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Glutamine plus glutamate (Glx), as well as N-acetylaspartate compounds, (NAAc), a marker of neuronal viability, are quantified with proton magnetic resonance spectroscopy (UsedAmongst younger (age ≤40 years-median split) bipolar-I vs HC subjects Glx was increased (p 0.001), while NAAc was reduced in WM (p 0.001). In GM, NAAc (p 0.001) and myo-inositol (p = 0.002) were reduced. Amongst older bipolar-I (vs HC) in WM regions we found reductions in: NAAc (p 0.001), glycerophospho-choline + phospho-choline (p 0.001), creatine + phospho-creatine (p 0.001) and myo-inositol (p 0.001); in GM only Glx was increased (p 0.005). Contrasts between bipolar-I and schizophrenia produced fewer results: amongst younger subjects, reduced NAAc (p 0.001) in WM and lower myo-inositol in GM (p = 0.04) in bipolar-I vs schizophrenia. In the older patients, bipolar-I had lower GM NAAc (p = 0.009) than schizophrenia.First, differential exposure to antipsychotic and mood stabilizing medication across the groups. Second, differences in substance use histories among the groups. Third, neglect of peripheral and ventral cortical and subcortical regions. Finally, limited power to detect bipolar/schizophrenia differences.Chronically-treated bipolar-I have increased Glx and reduced NAAc, suggestive of neuronal dysfunction. The NAAc reductions are more severe in bipolar-I than in schizophrenia patients.

Proton magnetic resonance spectroscopy (1H-MRS) studies have examined glutamatergic abnormalities in schizophrenia and bipolar-I disorders, mostly in single voxels. Though the critical nodes remain unknown, schizophrenia and bipolar-I involve brain networks with broad abnormalities. To provide insight on the biochemical differences that may underlie these networks, the combined glutamine and glutamate signal (Glx) and other metabolites were examined in patients in early psychosis with whole brain 1H-MRS imaging (1H-MRSI). Data were acquired in young schizophrenia subjects (N = 48), bipolar-I subjects (N = 21) and healthy controls (N = 51). Group contrasts for Glx, as well as for N-acetyl aspartate, choline, myo-inositol and creatine, from all voxels that met spectral quality criteria were analyzed in standardized brain space, followed by cluster-corrected level alpha-value (CCLAV ≤ 0.05) analysis. Schizophrenia subjects had higher Glx in the right middle cingulate gyrus (19 voxels, CCLAV = 0.05) than bipolar-I subjects. Healthy controls had intermediate Glx values, though not significant. Schizophrenia subjects also had higher N-acetyl aspartate (three clusters, left occipital, left frontal, right frontal), choline (two clusters, left and right frontal) and myo-inositol (one cluster, left frontal) than bipolar-I, with healthy controls having intermediate values. These increases were likely accounted for by antipsychotic medication effects in the schizophrenia subgroup for N-acetyl aspartate and choline. Likewise, creatine was increased in two clusters in treated vs. antipsychotic-naïve schizophrenia, supporting a medication effect. Conversely, the increments in Glx in right cingulate were not driven by antipsychotic medication exposure. We conclude that increments in Glx in the cingulate may be critical to the pathophysiology of schizophrenia and are consistent with the NMDA hypo-function model. This model however may be more specific to schizophrenia than to psychosis in general. Postmortem and neuromodulation schizophrenia studies focusing on right cingulate, may provide critical mechanistic and therapeutic advancements, respectively.

Key Points Question Are clinical and demographic factors associated with brain glutamate or glutamate plus glutamine (Glx) levels in schizophrenia? Findings In this mega-analysis of 1251 patients with schizophrenia and 1197 healthy volunteers, medial frontal cortex glutamatergic metabolite levels were lower in patients and negatively associated with the dose of antipsychotic medication, although a reduction in glutamate levels with age was not accelerated in patients with schizophrenia compared with healthy individuals. Higher medial frontal cortex and medial temporal lobe glutamate levels were associated with more severe symptoms in patients with schizophrenia. Meaning Lower brain glutamate levels may be associated with antipsychotic exposure rather than with greater age-related decline, whereas higher glutamate levels may serve as a biomarker of illness severity in patients with schizophrenia., Importance Proton magnetic resonance spectroscopy (1H-MRS) studies indicate that altered brain glutamatergic function may be associated with the pathophysiology of schizophrenia and the response to antipsychotic treatment. However, the association of altered glutamatergic function with clinical and demographic factors is unclear. Objective To assess the associations of age, symptom severity, level of functioning, and antipsychotic treatment with brain glutamatergic metabolites. Data Sources The MEDLINE database was searched to identify journal articles published between January 1, 1980, and June 3, 2020, using the following search terms: MRS or magnetic resonance spectroscopy and (1) schizophrenia or (2) psychosis or (3) UHR or (4) ARMS or (5) ultra-high risk or (6) clinical high risk or (7) genetic high risk or (8) prodrome* or (9) schizoaffective. Authors of 114 1H-MRS studies measuring glutamate (Glu) levels in patients with schizophrenia were contacted between January 2014 and June 2020 and asked to provide individual participant data. Study Selection In total, 45 1H-MRS studies contributed data. Data Extraction and Synthesis Associations of Glu, Glu plus glutamine (Glx), or total creatine plus phosphocreatine levels with age, antipsychotic medication dose, symptom severity, and functioning were assessed using linear mixed models, with study as a random factor. Main Outcomes and Measures Glu, Glx, and Cr values in the medial frontal cortex (MFC) and medial temporal lobe (MTL). Results In total, 42 studies were included, with data for 1251 patients with schizophrenia (mean [SD] age, 30.3 [10.4] years) and 1197 healthy volunteers (mean [SD] age, 27.5 [8.8] years). The MFC Glu (F1,1211.9 = 4.311, P = .04) and Glx (F1,1079.2 = 5.287, P = .02) levels were lower in patients than in healthy volunteers, and although creatine levels appeared lower in patients, the difference was not significant (F1,1395.9 = 3.622, P = .06). In both patients and volunteers, the MFC Glu level was negatively associated with age (Glu to Cr ratio, F1,1522.4 = 47.533, P, This mega-analysis assesses whether age, symptom severity, level of functioning, and antipsychotic treatment are associated with glutamate or glutamatergic metabolite levels measured with proton magnetic resonance spectroscopy in the medial frontal cortex or medial temporal lobe of patients with schizophrenia.

With a 40‐year history of use for in vivo studies, the terminology used to describe the methodology and results of magnetic resonance spectroscopy (MRS) has grown substantially and is not consistent in many aspects. Given the platform offered by this special issue on advanced MRS methodology, the authors decided to describe many of the implicated terms, to pinpoint differences in their meanings and to suggest specific uses or definitions. This work covers terms used to describe all aspects of MRS, starting from the description of the MR signal and its theoretical basis to acquisition methods, processing and to quantification procedures, as well as terms involved in describing results, for example, those used with regard to aspects of quality, reproducibility or indications of error. The descriptions of the meanings of such terms emerge from the descriptions of the basic concepts involved in MRS methods and examinations. This paper also includes specific suggestions for future use of terms where multiple conventions have emerged or coexisted in the past., This work defines terms and explains concepts used to describe all aspects of MR spectroscopy, starting from the definition of the MR signal and its theoretical basis to acquisition methods, processing and quantification procedures, as well as terms involved in describing results, including quality aspects, reproducibility or indications of error. Also featured are specific suggestions for future use of terms where multiple conventions have emerged or previously coexisted.

