GABA-edited MEGA-PRESS at 3 T: Does a measured macromolecule background improve linear combination modeling?

PURPOSE: The J-difference edited γ-aminobutyric acid (GABA) signal is contaminated by other co-edited signals-the largest of which originates from co-edited macromolecules (MMs)-and is consequently often reported as "GABA+." MM signals are broader and less well-characterized than the metabolites, and are commonly approximated using a Gaussian model parameterization. Experimentally measured MM signals are a consensus-recommended alternative to parameterized modeling; however, they are relatively under-studied in the context of edited MRS. METHODS: To address this limitation in the literature, we have acquired GABA-edited MEGA-PRESS data with pre-inversion to null metabolite signals in 13 healthy controls. An experimental MM basis function was derived from the mean across subjects. We further derived a new parameterization of the MM signals from the experimental data, using multiple Gaussians to accurately represent their observed asymmetry. The previous single-Gaussian parameterization, mean experimental MM spectrum and new multi-Gaussian parameterization were compared in a three-way analysis of a public MEGA-PRESS dataset of 61 healthy participants. RESULTS: Both the experimental MMs and the multi-Gaussian parameterization exhibited reduced fit residuals compared to the single-Gaussian approach (p = 0.034 and p = 0.031, respectively), suggesting they better represent the underlying data than the single-Gaussian parameterization. Furthermore, both experimentally derived models estimated larger MM fractional contribution to the GABA+ signal for the experimental MMs (58%) and multi-Gaussian parameterization (58%), compared to the single-Gaussian approach (50%). CONCLUSIONS: Our results indicate that single-Gaussian parameterization of edited MM signals is insufficient and that both experimentally derived GABA+ spectra and their parameterized replicas improve the modeling of GABA+ spectra.

Impact of acquisition and modeling parameters on the test-retest reproducibility of edited GABA.

Literature values vary widely for within-subject test-retest reproducibility of gamma-aminobutyric acid (GABA) measured with edited magnetic resonance spectroscopy (MRS). Reasons for this variation remain unclear. Here, we tested whether three acquisition parameters-(1) sequence complexity (two-experiment MEscher-GArwood Point RESolved Spectroscopy [MEGA-PRESS] vs. four-experiment Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy [HERMES]); (2) editing pulse duration (14 vs. 20 ms); and (3) scanner frequency drift (interleaved water referencing [IWR] turned ON vs. OFF)-and two linear combination modeling variations-(1) three different coedited macromolecule models (called "1to1GABA", "1to1GABAsoft", and "3to2MM" in the Osprey software package); and (2) 0.55- versus 0.4-ppm spline baseline knot spacing-affected the within-subject coefficient of variation of GABA + macromolecules (GABA+). We collected edited MRS data from the dorsal anterior cingulate cortex from 20 participants (mean age: 30.8 ± 9.5 years; 10 males). Test and retest scans were separated by removing the participant from the scanner for 5-10 min. Each acquisition consisted of two MEGA-PRESS and two HERMES sequences with editing pulse durations of 14 and 20 ms (referred to here as MEGA-14, MEGA-20, HERMES-14, and HERMES-20; all TE = 80 ms, 224 averages). We identified the best test-retest reproducibility following postprocessing with a composite model of the 0.9- and 3-ppm macromolecules ("3to2MM"); this model performed particularly well for the HERMES data. Furthermore, sparser (0.55- compared with 0.4-ppm) spline baseline knot spacing yielded generally better test-retest reproducibility for GABA+. Replicating our prior results, linear combination modeling in Osprey compared with simple peak fitting in Gannet resulted in substantially better test-retest reproducibility. However, reproducibility did not consistently differ for MEGA-PRESS compared with HERMES, for 14- compared with 20-ms editing pulses, or for IWR-ON versus IWR-OFF. These results highlight the importance of model selection for edited MRS studies of GABA+, particularly for clinical studies that focus on individual patient differences in GABA+ or changes following an intervention.

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.

Considerations for event-related gamma-aminobutyric acid functional magnetic resonance spectroscopy.

