癫痫发作过程中迷走神经刺激对癫痫的抑制作用

目的我们以前的研究发现大鼠海马神经元对刺激的敏感性在癫痫发作过程中是变化的,并且与神经电活动的非线性动力学特征密切相关。本研究观察在癫痫发作过程中迷走神经刺激(vagal nerve stimulation,VNS)对癫痫的抑制作用。方法在青霉素诱导的大鼠癫痫模型上,通过记录皮层脑电图和下肢肌电图观察癫痫发作情况,电刺激左侧颈部迷走神经,观察VNS对癫痫的抑制作用。结果VNS对癫痫活动有明显的抑制作用,其抑制作用随着刺激时间的延长而增加:同时发现VNS对癫痫的抑制作用在癫痫发作过程是不同的,癫痫发作开始阶段VNS的抑制作用较强,随着癫痫发作的发展,其抑制作用逐渐减弱。结论大鼠癫痫发作过程中大脑对VNS的敏感性是不同的,随着癫痫的发展,VNS对癫痫的抑制作用逐渐减弱。     

迷走神经刺激对癫痫大鼠行为及脑电图的影响

目的：观察颈部迷走神经干电刺激对癫痫大鼠行为及额叶、海马、杏仁核脑区放电的影响，为迷走神经刺激（Vagus Nerve Stimulation,VNS)抗痫机制研究提供理论依据。方法：利用脑立体定位手段，将电极埋入大鼠脑部双侧额叶皮质、海马和杏仁核，记录VNS前后由红藻氨酸（KA）诱发复杂部分性癫痫大鼠脑电变化并观察动物行为的改变。结果：VNS后大鼠癫痫强直－阵挛发作次数明显减少，首次发作潜伏期延长，癫痫发作平均持续时间缩短；VNS尤其对杏仁核放电有明显的抑制作用。结论：VNS能有效抑制KA诱发的复杂部分性癫痫发作，并且杏仁核可能是抑痫作用的关键核因。     

经皮迷走神经耳支刺激与迷走神经刺激对药物难治性癫痫大鼠治疗效果的比较

目的探讨经皮(耳甲腔)迷走神经耳支电刺激(ta-VNS)与迷走神经电刺激(VNS)对药物难治性癫痫(RE)大鼠癫痫发作治疗效果的差异。方法采用氯化锂-匹鲁卡品制备颞叶癫痫大鼠,苯巴比妥钠(PB)诱导筛选RE大鼠模型。在此基础上,将大鼠随机分为空白对照组(建模时用生理盐水代替匹鲁卡品)、RE组(不做刺激处理)、RE+ta-VNS组(经皮迷走神经耳支刺激)、RE+假ta-VNS组(耳甲腔处安置电极片但不通电)、RE+VNS组(迷走神经刺激)和RE+假VNS组(植入迷走神经刺激电极但不通电)。4周刺激结束后比较各组大鼠发作频率,断头取脑制作海马切片行Nissl和TUNEL染色观察各组海马神经元的形态学变化和损伤凋亡情况。结果 1 RE+ta-VNS组和RE+VNS组癫痫平均发作频率分别减少72.0%和80.7%,均与RE组有显著性差异(P0.05),RE+ta-VNS组和RE+VNS组之间差异无统计学意义(P=0.12),RE+假ta-VNS组、RE+假VNS组和RE组间无统计学差异。2 Nissl和TUNEL染色显示:与空白对照组相比RE组、RE+假ta-VNS组和RE+假VNS组大鼠海马神经元损伤严重,RE+ta-VNS组和RE+VNS组损伤较轻,RE+ta-VNS组和RE+VNS组之间差异无统计学意义。结论 ta-VNS和VNS均可显著低RE大鼠的癫痫发作次数、减轻海马神经元的损伤,两者的效果接近,但是ta-VNS具有无创性、副作用少等优点。     

