迷走神经电刺激治疗癫痫的现状与展望

Electrical vagus nerve stimulation （VNS） has been approved by FDA and is widely used in recent years for the treatment of epilepsy and possibly other medical conditions such as depression. The current success rate of VNS for epilepsy is about 50%, but there are complications, potential risks and cost concerns. One of the major limitations for this new therapy is that its antiseizure mechanisms are by no means clear. In particular, it is not known whether the therapeutic effect is vagal specific, what types of nerve fibers in the vagus nerve are contributing to the therapeutic effects, or what individual patients would benefit from the use of the expensive and invasive VNS implantation. There are controversies regarding how and where the VNS takes effect on epilepsy in the central nervous system. The poor understanding of VNS has inevitably limited the application and success of the therapy. The current review analyses the pros and cons of VNS for epilepsy in vis-à- vis other available therapies including Chinese medical methods, and explores the possible mechanisms in order to stimulate further improvement of this new technology.     

颈部迷走神经干刺激对癫痫大鼠脑内Fos样表达的影响

目的 研究颈部迷走神经干刺激（VNS）抑制癫痫发作上传通路过程中的关键核团及相关脑区。方法 利用红藻氨酸（KA）诱发大鼠复杂部分性癫痫发作。并结合Fos免疫组织化学方法观察左颈部迷走神经干电刺激后全脑及延髓内Fos的分布及电刺激的影响。结果 VNS后脑干双侧孤束核、蓝斑、臂旁核、中脑导水管周围灰质有很强的特异性Fos表达，外侧缰核、丘脑室旁核、菱形核、下丘脑室旁核、杏仁中央核、终纹床核、隔外侧核、梨状皮质等脑区亦可见Fos阳性细胞。预先给予电刺激后海马、齿状回、额、顶、颞皮质区域Fos表达明显受到抑制。结论 VNS后Fos阳性的脑区及核团可能是电刺激发挥抑痫作用的关键部位，其神经元活性的改变或递质调节可能间接或直接影响大脑皮质的功能。     

The anatomical basis for transcutaneous auricular vagus nerve stimulation

The array of end organ innervations of the vagus nerve, coupled with increased basic science evidence, has led to vagus nerve stimulation (VNS) being explored as a management option in a number of clinical disorders, such as heart failure, migraine and inflammatory bowel disease. Both invasive (surgically implanted) and non-invasive (transcutaneous) techniques of VNS exist. Transcutaneous VNS (tVNS) delivery systems rely on the cutaneous distribution of vagal afferents, either at the external ear (auricular branch of the vagus nerve) or at the neck (cervical branch of the vagus nerve), thus obviating the need for surgical implantation of a VNS delivery device and facilitating further investigations across a wide range of uses. The concept of electrically stimulating the auricular branch of the vagus nerve (ABVN), which provides somatosensory innervation to several aspects of the external ear, is relatively more recent compared with cervical VNS; thus, there is a relative paucity of literature surrounding its operation and functionality. Despite the increasing body of research exploring the therapeutic uses of auricular transcutaneous VNS (tVNS), a comprehensive review of the cutaneous, intracranial and central distribution of ABVN fibres has not been conducted to date. A review of the literature exploring the neuroanatomical basis of this neuromodulatory therapy is therefore timely. Our review article explores the neuroanatomy of the ABVN with reference to (1) clinical surveys examining Arnold’s reflex, (2) cadaveric studies, (3) fMRI studies, (4) electrophysiological studies, (5) acupuncture studies, (6) retrograde tracing studies and (7) studies measuring changes in autonomic (cardiovascular) parameters in response to auricular tVNS. We also provide an overview of the fibre composition of the ABVN and the effects of auricular tVNS on the central nervous system. Cadaveric studies, of which a limited number exist in the literature, would be the ‘gold-standard’ approach to studying the cutaneous map of the ABVN; thus, there is a need for more such studies to be conducted. Functional magnetic resonance imaging (fMRI) represents a useful surrogate modality for discerning the auricular sites most likely innervated by the ABVN and the most promising locations for auricular tVNS. However, given the heterogeneity in the results of such investigations and the various limitations of using fMRI, the current literature lacks a clear consensus on the auricular sites that are most densely innervated by the ABVN and whether the brain regions secondarily activated by electrical auricular tVNS depend on specific parameters. At present, it is reasonable to surmise that the concha and inner tragus are suitable locations for vagal modulation. Given the therapeutic potential of auricular tVNS, there remains a need for the cutaneous map of the ABVN to be further refined and the effects of various stimulation parameters and stimulation sites to be determined.     

