Brain Imaging and Behavior

, Volume 11, Issue 1, pp 30–37 | Cite as

Preliminary findings of cerebral responses on transcutaneous vagal nerve stimulation on experimental heat pain

  • Taras Usichenko
  • René Laqua
  • Bianca Leutzow
  • Martin Lotze
Original Research


Transcutaneous vagal nerve stimulation (TVNS) is a promising complementary method of pain relief. However, the neural networks associated with its analgesic effects are still to be elucidated. Therefore, we conducted two functional magnetic resonance imaging (fMRI) sessions, in a randomized order, with twenty healthy subjects who were exposed to experimental heat pain stimulation applied to the right forearm using a Contact Heat-Evoked Potential Stimulator. While in one session TVNS was administered bilaterally to the concha auriculae with maximal, non-painful intensity, the stimulation device was switched off in the other session (placebo condition). Pain thresholds were measured before and after each session. Heat stimulation elicited fMRI activation in cerebral pain processing regions. Activation magnitude in the secondary somatosensory cortex, posterior insula, anterior cingulate and caudate nucleus was associated with heat stimulation without TVNS. During TVNS, this association was only seen for the right anterior insula. TVNS decreased fMRI signals in the anterior cingulate cortex in comparison with the placebo condition; however, there was no relevant pain reducing effect over the group as a whole. In contrast, TVNS compared to the placebo condition showed an increased activation in the primary motor cortex, contralateral to the site of heat stimulation, and in the right amygdala. In conclusion, in the protocol used here, TVNS specifically modulated the cerebral response to heat pain, without having a direct effect on pain thresholds.


Transcutaneous vagal nerve stimulation (TVNS) Thermal pain Functional MRI Placebo stimulation 



The authors thank Vasyl Gizhko from the Department of Experimental Physics, University of Kiev, Ukraine, for his design and tests of the stimulation electrode; MTR GmbH, Germany for providing the TENS device; Dr. Konrad Meissner for providing the CHEPS thermode and the volunteers, who participated in this investigation. We would like to thank Henriette Hacker and Dr. Mike Cummings for carefully rechecking the manuscript for style and spelling mistakes.

Compliance with Ethical Standards

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, and the applicable revisions at the time of the investigation. Informed consent was obtained from all patients for being included in the study

Conflict of interest

Taras Usichenko, René Laqua, Bianca Leutzow and Martin Lotze declare that he/she has no conflict of interest.

Supplementary material

11682_2015_9502_MOESM1_ESM.docx (69 kb)
Supplementary Table (DOCX 68 kb)