迷走神经刺激对药物难治性癫痫大鼠脑内多药耐药蛋白过表达的抑制作用

目的 主要研究迷走神经刺激(VNS)对癫痫大鼠脑内多药耐药蛋白(P-gp)表达的调控作用.方法 采用氯化锂-匹鲁卡品制备颞叶癫痫大鼠,苯巴比妥钠(PB)诱导建立药物难治性癫痫(RE)大鼠模型.在此模型基础上,大鼠按随机数字表顺序分为四组:单纯VNS(A)组、VNS+ PB(B)组、假VNS+PB(C)组、生理盐水(D)组.VNS组行刺激电极植入术,通过改进的VNS参数(频率30 Hz,波宽500μs,电流0.75 mA,刺激时间30 s,间歇5min,12 h/d)进行电刺激,观察各组大鼠VNS前后发作次数,检测各组P-gp表达含量的变化.结果 (1)A、B组癫痫平均发作次数分别减少79.6％和85.9％,C、D组无明显改善;(2)B组P-gp过表达量与C组相比差异有统计学意义(P＜0.05),A组P-gp表达量较D组差异有统计学意义(P＜0.05).结论 VNS疗法可以有效降低RE的发作次数,对由药物引起的P-gp的过表达具有较强的抑制作用,与药物联合应用可以达到较好的治疗效果.     

迷走神经脉冲电刺激对大鼠癫痫部分性发作和全面发作的影响对照研究

目的定量研究迷走神经刺激(VNS)对大鼠杏仁核部分点燃和全面点燃的抑制作用差异.方法用强度3.0 mA的恒流脉冲电刺激2组动物(各15只)的左侧颈迷走神经干,观察发作抑制率(SIR)、平均行为级数下降比(MBSDR)、平均后放电时间下降比(MADTDR)和平均后放电阈值上升比(MADTIR)的组间差异.结果除MADTIR组间差异无显著性意义(P＞0.05)外,其余各指标组间差异均有非常显著性意义(P＜0.01).结论 VNS对大鼠全身性发作的发作频率和强度的抑制作用强于对部分性发作的抑制作用.     

迷走神经刺激对癫癎大鼠行为及脑电图的影响

目的 :观察颈部迷走神经干电刺激对癫大鼠行为及额叶、海马、杏仁核脑区放电的影响 ,为迷走神经刺激 (VagusNerveStimulation ,VNS)抑机制研究提供理论依据。方法 :利用脑立体定位手段 ,将电极埋入大鼠脑部双侧额叶皮质、海马和杏仁核 ,记录VNS前后由红藻氨酸 (KA)诱发复杂部分性癫大鼠脑电变化并观察动物行为的改变。结果 :VNS后大鼠癫强直 阵挛发作次数明显减少 ,首次发作潜伏期延长 ,癫发作平均持续时间缩短 ;VNS尤其对杏仁核放电有明显的抑制作用。结论 :VNS能有效抑制KA诱发的复杂部分性癫发作 ,并且杏仁核可能是抑作用的关键核团     

迷走神经刺激治疗难治性癫痫机制的研究进展

迷走神经刺激术是近二十年发展起来的治疗难治性癫痫的一种新方法.它能有效地减少癫痫发作频率、减轻发作程度,副作用少且容易耐受.尽管如此,VNS抗癫痫作用的原理仍然不清,许多学者都在对其作用机制进行探索.本文就目前VNS治疗癫痫机制的研究进展情况进行综述.     

迷走神经刺激治疗难治性癫痫

迷走神经刺激术 (VNS)是一种新的、非药物性治疗难治性癫痫的方法。自 1 988年 Penry首次将此项技术应用于临床以后 ,由于其疗效确切 ,尤其是对难治性复杂部分性发作控制 ,安全和易于耐受 ,VNS治疗难治性癫痫越来越受到重视 ,并且在世界各地陆续开展这项治疗。概　　况早在 30年代 ,人们就认识到 VNS可引起脑电活动的变化。大量的动物实验证实 ,VNS可控制或减轻化学性和最大电休克诱导的癫痫发作。 1 988年Penry等首先将此项技术应用于临床[2 ] ,并且取得了满意的效果。 1 990年美国德克萨斯州 Webster市的 Cybronics公司研制成功的…     

迷走神经刺激术治疗一例顽固性癫痫

正对药物难治性癫痫患者,应及早考虑外科手术治疗。外科治疗癫痫有常规切除术和电刺激术两类方法,对于因各种原因无法开颅切除,或者切除术后仍发作的癫痫患者,植入式迷走神经刺激术(Vagus nerve stimulation,VNS)是唯一经过美国食品药品监督管理局(Food and Drug Administration,FDA)批准的神经电刺激治疗手术。VNS具有控制癫痫发作效果良好,无需开颅,对脑组织及功能无损伤、风险低,提高患者生活质量,改善记忆、觉     

