Photovoltaic retinal prosthesis restores high-resolution responses to single-pixel stimulation in blind retinas

AbstractRetinal prostheses hold the promise of restoring vision in totally blind people. However, a decade of clinical trials highlighted quantitative limitations hampering the possibility of reaching this goal. A key challenge in retinal stimulation is to independently activate retinal neurons over a large portion of the subject’s visual field. Reaching such a goal would significantly improve the perception accuracy in retinal implants’ users, along with their spatial cognition, attention, ambient mapping and interaction with the environment. Here we show a wide-field, high-density and high-resolution photovoltaic epiretinal prosthesis for artificial vision (POLYRETINA). The prosthesis embeds 10,498 physically and functionally independent photovoltaic pixels, allowing for wide retinal coverage and high-resolution stimulation. Single-pixel illumination reproducibly induced network-mediated responses from retinal ganglion cells at safe irradiance levels. Furthermore, POLYRETINA allowed response discrimination with a high spatial resolution equivalent to the pixel pitch (120 µm) thanks to the network-mediated stimulation mechanism. This approach could allow mid-peripheral artificial vision in patients with retinitis pigmentosa.

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Single-pixel epiretinal stimulation with a wide-field and high-density retinal prosthesis for artificial vision

10.1101/2020.08.21.261461 ◽

2020 ◽

Author(s):

Naïg Aurelia Ludmilla Chenais ◽

Marta Jole Ildelfonsa Airaghi Leccardi ◽

Diego Ghezzi

Keyword(s):

High Resolution ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Dendritic Tree ◽

High Density ◽

Artificial Vision ◽

Wide Field ◽

Retinal Ganglion ◽

Retinal Stimulation ◽

Single Pixel

AbstractRetinal prostheses hold the promise of restoring artificial vision in profoundly and totally blind people. However, a decade of clinical trials highlighted quantitative limitations hampering the possibility to reach this goal. A key obstacle to suitable retinal stimulation is the ability to independently activate retinal neurons over a large portion of the subject’s visual field. Reaching such a goal would significantly improve the perception accuracy in the users of retinal implants, along with their spatial cognition, attention, ambient mapping and interaction with the environment. Here we show a wide-field, high-density and high-resolution photovoltaic epiretinal prosthesis for artificial vision. The prosthesis embeds 10,498 physically and functionally independent photovoltaic pixels allowing for both wide retinal coverage and high-resolution stimulation. Single-pixel illumination reproducibly induced network-mediated responses from retinal ganglion cells at safe irradiance levels. Furthermore, the prosthesis enables a sub-receptive field response resolution for retinal ganglion cells having a dendritic tree larger than the pixel’s pitch. This approach could allow the restoration of mid-peripheric artificial vision in patients with retinitis pigmentosa.

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Retinal Prosthetic Approaches to Enhance Visual Perception for Blind Patients

Micromachines ◽

10.3390/mi11050535 ◽

2020 ◽

Vol 11 (5) ◽

pp. 535 ◽

Cited By ~ 2

Author(s):

Shinyong Shim ◽

Kyungsik Eom ◽

Joonsoo Jeong ◽

Sung Kim

Keyword(s):

Visual Acuity ◽

Implantable Devices ◽

Artificial Vision ◽

Retinal Neurons ◽

Electrode Arrays ◽

Retinal Prostheses ◽

Future Directions ◽

Retinal Stimulation ◽

Made In ◽

Blind Patients

Retinal prostheses are implantable devices that aim to restore the vision of blind patients suffering from retinal degeneration, mainly by artificially stimulating the remaining retinal neurons. Some retinal prostheses have successfully reached the stage of clinical trials; however, these devices can only restore vision partially and remain insufficient to enable patients to conduct everyday life independently. The visual acuity of the artificial vision is limited by various factors from both engineering and physiological perspectives. To overcome those issues and further enhance the visual resolution of retinal prostheses, a variety of retinal prosthetic approaches have been proposed, based on optimization of the geometries of electrode arrays and stimulation pulse parameters. Other retinal stimulation modalities such as optics, ultrasound, and magnetics have also been utilized to address the limitations in conventional electrical stimulation. Although none of these approaches have been clinically proven to fully restore the function of a degenerated retina, the extensive efforts made in this field have demonstrated a series of encouraging findings for the next generation of retinal prostheses, and these could potentially enhance the visual acuity of retinal prostheses. In this article, a comprehensive and up-to-date overview of retinal prosthetic strategies is provided, with a specific focus on a quantitative assessment of visual acuity results from various retinal stimulation technologies. The aim is to highlight future directions toward high-resolution retinal prostheses.

