Mescher-Garwood Point-resolved Spectroscopy Research Articles

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.

Incorporation of edited MRS into clinical practice may improve care of patients with IDH-mutant glioma.

Isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion classify adult-type diffuse gliomas into three tumor subtypes with distinct prognosis. We aimed to evaluate the performance of edited magnetic resonance spectroscopy (MRS) for glioma subtyping in a clinical setting, via the quantification of D-2-hydroxyglutarate (2HG) and cystathionine. The delay between this noninvasive classification and the integrated histomolecular analysis was also quantified. Subjects with presumed low-grade glioma, eligible for surgery (cohort 1), and subjects with IDH-mutant glioma, previously treated and with progressive disease (cohort 2) were prospectively examined with a singlevoxel Mescher-Garwood point-resolved spectroscopy sequence at 3 T. Spectra were quantified using LCModel. The Cramér-Rao lower bounds (CRLB) threshold was set to 20%. Integrated histomolecular analysis according to the 2021 WHO classification was considered as a ground truth. Thirty-four consecutive subjects were enrolled. Due to poor spectra quality and lack of histological specimen, data from 26 subjects was analyzed. Twenty-one belonged to cohort 1 [11 females; median age: 42 years] and 5 to cohort 2 [3 females; median age: 48 years]. Edited MRS showed 100% specificity for detection of IDH mutation and 91% specificity for prediction of 1p/19q codeletion status. Sensitivities for prediction of IDH and 1p/19q codeletion were 62% and 33%, respectively. The median CRLB values were 14% (13 - 32) for IDH-mutant and 572% (554 - 999) for IDH-wild-type tumors. The time between MRS and surgery was longer for low-grade than high-grade gliomas (p = .03), yet the time between MRS and WHO diagnosis did not differ between grades (p = .07), possibly reflecting molecular analyses induced delays in high-grade gliomas. Our results, acquired in a clinic setting, confirmed that edited MRS is highly specific for both IDH mutation and 1p/19q codeletion predictions and can provide a faster prognosis stratification. In the upcoming IDH-inhibitor treatment era, incorporation of edited MRS into clinical workflow is desirable. 2HG = D-2-hydroxyglutarate; Cth = cystathionine. CRLB: Cramér-Rao lower bound; IDH: isocitrate dehydrogenase.

GABAergic imbalance in Parkinson’s disease–related depression determined with MEGA-PRESS

ObjectiveThe pathogenesis of depression in patients with Parkinson’s disease (PD) is poorly understood. Therefore, this study aimed to explore the changes in γ-aminobutyric acid (GABA) and glutamate plus glutamine (Glx) levels in patients with PD with or without depression determined using MEscher-GArwood Point Resolved Spectroscopy (MEGA-PRESS). Materials and methodsA total of 83 patients with primary PD and 24 healthy controls were included. Patients with PD were categorized into depressed PD (DPD, n = 19) and nondepressed PD (NDPD, n = 64) based on the 17-item Hamilton Depression Rating Scale. All participants underwent T1-weighted imaging and MEGA-PRESS sequence to acquire GABA+ and Glx values. The MEGA-PRESS sequence was conducted using 18.48 mL voxels in the left thalamus and medial frontal cortex. The GABA+, Glx, and creatine values were quantified using Gannet 3.1 software. ResultsThe GABA+ and Glx values were not significantly disparate between patients with PD and controls in the thalamus and medial frontal cortex. However, the levels of N-acetyl aspartate/creatine and choline/creatine in the left thalamus were significantly lower in patients with PD than in controls (P = .031, P = .009). The GABA+/Water and GABA+/Creatine in the medial frontal cortex were higher in DPD than in NDPD (P = .001, P = .004). The effects of depression on Glx or other metabolite levels were not evident, and no significant difference in metabolite values was noted in the left thalamus among all groups (P > .05). ConclusionsGABA+ levels increased in the medial frontal cortex in DPD, which may be more closely related to depressive pathology. Thus, alterations in GABAergic function in special brain structures may be related to the clinical manifestations of PD symptoms, and hence mediating this function might help in treating depression in PD.

