Background Depression is the most common form of mental disorder in community and health care settings and current treatments are far from satisfactory. Vagus nerve stimulation (VNS) is an FDA-approved somatic treatment for treatment-resistant depression. However, the involvement of surgery has limited VNS only to patients who have failed to respond to multiple treatment options. Transcutaneous VNS (tVNS) is a relatively new, non-invasive VNS method based on the rationale that there is afferent / efferent vagus nerve distribution on the surface of the ear. The safe and low-cost characteristics of tVNS have the potential to significantly expand the clinical application of VNS. Methods In this study, we investigated how tVNS can modulate the default mode network (DMN) functional connectivity (FC) in mild or moderate major depressive disorder (MDD) patients. Forty-nine MDD patients were recruited, and received tVNS or sham tVNS (stVNS) treatments. Result 34 patients completed the study and were included in data analysis. After one month of tVNS treatment, the 24-item Hamilton Depression Rating Scale (HAMD) score reduced significantly in the tVNS group as compared to the stVNS group. The FC between the DMN and anterior insula and parahippocampus decreased; the FC between the DMN and precuneus and orbital prefrontal cortex increased compared to stVNS. All these FC increases are also associated with HAMD reduction. Conclusions tVNS can significantly modulate the DMN FC of MDD patients; our results provide insights to elucidate the brain mechanism of tVNS treatment for MDD patients.

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.

Background Depression presents a significant burden to both patients and society. One treatment that has emerged is vagus nerve stimulation (VNS), an FDA-approved physical treatment for depressive disorders. However, the application of this intervention has been limited by the involvement of surgery and potential side effects. The aim of this study is to explore the effectiveness of stimulating the superficial branches of the vagus nerve as a solo treatment for MDD. Methods This is a nonrandomized, controlled study. The first cohort of patients (n = 91) only received transcutaneous auricular VNS (taVNS) for 12 weeks. In the second cohort (n = 69), patients first received 4 weeks of sham taVNS followed by 8 weeks of taVNS. All treatments were self-administered by the patients at home after they received training from the hospitals. The primary outcome measurement was the 24-item Hamilton Depression Rating Scale measured at weeks 0, 4, 8, and 12. Data analysis included a timelag analysis comparing 1) real and sham taVNS groups at week 4; 2) the real taVNS group at week 4 vs the sham taVNS group at week 8 (fourth week of real taVNS following 4 weeks of sham); and 3) the real taVNS group at week 8 vs the sham taVNS group at week 12 (eighth week of real taVNS following sham). Results After four weeks of treatment, MDD patients in the taVNS group showed greater improvement than that of the sham taVNS group as indicated by both Hamilton score changes as well as response and remission rates at week four. In addition, we also found that the clinical improvements continued until week 12 during taVNS. Limitations Patients were not randomized in this study. Conclusions Our results suggest that taVNS is a promising, safe, and cost-effective therapeutic method for mild and moderate MDD.

Adult neurogenesis in the dentate gyrus of the hippocampus is regulated by specific microglia groups and functionally implicated in behavioral responses to stress. However, the role of microglia in hippocampal neurogenesis and stress resilience remains unclear. We identified interleukin 4 (IL4)–driven microglia characterized by high expression of Arg1, which is critical in maintaining hippocampal neurogenesis and stress resistance. Decreasing Arg1+ microglia in the hippocampus by knocking down the microglial IL4R suppressed hippocampal neurogenesis and enhanced stress vulnerability. Increasing Arg1+ microglia in the hippocampus by enhancing IL4 signaling restored hippocampal neurogenesis and the resilience to stress-induced depression. Brain-derived neurotrophic factor (BDNF) was found necessary for the proneurogenesis effects of IL4-driven microglia. Together, our findings suggest that IL4-driven microglia in the hippocampus trigger BDNF-dependent neurogenesis responding to chronic stress, helping protect against depressive-like symptoms. These findings identify the modulation of a specific microglial phenotype as a treatment strategy for mood disorders.

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