To restore sight to ~150,000 veterans (and others) that are blind as the result of retinal degenerative diseases (e.g. macular degeneration or retinitis pigmentosa), several worldwide groups are 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. Ongoing clinical testing provides strong evidence that such devices have the potential to restore high levels of vision to the blind e.g. they enable shape recognition, improved ambulation and even allow some limited reading. Recent regulatory approval allows commercial sale of two of these devices, making this approach a viable treatment option. Unfortunately however, clinical results have been inconsistent and the quality of elicited percepts still remains crude in most patients. Because the quality of elicited vision is thought to arise directly from the pattern of neural activity elicited in the retina, we study and compare the patterns of neural activity that arise from different forms of stimulation with the goal of developing more effective stimulation methods. Targeting bipolar cells (retinal interneurons) with electric stimulation is thought to generally be advantageous because it utilizes the surviving retinal circuitry to create neural activity that presumably is a closer match to normal (physiological) signaling patterns, and therefore, easier for the brain to interpret. While most existing devices are thought to target bipolar cells, the actual benefits of this approach have not been evaluated previously and will be the focus of the first aim. Retinal degeneration can alter the synaptic pathways that shape bipolar-mediated patterns and we will therefore also evaluate how efficacy changes during the course of degeneration. Additional work from our lab suggests that the fading of percepts reported during clinical use may be tied to a loss of sensitivity that arises in response to repetitive activation of the retinal network (i.e. from bipolar cell activatin). We have new preliminary results that show considerable variability in the amount of loss and suggest that some of the cell types thought to mediate conscious vision may be the ones most sensitive to repetitive stimulation. Our goal in Aim 2 is to determine the sensitivity of all key cll types and evaluate whether the loss in sensitivity can be mitigated by alternative (repetitive) stimulation schemes.
The final aim will look at the effectiveness with which small electrodes create physio- logical signaling patterns. Our preliminary results suggest small electrodes are less effective in activating the network and we will study their effectiveness in both the healthy and degenerate retinas. To maximize the translational value of our work, all testing will be performed with a clone of one of the commercially available devices - the Alpha-IMS from Retina Implant, AG.

Public Health Relevance

It is estimated that over 150,000 veterans are blind as the result of retinal degenerative diseases such as macular degeneration or retinitis pigmentosa. Several groups are developing a retinal prosthetic - a device implanted within the retina that electrically stimulates surviving neurons - with the goal of restoring sight to the blind. In ongoing clinical testing, implanted devices allow shape recognition, improved mobility and even limited reading in a small percentage of patients. However, the overall quality of elicited vision remains limited and very inconsistent. Since percept quality arises directly from the neural activity elicited in the retina we are studying the neural activity arising from one of the commercially available devices. To maximize the translational value of the proposed aims, we are performing experiments in both the normal and degenerate retinas and are working with the manufacturer to speed up clinical implementation.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01RX001663-01A1
Application #
8867325
Study Section
Sensory Systems/Communication (RRD3)
Project Start
2015-01-01
Project End
2017-12-31
Budget Start
2015-01-01
Budget End
2015-12-31
Support Year
1
Fiscal Year
2015
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; Werginz, Paul; Fried, Shelley I (2018) Electric stimulus duration alters network-mediated responses depending on retinal ganglion cell type. J Neural Eng 15:036010
Lee, Seung Woo; Fried, Shelley I (2017) Enhanced Control of Cortical Pyramidal Neurons With Micromagnetic Stimulation. IEEE Trans Neural Syst Rehabil Eng 25:1375-1386
Freeman, Daniel K; O'Brien, Jonathan M; Kumar, Parshant et al. (2017) A Sub-millimeter, Inductively Powered Neural Stimulator. Front Neurosci 11:659
Im, Maesoon; Fried, Shelley I (2016) Directionally selective retinal ganglion cells suppress luminance responses during natural viewing. Sci Rep 6:35708
Lee, Seung Woo; Fallegger, Florian; Casse, Bernard D F et al. (2016) Implantable microcoils for intracortical magnetic stimulation. Sci Adv 2:e1600889
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
Im, Maesoon; Fried, Shelley I (2015) Indirect activation elicits strong correlations between light and electrical responses in ON but not OFF retinal ganglion cells. J Physiol 593:3577-96
Lee, Seung Woo; Fried, Shelley I (2015) Suppression of subthalamic nucleus activity by micromagnetic stimulation. IEEE Trans Neural Syst Rehabil Eng 23:116-27
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

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