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Retinotopic Responses in the Visual Cortex Elicited by Epiretinal Electrical Stimulation in Normal and Retinal Degenerate Rats

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Retinotopic Responses in the Visual Cortex Elicited by Epiretinal Electrical Stimulation in Normal and Retinal Degenerate Rats https://doi.org/10.1167/tvst.7.5.33 Article Retinotopic Responses in the Visual Cortex Elicited by Epiretinal Electrical Stimulation in Normal and Retinal Degenerate Rats Kiran Nimmagadda1,2 and James D. Weiland3,4 1 Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, USA 2 USC – Caltech MD/PhD Program, Los Angeles, CA, USA 3 Department of Biomedical Engineering, The University of Michigan, Ann Arbor, MI, USA 4 Department of Ophthalmology and Visual Sciences, The University of Michigan, Ann Arbor, MI, USA Correspondence: James D. Weiland, Purpose: Electronic retinal prostheses restore vision in people with outer retinal The University of Michigan, Bio- degeneration by electrically stimulating the inner retina. We characterized visual medical Engineering and Ophthal- cortex electrophysiologic response elicited by electrical stimulation of retina in mology, 2200 Bonisteel Blvd, 1107 normally sighted and retinal degenerate rats. Carl A. Gerstacker Building, Ann Methods: Nine normally sighted Long Evans and 11 S334ter line 3 retinal degenerate Arbor, MI 48109, USA. e-mail: (rd) rats were used to map cortical responses elicited by epiretinal electrical [email protected] stimulation in four quadrants of the retina. Six normal and six rd rats were used to Received: 12 February 2018 compare the dendritic spine density of neurons in the visual cortex. Accepted: 24 August 2018 Results: The rd rats required higher stimulus amplitudes to elicit responses in the Published: 31 October 2018 visual cortex. The cortical electrically evoked responses (EERs) for both healthy and rd rats show a dose-response characteristic with respect to the stimulus amplitude. The Keywords: electrical stimulation; EER maps in healthy rats show retinotopic organization. For rd rats, cortical retinotopy cortical electrophysiology; retino- is not well preserved. The neurons in the visual cortex of rd rats show a 10% higher topy;rat;retinitispigmentosa dendritic spine density than in the healthy rats. Citation: Nimmagadda K, Weiland Conclusions: Cortical activity maps, produced when epiretinal stimulation is applied JD. Retinotopic responses in the to quadrants of the retina, exhibit retinotopy in normal but not rd rats. This is likely visual cortex elicited by epiretinal due to a combination of degeneration of the retina and increased stimulus thresholds electrical stimulation in normal and in rd, which broadens the activated area of the retina. retinal degenerate rats. Trans Vis Sci Tech. 2018;7(5):33, https://doi.org/ Translational Relevance: Loss of retinotopy is evident in rd rats. If a similar loss of retinotopy is present in humans, retinal prostheses design must include flexibility to 10.1167/tvst.7.5.33 account for patient specific variability. Copyright 2018 The Authors RP is more severe and both are characterized by Introduction progressive loss of photoreceptors. The photoreceptor loss in AMD and RP can lead to complete blindness The two most common outer retinal degenerative and profound disability. It is estimated that approx- diseases are age-related macular degeneration (AMD) and retinitis pigmentosa (RP). RP is a general term imately 15 million people suffer from vision loss due for a disparate group of inherited diseases with over to these diseases worldwide, and these numbers are 200 genetic mutations that have been identified so far. expected to rise as the population ages. The etiology of AMD is multifactorial1,2 and includes The societal impact of outer retinal degenerative genetic mutations in photoreceptors and accumula- disorders is tremendous. These disorders are one of tion of drusen. Age, smoking, race (more common the leading causes of adult-onset blindness. Studies among Caucasians than among African-Americans or from multiple countries3,4 of patients with AMD has Hispanics/Latinos), and family history are the main shown that the disease has a significant emotional and risk factors for AMD. AMD is more prevalent, but functional impact on patients, providers, and society 1 TVST j 2018 j Vol. 7 j No. 5 j Article 33 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from tvst.arvojournals.org on 09/27/2021 Nimmagadda and Weiland overall. In the United States, there are approximately and electrical stimulus applied subretinally in nor- 700,000 new AMD patients each year,5,6 10% of who mally sighted rats.17 In this paper, we characterize will become legally blind. As the United States electrophysiologic response in the visual cortex of population ages, it is estimated7 that more elderly healthy Long Evans rats and retinal