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Author: James D. Weiland and Mark S. Humayu
Researchers are working on implantable neurostimulators to treat debilitating neurological conditions, including blindness.
Most functions of the human body are controlled by small electrical signals delivered via nerves. Thus, it is no surprise that electrical signals applied to the body from external sources can modulate physiological activity. In fact, reports of physiological electromodulation date back to the eighteenth century, but scientists of that time did not know enough about neurophysiology to understand the basic mechanism by which electricity could modulate biological activity. Today, with many advances in neuro-biology, medicine, and engineering, we can inform the design of clinically beneficial, implantable neurostimulation devices to treat a number of debilitating neurological diseases.
Implantable neural stimulators activate nerve cells, which are responsible for processing and communicating information between the brain and other parts of the body (Kandel et al., 1991). Specialized nerve cells called sensory receptors convert physical stimuli into electrical signals that can be relayed by other nerve cells to the brain. Because nerve cells are polarized, an electrical potential can be measured across the cell membrane. Transient changes in membrane potential signal to other cells that an event has occurred, and neural networks, composed of connected neurons, determine if that event, along with input from other cells, requires action by other parts of the nervous system. Events such as the onset of disease or an injury that damages nerve cells, particularly sensory cells, can result in significant disability for the affected individual, including loss of sensory input, diminished capability to process information, or reduced motor function.
How Electrostimulation Works
Activating a nerve cell by an electrical signal generated by an implanted device is more complicated than connecting two wires. The complexity arises partly from differences in carriers of the electrical charge. In metals, electrons carry the charge, whereas in the body, ions carry the charge. The conversion from electrons to ions occurs at the electrode, typically a metal or metal oxide, in direct contact with the extracellular fluid. An electrical signal applied to the electrode causes current to flow in the tissue via the movement of charged sodium, chloride, potassium, and other ions.
The end effect is to depolarize the nerve cell membrane. Depolarization beyond a certain level results in an action potential (as is the case with natural neural signaling). An electrode has this affect on many neurons in its vicinity, and the summed activity of these neurons is an electrically elicited sensation or modulated function.
A number of successful neurostimulators are in widespread use. For example, cochlear implants stimulate the auditory nerve enabling deaf people to hear, often well enough to talk on a telephone. Implantable neuro-transmitters can also relieve unrelenting pain that sometimes results from nerve damage or disease. For example, implantable devices that stimulate the lower spinal cord are known to decrease or even eliminate the feeling of pain.
A dramatic example of electrical stimulation is in the treatment of Parkinson’s disease. By stimulating a part of the brain called the thalamus, many symptoms of Parkinson’s subside almost immediately. Parkinson’s patients with uncontrollable tremor or rigidity that severely limits motor function show improved coordination within minutes of commencing stimulation.
Treating Blindness with Electrical Stimulation
Causes of Blindness
The retina is a light-sensitive, multilayer tissue that lines the interior surface of the back of the eye (Figure 1) (see http://webvision.med.utah.edu/). Photoreceptors (rods and cones) are the light-sensing cells of the retina; the other cells process photoreceptor signals and send information to the brain via the optic nerve. When photoreceptors degenerate due to disease, the retina can no longer respond to light. However, sufficient numbers of other retinal nerve cells remain so that the electrical stimulation of these cells results in the perception of light.
Diseases such as retinitis pigmentosa and age-related macular degeneration cause blindness for millions of people (Gehrs et al., 2010; Hartong et al., 2006) and are presently untreatable. At first, symptoms are subtle, such as difficulty seeing at night or blurred central vision, but ultimately, these conditions result in blindness. Given that vision is the sense by which people obtain most of their information about their surroundings, blindness has an extremely detrimental impact on the afflicted.
The Development of Electrical Stimulation
Electrical stimulation has been proposed as a treatment for blindness for decades, but only recently have systems consistent with clinical use been developed. The first documented use of electrical stimulation to create visual perception dates to 1755, when Charles LeRoy discharged a large capacitor through the head of a blind person, who described seeing “flames descending downwards” (Marg, 1991). Over time, as science, medicine, and engineering have progressed, it has become feasible to develop a permanent implant to stimulate the retina.
