Editing Pulse Research Articles

VALIDATION OF 2HG-TARGETTED MR SPECTROSCOPY FOR IDENTIFYING IDH-MUTANT GLIOMAS

Abstract AIMS Diffuse gliomas, the most common adult primary brain tumour, are classified by their histological and molecular characteristics and genetic profile. Isocitrate dehydrogenase (IDH) mutant gliomas correlate with longer mean survival and progression-free survival time. In tumour cells, IDH mutations lead to metabolic changes and the production of oncometabolite 2-hydroxyglutarate (2HG). MR spectroscopy (MRS) can assess metabolic changes in disease states in-vivo and non-invasively. In this study, we demonstrate a validation pathway for two advanced MRS methods to be used as IDH-mutation biomarkers in clinic. METHOD Simulated, phantom, and healthy volunteer experiments were performed to optimise and validate three MRS sequences tuned for measuring 2HG. A PRESS sequence was used with TR/TE of 2500/97 ms aiming at the 2HG peaks around 2.25 ppm. An edited PRESS sequence, named MEGA-PRESS, tailored to 2HG 4.02 ppm peak was used with TR/TE of 3000/68 ms, 128 averages, and with editing pulses at 1.9 and 7.5 ppm. A long TE semi-LASER MRS sequence, with improved voxel localisation, was also used (TR/TE: 2500/110 ms). RESULTS Simulations were performed to find optimised sequence parameters and to develop basis sets for analysing the phantom and healthy volunteer acquisitions. Tumour-mimicking phantoms with variable concentrations of 2HG and cystathionine were created and validated with 800 MHz NMR spectroscopy. Phantoms were then used to assess the sensitivity and specificity of the MRS for 2HG and cystathionine. MEGA-PRESS proved Synthetic in-vivo 2HG spectra, combined from healthy volunteers and simulated or phantom-2HG spectra, were used to assess the spectral quality needed to reliably measure 2HG. CONCLUSION MEGA-PRESS proved to be the most robust MRS method and demonstrated accurate and precise measurement of phantom and synthetic 2HG with acceptable SNR. Clinical validation of the technique will need to be performed on LGG patient population, and the overall accuracy will be compared with patient IDH mutation status.

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

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

Glutamate measurements using edited MRS.

To demonstrate J-difference coediting of glutamate using Hadamard encoding and reconstruction of Mescher-Garwood-edited spectroscopy (HERMES). 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. 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. 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.

Optimization of the flip angles of narrow-band editing pulses in J-difference edited MRS of lactate at 3T.

Application of highly selective editing RF pulses provides a means of minimizing co-editing of contaminants in J-difference MRS (MEGA), but it causes reduction in editing yield. We examined the flip angles (FAs) of narrow-band editing pulses to maximize the lactate edited signal with minimal co-editing of threonine. The effect of editing-pulse FA on the editing performance was examined, with numerical and phantom analyses, for bandwidths of 17.6-300 Hz in MEGA-PRESS editing of lactate at 3T. The FA and envelope of 46 ms Gaussian editing pulses were tailored to maximize the lactate edited signal at 1.3 ppm and minimize co-editing of threonine. The optimized editing-pulse FA MEGA scheme was tested in brain tumor patients. Simulation and phantom data indicated that the optimum FA of MEGA editing pulses is progressively larger than 180° as the editing-pulse bandwidth decreases. For 46 ms long 17.6 Hz bandwidth Gaussian pulses and other given sequence parameters, the lactate edited signal was maximum at the first and second editing-pulse FAs of 241° and 249°, respectively. The edit-on and difference-edited lactate peak areas of the optimized FA MEGA were greater by 43% and 25% compared to the 180°-FA MEGA, respectively. In-vivo data confirmed the simulation and phantom results. The lesions of the brain tumor patients showed elevated lactate and physiological levels of threonine. The lactate MEGA editing yield is significantly increased with editing-pulse FA much larger than 180° when the editing-pulse bandwidth is comparable to the lactate quartet frequency width.

