, Volume 11, Issue 3, pp 612–622 | Cite as

The P3 Event-Related Potential is a Biomarker for the Efficacy of Vagus Nerve Stimulation in Patients with Epilepsy

  • Leen De Taeye
  • Kristl Vonck
  • Marlies van Bochove
  • Paul Boon
  • Dirk Van Roost
  • Lies Mollet
  • Alfred Meurs
  • Veerle De Herdt
  • Evelien Carrette
  • Ine Dauwe
  • Stefanie Gadeyne
  • Pieter van Mierlo
  • Tom Verguts
  • Robrecht Raedt
Original Article


Currently, the mechanism of action of vagus nerve stimulation (VNS) is not fully understood, and it is unclear which factors determine a patient’s response to treatment. Recent preclinical experiments indicate that activation of the locus coeruleus noradrenergic system is critical for the antiepileptic effect of VNS. This study aims to evaluate the effect of VNS on noradrenergic signaling in the human brain through a noninvasive marker of locus coeruleus noradrenergic activity: the P3 component of the event-related potential. We investigated whether VNS differentially modulates the P3 component in VNS responders versus VNS nonresponders. 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 2 groups with regard to their reduction in mean monthly seizure frequency: 10 responders (>50 %) and 10 nonresponders (≤50 %). Two stimulation conditions were compared: VNS OFF and VNS ON. In each condition, the P3 component was measured during an auditory oddball paradigm. VNS induced a significant increase of the P3 amplitude at the parietal midline electrode, in VNS responders only. In addition, logistic regression analysis showed that the increase of P3 amplitude can be used as a noninvasive indicator for VNS responders. These results support the hypothesis that activation of the locus coeruleus noradrenergic system is associated with the antiepileptic effect of VNS. Modulation of the P3 amplitude should be further investigated as a noninvasive biomarker for the therapeutic efficacy of VNS in patients with refractory epilepsy.


Vagus nerve stimulation epilepsy event-related potentials P3 biomarker norepinephrine. 



L. De Taeye is supported by a Fonds Wetenschappelijk Onderzoek (FWO) aspirant grant. K. Vonck is supported by a Bijzonder Onderzoeksfonds (BOF) grant from Ghent University Hospital. P. Boon is supported by grants from FWO, grants from BOF, and by the Clinical Epilepsy Grant from Ghent University Hospital. M. van Bochove, L. Mollet, and T. Verguts are supported by grants from FWO. R. Raedt is supported by a BOF Tenure Track grant from Ghent University.

Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2014_272_MOESM1_ESM.pdf (1.2 mb)
ESM 1 (PDF 1225 kb)


