We seek to understand how the human retina enables the most fundamental and intricate aspects of our daily vision; and how visual capacities are disrupted in the face of retinal diseases. To achieve this, we develop and use high-resolution imaging tools that together enable us to see, stimulate, manipulate, and record the functional activity of individual retinal cells in living humans and animal models. Ultimately, we seek to apply this knowledge towards accelerating the next generation of treatments for retinal diseases. Some current projects include :
Contribution of the trichromatic cone mosaic to human spatial and color vision
Cone photoreceptors are sensitive to overlapping regions of the visible spectrum, have wide variability across individuals and limited knowledge of their arrangements is currently available in the central retina. Variations in intensity and wavelength are first encoded at the level of the cone mosaic which forms a single sheet of interleaved receptors. Sampling the visual world thus with only one spectral sample in space necessitates a comparison across multiple cones to retrieve variation in wavelength irrespective of intensity – a task that is achieved by postreceptoral neurons with center-surround antagonism. The rules by which these comparisons are undertaken and ultimately lead to the perception of form and color remain unknown. We use a combination of adaptive optics with eye-tracking to target light stimuli to individual cones of known spectral type and manipulate their activity with spectral, temporal, and spatial precision. Consequently, it has allowed us to study visual perception upon controlled activation of a single or a group of cones in a living human. Our preliminary experiments detailing the cellular map of sensations originating from the LMS cone mosaic have led to intriguing hypotheses pertaining to the role of the cone mosaic and its ensuing pathways in mediating spatial and color vision. Ultimately, this work will lay the foundation for computational models of visual processing, establish a new line of experiments to test model predictions linking physiology and perception, and eventually set the stage for a wider application of these tools to cellular-scale behavioral testing in retinal disease.
Optoretinography : All-optical measures of functional activity in the human retina
The optoreretinogram, or ORG, enables all-optical label-free monitoring of photoreceptor physiology in humans and has the potential to be applied to other retinal cell types as well. More generally, the ORG is defined as the non-invasive, optical imaging of light-induced functional activity in the retina and draws a parallel to the classical electroretinogram (ERG). Our implementation of ORG is rooted in classical interferometry and uses high-speed, phase-resolved line-scan optical coherence tomography to deliver it to the retina. Using this technique, our group has demonstrated the ability to visualize light-driven neural activity across a range of spatiotemporal resolution – from single cells to a collection of neurons, from nanometers to microns spatial scale, and from microseconds to milliseconds timescales, thus enabling a highly sensitive assay of how neurons interact with light. We are applying the ORG toward a deeper mechanistic understanding of early visual processing and eye disease and to provide entirely new avenues for accelerating therapeutic interventions.
Structure and function of photoreceptors in retinal degenerations
Photoreceptor cell death due to retinal degenerations is the leading cause of blindness in the developed world. Early disease diagnoses and response to treatments will both greatly benefit from a safe and sensitive biomarker for photoreceptor health. We employ a multimodal approach to this end, consisting of a) adaptive optics based imaging of photoreceptor structure and topography, b) microperimetry, i.e. measure the light sensitivity upon real-time retinal tracking and light stimulation of individual and collection of photoreceptors and c) optoretinography, i.e. measure the optical signature of light-induced electrophysiological activity that occurs upon transduction of photons to electrical signals in photoreceptors. Together, these enable a highly sensitive assay of the earliest manifestations of retinal disease and clinical endpoints that can be used to refine future therapies.