A preliminary study of dynamic neurochemical changes in the dorsolateral prefrontal cortex during working memory.

Working memory (WM) is one of the fundamental cognitive functions associated with the dorsolateral prefrontal cortex (DLPFC). However, the neurochemical mechanisms of WM, including the dynamic changes in neurometabolites such as glutamate and GABA in the DLPFC, remain unclear. Here, we investigated WM-related glutamate and GABA changes, alongside hemodynamic responses in the DLPFC, using a combination of functional magnetic resonance spectroscopy (fMRS) and functional magnetic resonance imaging (fMRI). During a WM task, we measured Glx (glutamate + glutamine) and GABA levels using GABA editing MEscher-GArwood Point REsolved Spectroscopy (MEGA-PRESS) sequence and blood-oxygen-level-dependent (BOLD) signal changes. In the DLPFC, we observed elevated Glx levels and increased BOLD signal changes during a 2-back task. Specifically, the Glx levels in the DLPFC were significantly higher during the 2-back task compared with fixation, although this difference was not significant when compared with a 0-back task. However, Glx levels during the 0-back task were higher than during fixation. Furthermore, there was a positive correlation between Glx levels in the DLPFC during the 2-back task and the corresponding BOLD signal changes. Notably, higher Glx increases were associated with increased DLPFC activation and lower WM task performance in individuals. No notable changes in DLPFC GABA levels were observed during WM processing. These findings suggest that the modulation of glutamatergic activity in the DLPFC may play a crucial role in both working memory processing and its associated performance outcomes.

MR Spectroscopy Assessment of Daily Variations of GABA Levels within the Parietal Lobe and Anterior Cingulate Gyrus Regions of Healthy Young Adults.

The changes that occur in the gamma-aminobutyric acid (GABA) levels within specific brain regions throughout the day are less clear. To evaluate the daily fluctuations of GABA levels within the parietal lobe (PL) and anterior cingulate gyrus (ACC) regions and explore their association with melatonin (MT) levels, heart rate (HR), and blood pressure. Prospective. 26 healthy young adults (15 males and 11 females aged 22-27 years). 3.0T, T1-weighted imaging, Mescher-Garwood point resolved spectroscopy (MEGA-PRESS) sequence. The acquired GABA signal contained the overlapping signals of macromolecules and homocarnosine, hence expressed as GABA+. The creatine (Cr) signal was applied as an endogenous reference. The GABA+, GABA+/Cr were measured at six different time points (1:00, 5:00, 9:00, 13:00, 17:00, and 21:00 hours) using MEGA-PRESS. The blood pressure, HR and sputum MT levels, were also acquired. The one-way repeated-measures analysis of variance (ANOVA) was used to evaluate the GABA, blood pressure, HR, and MT levels throughout the day. A general linear model was used to find the correlation between GABA and blood pressure, HR, and MT. P < 0.05 was statistically significant. Significant variations in GABA+/Cr and GABA+ levels were observed throughout the day within the PL region. The lowest levels were recorded at 9:00 hour (GABA+/Cr: 0.100 ± 0.003，GABA+:1.877 ± 0.051 i.u) and the highest levels were recorded at 21:00 hour (GABA+/Cr: 0.115 ± 0.003, GABA+:2.122 ± 0.052 i.u). The MT levels were positively correlated with GABA+/Cr (r = 0.301) and GABA+ (r = 0.312) within the ACC region. GABA+/Cr and GABA+ in ACC are positively correlated with MT. GABA levels in the PL have diurnal differences. These findings may indicate that the body's GABA level change in response to the light-dark cycle. 1 TECHNICAL EFFICACY: Stage 2.

Single-session reproducibility of MR spectroscopy measures of glutathione in the mesial temporal lobe with MEGA-PRESS.