  1. 1.
    Boon P, Vonck K, De Reuck J, Caemaert J. Vagus nerve stimulation for refractory epilepsy. Seizure 2001;10:448–455.PubMedCrossRefGoogle Scholar
  2. 2.
    Ben-Menachem E. Vagus-nerve stimulation for the treatment of epilepsy. Lancet Neurol 2002;1:477–482.PubMedCrossRefGoogle Scholar
  3. 3.
    George R, Sonnen A, Upton A, et al. A randomized controlled trial of chronic vagus nerve-stimulation for treatment of medically intractable seizures. Neurology 1995;45:224–230.CrossRefGoogle Scholar
  4. 4.
    Handforth A, DeGiorgio CM, Schachter SC, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology 1998;51:48–55.PubMedCrossRefGoogle Scholar
  5. 5.
    Privitera MD, Welty TE, Ficker DM, Welge J. Vagus nerve stimulation for partial seizures. Cochrane Database Syst Rev 2002:CD002896.Google Scholar
  6. 6.
    Vonck K, Boon P, D’Have N, Vandekerckhove T, O’Connor S, de Reuck J. Long-term results of vagus nerve stimulation in refractory epilepsy. Seizure 1999;8:328–334.PubMedCrossRefGoogle Scholar
  7. 7.
    DeGiorgio CM, Schachter SC, Handforth A, et al. Prospective long-term study of vagus nerve stimulation for the treatment of refractory seizures. Epilepsia 2000;41:1195–1200.PubMedCrossRefGoogle Scholar
  8. 8.
    De Herdt V, Boon P, Ceulemans B, et al. Vagus nerve stimulation for refractory epilepsy: A Belgian multicenter study. Eur J Paediatr Neurol 2007;11:261–269.PubMedCrossRefGoogle Scholar
  9. 9.
    Elliott RE, Morsi A, Kalhorn SP, et al. Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: Long-term outcomes and predictors of response. Epilepsy Behav 2011;20:57–63.PubMedCrossRefGoogle Scholar
  10. 10.
    Englot DJ, Chang EF, Auguste KI. Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response A review. J Neurosurg 2011;115:1248–1255.PubMedCrossRefGoogle Scholar
  11. 11.
    Fornai F, Ruffoli R, Giorgi FS, Paparelli A. The role of locus coeruleus in the antiepileptic activity induced by vagus nerve stimulation. Eur J Neurosci 2011;33:2169–2178.PubMedCrossRefGoogle Scholar
  12. 12.
    Raedt R, Clinckers R, Mollet L, et al. Increased hippocampal noradrenaline is a biomarker for efficacy of vagus nerve stimulation in a limbic seizure model. J Neurochem 2011;117:461–469.PubMedCrossRefGoogle Scholar
  13. 13.
    Polich J. Updating p300: An integrative theory of P3a and P3b. Clin Neurophysiol 2007;118:2128–2148.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Duncan CC, Barry RJ, Connolly JF, et al. Event-related potentials in clinical research: Guidelines for eliciting, recording, and quantifying mismatch negativity, P300, and N400. Clin Neurophysiol 2009;120:1883–1908.PubMedCrossRefGoogle Scholar
  15. 15.
    Nieuwenhuis S, Aston-Jones G, Cohen JD. Decision making, the p3, and the locus coeruleus-norepinephrine system. Psychol Bull 2005;131:510–532.PubMedCrossRefGoogle Scholar
  16. 16.
    Murphy PR, Robertson IH, Balsters JH, O’Connell R G. Pupillometry and P3 index the locus coeruleus-noradrenergic arousal function in humans. Psychophysiology 2011;48:1532–1543.PubMedCrossRefGoogle Scholar
  17. 17.
    Berridge CW, Waterhouse BD. The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Rev 2003;42:33–84.PubMedCrossRefGoogle Scholar
  18. 18.
    Sara SJ. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci 2009;10:211–223.PubMedCrossRefGoogle Scholar
  19. 19.
    Nieuwenhuis S, De Geus EJ, Aston-Jones G. The anatomical and functional relationship between the P3 and autonomic components of the orienting response. Psychophysiology 2011;48:162–175.CrossRefGoogle Scholar
  20. 20.
    Aston-Jones G, Cohen JD. An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. Annu Rev Neurosci 2005;28:403–450.PubMedCrossRefGoogle Scholar
  21. 21.
    Pineda JA, Foote SL, Neville HJ. Effects of locus coeruleus lesions on auditory, long-latency, event-related potentials in monkey. J Neurosci 1989;9:81–93.PubMedGoogle Scholar
