Two-dimensional linear-combination model fitting of magnetic resonance spectra to define the macromolecule baseline using FiTAID, a Fitting Tool for Arrays of Interrelated Datasets

To propose the determination of the macromolecular baseline (MMBL) in clinical 1H MR spectra based on T(1) and T(2) differentiation using 2D fitting in FiTAID, a general Fitting Tool for Arrays of Interrelated Datasets.

Characterization of the macromolecule baseline in localized (1)H-MR spectra of human brain

Short-echo-time magnetic resonance spectra of human brain contain broad contributions from macromolecules. As they are a priori of unknown shape and intensity, they pose a problem if one wants to quantitate the overlying spectral features from low-molecular-weight metabolites. On the other hand, the macromolecular contributions may provide relevant clinical information themselves, if properly evaluated. Several methods, based on T(1), T(2), or spectral shape, have previously been suggested to suppress or edit the macromolecule contributions. Here, a method is presented based on a series of saturation recovery scans and that allows for simultaneous recording of the macromolecular baseline and the fully relaxed metabolite spectrum. In comparison to an inversion recovery technique aimed at nulling signals from long-T(1) components, the saturation recovery method is less susceptible to T(1) differences inherent in signals from different metabolites or introduced by pathology. The saturation recovery method was used to quantitate the macromolecular baseline in white and/or gray matter locations of the human brain in 40 subjects. It was found that the content and composition of MR visible macromolecules depends on cerebral location, as well as the age of the investigated subject, while no gender dependence could be found.

Magnetization exchange with water and T(1) relaxation of the downfield resonances in human brain spectra at 3.0 T

The use of water suppression for in vivo proton MR spectroscopy diminishes the signal intensities from resonances that undergo magnetization exchange with water, particularly those downfield of water. To investigate these exchangeable resonances, an inversion transfer experiment was performed using the metabolite cycling technique for non-water-suppressed MR spectroscopy from a large brain voxel in 11 healthy volunteers at 3.0 T. The exchange rates of the most prominent peaks downfield of water were found to range from 0.5 to 8.9 s(-1), while the T(1) relaxation times in absence of exchange were found to range from 175 to 525 ms. These findings may help toward the assignments of the downfield resonances and a better understanding of the sources of contrast in chemical exchange saturation transfer imaging.

Effect of Acute Psychological Stress on Prefrontal GABA Concentration Determined by Proton Magnetic Resonance Spectroscopy

Objective Impaired function of the central gamma-aminobutyric acid (GABA) system, which provides the brain’s major inhibitory pathways, is thought to play an important role in the pathophysiology of anxiety disorders. The effect of acute psychological stress on the human GABA-ergic system is still unknown, however. The purpose of this study was to determine the effect of acute stress on prefrontal GABA levels. Method A recently developed noninvasive magnetic resonance spectroscopy method was used to measure changes in the GABA concentration of the prefrontal cortex in 10 healthy human subjects during a threat-of-shock condition and during a safe condition (two sessions on different days). The main outcome measure was the mean GABA concentration within a 3×3×2-cm3 voxel selected from the medial prefrontal cortex. Results Prefrontal GABA decreased by approximately 18% in the threat-of-shock condition relative to the safe condition. This reduction was specific to GABA, since the concentrations of N-acetyl-aspartate, choline-containing compounds, and glutamate/glutamine levels obtained in the same spectra did not change significantly. Conclusions This result appeared compatible with evidence from preclinical studies in rodents, which showed rapid presynaptic down-regulation of GABA-ergic neurotransmission in response to acute psychological stress. The molecular mechanism and functional significance of this reduced inhibitory effect of acute psychological stress in relation to impaired GABA-ergic function in anxiety disorders merit further investigation.

