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。     

Vagus Nerve Stimulation in 16 Children with Refractory Epilepsy

Summary: Purpose : Vagus nerve stimulation (VNS) has been reported to produce >90% reduction in the number of seizures in children with intractable epilepsy. These encouraging results need confirmation.
Methods : Sixteen children, 10 boys and 6 girls aged 4-19 years, were treated with VNS (Cyberonics, Webster, TX, U.S.A.) for 12-24 months. Seizure frequency, seizure severity, changes in quality of life (QOL: visual analogue scale), and side effects were recorded. Eight children had partial and 8 had generalized seizures; 4 of the latter had Lennox-Gastaut syndrome (LGS).
Results : During the tenth to twelfth month of VNS, 6 of 16 children experienced ≥50% reduction in seizure frequency. One girl became seizure-free. Seizure severity showed an average decrease in the score from 15 to 11. After 10 months of treatment, QOL was estimated to have improved ≥50% in 6 of 16 children. Reduction in seizure frequency, decreased seizure severity, and reported improvement in QOL did not entirely coincide. Six children experienced hoarseness, 1 had neck pain, 2 had hypersalivation, 2 experienced tiredness, 2 had aspiration episodes during liquid intake, and 6 had electrical transmission problems; in 4 the problem has been surgically corrected. Five stimulators were turned off due to lack of efficacy.
Conclusions : Six of 16 children with refractory epilepsy treated with VNS improved, with a reduction not only in seizure frequency but also in seizure severity and in QOL.     

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.     

Vagus Nerve Stimulation for Symptomatic Generalized Epilepsy: A Pilot Study

Summary: Purpose: Patients with symptomatic generalized epilepsy (SGE) may have antiepileptic drug (AED)-resistant mixed generalized seizures. Vagus nerve stimulation (VNS) reduces partial seizures and may help SGE.
Methods: We added VNS to stable AED therapy in five SGE patients. Nine-month postoperative VNS treatment seizure rates were compared to a 1 -month preoperative baseline.
Results: All patients had mixed generalized seizures, EEG generalized slow spike-and-wave and behavioral abnormalities. Median number of previous AEDs taken was 6 (range 5–12). Median baseline seizure rate was 75honth (range 29–1 10). VNS produced a median seizure rate production of -41% (range -40%–85%). Adverse events reported in one patient each were: incisional infection, choking sensation and voice change; and coughing (noted by two patients). One patient discontinued VNS due to coughing.
Conclusions: We conclude that VNS may be useful add-on therapy for SGE. A larger, controlled, and blinded trial may be warranted.     

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.     

A Pilot Study of Mood in Epilepsy Patients Treated with Vagus Nerve Stimulation

Context. Antiepileptic drugs (AEDs) are frequently used for their beneficial mood effects.Objective. We sought to determine if there was a quantifiable effect on mood of the vagus nerve stimulator (VNS) when used as an antiseizure treatment.Design. Mood was assessed before and 3 months after VNS implantation in adult epilepsy patients. A group of adult epilepsy patients on stable AED regimens were used as a comparison group. AED regimens were unchanged during the study. The change in mood scale scores across time was assessed by t test (intragroup) and two-factor repeated-measures ANOVA (intergroup).Setting. An epilepsy center in a university hospital was the setting.Subjects. Twenty consecutive adult epilepsy patients undergoing VNS implantation to improve seizure control and twenty adult seizure patients with no intervention were enrolled.Main outcome measures. The mood scales used were the Cornell Dysthymia Rating Scale (CDRS) and the Hamilton Depression (Ham-D), Hamilton Rating Scale for Anxiety (Ham-A), and Beck Depression Inventory (BDI) scales.Results. The VNS group showed a significant decrease in mood scale scores across time (t test CDRS P = 0.001, Ham-D P = 0.017, BDI P = 0.045), indicating a decrease in depressive symptoms. The Ham-A scores in the VNS group and the comparison group scores did not significantly change across time. There were no significant differences between groups across time, although the BDI approached significance at P = 0.07. The VNS group had a significant decrease in seizure frequency compared with the comparison group (P = 0.01). There was no difference in mood scales over time between the VNS treatment responders (defined by >50% decrease in seizure frequency) and nonresponders, suggesting dissociation between seizure frequency reduction and mood change.Conclusion. VNS treatment is associated with mood improvement as measured by multiple scales, but differences in mood scale scores over time between the VNS and a comparison group were not found.     

Self-Reported Mood Changes following 6 Months of Vagus Nerve Stimulation in Epilepsy Patients

Vagus nerve stimulation (VNS) for treatment of drug-resistant epileptic seizures has been reported to have additional positive mood effects as obtained by psychiatric ratings. To avoid rater bias effects, this study used self-report questionnaires and examined changes in self-reported mood and health-related quality of life following 6 months of VNS treatment. From 40 adult patients treated with VNS since the beginning of the study, 28 patients (mean age: 35.4 years) with unchanged medication were included. Repeated-measures MANOVA revealed a significant general mood improvement. Post hoc univariate tests obtained improvements of tenseness and dysphoria but not of depression, level of activity, or health-related quality of life. Mood and seizure outcome were correlated. VNS may improve unspecific states of indisposition and dysphoria. Absolute seizure reduction contributes to this antidysphoric effect. Since baseline depression scores were low, findings do not contradict but complement earlier reports of an antidepressive effect of VNS.     

