Functional OCT reveals anisotropic changes of retinal flicker-evoked vasodilation.

The purpose of this study is to verify the effect of anisotropic property of retinal biomechanics on vasodilation measurement. A custom-built optical coherence tomography (OCT) was used for time-lapse imaging of flicker stimulation-evoked vessel lumen changes in mouse retinas. A comparative analysis revealed significantly larger (18.21%) lumen dilation in the axial direction compared to the lateral (10.77%) direction. The axial lumen dilation predominantly resulted from the top vessel wall movement toward the vitreous direction, whereas the bottom vessel wall remained stable. This observation indicates that the traditional vasodilation measurement in the lateral direction may result in an underestimated value.

Integrating a Fundus Camera with High-Frequency Ultrasound for Precise Ocular Lesion Assessment.

Ultrasound A-scan is an important tool for quantitative assessment of ocular lesions. However, its usability is limited by the difficulty of accurately localizing the ultrasound probe to a lesion of interest. In this study, a transparent LiNbO3 single crystal ultrasound transducer was fabricated, and integrated with a widefield fundus camera to guide the ultrasound local position. The electrical impedance, phase spectrum, pulse-echo performance, and optical transmission spectrum of the ultrasound transducer were validated. The novel fundus camera-guided ultrasound probe was tested for in vivo measurement of rat eyes. Anterior and posterior segments of the rat eye could be unambiguously differentiated with the fundus photography-guided ultrasound measurement. A model eye was also used to verify the imaging performance of the prototype device in the human eye. The prototype shows the potential of being used in the clinic to accurately measure the thickness and echogenicity of ocular lesions in vivo.

Multispectral Fundus Photography of Choroidal Nevi With Trans-Palpebral Illumination.

Purpose: The purpose of this study was to investigate the spectral characteristics of choroidal nevi and assess the feasibility of quantifying the basal diameter of choroidal nevi using multispectral fundus images captured with trans-palpebral illumination. Methods: The study used a widefield fundus camera with multispectral (625 nm, 780 nm, 850 nm, and 970 nm) trans-palpebral illumination to examine eight subjects diagnosed with choroidal nevi. Geometric features of nevi, including border clarity, overlying drusen, and lesion basal diameter, were characterized. Clinical imagers, including scanning laser ophthalmoscopy (SLO), autofluorescence (AF), and optical coherence tomography (OCT), were utilized for comparative assessment. Results: Fundus images depicted nevi as dark regions with high contrast against the background. Near-infrared (NIR) fundus images provided enhanced visibility of lesion borders compared to visible fundus images and SLO images. Lesion-background contrast measurements revealed 635 nm SLO at 11% and 625 nm fundus at 42%. Significantly enhanced contrasts were observed in NIR fundus images at 780 nm (73%), 850 nm (63%), and 970 nm (67%). For quantifying the diameter of nevi, NIR fundus images at 780 nm and 850 nm yielded a deviation of less than 10% when compared to OCT measurements. Conclusions: NIR fundus photography with trans-palpebral illumination enhances nevi visibility and boundary definition compared to SLO. Agreement in diameter measurements with OCT validates the accuracy and reliability of this method for choroidal nevi assessment. Translational Relevance: Multispectral fundus imaging with trans-palpebral illumination improves choroidal nevi visibility and accurately measures basal diameter, promising to enhance clinical practices in screening, diagnosis, and monitoring of choroidal nevi.

Multispectral Fundus Photography of Choroidal Nevi with Trans-Palpebral Illumination.

