A Comprehensive Review of Vagus Nerve Stimulation for Depression

ObjectivesVagus nerve stimulation (VNS) is reemerging as an exciting form of brain stimulation, due in part to the development of its noninvasive counterpart transcutaneous auricular VNS. As the field grows, it is important to understand where VNS emerged from, including its history and the studies that were conducted over the past four decades. Here, we offer a comprehensive review of the history of VNS in the treatment of major depression.Materials and MethodsUsing PubMed, we reviewed the history of VNS and aggregated the literature into a narrative review of four key VNS epochs: 1) early invention and development of VNS, 2) path to Food and Drug Administration (FDA) approval for depression, 3) refinement of VNS treatment parameters, and 4) neuroimaging of VNS.ResultsVNS was described in the literature in the early 1900s; however, gained traction in the 1980s as Zabara and colleagues developed an implantable neurocybernetic prosthesis to treat epilepsy. As epilepsy trials proceed in the 1990s, promising mood effects emerged and were studied, ultimately leading to the approval of VNS for depression in 2005. Since then, there have been advances in understanding the mechanism of action. Imaging techniques like functional magnetic resonance imaging and positron emission tomography further aid in understanding direct brain effects of VNS.ConclusionsThe mood effects of VNS were discovered from clinical trials investigating the use of VNS for reducing seizures in epileptic patients. Since then, VNS has gone on to be FDA approved for depression. The field of VNS is growing, and as noninvasive VNS quickly advances, it is important to consider a historical perspective to develop future brain stimulation therapies.     

Transcutaneous Vagal Nerve Stimulation in Treatment-Resistant Depression: A Feasibility Study

BackgroundMajor depression (MD) contributes significantly to the global burden of disease with up to one-third of patients being treatment resistant. Therefore, the development of new treatment options for treatment-resistant depression (TRD) is needed. Vagus nerve stimulation (VNS) has shown mood improvements in patients with TRD. However, due to high costs related to the implantation and the invasive nature of VNS, an application with transcutaneous VNS (t-VNS) has been developed stimulating a vagal nerve branch in the earlobe (Arnold's nerve). A few studies with t-VNS in MD have shown a possible antidepressant effect, but feasibility is poorly described and patients with TRD have not been investigated.ObjectivesAs the full antidepressant effect of t-VNS takes months we wanted to assess feasibility and side effects of daily treatments.Materials and MethodsSingle-arm feasibility trial assessing compliance, usability, side effects, cognitive speed, and depression in a four-week period with a recommended t-VNS stimulation duration of four hours per day in patients with TRD. The primary outcome was compliance with 80% of the recommended daily treatment time.ResultsCompliance threshold was reached for 80.0% of the 20 included participants. Usability was acceptable. Side effects were few, mild or moderate, mostly as local effects at the contact point in the ear. The device was difficult to use for some participants. A statistically significant reduction in depression severity and an increase in cognitive speed were seen with unchanged suicidal ideation and sleep.ConclusionsWe would recommend larger long-term randomized studies of t-VNS to access any antidepressant effect in TRD. The design of the device might be improved for higher usability.     

迷走神经刺激治疗在神经精神疾病中的应用

迷走神经刺激（vagus nerve stimulation,VNS）作为一种影响脑功能活动的新方法,对神经功能再塑具有一定的影响。研究表明VNS对癫痫、抑郁和焦虑等神经精神疾病的治疗有效。本文就目前VNS治疗的临床应用作一综述。尽管VNS治疗的确切机制尚不清楚,但它为脑功能研究开辟了新的研究领域,对进一步认识一些神经精神疾病的病因具有十分重要的意义。随着研究的深入,VNS治疗方法不断改进和完善,将对一些神经精神疾病的临床治疗提供新的选择。     

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     

Vagus Nerve Stimulation for Intractable Epilepsy: Outcomes in Children and Adults

