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Non-invasive imaging plays a crucial role in diagnosing and studying eye diseases. However, existing photoacoustic ophthalmoscopy (PAOM) techniques in mice have limitations due to handling restrictions, suboptimal optical properties, limited availability of light sources and permissible light fluence at the retina. This study introduces an innovative approach that utilizes Rose Bengal, a contrast agent, to enhance PAOM contrast. This enables visualization of deeper structures like the choroidal microvasculature and sclera in the mouse eye using visible light. The integration of near-infrared-II optical coherence tomography (NIR-II OCT) provides additional tissue contrast and insights into potential NIR-II PAOM capabilities. To optimize imaging, we developed a cost-effective 3D printable mouse eye phantom and a fully 3D printable tip/tilt mouse platform. This solution elevates PAOM to a user-friendly technology, which can be used to address pressing research questions concerning several ocular diseases such as myopia, glaucoma and/or age-related macular degeneration in the future., Comment: 14 pages, 4 figures

$\bf{Purpose}$: To describe the 3D structural changes in both connective and neural tissues of the optic nerve head (ONH) that occur concurrently at different stages of glaucoma using traditional and AI-driven approaches. $\bf{Methods}$: We included 213 normal, 204 mild glaucoma (mean deviation [MD] $\ge$ -6.00 dB), 118 moderate glaucoma (MD of -6.01 to -12.00 dB), and 118 advanced glaucoma patients (MD < -12.00 dB). All subjects had their ONHs imaged in 3D with Spectralis optical coherence tomography. To describe the 3D structural phenotype of glaucoma as a function of severity, we used two different approaches: (1) We extracted human-defined 3D structural parameters of the ONH including retinal nerve fiber layer (RNFL) thickness, lamina cribrosa (LC) shape and depth at different stages of glaucoma; (2) we also employed a geometric deep learning method (i.e. PointNet) to identify the most important 3D structural features that differentiate ONHs from different glaucoma severity groups without any human input. $\bf{Results}$: We observed that the majority of ONH structural changes occurred in the early glaucoma stage, followed by a plateau effect in the later stages. Using PointNet, we also found that 3D ONH structural changes were present in both neural and connective tissues. In both approaches, we observed that structural changes were more prominent in the superior and inferior quadrant of the ONH, particularly in the RNFL, the prelamina, and the LC. As the severity of glaucoma increased, these changes became more diffuse (i.e. widespread), particularly in the LC. $\bf{Conclusions}$: In this study, we were able to uncover complex 3D structural changes of the ONH in both neural and connective tissues as a function of glaucoma severity. We hope to provide new insights into the complex pathophysiology of glaucoma that might help clinicians in their daily clinical care.

Purpose: (1) To develop a deep learning algorithm to automatically segment structures of the optic nerve head (ONH) and macula in 3D wide-field optical coherence tomography (OCT) scans; (2) To assess whether 3D macula or ONH structures (or the combination of both) provide the best diagnostic power for glaucoma. Methods: A cross-sectional comparative study was performed which included wide-field swept-source OCT scans from 319 glaucoma subjects and 298 non-glaucoma subjects. All scans were compensated to improve deep-tissue visibility. We developed a deep learning algorithm to automatically label all major ONH tissue structures by using 270 manually annotated B-scans for training. The performance of our algorithm was assessed using the Dice coefficient (DC). A glaucoma classification algorithm (3D CNN) was then designed using a combination of 500 OCT volumes and their corresponding automatically segmented masks. This algorithm was trained and tested on 3 datasets: OCT scans cropped to contain the macular tissues only, those to contain the ONH tissues only, and the full wide-field OCT scans. The classification performance for each dataset was reported using the AUC. Results: Our segmentation algorithm was able to segment ONH and macular tissues with a DC of 0.94 $\pm$ 0.003. The classification algorithm was best able to diagnose glaucoma using wide-field 3D-OCT volumes with an AUC of 0.99 $\pm$ 0.01, followed by ONH volumes with an AUC of 0.93 $\pm$ 0.06, and finally macular volumes with an AUC of 0.91 $\pm$ 0.11. Conclusions: this study showed that using wide-field OCT as compared to the typical OCT images containing just the ONH or macular may allow for a significantly improved glaucoma diagnosis. This may encourage the mainstream adoption of 3D wide-field OCT scans. For clinical AI studies that use traditional machines, we would recommend the use of ONH scans as opposed to macula scans., Comment: 23 pages, 5 figures

