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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., Comment: 16 pages in the manuscript with 11 page supplementary material

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.

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.

Surface analysis of the cortex is ubiquitous in human neuroimaging with MRI, e.g., for cortical registration, parcellation, or thickness estimation. The convoluted cortical geometry requires isotropic scans (e.g., 1mm MPRAGEs) and good gray-white matter contrast for 3D reconstruction. This precludes the analysis of most brain MRI scans acquired for clinical purposes. Analyzing such scans would enable neuroimaging studies with sample sizes that cannot be achieved with current research datasets, particularly for underrepresented populations and rare diseases. Here we present the first method for cortical reconstruction, registration, parcellation, and thickness estimation for clinical brain MRI scans of any resolution and pulse sequence. The methods has a learning component and a classical optimization module. The former uses domain randomization to train a CNN that predicts an implicit representation of the white matter and pial surfaces (a signed distance function) at 1mm isotropic resolution, independently of the pulse sequence and resolution of the input. The latter uses geometry processing to place the surfaces while accurately satisfying topological and geometric constraints, thus enabling subsequent parcellation and thickness estimation with existing methods. We present results on 5mm axial FLAIR scans from ADNI and on a highly heterogeneous clinical dataset with 5,000 scans. Code and data are publicly available at https://surfer.nmr.mgh.harvard.edu/fswiki/recon-all-clinical

Affine image registration is a cornerstone of medical image analysis. While classical algorithms can achieve excellent accuracy, they solve a time-consuming optimization for every image pair. Deep-learning (DL) methods learn a function that maps an image pair to an output transform. Evaluating the function is fast, but capturing large transforms can be challenging, and networks tend to struggle if a test-image characteristic shifts from the training domain, such as resolution. Most affine methods are agnostic to the anatomy the user wishes to align, meaning the registration will be inaccurate if algorithms consider all structures in the image. We address these shortcomings with SynthMorph, a fast, symmetric, diffeomorphic, and easy-to-use DL tool for joint affine-deformable registration of any brain image without preprocessing. First, we leverage a strategy that trains networks with widely varying images synthesized from label maps, yielding robust performance for image types unseen at training. Second, we optimize the spatial overlap of select anatomical labels. This enables networks to distinguish anatomy of interest from irrelevant structures, removing the need for preprocessing that excludes content that may impinge on anatomy-specific registration. Third, we combine the affine model with a deformable hypernetwork that lets users choose the optimal deformation-field regularity for their specific data, at registration time, in a fraction of the time required by classical methods. We analyze how competing architectures learn affine transforms and compare state-of-the-art registration tools across an extremely diverse set of neuroimaging data, aiming to truly capture the behavior of methods in the real world. SynthMorph demonstrates high accuracy and is available at https://w3id.org/synthmorph, as a single complete end-to-end solution for registration of brain MRI., Comment: 33 pages, 19 figures, 4 tables, affine registration, deformable registration, deep learning, hypernetwork, domain shift, neuroimaging, final published version

In this paper we describe and validate a longitudinal method for whole-brain segmentation of longitudinal MRI scans. It builds upon an existing whole-brain segmentation method that can handle multi-contrast data and robustly analyze images with white matter lesions. This method is here extended with subject-specific latent variables that encourage temporal consistency between its segmentation results, enabling it to better track subtle morphological changes in dozens of neuroanatomical structures and white matter lesions. We validate the proposed method on multiple datasets of control subjects and patients suffering from Alzheimer's disease and multiple sclerosis, and compare its results against those obtained with its original cross-sectional formulation and two benchmark longitudinal methods. The results indicate that the method attains a higher test-retest reliability, while being more sensitive to longitudinal disease effect differences between patient groups. An implementation is publicly available as part of the open-source neuroimaging package FreeSurfer.

