Mechanisms and state of the art of vagus nerve stimulation

Vagus nerve stimulation (VNS) is an established treatment of medically refractory partial-onset seizures. Recent data from an open-label multicenter pilot study also suggest a potential clinical usefulness in the acute and maintenance treatment of drug-resistant depressive disorder. Despite the fact that surgery is needed to implant the stimulating device, the option of long-term use largely devoid of severe side effects would give this treatment modality a privileged place in the management of drug-resistant depression. However, definite therapeutic effects of clinical significance remain to be confirmed in large, placebo-controlled trials. Besides the potential clinical usefulness, VNS can be used as a research tool in epilepsy patients implanted for clinical reasons, allowing neurophysiologic investigations of the parasympathetic system and its interactions with other parts of the central nervous system.     

单胺类递质在迷走神经刺激抗癫痫中的作用研究

目的探讨迷走神经刺激（ｖａｇｕｓｎｅｒｖｅｓｔｉｍｕｌａｔｉｏｎ,ＶＮＳ）抗癫痫的作用机制。方法成年健康Ｗｉｓｔａｒ大鼠３０只,随机分为正常对照组（ＮＣ组）、戊四氮（ｐｅｎｔｙｌｅｎｅｔｅｔｒａｚｏｌ,ＰＴＺ）致癫痫组（ＰＴＺ组）及ＶＮＳ后ＰＴＺ致癫痫组（ＶＮＳ组）。ＰＴＺ腹腔注射致癫痫后（６０ｍｇ／ｋｇ体重）,行左侧颈部迷走神经刺激。采用荧光光度法测定各组动物大脑顶叶皮层及海马的去甲肾上腺素（ＮＡ）、肾上腺素（Ａ）及五羟色胺（５ＨＴ）的含量。结果顶叶皮层Ａ及５ＨＴ的含量ＰＴＺ组明显高于ＮＣ组,而ＶＮＳ组则明显低于ＰＴＺ组;海马内ＮＡ、Ａ及５ＨＴ的含量ＰＴＺ组明显低于ＮＣ组,而ＶＮＳ组ＮＡ及５ＨＴ含量明显高于ＰＴＺ组。行为和ＥＥＧ结果显示,ＶＮＳ有明显的抗癫痫作用。结论单胺类递质ＮＡ、Ａ及５ＨＴ在ＶＮＳ抗癫痫中起重要作用。     

Increased extracellular concentrations of norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat

The vagus nerve is an important source of afferent information about visceral states and it provides input to the locus coeruleus (LC), the major source of norepinephrine (NE) in the brain. It has been suggested that the effects of electrical stimulation of the vagus nerve on learning and memory, mood, seizure suppression, and recovery of function following brain damage are mediated, in part, by the release of brain NE. The hypothesis that left vagus nerve stimulation (VNS) at the cervical level results in increased extracellular NE concentrations in the cortex and hippocampus was tested at four stimulus intensities: 0.0, 0.25, 0.5, and 1.0 mA. Stimulation at 0.0 and 0.25 mA had no effect on NE concentrations, while the 0.5 mA stimulation increased NE concentrations significantly in the hippocampus (23%), but not the cortex. However, 1.0 mA stimulation significantly increased NE concentrations in both the cortex (39%) and hippocampus (28%) bilaterally. The increases in NE were transient and confined to the stimulation periods. VNS did not alter NE concentrations in either structure during the inter-stimulation baseline periods. No differences were observed between NE levels in the initial baseline and the post-stimulation baselines. These findings support the hypothesis that VNS increases extracellular NE concentrations in both the hippocampus and cortex.     