Objectives. Vagus nerve stimulation (VNS) is an accepted treatment for medically intractable epilepsy. However, predictive factors associated with responsiveness to VNS remained unclear. We therefore sought to identify predictive factors that influence responsiveness to VNS in both children and adults. Materials and Methods. We evaluated a retrospective series of 31 patients who underwent VNS for intractable epilepsy at Asan Medical Center from 1998 to 2006. Eighteen patients were younger than 18 years, while 13 patients were aged 18 years or older. We assessed mean seizure frequency, the number of antiepileptic drugs each patient was taking, seizure type, etiology, age at seizure onset, age at implantation, and duration of epilepsy. Results. Forty‐three percent of all patients had a seizure reduction of more than 50%. Ten (59%) children had a 50% reduction in their seizures, while three adults (23%) had such a response. Two factors were significantly different between responders and non‐responders: age at implantation and age of seizure onset. In a logistic regression analysis, however, no factors were independently associated with the response to VNS. Transient hoarseness and cough were observed in eight of all patients and wound infection and generator failure in one patient each. Conclusions. These results suggest that VNS may be a more effective treatment in children with intractable epilepsy than in adults. It remains difficult to predict which patients will respond to VNS therapy.     

Vagus Nerve Stimulation for Patients in Residential Treatment Facilities

This analysis compared the effectiveness of vagus nerve stimulation (VNS) therapy among patients with intractable seizures: a group living in residential treatment facilities (RTF) with a group not living in RTFs (non-RTF). Among a constant cohort of patients with baseline, 3-month, and 12-month data, the RTF group had significantly (P < 0.05) larger numbers of patients with generalized seizures, previous callosotomy, psychiatric disorders, behavioral problems, and Rett's syndrome. Median seizure reductions after 3 months were 33% in the RTF group and 49% in the non-RTF group (P < 0.001); after 12 months, 50% (RTF) and 56% (non-RTF). After both 3 and 12 months, alertness, mood, postictal recovery, and cluster seizures improved in more than a third of patients in both groups. Because VNS therapy does not interact with medications and is delivered automatically, it should be seriously considered for patients with intractable epilepsy who reside in RTFs.     

Stimulation Parameters After Vagus Nerve Stimulator Replacement

Objectives. This study aims to assess tolerability and efficacy of stimulation parameters after vagus nerve stimulator (VNS) pulse generator replacement. Materials and Methods. We carried out an observational, retrospective study, reviewing our experience with VNS generator replacements in 28 epilepsy patients. Results. Seven patients had actual end of battery life (EOBL) (with symptoms), and 21 patients had asymptomatic projected EOBL. When we reprogrammed stimulation parameters postoperatively, 17 of the 28 patients could not tolerate the preoperative baseline current settings, even one year later. There were no differences in pre‐ vs. postoperative seizure rates between patients who did or did not return to baseline settings. Failure to return to baseline current was not related to previous VNS duration, same‐ vs. different‐battery generator replacements, or antiepileptic medication changes. Conclusions. After VNS generator replacement, patients’ common inability to tolerate preoperative current settings does not lead to more seizures. A chronic modification of the vagus nerve system's sensitivity to stimulation changes may be hypothesized.     

Transcutaneous Auricular Vagus Nerve Stimulation Combined With Slow Breathing: Speculations on Potential Applications and Technical Considerations

ObjectivesTranscutaneous auricular vagus nerve stimulation (taVNS) is a relatively novel noninvasive neurostimulation method that is believed to mimic the effects of invasive cervical VNS. It has recently been suggested that the effectiveness of taVNS can be enhanced by combining it with controlled slow breathing. Slow breathing modulates the activity of the vagus nerve and is used in behavioral medicine to decrease psychophysiological arousal. Based on studies that examine the effects of taVNS and slow breathing separately, this article speculates on some of the conditions in which this combination treatment may prove effective. Furthermore, based on findings from studies on the optimization of taVNS and slow breathing, this article provides guidance on how to combine taVNS with slow breathing.Materials and MethodsA nonsystematic review.ResultsBoth taVNS and slow breathing are considered promising add-on therapeutic approaches for anxiety and depressive disorders, chronic pain, cardiovascular diseases, and insomnia. Therefore, taVNS combined with slow breathing may produce additive or even synergistic beneficial effects in these conditions. Studies on respiratory-gated taVNS during spontaneous breathing suggest that taVNS should be delivered during expiration. Therefore, this article proposes to use taVNS as a breathing pacer to indicate when and for how long to exhale during slow breathing exercises.ConclusionsCombining taVNS with slow breathing seems to be a promising hybrid neurostimulation and behavioral intervention.     

