Segmentation of magnetic resonance images (MRI) facilitates analysis of human brain development by delineating anatomical structures. However, in infants and young children, accurate segmentation is challenging due to development and imaging constraints. Pediatric brain MRI is notoriously difficult to acquire, with inconsistent availability of imaging modalities, substantial non-head anatomy in the field of view, and frequent motion artifacts. This has led to specialized segmentation models that are often limited to specific image types or narrow age groups, or that are fragile for more variable images such as those acquired clinically. We address this method fragmentation with BabySeg, a deep learning brain segmentation framework for infants and young children that supports diverse MRI protocols, including repeat scans and image types unavailable during training. Our approach builds on recent domain randomization techniques, which synthesize training images far beyond realistic bounds to promote dataset shift invariance. We also describe a mechanism that enables models to flexibly pool and interact features from any number of input scans. We demonstrate state-of-the-art performance that matches or exceeds the accuracy of several existing methods for various age cohorts and input configurations using a single model, in a fraction of the runtime required by many existing tools.

Accurate registration of brain MRI scans is fundamental for cross-subject analysis in neuroscientific studies. This involves aligning both the cortical surface of the brain and the interior volume. Traditional methods treat volumetric and surface-based registration separately, which often leads to inconsistencies that limit downstream analyses. We propose a deep learning framework, NeurAlign, that registers 3D brain MRI images by jointly aligning both cortical and subcortical regions through a unified volume-and-surface-based representation. Our approach leverages an intermediate spherical coordinate space to bridge anatomical surface topology with volumetric anatomy, enabling consistent and anatomically accurate alignment. By integrating spherical registration into the learning, our method ensures geometric coherence between volume and surface domains. In a series of experiments on both in-domain and out-of-domain datasets, our method consistently outperforms both classical and machine learning-based registration methods-improving the Dice score by up to 7 points while maintaining regular deformation fields. Additionally, it is orders of magnitude faster than the standard method for this task, and is simpler to use because it requires no additional inputs beyond an MRI scan. With its superior accuracy, fast inference, and ease of use, NeurAlign sets a new standard for joint cortical and subcortical registration.

Deformable templates, or atlases, are images that represent a prototypical anatomy for a population, and are often enhanced with probabilistic anatomical label maps. They are commonly used in medical image analysis for population studies and computational anatomy tasks such as registration and segmentation. Because developing a template is a computationally expensive process, relatively few templates are available. As a result, analysis is often conducted with sub-optimal templates that are not truly representative of the study population, especially when there are large variations within this population. We propose a machine learning framework that uses convolutional registration neural networks to efficiently learn a function that outputs templates conditioned on subject-specific attributes, such as age and sex. We also leverage segmentations, when available, to produce anatomical segmentation maps for the resulting templates. The learned network can also be used to register subject images to the templates. We demonstrate our method on a compilation of 3D brain MRI datasets, and show that it can learn high-quality templates that are representative of populations. We find that annotated conditional templates enable better registration than their unlabeled unconditional counterparts, and outperform other templates construction methods.

Medical researchers and clinicians often need to perform novel segmentation tasks on a set of related images. Existing methods for segmenting a new dataset are either interactive, requiring substantial human effort for each image, or require an existing set of previously labeled images. We introduce a system, MultiverSeg, that enables practitioners to rapidly segment an entire new dataset without requiring access to any existing labeled data from that task or domain. Along with the image to segment, the model takes user interactions such as clicks, bounding boxes or scribbles as input, and predicts a segmentation. As the user segments more images, those images and segmentations become additional inputs to the model, providing context. As the context set of labeled images grows, the number of interactions required to segment each new image decreases. We demonstrate that MultiverSeg enables users to interactively segment new datasets efficiently, by amortizing the number of interactions per image to achieve an accurate segmentation. Compared to using a state-of-the-art interactive segmentation method, MultiverSeg reduced the total number of clicks by 36

