Anterior Cingulate Cortex Glutamate Research Articles

SA83. Brain Glutamate Levels and Antipsychotic Response in Schizophrenia

Background: There is considerable interest in identifying biomarkers of antipsychotic response in schizophrenia, and brain glutamate is one key candidate. Methods: In a series of 1H-MRS studies, we have investigated the relationship between brain glutamate and antipsychotic response. This includes cross-sectional studies in patients with early psychosis,1 and chronic schizophrenia.2,3 Longitudinally, within the OPTiMiSE consortium, we examined whether glutamate levels in first-episode psychosis (FEP; n = 72, <2 weeks antipsychotic medication) predict psychopathology after subsequent administration of oral amisulpride for 4 weeks. Finally, in an ongoing study in treatment-resistant schizophrenia, we investigate whether glutamate levels prior to clozapine initiation predict the degree of symptomatic response after 12 weeks of clozapine treatment. Results: The cross-sectional study in early psychosis1 found elevated glutamate in the anterior cingulate cortex (ACC) in patients who had reached remission compared to those who had not (T(30) = 3.02; P = .005). ACC glutamate level was positively associated with the severity of negative symptoms (r = .42; P = .017) and negatively associated with of global functioning (r = .47; P = .007). Our first cross-sectional study in chronic schizophrenia2 detected an elevation in ACC glutamate in treatment-resistant schizophrenia (TRS) compared to healthy volunteers (T(14) = 2.80, P = 0.01), which was not apparent in treatment responders (T(16) = 0.29, P = .77). The subsequent larger study3 found higher ACC glutamate levels in TRS than in treatment-responsive patients (T(35) = 2.34, P = .025). In the OPTiMiSE FEP cohort at baseline (prior to amisulpride treatment), ACC glutamate was positively correlated with the PANSS general score (r = .26; P = .03) and negatively correlated with the personal and social performance (PSP) score, (r = −.34; P = .006). Baseline glutamate in the ACC (r = −.38; P = .004) and thalamus (r = −.42; P = .003) were negatively correlated with PSP score after 4 weeks amisulpride. Baseline thalamic glutamate negatively correlated with the longitudinal reduction in the PANSS positive (r = −.35; P = .009) and total (r = −.28; P = .04) scores after 4 weeks amisulpride. An interim update on the ongoing clozapine study will also be provided. Conclusion: This series of studies has returned consistent findings that elevated ACC glutamate is associated with poor response to antipsychotics, more severe symptoms, and social dysfunction. Brain glutamate may relate to the magnitude of response to subsequent antipsychotic treatment.

Fronto-Striatal Glutamate in Autism Spectrum Disorder and Obsessive Compulsive Disorder.

Autism spectrum disorders (ASDs) and obsessive compulsive disorder (OCD) are often comorbid with the overlap based on compulsive behaviors. Although previous studies suggest glutamatergic deficits in fronto-striatal brain areas in both disorders, this is the first study to directly compare the glutamate concentrations across the two disorders with those in healthy control participants using both categorical and dimensional approaches. In the current multi-center study (four centers), we used proton magnetic resonance spectroscopy in 51 children with ASD, 29 with OCD, and 53 healthy controls (aged 8-13 years) to investigate glutamate (Glu) concentrations in two regions of the fronto-striatal circuit: midline anterior cingulate cortex (ACC) and left dorsal striatum. Spectra were processed with Linear Combination Model. Group comparisons were performed with one-way analyses of variance including sex, medication use, and scanner site as covariates. In addition, a dimensional analysis was performed, linking glutamate with a continuous measure of compulsivity across disorders. There was a main group effect for ACC glutamate (p=0.019). Contrast analyses showed increased glutamate both in children with ASD and OCD compared with controls (p=0.007), but no differences between the two disorders (p=0.770). Dimensional analyses revealed a positive correlation between compulsive behavior (measured with the Repetitive Behavior Scale) and ACC glutamate (rho=0.24, p=0.03). These findings were robust across sites. No differences were found in the striatum. The current findings confirm overlap between ASD and OCD in terms of glutamate involvement. Glutamate concentration in ACC seems to be associated with the severity of compulsive behavior.

Fronto-striatal glutamate in children with Tourette's disorder and attention-deficit/hyperactivity disorder.

