Transcutaneous electrical cranial-auricular acupoint stimulation versus escitalopram for mild-to-moderate depression: An assessor-blinded, randomized, non-inferiority trial.

AIM: Transcutaneous electrical cranial-auricular acupoint stimulation (TECAS) is a novel non-invasive therapy that stimulates acupoints innervated by the trigeminal and auricular vagus nerves. An assessor-blinded, randomized, non-inferiority trial was designed to compare the efficacy of TECAS and escitalopram in mild-to-moderate major depressive disorder. METHODS: 468 participants received two TECAS sessions per day at home (n = 233) or approximately 10-13 mg/day escitalopram (n = 235) for 8 weeks plus 4-week follow-up. The primary outcome was clinical response, defined as a baseline-to-endpoint ≥50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score. Secondary outcomes included remission rate, changes in the severity of depression, anxiety, sleep and life quality. RESULTS: The response rate was 66.4% on TECAS and 63.2% on escitalopram with a 3.2% difference (95% confidence interval [CI], -5.9% to 12.9%) in intention-to-treat analysis, and 68.5% versus 66.2% with a 2.3% difference (95% CI, -6.9% to 11.4%) in per-protocol analysis. The lower limit of 95% CI of the differences fell within the prespecified non-inferiority margin of -10% (P ≤ 0.004 for non-inferiority). Most secondary outcomes did not differ between the two groups. TECAS-treated participants who experienced psychological trauma displayed a markedly greater response than those without traumatic experience (81.3% vs 62.1%, P = 0.013). TECAS caused much fewer adverse events than escitalopram. CONCLUSIONS: TECAS was comparable to escitalopram in improving depression and related symptoms, with high acceptability, better safety profile, and particular efficacy in reducing trauma-associated depression. It could serve an effective portable therapy for mild-to-moderate depression.

Noninvasive Transcutaneous Auricular Vagal Nerve Stimulation Improves Gastric Slow Waves Impaired by Cold Stress in Healthy Subjects.

BACKGROUND/AIMS: Stress is known to inhibit gastric motility. The aim of this study was to investigate the effects and autonomic mechanisms of transcutaneous auricular vagal nerve stimulation (taVNS) on cold stress (CS)-induced impairment in gastric motility that are relevant to the brain-gut interactions in healthy volunteers. MATERIALS AND METHODS: Healthy volunteers (eight women; age 28.2 ± 1.8 years) were studied in four randomized sessions (control, CS, CS + taVNS, and CS + sham-electrical stimulation [sham-ES]). Each session was composed of 30 minutes in the fasting state and 30 minutes after a standard test meal. CS was induced during minutes 10 to 30 after the meal, whereas taVNS or sham-ES was performed during minutes 0 to 30 after the meal. The electrogastrogram and electrocardiogram were recorded for assessing gastric slow waves and autonomic functions, respectively. RESULTS: First, CS decreased the percentage of normal gastric slow waves (59.7% ± 9.8% vs 85.4% ± 4.5%, p < 0.001 vs control); this impairment was dramatically improved by taVNS (75.5% ± 6.3% vs 58.4% ± 12.5%, p < 0.001 vs sham-ES). Second, CS increased the symptom score (22.0 ± 12.1 vs 39.3 ± 11.5, p = 0.001 vs control); taVNS, but not sham-ES, reduced the symptom score (26.0 ± 12.2 vs 38.3 ± 21.6, p = 0.026 vs sham-ES). Third, CS decreased vagal activity assessed from the spectral analysis of heart rate variability (0.21 ± 0.10 vs 0.26 ± 0.11, p < 0.05 vs control) and increased the sympathovagal ratio (4.89 ± 1.94 vs 3.74 ± 1.32, p = 0.048 vs control); taVNS normalized CS-induced suppression in vagal activity (0.27 ± 0.13 vs 0.22 ± 0.10, p = 0.049 vs sham-ES; p > 0.05 vs control) and CS-induced increase in the sympathovagal ratio (3.28 ± 1.61 vs 4.28 ± 2.10, p = 0.042 vs sham-ES; p > 0.05 vs control). CONCLUSION: The noninvasive taVNS improves the CS-induced impairment in gastric pace-making activity, possibly by reversing the detrimental effect of CS on autonomic functions. taVNS may have a therapeutic potential for stress-induced gastric dysmotility.

