Glutamate Levels In Anterior Cingulate Cortex 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 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.

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.

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.

S7. INVESTIGATING THE LINK BETWEEN THE PERIPHERAL ENDOCANNABINOID SYSTEM AND CENTRAL GLUTAMATERGIC NEUROTRANSMISSION IN EARLY PSYCHOSIS: A 7T-MRS STUDY

BackgroundMeta-analytic evidence showed increased levels of peripheral endocannabinoid metabolites in psychotic illness. Alterations in the endocannabinoid system are believed to compromise glutamate and dopamine transmission, which play a central role in pathophysiological models of psychosis. I will present preliminary data from an ongoing high-field proton magnetic resonance spectroscopy (MRS) study aimed at investigating the association between peripheral levels of endocannabinoid system metabolites and central glutamate metabolism in individuals at their first non-affective psychotic episode (NA-FEP) and healthy controls.MethodsWe expect to recruit 17 NA-FEP and 20 healthy controls by January 2020. Currently, we recruited 12 NA-FEP and 18 healthy controls from two different research facilities (Imperial College London and University of Oxford) as part of a cross-sectional study. Participants underwent MRS scanning at 7-T with voxels placed in right dorsolateral prefrontal cortex (right-DLPFC), anterior cingulate cortex (ACC), and occipital cortex. Neuro-metabolites will be calculated using the unsuppressed water signal as reference. Endocannabinoid metabolites were quantified from serum samples, collected during the same imaging session.ResultsAnalyses are ongoing. Based on previous evidence, expected findings are: (i) reduced glutamate levels in the ACC and right-DLPFC of NA-FEP compared to controls; (ii) increased peripheral endocannabinoid metabolites in NA-FEP compared to controls; and (iii) inverse association between peripheral endocannabinoid metabolites and glutamate levels in ACC and right-DLPFC in NA-FEPDiscussionThis study will help clarifying the contribution of peripheral endocannabinoid system to central brain mechanisms of key relevance for psychotic illness. It will also add further evidence on the limited literature on high-resolution characterisation of brain metabolites in early psychosis. Strengths of the study include: (i) use of high-field MRS, which allows the estimation of glutamate-related compounds at higher precision than at lower field strength; (ii) reduced heterogeneity of the clinical sample (only male and NA-FEP). Limitations: small sample size and cross-sectional design.

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.

T164. NETWORK CONNECTIVITY SUPPORTING REWARD LEARNING DIFFERENTIALLY DISRUPTED IN TREATMENT RESISTANT SCHIZOPHRENIA

BackgroundIt is estimated that one third of patients with schizophrenia fail to adequately respond to antipsychotic medication, termed ‘treatment-resistance’. This occurs despite adequate blockade of D2 receptors in the brain. The parsimonious options are that treatment resistance could arise through a failure of cognitive control over the dopaminergic dysfunction in the striatum; or has a different primary non-dopaminergic mechanism that isn’t targeted by current antipsychotics. Contemporary models suggest that schizophrenia is associated with reduced reward prediction errors (RPE) and consequent aberrant salience driven by increased dopamine levels that ‘drown out’ phasic signals. This causes positive symptoms and impaired reward learning. However, RPE signalling in treatment-resistant patients appears intact despite sub-optimal behavioural performance. It is therefore unclear how reward learning is impaired in these patients.MethodsWe investigated how reward learning is disrupted at the network level in 21 medicated treatment-responsive and 20 medicated treatment-resistant patients with schizophrenia compared with 24 healthy controls (HC). Participants learnt to associate one of two emotional faces with a reward during a reinforcement learning task in an MRI scanner. Functional MRI BOLD signal was extracted from four brain regions (fusiform cortex, amygdala, caudate and anterior cingulate cortex (ACC)) activated in response to face cues and RPEs. These formed a network of interacting brain regions supporting reward learning. Dynamic Causal Modelling assessed how effective connectivity between regions in this cortico-striatal-limbic network is disrupted in each patient group compared to HC. Connectivity was also examined with respect to symptoms and salience. Finally, cognitive control and the role of glutamate were assessed by relating top-down connectivity from the ACC with glutamate levels measured from the same region of the ACC.ResultsIn responsive patients, there was enhanced top-down connectivity from the ACC to sensory regions (fusiform and amygdala) and reduced input to the caudate compared to HC. Increased top-down connectivity was inversely correlated with symptom severity and sensory-salience. This suggests the presence of an effective compensatory mechanism for unreliable sensory information in responsive patients. Resistant patients however showed normal network connectivity compared to HC except abnormal connectivity within the ACC. This supports an alternative, non-dopaminergic mechanism disrupting reward learning in this refractory group. Increasing connectivity from ACC to caudate was related to positive symptom severity and salience in this group. Moreover, ACC glutamate levels were related to key top-down connections in HC and responsive patients but were not related to any connections in resistant patients. This suggests that glutamate may not be modulating connectivity effectively in this network to exert cognitive control and update reward predictions.DiscussionIn summary, differential mechanisms underlie disrupted reward learning between responsive and resistant groups. Resistant patients show similar RPE signalling and network connectivity to HC suggesting their dopaminergic functioning is intact. Impaired glutamate function may present a key mechanism that disrupts reward learning – and why dopaminergic drugs are ineffective. This finding is important for developing new drugs (e.g. glutamatergic targets) and guiding treatment strategies (e.g. giving clozapine earlier) in resistant patients. Future research probing cognitive control mechanisms and glutamate function will be useful to elucidate this putative pathology in treatment resistance.