Rigid registration aims to determine the translations and rotations necessary to align features in a pair of images. While recent machine learning methods have become state-of-the-art for linear and deformable registration across subjects, they have demonstrated limitations when applied to longitudinal (within-subject) registration, where achieving precise alignment is critical. Building on an existing framework for anatomy-aware, acquisition-agnostic affine registration, we propose a model optimized for longitudinal, rigid brain registration. By training the model with synthetic within-subject pairs augmented with rigid and subtle nonlinear transforms, the model estimates more accurate rigid transforms than previous cross-subject networks and performs robustly on longitudinal registration pairs within and across magnetic resonance imaging (MRI) contrasts.

Current volumetric biomedical foundation models struggle to generalize as public 3D datasets are small and do not cover the broad diversity of medical procedures, conditions, anatomical regions, and imaging protocols. We address this by creating a representation learning method that instead anticipates strong domain shifts at training time itself. We first propose a data engine that synthesizes highly variable training samples that would enable generalization to new biomedical contexts. To then train a single 3D network for any voxel-level task, we develop a contrastive learning method that pretrains the network to be stable against nuisance imaging variation simulated by the data engine, a key inductive bias for generalization. This network's features can be used as robust representations of input images for downstream tasks and its weights provide a strong, _dataset-agnostic_ initialization for finetuning on new datasets. As a result, we set new standards across _both_ multimodality registration and few-shot segmentation, a first for any 3D biomedical vision model, all without (pre-)training on any existing dataset of real images.

We present MultiMorph, a fast and efficient method for constructing anatomical atlases on the fly. Atlases capture the canonical structure of a collection of images and are essential for quantifying anatomical variability across populations. However, current atlas construction methods often require days to weeks of computation, thereby discouraging rapid experimentation. As a result, many scientific studies rely on suboptimal, precomputed atlases from mismatched populations, negatively impacting downstream analyses. MultiMorph addresses these challenges with a feedforward model that rapidly produces high-quality, population-specific atlases in a single forward pass for any 3D brain dataset, without any fine-tuning or optimization. MultiMorph is based on a linear group-interaction layer that aggregates and shares features within the group of input images. Further, by leveraging auxiliary synthetic data, MultiMorph generalizes to new imaging modalities and population groups at test-time. Experimentally, MultiMorph outperforms state-of-the-art optimization-based and learning-based atlas construction methods in both small and large population settings, with a 100-fold reduction in time. This makes MultiMorph an accessible framework for biomedical researchers without machine learning expertise, enabling rapid, high-quality atlas generation for diverse studies.

Learning-based image reconstruction models, such as those based on the U-Net, require a large set of labeled images if good generalization is to be guaranteed. In some imaging domains, however, labeled data with pixel- or voxel-level label accuracy are scarce due to the cost of acquiring them. This problem is exacerbated further in domains like medical imaging, where there is no single ground truth label, resulting in large amounts of repeat variability in the labels. Therefore, training reconstruction networks to generalize better by learning from both labeled and unlabeled examples (called semi-supervised learning) is problem of practical and theoretical interest. However, traditional semi-supervised learning methods for image reconstruction often necessitate handcrafting a differentiable regularizer specific to some given imaging problem, which can be extremely time-consuming. In this work, we propose “supervision by denoising” (SUD), a framework to supervise reconstruction models using their own denoised output as labels. SUD unifies stochastic averaging and spatial denoising techniques under a spatio-temporal denoising framework and alternates denoising and model weight update steps in an optimization framework for semi-supervision. As example applications, we apply SUD to two problems from biomedical imaging—anatomical brain reconstruction (3D) and cortical parcellation (2D)—to demonstrate a significant improvement in reconstruction over supervised-only and ensembling baselines. Our code available at https://github.com/seannz/sud .

