Reproducibility of 7-T brain spectroscopy using an ultrashort echo time STimulated Echo Acquisition Mode sequence and automated voxel repositioning

Establishing the reproducibility of brain MRS is important for clinical studies so that researchers can evaluate changes in metabolites due to treatment or the course of a disease and better understand the brain in healthy and disordered states. Prior 7-T MRS reproducibility studies using the stimulated echo acquisition mode (STEAM) sequence have focused on the anterior cingulate cortex or posterior cingulate cortex and precuneus. The purpose of this study was to evaluate the reproducibility of metabolite measurements in the dorsolateral prefrontal cortex (DLPFC) using an ultrashort echo time (TE) STEAM sequence and automated voxel repositioning. Spectra were acquired during two scan sessions from nine subjects using the AutoAlign method for voxel repositioning. Reproducibility was evaluated with coefficients of variation (CVs) and percentage differences. The mean intrasubject CVs were less than 6% for the major metabolites glutamate, N-acetylaspartate, total creatine, total choline, and myo-inositol. The mean CVs were less than 20% for the smaller signals of GABA, glutamine, glutathione, and taurine. These results indicate that 7-T MRS using a STEAM sequence with ultrashort TE and automated voxel repositioning provides excellent reproducibility of metabolites in the DLPFC.     

Feasibility and reproducibility of neurochemical profile quantification in the human hippocampus at 3 T

Hippocampal dysfunction is known to be associated with several neurological and neuropsychiatric disorders such as Alzheimer's disease, epilepsy, schizophrenia and depression; therefore, there has been significant clinical interest in studying hippocampal neurochemistry. However, the hippocampus is a challenging region to study using ¹H MRS, hence the use of MRS for clinical research in this region has been limited. Our goal was therefore to investigate the feasibility of obtaining high‐quality hippocampal spectra that allow reliable quantification of a neurochemical profile and to establish inter‐session reproducibility of hippocampal MRS, including reproducibility of voxel placement, spectral quality and neurochemical concentrations. Ten healthy volunteers were scanned in two consecutive sessions using a standard clinical 3 T MR scanner. Neurochemical profiles were obtained with a short‐echo (T_E = 28 ms) semi‐LASER localization sequence from a relatively small (~4 mL) voxel that covered about 62% of the hippocampal volume as calculated from segmentation of T₁‐weighted images. Voxel composition was highly reproducible between sessions, with test–retest coefficients of variation (CVs) of 3.5% and 7.5% for gray and white matter volume fraction, respectively. Excellent signal‐to‐noise ratio (~54 based on the N‐acetylaspartate (NAA) methyl peak in non‐apodized spectra) and linewidths (~9 Hz for water) were achieved reproducibly in all subjects. The spectral quality allowed quantification of NAA, total choline, total creatine, myo‐inositol and glutamate with high scan–rescan reproducibility (CV ≤ 6%) and quantification precision (Cramér–Rao lower bound, CRLB < 9%). Four other metabolites, including glutathione and glucose, were quantified with scan–rescan CV below 20%. Therefore, the highly optimized, short‐echo semi‐LASER sequence together with FASTMAP shimming substantially improved the reproducibility and number of quantifiable metabolites relative to prior reports. In addition, the between‐session variation in metabolite concentrations, as well as CRLB, was lower than the between‐subject variation of the concentrations for most metabolites, indicating that the method has the sensitivity to detect inter‐individual differences in the healthy brain. Copyright © 2015 John Wiley & Sons, Ltd.     

Neurochemical changes in the rat prefrontal cortex following acute phencyclidine treatment: an in vivo localized 1H MRS study

