Towards contrast- and pathology-agnostic clinical fetal brain MRI segmentation using SynthSeg

Magnetic resonance imaging (MRI) has played a crucial role in fetal neurodevelopmental research. Structural annotations of MR images are an important step for quantitative analysis of the developing human brain, with Deep learning providing an automated alternative for this otherwise tedious manual process. However, segmentation performances of Convolutional Neural Networks often suffer from domain shift, where the network fails when applied to subjects that deviate from the distribution with which it is trained on. In this work, we aim to train networks capable of automatically segmenting fetal brain MRIs with a wide range of domain shifts pertaining to differences in subject physiology and acquisition environments, in particular shape-based differences commonly observed in pathological cases. We introduce a novel data-driven train-time sampling strategy that seeks to fully exploit the diversity of a given training dataset to enhance the domain generalizability of the trained networks. We adapted our sampler, together with other existing data augmentation techniques, to the SynthSeg framework, a generator that utilizes domain randomization to generate diverse training data, and ran thorough experimentations and ablation studies on a wide range of training/testing data to test the validity of the approaches. Our networks achieved notable improvements in the segmentation quality on testing subjects with intense anatomical abnormalities (p < 1e-4), though at the cost of a slighter decrease in performance in cases with fewer abnormalities. Our work also lays the foundation for future works on creating and adapting data-driven sampling strategies for other training pipelines.

Explainability of AI Uncertainty: Application to Multiple Sclerosis Lesion Segmentation on MRI

Trustworthy artificial intelligence (AI) is essential in healthcare, particularly for high-stakes tasks like medical image segmentation. Explainable AI and uncertainty quantification significantly enhance AI reliability by addressing key attributes such as robustness, usability, and explainability. Despite extensive technical advances in uncertainty quantification for medical imaging, understanding the clinical informativeness and interpretability of uncertainty remains limited. This study introduces a novel framework to explain the potential sources of predictive uncertainty, specifically in cortical lesion segmentation in multiple sclerosis using deep ensembles. The proposed analysis shifts the focus from the uncertainty-error relationship towards relevant medical and engineering factors. Our findings reveal that instance-wise uncertainty is strongly related to lesion size, shape, and cortical involvement. Expert rater feedback confirms that similar factors impede annotator confidence. Evaluations conducted on two datasets (206 patients, almost 2000 lesions) under both in-domain and distribution-shift conditions highlight the utility of the framework in different scenarios.

Automatic quality control in multi-centric fetal brain MRI super-resolution reconstruction

Quality control (QC) has long been considered essential to guarantee the reliability of neuroimaging studies. It is particularly important for fetal brain MRI, where acquisitions and image processing techniques are less standardized than in adult imaging. In this work, we focus on automated quality control of super-resolution reconstruction (SRR) volumes of fetal brain MRI, an important processing step where multiple stacks of thick 2D slices are registered together and combined to build a single, isotropic and artifact-free T2 weighted volume. We propose FetMRQC$_{SR}$, a machine-learning method that extracts more than 100 image quality metrics to predict image quality scores using a random forest model. This approach is well suited to a problem that is high dimensional, with highly heterogeneous data and small datasets. We validate FetMRQC$_{SR}$ in an out-of-domain (OOD) setting and report high performance (ROC AUC = 0.89), even when faced with data from an unknown site or SRR method. We also investigate failure cases and show that they occur in $45\%$ of the images due to ambiguous configurations for which the rating from the expert is arguable. These results are encouraging and illustrate how a non deep learning-based method like FetMRQC$_{SR}$ is well suited to this multifaceted problem. Our tool, along with all the code used to generate, train and evaluate the model will be released upon acceptance of the paper.

