Review Article

Glial responses to implanted electrodes in the brain

  • Nature Biomedical Engineering 1862877 (2017)
  • doi:10.1038/s41551-017-0154-1
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The use of implants that can electrically stimulate or record electrophysiological or neurochemical activity in nervous tissue is rapidly expanding. Despite remarkable results in clinical studies and increasing market approvals, the mechanisms underlying the therapeutic effects of neuroprosthetic and neuromodulation devices, as well as their side effects and reasons for their failure, remain poorly understood. A major assumption has been that the signal-generating neurons are the only important target cells of neural-interface technologies. However, recent evidence indicates that the supporting glial cells remodel the structure and function of neuronal networks and are an effector of stimulation-based therapy. Here, we reframe the traditional view of glia as a passive barrier, and discuss their role as an active determinant of the outcomes of device implantation. We also discuss the implications that this has on the development of bioelectronic medical devices.

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Change history

  • Correction 07 December 2017

    In the version of this Review Article originally published, in Fig. 4b, the label ‘Glutamate’ was mistakenly duplicated and an arrow between a purinergic P2 receptor and a glutamate transporter was missing. The figure has now been updated in all versions of the Review Article.


  1. 1.

    Kasthuri, N. & Lichtman, J. W. Neurocartography. Neuropsychopharmacology 35, 342–343 (2010).

  2. 2.

    Oberlaender, M. et al. Three-dimensional axon morphologies of individual layer 5 neurons indicate cell type-specific intracortical pathways for whisker motion and touch. Proc. Natl Acad. Sci USA 108, 4188–4193 (2011).

  3. 3.

    Kubota, Y. Untangling GABAergic wiring in the cortical microcircuit. Curr. Opin. Neurobiol. 26, 7–14 (2014).

  4. 4.

    Zhang, Y. & Barres, B. A. Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr. Opin. Neurobiol. 20, 588–594 (2010).

  5. 5.

    Miocinovic, S., Somayajula, S., Chitnis, S. & Vitek, J. L. History, applications, and mechanisms of deep brain stimulation. JAMA Neurol. 70, 163–171 (2013).

  6. 6.

    Herrington, T. M. et al. Mechanisms of deep brain stimulation. J. Neurophysiol. 115, 19–38 (2016).

  7. 7.

    Borton, D., Micera, S., Millán, J. del R. & Courtine, G. Personalized neuroprosthetics. Sci. Transl. Med. 5, 210rv2 (2013).

  8. 8.

    Jennings, J. H. & Stuber, G. D. Tools for resolving functional activity and connectivity within intact neural circuits. Curr. Biol. 24, R41–R50 (2014).

  9. 9.

    Henze, D. A. et al. Intracellular features predicted by extracellular recordings in the hippocampus in vivo. J. Neurophysiol. 84, 390–400 (2000).

  10. 10.

    Prasad, A. et al. Comprehensive characterization and failure modes of tungsten microwire arrays in chronic neural implants. J. Neural Eng. 9, 56015 (2012).

  11. 11.

    Barrese, J. C. et al. Failure mode analysis of silicon-based intracortical microelectrode arrays in non-human primates. J. Neural Eng. 10, 66014 (2013).

  12. 12.

    Ludwig, K. A. et al. Poly(3,4-ethylenedioxythiophene) (PEDOT) polymer coatings facilitate smaller neural recording electrodes. J. Neural Eng. 8, 14001 (2011).

  13. 13.

    Perge, J. A. et al. Intra-day signal instabilities affect decoding performance in an intracortical neural interface system. J. Neural Eng. 10, 36004 (2013).

  14. 14.

    Jackson, A. & Fetz, E. E. Compact movable microwire array for long-term chronic unit recording in cerebral cortex of primates. J. Neurophysiol. 98, 3109–3118 (2007).

  15. 15.

    Liu, X. et al. Stability of the interface between neural tissue and chronically implanted intracortical microelectrodes. IEEE Trans. Rehabil. Eng. 7, 315–326 (1999).

  16. 16.

    McCreery, D. B., Yuen, T. G. H., Agnew, W. F. & Bullara, L. A. A characterization of the effects on neuronal excitability due to prolonged microstimulation with chronically implanted microelectrodes. IEEE Trans. Biomed. Eng. 44, 931–939 (1997).

  17. 17.

    McCreery, D. B., Agnew, W. F. & Bullara, L. A. The effects of prolonged intracortical microstimulation on the excitability of pyramidal tract neurons in the cat. Ann. Biomed. Eng. 30, 107–119 (2002).

  18. 18.

    Prasad, A. et al. Abiotic-biotic characterization of Pt/Ir microelectrode arrays in chronic implants. Front. Neuroeng. 7, 2 (2014).

  19. 19.

    Cahoy, J. D. et al. A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J. Neurosci. 28, 264–278 (2008).

  20. 20.

    Pannasch, U. & Rouach, N. Emerging role for astroglial networks in information processing: from synapse to behavior. Trends Neurosci. 36, 405–417 (2013).

  21. 21.

    Virchow, R. Gesammelte Abhandlungen zur Wissenschaftlichen Medicin (Meidinger, Frankfurt, 1856).

  22. 22.

    Khakh, B. S. & Sofroniew, M. V. Diversity of astrocyte functions and phenotypes in neural circuits. Nat. Neurosci. 18, 942–952 (2015).

  23. 23.

    Burda, J. E., Bernstein, A. M. & Sofroniew, M. V. Astrocyte roles in traumatic brain injury. Exp. Neurol. 275, 305–315 (2016).

  24. 24.

    Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).

  25. 25.

    Sofroniew, M. V. Astrogliosis. Cold Spring Harb. Perspect. Biol. 7, a020420 (2014).

  26. 26.

    Kozai, T. D. Y., Jaquins-Gerstl, A. S., Vazquez, A. L., Michael, A. C. & Cui, X. T. Brain tissue responses to neural implants impact signal sensitivity and intervention strategies. ACS Chem. Neurosci. 6, 48–67 (2015).

  27. 27.