Acute phencyclidine (PCP) administration mimics some aspects of schizophrenia in rats, such as behavioral alterations, increased dopaminergic activity and prefrontal cortex dysfunction. In this study, we used single‐voxel ¹H‐MRS to investigate neurochemical changes in rat prefrontal cortex in vivo before and after an acute injection of PCP. A short‐echo time sequence (STEAM) was used to acquire spectra in a 32‐µL voxel positioned in the prefrontal cortex area of 12 rats anesthetized with isoflurane. Data were acquired for 30 min before and for 140 min after a bolus of PCP (10 mg/kg, n = 6) or saline (n = 6). Metabolites were quantified with the LCModel. Time courses for 14 metabolites were obtained with a temporal resolution of 10 min. The glutamine/glutamate ratio was significantly increased after PCP injection (p < 0.0001, pre‐ vs. post‐injection), while the total concentration of these two metabolites remained constant. Glucose was transiently increased (+70%) while lactate decreased after the injection (both p < 0.0001). Lactate, but not glucose and glutamine, returned to baseline levels after 140 min. These results show that an acute injection of PCP leads to changes in glutamate and glutamine concentrations, similar to what has been observed in schizophrenic patients, and after ketamine administration in humans. MRS studies of this pharmacological rat model may be useful for assessing the effects of potential anti‐psychotic drugs in vivo. Copyright © 2009 John Wiley & Sons, Ltd.     

Multi‐center reproducibility of neurochemical profiles in the human brain at 7 T

The purpose of this work was to harmonize data acquisition and post‐processing of single voxel proton MRS (¹H‐MRS) at 7 T, and to determine metabolite concentrations and the accuracy and reproducibility of metabolite levels in the adult human brain. This study was performed in compliance with local institutional human ethics committees. The same seven subjects were each examined twice using four different 7 T MR systems from two different vendors using an identical semi‐localization by adiabatic selective refocusing spectroscopy sequence. Neurochemical profiles were obtained from the posterior cingulate cortex (gray matter, GM) and the corona radiata (white matter, WM). Spectra were analyzed with LCModel, and sources of variation in concentrations (‘subject’, ‘institute’ and ‘random’) were identified with a variance component analysis. Concentrations of 10–11 metabolites, which were corrected for T₁, T₂, magnetization transfer effects and partial volume effects, were obtained with mean Cramér–Rao lower bounds below 20%. Data variances and mean concentrations in GM and WM were comparable for all institutions. The primary source of variance for glutamate, myo‐inositol, scyllo‐inositol, total creatine and total choline was between subjects. Variance sources for all other metabolites were associated with within‐subject and system noise, except for total N‐acetylaspartate, glutamine and glutathione, which were related to differences in signal‐to‐noise ratio and in shimming performance between vendors. After multi‐center harmonization of acquisition and post‐processing protocols, metabolite concentrations and the sizes and sources of their variations were established for neurochemical profiles in the healthy brain at 7 T, which can be used as guidance in future studies quantifying metabolite and neurotransmitter concentrations with ¹H‐MRS at ultra‐high magnetic field. Copyright © 2015 John Wiley & Sons, Ltd.     

Towards a neurochemical profile of the amygdala using short‐TE 1H magnetic resonance spectroscopy at 3 T

The amygdala plays a key role in emotional learning and in the processing of emotions. As disturbed amygdala function has been linked to several psychiatric conditions, a knowledge of its biochemistry, especially neurotransmitter levels, is highly desirable. The spin echo full intensity acquired localized (SPECIAL) sequence, together with a transmit/receive coil, was used to perform very short‐TE magnetic resonance spectroscopy at 3 T to determine the neurochemical profile in a spectroscopic voxel containing the amygdala in 21 healthy adult subjects. For spectral analysis, advanced data processing was applied in combination with a macromolecule baseline measured in the anterior cingulate for spectral fitting. The concentrations of total N‐acetylaspartate, total creatine, total choline, myo‐inositol and, for the first time, glutamate were quantified with high reliability (uncertainties far below 10%). For these metabolites, the inter‐individual variability, reflected by the relative standard deviations for the cohort studied, varied between 12% (glutamate) and 22% (myo‐inositol). Glutamine and glutathione could also be determined, albeit with lower precision. Retest on four subjects showed good reproducibility. The devised method allows the determination of metabolite concentrations in the amygdala voxel, including glutamate, provides an estimation of glutamine and glutathione, and may help in the study of disturbed amygdala metabolism in pathologies such as anxiety disorder, autism and major depression.     

