Jang Hee Ye

Retinal ganglion cell responses to voltage and current stimulation in wild-type and rd1 mouse retinas

Retinal prostheses are being developed to restore vision for those with retinal diseases such as retinitis pigmentosa or age-related macular degeneration. Since neural prostheses depend upon electrical stimulation to control neural activity, optimal stimulation parameters for successful encoding of visual information are one of the most important requirements to enable visual perception. In this paper, we focused on retinal ganglion cell (RGC) responses to different stimulation parameters and compared threshold charge densities in wild-type and rd1 mice. For this purpose, we used in vitro retinal preparations of wild-type and rd1 mice. When the neural network was stimulated with voltage- and current-controlled pulses, RGCs from both wild-type and rd1 mice responded; however the temporal pattern of RGC response is very different. In wild-type RGCs, a single peak within 100 ms appears, while multiple peaks (approximately four peaks) with ∼ 10 Hz rhythm within 400 ms appear in RGCs in the degenerated retina of rd1 mice. We find that an anodic phase-first biphasic voltage-controlled pulse is more efficient for stimulation than a biphasic current-controlled pulse based on lower threshold charge density. The threshold charge densities for activation of RGCs both with voltage- and current-controlled pulses are overall more elevated for the rd1 mouse than the wild-type mouse. Here, we propose the stimulus range for wild-type and rd1 retinas when the optimal modulation of a RGC response is possible.

Temporal response properties of retinal ganglion cells in rd1 mice evoked by amplitude-modulated electrical pulse trains.

PURPOSE The electrophysiological properties of degenerated retinas responding to amplitude-modulated electrical pulse trains were investigated to provide a guideline for the development of a stimulation strategy for retinal prostheses. METHODS The activities of retinal ganglion cells (RGCs) in response to amplitude-modulated pulse trains were recorded from an in vitro model of retinal prosthesis, which consisted of an rd1 mouse retinal patch attached to a planar multielectrode array. The ability of the population activities of RGCs to effectively represent, or encode, the information on the visual intensity time series, when the intensity of visual input is transformed to pulse amplitudes, was investigated. RESULTS An optimal pulse amplitude range was selected so that RGC firing rates increased monotonically and linearly. An approximately 10-Hz rhythm was observed in the field potentials from degenerated retinas, which resulted in a rhythmic burst of spontaneous spikes. Multiple peaks were present in poststimulus time histograms, with interpeak intervals corresponding to the oscillation frequency of the field potentials. Phase resetting of the field potential oscillation by stimulation was consistently observed. Despite a prominent alteration of the properties of electrically evoked firing with respect to normal retinas, RGC response strengths could be modulated by pulse amplitude. Accordingly, the temporal information of stimulation could be faithfully represented in the RGC firing patterns by an amplitude-modulated pulse train. CONCLUSIONS The results suggest that pulse amplitude modulation is a feasible means of implementing a stimulation strategy for retinal prostheses, despite the marked change in the physiological properties of RGCs in degenerated retinas.

Characterization of retinal ganglion cell activities evoked by temporally patterned electrical stimulation for the development of stimulus encoding strategies for retinal implants

For successful restoration of visual function by retinal implant, a method for electrical stimulation should be devised so that the evoked activities of retinal ganglion cells (RGCs) should convey sufficient information on visual input. By observing RGC activities under different stimulation constraints, it may be possible to determine optimal pulse parameters, such as pulse rate, intensity, and duration, for faithful transmission of visual information. To test the feasibility of this approach, we analyzed RGC spike trains evoked by temporally patterned stimulation from retinal patches mounted on a planar multielectrode array. Assuming that the intensity of uniform visual input is transformed to amplitudes of pulse trains, we attempted to determine optimal methods for modulating the pulse amplitude so that the information essential for the perception of intensity variation is properly represented in RGC responses. RGC firing rates could be modulated to track the temporal pattern of pulse amplitude variations, which implies that pulse amplitude modulation is a plausible means to enable perception of temporal visual patterns by retinal implants. As expected, specific pulse amplitude modulation parameters were crucial for proper encoding of visual input. RGC firing rates increased monotonically according to the pulse amplitude in a defined pulse amplitude range (20-60 microA). The similarity between the RGC firing rate and the temporal pulse intensity pattern was highest when the pulse amplitude was modulated within this range. The optimal pulse rate range could be similarly determined.