Changes in brain Glx in depressed bipolar patients treated with lamotrigine: A proton MRS study.

Lamotrigine is a useful treatment in bipolar depression but requires several weeks of dose titration before its clinical effects can be assessed. Animal experimental studies suggest that lamotrigine lowers glutamate release. The aim of the current study was to assess the effect of lamotrigine on brain glutamate in depressed bipolar patients and to determine whether baseline glutamate could be used to predict clinical response. We studied 21 bipolar patients who received lamotrigine treatment for a current episode of depression. Before starting lamotrigine and after 10-12 weeks treatment, patients underwent proton magnetic resonance spectroscopy (MRS) scanning at 3 Tesla where levels of glutamate (measured as Glx) were determined in anterior cingulate cortex (ACC). Overall, lamotrigine treatment had no significant effect on Glx levels in ACC. However, in patients who responded clinically to lamotrigine treatment Glx concentrations were significantly increased. Baseline levels of Glx did not predict response to lamotrigine. The main limitation of the study was the modest sample size. Most patients were medicated which may have modified the effect of lamotrigine on glutamate activity. MRS at 3T cannot give a reliable estimate of glutamate separate from its main metabolite, glutamine, and thus changes in Glx may not give a precise estimate of effects of lamotrigine on glutamate itself. Lamotrigine does not appear to have a direct effect on glutamate levels in ACC in bipolar patients. However, therapeutic improvement during lamotrigine was associated with increased Glx, suggesting that alterations in glutamatergic activity might be related to recovery from bipolar depression.

Relationship Between Cortical Excitation and Inhibition and Task-Induced Activation and Deactivation: A Combined Magnetic Resonance Spectroscopy and Functional Magnetic Resonance Imaging Study at 7T in First-Episode Psychosis

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 magnetic resonance spectroscopy and functional magnetic resonance imaging at 7T to investigate how measurements of glutamate and gamma-aminobutyric acid (GABA) relate to the blood oxygen level–dependent (BOLD) response during a cognitive task, and how these relationships are altered in schizophrenia. MethodsUsable functional magnetic resonance imaging data from 17 first-episode psychosis (FEP) patients (4 women, 13 men) and 21 matched healthy control subjects (HCs) (5 women, 16 men) were acquired during a Stroop task. Within- and between-group comparisons of the BOLD response were performed. Neurometabolite levels were measured in the dorsal anterior cingulate cortex. Two multiple regressions investigated how glutamate, glutamine, and GABA related to the BOLD response in HCs and FEP patients separately. A third investigated between-group differences in the relationships between the BOLD response and each of these neurometabolites. ResultsCompared with HCs, FEP patients showed an increased BOLD response within regions of the executive and default mode networks. In FEP patients, the relationship between anterior cingulate cortex glutamate levels and the BOLD response in regions of the posterior default mode network was opposite to that of HCs. In FEP patients but not HCs, anterior cingulate cortex GABA levels correlated with the local BOLD response and with the Stroop reaction time. ConclusionThese results suggest a mechanism whereby alterations in the relationship between cortical glutamate/GABA and BOLD response is disrupting the dynamic of major neural networks, possibly affecting cognition.

