The Response of Retinal Neurons to Electrical Stimulation: A Summary of In Vitro and In Vivo Animal Studies



The studies reviewed in this chapter are restricted to those that electrically stimulate the retina. The research studies reviewed in this chapter are further limited to those performed in animal models; the results of human clinical studies are covered in subsequent chapters.

The neural response to electrical stimulation is influenced (potentially) by a large number of stimulation-related variables (Chaps.  6–10). Stimulating electrodes can be constructed in different shapes and sizes and fabricated out of different materials. Arrays of multiple electrodes can be configured in many different arrangements and ultimately positioned on opposite sides of the retina, or even penetrate into the retina. In addition, the phase length, duration, amplitude and/or frequency of stimulus pulses can each vary, some by several orders of magnitude.

The neurobiology of the retina creates additional variables. There are five major classes of retinal neurons and each is a potential target of electrical stimulation. Each class can be subdivided into many different types; the anatomical and biophysical properties of each can vary considerably. Therefore, the response to electrical stimulation may also vary across types. Since each type is thought to convey different features of the visual world, stimulation methods that do not activate all types appropriately may not convey some or all of the important features of the visual scene.

Systematic study of the interactions between all engineering and neurobiological variables requires an extensive matrix of experiments. As a result, many basic ­questions remain unexplored. Here, we will focus on the experimental studies that have yielded the more important insights into either the mechanism by which retinal neurons respond to electrical stimulation or those that have led to improved stimulation­ methods. The final section of this chapter is devoted to a discussion of some important, unanswered questions.


Bipolar Cell Amacrine Cell Stimulate Electrode Retinal Neuron Stimulus 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.



Age-related macular degeneration


2-Amino-4-phosphonobutyric acid




Directionally selective


Electrically elicited cortical potentials


Local edge detector


Local field potential


(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate




Royal College of Surgeons


Retinal degeneration 1


Retinal ganglion cell


Retinitis pigmentosa



Support provided by Department of Veterans Affairs, Rehabilitation Research and Development Service.


