Vagus nerve stimulation in depression

Ever since the introduction of chemical and electrical convulsive treatment for psychiatric disorders in the 1930s and 1940s, biological techniques have been used extensively in the amelioration of a variety of psychiatric disorders. Techniques of recent vintage have included transcranial magnetic stimulation, deep brain stimulation and vagus nerve stimulation (VNS). Since VNS attenuates seizures in animal models, the treatment was initially developed and approved by the FDA for treatment of drug-resistant partial-onset epilepsy. Additional data, including the known neuroanatomy of the vagus nerve, effects of VNS on monoamines and mood improvement in patients with epilepsy who were treated with VNS, provided a rationale for further investigation in patients with primary mood disorders. VNS has been administered acutely for 10 weeks to 60 patients with treatment-resistant depression. Longer-term follow-up data has been analysed for the first 30 patients. Response rates have been at least 30% in the acute study. Similar to findings in epilepsy and in contrast to the usual results of long-term medication trials, longer term data regarding symptomatic and functional outcomes of depressed patients receiving VNS continue to look promising. As opposed to electroconvulsive therapy, VNS is not associated with cognitive impairment. These results have led to approval of VNS for the treatment of resistant depression (unipolar or bipolar) in both Europe and Canada. Currently, a pivotal double-blind acute study is underway in the US.     

Estimating the potential savings with vagus nerve stimulation for treatment-resistant depression: a payer perspective*

ABSTRACT

Objective: To provide a formula estimating potential reductions in healthcare utilization costs with adjunctive vagus nerve stimulation (VNS Therapy^?) in treatment-resistant depression (TRD).

Methods: This payer-perspective formula incorporates costs of treatment as usual for TRD patients from a published analysis of the MarketScan private payer claims database and the 2004 Medicare 5% standard analytic file. Estimated remission and response rates are from the published VNS pilot and pivotal studies. Costs were converted to 2008 US dollars per the US Bureau of Labor Statistics medical care costs, consumer price index. Device and implantation costs were calculated at $28?336.

Results: From the MarketScan and pooled outcomes data (VNS pilot and pivotal studies), potential per patient savings (hospitalization directly and indirectly related to depression) was $2974 at 5 years of device life, $23?539 at 8 years (moderate cost reduction scenario); $12?914 at 5 years, $40?935 at 8 years (optimistic scenario). Corresponding break-even device life was 4.57 and 3.62 years, respectively. From the Medicare file and pooled outcomes, potential per patient savings (inpatient and outpatient directly and indirectly related to depression) was $8358 at 5 years of device life, $32?385 at 8 years (moderate scenario); $19?837 at 5 years, $52?473 at 8 years (optimistic scenario). Corresponding break-even device life was 3.96 and 3.18 years, respectively.

Conclusions: The formula allows an evaluation of expected reductions in healthcare costs as a function of input cost variables, efficacy rates, and benefit scenarios. Cited costs differ relative to care settings, diagnostic principles, and procedural volume. This formula can help assess moderate-to-longer-term economic benefits of VNS for a particular institution. Results suggested that potential reductions in healthcare costs with VNS for TRD may be substantial. Break-even device life for the scenarios presented ranges between 2.3 and 5.7 years.

Trial registration: ClinicalTrials.gov identifier: NCT00533832.     

Vagus nerve stimulation therapy

Until recently, antiepileptic drugs and traditional epilepsy surgery were the two primary treatment options available to patients with epilepsy. Drug therapy, however, does not always control seizures and can be associated with negative side effects. Additionally, only a minority of patients are candidates for epilepsy surgery. Vagus nerve stimulation (VNS) therapy, approved by the US FDA in 1997, is now a treatment option that is effective in reducing seizure frequency and severity as well as improving patient quality of life without the pharmacological side effects associated with traditional antiepileptic drugs. Provided here is an overview of VNS therapy and the VNS therapy system, including the history of vagal nerve stimulation, patient selection guidelines and new indications currently under investigation for this novel therapy.     

Brain-derived neurotrophic factor serum concentrations in depressive patients during vagus nerve stimulation and repetitive transcranial magnetic stimulation

Background Vagus nerve stimulation (VNS) and repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex are brain stimulation techniques used as therapeutic interventions in major depression.Methods In this study, we report the impact of these stimulation techniques on serum concentrations of brain-derived neurotrophic factor (BDNF) in treatment-resistant patients with a diagnosis of major depression.Results We found no changes of BDNF serum concentrations and no association of neurotrophin concentrations in serum with clinical parameters in our sample.Conclusion Our preliminary results suggest that brain stimulation techniques—in contrast to several antidepressant medications—do not change BDNF serum concentrations.     