Magnetic resonance spectroscopy (MRS) measures neurochemicals in vivo. Glutathione (GSH) is a neuroprotective chemical shown to vary significantly in patients with Alzheimer's disease (AD). This work investigates the reproducibility of GSH measures in the mesial temporal lobe (MTL) to identify its potential clinical utility. MRS data were acquired from eight healthy volunteers (31.1±5.2 years; 4 male/female) using Mescher-Garwood-Point Resolved Spectroscopy (MEGA-PRESS) from the MTL in the left hemisphere across two scan sessions in the same visit. Total N-acetylaspartate (tNAA), choline (tCho), creatine (tCr), and GSH were quantified. Reproducibility of quantifications of these neurochemicals were tested using coefficient of variance (CV) between scan sessions. Reproducibility of voxel placement on the left MTL was calculated by measuring the tissue overlap and percent of hippocampus within that voxel. CV measured across different scan sessions in each individual, with a CV<15% was accepted as "good" reproducibility. Paired t-tests were carried out to establish the significant differences between the two scans across each individual with p<.05 as significant. TNAA (%CV = 7.2; p = .5), tCr (%CV = 7.8; p = .6) and tCho (%CV = 9.3; p = .4), and GSH (%CV = 22; p = .1). The dice coefficient that reflects the level of overlap of hippocampal tissue in the voxel was shown to be 0.8±0.1. Voxel tissue composition were: Scan 1 (cerebrospinal fluid [CSF]: 5 ± 1%, white matter [WM]: 52 ± 3%, gray matter [GM]: 43 ± 3%); Scan 2 (CSF: 5 ± 1%, WM: 52 ± 4%, GM: 44 ± 4%). The data suggest measures of abundant metabolites in the MTL using the MEGA-PRESS sequence has a high reproducibility. Reproducibility of GSH in this area was poorer requiring care when interpreting measures of GSH in the MTL for clinical translational purposes.

GABA and glutamate response to social processing: a functional MRS feasibility study.

Several studies have suggested that atypical social processing in neurodevelopmental conditions (e.g. autism) is associated with differences in excitation and inhibition, through changes in the levels of glutamate and gamma-aminobutyric acid (GABA). While associations between baseline metabolite levels and behaviours can be insightful, assessing the neurometabolic response of GABA and glutamate during social processing may explain altered neurochemical function in more depth. Thus far, there have been no attempts to determine whether changes in metabolite levels are detectable using functional MRS (fMRS) during social processing in a control population. We performed Mescher-Garwood point resolved spectroscopy edited fMRS to measure the dynamic response of GABA and glutamate in the superior temporal sulcus (STS) and visual cortex (V1) while viewing social stimuli, using a design that allows for analysis in both block and event-related approaches. Sliding window analyses were used to investigate GABA and glutamate dynamics at higher temporal resolution. The changes of GABA and glutamate levels with social stimulus were largely non-significant. A small decrease in GABA levels was observed during social stimulus presentation in V1, but no change was observed in STS. Conversely, non-social stimulus elicited changes in both GABA and glutamate levels in both regions. Our findings suggest that the current experimental design primarily captures effects of visual stimulation, not social processing. Here, we discuss the feasibility of using fMRS analysis approaches to assess changes in metabolite response.

Neurometabolic alterations in children and adolescents with functional neurological disorder

ObjectivesIn vivo magnetic resonance spectroscopy (MRS) was used to investigate neurometabolic homeostasis in children with functional neurological disorder (FND) in three regions of interest: supplementary motor area (SMA), anterior default mode network (aDMN), and posterior default mode network (dDMN). Metabolites assessed included N-acetyl aspartate (NAA), a marker of neuron function; myo-inositol (mI), a glial-cell marker; choline (Cho), a membrane marker; glutamate plus glutamine (Glx), a marker of excitatory neurotransmission; γ-aminobutyric acid (GABA), a marker of inhibitor neurotransmission; and creatine (Cr), an energy marker. The relationship between excitatory (glutamate and glutamine) and inhibitory (GABA) neurotransmitter (E/I) balance was also examined. MethodsMRS data were acquired for 32 children with mixed FND (25 girls, 7 boys, aged 10.00 to 16.08 years) and 41 healthy controls of similar age using both short echo point-resolved spectroscopy (PRESS) and Mescher-Garwood point-resolved spectroscopy (MEGAPRESS) sequences in the three regions of interest. ResultsIn the SMA, children with FND had lower NAA/Cr, mI/Cr (trend level), and GABA/Cr ratios. In the aDMN, no group differences in metabolite ratios were found. In the pDMN, children with FND had lower NAA/Cr and mI/Cr (trend level) ratios. While no group differences in E/I balance were found (FND vs. controls), E/I balance in the aDMN was lower in children with functional seizures—a subgroup within the FND group. Pearson correlations found that increased arousal (indexed by higher heart rate) was associated with lower mI/Cr in the SMA and pDMN. ConclusionsOur findings of multiple differences in neurometabolites in children with FND suggest dysfunction on multiple levels of the biological system: the neuron (lower NAA), the glial cell (lower mI), and inhibitory neurotransmission (lower GABA), as well as dysfunction in energy regulation in the subgroup with functional seizures.

