Retinal Imaging

Ultra-widefield (UWF) swept-source optical coherence tomography angiography (SS-OCTA) enables large-area retinal vascular imaging, yet vessel segmentation at this scale lacks dedicated public benchmarks and comprehensive evaluation for quantitative vascular analysis. We introduce WOIVES, to our knowledge the first publicly available UWF SS-OCTA vessel-segmentation dataset, comprising 206 eyes from 152 participants with a 24x20mm^2 field of view. WOIVES spans emmetropia to high myopia and provides soft probability vessel annotations. We further propose PG-Mamba, a visual state space model that enhances conventional directional scans with two complementary polar-coordinate scan orders. An auxiliary Dynamic FOV Gating module performs spatial modulation at the bottleneck. PG-Mamba outperformed seven competitive approaches on broad segmentation metrics under cross-validation. It achieved the lowest median absolute errors for vessel density, fractal dimension, and vessel length density. WOIVES is publicly available on Zenodo (DOI: 10.5281/zenodo.21904672), and the PG-Mamba code is available at https://github.com/syb1234567/PG-Mamba.

Patient identity errors can compromise longitudinal medical records, research databases, and downstream clinical decisions. We present a retinal biometric system for verifying claimed identities and retrieving the correct identity from color fundus images. We trained a 512-dimensional metric-learning encoder combining a ConvNeXtV2 backbone with ArcFace and triplet losses on 227,004 images from 21,851 patient-eye identities in the Rotterdam Study, spanning multiple imaging devices and up to 32.6 years of follow-up. The system was evaluated on held-out Rotterdam Study data and externally on the UK Biobank and Age-Related Eye Disease Study (AREDS). Before evaluation, we used the model to screen for identity inconsistencies and manually adjudicated flagged images, identifying incorrect assignments in 0.588% of Rotterdam Study images, 0.259% of UK Biobank images, and 0.164% of AREDS images. In retrospective-only verification after removing near-duplicate images, the system achieved AUROCs of 0.9998, 0.9997, and 0.9998 in the Rotterdam Study, UK Biobank, and AREDS, respectively. For identity retrieval using only previously acquired images, Recall@1 was 99.7%, 97.2%, and 97.6%, respectively, from galleries averaging 4436-8510 identities; the correct identity appeared among the top five results in at least 98.6% of cases. Performance remained robust across imaging devices and long follow-up intervals, while lower image quality and inconsistent retinal fields accounted for most failures. These findings establish retinal anatomy as a durable biometric signal, useful for safeguarding the integrity of longitudinal imaging records.

Diabetic retinopathy (DR) remains a leading cause of vision loss among working-age adults worldwide, making reliable severity grading clinically important. Despite strong performance, most deep models formulate DR grading as image-level classification and do not explicitly model clinically grounded evidence, such as lesion types and spatial relations. In this paper, we propose PARAGraph, a Pathology-Anatomy-Aware Hierarchical Graph framework for DR grading. PARAGraph represents each image as a three-level hierarchical graph with lesion-level nodes, intermediate category and region nodes, and global anatomical and semantic nodes. To incorporate medical priors into nodes, we construct an optic disc-fovea-anchored coordinate frame that provides a scale- and rotation-normalized retinal reference system. Within this frame, lesion nodes are encoded with category, normalized area, and anatomical coordinates. To mitigate noisy lesion segmentation, PARAGraph uses a dual-fusion strategy that introduces global visual context into a graph semantic node and a decision-level prediction branch, improving robustness when lesion evidence is unreliable. Extensive experiments on Messidor-2, APTOS, and DDR show that PARAGraph achieves consistent DR grading performance over state-of-the-art methods. Interpretability and robustness analyses further demonstrate that its predictions are clinically grounded, closely associated with lesion evidence and robust to lesion segmentation noise.

There has been a tremendous amount of image processing and machine learning research to measure and classify disease progression from live optical coherence tomography (OCT) imaging of the retina. The images considered here are large, complex, three-dimensional (3-D) and difficult to visualize effectively. Many current supervised machine learning approaches, \emph{e.g.} neural networks, are non-metric meaning that any features or measurements generated can introduce systematic distortion that may be correlated with underlying non-meaningful physiological differences. Here we present a metric learning approach using the normalized compression distance (NCD) combined with anisotropic structure-enhancing filters to quantify and visualize the principal differences among a collection of 3-D retinal images. We validate the NCD-measured structural differences between pairs of images against the physician-measured change in visual field function, achieving a prediction error of $\sim$ 0.5 dB, more accurate than non-metric deep learning approaches. The normalized compression vectors (NCV) are proposed as a feature set measuring visual differences among a collection of 3-D microscopy images. The utility of the NCV for visualizing and measuring patterns of change is demonstrated for a human with moderate non-progressing glaucoma and for a non-human primate model using intraocular pressure setting manipulation. We conclude with a brief simulation of non-metric embedding features, \emph{e.g.} from neural networks, introducing class-correlated statistical distortion.

