The Link Between GABA Levels and P300 Abnormalities in Schizophrenia Spectrum Disorders: Regional and Symptom-Based Insights

According to the excitation-inhibition imbalance theory, GABAergic and glutamatergic systems influence the clinical symptoms and particularly cognitive deficits in schizophrenia spectrum disorders (SSD). These systems have been found disrupted in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) in SSD, and are associated with P300 abnormalities in electroencephalography recordings. Therefore, we explored the relationships among MRS-derived GABA and Glx levels in the ACC and left DLPFC (lDLPFC), auditory P300 amplitudes and latencies, cognition, and symptom severity in SSD. We grouped patients into higher (SSD+) and lower (SSD-) symptom severity clusters based on PANSS total scores. P300 amplitudes were lower in SSD patients than healthy controls at central and parietal sites. SSD+ exhibited widespread reductions at frontal, central, and parietal areas, while SSD- showed reductions limited to the parietal region. GABA levels in the lDLPFC were higher in SSD- compared to controls and were positively associated with P300 amplitudes at central and parietal sites within SSD- and overall SSD group. Although P300 amplitudes positively correlated with the BACS composite scores and behavioral performance, lDLPFC GABA levels showed no direct association with cognitive or behavioral performance. ACC GABA, ACC Glx, and lDLPFC Glx levels showed no group differences or P300 associations. Our findings suggest P300 amplitude reductions as a marker of cognitive dysfunction in SSD, more pronounced in patients with higher disease severity, and that enhanced lDLPFC GABA may help offset these reductions. Our work provides the first empirical evidence of the interplay between the GABAergic system and cortical electrophysiological signal patterns mirroring cognitive dysfunction in SSD.