Publications

2024

1. Neurochemical Predictors of Generalised Learning Induced by Brain Stimulation and Training

   Shane E. Ehrhardt, Yohan Wards, Reuben Rideaux, and 13 more authors

   Journal of Neuroscience, Mar 2024

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

2. sLASER and PRESS Perform Similarly at Revealing Metabolite-Age Correlations at 3 T

   Steve C. N. Hui, Helge J. Zöllner, Tao Gong, and 9 more authors

   Magnetic Resonance in Medicine, Mar 2024

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   Purpose To compare the respective ability of PRESS and sLASER to reveal biological relationships, using age as a validation covariate at 3 T. Methods MRS data were acquired from 102 healthy volunteers using PRESS and sLASER in centrum semiovale and posterior cingulate cortex (PCC). Acquisition parameters included TR/TE = 2000/30 ms, 96 transients, and 2048 datapoints sampled at 2 kHz. Spectra were analyzed using Osprey. SNR, FWHM linewidth of total creatine, and metabolite concentrations were extracted. A linear model was used to compare SNR and linewidth. Paired t-tests were used to assess differences in metabolite measurements between PRESS and sLASER. Correlations were used to evaluate the relationship between PRESS and sLASER metabolite estimates, as well as the strength of each metabolite-age relationship. Coefficients of variation were calculated to assess inter-subject variability in each metabolite measurement. Results SNR and linewidth were significantly higher (p < 0.01) for sLASER than PRESS in PCC. Paired t-tests showed significant differences between PRESS and sLASER in most metabolite measurements. PRESS-sLASER measurements were significantly correlated (p < 0.05) for most metabolites. Metabolite-age relationships were consistently identified using both methods. Similar coefficients of variation were observed for most metabolites. Conclusion The study results suggest strong agreement between PRESS and sLASER in identifying relationships between brain metabolites and age in centrum semiovale and PCC data acquired at 3 T. sLASER is technically desirable due to the reduced chemical shift displacement artifact; however, PRESS performed similarly in homogeneous brain regions at clinical field strength.

3. Impact of Acquisition and Modeling Parameters on the Test–Retest Reproducibility of Edited GABA+

   Kathleen E. Hupfeld, Helge J. Zöllner, Steve C. N. Hui, and 6 more authors

   NMR in Biomedicine, Mar 2024

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   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.

4. Diffusion-Weighted MR Spectroscopy: Consensus, Recommendations, and Resources from Acquisition to Modeling

   Clémence Ligneul, Chloé Najac, André Döring, and 24 more authors

   Magnetic Resonance in Medicine, Mar 2024

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   Brain cell structure and function reflect neurodevelopment, plasticity, and aging; and changes can help flag pathological processes such as neurodegeneration and neuroinflammation. Accurate and quantitative methods to noninvasively disentangle cellular structural features are needed and are a substantial focus of brain research. Diffusion-weighted MRS (dMRS) gives access to diffusion properties of endogenous intracellular brain metabolites that are preferentially located inside specific brain cell populations. Despite its great potential, dMRS remains a challenging technique on all levels: from the data acquisition to the analysis, quantification, modeling, and interpretation of results. These challenges were the motivation behind the organization of the Lorentz Center workshop on “Best Practices & Tools for Diffusion MR Spectroscopy” held in Leiden, the Netherlands, in September 2021. During the workshop, the dMRS community established a set of recommendations to execute robust dMRS studies. This paper provides a description of the steps needed for acquiring, processing, fitting, and modeling dMRS data, and provides links to useful resources.

5. Metabolite T1 Relaxation Times Decrease across the Adult Lifespan

   Saipavitra Murali-Manohar, Aaron T. Gudmundson, Kathleen E. Hupfeld, and 9 more authors

   NMR in Biomedicine, Mar 2024

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   Relaxation correction is an integral step in quantifying brain metabolite concentrations measured by in vivo magnetic resonance spectroscopy (MRS). While most quantification routines assume constant T1 relaxation across age, it is possible that aging alters T1 relaxation rates, as is seen for T2 relaxation. Here, we investigate the age dependence of metabolite T1 relaxation times at 3 T in both gray- and white-matter-rich voxels using publicly available metabolite and metabolite-nulled (single inversion recovery TI = 600 ms) spectra acquired at 3 T using Point RESolved Spectroscopy (PRESS) localization. Data were acquired from voxels in the posterior cingulate cortex (PCC) and centrum semiovale (CSO) in 102 healthy volunteers across 5 decades of life (aged 20–69 years). All spectra were analyzed in Osprey v.2.4.0. To estimate T1 relaxation times for total N-acetyl aspartate at 2.0 ppm (tNAA2.0) and total creatine at 3.0 ppm (tCr3.0), the ratio of modeled metabolite residual amplitudes in the metabolite-nulled spectrum to the full metabolite signal was calculated using the single-inversion-recovery signal equation. Correlations between T1 and subject age were evaluated. Spearman correlations revealed that estimated T1 relaxation times of tNAA2.0 (rs = −0.27; p < 0.006) and tCr3.0 (rs = −0.40; p < 0.001) decreased significantly with age in white-matter-rich CSO, and less steeply for tNAA2.0 (rs = −0.228; p = 0.005) and (not significantly for) tCr3.0 (rs = −0.13; p = 0.196) in graymatter-rich PCC. The analysis harnessed a large publicly available cross-sectional dataset to test an important hypothesis, that metabolite T1 relaxation times change with age. This preliminary study stresses the importance of further work to measure age-normed metabolite T1 relaxation times for accurate quantification of metabolite levels in studies of aging.

6. Glutamate Measurements Using Edited MRS

   Muhammad G. Saleh, Andrew Prescot, Linda Chang, and 9 more authors

   Magnetic Resonance in Medicine, Mar 2024

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

7. Brain Glutathione and GABA+ Levels in Autistic Children

   Yulu Song, Kathleen E. Hupfeld, Christopher W. Davies-Jenkins, and 11 more authors

   Autism Research, Mar 2024

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   Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication challenges and repetitive behaviors. Altered neurometabolite levels, including glutathione (GSH) and gamma-aminobutyric acid (GABA), have been proposed as potential contributors to the biology underlying ASD. This study investigated whether cerebral GSH or GABA levels differ between a cohort of children aged 8–12 years with ASD (n = 52) and typically developing children (TDC, n = 49). A comprehensive analysis of GSH and GABA levels in multiple brain regions, including the primary motor cortex (SM1), thalamus (Thal), medial prefrontal cortex (mPFC), and supplementary motor area (SMA), was conducted using single-voxel HERMES MR spectroscopy at 3T. The results revealed no significant differences in cerebral GSH or GABA levels between the ASD and TDC groups across all examined regions. These findings suggest that the concentrations of GSH (an important antioxidant and neuromodulator) and GABA (a major inhibitory neurotransmitter) do not exhibit marked alterations in children with ASD compared to TDC. A statistically significant positive correlation was observed between GABA levels in the SM1 and Thal regions with ADHD inattention scores. No significant correlation was found between metabolite levels and hyper/impulsive scores of ADHD, measures of core ASD symptoms (ADOS-2, SRS-P) or adaptive behavior (ABAS-2). While both GSH and GABA have been implicated in various neurological disorders, the current study provides valuable insights into the specific context of ASD and highlights the need for further research to explore other neurochemical alterations that may contribute to the pathophysiology of this complex disorder.

8. Editorial: Variability and Reproducibility of Brain Imaging

   Meng-Yun Wang, Helge J. Zöllner, Meryem A. Yücel, and 1 more author

   Frontiers in Psychology, Mar 2024
9. Simultaneous Multi-Transient Linear-Combination Modeling of MRS Data Improves Uncertainty Estimation

   Helge Jörn Zöllner, Christopher Davies-Jenkins, Dunja Simicic, and 3 more authors

   Magnetic Resonance in Medicine, Mar 2024

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   Purpose The interest in applying and modeling dynamic MRS has recently grown. Two-dimensional modeling yields advantages for the precision of metabolite estimation in interrelated MRS data. However, it is unknown whether including all transients simultaneously in a 2D model without averaging (presuming a stable signal) performs similarly to one-dimensional (1D) modeling of the averaged spectrum. Therefore, we systematically investigated the accuracy, precision, and uncertainty estimation of both described model approaches. Methods Monte Carlo simulations of synthetic MRS data were used to compare the accuracy and uncertainty estimation of simultaneous 2D multitransient linear-combination modeling (LCM) with 1D-LCM of the average. A total of 2,500 data sets per condition with different noise representations of a 64-transient MRS experiment at six signal-to-noise levels for two separate spin systems (scyllo-inositol and gamma-aminobutyric acid) were analyzed. Additional data sets with different levels of noise correlation were also analyzed. Modeling accuracy was assessed by determining the relative bias of the estimated amplitudes against the ground truth, and modeling precision was determined by SDs and Cramér-Rao lower bounds (CRLBs). Results Amplitude estimates for 1D- and 2D-LCM agreed well and showed a similar level of bias compared with the ground truth. Estimated CRLBs agreed well between both models and with ground-truth CRLBs. For correlated noise, the estimated CRLBs increased with the correlation strength for the 1D-LCM but remained stable for the 2D-LCM. Conclusion Our results indicate that the model performance of 2D multitransient LCM is similar to averaged 1D-LCM. This validation on a simplified scenario serves as a necessary basis for further applications of 2D modeling.

2023

1. Altered Glutamate–Glutamine and Amide Proton Transfer-Weighted Values in the Hippocampus of Patients with Amnestic Mild Cognitive Impairment: A Novel Combined Imaging Diagnostic Marker

   Xin Chen, Tao Gong, Tong Chen, and 8 more authors

   Frontiers in Neuroscience, Feb 2023

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   Early diagnosis of amnestic mild cognitive impairment (aMCI) and timely management to delay the onset of Alzheimer’s disease (AD) would benefit patients. Pathological metabolic changes of excitatory/inhibitory neurotransmitters and abnormal protein deposition in the hippocampus of aMCI may provide a new clue to imaging diagnosis. However, the diagnostic performance using these hippocampal metabolite measurements is still unclear. We aimed to quantify right hippocampal glutamate–glutamine (Glx) and gamma-aminobutyric acid (GABA) levels as well as protein-based amide proton transfer-weighted (APTw) signals of patients with aMCI and investigate the diagnostic performance of these metabolites.

   In this cross-sectional study, 20 patients with aMCI and 20 age- and gender-matched healthy controls (HCs) underwent MEGA Point Resolved Spectroscopy (MEGA-PRESS) and APTw MR imaging at 3 T. GABA+, Glx, and APTw signals were measured in the right hippocampus. The GABA+ levels, Glx levels, Glx/GABA+ ratios, and APTw values were compared between the HCs and aMCI groups using the Mann–Whitney U test. Binary logistic regression and receiver operating characteristic (ROC) curve analyses were used to evaluate MEGA-PRESS and APTw parameters’ diagnostic performance.

   Compared with HCs, patients with aMCI had significantly lower Glx levels in the right hippocampus (7.02 ± 1.41 i.u. vs. 5.81 ± 1.33 i.u., P = 0.018). No significant changes in the GABA+ levels were observed in patients with aMCI (HCs vs. aMCI: 2.54 ± 0.28 i.u. vs. 2.47 ± 0.36 i.u., P = 0.620). In addition, Glx/GABA+ ratios between the two groups (HCs vs. aMCI: 2.79 ± 0.60 vs. 2.37 ± 0.55, P = 0.035) were significantly different. Compared with HCs, patients with aMCI showed higher APTw values in the right hippocampus (0.99 ± 0.26% vs. 1.26% ± 0.28, P = 0.006). The ROC curve analysis showed that Glx, GABA+, Glx/GABA+, and APTw values had an area under the curve (AUC) of 0.72, 0.55, 0.70, and 0.75, respectively, for diagnosing aMCI. In the ROC curve analysis, the AUC of the combination of the parameters increased to 0.88, which is much higher than that observed in the univariate analysis (P < 0.05).

   The combination of right hippocampal Glx levels and APTw values improved the diagnostic performance for aMCI, indicating it as a promising combined imaging diagnostic marker. Our study provided a potential imaging diagnostic strategy of aMCI, which may promote early detection of aMCI and facilitate timely intervention to delay the pathological progress toward AD.

2. Practical Considerations of Diffusion-Weighted MRS with Ultra-Strong Diffusion Gradients

   Christopher W. Davies-Jenkins, André Döring, Fabrizio Fasano, and 8 more authors

   Frontiers in Neuroscience, Dec 2023

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   Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) offers improved cellular specificity to microstructure—compared to water-based methods alone—but spatial resolution and SNR is severely reduced and slow-diffusing metabolites necessitate higher b-values to accurately characterize their diffusion properties. Ultra-strong gradients allow access to higher b-values per-unit time, higher SNR for a given b-value, and shorter diffusion times, but introduce additional challenges such as eddy-current artefacts, gradient non-uniformity, and mechanical vibrations.

   In this work, we present initial DW-MRS data acquired on a 3T Siemens Connectom scanner equipped with ultra-strong (300 mT/m) gradients. We explore the practical issues associated with this manner of acquisition, the steps that may be taken to mitigate their impact on the data, and the potential benefits of ultra-strong gradients for DW-MRS. An in-house DW-PRESS sequence and data processing pipeline were developed to mitigate the impact of these confounds. The interaction of TE, b-value, and maximum gradient amplitude was investigated using simulations and pilot data, whereby maximum gradient amplitude was restricted. Furthermore, two DW-MRS voxels in grey and white matter were acquired using ultra-strong gradients and high b-values.

