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Vagus nerve stimulation (VNS) is a therapy on medically refractory epilepsy, and recently reported to improve cognitive function including learning and memory. The thalamo-cortical system may underlie such VNS-induced cognitive improvements. Thus, the present study targeted the auditory cortex and thalamus in rats, and investigated whether and how VNS modulates stimulus-specific adaptation (SSA) of the neural activity in these nuclei. A depth electrode array recorded auditory evoked potentials from the auditory thalamus and cortex under an oddball paradigm either with or without VNS. Consequently, VNS weakened SSA in the cortex, but did not affect that in the thalamus, indicating that VNS has neuromodulatory effects on the cortical inhibitory system and the thalamo-cortical projections, but not on the feedforward projections from the auditory periphery up to thalamus.

Vagus nerve stimulation is a palliative treatment for medically intractable epilepsy. This treatment reduces the frequency and severity of seizures refractory to antiepileptic drugs. Implanted generator and helical electrodes electrically stimulate the left vagus nerve at the neck chronically and intermittently. This was the first electrostimulation therapy clinically introduced for epilepsy. This treatment approach is supported by randomized double-blind trials even though the anti-seizure effect of vagus nerve stimulation is palliative and not curative. In Western countries, particularly the United States, this therapy has become an important alternative treatment for a subpopulation of patients with drug-resistant seizures who are not good candidates for craniotomy. In Japan, vagus nerve stimulation therapy was finally approved in January 2010 and has been covered by public health insurance since July 2010. Here, the author reviews the history, efficacy, and safety of this treatment, surgical anatomy and physiology of the vagus nerve, and the putative mechanisms underlying inhibition of epileptic seizures and accompanying effect on the central nervous system. Further experimental and clinical studies regarding this treatment approach are required to elucidate the detailed mechanism of action, to clarify the predicting factors of favorable outcome, and to scientifically confirm the anti-seizure effect in children and in generalized seizures and the efficacy in improvement of cognitive function, development, and quality of life.

Vagus nerve stimulation (VNS) and stereotactic radiosurgery (SRS) represent novel and less invasive therapeutics for medically intractable epilepsy. VNS ushered in the recent advancement in clinical application of electrical stimulation therapy for epilepsy. Chronic stimulation of the left vagus nerve with implanted generator and electrodes inhibits seizure susceptibility of the cerebral cortices. Its efficacy and safety have been established by randomized clinical trials in 1990s in the Western countries and it has been widely accepted as a treatment option for patients with medically intractable epilepsy for whom brain surgery is not indicated or failed. Although the effect on seizures is not so dramatic, the less invasiveness and a wide range of indication have made VNS indispensable for comprehensive care of epilepsy. Since the devices are not approved for clinical use in Japan, there exist barriers to provide VNS to patients at present. Use of SRS for intractable epilepsy started in mid 90s as gamma knife surgery for mesial temporal lobe epilepsy. The marginal dose of 25 Gy to the medial temporal structures has been confirmed to be effective for seizure control, but there seems to be an unignorable risk of brain edema and radiation necrosis. It is still controversial whether the therapy is more effective and less invasive than brain surgery. A randomized clinical trial using the dose of 20 or 24 Gy is ongoing in the United States. SRS for intractable epilepsy associated with hypothalamic hamartoma has been advocated because of a high surgical morbidity, but further study is needed for standardization of the treatment. Substitute use of SRS for other surgical technique like callosotomy or disconnection of epileptic focus seems to be another direction worth pursuing.

The outcome of long-term vagus nerve stimulation (VNS) was evaluated in 13 Japanese patients with intractable epilepsy, all followed up for more than 4 years (48-91 months, median 56 months). VNS achieved a long-lasting and cumulative seizure-control effect in nine of 13 patients. The mean reduction of seizure frequency in the 1st to 4th year was 28%, 47%, 54%, and 63%, respectively. The percentage of patients with >60% seizure reduction in the 1st to 4th year was 15%, 46%, 54%, and 69%, respectively. One patient did not respond to the treatment at all. No patient became completely free from seizure or free from medication, but the number and/or dosage of antiepileptic drugs was reduced in five patients. Ten patients underwent exchange of the generator and continued treatment, and two patients underwent removal of the generator because of the unsatisfactory result. VNS controlled more disabling seizures earlier and more efficiently than less disabling seizures in seven patients. The cumulative reduction of seizures was partly associated with changes in the device setting toward increased stimulation. These effects were similar in patients with or without previous resective surgery. Long-term VNS therapy achieved a favorable outcome in a significant proportion of patients with intractable epilepsy.

