Manfredo Atzori

Louis Fabrice Tshimanga, Manfredo Atzori, Federico Del Pup et al.

In recent years, deep learning revolutionized machine learning and its applications, producing results comparable to human experts in several domains, including neuroscience. Each year, hundreds of scientific publications present applications of deep neural networks for biomedical data analysis. Due to the fast growth of the domain, it could be a complicated and extremely time-consuming task for worldwide researchers to have a clear perspective of the most recent and advanced software libraries. This work contributes to clarify the current situation in the domain, outlining the most useful libraries that implement and facilitate deep learning application to neuroscience, allowing scientists to identify the most suitable options for their research or clinical projects. This paper summarizes the main developments in Deep Learning and their relevance to Neuroscience; it then reviews neuroinformatic toolboxes and libraries, collected from the literature and from specific hubs of software projects oriented to neuroscience research. The selected tools are presented in tables detailing key features grouped by domain of application (e.g. data type, neuroscience area, task), model engineering (e.g. programming language, model customization) and technological aspect (e.g. interface, code source). The results show that, among a high number of available software tools, several libraries are standing out in terms of functionalities for neuroscience applications. The aggregation and discussion of this information can help the neuroscience community to devolop their research projects more efficiently and quickly, both by means of readily available tools, and by knowing which modules may be improved, connected or added.

Tommaso Giannantonio, Anna Alperovich, Piercosimo Semeraro et al.

Surgery for gliomas (intrinsic brain tumors), especially when low-grade, is challenging due to the infiltrative nature of the lesion. Currently, no real-time, intra-operative, label-free and wide-field tool is available to assist and guide the surgeon to find the relevant demarcations for these tumors. While marker-based methods exist for the high-grade glioma case, there is no convenient solution available for the low-grade case; thus, marker-free optical techniques represent an attractive option. Although RGB imaging is a standard tool in surgical microscopes, it does not contain sufficient information for tissue differentiation. We leverage the richer information from hyperspectral imaging (HSI), acquired with a snapscan camera in the 468-787 nm range, coupled to a surgical microscope, to build a deep-learning-based diagnostic tool for cancer resection with potential for intra-operative guidance. However, the main limitation of the HSI snapscan camera is the image acquisition time, limiting its widespread deployment in the operation theater. Here, we investigate the effect of HSI channel reduction and pre-selection to scope the design space for the development of cheaper and faster sensors. Neural networks are used to identify the most important spectral channels for tumor tissue differentiation, optimizing the trade-off between the number of channels and precision to enable real-time intra-surgical application. We evaluate the performance of our method on a clinical dataset that was acquired during surgery on five patients. By demonstrating the possibility to efficiently detect low-grade glioma, these results can lead to better cancer resection demarcations, potentially improving treatment effectiveness and patient outcome.

Marek Wodzinski, Artur Jurgas, Niccolo Marini et al.

Registration of brain scans with pathologies is difficult, yet important research area. The importance of this task motivated researchers to organize the BraTS-Reg challenge, jointly with IEEE ISBI 2022 and MICCAI 2022 conferences. The organizers introduced the task of aligning pre-operative to follow-up magnetic resonance images of glioma. The main difficulties are connected with the missing data leading to large, nonrigid, and noninvertible deformations. In this work, we describe our contributions to both the editions of the BraTS-Reg challenge. The proposed method is based on combined deep learning and instance optimization approaches. First, the instance optimization enriches the state-of-the-art LapIRN method to improve the generalizability and fine-details preservation. Second, an additional objective function weighting is introduced, based on the inverse consistency. The proposed method is fully unsupervised and exhibits high registration quality and robustness. The quantitative results on the external validation set are: (i) IEEE ISBI 2022 edition: 1.85, and 0.86, (ii) MICCAI 2022 edition: 1.71, and 0.86, in terms of the mean of median absolute error and robustness respectively. The method scored the 1st place during the IEEE ISBI 2022 version of the challenge and the 3rd place during the MICCAI 2022. Future work could transfer the inverse consistency-based weighting directly into the deep network training.

Federico Del Pup, Andrea Zanola, Louis Fabrice Tshimanga et al.