In vivo magnetic resonance spectroscopy by transverse relaxation encoding with narrowband decoupling

Cell pathology in neuropsychiatric disorders has mainly been accessible by analyzing postmortem tissue samples. Although molecular transverse relaxation informs local cellular microenvironment via molecule-environment interactions, precise determination of the transverse relaxation times of molecules with scalar couplings (J), such as glutamate and glutamine, has been difficult using in vivo magnetic resonance spectroscopy (MRS) technologies, whose approach to measuring transverse relaxation has not changed for decades. We introduce an in vivo MRS technique that utilizes frequency-selective editing pulses to achieve homonuclear decoupled chemical shift encoding in each column of the acquired two-dimensional dataset, freeing up the entire row dimension for transverse relaxation encoding with J-refocusing. This results in increased spectral resolution, minimized background signals, and markedly broadened dynamic range for transverse relaxation encoding. The in vivo within-subject coefficients of variation for the transverse relaxation times of glutamate and glutamine, measured using the proposed method in the human brain at 7 T, were found to be approximately 4%. Since glutamate predominantly resides in glutamatergic neurons and glutamine in glia in the brain, this noninvasive technique provides a way to probe cellular pathophysiology in neuropsychiatric disorders for characterizing disease progression and monitoring treatment response in a cell type-specific manner in vivo.

Influence of editing pulse flip angle on J-difference MR spectroscopy.

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. 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°). 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. 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.

Borehole measurements of adsorbed gas content in coals using stimulated diffusion nuclear magnetic resonance

We present an NMR measurement technique which has the unique ability to determine the in-situ adsorbed gas concentration within coal seams. The measurement of adsorbed gas content is of critical importance for operational safety and commercial resource evaluation in the development of coal mining operations and coal seam gas (CSG) resources. The current measurement technique involves laboratory core analysis, using a canister desorption measurement which is subject to significant measurement uncertainty due to the gas lost between coring and analysis. The NMR measurement technique enables in-situ measurement of fluid content within the coal seams without disturbing the coal seams. The technique utilises the stimulated echo diffusion editing (SEDE) pulse sequence which simultaneously captures relaxation and diffusion behaviour of fluids contained within coal seams. In this work, we have optimised the SEDE pulse sequence by using two diffusion times which are appropriate for capturing the diffusive behaviour of water and adsorbed gas. The measured signal captured by the SEDE sequence is inverted to provide a T2-StimD distribution. The appropriate interpretation of the T2-StimD distribution enables the determination of the free and adsorbed gas concentrations. The adsorbed gas concentration measured using the optimised SEDE sequence shows very good agreement with core canister desorption measurements. The sequence also enables the detection of free gas which is important for understanding the depressurisation of the coal seams and the impact on development strategies.

In vivo spectral editing of phosphorylethanolamine.

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. 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. 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. 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.

Prospective frequency and motion correction for edited 1H magnetic resonance spectroscopy

The major inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the dominant antioxidant glutathione (GSH) both play a crucial role in brain functioning and are involved in several neurodegenerative and psychiatric diseases. Magnetic resonance spectroscopy (MRS) is a unique way to measure these neurometabolites non-invasively, but the measurement is highly sensitive to head movements, and especially in specific patient groups, motion stabilization in MRS could be valuable. Conventional MRS is acquired at relatively short echo times (TE), however, for unambiguous detection of GABA and GSH, spectral editing techniques are typically used. These depend on longer TEs and use frequency selective spectral editing pulses to separate the low-intensity peaks of GABA and GSH from overlapping resonances, but results in further increased motion sensitivity. Low-intensity metabolite peaks are usually edited one-by-one, however, simultaneous editing of multiple metabolites can be achieved using a Hadamard scheme, resulting in a substantial reduction in scan time. To investigate and correct for motion sensitivity in both conventional short-TE MRS (PRESS) and edited MRS (HERMES), we implemented a navigator-based prospective motion correction strategy including reacquisition of corrupted data. PRESS and HERMES spectra were acquired without motion, with motion with correction (repeated twice), and with motion without correction. Results indicate that when sufficient retrospective outlier removal is used, no significant differences in concentration and spectral quality were observed between motion conditions, even without prospective correction. HERMES spectral editing data showed to be more sensitive to motion, as significant differences in metabolite estimates and variability of spectral quality measures were observed for tCr, GABA+ and GSH when only retrospective outlier removal was applied. When using both prospective and retrospective correction, spectral quality was improved to almost the level of the no-motion acquisition. No differences in metabolite ratios for GABA and GSH could be observed when using motion correction. In conclusion, edited MRS showed to be more prone to motion artifacts, and prospective motion correction can restore most of the spectral quality in both conventional and edited MRS.

