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

Self-supervised learning offers a compelling approach for medical imaging, where labeled data are scarce and acquisition costs are high. We present COJEPA, a self-supervised framework for volumetric brain MRI that combines a joint-embedding predictive architecture (JEPA) with a contrastive loss (CO), targeting two complementary properties: local predictivity and global discriminability. The model is trained without labels on T1-weighted structural MRI from two cohorts (HCP-YA and AABC, $N{=}2286$, ages 22 to 90), extending I-JEPA to 3D with foreground-aware block masking, a hierarchical convolutional patch embedding, and world-space sinusoidal positional encodings. We evaluate all three objectives across zero-shot twin retrieval, brain tumor segmentation (BraTS 2024), and age regression (OpenBHB). COJEPA achieves the best monozygotic twin recall at rank@1 (0.84), the best finetuning age MAE (2.55 years on OpenBHB 3.0T), and matches CO on BraTS whole-tumor Dice, demonstrating that the combined objective yields representations that are simultaneously discriminative and locally structured.

This work introduces MedForj, a suite of 3D foundational generative priors based on diffusion models. The MedForj models were trained on $72{,}659$ 1~mm isotropic 3D $T_1$-weighted MRI human brain image volumes from $38{,}174$ subjects, drawn from a curated corpus of $80{,}675$ volumes from $42{,}506$ subjects spanning $38$ publicly available datasets. These training images were manually inspected to exclude those with poor quality and excessive pathology, and otherwise were minimally processed. The models include six different diffusion training strategies: rectified flow, latent diffusion rectified flow, flow matching, velocity prediction, clean prediction, and noise prediction. Image samples produced by each of these models were compared to each other and against real, ground truth data under downstream segmentation distributions, FID, five inverse problems, and blind human inspection in an observer study. Flow matching was the strongest strategy overall, achieving the best inverse problem solving results at $28.80$~dB PSNR and $0.874$ SSIM averaged over the five forward problems, the highest rate of reconstructions judged real by blind human raters at $72.6\%$, and the closest per-structure match to real segmented anatomy in a permutation test. It was not best everywhere: rectified flow produced the most convincing unconditional samples in the observer study and the best FID, and the latent rectified-flow model achieved the smallest joint distributional distance to real anatomy. No other strategy, however, performed consistently well across all four evaluations. We therefore recommend flow matching as the default MedForj prior, while releasing every strategy so that the choice can be revisited per application. All model weights and corresponding code are publicly available at https://github.com/piksl-research/medforj.

Three-dimensional (3D) brain MRI is central to clinical neurology and neuro-oncology, where generative models could augment under-represented cohorts, simulate disease trajectories, and support privacy-preserving data sharing. Latent diffusion has been the go-to solution for modeling imaging data, but it places two competing demands on the tokenizer: encoder embeddings must retain the clinical information that downstream tasks act on, and the decoder must reconstruct anatomically faithful volumes. Existing reconstruction-driven tokenizers achieve the second at the expense of the first. To address this, we introduce a fully volumetric masked-autoencoder (MAE) based tokenizer for 3D brain MRI latent diffusion, decoupling encoder and decoder: a frozen 3D MAE encoder produces clinically informative embeddings, while a dedicated CNN decoder reconstructs voxels from a linear projection of those embeddings. We pretrain the encoder on 35,309 volumes from 18 public cohorts spanning four modalities, ten disease categories, and 200+ acquisition sites, and demonstrate its dual utility in two settings. First, on a 23-task linear-probing benchmark, the encoder outperforms or matches SOTA models (i.e., BrainIAC, BrainSegFounder, and MedicalNet) on 21 of 23 tasks. Second, a conditional diffusion transformer (DiT) trained on these clinically informative embeddings supports both conditional generation across six variables and patient-specific longitudinal forecasting. Together these results establish a single 3D brain-MRI embedding space capable of both downstream clinical tasks and controllable generation.