Ediction error; SN, substantia nigra.npj Schizophrenia (2015) 14001 ?2015 Schizophrenia International Research Group/Nature Publishing GroupSN glutamate and prediction error in schizophrenia DM White et alFigure 4. Correlation between PE-related BOLD signal and SN Glx. (a) In healthy controls, but not in patients with schizophrenia, there was a significant correlation between PE-related BOLD signal and SN Glx in the SN (analyses restricted to ventral striatum and midbrain/SN using small-volume correction; Po0.05). Clusters are overlaid on a single-subject T1 structural image. The numbers adjacent to the slices indicate y and z coordinates in Montreal Neurological Institute convention for coronal and axial slices, respectively. BOLD, blood oxygen level dependent; Glx, glutamate+glutamine; PE, prediction error; SN, substantia nigra. (b) order ��-Amatoxin Scatterplots showing the distribution of variance in the relationship between Glx and PE BOLD response in healthy controls (r = 0.74) and patients with schizophrenia (r = 0.30).between SZ and HC in the ventral striatum/nucleus accumbens (cluster 1: t = 3.45, kE = 18, x = 8, y = 7, z = – 7; cluster 2: t = 3.05, kE = 19, x = – 16, y = 9, z = – 13) and the midbrain/SN (cluster 1: t = 4.11, kE = 1,414, x = 6, y = – 30, z = – 12). Combined fMRI and MRS results In HC, but not SZ, we found a significant correlation between the PE-related BOLD signal in SN and SN Glx (Figure 4a; t = 4.60, kE = 100, x = – 12, y = – 23, z = – 19). Figure 4b scatterplots showing the distribution of variance in the relationship between Glx and PE BOLD response in HC (r = 0.74) and SZ (r = 0.30). DISCUSSION To our knowledge, this is the first study reporting the relationship between PE processing and SN Glx and its implications in schizophrenia. In SZ, we found abnormal PE-related neural response in the midbrain, ventral striatum, caudate, thalamus, orbitofrontal and dorsolateral prefrontal cortices as well as significantly 6-Methoxybaicalein cost elevated SN Glx. In HC, but not in SZ, the neural response to PE in the SN was positively correlated with SN Glx. These results suggest a role of glutamate in the neural coding of PE in HC, and that glutamatergic dysfunction might contribute to its abnormal coding in patients with schizophrenia. Despite differences in experimental design and analyses, several studies in medicated and unmedicated patients have identified neural abnormalities during the encoding of PE, most prominently in the ventral striatum.29 Although some studies investigated reward-conditioning paradigms on a trial-by-trial level,4,8,10 others7,9 examined PE trials generated after conditioning completion like we did. Starting after the 10th trial, the behavioral analyses of our PE task show that SZ had learned the?2015 Schizophrenia International Research Group/Nature Publishing Groupcontingencies of the task during the first 10 trials. Compared with HC, there were no differences in the amount of reward earned or the amount of PE generated by their response pattern. In addition, the analysis of task performance indicated that the distribution of choices made (right versus left) were not statistically different between groups. This finding is consistent with the results of others.30?2 After the 10th trial, when the expected value of each trial was known to the participants, PEs were analyzed as parametric modulators of reward delivery. Like others,4,7?0 we found abnormalities of PE in dopamine-rich areas, including the SN, ventral striatum, caudat.Ediction error; SN, substantia nigra.npj Schizophrenia (2015) 14001 ?2015 Schizophrenia International Research Group/Nature Publishing GroupSN glutamate and prediction error in schizophrenia DM White et alFigure 4. Correlation between PE-related BOLD signal and SN Glx. (a) In healthy controls, but not in patients with schizophrenia, there was a significant correlation between PE-related BOLD signal and SN Glx in the SN (analyses restricted to ventral striatum and midbrain/SN using small-volume correction; Po0.05). Clusters are overlaid on a single-subject T1 structural image. The numbers adjacent to the slices indicate y and z coordinates in Montreal Neurological Institute convention for coronal and axial slices, respectively. BOLD, blood oxygen level dependent; Glx, glutamate+glutamine; PE, prediction error; SN, substantia nigra. (b) Scatterplots showing the distribution of variance in the relationship between Glx and PE BOLD response in healthy controls (r = 0.74) and patients with schizophrenia (r = 0.30).between SZ and HC in the ventral striatum/nucleus accumbens (cluster 1: t = 3.45, kE = 18, x = 8, y = 7, z = – 7; cluster 2: t = 3.05, kE = 19, x = – 16, y = 9, z = – 13) and the midbrain/SN (cluster 1: t = 4.11, kE = 1,414, x = 6, y = – 30, z = – 12). Combined fMRI and MRS results In HC, but not SZ, we found a significant correlation between the PE-related BOLD signal in SN and SN Glx (Figure 4a; t = 4.60, kE = 100, x = – 12, y = – 23, z = – 19). Figure 4b scatterplots showing the distribution of variance in the relationship between Glx and PE BOLD response in HC (r = 0.74) and SZ (r = 0.30). DISCUSSION To our knowledge, this is the first study reporting the relationship between PE processing and SN Glx and its implications in schizophrenia. In SZ, we found abnormal PE-related neural response in the midbrain, ventral striatum, caudate, thalamus, orbitofrontal and dorsolateral prefrontal cortices as well as significantly elevated SN Glx. In HC, but not in SZ, the neural response to PE in the SN was positively correlated with SN Glx. These results suggest a role of glutamate in the neural coding of PE in HC, and that glutamatergic dysfunction might contribute to its abnormal coding in patients with schizophrenia. Despite differences in experimental design and analyses, several studies in medicated and unmedicated patients have identified neural abnormalities during the encoding of PE, most prominently in the ventral striatum.29 Although some studies investigated reward-conditioning paradigms on a trial-by-trial level,4,8,10 others7,9 examined PE trials generated after conditioning completion like we did. Starting after the 10th trial, the behavioral analyses of our PE task show that SZ had learned the?2015 Schizophrenia International Research Group/Nature Publishing Groupcontingencies of the task during the first 10 trials. Compared with HC, there were no differences in the amount of reward earned or the amount of PE generated by their response pattern. In addition, the analysis of task performance indicated that the distribution of choices made (right versus left) were not statistically different between groups. This finding is consistent with the results of others.30?2 After the 10th trial, when the expected value of each trial was known to the participants, PEs were analyzed as parametric modulators of reward delivery. Like others,4,7?0 we found abnormalities of PE in dopamine-rich areas, including the SN, ventral striatum, caudat.
