Anterior Cingulate Cortex Glutamate Research Articles

Treatment resistance NMDA receptor pathway polygenic score is associated with brain glutamate in schizophrenia.

Dysfunction of glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia and may be particularly relevant in severe, treatment-resistant symptoms. The underlying mechanism may involve hypofunction of the NMDA receptor. We investigated whether schizophrenia-related pathway polygenic scores, composed of genetic variants within NMDA receptor encoding genes, are associated with cortical glutamate in schizophrenia. Anterior cingulate cortex (ACC) glutamate was measured in 70 participants across 4 research sites using Proton Magnetic Resonance Spectroscopy (1H-MRS). Two NMDA receptor gene sets were sourced from the Molecular Signatories Database and NMDA receptor pathway polygenic scores were constructed using PRSet. The NMDA receptor pathway polygenic scores were weighted by single nucleotide polymorphism (SNP) associations with treatment-resistant schizophrenia, and associations with ACC glutamate were tested. We then tested whether NMDA receptor pathway polygenic scores with SNPs weighted by associations with non-treatment-resistant schizophrenia were associated with ACC glutamate. A higher NMDA receptor complex pathway polygenic score was significantly associated with lower ACC glutamate (β=-0.25, 95% CI=-0.49, -0.02, competitive p=0.03). When SNPs were weighted by associations with non-treatment-resistant schizophrenia, there was no association between the NMDA receptor complex pathway polygenic score and ACC glutamate (β=0.05, 95% CI=-0.18, 0.27, competitive p=0.79). These results provide initial evidence of an association between common genetic variation implicated in NMDA receptor function and ACC glutamate levels in schizophrenia. This association was specific to when the NMDA receptor complex pathway polygenic score was weighted by SNP associations with treatment-resistant schizophrenia.

Association between increased anterior cingulate glutamate and psychotic-like experiences, but not autistic traits in healthy volunteers

Despite many differences, autism spectrum disorder and schizophrenia spectrum disorder share environmental risk factors, genetic predispositions as well as neuronal abnormalities, and show similar cognitive deficits in working memory, perspective taking, or response inhibition. These shared abnormalities are already present in subclinical traits of these disorders. The literature proposes that changes in the inhibitory GABAergic and the excitatory glutamatergic system could explain underlying neuronal commonalities and differences. Using magnetic resonance spectroscopy (1H-MRS), we investigated the associations between glutamate concentrations in the anterior cingulate cortex (ACC), the left/right putamen, and left/right dorsolateral prefrontal cortex and psychotic-like experiences (Schizotypal Personality Questionnaire) and autistic traits (Autism Spectrum Quotient) in 53 healthy individuals (26 women). To investigate the contributions of glutamate concentrations in different cortical regions to symptom expression and their interactions, we used linear regression analyses. We found that only glutamate concentration in the ACC predicted psychotic-like experiences, but not autistic traits. Supporting this finding, a binomial logistic regression predicting median-split high and low risk groups for psychotic-like experiences revealed ACC glutamate levels as a significant predictor for group membership. Taken together, this study provides evidence that glutamate levels in the ACC are specifically linked to the expression of psychotic-like experiences, and may be a potential candidate in identifying early risk individuals prone to developing psychotic-like experiences.

Glutamate levels of the right and left anterior cingulate cortex in autistics adults

BackgroundThe neurobiology of Autism Spectrum Disorder (ASD) is still unknown. Alteration in glutamate metabolism might translate into an imbalance of the excitation/inhibition equilibrium of cortical networks that in turn are related to autistic symptoms, but previous studies using voxel located in bilateral anterior cingulate cortex (ACC) failed to show abnormalities in total glutamate level. Due to the functional differences in the right and left ACC, we sought to determine whether a difference between right and left ACC glutamate levels could be found when comparing ASD patients and control subjects. MethodsUsing single-voxel proton magnetic resonance spectroscopy (1H-MRS), we analyzed the glutamate + glutamine (Glx) concentrations in the left and right ACC of 19 ASD patients with normal IQs and 25 matched control subjects. ResultsNo overall group differences in Glx were shown, in the left ACC (p = 0.24) or in the right ACC (p = 0.11). ConclusionsNo significant alterations in Glx levels were detected in the left and right ACC in high-functioning autistic adults. In the excitatory/inhibitory imbalance framework, our data reinforce the critical need to analyze the GABAergic pathway, for better understanding of basic neuropathology in autism.

