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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 ( 1 H) 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., Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interest to disclose., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2019 Society for the Study of Addiction.)

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 ( 1 H 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)/H 2 O 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.

Although the neurotransmitters/modulators glutamate and, more recently, glycine have been implicated in the development and maintenance of Alcohol Use Disorder (AUD) in preclinical research, human proton magnetic resonance spectroscopy ( 1 H-MRS) studies have focused solely on the measurement of glutamate. The purpose of the present analysis was to examine the relative associations of brain glutamate and glycine levels with recent heavy drinking in 41 treatment naïve individuals with AUD using 1 H-MRS. The present study is the first that we are aware of to report in vivo brain glycine levels from an investigation of addiction. Dorsal Anterior Cingulate Cortex (dACC) glutamate and glycine concentration estimates were obtained using Two-Dimensional J-Resolved Point Resolved Spectroscopy at 3 Tesla, and past 2-week summary estimates of alcohol consumption were assessed via the Timeline Followback method. Glutamate (β = -0.44, t = -3.09, p = 0.004) and glycine (β = -0.68, t = -5.72, p <  0.001) were each significantly, inversely associated with number of heavy drinking days when considered alone. However, when both variables were simultaneously entered into a single regression model, the effect of glutamate was no longer significant (β = -0.11, t = -0.81, p = 0.42) whereas the effect of glycine remained significant (β = -0.62, t = -4.38, p < 0.001). The present study extends the literature by demonstrating a unique, inverse association of brain glycine levels with recent heavy drinking in treatment naïve individuals with AUD. If replicated and extended, these data could lead to enhanced knowledge of how glycinergic systems change with alcohol consumption and AUD progression leading to pharmacological interventional/preventative strategies that modulate brain glycine levels., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Trauma-related diagnoses such as posttraumatic stress disorder (PTSD) are prevalent in veterans. The identification of mechanisms related to stress vulnerability and development of PTSD specifically in a veteran population may aid in the prevention of PTSD and identification of novel treatment targets., Methods: Veterans with PTSD (n = 27), trauma-exposed veterans with no PTSD (TEC, n = 18) and non-trauma-exposed controls (NTEC, n = 28) underwent single-voxel proton ( 1 H) magnetic resonance spectroscopy (MRS) at 3 Tesla in the dorsal anterior cingulate cortex (dACC) using a two-dimensional (2D) J-resolved point spectroscopy sequence in addition to completing a clinical battery., Results: The PTSD and TEC groups demonstrated lower gamma-amino butyric acid (GABA)/H 2 O (p = 0.02) and glutamine (Gln)/H 2 O (p = 0.02) in the dACC as compared to the NTEC group. The PTSD group showed a trend towards higher Glu/GABA (p = 0.053) than the NTEC group. Further, GABA/H 2 O in the dACC correlated negatively with sleep symptoms in the PTSD group (p = 0.03) but not in the TEC and NTEC groups., Limitations: Cross-sectional study design, concomitant medications, single voxel measurement as opposed to global changes, absence of measure of childhood or severity of trauma and objective sleep measures, female participants not matched for menstrual cycle phase., Conclusions: Exposure to trauma in veterans may be associated with lower GABA/H 2 O and Gln/H 2 O in the dACC, suggesting disruption in the GABA-Gln-glutamate cycle. Further, altered Glu/GABA in the dACC in the PTSD group may indicate an excitatory-inhibitory imbalance. Further, lower GABA/H 2 O in the ACC was associated with poor sleep in the PTSD group. Treatments that restore GABAergic balance may be particularly effective in reducing sleep symptoms in PTSD., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (© 2018 by the Research Society on Alcoholism.)

Metabolite-specific, scalar spin-spin coupling constant (J)-editing 1 H MRS methods have become gold-standard for measuring brain γ-amino butyric acid (GABA) levels in human brain. Localized, two-dimensional (2D) 1 H MRS technology offers an attractive alternative as it significantly alleviates the problem of severe metabolite signal overlap associated with standard 1D MRS and retains spectroscopic information for all MRS-detectable species. However, for metabolites found at low concentration, a direct, in vivo, comprehensive methods comparison is challenging and has not been reported to date. Here, we document an assessment of comparability between 2D 1 H MRS and J-editing methods for measuring GABA in human brain. This clinical study is unique in that it involved chronic administration a GABA-amino transferase (AT) inhibitor (CPP-115), which induces substantial increases in brain GABA concentration, with normalization after washout. We report a qualitative and quantitative comparison between these two measurement techniques. In general, GABA concentration changes detected using J-editing were closely mirrored by the 2D 1 H MRS time courses. The data presented are particularly encouraging considering recent 2D 1 H MRS methodological advances are continuing to improve temporal resolution and spatial coverage for achieving whole-brain, multi-metabolite mapping.