    Buffo, A., Rolando, C. & Ceruti, S. Astrocytes in the damaged brain: molecular and cellular insights into their reactive response and healing potential. Biochem. Pharmacol. 79, 77–89 (2010).

  28. 28.

    Kozai, T. D. Y. et al. Reduction of neurovascular damage resulting from microelectrode insertion into the cerebral cortex using in vivo two-photon mapping. J. Neural Eng. 7, 46011 (2010).

  29. 29.

    Perry, V. H. & Teeling, J. Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin. Immunopathol. 35, 601–612 (2013).

  30. 30.

    Sofroniew, M. V. Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci. 32, 638–647 (2009).

  31. 31.

    Chew, S. S. L., Johnson, C. S., Green, C. R. & Danesh-Meyer, H. V. Role of connexin43 in central nervous system injury. Exp. Neurol. 225, 250–261 (2010).

  32. 32.

    Pannasch, U. et al. Astroglial networks scale synaptic activity and plasticity. Proc. Natl Acad. Sci. USA 108, 8467–8472 (2011).

  33. 33.

    Liu, J. Y. W. et al. Neuropathology of the blood–brain barrier and pharmaco-resistance in human epilepsy. Brain 135, 3115–3133 (2012).

  34. 34.

    Kozai, T. D. Y., Eles, J. R., Vazquez, A. L. & Cui, X. T. Two-photon imaging of chronically implanted neural electrodes: sealing methods and new insights. J. Neurosci. Methods 258, 46–55 (2016).

  35. 35.

    Jorfi, M., Skousen, J. L., Weder, C. & Capadona, J. R. Progress towards biocompatible intracortical microelectrodes for neural interfacing applications. J. Neural Eng. 12, 11001 (2015).

  36. 36.

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

  37. 37.

    Nolta, N. F., Christensen, M. B., Crane, P. D., Skousen, J. L. & Tresco, P. A. BBB leakage, astrogliosis, and tissue loss correlate with silicon microelectrode array recording performance. Biomaterials 53, 753–762 (2015).

  38. 38.

    Bekar, L. et al. Adenosine is crucial for deep brain stimulation–mediated attenuation of tremor. Nat. Med. 14, 75–80 (2008).

  39. 39.

    Lempka, S. F., Miocinovic, S., Johnson, M. D., Vitek, J. L. & McIntyre, C. C. In vivo impedance spectroscopy of deep brain stimulation electrodes. J. Neural Eng. 6, 46001 (2009).

  40. 40.

    Purcell, E. K., Thompson, D. E., Ludwig, K. A. & Kipke, D. R. Flavopiridol reduces the impedance of neural prostheses in vivo without affecting recording quality. J. Neurosci. Methods 183, 149–157 (2009).

  41. 41.

    Johnson, M. D., Otto, K. J. & Kipke, D. R. Repeated voltage biasing improves unit recordings by reducing resistive tissue impedances. IEEE Trans. Neural Syst. Rehabil. Eng. 13, 160–165 (2005).

  42. 42.

    Ludwig, K. A. et al. Chronic neural recordings using silicon microelectrode arrays electrochemically deposited with a poly(3,4-ethylenedioxythiophene) (PEDOT) film. J. Neural Eng. 3, 59–70 (2006).

  43. 43.

    Prasad, A. et al. Quantifying long-term microelectrode array functionality using chronic in vivo impedance testing. J. Neural Eng. 9, 26028 (2012).

  44. 44.

    McConnell, G. C. et al. Implanted neural electrodes cause chronic, local inflammation that is correlated with local neurodegeneration. J. Neural Eng. 6, 56003 (2009).

  45. 45.

    Tawfik, V. L. et al. Deep brain stimulation results in local glutamate and adenosine release: investigation into the role of astrocytes. Neurosurgery 67, 367–375 (2010).

  46. 46.

    McAdams, E. T., Lackermeier, A., McLaughlin, J. A., Macken, D. & Jossinet, J. The linear and non-linear electrical properties of the electrode–electrolyte interface. Biosens. Bioelectron. 10, 67–74 (1995).

  47. 47.

    Mercanzini, A., Colin, P., Bensadoun, J.-C., Bertsch, A. & Renaud, P. In vivo electrical impedance spectroscopy of tissue reaction to microelectrode arrays. IEEE Trans. Biomed. Eng. 56, 1909–1918 (2009).

  48. 48.

    Kozai, T. D. Y. et al. Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces. Nat. Mater. 11, 1065–1073 (2012).

  49. 49.

    Robblee, L. S., McHardy, J., Agnew, W. F. & Bullara, L. A. Electrical stimulation with Pt electrodes. VII. Dissolution of Pt electrodes during electrical stimulation of the cat cerebral cortex. J. Neurosci. Methods 9, 301–308 (1983).

  50. 50.

    Wei, X. F. et al. Impedance characteristics of deep brain stimulation electrodes in vitro and in vivo. J. Neural Eng. 6, 46008 (2009).

  51. 51.

    Merrill, D. R., Bikson, M. & Jefferys, J. G. R. Electrical stimulation of excitable tissue: design of efficacious and safe protocols. J. Neurosci. Methods 141, 171–198 (2005).

  52. 52.

    Otto, K. J., Johnson, M. D. & Kipke, D. R. Voltage pulses change neural interface properties and improve unit recordings with chronically implanted microelectrodes. IEEE Trans. Biomed. Eng. 53, 333–340 (2006).

  53. 53.

    Keese, C. R., Wegener, J., Walker, S. R. & Giaever, I. Electrical wound-healing assay for cells in vitro. Proc. Natl Acad. Sci. USA 101, 1554–1559 (2004).

  54. 54.

    Kilgore, K. L. & Bhadra, N. Nerve conduction block utilising high-frequency alternating current. Med. Biol. Eng. Comput. 42, 394–406 (2004).

  55. 55.

    McIntyre, C. C. et al. Extracellular stimulation of central neurons: influence of stimulus waveform and frequency on neuronal output. J. Neurophysiol. 88, 1592–604 (2002).

  56. 56.

    Nowak, L. G. & Bullier, J. Axons, but not cell bodies, are activated by electrical stimulation in cortical gray matter. Exp. Brain Res. 118, 477–488 (1998).

