Slow Hyperpolarization in Cortical Neurons: A Possible Mechanism Behind Vagus Nerve Simulation Therapy for Refractory Epilepsy?


Address correspondence and reprint requests to Dr. Aniko Zagon, Department of Anatomy and Developmental Biology, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. E-mail:


Summary: Purpose: Recent studies have shown that chronic, intermittent stimulation of the left vagus nerve (VNS) decreases the frequency, duration, and/or intensity of seizures in some patients with medically refractory focal seizures. Although VNS is being used in an increasing number of patients, the neuronal mechanism behind VNS therapy of refractory epileptic seizures is yet unclear.

Methods: In vivo intracellular recordings were used to study responses elicited by the VNS in pyramidal neurons of the parietal association cortex in anesthetized rats.

Results: Low-intensity trains of VNS, which activated predominantly myelinated fibers (100 μA, 30 Hz, 0.5 millisecond, 20 seconds), elicited a slow hyperpolarization (onset latency 17.4 ± 2.0 seconds, amplitude –4.7 ± 0.6 mV, duration 35 ± 3.2 seconds; n = 19). Increasing the intensity of VNS to recruit nonmyelinated vagal fibers (200 μA) led to an increase in the magnitude of the response in some neurons while failed to evoke a response in others. On increasing the stimulus intensity to 500 μA, only one in nine neurons exhibited a visible response. All recorded and visualised neurons were pyramidal cells in cortical layer V.

Conclusions: Stimulus intensities that activate predominantly myelinated fibers (less than 200 μA) were most effective to induce slow vagal hyperpolarization. It is suggested that slow hyperpolarization may be one of the mechanisms that underlie the seizure-reducing effect of VNS, by means of reducing the excitability in neurons that would be involved in propagation of seizure activity. As the balance of activity in myelinated and nonmyelinated primary vagal afferents influenced the effect of VNS stimulation, it is likely that the effect of VNS is modulated as changes occur in the underlying vagal tone.