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Objective In individuals with chronic tinnitus, our interest was to determine whether daily low-level electrical stimulation of the vagus nerve paired with tones (paired-VNSt) for tinnitus suppression had any adverse effects on motor-speech production and physiological acoustics of sustained vowels. Similarly, we were also interested in evaluating for changes in pure-tone thresholds, word-recognition performance, and minimum-masking levels. Both voice and hearing functions were measured repeatedly over a period of 1 year. Study design Longitudinal with repeated-measures. Methods Digitized samples of sustained frontal, midline, and back vowels (/e/, /o/, /ah/) were analyzed with computer software to quantify the degree of jitter, shimmer, and harmonic-to-noise ratio contained in these waveforms. Pure-tone thresholds, monosyllabic word-recognition performance, and MMLs were also evaluated for VNS alterations. Linear-regression analysis was the benchmark statistic used to document change over time in voice and hearing status from a baseline condition. Results Most of the regression functions for the vocal samples and audiometric variables had slope values that were not significantly different from zero. Four of the nine vocal functions showed a significant improvement over time, whereas three of the pure tone regression functions at 2-4 kHz showed some degree of decline; all changes observed were for the left ear, all were at adjacent frequencies, and all were ipsilateral to the side of VNS. However, mean pure-tone threshold changes did not exceed 4.29 dB from baseline and therefore, would not be considered clinically significant. In some individuals, larger threshold shifts were observed. No significant regression/slope effects were observed for word-recognition or MMLs. Conclusion Quantitative voice analysis and assessment of audiometric variables showed minimal if any evidence of adverse effects using paired-VNSt over a treatment period of 1 year. Therefore, we conclude that paired-VNSt is a safe tool for tinnitus abatement in humans without significant side effects. Level of evidence Level IV.

Stroke is a leading cause of disability worldwide, and in approximately 60% of individuals, upper limb deficits persist 6 months after stroke. These deficits adversely affect the functional use of the upper limb and restrict participation in day to day activities. An important goal of stroke rehabilitation is to improve the quality of life by enhancing functional independence and participation in activities. Since upper limb deficits are one of the best predictors of quality of life after stroke, effective interventions targeting these deficits may represent a means to improve quality of life. An increased understanding of the neurobiological processes underlying stroke recovery has led to the development of targeted approaches to improve motor deficits. One such targeted strategy uses brief bursts of Vagus Nerve Stimulation (VNS) paired with rehabilitation to enhance plasticity and support recovery of upper limb function after chronic stroke. Stimulation of the vagus nerve triggers release of plasticity promoting neuromodulators, such as acetylcholine and norepinephrine, throughout the cortex. Timed engagement of neuromodulators concurrent with motor training drives task-specific plasticity in the motor cortex to improve function and provides the basis for paired VNS therapy. A number of studies in preclinical models of ischemic stroke demonstrated that VNS paired with rehabilitative training significantly improved the recovery of forelimb motor function compared to rehabilitative training without VNS. The improvements were associated with synaptic reorganization of cortical motor networks and recruitment of residual motor neurons controlling the impaired forelimb, demonstrating the putative neurobiological mechanisms underlying recovery of motor function. These preclinical studies provided the basis for conducting two multi-site, randomized controlled pilot trials in individuals with moderate to severe upper limb weakness after chronic ischemic stroke. In both studies, VNS paired with rehabilitation improved motor deficits compared to rehabilitation alone. The trials provided support for a 120-patient pivotal study designed to evaluate the efficacy of paired VNS therapy in individuals with chronic ischemic stroke. This manuscript will discuss the neurobiological rationale for VNS therapy, provide an in-depth discussion of both animal and human studies of VNS therapy for stroke, and outline the challenges and opportunities for the future use of VNS therapy.

Stimulation of the vagus nerve for the treatment of refractory seizures of partial onset has been studied in two pilot studies and one randomized, blinded, parallel study. Results from the controlled study have been promising, but more information is required regarding the long-term safety and efficacy of vagus nerve stimulation. A cohort of the first 37 patients to finish the controlled study was examined on a long-term basis. The response of patients at 1 year and 18 months of stimulation revealed that efficacy does not decrease over time. The system is well-tolerated, and no major adverse events occurred with long-term exposure to the stimulation. Normal device end of service occurred in a majority of the patients, with most choosing to have their generators replaced. This analysis demonstrates that stimulation of the vagus nerve for the treatment of refractory epilepsy manifested by seizures of partial onset continues to be safe and effective over extended periods of time.

Over 100 patients have been treated for partial epilepsy using a NeuroCybernetic Prosthesis System (NCP). The NCP System is comprised of an implantable pulse generator, an implantable bipolar stimulating lead, and an external communication system. The lead delivers electrical impulses from the NCP Generator to the vagus nerve, and includes a connector end that plugs into the generator, a silicone insulated lead body, and the helical electrode array that attaches to the nerve. The surgical implantation technique has a significant impact on lead reliability and performance. The lead electrode has performed well to date. Modifications to further improve reliability have been implemented. Clinical experience, case history examples, and voltage measurements are examined. The lead electrode is an important component of the overall system and plays a significant part in the success of vagus nerve stimulation therapy.