   Simulations suggest T\textsubscript2-based SNR gains that are experimentally confirmed. Ultra-strong gradient acquisitions exhibit similar artefact profiles to those of lower gradient amplitude, suggesting adequate performance of artefact mitigation strategies. Gradient field non-uniformity influenced ADC estimates by up to 4% when left uncorrected. ADC and Kurtosis estimates for tNAA, tCho, and tCr align with previously published literature.

   In conclusion, we successfully implemented acquisition and data processing strategies for ultra-strong gradient DW-MRS and results indicate that confounding effects of the strong gradient system can be ameliorated, while achieving shorter diffusion times and improved metabolite SNR.

3. Fecal Microbial Transplantation Limits Neural Injury Severity and Functional Deficits in a Pediatric Piglet Traumatic Brain Injury Model

   Madison M. Fagan, Christina B. Welch, Kelly M. Scheulin, and 12 more authors

   Frontiers in Neuroscience, Sep 2023

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   Pediatric traumatic brain injury (TBI) is a leading cause of death and disability in children. Due to bidirectional communication between the brain and gut microbial population, introduction of key gut bacteria may mitigate critical TBI-induced secondary injury cascades, thus lessening neural damage and improving functional outcomes. The objective of this study was to determine the efficacy of a daily fecal microbial transplant (FMT) to alleviate neural injury severity, prevent gut dysbiosis, and improve functional recovery post TBI in a translational pediatric piglet model. Male piglets at 4-weeks of age were randomly assigned to Sham + saline, TBI + saline, or TBI + FMT treatment groups. A moderate/severe TBI was induced by controlled cortical impact and Sham pigs underwent craniectomy surgery only. FMT or saline were administered by oral gavage daily for 7 days. MRI was performed 1 day (1D) and 7 days (7D) post TBI. Fecal and cecal samples were collected for 16S rRNA gene sequencing. Ipsilateral brain and ileum tissue samples were collected for histological assessment. Gait and behavior testing were conducted at multiple timepoints. MRI showed that FMT treated animals demonstrated decreased lesion volume and hemorrhage volume at 7D post TBI as compared to 1D post TBI. Histological analysis revealed improved neuron and oligodendrocyte survival and restored ileum tissue morphology at 7D post TBI in FMT treated animals. Microbiome analysis indicated decreased dysbiosis in FMT treated animals with an increase in multiple probiotic Lactobacilli species, associated with anti-inflammatory therapeutic effects, in the cecum of the FMT treated animals, while non-treated TBI animals showed an increase in pathogenic bacteria, associated with inflammation and disease such in feces. FMT mediated enhanced cellular and tissue recovery resulted in improved motor function including stride and step length and voluntary motor activity in FMT treated animals. Here we report for the first time in a highly translatable pediatric piglet TBI model, the potential of FMT treatment to significantly limit cellular and tissue damage leading to improved functional outcomes following a TBI.

4. Meta-Analysis and Open-Source Database for in Vivo Brain Magnetic Resonance Spectroscopy in Health and Disease

   Aaron T. Gudmundson, Annie Koo, Anna Virovka, and 6 more authors

   Analytical Biochemistry, Sep 2023

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   Proton (1H) Magnetic Resonance Spectroscopy (MRS) is a non-invasive tool capable of quantifying brain metabolite concentrations in vivo. Prioritization of standardization and accessibility in the field has led to the development of universal pulse sequences, methodological consensus recommendations, and the development of open-source analysis software packages. One on-going challenge is methodological validation with ground-truth data. As ground-truths are rarely available for in vivo measurements, data simulations have become an important tool. The diverse literature of metabolite measurements has made it challenging to define ranges to be used within simulations. Especially for the development of deep learning and machine learning algorithms, simulations must be able to produce accurate spectra capturing all the nuances of in vivo data. Therefore, we sought to determine the physiological ranges and relaxation rates of brain metabolites which can be used both in data simulations and as reference estimates. Using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, we’ve identified relevant MRS research articles and created an open-source database containing methods, results, and other article information as a resource. Using this database, expectation values and ranges for metabolite concentrations and T2 relaxation times are established based upon a meta-analyses of healthy and diseased brains.

5. Harmonization of Multi-Scanner in Vivo Magnetic Resonance Spectroscopy: ENIGMA Consortium Task Group Considerations

   Ashley D. Harris, Houshang Amiri, Mariana Bento, and 19 more authors

   Frontiers in Neurology, Jan 2023

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   Magnetic resonance spectroscopy is a powerful, non-invasive, quantitative imaging technique that allows for the measurement of brain metabolites that has demonstrated utility in diagnosing and characterizing a broad range of neurological diseases. Its impact, however, has been limited due to small sample sizes and methodological variability in addition to intrinsic limitations of the method itself such as its sensitivity to motion. The lack of standardization from a data acquisition and data processing perspective makes it difficult to pool multiple studies and/or conduct multisite studies that are necessary for supporting clinically relevant findings. Based on the experience of the ENIGMA MRS work group and a review of the literature, this manuscript provides an overview of the current state of MRS data harmonization. Key factors that need to be taken into consideration when conducting both retrospective and prospective studies are described. These include (1) MRS acquisition issues such as pulse sequence, RF and B0 calibrations, echo time, and SNR; (2) data processing issues such as pre-processing steps, modeling, and quantitation; and (3) biological factors such as voxel location, age, sex, and pathology. Various approaches to MRS data harmonization are then described including meta-analysis, mega-analysis, linear modeling, ComBat and artificial intelligence approaches. The goal is to provide both novice and experienced readers with the necessary knowledge for conducting MRS data harmonization studies.

6. Brain Total Creatine Differs between Primary Progressive Aphasia (PPA) Subtypes and Correlates with Disease Severity

   Kathleen E. Hupfeld, Helge J. Zöllner, Georg Oeltzschner, and 7 more authors

   Neurobiology of Aging, Feb 2023

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   Primary progressive aphasia (PPA) is comprised of three subtypes: logopenic (lvPPA), non-fluent (nfvPPA), and semantic (svPPA). We used magnetic resonance spectroscopy (MRS) to measure tissue-corrected metabolite levels in the left inferior frontal gyrus (IFG) and right sensorimotor cortex (SMC) from 61 PPA patients. We aimed to: (1) characterize subtype differences in metabolites; and (2) test for metabolite associations with symptom severity. tCr differed by subtype across the left IFG and right SMC. tCr levels were lowest in lvPPA and highest in svPPA. tCr levels predicted lvPPA versus svPPA diagnosis. Higher IFG tCr and lower Glx correlated with greater disease severity. As tCr is involved in brain energy metabolism, svPPA pathology might involve changes in specific cellular energy processes. Perturbations to cellular energy homeostasis in language areas may contribute to symptoms. Reduced cortical excitatory capacity (i.e. lower Glx) in language regions may also contribute to symptoms. Thus, tCr may be useful for differentiating between PPA subtypes, and both tCr and Glx might have utility in understanding PPA mechanisms and tracking progression.

7. In-Vivo Magnetic Resonance Spectroscopy of Lactate as a Non-Invasive Biomarker of Dichloroacetate Activity in Cancer and Non-Cancer Central Nervous System Disorders

   David O. Kamson, Viveka Chinnasamy, Stuart A. Grossman, and 4 more authors

   Frontiers in Oncology, Mar 2023

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   The adverse effects of lactic acidosis in the cancer microenvironment have been increasingly recognized. Dichloroacetate (DCA) is an orally bioavailable, blood brain barrier penetrable drug that has been extensively studied in the treatment of mitochondrial neurologic conditions to reduce lactate production. Due to its effect reversing aerobic glycolysis (i.e., Warburg-effect) and thus lactic acidosis, DCA became a drug of interest in cancer as well. Magnetic resonance spectroscopy (MRS) is a well-established, non-invasive technique that allows detection of prominent metabolic changes, such as shifts in lactate or glutamate levels. Thus, MRS is a potential radiographic biomarker to allow spatial and temporal mapping of DCA treatment. In this systematic literature review, we gathered the available evidence on the use of various MRS techniques to track metabolic changes after DCA administration in neurologic and oncologic disorders. We included in vitro, animal, and human studies. Evidence confirms that DCA has substantial effects on lactate and glutamate levels in neurologic and oncologic disease, which are detectable by both experimental and routine clinical MRS approaches. Data from mitochondrial diseases show slower lactate changes in the central nervous system (CNS) that correlate better with clinical function compared to blood. This difference is most striking in focal impairments of lactate metabolism suggesting that MRS might provide data not captured by solely monitoring blood. In summary, our findings corroborate the feasibility of MRS as a pharmacokinetic/pharmacodynamic biomarker of DCA delivery in the CNS, that is ready to be integrated into currently ongoing and future human clinical trials using DCA.

8. Increased Cerebral Lactate Levels in Adults with Autism Spectrum Disorders Compared to Non-Autistic Controls: A Magnetic Resonance Spectroscopy Study

   Simon Maier, Kathrin Nickel, Thomas Lange, and 8 more authors

   Molecular Autism, Nov 2023

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   Autism spectrum disorder (ASD) encompasses a heterogeneous group with varied phenotypes and etiologies. Identifying pathogenic subgroups could facilitate targeted treatments. One promising avenue is investigating energy metabolism, as mitochondrial dysfunction has been implicated in a subgroup of ASD. Lactate, an indicator of energy metabolic anomalies, may serve as a potential biomarker for this subgroup. This study aimed to examine cerebral lactate (Lac+) levels in high-functioning adults with ASD, hypothesizing elevated mean Lac+ concentrations in contrast to neurotypical controls (NTCs).

9. Large-Scale Momentary Brain Co-Activation Patterns Are Associated with Hyperalgesia and Mediate Focal Neurochemistry and Cross-Network Functional Connectivity in Fibromyalgia

   Ishtiaq Mawla, Zirui Huang, Chelsea M. Kaplan, and 10 more authors

   PAIN, Dec 2023

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   Fibromyalgia has been characterized by augmented cross-network functional communication between the brain’s sensorimotor, default mode, and attentional (salience/ventral and dorsal) networks. However, the underlying mechanisms of these aberrant communication patterns are unknown. In this study, we sought to understand large-scale topographic patterns at instantaneous timepoints, known as co-activation patterns (CAPs). We found that a sustained pressure pain challenge temporally modulated the occurrence of CAPs. Using proton magnetic resonance spectroscopy, we found that greater basal excitatory over inhibitory neurotransmitter levels within the anterior insula orchestrated higher cross-network connectivity between the anterior insula and the default mode network through lower occurrence of a CAP encompassing the attentional networks during sustained pain. Moreover, we found that hyperalgesia in fibromyalgia was mediated through increased occurrence of a CAP encompassing the sensorimotor network during sustained pain. In conclusion, this study elucidates the role of momentary large-scale topographic brain patterns in shaping noxious information in patients with fibromyalgia, while laying the groundwork for using precise spatiotemporal dynamics of the brain for the potential development of therapeutics.

10. Functional MRS Studies of GABA and Glutamate/Glx – A Systematic Review and Meta-Analysis

    Duanghathai Pasanta, Jason L. He, Talitha Ford, and 3 more authors

    Neuroscience & Biobehavioral Reviews, Jan 2023

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    Functional magnetic resonance spectroscopy (fMRS) can be used to investigate neurometabolic responses to external stimuli in-vivo, but findings are inconsistent. We performed a systematic review and meta-analysis on fMRS studies of the primary neurotransmitters Glutamate (Glu), Glx (Glutamate + Glutamine), and GABA. Data were extracted, grouped by metabolite, stimulus domain, and brain region, and analysed by determining standardized effect sizes. The quality of individual studies was rated. When results were analysed by metabolite type small to moderate effect sizes of 0.29–0.47 (p < 0.05) were observed for changes in Glu and Glx regardless of stimulus domain and brain region, but no significant effects were observed for GABA. Further analysis suggests that Glu, Glx and GABA responses differ by stimulus domain or task and vary depending on the time course of stimulation and data acquisition. Here, we establish effect sizes and directionality of GABA, Glu and Glx response in fMRS. This work highlights the importance of standardised reporting and minimal best practice for fMRS research.

11. A Comprehensive Guide to MEGA-PRESS for GABA Measurement

    A. L. Peek, T. J. Rebbeck, A. M. Leaver, and 25 more authors

    Analytical Biochemistry, May 2023

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    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.