The use of sequential proton magnetic resonance spectroscopy (MRS) to follow glutamate and gamma-aminobutyric acid (GABA) changes during functional task-based paradigms, functional MRS (fMRS), has increased. This technique has been used to investigate GABA dynamics during both sensory and behavioural tasks, usually with long 'block design' paradigms. Recently, there has been an increase in interest in the use of short stimuli and 'event-related' tasks. While changes in glutamate can be readily followed by collecting multiple individual transients (or shots), measurement of GABA, especially at 3 T, is usually performed using editing techniques like Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS), which by its nature is a dual shot approach. This poses problems when considering an event-related experiment, where it is unclear when GABA may change, or how this may affect the individual subspectra of the MEGA-PRESS acquisition. To address this issue, MEGA-PRESS data were simulated to reflect the effect of a transient change in GABA concentration due to a short event-related stimulus. The change in GABA was simulated for both the ON and OFF subspectra, and the effect of three different conditions (increase only during ON acquisition, increase during OFF acquisition and increase across both) on the corresponding edited GABA spectrum was modelled. Results show that a transient increase in GABA that only occurs during the ON subspectral acquisition, while not changing the results much from when GABA is changed across both conditions, will give a much larger change in the edited GABA spectrum than a transient increase that occurs only during the OFF subspectral acquisition. These results suggest that researchers should think carefully about the design of any event-related fMRS studies using MEGA-PRESS, as well as the analysis of other functional paradigms where transient changes in GABA may be expected. Experimental design considerations are therefore discussed, and suggestions are made.

Magnetic Resonance Spectroscopy Spectral Registration Using Deep Learning.

BACKGROUND: Deep learning-based methods have been successfully applied to MRI image registration. However, there is a lack of deep learning-based registration methods for magnetic resonance spectroscopy (MRS) spectral registration (SR). PURPOSE: To investigate a convolutional neural network-based SR (CNN-SR) approach for simultaneous frequency-and-phase correction (FPC) of single-voxel Meshcher-Garwood point-resolved spectroscopy (MEGA-PRESS) MRS data. STUDY TYPE: Retrospective. SUBJECTS: Forty thousand simulated MEGA-PRESS datasets generated from FID Appliance (FID-A) were used and split into the following: 32,000/4000/4000 for training/validation/testing. A 101 MEGA-PRESS medial parietal lobe data retrieved from the Big GABA were used as the in vivo datasets. FIELD STRENGTH/SEQUENCE: 3T, MEGA-PRESS. ASSESSMENT: Evaluation of frequency and phase offsets mean absolute errors were performed for the simulation dataset. Evaluation of the choline interval variance was performed for the in vivo dataset. The magnitudes of the offsets introduced were -20 to 20 Hz and -90° to 90° and were uniformly distributed for the simulation dataset at different signal-to-noise ratio (SNR) levels. For the in vivo dataset, different additional magnitudes of offsets were introduced: small offsets (0-5 Hz; 0-20°), medium offsets (5-10 Hz; 20-45°), and large offsets (10-20 Hz; 45-90°). STATISTICAL TESTS: Two-tailed paired t-tests for model performances in the simulation and in vivo datasets were used and a P-value <0.05 was considered statistically significant. RESULTS: CNN-SR model was capable of correcting frequency offsets (0.014 ± 0.010 Hz at SNR 20 and 0.058 ± 0.050 Hz at SNR 2.5 with line broadening) and phase offsets (0.104 ± 0.076° at SNR 20 and 0.416 ± 0.317° at SNR 2.5 with line broadening). Using in vivo datasets, CNN-SR achieved the best performance without (0.000055 ± 0.000054) and with different magnitudes of additional frequency and phase offsets (i.e., 0.000062 ± 0.000068 at small, -0.000033 ± 0.000023 at medium, 0.000067 ± 0.000102 at large) applied. DATA CONCLUSION: The proposed CNN-SR method is an efficient and accurate approach for simultaneous FPC of single-voxel MEGA-PRESS MRS data. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Severity of prematurity and age impact early postnatal development of GABA and glutamate systems.

