A model of ganglion axon pathways accounts for percepts elicited by retinal implants.

Degenerative retinal diseases such as retinitis pigmentosa and macular degeneration cause irreversible vision loss in more than 10 million people worldwide. Retinal prostheses, now implanted in over 250 patients worldwide, electrically stimulate surviving cells in order to evoke neuronal responses that are interpreted by the brain as visual percepts ('phosphenes'). However, instead of seeing focal spots of light, current implant users perceive highly distorted phosphenes that vary in shape both across subjects and electrodes. We characterized these distortions by asking users of the Argus retinal prosthesis system (Second Sight Medical Products Inc.) to draw electrically elicited percepts on a touchscreen. Using ophthalmic fundus imaging and computational modeling, we show that elicited percepts can be accurately predicted by the topographic organization of optic nerve fiber bundles in each subject's retina, successfully replicating visual percepts ranging from 'blobs' to oriented 'streaks' and 'wedges' depending on the retinal location of the stimulating electrode. This provides the first evidence that activation of passing axon fibers accounts for the rich repertoire of phosphene shape commonly reported in psychophysical experiments, which can severely distort the quality of the generated visual experience. Overall our findings argue for more detailed modeling of biological detail across neural engineering applications

The Effects of Neurosteroids, such as Pregnenolone Sulfate and its receptor, TrpM3 in the Retina.

Pregnenolone sulfate (PregS) is the precursor to all steroid hormones and is produced in neurons in an activity dependent manner. Studies have shown that PregS production is upregulated during certain critical periods of development, such as in the first year of life in humans, during adolescence, and during pregnancy. Conversely, PregS is decreased during aging, as well as in several neurodevelopmental and neurodegenerative conditions. There are several known targets of PregS, such as a positive allosteric modulator NMDA receptors, sigma1 receptor, and as a negative allosteric modulator of GABA-A receptors. Recently a transient receptor potential channel, TrpM3 has been shown to be activated by PregS. TrpM3 is a heat sensitive (between 33-40oC), non-selective cation channel that is outwardly rectifying. PregS has been shown to increase the frequency of post-synaptic currents in the hippocampus and developing cerebellum, induce calcium transients in a subset of retinal ganglion cells, and enhance memory formation in rodents. Furthermore, PregS mediated TrpM3 activation induces calcium dependent transcription of early immediate genes, suggesting that activation of this channel may produce lasting effects on cells and systems in which it is activated. Because PregS is abundant during critical periods of development, we hypothesized that it may play a significant role during development. Furthermore, the role of PregS or its receptor TrpM3, has not previously been well characterized in the retina. To address this question, in this dissertation, we examine the role of the neurosteroid PregS and its receptor, TrpM3, on retinal waves, which are characteristic of specific stages of synaptic development and connectivity. Briefly, we show that PregS induces a TrpM3 dependent prolonged calcium transient, which is absent in the TrpM3-/- animals and increases the correlation of cell participation in waves. We also show that TrpM3 increases the frequency of post-synaptic currents, indicating a mechanism of action presynaptic to retinal ganglion cells, but that TrpM3 is expressed primarily in RGCs and Müller glia. Taken together, our results indicate that both PregS and TrpM3 are important in modulating spontaneous synaptic activity during development

Characterization of Retinal Ganglion Cell Responses to Electrical Stimulation Using White Noise

Retinitis pigmentosa and age-related macular degeneration are two leading causes of degenerative blindness. While there is still not a definitive course of treatment for either of these diseases, there is currently the world over, many different treatment strategies being explored. Of these various strategies, one of the most successful has been retinal implants. Retinal implants are microelectrode or photodiode arrays, that are implanted in the eye of a patient, to electrically stimulate the degenerating retina. Clinical trials have shown that many patients implanted with such a device, are able to regain a certain degree of functional vision. However, while the results of these ongoing clinical trials have been promising, there are still many technical challenges that need to be overcome. One of the biggest challenges facing present implants is the inability to preferentially stimulate different retinal pathways. This is because retinal implants use large-amplitude current or voltage pulses. This in turn leads to the indiscriminate activation of multiple classes of retinal ganglion cells (RGCs), and therefore, an overall reduction in the restored visual acuity. To tackle this issue, we decided to explore a novel stimulus paradigm, in which we present to the retina, a stream of smaller-amplitude subthreshold voltage pulses. By then correlating the retinal spikes to the stimuli preceding them, we calculate temporal input filters for various classes of RGCs, using a technique called spike-triggered averaging (STA). In doing this, we found that ON and OFF RGCs have electrical filters, which are very distinct from each other. This finding creates the possibility for the selective activation of the retina through the use of STA-based waveforms. Finally, using statistical models, we verify how well these temporal filters can predict RGC responses to novel electrical stimuli. In a broad sense, our work represents the successful application of systems engineering tools to retinal prosthetics, in an attempt to answer one of the field’s most difficult questions, namely selective stimulation of the retina