Alteration of intracerebral metabolites and subjective sleepiness by acute caffeine administration in adults.

Caffeine is the most widely consumed psychostimulant. Despite this, the effects of acute caffeine intake on brain metabolite levels remain largely unknown. We aimed to investigate the effect of acute caffeine intake on brain metabolite concentrations in different caffeine consumption habit groups and to explore the association between metabolite changes and sleepiness. Forty-five healthy adults were divided into groups based on their daily caffeine consumption: ≥1 cup/day, <1 cup/day, and no consumption. The exclusion criteria were the presence of neurological disorder, habitual consumption of mind-altering substances, and individuals who were unable to undergo magnetic resonance imaging. Mescher-Garwood point resolved spectroscopy and conventional spectroscopy data were acquired at 3 Tesla from voxels in the thalamus and posterior cingulate cortex (PCC). Subjective sleepiness was measured with the Karolinska Sleepiness Scale. The results of two-way repeated measures analysis of variance indicated a significant interaction effect between time and group for glutamate, glycerylphosphocholine and phosphocholine (GPC + PCH), myo-inositol, glutamate + glutamine (Glx), and creatine and phosphocreatine (Cr + PCr) of the thalamus (all P<0.01), and glutamate (P<0.0001), GPC + PCH (P=0.016), and Glx (P<0.0001) of the PCC. The change between pre- and post-caffeine intake results with significant reductions in γ-aminobutyric acid-positive macromolecule (GABA+) (thalamus, P=0.011), Glx (thalamus, P=0.002), glutamate (PCC, P<0.0001), and significant increments in GPC + PCH (thalamus, P=0.012 and PCC, P<0.0001), myo-inositol (thalamus, P=0.009), and Glx (PCC, P<0.0001). The change among the groups, with the ≥1 cup/day was significantly higher than the <1 cup/day or no consumption for glutamate (PCC, P=0.028), GPC (thalamus, P=0.001; PCC, P=0.026), and Cr + PCr (PCC, P=0.035); ≥1 cup/day was significantly lower than <1 cup/day and no consumption for glutamate (thalamus, P<0.0001), Cr + PCr (thalamus, P=0.003), Glx (thalamus, P=0.014), and myo-inositol (PCC, P=0.009). Bivariate correlation analysis revealed that GABA+ in the thalamus voxel (r=-0.7676; P<0.0001) was negatively correlated with subjective sleepiness. Higher caffeine consumption had a significant impact on brain metabolites. Magnetic resonance spectroscopy was sensitive in measuring brain metabolite fluctuations after caffeine intake, particularly the levels of GABA+ in the thalamus, which was significantly correlated with sleepiness.

