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A distinct biomarker of continuous transcutaneous vagus nerve stimulation treatment in major depressive disorder
Open accessAbstract
Background Major depression is the fourth leading cause of disability worldwide and poses a socioeconomic burden worldwide. Transcutaneous vagus nerve stimulation (tVNS) is a promising noninvasive clinical device that may reduce the severity of major depression. However, the neural mechanism underlying continuous tVNS has not yet been elucidated.Objective We aimed to explore the effect of hypothalamic subregion functional connectivity (FC) changes during continuous tVNS treatment on major depressive disorder (MDD) patients and to identify the potential biomarkers for treatment outcomes.Methods Forty-one mild to moderate MDD patients were recruited and received either real or sham tVNS treatment for 4 weeks. We used a seed-to-whole brain approach to estimate the FC changes of hypothalamic subregions and their surrounding control areas during continuous tVNS treatment and explored their association with clinical outcome changes after 4 weeks of treatment.Results Of the thirty-six patients that completed the study, those in the tVNS group had significantly lower scores on the 24-item Hamilton Depression (HAM-D) Rating Scale compared to the sham tVNS group after 4 weeks of treatment. The FC between the bilateral medial hypothalamus (MH) and rostral anterior cingulate cortex (rACC) was significantly decreased during tVNS but not during sham tVNS. The strength of this FC was significantly correlated with HAM-D improvements after 4 weeks of tVNS.Conclusion The FC between the bilateral MH and rACC may serve as a potential biomarker for the tVNS state and predict treatment responses. Our results provide insights into the neural modulation mechanisms of continuous tVNS and reveal a potential therapeutic target for MDD patients.
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“The interventions used in the control groups were all sham taVNS.[13–15]”
From Transcutaneous auricular vagus nerve stimulation in treating major depressive disorder: A systematic review and meta-analysis (2018) · cites this paper as [15]
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“In contrast, the confounding bias was not reported in any of these 2 trials.[14,15]”
From Transcutaneous auricular vagus nerve stimulation in treating major depressive disorder: A systematic review and meta-analysis (2018) · cites this paper as [15]
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“One studies recorded the side effects of transcutaneous auricular vagus nerve stimulation in treating major depressive disorder but did not report the adverse outcomes.[15]”
From Transcutaneous auricular vagus nerve stimulation in treating major depressive disorder: A systematic review and meta-analysis (2018) · cites this paper as [15]
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“Tu et al. [39] reported decreased connectivity between the bilateral medial hypothalamus and rACC in the taVNS group, correlating with symptom improvement.”
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“…movement (Dawson et al., 2016; Redgrave et al., 2018) or 15-min stimulations (Bretherton et al., 2019) have been applied. aVNS has been tested in the treatment of depression (Tu et al., 2018), drug-resistant epilepsy (Yang et al., 2023), and for motor recovery after stroke (Redgrave et al., 2018).”
Zhang, Z.-Q., Guo, Z., Lv, X., Sörös, P., Wang, X.-X., Wang, L., & Liu, C. (2022) · BMJ Open · doi:10.1136/bmjopen-2021-050446 · Cited by 5
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“…angular gyrus correlated with HAMD score improvement after ECT (100); decreased connectivity be-tween the medial hypothalamus and rostral ACC correlated with HAMD score improvement after tVNS (93); and a reduction in prefrontal alpha power correlated with HAMD score improvement after MST (47).”
Nayok, S. B., Sreeraj, V. S., Shivakumar, V., & Venkatasubramanian, G. (2023) · Indian Journal of Physiology and Pharmacology · doi:10.25259/ijpp_401_2022 · Cited by 4
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Zhang, S., He, H., Li, X., & Guo, Y. (2025) · Frontiers in Neurology · doi:10.3389/fneur.2025.1615635 · Cited by 4
Transcutaneous auricular vagus nerve stimulation in the treatment of depression
Kong, J., Wilson, G., & Rong, P. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-817933-8.00031-1 · Cited by 3
Lai, J., Liu, J. H., Zhang, L., Cao, J., Yang, H., Zhang, L., Fang, J., & Wang, X. T. (2025) · Heliyon · doi:10.1016/j.heliyon.2025.e42469 · Cited by 4
“More recently, the efficacy of transcutaneous auricular vagus nerve stimulation (t-VNS) combined with electrical stimulation for major depressive disorder [8 – 10], primary insomnia [11], epilepsy [12,13] and mild cognitive impairment [14] has been objectively evaluated.”