迷走神经刺激术治疗难治性癫痫的研究进展

<正>植入式刺激器对迷走神经进行慢性、间歇性电刺激作为一种新疗法应用于难治性癫痫,其可以显著降低癫痫发作的频率和严重程度,并提高患者生存质量,但机制尚未明了。本文就迷走神经刺激术(VNS)治疗难治性癫痫的机制及疗效的研究进展做一简要综述。1 VNS的神经解剖学基础迷走神经是体内行程最长、分布最广的混合性脑神经。其中,80%的纤维成分是躯体和内脏传入纤维,传递一般内脏的感觉冲动,在节状神经节之后继续投射到延髓孤束核     

Slow Hyperpolarization in Cortical Neurons: A Possible Mechanism Behind Vagus Nerve Simulation Therapy for Refractory Epilepsy?

PURPOSE: Recent studies have shown that chronic, intermittent stimulation of the left vagus nerve (VNS) decreases the frequency, duration, and/or intensity of seizures in some patients with medically refractory focal seizures. Although VNS is being used in an increasing number of patients, the neuronal mechanism behind VNS therapy of refractory epileptic seizures is yet unclear. METHODS: In vivo intracellular recordings were used to study responses elicited by the VNS in pyramidal neurons of the parietal association cortex in anesthetized rats. RESULTS: Low-intensity trains of VNS, which activated predominantly myelinated fibers (100 microA, 30 Hz, 0.5 millisecond, 20 seconds), elicited a slow hyperpolarization (onset latency 17.4 +/- 2.0 seconds, amplitude -4. 7 +/- 0.6 mV, duration 35 +/- 3.2 seconds; n = 19). Increasing the intensity of VNS to recruit nonmyelinated vagal fibers (200 microA) led to an increase in the magnitude of the response in some neurons while failed to evoke a response in others. On increasing the stimulus intensity to 500 microA, only one in nine neurons exhibited a visible response. All recorded and visualised neurons were pyramidal cells in cortical layer V. CONCLUSIONS: Stimulus intensities that activate predominantly myelinated fibers (less than 200 microA) were most effective to induce slow vagal hyperpolarization. It is suggested that slow hyperpolarization may be one of the mechanisms that underlie the seizure-reducing effect of VNS, by means of reducing the excitability in neurons that would be involved in propagation of seizure activity. As the balance of activity in myelinated and nonmyelinated primary vagal afferents influenced the effect of VNS stimulation, it is likely that the effect of VNS is modulated as changes occur in the underlying vagal tone.     

Effect of vagal nerve stimulation on auditory and visual event-related potentials

Chronic unilateral vagal nerve stimulation (VNS) has been recently introduced into the therapy for intractable epileptic seizures. Its effect on cognitive functions in VNS-treated patients remains controversial. The aim of the present study was to evaluate the possible impact of therapeutic VNS on cognitive functions by means of event-related potentials analysis. Ten patients with medically intractable epilepsy, who had been implanted with VNS devices, participated in the study. Auditory and visual event-related potentials (ERPs) were repeatedly recorded, first just before the implantation of VNS devices, and then again 3-6 months after the device activation. The effect of lower intensity stimulation on the P3 component of ERPs was assessed. No significant differences were found in auditory ERPs; the latencies of P3 as well as N2/P3 peak-to-peak amplitudes were virtually identical. The same was true for mean P3 latencies of visual ERPs. However, higher visual N2/P3 peak-to-peak amplitudes were observed in the responses to targets that followed VNS, with a significant finding at the electrodes investigated. When comparing the effect of VNS on visual N2/P3 amplitude in each electrode separately, the most expressive differences were found in the frontal region. This observation supports the theory of a possible positive effect of low-intensity VNS on the cognitive functions.     

