The Perceptual Effects of Chronic Retinal Stimulation



Can functional vision be restored in blind human subjects using a microelectronic retinal prosthesis? The initial indications suggest that, yes, it is possible. However, the visual experience of these subjects is nothing like a digital scoreboard-like movie, with each electrode acting as an independent pixel. The work described here in this chapter suggests that there are interactions between pulses and across electrodes, at the electrical, retinal, or even cortical level that influence the quality of the percept. In particular, this work addresses the question, “how does the percept change as a function of pulse timing on single and multiple electrodes”? The motivation for the work described here is that these interactions must be understood and predictable if we are to develop a functional tool for blind human patients. In this chapter, we review work evaluating perceptual effects using chronic electric stimulation in three different implantable systems.


Optical Coherence Tomography Pulse Train Electrode Array Retinal Surface Reference Pulse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Alternative forced-choice


Age-related macular degeneration


Bare light perception




Direct stimulation


Intelligent medical implants


Intelligent retinal implant


Lateral geniculate nucleus


Light perception


Microphotodiode array


No light perception


Optical coherence tomography


Retinal degeneration 1


Retinitis pigmentosa


Retinal pigment epithelium-specific 65 kDa protein


Second Sight Medical Products, Inc.


Primary visual cortex


Visual processing unit


  1. 1.
    Acland GM, Aguirre GD, Bennett J, et al. (2005), Long-term restoration of rod and cone vision by single dose rAAV-mediated gene transfer to the retina in a canine model of childhood blindness. Mol Ther, 12(6): p. 1072–82.CrossRefGoogle Scholar
  2. 2.
    Acland GM, Aguirre GD, Ray J, et al. (2001), Gene therapy restores vision in a canine model of childhood blindness. Nat Genet, 28(1): p. 92–5.CrossRefGoogle Scholar
  3. 3.
    Adrian ED, Matthews R (1928), The action of light on the eye: Part III. The interaction of retinal neurones. J Physiol, 65(3): p. 273–98.Google Scholar
  4. 4.
    Aguirre GK, Komaromy AM, Cideciyan AV, et al. (2007), Canine and human visual cortex intact and responsive despite early retinal blindness from RPE65 mutation. PLoS Med, 4(6): p. e230.CrossRefGoogle Scholar
  5. 5.
    Alitto HJ, Usrey WM (2008), Origin and dynamics of extraclassical suppression in the lateral geniculate nucleus of the macaque monkey. Neuron, 57(1): p. 135–46.CrossRefGoogle Scholar
  6. 6.
    Baccus SA, Meister M (2002), Fast and slow contrast adaptation in retinal circuitry. Neuron, 36(5): p. 909–19.CrossRefGoogle Scholar
  7. 7.
    Bainbridge JW, Smith AJ, Barker SS, et al. (2008), Effect of gene therapy on visual function in Leber’s congenital amaurosis. N Engl J Med, 358(21): p. 2231–9.CrossRefGoogle Scholar
  8. 8.
    Batten ML, Imanishi Y, Tu DC, et al. (2005), Pharmacological and rAAV gene therapy rescue of visual functions in a blind mouse model of Leber congenital amaurosis. [see comment]. PLoS Med, 2(11): p. e333.CrossRefGoogle Scholar
  9. 9.
    Berry MJ, Warland DK, Meister M (1997), The structure and precision of retinal spike trains. Proc Natl Acad Sci USA, 94(10): p. 5411–6.CrossRefGoogle Scholar
  10. 10.
