Flat electrode contacts for vagus nerve stimulation

Autoři: Jesse E. Bucksot aff001;  Andrew J. Wells aff001;  Kimiya C. Rahebi aff002;  Vishnoukumaar Sivaji aff001;  Mario Romero-Ortega aff001;  Michael P. Kilgard aff001;  Robert L. Rennaker, II aff001;  Seth A. Hays aff001
Působiště autorů: The University of Texas at Dallas, Erik Jonsson School of Engineering and Computer Science, Richardson, Texas, United States of America aff001;  Texas Biomedical Device Center, Richardson, Texas, United States of America aff002;  The University of Texas at Dallas, School of Behavioral Brain Sciences, Richardson, Texas, United States of America aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0215191


The majority of available systems for vagus nerve stimulation use helical stimulation electrodes, which cover the majority of the circumference of the nerve and produce largely uniform current density within the nerve. Flat stimulation electrodes that contact only one side of the nerve may provide advantages, including ease of fabrication. However, it is possible that the flat configuration will yield inefficient fiber recruitment due to a less uniform current distribution within the nerve. Here we tested the hypothesis that flat electrodes will require higher current amplitude to activate all large-diameter fibers throughout the whole cross-section of a nerve than circumferential designs. Computational modeling and in vivo experiments were performed to evaluate fiber recruitment in different nerves and different species using a variety of electrode designs. Initial results demonstrated similar fiber recruitment in the rat vagus and sciatic nerves with a standard circumferential cuff electrode and a cuff electrode modified to approximate a flat configuration. Follow up experiments comparing true flat electrodes to circumferential electrodes on the rabbit sciatic nerve confirmed that fiber recruitment was equivalent between the two designs. These findings demonstrate that flat electrodes represent a viable design for nerve stimulation that may provide advantages over the current circumferential designs for applications in which the goal is uniform activation of all fascicles within the nerve.

Klíčová slova:

Axons – Curve fitting – Functional electrical stimulation – Medical implants – Nerve fibers – Nerves – Rabbits – Sciatic nerves


1. Handforth A, DeGiorgio CM, Schachter SC, Uthman BM, Naritoku DK, Tecoma ES, et al. Vagus nerve stimulation therapy for partial-onset seizures. A randomized active-control trial. Neurology [Internet]. 1998;51(1):48–55. Available from: http://n.neurology.org/content/51/1/48 doi: 10.1212/wnl.51.1.48 9674777

2. Kimberley TJ, Pierce D, Prudente CN, Francisco GE, Yozbatiran N, Smith P, et al. Vagus Nerve Stimulation Paired With Upper Limb Rehabilitation After Chronic Stroke. Stroke. 2018;49:1–4.

3. De Ridder D, Vanneste S, Engineer ND, Kilgard MP. Safety and efficacy of vagus nerve stimulation paired with tones for the treatment of tinnitus: A case series. Neuromodulation Technol Neural Interface. 2014;17(2):170–9.

4. Tassorelli C, Grazzi L, de Tommaso M, Pierangeli G, Martelletti P, Rainero I, et al. Noninvasive vagus nerve stimulation as acute therapy for migraine. Neurology [Internet]. 2018;91(4):364–73. Available from: http://www.neurology.org/lookup/doi/10.1212/WNL.0000000000005857

5. Koopman FA, Chavan SS, Miljko S, Grazio S, Sokolovic S, Schuurman PR. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. PNAS. 2016;113(29).

6. Birmingham K, Gradinaru V, Anikeeva P, Grill WM, Pikov V, Mclaughlin B, et al. Bioelectronic medicines: a research roadmap. Nat Rev Drug Discov [Internet]. 2014;13. Available from: http://dx.doi.org/10.1038/

7. Yuan H, Silberstein SD. Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part III. Headache. 2015;56:479–90. doi: 10.1111/head.12649 26364805

8. Hamdi H, Spatola G, Lagarde S, Mcgonigal A, Paz-Paredes A, Bizeau A, et al. Use of Polyvinyl Alcohol Sponge Cubes for Vagal Nerve Stimulation: A Suggestion for the Wrapping. Oper Neurosurg. 2019;0(0):1–9.

9. Tan D, Schiefer M, Keith MW, Anderson R, Tyler DJ. Stability and selectivity of a chronic, multi-contact cuff electrode for sensory stimulation in a human amputee. J Neural Eng. 2015;12:859–62.