In this paper we describe an open-access collection of multimodal neuroimaging data in schizophrenia for release to the community. Data were acquired from approximately 100 patients with schizophrenia and 100 age-matched controls during rest as well as several task activation paradigms targeting a hierarchy of cognitive constructs. Neuroimaging data include structural MRI, functional MRI, diffusion MRI, MR spectroscopic imaging, and magnetoencephalography. For three of the hypothesis-driven projects, task activation paradigms were acquired on subsets of ~200 volunteers which examined a range of sensory and cognitive processes (e.g., auditory sensory gating, auditory/visual multisensory integration, visual transverse patterning). Neuropsychological data were also acquired and genetic material via saliva samples were collected from most of the participants and have been typed for both genome-wide polymorphism data as well as genome-wide methylation data. Some results are also presented from the individual studies as well as from our data-driven multimodal analyses (e.g., multimodal examinations of network structure and network dynamics and multitask fMRI data analysis across projects). All data will be released through the Mind Research Network’s collaborative informatics and neuroimaging suite (COINS). Electronic supplementary material The online version of this article (doi:10.1007/s12021-017-9338-9) contains supplementary material, which is available to authorized users.

Background Proton Magnetic Resonance Spectroscopy (1H-MRS) studies indicate that altered brain glutamate signalling contributes to the pathophysiology of schizophrenia and treatment response. However it is unclear whether clinical and demographic factors affect glutamate levels in the brain. Here we aim to determine the effects of age, antipsychotic medication, symptom severity and duration of illness on levels of glutamatergic metabolites and creatine, in a large multicentre dataset of patients with schizophrenia and healthy volunteers. Methods Authors of 1H-MRS studies in schizophrenia were contacted between January 2014 and August 2017 and asked to provide individual glutamate, Glx, glutamine and creatine values alongside demographic and clinical data. Forty-five 1H-MRS studies contributed data to the multicentre dataset, and data was available from 1194 healthy volunteers and 1526 patients with schizophrenia and those at high risk of developing psychosis. Results Age was associated with reduced glutamate levels in the medial frontal cortex, but the effect of aging was not accelerated in patients compared to healthy volunteers. Higher glutamate and Glx in the medial frontal and temporal lobes were associated with more severe symptoms, whereas Glx in subcortical regions, specifically the thalamus and striatum, did not relate to symptom severity. In the medial frontal cortex and striatum, exposure to antipsychotic medication was associated with lower levels of glutamatergic metabolites. Duration of illness was not associated with glutamatergic metabolites. Lastly, creatine in the medial frontal cortex and thalamus increased with age. Discussion These data suggest that future 1H-MRS studies should control for the effects of age, symptom severity, and antipsychotic medication exposure. Caution is needed when using creatine as a reference to scale metabolites.

Once a magnetic resonance spectroscopy (MRS) dataset has been acquired, several important steps must be taken to obtain the desired metabolite concentration measures. First, the data must be preprocessed to prepare them for analysis. Next, the intensity of the metabolite signal(s) of interest must be estimated. Finally, the measured metabolite signal intensities must be converted into scaled concentration units employing a quantitative reference signal to allow meaningful interpretation. In this paper, we will review these three main steps in the post-acquisition workflow of a single-voxel MRS experiment (preprocessing, analysis and quantification) and provide recommendations for best practices at each step.

White matter disruption has been repeatedly documented in schizophrenia consistent with microstructural disorganization (reduced fractional anisotropy (FA)) and axonal dysfunction (reduced N-acetylaspartate NAAc). However, the clinical significance of these abnormalities is poorly understood. Diffusion tensor and proton spectroscopic imaging where used to assess FA, axial diffusivity and radial diffusivity (RD), and supra-ventricular white matter NAAc, respectively, in 64 schizophrenia and 64 healthy subjects. Schizophrenia patients had reduced FA across several regions, with additional regions where FA correlated positively with positive symptoms severity. These regions included genu, body and splenium of corpus callosum, anterior and superior corona radiata, superior longitudinal and inferior fronto-occipital fasciculi, and internal capsule. The FA/symptoms relationships corresponded with opposite correlations between RD and positive symptoms. The schizophrenia group (SP group) had progressively reduced NAAc with age, and NAAc correlated negatively with positive symptoms. Cognition correlated positively with both FA and NAAc in controls, whereas in the SP group it had a negative correlation with NAAc and no significant relationship with FA. Antipsychotic dose did not account for the results. Correlates of psychosis, cognitive and negative symptoms can be found in white matter. The significant correlations between positive symptoms in schizophrenia and diffusion and NAAc measures suggest decreased axonal density with increased glial cells and higher myelination in this subpopulation. A separate set of abnormal relationships between cognition and FA/RD, as well as with NAAc, converge to suggest that in schizophrenia, white matter microstructure supports the two core illness domains: psychosis and cognitive/negative symptoms.

Vascular cognitive impairment (VCI) is a heterogeneous group of cerebrovascular diseases secondary to large and small vessel disease. We hypothesised that biomarkers obtained early in the disease could identify a homogeneous subpopulation with small vessel disease.We obtained disease markers in 62 patients with VCI that included neurological findings, neuropsychological tests, multimodal MR and cerebrospinal fluid measurements of albumin ratio, matrix metalloproteinases (MMPs), amyloid-β1-42 and phosphorylated-τ181. Proton MR spectroscopic imaging showed ischaemic white matter and permeability of the blood-brain barrier (BBB) was measured with dynamic contrast-enhanced MRI. We constructed a 10-point Binswanger disease score (BDS) with subjective and objective disease markers. In addition, an objective set of biomarkers was used for an exploratory factor analysis (EFA) to select patients with BD. Patients were followed for an average of 2 years to obtain clinical consensus diagnoses.An initial BDS of 6 or greater was significantly correlated with a final diagnosis of BD (p0.05; area under the curve (AUC)=0.79). EFA reduced nine objective biomarkers to four factors. The most predictive of BD was the factor containing the inflammatory biomarkers of increased BBB permeability, elevated albumin index and reduced MMP-2 index (factor 2; AUC=0.78). Both measures independently predicted a diagnosis of BD, and combining them improved the diagnostic accuracy.Biomarkers predicted the diagnosis of the BD type of subcortical ischaemic vascular disease. Using pathophysiological biomarkers to select homogeneous groups of patients needs to be tested in targeted treatment trials.

Transcranial direct current stimulation (tDCS) modulates glutamatergic neurotransmission and can be utilized as a novel treatment intervention for a multitude of populations. However, the exact mechanism by which tDCS modulates the brain׳s neural architecture, from the micro to macro scales, have yet to be investigated. Using a within-subjects design, resting-state functional magnetic resonance imaging (rs-fMRI) and proton magnetic resonance spectroscopy ((1)H MRS) were performed immediately before and after the administration of anodal tDCS over right parietal cortex. Group independent component analysis (ICA) was used to decompose fMRI scans into 75 brain networks, from which 12 resting-state networks were identified that had significant voxel-wise functional connectivity to anatomical regions of interest. (1)H MRS was used to obtain estimates of combined glutamate and glutamine (Glx) concentrations from bilateral intraparietal sulcus. Paired sample t-tests showed significantly increased Glx under the anodal electrode, but not in homologous regions of the contralateral hemisphere. Increases of within-network connectivity were observed within the superior parietal, inferior parietal, left frontal-parietal, salience and cerebellar intrinsic networks, and decreases in connectivity were observed in the anterior cingulate and the basal ganglia (p

Accurate measurement of brain metabolite concentrations with proton magnetic resonance spectroscopy (

BACKGROUND: Erythropoiesis stimulating agents (ESAs) are neuroprotective in cell and animal models of preterm birth. Prematurity has been shown to alter neurometabolite levels in children in studies using proton magnetic resonance spectroscopy (1H-MRS). We hypothesized that ESA treatment in premature infants would tend to normalize neurometabolites by 4-6 years of age. DESIGN/METHODS: Children in a longitudinal study of neurodevelopment underwent MRI and 1H-MRS at approximately 4 and 6 years of age. Prematurely born children (500-1250 grams birth weight) received ESAs (erythropoietin or darbepoetin) or placebo during their neonatal hospitalization, and these groups were compared to healthy term controls. 1H-MRS spectra were obtained from the anterior cingulate (gray matter) and frontal lobe white matter, assessing combined N-acetylaspartate and N-acetylaspartylglutamate (tNAA), myo-inositol, choline compounds (Cho), combined creatine and phosphocreatine, and combined glutamate and glutamine. RESULTS: No significant (p≤0.5) group differences were observed for any metabolite level. Significant age-related increases in white matter tNAA and Cho were observed, as well as a trend for increased gray matter tNAA. CONCLUSIONS: Neither prematurity nor neonatal ESA treatment were associated with differences in brain metabolite levels in the children of this study at a significance level of 0.05. These findings suggest that earlier differences that may have existed had normalized by 4-6 years of age or were too small to be statistically significant in the current sample.

