- Altered in Vivo Brain GABA and Glutamate Levels Are Associated with Multiple Sclerosis Central FatigueArm, Jameen, Oeltzschner, Georg, Al-iedani, Oun, Lea, Rod, Lechner-Scott, Jeannette, and Ramadan, SaadallahEuropean Journal of Radiology 2021
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.
- Neurotransmitters and Neurometabolites in Late-Life Depression: A Preliminary Magnetic Resonance Spectroscopy Study at 7TSmith, Gwenn S., Oeltzschner, Georg, Gould, Neda F., Leoutsakos, Jeannie-Marie S., Nassery, Najilla, Joo, Jin Hui, Kraut, Michael A., Edden, Richard A. E., Barker, Peter B., Wijtenburg, S. Andrea, Rowland, Laura M., and Workman, Clifford I.Journal of Affective Disorders 2021
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.
- Spectral Diffusion Analysis of Kidney Intravoxel Incoherent Motion MRI in Healthy Volunteers and Patients with Renal PathologiesStabinska, Julia, Ljimani, Alexandra, Zöllner, Helge Jörn, Wilken, Enrica, Benkert, Thomas, Limberg, Juliane, Esposito, Irene, Antoch, Gerald, and Wittsack, Hans-JörgMagnetic Resonance in Medicine 2021
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.
- Frequency and Phase Correction of J-Difference Edited MR Spectra Using Deep LearningTapper, Sofie, Mikkelsen, Mark, Dewey, Blake E., Zöllner, Helge J., Hui, Steve C. N., Oeltzschner, Georg, and Edden, Richard A. E.Magnetic Resonance in Medicine 2021
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\textdegree 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.
- Comparison of Different Linear-Combination Modeling Algorithms for Short-TE Proton SpectraZöllner, Helge J., Považan, Michal, Hui, Steve C. N., Tapper, Sofie, Edden, Richard A. E., and Oeltzschner, GeorgNMR in Biomedicine 2021
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.
- Osprey: Open-Source Processing, Reconstruction & Estimation of Magnetic Resonance Spectroscopy DataOeltzschner, Georg, Zöllner, Helge J., Hui, Steve C. N., Mikkelsen, Mark, Saleh, Muhammad G., Tapper, Sofie, and Edden, Richard A. E.Journal of Neuroscience Methods 2020
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.
- High γ-Aminobutyric Acid Content Within the Medial Prefrontal Cortex Is a Functional Signature of Somatic Symptoms Disorder in Patients With Parkinson’s DiseasePizzi, Stefano Delli, Franciotti, Raffaella, Ferretti, Antonio, Edden, Richard A. E., Zöllner, Helge J., Esposito, Roberto, Bubbico, Giovanna, Aiello, Claudia, Calvanese, Francesco, Sensi, Stefano L., Tartaro, Armando, Onofrj, Marco, and Bonanni, LauraMovement Disorders 2020
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. \textcopyright 2020 International Parkinson and Movement Disorder Society
- Comparison of Multivendor Single-Voxel MR Spectroscopy Data Acquired in Healthy Brain at 26 SitesPovažan, Michal, Mikkelsen, Mark, Berrington, Adam, Bhattacharyya, Pallab K., Brix, Maiken K., Buur, Pieter F., Cecil, Kim M., Chan, Kimberly L., Chen, David Y.T., Craven, Alexander R., Cuypers, Koen, Dacko, Michael, Duncan, Niall W., Dydak, Ulrike, Edmondson, David A., Ende, Gabriele, Ersland, Lars, Forbes, Megan A., Gao, Fei, Greenhouse, Ian, Harris, Ashley D., He, Naying, Heba, Stefanie, Hoggard, Nigel, Hsu, Tun-Wei, Jansen, Jacobus F. A., Kangarlu, Alayar, Lange, Thomas, Lebel, R. Marc, Li, Yan, Lin, Chien-Yuan E., Liou, Jy-Kang, Lirng, Jiing-Feng, Liu, Feng, Long, Joanna R., Ma, Ruoyun, Maes, Celine, Moreno-Ortega, Marta, Murray, Scott O., Noah, Sean, Noeske, Ralph, Noseworthy, Michael D., Oeltzschner, Georg, Porges, Eric C., Prisciandaro, James J., Puts, Nicolaas A. J., Roberts, Timothy P. L., Sack, Markus, Sailasuta, Napapon, Saleh, Muhammad G., Schallmo, Michael-Paul, Simard, Nicholas, Stoffers, Diederick, Swinnen, Stephan P., Tegenthoff, Martin, Truong, Peter, Wang, Guangbin, Wilkinson, Iain D., Wittsack, Hans-Jörg, Woods, Adam J., Xu, Hongmin, Yan, Fuhua, Zhang, Chencheng, Zipunnikov, Vadim, Zöllner, Helge J., Edden, Richard A.E., and Barker, Peter B.Radiology 2020
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 \pm 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.\textcopyright RSNA, 2020Online supplemental material is available for this article.