Gamma-aminobutyric acid (GABA) and glutamatergic system perturbations following premature birth may explain neurodevelopmental deficits in the absence of structural brain injury. Using GABA-edited spectroscopy (MEscher-GArwood Point Resolved Spectroscopy [MEGA-PRESS] on 3 T MRI), we have described in-vivo brain GABA+ (+macromolecules) and Glx (glutamate + glutamine) concentrations in term-born infants. We report previously unavailable comparative data on in-vivo GABA+ and Glx concentrations in the cerebellum, the right basal ganglia, and the right frontal lobe of preterm-born infants without structural brain injury. Seventy-five preterm-born (gestational age 27.8 ± 2.9 weeks) and 48 term-born (39.6 ± 0.9 weeks) infants yielded reliable MEGA-PRESS spectra acquired at post-menstrual age (PMA) of 40.2 ± 2.3 and 43.0 ± 2 weeks, respectively. GABA+ (median 2.44 institutional units [i.u.]) concentrations were highest in the cerebellum and Glx higher in the cerebellum (5.73 i.u.) and basal ganglia (5.16 i.u.), with lowest concentrations in the frontal lobe. Metabolite concentrations correlated positively with advancing PMA and postnatal age at MRI (Spearman's rho 0.2-0.6). Basal ganglia Glx and NAA, and frontal GABA+ and NAA concentrations were lower in preterm compared with term infants. Moderate preterm infants had lower metabolite concentrations than term and extreme preterm infants. Our findings emphasize the impact of premature extra-uterine stimuli on GABA-glutamate system development and may serve as early biomarkers of neurodevelopmental deficits.

Chronic 3,4-Methylenedioxymethamphetamine (MDMA) Use Is Related to Glutamate and GABA Concentrations in the Striatum But Not the Anterior Cingulate Cortex.

BACKGROUND: 3,4-Methylenedioxymethamphetamine (MDMA) is a widely used recreational substance inducing acute release of serotonin. Previous studies in chronic MDMA users demonstrated selective adaptations in the serotonin system, which were assumed to be associated with cognitive deficits. However, serotonin functions are strongly entangled with glutamate as well as γ-aminobutyric acid (GABA) neurotransmission, and studies in MDMA-exposed rats show long-term adaptations in glutamatergic and GABAergic signaling. METHODS: We used proton magnetic resonance spectroscopy (MRS) to measure the glutamate-glutamine complex (GLX) and GABA concentrations in the left striatum and medial anterior cingulate cortex (ACC) of 44 chronic but recently abstinent MDMA users and 42 MDMA-naïve healthy controls. While the Mescher-Garwood point-resolved-spectroscopy sequence (MEGA-PRESS) is best suited to quantify GABA, recent studies reported poor agreement between conventional short-echo-time PRESS and MEGA-PRESS for GLX measures. Here, we applied both sequences to assess their agreement and potential confounders underlying the diverging results. RESULTS: Chronic MDMA users showed elevated GLX levels in the striatum but not the ACC. Regarding GABA, we found no group difference in either region, although a negative association with MDMA use frequency was observed in the striatum. Overall, GLX measures from MEGA-PRESS, with its longer echo time, appeared to be less confounded by macromolecule signal than the short-echo-time PRESS and thus provided more robust results. CONCLUSION: Our findings suggest that MDMA use affects not only serotonin but also striatal GLX and GABA concentrations. These insights may offer new mechanistic explanations for cognitive deficits (e.g., impaired impulse control) observed in MDMA users.

A comprehensive guide to MEGA-PRESS for GABA measurement.

The aim of this guideline is to provide a series of evidence-based recommendations that allow those new to using MEGA-PRESS to produce high-quality data for the measurement of GABA levels using edited magnetic resonance spectroscopy with the MEGA-PRESS sequence at 3T. GABA is the main inhibitory neurotransmitter of the central nervous system and has been increasingly studied due to its relevance in many clinical disorders of the central nervous system. MEGA-PRESS is the most widely used method for quantification of GABA at 3T, but is technically challenging and operates at a low signal-to-noise ratio. Therefore, the acquisition of high-quality MRS data relies on avoiding numerous pitfalls and observing important caveats. The guideline was developed by a working party that consisted of experts in MRS and experts in guideline development and implementation, together with key stakeholders. Strictly following a translational framework, we first identified evidence using a systematically conducted scoping literature review, then synthesized and graded the quality of evidence that formed recommendations. These recommendations were then sent to a panel of 21 world leaders in MRS for feedback and approval using a modified-Delphi process across two rounds. The final guideline consists of 23 recommendations across six domains essential for GABA MRS acquisition (Parameters, Practicalities, Data acquisition, Confounders, Quality/reporting, Post-processing). Overall, 78% of recommendations were formed from high-quality evidence, and 91% received agreement from over 80% of the expert panel. These 23 expert-reviewed recommendations and accompanying extended documentation form a readily useable guideline to allow those new to using MEGA-PRESS to design appropriate MEGA-PRESS study protocols and generate high-quality data.

