Broadband selective excitation radiofrequency pulses for optimized localization in vivo.

PURPOSE: The aim of the study is to optimize the performance of localized 1 H MRS sequences at 3T, using the entire spin system of N-acetyl aspartate (NAA) as an example of the large chemical shift spread of all the metabolites routinely detected in vivo, including the amide region. We specifically focus on the design of the suitable broadband excitation radiofrequency (RF) pulses to minimize chemical shift artifacts. METHODS: The performance of the excitation and refocusing pulse shapes is evaluated with respect to NAA localization. Two new excitation RF pulses are developed to achieve optimized performance in the brain using single-voxel 1 H MRS at 3T. Numerical simulations and in vivo experiments are carried out to demonstrate the performance of the RF pulses. RESULTS: New excitation RF pulses with the same B1 requirements but larger excitation bandwidth (up to a factor of 2) are shown to significantly reduce localization artifacts. The large frequency spread of the entire NAA spin system necessitates the use of broadband excitation and refocusing pulses for MRS at 3T. CONCLUSION: To minimize chemical shift artifacts of metabolic compounds with spins in the amide area (>5 ppm) at 3T it is important to use broadband excitation and refocusing pulses.

Spectral editing in 1 H magnetic resonance spectroscopy: Experts' consensus recommendations.

Spectral editing in in vivo 1 H-MRS provides an effective means to measure low-concentration metabolite signals that cannot be reliably measured by conventional MRS techniques due to signal overlap, for example, γ-aminobutyric acid, glutathione and D-2-hydroxyglutarate. Spectral editing strategies utilize known J-coupling relationships within the metabolite of interest to discriminate their resonances from overlying signals. This consensus recommendation paper provides a brief overview of commonly used homonuclear editing techniques and considerations for data acquisition, processing and quantification. Also, we have listed the experts' recommendations for minimum requirements to achieve adequate spectral editing and reliable quantification. These include selecting the right editing sequence, dealing with frequency drift, handling unwanted coedited resonances, spectral fitting of edited spectra, setting up multicenter clinical trials and recommending sequence parameters to be reported in publications.

Methylsulfonylmethane (MSM): A chemical shift reference for 1 H MRS of human brain.

PURPOSE: We investigate the potential of a common dietary supplement, methylsulfonylmethane (MSM), to act as a chemical shift reference for in vivo 1 H MR spectroscopy (MRS). The scope of the investigation is 2-fold: (1) We use high-resolution nuclear MR (NMR) measurements of the chemical shift values of MSM to establish the stability of MSM resonance across the ranges of pH and temperature, and (2) we demonstrate MR properties of MSM in the healthy human brain. METHODS: The relationship of chemical shift with temperature and pH is examined using high-resolution 1 H NMR (14.1T) spectra of MSM in aqueous solution. MSM concentration in human brain tissue was measured as a function of time, together with the relaxation properties in the brain using 1 H MRS at 3T. RESULTS: The chemical shift of MSM remains stable in the range of the biologically relevant temperatures and pH values. The chemical shift at pH = 7.2 and 37°C was measured to be 3.142 ppm (relative to DSS, a common water-soluble NMR reference compound). Time course in the brain tissue in vivo confirmed an observable MSM signal 10 minutes after oral intake and a stable signal intensity within a ~3-hour window. CONCLUSION: The chemical and biological properties of MSM-rapid crossing of the blood-brain barrier, water solubility, a singlet resonance resolved from metabolite resonances, chemical shift stability with respect to pH/temperature, and stable temporal presence in the brain-lead us to propose its use as a frequency reference for MRS.

Detection of glucose in the human brain with 1 H MRS at 7 Tesla.

PURPOSE: A new method is proposed for noninvasive detection of glucose in vivo using proton MR spectroscopy at 7 Tesla. THEORY AND METHODS: The proposed method utilizes J-difference editing to uncover the resonance of beta-glucose (ß-glc) at 3.23 ppm, which is strongly overlapped with choline. Calculations using the density matrix formalism are used to maximize the signal-to-noise ratio of the ß-glc resonance at 3.23 ppm. The calculations are verified using phantom and in vivo data collected at 7 Tesla. RESULTS: The proposed method allows observation of the glucose signal at 3.23 ppm in the human brain spectrum. Additional co-edited resonances of N-acetylaspartylglutamatate and glutathione are also detected in the same experiment. CONCLUSION: The proposed method does not require carbon (13 C)- labeled glucose injections and 13 C hardware; as such, it has a potential to provide valuable information on intrinsic glucose concentration in the human brain in vivo. Magn Reson Med 76:1653-1660, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

Repeatability of proton magnetic resonance spectroscopy of the brain at 7 T: effect of scan time on semi-localized by adiabatic selective refocusing and short-echo time stimulated echo acquisition mode scans and their comparison.