In vivo 1H MRS study in microlitre voxels in the hippocampus of a mouse model of Down syndrome at 11.7 T

In this article, we report in vivo ¹H MRS performed in 1.8‐μL voxels in a mouse model of Down syndrome (DS). To characterise the excitation–inhibition imbalance observed in DS, metabolite concentrations in the hippocampi of adult Ts65Dn mice, which recapitulate features of DS, were compared with those of their euploid littermates at a voxel 42‐fold smaller than in a previously published study. Quantification of the metabolites was performed using a linear combination model. We detected 16 metabolites in the right and left hippocampi. Principal component analysis revealed that the absolute concentrations of the 16 detected metabolites could differentiate between Ts65Dn and euploid hippocampi. Although measurements in the left and right hippocampi were highly correlated, the concentration of individual metabolites was sometimes significantly different in the left and right structures. Thus, bilateral values from Ts65Dn and euploid mice were further compared with Hotelling's test. The level of glutamine was found to be significantly lower, whereas myo‐inositol was significantly higher, in the hippocampi of Ts65Dn relative to euploid mice. However, γ‐aminobutyric acid (GABA) and glutamate levels remained similar between the groups. Thus, the excitation–inhibition imbalance described in DS does not appear to be related to a radical change in the levels of either GABA or glutamate in the hippocampus. In conclusion, microliter MRS appears to be a valuable tool to detect changes associated with DS, which may be useful in investigating whether differences can be rescued after pharmacological treatments or supplementation with glutamine. Copyright © 2014 John Wiley & Sons, Ltd.     

Quantification of J‐resolved proton spectra in two‐dimensions with LCModel using GAMMA‐simulated basis sets at 4 Tesla

A two‐dimensional, J‐resolved magnetic resonance spectroscopic extraction approach was developed employing GAMMA‐simulated, LCModel basis‐sets. In this approach, a two‐dimensional J‐resolved (2D‐JPRESS) dataset was resolved into a series of one‐dimensional spectra where each spectrum was modeled and fitted with its theoretically customized LCModel template. Metabolite levels were derived from the total integral across the J‐series of spectra for each metabolite. Phantoms containing physiologic concentrations of the major brain chemicals were used for validation. Varying concentrations of glutamate and glutamine were evaluated at and around their accepted in vivo concentrations in order to compare the accuracy and precision of our method with 30 ms PRESS. We also assessed 2D‐JPRESS and 30 ms PRESS in vivo, in a single voxel within the parieto‐occipital cortex by scanning ten healthy volunteers once and a single healthy volunteer over nine repeated measures. Phantom studies demonstrated that serial fitting of 2D‐JPRESS spectra with simulated LCModel basis sets provided accurate concentration estimates for common metabolites including glutamate and glutamine. Our in vivo results using 2D‐JPRESS suggested superior reproducibility in measuring glutamine and glutamate relative to 30 ms PRESS. These novel methods have clear implications for clinical and research studies seeking to understand neurochemical dysfunction. Copyright © 2009 John Wiley & Sons, Ltd.     

Reproducibility of prefrontal γ-aminobutyric acid measurements with J-edited spectroscopy

γ‐Aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the human brain, and GABA‐ergic dysfunction has been implicated in a variety of neuropsychiatric disorders. Recent MRS techniques have allowed the quantification of GABA concentrations in vivo, and could therefore provide biologically relevant information. Few reports have formally characterized the reproducibility of these techniques, and differences in field strength, acquisition and processing parameters may result in large differences in measured GABA values. Here, we used a J‐edited, single‐voxel spectroscopy method of measurement of GABA + macromolecules (GABA + ) in the anterior cingulate cortex (ACC) and right frontal white matter (rFWM) at 3 T. We measured the coefficient of variation within subjects (CVw) and intra‐class correlation coefficients on two repeated scans obtained from 10 healthy volunteers with processing procedures developed in‐house for the quantification of GABA + and other major metabolites. In addition, by segmenting the spectroscopic voxel into cerebrospinal fluid, gray matter and white matter, and employing a linear regression technique to extrapolate metabolite values to pure gray and white matter, we determined metabolite differences between gray and white matter in ACC and rFWM. CVw values for GABA + /creatine, GABA + /H₂O, GABA + , creatine, partially co‐edited glutamate + glutamine (Glx)/creatine, partially co‐edited Glx and N‐acetylaspartic acid (NAA)/creatine were all below 12% in both ACC and rFWM. After extrapolation to pure gray and pure white matter, CVw values for all metabolites were below 16%. We found metabolite ratios between gray and white matter for GABA + /creatine, GABA + , creatine, partially co‐edited Glx and NAA/creatine to be 0.88 ± 0.21 (standard deviation), 1.52 ± 0.32, 1.77 ± 0.4, 2.69 ± 0.74 and 0.70 ± 0.05, respectively. This study validates a reproducible method for the quantification of brain metabolites, and provides information on gray/white matter differences that may be important in the interpretation of results in clinical populations. Published in 2011 by John Wiley & Sons, Ltd.     

