Healthy tissue inpainting has significant applications, including the generation of pseudo-healthy baselines for tumor growth models and the facilitation of image registration. In previous editions of the BraTS Local Synthesis of Healthy Brain Tissue via Inpainting Challenge, denoising diffusion probabilistic models (DDPMs) demonstrated qualitatively convincing results but suffered from low sampling speed. To mitigate this limitation, we adapted a 2D image generation approach, combining DDPMs with generative adversarial networks (GANs) and employing a variance-preserving noise schedule, for the task of 3D inpainting. Our experiments showed that the variance-preserving noise schedule and the selected reconstruction losses can be effectively utilized for high-quality 3D inpainting in a few time steps without requiring adversarial training. We applied our findings to a different architecture, a 3D wavelet diffusion model (WDM3D) that does not include a GAN component. The resulting model, denoted as fastWDM3D, obtained a SSIM of 0.8571, a MSE of 0.0079, and a PSNR of 22.26 on the BraTS inpainting test set. Remarkably, it achieved these scores using only two time steps, completing the 3D inpainting process in 1.81 s per image. When compared to other DDPMs used for healthy brain tissue inpainting, our model is up to 800 x faster while still achieving superior performance metrics. Our proposed method, fastWDM3D, represents a promising approach for fast and accurate healthy tissue inpainting. Our code is available at https://github.com/AliciaDurrer/fastWDM3D.
Regularization is essential in deformable image registration (DIR) to ensure that the estimated Deformation Vector Field (DVF) remains smooth, physically plausible, and anatomically consistent. However, fine-tuning regularization parameters in learning-based DIR frameworks is computationally expensive, often requiring multiple training iterations. To address this, we propose cIDI, a novel DIR framework based on Implicit Neural Representations (INRs) that conditions the registration process on regularization hyperparameters. Unlike conventional methods that require retraining for each regularization hyperparameter setting, cIDIR is trained over a prior distribution of these hyperparameters, then optimized over the regularization hyperparameters by using the segmentations masks as an observation. Additionally, cIDIR models a continuous and differentiable DVF, enabling seamless integration of advanced regularization techniques via automatic differentiation. Evaluated on the DIR-LAB dataset, $\operatorname{cIDIR}$ achieves high accuracy and robustness across the dataset.
Foundation models, pre-trained on large image datasets and capable of capturing rich feature representations, have recently shown potential for zero-shot image registration. However, their performance has mostly been tested in the context of rigid or less complex structures, such as the brain or abdominal organs, and it remains unclear whether these models can handle more challenging, deformable anatomy. Breast MRI registration is particularly difficult due to significant anatomical variation between patients, deformation caused by patient positioning, and the presence of thin and complex internal structure of fibroglandular tissue, where accurate alignment is crucial. Whether foundation model-based registration algorithms can address this level of complexity remains an open question. In this study, we provide a comprehensive evaluation of foundation model-based registration algorithms for breast MRI. We assess five pre-trained encoders, including DINO-v2, SAM, MedSAM, SSLSAM, and MedCLIP, across four key breast registration tasks that capture variations in different years and dates, sequences, modalities, and patient disease status (lesion versus no lesion). Our results show that foundation model-based algorithms such as SAM outperform traditional registration baselines for overall breast alignment, especially under large domain shifts, but struggle with capturing fine details of fibroglandular tissue. Interestingly, additional pre-training or fine-tuning on medical or breast-specific images in MedSAM and SSLSAM, does not improve registration performance and may even decrease it in some cases. Further work is needed to understand how domain-specific training influences registration and to explore targeted strategies that improve both global alignment and fine structure accuracy. We also publicly release our code at \href{https://github.com/mazurowski-lab/Foundation-based-reg}{Github}.
