One of the plausible mechanisms of schizophrenia is the so-called “gamma-amino butyric acid (GABA)-ergic origin hypothesis”, which originates from the hypofunction of N-methyl-D-aspartate (NMDA)-type of glutamate (Glu) receptor.¹ GABA, which is produced from Glu, is the chief inhibitory neurotransmitter and is thought to play an important role in the pathophysiology of schizophrenia.² In vivo GABA can be measured non-invasively by proton magnetic resonance spectroscopy (¹H-MRS), but unambiguous detection of GABA cannot be accomplished by conventional pulse sequences due to the overlapping of resonance peaks of GABA with other detectable metabolites. Yet, with the advent of technology, a MEGA-PRESS pulse sequence was developed to detect GABA.³ Glu, on the other hand, is the most importantly excitatory neurotransmitter in the brain, whereas Gln is the precursor and reaction product of Glu in the Glu/Gln cycle. Glx (summation of Glu and Gln) could access the entire brain pool of Glu and Gln. The anterior cingulate cortex (ACC) has been reported to exhibit morphological change in schizophrenia and activation deficits during cognitive tasks. More importantly, a prior study reported that levels of glutamic acid decarboxylase (GAD), which is a key enzyme in GABA synthesis, was found to be significantly reduced in schizophrenic patients compared with healthy controls (HC).⁴ In this pilot study, absolute concentrations of GABA, Glx, and other metabolites including N-acetyl-aspartate (NAA), choline (Cho) and creatine (Cr), were measured in the ACC of 9 medicated schizophrenic patients and 14 HC using ¹H-MRS at 3T. 9 schizophrenic patients who were effectively treated on a stable medication regimen (mean age=26.89±6.03 years; 5M4F; treatment duration ranging from 2-34 months) were recruited in this study. Of the 9 schizophrenic patients, 6 of them were of positive schizophrenia. 14 HC (mean age=27.64±5.93 years, 8M6F) were also recruited. All subjects underwent MR scan using 3.0T Achieva TX scanner, Philips Healthcare. MEGA-PRESS (TR/TE = 2000/68 ms; 320 signal averages) was used as volume selection method with single voxel of 3x3x3cm³ placed in the ACC for GABA measurement. PRESS (TR/TE = 2000/39 ms) with 2x2x2cm³ voxel placed in the ACC was also used for measurement of other metabolites, i.e. Glx, NAA, Cho, and Cr. GABA was measured and quantified using internal water as reference by GANNET 2.0 (Figure 1). Glx, NAA, Cho, and Cr were measured and quantified with cerebrospinal fluid normalization using internal water as reference by QUEST in jMRUI (4.0). Two-sample t-test was used to investigate any differences in metabolite concentrations between schizophrenic patients and HC. Pearson correlation coefficient (r) was calculated to assess the correlation between metabolite concentrations and Positive and Negative Syndrome Scale (PANSS) subscales scores within the schizophrenic patients. SPSS version 20.0 was used for statistical analysis and level of significance was set at 0.05.Absolute concentration of GABA ([GABA]_abs) was found to be significantly lower (p = 0.043) in schizophrenic patients (1.63 ± 0.20 mM) compared with HC (1.80 ± 0.14 mM), while absolute concentration of Glx ([Glx]_abs) was found to be significantly higher (p = 0.022) in schizophrenic patients (13.98 ± 5.75 mM) compared with HC (9.77 ± 2.28 mM) (Figure 2). Within the 9 schizophrenic patients, [Glx]_abs revealed a significant positive correlation with PANSS positive symptom subscale (r = 0.725, p = 0.027), but no significant correlation was found between [GABA]_abs and PANSS positive or negative symptom subscales. In addition, the schizophrenic patients’ [GABA]_abs and [Glx]_abs has no significant correlation but a negative trend (r = -0.592, p = 0.093) was found.In this study, significant lower [GABA]_abs level in the ACC of schizophrenic patients might provide evidence of abnormalities in GABAergic neurotransmission in schizophrenia. This finding might further complement the reduced levels of GAD shown in a prior study as GAD is an enzyme essential for GABA synthesis from Glu.¹ Elevations of [Glx]_abs in schizophrenic patients might probably reflect the dysfunction of NMDA receptors. We postulated that the elevated [Glx]_abs might be due to increase in Glu in the synaptic cleft owing to a paucity or hypofunctioning of NMDA receptors.¹ Although the behavioral effects of NMDA receptor hypofunction include both positive and negative symptoms,⁵ the significant positive correlation between [Glx]_abs and PANSS positive subscale might indicate Glx level is specific for positive symptoms in the ACC, while lack of significant correlation between GABA and negative symptoms might be due to a limited number of negative schizophrenic patients in our study. This pilot study provided evidence of abnormalities in GABAergic neurotransmission in schizophrenia in the ACC. Glx level might be specific for positive symptoms in schizophrenia.