Martin Reuter

Santiago Estrada, David Kügler, Emad Bahrami et al.

The hypothalamus plays a crucial role in the regulation of a broad range of physiological, behavioural, and cognitive functions. However, despite its importance, only a few small-scale neuroimaging studies have investigated its substructures, likely due to the lack of fully automated segmentation tools to address scalability and reproducibility issues of manual segmentation. While the only previous attempt to automatically sub-segment the hypothalamus with a neural network showed promise for 1.0 mm isotropic T1-weighted (T1w) MRI, there is a need for an automated tool to sub-segment also high-resolutional (HiRes) MR scans, as they are becoming widely available, and include structural detail also from multi-modal MRI. We, therefore, introduce a novel, fast, and fully automated deep learning method named HypVINN for sub-segmentation of the hypothalamus and adjacent structures on 0.8 mm isotropic T1w and T2w brain MR images that is robust to missing modalities. We extensively validate our model with respect to segmentation accuracy, generalizability, in-session test-retest reliability, and sensitivity to replicate hypothalamic volume effects (e.g. sex-differences). The proposed method exhibits high segmentation performance both for standalone T1w images as well as for T1w/T2w image pairs. Even with the additional capability to accept flexible inputs, our model matches or exceeds the performance of state-of-the-art methods with fixed inputs. We, further, demonstrate the generalizability of our method in experiments with 1.0 mm MR scans from both the Rhineland Study and the UK Biobank. Finally, HypVINN can perform the segmentation in less than a minute (GPU) and will be available in the open source FastSurfer neuroimaging software suite, offering a validated, efficient, and scalable solution for evaluating imaging-derived phenotypes of the hypothalamus.

Kersten Diers, Hannah Baumeister, Frank Jessen et al.

The hippocampus is one of the most studied neuroanatomical structures due to its involvement in attention, learning, and memory as well as its atrophy in ageing, neurological, and psychiatric diseases. Hippocampal shape changes, however, are complex and cannot be fully characterized by a single summary metric such as hippocampal volume as determined from MR images. In this work, we propose an automated, geometry-based approach for the unfolding, point-wise correspondence, and local analysis of hippocampal shape features such as thickness and curvature. Starting from an automated segmentation of hippocampal subfields, we create a 3D tetrahedral mesh model as well as a 3D intrinsic coordinate system of the hippocampal body. From this coordinate system, we derive local curvature and thickness estimates as well as a 2D sheet for hippocampal unfolding. We evaluate the performance of our algorithm with a series of experiments to quantify neurodegenerative changes in Mild Cognitive Impairment and Alzheimer's disease dementia. We find that hippocampal thickness estimates detect known differences between clinical groups and can determine the location of these effects on the hippocampal sheet. Further, thickness estimates improve classification of clinical groups and cognitively unimpaired controls when added as an additional predictor. Comparable results are obtained with different datasets and segmentation algorithms. Taken together, we replicate canonical findings on hippocampal volume/shape changes in dementia, extend them by gaining insight into their spatial localization on the hippocampal sheet, and provide additional, complementary information beyond traditional measures. We provide a new set of sensitive processing and analysis tools for the analysis of hippocampal geometry that allows comparisons across studies without relying on image registration or requiring manual intervention.

Clemens Pollak, David Kügler, Martin Reuter

Head motion is an omnipresent confounder of magnetic resonance image (MRI) analyses as it systematically affects morphometric measurements, even when visual quality control is performed. In order to estimate subtle head motion, that remains undetected by experts, we introduce a deep learning method to predict in-scanner head motion directly from T1-weighted (T1w), T2-weighted (T2w) and fluid-attenuated inversion recovery (FLAIR) images using motion estimates from an in-scanner depth camera as ground truth. Since we work with data from compliant healthy participants of the Rhineland Study, head motion and resulting imaging artifacts are less prevalent than in most clinical cohorts and more difficult to detect. Our method demonstrates improved performance compared to state-of-the-art motion estimation methods and can quantify drift and respiration movement independently. Finally, on unseen data, our predictions preserve the known, significant correlation with age.

Leonie Henschel, David Kügler, Lilla Zöllei et al.