This study investigates the potential of independent component analysis (ICA) to provide a data-driven approach for group level analysis of magnetic resonance (MR) spectra. ICA collectively analyzes data to identify maximally independent components, each of which captures covarying resonances, including those from different metabolic sources. A comparative evaluation of the ICA approach with the more established LCModel method in analyzing two different noise-free, artifact-free, simulated data sets of known compositions is presented. The results from such ideal simulations demonstrate the ability of data-driven ICA to decompose data and accurately extract components resembling modeled basis spectra from both data sets, whereas the LCModel results suffer when the underlying model deviates from assumptions, thus highlighting the sensitivity of model-based approaches to modeling inaccuracies. Analyses with simulated data show that independent component weights are good estimates of concentrations, even of metabolites with low intensity singlet peaks, such as scyllo-inositol. ICA is also applied to single voxel spectra from 193 subjects, without correcting for baseline variations, line-width broadening or noise. The results provide evidence that, despite the presence of confounding artifacts, ICA can be used to analyze in vivo spectra and extract resonances of interest. ICA is a promising technique for decomposing MR spectral data into components resembling metabolite resonances, and therefore has the potential to provide a data-driven alternative to the use of metabolite concentrations derived from curve-fitting individual spectra in making group comparisons.

Chronic, heavy alcohol consumption may affect the concentration of neurometabolites assessed with proton magnetic resonance spectroscopy (1H-MRS). We investigated the largest sample reported to date (N = 213) with the primary goal of determining how specific clinical features impact neurometabolite concentrations in an anterior cingulate gray matter voxel. This community dwelling sample included both treatment seeking and non-treatment seeking individuals. A healthy control group (N = 66) was matched for age and education. In multivariate analyses predicting neurometabolite concentrations, the heavy drinking group had greater concentrations overall. An age by group interaction was noted, as group difference across neurometabolites increased with age. More years drinking, but not more drinks per drinking day (DPDD) predicted greater concentrations of choline-containing compounds (Cho), creatine-phosphocreatine (Cre), glutamate-glutamine (Glx), and n-acetyl-aspartate (NAA). The effects of other clinical variables (depression, cigarette smoking, marijuana use) were negligible. After controlling for DPDD and years drinking, treatment-seeking status had no impact on neurometabolites. In the very oldest portion of the sample (mean age = 50), however, a negative relationship was seen between NAA and years drinking. These results suggest that the nature of neurometabolite abnormalities in chronic heavy drinkers may vary as a function of duration of abuse.

Glutamine plus glutamate (Glx), as well as N-acetylaspartate compounds (NAAc, N-acetylaspartate plus N-acetyl-aspartyl-glutamate), a marker of neuronal viability, can be quantified with proton magnetic resonance spectroscopy (1H-MRS). We used 1H-MRS imaging to assess Glx and NAAc, as well as total-choline (glycerophospho-choline plus phospho-choline), myo-inositol and total-creatine (creatine plus phosphocreatine) from an axial supraventricular slab of gray matter (GM, medial-frontal and medial-parietal) and white matter (WM, bilateral-frontal and bilateral-parietal) voxels. Schizophrenia subjects (N = 104) and healthy controls (N = 97) with a broad age range (16 to 65) were studied. In schizophrenia, Glx was increased in GM (P < .001) and WM (P = .01), regardless of age. However, with greater age, NAAc increased in GM (P < .001) but decreased in WM (P < .001) in schizophrenia. In patients, total creatine decreased with age in WM (P < .001). Finally, overall cognitive score correlated positively with WM neurometabolites in controls but negatively in the schizophrenia group (NAAc, P < .001; and creatine [only younger], P < .001). We speculate the results support an ongoing process of increased glutamate metabolism in schizophrenia. Later in the illness, disease progression is suggested by increased cortical compaction without neuronal loss (elevated NAAc) and reduced axonal integrity (lower NAAc). Furthermore, this process is associated with fundamentally altered relationships between neurometabolite concentrations and cognitive function in schizophrenia.

Mild traumatic brain injury is the most prevalent neurological insult and frequently results in neurobehavioural sequelae. However, little is known about the pathophysiology underlying the injury and how these injuries change as a function of time. Although diffusion tensor imaging holds promise for in vivo characterization of white matter pathology, both the direction and magnitude of anisotropic water diffusion abnormalities in axonal tracts are actively debated. The current study therefore represents both an independent replication effort (n = 28) of our previous findings (n = 22) of increased fractional anisotropy during semi-acute injury, as well as a prospective study (n = 26) on the putative recovery of diffusion abnormalities. Moreover, new analytical strategies were applied to capture spatially heterogeneous white matter injuries, which minimize implicit assumptions of uniform injury across diverse clinical presentations. Results indicate that whereas a general pattern of high anisotropic diffusion/low radial diffusivity was present in various white matter tracts in both the replication and original cohorts, this pattern was only consistently observed in the genu of the corpus callosum across both samples. Evidence for a greater number of localized clusters with increased anisotropic diffusion was identified across both cohorts at trend levels, confirming heterogeneity in white matter injury. Pooled analyses (50 patients; 50 controls) suggested that measures of diffusion within the genu were predictive of patient classification, albeit at very modest levels (71% accuracy). Finally, we observed evidence of recovery in lesion load in returning patients across a 4-month interval, which was correlated with a reduction in self-reported post-concussive symptomatology. In summary, the corpus callosum may serve as a common point of injury in mild traumatic brain injury secondary to anatomical (high frequency of long unmyelinated fibres) and biomechanics factors. A spatially heterogeneous pattern of increased anisotropic diffusion exists in various other white matter tracts, and these white matter anomalies appear to diminish with recovery. This macroscopic pattern of diffusion abnormalities may be associated with cytotoxic oedema following mechanical forces, resulting in changes in ionic homeostasis, and alterations in the ratio of intracellular and extracellular water. Animal models more specific to the types of mild traumatic brain injury typically incurred by humans are needed to confirm the histological correlates of these macroscopic markers of white matter pathology.

Objective.In previous studies cerebral blood flow (CBF) was found to be altered in patients with systemic lupus erythematosus (SLE) compared to controls. We investigated the relationships between CBF and clinical data from subjects with SLE with the aim of determining the pathologic factors underlying altered CBF in SLE.Methods.A total of 42 SLE subjects and 19 age- and sex-matched healthy control subjects were studied. Dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) was used to measure CBF. Patients and controls underwent complete clinical and laboratory evaluations in close proximity with their MRI studies.Results.A higher CBF was present in the SLE group and was independently associated in statistical models with higher systolic blood pressure (SBP; p < 0.01). The intensity of the relationships (slope of curve) between CBF and mean arterial blood pressure, diastolic blood pressure, or blood levels of tissue plasminogen activator in the SLE group was significantly blunted relative to the control group.Conclusion.These findings are consistent with an underlying cerebral hyperperfusion in SLE induced by elevated but nonhypertensive levels of SBP. The factors underlying this relationship may be functional and/or structural (atherosclerotic, thrombotic, thromboembolic, or vasculitic) cerebrovascular disease.