Regional metabolic differences in rat prefrontal cortex measured with in vivo 1H‐MRS correlate with regional histochemical differences

Many neurological/psychiatric disorders are associated with metabolic abnormalities in the brain observable with in vivo proton MRS (¹H‐MRS). The underlying molecular/cellular mechanisms and functional correlations of such metabolic alterations, however, are yet to be understood fully. The rodent prefrontal cortex (PFC) is comprised of multiple sub‐regions with distinctive cytoarchitecture and functions, providing a good model system to study the correlations among cerebral metabolism, regional cytoarchitecture and connectivity. In this study, the metabolic profiles in two voxels containing mainly the medial PFC (mPFC) and posterior part of the cingulate cortex (pCG), respectively, were measured with single‐voxel in vivo ¹H‐MRS in adult male rats. The levels of glutamine synthetase and glutamatergic synaptic proteins, including vesicular glutamate transporter 1, vesicular glutamate transporter 2 (VGLUT2) and post‐synaptic density protein 95 (PSD95), as well as the density of astrocytes, in these two regions were also compared semi‐quantitatively. It was shown that, relative to the pCG voxel, the mPFC voxel had significantly higher N‐acetyl aspartate, glutamate (Glu), glutamine (Gln), Glx (Glu + Gln), myo‐inositol and taurine levels. The VGLUT2/PSD95 levels and astrocyte density were also higher in the mPFC voxel than in the pCG voxel. Taken together, these results indicated that regional metabolic variations in the PFC of the adult male rat may reflect regional differences in the density of astrocytes and glutamatergic terminals associated with subcortical projections. The study provided a link between the Glu concentration measured with localized in vivo ¹H‐MRS and regional glutamatergic activities/connections in the rat PFC.     

In vivo and ex vivo evidence for ketamine-induced hyperglutamatergic activity in the cerebral cortex of the rat: Potential relevance to schizophrenia

Subanesthetic doses of ketamine, a noncompetitive N‐methyl‐D ‐aspartate (NMDA) receptor antagonist, impair prefrontal cortex (PFC) function in the rat and produce symptoms in humans similar to those observed in patients with schizophrenia. In the present study, in vivo ¹H‐MRS and ex vivo ¹H high‐resolution magic angle spinning (HR‐MAS) spectroscopy was used to examine the brain metabolism of rats treated with subanesthetic doses of ketamine (30 mg/kg) for 6 days. A single voxel localization sequence (PRESS, TR/TE = 4000/20 ms and NEX = 512) was used to acquire the spectra in a 30‐µl voxel positioned in the cerebral cortex (including mainly PFC) of the rats (ketamine group: n = 12; saline group: n = 12) anesthetized with isoflurane. After the in vivo ¹H‐MRS acquisition, the animals were sacrificed and the cerebral cortex tissues were extracted (ketamine group: n = 7; saline group: n = 7) for ex vivo ¹H HR‐MAS spectroscopy (CPMG sequence, 2.0‐s presaturation delay, 2.0‐s acquisition time, 128 transients and 4‐ms inter‐pulse delay) using a 500‐MHz NMR spectrometer. All proton metabolites were quantified using the LCModel. For the in vivo spectra, there was a significant increase in glutamate concentration in the cerebral cortex of the ketamine group compared with the controls (p < 0.05). For the ex vivo HR‐MAS spectra, there was a significant increase in the glutamate/total creatine ratio, and a decrease in the glutamine/total creatine and glutamine/glutamate ratios in the cerebral cortex tissue of the ketamine group compared with the controls. The results of the present study demonstrated that administration of subanesthetic doses of ketamine in the rat may exert at least part of their effect in the cerebral cortex by activation of glutamatergic neurotransmission. Copyright © 2011 John Wiley & Sons, Ltd.     

