MRS Voxel Research Articles

Spectral fitting using basis set modified by measured B0 field distribution.

This study sought to demonstrate and evaluate a novel spectral fitting method to improve quantification accuracy in the presence of large magnetic field distortion, especially with high fields. MRS experiments were performed using a point-resolved spectroscopy (PRESS)-type sequence at 7 T. A double-echo gradient echo (GRE) sequence was used to acquire B0 maps following MRS experiments. The basis set was modified based on the measured B0 distribution within the MRS voxel. Quantification results were obtained after fitting the measured MRS data using the modified basis set. The proposed method was validated using numerical Monte Carlo simulations, phantom measurements, and comparison of occipital lobe MRS measurements under homogeneous and inhomogeneous magnetic field conditions. In vivo results acquired from voxels placed in thalamus and prefrontal cortex regions close to the frontal sinus agreed well with published values. Instead of noise-amplifying complex division, the proposed method treats field variations as part of the signal model, thereby avoiding inherent statistical bias associated with regularization. Simulations and experiments showed that the proposed approach reliably quantified results in the presence of relatively large magnetic field distortion. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Association between baseline peri-infarct magnetic resonance spectroscopy and regional white matter atrophy after stroke.

Cerebral atrophy after stroke is associated with poor functional outcome. The prediction and prevention of post-stroke brain atrophy could therefore represent a target for neurorestorative therapies. We investigated the associations between peri-infarct metabolite concentrations measured by quantitative MRS and brain volume change in the infarct hemisphere after stroke. Twenty patients with ischemic stroke were enrolled. Patients underwent 3T-MRI within 1 week of onset, and at 1 and 3 months. At the baseline scan, an MRS voxel was placed manually in the peri-infarct area and another in the corresponding contralateral region. Volumetric analysis of T1 images was performed using two automated processing packages. Changes in gray and white matter volume were assessed as percentage change between 1 and 3 months. Mean concentrations (institutional units) of N-acetylaspartic acid (NAA) (6.1 vs 7.0, p = 0.039), total creatine (Cr+PCr) (5.4 vs 5.8, p = 0.043), and inositol (4.5 vs 5.0, p = 0.014), were significantly lower in the peri-infarct region compared with the contralateral hemisphere. There was a significant correlation between baseline peri-infarct NAA and white matter volume change in the infarct hemisphere between 1 and 3 months, with lower NAA being associated with subsequent white matter atrophy (Spearman's rho = 0.66, p = 0.010). The baseline concentration of Cr+PCr was also significantly correlated with white matter atrophy in the infarct hemisphere (Spearman's rho = 0.59, p = 0.027). Both of these associations were significant after adjustment for the false discovery rate and were validated using the secondary volumetric method. MRS may be useful in the prediction of white matter atrophy post-stroke and in the testing of novel neurorestorative therapies.

Metabolic change in the right dorsolateral prefrontal cortex and its correlation with symptom severity in patients with generalized anxiety disorder: Proton magnetic resonance spectroscopy at 3 Tesla.

A few neuroimaging studies have demonstrated the key brain areas associated with generalized anxiety disorder (GAD). However, the brain metabolic changes in the dorsolateral prefrontal cortex (DLPFC) of patients with GAD are unclear. This study utilized 3-Tesla proton magnetic resonance spectroscopy ((1) H-MRS) to assess the DLPFC metabolic change and its correlation with symptom severity in patients with GAD. Patients with GAD diagnosed using the DSM-IV-TR and age-matched healthy controls participated in this study. Brain metabolite concentrations were measured from a localized voxel on the DLPFC using 3-Tesla (1) H-MRS. Also, the volumetric composition of the gray matter and white matter volumes was assessed using voxel-based morphometry. The choline/creatine and choline/N-acetylaspartate ratios were significantly lower in patients than in controls. However, there were no significant differences in other metabolite ratios between the two groups. Choline concentrations were negatively correlated with anxiety levels as measured by the Hamilton Anxiety Rating Scale and the Generalized Anxiety Disorder Scale 7. There was no significant difference in the gray matter and white matter volumes in the MRS voxel between the two groups. The present study demonstrates that GAD is associated with low a level of choline/N-acetylaspartate in the DLPFC, which is closely related with symptom severity and cognitive dysfunction. This finding will be useful for an understanding of the neural mechanism associated with GAD.