  57. 57.

    Williams, J. C., Rennaker, R. L. & Kipke, D. R. Long-term neural recording characteristics of wire microelectrode arrays implanted in cerebral cortex. Brain Res. Protoc. 4, 303–313 (1999).

  58. 58.

    Preda, F. et al. Switching from constant voltage to constant current in deep brain stimulation: a multicenter experience of mixed implants for movement disorders. Eur. J. Neurol. 23, 190–195 (2016).

  59. 59.

    Timmermann, L. et al. Multiple-source current steering in subthalamic nucleus deep brain stimulation for Parkinson’s disease (the VANTAGE study): a non-randomised, prospective, multicentre, open-label study. Lancet Neurol. 14, 693–701 (2015).

  60. 60.

    McCreery, D. et al. Correlations between histology and neuronal activity recorded by microelectrodes implanted chronically in the cerebral cortex. J. Neural Eng. 13, 36012 (2016).

  61. 61.

    Williams, J. C., Hippensteel, J. A., Dilgen, J., Shain, W. & Kipke, D. R. Complex impedance spectroscopy for monitoring tissue responses to inserted neural implants. J. Neural Eng. 4, 410–423 (2007).

  62. 62.

    Suner, S., Fellows, M. R., Vargas-Irwin, C., Nakata, G. K. & Donoghue, J. P. Reliability of signals from a chronically implanted, silicon-based electrode array in non-human primate primary motor cortex. IEEE Trans. Neural Syst. Rehabil. Eng. 13, 524–541 (2005).

  63. 63.

    Jiang, J., Willett, F. R. & Taylor, D. M. Relationship between microelectrode array impedance and chronic recording quality of single units and local field potentials. In 2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society 3045–3048 (IEEE, 2014).

  64. 64.

    Kozai, T. D. Y. et al. Mechanical failure modes of chronically implanted planar silicon-based neural probes for laminar recording. Biomaterials 37, 25–39 (2015).

  65. 65.

    Malaga, K. A. et al. Data-driven model comparing the effects of glial scarring and interface interactions on chronic neural recordings in non-human primates. J. Neural Eng. 13, 16010 (2016).

  66. 66.

    Humphrey, D. R. & Schmidt, E. M. in Neurophysiological Techniques Vol. II (eds Boulton, A. A., Baker, G. B. & Vanderwolf, C. H.) 1–64 (Humana Press, New York, 1990).

  67. 67.

    Shoham, S. & Nagarajan, S. in Neuroprosthetics: Theory and Practice 448–465 (World Scientific, 2003).

  68. 68.

    Alivisatos, A. P. et al. Nanotools for neuroscience and brain activity mapping. ACS Nano 7, 1850–1866 (2013).

  69. 69.

    Clark, J. J. et al. Chronic microsensors for longitudinal, subsecond dopamine detection in behaving animals. Nat. Methods 7, 126–129 (2010).

  70. 70.

    Grahn, P. J. et al. A neurochemical closed-loop controller for deep brain stimulation: toward individualized smart neuromodulation therapies. Front. Neurosci. 8, 169 (2014).

  71. 71.

    Hascup, E. R. et al. Histological studies of the effects of chronic implantation of ceramic-based microelectrode arrays and microdialysis probes in rat prefrontal cortex. Brain Res. 1291, 12–20 (2009).

  72. 72.

    Phillips, P. E. M. & Wightman, R. M. Critical guidelines for validation of the selectivity of in-vivo chemical microsensors. Trends Anal. Chem. 22, 509–514 (2003).

  73. 73.

    Roitbak, T. & Sykov, E. Diffusion barriers evoked in the rat cortex by reactive astrogliosis. Glia 28, 40–48 (1999).

  74. 74.

    Hascup, E. R. et al. Rapid microelectrode measurements and the origin and regulation of extracellular glutamate in rat prefrontal cortex. J. Neurochem. 115, 1608–1620 (2010).

  75. 75.

    Melendez, R. I., Vuthiganon, J. & Kalivas, P. W. Regulation of extracellular glutamate in the prefrontal cortex: focus on the cystine glutamate exchanger and group I metabotropic glutamate receptors. J. Pharmacol. Exp. Ther. 314, 139–147 (2005).

  76. 76.

    Hille, B. Ion Channels of Excitable Membranes (Sinauer, Sunderland, MA, 2001).

  77. 77.

    Pietrobon, D. & Moskowitz, M. A. Chaos and commotion in the wake of cortical spreading depression and spreading depolarizations. Nat. Rev. Neurosci. 15, 379–393 (2014).

  78. 78.

    Haupt, C., Witte, O. W. & Frahm, C. Up-regulation of connexin43 in the glial scar following photothrombotic ischemic injury. Mol. Cell. Neurosci. 35, 89–99 (2007).

  79. 79.

    Karumbaiah, L. et al. Relationship between intracortical electrode design and chronic recording function. Biomaterials 34, 8061–8074 (2013).

  80. 80.

    Biran, R., Martin, D. C. & Tresco, P. A. Neuronal cell loss accompanies the brain tissue response to chronically implanted silicon microelectrode arrays. Exp. Neurol. 195, 115–126 (2005).

  81. 81.

    Karumbaiah, L. et al. The upregulation of specific interleukin (IL) receptor antagonists and paradoxical enhancement of neuronal apoptosis due to electrode induced strain and brain micromotion. Biomaterials 33, 5983–5996 (2012).

  82. 82.

    Kozai, T. D. Y. et al. Effects of caspase-1 knockout on chronic neural recording quality and longevity: insight into cellular and molecular mechanisms of the reactive tissue response. Biomaterials 35, 9620–9634 (2014).

  83. 83.

    Vezzani, A., French, J., Bartfai, T. & Baram, T. Z. The role of inflammation in epilepsy. Nat. Rev. Neurol. 7, 31–40 (2011).

  84. 84.

    Vezzani, A. & Viviani, B. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology 96, 70–82 (2015).

  85. 85.

    Zhou, C. et al. Interleukin-1β inhibits voltage-gated sodium currents in a time- and dose-dependent manner in cortical neurons. Neurochem. Res. 36, 1116–1123 (2011).