SelfEEG is an open-source Python library developed to assist researchers in conducting Self-Supervised Learning (SSL) experiments on electroencephalography (EEG) data. Its primary objective is to offer a user-friendly but highly customizable environment, enabling users to efficiently design and execute self-supervised learning tasks on EEG data. SelfEEG covers all the stages of a typical SSL pipeline, ranging from data import to model design and training. It includes modules specifically designed to: split data at various granularity levels (e.g., session-, subject-, or dataset-based splits); effectively manage data stored with different configurations (e.g., file extensions, data types) during mini-batch construction; provide a wide range of standard deep learning models, data augmentations and SSL baseline methods applied to EEG data. Most of the functionalities offered by selfEEG can be executed both on GPUs and CPUs, expanding its usability beyond the self-supervised learning area. Additionally, these functionalities can be employed for the analysis of other biomedical signals often coupled with EEGs, such as electromyography or electrocardiography data. These features make selfEEG a versatile deep learning tool for biomedical applications and a useful resource in SSL, one of the currently most active fields of Artificial Intelligence.

Louis Fabrice Tshimanga, Andrea Zanola, Federico Del Pup et al.

We present Token-UNet, adopting the TokenLearner and TokenFuser modules to encase Transformers into UNets. While Transformers have enabled global interactions among input elements in medical imaging, current computational challenges hinder their deployment on common hardware. Models like (Swin)UNETR adapt the UNet architecture by incorporating (Swin)Transformer encoders, which process tokens that each represent small subvolumes ($8^3$ voxels) of the input. The Transformer attention mechanism scales quadratically with the number of tokens, which is tied to the cubic scaling of 3D input resolution. This work reconsiders the role of convolution and attention, introducing Token-UNets, a family of 3D segmentation models that can operate in constrained computational environments and time frames. To mitigate computational demands, our approach maintains the convolutional encoder of UNet-like models, and applies TokenLearner to 3D feature maps. This module pools a preset number of tokens from local and global structures. Our results show this tokenization effectively encodes task-relevant information, yielding naturally interpretable attention maps. The memory footprint, computation times at inference, and parameter counts of our heaviest model are reduced to 33\%, 10\%, and 35\% of the SwinUNETR values, with better average performance (86.75\% $\pm 0.19\%$ Dice score for SwinUNETR vs our 87.21\% $\pm 0.35\%$). This work opens the way to more efficient trainings in contexts with limited computational resources, such as 3D medical imaging. Easing model optimization, fine-tuning, and transfer-learning in limited hardware settings can accelerate and diversify the development of approaches, for the benefit of the research community.

Marek Wodzinski, Niccolò Marini, Manfredo Atzori et al.

The automatic registration of differently stained whole slide images (WSIs) is crucial for improving diagnosis and prognosis by fusing complementary information emerging from different visible structures. It is also useful to quickly transfer annotations between consecutive or restained slides, thus significantly reducing the annotation time and associated costs. Nevertheless, the slide preparation is different for each stain and the tissue undergoes complex and large deformations. Therefore, a robust, efficient, and accurate registration method is highly desired by the scientific community and hospitals specializing in digital pathology. We propose a two-step hybrid method consisting of (i) deep learning- and feature-based initial alignment algorithm, and (ii) intensity-based nonrigid registration using the instance optimization. The proposed method does not require any fine-tuning to a particular dataset and can be used directly for any desired tissue type and stain. The method scored 1st place in the ACROBAT 2023 challenge. We evaluated using three open datasets: (i) ANHIR, (ii) ACROBAT, and (iii) HyReCo, and performed several ablation studies concerning the resolution used for registration and the initial alignment robustness and stability. The method achieves the most accurate results for the ACROBAT dataset, the cell-level registration accuracy for the restained slides from the HyReCo dataset, and is among the best methods evaluated on the ANHIR dataset. The method does not require any fine-tuning to a new datasets and can be used out-of-the-box for other types of microscopic images. The method is incorporated into the DeeperHistReg framework, allowing others to directly use it to register, transform, and save the WSIs at any desired pyramid level. The proposed method is a significant contribution to the WSI registration, thus advancing the field of digital pathology.