Initial clinical experiments that provided proof-of-principle involved briefly inserting a handheld electrode into the eye of a blind person, stimulating the retina, and asking the person to describe what he or she saw, if anything, and to describe the sensation (Humayun et al., 1996; Rizzo et al., 2003). These simple yet essential experiments established initial design parameters for a permanent implantable device.
Retinal Prostheses: General Description and Current Clinical Systems
A retinal prosthesis consists of several components that perform specific functions: a camera that converts photons to digital data; a processing unit that generates stimulus commands based on the image; analog drivers that produce stimulus current; and an array of stimulating electrodes to deliver stimulus current to the retina (Weiland et al., 2005).
As shown in Figure 2, the electrode array can be positioned in two locations in the eye, the epiretinal surface and the subretinal space. These anatomical locations have come to define the two basic approaches being investigated for retinal prostheses. An epi-retinal implant would rest on the inner limiting membrane of the retina, whereas a subretinal implant would be inserted into the space occupied by photoreceptors in a healthy retina.
Several clinical trials have been conducted to test systems in blind humans. For the sake of brevity, only the trials that have produced the most significant results are discussed below.
An externally powered, subretinal microphoto-diode array (Figure 3 top), developed by Retinal Implant GmbH, has been tested in 12 subjects (Zrenner et al., 2011). The device has 1,500 repeating units on a single silicon chip. Each unit has the following elements: a microphotodiode that senses light, digital and analog circuitry that scales a voltage stimulus based on the sensed light, and a microelectrode that applies the stimulus to the retina. The voltage stimulus pulse is supplied by a source outside the eye.
The best test subject was able to read large letters (although it took a long time to do so) and demon-strated visual acuity of approximately 20/1,000. Other subjects showed pattern recognition, light detection, and object discrimination.
The ARGUS II retinal prosthesis (produced by Second Sight Medical Products Inc.)1 has been implanted in 30 subjects (Figure 3, bottom). The device has 60 electrodes and an external camera unit that delivers image information wirelessly to the implant. The best result to date for visual acuity is 20/1,200 (Humayun et al., 2011).
Twenty-two of the 30 subjects were able to read letters. However, with the ARGUS II device (as with the subretinal device described above), reading letters took much longer than reading with natural vision. ARGUS II subjects also demonstrated improved mobility, could sense the direction of a moving object, and had improved hand-eye coordination (Ahuja et al., 2011).
Assessing the Results
The results described above for both devices have generated considerable excitement among researchers in ophthalmology, vision, and biomedical engineering. The possibility of restoring vision has captured the imagination of many, and reports from the human test subjects testify to the promise of an implantable retinal prosthesis. In controlled tests, improved mobility was clearly evident, and subjects reported more confidence during ambulation.
Nevertheless, based on an objective analysis of the data as a whole, one must conclude that we are a long way from being able to claim “restored vision.” By all measures, the tested individuals are still considered blind, even when the devices function well. The best reported visual acuity was 20/1,000, whereas the cutoff for legal blindness is 20/200 (normal vision is 20/20).
In addition, the field of view is limited. The field for ARGUS II extends to 20 degrees (the limit for legal blindness), but natural vision has a 180-degree field of view. The subretinal results were even more limited, with current implants providing a field of view of less than 15 degrees.
Challenges for Artificial Vision
Meeting the Basic Challenges
We will need both technical and biological advances to increase visual acuity with future implants. For instance, simulations of artificial vision project that about 1,000 individual pixels are necessary for visual function such as reading (at near normal speed) and face recognition. To reach this goal, we will need improvements in electronic packaging (the materials and assembly techniques that protect the circuits from saline). This will be particularly important for the subretinal device described above, which now relies on a thin-film approach to protecting the subretinal electronics, because a thick enclosure does not fit in the subretinal space. In addition, low-power integrated circuits must be developed that can both generate an effective stimulus pattern to evoke form perception and use power efficiently to ensure safety.
