Glutamate measurements using edited MRS.

PURPOSE: To demonstrate J-difference coediting of glutamate using Hadamard encoding and reconstruction of Mescher-Garwood-edited spectroscopy (HERMES). METHODS: Density-matrix simulations of HERMES (TE 80 ms) and 1D J-resolved (TE 31-229 ms) of glutamate (Glu), glutamine (Gln), γ-aminobutyric acid (GABA), and glutathione (GSH) were performed. HERMES comprised four sub-experiments with editing pulses applied as follows: (A) 1.9/4.56 ppm simultaneously (ONGABA /ONGSH ); (B) 1.9 ppm only (ONGABA /OFFGSH ); (C) 4.56 ppm only (OFFGABA /ONGSH ); and (D) 7.5 ppm (OFFGABA /OFFGSH ). Phantom HERMES and 1D J-resolved experiments of Glu were performed. Finally, in vivo HERMES (20-ms editing pulses) and 1D J-resolved (TE 31-229 ms) experiments were performed on 137 participants using 3 T MRI scanners. LCModel was used for quantification. RESULTS: HERMES simulation and phantom experiments show a Glu-edited signal at 2.34 ppm in the Hadamard sum combination A+B+C+D with no overlapping Gln signal. The J-resolved simulations and phantom experiments show substantial TE modulation of the Glu and Gln signals across the TEs, whose average yields a well-resolved Glu signal closely matching the Glu-edited signal from the HERMES sum spectrum. In vivo quantification of Glu show that the two methods are highly correlated (p < 0.001) with a bias of ∼10%, along with similar between-subject coefficients of variation (HERMES/TE-averaged: ∼7.3%/∼6.9%). Other Hadamard combinations produce the expected GABA-edited (A+B-C-D) or GSH-edited (A-B+C-D) signal. CONCLUSION: HERMES simulation and phantom experiments show the separation of Glu from Gln. In vivo HERMES experiments yield Glu (without Gln), GABA, and GSH in a single MRS scan.

Increased myoinositol in the anterior cingulate cortex of veterans with a history of traumatic brain injury: a proton magnetic resonance spectroscopy study.

Traumatic brain injury (TBI) is one of the most prevalent forms of morbidity in veterans and service members, with mild traumatic brain injury (mTBI) being the most common. The diagnosis of mTBI in veterans is difficult because of mixed etiologies and high comorbidity with other disorders such as posttraumatic stress disorder (PTSD), depression, and substance use. Advanced neuroimaging techniques such as magnetic resonance spectroscopy (MRS) may be useful in identifying neurochemical alterations in TBI, which may aid the development of new targets for therapeutic intervention. Veterans with (n = 53) and without a history of TBI (n = 26) underwent single-voxel proton magnetic resonance spectroscopy (1H MRS) at 3 Tesla in the anterior cingulate cortex (ACC) using a two-dimensional J-resolved point spectroscopy sequence in addition to completing a clinical battery. TBI diagnosis was made using the research version of the Ohio State University TBI Identification Method. An increased myoinositol (mI)/H2O ratio was observed in the ACC of the TBI group compared with the non-TBI group during the chronic stage of TBI (average of 139.7 mo after injury), which may be reflective of astrogliosis. Several metabolites in the ACC demonstrated significant associations with TBI variables, including number of TBI with loss of consciousness (LOC) and time since most severe TBI, suggesting that changes in some metabolites may be potential diagnostic and prognostic indicators.NEW & NOTEWORTHY In this study of veterans, we used a state-of-the-art neuroimaging tool to probe the neurometabolic profile of the anterior cingulate cortex in veterans with traumatic brain injury (TBI). We report significantly elevated myoinositol levels in veterans with TBI compared with those without TBI.

Intraindividual changes in brain GABA, glutamate, and glutamine during monitored abstinence from alcohol in treatment-naive individuals with alcohol use disorder.