Marek Wodzinski, Niccolò Marini, Manfredo Atzori et al.

DeeperHistReg is a software framework dedicated to registering whole slide images (WSIs) acquired using multiple stains. It allows one to perform the preprocessing, initial alignment, and nonrigid registration of WSIs acquired using multiple stains (e.g. hematoxylin \& eosin, immunochemistry). The framework implements several state-of-the-art registration algorithms and provides an interface to operate on arbitrary resolution of the WSIs (up to 200k x 200k). The framework is extensible and new algorithms can be easily integrated by other researchers. The framework is available both as a PyPI package and as a Docker container.

Federico Del Pup, Andrea Zanola, Louis Fabrice Tshimanga et al.

Deep learning is significantly advancing the analysis of electroencephalography (EEG) data by effectively discovering highly nonlinear patterns within the signals. Data partitioning and cross-validation are crucial for assessing model performance and ensuring study comparability, as they can produce varied results and data leakage due to specific signal properties (e.g., biometric). Such variability leads to incomparable studies and, increasingly, overestimated performance claims, which are detrimental to the field. Nevertheless, no comprehensive guidelines for proper data partitioning and cross-validation exist in the domain, nor is there a quantitative evaluation of their impact on model accuracy, reliability, and generalizability. To assist researchers in identifying optimal experimental strategies, this paper thoroughly investigates the role of data partitioning and cross-validation in evaluating EEG deep learning models. Five cross-validation settings are compared across three supervised cross-subject classification tasks (BCI, Parkinson's, and Alzheimer's disease detection) and four established architectures of increasing complexity (ShallowConvNet, EEGNet, DeepConvNet, and Temporal-based ResNet). The comparison of over 100,000 trained models underscores, first, the importance of using subject-based cross-validation strategies for evaluating EEG deep learning models, except when within-subject analyses are acceptable (e.g., BCI). Second, it highlights the greater reliability of nested approaches (N-LNSO) compared to non-nested counterparts, which are prone to data leakage and favor larger models overfitting to validation data. In conclusion, this work provides EEG deep learning researchers with an analysis of data partitioning and cross-validation and offers guidelines to avoid data leakage, currently undermining the domain with potentially overestimated performance claims.

Andrea Zanola, Louis Fabrice Tshimanga, Federico Del Pup et al.

This work presents xEEGNet, a novel, compact, and explainable neural network for EEG data analysis. It is fully interpretable and reduces overfitting through major parameter reduction. As an applicative use case, we focused on classifying common dementia conditions, Alzheimer's and frontotemporal dementia, versus controls. xEEGNet is broadly applicable to other neurological conditions involving spectral alterations. We initially used ShallowNet, a simple and popular model from the EEGNet-family. Its structure was analyzed and gradually modified to move from a "black box" to a more transparent model, without compromising performance. The learned kernels and weights were examined from a clinical standpoint to assess medical relevance. Model variants, including ShallowNet and the final xEEGNet, were evaluated using robust Nested-Leave-N-Subjects-Out cross-validation for unbiased performance estimates. Variability across data splits was explained using embedded EEG representations, grouped by class and set, with pairwise separability to quantify group distinction. Overfitting was assessed through training-validation loss correlation and training speed. xEEGNet uses only 168 parameters, 200 times fewer than ShallowNet, yet retains interpretability, resists overfitting, achieves comparable median performance (-1.5%), and reduces variability across splits. This variability is explained by embedded EEG representations: higher accuracy correlates with greater separation between test set controls and Alzheimer's cases, without significant influence from training data. xEEGNet's ability to filter specific EEG bands, learn band-specific topographies, and use relevant spectral features demonstrates its interpretability. While large deep learning models are often prioritized for performance, this study shows smaller architectures like xEEGNet can be equally effective in EEG pathology classification.

Federico Del Pup, Riccardo Brun, Filippo Iotti et al.