CPP-115, a next-generation γ-amino butyric acid (GABA)-aminotransferase (AT) inhibitor, shows comparable pharmacokinetics, improved safety and tolerability, and a more favorable toxicity profile when compared with vigabatrin. The pharmacodynamic characteristics of CPP-115 remain to be evaluated. The present study employed state-of-the-art proton magnetic resonance spectroscopy techniques to measure changes in brain GABA+ (the composite resonance of GABA, homocarnosine, and macromolecules) concentrations in healthy subjects receiving oral daily doses of CPP-115 or placebo. Six healthy adult males were randomized to receive either single daily 80 mg doses of CPP-115 (n=4) or placebo (n=2) for 6, 10, or 14 days. Metabolite-edited spectra and two-dimensional J-resolved spectroscopy data were acquired from the parietal-occipital cortex and supplementary motor area in all subjects. Four scans were performed in each subject that included a predrug baseline measure, two scans during the dosing timeframe, and a final scan that occurred 1 week after drug cessation. CPP-115 induced robust and significant increases in brain GABA+ concentrations that ranged between 52 and 141% higher than baseline values. Elevated GABA+ concentrations returned to baseline values following drug clearance. Subjects receiving placebo showed no significant changes in GABA+ concentration. CPP-115-induced changes were exclusive to GABA and homocarnosine, and CPP-115 afforded brain GABA+ concentration changes comparable to or greater than previous vigabatrin spectroscopy studies in healthy epilepsy-naive subjects. The return to baseline GABA+ concentration indicates the reversible GABA-AT resynthesis following drug washout. These preliminary data warrant further spectroscopy studies that characterize the acute pharmacodynamic effects of CPP-115 with additional dose-descending measures.

Background: Although cognitive deficits in bipolar disorder (BD) have been repeatedly observed, our understanding of these impairments at a mechanistic level remains limited. Few studies that investigated cognitive impairments in bipolar illness have examined the association with brain biochemistry. This pilot study utilized proton magnetic resonance spectroscopy ( 1 H-MRS) to evaluate the relationship between neurocognitive performance and brain metabolites in youth with BD., Methods: Thirty participants, twenty depressed BD participants and ten healthy comparison participants, ages 13-21, completed mood and executive function measures. 1 H-MRS data were also acquired from the anterior cingulate cortex (ACC) using two-dimensional (2D) J-resolved 1 H-MRS sequence. Proton metabolites including N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA) were quantified for both groups., Results: Participants with BD performed significantly lower on executive functioning measures than comparison participants. There were significant positive correlations between Wisconsin Card Sorting Test (WCST) performance and NAA (p < .001) and GABA (p < .01) in the ACC in bipolar youth, such that as WCST performance increased, both NAA and GABA levels increased., Limitations: Small sample size and lack of control for medications., Conclusions: These findings build on previous observations of biochemical alterations associated with BD and indicate that executive functioning deficits in bipolar youth are correlated with NAA and GABA. These results suggest that cognitive deficits occur early in the course of illness and may reflect risk factors associated with altered neurochemistry. Further investigation of the relationship between brain metabolites and cognition in BD may lead to important information for developing novel, targeted interventions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Intrusive memories, images, and hallucinations are hallmark symptoms of psychiatric disorders. Although often attributed to deficient inhibitory control by the prefrontal cortex, difficulty in controlling intrusive thoughts is also associated with hippocampal hyperactivity, arising from dysfunctional GABAergic interneurons. How hippocampal GABA contributes to stopping unwanted thoughts is unknown. Here we show that GABAergic inhibition of hippocampal retrieval activity forms a key link in a fronto-hippocampal inhibitory control pathway underlying thought suppression. Subjects viewed reminders of unwanted thoughts and tried to suppress retrieval while being scanned with functional magnetic resonance imaging. Suppression reduced hippocampal activity and memory for suppressed content. 1 H magnetic resonance spectroscopy revealed that greater resting concentrations of hippocampal GABA predicted better mnemonic control. Higher hippocampal, but not prefrontal GABA, predicted stronger fronto-hippocampal coupling during suppression, suggesting that interneurons local to the hippocampus implement control over intrusive thoughts. Stopping actions did not engage this pathway. These findings specify a multi-level mechanistic model of how the content of awareness is voluntarily controlled.

