.

Influence of editing pulse flip angle on J-difference MR spectroscopy.

PURPOSE: To investigate the editing-pulse flip angle (FA) dependence of editing efficiency and ultimately to maximize the edited signal of commonly edited MR spectroscopy (MRS) signals, such as gamma-aminobutyric acid (GABA) and lactate. METHODS: Density-matrix simulations were performed for a range of spin systems to find the editing-pulse FA for maximal editing efficiency. Simulations were confirmed by phantom experiments and in vivo measurements in 10 healthy participants using a 3T Philips scanner. Four MEGA-PRESS in vivo measurements targeting GABA+ and lactate were performed, comparing the conventional editing-pulse FA (FA = 180°) to the optimal one suggested by simulations (FA = 210°). RESULTS: Simulations and phantom experiments show that edited GABA and lactate signals are maximal at FA = 210°. Compared to conventional editing (FA = 180°), in vivo signals from GABA+ and lactate signals increase on average by 8.5% and 9.3%, respectively. CONCLUSION: Increasing the FA of editing-pulses in the MEGA-PRESS experiment from 180° to 210° increases the edited signals from GABA+ and lactate by about 9% in vivo.

In vivo spectral editing of phosphorylethanolamine.

PURPOSE: To demonstrate J-difference editing of phosphorylethanolamine (PE) with chemical shifts at 3.22 (PE3.22 ) and 3.98 (PE3.98 ) ppm, and compare the merits of two editing strategies. METHODS: Density-matrix simulations of MEGA-PRESS (Mescher-Garwood PRESS) for PE were performed at TEs ranging from 80 to 200 ms in steps of 2 ms, applying 20-ms editing pulses (ON/OFF) at (1) 3.98/7.5 ppm to detect PE3.22 and (2) 3.22/7.5 ppm to detect PE3.98 . Phantom experiments were performed using a PE phantom to validate simulation results. Ten subjects were scanned using a Philips 3T MRI scanner at TEs of 90 ms and 110 ms to edit PE3.22 and PE3.98 . Osprey was used for data processing, modeling, and quantification. RESULTS: Simulations show substantial TE modulation of the intensity and shape of the edited signals due to coupling evolution. Simulated and phantom integrals suggest that TEs of 110 ms and 90 ms were optimal for the edited detection of PE3.22 and PE3.98 , respectively. Phantom results indicated strong agreement with the simulated spectra and integrals. In vivo quantification of the PE3.22 /total creatine and PE3.98 /total creatine concentration ratio yielded values of 0.26 ± 0.04 (between-subject coefficient of variation [CV]: 15.4%) and 0.18 ± 0.04 (CV: 22.8%), respectively, at TE = 90 ms, and 0.24 ± 0.02 (CV: 8.2%) and 0.23 ± 0.04 (CV: 18.0%), respectively, at TE = 110 ms. CONCLUSION: Simulations and in vivo MEGA-PRESS of PE demonstrate that both PE3.22 and PE3.98 are potential candidates for editing, but PE3.22 at TE = 110 ms yields lower variation across TEs.

The macromolecular MR spectrum does not change with healthy aging.

PURPOSE: To acquire the mobile macromolecule (MM) spectrum from healthy participants, and to investigate changes in the signals with age and sex. METHODS: 102 volunteers (49 M/53 F) between 20 and 69 years were recruited for in vivo data acquisition in the centrum semiovale (CSO) and posterior cingulate cortex (PCC). Spectral data were acquired at 3T using PRESS localization with a voxel size of 30 × 26 × 26 mm3 , pre-inversion (TR/TI 2000/600 ms) and CHESS water suppression. Metabolite-nulled spectra were modeled to eliminate residual metabolite signals, which were then subtracted out to yield a "clean" MM spectrum using the Osprey software. Pearson's correlation coefficient was calculated between integrals and age for the 14 MM signals. One-way ANOVA was performed to determine differences between age groups. An independent t-test was carried out to determine differences between sexes. RESULTS: MM spectra were successfully acquired in 99 (CSO) and 96 (PCC) of 102 subjects. No significant correlations were seen between age and MM signals. One-way ANOVA also suggested no age-group differences for any MM peak (all p > .004). No differences were observed between sex groups. WM and GM voxel fractions showed a significant (p < .05) negative linear association with age in the WM-predominant CSO (R = -0.29) and GM-predominant PCC regions (R = -0.57) respectively while CSF increased significantly with age in both regions. CONCLUSION: Our findings suggest that a pre-defined MM basis function can be used for linear combination modeling of metabolite data from different age and sex groups.