  86. 86.

    Li, X., Chen, W., Sheng, J., Cao, D. & Wang, W. Interleukin-6 inhibits voltage-gated sodium channel activity of cultured rat spinal cord neurons. Acta Neuropsychiatr. 26, 170–177 (2014).

  87. 87.

    Zhou, C., Ye, H.-H., Wang, S.-Q. & Chai, Z. Interleukin-1β regulation of N-type Ca2+ channels in cortical neurons. Neurosci. Lett. 403, 181–185 (2006).

  88. 88.

    Ma, S.-H., Li, B., Huang, H.-W., Peng, Y.-P. & Qiu, Y.-H. Interleukin-6 inhibits L-type calcium channel activity of cultured cerebellar granule neurons. J. Physiol. Sci. 62, 385–392 (2012).

  89. 89.

    Liu, Z., Qiu, Y.-H., Li, B., Ma, S.-H. & Peng, Y.-P. Neuroprotection of interleukin-6 against NMDA-induced apoptosis and its signal-transduction mechanisms. Neurotox. Res. 19, 484–495 (2011).

  90. 90.

    Baldwin, K. T. & Eroglu, C. Molecular mechanisms of astrocyte-induced synaptogenesis. Curr. Opin. Neurobiol. 45, 113–120 (2017).

  91. 91.

    Salatino, J. W., Winter, B. M., Drazin, M. H. & Purcell, E. K. Functional remodeling of subtype-specific markers surrounding implanted neuroprostheses. J. Neurophysiol. 118, 194–202 (2017).

  92. 92.

    Weissberg, I. et al. Albumin induces excitatory synaptogenesis through astrocytic TGF-β/ALK5 signaling in a model of acquired epilepsy following blood-brain barrier dysfunction. Neurobiol. Dis. 78, 115–125 (2015).

  93. 93.

    Diniz, L. P. et al. Astrocyte transforming growth factor beta 1 promotes inhibitory synapse formation via CaM kinase II signaling. Glia 62, 1917–1931 (2014).

  94. 94.

    Lin, T.-n et al. Differential regulation of thrombospondin-1 and thrombospondin-2 after focal cerebral ischemia/reperfusion. Stroke 34, 177–186 (2003).

  95. 95.

    Carsten Möller, J. et al. Regulation of thrombospondin in the regenerating mouse facial motor nucleus. Glia 17, 121–132 (1996).

  96. 96.

    Tran, M. D. & Neary, J. T. Purinergic signaling induces thrombospondin-1 expression in astrocytes. Proc. Natl Acad. Sci. USA 103, 9321–9326 (2006).

  97. 97.

    Christopherson, K. S. et al. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120, 421–433 (2005).

  98. 98.

    Kerchner, G. A. & Nicoll, R. A. Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat. Rev. Neurosci. 9, 813–825 (2008).

  99. 99.

    Stellwagen, D. & Malenka, R. C. Synaptic scaling mediated by glial TNF-α. Nature 440, 1054–1059 (2006).

  100. 100.

    Beattie, E. C. et al. Control of synaptic strength by glial TNFalpha. Science 295, 2282–2285 (2002).

  101. 101.

    Chang, S.-Y., Shon, Y. M., Agnesi, F. & Lee, K. H. Microthalamotomy effect during deep brain stimulation: potential involvement of adenosine and glutamate efflux. In 2009 Annual International Conference of the IEEE Engineering in Medicine and Biology Society 3294–3297 (IEEE, 2009).

  102. 102.

    Dunwiddie, T. V., Diao, L. & Proctor, W. R. Adenine nucleotides undergo rapid, quantitative conversion to adenosine in the extracellular space in rat hippocampus. J. Neurosci. 17, 7673–7682 (1997).

  103. 103.

    Fredholm, B. & Dunwiddie, T. How does adenosine inhibit transmitter release? Trends Pharmacol. Sci. 9, 130–134 (1988).

  104. 104.

    Dunwiddie, T. V. & Fredholm, B. B. Adenosine A1 receptors inhibit adenylate cyclase activity and neurotransmitter release and hyperpolarize pyramidal neurons in rat hippocampus. J. Pharmacol. Exp. Ther. 249, 31–37 (1989).

  105. 105.

    Stone, T. W., Ceruti, S. & Abbracchio, M. P. in Adenosine Receptors in Health and Disease. Handbook of Experimental Pharmacology Vol. 193 (eds Wilson, C. & Mustafa, S.) 535–587 (Springer, Berlin, Heidelberg, 2009).

  106. 106.

    Ben Achour, S. & Pascual, O. Glia: the many ways to modulate synaptic plasticity. Neurochem. Int. 57, 440–445 (2010).

  107. 107.

    Gradinaru, V., Mogri, M., Thompson, K. R., Henderson, J. M. & Deisseroth, K. Optical deconstruction of parkinsonian neural circuitry. Science 324, 354–359 (2009).

  108. 108.

    Amiri, M., Montaseri, G. & Bahrami, F. On the role of astrocytes in synchronization of two coupled neurons: a mathematical perspective. Biol. Cybern. 105, 153–166 (2011).

  109. 109.

    Agulhon, C., Fiacco, T. A. & McCarthy, K. D. Hippocampal short- and long-term plasticity are not modulated by astrocyte Ca2+ signaling. Science 327, 1250–1254 (2010).

  110. 110.

    Strogatz, S. H. Exploring complex networks. Nature 410, 268–276 (2001).

  111. 111.

    Perea, G. & Araque, A. Astrocytes potentiate transmitter release at single hippocampal synapses. Science 317, 1083–1086 (2007).

  112. 112.

    Newman, E. A. New roles for astrocytes: regulation of synaptic transmission. Trends Neurosci. 26, 536–542 (2003).

  113. 113.

    Wetherington, J., Serrano, G. & Dingledine, R. Astrocytes in the epileptic brain. Neuron 58, 168–178 (2008).

  114. 114.

    Fellin, T. et al. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43, 729–743 (2004).

  115. 115.