BACKGROUND Methadone intoxication can cause respiratory depression, leading to hypoxia with subsequent coma and death. Delayed postanoxic leukoencephalopathy (DAL) has been reported with intoxication by carbon monoxide, narcotics, and other toxins. OBJECTIVE To investigate the metabolic derangement of the white matter (WM) and blood–brain barrier (BBB) after DAL caused by methadone overdose. DESIGN, SETTING, AND PATIENTS Case report of 2 patients with DAL after a single dose of “diverted” methadone used for pain control. RESULTS In both cases brain magnetic resonance imaging (MRI) revealed initial extensive bilateral restricted diffusion lesions within the WM. Follow-up MRI using proton magnetic resonance spectroscopic imaging (1H-MRSI) showed markedly lower N-acetylaspartate and higher choline within the WM. BBB permeability, calculated by Patlak graphical analysis of MRI T1 data obtained after contrast agent injection, showed disruption of the BBB within the WM lesions, which persisted longer than a year in 1 patient. Neuropsychological evaluation showed executive dysfunction in both patients. After 1 year, one patient recovered whereas the second remained impaired. CONCLUSIONS Methadone overdose can cause DAL with profound disturbances of neural metabolism and the BBB. The time course of these disturbances can be monitored with MR methods.

Transcranial direct current stimulation (tDCS) has been found to produce significant changes in behavior, including a large increase of learning and performance for a difficult visual perceptual task (Clark et al., NeuroImage 2010). The mechanisms by which tDCS produces these behavioral effects are currently uncertain. One hypothesis is that anodal tDCS leads to increased metabolic activity in the brain, which enhances cognitive and memory processes. Here we examined the neuronal mechanisms by which tDCS influences learning by measuring changes in brain metabolite concentrations using proton magnetic resonance spectroscopy ( 1 H MRS). As perception and learning can also influence neurochemistry, here we applied tDCS during rest. MRS data was obtained before and after 2.0 mA of anodal tDCS was applied for 30 min over electrode site P4, with the cathode placed on the contralateral arm. MRS data were acquired from the right parietal lobe beneath the anodal tDCS electrode, and from the homologous regions of the left hemisphere once before and once after tDCS. Significantly higher combined glutamate and glutamine levels were found in right parietal cortex, beneath the stimulating electrode, with non-significant increases in homologous regions of the opposite hemisphere. In addition, a significant interaction between hemispheres was found for tDCS effects on tNAA. These results suggest that changes in glutamatergic activity and tNAA may be related to the mechanisms by which tDCS influences learning and behavior.

Background and Purpose— Disruption of the blood–brain barrier has been proposed to be important in vascular cognitive impairment. Increased cerebrospinal fluid albumin and contrast-enhanced MRI provide supporting evidence, but quantification of the blood–brain barrier permeability in patients with vascular cognitive impairment is lacking. Therefore, we acquired dynamic contrast-enhanced MRI to quantify blood–brain barrier permeability in vascular cognitive impairment. Method— We studied 60 patients with suspected vascular cognitive impairment. They had neurological and neuropsychological testing, permeability measurements with dynamic contrast-enhanced MRI, and lumbar puncture to measure albumin index. Patients were separated clinically into subcortical ischemic vascular disease (SIVD), multiple and lacunar infarcts, and leukoaraiosis. Twenty volunteers were controls for the dynamic contrast-enhanced MRI studies, and control cerebrospinal fluid was obtained from 20 individuals undergoing spinal anesthesia for nonneurological problems. Results— Thirty-six patients were classified as SIVD, 8 as multiple and lacunar infarcts, and 9 as leukoaraiosis. The albumin index was significantly increased in the SIVD group compared with 20 control subjects. Permeabilities for the patients with vascular cognitive impairment measured by dynamic contrast-enhanced MRI were significantly increased over control subjects ( P P i values were elevated over control subjects in SIVD but were similar to multiple and lacunar infarcts. Conclusions— There was abnormal permeability in white matter in patients with SIVD as shown by dynamic contrast-enhanced MRI and albumin index. Future studies will be needed to determine the relationship of blood–brain barrier damage and development of white matter hyperintensities.

A 1H magnetic resonance spectroscopic imaging study at 3T and short echo time was conducted to evaluate both the reproducibility, as measured by the interscan coefficient of variation (CV), and test-retest reliability, as measured by the intraclass correlation coefficient (ICC), of measurements of glutamate (Glu), combined glutamate and glutamine (Glx), myo-inositol (mI), N-acetylaspartate, creatine, and choline in 21 healthy subjects. The effect of partial volume correction on these measures and the relationship of reproducibility and reliability to data quality were also examined. A 1H magnetic resonance spectroscopic imaging slice was prescribed above the lateral ventricles and single repeat scans were performed within 30 min to minimize physiologic variability. Interscan CVs based on all the voxels varied from 0.05 to 0.07 for N-acetylaspartate, creatine, and choline to 0.10-0.13 for mI, Glu, and Glx. Findings on the reproducibility of gray and white matter estimates of N-acetylaspartate, creatine, and choline are consistent with previous studies using longer echo times, with CVs in the range of 0.02-0.04 and ICC in the range of 0.65-0.90. CVs for Glu, Glx, and mI are much lower than reported in previous studies at 1.5 T, while white matter mI (CV=0.04, ICC=0.93) and gray matter Glx (CV=0.04, ICC=0.68) demonstrated both high reproducibility and test-retest reliability.

Breakdown of the blood-brain barrier (BBB), occurring in many neurological diseases, has been difficult to measure noninvasively in humans. Dynamic contrast-enhanced magnetic resonance imaging measures BBB permeability. However, important technical challenges remain and normative data from healthy humans is lacking. We report the implementation of a method for measuring BBB permeability, originally developed in animals, to estimate BBB permeability in both healthy subjects and patients with white matter pathology. Fast T(1) mapping was used to measure the leakage of contrast agent Gadolinium diethylene triamine pentaacetic acid (Gd-DTPA) from plasma into brain. A quarter of the standard Gd-DTPA dose for dynamic contrast-enhanced magnetic resonance imaging was found to give both sufficient contrast-to-noise and high T(1) sensitivity. The Patlak graphical approach was used to calculate the permeability from changes in 1/T(1). Permeability constants were compared with cerebrospinal fluid albumin index. The upper limit of the 95% confidence interval for white matter BBB permeability for normal subjects was 3 × 10(-4) L/g min. MRI measurements were not [corrected] correlated strongly with levels of cerebrospinal fluid albumin in those subjects undergoing lumbar puncture. Dynamic contrast-enhanced magnetic resonance imaging with low dose Gd-DTPA and fast T(1) imaging is a sensitive method to measure subtle differences in BBB permeability in humans and may have advantages over techniques based purely on the measurement of pixel contrast changes.

Syringes are used for diagnostic fluid aspiration and fine-needle aspiration biopsy in interventional procedures. We determined the benefits, disadvantages, and patient safety implications of syringe and needle size on vacuum generation, hand force requirements, biopsy/fluid yield, and needle control during aspiration procedures.Different sizes (1, 3, 5, 10, and 20 ml) of the conventional syringe and aspirating mechanical safety syringe, the reciprocating procedure device, were studied. Twenty operators performed aspiration procedures with the following outcomes measured: (1) vacuum (torr), (2) time to vacuum (s), (3) hand force to generate vacuum (torr-cm2), (4) operator difficulty during aspiration, (5) biopsy yield (mg), and (6) operator control of the needle tip position (mm).Vacuum increased tissue biopsy yield at all needle diameters (P0.002). Twenty-milliliter syringes achieved a vacuum of -517 torr but required far more strength to aspirate, and resulted in significant loss of needle control (P0.002). The 10-ml syringe generated only 15% less vacuum (-435 torr) than the 20-ml device and required much less hand strength. The mechanical syringe generated identical vacuum at all syringe sizes with less hand force (P0.002) and provided significantly enhanced needle control (P0.002).To optimize patient safety and control of the needle, and to maximize fluid and tissue yield during aspiration procedures, a two-handed technique and the smallest syringe size adequate for the procedure should be used. If precise needle control or one-handed operation is required, a mechanical safety syringe should be considered.