Macromolecular-Suppressed GABA-Edited MR Spectroscopy in the Posterior Cingulate Cortex of Patients With Acute Mild Traumatic Brain Injury.

BACKGROUND: Mild traumatic brain injury (mTBI) causes a number of molecular and cellular alterations. There is evidence of an imbalance between the main excitatory (glutamate, Glu) and the main inhibitory (gamma-aminobutyric acid [GABA]) neurotransmitters following mTBI. In vivo human GABA-Glu balance studies following mTBI are sparse. PURPOSE: To investigate the effect of acute mTBI on the GABA concentration measured in the posterior cingulate cortex (PCC) of pediatric patients by using the macromolecular (MM)-suppressed GABA J-editing technique. STUDY TYPE: Prospective patient and phantom. PARTICIPANTS: A total of 14 pediatric patients (mean age 16.0 ± 1.7) with acute mTBI (<3 days after trauma; Glasgow Coma Scale 15) and 16 healthy volunteers (mean age 16.9 ± 2.8). Phantom: 524 cm3 sphere containing 10 mM glycine, 10 mM GABA. FIELD STRENGTH/SEQUENCE: A 3 T, MEGA-PRESS pulse sequence. ASSESSMENT: GABA spectra were processed in Gannet software. MM-suppressed GABA editing efficiency was derived from the phantom study. Absolute GABA and glutamate + glutamine (Glx) concentrations were quantified using different types of correction and compared between groups. N-acetyl aspartate (NAA) and choline (Cho) levels relative to tCr were also compared. STATISTICAL TESTS: Shapiro-Wilk test, Mann-Whitney U test, Student t-test, Pearson or Spearman correlations. P < 0.01 was considered statistically significant. RESULTS: The MM-suppressed GABA editing efficiency was 0.63. GABA signal fit error was <16% for all participants. The GABA concentration in the PCC of the mTBI group was significantly different from that in healthy controls: GABA/tCr was higher by 27%, absolute GABA concentration with different types of correction was higher by ≈17%. No significant differences were observed in Glx concentrations (P ≥ 0.32) or in Glx/tCr (P ≥ 0.1), NAA/tCr (P = 0.55), and Cho/tCr levels (P = 0.85). DATA CONCLUSION: We report an increase in the GABA concentration in the PCC region in acute mTBI pediatric patients. This may suggest activation of GABA synthesis and impairment of the GABAergic system after acute mTBI. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 1.

J-difference GABA-edited MRS reveals altered cerebello-thalamo-cortical metabolism in patients with hepatic encephalopathy.

Hepatic encephalopathy (HE) is a common neurological manifestation of liver cirrhosis and is characterized by an increase of ammonia in the brain accompanied by a disrupted neurotransmitter balance, including the GABAergic and glutamatergic systems. The aim of this study is to investigate metabolic abnormalities in the cerebello-thalamo-cortical system of HE patients using GABA-edited MRS and links between metabolite levels, disease severity, critical flicker frequency (CFF), motor performance scores, and blood ammonia levels. GABA-edited MRS was performed in 35 participants (16 controls, 19 HE patients) on a clinical 3 T MRI system. MRS voxels were placed in the right cerebellum, left thalamus, and left motor cortex. Levels of GABA+ and of other metabolites of interest (glutamine, glutamate, myo-inositol, glutathione, total choline, total NAA, and total creatine) were assessed. Group differences in metabolite levels and associations with clinical metrics were tested. GABA+ levels were significantly increased in the cerebellum of patients with HE. GABA+ levels in the motor cortex were significantly decreased in HE patients, and correlated with the CFF (r = 0.73; p < .05) and motor performance scores (r = -0.65; p < .05). Well-established HE-typical metabolite patterns (increased glutamine, decreased myo-inositol and total choline) were confirmed in all three regions and were closely linked to clinical metrics. In summary, our findings provide further evidence for alterations in the GABAergic system in the cerebellum and motor cortex in HE. These changes were accompanied by characteristic patterns of osmolytes and oxidative stress markers in the cerebello-thalamo-cortical system. These metabolic disturbances are a likely contributor to HE motor symptoms in HE. In patients with hepatic encephalopathy, GABA+ levels in the cerebello-thalamo-cortical loop are significantly increased in the cerebellum and significantly decreased in the motor cortex. GABA+ levels in the motor cortex strongly correlate with critical flicker frequency (CFF) and motor performance score (pegboard test tPEG), but not blood ammonia levels (NH3).