12. More than One-Half of the Variance in in Vivo Proton MR Spectroscopy Metabolite Estimates Is Common to All Metabolites

    James J. Prisciandaro, Helge J. Zöllner, Saipavitra Murali-Manohar, and 2 more authors

    NMR in Biomedicine, May 2023

    Abs

    The present study characterized associations among brain metabolite levels, applying bivariate and multivariate (i.e., factor analysis) statistical methods to total creatine (tCr)-referenced estimates of the major Point RESolved Spectroscopy (PRESS) proton MR spectroscopy (1H-MRS) metabolites (i.e., total NAA/tCr, total choline/tCr, myo-inositol/tCr, glutamate + glutamine/tCr) acquired at 3 T from medial parietal lobe in a large (n = 299), well-characterized international cohort of healthy volunteers. Results supported the hypothesis that 1H-MRS–measured metabolite estimates are moderately intercorrelated (Mr = 0.42, SDr = 0.11, ps < 0.001), with more than one-half (i.e., 57%) of the total variability in metabolite estimates explained by a single common factor. Older age was significantly associated with lower levels of the identified common metabolite variance (CMV) factor (β = −0.09, p = 0.048), despite not being associated with levels of any individual metabolite. Holding CMV factor levels constant, females had significantly lower levels of total choline (i.e., unique metabolite variance; β = −0.19, p < 0.001), mirroring significant bivariate correlations between sex and total choline reported previously. Supplementary analysis of water-referenced metabolite estimates (i.e., including tCr/water) demonstrated lower, although still substantial, intercorrelations among metabolites, with 37% of total metabolite variance explained by a single common factor. If replicated, these results would suggest that applied 1H-MRS researchers shift their analytical framework from examining bivariate associations between individual metabolites and specialty-dependent (e.g., clinical, research) variables of interest (e.g., using t-tests) to examining multivariable (i.e., covariate) associations between multiple metabolites and specialty-dependent variables of interest (e.g., using multiple regression).

13. Impact of Gradient Scheme and Non-Linear Shimming on out-of-Voxel Echo Artifacts in Edited MRS

    Yulu Song, Helge J. Zöllner, Steve C. N. Hui, and 3 more authors

    NMR in Biomedicine, May 2023

    Abs

    Out-of-voxel (OOV) signals are common spurious echo artifacts in MRS. These signals often manifest in the spectrum as very strong “ripples,” which interfere with spectral quantification by overlapping with targeted metabolite resonances. Dephasing optimization through coherence order pathway selection (DOTCOPS) gradient schemes are algorithmically optimized to suppress all potential alternative coherence transfer pathways (CTPs), and should suppress unwanted OOV echoes. In addition, second-order shimming uses non-linear gradient fields to maximize field homogeneity inside the voxel, which unfortunately increases the diversity of local gradient fields outside of the voxel. Given that strong local spatial B0 gradients can refocus unintended CTPs, it is possible that OOVs are less prevalent when only linear first-order shimming is applied. Here we compare the size of unwanted OOV signals in Hadamard-edited (HERMES) data acquired with either a local gradient scheme (which we refer to here as “Shared”) or DOTCOPS, and with first- or second-order shimming. We collected data from 15 healthy volunteers in two brain regions (voxel size 30 × 26 × 26 mm3) from which it is challenging to acquire MRS data: medial prefrontal cortex and left temporal cortex. Characteristic OOV echoes were seen in both GABA- and GSH-edited spectra for both brain regions, gradient schemes, and shimming approaches. A linear mixed-effect model revealed a statistically significant difference in the average residual based on the gradient scheme in both GABA- (p < 0.001) and GSH-edited (p < 0.001) spectra: that is, the DOTCOPS gradient scheme resulted in smaller OOV artifacts compared with the Shared scheme. There were no significant differences in OOV artifacts associated with shimming method. Thus, these results suggest that the DOTCOPS gradient scheme for J-difference-edited PRESS acquisitions yields spectra with smaller OOV echo artifacts than the Shared gradient scheme implemented in a widely disseminated editing sequence.

14. Image Downsampling Expedited Adaptive Least-Squares (IDEAL) Fitting Improves Intravoxel Incoherent Motion (IVIM) Analysis in the Human Kidney

    Julia Stabinska, Helge J. Zöllner, Thomas A. Thiel, and 2 more authors

    Magnetic Resonance in Medicine, May 2023

    Abs

    Purpose To improve the reliability of intravoxel incoherent motion (IVIM) model parameter estimation for the DWI in the kidney using a novel image downsampling expedited adaptive least-squares (IDEAL) approach. Methods The robustness of IDEAL was investigated using simulated DW-MRI data corrupted with different levels of Rician noise. Subsequently, the performance of the proposed method was tested by fitting bi- and triexponential IVIM model to in vivo renal DWI data acquired on a clinical 3 Tesla MRI scanner and compared to conventional approaches (fixed D* and segmented fitting). Results The numerical simulations demonstrated that the IDEAL algorithm provides robust estimates of the IVIM parameters in the presence of noise (SNR of 20) as indicated by relatively low absolute percentage bias (maximal sMdPB <20%) and normalized RMSE (maximal RMSE <28%). The analysis of the in vivo data showed that the IDEAL-based IVIM parameter maps were less noisy and more visually appealing than those obtained using the fixed D* and segmented methods. Further, coefficients of variation for nearly all IVIM parameters were significantly reduced in cortex and medulla for IDEAL-based biexponential (coefficients of variation: 4%–50%) and triexponential (coefficients of variation: 7.5%–75%) IVIM modelling compared to the segmented (coefficients of variation: 4%–120%) and fixed D* (coefficients of variation: 17%–174%) methods, reflecting greater accuracy of this method. Conclusion The proposed fitting algorithm yields more robust IVIM parameter estimates and is less susceptible to poor SNR than the conventional fitting approaches. Thus, the IDEAL approach has the potential to improve the reliability of renal DW-MRI analysis for clinical applications.

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

    Josua Zimmermann, Niklaus Zölch, Rebecca Coray, and 12 more authors

    International Journal of Neuropsychopharmacology, Jun 2023

    Abs

    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.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.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.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.

16. Continuous Automated Analysis Workflow for MRS Studies

    Helge Jörn Zöllner, Christopher W. Davies-Jenkins, Erik G. Lee, and 6 more authors

    Journal of Medical Systems, Jul 2023

    Abs

    Magnetic resonance spectroscopy (MRS) can non-invasively measure levels of endogenous metabolites in living tissue and is of great interest to neuroscience and clinical research. To this day, MRS data analysis workflows differ substantially between groups, frequently requiring many manual steps to be performed on individual datasets, e.g., data renaming/sorting, manual execution of analysis scripts, and manual assessment of success/failure. Manual analysis practices are a substantial barrier to wider uptake of MRS. They also increase the likelihood of human error and prevent deployment of MRS at large scale. Here, we demonstrate an end-to-end workflow for fully automated data uptake, processing, and quality review.

17. Feasibility and Implications of Using Subject-Specific Macromolecular Spectra to Model Short Echo Time Magnetic Resonance Spectroscopy Data

    Helge J. Zöllner, Christopher W. Davies-Jenkins, Saipavitra Murali-Manohar, and 7 more authors

    NMR in Biomedicine, Jul 2023

    Abs

    Expert consensus recommends linear-combination modeling (LCM) of 1H MR spectra with sequence-specific simulated metabolite basis function and experimentally derived macromolecular (MM) basis functions. Measured MM basis functions are usually derived from metabolite-nulled spectra averaged across a small cohort. The use of subject-specific instead of cohort-averaged measured MM basis functions has not been studied widely. Furthermore, measured MM basis functions are not widely available to non-expert users, who commonly rely on parameterized MM signals internally simulated by LCM software. To investigate the impact of the choice of MM modeling, this study, therefore, compares metabolite level estimates between different MM modeling strategies (cohort-mean measured; subject-specific measured; parameterized) in a lifespan cohort and characterizes its impact on metabolite–age associations. 100 conventional (TE = 30 ms) and metabolite-nulled (TI = 650 ms) PRESS datasets, acquired from the medial parietal lobe in a lifespan cohort (20–70 years of age), were analyzed in Osprey. Short-TE spectra were modeled in Osprey using six different strategies to consider the MM baseline. Fully tissue- and relaxation-corrected metabolite levels were compared between MM strategies. Model performance was evaluated by model residuals, the Akaike information criterion (AIC), and the impact on metabolite–age associations. The choice of MM strategy had a significant impact on the mean metabolite level estimates and no major impact on variance. Correlation analysis revealed moderate-to-strong agreement between different MM strategies (r > 0.6). The lowest relative model residuals and AIC values were found for the cohort-mean measured MM. Metabolite–age associations were consistently found for two major singlet signals (total creatine (tCr])and total choline (tCho)) for all MM strategies; however, findings for metabolites that are less distinguishable from the background signals associations depended on the MM strategy. A variance partition analysis indicated that up to 44% of the total variance was related to the choice of MM strategy. Additionally, the variance partition analysis reproduced the metabolite–age association for tCr and tCho found in the simpler correlation analysis. In summary, the inclusion of a single high signal-to-noise ratio MM basis function (cohort-mean) in the short-TE LCM leads to more lower model residuals and AIC values compared with MM strategies with more degrees of freedom (Gaussian parametrization) or subject-specific MM information. Integration of multiple LCM analyses into a single statistical model potentially allows to identify the robustness in the detection of underlying effects (e.g., metabolite vs. age), reduces algorithm-based bias, and estimates algorithm-related variance.

2022

1. NIfTI-MRS: A Standard Data Format for Magnetic Resonance Spectroscopy

   William T. Clarke, Tiffany K. Bell, Uzay E. Emir, and 5 more authors

   Magnetic Resonance in Medicine, Jul 2022

   Abs

   Purpose Multiple data formats in the MRS community currently hinder data sharing and integration. NIfTI-MRS is proposed as a standard spectroscopy data format, implemented as an extension to the Neuroimaging informatics technology initiative (NIfTI) format. This standardized format can facilitate data sharing and algorithm development as well as ease integration of MRS analysis alongside other imaging modalities. Methods A file format using the NIfTI header extension framework incorporates essential spectroscopic metadata and additional encoding dimensions. A detailed description of the specification is provided. An open-source command-line conversion program is implemented to convert single-voxel and spectroscopic imaging data to NIfTI-MRS. Visualization of data in NIfTI-MRS is provided by development of a dedicated plugin for FSLeyes, the FMRIB Software Library (FSL) image viewer. Results Online documentation and 10 example datasets in the proposed format are provided. Code examples of NIfTI-MRS readers are implemented in common programming languages. Conversion software, spec2nii, currently converts 14 formats where data is stored in image-space to NIfTI-MRS, including Digital Imaging and Communications in Medicine (DICOM) and vendor proprietary formats. Conclusion NIfTI-MRS aims to solve issues arising from multiple data formats being used in the MRS community. Through a single conversion point, processing and analysis of MRS data are simplified, thereby lowering the barrier to use of MRS. Furthermore, it can serve as the basis for open data sharing, collaboration, and interoperability of analysis programs. Greater standardization and harmonization become possible. By aligning with the dominant format in neuroimaging, NIfTI-MRS enables the use of mature tools present in the imaging community, demonstrated in this work by using a dedicated imaging tool, FSLeyes, for visualization.

2. Comparison of Seven Modelling Algorithms for γ-Aminobutyric Acid–Edited Proton Magnetic Resonance Spectroscopy

   Alexander R. Craven, Pallab K. Bhattacharyya, William T. Clarke, and 14 more authors

   NMR in Biomedicine, Jul 2022

   Abs

   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.

3. Neurometabolic Timecourse of Healthy Aging

   Tao Gong, Steve C. N. Hui, Helge J. Zöllner, and 12 more authors

   NeuroImage, Dec 2022

   Abs

   Purpose The neurometabolic timecourse of healthy aging is not well-established, in part due to diversity of quantification methodology. In this study, a large structured cross-sectional cohort of male and female subjects throughout adulthood was recruited to investigate neurometabolic changes as a function of age, using consensus-recommended magnetic resonance spectroscopy quantification methods. Methods 102 healthy volunteers, with approximately equal numbers of male and female participants in each decade of age from the 20s, 30s, 40s, 50s, and 60s, were recruited with IRB approval. MR spectroscopic data were acquired on a 3T MRI scanner. Metabolite spectra were acquired using PRESS localization (TE=30 ms; 96 transients) in the centrum semiovale (CSO) and posterior cingulate cortex (PCC). Water-suppressed spectra were modeled using the Osprey algorithm, employing a basis set of 18 simulated metabolite basis functions and a cohort-mean measured macromolecular spectrum. Pearson correlations were conducted to assess relationships between metabolite concentrations and age for each voxel; Spearman correlations were conducted where metabolite distributions were non-normal. Paired t-tests were run to determine whether metabolite concentrations differed between the PCC and CSO. Finally, robust linear regressions were conducted to assess both age and sex as predictors of metabolite concentrations in the PCC and CSO and separately, to assess age, signal-noise ratio, and full width half maximum (FWHM) linewidth as predictors of metabolite concentrations. Results Data from four voxels were excluded (2 ethanol; 2 unacceptably large lipid signal). Statistically-significant age*metabolite Pearson correlations were observed for tCho (r(98)=0.33, p<0.001), tCr (r(98)=0.60, p<0.001), and mI (r(98)=0.32, p=0.001) in the CSO and for NAAG (r(98)=0.26, p=0.008), tCho(r(98)=0.33, p<0.001), tCr (r(98)=0.39, p<0.001), and Gln (r(98)=0.21, p=0.034) in the PCC. Spearman correlations for non-normal variables revealed a statistically significant correlation between sI and age in the CSO (r(86)=0.26, p=0.013). No significant correlations were seen between age and tNAA, NAA, Glx, Glu, GSH, PE, Lac, or Asp in either region (all p>0.20). Age associations for tCho, tCr, mI and sI in the CSO and for NAAG, tCho, and tCr in the PCC remained when controlling for sex in robust regressions. CSO NAAG and Asp, as well as PCC tNAA, sI, and Lac were higher in women; PCC Gln was higher in men. When including an age*sex interaction term in robust regression models, a significant age*sex interaction was seen for tCho (F(1,96)=11.53, p=0.001) and GSH (F(1,96)=7.15, p=0.009) in the CSO and tCho (F(1,96)=9.17, p=0.003), tCr (F(1,96)=9.59, p=0.003), mI (F(1,96)=6.48, p=0.012), and Lac (F(1,78)=6.50, p=0.016) in the PCC. In all significant interactions, metabolite levels increased with age in females, but not males. There was a significant positive correlation between linewidth and age. Age relationships with tCho, tCr, and mI in the CSO and tCho, tCr, mI, and sI in the PCC were significant after controlling for linewidth and FWHM in robust regressions. Conclusion The primary (correlation) results indicated age relationships for tCho, tCr, mI, and sI in the CSO and for NAAG, tCho, tCr, and Gln in the PCC, while no age correlations were found for tNAA, NAA, Glx, Glu, GSH, PE, Lac, or Asp in either region. Our results provide a normative foundation for future work investigating the neurometabolic time course of healthy aging using MRS.