Impact of bronchopulmonary dysplasia on brain GABA concentrations in preterm infants: Prospective cohort study

BackgroundBronchopulmonary dysplasia (BPD) is associated with cognitive-behavioral deficits in very preterm (VPT) infants, often in the absence of structural brain injury. Advanced GABA-editing techniques like Mescher-Garwood point resolved spectroscopy (MEGA-PRESS) can quantify in-vivo gamma-aminobutyric acid (GABA+, with macromolecules) and glutamate (Glx, with glutamine) concentrations to investigate for neurophysiologic perturbations in the developing brain of VPT infants. ObjectiveTo investigate the relationship between the severity of BPD and basal-ganglia GABA+ and Glx concentrations in VPT infants. MethodsMRI studies were performed on a 3 T scanner in a cohort of VPT infants [born ≤32 weeks gestational age (GA)] without major structural brain injury and healthy-term infants (>37 weeks GA) at term-equivalent age. MEGA-PRESS (TE68ms, TR2000ms, 256averages) sequence was acquired from the right basal-ganglia voxel (∼3cm3) and metabolite concentrations were quantified in institutional units (i.u.). We stratified VPT infants into no/mild (grade 0/1) and moderate-severe (grade 2/3) BPD. ResultsReliable MEGA-PRESS data was available from 63 subjects: 29 healthy-term and 34 VPT infants without major structural brain injury. VPT infants with moderate-severe BPD (n = 20) had the lowest right basal-ganglia GABA+ (median 1.88 vs. 2.28 vs. 2.12 i.u., p = 0.025) and GABA+/choline (0.73 vs. 0.99 vs. 0.88, p = 0.004) in comparison to infants with no/mild BPD and healthy-term infants. The GABA+/Glx ratio was lower (0.34 vs. 0.44, p = 0.034) in VPT infants with moderate-severe BPD than in infants with no/mild BPD. ConclusionsReduced GABA+ and GABA+/Glx in VPT infants with moderate-severe BPD indicate neurophysiologic perturbations which could serve as early biomarkers of future cognitive deficits.

Vespa: Integrated applications for RF pulse design, spectral simulation and MRS data analysis.

The Vespa package (Versatile Simulation, Pulses, and Analysis) is described and demonstrated. It provides workflows for developing and optimizing linear combination modeling (LCM) fitting for 1 H MRS data using intuitive graphical user interface interfaces for RF pulse design, spectral simulation, and MRS data analysis. Command line interfaces for embedding workflows in MR manufacturer platforms and utilities for synthetic dataset creation are included. Complete provenance is maintained for all steps in workflows. Vespa is written in Python for compatibility across operating systems. It embeds the PyGAMMA spectral simulation library for spectral simulation. Multiprocessing methods accelerate processing and visualization. Applications use the Vespa database for results storage and cross-application access. Three projects demonstrate pulse, sequence, simulation, and data analysis workflows: (1) short TE semi-LASER single-voxel spectroscopy (SVS)LCM fitting, (2) optimizing MEGA-PRESS (MEscher-GArwood Point RESolved Spectroscopy) flip angle and LCM fitting, and (3) creating a synthetic short TE dataset. The LCM workflows for in vivo basis set creation and spectral analysis showed reasonable results for both the short TE semi-LASER and MEGA-PRESS. Examples of pulses, simulations, and data fitting are shown in Vespa application interfaces for various steps to demonstrate the interactive workflow. Vespa provides an efficient and extensible platform for characterizing RF pulses, pulse design, spectral simulation optimization, and automated LCM fitting via an interactive platform. Modular design and command line interface make it easy to embed in other platforms. As open source, it is free to the MRS community for use and extension. Vespa source code and documentation are available through GitHub.

Evaluating Back-to-Back and Day-to-Day Reproducibility of Cortical GABA+ Measurements Using Proton Magnetic Resonance Spectroscopy (1H MRS).

