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Purpose: Because stress can aggravate vascular dysregulation (VD) in primary open-angle glaucoma (POAG), stress reduction by eye yoga (EY) was studied if this predictive, preventive, and personalized medical (3PM) approach could help normalize intraocular pressure (IOP), retinal vessel dynamics, and visual fields (VF). Patients and methods: POAG patients were randomized to an EY (n = 15) or control group (n = 12). EY was practiced daily for 1 h for 1 month at home using an iPod-audio guide while control patients read relaxing books daily. Results: After intervention, EY patients, but not controls, showed a 6.4% IOP reduction (p = 0.027) and had significant VF improvements (p < 0.001). After EY, pattern deviation recovered in VF regions where small microvessels showed reduced vasoconstriction (artery: p = 0.012; vein: p = 0.042) and improved mean artery diameter recovered significantly (p = 0.015). When pooling data of both groups, recovered VF regions, but not non-recovered fields, showed significantly larger arterial diameter gains (2.4 [− 0.3–5.3] MU) with no adverse events. Conclusions and 3PM recommendations.: Because EY reduces vasoconstriction and improves VF function in POAG, we propose the "eye ball retraction theory," whereby ocular muscle tension is induced by mental stress which is a contributing mechanism, or even the key mechanism, of POAG. Reducing stress by relaxation is therefore a remedy for it improves blood flow as the fundamental mechanism of vision recovery and restoration. VD reduction is therefore a valuable therapeutic target for glaucoma care and eye yoga home exercises are a safe and effective complementary 3PM method of POAG care. [ABSTRACT FROM AUTHOR]

X-linked retinitis pigmentosa (XLRP) is a severe inherited retinal degenerative disease characterized by progressive loss of photoreceptors and retinal pigment epithelium, leading to blindness. Predominantly affecting males due to mutations in the RPGR gene, XLRP currently lacks effective treatments beyond supportive care. Gene therapy has emerged as a promising approach to restore photoreceptor function by delivering functional copies of the RPGR gene. Recent clinical trials using AAV vectors, such as AAV5-RPGR and AGTC-501, have demonstrated encouraging results, including improvements in retinal sensitivity and visual function. While early successes like LUXTURNA have set the precedent for gene therapy in retinal diseases, adapting these strategies to XLRP presents unique challenges due to the complexity of RPGR mutations and the need for efficient photoreceptor targeting. Advances in vector design, including the use of optimized AAV serotypes with enhanced tropism for photoreceptors and specific promoters, have significantly improved gene delivery. Despite setbacks in some studies, ongoing research and clinical trials continue to refine these therapies, offering hope for patients affected by XLRP. This review explores the etiology and pathophysiology of XLRP, evaluates current treatment challenges, highlights recent clinical advances in gene therapy, and discusses future perspectives for bringing these therapies into clinical practice. [ABSTRACT FROM AUTHOR]

Javier Mendicute,1,2 Gorka Lauzirika,1,3 Igor Illarramendi,1 Itziar Martínez-Soroa1,2 1Miranza Begitek, Donostia - San Sebastián, 20012, Spain; 2Donostia University Hospital, Donostia - San Sebastián, 20014, Spain; 3R&D Department of Miranza Group, Donostia - San Sebastián, SpainCorrespondence: Gorka Lauzirika, Miranza Begitek, Teresa Calcutta Square, No. 7, Donostia - San Sebastián, 20012, Spain, Email gorka.lauzirika@miranza.esPurpose: To describe the visual, refractive, functional, and patient satisfaction outcomes of the Clareon® PanOptix® trifocal intraocular lens (IOL).Patients and Methods: This was a prospective longitudinal descriptive study. Patients who underwent cataract surgery with implantation of Clareon® PanOptix® (Alcon Laboratories, Inc.) were included. Monocular refractive outcomes and visual acuity at distance, intermediate, and near were evaluated 1- and 6-months post-op. Binocular contrast sensitivity (M&S® Technologies), binocular defocus curve, and patient satisfaction with the IOL Satisfaction (IOLSAT) and Questionnaire for Visual Disturbance (QUVID) questionaries were assessed at 6-month post-op.Results: Seventy-six Clareon® PanOptix® were implanted bilaterally in 38 patients. The mean age of the patients was 67.63± 5.18 years. At 1-month post-op, the monocular Corrected Distance Visual Acuity (CDVA), CIVA and CNVA were 0.00± 0.09, 0.02± 0.17, and 0.12± 0.12 LogMAR, respectively, and CDVA and CNVA were stable at 6-month post-op (p> 0.05). No statistical differences were found in post-op spherical equivalent at 1 and 6 months (− 0.08± 0.27 D and − 0.05± 0.24 D; p=0.351). A 100% of eyes were within ± 0.5 D at 1 month and 6-month post-op. Binocular defocus curve shows three peaks of maximum visual acuity (VA) at 0D (− 0.04± 0.08 LogMAR), at − 1.50D, and − 2.50 D (0.01± 0.10 LogMAR and 0.03± 0.07 LogMAR, respectively). Contrast sensitivity decreased at high spatial frequencies. In patient satisfaction, IOLSAT questionary reveals 78.94% patients “Never” or “Rarely” Needing Glasses and according QUVID questionnaire, 100% of patients report no hazy vision.Conclusion: The PanOptix® IOL platform with the new material Clareon® provides good visual outcomes for distance, intermediate, and near vision, with adequate contrast sensitivity and low visual disturbances.Keywords: cataract surgery, multifocal lens, vision restoration, phacoemulsification

Retinitis pigmentosa (RP) and Age-Related Macular Degeneration (AMD) are similar in that both result in photoreceptor degeneration leading to permanent progressive vision loss. This affords the possibility of implementing vision restoration techniques, where light signaling is restored to spared retinal circuitry to recreate vision. There are far more AMD patients (Wong et al., 2014), yet more resources have been put towards researching and developing vision restoration strategies for RP despite it rarity, because of the tractability of RP disease models. The hope is that these therapies will extend to the AMD population, however, many questions remain about how the implementation of prosthetic or optogenetic vision restoration technologies will translate between RP and AMD patients. In this review, we discuss the difference and similarities of RP and AMD with a focus on aspects expected to impact vision restoration strategies, and we identify key gaps in knowledge needed to further improve vision restoration technologies for a broad patient population. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) and Age-Related Macular Degeneration (AMD) are similar in that both result in photoreceptor degeneration leading to permanent progressive vision loss. This affords the possibility of implementing vision restoration techniques, where light signaling is restored to spared retinal circuitry to recreate vision. There are far more AMD patients (Wong et al., 2014), yet more resources have been put towards researching and developing vision restoration strategies for RP despite it rarity, because of the tractability of RP disease models. The hope is that these therapies will extend to the AMD population, however, many questions remain about how the implementation of prosthetic or optogenetic vision restoration technologies will translate between RP and AMD patients. In this review, we discuss the difference and similarities of RP and AMD with a focus on aspects expected to impact vision restoration strategies, and we identify key gaps in knowledge needed to further improve vision restoration technologies for a broad patient population.

