Activation induced changes in GABA: functional MRS at 7 T with MEGA-sLASER

Functional magnetic resonance spectroscopy (fMRS) has been used to assess the dynamic metabolic responses of the brain to a physiological stimulus non-invasively. However, only limited information on the dynamic functional response of γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain, is available. We aimed to measure the activation-induced changes in GABA unambiguously using a spectral editing method, instead of the conventional direct detection techniques used in previous fMRS studies. The Mescher-Garwood-semi-localised by adiabatic selective refocusing (MEGA-sLASER) sequence was developed at 7 T to obtain the time course of GABA concentration without macromolecular contamination. A significant decrease (−12±5%) in the GABA to total creatine ratio (GABA/tCr) was observed in the motor cortex during a period of 10 minutes of hand-clenching, compared to an initial baseline level (GABA/tCr = 0.11±0.02) at rest. An increase in the Glx (glutamate and glutamine) to tCr ratio was also found, which is in agreement with previous findings. In contrast, no significant changes in NAA/tCr and tCr were detected. With consistent and highly efficient editing performance for GABA detection and the advantage of visually identifying GABA resonances in the spectra, MEGA-sLASER is demonstrated to be an effective method for studying of dynamic changes in GABA at 7 T

Multi-vendor standardized sequence for edited magnetic resonance spectroscopy

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

Role of magnetic resonance spectroscopy in cerebral glutathione quantification for youth mental health:A systematic review

AIM: Oxidative stress is strongly implicated in many psychiatric disorders, which has resulted in the development of new interventions to attempt to perturb this pathology. A great deal of attention has been paid to glutathione, which is the brain's dominant antioxidant and plays a fundamental role in removing free radicals and other reactive oxygen species. Measurement of glutathione concentration in the brain in vivo can provide information on redox status and potential for oxidative stress to develop. Glutathione might also represent a marker to assess treatment response. METHODS: This paper systematically reviews studies that assess glutathione concentration (measured using magnetic resonance spectroscopy) in various mental health conditions. RESULTS: There is limited evidence showing altered brain glutathione concentration in mental disorders; the best evidence suggests glutathione is decreased in depression, but is not altered in bipolar disorder. The review then outlines the various methodological options for acquiring glutathione data using spectroscopy. CONCLUSIONS: Analysis of the minimum effect size measurable in existing studies indicates that increased number of participants is required to measure subtle but possibly important differences and move the field forward

Implementation of Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) for quantification of ɣ-aminobutyric acid (GABA) and glutathione (GSH)

The present study aimed to accelerate and improve accuracy of ɣ-aminobutyric acid (GABA) and glutathione (GSH) quantification. These metabolites, present at low concentrations in the brain, are challenging to detect using MR spectroscopy due to the fact that their resonance frequencies overlap with those of other more abundant metabolites. The advanced spectral editing techniques involving J-difference editing that are required to resolve the overlapping signals of these low concentration metabolites are not routinely available on clinical MRI scanners. In this work we implemented on a 3T Siemens Skyra MRI a novel MRS technique called Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) to simultaneously detect GABA and GSH, developed a novel postprocessing technique that simultaneously models the sum and various difference spectra, and evaluated the performance of the sequence and processing method both in phantoms and in vivo. HERMES was implemented by modifying the Siemens GABA-edited MEGA-PRESS WIP sequence to include two additional sub-experiments – one editing GSH with a single lobe pulse and one editing both GABA and GSH using a dual lobe pulse, and replacing the Siemens pulses with ‘universal' pulses similar to those used in a previous implementation of HERMES on a Philips platform. Performance was assessed in a phantom and 22 healthy adults, 15 of whom provided usable data (7 male, mean age 25.6 ± 2.7 yr). Three of the subjects were scanned 3 times to assess reproducibility. Data were processed and compared using a set of custom scripts in MATLAB. Following frequency and phase correction of individual averages with GANNET, we applied our custom simultaneous linear combination model that iteratively fit the concatenated sum and difference spectra using a least squares routine. SPM was used for tissue segmentation of structural images and FID-A to simulate high-resolution basis sets. The simultaneous modelling technique provided absolute quantification results for 15 metabolite moieties using internal unsuppressed water as a reference. The performance of the simultaneous fitting approach was compared to multiple independent fittings for HERCULES (Hadamard Editing Resolves Chemicals Using Linear-combination Estimation of Spectra) data that had been previously acquired on a 3T Philips Achieva MRI. Although the HERMES sequence implemented on the Siemens platform as part of this project was able to successfully edit both GABA and GSH, and generate line shapes consistent with the work by Saleh et al. (2016), quantification accuracy was disappointing. In the phantom data, GSH and GABA concentrations were both roughly 50% of known levels. Since the actual concentrations in vivo were not known, we were not able to establish accuracy, but quantification agreement between the MEGA-PRESS and HERMES sequences was poor for most metabolites. Specifically, GABA levels were two to three times higher than expected values using both HERMES and GABA-edited MEGA-PRESS. Despite poor absolute agreement, concentrations from HERMES and MEGA-PRESS data were moderately correlated, and HERMES data showed lower coefficients of variation across subjects, suggesting that it may be more reliable. HERMES was also more reproducible across scanning sessions and participants for more metabolites than GABA- or GSH-edited MEGA-PRESS. Our findings also showed that simultaneous fitting using the sum and difference spectra produces lower coefficients of variation for most metabolites than fittings to sum and difference spectra separately