Proton magnetic resonance spectroscopy (1 H-MRS) studies have demonstrated abnormal levels of a variety of neurometabolites in treatment-seeking individuals with moderate-severe alcohol use disorder (AUD) following acute withdrawal. In contrast, few studies have investigated neurochemical changes across early abstinence in less severe, treatment-naïve AUD. The present study, which represents the primary report of a research grant from ABMRF/The Alcohol Research Fund, measured dorsal anterior cingulate cortex (dACC) GABA, glutamate, and glutamine levels in treatment-naïve AUD (n = 23) via three 1 H-MRS scans spaced across a planned week of abstinence from alcohol. In addition to AUD participants, 12 light drinkers completed two scans, separated by 48 hours, to ensure that results in AUD were not produced by between-scan differences other than abstinence from alcohol. 1 H-MRS spectra were acquired in dACC at each scan using 2D J-resolved point-resolved spectroscopy. Linear mixed modeling results demonstrated a significant increase in GABA, but not glutamate or glutamine (Ps = .237-.626), levels between scans 1 and 2 (+8.88%, .041), with no difference between scans 2 and 3 (+1.00%, .836), in AUD but not LD (F = 1.24, .290) participants. Exploratory regression analyses tentatively revealed a number of significant prospective associations between changes in glutamine levels and heavy drinking, craving, and withdrawal symptoms. Most notably, the present study demonstrated return from abnormally low to normal GABA levels in treatment-naïve AUD within 3 days of their last drink; the pattern of results was consistent with glutamate and glutamine disturbances being exclusive to relatively more severe AUD.

Brain Glutamate, GABA, and Glutamine Levels and Associations with Recent Drinking in Treatment-Naïve Individuals with Alcohol Use Disorder Versus Light Drinkers.

BACKGROUND: Proton magnetic resonance spectroscopy (1 H-MRS) studies have demonstrated abnormal levels of a variety of neurometabolites in inpatients/outpatients with alcohol use disorder (AUD) following acute alcohol withdrawal relative to healthy controls. In contrast, few studies have compared neurometabolite levels between less severe, treatment-naïve AUD individuals and light drinkers (LD) or related them to recent alcohol consumption. The present study compared neurometabolite levels between treatment-naïve AUD and LD individuals. METHODS: Twenty treatment-naïve individuals with AUD and 20 demographically matched LD completed an 1 H-MRS scan, approximately 2.5 days following their last reported drink. 1 H-MRS data were acquired in dorsal anterior cingulate (dACC) using a 2-dimensional J-resolved point-resolved spectroscopy sequence. dACC neurometabolite levels, with a focus on glutamate, glutamine, and GABA, were compared between AUD and LD participants. The associations between metabolite levels and recent drinking were explored. RESULTS: AUD participants had significantly lower concentrations of GABA (Cohen's d = 0.79, p = 0.017) and glutamine (Cohen's d = 1.12, p = 0.005), but not glutamate (Cohen's d = 0.05, p = 0.893), relative to LD. As previously reported, AUD participants' glutamate and N-acetylaspartate concentrations were inversely associated with their number of heavy drinking days. In contrast, neither number of drinking (mean p = 0.56) nor heavy drinking (mean p = 0.47) days were associated with metabolite concentrations in LD. CONCLUSIONS: The present study demonstrated significantly lower levels of prefrontal γ-aminobutyric acid and glutamine in treatment-naïve individuals with AUD relative to LD. Whether these findings reflect the neurotoxic consequence and/or neuroadaptive response of alcohol consumption versus a predrinking trait, and therefore a more durable neurochemical disturbance, awaits elucidation from longitudinal studies.

Associations Between Recent Heavy Drinking and Dorsal Anterior Cingulate N-Acetylaspartate and Glutamate Concentrations in Non-Treatment-Seeking Individuals with Alcohol Dependence.