T173. GABA AND GLUTAMATE IN PATIENTS WITH 22Q11.2 DELETION SYNDROME AND HEALTHY VOLUNTEERS AND THE RELATION WITH COGNITION: A RANDOMIZED DOUBLE-BLIND 7TESLA PHARMACOLOGICAL MRS STUDY

Background22q11.2 deletion syndrome (22q11DS) is characterized by a microdeletion on the long arm of chromosome 22. The clinical phenotype of this syndrome is highly variable but symptoms include cognitive impairment, heart malformations, auto-immune problems and a high risk of developing a psychotic disorder. One of the genes located in the deleted region is PRODH which encodes proline dehydrogenase (PRODH). This enzyme is involved in converting proline to glutamate (GLU). GLU is involved in the pathophysiology of psychosis, particularly in cognitive symptoms (Lewis and Moghaddam 2006). Gamma-aminobutyric acid (GABA) is involved in cognition and psychosis as well (Vinkers et al. 2010). With this study we aimed to investigate GLUergic and GABAergic reactivity in the anterior cingulate cortex (ACC) and striatum in medication-free patients with 22q11DS with no psychiatric history and healthy controls (HC).MethodsThis was a randomized double-blind placebo controlled cross-over study. Groups were matched for age and gender. 12 patients with 22q11DS (mean age 35 years) and 20 HCs (mean age 31 years) were enrolled in the study. GABA and GLU, levels in the ACC and striatum were obtained twice with 7Tesla Magnetic Resonance Spectroscopy (MRS, STEAM): once after placebo and once after oral administration of 50 mg. riluzole (agent with anti-glutamate and pro-GABA action). Striatal and ACC GLU/GABA ratios were computed as well as GLUergic and GABAergic reactivity (placebo minus riluzole). In addition, within the 22q11DS group, the relationship between cognitive functions (memory and attention) measured with the CANTAB and GABA, GLU, GLU/GABA ratio, GABAergic reactivity and GLUergic in the ACC and striatum were examined.ResultsAnalyses of Covariance (ANCOVA) showed no baseline group differences in glutamate and GABA levels and GLU/GABA ratios (corrected for fraction of cerebral spinal fluid, CSF) in both brain regions. A repeated measures ANCOVA showed a trend level significant increase in striatal GABA concentrations after (p= 0.065). Riluzole had no significant effect on GLU (p= 0.303) and GLU/GABA ratios (p= 0.150) in the striatum. No medication X group interaction effects were found. Riluzole had no significant effect on GABA (p= 0.101), GLU (p= 0.847) and GLU/GABA ratio (p= 0.108) in the ACC. No group main effects and no medication X group interactions effects were found. However, a significant negative correlation was found between verbal memory (r= -0.650, p= 0.030) and ACC GLU levels, as well as GLUergic reactivity (r= -0.733, p= 0.010). Moreover, in the 22q11DS group, a significant negative correlation was found between attention (target sequence detection) and ACC GLU levels (r= -0.704, p= 0.016) as well as GLU/GABA ratio (r= -0.602, p= 0.050). Furthermore, sustained attention was positively associated with ACC GABA levels (r= 0.700, p= 0.024) and negatively associated with GLU/GABA ratio r= -0.639, p= 0.047) in these patients. Finally, a positive correlation was found between visual memory and striatal GLU levels (r= 0.616, p= 0.043).DiscussionThe present study did not demonstrate differences in ACC and striatal GLU and GABA levels, nor in GLUergig or GABAergic reactivity in response to riluzole between 22q11DS patients and controls. However, these results suggest a role for GLU and GABA in cognition in the 22q11DS group. Therefore, influencing these neurotransmitter systems might enhance cognitive functioning in these patients. More studies are required to replicate these findings.

