Katrin Amunts

Esteban Vaca, Miriam Menzel, Katrin Amunts et al.

Scattered Light Imaging (SLI) is a novel approach for microscopically revealing the fibre architecture of unstained brain sections. The measurements are obtained by illuminating brain sections from different angles and measuring the transmitted (scattered) light under normal incidence. The evaluation of scattering profiles commonly relies on a peak picking technique and feature extraction from the peaks, which allows quantitative determination of parallel and crossing in-plane nerve fibre directions for each image pixel. However, the estimation of the 3D orientation of the fibres cannot be assessed with the traditional methodology. We propose an unsupervised learning approach using spherical convolutions for estimating the 3D orientation of neural fibres, resulting in a more detailed interpretation of the fibre orientation distributions in the brain.

Jan-Oliver Kropp, Christian Schiffer, Katrin Amunts et al.

Recent advances in imaging and high-performance computing have made it possible to image the entire human brain at the cellular level. This is the basis to study the multi-scale architecture of the brain regarding its subdivision into brain areas and nuclei, cortical layers, columns, and cell clusters down to single cell morphology Methods for brain mapping and cell segmentation exploit such images to enable rapid and automated analysis of cytoarchitecture and cell distribution in complete series of histological sections. However, the presence of inevitable processing artifacts in the image data caused by missing sections, tears in the tissue, or staining variations remains the primary reason for gaps in the resulting image data. To this end we aim to provide a model that can fill in missing information in a reliable way, following the true cell distribution at different scales. Inspired by the recent success in image generation, we propose a denoising diffusion probabilistic model (DDPM), trained on light-microscopic scans of cell-body stained sections. We extend this model with the RePaint method to impute missing or replace corrupted image data. We show that our trained DDPM is able to generate highly realistic image information for this purpose, generating plausible cell statistics and cytoarchitectonic patterns. We validate its outputs using two established downstream task models trained on the same data.

Matthew Sutton, Katrin Amunts, Timo Dickscheid et al.

Foundation models increasingly offer potential to support interactive, agentic workflows that assist researchers during analysis and interpretation of image data. Such workflows often require coupling vision to language to provide a natural-language interface. However, paired image-text data needed to learn this coupling are scarce and difficult to obtain in many research and clinical settings. One such setting is microscopic analysis of cell-body-stained histological human brain sections, which enables the study of cytoarchitecture: cell density and morphology and their laminar and areal organization. Here, we propose a label-mediated method that generates meaningful captions from images by linking images and text only through a label, without requiring curated paired image-text data. Given the label, we automatically mine area descriptions from related literature and use them as synthetic captions reflecting canonical cytoarchitectonic attributes. An existing cytoarchitectonic vision foundation model (CytoNet) is then coupled to a large language model via an image-to-text training objective, enabling microscopy regions to be described in natural language. Across 57 brain areas, the resulting method produces plausible area-level descriptions and supports open-set use through explicit rejection of unseen areas. It matches the cytoarchitectonic reference label for in-scope patches with 90.6% accuracy and, with the area label masked, its descriptions remain discriminative enough to recover the area in an 8-way test with 68.6% accuracy. These results suggest that weak, label-mediated pairing can suffice to connect existing biomedical vision foundation models to language, providing a practical recipe for integrating natural-language in domains where fine-grained paired annotations are scarce.

Michael Schirner, Lia Domide, Dionysios Perdikis et al.

The Virtual Brain (TVB) is now available as open-source cloud ecosystem on EBRAINS, a shared digital research platform for brain science. It offers services for constructing, simulating and analysing brain network models (BNMs) including the TVB network simulator; magnetic resonance imaging (MRI) processing pipelines to extract structural and functional connectomes; multiscale co-simulation of spiking and large-scale networks; a domain specific language for automatic high-performance code generation from user-specified models; simulation-ready BNMs of patients and healthy volunteers; Bayesian inference of epilepsy spread; data and code for mouse brain simulation; and extensive educational material. TVB cloud services facilitate reproducible online collaboration and discovery of data assets, models, and software embedded in scalable and secure workflows, a precondition for research on large cohort data sets, better generalizability and clinical translation.

Alexander Oberstrass, Sascha E. A. Muenzing, Meiqi Niu et al.