degenerate (rd) persons will become blind from AMD than from S334ter line 3 rats elicited by electrical stimulation of glaucoma and diabetic retinopathy combined. A the retina. Electrophysiology recording using micro- value-based analysis8 of the societal burden of electrodes in the visual cortex provides a functional AMD estimates the yearly cost of the disease borne readout in the visual system of the effect of electrically by the United States economy to be $30 billion. stimulating the retina. The human (and rat) visual Because these studies are restricted to AMD, they cortex has an orderly arrangement of visual field underestimate the societal impact of the full spectrum processing, termed retinotopy. This retinotopic orga- of outer retinal degenerative diseases. While RP has a nization represents specificity in the spatial organiza- lower incidence than AMD, affecting approximately tion of connections in the various layers of the visual one in 2000 individuals worldwide,9 the individual system with respect to the visual field, and is an impact is more devastating and costlier due to the important element of functional vision. Maintenance earlier onset and greater severity of RP compared of retinotopy after photoreceptor loss is unclear. One with AMD. of the overarching goals in the development of retinal There is currently no known cure for vision loss prostheses is to provide functional vision for patients caused by outer retinal degeneration. Postmortem suffering from photoreceptor degeneration. Because histologic analysis of retinal tissue in RP and AMD retinotopy is a fundamental aspect of functional patients has given us valuable insight. Even when vision, our research aims to investigate the nature of photoreceptor cell loss is virtually complete, other cortical retinotopy elicited by the electrical stimula- cells in the retina generally survive,10 enough to be tion of the retina in normally sighted and blind rats. activated11 by electrical stimulus. This finding pro- This paper presents the first work in the study of vided the impetus for using implantable electronic visual cortex retinotopy in response to epiretinal retinal prostheses to provide functional vision for electrical stimulation of the healthy versus rd retina. patients with blindness due to photoreceptor degen- While the anatomic changes in the retina in response eration. Photoreceptor degeneration has been to photoreceptor degeneration are well studied, the shown12 to lead to extensive remodeling in the inner effect on visual cortex neurons has not been studied as retina. Electronic retinal prostheses electrically stim- extensively. We present preliminary comparison of ulate surviving neurons and circuitry in the inner anatomic differences in the visual cortex neurons retina and represent an emerging technology13 in the between normally sighted and blind rats using the treatment of such diseases. Golgi stain and comparing spine density. There has been limited previous research in characterizing in vivo visual cortex electrophysiology Materials and Methods response elicited by epiretinal electrical stimulation of retina. Published results have been limited to exper- Animals iments performed on three anesthetized cats that primarily investigated safety and surgical technique14 Healthy Long Evans (postnatal day P90–P120, n ¼ of stimulating electrode array implantation. Two 9) rats and S334ter line 3 rats with retinal degener- studies have compared cortical responses elicited by ation (rd) (P120–P300, n ¼ 11) were used for cortical photovoltaic subretinal prostheses with visual-evoked response mapping of electrical stimulation of retina in potentials15,16 in normally sighted and blind rats. four quadrants of the retina. The weight of the rd rats More recently, intrinsic optical imaging was used to ranged from 228 to 278 g (mean 256 g with standard study the visual cortex response elicited by light deviation of 21.1 g). The weight of the rd rats ranged stimulus versus electrical stimulus applied to subret- from 270 to 321 g (mean 298 g with standard inal electrode arrays in normally sighted rats.17 deviation of 19.3 g). The retinal degenerate rats were Rat models of retinal degeneration have greatly bred in the USC animal care facilities by mating improved the understanding of the pathophysiology17 homozygous S334ter line 3 rats with Long Evans rats of photoreceptor degenerative diseases. Rats have (Envigo, Hayward, CA). The homozygous S334ter also been used to characterize retinotopic maps of the line 3 rats for breeding were obtained from the Rat visual cortex activity18 in response to light stimulus Resource Research Center of the University of 2 TVST j 2018 j Vol. 7 j No. 5 j Article 33 Downloaded from tvst.arvojournals.org on 09/27/2021 Nimmagadda and Weiland Missouri. Because the mutation is dominant, all positioned midway within the
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