Electroencephalography (EEG) is establishing itself as an important, low-cost, noninvasive diagnostic tool for the early detection of Parkinson's Disease (PD). In this context, EEG-based Deep Learning (DL) models have shown promising results due to their ability to discover highly nonlinear patterns within the signal. However, current state-of-the-art DL models suffer from poor generalizability caused by high inter-subject variability. This high variability underscores the need for enhancing model generalizability by developing new architectures better tailored to EEG data. This paper introduces TransformEEG, a hybrid Convolutional-Transformer designed for Parkinson's disease detection using EEG data. Unlike transformer models based on the EEGNet structure, TransformEEG incorporates a depthwise convolutional tokenizer. This tokenizer is specialized in generating tokens composed by channel-specific features, which enables more effective feature mixing within the self-attention layers of the transformer encoder. To evaluate the proposed model, four public datasets comprising 290 subjects (140 PD patients, 150 healthy controls) were harmonized and aggregated. A 10-outer, 10-inner Nested-Leave-N-Subjects-Out (N-LNSO) cross-validation was performed to provide an unbiased comparison against seven other consolidated EEG deep learning models. TransformEEG achieved the highest balanced accuracy's median (78.45%) as well as the lowest interquartile range (6.37%) across all the N-LNSO partitions. When combined with data augmentation and threshold correction, median accuracy increased to 80.10%, with an interquartile range of 5.74%. In conclusion, TransformEEG produces more consistent and less skewed results. It demonstrates a substantial reduction in variability and more reliable PD detection using EEG data compared to the other investigated models.

Niccolò Marini, Stefano Marchesin, Lluis Borras Ferris et al.

The increasing availability of biomedical data is helping to design more robust deep learning (DL) algorithms to analyze biomedical samples. Currently, one of the main limitations to train DL algorithms to perform a specific task is the need for medical experts to label data. Automatic methods to label data exist, however automatic labels can be noisy and it is not completely clear when automatic labels can be adopted to train DL models. This paper aims to investigate under which circumstances automatic labels can be adopted to train a DL model on the classification of Whole Slide Images (WSI). The analysis involves multiple architectures, such as Convolutional Neural Networks (CNN) and Vision Transformer (ViT), and over 10000 WSIs, collected from three use cases: celiac disease, lung cancer and colon cancer, which one including respectively binary, multiclass and multilabel data. The results allow identifying 10% as the percentage of noisy labels that lead to train competitive models for the classification of WSIs. Therefore, an algorithm generating automatic labels needs to fit this criterion to be adopted. The application of the Semantic Knowledge Extractor Tool (SKET) algorithm to generate automatic labels leads to performance comparable to the one obtained with manual labels, since it generates a percentage of noisy labels between 2-5%. Automatic labels are as effective as manual ones, reaching solid performance comparable to the one obtained training models with manual labels.

Artur Jurgas, Marek Wodzinski, Marina D'Amato et al.

The problem of artifacts in whole slide image acquisition, prevalent in both clinical workflows and research-oriented settings, necessitates human intervention and re-scanning. Overcoming this challenge requires developing quality control algorithms, that are hindered by the limited availability of relevant annotated data in histopathology. The manual annotation of ground-truth for artifact detection methods is expensive and time-consuming. This work addresses the issue by proposing a method dedicated to augmenting whole slide images with artifacts. The tool seamlessly generates and blends artifacts from an external library to a given histopathology dataset. The augmented datasets are then utilized to train artifact classification methods. The evaluation shows their usefulness in classification of the artifacts, where they show an improvement from 0.10 to 0.01 AUROC depending on the artifact type. The framework, model, weights, and ground-truth annotations are freely released to facilitate open science and reproducible research.

Philippe Weitz, Masi Valkonen, Leslie Solorzano et al.

The alignment of tissue between histopathological whole-slide-images (WSI) is crucial for research and clinical applications. Advances in computing, deep learning, and availability of large WSI datasets have revolutionised WSI analysis. Therefore, the current state-of-the-art in WSI registration is unclear. To address this, we conducted the ACROBAT challenge, based on the largest WSI registration dataset to date, including 4,212 WSIs from 1,152 breast cancer patients. The challenge objective was to align WSIs of tissue that was stained with routine diagnostic immunohistochemistry to its H&E-stained counterpart. We compare the performance of eight WSI registration algorithms, including an investigation of the impact of different WSI properties and clinical covariates. We find that conceptually distinct WSI registration methods can lead to highly accurate registration performances and identify covariates that impact performances across methods. These results establish the current state-of-the-art in WSI registration and guide researchers in selecting and developing methods.