Auricular Vagus Nerve Stimulation Ameliorates Functional Dyspepsia with Depressive-Like Behavior and Inhibits the Hypothalamus-Pituitary-Adrenal Axis in a Rat Model.

BACKGROUND: The hypothalamus-pituitary-adrenal axis is the most important endocrine system to control irritability response. Functional dyspepsia (FD) is closely related to irritability. This study aimed to preliminarily explore the corticotropin-releasing factor (CRF) mechanism of auricular vagus nerve stimulation (aVNS) for FD model rats. METHODS: Sprague-Dawley adult male rats were randomly divided into normal group, model group, aVNS group, and sham-aVNS group. Except for the normal rats, all other rats were induced into the FD model through tail-clamping stimulation for 3 weeks. Once the rat model was developed successfully, rats in the aVNS group and sham-aVNS group were intervened with aVNS or sham-aVNS for 2 weeks. No intervention was given to rats in the normal and model groups. The effect of aVNS was assessed. The expressions of hippocampal corticotropin-releasing hormone receptor 1 (CRHR1), hypothalamus CRF, adrenocorticotropic hormone (ACTH), and corticosterone in serum were assessed. RESULTS: 1. Compared with normal rats, model-developing rats showed FD-like behavior. 2. Compared with model rats, rats in the aVNS group showed an improved general condition score and gastric motility, and increased horizontal and vertical motion scores. 3. The release of corticosterone, ACTH in serum, and CRF in the hypothalamus all increased in model rats but decreased with aVNS instead of sham-aVNS. 4. The expression of hippocampus CRHR1 was lower in model rats but higher in the aVNS group. CONCLUSION: aVNS ameliorates gastric motility and improves the mental state in the FD-like rat, probably via inhibiting the CRF pathway.

Pharmacokinetics and metabolites of glycosides and lignans of the stem bark of Magnolia officinalis in functional dyspepsia and normal rats using liquid chromatography-tandem mass spectrometry.

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.

Toward Diverse or Standardized: A Systematic Review Identifying Transcutaneous Stimulation of Auricular Branch of the Vagus Nerve in Nomenclature.

OBJECTIVES: After 20 years of development, there is confusion in the nomenclature of transcutaneous stimulation of the auricular branch of the vagus nerve (ABVN). We performed a systematic review of transcutaneous stimulation of ABVN in nomenclature. MATERIALS AND METHODS: A systematic search of the literature was carried out, using the bibliographic search engine PubMed. The search covered articles published up until June 11, 2020. We recorded the full nomenclature and abbreviated nomenclature same or similar to transcutaneous stimulation of ABVN in the selected eligible studies, as well as the time and author information of this nomenclature. RESULTS: From 261 studies, 67 full nomenclatures and 27 abbreviated nomenclatures were finally screened out, transcutaneous vagus nerve stimulation and tVNS are the most common nomenclature, accounting for 38.38% and 42.06%, respectively. In a total of 97 combinations of full nomenclatures and abbreviations, the most commonly used nomenclature for the combination of transcutaneous vagus nerve stimulation and tVNS, accounting for 30.28%. Interestingly, the combination of full nomenclatures and abbreviations is not always a one-to-one relationship, there are ten abbreviated nomenclatures corresponding to transcutaneous vagus nerve stimulation, and five full nomenclatures corresponding to tVNS. In addition, based on the analysis of the usage habits of nomenclature in 21 teams, it is found that only three teams have fixed habits, while other different teams or the same team do not always use the same nomenclature in their paper. CONCLUSIONS: The phenomenon of confusion in the nomenclature of transcutaneous stimulation of ABVN is obvious and shows a trend of diversity. The nomenclature of transcutaneous stimulation of ABVN needs to become more standardized in the future.

Comparative Effectiveness of Transcutaneous Auricular Vagus Nerve Stimulation vs Citalopram for Major Depressive Disorder: A Randomized Trial.