Registering airborne SAR with spaceborne optical images is crucial for SAR image interpretation and geo-localization. It is challenging for this cross-platform heterogeneous image registration due to significant geometric and radiation differences, which current methods fail to handle. To tackle these challenges, we propose a novel grid-based multimodal registration framework (Grid-Reg) across airborne and space-born platforms, including a new domain-robust descriptor extraction network, Hybrid Siamese Correlation Metric Learning Network (HSCMLNet) and a grid-based solver (Grid-solver) for transformation parameters estimation. Our Grid-Reg is based on detector-free and global matching loss rather than accurate keypoint correspondences. These accurate correspondences are inherently difficult in heterogeneous images with large geometric deformation. By Grid-Solver, our Grid-Reg estimates transformation parameters by optimizing robust global matching loss-based patch correspondences of whole images in a coarse-to-fine strategy. To robustly calculate the similarity between patches, specifically that have noise and change objects, we propose HSCMLNet, including a hybrid Siamese module to extract high-level features of multimodal images and a correlation learning module (CMLModule) based equiangular unit basis vectors (EUBVs). Moreover, we propose a manifold loss EUBVsLoss to constrain the normalized correlation between local embeddings of patches and EUBVs. Furthermore, we curate a new challenging benchmark dataset of SAR-to-optical registration using real-world UAV MiniSAR data and optical images from Google Earth. We extensively analyze factors affecting registration accuracy and compare our method with state-of-the-art techniques on this dataset, showing superior performance.
Cardiac diseases are among the leading causes of morbidity and mortality worldwide, which requires accurate and timely diagnostic strategies. In this study, we introduce an innovative approach that combines deep learning image registration with physics-informed regularization to predict the biomechanical properties of moving cardiac tissues and extract features for disease classification. We utilize the energy strain formulation of Neo-Hookean material to model cardiac tissue deformations, optimizing the deformation field while ensuring its physical and biomechanical coherence. This explainable approach not only improves image registration accuracy, but also provides insights into the underlying biomechanical processes of the cardiac tissues. Evaluation on the Automated Cardiac Diagnosis Challenge (ACDC) dataset achieved Dice scores of 0.945 for the left ventricular cavity, 0.908 for the right ventricular cavity, and 0.905 for the myocardium. Subsequently, we estimate the local strains within the moving heart and extract a detailed set of features used for cardiovascular disease classification. We evaluated five classification algorithms, Logistic Regression, Multi-Layer Perceptron, Support Vector Classifier, Random Forest, and Nearest Neighbour, and identified the most relevant features using a feature selection algorithm. The best performing classifier obtained a classification accuracy of 98% in the training set and 100% in the test set of the ACDC dataset. By integrating explainable artificial intelligence, this method empowers clinicians with a transparent understanding of the model's predictions based on cardiac mechanics, while also significantly improving the accuracy and reliability of cardiac disease diagnosis, paving the way for more personalized and effective patient care.
Image registration is used in many medical image analysis applications, such as tracking the motion of tissue in cardiac images, where cardiac kinematics can be an indicator of tissue health. Registration is a challenging problem for deep learning algorithms because ground truth transformations are not feasible to create, and because there are potentially multiple transformations that can produce images that appear correlated with the goal. Unsupervised methods have been proposed to learn to predict effective transformations, but these methods take significantly longer to predict than established baseline methods. For a deep learning method to see adoption in wider research and clinical settings, it should be designed to run in a reasonable time on common, mid-level hardware. Fast methods have been proposed for the task of image registration but often use patch-based methods which can affect registration accuracy for a highly dynamic organ such as the heart. In this thesis, a fast, volumetric registration model is proposed for the use of quantifying cardiac strain. The proposed Deep Learning Neural Network (DLNN) is designed to utilize an architecture that can compute convolutions incredibly efficiently, allowing the model to achieve registration fidelity similar to other state-of-the-art models while taking a fraction of the time to perform inference. The proposed fast and lightweight registration (FLIR) model is used to predict tissue motion which is then used to quantify the non-uniform strain experienced by the tissue. For acquisitions taken from the same patient at approximately the same time, it would be expected that strain values measured between the acquisitions would have very small differences. Using this metric, strain values computed using the FLIR method are shown to be very consistent.
