Summary: Purpose: Although vagus nerve stimulation (VNS)is now marketed throughout most of the world as a treatment for drug-resistant epilepsy, the therapeutic mechanism of action of VNS-induced seizure suppression has not yet been established. Elucidation of this mechanism is an important first step in the development of strategies to improve VNS efficacy. Because the locus coeruleus (LC) has been implicated in the antinociceptive effects of VNS, we chemically lesioned the LC in the present study to determine if it is a critical structure involved in the anticonvulsant mechanisms of VNS.Methods: Rats were chronically depleted of norepinephrine (NE) by a bilateral infusion of 6-hydroxydopamine (6-OHDA) into the LC. Two weeks later, they were tested with maximal electroshock (MES) to assess VNS-induced seizure suppresVagus nerve stimulation (VNS) is a novel therapy for the control of epilepsy. Clinical studies demonstrate that VNS reduces seizure frequency by >50% in 3040% of patients with previously intractable seizures (1). In contrast to ablative neurosurgical interventions, VNS is reversible and the stimulus parameters can be titrated to increase efficacy and reduce the incidence of side effects.The recent use of VNS in humans follows several reports that the technique successfully prevents or attenuates seizures in some animal models. Zanchetti et al.(2) and Stoica and Tudor (3,4) were among the fist to experiment with the anticonvulsant properties of VNS. They showed that VNS blocked spike-wave complexes induced by cortical strychnine application in cats. Subsequently, VNS was shown to provide seizure protection in other animal models. In rats, VNS reduces seizure activity induced by maximal electroshock (MES) (5,6), pentylenetetrazol (PTZ) (5-7), and penicillin (7,8). VNS has also been reported to afford protection against PTZAccepted March 3, 1998. sion. In another experiment, the LC was acutely inactivated with lidocaine, and seizure suppression was tested in a similar fashion.Results: VNS significantly reduced seizure severities of control rats. However, in animals with chronic or acute LC lesions, VNS-induced seizure suppression was attenuated.Conclusions: Our data indicate that the LC is involved in the circuitry necessary for the anticonvulsant effects of VNS. Seizure suppression by VNS may therefore depend on the release of NE, a neuromodulator that has anticonvulsant effects. These data suggest that noradrenergic agonists might enhance VNSinduced seizure suppression. Key Words: Vagus nerveLocus coeruleus-Norepinephrine-Anticonvulsant-Epilepsy.and strychnine-induced seizures in dogs (9) and from alumina-gel seizures in monkeys (10).Although the anticonvulsant efficacy of VNS is well established, the underlying mechanisms of its action have not been elucidated. Knowledge of these mechanisms might prove useful in improving clinical efficacy or even in devising new therapies. VNS may cause widespread release of inhibitory neurotransmitters, thereby preventing seizure discharge spread (5,l l), but this...

Currently available therapeutic interventions for treatment-resistant depression, including switch, combination, and augmentation strategies, are less than ideal. Observations of mood elevation during vagus nerve stimulation (VNS) therapy for pharmacoresistant epilepsy suggested a role for VNS therapy in refractory major depression and prompted clinical investigation of this neurostimulation modality. The VNS Therapy System has been available for treatment of pharmacoresistant epilepsy since 1997 and was approved by the US Food and Drug Administration for treatment-resistant depression in July, 2005. The physiology of the vagus nerve, mechanics of the VNS Therapy System, and efficacy and safety in pharmacoresistant epilepsy are reviewed. Promising results of VNS therapy for treatment-resistant depression have been forthcoming from both acute and long-term studies, evidenced in part by progressive improvements in depression rating scale scores during the 1st year of treatment with maintenance of response thereafter. VNS therapy is well tolerated in patients with either pharmacoresistant epilepsy or treatment-resistant depression. As in epilepsy, the mechanisms of VNS therapy of treatment-resistant depression are incompletely understood. However, evidence from neuroimaging and other studies suggests that VNS therapy acts via innervation of the nucleus tractus solitarius, with secondary projections to limbic and cortical structures that are involved in mood regulation, including brainstem regions that contain serotonergic (raphe nucleus) and noradrenergic (locus ceruleus) perikarya that project to the forebrain. Mechanisms that mediate the beneficial effects of VNS therapy for treatment-resistant depression remain obscure. Suggestions for future research directions are described.

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Summary:Purpose: Early animal studies of the therapeutic mechanisms of vagus nerve stimulation (VNS) suggested that seizure suppression requires maximal activation of small, unmyelinated vagal C fibers. However, effective therapeutic stimulation parameters appear to be subthreshold for these fibers in humans, and there are no clinical reports of the autonomic side effects that would be expected if these fibers were maximally activated. We report here that selective destruction of C fibers with capsaicin does not affect VNS-induced seizure suppression in rats.Methods: Rats were pretreated with capsaicin or vehicle in three injections over a 2-day period. A cuff electrode was later implanted on the left cervical vagus nerve. Two days after surgery, VNS was given to half of the capsaicin-and vehicletreated rats. The remaining rats were connected to the stimulator but did not receive VNS. Thirty seconds after VNS onset, seizures were induced by pentylenetetrazol (PTZ), and seizure severity was measured. Two days later, the reciprocal VNS treatment was given, and PTZ-induced seizure severity was again measured.Results: VNS effectively reduced seizure severity in both capsaicin-and vehicle-treated rats as compared with their non-VNS baselines.Conclusions: These results indicate that activation of vagal C fibers is not necessary for VNS-induced seizure suppression. Key Words: VNS-Capsaicin-Fibers-Pentylenetetrazol-Anticonvulsant-Epilepsy.Vagus nerve stimulation (VNS) is a novel anticonvulsant therapy now gaining prominence for the treatment of refractory epilepsy. Compared with conventional epilepsy neurosurgery, this technique involves a lower-risk surgery and results in fewer complications (1). The surgery in humans involves the placement of spiral electrodes on the left cervical vagus nerve, with intermittent stimulation provided by a neurocybernetic prosthesis (NCP) (Cyberonics, Inc., Houston, TX, U.S.A.) implanted subcutaneously in the upper chest. Clinical trials have found the device to reduce the incidence of complex partial seizures in the majority of patients tested, with 20-40% of patients achieving a >50% reduction in seizure frequency (2). Stimulation parameters are adjusted to produce a minimum of side effects. Some side effects, such as a tingling sensation in the neck and temporary hoarseness during stimulation, do persist; however, significant gastrointestinal, cardiac, or respiratory effects are not apparent (2).At the cervical level, the afferent component of the vagus nerve is a composite of myelinated A and B fibers, and unmyelinated C fibers, conveying sensory information from a number of organs, including the heart, lungs, liver, stomach, and intestines. The afferent C fibers are the most numerous, accounting for ∼65-80% of the fibers in the cervical vagal trunk (3). Early animal studies on the therapeutic mechanisms of VNS suggested that seizure suppression requires the activation of vagal C fibers (4). However, effective therapeutic stimulation parameters appear to be subthreshold for vagal C f...