BACKGROUND: Proton magnetic resonance spectroscopy ((1) H-MRS) studies have consistently found abnormal brain concentrations of N-acetylaspartate (NAA) and glutamate in individuals with alcohol use disorders (AUD) relative to light drinkers. However, most such studies have focused on individuals in treatment for severe alcohol dependence (AD), and few studies have investigated associations between neurochemical concentrations and recent alcohol consumption. This study focused on associations between recent drinking and prefrontal neurometabolite concentrations in nonsevere, non-treatment-seeking individuals with AUD. METHODS: Nineteen treatment-naïve alcohol-dependent individuals aged 21 to 40 completed a (1) H-MRS scan. Single-voxel (1) H-MRS spectra were acquired in dorsal anterior cingulate cortex (dACC) using a 2-dimensional J-resolved point resolved spectroscopy sequence. Associations between recent heavy drinking, assessed using the Timeline FollowBack, and dACC metabolite concentrations were estimated via regression controlling for within-voxel tissue composition. RESULTS: Participants provided a negative breathalyzer reading and reported between 1 and 5 days (M = 2.45, SD = 1.23) since their last drink. Number of heavy drinking days in the 14 days preceding the scan (M = 4.84, SD = 3.32) was significantly inversely associated with both glutamate/water (ß = -0.63, t(17) = -3.37, p = 0.004) and NAA/water concentrations (ß = -0.59, t(17) = -2.98, p = 0.008). CONCLUSIONS: This study extends the literature by demonstrating inverse associations between recent heavy drinking and dACC glutamate and NAA concentrations in a sample of nonsevere, non-treatment-seeking individuals with AD. These findings may support the hypothesis that amount of recent alcohol consumption may account for differences in neuronal metabolism, even in nonsevere, non-treatment-seeking alcoholics.

Molecular features assisting in diagnosis, surgery, and treatment decision making in low-grade gliomas.

The preferred management of suspected low-grade gliomas (LGGs) has been disputed, and the implications of molecular changes for medical and surgical management of LGGs are important to consider. Current strategies that make use of molecular markers and imaging techniques and therapeutic considerations offer additional options for management of LGGs. Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes suggest a role for this abnormal metabolic pathway in the pathogenesis and progression of these primary brain tumors. Use of magnetic resonance spectroscopy can provide preoperative detection of IDH-mutated gliomas and affect surgical planning. In addition, IDH1 and IDH2 mutation status may have an effect on surgical resectability of gliomas. The IDH-mutated tumors exhibit better prognosis throughout every grade of glioma, and mutation may be an early genetic event, preceding lineage-specific secondary and tertiary alterations that transform LGGs into secondary glioblastomas. The O6-methylguanine-DNAmethyltransferase (MGMT) promoter methylation and 1p19q codeletion status can predict sensitivity to chemotherapy and radiation in low- and intermediate-grade gliomas. Thus, these recent advances, which have led to a better understanding of how molecular, genetic, and epigenetic alterations influence the pathogenicity of the different histological grades of gliomas, can lead to better prognostication and may lead to specific targeted surgical interventions and medical therapies.

In vivo T(2) relaxation time measurement with echo-time averaging.

The accuracy of metabolite concentrations measured using in vivo proton ((1) H) MRS is enhanced following correction for spin-spin (T2 ) relaxation effects. In addition, metabolite proton T2 relaxation times provide unique information regarding cellular environment and molecular mobility. Echo-time (TE) averaging (1) H MRS involves the collection and averaging of multiple TE steps, which greatly simplifies resulting spectra due to the attenuation of spin-coupled and macromolecule resonances. Given the simplified spectral appearance and inherent metabolite T2 relaxation information, the aim of the present proof-of-concept study was to develop a novel data processing scheme to estimate metabolite T2 relaxation times from TE-averaged (1) H MRS data. Spectral simulations are used to validate the proposed TE-averaging methods for estimating methyl proton T2 relaxation times for N-acetyl aspartate, total creatine, and choline-containing compounds. The utility of the technique and its reproducibility are demonstrated using data obtained in vivo from the posterior-occipital cortex of 10 healthy control subjects. Compared with standard methods, distinct advantages of this approach include built-in macromolecule resonance attenuation, in vivo T2 estimates closer to reported values when maximum TE ≈ T2 , and the potential for T2 calculation of metabolite resonances otherwise inseparable in standard (1) H MRS spectra recorded in vivo.

Lower distress intolerance is associated with higher glutathione levels in adolescent cannabis users.

