Visual Prostheses

56-1 e possibility of restoring vision to blind patients using electricity began with the discovery that an electric charge delivered to a blind eye produces a sensation of light. is discovery was made by LeRoy in 1755. 1 However, it was not until 1966 that the rst human experiments in this eld began with Giles Brindley’s experiments with electrical stimulation of the visual cortex. 2 He used 180 cortical surface electrodes that were able to perceive spots of light called “phosphenes” but they were ill dened and could not be combined to make an image. is did fail to produce useful vision in these patients. Similar experiments by William Dobelle in 1974 essentially produced the same results. 3,4 Since these early experiments, eorts have been underway to produce penetrating arrays of elec trodes that oer the possibility of more closely spaced electrodes and therefore, higher-resolution cortical devices. 5–8 Richard Normann (University of Utah) has micromachined 100 electrodes out of silicon, which were primarily used for recording in the sensory cortex of animals. 5 Another group at the University of Michigan led by Ken Wise has also produced micromachined penetrating electrodes for recording. 6 In the 1990s, an eort at the National Institute of Health (NIH) headed by Terry Hambrecht made an array of 38 penetrating microelectrodes, which were implanted in a patient and yielded sepa rable phosphenes at electrode placements closer than that had been produced with surface electrodes. 7,8 Electronics for an implantable cortical prosthesis are being developed (with 1024 channels) at the Illinois Institute of Technology by Philip Troyk (personal communication). While the cortical-stimulation approaches have made progress, it has been hampered by the physiology. e processing that has occurred by the time the neural signals have reached the cortex is greater than the more distal sites such as the retina. is results in more complex phosphenes being perceived by the patient. e surgery and the implanted prosthesis do provide risks such as intracranial hemorrhage to a blind patient who has an otherwise normal brain. ese factors and the lack of availability of implantable electronics have limited the clinical application of these devices. e limitations of the cortical approach encouraged several groups in the United States over the last 10 years to explore the possibility of producing vision in patients with an intact optic nerve with damaged photoreceptors from stimulating the retina. 9–15 e likely candidate diseases are retinitis pigmentosa (RP) or age-related macular degeneration (AMD). It is dicult to determine exactly how many patients are blinded by these diseases since patients oen stop seeing their ophthalmologist aer being told there is nothing that can be done. However, estimates of legal blindness in the Western (developed world) run as high as 300,000 people with RP and 3,000,000 people with AMD. 1.2 million people are aicted (but not yet blind) with RP worldwide and 10 million people are aicted with AMD in the United States alone. 16 ere have emerged two major approaches to retinal stimulation—epiretinal and subretinal. In the epiretinal approach, electrodes are placed on top of the retina to produce phosphenes. In the subretinal Robert J. Greenberg Second Sight Inc. stimulate the retina. e epiretinal approach has been pursued by a team at the Johns Hopkins University led by Eugene de Juan and Mark Humayun 9,15 and another approach has been pursued at Harvard/MIT Centers led by Joseph Rizzo and John Wyatt. 10 Recently, Rizzo and Wyatt have decided to pursue the subretinal approach. Second Sight, a privately held company in Sylmar, CA is developing a chroni cally implantable epiretinal prosthesis. Six patients have been implanted with a rst-generation device containing 16 electrodes and a 60-electrode second-generation device should be implanted in patients soon. Patients with the rst device have shown the ability to read large letters, locate objects, and detect the direction of motion of objects and light. ey have also shown the ability to discriminate multiple levels of gray. e second-generation device is expected to work even better. e subretinal approach has been pursued by the Chow brothers in Chicago—one an ophthalmologist and the other an engi neer—who have formed a company called Optobionics (Chicago, IL). 