A review of studies on the therapeutic effect of vagus nerve stimulation

BACKGROUND： Vagus nerve widely innervates in the human body, and it has diverse physiological functions. Many new physiological functions are gradually found. Studies on its action mechanism have been gradually deepened. Vagus nerve stimulation （VNS） has been used for treatment of epilepsy and depression in clinic. OBJECTIVE： To retrospectively investigate the therapeutic effects and mechanism of VNS. RETRIEVE STRATEGY： A computer-based online research in Pubmed with the key words of ＂vagus nerve stimulation＂ published between February 1990 and October 2006 in English were systemically reviewed. Totally 583 articles were collected and primarily selected. Inclusive criteria： the mechanism of therapeutic effects of VNS-related literatures. Exclusive criteria： repetitive study. LITERATURE EVALUATION： According to inclusive criteria, of the 57 articles, which met the inclusive criteria, 42 were associated with the therapeutic function of VNS, and 15 with the mechanism of these related functions. DATA SYNTHESIS： Vagus nerve has special nerve innervation and wide projection with extensive physiological effects. Till now, VNS has been used in the therapy of epilepsy and depression, and exact clinical effects have been obtained. Further studies have discovered other functions of VNS, such as the effect on the memory power, cognition, and perception to pain. Thus, the studies about VNS become diverse. Just because of the special physiological functions of vagus nerve, VNS can bring some adverse reactions such as foreign body sensation, hoarseness, trigeminal neuralgia, etc. The mechanism of therapeutic function of VNS is still under exploration. CONCLUSION： As a mature surgical technique, VNS has been widely used in the therapy of epilepsy, depression, inflammation, analgesia, relieving itching, etc. Although the mechanism is still unclear, it brings obvious clinical effects.     

Human vagus nerve electrophysiology: a guide to vagus nerve stimulation parameters.

The authors studied human vagus nerve electrophysiology intraoperatively on 21 patients (age range: 4 to 31 years) during implantation of a vagus nerve stimulator for seizure control. The study was performed with direct electrical stimulation of the vagus nerve with various stimulation parameters resembling those employed by the Cyberonics NeuroCybernetic Prosthesis System (Houston, TX), which is used clinically for vagus nerve stimulation for treatment of seizures. Recordings were made directly from the rostral end of the vagus nerve. The response of the vagus nerve to various stimulus parameters in patients of different ages was studied. Based on the vagus nerve characteristics, age-related adjustments for stimulus parameters were recommended.     

The antidepressant-like effect of vagus nerve stimulation is mediated through the locus coeruleus

It has been shown that vagus nerve stimulation (VNS) has an antidepressant-like effect in the forced swim test. The mechanism of action underlying this effect is incompletely understood, but there is evidence suggesting that the locus coeruleus (LC) may play an important role. In this study, noradrenergic LC neurons were selectively lesioned to test their involvement in the antidepressant-like effect of VNS in the forced swim test.Forced swim test behavior was assessed in rats that were subjected to VNS or sham treatment. In half of the VNS-treated animals, the noradrenergic neurons from the LC were lesioned using the selective neurotoxin DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride], yielding three experimental arms: sham, VNS and DSP-4-VNS (n = 8 per group). Furthermore, the open field test was performed to evaluate locomotor activity. A dopamine-β-hydroxylase immunostaining was performed to confirm lesioning of noradrenergic LC neurons.VNS significantly reduced the percentage of immobility time in the forced swim test compared to sham treatment (median: 56%, interquartile range: 41% vs. median: 75%, interquartile range: 12%). This antidepressant-like effect of VNS could not be demonstrated in the DSP-4-VNS group (median: 79%, interquartile range: 33%). Locomotor activity in the open field test was not different between the three treatment arms. The absence of hippocampal dopamine-β-hydroxylase immunostaining in the DSP-4-treated rats confirmed the lesioning of noradrenergic neurons originating from the brainstem LC.The results of this study demonstrate that the noradrenergic neurons from the LC play an important role in the antidepressant-like effect of VNS.     

Chronic stimulation of the cat vagus nerve: effect on sleep and behavior

The effect of electrical vagus nerve stimulation (VNS) on sleep and behavior was analyzed in freely moving cats. Eight cats were prepared for 23-h sleep recordings. The left vagus nerve of four of them was stimulated during 1 min, five times at 1-h intervals, for 5 days. The VNS induces: ipsilateral myosis, blinking, licking, abdominal contractions, upward gaze, swallowing, and eventually yawning and compulsive eating, as well as an increase of ponto-geniculate-occipital (PGO) wave density and of the number of stages and total amount of rapid eye movement (REM) sleep. Besides, there was a sudden transition from waking stage to REM sleep. The present results suggest that VNS modifies sleep in the cat. This effect could be explained by an activation of the areas involved in the physiological mechanisms of sleep.     

