Juan Eugenio Iglesias

Sean I. Young, Yaël Balbastre, Adrian V. Dalca et al. · harvard

In recent years, learning-based image registration methods have gradually moved away from direct supervision with target warps to instead use self-supervision, with excellent results in several registration benchmarks. These approaches utilize a loss function that penalizes the intensity differences between the fixed and moving images, along with a suitable regularizer on the deformation. In this paper, we argue that the relative failure of supervised registration approaches can in part be blamed on the use of regular U-Nets, which are jointly tasked with feature extraction, feature matching, and estimation of deformation. We introduce one simple but crucial modification to the U-Net that disentangles feature extraction and matching from deformation prediction, allowing the U-Net to warp the features, across levels, as the deformation field is evolved. With this modification, direct supervision using target warps begins to outperform self-supervision approaches that require segmentations, presenting new directions for registration when images do not have segmentations. We hope that our findings in this preliminary workshop paper will re-ignite research interest in supervised image registration techniques. Our code is publicly available from https://github.com/balbasty/superwarp.

Junshen Xu, Daniel Moyer, P. Ellen Grant et al. · mit

Volumetric reconstruction of fetal brains from multiple stacks of MR slices, acquired in the presence of almost unpredictable and often severe subject motion, is a challenging task that is highly sensitive to the initialization of slice-to-volume transformations. We propose a novel slice-to-volume registration method using Transformers trained on synthetically transformed data, which model multiple stacks of MR slices as a sequence. With the attention mechanism, our model automatically detects the relevance between slices and predicts the transformation of one slice using information from other slices. We also estimate the underlying 3D volume to assist slice-to-volume registration and update the volume and transformations alternately to improve accuracy. Results on synthetic data show that our method achieves lower registration error and better reconstruction quality compared with existing state-of-the-art methods. Experiments with real-world MRI data are also performed to demonstrate the ability of the proposed model to improve the quality of 3D reconstruction under severe fetal motion.

Anahita Fathi Kazerooni, Nastaran Khalili, Xinyang Liu et al.

Pediatric central nervous system tumors are the leading cause of cancer-related deaths in children. The five-year survival rate for high-grade glioma in children is less than 20%. The development of new treatments is dependent upon multi-institutional collaborative clinical trials requiring reproducible and accurate centralized response assessment. We present the results of the BraTS-PEDs 2023 challenge, the first Brain Tumor Segmentation (BraTS) challenge focused on pediatric brain tumors. This challenge utilized data acquired from multiple international consortia dedicated to pediatric neuro-oncology and clinical trials. BraTS-PEDs 2023 aimed to evaluate volumetric segmentation algorithms for pediatric brain gliomas from magnetic resonance imaging using standardized quantitative performance evaluation metrics employed across the BraTS 2023 challenges. The top-performing AI approaches for pediatric tumor analysis included ensembles of nnU-Net and Swin UNETR, Auto3DSeg, or nnU-Net with a self-supervised framework. The BraTSPEDs 2023 challenge fostered collaboration between clinicians (neuro-oncologists, neuroradiologists) and AI/imaging scientists, promoting faster data sharing and the development of automated volumetric analysis techniques. These advancements could significantly benefit clinical trials and improve the care of children with brain tumors.

Matthew G. French, Gonzalo D. Maso Talou, Thiranja P. Babarenda Gamage et al. · harvard

In breast surgical planning, accurate registration of MR images across patient positions has the potential to improve the localisation of tumours during breast cancer treatment. While learning-based registration methods have recently become the state-of-the-art approach for most medical image registration tasks, these methods have yet to make inroads into breast image registration due to certain difficulties-the lack of rich texture information in breast MR images and the need for the deformations to be diffeomophic. In this work, we propose learning strategies for breast MR image registration that are amenable to diffeomorphic constraints, together with early experimental results from in-silico and in-vivo experiments. One key contribution of this work is a registration network which produces superior registration outcomes for breast images in addition to providing diffeomorphic guarantees.

Hongwei Bran Li, Chinmay Prabhakar, Suprosanna Shit et al.

Quantifying the perceptual similarity of two images is a long-standing problem in low-level computer vision. The natural image domain commonly relies on supervised learning, e.g., a pre-trained VGG, to obtain a latent representation. However, due to domain shift, pre-trained models from the natural image domain might not apply to other image domains, such as medical imaging. Notably, in medical imaging, evaluating the perceptual similarity is exclusively performed by specialists trained extensively in diverse medical fields. Thus, medical imaging remains devoid of task-specific, objective perceptual measures. This work answers the question: Is it necessary to rely on supervised learning to obtain an effective representation that could measure perceptual similarity, or is self-supervision sufficient? To understand whether recent contrastive self-supervised representation (CSR) may come to the rescue, we start with natural images and systematically evaluate CSR as a metric across numerous contemporary architectures and tasks and compare them with existing methods. We find that in the natural image domain, CSR behaves on par with the supervised one on several perceptual tests as a metric, and in the medical domain, CSR better quantifies perceptual similarity concerning the experts' ratings. We also demonstrate that CSR can significantly improve image quality in two image synthesis tasks. Finally, our extensive results suggest that perceptuality is an emergent property of CSR, which can be adapted to many image domains without requiring annotations.

Hannah Spitzer, Mathilde Ripart, Abdulah Fawaz et al.

Focal cortical dysplasia (FCD) is a leading cause of drug-resistant focal epilepsy, which can be cured by surgery. These lesions are extremely subtle and often missed even by expert neuroradiologists. "Ground truth" manual lesion masks are therefore expensive, limited and have large inter-rater variability. Existing FCD detection methods are limited by high numbers of false positive predictions, primarily due to vertex- or patch-based approaches that lack whole-brain context. Here, we propose to approach the problem as semantic segmentation using graph convolutional networks (GCN), which allows our model to learn spatial relationships between brain regions. To address the specific challenges of FCD identification, our proposed model includes an auxiliary loss to predict distance from the lesion to reduce false positives and a weak supervision classification loss to facilitate learning from uncertain lesion masks. On a multi-centre dataset of 1015 participants with surface-based features and manual lesion masks from structural MRI data, the proposed GCN achieved an AUC of 0.74, a significant improvement against a previously used vertex-wise multi-layer perceptron (MLP) classifier (AUC 0.64). With sensitivity thresholded at 67%, the GCN had a specificity of 71% in comparison to 49% when using the MLP. This improvement in specificity is vital for clinical integration of lesion-detection tools into the radiological workflow, through increasing clinical confidence in the use of AI radiological adjuncts and reducing the number of areas requiring expert review.

Asbjørn Munk, Stefano Cerri, Vardan Nersesjan et al.

Clinical deployment of automated brain MRI analysis faces a fundamental challenge: clinical data is heterogeneous and noisy, and high-quality labels are prohibitively costly to obtain. Self-supervised learning (SSL) can address this by leveraging the vast amounts of unlabeled data produced in clinical workflows to train robust \textit{foundation models} that adapt out-of-domain with minimal supervision. However, the development of foundation models for brain MRI has been limited by small pretraining datasets and in-domain benchmarking focused on high-quality, research-grade data. To address this gap, we organized the FOMO25 challenge as a satellite event at MICCAI 2025. FOMO25 provided participants with a large pretraining dataset, FOMO60K, and evaluated models on data sourced directly from clinical workflows in few-shot and out-of-domain settings. Tasks covered infarct classification, meningioma segmentation, and brain age regression, and considered both models trained on FOMO60K (method track) and any data (open track). Nineteen foundation models from sixteen teams were evaluated using a standardized containerized pipeline. Results show that (a) self-supervised pretraining improves generalization on clinical data under domain shift, with the strongest models trained \textit{out-of-domain} surpassing supervised baselines trained \textit{in-domain}. (b) No single pretraining objective benefits all tasks: MAE favors segmentation, hybrid reconstruction-contrastive objectives favor classification, and (c) strong performance was achieved by small pretrained models, and improvements from scaling model size and training duration did not yield reliable benefits.

