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.