Purpose: To investigate the spectral characteristics of choroidal nevi and assess the feasibility of quantifying the basal diameter of choroidal nevi using multispectral fundus images captured with trans-palpebral illumination. Methods: The study employed a widefield fundus camera with multispectral (625 nm, 780 nm, 850 nm, and 970 nm) trans-palpebral illumination. Geometric features of choroidal nevi, including border clarity, overlying drusen, and lesion basal diameter, were characterized. Clinical imagers, including scanning laser ophthalmoscopy (SLO), autofluorescence (AF), and optical coherence tomography (OCT), were utilized for comparative assessment. Results: Fundus images captured with trans-palpebral illumination depicted nevi as dark regions with high contrast against the background. Near-infrared (NIR) fundus images provided enhanced visibility of lesion borders compared to visible light fundus images and SLO images. Lesion-background contrast measurements revealed 635 nm SLO at 11% and 625 nm fundus at 42%. Significantly enhanced contrasts were observed in NIR fundus images at 780 nm (73%), 850 nm (63%), and 970 nm (67%). For quantifying the basal diameter of nevi, NIR fundus images at 780 nm and 850 nm yielded a deviation of less than 10% when compared to OCT B-scan measurements. Conclusion: NIR fundus photography with trans-palpebral illumination enhances nevi visibility and boundary definition compared to SLO. Agreement in basal diameter measurements with OCT validates the accuracy and reliability of this method for choroidal nevi assessment.

Evaluating spatial dependency of the spectral efficiency in trans-palpebral illumination for widefield fundus photography.

Multi-spectral widefield fundus photography is valuable for the clinical diagnosis and management of ocular conditions that may impact both central and peripheral regions of the retina and choroid. Trans-palpebral illumination has been demonstrated as an alternative to transpupillary illumination for widefield fundus photography without requiring pupil dilation. However, spectral efficiency can be complicated due to the spatial variance of the light property through the palpebra and sclera. This study aims to investigate the effect of light delivery location on spectral efficiency in trans-palpebral illumination. Four narrow-band light sources, covering both visible and near infrared (NIR) wavelengths, were used to evaluate spatial dependency of spectral illumination efficiency. Comparative analysis indicated a significant dependence of visible light efficiency on spatial location, while NIR light efficiency is only slightly affected by the illumination location. This study confirmed the pars plana as the optimal location for delivering visible light to achieve color imaging of the retina. Conversely, spatial location is not critical for NIR light imaging of the choroid.

Preserving polarization maintaining photons for enhanced contrast imaging of the retina.

The purpose of this study is to demonstrate the feasibility of using polarization maintaining photons for enhanced contrast imaging of the retina. Orthogonal-polarization control has been frequently used in conventional fundus imaging systems to minimize reflection artifacts. However, the orthogonal-polarization configuration also rejects the directly reflected photons, which preserve the polarization condition of incident light, from the superficial layer of the fundus, i.e., the retina, and thus reduce the contrast of retinal imaging. We report here a portable fundus camera which can simultaneously perform orthogonal-polarization control to reject back-reflected light from the ophthalmic lens and parallel-polarization control to preserve the backscattered light from the retina which partially maintains the polarization state of the incoming light. This portable device utilizes miniaturized indirect ophthalmoscopy illumination to achieve non-mydriatic imaging, with a snapshot field of view of 101° eye-angle (67° visual-angle). Comparative analysis of retinal images acquired with a traditional orthogonal-polarization fundus camera from both normal and diseased eyes was conducted to validate the usefulness of the proposed design. The parallel-polarization control for enhanced contrast in high dynamic range imaging has also been validated.

Color Fusion Effect on Deep Learning Classification of Uveal Melanoma.

Background: Reliable differentiation of uveal melanoma and choroidal nevi is crucial to guide appropriate treatment, preventing unnecessary procedures for benign lesions and ensuring timely treatment for potentially malignant cases. The purpose of this study is to validate deep learning classification of uveal melanoma and choroidal nevi, and to evaluate the effect of color fusion options on the classification performance. Methods: A total of 798 ultra-widefield retinal images of 438 patients were included in this retrospective study, comprising 157 patients diagnosed with UM and 281 patients diagnosed with choroidal nevus. Color fusion options, including early fusion, intermediate fusion and late fusion, were tested for deep learning image classification with a convolutional neural network (CNN). Specificity, sensitivity, F1-score, accuracy, and the area under the curve (AUC) of a receiver operating characteristic (ROC) were used to evaluate the classification performance. The saliency map visualization technique was used to understand the areas in the image that had the most influence on classification decisions of the CNN. Results: Color fusion options were observed to affect the deep learning performance significantly. For single-color learning, the red color image was observed to have superior performance compared to green and blue channels. For multi-color learning, the intermediate fusion is better than early and late fusion options. Conclusion: Deep learning is a promising approach for automated classification of uveal melanoma and choroidal nevi, and color fusion options can significantly affect the classification performance.