Karthik Gopinath, Douglas N. Greve, Colin Magdamo et al.

Surface-based analysis of the cerebral cortex is ubiquitous in human neuroimaging with MRI. It is crucial for cortical registration, parcellation, and thickness estimation. Traditionally, these analyses require high-resolution, isotropic scans with good gray-white matter contrast, typically a 1mm T1-weighted scan. This excludes most clinical MRI scans, which are often anisotropic and lack the necessary T1 contrast. To enable large-scale neuroimaging studies using vast clinical data, we introduce recon-all-clinical, a novel method for cortical reconstruction, registration, parcellation, and thickness estimation in brain MRI scans of any resolution and contrast. Our approach employs a hybrid analysis method that combines a convolutional neural network (CNN) trained with domain randomization to predict signed distance functions (SDFs) and classical geometry processing for accurate surface placement while maintaining topological and geometric constraints. The method does not require retraining for different acquisitions, thus simplifying the analysis of heterogeneous clinical datasets. We tested recon-all-clinical on multiple datasets, including over 19,000 clinical scans. The method consistently produced precise cortical reconstructions and high parcellation accuracy across varied MRI contrasts and resolutions. Cortical thickness estimates are precise enough to capture aging effects independently of MRI contrast, although accuracy varies with slice thickness. Our method is publicly available at https://surfer.nmr.mgh.harvard.edu/fswiki/recon-all-clinical, enabling researchers to perform detailed cortical analysis on the huge amounts of already existing clinical MRI scans. This advancement may be particularly valuable for studying rare diseases and underrepresented populations where research-grade MRI data is scarce.

Sean I. Young, Yaël Balbastre, Bruce Fischl et al. · harvard

In magnetic resonance imaging (MRI), slice-to-volume reconstruction (SVR) refers to computational reconstruction of an unknown 3D magnetic resonance volume from stacks of 2D slices corrupted by motion. While promising, current SVR methods require multiple slice stacks for accurate 3D reconstruction, leading to long scans and limiting their use in time-sensitive applications such as fetal fMRI. Here, we propose a SVR method that overcomes the shortcomings of previous work and produces state-of-the-art reconstructions in the presence of extreme inter-slice motion. Inspired by the recent success of single-view depth estimation methods, we formulate SVR as a single-stack motion estimation task and train a fully convolutional network to predict a motion stack for a given slice stack, producing a 3D reconstruction as a byproduct of the predicted motion. Extensive experiments on the SVR of adult and fetal brains demonstrate that our fully convolutional method is twice as accurate as previous SVR methods. Our code is available at github.com/seannz/svr.

Florian Kofler, Marcel Rosier, Mehdi Astaraki et al.

The Brain Tumor Segmentation (BraTS) cluster of challenges has significantly advanced brain tumor image analysis by providing large, curated datasets and addressing clinically relevant tasks. However, despite its success and popularity, algorithms and models developed through BraTS have seen limited adoption in both scientific and clinical communities. To accelerate their dissemination, we introduce BraTS orchestrator, an open-source Python package that provides seamless access to state-of-the-art segmentation and synthesis algorithms for diverse brain tumors from the BraTS challenge ecosystem. Available on GitHub (https://github.com/BrainLesion/BraTS), the package features intuitive tutorials designed for users with minimal programming experience, enabling both researchers and clinicians to easily deploy winning BraTS algorithms for inference. By abstracting the complexities of modern deep learning, BraTS orchestrator democratizes access to the specialized knowledge developed within the BraTS community, making these advances readily available to broader neuro-radiology and neuro-oncology audiences.

Xiaoling Hu, Karthik Gopinath, Peirong Liu et al.

Over recent years, deep learning based image registration has achieved impressive accuracy in many domains, including medical imaging and, specifically, human neuroimaging with magnetic resonance imaging (MRI). However, the uncertainty estimation associated with these methods has been largely limited to the application of generic techniques (e.g., Monte Carlo dropout) that do not exploit the peculiarities of the problem domain, particularly spatial modeling. Here, we propose a principled way to propagate uncertainties (epistemic or aleatoric) estimated at the level of spatial location by these methods, to the level of global transformation models, and further to downstream tasks. Specifically, we justify the choice of a Gaussian distribution for the local uncertainty modeling, and then propose a framework where uncertainties spread across hierarchical levels, depending on the choice of transformation model. Experiments on publicly available data sets show that Monte Carlo dropout correlates very poorly with the reference registration error, whereas our uncertainty estimates correlate much better. Crucially, the results also show that uncertainty-aware fitting of transformations improves the registration accuracy of brain MRI scans. Finally, we illustrate how sampling from the posterior distribution of the transformations can be used to propagate uncertainties to downstream neuroimaging tasks. Code is available at: https://github.com/HuXiaoling/Regre4Regis.

Chiara Mauri, Ryan Fritz, Jocelyn Mora et al.

The claustrum is a band-like gray matter structure located between putamen and insula whose exact functions are still actively researched. Its sheet-like structure makes it barely visible in in vivo Magnetic Resonance Imaging (MRI) scans at typical resolutions and neuroimaging tools for its study, including methods for automatic segmentation, are currently very limited. In this paper, we propose a contrast- and resolution-agnostic method for claustrum segmentation at ultra-high resolution (0.35 mm isotropic); the method is based on the SynthSeg segmentation framework (Billot et al., 2023), which leverages the use of synthetic training intensity images to achieve excellent generalization. In particular, SynthSeg requires only label maps to be trained, since corresponding intensity images are synthesized on the fly with random contrast and resolution. We trained a deep learning network for automatic claustrum segmentation, using claustrum manual labels obtained from 18 ultra-high resolution MRI scans (mostly ex vivo). We demonstrated the method to work on these 18 high resolution cases (Dice score = 0.632, mean surface distance = 0.458 mm, and volumetric similarity = 0.867 using 6-fold Cross Validation (CV)), and also on in vivo T1-weighted MRI scans at typical resolutions (~1 mm isotropic). We also demonstrated that the method is robust in a test-retest setting and when applied to multimodal imaging (T2-weighted, Proton Density and quantitative T1 scans). To the best of our knowledge this is the first accurate method for automatic ultra-high resolution claustrum segmentation, which is robust against changes in contrast and resolution. The method is released at https://github.com/chiara-mauri/claustrum_segmentation and as part of the neuroimaging package Freesurfer (Fischl, 2012).

Livia Rodrigues, Martina Bocchetta, Oula Puonti et al.