Speckle noise and retinal shadows within OCT B-scans occlude important edges, fine textures and deep tissues, preventing accurate and robust diagnosis by algorithms and clinicians. We developed a single process that successfully removed both noise and retinal shadows from unseen single-frame B-scans within 10.4ms. Mean average gradient magnitude (AGM) for the proposed algorithm was 57.2% higher than current state-of-the-art, while mean peak signal to noise ratio (PSNR), contrast to noise ratio (CNR), and structural similarity index metric (SSIM) increased by 11.1%, 154% and 187% respectively compared to single-frame B-scans. Mean intralayer contrast (ILC) improvement for the retinal nerve fiber layer (RNFL), photoreceptor layer (PR) and retinal pigment epithelium (RPE) layers decreased from 0.362 \pm 0.133 to 0.142 \pm 0.102, 0.449 \pm 0.116 to 0.0904 \pm 0.0769, 0.381 \pm 0.100 to 0.0590 \pm 0.0451 respectively. The proposed algorithm reduces the necessity for long image acquisition times, minimizes expensive hardware requirements and reduces motion artifacts in OCT images., Comment: 20 pages, 7 figures

Since the introduction of optical coherence tomography (OCT), it has been possible to study the complex 3D morphological changes of the optic nerve head (ONH) tissues that occur along with the progression of glaucoma. Although several deep learning (DL) techniques have been recently proposed for the automated extraction (segmentation) and quantification of these morphological changes, the device specific nature and the difficulty in preparing manual segmentations (training data) limit their clinical adoption. With several new manufacturers and next-generation OCT devices entering the market, the complexity in deploying DL algorithms clinically is only increasing. To address this, we propose a DL based 3D segmentation framework that is easily translatable across OCT devices in a label-free manner (i.e. without the need to manually re-segment data for each device). Specifically, we developed 2 sets of DL networks. The first (referred to as the enhancer) was able to enhance OCT image quality from 3 OCT devices, and harmonized image-characteristics across these devices. The second performed 3D segmentation of 6 important ONH tissue layers. We found that the use of the enhancer was critical for our segmentation network to achieve device independency. In other words, our 3D segmentation network trained on any of 3 devices successfully segmented ONH tissue layers from the other two devices with high performance (Dice coefficients > 0.92). With such an approach, we could automatically segment images from new OCT devices without ever needing manual segmentation data from such devices.

Optical coherence tomography (OCT) is a volumetric imaging modality that empowers clinicians and scientists to noninvasively visualize the cross-sections of biological samples. As the latest generation of its kind, Fourier-domain OCT (FD-OCT) offers a micrometer-scale axial resolution by taking advantage of coherence gating. Based on the current theory, it is believed the only way to obtain a higher-axial-resolution OCT image is to physically extend the system's spectral bandwidth given a certain central wavelength. Here, we showed the belief is wrong. We proposed a novel reconstruction framework, which integrates prior knowledge and exploits the \emph{shift-variance}, to retrospectively super-resolve OCT images without altering the system configurations. Both numerical and experimental results confirmed the processed image manifested an axial resolution beyond the previous theoretical prediction. We believe this result not only opens new horizons for future research directions in OCT reconstruction but also promises an immediate upgrade to tens of thousands of legacy OCT units currently deployed., Comment: 30 pages, 9 figures