Optimal electrical activation of retinal ganglion cells

Retinal prostheses are emerging as a viable therapy option for those blinded by degenerative eye conditions that destroy the photoreceptors of the retina but spare the retinal ganglion cells (RGCs). My research sought to address the issue of how a retinal prosthesis might best activate these cells by way of electrical stimulation. Whole-cell patch clamp recordings were made in explanted retinal wholemount preparations from normally-sighted rats. Stimulating electrodes were fabricated from nitrogen-doped ultra-nanocrystalline diamond (N-UNCD) and placed on the epiretinal surface, adjacent to the cell soma. Electrical stimuli were delivered against a distant monopolar return electrode. Using rectangular, biphasic constant current waveforms as employed by modern retinal prostheses, I examined which waveform parameters had the greatest effect on RGC activation thresholds. In a second set of experiments intracellular current injection was employed to assess the effectiveness of sinusoidal current waveforms in selectively activating different RGC subsets. These recordings were also used to validate a biophysical model of RGC activation. Where possible, recorded cells were identified and classified based on 3D confocal reconstruction of their morphology. Electrodes fabricated from N-UNCD were able to electrically activate RGCs while remaining well within the electrochemical limits of the material. They were found to exhibit high electrochemical stability and were resistant to morphological and electrochemical changes over one week of continuous pulsing at charge injection limits. Retinal ganglion cells invariably favoured cathodic-first biphasic current pulses of short first-phase duration, with a small interphase interval. The majority of cells (63\%) were most sensitive to a highly asymmetric waveform: a short-cathodic phase followed by a longer duration, lower amplitude anodic phase. Using the optimal interphase interval led to median charge savings of 14\% compared to the charge required in the absence of any inter-phase interval. Optimising phase duration resulted in median charge savings of 22\%. All RGCs became desensitised to repetitive electrical stimulation. The efficacy of a given stimulus delivered repeatedly decreased after the first stimulus, stabilising at a lower efficacy by the thirtieth pulse. This asymptotic efficacy decreased with increasing stimulus frequency. Cells with smaller somas and dendritic fields were better able to sustain repetitive activation at high frequency. Intracellular sinusoidal stimulation was used to demonstrate that certain RGC subsets, defined on the basis of morphological type, stratification, and size, were more responsive to high frequency stimulation. Simulated RGC responses were validated by experimental data, which confirmed that ON cell responses were heavily suppressed by stimulus frequencies of 20 Hz and higher. OFF cells, on the other hand, were able to sustain repetitive activation over all tested frequencies. Additional simulations suggest this difference may be plausibly attributed to the presence of low-voltage-activated calcium channels in OFF but not ON RGCs. The results of my work demonstrate that (a) N-UNCD is a suitable material for retinal prosthesis applications; (b) a careful choice of electrical waveform parameters can significantly improve prosthesis efficacy; and (c) it may be possible to bias neural activation for certain RGC populations by varying the frequency of stimulation

Inhibitory control of feature selectivity in an object motion sensitive circuit of the retina

Object motion sensitive (OMS) W3-retinal ganglion cells (W3-RGCs) in mice respond to local movements in a visual scene but remain silent during self-generated global image motion. The excitatory inputs that drive responses of W3-RGCs to local motion were recently characterized, but which inhibitory neurons suppress W3-RGCs’ responses to global motion, how these neurons encode motion information, and how their connections are organized along the excitatory circuit axis remains unknown. Here, we find that a genetically identified amacrine cell (AC) type, TH2-AC, exhibits fast responses to global motion and slow responses to local motion. Optogenetic stimulation shows that TH2-ACs provide strong GABAA receptor-mediated input to W3-RGCs but only weak input to upstream excitatory neurons. Cell-type-specific silencing reveals that temporally coded inhibition from TH2-ACs cancels W3-RGC spike responses to global but not local motion stimuli and, thus, controls the feature selectivity of OMS signals sent to the brain