    Silchenko, A. N. & Tass, P. A. Computational modeling of paroxysmal depolarization shifts in neurons induced by the glutamate release from astrocytes. Biol. Cybern. 98, 61–74 (2008).

  116. 116.

    Uhlhaas, P. J. & Singer, W. Neural synchrony in brain disorders: relevance for cognitive dysfunctions and pathophysiology. Neuron 52, 155–168 (2006).

  117. 117.

    Norden, D. M., Muccigrosso, M. M. & Godbout, J. P. Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease. Neuropharmacology 96, 29–41 (2015).

  118. 118.

    Vedam-Mai, V. et al. Deep brain stimulation and the role of astrocytes. Mol. Psychiatry 17, 124–31 (2012).

  119. 119.

    McIntyre, C. C. & Anderson, R. W. Deep brain stimulation mechanisms: the control of network activity via neurochemistry modulation. J. Neurochem. 139, 338–345 (2016).

  120. 120.

    Fenoy, A. J., Goetz, L., Chabardès, S. & Xia, Y. Deep brain stimulation: are astrocytes a key driver behind the scene? CNS Neurosci. Ther. 20, 191–201 (2014).

  121. 121.

    Vedam-Mai, V. et al. The national DBS brain tissue network pilot study: need for more tissue and more standardization. Cell Tissue Bank 12, 219–231 (2011).

  122. 122.

    Sun, D. A. et al. Postmortem analysis following 71 months of deep brain stimulation of the subthalamic nucleus for Parkinson disease. J. Neurosurg. 109, 325–329 (2008).

  123. 123.

    van Kuyck, K., Welkenhuysen, M., Arckens, L., Sciot, R. & Nuttin, B. Histological alterations induced by electrode implantation and electrical stimulation in the human brain: a review. Neuromodulation 10, 244–261 (2007).

  124. 124.

    Chang, S.-Y. et al. Wireless fast-scan cyclic voltammetry to monitor adenosine in patients with essential tremor during deep brain stimulation. Mayo Clin. Proc. 87, 760–765 (2012).

  125. 125.

    Van Gompel, J. J. et al. Increased cortical extracellular adenosine correlates with seizure termination. Epilepsia 55, 233–244 (2014).

  126. 126.

    Santello, M. & Volterra, A. TNFα in synaptic function: switching gears. Trends Neurosci. 35, 638–647 (2012).

  127. 127.

    Gellner, A.-K., Reis, J. & Fritsch, B. Glia: a neglected player in non-invasive direct current brain stimulation. Front. Cell. Neurosci. 10, 188 (2016).

  128. 128.

    Monai, H. et al. Calcium imaging reveals glial involvement in transcranial direct current stimulation-induced plasticity in mouse brain. Nat. Commun. 7, 11100 (2016).

  129. 129.

    Sasaki, T. et al. Application of an optogenetic byway for perturbing neuronal activity via glial photostimulation. Proc. Natl Acad. Sci. USA 109, 20720–20725 (2012).

  130. 130.

    Braun, R. et al. Transcranial direct current stimulation accelerates recovery of function, induces neurogenesis and recruits oligodendrocyte precursors in a rat model of stroke. Exp. Neurol. 279, 127–136 (2016).

  131. 131.

    Arsenault, D. et al. A novel combinational approach of microstimulation and bioluminescence imaging to study the mechanisms of action of cerebral electrical stimulation in mice. J. Physiol. 593, 2257–2278 (2015).

  132. 132.

    Matsuo, H. et al. Early transcutaneous electrical nerve stimulation reduces hyperalgesia and decreases activation of spinal glial cells in mice with neuropathic pain. Pain 155, 1888–1901 (2014).

  133. 133.

    Peruzzotti-Jametti, L. et al. Safety and efficacy of transcranial direct current stimulation in acute experimental ischemic stroke. Stroke 44, 3166–3174 (2013).

  134. 134.

    Iwasa, S. N., Babona-Pilipos, R. & Morshead, C. M. environmental factors that influence stem cell migration: an “electric field”. Stem Cells Int. 2017, 4276927 (2017).

  135. 135.

    Vedam-Mai, V. et al. Increased precursor cell proliferation after deep brain stimulation for Parkinson’s disease: a human study. PLoS ONE 9, e88770 (2014).

  136. 136.

    Toda, H., Hamani, C., Fawcett, A. P., Hutchison, W. D. & Lozano, A. M. The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation. J. Neurosurg. 108, 132–138 (2008).

  137. 137.

    Encinas, J. M., Hamani, C., Lozano, A. M. & Enikolopov, G. Neurogenic hippocampal targets of deep brain stimulation. J. Comp. Neurol. 519, 6–20 (2011).

  138. 138.

    Babona-Pilipos, R., Pritchard-Oh, A., Popovic, M. R. & Morshead, C. M. Biphasic monopolar electrical stimulation induces rapid and directed galvanotaxis in adult subependymal neural precursors. Stem Cell Res. Ther. 6, 67 (2015).

  139. 139.

    Rueger, M. A. et al. Multi-session transcranial direct current stimulation (tDCS) elicits inflammatory and regenerative processes in the rat brain. PLoS ONE 7, e43776 (2012).

  140. 140.

    Zhao, H., Steiger, A., Nohner, M. & Ye, H. specific intensity direct current (DC) electric field improves neural stem cell migration and enhances differentiation towards βIII tubulin+ neurons. PLoS ONE 10, e0129625 (2015).

  141. 141.

    Khaindrava, V. et al. High frequency stimulation of the subthalamic nucleus impacts adult neurogenesis in a rat model of Parkinson’s disease. Neurobiol. Dis. 42, 284–291 (2011).

  142. 142.

    Attwell, D. et al. Glial and neuronal control of brain blood flow. Nature 468, 232–243 (2010).

  143. 143.

    Zonta, M. et al. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat. Neurosci. 6, 43–50 (2003).

  144. 144.

    Filosa, J. A., Bonev, A. D. & Nelson, M. T. Calcium dynamics in cortical astrocytes and arterioles during neurovascular coupling. Circ. Res. 95, e73–e81 (2004).

  145. 145.