Maximizing domain generalization in fetal brain tissue segmentation: the role of synthetic data generation, intensity clustering and real image fine-tuning

Fetal brain tissue segmentation in magnetic resonance imaging (MRI) is a crucial tool that supports the understanding of neurodevelopment, yet it faces challenges due to the heterogeneity of data coming from different scanners and settings, and due to data scarcity. Recent approaches based on domain randomization, like SynthSeg, have shown a great potential for single source domain generalization, by simulating images with randomized contrast and image resolution from the label maps. In this work, we investigate how to maximize the out-of-domain (OOD) generalization potential of SynthSeg-based methods in fetal brain MRI. Specifically, when studying data generation, we demonstrate that the simple Gaussian mixture models used in SynthSeg enable more robust OOD generalization than physics-informed generation methods. We also investigate how intensity clustering can help create more faithful synthetic images, and observe that it is key to achieving a non-trivial OOD generalization capability when few label classes are available. Finally, by combining for the first time SynthSeg with modern fine-tuning approaches based on weight averaging, we show that fine-tuning a model pre-trained on synthetic data on a few real image-segmentation pairs in a new domain can lead to improvements in the target domain, but also in other domains. We summarize our findings as five key recommendations that we believe can guide practitioners who would like to develop SynthSeg-based approaches in other organs or modalities.

Ground-truth effects in learning-based fiber orientation distribution estimation in neonatal brains

Diffusion Magnetic Resonance Imaging (dMRI) is a non-invasive method for depicting brain microstructure in vivo. Fiber orientation distributions (FODs) are mathematical representations extensively used to map white matter fiber configurations. Recently, FOD estimation with deep neural networks has seen growing success, in particular, those of neonates estimated with fewer diffusion measurements. These methods are mostly trained on target FODs reconstructed with multi-shell multi-tissue constrained spherical deconvolution (MSMT-CSD), which might not be the ideal ground truth for developing brains. Here, we investigate this hypothesis by training a state-of-the-art model based on the U-Net architecture on both MSMT-CSD and single-shell three-tissue constrained spherical deconvolution (SS3T-CSD). Our results suggest that SS3T-CSD might be more suited for neonatal brains, given that the ratio between single and multiple fiber-estimated voxels with SS3T-CSD is more realistic compared to MSMT-CSD. Additionally, increasing the number of input gradient directions significantly improves performance with SS3T-CSD over MSMT-CSD. Finally, in an age domain-shift setting, SS3T-CSD maintains robust performance across age groups, indicating its potential for more accurate neonatal brain imaging.

Interpretability of Uncertainty: Exploring Cortical Lesion Segmentation in Multiple Sclerosis

Uncertainty quantification (UQ) has become critical for evaluating the reliability of artificial intelligence systems, especially in medical image segmentation. This study addresses the interpretability of instance-wise uncertainty values in deep learning models for focal lesion segmentation in magnetic resonance imaging, specifically cortical lesion (CL) segmentation in multiple sclerosis. CL segmentation presents several challenges, including the complexity of manual segmentation, high variability in annotation, data scarcity, and class imbalance, all of which contribute to aleatoric and epistemic uncertainty. We explore how UQ can be used not only to assess prediction reliability but also to provide insights into model behavior, detect biases, and verify the accuracy of UQ methods. Our research demonstrates the potential of instance-wise uncertainty values to offer post hoc global model explanations, serving as a sanity check for the model. The implementation is available at https://github.com/NataliiaMolch/interpret-lesion-unc.

Instance-level quantitative saliency in multiple sclerosis lesion segmentation

In recent years, explainable methods for artificial intelligence (XAI) have tried to reveal and describe models' decision mechanisms in the case of classification tasks. However, XAI for semantic segmentation and in particular for single instances has been little studied to date. Understanding the process underlying automatic segmentation of single instances is crucial to reveal what information was used to detect and segment a given object of interest. In this study, we proposed two instance-level explanation maps for semantic segmentation based on SmoothGrad and Grad-CAM++ methods. Then, we investigated their relevance for the detection and segmentation of white matter lesions (WML), a magnetic resonance imaging (MRI) biomarker in multiple sclerosis (MS). 687 patients diagnosed with MS for a total of 4043 FLAIR and MPRAGE MRI scans were collected at the University Hospital of Basel, Switzerland. Data were randomly split into training, validation and test sets to train a 3D U-Net for MS lesion segmentation. We observed 3050 true positive (TP), 1818 false positive (FP), and 789 false negative (FN) cases. We generated instance-level explanation maps for semantic segmentation, by developing two XAI methods based on SmoothGrad and Grad-CAM++. We investigated: 1) the distribution of gradients in saliency maps with respect to both input MRI sequences; 2) the model's response in the case of synthetic lesions; 3) the amount of perilesional tissue needed by the model to segment a lesion. Saliency maps (based on SmoothGrad) in FLAIR showed positive values inside a lesion and negative in its neighborhood. Peak values of saliency maps generated for these four groups of volumes presented distributions that differ significantly from one another, suggesting a quantitative nature of the proposed saliency. Contextual information of 7mm around the lesion border was required for their segmentation.