We introduce HyperMorph, a framework that facilitates efficient hyperparameter tuning in learning-based deformable image registration. Classical registration algorithms perform an iterative pair-wise optimization to compute a deformation field that aligns two images. Recent learning-based approaches leverage large image datasets to learn a function that rapidly estimates a deformation for a given image pair. In both strategies, the accuracy of the resulting spatial correspondences is strongly influenced by the choice of certain hyperparameter values. However, an effective hyperparameter search consumes substantial time and human effort as it often involves training multiple models for different fixed hyperparameter values and may lead to suboptimal registration. We propose an amortized hyperparameter learning strategy to alleviate this burden by learning the impact of hyperparameters on deformation fields. We design a meta network, or hypernetwork, that predicts the parameters of a registration network for input hyperparameters, thereby comprising a single model that generates the optimal deformation field corresponding to given hyperparameter values. This strategy enables fast, high-resolution hyperparameter search at test-time, reducing the inefficiency of traditional approaches while increasing flexibility. We also demonstrate additional benefits of HyperMorph, including enhanced robustness to model initialization and the ability to rapidly identify optimal hyperparameter values specific to a dataset, image contrast, task, or even anatomical region, all without the need to retrain models. We make our code publicly available at http://hypermorph.voxelmorph.net., Comment: Accepted for publication at the Journal of Machine Learning for Biomedical Imaging (MELBA) at https://www.melba-journal.org

Personal space (PS) is the distance that people prefer to maintain between themselves and unfamiliar others. Interpersonal intrusion into a given persons PS evokes discomfort, and an urge to move further apart. We hypothesized that in parietal cortex: 1. PS processing involves a previously-described threat-sensitive brain circuit, and 2. the spatial encoding of distance is transformed accordingly, from purely sensory to PS-related. These hypotheses were tested using 7T fMRI at high spatial resolution. In response to images of different visual stimuli across a range of virtual distances, we found two categories of distance encoding in functionally corresponding columns within parietal cortex. First, PD (personal distance) columns responded selectively to moving and stationary face images presented at virtual distances nearer (but not further) than each subjects behaviorally-defined PS boundary. In the majority of PD columns, BOLD response amplitudes increased monotonically and nonlinearly with increasing virtual face proximity. In the remaining PD columns, BOLD responses decreased with increasing proximity. These fMRI response functions appear related to previously-reported variations in subjective discomfort levels, and physiologic arousal, during intrusion into but not beyond personal space. Secondly, DD (disparity distance) columns in parietal cortex responded selectively to disparity-based near or far distances, in random dot stimuli, like disparity-selective columns described previously in occipital cortex. In parietal cortex, maps of DD columns were systematically non-overlapping (interdigitated) with the PD columns. These results suggest that the transformation of spatial information, from visual to higher-order, may be computed in multiple small sites, rather than across a larger cortical gradient, in parietal cortex., Comment: 19 pages, 10 figures and 1 table. Tootell and Nasiriavanaki share joint first authorship

Despite advances in data augmentation and transfer learning, convolutional neural networks (CNNs) difficultly generalise to unseen domains. When segmenting brain scans, CNNs are highly sensitive to changes in resolution and contrast: even within the same MRI modality, performance can decrease across datasets. Here we introduce SynthSeg, the first segmentation CNN robust against changes in contrast and resolution. SynthSeg is trained with synthetic data sampled from a generative model conditioned on segmentations. Crucially, we adopt a domain randomisation strategy where we fully randomise the contrast and resolution of the synthetic training data. Consequently, SynthSeg can segment real scans from a wide range of target domains without retraining or fine-tuning, which enables straightforward analysis of huge amounts of heterogeneous clinical data. Because SynthSeg only requires segmentations to be trained (no images), it can learn from labels obtained by automated methods on diverse populations (e.g., ageing and diseased), thus achieving robustness to a wide range of morphological variability. We demonstrate SynthSeg on 5,000 scans of six modalities (including CT) and ten resolutions, where it exhibits unparalleled generalisation compared with supervised CNNs, state-of-the-art domain adaptation, and Bayesian segmentation. Finally, we demonstrate the generalisability of SynthSeg by applying it to cardiac MRI and CT scans.

In this paper we propose a novel method for the segmentation of longitudinal brain MRI scans of patients suffering from Multiple Sclerosis. The method builds upon an existing cross-sectional method for simultaneous whole-brain and lesion segmentation, introducing subject-specific latent variables to encourage temporal consistency between longitudinal scans. It is very generally applicable, as it does not make any prior assumptions on the scanner, the MRI protocol, or the number and timing of longitudinal follow-up scans. Preliminary experiments on three longitudinal datasets indicate that the proposed method produces more reliable segmentations and detects disease effects better than the cross-sectional method it is based upon.