Absolute GABA spectroscopy with MEGA-PRESS and watermapping in sensorimotor and visual cortex and correlation to handedness

Background Quantification of g-aminobutyric acid (GABA) concentrations in the brain has been the subject of many studies [1]. Nevertheless, quantification procedures vary substantially, mainly in terms of choice of the concentration reference. While in some cases creatine (Cr) or N-acetyl aspartate (NAA) are assumed to be of quasi-constant concentration (intra and inter subject), this may not be the case in pathologies, so that the use of an unsuppressed water reference should prove more reliable. In this work, a “water concentration ground truth” from the MRS voxel is pulled from a watermapping technique presented in [2].

Computerized MRS voxel registration and partial volume effects in single voxel 1H-MRS

Partial volume effects in proton magnetic resonance spectroscopy in the brain have been studied previously in terms of proper water concentration calculations, but there is a lack of disclosure in terms of voxel placement techniques that would affect the calculations. The purpose of this study is to facilitate a fully automated MRS voxel registration method which is time efficient, accurate, and can be extended to all imaging modalities. A total of thirteen healthy adults underwent single voxel 1H-MRS scans in 3.0T MRI scanners. Transposition of a MRS voxel onto an anatomical scan is derived along with a full calculation of water concentration with a correction term to account for the partial volume effects. Five metabolites (tNAA, Glx, tCr, mI, and tCho) known to yield high reliability are studied. Pearson’s correlation analyses between tissue volume fractions and metabolite concentrations were statistically significant in parietal (tCr, Glx, and tNAA) lobe and occipital lobe (tNAA). MRS voxel overlaps quantified by dice metric over repeated visits yielded 60%~70% and coefficients of variance in metabolites concentration were 4%~10%. These findings reiterate an importance of considering the partial volume effects when tissue water is used as an internal concentration reference so as to avoid misinterpreting a morphometric difference as a metabolic difference.

Posteromedial cortex glutamate and GABA predict intrinsic functional connectivity of the default mode network

The balance between excitatory glutamatergic projection neurons and inhibitory GABAergic interneurons determines the function of cortical microcircuits. How these neurotransmitters relate to the functional status of an entire macro-scale network remains unknown. The posteromedial cortex (PMC) is the default mode network (DMN) node with the greatest functional connectivity; therefore, we hypothesized that PMC glutamate and GABA predict intrinsic functional connectivity (iFC) across the entire DMN. In 20 healthy men, we combined J-resolved magnetic resonance spectroscopy to measure glutamate and GABA in the PMC and resting fMRI followed by group Independent Components Analysis to extract the entire DMN. We showed that, controlling for age and partial GM volume in the MRS voxel, PMC glutamate and GABA explained about half of the variance of DMN iFC (represented by the network's beta coefficient for rest). Glutamate correlated positively and GABA correlated negatively with DMN iFC; in an alternative statistical model which included the glutamate/GABA ratio, the ratio correlated positively with DMN iFC. Age had no independent association with DMN iFC. No other network was associated with PMC glutamate or GABA. We conclude that regional neurotransmitter concentrations in a network node strongly predict network but not global brain iFC.

Novel Use of Proton Magnetic Resonance Spectroscopy (1HMRS) to Non-Invasively Assess Placental Metabolism