- Reduced Striatal GABA in Unmedicated Children with ADHD at 7TPuts, Nicolaas A., Ryan, Matthew, Oeltzschner, Georg, Horska, Alena, Edden, Richard A. E., and Mahone, E. MarkPsychiatry Research: Neuroimaging 2020
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.
- Effect of Age on GABA+ and Glutathione in a Pediatric SampleSaleh, M. G., Papantoni, A., Mikkelsen, M., Hui, S. C. N., Oeltzschner, G., Puts, N. A., Edden, R. a. E., and Carnell, S.American Journal of Neuroradiology 2020
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.
Both GABA+\textsubscriptH2O (r = 0.63, P = .002) and GABA+/Cr (r = 0.48, P = .026) significantly correlated with age, whereas glutathione measurements and GM\textsubscriptratio did not.
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.
- Simultaneous Edited MRS of GABA, Glutathione, and EthanolSaleh, Muhammad G., Wang, Min, Mikkelsen, Mark, Hui, Steve C. N., Oeltzschner, Georg, Boissoneault, Jeff, Stennett, Bethany, Edden, Richard A. E., and Porges, Eric C.NMR in Biomedicine 2020
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 \pm 0.012 for GABA/Cr, 0.037 \pm 0.006 for GSH/Cr, and 0.305 \pm 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.
- Simultaneous Editing of GABA and GSH with Hadamard-Encoded MR Spectroscopic ImagingChan, Kimberly L., Oeltzschner, Georg, Saleh, Muhammad G., Edden, Richard A. E., and Barker, Peter B.Magnetic Resonance in Medicine 2019
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.
- Big GABA II: Water-Referenced Edited MR Spectroscopy at 25 Research SitesMikkelsen, M., Rimbault, D. L., Barker, P. B., Bhattacharyya, P. K., Brix, M. K., Buur, P. F., Cecil, K. M., Chan, K. L., Chen, D. Y., Craven, A. R., Cuypers, K., Dacko, M., Duncan, N. W., Dydak, U., Edmondson, D. A., Ende, G., Ersland, L., Forbes, M. A., Gao, F., Greenhouse, I., Harris, A. D., He, N., Heba, S., Hoggard, N., Hsu, T. W., Jansen, J. F. A., Kangarlu, A., Lange, T., Lebel, R. M., Li, Y., Lin, C. E., Liou, J. K., Lirng, J. F., Liu, F., Long, J. R., Ma, R., Maes, C., Moreno-Ortega, M., Murray, S. O., Noah, S., Noeske, R., Noseworthy, M. D., Oeltzschner, G., Porges, E. C., Prisciandaro, J. J., Puts, N. A. J., Roberts, T. P. L., Sack, M., Sailasuta, N., Saleh, M. G., Schallmo, M. P., Simard, N., Stoffers, D., Swinnen, S. P., Tegenthoff, M., Truong, P., Wang, G., Wilkinson, I. D., Wittsack, H. J., Woods, A. J., Xu, H., Yan, F., Zhang, C., Zipunnikov, V., Zollner, H. J., and Edden, R. A. E.Neuroimage 2019
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.