Connecting Electrodes to the Retina
Even if the barriers described above can be overcome, we need a better understanding of how to connect the device to the retina and how the brain will respond to this type of input.
The subretinal device described above has 1,500 electrodes, but it does not achieve the visual acuity that would be possible if each electrode were acting independently. Higher visual acuity will require electrode arrays that are densely packed with small electrodes. However, to take advantage of this density, the electrode arrays must be consistently positioned in close contact with the retina.
Inconsistent positioning of the electrode array has been a major barrier for epiretinal implants. If electrode arrays can be developed that can conform to the surface of the retina and account for anatomical variations among patients, each electrode will be able to activate a small part of the retina, thereby increasing visual acuity.
Improving Stimulation and Rehabilitation
Better stimulation strategies will be necessary for perceptions to appear more natural. Currently, perceptions fade within seconds as neural adaptation mechanisms attenuate the artificial input. Researchers must focus on optimizing stimulus protocols to maximize user performance. Finally, rehabilitation strategies will be necessary to train users to maximize their performance with the implant.
The “Optogenetic” Approach
A new approach to artificial vision could potentially address some of the problems encountered with electronic retinal prostheses. The “optogenetic” technique would modify individual neurons to incorporate light-sensitive ion channels into the cell membrane; the most common light-sensitive channel is channelrhodopsin2 (ChR2) (Gradinaru et al., 2010). Ion channels are the means by which ions pass through the cell membrane, and membrane potential is influenced by whether channels are open or closed. When light of a specific wavelength is shone on the cell, ChR2 ion channels open, resulting in depolarization of the cell.
Bi et al. (2006) first demonstrated that this technique could be used to modify retinal ganglion cells, showing that light-evoked neural responses were present in a mouse model of retinal degeneration when the mouse retinal cells contained ChR2. Others have since expanded on this work.
The optogenetic approach has some significant advantages over the bioelectronic approach. By making each cell light sensitive, vision can potentially be restored to near-normal acuity. Also, by using light as the activating signal, the optics of the eye can focus an image on the retina. In other words, the optogenetic technique can come much closer to restoring natural vision than bioelectronic approaches.
Artificial vision based on optogenetics also has challenges that preclude clinical use. The main issue relates to sensitivity.
Currently, modified cells require that bright blue light (460 nm) be activated, roughly 7 orders of magnitude above the light-sensitivity threshold of normally sighted people. Thus, an external apparatus would still be required to convert an image from a camera into a light stimulus that interacts with the modified cells. In addition, it is not known if cells can be modified permanently, or if repeated injections would be needed.
Finally, it is not clear how such intense light would interact with a diseased retina, which has only remnant light sensitivity. A common symptom of retinitis pigmentosa, for example, is photophobia (discomfort in bright light), which is clearly not compatible with a therapy that requires intense light input into the eye.
These are interesting times for researchers on retinal prostheses. Clinical trials have shown both the promise and limitations of electrical stimulation as a treatment for blindness. People working in this field are constantly reminded of the wondrous sense of vision available to most of us, how reliant we are on our vision, and the devastating impact of vision loss. Given the complexity of vision, for the foreseeable future, prosthetic vision systems will clearly provide vision that is artificial in appearance and below the resolution necessary for complex, visually guided tasks.
However, even a slight improvement in vision can have a significant impact on quality of life. Restoring a person’s ability to see large objects and detect motion can increase confidence for navigating through unfamiliar environments. In addition, the brain has an amazing ability to adapt to new input, and an individual, through experience and training, can use other contextual and sensory information to improve his or her understanding of what is being “seen” via an artificial vision system.
Although important breakthroughs have been made, this field is still in the early stages. Moving toward the restoration of high-acuity vision will require concerted efforts by scientists, engineers, clinicians, and, most important, blind patients.
1Dr. Humayun has a financial interest in Second Sight medical Products Inc.
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