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Synaptic transmission constitutes the primary mode of communication between neurons. It is extensively studied in rodent but not human neocortex. We characterized synaptic transmission between pyramidal neurons in layers 2 and 3 using neurosurgically resected human middle temporal gyrus (MTG, Brodmann area 21), which is part of the distributed language circuitry. We find that local connectivity is comparable with mouse layer 2/3 connections in the anatomical homologue (temporal association area), but synaptic connections in human are 3-fold stronger and more reliable (0% vs 25% failure rates, respectively). We developed a theoretical approach to quantify properties of spinous synapses showing that synaptic conductance and voltage change in human dendritic spines are 3–4-folds larger compared with mouse, leading to significant NMDA receptor activation in human unitary connections. This model prediction was validated experimentally by showing that NMDA receptor activation increases the amplitude and prolongs decay of unitary excitatory postsynaptic potentials in human but not in mouse connections. Since NMDA-dependent recurrent excitation facilitates persistent activity (supporting working memory), our data uncovers cortical microcircuit properties in human that may contribute to language processing in MTG.

The CA1 region of the hippocampus is one of the most studied regions of the rodent brain, thought to play an important role in cognitive functions such as memory and spatial navigation. Despite a wealth of experimental data on its structure and function, it can be challenging to reconcile information obtained from diverse experimental approaches. To address this challenge, we present a community-driven, full-scalein silicomodel of the rat CA1 that integrates a broad range of experimental data, from synapse to network, including the reconstruction of its principal afferents, the Schaffer collaterals, and a model of the effects that acetylcholine has on the system. We have tested and validated each model component and the final network model, and made input data, assumptions, and strategies explicit and transparent. The flexibility of the model allows scientists to address a range of scientific questions. In this article, we describe the methods used to set up simulations that reproduce and extendin vitroandin vivoexperiments. Among several applications in the article, we focus on theta rhythm, a prominent hippocampal oscillation associated with various behavioral correlates and use our computer model to reproduce and reconcile experimental findings. Finally, we make data, code and model available through the hippocampushub.eu portal, which also provides an extensive set of analyses of the model and a user-friendly interface to facilitate adoption and usage. This neuroscience community-driven model represents a valuable tool for integrating diverse experimental data and provides a foundation for further research into the complex workings of the hippocampal CA1 region.

Recent advances in computational neuroscience have demonstrated the usefulness and importance of stochastic, spatial reaction-diffusion simulations. However, ever increasing model complexity renders traditional serial solvers, as well as naive parallel implementations, inadequate. This paper introduces a new generation of the STochastic Engine for Pathway Simulation (STEPS) project (http://steps.sourceforge.net/), denominated STEPS 4.0, and its core components which have been designed for improved scalability, performance, and memory efficiency. STEPS 4.0 aims to enable novel scientific studies of macroscopic systems such as whole cells while capturing their nanoscale details. This class of models is out of reach for serial solvers due to the vast quantity of computation in such detailed models, and also out of reach for naive parallel solvers due to the large memory footprint. Based on a distributed mesh solution, we introduce a new parallel stochastic reaction-diffusion solver and a deterministic membrane potential solver in STEPS 4.0. The distributed mesh, together with improved data layout and algorithm designs, significantly reduces the memory footprint of parallel simulations in STEPS 4.0. This enables massively parallel simulations on modern HPC clusters and overcomes the limitations of the previous parallel STEPS implementation. Current and future improvements to the solver are not sustainable without following proper software engineering principles. For this reason, we also give an overview of how the STEPS codebase and the development environment have been updated to follow modern software development practices. We benchmark performance improvement and memory footprint on three published models with different complexities, from a simple spatial stochastic reaction-diffusion model, to a more complex one that is coupled to a deterministic membrane potential solver to simulate the calcium burst activity of a Purkinje neuron. Simulation results of these models suggest that the new solution dramatically reduces the per-core memory consumption by more than a factor of 30, while maintaining similar or better performance and scalability.