γ-aminobutyric acid (GABA) is a major inhibitory neurotransmitter implicated in neuropsychiatric disorders. The best method for quantifying GABA is proton magnetic resonance spectroscopy (1H MRS). Considering that accurate measurements of GABA are affected by slight methodological alterations, demonstrating GABA reproducibility in healthy volunteers is essential before implementing the changes in vivo. Thus, our study aimed to evaluate the back-to-back (B2B) and day-to-day (D2D) reproducibility of GABA+ macromolecules (GABA+) using a 3 Tesla MRI scanner, the new 32-channel head coil (CHC), and Mescher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) technique with the scan time (approximately 10 min), adequate for psychiatric patients. The dorsomedial pre-frontal cortex/anterior cingulate cortex (dmPFC/ACC) was scanned in 29 and the dorsolateral pre-frontal cortex (dlPFC) in 28 healthy volunteers on two separate days. Gannet 3.1 was used to quantify GABA+. The reproducibility was evaluated by Pearson's r correlation, the interclass-correlation coefficient (ICC), and the coefficient of variation (CV%) (r/ICC/CV%). For Day 1, B2B reproducibility was 0.59/0.60/5.02% in the dmPFC/ACC and 0.74/0.73/5.15% for dlPFC. For Day 2, it was 0.60/0.59/6.26% for the dmPFC/ACC and 0.54/0.54/6.89 for dlPFC. D2D reproducibility of averaged GABA+ was 0.62/0.61/4.95% for the dmPFC/ACC and 0.58/0.58/5.85% for dlPFC. Our study found excellent GABA+ repeatability and reliability in the dmPFC/ACC and dlPFC.

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

BackgroundAbnormal 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. MethodsGlx (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. ResultsWhile 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. ConclusionsWe 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.

Changes in gamma-aminobutyric acid and glutamate/glutamine levels in the right thalamus of patients with episodic and chronic migraine: A proton magnetic resonance spectroscopy study.

To explore gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels in the right thalamus of patients with episodic migraine (EM) and chronic migraine (CM) and their effects on the chronification of migraine. Migraine affects approximately 1 billion people worldwide, with 2.5%-3% of people with EM progressing to CM each year. Magnetic resonance spectroscopy studies have revealed altered GABA and Glx levels in the thalamus of patients with migraine without aura, but these neurometabolic concentrations are underexplored in the thalamus of patients with CM. In this cross-sectional study, patients with EM and CM were recruited. Mescher-Garwood point resolved spectroscopy sequence was used to acquire neurotransmitter concentrations in the right thalamus of patients with EM and CM and matched healthy controls (HCs). A total of 26 patients (EM, n= 11; CM, n= 15) and 16 age- and sex-matched HCs were included in the analysis. There were significantly lower GABA+/Water levels in the right thalamus of the CM group (mean ± standard deviation: 2.27 ± 0.4 [institutional units]) than that of the HC group (2.74 ± 0.4) (p= 0.026; mean difference [MD]=-0.5 [i.u.]), and lower Glx/Cr levels in the EM group (mean ± SD: 0.11 ± < 0.1) than in the HCs (0.13 ± < 0.1) and CM group (0.13 ± < 0.1) (p= 0.023, MD < -0.1, and p= 0.034, MD < -0.1, respectively). The GABA+/Glx ratio was lower in the CM group (mean ± SD: 0.38 ± 0.1) compared to the EM group (0.47 ± 0.1) (p= 0.024; MD=-0.1). The area under the curve for GABA+/Water levels in differentiating patients with CM from HCs was 0.83 (95% confidence interval 0.68, 0.98; p= 0.004). Correlation analyses within the migraine group revealed no significant correlation between metabolite concentration levels and headache characteristics after Bonferroni correction. Reduced GABA+/Water levels and imbalance of excitation/inhibition in the right thalamus may contribute to migraine chronification.

Elevated GABA level in the precuneus and its association with pain intensity in patients with postherpetic neuralgia: An initial proton magnetic resonance spectroscopy study

