Ectrophysiological studies of midbrain dopamine neurons in primates show the firing of neurons increase when a reward exceeds what was predicted and decrease when a reward is less than predicted.2 In schizophrenia, it is hypothesized that known dopamine abnormalities3 could lead to aberrant encoding of PE signals.4 In this context, some symptoms could stem from aberrant attribution of salience to APTO-253MedChemExpress APTO-253 irrelevant stimuli, such as delusions, or from reduced attribution of salience to rewarding events, such as anhedonia.5,6 Imaging studies in schizophrenia have registered aberrant PE signals during reward processing and related these to symptoms.7?0 The revised glutamatergic hypothesis of schizophrenia proposes that blockade of N-methyl-D-aspartate receptors on -aminobutyric acid neurons could result in a disinhibition of glutamatergic neurons leading to excess APTO-253 biological activity glutamate release in projection areas.11,12 Because both the substantia nigra (SN) and the striatum receive glutamatergic projections from cortical areas,13,14 abnormal cortical glutamate transmission could affect these regions. Consistent with this model, a recent proton magneticresonance spectroscopy (1H-MRS) study found higher glutamate +glutamine (Glx) levels in the striatum of antipsychotic-naive patients with schizophrenia.15 We previously reported the results of a 1H-MRS study of the SN in medicated patients. Although we did not observe differences in Glx, the Glx/N-acetyl-aspartate ratio was significantly elevated in patients, possibly indexing a glutamatergic dysfunction.16 Therefore, glutamate dysfunction in the SN could affect reward processing. However, little is known about the contribution of glutamate to reward both in general and also to its dysfunction in schizophrenia. The aim of this study was to investigate the contribution of glutamate to PE signals in healthy controls (HC) and patients with schizophrenia. We combined functional MRI (fMRI) during PE processing with single-voxel 1H-MRS in the SN to obtain Glx measurements. We hypothesized that we would replicate findings of abnormal PE-related neural signals in the SN in patients. In addition, for the first time, we explore the contribution of Glx to PE-related neural signals and its implication in schizophrenia. MATERIALS AND METHODS ParticipantsWe enrolled 22 medicated participants with schizophrenia or schizoaffective disorder (SZ), recruited from outpatient clinics at the University of Alabama at Birmingham, and 19 matched HC, recruited via advertisement.1 Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, USA and 3Department of Electrical and Computer Engineering, Auburn University, Auburn, AL, USA. Correspondence: AC Lahti ([email protected]) Received 4 September 2014; revised 6 October 2014; accepted 8 October?2015 Schizophrenia International Research Group/Nature Publishing GroupSN glutamate and prediction error in schizophrenia DM White et alAfter being deemed able to give consent,17 informed consent was provided. Approval by the Institutional Review Board was obtained. All participants were recruited for a multimodal neuroimaging study of reward. Neurometabolite measurements of some participants have been included in another report.16 Diagnoses were established through review of medical records, two clinician consensus, and the Diagnostic Interview for Genetic.Ectrophysiological studies of midbrain dopamine neurons in primates show the firing of neurons increase when a reward exceeds what was predicted and decrease when a reward is less than predicted.2 In schizophrenia, it is hypothesized that known dopamine abnormalities3 could lead to aberrant encoding of PE signals.4 In this context, some symptoms could stem from aberrant attribution of salience to irrelevant stimuli, such as delusions, or from reduced attribution of salience to rewarding events, such as anhedonia.5,6 Imaging studies in schizophrenia have registered aberrant PE signals during reward processing and related these to symptoms.7?0 The revised glutamatergic hypothesis of schizophrenia proposes that blockade of N-methyl-D-aspartate receptors on -aminobutyric acid neurons could result in a disinhibition of glutamatergic neurons leading to excess glutamate release in projection areas.11,12 Because both the substantia nigra (SN) and the striatum receive glutamatergic projections from cortical areas,13,14 abnormal cortical glutamate transmission could affect these regions. Consistent with this model, a recent proton magneticresonance spectroscopy (1H-MRS) study found higher glutamate +glutamine (Glx) levels in the striatum of antipsychotic-naive patients with schizophrenia.15 We previously reported the results of a 1H-MRS study of the SN in medicated patients. Although we did not observe differences in Glx, the Glx/N-acetyl-aspartate ratio was significantly elevated in patients, possibly indexing a glutamatergic dysfunction.16 Therefore, glutamate dysfunction in the SN could affect reward processing. However, little is known about the contribution of glutamate to reward both in general and also to its dysfunction in schizophrenia. The aim of this study was to investigate the contribution of glutamate to PE signals in healthy controls (HC) and patients with schizophrenia. We combined functional MRI (fMRI) during PE processing with single-voxel 1H-MRS in the SN to obtain Glx measurements. We hypothesized that we would replicate findings of abnormal PE-related neural signals in the SN in patients. In addition, for the first time, we explore the contribution of Glx to PE-related neural signals and its implication in schizophrenia. MATERIALS AND METHODS ParticipantsWe enrolled 22 medicated participants with schizophrenia or schizoaffective disorder (SZ), recruited from outpatient clinics at the University of Alabama at Birmingham, and 19 matched HC, recruited via advertisement.1 Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA; 2Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, USA and 3Department of Electrical and Computer Engineering, Auburn University, Auburn, AL, USA. Correspondence: AC Lahti ([email protected]) Received 4 September 2014; revised 6 October 2014; accepted 8 October?2015 Schizophrenia International Research Group/Nature Publishing GroupSN glutamate and prediction error in schizophrenia DM White et alAfter being deemed able to give consent,17 informed consent was provided. Approval by the Institutional Review Board was obtained. All participants were recruited for a multimodal neuroimaging study of reward. Neurometabolite measurements of some participants have been included in another report.16 Diagnoses were established through review of medical records, two clinician consensus, and the Diagnostic Interview for Genetic.