  22. 22.
    Boon P, De Herdt V, Vonck K, Van Roost D. Clinical experience with vagus nerve stimulation and deep brain stimulation in epilepsy. Acta Neurochir Suppl 2007;97:273–280.PubMedCrossRefGoogle Scholar
  23. 23.
    Shahwan A, Bailey C, Maxiner W, Harvey AS. Vagus nerve stimulation for refractory epilepsy in children: More to VNS than seizure frequency reduction. Epilepsia 2009;50:1220–1228.PubMedCrossRefGoogle Scholar
  24. 24.
    Picton TW, Bentin S, Berg P, et al. Guidelines for using human event-related potentials to study cognition: Recording standards and publication criteria. Psychophysiology 2000;37:127–152.PubMedCrossRefGoogle Scholar
  25. 25.
    Luck SJ. An introduction to the event-related potential technique. MIT Press, Harvard, MA, 2005.Google Scholar
  26. 26.
    Kappenman ES, Kaiser ST, Robinson BM, et al. Response activation impairments in schizophrenia: Evidence from the lateralized readiness potential. Psychophysiology 2012;49:73–84.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Luck SJ, Mathalon DH, O’Donnell BF, et al. A roadmap for the development and validation of event-related potential biomarkers in schizophrenia research. Biol Psychiatry 2011;70:28–34.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Frodl T, Meisenzahl EM, Muller D, et al. The effect of the skull on event-related P300. Clin Neurophysiol 2001;112:1773–1776.PubMedCrossRefGoogle Scholar
  29. 29.
    Ahlfors SP, Han J, Lin FH, et al. Cancellation of EEG and MEG signals generated by extended and distributed sources. Hum Brain Mapp 2010;31:140–149.PubMedCentralPubMedGoogle Scholar
  30. 30.
    Hammond EJ, Uthman BM, Reid SA, Wilder BJ. Electrophysiologic studies of cervical vagus nerve stimulation in humans: II. Evoked potentials. Epilepsia 1992;33:1021–1028.PubMedCrossRefGoogle Scholar
  31. 31.
    Enoki H, Sanada S, Oka E, Ohtahara S. Event-related potentials in epileptic children treated with monotherapy. J Epilepsy 1995;8:219–226.CrossRefGoogle Scholar
  32. 32.
    Meador KJ, Loring DW, Moore EE, et al. Comparative cognitive effects of phenobarbital, phenytoin, and valproate in healthy adults. Neurology 1995;45:1494–1499.PubMedCrossRefGoogle Scholar
  33. 33.
    Kubota F, Kifune A, Shibata N, Akata T, Takeuchi K, Takahashi S. Study on the P300 of adult epileptic patients (unmedicated and medicated patients). J Epilepsy 1998;11:325–331.CrossRefGoogle Scholar
  34. 34.
    Brázdil M, Chadim P, Daniel P, et al. Effect of vagal nerve stimulation on auditory and visual event-related potentials. Eur J Neurol 2001;8:457–461.PubMedCrossRefGoogle Scholar
  35. 35.
    Caravaglios G, Natale E, Ferraro G, Fierro B, Raspanti G, Daniele O. Auditory event-related potentials (P300) in epileptic patients. Neurophysiol Clin 2001;31:121–129.PubMedCrossRefGoogle Scholar
  36. 36.
    Neuhaus AH, Luborzewski A, Rentzsch J, et al. P300 is enhanced in responders to vagus nerve stimulation for treatment of major depressive disorder. J Affect Disorders 2007;100:123–128.PubMedCrossRefGoogle Scholar
  37. 37.
    Elger G, Hoppe C, Falkai P, Rush AJ, Elger CE. Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Res 2000;42:203–210.PubMedCrossRefGoogle Scholar
  38. 38.
    Harden CL, Pulver MC, Ravdin LD, Nikolov B, Halper JP, Labar DR. A Pilot study of mood in epilepsy patients treated with vagus nerve stimulation. Epilepsy Behav 2000;1:93–99.PubMedCrossRefGoogle Scholar
  39. 39.
    Nahas Z, Marangell LB, Husain MM, et al. Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. J Clin Psychiatry 2005;66:1097–1104.PubMedCrossRefGoogle Scholar
  40. 40.
    Daban C, Martinez-Aran A, Cruz N, Vieta E. Safety and efficacy of vagus nerve stimulation in treatment-resistant depression. A systematic review. J Affect Disorders 2008;110:1–15.PubMedCrossRefGoogle Scholar
  41. 41.
    Kanner A, Schachter SC. Psychiatric controversies in epilepsy. Elsevier Science, Academic Press, Amsterdam, The Netherlands, 2010.Google Scholar