Despite the widespread adoption of foundation models as feature extractors for medical imaging, relatively little is understood about how different pretraining strategies influence the transferability of learned representations to weakly supervised ophthalmic imaging tasks. We investigate this question in ultra-widefield (UWF) retinal imaging by evaluating foundation model representations within a patch-based multiple instance learning (MIL) framework for disease classification on UWF images. We compare Vision Transformer encoders pretrained with supervised, Masked Autoencoder (MAE), and self-distillation objectives, while keeping the downstream aggregation architecture unchanged. Within a controlled comparison of ViT-B encoders pretrained on ImageNet-1k, the choice of pretraining objective substantially influenced frozen representation transfer, with supervised and self-distillation-based models outperforming MAE. A contemporary DINOv3 model pretrained at a larger scale achieved the strongest overall performance, with a quadratic weighted kappa of 0.863 for five-class diabetic retinopathy grading, comparable with DINOv1. Attention analysis further revealed distinct patch-aggregation behaviours associated with the different pretrained representations, while partial fine-tuning substantially reduced the performance gap for MAE. These findings suggest that pretraining strategy influences both representation transferability and the subsequent aggregation of patch-level evidence within MIL, resulting in differences in downstream classification performance.

Background and Objective: Generating realistic medical images with anatomically accurate segmentation masks helps address the shortage of annotated data in medical imaging, particularly in optical coherence tomography (OCT) of mouse eyes, where manual retinal layer delineation is labour-intensive due to tiny structures and required expertise, resulting in scarce datasets. While diffusion models perform well in medical image synthesis, joint image-mask generation has relied mainly on U-Net-based denoisers, leaving diffusion transformers largely unexplored. Methods: We propose a conditional dual-output Diffusion Transformer (DualDiT) for joint synthesis of OCT B-scans and segmentation masks of the upper retinal cell layers in ex vivo mouse retina. DualDiT encodes both modalities into a shared latent space via a pretrained VAE, concatenates their latent representations, and performs conditional diffusion over the joint tensor. We compared DualDiT against two adapted diffusion baselines: DDPM and LDM. Generative quality was assessed via Fréchet Inception Distance (FID) and spatial FID (sFID); practical utility via synthetic data augmentation for downstream U-Net segmentation; and perceptual realism via evaluation by three domain experts. Results: DualDiT achieved the best generative quality (FID 56.14, sFID 114.35), outperforming DDPM and LDM. Expert panels misclassified 46% of synthetic samples as real and 42% of real samples as synthetic. Adding DualDiT-generated images and masks improved Dice and IoU scores on a held-out segmentation test set. Conclusions: DualDiT shows that transformer-based diffusion models can effectively learn the joint distribution of OCT images and segmentation masks, surpassing DDPM- and LDM-based baselines in generative fidelity, downstream utility, and perceptual realism, highlighting its potential for data augmentation in annotation-scarce medical imaging.

Multimodal medical anomaly detection identifies samples deviating from normal patterns, where scarce abnormal cases make normality modeling from normal data practical. In retinal Optical Coherence Tomography (OCT) and OCT Angiography (OCTA) anomaly detection, existing unsupervised methods rely on visual feature distributions, reconstruction residuals, or encoder-decoder discrepancies, making anomaly scores depend on appearance-level deviations, while multimodal normality also contains semantic organization described in normal medical reports. To this end, we propose Report-Guided Mixture-of-Experts (ReMoE), which distills normal report semantics into an image-to-text prior student, builds modality-aware priors, and uses Report-Guided Modality Modulation (RMM) to modulate features through mixture-of-experts routing. Experiments on a private OCT/OCTA dataset with paired normal reports and a public OCTA500-3MM setting using a fixed normal report demonstrate state-of-the-art performance.

Deploying diabetic retinopathy (DR) screening models in primary care requires edge-efficient systems that remain accurate, safe, and reliable under domain shift. Multi-teacher knowledge distillation (KD) is a natural compression strategy, but existing approaches largely assume that all teachers provide equally trustworthy supervision. In our setting, this assumption fails: a strong CNN teacher (EfficientNet-B3, 0.876 QWK) and a weaker Transformer teacher (Swin-Base, 0.830 QWK) are complementary, yet the Transformer's logits can still mislead the student. We therefore propose OrthKD, a selective-trust distillation framework that transfers full supervision from the strong CNN, uses feature-only distillation from the weak ViT, and enforces orthogonality between teacher-specific student projections to encourage complementary rather than redundant evidence. This design preserves local lesion precision, injects global structural context, and improves robustness to distribution shift. On 132,049 retinal images, a 5.4M-parameter MobileNetV3 student reaches 0.885 QWK on EyePACS and improves zero-shot Messidor-2 performance from 0.507 to 0.728 QWK, while also achieving strong referral AUC and calibration. These results show that selectively distilling heterogeneous teachers can enable practical DR screening on resource-constrained devices.

