The link between GABA levels and P300 abnormalities in schizophrenia spectrum disorders: regional and symptom-based...

According to the excitation-inhibition imbalance theory, GABAergic and glutamatergic systems influence the clinical symptoms, 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 may contribute to 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 P3b subcomponent amplitudes and latencies, cognition, and symptom severity in SSD. In total, 107 patients and 107 healthy controls (HC) were included in the study, with the exact numbers varying across specific analyses. We grouped patients into higher (SSD+, N = 41) and lower (SSD-, N = 65) symptom severity clusters based on PANSS total scores. P3b amplitudes were lower in SSD patients than HC at central and parietal sites. SSD+ exhibited widespread P3b amplitude reductions, significant at parietal and trend-level at central and frontal regions, while SSD- showed a trend-level amplitude reduction limited to the parietal region. GABA levels in the lDLPFC were higher in SSD- compared to controls and were positively associated with P3b amplitudes at central and parietal sites within SSD- and overall SSD group. Although P3b 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 P3b associations. Our findings suggest P3b amplitude reductions as a marker of cognitive dysfunction in SSD, more pronounced in patients with higher illness severity, and that enhanced lDLPFC GABA may contribute to offsetting these reductions. Our work provides the first empirical evidence of the interplay between the GABAergic system and cortical electrophysiological signal patterns associated with cognitive dysfunction in SSD.