  1. 1.
    Ahuja AK, Behrend MR, Kuroda M, et al. (2008), An in vitro model of a retinal prosthesis. IEEE Trans Biomed Eng, 55(6): p. 1744–53.CrossRefGoogle Scholar
  2. 2.
    Caldwell JH, Daw NW (1978), New properties of rabbit retinal ganglion cells. J Physiol, 276: p. 257–76.Google Scholar
  3. 3.
    Carter-Dawson LD, LaVail MM, Sidman RL (1978), Differential effect of the rd mutation on rods and cones in the mouse retina. Invest Ophthalmol Vis Sci, 17(6): p. 489–98.Google Scholar
  4. 4.
    Cottaris NP, Elfar SD (2009), Assessing the efficacy of visual prostheses by decoding ms-LFPs: application to retinal implants. J Neural Eng, 6(2): 026007.CrossRefGoogle Scholar
  5. 5.
    D’Cruz PM, Yasumura D, Weir J, et al. (2000), Mutation of the receptor tyrosine kinase gene Mertk in the retinal dystrophic RCS rat. Hum Mol Genet, 9(4): p. 645–51.CrossRefGoogle Scholar
  6. 6.
    DeVries SH, Baylor DA (1997), Mosaic arrangement of ganglion cell receptive fields in rabbit retina. J Neurophysiol, 78(4): p. 2048–60.Google Scholar
  7. 7.
    Eckhorn R, Wilms M, Schanze T, et al. (2006), Visual resolution with retinal implants estimated from recordings in cat visual cortex. Vision Res, 46(17): p. 2675–90.CrossRefGoogle Scholar
  8. 8.
    Eger M, Wilms M, Eckhorn R, et al. (2005), Retino-cortical information transmission achievable with a retina implant. Biosystems, 79(1–3): p. 133–42.CrossRefGoogle Scholar
  9. 9.
    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
  10. 10.
    Fried SI, Lasker AC, Desai NJ, et al. (2009), Axonal sodium-channel bands shape the response to electric stimulation in retinal ganglion cells. J Neurophysiol, 101(4):p. 1972–87.CrossRefGoogle Scholar
  11. 11.
    Gekeler F, Messias A, Ottinger M, et al. (2006), Phosphenes electrically evoked with DTL electrodes: a study in patients with retinitis pigmentosa, glaucoma, and homonymous visual field loss and normal subjects. Invest Ophthalmol Vis Sci, 47(11): p. 4966–74.CrossRefGoogle Scholar
  12. 12.
    Greenberg R (1998). Analysis of electrical stimulation of the vertebrate retina – work towards a retinal prosthesis. Thesis, Biomedical Engineering, Johns Hopkins, Baltimore.Google Scholar
  13. 13.
    Greenberg RJ, Velte TJ, Humayun MS, et al. (1999), A computational model of electrical stimulation of the retinal ganglion cell. IEEE Trans Biomed Eng, 46(5): p. 505–14.CrossRefGoogle Scholar
  14. 14.
    Grilli M, Raiteri L, Patti L, et al. (2006), Modulation of the function of presynaptic alpha7 and non-alpha7 nicotinic receptors by the tryptophan metabolites, 5-hydroxyindole and kynurenate in mouse brain. Br J Pharmacol, 149(6): p. 724–32.CrossRefGoogle Scholar
  15. 15.
    Grumet AE, Wyatt JL, Jr., Rizzo JF, 3rd (2000), Multi-electrode stimulation and recording in the isolated retina. J Neurosci Methods, 101(1): p. 31–42.CrossRefGoogle Scholar
  16. 16.
    Grusser OJ, Creutzfeldt O (1957), [Neurophysiological basis of Brucke-Bartley effect; maxima of impulse frequency of retinal and cortical neurons in flickering light of middle frequency.]. Pflugers Arch, 263(6): p. 668–81.CrossRefGoogle Scholar
  17. 17.
    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
  18. 18.
    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
  19. 19.
    Jensen RJ, Rizzo JF, 3rd (2006), Thresholds for activation of rabbit retinal ganglion cells with a subretinal electrode. Exp Eye Res, 83(2): p. 367–73.CrossRefGoogle Scholar
  20. 20.
    Jensen RJ, Rizzo JF, 3rd (2007), Responses of ganglion cells to repetitive electrical stimulation of the retina. J Neural Eng, 4(1): p. S1–6.CrossRefGoogle Scholar
  21. 21.
    Jensen RJ, Rizzo JF, 3rd (2008), Activation of retinal ganglion cells in wild-type and rd1 mice through electrical stimulation of the retinal neural network. Vision Res, 48(14): p. 1562–8.CrossRefGoogle Scholar
  22. 22.
