Ординатура / Офтальмология / Английские материалы / Visual Prosthesis and Ophthalmic Devices New Hope in Sight_Rizzo, Tombran-Tink, Barnstable_2007

Fig. 3. The current intensity required to elicit a threshold TER (more than 30 V peak-to- peak amplitude) for monopolar monophasic cathodal stimuli and monopolar biphasic cathodalfirst stimuli. (Figure from ref. 19.)

RETINAL PROSTHESES

The development of a retinal prosthesis has been the most active area of visual prosthesis research in recent times (32). A number of technical issues have been identified in the development of intraocular retinal prostheses (33). The use of epiretinal/subretinal electrodes (32) or indeed suprachoroidal–transretinal stimulation with a return electrode placed in the vitreous chamber (34,35) requires invasive intraocular surgery, which may further damage the already diseased eye. The implanted components may cause mechanical damage to the intraocular tissues, and generate foreign body reactions. If the stimulation electronics are implanted wholly within the globe, this will generate challenges with ensuring hermetic encapsulation of the device, puts the retina at risk of damage from heat effects (36), and makes replacement of damaged devices a difficult procedure. The alternative use of a perscleral (37) connection to extraocular electronics creates a defect in the integrity of the globe, which may be a pathway for infection. It has proved difficult to safely and stably implant electrode arrays in the subretinal space or on the epiretinal surface. Subretinal arrays require a transretinal (38) or transchoroidal (39) approach for implantation, both of which may damage the retina or impair its blood supply from the choroidal circulation, while epiretinal arrays need to be attached with tacks (40) or adhesives (41). Both the arrays and the attachment methods may cause mechanical damage to the retina, and the electrodes may be dislodged because of the high velocities generated during saccadic movements of the eye.

Extraocular Retinal Stimulation

An alternative approach to an intraretinal implant for electrical stimulation of the underlying retina is an extraocular retinal prosthesis (ERP), which uses electrodes sutured to the scleral surface of the globe (42–44). Such a device would avoid many

Fig. 4. (A) Threshold current and threshold charge density for eliciting a 100 V transcallosal evoked response for a bipolar biphasic stimulus with phase durations between 100 s and 1000 s, for interelectrode spacings of 0.95 mm and 2.85 mm. (B) Calculations of voltage and energy at current intensities for eliciting a threshold TER of 100 V for interelectrode spacings of 0.95 mm and 2.85 mm. (Figure from ref. 19.)

of the difficulties associated with positioning electrodes within the cavity of the eye, and could be a simple way of restoring basic visual sensations to blind and severely visually impaired patients. However, the greater distance from the retina of the ERP would require larger electrodes and higher stimulus currents (45), which will limit the number and resolution of phosphenes that can be generated by an ERP, a distinct disadvantage compared with the resolution proposed for intraocular prostheses. Despite a lower phosphene resolution, the generation of even a few localized visual sensations may be of considerable benefit to blind patients (6), and at the very least may assist in restoring disturbed circadian rhythms (46).

Recently, a series of experiments was begun to investigate the feasibility of developing a low-resolution ERP for blind patients. As far as there is awareness, the only report of extraocular retinal stimulation is anecdotal (47) and no systematic animal or human study using a multielectrode ERP has been performed (32). To demonstrate the feasibility of an

Fig. 5. Electrical evoked potential (EEP) recorded from the ipsilateral cortex from bipolar stimulation between electrodes A and B. Single biphasic stimuli with a phase width of 1 ms (resulting in 2 ms pulses) were delivered with electrode A cathodal in the first phase. A suprathreshold stimulus of 3 mA elicits a characteristic EEP with early positive–negative and late negative–positive wave components. No EEP is elicited with a subthreshold stimulus of 0.01 mA. (Figure from ref. 43.)