PurposeThis study aimed to explore the changes in gamma-aminobutyric acid (GABA) and glutamate (Glu) levels, and their correlations with clinical indicators in patients with postherpetic neuralgia (PHN). MethodsA totally of 22 PHN patients and 21 sex-, age-, and education-matched healthy controls (HCs) underwent proton magnetic resonance spectroscopy scanning. The spectral data of GABA in the precuneus was obtained by Mescher-Garwood point-resolved spectroscopy, whereas the spectral data of Glu, total N-acetyl-l-aspartic acid (tNAA) and total choline (tCho) were obtained by point-resolved spectroscopy. The pain intensity of PHN was assessed by numeric rating scales (NRS). The edited GABA signal was displayed as GABA+ due to overlapping macromolecules and homocarnosine signals. Total creatine (tCr) level in individual was used as an endogenous reference. The neurometabolites levels of PHN patients were compared with those of healthy individuals and the correlations with clinical variables (pain duration and intensity) were analyzed. ResultsPHN patients had higher GABA+/tCr levels in the precuneus than HCs (P = 0.009), with no significant differences in the levels of Glu/ tCr, tNAA/ tCr and tCho/ tCr (all P > 0.05). The GABA+/ tCr levels were positively correlated with the NRS scores of the PHN patients (r = 0.473, P = 0.030). ConclusionIncreased GABA+/tCr levels in the precuneus and their association with pain intensity of PHN patients suggested a key role of the abnormalities of regional GABAergic neurons in the pathophysiological mechanisms of pain in PHN.

Frontal Metabolites and Alzheimer's Disease Biomarkers in Healthy Older Women and Women Diagnosed with Mild Cognitive Impairment.

Women account for two thirds of the prevalence and incidence of Alzheimer's disease (AD) and mild cognitive impairment (MCI). Evidence suggest that sex may differently influence the expression of proteins amyloid-beta (Aβ1-42) and tau, for which early detection is crucial in prevention of the disease. We investigated the effect of aging and cerebrospinal fluid (CSF) levels of Aβ1-42 and tau on frontal metabolites measured with proton magnetic resonance spectroscopy (MRS) in a cohort of cognitively normal older women and women with MCI. 3T single-voxel MRS was performed on the medial frontal cortex, using Point Resolved Spectroscopy (PRESS) and Mescher-Garwood Point Resolved Spectroscopy (MEGA-PRESS) in 120 women (age range 50-85). CSF samples of Aβ1-42 and tau and scores of general cognition were also obtained. Levels of frontal gamma aminobutyric acid (GABA+) were predicted by age, independently of disease and CSF biomarkers. Importantly, levels of GABA+ were reduced in MCI patients. Additionally, we found that levels of N-acetylaspartate relative to myo-inositol (tNAA/mI) predicted cognition in MCI patients only and were not related to CSF biomarkers. This study is the first to demonstrate a strong association between frontal GABA+ levels and neurological aging in a sample consisting exclusively of healthy older women with various levels of CSF tau and Aβ1-42 and women with MCI. Importantly, our results show no correlation between CSF biomarkers and MRS metabolites in this sample.

Decreased Brain GABA Levels in Patients with Migraine Without Aura: An Exploratory Proton Magnetic Resonance Spectroscopy Study

Increasing neurophysiological studies had revealed that regional excitation-inhibition imbalance in the brain played a key role in the pathogenesis of migraine. This study aimed to explore the alterations in gamma-aminobutyric acid (GABA) and glutamate/glutamine complex (Glx) levels in the anterior cingulate gyrus (ACC) and medial prefrontal lobe (mPFC) of patients with migraine without aura (MWoA) and investigate the correlation between neurotransmitter levels and clinical indicators. A total of 28 patients with MWoA and 28 sex-, age-, and education level–matched healthy controls (HCs) underwent single-voxel proton magnetic resonance spectroscopy scanning at 3.0 Tesla. MEscher-Garwood Point RESolved Spectroscopy (MEGA-PRESS) sequence was performed to acquire the spectral data of GABA and Glx in the ACC and mPFC. The clinical indicators and anxiety-depression states of all participants were assessed. The acquired GABA signal contained the overlapping signals of macromolecules and homocarnosine, hence expressed as GABA+. The creatine (Cr) signal was applied as an endogenous reference. We observed that GABA+/Cr levels were significantly lower in ACC and mPFC of patients with MWoA than of HCs, with no significant difference in Glx levels. Negative correlations between GABA+/Cr levels and attack frequency were found in the ACC and mPFC regions of patients. These results suggested that there might be a close relationship between ACC and mPFC GABAergic neurons abnormalities and the pathophysiological mechanisms of MWoA. It might be beneficial to targeted treatment for patients with MWoA.