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.

MR spectroscopy frequency and phase correction using convolutional neural networks.

PURPOSE: To introduce a novel convolutional neural network (CNN)-based approach for frequency-and-phase correction (FPC) of MR spectroscopy (MRS) spectra to achieve fast and accurate FPC of single-voxel MEGA-PRESS MRS data. METHODS: Two neural networks (one for frequency and one for phase) were trained and validated using published simulated and in vivo MEGA-PRESS MRS dataset with wide-range artificial frequency and phase offsets applied. The CNN-based approach was subsequently tested and compared to the current deep learning solution: multilayer perceptrons (MLP). Furthermore, random noise was added to the original simulated dataset to further investigate the model performance at varied signal-to-noise ratio (SNR) levels (i.e., 10, 5, and 2.5). Additional frequency and phase offsets (i.e., small, moderate, large) were also applied to the in vivo dataset, and the CNN model was compared to the conventional approach SR and model-based SR implementation (mSR). RESULTS: The CNN model is more robust to noise compared to the MLP-based approach due to having smaller mean absolute errors in both frequency (0.01 ± 0.01 Hz at SNR = 10 and 0.01 ± 0.02 Hz at SNR = 2.5) and phase (0.12 ± 0.09° at SNR = 10 and -0.07 ± 0.44° at SNR = 2.5) offset prediction. Furthermore, better performance was demonstrated for FPC when compared to the MLP-based approach, and SR when applied to the in vivo dataset for both with and without additional offsets. CONCLUSION: A CNN-based approach provides a solution to the automated preprocessing of MRS data, and the experimental results demonstrate the quantitatively improved spectra quality compared to the state-of-the-art approach.

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.

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.

Comparison of linear combination modeling strategies for edited magnetic resonance spectroscopy at 3 T.

J-difference-edited spectroscopy is a valuable approach for the in vivo detection of γ-aminobutyric-acid (GABA) with magnetic resonance spectroscopy (MRS). A recent expert consensus article recommends linear combination modeling (LCM) of edited MRS but does not give specific details regarding implementation. This study explores different modeling strategies to adapt LCM for GABA-edited MRS. Sixty-one medial parietal lobe GABA-edited MEGA-PRESS spectra from a recent 3-T multisite study were modeled using 102 different strategies combining six different approaches to account for co-edited macromolecules (MMs), three modeling ranges, three baseline knot spacings, and the use of basis sets with or without homocarnosine. The resulting GABA and GABA+ estimates (quantified relative to total creatine), the residuals at different ranges, standard deviations and coefficients of variation (CVs), and Akaike information criteria, were used to evaluate the models' performance. Significantly different GABA+ and GABA estimates were found when a well-parameterized MM3co basis function was included in the model. The mean GABA estimates were significantly lower when modeling MM3co , while the CVs were similar. A sparser spline knot spacing led to lower variation in the GABA and GABA+ estimates, and a narrower modeling range-only including the signals of interest-did not substantially improve or degrade modeling performance. Additionally, the results suggest that LCM can separate GABA and the underlying co-edited MM3co . Incorporating homocarnosine into the modeling did not significantly improve variance in GABA+ estimates. In conclusion, GABA-edited MRS is most appropriately quantified by LCM with a well-parameterized co-edited MM3co basis function with a constraint to the nonoverlapped MM0.93 , in combination with a sparse spline knot spacing (0.55 ppm) and a modeling range of 0.5-4 ppm.

Assessment of the Precision in Measuring Glutathione at 3 T With a MEGA-PRESS Sequence in Primary Motor Cortex and Occipital Cortex.