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.

Glutamatergic Neurometabolite Levels in Bipolar Disorder: A Systematic Review and Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies

BackgroundThe glutamatergic system is thought to play an important role in the pathophysiology of bipolar disorder (BD). While there has been an increase in proton magnetic resonance spectroscopy studies examining this neurotransmission system, the results are inconsistent. Possible reasons for the inconsistency, including clinical features such as mood state and childhood versus adulthood age, were not addressed in previous meta-analyses. MethodsThis systematic review and meta-analysis of proton magnetic resonance spectroscopy studies of BD included 40 studies, with 1135 patients with BD and 964 healthy control (HC) subjects. ResultsGlutamate plus glutamine and glutamine levels in the anterior cingulate cortex of patients with BD were significantly elevated compared with those of HC subjects (standardized mean difference = 0.42, 0.48, respectively). Subgroup analyses showed that adult BD patients had significantly higher levels of glutamate plus glutamine than adult HC subjects, but this was not the case in pediatric patients. For mood states, anterior cingulate cortex glutamate plus glutamine levels were higher in patients with bipolar depression than those in HC subjects. ConclusionsOur results imply that glutamatergic dysfunction in the anterior cingulate cortex may be implicated in the pathophysiology of BD, which is most evident in adult BD patients and patients with bipolar depression.

Variants in the zinc transporter-3 encoding gene (SLC30A3) in schizophrenia and bipolar disorder: Effects on brain glutamate-A pilot study.

Zinc transporter 3 (ZnT3) has been implicated in the aetiopathology of schizophrenia. In this pilot study, we tested the hypothesis that the presence of a minor allele of two variants in the gene encoding ZnT3 (SLC30A3) affects brain glutamate and cognitive activity in patients with schizophrenia and bipolar affective disorder. Fifteen patients with schizophrenia (SCZ), 15 with bipolar affective disorder type 2 (BD), and 14 healthy volunteers (HV) were genotyped for two SLC30A3 single nucleotide polymorphisms (rs11126936 and rs11126929). They also underwent structural and functional MRI (n-back) imaging as well as static (PRESS) and functional magnetic resonance spectroscopy (n-back) on a 3 Tesla MRI system. SCZ with at least one copy of the minor allele showed reductions in dorsal anterior cingulate cortex glutamate during the n-back task, whereas SCZ without the minor allele showed an increase in glutamate. BD with the minor allele had reduced glutamate in the anterior cingulate cortex (p < 0.05). There was no effect of SLC30A3 genotype on BOLD activation during n-back or on cortical brain volume. This study supports the further investigation of SLC30A3 and its role in glutamatergic neurotransmission and in the neuropathology of mental illness.

The Relationships between Dopaminergic, Glutamatergic, and Cognitive Functioning in 22q11.2 Deletion Syndrome: A Cross-Sectional, Multimodal 1H-MRS and 18F-Fallypride PET Study.