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

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. Thirty-nine MR spectra were acquired and reported prospectively in patients with suspected glioma using a 3T 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. The threshold for test positivity was set according to the ROC curve at 1mM. 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]. 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.

Left Dorsolateral Prefrontal Cortex Glx/tCr Predicts Efficacy of High Frequency 4- to 6-Week rTMS Treatment and Is Associated With Symptom Improvement in Adults With Major Depressive Disorder: Findings From a Pilot Study.

About 20–40% of estimated 121 million patients with major depressive disorder (MDD) are not adequately responsive to medication treatment. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive, non-convulsive neuromodulation/neurostimulation method, has gained popularity in treatment of MDD. Because of the high cost involved in rTMS therapy, ability to predict the therapy effectiveness is both clinically and cost wise significant. This study seeks an imaging biomarker to predict efficacy of rTMS treatment using a standard high frequency 10-Hz 4- to 6-week protocol in adult population. Given the significance of excitatory and inhibitory neurotransmitters glutamate (Glu) and gamma aminobutyric acid (GABA) in the pathophysiology of MDD, and the involvement of the site of rTMS application, left dorsolateral prefrontal cortex (lDLPFC), in MDD, we explored lDLPFC Glx (Glu + glutamine) and GABA levels, measured by single voxel magnetic resonance spectroscopy (MRS) with total creatine (tCr; sum of creatine and phosphocreatine) as reference, as possible biomarkers of rTMS response prediction. Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) MRS data from 7 patients (40–74 y) were used in the study; 6 of these patients were scanned before and after 6 weeks of rTMS therapy. Findings from this study show inverse correlation between pretreatment lDLPFC Glx/tCr and (i) posttreatment depression score and (ii) change in depression score, suggesting higher Glx/tCr as a predictor of treatment efficacy. In addition association was observed between changes in depression scores and changes in Glx/tCr ratio. The preliminary findings did not show any such association between GABA/tCr and depression score.

Regional Differences in Gamma-Aminobutyric Acid and Glutamate Concentrations in the Healthy Newborn Brain.

Gamma-aminobutyric acid and glutamate system disruptions may underlie neonatal brain injury. However, in vivo investigations are challenged by the need for special 1H-MR spectroscopy sequences for the reliable measurement of the neurotransmitters in this population. We used J-edited 1H-MR spectroscopy (Mescher-Garwood point-resolved spectroscopy) to quantify regional in vivo gamma-aminobutyric acid and glutamate concentrations during the early postnatal period in healthy neonates. We prospectively enrolled healthy neonates and acquired Mescher-Garwood point-resolved spectroscopy spectra on a 3T MR imaging scanner from voxels located in the cerebellum, the right basal ganglia, and the right frontal lobe. CSF-corrected metabolite concentrations were compared for regional variations and cross-sectional temporal trends with advancing age. Fifty-eight neonates with acceptable spectra acquired at postmenstrual age of 39.1 (SD, 1.3) weeks were included for analysis. Gamma-aminobutyric acid (+ macromolecule) (2.56 [SD, 0.1]) i.u., glutamate (3.80 [SD, 0.2]), Cho, and mIns concentrations were highest in the cerebellum, whereas NAA (6.72 [SD, 0.2]), NAA/Cho, Cr/Cho, and Glx/Cho were highest in the basal ganglia. Frontal gamma-aminobutyric acid (1.63 [SD, 0.1]), Glx (4.33 [SD, 0.3]), Cr (3.64 [SD, 0.2]), and Cho concentrations were the lowest among the ROIs. Glx, NAA, and Cr demonstrated a significant adjusted increase with postmenstrual age (β = 0.2-0.35), whereas gamma-aminobutyric acid and Cho did not. We report normative regional variations and temporal trends of in vivo gamma-aminobutyric acid and glutamate concentrations reflecting the functional and maturational status of 3 distinct brain regions of the neonate. These measures will serve as important normative values to allow early detection of subtle neurometabolic alterations in high-risk neonates.