A comprehensive understanding of the organizational principles in the human brain requires, among other factors, well-quantifiable descriptors of nerve fiber architecture. Three-dimensional polarized light imaging (3D-PLI) is a microscopic imaging technique that enables insights into the fine-grained organization of myelinated nerve fibers with high resolution. Descriptors characterizing the fiber architecture observed in 3D-PLI would enable downstream analysis tasks such as multimodal correlation studies, clustering, and mapping. However, best practices for observer-independent characterization of fiber architecture in 3D-PLI are not yet available. To this end, we propose the application of a fully data-driven approach to characterize nerve fiber architecture in 3D-PLI images using self-supervised representation learning. We introduce a 3D-Context Contrastive Learning (CL-3D) objective that utilizes the spatial neighborhood of texture examples across histological brain sections of a 3D reconstructed volume to sample positive pairs for contrastive learning. We combine this sampling strategy with specifically designed image augmentations to gain robustness to typical variations in 3D-PLI parameter maps. The approach is demonstrated for the 3D reconstructed occipital lobe of a vervet monkey brain. We show that extracted features are highly sensitive to different configurations of nerve fibers, yet robust to variations between consecutive brain sections arising from histological processing. We demonstrate their practical applicability for retrieving clusters of homogeneous fiber architecture, performing classification with minimal annotations, and query-based retrieval of characteristic components of fiber architecture such as U-fibers.

Alexander Oberstrass, Jordan DeKraker, Nicola Palomero-Gallagher et al.

Understanding the cortical organization of the human brain requires interpretable descriptors for distinct structural and functional imaging data. 3D polarized light imaging (3D-PLI) is an imaging modality for visualizing fiber architecture in postmortem brains with high resolution that also captures the presence of cell bodies, for example, to identify hippocampal subfields. The rich texture in 3D-PLI images, however, makes this modality particularly difficult to analyze and best practices for characterizing architectonic patterns still need to be established. In this work, we demonstrate a novel method to analyze the regional organization of the human hippocampus in 3D-PLI by combining recent advances in unfolding methods with deep texture features obtained using a self-supervised contrastive learning approach. We identify clusters in the representations that correspond well with classical descriptions of hippocampal subfields, lending validity to the developed methodology.

Christian Schiffer, Zeynep Boztoprak, Jan-Oliver Kropp et al.

To study how the human brain works, we need to explore the organization of the cerebral cortex and its detailed cellular architecture. We introduce CytoNet, a foundation model that encodes high-resolution microscopic image patches of the cerebral cortex into highly expressive feature representations, enabling comprehensive brain analyses. CytoNet employs self-supervised learning using spatial proximity as a powerful training signal, without requiring manual labelling. The resulting features are anatomically sound and biologically relevant. They encode general aspects of cortical architecture and unique brain-specific traits. We demonstrate top-tier performance in tasks such as cortical area classification, cortical layer segmentation, cell morphology estimation, and unsupervised brain region mapping. As a foundation model, CytoNet offers a consistent framework for studying cortical microarchitecture, supporting analyses of its relationship with other structural and functional brain features, and paving the way for diverse neuroscientific investigations.

Eric Upschulte, Stefan Harmeling, Katrin Amunts et al.

We present a conceptually simple framework for object instance segmentation called Contour Proposal Network (CPN), which detects possibly overlapping objects in an image while simultaneously fitting closed object contours using an interpretable, fixed-sized representation based on Fourier Descriptors. The CPN can incorporate state of the art object detection architectures as backbone networks into a single-stage instance segmentation model that can be trained end-to-end. We construct CPN models with different backbone networks, and apply them to instance segmentation of cells in datasets from different modalities. In our experiments, we show CPNs that outperform U-Nets and Mask R-CNNs in instance segmentation accuracy, and present variants with execution times suitable for real-time applications. The trained models generalize well across different domains of cell types. Since the main assumption of the framework are closed object contours, it is applicable to a wide range of detection problems also outside the biomedical domain. An implementation of the model architecture in PyTorch is freely available.

Christian Schiffer, Stefan Harmeling, Katrin Amunts et al.

Cytoarchitecture describes the spatial organization of neuronal cells in the brain, including their arrangement into layers and columns with respect to cell density, orientation, or presence of certain cell types. It allows to segregate the brain into cortical areas and subcortical nuclei, links structure with connectivity and function, and provides a microstructural reference for human brain atlases. Mapping boundaries between areas requires to scan histological sections at microscopic resolution. While recent high-throughput scanners allow to scan a complete human brain in the order of a year, it is practically impossible to delineate regions at the same pace using the established gold standard method. Researchers have recently addressed cytoarchitectonic mapping of cortical regions with deep neural networks, relying on image patches from individual 2D sections for classification. However, the 3D context, which is needed to disambiguate complex or obliquely cut brain regions, is not taken into account. In this work, we combine 2D histology with 3D topology by reformulating the mapping task as a node classification problem on an approximate 3D midsurface mesh through the isocortex. We extract deep features from cortical patches in 2D histological sections which are descriptive of cytoarchitecture, and assign them to the corresponding nodes on the 3D mesh to construct a large attributed graph. By solving the brain mapping problem on this graph using graph neural networks, we obtain significantly improved classification results. The proposed framework lends itself nicely to integration of additional neuroanatomical priors for mapping.

Christian Schiffer, Katrin Amunts, Stefan Harmeling et al.