Astrocytes connect the vasculature to neurons mediating the supply of nutrients and biochemicals. They are involved in a growing number of physiological and pathophysiological processes that result from biophysical, physiological, and molecular interactions in this neuro-glia-vascular ensemble (NGV). The lack of a detailed cytoarchitecture severely restricts the understanding of how they support brain function. To address this problem, we used data from multiple sources to create a data-driven digital reconstruction of the NGV at micrometer anatomical resolution. We reconstructed 0.2 mm3 of the rat somatosensory cortex with 16 000 morphologically detailed neurons, 2500 protoplasmic astrocytes, and its microvasculature. The consistency of the reconstruction with a wide array of experimental measurements allows novel predictions of the NGV organization, allowing the anatomical reconstruction of overlapping astrocytic microdomains and the quantification of endfeet connecting each astrocyte to the vasculature, as well as the extent to which they cover the latter. Structural analysis showed that astrocytes optimize their positions to provide uniform vascular coverage for trophic support and signaling. However, this optimal organization rapidly declines as their density increases. The NGV digital reconstruction is a resource that will enable a better understanding of the anatomical principles and geometric constraints, which govern how astrocytes support brain function.

Motivation Astrocytes, the most abundant glial cells in the mammalian brain, have an instrumental role in developing neuronal circuits. They contribute to the physical structuring of the brain, modulating synaptic activity and maintaining the blood–brain barrier in addition to other significant aspects that impact brain function. Biophysically, detailed astrocytic models are key to unraveling their functional mechanisms via molecular simulations at microscopic scales. Detailed, and complete, biological reconstructions of astrocytic cells are sparse. Nonetheless, data-driven digital reconstruction of astroglial morphologies that are statistically identical to biological counterparts are becoming available. We use those synthetic morphologies to generate astrocytic meshes with realistic geometries, making it possible to perform these simulations. Results We present an unconditionally robust method capable of reconstructing high fidelity polygonal meshes of astroglial cells from algorithmically-synthesized morphologies. Our method uses implicit surfaces, or metaballs, to skin the different structural components of astrocytes and then blend them in a seamless fashion. We also provide an end-to-end pipeline to produce optimized two- and three-dimensional meshes for visual analytics and simulations, respectively. The performance of our pipeline has been assessed with a group of 5000 astroglial morphologies and the geometric metrics of the resulting meshes are evaluated. The usability of the meshes is then demonstrated with different use cases. Availability and implementation Our metaball skinning algorithm is implemented in Blender 2.82 relying on its Python API (Application Programming Interface). To make it accessible to computational biologists and neuroscientists, the implementation has been integrated into NeuroMorphoVis, an open source and domain specific package that is primarily designed for neuronal morphology visualization and meshing. Supplementary information Supplementary data are available at Bioinformatics online.

The function of the neocortex is fundamentally determined by its repeating microcircuit motif, but also by its rich, hierarchical, interregional structure with a highly specific laminar architecture. The last decade has seen the emergence of extensive new data sets on anatomy and connectivity at the whole brain scale, providing promising new directions for studies of cortical function that take into account the inseparability of whole-brain and microcircuit architectures. Here, we present a data-driven computational model of the anatomy of non-barrel primary somatosensory cortex of juvenile rat, which integrates whole-brain scale data while providing cellular and subcellular specificity. This multiscale integration was achieved by building the morphologically detailed model of cortical circuitry embedded within a volumetric, digital brain atlas. The model consists of 4.2 million morphologically detailed neurons belonging to 60 different morphological types, placed in the nonbarrel subregions of the Paxinos and Watson atlas. They are connected by 13.2 billion synapses determined by axo-dendritic overlap, comprising local connectivity and long-range connectivity defined by topographic mappings between subregions and laminar axonal projection profiles, both parameterized by whole brain data sets. Additionally, we incorporated core- and matrix-type thalamocortical projection systems, associated with sensory and higher-order extrinsic inputs, respectively. An analysis of the modeled synaptic connectivity revealed a highly nonrandom topology with substantial structural differences but also synergy between local and long-range connectivity. Long-range connections featured a more divergent structure with a comparatively small group of neurons serving as hubs to distribute excitation to far away locations. Taken together with analyses at different spatial granularities, these results support the notion that local and interregional connectivity exist on a spectrum of scales, rather than as separate and distinct networks, as is commonly assumed. Finally, we predicted how the emergence of primary sensory cortical maps is constrained by the anatomy of thalamo-cortical projections. A subvolume of the model comprising 211,712 neurons in the front limb, jaw, and dysgranular zone has been made freely and openly available to the community.