Background: Individuals with 22q11.2 deletion syndrome (22q11DS) are at increased risk of developing psychosis and cognitive impairments, which may be related to dopaminergic and glutamatergic abnormalities. Therefore, in this exploratory study, we examined the association between dopaminergic and glutamatergic functioning in 22q11DS. Additionally, the associations between glutamatergic functioning and brain volumes in 22q11DS and healthy controls (HC), as well as those between dopaminergic and cognitive functioning in 22q11DS, were also examined. Methods: In this cross-sectional, multimodal imaging study, glutamate, glutamine, and their combined concentration (Glx) were assessed in the anterior cingulate cortex (ACC) and striatum in 17 22q11DS patients and 20 HC using 7T proton magnetic resonance spectroscopy. Ten 22q11DS patients also underwent 18F-fallypride positron emission tomography to measure dopamine D2/3 receptor (D2/3R) availability in the ACC and striatum. Cognitive performance was assessed with the Cambridge Neuropsychological Test Automated Battery. Results: No significant associations were found between ACC or striatal (1) glutamate, glutamine, or Glx concentrations and (2) D2/3R availability. In HC but not in 22q11DS patients, we found a significant relationship between ACC volume and ACC glutamate, glutamine, and Glx concentration. In addition, some aspects of cognitive functioning were significantly associated with D2/3R availability in 22q11DS. However, none of the associations remained significant after Bonferroni correction. Conclusions: Although our results did not reach statistical significance, our findings suggest an association between glutamatergic functioning and brain volume in HC but not in 22q11DS. Additionally, D2/3R availability seems to be related to cognitive functioning in 22q11DS. Studies in larger samples are needed to further elucidate our findings.

Impaired verbal memory function is related to anterior cingulate glutamate levels in schizophrenia: findings from the STRATA study

Impaired cognition is associated with lower quality of life and poor outcomes in schizophrenia. Brain glutamate may contribute to both clinical outcomes and cognition, but these relationships are not well-understood. We studied a multicentre cohort of 85 participants with non-affective psychosis using proton magnetic resonance spectroscopy. Glutamate neurometabolites were measured in the anterior cingulate cortex (ACC). Cognition was assessed using the Brief Assessment for Cognition in Schizophrenia (BACS). Patients were categorised as antipsychotic responders or non-responders based on treatment history and current symptom severity. Inverted U-shaped associations between glutamate or Glx (glutamate + glutamine) with BACS subscale and total scores were examined with regression analyses. We then tested for an interaction effect of the antipsychotic response group on the relationship between glutamate and cognition. ACC glutamate and Glx had a positive linear association with verbal memory after adjusting for age, sex and chlorpromazine equivalent dose (glutamate, β = 3.73, 95% CI = 1.26–6.20, P = 0.004; Glx, β = 3.38, 95% CI = 0.84–5.91, P = 0.01). This association did not differ between good and poor antipsychotic response groups. ACC glutamate was also positively associated with total BACS score (β = 3.12, 95% CI = 0.01–6.23, P = 0.046), but this was not significant after controlling for antipsychotic dose. Lower glutamatergic metabolites in the ACC were associated with worse verbal memory, and this relationship was independent of antipsychotic response. Further research on relationships between glutamate and cognition in antipsychotic responsive and non-responsive illness could aid the stratification of patient groups for targeted treatment interventions.

Anterior cingulate glutamate levels associate with functional activation and connectivity during sensory integration in schizophrenia: a multimodal 1H-MRS and fMRI study.

Glutamatergic dysfunction has been implicated in sensory integration deficits in schizophrenia, yet how glutamatergic function contributes to behavioural impairments and neural activities of sensory integration remains unknown. Fifty schizophrenia patients and 43 healthy controls completed behavioural assessments for sensory integration and underwent magnetic resonance spectroscopy (MRS) for measuring the anterior cingulate cortex (ACC) glutamate levels. The correlation between glutamate levels and behavioural sensory integration deficits was examined in each group. A subsample of 20 pairs of patients and controls further completed an audiovisual sensory integration functional magnetic resonance imaging (fMRI) task. Blood Oxygenation Level Dependent (BOLD) activation and task-dependent functional connectivity (FC) were assessed based on fMRI data. Full factorial analyses were performed to examine the Group-by-Glutamate Level interaction effects on fMRI measurements (group differences in correlation between glutamate levels and fMRI measurements) and the correlation between glutamate levels and fMRI measurements within each group. We found that schizophrenia patients exhibited impaired sensory integration which was positively correlated with ACC glutamate levels. Multimodal analyses showed significantly Group-by-Glutamate Level interaction effects on BOLD activation as well as task-dependent FC in a 'cortico-subcortical-cortical' network (including medial frontal gyrus, precuneus, ACC, middle cingulate gyrus, thalamus and caudate) with positive correlations in patients and negative in controls. Our findings indicate that ACC glutamate influences neural activities in a large-scale network during sensory integration, but the effects have opposite directionality between schizophrenia patients and healthy people. This implicates the crucial role of glutamatergic system in sensory integration processing in schizophrenia.