ERP, and evaluate stimulus and electrode configurations, we needed to develop a suitable electrode array, demonstrate its method of attachment to the eye, show that stimulation through the sclera can elicit retinal excitation and that the charge density for retinal stimulation is at a safe level for chronic neural stimulation. In order to evaluate whether useful sensations can be produced we also needed to show that an ERP causes localized retinal stimulation, which can be expected to produce localized phosphenes in the visual field for blind patients. We also needed to obtain information about the effects of electrode spacing and orientation, which will allow to design prosthesis suitable for human implantation.

The electrode array used in the ERP studies is the same array that was used in the studies of a cortical visual prosthesis (Fig. 1). The multielectrode array is easily attached to the scleral surface of the eye by suturing the silicon carrier directly to the sclera, with the long axis of the array parallel to the horizontal meridian of the eye (44). Bipolar biphasic stimulation of the underlying retina was performed between pairs of electrodes on the array, and its effectiveness was assessed by recording cortical evoked activity (electrical evoked potential [EEP]) using a low-impedance subdural electrode positioned on the cortical surface over the primary visual cortex (area 17). Bipolar stimulation with the array is effective in exciting the retina and eliciting an EEP at the visual cortex (Fig. 5). The EEP waveform is similar to those described in previous studies of retinal stimulation in cats (35,48,49).

Biphasic pulses with a current intensity of 500 A and phase duration of 500 s were able to elicit an EEP with amplitude 1.5 times the average noise amplitude. The

Fig. 6. Amplitudes of the early components of the electrical evoked potential (Early Response – Upper graph), and the late components of the electrical evoked potential (Late Response – Lower graph). Bipolar biphasic stimulation between adjacent electrodes A (cathodal first phase) and B (anodal first phase) was carried out with 500 µs (open points) and 1000 µs (solid points) pulses. Data points are mean +/− SE. Responses recorded from the ipsilateral cortex are shown as squares, and responses recorded from the contralateral cortex are shown as circles. For the early response (upper graph) responses for both stimulus pulse durations are shown in the same figure. For the late response (lower graph), responses from 500 µs pulses are shown in the left

diameter of electrodes on the array was 700 µm, giving a surface area of 3.85 × 10−3 cm2, resulting in a threshold charge density of 64.96 µC/cm2, which is lower than the safe limits for charge injection with platinum electrodes (10,50). In the cat as in the human, the lateral retina projects to the ipsilateral primary visual cortex and the fibers from the medial retina cross at the optic chiasm to pass to the contralateral primary visual cortex. The ERP in the experiments was laterally placed on the globe of the eye, and if localized stimulation of the retina was occurring then stimulation should produce an

Fig. 7. Average ipsilateral and contralateral electrical evoked potential responses for extraocular stimulation with 500 µs pulses through electrode pairs at center-to-center interelectrode separations of 0.95 mm, 1.90 mm, and 2.85 mm. Ipsilateral responses are labeled according to interelectrode separation. Contralateral responses are labeled with “CL” before spacing distance. Data points are mean +/− SE. (Figure from ref. 43.)

EEP that was localized to the ipsilateral primary visual cortex. This was clearly the case with the ERP (Fig. 6), and with one hemisphere activated, any phosphenes generated would be expected to be localized to 50% of the visual field (51). Further estimation of phosphene localization using an ERP will require more detailed retinal stimulation and mapping of the visual cortical responses in animal models and psychophysical studies with human patients.

As was the case with cortical stimulation using this multielectrode array, retinal stimulation with electrodes at a spacing of 2.85 mm elicited the highest EEP responses. This may be because more area of the retina is activated, or because it decreases the shunting of current that may occur between closely spaced electrodes (27). Even with the largest electrode spacing tested EEPs were still restricted to the ipsilateral hemisphere (Fig. 7).

By placing electrodes on the external scleral surface of the eye, the need for invasive intraocular surgery, placement of a foreign body within the cavity of the eye, and miniaturization of stimulation electronics is avoided, as is the possibility of direct injury to the retina. Although, an ERP would only function as a low-resolution prosthesis, the results of the experiments suggest that it may be a feasible approach to develop a retinal prosthesis. Further experiments on animal models with retinal degeneration, and more detailed cortical mapping will allow to assess more fully the localization of retinal stimulation, and evaluate thresholds for stimulation of the diseased retina. Human studies will be needed to evaluate the psychophysical properties of the phosphene sensations produced by extraocular retinal stimulation.

