Acute Cortical Excitability Change is Associated with Long-Term Working Memory Improvement by HD-tDCS Treatment in Schizophrenia: a TMS-EEG Study

BACKGROUND AND HYPOTHESIS: Working memory (WM) deficits are a core cognitive impairment in schizophrenia (SCZ). High-definition transcranial direct current stimulation (HD-tDCS) targeting the dorsolateral prefrontal cortex (DLPFC) has shown promise for improving WM, yet biomarkers indicating its efficacy remain limited. We hypothesized that HD-tDCS would enhance WM in SCZ and that changes in transcranial magnetic stimulation combined with electroencephalography (TMS-EEG) metrics can serve as potential biomarkers of treatment response. STUDY DESIGN: Sixty-three SCZ patients were randomized to receive either active (n = 32) or sham (n = 31) HD-tDCS. WM was assessed using the accuracy (ACC) and reaction time (RT) of the 2-back task before and after the 20-day intervention. TMS-EEG was conducted before and after the first HD-tDCS session to measure cortical responses. Changes in global mean field amplitude (GMFA) components were analyzed for their association with WM improvement. STUDY RESULTS: Active HD-tDCS significantly improved ACC (P<.001) and reduced RT (P<.001), whereas performance remained unchanged in the sham (all P>.05). A single session of active HD-tDCS reduced the N45 amplitude (P=.038), with no significant differences observed in the sham (all P>.05). The N45 reduction correlated with the ACC improvement (r = -0.452, P=.009). Stepwise regression confirmed the N45 reduction as a significant contributor of ACC improvement (β = -0.03, t = -2.15, P=.040). CONCLUSIONS: HD-tDCS effectively improved WM in SCZ patients. Reduction in N45 amplitude may serve as a neurophysiological marker of HD-tDCS treatment response.