Neuromodulators associated with arousal modulate learning and memory, but most of these substances do not freely enter the brain from the periphery. In rodents, these neuromodulators act in part by initiating neural messages that travel via the vagus nerve to the brain, and electrical stimulation of the vagus enhances memory. We now extend that finding to human verbal learning. We examined word-recognition memory in patients enrolled in a clinical study evaluating the capacity of vagus nerve stimulation to control epilepsy. Stimulation administered after learning significantly enhanced retention. These findings confirm in humans the hypothesis that vagus nerve activation modulates memory formation similarly to arousal.

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...

The vagus nerve is an important source of afferent information about visceral states and it provides input to the locus coeruleus (LC), the major source of norepinephrine (NE) in the brain. It has been suggested that the effects of electrical stimulation of the vagus nerve on learning and memory, mood, seizure suppression, and recovery of function following brain damage are mediated, in part, by the release of brain NE. The hypothesis that left vagus nerve stimulation (VNS) at the cervical level results in increased extracellular NE concentrations in the cortex and hippocampus was tested at four stimulus intensities 0.0, 0.25, 0.5, and 1.0 mA. Stimulation at 0.0 and 0.25 mA had no effect on NE concentrations, while the 0.5 mA stimulation increased NE concentrations significantly in the hippocampus (23%), but not the cortex. However, 1.0 mA stimulation significantly increased NE concentrations in both the cortex (39%) and hippocampus (28%) bilaterally. The increases in NE were transient and confined to the stimulation periods. VNS did not alter NE concentrations in either structure during the inter-stimulation baseline periods. No differences were observed between NE levels in the initial baseline and the post-stimulation baselines. These findings support the hypothesis that VNS increases extracellular NE concentrations in both the hippocampus and cortex.

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