Bipolar disorder (BD) and alcohol dependence (AD) frequently co-occur, and co-occurring BD and AD are associated with devastating public health costs. Minimal neurobiological research exists to guide the development of effective treatments for this treatment-resistant population. We believe the present study represents the first investigation of prefrontal gamma-aminobutyric acid (GABA) and glutamate levels in co-occurring BD and current AD. The participants were 78 individuals who met DSM-IV criteria for BD I/II and current AD (n=20), BD I/II alone (n=19), current AD alone (n=20) or no diagnosis (n=19). The participants completed a baseline diagnostic visit, then returned approximately 4 days later for a two-dimensional J-resolved proton magnetic resonance spectroscopy ( 1 H-MRS) acquisition in dorsal anterior cingulate cortex (dACC). All participants were required to demonstrate ⩾1 week of abstinence from alcohol/drugs via serial biomarker testing before 1 H-MRS. A 2 × 2 factorial analysis of variance of cerebrospinal fluid (CSF)-corrected GABA/water concentrations demonstrated a significant BD × AD interaction (F=2.91, P<0.05), signifying uniquely low levels of GABA in BD+AD; this effect doubled when the sample was restricted to individuals who consumed alcohol within 2 weeks of 1 H-MRS. There were no overall effects of BD/AD on CSF-corrected glutamate/water levels. However, the BD × AD interaction, signifying uniquely low levels of glutamate in BD+AD, approached statistical significance (F=3.83, P=0.06) in individuals who consumed alcohol within 2 weeks of 1 H-MRS. The dACC GABA levels were significantly, negatively associated with Barratt Impulsiveness Scale (r=-0.28, P=0.02) and Obsessive Compulsive Drinking Scale (r=-0.35, P<0.01) scores. If replicated, these results may suggest that future treatment studies should preferentially evaluate therapeutics in BD+AD known to increase prefrontal GABA and glutamate levels.

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 (β = -0.63, t(17) = -3.37, p = 0.004) and NAA/water concentrations (β = -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., (Copyright © 2016 by the Research Society on Alcoholism.)

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.

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., (Copyright © 2014 John Wiley & Sons, Ltd.)

Pediatric bipolar disorder is a severe mental illness whose pathophysiology is poorly understood and for which there is an urgent need for improved diagnosis and treatment. MR spectroscopy is a neuroimaging method capable of in vivo measurement of neurochemicals relevant to bipolar disorder neurobiology. MR spectroscopy studies of adult bipolar disorder provide consistent evidence for alterations in the glutamate system and mitochondrial function. In bipolar disorder, these 2 phenomena may be linked because 85% of glucose in the brain is consumed by glutamatergic neurotransmission and the conversion of glutamate to glutamine. The purpose of this article is to review the MR spectroscopic imaging literature in pediatric bipolar disorder, at-risk samples, and severe mood dysregulation, with a focus on the published findings that are relevant to glutamatergic and mitochondrial functioning. Potential directions for future MR spectroscopy studies of the glutamate system and mitochondrial dysfunction in pediatric bipolar disorder are discussed., (© 2014 by American Journal of Neuroradiology.)