  42. 42.
    Kanner AM. Depression and epilepsy: A bidirectional relation? Epilepsia 2011;52:21–27.PubMedCrossRefGoogle Scholar
  43. 43.
    Jobe PC. Common pathogenic mechanisms between depression and epilepsy: an experimental perspective. Epilepsy Behav 2003;4:S14-S24.PubMedCrossRefGoogle Scholar
  44. 44.
    Van Bockstaele EJ, Peoples J, Telegan P. Efferent projections of the nucleus of the solitary tract to peri-locus coeruleus dendrites in rat brain: Evidence for a monosynaptic pathway. J Comp Neurol 1999;412:410–428.PubMedCrossRefGoogle Scholar
  45. 45.
    Groves DA, Bowman EM, Brown VJ. Recordings from the rat locus coeruleus during acute vagal nerve stimulation in the anaesthetised rat. Neurosci Lett 2005;379:174–179.PubMedCrossRefGoogle Scholar
  46. 46.
    Dorr AE, Debonnel G. Effect of vagus nerve stimulation on serotonergic and noradrenergic transmission. J Pharmacol Exp Ther 2006;318:890–898.PubMedCrossRefGoogle Scholar
  47. 47.
    Roosevelt RW, Smith DC, Clough RW, Jensen RA, Browning RA. Increased extracellular concentrations of norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat. Brain Res 2006;1119:124–132.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Hassert DL, Miyashita T, Williams CL. The effects of peripheral vagal nerve stimulation at a memory-modulating intensity on norepinephrine output in the basolateral amygdala. Behav Neurosci 2004;118:79–88.PubMedCrossRefGoogle Scholar
  49. 49.
    Follesa P, Biggio F, Gorini G, et al. Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain. Brain Res 2007;1179:28–34.PubMedCrossRefGoogle Scholar
  50. 50.
    Krahl SE, Clark KB, Smith DC, Browning RA. Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation. Epilepsia 1998;39:709–714.PubMedCrossRefGoogle Scholar
  51. 51.
    Clark KB, Naritoku DK, Smith DC, Browning RA, Jensen RA. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nat Neurosci 1999;2:94–98.PubMedCrossRefGoogle Scholar
  52. 52.
    Aldenkamp AP, Majoie HJM, Berfelo MW, et al. Long-term effects of 24-month treatment with vagus nerve stimulation on behaviour in children with Lennox-Gastaut syndrome. Epilepsy Behav 2002;3:475–479.PubMedCrossRefGoogle Scholar
  53. 53.
    Sackeim HA, Keilp JG, Rush AJ, et al. The effects of vagus nerve stimulation on cognitive performance in patients with treatment-resistant depression. Neuropsychiatry Neuropsychol Behave Neurol 2001;14:53–62.Google Scholar
  54. 54.
    Sjogren MJC, Hellstrom PTO, Jonsson MAG, Runnerstam M, Silander HC, Ben-Menachem E. Cognition-enhancing effect of vagus nerve stimulation in patients with Alzheimer’s disease: A pilot study. J Clin Psychiat 2002;63:972–980.CrossRefGoogle Scholar
  55. 55.
    Sara SJ, Bouret S. Orienting and reorienting: The locus coeruleus mediates cognition through arousal. Neuron 2012;76:130–141.PubMedCrossRefGoogle Scholar
  56. 56.
    Stefan H, Kreiselmeyer G, Kerling F, et al. Transcutaneous vagus nerve stimulation (t-VNS) in pharmacoresistant epilepsies: a proof of concept trial. Epilepsia 2012;53:e115-e118.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2014

Authors and Affiliations

  • Leen De Taeye
    • 1
  • Kristl Vonck
    • 1
  • Marlies van Bochove
    • 2
  • Paul Boon
    • 1
  • Dirk Van Roost
    • 3
  • Lies Mollet
    • 1
  • Alfred Meurs
    • 1
  • Veerle De Herdt
    • 1
  • Evelien Carrette
    • 1
  • Ine Dauwe
    • 1
  • Stefanie Gadeyne
    • 1
  • Pieter van Mierlo
    • 4
  • Tom Verguts
    • 2
  • Robrecht Raedt
    • 1
  1. 1.LCEN3, Department of NeurologyGhent UniversityGhentBelgium
  2. 2.Department of Experimental PsychologyGhent UniversityGhentBelgium
  3. 3.Department of NeurosurgeryGhent University HospitalGhentBelgium
  4. 4.MEDISIP, Department of Electronics and Information SystemsGhent UniversityGhentBelgium

Personalised recommendations