Flow Matching-enabled Test-Time Refinement for Unsupervised Cardiac MR Registration

Quantitative cardiac magnetic resonance imaging (MRI) enables non-invasive myocardial tissue characterization but relies on robust motion correction within these variable-length, variable-contrast image sequences. Groupwise registration, which simultaneously aligns all images, has shown greater robustness than pairwise registration for motion correction. However, current deep-learning-based groupwise registration methods cannot generalize across MRI sequences: the architecture typically encodes input data as a fixed-length channel stack, which rigidly couples network design to protocol-specific sequence length, input ordering, and contrast dynamics. At inference time, any change in imaging protocols will render the network unusable. In this work, we introduce \AnyTwoReg, a new set-based groupwise registration framework that takes a quantitative MRI sequence as an unordered set. This set formulation fundamentally decouples network design from sequence length and input ordering. By utilizing a shared encoder and correlation-guided feature aggregation, \AnyTwoReg constructs a permutation-invariant canonical reference for registration, and learns a permutation-equivariant mapping from images to deformation fields. Additionally, we extract contrast-insensitive image features from an existing foundation model to handle extreme contrast variations. Trained exclusively on a single public $T_1$ mapping dataset (STONE, sequence length $L=11$), \AnyTwoReg generalizes to two unseen quantitative MRI datasets (MOLLI, ASL) with variable lengths ($L \in [11, 60]$) and different contrast dynamics. It achieves strong cross-protocol generalization in a zero-shot manner, and consistently improves downstream quantitative mapping quality. Notably, while designed for quantitative MRI sequences, our framework is directly applicable to Cine MRI sequences for inter-cardiac-phase registration.

Conventional image registration algorithms are robust to domain shifts and achieve low errors, but they are slow and computationally expensive. Deep-learning methods are efficient at inference-time, but face challenges in out-of-domain samples. We propose Recursive Uncertainty-Gated Image Registration (RUGI), an algorithm for iteratively refining deformation fields predicted by learning-based registration models. At each iteration, the registration model predicts an incremental deformation, and a gating map modulates the update. Refinements are hence concentrated in regions that remain difficult to register. We explore two gating strategies: a learned uncertainty-based approach and an image residual error approach. We evaluate RUGI on cardiac MRI and echocardiography datasets and show consistent improvements over single-step inference. Ablation experiments demonstrate that iterative refinement alone improves registration, but informative spatial gating provides a significant additional benefit. The error-gated variant of RUGI can also be applied directly to existing pretrained models; applied to VoxelMorph, TransMorph, and CycleMorph, it yields MSE reductions of 27-37% with no modification to the original training procedure. The improvements in registration performance are reflected in decreased errors in ejection fraction estimation relative to ground truths. These results demonstrate that spatially selective iterative refinement provides an effective strategy to improve registration accuracy at inference-time.

Cine cardiovascular magnetic resonance (CMR) captures the cardiac cycle as a four-dimensional (4D) sequence, but standard acquisition requires electrocardiogram (ECG) gating and repeated breath holds. Visual realism alone does not establish accurate patient-specific ejection fraction (EF) or ventricular volumes. We present PhaseFlow3D, a generative framework that synthesizes a complete 4D cine sequence from a single end-diastolic (ED) three-dimensional (3D) volume without ECG. To capture asymmetric systolic and diastolic dynamics, it represents the cardiac cycle as a piecewise linear phase anchored at ED and end-systolic (ES) time points. At inference, a population-level canonical template supplies this phase without patient-specific temporal information. A phase-conditioned rectified flow model generates a cardiac motion trajectory in latent space. Radial Contraction Decomposition converts each latent state into a 3D displacement field, combining a physics-informed radial component for centripetal myocardial contraction with an image-conditioned residual for rotation and out-of-plane motion. Each frame is generated by directly warping the ED volume, bypassing variational autoencoder decoding. On the combined ACDC and M&Ms benchmark, PhaseFlow3D achieves the lowest EF mean absolute error, the only positive left-ventricular volume-curve $R^2$, and the best distributional quality among compared methods. Ablations confirm each component's contribution. Downstream evaluations demonstrate the utility of the synthesized sequences and displacement fields for segmentation, pathology classification, label propagation, and myocardial strain analysis.