ObjectiveBoth Tourette's disorder (TD) and attention-deficit/hyperactivity disorder (ADHD) have been related to abnormalities in glutamatergic neurochemistry in the fronto-striatal circuitry. TD and ADHD often co-occur and the neural underpinnings of this co-occurrence have been insufficiently investigated in prior studies.MethodWe used proton magnetic resonance spectroscopy (1H-MRS) in children between 8 and 12 years of age (TD n = 15, ADHD n = 39, TD + ADHD n = 29, and healthy controls n = 53) as an in vivo method of evaluating glutamate concentrations in the fronto-striatal circuit. Spectra were collected on a 3 Tesla Siemens scanner from two voxels in each participant: the anterior cingulate cortex (ACC) and the left dorsal striatum. LC-model was used to process spectra and generate glutamate concentrations in institutional units. A one-way analysis of variance was performed to determine significant effects of diagnostic group on glutamate concentrations.ResultsWe did not find any group differences in glutamate concentrations in either the ACC (F(3132) = 0.97, p = 0.41) or striatum (F(3121) = 0.59, p = 0.62). Furthermore, variation in glutamate concentration in these regions was unrelated to age, sex, medication use, IQ, tic, or ADHD severity. Obsessive–compulsive (OC) symptoms were positively correlated with ACC glutamate concentration within the participants with TD (rho = 0.35, puncorrected = 0.02).ConclusionWe found no evidence for glutamatergic neuropathology in TD or ADHD within the fronto-striatal circuits. However, the correlation of OC-symptoms with ACC glutamate concentrations suggests that altered glutamatergic transmission is involved in OC-symptoms within TD, but this needs further investigation.

Temporal Dynamics of Antidepressant Ketamine Effects on Glutamine Cycling Follow Regional Fingerprints of AMPA and NMDA Receptor Densities.

The anterior cingulate cortex (ACC) has shown decreased glutamate levels in patients with major depressive disorder. Subanesthetic doses of ketamine were repeatedly shown to improve depressive symptoms within 24 h after infusion and this antidepressant effect was attributed to increased α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) throughput. To elucidate ketamine's mechanism of action, we tested whether the clinical time course of the improvement is mirrored by the change of glutamine/glutamate ratio and if such effects show a regional and temporal specificity in two distinct subdivisions of ACC with different AMPA/N-methyl-D-aspartate receptor profiles. In a double-blind, placebo-controlled intravenous infusion study of ketamine, we measured glutamate and glutamine in the pregenual ACC (pgACC) and the anterior midcingulate cortex at 1 and 24 h post infusion with magnetic resonance spectroscopy at 7 T. A significant interaction of time, region, and treatment was found for the glutamine/glutamate ratios (placebo, n=14; ketamine, n=12). Post-hoc analyses revealed that the glutamine/glutamate ratio increased significantly in the ketamine group, compared with placebo, specifically in the pgACC after 24 h. The glutamine/glutamate increase in the pgACC caused by ketamine at 24 h post infusion was reproduced in an enlarged sample (placebo, n=24; ketamine, n=20). Our results support a significant temporal and regional response in glutamine/glutamate ratios to a single subanesthetic dose of ketamine, which mirrors the time course of the antidepressant response and reversal of the molecular deficits in patients and which may be associated with the histoarchitectonical receptor fingerprints of the ACC subregions.

Age-related changes in anterior cingulate cortex glutamate in schizophrenia: A 1H MRS Study at 7 Tesla

The extent of age-related changes in glutamate and other neurometabolites in the anterior cingulate cortex (ACC) in individuals with schizophrenia remain unclear. Magnetic resonance spectroscopy (MRS) at 7T, which yields precise measurements of various metabolites and can distinguish glutamate from glutamine, was used to determine levels of ACC glutamate and other metabolites in 24 individuals with schizophrenia and 24 matched controls. Multiple regression analysis revealed that ACC glutamate decreased with age in patients but not controls. No changes were detected in levels of glutamine, N-acetylaspartate, N-acetylaspartylglutamic acid, myo-inositol, GABA, glutathione, total creatine, and total choline. These results suggest that age may be an important modifier of ACC glutamate in schizophrenia.