4. The Macromolecular MR Spectrum Does Not Change with Healthy Aging

   Steve C. N. Hui, Tao Gong, Helge J. Zöllner, and 11 more authors

   Magnetic Resonance in Medicine, Dec 2022

   Abs

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

5. MRSCloud: A Cloud-Based MRS Tool for Basis Set Simulation

   Steve C. N. Hui, Muhammad G. Saleh, Helge J. Zöllner, and 9 more authors

   Magnetic Resonance in Medicine, Dec 2022

   Abs

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

6. In Vivo Spectral Editing of Phosphorylethanolamine

   Steve C. N. Hui, Helge J. Zöllner, Georg Oeltzschner, and 2 more authors

   Magnetic Resonance in Medicine, Dec 2022

   Abs

   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. Keywords: Magnetic resonance spectroscopy, MEGA-PRESS, spectral editing, phosphorylethanolamine

7. The Value of Zero-Filling in in Vivo MRS

   Saipavitra Murali-Manohar, Georg Oeltzschner, Peter B. Barker, and 1 more author

   Magnetic Resonance Imaging, Nov 2022
8. Community-Organized Resources for Reproducible MRS Data Analysis

   Brian J. Soher, William T. Clarke, Martin Wilson, and 2 more authors

   Magnetic Resonance in Medicine, Nov 2022
9. Importance of Linear Combination Modeling for Quantification of Glutathione and γ-Aminobutyric Acid Levels Using Hadamard-Edited Magnetic Resonance Spectroscopy

   Yulu Song, Helge J. Zöllner, Steve C. N. Hui, and 4 more authors

   Frontiers in Psychiatry, Nov 2022

   Abs

   BackgroundJ-difference-edited 1H-MR spectra require modeling to quantify signals of low-concentration metabolites. Two main approaches are used for this spectral modeling: simple peak fitting and linear combination modeling (LCM) with a simulated basis set. Recent consensus recommended LCM as the method of choice for the spectral analysis of edited data.PurposeThe aim of this study is to compare the performance of simple peak fitting and LCM in a test-retest dataset, hypothesizing that the more sophisticated LCM approach would improve quantification of Hadamard-edited data compared with simple peak fitting.MethodsA test–retest dataset was re-analyzed using Gannet (simple peak fitting) and Osprey (LCM). These data were obtained from the dorsal anterior cingulate cortex of twelve healthy volunteers, with TE = 80 ms for HERMES and TE = 120 ms for MEGA-PRESS of glutathione (GSH). Within-subject coefficients of variation (CVs) were calculated to quantify between-scan reproducibility of each metabolite estimate.ResultsThe reproducibility of HERMES GSH estimates was substantially improved using LCM compared to simple peak fitting, from a CV of 19.0–9.9%. For MEGA-PRESS GSH data, reproducibility was similar using LCM and simple peak fitting, with CVs of 7.3 and 8.8%. GABA + CVs from HERMES were 16.7 and 15.2%, respectively for the two models.ConclusionLCM with simulated basis functions substantially improved the reproducibility of GSH quantification for HERMES data.

10. Continuous and Intermittent Theta Burst Stimulation to the Visual Cortex Do Not Alter GABA and Glutamate Concentrations Measured by Magnetic Resonance Spectroscopy

    Karlene S. Stoby, Sara A. Rafique, Georg Oeltzschner, and 1 more author

    Brain and Behavior, Nov 2022

    Abs

    Background Theta burst stimulation (TBS), a form of repetitive transcranial magnetic stimulation (rTMS), uses repeated high-frequency bursts to non-invasively modulate neural processes in the brain. An intermittent TBS (iTBS) protocol is generally considered “excitatory,” while continuous TBS (cTBS) is considered “inhibitory.” However, the majority of work that has led to these effects being associated with the respective protocols has been done in the motor cortex, and it is well established that TMS can have variable effects across the brain. Objectives and method We investigated the effects of iTBS and cTBS to the primary visual cortex (V1) on composite levels of gamma-aminobutyric acid + co-edited macromolecules (GABA+) and glutamate + glutamine (Glx) since these are key inhibitory and excitatory neurotransmitters, respectively. Participants received a single session of cTBS, iTBS, or sham TBS to V1. GABA+ and Glx were quantified in vivo at the stimulation site using spectral-edited proton magnetic resonance spectroscopy (1H-MRS) at 3T. Baseline pre-TBS GABA+ and Glx levels were compared to immediate post-TBS and 1 h post-TBS levels. Results There were no significant changes in GABA+ or Glx following either of the TBS conditions. Visual cortical excitability, measured using phosphene thresholds, remained unchanged following both cTBS and iTBS conditions. There was no relationship between excitability thresholds and GABA+ or Glx levels. However, TBS did alter the relationship between GABA+ and Glx for up to 1 h following stimulation. Conclusions These findings demonstrate that a single session of TBS to the visual cortex can be used without significant effects on the tonic levels of these key neurotransmitters; and add to our understanding that TBS has differential effects at visual, motor, and frontal cortices.

11. Influence of Editing Pulse Flip Angle on J-Difference MR Spectroscopy

    Sofie Tapper, Steve C. N. Hui, Muhammad G. Saleh, and 5 more authors

    Magnetic Resonance in Medicine, Nov 2022

    Abs

    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.

12. Comparison of Linear Combination Modeling Strategies for Edited Magnetic Resonance Spectroscopy at 3 T

    Helge J. Zöllner, Sofie Tapper, Steve C. N. Hui, and 3 more authors

    NMR in Biomedicine, Nov 2022

    Abs

    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.

2021

1. Altered in Vivo Brain GABA and Glutamate Levels Are Associated with Multiple Sclerosis Central Fatigue

   Jameen Arm, Georg Oeltzschner, Oun Al-iedani, and 3 more authors

   European Journal of Radiology, Apr 2021

   Abs

   Purpose Fatigue is a common symptom in patients with multiple sclerosis (MS) with unknown pathophysiology. Dysfunction of the GABAergic/glutamatergic pathways involving inhibitory and excitatory neurotransmitters such as  γ-aminobutyric acid (GABA) and glutamine\,+ glutamate pool (Glx) have been implicated in several neurological disorders. This study is aimed to evaluate the potential role of GABA and Glx in the origin of central fatigue in relapse remitting MS (RRMS) patients. Methods 24 RRMS patients and 16 age- and sex-matched healthy controls (HC) were scanned using Mescher-Garwood point resolved spectroscopy (MEGA-PRESS) with a 3 T system to quantify GABA+ and Glx from prefrontal (PFC) and sensorimotor (SMC) cortices. Self-reported fatigue status was measured on all participants using the Modified Fatigue Impact Scale (MFIS). Results RRMS patients had higher fatigue scores relative to HC (p\,≤ 0.05). Compared to HC, Glx levels in RRMS patients were significantly decreased in SMC (p\,= 0.04). Significant correlations were found between fatigue scores and GABA+ (r = -0.531, p\,= 0.008) and Glx (r = 0.511, p\,= 0.018) in PFC. Physical fatigue was negatively correlated with GABA+ in SMC and PFC (r = -0.428 and -0.472 respectively, p\,≤ 0.04) and positively with PFC Glx (r = 0.480, p\,= 0.028). Conclusion The associations between fatigue and GABA\,+ and Glx suggest that there might be dysregulation of GABAergic/glutamatergic neurotransmission in the pathophysiological mechanism of central fatigue in MS.

2. Region-Specific Elevations of Glutamate + Glutamine Correlate with the Sensory Symptoms of Autism Spectrum Disorders

   Jason L. He, Georg Oeltzschner, Mark Mikkelsen, and 7 more authors

   Translational Psychiatry, Jul 2021

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   Individuals on the autism spectrum are often reported as being hyper- and/or hyporeactive to sensory input. These sensory symptoms were one of the key observations that led to the development of the altered excitation-inhibition (E-I) model of autism, which posits that an increase ratio of excitatory to inhibitory signaling may explain certain phenotypical expressions of autism spectrum disorders (ASD). While there has been strong support for the altered E-I model of autism, much of the evidence has come from animal models. With regard to in-vivo human studies, evidence for altered E-I balance in ASD come from studies adopting magnetic resonance spectroscopy (MRS). Spectral-edited MRS can be used to provide measures of the levels of GABA\,+\,(GABA\,+ macromolecules) and Glx (glutamate\,+ glutamine) in specific brain regions as proxy markers of inhibition and excitation respectively. In the current study, we found region-specific elevations of Glx in the primary sensorimotor cortex (SM1) in ASD. There were no group differences of GABA+ in either the SM1 or thalamus. Higher levels of Glx were associated with more parent reported difficulties of sensory hyper- and hyporeactivity, as well as reduced feed-forward inhibition during tactile perception in children with ASD. Critically, the finding of elevated Glx provides strong empirical support for increased excitation in ASD. Our results also provide a clear link between Glx and the sensory symptoms of ASD at both behavioral and perceptual levels.

3. Frequency Drift in MR Spectroscopy at 3T

   Steve C. N. Hui, Mark Mikkelsen, Helge J. Zöllner, and 132 more authors

   NeuroImage, Nov 2021

   Abs

   Purpose Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. Method A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson’s and intraclass correlation coefficients (ICC). Results Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. Discussion This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

4. Quantification of Sodium Relaxation Times and Concentrations as Surrogates of Proteoglycan Content of Patellar CARTILAGE at 3T MRI

   Benedikt Kamp, Miriam Frenken, Jan M. Henke, and 9 more authors

   Diagnostics, Nov 2021

   Abs

   Sodium MRI has the potential to depict cartilage health accurately, but synovial fluid can influence the estimation of sodium parameters of cartilage. Therefore, this study aimed to reduce the impact of synovial fluid to render the quantitative compositional analyses of cartilage tissue technically more robust. Two dedicated protocols were applied for determining sodium T1 and T2* relaxation times. For each protocol, data were acquired from 10 healthy volunteers and one patient with patellar cartilage damage. Data recorded with multiple repetition times for T1 measurement and multi-echo data acquired with an additional inversion recovery pulse for T2* measurement were analysed using biexponential models to differentiate longitudinal relaxation components of cartilage (T1,car) and synovial fluid (T1,syn), and short (T2s*) from long (T2l*) transversal relaxation components. Sodium relaxation times and concentration estimates in patellar cartilage were successfully determined: T1,car = 14.5 ± 0.7 ms; T1,syn = 37.9 ± 2.9 ms; c(T1-protocol) = 200 ± 48 mmol/L; T2s* = 0.4 ± 0.1 ms; T2l* = 12.6 ± 0.7 ms; c(T2*-protocol) = 215 ± 44 mmol/L for healthy volunteers. In conclusion, a robust determination of sodium relaxation times is possible at a clinical field strength of 3T to quantify sodium concentrations, which might be a valuable tool to determine cartilage health.

5. Greater Somatosensory Afference with Acupuncture Increases Primary Somatosensory Connectivity and Alleviates Fibromyalgia Pain via Insular GABA: A Randomized Neuroimaging Trial

   Ishtiaq Mawla, Eric Ichesco, Helge J. Zöllner, and 11 more authors

   Arthritis & Rheumatology, Nov 2021

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   Objective Acupuncture is a complex multi-component treatment that has shown promise for the treatment of Fibromyalgia (FM), however, clinical trials have shown mixed results, possibly due to heterogeneous methodology and lack of understanding of the underlying mechanism of action. We sought to understand the specific contribution of somatosensory afference to improvements in clinical pain, and the specific brain circuits involved. Methods 76 FM patients were randomized to receive 8 weeks (2 treatments/week) of electroacupuncture (EA, with somatosensory afference) or mock laser acupuncture (ML, with no somatosensory afference). Brief Pain Inventory (BPI) Severity, resting state functional MRI (rs-fMRI), and proton magnetic resonance spectroscopy (1H-MRS) in the right anterior insula (aINS) were collected at pre- and post-treatment. Results FM patients receiving EA experienced a greater reduction in pain severity compared to ML (mean difference, EA=-1.14, ML=-0.46, Group x Time interaction, p=0.036). Participants receiving EA, as compared to ML, also displayed increased resting functional connectivity between the primary somatosensory cortical representation of the leg (S1leg; i.e. S1 subregion activated by EA) and aINS. Increase in S1leg-aINS connectivity was associated with reductions in BPI severity (r=-0.44, p=0.01) and increases in aINS gamma-aminobutyric acid (GABA+) (r=-0.48, p=0.046) following EA. Moreover, increases in aINS GABA+ was associated with reductions in BPI severity (r=-0.59, p=0.01). Finally, post-EA changes in aINS GABA+ mediated the relationship between changes in S1leg-aINS and BPI severity, bootstrapped CI=[-0.533, -0.037]. Conclusion The somatosensory component of acupuncture modulates primary somatosensory functional connectivity in association with insular neurochemistry to reduce pain severity in FM.

