Proton magnetic resonance spectroscopy ( 1 H-MRS) has been used to demonstrate metabolic changes in the visual cortex on visual stimulation. Small (2% to 11%) but significant stimulation induced increases in lactate, glutamate, and glutathione were observed along with decreases in aspartate, glutamine, and glycine, using 1 H-MRS at 7 T during single and repeated visual stimulation. In addition, decreases in glucose and increases in c-aminobutyric acid (GABA) were seen but did not reach significance. Changes in glutamate and aspartate are indicative of increased activity of the malate-aspartate shuttle, which taken together with the opposite changes in glucose and lactate, reflect the expected increase in brain energy metabolism. These results are in agreement with those of Mangia et al. In addition, increases in glutamate and GABA coupled with the decrease in glutamine can be interpreted in terms of increased activity of the neurotransmitter cycles. An entirely new observation is the increase of glutathione during prolonged visual stimuli. The similarity of its time course to that of glutamate suggests that it may be a response to the increased release of glutamate or to the increased production of reactive oxygen species. Together, these observations constitute the most detailed analysis to date of functional changes in human brain metabolites.

After the landmark studies reporting changes in the cerebral metabolic rate of glucose (CMR Glc ) in excess of those in oxygen (CMR O2 ) during physiological stimulation, several studies have examined the fate of the extra carbon taken up by the brain, reporting a wide range of changes in brain lactate from 20% to 250%. The present study reports functional magnetic resonance spectroscopy measurements at 7 Tesla using the enhanced sensitivity to study a small cohort (n 5 6). Small increases in lactate (19% 6 4%, P < 0.05) and glutamate (4% 6 1%, P < 0.001) were seen within the first 2 min of activation. With the exception of glucose (12% 6 5%, P < 0.001), no other metabolite concentration changes beyond experimental error were significantly observed. Therefore, the present study confirms that lactate and glutamate changes during physiological stimulation are small (i.e. below 20%) and shows that the increased sensitivity allows reproduction of previous results with fewer subjects. In addition, the initial rate of glutamate and lactate concentration increases implies an increase in CMR O2 that is slightly below that of CMR Glc during the first 1-2 min of activation. V V C 2013 Wiley Periodicals, Inc.

Proton MR spectra of the brain, especially those measured at short and intermediate echo times, contain signals from mobile macromolecules (MM). A description of the main MM is provided in this consensus paper. These broad peaks of MM underlie the narrower peaks of metabolites and often complicate their quantification but they also may have potential importance as biomarkers in specific diseases. Thus, separation of broad MM signals from low molecular weight metabolites enables accurate determination of metabolite concentrations and is of primary interest in many studies. Other studies attempt to understand the origin of the MM spectrum, to decompose it into individual spectral regions or peaks and to use the components of the MM spectrum as markers of various physiological or pathological conditions in biomedical research or clinical practice. The aim of this consensus paper is to provide an overview and some recommendations on how to handle the MM signals in different types of studies together with a list of open issues in the field, which are all summarized at the end of the paper.

a b s t r a c t a r t i c l e i n f oRecent studies at high field (7 Tesla) have reported small metabolite changes, in particular lactate and glutamate (below 0.3 μmol/g) during visual stimulation. These studies have been limited to the visual cortex because of its high energy metabolism and good magnetic resonance spectroscopy (MRS) sensitivity using surface coil. The aim of this study was to extend functional MRS (fMRS) to investigate for the first time the metabolite changes during motor activation at 7 T. Small but sustained increases in lactate (0.17 μmol/g ± 0.05 μmol/g, p b 0.001) and glutamate (0.17 μmol/g ± 0.09 μmol/g, p b 0.005) were detected during motor activation followed by a return to the baseline after the end of activation. The present study demonstrates that increases in lactate and glutamate during motor stimulation are small, but similar to those observed during visual stimulation. From the observed glutamate and lactate increase, we inferred that these metabolite changes may be a general manifestation of the increased neuronal activity. In addition, we propose that the measured metabolite concentration increases imply an increase in ΔCMR O2 that is transiently below that of ΔCMR Glc during the first 1 to 2 min of the stimulation.© 2014 Elsevier Inc. All rights reserved. IntroductionFunctional MR spectroscopy (fMRS) provides direct insights into brain metabolism by investigating the metabolic response of the brain to a physiological stimulus. The high spectral resolution and signal-tonoise ratio (SNR) of fMRS at high field (N3 Tesla) improve the accuracy and precision of the quantification of many brain metabolites (Mekle et al., 2009;Tkac et al., 2001Tkac et al., , 2009. In addition to the increased chemical shift dispersion, a high time resolution is of advantage for the characterization of the small transient changes observed. Recent fMRS studies (Lin et al., 2012;Mangia et al., 2007b;Schaller et al., 2013) at high field (7 Tesla) reported small metabolite concentration changes during visual stimulation (around 0.2 μmol/g). In particular, a very small lactate concentration increase between 10 and 23% has been observed. Recently, functional diffusion-weighted MRS has been used to investigate metabolite ADC changes as a potential consequence of micro structural changes during activation (Branzoli et al., 2013).The lactate increase observed during visual stimulation has been suggested to explain the mismatch of cerebral metabolic rate of change for glucose (ΔCMR Glc ) (or cerebral blood flow, CBF) and cerebral metabolic rate of change for oxygen (ΔCMR O2 ) during brain activation. However, many studies have reported different results concerning the transient mismatch of ΔCMR Glc , CBF and ΔCMR O2 during functional activity (reviewed in Buxton (2010)). The characterization of these changes has been reported in positron emission tomography (PET) (Fox and