Upper brainstem GABA levels in Parkinson's disease.

OBJECTIVE: The dopaminergic pathology of Parkinson's disease (PD) impacts circuits involving GABAergic neurons, especially in the brainstem, where the disease manifests early. The aim of this study is to test the hypothesis that levels of gamma-aminobutyric acid (GABA) in the upper brainstem are reduced in patients with PD compared to healthy controls, using edited magnetic resonance spectroscopy (MRS of GABA +). MATERIALS AND METHODS: GABA + levels were examined in 18 PD patients and 18 age- and sex-matched healthy controls (HCs). GABA + -edited MRS was performed in 7.5-ml voxels in the upper brainstem, and the spectra were processed using the Gannet software. Differences in GABA + levels between the two groups were analyzed using independent t test analysis. RESULTS: GABA + levels were significantly lower (p < 0.05) in the upper brainstem of the patients with PD (4.57 ± 0.94 mM) than the HCs (5.89 ± 1.16 mM). CONCLUSION: The lower GABA + levels in the upper brainstem of the PD patients suggest that a GABAergic deficit in the brainstem may contribute to the pathology in PD.

GSH and GABA decreases in IDH1-mutated low-grade gliomas detected by HERMES spectral editing at 3 T in vivo.

Isocitrate dehydrogenase 1 (IDH1) mutational status is an important prognostic biomarker in gliomas. γ-aminobutyric acid (GABA) and reduced glutathione (GSH) play an important role in energy production, which is related to tumor progression. Hadamard Encoding and Reconstruction of Mega-Edited Spectroscopy (HERMES) is able to detect GABA and GSH in healthy controls. This study aims to examine GABA and GSH alterations in IDH1-mutated low-grade gliomas using HERMES. We prospectively enrolled 14 suspected low-grade gliomas and 6 healthy control patients in this study, all cases underwent a 3 T MRI scan, including T1-weighted imaging and HERMES acquisition with a volume of interest 3 × 3 × 3 cm3. HERMES detects a "GABA+" signal that includes contributions from macromolecules and homocarnosine. GABA+ and GSH in tumor foci (group 1), contralateral cerebral regions (group 2) and healthy controls (group 3) were quantified using Gannet. The fitting errors and SNR of HERMES for GABA+ and GSH were analyzed; FWHM of the unsuppressed water signal was also recorded. The Wilcoxon signed-rank test was performed to test for differences between contralateral GABA+ and GSH levels, and differences in GABA+, GSH and fitting errors/SNR between the three groups were analyzed using analysis of variance (ANOVA). Eleven IDH1-mutant low-grade gliomas (5 Female and 6 Male, age 33-69) and 6 healthy subjects (2 Female and 4 Male, age 35-60) were finally enrolled this study. The mean water linewidth across all subjects was 9.67 ± 2.28 Hz. The Wilcoxon signed-rank test revealed that GABA+ and GSH were decreased significantly in glioma foci compared with contralateral regions, whereas no differences were seen between the left and right regions in healthy controls. ANOVA showed that GABA+ and GSH levels in tumor were lower than contralaterally and in healthy controls, while no differences were observed between the contralateral healthy tissue and healthy controls. No differences of fitting errors or SNR were found between tumors, contralateral regions or healthy controls. Our results suggest that HERMES is a reliable tool to simultaneously measure GABA and GSH alterations in low-grade gliomas with IDH1 mutations.