Automated detection of vision impairing retina-based ocular conditions from fundus images is important for early screening, timely referral and reducing dependency on specialist-only assessment, for which neural network-based deep learning (DL) models have been widely utilized. However, explainability of the DL frameworks remains a major bottleneck for clinical adoption, particularly when model decisions are not linked to retinal regions that are clinically meaningful. To address this issue, this study presents CounterFundus, a novel CycleGAN-driven counterfactual explainability framework, integrating EfficientNet-B5-based retinal disease detection with visually interpretable disease-to-normal fundus image translation. For each pathological image, the counterfactual yielded by the CycleGAN generator represents an estimated healthy counterpart and the resultant difference map is utilized to localize disease-associated retinal changes. Unlike conventional post-hoc saliency methods, CounterFundus provides counterfactual explanations through visually plausible disease-to-normal retinal translation. Thereafter, to quantify the spatial agreement between counterfactual difference maps and classifier saliency, the Counterfactual-Classifier Alignment Score (CCAS) is introduced, embedding Spearman correlation, binary IoU and pointing accuracy into a single assessment protocol. To this end, EigenCAM-aligned evaluation demonstrates that the generated counterfactual explanations remain spatially consistent with classifier-relevant retinal evidence across all CCAS dimensions. Along with that, ablation studies further confirm that CCAS-filtered counterfactual augmentation improves the downstream classification performance in fundus images, establishing CounterFundus as a clinically-grounded, explainable artificially intelligence (XAI) framework for retinal disease detection.

Deep models for retinal optical coherence tomography (OCT) classification report high accuracy but rarely report whether their confidence can be trusted -- a gap that matters when a wrong-but-confident reading delays sight-saving treatment. We pair a hybrid convolutional-Transformer encoder with a gradient-boosting (XGBoost) classification head and a three-part clinical safety layer: confidence calibration, out-of-distribution (OOD) rejection, and per-prediction uncertainty flagging. On four-class OCT (84,495 scans) the model reaches 95.4% accuracy while cutting calibration error twelve-fold (expected calibration error, ECE = 0.0024), so the confidence it reports tracks its true accuracy. To our knowledge this is the first OCT classifier to validate all three safety mechanisms jointly, with public weights and reproducible multi-seed evaluation.

Diabetic retinopathy (DR) is a local retinal lesion process and a visible manifestation of systemic microvascular injury. Modern retinal AI can grade images accurately, but often leaves unanswered how local lesion evidence, retinal vascular structure, and systemic disease pathways are connected. This paper introduces \emph{Causal-RetiGraph}, a compact biomedical informatics framework that links retinal graph phenotypes with NHANES-anchored pathway modelling. The retinal-image fold constructs an interpretable $X1234$ phenotype from vessel maps, lesion evidence, image embeddings, and AutoMorph biomarkers through spatial $X_{12}$ and Jacobian $X_{34}$ branches. The NHANES fold models systemic exposures, covariates, a same-subject retinal mediator family $R^*$, and downstream outcome families. $X1234$ is used for retinal support and pathway prioritisation, while $R^*$ is used for participant-level pathway summaries. On the retinal fold, $X1234$ achieves 0.9055 binary DR accuracy and 0.9711 AUROC, with graded DR QWK of 0.8312. The results show that lesion and biomarker streams improve contextual retinal representation under scarce and imbalanced data. In NHANES, HbA1c, urine albumin, pulse pressure, fasting glucose, and systolic blood pressure are the strongest binary DR anchors. Participant-level pathway analysis identifies glycaemic--renal and glycaemic--haemodynamic pathways as the clearest mediator-style signals. These results suggest that retinal graph phenotypes can help prioritise systemic pathways in DR while preserving the distinction between image-derived support and same-subject mediation.

In recent years, most research on multimodal salient object detection (SOD) and camouflaged object detection (COD) typically aims to improve performance through complex cross-modal feature fusion and decoding structures. However, this approach leads to an excessively large model parameter scale and often fails to deliver satisfactory detection performance due to structural redundancy. In contrast, the human visual process is able to efficiently perform salient and camouflaged object identification without such complex structures. This contrast raises an important question: Can we draw conceptual inspiration from the human visual process to achieve a simpler modeling strategy, and still realize accurate and efficient object detection? To answer this question, we propose HVPNet, a simple yet general bio-inspired computational architecture. Drawing on the multi-layered information integration of the retina as a conceptual metaphor, we designed a Retinal Integration Module (RIM), which effectively integrates multimodal features through a level-specific multi-stage integration strategy. To fully exploit these features, we further design a cortical decoder (CD) that breaks down the decoding process into low- and high-level visual stages, abstracting the hierarchical processing in the human visual cortex. Benefiting from these designs, HVPNet can readily extend to seven tasks across four modalities. Without bells and whistles, it establishes an excellent accuracy-efficiency trade-off across 22 datasets spanning these seven tasks. Our code is available at https://github.com/jiaweiXu1029/HVPNet.

