Schizophrenia is a chronic progressive psychiatric disorder that alters perception, cognition, and behavior. It is known to be associated with hippocampal abnormalities including reduced volume, increased basal perfusion, decreased activation during certain memory tasks, decreased neurogenesis and reduced connectivity ^1-5. The metabolic substrates of these pathologies, however, are not yet elucidated, due in part to inconsistent proton MR spectroscopy (¹H MRS) results. We present data of absolute n-acetyl-aspartate (NAA), creatine (Cr), and choline (Cho) concentrations within the hippocampus of schizophrenia patients and controls, obtained with 3D multi-voxel ¹H-MRS at 3 T. Higher field strength (compared to 1.5 T in most earlier studies) and 3D ¹H-MRS (compared to earlier single-voxel reports) allowed us to examine the hippocampus despite its irregular shape at high signal-to-noise ratio and spatial resolution. Our goal was to test the hypothesis that compared to controls, schizophrenia patients will show decreased NAA, reflecting neuronal damage, and reduced hippocampal volume, the morphological consequences of this loss.Twenty-four patients (Table 1) were recruited along with seven age- and gender-matched healthy controls (4 males and 3 female) 37.1±11.4 years old. Experiments were done at 3 T. Following MP-RAGE acquisition and B₀ shimming, 6×9×2 cm (AP×LR×IS) =108 cm^{3 1}H-MRS VOI (PRESS TE/TR=35/1400 ms) was placed over the hippocampus (Fig. 1), and encoded to form 216 voxels, each 1.0×1.0×0.5 cm³. Quantification was performed using the phantom replacement method with corrections for T₁ and T₂ relaxation times. Bilateral hippocampal masks were manually traced on the MP-RAGE images, as shown in Fig. 1a. Masks of cerebro-spinal fluid, gray and white matter (CSF, GM, WM) were obtained using SPM12. The ¹H-MRS and segmented data was combined and only ¹H-MRS voxels fulfilling the following criteria were retained: >30% hippocampus; <30% CSF; metabolite Cramer-Rao lower bounds <20%; metabolite linewidths between 4 and 13 Hz (Fig. 2). The global GM and WM levels of each metabolite in the remaining N≥2 hippocampus voxels were calculated using linear regression. Analysis of covariance and Mann-Whitney tests at the two-sided 5% significance levels were used to compare the groups in terms of metabolism and volumetry.Seven patients were excluded from the analysis due to poor spectra quality resulting from excessive, medication-related motion during the scan, leaving 17 (9 male, 8 female) patients, 40.1±10.5 years old for the analysis (Table 1). No controls were excluded. Our shimming procedure yielded an average metabolites voxel linewidth of 9.1±4.0 Hz. The average number of voxels per subject that passed the selection criteria (see Fig. 2) described above and used to estimate the NAA, Cr, and Cho concentrations were: 10.3±4.4, 7.8±3.9, and 6.5±3.1. Average hippocampal (GM) metabolite concentrations and the bilateral volumes [obtained by summing all pixels in the right and left outlined volumes (See Fig. 1a)], are given in Table 2. Analysis by group revealed significantly higher Cho concentration (+28%, p<0.05) in the hippocampi of patients than controls’, even after adjusting for age and gender, as shown in Table 2 and Fig. 3. The coefficient of variance for the Cho concentration was almost twice as large in patients as in controls (0.34 versus 0.18). The concentrations of NAA and Cr were not significantly different between the two groups. The bilateral hippocampal volume was ~10% lower in patients than controls (p<0.05).Surprisingly, the findings did not support our hypothesis that patients with schizophrenia would exhibit decreased NAA levels reflecting hippocampal neuronal dysfunction compared with healthy controls, as is generally reported in ¹H-MRS literature ^6,7. The observed increased Cho without change in NAA suggests an inflammatory process that predominantly affects glial rather than neuronal cells. The lower hippocampal volume observed in the patients is consistent with prior reports ², while its lack of correlation with NAA suggests that it may be a developmental trait rather than a result of neurodegeneration. Some of the study's limitations were: small sample size limiting the statistical power; varying disease durations and medication regimens; and lower spectral quality compared to other brain regions due to the anatomical milieu of the hippocampus (e.g. near the signal-distorting air filled sinuses), causing data exclusion and precluding the study of other metabolites. Our results are nevertheless consistent with neuropathology reports of neither gliosis nor net neuronal loss ^8-10, and should motivate further studies to validate these findings addressing the above-mentioned limitations.