Investigating structural subdivisions of the anterior cingulate cortex in schizophrenia, with implications for treatment resistance and glutamatergic levels.

Background:Abnormalities in the anterior cingulate cortex (ACC) are thought to play an important role in the pathophysiology of schizophrenia. Given regional variations in ACC structure, the present study aimed to examine ACC structural subdivisions and their relationships to treatment resistance and glutamatergic levels in schizophrenia.Methods:This study included 100 patients with schizophrenia and 52 healthy controls from 2 cohorts. We applied non-negative matrix factorization to identify accurate and stable spatial components of ACC structure. Between groups, we compared ACC structural indices in each spatial component based on treatment resistance or response and tested relationships with ACC glutamate + glutamine levels.Results:We detected reductions in cortical thickness and increases in mean diffusivity in the spatial components on the surface of the cingulate sulcus, especially in patients with treatment-resistant and clozapine-resistant schizophrenia. Notably, mean diffusivity in these components was higher in patients who did not respond to clozapine compared to those who did. Furthermore, these ACC structural alterations were related to elevated ACC glutamate + glutamine levels but not related to symptomatology or antipsychotic dose.Limitations:Sample sizes, cross-sectional findings and mixed antipsychotic status were limitations of this study.Conclusion:This study identified reproducible abnormalities in ACC structures in patients with treatment-resistant and clozapine-resistant schizophrenia. Given that these spatial components play a role in inhibitory control, the present study strengthens the notion that glutamate-related disinhibition is a common biological feature of treatment resistance in schizophrenia.

A multimodal neuroimaging study investigating resting-state connectivity, glutamate and GABA at 7 T in first-episode psychosis.

Background:The major excitatory and inhibitory neurometabolites in the brain, glutamate and γ-aminobutyric acid (GABA), respectively, are related to the functional MRI signal. Disruption of resting-state functional MRI signals has been reported in psychosis spectrum disorders, but few studies have investigated the role of these metabolites in this context.Methods:We included 19 patients with first-episode psychosis and 21 healthy controls in this combined magnetic resonance spectroscopy (MRS) and resting-state functional connectivity study. All imaging was performed on a Siemens Magnetom 7 T MRI scanner. Both the MRS voxel and the seed for functional connectivity analysis were located in the dorsal anterior cingulate cortex (ACC). We used multiple regressions to test for an interaction between ACC brain connectivity, diagnosis and neurometabolites.Results:ACC brain connectivity was altered in first-episode psychosis. The relationship between ACC glutamate and ACC functional connectivity differed between patients with first-episode psychosis and healthy controls in the precuneus, retrosplenial cortex, supramarginal gyrus and angular gyrus. As well, the relationship between ACC GABA and ACC functional connectivity differed between groups in the caudate, putamen and supramarginal gyrus.Limitations:We used a small sample size. As well, although they were not chronically medicated, all participants were medicated during the study.Conclusion:We demonstrated a link between the major excitatory and inhibitory brain metabolites and resting-state functional connectivity in healthy participants, as well as an alteration in this relationship in patients with first-episode psychosis. Combining data from different imaging modalities may help our mechanistic understanding of the relationship between major neurometabolites and brain network dynamics, and shed light on the pathophysiology of first-episode psychosis.