- Advanced Hadamard-Encoded Editing of Seven Low-Concentration Brain Metabolites: Principles of HERCULESOeltzschner, Georg, Saleh, Muhammad G., Rimbault, Daniel, Mikkelsen, Mark, Chan, Kimberly L., Puts, Nicolaas A.J., and Edden, Richard A.E.NeuroImage 2019
PURPOSE To demonstrate the framework of a novel Hadamard-encoded spectral editing approach for simultaneously detecting multiple low-concentration brain metabolites in vivo at 3T. METHODS HERCULES (Hadamard Editing Resolves Chemicals Using Linear-combination Estimation of Spectra) is a four-step Hadamard-encoded editing scheme. 20-ms editing pulses are applied at: (A) 4.58 and 1.9 ppm; (B) 4.18 and 1.9 ppm; (C) 4.58 ppm; and (D) 4.18 ppm. Edited signals from γ-aminobutyric acid (GABA), glutathione (GSH), ascorbate (Asc), N-acetylaspartate (NAA), N-acetylaspartylglutamate (NAAG), aspartate (Asp), lactate (Lac), and likely 2-hydroxyglutarate (2-HG) are separated with reduced signal overlap into distinct Hadamard combinations: (A+B+C+D); (A+B–C–D); and (A–B+C–D). HERCULES uses a novel multiplexed linear-combination modeling approach, fitting all three Hadamard combinations at the same time, maximizing the amount of information used for model parameter estimation, in order to quantify the levels of these compounds. Fitting also allows estimation of the levels of total choline (tCho), myo-inositol (Ins), glutamate (Glu), and glutamine (Gln). Quantitative HERCULES results were compared between two grey- and white-matter-rich brain regions (11 min acquisition time each) in 10 healthy volunteers. Coefficients of variation (CV) of quantified measurements from the HERCULES fitting approach were compared against those from a single-spectrum fitting approach, and against estimates from short-TE PRESS data. RESULTS HERCULES successfully segregates overlapping resonances into separate Hadamard combinations, allowing for the estimation of levels of seven coupled metabolites that would usually require a single 11-min editing experiment each. Metabolite levels and CVs agree well with published values. CVs of quantified measurements from the multiplexed HERCULES fitting approach outperform single-spectrum fitting and short-TE PRESS for most of the edited metabolites, performing only slightly to moderately worse than the fitting method that gives the lowest CVs for tCho, NAA, NAAG, and Asp. CONCLUSION HERCULES is a new experimental approach with the potential for simultaneous editing and multiplexed fitting of up to seven coupled low-concentration and six high-concentration metabolites within a single 11-min acquisition at 3T.
- Neurometabolites and Associations with Cognitive Deficits in Mild Cognitive Impairment: A Magnetic Resonance Spectroscopy Study at 7 TeslaOeltzschner, Georg, Wijtenburg, S. Andrea, Mikkelsen, Mark, Edden, Richard A. E., Barker, Peter B., Joo, Jin Hui, Leoutsakos, Jeannie-Marie S., Rowland, Laura M., Workman, Clifford I., and Smith, Gwenn S.Neurobiology of Aging 2019
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.
- Biallelic Mutation of Human SLC6A6 Encoding the Taurine Transporter TAUT Is Linked to Early Retinal DegenerationPreising, Markus N., Görg, Boris, Friedburg, Christoph, Qvartskhava, Natalia, Budde, Birgit S., Bonus, Michele, Toliat, Mohammad R., Pfleger, Christopher, Altmüller, Janine, Herebian, Diran, Beyer, Mila, Zöllner, Helge J., Wittsack, Hans-Jörg, Schaper, Jörg, Klee, Dirk, Zechner, Ulrich, Nürnberg, Peter, Schipper, Jörg, Schnitzler, Alfons, Gohlke, Holger, Lorenz, Birgit, Häussinger, Dieter, and Bolz, Hanno J.The FASEB Journal 2019
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
- Multi-Vendor Standardized Sequence for Edited Magnetic Resonance SpectroscopySaleh, Muhammad G., Rimbault, Daniel, Mikkelsen, Mark, Oeltzschner, Georg, Wang, Anna M., Jiang, Dengrong, Alhamud, Ali, Near, Jamie, Schär, Michael, Noeske, Ralph, Murdoch, James B., Ersland, Lars, Craven, Alexander R., Dwyer, Gerard Eric, Grüner, Eli Renate, Pan, Li, Ahn, Sinyeob, and Edden, Richard A. E.NeuroImage 2019
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.
- Reproducibility of Brain MRS in Older Healthy Adults at 7TWijtenburg, S. Andrea, Rowland, Laura M., Oeltzschner, Georg, Barker, Peter B., Workman, Clifford I., and Smith, Gwenn S.NMR in Biomedicine 2019
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 \pm 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.
- Chemical Exchange Saturation Transfer Imaging in Hepatic EncephalopathyZöllner, Helge Jörn, Butz, Markus, Jördens, Markus, Füllenbach, Nur-Deniz, Häussinger, Dieter, Schmitt, Benjamin, Wittsack, Hans-Jörg, and Schnitzler, AlfonsNeuroImage: Clinical 2019
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.
