Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis.

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan's unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = -0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = -0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = -0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = -0.02, p < 0.001) and frontal white matter Glx (z = -0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

Preprocessing, analysis and quantification in single-voxel magnetic resonance spectroscopy: experts' consensus recommendations.

Once an 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 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.

Terminology and concepts for the characterization of in vivo MR spectroscopy methods and MR spectra: Background and experts' consensus recommendations.

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.

Errors in 1 H-MRS estimates of brain metabolite concentrations caused by failing to take into account tissue-specific signal relaxation.

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.

The long-term effect of erythropoiesis stimulating agents given to preterm infants: a proton magnetic resonance spectroscopy study on neurometabolites in early childhood.

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). OBJECTIVE: We hypothesized that ESA treatment in premature infants would tend to normalize neurometabolites by 4-6 years of age. MATERIALS AND METHODS: Children in a longitudinal study of neurodevelopment underwent MRI and 1H-MRS at approximately 4 years and 6 years of age. Prematurely born children (500-1,250 g 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. CONCLUSION: Neither prematurity nor neonatal ESA treatment was 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 might have existed had normalized by 4-6 years of age or were too small to be statistically significant in the current sample.

Validation of biomarkers in subcortical ischaemic vascular disease of the Binswanger type: approach to targeted treatment trials.

OBJECTIVES: 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. METHODS: 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-ß1-42 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. RESULTS: An initial BDS of 6 or greater was significantly correlated with a final diagnosis of BD (p<0.05; 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. CONCLUSIONS: 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.

Preliminary study of the association of white-matter metabolite concentrations with disease severity in patients with Huntington's disease.

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.

1H-MR spectroscopy metabolite levels correlate with executive function in vascular cognitive impairment.

BACKGROUND: White matter hyperintensities (WMHs) are associated with vascular cognitive impairment (VCI) but fail to correlate with neuropsychological measures. As proton MR spectroscopy ((1)H-MRS) can identify ischaemic tissue, we hypothesised that MRS detectable brain metabolites would be superior to WMHs in predicting performance on neuropsychological tests. METHODS: 60 patients with suspected VCI underwent clinical, neuropsychological, MRI and CSF studies. They were diagnosed as having subcortical ischaemic vascular disease (SIVD), multiple infarcts, mixed dementia and leukoaraiosis. We measured brain metabolites in a white matter region above the lateral ventricles with (1)H-MRS and WMH volume in this region and throughout the brain. RESULTS: We found a significant correlation between both total creatine (Cr) and N-acetylaspartyl compounds (NAA) and standardised neuropsychological test scores. Cr levels in white matter correlated significantly with executive function (p=0.001), attention (p=0.03) and overall T score (p=0.007). When lesion volume was added as a covariate, NAA also showed a significant correlation with executive function (p=0.003) and overall T score (p=0.015). Furthermore, while metabolite levels also correlated with total white matter lesion volume, adjusting the Cr levels for lesion volume did not diminish the strength of the association between Cr levels and neuropsychological scores. The lowest metabolite levels and neuropsychological scores were found in the SIVD group. Finally, lesion volume alone did not correlate significantly with any neuropsychological test score. CONCLUSION: These results suggest that estimates of neurometabolite levels provide additional and useful information concerning cognitive function in VCI not obtainable by measurements of lesion load.

Biomarkers of increased diffusion anisotropy in semi-acute mild traumatic brain injury: a longitudinal perspective.

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.

Blood-brain barrier permeability abnormalities in vascular cognitive impairment.

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<0.05). Patient age did not correlate with either the blood-brain barrier permeability or albumin index. Highest albumin index values were seen in the SIVD group (P<0.05) and were significantly increased over multiple and lacunar infarcts. K(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.

Functional connectivity in mild traumatic brain injury.