The effects of vasodilating drugs and vasoconstrictor nerve stimulation on oxygen uptake in skeletal muscle

Oxygen uptake was studied in skeletal muscle of cat, dog, fox and hare during i.a. infusion of acetylcholine, isoproterenol, and histamine. All agents produced similar effects in the different species. After a brief initial increase, the calculated oxygen uptake returned to near resting levels and remained so throughout the infusion period.

During acetylcholine infusion and concomitant vasoconstrictor nerve stimulation, the oxygen uptake decreased compared to resting levels although blood flow was increased. During motor nerve stimulation, the oxygen uptake increased considerably and acetylcholine infusion did not change the magnitude of that increase.

It is concluded that acetylcholine, isoproterenol, and histamine do not influence the capillary surface area to such an extent as to cause major changes in the oxygen uptake of the resting skeletal muscle. On the other hand, sympathetic vasoconstrictor nerve stimulation decreased oxygen uptake, even during increased blood flow, indicating that under those circumstances the capillary surface area is considerably decreased.     

Auricular Transcutaneous Vagus Nerve Stimulation Diminishes Alpha-Band–Related Inhibitory Gating Processes During Conflict Monitoring in Frontal Cortices

BackgroundPursuing goals is compromised when being confronted with interfering information. In such situations, conflict monitoring is important. Theoretical considerations on the neurobiology of response selection and control suggest that auricular transcutaneous vagus nerve stimulation (atVNS) should modulate conflict monitoring. However, the neurophysiological-functional neuroanatomical underpinnings are still not understood.MethodsAtVNS was applied in a randomized crossover study design (n = 45). During atVNS or sham stimulation, conflict monitoring was assessed using a Flanker task. EEG data were recorded and analyzed with focus on theta and alpha band activity. Beamforming was applied to examine functional neuroanatomical correlates of atVNS-induced EEG modulations. Moreover, temporal EEG signal decomposition was applied to examine different coding levels in alpha and theta band activity.ResultsAtVNS compromised conflict monitoring processes when it was applied at the second appointment in the crossover study design. On a neurophysiological level, atVNS exerted specific effects because only alpha-band activity was modulated. Alpha-band activity was lower in middle and superior prefrontal regions during atVNS stimulation and thus lower when there was also a decline in task performance. The same direction of alpha-band modulations was evident in fractions of the alpha-band activity coding stimulus-related processes, stimulus-response translation processes, and motor response–related processes.ConclusionsThe combination of prior task experience and atVNS compromises conflict monitoring processes. This is likely due to reduction of the alpha-band–associated inhibitory gating process on interfering information in frontal cortices. Future research should pay considerable attention to boundary conditions affecting the direction of atVNS effects.     

加巴喷丁联合经皮神经电刺激治疗带状疱疹后遗神经痛临床观察

目的 观察加巴喷丁联合经皮神经电刺激治疗带状疱疹后遗神经痛的疗效.方法 40例带状疱疹后遗神经痛患者,随机分成两组,A组(n=20)给予口服加巴喷丁治疗;B组(n=20)服用与A组相同剂量加巴喷丁,同时在其患处给予每日1次经皮神经电刺激治疗,分别观察两组患者治疗前以及治疗后3d,5d,7d,14d,28d的疼痛程度变化,以视觉模拟评分(VAS)评定治疗效果.结果 治疗后两组患者VAS评分均明显下降(P＜0.05),且B组VAS评分明显低于A组(P＜0.05).结论 加巴喷丁联合经皮神经电刺激是治疗带状疱疹后遗神经痛的一种有效方法.     

