Multiple consecutive-biphasic pulse stimulation improves spatially localized firing of retinal ganglion cells in the degenerate retina

Jungryul Ahn,유용석,구용숙 대한약리학회 2023 The Korean Journal of Physiology & Pharmacology Vol.27 No.6

Retinal prostheses have shown some clinical success in restoring vision in patients with retinitis pigmentosa. However, the post-implantation visual acuity does not exceed that of legal blindness. The reason for the poor visual acuity might be that (1) degenerate retinal ganglion cells (RGCs) are less responsive to electrical stimulation than normal RGCs, and (2) electrically-evoked RGC spikes show a more widespread not focal response. The single-biphasic pulse electrical stimulation, commonly used in artificial vision, has limitations in addressing these issues. In this study, we propose the benefit of multiple consecutive-biphasic pulse stimulation. We used C57BL/6J mice and C3H/HeJ (rd1) mice for the normal retina and retinal degeneration model. An 8 × 8 multi-electrode array was used to record electrically-evoked RGC spikes. We compared RGC responses when increasing the amplitude of a single biphasic pulse versus increasing the number of consecutive biphasic pulses at the same stimulus charge. Increasing the amplitude of a single biphasic pulse induced more RGC spike firing while the spatial resolution of RGC populations decreased. For multiple consecutive-biphasic pulse stimulation, RGC firing increased as the number of pulses increased, and the spatial resolution of RGC populations was well preserved even up to 5 pulses. Multiple consecutive-biphasic pulse stimulation using two or three pulses in degenerate retinas induced as much RGC spike firing as in normal retinas. These findings suggest that the newly proposed multiple consecutive-biphasic pulse stimulation can improve the visual acuity in prosthesis-implanted patients.

Spike-triggered Clustering for Retinal Ganglion Cell Classification

안정렬,유용석,구용숙 한국뇌신경과학회 2020 Experimental Neurobiology Vol.29 No.6

Retinal ganglion cells (RGCs), the retina’s output neurons, encode visual information through spiking. The RGC receptive field (RF) represents the basic unit of visual information processing in the retina. RFs are commonly estimated using the spike-triggered average (STA), which is the average of the stimulus patterns to which a given RGC is sensitive. Whereas STA, based on the concept of the average, is simple and intuitive, it leaves more complex structures in the RFs undetected. Alternatively, spike-triggered covariance (STC) analysis provides information on second-order RF statistics. However, STC is computationally cumbersome and difficult to interpret. Thus, the objective of this study was to propose and validate a new computational method, called spike-triggered clustering (STCL), specific for multimodal RFs. Specifically, RFs were fit with a Gaussian mixture model, which provides the means and covariances of multiple RF clusters. The proposed method recovered bipolar stimulus patterns in the RFs of ON-OFF cells, while the STA identified only ON and OFF RGCs, and the remaining RGCs were labeled as unknown types. In contrast, our new STCL analysis distinguished ON-OFF RGCs from the ON, OFF, and unknown RGC types classified by STA. Thus, the proposed method enables us to include ON-OFF RGCs prior to retinal information analysis.

The advantage of topographic prominence-adopted filter for the detection of short-latency spikes of retinal ganglion cells

안정열,최명환,김광수,Solomon S. Senok,조동일,구교인,구용숙 대한약리학회 2017 The Korean Journal of Physiology & Pharmacology Vol.21 No.5