BackgroundPlacental insufficiency is a major cause of antepartum stillbirth and fetal growth restriction (FGR). In affected pregnancies, delivery is expedited when the risks of ongoing pregnancy outweigh those of prematurity. Current tests are unable to assess placental function and determine optimal timing for delivery. An accurate, non-invasive test that clearly defines the failing placenta would address a major unmet clinical need. Proton magnetic resonance spectroscopy (1H MRS) can be used to assess the metabolic profile of tissue in-vivo. In FGR pregnancies, a reduction in N-acetylaspartate (NAA)/choline ratio and detection of lactate methyl are emerging as biomarkers of impaired neuronal metabolism and fetal hypoxia, respectively. However, fetal brain hypoxia is a late and sometimes fatal event in placental compromise, limiting clinical utility of brain 1H MRS to prevent stillbirth. We hypothesised that abnormal placental 1H MRS may be an earlier biomarker of intrauterine hypoxia, affording the opportunity to optimise timing of delivery in at-risk fetuses.Methods and FindingsWe recruited three women with severe placental insufficiency/FGR and three matched controls. Using a 3T MR system and a combination of phased-array coils, a 20×20×40 mm1H MRS voxel was selected along the ‘long-axis’ of the placenta with saturation bands placed around the voxel to prevent contaminant signals. A significant choline peak (choline/lipid ratio 1.35–1.79) was detected in all healthy placentae. In contrast, in pregnancies complicated by FGR, the choline/lipid ratio was ≤0.02 in all placentae, despite preservation of the lipid peak (p<0.001).ConclusionsThis novel proof-of-concept study suggests that in severe placental insufficiency/FGR, the observed 60-fold reduction in the choline/lipid ratio by 1H MRS may represent an early biomarker of critical placental insufficiency. Further studies will determine performance of this test and the potential role of 1H-MRS in the in-vivo assessment of placental function to inform timing of delivery.

Absolute quantitation of brain metabolites with respect to heterogeneous tissue compositions in 1H-MR spectroscopic volumes

Referencing metabolite intensities to the tissue water intensity is commonly applied to determine metabolite concentrations from in vivo (1)H-MRS brain data. However, since the water concentration and relaxation properties differ between grey matter, white matter and cerebrospinal fluid (CSF), the volume fractions of these compartments have to be considered in MRS voxels. The impact of partial volume correction was validated by phantom measurements in voxels containing mixtures of solutions with different NAA and water concentrations as well as by analyzing in vivo (1)H-MRS brain data acquired with various voxel compositions. Phantom measurements indicated substantial underestimation of NAA concentrations when assuming homogeneously composed voxels, especially for voxels containing solution, which simulated CSF (error: ≤ 92%). This bias was substantially reduced by taking into account voxel composition (error: ≤ 10%). In the in vivo study, tissue correction reduced the overall variation of quantified metabolites by up to 35% and revealed the expected metabolic differences between various brain tissues. Tissue composition affects extraction of metabolite concentrations and may cause misinterpretations when comparing measurements performed with different voxel sizes. This variation can be reduced by considering the different tissue types by means of combined analysis of spectroscopic and imaging data.

Down syndrome with and without dementia: An in vivo proton Magnetic Resonance Spectroscopy study with implications for Alzheimer's disease

It is poorly understood why people with Down syndrome (DS) are at extremely high-risk of developing Alzheimer's disease (AD) compared to the general population. One explanation may be related to their extra copy of risk factors modulated by chromosome 21. Myo-inositol (mI), whose transporter gene is located on chromosome 21, has been associated with dementia in the non-DS population; however, nobody has contrasted brain mI in DS with (DS+) and without (DS-) dementia to other non-DS groups. Our primary aim was to compare the hippocampal concentration of mI ([mI]) and other brain metabolites such as N-acetylaspartate (NAA; a proxy measure of neuronal density and mitochondrial function) in DS+, DS-, and age-matched healthy controls using proton Magnetic Resonance Spectroscopy (((1))H-MRS). We compared hippocampal [mI] and other metabolites in 35 individuals with genetically-confirmed DS [DS+ (n=17, age=53±6) and DS- (n=18, age=47±8)] to age-matched healthy controls (n=13, age=51±10) adjusting for proportion of the MRS voxel occupied by cerebrospinal spinal fluid, and gray/white matter. DS+ had a significantly higher [mI] than both DS- and healthy controls. In contrast neither DS+ nor DS- differed significantly from controls in [NAA] (although NAA in DS+ was significantly lower than DS-). Our secondary aim of comparing brain metabolites in DS+ and DS- to Alzheimer's disease (AD; n=39; age=77±5) revealed that the DS+ group had significantly elevated [mI] compared to AD or DS-. [mI] may modify risk for dementia in this vulnerable population.