Observation and identification of metabolites emerging during postmortem decomposition of brain tissue by means of in situ 1H-magnetic resonance spectroscopy

Postmortem decomposition of brain tissue was investigated by (1)H-magnetic resonance spectroscopy (MRS) in a sheep head model and selected human cases. Aiming at the eventual estimation of postmortem intervals in forensic medicine, this study focuses on the characterization and identification of newly observed metabolites. In situ single-voxel (1)H-MRS at 1.5 T was complemented by multidimensional homo- and heteronuclear high-resolution NMR spectroscopy of an extract of sheep brain tissue. The inclusion of spectra of model solutions in the program LC Model confirmed the assignments in situ. The first postmortem phase was characterized mainly by changes in the concentrations of metabolites usually observed in vivo and by the appearance of previously reported decay products. About 3 days postmortem, new metabolites, including free trimethylammonium, propionate, butyrate, and iso-butyrate, started to appear in situ. Since the observed metabolites and the time course is comparable in sheep and human brain tissue, the model system seems to be appropriate.

Visibility of vascular phenylalanine in dynamic uptake studies in humans using magnetic resonance spectroscopy

In general, vascular contributions to the in vivo magnetic resonance (MR) brain spectrum are too small to be relevant. In cerebral uptake studies, however, vascular contributions may constitute a major confounder. MR visibility of vascular Phe was investigated by recording localized spectra from fully oxygenated and well-mixed whole blood. Blood Phe levels determined by MR spectroscopy (MRS) and ion-exchange chromatography showed excellent correlation. In addition, effects of blood flow were shown to have a small effect on signal amplitude with the MRS methodology used. Hence, blood Phe is almost completely MR visible at 1.5 T, even though it is severely broadened at higher fields. Without appropriate correction, cerebral Phe influx in studies of brain Phe uptake in phenylketonuria patients or healthy subjects would appear to be faster and lead to higher levels. Similar effects are envisaged for studies of ethanol or glucose uptake across the blood-brain barrier.

Issues of spectral quality in clinical 1H-magnetic resonance spectroscopy and a gallery of artifacts

In spite of the facts that magnetic resonance spectroscopy (MRS) is applied as clinical tool in non-specialized institutions and that semi-automatic acquisition and processing tools can be used to produce quantitative information from MRS exams without expert information, issues of spectral quality and quality assessment are neglected in the literature of MR spectroscopy. Even worse, there is no consensus among experts on concepts or detailed criteria of quality assessment for MR spectra. Furthermore, artifacts are not at all conspicuous in MRS and can easily be taken for true, interpretable features. This article aims to increase interest in issues of spectral quality and quality assessment, to start a larger debate on generally accepted criteria that spectra must fulfil to be clinically and scientifically acceptable, and to provide a sample gallery of artifacts, which can be used to raise awareness for potential pitfalls in MRS.

On the use of Cramér-Rao minimum variance bounds for the design of magnetic resonance spectroscopy experiments

Localized Magnetic Resonance Spectroscopy (MRS) is in widespread use for clinical brain research. Standard acquisition sequences to obtain one-dimensional spectra suffer from substantial overlap of spectral contributions from many metabolites. Therefore, specially tuned editing sequences or two-dimensional acquisition schemes are applied to extend the information content. Tuning specific acquisition parameters allows to make the sequences more efficient or more specific for certain target metabolites. Cramér-Rao bounds have been used in other fields for optimization of experiments and are now shown to be very useful as design criteria for localized MRS sequence optimization. The principle is illustrated for one- and two-dimensional MRS, in particular the 2D separation experiment, where the usual restriction to equidistant echo time spacings and equal acquisition times per echo time can be abolished. Particular emphasis is placed on optimizing experiments for quantification of GABA and glutamate. The basic principles are verified by Monte Carlo simulations and in vivo for repeated acquisitions of generalized two-dimensional separation brain spectra obtained from healthy subjects and expanded by bootstrapping for better definition of the quantification uncertainties.