Fast and accurate segmentation of neonatal brain images is highly desired to better understand and detect changes during development and disease. Yet, the limited availability of ground truth datasets, lack of standardized acquisition protocols, and wide variations of head positioning pose challenges for method development. A few automated image analysis pipelines exist for newborn brain MRI segmentation, but they often rely on time-consuming procedures and require resampling to a common resolution, subject to loss of information due to interpolation and down-sampling. Without registration and image resampling, variations with respect to head positions and voxel resolutions have to be addressed differently. In deep-learning, external augmentations are traditionally used to artificially expand the representation of spatial variability, increasing the training dataset size and robustness. However, these transformations in the image space still require resampling, reducing accuracy specifically in the context of label interpolation. We recently introduced the concept of resolution-independence with the Voxel-size Independent Neural Network framework, VINN. Here, we extend this concept by additionally shifting all rigid-transforms into the network architecture with a four degree of freedom (4-DOF) transform module, enabling resolution-aware internal augmentations (VINNA). In this work we show that VINNA (i) significantly outperforms state-of-the-art external augmentation approaches, (ii) effectively addresses the head variations present specifically in newborn datasets, and (iii) retains high segmentation accuracy across a range of resolutions (0.5-1.0 mm). The 4-DOF transform module is a powerful, general approach to implement spatial augmentation without requiring image or label interpolation. The specific network application to newborns will be made publicly available as VINNA4neonates.

Leonie Henschel, David Kügler, Derek S Andrews et al.

Exploration of bias has significant impact on the transparency and applicability of deep learning pipelines in medical settings, yet is so far woefully understudied. In this paper, we consider two separate groups for which training data is only available at differing image resolutions. For group H, available images and labels are at the preferred high resolution while for group L only deprecated lower resolution data exist. We analyse how this resolution-bias in the data distribution propagates to systematically biased predictions for group L at higher resolutions. Our results demonstrate that single-resolution training settings result in significant loss of volumetric group differences that translate to erroneous segmentations as measured by DSC and subsequent classification failures on the low resolution group. We further explore how training data across resolutions can be used to combat this systematic bias. Specifically, we investigate the effect of image resampling, scale augmentation and resolution independence and demonstrate that biases can effectively be reduced with multi-resolution approaches.

Tobias Kiecker, Jan Arne Sparka, Martin Reuter et al.

Maintaining consistency between code and documentation is a crucial yet frequently overlooked aspect of software development. Even minor mismatches can confuse API users, introduce new bugs, and increase overall maintenance effort. This creates demand for automated solutions that can assist developers in identifying code-documentation inconsistencies. However, since automatic reports still require human confirmation, false positives carry serious consequences: wasting developer time and discouraging practical adoption. We introduce CASCADE (Consistency Analysis for Source Code And Documentation through Execution), a novel tool for detecting inconsistencies with a strong emphasis on reducing false positives. CASCADE leverages Large Language Models (LLMs) to generate unit tests directly from natural-language documentation. Since these tests are derived from the documentation, any failure during execution indicates a potential mismatch between the documented and actual behavior of the code. To minimize false positives, CASCADE also generates code from the documentation to cross-check the generated tests. By design, an inconsistency is reported only when two conditions are met: the existing code fails a test, while the code generated from the documentation passes the same test. We evaluated CASCADE on a novel dataset of 71 inconsistent and 814 consistent code-documentation pairs drawn from open-source Java projects. Further, we applied CASCADE to additional Java, C#, and Rust repositories, where we uncovered 13 previously unknown inconsistencies, of which 10 have subsequently been fixed, demonstrating both CASCADE's precision and its applicability to real-world codebases.

Nicolás Nieto, Simon B. Eickhoff, Christian Jung et al.

Machine learning (ML) models benefit from large datasets. Collecting data in biomedical domains is costly and challenging, hence, combining datasets has become a common practice. However, datasets obtained under different conditions could present undesired site-specific variability. Data harmonization methods aim to remove site-specific variance while retaining biologically relevant information. This study evaluates the effectiveness of popularly used ComBat-based methods for harmonizing data in scenarios where the class balance is not equal across sites. We find that these methods struggle with data leakage issues. To overcome this problem, we propose a novel approach PrettYharmonize, designed to harmonize data by pretending the target labels. We validate our approach using controlled datasets designed to benchmark the utility of harmonization. Finally, using real-world MRI and clinical data, we compare leakage-prone methods with PrettYharmonize and show that it achieves comparable performance while avoiding data leakage, particularly in site-target-dependence scenarios.

Clemens Pollak, Kersten Diers, Santiago Estrada et al.

