Hippocampus and striatum show distinct contributions to longitudinal changes in value-based learning in middle childhood.

The hippocampal-dependent memory system and striatal-dependent memory system modulate reinforcement learning depending on feedback timing in adults, but their contributions during development remain unclear. In a 2-year longitudinal study, 6-to-7-year-old children performed a reinforcement learning task in which they received feedback immediately or with a short delay following their response. Children's learning was found to be sensitive to feedback timing modulations in their reaction time and inverse temperature parameter, which quantifies value-guided decision-making. They showed longitudinal improvements towards more optimal value-based learning, and their hippocampal volume showed protracted maturation. Better delayed model-derived learning covaried with larger hippocampal volume longitudinally, in line with the adult literature. In contrast, a larger striatal volume in children was associated with both better immediate and delayed model-derived learning longitudinally. These findings show, for the first time, an early hippocampal contribution to the dynamic development of reinforcement learning in middle childhood, with neurally less differentiated and more cooperative memory systems than in adults.

Accelerating spiking neural network simulations with PymoNNto and PymoNNtorch.

Spiking neural network simulations are a central tool in Computational Neuroscience, Artificial Intelligence, and Neuromorphic Engineering research. A broad range of simulators and software frameworks for such simulations exist with different target application areas. Among these, PymoNNto is a recent Python-based toolbox for spiking neural network simulations that emphasizes the embedding of custom code in a modular and flexible way. While PymoNNto already supports GPU implementations, its backend relies on NumPy operations. Here we introduce PymoNNtorch, which is natively implemented with PyTorch while retaining PymoNNto's modular design. Furthermore, we demonstrate how changes to the implementations of common network operations in combination with PymoNNtorch's native GPU support can offer speed-up over conventional simulators like NEST, ANNarchy, and Brian 2 in certain situations. Overall, we show how PymoNNto's modular and flexible design in combination with PymoNNtorch's GPU acceleration and optimized indexing operations facilitate research and development of spiking neural networks in the Python programming language.

[Histomolecular classification of urothelial carcinoma of the urinary bladder : From histological phenotype to genotype and back]. / Histomolekulare Klassifikation des Urothelkarzinoms der Harnblase : Vom histologischen Phänotyp zum Genotyp und zurück.

BACKGROUND: Of all urothelial carcinomas (UCs), 25% are muscle invasive and associated with a 5-year overall survival rate of 50%. Findings regarding the molecular classification of muscle-invasive urothelial carcinomas (MIUCs) have not yet found their way into clinical practice. OBJECTIVES: Prediction of molecular consensus subtypes in MIUCs with artificial intelligence (AI) based on histologic hematoxylin-eosin (HE) sections. METHODS: Pathologic review and annotation of The Cancer Genome Atlas (TCGA) Bladder Cancer (BLCA) Cohort (N = 412) and the Dr. Senckenberg Institute of Pathology (SIP) BLCA Cohort (N = 181). An AI model for the prediction of molecular subtypes based on annotated histomorphology was trained. RESULTS: For a five-fold cross-validation with TCGA cases (N = 274), an internal TCGA test set (N = 18) and an external SIP test set (N = 27), we reached mean area under the receiver operating characteristic curve (AUROC) scores of 0.73, 0.8 and 0.75 for the classification of the used molecular subtypes "luminal", "basal/squamous" and "stroma-rich". By training on correlations to individual molecular subtypes, rather than training on one subtype assignment per case, the AI prediction of subtypes could be significantly improved. DISCUSSION: Follow-up studies with RNA extraction from various areas of AI-predicted molecular heterogeneity may improve molecular classifications and thereby AI algorithms trained on these classifications.

A developmental increase of inhibition promotes the emergence of hippocampal ripples.

Sharp wave-ripples (SPW-Rs) are a hippocampal network phenomenon critical for memory consolidation and planning. SPW-Rs have been extensively studied in the adult brain, yet their developmental trajectory is poorly understood. While SPWs have been recorded in rodents shortly after birth, the time point and mechanisms of ripple emergence are still unclear. Here, we combine in vivo electrophysiology with optogenetics and chemogenetics in 4 to 12-day-old mice to address this knowledge gap. We show that ripples are robustly detected and induced by light stimulation of channelrhodopsin-2-transfected CA1 pyramidal neurons only from postnatal day 10 onwards. Leveraging a spiking neural network model, we mechanistically link the maturation of inhibition and ripple emergence. We corroborate these findings by reducing ripple rate upon chemogenetic silencing of CA1 interneurons. Finally, we show that early SPW-Rs elicit a more robust prefrontal cortex response than SPWs lacking ripples. Thus, development of inhibition promotes ripples emergence.

Models of vision need some action.

