Amplitude Modulation-based Electrical Stimulation for Encoding Multipixel Spatiotemporal Visual Information in Retinal Neural Activities

Retinal implants have been developed as a promising way to restore partial vision for the blind. The observation and analysis of neural activities can offer valuable insights for successful prosthetic electrical stimulation. Retinal ganglion cell (RGC) activities have been investigated to provide knowledge on the requirements for electrical stimulation, such as threshold current and the effect of stimulation waveforms. To develop a detailed ‘stimulation strategy’ for faithful delivery of spatiotemporal visual information to the brain, it is essential to examine both the temporal and spatial characteristics of RGC responses, whereas previous studies were mainly focused on one or the other. In this study, we investigate whether the spatiotemporal visual information can be decoded from the RGC network activity evoked by patterned electrical stimulation. Along with a thorough characterization of spatial spreading of stimulation current and temporal information encoding, we demonstrated that multipixel spatiotemporal visual information can be accurately decoded from the population activities of RGCs stimulated by amplitude-modulated pulse trains. We also found that the details of stimulation, such as pulse amplitude range and pulse rate, were crucial for accurate decoding. Overall, the results suggest that useful visual function may be restored by amplitude modulation-based retinal stimulation.

Effect of Stimulus Waveform of Biphasic Current Pulse on Retinal Ganglion Cell Responses in Retinal Degeneration (rd1) mice

A retinal prosthesis is being developed for the restoration of vision in patients with retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Determining optimal electrical stimulation parameters for the prosthesis is one of the most important elements for the development of a viable retinal prosthesis. Here, we investigated the effects of different charge-balanced biphasic pulses with regard to their effectiveness in evoking retinal ganglion cell (RGC) responses. Retinal degeneration (rd1) mice were used (n=17). From the ex-vivo retinal preparation, retinal patches were placed ganglion cell layer down onto an 8x8 multielectrode array (MEA) and RGC responses were recorded while applying electrical stimuli. For asymmetric pulses, 1st phase of the pulse is the same with symmetric pulse but the amplitude of 2nd phase of the pulse is less than 10 microA and charge balanced condition is satisfied by lengthening the duration of the pulse. For intensities (or duration) modulation, duration (or amplitude) of the pulse was fixed to 500 micros (30 microA), changing the intensities (or duration) from 2 to 60 microA (60 to 1000 micros). RGCs were classified as response-positive when PSTH showed multiple (3~4) peaks within 400 ms post stimulus and the number of spikes was at least 30% more than that for the immediate pre-stimulus 400 ms period. RGC responses were well modulated both with anodic and cathodic phase-1st biphasic pulses. Cathodic phase-1st pulses produced significantly better modulation of RGC activity than anodic phase-1st pulses regardless of symmetry of the pulse.

Electrophysiological and Histologic Evaluation of the Time Course of Retinal Degeneration in the rd10 Mouse Model of Retinitis Pigmentosa

Among several animal models of retinitis pigmentosa (RP), the more recently developed rd10 mouse with later onset and slower rate of retinal degeneration than rd1 mouse is a more suitable model for testing therapeutic modalities. We therefore investigated the time course of retinal degeneration in rd10 mice before adopting this model in our interventional studies. Electroretinogram (ERG) recordings were carried out in postnatal weeks (PW) 3~5 rd10 (n=23) and wild-type (wt) mice (n=26). We compared the amplitude and implicit time of the b-wave of ERG records from wt and rd10 mice. Our results showed that b-wave amplitudes in rd10 mice were significantly lower and the implicit time of b-waves in rd10 mice were also significantly slower than that in wt mice (20~160 microV vs. 350~480 microV; 55~75 ms vs. 100~150 ms: p<0.001) through PW3 to PW5. The most drastic changes in ERG amplitudes and latencies were observed during PW3 to PW4. In multichannel recording of rd10 retina in PW2 to PW4.5, we found no significant difference in mean spike frequency, but the frequency of power spectral peak of local field potential at PW3 and PW3.5 is significantly different among other age groups (p<0.05). Histologic examination of rd10 retinae showed significant decrease in thickness of the outer nuclear layer at PW3. TUNEL positive cells were most frequently observed at PW3. From these data, we confirm that in the rd10 mouse, the most precipitous retinal degeneration occurs between PW3~PW4 and that photoreceptor degeneration is complete by PW5.

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

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 8x8 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.