Anterior Cingulate Cortex Glx Research Articles

Endocannabinoid levels in plasma and neurotransmitters in the brain: a preliminary report on patients with a psychotic disorder and healthy individuals.

Interactions between the endocannabinoid system (ECS) and neurotransmitter systems might mediate the risk of developing a schizophrenia spectrum disorder (SSD). Consequently, we investigated in patients with SSD and healthy controls (HC) the relations between (1) plasma concentrations of two prototypical endocannabinoids (N-arachidonoylethanolamine [anandamide] and 2-arachidonoylglycerol [2-AG]) and (2) striatal dopamine synthesis capacity (DSC), and glutamate and y-aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC). As anandamide and 2-AG might reduce the activity of these neurotransmitters, we hypothesized negative correlations between their plasma levels and the abovementioned neurotransmitters in both groups. Blood samples were obtained from 18 patients and 16 HC to measure anandamide and 2-AG plasma concentrations. For all subjects, we acquired proton magnetic resonance spectroscopy scans to assess Glx (i.e. glutamate plus glutamine) and GABA + (i.e. GABA plus macromolecules) concentrations in the ACC. Ten patients and 14 HC also underwent [18F]F-DOPA positron emission tomography for assessment of striatal DSC. Multiple linear regression analyses were used to investigate the relations between the outcome measures. A negative association between 2-AG plasma concentration and ACC Glx concentration was found in patients (p = 0.008). We found no evidence of other significant relationships between 2-AG or anandamide plasma concentrations and dopaminergic, glutamatergic, or GABAergic measures in either group. Our preliminary results suggest an association between peripheral 2-AG and ACC Glx levels in patients.

Anterior cingulate glutamate metabolites as a predictor of antipsychotic response in first episode psychosis: data from the STRATA collaboration

Elevated brain glutamate has been implicated in non-response to antipsychotic medication in schizophrenia. Biomarkers that can accurately predict antipsychotic non-response from the first episode of psychosis (FEP) could allow stratification of patients; for example, patients predicted not to respond to standard antipsychotics could be fast-tracked to clozapine. Using proton magnetic resonance spectroscopy (1H-MRS), we examined the ability of glutamate and Glx (glutamate plus glutamine) in the anterior cingulate cortex (ACC) and caudate to predict response to antipsychotic treatment. A total of 89 minimally medicated patients with FEP not meeting symptomatic criteria for remission were recruited across two study sites. 1H-MRS and clinical data were acquired at baseline, 2 and 6 weeks. Response was defined as >20% reduction in Positive and Negative Syndrome Scale (PANSS) Total score from baseline to 6 weeks. In the ACC, baseline glutamate and Glx were higher in Non-Responders and significantly predicted response (P < 0.02; n = 42). Overall accuracy was greatest for ACC Glx (69%) and increased to 75% when symptom severity at baseline was included in the model. Glutamate metabolites in the caudate were not associated with response, and there was no significant change in glutamate metabolites over time in either region. These results add to the evidence linking elevations in ACC glutamate metabolites to a poor antipsychotic response. They indicate that glutamate may have utility in predicting response during early treatment of first episode psychosis. Improvements in accuracy may be made by combining glutamate measures with other response biomarkers.

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

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

O2.2. EVALUATION OF THE RELATIONSHIP BETWEEN GLUTAMATE AND BRAIN CONNECTIVITY IN ANTIPSYCHOTIC-NAïVE FIRST EPISODE PATIENTS – A COMBINED MAGNETIC RESONANCE SPECTROSCOPY AND RESTING STATE FUNCTIONAL CONNECTIVITY MRI STUDY