10. Boretius T, Badia J, Pascual-Font A, Schuettler M, Navarro X, Yoshida K, et al. A transverse intrafascicular multichannel electrode (TIME) to interface with the peripheral nerve. Biosens Bioelectron [Internet]. 2010;26(1):62–9. Available from: doi: 10.1016/j.bios.2010.05.010 20627510

11. Badia J, Boretius T, Andreu D, Azevedo-Coste C, Stieglitz T, Navarro X. Comparative analysis of transverse intrafascicular multichannel, longitudinal intrafascicular and multipolar cuff electrodes for the selective stimulation of nerve fascicles. J Neural Eng. 2011;8(3).

12. Aristovich K, Donega M, Fjordbakk C, Tarotin I, Christopher A, Chapman R, et al. Complete optimisation and in-vivo validation of the spatially selective multielectode array for vagus nerve neuromodulation. arXiv. 2018;1903.12459.

13. Mourdoukoutas AP, Truong DQ, Adair DK, Simon BJ, Bikson M. High-Resolution Multi-Scale Computational Model for Non-Invasive Cervical Vagus Nerve Stimulation. Neuromodulation Technol Neural Interface [Internet]. 2018;21(3). Available from: http://doi.wiley.com/10.1111/ner.12706

14. Helmers SL, Begnaud J, Cowley A, Corwin HM, Edwards JC, Holder DL, et al. Application of a computational model of vagus nerve stimulation. Acta Neurol Scand. 2012;126(5):336–43. doi: 10.1111/j.1600-0404.2012.01656.x 22360378


16. Woodbury JW, Woodbury DM. Vagal Stimulation Reduces the Severity of Maximal Electroshock Seizures in Intact Rats: Use of a Cuff Electrode for Stimulating and Recording. Pacing Clin Electrophysiol. 1991;14(1):94–107. doi: 10.1111/j.1540-8159.1991.tb04053.x 1705342

17. Varejão ASP, Cabrita AM, Meek MF, Bulas-Cruz J, Melo-Pinto P, Raimondo S, et al. Functional and Morphological Assessment of a Standardized Rat Sciatic Nerve Crush Injury with a Non-Serrated Clamp. J Neurotrauma [Internet]. 2004;21(11):1652–70. Available from: doi: 10.1089/neu.2004.21.1652 15684656

18. Grinberg Y, Schiefer MA, Tyler DJ, Gustafson KJ. Fascicular perineurium thickness, size, and position affect model predictions of neural excitation. IEEE Trans Neural Syst Rehabil Eng. 2008;16(6):572–81. doi: 10.1109/TNSRE.2008.2010348 19144589

19. Yoo PB, Lubock NB, Hincapie JG, Ruble SB, Hamann JJ, Grill WM. High-resolution measurement of electrically-evoked vagus nerve activity in the anesthetized dog. J Neural Eng. 2013;10(2).

20. Somann JP, Albors GO, Neihouser K V., Lu KH, Liu Z, Ward MP, et al. Chronic cuffing of cervical vagus nerve inhibits efferent fiber integrity in rat model. J Neural Eng. 2018;15(3).

21. Islam MS, Oliveira MC, Wang Y, Henry FP, Randolph MA, Park BH, et al. Extracting structural features of rat sciatic nerve using polarization-sensitive spectral domain optical coherence tomography. J Biomed Opt [Internet]. 2012;17(5):056012. Available from: http://biomedicaloptics.spiedigitallibrary.org/article.aspx?doi=10.1117/1.JBO.17.5.056012 22612135

22. Tyler DJ, Durand DM. Functionally selective peripheral nerve stimulation with a flat interface nerve electrode. IEEE Trans Neural Syst Rehabil Eng. 2002;10(4):294–303. doi: 10.1109/TNSRE.2002.806840 12611367

23. Veltink PH, Van Veen BK, Struijk JJ, Holsheimer J, Boom HBK. A Modeling Study of Nerve Fascicle Stimulation. IEEE Trans Biomed Eng. 1989;36(7):683–92. doi: 10.1109/10.32100 2744792

24. Goodall E V., Kosterman LM, Holsheimer J, Struijk JJ. Modeling Study of Activation and Propagation Delays During Stimulation of Peripheral Nerve Fibers with a Tripolar Cuff Electrode. IEEE Trans Rehabil Eng. 1995;3(3):272–82.