Flexible MEGA editing scheme with asymmetric adiabatic pulses applied for measurement of lactate in human brain.

A flexible MEGA editing scheme which decouples the editing efficiency from TE is proposed and the utility of asymmetric adiabatic pulses for this new technique is explored. It is demonstrated that the method enables robust measurement of lactate in healthy human brain. The proposed variation of the MEGA scheme applies editing pulses in both acquired spectra, ensuring that the difference in J-evolution of the target resonance leads to maximal signal yield in the difference spectrum for arbitrary TE. A MEGA-sLASER sequence is augmented with asymmetric adiabatic editing pulses for enhanced flexibility and immunity to miscalibration and inhomogeneities. The technique is validated and optimized for flexible lactate editing via a simple analytical model, numerical simulations and in vitro experiments. The relaxation constant of lactate is determined in vivo via multiple-TE measurements with the proposed method and a dedicated postprocessing and quantification approach. Asymmetric adiabatic editing pulses improve robustness and facilitate efficient J-editing in sequences or protocols with strong timing constraints. Single voxel measurements using the proposed MEGA scheme in the occipital cortex of six healthy subjects yield a relaxation constant of ms for the methyl resonance of lactate at a field strength of 3T. The proposed MEGA editing scheme allows for novel kinds of J-editing experiments and promises to be an asset to robust measurement of lactate and potentially other J-coupled metabolites in vivo.

Signal enhancement of glutamine and glutathione by single-step spectral editing

A single-step spectral editing approach using an always-on editing pulse was proposed to enhance the signals of strongly coupled spins. Specifically, a single-step spectral editing sequence with an always-on editing pulse applied at 2.12 ppm was used to enhance glutamine (Gln) and glutathione (GSH) signals at TE = 56 ms on a 7 T scanner. Density matrix simulations demonstrated that the current method (TE = 56 ms) led to large signal enhancement of at least 61% for Gln and 51% for GSH compared to a previous single-step method (TE = 106 ms). Monte Carlo simulations showed that the current method reduced noise-originated variations by 31% for Gln and 26% for GSH compared to a previous three-step spectral editing method from which the present method was derived.

MEGA‐PRESS of GABA+: Influences of acquisition parameters

γ-aminobutyric acid (GABA) was the first molecule that was edited with MEGA-PRESS. GABA edited spectroscopy is challenged by limited selectivity of editing pulses. Coediting of resonances from macromolecules (MM) is the greatest single limitation of GABA edited spectroscopy. In this contribution, relative signal contributions from GABA, MM and homocarnosine to the total MEGA-PRESS edited signal at ~3ppm, i.e., GABA+, are simulated at 3 tesla using several acquisition schemes. The base scheme is modeled after those currently supplied by vendors: it uses typical pulse shapes and lengths, it minimizes the first echo time (TE), and the delay between the editing pulses is kept at TE/2. Edited spectra are simulated for imperfect acquisition parameters such as incorrect frequency, larger chemical shift displacement, incorrect transmit B1 -field calibration for localization and editing pulses, and longer TE. An alternative timing scheme and longer editing pulses are also considered. Additional simulations are performed for symmetric editing around the MM frequency to suppress the MM signal. The relative influences of these acquisition parameters on the constituents of GABA+ are examined from the perspective of modern experimental designs for investigating brain GABA concentration differences in healthy and diseased humans. Other factors that influence signal contributions, such as T1 and T2 relaxation times are also considered.