Residing at high altitude may lead to reduced blood oxygen saturation in the brain and altered metabolism in frontal cortical brain areas, probably due to chronic hypobaric hypoxia. These changes may underlie the increased rates of depression and suicidal behavior that have been associated with life at higher altitudes. To test the hypothesis that hypobaric hypoxia is responsible for development of mood disorders due to alterations in neurochemistry, we assessed depression-like behavior in parallel to levels of brain metabolites in rats housed at simulated altitude. 32 female Sprague Dawley rats were housed either in a hypobaric hypoxia chamber at 10,000 ft of simulated altitude for 1 week or at local conditions (4500 ft of elevation in Salt Lake City, Utah). Depression-like behavior was assessed using the forced swim test (FST) and levels of neurometabolites were estimated by in vivo proton magnetic resonance spectroscopy in the frontal cortex, the striatum and the hippocampus at baseline and after a week of exposure to hypobaric hypoxia. After hypoxia exposure the animals demonstrated increased immobility behavior and shortened latency to immobility in the FST. Elevated ratios of myo-inositol, glutamate, and the sum of myo-inositol and glycine to total creatine were observed in the frontal cortex of hypoxia treated rats. A decrease in the ratio of alanine to total creatine was also noted. This study shows that hypoxia induced alterations in frontal lobe brain metabolites, aggravated depression-like behavior and might be a factor in increased rates of psychiatric disorders observed in populations living at high altitudes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Delayed diagnosis in bipolar disorder (BD) due to misdiagnosis as major depressive disorder (MDD) is a significant public health concern. Thus, identification of relevant diagnostic biomarkers is a critical unmet need, particularly early in the course of illness. The anterior cingulate cortex (ACC) is thought to play an important role in mood disorder pathophysiology. Case-control studies utilizing proton-1 magnetic resonance spectroscopy ((1)H-MRS) have found increased total choline levels in several brain regions in MDD. However, there are no published (1)H-MRS reports directly comparing adolescents with MDD and BD. We hypothesized that ACC choline levels would be increased in adolescents with unipolar versus bipolar depression., Methods: We studied depressed adolescents with MDD (n=28; mean age 17.0±2.1 years) and BD (n=9; 17.3±3.1 years). A Siemens Verio 3-Tesla clinical MRI system was used to acquire scans, using a single-voxel PRESS sequence. The voxel (18.75 cm(3)) was positioned on the ACC in the midsagittal plane. To remove potential gender effects, only female adolescent participants were included. Data were analyzed using the ANOVA and post-hoc Tukey tests., Results: A significantly increased ACC choline/creatine ratio was observed in participants with MDD (mean=0.253±0.021) compared to BD (mean=0.219±0.020) (p=0.0002). There were no significant differences in the other (1)H-MRS metabolites., Limitations: Cross sectional design, single gender sample, limited sample size., Conclusions: The present findings suggest that ACC total choline may have the potential to serve as a diagnostic biomarker in adolescent mood disorders., (Copyright © 2014 Elsevier B.V. All rights reserved.)

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., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: An increasing body of evidence from neuropsychological and neuroimaging studies suggests that exposure to marijuana throughout adolescence disrupts key cortical maturation processes occurring during this developmental phase. GABA-modulating pharmacologic treatments that elevate brain GABA concentration recently have been shown to decrease withdrawal symptoms and improve executive functioning in marijuana-dependent adult subjects. The goal of this study was to investigate whether the lower ACC glutamate previously reported in adolescent chronic marijuana smokers is associated with lower ACC GABA levels., Methods: Standard and metabolite-edited proton MRS data were acquired from adolescent marijuana users (N=13) and similarly aged non-using controls (N=16) using a clinical 3T MRI system., Results: The adolescent marijuana-using cohort showed significantly lower ACC GABA levels (-22%, p=0.03), which paralleled significantly lower ACC glutamate levels (-14%, p=0.01). Importantly, the lower ACC GABA and glutamate levels detected in the adolescent cohort remained significant after controlling for age and sex., Conclusions: The present spectroscopic findings support functional neuroimaging data documenting cingulate dysfunction in marijuana-dependent adolescents. Glutamatergic and GABAergic abnormalities potentially underlie cingulate dysfunction in adolescent chronic marijuana users, and the opportunity for testing suitable pharmacologic treatments with a non-invasive pharmacodynamic evaluation exists., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

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., (Copyright © 2012 Wiley Periodicals, Inc.)

(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., (Copyright © 2012 John Wiley & Sons, Ltd.)