A combined diffusion tensor imaging and magnetic resonance spectroscopy study of patients with schizophrenia

Diffusion tensor imaging (DTI) studies in schizophrenia consistently show global reductions in fractional anisotropy (FA), a putative marker of white matter integrity. The cingulum bundle, which facilitates communication between the anterior cingulate cortex (ACC) and hippocampus, is frequently implicated in schizophrenia. Magnetic resonance spectroscopy (MRS) studies report metabolic abnormalities in the ACC and hippocampus of patients. Combining DTI and MRS offers exploration of the relationship between cortical neuronal biochemistry and the integrity of white matter tracts connecting specific cortical regions; however, few studies have attempted this in schizophrenia. Twenty-nine schizophrenia patients and twenty controls participated in this 3 T imaging study in which we used DTI and tract-based spatial statistics (TBSS) to assess white matter integrity and MRS to quantify metabolites in the ACC and hippocampus. We found FA reductions with overlapping radial diffusivity (RD) elevations in patients in multiple tracts, suggesting white matter abnormalities in schizophrenia are driven by loss of myelin integrity. In controls, we found significant negative correlations between hippocampal N-acetylaspartate/creatine and RD and axial diffusivity (AD) as well as a significant negative correlation between FA and ACC glutamate+glutamine/creatine in the hippocampal part of the cingulum bundle. It is possible that the extent of myelin damage could have resulted in the absence of DTI–MRS correlations in our patient group. In conclusion, we demonstrate the potential utility of a multi-modal neuroimaging approach to help further our understanding of the relationship between white matter microstructure and neurochemistry in distinct cortical regions connected by white matter tracts.

Treatment-Resistant Schizophrenia Patients Show Elevated Anterior Cingulate Cortex Glutamate Compared to Treatment-Responsive.

Resistance to antipsychotic treatment is a significant clinical problem in patients with schizophrenia with approximately 1 in 3 showing limited or no response to repeated treatments with antipsychotic medication. The neurobiological basis for treatment resistance is unknown but recent evidence implicates glutamatergic function in the anterior cingulate cortex. We examined glutamate levels of chronically ill treatment-resistant patients directly compared to treatment-responsive patients. We acquired proton magnetic resonance spectroscopy (1H-MRS) at 3 Tesla from 21 treatment-resistant and 20 treatment-responsive patients. All participants had a DSM-IV diagnosis of schizophrenia. Treatment-resistant patients were classified using the modified Kane criteria. The groups were matched for age, sex, smoking status, and illness duration. Glutamate to creatine ratio levels were higher in treatment-resistant patients (Mean [SD] = 1.57 [0.24]) than in treatment-responsive patients (Mean[SD] = 1.38 [0.23]), (T[35] = 2.34, P = .025, 2-tailed), with a large effect size of d = 0.76. A model assuming 2 populations showed a 25% improvement in the fit of the Akaike weights (0.55) over a model assuming 1 population (0.44), producing group values almost identical to actual group means. Increased anterior cingulate glutamate level is associated with treatment-resistant schizophrenia. This appears to be a stable neurobiological trait of treatment-resistant patients. We discuss possible explanations for glutamatergic dysfunction playing a significant role in resistance to conventional antipsychotic treatments, which are all dopamine-2 receptor blockers. Our findings suggest that glutamatergic treatments may be particularly effective in resistant patients and that 1H-MRS glutamate indices can potentially have clinical use.

A Longitudinal (6-week) 3T 1H-MRS Study on the Effects of Lithium Treatment on Anterior Cingulate Cortex Metabolites in Bipolar Depression

The anterior cingulate cortex (ACC) is a key area in mood regulation. To date, no longitudinal study has specifically evaluated lithium׳s effects on ACC metabolites using 1H-MRS, as well as its association with clinical improvement in bipolar depression. This 1H-MRS (TE=35ms) study evaluated 24 drug-free BD patients during depressive episodes and after lithium treatment at therapeutic levels. Brain metabolite levels (N-acetyl aspartate (NAA), creatine (tCr), choline, myo-inositol, and glutamate levels) were measured in the ACC at baseline (week 0) and after lithium monotherapy (week 6). The present investigation showed that ACC glutamate (Glu/tCr) and glutamate+glutamine (Glx/tCr) significantly increased after six weeks of lithium therapy. Regarding the association with clinical improvement, remitters showed an increase in myoinositol levels (mI/tCr) after lithium treatment compared to non-remitters. The present findings reinforce a role for ACC glutamate-glutamine cycling and myoinositol pathway as key targets for lithium׳s therapeutic effects in BD.

Cross-sectional Study of Glutamate in the Anterior Cingulate and Hippocampus in Schizophrenia.