In vivo 1H MRS detection of cystathionine in human brain tumors

To report the technical aspects of noninvasive detection of cystathionine in human brain glioma with edited MRS, and to investigate possible further acquisition improvements for robust quantification of this metabolite. In vivo 1 H MR spectra were acquired at 3 T in 15 participants with an isocitrate dehydrogenase-mutated glioma using a MEGA-PRESS (MEscher GArwood point resolved spectroscopy) sequence previously employed for 2-hydroxyglutarate detection (TR = 2 s, TE = 68 ms). The editing pulse was applied at 1.9 ppm for the edit-on condition and at 7.5 ppm for the edit-off condition. To evaluate the editing efficiency, spectra were acquired in 1 participant by placing the editing pulse for the edit-on condition at 1.9, 2.03, and 2.16 ppm. Cystathionine concentration was quantified using LCModel and a simulated basis set. To confirm chemical shifts and J-coupling values of cystathionine, the 1 H NMR cystathionine spectrum was measured using a high-resolution 500 MHz spectrometer. In 12 gliomas, cystathionine was observed in the in vivo edited MR spectra at 2.72 and 3.85 ppm and quantified. The signal intensity of the cystathionine resonance at 2.72 ppm increased 1.7 and 2.13 times when the editing pulse was moved to 2.03 and 2.16 ppm, respectively. Cystathionine was not detectable in normal brain tissue. Cystathionine can be detected in vivo by edited MRS using the same protocol as for 2-hydroxyglutarate detection. This finding may enable a more accurate, noninvasive investigation of cellular metabolism in glioma.

Advanced Hadamard-encoded editing of seven low-concentration brain metabolites: Principles of HERCULES

PurposeTo demonstrate the framework of a novel Hadamard-encoded spectral editing approach for simultaneously detecting multiple low-concentration brain metabolites in vivo at 3T. MethodsHERCULES (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. ResultsHERCULES 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. ConclusionHERCULES 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.

Whole-slice mapping of GABA and GABA+ at 7T via adiabatic MEGA-editing, real-time instability correction, and concentric circle readout

An adiabatic MEscher-GArwood (MEGA)-editing scheme, using asymmetric hyperbolic secant editing pulses, was developed and implemented in a B1+-insensitive, 1D-semiLASER (Localization by Adiabatic SElective Refocusing) MR spectroscopic imaging (MRSI) sequence for the non-invasive mapping of γ-aminobutyric acid (GABA) over a whole brain slice. Our approach exploits the advantages of edited-MRSI at 7T while tackling challenges that arise with ultra-high-field-scans. Spatial-spectral encoding, using density-weighted, concentric circle echo planar trajectory readout, enabled substantial MRSI acceleration and an improved point-spread-function, thereby reducing extracranial lipid signals. Subject motion and scanner instabilities were corrected in real-time using volumetric navigators optimized for 7T, in combination with selective reacquisition of corrupted data to ensure robust subtraction-based MEGA-editing.Simulations and phantom measurements of the adiabatic MEGA-editing scheme demonstrated stable editing efficiency even in the presence of ±0.15 ppm editing frequency offsets and B1+ variations of up to ±30% (as typically encountered in vivo at 7T), in contrast to conventional Gaussian editing pulses. Volunteer measurements were performed with and without global inversion recovery (IR) to study regional GABA levels and their underlying, co-edited, macromolecular (MM) signals at 2.99 ppm. High-quality in vivo spectra allowed mapping of pure GABA and MM-contaminated GABA+ (GABA + MM) along with Glx (Glu + Gln), with high-resolution (eff. voxel size: 1.4 cm3) and whole-slice coverage in 24 min scan time. Metabolic ratio maps of GABA/tNAA, GABA+/tNAA, and Glx/tNAA were correlated linearly with the gray matter fraction of each voxel. A 2.15-fold increase in gray matter to white matter contrast was observed for GABA when enabling IR, which we attribute to the higher abundance of macromolecules at 2.99 ppm in the white matter than in the gray matter.In conclusion, adiabatic MEGA-editing with 1D-semiLASER selection is as a promising approach for edited-MRSI at 7T. Our sequence capitalizes on the benefits of ultra-high-field MRSI while successfully mitigating the challenges related to B0/B1+ inhomogeneities, prolonged scan times, and motion/scanner instability artifacts. Robust and accurate 2D mapping has been shown for the neurotransmitters GABA and Glx.