    Bi A, Cui J, Ma YP, et al. (2006), Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration. Neuron, 50(1): p. 23–33.CrossRefGoogle Scholar
  11. 11.
    Brindley GS, Lewin WS (1968), The sensations produced by electrical stimulation of the visual cortex. J Physiol, 196(2): p. 479–93.Google Scholar
  12. 12.
    Brummer SB, Robblee LS, Hambrecht FT (1983), Criteria for selecting electrodes for electrical stimulation: theoretical and practical considerations. Ann NY Acad Sci, 405: p. 159–71.CrossRefGoogle Scholar
  13. 13.
    Brummer SB, Turner MJ (1975), Electrical stimulation of the nervous system: the principle of safe charge injection with noble metal electrodes. Bioelectrochem Bioenerg, 2: p. 13.CrossRefGoogle Scholar
  14. 14.
    Caspi A, Dorn JD, McClure KH, Humayun MS, Greenberg RJ, McMahon MJ (2009), Feasibility study of a retinal prosthesis: spatial vision with a 16-electrode implant. Arch Ophthalmol, 127(4): p. 398–401.CrossRefGoogle Scholar
  15. 15.
    Chader GJ (2002), Animal models in research on retinal degenerations: past progress and future hope. Vision Res, 42(4): p. 393–9.CrossRefGoogle Scholar
  16. 16.
    Chander D, Chichilnisky EJ (2001), Adaptation to temporal contrast in primate and salamander retina. J Neurosci, 21(24): p. 9904–16.Google Scholar
  17. 17.
    Coates S, Thwaites B (2000), The strength-duration curve and its importance in pacing efficiency: a study of 325 pacing leads in 229 patients. Pacing Clin Electrophysiol, 23(8): p. 1273–7.CrossRefGoogle Scholar
  18. 18.
    Congdon N, O’Colmain B, Klaver CC, et al. (2004), Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol, 122(4): p. 477–85.CrossRefGoogle Scholar
  19. 19.
    Daiger SP, Bowne SJ, Sullivan LS (2007), Perspective on genes and mutations causing retinitis pigmentosa. Arch Ophthalmol, 125(2): p. 151–8.CrossRefGoogle Scholar
  20. 20.
    Dan Y, Atick J, Reid R (1996), Efficient coding of natural scenes in the lateral geniculate nucleus: experimental test of a computational theory. J Neurosci, 16: p. 3351–62.Google Scholar
  21. 21.
    de Balthasar C, Patel S, Roy A, et al. (2008), Factors affecting perceptual thresholds in epiretinal prostheses. Invest Ophthalmol Vis Sci, 49(6): p. 2303–14.CrossRefGoogle Scholar
  22. 22.
    Dobelle WH (1974), Introduction to sensory prostheses for the blind and deaf. Trans Am Soc Artif Intern Organs, 20B: p. 761.Google Scholar
  23. 23.
    Field GD, Chichilnisky EJ (2007), Information processing in the primate retina: circuitry and coding. Annu Rev Neurosci, 30: p. 1–30.CrossRefGoogle Scholar
  24. 24.
    Foerster O (1929), Beitrage zur pathophysiologie der sehbahn und der spehsphare. J Psychol Neurol (Lpz), 39: p. 435.Google Scholar
  25. 25.
    Fried SI, Hsueh HA, Werblin FS (2006), A method for generating precise temporal patterns of retinal spiking using prosthetic stimulation. J Neurophysiol, 95(2): p. 970–8.CrossRefGoogle Scholar
  26. 26.
    Geddes LA (2004), Accuracy limitations of chronaxie values. IEEE Trans Biomed Eng, 51(1): p. 176–81.CrossRefGoogle Scholar
  27. 27.
    Greenberg RJ (1998), Analysis of electrical stimulation of the vertebrate retina – work towards a retinal prosthesis. Thesis, The Johns Hopkins University.Google Scholar
  28. 28.
    Greenwald SH, Horsager A, Humayun MS, Greenberg RJ, McMahon MJ, Fine I (2009), Brightness as a function of current amplitude in human retinal electrical stimulation. Invest Ophthalmol Vis Sci, 50(11): p. 5017–25.CrossRefGoogle Scholar
  29. 29.