The hypothalamus is a small structure located in the center of the brain and is involved in significant functions such as sleeping, temperature, and appetite control. Various neurological disorders are also associated with hypothalamic abnormalities. Automated image analysis of this structure from brain MRI is thus highly desirable to study the hypothalamus in vivo. However, most automated segmentation tools currently available focus exclusively on T1w images. In this study, we introduce H-SynEx, a machine learning method for automated segmentation of hypothalamic subregions that generalizes across different MRI sequences and resolutions without retraining. H-synEx was trained with synthetic images built from label maps derived from ultra-high resolution ex vivo MRI scans, which enables finer-grained manual segmentation when compared with 1mm isometric in vivo images. We validated our method using Dice Coefficient (DSC) and Average Hausdorff distance (AVD) across in vivo images from six different datasets with six different MRI sequences (T1, T2, proton density, quantitative T1, fractional anisotrophy, and FLAIR). Statistical analysis compared hypothalamic subregion volumes in controls, Alzheimer's disease (AD), and behavioral variant frontotemporal dementia (bvFTD) subjects using the Area Under the Receiving Operating Characteristic curve (AUROC) and Wilcoxon rank sum test. Our results show that H-SynEx successfully leverages information from ultra-high resolution scans to segment in vivo from different MRI sequences. Our automated segmentation was able to discriminate controls versus Alzheimer's Disease patients on FLAIR images with 5mm spacing. H-SynEx is openly available at https://github.com/liviamarodrigues/hsynex.

Karthik Gopinath, Annabel Sorby-Adams, Jonathan W. Ramirez et al.

Three-dimensional reconstruction of cortical surfaces from MRI for morphometric analysis is fundamental for understanding brain structure. While high-field MRI (HF-MRI) is standard in research and clinical settings, its limited availability hinders widespread use. Low-field MRI (LF-MRI), particularly portable systems, offers a cost-effective and accessible alternative. However, existing cortical surface analysis tools are optimized for high-resolution HF-MRI and struggle with the lower signal-to-noise ratio and resolution of LF-MRI. In this work, we present a machine learning method for 3D reconstruction and analysis of portable LF-MRI across a range of contrasts and resolutions. Our method works "out of the box" without retraining. It uses a 3D U-Net trained on synthetic LF-MRI to predict signed distance functions of cortical surfaces, followed by geometric processing to ensure topological accuracy. We evaluate our method using paired HF/LF-MRI scans of the same subjects, showing that LF-MRI surface reconstruction accuracy depends on acquisition parameters, including contrast type (T1 vs T2), orientation (axial vs isotropic), and resolution. A 3mm isotropic T2-weighted scan acquired in under 4 minutes, yields strong agreement with HF-derived surfaces: surface area correlates at r=0.96, cortical parcellations reach Dice=0.98, and gray matter volume achieves r=0.93. Cortical thickness remains more challenging with correlations up to r=0.70, reflecting the difficulty of sub-mm precision with 3mm voxels. We further validate our method on challenging postmortem LF-MRI, demonstrating its robustness. Our method represents a step toward enabling cortical surface analysis on portable LF-MRI. Code is available at https://surfer.nmr.mgh.harvard.edu/fswiki/ReconAny

Lin Tian, Sean I. Young, Jonathan Williams Ramirez et al. · harvard

Correlation of neuropathology with MRI has the potential to transfer microscopic signatures of pathology to invivo scans. Recently, a classical registration method has been proposed, to build these correlations from 3D reconstructed stacks of dissection photographs, which are routinely taken at brain banks. These photographs bypass the need for exvivo MRI, which is not widely accessible. However, this method requires a full stack of brain slabs and a reference mask (e.g., acquired with a surface scanner), which severely limits the applicability of the technique. Here we propose RefFree, a dissection photograph reconstruction method without external reference. RefFree is a learning approach that estimates the 3D coordinates in the atlas space for every pixel in every photograph; simple least-squares fitting can then be used to compute the 3D reconstruction. As a by-product, RefFree also produces an atlas-based segmentation of the reconstructed stack. RefFree is trained on synthetic photographs generated from digitally sliced 3D MRI data, with randomized appearance for enhanced generalization ability. Experiments on simulated and real data show that RefFree achieves performance comparable to the baseline method without an explicit reference while also enabling reconstruction of partial stacks. Our code is available at https://github.com/lintian-a/reffree.

Xiaoling Hu, Xiangrui Zeng, Oula Puonti et al. · harvard

Domain randomization through synthesis is a powerful strategy to train networks that are unbiased with respect to the domain of the input images. Randomization allows networks to see a virtually infinite range of intensities and artifacts during training, thereby minimizing overfitting to appearance and maximizing generalization to unseen data. Although powerful, this approach relies on the accurate tuning of a large set of hyperparameters that govern the probabilistic distribution of the synthesized images. Instead of manually tuning these parameters, we introduce Learn2Synth, a novel procedure in which synthesis parameters are learned using a small set of real labeled data. Unlike methods that impose constraints to align synthetic data with real data (e.g., contrastive or adversarial techniques), which risk misaligning the image and its label map, we tune an augmentation engine such that a segmentation network trained on synthetic data has optimal accuracy when applied to real data. This approach allows the training procedure to benefit from real labeled examples, without ever using these real examples to train the segmentation network, which avoids biasing the network towards the properties of the training set. Specifically, we develop parametric and nonparametric strategies to enhance synthetic images in a way that improves the performance of the segmentation network. We demonstrate the effectiveness of this learning strategy on synthetic and real-world brain scans. Code is available at: https://github.com/HuXiaoling/Learn2Synth.

Hongwei Bran Li, Matthew S. Rosen, Shahin Nasr et al.

High-resolution fMRI provides a window into the brain's mesoscale organization. Yet, higher spatial resolution increases scan times, to compensate for the low signal and contrast-to-noise ratio. This work introduces a deep learning-based 3D super-resolution (SR) method for fMRI. By incorporating a resolution-agnostic image augmentation framework, our method adapts to varying voxel sizes without retraining. We apply this innovative technique to localize fine-scale motion-selective sites in the early visual areas. Detection of these sites typically requires a resolution higher than 1 mm isotropic, whereas here, we visualize them based on lower resolution (2-3mm isotropic) fMRI data. Remarkably, the super-resolved fMRI is able to recover high-frequency detail of the interdigitated organization of these sites (relative to the color-selective sites), even with training data sourced from different subjects and experimental paradigms -- including non-visual resting-state fMRI, underscoring its robustness and versatility. Quantitative and qualitative results indicate that our method has the potential to enhance the spatial resolution of fMRI, leading to a drastic reduction in acquisition time.

Mark D. Olchanyi, Annabel Sorby-Adams, John Kirsch et al.

Portable, ultra-low-field (ULF) magnetic resonance imaging has the potential to expand access to neuroimaging but currently suffers from coarse spatial and angular resolutions and low signal-to-noise ratios. Diffusion tensor imaging (DTI), a sequence tailored to detect and reconstruct white matter tracts within the brain, is particularly prone to such imaging degradation due to inherent sequence design coupled with prolonged scan times. In addition, ULF DTI scans exhibit artifacting that spans both the space and angular domains, requiring a custom modelling algorithm for subsequent correction. We introduce a nine-direction, single-shell ULF DTI sequence, as well as a companion Bayesian bias field correction algorithm that possesses angular dependence and convolutional neural network-based superresolution algorithm that is generalizable across DTI datasets and does not require re-training (''DiffSR''). We show through a synthetic downsampling experiment and white matter assessment in real, matched ULF and high-field DTI scans that these algorithms can recover microstructural and volumetric white matter information at ULF. We also show that DiffSR can be directly applied to white matter-based Alzheimers disease classification in synthetically degraded scans, with notable improvements in agreement between DTI metrics, as compared to un-degraded scans. We freely disseminate the Bayesian bias correction algorithm and DiffSR with the goal of furthering progress on both ULF reconstruction methods and general DTI sequence harmonization. We release all code related to DiffSR for $\href{https://github.com/markolchanyi/DiffSR}{public \space use}$.

