Research in schizophrenia has recently turned its attention to deficits in the glutamatergic system as a potential etiological factor. Findings of deviant glutamate (Glu)¹ and glutamine (Gln)^2,3 levels in various brain regions in schizophrenic patients support the glutamate hypothesis of schizophrenia⁴. However, the literature is inconclusive as for the direction of differences between healthy and diseased brain and, due to the difficulty to determine Glu and Gln separately, often reports only their sum, Glx, which weakens the significance. Alterations of thickness and volume of the left superior temporal gyrus (STG) have been well established as endophenotype of schizophrenia⁵ but this region has not been examined in schizophrenic patients using MR spectroscopy as yet. Therefore we performed proton MRS in the left STG of schizophrenic patients and healthy controls, focusing on the separate quantification of glutamatergic metabolites. In addition, the relationships between Glu in STG and personality traits were investigated.Nineteen chronic, medicated schizophrenic patients and 21 sex and age matched healthy volunteers participated in the study. MR measurements were performed on a 3T Verio scanner (Siemens Healthcare, Erlangen, Germany) using a 32-channel receive head coil. Following MPRAGE imaging and adjustment of all first and second order shims using FAST(EST)MAP, MR spectra were acquired from a voxel of 20 x 30 x 20 mm³ encompassing the left STG positioned below the upper bank of the temporal cortex (Fig. 1), using the spin echo full intensity acquired localized (SPECIAL) method⁶ with TR = 3 s, TE = 8.5 ms, 256 averages and 1024 ms acquisition time. Spectra were retrospectively corrected for frequency drift, analyzed using LCModel with a simulated basis set containing 20 metabolites, and referenced to an unsuppressed water scan. Amplitudes were corrected for relaxation using values for T1 and T2 measured for Glu at 3 T^7,8, and for the amount of cerebrospinal fluid (CSF) in the voxels from the segmented T1-weighted images using SPM8. Personality traits were obtained using the NEO Five-Factor Inventory (the personality dimensions neuroticism, extraversion, openness, agreeableness and conscientiousness).The mean linewidth of water spectra from the STG voxel after shimming (± SD) amounted to (7.9 ± 0.7) Hz. Linewidths did not differ significantly between controls and patients. Fig. 1 illustrates the quality of the SPECIAL spectra from STG and shows the fit results for Glu and Gln and the residual. Cramér-Rao lower bounds (CRLB) returned by LCModel were all far below 10 % for Glu (4.3 ± 0.8) %, whereas for Gln values of three patients and three controls were omitted because CRLB exceeded 20 %. Glu concentration (in mmol/l, mean ± SD) in the left STG was significantly higher in patients (9.19 ± 1.11) than in controls (8.15 ± 1.23, p = 0.008). Likewise, Gln in patients exceeded that in controls (1.99 ± 0.56 vs. 1.74 ± 0.57), but reflecting a weak trend only (p = 0.17). The mean CSF fractions in STG of patients and control subjects did not differ significantly, indicating that the concentration differences were not feigned by different CSF contents in the voxels. No differences in the concentrations of N-acetylaspartate, total creatine, total choline and myo-inositol between control subjects and patients were observed. Of the neuropsychological tests used, different scores for patients and controls were observed for neuroticism (25.6 ± 6.3 vs. 15.9 ± 7.5, p = 0.0001) and extraversion (21.7 ± 4.7 vs. 27.6 ± 3.9, p = 0.0001). In patients, there was a significant negative correlation of the neuroticism score with Glu concentration (p = 0.018, Fig. 2).Using the described methodology permits to determine glutamate concentrations with excellent precision. For glutamine the precision was considerably lower but still permitted to use most of the datasets for separately comparing glutamine and glutamate levels in the STG. Our results demonstrate elevated glutamate in the left STG and thus suggest dysfunctional glutamatergic neurotransmission in an area which reflects an endophenotype of schizophrenia. Glutamine in patients might be elevated as well, but the increased statistical uncertainty due to the larger error when measuring a metabolite of low concentration requires a larger sample to be analyzed. Taken together with recent reports, we confirm widespread Glu increase in cortical brain regions in schizophrenia. Whether these deviations constitute etiological or consequential findings remains to be elucidated. Although differing in the tests used, our results concerning neuroticism and extraversion are in line with others⁹ that show glutamatergic metabolites in other cortical regions to be associated with neuropsychological test deficits in schizophrenia. Increased glutamate might reflect a compensatory mechanism to neuroticism in schizophrenic patients.