There has been growing support for dysfunctions of the excitatory glutamatergic system and its implications for the psychophysiology of schizophrenia. However, previous studies reported mixed results regarding glutamate concentrations in schizophrenia with varying deviations across brain regions. We used an optimized proton magnetic resonance spectroscopy procedure to measure absolute glutamate concentrations in the left hippocampal region and the anterior cingulate cortex (ACC) in 29 medicated patients with schizophrenia and in 29 control participants without mental disorder. The glutamate concentrations were significantly lower in the ACC but higher in the hippocampus of patients compared to controls. ACC and hippocampal glutamate concentrations correlated positively in patients but not in controls. ACC glutamate was weakly associated with Clinical Global Impression score and duration of illness in patients. Glutamate concentrations in schizophrenia deviate from controls and show associations with disease severity. A higher concentration of hippocampal glutamate in schizophrenia compared to controls is shown. The association between ACC and hippocampus glutamate concentrations in patients with schizophrenia suggests an abnormal coupling of excitatory systems compared to controls as predicted by previous glutamate models of schizophrenia.

Vitamin D3 Supplemental Treatment for Mania in Youth with Bipolar Spectrum Disorders.

We aimed to determine the effect of an open-label 8 week Vitamin D3 supplementation on manic symptoms, anterior cingulate cortex (ACC) glutamate, and γ-aminobutyric acid (GABA) in youth exhibiting symptoms of mania; that is, patients with bipolar spectrum disorders (BSD). We hypothesized that an 8 week Vitamin D3 supplementation would improve symptoms of mania, decrease ACC glutamate, and increase ACC GABA in BSD patients. Single time point metabolite levels were also evaluated in typically developing children (TD). The BSD group included patients not only diagnosed with BD but also those exhibiting bipolar symptomology, including BD not otherwise specified (BD-NOS) and subthreshold mood ratings (Young Mania Rating Scale [YMRS] ≥8 and Clinical Global Impressions - Severity [CGI-S] ≥3). Inclusion criteria were: male or female participants, 6-17 years old. Sixteen youth with BSD exhibiting manic symptoms and 19 TD were included. BSD patients were asked to a take daily dose (2000 IU) of Vitamin D3 (for 8 weeks) as a supplement. Neuroimaging data were acquired in both groups at baseline, and also for the BSD group at the end of 8 week Vitamin D3 supplementation. Baseline ACC GABA/creatine (Cr) was lower in BSD than in TD (F[1,31]=8.91, p=0.007). Following an 8 week Vitamin D3 supplementation, in BSD patients, there was a significant decrease in YMRS scores (t=-3.66, p=0.002, df=15) and Children's Depression Rating Scale (CDRS) scores (t=-2.93, p=0.01, df=15); and a significant increase in ACC GABA (t=3.18, p=0.007, df=14). Following an 8 week open label trial with Vitamin D3, BSD patients exhibited improvement in their mood symptoms in conjunction with their brain neurochemistry.

Relationship between brain glutamate levels and clinical outcome in individuals at ultra high risk of psychosis.

Alterations in brain glutamate levels may be associated with psychosis risk, but the relationship to clinical outcome in at-risk individuals is unknown. Glutamate concentration was measured in the left thalamus and anterior cingulate cortex (ACC) using 3-Tesla proton magnetic resonance spectroscopy in 75 participants at ultra high risk (UHR) of psychosis and 56 healthy controls. The severity of attenuated positive symptoms and overall functioning were assessed. Measures were repeated in 51 UHR and 33 Control subjects after a mean of 18 months. UHR subjects were allocated to either remission (no longer meeting UHR criteria) or non-remission (meeting UHR or psychosis criteria) status on follow-up assessment. Thalamic glutamate levels at presentation were lower in the UHR non-remission (N=29) compared with the remission group (N=22) (t(49)=3.03; P=0.004), and were associated with an increase in the severity of total positive symptoms over time (r=-0.33; df=47; P=0.02), most notably abnormal thought content (r=-0.442; df=47; P=0.003). In the UHR group, ACC glutamate levels were lower at follow-up compared with baseline (F(80)=4.28; P=0.04). These findings suggest that measures of brain glutamate function may be useful as predictors of clinical outcome in individuals at high risk of psychosis.