Establishing reliable MR spectroscopy techniques for measuring GABA and Glutathione in the human brain

Background: Proton MR spectroscopy (MRS) is a well-established method for measuring the relative concentration of a wide range of metabolites in the human brain noninvasively. Lately, more advanced spectroscopic techniques, such as MEGAPRESS, have emerged enabling us to measure low concentrated metabolites with complex peak splitting patterns. Examples of such metabolites are the main inhibitory brain neurotransmitter, g-aminobutyric acid (GABA), and the main brain antioxidant, glutathione (GSH). Impairment of both GABA and GSH have been implicated in the pathophysiology of several psychiatric and neurodegenerative disorders, including schizophrenia, bipolar disorder, autism spectrum disorder (ASD), multiple sclerosis, Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson disease. An accurate and reliable quantification of these metabolites in vivo is therefore of utmost interest and clinical relevance. The PhD started with an ASD focus, setting out to examine brain MRS measurable differences between boys with ASD and controls. The focus, however, soon shifted to the methodological aspect of MRS, with a desire to contribute in establishing reliable MRS techniques for measuring GABA and GSH in the human brain. Aims: The aim of the ASD study was to explore the excitatory/inhibitory hypothesis in children with ASD by looking for imbalances in brain metabolites in boys with ASD compared with typically developing controls with standard and advanced MRS techniques. Validating GABA and GSH edited MEGA-PRESS, and comparing these sequences to the standard single voxel measurements; short TE STEAM and PRESS sequence. Methods: Four different studies were performed, all on a 3.0 T GE MRI scanner. The ASD study: 14 boys with ASD and 24 age-matched controls were examined with both the GABA edited MEGA-PRESS and PRESS sequence. Autism symptom severity were reported by the Autism Spectrum Screening Questionnaire (ASSQ). The GABA reprod study: Two 20 min long GABA edited MEGA-PRESS acquisition were performed in 21 healthy young male volunteers. The participants were scanned twice with identical protocols. By applying a timewindowing approach, within-and between-session reproducibility was calculated. The “Christmas phantom” study: 122 GSH edited MEGA-PRESS and PRESS spectra of a phantom containing GSH were acquired over a time period of 11 days. The resulting decaying GSH curve (GSH oxidizes to GSSG) were modelled. A 1-year-after follow-up acquisition for both sequences was also performed. The GSH reprod study: GSH edited MEGA-PRESS and short TE STEAM and PRESS acquisitions were performed in 36 healthy volunteers. The participants were scanned twice with identical protocols, one week apart. The timewindowing approach was applied for within- and between-session reproducibility for GSH edited MEGA-PRESS. Differences between quantified GSH levels between males and females were examined, and the three different methods of measuring GSH were evaluated. Main Results: There was a significant negative correlation in the ASD group between ASSQ and GABA levels, however there was no significant difference between the ASD group and the control group in MEGA-PRESS measured GABA levels. Increasing the number of repetitions in GABA edited MEGA-PRESS showed improvements for within- and between-session reproducibility up to about 218 paired repetitions (scan length ~ 13 min). Gannet combined with LCModel proved the best method processing the GABA data. Both GSH edited MEGA-PRESS and PRESS were able to measure the degradation of GSH in the phantom, however the modelled GSH edited MEGA-PRESS degradation curve was more accurate than PRESS. Between-session variability of GSH edited MEGA-PRESS stabilised at around 128 paired repetitions (~8 min). There were no significant correlations between GSH measured with MEGA-PRESS, STEAM and PRESS, and no differences in measured GSH levels between males and females. Conclusion: In line with other studies, the ASD participants have GABA values that seem to change with their clinical severity although there was no group difference with healthy controls. For both GABA and GSH, it is possible to acquire reproducible MEGA-PRESS measurements. GSH edited MEGA-PRESS measurements have somewhat higher coefficient of variation (meaning lower reproducibility), but stabilises at a shorter scan length than GABA edited MEGA-PRESS. MEGA-PRESS is more accurate that both PRESS and STEAM in measuring GSH for in vivo measurements. This is also reflected in its in vitro quantification, where the PRESS measurements fit of GSH seem to include oxidised GSH