CONCLUSIONS

The aim of the research is to develop visual prostheses for blind and severely visually impaired patients that could be adapted from the neurostimulation and electrode technology that is already available in other neuroprosthetic devices, such as cochlear implants, auditory brainstem implants, and devices for functional neuromuscular stimulation. This would avoid the need to develop new neural stimulation technology, and allow to use devices and materials that already had a good safety and biocompatibility profile in human trials. A visual prosthesis needs to be safe and effective in activating the visual system to produce phosphene sensations and characteristics that are achievable using surface electrode arrays. Such a device could lead to the development of a clinically useful visual prosthesis in the short-term, and allow more detailed studies of phosphene perception to occur in chronic human trials.

ACKNOWLEDGMENTS

The authors’ research described in this chapter has been supported by Ophthalmic Research Institute of Australia, The University of New South Wales, Retina Australia, the Brain Foundation, and the National Health & Medical Research Council, Australia. Some equipment used in this research were provided at no expense by Cochlear Ltd.

REFERENCES

1.Weih L, McCarty CA, Taylor HR. Functional implications of vision impairment. Clin Exp Ophthalmol 2000;28(3):153–155.

2.Sack RL, Lewy AJ, Blood ML, Keith LD, Nakagawa H. Circadian rhythm abnormalities in totally blind people: incidence and clinical significance. J Clin Endocrinol Metab 1992;75(1):127–134.

3.DeLeo D, Hickey PA, Meneghel G, Cantor CH. Blindness, fear of sight loss, and suicide. Psychosomatics 1999;40(4):339–344.

4.Attebo K, Mitchell P, Smith W. Visual acuity and the causes of visual loss in Australia. The Blue Mountains Eye Study. Ophthalmology 1996;103(3):357–364.

5.Chiang YP, Bassi LJ, Javitt JC. Federal budgetary costs of blindness. Milbank Q 1992; 70(2):319–340.

6.Ross RD. Is perception of light useful to the blind patient? (comment). Arch Ophthalmol 1998;116(2):236–238.

7.Krumpaszky G, Klauss V. Epidemiology of blindness and eye disease. Ophthalmologica 1996;210(1):1–84.

8.Sharma RK, Ehinger B. Management of hereditary retinal degenerations: present status and future directions. Surv Ophthalmol 1999;43(5):427–444.

9.Maynard EM. Visual prostheses. Ann Rev Biomed Eng 2001;3:145–168.

10.Margalit E, Maia M, Weiland JD, et al. Retinal prosthesis for the blind. Surv Ophthalmol 2002;47(4):335–356.

11.Dobelle WH. Artificial vision for the blind by connecting a television camera to the visual cortex. ASAIO J 2000;46(1):3–9.

12.Le Roy M. (Mémoire) Ou I’on rende compte de quelques tentatives que I’on a faites pour guérir plusieurs maladies par l’électricité. Mém Mat Phys Acad Roy Sci Paris 1775;60:98.

13.Brindley GS, Lewin WS. The sensations produced by electrical stimulation of the visual cortex. J Physiol (Lond) 1968;196(2):479–493.

14.Button J, Putnam T. Visual responses to cortical stimulation in the blind. J Iowa State Med Soc 1962;52:17–21.

15.Dobelle WH, Mladejovsky MG. Phosphenes produced by electrical stimulation of human occipital cortex, and their application to the development of a prosthesis for the blind. J Physiol (Lond) 1974;243(2):553–576.

16.Dobelle WH, Quest DO, Antunes JL, Roberts TS, Girvin JP. Artificial vision for the blind by electrical stimulation of the visual cortex. Neurosurgery 1979;5(4):521–527.

17.Normann RA, Maynard EM, Rousche PJ, Warren DJ. A neural interface for a cortical vision prosthesis. Vision Res 1999;39(15):2577–2587.

