Flow Matching with In-Context Priors for Out-of-Distribution Brain Dynamics
Authors: Sam Gijsen, Michał Łukomski, Marc-André Schulz, Kerstin Ritter
Organizations: Hertie Institute for AI in Brain Health, University of Tübingen, Germany · Tübingen AI Center, University of Tübingen, Germany · Charité – Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy, Germany · German Center for Mental Health (DZPG), partner site Tübingen, Germany
Flow matching and diffusion models enable conditional generation across domains ranging from images to proteins, with recent extensions to out-of-distribution contexts. Yet generative models of neural time series have largely remained restricted to categorical conditioning, precluding compositional and zero-shot generalization. In this work, we propose a per-timestep conditioned diffusion transformer for generating realistic fMRI brain dynamics during unseen cognitive tasks by injecting both compositional language and optional spatial priors in-context. Such zero-shot generation could enable counterfactual neuroscience by supporting in-silico design and evaluation of novel cognitive experiments before empirical validation. Leveraging this model, we evaluate across hundreds of held-out task conditions and characterize predictive performance in relation to the training manifold. From language alone, the model recovers region-specific recruitment across tasks and held-out spatial activation patterns. Spatial priors, when available, complement the text pathway by anchoring generation in regions of task space where language alone degrades, while retaining the compositional structure needed for counterfactual task specification. To our knowledge this is the first generative model of whole-cortex fMRI dynamics for unseen cognitive tasks, advancing counterfactual neuroscience and data-driven experimental design.
Whole-brain 4D fMRI generation is valuable for modeling functional brain dynamics, yet existing fMRI foundation models mainly target representation learning and downstream prediction rather than conditional predictive generation. We introduce BrainWorld, a structural-prior-conditioned generative model for whole-brain 4D fMRI dynamics. BrainWorld uses sMRI as subject-level anatomical context to guide future fMRI generation, integrating structural information into the denoising process rather than treating it as a parallel modality. Evaluated on 22 datasets spanning diverse cohorts and brain states, BrainWorld generates stable 4D fMRI trajectories up to 400 frames, improves downstream performance through generated-example augmentation, and learns transferable multimodal representations that outperform baselines. Together, these results establish BrainWorld as a condition-aware generative framework for long-horizon brain dynamics modeling and multimodal representation learning.
Task-based fMRI provides a direct readout of task-evoked neural dynamics, but it is expensive and difficult to acquire at scale, motivating rest-to-task synthesis from widely available resting-state fMRI (rsfMRI). We propose FM-fMRI, an event-conditioned flow-matching model that learns a continuous-time conditional vector field to generate task ROI time series from a subject's rsfMRI and the task event information. The formulation enables fast ODE-based sampling and flexible conditioning over heterogeneous event schedules. Rather than optimizing for pointwise reconstruction, we evaluated generated signals using complementary criteria that probe temporal and spectral structure, subject and group-level connectome consistency, and distributional alignment. On the public Human Connectome Project and internal BioPoint autism cohort, FM-fMRI achieves the strongest spectral and connectivity agreement and improved distribution-level matching over conditional diffusion, generative adversarial networks (GANs), and variational autoencoders (VAEs) baselines. Furthermore, we augment the BioPoint cohort by synthesizing task-fMRI ROI time series with our method, improving downstream autism classification and demonstrating practical utility in data-limited clinical settings. The code will be available on GitHub.
Current fMRI foundation models primarily rely on a limited range of brain states and mismatched pretraining tasks, restricting their ability to learn generalized representations across diverse brain states. We present Brain-DiT, a universal multi-state fMRI foundation model pretrained on 349,898 sessions from 24 datasets spanning resting, task, naturalistic, disease, and sleep states. Unlike prior fMRI foundation models that rely on masked reconstruction in the raw-signal space or a latent space, Brain-DiT adopts metadata-conditioned diffusion pretraining with a Diffusion Transformer (DiT), enabling the model to learn multi-scale representations that capture both fine-grained functional structure and global semantics. Across extensive evaluations and ablations on 7 downstream tasks, we find consistent evidence that diffusion-based generative pretraining is a stronger proxy than reconstruction or alignment, with metadata-conditioned pretraining further improving downstream performance by disentangling intrinsic neural dynamics from population-level variability. We also observe that downstream tasks exhibit distinct preferences for representational scale: ADNI classification benefits more from global semantic representations, whereas age/sex prediction comparatively relies more on fine-grained local structure.