O3.7. EFFECT OF N-ACETYLCYSTEINE ON BRAIN GLUTAMATE LEVELS AND RESTING PERFUSION IN SCHIZOPHRENIA

BackgroundSchizophrenia may be associated with elevations in glutamate levels in the anterior cingulate cortex (ACC), and this may be particularly apparent in patients who have not responded well to conventional antipsychotic treatment (Egerton et al., 2012; Mouchliantis et al., 2016). This suggests that compounds that can decrease ACC glutamate levels may have therapeutic potential for this group. N-acetylcysteine (NAC) is one such compound, currently under investigation as an adjunctive therapy for schizophrenia. The effects of NAC on brain glutamate levels and physiology in schizophrenia have not been previously evaluated. The primary aim of this study was to examine whether a single oral dose of NAC can alter brain glutamate levels in schizophrenia. The secondary aim was to characterise the effects of NAC on regional brain perfusion.MethodsIn a double-blind placebo-controlled crossover study, twenty patients with a diagnosis of schizophrenia underwent two 3 Tesla MRI scans, performed one week apart, and following administration of a single oral dose of 2400mg NAC or matching placebo. Proton magnetic resonance spectroscopy (1H-MRS) was used to investigate the effect of NAC on glutamate and Glx (glutamate plus glutamine) levels scaled to creatine (Cr) in the anterior cingulate cortex (ACC) and in the right caudate nucleus. Pulsed continuous arterial spin labelling (pCASL) was used to measure the effects of NAC on resting cerebral blood flow (CBF) in the same regions. 1H-MRS spectra were analysed using LCModel version 6.3-0I using a standard basis set. Individual CBF maps were pre-processed in the Automatic Software for ASL Processing (ASAP) toolbox running in SPM-8 in Matlab 6.5. The effects of NAC on 1H-MRS metabolite levels were determined using paired samples t-tests. Changes in rCBF were determined using within-subjects, second-level analysis implemented in SPM-8.ResultsIn the ACC, Glx/Cr was significantly reduced in the NAC compared to placebo condition (t(17) = 2.40; P = .03, d = 0.64). There was no significant effect of condition on Glu/Cr in the ACC, or on Glx/Cr or Glu/Cr in the right caudate nucleus, or on any of the other metabolites quantifiable from the 1H-MRS spectra. There were no significant differences in CBF in the ACC (mean (SD) placebo = 47.22 (8.81); NAC = 46.83 (7.29); t(18) = .349, P = .73) or in the right caudate nucleus (mean (SD) placebo = 37.51 (7.48); NAC = 37.77 (6.71); t(18) -.310, P = .76) in the NAC compared to placebo condition. There was also no significant difference in global CBF between conditions (mean (SD) placebo = 39.64 (10.02); NAC = 40.03 (9.13); t(18) = -.398, P = .70).DiscussionThese results provide preliminary evidence that NAC may reduce ACC glutamate metabolites in schizophrenia. Future studies will need to determine the extent to which reductions in glutamate metabolites following a single dose of a glutamatergic compound are indicative of longer-term efficacy in improving symptoms.