Intrinsic signal optoretinography revealing AD-induced retinal photoreceptor hyperexcitability before a detectable morphological abnormality.

Neuronal hyperexcitability promises an early biomarker of Alzheimer's disease (AD). However, in vivo detection of neuronal hyperexcitability in the brain is technically challenging. The retina, one part of the central nervous system, presents a unique window for noninvasive monitoring of the brain function. This study aims to test the feasibility of using intrinsic signal optoretinography (ORG) for mapping retinal hyperexcitability associated with early-stage AD. Custom-designed optical coherence tomography (OCT) was employed for both morphological measurement and functional ORG of wild-type mice and 3xTg-AD mice. Comparative analysis revealed AD-induced retinal photoreceptor hyperexcitability prior to detectable structural degeneration.

Deep learning for artery-vein classification in optical coherence tomography angiography.

Major retinopathies can differentially impact the arteries and veins. Traditional fundus photography provides limited resolution for visualizing retinal vascular details. Optical coherence tomography (OCT) can provide improved resolution for retinal imaging. However, it cannot discern capillary-level structures due to the limited image contrast. As a functional extension of OCT modality, optical coherence tomography angiography (OCTA) is a non-invasive, label-free method for enhanced contrast visualization of retinal vasculatures at the capillary level. Recently differential artery-vein (AV) analysis in OCTA has been demonstrated to improve the sensitivity for staging of retinopathies. Therefore, AV classification is an essential step for disease detection and diagnosis. However, current methods for AV classification in OCTA have employed multiple imagers, that is, fundus photography and OCT, and complex algorithms, thereby making it difficult for clinical deployment. On the contrary, deep learning (DL) algorithms may be able to reduce computational complexity and automate AV classification. In this article, we summarize traditional AV classification methods, recent DL methods for AV classification in OCTA, and discuss methods for interpretability in DL models.

Normalized Blood Flow Index in Optical Coherence Tomography Angiography Provides a Sensitive Biomarker of Early Diabetic Retinopathy.

Purpose: To evaluate the sensitivity of normalized blood flow index (NBFI) for detecting early diabetic retinopathy (DR). Methods: Optical coherence tomography angiography (OCTA) images of healthy controls, diabetic patients without DR (NoDR), and patients with mild nonproliferative DR (NPDR) were analyzed in this study. The OCTA images were centered on the fovea and covered a 6 mm × 6 mm area. Enface projections of the superficial vascular plexus (SVP) and the deep capillary plexus (DCP) were obtained for the quantitative OCTA feature analysis. Three quantitative OCTA features were examined: blood vessel density (BVD), blood flow flux (BFF), and NBFI. Each feature was calculated from both the SVP and DCP and their sensitivities to distinguish the three cohorts of the study were evaluated. Results: The only quantitative feature capable of distinguishing all three cohorts was NBFI in the DCP image. Comparative study revealed that both BVD and BFF were able to distinguish the controls and NoDR from mild NPDR. However, neither BVD nor BFF was sensitive enough to separate NoDR from the healthy controls. Conclusions: The NBFI has been demonstrated as a sensitive biomarker of early DR, revealing retinal blood flow abnormality better than traditional BVD and BFF. The NBFI in the DCP was verified as the most sensitive biomarker, supporting that diabetes affects the DCP earlier than SVP in DR. Translational Relevance: NBFI provides a robust biomarker for quantitative analysis of DR-caused blood flow abnormalities, promising early detection and objective classification of DR.

Rotational Distortion and Compensation in Optical Coherence Tomography with Anisotropic Pixel Resolution.