Direct in vivo measurement of glycine and the neurochemical profile in the rat medulla oblongata

The medulla oblongata (MO) contains a high density of glycinergic synapses and a particularly high concentration of glycine. The aims of this study were to measure directly in vivo the neurochemical profile, including glycine, in MO using a spin‐echo‐based ¹H MRS sequence at TE = 2.8 ms and to compare it with three other brain regions (cortex, striatum and hippocampus) in the rat. Glycine was quantified in MO at TE = 2.8 ms with a Cramér–Rao lower bound (CRLB) of approximately 5%. As a result of the relatively low level of glycine in the other three regions, the measurement of glycine was performed at TE = 20 ms, which provides a favorable J‐modulation of overlapping myo‐inositol resonance. The other 14 metabolites composing the neurochemical profile were quantified in vivo in MO with CRLBs below 25%. Absolute concentrations of metabolites in MO, such as glutamate, glutamine, γ‐aminobutyrate, taurine and glycine, were in the range of previous in vitro quantifications in tissue extracts. Compared with the other regions, MO had a three‐fold higher glycine concentration, and was characterised by reduced (p < 0.001) concentrations of glutamate (?50 ± 4%), glutamine (–54 ± 3%) and taurine (?78 ± 3%). This study suggests that the functional specialisation of distinct brain regions is reflected in the neurochemical profile. Copyright © 2010 John Wiley & Sons, Ltd.     

Phase‐adjusted echo time (PATE)‐averaging 1H MRS: application for improved glutamine quantification at 2.89 T

¹H MRS investigations have reported altered glutamatergic neurotransmission in a variety of psychiatric disorders. The unraveling of glutamate from glutamine resonances is crucial for the interpretation of these observations, although this remains a challenge at clinical static magnetic field strengths. Glutamate resolution can be improved through an approach known as echo time (TE) averaging, which involves the acquisition and subsequent averaging of multiple TE steps. The process of TE averaging retains the central component of the glutamate methylene multiplet at 2.35 ppm, with the simultaneous attenuation of overlapping phase‐modulated coupled resonances of glutamine and N‐acetylaspartate. We have developed a novel post‐processing approach, termed phase‐adjusted echo time (PATE) averaging, for the retrieval of glutamine signals from a TE‐averaged ¹H MRS dataset. The method works by the application of an optimal TE‐specific phase term, which is derived from spectral simulation, prior to averaging over TE space. The simulation procedures and preliminary in vivo spectra acquired from the human frontal lobe at 2.89 T are presented. Three metabolite normalization schemes were developed to evaluate the frontal lobe test–retest reliability for glutamine measurement in six subjects, and the resulting values were comparable with previous reports for within‐subject (9–14%) and inter‐subject (14–20%) measures. Using the acquisition parameters and TE range described, glutamine quantification is possible in approximately 10 min. The post‐processing methods described can also be applied retrospectively to extract glutamine and glutamate levels from previously acquired TE‐averaged ¹H MRS datasets. Copyright © 2012 John Wiley & Sons, Ltd.     

Expanded neurochemical profile in the early stage of Huntington disease using proton magnetic resonance spectroscopy