Individual variability in the shape and amplitude of the BOLD‐HRF correlates with endogenous GABAergic inhibition

It has previously been demonstrated that there is a negative correlation between the amplitude of the BOLD response and resting γ amino-butyric acid (GABA) concentration in visual cortex. The work here is the first to empirically characterize individual variability in the haemodynamic response functions (HRFs) in response to a simple visual stimulus and baseline GABA concentration in a population of young adult males (n = 15, aged 20-28 years). The results demonstrate that GABA concentration is negatively correlated with BOLD response amplitude (r = -0.64, P < 0.02) and positively correlated with HRF width (r = 0.67, P < 0.002), that is, individuals with higher resting GABA concentration tend to exhibit smaller and wider HRFs. No correlations were observed with resting cerebral blood flow and GABA concentration and similarly, no correlations were observed between GABA and the proportional tissue content of the MRS voxel. We argue that correlation of the height of the HRF is supportive of the view that the previously observed correlations between BOLD amplitudes and GABA are reflective of differences in neuronal activity. However, the changes in HRF shape in individuals with higher baseline GABA levels are suggestive that differing vascular response characteristics may also make a significant contribution. Our results reinforce the view that variability in endogenous factors, such as neurotransmitter concentration, can have a profound effect on the vascular haemodynamic response. This has important implications for between-cohort fMRI studies in which variation in parameters such as GABA concentration may lead to group differences in the BOLD signal.

Improved reproducibility of MRS regional brain thermometry by ‘amplitude‐weighted combination’

Brain temperature is important in stroke and trauma. In birth asphyxia, hypothermia improves outcome, but local brain temperature information is needed to optimise therapy. The proton MRS water chemical shift (δ(water) ) is temperature dependent, and the in vivo brain temperature has often been estimated by measuring δ(water) relative to the N-acetylaspartate (NAA) singlet methyl resonance. However, the NAA peak amplitude may be reduced if cerebrospinal fluid occupies part of the MRS voxel and because of the lower concentration in immaturity, pathology and neonatal white matter. These factors can increase random and systematic δ(NAA) errors and also, therefore, MRS brain temperature errors. The aim of this study was to improve MRS brain temperature reproducibility and resilience to pathological, developmental and regional peak amplitude variations by amplitude-weighted combination (AWC) of brain temperatures (T(Cho) , T(Cr) and T(NAA) ) determined using the prominent choline (Cho), total creatine (Cr) and NAA resonances separately as chemical shift references. δ(water) - δ(Cho) , δ(water) - δ(Cr) and δ(water) - δ(NAA) were calibrated against tympanic temperature in piglet brain at 7 T (2.5-cm-diameter surface coil over the parietal lobes; binomial water suppression spin-echo sequence; TE = 540 ms; TR = 5 s). Eight normal human infants underwent thalamic region (Thal) and five occipito-parietal (OP) cerebral MRS at 2.4 T [point-resolved spectroscopy (PRESS) localisation; cubic voxel, 8 mL; water suppression off; TE = 270 ms; TR = 2 s]. AWC with T(Cho) , T(Cr) and T(NAA) weighted by the squared Cho, Cr and NAA peak amplitudes provided the smallest intersubject standard deviations: Thal, 0.45°C; OP, 0.33°C (for T(NAA) values of 0.65°C and 1.12°C, respectively). AWC provided resilience against simulated pathological alterations in Cho, Cr and NAA peak amplitudes, with Thal and OP T(AWC) changing by less than 0.04°C. AWC improves both intersubject reproducibility of MRS temperature estimation and resilience against pathological, anatomical and developmental variation of Cho, Cr and NAA peak amplitudes.

Acquisition-weighted MRSI for Detection and Quantification of BNCT 10B-carrier L-p-boronophenylalanine-fructose Complex, a Phantom Study

Proton magnetic resonance spectroscopy (1H MRS) is a potential method to detect and quantify a boron neutron capture therapy 10B-carrier compound, L-p-boronophenylalanine (BPA), in the brain. However, optimal positioning of MRS voxel to capture tissue with maximal BPA concentration can be challenging. Three dimensional proton magnetic resonance spectroscopic imaging (3D 1H MRSI) provides spectral data covering a large spatial volume, which is a major advantage in detecting and quantifying BPA. BPA detection limit in phantom conditions was determined at 1.5 T using a 3D 1H MRSI protocol with clinically acceptable nominal spatial resolution and duration. Quantification tests for aqueous phantom were performed using both single voxel MRS and 3D MRSI. In 3D MRSI, BPA detection limit was approximately 1.0 mM and BPA quantification accuracy was better than +/-5%. The results suggest that MRSI would be a feasible method for in vivo BPA evaluation in clinical conditions.