O6.2. NEUROBIOLOGY OF PSYCHOMETRIC SCHIZOTYPY: INSIGHTS FROM MULTIMODAL IMAGING RESEARCH

BackgroundThe continuum approach to psychosis proposes a dimensional continuity between the neurobiology of subclinical psychotic-like experiences in healthy individuals (or schizotypy) and psychotic symptoms in clinically relevant psychosis (Linscott and van Os, 2013, Nelson et al., 2013). Preclinical models propose that cortical glutamate dysfunction related to cortico-limbic-striatal hyper-responsivity to stress may underlie both hippocampal and striatal overdrive as well as gray matter loss associated with schizophrenia-like behaviors (Berretta et al., 2001, Lodge and Grace, 2011). Our recent studies investigated whether changes in brain glutamate are present in healthy individuals with high psychometric schizotypy, and whether these are related to changes in (1) corticolimbic response to emotion and (2) gray matter volume (GMV).MethodsForty-eight healthy participants were recruited based on their score on the O-LIFE questionnaire (Mason et al., 2005), after pre-screening 250 respondents to online advertisement. Participants with high levels of unusual experiences (HS group; that is, scored >7 on the Unusual Experiences (UE) subscale of the O-LIFE), and participants with low UE (LS group; that is, <2 on O-LIFE UE subscale), were invited to participate. Groups were matched by age, gender and IQ. A structural MRI scan, glutamate proton magnetic resonance spectroscopy in the anterior cingulate cortex (ACC), and functional magnetic resonance imaging (fMRI) measuring corticolimbic response during emotional processing were acquired at 3T in a single session. Glutamate levels were analyzed using LCModel 6.3-1L. Voxel-based morphometry was applied to quantify GMV and both GMV and fMRI group level analyses were run using SPM12. Standalone imaging results as well as fMRI/sMRI × glutamate interactions were considered significant after voxel-wise P<0.05 family-wise error correction.ResultsWhile viewing emotional pictures, HS individuals showed greater activation than did subjects with LS in the caudate, and marginally in the ACC, hippocampus, medial prefrontal cortex (MPFC) and putamen. Although no between-group differences were found in glutamate concentrations, within the HS group ACC glutamate was negatively correlated with striatal activation (bilaterally in caudate and in left putamen at P < 0.05) and marginally with MPFC (P = 0.052) and amygdala (left: P = 0.062; right: P = 0.079), correlations that were not present in LS subjects. Structurally, subjects with HS showed GMV decreases in the rolandic operculum/superior temporal gyrus (P < 0.05) at the whole-brain level, and significant increases in GMV were also detected using ROI in the precuneus and ACC (both P < 0.05). Furthermore, in HS subjects ACC glutamate levels were negatively correlated with GMV in the ACC (P < 0.05). Such association was absent in LS. These findings provide, to our knowledge, the first evidence that brain glutamate levels are associated with emotional hyper-responsivity and volumetric changes in HS in brain regions thought to be critical in the pathophysiology of psychotic symptoms.DiscussionCollectively, these results are in line with a dimensional view of psychosis by suggesting that interactions between brain structure, neurochemistry, and functional response to emotion within a corticolimbic circuit are involved in the expression of psychotic-like experiences at non-clinical and clinical levels. These findings may also serve as evidence of potentially protective mechanisms, as our studies involved high-functioning individuals with HS and some of the observed effects are opposite to what would have been predicted from studies in clinical groups.

25.2 UNDERSTANDING WHITE MATTER PATHOLOGY IN SCHIZOPHRENIA USING DIFFUSION TENSOR IMAGING AND MAGNETIC RESONANCE SPECTROSCOPY

BackgroundDiffusion tensor imaging (DTI) studies in schizophrenia consistently show global reductions in fractional anisotropy (FA), a putative marker of white matter integrity. Because magnetic resonance spectroscopy (MRS) studies permit for the non-invasive measurements of neurometabolites, such as N-acetylaspartate (NAA), a marker of neuronal integrity, and glutamate, which can be neurotoxic when over-released, this technique provides further understanding of the relationship between white matter microstructure and neuronal function.MethodsTwenty-nine schizophrenia patients and twenty controls participated in this 3T imaging study where we used DTI and tract-based spatial statistics (TBSS) to assess white matter integrity of the cingulum bundle and MRS to quantify NAA and glutamate in the anterior cingulate cortex (ACC) and hippocampus, i.e. in cortico-limbic regions connected by the cingulum bundle.ResultsWe 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, but not in patients, high hippocampal NAA levels were significantly associated with low RD in the hippocampal part of the cingulum, and low ACC glutamate levels were significantly associated with high FA in the hippocampus part of the cingulum.DiscussionIn 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.

Glutamate Levels and Resting Cerebral Blood Flow in Anterior Cingulate Cortex Are Associated at Rest and Immediately Following Infusion of S-Ketamine in Healthy Volunteers.

Progressive loss of brain tissue is seen in some patients with schizophrenia and might be caused by increased levels of glutamate and resting cerebral blood flow (rCBF) alterations. Animal studies suggest that the normalisation of glutamate levels decreases rCBF and prevents structural changes in hippocampus. However, the relationship between glutamate and rCBF in anterior cingulate cortex (ACC) of humans has not been studied in the absence of antipsychotics and illness chronicity. Ketamine is a noncompetitive N-methyl-D-aspartate receptor antagonist that transiently induces schizophrenia-like symptoms and neurobiological disturbances in healthy volunteers (HVs). Here, we used S-ketamine challenge to assess if glutamate levels were associated with rCBF in ACC in 25 male HVs. Second, we explored if S-ketamine changed the neural activity as reflected by rCBF alterations in thalamus (Thal) and accumbens that are connected with ACC. Glutamatergic metabolites were measured in ACC with magnetic resonance (MR) spectroscopy and whole-brain rCBF with pseudo-continuous arterial spin labelling on a 3-T MR scanner before, during, and after infusion of S-ketamine (total dose 0.375 mg/kg). In ACC, glutamate levels were associated with rCBF before (p < 0.05) and immediately following S-ketamine infusion (p = 0.03), but not during and after. S-Ketamine increased rCBF in ACC (p < 0.001) but not the levels of glutamate (p = 0.96). In subcortical regions, S-ketamine altered rCBF in left Thal (p = 0.03). Our results suggest that glutamate levels in ACC are associated with rCBF at rest and in the initial phase of an increase. Furthermore, S-ketamine challenge transiently induces abnormal activation of ACC and left Thal that both are implicated in the pathophysiology of schizophrenia. Future longitudinal studies should investigate if increased glutamate and rCBF are related to the progressive loss of brain tissue in initially first-episode patients.

