Depression is a highly prevalent disorder, and its treatment is far from satisfactory. There is an urgent need to develop a new treatment for depression. Although still at its early stage, ...transcutaneous auricular vagus nerve stimulation (taVNS) has shown promising potential for treating depression. In this article, we first summarize the results of clinical studies on the treatment effect of taVNS on depression. Then, we re-analyze a previous study to identify the specific symptoms taVNS can relieve as indicated by subscores of the 24-item Hamilton Depression Scale in patients with depression. We found that taVNS can significantly reduce multiple symptoms of depression patients, including anxiety, psychomotor retardation, sleep disturbance, and hopelessness. Next, we pose several hypotheses on the mechanism of taVNS treatment of depression, including directly and indirectly modulating the activity and connectivity of key brain regions involved in depression and mood regulation; inhibiting neuro-inflammatory sensitization; modulating hippocampal neurogenesis; and regulating the microbiome-brain-gut axis. Finally, we outline current challenges and lay out the future directions of taVNS treatment of depression, which include (1) intensively comparing stimulation parameters and "dose effect" (treatment frequency and duration) to maximize the treatment effect of taVNS; (2) exploring the effect of taVNS on disorders comorbid with depression (such as chronic pain disorders, cardiovascular disorder, and autism) to provide new "two-for-one" treatment approaches for patients with these disorders; and (3) applying multiple scale methods to explore the underlying mechanism of taVNS.
Sensory and sympathetic nerves have been shown to promote the progression of endometriosis through the release of neuromediators and the lesional activation of respective receptors. The role of vagus ...nerves (VN) in lesional progression, however, is completely unclear, despite the signs suggestive of increased sympathetic tone in women with endometriosis. This study was undertaken to investigate whether VN plays any role in the progression of endometriosis. We recruited 45 patients with endometriosis and 42 healthy women, who were given electrocardiogram test and their heart rate variability was evaluated. In addition, three prospective, and randomized mouse experiments were conducted that evaluated, respectively, the effect of vagotomy, the effect of VN stimulation (VNS), and the therapeutic potential of VNS after the endometriosis was well established. All lesions were excised, weighed, and processed for immunohistochemistry and histochemistry analysis of select markers for lesional progression and fibrosis. We found that endometriosis patients exhibited reduced vagal activity as compared with controls, indicative of disrupted autonomic balance. Vagotomy increased while VNS decreased the lesion weight as compared with control mice, concomitant with more progressive and retarded lesion development and fibrogenesis, respectively. In addition, VNS demonstrated promising therapeutic effect, as evidenced by significantly reduced lesion weight, more attenuated lesional progression concomitant with improved hyperalgesia. Taken together, our data indicate that VN activity may play a dampening role in the progression of endometriosis. Consequently, boosting the VN activity may have therapeutic potentials for patients with endometriosis.
Abstract 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 patients in the sham taVNS group as indicated by 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.
Stress-induced neuroinflammation was considered to play a critical role in the pathogenesis of depression. Transcutaneous auricular vagus nerve stimulation (taVNS) is a relatively non-invasive ...alternative treatment for patients suffering from major depressive disorder. The anti-inflammatory signal of vagus nerve is mediated by α7 nicotinic acetylcholine receptor (α7nAchR), and the hippocampus, the region with the most distribution of α7nAchR, regulates emotions. Here, we investigated the role of α7nAchR mediating hippocampal neuroinflammation in taVNS antidepressant effect though homozygous α7nAChR (-/-) gene knockout and α7nAchR antagonist (methyllycaconitine, MLA).
There were control, model, taVNS, α7nAChR(-/-) + taVNS, hippocampus (Hi) MLA + taVNS and Hi saline + taVNS groups. We used the chronic unpredicted mild stress (CUMS) method to establish depressive model rats for 42 days, excepting control group. After the successful modeling, except the control and model, the rats in the other groups were given taVNS, which was applied through an electroacupuncture apparatus at the auricular concha (2/15 Hz, 2 mA, 30 min/days) for 21 days. Behavioral tests were conducted at baseline, after modeling and after taVNS intervention, including sucrose preference test (SPT), open field test (OFT) and forced swimming test (FST). These tests are widely used to evaluate depression-like behavior in rats. The samples were taken after experiment, the expressions of α7nAchR, NF-κB p65, IL-1β and the morphology of microglia were detected.