Effective representation of Regions of Interest (ROI) and independent alignment of these ROIs can significantly enhance the performance of deformable medical image registration (DMIR). However, current learning-based DMIR methods have limitations. Unsupervised techniques disregard ROI representation and proceed directly with aligning pairs of images, while weakly-supervised methods heavily depend on label constraints to facilitate registration. To address these issues, we introduce a novel ROI-based registration approach named EASR-DCN. Our method represents medical images through effective ROIs and achieves independent alignment of these ROIs without requiring labels. Specifically, we first used a Gaussian mixture model for intensity analysis to represent images using multiple effective ROIs with distinct intensities. Furthermore, we propose a novel Divide-and-Conquer Network (DCN) to process these ROIs through separate channels to learn feature alignments for each ROI. The resultant correspondences are seamlessly integrated to generate a comprehensive displacement vector field. Extensive experiments were performed on three MRI and one CT datasets to showcase the superior accuracy and deformation reduction efficacy of our EASR-DCN. Compared to VoxelMorph, our EASR-DCN achieved improvements of 10.31\% in the Dice score for brain MRI, 13.01\% for cardiac MRI, and 5.75\% for hippocampus MRI, highlighting its promising potential for clinical applications. The code for this work will be released upon acceptance of the paper.
Temporal modeling on regular respiration-induced motions is crucial to image-guided clinical applications. Existing methods cannot simulate temporal motions unless high-dose imaging scans including starting and ending frames exist simultaneously. However, in the preoperative data acquisition stage, the slight movement of patients may result in dynamic backgrounds between the first and last frames in a respiratory period. This additional deviation can hardly be removed by image registration, thus affecting the temporal modeling. To address that limitation, we pioneeringly simulate the regular motion process via the image-to-video (I2V) synthesis framework, which animates with the first frame to forecast future frames of a given length. Besides, to promote the temporal consistency of animated videos, we devise the Temporal Differential Diffusion Model to generate temporal differential fields, which measure the relative differential representations between adjacent frames. The prompt attention layer is devised for fine-grained differential fields, and the field augmented layer is adopted to better interact these fields with the I2V framework, promoting more accurate temporal variation of synthesized videos. Extensive results on ACDC cardiac and 4D Lung datasets reveal that our approach simulates 4D videos along the intrinsic motion trajectory, rivaling other competitive methods on perceptual similarity and temporal consistency. Codes will be available soon.
Recent developments in neural networks have improved deformable image registration (DIR) by amortizing iterative optimization, enabling fast and accurate DIR results. However, learning-based methods often face challenges with limited training data, large deformations, and tend to underperform compared to iterative approaches when label supervision is unavailable. While iterative methods can achieve higher accuracy in such scenarios, they are considerably slower than learning-based methods. To address these limitations, we propose VoxelOpt, a discrete optimization-based DIR framework that combines the strengths of learning-based and iterative methods to achieve a better balance between registration accuracy and runtime. VoxelOpt uses displacement entropy from local cost volumes to measure displacement signal strength at each voxel, which differs from earlier approaches in three key aspects. First, it introduces voxel-wise adaptive message passing, where voxels with lower entropy receives less influence from their neighbors. Second, it employs a multi-level image pyramid with 27-neighbor cost volumes at each level, avoiding exponential complexity growth. Third, it replaces hand-crafted features or contrastive learning with a pretrained foundational segmentation model for feature extraction. In abdominal CT registration, these changes allow VoxelOpt to outperform leading iterative in both efficiency and accuracy, while matching state-of-the-art learning-based methods trained with label supervision. The source code will be available at https://github.com/tinymilky/VoxelOpt
Computational modeling of the brain has become a key part of understanding how the brain clears metabolic waste, but patient-specific modeling on a significant scale is still out of reach with current methods. We introduce a novel approach for leveraging model order reduction techniques in computational models of brain geometries to alleviate computational costs involved in numerical simulations. Using image registration methods based on magnetic resonance imaging, we compute inter-brain mappings which allow previously computed solutions on other geometries to be mapped on to a new geometry. We investigate this approach on two example problems typical of modeling of glymphatic function, applied to a dataset of 101 MRI of human patients. We discuss the applicability of the method when applied to a patient with no known neurological disease, as well as a patient diagnosed with idiopathic Normal Pressure Hydrocephalus displaying significantly enlarged ventricles
Recent work has shown improved lesion detectability and flexibility to reconstruction hyperparameters (e.g. scanner geometry or dose level) when PET images are reconstructed by leveraging pre-trained diffusion models. Such methods train a diffusion model (without sinogram data) on high-quality, but still noisy, PET images. In this work, we propose a simple method for generating subject-specific PET images from a dataset of multi-subject PET-MR scans, synthesizing "pseudo-PET" images by transforming between different patients' anatomy using image registration. The images we synthesize retain information from the subject's MR scan, leading to higher resolution and the retention of anatomical features compared to the original set of PET images. With simulated and real [$^{18}$F]FDG datasets, we show that pre-training a personalized diffusion model with subject-specific "pseudo-PET" images improves reconstruction accuracy with low-count data. In particular, the method shows promise in combining information from a guidance MR scan without overly imposing anatomical features, demonstrating an improved trade-off between reconstructing PET-unique image features versus features present in both PET and MR. We believe this approach for generating and utilizing synthetic data has further applications to medical imaging tasks, particularly because patient-specific PET images can be generated without resorting to generative deep learning or large training datasets.