Keywords:Proton single voxel spectroscopy Ultra high magnetic field of 14.1 T Rat brain LCModel Quantification accuracy a b s t r a c t Ultra-short echo-time proton single voxel spectra of rat brain were obtained on a 14.1 T 26 cm horizontal bore system. At this field, the fitted linewidth in the brain tissue of adult rats was about 11 Hz. New, separated resonances ascribed to phosphocholine, glycerophosphocholine and N-acetylaspartate were detected for the first time in vivo in the spectral range of 4.2-4.4 ppm. Moreover, improved separation of the resonances of lactate, alanine, c-aminobutyrate, glutamate and glutathione was observed. Metabolite concentrations were estimated by fitting in vivo spectra to a linear combination of simulated spectra of individual metabolites and a measured spectrum of macromolecules (LCModel). The calculated concentrations of metabolites were generally in excellent agreement with those obtained at 9.4 T. These initial results further indicated that increasing magnetic field strength to 14.1 T enhanced spectral resolution in 1 H NMR spectroscopy. This implies that the quantification of the neurochemical profile in rodent brain can be achieved with improved accuracy and precision.

Conventional proton MRS has been successfully utilized to noninvasively assess tissue biochemistry in conditions that result in large changes in metabolite levels. For more challenging applications, namely, in conditions which result in subtle metabolite changes, the limitations of vendor-provided MRS protocols are increasingly recognized, especially when used at high fields (≥3 T) where chemical shift displacement errors, B 0 and B 1 inhomogeneities and limitations in the transmit B 1 field become prominent. To overcome the limitations of conventional MRS protocols at 3 and 7 T, the use of advanced MRS methodology, including pulse sequences and adjustment procedures, is recommended. Specifically, the semiadiabatic LASER sequence is recommended when T E values of 25-30 ms are acceptable, and the semiadiabatic SPE-CIAL sequence is suggested as an alternative when shorter T E values are critical.The magnetic field B 0 homogeneity should be optimized and RF pulses should be calibrated for each voxel. Unsuppressed water signal should be acquired for eddy current correction and preferably also for metabolite quantification. Metabolite and water data should be saved in single shots to facilitate phase and frequency alignment and to exclude motion-corrupted shots. Final averaged spectra should be evaluated for SNR, linewidth, water suppression efficiency and the presence of unwanted coherences. Spectra that do not fit predefined quality criteria should be excluded from further analysis. Commercially available tools to acquire all data in consistent anatomical locations are recommended for voxel prescriptions, in particular in longitudinal studies. To enable the larger MRS community to take advantage of these advanced methods, a list of resources for these advanced protocols on the major clinical platforms is provided. Finally, a set of recommendations are provided for vendors to enable development of advanced MRS on standard platforms, including implementation of advanced localization sequences, tools for quality assurance on the scanner, and tools for prospective volume tracking and dynamic linear shim corrections.

Biomarker-guided treatments are needed in psychiatry, and previous data suggest oxidative stress may be a target in schizophrenia. A previous add-on trial with the antioxidant N-acetylcysteine (NAC) led to negative symptom reductions in chronic patients. We aim to study NAC’s impact on symptoms and neurocognition in early psychosis (EP) and to explore whether glutathione (GSH)/redox markers could represent valid biomarkers to guide treatment. In a double-blind, randomized, placebo-controlled trial in 63 EP patients, we assessed the effect of NAC supplementation (2700 mg/day, 6 months) on PANSS, neurocognition, and redox markers (brain GSH [GSHmPFC], blood cells GSH levels [GSHBC], GSH peroxidase activity [GPxBC]). No changes in negative or positive symptoms or functional outcome were observed with NAC, but significant improvements were found in favor of NAC on neurocognition (processing speed). NAC also led to increases of GSHmPFC by 23% (P = .005) and GSHBC by 19% (P = .05). In patients with high-baseline GPxBC compared to low-baseline GPxBC, subgroup explorations revealed a link between changes of positive symptoms and changes of redox status with NAC. In conclusion, NAC supplementation in a limited sample of EP patients did not improve negative symptoms, which were at modest baseline levels. However, NAC led to some neurocognitive improvements and an increase in brain GSH levels, indicating good target engagement. Blood GPx activity, a redox peripheral index associated with brain GSH levels, could help identify a subgroup of patients who improve their positive symptoms with NAC. Thus, future trials with antioxidants in EP should consider biomarker-guided treatment.

To date, only a couple of functional MR spectroscopy (fMRS) studies were conducted in rats. Due to the low temporal resolution of 1 H MRS techniques, prolonged stimulation paradigms are necessary for investigating the metabolic outcome in the rat brain during functional challenge. However, sustained activation of cortical areas is usually difficult to obtain due to neural adaptation. Anesthesia, habituation, high variability of the basal state metabolite concentrations as well as low concentrations of the metabolites of interest such as lactate (Lac), glucose (Glc) or γ-aminobutyric acid (GABA) and small expected changes of metabolite concentrations need to be addressed. In the present study, the rat barrel cortex was reliably and reproducibly activated through sustained trigeminal nerve (TGN) stimulation. In addition, TGN stimulation induced significant positive changes in lactate (+1.01 μmol/g, p b 0.008) and glutamate (+0.92 μmol/g, p b 0.02) and significant negative aspartate changes (−0.63 μmol/g, p b 0.004) using functional 1 H MRS at 9.4 T in agreement with previous changes observed in human fMRS studies. Finally, for the first time, the dynamics of lactate, glucose, aspartate and glutamate concentrations during sustained somatosensory activation in rats using fMRS were assessed. These results allow demonstrating the feasibility of fMRS measurements during prolonged barrel cortex activation in rats.