    Jensen RJ, Rizzo JF (2009), Activation of ganglion cells in wild-type and rd1 mouse retinas with monophasic and biphasic current pulses. J Neural Eng, 6(3): 035004.CrossRefGoogle Scholar
  23. 23.
    Jensen RJ, Rizzo JF, 3rd, 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
  24. 24.
    Jensen RJ, Ziv OR, Rizzo JF (2005), Responses of rabbit retinal ganglion cells to electrical stimulation with an epiretinal electrode. J Neural Eng, 2(1): p. S16–21.CrossRefGoogle Scholar
  25. 25.
    Jensen RJ, Ziv OR, Rizzo JF, 3rd (2005), Thresholds for activation of rabbit retinal ganglion cells with relatively large, extracellular microelectrodes. Invest Ophthalmol Vis Sci, 46(4): p. 1486–96.CrossRefGoogle Scholar
  26. 26.
    Kruse W, Eckhorn R (1996), Inhibition of sustained gamma oscillations (35-80 Hz) by fast transient responses in cat visual cortex. Proc Natl Acad Sci USA, 93(12): p. 6112–7.CrossRefGoogle Scholar
  27. 27.
    Logothetis NK (2002), The neural basis of the blood-oxygen-level-dependent functional magnetic resonance imaging signal. Philos Trans R Soc Lond B Biol Sci, 357(1424): p. 1003–37.CrossRefGoogle Scholar
  28. 28.
    Margalit E, Thoreson WB (2006), Inner retinal mechanisms engaged by retinal electrical stimulation. Invest Ophthalmol Vis Sci, 47(6): p. 2606–12.CrossRefGoogle Scholar
  29. 29.
    Margolis DJ, Newkirk G, Euler T, Detwiler PB (2008), Functional stability of retinal ganglion cells after degeneration-induced changes in synaptic input. J Neurosci, 28(25): p. 6526–36.CrossRefGoogle Scholar
  30. 30.
    Mastronarde DN (1989), Correlated firing of retinal ganglion cells. Trends Neurosci, 12: p. 75–80.CrossRefGoogle Scholar
  31. 31.
    Meister M, Lagnado L, Baylor DA (1995), Concerted signaling by retinal ganglion-cells. Science, 270(5239): p. 1207–10.CrossRefGoogle Scholar
  32. 32.
    Mitzdorf U (1985), Current source-density method and application in cat cerebral cortex: investigation of evoked potentials and EEG phenomena. Physiol Rev, 65(1): p. 37–100.Google Scholar
  33. 33.
    Mitzdorf U (1987), Properties of the evoked potential generators: current source-density analysis of visually evoked potentials in the cat cortex. Int J Neurosci, 33(1–2): p. 33–59.CrossRefGoogle Scholar
  34. 34.
    Nandrot E, Dufour EM, Provost AC, et al. (2000), Homozygous deletion in the coding sequence of the c-mer gene in RCS rats unravels general mechanisms of physiological cell adhesion and apoptosis. Neurobiol Dis, 7(6 Pt B): p. 586–99.CrossRefGoogle Scholar
  35. 35.
    O’Brien BJ, Isayama T, Richardson R, Berson DM (2002), Intrinsic physiological properties of cat retinal ganglion cells. J Physiol, 538(Pt 3): p. 787–802.CrossRefGoogle Scholar
  36. 36.
    O’Hearn TM, Sadda SR, Weiland JD, et al. (2006), Electrical stimulation in normal and retinal degeneration (rd1) isolated mouse retina. Vision Res, 46(19): p. 3198–204.CrossRefGoogle Scholar
  37. 37.
    Pennesi ME, Nishikawa S, Matthes MT, et al. (2008), The relationship of photoreceptor degeneration to retinal vascular development and loss in mutant rhodopsin transgenic and RCS rats. Exp Eye Res, 87(6): p. 561–70.CrossRefGoogle Scholar
  38. 38.
    Pu M, Xu L, Zhang H (2006), Visual response properties of retinal ganglion cells in the royal college of surgeons dystrophic rat. Invest Ophthalmol Vis Sci, 47(8): p. 3579–85.CrossRefGoogle Scholar
  39. 39.
    Rager G, Singer W (1998), The response of cat visual cortex to flicker stimuli of variable frequency. Eur J Neurosci, 10(5): p. 1856–77.CrossRefGoogle Scholar
  40. 40.
    Resatz S, Rattay F (2004), A model for the electrically stimulated retina. Math Comput Model Dyn Syst, 10(2): p. 93–106.MATHGoogle Scholar
  41. 41.
    Rizzo JF, 3rd, 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
  42. 42.
    Roska B, Werblin F (2001), Vertical interactions across ten parallel, stacked representations in the mammalian retina. Nature, 410(6828): p. 583–7.CrossRefGoogle Scholar