Jesper Duemose Nielsen, Karthik Gopinath, Andrew Hoopes et al.

Surface-based cortical analysis is valuable for a variety of neuroimaging tasks, such as spatial normalization, parcellation, and gray matter (GM) thickness estimation. However, most tools for estimating cortical surfaces work exclusively on scans with at least 1 mm isotropic resolution and are tuned to a specific magnetic resonance (MR) contrast, often T1-weighted (T1w). This precludes application using most clinical MR scans, which are very heterogeneous in terms of contrast and resolution. Here, we use synthetic domain-randomized data to train the first neural network for explicit estimation of cortical surfaces from scans of any contrast and resolution, without retraining. Our method deforms a template mesh to the white matter (WM) surface, which guarantees topological correctness. This mesh is further deformed to estimate the GM surface. We compare our method to recon-all-clinical (RAC), an implicit surface reconstruction method which is currently the only other tool capable of processing heterogeneous clinical MR scans, on ADNI and a large clinical dataset (n=1,332). We show a approximately 50 % reduction in cortical thickness error (from 0.50 to 0.24 mm) with respect to RAC and better recovery of the aging-related cortical thinning patterns detected by FreeSurfer on high-resolution T1w scans. Our method enables fast and accurate surface reconstruction of clinical scans, allowing studies (1) with sample sizes far beyond what is feasible in a research setting, and (2) of clinical populations that are difficult to enroll in research studies. The code is publicly available at https://github.com/simnibs/brainnet.

Adria Casamitjana, Juan Eugenio Iglesias, Raul Tudela et al.

We present a pipeline for unbiased and robust multimodal registration of neuroimaging modalities with minimal pre-processing. While typical multimodal studies need to use multiple independent processing pipelines, with diverse options and hyperparameters, we propose a single and structured framework to jointly process different image modalities. The use of state-of-the-art learning-based techniques enables fast inferences, which makes the presented method suitable for large-scale and/or multi-cohort datasets with a diverse number of modalities per session. The pipeline currently works with structural MRI, resting state fMRI and amyloid PET images. We show the predictive power of the derived biomarkers using in a case-control study and study the cross-modal relationship between different image modalities. The code can be found in https: //github.com/acasamitjana/JUMP.

Adrià Casamitjana, Roser Sala-Llonch, Karim Lekadir et al.

We present USLR, a computational framework for longitudinal registration of brain MRI scans to estimate nonlinear image trajectories that are smooth across time, unbiased to any timepoint, and robust to imaging artefacts. It operates on the Lie algebra parameterisation of spatial transforms (which is compatible with rigid transforms and stationary velocity fields for nonlinear deformation) and takes advantage of log-domain properties to solve the problem using Bayesian inference. USRL estimates rigid and nonlinear registrations that: (i) bring all timepoints to an unbiased subject-specific space; and (i) compute a smooth trajectory across the imaging time-series. We capitalise on learning-based registration algorithms and closed-form expressions for fast inference. A use-case Alzheimer's disease study is used to showcase the benefits of the pipeline in multiple fronts, such as time-consistent image segmentation to reduce intra-subject variability, subject-specific prediction or population analysis using tensor-based morphometry. We demonstrate that such approach improves upon cross-sectional methods in identifying group differences, which can be helpful in detecting more subtle atrophy levels or in reducing sample sizes in clinical trials. The code is publicly available in https://github.com/acasamitjana/uslr

Adrià Casamitjana, Matteo Mancini, Juan Eugenio Iglesias

Nonlinear inter-modality registration is often challenging due to the lack of objective functions that are good proxies for alignment. Here we propose a synthesis-by-registration method to convert this problem into an easier intra-modality task. We introduce a registration loss for weakly supervised image translation between domains that does not require perfectly aligned training data. This loss capitalises on a registration U-Net with frozen weights, to drive a synthesis CNN towards the desired translation. We complement this loss with a structure preserving constraint based on contrastive learning, which prevents blurring and content shifts due to overfitting. We apply this method to the registration of histological sections to MRI slices, a key step in 3D histology reconstruction. Results on two different public datasets show improvements over registration based on mutual information (13% reduction in landmark error) and synthesis-based algorithms such as CycleGAN (11% reduction), and are comparable to a registration CNN with label supervision. Code and data are publicly available at \url{https://github.com/acasamitjana/SynthByReg}

Adrià Casamitjana, Marco Lorenzi, Sebastiano Ferraris et al.

Joint registration of a stack of 2D histological sections to recover 3D structure (``3D histology reconstruction'') finds application in areas such as atlas building and validation of \emph{in vivo} imaging. Straightforward pairwise registration of neighbouring sections yields smooth reconstructions but has well-known problems such as ``banana effect'' (straightening of curved structures) and ``z-shift'' (drift). While these problems can be alleviated with an external, linearly aligned reference (e.g., Magnetic Resonance (MR) images), registration is often inaccurate due to contrast differences and the strong nonlinear distortion of the tissue, including artefacts such as folds and tears. In this paper, we present a probabilistic model of spatial deformation that yields reconstructions for multiple histological stains that that are jointly smooth, robust to outliers, and follow the reference shape. The model relies on a spanning tree of latent transforms connecting all the sections and slices of the reference volume, and assumes that the registration between any pair of images can be see as a noisy version of the composition of (possibly inverted) latent transforms connecting the two images. Bayesian inference is used to compute the most likely latent transforms given a set of pairwise registrations between image pairs within and across modalities. The framework is used for accurate 3D reconstruction of two stains (Nissl and parvalbumin) from the Allen human brain atlas, showing its benefits on real data with severe distortions. Moreover, we also provide the registration of the reconstructed volume to MNI space, bridging the gaps between two of the most widely used atlases in histology and MRI. The 3D reconstructed volumes and atlas registration can be downloaded from https://openneuro.org/datasets/ds003590. The code is freely available at https://github.com/acasamitjana/3dhirest.

Loic Peter, Daniel C. Alexander, Caroline Magnain et al.

Landmark correspondences are a widely used type of gold standard in image registration. However, the manual placement of corresponding points is subject to high inter-user variability in the chosen annotated locations and in the interpretation of visual ambiguities. In this paper, we introduce a principled strategy for the construction of a gold standard in deformable registration. Our framework: (i) iteratively suggests the most informative location to annotate next, taking into account its redundancy with previous annotations; (ii) extends traditional pointwise annotations by accounting for the spatial uncertainty of each annotation, which can either be directly specified by the user, or aggregated from pointwise annotations from multiple experts; and (iii) naturally provides a new strategy for the evaluation of deformable registration algorithms. Our approach is validated on four different registration tasks. The experimental results show the efficacy of suggesting annotations according to their informativeness, and an improved capacity to assess the quality of the outputs of registration algorithms. In addition, our approach yields, from sparse annotations only, a dense visualization of the errors made by a registration method. The source code of our approach supporting both 2D and 3D data is publicly available at https://github.com/LoicPeter/evaluation-deformable-registration.

