Chronic Vagus Nerve Stimulation Increases the Latency of the Thalamocortical Somatosensory Evoked Potential

The Neurocybernetic Prosthesis (NCP) is a pacemaker-like device that has been designed to provide chronic intermittent vagus nerve stimulation. It is currently under study for the treatment of refractory partial onset epilepsy, and preliminary studies have indicated that partial onset seizures are improved by this therapy. The mechanisms by which it exerts its antiepileptic effect are not well understood. Although there are extensive pathways to the forebrain from the nuclei of the vagus nerve, the evidence that the NCP alters neural transmission outside the vagal system is limited. We prospectively examined Somatosensory and brain stem auditory evoked potentials (BAEPs) in three patients receiving NCP implantation to determine if changes in these studies occur as a result of chronic vagus nerve stimulation. The results demonstrate a significant prolongation of the cervicomedullary to thalamocortical potential (N13–N20) interval on Somatosensory evoked potential (SSEP) studies following activation of the device. No other significant changes were seen on SSEP or BAEP in the NCP implanted patients or normal controls. The findings suggest that chronic vagus nerve stimulation does alter neuronal networks outside of the brain stem vagus system, and may potentially provide a means to clinically monitor and titrate this therapy.     

Clinical Experience with a Helical Bipolar Stimulating Lead

Over 100 patients have been treated for partial epilepsy using a NeuroCybernetic Prosthesis System (NCP). The NCP System is comprised of an impluntable pulse generator, an implantable bipolar stimulating lead, and an external communication system. The lead delivers electrical impulses from the NCP Generator to the vagus nerve, and includes a connector end that plugs into the generator, a silicone insulated lead body, and the helical electrode array that attaches to the nerve. The surgical implantation technique has a significant impact on lead reliability and performance. The lead electrode has performed well to date. Modifications to further improve reliability have been implemented. Clinical experience, case history examples, and voltage measurements are examined. The lead electrode is an important component of the overall system and plays a significant part in the success of vagus nerve stimulation therapy.     

Treatment of Refractory Partial Seizures: Preliminary Results of a Controlled Study

Vagus nerve stimulation for the treatment of epilepsy has been studied in medically refractory patients with partial seizures in a randomized, blinded, parallel study. After a 3-month baseline period, the patients were implanted with the Neurocybernetic Prosthesis (NCP) system consisting of the NCP Generator and the Bipolar Vagal Stimulation Lead. Two stimulation paradigms were used, HIGH, which delivers what is considered to be optimal stimulation parameters and LOW, which is considered to be less or noneffective. The system and vagus nerve stimulation were well tolerated and few adverse events have been attributed to either. One patient experienced a period of direct current to the nerve due to a generator malfunction. This resulted in paralysis of the left vocal cord. Efficacy analysis on the first 37 patients to complete the controlled portion of the study has shown that the patients in the HIGH group experienced a mean reduction in seizure frequency of 33.3% and patients in the LOW group experienced a mean reduction in seizure frequency of 8.4%. The difference between the groups is statistically significant with a P value of 0.025. Analysis of seizure duration and intensity does not show any significant change. Ratings of the patient's overall condition fay the patient, investigator, and companion as a measurement of "quality of life" also show improvement in the HIGH group. The results of this interim study demonstrate that vagus nerve stimulation is a safe and effective method of treating partial epileptic seizures.     

Vagal Stimulation for Control of Complex Partial Seizures in Medically Refractory Epileptic Patients

