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Alignment of Visible-Light Optical Coherence Tomography Fibergrams with Confocal Images of the Same Mouse Retina

In recent years, in vivo retinal imaging, which provides non-invasive, real-time, and longitudinal information about biological systems and processes, has ...

Northwestern University

The role of CT perfusion (CTP) in the management of patients with acute ischemic stroke (AIS) remains a matter of debate. The primary aim of this study was to evaluate the correlation between the areas of infarction and penumbra on CTP scans and functional outcome in patients with AIS.

Topographic correlation of infarct area on CT perfusion with functional outcome in acute ischemic stroke.

To validate the ability of visible-light optical coherence tomography (vis-OCT) in imaging the full Schlemm's canal (SC) and its surrounding limbal vascular network in mice in vivo through a compound circumlimbal scan.

In Vivo Imaging of Schlemm's Canal and Limbal Vascular Network in Mouse Using Visible-Light OCT.

Recent development of visible-light optical coherence tomography (vis-OCT) has introduced new applications for noninvasive spectroscopic imaging. However, the measured spectra may be altered by spectrally dependent roll-off (SDR). We formulated a mathematical model for SDR that accounted for nonuniform wavenumber spacing, optical aberrations, and misalignments in the spectrometer. We simulated SDR based on this model and found strong agreement with measurements from a vis-OCT system. We verified that SDR altered spectroscopic measurements of fully oxygenated blood. We corrected these alterations by normalizing each spectrally dependent A-line by the measured SDR of the spectrometer. Our investigations of SDR are critical for informing OCT spectrometer design, alignment, and spectroscopic measurements.

Spectrally dependent roll-off in visible-light optical coherence tomography.

To develop a practical technique for visualizing and quantifying retinal ganglion cell (RGC) axon bundles .

Visible-Light Optical Coherence Tomography Fibergraphy for Quantitative Imaging of Retinal Ganglion Cell Axon Bundles.

The growth of the mouse eye and retina after birth is a dynamic, highly regulated process. In this study, we applied visible-light optical coherence tomography (vis-OCT), a non-invasive imaging technique, to examine developing retinal layer structures after eye-opening. We introduced a resampled circumpapillary B-scan averaging technique to improve the inter-layer contrast, enabling retinal layer thickness measurements as early as postnatal day 13 (P13) - right after eye-opening. We confirmed vis-OCT measurements using ex vivo confocal microscopy of retinal sections at different ages. Our results demonstrate that vis-OCT can visualize the developmental murine retinal layer structure in vivo, which offers us new opportunities to better characterize the pathological alterations in mouse models of developmental eye diseases.

In vivo imaging of the inner retinal layer structure in mice after eye-opening using visible-light optical coherence tomography.

Retinal ganglion cells (RGCs) exhibit compartmentalized organization, receiving synaptic inputs through their dendrites and transmitting visual information from the retina to the brain through the optic nerve. Little is known about the structure of RGC axon bundles extending from individual RGC somas to the optic nerve head (ONH) and how they respond to disease insults. We recently introduced visible-light optical coherence tomography fibergraphy (vis-OCTF), a technique for directly visualizing and analyzing mouse RGC axon bundles  In this study, we validated vis-OCTF's ability to quantify RGC axon bundles with an increased number of RGCs using mice deficient in BCL2-associated X protein (BAX). Next, we performed optic nerve crush (ONC) injury on wild-type (WT) mice and showed that the changes in RGC axon bundle width and thickness were location-dependent. Our work demonstrates the potential of vis-OCTF to longitudinally quantify and track RGC damage at single axon bundle level in optic neuropathies. Nearly all clinical and preclinical studies measure the retinal nerve fiber (RNFL) thickness as the sole indicator of retinal ganglion cell (RGC) damage without investigating RGC axon bundles directly. We demonstrated visible-light optical coherence tomography fibergraphy (vis-OCTF) to directly quantify global and regional RGC axon bundle organizations  as a new biomarker for RGC health. We validated  vis-OCTF measures using both confocal microscopy of the immunostained flat-mounted retina and numerical simulations. Vis-OCTF for monitoring RGC axon bundle organization has the potential to bring new insight into RGC damage in optic neuropathies.

Global and Regional Damages in Retinal Ganglion Cell Axon Bundles Monitored Non-Invasively by Visible-Light Optical Coherence Tomography Fibergraphy.