Depression-like behavior and hippocampal neuroinflammation in CUMS model rats were manifested by down-regulated expression of α7nAchR, up-regulated expression of NF-κB p65 and IL-1β, and the morphology of microglia was in amoebic-like activated state. TaVNS could significantly reverse the above-mentioned phenomena, but had rare improvement effect for α7nAChR(-/-) rats and Hi MLA rats.
The antidepressant effect of taVNS is related to hippocampal α7nAchR/NF-κB signal pathway.
Background
Depression is a common psychiatric disorder in diabetic patients. Depressive mood associated with obesity/metabolic disorders is related to the inflammatory response caused by long‐term ...consumption of high‐fat diets, but its molecular mechanism is unclear. In this study, we investigated whether the antidepressant effect of transcutaneous auricular vagus nerve stimulation (taVNS) in high‐fat diet rats works through the P2X7R/NLRP3/IL‐1β pathway.
Methods
We first used 16S rRNA gene sequencing analysis and LC–MS metabolomics assays in Zucker diabetic fatty (ZDF) rats with long‐term high‐fat diet (Purina #5008) induced significant depression‐like behaviors. Next, the forced swimming test (FST) and open field test (OFT) were measured to evaluate the antidepressive effect of taVNS. Immunofluorescence and western blotting (WB) were used to measure the microglia state and the expression of P2X7R, NLRP3, and IL‐1β in PFC.
Results
Purina#5008 diet induced significant depression‐like behaviors in ZDF rats and was closely related to purine and inflammatory metabolites. Consecutive taVNS increased plasma insulin concentration, reduced glycated hemoglobin and glucagon content in ZDF rats, significantly improved the depressive‐like phenotype in ZDF rats through reducing the microglia activity, and increased the expression of P2X7R, NLRP3, and IL‐1β in the prefrontal cortex (PFC).
Conclusion
The P2X7R/NLRP3/IL‐1β signaling pathway may play an important role in the antidepressant‐like behavior of taVNS, which provides a promising mechanism for taVNS clinical treatment of diabetes combined with depression.
Transcutaneous auricular vagus nerve stimulation can reduce the depression‐like behaviors of high‐fat diet‐induced ZDF rats by modulating the anti‐inflammatory effects generated by the P2X7R/NLRP3/IL‐1β signaling pathway in the PFC, which provides a promising mechanism for taVNS clinical treatment of diabetes combined with depression.
Background
Transcutaneous auricular vagus nerve stimulation (taVNS) is a crucial neuromodulation therapy for depression, yet its molecular mechanism remains unclear. Here, we aim to unveil the ...underlying mechanisms of antidepression by systematically evaluating the change of gene expression in different brain regions (i.e., hippocampus, anterior cingulate cortex, and medial prefrontal cortex).
Methods
The adolescent depression rat model was established by chronic unpredictable mild stress (CUMS), followed by the taVNS treatment for 3 weeks. The open field test (OFT), forced swimming test (FST), elevated plus maze test (EPM), and new object recognition (NOR) test were used to evaluate depressive‐ and anxiety‐like behaviors. Gene expression analysis of three brain regions was conducted by RNA sequencing (RNA‐seq) and further bioinformatics methods.
Results
The depressive‐ and anxiety‐like behaviors in CUMS‐exposed rats were manifested by decreased spontaneous locomotor activity of OFT, increased immobility time of FST, increased entries and time in the closed arms of EPM, and decreased new object index of NOR. Furthermore, CUMS exposure also led to alterations in gene expression within the hippocampus (HIP), anterior cingulate cortex (ACC), and medial prefrontal cortex (mPFC), suggesting a potential link between adolescent stress and pathological changes within these brain regions. TaVNS could significantly ameliorate depressive‐ and anxiety‐like behaviors. Its effects on these three brain regions were found related to regulation of the metabolism, and there were some brain region‐specific findings. Compared with ACC and mPFC, taVNS has a more concrete effect on HIP by regulating the inflammation response and glycolysis.