Chronic intermittent stimulation of the vagus nerve is a new method currently being tested for the treatment of medically intractable complex partial seizures (CPS). We have studied the effects of vagal stimulation in nine patients with CPS for 4-16 months to determine its safety and efficacy. With the patients maintained on constant dosages of antiepileptic drugs, we recorded the electroencephalogram and electrocardiogram, and performed clinical laboratory tests and gastric analysis over a 6-week baseline period. The neurocybernetic prosthesis (NCP) was then implanted and connected to two spiral electrodes wound around the left vagus nerve. After a 4-week placebo period, vagal stimulation was started. Stimulation parameters were increased stepwise at monthly intervals until patients were being stimulated for 30-second periods at 20-50 Hz with 1-2 mA of current at 250-500 microseconds pulses. A second 4-week placebo period was added 3 months after the implantation. Thereafter, vagal stimulation was resumed and self-stimulation with magnetic activation was allowed for a 1-minute period at the onset of an aura. Six patients had a significant reduction in the frequency, intensity, or duration of seizures. All patients tolerated the implantation and stimulation well and none reported pain, discomfort, or important changes in their daily activities, sleep habits, eating, swallowing, or breathing. There were no remarkable changes in blood pressure or heart rate.     

Practical issues and concepts in vagus nerve stimulation: a nursing review.

Estimates of epilepsy incidence among the U.S. population range between 0.5% and 1%. The most common type of seizure in adult patients is partial onset. Approximately 20% of these patients are refractory to antiepileptic drug therapy and experience intolerable side effects such as confusion, dizziness, weight gain, lethargy, and ataxia. The ketogenic diet appears to be beneficial for children but is not considered a standard option for adults. Epilepsy surgery can be an option for many and may offer control or a reduction in seizures. However, many patients are opposed to cranial surgery or may not tolerate the ketogenic diet. Recent advances in biomedical technology and perfection in surgical techniques have shown vagus nerve stimulation (VNS) using the Neuro Cybernetic Prosthesis (NCP) system is an effective new treatment option in reducing seizure frequency. On July 16, 1997, the U.S. Food and Drug Administration (FDA) approved the use of the NCP for vagus nerve stimulation, as an adjunctive treatment for refractory partial onset seizures in adults and adolescents over 12 years of age. Murphy et al. and Wheless have reported similar results in children younger than 12 years. VNS represents the first therapy using a medical device approved by the FDA for the treatment of refractory seizures. An estimated 10,000 patients have been implanted with the device.     

中国首例人体残肢神经信息控制电子假肢实验研究快报

目的我们首次采集1例志愿者残肢的神经电信号以研究利用神经信息控制假肢模拟装置的可能性及可行性。方法将自制神经束内电极分别直接插入患者残肢上臂桡、尺及正中神经的神经束内，电极远端连接7自由度神经信息控制假肢模拟装置，以神经束外电极作参考电极。患者经过相关训练后，嘱其在清醒状态下用脑意识控制患侧作假想的指伸、屈动作，并观察模拟假肢装置的反应。结果当患者用脑意识控制患侧作各种假想动作时，我们发现从桡神经导出的神经信息能够成功地触发假肢模拟装置作伸指动作，但无法实现闭合。从其它神经导出的信息均未能有效驱动假肢装置发生动作。从同一神经内的两个神经束内电极引出的神经信息亦未能有效驱动假肢装置发生动作。结论神经束内电极可为神经信息控制假肢模拟装置提供残肢神经信息，但还需更深入地研究。     

ON THE DIFFERENCES IN THE EFFECTS OF STIMULATION OF THE TWO VAGUS NERVES ON RATE AND CONDUCTION OF THE DOG'S HEART

It may be concluded from the results obtained in these experiments : 1. That stimulation of the right vagus nerve in the dog usually causes arrest of all the chambers of the heart. 2. That stimulation of the left vagus nerve exerts a moderate negative chronotropic effect on the auricles. 3. That stimulation of the left vagus nerve has a profound effect on the conduction of impulses over the auriculoventricular system. 4. That the degree of effect exercised on the auriculoventricular system by stimulation of the left vagus nerve varies. In some dogs conduction is depressed to an extent which causes only a delay in the conduction of impulses from auricles to ventricles (P-R time) ; in other dogs the conduction is depressed to a degree which results in incomplete heart-block; while in still other dogs conduction is so depressed that although the auricles continue to contract, no impulses pass from them to the ventricles. 5. That when stimulation of either the right or left vagus nerve causes asystole of nomotopic ventricular contractions, ectopic ventricular contractions may occur. 6. That the time which elapses before ectopic ventricular contractions occur depends upon the irritability of the ventricular muscle, and this may vary in different dogs. 7. That stimulation of the left vagus nerve may rarely cause sino-auricular block. Possibly stimulation of the right nerve may also produce this effect. 8. That there is consequently usually a great qualitative difference in the action of the two vagus nerves on the heart of the dog.     

Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis

The innate immune system protects against infection and tissue injury through the specialized organs of the reticuloendothelial system, including the lungs, liver, and spleen. The central nervous system regulates innate immune responses via the vagus nerve, a mechanism termed the cholinergic antiinflammatory pathway. Vagus nerve stimulation inhibits proinflammatory cytokine production by signaling through the alpha7 nicotinic acetylcholine receptor subunit. Previously, the functional relationship between the cholinergic antiinflammatory pathway and the reticuloendothelial system was unknown. Here we show that vagus nerve stimulation fails to inhibit tumor necrosis factor (TNF) production in splenectomized animals during lethal endotoxemia. Selective lesioning of the common celiac nerve abolishes TNF suppression by vagus nerve stimulation, suggesting that the cholinergic pathway is functionally hard wired to the spleen via this branch of the vagus nerve. Administration of nicotine, an alpha7 agonist that mimics vagus nerve stimulation, increases proinflammatory cytokine production and lethality from polymicrobial sepsis in splenectomized mice, indicating that the spleen is critical to the protective response of the cholinergic pathway. These results reveal a specific, physiological connection between the nervous and innate immune systems that may be exploited through either electrical vagus nerve stimulation or administration of alpha7 agonists to inhibit proinflammatory cytokine production during infection and tissue injury.     

兔迷走神经压迫后对血液流变学的影响

目的通过手术造成兔颈总动脉对迷走神经稳定的压迫,检验血液流变学的变化。方法构建手术组动物模型,将25只新西兰兔的迷走神经与颈部结缔组织固定,造成颈总动脉对迷走神经的持续压迫。同时将25只未经手术处理的新西兰兔作为对照组,采血后用血液流变学分析仪进行检测。结果兔颈迷走神经被压迫后,全血黏度高切指数、全血黏度低切指数,红细胞聚集指数、纤维蛋白原等多项指标和非手术对照组比较,差异有统计学意义（P〈O．05）。结论兔颈总动脉的压迫刺激左侧颈部迷走神经,可以导致兔血液流变学指标发生异常的变化。     

Vagus nerve stimulation therapy for treatment of drug-resistant epilepsy and depression

Vagal nerve stimulation therapy is a new adjunctive treatment for drug-resistant epilepsy and depression. It consists of a pulse generator that transmits impulses to the left vagus nerve via an implantable electrode and can be performed by surgeons familiar with the anatomy of the cervical vagus nerve. The minimum age for vagal nerve stimulation therapy for epilepsy is 12 years, and for depression, 18 years. Hoarseness and cough are the most common side effects. Response rates to vagal nerve stimulation therapy vary and depend on several other factors. If used as adjunctive therapy, vagal nerve stimulation has shown better control of seizures or depression at smaller doses of antiepileptic or antidepressive medications and also results in decreased dose-dependent side effects. Vagal nerve stimulation therapy appears safe as an adjunctive treatment for drug-resistant epilepsy and depression. Long-term data are needed to better define its ultimate role in various subsets of patients.     