Bowers et al. focus their criticisms on research that compares behavioral and brain data from the ventral stream with a class of deep neural networks for object recognition. While they are right to identify issues with current benchmarking research programs, they overlook a much more fundamental limitation of this literature: Disregarding the importance of action and interaction for perception.

Utilizing 2D-region-based CNNs for automatic dendritic spine detection in 3D live cell imaging.

Dendritic spines are considered a morphological proxy for excitatory synapses, rendering them a target of many different lines of research. Over recent years, it has become possible to simultaneously image large numbers of dendritic spines in 3D volumes of neural tissue. In contrast, currently no automated method for 3D spine detection exists that comes close to the detection performance reached by human experts. However, exploiting such datasets requires new tools for the fully automated detection and analysis of large numbers of spines. Here, we developed an efficient analysis pipeline to detect large numbers of dendritic spines in volumetric fluorescence imaging data acquired by two-photon imaging in vivo. The core of our pipeline is a deep convolutional neural network that was pretrained on a general-purpose image library and then optimized on the spine detection task. This transfer learning approach is data efficient while achieving a high detection precision. To train and validate the model we generated a labeled dataset using five human expert annotators to account for the variability in human spine detection. The pipeline enables fully automated dendritic spine detection reaching a performance slightly below that of the human experts. Our method for spine detection is fast, accurate and robust, and thus well suited for large-scale datasets with thousands of spines. The code is easily applicable to new datasets, achieving high detection performance, even without any retraining or adjustment of model parameters.

Variability in infant social responsiveness: Age and situational differences in attention-following.

Attention following (AF) is a cornerstone of social cognitive development and a longstanding topic of infancy research. However, there is conflicting evidence regarding the development of AF. One reason for discrepant findings could be that infants' AF responses do not generalize across settings, and are influenced by situational factors. Theories of AF development based on data collected in laboratory paradigms might skew our understanding of infants' everyday AF. To reveal more generalizable patterns of infant AF development, we compared healthy, North American infants' (N = 48) AF developmental trajectories between a controlled laboratory paradigm and a naturalistic, home-based, parent-directed paradigm. Longitudinal micro-behavioral coding was analyzed to compare individual infants' AF between the two settings every month from 6 to 9 months of age. We aimed to (1) examine longitudinal development of infant AF in two settings; (2) compare AF development between settings, and (3) explore differences in adult cueing behaviors that influence AF. We found that longitudinal trajectories of AF differed between home and lab, with more AF at home in earlier months. Additionally, AF at home was related to maternal cueing variables including bid duration and frequency. These results have implications for the assessment of infants' developing social attention behaviors.

Biological complexity facilitates tuning of the neuronal parameter space.

The electrical and computational properties of neurons in our brains are determined by a rich repertoire of membrane-spanning ion channels and elaborate dendritic trees. However, the precise reason for this inherent complexity remains unknown, given that simpler models with fewer ion channels are also able to functionally reproduce the behaviour of some neurons. Here, we stochastically varied the ion channel densities of a biophysically detailed dentate gyrus granule cell model to produce a large population of putative granule cells, comparing those with all 15 original ion channels to their reduced but functional counterparts containing only 5 ion channels. Strikingly, valid parameter combinations in the full models were dramatically more frequent at ~6% vs. ~1% in the simpler model. The full models were also more stable in the face of perturbations to channel expression levels. Scaling up the numbers of ion channels artificially in the reduced models recovered these advantages confirming the key contribution of the actual number of ion channel types. We conclude that the diversity of ion channels gives a neuron greater flexibility and robustness to achieve a target excitability.

Synaptic logistics: Competing over shared resources.

High turnover rates of synaptic proteins imply that synapses constantly need to replace their constituent building blocks. This requires sophisticated supply chains and potentially exposes synapses to shortages as they compete for limited resources. Interestingly, competition in neurons has been observed at different scales. Whether it is competition of receptors for binding sites inside a single synapse or synapses fighting for resources to grow. Here we review the implications of such competition for synaptic function and plasticity. We identify multiple mechanisms that synapses use to safeguard themselves against supply shortages and identify a fundamental neurologistic trade-off governing the sizes of reserve pools of essential synaptic building blocks.

Degeneracy in epilepsy: multiple routes to hyperexcitable brain circuits and their repair.

Due to its complex and multifaceted nature, developing effective treatments for epilepsy is still a major challenge. To deal with this complexity we introduce the concept of degeneracy to the field of epilepsy research: the ability of disparate elements to cause an analogous function or malfunction. Here, we review examples of epilepsy-related degeneracy at multiple levels of brain organisation, ranging from the cellular to the network and systems level. Based on these insights, we outline new multiscale and population modelling approaches to disentangle the complex web of interactions underlying epilepsy and to design personalised multitarget therapies.