18.Chowdhury V, Morley JW, Coroneo MT. An in-vivo paradigm for the evaluation of stimulating electrodes for use with a visual prosthesis. Aust N Z J Surg 2004;74(5):372–378.

19.Chowdhury V, Morley JW, Coroneo MT. Surface stimulation of the brain with a prototype array for a visual cortex prosthesis. J Clin Neurosci 2004;11(7):750–755.

20.Curtis HJ. Intercortical connections of corpus callosum as indicated by evoked potentials. J Neurophysiol 1940;3:405–413.

21. Curtis HJ. An analysis of cortical potentials mediated by the corpus callosum. J Neurophysiol 1940;3:414–421.

22.Chang HT. Cortical response to activity of callosal neurons. J Neurophysiol 1953;16: 117–131.

23.Peacock SM. Activity of anterior suprasylvian gyrus in response to transcallosal afferent volleys. J Neurophysiol 1957;20:140–155.

24.Kawamura K. Corticocortical fiber connections of the cat cerebrum. 2. The parietal region. Brain Res 1973;51:23–40.

25.Testerman RL. The cortical response to callosal stimulation: a model for determining safe and efficient stimulus parameters. Ann Biomed Eng 1978;6(4):438–452.

26.Sollmann WP, Laszig R, Marangos N. Surgical experiences in 58 cases using the Nucleus 22 multichannel auditory brainstem implant. J Laryngol Otol Suppl 2000;27:23–26.

27.Jayakar P. Physiological principles of electrical stimulation. Adv Neurol 1993;63:17–27.

28.Finn WE, LoPresti PG. Handbook of neuroprosthetic methods. Boca Raton: CRC Press, 2003.

29.Yeomans JS. Principles of Brain Stimulation. New York: Oxford University Press, 1990.

30.McCreery D, Agnew WF. Neuronal and axonal injury during functional electrical stimulation. Ann Int Conf IEEE Eng Med Biol Soc 1990;12(4):1488–1489.

31.McCreery DB, Agnew WF, Yuen TG, Bullara L. Charge density and charge per phase as cofactors in neural injury induced by electrical stimulation. IEEE Trans Biomed Eng 1990;37(10):996–1001.

32.Weiland J, Liu W, Humayun MS. Retinal prosthesis. Annu Rev Biomed Eng 2005;7: 361–401.

33.Rizzo JF, Wyatt J, Humayun M, et al. Retinal prosthesis: an encouraging first decade with major challenges ahead. Ophthalmology 2001;108(1):13–14.

34.Kanda H, Morimoto T, Fujikado T, Tano Y, Fukuda Y, Sawai H. Electrophysiological studies of the feasibility of suprachoroidal-transretinal stimulation for artificial vision in normal and RCS rats. Invest Ophthalmol Vis Sci 2004;45(2):560–566.

35.Sakaguchi H, Fujikado T, Fang X, et al. Transretinal electrical stimulation with a suprachoroidal multichannel electrode in rabbit eyes. Jpn J Ophthalmol 2004;48(5):515.

36.Piyathaisere DV, Margalit E, Chen SJ, et al. Heat effects on the retina. Ophthalmic Surg Lasers Imaging 2003;34(2):114–120.

37.Humayun MS, Weiland JD, Fujii GY, et al. Visual perception in a blind subject with a chronic microelectronic retinal prosthesis. Vision Res 2003;43(24):2573–2581.

38.Chow AY, Pardue MT, Chow VY, et al. Implantation of silicon chip microphotodiode arrays into the cat subretinal space. IEEE Trans Neural Syst Rehabil Eng 2001;9(1):86–95.

39.Shinoda K, Gekeler F, Eckert E, Zrenner E, Gabel V-P, Kobuch K. Externo-Implantation, - explantation and postoperative follow up of subretinal electronic devices. ARVO Meeting Abstracts 2002;43(12):4471.

