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Artificial Sight Just because we don't understand how the brain interprets the messages it gets from the eye doesn't mean we can't help the bl ind see again By Gregory Cerio Photography by James Smolka DISCOVER Vol. 22 No. 08 | August 2001 I tried an experiment not long ago, an experiment that involved eyesight. The goal was to experience what it's like to be on the cutting edge of vision technology. It was a test that, fortunately or unfortunately, I am well qualified to perform. You see, back in the 1960s, when I was 4 years old, I had a terrible accident. My sister Camille and I had gotten hold of two of those old, long-necked bottles of Pepsi, capped and full of soda. Morons that we were, we began playing The Three Musketeers, fencing with the glass bottles, clacking them together like swords. A shard flew into my right eye; Camille's legs were torn up a bit (our poor parents . . .). Surgery saved my eye, but the sight I have has always been extremely poor. I can just about make out the largest letter on the Snellen visual acuity chart. Luckily my left eye is fine, but I wanted to find out how well I could get around with my right. I put cotton and tape over my good eye and took a walk. The room was brightly lit. I could make out doorways and see furniture as vague shapes, enough to distinguish a chair from a desk. I made my way outside to the newsstand and bought Wint O Green LifeSavers without tripping or falling. I couldn't watch TV. I certainly couldn't read. I couldn't really recognize faces. But I could see a friend hold her arms wide to give me a hug. It wasn't much. But even the vision in my bad eye would mean the world to people like Harry Woehrle, who was blinded by retinitis pigmentosa, a hereditary disease that destroys the Glasses like these, developed by photoreceptor cells of the eye. He began to lose his sight as a young man. Now he can barely Wentai Liu and Chris DeMarco at remember his children's faces. Recently remarried, he has never seen his wife, Carol. North Carolina State University in Raleigh in collaboration w ith Johns Hopkins, may one day, along with a Today Woehrle has hope that he might be able to see his loved ones again. He is a tes t subject retinal implant, help the blind see. for the Intraocular Retinal Prosthesis Group of the Wilmer Eye Institute at Johns Hopkins Harry Woehrle, a research subj ect at University, one of the leading programs in artificial vision research — a field that aims to use Hopkins, models the glasses: The tiny camera on the frame transmits chip-driven microelectrodes to stimulate dormant neural tiss ues in the visual pathways of the an analog signal that is digitized and blind. During the next year, Harry may be among the first to take an eye -chip shakedown cruise. sent on its way— w ith luck— to the brain. Hopkins researchers intend to implant pea-sized chip arrays into the eyes of a small group of blind volunteers like Woehrle as part of a yearlong, FDA-approved safety and feasibility trial. The array consists of a signal processor and microelectrodes that will excite neurons in the retina in a pattern that corresponds to the view of the world as captured by a camera mounted on a pair of glasses. No one expects miracles. Giving patients the sort of eyesight I experience in my torn -up eye would be considered a thundering success. "If we can eventually help some blind people just to see a little bit, enough to get around unaided, that will be very exciting," says eye surgeon Mark Humayun, director of the Hopkins project. If retinal -chip implants work, they will aid only a fraction of the blind. (It will not help those born blind or those without a functioning optic nerve, and so o ther researchers are attempting to pipe patterned electronic stimuli directly into the brain's visual cortex, the place where sight is actually formed — see "Straight to the Brain.") The eye is a supremely refined, highly organized instrument that acts, in effect, as a digital image processor. After light o f different frequencies enters through the lens and cornea, it strikes the retina, the image -capturing membrane at the back of the eye. Less than 0.04 inches thick, the retina is ever so dense, with 10 layers of tissue containing more than 1 million neural cells and upwards of 150 million photoreceptor cells — the rods and cones. Photons of light prompt the rods and cones to release bursts of electrochemical charges. These charges set off a signal-processing chain, which digitizes the light into neural messages that travel through the optic nerve to the visual cortex. An y breakdown along that route can end the transmission. "Human beings have as much sensory processing circuitry de voted to sight as a bat has for hearing," notes James Weiland, a biomedical engineer who is studying the interface between the electronics and the retina for the Hopkins team. "Replacing even a piece of that circuitry is an awesome task." The Hopkins group and an equally prominent team at Harvard University and the Massachusetts Institute of Technology have both elected to go with an "epiretinal" chip that will rest against the inner wall of the eye. Success is far from assured, but faith in the idea is based partly on the accomplishments of the cochlear implant, a device that has helped many deaf people hear again. The cochlear implant is a bit baffling: Scientists do not fully understand how the brain learns to recognize speech as well as it does with the limited information the implant provi des. The cause of