E, and thalamus. In addition, in HC, correlation with the PE signal was also observed in dorsal anterior cingulate cortex and posterior parietal cortex, implying that executive processes were engaged. Interestingly, those regions were not differentially associated with the PE signal in patients, suggesting that abnormalities in PE in patients originate from bottom-up rather than top-down processing. Like others, we observed abnormal PE signals in patients who were medicated (mainly second-generation antipsychotics), indicating that dopamine D2 blockade does not normalize PE abnormalities. Interestingly, a study in first-episode patients found normalization of a reward anticipation-related ventral striatum hypofunction after treatment.33 It remains to be determined whether treatment does in fact reduce, but obviously not normalize, PE abnormalities, and whether treatment has a differential effect on PE dysfunction in first episode compared with chronic patients with schizophrenia. Our finding of L-660711 sodium saltMedChemExpress MK-571 (sodium salt) elevated SN Glx in SZ is consistent with previous finding of elevated Glx measured in the striatum,15 putatively suggesting excessive glutamate release from cortical glutamatergic projections to basal ganglia. However, although elevated striatum Glx was observed in unmedicated patients, our observations derive from medicated patients. The participants enrolled in this study overlap with those included in a prior report where,npj Schizophrenia (2015)SN glutamate and prediction error in schizophrenia DM White et al6 although no differences in Glx were observed, the Glx/N-acetylaspartate ratio was significantly elevated in patients, possibly indexing a glutamatergic dysfunction.16 Our findings are also consistent with the identification of abnormal expression of Nmethyl-D-aspartate receptor-associated LY2510924 chemical information intracellular proteins in the SN in schizophrenia.34 In addition to cortical projections, glutamatergic projections to the ventral tegmental area originate from subcortical structures, including the subthalamic nucleus and the pedunculopontine tegmentum.35 Increased SN Glx might also reflect a local, rather than a projected disturbance. Recent optogenetic studies in rodents have demonstrated that mesolimbic dopaminergic neurons release glutamate in the nucleus accumbens, suggesting colocalization of glutamate and dopamine receptors in some midbrain neurons.36,37 Glutamatergic abnormalities have now been identified in schizophrenia in the basal ganglia, hippocampus, and medial prefrontal cortex.15,38?0 It remains to be determined whether these abnormalities originate from a similar local dysfunction, such as -aminobutyric acid interneuron abnormalities, or whether they are connected, one impacting the others, and the extent to which they are affected by treatment. In HC, we observed a correlation between the PE signal and SN Glx in the SN. Given that the burst firing of dopamine neurons recorded during PE signals can be driven by application of glutamate to dopamine neurons or by stimulation of glutamatergic afferents,41 it is tempting to speculate that this correlation reflects the drive of glutamatergic projections to dopamine neurons in the SN. In the context of elevated SN Glx, the correlation between PE signal and Glx was not present in patients, suggesting that glutamatergic dysfunction could contribute to aberrant PE signaling. Consistent with our findings, low-dose administration of the N-methyl-D-aspartate antagonist ketamine disrupts error-dep.E, and thalamus. In addition, in HC, correlation with the PE signal was also observed in dorsal anterior cingulate cortex and posterior parietal cortex, implying that executive processes were engaged. Interestingly, those regions were not differentially associated with the PE signal in patients, suggesting that abnormalities in PE in patients originate from bottom-up rather than top-down processing. Like others, we observed abnormal PE signals in patients who were medicated (mainly second-generation antipsychotics), indicating that dopamine D2 blockade does not normalize PE abnormalities. Interestingly, a study in first-episode patients found normalization of a reward anticipation-related ventral striatum hypofunction after treatment.33 It remains to be determined whether treatment does in fact reduce, but obviously not normalize, PE abnormalities, and whether treatment has a differential effect on PE dysfunction in first episode compared with chronic patients with schizophrenia. Our finding of elevated SN Glx in SZ is consistent with previous finding of elevated Glx measured in the striatum,15 putatively suggesting excessive glutamate release from cortical glutamatergic projections to basal ganglia. However, although elevated striatum Glx was observed in unmedicated patients, our observations derive from medicated patients. The participants enrolled in this study overlap with those included in a prior report where,npj Schizophrenia (2015)SN glutamate and prediction error in schizophrenia DM White et al6 although no differences in Glx were observed, the Glx/N-acetylaspartate ratio was significantly elevated in patients, possibly indexing a glutamatergic dysfunction.16 Our findings are also consistent with the identification of abnormal expression of Nmethyl-D-aspartate receptor-associated intracellular proteins in the SN in schizophrenia.34 In addition to cortical projections, glutamatergic projections to the ventral tegmental area originate from subcortical structures, including the subthalamic nucleus and the pedunculopontine tegmentum.35 Increased SN Glx might also reflect a local, rather than a projected disturbance. Recent optogenetic studies in rodents have demonstrated that mesolimbic dopaminergic neurons release glutamate in the nucleus accumbens, suggesting colocalization of glutamate and dopamine receptors in some midbrain neurons.36,37 Glutamatergic abnormalities have now been identified in schizophrenia in the basal ganglia, hippocampus, and medial prefrontal cortex.15,38?0 It remains to be determined whether these abnormalities originate from a similar local dysfunction, such as -aminobutyric acid interneuron abnormalities, or whether they are connected, one impacting the others, and the extent to which they are affected by treatment. In HC, we observed a correlation between the PE signal and SN Glx in the SN. Given that the burst firing of dopamine neurons recorded during PE signals can be driven by application of glutamate to dopamine neurons or by stimulation of glutamatergic afferents,41 it is tempting to speculate that this correlation reflects the drive of glutamatergic projections to dopamine neurons in the SN. In the context of elevated SN Glx, the correlation between PE signal and Glx was not present in patients, suggesting that glutamatergic dysfunction could contribute to aberrant PE signaling. Consistent with our findings, low-dose administration of the N-methyl-D-aspartate antagonist ketamine disrupts error-dep.