Pain control by vagus nerve stimulation: from animal to man...and back

Vagus nerve stimulation (VNS), already used as a treatment for refractory epilepsy, has also been assessed for its analgesic effect. Numerous studies report that electrical stimulation of vagal afferents inhibits spinal nociceptive reflexes and transmission. However, results are partly contradictory, showing that the VNS effects depend on the stimulation parameters. Clinical data have been collected from VNS-implanted epileptic patients in whom pain thresholds were measured and the VNS effect on co-existing headaches was assessed. In addition, in 2 pilot studies of a few patients, VNS was used to treat resistant chronic headaches and migraines. Taken together these clinical studies tend to confirm the analgesic effect of VNS and to suggest its potential utility in chronic headache patients. In order to better define the nature of neuronal and behavioural changes induced by VNS with devices used in humans and to determine the most adequate stimulation stimulation protocols, we have used a commercially available stimulator (NCP-Cyberonics) for prolonged VNS in rats. Our results show a clear antinociceptive effect of VNS in models of acute or inflammatory pain with different stimulation protocols including the one used in epileptic patients. Using immunocytochemical methods, we find that activity changes in spinal trigeminal nucleus neurons could underlie at least part of the VNS-induced analgesia.     

Vagal nerve stimulation--the Norwegian experience.

The purpose of this open retrospective study was to analyze the efficacy and tolerability of vagal nerve stimulation (VNS) in a Norwegian cohort of referral patients with refractory epileptic seizures. A total of 47 patients have been assessed after a mean follow-up time of 2.7 years. Mean age was 34.4 years, mean duration of epilepsy was 25.3 years. Forty-two patients (89%) had localization-related epilepsy, 36 patients (77%) had daily seizures. The patients had tried on average 9.5 antiepileptic drugs, and 12 patients (26%) had undergone epilepsy surgery.Sixteen patients (34%) had >50% reduction of seizure frequency with VNS, of which one patient became seizure free. The stimulation was generally well tolerated, but three patients requested the device removed because of troublesome side effects.We conclude that VNS is an efficacious and safe mode of treatment that should be offered to patients with medically and surgically refractory seizures.     

Brain Blood Flow Alterations Induced by Therapeutic Vagus Nerve Stimulation in Partial Epilepsy: I. Acute Effects at High and Low Levels of Stimulation

Summary: Purpose: Left cervical vagus nerve stimulation (VNS) decreases complex partial seizures (CPS) by unknown mechanisms of action. We hypothesized that therapeutic VNS alters synaptic activities at vagal afferent terminations and in sites that receive polysynaptic projections from these medullary nuclei.
Methods: Ten patients with partial epilepsy underwent positron emission tomographic (PET) measurements of cerebral blood flow (BF) three times before and three times during VNS. Parameters for VNS were at high levels for 5 patients and at low levels for 5. Resting BF measurements were subtracted from measurements during VNS in each subject. Subtraction data were averaged in each of 2 groups of 5 patients. t Tests were applied to BF changes in brain regions that receive vagal afferents and projections (significant at p < O.05, corrected for repeated measures).
Results: In both the low- and high-stimulation groups during VNS, brain BF was (a) increased in the rostral, dorsal-central medulla; (b) increased in the right postcentral gyrus, (c) increased bilaterally in the hypothalami, thalami, and insular cortexes, and in cerebellar hemispheres inferiorly; and (d) decreased bilaterally in hippocampus, amygdala, and posterior cingulate gyri. The high-stimulation group had greater volumes of activation and deactivation sites.
Conclusions: Our findings suggest that left cervical VNS acutely increases synaptic activity in structures directly innervated by central vagal structures and areas that process left-sided somatosensory information, but VNS also acutely alters synaptic activity in multiple limbic system structures bilaterally. These findings may reflect sites of therapeutic actions of VNS.     

An analysis of quality of life (QOL) in patients with epilepsy and comorbid psychogenic nonepileptic seizures (PNES) after vagus nerve stimulation (VNS)

