Peijing Rong

Transcutaneous Vagus Nerve Stimulation Modulates Default Mode Network in Major Depressive Disorder

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 a Food and Drug Administration 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, noninvasive 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. RESULTS Thirty-four patients completed the study and were included in data analysis. After 1 month of tVNS treatment, the 24-item Hamilton Depression Rating Scale score reduced significantly in the tVNS group as compared with 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 with stVNS. All these FC increases are also associated with 24-item Hamilton Depression Rating Scale 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.

Transcutaneous auricular vagus nerve stimulation as a complementary therapy for pediatric epilepsy: a pilot trial.

OBJECTIVE We investigated the safety and efficacy of transcutaneous auricular vagus nerve stimulation (ta-VNS) for the treatment of pediatric epilepsy. METHODS Fourteen pediatric patients with intractable epilepsy were treated by ta-VNS of the bilateral auricular concha using an ear vagus nerve stimulator. The baseline seizure frequency was compared with that after 8weeks, from week 9 to 16 and from week 17 to the end of week 24, according to the seizure diaries of the patients. RESULTS One patient dropped out after 8weeks of treatment due to lack of efficacy, while the remaining 13 patients completed the 24-week study without any change in medication regimen. The mean reduction in seizure frequency relative to baseline was 31.83% after week 8, 54.13% from week 9 to 16 and 54.21% from week 17 to the end of week 24. The responder rate was 28.57% after 8weeks, 53.85% from week 9 to 16 and 53.85% from week 17 to the end of week 24. No severe adverse events were reported during treatment. CONCLUSION Transcutaneous auricular VNS may be a complementary treatment option for reducing seizure frequency in pediatric patients with intractable epilepsy and should be further studied.

A C-fiber reflex inhibition induced by electroacupuncture with different intensities applied at homotopic and heterotopic acupoints in rats selectively destructive effects on myelinated and unmyelinated afferent fibers

The aims of this study were to explore the C-fiber reflex inhibition induced by electroacupuncture with different intensities applied at homotopic or heterotopic acupoints, and to determine the influence selectively destroyed myelinated and unmyelinated afferent fibers on the C-fiber reflex inhibition. In the ipsilateral local acupoint, the general behavior of the C-fiber reflex can be depressed by electroacupuncture below the threshold of Adelta-fiber activation. Electroacupuncture stimulation within the intensity of Adelta-fiber activation applied to the ipsilateral limb pretreated with cobra venom did not elicit inhibition of C-fiber reflex in rats with demyelinated sciatic nerve. However, heterotopic electroacupuncture below the threshold of Adelta-fiber activation was totally ineffective. In contralateral heterotopic acupoints, the C-fiber reflex can be depressed only by electroacupuncture with stimulating intensities exceeding thresholds of Adelta and C-fiber activation. Electroacupuncture stimuli applied to capsaicin-pretreated limb in the intensities of threshold of Adelta-fiber and treble thresholds of C-fiber activation produced only a little inhibition of C-fiber reflex. Inhibitory intensity was roughly similar to that induced by the stimulation with intensity for the activation of Adelta-fiber in normal animal. In the spinalized animals transections at T6-T7 segments, regardless of intensities, the homotopic electroacupuncture stimulation only induced moderate depression of C-fiber reflex similar to that of Adelta-fiber activation; whereas, no matter what intensities of application, the inhibitory effects of C-fiber reflex disappeared totally by using heterotopic noxious electroacupuncture in these animals.

Transcutaneous vagus nerve stimulation for the treatment of depression: a study protocol for a double blinded randomized clinical trial