Improving cross-domain brain tissue segmentation in fetal MRI with synthetic data

Segmentation of fetal brain tissue from magnetic resonance imaging (MRI) plays a crucial role in the study of in utero neurodevelopment. However, automated tools face substantial domain shift challenges as they must be robust to highly heterogeneous clinical data, often limited in numbers and lacking annotations. Indeed, high variability of the fetal brain morphology, MRI acquisition parameters, and superresolution reconstruction (SR) algorithms adversely affect the model's performance when evaluated out-of-domain. In this work, we introduce FetalSynthSeg, a domain randomization method to segment fetal brain MRI, inspired by SynthSeg. Our results show that models trained solely on synthetic data outperform models trained on real data in out-ofdomain settings, validated on a 120-subject cross-domain dataset. Furthermore, we extend our evaluation to 40 subjects acquired using lowfield (0.55T) MRI and reconstructed with novel SR models, showcasing robustness across different magnetic field strengths and SR algorithms. Leveraging a generative synthetic approach, we tackle the domain shift problem in fetal brain MRI and offer compelling prospects for applications in fields with limited and highly heterogeneous data.

Multi-Center Fetal Brain Tissue Annotation (FeTA) Challenge 2022 Results

Segmentation is a critical step in analyzing the developing human fetal brain. There have been vast improvements in automatic segmentation methods in the past several years, and the Fetal Brain Tissue Annotation (FeTA) Challenge 2021 helped to establish an excellent standard of fetal brain segmentation. However, FeTA 2021 was a single center study, and the generalizability of algorithms across different imaging centers remains unsolved, limiting real-world clinical applicability. The multi-center FeTA Challenge 2022 focuses on advancing the generalizability of fetal brain segmentation algorithms for magnetic resonance imaging (MRI). In FeTA 2022, the training dataset contained images and corresponding manually annotated multi-class labels from two imaging centers, and the testing data contained images from these two imaging centers as well as two additional unseen centers. The data from different centers varied in many aspects, including scanners used, imaging parameters, and fetal brain super-resolution algorithms applied. 16 teams participated in the challenge, and 17 algorithms were evaluated. Here, a detailed overview and analysis of the challenge results are provided, focusing on the generalizability of the submissions. Both in- and out of domain, the white matter and ventricles were segmented with the highest accuracy, while the most challenging structure remains the cerebral cortex due to anatomical complexity. The FeTA Challenge 2022 was able to successfully evaluate and advance generalizability of multi-class fetal brain tissue segmentation algorithms for MRI and it continues to benchmark new algorithms. The resulting new methods contribute to improving the analysis of brain development in utero.

Cross-Age and Cross-Site Domain Shift Impacts on Deep Learning-Based White Matter Fiber Estimation in Newborn and Baby Brains

Deep learning models have shown great promise in estimating tissue microstructure from limited diffusion magnetic resonance imaging data. However, these models face domain shift challenges when test and train data are from different scanners and protocols, or when the models are applied to data with inherent variations such as the developing brains of infants and children scanned at various ages. Several techniques have been proposed to address some of these challenges, such as data harmonization or domain adaptation in the adult brain. However, those techniques remain unexplored for the estimation of fiber orientation distribution functions in the rapidly developing brains of infants. In this work, we extensively investigate the age effect and domain shift within and across two different cohorts of 201 newborns and 165 babies using the Method of Moments and fine-tuning strategies. Our results show that reduced variations in the microstructural development of babies in comparison to newborns directly impact the deep learning models' cross-age performance. We also demonstrate that a small number of target domain samples can significantly mitigate domain shift problems.