How to learn with intentional mistakes: NoisyEnsembles to overcome poor tissue quality for deep learning in computational pathology.

There is a lot of recent interest in the field of computational pathology, as many algorithms are introduced to detect, for example, cancer lesions or molecular features. However, there is a large gap between artificial intelligence (AI) technology and practice, since only a small fraction of the applications is used in routine diagnostics. The main problems are the transferability of convolutional neural network (CNN) models to data from other sources and the identification of uncertain predictions. The role of tissue quality itself is also largely unknown. Here, we demonstrated that samples of the TCGA ovarian cancer (TCGA-OV) dataset from different tissue sources have different quality characteristics and that CNN performance is linked to this property. CNNs performed best on high-quality data. Quality control tools were partially able to identify low-quality tiles, but their use did not increase the performance of the trained CNNs. Furthermore, we trained NoisyEnsembles by introducing label noise during training. These NoisyEnsembles could improve CNN performance for low-quality, unknown datasets. Moreover, the performance increases as the ensemble become more consistent, suggesting that incorrect predictions could be discarded efficiently to avoid wrong diagnostic decisions.

A mathematical model of neuroimmune interactions in epileptogenesis for discovering treatment strategies.

The development of epilepsy (epileptogenesis) involves a complex interplay of neuronal and immune processes. Here, we present a first-of-its-kind mathematical model to better understand the relationships among these processes. Our model describes the interaction between neuroinflammation, blood-brain barrier disruption, neuronal loss, circuit remodeling, and seizures. Formulated as a system of nonlinear differential equations, the model reproduces the available data from three animal models. The model successfully describes characteristic features of epileptogenesis such as its paradoxically long timescales (up to decades) despite short and transient injuries or the existence of qualitatively different outcomes for varying injury intensity. In line with the concept of degeneracy, our simulations reveal multiple routes toward epilepsy with neuronal loss as a sufficient but non-necessary component. Finally, we show that our model allows for in silico predictions of therapeutic strategies, revealing injury-specific therapeutic targets and optimal time windows for intervention.

Recurrent processing improves occluded object recognition and gives rise to perceptual hysteresis.

Over the past decades, object recognition has been predominantly studied and modelled as a feedforward process. This notion was supported by the fast response times in psychophysical and neurophysiological experiments and the recent success of deep feedforward neural networks for object recognition. Recently, however, this prevalent view has shifted and recurrent connectivity in the brain is now believed to contribute significantly to object recognition - especially under challenging conditions, including the recognition of partially occluded objects. Moreover, recurrent dynamics might be the key to understanding perceptual phenomena such as perceptual hysteresis. In this work we investigate if and how artificial neural networks can benefit from recurrent connections. We systematically compare architectures comprised of bottom-up, lateral, and top-down connections. To evaluate the impact of recurrent connections for occluded object recognition, we introduce three stereoscopic occluded object datasets, which span the range from classifying partially occluded hand-written digits to recognizing three-dimensional objects. We find that recurrent architectures perform significantly better than parameter-matched feedforward models. An analysis of the hidden representation of the models suggests that occluders are progressively discounted in later time steps of processing. We demonstrate that feedback can correct the initial misclassifications over time and that the recurrent dynamics lead to perceptual hysteresis. Overall, our results emphasize the importance of recurrent feedback for object recognition in difficult situations.

PymoNNto: A Flexible Modular Toolbox for Designing Brain-Inspired Neural Networks.

The Python Modular Neural Network Toolbox (PymoNNto) provides a versatile and adaptable Python-based framework to develop and investigate brain-inspired neural networks. In contrast to other commonly used simulators such as Brian2 and NEST, PymoNNto imposes only minimal restrictions for implementation and execution. The basic structure of PymoNNto consists of one network class with several neuron- and synapse-groups. The behaviour of each group can be flexibly defined by exchangeable modules. The implementation of these modules is up to the user and only limited by Python itself. Behaviours can be implemented in Python, Numpy, Tensorflow, and other libraries to perform computations on CPUs and GPUs. PymoNNto comes with convenient high level behaviour modules, allowing differential equation-based implementations similar to Brian2, and an adaptable modular Graphical User Interface for real-time observation and modification of the simulated network and its parameters.

The development of active binocular vision under normal and alternate rearing conditions.

The development of binocular vision is an active learning process comprising the development of disparity tuned neurons in visual cortex and the establishment of precise vergence control of the eyes. We present a computational model for the learning and self-calibration of active binocular vision based on the Active Efficient Coding framework, an extension of classic efficient coding ideas to active perception. Under normal rearing conditions with naturalistic input, the model develops disparity tuned neurons and precise vergence control, allowing it to correctly interpret random dot stereograms. Under altered rearing conditions modeled after neurophysiological experiments, the model qualitatively reproduces key experimental findings on changes in binocularity and disparity tuning. Furthermore, the model makes testable predictions regarding how altered rearing conditions impede the learning of precise vergence control. Finally, the model predicts a surprising new effect that impaired vergence control affects the statistics of orientation tuning in visual cortical neurons.

