In the September 2013 issue of AccessWorld, we described four groundbreaking advances in low vision enhancement, including the Implantable Miniature Telescope from VisionCare Ophthalmic Technologies, and the Argus II Retinal Prosthesis from Second Sight. The first of these is a pea-size telescopic lens that increases the useable vision of individuals who have lost central vision due to end-stage age-related onset macular degeneration. The Argus II is aimed toward people with late-stage retinitis pigmentosa (RP). The Argus II uses a wireless signal to stimulate the optic nerve directly via an implanted array of electrodes, bypassing the rods and cones damaged by RP.
As remarkable as these solutions may be, they do have one stumbling block in common: they each assume the recipient possesses a functioning optic nerve that can adequately transmit visual signals to the brain for processing. But what if the optic nerve has been damaged by glaucoma, multiple sclerosis, or trauma? Might there be some way to mend these most complex and fragile of nerve fibers? Or even better, bypass them altogether?
In this article we will describe two recent research breakthroughs—one that shows the potential to help regenerate damaged optic nerves, and the second, a system called Gennaris, that may produce vision without the optic nerve, or even the eye itself.
Regenerating an Optic Nerve
The optic nerve is one of the most important nerves in the body, second only to the spinal cord (the spinal cord includes thousands of nerve strands while the optic nerve has but one). So fifteen years ago when Zhigang He, Professor of neurology at the Boston Children's Hospital F.M. Kirby Neurobiology Center set up a lab to investigate ways to regenerate nerve fibers in people with spinal cord injuries, he decided the best place to start would be to attempt neural regeneration in damaged optic nerves as a proxy.
Others have tried optic nerve regeneration or repair. The first attempts spliced bits of the sciatic nerve to replace damaged optic nerve. Most axons didn't regrow. About eight years ago, Dr. He's group tried gene excision to delete or block tumor-suppressing genes. This prompted some optic nerve regeneration, but it also increased cancer risks. Their recent work with Dr. Joshua Sanes at Harvard found a gene therapy strategy to enhance growth factor activities, which could mimic the regeneration effects induced by tumor suppressor deletion. Nevertheless, the number of regenerated axons by these approaches was limited.
He and his co-senior-researcher, Boston Children's Hospital Assistant Professor of neurology Michela Fagiolini, took gene therapy a step further. They used a gene therapy virus called AAV to deliver three factors to boost growth factor responses into the retina, which is part of the optic nerve system.
"Over time we were able to regenerate increasingly longer nerve fibers in mice with damaged optic nerves," he reports. "Unfortunately, the new neural fibers did not transmit impulses, known as action potentials, all the way from the eye to the brain, so there was no new vision."
He and Fagiolini traced the problem to the fact that the new nerve fibers were growing without the fatty sheath called Myelin. Myelin insulates nerve fibers and keeps neural signals on track, much as the insulation surrounding a copper wire directs electrical current to the lamp instead of into the wall studs and outlets.
Turning to the medical literature, he and Fagiolini read about a potassium channel blocker called 4-aminopyridine (4-AP) which is known to improve message conduction in nerve fibers that lack sufficient Myelin. Indeed, 4-AP is marketed as AMPYRA to treat MS-related walking difficulties, which also involve a loss of myelin.
"When we administered 4-TP the signals were able to go the distance," says Fagiolini. A separate lab, where they did not know which of the blind mice had been treated, confirmed that the treated mice responded to moving bars of light while the control group did not.
"There is still considerable work to be done before this treatment is ready for human trials," He says. For example, the team used a gene therapy virus to deliver the growth factors that stimulated optic nerve regeneration, but He and Fagiolini believe they can produce an injectable "cocktail" of growth factor proteins that could be equally effective. "We're trying to better understand the mechanisms and how often the proteins would have to be injected," says He.
Also yet to be solved are the potential side effects of using 4-AP to increase optic nerve signal transmission. The medication can cause seizures if given chronically, so He and Fagiolini have begun testing non-FDA approved 4-AP derivatives which would be safer for long-term use. Despite the remaining hurdles, He and Fagiolini remain optimistic. "At least now we have a paradigm we can use to move forward," He says.
