High-Resolution Flow Imaging of Optic Nerve Head and Retrolaminar Microvascular Circulation

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Glaucoma is a leading cause of irreversible blindness worldwide, affecting over 2.2 million Americans. Although elevated intraocular pressure (IOP) is the primary risk factor for the development of the disease, the mechanisms by which elevated IOP eventually leads to damage and loss of neural flow function for optic never head (ONH) are still unclear. It is also unclear how sensitivity to IOP varies and interacts with other risk factors for glaucoma, such as aging and race. ONH is the principal site of damage in glaucoma, and the blood flow in the ONH and its perfusion directly related retrobulbar circulation have been recognized as an important role in glaucoma patients, particularly in a subgroup of primary open-angle glaucoma and normal-tension glaucoma. Currently, optical coherence tomography (OCT) and its angiographic extension (OCT-A) are, at present, clinically accepted technologies for ophthalmic imaging. Previous OCT systems were able to demonstrate blood-flow in two-dimensional B-scan images based on decorrelation and/or Doppler effects, this capability excited minimal interest. It was only with the development of high-speed OCT systems that could acquire multiple 3D scans fast enough to produce en-face images of the retinal/choroidal vasculature that OCT-A became in short order a standard ophthalmic imaging clinical modality, even replacing fluorescein angiography to a great extent. A limitation of OCT, however, it is its inability to image ONH and posterior segment of eye that beyond the opaque sclera tissue due to limitation of OCT penetration. Instead, ultrasound color Doppler methods have long offered a means for visualizing and characterizing flow, even in optically inaccessible areas such as the ONH and posterior pole of the eye. However, the spatial resolution of conventional line-by-line scan ultrasound imaging is fundamentally hindered by the diffraction limit of the ultrasound wave, resulting in less ability to characterize the fine vasculature network of the deep eye. Since ultrasound contrast agents such as microbubble are much smaller than the wavelength of ultrasound, acquisition and localization of successive ultrafast frames containing microbubbles may provide an opportunity to reconstruct and map both flow velocity and microvessel density map with a ten-fold resolution improvement than conventional ultrasound imaging, which is defined as super- resolution ultrasound microvessel imaging herein. In this proposal, we will develop high frequency ultrasonic 2D array with frequencies in the range from 15 to 20 MHz which will be interfaced to a fully configurable ultrasound imaging system (Verasonics, Kirkland, WA). The combination of novel compounding plane wave image technology and 3D ultrasound microbubble localization/tracking algorithm will be able to provide high-resolution microvessel blood flow imaging of ONH and retrobulbar circulation. We have three aims: 1) Fabricate high-frequency 2D array and integrate 2D array with configurable imaging system; 2) Implement 3D plane-wave imaging and develop 3D super-resolution ultrasound microvessel imaging algorithm using flow phantoms; 3) Conduct in vivo rabbit eye imaging to assess blood density and flow velocity on ONH and retrobulbar vessels with different IOPs. Success of this study will pave the way towards pursuing clinical application of Glaucoma.