6. Increase in ACC GABA+ Levels Correlate with Decrease in Migraine Frequency, Intensity and Disability over Time

   Aimie L. Peek, Andrew M. Leaver, Sheryl Foster, and 7 more authors

   The Journal of Headache and Pain, Dec 2021

   Abs

   An imbalance between inhibitory and excitatory neurometabolites has been implicated in chronic pain. Prior work identified elevated levels of Gamma-aminobutyric acid + macromolecules (“GABA+”) using magnetic resonance spectroscopy (MRS) in people with migraine. What is not understood is whether this increase in GABA+ is a cause, or consequence of living with, chronic migraine. Therefore, to further elucidate the nature of the elevated GABA+ levels reported in migraine, this study aimed to observe how GABA+ levels change in response to changes in the clinical characteristics of migraine over time.

7. Increased GABA+ in People With Migraine, Headache, and Pain Conditions- A Potential Marker of Pain

   Aimie L Peek, Andrew M Leaver, Sheryl Foster, and 8 more authors

   The Journal of Pain, Dec 2021

   Abs

   Treatment outcomes for migraine and other chronic headache and pain conditions typically demonstrate modest results. A greater understanding of underlying pain mechanisms may better inform treatments and improve outcomes. Increased GABA+ has been identified in recent studies of migraine, however, it is unclear if this is present in other headache, and pain conditions. We primarily investigated GABA+ levels in the posterior cingulate gyrus (PCG) of people with migraine, whiplash-headache and low back pain compared to age- and sex-matched controls, GABA+ levels in the anterior cingulate cortex (ACC) and thalamus formed secondary aims. Using a cross-sectional design, we studied people with migraine, whiplash-headache or low back pain (n = 56) and compared them with a pool of age- and sex-matched controls (n = 22). We used spectral-edited magnetic resonance spectroscopy at 3T (MEGA-PRESS) to determine levels of GABA+ in the PCG, ACC and thalamus. PCG GABA+ levels were significantly higher in people with migraine and low back pain compared with controls (eg, migraine 4.89 IU ± 0.62 vs controls 4.62 IU ± 0.38; P = .02). Higher GABA+ levels in the PCG were not unique to migraine and could reflect a mechanism of chronic pain in general. A better understanding of pain at a neurochemical level informs the development of treatments that target aberrant brain neurochemistry to improve patient outcomes. Perspective This study provides insights into the underlying mechanisms of chronic pain. Higher levels of GABA+ in the PCG may reflect an underlying mechanism of chronic headache and pain conditions. This knowledge may help improve patient outcomes through developing treatments that specifically address this aberrant brain neurochemistry.

8. Neurotransmitters and Neurometabolites in Late-Life Depression: A Preliminary Magnetic Resonance Spectroscopy Study at 7T

   Gwenn S. Smith, Georg Oeltzschner, Neda F. Gould, and 9 more authors

   Journal of Affective Disorders, Jan 2021

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   Background Magnetic resonance spectroscopy (MRS) methods have quantified changes in levels of neurotransmitters and neurometabolites in patients with major depression across the lifespan. The application of 7T field strengths and greater have not been a major focus of study in patients with late-life depression (LLD). Methods Nine LLD patients who met DSM-IV criteria for a current major depressive episode and nine non-depressed, healthy, age-matched controls underwent clinical and neuropsychological assessment and single-voxel 7T 1H-MRS at baseline and after 10-12 weeks of antidepressant treatment (Citalopram; patients only). Spectra were acquired from two brain regions implicated in both depressive symptoms and neuropsychological deficits in LLD, the anterior (ACC) and posterior cingulate (PCC). Levels of γ-aminobutyric acid (GABA), glutamate (Glu), glutathione (GSH), N-acetylaspartylglutamate (NAAG), N-acetylaspartate (NAA), and myo-inositol (mI) were quantified relative to total creatine (tCr) using linear-combination modeling. Results Baseline Glu/tCr levels were not significantly different between groups. Decreased Glu/tCr levels after Citalopram treatment were observed in a subset of LLD patients. Exploratory analyses showed that LLD patients had lower NAA levels in the PCC relative to controls. Higher levels of ml in the LLD patients relative to the controls and decreases after Citalopram treatment had large effect sizes but were not statistically significant. Further, decreases in PCC Glu/tCr and increases in ACC GSH/tCr were associated with improvement in depressive symptoms. Limitations Sample size. Conclusions These preliminary results suggest a role of neurochemicals and neurometabolites in the neurobiology of LLD and antidepressant treatment response.

9. Edited Magnetic Resonance Spectroscopy in the Neonatal Brain

   Yulu Song, Peter J. Lally, Maria Yanez Lopez, and 16 more authors

   Neuroradiology, Oct 2021

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   J-difference-edited spectroscopy is a valuable approach for the detection of low-concentration metabolites with magnetic resonance spectroscopy (MRS). Currently, few edited MRS studies are performed in neonates due to suboptimal signal-to-noise ratio, relatively long acquisition times, and vulnerability to motion artifacts. Nonetheless, the technique presents an exciting opportunity in pediatric imaging research to study rapid maturational changes of neurotransmitter systems and other metabolic systems in early postnatal life. Studying these metabolic processes is vital to understanding the widespread and rapid structural and functional changes that occur in the first years of life. The overarching goal of this review is to provide an introduction to edited MRS for neonates, including the current state-of-the-art in editing methods and editable metabolites, as well as to review the current literature applying edited MRS to the neonatal brain. Existing challenges and future opportunities, including the lack of age-specific reference data, are also discussed.

10. Spectral Diffusion Analysis of Kidney Intravoxel Incoherent Motion MRI in Healthy Volunteers and Patients with Renal Pathologies

    Julia Stabinska, Alexandra Ljimani, Helge Jörn Zöllner, and 6 more authors

    Magnetic Resonance in Medicine, Oct 2021

    Abs

    Purpose To assess the feasibility of measuring tubular and vascular signal fractions in the human kidney using nonnegative least-square (NNLS) analysis of intravoxel incoherent motion data collected in healthy volunteers and patients with renal pathologies. Methods MR imaging was performed at 3 Tesla in 12 healthy subjects and 3 patients with various kidney pathologies (fibrotic kidney disease, failed renal graft, and renal masses). Relative signal fractions f and mean diffusivities of the diffusion components in the cortex, medulla, and renal lesions were obtained using the regularized NNLS fitting of the intravoxel incoherent motion data. Test–retest repeatability of the NNLS approach was tested in 5 volunteers scanned twice. Results In the healthy kidneys, the NNLS method yielded diffusion spectra with 3 distinguishable components that may be linked to the slow tissue water diffusion, intermediate tubular and vascular flow, and fast blood flow in larger vessels with the relative signal fractions, fslow, finterm and ffast, respectively. In the pathological kidneys, the diffusion spectra varied substantially from those acquired in the healthy kidneys. Overall, the renal cyst showed substantially higher finterm and lower fslow, whereas the fibrotic kidney, failed renal graft, and renal cell carcinoma demonstrated the opposite trend. Conclusion NNLS-based intravoxel incoherent motion could potentially become a valuable tool in assessing changes in tubular and vascular volume fractions under pathophysiological conditions.

11. Frequency and Phase Correction of J-Difference Edited MR Spectra Using Deep Learning

    Sofie Tapper, Mark Mikkelsen, Blake E. Dewey, and 4 more authors

    Magnetic Resonance in Medicine, Oct 2021

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    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.

12. Comparison of Different Linear-Combination Modeling Algorithms for Short-TE Proton Spectra

    Helge J. Zöllner, Michal Považan, Steve C. N. Hui, and 3 more authors

    NMR in Biomedicine, Oct 2021

    Abs

    Short-TE proton MRS is used to study metabolism in the human brain. Common analysis methods model the data as a linear combination of metabolite basis spectra. This large-scale multi-site study compares the levels of the four major metabolite complexes in short-TE spectra estimated by three linear-combination modeling (LCM) algorithms. 277 medial parietal lobe short-TE PRESS spectra (TE = 35 ms) from a recent 3 T multi-site study were preprocessed with the Osprey software. The resulting spectra were modeled with Osprey, Tarquin and LCModel, using the same three vendor-specific basis sets (GE, Philips and Siemens) for each algorithm. Levels of total N-acetylaspartate (tNAA), total choline (tCho), myo-inositol (mI) and glutamate + glutamine (Glx) were quantified with respect to total creatine (tCr). Group means and coefficient of variations of metabolite estimates agreed well for tNAA and tCho across vendors and algorithms, but substantially less so for Glx and mI, with mI systematically estimated as lower by Tarquin. The cohort mean coefficient of determination for all pairs of LCM algorithms across all datasets and metabolites was = 0.39, indicating generally only moderate agreement of individual metabolite estimates between algorithms. There was a significant correlation between local baseline amplitude and metabolite estimates (cohort mean = 0.10). While mean estimates of major metabolite complexes broadly agree between linear-combination modeling algorithms at group level, correlations between algorithms are only weak-to-moderate, despite standardized preprocessing, a large sample of young, healthy and cooperative subjects, and high spectral quality. These findings raise concerns about the comparability of MRS studies, which typically use one LCM software and much smaller sample sizes.

13. In Silico GABA+ MEGA-PRESS: Effects of Signal-to-Noise Ratio and Linewidth on Modeling the 3 Ppm GABA+ Resonance

    Helge Jörn Zöllner, Georg Oeltzschner, Alfons Schnitzler, and 1 more author

    NMR in Biomedicine, Oct 2021

    Abs

    To investigate the GABA+ modeling accuracy of MEGA-PRESS GABA+-edited MRS data with various spectral quality scenarios, the influence of varying signal-to-noise ratio (SNR) and linewidth on the model estimates was quantified. MEGA-PRESS data from 46 volunteers were averaged to generate a template MEGA-PRESS spectrum, which was modeled and quantified to generate a GABA+ level ground truth. This spectrum was then manipulated by adding 427 combinations of varying artificial noise levels and line broadening, mimicking variations in GABA+ SNR and B0 homogeneity. GABA+ modeling and quantification was performed with 100 simulated spectra per condition using automated routines in both Gannet 3.0 and Tarquin. The GABA+ estimation error was calculated as the relative deviation to the quantified GABA+ ground truth levels to assess the accuracy of GABA+ modeling. Finally, the accordance between the simulations and different in vivo scenarios was assessed. The GABA+ estimation error was smaller than 5% for all GABA+ SNR values with creatine linewidths lower than 9.7 Hz in Gannet 3.0 or unequal 10.6 Hz in Tarquin. The standard deviation of the GABA+ amplitude over 100 spectra per condition varied between 3.1 and 17% (Gannet 3.0) and between 1 and 11% (Tarquin) over the in vivo relevant GABA+ SNR range between 2.6 and 3.5. GABA+ edited studies might be realized for voxels with low GABA+ SNR at the cost of higher group-level variance. The accuracy of GABA+ modeling had no relation to commonly used quality metrics. The Tarquin algorithm was found to be more robust against linewidth changes than the fitting algorithm in Gannet.

2020

1. Osprey: Open-Source Processing, Reconstruction & Estimation of Magnetic Resonance Spectroscopy Data

   Georg Oeltzschner, Helge J. Zöllner, Steve C. N. Hui, and 4 more authors

   Journal of Neuroscience Methods, Sep 2020

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

2. High γ-Aminobutyric Acid Content Within the Medial Prefrontal Cortex Is a Functional Signature of Somatic Symptoms Disorder in Patients With Parkinson’s Disease

   Stefano Delli Pizzi, Raffaella Franciotti, Antonio Ferretti, and 10 more authors

   Movement Disorders, Sep 2020

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   Background The dysfunctional activity of the medial prefrontal cortex has been associated with the appearance of the somatic symptom disorder, a key feature of the Parkinson’s disease (PD) psychosis complex. Objectives The objectives of this study were to investigate whether the basal contents of inhibitory γ-aminobutyric acid and excitatory glutamate plus glutamine neurotransmitter levels are changed in the medial prefrontal cortex of patients with PD with somatic symptom disorder and whether this alteration represents a marker of susceptibility of PD to somatic symptom disorder, thus representing a signature of psychosis complex of PD. Methods Levels of the γ-aminobutyric acid and glutamate plus glutamine were investigated, at rest, with proton magnetic resonance spectroscopy. Total creatine was used as an internal reference. The study cohort included 23 patients with somatic symptom disorder plus PD, 19 patients with PD without somatic symptom disorder, 19 healthy control subjects, and 14 individuals with somatic symptom disorder who did not show other psychiatric or neurological disorders. Results We found that, compared with patients with PD without somatic symptom disorder or healthy control individuals, patients with somatic symptom disorder, with or without PD, show increased γ-aminobutyric acid/total creatine levels in the medial prefrontal cortex. The medial prefrontal cortex contents of glutamate plus glutamine/total creatine levels or γ-aminobutyric acid/glutamate plus glutamine were not different among groups. Conclusions Our findings highlight a crucial pathophysiologic role played by high γ-aminobutyric acid within the medial prefrontal cortex in the production of somatic symptom disorder. This phenomenon represents a signature of psychosis complex in patients with PD. © 2020 International Parkinson and Movement Disorder Society

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

   Michal Považan, Mark Mikkelsen, Adam Berrington, and 64 more authors

   Radiology, Feb 2020

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   BackgroundThe 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.PurposeTo 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 MethodsAn 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).ResultsIn 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).ConclusionMultisite 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, 2020Online supplemental material is available for this article.