Osprey: Open-source processing, reconstruction & estimation of magnetic resonance spectroscopy data.

BACKGROUND: Processing and quantitative analysis of magnetic resonance spectroscopy (MRS) data are far from standardized and require interfacing with third-party software. Here, we present Osprey, a fully integrated open-source data analysis pipeline for MRS data, with seamless integration of pre-processing, linear-combination modelling, quantification, and data visualization. NEW METHOD: Osprey loads multiple common MRS data formats, performs phased-array coil combination, frequency-and phase-correction of individual transients, signal averaging and Fourier transformation. Linear combination modelling of the processed spectrum is carried out using simulated basis sets and a spline baseline. The MRS voxel is coregistered to an anatomical image, which is segmented for tissue correction and quantification is performed based upon modelling parameters and tissue segmentation. The results of each analysis step are visualized in the Osprey GUI. The analysis pipeline is demonstrated in 12 PRESS, 11 MEGA-PRESS, and 8 HERMES datasets acquired in healthy subjects. RESULTS: Osprey successfully loads, processes, models, and quantifies MRS data acquired with a variety of conventional and spectral editing techniques. COMPARISON WITH EXISTING METHOD(S): Osprey is the first MRS software to combine uniform pre-processing, linear-combination modelling, tissue correction and quantification into a coherent ecosystem. Compared to existing compiled, often closed-source modelling software, Osprey's open-source code philosophy allows researchers to integrate state-of-the-art data processing and modelling routines, and potentially converge towards standardization of analysis. CONCLUSIONS: Osprey combines robust, peer-reviewed data processing methods into a modular workflow that is easily augmented by community developers, allowing the rapid implementation of new methods.

Diffusion tensor imaging point to ongoing functional impairment in HIV-infected children at age 5, undetectable using standard neurodevelopmental assessments.

BACKGROUND: Perinatal HIV infection negatively impacts cognitive functioning of children, main domains affected are working memory, processing speed and executive function. Early ART, even when interrupted, improves neurodevelopmental outcomes. Diffusion tension imaging (DTI) is a sensitive tool assessing white matter damage. We hypothesised that white matter measures in regions showing HIV-related alterations will be associated with lower neurodevelopmental scores in specific domains related to the functionality of the affected tracts. METHODS: DTI was performed on children in a neurodevelopmental sub study from the Children with HIV Early Antiretroviral (CHER) trial. Voxel-based group comparisons to determine regions where fractional anisotropy and mean diffusion differed between HIV+ and uninfected children were done. Locations of clusters showing group differences were identified using the Harvard-Oxford cortical and subcortical and John Hopkins University WM tractography atlases provided in FSL. This is a second review of DTI data in this cohort, which was reported in a previous study. Neurodevelopmental assessments including GMDS and Beery-Buktenica tests were performed and correlated with DTI parameters in abnormal white matter. RESULTS: 38 HIV+ children (14 male, mean age 64.7 months) and 11 controls (4 male, mean age 67.7 months) were imaged. Two clusters with lower fractional anisotropy and 7 clusters with increased mean diffusion were identified in the HIV+ group. The only neurodevelopmental domain with a trend of difference between the HIV+ children and controls (p = 0.08), was Personal Social Quotient which correlated to improved myelination of the forceps minor in the control group. As a combined group there was a negative correlation between visual perception and radial diffusion in the right superior longitudinal fasciculus and left inferior longitudinal fasciculus, which may be related to the fact that these tracts, forming part of the visual perception pathway, are at a crucial state of development at age 5. CONCLUSION: Even directed neurodevelopmental tests will underestimate the degree of microstructural white matter damage detected by DTI. The visual perception deficit detected in the entire study population should be further examined in a larger study.

Motion correction in magnetic resonance spectroscopy.

