pressing need for spatial or temporal information. The study from Cottaris and Elfar [4] however suggests that such a tradeoff may not be necessary since they did not see a decrease in spatial resolution; additional studies are needed to resolve this.

12.6  Suggestions for Future Studies

Several important research goals emerge from a review of the studies to date. First, the thresholds associated with eliciting activity in RGCs during animal studies are consistently low – well below the charge density limits considered to be safe for electrodes. These low levels are in contrast to the much higher thresholds required to elicit percepts during clinical trials [17, 18, 41]. Elevated thresholds raise many concerns. For example, larger power supplies that generate more heat will be required. Also, the diameter of the stimulating electrodes will need to be increased in order to maintain charge densities below established safety levels. Unfortunately, increasing the size of the electrode reduces the potential resolution of these devices.

The reasons underlying the threshold differences are not well understood. Possibilities include structural and functional alterations in the diseased retina, variability in the distance between electrode and neurons (smaller and more controllable during animal studies), uncertainty in the intactness of the ascending visual pathways in patients that have been blind for many years, and appropriateness of the stimulation methods used to elicit clinical percepts. Studies that systematically elucidate which factors contribute most to threshold differences are needed. Presumably, an improved understanding of the factors that influence thresholds will lead to more efficient stimulation methods for eliciting clinical percepts.

A second research goal that emerges is to develop better methods of stimulation. Existing retinal prosthetics typically use stimulating electrodes with diameters that are 10–20 times larger than the diameter of RGC somata. Stimulation from these larger electrodes presumably results in similar patterns of elicited neural activity in large numbers of RGCs situated in and around the electrode region. Light responses from neighboring RGCs (of different types) utilize different patterns of spike activity – differences can include variations in both spike frequency and total spike count. Thus, the prosthetic elicited patterns of activity are considerably different than normal physiological patterns. Stimulation methods that bring the elicited neural activity closer to physiological patterns are likely to improve the quality of elicited vision, even if every aspect of normal signaling patterns cannot be replicated by existing devices.

The need for improved stimulation methods becomes even more necessary after considering the likely clinical applications for retinal prosthetics. The most common form of retinal blindness arises from age-related macular degeneration (AMD). However many patients with AMD retain some useful peripheral vision. Therefore, surgical implantation of the prosthetic needs to provide clinical benefit that outweighs the risk of damage to existing vision. Sophisticated methods of activation will be to needed to achieve these high levels of vision. For patients that are

completely­ blind, the criteria for success may be lower but will still need to meet or exceed the information provided from a white cane or guide dog in order to justify the risk and the costs associated with implantation. Once again, fairly complex methods of stimulation are likely to be needed.

The third research goal is to develop a better understanding of the changes that occur in the retina as part of the degenerative process. For example, studies that show that background spiking levels increase in RGCs of the degenerate retina suggest that the prosthetic may not only need to create spiking activity, it may also need to suppress activity as well. Changes in baseline activity must be fully understood before appropriate stimulation schemes can be developed. In addition, several genetic models of retinal degeneration exhibit drastic changes in both cell structure and synaptic connections. If portions of the inner retina are destroyed, stimulation schemes that target neurons presynaptic to RGCs may not be effective. It is necessary to fully understand these changes before appropriate stimulation methods can rationally be developed. Interestingly, since clinical trials (in blind subjects) indicate that large areas of the human retina remain viable and that retinotopic wiring persists, it is possible that the degenerative process in humans may be less severe than those reported in laboratory animals.

Finally, while methods for selective activation of individual types of RGCs await development, they promise great insight to our understanding of visual processing. For example, if it were possible to selectively activate a single population of RGCs (e.g. midget or parasol), its role in visual perception could be explored. If more than one population could be independently activated, knowledge of how multiple RGC types act in concert could also be explored (e.g. do spikes from the two types need to be generated synchronously?). Similar studies could be performed to elucidate the roles of the ON and OFF systems – a possibility arising from work that indicates these two types may have different thresholds in response to subretinal stimulation. Questions such as these have been difficult to explore using more conventional research tools but offer tremendous insight into the function of the visual system once appropriate methods are developed.

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

References

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.

2.Caldwell JH, Daw NW (1978), New properties of rabbit retinal ganglion cells. J Physiol, 276: p. 257–76.

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.

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.

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.

6.DeVries SH, Baylor DA (1997), Mosaic arrangement of ganglion cell receptive fields in rabbit retina. J Neurophysiol, 78(4): p. 2048–60.

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.

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.

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.

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.

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.

12. Greenberg R (1998). Analysis of electrical stimulation of the vertebrate retina – work towards a retinal prosthesis. Thesis, Biomedical Engineering, Johns Hopkins, Baltimore.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

28. Margalit E, Thoreson WB (2006), Inner retinal mechanisms engaged by retinal electrical stimulation. Invest Ophthalmol Vis Sci, 47(6): p. 2606–12.

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.

30. Mastronarde DN (1989), Correlated firing of retinal ganglion cells. Trends Neurosci, 12: p. 75–80.

31. Meister M, Lagnado L, Baylor DA (1995), Concerted signaling by retinal ganglion-cells.

Science, 270(5239): p. 1207–10.

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.

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.

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.

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.

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.

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.

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.

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.

40. Resatz S, Rattay F (2004), A model for the electrically stimulated retina. Math Comput Model Dyn Syst, 10(2): p. 93–106.

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.

42. Roska B, Werblin F (2001), Vertical interactions across ten parallel, stacked representations in the mammalian retina. Nature, 410(6828): p. 583–7.

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.

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.

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.

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.

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.

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.

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.

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.

51. Slaughter MM, Miller RF (1981), 2-amino-4-phosphonobutyric acid: a new pharmacological tool for retina research. Science, 211(4478): p. 182–5.

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.

258 S.I. Fried and R.J. Jensen

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.

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.

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.

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.

57. Wang J, Simonavicius N, Wu X, et al. (2006), Kynurenic acid as a ligand for orphan G proteincoupled receptor GPR35. J Biol Chem, 281(31): p. 22021–8.

58. Wassle H (2004), Parallel processing in the mammalian retina. Nat Rev Neurosci, 5(10): p. 747–57.

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.

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).

Chapter 13

Findings from Acute Retinal Stimulation in Blind Patients

Peter Walter and Gernot Roessler

Abstract  In acute retinal stimulation experiments retinal stimulators are inserted into the eye, activated, and responses from patients to electrical stimulation are recorded. These tests were done to obtain evidence that the principle of electrical stimulation of the retina works in terms of elicitation of phosphenes or visual perception, respectively. These tests were also done to narrow the parameter range for electrode size and stimulation energy before efforts were undertaken to fabricate a device for chronic stimulation. Results from such tests were also helpful to describe possible perception patterns of patients and also to estimate possible visual acuities after implantation. Usually these tests were done in local anaesthesia so that the patient can respond verbally or by means of an interface to the stimulation. In different experiments rheobase and chronaxie data were reported showing a large variation depending on the device and on individual factors such as the disease state or the proximity between the electrode and the retina. Possible spatial and temporal resolution data were calculated from such experiments demonstrating that the concept of retinal stimulation in blind RP subjects can really help to restore some useful visual function in such patients.

Abbreviations

P. Walter (*)

Department of Ophthalmology, RWTH Aachen University, Pauwelsstr. 30, 52074 Aachen, Germany

e-mail: pwalter@ukaachen.de