Clinical issues in considering vagus nerve stimulation for treatment-resistant depression

This review briefly discusses the clinical and basic science rationale for vagus nerve stimulation (VNS) in treatment-resistant depression (TRD). As the number of treatment failures for depression increases, the likelihood of achieving remission during acute treatment decreases, and the risk of relapse increases with the number of treatment failures. Two open trials of adjunctive VNS for TRD showed positive acute results and a growing benefit over time. The results of the acute randomized controlled trial were not significant for the primary outcome (response by HRSD-24), but the secondary measure (IDS-SR-30) was significant for VNS. A 12-month nonrandomized comparative analysis of patients receiving adjunctive VNS with TRD patients receiving treatment as usual showed significant results favoring VNS. Post hoc analyses found that this difference was not accounted for baseline differences nor by intercurrent treatment. While VNS is well tolerated, the optimal dosing strategies have not been determined nor have clinically useful predictors of who will respond to the treatment. Given the profound effects of TRD upon the daily lives of patients and that a substantial number of VNS patients receive benefit, VNS is a useful option for managing patients with TRD.     

Sleep disordered breathing in children receiving vagus nerve stimulation therapy

ObjectiveThe effects of vagus nerve stimulation (VNS) on sleep disordered breathing (SDB) have been reported in limited case series. Detailed studies, particularly in the pediatric population, have not been performed. The primary purpose of this study is to describe clinical characteristics, polysomnographic findings, and management of children treated with VNS.MethodsA retrospective review of medical records and polysomnography data was performed in patients ages 0–20 years old receiving VNS therapy for refractory epilepsy at Cincinnati Children's Hospital Medical Center.Results22 subjects met the inclusion criteria. 50% were male. The mean age at the time of VNS insertion was 8.4 ± 4.0 years. The mean age at the first PSG was 10.6 ± 4.3 years. Common presentations to sleep clinics included snoring (77.3%), frequent nighttime awakening (68.1%), and parasomnias (63.6%). The median apnea-hypopnea index (AHI) was 4.5/hr (IQR 3.0–13.1) and the median obstructive index (OI) was 4.1/hr (1.5–12.8). Obstructive sleep apnea (OSA) was diagnosed after VNS insertion in 19 patients (86.4%), 8 of which (36.3%) had severe OSA. Six patients (27.3%) had significant hypoventilation. For management, 6 patients (27.2%) were treated with bilevel PAP, 3 patients (13.6%) with CPAP, 2 patients (9.1%) with ventilator, 4 patients (18.2%) with upper airway surgeries, and 9 patients (40.9%) received medications only.ConclusionsSDB is common in pediatric patients with medically refractory epilepsy managed with VNS who were referred to sleep medicine clinics. Both OSA and nocturnal alveolar hypoventilation are relatively common in this population. Management of SDB often involves the use of positive airway pressure therapy or upper airway surgeries. Further studies are needed to assess the prevalence, risk factors, and the effect of treatments on epilepsy control. This study highlights the need for screening of SDB prior to and following VNS implantation.     

Effect of vagus nerve stimulation on creativity and cognitive flexibility

OBJECTIVE: The purpose of this study was to determine whether vagus nerve stimulation influences cognitive flexibility and creativity. METHODS: Ten subjects, in whom vagus nerve stimulators had been implanted for the treatment of intractable seizures, performed tasks that assessed cognitive flexibility (solving anagrams), creativity (Torrance Test), and memory (Hopkins Verbal Learning Test) during actual and sham vagus nerve stimulation. RESULTS: Vagus nerve stimulation impaired cognitive flexibility and creativity, but these results could not be explained by the induction of a general encephalopathy because VNS did not impair learning and improved retention. CONCLUSIONS: The means by which vagus nerve stimulation impairs cognitive flexibility and creative thinking is probably related to increased activity of the locus coeruleus-central adrenergic system that increases the signal-to-noise ratio and improves the brain's ability to attend to sensory input, but decreases its ability to recruit large-scale networks.     

The effects of vagus nerve stimulation on decision-making

Subcortical and brainstem structures are increasingly becoming recognized as important contributors to higher cognitive functioning. Decision-making is one such function, particularly as viewed within the framework of the somatic marker hypothesis (SMH). The SMH views the participation in decision-making by the body proper as integral to emotional biasing and hence key to choosing in an advantageous manner. This study focuses on the vagus nerves as a possible conduit for somatic afferent signals pertinent to decision-making. We tested eight epileptic patients with implanted left vagus nerve stimulators. To assess decision-making we used the gambling task, which is sensitive to real-life decision-making deficits. Using a counterbalanced design, each participant performed the gambling task under a condition in which low-level vagus nerve stimulation (VNS) was covertly delivered, and another condition in which no VNS was delivered. Participants showed improved performance, that is, made more advantageous choices, in the stimulated relative to the un-stimulated condition. Although these results should be viewed as preliminary, they suggest that the vagus nerve is a conduit for afferent somatic signals that can influence decision-making.     