OBJECTIVES: Major depressive disorder (MDD) is one of the most common mental illnesses. This study aims to investigate the effectiveness of transcutaneous auricular vagus nerve stimulation (taVNS) compared with the effectiveness of citalopram, a commonly used antidepressant, in patients with depression. MATERIAL AND METHODS: A total of 107 male and female patients with MDD (55 in the taVNS group and 52 in the citalopram group) were enrolled in a prospective 12-week, single-blind, comparative effectiveness trial. Participants were recruited from the outpatient departments of three hospitals in China. Participants were randomly assigned to either taVNS treatment (eight weeks, twice per day, with an additional four-week follow-up) or citalopram treatment (12 weeks, 40 mg/d). The primary outcome was the 17-item Hamilton Depression Rating Scale (HAM-D17) measured every two weeks by trained interviewers blinded to the treatment assignment. The secondary end points included the 14-item Hamilton Anxiety Scale and peripheral blood biochemical indexes. RESULTS: The HAM-D17 scores were reduced in both treatment groups; however, there was no significant group-by-time interaction (95% CI: -0.07 to 0.15, p = 0.79). Nevertheless, we found that taVNS produced a significantly higher remission rate at week four and week six than citalopram. Both treatments were associated with significant changes in the peripheral blood levels of 5-hydroxytryptamine, dopamine, γ-aminobutyric acid, and noradrenaline, but there was no significant difference between the two groups. CONCLUSION: taVNS resulted in symptom improvement similar to that of citalopram; thus, taVNS should be considered as a therapeutic option in the multidisciplinary management of MDD. Nevertheless, owing to the design of this study, it cannot be ruled out that the reduction in depression severity in both treatment groups could be a placebo effect.

Transcutaneous auricular vagal nerve stimulation improves functional dyspepsia by enhancing vagal efferent activity.

This study was designed to investigate whether transcutaneous auricular vagal nerve stimulation (taVNS) would be able to improve major pathophysiologies of functional dyspepsia (FD) in patients with FD. Thirty-six patients with FD (21 F) were studied in two sessions (taVNS and sham-ES). Physiological measurements, including gastric slow waves, gastric accommodation, and autonomic functions, were assessed by the electrogastrogram (EGG), a nutrient drink test and the spectral analysis of heart rate variability derived from the electrocardiogram (ECG), respectively. Thirty-six patients with FD (25 F) were randomized to receive 2-wk taVNS or sham-ES. The dyspeptic symptom scales, anxiety and depression scores, and the same physiological measurements were assessed at the beginning and the end of the 2-wk treatment. In comparison with sham-ES, acute taVNS improved gastric accommodation (P = 0.008), increased the percentage of normal gastric slow waves (%NSW, fasting: P = 0.010; fed: P = 0.007) and vagal activity (fasting: P = 0.056; fed: P = 0.026). In comparison with baseline, 2-wk taVNS but not sham-ES reduced symptoms of dyspepsia (P = 0.010), decreased the scores of anxiety (P = 0.002) and depression (P < 0.001), and improved gastric accommodation (P < 0.001) and the %NSW (fasting: P < 0.05; fed: P < 0.05) by enhancing vagal efferent activity (fasting: P = 0.015; fed: P = 0.048). Compared with the HC, the patients showed increased anxiety (P < 0.001) and depression (P < 0.001), and decreased gastric accommodation (P < 0.001) and %NSW (P < 0.001) as well as decreased vagal activity (fasting: P = 0.047). The noninvasive taVNS has a therapeutic potential for treating nonsevere FD by improving gastric accommodation and gastric pace-making activity via enhancing vagal activity.NEW & NOTEWORTHY Treatment of functional dyspepsia is difficult due to various pathophysiological factors. The proposed method of transcutaneous auricular vagal nerve stimulation improves symptoms of both dyspepsia and depression/anxiety, and gastric functions (accommodation and slow waves), possibly mediated via the enhancement of vagal efferent activity. This noninvasive and easy-to-implement neuromodulation method will be well received by patients and healthcare providers.

Mechanisms underlying antidepressant effect of transcutaneous auricular vagus nerve stimulation on CUMS model rats based on hippocampal α7nAchR/NF-κB signal pathway.

BACKGROUND: 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). METHODS: 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-1ß and the morphology of microglia were detected. RESULTS: 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-1ß, 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. CONCLUSION: The antidepressant effect of taVNS is related to hippocampal α7nAchR/NF-κB signal pathway.

Effects of Transcutaneous Auricular Vagus Nerve Stimulation on Peripheral and Central Tumor Necrosis Factor Alpha in Rats with Depression-Chronic Somatic Pain Comorbidity.