Neuroanatomical changes in people with high schizotypy: relationship to glutamate levels.

Cortical glutamatergic dysfunction is thought to be fundamental for psychosis development, and may lead to structural degeneration through excitotoxicity. Glutamate levels have been related to gray matter volume (GMV) alterations in people at ultra-high risk of psychosis, and we previously reported GMV changes in individuals with high schizotypy (HS), which refers to the expression of schizophrenia-like characteristics in healthy people. This study sought to examine whether GMV changes in HS subjects are related to glutamate levels. We selected 22 healthy subjects with HS and 23 healthy subjects with low schizotypy (LS) based on their rating on a self-report questionnaire for psychotic-like experiences. Glutamate levels were measured in the bilateral anterior cingulate cortex (ACC) using proton magnetic resonance spectroscopy, and GMV was assessed using voxel-based morphometry. Subjects with HS showed GMV decreases in the rolandic operculum/superior temporal gyrus (pFWE = 0.045). Significant increases in GMV were also detected in HS, in the precuneus (pFWE = 0.043), thereby replicating our previous finding in a separate cohort, as well as in the ACC (pFWE = 0.041). While the HS and LS groups did not differ in ACC glutamate levels, in HS subjects ACC glutamate was negatively correlated with ACC GMV (pFWE = 0.026). Such association was absent in LS. Our study shows that GMV findings in schizotypy are related to glutamate levels, supporting the hypothesis that glutamatergic function may lead to structural changes associated with the expression of psychotic-like experiences.

Cerebral dopaminergic and glutamatergic transmission relate to different subjective responses of acute alcohol intake: an in vivo multimodal imaging study.

Converging preclinical evidence links extrastriatal dopamine release and glutamatergic transmission via the metabotropic glutamate receptor 5 (mGluR5) to the rewarding properties of alcohol. To date, human evidence is lacking on how and where in the brain these processes occur. Mesocorticolimbic dopamine release upon intravenous alcohol administration and mGluR5 availability were measured in 11 moderate social drinkers by single-session [18 F]fallypride and [18 F]FPEB positron emission tomography, respectively. Additionally, baseline and postalcohol glutamate and glutamine levels in the anterior cingulate cortex (ACC) were measured by using proton-magnetic resonance spectroscopy. To investigate differences in reward domains linked to both neurotransmitters, regional imaging data were related to subjective alcohol responses. Alcohol induced significant [18 F]fallypride displacement in the prefrontal cortex (PFC), temporal and parietal cortices and thalamus (P<0.05, corrected for multiple comparisons). Dopamine release in the ACC and orbitofrontal and ventromedial PFCs were correlated with subjective 'liking' and 'wanting' effects (P<0.05). In contrast, baseline mGluR5 availability was positively correlated with the 'high' effect of alcohol in dorsolateral, ventrolateral and ventromedial PFCs and in the medial temporal lobe, thalamus and caudate nucleus (P<0.05). Although neither proton-magnetic resonance spectroscopy glutamate nor glutamine levels were affected by alcohol, baseline ACC glutamate levels were negatively associated with the alcohol 'liking' effect (P<0.003). These data reveal new mechanistic understanding and differential neurobiological underpinnings of the effects of acute alcohol consumption on human behavior. Specifically, prefrontal dopamine release may encode alcohol 'liking' and 'wanting' effects in specific areas underlying value processing and motivation, whereas mGluR5 availability in distinct prefrontal-temporal-subcortical regions is more related to the alcohol 'high' effect.

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.

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.