电针神经刺激治疗前列腺癌术后尿失禁疗效分析

目的：评价电针神经刺激疗法治疗前列腺癌根治术后尿失禁的临床疗效。方法：选择2010年9月—2015年8月前列腺癌根治术后尿失禁患者32例,予电针神经刺激疗法治疗,取穴“骶四穴”,治疗时间60 min/次,每周3次,疗程1个月。记录治疗前和治疗结束时的症状积分、盆底肌能力评分并评定疗效。结果：患者症状评分从治疗前的（17.36±3.53）分降至治疗后的（8.79±2.65）分,差异有统计学意义（P＜0.01）;盆底肌肉功能评分从治疗前的（47.21±10.38）分上升至（77.72±9.21）分,差异有统计学意义（P＜0.01）。治疗结束时临床有效率为81.25%（26/32）。结论：电针神经刺激疗法治疗前列腺癌根治术后尿失禁效果良好,且无明显不良反应,可作为前列腺癌根治术后尿失禁的首选物理治疗方法。     

电刺激迷走神经对血管壁c-kit+细胞迁移和分化的影响

目的　观察电刺激迷走神经对颈动脉损伤大鼠血管壁c-kit+细胞迁移和分化的影响。方法　将24只SD大鼠随机分为假手术组、模型组、迷走神经刺激组,每组8只。制备SD大鼠左颈总动脉球囊损伤模型后,迷走神经刺激组电刺激左侧迷走神经。通过HE染色及免疫组织化学染色分别观察血管内膜厚度和c-kit+细胞在血管壁中的分布;酶联免疫吸附试验（ELISA）检测大鼠血清中肿瘤坏死因子（TNF）-α和白细胞介素（IL）-6水平。原代培养血管壁c-kit+细胞,分为对照组（不加入乙酰胆碱）、1×10-5 mol/L乙酰胆碱组、1×10-8 mol/L乙酰胆碱组及1×10-5 mol/L乙酰胆碱+α7烟碱样乙酰胆碱受体（α7nAChR）拮抗剂组。Transwell检测细胞迁移能力变化,Western blot检测平滑肌22α（SM22α）蛋白表达。结果　（1）与模型组比较,迷走神经刺激组新生内膜厚度变薄,新生内膜中c-kit+细胞数量减少（P＜0.05）,血清TNF-α和IL-6水平也下降（P＜0.01）。（2）乙酰胆碱抑制c-kit+细胞迁移,上调SM22α的表达,α7nAChR拮抗剂可逆转上述效应。结论　迷走神经通过抑制c-kit+细胞迁移并促进其向平滑肌细胞分化而抑制新生内膜形成,其作用机制可能与神经末梢释放的递质乙酰胆碱结合α7nAChR,进而激活抗炎系统有关。     

Antinociceptive action of captopril and transcutaneous electric nerve stimulation in Mus musculus mice

1. In the present study, the antinociceptive action of captopril was investigated, as well as its association with transcutaneous electric nerve stimulation (TENS), in mice under nociceptive stimulation. 2. The modulation of abdominal contortions (writhes) produced by acetic acid was observed in order to evaluate captopril pain stimuli blockade. 3. The administration of captopril produced a significant reduction of nociception, which was further reduced when captopril was associated with TENS. 4. Apparently this increase in the inhibition of nociception was produced by an indirect mechanism, involving opioid liberation by TENS and an enzymatic inhibition induced by captopril and this may lead to clinical applications of captopril and TENS association in pain relief.     

Comparison of corelease of noradrenaline and ATP evoked by hypogastric nerve stimulation and field stimulation in guinea-pig vas deferens

Contractions and overflow of tritium and ATP elicited by hypogastric nerve stimulation (HNS) and field stimulation (FS) were studied in the guinea-pig isolated vas deferens preincubated with [³H]-noradrenaline. ATP was measured by means of the luciferin-luciferase technique.HNS and FS elicited contraction, tritium overflow and ATP overflow. HNS at supramaximal current strength produced smaller responses than did FS at supramaximal current strength (210 pulses/7 Hz). Supramaximal HNS and submaximal FS were used in the remainder of the study. Prazosin (0.3 mol/l) reduced contractions and the overflow of ATP elicited by both HNS and FS; the evoked overflow of tritium was not changed (210 pulses/7 Hz). Combined administration of prazosin (0.3 mol/l) and suramin (300 mol/l) abolished contractions and reduced the overflow of ATP elicited by both HNS and FS slightly more than did prazosin alone; tritium overflow again was not changed (210 pulses/7 Hz). Contractions, tritium overflow and ATP overflow increased with the frequency of both HNS and FS (from 7 to 25 Hz; 210 pulses); the increase in ATP overflow with frequency was more marked than the increase in tritium overflow. The preferential increase of ATP overflow with the frequency of HNS and FS persisted in the combined presence of prazosin (0.3 mol/l) and suramin (300 mol/l).The study confirms for HNS, a more physiologic way of sympathetic nerve stimulation, several observations previously obtained with FS. First, HNS-evoked ATP release is detectable as an overflow of ATP into the superfusion fluid. Second, a large part of the HNS-evoked release of ATP is postjunctional in origin, due to activation of post-junctional ₁-adrenoceptors and presumably P₂-purinoceptors. Third, the average neural release of ATP per pulse facilitates with the frequency of stimulation to a greater extent than the average release of noradrenaline per pulse.     