Abstract Vision restoration is one of the most promising applications of optogenetics. However, it is limited due to the poor-sensitivity, slow-kinetics and narrow band absorption spectra of opsins. Here, a detailed theoretical study of retinal ganglion neurons (RGNs) expressed with ChRmine, ReaChR, CoChR, CatCh and their mutants, with near monochromatic LEDs, and broadband sunlight, halogen lamp, RGB LED light, and pure white light sources has been presented. All the opsins exhibit improved light sensitivity and larger photocurrent on illuminating with broadband light sources compared to narrow band LEDs. ChRmine allows firing at ambient sunlight (1.5 nW/mm2) and pure white light (1.2 nW/mm2), which is lowest among the opsins considered. The broadband activation spectrum of ChRmine and its mutants is also useful to restore color sensitivity. Although ChRmine exhibits slower turn-off kinetics with broadband light, high-fidelity spikes can be evoked upto 50 Hz. This limit extends upto 80 Hz with the improved hsChRmine mutant although it requires double the irradiance compared to ChRmine. The present study shows that ChRmine and its mutants allow activation of RGNs with ambient light which is useful for goggle-free white light optogenetic retinal prostheses with improved quality of restored vision.

Vision restoration is one of the most promising applications of optogenetics. However, it is limited due to the poor-sensitivity, slow-kinetics and narrow band absorption spectra of opsins. Here, a detailed theoretical study of retinal ganglion neurons (RGNs) expressed with ChRmine, ReaChR, CoChR, CatCh and their mutants, with near monochromatic LEDs, and broadband sunlight, halogen lamp, RGB LED light, and pure white light sources has been presented. All the opsins exhibit improved light sensitivity and larger photocurrent on illuminating with broadband light sources compared to narrow band LEDs. ChRmine allows firing at ambient sunlight (1.5 nW/mm2) and pure white light (1.2 nW/mm2), which is lowest among the opsins considered. The broadband activation spectrum of ChRmine and its mutants is also useful to restore color sensitivity. Although ChRmine exhibits slower turn-off kinetics with broadband light, high-fidelity spikes can be evoked upto 50 Hz. This limit extends upto 80 Hz with the improved hsChRmine mutant although it requires double the irradiance compared to ChRmine. The present study shows that ChRmine and its mutants allow activation of RGNs with ambient light which is useful for goggle-free white light optogenetic retinal prostheses with improved quality of restored vision. [ABSTRACT FROM AUTHOR]

Introduction: Ultra low vision (ULV) refers to profound visual impairment where an individual cannot read even the top line of letters on an ETDRS chart from a distance of 0.5 m. There are limited tools available to assess visual ability in ULV. The aim of this study was to develop and calibrate a new performance test, Wilmer VRH, to assess hand-eye coordination in individuals with ULV. Methods: A set of 55 activities was developed for presentation in a virtual reality (VR) headset. Activities were grouped into 2-step and 5-step items. Participants performed a range of tasks involving reaching and grasping, stacking, sorting, pointing, throwing, and cutting. Data were collected from 20 healthy volunteers under normal vision (NV) and simulated ULV (sULV) conditions, and from 33 participants with ULV. Data were analyzed using the method of successive dichotomizations (MSD), a polytomous Rasch model, to estimate item (difficulty) and person (ability) measures. MSD was applied separately to 2-step and 5-step performance data, then merged to a single equal interval scale. Results: The mean ±SD of completion rates were 98.6 ± 1.8%, 78.2 ± 12.5% and 61.1 ±34.2% for NV, sULV and ULV, respectively. Item measures ranged from -1.09 to 5.7 logits and - 4.3 to 4.08 logits and person measures ranged from -0.03 to 4.2 logits and -3.5 to 5.2 logits in sULV and ULV groups, respectively. Ninety percent of item infits were within the desired range of [0.5,1.5], and 97% of person infits were within that range. Together with item and person reliabilities of 0.94 and 0.91 respectively, this demonstrates unidimensionality of Wilmer VRH. A Person Item map showed that the items were well-targeted to the sample of individuals with ULV in the study. Discussion: We present the development of a calibrated set of activities in VR that can be used to assess hand-eye coordination in individuals with ULV. This helps bridge a gap in the field by providing a validated outcome measure that can be used in vision restoration trials that recruit people with ULV, and to assess rehabilitation outcomes in people with ULV. [ABSTRACT FROM AUTHOR]

Many forms of artificial sight recovery, such as electronic implants and optogenetic proteins, generally cause simultaneous, rather than complementary firing of on- and off-center retinal cells. Here, using virtual patients-sighted individuals viewing distorted input-we examine whether plasticity might compensate for abnormal neuronal population responses. Five participants were dichoptically presented with a combination of original and contrast-reversed images. Each image (I) and its contrast-reverse (I') was filtered using a radial checkerboard (F) in Fourier space and its inverse (F'). [I * F'] + [I' * F] was presented to one eye, and [I * F] + [I' * F'] was presented to the other, such that regions of the image that produced on-center responses in one eye produced off-center responses in the other eye, and vice versa. Participants continuously improved in a naturalistic object discrimination task over 20 one-hour sessions. Pre-training and post-training tests suggest that performance improvements were due to two learning processes: learning to recognize objects with reduced visual information and learning to suppress contrast-reversed image information in a non-eye-selective manner. These results suggest that, with training, it may be possible to adapt to the unnatural on- and off-cell population responses produced by electronic and optogenetic sight recovery technologies.

Optogenetic gene therapies offer a promising strategy for restoring vision to patients with retinal degenerative diseases, such as retinitis pigmentosa (RP). Several clinical trials have begun in this area using different vectors and optogenetic proteins (Clinical Identifiers: NCT02556736, NCT03326336, NCT04945772, and NCT04278131). Here we present preclinical efficacy and safety data for the NCT04278131 trial, which uses an AAV2 vector and Chronos as the optogenetic protein. Efficacy was assessed in mice in a dose-dependent manner using electroretinograms (ERGs). Safety was assessed in rats, nonhuman primates, and mice, using several tests, including immunohistochemical analyses and cell counts (rats), electroretinograms (nonhuman primates), and ocular toxicology assays (mice). The results showed that Chronos-expressing vectors were efficacious over a broad range of vector doses and stimulating light intensities, and were well tolerated: no test article-related findings were observed in the anatomical and electrophysiological assays performed.