Altered Anterior Cingulate Neurochemistry in Emerging Adult Binge Drinkers with a History of Alcohol‐Induced Blackouts

Binge alcohol consumption is associated with multiple neurobiological consequences, including altered neurophysiology, brain structure, and functional activation. Magnetic resonance spectroscopy (MRS) studies have demonstrated neurochemical alterations in the frontal lobe of alcohol users, although most studies focused on older, alcohol-dependent subjects. In this study, neurochemical data were acquired using MRS at 4.0 Tesla from emerging adults (18 to 24 years old) who were binge alcohol drinkers (BD, n = 23) or light drinkers (LD, n = 31). Since binge drinking is also associated with increased prevalence of experiencing an alcohol-induced blackout, BD were stratified into alcohol-induced blackout (BDBO) and non-blackout (BDN) groups. Overall, BD had significantly lower gamma amino-butyric acid (GABA) and N-acetyl-aspartate (NAA) in the anterior cingulate cortex (ACC) than LD. When stratified by blackout history, BDBO also had lower ACC glutamate (Glu) than LD. No group differences in MRS metabolites were observed in the parietal-occipital cortex. Lower ACC GABA and Glu remained significant after accounting for lower gray matter content in BD, however, NAA differences were no longer evident. In addition, low ACC GABA levels were associated with greater alcohol use consequences, and worse response inhibition and attention/mental flexibility in BD. These data indicate that binge drinking affects frontal lobe neurochemistry, more so in those who had experienced an alcohol-induced blackout. Characterization of the neurochemical profiles associated with binge alcohol consumption and blackout history may help identify unique risk factors for the later manifestation of alcohol abuse and dependence, in young individuals who are heavy, frequent drinkers, but who do not meet the criteria for alcohol abuse disorders.

114. Inflammation induced changes in Anterior Cingulate Cortex Glutamate is associated with Depression and Fatigue

Behavioral symptoms including depression and fatigue are well-known consequences of activated peripheral immunity. Increased glutamate turnover in mood-regulating brain regions targeted by inflammatory mediators such as cytokines might mediate this relationship. We used single voxel proton magnetic resonance spectroscopy (MRS) to quantify glutamate concentrations in the anterior cingulate cortex (ACC) before and after four weeks of exposure to interferon (IFN)-alpha. IFN-alpha is an inflammatory cytokine used in the treatment of hepatitis C virus (HCV) infection that is known to cause depression and fatigue up to 50% of patients depending on the dose. Sixteen HCV patients underwent MRS scans, behavior ratings and immune marker assessments before and after 4 weeks of IFN-alpha treatment. Fourteen HCV control patients awaiting IFN-alpha therapy were studied in parallel. IFN-alpha administration was associated with significant increases in glutamate concentrations measured as glutamate/creatine (Glu/Cr) ratios in the ACC. Increases in the Glu/Cr ratio in the ACC was in turn correlated with increases in plasma soluble tumor necrosis factor 2 receptor (r = 0.54, p < 0.002), depression (r = 0.53, p < 0.003) and fatigue (r = 0.41, p < 0.03). The above findings are consistent with previously reported changes in ACC function among HCV patients following IFN-alpha treatment and among healthy volunteers administered immune stimuli including typhoid vaccination. These data suggest that altered glutamate metabolism as a result of impaired glial function may contribute to ACC changes following immune activation.