Learning causal models from fragmented biomedical data is challenging because clinical, molecular, and imaging variables are often incomplete or not jointly observed. We propose RetiSEM, a domain-constrained structural equation modelling (SEM) framework for causal graph recovery and mediation analysis under limited multimodal resources. This proposed work organises variables into biologically informed blocks, applies forbidden-edge constraints, and decomposes pathway-level effects into TE, NDE, and NIE components. We evaluate RetiSEM across ten synthetic benchmark scenarios that vary in dimensionality, nonlinearity, causal depth, and pathway structure, together with a fragmented real-world setting that combines NHANES clinical variables with externally derived retinal representations. This approach achieves lower structural error and higher causal accuracy than unconstrained baselines across the synthetic benchmarks. In the real-data analysis, retinal variables behave mainly as downstream biomarker-like indicators, with smaller but detectable indirect effects. These findings support our strategy as an interpretable framework for testing structured causal hypotheses in limited-resource biomedical AI. The code and resources for this work are publicly available at: https://github.com/Inamullah-Colab/ReitSEM.

Large-scale pretrained foundation models have revolutionized general medical screening, but often falter on rare diseases because such conditions are underrepresented in real-world clinical datasets. While retrieval-augmented diagnosis attempts to mitigate this, conventional static methods frequently succumb to the hubness problem, retrieving visually similar but semantically incorrect common diseases. To address this, we propose Evo-RAD, a self-evolving agentic framework that transforms evidence acquisition into a dynamic decision-making task. We formulate retrieval as a Markov Decision Process (MDP) where a graphbased agent observes the reference set state and executes actions to purge discordant evidence (DELETE), acquire pathologically consistent samples (INSERT), or conclude the evolution (TERMINATE). Optimized via Group Relative Policy Optimization (GRPO) with a homogeneityaware reward, the agent learns to maximize the diagnostic homogeneity of the support reference set. Experiments on retinal disease benchmarks show that Evo-RAD substantially improves rare-disease diagnosis, outperforming retinal foundation models by +21.04%, while also surpassing retrieval-based and parameter-efficient fine-tuning methods by +3.56%. Code is available at https://github.com/SDH-Lab/Evo-RAD.

The retina offers a noninvasive window into neurodegenerative disease, capturing subtle structural patterns associated with a risk of future cognitive decline. Vision-language alignment frameworks such as REVEAL have shown that pairing retinal fundus images with structured clinical risk narratives improves early prediction of Alzheimer's disease (AD). A key design choice in these approaches is the use of phenotypic grouping, where individuals with similar risk profiles are treated as multi-positive pairs during contrastive learning. However, existing methods operationalize phenotypic similarity as a discrete construct, relying on hard group assignments that impose rigid supervision and decouple group formation from representation learning. We propose a continuous formulation of phenotypic structure within contrastive learning. Rather than assigning samples to fixed clusters, we model inter-subject similarity as a differentiable weighting function derived from intra-modality embedding similarities in both retinal images and risk profiles. These weights define soft multi-positive relationships through a continuous aggregation operator, enabling graded supervision that reflects the spectrum nature of disease risk. We further introduce a soft-target contrastive objective that jointly learns cross-modal alignment and phenotypic structure in an end-to-end manner. Evaluated on UK Biobank retinal imaging data for incident AD prediction, the proposed framework consistently outperforms discrete group-based contrastive learning and standard vision-language baselines. By treating phenotypic similarity as a learnable, continuous signal rather than a fixed grouping rule, our approach provides a principled and robust foundation for population-scale neurodegenerative risk modeling from multi-modal retinal and clinical data.

Objective: Diseases such as age-related macular degeneration and retinitis pigmentosa cause the degradation of the photoreceptor layer. One approach to restore vision is to electrically stimulate the surviving retinal ganglion cells with a microelectrode array such as epiretinal implants. Epiretinal implants are known to generate visible anisotropic shapes elongated along the axon fascicles of neighboring retinal ganglion cells. Recent work has demonstrated that to obtain isotropic pixel-like shapes, it is possible to map axon fascicles and avoid stimulating them by inactivating electrodes or lowering stimulation current levels. Avoiding axon fascicle stimulation aims to remove brushstroke-like shapes in favor of a more reduced set of pixel-like shapes. Approach: In this study, we propose the use of isotropic and anisotropic shapes to render intelligible images on the retina of a virtual patient in a reinforcement learning environment named rlretina. The environment formalizes the task as using brushstrokes in a stroke-based rendering task. Main Results: We train a deep reinforcement learning agent that learns to assemble isotropic and anisotropic shapes to form an image. We investigate which error-based or perception-based metrics is adequate to reward the agent. The agent is trained in a model-based data generation fashion using the psychophysically validated axon map model to render images as perceived by different virtual patients. We show that the agent can generate more intelligible images compared to the naive method in different virtual patients. Significance: This work shares a new way to address epiretinal stimulation that constitutes a first step towards improving visual acuity in artificially-restored vision using anisotropic phosphenes.