Conclusion
taVNS is capable of ameliorating adolescent depressive‐ and anxiety‐like behaviors by regulating plenty of genes in the three brain regions. Suppressed level of inflammatory response and enhanced glycolysis manifests the dominant role of taVNS in HIP, which provides a theoretical foundation and data support for the molecular mechanism of antidepression by taVNS.
Transcutaneous auricular vagus nerve stimulation has the capability to improve depressive‐ and anxiety‐like behaviors in adolescent rats by regulating numerous genes in three key brain regions associated with emotions.
The stem bark of Magnolia officinalis is a traditional Chinese medicine for the treatment of abdominal distention and functional dyspepsia. The pharmacokinetics of three glycosides (magnoloside A, ...magnoloside B, and syringin) and two lignans (honokiol and magnolol) in both normal and functional dyspepsia rats were firstly investigated by ultra‐performance liquid chromatography‐triple quadrupole mass spectrometry method and the influences of the coexisting compounds on the pharmacokinetic parameters of honokiol and magnolol were also studied. It was found that all of the five target compounds were quickly absorbed and eliminated in both normal and functional dyspepsia rats, while, their residence time was significantly decreased in pathological states except magnoloside A. The coexisting compounds in the stem bark of M. officinalis significantly reduced absorption and increased elimination of honokiol in vivo. It's worth noticing that the volume of distribution of lignan was quite lower than that of a glycoside. Moreover, the metabolic profiling of magnoloside A, honokiol, and magnolol in vivo was analyzed by ultra‐performance liquid chromatography‐quadrupole time‐of‐flight mass spectrometry method, from which three prototypes were identified and 35 metabolites were putatively characterized, and 18 unknown metabolites were reasonably characterized for the first time. The results indicated that sulfation and glucuronidation were the main metabolic pathways of honokiol and magnolol.
Background
Transcutaneous auricular vagus nerve stimulation (taVNS) is a vital neuromodulation for the treatment of depression, but its antidepressant molecular mechanism is unclear. The α7 nicotinic ...acetylcholine receptor (α7nAchR) is a key mediator of the vagus nerve that mediates its anti‐inflammatory efficacy. Here, we investigated whether the antidepressant effect of taVNS in chronic unpredicted mild stress (CUMS)‐exposed rats works through the α7nAchR/JAK2/STAT3/NF‐κB pathway.
Methods
The depression model was established by CUMS for continuous 6 weeks in rats. From the 4th week of the experiment, CUMS‐exposed rats were subjected to taVNS for 3 weeks. To clarify the role of α7nAchR in the antidepressant effect of taVNS, we used α7nAchR−/− gene knockout rats. The sucrose preference test (SPT), open field test (OFT), and forced swimming test (FST) were used to evaluate depression‐like behaviors of rats. Immunofluorescent staining was used to observe the morphology of microglia in the hypothalamus. Western blot was used to examine the protein expression of α7nAchR, p‐JAK2, p‐STAT3, IL‐1β, NF‐κB p65, and p‐NF‐κB p65 in the hypothalamus.
Results
Depression‐like behaviors in CUMS‐exposed rats were manifested by decreased SPT ratio, increased FST immobility time, decreased total distance, vertical movement score, and activity time of OFT. Hypothalamic neuroinflammation in CUMS‐exposed rats was manifested by an amoebic‐like activated state of microglia, downregulated expression of α7nAchR, p‐JAK2, p‐STAT3, and upregulated expression of NF‐κB p65, p‐NF‐κB p65, and IL‐1β. TaVNS could significantly reverse the above‐mentioned phenomena, but had a poor improvement effect for CUMS‐exposed α7nAchR−/− rats.
Conclusion
The hypothalamic α7nAchR/JAK2/STAT3/NF‐κB signaling pathway may play an important role in the antidepressant‐like behavior of taVNS.