Depression and pain disorders share a high degree of comorbidity. Inflammatory mechanisms play an important role in the pathogenesis of depression-chronic somatic pain comorbidity. In this study, we investigated the effects of acupuncture on blood and brain regional tumor necrosis factor alpha (TNF-α) in rats with depression and chronic somatic pain comorbidity. Forty Sprague-Dawley rats were randomly divided into the following 4 groups with 10 each: control, model, model treated with transcutaneous auricular vagus nerve stimulation (taVNS), and model treated with electroacupuncture (EA). Chronic unpredictable mild stress (CUMS) with chronic constriction injury of the sciatic nerve (CCI) was used to produce depression and chronic somatic pain comorbidity in the latter 3 groups. The rats of the taVNS and EA groups received, respectively, taVNS and EA at ST 36 for 28 days. Pain intensity was measured using a mechanical withdrawal threshold and thermal stimulation latency once biweekly. Depressive behavior was examined using a sucrose preference test at baseline and the end of modeling and intervention. The level of plasma TNF-α and the expression of TNF-α in the prefrontal cortex (PFC), hippocampus, amygdala, and hypothalamus were measured. While CUMS plus CCI produced remarkable depression-like behavior and pain disorders, EA and taVNS significantly improved depression and reduced pain intensity. CUMS plus CCI also resulted in a significant increase in plasma TNF-α level and the expression in all brain regions examined compared to the intact controls. Both EA and taVNS interventions, however, suppressed the elevated level of TNF-α. These results suggest that EA and taVNS have antidepressant and analgesic effects. Such effects may be associated with the suppression of TNF-α-related neuroinflammation.

Assessor- and participant-blinded, randomized controlled trial of dense cranial electroacupuncture stimulation plus body acupuncture for neuropsychiatric sequelae of stroke.

AIM: Acupuncture has benefits in the rehabilitation of neuropsychiatric sequelae of stroke. This study was aimed to evaluate the effectiveness of dense cranial electroacupuncture stimulation plus body acupuncture (DCEAS+BA) in treating poststroke depression (PSD), functional disability, and cognitive deterioration. METHODS: In this assessor- and participant-blinded, randomized controlled trial, 91 stroke patients who initially had PSD were randomly assigned to either DCEAS+BA (n = 45) or minimum acupuncture stimulation as controls (n = 46) for three sessions per week over 8 consecutive weeks. The primary outcome was baseline-to-end-point change in score of the 17-item Hamilton Depression Rating Scale. Secondary outcomes included the Montgomery-Åsberg Depression Rating Scale for depressive symptoms, the Barthel Index for functional disability, and the Montreal Cognitive Assessment for cognitive function. RESULTS: DCEAS+BA-treated patients showed strikingly greater end-point reduction than MAS-treated patients in scores of the three symptom domains. The clinical response rate, defined as an at least 50% baseline-to-end-point reduction in 17-item Hamilton Depression Rating Scale score, was markedly higher in the DCEAS+BA-treated group than that of controls (40.0% vs 17.4%, P = 0.031). Incidence of adverse events was not different in the two groups. Subgroup analysis revealed that DCEAS+BA with electrical stimulation on forehead acupoints was more apparent in reducing Barthel-Index-measured disability than that without electrical stimulation. CONCLUSION: DCEAS+BA, particularly with electrical stimulation on forehead acupoints, reduces PSD, functional disability, and cognitive deterioration of stroke patients. It can serve as an effective rehabilitation therapy for neuropsychiatric sequelae of stroke.

Auricular vagus nerve stimulation enhances central serotonergic function and inhibits diabetic neuropathy development in Zucker fatty rats.

Painful neuropathy is a frequent comorbidity in diabetes. Zucker diabetic fatty (fa/fa) rats develop type 2 diabetes spontaneously with aging and show nociceptive hypersensitivity at the age of 13 weeks. In preclinical and clinical studies, the treatment of diabetic neuropathy is challenging, but complementary medicine such as transcutaneous auricular vagus nerve stimulation (taVNS) appears beneficial to the relief of neuropathic pain. However, the mechanism behind the effectiveness of taVNS remains unclear. In this study, we show that daily 30-min taVNS (2/15 Hz, 2 mA) for consecutive 27 days effectively inhibited the development of nociceptive hypersensitivity in Zucker diabetic fatty rats as detected by thermal hyperalgesia and mechanical allodynia in hindpaw. We also demonstrated that this beneficial effect in nociceptive behavior is related to an elevated serotonin (5-HT) plasma concentration and an upregulated expression of 5-HT receptor type 1A (5-HT1AR) in hypothalamus. We conclude that daily 30-min taVNS sessions lessen diabetic neuropathy development by enhancing serotonergic function in genetically diabetes prone individuals. Perspective This article presents taVNS as a new approach to inhibit the development of diabetic neuropathy in genetically prone individuals. This approach could potentially help clinicians who seek to avoid the complication of neuropathic pain in diabetic patient or to relieve the pain if there was one.