Juan Eugenio Iglesias, Benjamin Billot, Yael Balbastre et al.

Most existing algorithms for automatic 3D morphometry of human brain MRI scans are designed for data with near-isotropic voxels at approximately 1 mm resolution, and frequently have contrast constraints as well - typically requiring T1 scans (e.g., MP-RAGE). This limitation prevents the analysis of millions of MRI scans acquired with large inter-slice spacing ("thick slice") in clinical settings every year. The inability to quantitatively analyze these scans hinders the adoption of quantitative neuroimaging in healthcare, and precludes research studies that could attain huge sample sizes and hence greatly improve our understanding of the human brain. Recent advances in CNNs are producing outstanding results in super-resolution and contrast synthesis of MRI. However, these approaches are very sensitive to the contrast, resolution and orientation of the input images, and thus do not generalize to diverse clinical acquisition protocols - even within sites. Here we present SynthSR, a method to train a CNN that receives one or more thick-slice scans with different contrast, resolution and orientation, and produces an isotropic scan of canonical contrast (typically a 1 mm MP-RAGE). The presented method does not require any preprocessing, e.g., skull stripping or bias field correction. Crucially, SynthSR trains on synthetic input images generated from 3D segmentations, and can thus be used to train CNNs for any combination of contrasts, resolutions and orientations without high-resolution training data. We test the images generated with SynthSR in an array of common downstream analyses, and show that they can be reliably used for subcortical segmentation and volumetry, image registration (e.g., for tensor-based morphometry), and, if some image quality requirements are met, even cortical thickness morphometry. The source code is publicly available at github.com/BBillot/SynthSR.

Yunguan Fu, Nina Montaña Brown, Shaheer U. Saeed et al.

DeepReg (https://github.com/DeepRegNet/DeepReg) is a community-supported open-source toolkit for research and education in medical image registration using deep learning.

Henry Tregidgo, Adria Casamitjana, Caitlin Latimer et al.

Neuroimaging to neuropathology correlation (NTNC) promises to enable the transfer of microscopic signatures of pathology to in vivo imaging with MRI, ultimately enhancing clinical care. NTNC traditionally requires a volumetric MRI scan, acquired either ex vivo or a short time prior to death. Unfortunately, ex vivo MRI is difficult and costly, and recent premortem scans of sufficient quality are seldom available. To bridge this gap, we present methodology to 3D reconstruct and segment full brain image volumes from brain dissection photographs, which are routinely acquired at many brain banks and neuropathology departments. The 3D reconstruction is achieved via a joint registration framework, which uses a reference volume other than MRI. This volume may represent either the sample at hand (e.g., a surface 3D scan) or the general population (a probabilistic atlas). In addition, we present a Bayesian method to segment the 3D reconstructed photographic volumes into 36 neuroanatomical structures, which is robust to nonuniform brightness within and across photographs. We evaluate our methods on a dataset with 24 brains, using Dice scores and volume correlations. The results show that dissection photography is a valid replacement for ex vivo MRI in many volumetric analyses, opening an avenue for MRI-free NTNC, including retrospective data. The code is available at https://github.com/htregidgo/DissectionPhotoVolumes.

Nalini M. Singh, Juan Eugenio Iglesias, Elfar Adalsteinsson et al.

We propose neural network layers that explicitly combine frequency and image feature representations and show that they can be used as a versatile building block for reconstruction from frequency space data. Our work is motivated by the challenges arising in MRI acquisition where the signal is a corrupted Fourier transform of the desired image. The proposed joint learning schemes enable both correction of artifacts native to the frequency space and manipulation of image space representations to reconstruct coherent image structures at every layer of the network. This is in contrast to most current deep learning approaches for image reconstruction that treat frequency and image space features separately and often operate exclusively in one of the two spaces. We demonstrate the advantages of joint convolutional learning for a variety of tasks, including motion correction, denoising, reconstruction from undersampled acquisitions, and combined undersampling and motion correction on simulated and real world multicoil MRI data. The joint models produce consistently high quality output images across all tasks and datasets. When integrated into a state of the art unrolled optimization network with physics-inspired data consistency constraints for undersampled reconstruction, the proposed architectures significantly improve the optimization landscape, which yields an order of magnitude reduction of training time. This result suggests that joint representations are particularly well suited for MRI signals in deep learning networks. Our code and pretrained models are publicly available at https://github.com/nalinimsingh/interlacer.

Evan M. Yu, Juan Eugenio Iglesias, Adrian V. Dalca et al.

Deep neural networks are powerful tools for biomedical image segmentation. These models are often trained with heavy supervision, relying on pairs of images and corresponding voxel-level labels. However, obtaining segmentations of anatomical regions on a large number of cases can be prohibitively expensive. Thus there is a strong need for deep learning-based segmentation tools that do not require heavy supervision and can continuously adapt. In this paper, we propose a novel perspective of segmentation as a discrete representation learning problem, and present a variational autoencoder segmentation strategy that is flexible and adaptive. Our method, called Segmentation Auto-Encoder (SAE), leverages all available unlabeled scans and merely requires a segmentation prior, which can be a single unpaired segmentation image. In experiments, we apply SAE to brain MRI scans. Our results show that SAE can produce good quality segmentations, particularly when the prior is good. We demonstrate that a Markov Random Field prior can yield significantly better results than a spatially independent prior. Our code is freely available at https://github.com/evanmy/sae.

Malte Hoffmann, Benjamin Billot, Douglas N. Greve et al.

We introduce a strategy for learning image registration without acquired imaging data, producing powerful networks agnostic to contrast introduced by magnetic resonance imaging (MRI). While classical registration methods accurately estimate the spatial correspondence between images, they solve an optimization problem for every new image pair. Learning-based techniques are fast at test time but limited to registering images with contrasts and geometric content similar to those seen during training. We propose to remove this dependency on training data by leveraging a generative strategy for diverse synthetic label maps and images that exposes networks to a wide range of variability, forcing them to learn more invariant features. This approach results in powerful networks that accurately generalize to a broad array of MRI contrasts. We present extensive experiments with a focus on 3D neuroimaging, showing that this strategy enables robust and accurate registration of arbitrary MRI contrasts even if the target contrast is not seen by the networks during training. We demonstrate registration accuracy surpassing the state of the art both within and across contrasts, using a single model. Critically, training on arbitrary shapes synthesized from noise distributions results in competitive performance, removing the dependency on acquired data of any kind. Additionally, since anatomical label maps are often available for the anatomy of interest, we show that synthesizing images from these dramatically boosts performance, while still avoiding the need for real intensity images. Our code is available at https://w3id.org/synthmorph.

Benjamin Billot, Eleanor D. Robinson, Adrian V. Dalca et al.

Partial voluming (PV) is arguably the last crucial unsolved problem in Bayesian segmentation of brain MRI with probabilistic atlases. PV occurs when voxels contain multiple tissue classes, giving rise to image intensities that may not be representative of any one of the underlying classes. PV is particularly problematic for segmentation when there is a large resolution gap between the atlas and the test scan, e.g., when segmenting clinical scans with thick slices, or when using a high-resolution atlas. In this work, we present PV-SynthSeg, a convolutional neural network (CNN) that tackles this problem by directly learning a mapping between (possibly multi-modal) low resolution (LR) scans and underlying high resolution (HR) segmentations. PV-SynthSeg simulates LR images from HR label maps with a generative model of PV, and can be trained to segment scans of any desired target contrast and resolution, even for previously unseen modalities where neither images nor segmentations are available at training. PV-SynthSeg does not require any preprocessing, and runs in seconds. We demonstrate the accuracy and flexibility of the method with extensive experiments on three datasets and 2,680 scans. The code is available at https://github.com/BBillot/SynthSeg.