4. Reduced Striatal GABA in Unmedicated Children with ADHD at 7T

   Nicolaas A. Puts, Matthew Ryan, Georg Oeltzschner, and 3 more authors

   Psychiatry Research: Neuroimaging, Jul 2020

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   Attention-deficit hyperactive disorder (ADHD) is characterized by inattention and increased impulsive and hypermotoric behaviors.Despite the high prevalence and impact of ADHD, little is known about the underlying neurophysiology of ADHD. The main inhibitory and excitatory neurotransmitters γ-aminobutyric acid (GABA) and glutamate are receiving increased attention in ADHD and can be measured using Magnetic Resonance Spectroscopy (MRS). However, MRS studies in ADHD are limited. We measured GABA and glutamate in young unmedicated participants, utilizing high magnetic field strength. Fifty unmedicated children (26 with ADHD, 24 controls) aged 5–9 years completed MRS at 7T and behavioral testing. GABA and glutamate were measured in dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), premotor cortex (PMC), and striatum, and estimated using LCModel. Children with ADHD showed poorer inhibitory control and significantly reduced GABA/Cr in the striatum, but not in ACC, DLPFC, or PMC regions. There were no significant group differences for Glu/Cr levels, or correlations with behavioral manifestations of ADHD. The primary finding of this study is a reduction of striatal GABA levels in unmedicated children with ADHD at 7T. These findings provide guidance for future studies or interventions. Reduced striatal GABA may be a marker for specific GABA-related treatment for ADHD.

5. Effect of Age on GABA+ and Glutathione in a Pediatric Sample

   M. G. Saleh, A. Papantoni, M. Mikkelsen, and 5 more authors

   American Journal of Neuroradiology, Jun 2020

   Abs

   BACKGROUND AND PURPOSE:

   Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the human brain and is implicated in several neuropathologies. Glutathione is a major antioxidant in the brain and is considered a marker of oxidative stress. Several studies have reported age-related declines in GABA levels in adulthood, but the trajectory of both GABA and glutathione during childhood has not been well explored. The aim of this study is to establish how GABA and glutathione vary with age during early development.

   MATERIALS AND METHODS:

   Twenty-three healthy children (5.6–13.9 years of age) were recruited for this study. MR imaging/MR spectroscopy experiments were conducted on a 3T MR scanner. A 27-mL MR spectroscopy voxel was positioned in the frontal lobe. J-difference edited MR spectroscopy was used to spectrally edit GABA and glutathione. Data were analyzed using the Gannet software, and GABA+ (GABA + macromolecules/homocarnosine) and glutathione were quantified using water (GABA+\textsubscriptH2O and Glutathione\textsubscriptH2O) and Cr (GABA+/Cr and glutathione/Cr) as concentration references. Also, the relative gray matter contribution to the voxel volume (GM\textsubscriptratio) was estimated from structural images. Pearson correlation coefficients were used to examine the association between age and GABA+\textsubscriptH2O (and glutathione\textsubscriptH2O), between age and GABA+/Cr (and glutathione/Cr), and between age and GM\textsubscriptratio.

   RESULTS:

   Both GABA+\textsubscriptH2O (\emphr =\emph 0.63, \emphP = .002) and GABA+/Cr (\emphr =\emph 0.48, \emphP = .026) significantly correlated with age, whereas glutathione measurements and GM\textsubscriptratio did not.

   CONCLUSIONS:

   We demonstrate increases in GABA and no differences in glutathione with age in a healthy pediatric sample. This study provides insight into neuronal maturation in children and may facilitate better understanding of normative behavioral development and the pathophysiology of developmental disorders.

6. Simultaneous Edited MRS of GABA, Glutathione, and Ethanol

   Muhammad G. Saleh, Min Wang, Mark Mikkelsen, and 6 more authors

   NMR in Biomedicine, Jun 2020

   Abs

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

2019

1. Simultaneous Editing of GABA and GSH with Hadamard-Encoded MR Spectroscopic Imaging

   Kimberly L. Chan, Georg Oeltzschner, Muhammad G. Saleh, and 2 more authors

   Magnetic Resonance in Medicine, Jun 2019

   Abs

   Purpose To evaluate the feasibility of simultaneous MR spectroscopic imaging (MRSI) of gamma-aminobutyric acid (GABA) and glutathione (GSH) in the human brain using Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES). Methods Point RESolved Spectroscopy (PRESS)-localized MRSI was performed in GABA and GSH phantoms and in the human brain (n = 3) using HERMES editing and compared to conventional MEGA editing of each metabolite. Multiplet patterns, signal intensities, and metabolite crosstalk were compared between methods. GABA+ and GSH levels were compared between methods for bias and variability. Linear regression of HERMES-MRSI GABA+/H2O and GSH/H2O versus gray matter (GM) fraction were performed to assess differences between GM and white matter (WM). Results Phantom HERMES-MRSI scans gave comparable GABA+ and GSH signals to MEGA-MRSI across the PRESS-localized volume. In vivo, HERMES-reconstructed GABA+ and GSH values had minimal measurement bias and variability relative to MEGA-MRSI. Intersubject coefficients of variation (CV) from two regions within the PRESS-localized volume for HERMES and MEGA were 6-12% for GABA+ and 6-19% for GSH. Interregion CVs were 5–15% for GABA+ and 3–17% for GSH. The GABA+/H2O and GSH/H2O ratios were 1.8 times higher and 1.9 times higher, respectively, in GM than in WM. Conclusion HERMES-MRSI of GABA+ and GSH was found to be practical in the human brain with minimal measurement bias and comparable variability to separate MEGA-edited acquisitions of each metabolite performed in double the scan time. The HERMES-MRSI is a promising method for simultaneously mapping the distribution of multiple low-concentration metabolites.

2. Big GABA II: Water-Referenced Edited MR Spectroscopy at 25 Research Sites

   M. Mikkelsen, D. L. Rimbault, P. B. Barker, and 63 more authors

   Neuroimage, May 2019

   Abs

   Accurate and reliable quantification of brain metabolites measured in vivo using (1)H 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 gamma-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.

3. Neurometabolites and Associations with Cognitive Deficits in Mild Cognitive Impairment: A Magnetic Resonance Spectroscopy Study at 7 Tesla

   Georg Oeltzschner, S. Andrea Wijtenburg, Mark Mikkelsen, and 7 more authors

   Neurobiology of Aging, Jan 2019

   Abs

   The levels of several brain metabolites were investigated in the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) in 13 healthy controls (HC) and 13 patients with mild cognitive impairment (MCI) using single-voxel magnetic resonance spectroscopy at 7T. Levels of γ-aminobutyric acid (GABA), glutamate (Glu), glutathione (GSH), N-acetylaspartylglutamate (NAAG), N-acetylaspartate (NAA), and myo-inositol (mI) were quantified relative to total creatine (tCr). The effect of diagnosis on metabolite levels, and relationships between metabolite levels and memory and executive function, correcting for age, were investigated. MCI patients showed significantly decreased GABA/tCr (ACC, PCC), Glu/tCr (PCC), and NAA/tCr (PCC), and significantly increased mI/tCr (ACC). In the combined group, worse episodic verbal memory performance was correlated with lower Glu/tCr (PCC), lower NAA/tCr (PCC), and higher mI/tCr (ACC, PCC). Worse verbal fluency performance was correlated with lower GSH/tCr (PCC). In summary, MCI is associated with decreased GABA and Glu, most consistently in the PCC. Further studies in larger patient samples should be undertaken to determine the utility of 7T magnetic resonance spectroscopy in detecting MCI-related neurochemical changes.

4. Biallelic Mutation of Human SLC6A6 Encoding the Taurine Transporter TAUT Is Linked to Early Retinal Degeneration

   Markus N. Preising, Boris Görg, Christoph Friedburg, and 20 more authors

   The FASEB Journal, Jan 2019

   Abs

   We previously reported that inactivation of the transmembrane taurine transporter (TauT or solute carrier 6a6) causes early retinal degeneration in mice. Compatible with taurine’s indispensability for cell volume homeostasis, protein stabilization, cytoprotection, antioxidation, and immuno- and neuromodulation, mice develop multisystemic dysfunctions (hearing loss; liver fibrosis; and behavioral, heart, and skeletal muscle abnormalities) later on. Here, by genetic, cell biologic, in vivo 1H–magnetic resonance spectroscopy and molecular dynamics simulation studies, we conducted in-depth characterization of a novel disorder: human TAUT deficiency. Loss of TAUT function due to a homozygous missense mutation caused panretinal degeneration in 2 brothers. TAUTp.A78E still localized in the plasma membrane but is predicted to impact structural stabilization. 3H-taurine uptake by peripheral blood mononuclear cells was reduced by 95%, and taurine levels were severely reduced in plasma, skeletal muscle, and brain. Extraocular dysfunctions were not yet detected, but significantly increased urinary excretion of 8-oxo-7,8-dihydroguanosine indicated generally enhanced (yet clinically unapparent) oxidative stress and RNA oxidation, warranting continuous broad surveillance.—Preising, M. N., Görg, B., Friedburg, C., Qvartskhava, N., Budde, B. S., Bonus, M., Toliat, M. R., Pfleger, C., Altmüller, J., Herebian, D., Beyer, M., Zöllner, H. J., Wittsack, H.-J., Schaper, J., Klee, D., Zechner, U., Nürnberg, P., Schipper, J., Schnitzler, A., Gohlke, H., Lorenz, B., Häussinger, D., Bolz, H. J. Biallelic mutation of human SLC6A6 encoding the taurine transporter TAUT is linked to early retinal degeneration. FASEB J. 33, 11507–11527 (2019). www.fasebj.org

5. Multi-Vendor Standardized Sequence for Edited Magnetic Resonance Spectroscopy

   Muhammad G. Saleh, Daniel Rimbault, Mark Mikkelsen, and 15 more authors

   NeuroImage, Apr 2019

   Abs

   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.

6. Reproducibility of Brain MRS in Older Healthy Adults at 7T

   S. Andrea Wijtenburg, Laura M. Rowland, Georg Oeltzschner, and 3 more authors

   NMR in Biomedicine, Apr 2019

   Abs

   To date, the majority of MRS reproducibility studies have been conducted in healthy younger adults, with only a few conducted in older adults at 3 T. With the growing interest in applying MRS methods to study the longitudinal course and effects of treatments in neurodegenerative disease, it is important to establish reproducibility in age-matched controls, especially in older individuals. In this study, spectroscopic data were acquired using a stimulated echo acquisition mode (STEAM) localization technique in two regions (anterior and posterior cingulate cortices—ACC, PCC, respectively) in 10 healthy, cognitively normal older adults (64 ± 8.1 years). Reproducibility was assessed via mean coefficients of variation (CVs) and relative differences (RDs) calculated across two visits performed 2–3 months apart. Metabolites with high signal-to-noise ratio (SNR) such as NAA, tCho, and Glu had mean CVs of 10% or less and mean RDs of 15% or less across both regions. Metabolites with lower SNR such as GABA and Gln had slightly higher mean CVs of 22% or less and mean RDs of 27% or less across both regions. These results demonstrate the feasibility of acquiring MRS data at 7 T in older subjects, and establish that the spectroscopic data are reproducible in both the ACC and PCC in older, healthy subjects to the same extent as in previous studies in young subjects.

7. Chemical Exchange Saturation Transfer Imaging in Hepatic Encephalopathy

   Helge Jörn Zöllner, Markus Butz, Markus Jördens, and 5 more authors

   NeuroImage: Clinical, Jan 2019

   Abs

   Hepatic encephalopathy (HE) is a common complication in liver cirrhosis and associated with an invasion of ammonia into the brain through the blood-brain barrier. Resulting higher ammonia concentrations in the brain are suggested to lead to a dose-dependent gradual increase of HE severity and an associated impairment of brain function. Amide proton transfer-weighted (APTw) chemical exchange saturation transfer (CEST) imaging has been found to be sensitive to ammonia concentration. The aim of this work was to study APTw CEST imaging in patients with HE and to investigate the relationship between disease severity, critical flicker frequency (CFF), psychometric test scores, blood ammonia, and APTw signals in different brain regions. Whole-brain APTw CEST images were acquired in 34 participants (14 controls, 20 patients (10 minimal HE, 10 manifest HE)) on a 3 T clinical MRI system accompanied by T1 mapping and structural images. T1 normalized magnetization transfer ratio asymmetry analysis was performed around 3 ppm after B0 and B1 correction to create APTw images. All APTw images were spatially normalized into a cohort space to allow direct comparison. APTw images in 6 brain regions (cerebellum, occipital cortex, putamen, thalamus, caudate, white matter) were tested for group differences as well as the link to CFF, psychometric test scores, and blood ammonia. A decrease in APTw intensities was found in the cerebellum and the occipital cortex of manifest HE patients. In addition, APTw intensities in the cerebellum correlated positively with several psychometric scores, such as the fine motor performance scores MLS1 for hand steadiness / tremor (r\,= 0.466; p\,=\,.044) and WRT2 for motor reaction time (r\,= 0.523; p\,=\,.022). Moreover, a negative correlation between APTw intensities and blood ammonia was found for the cerebellum (r\,=\,−0.615; p\,=\,.007) and the occipital cortex (r\,=\,−0.478; p\,=\,.045). An increase of APTw intensities was observed in the putamen of patients with minimal HE and correlated negatively with the CFF (r\,=\,−0.423; p\,=\,.013). Our findings demonstrate that HE is associated with regional differential alterations in APTw signals. These variations are most likely a consequence of hyperammonemia or hepatocerebral degeneration processes, and develop in parallel with disease severity.

