Quantification of glutathione and its associated spontaneous neuronal activity in major depressive disorder and obsessive-compulsive disorder.

BACKGROUND: Glutathione (GSH) is a crucial antioxidant in the human brain. Although proton magnetic resonance spectroscopy (MRS) using the MEscher-GArwood Point RESolved Spectroscopy (MEGA-PRESS) sequence is highly recommended, limited literature has measured cortical GSH using this method in major psychiatric disorders. METHODS: By combining MRS using the MEGA-PRESS and resting-state functional magnetic resonance imaging, we quantified brain GSH and glutamate in the medial prefrontal cortex (mPFC) and precuneus and explore relationships between the GSH levels and intrinsic neuronal activity as well as clinical symptoms among the three groups of healthy controls (HCs, N=30), major depressive disorder (MDD, N=28), and obsessive-compulsive disorder (OCD, N=28). RESULTS: GSH concentrations were lower in both the mPFC and precuneus in both the MDD and OCD groups compared to HCs. In HCs, positive correlations were noted between the GSH and glutamate levels, and between GSH and fractional amplitude of low-frequency fluctuations (fALFF) in both regions. However, while these correlations were absent in both patient groups, they showed a weak positive correlation between glutamate and fALFF values. Moreover, GSH levels negatively correlated with depressive and compulsive symptoms in MDD and OCD, respectively. CONCLUSIONS: These findings suggest that reduced GSH levels and an imbalance between GSH and glutamate could increase oxidative stress and alter neurotransmitter signaling, leading to disruptions in GSH-related neurochemical-neuronal coupling and psychopathologies across MDD and OCD. Understanding these mechanisms could provide valuable insights into the underlying processes of these disorders, potentially becoming a springboard for future directions and advancing our knowledge of their neurobiological foundations.

Advanced Hyperpolarized 13C Metabolic Imaging Protocol for Patients with Gliomas: A Comprehensive Multimodal MRI Approach.

This study aimed to implement a multimodal 1H/HP-13C imaging protocol to augment the serial monitoring of patients with glioma, while simultaneously pursuing methods for improving the robustness of HP-13C metabolic data. A total of 100 1H/HP [1-13C]-pyruvate MR examinations (104 HP-13C datasets) were acquired from 42 patients according to the comprehensive multimodal glioma imaging protocol. Serial data coverage, accuracy of frequency reference, and acquisition delay were evaluated using a mixed-effects model to account for multiple exams per patient. Serial atlas-based HP-13C MRI demonstrated consistency in volumetric coverage measured by inter-exam dice coefficients (0.977 ± 0.008, mean ± SD; four patients/11 exams). The atlas-derived prescription provided significantly improved data quality compared to manually prescribed acquisitions (n = 26/78; p = 0.04). The water-based method for referencing [1-13C]-pyruvate center frequency significantly reduced off-resonance excitation relative to the coil-embedded [13C]-urea phantom (4.1 ± 3.7 Hz vs. 9.9 ± 10.7 Hz; p = 0.0007). Significantly improved capture of tracer inflow was achieved with the 2-s versus 5-s HP-13C MRI acquisition delay (p = 0.007). This study demonstrated the implementation of a comprehensive multimodal 1H/HP-13C MR protocol emphasizing the monitoring of steady-state/dynamic metabolism in patients with glioma.

GABA, glutamatergic dynamics and BOLD contrast assessed concurrently using functional MRS during a cognitive task.