BackgroundDepressive disorders are the most common form of mental disorders in community and health care settings. Unfortunately, the treatment of Major Depressive Disorder (MDD) is far from satisfactory. Vagus nerve stimulation (VNS) is a relatively new and promising physical treatment for depressive disorders. One particularly appealing element of VNS is the long-term benefit in mood regulation. However, because this intervention involves surgery, perioperative risks, and potentially significant side effects, this treatment has been limited to those patients with treatment-resistant depression who have failed medication trials and exhausted established somatic treatments for major depression, due to intolerance or lack of response.This double-blinded randomized clinical trial aims to overcome these limitations by introducing a novel method of stimulating superficial branches of the vagus nerve on the ear to treat MDD. The rationale is that direct stimulation of the afferent nerve fibers on the ear area with afferent vagus nerve distribution should produce a similar effect as classic VNS in reducing depressive symptoms without the burden of surgical intervention.DesignOne hundred twenty cases (60 males) of volunteer patients with mild and moderate depression will be randomly divided into transcutaneous vagus nerve stimulation group (tVNS) and sham tVNS group. The treatment period lasts 4 months and all clinical and physiological measurements are acquired at the beginning and the end of the treatment period.DiscussionThis study has the potential to significantly extend the application of VNS treatment for MDD and other disorders (including epilepsy, bipolar disorder, and morbid obesity), resulting in direct benefit to the patients suffering from these highly prevalent disorders. In addition, the results of this double-blinded clinical trial will shed new light on our understanding of acupuncture point specificity, and development of methodologies in clinical trials of acupuncture treatment.Trials registrationClinical Trials. ChiCTR-TRC-11001201 http://www.chictr.org/cn/

The pain-relieving effects induced by electroacupuncture with different intensities at homotopic and heterotopic acupoints in humans.

The purpose of the present study was to investigate the relationship between the distribution of the analgesic area when different intensities of stimulation were applied to homotopic and heterotopic acupoints. The experiments were performed on volunteers; the left sural nerve was stimulated by a volley of eight rectangular pulses delivered at a frequency of 400 Hz. Electromyographic reflex responses (EMGs) were recorded from the ipsi-lateral biceps femoris muscle. Electroacupuncture stimuli were given on the skin overlying the Zusanli point (St 36), and the strengths chosen were times of the threshold eliciting a nociceptive reflex (T(RIII)) response (0.6, 0.8, 1.0, T(RIII) and T(supra-RIII), respectively). The effects of homotopic and heterotopic stimuli applied to St 36 on the pain sensation and the R(III), reflex elicited by stimulation of the left sural nerve were observed to explore the pain-relief and R(III) reflex-inhibition produced by stimulation of the St 36 point with different intensities. Both the nociceptive reflex and painful sensation evoked by stimulating the sural nerve were similarly inhibited by electroacupuncture at less than T(RIII) applied to the ipsi-lateral acupoint. In other words, acupuncture with an innocuous intensity can produce homotopic pain-alleviating effects and reflex suppression. With contra-lateral electroacupuncture at the St 36 acupoint, innocuous intensities cannot produce heterotopic pain-relieving effects; these inhibitions were only observed at electroacupuncture intensities similar to the T(RIII) threshold. These results suggest that local acupuncture-induced analgesia is effective with activation of large afferent fibers, whereas heterotopic acupuncture-induced analgesia is only effective with intensities strong enough to excite small afferent fibers. Local analgesic effects of acupoint stimulation involve segmental inhibition, whereas systemic analgesic effects of acupoint stimulation are involved in contra-lateral effects. The latter may recruit the diffuse noxious inhibitory controls (DNIC) system. The specific function of an acupoint is determined by the anatomical relationship between the disease focus and the segmental location of the acupoint.

Effects of Electroacupuncture at Auricular Concha Region on the Depressive Status of Unpredictable Chronic Mild Stress Rat Models

To explore new noninvasive treatment options for depression, this study investigated the effects of electroacupuncture (EA) at the auricular concha region (ACR) of depression rat models. Depression in rats was induced by unpredictable chronic mild stress (UCMS) combined with isolation for 21 days. Eighty male Wistar rats were randomly assigned into four groups: normal, UCMS alone, UCMS with EA-ACR treatment, and UCMS with EA-ear-tip treatment. Rats under inhaled anesthesia were treated once daily for 14 days. The results showed that blood pressure and heart rate were significantly reduced in the EA-ACR group than in the UCMS alone group or the EA-ear-tip group. The open-field test scores significantly decreased in the UCMS alone and EA-ear-tip groups but not in the EA-ACR group. Both EA treatments downregulated levels of plasma cortisol and ACTH in UCMS rats back to normal levels. The present study suggested that EA-ACR can elicit similar cardioinhibitory effects as vagus nerve stimulation (VNS), and EA-ACR significantly antagonized UCMS-induced depressive status in UCMS rats. The antidepressant effect of EA-ACR is possibly mediated via the normalization of the hypothalamic-pituitary-adrenal (HPA) axis hyperactivity.

Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: A nonrandomized controlled pilot study

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.