The striatum is a well‐known region affected in Huntington disease (HD). However, other regions, including the visual cortex, are implicated. We have identified previously an abnormal energy response in the visual cortex of patients at an early stage of HD using ³¹P magnetic resonance spectroscopy (³¹P MRS). We therefore sought to further characterize these metabolic alterations with ¹H MRS using a well‐validated semi‐localized by adiabatic selective refocusing (semi‐LASER) sequence that allows the measurement of an expanded number of neurometabolites. Ten early affected patients [Unified Huntington Disease Rating Scale (UHDRS), total motor score = 13.6 ± 10.8] and 10 healthy volunteers of similar age and body mass index (BMI) were recruited for the study. We performed ¹H MRS in the striatum – the region that is primarily affected in HD – and the visual cortex. The protocol allowed a reliable quantification of 10 metabolites in the visual cortex and eight in the striatum, compared with three to five metabolites in previous ¹H MRS studies performed in HD. We identified higher total creatine (p < 0.05) in the visual cortex and lower glutamate (p < 0.001) and total creatine (p < 0.05) in the striatum of patients with HD compared with controls. Less abundant neurometabolites [glutamine, γ‐aminobutyric acid (GABA), glutathione, aspartate] showed similar concentrations in both groups. The protocol allowed the measurement of several additional metabolites compared with standard vendor protocols. Our study points to early changes in metabolites involved in energy metabolism in the visual cortex and striatum of patients with HD. Decreased striatal glutamate could reflect early neuronal dysfunction or impaired glutamatergic neurotransmission.     

Longitudinal 1H MRS of rat forebrain from infancy to adulthood reveals adolescence as a distinctive phase of neurometabolite development

This study represents the first longitudinal, within‐subject ¹H MRS investigation of the developing rat brain spanning infancy, adolescence and early adulthood. We obtained neurometabolite profiles from a voxel located in a central location of the forebrain, centered on the striatum, with smaller contributions for the cortex, thalamus and hypothalamus, on postnatal days 7, 35 and 60. Water‐scaled metabolite signals were corrected for T₁ effects and quantified using the automated processing software LCModel, yielding molal concentrations. Our findings indicate age‐related concentration changes in N‐acetylaspartate + N‐acetylaspartylglutamate, myo‐inositol, glutamate + glutamine, taurine, creatine + phosphocreatine and glycerophosphocholine + phosphocholine. Using a repeated measures design and analysis, we identified significant neurodevelopment changes across all three developmental ages and identified adolescence as a distinctive phase in normative neurometabolic brain development. Between postnatal days 35 and 60, changes were observed in the concentrations of N‐acetylaspartate + N‐acetylaspartylglutamate, glutamate + glutamine and glycerophosphocholine + phosphocholine. Our data replicate past studies of early neurometabolite development and, for the first time, link maturational profiles in the same subjects across infancy, adolescence and adulthood. Copyright © 2013 John Wiley & Sons, Ltd.     

Localized MRS reliability of in vivo glutamate at 3 T in shortened scan times: a feasibility study

Glutamate is the prime excitatory neurotransmitter in the mammalian brain and has been implicated in a wide range of psychiatric conditions. To improve the applicability and clinical reach of magnetic resonance spectroscopy (MRS), research is needed to develop shortened, yet reliable, MRS scanning procedures for standard 1.5–3‐T clinical magnetic resonance imaging (MRI) systems, particularly with young or vulnerable populations unable to tolerate longer protocols. To this end, we evaluated the test–retest reliability of a shortened J ‐resolved MRS sequence in healthy adolescents (n  = 22) aged 12–14 years. Participants underwent a series of sequential 6‐min MRS scans, with the participants remaining in situ between successive scans. Glutamate and other metabolites were acquired from the rostral anterior cingulate cortex, as glutamatergic function in this region has been implicated in a number of psychiatric illnesses. Thirteen neurochemicals were quantified as ratios to total creatine, and reliability scores were expressed as the percentage difference between the two scans for each metabolite. Test–retest assessment of glutamate was reliable, as scores were less than 10% different (7.1 ± 4.2%), and glutamate values across scans were significantly correlated (Pearson r  = 0.680, p  < 10^?4). Several other neurochemicals demonstrated satisfactory reliability, including choline (Cho) (7.4 ± 5.6%), glutathione (GSH) (8.6 ± 4.1%), myo‐inositol (mI) (6.5 ± 7.1%) and N ‐acetylaspartate (NAA) (3.5 ± 3.6%), with test–retest correlations ranging from 0.747 to 0.953. A number of metabolites, however, did not demonstrate acceptable test–retest reliability using the current J ‐resolved MRS sequence, ranging from 13.8 ± 13.7% (aspartate, Asp) to 45.9 ± 38.3% (glycine, Gly). Collectively, test–retest analyses suggest that clinically viable quantitative data can be obtained on standard MRI systems for glutamate, as well as the other metabolites, during short scan times in a traditionally challenging brain region.     