Magnetic resonance imaging of fetal and neonatal brains reveals rapid neurodevelopment marked by substantial anatomical changes unfolding within days. Studying this critical stage of the developing human brain, therefore, requires accurate brain models-referred to as atlases-of high spatial and temporal resolution. To meet these demands, established traditional atlases and recently proposed deep learning-based methods rely on large and comprehensive datasets. This poses a major challenge for studying brains in the presence of pathologies for which data remains scarce. We address this limitation with CINeMA (Conditional Implicit Neural Multi-Modal Atlas), a novel framework for creating high-resolution, spatio-temporal, multimodal brain atlases, suitable for low-data settings. Unlike established methods, CINeMA operates in latent space, avoiding compute-intensive image registration and reducing atlas construction times from days to minutes. Furthermore, it enables flexible conditioning on anatomical features including GA, birth age, and pathologies like ventriculomegaly (VM) and agenesis of the corpus callosum (ACC). CINeMA supports downstream tasks such as tissue segmentation and age prediction whereas its generative properties enable synthetic data creation and anatomically informed data augmentation. Surpassing state-of-the-art methods in accuracy, efficiency, and versatility, CINeMA represents a powerful tool for advancing brain research. We release the code and atlases at https://github.com/m-dannecker/CINeMA.
Learning-based deformable image registration (DIR) accelerates alignment by amortizing traditional optimization via neural networks. Label supervision further enhances accuracy, enabling efficient and precise nonlinear alignment of unseen scans. However, images with sparse features amid large smooth regions, such as retinal vessels, introduce aperture and large-displacement challenges that unsupervised DIR methods struggle to address. This limitation occurs because neural networks predict deformation fields in a single forward pass, leaving fields unconstrained post-training and shifting the regularization burden entirely to network weights. To address these issues, we introduce SmoothProper, a plug-and-play neural module enforcing smoothness and promoting message passing within the network's forward pass. By integrating a duality-based optimization layer with tailored interaction terms, SmoothProper efficiently propagates flow signals across spatial locations, enforces smoothness, and preserves structural consistency. It is model-agnostic, seamlessly integrates into existing registration frameworks with minimal parameter overhead, and eliminates regularizer hyperparameter tuning. Preliminary results on a retinal vessel dataset exhibiting aperture and large-displacement challenges demonstrate our method reduces registration error to 1.88 pixels on 2912x2912 images, marking the first unsupervised DIR approach to effectively address both challenges. The source code will be available at https://github.com/tinymilky/SmoothProper.