Retinal imaging provides a non-invasive window into systemic microvascular health and has emerged as a potential biomarker for systemic diseases. However, whether retinal features encode biologically meaningful systemic signals that can be reliably interpreted using explainable artificial intelligence (XAI) remains unclear. An explainable multi-task deep learning framework was developed to investigate associations between retinal microvascular features and systemic abnormalities in Type 2 Diabetes Mellitus. A total of 11,011 fundus images from 2,719 individuals were analysed using a shared neural network with task-specific heads for glycaemic status, kidney abnormality, and multi-system involvement. Model interpretability was evaluated using Gradient-weighted Class Activation Mapping (Grad-CAM), anatomical masking, and vessel alignment analysis. The framework demonstrated task-dependent predictive performance, with the best discrimination observed for kidney abnormality (AUC up to 0.63), whereas glycaemic status prediction showed limited performance (AUC = 0.49-0.61). Explainability analyses consistently localized model attention to retinal vessels and peripapillary regions. Masking experiments showed that occlusion of vascular regions caused the greatest performance decline, indicating that retinal vessels were the primary predictive source. Different architectures exhibited heterogeneous attention patterns, suggesting multiple representational pathways for systemic signal encoding. This pilot study demonstrates that retinal microvascular features contain measurable signals associated with systemic abnormalities, particularly microvascular damage. By integrating multi-task learning with quantitative XAI validation, this framework advances retinal imaging toward interpretable digital biomarkers for systemic risk stratification in diabetes.

Background: Type 2 diabetes mellitus (T2DM) is increasingly recognised as a systemic disease characterised by coordinated dysfunction across metabolic, renal, lipid, and inflammatory pathways. Existing clinical assessments often fail to capture this multi-dimensional burden. Methods: We conducted a retrospective study of 1,195 patients using routinely collected laboratory biomarkers. System-level abnormality indices were constructed to quantify organ-specific dysfunction, and multi-system involvement was defined as abnormalities in two or more systems. Supervised machine learning models, including logistic regression, random forest, and gradient boosting, were trained to predict multi-system dysregulation. Model interpretability was achieved using SHapley Additive exPlanations (SHAP). Results: The gradient boosting model demonstrated near-perfect discrimination (AUC = 1.000), significantly outperforming logistic regression (AUC = 0.925). Feature attribution analysis revealed that hyperglycaemia, renal impairment, dyslipidaemia, and inflammation were the dominant drivers of multi-system risk. Dose-response relationships observed in partial dependence analyses further supported the biological plausibility of model predictions. Conclusion: This study presents an interpretable, data-driven framework for quantifying systemic disease burden in T2DM. By linking routine biomarkers to multi-organ dysfunction, our approach provides both predictive accuracy and mechanistic insight, offering potential for improved risk stratification and precision medicine in diabetes care. The data and code used in this study are openly available on GitHub at: https://github.com/MiniHanWang/Type-2-Diabetes-1.git

Retinal diagnosis is inherently bilateral: clinicians compare homologous structures across eyes (e.g., optic disc asymmetry), yet most deep models operate on monocular representations. We investigate whether explicit structural correspondence improves diagnosis, and propose Anatomy-Slot to operationalize this hypothesis. Anatomy-Slot introduces an unsupervised anatomical bottleneck by decomposing patch tokens into a set of emergent, structurally-coherent slots that correspond to anatomical regions, then aligning these slots across eyes via bidirectional cross-attention. On ODIR-5K with $n=10$ seeds, the method improves AUC by $4.2$ points over a matched ViT-L baseline (95% CIs; Wilcoxon signed-rank test, $W=0$, $p=0.002$). Pairing disruption and stress testing under Gaussian noise provide controlled tests of correspondence dependence and robustness under corruption. We further report quantitative optic disc grounding on REFUGE and cross-attention localization analysis. Beyond the reported gains, these results indicate that object-centric anatomical correspondence offers a principled path toward interpretable diagnostic systems aligned with clinical bilateral comparison.

Retinal image-based eye tracking is widely used in ophthalmic imaging and vision science, and is a promising path to deliver higher gaze accuracy than the pupil- and cornea-based approaches commonly used in modern AR/VR devices. Nevertheless, existing retinal tracking algorithms still primarily rely on classical template-matching registration, which can be insufficiently robust to retinal feature variability and real-world imaging conditions. In this work, we propose a novel weakly-supervised, learning-based framework for robust retinal eye tracking. Initial studies demonstrate high accuracy, achieving the 95th-percentile gaze error < 0.45 deg across a cohort of 6 participants.

Optical coherence tomography (OCT), a commonly used retinal imaging modality, plays a central role in retinal disease diagnosis by providing high-resolution visualization of retinal layers. While deep learning (DL) has achieved expert-level accuracy in OCT-based retinal disease detection, its "black box" nature poses challenges for clinical adoption, where explainability is essential for clinical trust and regulatory approval. Existing post-hoc explainable AI (XAI) methods often struggle to delineate fine-grained lesion structures, respect anatomical boundaries, or suppress noise, limiting the trustworthiness of their explanations. To bridge these gaps, we propose a Structure-Aware Interpretable Learning (SAIL) framework that integrates retinal anatomical priors at the representation level and couples them with semantic features via a fusion design. Without modifying standard post-hoc explainability methods, this representation yields sharper and more anatomically aligned attribution maps. Comprehensive experiments on diverse OCT datasets demonstrate that our structure-aware method consistently enhances interpretability, producing clinically meaningful and anatomy-aware explanations. Ablation studies further show that strong interpretability requires both structural priors and semantic features, and that properly fusing the two is critical to achieve the best explanation quality. Together, these results highlight structure-aware representations as a key step toward reliable explainability in OCT.