Metabolic correlatives of brain activity in a FOS epilepsy patient

The correlation and the interactions between neuronal activity and underlying metabolic dynamics are still a matter of debate, especially in pathological conditions. This study reports findings obtained on a subject suffering from fixation‐off sensitivity (FOS) epilepsy, exploited as a model system of triggerable anomalous electrical activity. Functional Magnetic Resonance Spectroscopy was used to investigate the metabolic response to visual spike‐inducing stimuli in a single voxel placed in the temporo‐occipital lobe of a FOS epilepsy patient. MRS measurements were additionally performed on a control group of five healthy volunteers. The FOS patient also underwent an EEG session with the same stimulus paradigm. Uniquely in the FOS patient, glutamate and glutamine concentration increased during the first 10 min of stimulation and then returned to baseline. On the other hand, FOS‐induced epileptic activity (spiking) endured throughout all the stimulation epoch. The observed metabolic dynamics may be likely linked to a complex interplay between alterations of the metabolic pathways of glutamate and modulation of the neuronal activity. Copyright © 2009 John Wiley & Sons, Ltd.     

Regional neurochemical profiles in the human brain measured by 1H MRS at 7 T using local B1 shimming

Increased sensitivity and chemical shift dispersion at ultra‐high magnetic fields enable the precise quantification of an extended range of brain metabolites from ¹H MRS. However, all previous neurochemical profiling studies using single‐voxel MRS at 7 T have been limited to data acquired from the occipital lobe with half‐volume coils. The challenges of ¹H MRS of the human brain at 7 T include short T₂ and complex B₁ distribution that imposes limitations on the maximum achievable B₁ strength. In this study, the feasibility of acquiring and quantifying short‐echo (TE = 8 ms), single‐voxel ¹H MR spectra from multiple brain regions was demonstrated by utilizing a 16‐channel transceiver array coil with 16 independent transmit channels, allowing local transmit B₁ (B₁⁺) shimming. Spectra were acquired from volumes of interest of 1–8 mL in brain regions that are of interest for various neurological disorders: frontal white matter, posterior cingulate, putamen, substantia nigra, pons and cerebellar vermis. Local B₁⁺ shimming substantially increased the transmit efficiency, especially in the peripheral and ventral brain regions. By optimizing a STEAM sequence for utilization with a 16‐channel coil, artifact‐free spectra were acquired with a small chemical shift displacement error (<5% /ppm/direction) from all regions. The high signal‐to‐noise ratio enabled the quantification of neurochemical profiles consisting of at least nine metabolites, including γ‐aminobutyric acid, glutamate and glutathione, in all brain regions. Significant differences in neurochemical profiles were observed between brain regions. For example, γ‐aminobutyric acid levels were highest in the substantia nigra, total creatine was highest in the cerebellar vermis and total choline was highest in the pons, consistent with the known biochemistry of these regions. These findings demonstrate that single‐voxel ¹H MRS at ultra‐high field can reliably detect region‐specific neurochemical patterns in the human brain, and has the potential to objectively detect alterations in neurochemical profiles associated with neurological diseases. Copyright © 2011 John Wiley & Sons, Ltd.     

Longitudinal (1) H MRS assessment of the thalamus in a Coriaria lactone-induced rhesus monkey status epilepticus model

Neurophysiological, biochemical and anatomical evidence implicates the thalamus as playing a role in epileptic seizures. Until recently, however, longitudinal characterization of in vivo thalamus dynamics had not been reported. In this study, we investigated the metabolism in the thalamus to identify the changes that occur following Coriaria lactone (CL)‐induced status epilepticus (SE) and to observe whether the epileptiform discharges could present a difference between the left and right thalami. Five rhesus monkeys underwent whole‐brain MRI and single‐voxel MRS on a Siemens Trio Tim 3‐T MR scanner with a 12‐channel head coil. Spectra were processed using LCModel. Scans were performed in five animals before SE and at 1, 7, 21 and 42 days after the onset of SE. Statistical analysis of the data obtained demonstrated no significant difference in the bilateral thalamus of healthy macaques. Our MRS data showed symmetrical distributions of N‐acetylaspartate in the right and left thalami after SE (p = 0.003). In addition, this longitudinal study demonstrated elevated glutamate/glutamine (p < 0.05) and reduced myo‐inositol (p < 0.05) in the bilateral thalamus 1 day after SE, and all metabolites approached their baseline levels by the fifth scan. Our results demonstrate that metabolic changes occur in the thalamus during CL‐induced SE in rhesus monkeys. The various metabolic changes may indicate that the left thalamus is more vulnerable to epileptic strike. Copyright © 2012 John Wiley & Sons, Ltd.     

