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Focal stimulation of the sheep motor cortex with a chronically implanted minimally invasive electrode array mounted on an endovascular stent

Nature Biomedical Engineeringvolume 2pages907914 (2018) | Download Citation


Direct electrical stimulation of the brain can alleviate symptoms associated with Parkinson’s disease, depression, epilepsy and other neurological disorders. However, access to the brain requires invasive procedures, such as the removal of a portion of the skull or the drilling of a burr hole. Also, electrode implantation into tissue can cause inflammatory tissue responses and brain trauma, and lead to device failure. Here, we report the development and application of a chronically implanted platinum electrode array mounted on a nitinol endovascular stent for the localized stimulation of cortical tissue from within a blood vessel. Following percutaneous angiographic implantation of the device in sheep, we observed stimulation-induced responses of the facial muscles and limbs of the animals, similar to those evoked by electrodes implanted via invasive surgery. Proximity of the electrode to the motor cortex, yet not its orientation, was integral to achieving reliable responses from discrete neuronal populations. The minimally invasive endovascular surgical approach offered by the stent-mounted electrode array might enable safe and efficacious stimulation of focal regions in the brain.

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The datasets generated and analysed during the study are available from the corresponding author upon reasonable request.

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  1. 1.

    Wilson, B. S. et al. Better speech recognition with cochlear implants. Nature 352, 236–238 (1991).

  2. 2.

    Opie, N. L. et al. Optical coherence tomography-guided retinal prosthesis design: model of degenerated retinal curvature and thickness for patient-specific devices. Artif. Organs 38, E82–E94 (2014).

  3. 3.

    Weiland, J. D., Cho, A. K. & Humayun, M. S. Retinal prostheses: current clinical results and future needs. Ophthalmology 118, 2227–2237 (2011).

  4. 4.

    Deuschl, G. et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N. Engl. J. Med. 355, 896–908 (2006).

  5. 5.

    Mayberg, H. S. et al. Deep brain stimulation for treatment-resistant depression. Neuron 45, 651–660 (2005).

  6. 6.

    Cook, M. J. et al. Prediction of seizure likelihood with a long-term, implanted seizure advisory system in patients with drug-resistant epilepsy: a first-in-man study. Lancet Neurol. 12, 563–571 (2013).

  7. 7.

    Theodore, W. H. & Fisher, R. S. Brain stimulation for epilepsy. Lancet Neurol. 3, 111–118 (2004).

  8. 8.

    Morrell, M. J. et al. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology 77, 1295–1304 (2011).

  9. 9.

    Fisher, R. et al. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 51, 899–908 (2010).

  10. 10.

    Hochberg, L. R. et al. Reach and grasp by people with tetraplegia using a neurally controlled robotic arm. Nature 485, 372–375 (2012).

  11. 11.

    Wang, W. et al. An electrocorticographic brain interface in an individual with tetraplegia. PLoS ONE 8, e55344 (2013).

  12. 12.

    Yanagisawa, T. et al. Electrocorticographic control of a prosthetic arm in paralyzed patients. Ann. Neurol. 71, 353–361 (2012).

  13. 13.

    Hamer, H. M. et al. Complications of invasive video-EEG monitoring with subdural grid electrodes. Neurology 58, 97–103 (2002).

  14. 14.

    Tebo, C. C., Evins, A. I., Christos, P. J., Kwon, J. & Schwartz, T. H. Evolution of cranial epilepsy surgery complication rates: a 32-year systematic review and meta-analysis. J. Neurosurg. 120, 1415–1427 (2014).

  15. 15.

    Nowinski, W. L. et al. Simulation and assessment of cerebrovascular damage in deep brain stimulation using a stereotactic atlas of vasculature and structure derived from multiple 3- and 7-tesla scans. J. Neurosurg. 113, 1234–1241 (2010).

  16. 16.

    Ben-Haim, S., Asaad, W. F., Gale, J. T. & Eskandar, E. N. Risk factors for hemorrhage during microelectrode-guided deep brain stimulation and the introduction of an improved microelectrode design. Neurosurgery 64, 754–762 (2009); discussion 64, 762–753 (2009).

  17. 17.

    Cardinale, F. et al. Stereoelectroencephalography: surgical methodology, safety, and stereotactic application accuracy in 500 procedures. Neurosurgery 72, 353–366 (2013); discussion 72, 366 (2013).