Most inherited retinal dystrophies display progressive photoreceptor cell degeneration leading to severe visual impairment. Optogenetic reactivation of inner retinal neurons is a promising avenue to restore vision in retinas having lost their photoreceptors. Expression of optogenetic proteins in surviving ganglion cells, the retinal output, allows them to take on the lost photoreceptive function. Nonetheless, this creates an exclusively ON retina by expression of depolarizing optogenetic proteins in all classes of ganglion cells, whereas a normal retina extracts several features from the visual scene, with different ganglion cells detecting light increase (ON) and light decrease (OFF). Refinement of this therapeutic strategy should thus aim at restoring these computations. Here we used a vector that targets gene expression to a specific interneuron of the retina called the AII amacrine cell. AII amacrine cells simultaneously activate the ON pathway and inhibit the OFF pathway. We show that the optogenetic stimulation of AII amacrine cells allows restoration of both ON and OFF responses in the retina, but also mediates other types of retinal processing such as sustained and transient responses. Targeting amacrine cells with optogenetics is thus a promising avenue to restore better retinal function and visual perception in patients suffering from retinal degeneration.

IntroductionUltra low vision (ULV) refers to profound visual impairment where an individual cannot read even the top line of letters on an ETDRS chart from a distance of 0.5 m. There are limited tools available to assess visual ability in ULV. The aim of this study was to develop and calibrate a new performance test, Wilmer VRH, to assess hand-eye coordination in individuals with ULV.MethodsA set of 55 activities was developed for presentation in a virtual reality (VR) headset. Activities were grouped into 2-step and 5-step items. Participants performed a range of tasks involving reaching and grasping, stacking, sorting, pointing, throwing, and cutting. Data were collected from 20 healthy volunteers under normal vision (NV) and simulated ULV (sULV) conditions, and from 33 participants with ULV. Data were analyzed using the method of successive dichotomizations (MSD), a polytomous Rasch model, to estimate item (difficulty) and person (ability) measures. MSD was applied separately to 2-step and 5-step performance data, then merged to a single equal interval scale.ResultsThe mean ±SD of completion rates were 98.6 ± 1.8%, 78.2 ± 12.5% and 61.1 ±34.2% for NV, sULV and ULV, respectively. Item measures ranged from −1.09 to 5.7 logits and − 4.3 to 4.08 logits and person measures ranged from −0.03 to 4.2 logits and −3.5 to 5.2 logits in sULV and ULV groups, respectively. Ninety percent of item infits were within the desired range of [0.5,1.5], and 97% of person infits were within that range. Together with item and person reliabilities of 0.94 and 0.91 respectively, this demonstrates unidimensionality of Wilmer VRH. A Person Item map showed that the items were well-targeted to the sample of individuals with ULV in the study.DiscussionWe present the development of a calibrated set of activities in VR that can be used to assess hand-eye coordination in individuals with ULV. This helps bridge a gap in the field by providing a validated outcome measure that can be used in vision restoration trials that recruit people with ULV, and to assess rehabilitation outcomes in people with ULV.

Purpose: The Retinal Ganglion Cell (RGC) Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) consortium was founded in 2021 to help address the numerous scientific and clinical obstacles that impede development of vision-restorative treatments for patients with optic neuropathies. The goals of the RReSTORe consortium are: (1) to define and prioritize the most critical challenges and questions related to RGC regeneration; (2) to brainstorm innovative tools and experimental approaches to meet these challenges; and (3) to foster opportunities for collaborative scientific research among diverse investigators. Design and Participants: The RReSTORe consortium currently includes > 220 members spanning all career stages worldwide and is directed by an organizing committee comprised of 15 leading scientists and physician-scientists of diverse backgrounds. Methods: Herein, we describe the structure and organization of the RReSTORe consortium, its activities to date, and the perceived impact that the consortium has had on the field based on a survey of participants. Results: In addition to helping propel the field of regenerative medicine as applied to optic neuropathies, the RReSTORe consortium serves as a framework for developing large collaborative groups aimed at tackling audacious goals that may be expanded beyond ophthalmology and vision science. Conclusions: The development of innovative interventions capable of restoring vision for patients suffering from optic neuropathy would be transformative for the ophthalmology field, and may set the stage for functional restoration in other central nervous system disorders. By coordinating large-scale, international collaborations among scientists with diverse and complementary expertise, we are confident that the RReSTORe consortium will help to accelerate the field toward clinical translation. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Loss of photoreceptors in retinal degenerative diseases also impacts the inner retina: bipolar cell dendrites retract, neurons rewire, and protein expression changes. ON-bipolar cells (OBCs) represent an attractive target for optogenetic vision restoration. However, the above-described maladaptations may negatively impact the quality of restored vision. To investigate this question, we employed human post-mortem retinas and transgenic rd1_Opto-mGluR6 mice expressing the optogenetic construct Opto-mGluR6 in OBCs and carrying the retinal degeneration rd1 mutation. We found significant changes in delayed rectifier potassium channel expression in OBCs of degenerative retinas. In particular, we found an increase in Kv1.3 expression already in early stages of degeneration. Immunohistochemistry localized Kv1.3 channels specifically to OBC axons. In whole-cell patch-clamp experiments, OBCs in the degenerated murine retina were less responsive, which could be reversed by application of the specific Kv1.3 antagonist Psora-4. Notably, Kv1.3 block significantly increased the amplitude and kinetics of Opto-mGluR6-mediated light responses in OBCs of the blind retina and increased the signal-to-noise ratio of light-triggered responses in retinal ganglion cells. We propose that reduction in Kv1.3 activity in the degenerated retina, either by pharmacological block or by KCNA3 gene silencing, could improve the quality of restored vision. [ABSTRACT FROM AUTHOR]

Inherited progressive degeneration of photoreceptors such as retinitis pigmentosa (RP) is the most common cause of blindness leading to severe vision impairment affecting 〜1 in 5,000 people worldwide. Although the function and morphology of the photoreceptors get disrupted, there is evidence that the inner retinal neurons such as bipolar cells and the retinal ganglion cells are left intact until later stages. Among several innovative therapeutic options aiming to restore vision, optogenetic therapy can bestow light sensitivity to remaining retinal neurons by ectopic expression of light-sensitive proteins. Since the advent of this technique, a diverse class of opsins (microbial and mammalian opsins), chimeric proteins, ligand-gated ion channels, and switchable opsins have been used to study their potential in vision restoration. These proteins differ in their excitation spectra, response kinetics, and signal amplification cascade. Although most of the studies have reported high fidelity of responses in the retina, only a handful of them have achieved functional vision in the visual cortex. This review is a summary of the visuocortical and behavioral responses after optogenetic treatment of the degenerated retina. This clarifies to what extent improved and meaningful vision can be obtained for therapeutic efficacy and continued clinical progress. [ABSTRACT FROM AUTHOR]