Ultraliser is a neuroscience-specific software framework capable of creating accurate and biologically realistic 3D models of complex neuroscientific structures at intracellular (e.g. mitochondria and endoplasmic reticula), cellular (e.g. neurons and glia) and even multicellular scales of resolution (e.g. cerebral vasculature and minicolumns). Resulting models are exported as triangulated surface meshes and annotated volumes for multiple applications in in silico neuroscience, allowing scalable supercomputer simulations that can unravel intricate cellular structure-function relationships. Ultraliser implements a high performance and unconditionally robust voxelization engine adapted to create optimized watertight surface meshes and annotated voxel grids from arbitrary non-watertight triangular soups, digitized morphological skeletons or binary volumetric masks. The framework represents a major leap forward in simulation-based neuroscience, making it possible to employ high-resolution 3D structural models for quantification of surface areas and volumes, which are of the utmost importance for cellular and system simulations. The power of Ultraliser is demonstrated with several use cases in which hundreds of models are created for potential application in diverse types of simulations. Ultraliser is publicly released under the GNU GPL3 license on GitHub (BlueBrain/Ultraliser).SignificanceThere is crystal clear evidence on the impact of cell shape on its signaling mechanisms. Structural models can therefore be insightful to realize the function; the more realistic the structure can be, the further we get insights into the function. Creating realistic structural models from existing ones is challenging, particularly when needed for detailed subcellular simulations. We present Ultraliser, a neuroscience-dedicated framework capable of building these structural models with realistic and detailed cellular geometries that can be used for simulations.Key pointsUltraliser creates spatial models of neuro-glia-vascular (NGV) structures with realistic geometries.Ultraliser creates high fidelity watertight manifolds and large scale volumes from centerline descriptions, non-watertight surfaces, and binary masks.Resulting models enable scalable in silico experiments that can probe intricate structure-function relationships.The framework is unrivalled both in ease-of-use and in the accuracy of resulting geometry representing a major leap forward in simulation-based neuroscience.

Using the example of four maps, this essay discusses how the cartography of the oceans enabled perceptions of the earth as a whole and as a continuous realm of possibilities during the nineteenth century. Nautical charts, produced for practical navigation and committed to the precision ethics of physical geography, facilitated the participation of ports such as Bremen in overseas trade. Ocean maps, aiming at providing an overview and filling sea areas with scientific, political, or travel-related information, visualized thinking in global contexts and positioned marine and terrestrial spaces in new relations. Finally, maps of island colonies show the problems that accompanied the overseas communication of knowledge and how cartographers, by overwriting uncertainties, also inscribed ignorance into maps. All in all, from the perspective of the cartography of the oceans, a specific globality emerges that can be regarded as a distinctive cartographic reality.

Between 1966 to 1969, Bernhard Grzimek (Frankfurt Zoological Society, FZS) introduced chimpanzees (Pan troglodytes) previously held in European institutions to Rubondo Island in Lake Victoria in Tanzania. Earlier publications report various numbers of released animals and that all founders originated from West Africa. We revise these assumptions through consultation of archived FZS records and genetic analyses of surviving descendants. Accordingly, 17 chimpanzees were transported to Africa in four waves, with male–female ratios of 3:8, 1:0, 1:0 and 2:2; one female died in transit. Thus, 16 chimpanzees were released in total. FZS and studbook records allocate a West African provenance to only 19% of the founders and a generic “Africa” origin to 56%. Still, studbook records render it unlikely that any of the founders were captive-born. In addition, our genetic analyses based on biological samples from the current descendants trace the geographical origin of their ancestors back to West Africa (P. t. verus) and Central Africa (P. t. troglodytes). Based on counts of individuals and night nests, we estimate that the population, since 1969, grew to around 35 individuals in 2014 (annual increase 3.3%). Thus, chimpanzees released onto a large forested island free from predators or hunting pressure, habitat destruction and conspecific competition can form a self-sustaining island population without human support.

The hippocampus is a widely studied brain region thought to play an important role in higher cognitive functions such as learning, memory, and navigation. The amount of data on this region increases every day and delineates a complex and fragmented picture, but an integrated understanding of hippocampal function remains elusive. Computational methods can help to move the research forward, and reconstructing a full-scale model of the hippocampus is a challenging yet feasible task that the research community should undertake.In this chapter, we present strategies for reconstructing a large-scale model of the hippocampus. Based on a previously published approach to reconstruct and simulate brain tissue, which is also explained in Chap. 10 , we discuss the characteristics of the hippocampus in the light of its special anatomical and physiological features, data availability, and existing large-scale hippocampus models. A large-scale model of the hippocampus is a compound model of several building blocks: ion channels, morphologies, single cell models, connections, synapses. We discuss each of those building blocks separately and discuss how to merge them back and simulate the resulting network model.