    Guven D, Weiland J, Maghribi M, et al. (2006), Implantation of an inactive epiretinal poly (di methyl) siloxane electrode arrays in dogs. Exp Eye Res, 82: p. 81–9.CrossRefGoogle Scholar
  30. 30.
    Hecht S, Shlaer S, Pirenne MH (1942), Energy at the threshold of vision. Science, 93(2425): p. 585–7.CrossRefGoogle Scholar
  31. 31.
    Hesse L, Schanze T, Wilms M, Eger M (2000), Implantation of retina stimulation electrodes and recording of electrical stimulation responses in the visual cortex of the cat. Graefes Arch Clin Exp Ophthalmol, 238: p. 840.CrossRefGoogle Scholar
  32. 32.
    Heynen H, van Norren D (1985), Origin of the electroretinogram in the intact macaque eye – II. Current source-density analysis. Vision Res, 25(5): p. 709.CrossRefGoogle Scholar
  33. 33.
    Horsager A, Greenwald SH, Weiland JD, et al. (2009), Predicting visual sensitivity in retinal prosthesis patients. Invest Ophthalmol Vis Sci, 50(4): p. 1483–91.CrossRefGoogle Scholar
  34. 34.
    Hubel DH, Wiesel TN (1962), Receptive fields, binocular interaction and functional architecture in the cat’s visual cortex. J Physiol, 160: p. 106–54.Google Scholar
  35. 35.
    Humayun MS, de Juan E Jr, Dagnelie G, et al. (1996), Visual perception elicited by electrical stimulation of retina in blind humans. Arch Ophthalmol, 114(1): p. 40–6.Google Scholar
  36. 36.
    Humayun MS, de Juan E Jr, Weiland JD, et al. (1999), Pattern electrical stimulation of the human retina. Vision Res, 39(15): p. 2569–76.CrossRefGoogle Scholar
  37. 37.
    Humayun MS, Weiland JD, Fujii GY, et al. (2003), Visual perception in a blind subject with a chronic microelectronic retinal prosthesis. Vision Res, 43(24): p. 2573–81.CrossRefGoogle Scholar
  38. 38.
    Jensen RJ, Rizzo JF III, Ziv OR, et al. (2003), Thresholds for Activation of rabbit retinal ganglion cells with an ultrafine, extracellular microelectrode. Invest Ophthalmol Vis Sci, 44(8): p. 3533–43.CrossRefGoogle Scholar
  39. 39.
    Jensen RJ, Ziv OR, Rizzo JF (2005), Responses of rabbit retinal ganglion cells to electrical stimulation with an epiretinal electrode. J Neural Eng, 2: p. S16–21.CrossRefGoogle Scholar
  40. 40.
    Jones BW, Watt CB, Frederick JM, et al. (2003), Retinal remodeling triggered by photoreceptor degenerations. J Comp Neurol, 464(1): p. 1–16.CrossRefGoogle Scholar
  41. 41.
    Lagali PS, Balya D, Awatramani GB, et al. (2008), Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration. Nat Neurosci, 11(6): p. 667–75.CrossRefGoogle Scholar
  42. 42.
    LeRoy C (1755), Ou l’on rend compte de quelques tentatives que l’on a faites pour guerir plusieurs maladies par l’electricite. Hist Acad Roy Sciences (Paris), 60: p. 87–95.Google Scholar
  43. 43.
    Lin B, Koizumi A, Tanaka N, et al. (2008), Restoration of visual function in retinal dege­neration mice by ectopic expression of melanopsin. Proc Natl Acad Sci USA, 105(41): p. 16009–14.CrossRefGoogle Scholar
  44. 44.
    Lowenstein K, Borchardt M (1918), Symptomatologie und elektrische Reizung bei einer SchuBverletzung des Hinterhauptlappens. Dtsch Z Nervenheilk, 58: p. 264–92.CrossRefGoogle Scholar
  45. 45.
    Mahadevappa M, Weiland JD, Yanai D, et al. (2005), Perceptual thresholds and electrode impedance in three retinal prosthesis subjects. IEEE Trans Neural Syst Rehabil Eng, 13(2): p. 201–6.CrossRefGoogle Scholar
  46. 46.
    Marc RE, Jones BW, Watt CB, Strettoi E (2003), Neural remodeling in retinal degeneration. Prog Retin Eye Res, 22(5): p. 607–55.CrossRefGoogle Scholar
  47. 47.