A recurring issue in functional neuroimaging is how to link task-driven haemodynamic blood oxygen level dependent functional MRI (BOLD-fMRI) responses to underlying neurochemistry at the synaptic level. Glutamate and γ-aminobutyric acid (GABA), the major excitatory and inhibitory neurotransmitters respectively, are typically measured with MRS sequences separately from fMRI, in the absence of a task. The present study aims to resolve this disconnect, developing acquisition and processing techniques to simultaneously assess GABA, glutamate and glutamine (Glx) and BOLD in relation to a cognitive task, at 3 T. Healthy subjects (N = 81) performed a cognitive task (Eriksen flanker), which was presented visually in a task-OFF, task-ON block design, with individual event onset timing jittered with respect to the MRS readout. fMRS data were acquired from the medial anterior cingulate cortex during task performance, using an adapted MEGA-PRESS implementation incorporating unsuppressed water-reference signals at a regular interval. These allowed for continuous assessment of BOLD activation, through T2 *-related changes in water linewidth. BOLD-fMRI data were additionally acquired. A novel linear model was used to extract modelled metabolite spectra associated with discrete functional stimuli, building on well established processing and quantification tools. Behavioural outcomes from the flanker task, and activation patterns from the BOLD-fMRI sequence, were as expected from the literature. BOLD response assessed through fMRS showed a significant correlation with fMRI, specific to the fMRS-targeted region of interest; fMRS-assessed BOLD additionally correlated with lengthening of response time in the incongruent flanker condition. While no significant task-related changes were observed for GABA+, a significant increase in measured Glx levels (~8.8%) was found between task-OFF and task-ON periods. These findings verify the efficacy of our protocol and analysis pipelines for the simultaneous assessment of metabolite dynamics and BOLD. As well as establishing a robust basis for further work using these techniques, we also identify a number of clear directions for further refinement in future studies.

Prefrontal Glutathione Levels in Major Depressive Disorder Are Linked to a Lack of Positive Affect.

Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders, with symptoms including persistent sadness and loss of interest. MDD is associated with neurochemical alterations in GABA, glutamate, and glutamine levels but, to date, few studies have examined changes in glutathione (GSH) in MDD. This study investigated changes in GSH in an unmedicated group of young adults, including 46 participants with current (n = 12) or past MDD (n = 34) and 20 healthy controls. Glutathione levels were assessed from GSH-edited magnetic resonance (MR) spectra, acquired from a voxel in the left prefrontal cortex, and depressive symptoms were evaluated with validated questionnaires and clinical assessments. Cortisol levels were also assessed as a marker for acute stress. Participants with current MDD demonstrated elevated GSH in comparison to participants with past MDD and controls, although the results could be influenced by differences in tissue composition within the MRS voxel. In addition, participants with both current and past MDD showed elevated cortisol levels in comparison to controls. No significant association was observed between GSH and cortisol levels, but elevated GSH levels were associated with a decrease in positive affect. These results demonstrate for the first time that elevated GSH in current but not past depression may reflect a state rather than a trait neurobiological change, related to a loss of positive affect.

Functional Changes in GABA and Glutamate during Motor Learning.

Functional magnetic resonance spectroscopy (fMRS) of GABA at 3 T poses additional challenges compared with fMRS of other metabolites because of the difficulties of measuring GABA levels; GABA is present in the brain at relatively low concentrations, and its signal is overlapped by higher concentration metabolites. Using 7 T fMRS, GABA levels have been shown to decrease specifically during motor learning (and not during a control task). Though the use of 7 T is appealing, access is limited. For GABA fMRS to be widely accessible, it is essential to develop this method at 3 T. Nine healthy right-handed participants completed a motor learning and a control button-pressing task. fMRS data were acquired from the left sensorimotor cortex during the task using a continuous GABA-edited MEGA-PRESS acquisition at 3 T. We found no significant changes in GABA+/tCr, Glx/tCr, or Glu/tCr levels in either task; however, we show a positive relationship between motor learning and glutamate levels both at rest and at the start of the task. Though further refinement and validation of this method is needed, this study represents a further step in using fMRS at 3 T to probe GABA levels in both healthy cognition and clinical disorders.

Evaluation of Prefrontal γ-Aminobutyric Acid and Glutamate Levels in Individuals With Major Depressive Disorder Using Proton Magnetic Resonance Spectroscopy.