Optical Coherence Tomography (OCT) has become one of the most used imaging modality in ophthalmology. It provides high-resolution, non-invasive visualization of retinal microarchitecture. The automated analysis of OCT images through representation learning has emerged as a central research frontier. This has mainly been driven by the clinical need to process large acquisition volumes. The objective is to reduce the reliance on expert annotation, and improve diagnostic consistency across devices and populations. This survey provides a comprehensive and structured review of representation learning methods for retinal OCT image analysis. It covers the period from early deep learning approaches to the most recent developments in foundation models and vision-language systems. We organize the literature along a principled taxonomy of learning paradigms, encompassing supervised learning with CNN-based and transformer-based architectures, self-supervised and semi-supervised methods, generative approaches, as well as 3D volumetric modeling, multimodal representation learning, and large-scale pretrained foundation models. For each paradigm, we analyze the core methodological contributions, identify persistent limitations, and trace the connections between successive approaches. We further provide a structured overview of publicly available OCT datasets, discuss evaluation protocol considerations, and present a unified problem formulation that situates each learning paradigm within a common mathematical framework. Building on this analysis, we identify and discuss the most pressing open research directions emerging in the literature. This includes volumetric foundation model pretraining, uncertainty-aware representation learning, federated and privacy-preserving training, fairness and bias mitigation, concept-based interpretability,...

The systemic, metabolic, lifestyle factors have established associations with Alzheimer's Disease (AD) through epidemiologic and AD-specific biomarker studies. Whether colored fundus photography (CFP) contains retinal structural signatures corresponding to these AD-related risk domains remains unclear. To determine whether deep learning (DL) models can predict 12 AD-related risk factors from CFP and to characterize the retinal structures underlying these predictions, thereby assessing whether CFP reflects pathways to AD vulnerability. Using 62,876 CFPs from 44,501 unique participants from the UK Biobank, DL models were trained to predict 12 factors linked to AD incidence: 6 categorical (sex, smoking, sleeplessness, economic status, alcohol use, depression) and 6 continuous (age, age at completing education, BMI, systolic, diastolic blood pressure, HbA1c). Model performance, model saliency, and saliency-derived scores (CAM-Score) were evaluated and compared to retinal morphometry. The scores were also compared between incident-AD cases (average 8.55 years before onset) and matched controls. Performance of DL ranged from AUROC= 0.5654-0.9480 for categorical and R2=-0.0291-0.7620 for continuous factors, outperforming most of the morphometry-machine learning models. Saliency-based score consistently highlighted biologically meaningful regions, particularly the optic nerve head and retinal vasculature. It also aligned with present morphometric variations. Several saliency-based scores differed significantly between incident AD and matched controls, suggesting potential overlap between retinal correlates of risk factors and preclinical AD-associated changes. CFP encodes retinal signatures linked to AD risk factors. Although not diagnostic, DL-derived retinal representations may uncover biologically meaningful risk-related structural changes mirroring the potential AD vulnerability.

The quality of diabetic retinopathy (DR) screening relies on the ability to correctly grade severity; however, many deep-learning (DL) classifiers cannot be easily interpreted in the clinical context. This study presents a methodology that combines strong discriminative models with multimodal explanations, converting retinal pixels into clinically interpretable outputs. Using the APTOS 2019 benchmark, we evaluated six representative CNN- and transformer-based backbones under a controlled protocol with stratified five-fold cross-validation. We then compared ensembling strategies (hard voting, weighted soft voting, stacking) and investigated a hybrid class-level fusion variant to exploit grade-specific advantages. For interpretability, we produced Grad-CAM++ visual attribution maps and short textual rationales using vision-language models (VLMs) conditioned on the fundus image and classifier outputs under conservative prompting constraints. Modern CNN backbones (ResNet-50 and ConvNeXt-Tiny) provided the strongest single-model baselines, with cross-validated QWK up to 0.919 and 0.914, respectively. Ensembling improved ordinal agreement, and weighted soft voting was the most consistent across folds (QWK 0.934 +/- 0.017). Hybrid class-level fusion was competitive but did not yield a statistically reliable improvement over standard fusion in paired fold comparisons (Holm-adjusted p >= 1.000). For explanation quality, Grad-CAM++ offered plausible but coarse localization, and VLM rationales were generally grade-consistent. Quantitatively, VLM variants showed a trade-off between clinical completeness and template-level semantic similarity (coverage 0.700 vs. BERTScore 0.072), while image-text alignment was comparable (CLIPScore approximately 0.34).