Cortical surface parcellation is a fundamental task in both basic neuroscience research and clinical applications, enabling more accurate mapping of brain regions. Model-based and learning-based approaches for automated parcellation alleviate the need for manual labeling. Despite the advancement in parcellation performance, learning-based methods shift away from registration and atlas propagation without exploring the reason for the improvement compared to traditional methods. In this study, we present JParc, a joint cortical registration and parcellation framework, that outperforms existing state-of-the-art parcellation methods. In rigorous experiments, we demonstrate that the enhanced performance of JParc is primarily attributable to accurate cortical registration and a learned parcellation atlas. By leveraging a shallow subnetwork to fine-tune the propagated atlas labels, JParc achieves a Dice score greater than 90

Skull-stripping is the removal of background and non-brain anatomical features from brain images. While many skull-stripping tools exist, few target pediatric populations. With the emergence of multi-institutional pediatric data acquisition efforts to broaden the understanding of perinatal brain development, it is essential to develop robust and well-tested tools ready for the relevant data processing. However, the broad range of neuroanatomical variation in the developing brain, combined with additional challenges such as high motion levels, as well as shoulder and chest signal in the images, leaves many adult-specific tools ill-suited for pediatric skull-stripping. Building on an existing framework for robust and accurate skull-stripping, we propose developmental SynthStrip (d-SynthStrip), a skull-stripping model tailored to pediatric images. This framework exposes networks to highly variable images synthesized from label maps. Our model substantially outperforms pediatric baselines across scan types and age cohorts. In addition, the <1-minute runtime of our tool compares favorably to the fastest baselines. We distribute our model at https://w3id.org/synthstrip.

We present VoxelPrompt, an end-to-end image analysis agent that tackles free-form radiological tasks. Given any number of volumetric medical images and a natural language prompt, VoxelPrompt integrates a language model that generates executable code to invoke a jointly-trained, adaptable vision network. This code further carries out analytical steps to address practical quantitative aims, such as measuring the growth of a tumor across visits. The pipelines generated by VoxelPrompt automate analyses that currently require practitioners to painstakingly combine multiple specialized vision and statistical tools. We evaluate VoxelPrompt using diverse neuroimaging tasks and show that it can delineate hundreds of anatomical and pathological features, measure complex morphological properties, and perform open-language analysis of lesion characteristics. VoxelPrompt performs these objectives with an accuracy similar to that of specialist single-task models for image analysis, while facilitating a broad range of compositional biomedical workflows.

Hypernetworks, neural networks that predict the parameters of another neural network, are powerful models that have been successfully used in diverse applications from image generation to multi-task learning. Unfortunately, existing hypernetworks are often challenging to train. Training typically converges far more slowly than for non-hypernetwork models, and the rate of convergence can be very sensitive to hyperparameter choices. In this work, we identify a fundamental and previously unidentified problem that contributes to the challenge of training hypernetworks: a magnitude proportionality between the inputs and outputs of the hypernetwork. We demonstrate both analytically and empirically that this can lead to unstable optimization, thereby slowing down convergence, and sometimes even preventing any learning. We present a simple solution to this problem using a revised hypernetwork formulation that we call Magnitude Invariant Parametrizations (MIP). We demonstrate the proposed solution on several hypernetwork tasks, where it consistently stabilizes training and achieves faster convergence. Furthermore, we perform a comprehensive ablation study including choices of activation function, normalization strategies, input dimensionality, and hypernetwork architecture; and find that MIP improves training in all scenarios. We provide easy-to-use code that can turn existing networks into MIP-based hypernetworks.

