Summary Azobenzene photoswitches confer light sensitivity onto retinal ganglion cells (RGCs) in blind mice, making these compounds promising candidates as vision-restoring drugs in humans with degenerative blindness. Remarkably, photosensitization manifests only in animals with photoreceptor degeneration and is absent from those with intact rods and cones. Here we show that P2X receptors mediate the entry of photoswitches into RGCs where they associate with voltage-gated ion channels, enabling light to control action potential firing. All charged photoswitch compounds require permeation through P2X receptors, whose gene expression is upregulated in the blind retina. Photoswitches and membrane-impermeant fluorescent dyes likewise penetrate through P2X receptors to label a subset of RGCs in the degenerated retina. Electrophysiological recordings and mapping of fluorescently-labeled RGC dendritic projections together indicate that photosensitization is highly selective for OFF-RGCs. Hence P2X receptors are a natural conduit allowing cell type-selective and degeneration-specific delivery of photoswitches to restore visual function in blinding disease.

Highlights d Photoreceptor degeneration leads to retinal ganglion cell hyperactivity d Hyperactivity is triggered by overproduction of retinoic acid (RA) d Blocking the RA receptor with drug or gene therapy reduces hyperactivity d RA receptor blockade augments light-evoked behaviors in vision-impaired mice

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Background: Objective tools for prognosis and disease progression monitoring in multiple sclerosis (MS) are lacking. The visuomotor system could be used to track motor dysfunction at the micron scale through the monitoring of fixational microsaccades. Aims: The aim of this study was to evaluate whether microsaccades are correlated with standard MS disability metrics and to assess whether these methods play a predictive role in MS disability. Method: We used a custom-built retinal eye tracker, the tracking scanning laser ophthalmoscope (TSLO), to record fixation in 111 participants with MS and 100 unaffected controls. Results: In MS participants, a greater number of microsaccades showed significant association with higher Expanded Disability Status Scale score (EDSS, p < 0.001), nine-hole peg test (non-dominant: p = 0.006), Symbol Digit Modalities Test (SMDT, p = 0.014), and Functional Systems Scores (FSS) including brainstem ( p = 0.005), cerebellar ( p = 0.011), and pyramidal ( p = 0.009). Both brainstem FSS and patient-reported fatigue showed significant associations with microsaccade number, amplitude, and peak acceleration. Participants with MS showed a statistically different average number ( p = 0.020), peak vertical acceleration ( p = 0.003), and vertical amplitude ( p < 0.001) versus controls. Logistic regression models for MS disability were created using TSLO microsaccade metrics and paraclinical tests with ⩾80% accuracy. Conclusion: Microsaccades provide objective measurements of MS disability level and disease worsening.

Purpose The purpose of this study was to characterize the benign biological variance of fixational microsaccades in a control population using a tracking scanning laser ophthalmoscope (TSLO), accounting for machine accuracy and precision, to determine ideal testing conditions to detect pathologic change in fixational eye motion (FEM). Methods We quantified the accuracy and precision of the TSLO, analyzing measurements made by three operators on a model eye. Repeated, 10-second retinal motion traces were then recorded in 17 controls, 3 times a day (morning, afternoon, and evening), on 3 separate days. Microsaccade metrics (MMs) of frequency, average amplitude, peak velocity, and peak acceleration were extracted. Trace to trace, interday, and intraday variability were calculated across all subjects. Results Intra-operator and machine variation contributed minimally to total variation, with only 0.007% and 0.14% contribution for frequency and amplitude respectively. Bias was detected, with lower accuracy for higher amplitudes. Participants had an average (SD) microsaccade frequency of 0.84 Hz (0.52 Hz), amplitude of 0.32 degrees (0.11 degrees), peak velocity of 43.68 degrees/s (14.02 degrees/s), and peak acceleration of 13,920.04 degrees/s 2 (4,186.84 degrees/s 2 ). The first trace recorded within a session significantly differed from the second two in both microsaccade acceleration and velocity ( P < 0.05), and frequency was 0.098 Hz higher in the evenings ( P < 0.05). There was no MM difference between days and no evidence of a session-level learning effect ( P > 0.05). Conclusions The TSLO is both accurate and precise. However, biological inter- and intra-individual variance is present. Trace to trace variability and time of day should be accounted for to optimize detection of pathologic change.