- Connecting Occipital Alpha Band Peak Frequency, Visual Temporal Resolution, and Occipital GABA Levels in Healthy Participants and Hepatic Encephalopathy PatientsBaumgarten, Thomas J., Neugebauer, Julia, Oeltzschner, Georg, Füllenbach, Nur-Deniz, Kircheis, Gerald, Häussinger, Dieter, Lange, Joachim, Wittsack, Hans-Jörg, Butz, Markus, and Schnitzler, AlfonsNeuroImage: Clinical 2018
- Opposite Dynamics of GABA and Glutamate Levels in the Occipital Cortex during Visual ProcessingKurcyus, Katarzyna, Annac, Efsun, Hanning, Nina M., Harris, Ashley D., Oeltzschner, Georg, Edden, Richard, and Riedl, ValentinThe Journal of Neuroscience 2018
- Effects of Eddy Currents on Selective Spectral Editing Experiments at 3TOeltzschner, Georg, Snoussi, Karim, Puts, Nicolaas A., Mikkelsen, Mark, Harris, Ashley D., Pradhan, Subechhya, Tsapkini, Kyrana, Schär, Michael, Barker, Peter B., and Edden, Richard A. E.Journal of Magnetic Resonance Imaging 2018
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 (∆f) between the actual vs. nominal expected saturation frequency. Results Saturation-offset N-acetyl-aspartate-phantom experiments show that ∆f varied with voxel orientation, ranging from 10.4 Hz (unrotated) to 6.4 Hz (45\textdegree rotation about the caudal–cranial axis) and 0.4 Hz (45\textdegree 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 ∆f (to ∼2 Hz). Water-suppression crusher gradients also introduced a frequency offset, with ∆f = 0.6 Hz (“excitation” water suppression), compared to 10.2 Hz (no water suppression). In vivo spectra showed a negative edited “GABA” signal, suggesting ∆f 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.
- Hadamard Editing of Glutathione and Macromolecule-Suppressed GABAOeltzschner, Georg, Chan, Kimberly L., Saleh, Muhammad G., Mikkelsen, Mark, Puts, Nicolaas A., and Edden, Richard A. E.NMR in Biomedicine 2018
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 \pm 0.15 i.u. (0.59 \pm 0.12 i.u.) for MM-suppressed HERMES, and 1.13 \pm 0.09 i.u. (0.66 \pm 0.09 i.u.) for MEGA-PRESS. Mean GABA (and GSH) differences between MM-suppressed HERMES and MEGA-PRESS were –0.03 \pm 0.11 i.u. (–0.07 \pm 0.11 i.u.). The mean signal-to-noise ratio (SNR) improvement of MM-suppressed HERMES over MEGA-PRESS was 1.45 \pm 0.25 for GABA and 1.32 \pm 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.
- J-Difference-Edited MRS Measures of γ-Aminobutyric Acid before and after Acute Caffeine AdministrationOeltzschner, Georg, Zöllner, Helge J., Jonuscheit, Marc, Lanzman, Rotem S., Schnitzler, Alfons, and Wittsack, Hans-JörgMagnetic Resonance in Medicine 2018
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.
- Simultaneous Editing of GABA and Glutathione at 7T Using Semi-LASER LocalizationSaleh, Muhammad G., Mikkelsen, Mark, Oeltzschner, Georg, Chan, Kimberly L., Berrington, Adam, Barker, Peter B., and Edden, Richard A. E.Magnetic Resonance in Medicine 2018
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 \texttimes 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 \pm 0.254 i.u. and 1.053 \pm 0.248 i.u; P > 0.985) or GSH (0.300 \pm 0.091 i.u. and 0.302 \pm 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. \textcopyright 2017 International Society for Magnetic Resonance in Medicine.
- Ammonia-Weighted Imaging by Chemical Exchange Saturation Transfer MRI at 3 TZöllner, Helge Jörn, Butz, Markus, Kircheis, Gerald, Klinker, Stefan, Häussinger, Dieter, Schmitt, Benjamin, Schnitzler, Alfons, and Wittsack, Hans-JörgNMR in Biomedicine 2018
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.
- Simultaneous Measurement of Aspartate, NAA, and NAAG Using HERMES Spectral Editing at 3 TeslaChan, Kimberly L., Saleh, Muhammad G., Oeltzschner, Georg, Barker, Peter B., and Edden, Richard A. E.NeuroImage 2017
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.
- Spatial Hadamard Encoding of J-Edited Spectroscopy Using Slice-Selective Editing PulsesChan, Kimberly L., Oeltzschner, Georg, Schär, Michael, Barker, Peter B., and Edden, Richard A. E.NMR in Biomedicine 2017
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.
