BrainG3N: A Dual-Purpose Tokenizer for Controllable 3D Brain MRI Generation
Authors: Max Van Puyvelde, Ibrahim Gulluk, Wim Van Criekinge, Olivier Gevaert
Abstract
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.
High-fidelity 3D MRI synthesis requires both globally coherent anatomy and fine-grained voxel-level detail. Although latent diffusion makes volumetric generation tractable, its image autoencoder introduces a reconstruction bottleneck that can limit the fine detail recoverable in the final volume. We present VoxStruct3D, a voxel-space flow-matching framework that directly models full-resolution MRI volumes using a clean-data prediction objective. Its Volumetric Voxel Generator (VVG) combines factorized 3D patch embedding with overlapping upsampling, time-modulated residual refinement, and skip fusion, enabling neighboring tokens to jointly reconstruct shared voxel regions and suppress patch-boundary artifacts. To complement direct voxel-space modeling with an explicit anatomical prior, we further introduce a Structure-First, Image-Follows (SFIF) strategy. A frozen pretrained 3D medical encoder and a StructVAE extract compact structure tokens that preserve dominant anatomy, while a structure-leading schedule keeps their trajectory ahead of the image trajectory. Patch-Aligned RoPE spatially aligns the unequal token grids, and asymmetric attention enforces one-way guidance from structure to image. Experiments on pathological and healthy T1-weighted brain MRI datasets show that VoxStruct3D achieves the strongest overall performance across feature-distribution alignment, sample diversity, and perceptual quality, producing anatomically coherent and visually realistic volumes.
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.
Latent diffusion models now dominate medical image generation, and every such pipeline rests on a \emph{tokenizer} that compresses images into the latent codes for image generation to operate on. Thereby, the tokenizer choice bounds every downstream task from reconstruction fidelity and generation quality to the representations available for downstream analysis. Yet, medical imaging pipelines routinely utilize tokenizers from natural imaging on the hypothesis that their behavior carries over. However, this is an assumption never tested in the medical imaging regime, where datasets are orders of magnitude smaller and images exhibit far lower inter-sample variance. We present a systematic evaluation of medical image tokenizers evaluating thirty configurations across ten model families on twelve datasets at three compression factors, spanning reconstruction, generation, latent geometry, downstream classification, and memorization. We find that (1) performance on image reconstruction and generation strongly correlate, unlike prior reports on natural images; (2) modern tokenizers use nearly all of their codebook entries, but still leave most of the latent space unused; (3) training-set memorization is mild and is further suppressed by stronger latent space compression; and (4) discrete quantization can largely preserve downstream classification, with lookup-free schemes being the main exception.