Transcutaneous vagus nerve stimulation modulates amygdala functional connectivity in patients with depression

BACKGROUND The amygdala is a key region in emotion processing, and studies have suggested that amygdala-frontal functional connectivity deficits could be modulated by antidepressants in major depressive disorder (MDD). Transcutaneous vagus nerve stimulation (tVNS), a non-invasive, peripheral neuromodulation method at the ear, has shown promising results in treating major depressive disorder (MDD) in several pilot studies. However, the neural mechanism underlying tVNS treatment of depression has not been fully investigated. In this study, we investigated how tVNS can modulate the amygdala-lateral prefrontal network resting state functional connectivity (rsFC) in mild or moderate major depressive disorder (MDD) patients. METHODS Forty-nine MDD patients were recruited and received tVNS or sham tVNS (stVNS) treatments for four weeks. Resting state fMRI scans were applied before and after treatments. RESULTS After 1 month of tVNS treatment, the 24-item Hamilton Depression Rating Scale (HAMD) scores were reduced significantly in the tVNS group as compared with the sham tVNS group. The rsFC in the tVNS group between the right amygdala and left dorsolateral prefrontal cortex was increased compared with sham tVNS. All the rsFC increases were also associated with HAMD reduction as well as reductions in the anxiety and retardation HAMD subscales. CONCLUSIONS tVNS can significantly modulate the amygdala-lateral prefrontal rsFC of MDD patients; our results provide insights into the brain mechanism of tVNS treatment for MDD patients.

Mechanism of acupuncture regulating visceral sensation and mobility.

Chinese ancient medical scientists have long focused on the internal and external contacts between acupoints on the surface of the body and the viscera. The Miraculous Pivot (it is one of the earliest medical classics in China) stated, “Twelve regular channels belong to the zang-fu organs internally, and connect to the extremities and joints externally.” Traditional Chinese medicine considers acupoints as defined areas where the Qi of viscera and meridians are transfused. These include the reaction points of visceral diseases on the body surface as well as the acupuncture trigger points that promote the flow of Qi and blood, and regulate visceral function. Chinese ancient medical scientists classified the specificity of the main acupoints in the body based on the meridian doctrine, which has been instructing clinical application for about 2000 years. Laws on the domino effect of acupoints have mainly focused on conclusions to clinical experiences. Indications of some acupoints exceed the practical paradigm since the excessive extension occurred during theory derivation. The current research direction on acupuncture focuses on three aspects: the effectiveness of acupuncture and moxibustion; the relevances and associations between meridians and viscera; and the physical and chemical properties and relevant physical basis of acupoints. The relevance between meridians and viscera is the central theory in the meridian doctrine, and acupoints are regarded as an important link in the relationship between meridians and viscera. Specific relationships between acupoints and target organs exist. Stimulating different acupoints on the body surface can help deal with different diseases, especially visceral diseases. In addition, acupoints have a dual function of reflecting and treating visceral diseases. There is no systemic research available on acupoint specificity, despite current knowledge and clinical experiences, which results in a weak foundation for acupuncture theory. This study focuses on the relevance and associations between meridians and viscera. A summary of the mechanisms of acupuncture regulating visceral sensation and mobility and the specific relationships between acupoints and their target organs are presented in this review.

Observation of Pain-Sensitive Points along the Meridians in Patients with Gastric Ulcer or Gastritis

This study aims to investigate the sensitization of human skin points along certain meridians related to visceral disease by using the pressure-pain threshold (PPT) as an indicator. We detected and compared the PPTs of people with and without gastric ulcer or gastritis on the related acupoints, abdomen area, and back area with von Frey detector and observed the similarities and differences under their respective physiological and pathological states. The results showed that (1) the PPTs of patients with gastric ulcer on related acupoints decreased significantly compared with the control group; (2) there was no significant difference in PPT between the chosen points of the measured meridian and the adjacent nonacupoints; (3) there was an apparent distribution of tender points on the relevant abdomen and back regions of patients with gastric ulcer or gastritis, but none was found on the control group; (4) the pain-sensitive points of gastric ulcer and gastritis patients were BURONG (ST19), LIANGMEN (ST21), and HUAROUMEN (ST24) of the stomach meridian on the abdominal region and PISHU (BL20), WEISHU (BL21), and WEICANG (BL50) on the back, among others The results suggest that the practical significance of acupoints may lie in its role as a relatively sensitive functional area. In a pathological state, the reflex points on the skin which are related to certain visceral organs become sensitive and functionally intensify.