Efficacy and Safety of Treatment with Transcutaneous Vagus Nerve Stimulation in 17 Patients with Refractory Epilepsy Evaluated by Electroencephalogram, Seizure Frequency, and Quality of Life.

BACKGROUND This study aimed to investigate the efficacy and safety of treatment with transcutaneous vagus nerve stimulation (tVNS) for patients with refractory epilepsy by evaluation of the frequency of seizures, electroencephalogram (EEG) changes, and quality of life on follow-up at three months and six months. MATERIAL AND METHODS EEG evaluation followed baseline evaluation with EEG at three months and six months following tVNS treatment. The frequency of seizures was recorded during the six-month study period. Before and after tVNS treatment, patients completed the Self-Rating Anxiety Scale (SAS), the Self-Rating Depression Scale (SDS), the Liverpool Seizure Severity Scale (LSSS), the Quality of Life in Epilepsy Inventory (QOLIE-31), and the Pittsburg Sleep Quality Index (PSQI). RESULTS Seventeen patients completed six months of tVNS treatment. Following three months of tVNS therapy, the frequency of epileptic seizures decreased in 13/17 subjects, with an average reduced seizure rate of 31.3%. Following six months of tVNS treatment, the frequency of epileptic seizures decreased in 16/17 subjects, with an average reduced seizure rate of 64.4%. There were 14/17 cases with abnormal EEG at baseline; 2/17 patients had improved EEGs by three months, and 10/17 patients had improved EEGs by six months. During the study period, there were no adverse events associated with tVNS treatment, but the effects on sleep were inconclusive. CONCLUSIONS This preliminary study showed that tVNS was an effective and safe adjuvant treatment for refractory epilepsy that reduced seizure frequency and reduced abnormal EEG changes following clinical improvement.

Psychosocial interventions for Alzheimer's disease cognitive symptoms: a Bayesian network meta-analysis.

BACKGROUND: Alzheimer disease (AD) is the most common type of dementia with cognitive decline as one of the core symptoms in older adults. Numerous studies have suggested the value of psychosocial interventions to improve cognition in this population, but which one should be preferred are still matters of controversy. Consequently, we aim to compare and rank different psychosocial interventions in the management of mild to moderate AD with cognitive symptoms. METHODS: We did a network meta-analysis to identify both direct and indirect evidence in relevant studies. We searched MEDLINE, EMBASE, PsycINFO through the OVID database, CENTRAL through the Cochrane Library for clinical randomized controlled trials investigating psychosocial interventions of cognitive symptoms in patients with Alzheimer disease, published up to August 31, 2017. We included trials of home-based exercise(HE), group exercise(GE), walking program(WP), reminiscence therapy(RT), art therapy(AT) or the combination of psychosocial interventions and acetylcholinesterase inhibitor (ChEIs). We extracted the relevant information from these trials with a predefined data extraction sheet and assessed the risk of bias with the Cochrane risk of bias tool. The outcomes investigated were Mini-Mental State Examination (MMSE) and compliance. We did a pair-wise meta-analysis using the fixed-effects model and then did a random-effects network meta-analysis within a Bayesian framework. RESULTS: We deemed 10 trials eligible, including 682 patients and 11 treatments. The quality of included study was rated as low in most comparison with Cochrane tools. Treatment effects from the network meta-analysis showed WP was better than control (SMD 4.89, 95% CI -0.07 to 10.00) while cognitive training and acetylcholinesterase inhibitor (CT + ChEIs) was significantly better than the other treatments, when compared with simple ChEIs treatment, assessed by MMSE. In terms of compliance, the pair-wise meta-analysis indicated that WP and HE are better than GE and AT, while CT + ChEIs, CST + ChEIs are better than other combined interventions. CONCLUSION: Our study confirmed the effectiveness of psychosocial interventions for improving cognition or slowing down the progression of cognitive impairment in AD patients and recommended several interventions for clinical practice.

[Effect of Needle Embedded in Neiguan (PC6) on Changes of ECG in Chronic Myocardial Ischemia Model Mini-pigs].