Purinergic Signaling in the Retina: From Development to Disease

Retinal injuries and diseases are major causes of human disability involving vision impairment by the progressive and permanent loss of retinal neurons. During development, assembly of this tissue entails a successive and overlapping, signal-regulated engagement of complex events that include proliferation of progenitors, neurogenesis, cell death, neurochemical differentiation and synaptogenesis. During retinal damage, several of these events are re-activated with both protective and detrimental consequences. Purines and pyrimidines, along with their metabolites are emerging as important molecules regulating both retinal development and the tissue\u27s responses to damage. The present review provides an overview of the purinergic signaling in the developing and injured retina. Recent findings on the presence of vesicular and channel-mediated ATP release by retinal and retinal pigment epithelial cells, adenosine synthesis and release, expression of receptors and intracellular signaling pathways activated by purinergic signaling in retinal cells are reported. The pathways by which purinergic receptors modulate retinal cell proliferation, migration and death of retinal cells during development and injury are summarized. The contribution of nucleotides to the self-repair of the injured zebrafish retina is also discussed. © 2018 Elsevier Inc

Encoding of saccadic scene changes in the mouse retina

The task of the visual system is to extract behaviourally relevant information from the visual scene. A common strategy for most animals ranging from insects to humans is to constantly reposition gaze by making saccades within the scene. This ‘fixate and saccade’ strategy seems to pose a challenge, as it introduces a highly blurred image on the retina during a saccade, but at the same time acquires a ‘snapshot’ of the world during every fixation. The visual signals on the retina are thus segmented into brief image fixations separated by global motion. What is the response of a ganglion cell to ‘motion blur’ caused by a saccade, and how does it influence the response to subsequent fixations? Also, how does the global motion signal influence the response dynamics of a ganglion cell? In this thesis, we addressed these questions by two complementary approaches. First, we analysed the retinal ganglion cell responses to simulated saccades. We analysed two important aspects of the response - 1) response during a saccade-like motion, 2) response to fixation images. For about half of the recorded cells, we found strong spiking activity during the saccade. This supports the idea that the retina actively encodes the saccade and may signal the abrupt scene change to downstream brain areas. Furthermore, we characterized the responses to the newly fixated image. While there appears to be only little influence of the preceding motion signal itself on these responses, the responses depended strongly on the image content during the fixation period prior to the saccade. Thus, saccadic vision may provide ‘temporal context’ to each fixation, and ganglion cells encode image transitions rather than currently fixated images. Based on this perspective, we classified retinal ganglion cells into five response types, suggesting that the retina encodes at least five parallel channels of information under saccadic visual stimulation. The five response types identified in this study are as follows: 1) Classical Encoders - Response only to preferred stimuli; 2) Offset Detectors - Response only to the saccade; 3) Indifferent Encoders - Response to all fixated images; 4) Change Detectors - Response only when the new image after the saccade differs from the previous image; 5) Similarity Detectors - Response only when the new image after the saccade is similar to the previous image. Second, we analysed the influence of global motion signals on the response of a retinal ganglion cell to the stimulus in its receptive field. The stimulus beyond the receptive field is designated as remote stimulus. We chose simple stimulus that represent various configurations used in earlier studies, thus allowing us to compare our results. We show that the remote stimulus both enhances and suppresses the mean firing rate, but only suppresses the evoked activity. Furthermore, we show that the remote stimulus decreases the contrast sensitivity and modifies the response gain. Thus, the ganglion cells encode the stimulus in relation to the whole scene, rather than purely respond to the stimulus in the receptive field. Our results suggest that the global motion signals provide ‘spatial context’ to the response of the stimulus within the receptive field

Feasibility Assessment of an Optically Powered Digital Retinal Prosthesis Architecture for Retinal Ganglion Cell Stimulation

Clinical trials previously demonstrated the notable capacity to elicit visual percepts in blind patients affected with retinal diseases by electrically stimulating the remaining neurons on the retina. However, these implants restored very limited visual acuity and required transcutaneous cables traversing the eyeball, leading to reduced reliability and complex surgery with high postoperative infection risks. To overcome the limitations imposed by cables, a retinal implant architecture in which near-infrared illumination carries both power and data through the pupil to a digital stimulation controller is presented. A high efficiency multi-junction photovoltaic cell transduces the optical power to a CMOS stimulator capable of delivering flexible interleaved sequential stimulation through a diamond microelectrode array. To demonstrate the capacity to elicit a neural response with this approach while complying with the optical irradiance limit at the pupil, fluorescence imaging with a calcium indicator is used on a degenerate rat retina. The power delivered by the laser at the permissible irradiance of 4 mW/mm2 at 850 nm is shown to be sufficient to both power the stimulator ASIC and elicit a response in retinal ganglion cells (RGCs), with the ability to generate of up to 35 000 pulses per second at the average stimulation threshold. This confirms the feasibility of generating a response in RGCs with an infrared-powered digital architecture capable of delivering complex sequential stimulation patterns at high repetition rates, albeit with some limitations.Comment: 11 pages, 13 figure