In vivo proton magnetic resonance spectroscopy and spectroscopic imaging (MRS/MRSI) are valuable tools to study normal and abnormal human brain physiology. However, they are sensitive to motion, due to strong crusher gradients, long acquisition times, reliance on high magnetic field homogeneity, and particular acquisition methods such as spectral editing. The effects of motion include incorrect spatial localization, phase fluctuations, incoherent averaging, line broadening, and ultimately quantitation errors. Several retrospective methods have been proposed to correct motion-related artifacts. Recent advances in hardware also allow prospective (real-time) correction of the effects of motion, including adjusting voxel location, center frequency, and magnetic field homogeneity. This article reviews prospective and retrospective methods available in the literature and their implications for clinical MRS/MRSI. In combination, these methods can attenuate or eliminate most motion-related artifacts and facilitate the acquisition of high-quality data in the clinical research setting.

Comparison of Multivendor Single-Voxel MR Spectroscopy Data Acquired in Healthy Brain at 26 Sites.

Background The hardware and software differences between MR vendors and individual sites influence the quantification of MR spectroscopy data. An analysis of a large data set may help to better understand sources of the total variance in quantified metabolite levels. Purpose To compare multisite quantitative brain MR spectroscopy data acquired in healthy participants at 26 sites by using the vendor-supplied single-voxel point-resolved spectroscopy (PRESS) sequence. Materials and Methods An MR spectroscopy protocol to acquire short-echo-time PRESS data from the midparietal region of the brain was disseminated to 26 research sites operating 3.0-T MR scanners from three different vendors. In this prospective study, healthy participants were scanned between July 2016 and December 2017. Data were analyzed by using software with simulated basis sets customized for each vendor implementation. The proportion of total variance attributed to vendor-, site-, and participant-related effects was estimated by using a linear mixed-effects model. P values were derived through parametric bootstrapping of the linear mixed-effects models (denoted Pboot). Results In total, 296 participants (mean age, 26 years ± 4.6; 155 women and 141 men) were scanned. Good-quality data were recorded from all sites, as evidenced by a consistent linewidth of N-acetylaspartate (range, 4.4-5.0 Hz), signal-to-noise ratio (range, 174-289), and low Cramér-Rao lower bounds (≤5%) for all of the major metabolites. Among the major metabolites, no vendor effects were found for levels of myo-inositol (Pboot > .90), N-acetylaspartate and N-acetylaspartylglutamate (Pboot = .13), or glutamate and glutamine (Pboot = .11). Among the smaller resonances, no vendor effects were found for ascorbate (Pboot = .08), aspartate (Pboot > .90), glutathione (Pboot > .90), or lactate (Pboot = .28). Conclusion Multisite multivendor single-voxel MR spectroscopy studies performed at 3.0 T can yield results that are coherent across vendors, provided that vendor differences in pulse sequence implementation are accounted for in data analysis. However, the site-related effects on variability were more profound and suggest the need for further standardization of spectroscopic protocols. © RSNA, 2020 Online supplemental material is available for this article.

Simultaneous edited MRS of GABA, glutathione, and ethanol.

The aim of this work was to develop simultaneous edited MRS of γ-aminobutyric acid (GABA), glutathione (GSH), and ethanol (EtOH) using Hadamard encoding and reconstruction of MEGA-edited spectroscopy (HERMES) at 3T. Density-matrix simulations of HERMES were carried out and compared with phantom experiments. In vivo experiments were performed in six healthy volunteers about 30 min after alcohol consumption. Simulations of HERMES showed GABA-, GSH-, and EtOH-edited spectra with low levels of crosstalk and excellent agreement with phantom spectra. In vivo experiments showed well edited GABA signals at 3.0 ppm, GSH at 2.95 ppm, and EtOH at 1.18 ppm in the respective Hadamard combination spectra. Measured integral ratios were 0.082 ± 0.012 for GABA/Cr, 0.037 ± 0.006 for GSH/Cr, and 0.305 ± 0.129 for EtOH/Cr. Simulated, phantom, and in vivo measurements of HERMES show excellent separation of GABA-, GSH-, and EtOH-edited signals with negligible levels of crosstalk. HERMES allows a threefold acceleration of editing while maintaining spectral quality compared with sequentially acquired MEGA-PRESS measurements.