Rationale: Chronic cocaine exposure has been associated with progressive brain structural and functional changes. Clarifying mechanisms underlying cocaine's progressive brain effects may help in the development of effective cocaine abuse treatments., Objectives: We used a controlled squirrel monkey model of chronic cocaine exposure (45 mg/kg/week for 9 months) combined with ultra-high magnetic field (9.4 T) proton magnetic resonance spectroscopy to prospectively measure putamen metabolite changes., Methods: Proton metabolites were measured with a STEAM sequence, quantified with LCModel using a simulated basis set, and expressed as metabolite/total creatine (tCr) ratios., Results: We found cocaine-induced time-dependent changes in putamen glutamate/tCr and glutamine/tCr metabolite ratios suggestive of altered glutamate compartmentalization, neurotransmission, and metabolism. By contrast, saline-treated monkeys exhibited no metabolite changes over time. The time course of cocaine-induced metabolite abnormalities we detected is consistent with the apparent time course of glutamate abnormalities identified in a cross-sectional study in human cocaine users, as well as with microdialysis findings in rodent models of repeated cocaine exposure., Conclusions: Together, these findings suggests that this squirrel monkey model may be useful for characterizing glutamatergic changes associated with cocaine exposure and for determining efficacies of treatments designed to mitigate cocaine-induced glutamatergic system dysfunction.