    Marg E (1991), Magnetostimulation of vision: direct noninvasive stimulation of the retina and the visual brain. Optom Vis Sci, 68(6): p. 427–40.CrossRefGoogle Scholar
  48. 48.
    McCreery DB, Agnew WF (1990), Mechanisms of stimulation-induced neural damage and their relation to guidelines for safe stimulation, in Neural Prostheses Fundamental Studies, Agnew WF, McCreery DB, Editors. Prentice Hall: New Jersey, p. 297.Google Scholar
  49. 49.
    McCreery DB, Agnew WF, Yuen TG, Bullara LA (1988), Comparison of neural damage induced by electrical stimulation with faradaic and capacitor electrodes. Ann Biomed Eng, 16(5): p. 463.CrossRefGoogle Scholar
  50. 50.
    Murphey DK, Maunsell JH (2007), Behavioral detection of electrical microstimulation in different cortical visual areas. Curr Biol, 17(10): p. 862–7.CrossRefGoogle Scholar
  51. 51.
    Palanker D, Vankov A, Huie P, Baccus S (2005), Design of a high-resolution optoelectronic retinal prosthesis. J Neural Eng, 2: p. S105–20.CrossRefGoogle Scholar
  52. 52.
    Pawlyk BS, Smith AJ, Buch PK, et al. (2005), Gene replacement therapy rescues photoreceptor degeneration in a murine model of Leber congenital amaurosis lacking RPGRIP. Invest Ophthalmol Vis Sci, 46(9): p. 3039–45.CrossRefGoogle Scholar
  53. 53.
    Penfield W, Rasmussen T (1952), The Cerebral Cortex of Man. New York: Macmillan. p. 135.Google Scholar
  54. 54.
    Pezaris JS, Reid RC (2007), Demonstration of artificial visual percepts generated through thalamic microstimulation. Proc Natl Acad Sci USA, 104(18): p. 7670–5.CrossRefGoogle Scholar
  55. 55.
    Reid RC, Victor JD, Shapley RM (1992), Broadband temporal stimuli decrease the integration time of neurons in cat striate cortex. Vis Neurosci, 9(1): p. 39–45.CrossRefGoogle Scholar
  56. 56.
    Richard G, et al. (2007), Chronic epiretinal chip implant in blind patients with retinitis pigmentosa: long-term clinical results. Invest Ophthalmol Vis Sci, 48: ARVO E-Abstract 989.Google Scholar
  57. 57.
    Richard G, et al. (2008), Visual perception after long-term implantation of a retinal implant. Invest Ophthalmol Vis Sci, 49: ARVO E-Abstract 245.Google Scholar
  58. 58.
    Richard G, et al. (2009), Long-term stability of stimulation thresholds obtained from a human patient with a prototype of an epiretinal retina prosthesis. Invest Ophthalmol Vis Sci, 50: ARVO E-Abstract 634.Google Scholar
  59. 59.
    Rieke F (2001), Temporal contrast adaptation in salamander bipolar cells. J Neurosci, 21(23): p. 9445–54.Google Scholar
  60. 60.
    Rieke F, Warland D, de Ruyter van Steveninck RR, Bialek W (1997), Spikes: Exploring the Neural Code. Cambridge, MA: MIT Press.Google Scholar
  61. 61.
    Rizzo JF III, Wyatt J, Loewenstein J, et al. (2003), Perceptual efficacy of electrical stimulation of human retina with a microelectrode array during short-term surgical trials. Invest Ophthalmol Vis Sci, 44(12): p. 5362–9.CrossRefGoogle Scholar
  62. 62.
    Schmidt EM, Bak MJ, Hambrecht FT, et al. (1996), Feasibility of a visual prosthesis for the blind based on intracortical microstimulation of the visual cortex. Brain, 119(Pt 2): p. 507.CrossRefGoogle Scholar
  63. 63.
    Schnapf JL, Kraft TW, Baylor DA (1987), Spectral sensitivity of human cone photoreceptors. Nature, 325(6103): p. 439–41.CrossRefGoogle Scholar
  64. 64.
    Sekirnjak C, Hottowy P, Sher A, et al. (2006), Electrical stimulation of mammalian retinal ganglion cells with multi-electrode arrays. J Neurophysiol, 95(6): p. 3311–27.CrossRefGoogle Scholar