New techniques for quantification of biomarkers and metabolites by magnetic resonance imaging and spectroscopy

Since its early beginnings, almost five decades ago, MRI has revolutionised medical imaging, sustaining an active field of research into new applications, and improved understanding of the underlying mechanisms. Its complexity and flexibility, as a non-invasive imaging modality is simultaneously, an asset and a challenge. Quantitative imaging provides a particular challenge due to an increased sensitivity to experimental variations. The development of accurate and robust methods for quantitative magnetic resonance requires protocols to be carefully calibrated to produce consistent results. This necessitates the use of test objects with known, stable, configurable characteristics. This thesis is aimed at the development of these test objects, and their use within quantitative imaging, spectroscopy, and the development of new techniques.First, a set of magnetic resonance test objects were created, and their relaxation properties assessed. T1 and T2 are calculated using spin, and multi-spin echo sequences respectively. Several contrast and gelling agents were assessed, and the relaxivity estimated in each case. The protocol dependence of T1 estimation methods is examined using a phantom and in-vivo study. Saturation and inversion recovery estimations are compared to variable flip angle methods, and the statistical distributions of T1 maps quantified. A series of calibrated phantom studies are conducted, assessing the analysis methods used for in-vivo magnetic resonance spectroscopy. The concentration of brain metabolites is varied within liquid and gel phantoms, and the ratio of GABA to NAA is calculated using a number of analysis tools, and in-house software.Finally, a magnetic resonance spectroscopy Hamiltonian simulator is implemented in Matlab. The simulator is utilised by collaborators in developing a quantum control framework. Optimal control is used to generate chemically selective RF pulses, and initial experimental implementations explored.The quantitative methods were found to exhibit both acquisition and analysis method dependencies. However, results were largely consistent within methodology, highlighting the need for consistency across sites to ensure valid comparison. The the-oretical development of novel RF pulses has been successful, but much work remains to approach experimental implementation

ACCELERATING EDITED MAGNETIC RESONANCE SPECTROSCOPY AND SPECTROSCOPIC IMAGING OF THE HUMAN BRAIN AT 3T

Edited magnetic resonance spectroscopy is a method capable of probing biochemical processes non-invasively, but suffers from an inherently low signal-to-noise which results in long acquisition times. Increasing the efficiency of these scans would reduce these acquisition times and can increase the number of scans, and consequently the amount of information, that can be acquired within a time-limited scan session in clinical and research settings. This thesis addresses this need with methods to increase the number of metabolites and regions that can be detected within a single scan as well as a method to reduce the duration of the preparation pulses. In particular, we demonstrate the ability of two techniques to detected glutathione and lactate simultaneously. We then move on to introduce ‘Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy’ (HERMES) and demonstrate that it can detect two and three metabolites simultaneously. As an example of this method, a scheme for separately detecting N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) is presented. This scheme is then extended to separately edit Aspartate in addition to NAA and NAAG. All multi-metabolite editing schemes are shown to be capable of optimally detecting each metabolite separately in simulations, phantom, and in vivo experiments. Relative to separate acquisitions of each metabolite separately, multi-metabolite editing results in a scan time reduction of two-fold and three-fold for editing two metabolites and three metabolites respectively. This thesis then introduces and evaluates methods for multi-region editing. First, a new technique ‘Spatial Hadamard Editing and Reconstruction for Parallel Acquisition’ (SHERPA) is introduced and found to be capable of separating the GABA-edited spectra from two voxels. HERMES is then extended for use with magnetic resonance spectroscopic imaging (MRSI) and is found to be also introduced and is shown to decrease subtraction artifacts in GABA-edited spectra. Lastly, a short-duration water suppression technique compatible for use with fast editedMRSI sequences is introduced and is shown to suppress water better than VAPOR. Readers: Peter Barker, DPhil and Richard Edden, Ph