Cannabis (CB) use and psychological stressors increase oxidative stress in the brain. Glutathione (GSH), the most abundant antioxidant in the brain, protects against oxidative stress. Furthermore, distress intolerance, the inability to tolerate psychological or physiological stress is a risk factor for CB use. The relationship between CB use, brain GSH levels and distress intolerance remains unknown. Therefore, we examined GSH levels in the anterior cingulate cortex (ACC), as a measure of oxidative stress, and its relationship with distress intolerance in adolescent CB users and healthy controls (HC). Sixteen HC and 17 CB-using adolescents were included in the analysis. GSH levels were measured in the ACC using a metabolite-edited proton magnetic resonance spectroscopy sequence on a 3 T scanner. Distress intolerance was assessed using the Distress Intolerance Index (DII) and CB use was evaluated using a structured clinical interview. In the CB group, lower CSF-corrected GSH levels in the ACC were correlated with higher DII scores. However, no significant between group differences were observed for ACC CSF-corrected GSH levels or on DII scores. No significant correlations were observed in the HC group between GSH levels and DII. Our findings suggests that the association between lower GSH levels and greater distress intolerance in CB users might reflect alterations in the balance between protective and oxidative stress conditions linked to the ability to tolerate distress. Further examination into this relationship can provide important insights into neurobiological correlates and risk factors associated with CB use to help inform preventive and treatment targets in the future.

Two-dimensional J-resolved proton MR spectroscopy and prior knowledge fitting (ProFit) in the frontal and parietal lobes of healthy volunteers: assessment of metabolite discrimination and general reproducibility.

PURPOSE: To investigate human brain metabolite discriminability and general measurement reproducibility of two-dimensional (2D) J-resolved (1)H MRS and Prior Knowledge Fitting (ProFit). MATERIALS AND METHODS: 2D J-resolved (1)H MRS spectra were acquired from the anterior cingulate cortex (ACC) and the parietal-occipital cortex (POC) of 10 healthy subjects at a magnetic field strength of 2.9 Tesla. Amplitude correlation matrices were constructed for each subject and brain region to assess metabolite discriminability. ProFit-estimated metabolite peak areas were normalized to a water reference signal, and intra- and inter-subject reproducibility was evaluated. RESULTS: Favorable between-metabolite correlation coefficients (<20%) were observed for a range of metabolites. Lower correlation coefficients between a given pair of metabolite estimates were consistently observed for POC metabolites. The group mean correlation coefficient existing between glutamate and glutamine was calculated as -18% and -13% for ACC and POC, respectively. Most ACC and POC metabolites showed intra- and inter-subject CV values of <15% and <20%, respectively. CONCLUSION: The observed Glu and Gln signal discrimination makes these techniques suitable for investigating a variety of psychiatric disorders. Intra- and inter-subject metabolite level reproducibility was comparable to the existing literature findings. These data serve as a valuable benchmark for assessing future modifications to 2D (1)H MRS data acquisition and ProFit analysis.

Brain gamma-aminobutyric acid (GABA) abnormalities in bipolar disorder.

OBJECTIVES: Gamma-aminobutyric acid (GABA) abnormalities have been implicated in bipolar disorder. However, due to discrepant studies measuring postmortem, cerebrospinal fluid, plasma, and in vivo brain levels of GABA, the nature of these abnormalities is unclear. Using proton magnetic resonance spectroscopy, we investigated tissue levels of GABA in the anterior cingulate cortex and parieto-occipital cortex of participants with bipolar disorder and healthy controls. METHODS: Fourteen stably medicated euthymic outpatients with bipolar disorder type I (mean age 32.6 years, eight male) and 14 healthy control participants (mean age 36.9 years, 10 male) completed a proton magnetic resonance spectroscopy scan at 4-Tesla after providing informed consent. We collected data from two 16.7-mL voxels using MEGAPRESS, and they were analyzed using LCModel. RESULTS: GABA/creatine ratios were elevated in bipolar disorder participants compared to healthy controls [F(1,21) = 4.4, p = 0.048] in the anterior cingulate cortex (25.1% elevation) and the parieto-occipital cortex (14.6% elevation). Bipolar disorder participants not taking GABA-modulating medications demonstrated greater GABA/creatine elevations than patients taking GABA-modulating medications. CONCLUSIONS: We found higher GABA/creatine levels in euthymic bipolar disorder outpatients compared to healthy controls, and the extent of this elevation may be affected by the use of GABA-modulating medications. Our findings suggest that elevated brain GABA levels in bipolar disorder may be associated with GABAergic dysfunction and that GABA-modulating medications reduce GABA levels in this condition.

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

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

Examination of gamma-aminobutyric acid and glutamate-glutamine levels in association with impulsive behavior in adolescent marijuana users.