Accurate image registration is essential for eye movement compensation in optical coherence tomography (OCT) and OCT angiography (OCTA). The spatial resolution of an OCT instrument is typically anisotropic, i.e., has different resolutions in the lateral and axial dimensions. When OCT images have anisotropic pixel resolution, residual distortion (RD) and false translation (FT) are always observed after image registration for rotational movement. In this study, RD and FT were quantitively analyzed over different degrees of rotational movement and various lateral and axial pixel resolution ratio (RL/RA) values. The RD and FT provide the evaluation criteria for image registration. The theoretical analysis confirmed that the RD and FT increase significantly with the rotation degree and RL/RA. An image resizing assisting registration (RAR) strategy was proposed for accurate image registration. The performance of direct registration (DR) and RAR for retinal OCT and OCTA images were quantitatively compared. Experimental results confirmed that unnormalized RL/RA causes RD and FT; RAR can effectively improve the performance of OCT and OCTA image registration and distortion compensation.

Portable widefield fundus camera with high dynamic range imaging capability.

Fundus photography is indispensable for the clinical detection and management of eye diseases. Low image contrast and small field of view (FOV) are common limitations of conventional fundus photography, making it difficult to detect subtle abnormalities at the early stages of eye diseases. Further improvements in image contrast and FOV coverage are important for early disease detection and reliable treatment assessment. We report here a portable, wide FOV fundus camera with high dynamic range (HDR) imaging capability. Miniaturized indirect ophthalmoscopy illumination was employed to achieve the portable design for nonmydriatic, widefield fundus photography. Orthogonal polarization control was used to eliminate illumination reflectance artifacts. With independent power controls, three fundus images were sequentially acquired and fused to achieve HDR function for local image contrast enhancement. A 101° eye-angle (67° visual-angle) snapshot FOV was achieved for nonmydriatic fundus photography. The effective FOV was readily expanded up to 190° eye-angle (134° visual-angle) with the aid of a fixation target without the need for pharmacologic pupillary dilation. The effectiveness of HDR imaging was validated with both normal healthy and pathologic eyes, compared to a conventional fundus camera.

COMPARATIVE ANALYSIS OF OCT AND OCT ANGIOGRAPHY CHARACTERISTICS IN EARLY DIABETIC RETINOPATHY.

PURPOSE: To assess the quantitative characteristics of optical coherence tomography (OCT) and OCT angiography (OCTA) for the objective detection of early diabetic retinopathy (DR). METHODS: This was a retrospective and cross-sectional study, which was carried out at a tertiary academic practice with a subspecialty. Twenty control participants, 15 people with diabetics without retinopathy (NoDR), and 22 people with mild nonproliferative diabetic retinopathy (NPDR) were included in this study. Quantitative OCT characteristics were derived from the photoreceptor hyperreflective bands, i.e., inner segment ellipsoid (ISe) and retinal pigment epithelium (RPE). OCTA characteristics, including vessel diameter index (VDI), vessel perimeter index (VPI), and vessel skeleton density (VSD), were evaluated. RESULTS: Quantitative OCT analysis indicated that the ISe intensity was significantly trending downward with DR advancement. Comparative OCTA revealed VDI, VPI, and VSD as the most sensitive characteristics of DR. Correlation analysis of OCT and OCTA characteristics revealed weak variable correlation between the two imaging modalities. CONCLUSION: Quantitative OCT and OCTA analyses revealed photoreceptor and vascular distortions in early DR. Comparative analysis revealed that the OCT intensity ratio, ISe/RPE, has the best sensitivity for early DR detection. Weak variable correlation of the OCT and OCTA characteristics suggests that OCT and OCTA are providing supplementary information for DR detection and classification.

Adaptive vessel tracing and segmentation in OCT enables the robust detection of wall-to-lumen ratio abnormalities in 5xFAD mice.