25. Frieswijk TA, Smit JPA, Rutten WLC, Boom HBK. Force-current relationships in intraneural stimulation: Role of extraneural medium and motor fibre clustering. Med Biol Eng Comput. 1998;36(4):422–9. doi: 10.1007/bf02523209 10198524

26. Arle JE, Carlson KW, Mei L. Investigation of mechanisms of vagus nerve stimulation for seizure using finite element modeling. Epilepsy Res [Internet]. 2016;126:109–18. Available from: doi: 10.1016/j.eplepsyres.2016.07.009 27484491

27. McIntyre CC, Richardson AG, Grill WM. Modeling the Excitability of Mammalian Nerve Fibers: Influence of Afterpotentials on the Recovery Cycle. J Neurophysiol [Internet]. 2002;87(2):995–1006. Available from: doi: 10.1152/jn.00353.2001 11826063

28. Ikeda M, Oka Y. The relationship between nerve conduction velocity and fiber morphology during peripheral nerve regeneration. Brain Behav. 2012;2(4):382–90. doi: 10.1002/brb3.61 22950042

29. Germana G, Muglia U, Santoro M, Abbate F, Laura R, Gugliotta MA, et al. Morphometric analysis of sciatic nerve and its main branches in the rabbit. Biol Struct Morphog [Internet]. 1992;4(1):11–5. Available from: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1420593 1420593

30. Chang R, Strochlic D, Williams E, Umans B, Liberles S. Vagal Sensory Neuron Subtypes that Differentially Control Breathing. Cell. 2015;161(3):622–33. doi: 10.1016/j.cell.2015.03.022 25892222

31. McAllen RM, Shafton AD, Bratton BO, Trevaks D, Furness JB. Calibration of thresholds for functional engagement of vagal A, B and C fiber groups in vivo. Bioelectron Med. 2018;1(1):21–7.


33. Hursh JB. Conduction Velocity and Diameter of Nerve Fibers. Am J Physiol. 1939;127(1):131–9.

34. Rios MU, Bucksot JE, Rahebi KC, Engineer CT, Michael P. Protocol for Construction of Rat Nerve Stimulation Cuff Electrodes. Methods Protoc. 2019;2(19):1–27.

35. Sivaji V, Grasse DW, Hays SA, Kilgard MP, Rennaker RL, Bucksot JE, et al. ReStore: A wireless peripheral nerve stimulation system. J Neurosci Methods [Internet]. 2019;320(January):26–36. Available from: https://doi.org/10.1016/j.jneumeth.2019.02.010

36. Branner A, Stein RB, Fernandez E, Aoyagi Y, Normann RA. Long-Term Stimulation and Recording with a Penetrating Microelectrode Array in Cat Sciatic Nerve. IEEE Trans Biomed Eng. 2004;51(1):146–57. doi: 10.1109/TBME.2003.820321 14723504

37. Borland MS, Vrana WA, Moreno NA, Fogarty EA, Buell EP, Sharma P, et al. Cortical Map Plasticity as a Function of Vagus Nerve Stimulation Intensity. Brain Stimul. 2016;9(1):117–23. doi: 10.1016/j.brs.2015.08.018 26460200

38. Ganzer PD, Darrow MJ, Meyers EC, Solorzano BR, Ruiz AD, Robertson NM, et al. Closed-loop neuromodulation restores network connectivity and motor control after spinal cord injury. Elife [Internet]. 2018;7:1–19. Available from: https://elifesciences.org/articles/32058

39. Loerwald KW, Borland MS, Rennaker RL, Hays SA, Kilgard MP. The interaction of pulse width and current intensity on the extent of cortical plasticity evoked by vagus nerve stimulation. Brain Stimul [Internet]. 2017;11(2):271–7. Available from: doi: 10.1016/j.brs.2017.11.007 29174302

40. Hammer N, Löffler S, Cakmak YO, Ondruschka B, Planitzer U, Schultz M, et al. Cervical vagus nerve morphometry and vascularity in the context of nerve stimulation—A cadaveric study. Sci Rep [Internet]. 2018;8(1):7997. Available from: http://www.nature.com/articles/s41598-018-26135-8 doi: 10.1038/s41598-018-26135-8 29789596

41. Cogan SF. Neural Stimulation and Recording Electrodes. Annu Rev Biomed Eng [Internet]. 2008;10:275–309. Available from: www.annualreviews.org doi: 10.1146/annurev.bioeng.10.061807.160518 18429704

42. Ben‐Menachem E, Mañon‐Espaillat R, Ristanovic R, Wilder BJ, Stefan H, Mirza W, et al. Vagus Nerve Stimulation for Treatment of Partial Seizures: 1. A Controlled Study of Effect on Seizures. Epilepsia. 1994;35(3):616–26. doi: 10.1111/j.1528-1157.1994.tb02482.x 8026408

43. Kent AR, Grill WM. Model-based analysis and design of nerve cuff electrodes for restoring bladder function by selective stimulation of the pudendal nerve. J Neural Eng. 2013;10(3).