Vagal-evoked activity in the parafascicular nucleus of the primate thalamus

The physiological effects of ascending vagal afferent activity in the primate forebrain have not been established, and because vagus nerve stimulation (VNS) is useful clinically for treatment of epilepsy and depression, these actions need to be identified. We used a roving microelectrode to record vagal-evoked potentials in the thalamus of the macaque monkey. In addition to the anticipated activation in the gustatory/visceral thalamic relay nucleus, we found an unexpectedly larger and earlier response focus with multi-unit discharges in the adjacent parafascicular nucleus. These data reveal a potent vagal input to this intralaminar nucleus, which is normally considered to be involved in motor control. This finding indicates that a role for this vagal activation site in the anti-epileptic effects of VNS needs to be considered.     

Vagus nerve stimulation does not affect spatial memory in fast rats, but has both anti-convulsive and pro-convulsive effects on amygdala-kindled seizures

Vagus nerve stimulation (VNS) is an adjunctive treatment for refractory epilepsy. Using a seizure-prone Fast-kindling rat strain with known comorbid behavioral features, we investigated the effects of VNS on spatial memory, epileptogenesis, kindled seizures and body weight.

Electrodes were implanted in both amygdalae and around the left vagus nerve of 17 rats. Following recovery, rats were tested in the Morris water-maze utilizing a fixed platform paradigm. The VNS group received 2 h of stimulation prior to entering the Morris water-maze. Rats were then tested in the kindling paradigm wherein the VNS group received 2 h of stimulation prior to daily kindling stimulation. Finally, the abortive effects of acute VNS against kindling-induced seizures were determined in fully kindled rats by applying VNS immediately after the kindling pulse. Body weight, water consumption and food intake were measured throughout.

Memory performance in the Morris water-maze was not different between control and vagus nerve stimulation rats. Similarly, kindling rate was unaffected by antecedent VNS. However, pro-convulsive effects (P<0.05) were noted, when VNS was administered prior to the kindling pulse in fully kindled rats. Yet, paradoxically, VNS showed anti-convulsant effects (P<0.01) in those rats when applied immediately after the kindling stimulus. Body weight was significantly lower throughout kindling (P<0.01) in VNS-treated rats compared with controls, which was associated with reduced food intake (P<0.05), but without difference in water consumption.

VNS appears to be devoid of significant cognitive side effects in the Morris water-maze in Fast rats. Although VNS exhibited no prophylactic effect on epileptogenesis or seizure severity when applied prior to the kindling stimulus, it showed significant anti-convulsant effects in fully kindled rats when applied after seizure initiation. Lastly, VNS prevented the weight gain associated with kindling through reduced food intake.     

Vagus nerve stimulation potentiates hippocampal LTP in freely-moving rats

Previous studies have demonstrated that electrical stimulation of the vagus nerve (VNS) delivered at a moderate intensity following a learning experience enhances memory in laboratory rats and human subjects, while VNS at lower or higher intensities has little or no effect. This finding suggests that VNS may affect memory processes by modulating neural plasticity in brain structures associated with memory storage such as the hippocampus. To test this hypothesis, the present study investigated the modulatory effect of VNS on the development of long-term potentiation (LTP) in the dentate gyrus of freely-moving rats. Rats receiving 0.4 mA VNS showed enhanced potentiation of the population spike amplitude for at least 24 h after tetanus relative to the sham-stimulation group. In contrast, no such effect was observed with 0.2 mA VNS. Stimulation at 0.8 mA had a short-term effect and tended to enhance early LTP, but to a lesser extent than did 0.4 mA. The 0.4 mA stimulation was the same intensity that was previously shown to enhance retention performance in an inhibitory avoidance task. These findings suggest that the neural mechanisms underlying the mnemonic effect of VNS may involve modulating synaptic plasticity in the hippocampus. These data also suggest that neural activity in the vagus nerve, occurring as a result of changes in peripheral state, is an important mechanism by which emotional experiences and arousal can enhance the storage of memories of those experiences.     