神经电刺激仪电流强度对糖尿病兔坐骨神经阻滞的影响

目的观察神经电刺激仪电流大小对糖尿病兔坐骨神经定位的影响。方法静脉注射链脲菌素复制糖尿病兔模型,神经电刺激仪起始电流分别为1mA(高电流组)或0.5mA(低电流组)定位糖尿病兔坐骨神经,记录最低刺激电流,固定阻滞针注射0.5mL墨水后,将相应组织冰冻切片,观察墨水渗入神经的程度。结果低电流组,阻滞针与坐骨神经距离平均为―(1.3±0.4)mm;高电流组,阻滞针与坐骨神经距离平均为(1.4±0.2)mm。低电流和高电流组分别有16只和2只实验兔墨水直接注入坐骨神经(P<0.05)。结论在链脲菌素建立的糖尿病兔模型中,神经电刺激电流大小与阻滞针-坐骨神经距离成正相关。     

Chronic impairment of the vagus nerve function leads to inhibition of dopamine but not serotonin neurons in rat brain structures

BackgroundRecent clinical studies have shown that the dorsal motor nucleus of the vagus nerve is one of the brain areas that are the earliest affected by α-synuclein and Lewy body pathology in Parkinson's disease. This observation raises the question: how the vagus nerve dysfunction affects the dopamine system in the brain?MethodsThe rats underwent surgical implantation of the microchip (MC) in the abdominal region of the vagus. In this study, we examined the effect of chronic, unilateral electrical stimulation of the left nerve vagus, of two different types: low-frequency (MCL) and physiological stimulation (MCPh) on the dopamine and serotonin metabolism determined by high-pressure chromatography with electrochemical detection in rat brain structures.ResultsMCL electrical stimulation of the left nerve vagus in contrast to MCPh stimulation, produced a significant inhibition of dopamine system in rat brain structures. Ex vivo biochemical experiments clearly suggest that MCL opposite to MCPh impaired the function of dopamine system similarly to vagotomy.ConclusionWe suggest a close relationship between the peripheral vagus nerve impairment and the inhibition of dopamine system in the brain structures. This is the first report of such relationship which may suggest that mental changes (pro-depressive) could occur in the first stage of Parkinson's disease far ahead of motor impairment.     

Vagus nerve stimulation: current status and clinical applications

Despite the recent introduction of new anti-epileptic drugs (AEDs), many patients with epilepsy, especially those with partial-onset seizures, continue to have seizures that are refractory to pharmacotherapy. Other patients are unable to tolerate the side-effects of AEDs given singly or in combination. Cerebral resective surgery may be an option for a sub-group of these patients; however, many patients with refractory partial epilepsy are not optimal candidates for epilepsy surgery. Consequently, the introduction of left vagus nerve stimulation (VNS) for those patients who have been afflicted by seizures or medication side-effects has opened up a new, non-pharmacological approach to epilepsy treatment. The mechanism of action of VNS is uncertain. VNS exerts an anticonvulsant effect in a variety of animal seizure models; has no effect on hepatic metabolic processes, serum concentrations of AEDS, or laboratory values; and has no clinically significant effect on vagally-mediated physiological processes. VNS is safe and well-tolerated in patients with long-standing, medically-refractory, partial-onset epilepsy. Adverse effects are usually mild to moderate in severity and related to stimulation, and almost always resolve with adjustment in stimulation settings. Controlled studies of patients on AED therapy show that adjunctive VNS is effective for partial-onset seizures when given every 5 min for 30 s intervals. Results of studies in paediatric patients are encouraging.     