BACKGROUND: Adolescent marijuana (MJ) use has been associated with alterations in brain structure and function as well as behavior. Examination of neurochemical correlates such as GABA (gamma-aminobutyric acid) and Glx (glutamate + glutamine) in MJ users remains limited. Impulsivity, identified as a risk factor and consequence of MJ use, has been associated with GABA and Glx levels in healthy and clinical populations. However, this relationship has not been investigated in MJ users. In this study, we examined levels of GABA and Glx in the anterior cingulate cortex (ACC) and its relationship with impulsive behavior in MJ-using adolescents and healthy controls. METHODS: Healthy control subjects (HC; N = 21) and MJ-using adolescents (N = 18) completed a metabolite-edited 1H MRS exam to measure ACC GABA and Glx levels, a structured clinical interview to assess MJ use, and the Barratt Impulsivity Scale (BIS-11) to evaluate impulsive behavior. RESULTS: Adolescent MJ users had significantly lower tissue-corrected GABA (with macromolecules; GABA+) levels (p = 0.029) compared to HC's. No significant between-group differences were observed in ACC Glx levels. Assessment of impulsive behavior demonstrated no significant between-group differences in motor, non-planning, attention, and total impulsivity scores. Additionally, impulsivity measures and tissue-corrected GABA+ or Glx levels were not significantly correlated in either group. CONCLUSION: Lower GABA levels in MJ users may indicate alterations in excitatory-inhibitory mechanisms critical for neurodevelopment. Although no significant relationships were observed between impulsive measures and GABA or Glx levels in both groups, further investigations are needed examining the relationship between neurochemical correlates, behavior, and adolescent MJ use.

Neurochemical alterations in adolescent chronic marijuana smokers: a proton MRS study.

Converging evidence from neuroimaging and neuropsychological studies indicates that heavy marijuana use is associated with cingulate dysfunction. However, there has been limited human data documenting in vivo biochemical brain changes after chronic marijuana exposure. Previous proton magnetic resonance spectroscopy studies have demonstrated reduced basal ganglia glutamate and dorsolateral prefrontal cortex N-acetyl aspartate levels in adult chronic marijuana users. Similar studies have not been reported in adolescent populations. The present study used proton magnetic resonance spectroscopy to determine whether reductions in glutamate, N-acetyl aspartate and/or other proton metabolite concentrations would be found in the anterior cingulate cortex (ACC) of adolescent marijuana users compared with non-using controls. Adolescent marijuana users (N=17; average age 17.8 years) and similarly aged healthy control subjects (N=17; average age 16.2 years) were scanned using a Siemens 3T Trio MRI system. Proton magnetic resonance spectroscopy data were acquired from a 22.5 mL voxel positioned bilaterally within the ACC. Spectra were fitted using commercial software and all metabolite integrals were normalized to the scaled unsuppressed water integral. Analysis of variance and analysis of covariance were performed to compare between-group metabolite levels. The marijuana-using cohort showed statistically significant reductions in anterior cingulate glutamate (-15%, p<0.01), N-acetyl aspartate (-13%, p=0.02), total creatine (-10%, p<0.01) and myo-inositol (-10%, p=0.03). Within-voxel tissue-type segmentation did not reveal any significant differences in gray/white matter or cerebrospinal fluid content between the two groups. The reduced glutamate and N-acetyl aspartate levels in the adolescent marijuana-using cohort are consistent with precedent human (1)H MRS data, and likely reflect an alteration of anterior cingulate glutamatergic neurotransmission and neuronal integrity within these individuals. The reduced total creatine and myo-inositol levels observed in these subjects might infer altered ACC energetic status and glial metabolism, respectively. These results expand on previous functional MRI data reporting altered cingulate function in individuals with marijuana-abuse.

Effect of moderate altitude on human cerebral metabolite levels: A preliminary, multi-site, proton magnetic resonance spectroscopy investigation.