Glutamate normalization with ECT treatment response in major depression

Though psychotherapy, medications and brain stimulation are used to treat major depressive disorder (MDD), treatment response depends on several individualized clinical factors and frequently requires multiple treatment trials. To guide more effective personalized interventions, there is thus a need to identify biological markers to elucidate the mechanisms of response to predict treatment outcomes in MDD. Prior evidence suggests neurochemical disturbances in mood regulating networks, including the anterior cingulate cortex (ACC) and connected prefrontal and subcortical centers, contribute to MDD and play a role in treatment response1–4. To identify treatment-related changes in neurochemical markers implicated in MDD2, 4, 5, we applied single-voxel Proton Magnetic Resonance Spectroscopy (1HMRS) for cross sectional and longitudinal analysis of ACC glutamate (Glu), choline (Cho) and N-acetyl aspartate (NAA) in 10 patients with DSM-IVR diagnoses of MDD (mean age: 44.0 years, 7.93 SD; 6 females) followed prospectively during Index treatment and 10 demographically similar controls (mean age: 39.03 years, 9.55 SD; 6 females). Electroconvulsive therapy (ECT) was used as the therapeutic modality since it is a highly effective procedure for treating severe MDD that elicits rapid response in eligible individuals6. Patients were assessed at three time points: baseline, and after the 2nd and 6th ECT sessions, corresponding to ~48 hrs and 2 weeks post treatment initiation (see Supplementary Information (SI) for clinical details). The Hamilton (HAMD) and Montgomery-Asberg (MADRS) Depression Rating Scales recorded therapeutic response. Controls were assessed twice, ~2-weeks apart, to determine disease effects, normative values and to estimate the variance of serial scanning. All subjects, without neurological disorders, alcohol/substance abuse or dementia, provided UCLA Institutional Review Board-approved informed consent. High-resolution T1-weighted MPRAGE structural (FOV: 256; voxel size: 1 mm3; TR/TE: 2200/5.16 ms; flip angle: 12°) and single-voxel Point Resolved Spectroscopy (PRESS) acquisitions (TR/TE: 2000/30 ms; spectral width 2000 Hz; 1024 points) with (128 averages) and without water suppression (8 averages) were collected on a Siemens 3T Allegra system. Automatic and manual 3D shimming was applied to reduce B0 inhomogeneity for voxels (20×18×12 mm3) placed in midline anterior ACC gray matter [Fig 1A; see SI]. LCModel computed the levels of Glu, Cho and NAA relative to the unsuppressed water signal. Derived metabolites levels were corrected for voxel CSF content using corresponding tissue classified T1-weighted images7. Figure 1 A) Voxel placement and 1HMRS spectra in a single subject, B) Mean CSF-adjusted glutamate (left), NAA (middle) and choline (right) levels at each time point in patients and controls indicating significant disease effects (purple), group by time interactions ... Metabolites (with variances 0.50). For baseline comparisons, including age and gender as covariates, main effects of diagnosis were observed for Glu only, F(1,19)=8.61, p<.01 (lower in patients). General Linear Mixed Models (GLMMs) including metabolites from each time point and a subject variable to control for within-subject correlations, also showed a significant diagnosis by time interaction for Glu, F(1, 21.98)=4.94, p<.037. Glu levels increased significantly over time in patients approximating normal levels, F(2, 16.56)=4.05, p<.037, but remained stable in controls (p=.47). In patients, subsequent pairwise comparisons showed significant Glu elevations between baseline and the 6th ECT, p<.018. In the absence of overall effects of time, pairwise comparisons in patients also showed significant decreases in NAA, p<.048, and increases in Cho, p<.047 between baseline and the 6th ECT [Fig 1B]. HAMD and MADRS scores improved significantly with treatment, F(2, 16.67)=29.48 and F(2, 13.12)=19.79, both p<.0001. Variations in Glu correlated with MADRS scores across time, F(1, 15.78)=4.49, p<.05. Baseline Cho levels correlated significantly with overall change in HAMD ratings, r=.85, p<.0001; baseline Glu levels also showed a trend for predicting HAMD change, r=.59, p<.08 [Fig 1C]. MDD-related reductions in ACC glutamate normalize with ECT treatment and associate with clinically determined therapeutic response. Results are in line with prior reports indicating glutamate deficits in MDD2, 4 and extend earlier observations of increased glutamate/glutamine (Glx) in the left ACC in patients treated with ECT8, shown here to also mirror clinical response. NAA and Choline, though not discriminating diagnostic groups at baseline, also showed treatment effects in patients. Together, these neurochemical changes suggest treatment-induced neuroplasticity in the structure, density and integrity of mature neurons9 and/or may reflect changes relating to adult neurogenesis in connected hippocampal and subventricular regions10. Results also support that neurochemical signatures in the ACC may predict future therapeutic response through mechanisms potentially overlapping with other forms of treatment. Studies including additional treatment modalities, larger samples, and longer follow-ups with relapse rates may confirm these observations.

Ketamine effects on brain GABA and glutamate levels with 1H-MRS: relationship to ketamine-induced psychopathology

Preclinical studies suggest that ketamine-induced psychopathology is mediated, in part, by increased glutamate release, hypothesized to occur via inhibition of GABAergic interneurons. Using proton magnetic resonance spectroscopy (1H-MRS), we tested this hypothesis in healthy humans. Ketamine increased anterior cingulate cortex glutamate levels, which correlated with the degree of positive psychotic symptoms. Ketamine did not affect subcortical gamma-aminobutyric acid (GABA) levels.