Importance: Major depressive disorder (MDD) is one of the most prevalent illnesses worldwide. Perturbations of the major inhibitory and excitatory neurotransmitters, γ-aminobutyric acid (GABA) and glutamate (Glu), respectively, as well as Glx (Glu or glutamine [Gln]) have been extensively reported in a multitude of brain areas of individuals with depression, but few studies have examined changes in Gln, the metabolic counterpart of synaptic Glu. Objective: To investigate changes in GABA, Glx, Glu, and Gln levels in a voxel in the left dorsolateral prefrontal cortex of participants with no, past, and current MDD using proton magnetic resonance spectroscopy (1H-MRS). Design, Setting, and Participants: This community-based study used a cross-sectional design using 3-T 1H-MRS in participants not taking MDD medication recruited from the community. The sample consisted of 251 healthy controls, 98 participants with a history of past MDD, and 47 participants who met the diagnostic criteria for current MDD. Diagnostic groups were comparable regarding age, education, income, and diet. Data were collected from March 2014 to October 2021, and data were analyzed from October 2021 to June 2022. Main Outcomes and Measures: GABA, Glx, Glu, and Gln concentrations in the left dorsolateral prefrontal cortex. Results: Of 396 included participants, 258 (65.2%) were female, and the mean (SD) age was 25.0 (4.7) years. Compared with healthy controls, those with past MDD and current MDD had lower GABA concentrations (mean [SEM] concentration: healthy controls, 2.70 [0.03] mmol/L; past MDD, 2.49 [0.05] mmol/L; current MDD, 2.54 [0.07] mmol/L; 92 with past MDD vs 236 healthy controls: r = 0.18; P = .002; 44 with current MDD vs 236 healthy controls: r = 0.13; P = .04). Compared with healthy controls, those with past MDD also had lower Glu concentrations (mean [SEM] concentration: healthy controls, 7.52 [0.06] mmol/L; past MDD, 7.23 [0.11] mmol/L; 93 with past MDD vs 234 healthy controls: r = 0.16; P = .01) and higher Gln concentrations (mean [SEM] concentration: healthy controls, 1.63 [0.04] mmol/L; past MDD, 1.84 [0.07] mmol/L; 66 with past MDD 153 healthy controls: r = 0.17; P = .04). Conclusions and Relevance: In a large, mostly medication-free community sample, reduced prefrontal GABA concentrations were associated with past MDD, consistent with histopathologic studies reporting reduced glial cell and GABA cell density in the prefrontal cortex in individuals with depression. Patients with MDD also demonstrated increased Gln levels, indicative of increased synaptic Glu release, adding to previous evidence for the Glu hypothesis of MDD.

Across-vendor standardization of semi-LASER for single-voxel MRS at 3T.

The semi-adiabatic localization by adiabatic selective refocusing (sLASER) sequence provides single-shot full intensity signal with clean localization and minimal chemical shift displacement error and was recommended by the international MRS Consensus Group as the preferred localization sequence at high- and ultra-high fields. Across-vendor standardization of the sLASER sequence at 3 tesla has been challenging due to the B1 requirements of the adiabatic inversion pulses and maximum B1 limitations on some platforms. The aims of this study were to design a short-echo sLASER sequence that can be executed within a B1 limit of 15 µT by taking advantage of gradient-modulated RF pulses, to implement it on three major platforms and to evaluate the between-vendor reproducibility of its perfomance with phantoms and in vivo. In addition, voxel-based first and second order B0 shimming and voxel-based B1 adjustments of RF pulses were implemented on all platforms. Amongst the gradient-modulated pulses considered (GOIA, FOCI and BASSI), GOIA-WURST was identified as the optimal refocusing pulse that provides good voxel selection within a maximum B1 of 15 µT based on localization efficiency, contamination error and ripple artifacts of the inversion profile. An sLASER sequence (30 ms echo time) that incorporates VAPOR water suppression and 3D outer volume suppression was implemented with identical parameters (RF pulse type and duration, spoiler gradients and inter-pulse delays) on GE, Philips and Siemens and generated identical spectra on the GE 'Braino' phantom between vendors. High-quality spectra were consistently obtained in multiple regions (cerebellar white matter, hippocampus, pons, posterior cingulate cortex and putamen) in the human brain across vendors (5 subjects scanned per vendor per region; mean signal-to-noise ratio > 33; mean water linewidth between 6.5 Hz to 11.4 Hz). The harmonized sLASER protocol is expected to produce high reproducibility of MRS across sites thereby allowing large multi-site studies with clinical cohorts.