THE INFLUENCE OF THE VAGUS NERVES ON THE FARADIZED AURICLES IN THE DOG'S HEART

An abnormal auricular activity is produced by faradization of the right auricle of the dog, which frequently becomes established and continues for varying periods of time after faradization is discontinued. This auricular activity consists of a rapid auricular tachycardia coexisting with true auricular fibrillation. In some dogs the auricles are thrown into this abnormal activity more readily by faradization after the vagi have been cut than before. Cutting the nerves has little or no effect on the abnormal auricular activity, but the ventricular rate may be much increased if the vagi are cut after the abnormal auricular activity has been established, apparently because of an improvement in the auriculoventricular conductivity. Stimulation of the right vagus nerve changes the character of the activity of the faradized auricles by inhibiting the auricular tachycardia while the fibrillation is uninfluenced. Stimulation of the left vagus nerve has little or no apparent inhibitory effect on the auricular tachycardia, but has possibly an inhibitory effect on the auricular fibrillation. Vagus stimulation increases the susceptibility of the auricles to faradization. The abnormal activity set up by faradization may be established in hearts otherwise refractory by vagus stimulation of short duration following the faradization. Vagus stimulation usually holds the auricles in the abnormal activity set up by faradization as long as it is continued in hearts in which, without vagus stimulation, the sequential beat always returns as soon as faradization is stopped. The right vagus is more effectual in this respect than the left. In some hearts vagus stimulation alone is capable of initiating the same abnormal auricular activity which is caused by auricular faradization. The normal sequential beat is often restored by vagus stimulation. It replaces the abnormal auricular activity not during, but a few seconds after, the termination of vagus stimulation. Left vagus stimulation is somewhat more effectual in producing this result than right vagus stimulation.     

Modulating the Inflammatory Reflex in Rats Using Low-Intensity Focused Ultrasound Stimulation of the Vagus Nerve

Tumor necrosis factor α (TNF-α) is linked to several chronic inflammatory diseases. Electrical vagus nerve stimulation reduces serum TNF-α levels but may cause chronic nerve damage and requires surgery. Alternatively, we proposed focused ultrasound stimulation of the vagus nerve (uVNS), which can be applied non-invasively. In this study, we induced an inflammatory response in rats using lipopolysaccharides (LPS) and collected blood to analyze the effects of uVNS on cytokine concentrations. We applied one or three 5-min pulsed focused ultrasound stimulation treatments to the vagus nerve (250 kHz, I_SPPA?=?3 W/cm²). Animals receiving a single ultrasound application had an average reduction in TNF-α levels of 19%, similar to the 16% reduction observed in electrically stimulated animals. With multiple applications, uVNS therapy statistically reduced serum TNF-α levels by 73% compared with control animals without any observed damage to the nerve. These findings suggest that uVNS is a suitable way to attenuate TNF-α levels.     

胃扩张模型大鼠迷走神经背核胃相关神经元对不同针刺穴位的反应

背景：课题组的前期工作主要围绕孤束核在接受胃伤害性刺激和针刺穴位反应中所扮演的角色展开研究,而迷走神经背核与孤束核、最后区一起作为迷走神经复合体中不可或缺的组成部分,在调节胃功能中发挥了重要的作用。目的：观察针刺“足三里”、“内关”、“脾俞”、“肾俞”等不同神经节段穴位对胃扩张模型大鼠迷走神经背核胃相关神经元的影响。方法：在成功构建大鼠胃扩张造模的基础上,采用神经电生理学的方法,运用细胞外记录技术,找出迷走神经背核胃相关神经元,予以手针刺激“足三里”、“内关”、“脾俞”、“肾俞”等不同神经节段穴位各15s,记录来自体表的刺激对迷走神经背核胃相关神经元的影响。结果与结论：24只大鼠共记录到90个神经元放电,90个下丘脑室旁核神经元中与胃扩张相关的神经元有54个,54个胃扩张相关神经元中,对针刺足三里、内关、脾俞、肾俞有反应的神经元个数分别为44,39,38,27,有反应的神经元出现比例分别为82%,72%,70%,50%。提示针刺不同神经节段穴位均能不同程度地激活迷走神经背核参与调节胃运动。     

Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis

OBJECTIVE: Electrical vagus nerve stimulation inhibits proinflammatory cytokine production and prevents shock during lethal systemic inflammation through an alpha7 nicotinic acetylcholine receptor (alpha7nAChR)-dependent pathway to the spleen, termed the cholinergic anti-inflammatory pathway. Pharmacologic alpha7nAChR agonists inhibit production of the critical proinflammatory mediator high mobility group box 1 (HMGB1) and rescue mice from lethal polymicrobial sepsis. Here we developed a method of transcutaneous mechanical vagus nerve stimulation and then investigated whether this therapy can protect mice against sepsis lethality. DESIGN: Prospective, randomized study. SETTING: Institute-based research laboratory. SUBJECTS: Male BALB/c mice. INTERVENTIONS: Mice received lipopolysaccharide to induce lethal endotoxemia or underwent cecal ligation and puncture to induce polymicrobial sepsis. Mice were then randomized to receive electrical, transcutaneous, or sham vagus nerve stimulation and were followed for survival or euthanized at predetermined time points for cytokine analysis. MEASUREMENTS AND MAIN RESULTS: Transcutaneous vagus nerve stimulation dose-dependently reduced systemic tumor necrosis factor levels during lethal endotoxemia. Treatment with transcutaneous vagus nerve stimulation inhibited HMGB1 levels and improved survival in mice with polymicrobial sepsis, even when administered 24 hrs after the onset of disease. CONCLUSIONS: Transcutaneous vagus nerve stimulation is an efficacious treatment for mice with lethal endotoxemia or polymicrobial sepsis.     

Pharmacological stimulation of the cholinergic antiinflammatory pathway

Efferent activity in the vagus nerve can prevent endotoxin-induced shock by attenuating tumor necrosis factor (TNF) synthesis. Termed the "cholinergic antiinflammatory pathway," inhibition of TNF synthesis is dependent on nicotinic alpha-bungarotoxin-sensitive acetylcholine receptors on macrophages. Vagus nerve firing is also stimulated by CNI-1493, a tetravalent guanylhydrazone molecule that inhibits systemic inflammation. Here, we studied the effects of pharmacological and electrical stimulation of the intact vagus nerve in adult male Lewis rats subjected to endotoxin-induced shock to determine whether intact vagus nerve signaling is required for the antiinflammatory action of CNI-1493. CNI-1493 administered via the intracerebroventricular route was 100,000-fold more effective in suppressing endotoxin-induced TNF release and shock as compared with intravenous dosing. Surgical or chemical vagotomy rendered animals sensitive to TNF release and shock, despite treatment with CNI-1493, indicating that an intact cholinergic antiinflammatory pathway is required for antiinflammatory efficacy in vivo. Electrical stimulation of either the right or left intact vagus nerve conferred significant protection against endotoxin-induced shock, and specifically attenuated serum and myocardial TNF, but not pulmonary TNF synthesis, as compared with sham-operated animals. Together, these results indicate that stimulation of the cholinergic antiinflammatory pathway by either pharmacological or electrical methods can attenuate the systemic inflammatory response to endotoxin-induced shock.     

THE INFLUENCE OF THE VAGUS NERVES UPON CONDUCTION BETWEEN AURICLES AND VENTRICLES IN THE DOG DURING AURICULAR FIBRILLATION

The experiments that have been reported indicate that stimulation of either the right vagus or the left vagus nerve is equally effectual in blocking impulses from the auricles to the ventricles when auricular fibrillation is present. Stimulation of the left vagus nerve is as effectual in blocking impulses from the normally beating auricles as from the auricles when in a state of fibrillation, and the type of auricular activity has apparently no influence on the effect which stimulation of the left vagus has on auriculoventricular conduction.     

帕金森病患者颈部迷走神经超声声像横截面积与临床特征的相关性分析

目的 应用超声探查帕金森病(Parkinson's disease,PD)患者和健康人群颈部迷走神经横截面积,探讨PD患者颈部迷走神经横截面积与临床特征的相关性.方法 30例PD患者为观察组,同期31例体检健康者为对照组.观察组采用统一PD评分量表Ⅲ(unified Parkinson's disease rating...     

