In vivo 1H NMR spectroscopy of the human brain at 7 T.

In vivo 1H NMR spectra from the human brain were measured at 7 T. Ultrashort echo-time STEAM was used to minimize J-modulation and signal attenuation caused by the shorter T2 of metabolites. Precise adjustment of higher-order shims, which was achieved with FASTMAP, was crucial to benefit from this high magnetic field. Sensitivity improvements were evident from single-shot spectra and from the direct detection of glucose at 5.23 ppm in 8-ml volumes. The linewidth of the creatine methyl resonance was at best 9 Hz. In spite of the increased linewidth of singlet resonances at 7 T, the ability to resolve overlapping multiplets of J-coupled spin systems, such as glutamine and glutamate, was substantially increased. Characteristic spectral patterns of metabolites, e.g., myo-inositol and taurine, were discernible in the in vivo spectra, which facilitated an unambiguous signal assignment.     

Localized in vivo human 1H MRS at very short echo times.

A new point-resolved spectroscopy (PRESS) sequence was developed that allows localized human proton MR spectra to be acquired at echo times (TEs) of 10 ms or less. The method was implemented on a 4 Tesla Varian research console and a clinical 3 Tesla Siemens Trio scanner. Human brain spectra acquired in vivo from the prefrontal cortex at TE=8 ms showed improved signals from coupled resonances (such as glutamate, glutamine, and myo-inositol) compared to spectra acquired at TE=30 ms. These improvements should result in more accurate quantitation of these metabolites.     

Maturation of the human fetal brain as observed by 1H MR spectroscopy.

Proton MRS was used to monitor cerebral metabolite tissue levels in 35 normal fetuses during development in the gestational age range of 30-41 weeks. First, MRI in three orthogonal orientations was performed. A volume of interest (VOI) (15-43 cc) of fetal brain tissue was then selected for (1)H MRS. For localization, two pulse sequences (stimulated echo acquisition mode (STEAM) at TE = 20 ms, and point-resolved spectroscopy (PRESS) at TE = 135 ms) were applied. The MR spectra of the brain showed signals for inositol (Ino), choline (Cho), creatine (Cr), and N-acetyl (NA) compounds. From 30 to 41 weeks the absolute tissue level of NA, and the ratios of NA/Cr and NA/Cho increased, whereas the ratio of Cho/Cr decreased. These changes reflect maturation of the brain. Considering the diagnostic value of proton MRS in pediatric neurology, this new approach may also be useful for characterizing pathological conditions in the fetal brain.     

31P-{1H} echo-planar spectroscopic imaging of the human brain in vivo.

Echo-planar spectroscopic imaging (EPSI) is one of the fastest spectroscopic imaging (SI) methods. It has been applied to (1)H MR spectroscopy (MRS) studies of the human brain in vivo. However, to our knowledge, EPSI with detection of the (31)P nucleus to monitor phosphorus-containing neurometabolites has not yet been considered. In this work, eight different (31)P-{(1)H} EPSI sequence versions with spectral widths ranging from 313 Hz to 2.27 kHz were implemented on a clinical 1.5T whole-body MR tomograph. The sequence versions utilized the heteronuclear nuclear Overhauser effect (NOE) for (31)P signal enhancement. The sensitivity observed in experiments with model solutions was in good agreement with theoretical predictions. In vivo measurements performed on healthy volunteers (N = 16) demonstrated the feasibility of performing two-dimensional (2D) (31)P-{(1)H} EPSI in the human brain, and the technique enabled fast acquisition of well-resolved localized spectra.     

Reliable detection of macromolecules in single-volume 1H NMR spectra of the human brain.