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.

Advanced single voxel 1 H magnetic resonance spectroscopy techniques in humans: Experts' consensus recommendations.

Conventional proton MRS has been successfully utilized to noninvasively assess tissue biochemistry in conditions that result in large changes in metabolite levels. For more challenging applications, namely, in conditions which result in subtle metabolite changes, the limitations of vendor-provided MRS protocols are increasingly recognized, especially when used at high fields (≥3 T) where chemical shift displacement errors, B0 and B1 inhomogeneities and limitations in the transmit B1 field become prominent. To overcome the limitations of conventional MRS protocols at 3 and 7 T, the use of advanced MRS methodology, including pulse sequences and adjustment procedures, is recommended. Specifically, the semiadiabatic LASER sequence is recommended when TE values of 25-30 ms are acceptable, and the semiadiabatic SPECIAL sequence is suggested as an alternative when shorter TE values are critical. The magnetic field B0 homogeneity should be optimized and RF pulses should be calibrated for each voxel. Unsuppressed water signal should be acquired for eddy current correction and preferably also for metabolite quantification. Metabolite and water data should be saved in single shots to facilitate phase and frequency alignment and to exclude motion-corrupted shots. Final averaged spectra should be evaluated for SNR, linewidth, water suppression efficiency and the presence of unwanted coherences. Spectra that do not fit predefined quality criteria should be excluded from further analysis. Commercially available tools to acquire all data in consistent anatomical locations are recommended for voxel prescriptions, in particular in longitudinal studies. To enable the larger MRS community to take advantage of these advanced methods, a list of resources for these advanced protocols on the major clinical platforms is provided. Finally, a set of recommendations are provided for vendors to enable development of advanced MRS on standard platforms, including implementation of advanced localization sequences, tools for quality assurance on the scanner, and tools for prospective volume tracking and dynamic linear shim corrections.

UTE-SPECIAL for3D localization at an echo time of 4 ms on a clinical 3 T scanner.

Reducing the echo time of magnetic resonance spectroscopy experiments is appealing because it increases the available signal and reduces J-evolution of coupled metabolites. In this manuscript a novel sequence, referred to as Ultrashort echo TimE, SPin ECho, full Intensity Acquired Localized (UTE-SPECIAL), is described which is able to achieve ultrashort echo times (4 ms) on a standard clinical 3 T MR system while recovering the entirety of the available magnetization. UTE-SPECIAL obtains full 3D spatial localization through a 2D adiabatic inversion pulse which is cycled "on" and "off" every other repetition, in combination with a slice-selective excitation pulse. In addition to an ultrashort echo time, UTE-SPECIAL has negligible chemical shift displacement artefact and, because it uses no slice-selective refocusing pulse, has no signal cancellation at the borders for J-coupled metabolites. Spectra with an ultrashort echo time of 4 ms are demonstrated in vivo at 3 T, as well as J-resolved spectra obtained in a phantom and a healthy volunteer.

Overdiscrete echo-planar spectroscopic imaging with correlated higher-order phase correction.

PURPOSE: To introduce a robust methodology for fast 1 H MRSI of the brain at 3T with improved SNR and reduced phase-related artifacts. METHOD: An accelerated acquisition scheme using echo-planar spectroscopic imaging (EPSI) was combined with the overdiscrete reconstruction framework. This approach enables the interleaved acquisition of a water reference scan at each phase encoding step, maximizing its correlation with the water-suppressed measurement. Moreover, a generalized high-order phase correction was incorporated into the reconstruction pipeline. The spatial-temporal phase correction term was estimated from the reference scan and interpolated to high resolution using a polynomial basis. The method was implemented at 3T and validated with phantom and in vivo experiments. RESULTS: The methodology showed the elimination of spectral artifacts generated by phase disturbances and achieved mean SNR gains in vivo of 3.18 and 1.19 compared to standard reconstructions with corrections performed at nominal and high resolution, respectively. EPSI scans with interleaved water acquisition showed to be robust to system instabilities and potentially to patient motion. Moreover, phase distortions were effectively corrected in a single step, avoiding additional reference measurements and post-processing steps. CONCLUSION: The overdiscrete reconstruction framework with high-order phase correction allowed to effectively correct for distortions, related to B0 inhomogeneities, B0 drift, eddy currents, and system vibrations. Furthermore, the presented reconstruction method, combined with EPSI acquisitions, demonstrated improved measurement stability, substantial SNR enhancement, better spectral linewidth, and effective artifact removal.