Benjamin Billot, Douglas Greve, Koen Van Leemput et al.

We present a deep learning strategy that enables, for the first time, contrast-agnostic semantic segmentation of completely unpreprocessed brain MRI scans, without requiring additional training or fine-tuning for new modalities. Classical Bayesian methods address this segmentation problem with unsupervised intensity models, but require significant computational resources. In contrast, learning-based methods can be fast at test time, but are sensitive to the data available at training. Our proposed learning method, SynthSeg, leverages a set of training segmentations (no intensity images required) to generate synthetic sample images of widely varying contrasts on the fly during training. These samples are produced using the generative model of the classical Bayesian segmentation framework, with randomly sampled parameters for appearance, deformation, noise, and bias field. Because each mini-batch has a different synthetic contrast, the final network is not biased towards any MRI contrast. We comprehensively evaluate our approach on four datasets comprising over 1,000 subjects and four types of MR contrast. The results show that our approach successfully segments every contrast in the data, performing slightly better than classical Bayesian segmentation, and three orders of magnitude faster. Moreover, even within the same type of MRI contrast, our strategy generalizes significantly better across datasets, compared to training using real images. Finally, we find that synthesizing a broad range of contrasts, even if unrealistic, increases the generalization of the neural network. Our code and model are open source at https://github.com/BBillot/SynthSeg.

Pablo Laso, Stefano Cerri, Annabel Sorby-Adams et al.

Brain atrophy and white matter hyperintensity (WMH) are critical neuroimaging features for ascertaining brain injury in cerebrovascular disease and multiple sclerosis. Automated segmentation and quantification is desirable but existing methods require high-resolution MRI with good signal-to-noise ratio (SNR). This precludes application to clinical and low-field portable MRI (pMRI) scans, thus hampering large-scale tracking of atrophy and WMH progression, especially in underserved areas where pMRI has huge potential. Here we present a method that segments white matter hyperintensity and 36 brain regions from scans of any resolution and contrast (including pMRI) without retraining. We show results on eight public datasets and on a private dataset with paired high- and low-field scans (3T and 64mT), where we attain strong correlation between the WMH ($ρ$=.85) and hippocampal volumes (r=.89) estimated at both fields. Our method is publicly available as part of FreeSurfer, at: http://surfer.nmr.mgh.harvard.edu/fswiki/WMH-SynthSeg.

Dominic LaBella, Ujjwal Baid, Omaditya Khanna et al.

We describe the design and results from the BraTS 2023 Intracranial Meningioma Segmentation Challenge. The BraTS Meningioma Challenge differed from prior BraTS Glioma challenges in that it focused on meningiomas, which are typically benign extra-axial tumors with diverse radiologic and anatomical presentation and a propensity for multiplicity. Nine participating teams each developed deep-learning automated segmentation models using image data from the largest multi-institutional systematically expert annotated multilabel multi-sequence meningioma MRI dataset to date, which included 1000 training set cases, 141 validation set cases, and 283 hidden test set cases. Each case included T2, FLAIR, T1, and T1Gd brain MRI sequences with associated tumor compartment labels delineating enhancing tumor, non-enhancing tumor, and surrounding non-enhancing FLAIR hyperintensity. Participant automated segmentation models were evaluated and ranked based on a scoring system evaluating lesion-wise metrics including dice similarity coefficient (DSC) and 95% Hausdorff Distance. The top ranked team had a lesion-wise median dice similarity coefficient (DSC) of 0.976, 0.976, and 0.964 for enhancing tumor, tumor core, and whole tumor, respectively and a corresponding average DSC of 0.899, 0.904, and 0.871, respectively. These results serve as state-of-the-art benchmarks for future pre-operative meningioma automated segmentation algorithms. Additionally, we found that 1286 of 1424 cases (90.3%) had at least 1 compartment voxel abutting the edge of the skull-stripped image edge, which requires further investigation into optimal pre-processing face anonymization steps.

Anahita Fathi Kazerooni, Nastaran Khalili, Xinyang Liu et al.

Pediatric tumors of the central nervous system are the most common cause of cancer-related death in children. The five-year survival rate for high-grade gliomas in children is less than 20%. Due to their rarity, the diagnosis of these entities is often delayed, their treatment is mainly based on historic treatment concepts, and clinical trials require multi-institutional collaborations. Here we present the CBTN-CONNECT-DIPGR-ASNR-MICCAI BraTS-PEDs challenge, focused on pediatric brain tumors with data acquired across multiple international consortia dedicated to pediatric neuro-oncology and clinical trials. The CBTN-CONNECT-DIPGR-ASNR-MICCAI BraTS-PEDs challenge brings together clinicians and AI/imaging scientists to lead to faster development of automated segmentation techniques that could benefit clinical trials, and ultimately the care of children with brain tumors.

Karthik Gopinath, Xiaoling Hu, Malte Hoffmann et al.

In human neuroimaging studies, atlas registration enables mapping MRI scans to a common coordinate frame, which is necessary to aggregate data from multiple subjects. Machine learning registration methods have achieved excellent speed and accuracy but lack interpretability and flexibility at test time (since their deformation model is fixed). More recently, keypoint-based methods have been proposed to tackle these issues, but their accuracy is still subpar, particularly when fitting nonlinear transforms. Here we propose Registration by Regression (RbR), a novel atlas registration framework that: is highly robust and flexible; can be trained with cheaply obtained data; and operates on a single channel, such that it can also be used as pretraining for other tasks. RbR predicts the (x, y, z) atlas coordinates for every voxel of the input scan (i.e., every voxel is a keypoint), and then uses closed-form expressions to quickly fit transforms using a wide array of possible deformation models, including affine and nonlinear (e.g., Bspline, Demons, invertible diffeomorphic models, etc.). Robustness is provided by the large number of voxels informing the registration and can be further increased by robust estimators like RANSAC. Experiments on independent public datasets show that RbR yields more accurate registration than competing keypoint approaches, over a wide range of deformation models.

Ana Lawry Aguila, Peirong Liu, Oula Puonti et al.

Supervised machine learning has enabled accurate pathology detection in brain MRI, but requires training data from diseased subjects that may not be readily available in some scenarios, for example, in the case of rare diseases. Reconstruction-based unsupervised anomaly detection, in particular using diffusion models, has gained popularity in the medical field as it allows for training on healthy images alone, eliminating the need for large disease-specific cohorts. These methods assume that a model trained on normal data cannot accurately represent or reconstruct anomalies. However, this assumption often fails with models failing to reconstruct healthy tissue or accurately reconstruct abnormal regions i.e., failing to remove anomalies. In this work, we introduce a novel conditional diffusion model framework for anomaly detection and healthy image reconstruction in brain MRI. Our weakly supervised approach integrates synthetically generated pseudo-pathology images into the modeling process to better guide the reconstruction of healthy images. To generate these pseudo-pathologies, we apply fluid-driven anomaly randomization to augment real pathology segmentation maps from an auxiliary dataset, ensuring that the synthetic anomalies are both realistic and anatomically coherent. We evaluate our model's ability to detect pathology, using both synthetic anomaly datasets and real pathology from the ATLAS dataset. In our extensive experiments, our model: (i) consistently outperforms variational autoencoders, and conditional and unconditional latent diffusion; and (ii) surpasses on most datasets, the performance of supervised inpainting methods with access to paired diseased/healthy images.