Associations between anterior cingulate cortex glutamate and γ-aminobutyric acid concentrations and the harm avoidance temperament

Converging lines of evidence have suggested that the personality traits might have neurobiological underpinnings. The anterior cingulate cortex (ACC) has been implicated to play an important role in the human fear and anxiety. Functional and structural characteristics of ACC have been suggested to be associated with the harm avoidance (HA) temperament, one of the important temperament dimensions. Therefore, we aimed to investigate correlations between neurometabolite concentrations in ACC, specifically glutamate and γ-aminobutyric acid (GABA), which are major excitatory and inhibitory neurotransmitters, respectively, and HA scores. Neurometabolite concentrations were measured using high resolution single voxel proton magnetic resonance spectroscopy ( 1H-MRS), and the HA temperament was evaluated using the Temperament and Character Inventory (TCI). Correlations between HA scores from 37 participants (21 men/16 women, age of 30.3 ± 7.0) and glutamate and GABA concentrations in the mid-ACC region were evaluated. HA scores correlated negatively with glutamate concentrations in ACC (partial correlation, R = −0.54, df = 33, P = 0.001) and positively with GABA concentrations in ACC (partial correlation, R = 0.48, df = 30, P = 0.005). These findings suggest that glutamate and GABA concentrations in ACC are closely related to levels of the HA temperament in healthy subjects.

Association between cerebral glutamate and human behaviour: The sensation seeking personality trait

Introduction: Brain imaging studies have linked the anterior cingulate cortex (ACC) to motivation, drive, and personality traits like novelty and sensation seeking. Animal studies have shown glutamatergic neurotransmission to be important in ACC function as well as motivated behaviour. However, the role of glutamate in related personality traits like sensation seeking has not been investigated in humans. Methods: The associations between sensation seeking personality scores and absolute glutamate concentrations in the ACC and the hippocampal region measured by 3-Tesla proton magnetic resonance spectroscopy (1H-MRS) were investigated. Results: ACC glutamate concentration was negatively correlated with the sensation seeking sum score and the experience seeking subscore. A weak negative correlation was also observed between the hippocampal glutamate and the sensation seeking sum score. The reexamination of the glutamate concentration after 4 weeks revealed a similar relationship with sensation seeking. Discussion: Although preliminary, the results are in line with the key role of the ACC for motivation and executive control and with the impact of glutamate on novelty related behaviour observed in animal experiments. The role of the hippocampus for novelty processing is discussed. Glutamate measurement with 1H-MRS may facilitate the understanding of biological underpinnings of personality traits and psychiatric diseases associated with dysfunctions in motivation and drive.

Topiramate raises anterior cingulate cortex glutamine levels in healthy men; a 4.0 T magnetic resonance spectroscopy study

Potential mechanisms of action of topiramate include alterations of glutamatergic and GABAergic systems. In particular, topiramate has been shown to increase occipital cortex GABA levels, as measured using proton magnetic resonance spectroscopy (MRS). The purpose of this study was to measure the effect of acute oral topiramate on the GABA precursors glutamate and glutamine in the anterior cingulate cortex (ACC) and occipital lobe (OL) using high-field (4.0 T) proton MRS (1H MRS). Proton MR spectra were acquired from healthy men at three times: at baseline and 2 and 6 h after ingesting 50 (N=5) or 100 mg (N=5) of topiramate. Blood samples were acquired prior to each scan for the purpose of obtaining serum topiramate levels. A 100-mg dose of topiramate significantly increased ACC glutamine levels within 2 h of ingestion and OL glutamine levels within 6 h of ingestion. There were no measured significant effects of topiramate on ACC or OL glutamate levels. A 100-mg dose of oral topiramate increased serum topiramate and ACC glutamine levels within 2 h. OL glutamine levels increased within 6 h. Increased brain glutamine levels may be a consequence of topiramate positively modulating GABAA receptors. This result is of interest given the possible role for topiramate in the treatment of epilepsy, migraine headache, bipolar disorder, eating disorders, and alcohol dependence.

Morphine decreases extracellular levels of glutamate in the anterior cingulate cortex: an in vivo microdialysis study in freely moving rats

In the present study, we investigated the effect of morphine on the extracellular levels of glutamate in the anterior cingulate cortex (ACC) in freely moving rats using in vivo microdialysis coupled to high performance liquid chromatography and electrochemical detection. The results showed that either acute or chronic morphine treatment decreased the extracellular levels of glutamate in the ACC. Naloxone could reverse the decrease induced by chronic morphine treatment. The present study provided the first neurochemical evidence that morphine decreased extracellular levels of glutamate in the ACC, suggesting that glutamate in ACC is involved in the central actions of morphine.