Quantitative correlation between (1)H MRS and dynamic contrast-enhanced MRI of human breast cancer.

Proton magnetic resonance spectroscopy ((1)H MRS) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) provide functional information, including vascular volume, vascular permeability and choline (Cho) metabolism. In this study, we applied these two imaging modalities to quantitatively characterize 36 malignant breast lesions in 32 patients and analyzed the correlation between them. Cho concentration was quantified by single-voxel (1)H MRS using water as an internal reference. The measured Cho levels ranged from 0.32 to 10.47 mmol/kg, consistent with previously reported values. In 25 mass-type lesions, the Cho concentration was significantly correlated with tumor size (r=.69, P<.0002). In addition, the Cho level was found to be significantly higher in lesions presenting as mass-type lesions compared to non-mass-type diffuse enhancements (P=.035). The enhancement kinetics from tissues covered within each MRS voxel were measured and analyzed with a two-compartmental model to obtain pharmacokinetic parameters K(trans) and k(ep). A significant correlation was found between the Cho level and the pharmacokinetic parameter k(ep) (r=.62, P<.0001), indicating that tissues with a high Cho level have higher wash-out rates in DCE MRI. The results suggest a correlation between Cho metabolism and angiogenesis activity, which might be explained by the association of Cho with cell replication and angiogenesis required to support tumor growth.

Determination of regional brain temperature using proton magnetic resonance spectroscopy to assess brain–body temperature differences in healthy human subjects

Proton magnetic resonance spectroscopy ((1)H MRS) was used to determine brain temperature in healthy volunteers. Partially water-suppressed (1)H MRS data sets were acquired at 3T from four different gray matter (GM)/white matter (WM) volumes. Brain temperatures were determined from the chemical-shift difference between the CH(3) of N-acetyl aspartate (NAA) at 2.01 ppm and water. Brain temperatures in (1)H MRS voxels of 2 x 2 x 2 cm(3) showed no substantial heterogeneity. The volume-averaged temperature from single-voxel spectroscopy was compared with body temperatures obtained from the oral cavity, tympanum, and temporal artery regions. The mean brain parenchyma temperature was 0.5 degrees C cooler than readings obtained from three extra-brain sites (P < 0.01). (1)H MRS imaging (MRSI) data were acquired from a slice encompassing the single-voxel volumes to assess the ability of spectroscopic imaging to determine regional brain temperature within the imaging slice. Brain temperature away from the center of the brain determined by MRSI differed from that obtained by single-voxel MRS in the same brain region, possibly due to a poor line width (LW) in MRSI. The data are discussed in the light of proposed brain-body temperature gradients and the use of (1)H MRSI to monitor brain temperature in pathologies, such as brain trauma.

MRI &amp; 31P MRS studies of brain energetics in a model of cerebral vasoconstriction

Ischaemic brain events necessitate prompt diagnosis and clinical intervention if the ischaemia is to be reversed. At present, MR is unable to distinguish between reversibly and irreversibly damaged tissue. Although apparent diffusion coefficient (ADC) MRI is established as a sensitive indicator of acute ischaemia, an unresolved challenge is to non-invasively distinguish between reversibly and irreversibly damaged tissue early in the ischaemic event. Endothelin-1 (ET-1) produces a potent and prolonged vasoconstrictive effect on the brain vasculature and has been used as a model of low flow ischaemia in the rat brain. We hypothesise that a focal striatal injection of ET-1 creates a graduated lesion consisting of both reversibly and irreversibly damaged tissue. A longitudinal study of MR-visible changes following intrastriatal ET-1 injection in the juvenile rat brain was conducted and correlated with the metabolic status of brain tissue using phosphorus (31P) MRS. Male Wistar rats (50-55 g) were anaesthetised by inhalation using 2% isoflurane in 70% N2O:30% O2. Using a minimally-invasive stereotaxic procedure, 160pmoles of ET-1 was injected in a volume of 1.0 l of sterile saline into the striatum (n=8). Animals were positioned in a purpose-built head restraint system and a 2 cm-diameter single-turn circular surface phosphorus coil was placed over the animal's head. Anaesthesia was maintained in the magnet using 1% isoflurane in 70% N2O:30% O2. T1 and T2-weighted images, DWI and 31P spectra were obtained using a 7 T horizontal bore magnet (Magnex Scientific) interfaced to a Varian/SISCO spectrometer (Varian, Palo Alto, CA, USA). We observed a significant decrease in the ADC around the site of injection at 2.5 h post-injection [Figure 1a & e]. MRI was repeated at 6, 24 and 72 hrs over which time ADC changes resolved in the periphery of the lesion, but remained low at the core. These findings suggest that the tissue at the core of the lesion may be irreversibly damaged whereas normalisation of ADC in the periphery may be indicative of reversibly damaged tissue. 31P spectra from the whole of the injected hemisphere did not detect any reductions in the PCr to ATP ratio. Significant changes in these metabolites may only occur in the speculated irreversibly damaged core of the lesion, which constitutes less than 25% of the 31P MRS voxel. The inclusion of a significant volume of healthy tissue in the 31P MRS voxel may explain the absence of a change in metabolite levels. Ongoing studies are investigating the perfusion changes in the core and peripheral regions of ET-1-induced focal lesions and their correlation with ADC changes.