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 (<3 weeks postinjury) and in late recovery (3-5 month) phases. METHODS: Twenty-seven semiacute mTBI patients and 26 gender, age, and education-matched controls were studied. Fifteen of 27 patients returned for a follow-up visit 3-5 months postinjury. The main dependent variables were spontaneous fluctuations (temporal correlation) in the default-mode (DMN) and fronto-parietal task-related networks as measured by fMRI. RESULTS: Significant differences in self-reported cognitive, emotional, and somatic complaints were observed (all P < 0.05), despite normal clinical (T1 and T2) imaging and neuropsychological testing results. Mild TBI patients demonstrated decreased functional connectivity within the DMN and hyper-connectivity between the DMN and lateral prefrontal cortex. Measures of functional connectivity exhibited high levels of sensitivity and specificity for patient classification and predicted cognitive complaints in the semi-acute injury stage. However, no changes in functional connectivity were observed across a 4-month recovery period. CONCLUSIONS: Abnormal connectivity between the DMN and frontal cortex may provide objective biomarkers of mTBI and underlie cognitive impairment.

Quantitative measurement of blood-brain barrier permeability in human using dynamic contrast-enhanced MRI with fast T1 mapping.

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.

Test-retest reliability and reproducibility of short-echo-time spectroscopic imaging of human brain at 3T.

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.

Anterior cingulate and frontal lobe white matter spectroscopy in early childhood of former very LBW premature infants.

Neurometabolic sequelae of children born at very LBW (VLBW) are not well characterized in early childhood. Proton magnetic resonance spectroscopy (1H-MRS) and developmental assessments were acquired from children age 18-22 mo (16 VLBW/7 term) and 3-4 y (12 VLBW/8 term) from the anterior cingulate and left frontal periventricular white matter. Metabolites obtained included combined N-acetylaspartylglutamate and N-acetylaspartate (NAA), total choline-containing compounds (Cho), combined glutamate and glutamine (Glx), combined creatine and phosphocreatine (Cr), myoinositol (mI), and the following ratios: NAA/Cr, Cho/Cr, Glx/Cr, mI/Cr, and NAA/Cho. Significant differences were present only in white matter: at 18-22 mo, NAA was decreased in VLBW children (p < 0.04), and at 3-4 y, VLBW children showed lower Cr (p < 0.01), lower NAA/Cho (p < 0.005), higher Glx/Cr (p < 0.02), and higher Cho/Cr (p < 0.005). On developmental testing, VLBW children scored lower on language expression (p < 0.05) and on the A-not-B test of early executive function (p < 0.01) at 18-22 mo and had lower verbal intelligence quotient (IQ) (p < 0.005), performance IQ (p < 0.04), and several measures of early executive function including the bear-dragon test (p < 0.004), gift delay (p < 0.07), and summary categorization score (p < 0.03) at 3-4 y. VLBW children may have neurometabolic and developmental abnormalities that persist at least through early childhood.

Increased Glutamate Plus Glutamine in the Right Middle Cingulate in Early Schizophrenia but Not in Bipolar Psychosis: A Whole Brain 1H-MRS Study.

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.

Association of Age, Antipsychotic Medication, and Symptom Severity in Schizophrenia With Proton Magnetic Resonance Spectroscopy Brain Glutamate Level: A Mega-analysis of Individual Participant-Level Data.

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 < .001; cerebrospinal fluid-corrected Glu, F1,1216.7 = 5.610, P = .02), showing a 0.2-unit reduction per decade. In patients, antipsychotic dose (in chlorpromazine equivalents) was negatively associated with MFC Glu (estimate, 0.10 reduction per 100 mg; SE, 0.03) and MFC Glx (estimate, -0.11; SE, 0.04) levels. The MFC Glu to Cr ratio was positively associated with total symptom severity (estimate, 0.01 per 10 points; SE, 0.005) and positive symptom severity (estimate, 0.04; SE, 0.02) and was negatively associated with level of global functioning (estimate, 0.04; SE, 0.01). In the MTL, the Glx to Cr ratio was positively associated with total symptom severity (estimate, 0.06; SE, 0.03), negative symptoms (estimate, 0.2; SE, 0.07), and worse Clinical Global Impression score (estimate, 0.2 per point; SE, 0.06). The MFC creatine level increased with age (estimate, 0.2; SE, 0.05) but was not associated with either symptom severity or antipsychotic medication dose. Conclusions and Relevance: Findings from this mega-analysis suggest that lower brain Glu levels in patients with schizophrenia may be associated with antipsychotic medication exposure rather than with greater age-related decline. Higher brain Glu levels may act as a biomarker of illness severity in schizophrenia.