Purpose: To remove retinal shadows from optical coherence tomography (OCT) images of the optic nerve head(ONH). Methods:2328 OCT images acquired through the center of the ONH using a Spectralis OCT machine for both eyes of 13 subjects were used to train a generative adversarial network (GAN) using a custom loss function. Image quality was assessed qualitatively (for artifacts) and quantitatively using the intralayer contrast: a measure of shadow visibility ranging from 0 (shadow-free) to 1 (strong shadow) and compared to compensated images. This was computed in the Retinal Nerve Fiber Layer (RNFL), the Inner Plexiform Layer (IPL), the Photoreceptor layer (PR) and the Retinal Pigment Epithelium (RPE) layers. Results: Output images had improved intralayer contrast in all ONH tissue layers. On average the intralayer contrast decreased by 33.7$\pm$6.81%, 28.8$\pm$10.4%, 35.9$\pm$13.0%, and43.0$\pm$19.5%for the RNFL, IPL, PR, and RPE layers respectively, indicating successful shadow removal across all depths. This compared to 70.3$\pm$22.7%, 33.9$\pm$11.5%, 47.0$\pm$11.2%, 26.7$\pm$19.0%for compensation. Output images were also free from artifacts commonly observed with compensation. Conclusions: DeshadowGAN significantly corrected blood vessel shadows in OCT images of the ONH. Our algorithm may be considered as a pre-processing step to improve the performance of a wide range of algorithms including those currently being used for OCT image segmentation, denoising, and classification. Translational Relevance: DeshadowGAN could be integrated to existing OCT devices to improve the diagnosis and prognosis of ocular pathologies.

Deep learning has recently gained high interest in ophthalmology, due to its ability to detect clinically significant features for diagnosis and prognosis. Despite these significant advances, little is known about the ability of various deep learning systems to be embedded within ophthalmic imaging devices, allowing automated image acquisition. In this work, we will review the existing and future directions for "active acquisition" embedded deep learning, leading to as high quality images with little intervention by the human operator. In clinical practice, the improved image quality should translate into more robust deep learning-based clinical diagnostics. Embedded deep learning will be enabled by the constantly improving hardware performance with low cost. We will briefly review possible computation methods in larger clinical systems. Briefly, they can be included in a three-layer framework composed of edge, fog and cloud layers, the former being performed at a device-level. Improved edge layer performance via "active acquisition" serves as an automatic data curation operator translating to better quality data in electronic health records (EHRs), as well as on the cloud layer, for improved deep learning-based clinical data mining., Comment: This work has been submitted to "Therapeutic Advances in Ophthalmology" for possible publication 17 pages, 5 figures

Purpose: To develop a deep learning approach to de-noise optical coherence tomography (OCT) B-scans of the optic nerve head (ONH). Methods: Volume scans consisting of 97 horizontal B-scans were acquired through the center of the ONH using a commercial OCT device (Spectralis) for both eyes of 20 subjects. For each eye, single-frame (without signal averaging), and multi-frame (75x signal averaging) volume scans were obtained. A custom deep learning network was then designed and trained with 2,328 "clean B-scans" (multi-frame B-scans), and their corresponding "noisy B-scans" (clean B-scans + gaussian noise) to de-noise the single-frame B-scans. The performance of the de-noising algorithm was assessed qualitatively, and quantitatively on 1,552 B-scans using the signal to noise ratio (SNR), contrast to noise ratio (CNR), and mean structural similarity index metrics (MSSIM). Results: The proposed algorithm successfully denoised unseen single-frame OCT B-scans. The denoised B-scans were qualitatively similar to their corresponding multi-frame B-scans, with enhanced visibility of the ONH tissues. The mean SNR increased from $4.02 \pm 0.68$ dB (single-frame) to $8.14 \pm 1.03$ dB (denoised). For all the ONH tissues, the mean CNR increased from $3.50 \pm 0.56$ (single-frame) to $7.63 \pm 1.81$ (denoised). The MSSIM increased from $0.13 \pm 0.02$ (single frame) to $0.65 \pm 0.03$ (denoised) when compared with the corresponding multi-frame B-scans. Conclusions: Our deep learning algorithm can denoise a single-frame OCT B-scan of the ONH in under 20 ms, thus offering a framework to obtain superior quality OCT B-scans with reduced scanning times and minimal patient discomfort.