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.

Methodological consensus on clinical proton MRS of the brain: Review and recommendations.

Proton MRS (1 H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good-quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi-adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B0 ) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use.

MEGA-PRESS and PRESS measure oxidation of glutathione in a phantom.

PURPOSE: Investigate the possibility of measuring changes in glutathione (GSH) concentration using the MRS PRESS and MEGA-PRESS sequences by tracking the natural oxidation of GSH, and to examine the accuracy of the two methods. METHODS: 122 GSH edited MEGA-PRESS and PRESS acquisitions were acquired on a "braino" based phantom +3.0 mM GSH during a period of 11 days. All spectra were analyzed in LCModel. (The MEGA-PRESS data were first preprocessed in Matlab). Degradation curves were modeled. A one year follow-up on the same phantom and measurements from a similar phantom without GSH and one pure GSH phantom were also included. RESULTS: Both MEGA-PRESS and PRESS showed degradation of the measured GSH signal. Modeling the exponential decay of the GSH signal in MEGA-PRESS and PRESS gave for t = 0; 2.9 i.u. for MEGA-PRESS and 2.3 i.u. for PRESS. As t increased, the GSH concentration converged to zero for MEGA-PRESS but not for PRESS (0.7 i.u.). GSH for the one year follow up were 0.0 i.u. for MEGA-PRESS and 0.6 i.u. for PRESS. Similar phantom without GSH yielded 0.0 i.u. for both MEGA-PRESS and PRESS. CONCLUSION: It is possible to measure changes in GSH concentration in a phantom using both PRESS and MEGA-PRESS techniques, however the PRESS spectrum appears to include oxidized GSH (GSSG). In addition, GSH edited MEGA-PRESS measurement gives more precise values at lower GSH concentrations.

Multi-vendor standardized sequence for edited magnetic resonance spectroscopy.

Spectral editing allows direct measurement of low-concentration metabolites, such as GABA, glutathione (GSH) and lactate (Lac), relevant for understanding brain (patho)physiology. The most widely used spectral editing technique is MEGA-PRESS, which has been diversely implemented across research sites and vendors, resulting in variations in the final resolved edited signal. In this paper, we describe an effort to develop a new universal MEGA-PRESS sequence with HERMES functionality for the major MR vendor platforms with standardized RF pulse shapes, durations, amplitudes and timings. New RF pulses were generated for the universal sequence. Phantom experiments were conducted on Philips, Siemens, GE and Canon 3 T MRI scanners using 32-channel head coils. In vivo experiments were performed on the same six subjects on Philips and Siemens scanners, and on two additional subjects, one on GE and one on Canon scanners. On each platform, edited MRS experiments were conducted with the vendor-native and universal MEGA-PRESS sequences for GABA (TE = 68 ms) and Lac editing (TE = 140 ms). Additionally, HERMES for GABA and GSH was performed using the universal sequence at TE = 80 ms. The universal sequence improves inter-vendor similarity of GABA-edited and Lac-edited MEGA-PRESS spectra. The universal HERMES sequence yields both GABA- and GSH-edited spectra with negligible levels of crosstalk on all four platforms, and with strong agreement among vendors for both edited spectra. In vivo GABA+/Cr, Lac/Cr and GSH/Cr ratios showed relatively low variation between scanners using the universal sequence. In conclusion, phantom and in vivo experiments demonstrate successful implementation of the universal sequence across all four major vendors, allowing editing of several metabolites across a range of TEs.

Imaging glutamate redistribution after acute N-acetylcysteine administration: A simultaneous PET/MR study.