The wall-to-lumen ratio (WLR) of retinal blood vessels promises a sensitive marker for the physiological assessment of eye conditions. However, in vivo measurement of vessel wall thickness and lumen diameter is still technically challenging, hindering the wide application of WLR in research and clinical settings. In this study, we demonstrate the feasibility of using optical coherence tomography (OCT) as one practical method for in vivo quantification of WLR in the retina. Based on three-dimensional vessel tracing, lateral en face and axial B-scan profiles of individual vessels were constructed. By employing adaptive depth segmentation that adjusts to the individual positions of each blood vessel for en face OCT projection, the vessel wall thickness and lumen diameter could be reliably quantified. A comparative study of control and 5xFAD mice confirmed WLR as a sensitive marker of the eye condition.

Light color efficiency-balanced trans-palpebral illumination for widefield fundus photography of the retina and choroid.

A wide-field fundus camera, which can selectively evaluate the retina and choroid, is desirable for better detection and treatment evaluation of eye diseases. Trans-palpebral illumination has been demonstrated for wide-field fundus photography, but its application for true-color retinal imaging is challenging due to the light efficiency delivered through the eyelid and sclera is highly wavelength dependent. This study is to test the feasibility of true-color retinal imaging using efficiency-balanced visible light illumination, and to validate multiple spectral imaging (MSI) of the retina and choroid. 530 nm, 625 nm, 780 nm and 970 nm light emission diodes (LED)s are used to quantitatively evaluate the spectral efficiency of the trans-palpebral illumination. In comparison with 530 nm illumination, the 625 nm, 780 nm and 970 nm light efficiencies are 30.25, 523.05, and 1238.35 times higher. The light efficiency-balanced 530 nm and 625 nm illumination control can be used to produce true-color retinal image with contrast enhancement. The 780 nm light image enhances the visibility of choroidal vasculature, and the 970 nm image is predominated by large veins in the choroid. Without the need of pharmacological pupillary dilation, a 140° eye-angle field of view (FOV) is demonstrated in a snapshot fundus image. In coordination with a fixation target, the FOV can be readily expanded over the equator of the eye to visualize vortex ampullas.

ADC-Net: An Open-Source Deep Learning Network for Automated Dispersion Compensation in Optical Coherence Tomography.

Chromatic dispersion is a common problem to degrade the system resolution in optical coherence tomography (OCT). This study is to develop a deep learning network for automated dispersion compensation (ADC-Net) in OCT. The ADC-Net is based on a modified UNet architecture which employs an encoder-decoder pipeline. The input section encompasses partially compensated OCT B-scans with individual retinal layers optimized. Corresponding output is a fully compensated OCT B-scan with all retinal layers optimized. Two numeric parameters, i.e., peak signal to noise ratio (PSNR) and structural similarity index metric computed at multiple scales (MS-SSIM), were used for objective assessment of the ADC-Net performance and optimal values of 29.95 ± 2.52 dB and 0.97 ± 0.014 were obtained respectively. Comparative analysis of training models, including single, three, five, seven and nine input channels were implemented. The mode with five-input channels was observed to be optimal for ADC-Net training to achieve robust dispersion compensation in OCT.

Functional Optical Coherence Tomography for Intrinsic Signal Optoretinography: Recent Developments and Deployment Challenges.

Intrinsic optical signal (IOS) imaging of the retina, also termed as optoretinogram or optoretinography (ORG), promises a non-invasive method for the objective assessment of retinal function. By providing the unparalleled capability to differentiate individual retinal layers, functional optical coherence tomography (OCT) has been actively investigated for intrinsic signal ORG measurements. However, clinical deployment of functional OCT for quantitative ORG is still challenging due to the lack of a standardized imaging protocol and the complication of IOS sources and mechanisms. This article aims to summarize recent developments of functional OCT for ORG measurement, OCT intensity- and phase-based IOS processing. Technical challenges and perspectives of quantitative IOS analysis and ORG interpretations are discussed.

Depth-resolved vascular profile features for artery-vein classification in OCT and OCT angiography of human retina.