2018

1. Connecting Occipital Alpha Band Peak Frequency, Visual Temporal Resolution, and Occipital GABA Levels in Healthy Participants and Hepatic Encephalopathy Patients

   Thomas J. Baumgarten, Julia Neugebauer, Georg Oeltzschner, and 7 more authors

   NeuroImage: Clinical, Jan 2018
2. Opposite Dynamics of GABA and Glutamate Levels in the Occipital Cortex during Visual Processing

   Katarzyna Kurcyus, Efsun Annac, Nina M. Hanning, and 4 more authors

   The Journal of Neuroscience, Jan 2018
3. Effects of Eddy Currents on Selective Spectral Editing Experiments at 3T

   Georg Oeltzschner, Karim Snoussi, Nicolaas A. Puts, and 7 more authors

   Journal of Magnetic Resonance Imaging, Jan 2018

   Abs

   Purpose To investigate frequency-offset effects in edited magnetic resonance spectroscopy (MRS) experiments arising from B0 eddy currents. Materials and Methods Macromolecule-suppressed (MM-suppressed) γ-aminobutyric acid (GABA)-edited experiments were performed at 3T. Saturation-offset series of MEGA-PRESS experiments were performed in phantoms, in order to investigate different aspects of the relationship between the effective editing frequencies and eddy currents associated with gradient pulses in the sequence. Difference integrals were quantified for each series, and the offset dependence of the integrals was analyzed to quantify the difference in frequency (Δf) between the actual vs. nominal expected saturation frequency. Results Saturation-offset N-acetyl-aspartate-phantom experiments show that Δf varied with voxel orientation, ranging from 10.4 Hz (unrotated) to 6.4 Hz (45° rotation about the caudal–cranial axis) and 0.4 Hz (45° rotation about left–right axis), indicating that gradient-related B0 eddy currents vary with crusher-gradient orientation. Fixing the crusher-gradient coordinate-frame substantially reduced the orientation dependence of Δf (to ∼2 Hz). Water-suppression crusher gradients also introduced a frequency offset, with Δf = 0.6 Hz (“excitation” water suppression), compared to 10.2 Hz (no water suppression). In vivo spectra showed a negative edited “GABA” signal, suggesting Δf on the order of 10 Hz; with fixed crusher-gradient coordinate-frame, the expected positive edited “GABA” signal was observed. Conclusion Eddy currents associated with pulsed field gradients may have a considerable impact on highly frequency-selective spectral-editing experiments, such as MM-suppressed GABA editing at 3T. Careful selection of crusher gradient orientation may ameliorate these effects. Level of Evidence: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:673–681.

4. Hadamard Editing of Glutathione and Macromolecule-Suppressed GABA

   Georg Oeltzschner, Kimberly L. Chan, Muhammad G. Saleh, and 3 more authors

   NMR in Biomedicine, Jan 2018

   Abs

   The primary inhibitory neurotransmitter γ-aminobutyric acid (GABA) and the major antioxidant glutathione (GSH) are compounds of high importance for the function and integrity of the human brain. In this study, a method for simultaneous J-difference spectral-edited magnetic resonance spectroscopy (MRS) of GSH and GABA with suppression of macromolecular (MM) signals at 3 T is proposed. MM-suppressed Hadamard encoding and reconstruction of MEGA (Mescher–Garwood)-edited spectroscopy (HERMES) consists of four sub-experiments (TE = 80 ms), with 20-ms editing pulses applied at: (A) 4.56 and 1.9 ppm; (B) 4.56 and 1.5 ppm; (C) 1.9 ppm; and (D) 1.5 ppm. One Hadamard combination (A + B – C – D) yields GSH-edited spectra, and another (A – B + C – D) yields GABA-edited spectra, with symmetric suppression of the co-edited MM signal. MM-suppressed HERMES, conventional HERMES and separate Mescher–Garwood point-resolved spectroscopy (MEGA-PRESS) data were successfully acquired from a (33 mm)3 voxel in the parietal lobe in 10 healthy subjects. GSH- and GABA-edited MM-suppressed HERMES spectra were in close agreement with the respective MEGA-PRESS spectra. Mean GABA (and GSH) estimates were 1.10 ± 0.15 i.u. (0.59 ± 0.12 i.u.) for MM-suppressed HERMES, and 1.13 ± 0.09 i.u. (0.66 ± 0.09 i.u.) for MEGA-PRESS. Mean GABA (and GSH) differences between MM-suppressed HERMES and MEGA-PRESS were –0.03 ± 0.11 i.u. (–0.07 ± 0.11 i.u.). The mean signal-to-noise ratio (SNR) improvement of MM-suppressed HERMES over MEGA-PRESS was 1.45 ± 0.25 for GABA and 1.32 ± 0.24 for GSH. These results indicate that symmetric suppression of the MM signal can be accommodated into the Hadamard editing framework. Compared with sequential single-metabolite MEGA-PRESS experiments, MM-suppressed HERMES allows for simultaneous edited measurements of GSH and GABA without MM contamination in only half the scan time, and SNR is maintained.

5. J-Difference-Edited MRS Measures of γ-Aminobutyric Acid before and after Acute Caffeine Administration

   Georg Oeltzschner, Helge J. Zöllner, Marc Jonuscheit, and 3 more authors

   Magnetic Resonance in Medicine, Jan 2018

   Abs

   Purpose The aim of this study was to investigate potential effects of acute caffeine intake on J-difference-edited MRS measures of the primary inhibitory neurotransmitter γ-aminobutyric acid (GABA). Methods J-difference-edited Mescher-Garwood PRESS (MEGA-PRESS) and conventional PRESS data were acquired at 3T from voxels in the anterior cingulate and occipital area of the brain in 15 healthy subjects, before and after oral intake of a 200-mg caffeine dose. MEGA-PRESS data were analyzed with the MATLAB-based Gannet tool to estimate GABA+ macromolecule (GABA+) levels, while PRESS data were analyzed with LCModel to estimate levels of glutamate, glutamate+glutamine, N-acetylaspartate, and myo-inositol. All metabolites were quantified with respect to the internal reference compounds creatine and tissue water, and compared between the pre- and post-caffeine intake condition. Results For both MRS voxels, mean GABA+ estimates did not differ before and after caffeine intake. Slightly lower estimates of myo-inositol were observed after caffeine intake in both voxels. N-acetylaspartate, glutamate, and glutamate+glutamine did not show significant differences between conditions. Conclusion Mean GABA+ estimates from J-difference-edited MRS in two different brain regions are not altered by acute oral administration of caffeine. These findings may increase subject recruitment efficiency for MRS studies.

6. Simultaneous Editing of GABA and Glutathione at 7T Using Semi-LASER Localization

   Muhammad G. Saleh, Mark Mikkelsen, Georg Oeltzschner, and 4 more authors

   Magnetic Resonance in Medicine, Jan 2018

   Abs

   Purpose To demonstrate simultaneous editing of the two most commonly edited and overlapping signals, γ-aminobutyric acid (GABA), and glutathione (GSH), with Hadamard encoding and reconstruction of MEGA-edited spectroscopy (HERMES) using sLASER localization at 7T. Methods Density matrix simulations of HERMES at 7T were carried out and compared with phantom experiments. Additional phantom experiments were performed to characterize the echo time (TE) -dependent modulation of GABA- and GSH-edited HERMES spectra at TE of 80–160 ms. In vivo experiments were performed in 10 healthy volunteers, comparing HERMES (11 min) to sequentially acquired MEGA-sLASER detection of GABA and GSH (2 × 11 min). Results Simulations of HERMES show GABA- and GSH-edited spectra with negligible levels of crosstalk, and give modest agreement with phantom spectra. The TE series of GABA- and GSH-edited HERMES spectra modulate as a result of T2 relaxation and coupling evolution, with GABA showing a stronger TE-dependence. In vivo HERMES experiments show well-edited GABA and GSH signals. Measured concentrations are not statistically different between HERMES and MEGA-sLASER for GABA (1. 051 ± 0.254 i.u. and 1.053 ± 0.248 i.u; P > 0.985) or GSH (0.300 ± 0.091 i.u. and 0.302 ± 0.093 i.u; P > 0.940). Conclusion Simulated, phantom and in vivo measurements of HERMES show excellent segregation of GABA- and GSH-edited signals, and excellent agreement with separately acquired MEGA-sLASER data. HERMES allows two-fold acceleration of editing while maintaining spectral quality compared with sequentially acquired MEGA-sLASER measurements. Magn Reson Med 80:474–479, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

7. Ammonia-Weighted Imaging by Chemical Exchange Saturation Transfer MRI at 3 T

   Helge Jörn Zöllner, Markus Butz, Gerald Kircheis, and 5 more authors

   NMR in Biomedicine, Jan 2018

   Abs

   Hepatic encephalopathy (HE) is triggered by liver cirrhosis and is associated with an increased ammonia level within the brain tissue. The goal of this study was to investigate effects of ammonia on in vitro amide proton transfer (APT)-weighted chemical exchange saturation transfer (CEST) imaging in order to develop an ammonia-sensitive brain imaging method. APT-weighted CEST imaging was performed on phantom solutions including pure ammonia, bovine serum albumin (BSA), and tissue homogenate samples doped with various ammonia concentrations. All CEST data were assessed by magnetization transfer ratio asymmetry. In addition, optical methods were used to determine possible structural changes of the proteins in the BSA phantom. In vivo feasibility measurements were acquired in one healthy participant and two patients suffering from HE, a disease associated with increased brain ammonia levels. The CEST effect of pure ammonia showed a base-catalyzed behavior. At pH values greater than 5.6 no CEST effect was observed. The APT-weighted signal was significantly reduced for ammonia concentrations of 5mM or more at fixed pH values within the different protein phantom solutions. The optical methods revealed no protein aggregation or denaturation for ammonia concentrations less than 5mM. The in vivo measurements showed tissue specific and global reduction of the observed CEST signal in patients with HE, possibly linked to pathologically increased ammonia levels. APT-weighted CEST imaging is sensitive to changes in ammonia concentrations. Thus, it seems useful for the investigation of pathologies with altered tissue ammonia concentrations such as HE. However, the underlying mechanism needs to be explored in more detail in future in vitro and in vivo investigations.

2017

1. Simultaneous Measurement of Aspartate, NAA, and NAAG Using HERMES Spectral Editing at 3 Tesla

   Kimberly L. Chan, Muhammad G. Saleh, Georg Oeltzschner, and 2 more authors

   NeuroImage, Jul 2017

   Abs

   It has previously been shown that the HERMES method (‘Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy’) can be used to simultaneously edit pairs of metabolites (such as N-acetyl-aspartate (NAA) and N-acetyl aspartyl glutamate (NAAG), or glutathione and GABA). In this study, HERMES is extended for the simultaneous editing of three overlapping signals, and illustrated for the example of NAA, NAAG and Aspartate (Asp). Density-matrix simulations were performed in order to optimize the HERMES sequence. The method was tested in NAA and Asp phantoms, and applied to the centrum semiovale of the nine healthy control subjects that were scanned at 3T. Both simulations and phantom experiments showed similar metabolite multiplet patterns with good segregation of all three metabolites. In vivo measurements show consistent relative signal intensities and multiplet patterns with concentrations in agreement with literature values. Simulations indicate co-editing of glutathione, glutamine, and glutamate, but their signals do not significantly overlap with the detected aspartyl resonances. This study demonstrates that a four-step Hadamard-encoded editing scheme can be used to simultaneously edit three otherwise overlapping metabolites, and can measure NAA, NAAG, and Asp in vivo in the brain at 3T with minimal crosstalk.

2. Spatial Hadamard Encoding of J-Edited Spectroscopy Using Slice-Selective Editing Pulses

   Kimberly L. Chan, Georg Oeltzschner, Michael Schär, and 2 more authors

   NMR in Biomedicine, Jul 2017

   Abs

   A new approach for simultaneous dual-voxel J-difference spectral editing is described, which uses spatially selective spectral-editing pulses and Hadamard encoding. A theoretical framework for spatial Hadamard editing and reconstruction for parallel acquisition (SHERPA) was developed, applying gradient pulses during the frequency-selective editing pulses. Spectral simulations were performed for either one (gamma-aminobutyric acid, GABA) or two molecules (glutathione and lactate) simultaneously detected in two voxels. The method was tested in a two-compartment GABA phantom, and finally applied to the left and right hemispheres of 10 normal control subjects, scanned at 3 T. SHERPA was successfully implemented at 3 T and gave results in close agreement with conventional MEGA-PRESS scans in both the phantom and in vivo experiments. Simulations for GABA editing for (3 cm)3 voxels in the left and right hemispheres suggest that both editing efficiency losses and contamination between voxels are about 2%. Compared with conventional single-voxel single-metabolite J-difference editing, two- or fourfold acceleration is possible without significant loss of SNR using the SHERPA method. Unlike some other dual-voxel methods, the method can be used with single-channel receiver coils, and there is no SNR loss due to unfavorable receive-coil geometry factors.