  1. Aicher, S. A., & Randich, A. (1988). Effects of intrathecal antagonists on the antinociception, hypotension, and bradycardia produced by intravenous administration of [D-Ala2]-methionine enkephalinamide (DALA) in the rat. Pharmacology Biochemistry and Behavior, 30(1), 65–72.CrossRefGoogle Scholar
  2. Alexander, G. E., DeLong, M. R., & Strick, P. L. (1986). Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annual Review of Neuroscience, 9, 357–381.CrossRefPubMedGoogle Scholar
  3. Anders, S., Lotze, M., Erb, M., Grodd, W., & Birbaumer, N. (2004). Brain activity underlying emotional valence and arousal: A response-related fMRI study. Human Brain Mapping, 23(4), 200–209.CrossRefPubMedGoogle Scholar
  4. Apkarian, A. V., Bushnell, M. C., Treede, R. D., & Zubieta, J. K. (2005). Human brain mechanisms of pain perception and regulation in health and disease. European Journal of Pain, 9(4), 463–484.CrossRefPubMedGoogle Scholar
  5. Becerra, L. R., Breiter, H. C., Stojanovic, M., Fishman, S., Edwards, A., Comite, A. R., et al. (1999). Human brain activation under controlled thermal stimulation and habituation to noxious heat: an fMRI study. Magnetic Resonance in Medicine, 41(5), 1044–1057.CrossRefPubMedGoogle Scholar
  6. Brown, C. A., Seymour, B., El-Deredy, W., & Jones, A. K. (2008). Confidence in beliefs about pain predicts expectancy effects on pain perception and anticipatory processing in right anterior insula. Pain, 139(3), 324–332.CrossRefPubMedGoogle Scholar
  7. Brown, J. E., Chatterjee, N., Younger, J., & Mackey, S. (2011). Towards a physiology-based measure of pain: patterns of human brain activity distinguish painful from non-painful thermal stimulation. PloS One, 6(9), e24124.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bush, G., Luu, P., & Posner, M. I. (2000). Cognitive and emotional influences in anterior cingulate cortex. Trends in Cognitive Science, 4(6), 215–222.CrossRefGoogle Scholar
  9. Craig, A. D., Chen, K., Bandy, D., & Reiman, E. M. (2000). Thermosensory activation of insular cortex. Nature Neuroscience, 3(2), 184–190.CrossRefPubMedGoogle Scholar
  10. Dietrich, S., Smith, J., Scherzinger, C., Hofmann-Preiss, K., Freitag, T., Eisenkolb, A., et al. (2008). A novel transcutaneous vagus nerve stimulation leads to brainstem and cerebral activations measured by functional MRI. Biomed Tech, 53(3), 104–111.CrossRefGoogle Scholar
  11. Duerden, E. G., & Albanese, M. C. (2013). Localization of pain-related brain activation: a meta-analysis of neuroimaging data. Human Brain Mapping, 34(1), 109–149.CrossRefPubMedGoogle Scholar
  12. Eichhammer, P. (2011). (2011). Potential for transcutaneous vagus nerve stimulation in pain management. Pain Manag, 1(4), 287–289.CrossRefPubMedGoogle Scholar
  13. Freund, W., Klug, R., Weber, F., Stuber, G., Schmitz, B., & Wunderlich, A. P. (2009). Perception and suppression of thermally induced pain: a fMRI study. Somatosensory and Motor Research, 26(1), 1–10.CrossRefPubMedGoogle Scholar
  14. Friebel, U., Eickhoff, S. B., & Lotze, M. (2011). Coordinate-based meta-analysis of experimentally induced and chronic persistent neuropathic pain. NeuroImage, 58(4), 1070–1080.CrossRefPubMedGoogle Scholar
  15. George, M. S., Nahas, Z., Borckardt, J. J., Anderson, B., Burns, C., Kose, S., & Short, E. B. (2007). Vagus nerve stimulation for the treatment of depression and other neuropsychiatric disorders. Expert Review of Neurotherapeutics, 7(1), 63–74.CrossRefPubMedGoogle Scholar
  16. Gray H. (1918). Anatomy of the human body. X. The organs of the senses and the common integument. The external ear. Lea & Febiger 146.Google Scholar
  17. Grosen, K., Fischer, I. W., Olesen, A. E., & Drewes, A. M. (2013). Can quantitative sensory testing predict responses to analgesic treatment? European Journal of Pain, 17(9), 1267–1280.CrossRefPubMedGoogle Scholar
  18. Ingvar, M. (1999). Pain and functional imaging. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 354(1387), 1347–1358.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Johnson, M. I., Hajela, V. K., Ashton, C. H., & Thompson, J. W. (1991). The effects of auricular transcutaneous electrical nerve stimulation (TENS) on experimental pain threshold and autonomic function in healthy subjects. Pain, 46(3), 337–342.CrossRefPubMedGoogle Scholar
  20. Jürgens, T. P., Sawatzki, A., Henrich, F., Magerl, W., & May, A. (2014). An improved model of heat-induced hyperalgesia--repetitive phasic heat pain causing primary hyperalgesia to heat and secondary hyperalgesia to pinprick and light touch. PLoS One, 9(6), e99507.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Kirchner, A., Birklein, F., Stefan, H., & Handwerker, H. O. (2000). Left vagus nerve stimulation suppresses experimentally induced pain. Neurology, 55(1), 1167–1171.CrossRefPubMedGoogle Scholar
  22. Kraus, T., Hösl, K., Kiess, O., Schanze, A., Kornhuber, J., & Forster, C. (2007). BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation. Journal of Neural Transmission, 114(11), 1485–1493.CrossRefPubMedGoogle Scholar
