Beyond Representation Learning: A Systematic Study of Joint-Embedding Predictive Generation for 3D Brain MRI

Joint-embedding predictive architectures (JEPAs) have primarily been developed for self-supervised representation learning. Denoising JEPA (D-JEPA) recently demonstrated strong generative capabilities on natural images, yet the applicability to 3D medical imaging remains unexplored. Building on the D-JEPA framework, we present Med-D-JEPA, a systematic adaptation and evaluation of joint-embedding predictive generation for 3D brain MRI. Med-D-JEPA operates on continuous latent tokens produced by a 3D KL-regularized adversarial variational autoencoder, and combines masked context prediction, representation-level alignment, per-token diffusion, and iterative next-set-of-token sampling. We evaluate unconditional and class-conditional generation quality on BraTS2019 and OASIS-1 datasets; downstream classification utility; and preliminary whole-tumor segmentation on BraTS2020. Across different generation settings, Med-D-JEPA achieves superior or competitive performance compared to several strong baselines on fidelity and diversity metrics. Compared to training with real samples, Med-D-JEPA-based synthetic pretraining improves classification AUC from 0.63 to 0.85 on BraTS2019 and from 0.78 to 0.87 on OASIS-1. In the segmentation study, pretraining on Med-D-JEPA samples improves Dice from 0.74 to 0.80 and reduces HD95 from 13.40 to 9.56 mm. These findings establish joint-embedding predictive generation as a promising direction for 3D medical image synthesis and encourage further research in this direction.

AnaDiffusion: Anatomically CompositionalLatent Diffusion for Controllable 3D Brain MRI Generation

3D brain MRI generation has made significant advances in medical imaging, simulation, and controllable anatomical analysis. However, existing generative models typically synthesize 3D volumes monolithically, often overlooking regional anatomical structures and limiting local controllability. To address these limitations, we introduce AnaDiffusion, an anatomically compositional latent diffusion framework that factorizes the generation process into distinct, anatomically meaningful regions, followed by part-to-whole assembly and global refinement. Our approach first trains part diffusion models to capture local structural priors. We then inject an assembled anatomical composite of the parts into the whole-brain latent representation and continue denoising. This mechanism enables the model to resolve global context while preserving the injected anatomy. As a result, AnaDiffusion produces both explicit part assets and a globally coherent volume, thereby enabling controllable part editing without requiring subject-specific dense segmentation maps at inference time while maintaining consistent part-to-whole brain structure. On the subject-disjoint ADNI test split, AnaDiffusion achieves the lowest FID across the whole brain, left and right hemispheres, cerebellar-brainstem complex, and seam regions. It also achieves the best cerebellar and second-best ventricular and brainstem absolute Cohen's d values among the evaluated methods. In localized editing experiments, paired MS-SSIM demonstrates high target transfer and off-target preservation, supporting controllable part replacement with minimal unintended anatomical alterations.

Evaluation of Clinically Steerable Retinal Image Generation from Foundation Model Latent Spaces

Medical foundation models learn latent representations of clinically meaningful phenotypes, yet their ability to support controllable image generation remains largely unexplored. We evaluate four retinal foundation models within the representation tokenizer framework and examine whether demographic and clinical information encoded in latent representations from foundation models is preserved during synthetic image generation. We show that generated representations and images faithfully inherit phenotype information when evaluated within their originating foundation models, consistently outperforming conventional latent diffusion on multiple downstream prediction tasks. However, these gains largely disappear when evaluated using classifiers trained on real images, revealing a previously uncharacterised synthetic-to-real representation gap. These findings demonstrate that foundation-model latent spaces provide a powerful substrate for controllable retinal synthesis while highlighting the need to better align synthetic representations with real-image distributions.

Assessment of Conditional Diffusion Model for Synthetic Histopathology Image Generation

Synthetic histopathology image generation has emerged as an approach that may address data scarcity in computational pathology, yet current evaluation methodologies may not fully assess synthetic data quality for medical applications. This work investigates and addresses limitations in existing evaluation metrics, investigating an approach for assessing synthetic histopathology image quality through domain-specific metrics and downstream task validation. We show that conventional synthetic data evaluation metrics such as Frechet Inception Distance (FID) and Inception Score (IS) may have limitations when applied to histopathology images due to their reliance on ImageNet-pretrained feature extractors. To address these limitations, we propose for consideration modified FID and IS approaches utilizing foundation models pretrained on digital pathology datasets, supplemented by precision-recall based metrics as part of an additional quality assessment. Using conditional denoising diffusion models trained on four benchmark datasets, with a two-step training approach, we generated synthetic datasets with systematically varied quality characteristics. We also measured the correlation between the synthetic data quality metrics with downstream nuclei segmentation performance using common metrics including the aggregated Jaccard index (AJI+) and the Dice coefficient. The study results suggest that pathology-specific metrics may provide improved discriminative power. Specifically, the modified Inception Score indicates higher correlation with downstream task performance (r=0.6096 with AJI+, p=0.0122), compared to the original IS (r=0.0708, p=0.7944). Our observations indicate that increasing the variety of generated training data has a higher positive correlation with segmentation model performance than improving the visual fidelity of individual generated images.

