Neural Responses to Multielectrode Stimulation of Healthy and Degenerate Retina

Halupka, Kerry J.; Abbott, Carla J; Wong, Yan T.; Cloherty, Shaun L.; Grayden, David B.; Burkitt, Anthony N.; Sergeev, Evgeni N.; Luu, Chi D; Brandli, Alice; Allen, Penelope J; Meffin, Hamish; Shivdasani, Mohit N.

doi:10.1167/iovs.16-21290

Cited by 22 publications

(19 citation statements)

References 62 publications

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“…The fact that responses were largely similar suggests that the response differences that arise between different types of RGCs are lost as the neural signal propagates from the retina to V1, at least for the stimulating conditions used here. We cannot rule out the possibility that response differences exist in the lateral direction (Halupka et al, 2017), e.g., beyond the region captured by our single penetrating electrode, and this will be interesting to explore in future studies. The spikes that occurred after the period of inhibition were thought to be the recovery of spontaneous spikes and not an additional phase of the electrically elicited response – this is because cells with a low spontaneous rate did not show spikes at the end of the inhibition period.…”

Section: Discussionmentioning

confidence: 99%

Response of Mouse Visual Cortical Neurons to Electric Stimulation of the Retina

2019

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Retinal prostheses strive to restore vision to the blind by electrically stimulating the neurons that survive the disease process. Clinical effectiveness has been limited however, and much ongoing effort is devoted toward the development of improved stimulation strategies, especially ones that better replicate physiological patterns of neural signaling. Here, to better understand the potential effectiveness of different stimulation strategies, we explore the responses of neurons in the primary visual cortex to electric stimulation of the retina. A 16-channel implantable microprobe was used to record single unit activities in vivo from each layer of the mouse visual cortex. Layers were identified by electrode depth as well as spontaneous rate. Cell types were classified as excitatory or inhibitory based on their spike waveform and as ON, OFF, or ON-OFF based on the polarity of their light response. After classification, electric stimulation was delivered via a wire electrode placed on the surface of cornea (extraocularly) and responses were recorded from the cortex contralateral to the stimulated eye. Responses to electric stimulation were highly similar across cell types and layers. Responses (spike counts) increased as a function of the amplitude of stimulation, and although there was some variance across cells, the sensitivity to amplitude was largely similar across all cell types. Suppression of responses was observed for pulse rates ≥3 pulses per second (PPS) but did not originate in the retina as RGC responses remained stable to rates up to 5 PPS. Low-frequency sinusoids delivered to the retina replicated the out-of-phase responses that occur naturally in ON vs. OFF RGCs. Intriguingly, out-of-phase signaling persisted in V1 neurons, suggesting key aspects of neural signaling are preserved during transmission along visual pathways. Our results describe an approach to evaluate responses of cortical neurons to electric stimulation of the retina. By examining the responses of single cells, we were able to show that some retinal stimulation strategies can indeed better match the neural signaling patterns used by the healthy visual system. Because cortical signaling is better correlated to psychophysical percepts, the ability to evaluate which strategies produce physiological-like cortical responses may help to facilitate better clinical outcomes.

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Section: Discussionmentioning

confidence: 99%

Response of Mouse Visual Cortical Neurons to Electric Stimulation of the Retina

2019

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“…Therefore, considering animal welfare, limiting the blindness in one eye by direct drug application could be a good alternative to systemic application. Intravitreal injection to induce RD has been tried with various drugs in various kind of animals [2021222324252627]. Rösch et al determined that intravitreal application of MNU leads to unilateral photoreceptor degeneration in mice, thereby avoiding systemic side effects [20].…”

Section: Introductionmentioning

confidence: 99%

Development of a Post-vitrectomy Injection of N-methyl-N-nitrosourea as a Localized Retinal Degeneration Rabbit Model