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Naturalistic spatiotemporal stimulus modulation during epiretinal stimulation increases the persistence of retinal ganglion cell responsivity

10.1101/2020.11.18.386961 ◽

2020 ◽

Author(s):

Naïg Aurélia Ludmilla Chenais ◽

Marta Jole Ildelfonsa Airaghi Leccardi ◽

Diego Ghezzi

Keyword(s):

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Artificial Vision ◽

Retinal Ganglion ◽

Electric Pulses ◽

Retinal Stimulation ◽

Electrophysiological Recordings ◽

Stimulus Modulation ◽

Stimulation Of ◽

Blind Patients

AbstractObjectiveRetinal stimulation in blind patients evokes the sensation of discrete points of light called phosphenes, which allows them performing visual guided tasks, such as orientation, navigation, object recognition, object manipulation and reading. However, the clinical benefit of artificial vision in profoundly blind patients is still tenuous, as several engineering and biophysical obstacles keep it away from natural perception. The relative preservation of the inner retinal neurons in hereditary degenerative retinal diseases, such as retinitis pigmentosa, supports artificial vision through the network-mediated stimulation of retinal ganglion cells. However, the response of retinal ganglion cells to repeated electrical stimulation rapidly declines, primarily because of the intrinsic desensitisation of their excitatory network. In patients, upon repetitive stimulation, phosphenes fade out in less than half of a second, which drastically limits the understanding of the percept.ApproachA more naturalistic stimulation strategy, based on spatiotemporal modulation of electric pulses, could overcome the desensitisation of retinal ganglion cells. To investigate this hypothesis, we performed network-mediated epiretinal stimulations paired to electrophysiological recordings in retinas explanted from both male and female retinal degeneration 10 mice.Main resultsThe results showed that the spatial and temporal modulation of the network-mediated epiretinal stimulation prolonged the responsivity of retinal ganglion cells from 400 ms up to 4.2 s.SignificanceA time-varied, non-stationary and interrupted stimulation of the retinal network, mimicking involuntary microsaccades, might reduce the fading of the visual percept and improve the clinical efficacy of retinal implants.

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Epiretinal stimulation with local returns enhances selectivity at cellular resolution

10.1101/275958 ◽

2018 ◽

Author(s):

Victoria H. Fan ◽

Lauren E. Grosberg ◽

Sasidhar S. Madugula ◽

Pawel Hottowy ◽

Wladyslaw Dabrowski ◽

...

Keyword(s):

Ganglion Cells ◽

Electrode Array ◽

Artificial Vision ◽

Retinal Ganglion ◽

Retinal Neurons ◽

Cellular Resolution ◽

Electrode Recording ◽

Current Spread ◽

Evoked Activity

AbstractObjectiveEpiretinal prostheses are designed to restore vision in people blinded by photoreceptor degenerative diseases, by directly activating retinal ganglion cells (RGCs) using an electrode array implanted on the retina. In present-day clinical devices, current spread from the stimulating electrode to a distant return electrode often results in the activation of many cells, potentially limiting the quality of artificial vision. In the laboratory, epiretinal activation of RGCs with cellular resolution has been demonstrated with small electrodes, but distant returns may still cause undesirable current spread. Here, the ability of local return stimulation to improve the selective activation of RGCs at cellular resolution was evaluated.ApproachA custom multi-electrode array (512 electrodes, 10 μm diameter, 60 μm pitch) was used to simultaneously stimulate and record from RGCs in isolated primate retina. Stimulation near the RGC soma with a single electrode and a distant return was compared to stimulation in which the return was provided by six neighboring electrodes.Main resultsLocal return stimulation enhanced the capability to activate cells near the central electrode (<30 μm) while avoiding cells farther away (>30 μm). This resulted in an improved ability to selectively activate ON and OFF cells, including cells encoding immediately adjacent regions in the visual field.SignificanceThese results suggest that a device that restricts the electric field through local returns could optimize activation of neurons at cellular resolution, improving the quality of artificial vision.Novelty & SignificanceThe effectiveness of local return stimulation for enhancing the electrical activation of retinal neurons was tested using high-density multi-electrode recording and stimulation in isolated macaque retina. The results suggest that local returns may reduce unwanted evoked activity and thus optimize the selectivity of stimulation at cellular resolution. Similar patterns could be implemented in a future high-resolution prosthesis to permit a more faithful replication of normal retinal activity for the treatment of incurable blindness.