Cytoarchitectonic maps provide microstructural reference parcellations of the brain, describing its organization in terms of the spatial arrangement of neuronal cell bodies as measured from histological tissue sections. Recent work provided the first automatic segmentations of cytoarchitectonic areas in the visual system using Convolutional Neural Networks. We aim to extend this approach to become applicable to a wider range of brain areas, envisioning a solution for mapping the complete human brain. Inspired by recent success in image classification, we propose a contrastive learning objective for encoding microscopic image patches into robust microstructural features, which are efficient for cytoarchitectonic area classification. We show that a model pre-trained using this learning task outperforms a model trained from scratch, as well as a model pre-trained on a recently proposed auxiliary task. We perform cluster analysis in the feature space to show that the learned representations form anatomically meaningful groups.

Christian Schiffer, Hannah Spitzer, Kai Kiwitz et al.

Human brain atlases provide spatial reference systems for data characterizing brain organization at different levels, coming from different brains. Cytoarchitecture is a basic principle of the microstructural organization of the brain, as regional differences in the arrangement and composition of neuronal cells are indicators of changes in connectivity and function. Automated scanning procedures and observer-independent methods are prerequisites to reliably identify cytoarchitectonic areas, and to achieve reproducible models of brain segregation. Time becomes a key factor when moving from the analysis of single regions of interest towards high-throughput scanning of large series of whole-brain sections. Here we present a new workflow for mapping cytoarchitectonic areas in large series of cell-body stained histological sections of human postmortem brains. It is based on a Deep Convolutional Neural Network (CNN), which is trained on a pair of section images with annotations, with a large number of un-annotated sections in between. The model learns to create all missing annotations in between with high accuracy, and faster than our previous workflow based on observer-independent mapping. The new workflow does not require preceding 3D-reconstruction of sections, and is robust against histological artefacts. It processes large data sets with sizes in the order of multiple Terabytes efficiently. The workflow was integrated into a web interface, to allow access without expertise in deep learning and batch computing. Applying deep neural networks for cytoarchitectonic mapping opens new perspectives to enable high-resolution models of brain areas, introducing CNNs to identify borders of brain areas.

Sharib Ali, Martin Schober, Philipp Schlöme et al.

3D reconstruction of the fiber connectivity of the rat brain at microscopic scale enables gaining detailed insight about the complex structural organization of the brain. We introduce a new method for registration and 3D reconstruction of high- and ultra-high resolution (64 $μ$m and 1.3 $μ$m pixel size) histological images of a Wistar rat brain acquired by 3D polarized light imaging (3D-PLI). Our method exploits multi-scale and multi-modal 3D-PLI data up to cellular resolution. We propose a new feature transform-based similarity measure and a weighted regularization scheme for accurate and robust non-rigid registration. To transform the 1.3 $μ$m ultra-high resolution data to the reference blockface images a feature-based registration method followed by a non-rigid registration is proposed. Our approach has been successfully applied to 278 histological sections of a rat brain and the performance has been quantitatively evaluated using manually placed landmarks by an expert.

Hannah Spitzer, Kai Kiwitz, Katrin Amunts et al.

Cytoarchitectonic parcellations of the human brain serve as anatomical references in multimodal atlas frameworks. They are based on analysis of cell-body stained histological sections and the identification of borders between brain areas. The de-facto standard involves a semi-automatic, reproducible border detection, but does not scale with high-throughput imaging in large series of sections at microscopical resolution. Automatic parcellation, however, is extremely challenging due to high variation in the data, and the need for a large field of view at microscopic resolution. The performance of a recently proposed Convolutional Neural Network model that addresses this problem especially suffers from the naturally limited amount of expert annotations for training. To circumvent this limitation, we propose to pre-train neural networks on a self-supervised auxiliary task, predicting the 3D distance between two patches sampled from the same brain. Compared to a random initialization, fine-tuning from these networks results in significantly better segmentations. We show that the self-supervised model has implicitly learned to distinguish several cortical brain areas -- a strong indicator that the proposed auxiliary task is appropriate for cytoarchitectonic mapping.

Hannah Spitzer, Katrin Amunts, Stefan Harmeling et al.

Microscopic analysis of histological sections is considered the "gold standard" to verify structural parcellations in the human brain. Its high resolution allows the study of laminar and columnar patterns of cell distributions, which build an important basis for the simulation of cortical areas and networks. However, such cytoarchitectonic mapping is a semiautomatic, time consuming process that does not scale with high throughput imaging. We present an automatic approach for parcellating histological sections at 2um resolution. It is based on a convolutional neural network that combines topological information from probabilistic atlases with the texture features learned from high-resolution cell-body stained images. The model is applied to visual areas and trained on a sparse set of partial annotations. We show how predictions are transferable to new brains and spatially consistent across sections.