Recordings from the rat locus coeruleus during acute vagal nerve stimulation in the anaesthetised rat

Vagal nerve stimulation (VNS) is used as a treatment for Epilepsy and is currently under investigation as a treatment for depression (see [M.S. George, Z. Nahas, X. Li, F.A. Kozel, B. Anderson, K. Yamanaka, J.H. Chae, M.J. Foust, Novel treatments of mood disorders based on brain circuitry (ECT, MST, TMS, VNS, DBS), Semin. Clin. Neuropsychiatry 7 (2002) 293–304; M.S. George, A.J. Rush, H.A. Sackeim, L.B. Marangell, Vagus nerve stimulation (VNS): utility in neuropsychiatric disorders, Int. J. Neuropsychopharmacol. 6 (2003) 73–83] for reviews). The mechanism of action of VNS is not fully understood [E. Ben-Menachem, Vagus-nerve stimulation for the treatment of epilepsy, Lancet Neurol. 1 (2002) 477–482] despite numerous imaging investigations (see [E. Ben-Menachem, Vagus-nerve stimulation for the treatment of epilepsy, Lancet Neurol. 1 (2002) 477–482; M.S. George, Z. Nahas, X. Li, F.A. Kozel, B. Anderson, K. Yamanaka, J.H. Chae, M.J. Foust, Novel treatments of mood disorders based on brain circuitry (ECT, MST, TMS, VNS, DBS), Semin. Clin. Neuropsychiatry 7 (2002) 293–304; M.S. George, A.J. Rush, H.A. Sackeim, L.B. Marangell, Vagus nerve stimulation (VNS): utility in neuropsychiatric disorders, Int J Neuropsychopharmacol 6 (2003) 73–83; M.S. George, H.A. Sackeim, L.B. Marangell, M.M. Husain, Z. Nahas, S.H. Lisanby, J.C. Ballenger, A.J. Rush, Vagus nerve stimulation. A potential therapy for resistant depression? Psychiatr. Clin. North Am. 23 (2000) 757–783] for reviews). However, there is some evidence to suggest that the locus coeruleus may play a role modulating the effects of VNS. This study investigated the effects of VNS (0.3 mA), of sufficient intensity to recruit the A and B fibre components of the vagus [D.M. Woodbury, J.W. Woodbury, Effects of vagal stimulation on experimentally induced seizures in rats, Epilepsia 31 (Suppl. 2) (1990) S7–S19], on the discharge rate of single neurons from the locus coeruleus. This study is the first to demonstrate a direct neuronal response from the locus coeruleus following acute challenge of VNS in the anaesthetised rat. The results of this study indicate that neuronal activity of the locus coeruleus is modulated by VNS. This pathway through the locus coeruleus may be significant for mediating the clinical effects of VNS.     

Vagus nerve stimulation in intractable childhood epilepsy: a Korean multicenter experience

We evaluated the long-term outcome of vagus nerve stimulation (VNS) in 28 children with refractory epilepsy. Of these 28 children, 15 (53.6%) showed a >50% reduction in seizure frequency and 9 (32.1%) had a >75% reduction. When we compared seizure reduction rates according to seizure types (generalized vs. partial) and etiologies (symptomatic vs. cryptogenic), we found no significant differences. In addition, there was no correlation between the length of the stimulation period and treatment effect. The seizure reduction rate, however, tended to be inversely related to the seizure duration before VNS implantation and age at the time of VNS therapy. VNS also improved quality of life in this group of patients, including improved memory in 9 (32.1%), improved mood in 12 (42.9%), improved behavior in 11 (39.3%), improved alertness in 12 (42.9%), improved achievement in 6 (21.4%), and improved verbal skills in 8 (28.6%). Adverse events included hoarseness in 7 patients, dyspnea at sleep in 2 patients, and wound infection in 1 patient, but all were transient and successfully managed by careful follow-up and adjustment of parameters. These results indicate that VNS is a safe and effective alternative therapy for pediatric refractory epilepsy, without significant adverse events.     