Vagus nerve stimulation therapy in depression and epilepsy: therapeutic parameter settings

Vagus nerve stimulation (VNS) therapy is an effective adjunctive treatment for chronic or recurrent treatment-resistant depression in adults, and for pharmacoresistant epilepsy in adults and adolescents. VNS therapy is administered through an implanted pulse generator that delivers programmed electrical pulses through an implanted lead to the left vagus nerve. Programmable pulse parameters include output current, frequency, pulse width, and ON/OFF times. Within a range of typical values, individual patients respond best to different combinations of parameter settings. The physician must identify the optimum settings for each patient while balancing the goals of maximizing efficacy, minimizing side effects, and preserving battery life. Output current is gradually increased from 0.25 mA to the maximum tolerable level (maximum, 3.5 mA); typical therapeutic settings range from 1.0 to 1.5 mA. Greater output current is associated with increased side effects, including voice alteration, cough, a feeling of throat tightening, and dyspnea. Frequency is typically programmed at 20 Hz in depression and 30 Hz in epilepsy. Pulse width is typically 250 or 500 micros. The recommended initial ON time is 30 s, followed by 5 min OFF; OFF time > ON time is recommended. As with pharmacotherapy, VNS therapy must be adjusted in a gradual, systematic fashion to individualize therapy for each patient.     

Heart Rate Control Via Vagus Nerve Stimulation

Objectives. There is ample and well‐established evidence that direct electrical stimulation of the vagus nerve can change heart rate in animals and humans. Since tachyarrhythmias cannot always be controlled through medication, we sought, in this pilot study, to elucidate whether a clinical implantable lead system that is used in cervical vagus nerve stimulation therapy (VNS therapy) also can be used for control of heart rate, and tachycardia in particular. Materials and Methods. Experiments were carried out in three pigs (weight 21–26 kg) under general anesthesia. The right and left vagus nerves in the neck region were exposed by dissection, and bipolar, multiturn, helical, silicone leads were wrapped around the vagus nerves. Stimulation was applied by an external device with multivariable settings: frequency 10–100 Hz, pulse duration 100–700 µsec; delay 0–0.5 msec; current 0.5–14 mA. Measurements were performed under normal sinus rhythm (RR‐interval 501 ± 30 msec) and during isoprenaline‐induced tachycardia (RR‐interval 284 ± 11 msec). Results. VNS, under optimal pacing conditions (100 Hz; 5 mA; 0.2 msec; 70 msec delay), in an electrocardiogram‐triggered (ECG‐triggered) pacing mode, increased RR‐intervals by approximately 40%, irrespective of the duration of the RR‐interval preceding VNS. The maximum effect on heart rate was established within approximately 5 sec after the onset of stimulation and was reversible and reproducible. No differences were found between stimulation of the right or left vagus nerve. Conclusion. VNS can be used effectively and rapidly to decrease heart rate, in acute settings, when connected to an external pacing system. Future devices that are fully implantable may be used for nonpharmacological treatment of illnesses in which tachycardia results in deterioration of cardiac function.     

Impact of Cardiac-Based Vagus Nerve Stimulation Closed-Loop Stimulation on the Seizure Outcome of Patients With Generalized Epilepsy: A Prospective,Individual-Control Study

ObjectivesWe designed a prospective, individual-controlled study to evaluate the effect of cardiac-based VNS (cbVNS) in a cohort of patients with generalized epilepsy (GE).Materials and MethodsTwenty patients were included. They were followed up for six months under regular VNS (rVNS) and subsequently for six months during cbVNS. Stimulation parameters were 500 μsec, 30 Hz, and up to 2.5 mA. Seizure frequency was documented after two, four, and six months during the rVNS and cbVNS phases. Patients with at least 50% seizure frequency reduction were considered responders. The total and relative amount of stimulation cycles generated by both rVNS and cbVNS activation were documented. Findings during rVNS were compared to baseline and cbVNS data were compared to those during rVNS.ResultsThere was a significant decrease in mean seizure frequency (61% [95% CI, 48-74]; p < 0.001) during the rVNS phase compared to baseline. There was no additional significant (16% [95% CI, 4-35]; p = 0.097) mean seizure frequency reduction during cbVNS compared to the rVNS phase. Fifteen patients (75%) were considered responders after rVNS. Four patients (20%) were considered responders after six months of cbVNS. During the cbVNS phase, the mean total number of cycles/day was 346, 354, and 333 for months two, four, and six, respectively; the cycles generated by rVNS were 142, 138, and 146 for months two, four, and six, respectively; and cycles generated by cbVNS were 204, 215, and 186 for months two, four, and six, respectively. There was no relationship between the mean total number of cycles (−6[95% CI, −85 to 72]; p = 0.431), the mean number of auto-stimulation cycles (27[95% CI,−112 to 166]; p = 0.139), the mean number of regular cycles (−33[95% CI,−123 to 57]; p = 0.122), or the mean percentage of auto-stimulation cycles (13[95% CI,19- 45]; p = 0.109) and outcome during the cbVNS phase. Eight patients showed some decrease in seizure frequency during cbVNS.ConclusionsrVNS was effective in reducing seizure frequency in patients with generalized epilepsy, but activation of the cbVNS feature did not add significantly to rVNS efficacy. On the other hand, although not statistically significant, 40% of the patients showed some reduction in seizure frequency, which might prove useful at an individual level.     

