BrainNormalizer: Anatomy-Informed Pseudo-Healthy Brain Reconstruction from Tumor MRI via Edge-Guided ControlNet
Authors: Min Gu Kwak, Yeonju Lee, Hairong Wang, Kristin R. Swanson, Jing Li
Organizations: Department of Health and Rehabilitation Sciences, University of Pittsburgh, Pittsburgh, PA, USA · H. Milton Stewart School of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA,2026 USA · Operations Research and Industrial Engineering, Cockrell School of Engineering, University of Texas at Austin, Austin, TX, USAJul · MOSAIC Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA · Computational Biomedicine and Pathology/Lab Medicine, Department of Neurosurgery, Mayo Clinic Arizona, Phoenix, AZ, USA
Brain tumors induce complex structural deformations that obscure the patient' s original neuroanatomy, making it difficult to distinguish tumor-induced changes from inherent anatomical variability. Reconstructing a subject-specific pseudo-healthy brain can provide a critical reference for such analysis, but this task is inherently counterfactual, as paired pre-tumor scans and explicit healthy guidance are unavailable. We propose BrainNormalizer, a diffusion-based framework for subject-specific pseudo-healthy brain MRI reconstruction that enables anatomy-informed reconstruction without requiring paired data or explicit healthy references. The framework learns anatomical priors and edge-based structural conditioning through a two-stage training strategy consisting of inpainting-based diffusion fine-tuning and ControlNet-based edge conditioning. At inference, counterfactual pseudo-healthy reconstruction is achieved through a deliberate misalignment strategy, where tumorous inputs are paired with non-tumorous prompts and mirrored contralateral edge maps. This allows subject-specific anatomical guidance to be constructed from the patient's own anatomy, enabling anatomically consistent pseudo-healthy reconstruction that preserves individual structural characteristics. Experiments on the BraTS2020 dataset demonstrate that BrainNormalizer achieves improved distributional realism, symmetry-based structural consistency, and reduced false positive detection compared to existing methods. These results indicate that the proposed framework provides a principled approach for subject-specific counterfactual reconstruction and supports downstream analysis of tumor-induced deformation.
The ASNR-MICCAI BraTS Local Synthesis (Inpainting) task asks for the anatomically plausible completion of healthy brain tissue within a masked region of a T1-weighted MRI, providing a tumor-free anatomical reference for downstream analysis. As the task is scored by distortion metrics (SSIM, PSNR, MSE), we build a deterministic regression model and focus on giving it inductive biases tailored to inpainting. Our network follows the U-DiT principle of performing self-attention on a downsampled token grid: a volumetric encoder-decoder imports long-range context through a downsampled global self-attention block with three-dimensional rotary position embeddings, while convolutions and skip connections preserve high-frequency detail. Two ideas drive our results. First, we constrain the attention so that occluded ("void") tokens attend only to known-healthy tokens of the same volume, with a learned bias toward each query's contralateral homologue, forcing the completion to be inferred from observed anatomy rather than from other unknown regions. Second, we add a contralateral-symmetry input that supplies the mirrored healthy hemisphere as a patient-specific prior; since the brain is approximately bilaterally symmetric and lesions are typically unilateral, this prior improves the distortion metrics at matched structural similarity. On the official BraTS-2026 validation leaderboard our submission reaches a mean healthy-region SSIM of 0.864, PSNR of 24.7,dB and MSE of 4.6×10−3 over 219 cases. We further analyse the residual smoothness inherent to distortion-optimal regression and discuss its implications for anatomical realism.
Medical image inpainting has the potential to improve automated brain MRI analysis by reconstructing healthy tissue within pathological regions. We introduce RARF, a task-agnostic region-aware rectified flow framework for masked data generation. We instantiate the framework for 3D brain MRI inpainting as our submission to the BraTS Inpainting Challenge 2026. RARF restricts the stochastic interpolation process to the inpainting region, while the observed voxels remain fixed and provide patient-specific anatomical context. A three-dimensional neural network receives the partially voided image, with Gaussian noise filling the missing region, together with the inpainting mask and the corresponding timestep. The model is trained using masked flow-matching and reconstruction-consistency objectives, combined with mask-aware preprocessing and data augmentation. During inference, the learned velocity field transports the initial noise toward a plausible reconstruction of the missing tissue, which is then combined with the unchanged observed anatomy. Experiments under the BraTS evaluation protocol show that the proposed approach produces competitive reconstructions while maintaining anatomical consistency. Source code is available at: https://github.com/TomasGuija/rarf.
Tomas Guija-Valiente, Blanca Rodriguez-Gonzalez, Norberto Malpica +1
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.