In short echo time proton MR spectra of the brain, resonances from macromolecules are visible. The macromolecular resonances in the 0.5-2.0 ppm region can be affected by lipid contamination arising from fat-containing regions outside the selected volume of interest (VOI). This study demonstrates that considerable lipid contamination may remain in stimulated echo acquisition mode (STEAM) spectra even if the spoiling of unwanted coherences is sufficient and the VOI is placed 2 cm or more away from fat-containing regions. The observed contamination was attributed to residual remote out-of-volume excitation, although only very small out-of-slice ripples of less than 0.2% of the in-slice excitation were found in the calculated excitation profile of the RF pulses. Spatial presaturation of fat-containing regions led to a sufficient suppression of the contamination and enabled the detection of highly reproducible macromolecular resonances. Thus, in single-volume spectroscopy as well as in spectroscopic imaging (SI or CSI), the combination of volume selection and outer volume presaturation, each in three dimensions, is highly recommended to ensure accurate detection and reliable evaluation of even small pathological alterations in macromolecules, e.g., proteins or lipids, or other resonances in the 0.5-2.0 ppm region.     

Brain metabolite composition during early human brain development as measured by quantitative in vivo 1H magnetic resonance spectroscopy.

Biochemical maturation of the brain can be studied noninvasively by (1)H magnetic resonance spectroscopy (MRS) in human infants. Detailed time courses of cerebral tissue contents are known for the most abundant metabolites only, and whether or not premature birth affects biochemical maturation of the brain is disputed. Hence, the last trimester of gestation was observed in infants born prematurely, and their cerebral metabolite contents at birth and at expected term were compared with those of fullterm infants. Successful quantitative short-TE (1)H MRS was performed in three cerebral locations in 21 infants in 28 sessions (gestational age 32-43 weeks). The spectra were analyzed with linear combination model fitting, considerably extending the range of observable metabolites to include acetate, alanine, aspartate, cholines, creatines, gamma-aminobutyrate, glucose, glutamine, glutamate, glutathione, glycine, lactate, myo-inositol, macromolecular contributions, N-acetylaspartate, N-acetylaspartylglutamate, o-phosphoethanolamine, scyllo-inositol, taurine, and threonine. Significant effects of age and location were found for many metabolites, including the previously observed neuronal maturation reflected by an increase in N-acetylaspartate. Absolute brain metabolite content in premature infants at term was not considerably different from that in fullterm infants, indicating that prematurity did not affect biochemical brain maturation substantially in the studied population, which did not include infants of extremely low birthweight.     

1H-localized broadband 13C NMR spectroscopy of the rat brain in vivo at 9.4 T.

Localized (13)C NMR spectra were obtained from the rat brain in vivo over a broad spectral range (15-100 ppm) with minimal chemical-shift displacement error (<10%) using semi-adiabatic distortionless enhancement by polarization transfer (DEPT) combined with (1)H localization. A new gradient dephasing scheme was employed to eliminate unwanted coherences generated by DEPT when using surface coils with highly inhomogeneous B(1) fields. Excellent sensitivity was evident from the simultaneous detection of natural abundance signals for N-acetylaspartate, myo-inositol, and glutamate in the rat brain in vivo at 9.4 T. After infusion of (13)C-labeled glucose, up to 18 (13)C resonances were simultaneously measured in the rat brain, including glutamate C2, C3, C4, glutamine C2, C3, C4, aspartate C2, C3, glucose C1, C6, N-acetyl-aspartate C2, C3, C6, as well as GABA C2, lactate C3, and alanine C3. (13)C-(13)C multiplets corresponding to multiply labeled compounds were clearly observed, suggesting that extensive isotopomer analysis is possible in vivo. This unprecedented amount of information will be useful for metabolic modeling studies aimed at understanding brain energy metabolism and neurotransmission in the rodent brain.     

Implementation issues of multivoxel STEAM-localized 1H spectroscopy.