A retinal prosthesis, also known as a bionic eye, is a device that can be implanted to partially restore vision in patients with retinal diseases that have resulted in the loss of photoreceptors (e.g., age-related macular degeneration and retinitis pigmentosa). Recently, there have been major breakthroughs in retinal prosthesis technology, with the creation of numerous types of implants, including epiretinal, subretinal, and suprachoroidal sensors. These devices can stimulate the remaining cells in the retina with electric signals to create a visual sensation. A literature review of the pre-clinical and clinical studies published between 2017 and 2023 is conducted. This narrative review delves into the retinal anatomy, physiology, pathology, and principles underlying electronic retinal prostheses. Engineering aspects are explored, including electrode–retina alignment, electrode size and material, charge density, resolution limits, spatial selectivity, and bidirectional closed-loop systems. This article also discusses clinical aspects, focusing on safety, adverse events, visual function, outcomes, and the importance of rehabilitation programs. Moreover, there is ongoing debate over whether implantable retinal devices still offer a promising approach for the treatment of retinal diseases, considering the recent emergence of cell-based and gene-based therapies as well as optogenetics. This review compares retinal prostheses with these alternative therapies, providing a balanced perspective on their advantages and limitations. The recent advancements in retinal prosthesis technology are also outlined, emphasizing progress in engineering and the outlook of retinal prostheses. While acknowledging the challenges and complexities of the technology, this article highlights the significant potential of retinal prostheses for vision restoration in individuals with retinal diseases and calls for continued research and development to refine and enhance their performance, ultimately improving patient outcomes and quality of life. [ABSTRACT FROM AUTHOR]

Retinal organoid technology enables generation of an inexhaustible supply of three-dimensional retinal tissue from human pluripotent stem cells (hPSCs) for regenerative medicine applications. The high similarity of organoid-derived retinal tissue and transplantable human fetal retina provides an opportunity for evaluating and modeling retinal tissue replacement strategies in relevant animal models in the effort to develop a functional retinal patch to restore vision in patients with profound blindness caused by retinal degeneration. Because of the complexity of this very promising approach requiring specialized stem cell and grafting techniques, the tasks of retinal tissue derivation and transplantation are frequently split between geographically distant teams. Delivery of delicate and perishable neural tissue such as retina to the surgical sites requires a reliable shipping protocol and also controlled temperature conditions with damage-reporting mechanisms in place to prevent transplantation of tissue damaged in transit into expensive animal models. We have developed a robust overnight tissue shipping protocol providing reliable temperature control, live monitoring of the shipment conditions and physical location of the package, and damage reporting at the time of delivery. This allows for shipping of viable (transplantation-competent) hPSC-derived retinal tissue over large distances, thus enabling stem cell and surgical teams from different parts of the country to work together and maximize successful engraftment of organoid-derived retinal tissue. Although this protocol was developed for preclinical in vivo studies in animal models, it is potentially translatable for clinical transplantation in the future and will contribute to developing clinical protocols for restoring vision in patients with retinal degeneration.

Age-related macular degeneration is one of the leading causes of irreversible vision loss in ageing populations worldwide. The PRIMA bionic vision system is a photovoltaic substitute for lost photoreceptors that is designed for patients with atrophic dry age-related macular degeneration. The subretinal implant, activated by near-infrared light from augmented-reality glasses, provides central prosthetic vision, perceived simultaneously with peripheral natural vision. This editorial reviews PRIMA’s mode of action, clinical trial data and potential impact on clinical practice. [ABSTRACT FROM AUTHOR]

Inherited progressive degeneration of photoreceptors such as retinitis pigmentosa (RP) is the most common cause of blindness leading to severe vision impairment affecting ~1 in 5,000 people worldwide. Although the function and morphology of the photoreceptors get disrupted, there is evidence that the inner retinal neurons such as bipolar cells and the retinal ganglion cells are left intact until later stages. Among several innovative therapeutic options aiming to restore vision, optogenetic therapy can bestow light sensitivity to remaining retinal neurons by ectopic expression of light-sensitive proteins. Since the advent of this technique, a diverse class of opsins (microbial and mammalian opsins), chimeric proteins, ligand-gated ion channels, and switchable opsins have been used to study their potential in vision restoration. These proteins differ in their excitation spectra, response kinetics, and signal amplification cascade. Although most of the studies have reported high fidelity of responses in the retina, only a handful of them have achieved functional vision in the visual cortex. This review is a summary of the visuocortical and behavioral responses after optogenetic treatment of the degenerated retina. This clarifies to what extent improved and meaningful vision can be obtained for therapeutic efficacy and continued clinical progress.

The optic nerve is the second cranial nerve (CN II) that connects and transmits visual information between the retina and the brain. Severe damage to the optic nerve often leads to distorted vision, vision loss, and even blindness. Such damage can be caused by various types of degenerative diseases, such as glaucoma and traumatic optic neuropathy, and result in an impaired visual pathway. To date, researchers have not found a viable therapeutic method to restore the impaired visual pathway; however, in this paper, a newly synthesized model is proposed to bypass the damaged portion of the visual pathway and set up a direct connection between a stimulated visual input and the visual cortex (VC) using Low-frequency Ring-transducer Ultrasound Stimulation (LRUS). In this study, by utilizing and integrating various advanced ultrasonic and neurological technologies, the following advantages are achieved by the proposed LRUS model: 1. This is a non-invasive procedure that uses enhanced sound field intensity to overcome the loss of ultrasound signal due to the blockage of the skull. 2. The simulated visual signal generated by LRUS in the visual-cortex-elicited neuronal response in the visual cortex is comparable to light stimulation of the retina. The result was confirmed by a combination of real-time electrophysiology and fiber photometry. 3. VC showed a faster response rate under LRUS than light stimulation through the retina. These results suggest a potential non-invasive therapeutic method for restoring vision in optic-nerve-impaired patients using ultrasound stimulation (US). [ABSTRACT FROM AUTHOR]

Purpose: Vision loss in glaucoma is not only associated with elevated intraocular pressure and neurodegeneration, but vascular dysregulation (VD) is a major factor. To optimize therapy, an improved understanding of concepts of predictive, preventive, and personalized medicine (3PM) is needed which is based on a more detailed understanding of VD pathology. Specifically, to learn if the root cause of glaucomatous vision loss is of neuronal (degeneration) or vascular origin, we now studied neurovascular coupling (NVC) and vessel morphology and their relationship to vision loss in glaucoma. Methods: In patients with primary open angle glaucoma (POAG) (n = 30) and healthy controls (n = 22), NVC was studied using dynamic vessel analyzer to quantify retinal vessel diameter before, during, and after flicker light stimulation to evaluate the dilation response following neuronal activation. Vessel features and dilation were then related to branch level and visual field impairment. Results: Retinal arterial and venous vessels had significantly smaller diameters in patients with POAG in comparison to controls. However, both arterial and venous dilation reached normal values during neuronal activation despite their smaller diameters. This was largely independent of visual field depth and varied among patients. Conclusions: Because dilation/constriction is normal, VD in POAG can be explained by chronic vasoconstriction which limits energy supply to retinal (and brain) neurons with subsequent hypo-metabolism ("silent" neurons) or neuronal cell death. We propose that the root cause of POAG is primarily of vascular and not neuronal origin. This understanding can help to better personalize POAG therapy of not only targeting eye pressure but also vasoconstriction to prevent low vision, slowing its progression and supporting recovery and restoration. Trial registration: ClinicalTrials.gov, # NCT04037384 on July 3, 2019. [ABSTRACT FROM AUTHOR]

Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation and asked whether altered mitochondrial dynamics in ECs impinge on vascular barrier integrity and neurodegeneration. We show that ocular hypertension, a major risk factor to develop glaucoma, induced mitochondrial fragmentation in retinal capillary ECs accompanied by increased oxidative stress and ultrastructural defects. Analysis of EC mitochondrial components revealed overactivation of dynamin-related protein 1 (DRP1), a central regulator of mitochondrial fission, during glaucomatous damage. Pharmacological inhibition or EC-specific in vivo gene delivery of a dominant negative DRP1 mutant was sufficient to rescue mitochondrial volume, reduce vascular leakage, and increase expression of the tight junction claudin-5 (CLDN5). We further demonstrate that EC-targeted CLDN5 gene augmentation restored blood-retinal-barrier integrity, promoted neuronal survival, and improved light-evoked visual behaviors in glaucomatous mice. Our findings reveal that preserving mitochondrial homeostasis and EC function are valuable strategies to enhance neuroprotection and improve vision in glaucoma., Competing Interests: COMPETING INTERESTS The authors declare that they have no competing interests.

Retinitis pigmentosa, an inherited form of retinal degeneration, is characterized by a progressive loss of rods and subsequent degeneration of cones, leading to blindness. However, the remaining neural portion of the retina (bipolar and ganglion cells) remains anatomically and functionally intact for an extended time. A possible treatment to restore the light sensitivity of the retina consists of rendering the remaining retinal cells photosensitive using optogenetic tools like, for example, Opto-mGluR6, a light-sensitive mGluR6 receptor. We have previously demonstrated that AAV vector-mediated expression of Opto-mGluR6 in ON-bipolar cells restores visual function in otherwise blind mice. However, classical gene supplementation therapy still suffers from high off-target expression rates and uncontrollable target gene expression levels that may lead to either cytotoxicity or lack of functional restoration. To address these issues and achieve cell-specific and endogenously controlled Opto-mGluR6 expression, we employed the CRISPR/Cas technology—in particular, homology-independent targeted integration (HITI) and microhomology-dependent targeted integration (MITI)—to knock-in the Opto-mGluR6 gene behind the ON-bipolar cell-specific GRM6 promoter. We compared four Cas systems in vitro and show that SpCas9 for HITI and LbCpf1 for MITI are well suited to promoting knock-in. As AAV2-mediated ON-bipolar cell transduction resulted in inefficiency, we evaluated Exo-AAVs as delivery vehicles and found Exo-AAV1 efficient for targeting ON-bipolar cells. We demonstrate that intravitreal injection of Exo-AAV1 carrying vectors that promote MITI significantly improved visual acuity in otherwise blind rd1 mice. We conclude by confirming and providing a qualitative evaluation of the MITI-mediated knock-in in the correct genomic locus.

As neuroscience and rehabilitative techniques advance, age-old questions concerning the visual experience of those who gain sight after blindness, once thought to be philosophical alone, take center stage and become the target for scientific inquiries. In this study, we employ a battery of visual perception tasks to study the unique experience of a small group of children who have undergone vision-restoring cataract removal surgery as part of the Himalayan Cataract Project. We tested their abilities to perceive in three dimensions (3D) using a binocular rivalry task and the Brock string task, perceive visual illusions, use cross-modal mappings between touch and vision, and spatially group based on geometric cues. Some of the children in this study gained a sense of sight for the first time in their lives, having been born with bilateral congenital cataracts, while others suffered late-onset blindness in one eye alone. This study simultaneously supports yet raises further questions concerning Hubel and Wiesel’s critical periods theory and provides additional insight into Molyneux’s problem, the ability to correlate vision with touch quickly. We suggest that our findings present a relatively unexplored intermediate stage of 3D vision development. Importantly, we spotlight some essential geometrical perception visual abilities that strengthen the idea that spontaneous geometry intuitions arise independently from visual experience (and education), thus replicating and extending previous studies. We incorporate a new model, not previously explored, of testing children with congenital cataract removal surgeries who perform the task via vision. In contrast, previous work has explored these abilities in the congenitally blind via touch. Taken together, our findings provide insight into the development of what is commonly known as the visual system in the visually deprived and highlight the need to further empirically explore an amodal, task-based interpretation of specializations in the development and structure of the brain. Moreover, we propose a novel objective method, based on a simple binocular rivalry task and the Brock string task, for determining congenital (early) vs. late blindness where medical history and records are partial or lacking (e.g., as is often the case in cataract removal cases).

Photopharmacological compounds such as azobenzene-based photoswitches have been shown to control the conductivity of ionic channels in a light-dependent manner and are considered a potential strategy to restore vision in patients with end-stage photoreceptor degeneration. Here, we report the effects of DENAQ, a second-generation azobenzene-based photoswitch on retinal ganglion cells (RGC) in canine retinas using multi-electrode array (MEA) recordings (from nine degenerated and six WT retinas). DENAQ treatment conferred increased light sensitivity to RGCs in degenerated canine retinas. RGC light responses were observed in degenerated retinas following ex vivo application of 1 mM DENAQ (n = 6) or after in vivo DENAQ injection (n = 3, 150 μL, 3–10 mM) using 455 nm light at intensities as low as 0.2 mW/cm2. The number of light-sensitive cells and the per cell response amplitude increased with light intensity up to the maximum tested intensity of 85 mW/cm2. Application of DENAQ to degenerated retinas with partially preserved cone function caused appearance of DENAQ-driven responses both in cone-driven and previously non-responsive RGCs, and disappearance of cone-driven responses. Repeated stimulation slowed activation and accelerated recovery of the DENAQ-driven responses. The latter is likely responsible for the delayed appearance of a response to 4 Hz flicker stimulation. Limited aqueous solubility of DENAQ results in focal drug aggregates associated with ocular toxicity. While this limits the therapeutic potential of DENAQ, more potent third-generation photoswitches may be more promising, especially when delivered in a slow-release formulation that prevents drug aggregation. [ABSTRACT FROM AUTHOR]

Vision restoration strategies aim to reestablish vision by replacing the function of lost photoreceptors with optoelectronic hardware or through gene therapy. One complication to these approaches is that retinal circuitry undergoes remodeling after photoreceptor loss. Circuit remodeling following perturbation is ubiquitous in the nervous system and understanding these changes is crucial for treating neurodegeneration. Spontaneous oscillations that arise during retinal degeneration have been well-studied, however, other changes in the spatiotemporal processing of evoked and spontaneous activity have received less attention. Here we use subretinal electrical stimulation to measure the spatial and temporal spread of both spontaneous and evoked activity during retinal degeneration. We found that electrical stimulation synchronizes spontaneous oscillatory activity, over space and through time, thus leading to increased correlations in ganglion cell activity. Intriguingly, we found that spatial selectivity was maintained in rd10 retina for evoked responses, with spatial receptive fields comparable to wt retina. These findings indicate that different biophysical mechanisms are involved in mediating feed forward excitation, and the lateral spread of spontaneous activity in the rd10 retina, lending support toward the possibility of high-resolution vision restoration. [ABSTRACT FROM AUTHOR]

