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

Abstract

PurposeElectronic retinal prostheses restore vision in people with outer retinal degeneration by electrically stimulating the inner retina. We characterized visual cortex electrophysiologic response elicited by electrical stimulation of retina in normally sighted and retinal degenerate rats.MethodsNine normally sighted Long Evans and 11 S334ter line 3 retinal degenerate (rd) rats were used to map cortical responses elicited by epiretinal electrical stimulation in four quadrants of the retina. Six normal and six rd rats were used to compare the dendritic spine density of neurons in the visual cortex.ResultsThe rd rats required higher stimulus amplitudes to elicit responses in the 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 EER maps in healthy rats show retinotopic organization. For rd rats, cortical retinotopy is not well preserved. The neurons in the visual cortex of rd rats show a 10% higher dendritic spine density than in the healthy rats.ConclusionsCortical activity maps, produced when epiretinal stimulation is applied to quadrants of the retina, exhibit retinotopy in normal but not rd rats. This is likely due to a combination of degeneration of the retina and increased stimulus thresholds in rd, which broadens the activated area of the retina.Translational RelevanceLoss of retinotopy is evident in rd rats. If a similar loss of retinotopy is present in humans, retinal prostheses design must include flexibility to account for patient specific variability.

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

“…The responses to pulsatile electrical stimulation were brief, typically persisting for ∼50 ms but always less than 100 ms. While the limited duration is consistent with previous studies (Cicione et al, 2012; Shivdasani et al, 2012; Nimmagadda and Weiland, 2018), they were still somewhat surprising given the prolonged duration in retinal neurons, e.g., spiking responses persisted for ∼150 ms in OFF RGCs and almost 200 ms in ON RGCs (Figure 5A). While it is possible that the different durations arise from methodological differences ( in vitro measurements in the retinal explant utilizing a small stimulating electrode vs. in vivo stimulation utilizing a much larger extraocular stimulating electrode), previous studies using a wide range of electrode locations, also report relatively short response durations using smaller, implanted electrodes (Eckhorn et al, 2006; Cicione et al, 2012; Shivdasani et al, 2012; Villalobos et al, 2014).…”

Monitoring Cortical Response and Electrode-Retina Impedance Under Epiretinal Stimulation in Rats

“…Table II summarizes the preclinical studies that have used electrode-retina impedance as a tool to guide or study surgical location. Preclinical studies of retinal prostheses with suprachoroidal stimulation arrays implanted between sclera and choroid [22,42] and epiretinal stimulation electrode arrays implanted in the vitreous cavity of the eye [23][24][25]46] pursued the impedance measurement approach to position the electrode array to the target neural tissue. Impedance spectroscopy over a wide range of frequency was used as a post-implantation monitoring tool in a subretinal study [37].…”

“…Electrode-retina distance is correlated with perceptual thresholds and thus visual perception [16][17][18][19]. Though the correlation between electrode-retina distance and electrical thresholds of stimulation has been shown across numerous animal models including mammals [20][21][22] and rodents [23][24][25], detailed studies of a range of electrode-retina proximity and its impact on cortical activation are limited.…”

“…In an early study, Shah et al demonstrated that electrode-retina impedance was strongly influenced by the location of the electrode in the eye and electrode diameter. Three epiretinal studies showed that impedance could be used to precisely position the epiretinal electrode on the retinal surface in rat models based on the inverse proportionality between single-frequency impedance and retinal proximity [23][24][25]. While impedance can be used faithfully to position the epiretinal electrode (array) on the retina, retinal compression remains undetected at high impedance level.…”

A Multi-Channel Asynchronous Neurostimulator With Artifact Suppression for Neural Code-Based Stimulations

“…Neural interface technology has made much progress in recent years aiming to advance basic neuroscience research and provide therapies to patients with neurological damages or diseases. Researchers have been using neural interface as a tool to record and manipulate neural circuits to study neural correlates of sensory, motor, and cognitive functions (Brecht et al, 2004; Nimmagada and Weiland, 2018; Salas et al, 2018). In the clinic, deep brain stimulation (DBS) has provided treatments to various neurological disorders such as epilepsy (Lee et al, 2015), depression (Schläpfer and Kayser, 2014), Parkinson’s disease (Voges et al, 2007), memory loss (Hamani et al, 2008), and Tourette’s syndrome (Ackermans et al, 2006).…”