An evaluation of the reproducibility of 1H-MRS GABA and GSH levels acquired in healthy volunteers with J-difference editing sequences at varying echo times.

Recent advances in J-difference-edited proton magnetic resonance spectroscopy (1H MRS) data acquisition and processing have led to the development of Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) techniques, which enable the simultaneous measurement of ɣ-aminobutyric acid (GABA), the primary inhibitory amino acid neurotransmitter in the central nervous system, and of glutathione (GSH), the most abundant antioxidant in living tissue, at the commonly available magnetic field strength of 3 T. However, the reproducibility of brain levels of GABA and GSH measured across multiple scans in human subjects using HERMES remains to be established. In the present study, twelve healthy volunteers completed two consecutive HERMES scans of the dorsal anterior cingulate cortex (dACC) to assess the test-retest reproducibility of the technique for GABA and GSH measurements at TE = 80 ms. Eleven of the twelve participants additionally completed two consecutive MEGA-PRESS scans at TE = 120 ms, with editing pulses configured for GSH acquisition, to compare the reliability of GSH in the same voxel measured using the standard MEGA-PRESS at TE = 120 ms. The primary findings of study were that, 1) the coefficient of variation (CV) of measuring GABA with HERMES was 16.7%, which is in agreement with the reliability we previously reported for measuring GABA using MEGA-PRESS; and 2) the reliability of measuring GSH with MEGA-PRESS at TE = 120 ms was more than twice as high as that for measuring the antioxidant with HERMES at TE = 80 ms (CV = 7.3% vs. 19.0% respectively). These findings suggest that HERMES and MEGA-PRESS offer similar reliabilities for measuring GABA, while MEGA-PRESS at TE = 120 ms is more reliable for measuring GSH relative to HERMES at TE = 80 ms.

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.

Simultaneous editing of GABA and GSH with Hadamard-encoded MR spectroscopic imaging.

PURPOSE: To evaluate the feasibility of simultaneous MR spectroscopic imaging (MRSI) of gamma-aminobutyric acid (GABA) and glutathione (GSH) in the human brain using Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES). METHODS: Point RESolved Spectroscopy (PRESS)-localized MRSI was performed in GABA and GSH phantoms and in the human brain (n = 3) using HERMES editing and compared to conventional MEGA editing of each metabolite. Multiplet patterns, signal intensities, and metabolite crosstalk were compared between methods. GABA+ and GSH levels were compared between methods for bias and variability. Linear regression of HERMES-MRSI GABA+/H2 O and GSH/H2 O versus gray matter (GM) fraction were performed to assess differences between GM and white matter (WM). RESULTS: Phantom HERMES-MRSI scans gave comparable GABA+ and GSH signals to MEGA-MRSI across the PRESS-localized volume. In vivo, HERMES-reconstructed GABA+ and GSH values had minimal measurement bias and variability relative to MEGA-MRSI. Intersubject coefficients of variation (CV) from two regions within the PRESS-localized volume for HERMES and MEGA were 6-12% for GABA+ and 6-19% for GSH. Interregion CVs were 5-15% for GABA+ and 3-17% for GSH. The GABA+/H2 O and GSH/H2 O ratios were ~1.8 times higher and ~1.9 times higher, respectively, in GM than in WM. CONCLUSION: HERMES-MRSI of GABA+ and GSH was found to be practical in the human brain with minimal measurement bias and comparable variability to separate MEGA-edited acquisitions of each metabolite performed in double the scan time. The HERMES-MRSI is a promising method for simultaneously mapping the distribution of multiple low-concentration metabolites.