The advent of optogenetics has ushered in a new era in neuroscience where spatiotemporal control of neurons is possible through light application. These tools used to study neural circuits can also be used therapeutically to restore vision. In order to recapitulate the broad spectral and light sensitivities along with high temporal sensitivity found in human vision, researchers have identified and developed new optogenetic tools. There are two major kinds of optogenetic effectors employed in vision restoration: ion channels and G-protein coupled receptors (GPCRs). Ion channel based optogenetic therapies require high intensity light that can be unsafe at lower wavelengths, so work has been done to expand and red-shift the excitation spectra of these channels. Light activatable GPCRs are much more sensitive to light than their ion channel counterparts but are slower kinetically in terms of both activation and inactivation. This review article examines the latest optogenetic ion channel and GPCR candidates for vision restoration based on light and temporal sensitivity.

Vision restoration strategies aim to reestablish vision by replacing the function of lost photoreceptors with optoelectronic hardware or through gene therapy. One complication to these approaches is that retinal circuitry undergoes remodeling after photoreceptor loss. Circuit remodeling following perturbation is ubiquitous in the nervous system and understanding these changes is crucial for treating neurodegeneration. Spontaneous oscillations that arise during retinal degeneration have been well-studied, however, other changes in the spatiotemporal processing of evoked and spontaneous activity have received less attention. Here we use subretinal electrical stimulation to measure the spatial and temporal spread of both spontaneous and evoked activity during retinal degeneration. We found that electrical stimulation synchronizes spontaneous oscillatory activity, over space and through time, thus leading to increased correlations in ganglion cell activity. Intriguingly, we found that spatial selectivity was maintained in rd10 retina for evoked responses, with spatial receptive fields comparable to wt retina. These findings indicate that different biophysical mechanisms are involved in mediating feed forward excitation, and the lateral spread of spontaneous activity in the rd10 retina, lending support toward the possibility of high-resolution vision restoration.

Clinical results with photovoltaic subretinal prosthesis (PRIMA) demonstrated restoration of sight via electrical stimulation of the interneurons in degenerated retina, with resolution matching the 100 μm pixel size. Since scaling the pixels below 75 μm in the current bipolar planar geometry will significantly limit the penetration depth of the electric field and increase stimulation threshold, we explore the possibility of using smaller pixels based on a novel 3-dimensional honeycomb-shaped design. We assessed the long-term biocompatibility and stability of these arrays in rats by investigating the anatomical integration of the retina with flat and 3D implants and response to electrical stimulation over lifetime – up to 32–36 weeks post-implantation in aged rats. With both flat and 3D implants, signals elicited in the visual cortex decreased after the day of implantation by more than 3-fold, and gradually recovered over the next 12–16 weeks. With 25 μm high honeycomb walls, the majority of bipolar cells migrate into the wells, while amacrine and ganglion cells remain above the cavities, which is essential for selective network-mediated stimulation of the retina. Retinal thickness and full-field stimulation threshold with 40 μm-wide honeycomb pixels were comparable to those with planar devices – 0.05 mW/mm2 with 10 ms pulses. However, fewer cells from the inner nuclear layer migrated into the 20 μm-wide wells, and stimulation threshold increased over 12–16 weeks, before stabilizing at about 0.08 mW/mm2. Such threshold is still significantly lower than 1.8 mW/mm2 with a previous design of flat bipolar pixels, confirming the promise of the 3D honeycomb-based approach to high resolution subretinal prosthesis. [ABSTRACT FROM AUTHOR]

Globally, it is estimated there are more than 2.2 billion visually impaired people. Visual diseases such as retinitis pigmentosa, age-related macular degeneration, glaucoma, and optic neuritis can cause irreversible profound vision loss. Many groups have investigated different approaches such as microelectronic prostheses, optogenetics, stem cell therapy, and gene therapy to restore vision. However, these methods have some limitations such as invasive implantation surgery and unknown long-term risk of genetic manipulation. In addition to the safety of ultrasound as a medical imaging modality, ultrasound stimulation can be a viable non-invasive alternative approach for the sight restoration because of its ability to non-invasively control neuronal activities. Indeed, recent studies have demonstrated ultrasound stimulation can successfully modulate retinal/brain neuronal activities without causing any damage to the nerve cells. Superior penetration depth and high spatial resolution of focused ultrasound can open a new avenue in neuromodulation researches. This review summarizes the latest research results about neural responses to ultrasound stimulation. Also, this work provides an overview of technical viewpoints in the future design of a miniaturized ultrasound transducer for a non-invasive acoustic visual prosthesis for non-surgical and painless restoration of vision. [ABSTRACT FROM AUTHOR]

Background: Vision restoration has been one of the most sought‐after goals of ophthalmology because of its inception. Despite these problems being tackled from numerous different perspectives, a concrete solution has not yet been achieved. An optimal solution will have significant implications on the patient's quality of life, socioeconomic status, and mental health. Methods: This article will explore new and innovative approaches with one common aim—to restore functional vision for the visually impaired. These novel techniques include 3D bioprinting, stem cell therapy, gene therapy, implantable devices, and optogenetics. Results: While the techniques mentioned above show significant promise, they are currently in various stages of development ranging from clinical trials to commercial availability. Restoration of minimal vision in specific cases has already been achieved by the different methods but optimization of different parameters like biocompatibility, spatiotemporal resolution, and minimizing the costs are essential for widespread use. Conclusion: The developments over the past decade have resulted in multiple milestones in each of the techniques with many solutions getting approved by the FDA. This article will compare these novel techniques and highlight the major advantages and drawbacks of each of them. [ABSTRACT FROM AUTHOR]

Globally, it is estimated there are more than 2.2 billion visually impaired people. Visual diseases such as retinitis pigmentosa, age-related macular degeneration, glaucoma, and optic neuritis can cause irreversible profound vision loss. Many groups have investigated different approaches such as microelectronic prostheses, optogenetics, stem cell therapy, and gene therapy to restore vision. However, these methods have some limitations such as invasive implantation surgery and unknown long-term risk of genetic manipulation. In addition to the safety of ultrasound as a medical imaging modality, ultrasound stimulation can be a viable non-invasive alternative approach for the sight restoration because of its ability to non-invasively control neuronal activities. Indeed, recent studies have demonstrated ultrasound stimulation can successfully modulate retinal/brain neuronal activities without causing any damage to the nerve cells. Superior penetration depth and high spatial resolution of focused ultrasound can open a new avenue in neuromodulation researches. This review summarizes the latest research results about neural responses to ultrasound stimulation. Also, this work provides an overview of technical viewpoints in the future design of a miniaturized ultrasound transducer for a non-invasive acoustic visual prosthesis for non-surgical and painless restoration of vision.