BACKGROUND: Glutathione (GSH) is an important brain antioxidant and a number of studies have reported its measurement by edited and nonedited localized 1 H spectroscopy techniques within a range of applications in healthy volunteers and disease states. Good test-retest reproducibility is key when assessing the efficacy of treatments aimed at modulating GSH levels within the central nervous system or when noninvasively assessing changes in GSH content over time. PURPOSE: To evaluate the intraday (in vitro and in vivo) and 1-month apart (in vivo) test-retest reproducibility of GSH measurements from GSH-edited MEGA-PRESS acquisitions at 3 T in a phantom and in the brain of a cohort of middle-aged and older healthy volunteers. STUDY TYPE: Prospective. SUBJECTS/PHANTOMS: A phantom containing physiological concentrations of GSH and metabolites with overlapping spectral signatures and 10 healthy volunteers (4 F, 6 M, 55 ± 14 years old). FIELD STRENGTH/SEQUENCE: GSH-edited spectra were acquired at 3 T using the MEGA-PRESS sequence. ASSESSMENT: The phantom was scanned twice and the healthy subjects were scanned three times (on two separate days, 1 month apart). GSH was quantified from each acquisition, with the in vivo voxels placed at the primary motor cortex (PMC) and the occipital cortex (OCC). STATISTICAL TESTS: Mean coefficients of variation (CV) were used to assess short-term (in vitro and in vivo) and longer-term (in vivo) test-retest reproducibility. RESULTS: In vitro, the CV was 2.3%. In vivo, the mean intraday CV was 3.3% in the PMC and 2.4% in the OCC, while the CVs at 1 month apart were 4.6% in the PMC and 7.8% in the OCC. DATA CONCLUSION: GSH-edited MEGA-PRESS spectroscopy allows measurement of GSH with excellent precision. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Diagnostic performance of edited 2HG MR spectroscopy of central glioma in the clinical environment.

OBJECTIVE: Oncometabolite D-2-hydroxyglutarate (2HG) is pooled in isocitrate dehydrogenase (IDH)-mutant glioma cells. Detecting 2HG by MR spectroscopy (MRS) has been proven viable in the last decade but has not entirely found its way into the clinical routine. This study aimed to explore the adoption of 2HG MRS while acknowledging factors that influence its performance in the clinical environment. METHODS: Thirty-nine MR spectra were acquired and reported prospectively in patients with suspected glioma using a 3 T system with Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence utilizing averaged free induction decay (FID) signals. Postprocessing and evaluation of spectra were performed with jMRUI and LCModel. 2HG concentration estimates, 2HG/Cr ratio, together with quality measures, including Cramér-Rao lower bounds (CRLBs), full-width at half-maximum (FWHM) values, and signal-to-noise ratio (SNR) were calculated using LCModel. Immunohistochemistry and genomic analysis results used as a ground truth were available for 15 patients. RESULTS: The threshold for test positivity was set according to the ROC curve at 1 mM. Calculated sensitivity was 57.14% (95% CI 0.20-0.88), specificity 87.5% (95% CI 0.46-0.99), positive predictive value 80%, and negative predictive value 70%. Overall diagnostic accuracy was 73.33% (95% CI 0.45-0.92). The 2HG/Cr ratio with the cutoff value 0.085 significantly improved sensitivity and overall diagnostic accuracy [85.71%, 95% CI 0.42-1.00 and 86.67%, (95% CI 0.60-0.98), respectively]. CONCLUSION: Multiple factors compromising spectral quality in the clinical adoption of edited 2HG MRS resulted in diminished sensitivity but clinically acceptable specificity. Furthermore, the 2HG/Cr ratio performs better than the sole 2HG concentration estimate in the pre-operative setting.

Gamma-aminobutyric acid (GABA) levels in the midcingulate cortex and clozapine response in patients with treatment-resistant schizophrenia: A proton magnetic resonance spectroscopy (1 H-MRS) study.