  18. 18.

    Bronstein, J. M. et al. Deep brain stimulation for Parkinson disease: an expert consensus and review of key issues. Arch. Neurol. 68, 165 (2011).

  19. 19.

    Lyons, K. E., Wilkinson, S. B., Overman, J. & Pahwa, R. Surgical and hardware complications of subthalamic stimulation: a series of 160 procedures. Neurology 63, 612–616 (2004).

  20. 20.

    Boviatsis, E. J., Stavrinou, L. C., Themistocleous, M., Kouyialis, A. T. & Sakas, D. E. Surgical and hardware complications of deep brain stimulation. A seven-year experience and review of the literature. Acta Neurochir. (Wien) 152, 2053–2062 (2010).

  21. 21.

    Grill, W. M. Safety considerations for deep brain stimulation: review and analysis. Expert Rev. Med. Devices 2, 409–420 (2005).

  22. 22.

    Koller, W. C., Lyons, K. E., Wilkinson, S. B., Troster, A. I. & Pahwa, R. Long-term safety and efficacy of unilateral deep brain stimulation of the thalamus in essential tremor. Mov. Disord. 16, 464–468 (2001).

  23. 23.

    Oh, M. Y., Abosch, A., Kim, S. H., Lang, A. E. & Lozano, A. M. Long-term hardware-related complications of deep brain stimulation. Neurosurgery 50, 1268–1274 (2002).

  24. 24.

    Summary of Safety and Effectiveness Data: Activa Parkinson’s Control Therapy Activa PMA P960009 (FDA, 1997).

  25. 25.

    Polikov, V. S., Tresco, P. A. & Reichert, W. M. Response of brain tissue to chronically implanted neural electrodes. J. Neurosci. Methods 148, 1–18 (2005).

  26. 26.

    Saxena, T. et al. The impact of chronic blood–brain barrier breach on intracortical electrode function. Biomaterials 34, 4703–4713 (2013).

  27. 27.

    Butson, C. R., Maks, C. B. & McIntyre, C. C. Sources and effects of electrode impedance during deep brain stimulation. Clin. Neurophysiol. 117, 447–454 (2006).

  28. 28.

    Freeman, W. J., Rogers, L. J., Holmes, M. D. & Silbergeld, D. L. Spatial spectral analysis of human electrocorticograms including the alpha and gamma bands. J. Neurosci. Methods 95, 111–121 (2000).

  29. 29.

    Staba, R. J., Wilson, C. L., Bragin, A., Fried, I. & Engel, J. Jr Quantitative analysis of high-frequency oscillations (80–500 Hz) recorded in human epileptic hippocampus and entorhinal cortex. J. Neurophysiol. 88, 1743–1752 (2002).

  30. 30.

    Ball, T., Kern, M., Mutschler, I., Aertsen, A. & Schulze-Bonhage, A. Signal quality of simultaneously recorded invasive and non-invasive EEG. Neuroimage 46, 708–716 (2009).

  31. 31.

    Schwartz, A. B., Cui, X. T., Weber, D. J. & Moran, D. W. Brain-controlled interfaces: movement restoration with neural prosthetics. Neuron 52, 205–220 (2006).

  32. 32.

    Watanabe, H., Takahashi, H., Nakao, M., Walton, K. & Llinas, R. R. Intravascular neural interface with nanowire electrode. Electron. Commun. Jpn 92, 29–37 (2009).

  33. 33.

    Kunieda, T. et al. Use of cavernous sinus EEG in the detection of seizure onset and spread in mesial temporal lobe epilepsy. Epilepsia 41, 1411–1419 (2000).

  34. 34.

    Stoeter, P., Dieterle, L., Meyer, A. & Prey, N. Intracranial electroencephalographic and evoked-potential recording from intravascular guide wires. Am. J. Neuroradiol. 16, 1214–1217 (1995).

  35. 35.

    Penn, R. D., Hilal, S. K., Michelsen, W. J., Goldensohn, E. S. & Driller, J. Intravascular intracranial EEG recording. Technical note. J. Neurosurg. 38, 239–243 (1973).

  36. 36.

    Ahmed, R. M. et al. Transverse sinus stenting for idiopathic intracranial hypertension: a review of 52 patients and of model predictions. Am. J. Neuroradiol. 32, 1408–1414 (2011).

  37. 37.