This study is to characterize reflectance profiles of retinal blood vessels in optical coherence tomography (OCT), and to test the potential of using these vascular features to guide artery-vein classification in OCT angiography (OCTA) of the human retina. Depth-resolved OCT reveals unique features of retinal arteries and veins. Retinal arteries show hyper-reflective boundaries at both upper (inner side towards the vitreous) and lower (outer side towards the choroid) walls. In contrast, retinal veins reveal hyper-reflectivity at the upper boundary only. Uniform lumen intensity was observed in both small and large arteries. However, the venous lumen intensity was dependent on the vessel size. Small veins exhibit a hyper-reflective zone at the bottom half of the lumen, while large veins show a hypo-reflective zone at the bottom half of the lumen.

QUANTITATIVE OPTICAL COHERENCE TOMOGRAPHY REVEALS ROD PHOTORECEPTOR DEGENERATION in EARLY DIABETIC RETINOPATHY.

PURPOSE: This study is to test the feasibility of optical coherence tomography (OCT) detection of photoreceptor abnormality and to verify that the photoreceptor abnormality is rod predominated in early diabetic retinopathy (DR). METHODS: OCT images were acquired from normal eyes, diabetic eyes with no DR, and mild nonproliferative DR (NPDR). Quantitative features, including thickness measurements quantifying band distances and reflectance intensity features among the external limiting membrane, inner segment ellipsoid, interdigitation zone, and retinal pigment epithelium were determined. Comparative OCT analysis of central fovea, parafovea, and perifovea were implemented to verify that the photoreceptor abnormality is rod predominated in early DR. RESULTS: Thickness abnormalities between the inner segment ellipsoid and interdigitation zone also showed a decreasing trend among cohorts. Reflectance abnormalities of the external limiting membrane, interdigitation zone, and inner segment ellipsoid were observed between healthy, no DR, and mild NPDR eyes. The normalized inner segment ellipsoid/retinal pigment epithelium intensity ratio revealed a significant decreasing trend in the perifovea, but no detectable difference in central fovea. CONCLUSION: Quantitative OCT analysis consistently revealed outer retina, i.e., photoreceptor changes in diabetic patients with no DR and mild NPDR. Comparative analysis of central fovea, parafovea, and perifovea confirmed that the photoreceptor abnormality is rod-predominated in early DR.

Optical coherence elastography for assessing the influence of intraocular pressure on elastic wave dispersion in the cornea.

The cornea is a highly specialized organ that relies on its mechanical stiffness to maintain its aspheric geometry and refractive power, and corneal diseases such as keratoconus have been linked to abnormal tissue stiffness and biomechanics. Dynamic optical coherence elastography (OCE) is a clinically promising non-contact and non-destructive imaging technique that can provide measurements of corneal tissue stiffness directly in vivo. The method relies on the concepts of elastography where shear waves are generated and imaged within a tissue to obtain mechanical properties such as tissue stiffness. The accuracy of OCE-based measurements is ultimately dependent on the mathematical theories used to model wave behavior in the tissue of interest. In the cornea, elastic waves propagate as guided wave modes which are highly dispersive and can be mathematically complex to model. While recent groups have developed detailed theories for estimating corneal tissue properties from guided wave behavior, the effects of intraocular pressure (IOP)-induced prestress have not yet been considered. It is known that prestress alone can strongly influence wave behavior, in addition to the associated non-linear changes in tissue properties. This present study shows that failure to account for the effects of prestress may result in overestimations of the corneal shear moduli, particularly at high IOPs. We first examined the potential effects of IOP and IOP-induced prestress using a combination of approximate mathematical theories describing wave behavior in thin plates with observations made from data published in the OCE literature. Through wave dispersion analysis, we deduce that IOP introduces a tensile hoop stress and may also influence an elastic foundational effect that were observable in the low-frequency components of the dispersion curves. These effects were incorporated into recently developed models of wave behavior in nearly incompressible, transversely isotropic (NITI) materials. Fitting of the modified NITI model with ex vivo porcine corneal data demonstrated that incorporation of the effects of IOP resulted in reduced estimates of corneal shear moduli. We believe this demonstrates that overestimation of corneal stiffness occurs if IOP is not taken into consideration. Our work may be helpful in separating inherent corneal stiffness properties that are independent of IOP; changes in these properties and in IOP are distinct, clinically relevant issues that affect the cornea health.