Effect of Long-Term Treatment with Vagus Nerve Stimulation on Mood and Quality of Life in Korean Patients with Drug-Resistant Epilepsy

Background and PurposeThis study aimed to determine the long-term effects of vagus nerve stimulation (VNS) treatment on suicidality, mood-related symptoms, and quality of life (QOL) in patients with drug-resistant epilepsy (DRE). We also investigated the relationships among these main effects, clinical characteristics, and VNS parameters.MethodsAmong 35 epilepsy patients who underwent VNS implantation consecutively in our epilepsy center, 25 patients were recruited to this study for assessing the effects of VNS on suicidality, mood-related symptoms, and QOL. The differences in these variables between before and after VNS treatment were analyzed statistically using paired t-tests. Multiple linear regression analyses were also performed to determine how the patients'' demographic and clinical characteristics influenced the variables that showed statistically significant changes after long-term VNS treatment.ResultsAfter VNS, our patients showed significant improvements not only in the mean seizure frequency but also in suicidality, depression, and QOL. The reduction in depression was associated with the improvement in QOL and more-severe depression at baseline. The reduction in suicidality was associated with higher suicidality at baseline, smaller changes in depression, and less-severe depression at baseline. Improved QOL was associated with lower suicidality at baseline.ConclusionsThis study found that VNS decreased the mean seizure frequency in patients with DRE, and also improved their depression, suicidality, and QOL. These results provide further evidence for therapeutic effect of VNS on psychological comorbidities of patients with DRE.     

Transcutaneous Auricular Vagus Nerve Stimulation: From Concept to Application

Whether in the West or the East, the connection between the ear and the rest of the body has been explored for a long time. Especially in the past century or more, the relevant theoretical and applied research on the ear has greatly promoted the development of ear therapy, and finally the concept of transcutaneous auricular vagus nerve stimulation (taVNS) has been proposed. The purpose of taVNS is to treat a disease non-invasively by applying electrical current to the cutaneous receptive field formed by the auricular branch of the vagus nerve in the outer ear. In the past two decades, taVNS has been a topic of basic, clinical, and transformation research. It has been applied as an alternative to drug treatment for a variety of diseases. Based on the rapid understanding of the application of taVNS to human health and disease, some limitations in the development of this field have also been gradually exposed. Here, we comprehensively review the origin and research status of the field.     

Vagus Nerve Stimulation

Summary: Left vagus nerve stimulation (VNS) is a promising new treatment for epilepsy. In 1997, VNS was approved in the United States as an adjunctive treatment for medically refractory partial-onset seizures in adults and adolescents. For some patients with partial-onset seizures, the adverse effects of antiepileptic drugs (AEDs) are intolerable; for others, no single AED or combination of anticonvulsant agents is effective. Cerebral resective surgery is an option to pharmacotherapy in some cases, but many patients with partial-onset seizures are not optimal candidates for intracranial surgery. VNS entails implantation of a programmable signal generator—the Neurocybernetic Prosthesis (NCP)—in the chest cavity. The stimulating electrodes of the NCP carry electrical signals from the generator to the left vagus nerve. Although the mechanism of action of VNS is not known, controlled studies have shown that it is safe and well-tolerated by patients with long-standing partial-onset epilepsy. Side effects, which are generally of mild to moderate severity, almost always disappear after the stimulation settings are adjusted. Encouraging results have also been reported in pediatric patients.