Objective To observe the effect of needle embedded in Neiguan (PC6) on electro- cardiogram (ECG) changes in model mini-pigs with chronic myocardial ischemia. Methods The protein shrink narrow ring (Ameroid Ring) was placed in the proximal part of the left coronary anterior descend- ing branch of 12 Chinese mini-pigs to prepare animal model. One died during the modeling. Chronic myo- cardial ischemia mini-pig models were established after 4 weeks. Successfully modeled 11 mini-pigs were divided into the test group (n =6) and the control group (n =5). Needle were embedded in Neiguan (PC6) of the test group and Zusanli (ST36) of the control group at week 4 after modeling. Electroacupuncture (EA) at corresponding acupoint twice (once before embedding and at week 2 after embedding) , 20 min each time. Changes of Q wave of ECG, heart rate, and ST-T interval were observed in the two groups be- fore and after modeling, before and after EA. Results Compared with before modeling in the same group, the absolute value of Q wave both increased in the two groups after modeling (P <0. 05, P <0. 01J. No statistical difference existed in heart rate in the two groups between before and after modeling (P> 0. 05). Compared with before needling in the same group, ST-T interval was prolonged in the test group (P <0. 05). Compared with the control group at the same time point, the absolute value of Q wave was re- duced before EA, ST-T interval was prolonged after EA in the test group (P <0. 05). No statistical differ- ence existed in heart rate between the control group and the test group before EA (P >0. 05). Conclusion Needle embedded in Neiguan (PC6) could arrive at therapeutic effect of myocardial ischemia possibly through improving myocardial blood supply.

The Beneficial Effects of Electro-acupuncture at PC6 (Neiguan-point) of Gene and Protein Expressions of Classical Inward-rectifier Potassium Channels in Myocardial Ischemic Rats.

This study is aim to investigate the effect of electro-acupuncture at PC6 (Neiguan-point) on the gene and protein expressions of classical inward-rectifier potassium channels (Kir) in myocardial ischemia (MI) rats induced by isoproterenol (ISO). With ten for each one, 50 rats were divided into 5 groups which were control group, MI group, PC6 group, LU7 (Lieque-point) group and non-acupoint group. The control group was injected normal saline solution (85 mg/kg), the other groups were injected ISO (85 mg/kg). All the rats were injected once daily for two days and recorded electrocardiograms (ECGs) after every injection. Electro-acupuncture (EA) was operated at PC6, LU7 and non-acupoint respectively in the rats of PC6 group, LU7 group and non-acupoint group after twice injections. EA was performed to these three groups with disperse-dense wave (4-20 Hz), pulse amplitude of 14V, 20 mins a day remaining 7 days. The gene and protein expressions of Kir2.1, Kir2.2 and Kir2.3 were analyzed by Western Immunoblotting Technology (Western Blot) and Real-time Fluorescence Quantitative Polymerase Chain Reaction (RT-PCR). But it is regrettable that we did not detect meaningful gene and protein expressions Kir2.3, and the expressions of Kir2.1 and Kir2.2 in MI induced groups were lower [The gene and protein decreased 39.4 ± 27.3% and 38.7 ± 17.1% respectively.] than control group (P < 0.05). Compared with MI group, the results of PC6 group and LU7 group increased [PC6 group: the gene and protein increased 42.9 25.0% and 42.2 ± 10.0% respectively. LU7 group: the gene and protein increased 23.8 ± 50.1% and 21.1 ± 32.5% respectively.] obviously (P < 0.05) after EA, furthermore the expressions of PC6 group were higher [The gene and protein increased 15.4 ± 16.7% and 17.3 ± 60% respectively.] than LU7 group (P < 0.05). The results show that PC6 has a better positive effect than LU7 on MI rats, and the mechanism is probably that EA at PC6 can significantly increase the gene and protein expressions of Kir2.1 and Kir2.2.

Effect of acupuncture at Neiguan (PC 6) on cardiac function using echocardiography in myocardial ischemia rats induced by isoproterenol.