神经电刺激下的人体增强研究进展

近年来,许多研究探索人类记忆、学习、情绪调控等认知功能、感知功能、运动功能的神经电刺激增强。脑机接口可用作更精细化的神经电刺激,它的信息读写性能提升也得到研究。非侵入式刺激以经颅直流电刺激(tDCS)为代表,实施较为便捷,但是在长期有效性和刺激精度方面需要进一步提升。侵入式刺激方式以脑深部电刺激(DBS)、迷走神经刺激(VNS)为代表,已经在临床上取得了广泛的认可和应用,刺激具备高精度特性,但是在增强方面的研究与应用上存在限制。对以上研究进展进行综述,并对人体增强研究的局限和发展趋势进行评论。     

Antiepileptic effect of electroacupuncture vs. vagus nerve stimulation in the rat thalamus

Our previous study has shown that both electroacupuncture (EA) and vagus nerve stimulation (VNS) can inhibit cortical epileptiform activities induced by pentylenetetrazole (PTZ). The current study compared the effects of EA and VNS on thalamic neuronal responses to PTZ-induced epileptiform activities. Under general anesthesia, extracellular single unit recordings were made from 49 single neurons in the rat ventrobasal (VB) thalamus. The left vagus nerve was stimulated at 30 Hz, 1 or 3 mA for 5 min. For EA, "Dazhui" acupoint (GV14) was stimulated with the same parameters. It was found that (1) the VB thalamic neurons showed epileptiform activities after PTZ injection; (2) VNS and EA could predominantly inhibit the PTZ-induced epileptiform activities in the thalamic neurons. The higher intensity stimulation (3 mA) in either VNS or EA was, however, not associated with a greater inhibition. Our study suggests that both EA and VNS reduce epileptiform activities at the thalamic level, and EA may be an alternative to VNS.     

Early seizure detection in rats based on vagus nerve activity

Continuous, scheduled vagus nerve stimulation (VNS) is used for the treatment of refractory epilepsy. On-demand VNS, started prior to or at the onset of a seizure may improve the effect of the treatment, however, this requires seizures to be predicted or detected early. This study investigates the possibility of early seizure detection based on the cervical vagus electroneurogram (VENG). Fourteen anesthetized rats received an intravenous infusion (IV) of either saline (control, n = 6) or pentylenetetrazol (PTZ) diluted in saline (PTZ-treated, n = 8). A cardiac-related VENG profile (CrVENG) was derived by using R-peak triggered averaging of the VENG energy. Following, changes in this profile were evaluated as a seizure predictor. Using left nerve VENG, seizures were detected in all PTZ-treated rats 103 ± 51 s (mean ± SD) before they developed tonic seizures. Control rats did not develop seizures and our method did also not detected seizures in these rats. Seizures can be early detecting based on left nerve VENG in anesthetized rats. Preictal CrVENG changes may reflect central-mediated changes and/or changes in the relation between the respiration and the cardiac cycle. Further research is needed to evaluate the method in awake and freely moving animals and eventually in humans.     

Neuroprotective effects of vagus nerve stimulation on hippocampal neurons in intractable epilepsy

Vagus nerve stimulation (VNS) and electroacupuncture (EA) at specific acupoints have both shown promising anticonvulsant effects in intractable epilepsy patients. The differences between these therapies are target selection and stimulation parameter modulation. It has been demonstrated that EA of the extremities results in stimulation of the VN and protection of hippocampus neurons, possibly by an anti-inflammatory response. Similarly, VNS can also suppress neural inflammatory responses, implying that VNS may protect hippocampal neurons against seizure-induced damage.     

Enhanced recognition memory following vagus nerve stimulation in human subjects

Neuromodulators associated with arousal modulate learning and memory, but most of these substances do not freely enter the brain from the periphery. In rodents, these neuromodulators act in part by initiating neural messages that travel via the vagus nerve to the brain, and electrical stimulation of the vagus enhances memory. We now extend that finding to human verbal learning. We examined word-recognition memory in patients enrolled in a clinical study evaluating the capacity of vagus nerve stimulation to control epilepsy. Stimulation administered after learning significantly enhanced retention. These findings confirm in humans the hypothesis that vagus nerve activation modulates memory formation similarly to arousal.     

Neuroprotective effects of vagus nerve stimulation on hippocampal neurons in intractable epilepsy

Vagus nerve stimulation (VNS) and electroacupuncture (EA) at specific acupoints have both shown promising anticonvulsant effects in intractable epilepsy patients. The differences between these therapies are target selection and stimulation parameter modulation. It has been demonstrated that EA of the extremities results in stimulation of the VN and protection of hippocampus neurons, possibly by an anti-inflammatory response. Similarly, VNS can also suppress neural inflammatory responses, implying that VNS may protect hippocampal neurons against seizure-induced damage.     