    Puffer, R. C., Mustafa, W. & Lanzino, G. Venous sinus stenting for idiopathic intracranial hypertension: a review of the literature. J. Neurointerv. Surg. 5, 483–486 (2013).

  38. 38.

    Oxley, T. J. et al. Minimally invasive endovascular stent-electrode array for high-fidelity, chronic recordings of cortical neural activity. Nat. Biotechnol. 34, 320–327 (2016).

  39. 39.

    Bower, M. R. et al. Intravenous recording of intracranial, broadband EEG. J. Neurosci. Methods 214, 21–26 (2013).

  40. 40.

    Opie, N. L. et al. Chronic impedance spectroscopy of an endovascular stent-electrode array. J. Neural Eng. 13, 046020 (2016).

  41. 41.

    Opie, N. L. et al. Micro-CT and histological evaluation of an neural interface implanted within a blood vessel. IEEE Trans. Biomed. Eng. 64, 928–934 (2017).

  42. 42.

    Opie, N. L. et al. Feasibility of a chronic, minimally invasive endovascular neural interface. In 38th Annual International Conference of the IEEE Engineering in Medicine and Biology Society 4455–4458 (IEEE, 2016).

  43. 43.

    Teplitzky, B. A., Connolly, A. T., Bajwa, J. A. & Johnson, M. D. Computational modeling of an endovascular approach to deep brain stimulation. J. Neural Eng. 11, 026011 (2014).

  44. 44.

    Liyanage, K. A. et al. Development and implementation of a corriedale ovine brain atlas for use in atlas-based segmentation. PLoS ONE 11, e0155974 (2016).

  45. 45.

    Oxley, T. J. et al. An ovine model of cerebral catheter venography for implantation of an endovascular neural interface. J. Neurosurg. 128, 1020–1027 (2018).

  46. 46.

    Awan, N. R., Lozano, A. & Hamani, C. Deep brain stimulation: current and future perspectives. Neurosurg. Focus 27, E2 (2009).

  47. 47.

    Lyons, M. K. Deep brain stimulation: current and future clinical applications. Mayo Clin. Proc. 86, 662–672 (2011).

  48. 48.

    Tierney, T. S., Sankar, T. & Lozano, A. M. Deep brain stimulation emerging indications. Prog. Brain Res. 194, 83–95 (2011).

  49. 49.

    Hauptman, J. S., DeSalles, A. A., Espinoza, R., Sedrak, M. & Ishida, W. Potential surgical targets for deep brain stimulation in treatment-resistant depression. Neurosurg. Focus 25, E3 (2008).

  50. 50.

    Benabid, A. L. & Torres, N. New targets for DBS. Parkinsonism Relat. Disord. 18 (Suppl. 1), S21–S23 (2012).

  51. 51.

    Mallet, L. et al. Subthalamic nucleus stimulation in severe obsessive-compulsive disorder. N. Engl. J. Med. 359, 2121–2134 (2008).

  52. 52.

    John, S. E. et al. The ovine motor cortex: a review of functional mapping and cytoarchitecture. Neurosci. Biobehav. Rev. 80, 306–315 (2017).

  53. 53.

    Dexler, H. & Margulies, A. Über die pyramidenbahn des schafes und der ziege. Gegenbaurs Morphol. Jahrb. 35, 413–449 (1906).

  54. 54.

    Ebinger, P. A cytoarchitectonic volumetric comparison of the area gigantopyramidalis in wild and domestic sheep. Anat. Embryol. (Berl.) 147, 167–175 (1975).

  55. 55.

    Lewis, B. On the comparative structure of the cortex cerebri. Proc. R. Soc. Lond. 29, 234–237 (1879).

  56. 56.

    Rose, J. E. A cytoarchitectural study of the sheep cortex. J. Comp. Neurol. 76, 1–55 (1942).

  57. 57.

    Klug, D. et al. Risk factors related to infections of implanted pacemakers and cardioverter-defibrillators: results of a large prospective study. Circulation 116, 1349–1355 (2007).

  58. 58.

    de Vries, L. M. et al. Trends in replacement of pacemaker leads in the Netherlands: a long-term nationwide follow-up study. Pacing Clin. Electrophysiol. (2018).

  59. 59.

    Bundy, D. T. et al. Characterization of the effects of the human dura on macro- and micro-electrocorticographic recordings. J. Neural Eng. 11, 016006 (2014).

  60. 60.