40.Majji AB, Humayun MS, Weiland JD, Suzuki S, D’Anna SA, de Juan E Jr. Long-term histological and electrophysiological results of an inactive epiretinal electrode array implantation in dogs. Invest Ophthalmol Vis Sci 2002;40(9):2073–2081.

41.Margalit E, Fujii GY, Lai JC, et al. Bioadhesives for intraocular use. Retina 2000;20(5): 469–477.

42.Chowdhury V, Morley JW, Coroneo MT. Evaluation of extraocular electrodes for a retinal prosthesis from evoked potentials in cat visual cortex. J Clin Neurosci 2005a;12(5): 574–579.

43.Chowdhury V, Morley JW, Coroneo MT. Stimulation of the retina with a multielectrode extraocular visual prosthesis. Aust N Z J Surg 2005;75:697–704.

44.Chowdhury V, Morley JW, Coroneo MT. Feasibility of Extraocular Stimulation for a Retinal Prosthesis. Can J Ophthalmol 2005c;40:563–572.

45.Ranck JB. Extracellular Stimulation. In: Patterson MM, Kesner RP, eds. Electrical stimulation research techniques. New York: Academic Press, 1981:1–36.

46.Chiquet C, Dkhissi-Benyahya O, Cooper HM. Is the study of blind patients useful for understanding light perception? Arch Ophthalmol 1999;117(6):848.

47.Humayun MS, Prince M, de Juan E Jr., et al. Morphometric analysis of the extramacular retina from postmortem eyes with retinitis pigmentosa. Invest Ophthalmol Vis Sci 1999;40(1): 143–148.

48.Dawson WW, Radtke ND. The electrical stimulation of the retina by indwelling electrodes. Invest Ophthalmol Vis Sci 1977;6(3):249–252.

49.Schanze T, Wilms M, Eger M, Hesse L, Eckhorn R. Activation zones in cat visual cortex evoked by electrical retina stimulation. Graefes Arch Clin Exp Ophthalmol 2002;240(11): 947–954.

50.Robblee LS, Cogan SF. Metals for medical electrodes. In: Bever MB, ed. Encyclopedia of materials science and engineering. Oxford Pergamon Press, 1986; pp. 276–281.

51.Lamme VA, Super H, Landman R, Roelfsema PR, Spekreijse H. The role of primary visual cortex (V1) in visual awareness. Vision Res 2000;40(10–12):1507–1521.

Fig. 1. Diagram illustrating aqueous humor dynamics. Arrows indicate the direction of aqueous humor flow from the ciliary body (located in the posterior chamber) through the pupil, into the anterior chamber, and exiting the eye through the trabecular meshwork (conventional outflow pathway) or uvea (uveoscleral/unconventional outflow pathway) (Reprinted with permission from Elsevier [1]).

Ocular Anatomy and Physiology

Aqueous Humor Dynamics

IOP is regulated by a balance between the secretion and drainage of aqueous humor from the eye (Fig. 1). Aqueous humor is secreted posterior to the iris by the nonpigmented ciliary epithelium of the ciliary body and this fluid then flows anteriorly through the pupil to the anterior chamber. Aqueous humor exits the eye into the venous circulation through the trabecular meshwork (conventional outflow pathway) and independently through the uveoscleral pathway (unconventional outflow pathway) (Fig. 1).

Retinal Ganglion Cells and Optic Nerve

Axons from the retinal ganglion cells consist of the innermost layer of the retina, the nerve fiber layer (Fig. 2B). These axons converge on the optic disc and form the optic nerve, which contains a central depression called the cup. Most optic nerves have a visible physiological cup, which is surrounded by a neuroretinal rim (Fig. 2A). The human optic nerve contains approx 1 million nerve fibers (Fig. 2C), which exit the eye after passing through the lamina cribrosa, a series of perforated connective tissue sheets, and synapse in the lateral geniculate nucleus of the brain (1). Trophic factors are transported both retrogradely from the axonal terminals of the retinal ganglion cells to their cell bodies in the inner retina as well as anterogradely from the retinal ganglion cell