Ione Fine - US grants

[unreadable] DESCRIPTION (provided by applicant): A recently developed surgical procedure, limbal stem cell replacement, now permits corneal replacement in many patients who were previously ineligible for surgery. Many of these patients have suffered long-term visual deprivation, thus providing an extremely rare opportunity to examine how visual function is dependent on experience. We will study: (1) The neural site of deprivation-based acuity loss. We will partition the sites of deprivation-based resolution loss between the optics, lateral geniculate nucleus, and primary and secondary visual areas, using a conjunction of the psychophysical (external) contrast sensitivity function, the interferometric contrast sensitivity function and the neural response function within the lateral geniculate nucleus, striate, and extrastriate visual areas measured using functional magnetic resonance imaging (fMRI). (2) Behavioral losses as a function of deprivation. Preliminary data suggests that long-term visual deprivation also results in deficits in higher-level visual processes, such as the processing of configural form, objects, and faces. In contrast, color and motion processing seems relatively unaffected by long periods of deprivation. We will test our patients on a wide range of behavioral tasks to see how the effects of deprivation interact with task. (3) The neural site of behavioral losses. We will define, based on both anatomical and functional criteria, a wide range of cortical visual areas, including the lateral geniculate nucleus, areas V1-V4, motion area MT+ and regions in the fusiform lingual gyd thought to be responsible for face and object processing. We will compare patients' behavioral performance to the size and sensitivity of these visual areas. Besides being a unique opportunity to study the effects of deprivation on the human visual system, this research should provide patients who are undergoing sight recovery procedures with information as to what sort of sight they should expect postoperatively. Stem cell replacement is a major operation that is becoming more and more common, and other techniques for sight restoration, such as retinal prostheses, have shown remarkable progress in recent years. It is important that patients are given an accurate estimation of risks and benefits when being given the option of undergoing sight-recovery procedures. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): While the effects of visual deprivation have been well studied in animal models, much less is known about the effects of blindness on human early visual pathways. Understanding the effects of visual deprivation on early visual pathways in humans is important for two reasons. First, a deeper understanding of the effects of blindness will prove increasingly important as new sight restoration procedures (such as retinal prosthetic implants, epithelial stem cell replacements, gene therapies and retinal transplants) become available over the next few decades. Second, blindness due to peripheral causes is an excellent model system for understanding prenatal, postnatal and adult cortical plasticity. We propose to use a combination of state-of-the-art MR imaging techniques to examine the effects of blindness on human sub-cortical and cortical visual pathways. Four subject groups will be compared: anophthalmic (born without eyes), non-anophthalmic congenitally blind, late blind and normally sighted control subjects. High resolution structural imaging will be used to measure changes in the size of the lateral geniculate nucleus and changes in the size and myelination patterns of area V1 as a consequence of early blindness. Probabilistic tractography will be used to measure the effects of early blindness on connections between the lateral geniculate nucleus and V1, and between V1 and the corpus callosum. Magnetic resonance spectroscopy will be used to examine the neurochemical effects of blindness on myelination processes and metabolic, cholinergic, and GABA-ergic pathways within blind individuals. Our inclusion of anophthalmic, early blind and late blind subjects will allow us to compare the effects of embryonic development, postnatal development, and adult visual deprivation on sub-cortical and cortical development in humans. This work is likely to have significance not only for understanding development of the human visual system, but also for understanding large-scale developmental sub-cortical and cortical plasticity in general.

ABSTRACT The field of sight restoration has made dramatic progress over the last decade. Two types of retinal implants have been commercially approved, and several other designs are in development worldwide. In addition, two groups are actively implanting and developing cortical electronic implants. The first optogenetic clinical trial has begun, with many others likely in the next two years. Within a decade, many blind individuals are likely to be offered a wide range of options for sight restoration that depend on widely different technologies. Interactions between implant electronics and the underlying neurophysiology of the retina or cortex mean that the vision provided by most of these technologies will differ substantially from normal sight. The question of this proposal is ? What role can cortical plasticity play in helping patients make use of this artificial visual input? Over the past 15 years our research group has been generating computational models, developed using a combination of physiological and psychophysical data, which can predict the percepts that patients might experience for a variety of sight recovery technologies. We propose to use these models to simulate, within visually normal participants, four critical neurophysiological distortions inherent in sight restoration technologies: Aim 1. Abnormal neuronal population responses during retinal stimulation: Simultaneous stimulation of on and off cells. Aim 2. Spatial distortions: Stimulation of retinal ganglion cell axons. Aim 3. Abnormal cortical neuronal population responses: Distortions induced by the V1 neural architecture. Aim 4. Temporal blurring due to slow optogenetic kinetics. Our goal is to use normally sighted participants, viewing distorted visual input, as ?virtual patients? to learn which spatiotemporal distortions can be compensated for by plasticity, and which must be compensated for in device design. This will provide device manufacturers with a more nuanced understanding of the abilities and limits of visual perceptual adaptability. Finally, this work will provide novel insights regarding the fundamental mechanisms of cortical plasticity by asking whether, in adulthood, it is possible to reconfigure the fundamental building blocks of visual perception?