OBJECTIVE: To investigate the effect of acupuncture at Neiguan (PC 6) on cardiac function using echocardiography in rat models of myocardial ischemia (MI) induced by isoproterenol (ISO). METHODS: Twenty-seven Sprague-Dawley rats were randomly assigned to normal, model, and acupuncture groups. The model and acupuncture groups were given injections of ISO (85 mg/kg) to establish the MI model. After model establishment, the acupuncture group was treated with acupuncture at Neiguan (PC 6) for 30 min. Echocardiography was used to monitor diastolic and systolic function for 30 min starting from the time after the acupuncture needles were removed. Changes in the length of left ventricular internal diameter at end-diastole (LVIDd), length of left ventricular internal diameter at end-systole (LVIDs), the ratio of mitral peak velocity at early diastole and atrial contraction (E/A), ejection fraction (EF), fractional shortening (FS), and stroke volume (SV) were measured. RESULTS: Compared with the model group at 0 and 15 min after needles were removed, the means of LVIDd and LVIDs were significantly lower (P < 0.01) and E/A, EF, FS, and SV significantly higher (P < 0.01) in the acupuncture group. In the acupuncture group, the means of LVIDd and LVIDs 15 min after the needles were removed were significantly higher (P < 0.01) than those at 0 min. The means of E/A, EF, FS, and SV significantly decreased (P < 0.01) from 0 to 15 min in the acupuncture group. CONCLUSION: These findings indicate that acupuncture at Neiguan (PC 6) can affect cardiac function by increasing left ventricular diastolic and systolic function in MI rat models, but the effect only lasts for 15 min.

Transcutaneous vagus nerve stimulation for refractory epilepsy: a randomized controlled trial.

This trial was designed to test the safety and effectiveness of transcutaneous auricular vagus nerve stimulation (ta-VNS) for patients with refractory epilepsy.Pre-trial：144 patients were randomly assigned to ta-VNS group (n=98) or transcutaneous auricular non-vagus nerve stimulation (tn-VNS) control group (n=46). Treatment was conducted twice per day for 24 weeks. After 8, 16 and 24 weeks of treatment，the patients were evaluated according to the Modified Engel Scale (four classes). After 8 weeks，according to the medical ethic design, patients in tn-VNS group were switched into ta-VNS group uniquely. After 8 weeks' treatment 41.0% and 27.5% of patients from ta-VNS and tn-VNS groups, respectively, experienced reduction in seizure frequency that reached I, II and III levels according to the standards of the Modified Engel Scale compared with the baselines, indicating significant difference in seizure reduction between the two groups. After 24 weeks of treatment, ta-VNS patients had a 47.7% reduction, and tn-VNS, with an additional 16 weeks of treatment, reached 47.5% in reduction. After 8 weeks' treatment, the percentages of average seizure frequency in ta-VNS and tn-VNS were reduced by 42.6% and 11.5% respectively, providing a statistically significant difference in the results between the two groups (P<0.05). In addition, there were significant improvements in electroencephalograph (EEG) and the quality of daily life of the patients after treatment.The results show that this ta-VNS treatment can effectively reduce the frequency of seizures and improve the patient's quality of life. This may be an effective treatment for refractory epilepsy. At the same time，it is also safe，economic, and widely applicable.

Effect of transcutaneous auricular vagus nerve stimulation on impaired glucose tolerance: a pilot randomized study.

BACKGROUND: Impaired glucose tolerance (IGT) is a pre-diabetic state of hyperglycemia that is associated with insulin resistance, increased risk of type II diabetes, and cardiovascular pathology. Recently, investigators hypothesized that decreased vagus nerve activity may be the underlying mechanism of metabolic syndrome including obesity, elevated glucose levels, and high blood pressure. METHODS: In this pilot randomized clinical trial, we compared the efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) and sham taVNS on patients with IGT. 72 participants with IGT were single-blinded and were randomly allocated by computer-generated envelope to either taVNS or sham taVNS treatment groups. In addition, 30 IGT adults were recruited as a control population and not assigned treatment so as to monitor the natural fluctuation of glucose tolerance in IGT patients. All treatments were self-administered by the patients at home after training at the hospital. Patients were instructed to fill in a patient diary booklet each day to describe any side effects after each treatment. The treatment period was 12 weeks in duration. Baseline comparison between treatment and control group showed no difference in weight, BMI, or measures of systolic blood pressure, diastolic blood pressure, fasting plasma glucose (FPG), 2-hour plasma glucose (2hPG), or glycosylated hemoglobin (HbAlc). RESULTS: 100 participants completed the study and were included in data analysis. Two female patients (one in the taVNS group, one in the sham taVNS group) dropped out of the study due to stimulation-evoked dizziness. The symptoms were relieved after stopping treatment. Compared with sham taVNS, taVNS significantly reduced the two-hour glucose tolerance (F(2) = 5.79, p = 0.004). In addition, we found that taVNS significantly decreased (F(1) = 4.21, p = 0.044) systolic blood pressure over time compared with sham taVNS. Compared with the no-treatment control group, patients receiving taVNS significantly differed in measures of FPG (F(2) = 10.62, p < 0.001), 2hPG F(2) = 25.18, p < 0.001) and HbAlc (F(1) = 12.79, p = 0.001) over the course of the 12 week treatment period. CONCLUSIONS: Our study suggests that taVNS is a promising, simple, and cost-effective treatment for IGT/ pre-diabetes with only slight risk of mild side-effects.