BACKGROUND: Proton magnetic resonance spectroscopy (MRS) provides a unique opportunity for in vivo measurements of the brain's metabolic profile. Two methods of mainstream data acquisition are compared at 7 T, which provides certain advantages as well as challenges. The two representative methods have seldom been compared in terms of measured metabolite concentrations and different scan times. The current study investigated proton MRS of the posterior cingulate cortex using a semi-localized by adiabatic selective refocusing (sLASER) sequence and a short echo time (TE) stimulated echo acquisition mode (sSTEAM) sequence, and it compared their reliability and repeatability at 7 T using a 32-channel head coil. METHODS: Sixteen healthy subjects were prospectively enrolled and scanned twice with an off-bed interval between scans. The scan parameters for sLASER were a TR/TE of 6.5 s/32 ms and 32 and 48 averages (sLASER×32 and sLASER×48, respectively). The scan parameters for sSTEAM were a TR/TE of 4 s/5 ms and 32, 48, and 64 averages (sSTEAM4×32, sSTEAM4×48, and sSTEAM4×64, respectively) in addition to that with a TR/TE of 8 s/5 ms and 32 averages (sSTEAM8×32). Data were analyzed using LCModel. Metabolites quantified with Cramér-Rao lower bounds (CRLBs) >50% were classified as not detected, and metabolites quantified with mean or median CRLBs ≤20% were included for further analysis. The SNR, CRLBs, coefficient of variation (CV), and metabolite concentrations were statistically compared using the Shapiro-Wilk test, one-way ANOVA, or the Friedman test. RESULTS: The sLASER spectra for N-acetylaspartate + N-acetylaspartylglutamate (tNAA) and glutamate (Glu) had a comparable or higher SNR than sSTEAM spectra. Ten metabolites had lower CRLBs than prefixed thresholds: aspartate (Asp), γ-aminobutyric acid (GABA), glutamine (Gln), Glu, glutathione (GSH), myo-inositol (Ins), taurine (Tau), the total amount of phosphocholine + glycerophosphocholine (tCho), creatine + phosphocreatine (tCr), and tNAA. Performance of the two sequences was satisfactory except for GABA, for which sLASER yielded higher CRLBs (≥18%) than sSTEAM. Some significant differences in CRLBs were noted, but they were ≤2% except for GABA and Gln. Signal averaging significantly lowered CRLBs for some metabolites but only by a small amount. Measurement repeatability as indicated by median CVs was ≤10% for Gln, Glu, Ins, tCho, tCr, and tNAA in all scans, and that for Asp, GABA, GSH, and Tau was ≥10% under some scanning conditions. The CV for GABA according to sLASER was significantly higher than that according to sSTEAM, whereas the CV for Ins was higher according to sSTEAM. An increase in signal averaging contribute little to lower CVs except for Ins. CONCLUSIONS: Both sequences quantified brain metabolites with a high degree of precision and repeatability. They are comparable except for GABA, for which sSTEAM would be a better choice.

Improvement of resolution for brain coupled metabolites by optimized (1)H MRS at 7T.

Resolution enhancement for glutamate (Glu), glutamine (Gln) and glutathione (GSH) in the human brain by TE-optimized point-resolved spectroscopy (PRESS) at 7 T is reported. Sub-TE dependences of the multiplets of Glu, Gln, GSH, γ-aminobutyric acid (GABA) and N-acetylaspartate (NAA) at 2.2-2.6 ppm were investigated with density matrix simulations, incorporating three-dimensional volume localization. The numerical simulations indicated that the C4-proton multiplets can be completely separated with (TE(1), TE(2)) = (37, 63) ms, as a result of a narrowing of the multiplets and suppression of the NAA 2.5 ppm signal. Phantom experiments reproduced the signal yield and lineshape from simulations within experimental errors. In vivo tests of optimized PRESS were conducted on the prefrontal cortex of six healthy volunteers. In spectral fitting by LCModel, Cramér-Rao lower bounds (CRLBs) of Glu, Gln and GSH were 2 ± 1, 5 ± 1 and 6 ± 2 (mean ± SD), respectively. To evaluate the performance of the optimized PRESS method under identical experimental conditions, stimulated-echo spectra were acquired with (TE, TM) = (14, 37) and (74, 68) ms. The CRLB of Glu was similar between PRESS and short-TE stimulated-echo acquisition mode (STEAM), but the CRLBs of Gln and GSH were lower in PRESS than in both STEAM acquisitions.