Electrical stimulation through retinal prosthesis elicits both short and long-latency retinal ganglion cell (RGC) spikes. Because the short-latency RGC spike is usually obscured by electrical stimulus artifact, it is very important to isolate spike from stimulus artifact. Previously, we showed that topographic prominence (TP) discriminator based algorithm is valid and useful for artifact subtraction. In this study, we compared the performance of forward backward (FB) filter only vs. TP-adopted FB filter for artifact subtraction. From the extracted retinae of rd1 mice, we recorded RGC spikes with 8×8 multielectrode array (MEA). The recorded signals were classified into four groups by distances between the stimulation and recording electrodes on MEA (200-400, 400-600, 600-800, 800-1000 μm). Fifty cathodic phase-1st biphasic current pulses (duration 500 μs, intensity 5, 10, 20, 30, 40, 50, 60 μA) were applied at every 1 sec. We compared false positive error and false negative error in FB filter and TP-adopted FB filter. By implementing TP-adopted FB filter, short-latency spike can be detected better regarding sensitivity and specificity for detecting spikes regardless of the strength of stimulus and the distance between stimulus and recording electrodes.

최적선형필터를 이용한 망막신경절세포 Spike Train으로부터의 시각자극 세기 변화 추정

류상백,김두희,예장희,김경환,구용숙,Ryu, Sang-Baek,Kim, Doo-Hee,Ye, Jang-Hee,Kim, Kyung-Hwan,Goo, Yong-Sook 대한의용생체공학회 2007 의공학회지 Vol.28 No.2

As a preliminary study for the development of electrical stimulation strategy of artificial retina, we set up a method fur the reconstruction of input intensity variation from retinal ganglion cell(RGC) responses. In order to estimate light intensity variation, we used an optimal linear filter trained from given stimulus intensity variation and multiple single unit spike trains from RGCs. By applying ON/OFF stimulation(ON duration: 2 sec, OFF duration: 5 sec) repetitively, we identified three functional types of ganglion cells according to when they respond to the ON/OFF stimulus actively: ON cell, OFF cell, and ON-OFF cell. Experiments were also performed using a Gaussian random stimulus and a binary random stimulus. The input intensity was updated once every 90 msec(i. e. 11 Hz) to present the stimulus. The result of reconstructing 11 Hz Gaussian and binary random stimulus was not satisfactory and showed low correlation between the original and reconstructed stimulus. In the case of ON/OFF stimulus in which temporal variation is slow, successful reconstruction was achieved and the correlation coefficient was as high as 0.8.

The advantage of topographic prominence-adopted filter for the detection of short-latency spikes of retinal ganglion cells

Ahn, Jungryul,Choi, Myoung-Hwan,Kim, Kwangsoo,Senok, Solomon S.,Cho, Dong-il Dan,Koo, Kyo-in,Goo, Yongsook The Korean Society of Pharmacology 2017 The Korean Journal of Physiology & Pharmacology Vol.21 No.5

Electrical stimulation through retinal prosthesis elicits both short and long-latency retinal ganglion cell (RGC) spikes. Because the short-latency RGC spike is usually obscured by electrical stimulus artifact, it is very important to isolate spike from stimulus artifact. Previously, we showed that topographic prominence (TP) discriminator based algorithm is valid and useful for artifact subtraction. In this study, we compared the performance of forward backward (FB) filter only vs. TP-adopted FB filter for artifact subtraction. From the extracted retinae of rd1 mice, we recorded RGC spikes with $8{\times}8$ multielectrode array (MEA). The recorded signals were classified into four groups by distances between the stimulation and recording electrodes on MEA (200-400, 400-600, 600-800, $800-1000{\mu}m$). Fifty cathodic phase-$1^{st}$ biphasic current pulses (duration $500{\mu}s$, intensity 5, 10, 20, 30, 40, 50, $60{\mu}A$) were applied at every 1 sec. We compared false positive error and false negative error in FB filter and TP-adopted FB filter. By implementing TP-adopted FB filter, short-latency spike can be detected better regarding sensitivity and specificity for detecting spikes regardless of the strength of stimulus and the distance between stimulus and recording electrodes.