Stimulus-induced brain lactate: effects of aging and prolonged wakefulness.

Both aging and sleep deprivation disturb the functions of the frontal lobes. Deficits in brain energy metabolism have been reported in these conditions. Neurons use not only glucose but also lactate as their energy substrate. The physiological response to elevated neuronal activity is a transient increase in lactate concentrations in the stimulated area. We have previously shown that cognitive stimulation increases brain lactate. To study the effect of prolonged wakefulness on the lactate response we designed an experiment to assess brain lactate levels during a 40-h sleep deprivation period in young (19-24 years old; n = 13) and in aged (60-68 years old; n = 12) healthy female volunteers. Brain lactate levels were assessed with proton MR-spectroscopy ((1)H MRS) during the performance of a silent word generation task. The (1)H MRS voxel location was individually selected, using functional magnetic resonance imaging, to cover the activated area in the left frontal lobe. The degree of sleepiness was verified using vigilance tests and self-rating scales. In the young alert subjects, the silent word generation test induced a 40% increase in lactate, but during the prolonged wakefulness period this response disappeared. In the aged subjects, the lactate response could not be detected even in the alert state. We propose that the absence of the lactate response may be a sign of malfunctioning of normal brain energy metabolism. The behavioral effects of prolonged wakefulness and aging may arise from this dysfunction.

N-Acetylaspartate and creatine levels measured by (1)H MRS relate to recognition memory.

To investigate the relationship between recognition memory and metabolite levels in medial structures of the temporal lobes in the living human brain. Proton MRS ((1)H MRS) and the intracarotid amobarbital test were performed in 16 epileptic patients found suitable for temporal lobectomy. All patients had mesial temporal sclerosis. Metabolite ratios between N:-acetylaspartate (NAA), creatine and phosphocreatine (Cr + PCr), and choline-containing compounds (Cho) [NAA/(Cr + PCr), NAA/Cho, and NAA/(Cr + PCr + Cho)] were calculated for (1)H MRS voxels that included the amygdala, anterior half of the hippocampus, and underlying subiculum. Metabolite ratios were correlated with unilateral memory scores estimated by the intracarotid amobarbital test for words, objects, faces, and total score. The total memory score, memory for objects and faces, and NAA/(Cr + PCr) were significantly lower for the hemisphere ipsilateral to the resection. The asymmetry indexes for NAA/(Cr + PCr) correlated with asymmetry indexes for words (rho = 0.82, p = 0.0001) and total memory (rho = 0. 72, p = 0.002). Analysis of memory scores and metabolite ratios from all 32 hemispheres revealed a correlation between NAA/(Cr + PCr) and memory for words (rho = 0.45, p = 0.009). A correlation between memory for words and NAA/(Cr + PCr) existed in the contralateral (rho = 0.58, p = 0.019) and in the right (rho = 0.51, p = 0.045) hemispheres, and a trend was found in the left hemispheres (rho = 0. 48, p = 0.06). There is a correlation between memory for words and the NAA/(Cr + PCr) ratio from medial temporal structures in patients with mesial temporal sclerosis. The findings suggest that medial temporal structures and adjacent neocortex play a significant role in recognition memory in humans, particularly for words.