Background: Cigarette smoking is the leading preventable cause of death. Unfortunately, the majority of smokers who attempt to quit smoking relapse within weeks. Abnormal dorsal anterior cingulate cortex (dACC) function may contribute to tobacco smoking relapse vulnerability. Growing evidence suggests that glutamate neurotransmission is involved in mediating nicotine dependence. We hypothesized that prior to a cessation attempt, dACC glutamate levels would be lower in relapse vulnerable smokers., Methods: Proton magnetic resonance spectra (MRS) were obtained from dACC and a control region, the parieto-occipital cortex (POC), using two-dimensional J-resolved MRS at 4T and analyzed using LCModel. Nine nicotine-dependent women were scanned prior to making a quit attempt. Subjects then were divided into two groups; those able to maintain subsequent abstinence aided by nicotine replacement therapy (NRT) and those who slipped while on NRT (smoked any part of a cigarette after attaining at least 24h of abstinence)., Results: Slip subjects exhibited significantly reduced dACC MRS glutamate (Glu/Cr) levels (p<0.03) compared to abstinent subjects. This effect was not observed in the POC control region., Conclusions: Our preliminary findings suggest that dACC Glu levels as measured with MRS may help identify and/or be a biomarker for relapse vulnerable smokers. Future research following up on these findings may help clarify the role of dACC Glu in smoking dependence that may lead to new treatment strategies., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Abnormalities in glutamatergic neurotransmission are implicated in several psychiatric disorders, but in vivo neurochemical studies of the glutamate (Glu) system have been hampered by a lack of adequate probes. By contrast, glutamine (Gln) and Glu can be quantified separately in proton magnetic resonance spectroscopy studies in vivo. Accumulating evidence suggests that the Gln/Glu ratio is a putative index of glutamatergic neurotransmission but interpretation of changes in the Gln/Glu ratio depends on the conditions of the system, including ammonia levels., Methods: Here, we explored whether variation in GLS1 (the gene encoding the brain isoform of glutaminase, which catalyzes Gln-to-Glu conversion) is associated with Gln/Glu measured in vivo in two brain regions (anterior cingulate cortex, parieto-occipital cortex)., Results: A specific haplotype of four single nucleotide polymorphisms within GLS1 was significantly associated with Gln/Glu in the parieto-occipital cortex in an magnetic resonance spectroscopy-genetics dataset optimized for Gln/Glu detection (n = 42). This finding was replicated in a second magnetic resonance spectroscopy dataset that was optimized for γ-aminobutyric acid detection where Gln and Glu measurements could still be extracted (n = 40)., Conclusions: These findings suggest that genetic variation in a key component of glutamatergic machinery is associated with a putative in vivo index of glutamatergic neurotransmission. Thus, GLS1 genotype might provide insight into normal brain function and into the pathophysiology of many psychiatric conditions where glutamatergic neurotransmission has been implicated. It might also serve as a biomarker for predicting response to existing and novel therapeutic interventions in psychiatry that target glutamatergic neurotransmission., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Magnetic resonance spectroscopy (MRS) can provide in vivo information about metabolite levels across multiple brain regions. This study used MRS to examine concentrations of N-acetylaspartate (NAA), a marker of neuronal integrity and function, and choline (Cho), which is related to the amount of cell membrane per unit volume, in anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) in healthy individuals. Data were drawn from two experiments which examined glutamatergic and GABAergic signaling in schizophrenia and bipolar disorder. After controlling for gray matter percentages, NAA/creatine (Cr) was 18% higher in POC than in ACC (p<0.001); Cho/Cr was 46% lower in POC than in ACC (p<0.001). There was an effect of study (p<0.001 for both metabolites), but no region by study interaction (NAA p=0.101, Cho p=0.850). Since NAA is localized to the intracellular space, these data suggest that ACC neuronal compartment is reduced as compared with POC, or that there is a lower concentration of NAA per cell in the ACC than POC, or both. Since elevated Cho suggests more cell membrane per unit volume, reduced NAA in ACC appears to be coupled with increases in overall cell membrane compartment. These findings are consistent with a number of previous studies using proton MRS which found increasing NAA and decreasing Cho moving caudally, and with postmortem anatomical studies which found neurons in more widely spaced bundles in ACC when compared to parietal and occipital cortices. MRS may be a useful tool for studying physical properties of the living human brain., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Despite widely replicated abnormalities of gamma-aminobutyric acid (GABA) neurons in schizophrenia postmortem, few studies have measured tissue GABA levels in vivo. We used proton magnetic resonance spectroscopy to measure tissue GABA levels in participants with schizophrenia and healthy control subjects in the anterior cingulate cortex and parieto-occipital cortex., Methods: Twenty-one schizophrenia participants effectively treated on a stable medication regimen (mean age 39.0, 14 male) and 19 healthy control subjects (mean age 36.3, 12 male) underwent a proton magnetic resonance spectroscopy scan using GABA-selective editing at 4 Tesla after providing informed consent. Data were collected from two 16.7-mL voxels and analyzed using LCModel., Results: We found elevations in GABA/creatine in the schizophrenia group compared with control subjects [F(1,65) = 4.149, p = .046] in both brain areas (15.5% elevation in anterior cingulate cortex, 11.9% in parieto-occipital cortex). We also found a positive correlation between GABA/creatine and glutamate/creatine, which was not accounted for by % GM or brain region., Conclusions: We found elevated GABA/creatinine in participants with chronically treated schizophrenia. Postmortem studies report evidence for dysfunctional GABAergic neurotransmission in schizophrenia. Elevated GABA levels, whether primary to illness or compensatory to another process, may be associated with dysfunctional GABAergic neurotransmission in chronic schizophrenia., (Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Glutamatergic abnormalities may underlie bipolar disorder (BD). The glutamate-modulating drug riluzole may be efficacious in bipolar depression, but few in vivo studies have examined its effect on glutamatergic neurotransmission. We conducted an exploratory study of the effect of riluzole on brain glutamine/glutamate (Gln/Glu) ratios and levels of N-acetylaspartate (NAA). We administered open-label riluzole 100-200 mg daily for 6 weeks to 14 patients with bipolar depression and obtained imaging data from 8-cm(3) voxels in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) at baseline, day 2, and week 6 of treatment, using two-dimensional J-resolved proton magnetic resonance spectroscopy at 4 T. Imaging data were analyzed using the spectral-fitting package, LCModel; statistical analysis used random effects mixed models. Riluzole significantly reduced Hamilton Depression Rating Scale (HAM-D) scores (d=3.4; p<0.001). Gln/Glu ratios increased significantly by day 2 of riluzole treatment (Cohen's d=1.2; p=0.023). NAA levels increased significantly from baseline to week 6 (d=1.2; p=0.035). Reduction in HAM-D scores was positively associated with increases in NAA from baseline to week 6 in the ACC (d=1.4; p=0.053), but was negatively associated in the POC (d=9.6; p<0.001). Riluzole seems to rapidly increase Gln/Glu ratios-suggesting increased glutamate-glutamine cycling, which may subsequently enhance neuronal plasticity and reduce depressive symptoms. Further investigation of the Gln/Glu ratio as a possible early biomarker of response to glutamate-modulating therapies is warranted.

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., (Copyright (c) 2009 Wiley-Liss, Inc.)