Reliable automated analysis of Optical Coherence Tomography (OCT) imaging is crucial for diagnosing retinal disorders but faces a critical barrier: the need for expensive, labor-intensive expert annotations. Supervised deep learning models struggle to generalize across diverse pathologies, imaging devices, and patient populations due to their restricted vocabulary of annotated abnormalities. We propose an unsupervised anomaly detection framework that learns the normative distribution of healthy retinal anatomy without lesion annotations, directly addressing annotation efficiency challenges in clinical deployment. Our approach leverages a discrete latent model trained on normal B-scans to capture OCT-specific structural patterns. To enhance clinical robustness, we incorporate retinal layer-aware supervision and structured triplet learning to separate healthy from pathological representations, improving model reliability across varied imaging conditions. During inference, anomalies are detected and localized via reconstruction discrepancies, enabling both image and pixel-level identification without requiring disease-specific labels. On the Kermany dataset (AUROC: 0.799), our method substantially outperforms VAE, VQVAE, VQGAN, and f-AnoGAN baselines. Critically, cross-dataset evaluation on Srinivasan achieves AUROC 0.884 with superior generalization, demonstrating robust domain adaptation. On the external RETOUCH benchmark, unsupervised anomaly segmentation achieves competitive Dice (0.200) and mIoU (0.117) scores, validating reproducibility across institutions.

Retinal laser speckle contrast imaging (LSCI) is a noninvasive optical modality for monitoring retinal blood flow dynamics. However, conventional temporal LSCI (tLSCI) reconstruction relies on sufficiently long speckle sequences to obtain stable temporal statistics, which makes it vulnerable to acquisition disturbances and limits effective temporal resolution. A physically informed reconstruction framework, termed RetinaDiff (Retinal Diffusion Model), is proposed for retinal tLSCI that is robust to motion and requires only a few frames. In RetinaDiff, registration based on phase correlation is first applied to stabilize the raw speckle sequence before contrast computation, reducing interframe misalignment so that fluctuations at each pixel primarily reflect true flow dynamics. This step provides a physics prior corrected for motion and a high quality multiframe tLSCI reference. Next, guided by the physics prior, a conditional diffusion model performs inverse reconstruction by jointly conditioning on the registered speckle sequence and the corrected prior. Experiments on data acquired with a retinal LSCI system developed in house show improved structural continuity and statistical stability compared with direct reconstruction from few frames and representative baselines. The framework also remains effective in a small number of extremely challenging cases, where both the direct 5-frame input and the conventional multiframe reconstruction are severely degraded. Overall, this work provides a practical and physically grounded route for reliable retinal tLSCI reconstruction from extremely limited frames. The source code and model weights will be publicly available at https://github.com/QianChen113/RetinaDiff.

Diabetic retinopathy (DR) is a leading cause of vision impairment worldwide, and automated grading systems play a crucial role in large-scale screening programs. However, deep learning models often exhibit degraded performance when deployed across datasets acquired under different imaging conditions. This study presents a robust dual-resolution deep learning framework for DR grading that integrates attention-based feature fusion with ordinal regression to improve cross-dataset generalization. The proposed method employs two parallel EfficientNet backbones operating at different spatial resolutions to capture complementary retinal features. A learnable attention mechanism adaptively fuses multi-resolution representations, while an ordinal regression formulation based on the cumulative link model (CORAL) explicitly accounts for the ordered nature of DR severity levels. To mitigate domain discrepancies between datasets, a preprocessing strategy combining circular cropping, contrast enhancement, and histogram matching is applied. The model was trained on the APTOS 2019 dataset and evaluated on both an internal validation split and an external Messidor-2 test set. Experimental results demonstrate strong grading performance, achieving a quadratic weighted kappa (QWK) of 0.88 on the APTOS validation set and 0.68 on the unseen Messidor-2 dataset, indicating improved robustness for cross-dataset DR grading applications.

Automating medical reports for retinal images requires a sophisticated blend of visual pattern recognition and deep clinical knowledge. Current Large Vision-Language Models (LVLMs) often struggle in specialized medical fields where data is scarce, leading to models that overfit and miss subtle but critical pathologies. To address this, we introduce DREAM (Dynamic Retinal Enhancement with Adaptive Multi-modal Fusion), a novel framework for high-fidelity medical report generation that excels even with limited data. DREAM employs a unique two-stage fusion mechanism that intelligently integrates visual data with clinical keywords curated by ophthalmologists. First, the Abstractor module maps image and keyword features into a shared space, enhancing visual data with pathology-relevant insights. Next, the Adaptor performs adaptive multi-modal fusion, dynamically weighting the importance of each modality using learnable parameters to create a unified representation. To ensure the model's outputs are semantically grounded in clinical reality, a Contrastive Alignment module aligns these fused representations with ground-truth medical reports during training. By combining medical expertise with an efficient fusion strategy, DREAM sets a new state-of-the-art on the DeepEyeNet benchmark, achieving a BLEU-4 score of 0.241, and further demonstrates strong generalization to the ROCO dataset.