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Differential stimulation of the retina with glutamate toward a neurotransmitter-based retinal prosthesis

10.1101/060681 ◽

2016 ◽

Author(s):

Corey M. Rountree ◽

Samsoon Inayat ◽

John B. Troy ◽

Laxman Saggere

Keyword(s):

Visual Information ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Retinal Prostheses ◽

Retinal Stimulation ◽

Stimulation Parameters ◽

Normal Means ◽

Retinal Pathways ◽

Pulsatile Delivery ◽

Stimulation Of

ABSTRACTSubretinal stimulation of the retina with neurotransmitters, the normal means of conveying visual information, is a potentially better alternative to electrical stimulation widely used in current retinal prostheses for treating blindness from photoreceptor degenerative diseases. Yet, no retinal stimulation study exploiting the inner retinal pathways exists. Here, we demonstrate the feasibility of differentially stimulating retinal ganglion cells (RGCs) through the inner nuclear layer of the retina with glutamate, a primary neurotransmitter chemical, in a biomimetic way. We show that controlled pulsatile delivery of glutamate into the subsurface of explanted wild-type rat retinas elicits highly localized simultaneous inhibitory and excitatory spike rate responses in OFF and ON RGCs. We also present the spatiotemporal characteristics of RGC responses to subretinally injected glutamate and the therapeutic stimulation parameters. Our findings could pave the way for future development of a neurotransmitter-based subretinal prosthesis offering more naturalistic vision and better visual acuity than electrical prostheses.

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Retinal Prostheses

Journal of VitreoRetinal Diseases ◽

10.1177/2474126417702067 ◽

2017 ◽

Vol 1 (3) ◽

pp. 204-213 ◽

Cited By ~ 2

Author(s):

Hossein Nazari ◽

Paulo Falabella ◽

Lan Yue ◽

James Weiland ◽

Mark S. Humayun

Keyword(s):

Retinal Degeneration ◽

Visual Information ◽

Microelectrode Array ◽

Electrode Array ◽

Lateral Geniculate Body ◽

Occipital Cortex ◽

Artificial Vision ◽

Retinal Neurons ◽

Retinal Prostheses ◽

Retinal Stimulation

Artificial vision is restoring sight by electrical stimulation of the visual system at the level of retina, optic nerve, lateral geniculate body, or occipital cortex. The development of artificial vision began with occipital cortex prosthesis; however, retinal prosthesis has advanced faster in recent years. Currently, multiple efforts are focused on finding the optimal approach for restoring vision through an implantable retinal microelectrode array system. Retinal prostheses function by stimulating the inner retinal neurons that survive retinal degeneration. In these devices, the visual information, gathered by a light detector, is transformed into controlled patterns of electrical pulses, which are in turn delivered to the surviving retinal neurons by an electrode array. Retinal prostheses are classified based on where the stimulating array is implanted (ie, epiretinal, subretinal, suprachoroidal, or episcleral). Recent regulatory approval of 2 retinal prostheses has greatly escalated interest in the potential of these devices to treat blindness secondary to outer retinal degeneration. This review will focus on the technical and operational features and functional outcomes of clinically tested retinal prostheses. We will discuss the major barriers and some of the more promising solutions to improve the outcomes of restoring vision with electrical retinal stimulation.