Epidemiological studies show that altitude-of-residence is an independent risk factor for worsening rates of mood disorders, substance abuse, and suicide. Proton (1H) magnetic resonance spectroscopy (MRS) studies in rodent models of moderate-to-high altitude exposure have documented significant alterations in total creatine, glutamate, and myo-inositol, neurometabolites involved in bioenergetic homeostasis and neuronal/glial cell function. This preliminary study utilized 3 Tesla 1H MRS to study anterior cingulate cortex (ACC) and parietal-occipital cortex (POC) neurochemistry in healthy subjects residing in Utah (n = 19), Massachusetts (n = 10), and South Carolina (n = 10), to test the hypothesis that individuals residing at moderate altitude (Utah; 1,372 m) would show neurometabolite alterations vs. subjects living at sea level. Expressed as ratios to total N-acetyl aspartate (NAA), Utah participants showed lower ACC (p = 0.03) and POC (p < 0.01) total creatine, a trend towards lower ACC glutamate (p = 0.06), and lower POC myo-inositol (p = 0.02). Study limitations include small sample sizes and uncorrected multiple comparisons. To our knowledge, this is the first MRS investigation to identify potential neurochemical differences in individuals residing at moderate altitudes vs. sea level, warranting future 1H MRS studies in larger cohorts and across a range of altitudes-of-residence.

An exploratory proton MRS examination of gamma-aminobutyric acid, glutamate, and glutamine and their relationship to affective aspects of chronic pain.

Veterans experience chronic pain more frequently than civilians. Identification of neurobiological mechanisms underlying the pathophysiology of chronic pain in a veteran population may aid in the development of novel treatment targets. In this pilot proof-of-concept study, veterans with chronic pain (N = 61) and no chronic pain (N = 19) completed clinical interviews, self-report questionnaires inquiring about pain history, interference of pain with daily life, and pain catastrophizing, as well as measures of depressive and anxious symptoms. Veterans also underwent single-voxel proton (1H) magnetic resonance spectroscopy (MRS) at 3 T in the anterior cingulate cortex (ACC) using a two-dimensional (2D) J-resolved point spectroscopy sequence. We found no group difference in neurometabolites between veterans with and without chronic pain; however, pain intensity, negative thinking about pain, and description of pain in affective terms were associated with lower GABA/Cre in the ACC. In addition, the Glu/GABA ratio in the ACC was positively associated with anxiety and depressive symptoms in veterans with chronic pain. Reductions in GABA in the ACC may contribute to increased pain intensity and greater pain catastrophizing in veterans with chronic pain. Furthermore, a disturbance in the excitatory-inhibitory balance may contribute to the anxious and depressive symptoms related to chronic pain. Given the pilot nature of the study, these findings must be considered preliminary.

T2 relaxation time abnormalities in bipolar disorder and schizophrenia.

There are substantial abnormalities in the number, density, and size of cortical neurons and glial cells in bipolar disorder and schizophrenia. Because molecule-microenvironment interactions modulate metabolite signals characteristics, these cellular abnormalities may impact transverse (T2) relaxation times. We measured T2 relaxation times for three intracellular metabolites (N-acetylaspartate+N-acetylaspartylglutamate, creatine+phosphocreatine, and choline-containing compounds) in the anterior cingulate cortex and parieto-occipital cortex from 20 healthy subjects, 15 patients with bipolar disorder, and 15 patients with schizophrenia at 4 T. Spectra used in T2 quantification were collected from 8-cc voxels with varying echo times (30 to 500 ms, in 10-ms steps). Both bipolar disorder and schizophrenia groups had numerically shorter T2 relaxation times than the healthy subjects group in both regions; these differences reached statistical significance for creatine+phosphocreatine and choline-containing compounds in bipolar disorder and for choline-containing compounds in schizophrenia. Metabolite T2 relaxation time shortening is consistent with reduced cell volumes and altered macromolecule structures, and with prolonged water T2 relaxation times reported in bipolar disorder and schizophrenia. These findings suggest that metabolite concentrations reported in magnetic resonance spectroscopy studies of psychiatric conditions may be confounded by T2 relaxation and highlight the importance of measuring and correcting for this variable.

Supplementation with a putative calorie restriction mimetic micronutrient blend increases glutathione concentrations and improves neuroenergetics in brain of healthy middle-aged men and women.