Single-voxel STEAM-localized spectroscopy studies of neuropsychiatric patients yield high-quality data at short echo times, but are often limited to only a few regions of interest due to the linear increase of acquisition time with the number of regions examined. A multivoxel STEAM approach increases the number of regions of interest examined with a less than linear increase in acquisition time. Several implementation issues were considered, especially the signal contribution of outer voxel stimulated echoes (OVSE), which can lead to systematic errors in the quantification of relative metabolite concentrations. The relative signal contribution of OVSEs was found to be as great as 30% in phantoms. Gradient polarity switching completely canceled the contribution of OVSEs. A two-voxel STEAM approach produces phantom and in vivo data quality comparable to single-voxel STEAM in practically half the time. Quantification precision and accuracy are preserved in phantoms and in vivo.     

Analysis of macromolecule resonances in 1H NMR spectra of human brain

Macromolecule resonances underlying metabolites in ¹H NMR spectra were investigated in temporal lobe biopsy tissue from epilepsy patients and from localized ¹H spectra of the brains of healthy volunteers. The ¹H NMR spectrum of brain tissue was cornpared with that of cytosol and dialyzed cytosol after removal of low molecular weight molecules (4500 daltons) at 8.4 and 2.1 Tesla. The assignment of specific resonances to macromolecules in 2.1 Tesla, short- TE, localized human brain ¹H NMR spectra in vivo was made on the basis of a J-editing method using the spectral parameters (δ, J) and connectivities determined from 2D experiments in vitro. Two prominent corinectivities associated with macromolecules in vitro (0.93–2.05 δ and 1.6–3.00 δ) were also detected in vivo by the J-editing method. Advantage was taken of the large difference in measured T₁ relaxation times between macromolecule and metabolite resonances in the brain spectrum to acquire ‘metabolite-nulled’ macromolecule spectra. These spectra appear identical to the spectra of macromolecules isolated in vitro.     

1H mrs of human brain abscesses in vivo and in vitro

Five patients, each with a brain abscess, were examined by means of ¹H MR spectroscopic imaging in vivo. The aspirated pus was analyzed in vitro by means of 1D and 2D COSY ¹H MRS. In addition to resonance lines from compounds (lactate, alanine and lipids) often found in the spectra from intracranial tumors, resonance lines were detected from a number of markers of infectious involvement (acetate, succinate, and various amino acids). These results suggest that ¹H MRS in vivo might contribute in establishing noninvasively a differential diagnosis between brain abscess and tumor.     

Detection of an antioxidant profile in the human brain in vivo via double editing with MEGA-PRESS.

Vitamin C (ascorbate) and glutathione (GSH) are the two most concentrated non-enzymatic antioxidants in the human brain. Double editing with (DEW) MEGA-PRESS at 4T was designed in this study to measure both antioxidants in the same amount of time previously required to measure one. In the occipital lobe of four human subjects, resolved ascorbate (Asc) and GSH resonances were detected repeatedly and simultaneously using DEW MEGA-PRESS. The Asc and GSH concentrations measured using LCModel analysis of DEW MEGA-PRESS spectra were 0.8 +/- 0.1 and 1.0 +/- 0.1 micromol/g (mean +/- SD), with average Cramer-Rao lower bounds (CRLB) of 10% and 7%, respectively. Aside from the effects of J-modulation at a common echo time (TE), double editing did not compromise sensitivity. To determine the extent to which the oxidized forms of Asc and GSH contribute to DEW MEGA-PRESS spectra in vivo, chemical shifts and coupling constants for dehydroascorbate (DHA) and oxidized glutathione (GSSG) were measured at physiologic pH and temperature. DHA does not contribute to the 3.73 ppm DEW MEGA-PRESS Asc resonance. GSSG contributions to the DEW MEGA-PRESS GSH resonance (3.0 ppm) are negligible under physiologic conditions, and would be evidenced by a distinct GSSG resonance (3.3 ppm) at exceptionally high concentrations.     

In vivo detection of brain glycine with echo-time-averaged (1)H magnetic resonance spectroscopy at 4.0 T.