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Virtual reality validation of naturalistic modulation strategies to counteract fading in retinal stimulation

10.1101/2021.11.17.468930 ◽

2021 ◽

Author(s):

Jacob Thomas Thorn ◽

Naig Aurelia Ludmilla Chenais ◽

Sandrine Hinrichs ◽

Marion Chatelain ◽

Diego Ghezzi

Keyword(s):

Virtual Reality ◽

Ganglion Cells ◽

Head Rotation ◽

Head Movements ◽

Artificial Vision ◽

Retinal Ganglion ◽

Pulse Trains ◽

Retinal Stimulation ◽

Active Scanning ◽

Task Significance

Objective: Temporal resolution is a key challenge in artificial vision. Several prosthetic approaches are limited by the perceptual fading of evoked phosphenes upon repeated stimulation from the same electrode. Therefore, implanted patients are forced to perform active scanning, via head movements, to refresh the visual field viewed by the camera. However, active scanning is a draining task, and it is crucial to find compensatory strategies to reduce it. Approach: To address this question, we implemented perceptual fading in simulated prosthetic vision using virtual reality. Then, we quantified the effect of fading on two indicators: the time to complete a reading task and the head rotation during the task. We also tested if stimulation strategies previously proposed to increase the persistence of responses in retinal ganglion cells to electrical stimulation could improve these indicators. Main results: This study shows that stimulation strategies based on interrupted pulse trains and randomisation of the pulse duration allows significant reduction of both the time to complete the task and the head rotation during the task. Significance: The stimulation strategy used in retinal implants is crucial to counteract perceptual fading and to reduce active head scanning during prosthetic vision. In turn, less active scanning might improve the patient's comfort in artificial vision.

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Architecture of retinal projections to the central circadian pacemaker

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1523629113 ◽

2016 ◽

Vol 113 (21) ◽

pp. 6047-6052 ◽

Cited By ~ 53

Author(s):

Diego Carlos Fernandez ◽

Yi-Ting Chang ◽

Samer Hattar ◽

Shih-Kuo Chen

Keyword(s):

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Microscopic Analysis ◽

Brain Regions ◽

Retinal Ganglion ◽

Circadian Pacemaker ◽

Retinal Neurons ◽

Retinal Input ◽

Innervation Patterns ◽

Left And Right

The suprachiasmatic nucleus (SCN) receives direct retinal input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) for circadian photoentrainment. Interestingly, the SCN is the only brain region that receives equal inputs from the left and right eyes. Despite morphological assessments showing that axonal fibers originating from ipRGCs cover the entire SCN, physiological evidence suggests that only vasoactive intestinal polypeptide (VIP)/gastrin-releasing peptide (GRP) cells located ventrally in the SCN receive retinal input. It is still unclear, therefore, which subpopulation of SCN neurons receives synaptic input from the retina and how the SCN receives equal inputs from both eyes. Here, using single ipRGC axonal tracing and a confocal microscopic analysis in mice, we show that ipRGCs have elaborate innervation patterns throughout the entire SCN. Unlike conventional retinal ganglion cells (RGCs) that innervate visual targets either ipsilaterally or contralaterally, a single ipRGC can bilaterally innervate the SCN. ipRGCs form synaptic contacts with major peptidergic cells of the SCN, including VIP, GRP, and arginine vasopressin (AVP) neurons, with each ipRGC innervating specific subdomains of the SCN. Furthermore, a single SCN-projecting ipRGC can send collateral inputs to many other brain regions. However, the size and complexity of the axonal arborizations in non-SCN regions are less elaborate than those in the SCN. Our results provide a better understanding of how retinal neurons connect to the central circadian pacemaker to synchronize endogenous circadian clocks with the solar day.

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Radial migration: Retinal neurons hold on for the ride

The Journal of Cell Biology ◽

10.1083/jcb.201609135 ◽

2016 ◽

Vol 215 (2) ◽

pp. 147-149 ◽

Cited By ~ 4

Author(s):

Jeremy N. Kay

Keyword(s):

Nervous System ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Retinal Neurons ◽

Newborn Neuron ◽

Radial Migration ◽

Biological Basis ◽

Cell Biol

Newborn neuron radial migration is a key force shaping the nervous system. In this issue, Icha et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201604095) use zebrafish retinal ganglion cells as a model to investigate the cell biological basis of radial migration and the consequences for retinal histogenesis when migration is impaired.

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