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Transcranial temporal interference stimulation for treating bipolar disorder with depressive episodes: a feasibility Study

Molecular Psychiatry volume 30, pages 6099–6106 (2025)Cite this article

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Abstract

Bipolar depression (BD-D) is a significant clinical challenge associated with high disease burden. Transcranial temporal interference stimulation (tTIS), a novel and noninvasive approach for targeting deep brain structures, was investigated for its efficacy and safety in BD-D patients in this trial. Thirty-six patients were recruited for a single-arm, open-label trial, and 25 completed the 5-day intervention consisting of 10 tTIS sessions targeting the left nucleus accumbens. Each session lasted 20 min, with a maximum current intensity of 2 mA and an envelope stimulation frequency of 40 Hz. Significant symptom reductions were observed following treatment, with mean HAMD-17 scores decreasing from 23.36 to 16.16 (p < 0.0001), MADRS scores from 39.12 to 31.28 (p < 0.01), HAMA scores from 19.68 to 15.44 (p < 0.05), and QIDS scores from 13.52to 9.68 (p < 0.001). Eleven participants (44.0%) met improvement criteria and seven (28.0%) achieved response. Cognitive assessments indicated improvements in memory and executive function, and changes in reward-related brain activity correlated positively with symptom reduction. Adverse events were mild, mainly transient scalp discomfort. These findings provide preliminary evidence supporting the efficacy and safety of tTIS for alleviating depressive symptoms and cognitive impairments in BD-D.

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Fig. 1: Effects of tTIS intervention on depressive and anxiety symptoms.
Fig. 2: Cognitive improvement following tTIS intervention.
Fig. 3: MID task design and fMRI results.

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Data availability

The datasets used in this study are from a clinical trial conducted at the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, and are not publicly available due to potential privacy concerns related to research participants. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

Code availability

The datasets used in this study are from a clinical trial conducted at the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China, and are not publicly available due to potential privacy concerns related to research participants. Any additional information required to reanalyze the data reported in this paper is available from the lead contact upon request.

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Acknowledgements

Research supported by the National Key Research and Development Program of China (2023YFC2506200), the “Pioneer” and “Leading Goose” R&D Program of Zhejiang (2025C01137), the Research Project of Jinan Microecological Biomedicine Shandong Laboratory (No. JNL-2023001B), the Innovation team for precision diagnosis and treatment of major brain diseases (No. 2020R01001), Chinese Medical Education Association (2022KTZ004), the Ministry Key Project (GW089000), the National Natural Science Foundation of China (52407261, 82201675) and the Fundamental Research Funds for the Central Universities (226-2022-00193, 226-2022-00002, 2023ZFJH01-01, 2024ZFJH01-01).

Author information

Author notes

  1. These authors contributed equally: Hetong Zhou, Minmin Wang, Shuangyu Qi.

  2. These authors jointly supervised this work: Hui Zhou, Shaomin Zhang, Shaohua Hu.

Authors and Affiliations

  1. Department of Psychiatry, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Hetong Zhou, Shuangyu Qi, Qianfeng Chen, Jianbo Lai & Shaohua Hu

  2. Qiushi Academy for Advanced Studies, Zhejiang University, Hangzhou, China

    Minmin Wang & Shaomin Zhang

  3. Westlake Institute for Optoelectronics, Westlake University, HangZhou, China

    Minmin Wang

  4. School of Electronic Science and Engineering, Nanjing University, Nanjing, China

    Zhengping Wu

  5. State Key Laboratory of Cognitive Science and Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China

    Ruobing Liu & Liang Wang

  6. Department of Psychology, University of Chinese Academy of Sciences, Beijing, China

    Ruobing Liu & Liang Wang

  7. The State Key Lab of Brain-Machine Intelligence, Zhejiang University, Hangzhou, China

    Hui Zhou, Shaomin Zhang & Shaohua Hu

  8. Department of Psychology and Behavioral Sciences, Zhejiang University, Hangzhou, China

    Hui Zhou

  9. Nanhu Brain-computer Interface institute, Hangzhou, China

    Shaohua Hu

  10. The Zhejiang Key Laboratory of Precision Psychiatry, Hangzhou, China

    Shaohua Hu

  11. MOE Frontier Science Center for Brain Science and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou, China

    Shaohua Hu

  12. Brain Research Institute of Zhejiang University, Hangzhou, China

    Shaohua Hu

  13. Zhejiang Engineering Center for Mathematical Mental Health, Hangzhou, China

    Shaohua Hu

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Contributions

S Hu, S Zhang, and Hui Zhou had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: S Hu, S Zhang, Hui Zhou and M Wang. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: H Zhou, M Wang. Critical review of the manuscript for important intellectual content: All authors. Statistical analysis: H Zhou, M Wang. Obtained funding: S Hu and S Zhang. Administrative, technical, or material support: M Wang, SQ, Q Chen, Z Wu, J Tang and L Wang. Supervision: S Hu, S Zhang, and Hui Zhou.

Corresponding authors

Correspondence to Hui Zhou, Shaomin Zhang or Shaohua Hu.

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The authors declare no competing interests.

Ethics approval and consent to participate

This study was conducted in accordance with the Declaration of Helsinki and relevant institutional and national guidelines and regulations. The protocol was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine (2022-019,2025B-0160). The trial was registered at ClinicalTrials.gov (NCT06516991). Written informed consent was obtained from each patient and their legal guardian prior to enrolment.

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Zhou, H., Wang, M., Qi, S. et al. Transcranial temporal interference stimulation for treating bipolar disorder with depressive episodes: a feasibility Study. Mol Psychiatry 30, 6099–6106 (2025). https://doi.org/10.1038/s41380-025-03292-7

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