    Takano, T. et al. Astrocyte-mediated control of cerebral blood flow. Nat. Neurosci. 9, 260–267 (2006).

  146. 146.

    Ke, B., Liu, T.-T., Liu, C., Xiang, H. & Xiong, J. Dorsal subthalamic nucleus electrical stimulation for drug/treatment-refractory epilepsy may modulate melanocortinergic signaling in astrocytes. Epilepsy Behav. 36, 6–8 (2014).

  147. 147.

    Seymour, J. P., Wu, F., Wise, K. D. & Yoon, E. State-of-the-art MEMS and microsystem tools for brain research. Microsyst. Nanoeng. 3, 16066 (2017).

  148. 148.

    Seymour, J. P. & Kipke, D. R. Neural probe design for reduced tissue encapsulation in CNS. Biomaterials 28, 3594–607 (2007).

  149. 149.

    Loane, D. J. et al. Progressive neurodegeneration after experimental brain trauma: association with chronic microglial activation. J. Neuropathol. Exp. Neurol. 73, 14–29 (2014).

  150. 150.

    Johnson, V. E. et al. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain 136, 28–42 (2013).

  151. 151.

    Perry, V. H., Nicoll, J. A. R. & Holmes, C. Microglia in neurodegenerative disease. Nat. Rev. Neurol. 6, 193–201 (2010).

  152. 152.

    Glass, C. K., Saijo, K., Winner, B., Marchetto, M. C. & Gage, F. H. Mechanisms underlying inflammation in neurodegeneration. Cell 140, 918–934 (2010).

  153. 153.

    Henry, C. J., Huang, Y., Wynne, A. M. & Godbout, J. P. Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1β and anti-inflammatory IL-10 cytokines. Brain. Behav. Immun. 23, 309–317 (2009).

  154. 154.

    Frank, M. G. et al. mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging. Neurobiol. Aging 27, 717–722 (2006).

  155. 155.

    Cunningham, C., Wilcockson, D. C., Campion, S., Lunnon, K. & Perry, V. H. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J. Neurosci. 25, 9275–9284 (2005).

  156. 156.

    Lacour, S. P. et al. Materials and technologies for soft implantable neuroprostheses. Nat. Rev. Mater. 1, 16063 (2016).

  157. 157.

    Wellman, S. M. et al. A materials roadmap to functional neural interface design. Adv. Funct. Mater. (2017).

  158. 158.

    Moshayedi, P. et al. The relationship between glial cell mechanosensitivity and foreign body reactions in the central nervous system. Biomaterials 35, 3919–3925 (2014).

  159. 159.

    Velliste, M., Perel, S., Spalding, M. C., Whitford, A. S. & Schwartz, A. B. Cortical control of a prosthetic arm for self-feeding. Nature 453, 1098–1101 (2008).

  160. 160.

    Collinger, J. L. et al. High-performance neuroprosthetic control by an individual with tetraplegia. Lancet 381, 557–564 (2013).

  161. 161.

    Nguyen, J. K. et al. Mechanically-compliant intracortical implants reduce the neuroinflammatory response. J. Neural Eng. 11, 56014 (2014).

  162. 162.

    Kolarcik, C. L. et al. Elastomeric and soft conducting microwires for implantable neural interfaces. Soft Matter 11, 4847–4861 (2015).

  163. 163.

    Hess, A. E. et al. Development of a stimuli-responsive polymer nanocomposite toward biologically optimized, MEMS-based neural probes. J. Micromech. Microeng. 21, 54009 (2011).

  164. 164.

    Ware, T. et al. Thiol-ene/acrylate substrates for softening intracortical electrodes. J. Biomed. Mater. Res. Part B Appl. Biomater. 102, 1–11 (2014).

  165. 165.

    Ware, T. et al. Fabrication of responsive, softening neural interfaces. Adv. Funct. Mater. 22, 3470–3479 (2012).

  166. 166.

    Capadona, J. R. et al. Mechanically adaptive nanocomposites for neural interfacing. MRS Bull. 37, 581–589 (2012).

  167. 167.

    Capadona, J. R., Shanmuganathan, K., Tyler, D. J., Rowan, S. J. & Weder, C. Stimuli-responsive polymer nanocomposites inspired by the sea cucumber dermis. Science 319, 1370–1374 (2008).

  168. 168.

    Harris, J. P. et al. Mechanically adaptive intracortical implants improve the proximity of neuronal cell bodies. J. Neural Eng. 8, 66011 (2011).

  169. 169.

    Ware, T. et al. Three-dimensional flexible electronics enabled by shape memory polymer substrates for responsive neural interfaces. Macromol. Mater. Eng. 297, 1193–1202 (2012).

  170. 170.

    Chen, R., Canales, A. & Anikeeva, P. Neural recording and modulation technologies. Nat. Rev. Mater. 2, 16093 (2017).

  171. 171.

    Fu, T.-M. et al. Stable long-term chronic brain mapping at the single-neuron level. Nat. Methods 13, 875–882 (2016).

  172. 172.

    Hong, G. et al. Syringe Injectable electronics: precise targeted delivery with quantitative input/output connectivity. Nano Lett. 15, 6979–6984 (2015).

  173. 173.

    Luan, L. et al. Ultraflexible nanoelectronic probes form reliable, glial scar–free neural integration. Sci. Adv. 3, e1601966 (2017).

  174. 174.

    Kim, B. J. et al. 3D parylene sheath neural probe for chronic recordings. J. Neural Eng. 10, 045002 (2013).

  175. 175.

    Kim, T. et al. Injectable, cellular-scale optoelectronics with applications for wireless optogenetics. Science 340, 211–216 (2013).

  176. 176.

    Park, S. II et al. Soft, stretchable, fully implantable miniaturized optoelectronic systems for wireless optogenetics. Nat. Biotechnol. 33, 1280–1286 (2015).

  177. 177.

    Metallo, C. & Trimmer, B. A. Silk coating as a novel delivery system and reversible adhesive for stiffening and shaping flexible probes. J. Biol. Methods 2, e13 (2015).

  178. 178.

    Kozai, T. D. Y. et al. Chronic tissue response to carboxymethyl cellulose based dissolvable insertion needle for ultra-small neural probes. Biomaterials 35, 9255–9268 (2014).