Glutamate is the most abundant excitatory neurotransmitter in the human brain, but in vivo imaging of acute fluctuations in glutamatergic levels has not been well established. The purpose of this study was to examine acute changes in glutamate after stimulation with N-acetylcysteine (NAC) using a simultaneous positron emission tomography/magnetic resonance spectroscopy (PET/MRS) approach. Ten healthy adult males were examined in two scanning sessions, and 5g NAC was administered 1 h prior to one of the scan sessions. Simultaneous PET/MR data were acquired using an integrated 3T PET/MR scanner. Glutamate (Glu), glutamine (Gln), and glutamate + glutamine (Glx) levels were assessed from MRS data collected from the basal ganglia with PRESS and from the left prefrontal cortex with PRESS and MEGAPRESS, and mGluR5 binding (BPND) was assessed from PET data collected with [18F]PSS232. NAC administration was associated with a significant reduction in Glx and Gln in the basal ganglia spectra, and in Glx in the frontal MEGAPRESS spectra (p < 0.05); no differences in [18F]PSS232 BPND were observed with NAC, although a correlation between pre-/post-treatment Glx and baseline BPnd was found. The MRS-visible Glx signal is sensitive to acute fluctuations in glutamate. The change in Glx was mostly driven by a change in Gln, lending weight to the notion that Gln can provide a proxy marker for neurotransmitter/synaptic glutamate. [18F]PSS232 binding is not sensitive to acute glutamate shifts independently, but was associated with the extent of glutamate liberation upon NAC stimulation.

High-resolution echo-planar spectroscopic imaging at ultra-high field.

MR spectroscopic imaging (MRSI) at ultra-high field (≥7 T) benefits from improved sensitivity that allows the detection of low-concentration metabolites in the brain. However, optimized acquisition techniques are required to overcome inherent limitations of MRSI at ultra-high field. This work describes an optimized method for fast high-resolution 1 H-MRSI of the brain at 7 T. The proposed acquisition sequence combines precise volume localization using semi-localization by adiabatic selective refocusing, fast spatial encoding using high-bandwidth symmetric echo-planar spectroscopic imaging (EPSI), and robust water suppression with variable power and optimized relaxation delays. This showed improved robustness to B0 and B1+ inhomogeneities, eddy currents, nuisance signal contamination and system instabilities. Furthermore, a method for correction of phase inconsistencies in symmetric EPSI enabled high-bandwidth measurements at 7 T. The proposed correction effectively removed spectral ghosting using a single-shot water reference scan. This framework was tested in healthy volunteers at 7 T and spectral quality was compared with lower-spatial-resolution scans, measured at 3 T using the same methodology. A gain in the signal-to-noise ratio (SNR) per unit volume and unit time of 1.57 was achieved, keeping acquisition time short (5 min) and the specific absorption rate within the permitted limits. This SNR enhancement obtained at ultra-high field enabled high-resolution (0.25-0.375 mL) metabolite mapping of the brain within a clinically feasible scan time. The correlation of the reconstructed maps with anatomical structures was observed, showing the diagnostic potential of the technique.

GABA editing with macromolecule suppression using an improved MEGA-SPECIAL sequence.

PURPOSE: The most common γ-aminobutyric-acid (GABA) editing approach, MEGA-PRESS, uses J-editing to measure GABA distinct from larger overlapping metabolites, but suffers contamination from coedited macromolecules (MMs) comprising 40 to 60% of the observed signal. MEGA-SPECIAL is an alternative method with better MM suppression, but is not widely used primarily because of its relatively poor spatial localization. Our goal was to develop an improved MM-suppressed GABA editing sequence at 3 Tesla. METHODS: We modified a single-voxel MEGA-SPECIAL sequence with an oscillating readout gradient for improved spatial localization, and used very selective 30-ms editing pulses for improved suppression of coedited MMs. RESULTS: Simulation and in vivo experiments confirmed excellent MM suppression, insensitive to the range of B0 frequency drifts typically encountered in vivo. Both intersubject and intrasubject studies showed that MMs, when suppressed by the improved MEGA-SPECIAL method, contributed approximately 40% to the corresponding MEGA-PRESS measurements. From the intersubject study, the coefficient of variation for GABA+/Cre (MEGA-PRESS) was 11.2% versus 7% for GABA/Cre (improved MEGA-SPECIAL), demonstrating significantly reduced variance (P = 0.005), likely coming from coedited MMs. CONCLUSIONS: This improved MEGA-SPECIAL sequence provides unbiased GABA measurements with reduced variance as compared with conventional MEGA-PRESS. This approach is also relatively insensitive to the range of B0 drifts typically observed in in vivo human studies. Magn Reson Med 79:41-47, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Big GABA: Edited MR spectroscopy at 24 research sites.