Detection of metabolite changes in response to a varying visual stimulation paradigm using short‐TE 1H MRS at 7 T

The two‐fold benefit of ¹H magnetic resonance spectroscopy (MRS) at high B₀ fields – enhanced sensitivity and increased spectral dispersion – has been used previously to study dynamic changes in metabolite concentrations in the human brain in response to visual stimulation. In these studies, a strong visual on/off stimulus was combined with MRS data acquisition in a voxel location in the occipital cortex determined by an initial functional magnetic resonance imaging experiment. However, 1) to exclude the possibility of systemic effects (heartbeat, blood flow, etc.), which tend to be different for on/off conditions, a modified stimulation condition not affecting the target voxel needs to be employed, and 2) to assess important neurotransmitters of low concentration, in particular γ‐aminobutyric acid (GABA), it may be advantageous to analyze steady‐state, rather than dynamic, conditions. Thus, the aim of this study was to use short‐TE ¹H MRS methodology at 7 T to detect differences in steady‐state metabolite levels in response to a varying stimulation paradigm in the human visual cortex. The two different stimulation conditions were termed voxel and control activation. Localized MR spectra were acquired using the SPECIAL (spin‐echo full‐intensity acquired localized) sequence. Data were analyzed using LCModel. Fifteen individual metabolites were reliably quantified. On comparison of steady‐state concentrations for voxel versus control activation, a decrease in GABA of 0.05 mmol/L (5%) and an increase in lactate of 0.04 mmol/L (7%) were found to be the only significant effects. The observed reduction in GABA can be interpreted as reduced neuronal inhibition during voxel activation, whereas the increase in lactate hints at an intensification of anaerobic glycolysis. Differences from previous studies, notably the absence of any changes in glutamate, are attributed to the modified experimental conditions. This study demonstrates that the use of advanced ¹H MRS methodology at 7 T allows the detection of subtle changes in metabolite concentrations involved in neuronal activation and inhibition.     

Improvements in high-field localized MRS of the medial temporal lobe in humans using new deformable high-dielectric materials

The intrinsic nonuniformities in the transmit radiofrequency field from standard quadrature volume resonators at high field are particularly problematic for localized MRS in areas such as the temporal lobe, where a low signal‐to‐noise ratio and poor metabolite quantification result from destructive B field interference, in addition to line broadening and signal loss from strong susceptibility gradients. MRS of the temporal lobe has been performed in a number of neurodegenerative diseases at clinical fields, but a relatively low signal‐to‐noise ratio has prevented the reliable quantification of, for example, glutamate and glutamine, which are thought to play a key role in disease progression. Using a recently developed high‐dielectric‐constant material placed around the head, localized MRS of the medial temporal lobe using the stimulated echo acquisition mode sequence was acquired at 7 T. The presence of the material increased the signal‐to‐noise ratio of MRS by a factor of two without significantly reducing the sensitivity in other areas of the brain, as shown by the measured B maps. An increase in the receive sensitivity B was also measured close to the pads. The spectral linewidth of the unsuppressed water peak within the voxel of interest was reduced slightly by the introduction of the dielectric pads (although not to a statistically significant degree), a result confirmed by using a pad composed of lipid. Using LCmodel for quantitative analysis of metabolite concentrations, the increase in signal‐to‐noise ratio and the slight decrease in spectral linewidth contributed to statistically significant reductions in the Cramer–Rao lower bounds (CRLBs), also allowing the levels of glutamate and glutamine to be quantified with CRLBs below 20%. Copyright © 2010 John Wiley & Sons, Ltd.