Accurate measurement of brain metabolite concentrations with proton magnetic resonance spectroscopy (1 H-MRS) can be problematic because of large voxels with mixed tissue composition, requiring adjustment for differing relaxation rates in each tissue if absolute concentration estimates are desired. Adjusting for tissue-specific metabolite signal relaxation, however, also requires a knowledge of the relative concentrations of the metabolite in gray (GM) and white (WM) matter, which are not known a priori. Expressions for the estimation of the molality and molarity of brain metabolites with 1 H-MRS are extended to account for tissue-specific relaxation of the metabolite signals and examined under different assumptions with simulated and real data. Although the modified equations have two unknowns, and hence are unsolvable explicitly, they are nonetheless useful for the estimation of the effect of tissue-specific metabolite relaxation rates on concentration estimates under a range of assumptions and experimental parameters using simulated and real data. In simulated data using reported GM and WM T1 and T2 times for N-acetylaspartate (NAA) at 3 T and a hypothetical GM/WM NAA ratio, errors of 6.5-7.8% in concentrations resulted when TR = 1.5 s and TE = 0.144 s, but were reduced to less than 0.5% when TR = 6 s and TE = 0.006 s. In real data obtained at TR/TE = 1.5 s/0.04 s, the difference in the results (4%) was similar to that obtained with simulated data when assuming tissue-specific relaxation times rather than GM-WM-averaged times. Using the expressions introduced in this article, these results can be extrapolated to any metabolite or set of assumptions regarding tissue-specific relaxation. Furthermore, although serving to bound the problem, this work underscores the challenge of correcting for relaxation effects, given that relaxation times are generally not known and impractical to measure in most studies. To minimize such effects, the data should be acquired with pulse sequence parameters that minimize the effect of signal relaxation.

Single-voxel proton magnetic resonance imaging ((1)H-MRS) and proton MR spectroscopic imaging ((1)H-MRSI) were used to compare brain metabolite levels in semi-acute mild traumatic brain injury (mTBI) patients (n = 10) and matched healthy controls (n = 9). The (1)H-MRS voxel was positioned in the splenium, a region known to be susceptible to axonal injury in TBI, and a single (1)H-MRSI slice was positioned above the lateral ventricles. To increase sensitivity to the glutamate (Glu) and the combined glutamate-glutamine (Glx) signal, an inter-pulse echo time shown to emphasize the major Glu signals was used along with an analysis method that reduces partial volume errors by using water as a concentration standard. Our preliminary findings indicate significantly lower levels of gray matter Glx and higher levels of white matter creatine-phosphocreatine (Cr) in mTBI subjects relative to healthy controls. Furthermore, Cr levels were predictive of executive function and emotional distress in the combined groups. These results suggest that perturbations in Cr, a critical component of the brain's energy metabolism, and Glu, the brain's major neurotransmitter, may occur following mTBI. Moreover, the different pattern of results for gray and white matter suggests tissue-specific metabolic responses to mTBI.

The semiacute phase of mild traumatic brain injury (mTBI) is associated with deficits in the cognitive domains of attention, memory, and executive function, which previous work suggests may be related to a specific deficit in disengaging attentional focus. However, to date, there have only been a few studies that have employed dynamic imaging techniques to investigate the potential neurological basis of these cognitive deficits during the semiacute stage of injury. Therefore, event-related functional magnetic resonance imaging was used to investigate the neurological correlates of attentional dysfunction in a clinically homogeneous sample of 16 patients with mTBI during the semiacute phase of injury (

The use of tissue water as a concentration standard in proton magnetic resonance spectroscopy (1H-MRS) of the brain requires that the water proton signal be adjusted for relaxation and partial volume effects. While single voxel 1H-MRS studies have often included measurements of water proton T1, T2, and density based on additional 1H-MRS acquisitions (e.g., at multiple echo or repetition times), this approach is not practical for 1H-MRS imaging (1H-MRSI). In this report we demonstrate a method for using in situ measurements of water T1, T2, and density to calculate metabolite concentrations from 1H-MRSI data. The relaxation and density data are coregistered with the 1H-MRSI data and provide detailed information on the water signal appropriate to the individual subject and tissue region. We present data from both healthy subjects and a subject with brain lesions, underscoring the importance of water parameter measurements on a subject-by-subject and voxel-by-voxel basis. Magn Reson Med, 2009. © 2009 Wiley-Liss, Inc.

A broadly accepted definition of creativity refers to the production of something both novel and useful within a given social context. Studies of patients with neurological and psychiatric disorders and neuroimaging studies of healthy controls have each drawn attention to frontal and temporal lobe contributions to creativity. Based on previous magnetic resonance (MR) spectroscopy studies demonstrating relationships between cognitive ability and concentrations ofN-acetyl-aspartate (NAA), a common neurometabolite, we hypothesized that NAA assessed in gray and white matter (from a supraventricular slab) would relate to laboratory measures of creativity. MR imaging and divergent thinking measures were obtained in a cohort of 56 healthy controls. Independent judges ranked the creative products of each participant, from which a “Composite Creativity Index” (CCI) was created. Different patterns of correlations between NAA and CCI were found in higher verbal ability versus lower verbal ability participants, providing neurobiological support for a critical “threshold” regarding the relationship between intelligence and creativity. To our knowledge, this is the first report assessing the relationship between brain chemistry and creative cognition, as measured with divergent thinking, in a cohort comprised exclusively of normal, healthy participants.

Neuronal communication in the brain involves electrochemical currents, which produce magnetic fields. Stimulus-evoked brain responses lead to changes in these fields and can be studied using magneto- and electro-encephalography (MEG/EEG). In this paper we model the spatiotemporal distribution of the magnetic field of a physiologically idealized but anatomically realistic neuron to assess the possibility of using magnetic resonance imaging (MRI) for directly mapping the neuronal currents in the human brain. Our results show that the magnetic field several centimeters from the centre of the neuron is well approximated by a dipole source, but the field close to the neuron is not, a finding particularly important for understanding the possible contrast mechanism underlying the use of MRI to detect and locate these currents. We discuss the importance of the spatiotemporal characteristics of the magnetic field in cortical tissue for evaluating and optimizing an experiment based on this mechanism and establish an upper bound for the expected MRI signal change due to stimulus-induced cortical response. Our simulations show that the expected change of the signal magnitude is 1.6% and its phase shift is 1°. An unexpected finding of this work is that the cortical orientation with respect to the external magnetic field has little effect on the predicted MRI contrast. This encouraging result shows that magnetic resonance contrast directly based on the neuronal currents present in the cortex is theoretically a feasible imaging technique. MRI contrast generation based on neuronal currents depends on the dendritic architecture and we obtained high-resolution optical images of cortical tissue to discuss the spatial structure of the magnetic field in grey matter.