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

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

Brain glutamate concentration in men with early psychosis: a magnetic resonance spectroscopy case\u2013control study at 7\u2009T

Abnormalities in glutamate neurotransmission are linked to psychotic symptoms and cognitive dysfunction in schizophrenia. magnetic resonance spectroscopy (MRS) provides an acceptable means of measuring glutamate in the human brain but findings from patient studies at conventional magnetic field strength show considerable heterogeneity. Ultra-high-field MRS offers greater precision in glutamate measurement, particularly in delineation of glutamate from its precursor and metabolite, glutamine. This study aimed to use high-field (7 T) MRS to measure concentrations of glutamate and glutamine in three brain regions, anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC) and putamen (PUT), in young men with early psychosis. MRS was performed in 17 male participants with early psychosis and 18 healthy age-matched controls. Neurometabolite levels were calculated with unsuppressed water signal as the reference and corrected for individual grey matter, white matter and cerebrospinal fluid concentration. Cognitive function was measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Compared to controls, patients with early psychosis had lower concentrations of glutamate and glutamine in ACC. No differences were apparent in the DLPFC and PUT. In patients with early psychosis, there was a highly significant correlation between glutamate concentration in ACC and performance on the BACS, though the numbers available for this analysis were small. Our finding of lower glutamate levels in ACC in patients with schizophrenia is consistent with a recent meta-analysis of 7 T studies and suggests that this abnormality is present in both patients with early psychosis and those with longer-established illness. The possible link between ACC glutamate and cognitive performance requires replication in larger studies.

Inflammatory Cytokines and Anterior Cingulate Cortex Glutamate in Adolescent Depression

Animal studies of stress and related conditions, including depression, have shown that elevated peripheral levels of inflammatory cytokines have downstream consequences on glutamate (Glu) in the brain. Although studies with depressed adults have reported evidence of higher inflammation but lower Glu in the anterior cingulate cortex (ACC), the extent to which peripheral inflammation contributes to glutamatergic abnormalities in adolescents with depression is not well understood. It is also unclear whether antioxidants, such as ascorbate (Asc), may buffer against the effects of inflammation on Glu metabolism.

Anterior Cingulate Cortex Glutamate Levels Are Related to Response to Initial Antipsychotic Treatment in Drug-Naive First-Episode Schizophrenia Patients.

The glutamatergic system has previously been shown to be involved in the pathophysiology of schizophrenia and the mechanisms of action of antipsychotic treatment. The present study aimed to investigate the relationship between the levels of glutamate (Glu) or Glu/total creatine (Glu/Cr+PCr) in the anterior cingulate cortex (ACC) and psychiatric symptoms as well as the response to antipsychotic treatment. We performed proton magnetic resonance spectroscopy (1H–MRS) to measure Glu and Glu/Cr+PCr in the ACC of 35 drug-naïve first-episode schizophrenia (FES) patients and 40 well-matched healthy controls (HCs). After scanning, we treated the patients with risperidone for eight weeks. Remission status was based on the Positive and Negative Syndrome Scale (PANSS) scores at week 8. At baseline, there were no significant differences in the levels of Glu or Glu/Cr+PCr in the ACC between drug-naïve FES patients and HCs. Lower baseline levels of Glu/Cr+PCr but not Glu in the ACC were associated with more severe negative symptoms of schizophrenia. Compared to the remission group (RM), the non-remission group (NRM) had lower baseline ACC Glu levels (P < 0.05). Our results suggest that ACC Glu levels may be related to the severity of symptoms in the early stages of schizophrenia and therefore may be a marker with which to evaluate the treatment effect of antipsychotics in schizophrenia patients.

Dopamine and Glutamate in Antipsychotic-Responsive Compared With Antipsychotic-Nonresponsive Psychosis: A Multicenter Positron Emission Tomography and Magnetic Resonance Spectroscopy Study (STRATA).