    Torres Valderrama, A., Oostenveld, R., Vansteensel, M. J., Huiskamp, G. M. & Ramsey, N. F. Gain of the human dura in vivo and its effects on invasive brain signal feature detection. J. Neurosci. Methods 187, 270–279 (2010).

  61. 61.

    Slutzky, M. W. et al. Optimal spacing of surface electrode arrays for brain-machine interface applications. J. Neural Eng. 7, 026004 (2010).

  62. 62.

    John, S. E. et al. Signal quality of simultaneously recorded endovascular, subdural and epidural signals are comparable. Sci. Rep. 8, 8427 (2018).

  63. 63.

    King, J. L. The pyramid tract and other descending paths in the spinal cord of the sheep. Q. J. Exp. Physiol. 4, 133–149 (1911).

  64. 64.

    Murray, E. A. & Coulter, J. D. Organization of corticospinal neurons in the monkey. J. Comp. Neurol. 195, 339–365 (1981).

  65. 65.

    Nudo, R. J. & Masterton, R. B. Descending pathways to the spinal cord, III: Sites of origin of the corticospinal tract. J. Comp. Neurol. 296, 559–583 (1990).

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This research was supported by the following grants: US Defense Advanced Research Projects Agency (DARPA) Microsystems Technology Office contract N66001-12-1-4045; Office of Naval Research (ONR) Global N62909-14-1-N020; National Health and Medical Research Council of Australia (NHMRC) Project Grant APP1062532. N.L.O. acknowledges the support of Westpac for the Bicentennial Research Fellowship.

Author information

Author notes

  1. These authors contributed equally: Nicholas L. Opie, Sam E. John.


  1. Vascular Bionics Laboratory, Department of Medicine (Royal Melbourne Hospital), University of Melbourne, Parkville, Victoria, Australia

    • Nicholas L. Opie
    • , Sam E. John
    • , Gil S. Rind
    • , Stephen M. Ronayne
    • , Yan T. Wong
    • , Giulia Gerboni
    • , Peter E. Yoo
    • , Timothy J. H. Lovell
    • , Theodore C. M. Scordas
    • , Stefan L. Wilson
    • , Terence J. O’Brien
    • , David B. Grayden
    • , Clive N. May
    •  & Thomas J. Oxley
  2. Synchron Inc., Palo Alto, CA, USA

    • Nicholas L. Opie
    • , Sam E. John
    • , Gil S. Rind
    • , Stephen M. Ronayne
    •  & Thomas J. Oxley
  3. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia

    • Nicholas L. Opie
    • , Gil S. Rind
    • , Stephen M. Ronayne
    • , Anthony Dornom
    • , Thomas Vale
    • , Clive N. May
    •  & Thomas J. Oxley
  4. Department of Biomedical Engineering, University of Melbourne, Parkville, Victoria, Australia

    • Sam E. John
    • , Giulia Gerboni
    •  & David B. Grayden
  5. Department of Physiology, Monash University, Clayton, Victoria, Australia

    • Yan T. Wong
  6. Department of Electrical and Computer Systems Engineering, Monash University, Clayton, Victoria, Australia

    • Yan T. Wong
  7. Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, Australia

    • Peter E. Yoo
  8. Department of Radiology, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria, Australia

    • Timothy J. H. Lovell


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N.L.O., S.E.J., D.B.G., T.J.H.L., C.N.M., T.J.O'Brien and T.J.Oxley designed the research. N.L.O., S.E.J., G.S.R., S.M.R., Y.T.W., G.G., C.N.M., P.E.Y., A.D., S.L.W., T.C.M.S., T.J.H.L., T.V. and T.J.Oxley performed the experiments. N.L.O., S.M.R. and G.G. fabricated the devices, and N.L.O., S.E.J., Y.T.W., S.L.W., T.C.M.S., D.B.G. and G.G. analysed the data, N.L.O. wrote the manuscript. All authors read and approved the final manuscript.

Competing interests

N.L.O., G.S.R., S.M.R., S.E.J. and T.J.Oxley. have a financial interest in Synchron Inc. All other authors have no competing interests.

Corresponding author

Correspondence to Nicholas L. Opie.

Supplementary Information

  1. Supplementary Information

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  2. Reporting Summary

  3. Supplementary Video 1

    Minimally invasive angiographic delivery and deployment of a stent electrode array to the motor cortex in sheep

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