Transcutaneous auricular vagus nerve stimulation (taVNS) activates the nucleus of tract solitary by stimulating the auricular branch of the vagus nerve and then projects to the hypothalamus, which inhibits the activated microglia. TaVNS enhances the expression of α7nAchR in the hypothalamus, activates the JAK2/STAT3 pathway, and inhibits the NF‐κB pathway, thus attenuating the secretion of IL‐1β and improving the depressive‐like behaviors in CUMS rats.
As a common mental disorder, depression is one of the leading causes of disability around the world. Clinical studies have shown that acupuncture is an effective therapy without obvious side effects ...compared to limited efficacy and adverse reactions of drug therapy, cognitive behavioral therapy, and neuromodulation technology in treating depression. The objective of this review is to systematically evaluate whether acupuncture therapies for depression are safe and effective in order to provide a high‐quality reference for clinical trials of acupuncture. A systematic search of the literature was carried out through bibliographic search engine PubMed. Subsequently, the study design, intervention methods, control group, results, and safety of acupuncture were analyzed. The results showed that acupuncture as an adjunct to antidepressants or as a single treatment can exert a positive impact on patients' depressive symptoms. Compared with antidepressants, acupuncture has the advantages of fast onset and long‐term efficacy in the treatment of depression, and can enhance the efficacy of antidepressants. Moreover, the efficacy and safety of acupuncture in the treatment of depression maybe related to the qualification of the acupuncturist, the selection of acupoints, and intervention measures.
摘要: 抑郁症是一种影响患者思想、行为及躯体的常见精神疾病，是全球致残的主要原因之一。药物疗法、认知行为疗法和神经调控技术是抑郁症的常规治疗方法，但这些方法疗效有限，容易引发不良反应。临床研究表明，针刺是一种有效治疗精神疾病的方法，且没有明显的副作用。本文的目的是系统评价针刺疗法治疗抑郁症是否安全有效及针刺干预措施对疗效的影响，以期为开展高质量的针刺临床试验提供参考。我们使用 PubMed 对文献进行了系统检索。对研究的结果和安全性进行分析。结果显示，针刺无论是作为抗抑郁药的辅助疗法还是单一疗法， 其对患者的抑郁症状改善均有积极作用。与抗抑郁药相比，针刺治疗抑郁症具有起效快，疗效持久的优势，并且可增强抗抑郁药物疗效。此外，针刺抗抑郁的疗效和安全性可能与针刺操作者的资质、穴位选取及干预措施等因素有关。
Zucker diabetic fatty (ZDF) rats that harbor a mutation in the leptin receptor innately develop type 2 diabetes (T2D) with obesity. Transcutaneous auricular vagal nerve stimulation (taVNS) has an ...antidiabetic effect in ZDF rats. However, the underlying mechanisms of the weight-gain attenuating effect in ZDF rats by taVNS is still unclear. This study aimed to assess whether the weight-gain attenuating effect of taVNS in ZDF rats is associated with changes in the central nervous system (CNS) expression of P2Y1 receptors (P2Y1R). Adult male ZDF rats were subjected to taVNS and transcutaneous non-vagal nerve stimulation (tnVNS). Their food intake and body weight were recorded daily and weekly, respectively. P2Y1R expression in the hypothalamus, amygdala, and hippocampus was evaluated by western blotting. Hypothalamic P2Y1R expressing cells were detected using immunohistochemistry. Naïve ZDF rats were much heavier (p < 0.05) than their lean littermates (ZL rats), with elevated hypothalamic P2Y1R expression (p < 0.05). Further, taVNS but not tnVNS attenuated weight gain (p < 0.05) without decreasing food intake (p > 0.05) and suppressed hypothalamic P2Y1R expression in ZDF rats (p < 0.05). Moreover, P2Y1R showed major expression in astrocytes of ZDF rats’ hypothalamus. ZDF rats innately develop obesity associated with elevated hypothalamic P2Y1R expression. taVNS attenuates weight gain in ZDF rats without changes in food intake, suggesting increased energy expenditure. Whether the reduced hypothalamic P2Y1R expression in response to taVNS is mechanistically linked to the increased energy expenditure remains to be determined.
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