- Big GABA: Edited MR Spectroscopy at 24 Research SitesMikkelsen, M., Barker, P.B., Bhattacharyya, P.K., Brix, M.K., Buur, P.F., Cecil, K.M., Chan, K.L., Chen, D.Y.-T., Craven, A.R., Cuypers, K., Dacko, M., Duncan, N.W., Dydak, U., Edmondson, D.A., Ende, G., Ersland, L., Gao, F., Greenhouse, I., Harris, A.D., He, N., Heba, S., Hoggard, N., Hsu, T.-W., Jansen, J.F.A., Kangarlu, A., Lange, T., Lebel, R.M., Li, Y., Lin, C.-Y.E., Liou, J.-K., Lirng, J.-F., Liu, F., Ma, R., Maes, C., Moreno-Ortega, M., Murray, S.O., Noah, S., Noeske, R., Noseworthy, M.D., Oeltzschner, G., Prisciandaro, J.J., Puts, N.A.J., Roberts, T.P.L., Sack, M., Sailasuta, N., Saleh, M.G., Schallmo, M.-P., Simard, N., Swinnen, S.P., Tegenthoff, M., Truong, P., Wang, G., Wilkinson, I.D., Wittsack, H.-J., Xu, H., Yan, F., Zhang, C., Zipunnikov, V., Zöllner, H.J., and Edden, R.A.E.NeuroImage 2017
\textcopyright 2017 Elsevier Inc. 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.
- Frequency and Phase Correction for Multiplexed Edited MRS of GABA and GlutathioneMikkelsen, Mark, Saleh, Muhammad G., Near, Jamie, Chan, Kimberly L., Gong, Tao, Harris, Ashley D., Oeltzschner, Georg, Puts, Nicolaas A.J., Cecil, Kim M., Wilkinson, Iain D., and Edden, Richard A.E.Magnetic Resonance in Medicine 2017
- Dual-Volume Excitation and Parallel Reconstruction for J-Difference-Edited MR SpectroscopyOeltzschner, Georg, Puts, Nicolaas A J, Chan, Kimberly L., Boer, Vincent O., Barker, Peter B., and Edden, Richard A EMagnetic Resonance in Medicine 2017
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 \pm 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. \textcopyright 2016 International Society for Magnetic Resonance in Medicine.
- Beta Peak Frequencies at Rest Correlate with Endogenous GABA+/Cr Concentrations in Sensorimotor Cortex AreasBaumgarten, Thomas J., Oeltzschner, Georg, Hoogenboom, Nienke, Wittsack, Hans-Jörg, Schnitzler, Alfons, and Lange, JoachimPLOS ONE 2016
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.
- Prospective Frequency Correction for Macromolecule-Suppressed GABA Editing at 3TEdden, Richard A E, Oeltzschner, Georg, Harris, Ashley D., Puts, Nicolaas A J, Chan, Kimberly L., Boer, Vincent O., Sch??r, Michael, and Barker, Peter B.Journal of Magnetic Resonance Imaging 2016
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.
- Covert Hepatic Encephalopathy: Elevated Total Glutathione and Absence of Brain Water Content ChangesOeltzschner, Georg, Butz, Markus, Wickrath, Frithjof, Wittsack, Hans-Jörg, and Schnitzler, AlfonsMetabolic Brain Disease 2016
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.
- Use of Quantitative Brain Water Imaging as Concentration Reference for J-Edited MR Spectroscopy of GABAOeltzschner, Georg, Schnitzler, Alfons, Wickrath, Frithjof, Zöllner, Helge Jörn, and Wittsack, Hans-JörgMagnetic Resonance Imaging 2016
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\pm0.35mM in controls, and significantly higher (P<0.01) than in mHE (1.15\pm0.28mM) and HE 1 patients (1.18\pm0.09mM). Results from the tissue-dependent approach (1.58\pm0.30mM (controls), 1.10\pm0.27mM (mHE) and 1.12\pm0.12mM (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.
- Simultaneous Edited MRS of GABA and GlutathioneSaleh, Muhammad G., Oeltzschner, Georg, Chan, Kimberly L., Puts, Nicolaas A J, Mikkelsen, Mark, Sch??r, Michael, Harris, Ashley D., and Edden, Richard A ENeuroImage 2016
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 ??-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 80??ms, 20-ms editing pulses are applied at 4.56??ppm (on GSH),1.9??ppm (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.
- Low Visual Cortex GABA Levels in Hepatic Encephalopathy: Links to Blood Ammonia, Critical Flicker Frequency, and Brain OsmolytesOeltzschner, Georg, Butz, Markus, Baumgarten, Thomas J., Hoogenboom, Nienke, Wittsack, Hans-Jörg, and Schnitzler, AlfonsMetabolic Brain Disease 2015
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.
- Pilot Study of Iopamidol-Based Quantitative pH Imaging on a Clinical 3T MR ScannerMüller-Lutz, Anja, Khalil, Nadia, Schmitt, Benjamin, Jellus, Vladimir, Pentang, Gael, Oeltzschner, Georg, Antoch, Gerald, Lanzman, Rotem S., and Wittsack, Hans-JörgMagnetic Resonance Materials in Physics, Biology and Medicine 2014
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.