Oral high-dose glycine administration has been used as an adjuvant treatment for schizophrenia to enhance glutamate neurotransmission and mitigate glutamate system hypofunction thought to contribute to the disorder. Prior studies in schizophrenia subjects documented clinical improvements after 2 weeks of oral glycine administration, suggesting that brain glycine levels are sufficiently elevated to evoke a clinical response within that time frame. However, no human study has reported on brain glycine changes induced by its administration. We utilized a noninvasive proton magnetic resonance spectroscopy ((1)H-MRS) technique termed echo time-averaged (TEAV) (1)H-MRS, which permits noninvasive quantification of brain glycine in vivo, to determine whether 2 weeks of oral glycine administration (peak dose of 0.8 g/kg/day) increased brain glycine/creatine (Gly/Cr) ratios in 11 healthy adult men. In scans obtained 17 h after the last glycine dose, brain (Gly/Cr) ratios were significantly increased. The data indicate that it is possible to measure brain glycine changes with proton spectroscopy. Developing a more comprehensive understanding of human brain glycine dynamics may lead to optimized use of glycine site agonists and glycine transporter inhibitors to treat schizophrenia, and possibly to treat other disorders associated with glutamate system dysfunction.

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., (2009 John Wiley & Sons, Ltd.)

Background: Zolpidem is a nonbenzodiazepine sedative/hypnotic that acts at GABA(A) receptors to influence inhibitory neurotransmission throughout the central nervous system. A great deal is known about the behavioral effects of this drug in humans and laboratory animals, but little is known about zolpidem's specific effects on neurochemistry in vivo., Objectives: We evaluated how acute administration of zolpidem affected levels of GABA, glutamate, glutamine, and other brain metabolites., Materials and Methods: Proton magnetic resonance spectroscopy ((1)H MRS) at 4 T was employed to measure the effects of zolpidem on brain chemistry in 19 healthy volunteers. Participants underwent scanning following acute oral administration of a therapeutic dose of zolpidem (10 mg) in a within-subject, single-blind, placebo-controlled, single-visit study. In addition to neurochemical measurements from single voxels within the anterior cingulate (ACC) and thalamus, a series of questionnaires were administered periodically throughout the experimental session to assess subjective mood states., Results: Zolpidem reduced GABA levels in the thalamus, but not the ACC. There were no treatment effects with respect to other metabolite levels. Self-reported ratings of "dizzy," "nauseous," "confused," and "bad effects" were increased relative to placebo, as were ratings on the sedation/intoxication (PCAG) and psychotomimetic/dysphoria (LSD) scales of the Addiction Research Center Inventory. Moreover, there was a significant correlation between the decrease in GABA and "dizzy.", Conclusions: Zolpidem engendered primarily dysphoric-like effects and the correlation between reduced thalamic GABA and "dizzy" may be a function of zolpidem's interaction with alpha1GABA(A) receptors in the cerebellum, projecting through the vestibular system to the thalamus.

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.

Background: At excitatory synapses, glutamate released from neurons is taken up by glial cells and converted to glutamine, which is cycled back to neurons. Alterations in this system are believed to play a role in the pathophysiology of bipolar disorder, but they have not been characterized in vivo. We examined the glutamine/glutamate ratio and levels of other metabolites in acute mania and schizophrenia in this exploratory study., Methods: Data were obtained from 2 x 2 x 2 cm voxels in the anterior cingulate cortex (ACC) and parieto-occipital cortex (POC) using two-dimensional J-resolved proton magnetic resonance spectroscopy at 4 Tesla and analyzed using LCModel. Fifteen bipolar disorder patients with acute mania and 17 schizophrenia patients with acute psychosis were recruited from an inpatient unit; 21 matched healthy control subjects were also studied. Glutamine/glutamate ratio and N-acetylaspartate, creatine, choline, and myo-inositol levels were evaluated in a repeated measures design. Medication effects and relationship to demographic and clinical variables were analyzed., Results: Glutamine/glutamate ratio was significantly higher in ACC and POC in bipolar disorder, but not schizophrenia, compared with healthy control subjects. N-acetylaspartate was significantly lower in the ACC in schizophrenia. Patients on and off lithium, anticonvulsants, or benzodiazepines had similar glutamine/glutamate ratios., Conclusions: The elevated glutamine/glutamate ratio is consistent with glutamatergic overactivity and/or defective neuronal-glial coupling in acute mania, although medication effects cannot be ruled out. Abnormalities in glutamatergic neurotransmission and glial cell function in bipolar disorder may represent targets for novel therapeutic interventions.