most deafness is the loss of "hair cells"— antennalike cells that line the cochlea, a snail-shaped section of the inner ear. In healthy people, the hair cells pick up sound vibrations and translate them into electrochemical signals that are sent to the auditory nerve. The cochlear implant takes sound passed through a microphone and a sound processor and sends impulses to electrodes in the cochlea, which passes a signal to the auditory nerve. The device has restored a degree of hearing for 25,000 people. This array of microelectrodes Vision researchers are counting on the incredible plasticity demonstrated by the brain in response to was implanted in a human eye the cochlear implant. William Heetderks, head of the neural prosthesis program at the National at Johns Hopkins last year. Institutes of Health, says, "This implant has gotten a lot of people wondering how the auditory system When the array was charged in an E-shaped pattern, the works. Given how little information is going into the brain, it's amazing the implant works as well as it patient successfully saw the does." If the brain is so resilient, he adds, "something similar may happen with the visu al prosthesis." letter E. Photograph courtesy of the The operation of the retinal implant systems being designed by the Harvard/MIT and Hopkins teams is Intraocular Retinal Prosthesis similar to that of the cochlear implant: Data is taken up, encoded, then transmitted as patterned Group 2001/The Wilmer Eye Institute at Johns Hopkins stimuli. Here's how the nearly identical epiretinal implants will work: A tiny, charge-coupled device University. (CCD) camera, mounted on an eyeglass frame, captures and digitizes images of the outside world. The digital signal is sent to a belt pack that supplies power and transmits the data to the retinal chip by means of radio waves. The inch-long chip, which curves along the inner wall of the retina, contains a signal processor and as many as 100 disk -shaped platinum electrodes, each about the size of the tip of a human eyelash. The decoded signal from the CCD controls the firing pattern of the electrodes, which stimulate healthy neural cells that lie beneath the retina's inner surface. While it seems like a straightforward system, the approach is fraught with challenges — and much work needs to be done before a fully functioning chip that works inside the eye is available. First, no one knows if the retina will tolerate a foreign devi ce for a period of years. The eye is delicate and has difficulty fighting infection. Ideally, the epiretinal chip will be a permanent installation, but the Hopkins team has never left a chip inside a human eye for longer than 45 minutes. The Harvard/MIT group has kept an array ins ide an eye for a few months. This is going to be one of those "there's only one way to find out" s cenarios. Hopkins researchers are confident the eye can live with the chip; they are more concerned about the microelectronics soaking in the equivalent of a t ub of salt water— the vitreous humor, the watery gel that gives an eyeball its turgidity. "Imagin e throwing a television set into the ocean," says Robert Greenberg, a former member of the Hopkins team. This is just half the problem, possibly the simpler half. Weiland believes "the human body will protect itself. What we need to do is protect the chip from the body." To solve that problem, the team has devised a hermetic seal for the chip made of titanium and ceramic that is impervious even to helium atoms, which are smal ler than water molecules. The fineness of the retinal membrane, especially when coupled with the eye's rapid movements, poses another challenge. "The notion of putting a computer chip, this slab of silicon, on the retina is problematic," says Joseph Rizzo, codirector with Jo hn Wyatt of the Harvard/MIT project. "The retina is the most delicate part of the eye, and you need a delicate way of communicating with it. Putting this brick on a surface that's like wet tissue paper, then shaking the wet tissue paper back and forth — it's not going to be good." Ideally, says Rizzo, what's needed is a mechanism that can hold the implant stable while suspending the device just above the retina. His group has experimented with a ring-shaped platform tucked behind the iris. The platform supports the implant's signal processor, while the microelectrode array is gently draped down to the retina on a ribbon of silicone-coated wires and held in place by a bonding agent. The Hopkins researchers intend to use tiny metal tacks to keep their implant in place. The nature of the contact point between the retina and the stimulating electrodes raises tough issues that are as much a matter of physics as biology. The optic neurons that researchers are trying to stimulate are 50 to 100 micrometers beneath the retinal surface— only the width of a couple of hairs, but a huge distance in cellular terms. An electrical charge strong enough to stimulate these neurons sufficiently may generate so much heat that it burns retinal tissue. A less powerful, safer charge, however, ma y not stimulate neurons at all. Researchers have also struggled with questions regarding the proper frequency and kind of electrical current to use. Because the retinal tissue will build up a charge, they plan to use an alternating current so that the negati ve phase will cancel the positive phase of the charge before electricity can accumulate in the eye. Finally, there is the matter of the size of the electrodes. As scientists try to create detailed vision, they are faced with a