Effect of sequential nursing care combined with communication intervention on visual recovery and pain after cataract ultrasound emulsification.

BACKGROUND: Cataracts are a common ophthalmic disease and postoperative vision recovery is crucial to patient quality of life. Rational and efficient care models play an important role in promoting vision recovery. AIM: To evaluate the clinical effectiveness of procedural nursing care combined with communication intervention in vision recovery after cataract ultrasound emulsification. METHODS: A randomized controlled study was conducted on 100 patients with cataracts who underwent ultrasound emulsification surgery. They were randomly assigned to an experimental group or a control group. The experimental group received procedural nursing combined with Connect, Introduce, Communicate, Ask, Respond, Exit (CICARE) communication intervention, whereas the control group received conventional nursing. The effectiveness of the nursing model was assessed by comparing differences in vision recovery, pain scores, and mental health status between the two groups. RESULTS: It was found that over time the visual acuity of patients in both groups gradually recovered and patients in the experimental group had lower pain scores and superior mental health status than the control group (P < 0.05). CONCLUSION: Procedural nursing combined with CICARE communication intervention has positive effects on vision recovery in patients after cataract ultrasound emulsification.

Foveal Retinal Ganglion Cells Develop Altered Calcium Dynamics Weeks After Photoreceptor Ablation.

Purpose: Physiological changes in retinal ganglion cells (RGCs) have been reported in rodent models of photoreceptor (PR) loss, but this has not been investigated in primates. By expressing both a calcium indicator (GCaMP6s) and an optogenetic actuator (ChrimsonR) in foveal RGCs of the macaque, we reactivated RGCs in vivo and assessed their response in the weeks and years after PR loss. Design: We used an in vivo calcium imaging approach to record optogenetically evoked activity in deafferented RGCs in primate fovea. Cellular scale recordings were made longitudinally over a 10-week period after PR ablation and compared with responses from RGCs that had lost PR input >2 years prior. Participants: Three eyes received PR ablation, the right eye of a male Macaca mulatta (M1), the left eye of a female Macaca fascicularis (M2), and the right eye of a male Macaca fascicularis (M3). Two animals were used for in vivo recording, 1 for histological assessment. Methods: Cones were ablated with an ultrafast laser delivered through an adaptive optics scanning light ophthalmoscope (AOSLO). A 0.5 second pulse of 25 Hz 660 nm light optogenetically stimulated RGCs, and the resulting GCaMP fluorescence signal was recorded using an AOSLO. Measurements were repeated over 10 weeks immediately after PR ablation, at 2.3 years and in control RGCs. Main Outcome Measures: The calcium rise time, decay constant, and sensitivity index of optogenetic-mediated RGC were derived from GCaMP fluorescence recordings from 221 RGCs (animal M1) and 218 RGCs (animal M2) in vivo. Results: After PR ablation, the mean decay constant of the calcium response in RGCs decreased 1.5-fold (standard deviation 1.6 ± 0.5 seconds to 0.6 ± 0.3 seconds) over the 10-week observation period in subject 1 and 2.1-fold (standard deviation 2.5 ± 0.5 seconds to 1.2 ± 0.2 seconds) within 8 weeks in subject 2. Calcium rise time and sensitivity index were stable. Optogenetic reactivation remained possible 2.3 years after PR ablation. Conclusions: Altered calcium dynamics developed in primate foveal RGCs in the weeks after PR ablation. The mean decay constant of optogenetic-mediated calcium responses decreased 1.5- to twofold. This is the first report of this phenomenon in primate retina and further work is required to understand the role these changes play in cell survival and activity. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

3D electronic implants in subretinal space: Long-term follow-up in rodents.

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.

Theoretical prediction of broadband ambient light optogenetic vision restoration with ChRmine and its mutants.

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.

Enhancing Prosthetic Vision by Upgrade of a Subretinal Photovoltaic Implant in situ.

In patients with atrophic age-related macular degeneration, subretinal photovoltaic implant (PRIMA) provided visual acuity up to 20/440, matching its 100µm pixels size. Next-generation implants with smaller pixels should significantly improve the acuity. This study in rats evaluates removal of a subretinal implant, replacement with a newer device, and the resulting grating acuity in-vivo. Six weeks after the initial implantation with planar and 3-dimensional devices, the retina was re-detached, and the devices were successfully removed. Histology demonstrated a preserved inner nuclear layer. Re-implantation of new devices into the same location demonstrated retinal re-attachment to a new implant. New devices with 22µm pixels increased the grating acuity from the 100µm capability of PRIMA implants to 28µm, reaching the limit of natural resolution in rats. Reimplanted devices exhibited the same stimulation threshold as for the first implantation of the same implants in a control group. This study demonstrates the feasibility of safely upgrading the subretinal photovoltaic implants to improve prosthetic visual acuity.

Appropriate patient population for future visual system axon regeneration therapies.