  179. 179.

    Seymour, J. P., Langhals, N. B., Anderson, D. J. & Kipke, D. R. Novel multi-sided, microelectrode arrays for implantable neural applications. Biomed. Microdevices 13, 441–451 (2011).

  180. 180.

    Skousen, J. L. et al. Reducing surface area while maintaining implant penetrating profile lowers the brain foreign body response to chronically implanted planar silicon microelectrode arrays. Prog. Brain Res. 194, 167–80 (2011).

  181. 181.

    Chen, C. S., Mrksich, M., Huang, S., Whitesides, G. M. & Ingber, D. E. Geometric control of cell life and death. Science 276, 1425–1428 (1997).

  182. 182.

    Chen, C. S., Tan, J. & Tien, J. Mechanotransduction at cell-matrix and cell-cell contacts. Annu. Rev. Biomed. Eng. 6, 275–302 (2004).

  183. 183.

    Turner, A. M. P. et al. Attachment of astroglial cells to microfabricated pillar arrays of different geometries. J. Biomed. Mater. Res. 51, 430–441 (2000).

  184. 184.

    Sanders, J. E., Stiles, C. E. & Hayes, C. L. Tissue response to single-polymer fibers of varying diameters: evaluation of fibrous encapsulation and macrophage density. J. Biomed. Mater. Res. 52, 231–237 (2000).

  185. 185.

    Bernatchez, S., Parks, P. J. & Gibbons, D. F. Interaction of macrophages with fibrous materials in vitro. Biomaterials 17, 2077–2086 (1996).

  186. 186.

    Gällentoft, L. et al. Size-dependent long-term tissue response to biostable nanowires in the brain. Biomaterials 42, 172–183 (2015).

  187. 187.

    Skousen, J. L., Bridge, M. J. & Tresco, P. A. A strategy to passively reduce neuroinflammation surrounding devices implanted chronically in brain tissue by manipulating device surface permeability. Biomaterials 36, 33–43 (2015).

  188. 188.

    Saxena, T. & Bellamkonda, R. V. Implantable electronics: a sensor web for neurons. Nat. Mater. 14, 1190–1191 (2015).

  189. 189.

    Xie, C. et al. Three-dimensional macroporous nanoelectronic networks as minimally invasive brain probes. Nat. Mater. 14, 1286–1292 (2015).

  190. 190.

    Liu, J. et al. Syringe-injectable electronics. Nat. Nanotech. 10, 629–636 (2015).

  191. 191.

    Fattahi, P., Yang, G., Kim, G. & Abidian, M. R. A review of organic and inorganic biomaterials for neural interfaces. Adv. Mater. 26, 1846–1885 (2014).

  192. 192.

    Green, R. & Abidian, M. R. Conducting polymers for neural prosthetic and neural interface applications. Adv. Mater. 27, 7620–7637 (2015).

  193. 193.

    Kolarcik, C. L. et al. In vivo effects of L1 coating on inflammation and neuronal health at the electrode–tissue interface in rat spinal cord and dorsal root ganglion. Acta Biomater. 8, 3561–3575 (2012).

  194. 194.

    Rao, L., Zhou, H., Li, T., Li, C. & Duan, Y. Y. Polyethylene glycol-containing polyurethane hydrogel coatings for improving the biocompatibility of neural electrodes. Acta Biomater. 8, 2233–2242 (2012).

  195. 195.

    Kim, D.-H. et al. Dissolvable films of silk fibroin for ultrathin conformal bio-integrated electronics. Nat. Mater. 9, 511–517 (2010).

  196. 196.

    Tien, L. W. et al. Silk as a multifunctional biomaterial substrate for reduced glial scarring around brain-penetrating electrodes. Adv. Funct. Mater. 23, 3185–3193 (2013).

  197. 197.

    Zhong, Y. & Bellamkonda, R. V. Dexamethasone-coated neural probes elicit attenuated inflammatory response and neuronal loss compared to uncoated neural probes. Brain Res. 1148, 15–27 (2007).

  198. 198.

    He, W., McConnell, G. C., Schneider, T. M. & Bellamkonda, R. V. A novel anti-inflammatory surface for neural electrodes. Adv. Mater. 19, 3529–3533 (2007).

  199. 199.

    Mercanzini, A. et al. Controlled release nanoparticle-embedded coatings reduce the tissue reaction to neuroprostheses. J. Control. Release 145, 196–202 (2010).

  200. 200.

    Abidian, M. R. & Martin, D. C. Multifunctional nanobiomaterials for neural interfaces. Adv. Funct. Mater. 19, 573–585 (2009).

  201. 201.

    Bezuidenhout, D. et al. Covalent incorporation and controlled release of active dexamethasone from injectable polyethylene glycol hydrogels. J. Biomed. Mater. Res. Part A 101A, 1311–1318 (2013).

  202. 202.

    Gutowski, S. M. et al. Protease-degradable PEG-maleimide coating with on-demand release of IL-1Ra to improve tissue response to neural electrodes. Biomaterials 44, 55–70 (2015).

  203. 203.

    Wadhwa, R., Lagenaur, C. F. & Cui, X. T. Electrochemically controlled release of dexamethasone from conducting polymer polypyrrole coated electrode. J. Control. Release 110, 531–541 (2006).

  204. 204.

    Kim, Y. et al. Stretchable nanoparticle conductors with self-organized conductive pathways. Nature 500, 59–63 (2013).

  205. 205.

    Abidian, M. R., Ludwig, K. A., Marzullo, T. C., Martin, D. C. & Kipke, D. R. Interfacing conducting polymer nanotubes with the central nervous system: chronic neural recording using poly(3,4-ethylenedioxythiophene) nanotubes. Adv. Mater. 21, 3764–3770 (2009).

  206. 206.

    Keefer, E. W., Botterman, B. R., Romero, M. I., Rossi, A. F. & Gross, G. W. Carbon nanotube coating improves neuronal recordings. Nat. Nanotech. 3, 434–439 (2008).

  207. 207.

