Abstract
Gamma-band neural oscillations are critically involved in working memory and are disrupted in schizophrenia. Transcranial alternating current stimulation (tACS) at gamma frequency is a promising noninvasive approach to restore oscillatory synchrony and enhance cognition. This randomized, double-blind trial tested whether 40 Hz tACS targeting frontoparietal networks modulates gamma-band activity and connectivity during working memory, and whether these electrophysiological changes relate to cognition in schizophrenia. Patients with schizophrenia (n = 33) were randomized to 10 sessions of active or sham tACS over the left dorsolateral prefrontal cortex (F3) and right parietal cortex (P4), with cognition assessed using standardized neurocognitive measures (MATRICS Consensus Cognitive Battery, MCCB) and an n-back working-memory task. EEG during an n-back task was recorded pre- and post-intervention to assess gamma power, phase-locking value (PLV), and phase-amplitude coupling (PAC). A significant Group × Time interaction indicated that 1-back minus 0-back PLV increased in the active group but not in sham (P = 0.048, Cohen’s d = 1.08). For PAC, a significant interaction showed that delta-high gamma coupling at F3 remained stable in the active group but declined in sham (P = 0.036, Cohen’s d = 1.00). There was no significant correlation with n-back measures of working memory, but an exploratory significant finding linking this modulation to visual learning at 4-week follow-up. No significant group differences were found for MCCB total scores; however, a significant Group × Time interaction emerged for 0-back accuracy during EEG recording (P = 0.029, Cohen’s d = 1.19). These findings demonstrate that 40 Hz tACS can enhance and preserve gamma synchrony in frontoparietal circuits during working memory. The maintained delta-gamma coupling in our exploratory findings on visual learning may suggest a relationship to sustained improvements in cognition over time, but needs additional confirmation.
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Data availability
The datasets generated and/or analyzed during the current study are not publicly available due to patient privacy and ethical restrictions but are available from the corresponding author upon reasonable request.
Code availability
The analysis code used in this study is not publicly available but can be obtained from the corresponding author upon reasonable request.
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Funding
Funding for this study was provided through several grants. The National Natural Science Foundation of China (82201656, 82101543), the Science and Technology Commission of Shanghai Municipality (19411969400), Shanghai Clinical Research Center for Mental Health (19MC1911100), and the Feixiang Program of Shanghai Mental Health Center (2022-FX-04).
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YL: Formal analysis, investigation, visualization, funding acquisition, writing-original draft, and writing-review and editing. XYC: Investigation, funding acquisition, and writing-review and editing. HJ: Conceptualization, methodology, and writing-review and editing. WL: Data acquisition, and writing-review and editing. FYY: Writing-review and editing. THZ: Methodology, and writing-review and editing. YYT: Methodology, and writing-review and editing. JJW: Methodology, and writing-review and editing. JMD: Conceptualization, methodology, and writing-review and editing. SHH: Writing-review and editing. RCS: Conceptualization, methodology, project administration, and writing-review and editing. CBL: Conceptualization, supervision, methodology, project administration, funding acquisition, and writing-review and editing.
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Liu, Y., Cao, X., Jin, H. et al. Effects of 40 Hz transcranial alternating current stimulation on neural synchronization and cognitive correlates in schizophrenia: An EEG study. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-03917-7
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DOI: https://doi.org/10.1038/s41398-026-03917-7
