Evaluation and Correlation of Morphological, Blood Flow and Physiological Retinal Changes in a Rat Model of Glaucoma with a Combined Optical Coherence Tomography and Electroretinography System

Abstract

Glaucoma is a chronic disease associated with progressive dysfunction of the retinal ganglion cells (RGC), reduction of the retinal blood flow, thinning of the retinal nerve fiber layer (RNFL) and deformation of the optical nerve head (ONH). It is the second leading cause of blindness worldwide, with an estimate of 64.3 million people between the ages of 40 to 80 years affected in 2013, 76.7 million by 2020, and 111.8 million by 2040. Currently, there is no cure for glaucoma and any clinically available pharmaceutical or surgical approaches to treating the disease can only slow its progression. Therefore, early detection and treatment are essential for managing the glaucoma progression. Elevated intraocular pressure (IOP) is one of the most well studied and documented pathogenic risk factors for open-angle glaucoma (OAG), and as such, numerous animal models have been developed to study the acute and chronic IOP elevation effect on the ONH structure, retinal blood perfusion and RGC function. However, most of these studies utilized static chronic IOP elevation, while the relation between the IOP dynamics and the progression of glaucoma is still poorly understood. Joos et al proposed a rat model of glaucoma that utilized a dynamic approach to IOP elevation by use of a vascular loop that consists of short duration (~1h), intermittent IOP elevation. This model resembles closely the daily IOP spiking observed in glaucomatous patients, especially during the early stages of the disease. Better understanding of how the retina (human and animal) responds to such intermittent spikes of the IOP can provide ophthalmologists with valuable information on the origins and early stages of glaucoma development when treatment would be most efficient, as well as insights into developing new therapeutic approaches for glaucoma. Over the past few decades, a number of ex-vivo and in-vivo optical imaging modalities ranging from histopathology to confocal microscopy and optical coherence tomography (OCT) have been used to image changes in the morphology of the retina and the optic nerve head (ONH) in human subjects and animal models of OAG. Laser Doppler Flowmetry, Doppler OCT (DOCT) and Optical Coherence Angiography (OCTA) have been utilized to image and quantify changes in the total retinal blood flow and the blood perfusion in retinal capillaries during IOP elevation. Furthermore, electroretinography (ERG) has been used to assess changes in the retinal function (response to visual stimulation) during elevated IOP. However, all previous studies collected information about the morphological, functional and blood flow / perfusion changes in the retina during elevated IOP separately, at different time points, which prevented the researchers from correlating those changes and uncovering the relationship between them, typically referred to as neurovascular coupling. Since OCT provides both intensity and phase information in a single acquisition, this imaging technology is able to assess changes in the retinal morphology, function and blood flow/perfusion in-vivo and simultaneously. Therefore, the main goals of this PhD project were to: • Develop a combined OCT+ERG imaging system that can image in-vivo and record simultaneously, changes in the retinal morphology, retinal response to visual stimulation and retinal blood flow / perfusion at normal and elevated IOP. • Test the performance of the OCT+ERG system in a rat model of glaucoma. • Utilize the OCT+ERG technology and the dynamic IOP rat model of glaucoma based on the vascular loop, to investigate the effects of acute and chronic IOP elevation to ischemic and non-ischemic IOP levels on the rat retina. • Utilize the OCT+ERG technology to investigate neurovascular coupling in the rat retina at normal and abnormal IOP levels. Results from this PhD research have been published or summarized in manuscripts that are currently under review. Therefore, this PhD thesis was prepared in such a way that individual manuscripts represent separate thesis chapters.