HD-tDCS modulation of the DLPFC-HPC-EC pathway to enhance working memory in schizophrenia: a TMS-EEG Study

Schizophrenia (SCZ) is characterized by cognitive impairments, particularly in working memory (WM), which significantly impact patients' functional outcomes, yet effective interventions for these cognitive deficits remain limited. This randomized, double-blind, sham-controlled study aimed to investigate whether a single session of high-definition transcranial direct current stimulation (HD-tDCS) targeting the left dorsolateral prefrontal cortex (DLPFC) can improve WM in patients with SCZ and to elucidate the underlying neural mechanisms. A total of 69 patients with SCZ were randomly assigned to active HD-tDCS (n = 34) or sham HD-tDCS (n = 35). WM performance was assessed using a 2-back task, and neural activity was evaluated via TMS-EEG to measure changes in excitability and connectivity across the DLPFC, hippocampus (HPC), and entorhinal cortex (EC). Active HD-tDCS significantly improved WM task accuracy (p < 0.001) and reduced reaction times (p < 0.01) compared to the sham group. TMS-EEG analyses revealed reduced neural excitability in the EC and HPC following active stimulation, with changes in EC activity correlating with improved WM accuracy. Mediation analyses suggested that HD-tDCS modulates WM through a statistically modeled DLPFC-HPC-EC neural pathway, with the HPC acting as a full mediator. These findings provide evidence that a single session of HD-tDCS targeting the DLPFC enhances WM in SCZ patients, potentially by modulating the DLPFC-HPC-EC functional cascade, highlighting its potential as a non-invasive intervention for cognitive impairments in SCZ and offering insights into its underlying mechanisms.