Age-related glutamate and glutamine concentration changes in normal human brain: 1H MR spectroscopy study at 4 T.

Proton magnetic resonance spectroscopy was performed at 4 T to determine effects of age, region and gender on glutamate and glutamine in the normal human brain. Furthermore, glutamate and glutamine alterations with age were tested for correlations with other cerebral metabolites. Two 8 cm3 volumes were selected in corona radiata and mesial motor cortex in normal subjects (N = 24) between 24 and 68 years old. Older subjects had lower glutamate concentration in the motor cortex compared to younger subjects (p < 0.001). In corona radiata, older subjects demonstrated a trend in higher glutamine compared to younger subjects (p = 0.05). Glutamate in the motor cortex was positively correlated with glutamine, N-acetyl aspartate and creatine. Reduced glutamate and N-acetyl aspartate in the motor cortex is consistent with neuronal loss/shrinkage with age. In conclusion, different patterns in association with normal aging in these brain regions were detected in this study.

(1)H MRS detection of glycine residue of reduced glutathione in vivo.

Glutathione (GSH) is a powerful antioxidant found inside different kinds of cells, including those of the central nervous system. Detection of GSH in the human brain using (1)H MR spectroscopy is hindered by low concentration and spectral overlap with other metabolites. Previous MRS methods focused mainly on the detection of the cysteine residue (GSH-Cys) via editing schemes. This study focuses on the detection of the glycine residue (GSH-Gly), which is overlapped by glutamate and glutamine (Glx) under physiological pH and temperature. The first goal of the study was to obtain the spectral parameters for characterization of the GSH-Gly signal under physiological conditions. The second goal was to investigate a new method of separating GSH-Gly from Glx in vivo. The characterization of the signal was carried out by utilization of numerical simulations as well as experiments over a wide range of magnetic fields (4.0-14T). The proposed separation scheme utilizes J-difference editing to quantify the Glx contribution to separate it from the GSH-Gly signal. The presented method retains 100% of the GSH-Gly signal. The overall increase in signal to noise ratio of the targeted resonance is calculated to yield a significant SNR improvement compared to previously used methods that target GSH-Cys residue. This allows shorter acquisition times for in vivo human clinical studies.

BMI and neuronal integrity in healthy, cognitively normal elderly: a proton magnetic resonance spectroscopy study.

Recent studies associated excess body weight with brain structural alterations, poorer cognitive function, and lower prefrontal glucose metabolism. We found that higher BMI was related to lower concentrations of N-acetyl-aspartate (NAA, a marker of neuronal integrity) in a healthy middle-aged cohort, especially in frontal lobe. Here, we evaluated whether NAA was also associated with BMI in a healthy elderly cohort. We used 4 Tesla proton magnetic resonance spectroscopy ((1)H MRS) data from 23 healthy, cognitively normal elderly participants (69.4 +/- 6.9 years; 12 females) and measured concentrations of NAA, glutamate (Glu, involved in cellular metabolism), choline-containing compounds (Cho, involved in membrane metabolism), and creatine (Cr, involved in high-energy metabolism) in anterior (ACC) and posterior cingulate cortices (PCC). After adjustment for age, greater BMI was related to lower NAA/Cr and NAA/Cho ratios (beta < -0.56, P < 0.008) and lower Glu/Cr and Glu/Cho ratios (beta < -0.46, P < 0.02) in ACC. These associations were not significant in PCC (beta > -0.36, P > 0.09). The existence of an association between NAA and BMI in ACC but not in PCC is consistent with our previous study in healthy middle-aged individuals and with reports of lower frontal glucose metabolism in young healthy individuals with elevated BMI. Taken together, these results provide evidence that elevated BMI is associated with neuronal abnormalities mostly in frontal brain regions that subserve higher cognitive functions and impulse control. Future studies need to evaluate whether these metabolite abnormalities are involved in the development and maintenance of weight problems.

RF pulses for in vivo spectroscopy at high field designed under conditions of limited power using optimal control.