Aniridia is a panocular condition characterized by impaired eye development and vision, which is mainly due to the haploinsufficiency of the paired-box-6 (PAX6) gene. Like what is seen in aniridia patients, Pax6-deficient mice Pax6 exhibit a varied degree of ocular damage and impaired vision. Our previous studies showed that these phenotypes were partially rescued by PD0325901, a mitogen-activated protein kinase kinase (MEK or MAP2K) inhibitor. In this study, we assessed the long-term efficacy of PD0325901 treatment in retinal health and visual behavior. At about one year after the postnatal treatment with PD0325901, Pax6 mice showed robust improvements in retina size and visual acuity, and the elevated intraocular pressure (IOP) was also alleviated, compared to age-matched mice treated with vehicles only. Moreover, the Pax6 eyes showed disorganized retinal ganglion cell (RGC) axon bundles and retinal layers, which we termed as hotspots. We found that the PD treatment reduced the number and size of hotspots in the Pax6 retinas. Taken together, our results suggest that PD0325901 may serve as an efficacious intervention in protecting retina and visual function in aniridia-afflicted subjects.

Long-term retinal protection by MEK inhibition in Pax6 haploinsufficiency mice.

Loeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder characterized by a classic triad of hypertelorism, bifid uvula and/or cleft palate, and generalized arterial tortuosity. There are limited data on the prevalence and rupture risk of intracranial aneurysms (IAs) in the setting of LDS, with no established guidelines.

Intracranial Aneurysms in Loeys-Dietz Syndrome: A Multicenter Propensity-Matched Analysis.

Retinal ganglion cells (RGCs) are heterogeneous projection neurons that convey distinct visual features from the retina to brain. Here, we present a high-throughput in vivo RGC activity assay in response to light stimulation using noninvasive Ca imaging of thousands of RGCs simultaneously in living mice. Population and single-cell analyses of longitudinal RGC Ca imaging reveal distinct functional responses of RGCs and unprecedented individual RGC activity conversions during traumatic and glaucomatous degeneration. This study establishes a foundation for future in vivo RGC function classifications and longitudinal activity evaluations using more advanced imaging techniques and visual stimuli under normal, disease, and neural repair conditions. These analyses can be performed at both the population and single-cell levels using temporal and spatial information, which will be invaluable for understanding RGC pathophysiology and identifying functional biomarkers for diverse optic neuropathies.

Longitudinal in vivo Ca imaging reveals dynamic activity changes of diseased retinal ganglion cells at the single-cell level.

Retinal oxygen saturation (sO) provides essential information about the eye's response to pathological changes that can result in vision loss. Visible-light optical coherence tomography (vis-OCT) is a noninvasive tool that has the potential to measure retinal sO in a clinical setting. However, its reliability is currently limited by unwanted signals referred to as spectral contaminants (SCs), and a comprehensive strategy to isolate true oxygen-dependent signals from SCs in vis-OCT is lacking.

Adaptive spectroscopic visible-light optical coherence tomography for clinical retinal oximetry.

We developed a new analytic tool based on visible-light optical coherence tomography fibergraphy (vis-OCTF) to longitudinally track individual axon bundle transformation as a new in vivo biomarker for retinal ganglion cell (RGC) damage.

Longitudinal Analysis of Retinal Ganglion Cell Damage at Individual Axon Bundle Level in Mice Using Visible-Light Optical Coherence Tomography Fibergraphy.

Article	Year
Topographic correlation of infarct area on CT perfusion with functional outcome in acute ischemic stroke. Journal of neurosurgery\| PubMed ID: 30641833	2019
In Vivo Imaging of Schlemm's Canal and Limbal Vascular Network in Mouse Using Visible-Light OCT. Investigative ophthalmology & visual science\| PubMed ID: 32068793	2020
Spectrally dependent roll-off in visible-light optical coherence tomography. Optics letters\| PubMed ID: 32356845	2020
Visible-Light Optical Coherence Tomography Fibergraphy for Quantitative Imaging of Retinal Ganglion Cell Axon Bundles. Translational vision science & technology\| PubMed ID: 33110707	2020
In vivo imaging of the inner retinal layer structure in mice after eye-opening using visible-light optical coherence tomography. Experimental eye research\| PubMed ID: 34492282	2021
Global and Regional Damages in Retinal Ganglion Cell Axon Bundles Monitored Non-Invasively by Visible-Light Optical Coherence Tomography Fibergraphy. The Journal of neuroscience : the official journal of the Society for Neuroscience\| PubMed ID: 34702745	2021
Long-term retinal protection by MEK inhibition in Pax6 haploinsufficiency mice. Experimental eye research\| PubMed ID: 35245513	2022
Intracranial Aneurysms in Loeys-Dietz Syndrome: A Multicenter Propensity-Matched Analysis. Neurosurgery\| PubMed ID: 35876667	2022
Longitudinal in vivo Ca imaging reveals dynamic activity changes of diseased retinal ganglion cells at the single-cell level. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 36409915	2022
Adaptive spectroscopic visible-light optical coherence tomography for clinical retinal oximetry. Communications medicine\| PubMed ID: 37095177	2023
Longitudinal Analysis of Retinal Ganglion Cell Damage at Individual Axon Bundle Level in Mice Using Visible-Light Optical Coherence Tomography Fibergraphy. Translational vision science & technology\| PubMed ID: 37163286	2023

David A. Miller

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