Ahn

Cha

et al. 2019

Exp Neurobiol

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Since genetic models for retinal degeneration (RD) in animals larger than rodents have not been firmly established to date, we sought in the present study to develop a new rabbit model of drug-induced RD. First, intravitreal injection of N-methyl-N-nitrosourea (MNU) without vitrectomy in rabbits was performed with different doses. One month after injection, morphological changes in the retinas were identified with ultra-wide-field color fundus photography (FP) and fundus autofluorescence (AF) imaging as well as spectral-domain optical coherence tomography (OCT). Notably, the degree of RD was not consistently correlated with MNU dose. Then, to check the effects of vitrectomy on MNU-induced RD, the intravitreal injection of MNU after vitrectomy in rabbits was also performed with different doses. In OCT, while there were no significant changes in the retinas for injections up to 0.1 mg (i.e., sham, 0.05 mg, and 0.1 mg), outer retinal atrophy and retinal atrophy of the whole layer were observed with MNU injections of 0.3 mg and 0.5 mg, respectively. With this outcome, 0.2 mg MNU was chosen to be injected into rabbit eyes (n=10) at two weeks after vitrectomy for further study. Six weeks after injection, morphological identification with FP, AF, OCT, and histology clearly showed localized outer RD - clearly bordered non-degenerated and degenerated outer retinal area - in all rabbits. We suggest our post-vitrectomy MNU-induced RD rabbit model could be used as an interim animal model for visual prosthetics before the transition to larger animal models.

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“…9 A-iii and -iv) or dark adaptation (Fig. 9 A-i and ii), which means that the PAMAM injection does not influence the cone and rod functions in the retina (30,31). There was also no obvious difference in the light adaptation after the PAMAM treatment with 100 μg/mL postoperatively one-week ( Fig.…”

Section: In Vivo Biocompatibility Evaluationmentioning

confidence: 83%

Are PAMAM dendrimers safe for ocular applications? -- Toxicological evaluation in ocular cells and intraocular tissues

Chen

Tang

Wen

et al. 2020

Preprint

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Backgrounds: The human eye is a sophisticated and sensitive sensory organ. Due to its dynamic and static barriers, efficient drug therapy for eye diseases is problematic. Polymeric delivery systems have been rapidly developed to overcome this problem, where polymeric dendrimers have received much attention for their unique structures. However, there is insufficient research on whether dendrimer nanomaterials could be used in ophthalmology. Poly (amidoamine) (PAMAM) is a kind of commercialized and extensively used dendrimer. Herein the ocular cytotoxicity and biosafety of PAMAM dendrimers were deeply evaluated by conducting in vitro and in vivo experiments on ocular systems. The effects of generation (G4.0, G5.0, and G6.0) and concentration on cell metabolism, apoptosis, and oxidative damage were carried out. Ocular irritation and intravitreal injection effects were also measured. Results: The results showed that the cytotoxicity of PAMAM increased with increasing generation number. PAMAM at a concentration that below 50 μg/mL was less harmful to the ocular tissues, whereas it caused apparent damage when above 50 μg/mL in the investigated situation. Moreover, singlet oxygen generation was detected in the cells after 50 μg/mL (and above) PAMAM treatment. The in vivo results show that there is no macroscopic structural change observed from fundus and histopathological section images, whereas it shows more functional impairment according to optical coherence tomography (OCT) and electroretinogram (ERG) when treated by 100 μg/mL PAMAM. Conclusion: Overall, a higher concentration of PAMAM, such as above 50 μg/mL, may cause ocular functional damage. The concentrations that are (or lower than) 50 μg/mL showed good biocompatibility and biosafety in human ocular cells and tissues.

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Neural Responses to Multielectrode Stimulation of Healthy and Degenerate Retina

Abstract: Significant differences exist between cortical responses to stimulation of healthy and degenerate retinae. Our results highlight the importance of using a retinal degeneration model when evaluating the efficacy of novel stimulation paradigms.

Cited by 22 publications

References 62 publications

Response of Mouse Visual Cortical Neurons to Electric Stimulation of the Retina

Response of Mouse Visual Cortical Neurons to Electric Stimulation of the Retina

Development of a Post-vitrectomy Injection of N-methyl-N-nitrosourea as a Localized Retinal Degeneration Rabbit Model

Are PAMAM dendrimers safe for ocular applications? -- Toxicological evaluation in ocular cells and intraocular tissues

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