The beneficial effect of electro-acupuncture given at PC6 (Neiguan-point) by the increase in cardiac transient outward K+ current channel which depends on the gene and protein expressions in artificially induced myocardial ischemia rats.

This study explored the mechanism of electro-acupuncture (EA) at PC6 to improve the heart function by regulating the cardiac transient outward potassium current (= Ito) channel in myocardial ischemia (MI). Kv1.4 is the main component of the slow Ito (Ito.s) channel. Kv4.2 and Kv4.3 are the main components of the fast Ito (Ito.f) channel. KChIP2 is a compound protein of Ito channel. In this experiment, MI was induced by injecting isoproterenol in rats, and the gene and protein expressions of Kv1.4, Kv4.2, Kv4.3 and KChIP2 were lower [The gene and protein decreased (42.8 ± 4.3)% and (37.2 ± 4.7)% respectively.] than the control rats significantly (p < 0.05). After MI induction, the MI rats were divided into three groups, including PC6, LU7 (Lieque-point) and Non-acupoint group which were acupunctured at once a day for 7 days respectively. After EA at PC6 and LU7, the gene and protein expressions showed obvious increased [EA at PC6: the gene and protein increased (50.24 ± 5.4)% and (39.14 ± 5.3)% respectively. EA at LU7: the gene and protein increased (24.6 ± 2.8)% and (22.04 ± 5.5)% respectively] and they are all higher than MI rats significantly (p < 0.05). EA at PC6 and LU7 showed the same variation, and the effects of EA at PC6 and LU7 were better than Non-acupuncture-point (p < 0.05). The effects of EA at PC6 were significantly better [The gene and protein increased (19.74 ± 2.7)% and (14.14 ± 4.4)% respectively] than LU7 (p < 0.05). PC6 is an acupoint of the pericardium meridian, and the pericardium meridian which corresponds to adrenal gland according to Omura Y's research, can affect the heart function directly LU7 belong to the lung meridian, and the lung plays an important factor in blood circulation according to TCM. So PC6 is more effective than LU7 on heart function regulation. The results suggested that PC6 showed the target effect of meridian specificity on regulating the Kv channel in MI.

Electroacupuncture of neiguan (PC 6) inhibits enhanced voltage-gated sodium currents in ischemic ventricular myocytes.

OBJECTIVE: To examine the effect of electroacupuncture (EA) at bilateral Neiguan (PC 6) on voltage-gated Na+ currents (I(Na)) and channels (Na(v)) in ischemic ventricular myocytes. METHODS: EA serum was prepared from six male adult Sprague-Dawley rats that had received EA at bilateral Neiguan (PC 6). Eighteen ventricular myocytes were prepared from six SD rats using an enzymolysis approach. Myocardial ischemia was mimicked by perfusion of ischemic solution. Whole-cell patch-clamping was used to record three currents evoked from isolated cells. The first current was the control, and recorded in absence of ischemic solution current. The second was the ischemic current, and recorded after perfusion of ischemic solution for 5 min, while the EA current was last, and recorded after perfusion of EA serum for 5 min. Na(v) kinetic curves were fitted using related formulas. RESULTS: Compared with those in controls, in the presence of ischemic solution, peak amplitudes of I(Na) significantly increased from - 40 mV to +30 mV, and half-maximal inactivation potentials of Na(v) increased significantly, while half-maximal activation potentials, slope factors and the recovery time from inactivation to activation of Na(v) were unchanged. Compared with those in the ischemic solution, in the presence of EA serum, peak ischemic current amplitudes significantly reduced from - 40 mV to +40 mV, and half-maximal inactivation potentials were restored, while half-maximal activation potentials, slope factors and the recovery time from inactivation to activation of Na(v) were unchanged. CONCLUSION: EA at bilateral Neiguan (PC 6) can reduce enhanced I(Na) via restoration of delayed Na(v) inactivation in ischemic ventricular myocytes.