Vaishnavi B Mohan¹ (), Ezgi Irmak Yucel¹, Nil Altinordu¹, Geoffrey M Boynton¹, Ione Fine¹; ¹University of Washington

Introduction: Optogenetics is a promising technology to restore vision in individuals with blindness due to retinal disorders. Light-sensitive proteins (opsins) are introduced intravitreally and bind to surviving non-photosensitive retinal cells to elicit a neural response to visual stimuli. Much of this research is done with mouse models, where it is not obvious how a given opsin would translate to human visual perception. Our goal was to provide estimates of potential patients’ spatio-temporal contrast sensitivity and perceptual experiences. We created ‘virtual patients’ consisting of neurotypical subjects viewing stimuli modified to match the temporal properties of two state-of-the-art opsins 4xBGAG12,460:SNAP-mGluR2 and ChRmine. Methods: A non-linear model based on single cell electrophysiological data describing the sensitivity and temporal dynamics of each opsin was used to spatiotemporally modulate a counterphase modulated Gabor stimulus to replicate the predicted retinal stimulus of optogenetic patients. Contrast detection thresholds for optogenetic and control stimuli were obtained using a 2AFC quick CSF Bayesian adaptive procedure across a range of spatial and temporal frequencies. Results: Contrast sensitivity for 4xBGAG12,460:SNAP-mGluR2 declined rapidly with increasing temporal frequency compared to the control stimulus, consistent with this opsin’s slow temporal dynamics. Sensitivity to opsin ChRmine was lower overall, but there was little decline in sensitivity at higher temporal frequencies. Conclusion: Using this virtual patient paradigm, we demonstrate the trade-off between sensitivity and temporal resolution for two example opsins. 4xBGAG12,460:SNAP-mGluR2 would be expected to outperform ChRmine under many laboratory tests, such as a Snellen eye chart for a patient capable of maintaining stable fixation. However ChRmine would be predicted to outperform 4xBGAG12,460:SNAP-mGluR2 during outdoor navigation in daylight. Ultimately, our goal is to predict patients’ performance across a wide range of clinically relevant tasks directly from an opsin’s temporal dynamics, paving the way for informed optimization of sight-restoration therapies before clinical application.

Acknowledgements: NIH grant R01EY014645