New Features of Receptive Fields in Mouse Retina through Spike-triggered Covariance

안정열,Bodo Rueckauer,유용석,Yongsook Goo 한국뇌신경과학회 2020 Experimental Neurobiology Vol.29 No.1

Retinal ganglion cells (RGCs) encode various spatiotemporal features of visual information into spiking patterns. The receptive field (RF) of each RGC is usually calculated by spike-triggered average (STA), which is fast and easy to understand, but limited to simple and unimodal RFs. As an alternative, spike-triggered covariance (STC) has been proposed to characterize more complex patterns in RFs. This study compares STA and STC for the characterization of RFs and demonstrates that STC has an advantage over STA for identifying novel spatiotemporal features of RFs in mouse RGCs. We first classified mouse RGCs into ON, OFF, and ON/OFF cells according to their response to full-field light stimulus, and then investigated the spatiotemporal patterns of RFs with random checkerboard stimulation, using both STA and STC analysis. We propose five sub-types (T1-T5) in the STC of mouse RGCs together with their physiological implications. In particular, the relatively slow biphasic pattern (T1) could be related to excitatory inputs from bipolar cells. The transient biphasic pattern (T2) allows one to characterize complex patterns in RFs of ON/OFF cells. The other patterns (T3-T5), which are contrasting, alternating, and monophasic patterns, could be related to inhibitory inputs from amacrine cells. Thus, combining STA and STC and considering the proposed sub-types unveil novel characteristics of RFs in the mouse retina and offer a more holistic understanding of the neural coding mechanisms of mouse RGCs.

Accurate Representation of Light-intensity Information by the Neural Activities of Independently Firing Retinal Ganglion Cells

류상백,예장희,김치현,구용숙,김경환 대한약리학회 2009 The Korean Journal of Physiology & Pharmacology Vol.13 No.3

For successful restoration of visual function by a visual neural prosthesis such as retinal implant, electrical stimulation should evoke neural responses so that the information on visual input is properly represented. A stimulation strategy, which means a method for generating stimulation waveforms based on visual input, should be developed for this purpose. We proposed to use the decoding of visual input from retinal ganglion cell (RGC) responses for the evaluation of stimulus encoding strategy. This is based on the assumption that reliable encoding of visual information in RGC responses is required to enable successful visual perception. The main purpose of this study was to determine the influence of inter-dependence among stimulated RGCs activities on decoding accuracy. Light intensity variations were decoded from multiunit RGC spike trains using an optimal linear filter. More accurate decoding was possible when different types of RGCs were used together as input. Decoding accuracy was enhanced with independently firing RGCs compared to synchronously firing RGCs. This implies that stimulation of independently-firing RGCs and RGCs of different types may be beneficial for visual function restoration by retinal prosthesis.

전기자극펄스에 대한 변성망막 신경절세포의 응답특성 분석

류상백,이종승,예장희,구용숙,김지현,김경환,Ryu, Sang-Baek,Lee, Jong-Seung,Ye, Jang-Hee,Goo, Yong-Sook,Kim, Chi-Hyun,Kim, Kyung-Hwan 대한의용생체공학회 2009 의공학회지 Vol.30 No.4

For the reliable transmission of meaningful visual information using prosthetic electrical stimulation, it is required to develop an effective stimulation strategy for the generation of electrical pulse trains based on input visual information. The characteristics of neuronal activities of retinal ganglion cells (RGCs) evoked by electrical stimulation should be understood for this purpose. In this study, for the development of an optimal stimulation strategy for visual prosthesis, we analyzed the neuronal responses of RGCs in rd1 mouse, photoreceptor-degenerated retina of animal model of retinal diseases (retinitis pigmentosa). Based on the in-vitro model of epiretinal prosthesis which consists of planar multielectrode array (MEA) and retinal patch, we recorded and analyzed multiunit RGC activities evoked by amplitude-modulated electrical pulse trains. Two modes of responses were observed. Short-latency responses occurring at 3 ms after the stimulation were estimated to be from direct stimulation of RGCs. Long-latency responses were also observed mainly at 2 - 100 ms after stimulation and showed rhythmic firing with same frequency as the oscillatory background field potential. The long-latency responses could be modulated by pulse amplitude and duration. From the results, we expect that optimal stimulation conditions such as pulse amplitude and pulse duration can be determined for the successful transmission of visual information by electrical stimulation.