It has previously been shown that it is possible to derive a new class of biophysically detailed brain tissue models when one computationally analyzes and exploits the interdependencies or the multi-modal and multi-scale organization of the brain. These reconstructions, sometimes referred to as digital twins, enable a spectrum of scientific investigations. Building such models has become possible because of increase in quantitative data but also advances in computational capabilities, algorithmic and methodological innovations. This chapter presents the computational science concepts that provide the foundation to the data-driven approach to reconstructing and simulating brain tissue as developed by the EPFL Blue Brain Project, which was originally applied to neocortical microcircuitry and extended to other brain regions. Accordingly, the chapter covers aspects such as a knowledge graph-based data organization and the importance of the concept of a dataset release. We illustrate algorithmic advances in finding suitable parameters for electrical models of neurons or how spatial constraints can be exploited for predicting synaptic connections. Furthermore, we explain how in silico experimentation with such models necessitates specific addressing schemes or requires strategies for an efficient simulation. The entire data-driven approach relies on the systematic validation of the model. We conclude by discussing complementary strategies that not only enable judging the fidelity of the model but also form the basis for its systematic refinements.

The evaluation of small degree polynomials is critical for the computation of elementary functions. It has been extensively studied and is well documented. In this article, we evaluate existing methods for polynomial evaluation on superscalar architecture. In addition, we have completed this work with a factorization method, which is surprisingly neglected in the literature. This work focuses on out-of-order Intel processors, amongst others, of which computational units are available. Moreover, we applied our work on the elementary function e x that requires, in the current implementation, an evaluation of a polynomial of degree 10 for a satisfying precision and performance. Our results show that the factorization scheme is the fastest in benchmarks, and that latency and throughput are intrinsically dependent on each other on superscalar architecture.

Motivation: Accurate morphological models of brain vasculature are key to modeling and simulating cerebral blood flow in realistic vascular networks. This in silico approach is fundamental to revealing the principles of neurovascular coupling. Validating those vascular morphologies entails performing certain visual analysis tasks that cannot be accomplished with generic visualization frameworks. This limitation has a substantial impact on the accuracy of the vascular models employed in the simulation., Results: We present VessMorphoVis, an integrated suite of toolboxes for interactive visualization and analysis of vast brain vascular networks represented by morphological graphs segmented originally from imaging or microscopy stacks. Our workflow leverages the outstanding potentials of Blender, aiming to establish an integrated, extensible and domain-specific framework capable of interactive visualization, analysis, repair, high-fidelity meshing and high-quality rendering of vascular morphologies. Based on the initial feedback of the users, we anticipate that our framework will be an essential component in vascular modeling and simulation in the future, filling a gap that is at present largely unfulfilled.

Domain-specific languages (DSLs) play an increasingly important role in the generation of high performing software. They allow the user to exploit domain knowledge for the generation of more efficient code on target architectures. Here, we describe a new code generation framework (NMODL) for an existing DSL in the NEURON framework, a widely used software for massively parallel simulation of biophysically detailed brain tissue models. Existing NMODL DSL transpilers lack either essential features to generate optimized code or capability to parse the diversity of existing models in the user community. Our NMODL framework has been tested against a large number of previously published user models and offers high-level domain-specific optimizations and symbolic algebraic simplifications before target code generation. NMODL implements multiple SIMD and SPMD targets optimized for modern hardware. When comparing NMODL-generated kernels with NEURON we observe a speedup of up to 20\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\times $$\end{document}, resulting in overall speedups of two different production simulations by \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\sim }{7}{\times }$$\end{document}. When compared to SIMD optimized kernels that heavily relied on auto-vectorization by the compiler still a speedup of up to \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\sim }{2}{\times }$$\end{document} is observed.

We present here an online platform for sharing resources underlying publications in neuroscience. It enables authors to easily upload and distribute digital resources, such as data, code, and notebooks, in a structured and systematic way. Interactivity is a prominent feature of the Live Papers, with features to download, visualise or simulate data, models and results presented in the corresponding publications. The resources are hosted on reliable data storage servers to ensure long term availability and easy accessibility. All data are managed via the EBRAINS Knowledge Graph, thereby helping maintain data provenance, and enabling tight integration with tools and services offered under the EBRAINS ecosystem.