Foundation models are used to extract transferable representations from large amounts of unlabeled data, typically via self-supervised learning (SSL). However, many of these models rely on architectures that offer limited interpretability, a critical issue in high-stakes domains such as medical imaging. We propose \model, a foundation model that is interpretable-by-design via a BagNet backbone whose small receptive fields generate class evidence maps that are faithful to the model's decision-making process. Additionally, \model{} incorporates a $2D$ projection layer during pretraining that enables direct visualization of the representation space, providing a dataset-level view of the learned structure including meaningful clinical clusters as well as potential spurious correlations. We trained \model{} on over 800,000 color fundus photographs from various sources to learn generalizable representations for different downstream tasks. Our model achieves performance comparable to RETFound, which has $16\times$ more parameters, while providing interpretable predictions on out-of-distribution data. These results suggest that large-scale SSL pretraining paired with inherent interpretability can lead to robust representations for retinal imaging. Code and pretrained models are available at \href{https://anonymous.4open.science/r/dual-ifm-3D5A/README.md}{www.anonymous.4open.science/dual-IFM}.

Multimodal large language models (MLLMs) have recently demonstrated remarkable reasoning abilities under reinforcement learning (RL) paradigm. However, most existing multimodal medical reasoning models focus on basic reasoning, which refers to shallow inference based on visual feature matching. In contrast, real-world clinical diagnosis extends beyond basic reasoning, demanding complex reasoning that integrates heterogeneous clinical information (such as chief complaints and medical history) with multimodal medical imaging data. To bridge this gap, we introduce MM-Retinal-Reason, an ophthalmic multimodal dataset covering the full spectrum of perception and reasoning. Specifically, it is the first dataset in ophthalmology to encompass both basic and complex reasoning tasks with Chain-of-Thought (CoT) trajectories, aiming to enhance visual-centric reasoning and emulate realistic clinical decision-making. Building upon MM-Retinal-Reason, we propose OphthaReason, the first RL-enhanced ophthalmic multimodal reasoning model with step-by-step reasoning traces. To enable flexible adaptation to both basic and complex reasoning tasks, we further introduce Uncertainty-Aware Dynamic Thinking (UADT), which estimates sample-level uncertainty via entropy and dynamically modulates exploration depth through a shaped advantage mechanism. Comprehensive experiments demonstrate the effectiveness of our model on both basic and complex reasoning tasks, outperforming general-purpose MLLMs, medical MLLMs, RL-based medical MLLMs, and ophthalmic MLLMs by at least 15.47%. Project Page: \href{https://github.com/lxirich/OphthaReason}{link}.

Even during fixation the human eye is constantly in low amplitude motion, jittering over small angles in random directions at up to 100Hz. This motion results in all features of the image on the retina constantly traversing a number of cones, yet objects which are stable in the world are perceived to be stable, and any object which is moving in the world is perceived to be moving. A series of experiments carried out over a dozen years revealed the psychophysics of visual stabilization to be more nuanced than might be assumed, say, from the mechanics of stabilization of camera images, or what might be assumed to be the simplest solution from an evolutionary perspective. The psychophysics revealed by the experiments strongly implies a specific set of operations on retinal signals resulting in the observed stabilization behavior. The presentation is in two levels. First is a functional description of the action of the mechanism that is very likely responsible for the experimentally observed behavior. Second is a more speculative proposal of circuit-level neural elements that might implement the functional behavior.

Early detection of vision-threatening conditions such as diabetic retinopathy, glaucoma, and age-related macular degeneration depends on retinal fundus image analysis, but manual assessment is slow and expert-dependent. Automated convolutional neural networks classify fundus images accurately yet act as black boxes, and existing retinal vessel segmentation methods lose discriminative power under pathology and seldom exploit attention or transformer backbones. Using the FIVES and DRIVE fundus datasets, we develop a two-pipeline framework that pairs four-class disease classification with attention- and transformer-based vessel segmentation, organised in three stages: (1) FIVES images are augmented by rotation and horizontal and vertical flips and used to fine-tune eight ImageNet-pretrained CNNs: ResNet101, DenseNet169, Xception, InceptionV3, DenseNet121, InceptionResNetV2, ResNet50, and EfficientNetB0. (2) Five gradient-based explanation methods, Grad-CAM, Grad-CAM++, Score-CAM, Faster Score-CAM, and Layer-CAM, are computed on the final convolutional block of each classifier and compared qualitatively across architectures. (3) Ten U-Net variants are benchmarked for vessel segmentation: TransUNet (hybrid CNN--Transformer encoder) and Attention U-Net (gated skip connections), evaluated with ResNet50V2, ResNet101V2, and ResNet152V2 backbones, along with additional Attention U-Net configurations using DenseNet backbones, and the fully transformer-based Swin-UNet. ResNet101 gives the highest classification accuracy: 94.17% (F1 0.942) $>$ 88.33% for EfficientNetB0. For segmentation, the architecture ranking is consistent on both datasets: Attention U-Net $>$ TransUNet $>$ Swin-UNet. The strongest configuration is Attention U-Net with a ResNet101V2 backbone: FIVES IoU 0.722, Dice 0.838; DRIVE IoU 0.648, Dice 0.787, lifting DRIVE IoU 60.80 $\rightarrow$ 64.83 over a prior custom U-Net.