The corpus callosum, the largest commissural structure in the human brain, is a central focus in research on aging and neurological diseases. It is also a critical target for interventions such as deep brain stimulation and serves as an important biomarker in clinical trials, including those investigating remyelination therapies. Despite extensive research on corpus callosum segmentation, few publicly available tools provide a comprehensive and automated analysis pipeline. To address this gap, we present FastSurfer-CC, an efficient and fully automated framework for corpus callosum morphometry. FastSurfer-CC automatically identifies mid-sagittal slices, segments the corpus callosum and fornix, localizes the anterior and posterior commissures to standardize head positioning, generates thickness profiles and subdivisions, and extracts eight shape metrics for statistical analysis. We demonstrate that FastSurfer-CC outperforms existing specialized tools across the individual tasks. Moreover, our method reveals statistically significant differences between Huntington's disease patients and healthy controls that are not detected by the current state-of-the-art.

Sebastian Rassmann, David Kügler, Christian Ewert et al.

While Generative Adversarial Nets (GANs) and Diffusion Models (DMs) have achieved impressive results in natural image synthesis, their core strengths - creativity and realism - can be detrimental in medical applications, where accuracy and fidelity are paramount. These models instead risk introducing hallucinations and replication of unwanted acquisition noise. Here, we propose YODA (You Only Denoise once - or Average), a 2.5D diffusion-based framework for medical image translation (MIT). Consistent with DM theory, we find that conventional diffusion sampling stochastically replicates noise. To mitigate this, we draw and average multiple samples, akin to physical signal averaging. As this effectively approximates the DM's expected value, we term this Expectation-Approximation (ExpA) sampling. We additionally propose regression sampling YODA, which retains the initial DM prediction and omits iterative refinement to produce noise-free images in a single step. Across five diverse multi-modal datasets - including multi-contrast brain MRI and pelvic MRI-CT - we demonstrate that regression sampling is not only substantially more efficient but also matches or exceeds image quality of full diffusion sampling even with ExpA. Our results reveal that iterative refinement solely enhances perceptual realism without benefiting information translation, which we confirm in relevant downstream tasks. YODA outperforms eight state-of-the-art DMs and GANs and challenges the presumed superiority of DMs and GANs over computationally cheap regression models for high-quality MIT. Furthermore, we show that YODA-translated images are interchangeable with, or even superior to, physical acquisitions for several medical applications.

Leonie Henschel, David Kügler, Martin Reuter

Leading neuroimaging studies have pushed 3T MRI acquisition resolutions below 1.0 mm for improved structure definition and morphometry. Yet, only few, time-intensive automated image analysis pipelines have been validated for high-resolution (HiRes) settings. Efficient deep learning approaches, on the other hand, rarely support more than one fixed resolution (usually 1.0 mm). Furthermore, the lack of a standard submillimeter resolution as well as limited availability of diverse HiRes data with sufficient coverage of scanner, age, diseases, or genetic variance poses additional, unsolved challenges for training HiRes networks. Incorporating resolution-independence into deep learning-based segmentation, i.e., the ability to segment images at their native resolution across a range of different voxel sizes, promises to overcome these challenges, yet no such approach currently exists. We now fill this gap by introducing a Voxelsize Independent Neural Network (VINN) for resolution-independent segmentation tasks and present FastSurferVINN, which (i) establishes and implements resolution-independence for deep learning as the first method simultaneously supporting 0.7-1.0 mm whole brain segmentation, (ii) significantly outperforms state-of-the-art methods across resolutions, and (iii) mitigates the data imbalance problem present in HiRes datasets. Overall, internal resolution-independence mutually benefits both HiRes and 1.0 mm MRI segmentation. With our rigorously validated FastSurferVINN we distribute a rapid tool for morphometric neuroimage analysis. The VINN architecture, furthermore, represents an efficient resolution-independent segmentation method for wider application

Malte Hoffmann, Esra Abaci Turk, Borjan Gagoski et al.

In fetal-brain MRI, head-pose changes between prescription and acquisition present a challenge to obtaining the standard sagittal, coronal and axial views essential to clinical assessment. As motion limits acquisitions to thick slices that preclude retrospective resampling, technologists repeat ~55-second stack-of-slices scans (HASTE) with incrementally reoriented field of view numerous times, deducing the head pose from previous stacks. To address this inefficient workflow, we propose a robust head-pose detection algorithm using full-uterus scout scans (EPI) which take ~5 seconds to acquire. Our ~2-second procedure automatically locates the fetal brain and eyes, which we derive from maximally stable extremal regions (MSERs). The success rate of the method exceeds 94% in the third trimester, outperforming a trained technologist by up to 20%. The pipeline may be used to automatically orient the anatomical sequence, removing the need to estimate the head pose from 2D views and reducing delays during which motion can occur.