The last major review of progress toward a chemical retinal prosthesis was a decade ago. Many important advancements have been made since then with the aim of producing an implantable device for animal testing. We review that work here discussing the potential advantages a chemical retinal prosthesis may possess, the spatial and temporal resolutions it might provide, the materials from which an implant might be constructed and its likely effectiveness in stimulating the retina in a natural fashion. Consideration is also given to implant biocompatibility, excitotoxicity of dispensed glutamate and known changes to photoreceptor degenerate retinas. [ABSTRACT FROM AUTHOR]

Given the rising number of patients with blindness from macular, optic nerve, and visual pathway disease, there is considerable interest in the potential of electrical stimulation devices to restore vision. Electrical devices for restoration of visual function can be grouped into three categories: (1) visual prostheses whose goal is to bypass damaged areas and directly activate downstream intact portions of the visual pathway; (2) electric field stimulation whose goal is to activate endogenous transcriptional and molecular signaling pathways to promote neuroprotection and neuro-regeneration; and (3) neuromodulation whose stimulation would resuscitate neural circuits vital to coordinating responses to visual input. In this review, we discuss these three approaches, describe advances made in the different fields, and comment on limitations and potential future directions. [ABSTRACT FROM AUTHOR]

Optogenetic gene therapy holds promise to restore high-quality vision in blind patients and recently reached clinical trials. Although the ON-bipolar cells, the first retinal interneurons, make the most attractive targets for optogenetic vision restoration, they have remained inaccessible to human gene therapy due to the lack of a robust cell-specific promoter. We describe the design and functional evaluation of 770En_454P(hGRM6), a human GRM6 gene-derived, short promoter that drives strong and highly specific expression in both the rod- and cone-type ON-bipolar cells of the human retina. Expression also in cone-type ON-bipolar cells is of importance, since the cone-dominated macula mediates high-acuity vision and is the primary target of gene therapies. 770En_454P(hGRM6)-driven middle-wave opsin expression in ON-bipolar cells achieved lasting restoration of high visual acuity in the rd1 mouse model of late retinal degeneration. The new promoter enables precise manipulation of the inner retinal network and paves the way for clinical application of gene therapies for high-resolution optogenetic vision restoration, raising hopes of significantly improving the life quality of people suffering from blindness.

The last major review of progress toward a chemical retinal prosthesis was a decade ago. Many important advancements have been made since then with the aim of producing an implantable device for animal testing. We review that work here discussing the potential advantages a chemical retinal prosthesis may possess, the spatial and temporal resolutions it might provide, the materials from which an implant might be constructed and its likely effectiveness in stimulating the retina in a natural fashion. Consideration is also given to implant biocompatibility, excitotoxicity of dispensed glutamate and known changes to photoreceptor degenerate retinas.

The visual pathways that guide actions do not necessarily mediate conscious perception. Patients with primary visual cortex (V1) damage lose conscious perception but often retain unconscious abilities (e.g. blindsight). Here, we asked if saccade accuracy and post-saccadic following responses (PFRs) that automatically track target motion upon saccade landing are retained when conscious perception is lost. We contrasted these behaviors in the blind and intact fields of 11 chronic V1-stroke patients, and in 8 visually intact controls. Saccade accuracy was relatively normal in all cases. Stroke patients also had normal PFR in their intact fields, but no PFR in their blind fields. Thus, V1 damage did not spare the unconscious visual processing necessary for automatic, post-saccadic smooth eye movements. Importantly, visual training that recovered motion perception in the blind field did not restore the PFR, suggesting a clear dissociation between pathways mediating perceptual restoration and automatic actions in the V1-damaged visual system.

Optic nerve disorders significantly contribute to visual impairment with irreversible visual deficits. Current treatments have limited efficacy in resolving chronic visual deficits, necessitating novel therapeutic strategies. Neurorehabilitation techniques, including repetitive transorbital alternating current stimulation (rtACS), have emerged as promising approaches to restore lost visual function through the ability to modulate brain activity. However, the evidence on the effectiveness of rtACS remains inconclusive, warranting a systematic review to assess its potential as a therapeutic intervention for optic nerve-related visual deficits. This study exclusively evaluated the effectiveness of rtACS for visual field restoration in patients with optic nerve damage, including only randomized controlled trials (RCTs) that met the strict eligibility criteria. A thorough screening and data extraction process was conducted by independent reviewers, followed by a meta-analysis to assess the statistical significance and heterogeneity of the included studies. The improvement in the visual field in the rtACS compared to the sham group was the primary outcome, and visual acuity improvement was the secondary outcome. This study included three RCTs that evaluated the effects of rtACS compared to sham control in treating optic nerve damage. In regard to visual field (VF), the results revealed a significant improvement in the detection accuracy of the rtACS group compared to the control group, with a pooled mean difference of 32.06 [95% CI: 19.2, 51.2] (p=0.001, I2= 0%). The near and far vision revealed no statistically significant difference between both groups. Based on the systematic review, the use of rtACS shows a promising effect in improving the detection accuracy of the VF for patients with optic nerve damage, with a significant benefit over sham control. However, the effects on other visual outcomes were minimal, and safety data was limited. Further high-quality trials are needed to corroborate the findings and provide a more comprehensive evaluation of its efficacy and safety for treating optic nerve-related visual deficits., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Alsudais et al.)

The National Eye Institute (NEI) hosted a workshop on November 19, 2014, as part of the Audacious Goals Initiative (AGI), an NEI-led effort to rapidly expand therapies for eye diseases through coordinated research funding. The central audacious goal aims to demonstrate by 2025 the restoration of usable vision in humans through the regeneration of neurons and neural connections in the eye and visual system. This workshop focused on identifying promising strategies for optic nerve regeneration. Its principal objective was to solicit input on future AGI-related funding announcements, and specifically to ask, where are we now in our scientific progress, and what progress should we reach for in the coming years? A full report was generated as a white paper posted on the NEI Web site; this report summarizes the discussion and outcomes from the meeting and serves as guidance for future funding of research that focuses on optic nerve regeneration.