Localized in vivo spectroscopy at high magnetic field strength (>3T) is susceptible to localization artifacts such as the chemical shift artifact and the spatial interference artifact for J-coupled spins. This latter artifact results in regions of anomalous phase for J-coupled spins. These artifacts are exacerbated at high magnetic field due to the increased frequency dispersion, coupled with the limited RF pulse bandwidths used for localization. Approaches to minimize these artifacts include increasing the bandwidth of the frequency selective excitation pulses, and the use of frequency selective saturation pulses to suppress the signals in the regions with anomalous phase. The goal of this article is to demonstrate the efficacy of optimal control methods to provide broader bandwidth frequency selective pulses for in vivo spectroscopy in the presence of limited RF power. It is demonstrated by examples that the use of optimal control methods enable the generation of (i) improved bandwidth selective excitation pulses, (ii) more efficient selective inversion pulses to be used for generation of spin echoes, and (iii) improved frequency selective saturation pulses. While optimal control also allows for the generation of frequency selective spin echo pulses, it is argued that it is more efficient to use dual inversion pulses for broadband generation of spin echoes. Finally, the optimal control routines and example RF pulses are made available for downloading.

Numerical simulations of localized high field 1H MR spectroscopy.

The limited bandwidths of volume selective RF pulses in localized in vivo MRS experiments introduce spatial artifacts that complicate spectral quantification of J-coupled metabolites. These effects are commonly referred to as a spatial interference or "four compartment" artifacts and are more pronounced at higher field strengths. The main focus of this study is to develop a generalized approach to numerical simulations that combines full density matrix calculations with 3D localization to investigate the spatial artifacts and to provide accurate prior knowledge for spectral fitting. Full density matrix calculations with 3D localization using experimental pulses were carried out for PRESS (TE=20, 70 ms), STEAM (TE=20, 70 ms) and LASER (TE=70 ms) pulse sequences and compared to non-localized simulations and to phantom solution data at 4 T. Additional simulations at 1.5 and 7 T were carried out for STEAM and PRESS (TE=20 ms). Four brain metabolites that represented a range from weak to strong J-coupling networks were included in the simulations (lactate, N-acetylaspartate, glutamate and myo-inositol). For longer TE, full 3D localization was necessary to achieve agreement between the simulations and phantom solution spectra for the majority of cases in all pulse sequence simulations. For short echo time (TE=20 ms), ideal pulses without localizing gradients gave results that were in agreement with phantom results at 4 T for STEAM, but not for PRESS (TE=20). Numerical simulations that incorporate volume localization using experimental RF pulses are shown to be a powerful tool for generation of accurate metabolic basis sets for spectral fitting and for optimization of experimental parameters.

Elimination of spatial interference in PRESS-localized editing spectroscopy.

Unambiguous detection of gamma-amino butyric acid (GABA) in the human brain is hindered by low concentration and spectral overlap with other metabolites. The popular MEGA-PRESS (PRESS: point-resolved spectroscopic sequence) method allows spectral separation of GABA from other metabolites, but suffers from a significant signal-to-noise ratio (SNR) reduction due to the 4-compartment artifact. An alternative PRESS localization technique (PRESS+4) was investigated and compared to MEGA-PRESS using numerical simulations, phantom, and in vivo experiments. It was shown that while the MEGA-PRESS method suffers significant signal loss ( approximately equal 20% for the difference spectrum), GABA signal intensity in PRESS+4 is reduced by only 2% compared to the nonlocalized condition at 4T. The improved method retains important features of the popular MEGA-PRESS such as additional water suppression and macromolecular elimination as demonstrated in human brain experiments. This method is not limited to GABA J-difference editing, but can be applied in any PRESS-based experiments. It should prove particularly useful at higher field, where the 4-compartment artifact is especially detrimental.

Scyllo-inositol in normal aging human brain: 1H magnetic resonance spectroscopy study at 4 Tesla.

The scyllo-inositol and myo-inositol concentrations of 24 normal human subjects were measured in vivo using 1H magnetic resonance spectroscopy at 4 T. Single-voxel short-echo (TE = 15 ms) metabolite spectra were collected from the white matter region of the corona radiata. Test-retest studies performed on 10 normal subjects demonstrated coefficient of variation for scyllo-inositol measurement of 37%, compared with 6% for N-acetyl aspartate. Comparisons between old and young subjects showed higher concentration of scyllo-inositol and myo-inositol in older subjects and a trend for a correlation between scyllo-inositol and myo-inositol levels across subjects.