A foundation for systematic analysis of transformers and RNNs for tractography

Diffusion MRI (dMRI) tractography is the only noninvasive approach for mapping white-matter pathways in the living human brain. It represents each brain as a tractogram: a large, unordered set of three-dimensional streamlines that includes information about both local streamline geometry and whole-brain anatomical organization. This structure makes tractograms a natural but challenging target for representation learning. Existing methods treat streamline classification and subject-level prediction as separate problems: streamline classifiers focus on geometric patterns, whereas subject-level prediction often depends on hand-crafted features. As a result, current methods do not learn reusable representations that connect streamline anatomy with whole-brain inter-subject variation. Here we introduce TractFM, a tractogram foundation model that learns reusable representations directly from whole-brain streamline sets. TractFM combines a local streamline encoder with a permutation-equivariant tractogram encoder, allowing all streamlines from a subject to be contextualized jointly in a single forward pass. Pretraining on dense anatomical tract parcellation, i.e., assigning anatomical labels to individual streamlines, yields two complementary representations: contextualized streamline-level embeddings for tract parcellation and compact subject-level descriptors for downstream prediction of subject phenotypes. Across three tractography algorithms and five dMRI datasets, TractFM transfers to both streamline-level and subject-level tasks. Its frozen representations achieve accurate tract parcellation and predict age and sex across independent datasets. These results show that whole-brain geometric context, learned once, can generalize across tractography pipelines, datasets, and prediction tasks.

Diffusion MRI (dMRI) tractography enables non-invasive reconstruction of white-matter pathways, but its accuracy is fundamentally limited by indirect, low-resolution measurements of axonal organization. Tracer injection studies in non-human primates provide a gold standard for validating dMRI tractography. This, however, requires time-consuming manual annotation of fiber bundles in histology sections. We propose a synthetic-data augmented framework for automated fiber bundle segmentation in macaque tracer histology. Our approach uses ex vivo dMRI tractography as a generative prior to synthesize 2D image patches for training. This provides us with sufficiently realistic foreground texture, which we compose with backgrounds from blockface photos and diversify via domain randomization. A 2D U-Net is trained on mixed real and synthetic patches. Experiments on held-out brains demonstrate improved generalization across brains and fiber bundle densities compared to training with real data only. Training with synthetic data only leads to poor performance, underscoring the need for real supervision. Overall, our approach achieves performance comparable to the state-of-the-art while requiring 3x less manually annotated data.

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.