  43. 43.
    Sachs HG, Gekeler F, Schwahn H, et al. (2005), Implantation of stimulation electrodes in the subretinal space to demonstrate cortical responses in Yucatan minipig in the course of visual prosthesis development. Eur J Ophthalmol, 15(4): p. 493–9.Google Scholar
  44. 44.
    Salzmann J, Linderholm OP, Guyomard JL, et al. (2006), Subretinal electrode implantation in the P23H rat for chronic stimulations. Br J Ophthalmol, 90(9): p. 1183–7.CrossRefGoogle Scholar
  45. 45.
    Schanze T, Greve N, Hesse L (2003), Towards the cortical representation of form and motion stimuli generated by a retina implant. Graefes Arch Clin Exp Ophthalmol, 241(8): p. 685–93.CrossRefGoogle Scholar
  46. 46.
    Schanze T, Wilms M, Eger M, et al. (2002), Activation zones in cat visual cortex evoked by electrical retina stimulation. Graefes Arch Clin Exp Ophthalmol, 240(11): p. 947–54.CrossRefGoogle Scholar
  47. 47.
    Schiefer MA, Grill WM (2006), Sites of neuronal excitation by epiretinal electrical stimulation. IEEE Trans Neural Syst Rehabil Eng, 14(1): p. 5–13.CrossRefGoogle Scholar
  48. 48.
    Schwahn HN, Gekeler F, Kohler K, et al. (2001), Studies on the feasibility of a subretinal visual prosthesis: data from Yucatan micropig and rabbit. Graefes Arch Clin Exp Ophthalmol, 239(12): p. 961–7.CrossRefGoogle Scholar
  49. 49.
    Sekirnjak C, Hottowy P, Sher A, et al. (2006), Electrical stimulation of mammalian retinal ganglion cells with multielectrode arrays. J Neurophysiol, 95(6): p. 3311–27.CrossRefGoogle Scholar
  50. 50.
    Sekirnjak C, Hottowy P, Sher A, et al. (2008), High-resolution electrical stimulation of primate retina for epiretinal implant design. J Neurosci, 28(17): p. 4446–56.CrossRefGoogle Scholar
  51. 51.
    Slaughter MM, Miller RF (1981), 2-amino-4-phosphonobutyric acid: a new pharmacological tool for retina research. Science, 211(4478): p. 182–5.CrossRefGoogle Scholar
  52. 52.
    Stasheff SF (2008), Emergence of sustained spontaneous hyperactivity and temporary preservation of OFF responses in ganglion cells of the retinal degeneration (rd1) mouse. J Neurophysiol, 99(3): p. 1408–21.CrossRefGoogle Scholar
  53. 53.
    Stett A, Barth W, Weiss S, et al. (2000), Electrical multisite stimulation of the isolated chicken retina. Vision Res, 40(13): p. 1785–95.CrossRefGoogle Scholar
  54. 54.
    Stett A, Mai A, Herrmann T (2007), Retinal charge sensitivity and spatial discrimination obtainable by subretinal implants: key lessons learned from isolated chicken retina. J Neural Eng, 4(1): p. S7–16.CrossRefGoogle Scholar
  55. 55.
    Suzuki S, Humayun MS, Weiland JD, et al. (2004), Comparison of electrical stimulation thresholds in normal and retinal degenerated mouse retina. Jpn J Ophthalmol, 48(4): p. 345–9.Google Scholar
  56. 56.
    Tehovnik EJ, Tolias AS, Sultan F, et al. (2006), Direct and indirect activation of cortical neurons by electrical microstimulation. J Neurophysiol, 96(2): p. 512–21.CrossRefGoogle Scholar
  57. 57.
    Wang J, Simonavicius N, Wu X, et al. (2006), Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J Biol Chem, 281(31): p. 22021–8.CrossRefGoogle Scholar
  58. 58.
    Wassle H (2004), Parallel processing in the mammalian retina. Nat Rev Neurosci, 5(10): p. 747–57.CrossRefGoogle Scholar
  59. 59.
    Wilms M, Eger M, Schanze T, Eckhorn R (2003), Visual resolution with epi-retinal electrical stimulation estimated from activation profiles in cat visual cortex. Vis Neurosci, 20(5): p. 543–55.CrossRefGoogle Scholar
  60. 60.
    Zrenner E, Besch D, Bartz-Schmidt KU, et al. (2006), Subretinal chronic multielectrode arrays implanted in blind patients. Invest Ophthalmol Vis Sci, 47(1538).Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.VA Boston Healthcare SystemBostonUSA
  2. 2.Massachusetts General Hospital & Harvard Medical SchoolBostonUSA

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