A number of blinding diseases caused by damage to the optic nerve result in progressive vision loss or loss of visual acuity. Secondary glaucoma results from traumatic injuries, pseudoexfoliation or pigmentary dispersion syndrome. Progressive peripheral vision loss is common to all secondary glaucoma irrespective of the initial event. Axon regeneration is a potential therapeutic avenue to restore lost vision in these patients. In contrast to the usual approach of having the worst possible patient population for initial therapies, axon regeneration may require consideration of appropriate patient population even for initial treatment trials. The current state of axon regeneration therapies, their potential future and suitable patient population when ready is discussed in this perspective. The selection of patients are important for adoption of axon regeneration specifically in the areas of central nervous system regenerative medicine. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology Neurological Diseases > Biomedical Engineering Metabolic Diseases > Molecular and Cellular Physiology.

The Retinal Ganglion Cell Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration Consortium.

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 Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Optogenetic targeting of AII amacrine cells restores retinal computations performed by the inner retina.

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.

Cellular migration into a subretinal honeycomb-shaped prosthesis for high-resolution prosthetic vision.

In patients blinded by geographic atrophy, a subretinal photovoltaic implant with 100 µm pixels provided visual acuity closely matching the pixel pitch. However, such flat bipolar pixels cannot be scaled below 75 µm, limiting the attainable visual acuity. This limitation can be overcome by shaping the electric field with 3-dimensional (3-D) electrodes. In particular, elevating the return electrode on top of the honeycomb-shaped vertical walls surrounding each pixel extends the electric field vertically and decouples its penetration into tissue from the pixel width. This approach relies on migration of the retinal cells into the honeycomb wells. Here, we demonstrate that majority of the inner retinal neurons migrate into the 25 µm deep wells, leaving the third-order neurons, such as amacrine and ganglion cells, outside. This enables selective stimulation of the second-order neurons inside the wells, thus preserving the intraretinal signal processing in prosthetic vision. Comparable glial response to that with flat implants suggests that migration and separation of the retinal cells by the walls does not cause additional stress. Furthermore, retinal migration into the honeycombs does not negatively affect its electrical excitability, while grating acuity matches the pixel pitch down to 40 µm and reaches the 27 µm limit of natural resolution in rats with 20 µm pixels. These findings pave the way for 3-D subretinal prostheses with pixel sizes of cellular dimensions.

Current approaches to vision restoration using optogenetic therapy.

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.

Selective Block of Upregulated Kv1.3 Potassium Channels in ON-Bipolar Cells of the Blind Retina Enhances Optogenetically Restored Signaling.

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.

Retinal Prostheses: Engineering and Clinical Perspectives for Vision Restoration.

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.

A clinically viable approach to restoring visual function using optogenetic gene therapy.

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.

Non-Invasive Hybrid Ultrasound Stimulation of Visual Cortex In Vivo.

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).

Vascular dysregulation in glaucoma: retinal vasoconstriction and normal neurovascular coupling in altitudinal visual field defects.

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.

Functional integrity of visual coding following advanced photoreceptor degeneration.

Photoreceptor degeneration sufficient to produce severe visual loss often spares the inner retina. This raises hope for vision restoration treatments using optogenetics or electrical stimulation, which generate a replacement light input signal in surviving neurons. The success of these approaches is dependent on the capacity of surviving circuits of the visual system to generate and propagate an appropriate visual code in the face of neuroanatomical remodeling. To determine whether retinally degenerate animals possess this capacity, we generated a transgenic mouse model expressing the optogenetic actuator ReaChR in ON bipolar cells (second-order neurons in the visual projection). After crossing this with the rd1 model of photoreceptor degeneration, we compared ReaChR-derived responses with photoreceptor-driven responses in wild-type (WT) mice at the level of retinal ganglion cells and the visual thalamus. The ReaChR-driven responses in rd1 animals showed low photosensitivity, but in other respects generated a visual code that was very similar to the WT. ReaChR rd1 responses had high trial-to-trial reproducibility and showed sensitivity normalization to code contrast across background intensities. At the single unit level, ReaChR-derived responses exhibited broadly similar variations in response polarity, contrast sensitivity, and temporal frequency tuning as the WT. Units from the WT and ReaChR rd1 mice clustered together when subjected to unsupervised community detection based on stimulus-response properties. Our data reveal an impressive ability for surviving circuitry to recreate a rich visual code following advanced retinal degeneration and are promising for regenerative medicine in the central nervous system.

Measuring visually guided motor performance in ultra low vision using virtual reality.

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.

Photochemical Restoration of Light Sensitivity in the Degenerated Canine Retina.

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.

Differences in the spatial fidelity of evoked and spontaneous signals in the degenerating retina.

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.

Instrumental Activities of Daily Living Tools in Very-Low Vision: Ready for Use in Trials?

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.