Electrically-evoked Neural Activities of rd1 Mice Retinal Ganglion Cells by Repetitive Pulse Stimulation

For successful visual perception by visual prosthesis using electrical stimulation, it is essential to develop an effective stimulation strategy based on understanding of retinal ganglion cell (RGC) responses to electrical stimulation. We studied RGC responses to repetitive electrical stimulation pulses to develop a stimulation strategy using stimulation pulse frequency modulation. Retinal patches of photoreceptor-degenerated retinas from rd1 mice were attached to a planar multi-electrode array (MEA) and RGC spike trains responding to electrical stimulation pulse trains with various pulse frequencies were observed. RGC responses were strongly dependent on inter-pulse interval when it was varied from 500 to 10 ms. Although the evoked spikes were suppressed with increasing pulse rate, the number of evoked spikes were >60% of the maximal responses when the inter-pulse intervals exceeded 100 ms. Based on this, we investigated the modulation of evoked RGC firing rates while increasing the pulse frequency from 1 to 10 pulses per second (or Hz) to deduce the optimal pulse frequency range for modulation of RGC response strength. RGC response strength monotonically and linearly increased within the stimulation frequency of 1~9 Hz. The results suggest that the evoked neural activities of RGCs in degenerated retina can be reliably controlled by pulse frequency modulation, and may be used as a stimulation strategy for visual neural prosthesis.

Comparison of Voltage Parameters for the Stimulation of Normal and Degenerate Retina

Retinal prosthesis is regarded as a promising method for restoring vision for the blind with retinal diseases such as retinitis pigmentosa (RP) and age related macular degeneration (ARMD). Among the several prerequisites for retinal prosthesis to succeed, one of the most important is the optimization of electrical stimuli applied through the prosthesis. Since the electrical characteristics of diseased retina are expected to be different with those of normal retina, we investigated different voltage parameters to stimulate normal and degenerate retina. The retinal degeneration model (rd/rd mouse) was compared against control mice. Voltage stimulations were delivered via one channel of 60 channels 8x8 multi-electrode array (MEA), and ganglion cell activities were recorded with the remaining 58 channels. The parameters of voltage stimulation were set based on previous experiment with rabbit. Evoked ganglion cell responses were counted during a 10 ~ 20 ms time span after the stimulation. The voltage amplitudes and voltage durations were set to obtain consistent values for ganglion cell responses. When the same stimulus was applied on the rd/rd mouse, evoked ganglion cell responses were rarely observed. The distribution patterns of evoked responses appeared only on a site distant from the stimulation electrode on the rd/rd retina. Conversely, in normal retina, evenly distributed response patterns were observed. Since the charge intensity tends to decrease with the distance from stimulation electrode, the uneven patterns from the rd/rd mouse retina suggest that lower charge is required to evoke a response from rd/rd retina. Further study is necessary to have concrete stimulation parameters for testing rd/rd mice retina.

Electrical Stimulation of Isolated Rabbit Retina

Several research groups in the world are trying to restore useful vision for the patients of degenerate retina, such as retinitis pigmentosa (RP) and age related macular degeneration (ARMD) with retinal prosthesis. Recently Korean consortium launched for developing retinal prosthesis and as part of Korean retinal prosthesis project we provide preliminary experimental results regarding voltage parameters for the stimulation of isolated retina. Voltage stimulus was delivered via one of the channel of microelectrode array (MEA) and ganglion cell activities were recorded with remained 59 channels. We changed the voltage amplitude from 0.5 V to 3 V, which showed that threshold level for reliable ganglion cell response was 1.5 V. The calculated threshold for charge densities was 2123 muC/cm2 and charge delivery was 15 nC/phase. When we changed the stimulus duration from 100 mus to 1200 mus with fixed voltage of 2 V, the threshold level was 300 mus. The calculated charge densities and charge delivery were 1698 muC/cm 2 and 12 nC/phase, respectively. Even after the block of on-bipolar cell with L-(1)-2-amino-4-phosphonobutyric acid (APB), electrical stimulus evoked ganglion cell activities

Comparison of electrically-evoked ganglion cell responses in normal and degenerate retina

Retinal prosthesis is regarded as a promising method for restoring vision for the blind with retinal diseases such as retinitis pigmentosa (RP) and age related macular degeneration (ARMD). Among the several prerequisites for retinal prosthesis to succeed, one of the most important factors is the optimization of electrical stimulation applied through the prosthesis. From the previous study, we showed that the electrical characteristics of diseased retina are different from those of normal retina. For the next step, we compared electrically evoked response properties of retinal ganglion cells and established the thresholds for charge density in normal and rd1 mouse using multi-electrode array (MEA). The threshold for charge density was higher in rd1 mouse. The mean values were 254.78 μC/cm2 and 424.62 μC/cm2 in normal and rd1 mouse, respectively.