Many real-world settings require registration of a pair of medical images that differ in spatial resolution, which may arise from differences in image acquisition parameters like pixel spacing, slice thickness, and field-of-view. However, all previous machine learning-based registration techniques resample images onto a fixed resolution. This is suboptimal because resampling can introduce artifacts due to interpolation. To address this, we present RealKeyMorph (RKM), a resolution-agnostic method for image registration. RKM is an extension of KeyMorph, a registration framework which works by training a network to learn corresponding keypoints for a given pair of images, after which a closed-form keypoint matching step is used to derive the transformation that aligns them. To avoid resampling and enable operating on the raw data, RKM outputs keypoints in real-world coordinates of the scanner. To do this, we leverage the affine matrix produced by the scanner (e.g., MRI machine) that encodes the mapping from voxel coordinates to real world coordinates. By transforming keypoints into real-world space and integrating this into the training process, RKM effectively enables the extracted keypoints to be resolution-agnostic. In our experiments, we demonstrate the advantages of RKM on the registration task for orthogonal 2D stacks of abdominal MRIs, as well as 3D volumes with varying resolutions in brain datasets.
Deformable medical image registration is an essential task in computer-assisted interventions. This problem is particularly relevant to oncological treatments, where precise image alignment is necessary for tracking tumor growth, assessing treatment response, and ensuring accurate delivery of therapies. Recent AI methods can outperform traditional techniques in accuracy and speed, yet they often produce unreliable deformations that limit their clinical adoption. In this work, we address this challenge and introduce a novel implicit registration framework that can predict accurate and reliable deformations. Our insight is to reformulate image registration as a signal reconstruction problem: we learn a kernel function that can recover the dense displacement field from sparse keypoint correspondences. We integrate our method in a novel hierarchical architecture, and estimate the displacement field in a coarse-to-fine manner. Our formulation also allows for efficient refinement at test time, permitting clinicians to easily adjust registrations when needed. We validate our method on challenging intra-patient thoracic and abdominal zero-shot registration tasks, using public and internal datasets from the local University Hospital. Our method not only shows competitive accuracy to state-of-the-art approaches, but also bridges the generalization gap between implicit and explicit registration techniques. In particular, our method generates deformations that better preserve anatomical relationships and matches the performance of specialized commercial systems, underscoring its potential for clinical adoption.
Magnetic resonance imaging (MRI) exhibits rich and clinically useful endogenous contrast mechanisms, which can differentiate soft tissues and are sensitive to flow, diffusion, magnetic susceptibility, blood oxygenation level, and more. However, MRI sensitivity is ultimately constrained by Nuclear Magnetic Resonance (NMR) physics, and its spatiotemporal resolution is limited by SNR and spatial encoding. On the other hand, miniaturized implantable sensors offer highly localized physiological information, yet communication and localization can be challenging when multiple implants are present. This paper introduces the MRDust, an active ``contrast agent" that integrates active sensor implants with MRI, enabling the direct encoding of highly localized physiological data into MR images to augment the anatomical images. MRDust employs a micrometer-scale on-chip coil to actively modulate the local magnetic field, enabling MR signal amplitude and phase modulation for digital data transmission. Since MRI inherently captures the anatomical tissue structure, this method has the potential to enable simultaneous data communication, localization, and image registration with multiple implants. This paper presents the underlying physical principles, design tradeoffs, and design methodology for this approach. To validate the concept, a 900 $\times$ 990 $\mu$m$^2$ chip was designed using TSMC 28 nm technology, with an on-chip coil measuring 630 $\mu$m in diameter. The chip was tested with custom hardware in an MR750W GE3T MRI scanner. Successful voxel amplitude modulation is demonstrated with Spin-Echo Echo-Planar-Imaging (SE-EPI) sequence, achieving a contrast-to-noise ratio (CNR) of 25.58 with a power consumption of 130 $\mu$W.