Dong, S., Hao, F., Xue, B., Wu, S., Zhong, R., Liao, Z., Han, H., & Fang, X. (2025) · Food Science and Human Wellness · doi:10.26599/fshw.2024.9250201 · Cited by 2
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“Moreover, research by Tu et al. indicated that after four weeks of taVNS treatment, patients in the real stimulation group showed signi fi cantly lower scores on the HAMD scores compared to the sham group (54).”
Ji, T.-Z., Li, X. Z., Shen, J., Wang, W. Q., & Xie, L. (2026) · BMC Pregnancy and Childbirth · doi:10.1186/s12884-026-09189-9 · Cited by 2
“Clinical studies have demonstrated that taVNS can improve depressive symptoms in patients with major depressive disorder and related conditions, with favorable safety and tolerability profiles [18, 19, 22].”
Opportunities and trends of transcutaneous auricular vagus nerve stimulation
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“…of the hypothalamus such as medial, lateral, anterior, and posterior, although none had the spatial acuity to robustly target specific hypothalamic regions as we had done in this investigation ( Ferraro et al., 2018; Kullmann et al., 2014; Meylakh et al., 2020; Tu et al., 2018; Zhang et al., 2018).”
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Distribuição de vídeo sobre uma rede IEEE 802.11n
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Transcutaneous Vagal Nerve Stimulation in Trauma Spectrum Psychiatric Disorders
Bremner, J. D., Wittbrodt, M. T., Gurel, N. Z., Shandhi, M. M. H., Gazi, A. H., Park, J., & Inan, O. T. (2023) · Neuromethods · doi:10.1007/978-1-0716-3465-3_8
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Neurostimulation Tools and Approaches
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Bremner, J. D., Wittbrodt, M. T., Gurel, N. Z., Nye, J. A., Shandhi, M. M. H., Gazi, A. H., Shah, A. J., Amorim, V., Pearce, B. D., Vaccarino, V., et al. (2025) · Journal of Affective Disorders Reports · doi:10.1016/j.jadr.2025.101014
“…subjects (Badran et al., 2018; Frangos et al., 2015; Yakunina et al., 2017) and patients with depression (Fang et al., 2017, 2016; Liu et al., 2016; Tu et al., 2018; Wang et al., 2018) and the neck (tcVNS) in healthy human subjects (Bremner et al., 2019; Frangos and Komisaruk, 2017a; Wittbrodt et…”
Ali, N. F., Tariq, U., & Al-Nashash, H. A. (2026) · IEEE Sensors Journal · doi:10.1109/jsen.2026.3673727
Vagus Nerve Stimulation for Neuromodulation: Evolution from Bench to Bedside
Vannemreddy, P. S. S. V., & Slavin, K. V. (2026) · Neurology International · doi:10.3390/neurolint18050094
“Similarly other authors also established the efficacy of VNS in refractory depression [39], along with fMRI documentation [40–43].”
Metadata
- Authors
- Tu, Y., Fang, J., Cao, J., Wang, Z., Park, J., Jorgenson, K., Lang, C., Liu, J., Zhang, G., Zhao, Y., Zhu, B., Rong, P., & Kong, J.
- Affiliations
- Harvard University (US)
- China Academy of Chinese Medical Sciences (CN)
- Corresponding author
- Rong, Peijing
- Kong, Jian
- ORCID
- Venue
- Brain stimulation
- Publisher
- Elsevier BV
- Published
- 2018-05
- Volume
- 11
- Issue
- 3
- Pages
- 501-508
- ISSN
- 1876-4754 (ISSN-L)
- 1935-861X
- PMC
- PMC5930128
- OpenAlex
- W2792997548
- Cited by
- 104
- References
- 66
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 15 · 2023: 12 · 2022: 13 · 2021: 21 · 2020: 10 · 2019: 4 · 2018: 3
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain stimulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Beijing Municipal Science & Technology Commission (Z161100002616003)
- National Natural Science Foundation of China (81471389, 81473780, 81303056, 81674072, 81774433)
- NIH/NCCIH (R01AT006364, R01AT008563, R21AT008707, R61AT009310, P01AT006663)
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Life Sciences › Neuroscience › Neurology › Transcranial Magnetic Stimulation Studies
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Keywords
- transcutaneous vagus nerve stimulation, major depressive disorder, functional connectivity, medial hypothalamus, rostral anterior cingulate cortex, treatment response biomarkers, Hamilton Depression Rating Scale
- MeSH terms
- Adolescent, Adult, Aged, Brain, Major Depressive Disorder, Transcutaneous Electric Nerve Stimulation, Female, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Vagus Nerve, Biomarkers, Treatment Outcome, Vagus Nerve Stimulation, Young Adult
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