44. Qing KY, Wasilczuk KM, Ward MP, Phillips EH, Vlachos PP, Goergen CJ, et al. B fibers are the best predictors of cardiac activity during Vagus nerve stimulation. Bioelectron Med. 2018;4(5):1–11.

45. Cheung KC. Implantable microscale neural interfaces. Biomed Microdevices. 2007;9:923–38. doi: 10.1007/s10544-006-9045-z 17252207

46. Clark KB, Krahl SE, Smith DC, Jensen RA. Post-training unilateral vagal stimulation enhances retention performance in the rat. Vol. 63, Neurobiology of Learning and Memory. 1995. p. 213–6. doi: 10.1006/nlme.1995.1024 7670833

47. Clark KB, Smith DC, Hassert DL, Browning RA, Naritoku DK, Jensen RA. Posttraining Electrical Stimulation of Vagal Afferents with Concomitant Vagal Efferent Inactivation Enhances Memory Storage Processes in the Rat. Neurobiol Learn Mem. 1998;70(3):364–73. doi: 10.1006/nlme.1998.3863 9774527

48. Clark KB, Naritoku DK, Smith DC, Browning RA, Jensen RA. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nat Neurosci [Internet]. 1999;2(1):94–8. Available from: http://neurosci.nature.com doi: 10.1038/4600 10195186

49. Zuo Y, Smith DC, Jensen RA. Vagus nerve stimulation potentiates hippocampal LTP in freely-moving rats. Physiol Behav [Internet]. 2007;90:583–9. Available from: https://ac.els-cdn.com/S0031938406004963/1-s2.0-S0031938406004963-main.pdf?_tid=9a134a03-79fd-4530-8d64-e33eecd8ddf7&acdnat=1534354220_560f2f94ec5032890fbe8a759e9cf349 doi: 10.1016/j.physbeh.2006.11.009 17207505

50. Urban B, Jr NB. Combined epidural and peripheral nerve stimulation for relief of pain. Description of technique and preliminary results. J Neurosurg. 1982;57(3):365–9. doi: 10.3171/jns.1982.57.3.0365 6212652

51. Horch K, Member S, Meek S, Taylor TG, Hutchinson DT. Object Discrimination With an Artificial Hand Using Electrical Stimulation of Peripheral Tactile and Proprioceptive Pathways With Intrafascicular Electrodes. IEEE Trans Neural Syst Rehabil Eng. 2011;19(5):483–9. doi: 10.1109/TNSRE.2011.2162635 21859607

52. Strege DW, Cooney WP, Wood MB, Johnson SJ, Metcalf BJ. Chronic Peripheral Nerve Pain Treated With Direct Electrical Nerve Stimulation. J Hand Surg Am. 1994;19(6):931–9. doi: 10.1016/0363-5023(94)90092-2 7876491

53. Kapural L, Mekhail N, Hayek S, Stanton-Hicks M, Malak O. Occipital nerve electrical stimulation via the midline approach and subcutaneous surgical leads for treatment of severe occipital neuralgia: a pilot study. Anesth Analg. 2005;101(1):171–4. doi: 10.1213/01.ANE.0000156207.73396.8E 15976227

54. Cogan SF, Ludwig KA, Welle CG, Takmakov P. Tissue damage thresholds during therapeutic electrical stimulation. J Neural Eng. 2016;13(021001).

55. Hammer N, Glätzner J, Feja C, Kühne C, Meixensberger J, Planitzer U, et al. Human vagus nerve branching in the cervical region. PLoS One. 2015;10(2).

56. McCreery DB, Agnew WF, Yuen TGH, Bullara LA. Relationship between stimulus amplitude, stimulus frequency and neural damage during electrical stimulation of sciatic nerve of cat. Med Biol Eng Comput. 1995;33:426–9. doi: 10.1007/bf02510526 7666690

Článek vyšel v časopise


2019 Číslo 11