Aspiration: A Potential Complication to Vagus Nerve Stimulation

Summary: Purpose: Vagus nerve stimulation (VNS) is reported to reduce the frequency of seizures in children and adults without causing serious side effects. However, clinical observation of swallowing difficulties in 2 children treated with VNS made further investigation necessary.
Methods: Seven patients aged 4–18 years and treated with VNS for 6–14 months were investigated with videoradiography during barium swallow. The children performed 5–30 barium swallow investigations with the VNS device turned off, running as programmed, or set at continuous stimulations. The degree of aspiration was scored from 0 to 3.
Results: In 5 of 7 children, of whom reported transient swallowing difficulties, no change in the degree of aspiration was noted. The 2 children with swallowing difficulties, however, showed increased aspiration score when the stimulator was set at continuous stimulations. In 1 the score also appeared to increase with the VNS running as programmed (p > O.05). Both children had severe mental and motor disabilities.
Conclusions: Before and during VNS treatment patients should be evaluated with regard to swallowing problems. There needs to be an easy way to turn the device on and off to avoid aspirations, a hazardous and potentially life-threatening complication of VNS.     

Enhancing Rehabilitative Therapies with Vagus Nerve Stimulation

Pathological neural activity could be treated by directing specific plasticity to renormalize circuits and restore function. Rehabilitative therapies aim to promote adaptive circuit changes after neurological disease or injury, but insufficient or maladaptive plasticity often prevents a full recovery. The development of adjunctive strategies that broadly support plasticity to facilitate the benefits of rehabilitative interventions has the potential to improve treatment of a wide range of neurological disorders. Recently, stimulation of the vagus nerve in conjunction with rehabilitation has emerged as one such potential targeted plasticity therapy. Vagus nerve stimulation (VNS) drives activation of neuromodulatory nuclei that are associated with plasticity, including the cholinergic basal forebrain and the noradrenergic locus coeruleus. Repeatedly pairing brief bursts of VNS sensory or motor events drives robust, event-specific plasticity in neural circuits. Animal models of chronic tinnitus, ischemic stroke, intracerebral hemorrhage, traumatic brain injury, and post-traumatic stress disorder benefit from delivery of VNS paired with successful trials during rehabilitative training. Moreover, mounting evidence from pilot clinical trials provides an initial indication that VNS-based targeted plasticity therapies may be effective in patients with neurological diseases and injuries. Here, I provide a discussion of the current uses and potential future applications of VNS-based targeted plasticity therapies in animal models and patients, and outline challenges for clinical implementation.     

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.     

Vagus Nerve Stimulation in the Developmentally Disabled

Vagus nerve stimulation (VNS) with the neuro cybernetic prosthesis (NCP) is an approved treatment of partial seizures for patients 12 years and older. Developmentally disabled or mentally retarded patients with epilepsy may also benefit from VNS; however, their evaluation and management pose greater problems. A retrospective chart review was conducted on all patients diagnosed with mild to severe mental retardation who had an NCP implanted. Records of these 21 patients, ranging in age from 3 to 56 years, were reviewed regarding VNS efficacy, side effects, behavioral changes, and alterations in antiepileptic drugs (AEDs). Seizure types included partial onset and generalized. Sixteen patients had clearly evaluable seizures both pre- and postimplant, with a greater than 50% reduction in seizures noted in 68% (11/16) after 6 months of implant. There were no adverse events that prevented chronic stimulation. Institutional staff and family members were provided with both pre- and postoperative education on VNS and magnet use. VNS appeared to be an effective and well-tolerated therapy in this group of developmentally disabled patients with refractory epilepsy.     

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: 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 Induces a Sustained Anticonvulsant Effect

Summary: Purpose: Stimulation of the vagus nerve can effectively abort several types of experimentally induced seizures in animals when administered near the time of seizure onset. Indirect evidence from human trials and animal studies suggests that the anticonvulsant effects of vagus nerve stimulation (VNS) extend beyond the duration of stimulation. We used the pentylenetetrazol model to determine whether VNS exerts a persistent anticonvulsant effect.
Methods: VNS (1 mA, 30 Hz, 500 μs pulse width) was administered continuously for 0, 1, or 60 min, or intermittently (30 s on, 5 min off) for 60 min, to awake and freely moving animals. After the end of stimulation, pentylenetetrazol (50 mg/kg i.p.) was administered to induce seizures. Time-course studies were also performed, consisting of 60 min of VNS followed by pentylenetetrazol injection after 0, 3-, 5-, and 10-min intervals.
Results: The greatest anticonvulsant effect occurred after 60 min of continuous VNS, which prevented convulsions in four of 12 rats and reduced significantly seizure duration, the total number of seizures, and number of tonic seizures. Intermittent VNS was less effective than continuous stimulation for 60 min, but more effective than that for 1 min. The anticonvulsant effect declined in a time-dependent fashion after discontinuation of VNS, with return to nonstimulated control values by 10 min.
Conclusions: The results of this study verify a persistent VNS-induced anticonvulsant effect and indicate that its efficacy is dependent on the cumulative stimulus duration.