Cardiovascular autonomic effects of vagus nerve stimulation

Clinical Autonomic Research - The vagus nerve is responsible for the parasympathetic innervation of the major thoracic and abdominal organs. It also carries sensory afferent fibres from these...     

Animal models for vagus nerve stimulation in epilepsy

Vagus nerve stimulation (VNS) is a moderately effective adjunctive treatment for patients suffering from medically refractory epilepsy and is explored as a treatment option for several other disorders. The present review provides a critical appraisal of the studies on VNS in animal models of seizures and epilepsy. So far, these studies mostly applied short-term VNS in seizure models, demonstrating that VNS can suppress and prevent seizures and affect epileptogenesis. However, the mechanism of action is still largely unknown. Moreover, studies with a clinically more relevant setup where VNS is chronically applied in epilepsy models are scarce. Future directions for research and the application of this technology in animal models of epilepsy are discussed.     

Electroconvulsive therapy in patients with vagus nerve stimulation

Numerous studies have demonstrated the safety and efficacy of electroconvulsive therapy (ECT) for various psychiatric conditions, and it has been approved by the Food and Drug Administration for the treatment of refractory depression. Recently, the Food and Drug Administration also approved vagus nerve stimulation as a treatment for chronic or recurrent depression. Although electrical stimulation is used for both ECT and vagus nerve stimulation, the mechanisms of their action are very different. The American Psychiatric Association task force identifies no absolute contraindications to the use of ECT. The authors present 2 interesting cases of successful ECT in combination with vagus nerve stimulator.     

Late onset bradyarrhythmia during vagus nerve stimulation

Vagus nerve stimulation (VNS) is widely used to treat refractory epilepsy. It is usually safe and has few side effects. Cardiac arrhythmia has been reported during lead tests performed during implantation of the device, but never during regular treatment. We report here a case where vagally induced bradyarrhythmia, perfectly correlated with the stimulation periods, suddenly occurred two years and four months after the VNS implantation. The diagnosis was based on the appearance of syncope-like episodes. No specific cause could be found to explain the appearance of the episodes. To our knowledge, this is the first report on this severe and life-threatening side effect of VNS and should alert clinicians to its possibility. However, considering the large number of VNS implantations performed worldwide, it must be regarded as an extremely rare complication.     

Late-onset periodic asystolia during vagus nerve stimulation

Cardiac changes may occasionally occur during vagus nerve stimulation (VNS) used in epileptic patients. As they can be potentially life-threatening, it is important to detect them, and this is why an intraoperative test is performed during the implantation. Few cases of asystole during this test have been described. Only one patient with late-onset bradyarrythmia caused by VNS has been reported. This patient had been implanted 2 years and 4 months before the episode. We present another case of late asystole in a patient whose VNS had been implanted 9 years before the arrhythmia onset. In our patient, each run of stimulation produced bradyarrhythmias and very often severe asystolia due to atrium-ventricular block.     

Neurostimulation: vagus nerve stimulation and beyond

Patients with medically intractable epilepsy who are not candidates for epilepsy surgery could benefit from neurostimulation. At this time, vagus nerve stimulation (VNS) therapy is the only Food and Drug Administation-approved neurostimulation modality; it has been shown to be efficacious and just as well tolerated in children and adolescents as in adults. Notwithstanding the initial cost of the device and implantation, VNS therapy has been shown to be a cost-effective treatment, reducing direct medical costs and improving health-related quality of life measures. Deep brain stimulation of various brain regions, especially the anterior nucleus of the thalamus and responsive neurostimulation, also appear effective but are not yet approved for clinical use. Repetitive transcranial magnetic stimulation, which is also in early clinical development, is promising and could become available in the not too distant future.