To restore sight to ~150,000 veterans that are blind as the result of retinal degenerative diseases (e.g. macular degeneration or retinitis pigmentosa), our group and others are actively developing a retinal prosthetic - a device designed to restore vision by electrically stimulating inner retinal neurons, large numbers of which have been shown to survive the degeneration process. Recent clinical trials provide strong evidence that such devices can restore high levels of vision (e.g. reading) to the blind. However, clinical results are still highly inconsistent and percept quality remains somewhat crude. Because the quality of elicited vision is thought to arise directly from the pattern of neural activity elicited in the retina, we are developing new stimulation methods that create specific patterns of activity. Electrodes from the sub-retinal implant are positioned adjacent to bipolar cells (in the space previously occupied by the photoreceptors). While bipolar cells are thought to be the target of sub-retinal stimulation, little is known about how these neurons respond to stimulation, and, whether different parameters of stimulation alter their response. In addition, inhibitory amacrine cells are also closely situated to the stimulating electrodes and, as a result, may also be activated by stimulation. Activation of amacrine cells is thought to suppress the retinal response to further stimulation. Patch clamp measurements are a powerful tool for studying this kind of response as they allow two important components of the elicited response to be measured: (1) the excitatory (or inhibitory) input to ganglion cells can be measured directly (a measure of bipolar or amacrine cell activation), and (2) individual spikes can be measured in ganglion cells - pharmacological manipulation allows the spikes arising from bipolar cell activation to be distinguished. Thus, we can directly measure the activation levels of bipolar or amacrine cells to different types of stimulation. Our lab has much experience making these sorts of measurements and preliminary results suggest that different types of stimulus waveforms can greatly affect the bipolar cell response. In addition, it is important to understand whether bipolar cells remain responsive to stimulation as the retina degenerates. Therefore, we will study the responsiveness of retinal neurons to stimulation at various stages of retinal degeneration in the rd10 mouse. Findings from this study will inform the stimulation methods of our own device as well as by the devices of other research groups and will lead to improvements in the quality of elicited vision.

Public Health Relevance

It is estimated that over 150,000 veterans are blind as the result of retinal degenerative diseases such as macular degeneration (AMD) or retinitis pigmentosa. These diseases are more prevalent in the older veteran population and, as a result, the problems associated with blindness are likely to persist, or even get worse, as a new generation of soldiers age. To restore sight to such patients, our group is developing a retinal prosthetic - a device implanted within the retina that electrically stimulates surviving neurons. Visual percepts have been successfully elicited in the blind with these devices but their quality remains inconsistent and somewhat limited. Since percept quality is thought to result from the pattern of neural activity elicited in the retina, we are studying how to elicit more effective patterns. To further evaluate effectiveness, testing will be performed in control animals as well as in rd10, a well-established rat model of retinal degeneration.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01RX000350-01A1
Application #
8083729
Study Section
Rehabilitation Engineering & Prosthetics/Orthotics (RRD7)
Project Start
2011-04-01
Project End
2014-03-31
Budget Start
2011-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2011
Total Cost
Indirect Cost
Name
VA Boston Health Care System
Department
Type
DUNS #
034432265
City
Boston
State
MA
Country
United States
Zip Code
02130
Im, Maesoon; Fried, Shelley I (2016) Directionally selective retinal ganglion cells suppress luminance responses during natural viewing. Sci Rep 6:35708
Im, Maesoon; Fried, Shelley I (2016) Temporal properties of network-mediated responses to repetitive stimuli are dependent upon retinal ganglion cell type. J Neural Eng 13:025002
Twyford, Perry; Fried, Shelley (2016) The Retinal Response to Sinusoidal Electrical Stimulation. IEEE Trans Neural Syst Rehabil Eng 24:413-23
Lee, Seung Woo; Fried, Shelley I (2015) Suppression of subthalamic nucleus activity by micromagnetic stimulation. IEEE Trans Neural Syst Rehabil Eng 23:116-27
Werginz, P; Fried, S I; Rattay, F (2014) Influence of the sodium channel band on retinal ganglion cell excitation during electric stimulation--a modeling study. Neuroscience 266:162-77
Lee, Seung Woo; Fried, Shelley I (2014) The response of L5 pyramidal neurons of the PFC to magnetic stimulation from a micro-coil. Conf Proc IEEE Eng Med Biol Soc 2014:6125-8
Twyford, Perry; Cai, Changsi; Fried, Shelley (2014) Differential responses to high-frequency electrical stimulation in ON and OFF retinal ganglion cells. J Neural Eng 11:025001
Cai, Changsi; Twyford, Perry; Fried, Shelley (2013) The response of retinal neurons to high-frequency stimulation. J Neural Eng 10:036009
Lee, Seung Woo; Eddington, Donald K; Fried, Shelley I (2013) Responses to pulsatile subretinal electric stimulation: effects of amplitude and duration. J Neurophysiol 109:1954-68
Fang, Yuan; Cho, Kin-Sang; Tchedre, Kissaou et al. (2013) Ephrin-A3 suppresses Wnt signaling to control retinal stem cell potency. Stem Cells 31:349-59

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