Growing evidence suggests that temporally proximal acute concussions and repetitive subconcussive head injuries may lead to long-term neurological deficits. However, the underlying mechanisms of injury and their relative time-scales are not well documented in human injury models. The current study therefore investigated whether biomarkers of brain chemistry (magnetic resonance [MR] spectroscopy: N-acetylaspartate [NAA], combined glutamate and glutamine [Glx], total creatine [Cre], choline compounds [Cho], and myo-inositol [mI]) and structure (cortical thickness, white matter [WM]/subcortical volume) differed between mixed martial artists (MMA; n = 13) and matched healthy controls (HC) without a history of contact sport participation (HC; n = 14). A subset of participants (MMA = 9; HC = 10) returned for follow-up visits, with MMA (n = 3) with clinician-documented acute concussions also scanned serially. As expected, MMA self-reported a higher incidence of previous concussions and significantly more cognitive symptoms during prior concussion recovery. Fighters also exhibited reduced memory and processing speed relative to controls on neuropsychological testing coupled with cortical thinning in the left posterior cingulate gyrus and right occipital cortex at baseline assessment. Over a 1-year follow-up period, MMA experienced a significant decrease in both WM volume and NAA concentration, as well as relative thinning in the left middle and superior frontal gyri. These longitudinal changes did not correlate with self-reported metrics of injury (i.e., fight diary). In contrast, HC did not exhibit significant longitudinal changes over a 4-month follow-up period (p 0.05). Collectively, current results provide preliminary evidence of progressive changes in brain chemistry and structure over a relatively short time period in individuals with high exposure to repetitive head hits. These findings require replication in independent samples.

Using in vivo proton magnetic resonance spectroscopy (1H-MRS), a new peak resonating at 2.13 ppm post-exercise has been attributed in the literature to the acetyl groups of acetylcarnitine. Since this peak is inconsistently generated by various submaximal exercise regimens, this study aimed at (a) verification of the previous chemical assignment, (b) determination of exercise conditions necessary for its induction, and (c) documentation of the recovery kinetics through 60 minutes following exercise. Ten healthy males (31 +/- 4 yr) cycled continuously for 45 minutes with intensity alternating between 50% (3 min) and 110% (2 min) of ventilatory threshold (VT). 1H-MR spectra were acquired from the vastus lateralis before and for 60 minutes following exercise. The peak at 2.13 ppm was not quantifiable at rest in any subject. However, it was present in all subjects following intense exercise (p0.0001), and expressed the chemical characteristics of an acetyl-containing compound. The estimated concentration, accumulation with high-intensity exercise, the presence as a single peak at 2.13 ppm, and the chemical shift were all consistent with the chemical and biophysical characteristics of acetyl groups associated with acetylcarnitine. This study provides further evidence that acetyl groups are robustly generated by intense exercise, and that the accumulation of acetyl groups in healthy subjects is dependent on the degree of exercise intensity. 1H-MRS may be used for the noninvasive study of muscle metabolism during exercise and recovery and may have special applications for studying the generation and transport of acetyl compounds, including acetylcarnitine.

Superfused cortical brain slices from neonatal rats demonstrated large increases in levels of NMR-detectable lipids after sample preparation and perfusion with standard artificial CSF. These increases were reduced by an average of 58% by perfusion with buffer with low (no added) Ca 2+ or by perfusion in Ca 2+ -free buffer. Perfusion with buffer with elevated MgSO 4 (10 mmol/L) reduced the lipid changes by 47%. A reduction of 88% was observed in samples perfused in buffer with both low Ca 2+ and high Mg 2+ , suggesting a role for Mg 2+ in reducing lipolysis distinct from its known ability to block Ca 2+ influx.

Proton magnetic resonance spectroscopy is used to measure several metabolites in cortical gray and white matter in patients with Huntington’s disease. The preliminary results show that CAG-repeat length correlates with white-matter N-acetylaspartate concentrations, and disease severity correlates with several metabolites.

Importance The N -methyl-d-aspartic acid receptor hypofunction model of schizophrenia predicts a paradoxical increase in synaptic glutamate release. In vivo measurement of glutamatergic neurotransmission in humans is challenging, but glutamine, the principal metabolite of synaptic glutamate, can be quantified with proton magnetic resonance spectroscopy ( 1 H-MRS). Although a few studies have measured glutamate, glutamine, and glutamine to glutamate ratio, it is not clear which of these 1 H-MRS indices of glutamatergic neurotransmission is altered in schizophrenia. Objective To examine glutamine, glutamate, and glutamine to glutamate ratio in the dorsal anterior cingulate, as well as their relationships with symptoms and cognition in schizophrenia. Design, Setting, and Participants Cross-sectional design using 3-T 1 H-MRS in participants recruited from university-based psychiatric outpatient clinics who underwent neuroimaging at an affiliated research facility. Participants were 84 patients with a DSM-IV-TR diagnosis of schizophrenia and 81 psychiatrically healthy volunteers, matched in age, sex, ethnicity, and occupational level to the head of household of family of origin. Main Outcomes and Measures Glutamine, glutamate, and glutamine to glutamate ratio. Also symptoms and cognition. Results Glutamine was increased in the schizophrenia group ( P = .01) as well as the glutamine to glutamate ratio ( P = .007) but not glutamate ( P = .89). Glutamine levels were positively correlated with severity of psychotic symptoms ( P = .02). Choline was also increased in schizophrenia ( P = .002). Conclusions and Relevance Elevated glutamine, which was directly related to psychotic symptoms, is consistent with increased glutamatergic synaptic release in schizophrenia, as predicted by the N -methyl-d-aspartic acid receptor hypofunction model. Further understanding the underlying mechanism of glutamatergic dysfunction in schizophrenia may lead to new pharmacological strategies to treat psychosis.

Magnetic resonance spectroscopy (MRS) studies on traumatic brain injury (TBI) have shown that the neuronal metabolite N-acetylaspartate (NAA) may be reduced in regions of brain remote from sites of focal injury. Such reductions have generally been attributed to diffuse axonal injury (DAI) or neuron death. The aim of the present study was to investigate the contribution of metabolic depression, in the absence of DAI or cell death, to remote NAA reduction after TBI. The right sensorimotor cortices of adult rats were injured by weight drop. Two and six days later, tissue slices from the ipsilateral occipital cortex, or from the same region in uninjured rats, were superfused and examined by 1H-MRS. The occipital cortex has been shown to have negligible DAI or cell death but marked transient metabolic depression in this model of TBI. Two days after injury, the ratio of the NAA peak height to the total creatine peak height (NAA/TCr) was 14% lower than in control samples. Six days after injury, NAA/TCr recovered to within 7% of the control value. The time course of NAA/TCr decrease and recovery was similar to the time courses of widespread depression and recovery of 2-deoxyglucose uptake and mitochondrial alpha-glycerophosphate dehydrogenase activity measured previously in this model of TBI. Together, these results suggest that at least one component of remote NAA depression after TBI may be associated with a widespread and reversible metabolic depression that is unrelated to either DAI or cell death.

NMR-visible mobile lipid (ML) has been observed in aggressive tumors and also in in vitro tumor cell models subjected to growth-inhibiting conditions, such as confluence or low-pH stress. The aim of the present study was to determine if ML production after confluence or low pH stress in a cultured cell model of brain tumor is due to growth arrest alone. ML was observed in situ by one- and two-dimensional (1)H NMR in viable but growth-arrested C6 glioma cells superfused for a period of 48 h after harvesting. The rate of ML production in cells harvested at subconfluence was compared to the rate in cells confluent for one cell cycle and to the rate in subconfluent-harvested cells superfused at low pH (pH 6.1). Confluent-harvested cells produced ML at a markedly greater rate than that of cells harvested at subconfluence, suggesting the involvement of prior cell-cell contact rather than simple growth arrest. A high rate was also observed in subconfluent-harvested cells subjected to low pH, indicating that ML in pH-stressed cells also does not arise from growth arrest alone. Furthermore, two-dimensional data on the degree of unsaturation of the ML fatty acyl chains and one-dimensional (31)P and two-dimensional (1)H NMR data on the GPC content of the cells suggest distinct metabolic pathways for the production of ML following confluence and low-pH stress.