  23. Kraus, T., Kiess, O., Hösl, K., Terekhin, P., Kornhuber, J., & Forster, C. (2013). CNS BOLD fMRI effects of sham-controlled transcutaneous electrical nerve stimulation in the left outer auditory canal - a pilot study. Brain Stimulation, 6(5), 798–804.CrossRefPubMedGoogle Scholar
  24. Kroemer, N. B., Guevara, A., Vollstädt-Klein, S., & Smolka, M. N. (2013). Nicotine alters food-cue reactivity via networks extending from the hypothalamus. Neuropsychopharmacology, 38(11), 2307–2314.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Laqua, R., Leutzow, B., Wendt, M., & Usichenko, T. (2014). Transcutaneous vagal nerve stimulation may elicit anti- and pro-nociceptive effects under experimentally-induced pain - a crossover placebo-controlled investigation. Autonomic Neuroscience, 185(10), 120–122.CrossRefPubMedGoogle Scholar
  26. Lehéricy, S., Ducros, M., Van de Moortele, P. F., Francois, C., Thivard, L., Poupon, C., et al. (2004). Diffusion tensor fiber tracking shows distinct corticostriatal circuits in humans. Annals of Neurology, 55(4), 522–529.CrossRefPubMedGoogle Scholar
  27. Leutzow, B., Lange, J., Gibb, A., Schroeder, H., Nowak, A., Wendt, M., & Usichenko, T. I. (2013). Vagal sensory evoked potentials disappear under the neuromuscular block – an experimental study. Brain Stimulation, 6(5), 812–816.CrossRefPubMedGoogle Scholar
  28. Lickteig, R., Lotze, M., & Kordass, B. (2013). Successful therapy for temporomandibular pain alters anterior insula and cerebellar representations of occlusion. Cephalgia, 33(15), 1248–1257.CrossRefGoogle Scholar
  29. Multon, S., & Schoenen, J. (2005). Pain control by vagus nerve stimulation: from animal to man…and back. Acta Neurologica Belgica, 105(2), 62–67.PubMedGoogle Scholar
  30. Naccache, L., Dehaene, S., Cohen, L., Habert, M. O., Guichart-Gomez, E., Galanaud, D., & Willer, J. C. (2005). Effortless control: executive attention and conscious feeling of mental effort are dissociable. Neuropsychologia, 43(9), 1318–1328.CrossRefPubMedGoogle Scholar
  31. Napadow, V., Edwards, R. R., Cahalan, C. M., Mensing, G., Greenbaum, S., Valovska, A., et al. (2012). Evoked pain analgesia in chronic pelvic pain patients using respiratory-gated auricular vagal afferent nerve stimulation. Pain Medicine, 13(6), 777–789.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Nomura, S., & Mizuno, N. (1984). Central distribution of primary afferent fibers in the Arnold’s nerve (the auricular branch of the vagus nerve): a transganglionic HRP study in the cat. Brain Research, 292(2), 199–205.CrossRefPubMedGoogle Scholar
  33. Ossipov, M. H., Dussor, G. O., & Porreca, F. (2010). Central modulation of pain. The Journal of Clinical Investigation, 120(11), 3779–3787.CrossRefPubMedPubMedCentralGoogle Scholar
  34. PATHWAY Pain & Sensory Evaluation System. (2008). System Overview (8th ed., p. 17). Israel: Medoc Ltd.Google Scholar
  35. Peuker, E. T., & Filler, T. J. (2002). Nerve supply of the human auricle. Clinical Anatomy, 15(1), 35–37.CrossRefPubMedGoogle Scholar
  36. Randich, A., Ren, K., & Gebhart, G. F. (1990). Electrical stimulation of cervical vagal afferents. II. Central relays for behavioral antinociception and arterial blood pressure decreases. Journal of Neurophysiology, 64(4), 1115–1124.PubMedGoogle Scholar
  37. Rinaman, L. (2010). Ascending projections from the caudal visceral nucleus of the solitary tract to brain regions involved in food intake and energy expenditure. Brain Research, 1350(9), 18–34.CrossRefPubMedPubMedCentralGoogle Scholar
  38. Romoli, M., Allais, G., Airola, G., Benedetto, C., Mana, O., Giacobbe, M., et al. (2014). Ear acupuncture and fMRI: a pilot study for assessing the specificity of auricular points. Neurological Sciences, 35(S1), 189–193.CrossRefPubMedGoogle Scholar
  39. Seifert, F., Bschorer, K., De Col, R., Filitz, J., Peltz, E., Koppert, W., & Maihöfner, C. (2009). Medial prefrontal cortex activity is predictive for hyperalgesia and pharmacological antihyperalgesia. The Journal of Neuroscience, 29(19), 6167–6175.CrossRefPubMedGoogle Scholar
  40. Tzourio-Mazoyer, N., Landeau, B., Papathanassiou, D., Crivello, F., Etard, O., Delcroix, N., et al. (2002). Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject. NeuroImage, 15(1), 273–289.CrossRefPubMedGoogle Scholar
  41. Ventureyra, E. C. (2000). Transcutaneous vagus nerve stimulation for partial onset seizure therapy. A new concept. Child Nerv Syst, 16(2), 101–102.CrossRefGoogle Scholar
  42. Ziv, M., Tomer, R., Defrin, R., & Hendler, T. (2010). Individual sensitivity to pain expectancy is related to differential activation of the hippocampus and amygdala. Human Brain Mapping, 31(2), 326–338.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Anesthesiology, Intensive Care Medicine, Emergency Medicine and Pain MedicineUniversity Medicine GreifswaldGreifswaldGermany
  2. 2.Institute of Diagnostic and Interventional NeuroradiologyUniversity Hospital BernBernSwitzerland
  3. 3.Institute for Diagnostic Radiology and NeuroradiologyUniversity Medicine GreifswaldGreifswaldGermany

Personalised recommendations