    Abidian, M. R., Corey, J. M., Kipke, D. R. & Martin, D. C. Conducting-polymer nanotubes improve electrical properties, mechanical adhesion, neural attachment, and neurite outgrowth of neural electrodes. Small 6, 421–429 (2010).

  208. 208.

    Eles, J. R. et al. Neuroadhesive L1 coating attenuates acute microglial encapsulation of neural electrodes as revealed by live two-photon microscopy. Biomaterials 113, 279–292 (2017).

  209. 209.

    Singh, A. V. et al. Astrocytes increase ATP exocytosis mediated calcium signaling in response to microgroove structures. Sci. Rep. 5, 7847 (2015).

  210. 210.

    Min, S. K. et al. Effect of topography of an electrospun nanofiber on modulation of activity of primary rat astrocytes. Neurosci. Lett. 534, 80–84 (2013).

  211. 211.

    Zuidema, J. M. et al. Enhanced GLT-1 mediated glutamate uptake and migration of primary astrocytes directed by fibronectin-coated electrospun poly-l-lactic acid fibers. Biomaterials 35, 1439–1449 (2014).

  212. 212.

    Vishwakarma, A. et al. Engineering immunomodulatory biomaterials to tune the inflammatory response. Trends Biotechnol. 34, 470–482 (2016).

  213. 213.

    Webber, M. J., Appel, E. A., Meijer, E. W. & Langer, R. Supramolecular biomaterials. Nat. Mater. 15, 13–26 (2016).

  214. 214.

    Lu, Y., Aimetti, A. A., Langer, R. & Gu, Z. Bioresponsive materials. Nat. Rev. Mater. 2, 16075 (2016).

  215. 215.

    Jackson, A., Mavoori, J. & Fetz, E. E. Long-term motor cortex plasticity induced by an electronic neural implant. Nature 444, 56–60 (2006).

  216. 216.

    Hampson, R. E. et al. Facilitation and restoration of cognitive function in primate prefrontal cortex by a neuroprosthesis that utilizes minicolumn-specific neural firing. J. Neural Eng. 9, 056012 (2012).

  217. 217.

    Kipke, D. R., Vetter, R. J., Williams, J. C. & Hetke, J. F. Silicon-substrate intracortical microelectrode arrays for long-term recording of neuronal spike activity in cerebral cortex. IEEE Trans. Neural Syst. Rehabil. Eng. 11, 151–155 (2003).

  218. 218.

    Kindlmann, G. et al. Imaging of Utah electrode array, implanted in cochlear nerve. Digit. Biol. Emerg. Paradig. 6–7 (2003).

  219. 219.

    Moss, J., Ryder, T., Aziz, T. Z., Graeber, M. B. & Bain, P. G. Electron microscopy of tissue adherent to explanted electrodes in dystonia and Parkinson’s disease. Brain 127, 2755–2763 (2004).

  220. 220.

    Kozai, T. D. Y., Vazquez, A. L., Weaver, C. L., Kim, S.-G. & Cui, X. T. In vivo two-photon microscopy reveals immediate microglial reaction to implantation of microelectrode through extension of processes. J. Neural Eng. 9, 066001 (2012).

  221. 221.

    Ludwig, K. A. et al. Using a common average reference to improve cortical neuron recordings from microelectrode arrays. J. Neurophysiol. 101, 1679–1689 (2009).

  222. 222.

    Nishiyama, A., Komitova, M., Suzuki, R. & Zhu, X. Polydendrocytes (NG2 cells): multifunctional cells with lineage plasticity. Nat. Rev. Neurosci. 10, 9–22 (2009).

  223. 223.

    Richardson, W. D., Young, K. M., Tripathi, R. B. & McKenzie, I. NG2-glia as multipotent neural stem cells: fact or fantasy? Neuron 70, 661–73 (2011).

  224. 224.

    Dimou, L. & Gallo, V. NG2-glia and their functions in the central nervous system. Glia 63, 1429–1451 (2015).

  225. 225.

    Crisan, M. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008).

  226. 226.

    Scadden, D. T. The stem-cell niche as an entity of action. Nature 441, 1075–1079 (2006).

  227. 227.

    Hall, C. N. et al. Capillary pericytes regulate cerebral blood flow in health and disease. Nature 508, 55–60 (2014).

  228. 228.

    Fidler, P. S. et al. Comparing astrocytic cell lines that are inhibitory or permissive for axon growth: the major axon-inhibitory proteoglycan is NG2. J. Neurosci. 19, 8778–8788 (1999).

  229. 229.

    Rivers, L. E. et al. PDGFRA/NG2 glia generate myelinating oligodendrocytes and piriform projection neurons in adult mice. Nat. Neurosci. 11, 1392–1401 (2008).

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J.W.S. was supported by National Institutes of Health (NIH) 1R21NS094900, T.D.Y.K. was supported by NIH 1R01NS094396, K.A.L. was supported by The Grainger Foundation, and E.K.P. was supported by NIH 1R21NS094900 and 5R03NS095202. The authors thank J. Eles for assistance collecting in vivo imaging data (Fig. 2a), D. Thompson and S. Yandamuri for assistance collecting data presented in Fig. 3, and M.-C. Senut of Biomilab, LLC, for providing feedback.

Author information


  1. Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA

    • Joseph W. Salatino
    •  & Erin K. Purcell
  2. Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, USA

    • Joseph W. Salatino
    •  & Erin K. Purcell
  3. Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA

    • Kip A. Ludwig
  4. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA

    • Takashi D. Y. Kozai
  5. Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA, USA

    • Takashi D. Y. Kozai
  6. McGowan Institute of Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    • Takashi D. Y. Kozai
  7. Neurotech Center, University of Pittsburgh Brain Institute, Pittsburgh, PA, USA

    • Takashi D. Y. Kozai
  8. Department of Electrical and Computer Engineering, Michigan State University, East Lansing, MI, USA

    • Erin K. Purcell
  9. Neuroscience Program, Michigan State University, East Lansing, MI, USA

    • Erin K. Purcell


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All authors contributed to researching the data and discussing the content of the manuscript, and to writing, reviewing and editing it.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Erin K. Purcell.