Short-echo gradient-enhanced nuclear magnetic resonance (NMR) spectroscopy was utilized to identify mobile lipids in perfused neonate and juvenile rat brain slices. Lipid signals were present at low levels within 1 hr of tissue preparation and increased with time under standard perfusion conditions and in the presence of high phosphocreatine and low lactate levels. Both one- and two-dimensional NMR spectra demonstrate peaks consistent with the generation of free fatty acids or neutral lipids following tissue trauma. The present work demonstrates that injury-induced mobile lipids may make appreciable contributions to regions of brain tissue spectra that have recently been assigned to lactate or polypeptides alone.

ObjectivesThe aim of this study was to determine whether Libman-Sacks endocarditis is a pathogenic factor for cerebrovascular disease (CVD) in systemic lupus erythematosus (SLE).BackgroundA cardioembolic pathogenesis of SLE CVD manifested as: 1) neuropsychiatric systemic lupus erythematosus (NPSLE), including stroke and transient ischemic attacks (TIA); 2) neurocognitive dysfunction; and 3) magnetic resonance imaging of focal brain lesions has not been established.MethodsA 6-year study of 30 patients with acute NPSLE (27 women, 38 ± 12 years of age), 46 age- and sex-matched SLE controls without NPSLE (42 women, 36 ± 12 years of age), and 26 age- and sex-matched healthy controls (22 women, 34 ± 11 years of age) who underwent clinical and laboratory evaluations, transesophageal echocardiography, carotid duplex ultrasound, transcranial Doppler ultrasound, neurocognitive testing, and brain magnetic resonance imaging/magnetic resonance angiography. Patients with NPSLE were re-evaluated after 4.5 months of therapy. All patients were followed clinically for a median of 52 months.ResultsLibman-Sacks vegetations (87%), cerebromicroembolism (27% with 2.5 times more events per hour), neurocognitive dysfunction (60%), and cerebral infarcts (47%) were more common in NPSLE than in SLE (28%, 20%, 33%, and 0%) and healthy controls (8%, 0%, 4%, and 0%, respectively) (all p ≤ 0.009). Patients with vegetations had 3 times more cerebromicroemboli per hour, lower cerebral blood flow, more strokes/TIA and overall NPSLE events, neurocognitive dysfunction, cerebral infarcts, and brain lesion load than those without (all p ≤ 0.01). Libman-Sacks vegetations were independent risk factors of NPSLE (odds ratio [OR]: 13.4; p < 0.001), neurocognitive dysfunction (OR: 8.0; p = 0.01), brain lesions (OR: 5.6; p = 0.004), and all 3 outcomes combined (OR: 7.5; p < 0.001). Follow-up re-evaluations in 18 of 23 (78%) surviving patients with NPSLE demonstrated improvement of vegetations, microembolism, brain perfusion, neurocognitive dysfunction, and lesion load (all p ≤ 0.04). Finally, patients with vegetations had reduced event-free survival time to stroke/TIA, cognitive disability, or death (p = 0.007).ConclusionsThe presence of Libman-Sacks endocarditis in patients with SLE was associated with a higher risk for embolic CVD. This suggests that Libman-Sacks endocarditis may be a source of cerebral emboli.

To investigate the biochemical correlates of normal personality we utilized proton magnetic resonance spectroscopy ((1)H-MRS). Our sample consisted of 60 subjects ranging in age from 18 to 32 (27 females). Personality was assessed with the NEO Five-Factor Inventory (NEO-FFI). We measured brain biochemistry within the precuneus, the cingulate cortex, and underlying white matter. We hypothesized that brain biochemistry within these regions would predict individual differences across major domains of personality functioning. Biochemical models were fit for all personality domains including Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness. Our findings involved differing concentrations of Choline (Cho), Creatine (Cre), and N-acetylaspartate (NAA) in regions both within (i.e., posterior cingulate cortex) and white matter underlying (i.e., precuneus) the Default Mode Network (DMN). These results add to an emerging literature regarding personality neuroscience, and implicate biochemical integrity within the default mode network as constraining major personality domains within normal human subjects.

Background Although variations in neurometabolite concentrations occur in diverse neuropsychiatric and neurodegenerative disorders, little is known about the nature of underlying genetic influences. The current study investigated the importance of a specific type of genetic mutation, copy number variation (CNV), for neurometabolite concentrations in a bilateral anterior cingulate voxel. Methods These neurometabolic signals were quantified using proton magnetic resonance spectroscopy ( 1 H-MRS): N-acetylaspartate (NAA), creatine-phosphocreatine (Cre), glutamate/glutamine (Glx), myoinositol (mI), and phosphorylcholine-glycerol phosphorylcholine (Cho). Genetic data were collected using the Illumina 1MDuoBeadChip Array from a sample adults with alcohol use disorders ( n = 146). Results The number of base pairs lost through rare copy number deletions (occurring in less than 5% of our sample) predicted lower NAA, Cre, mI, and Glx. More total rare deletions also predicted lower NAA, Cre, and Glx. Principal components analyses of the five neurometabolites identified two correlated components, the first comprised of NAA, Glx, and Cre, and the second comprised of Cho, mI, and to a lesser extent, Cre. The number and length of rare deletions were correlated with the first component, capturing approximately 10% of phenotypic variance, but not the second component. Conclusions These results suggest that mutation load affects neurometabolite concentrations, potentially increasing risk for neuropsychiatric disorders. The greater effect of CVNs on NAA, Glx, and Cre may reflect a greater sensitivity to the effects of mutations (i.e., reduced canalization) for neurometabolites related to metabolic activity and cellular energetics, due to extensive recent selection pressure on these phenotypes in the human lineage.

Objectives: Research suggests that the majority of mild traumatic brain injury (mTBI) patients exhibit both cognitive and emotional dysfunction within the first weeks of injury, followed by symptom resolution 3–6 months postinjury. The neuronal correlates of said dysfunction are difficult to detect with standard clinical neuroimaging, complicating differential diagnosis and early identification of patients who may not recover. This study examined whether resting state functional magnetic resonance imaging (fMRI) provides objective markers of injury and predicts cognitive, emotional, and somatic complaints in mTBI patients semiacutely (

Despite the prevalence and impact of mild traumatic brain injury (mTBI), common clinical assessment methods for mTBI have insufficient sensitivity and specificity. Moreover, few researchers have attempted to document underlying changes in physiology as a function of recovery from mTBI. Proton magnetic resonance spectroscopy (1H-MRS) was used to assess neurometabolite concentrations in a supraventricular tissue slab in 30 individuals with semi-acute mTBI, and 30 sex-, age-, and education-matched controls. No significant group differences were evident on traditional measures of attention, memory, working memory, processing speed, and executive skills, though the mTBI group reported significantly more somatic, cognitive, and emotional symptoms. At a mean of 13 days post-injury, white matter concentrations of creatine (Cre) and phosphocreatine (PCre) and the combined glutamate-glutamine signal (Glx) were elevated in the mTBI group, while gray matter concentrations of Glx were reduced. Partial normalization of these three neurometabolites and N-acetyl aspartate occurred in the early days post-injury, during the semi-acute period of recovery. In addition, 17 mTBI patients (57%) returned for a follow-up evaluation (mean = 120 days post-injury). A significant group × time interaction indicated recovery in the mTBI group for gray matter Glx, and trends toward recovery in white matter Cre and Glx. An estimate of premorbid intelligence predicted the magnitude of neurometabolite normalization over the follow-up interval for the mTBI group, indicating that biological factors underlying intelligence may also be associated with more rapid recovery.