Niccoló Marini, Manfredo Atzori, Sebastian Otálora et al.

Computational pathology is a domain that aims to develop algorithms to automatically analyze large digitized histopathology images, called whole slide images (WSI). WSIs are produced scanning thin tissue samples that are stained to make specific structures visible. They show stain colour heterogeneity due to different preparation and scanning settings applied across medical centers. Stain colour heterogeneity is a problem to train convolutional neural networks (CNN), the state-of-the-art algorithms for most computational pathology tasks, since CNNs usually underperform when tested on images including different stain variations than those within data used to train the CNN. Despite several methods that were developed, stain colour heterogeneity is still an unsolved challenge that limits the development of CNNs that can generalize on data from several medical centers. This paper aims to present a novel method to train CNNs that better generalize on data including several colour variations. The method, called H&E-adversarial CNN, exploits H&E matrix information to learn stain-invariant features during the training. The method is evaluated on the classification of colon and prostate histopathology images, involving eleven heterogeneous datasets, and compared with five other techniques used to handle stain colour heterogeneity. H&E-adversarial CNNs show an improvement in performance compared to the other algorithms, demonstrating that it can help to better deal with stain colour heterogeneous images.

Bhakti Baheti, Satrajit Chakrabarty, Hamed Akbari et al.

Registration of longitudinal brain MRI scans containing pathologies is challenging due to dramatic changes in tissue appearance. Although there has been progress in developing general-purpose medical image registration techniques, they have not yet attained the requisite precision and reliability for this task, highlighting its inherent complexity. Here we describe the Brain Tumor Sequence Registration (BraTS-Reg) challenge, as the first public benchmark environment for deformable registration algorithms focusing on estimating correspondences between pre-operative and follow-up scans of the same patient diagnosed with a diffuse brain glioma. The BraTS-Reg data comprise de-identified multi-institutional multi-parametric MRI (mpMRI) scans, curated for size and resolution according to a canonical anatomical template, and divided into training, validation, and testing sets. Clinical experts annotated ground truth (GT) landmark points of anatomical locations distinct across the temporal domain. Quantitative evaluation and ranking were based on the Median Euclidean Error (MEE), Robustness, and the determinant of the Jacobian of the displacement field. The top-ranked methodologies yielded similar performance across all evaluation metrics and shared several methodological commonalities, including pre-alignment, deep neural networks, inverse consistency analysis, and test-time instance optimization per-case basis as a post-processing step. The top-ranked method attained the MEE at or below that of the inter-rater variability for approximately 60% of the evaluated landmarks, underscoring the scope for further accuracy and robustness improvements, especially relative to human experts. The aim of BraTS-Reg is to continue to serve as an active resource for research, with the data and online evaluation tools accessible at https://bratsreg.github.io/.

Andrea Gigli, Arjan Gijsberts, Valentina Gregori et al.

The instability of myoelectric signals over time complicates their use to control highly articulated prostheses. To address this problem, studies have tried to combine surface electromyography with modalities that are less affected by the amputation and environment, such as accelerometry or gaze information. In the latter case, the hypothesis is that a subject looks at the object he or she intends to manipulate and that knowing this object's affordances allows to constrain the set of possible grasps. In this paper, we develop an automated way to detect stable fixations and show that gaze information is indeed helpful in predicting hand movements. In our multimodal approach, we automatically detect stable gazes and segment an object of interest around the subject's fixation in the visual frame. The patch extracted around this object is subsequently fed through an off-the-shelf deep convolutional neural network to obtain a high level feature representation, which is then combined with traditional surface electromyography in the classification stage. Tests have been performed on a dataset acquired from five intact subjects who performed ten types of grasps on various objects as well as in a functional setting. They show that the addition of gaze information increases the classification accuracy considerably. Further analysis demonstrates that this improvement is consistent for all grasps and concentrated during the movement onset and offset.