Effects of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study.

BACKGROUND: The need for effective, long-term treatment for recurrent or chronic, treatment-resistant depression is well established. METHODS: This naturalistic follow-up describes outpatients with nonpsychotic major depressive (n = 185) or bipolar (I or II) disorder, depressed phase (n = 20) who initially received 10 weeks of active (n = 110) or sham vagus nerve stimulation (VNS) (n = 95). The initial active group received another 9 months, while the initial sham group received 12 months of VNS. Participants received antidepressant treatments and VNS, both of which could be adjusted. RESULTS: The primary analysis (repeated measures linear regression) revealed a significant reduction in 24-item Hamilton Rating Scale for Depression (HRSD(24)) scores (average improvement, .45 points [SE = .05] per month (p < .001). At exit, HRSD(24) response rate was 27.2% (55/202); remission rate (HRSD(24) < or = 9) was 15.8% (32/202). Montgomery Asberg Depression Rating Scale (28.2% [57/202]) and Clinical Global Impression-Improvement (34.0% [68/200]) showed similar response rates. Voice alteration, dyspnea, and neck pain were the most frequently reported adverse events. CONCLUSIONS: These 1-year open trial data found VNS to be well tolerated, suggesting a potential long-term, growing benefit in treatment-resistant depression, albeit in the context of changes in depression treatments. Comparative long-term data are needed to determine whether these benefits can be attributed to VNS.     

Effect of vagal nerve stimulation in a case of Tourette's syndrome and complex partial epilepsy.

We report on a 30-year-old man with Tourette's syndrome (TS) and medication-refractory epilepsy whose tics improved after implantation of a vagal nerve stimulator (VNS). To verify the patient's observation, we performed a blinded video assessment using the modified Rush video-based tic rating scale. The patient underwent two separate video recordings (VNS on and VNS off). A rater, blinded to patient's VNS status, evaluated the videos with the modified Rush video-based tic rating scale. There were improvements in total tic score and motor and phonic tic frequency. If verified by controlled clinical trials, this observation may provide insights into the pathophysiology of tics and may lead to a novel therapy for patients with severe TS.     

A review of functional neuroimaging studies of vagus nerve stimulation (VNS)

Vagus nerve stimulation (VNS) is a new method for preventing and treating seizures, and shows promise as a potential new antidepressant. The mechanisms of action of VNS are still unknown, although the afferent direct and secondary connections of the vagus nerve are well established and are the most likely route of VNS brain effects. Over the past several years, many groups have used functional brain imaging to better understand VNS effects on the brain. Since these studies differ somewhat in their methodologies, findings and conclusions, at first glance, this literature may appear inconsistent. Although disagreement exists regarding the specific locations and the direction of brain activation, the differences across studies are largely due to different methods, and the results are not entirely inconsistent. We provide an overview of these functional imaging studies of VNS. PET (positron emission tomography) and SPECT (single photon emission computed tomography) studies have implicated several brain areas affected by VNS, without being able to define the key structures consistently and immediately activated by VNS. BOLD (blood oxygen level dependent) fMRI (functional magnetic resonance imaging), with its relatively high spatio-temporal resolution, performed during VNS, can reveal the location and level of the brain's immediate response to VNS. As a whole, these studies demonstrate that VNS causes immediate and longer-term changes in brain regions with vagus innervations and which have been implicated in neuropsychiatric disorders. These include the thalamus, cerebellum, orbitofrontal cortex, limbic system, hypothalamus, and medulla. Functional neuroimaging studies have the potential to provide greater insight into the brain circuitry behind the activity of VNS.     

A retrospective analysis of the effects of magnet-activated stimulation in conjunction with vagus nerve stimulation therapy

Vagus nerve stimulation (VNS) therapy offers two methods to help control seizures, automatic stimulation delivered at programmed intervals and on-demand stimulation initiated with a magnet. This study retrospectively analyzes magnet use during the E03 and E04 clinical trials of VNS therapy. Magnet activation that aborted, decreased, terminated, or diminished a seizure was classified as an improvement; for purposes of evaluation, the patient was considered to have received a benefit. When patients in the E03 trial used magnets to activate stimulation, patients with active magnets were more likely to report seizure improvement than patients with inactive magnets (P=0.0479, Fisher's test). In the E04 trial, 22% of patients using the magnet reported seizure termination and 31% reported seizure diminution. Unrelated to seizure reduction with programmed VNS therapy, approximately half of the patients who used the magnet in this study received some benefit. Additional studies can provide a better understanding of this unique mode of delivering antiseizure therapy.     