Background: Vagus nerve stimulation (VNS) is an established palliative surgical treatment for refractory epilepsy. Recently, pairing VNS with rehabilitation received growing attention for their joint effect on neural plasticity. However, objective biological measurements proving the interaction between VNS effects and cortical recruitment are lacking. Studies reported that VNS induced little blood flow increase in the cerebral cortex. Objective: This study tested the hypothesis that pairing VNS with a cognitive task amplifies task-induced cerebral blood flow (CBF). Methods: This study included 21 patients implanted with vagus nerve stimulator to treat refractory epilepsy. Near-infrared spectroscopy (NIRS) with sensors on the forehead measured CBF changes in the frontal cortices in response to VNS. Cerebral blood flow was measured when VNS was delivered during a resting state or a verbal fluency task. We analyzed the VNS effect on CBF in relation to stimulation intensity and clinical responsiveness. Results: We observed no CBF change when VNS was delivered during rest, irrespective of stimulation intensity or responsiveness. Cerebral blood flow changed significantly when a verbal fluency task was paired with VNS in a stimulation intensity-dependent manner. Cerebral blood flow changes in the non-responders showed no intensity-dependency. Conclusion: Our results could be an important biological proof of the interaction between VNS effects and cortical recruitment, supporting the validity of pairing VNS with rehabilitation. [ABSTRACT FROM AUTHOR]

SUMMARY Vagus nerve stimulation (VNS) causes neuromodulatory effects in the cerebral cortex, which are useful not only for therapy on intractable epilepsy but also for enhancement of higher brain functions such as cognition and memory. Recently, it has been reported that VNS may also affect auditory-evoked neutral activities. However, it remains to be elucidated how and where VNS modulates neutral activities in the auditory cortex. Here, we examined effects of VNS on adaptation of neutral activities in response to repeated stimuli in the rat auditory cortex. Both a surface and depth microelectrode array recorded auditory-evoked potentials in response to click train and oddball stimuli. We quantified a repetition rate transfer function and common stimulus-specific adaptation (SSA) index from the amplitude of middle-latency response (PI). Consequently, VNS affected temporal response property and increased SSA in the layer 1 and 5/6 of auditory cortex. This result suggests that VNS strengthens adaptation in the auditory cortex in a layer-specific manner. [ABSTRACT FROM AUTHOR]

SUMMARY Vagus nerve stimulation (VNS) is a palliative treatment for intractable epilepsy. Therapeutic mechanisms of VNS have not been elucidated. In this study, we measured the local field potential (LFP) with high-spatial resolution using a microelectrode array in adult rats, and analyzed VNS-induced phase modulation at a local network level. Eight adult Wistar rats (270-330 g) were used. Each rat underwent implantation of a VNS system under 1.5% isoflurane anesthesia. One week after implantation, right temporal craniotomy was performed under the same anesthesia as previously. Subsequently, a microelectrode array was placed in the temporal lobe cortex, and the LFP was recorded with a sampling rate of 1000 Hz. Phase-locking values (PLV) between all pairs of electrodes in varied frequency bands were calculated in order to evaluate the effect of VNS in terms of synchrony of neuronal activities. The PLV was calculated both in a normal state and in an epileptic state induced by kainic acid. VNS increased the PLV in a normal state, particularly in the high-γ band. In an epileptic state, on the other hand, VNS increased the PLV in the high-γ band and decreased the PLV in the δ and low-β bands. These results suggest that VNS modulates neural activities in a band-specific and state-dependent manner so as to keep cortical synchrony within the optimal state. [ABSTRACT FROM AUTHOR]

SUMMARY Vagus nerve stimulation (VNS) is a surgical treatment for intractable epilepsy. Although VNS has been used to treat more than 60,000 patients, the precise therapeutic mechanism of action has not been elucidated. Here, we hypothesize that VNS modulates the local synchronization of cortical activities and thus inhibits seizures. In order to verify this hypothesis, we mapped local field potentials (LFPs) with high-spatial resolution using a microelectrode array from the temporal cortices of adult rats and analyzed VNS-induced phase modulation at the local network level. VNS significantly increased the phase locking value (PLV), an index of synchronization, specifically at the gamma band. The optimal stimulation pulse of VNS was 0.5 mA delivered at 10 Hz. This PLV modulation was most effective when the interelectrode distance was about 1.6 mm. Gamma-band PLVs within the auditory cortex increased more significantly than those between the auditory and nonauditory cortices, while alpha- and low-beta PLV exhibited more synchronization between the auditory and nonauditory cortices. These results demonstrate that VNS modulates cortical synchronization in a band specific manner, and has some implications for the mechanism of action of VNS. [ABSTRACT FROM AUTHOR]

Abstract: Background: Vagus nerve stimulation (VNS) is a palliative treatment for drug resistant epilepsy for which the efficacy and safety are well established. Accumulating evidence suggests that ascending vagal signals modulate abnormal cortical excitability via various pathways. However, there is no direct evidence for an ascending conduction of neural impulses in a clinical case of VNS. Objective: We recorded and analyzed the short-latency components of the vagus nerve (VN) evoked potential (EP) from the viewpoint of determining whether or not it is a marker for the ascending neural conduction. Methods: EPs within 20 ms were prospectively recorded simultaneously from a surgical wound in the neck and at multiple scalp sites during implantation surgery in 25 patients with drug-resistant epilepsy. Electrical stimulation was delivered using the clinical VNS Therapy system. A recording was made before and after a muscle relaxant was administered, when changing the rostrocaudal position of stimulation, or when stimulating the ansa cervicalis instead of the VN. Results: The short-latency components consisted of four peaks. The early component around 3 ms, which was most prominent in A1–Cz, remained unchanged after muscle relaxation while the later peaks disappeared. Rostral transition of the stimulation resulted in an earlier shift of the early component. The estimated conduction velocity was 27.4 ± 10.2 m/s. Stimulation of the ansa cervicalis induced no EP. Conclusions: The early component was regarded as directly resulting from ascending neural conduction of A fibers of the VN, probably originating around the jugular foramen. Recording of VN-EP might document the cause of treatment failure in some patients. [Copyright &y& Elsevier]