14 ey implanted 10 patients in an initial feasibility study that showed some temporary subjective improvements in vision that Optobionics believes was caused by a secondary neurotrophic eect and not direct stimulation by the implant and, more recently, they have implanted 20 additional patients at three centers with better vision than the rst group. Subretinal and epiretinal implants are also being pursued in Germany by large groups led by Eberhart Zrenner 11 and Rolf Eckmiller, 12 respectively. Two companies have been formed in Germany by these individuals as well. ere is also a group in Japan at Nagoya University led by Tohru Yagi. is group is primarily focused on cultured neuron preparations (personal communication). Finally, there is a group at the Neural Rehabilitation Engineering Laboratory in Brussels, Belgium led by Claude Veraart who has implanted a nerve cu electrode with four electrodes around the optic nerve of a blind patient. at patient is able to identify which quadrant she sees a phosphene. 17 Recently, a second patient has been implanted with an eight-channel device. e new device was implanted inside the ocular orbit and has not performed as well as the rst implant. On February 19, 2000, the inaugural symposium of the Alfred Mann Institute-University of Southern California (AMI-USC) titled, “Can We Make the Blind See?—Prospects for Restoring Vision to the Blind” was held. e lecturers included Dean Baker, director of the AMI-USC; Gerald Loeb, an FES (functional electrical stimulation) researcher at the AMI-USC; Dean Bok, a retinal physiologist from UCLA (University of California, Los Angeles); retinal prosthesis researchers—Robert Greenberg, Mark Humayun, Joseph Rizzo, John Wyatt, and Alan Chow; cortical prosthesis researchers—Richard Normann and Philip Troyk; and Dana Ballard, a visual psychophysicist from the University of Rochester. Dr. Baker provided the welcome and Dr. Loeb gave a brief history of neural prosthetics. Dr. Bok’s talk highlighted biological approaches to inherited retinal degenerations, which result in photoreceptor loss. He chose to talk about two genes (rhodopsin and retinal degeneration slow (RDS)) whose mutations cause a form of autosomal-dominant inherited blindness—RP. 18 He discussed the biological approaches of these diseases. Specically, he described the work by Matthew LaVail, William Hauswirth, and Al Lewin Laboratories where subretinal injections were performed in transgenic rats carrying one of the rhodopsin mutations (P23H). By injecting viral-vectored ribozymes for the selective destruction of mutant mRNA produced by the P23H mutation, there was a dramatic arrest in the photoreceptor degeneration. Dr. Bok also spoke about his own work with Matthew LaVail and William Hauswirth laboratories where a viral-vectored secreted form of ciliary neurotrophic factor (CNTF) was injected subretinally. When tested with transgenic rats containing an RDS mutation (peripherin P216 L), the photoreceptor loss was again slowed (Figure 56.1). Aer Dr. Greenberg gave a brief introduction to retinal prosthetics, Mark Humayun spoke about the epiretinal prosthesis eorts at the Johns Hopkins University. 9,15 He spoke about recent experiments of intraocular electrical stimulation in RP and AMD patients. Under local anesthesia, dierent stimulat ing electrodes were inserted through the eye wall and positioned over the surface of the retina. e data from the 10 most recently tested patients were reported. ese awake patients reported simple forms in response to pattern electrical stimulation of the retina. A nonickering perception was created with stimulating frequencies between 40 and 50 Hz. e stimulation threshold was also dependent on the targeted retinal area (higher in the extramacular region). Next, Joseph Rizzo and John Wyatt spoke about the work at the Massachusetts Eye and Ear Inrmary and the Massachusetts Institute of Technology (MEEI-MIT). 10 ey reported tests on six humans tested intraocularly similar to the tests performed at the Johns Hopkins Medical Center. Using microfabri cated electrode arrays placed in contact with the retina, ve patients blinded from RP and one volunteer with normal vision were tested. e normal volunteer was having their eye enucleated because of a can cer. eir most signicant results included: (1) safe contact of the retina with a microfabricated array, (2) determination of strength–duration curves in two volunteers, and (3) creation of visual percepts with crude form. In the best cases, the volunteers were able to distinguish two spots of light when two elec trodes separated by roughly 2° of visual angle were driven. e thresholds reported exceed the accepted charge-density limits for chronic neural stimulation for the electrodes used. It was suggested that the quality of these results would improve with a chronically implantable prosthesis. Alan Chow from Optobionics spoke about his Articial Silicon Retina™(ASR). 