Vagus nerve stimulation for the treatment of epilepsy has been studied in medically refractory patients with partial seizures in a randomized, blinded, parallel study. After a 3-month baseline period, the patients were implanted with the Neurocybernetic Prosthesis (NCP) system consisting of the NCP Generator and the Bipolar Vagal Stimulation Lead. Two stimulation paradigms were used, HIGH, which delivers what is considered to be optimal stimulation parameters and LOW, which is considered to be less or noneffective. The system and vagus nerve stimulation were well tolerated and few adverse events have been attributed to either. One patient experienced a period of direct current to the nerve due to a generator malfunction. This resulted in paralysis of the left vocal cord. Efficacy analysis on the first 37 patients to complete the controlled portion of the study has shown that the patients in the HIGH group experienced a mean reduction in seizure frequency of 33.3% and patients in the LOW group experienced a mean reduction in seizure frequency of 8.4%. The difference between the groups is statistically significant with a P value of 0.025. Analysis of seizure duration and intensity does not show any significant change. Ratings of the patient's overall condition fay the patient, investigator, and companion as a measurement of “quality of life” also show improvement in the HIGH group. The results of this interim study demonstrate that vagus nerve stimulation is a safe and effective method of treating partial epileptic seizures.

The neurocybernetic prosthesis system (NCP) is an implantable, multiprogrammable pulse generator that delivers constant current electrical signals to the vagus nerve for the purpose of reducing the frequency and severity of epileptic seizures. The signals are delivered on a predetermined schedule, or may be initiated by the patient with an external magnet. The device is implanted in a subcutaneous pocket in the chest just below the clavicle, similar to pacemaker placement. The stimulation signal is transmitted from the prosthesis to the vagus nerve through a lead connected to an electrode which is a multi-turn silicone helix, with a platinum band on the inner turn of one helix. The prosthesis can be programmed with any IBM- compatible personal computer using NCP software and a programming wand.

Summary: The neurocybernetic prosthesis (Cyberonics, Inc.) is an implantable, multiprogrammable pulse generator that delivers constant current electrical signals to the vagus nerve for the purpose of reducing the frequency and/or severity of epileptic seizures. The device is implanted in a subcutaneous chest pocket just below the clavicle, similar to cardiac pacemaker placement. The stimulation signal is transmitted from the prosthesis to the vagus nerve through a stimulation lead. The prosthesis can be programmed using any IBM-compatible personal computer with programming software and a programming wand. The electrodes used in the first group of patients were found to break at an unacceptable rate. Design modifications appear to have resolved this problem.

Objective—To evaluate safety and efficacy of vagal nerve stimulation in dogs with refractory epilepsy. Design—Placebo-controlled, double-masked, crossover study. Animals—10 dogs with poorly controlled seizures. Procedure—A programmable pacemaker-like device designed to deliver intermittent stimulation to the left cervical trunk of the vagus was surgically implanted in each dog. Dogs were assigned randomly to two 13- week test periods, 1 with nerve stimulation and 1 without nerve stimulation. Owners recorded data on seizure frequency, duration, and intensity, as well as adverse effects. Results—No significant difference in seizure frequency, duration, or severity was detected between overall 13-week treatment and control periods. During the final 4 weeks of the treatment period, a significant decrease in mean seizure frequency (34.4%) was detected, compared with the control period. Complications included transient bradycardia, asystole, and apnea during intraoperative device testing, and seroma formation, subcutaneous migration of the generator, and transient Horner's syndrome during the 14-day period between surgery and suture removal. No adverse effects of stimulation were detected, and most owners were satisfied with the treatment. Conclusions and Clinical Relevance—Vagal nerve stimulation is a potentially safe approach to seizure control that appears to be efficacious in certain dogs and should be considered a possible treatment option when antiepileptic medications are ineffective. (J Am Vet Med Assoc 2002;221:977–983)

Background: Chronic vagus nerve stimulation (VNS) continues to be evaluated as an adjunctive treatment for medically intractable seizures. A previous randomized controlled trial of 114 patients demonstrated a significant decrease in seizure frequency during 3 months of VNS at effective stimulation levels. Objective: To evaluate the efficacy of 1 year of VNS therapy for the treatment of medically refractory partial seizures and the relationship between initial and longterm response. Patients and Methods: All patients exiting the randomized controlled study of VNS for treatment of medically refractory partial seizures were offered indefinite treatment extension as part of an open-label trial. One hundred (88%) of 114 patients completed 12 months of VNS treatment at effective stimulation levels. Fourteen patients discontinued VNS treatment prior to 1 year, principally because of the treatment's lack of efficacy. These 14 patients were retained in the present analysis using an intent-to-treat approach. Antiepileptic drug use was monitored throughout the trial. Seizure frequency was analyzed in 4 sequential 3-month treatment periods. Results: Compared with pretreatment baseline, there was a significant decrease in seizure frequency during each of the 3-month treatment periods. Seizure frequency was reduced by a median of 20% during the first 3 months of VNS treatment and by 32% during stimulation months 10 through 12. Response during the first 3 months of VNS treatment was a statistically significant predictor of response at months 10 through 12. The observed reduction in seizure frequency was not explained by overall changes in antiepileptic drug use. Conclusions: The results indicate that VNS remains an effective adjunctive therapy for medically refractory partial seizures over a period of at least 1 year. Response during the first 3 months of treatment is predictive of longterm response.