迷走神经电刺激对大鼠肠缺血再灌注后肠损伤的影响

目的:观察迷走神经电刺激对大鼠肠缺血再灌注（I/R）后肠损伤的影响。 方法:30只雄性Wistar大鼠，双侧颈迷走神经切断后，随机分为3组（n=10）：（1）肠缺血再灌注（I/R）组：暴露腹腔后夹闭肠系膜上动脉（SMA）1 h，开放再灌注2 h；（2）迷走神经刺激（VNS）组：在夹闭前及再灌注开始均以5 V、2 ms和1 Hz强度的电能持续刺激左颈部迷走神经远端20 min；（3）假手术对照(SC)组：仅暴露腹腔，不行SMA夹闭及电刺激。颈动脉插管监测平均动脉压（MAP）。所有动物在再灌注2 h后处死，取小肠组织行光学、电子显微镜观察肠粘膜损伤程度并行改良的Chiu’s评分；检测血浆丙二醛（MDA）、肿瘤坏死因子（TNFα）含量。 结果:各组大鼠MAP在缺血期基本保持平稳。而在再灌注期，I/R组的MAP随时间延长明显低于SC组（P＜0.05），而VNS组能明显拮抗MAP下降（P＜0.05）。光学、电子显微镜观察显示I/R后肠组织出现不同程度的损伤，I/R组最为严重，而VNS组相对较轻；但两组的改良Chiu’s评分值显著高于SC组（P＜0.01），VNS组的评分值明显低于I/R组（P＜0.01）。I/R组血浆MDA、TNFα含量明显高于SC组和VNS组（P＜0.05，P＜0.01）；VNS组血浆MDA含量高于SC组（P＜0.05），VNS组血浆TNFα与SC组无显著差异（P＞0.05）。 结论:电刺激迷走神经能显著减轻I/R肠粘膜结构的病理改变并使再灌注期的循环血压得到一定改善，其保护效应可能与减少脂质过氧化、下调TNFα生成有关。     

迷走神经刺激术对脑干孤束核部位GABA含量的影响

目的:探讨迷走神经刺激术(VNS)抗癫痫作用的机制是否为VNS引起孤束核部位GABA含量变化。方法:通过Waters高效液相色谱系统分析32只接受不同持续时间迷走神经刺激的大鼠脑干孤束核部位主要兴奋及抑制性氨基酸含量的变化。结果:1小时持续刺激组孤束核部位GABA含量较对照组升高且差异有显著意义。结论:迷走神经刺激术可能通过升高孤束核部位的GABA含量起到抗癫痫作用。     

Right-sided vagus nerve stimulation inhibits induced spinal cord seizures

We have previously shown that left-sided vagus nerve stimulation results in cessation of induced spinal cord seizures. To test our hypothesis that right-sided vagus nerve stimulation will also abort seizure activity, we have initiated seizures in the spinal cord and then performed right-sided vagus nerve stimulation in an animal model. Four pigs were anesthetized and placed in the lateral position and a small laminectomy performed in the lumbar region. Topical penicillin, a known epileptogenic drug to the cerebral cortex and spinal cord, was next applied to the dorsal surface of the exposed cord. With the exception of the control animal, once seizure activity was discernible via motor convulsion or increased electrical activity, the right vagus nerve previously isolated in the neck was stimulated. Following multiple stimulations of the vagus nerve and with seizure activity confirmed, the cord was transected in the midthoracic region and vagus nerve stimulation performed. Right-sided vagus nerve stimulation resulted in cessation of spinal cord seizure activity in all animals. Transection of the spinal cord superior to the site of seizure induction resulted in the ineffectiveness of vagus nerve stimulation in causing cessation of seizure activity in all study animals. As with left-sided vagus nerve stimulation, right-sided vagus nerve stimulation results in cessation of induced spinal cord seizures. Additionally, the effects of right-sided vagus nerve stimulation on induced spinal cord seizures involve descending spinal pathways. These data may aid in the development of alternative mechanisms for electrical stimulation for patients with medically intractable seizures and add to our knowledge regarding the mechanism for seizure cessation following peripheral nerve stimulation.     