The Mind's Eye
Regenerating the optic nerve could help millions, but what if we could bypass the optic nerve altogether and see without one, or even without physical eyes? That's the goal of Arthur Lowery, Professor of electrical and computer systems engineering at Australia's Monash University. Lowery and his team are currently working on Gennaris, a system that will stimulate the brain's visual cortex directly, sending a grid of electrical impulses that the brain can interpret as recognizable patterns of light and dark.
Research into "brain" vision goes back to the 1960s. "At that time you needed a room full of equipment to get any results at all," observes Lowery. "Even as little as ten or fifteen years ago, producing a grid of three hundred points of light meant passing a bundle of 300 separate wires from the brain to a large, external video camera." Lowery and his team are building on this previous work, taking advantage of the considerable progress which has been made over the past decade in processing power, component miniaturization, wireless data transmission, and induction power transmission such as that now found on some cell phones which can be placed atop the charger instead of needing to be plugged in.
In normal vision, light passes through the eye's pupil and lens and stimulates rods and cones, which are the photo-receptive cells covering the retina. These photochemical signals are transformed into neural impulses, which in turn are transmitted along the optic nerve to the visual cortex. There, the brain turns these impulses into recognizable shapes and images, otherwise known as vision.
As it happens, the neurons in the visual cortex can also be stimulated by contact with tiny electrodes. "We know from previous research that we can produce flashes of light that appear in roughly the same spot whenever that same region of the visual cortex is stimulated," states Lowery. "If we can create a number of these flashes more or less simultaneously, we can create a rudimentary grid of light and dark the brain could interpret as an image." Imagine a square of sixteen light bulbs creating the letter O by switching on the twelve perimeter bulbs and leaving the four center lights turned off. Or a letter L created by braille dots 1, 2, and 3, with the rest of the cell left blank.
The Gennaris team hopes to create just such a grid using tiny ceramic tiles embedded directly onto a test subject's visual cortex. "Each tile is approximately 9 millimeters square—about a third of an inch—with forty-three working electrodes on each tile," Lowery explains. "These electrodes will penetrate 1.5 to 2 millimeters into the visual cortex, reaching what is known as Layer Four, the brain region most directly stimulated by the optic nerve."
A small video camera will transmit real-time imagery to a pocket-size processing unit. There, special algorithms will determine the most essential aspects of each image and break them down into a running series of grids of light and dark. The grids will be streamed wirelessly to a magnetic induction coil placed against the back of the patient's head nearest the visual cortex. The induction coil will be able to remotely spawn a tiny charge in each of the electrodes as appropriate, which will then stimulate the visual cortex much the same way as the optic nerve would normally do.
"We will actually have an advantage over implanted retinal prosthetics," says Lowery. "Most of our sharpest vision takes place in a tiny portion of the retina rich in rods and cones known as the fovea. The fovea is only about a square millimeter in size, so intraocular prosthetics must also make use of retinal tissue more associated with peripheral vision. The brain area that actually processes central vision is twenty-five times larger than the retinal tissue it services, however, which gives us potentially twenty-five times the resolution of a retinal implant."
Lowery and his team hope to initiate their first clinical trials by the end of 2016. "We plan to begin with four tiles, but eventually we hope to increase that number to eleven," he states. "We also hope to reach ten frames a second in transmission speed." According to Lowery, the resolution could also potentially be enhanced many times over by coating the electrodes with special hormones called brain-derived neurotropic factors. "Instead of poking the brain neurons with electrodes, these chemicals would actually encourage the neurons to reach out and make contact and new connections, as though the electrodes were other brain cells."
Also according to Lowery, realistic depictions of the world around us are not the be all and end all of Gennaris's potential. "We already have facial recognition that does a great job of identifying people. Imagine a special icon representing your husband or wife, others for each of your children that could include emotional content, smiles, tears, and the like. Direction and distance markers for doors, elevators, and windows would also be possible. We could even generate runway-light-like guidance systems to help navigate a warren of unfamiliar corridors, pointing out obstacles along the way."
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