咽喉部手术中迷走神经反射的观察及处理

目的探讨咽喉部手术过程中迷走神经发射发生的原因及处理方法。方法对342例在支撑喉镜下行咽喉部手术的患者采用术前选用足量抗胆碱药物、控制麻醉深度、操作动作保持轻柔、术中严密观察心率、血压变化等方法,减少迷走神经反射发生率。结果所有患者手术过程5~10 min,放入支撑喉镜时,共发生迷走神经反射32例,发生率为9.4%。结论对咽喉部手术患者术前进行充分准备,术中密切观察,发生迷走神经反射时及时处理,可有效控制咽喉手术过程中迷走反射的发生及不良后果。     

STUDIES WITH THE ELECTROCARDIOGRAPH ON THE ACTION OF THE VAGUS NERVE ON THE HUMAN HEART : II. THE EFFECTS OF VAGUS STIMULATION ON THE HEARTS OF CHILDREN WITH CHRONIC VALVULAR DISEASE.

The electrocardiographic records taken during vagus stimulation by pressure from children suffering with chronic heart disease have shown that the stimulation of the vagi in these cases is strikingly effectual. In some of the cases, a definite difference was demonstrated between the action of the right and left vagi. The control of the rate of the heart-beat seemed to predominate usually in the right vagus nerve, while the control of stimulus conduction from auricles to ventricles apparently predominated usually in the left vagus. This difference in the two nerves probably exists on account of the difference in their anatomical distribution, the right vagus going especially to that part of the heart which controls the rate of contraction, the sinus node above the right auricle, and the left vagus going especially to that part in which the conducting mechanism is found. Each nerve, however, has to a lesser degree the function which predominates in the other. The whole heart seems to respond, as a rule, more promptly to right than to left vagus pressure, and fairly constant differences have been seen in the effects which stimulation of each nerve has on the various waves of the electrocardiograms. The stimulation of each vagus may influence directly the contractions of the ventricles, causing great diminution in their force. Right vagus stimulation was followed at times by a complete dissociation of auricles and ventricles. The auricular rhythm was slowed sufficiently at this time to allow the ventricles, whose inherent rhythmicity is apparently unaffected by right vagus stimulation, to take up their own independent rhythm. The heightened ventricular rhythmicity in these cases allowed this to take place after only moderate slowing of the auricles. The independent ventricular rhythm was sometimes established in the region of the node of Tawara, for no disturbance of the ventricular portion of the electrocardiogram occurred. At another time, some other point in the ventricles inaugurated the stimuli of the independent ventricular contractions and an abnormal electrocardiogram resulted. The resemblance of our curves, showing dissociation, to those obtained during right vagus and left accelerator stimulation in dogs is definite. That analogy, the clinical picture, and the form of the electrocardiograms of these cases have led us to the belief that an important feature in the pathological physiology of these cases is hypertonus of the cardiac accelerator nerves. This factor, as a cause of symptoms and as a hindrance to the establishment of cardiac rest, may prove of great importance, against which a new form of cardiac therapeutics must be directed.     

迷走神经刺激治疗癫痫的实验和临床研究

目的通过动物实验,探讨迷走神经刺激治疗癫痫的有效性和最佳刺激参数,并对临床上癫痫持续状态病人进行疗效研究。方法应用士的宁制成动物癫痫模型,手术后直接刺激左侧迷走神经,应用不同的刺激参数组合进行刺激。对临床上癫痫持续状态的病人,经皮间接刺激迷走神经进行疗效观察。结果应用波宽２ｍｓ、频率１００Ｈｚ、电压１０Ｖ的组合参数刺激,全部实验动物的强直性发作立刻得到控制、痫样放电立即消失,脑电图恢复正常。选择病人可以耐受的电压幅度连续电脉冲刺激左侧颈部迷走神经体表投影区,进行经皮间接刺激治疗不同类型癫痫持续状态,结果完全控制率为８３．３％。有效率达１００％。结论刺激左侧迷走神经治疗癫痫和经皮刺激迷走神经治疗癫痫持续状态有效,但刺激参数至关重要。