14 ASRs are semicon ductor-based silicon chip microphotodiode arrays (microscopic solar cells) designed to be surgically implanted into the subretinal space. e arrays are approximately 2–3 mm in diameter, 50–75 μm thick. Dr. Chow reported a successful electrical stimulation of normal animal retinas. Robert Greenberg spoke about “Second Sight” and its mission of producing a chronically implantable retinal prosthesis. “Second Sight” has chosen a retinal prosthesis approach over the cortical approach because of concerns of patient safety even though the cortical approach has the potential to treat the largest number of blind patients (since it does not require the patients to have an intact retina or an optic nerve). Second Sight has also chosen the epiretinal approach (see Figure 56.2) over the subretinal approach because of the belief that the photodiodes used by Dr. Chow and Dr. Zrenner will not be able to produce enough electrical energy to stimulate abnormal human retinas. Richard Normann from the University of Utah spoke about his electrode arrays that have been used to record both acute and chronic electrophysiological recordings from various brain structures in monkeys, cats, and rats. 5 e standard array is a 4.2-mm square grid with 100 silicon microelectrodes, 1.0 mm long and a spacing of 0.4 mm (see Figure 56.3). Dr. Normann also spoke about his new Utah slant array (USA) electrodes that have been used to record from the peripheral nerve. Philip Troyk from the Illinois Institute of Technology spoke about the issues of implantable hard ware. One issue raised was that the next-generation neuroprostheses will be 5–10 times denser, elec trically and physically than current neuroprosthetic devices. Dr. Troyk discussed the need for heat dissipation by implanted prosthetics, particularly eye-mounted devices. e data were presented where a suspended-carrier closed-loop Class-E transcutaneous magnetic link was used to generate data-transmission rates of over 1 Mbit/s with a 5 MHz carrier. 19 Dr. Troyk also pointed out that the FIGURE 56.1 Experimental protocol for intraocular patient testing at the Johns Hopkins Medical Center. stimulation strategies to produce usable sight are still unknown. When reliable implantable hardware systems become available, testing can begin to devise ecacious image-to-stimulation transforma tions. It is important that the implantable hardware developed at this phase does not restrict the nature of the stimulation sequences from the standpoint of amplitude, pulse–width, frequency, and temporal modulation. en, Dana Ballard from the University of Rochester discussed the visual representations that aect sensorimotor task performance. 20 e volunteers were shown videos of a simulated driving environ ment and their eye movements were monitored. By tracking saccadic eye movements, inferences can be drawn by describing the underlying cortical processing. 21 Finally, a panel discussion was convened where the relative merits of the dierent approaches to visual prosthetics were debated. e session ended with a general consensus that visual prostheses are technically feasible and that chronically implanted devices and clinical testing are a necessary next step to assess the ecacy. Retina Area of photorecep tors destroyed by disease Photo receptors Ganglion cells Eyeball Laser or RF Enlarged area Implant Video camera Electrodes FIGURE 56.2 Concept for an epiretinal prosthesis. FIGURE 56.3 Penetrating cortical electrode array designed by Richard Normann’s laboratory. Acknowledgment is chapter resulted from the inaugural symposium of the Alfred E. Mann Institute for Biomedical Engineering at the University of Southern California, Los Angeles, California on February 19, 2000. e Alfred E. Mann Institute for Biomedical Engineering at the University of Southern California (AMI USC) was established with a $150 million donation by Mr Mann to the University and has as its goal the transfer of university research to the public sector for the benet of patients. 1. Clausen, J. Visual sensations (phosphenes) produced by AC sine wave stimulation. Acta Physiol. Neurol. Scand. Suppl. 94:1–101, 1955. 2. 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