  65. 65.
    Shah S, Hines A, Zhou D, et al. (2007), Electrical properties of retinal-electrode interface. J Neural Eng, 4(1): p. S24–9.CrossRefGoogle Scholar
  66. 66.
    Shannon RV (1989), A model of threshold for pulsatile electrical stimulation of cochlear implants. Hear Res, 40(3): p. 197–204.CrossRefGoogle Scholar
  67. 67.
    Shannon RV (1992), A model of safe levels for electrical stimulation. IEEE Trans Biomed Eng, 39(4): p. 424–6.CrossRefGoogle Scholar
  68. 68.
    Stevens SS (1960), Psychophysics of sensory function. Am Sci, 48: p. 226–52.Google Scholar
  69. 69.
    Thylefors B, Negrel AD, Pararajasegaram R, Dadzie KY (1995), Available data on blindness (update 1994). Ophthalmic Epidemiol, 2(1): p. 5–39.CrossRefGoogle Scholar
  70. 70.
    Uzzell VJ, Chichilnisky EJ (2004), Precision of spike trains in primate retinal ganglion cells. J Neurophysiol, 92(2): p. 780–9.CrossRefGoogle Scholar
  71. 71.
    Walter P, Szurman P, Vobig M, et al. (1999), Successful long-term implantation of electrically inactive epiretinal microelectrode arrays in rabbits. Retina, 19(6): p. 546–52.CrossRefGoogle Scholar
  72. 72.
    Wang H, Peca J, Matsuzaki M, et al. (2007), High-speed mapping of synaptic connectivity using photostimulation in Channelrhodopsin-2 transgenic mice. Proc Natl Acad Sci USA, 104(19): p. 8143–8.CrossRefGoogle Scholar
  73. 73.
    Wang X, Wei Y, Vaingankar V, et al. (2007), Feedforward excitation and inhibition evoke dual modes of firing in the cat’s visual thalamus during naturalistic viewing. Neuron, 55(3): p. 465–78.CrossRefGoogle Scholar
  74. 74.
    Watson AB (1986), Temporal sensitivity, in Handbook of Perception and Human Performance, Boff K, Kaufman L, Thomas J, Editors. Wiley: New York.Google Scholar
  75. 75.
    Weiland JD, Humayun MS, Dagnelie G, et al. (1999), Understanding the origin of visual percepts elicited by electrical stimulation of the human retina. Graefes Arch Clin Exp Ophthalmol, 237(12): p. 1007–13.CrossRefGoogle Scholar
  76. 76.
    Yanai D, Lakhanpal RR, Weiland JD, et al. (2003), The value of preoperative tests in the selection of blind patients for a permanent microelectronic implant. Trans Am Ophthalmol Soc, 101: p. 223–8; discussion 228–30.Google Scholar
  77. 77.
    Yanai D, Weiland JD, Mahadevappa M, et al. (2007), Visual performance using a retinal prosthesis in three subjects with retinitis pigmentosa. Am J Ophthalmol, 143(5): p. 820–7.CrossRefGoogle Scholar
  78. 78.
    Zrenner E (2007), Restoring neuroretinal function: new potentials. Doc Ophthalmol, 115: p. 56–9.Google Scholar
  79. 79.
    Zrenner E, et al. (2007), Psychometric analysis of visual sensations mediated by subretinal microelectrode arrays implanted into blind retinitis pigmentosa patients. Invest Ophthalmol Vis Sci, 48: ARVO E-Abstract 645.Google Scholar
  80. 80.
    Zrenner E, et al. (2006), Subretinal chronic multi-electrode arrays implanted in blind patients. Invest Ophthalmol Vis Sci, 47: ARVO E-Abstract 551.Google Scholar
  81. 81.
    Zrenner E, et al. (2009), Blind retinitis pigmentosa patients can read letters and recognize the direction of fine stripe patterns with subretinal electronic implants. Invest Ophthalmol Vis Sci, 50: ARVO E-Abstract 456.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Eos Neuroscience, Inc.Los AngelesUSA
  2. 2.Department of OphthalmologyUniversity of Southern CaliforniaLos AngelesUSA

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