PurposePatients with epilepsy (PWE) may suffer from comorbid psychogenic nonepileptic seizures (PNES). The efficacy of vagus nerve stimulation (VNS) in the treatment of epilepsy and depression is established, however the impact on PNES is unknown. Since many patients with PNES have comorbid depression, we explored the impact on quality of life (QOL) that VNS has on PWE and PNES.MethodsThe video electroencephalogram (vEEG) of all patients who underwent VNS at our institution was reviewed. Patients diagnosed with both psychogenic seizures and epileptic seizures on their vEEG were included in this study. These patients were contacted, and given a QOLIE-31 survey to assess their quality of life after VNS. Patients also completed a separate survey created by our group to categorize the quartile of their improvement. Pre-operative psychiatric disease was retrospectively reviewed.ResultsFrom a period of 2001 to 2016, 518 patients underwent placement of VNS for drug resistant epilepsy (DRE) at our institution. In total, 16 patients were diagnosed with both epilepsy and PNES. 11/16 patients responded to our questionnaire and survey. 9 out of 11 patients felt that their epileptic seizures had improved after VNS, while 7 of the 11 patients felt that their psychogenic episodes had improved. 2(28.6%), 1 (14.3%), and 4 (57.1%) of participants said their PNES improved by 25–50%, 50–75%, and 75–100%, respectively. 3(27.3%), 3 (27.3%), 1 (9.1%), and 4 (36.4%) of the participants said their epileptic seizures improved by 0–25%, 25–50%, 50–75%, and 75–100%, respectively. The average overall score for quality of life for the study participants was found to be 51 (± 8) out of 100.ConclusionPatients with epilepsy and comorbid PNES may benefit from VNS. It is unclear whether the benefit is conferred strictly from decreased epileptic seizure burden. The possible effect on PNES may be related to the known effect of VNS on depression. Further studies are necessary to elucidate the role of VNS in the treatment of PNES and possibly other psychiatric disease.     

Neuromodulation with levetiracetam and vagus nerve stimulation in experimental animal models of epilepsy

Epilepsy is a neurological disorder consisting of recurrent seizures, resulting from excessive, uncontrolled electrical activity in the brain. Epilepsy treatment is successful in the majority of the cases; however; still one third of the epilepsy patients are refractory to treatment. Besides the ongoing research on the efficacy of antiepileptic treatments in suppressing seizures (anti-seizure effect), we want to seek for therapies that can lead to plastic, neuromodulatory changes in the epileptic network. Neuropharmacological therapy with levetiracetam (LEV) and vagus nerve stimulation (VNS) are two novel treatments for refractory epilepsy. LEV acts rapidly on seizures in both animal models and humans. In addition, preclinical studies suggest that LEV may have antiepileptogenic and neuroprotective effects, with the potential to slow or arrest disease progression. VNS as well can have an immediate effect on seizures in epilepsy models and patients with, in addition, a cumulative effect after prolonged treatment. Studies in man are hampered by the heterogeneity of patient populations and the difficulty to study therapy-related effects in a systematic way. Therefore, investigation was performed utilizing two rodent models mimicking epilepsy in humans. Genetic absence epilepsy rats from Strasbourg (GAERS) have inborn absence epilepsy and Fast rats have a genetically determined sensitivity for electrical amygdala kindling, which is an excellent model of temporal lobe epilepsy. Our findings support the hypothesis that treatment with LEV and VNS can be considered as neuromodulatory: changes are induced in central nervous system function or organization as a result of influencing and initiating neurophysiological signals.     

Destruction of peripheral C-fibers does not alter subsequent vagus nerve stimulation-induced seizure suppression in rats

PURPOSE: Early animal studies of the therapeutic mechanisms of vagus nerve stimulation (VNS) suggested that seizure suppression requires maximal activation of small, unmyelinated vagal C fibers. However, effective therapeutic stimulation parameters appear to be subthreshold for these fibers in humans, and there are no clinical reports of the autonomic side effects that would be expected if these fibers were maximally activated. We report here that selective destruction of C fibers with capsaicin does not affect VNS-induced seizure suppression in rats. METHODS: Rats were pretreated with capsaicin or vehicle in three injections over a 2-day period. A cuff electrode was later implanted on the left cervical vagus nerve. Two days after surgery, VNS was given to half of the capsaicin- and vehicle-treated rats. The remaining rats were connected to the stimulator but did not receive VNS. Thirty seconds after VNS onset, seizures were induced by pentylenetetrazol (PTZ), and seizure severity was measured. Two days later, the reciprocal VNS treatment was given, and PTZ-induced seizure severity was again measured. RESULTS: VNS effectively reduced seizure severity in both capsaicin- and vehicle-treated rats as compared with their non-VNS baselines. CONCLUSIONS: These results indicate that activation of vagal C fibers is not necessary for VNS-induced seizure suppression.