Spontaneous Oscillatory Rhythm in Retinal Activities of Two Retinal Degeneration (rd1 and rd10) Mice

Goo, Yong-Sook,Ahn, Kun-No,Song, Yeong-Jun,Ahn, Su-Heok,Han, Seung-Kee,Ryu, Sang-Baek,Kim, Kyung-Hwan The Korean Society of Pharmacology 2011 The Korean Journal of Physiology & Pharmacology Vol.15 No.6

Previously, we reported that besides retinal ganglion cell (RGC) spike, there is ~10 Hz oscillatory rhythmic activity in local field potential (LFP) in retinal degeneration model, rd1 mice. The more recently identified rd10 mice have a later onset and slower rate of photoreceptor degeneration than the rd1 mice, providing more therapeutic potential. In this study, before adapting rd10 mice as a new animal model for our electrical stimulation study, we investigated electrical characteristics of rd10 mice. From the raw waveform of recording using $8{\times}8$ microelectrode array (MEA) from in vitro-whole mount retina, RGC spikes and LFP were isolated by using different filter setting. Fourier transform was performed for detection of frequency of bursting RGC spikes and oscillatory field potential (OFP). In rd1 mice, ~10 Hz rhythmic burst of spontaneous RGC spikes is always phase-locked with the OFP and this phase-locking property is preserved regardless of postnatal ages. However, in rd10 mice, there is a strong phase-locking tendency between the spectral peak of bursting RGC spikes (~5 Hz) and the first peak of OFP (~5 Hz) across different age groups. But this phase-locking property is not robust as in rd1 retina, but maintains for a few seconds. Since rd1 and rd10 retina show phase-locking property at different frequency (~10 Hz vs. ~5 Hz), we expect different response patterns to electrical stimulus between rd1 and rd10 retina. Therefore, to extract optimal stimulation parameters in rd10 retina, first we might define selection criteria for responding rd10 ganglion cells to electrical stimulus.

Spontaneous Oscillatory Rhythm in Retinal Activities of Two Retinal Degeneration (rd1 and rd10) Mice

구용숙,Kun No Ahn,Yeong Jun Song,Su Heok Ahn,한승기,류상백,김경환 대한약리학회 2011 The Korean Journal of Physiology & Pharmacology Vol.15 No.6

Previously, we reported that besides retinal ganglion cell (RGC) spike, there is ∼10 Hz oscillatory rhythmic activity in local field potential (LFP) in retinal degeneration model, rd1 mice. The more recently identified rd10 mice have a later onset and slower rate of photoreceptor degeneration than the rd1 mice, providing more therapeutic potential. In this study, before adapting rd10 mice as a new animal model for our electrical stimulation study, we investigated electrical characteristics of rd10 mice. From the raw waveform of recording using 8×8 microelectrode array (MEA) from in vitro-whole mount retina, RGC spikes and LFP were isolated by using different filter setting. Fourier transform was performed for detection of frequency of bursting RGC spikes and oscillatory field potential (OFP). In rd1 mice, ∼10 Hz rhythmic burst of spontaneous RGC spikes is always phase-locked with the OFP and this phase-locking property is preserved regardless of postnatal ages. However, in rd10 mice, there is a strong phase-locking tendency between the spectral peak of bursting RGC spikes (∼5 Hz) and the first peak of OFP (∼5 Hz) across different age groups. But this phase-locking property is not robust as in rd1 retina, but maintains for a few seconds. Since rd1 and rd10 retina show phase-locking property at different frequency (∼10 Hz vs. ∼5 Hz), we expect different response patterns to electrical stimulus between rd1 and rd10 retina. Therefore, to extract optimal stimulation parameters in rd10 retina, first we might define selection criteria for responding rd10 ganglion cells to electrical stimulus.