Synthetic data have emerged as an attractive option for developing machine-learning methods in human neuroimaging, particularly in magnetic resonance imaging (MRI)-a modality where image contrast depends enormously on acquisition hardware and parameters. This retrospective paper reviews a family of recently proposed methods, based on synthetic data, for generalizable machine learning in brain MRI analysis. Central to this framework is the concept of domain randomization, which involves training neural networks on a vastly diverse array of synthetically generated images with random contrast properties. This technique has enabled robust, adaptable models that are capable of handling diverse MRI contrasts, resolutions, and pathologies, while working out-of-the-box, without retraining. We have successfully applied this method to tasks such as whole-brain segmentation (SynthSeg), skull-stripping (SynthStrip), registration (SynthMorph, EasyReg), super-resolution, and MR contrast transfer (SynthSR). Beyond these applications, the paper discusses other possible use cases and future work in our methodology. Neural networks trained with synthetic data enable the analysis of clinical MRI, including large retrospective datasets, while greatly alleviating (and sometimes eliminating) the need for substantial labeled datasets, and offer enormous potential as robust tools to address various research goals.

We present open-source tools for three-dimensional (3D) analysis of photographs of dissected slices of human brains, which are routinely acquired in brain banks but seldom used for quantitative analysis. Our tools can: (1) 3D reconstruct a volume from the photographs and, optionally, a surface scan; and (2) produce a high-resolution 3D segmentation into 11 brain regions per hemisphere (22 in total), independently of the slice thickness. Our tools can be used as a substitute for ex vivo magnetic resonance imaging (MRI), which requires access to an MRI scanner, ex vivo scanning expertise, and considerable financial resources. We tested our tools on synthetic and real data from two NIH Alzheimer’s Disease Research Centers. The results show that our methodology yields accurate 3D reconstructions, segmentations, and volumetric measurements that are highly correlated to those from MRI. Our method also detects expected differences between post mortem confirmed Alzheimer’s disease cases and controls. The tools are available in our widespread neuroimaging suite ‘FreeSurfer’ ( https://surfer.nmr.mgh.harvard.edu/fswiki/PhotoTools ).

We tackle classification based on brain connectivity derived from diffusion magnetic resonance images. We propose a machine-learning model inspired by graph convolutional networks (GCNs), which takes a brain connectivity input graph and processes the data separately through a parallel GCN mechanism with multiple heads. The proposed network is a simple design that employs different heads involving graph convolutions focused on edges and nodes, capturing representations from the input data thoroughly. To test the ability of our model to extract complementary and representative features from brain connectivity data, we chose the task of sex classification. This quantifies the degree to which the connectome varies depending on the sex, which is important for improving our understanding of health and disease in both sexes. We show experiments on two publicly available datasets: PREVENT-AD (347 subjects) and OASIS3 (771 subjects). The proposed model demonstrates the highest performance compared to the existing machine-learning algorithms we tested, including classical methods and (graph and non-graph) deep learning. We provide a detailed analysis of each component of our model.

Medical image segmentation is a crucial part of both scientific research and clinical care. With enough labelled data, deep learning models can be trained to accurately automate specific medical image segmentation tasks. However, manually segmenting images to create training data is highly labor intensive and requires domain expertise. We present ScribblePrompt, a flexible neural network based interactive segmentation tool for biomedical imaging that enables human annotators to segment previously unseen structures using scribbles, clicks, and bounding boxes. Through rigorous quantitative experiments, we demonstrate that given comparable amounts of interaction, ScribblePrompt produces more accurate segmentations than previous methods on datasets unseen during training. In a user study with domain experts, ScribblePrompt reduced annotation time by 28\% while improving Dice by 15\% compared to the next best method. ScribblePrompt's success rests on a set of careful design decisions. These include a training strategy that incorporates both a highly diverse set of images and tasks, novel algorithms for simulated user interactions and labels, and a network that enables fast inference. We showcase ScribblePrompt in an interactive online demo: https://huggingface.co/spaces/anon5167/ScribblePrompt