Decoding of retinal ganglion cell spike trains evoked by temporally patterned electrical stimulation

For successful restoration of vision by retinal prostheses, the neural activity of retinal ganglion cells (RGCs) evoked by electrical stimulation should represent the information of spatiotemporal patterns of visual input. We propose a method to evaluate the effectiveness of stimulation pulse trains so that the crucial temporal information of a visual input is accurately represented in the RGC responses as the amplitudes of pulse trains are modulated according to the light intensity. This was enabled by spike train decoding. The effectiveness of the stimulation was evaluated by the accuracy of decoding pulse amplitude from the RGC spike train, i.e., by the similarity between the original and the decoded pulse amplitude time series. When the parameters of stimulation were suitably determined, the RGC responses were reliably modulated by varying the amplitude of electrical pulses. Accordingly, the temporal pattern of pulse amplitudes could be successfully decoded from multiunit RGC spike trains. The range of pulse amplitude and the pulse rate were critical for accurate representation of input information in RGC responses. These results suggest that pulse amplitude modulation is a feasible means to encode temporal visual information by RGC spike trains and thus to implement stimulus encoding strategies for retinal prostheses.

Decoding of temporal visual information from electrically evoked retinal ganglion cell activities in photoreceptor-degenerated retinas.

PURPOSE To restore visual function via the prosthetic stimulation of retina, visual information must be properly represented in the electrically evoked neural activity of retinal ganglion cells (RGCs). In this study, the RGC responses in photoreceptor-degenerated retinas were shown to actually encode temporal information on visual input when they were stimulated by biphasic pulse trains with amplitude modulation. METHODS Multiple RGC spike trains were recorded from rd1 mouse retinal patches mounted on planar microelectrode arrays while being stimulated by pulse trains with amplitudes modulated by the intensity variation of a natural scene. To reconstruct the time series of pulse train amplitudes from the evoked RGC activity, spike train decoding was performed. The accuracy of decoding-that is, the similarity between the original and decoded pulse amplitudes-was observed, to evaluate the appropriateness of the stimulation. RESULTS The response strengths of the RGCs could be successfully modulated when the pulse amplitude was varied between 2 and 20 μA. When the amplitude modulation range and pulse rates were determined elaborately, the temporal profile of the intensity could be successfully decoded from RGC spike trains, although abnormal oscillatory background rhythms (~10 Hz) were consistently present in the rd1 spike activity. CONCLUSIONS The results extend previous findings on the possibility of visual information encoding by electrical stimulation of normal retinas to stimulate degenerated retinas, in which neural activity is significantly altered. This supports the feasibility of encoding of temporal information by retinal prostheses.

Retinal ganglion cell (RGC) responses to different voltage stimulation parameters in rd1 mouse retina

Retinal prostheses are being developed to restore vision for the blind with retinal diseases such as retinitis pigmentosa (RP) or age-related macular degeneration (AMD). Since neural prostheses depend upon electrical stimulation to control neural activity, optimal stimulation parameters for successful encoding of visual information are one of the most important requirements to enable visual perception. Therefore, in this paper, we focused on RGC responses to different stimulation parameters in degenerated retina. For this purpose, we used in vitro preparation of rd1 mice retina on microelectrode arrays. When the neural network of rd1 mice retinas is stimulated with voltage-controlled pulses, RGCs in degenerated retina also respond to voltage amplitude or voltage duration modulation as well in wild-type RGCs. But the temporal pattern of RGCs response is very different; in wild-type RGCs, single peak within 100 ms appears while in RGCs in degenerated retina multiple peaks (∼4 peaks) with ∼10 Hz rhythm within 400 ms appear. The threshold charge densities for activation of RGCs in rd1 mouse retinas were on average 70.50 ∼ 99.87 µC/cm2 in the experiment of voltage amplitude modulation and 120.5 ∼ 170.6 µC/cm2 in the experiment of voltage duration modulation.