Biochemical support for the "threshold" theory of creativity: a magnetic resonance spectroscopy study.

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 of N-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.

Glutamatergic hypo-function in the left superior and middle temporal gyri in early schizophrenia: a data-driven three-dimensional proton spectroscopic imaging study.

Proton magnetic resonance spectroscopy (1H-MRS) studies have examined glutamatergic abnormalities in schizophrenia, mostly in single voxels. Though the critical brain nodes remain unknown, schizophrenia involves networks with broad abnormalities. Hence, glutamine plus glutamate (Glx) and other metabolites were examined with whole-brain 1H-MRS, in early schizophrenia. Three dimensional 1H-MRS was acquired in young schizophrenia subjects (N = 36, 19 antipsychotic-naïve and 17 antipsychotic-treated) and healthy controls (HC, N = 29). Glx (as well as N-acetylaspartate, choline, myo-inositol and creatine) group contrasts from all individual voxels that met spectral quality, were analyzed in common brain space, followed by cluster-corrected level alpha-value (CCLAV ≤ 0.05). Schizophrenia subjects had lower Glx in the left superior (STG) and middle temporal gyri (16 voxels, CCLAV = 0.04) and increased creatine in two clusters involving left temporal, parietal and occipital regions (32, and 18 voxels, CCLAV = 0.02 and 0.04, respectively). Antipsychotic-treated and naïve patients (vs HC) had similar Glx reductions (8/16 vs 10/16 voxels respectively, but CCLAV's > 0.05). However, creatine was higher in antipsychotic-treated vs HC's in a larger left hemisphere cluster (100 voxels, CCLAV = 0.01). Also in treated patients, choline was increased in left middle frontal gyrus (18 voxels, CCLAV = 0.04). Finally in antipsychotic-naive patients, NAA was reduced in right frontal gyri (19 voxels, CCLAV = 0.05) and myo-inositol was reduced in the left cerebellum (34 voxels, CCLAV = 0.02). We conclude that data-driven spectroscopic brain examination supports that reductions in Glx in the left STG may be critical to the pathophysiology of schizophrenia. Postmortem and neuromodulation schizophrenia studies focusing on left STG, may provide critical mechanistic and therapeutic advancements, respectively.

Auditory orienting and inhibition of return in mild traumatic brain injury: a FMRI study.

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 (<3 weeks). Behaviorally, patients with mTBI exhibited deficits in disengaging and reorienting auditory attention following invalid cues as well as a failure to inhibit attentional allocation to a cued spatial location compared to a group of matched controls. Accordingly, patients with mTBI also exhibited hypoactivation within thalamus, striatum, midbrain nuclei, and cerebellum across all trials as well as hypoactivation in the right posterior parietal cortex, presupplementary motor area, bilateral frontal eye fields, and right ventrolateral prefrontal cortex during attentional disengagement. Finally, the hemodynamic response within several regions of the attentional network predicted response times better for controls than for patients with mTBI. These objective neurological findings represent a potential biomarker for the behavioral deficits in spatial attention that characterize the initial recovery phase of mTBI.

Imaging intelligence with proton magnetic resonance spectroscopy.

Proton magnetic resonance spectroscopy ((1)H-MRS) is a technique for the assay of brain neurochemistry in vivo. N-acetylaspartate (NAA), the most prominent metabolite visible within the (1)H-MRS spectrum, is found primarily within neurons. The current study was designed to further elucidate NAA-cognition relationships, particularly whether such relationships are moderated by sex, or tissue type (gray or white matter). We administered standard measures of intelligence to 63 young, healthy subjects and obtained spectroscopic imaging data within a slab of tissue superior to the lateral ventricles. We found that lower NAA within right anterior gray matter predicted better performance VIQ (F=6.83, p=.011, r(2)=.10), while higher NAA within the right posterior gray matter region predicted better PIQ (F=8.175, p=.006, r(2)=.12). These findings add to the small but growing body of literature linking brain biochemistry to intelligence in normal healthy subjects using (1)H-MRSI.