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., Comment: 16 pages, 15 figures, 3 tables, deformable image registration, data independence, deep learning, MRI-contrast invariance, anatomy agnosticism, final published version

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., Comment: 19 pages, 5 figures

With the advent of convolutional neural networks~(CNN), supervised learning methods are increasingly being used for whole brain segmentation. However, a large, manually annotated training dataset of labeled brain images required to train such supervised methods is frequently difficult to obtain or create. In addition, existing training datasets are generally acquired with a homogeneous magnetic resonance imaging~(MRI) acquisition protocol. CNNs trained on such datasets are unable to generalize on test data with different acquisition protocols. Modern neuroimaging studies and clinical trials are necessarily multi-center initiatives with a wide variety of acquisition protocols. Despite stringent protocol harmonization practices, it is very difficult to standardize the gamut of MRI imaging parameters across scanners, field strengths, receive coils etc., that affect image contrast. In this paper we propose a CNN-based segmentation algorithm that, in addition to being highly accurate and fast, is also resilient to variation in the input acquisition. Our approach relies on building approximate forward models of pulse sequences that produce a typical test image. For a given pulse sequence, we use its forward model to generate plausible, synthetic training examples that appear as if they were acquired in a scanner with that pulse sequence. Sampling over a wide variety of pulse sequences results in a wide variety of augmented training examples that help build an image contrast invariant model. Our method trains a single CNN that can segment input MRI images with acquisition parameters as disparate as $T_1$-weighted and $T_2$-weighted contrasts with only $T_1$-weighted training data. The segmentations generated are highly accurate with state-of-the-art results~(overall Dice overlap$=0.94$), with a fast run time~($\approx$ 45 seconds), and consistent across a wide range of acquisition protocols., Comment: Typo in author name corrected. Greves -> Greve

The human thalamus is a brain structure that comprises numerous, highly specific nuclei. Since these nuclei are known to have different functions and to be connected to different areas of the cerebral cortex, it is of great interest for the neuroimaging community to study their volume, shape and connectivity in vivo with MRI. In this study, we present a probabilistic atlas of the thalamic nuclei built using ex vivo brain MRI scans and histological data, as well as the application of the atlas to in vivo MRI segmentation. The atlas was built using manual delineation of 26 thalamic nuclei on the serial histology of 12 whole thalami from six autopsy samples, combined with manual segmentations of the whole thalamus and surrounding structures (caudate, putamen, hippocampus, etc.) made on in vivo brain MR data from 39 subjects. The 3D structure of the histological data and corresponding manual segmentations was recovered using the ex vivo MRI as reference frame, and stacks of blockface photographs acquired during the sectioning as intermediate target. The atlas, which was encoded as an adaptive tetrahedral mesh, shows a good agreement with with previous histological studies of the thalamus in terms of volumes of representative nuclei. When applied to segmentation of in vivo scans using Bayesian inference, the atlas shows excellent test-retest reliability, robustness to changes in input MRI contrast, and ability to detect differential thalamic effects in subjects with Alzheimer's disease. The probabilistic atlas and companion segmentation tool are publicly available as part of the neuroimaging package FreeSurfer.

Parametric images provide insight into the spatial distribution of physiological parameters, but they are often extremely noisy, due to low SNR of tomographic data. Direct estimation from projections allows accurate noise modeling, improving the results of post-reconstruction fitting. We propose a method, which we name kinetic compressive sensing (KCS), based on a hierarchical Bayesian model and on a novel reconstruction algorithm, that encodes sparsity of kinetic parameters. Parametric maps are reconstructed by maximizing the joint probability, with an Iterated Conditional Modes (ICM) approach, alternating the optimization of activity time series (OS-MAP-OSL), and kinetic parameters (MAP-LM). We evaluated the proposed algorithm on a simulated dynamic phantom: a bias/variance study confirmed how direct estimates can improve the quality of parametric maps over a post-reconstruction fitting, and showed how the novel sparsity prior can further reduce their variance, without affecting bias. Real FDG PET human brain data (Siemens mMR, 40min) images were also processed. Results enforced how the proposed KCS-regularized direct method can produce spatially coherent images and parametric maps, with lower spatial noise and better tissue contrast. A GPU-based open source implementation of the algorithm is provided., Comment: 5 pages, 6 figures, Submitted to the Conference Record of "IEEE Nuclear Science Symposium and Medical Imaging Conference (IEEE NSS-MIC) 2017"