Star-convex shapes arise across bio-microscopy and radiology in the form of nuclei, nodules, metastases, and other units. Existing instance segmentation networks for such structures train on densely labeled instances for each dataset, which requires substantial and often impractical manual annotation effort. Further, significant reengineering or finetuning is needed when presented with new datasets and imaging modalities due to changes in contrast, shape, orientation, resolution, and density. We present AnyStar, a domain-randomized generative model that simulates synthetic training data of blob-like objects with randomized appearance, environments, and imaging physics to train general-purpose star-convex instance segmentation networks. As a result, networks trained using our generative model do not require annotated images from un-seen datasets. A single network trained on our synthesized data accurately 3D segments C. elegans and P. dumerilii nuclei in fluorescence microscopy, mouse cortical nuclei in μCT, zebrafish brain nuclei in EM, and placental cotyledons in human fetal MRI, all without any retraining, finetuning, transfer learning, or domain adaptation. Code is available at https://github.com/neel-dey/AnyStar.

We present a keypoint-based foundation model for general purpose brain MRI registration, based on the recently-proposed KeyMorph framework. Our model, called BrainMorph, serves as a tool that supports multi-modal, pairwise, and scalable groupwise registration. BrainMorph is trained on a massive dataset of over 100,000 3D volumes, skull-stripped and non-skull-stripped, from nearly 16,000 unique healthy and diseased subjects. BrainMorph is robust to large misalignments, interpretable via interrogating automatically-extracted keypoints, and enables rapid and controllable generation of many plausible transformations with different alignment types and different degrees of nonlinearity at test-time. We demonstrate the superiority of BrainMorph in solving 3D rigid, affine, and nonlinear registration on a variety of multi-modal brain MRI scans of healthy and diseased subjects, in both the pairwise and groupwise setting. In particular, we show registration accuracy and speeds that surpass many classical and learning-based methods, especially in the context of large initial misalignments and large group settings. All code and models are available at https://github.com/alanqrwang/brainmorph.

Recent models pre-trained on image-text pairs can learn rich vision-language representations that improve downstream tasks, such as image classification. However, because of the absence of paired text/image descriptions in many domains, it is difficult to fine-tune these models for many downstream tasks. In this work, we propose GIST -- a method for generating $\textit{image-specific}$ $\textit{fine-grained}$ text descriptions from image-only datasets. Our findings include 1) prompting a pretrained large language model with $\textit{domain-specific}$ prompts generates diverse fine-grained text descriptions that capture the full range of inter-class and intra-class differences, 2) using a pretrained vision-language model to match each training image to the most relevant text descriptions creates image-specific image-text pairs, and 3) summarizing the matched text using a large language model prior to fine-tuning the image encoder improves the utility of the learned representations. We demonstrate the utility of GIST by fine-tuning vision-language models on the output of GIST to learn an aligned vision-language representation space. We evaluate this learned representation space in full-shot and few-shot scenarios across four diverse fine-grained classification datasets, each from a different domain. Our method achieves an average of 1.1% improvement in accuracy over the existing state-of-the-art image-text classification method and 4.1% improvement in accuracy over CLIP linear probes on full-shot datasets. Our method achieves similar improvements across few-shot regimes. Code will be made publicly available upon publication.

Surface-based cortical registration is an important topic in medical image analysis and facilitates many downstream applications. Current approaches for cortical registration are mainly driven by geometric features, such as sulcal depth and curvature, and often assume that registration of folding patterns leads to alignment of brain function. However, functional variability of anatomically corresponding areas across subjects has been widely reported, particularly in higher-order cognitive areas. In this work, we present JOSA, a novel cortical registration framework that jointly models the mismatch between geometry and function while simultaneously learning an unbiased population-specific atlas. Using a semi-supervised training strategy, JOSA achieves superior registration performance in both geometry and function to the state-of-the-art methods but without requiring functional data at inference. This learning framework can be extended to any auxiliary data to guide spherical registration that is available during training but is difficult or impossible to obtain during inference, such as parcellations, architectonic identity, transcriptomic information, and molecular profiles. By recognizing the mismatch between geometry and function, JOSA provides new insights into the future development of registration methods using joint analysis of brain structure and function.