Magnetic resonance spectroscopy (MRS) is the only biomedical imaging method that can noninvasively detect endogenous signals from the neurotransmitter γ-aminobutyric acid (GABA) in the human brain. Its increasing popularity has been aided by improvements in scanner hardware and acquisition methodology, as well as by broader access to pulse sequences that can selectively detect GABA, in particular J-difference spectral editing sequences. Nevertheless, implementations of GABA-edited MRS remain diverse across research sites, making comparisons between studies challenging. This large-scale multi-vendor, multi-site study seeks to better understand the factors that impact measurement outcomes of GABA-edited MRS. An international consortium of 24 research sites was formed. Data from 272 healthy adults were acquired on scanners from the three major MRI vendors and analyzed using the Gannet processing pipeline. MRS data were acquired in the medial parietal lobe with standard GABA+ and macromolecule- (MM-) suppressed GABA editing. The coefficient of variation across the entire cohort was 12% for GABA+ measurements and 28% for MM-suppressed GABA measurements. A multilevel analysis revealed that most of the variance (72%) in the GABA+ data was accounted for by differences between participants within-site, while site-level differences accounted for comparatively more variance (20%) than vendor-level differences (8%). For MM-suppressed GABA data, the variance was distributed equally between site- (50%) and participant-level (50%) differences. The findings show that GABA+ measurements exhibit strong agreement when implemented with a standard protocol. There is, however, increased variability for MM-suppressed GABA measurements that is attributed in part to differences in site-to-site data acquisition. This study's protocol establishes a framework for future methodological standardization of GABA-edited MRS, while the results provide valuable benchmarks for the MRS community.

Within- and between-session reproducibility of GABA measurements with MR spectroscopy.

PURPOSE: The reproducibility of the MEGA-PRESS (MEshcher-GArwood Point RESolved Spectroscopy) MR spectroscopy sequence for the measurement of gamma- aminobutyric acid (GABA) is addressed, focusing on optimizing the number of repetitions at two voxel locations in the human brain and associated possibilities in analysis tools. MATERIALS AND METHODS: Two 20-min MEGA-PRESS acquisitions were run (echo time = 68 ms, repetition time = 1800 ms, repetitions = 328): one from a 21 mL volume in the anterior cingulate cortex (ACC) and one from a 22 mL volume in the left Broca's area in 21 healthy male volunteers (age 32 years ± 6[SD]). Subjects were scanned twice with identical protocols, 1 week apart. Data were acquired on a 3 Tesla GE Discovery 750 scanner using a 32-channel head coil. Spectroscopy data were partitioned into shorter epochs, numerically equivalent to scans of progressively increasing duration, and compared both within and between sessions. Three different analysis schemes were applied: (1) Vendor prototype preprocessor, with quantification by LCModel. (2) Pure Gannet pipeline. (3) Preprocessing with Gannet, and quantification with LCModel. The coefficient of variation (CV) were calculated as a measure of reproducibility. RESULTS: Increasing the number of repetitions showed improvements for within- and between-session reproducibility up to around 218 repetitions. (CV ranging from 4 to 14%). Gannet combined with LCModel approach proved the best method. (CV = 4-5%). Measurements from the ACC area had higher CVs than the Broca area. (CV = 6-14% versus 4-7%). CONCLUSION: Measurement in the Broca area yields better reproducibility than the ACC. With appropriate acquisition times and preprocessing tools, measurements from the ACC area are also reliable. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:421-430.