Bipolar cells have become successful targets for optogenetic gene therapies that restore vision after photoreceptor degeneration. However, degeneration was shown to cause changes in neuronal connectivity and protein expression, which may impact the quality of synthetically restored signaling. Further, the expression of an optogenetic protein may alter passive membrane properties of bipolar cells affecting signal propagation. We here investigated the passive membrane properties of rod bipolar cells in three different systems, the healthy retina, the degenerated retina, and the degenerated retina expressing the optogenetic actuator Opto-mGluR6. We found that, based on the shape of their current-voltage relations, rod bipolar cells in healthy and degenerated retinas form two clear functional groups (type 1 and type 2 cells). Depolarizing the membrane potential changed recorded current-voltage curves from type 1 to type 2, confirming a single cell identity with two functional states. Expression of Opto-mGluR6 did not alter the passive properties of the rod bipolar cell. With progressing degeneration, dominant outward rectifying currents recorded in type 2 rod bipolar cells decreased significantly. We demonstrate that this is caused by a downregulation of BK channel expression in the degenerated retina. Since this BK conductance will normally recover the membrane potential after RBCs are excited by open TRPM1 channels, a loss in BK will decrease high-pass filtering at the rod bipolar cell level. A better understanding of the changes of bipolar cell physiology during retinal degeneration may pave the way to optimize future treatment strategies of blindness.

Bipolar cells have become successful targets for optogenetic gene therapies that restore vision after photoreceptor degeneration. However, degeneration was shown to cause changes in neuronal connectivity and protein expression, which may impact the quality of synthetically restored signaling. Further, the expression of an optogenetic protein may alter passive membrane properties of bipolar cells affecting signal propagation. We here investigated the passive membrane properties of rod bipolar cells in three different systems, the healthy retina, the degenerated retina, and the degenerated retina expressing the optogenetic actuator Opto-mGluR6. We found that, based on the shape of their current-voltage relations, rod bipolar cells in healthy and degenerated retinas form two clear functional groups (type 1 and type 2 cells). Depolarizing the membrane potential changed recorded current-voltage curves from type 1 to type 2, confirming a single cell identity with two functional states. Expression of Opto-mGluR6 did not alter the passive properties of the rod bipolar cell. With progressing degeneration, dominant outward rectifying currents recorded in type 2 rod bipolar cells decreased significantly. We demonstrate that this is caused by a downregulation of BK channel expression in the degenerated retina. Since this BK conductance will normally recover the membrane potential after RBCs are excited by open TRPM1 channels, a loss in BK will decrease high-pass filtering at the rod bipolar cell level. A better understanding of the changes of bipolar cell physiology during retinal degeneration may pave the way to optimize future treatment strategies of blindness. [ABSTRACT FROM AUTHOR]

Background: Cortical blindness is a form of severe vision loss that is caused by damage to the primary visual cortex (V1) or its afferents. This condition has devastating effects on quality of life and independence. While there are few treatments currently available, accumulating evidence shows that certain visual functions can be restored with appropriate perceptual training: Stimulus sensitivity can be increased within portions of the blind visual field. However, this increased sensitivity often remains highly specific to the trained stimulus, limiting the overall improvement in visual function. Objective: Recent advances in the field of perceptual learning show that such specificity can be overcome with training paradigms that leverage the properties of higher-level visual cortical structures, which have greater capacity to generalize across stimulus positions and features. This targeting can be accomplished by using more complex training stimuli that elicit robust responses in these visual structures. Methods: We trained cortically blind subjects with a complex optic flow motion stimulus that was presented in a location of their blind field. Participants were instructed to train with the stimulus at home for approximately 30 minutes per day. Once performance plateaued, the stimulus was moved deeper into the blind field. A battery of pre- and post-training measures, with careful eye tracking, was performed to quantify the improvements. Results: We show that 1) optic flow motion discrimination can be relearned in cortically blind fields; 2) training with an optic flow stimulus can lead to improvements that transfer to different tasks and untrained locations; and 3) such training leads to a significant expansion of the visual field. The observed expansion of the visual field was present even when eye movements were carefully controlled. Finally, we show that regular training is critical for improved visual function, as sporadic training reduced the benefits of training, even when the total numbers of training sessions were equated. Conclusions: These findings are consistent with the hypothesis that complex training stimuli can improve outcomes in cortical blindness, provided that patients adhere to a regular training regimen. Nevertheless, such interventions remain limited in their ability to restore functional vision. [ABSTRACT FROM AUTHOR]

Traditional endpoints assessing visual function are limited by their responsiveness to interventions restoring or maintaining vision. An alternative concept is assessing instrumental activities of daily living (IADL). Herein, we review all available vision-specific IADL instruments relevant for vision restoration trials and report data for the most promising instrument. Six relevant instruments exist: The Low Vision Functional Status Evaluation (LVFSE), Timed IADL (TIADL), Melbourne Low-Vision Activities of Daily Living Index (MLVAI), Assessment of Disability Related to Vision (ADREV), Functional Low-Vision Observer Rated Assessment (FLORA), and Very Low Vision IADL (IADL-VLV). Both internal consistency and test-retest data were available for the LVFSE, MLVAI, and IADL-VLV. In a sample from a low-vision clinic (n = 51; age 57 ± 16 years), we report additional validation data on the IVI-VLV including test–retest reliability (intraclass correlation coefficient 0.981 [0.961; 0.991]). The LVSFE was noticeably less reliable than the MLVAI and the IADL-VLV. Content and construct validity data were available for the LVFSE, TIADL, MLVAI, ADREV, and IADL-VLV, but only the MLVAI and IADL-VLV were developed for an ultra-low vision context. Ceiling effects were present across instruments. Thus, of all appropriate IADL instruments related to vision, the IADL-VLV and MLVAI best meet existing requirements for use in vision restoration trials, e.g., in gene therapies or visual prostheses in inherited retinal diseases, but require further validation.

Summary: Optic nerve electrical stimulation is a promising technique to restore vision in blind subjects. Machine learning methods can be used to select effective stimulation protocols, but they require a model of the stimulated system to generate enough training data. Here, we use a convolutional neural network (CNN) as a model of the ventral visual stream. A genetic algorithm drives the activation of the units in a layer of the CNN representing a cortical region toward a desired pattern, by refining the activation imposed at a layer representing the optic nerve. To simulate the pattern of activation elicited by the sites of an electrode array, a simple point-source model was introduced and its optimization process was investigated for static and dynamic scenes. Psychophysical data confirm that our stimulation evolution framework produces results compatible with natural vision. Machine learning approaches could become a very powerful tool to optimize and personalize neuroprosthetic systems. The bigger picture: Electrical stimulation of the optic nerve can allow the restoration of lost visual functions in an effective and clinically exploitable way. To achieve this goal, it is crucial to develop a suitable approach to target selectively nerve fiber subpopulations that mediate different sensations but share similar locations in the nerve. In the present work, we use a simple computational model of the primate visual system to show that it is possible to optimize the stimulation at the level of the optic nerve to replicate a pattern of activity in a cortical region, producing, at the same time, reliable sensations. This result could produce nerve stimulation patterns that exploit the convergent nature of the visual system to “correct” the representation error introduced at the nerve level. In the long term, this would lead to eliciting naturalistic sensations from non-intuitive protocols that exploit machine learning to overcome the technological limits of nerve interfaces.