3. Big GABA: Edited MR Spectroscopy at 24 Research Sites

   Mark Mikkelsen, Peter B. Barker, Pallab K. Bhattacharyya, and 57 more authors

   NeuroImage, Oct 2017

   Abs

   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.

4. Frequency and Phase Correction for Multiplexed Edited MRS of GABA and Glutathione

   Mark Mikkelsen, Muhammad G. Saleh, Jamie Near, and 8 more authors

   Magnetic Resonance in Medicine, Oct 2017
5. Dual-Volume Excitation and Parallel Reconstruction for J-Difference-Edited MR Spectroscopy

   Georg Oeltzschner, Nicolaas A J Puts, Kimberly L. Chan, and 3 more authors

   Magnetic Resonance in Medicine, Oct 2017

   Abs

   PURPOSE To develop J-difference editing with parallel reconstruction in accelerated multivoxel (PRIAM) for simultaneous measurement in two separate brain regions of γ-aminobutyric acid (GABA) or glutathione. METHODS PRIAM separates signals from two simultaneously excited voxels using receiver-coil sensitivity profiles. PRIAM was implemented into Mescher-Garwood (MEGA) edited experiments at 3 Tesla (T), and validated by acquiring dual-voxel MEGA-PRIAM (and compared with conventional single-voxel MEGA-PRESS) spectra from a GABA/glutathione phantom, and 11 healthy participants. RESULTS MEGA-PRIAM effectively separated phantom spectra with ∼3-4% between-voxel contamination. GABA and glutathione measurements agreed well with those obtained using single-voxel MEGA-PRESS (mean difference was below 2% in GABA levels, and below 7% in glutathione levels). In vivo, GABA- and glutathione-edited spectra were successfully reconstructed with a mean in vivo g-factor of 1.025 (typical voxel-center separation: 7-8 cm). MEGA-PRIAM experiments showed higher signal-to-noise ratio than sequential single-voxel experiments of the same total duration (mean improvement 1.38 ± 0.24). CONCLUSIONS Simultaneous acquisition of J-difference-edited GABA or glutathione spectra from two voxels is feasible at 3 T. MEGA-PRIAM increases data acquisition rates compared with MEGA-PRESS by a factor of 2. Magn Reson Med, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

2016

1. Beta Peak Frequencies at Rest Correlate with Endogenous GABA+/Cr Concentrations in Sensorimotor Cortex Areas

   Thomas J. Baumgarten, Georg Oeltzschner, Nienke Hoogenboom, and 3 more authors

   PLOS ONE, Jun 2016

   Abs

   Neuronal oscillatory activity in the beta band (15–30 Hz) is a prominent signal within the human sensorimotor cortex. Computational modeling and pharmacological modulation studies suggest an influence of GABAergic interneurons on the generation of beta band oscillations. Accordingly, studies in humans have demonstrated a correlation between GABA concentrations and power of beta band oscillations. It remains unclear, however, if GABA concentrations also influence beta peak frequencies and whether this influence is present in the sensorimotor cortex at rest and without pharmacological modulation. In the present study, we investigated the relation between endogenous GABA concentration (measured by magnetic resonance spectroscopy) and beta oscillations (measured by magnetoencephalography) at rest in humans. GABA concentrations and beta band oscillations were measured for left and right sensorimotor and occipital cortex areas. A significant positive linear correlation between GABA concentration and beta peak frequency was found for the left sensorimotor cortex, whereas no significant correlations were found for the right sensorimotor and the occipital cortex. The results show a novel connection between endogenous GABA concentration and beta peak frequency at rest. This finding supports previous results that demonstrated a connection between oscillatory beta activity and pharmacologically modulated GABA concentration in the sensorimotor cortex. Furthermore, the results demonstrate that for a predominantly right-handed sample, the correlation between beta band oscillations and endogenous GABA concentrations is evident only in the left sensorimotor cortex.

2. Prospective Frequency Correction for Macromolecule-Suppressed GABA Editing at 3T

   Richard A E Edden, Georg Oeltzschner, Ashley D. Harris, and 5 more authors

   Journal of Magnetic Resonance Imaging, Jun 2016

   Abs

   PURPOSE: To investigate the effects of B0 field offsets and drift on macromolecule (MM)-suppressed GABA-editing experiments, and to implement and test a prospective correction scheme. "Symmetric" editing schemes are proposed to suppress unwanted coedited MM signals in GABA editing. MATERIALS AND METHODS: Full density-matrix simulations of both conventional (nonsymmetric) and symmetric MM-suppressed editing schemes were performed for the GABA spin system to evaluate their offset-dependence. Phantom and in vivo (15 subjects at 3T) GABA-edited experiments with symmetrical suppression of MM signals were performed to quantify the effects of field offsets on the total GABA+MM signal (designated GABA+). A prospective frequency correction method based on interleaved water referencing (IWR) acquisitions was implemented and its experimental performance evaluated during positive and negative drift. RESULTS: Simulations show that the signal from MM-suppressed symmetrical editing schemes is an order of magnitude more susceptible to field offsets than the signal from nonsymmetric editing schemes. The MM-suppressed GABA signal changes by 8.6% per Hz for small field offsets. IWR significantly reduces variance in the field offset and measured GABA levels (both P < 0.001 by F-tests), maintaining symmetric suppression of MM signal. CONCLUSION: Symmetrical editing schemes substantially increase the dependence of measurements on B0 field offsets, which can arise due to patient movement and/or scanner instability. It is recommended that symmetrical editing should be used in combination with effective B0 stabilization, such as that provided by IWR. J. Magn. Reson. Imaging 2016;44:1474-1482.

3. Covert Hepatic Encephalopathy: Elevated Total Glutathione and Absence of Brain Water Content Changes

   Georg Oeltzschner, Markus Butz, Frithjof Wickrath, and 2 more authors

   Metabolic Brain Disease, Jun 2016

   Abs

   Recent pathophysiological models suggest that oxidative stress and hyperammonemia lead to a mild brain oedema in hepatic encephalopathy (HE). Glutathione (GSx) is a major cellular antioxidant and known to be involved in the interception of both. The aim of this work was to study total glutathione levels in covert HE (minimal HE and HE grade 1) and to investigate their relationship with local brain water content, levels of glutamine (Gln), myo-inositol (mI), neurotransmitter levels, critical flicker frequency (CFF), and blood ammonia. Proton magnetic resonance spectroscopy (1H MRS) data were analysed from visual and sensorimotor cortices of thirty patients with covert HE and 16 age-matched healthy controls. Total glutathione levels (GSx/Cr) were quantified with respect to creatine. Furthermore, quantitative MRI brain water content measures were evaluated. Data were tested for links with the CFF and blood ammonia. GSx/Cr was elevated in the visual (mHE) and sensorimotor (mHE, HE 1) MRS volumes and correlated with blood ammonia levels (both P < 0.001). It was further linked to Gln/Cr and mI/Cr (P < 0.01 in visual, P < 0.001 in sensorimotor) and to GABA/Cr (P < 0.01 in visual). Visual GSx/Cr correlated with brain water content in the thalamus, nucleus caudatus, and visual cortex (P < 0.01). Brain water measures did neither show group effects nor correlations with CFF or blood ammonia. Elevated total glutathione levels in covert HE (< HE 2) correlate with blood ammonia and may be a regional-specific reaction to hyperammonemia and oxidative stress. Brain water content is locally linked to visual glutathione levels, but appears not to be associated with changes of clinical parameters. This might suggest that cerebral oedema is only marginally responsible for the symptoms of covert HE.

4. Use of Quantitative Brain Water Imaging as Concentration Reference for J-Edited MR Spectroscopy of GABA

   Georg Oeltzschner, Alfons Schnitzler, Frithjof Wickrath, and 2 more authors

   Magnetic Resonance Imaging, Oct 2016

   Abs

   Purpose To compare two different methods of obtaining the water reference for determination of quantitative water-scaled in vivo concentration estimates of γ-aminobutyric acid (GABA). Methods Water-scaled GABA estimates from localized J-difference edited MR spectroscopy experiments can be computed using standard values for tissue-specific water content and relaxation times. Water content and relaxation may, however, be altered in pathology. This work re-analyzed data from a recent study in healthy controls and patients with minimal (mHE) or grade I (HE 1) hepatic encephalopathy, a disease associated with slight elevation of brain water content. J-difference edited MR spectroscopy data were combined with quantitative brain water measures, which provided individual water density references and T1 relaxation times. Resulting GABA estimates were compared to concentration values obtained using standard tissue-specific water content and relaxation values. Results Occipital GABA concentration values obtained from individual water and T1 maps were 1.64±0.35mM in controls, and significantly higher (P<0.01) than in mHE (1.15±0.28mM) and HE 1 patients (1.18±0.09mM). Results from the tissue-dependent approach (1.58±0.30mM (controls), 1.10±0.27mM (mHE) and 1.12±0.12mM (HE 1)) were slightly lower (P<0.05 in each group). Conclusion Water-scaled in vivo GABA estimates can be obtained with individual water density and T1 relaxation mapping. This approach may be useful for studying GABA levels in pathologies with substantial brain water content or relaxation changes.

5. Simultaneous Edited MRS of GABA and Glutathione

   Muhammad G. Saleh, Georg Oeltzschner, Kimberly L. Chan, and 5 more authors

   NeuroImage, Nov 2016

   Abs

   Edited MRS allows the detection of low-concentration metabolites, whose signals are not resolved in the MR spectrum. Tailored acquisitions can be designed to detect, for example, the inhibitory neurotransmitter γ-aminobutyric acid (GABA), or the reduction-oxidation (redox) compound glutathione (GSH), and single-voxel edited experiments are generally acquired at a rate of one metabolite-per-experiment. We demonstrate that simultaneous detection of the overlapping signals of GABA and GSH is possible using Hadamard Encoding and Reconstruction of Mega-Edited Spectroscopy (HERMES). HERMES applies orthogonal editing encoding (following a Hadamard scheme), such that GSH- and GABA-edited difference spectra can be reconstructed from a single multiplexed experiment. At a TE of 80ms, 20-ms editing pulses are applied at 4.56ppm (on GSH),1.9ppm (on GABA), both offsets (using a dual-lobe cosine-modulated pulse) or neither. Hadamard combinations of the four sub-experiments yield GABA and GSH difference spectra. It is shown that HERMES gives excellent separation of the edited GABA and GSH signals in phantoms, and resulting edited lineshapes agree well with separate Mescher-Garwood Point-resolved Spectroscopy (MEGA-PRESS) acquisitions. In vivo, the quality and signal-to-noise ratio (SNR) of HERMES spectra are similar to those of sequentially acquired MEGA-PRESS spectra, with the benefit of saving half the acquisition time.

2015

1. Low Visual Cortex GABA Levels in Hepatic Encephalopathy: Links to Blood Ammonia, Critical Flicker Frequency, and Brain Osmolytes

   Georg Oeltzschner, Markus Butz, Thomas J. Baumgarten, and 3 more authors

   Metabolic Brain Disease, Dec 2015

   Abs

   The pathogenesis of hepatic encephalopathy (HE) is not fully understood yet. Hyperammonemia due to liver failure and subsequent disturbance of cerebral osmolytic balance is thought to play a pivotal role in the emergence of HE. The aim of this in-vivo MR spectroscopy study was to investigate the levels of γ-aminobutyric acid (GABA) and its correlations with clinical symptoms of HE, blood ammonia, critical flicker frequency, and osmolytic levels. Thirty patients with minimal HE or HE1 and 16 age-matched healthy controls underwent graduation of HE according to the West-Haven criteria and including the critical flicker frequency (CFF), neuropsychometric testing and blood testing. Edited proton magnetic resonance spectroscopy (1H MRS) was used to non-invasively measure the concentrations of GABA, glutamate (Glu), glutamine (Gln), and myo-inositol (mI) - all normalized to creatine (Cr) - in visual and sensorimotor cortex. GABA/Cr in the visual area was significantly decreased in mHE and HE1 patients and correlated both to the CFF (r = 0.401, P = 0.013) and blood ammonia levels (r = −0.434, P = 0.006). Visual GABA/Cr was also strongly linked to mI/Cr (r = 0.720, P < 0.001) and Gln/Cr (r = −0.699, P < 0.001). No group differences or correlations were found for GABA/Cr in the sensorimotor area. Hepatic encephalopathy is associated with a regional specific decrease of GABA levels in the visual cortex, while no changes were revealed for the sensorimotor cortex. Correlations of visual GABA/Cr with CFF, blood ammonia, and osmolytic regulators mI and Gln indicate that decreased visual GABA levels might contribute to HE symptoms, most likely as a consequence of hyperammonemia.

2014

1. Pilot Study of Iopamidol-Based Quantitative pH Imaging on a Clinical 3T MR Scanner

   Anja Müller-Lutz, Nadia Khalil, Benjamin Schmitt, and 6 more authors

   Magnetic Resonance Materials in Physics, Biology and Medicine, Dec 2014

   Abs

   The objective of this study was to show the feasibility to perform Iopamidol-based pH imaging via clinical 3T magnetic resonance imaging (MRI) using chemical exchange saturation transfer (CEST) imaging with pulse train presaturation.