BackgroundSchizophrenia is thought to be a disorder of brain dysconnectivity. An imbalance between cortical excitation/inhibition is also implicated, but the link between these abnormalities remains unclear. The present study used resting state functional connectivity MRI (rs-fcMRI) and magnetic resonance spectroscopy (MRS) to investigate how measurements of glutamate + glutamine (Glx) in the anterior cingulate cortex (ACC) relate to rs-fcMRI in medication-naïve first episode psychosis (FEP) subjects compared to healthy controls (HC). Based on our previous findings, we hypothesized that in HC would show correlations between Glx and rs-fMRI in the salience and default mode network, but these relationships would be altered in FEP.MethodsData from 53 HC (age = 24.70 ±6.23, 34M/19F) and 60 FEP (age = 24.08 ±6.29, 38M/22F) were analyzed. To obtain MRS data, a voxel was placed in the ACC (PRESS, TR/TE = 2000/80ms). Metabolite concentrations were quantified with respect to internal water using the AMARES algorithm in jMRUI. rs-fMRI data were processed using a standard preprocessing pipeline in the CONN toolbox. BOLD signal from a priori brain regions of interest from posterior cingulate cortex (default mode network, DMN), anterior cingulate cortex (salience network, SN), and right posterior parietal cortex (central executive network, CEN) were extracted and correlated with the rest of the brain to measure functional connectivity (FC). Group analyses were performed on Glx, FC, and Glx-FC interactions while controlling for age, gender, and motion when applicable. FC and Glx-FC analyses were performed using small volume correction [(p < 0.01, threshold-free cluster enhancement corrected (TFCE)].ResultsNo significant between-group differences were found in Glx concentration in the ACC [F(1, 108) = 0.34, p = 0.56], but reduced FC was found on each network in FEP compared to HC (pTFCE corrected). Group Glx-FC interactions were found in the form of positive correlations between Glx and FC in DMN and SN in the HC group, but not in FEP; and negative correlations in CEN in HC, but not in FEP.DiscussionWhile we did not find significant group differences in ACC Glx measurements, ACC Glx modulated FC differentially in FEP and HC. Positive correlations between Glx and FC were found in the SN and DMN, suggesting long range modulation of the two networks in HC, but not in FEP. Additionally, negative correlations between Glx and FC were found in CEN in HC, but not in FEP. Overall, these results suggest that even in the absence of group differences in Glx concentration, the long-range modulation of these 3 networks by ACC Glx is altered in FEP.

T19. GLUTAMATE AND RESPONSE TO CLOZAPINE IN TREATMENT RESISTANT SCHIZOPHRENIA

BackgroundThe mechanisms that underlie and may mediate the therapeutic response to clozapine in treatment resistant schizophrenia (TRS) are unclear. Basic science studies have indicated that clozapine may modulate brain glutamate, but this has not yet been investigated in man. The aim of this study was to determine whether clozapine alters brain glutamate levels in patients with TRS, and the associations with clinical outcome.MethodsThe study included patients with TRS who were about to start clozapine as part of their normal clinical care. Glutamate levels were measured in the anterior cingulate cortex (ACC) and right caudate nucleus using proton magnetic resonance spectroscopy (1H-MRS) before clozapine initiation (n=37) and again after 12-weeks of clozapine treatment (n=27). Symptoms were principally assessed using the PANSS. 1H-MRS scans were also acquired in a comparator group of healthy volunteers (n = 16).ResultsOver the 12 weeks of clozapine treatment there was a significant reduction in glutamate in the caudate (n = 22, F = 7.61 P < 0.05) but not in the ACC. The percentage reduction in caudate glutamate was positively associated with the percentage reduction in total PANSS score (n = 23, r = 0.42, P = 0.04). ACC Glx (glutamate plus glutamine) prior to clozapine initiation was higher in patients with TRS than in healthy volunteers (P=0.03).DiscussionImprovements in symptoms following clozapine initiation in TRS may be related to reductions in glutamate in the caudate nucleus. In contrast, ACC glutamate levels appear to remain high during the first three months of clozapine treatment.

Altered anterior cingulate glutamatergic metabolism in depressed adolescents with current suicidal ideation

The anterior cingulate cortex (ACC) is involved in emotion regulation and salience processing. Prior research has implicated ACC dysfunction in suicidal ideation (SI) and suicidal behavior. This study aimed to quantify ACC glutamatergic concentrations and to examine relationships with SI in a sample of healthy and depressed adolescents. Forty adolescents underwent clinical evaluation and proton magnetic resonance spectroscopy (1H-MRS) at 3 T, utilizing a 2-dimensional J-averaged PRESS sequence sampling a medial pregenual ACC voxel. Cerebrospinal fluid-corrected ACC metabolite concentrations were compared between healthy control (HC, n = 16), depressed without SI (Dep/SI−, n = 13), and depressed with SI (Dep/SI+, n = 11) youth using general linear models covarying for age, sex, and psychotropic medication use. Relationships between ACC metabolites and continuous measures of SI were examined using multiple linear regressions. ROC analysis was used to determine the ability of glutamate+glutamine (Glx) and the N-acetylaspartate (NAA)/Glx ratio to discriminate Dep/SI− and Dep/SI+ adolescents. Dep/SI+ adolescents had higher Glx than Dep/SI− participants (padj = 0.012) and had lower NAA/Glx than both Dep/SI− (padj = 0.002) and HC adolescents (padj = 0.039). There were significant relationships between SI intensity and Glx (pFDR = 0.026), SI severity and NAA/Glx (pFDR = 0.012), and SI intensity and NAA/Glx (pFDR = 0.004). ACC Glx and NAA/Glx discriminated Dep/SI− from Dep/SI+ participants. Uncoupled NAA−glutamatergic metabolism in the ACC may play a role in suicidal ideation and behavior. Longitudinal studies are needed to establish whether aberrant glutamatergic metabolism corresponds to acute or chronic suicide risk. Glutamatergic biomarkers may be promising targets for novel risk assessment and interventional strategies for suicidal ideation and behavior.

