Neurophysiological Signatures of Negative Symptom Improvement After High-Definition Transcranial Direct Current Stimulation: A Transcranial Magnetic Stimulation-Electroencephalography Study.

BACKGROUND: Schizophrenia remains a major health challenge, partly because conventional antipsychotics show limited efficacy for negative symptoms. High-definition transcranial direct current stimulation (HD-tDCS) may improve these symptoms, but its neurophysiological mechanisms remain unclear. METHODS: This study included two phases. First, 103 patients with schizophrenia and 76 healthy controls underwent transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) to assess cortical excitation and inhibition; patients also completed PANSS assessments. Second, patients were randomized in a double-blind trial to receive 20 sessions of 1.5 mA anodal HD-tDCS targeting the left DLPFC or sham stimulation (active: 52; sham: 51), followed by post-intervention TMS-EEG. RESULTS: At baseline, patients showed reduced N100 amplitudes compared with controls (p = 0.005), which correlated with negative symptom severity (r = -0.28, p = 0.025). Active HD-tDCS improved negative (d = -1.46), positive (d = -0.59), and general psychopathology symptoms (d = -1.13). These improvements were accompanied by N100 normalization (p = 0.013), and N100 changes were specifically associated with negative symptom improvement (p = 0.01), but not other symptom domains. Exploratory source-space analyses showed limbic-network SCD increases and symptom associations after active HD-tDCS (p = 0.04), but these effects did not survive FDR correction. CONCLUSIONS: Left DLPFC-targeted HD-tDCS improves negative symptoms in schizophrenia, potentially by restoring cortical inhibitory function, with exploratory evidence suggesting possible involvement of prefrontal-limbic network plasticity. N100 normalization may represent a signature of treatment response.