Santiago Estrada, Ran Lu, Kersten Diers et al.

The neuroimage analysis community has neglected the automated segmentation of the olfactory bulb (OB) despite its crucial role in olfactory function. The lack of an automatic processing method for the OB can be explained by its challenging properties. Nonetheless, recent advances in MRI acquisition techniques and resolution have allowed raters to generate more reliable manual annotations. Furthermore, the high accuracy of deep learning methods for solving semantic segmentation problems provides us with an option to reliably assess even small structures. In this work, we introduce a novel, fast, and fully automated deep learning pipeline to accurately segment OB tissue on sub-millimeter T2-weighted (T2w) whole-brain MR images. To this end, we designed a three-stage pipeline: (1) Localization of a region containing both OBs using FastSurferCNN, (2) Segmentation of OB tissue within the localized region through four independent AttFastSurferCNN - a novel deep learning architecture with a self-attention mechanism to improve modeling of contextual information, and (3) Ensemble of the predicted label maps. The OB pipeline exhibits high performance in terms of boundary delineation, OB localization, and volume estimation across a wide range of ages in 203 participants of the Rhineland Study. Moreover, it also generalizes to scans of an independent dataset never encountered during training, the Human Connectome Project (HCP), with different acquisition parameters and demographics, evaluated in 30 cases at the native 0.7mm HCP resolution, and the default 0.8mm pipeline resolution. We extensively validated our pipeline not only with respect to segmentation accuracy but also to known OB volume effects, where it can sensitively replicate age effects.

Christian Ewert, David Kügler, Anastasia Yendiki et al.

Deep learning approaches for diffusion MRI have so far focused primarily on voxel-based segmentation of lesions or white-matter fiber tracts. A drawback of representing tracts as volumetric labels, rather than sets of streamlines, is that it precludes point-wise analyses of microstructural or geometric features along a tract. Traditional tractography pipelines, which do allow such analyses, can benefit from detailed whole-brain segmentations to guide tract reconstruction. Here, we introduce fast, deep learning-based segmentation of 170 anatomical regions directly on diffusion-weighted MR images, removing the dependency of conventional segmentation methods on T 1-weighted images and slow pre-processing pipelines. Working natively in diffusion space avoids non-linear distortions and registration errors across modalities, as well as interpolation artifacts. We demonstrate consistent segmentation results between 0 .70 and 0 .87 Dice depending on the tissue type. We investigate various combinations of diffusion-derived inputs and show generalization across different numbers of gradient directions. Finally, integrating our approach to provide anatomical priors for tractography pipelines, such as TRACULA, removes hours of pre-processing time and permits processing even in the absence of high-quality T 1-weighted scans, without degrading the quality of the resulting tract estimates.

Leonie Henschel, Sailesh Conjeti, Santiago Estrada et al.

Traditional neuroimage analysis pipelines involve computationally intensive, time-consuming optimization steps, and thus, do not scale well to large cohort studies with thousands or tens of thousands of individuals. In this work we propose a fast and accurate deep learning based neuroimaging pipeline for the automated processing of structural human brain MRI scans, replicating FreeSurfer's anatomical segmentation including surface reconstruction and cortical parcellation. To this end, we introduce an advanced deep learning architecture capable of whole brain segmentation into 95 classes. The network architecture incorporates local and global competition via competitive dense blocks and competitive skip pathways, as well as multi-slice information aggregation that specifically tailor network performance towards accurate segmentation of both cortical and sub-cortical structures. Further, we perform fast cortical surface reconstruction and thickness analysis by introducing a spectral spherical embedding and by directly mapping the cortical labels from the image to the surface. This approach provides a full FreeSurfer alternative for volumetric analysis (in under 1 minute) and surface-based thickness analysis (within only around 1h runtime). For sustainability of this approach we perform extensive validation: we assert high segmentation accuracy on several unseen datasets, measure generalizability and demonstrate increased test-retest reliability, and high sensitivity to group differences in dementia.

Santiago Estrada, Ran Lu, Sailesh Conjeti et al.