Intra-Regional Glu-GABA vs Inter-Regional Glu-Glu Imbalance: A 1H-MRS Study of the Neurochemistry of Auditory Verbal Hallucinations in Schizophrenia.

Glutamate (Glu), gamma amino-butyric acid (GABA), and excitatory/inhibitory (E/I) imbalance have inconsistently been implicated in the etiology of schizophrenia. Elevated Glu levels in language regions have been suggested to mediate auditory verbal hallucinations (AVH), the same regions previously associated with neuronal hyperactivity during AVHs. It is, however, not known whether alterations in Glu levels are accompanied by corresponding GABA alterations, nor is it known if Glu levels are affected in brain regions with known neuronal hypo-activity. Using magnetic resonance spectroscopy (MRS), we measured Glx (Glu+glutamine) and GABA+ levels in the anterior cingulate cortex (ACC), left and right superior temporal gyrus (STG), and left inferior frontal gyrus (IFG), in a sample of 77 schizophrenia patients and 77 healthy controls. Two MRS-protocols were used. Results showed a marginally significant positive correlation in the left STG between Glx and AVHs, whereas a significant negative correlation was found in the ACC. In addition, high-hallucinating patients as a group showed decreased ACC and increased left STG Glx levels compared to low-hallucinating patients, with the healthy controls in between the 2 hallucinating groups. No significant differences were found for GABA+ levels. It is discussed that reduced ACC Glx levels reflect an inability of AVH patients to cognitively inhibit their “voices” through neuronal hypo-activity, which in turn originates from increased left STG Glu levels and neuronal hyperactivity. A revised E/I-imbalance model is proposed where Glu-Glu imbalance between brain regions is emphasized rather than Glu-GABA imbalance within regions, for the understanding of the underlying neurochemistry of AVHs.

An MRI Study of the Metabolic and Structural Abnormalities in Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is a neuropsychiatric illness characterized by obsessions and/or compulsions. Its pathophysiology is still not well understood but it is known that the cortico-striatal-thalamic-cortical (CSTC) circuitry plays an important role. Here, we used a multi-method MRI approach combining proton magnetic resonance spectroscopy (H1-MRS) and diffusion tensor imaging (DTI) techniques to investigate both the metabolic and the microstructural white matter (WM) changes of the anterior cingulate cortex (ACC) in OCD patients as compared to healthy controls. Twenty-three OCD patients and 21 age-, sex-, and education-matched healthy volunteers participated in the study. Our 1H-MRS findings show increased levels of Glx in ACC in OCD. Further, significantly lower fractional anisotropy (FA) values were observed in OCD patients’ left cingulate bundle (CB) as compared to healthy controls. Finally, there was a negative correlation between FA in the left CB and level of obsessions, as well as the duration of the illness. Our findings reinforce the involvement of CSTC bundles in pathophysiology of OCD, pointing to a specific role of glutamate (glutamine) and WM integrity.

Delayed circadian phase is linked to glutamatergic functions in young people with affective disorders: a proton magnetic resonance spectroscopy study.

BackgroundWhile the association between affective disorders and sleep and circadian disturbance is well established, little is known about the neurobiology underpinning these relationships. In this study, we sought to determine the relationship between a marker of circadian rhythm and neuronal integrity (N-Acetyl Aspartate, NAA), oxidative stress (glutathione, GSH) and neuronal-glial dysfunction (Glutamate + Glutamine, Glx).MethodsFifty-three young adults (age range 15–33 years, mean = 21.8, sd = 4.3) with emerging affective disorders were recruited from a specialized tertiary referral service. Participants underwent clinical assessment and actigraphy monitoring, from which sleep midpoint was calculated as a marker of circadian rhythm. Proton magnetic resonance spectroscopy was performed in the anterior cingulate cortex (ACC). The metabolites NAA, GSH and Glx were obtained, and expressed as a ratio to Creatine.ResultsNeither NAA or GSH were associated with sleep midpoint. However, higher levels of ACC Glx were associated with later sleep midpoints (rho = 0.35, p = 0.013). This relationship appeared to be independent of age and depression severity.ConclusionsThis study is the first to demonstrate that delayed circadian phase is related to altered glutamatergic processes. It is aligned with animal research linking circadian rhythms with glutamatergic neurotransmission as well as clinical studies showing changes in glutamate with sleep interventions. Further studies may seek to examine the role of glutamate modulators for circadian misalignment.