迷走神经刺激术在难治性癫痫领域的临床进展

迷走神经刺激术(vagus nerve stimulation,VNS)是通过躯体性刺激治疗神经-精神疾病的一种方法.自1883年以来,许多学者对VNS的抗癫痫作用进行了研究,最终认为VNS是治疗难治性癫痫的新途径[1-3].1997年7月VNS首次通过美国食品药物管理局(FDA)认证,用于成人和年龄大于12岁青少年癫痫的辅助治疗.目前为止全球已经有超过100 000的患者接受了VNS治疗[4].     

Right-sided vagus nerve stimulation as a treatment for refractory epilepsy in humans

PURPOSE: We present three children who underwent right-sided vagus nerve stimulation (R-VNS). This treatment option for people with refractory epilepsy has not been described in children. METHODS: We reviewed our database of >350 patients implanted with vagus nerve stimulators and now describe our experience in three patients with R-VNS for the treatment of intractable seizures. All three patients improved dramatically with left-sided vagus nerve stimulation (L-VNS), but the devices had to be removed because of infection. The patients were thought to be at high risk for nerve injury if they were reapproached for L-VNSs; therefore R-VNSs were implanted. RESULTS: All three patients with an R-VNS had a reduction in seizures. Our first patient has had an R-VNS for 5 years; he has been seizure free for >2 years on R-VNS monotherapy. The second patient had an R-VNS for 8 months. His seizure control improved slightly, but not as dramatically as with L-VNS. The third child has had an R-VNS for >7 months and has cessation of his most disabling seizure type (generalized tonic-clonic seizures). None of the patients had cardiac side effects from therapeutic R-VNS. However, two of the three patients had respiratory events with R-VNS. CONCLUSIONS: VNS is known to be an effective treatment in pharmacoresistant epilepsy. R-VNS should be considered if a patient has significant benefit from L-VNS but is unable to continue with L-VNS. R-VNS appears also to have antiepilepsy effects. Additionally, our case report suggests that in some patients, a differential response is found regarding seizure control with R-VNS or L-VNS, raising the question whether L-VNS failures should pursue a trial of R-VNS. Patients should be cautioned and monitored for reactive airway disease if they undergo R-VNS. More research is needed to compare the effects of right- and left-sided VNS on cardiac and pulmonary function in humans and to determine which has the best antiseizure effect.     

Effect of vagal nerve stimulation on patients with bitemporal epilepsy

Patients with bitemporal epilepsy are characterized by the existence of independent bitemporal seizure onset zones. The aim of this study was to evaluate the effect of chronic vagal nerve stimulation (VNS) on eight patients with bitemporal epilepsy. We demonstrated the gradually increased effect of VNS on the reduction of seizures as compared with baseline seizure frequency in patients with bitemporal epilepsy. The average seizure reduction increased from 4.2% at the 3-month follow-up visit to 18.2, 34.4 and 42.2% at the 6, 12 and 18-month follow-up visits. Similarly, a >or=50% reduction of complex partial seizures was reported at the 3-month follow-up visit in no patients (0%); at the 6-month follow-up visit in one patient (12.5%); at the 12-month follow-up visit in three patients (37.5%); and at the 18-month follow-up visit in five patients (62.5%). These data demonstrate the positive and long-lasting effect of VNS on seizure reduction in patients with intractable bitemporal epilepsy. The main mechanism of this chronic effect is not fully understood.     

We could predict good responders to vagus nerve stimulation: A surrogate marker by slow cortical potential shift

Objective

We investigated whether vagus nerve stimulation (VNS) induces a positive shift of slow cortical potentials (SCPs) in patients with >50% seizure reduction (responders) but not in non-responders.

Effects of vagus nerve stimulation on sleep-related breathing in epilepsy patients

PURPOSE: To describe the effects of vagus nerve stimulation (VNS) on sleep-related breathing in a sample of 16 epilepsy patients. METHODS: Sixteen adults with medically refractory epilepsy (nine men, seven women, ages 21-58 years) underwent baseline polysomnograms (PSGs). Three months after VNS therapy was initiated, PSGs were repeated. In addition, patient 7 had a study with esophageal pressure monitoring, and patient 1 had a continuous positive airway pressure (CPAP) trial. RESULTS: Baseline PSGs: One of 16 patients had an apnea-hypopnea index (AHI) >5 (6.8). Treatment PSGs: Five of 16 patients had treatment AHIs >5. Respiratory events were more frequent during periods with VNS activation (on-time) than without VNS activation (off-time; p = 0.016). Follow-up studies: Esophageal pressure monitoring in patient 7 showed crescendos in esophageal pressure during VNS activation, supporting an obstructive pattern. The CPAP trial of patient 1 showed that all respiratory events were associated with VNS stimulation at low CPAP levels. They were resolved at higher CPAP levels. CONCLUSIONS: Treatment with VNS affects respiration during sleep and should be used with care, particularly in patients with preexisting obstructive sleep apnea. The AHI after VNS treatment remained <5 in the majority of patients and was only mildly elevated (<12) in five patients. In one patient, CPAP resolved VNS-related respiratory events.     

