Pathology of damaging electrical stimulation in the retina
Introduction
An electronic retinal prosthesis has been proposed to restore vision in patients with blindness due to retinitis pigmentosa (RP) and age- related macular degeneration (Zrenner, 2002, Weiland et al., 2005). In both conditions, photoreceptor death ultimately leads to significant loss in visual acuity and in many cases blindness. Although the wiring of the retina is altered with progressive degeneration (Marc et al., 2003), inner retina neurons are still present (Stone et al., 1992, Santos et al., 1997, Humayun et al., 1999). Retinal prostheses are designed to create the sensation of vision by activating inner retina neurons with small pulses of electricity. This stimulation results in depolarization of the cells and the initiation of retinal ganglion cell action potentials, which the visual system perceives as a light stimulus at the retina. The principle of electrical activation of sensory systems is well established by years of experimentation and by the success of the cochlear implant. Clinical trials of prototype retinal prostheses have demonstrated that subjects see light in response to electrical stimulation and that simple visual tasks can be performed (Mahadevappa et al., 2005, Hornig et al., 2006, Zrenner et al., 2006). Despite the many technological obstacles to producing a device that interfaces with the neural retina, potential advantages to this approach include the applicability to all forms of photoreceptor degeneration.
The purpose of this study was to investigate the pathology of retinal damage due to high charge density stimulation. The need for this investigation stems from the fact that a retinal prosthesis must be both effective and safe, but most of the biological research in retinal prostheses has focused on the issue of effectiveness, including electrophysiology in animal models and psychophysics in human test subjects (Rizzo et al., 2004, Mahadevappa et al., 2005, Sekirnjak et al., 2006). While a few studies have shown that low levels of stimulation are safe (Guven et al., 2005, Pardue et al., 2005), no study has investigated the pathology of damage created by electrical stimulation of the retina. It is important to study the effects of high charge density stimulation, since data from human clinical trials has not shown any decrease in threshold charge related to decreased electrode diameter (Guven et al., 2006). Increasing the resolution of a retinal prosthesis may require smaller electrodes that can be densely placed in contact in the central retina. If electrode sizes shrink, but stimulus charge stays constant, charge density will increase.
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Animals
All animal experiments adhered to Association for Research in Vision and Ophthalmology guidelines and were approved by the University of Southern California Institutional Animal Care and Use Committee. Twenty adult Long Evans pigmented rats were included in this study (age 3–7 months) with experiments performed on one eye in each animal.
Experimental groups
There were two experimental groups: Group 1 (stimulating electrode near, but not contacting the retina) and Group 2 (stimulating electrode contacting the
Operative and post-operative observations
The electrode could be positioned routinely without causing retinal detachment or intraocular bleeding. Small pre-retinal hemorrhage was noted in two rats at the end of the surgery but this was resolved after 2 weeks. Due to post-operative corneal haziness, ocular photography could only be obtained in a limited number of rats; however, indirect examinations were performed in all rats. The indirect exam observations were consistent within groups. All rats in Group 1 (no contact, 0, 0.05, and 0.2
Discussion
Neural damage from electrical stimulation has been investigated in other neural systems (McCreery et al., 1990, McCreery et al., 1997) The principle of charge balanced stimulation was established over 40 years ago (Lilly and Sheer, 1961). Since then, a number of studies have investigated issues such as electrode materials for safe stimulation (Rose and Robblee, 1990, Weiland et al., 2002), neural injury from stimulation (Agnew et al., 1986), and neural survival with long-term stimulation (Leake
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