Vagus nerve stimulation (VNS): utility in neuropsychiatric disorders

Early in the last century, neuroscientists initially speculated that it might be possible to influence brain activity and associated behaviours by stimulating the vagus nerve in the neck. Several animal studies pointed to this possibility. In the 1980s, Zabara discovered that vagus nerve stimulation (VNS) could reduce or eliminate seizures in dogs. His discovery led to enhanced methods of direct VNS and the development of an implantable device for human VNS. VNS is now an accepted long-term treatment for epilepsy, used by over 15000 patients worldwide. Many have wondered whether VNS could treat other neuropsychiatric disorders. This paper reviews the neurobiology involved in VNS, highlights the VNS clinical findings to date, and discusses potential VNS research opportunities for both clinical and basic investigators. Comments on the clinical utility of VNS in actual clinical practice are provided.     

急慢性迷走神经刺激对大鼠海洛因复吸行为的影响及作用机制

目的:探讨急慢性迷走神经刺激(VNS)对大鼠海洛因复吸行为可能的干预作用及机制。方法:SD大鼠每天进行4h的海洛因自身给药训练,持续14d,建立具有强迫性觅药和给药特征的自身给药模型。随后所有大鼠植入VNS电极,恢复后进行10d的海洛因觅药行为消退训练,期间分组给予急性VNS、慢性VNS或假刺激。消退结束后测定各组大鼠条件性线索诱导下的海洛因觅药行为的恢复(即海洛因复吸行为)。免疫荧光法检测中枢核团c-Fos的表达水平。结果:海洛因复吸行为测定结果显示,与假刺激对照组比较,急性VNS组和慢性VNS组的有效鼻触数均明显降低(P<0.01)。免疫荧光的结果显示,与对照组比较,急性VNS组(P<0.05)和慢性VNS组(P<0.01)中央杏仁核(Ce)的c-Fos表达水平均明显降低,而边缘下区(IL)的c-Fos表达水平均明显升高(P<0.05)。结论:急慢性VNS均能够显著抑制大鼠的海洛因复吸行为,其机制可能与Ce和IL脑区神经元激活的改变有关。     

Co-transmitter mediated facilitation by sympathetic nerve stimulation of evoked acetylcholine release from the rabbit perfused atria preparation

Rabbit atria were isolated with the extrinsic right sympathetic and vagus nerves attached and perfused with Tyrode solution. Acetylcholine overflow was determined after labelling of the transmitter stores with [¹⁴C]choline and fractionation of the radioactivity on cation exchange columns. Sympathetic nerve stimulation (SNS, 2 Hz, 3 min) carried out together with vagus nerve stimulation (VNS, 2 Hz, 3 min), but each SNS pulse preceding a vagal one by 19 ms, caused a facilitation of acetylcholine overflow of about 60% versus independent controls in the absence of SNS. Antagonists of putative neurotransmitters were tested to find out the prejunctional mediator involved in the facilitation.The facilitation was not significantly reduced by prazosin, rauwolscine, idazoxan, or propranolol, excluding mediation by - or \-adrenoceptors. However, guanethidine abolished evoked noradrenaline release and facilitation, suggesting that it is due to a compound co-released with noradrenaline from postganglionic noradrenergic nerves. Pretreatment of rabbits with reserpine which reduced noradrenaline content of atria and SNS evoked overflow by 94% did not affect the facilitation of acetylcholine release which, due to the cardiostimulatory action of SNS being absent, resulted in enhanced depression of atrial force. We conclude that the facilitation is due to release of a reserpine-resistant co-transmitter from sympathetic nerves.Possible mediation of the facilitation by ATP through P_2X- or P_2Y-purinoceptors was excluded by ineffectiveness of , \-methylene ATP-preperfusion, of suramin and cibacron blue, respectively. However, the selective A₂ adenosine receptor antagonist CP 66,713 reduced the facilitation by 25% whereas DPCPX (A₁-selective) had no effect. Of the non-subtype-selective antagonists only 8-phenyltheophylline but not XAC decreased the facilitation by 40%. Mediation of the facilitation by tachykinin-, angiotensin-, opioid, AMPA/kainate-, M₁ muscarinic, 5-hydroxytryptamine 5-HT_1–4-receptors, or by nitric oxide, was excluded by administration of respective antagonists or inhibitors. Thus, whilst adenosine seems to be responsible for about one-fourth of the effect of sympathetic nerve stimulation, the major part of the facilitation of acetylcholine release remains unexplained.Under conditions of a low rate of evoked acetylcholine overflow prazosin enhanced the facilitatory action of SNS, suggesting an ₁-adrenoceptor mediated prejunctional inhibition of acetylcholine release.