BACKGROUND: Gamma-Aminobutyric Acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABAergic dysfunction has been implicated in the pathophysiology of schizophrenia. Clozapine, the only approved drug for treatment-resistant schizophrenia (TRS), involves the GABAergic system as one of its targets. However, no studies have investigated the relationship between brain GABA levels, as measured by proton magnetic resonance spectroscopy (1 H-MRS), and clozapine response in patients with TRS. METHODS: This study enrolled patients with TRS who did not respond to clozapine (ultra-resistant schizophrenia: URS) and who responded to clozapine (non-URS), patients with schizophrenia who responded to first-line antipsychotics (first-line responders: FLR), and healthy controls (HCs). We measured GABA levels in the midcingulate cortex (MCC) using 3T 1 H-MRS and compared these levels among the groups. The associations between GABA levels and symptom severity were also explored within the patient groups. RESULTS: A total of 98 participants (URS: n = 22; non-URS: n = 25; FLR: n = 16; HCs: n = 35) completed the study. We found overall group differences in MCC GABA levels (F(3,86) = 3.25, P = 0.04). Specifically, patients with URS showed higher GABA levels compared to those with non-URS (F(1,52) = 8.40, P = 0.03, Cohen's d = 0.84). MCC GABA levels showed no associations with any of the symptom severity scores within each group or the entire patient group. CONCLUSION: Our study is the first to report elevated GABA levels in the MCC in patients with schizophrenia resistant to clozapine treatment compared with those responsive to clozapine. Longitudinal studies are required to evaluate if GABA levels are a suitable biomarker to predict clozapine resistance.

Frequency and phase correction of J-difference edited MR spectra using deep learning.

PURPOSE: To investigate whether a deep learning-based (DL) approach can be used for frequency-and-phase correction (FPC) of MEGA-edited MRS data. METHODS: Two neural networks (1 for frequency, 1 for phase) consisting of fully connected layers were trained and validated using simulated MEGA-edited MRS data. This DL-FPC was subsequently tested and compared to a conventional approach (spectral registration [SR]) and to a model-based SR implementation (mSR) using in vivo MEGA-edited MRS datasets. Additional artificial offsets were added to these datasets to further investigate performance. RESULTS: The validation showed that DL-based FPC was capable of correcting within 0.03 Hz of frequency and 0.4°of phase offset for unseen simulated data. DL-based FPC performed similarly to SR for the unmanipulated in vivo test datasets. When additional offsets were added to these datasets, the networks still performed well. However, although SR accurately corrected for smaller offsets, it often failed for larger offsets. The mSR algorithm performed well for larger offsets, which was because the model was generated from the in vivo datasets. In addition, the computation times were much shorter using DL-based FPC or mSR compared to SR for heavily distorted spectra. CONCLUSION: These results represent a proof of principle for the use of DL for preprocessing MRS data.

Repeatability and reliability of GABA measurements with magnetic resonance spectroscopy in healthy young adults.

PURPOSE: Gamma-aminobutyric acid (GABA) abnormalities have been implicated in a range of neuropsychiatric disorders. Despite substantial interest in probing GABA in vivo, human imaging studies relying on magnetic resonance spectroscopy (MRS) have generally been hindered by technical challenges, including GABA's relatively low concentration and spectral overlap with other metabolites. Although past studies have shown moderate-to-strong test-retest repeatability and reliability of GABA within certain brain regions, many of these studies have been limited by small sample sizes. METHODS: GABA+ (macromolecular-contaminated) test-retest reliability and repeatability were assessed via a Meshcher-Garwood point resolved spectroscopy (MEGA-PRESS) MRS sequence in the rostral anterior cingulate cortex (rACC; n = 21) and dorsolateral prefrontal cortex (dlPFC; n = 20) in healthy young adults. Data were collected on a 3T scanner (Siemens Prisma, Siemens Healthcare, Erlangen, Germany) and GABA+ results were reported in reference to both total creatine (GABA+/tCr) and water (GABA+/water). RESULTS: Results showed strong test-retest repeatability (mean GABA+/tCr coefficient of variation [CV] = 4.6%; mean GABA+/water CV = 4.0%) and reliability (GABA+/tCr intraclass correlation coefficient [ICC] = 0.77; GABA+/water ICC = 0.87) in the dlPFC. The rACC showed acceptable (but comparatively lower) repeatability (mean GABA+/tCr CV = 8.0%; mean GABA+/water CV = 7.5%), yet low-moderate reliability (GABA+/tCr ICC = 0.40; GABA+/water ICC = 0.44). CONCLUSION: The present study found excellent GABA+ MRS repeatability and reliability in the dlPFC. The rACC showed inferior results, possibly because of a combination of shimming impedance and measurement error. These data suggest that MEGA-PRESS can be utilized to reliably distinguish participants based on dlPFC GABA+ levels, whereas the mixed results in the rACC merit further investigation.