A single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) method is described that enables the in vivo measurement of endogenous brain glycine (Gly) levels in human subjects. At 4.0 T, TE-averaging (1)H-MRS dramatically attenuates the overlapping myo-inositol (mI) resonances at 3.52 ppm, permitting a more reliable measure of the Gly singlet peak. This methodology initially is described and tested in phantoms. The phantom data infers that the 3.55-ppm peak predominantly is Gly with a smaller contribution from mI. The composite resonance thus is differentiated from pure Gly and mI and is labeled Gly*. The mI contribution was calculated as <2% of the total Gly* signal for a 1:1 mI/Gly mixture. The technique subsequently was used to acquire TE-averaged (1)H-MRS data from the occipital cortex of healthy control subjects. The resultant spectra closely resembled experimental phantom data. LC-model analysis provided a means for quantifying TE-averaged (1)H-MRS spectra and a mean test-retest variability measure of 15% was established for brain Gly* levels in studies of six healthy subjects.     

Quantitation of simulated short echo time 1H human brain spectra by LCModel and AMARES.

LCModel and AMARES, two widely used quantitation tools for magnetic resonance spectroscopy (MRS) data, were employed to analyze simulated spectra similar to those typically obtained at short echo times (TEs) in the human brain at 1.5 T. The study focused mainly on the influence of signal-to-noise ratios (SNRs) and different linewidths on the accuracy and precision of the quantification results, and their effectiveness in accounting for the broad signal contribution of macromolecules and lipids (often called the baseline in in vivo MRS). When applied in their standard configuration (i.e., fitting a spline as a baseline for LCModel, and weighting the first data points for AMARES), both methods performed comparably but with their own characteristics. LCModel and AMARES quantitation benefited considerably from the incorporation of baseline information into the prior knowledge. However, the more accurate quantitation of the sum of glutamate and glutamine (Glx) favored the use of LCModel. Metabolite-to-creatine ratios estimated by LCModel with extended prior knowledge are more accurate than absolute concentrations, and are nearly independent of SNR and line broadening.     

脑胶质瘤模型在体1H磁共振波谱研究

采用磁共振波谱仪在体观察大鼠C6胶质瘤的代谢及生化改变，为^1H磁共振波谱临床应用打下基础。40只Wister大鼠分为正常组（10只）和肿瘤组（30只），大鼠脑右尾状核接种C6细胞。MRI动态观察瘤组织改变，采用点分辨波谱法（PRESS：point resolved spectroscopy)行^1H磁共振波谱检测。正常大鼠^1H波谱检出N－乙酰门冬氨酸（NAA）、胆碱类化合物（Cho)、肌酸和磷酸肌酸（Cr PCr)、谷氨酸和谷氨酰胺（Glu Gln)、脂质（Lip)、乳酸（Lac)。C6胶质瘤NAA较正常组明显降低，NAA／Cho较正常组明显降低（P＜0．01），NAA／Cr较正常组也明显下降（P＜0．05），Cho/Cr明显升高（P＜0．01），Lac升高。表明高场强磁共振波谱仪可以精确观察在体大鼠C6胶质瘤的^1H磁共振波谱，对肿瘤的代谢及生化改变进行监测。     

In vivo 31P magnetic resonance spectroscopy of human brain at 7 T: an initial experience.

In vivo (31)P spectra were acquired from the human primary visual cortex at 7 T. The relaxation times of the cerebral metabolites, intracellular pH, rate constant (k(f)) of the creatine kinase (CK) reaction, and nuclear Overhauser enhancement (NOE) on the detected phosphorus moieties from irradiation of the water spins were measured from normal subjects. With a 5-cm-diameter surface coil, 3D (31)P chemical shift imaging was performed with a spatial resolution of 7.5 ml and an acquisition resolution of 8 min, resulting in a signal-to-noise ratio (SNR) for phosphocreatine (PCr) resonance of 32. The apparent T(1) and T(2) of PCr measured at 7 T were 3.37 +/- 0.29 s and 132.0 +/- 12.8 ms, respectively, which were considerably longer than those of adenosine triphosphate (ATP) (T(1): 1.02-1.27 s; T(2): 25-26 ms). The NOE measured in this study was 24.3% +/- 1.6% for PCr, and 10% for ATP. The k(f) measured in the human primary visual cortex was 0.24 +/- 0.03 s(-1). The results from this study suggest that ultra-high-field strength is advantageous for performing in vivo (31)P magnetic resonance spectroscopy (MRS) in the human brain.     