Quantitative 1H-magnetic resonance spectroscopy of human brain: Influence of composition and parameterization of the basis set in linear combination model-fitting

Localized short-echo-time (1)H-MR spectra of human brain contain contributions of many low-molecular-weight metabolites and baseline contributions of macromolecules. Two approaches to model such spectra are compared and the data acquisition sequence, optimized for reproducibility, is presented. Modeling relies on prior knowledge constraints and linear combination of metabolite spectra. Investigated was what can be gained by basis parameterization, i.e., description of basis spectra as sums of parametric lineshapes. Effects of basis composition and addition of experimentally measured macromolecular baselines were investigated also. Both fitting methods yielded quantitatively similar values, model deviations, error estimates, and reproducibility in the evaluation of 64 spectra of human gray and white matter from 40 subjects. Major advantages of parameterized basis functions are the possibilities to evaluate fitting parameters separately, to treat subgroup spectra as independent moieties, and to incorporate deviations from straightforward metabolite models. It was found that most of the 22 basis metabolites used may provide meaningful data when comparing patient cohorts. In individual spectra, sums of closely related metabolites are often more meaningful. Inclusion of a macromolecular basis component leads to relatively small, but significantly different tissue content for most metabolites. It provides a means to quantitate baseline contributions that may contain crucial clinical information.

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.

Magnetic resonance spectroscopy investigations of functionally defined language areas in schizophrenia patients with and without auditory hallucinations

Background: Cerebral dysfunction occurring in mental disorders can show metabolic disturbances which are limited to circumscribed brain areas. Auditory hallucinations have been shown to be related to defined cortical areas linked to specific language functions. Here, we investigated if the study of metabolic changes in auditory hallucinations requires a functional rather than an anatomical definition of their location and size to allow a reliable investigation by magnetic resonance spectroscopy (MRS). Methods: Schizophrenia patients with (AH; n = 12) and without hallucinations (NH; n = 8) and healthy controls (HC; n = 11) underwent a verbal fluency task in functional MRI (fMRI) to functionally define Broca's and Wernicke's areas. Left and right Heschl's gyri were defined anatomically. Results: The mean distances in native space between the fMRI-defined regions and a corresponding anatomically defined area were 12.4 ± 6.1 mm (range: 2.7–36.1 mm) for Broca's area and 16.8 ± 6.2 mm (range: 4.5–26.4 mm) for Wernicke's area, respectively. Hence, the spatial variance was of similar extent as the size of the investigated regions. Splitting the investigations into a single voxel examination in the frontal brain and a spectroscopic imaging part for the more homogeneous field areas led to good spectral quality for almost all spectra. In Broca's area, there was a significant group effect (p = 0.03) with lower levels of N-acetyl-aspartate (NAA) in NH compared to HC (p = 0.02). There were positive associations of NAA levels in the left Heschl's gyrus with total (p = 0.03) and negative (p = 0.006) PANSS scores. In Broca's area, there was a negative association of myo-inositol levels with total PANSS scores (p = 0.008). Conclusion: This study supports the neurodegenerative hypothesis of schizophrenia only in a frontal region whereas the results obtained from temporal regions are in contrast to the majority of previous studies. Future research should test the hypothesis raised by this study that a functional definition of language regions is needed if neurochemical imbalances are expected to be restricted to functional foci.

Visibility of lipid resonances in HR-MAS spectra of brain biopsies subject to spinning rate variation.

Lipid resonances from mobile lipids can be observed by (1)H NMR spectroscopy in multiple tissues and have also been associated with malignancy. In order to use lipid resonances as a marker for disease, a reference standard from a healthy tissue has to be established taking the influence of variable factors like the spinning rate into account. The purpose of our study was to investigate the effect of spinning rate variation on the HR-MAS pattern of lipid resonances in non-neoplastic brain biopsies from different regions and visualize polar and non-polar lipids by fluorescence microscopy using Nile Red staining. (1)H HR-MAS NMR spectroscopy demonstrated higher lipid peak intensities in normal sheep brain pure white matter biopsies compared to mixed white and gray matter biopsies and pure gray matter biopsies. High spinning rates increased the visibility particularly of the methyl resonances at 1.3 and the methylene resonance at 0.89ppm in white matter biopsies stronger compared to thalamus and brainstem biopsies, and gray matter biopsies. The absence of lipid droplets and presence of a large number of myelin sheaths observed in white matter by Nile Red fluorescence microscopy suggest that the observed lipid resonances originate from the macromolecular pool of lipid protons of the myelin sheath's plasma membranes. When using lipid contents as a marker for disease, the variable behavior of lipid resonances in different neuroanatomical regions of the brain and at variable spinning rates should be considered. The findings may open up interesting possibilities for investigating lipids in myelin sheaths.