Local Label-Informed Feature Transfer for Generating Ground-Truth Medical Images: A Comparison of GAN- and Diffusion-Based Approaches

Validating Explainable Artificial Intelligence (XAI) methods in medical imaging requires ground-truth data with known locations of informative features. However, current approaches rely on expert annotations, which are prone to labeling errors, or on hand-crafted artificial perturbations superimposed onto healthy images to mimic lesions or malignant features, which lack clinical realism. We present Local Label-Informed Feature Transfer (LLIFT), a framework for generating semi-synthetic brain magnetic resonance images with realistic lesions placed in user-controlled regions, which does not require pixel-level lesion annotations during training. We implement LLIFT with two generative paradigms: LLIFT-GAN, a custom GAN that learns pathological features from binary class labels alone, and LLIFT-DM, a diffusion-based inpainting pipeline conditioned on bounding-box masks via ControlNet. Both approaches are evaluated on brain magnetic resonance imaging data derived from the Human Connectome Project. In evaluations, both achieve Fréchet Inception Distance scores, with respect to the real pathological distribution, that are comparable to the inter-class reference between healthy and pathological images in the given dataset. Furthermore, qualitative inspection confirms the realism of lesion structures. The resulting benchmark datasets provide spatially controlled ground truth data for evaluating XAI methods in medical imaging.

Improving Medical Image Generative Models with Fréchet Distance Loss

Diffusion generative models have demonstrated immense potential for synthetic medical image generation. However, these models often struggle to capture complex morphological characteristics of heterogeneous tumors with irregular boundaries, limiting their utility for downstream clinical tasks such as segmentation. This limitation stems from the standard denoising objective: minimizing a per-pixel error, which smooths high-variance irregular structures characteristic of tumors. To address this, we propose finetuning these generative models with Fréchet Distance loss (FD-loss). FD-loss aligns the first and second order feature statistics of real and generated images in a pretrained encoder space, encouraging the generator to capture complex structural variations characteristic of heterogeneous tumors. We integrate FD-loss across diverse architectural settings, using both natural- and medical-image encoders on multiple liver and brain cancer datasets spanning CT and MRI modalities. Downstream segmentation networks trained on our FD-regularized synthetic data consistently achieve superior performance, improving tumor DSC by $>$$5\%$ over unregularized synthetic augmentation alone. Qualitative analysis suggests these gains are associated with more faithful tumor synthesis and fewer segmentation hallucinations. Our results show FD-loss as an effective regularizer for medical image generative models to improve clinical workflows.

Controllable Generation of Diverse Dermatological Imagery for Fair and Efficient Malignancy Classification

Accurate dermatological diagnosis naturally necessitates equitable performance across diverse populations, yet a systematic lack of expertly annotated images, especially for underrepresented skin tones and rare diseases, impedes progress toward measurably fair methods. We introduce cgDDI (Controllable Generation of Diverse Dermatological Imagery), a hybrid framework that (1) synthesizes realistic healthy skin samples without disturbing other input properties, (2) maps single-sample rare lesions onto novel skin-tones and locations non-parametrically, and (3) allows for efficient parametric generation with as few as 10 training samples. The framework supports both human and automated segmentation masking, enabling scalability to datasets without pre-made lesion masks. We grow a 656-image dataset by more than 400x and validate across two datasets: biopsy-confirmed Diverse Dermatology Images (DDI) and expert-verified Fitzpatrick17k (F17k). On the DDI benchmark, we achieve malignancy classification accuracy of 86.4% under synthetic-only training and 90.9% state-of-the-art performance with real data fine-tuning, alongside leading fairness metrics. Cross-dataset experiments show +13.9% accuracy improvements on unseen F17k data despite minimal disease overlap. We openly release 266k+ synthetic images, code, and generative models to further support fairness research at https://github.com/hectorcarrion/ControllableGenDDI.

MIRAGE: Retrieval and Generation of Multimodal Images and Texts for Medical Education

Access to diverse, well-annotated medical images with interactive learning tools is fundamental for training practitioners in medicine and related fields to improve their diagnostic skills and understanding of anatomical structures. While medical atlases are valuable, they are often impractical due to their size and lack of interactivity, whereas online image search may provide mislabeled or incomplete material. To address this, we propose MIRAGE, a multimodal medical text and image retrieval and generation system that allows users to find and generate clinically relevant images from trustworthy sources by mapping both text and images to a shared latent space, enabling semantically meaningful queries. The system is based on a fine-tuned medical version of CLIP (MedICaT-ROCO), trained with the ROCO dataset, obtained from PubMed Central. MIRAGE allows users to give prompts to retrieve images, generate synthetic ones through a medical diffusion model (Prompt2MedImage) and receive enriched descriptions from a large language model (Dolly-v2-3b). It also supports a dual search option, enabling the visual comparison of different medical conditions. A key advantage of the system is that it relies entirely on publicly available pretrained models, ensuring reproducibility and accessibility. Our goal is to provide a free, transparent and easy-to-use didactic tool for medical students, especially those without programming skills. The system features an interface that enables interactive and personalized visual learning through medical image retrieval and generation. The system is accessible to medical students worldwide without requiring local computational resources or technical expertise, and is currently deployed on Kaggle: http://www-vpu.eps.uam.es/mirage