Abstracts

Rationale: The mechanism of action of vagus nerve stimulation (VNS) is currently not fully understood and it is unclear which factors determine the patient's response to the treatment. Recent preclinical experiments in animal models for epilepsy have indicated that activation of the locus coeruleus (LC) noradrenergic system is critical for the anti-epileptic effect of VNS. The aim of the present study is to evaluate the effect of VNS on noradrenergic signaling in the human brain via a non-invasive marker of LC noradrenergic activity, i.e. the P300 component of the event related potential. We investigated whether VNS differentially modulates LC noradrenergic activity in VNS responders versus VNS non-responders. Methods: For this purpose, we recruited 20 patients with refractory epilepsy who had been treated with VNS for at least 18 months. Patients were divided into two groups with regards to their reduction in mean monthly seizure frequency: 10 responders (> 50%) and 10 non-responders (< 50%). Two conditions were compared: VNS OFF, VNS ON (duty cycle was always 7s ON/18s OFF, other stimulation parameters were patient-specific therapeutic parameters: output current 0.75-3.00 mA, frequency 20-30 Hz and pulse width 250-500 s). During each condition the oddball P300 component to deviant auditory stimuli was recorded. The amplitude and latency of the P300 component were compared between both conditions in the group of responders and non-responders.Results: VNS induces a significant increase of the oddball P300 amplitude at the parietal midline electrode, in VNS responders only. When the VNS ON and OFF conditions were compared, the amplitude of the oddball P300 was significantly increased in responders (amplitude OFF 4.2 2.3 V and ON 5.3 2.5 V, p=0.005), while in non-responders this increase was not observed (amplitude OFF 6.9 4.3 V and ON 6.4 4.0 V, p=0.3). In addition, a significant positive linear relationship was found between the mean monthly seizure reduction by VNS and the VNS-induced increase of the P300 amplitude (p=0.039). No significant differences were found in the latency of the P300 component between the ON and OFF conditions in both groups.Conclusions: These results suggest that VNS-induced activation of the LC noradrenergic signaling is required to achieve a therapeutic effect of VNS. Modulation of the P300 amplitude may be useful as a non-invasive biomarker to predict therapeutic efficacy of VNS in patients with refractory epilepsy.