Xiaoling Hu, Annabel Sorby-Adams, Frederik Barkhof et al.

White matter hyperintensities (WMH) are a hallmark of cerebrovascular disease and multiple sclerosis. Automated WMH segmentation methods enable quantitative analysis via estimation of total lesion load, spatial distribution of lesions, and number of lesions (i.e., number of connected components after thresholding), all of which are correlated with patient outcomes. While the two former measures can generally be estimated robustly, the number of lesions is highly sensitive to noise and segmentation mistakes -- even when small connected components are eroded or disregarded. In this article, we present P-Count, an algebraic WMH counting tool based on persistent homology that accounts for the topological features of WM lesions in a robust manner. Using computational geometry, P-Count takes the persistence of connected components into consideration, effectively filtering out the noisy WMH positives, resulting in a more accurate count of true lesions. We validated P-Count on the ISBI2015 longitudinal lesion segmentation dataset, where it produces significantly more accurate results than direct thresholding.

Asbjørn Munk, Stefano Cerri, Jakob Ambsdorf et al.

We present FOMO60K, a large-scale, heterogeneous dataset of 60,529 brain Magnetic Resonance Imaging (MRI) scans from 13,900 sessions and 11,187 subjects, aggregated from 16 publicly available sources. The dataset includes both clinical- and research-grade images, multiple MRI sequences, and a wide range of anatomical and pathological variability, including scans with large brain anomalies. Minimal preprocessing was applied to preserve the original image characteristics while reducing barriers to entry for new users. Accompanying code for self-supervised pretraining and finetuning is provided. FOMO60K is intended to support the development and benchmarking of self-supervised learning methods in medical imaging at scale.

Ana Lawry Aguila, Dina Zemlyanker, You Cheng et al.

Diffusion models have recently emerged as powerful generative models in medical imaging. However, it remains a major challenge to combine these data-driven models with domain knowledge to guide brain imaging problems. In neuroimaging, Bayesian inverse problems have long provided a successful framework for inference tasks, where incorporating domain knowledge of the imaging process enables robust performance without requiring extensive training data. However, the anatomical modeling component of these approaches typically relies on classical mathematical priors that often fail to capture the complex structure of brain anatomy. In this work, we present the first general-purpose application of diffusion models as priors for solving a wide range of medical imaging inverse problems. Our approach leverages a score-based diffusion prior trained extensively on diverse brain MRI data, paired with flexible forward models that capture common image processing tasks such as super-resolution, bias field correction, inpainting, and combinations thereof. We further demonstrate how our framework can refine outputs from existing deep learning methods to improve anatomical fidelity. Experiments on heterogeneous clinical and research MRI data show that our method achieves state-of-the-art performance producing consistent, high-quality solutions without requiring paired training datasets. These results highlight the potential of diffusion priors as versatile tools for brain MRI analysis.

Ana Lawry Aguila, Peirong Liu, Marina Crespo Aguirre et al.

Generating healthy counterfactuals from pathological images holds significant promise in medical imaging, e.g., in anomaly detection or for application of analysis tools that are designed for healthy scans. These counterfactuals should represent what a patient's scan would plausibly look like in the absence of pathology, preserving individual anatomical characteristics while modifying only the pathological regions. Denoising diffusion probabilistic models (DDPMs) have become popular methods for generating healthy counterfactuals of pathology data. Typically, this involves training on solely healthy data with the assumption that a partial denoising process will be unable to model disease regions and will instead reconstruct a closely matched healthy counterpart. More recent methods have incorporated synthetic pathological images to better guide the diffusion process. However, it remains challenging to guide the generative process in a way that effectively balances the removal of anomalies with the retention of subject-specific features. To solve this problem, we propose a novel application of denoising diffusion bridge models (DDBMs) - which, unlike DDPMs, condition the diffusion process not only on the initial point (i.e., the healthy image), but also on the final point (i.e., a corresponding synthetically generated pathological image). Treating the pathological image as a structurally informative prior enables us to generate counterfactuals that closely match the patient's anatomy while selectively removing pathology. The results show that our DDBM outperforms previously proposed diffusion models and fully supervised approaches at segmentation and anomaly detection tasks.

Lin Tian, Xiaoling Hu, Juan Eugenio Iglesias · harvard

Accurate image registration is essential for downstream applications, yet current deep registration networks provide limited indications of whether and when their predictions are reliable. Existing uncertainty estimation strategies, such as Bayesian methods, ensembles, or MC dropout, require architectural changes or retraining, limiting their applicability to pretrained registration networks. Instead, we propose a test-time uncertainty estimation framework that is compatible with any pretrained networks. Our framework is grounded in the transformation equivariance property of registration, which states that the true mapping between two images should remain consistent under spatial perturbations of the input. By analyzing the variance of network predictions under such perturbations, we derive a theoretical decomposition of perturbation-based uncertainty in registration. This decomposition separates into two terms: (i) an intrinsic spread, reflecting epistemic noise, and (ii) a bias jitter, capturing how systematic error drifts under perturbations. Across four anatomical structures (brain, cardiac, abdominal, and lung) and multiple registration models (uniGradICON, SynthMorph), the uncertainty maps correlate consistently with registration errors and highlight regions requiring caution. Our framework turns any pretrained registration network into a risk-aware tool at test time, placing medical image registration one step closer to safe deployment in clinical and large-scale research settings.

Jonathan Williams Ramirez, Dina Zemlyanker, Lucas Deden-Binder et al.

Advances in image registration and machine learning have recently enabled volumetric analysis of postmortem brain tissue from conventional photographs of coronal slabs, which are routinely collected in brain banks and neuropathology laboratories worldwide. One caveat of this methodology is the requirement of segmentation of the tissue from photographs, which currently requires costly manual intervention. In this article, we present a deep learning model to automate this process. The automatic segmentation tool relies on a U-Net architecture that was trained with a combination of 1,414 manually segmented images of both fixed and fresh tissue, from specimens with varying diagnoses, photographed at two different sites. Automated model predictions on a subset of photographs not seen in training were analyzed to estimate performance compared to manual labels, including both inter- and intra-rater variability. Our model achieved a median Dice score over 0.98, mean surface distance under 0.4mm, and 95\% Hausdorff distance under 1.60mm, which approaches inter-/intra-rater levels. Our tool is publicly available at surfer.nmr.mgh.harvard.edu/fswiki/PhotoTools.

Ana Lawry Aguila, Ayodeji Ijishakin, Juan Eugenio Iglesias et al.

Applying machine learning to real-world medical data, e.g. from hospital archives, has the potential to revolutionize disease detection in brain images. However, detecting pathology in such heterogeneous cohorts is a difficult challenge. Normative modeling, a form of unsupervised anomaly detection, offers a promising approach to studying such cohorts where the ``normal'' behavior is modeled and can be used at subject level to detect deviations relating to disease pathology. Diffusion models have emerged as powerful tools for anomaly detection due to their ability to capture complex data distributions and generate high-quality images. Their performance relies on image restoration; differences between the original and restored images highlight potential abnormalities. However, unlike normative models, these diffusion model approaches do not incorporate clinical information which provides important context to guide the disease detection process. Furthermore, standard approaches often poorly restore healthy regions, resulting in poor reconstructions and suboptimal detection performance. We present CADD, the first conditional diffusion model for normative modeling in 3D images. To guide the healthy restoration process, we propose a novel inference inpainting strategy which balances anomaly removal with retention of subject-specific features. Evaluated on three challenging datasets, including clinical scans, which may have lower contrast, thicker slices, and motion artifacts, CADD achieves state-of-the-art performance in detecting neurological abnormalities in heterogeneous cohorts.