Purpose: Development of a fast and fully automated deep learning pipeline (FatSegNet) to accurately identify, segment, and quantify abdominal adipose tissue on Dixon MRI from the Rhineland Study - a large prospective population-based study. Method: FatSegNet is composed of three stages: (i) consistent localization of the abdominal region using two 2D-Competitive Dense Fully Convolutional Networks (CDFNet), (ii) segmentation of adipose tissue on three views by independent CDFNets, and (iii) view aggregation. FatSegNet is trained with 33 manually annotated subjects, and validated by: 1) comparison of segmentation accuracy against a testingset covering a wide range of body mass index (BMI), 2) test-retest reliability, and 3) robustness in a large cohort study. Results: The CDFNet demonstrates increased robustness compared to traditional deep learning networks. FatSegNet dice score outperforms manual raters on the abdominal visceral adipose tissue (VAT, 0.828 vs. 0.788), and produces comparable results on subcutaneous adipose tissue (SAT, 0.973 vs. 0.982). The pipeline has very small test-retest absolute percentage difference and excellent agreement between scan sessions (VAT: APD = 2.957%, ICC=0.998 and SAT: APD= 3.254%, ICC=0.996). Conclusion: FatSegNet can reliably analyze a 3D Dixon MRI in1 min. It generalizes well to different body shapes, sensitively replicates known VAT and SAT volume effects in a large cohort study, and permits localized analysis of fat compartments.

Santiago Estrada, Sailesh Conjeti, Muneer Ahmad et al.

Increased information sharing through short and long-range skip connections between layers in fully convolutional networks have demonstrated significant improvement in performance for semantic segmentation. In this paper, we propose Competitive Dense Fully Convolutional Networks (CDFNet) by introducing competitive maxout activations in place of naive feature concatenation for inducing competition amongst layers. Within CDFNet, we propose two architectural contributions, namely competitive dense block (CDB) and competitive unpooling block (CUB) to induce competition at local and global scales for short and long-range skip connections respectively. This extension is demonstrated to boost learning of specialized sub-networks targeted at segmenting specific anatomies, which in turn eases the training of complex tasks. We present the proof-of-concept on the challenging task of whole body segmentation in the publicly available VISCERAL benchmark and demonstrate improved performance over multiple learning and registration based state-of-the-art methods.

Muneer Ahmad Dedmari, Sailesh Conjeti, Santiago Estrada et al.

Undersampling the k-space data is widely adopted for acceleration of Magnetic Resonance Imaging (MRI). Current deep learning based approaches for supervised learning of MRI image reconstruction employ real-valued operations and representations by treating complex valued k-space/spatial-space as real values. In this paper, we propose complex dense fully convolutional neural network ($\mathbb{C}$DFNet) for learning to de-alias the reconstruction artifacts within undersampled MRI images. We fashioned a densely-connected fully convolutional block tailored for complex-valued inputs by introducing dedicated layers such as complex convolution, batch normalization, non-linearities etc. $\mathbb{C}$DFNet leverages the inherently complex-valued nature of input k-space and learns richer representations. We demonstrate improved perceptual quality and recovery of anatomical structures through $\mathbb{C}$DFNet in contrast to its real-valued counterparts.

Christian Wachinger, Martin Reuter, Tassilo Klein

We introduce DeepNAT, a 3D Deep convolutional neural network for the automatic segmentation of NeuroAnaTomy in T1-weighted magnetic resonance images. DeepNAT is an end-to-end learning-based approach to brain segmentation that jointly learns an abstract feature representation and a multi-class classification. We propose a 3D patch-based approach, where we do not only predict the center voxel of the patch but also neighbors, which is formulated as multi-task learning. To address a class imbalance problem, we arrange two networks hierarchically, where the first one separates foreground from background, and the second one identifies 25 brain structures on the foreground. Since patches lack spatial context, we augment them with coordinates. To this end, we introduce a novel intrinsic parameterization of the brain volume, formed by eigenfunctions of the Laplace-Beltrami operator. As network architecture, we use three convolutional layers with pooling, batch normalization, and non-linearities, followed by fully connected layers with dropout. The final segmentation is inferred from the probabilistic output of the network with a 3D fully connected conditional random field, which ensures label agreement between close voxels. The roughly 2.7 million parameters in the network are learned with stochastic gradient descent. Our results show that DeepNAT compares favorably to state-of-the-art methods. Finally, the purely learning-based method may have a high potential for the adaptation to young, old, or diseased brains by fine-tuning the pre-trained network with a small training sample on the target application, where the availability of larger datasets with manual annotations may boost the overall segmentation accuracy in the future.