Deep brain stimulation, vagal nerve stimulation and transcranial stimulation: An overview of stimulation parameters and neurotransmitter release

Neurological disorders are among the most challenging medical problems faced by science today. To treat these disorders more effectively, new technologies are being developed by reviving old ideas such as brain stimulation. This review aims to compile stimulation techniques that are currently in use to explore or treat neurological disorders. Transcranial magnetic stimulation is a non-invasive method of modulating neuronal activity with induced electric currents. Other more invasive methods, such as deep brain stimulation and vagal nerve stimulation, use implanted probes to introduce brain activity alterations. Scientific and clinical applications have largely preceded the development of extensive animal models, presenting a challenge for researchers. This has left researchers with information on alleviating symptoms in humans but without solid research as to the mechanisms and neurobiological effects of the devices. This review combines stimulation parameters developed in animal models and stimulation techniques used in human treatment; thus, resulting in a greater understanding of the mechanisms and neurobiological effects of neuromodulation devices.     

迷走神经刺激术治疗药物难治性癫痫的初步研究

目的 探讨迷走神经刺激术治疗药物难治性癫痫的方法及效果. 方法 回顾性分析上海交通大学医学院附属仁济医院神经外科自2007年1月至2011年1月收治的14例药物难治性、全身性癫痫患者临床资料,其中脑炎后继发癫痫6例,外伤后继发癫痫3例,原因不明5例,所有患者均行左侧迷走神经刺激术治疗.术后3周内开机,初始刺激参数为:刺激电流0.25 mA,频率30 Hz,刺激时间30 s,间歇时间5 min,脉宽500 μs.刺激电流强度以0.25 mA为一调整单位逐渐递增,并综合其他参数调控以到达满意疗效. 结果 随访3月以上,14例患者术后发作频率平均减少63.6％,其中3例发作频率减少＜50％,11例发作频率减少≥50％,6例发作频率减少＞80％,2例发作停止.5例患者使用磁铁后发作控制得到改善. 结论 迷走神经刺激术是一种治疗药物难治性癫痫有效、安全的方法,对全身性癫痫发作患者同样有效.     

Efficacy and long-term tuning parameters of vagus nerve stimulation in long-term treated depressive patients

Vagus nerve stimulation (VNS) is a promising neurostimulation tool for the treatment of treatment-resistant depression. Here, we report the effects of positive remission rates and tuning parameters in a group of 18 (6 female, 12 male, mean age 54) long-term treated patients.Treatment varied between 3 and 200 months (mean 104.9 months). Mean stimulation intensity was 1.46 mA, ranging from 0.5 to 2.0 mA and high-frequency stimulation of 20–25 Hz (mean 23.61 Hz).The remission rates in our study population clearly indicate ongoing positive effects of VNS and highlight stimulation tunings between 0.5 and 2.0 mA and 20–25 Hz as best dosage for achieving remittance in long-term treatment of VNS.     

Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial.

BACKGROUND: Vagus nerve stimulation (VNS) alters both concentrations of neurotransmitters or their metabolites and functional activity of central nervous system regions dysregulated in mood disorders. An open trial has suggested efficacy. METHODS: This 10-week, acute, randomized, controlled, masked trial compared adjunctive VNS with sham treatment in 235 outpatients with nonpsychotic major depressive disorder (n = 210) or nonpsychotic, depressed phase, bipolar disorder (n = 25). In the current episode, participants had not responded adequately to between two and six research-qualified medication trials. A two-week, single-blind recovery period (no stimulation) and then 10 weeks of masked active or sham VNS followed implantation. Medications were kept stable. Primary efficacy outcome among 222 evaluable participants was based on response rates (>/=50% reduction from baseline on the 24-item Hamilton Rating Scale for Depression [HRSD(24)]). RESULTS: At 10-weeks, HRSD(24) response rates were 15.2% for the active (n = 112) and 10.0% for the sham (n = 110) groups (p = .251, last observation carried forward [LOCF]). Response rates with a secondary outcome, the Inventory of Depressive Symptomatology - Self-Report (IDS-SR(30)), were 17.0% (active) and 7.3% (sham) (p = .032, LOCF). VNS was well tolerated; 1% (3/235) left the study because of adverse events. CONCLUSIONS: This study did not yield definitive evidence of short-term efficacy for adjunctive VNS in treatment-resistant depression.