A 1H magnetic resonance spectroscopic imaging study at 3T and short echo time was conducted to evaluate both the reproducibility, as measured by the interscan coefficient of variation (CV), and test-retest reliability, as measured by the intraclass correlation coefficient (ICC), of measurements of glutamate (Glu), combined glutamate and glutamine (Glx), myo-inositol (mI), N-acetylaspartate, creatine, and choline in 21 healthy subjects. The effect of partial volume correction on these measures and the relationship of reproducibility and reliability to data quality were also examined. A 1H magnetic resonance spectroscopic imaging slice was prescribed above the lateral ventricles and single repeat scans were performed within 30 min to minimize physiologic variability. Interscan CVs based on all the voxels varied from 0.05 to 0.07 for N-acetylaspartate, creatine, and choline to 0.10-0.13 for mI, Glu, and Glx. Findings on the reproducibility of gray and white matter estimates of N-acetylaspartate, creatine, and choline are consistent with previous studies using longer echo times, with CVs in the range of 0.02-0.04 and ICC in the range of 0.65-0.90. CVs for Glu, Glx, and mI are much lower than reported in previous studies at 1.5 T, while white matter mI (CV=0.04, ICC=0.93) and gray matter Glx (CV=0.04, ICC=0.68) demonstrated both high reproducibility and test-retest reliability.

Objective.Studies that have examined abnormalities in cerebral blood flow (CBF) in patients with systemic lupus erythematosus (SLE) reported CBF relative to a region assumed to be normal in the brain. We examined the absolute differences in both regional CBF and cerebral blood volume (CBV) between patients with SLE and healthy controls.Methods.CBF and CBV were measured with dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI), a technique that provides an alternative to radionuclide perfusion studies and permits quantitative anatomic, CBF, and CBV imaging in a single scanning session. CBF and CBV were measured in lesions and in normal-appearing tissue in the major cerebral and subcortical brain regions. Unlike most perfusion studies in SLE, CBF and CBV values were not normalized to a region of the brain assumed to be healthy.Results.CBF and CBV within MRI-visible lesions were markedly reduced relative to surrounding normal-appearing white matter. CBF and CBV in normal-appearing tissue were both higher in SLE patient groups, with or without lesions, relative to the control group.Conclusion.DSC MRI, without normalization to a region presumed to be healthy, revealed that CBF and CBV in normal-appearing tissue in patients with SLE was higher than CBF and CBV in controls. Since this finding was made in subgroups of patients with and without lesions, the higher CBF and CBV appear to precede lesion pathology.

Breakdown of the blood-brain barrier (BBB), occurring in many neurological diseases, has been difficult to measure noninvasively in humans. Dynamic contrast-enhanced magnetic resonance imaging measures BBB permeability. However, important technical challenges remain and normative data from healthy humans is lacking. We report the implementation of a method for measuring BBB permeability, originally developed in animals, to estimate BBB permeability in both healthy subjects and patients with white matter pathology. Fast T(1) mapping was used to measure the leakage of contrast agent Gadolinium diethylene triamine pentaacetic acid (Gd-DTPA) from plasma into brain. A quarter of the standard Gd-DTPA dose for dynamic contrast-enhanced magnetic resonance imaging was found to give both sufficient contrast-to-noise and high T(1) sensitivity. The Patlak graphical approach was used to calculate the permeability from changes in 1/T(1). Permeability constants were compared with cerebrospinal fluid albumin index. The upper limit of the 95% confidence interval for white matter BBB permeability for normal subjects was 3 × 10(-4) L/g min. MRI measurements were not [corrected] correlated strongly with levels of cerebrospinal fluid albumin in those subjects undergoing lumbar puncture. Dynamic contrast-enhanced magnetic resonance imaging with low dose Gd-DTPA and fast T(1) imaging is a sensitive method to measure subtle differences in BBB permeability in humans and may have advantages over techniques based purely on the measurement of pixel contrast changes.

Background Cognitive deficits in schizophrenia may be related to glutamatergic dysfunction, but in vivo measurement of glutamate metabolism has been challenging. We examined the relationship between glutamate metabolism and cognitive function in schizophrenia. Methods Thirty subjects with DSM-IV schizophrenia and 28 healthy volunteers were studied using 4 Tesla proton echo planar spectroscopic imaging. Glutamate plus glutamine (Glx), N-acetylaspartate compounds, and Inositol concentrations in gray and white matter and broad neuropsychological function were assessed in all subjects. Results Glutamate plus glutamine was positively correlated with overall cognitive performance in the schizophrenia group ( p = .0006), accounting for about 36% of the variance. No correlation was found in control subjects. Group-averaged Glx levels were similar in schizophrenia and control subjects. N-acetylaspartate compounds were reduced in cortical gray matter in the younger schizophrenia subjects (age p = .04) compared with age-matched control subjects. Inositol was increased in cortical gray ( p = .002) and white matter ( p = .02) in the older schizophrenia subjects (age > 30) compared with age-matched control subjects. Conclusions Although not reduced in schizophrenia as a group, lower Glx levels correlates with impaired cognition in the illness. This suggests heterogeneity in mechanisms that regulate glutamate function in schizophrenia. Patients with reduced glutamatergic reserves may be rendered into a more severe hypoglutamatergic state with cognitive consequences. Reduced cortical gray matter N-acetylaspartate compound concentration early in the illness with normalization in older subjects is consistent with a process of early dendritic retraction with subsequent increased neuronal packing. Later in the illness, Inositol elevation suggests glial involvement.

The magnetic properties and water dynamics of human red blood cells were examined by analysis of the water proton spectra of suspensions of oxygenated, deoxygenated, carbon monoxide-treated, and methemoglobin-containing cells at a magnetic field strength of 7.05 T. Total lineshape analysis of spectra from deoxygenated red blood cell suspensions was performed to determine the transmembrane water exchange rate, the contribution of diffusion in local magnetic field gradients to the transverse relaxation rate, and the difference between the intra- and extracellular chemical shifts of water protons. Mathematical models are proposed to account for the dependence of the chemical shifts and linewidths of these spectra on the magnetic susceptibility or density of the cells.

Accumulation of mitochondrial DNA deletions and the resultant impaired oxidative phosphorylation may play a pathogenic role in the mediation of age-related sarcopenia.Twenty four participants of the New Mexico Aging Process Study were classified as normal lean (n = 15) or sarcopenic (n = 9) based on body composition determined by Dual Energy x-ray Absorptiometry. Complex I and Complex IV activities were measured in the skeletal muscle samples obtained from gastrocnemius muscle. A two-stage nested polymerase chain reaction strategy was used to identify the mitochondrial DNA deletions in the entire mitochondrial genome in the skeletal muscle samples.Although Complex I activity was not significantly different (5.5 +/- 0.9 vs. 4.6 +/- 0.7 mU/mg protein, P0.05), Complex IV activity was higher in sarcopenic subjects (1.4 +/- 0.3 vs. 1.0 +/- 0.1 mU/mg protein, P0.05). Mitochondrial DNA deletions were mostly located in the region of Complex I and spanned from nicotinamide adenine dinucleotide dehydrogenase 1 to nicotinamide adenine dinucleotide dehydrogenase 6. Deletions in the 8,577-10,407 bp and 10,233-11,249 bp regions were associated with a significant decrease in Complex I activity (P0.05 and P = 0.02, respectively). Total cumulative deletion, defined as the sum of individual length of deletions in a subject, was comparable in subjects with and without sarcopenia (1760 +/- 726 vs. 1782 +/- 888 bp, P0.05). The magnitude of mitochondrial DNA deletion, however, correlated positively with lean body mass (r = 0.43, P0.05).Thus, mitochondrial DNA deletions are common in elderly subjects and are negatively related to Complex I activity. The positive association between mitochondrial DNA deletions and lean body mass needs to be confirmed by studies in a larger study population.

Asymmetric 7 T proton NMR signals of water in RBC suspensions containing intracellular deoxyhemoglobin are composites of chemically shifted extracellular and intracellular resonances broadened by gradient diffusion and modulated by transmembrane water exchange. This allows assessment of field dependences of acute hematoma intensities in proton MRIs at lower field strengths (