catch-22. Say each electrode is meant to create a pixel, as on a TV screen. Small electrodes will deliver a very localized stimulation to nerve cells, presumably resulting in more pixels and a sharper picture. But because the charge coming out of a smaller electrode is more concentrated, the charge is more likely to burn the retina. A larger electrode delivers a safer, more diffused charge but would create a fatter pixel and a less distinct image. After years spent working with human and animal subjects, Hopkins researchers have settled on electrodes 200 to 400 micrometers in size— tiny in real terms, but still 10 to 20 times the size of human neural cells. For now team members believe they have found a happy medium — the right charge level, the right frequency, and an electrode that can deliver a safe charge and a useful stimulus. Other artificial-vision researchers are not satisfied. "These retinas are very degenerated, and in order to get them to be responsive you have to stimulate them more strongly than a normal retina," says Rizzo. "In our experiments, that amount of charge can be unsafe. I think that the way this issue will resolve itself isn't known yet." Even if researchers meet these challenges, a larger question remains: Will the brain be able to figure out what's going on? It would help if we understood what goes on in the mind of a healthy, seeing person. But we don't. "Nobody understands why or how perception exists. It's the question that has beset neuroscience," says Richard Normann, head of the cortical implant project at the University of Utah (see "Straight to the Brain"). "Why is a stop sign seen as red? Why is grass green? Nobody knows." Test subjects at Hopkins have identified a box shape. Patients in the Harvard/MIT group, blind for many years, have seen spots of light. Harry Woehrle, w ith his w ife, Carol, hopes he w ill receive a retinal implant. "I have This is unknown scientific territory. Technology already exists that can tell the body to modify no trepidation, even though no one knows w hat's going to happen until the its behavior: pacemakers that jolt the heart into pumping rhythmically and ele ctrical thing is in there." stimulators that allow quadriplegics to grasp, but these devices merely provoke muscular contractions. The cochlear implant basically buys the brain ingredients and then lets it cook the dinner. But the goal of art ificial vision is to tell the brain something concrete and specific: We are firing electrodes in a pattern representing a doorway— see it. For now it's as if, in trying to communicate with the brain, scientists were writing a note to aliens from another planet. "We don't know the language," says Rizzo. "It's sort of like having the letters but not knowing how to combine them into words. And we don't even know all the letters. In this work, we know that the frequency and strength of the signal matters and all that, but there's no dou bt that there are crucial variables about which we have no information or knowledge yet." Humayun at Hopkins is willing to let the answers work themselves out once implants are inside people. He puts the timetable f or a working, marketable retinal prosthesis at three to five years. Rizzo says that "if a safe implant with a reasonably high chance of success can be built at all," it is likely to take five to 10 years. Rizzo's team is not planning to run a trial anytime soon . "Being first would be nice, but it's not the highest priority," says Rizzo. "To move ahead with implantations, researchers should have very high confidence that the device can be left in safely for a long time and a reasonable level of confidence that the device would p rovide useful information to us and benefit to the patient. Right now that's a tall order." For his own part, Humayun says: "I hope that, as scientists, we have enough integrity and love for our patients not to do anything hastily and to put only the best device possible in patients. As long as we work ethically and exercise care, I think we need to work faster so that millions of blind people, we hope, will be able to see sooner." One person who agrees is Harry Woehrle. He has another important reason for wanting to go ahead with the trial. "I have nine grandchildren," he says, "and retinitis pigmentosa is an inherited disease. None of them has shown any sign of a problem, tha nk goodness. But if I can do something that might benefit them or kids in other generations, I'm all for i t." A Taste of Sight Instead of trying to replicate the intricate workings of the eye, University of Wisconsin researchers have found a shortcut f or transmitting crude pictures to the brain. The tongue human-machine interface, developed by Paul Bach-y-Rita and Kurt Kaczmarek, is a small patch made of tiny disks of gold attached to a flexible ribbon cable containing 144 electrodes. The patch can be c onnected to a camera and transmitter and activated in patterns to draw a rough sketch on a person's tongu e. The patch could be placed anywhere on the body, but skin isn't a great conductor of electrical signals, so the team picked th e tongue as the ideal interface. Packed with nerves and constantly bathed in highly conductive saliva, it requires only 3 perc ent of the voltage needed to create the equivalent sensation on a fingertip. Those who have tried the patch describe the feeling as a mild tingling, vibrating, or tickling. So far they ha ve used the pat terned pulses to navigate mazes or decipher simple graphics and found that their brains quickly adapt and start to "see" the scene. Bach -y- Rita points out that "the brain is very malleable," and because it is used to getting information as pulses along a nerve, "i t doesn't matter whether those pulses are coming from the eye or the big toe, once the brain has been trained to process them visually." The current prototype looks like a broad, electrode-studded tongue depressor; within five years Bach-y-Rita plans to build a smaller model, which would be discreetly concealed in a retainerlike frame. The resulting images could provide vision equivalent to about 20/830. "I don't think anyone's ever going to be able to sit down and watch TV with this thing," he says, "but in terms of re cognizing shapes and basic navigation, it's more than adequate." — Jocelyn Selim and Christine Soares Who's Got Good Eyes? If you had the eyesight of an eagle, you could read this article from a football field away. (Downside: Your eyes would be th e size of tennis balls.) If you had the eyesight of a dragonfly, you could read this magazine if it was held behind your head. (Downside: eyes the size of basketballs.) If you had the eyesight of a rhesus monkey, you could read this page if it was less than an inch in front of your eyes. (Downside: You'd be a rhesus monkey.) In the context of all creatures, we have eyes that are, well, not bad. "On a scale of one to 10, we rate about a seven," says Phillip Pickett, a veterinary ophthalmologist at Virginia Tech. "Raptors rate a 10 . Rats are about a one. They're good at detecting motion, but that's about it." As Pickett points out, when it comes to sight, "best" can be defined several ways. One measure is distance. Hawks and eagles can spot a mouse in a field from hundreds of feet in the air. Then there's color. Human beings see three colors — red, green, and blue. Pigeons see violet, blue, blue-green, and yellow; bees perceive ultraviolet light, enabling them to discern the UV color patterns flowers make when producing nectar. These evolutionary adaptations allow animals to excel at a particular task. Humans evolved with senses in balance, so we aren't reliant on any o ne in particular. People who can't see have lives as full and rich as anyone else. Indeed, it's arguable that our development has been limited by our eyesight. "Think about how early philosophy and cosmology were determined by what we could see — flat-earth theory, geocentrism, and the like," says Michael Robinson, former director of the National Zoo. "It wasn't until we extended our visual capabilities with telescopes and such that we realized our true place in the universe." — G.C Straight to the Brain "We don't see with our eyes, we see with our brains" is a favorite maxim of vision researchers — so jacking directly into the visual cortex of the brain would seem to be the most straightforward way to send it images. However, the brain is far more complex t han the eye. Neuroscientists are still trying to figure out how the visual cortex translates a code of electrical pulses from th e eyes into the 3-D color moving pictures we perceive as sight. Figuring out how to simulate that effect remains a still taller order. As early as 1929, brain researchers knew that touching an electrode to the visual cortex of a conscious test subject produced the perception of a spot of light, dubbed a phosphene. Starting in the early 1970s, National Institutes of Health researchers wor ked toward a visual cortex prosthesis, culminating with a human experiment in 1995. Thirty-eight electrodes were implanted in the brain of a 42-year-old blind woman, and the NIH team tried to activate them. Results were mixed. The study demonstrated that phosphene percepts could be elicited even after 22 years of blindness, and that simple shapes could be constructed from th e phosphenes. Yet the brightness and duration of the phosphenes the woman saw didn't correspond predictably to the stimulation. By the second month of testing, half the slender electrodes had broken. NIH pulled the plug on further human experimentation, concluding that visual cortex work "wasn't ready for prime time in people," says Audrey Penn, acting deputy director of the Nat ional Institute of Neurological Disorders and Stroke. Today, Richard Normann at the University of Utah believes he is close to sol ving potential hardware problems for a visual cortex prosthesis with his Utah Electrode Array. The UEA is a single unit, about 0.16 inch square, with 100 silicon electrodes, each one- third the width of a human hair. Once the UEA is inserted, each electrode nestles between many neurons so that the implant floats with the brain's natural movement inside the skull, reducing the risk of electrode breakage or tissue damage. Because the ele ctrode tips are in direct contact with neurons, far less power is needed to produce phosphenes than an eye chip would require to send a useful signal across retinal tissue. Eventually, Normann thinks, a 625 -electrode version of the UEA could produce something on the order of a 625-pixel view of the world— enough perhaps to read text and probably adequate for navigating everyday terrain. — Christine Soares To learn about the research being conducted by the Intraocular Retinal Prosthesis Group at Johns Hopkins, see www.irp.jhu.edu. MIT's Retinal Implant Project home page can be found at rleweb.mit.edu/retina. Find more about the tongue sens or, as well as a photo, at www.engr.wisc.edu/news/headlines/2001/Mar26.html. Richard Normann's home page is www.bioen.utah.edu/faculty/RAN, and the Web page of the Center for Neural Interfaces can be found at www.bioen.utah.edu/cni.