The variability in the response to antipsychotic medication in schizophrenia may reflect between-patient differences in neurobiology. Recent cross-sectional neuroimaging studies suggest that a poorer therapeutic response is associated with relatively normal striatal dopamine synthesis capacity but elevated anterior cingulate cortex (ACC) glutamate levels. We sought to test whether these measures can differentiate patients with psychosis who are antipsychotic responsive from those who are antipsychotic nonresponsive in a multicenter cross-sectional study. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure glutamate levels (Glucorr) in the ACC and in the right striatum in 92 patients across 4 sites (48 responders [R] and 44 nonresponders [NR]). In 54 patients at 2 sites (25 R and 29 NR), we additionally acquired 3,4-dihydroxy-6-[18F]fluoro-l-phenylalanine (18F-DOPA) positron emission tomography (PET) to index striatal dopamine function (Kicer, min−1). The mean ACC Glucorr was higher in the NR than the R group after adjustment for age and sex (F1,80 = 4.27; P = .04). This was associated with an area under the curve for the group discrimination of 0.59. There were no group differences in striatal dopamine function or striatal Glucorr. The results provide partial further support for a role of ACC glutamate, but not striatal dopamine synthesis, in determining the nature of the response to antipsychotic medication. The low discriminative accuracy might be improved in groups with greater clinical separation or increased in future studies that focus on the antipsychotic response at an earlier stage of the disorder and integrate other candidate predictive biomarkers. Greater harmonization of multicenter PET and 1H-MRS may also improve sensitivity.

Glutamatergic and GABAergic reactivity and cognition in 22q11.2 deletion syndrome and healthy volunteers: A randomized double-blind 7-Tesla pharmacological MRS study.

Aims:22q11.2 deletion syndrome (22q11.2DS) is associated with impaired cognitive functioning. Glutamatergic pathways have been linked with cognition and are hypothesized to be disrupted in 22q11.2DS patients, possibly ‘shifting’ the excitatory (glutamate)/inhibitory (GABA) balance. Hence, the glutamate/GABA balance may constitute a target for pharmacological treatment. We aimed to examine alterations of glutamate/GABA metabolites in 22q11.2DS in vivo using riluzole, a compound with glutamate/GABA-modulating action, as pharmacological challenge.Methods:Seventeen 22q11.2DS patients and 20 matched healthy controls were enrolled in this randomized double-blind placebo-controlled crossover study. Glutamate and glutamine concentrations in the anterior cingulate cortex (ACC) and striatum, as well as ACC GABA concentrations were obtained after placebo and after a single dose of 50 mg riluzole using 7-Tesla magnetic resonance spectroscopy (MRS). Within the 22q11.2DS group, the relationship between metabolite concentrations and cognition was examined.Results:No group differences were found in ACC and striatal metabolite concentrations following placebo. Riluzole numerically decreased ACC (η2 = 0.094) but not striatal glutamate concentrations as well as ACC GABA concentrations (η2 = 0.176) in all subjects. In both regions, riluzole did not alter glutamine concentration. No interaction effects were found. Although not significant after Bonferroni correction, ACC glutamate concentrations were inversely correlated with cognitive functions in 22q11.2DS patients.Discussion:We did not demonstrate altered ACC and striatal metabolite concentrations in 22q11.2DS. Nevertheless, these results suggest that glutamate and GABA can be modulated with a single dose of riluzole. Possibly, riluzole may have memory-enhancing effects in 22q11.2DS. Future studies should examine the long-term effects of riluzole on cognition.

O6.3. ASSOCIATIONS BETWEEN COGNITIVE FUNCTION AND CORTICAL LEVELS OF GLUTAMATE AND GABA IN ANTIPSYCHOTIC-NAïVE PATIENTS WITH SCHIZOPHRENIA OR PSYCHOSIS