Active head rolls enhance sonar-based auditory localization performance.

Animals utilize a variety of active sensing mechanisms to perceive the world around them. Echolocating bats are an excellent model for the study of active auditory localization. The big brown bat (Eptesicus fuscus), for instance, employs active head roll movements during sonar prey tracking. The function of head rolls in sound source localization is not well understood. Here, we propose an echolocation model with multi-axis head rotation to investigate the effect of active head roll movements on sound localization performance. The model autonomously learns to align the bat's head direction towards the target. We show that a model with active head roll movements better localizes targets than a model without head rolls. Furthermore, we demonstrate that active head rolls also reduce the time required for localization in elevation. Finally, our model offers key insights to sound localization cues used by echolocating bats employing active head movements during echolocation.

Active efficient coding explains the development of binocular vision and its failure in amblyopia.

The development of vision during the first months of life is an active process that comprises the learning of appropriate neural representations and the learning of accurate eye movements. While it has long been suspected that the two learning processes are coupled, there is still no widely accepted theoretical framework describing this joint development. Here, we propose a computational model of the development of active binocular vision to fill this gap. The model is based on a formulation of the active efficient coding theory, which proposes that eye movements as well as stimulus encoding are jointly adapted to maximize the overall coding efficiency. Under healthy conditions, the model self-calibrates to perform accurate vergence and accommodation eye movements. It exploits disparity cues to deduce the direction of defocus, which leads to coordinated vergence and accommodation responses. In a simulated anisometropic case, where the refraction power of the two eyes differs, an amblyopia-like state develops in which the foveal region of one eye is suppressed due to inputs from the other eye. After correcting for refractive errors, the model can only reach healthy performance levels if receptive fields are still plastic, in line with findings on a critical period for binocular vision development. Overall, our model offers a unifying conceptual framework for understanding the development of binocular vision.

A Model of Brain Folding Based on Strong Local and Weak Long-Range Connectivity Requirements.

Throughout the animal kingdom, the structure of the central nervous system varies widely from distributed ganglia in worms to compact brains with varying degrees of folding in mammals. The differences in structure may indicate a fundamentally different circuit organization. However, the folded brain most likely is a direct result of mechanical forces when considering that a larger surface area of cortex packs into the restricted volume provided by the skull. Here, we introduce a computational model that instead of modeling mechanical forces relies on dimension reduction methods to place neurons according to specific connectivity requirements. For a simplified connectivity with strong local and weak long-range connections, our model predicts a transition from separate ganglia through smooth brain structures to heavily folded brains as the number of cortical columns increases. The model reproduces experimentally determined relationships between metrics of cortical folding and its pathological phenotypes in lissencephaly, polymicrogyria, microcephaly, autism, and schizophrenia. This suggests that mechanical forces that are known to lead to cortical folding may synergistically contribute to arrangements that reduce wiring. Our model provides a unified conceptual understanding of gyrification linking cellular connectivity and macroscopic structures in large-scale neural network models of the brain.

Editorial: Linking experimental and computational connectomics.

Large-scale in silico experimentation depends on the generation of connectomes beyond available anatomical structure. We suggest that linking research across the fields of experimental connectomics, theoretical neuroscience, and high-performance computing can enable a new generation of models bridging the gap between biophysical detail and global function. This Focus Feature on "Linking Experimental and Computational Connectomics" aims to bring together some examples from these domains as a step toward the development of more comprehensive generative models of multiscale connectomes.

Autonomous Development of Active Binocular and Motion Vision Through Active Efficient Coding.

We present a model for the autonomous and simultaneous learning of active binocular and motion vision. The model is based on the Active Efficient Coding (AEC) framework, a recent generalization of classic efficient coding theories to active perception. The model learns how to efficiently encode the incoming visual signals generated by an object moving in 3-D through sparse coding. Simultaneously, it learns how to produce eye movements that further improve the efficiency of the sensory coding. This learning is driven by an intrinsic motivation to maximize the system's coding efficiency. We test our approach on the humanoid robot iCub using simulations. The model demonstrates self-calibration of accurate object fixation and tracking of moving objects. Our results show that the model keeps improving until it hits physical constraints such as camera or motor resolution, or limits on its internal coding capacity. Furthermore, we show that the emerging sensory tuning properties are in line with results on disparity, motion, and motion-in-depth tuning in the visual cortex of mammals. The model suggests that vergence and tracking eye movements can be viewed as fundamentally having the same objective of maximizing the coding efficiency of the visual system and that they can be learned and calibrated jointly through AEC.