一种无线闭环迷走神经刺激器及系统

为了治疗药物难治性癫痫,提出一种无线闭环迷走神经刺激器及系统,包括头戴式头皮脑电记录器、迷走神经刺激器、电磁耦合能量发射器和控制应用App,设计一种可以分离局部场电位和动作电位的生物信号前置放大器,一种刺激脉冲参数可调的迷走神经刺激器,一种电磁耦合能量发射器以及一个控制应用App。使用海岸线参数检测算法判定癫痫脑电信号的产生。测试结果表明,生物信号前置放大器对局部场电位和动作电位的放大增益分别为40和60 dB。迷走神经刺激器接收到来自控制应用App的刺激参数后,可以产生对应参数的双极性刺激脉冲。当发射器发射功率为30 dBm,发射线圈和接收线圈距离2 cm时,电磁耦合能量传输效率最大为15.4%。海岸线参数算法的正检率为88%。     

Vagus nerve stimulation inhibits heroin-seeking behavior induced by heroin priming or heroin-associated cues in rats

Vagus nerve stimulation has been used for the treatment of neuropsychiatric disorders, such as epilepsy. However, little is known whether it is also effective for the treatment of heroin dependence, in particular for relapse to heroin seeking. In the present study, we investigated the effects of vagus nerve stimulation on reinstatement (relapse) of heroin-seeking behavior induced by heroin priming or heroin-associated cues. The rats were trained for heroin self-administration for 14days and followed by extinction training in which heroin was replaced by saline and heroin-associated cues were turned off. In addition, animals were also received daily electric stimulation of vagus nerve (30Hz, pulse width of 0.5ms, 0.5mA (low-intensity) or 1mA (high-intensity); 30s on, 5min off; 10 continuous cycle per day) or false stimulation during extinction training. We found that such vagus nerve stimulation significantly inhibited heroin priming (0.25mg/kg, s.c.) - or heroin-associated conditioned cue-induced reinstatement of drug-seeking behavior, when compared to false stimulation control. Further, such a behavioral inhibition was correlated to a reduction in the expression of FosB and an increase in the expression of phosphorylation of cAMP response element binding protein (p-CREB) in nucleus accumbens. The data suggest that vagus nerve stimulation may inhibit heroin- or heroin cue-induced relapse, possibly by regulation of the expression of Fos and CREB in nucleus accumbens.     

Chronic vagus nerve stimulation improves alertness and reduces rapid eye movement sleep in patients affected by refractory epilepsy

OBJECTIVE: Our study aimed to evaluate the existence and entity of changes in sleep structure following vagus nerve stimulation in patients with refractory epilepsy. METHOD: A polysomnographic study was performed on the nocturnal sleep of 10 subjects with refractory epilepsy. Subjects were recorded both in baseline conditions and after chronic vagus nerve stimulation. Sleep parameters of the entire night were evaluated. Mean power value of slow-wave activity was computed in the first non-rapid eye movement sleep cycle. A sleep-wake diary evaluated quantity of both nocturnal and daytime sleep, while visual-analog scales assessed quality of sleep and wake. The differences between the 2 conditions underwent parametric and nonparametric statistical evaluation. RESULTS: Vagus nerve stimulation produced a significant reduction in REM sleep (in all subjects with vagus nerve stimulus intensity greater than 1.5 milliampere, but not in the only patient with a stimulus intensity less than 1.5 milliampere), along with an increase in the number of awakenings, percentage of wake after sleep onset, and stage 1 sleep. Data from a sleep-wake questionnaire show a decrease in both nocturnal sleep and daytime naps and an increased daytime alertness, while the quality of wakefulness is globally improved. Spectral analysis shows an enhancement of delta power during non-rapid eye movement sleep. CONCLUSIONS: Our data demonstrate major effects of vagus nerve stimulation on both daytime alertness (which is improved) and nocturnal rapid eye movement sleep (which is reduced). These effects could be interpreted as the result of a destabilizing action of vagus nerve stimulation on neural structures regulating sleep-wake and rapid eye movement/non-rapid eye movement sleep cycles. Lower intensity vagus nerve stimulation seems only to improve alertness; higher intensity vagus nerve stimulation seems able to exert an adjunctive rapid eye movement sleep-attenuating effect.