BACKGROUND: Caloric restriction (CR) without micronutrient deficiency has been shown to increase both lifespan and healthspan. In animals, CR has been demonstrated to increase glutathione (GSH), a neuroprotective antioxidant, in the brain and preserve brain mitochondrial function by altering neuroenergetics. In humans it has been associated with improvements in mood states and cognitive function. However, most CR studies have employed a 30-60% reduction in calories which is likely too stringent for most people to adhere to long-term. Thus, there is an unmet need for nutritional supplements which can mimic the biological effects of CR, without the need for calorie limitations. AIM: The purpose of the present randomized, placebo-controlled clinical trial was to use Proton (1H) Magnetic Resonance Spectroscopic (MRS) measurements to determine non-invasively whether a blend of micronutrients, a putative CR mimetic, positively modulates metabolites related to neuroprotection and neuroenergetics in the brain. METHODS: Healthy middle-aged men and women (N = 63 [33 women]; age: 40-60 years) were randomized in a double-blind manner to 6 weeks supplementation with either the putative CR mimetic or placebo. At baseline and 6 weeks, subjects underwent MRS at 3 T to investigate changes in brain chemistry, including the neurometabolites: GSH, Glutamate (Glu), Glutamine (Gln) and N-Acetylaspartate (NAA). RESULTS: GSH, a marker of antioxidant and cellular redox status, increased in the brain of participants in the supplement group. The supplement group also showed an increase in the Glu/Gln ratio, a marker of excitatory neurotransmission and bioenergetics. A trend for an increase in NAA/H2O, a marker of neuronal integrity, was observed in females in the supplement group. CONCLUSIONS: The present study reveals that 6-weeks daily supplementation with a micronutrient blend elicits positive changes in brain neurochemistry. This is the first study to demonstrate that a putative CR mimetic increases brain GSH concentrations and improves neuroprotection and neuroenergetics in the brain of healthy humans. This study was registered at www.clinicaltrials.gov as NCT02439983.

Excitatory neurotransmitters in brain regions in interictal migraine patients.

OBJECTIVE: To examine biochemical differences in the anterior cingulate cortex (ACC) and insula during the interictal phase of migraine patients. We hypothesized that there may be differences in levels of excitatory amino acid neurotransmitters and/or their derivatives in migraine group based on their increased sensitivity to pain. METHODS: 2D J-resolved proton magnetic resonance spectroscopy (1H-MRS) data were acquired at 4.0 Tesla (T) from the ACC and insula in 10 migraine patients (7 women, 3 men, age 43 +/- 11 years) and 8 age gender matched controls (7 women, 3 men, age 41 +/- 9 years). RESULTS: Standard statistical analyses including analysis of variance (ANOVA) showed no significant metabolite differences between the two subject cohorts in the ACC nor the insula. However, linear discriminant analysis (LDA) introduced a clear separation between subject cohorts based on N-acetyl aspartylglutamate (NAAG) and glutamine (Gln) in the ACC and insula. CONCLUSION: These results are consistent with glutamatergic abnormalities in the ACC and insula in migraine patients during their interictal period compared to healthy controls. An alteration in excitatory amino acid neurotransmitters and their derivatives may be a contributing factor for migraineurs for a decrease in sensitivity for migraine or a consequence of the chronic migraine state. Such findings, if extrapolated to other regions of the brain would offer new opportunities to modulate central system as interictal or preemptive medications in these patients.

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

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

Creatine abnormalities in schizophrenia and bipolar disorder.

Total creatine (Cr) levels are widely used as an internal reference for the quantification of other metabolites in (1)H magnetic resonance spectroscopy (MRS). However, Cr plays an important role in brain energy metabolism, and its levels can be modulated by conditions of energy production and demand. Therefore, abnormal Cr levels in patient vs. control populations could confound the utility of this metabolite as an internal reference. We quantified Cr levels in 22 healthy controls, 15 acutely manic patients with bipolar disorder and 15 acutely ill patients with schizophrenia using (1)H MRS in the anterior cingulate cortex, and the parieto-occipital cortex at 4 Tesla. Patients with schizophrenia had a statistically significant reduction in Cr levels as compared with controls; bipolar disorder patients showed no difference in Cr as compared with controls. In addition, older age was associated with reductions in Cr in healthy controls, but not in patients with either disorder. These findings indicate that the use of Cr as an internal reference in schizophrenia MRS research is problematic unless Cr levels are shown to be normal in the study population. They also add to the literature on bioenergetic abnormalities in schizophrenia.