Latent Representation Learning from 3D Brain MRI for Latent Analysis and Prediction in Multiple Sclerosis

Learning a robust Variational Autoencoder (VAE) is a fundamental step for many deep learning applications in medical image analysis, such as MRI synthesizes. Existing brain VAEs predominantly focus on single-modality data (i.e., T1-weighted MRI), overlooking the complementary diagnostic value of other modalities like T2-weighted MRIs. Here, we propose a modality-aware and anatomically grounded 3D vector-quantized VAE (VQ-VAE) for reconstructing multi-modal brain MRIs. Called NeuroQuant, it first learns a shared latent representation across modalities using factorized multi-axis attention, which can capture relationships between distant brain regions. It then employs a dual-stream 3D encoder that explicitly separates the encoding of modality-invariant anatomical structures from modality-dependent appearance. Next, the anatomical encoding is discretized using a shared codebook and combined with modality-specific appearance features via Feature-wise Linear Modulation (FiLM) during the decoding phase. This entire approach is trained using a joint 2D/3D strategy in order to account for the slice-based acquisition of 3D MRI data. Extensive experiments on two multi-modal brain MRI datasets demonstrate that NeuroQuant achieves superior reconstruction fidelity compared to existing VAEs, enabling a scalable foundation for downstream generative modeling and cross-modal brain image analysis.

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.

Self-supervised learning (SSL) has advanced medical image analysis be enabling learning form large unlabelled data. However, in brain magnetic resonance imaging (MRI), most 3D models remain specialized for either segmentation of classification, limiting their ability to generalize across datasets, imaging protocols,, and downstream tasks. This lack of transferability constrains the clinical utility of 3D MRI models, despite the availability of unlabeled volumetric data. We present Volta-3D, a self-supervised 3D Vision Transformer framework designed to learn transferable volumetric representations. Volta-3D jointly aligns global class-style tokens and local patch tokens within a student-teacher paradigm and enforces fine-grained structural reconstruction. This combined global-local alignment addresses the limited semantic diversity and subtle anatomical characteristics of brain MRI, which challenges existing SSL approaches. We evaluate Volta-3D on multiple out-of-distribution downstream tasks, including hippocampal segmentation and classification of sex and Alzheimer's disease versus healthy controls. Across all tasks, representations learned by Volta-3D outperform randomly initialized baselines, demonstrating improved transferability and robustness under domain shift. Hence jointly enforcing global semantic consistency and local structural learning during pretraining enables broader concept learning from unlabeled brain MRI data. Overall VolTA-3D supports effective multi-task downstream performance with task-specific pertaining, a step towards generalizable and clinically viable 3D models.