Robust analysis of short echo time (1)H MRSI of human brain.

Short echo time proton MR Spectroscopic Imaging (MRSI) suffers from low signal-to-noise ratio (SNR), limiting accuracy to estimate metabolite intensities. A method to coherently sum spectra in a region of interest of the human brain by appropriate peak alignment was developed to yield a mean spectrum with increased SNR. Furthermore, principal component (PC) spectra were calculated to estimate the variance of the mean spectrum. The mean or alternatively the first PC (PC(1)) spectrum from the same region can be used for quantitation of peak areas of metabolites in the human brain at increased SNR. Monte Carlo simulations showed that both mean and PC(1) spectra were more accurate in estimating regional metabolite concentrations than solutions that regress individual spectra against the tissue compositions of MRSI voxels. Back-to-back MRSI studies on 10 healthy volunteers showed that mean spectra markedly improved reliability of brain metabolite measurements, most notably for myo-inositol, as compared to regression methods.     

1H chemical shift imaging reveals loss of brain tumor choline signal after administration of Gd-contrast

¹H MR spectra obtained by chemical shift imaging (CSI) of contrast-enhancing brain tumors before and after the administration of Gd-contrast agent were quantitated and compared with the results in normal brain tissue included in the volume of interest. Twenty-seven combined magnetic resonance imaging and spectroscopy (MRI, MRS) examinations of brain tumor lesions included T₁-weighted MRI and CSI (TR/TE 1500/135 ms double-spin echo) repeated 5–10 min after the administration of Gd-contrast agent (0.1–0.2 mM). In ¹H MR spectra of contrast-enhancing tumor Gd-contrast induced a mean loss of 15% of the peak area of choline-containing compounds (Cho, P < 0.001) that was correlated with precontrast Cho linewidth (r = ?0.72, P < 0.00001). This phenomenon limits the diagnostic use of brain tumor MRS examinations performed immediately after contrast-enhanced MRI.     

Highly resolved in vivo 1H NMR spectroscopy of the mouse brain at 9.4 T.

An efficient shim system and an optimized localization sequence were used to measure in vivo 1H NMR spectra from cerebral cortex, hippocampus, striatum, and cerebellum of C57BL/6 mice at 9.4 T. The combination of automatic first- and second-order shimming (FASTMAP) with strong custom-designed second-order shim coils (shim strength up to 0.04 mT/cm2) was crucial to achieve high spectral resolution (water line width of 11-14 Hz). Requirements for second-order shim strengths to compensate field inhomogeneities in the mouse brain at 9.4 T were assessed. The achieved spectral quality (resolution, S/N, water suppression, localization performance) allowed reliable quantification of 16 brain metabolites (LCModel analysis) from 5-10-microL brain volumes. Significant regional differences (up to 2-fold, P < 0.05) were found for all quantified metabolites but Asp, Glc, and Gln. In contrast, 1H NMR spectra measured from the striatum of C57BL/6, CBA, and CBA/BL6 mice revealed only small (<13%, P < 0.05) interstrain differences in Gln, Glu, Ins, Lac, NAAG, and PE. It is concluded that 1H NMR spectroscopy at 9.4 T can provide precise biochemical information from distinct regions of the mouse brain noninvasively that can be used for monitoring of disease progression and treatment as well as phenotyping in transgenic mice models.