ProgFormer: Hierarchical Voxel Diffusion Transformer for Longitudinal Brain MRI Prediction
Authors: Dexuan Ding, Yuankai Qi, Luping Zhou, Jian Yang, Quan Z. Sheng, Ming-Hsuan Yang
Organizations: Macquarie University · University of Sydney · University of California Merced
Abstract
Predicting future structural MRI of a brain is challenging because longitudinal changes are often subtle and confined to specific anatomical regions, while most subject-specific brain structure remains stable over time. An effective model should therefore preserve global brain structural consistency while remaining sensitive to fine-grained disease progression. Existing latent-space-based methods improve computational efficiency, but suffer from information loss during their compression-reconstruction procedure. In contrast, direct voxel-space methods avoid latent reconstruction but commonly use a unified prediction pathway to model brain structure and progression-related changes. Subtle local changes may therefore be overshadowed by the dominant stable brain structure. To address these challenges, we propose ProgFormer, a hierarchical voxel-space Diffusion Transformer for longitudinal brain MRI prediction. ProgFormer uses a coarse pathway to perform the primary volumetric prediction from 3D patch tokens. This pathway models overall brain structure and longitudinal context. The fine pathway then uses the coarse representations as spatio-temporal grounding for voxel-level refinement within individual patches. The two pathways jointly estimate a velocity field directly in voxel space through conditional flow matching, enabling end-to-end prediction without a separately learned image autoencoder. The predicted future scan is then generated from Gaussian noise by integrating the estimated velocity field over a sequence of Euler steps. Extensive experimental results on three widely used benchmarks, ADNI, AIBL, and OASIS, under both pairwise and trajectory settings demonstrate favourable performance compared against several state-of-the-art methods.
Accurately modeling longitudinal brain MRI progression is crucial for understanding neurodegenerative diseases and predicting individualized structural changes. Existing state-of-the-art approaches, such as Brain Latent Progression (BrLP), often use multi-stage training pipelines with auxiliary conditioning modules but suffer from architectural complexity, suboptimal use of conditional clinical covariates, and limited guarantees of anatomical consistency. We propose Anatomically Guided Latent Diffusion Model (AG-LDM), a segmentation-guided framework that enforces anatomically consistent progression while substantially simplifying the training pipeline. AG-LDM conditions latent diffusion by directly fusing baseline anatomy, noisy follow-up states, and clinical covariates at the input level, a strategy that avoids auxiliary control networks by learning a unified, end-to-end model that represents both anatomy and progression. A lightweight 3D tissue segmentation model (WarpSeg) provides explicit anatomical supervision during both autoencoder fine-tuning and diffusion model training, ensuring consistent brain tissue boundaries and morphometric fidelity. Experiments on 31,713 ADNI longitudinal pairs and zero-shot evaluation on OASIS-3 demonstrate that AG-LDM matches or surpasses more complex diffusion models, achieving highly competitive image quality and 15-20% reduction in volumetric errors in generated images. AG-LDM also exhibits markedly stronger utilization of temporal and clinical covariates (3.5-31.5x higher covariate sensitivity than BrLP) and generates biologically plausible counterfactual trajectories, accurately capturing hallmarks of Alzheimer's progression such as limbic atrophy and ventricular expansion. These results highlight AG-LDM as an efficient, anatomically grounded framework for reliable brain MRI progression modeling.
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.
Forecasting the future anatomy of slow-evolving neurodegenerative diseases could enable earlier, more targeted intervention and improve clinical trial design, but it remains challenging because true progression signals are subtle in longitudinal MRI. In this low-signal regime, transferring modern generative sequence models directly is unreliable: training is dominated by stable baseline anatomy and confounded by dense, sample-specific nuisance variation. We first provide a theoretical analysis that explains these failures through two modes. Identity collapse occurs when optimization is driven toward reproducing the current anatomy, which prevents the model from learning faint temporal change. The continuous interpolation trap arises when standard smooth networks cannot separate localized biological drift from pervasive noise, which leads to spurious changes that diffuse across the volume. To address both issues, we propose Latent Drift, a progressive generative framework that learns change in a compressed semantic representation rather than synthesizing full-resolution anatomy. This design removes pixel-level identity from the prediction target and concentrates model capacity on progression-relevant dynamics. We further apply Finite Scalar Quantization to the learned change representation, which suppresses small, high-frequency nuisance fluctuations while preserving consistent structural drift. Experiments on longitudinal 3D brain MRI show that Latent Drift improves patient-specific neuro-forecasting over diffusion and autoregressive transformer baselines across generative fidelity and clinically relevant evaluation metrics. Project page: \href{https://cutepkq.github.io/latent-drift}{https://cutepkq.github.io/latent-drift}.