Neurovascular Coupling in healthy human retina evaluated with Optical Coherence Tomography

Abstract

Retinal neurodegenerative diseases such as glaucoma, age-related macular degeneration (AMD), diabetic retinopathy, and retinitis pigmentosa affect millions of people worldwide and pose a significant burden on public health and the economy. Glaucoma, impacting approximately 80 million people globally, is a leading cause of irreversible blindness. In 2019, an estimated 19.8 million Americans (12.6%) were living with AMD, of which about 1.49 million people faced vision-threatening conditions. An estimated 9.6 million people were living with diabetic retinopathy in 2021, with about 1.84 million of them experiencing vision-threatening stages. In the United States alone, vision impairments- including those resulting from these retinal diseases- cost an estimated $139 billion annually.

Retinal neurodegenerative diseases not only cause progressive damage to the retinal morphology and vascular network, but also cause acute and transient metabolic, physiological, and blood flow changes at the early stages of the disease development which become permanent and chronic at the advanced stages of the disease. Neurovascular Coupling (NVC) refers to the transient vasodilation and increased retinal blood flow resulting from the increased metabolic activity of retinal neurons in response to visual stimulation.

Over the past few decades, a range of imaging techniques from clinical ophthalmoscope and confocal microscopy to adaptive optics scanning laser ophthalmoscope and optical coherence tomography (OCT) have been used ex vivo and in vivo to study components of the neurovascular coupling and its underlying mechanisms. Techniques such as Laser Doppler Velocimetry, Optical Coherence Tomography Angiography (OCTA), and Doppler Optical Coherence Tomography (D-OCT) have been used to observe the vascular responses of the retina caused by visual stimulation. Additionally, Electroretinography (ERG) has been widely used in clinical settings to evaluate the electrical activity of the neuronal retina. More recently, an optical equivalent to ERG, Optoretinography (ORG) was developed and OCT technology, imaging protocols, and image processing algorithms were designed to conduct OCT-based ORG studies in the human and animal retina. However, most of the Doppler OCT, OCTA, and ORG studies have examined components of the neurovascular coupling separately, potentially overlooking the dynamic interactions and comprehensive responses inherent in neurovascular coupling.

OCT, which acquires simultaneously both intensity and phase information, is particularly well-suited for investigating neurovascular coupling in the retina, as it enables a completely non-invasive approach for simultaneous monitoring of retinal blood flow dynamics and neuronal responses. The integration of a commercial ERG system with a research-grade OCT modality adds further value by offering easy control of the visual stimulus, use of clinically established ERG protocols designed to elicit responses from specific types of retinal neuronal cells, and using the ERG recordings to validate the visually-evoked neuronal responses. The main objectives of this PhD thesis were:

1. To develop a combined OCT+ERG imaging system to conduct in vivo and simultaneously morphological and functional imaging that can be utilized for investigating neurovascular coupling in the human retina.

2. To evaluate the performance and capabilities of the OCT+ERG system, imaging protocols, and image processing algorithms by conducting a pilot study on healthy human subjects.

3. To utilize the OCT+ERG technology to explore the neurovascular coupling mechanisms in the healthy human retina by extracting vascular and neuronal responses from different retinal layers simultaneously.

4. To examine the effects of different wavelengths and flicker frequencies on the dynamic retinal blood flow changes evoked by visual stimulation, providing deeper insights into the mechanisms of neurovascular coupling.

Results from this PhD research have been summarized in three manuscripts that are either under review or under preparation for submission. Therefore, this PhD thesis was prepared in such a way that individual manuscripts represent separate thesis chapters.