Immediate and long-term effects of orbitofrontal cortex stimulation on EEG microstates in schizophrenia

Repetitive transcranial magnetic stimulation (rTMS) targeting the orbitofrontal cortex (OFC) has shown promise in treating schizophrenia, yet its immediate and long-term effects on brain dynamics remain unclear. This study investigated the electrophysiological impact of OFC-rTMS by analyzing EEG microstates in patients with schizophrenia and healthy controls. A total of 87 patients were randomized to receive either 20 sessions of 1 Hz OFC-rTMS or sham stimulation, while 51 healthy controls received a single active rTMS session. Resting-state EEG recordings were obtained at baseline, immediately after the first session, and following the full course of treatment. Microstate analysis was performed by clustering EEG topographies into four canonical classes and extracting temporal features. At baseline, patients exhibited elevated microstate C and reduced microstate D compared to controls. A single active session reduced microstate C occurrence in both groups, with no changes observed in the sham group. After 20 sessions, the active rTMS group showed a sustained decrease in microstate C and increased microstate D across multiple metrics. Notably, exploratory subgroup analysis revealed that clinical responders to OFC-rTMS exhibited greater immediate reductions in microstate C following the first session compared to non-responders. These findings suggest that OFC-rTMS induces both immediate and long-term modulation of EEG microstates in schizophrenia, particularly normalizing abnormalities in microstate C. Early EEG responses may serve as potential biomarkers for long-term therapeutic response.