The correlation between abnormal metabolism in anterior cingulum cortex and executive dysfunction with major depression patients before and after antidepressant treatment

Objective To investigate neuro-biochemical changes of bilateral anterior cingulate cortex (ACC) in the patients with major depressive disorder (MDD) and the correlation between abnormal metabolism and the cognitive function before and after treatment. Methods Fifteen patients with major depression and 15 age-, sex- and education-matched healthy controls (HC) were involved. The neurochemical abnormalities including the levels of N-acetylaspartate (NAA), choline-containing compounds, glutamate/glutamine and myoinostol were measured by single-voxel proton magnetic resonance spectroscopic (1H-MRS). The subjects were then assessed with executive function with neuropsychological tests including Wisconsin cards sorting test (WCST), verbal fluency Task (vF), StrooP Color and Word Test(SCWT). After this, the patients took selectivity serotonin reuptake inhibitors (SSRIs) for eight weeks. Then, we examined the changes in NAA, Cho, Glx and MI in ACC of patients and assessed their executive function with the neuropsychological tests again. Results 1) In ACC, baseline NAA((7.36±1.67)mmol/L), GLx((11.68±1.65)mmol/L) and MI levels ((5.28±0.66)mmol/L)were significantly lower in MDD compared to those of HC(NAA(9.27±1.37)mmol/L、Glx(15.20±1.91)mmol/L、MI(7.80±2.73)mmol/L)(P<0.01); After treatment, the NAA ((9.34±2.45)mmol/L)and Glx ((16.79±3.96)mmol/L)increased significantly after treatment compared to those prior to pretreatment(NAA(7.36±1.67)mmol/L, Glx(11.68±1.65)mmol/L, P<0.05).2) The normal controls exhibited better in Performance of WCST and Performance of completion time of SCWT than our MDD patients (P<0.05 or P<0.01). The patients made significant improvements in Performance of WCST and completion time of SCWT(C form) after treatment (P<0.05 or P<0.01). 3) In post-treatment MDD, the ACC Glx level was significantly positively correlated with the categories completes of WCST (r=0.739, P=0.009) and inversely related with the numbers to complete the first categories of WCST (r=-0.699, P=0.017) and the completion time of SCWT(C form) (r=-0.651, P=0.030); elevated MI(r=-0.705, P=0.023)and NAA(r=-0.735, P=0.010)levels in ACC of post-treatment MDD were both negatively correlated with the numbers to complete the first categories of WCST. Conclusion The ACC may be a key region involved in antidepressant treatment in MDD. The increased ACC NAA, Glx and MI in MDD after treatment may be significantly correlated with the improve of executive function. Key words: Major depressive disorder; Anterior cingutate; Magnetic resonance spectroscopy; Executive dysfunction

Reduced Anterior Cingulate Cortex Glutamatergic Concentrations in Childhood Major Depression

To examine in vivo glutamatergic neurochemical alterations in the anterior cingulate cortex of children with major depressive disorder (MDD). Single-voxel proton magnetic resonance spectroscopic (H-MRS) examinations of the anterior cingulate cortex were conducted in 13 psychotropic-naïve children and adolescents with MDD and 13 age- and sex-matched healthy children and adolescents. Ten of the 13 MDD patient-control pairs also had a H-MRS examination of occipital cortex. Anterior cingulate glutamatergic (Glx) concentrations were significantly lower (19% decrease) in MDD patients versus controls (9.27 +/- 0.43 versus 11.47 +/- 0.26, respectively, p = 0.000). Reduced anterior cingulate Glx in MDD patients was associated with increased severity of functional impairment. These results remained comparably significant after controlling for age and anterior cingulate volume. Occipital cortex Glx did not differ between MDD patients and controls. These preliminary findings provide new evidence of localized functional neurochemical marker alterations in Glx in anterior cingulate cortex in pediatric MDD. Altered anterior cingulate Glx neurotransmission may be involved in the pathogenesis of MDD.