Percutaneous Coronary Intervention (PCI) is a minimally invasive procedure that improves coronary blood flow and treats coronary artery disease. Although PCI typically requires 2D X-ray angiography (XRA) to guide catheter placement at real-time, computed tomography angiography (CTA) may substantially improve PCI by providing precise information of 3D vascular anatomy and status. To leverage real-time XRA and detailed 3D CTA anatomy for PCI, accurate multimodal image registration of XRA and CTA is required, to guide the procedure and avoid complications. This is a challenging process as it requires registration of images from different geometrical modalities (2D -> 3D and vice versa), with variations in contrast and noise levels. In this paper, we propose a novel multimodal coronary artery image registration method based on a swarm optimization algorithm, which effectively addresses challenges such as large deformations, low contrast, and noise across these imaging modalities. Our algorithm consists of two main modules: 1) preprocessing of XRA and CTA images separately, and 2) a registration module based on feature extraction using the Steger and Superpixel Particle Swarm Optimization algorithms. Our technique was evaluated on a pilot dataset of 28 pairs of XRA and CTA images from 10 patients who underwent PCI. The algorithm was compared with four state-of-the-art (SOTA) methods in terms of registration accuracy, robustness, and efficiency. Our method outperformed the selected SOTA baselines in all aspects. Experimental results demonstrate the significant effectiveness of our algorithm, surpassing the previous benchmarks and proposes a novel clinical approach that can potentially have merit for improving patient outcomes in coronary artery disease.
Recent advances in deep learning-based medical image registration have shown that training deep neural networks~(DNNs) does not necessarily require medical images. Previous work showed that DNNs trained on randomly generated images with carefully designed noise and contrast properties can still generalize well to unseen medical data. Building on this insight, we propose using registration between random images as a proxy task for pretraining a foundation model for image registration. Empirical results show that our pretraining strategy improves registration accuracy, reduces the amount of domain-specific data needed to achieve competitive performance, and accelerates convergence during downstream training, thereby enhancing computational efficiency.
Medical image challenges have played a transformative role in advancing the field, catalyzing algorithmic innovation and establishing new performance standards across diverse clinical applications. Image registration, a foundational task in neuroimaging pipelines, has similarly benefited from the Learn2Reg initiative. Building on this foundation, we introduce the Large-scale Unsupervised Brain MRI Image Registration (LUMIR) challenge, a next-generation benchmark designed to assess and advance unsupervised brain MRI registration. Distinct from prior challenges that leveraged anatomical label maps for supervision, LUMIR removes this dependency by providing over 4,000 preprocessed T1-weighted brain MRIs for training without any label maps, encouraging biologically plausible deformation modeling through self-supervision. In addition to evaluating performance on 590 held-out test subjects, LUMIR introduces a rigorous suite of zero-shot generalization tasks, spanning out-of-domain imaging modalities (e.g., FLAIR, T2-weighted, T2*-weighted), disease populations (e.g., Alzheimer's disease), acquisition protocols (e.g., 9.4T MRI), and species (e.g., macaque brains). A total of 1,158 subjects and over 4,000 image pairs were included for evaluation. Performance was assessed using both segmentation-based metrics (Dice coefficient, 95th percentile Hausdorff distance) and landmark-based registration accuracy (target registration error). Across both in-domain and zero-shot tasks, deep learning-based methods consistently achieved state-of-the-art accuracy while producing anatomically plausible deformation fields. The top-performing deep learning-based models demonstrated diffeomorphic properties and inverse consistency, outperforming several leading optimization-based methods, and showing strong robustness to most domain shifts, the exception being a drop in performance on out-of-domain contrasts.
The principle of translation equivariance (if an input image is translated an output image should be translated by the same amount), led to the development of convolutional neural networks that revolutionized machine vision. Other symmetries, like rotations and reflections, play a similarly critical role, especially in biomedical image analysis, but exploiting these symmetries has not seen wide adoption. We hypothesize that this is partially due to the mathematical complexity of methods used to exploit these symmetries, which often rely on representation theory, a bespoke concept in differential geometry and group theory. In this work, we show that the same equivariance can be achieved using a simple form of convolution kernels that we call ``moment kernels,'' and prove that all equivariant kernels must take this form. These are a set of radially symmetric functions of a spatial position $x$, multiplied by powers of the components of $x$ or the identity matrix. We implement equivariant neural networks using standard convolution modules, and provide architectures to execute several biomedical image analysis tasks that depend on equivariance principles: classification (outputs are invariant under orthogonal transforms), 3D image registration (outputs transform like a vector), and cell segmentation (quadratic forms defining ellipses transform like a matrix).