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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 Engineering volume 2, pages 907–914 (2018)Cite this article

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Abstract

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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Fig. 1: Delivery of the Stentrode to the motor cortex.
Fig. 2: Effect of electrode placement on the stimulation-induced response.
Fig. 3: Somatotopy of endovascular, subdural and penetrating cortical stimulation.
Fig. 4: Effect of orientation on electrode efficacy.

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Data availability

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

References

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

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

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

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    PubMed  Google Scholar 

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

  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).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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. 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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

  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).

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

  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).

    Article  Google Scholar 

  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. https://doi.org/10.1111/pace.13371 (2018).

  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).

    Article  Google Scholar 

  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).

    Article  Google Scholar 

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

    Article  Google Scholar 

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

    Article  Google Scholar 

  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).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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Acknowledgements

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.

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Author notes

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

Authors and Affiliations

  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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Contributions

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.

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Correspondence to Nicholas L. Opie.

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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.

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Supplementary Video 1

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

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Opie, N.L., John, S.E., Rind, G.S. et al. Focal stimulation of the sheep motor cortex with a chronically implanted minimally invasive electrode array mounted on an endovascular stent. Nat Biomed Eng 2, 907–914 (2018). https://doi.org/10.1038/s41551-018-0321-z

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