Unlabelled: Hunter syndrome is a rare genetic lysosomal storage disease that is caused by a deficiency, or absence, of iduronate-2-sulphatase, an enzyme needed to break down specific glycosaminoglycans (GAGs). As a result, GAGs build up in various tissues throughout the body leading to adverse neurological and non-neurological effects. This literature review focuses on the neurological findings. Although few magnetic resonance imaging studies have been conducted, those done have shown that patients with Hunter syndrome generally exhibit brain atrophy, enlarged periventricular spaces and ventriculomegaly. Similar findings have been reported in other mucopolysaccharide disorders. Enzyme replacement therapy is a novel treatment which has had success in treating peripheral disease in mice and humans., Conclusion: Future studies should focus on how structural and chemical signatures in the brain of Hunter patients are altered before and after enzyme replacement therapy, and how those alterations correlate with clinical outcome.

A single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) method is described that enables the in vivo measurement of endogenous brain glycine (Gly) levels in human subjects. At 4.0 T, TE-averaging (1)H-MRS dramatically attenuates the overlapping myo-inositol (mI) resonances at 3.52 ppm, permitting a more reliable measure of the Gly singlet peak. This methodology initially is described and tested in phantoms. The phantom data infers that the 3.55-ppm peak predominantly is Gly with a smaller contribution from mI. The composite resonance thus is differentiated from pure Gly and mI and is labeled Gly*. The mI contribution was calculated as <2% of the total Gly* signal for a 1:1 mI/Gly mixture. The technique subsequently was used to acquire TE-averaged (1)H-MRS data from the occipital cortex of healthy control subjects. The resultant spectra closely resembled experimental phantom data. LC-model analysis provided a means for quantifying TE-averaged (1)H-MRS spectra and a mean test-retest variability measure of 15% was established for brain Gly* levels in studies of six healthy subjects., (Magn Reson Med, 2006. (c) 2006 Wiley-Liss, Inc.)

Purpose: To develop 2D 1H-MRS measurement sequences for the evaluation of bone marrow lipids, and to assess these measurement sequences in healthy and diseased bone marrow., Materials and Methods: Single-voxel localized variants of COSY and DQF-COSY 2D 1H-MRS sequences were developed for use at 1.5 T to investigate the biochemical composition of human bone marrow in vivo. The performance of each sequence was initially tested in vitro using lipid phantoms. An unsaturated lipid proton index was developed to interrogate the degree of unsaturation within the triacylglyceride (TAG) acyl chains. Localized 2D 1H-MRS data were obtained from the bone marrow of healthy controls (N = 6), patients presenting with acute leukemia (N = 6) and patients with acute leukemia in remission (N = 4)., Results: The COSY and DQF-COSY data recorded from all subject cohorts were similar, and the unsaturated lipid proton index did not reveal significant differences between patient groups. Variations in water content and measured relaxation times showed minor differences between the measurement groups., Conclusions: No significant differences were observed in the spectra obtained from bone marrow using the 2D 1H-MRS sequences. A novel unsaturated lipid proton index was developed., ((c) 2005 Wiley-Liss, Inc.)

Proton (hydrogen 1) magnetic resonance (MR) spectroscopy was used to study model and porcine bile in vitro. The method was subsequently developed to facilitate the acquisition of in vivo 1H MR spectra from the gallbladder bile of 10 human volunteers. Signals attributable to phosphotidylcholine and conjugated bile acid protons were observed in eight of the 10 volunteers. Phosphotidylcholine concentrations were estimated, and five values (mean = 35.8 mmol/L, SD = 9.8) were within the expected range of levels in human bile. Findings in this preliminary investigation indicate that human gallbladder bile can be qualitatively and quantitatively studied noninvasively with 1H MR spectroscopy., (Copyright RSNA, 2003)

The sampling of gall bladder bile for analytical studies remains an invasive procedure. We demonstrate the application of the non-invasive methodology of (1)H-MR spectroscopy to the qualitative and quantitative assessment of human gall bladder bile in vivo. Spectral profiles in vivo are shown in relation to model and porcine gall bladder bile and the quantitation in man of the trimethylamine (choline) and lecithin concentrations were estimated to range from 25.9 mM to 48.4 mM (mean: 35.8 mM, standard deviation: 9.8). The composition of human gall bladder bile together with the quantitation of various constituents can be studied non-invasively in vivo.