12.4 BRAIN LACTATE IS RELATED TO COGNITION IN SCHIZOPHRENIA

Laura Rowland, University of Maryland School of Med: Bioenergetic function may be altered in schizophrenia as supported by post-mortem, preclinical, cerebrospinal fluid, and 31P-magnetic resonance spectroscopy (MRS) research. Impairments in bioenergetic function may lead to cognitive and functional dysfunction, characteristics of the illness. First, a 7T MRS study that tested the hypothesis that frontal lactate concentrations are elevated in schizophrenia and related to cognitive impairments will be presented. Second, recent advances in brain lactate measurements with 3T MRS will be presented.MethodsTwenty-nine controls and 27 participants with schizophrenia completed the study. MRS scanning was conducted on a Philips ‘Achieva’ 7T scanner, and spectra were acquired from a frontal voxel using STEAM (TE/TM/TR=14/33/3000 ms, 128 NEX, 16 NEX water). Participants completed the MATRICS Consensus Cognitive Battery (MCCB) for cognitive function and UCSD Performance-Based Skills Assessment (UPSA) for functional capacity. The relationships between lactate, MCCB, and UPSA were examined. 3T MRS test-retest measures of lactate were conducted on a Siemens Prisma scanner using spectra editing (TE/TR=140/3, editing pulse at 4.1ppm with 30Hz bandwidth, 360 NEX, 16 NEX water).ResultsPatients had significantly higher lactate compared to controls (p = 0.045). Higher lactate was associated with poorer general cognitive function (r=-0.36, p=0.01) Visual learning, processing speed, and reasoning/problem solving cognitive domains showed the strongest relationships with lactate. Poorer functional capacity (r=-0.43, p=0.001) was also related to higher lactate. 3T spectral editing studies showed excellent reproducibility with a mean coefficient of variation of 4%.DiscussionHigher frontal lactate levels in schizophrenia support the hypothesis that brain bioenergetics are altered and related to cognitive and functional impairments in schizophrenia. Higher lactate could be due to inefficient aerobic metabolism causing a shift towards anaerobic metabolism or poor utilization of lactate. Lactate measurements are doable at 3T field strength and may be a useful biomarker of cognition in schizophrenia. Interventions to promote efficient mitochondrial energy metabolism may prove useful for enhancing cognition and alleviating functional impairments in schizophrenia.

Simultaneous measurement of glutamate, glutamine, GABA, and glutathione by spectral editing without subtraction.