BackgroundDysfunctional glutamatergic and gamma-aminobutyric acid (GABA)ergic neurotransmission may be part of the schizophrenia pathophysiology and underlie cognitive deficits. Abnormal levels of glutamate and GABA have been found in patients with first-episode psychosis or schizophrenia, and studies of mainly medicated patients have reported correlations between cortical glutamate and GABA levels and cognitive performance. However, the association between metabolites and cognitive deficits may be altered by treatment. Therefore, we investigated if glutamate and GABA levels in dorsal anterior cingulate cortex were associated with cognitive function in a large group of antipsychotic-naïve patients compared with matched healthy controls and tested the hypothesis that cognitive deficits in patients are related to altered levels of glutamate and GABA.MethodsWe recruited 56 antipsychotic-naïve patients with schizophrenia or psychotic disorder and 51 healthy controls matched for age, sex, and parental education. Magnetic resonance spectroscopy was used to measure glutamate and GABA levels in dorsal anterior cingulate cortex (ACC) on a 3T scanner. The cognitive domains attention (outcome was rapid visual information processing A’ (RVP A’)) and working memory (outcome was spatial working memory (SWM) strategy) were assessed with the Cambridge Neuropsychological Test Automated Battery, and premorbid intelligence estimated with the Danish Adult Reading Test (DART) (outcome was number of words correctly pronounced). A multivariate linear regression model was used to evaluate if levels of glutamate and GABA were different in patients compared with healthy controls, and thereafter to test if glutamate and GABA levels were associated with cognitive performance in the two groups (significant main effect) and if the association differed (significant interaction). SWM strategy score were logarithmically transformed because of non-normality.ResultsLevels of GABA in dorsal ACC were lower in the antipsychotic-naïve patients compared with healthy controls (SCZ: 2.24±0.35; HC: 2.40±0.33, p=0.03), but glutamate levels did not differ significantly between patients and healthy controls (SCZ: 10.75±1.45; HC: 10.91±1.17, p=0.54). Patients performed significantly worse than healthy controls in tests of attention (mean RVP A’ score SCZ: 0.89±0.05; HC: 0.94±0.04, p<0.001) and premorbid IQ (mean DART score SCZ: 17.4±6.5; HC: 21.5±5.3, p=0.001), whereas groups did not differ significantly in SWM strategy score (Median score SCZ: 27.0 (22.0–32.0); HC: 23.0 (19.0–30.0), p=0.18). Higher levels of glutamate were associated with better performance in tests of attention (b=0.01, p=0.016) and SWM (b=-0.02, p=0.008, higher score indicates worse performance) in both patients and healthy controls. The association between cognitive performance and glutamate did not differ significantly between the two groups (both interactions insignificant).There were no significant associations between cognitive function and levels of GABA in dorsal ACC.DiscussionThis is the largest study of antipsychotic-naïve patients to date to investigate the association between cortical glutamate and GABA levels and cognitive function. We found no group differences in levels of glutamate, but lower GABA levels, which indicates reduced GABAergic neurotransmission in dorsal ACC in the pathophysiology of schizophrenia and psychosis.Higher levels of glutamate in dorsal ACC were associated with better cognitive function. However, glutamate levels did not explain the differences in cognitive performance between patients and healthy controls, indicating that other neurotransmitters are important as well.

S172. GLUTAMATE RELATED CONNECTIVITY DISTURBANCES OF THE SALIENCE AND DEFAULT MODE NETWORKS IN PSYCHOSIS

BackgroundCortical dysconnectivity and dysfunctional glutamatergic signalling are both implicated in the pathophysiology of psychotic illness. The relationship between these two systems, and the relevance to psychotic disorders remains unknown.Methods50 individuals with a psychotic disorder and 54 healthy controls received baseline imaging using 1H-MRS to measure anterior cingulate glutamate concentrations, and resting state MRI to characterise functional brain networks. These measures were subsequently repeated following 3 days treatment with either the glutamatergic regulator riluzole (N=36), or a dopamine antagonist (N=14). The network-based statistic was used to examine relationships between glutamate concentrations and connectivity of the salience and default mode networks in patients and controls, and to investigate how this changed following pharmacological manipulation.ResultsIn healthy controls higher baseline anterior cingulate glutamate concentrations were associated with reduced salience network connectivity, particularly for interhemispheric connections. This pattern was not seen in patients, and the greater the divergence from the relationship observed in controls, the greater the severity of negative symptoms. Default mode-salience internetwork connectivity was greater in patients compared to controls, and inversely correlated with baseline glutamate concentrations. Furthermore, riluzole associated changes in glutamate concentrations were associated with an inverse change in internetwork connectivity suggesting a causal relationship.DiscussionIndividuals with a psychotic disorder showed marked alterations in the relationship between anterior cingulate cortex glutamate concentration and connectivity of the salience and default mode networks. A pharmacological challenge with a glutamate regulating agent modulated this association, highlighting that the relationship is potentially malleable.

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.