Raghav Mehta, Karthik Gopinath, Ben Glocker et al.

We propose UNSURF, a novel uncertainty measure for cortical surface reconstruction of clinical brain MRI scans of any orientation, resolution, and contrast. It relies on the discrepancy between predicted voxel-wise signed distance functions (SDFs) and the actual SDFs of the fitted surfaces. Our experiments on real clinical scans show that traditional uncertainty measures, such as voxel-wise Monte Carlo variance, are not suitable for modeling the uncertainty of surface placement. Our results demonstrate that UNSURF estimates correlate well with the ground truth errors and: \textit{(i)}~enable effective automated quality control of surface reconstructions at the subject-, parcel-, mesh node-level; and \textit{(ii)}~improve performance on a downstream Alzheimer's disease classification task.

Xiaoling Hu, Peirong Liu, Dina Zemlyanker et al.

Although deep learning has shown great success in 3D brain MRI segmentation, achieving accurate and efficient segmentation of ultra-high-resolution brain images remains challenging due to the lack of labeled training data for fine-scale anatomical structures and high computational demands. In this work, we propose a novel framework that leverages easily accessible, low-resolution coarse labels as spatial references and guidance, without incurring additional annotation cost. Instead of directly predicting discrete segmentation maps, our approach regresses per-class signed distance transform maps, enabling smooth, boundary-aware supervision. Furthermore, to enhance scalability, generalizability, and efficiency, we introduce a scalable class-conditional segmentation strategy, where the model learns to segment one class at a time conditioned on a class-specific input. This novel design not only reduces memory consumption during both training and testing, but also allows the model to generalize to unseen anatomical classes. We validate our method through comprehensive experiments on both synthetic and real-world datasets, demonstrating its superior performance and scalability compared to conventional segmentation approaches.

Livia Rodrigues, Martina Bocchetta, Oula Puonti et al.

Segmentation of brain structures on magnetic resonance imaging (MRI) is a highly relevant neuroimaging topic, as it is a prerequisite for different analyses such as volumetry or shape analysis. Automated segmentation facilitates the study of brain structures in larger cohorts when compared with manual segmentation, which is time-consuming. However, the development of most automated methods relies on large and manually annotated datasets, which limits the generalizability of these methods. Recently, new techniques using synthetic images have emerged, reducing the need for manual annotation. Here we provide HELM, Hypothalamic ex vivo Label Maps, a dataset composed of label maps built from publicly available ultra-high resolution ex vivo MRI from 10 whole hemispheres, which can be used to develop segmentation methods using synthetic data. The label maps are obtained with a combination of manual labels for the hypothalamic regions and automated segmentations for the rest of the brain, and mirrored to simulate entire brains. We also provide the pre-processed ex vivo scans, as this dataset can support future projects to include other structures after these are manually segmented.

Maruf Adewole, Jeffrey D. Rudie, Anu Gbadamosi et al.

Gliomas are the most common type of primary brain tumors. Although gliomas are relatively rare, they are among the deadliest types of cancer, with a survival rate of less than 2 years after diagnosis. Gliomas are challenging to diagnose, hard to treat and inherently resistant to conventional therapy. Years of extensive research to improve diagnosis and treatment of gliomas have decreased mortality rates across the Global North, while chances of survival among individuals in low- and middle-income countries (LMICs) remain unchanged and are significantly worse in Sub-Saharan Africa (SSA) populations. Long-term survival with glioma is associated with the identification of appropriate pathological features on brain MRI and confirmation by histopathology. Since 2012, the Brain Tumor Segmentation (BraTS) Challenge have evaluated state-of-the-art machine learning methods to detect, characterize, and classify gliomas. However, it is unclear if the state-of-the-art methods can be widely implemented in SSA given the extensive use of lower-quality MRI technology, which produces poor image contrast and resolution and more importantly, the propensity for late presentation of disease at advanced stages as well as the unique characteristics of gliomas in SSA (i.e., suspected higher rates of gliomatosis cerebri). Thus, the BraTS-Africa Challenge provides a unique opportunity to include brain MRI glioma cases from SSA in global efforts through the BraTS Challenge to develop and evaluate computer-aided-diagnostic (CAD) methods for the detection and characterization of glioma in resource-limited settings, where the potential for CAD tools to transform healthcare are more likely.

Anahita Fathi Kazerooni, Nastaran Khalili, Xinyang Liu et al.

Pediatric tumors of the central nervous system are the most common cause of cancer-related death in children. The five-year survival rate for high-grade gliomas in children is less than 20\%. Due to their rarity, the diagnosis of these entities is often delayed, their treatment is mainly based on historic treatment concepts, and clinical trials require multi-institutional collaborations. The MICCAI Brain Tumor Segmentation (BraTS) Challenge is a landmark community benchmark event with a successful history of 12 years of resource creation for the segmentation and analysis of adult glioma. Here we present the CBTN-CONNECT-DIPGR-ASNR-MICCAI BraTS-PEDs 2023 challenge, which represents the first BraTS challenge focused on pediatric brain tumors with data acquired across multiple international consortia dedicated to pediatric neuro-oncology and clinical trials. The BraTS-PEDs 2023 challenge focuses on benchmarking the development of volumentric segmentation algorithms for pediatric brain glioma through standardized quantitative performance evaluation metrics utilized across the BraTS 2023 cluster of challenges. Models gaining knowledge from the BraTS-PEDs multi-parametric structural MRI (mpMRI) training data will be evaluated on separate validation and unseen test mpMRI dataof high-grade pediatric glioma. The CBTN-CONNECT-DIPGR-ASNR-MICCAI BraTS-PEDs 2023 challenge brings together clinicians and AI/imaging scientists to lead to faster development of automated segmentation techniques that could benefit clinical trials, and ultimately the care of children with brain tumors.

Hongwei Bran Li, Gian Marco Conte, Qingqiao Hu et al.

Automated brain tumor segmentation methods have become well-established and reached performance levels offering clear clinical utility. These methods typically rely on four input magnetic resonance imaging (MRI) modalities: T1-weighted images with and without contrast enhancement, T2-weighted images, and FLAIR images. However, some sequences are often missing in clinical practice due to time constraints or image artifacts, such as patient motion. Consequently, the ability to substitute missing modalities and gain segmentation performance is highly desirable and necessary for the broader adoption of these algorithms in the clinical routine. In this work, we present the establishment of the Brain MR Image Synthesis Benchmark (BraSyn) in conjunction with the Medical Image Computing and Computer-Assisted Intervention (MICCAI) 2023. The primary objective of this challenge is to evaluate image synthesis methods that can realistically generate missing MRI modalities when multiple available images are provided. The ultimate aim is to facilitate automated brain tumor segmentation pipelines. The image dataset used in the benchmark is diverse and multi-modal, created through collaboration with various hospitals and research institutions.