To simultaneously measure glutamate, glutamine, γ-aminobutyric acid (GABA), and glutathione using spectral editing without subtraction at 7T. A novel spectral editing approach was proposed to simultaneously measure glutamate, glutamine, GABA, and glutathione using a TE of 56 ms at 7T. By numerical optimization of sequence timing in the presence of an editing pulse, the 4 metabolites all form relatively intense pseudo singlets with maximized peak amplitudes and minimized peak linewidths in 1 of the 3 interleaved spectra. For measuring glutamate, glutamine, and glutathione, the editing pulse targets the H3 protons of these metabolites near 2.12 parts per million. Both GABA H2 and H4 resonances are fully utilized in spectral fitting. Concentration levels (/[total creatine]) of glutamate, glutamine, GABA, and glutathione from an 8 mL voxel in the pregenual anterior cingulate cortex of 5 healthy volunteers were found to be 1.26 ± 0.13, 0.33 ± 0.06, 0.13 ± 0.03, and 0.27 ± 0.03, respectively, with within-subject coefficient of variation at 3.2%, 8.2%, 7.1%, and 10.2%, respectively. The total scan time was less than 4.5 min. The proposed new technique does not require data subtraction. The 3 major metabolites of the glutamatergic and GABAergic systems and the oxidative stress marker glutathione were all measured in 1 short scan with high precision.

Hadamard editing of glutathione and macromolecule-suppressed GABA.

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.

Reliable and Reproducible GABA Measurements Using Automated Spectral Prescription at Ultra-High Field

Purpose: To evaluate spectral acquisition processes important for obtaining reliable and reproducible γ-aminobutyric acid (GABA) signals from volunteers in brain regions that are frequently used for neuroimaging studies [anterior cingulate cortex (ACC), superior temporal gyrus, and caudate] at ultra-high field.Methods: Ten healthy volunteers were studied using a single-voxel Point-RESolved Spectrosocpy (PRESS) sequence with band selective inversion with gradient dephasing pulses (BASING). The editing pulse was designed to be symmetrically placed at 2.0 and 1.4 ppm in the two cycles to reduce the co-editing of macro-molecules (MM). Spectral data were obtained with phase encoding matrix 8 × 8 × 1 and two editing cycles or 1 × 1 × 1 and 64 editing/64 non-editing. The total acquisition time was approximately 4.5 min for each acquisition. An automated MRS prescription method was utilized for the placement of the GABA scan location in 5/10 subjects. Three regions of interest were predefined in the MNI152 space and then registered and transformed to subject space. These volunteers also had repeat scans to examine between-session reproducibility.Results: The placement of editing pulses symmetrically at 1.7 ppm reduced the effect of MM contributions and provided more accurate GABA estimation. Chemical shift misregistration errors caused by classic PRESS localization sequence are more significant at ultra-high field strength. Therefore, a large over-excitation factor was needed to reduce this error. Furthermore, the inefficiency of saturation bands and unspoiled coherence could also interfere with the quality of the data. Reliable recovery of metabolite signals resulted from the implementation of 8 × 8 × 1 phase encoding that successfully removed artifacts and errors, without compromising the total acquisition time. Between successive scans on the same subject, dice overlap ratios of the excited spectral volume between the two scans were in the range of 92–95%. Within subject variability of metabolites between two repeat scans was smaller in the ACC and left superior temporal gyrus when compared to that in the right caudate, with averaged coefficients of variation being 3.6, 6.0, and 16.9%, respectively.Conclusion: This study demonstrated the feasibility of obtaining reliable and reproducible GABA measurements at ultra-high field.

Retrospective correction of frequency drift in spectral editing: The GABA editing example.

GABA levels can be measured using proton MRS with a two-step editing sequence. However due to the low concentration of GABA, long acquisition time is usually needed to achieve sufficient SNR to detect small differences in many psychiatric disorders. During this long scan time the frequency offset of the measured voxel can change because of magnetic field drift and patient movement. This drift will change the frequency of the editing pulse relative to that of metabolites, leading to errors in quantification. In this article we describe a retrospective method to correct for frequency drift in spectral editing. A series of reference signals for each metabolite was generated for a range of frequency offsets and then averaged together based on the history of frequency changes over the scan. These customized basis sets were used to fit the in vivo data. Our results demonstrate the effectiveness of the correction method and the remarkable robustness of a GABA editing technique with a top hat editing profile in the presence of frequency drift.