Many neurodegenerative diseases are associated with the death of specific neuron types in particular brain regions. What makes the death of specific neuron types particularly harmful for the integrity and dynamics of the respective network is not well understood. To start addressing this question we used the most up-to-date biologically-realistic dense neocortical microcircuit (NMC) of rodent, which has reconstructed a volume of 0.3 mm3 and containing 31,000 neurons, 36 million synapses, and 55 morphological cell types arranged in 6 cortical layers. Using modern network science tools, we identified “hub-neurons” in the NMC, that are connected synaptically to a large number of their neighbors and systematically examined the impact of abolishing these cells. In general, the structural integrity of the network is robust to cells’ attack; yet, attacking hub neurons strongly impacted the “small worldness” topology of the network, whereas similar attacks on random neurons have a negligible effect. Such hub-specific attacks are also impactful on the network dynamics, both when the network is at its spontaneous synchronous state and when it was presented with synchronized thalamo-cortical visual-like input. We found that attacking layer 5 hub neurons are most harmful to the structural and functional integrity of the NMC. The significance of our results for understanding the role of specific neuron types and cortical layers for disease manifestation is discussed.

The acquisition of high quality maps of gene expression in the rodent brain is of fundamental importance to the neuroscience community. The generation of such datasets relies on registering individual gene expression images to a reference volume, a task encumbered by the diversity of staining techniques employed, and by deformations and artifacts in the soft tissue. Recently, deep learning models have garnered particular interest as a viable alternative to traditional intensity-based algorithms for image registration. In this work, we propose a supervised learning model for general multimodal 2D registration tasks, trained with a perceptual similarity loss on a dataset labeled by a human expert and augmented by synthetic local deformations. We demonstrate the results of our approach on the Allen Mouse Brain Atlas (AMBA), comprising whole brain Nissl and gene expression stains. We show that our framework and design of the loss function result in accurate and smooth predictions. Our model is able to generalize to unseen gene expressions and coronal sections, outperforming traditional intensity-based approaches in aligning complex brain structures.

International audience; In 2020 the world was hit by the COVID-19 pandemic putting entire governments and civil societies in crisis mode. Around the globe unprecedented shortages of equipment and qualified personnel were reported in hospitals and diagnostic laboratories. When a crisis is global, supply chains are strained worldwide and external help may not be readily available. In Switzerland, as part of the efforts of the Swiss National COVID-19 Science Task Force, we developed a tailor-made web-based tool where needs and offers for critical laboratory equipment and expertise can be brought together, coordinated, prioritized, and validated. This Academic Resources for COVID-19 (ARC) Platform presents the specialized needs of diagnostic laboratories to academic research groups at universities, allowing the sourcing of said needs from unconventional supply channels, while keeping the entities tasked with coordination of the crisis response in control of each part of the process. An instance of the ARC Platform is operated in Switzerland (arc.epfl.ch) catering to the diagnostic efforts in Switzerland and sourcing from the Swiss academic sector. The underlying technology has been released as open source so that others can adopt the customizable web-platform for need/supply match-making in their own relief efforts, during the COVID-19 pandemic or any future disaster.

Astrocytes connect the vasculature to neurons and mediate the supply of nutrients and biochemicals. They also remove metabolites from the neurons and extracellular environment. They are involved in a growing number of physiological and pathophysiological processes. Understanding the biophysical, physiological, and molecular interactions in this neuro-glia-vascular ensemble (NGV) and how they support brain function is severely restricted by the lack of detailed cytoarchitecture. To address this problem, we used data from multiple sources to create a data-driven digital reconstruction of the NGV at micrometer anatomical resolution. We reconstructed 0.2 mm3 of rat somatosensory cortical tissue with approximately 16000 morphologically detailed neurons, its microvasculature, and approximately 2500 morphologically detailed protoplasmic astrocytes. The consistency of the reconstruction with a wide array of experimental measurements allows novel predictions of the numbers and locations of astrocytes and astrocytic processes that support different types of neurons. This allows anatomical reconstruction of the spatial microdomains of astrocytes and their overlapping regions. The number and locations of end-feet connecting each astrocyte to the vasculature can be determined as well as the extent to which they cover the microvasculature. The structural analysis of the NGV circuit showed that astrocytic shape and numbers are constrained by vasculature’s spatial occupancy and their functional role to form NGV connections. The digital reconstruction of the NGV is a resource that will enable a better understanding of the anatomical principles and geometric constraints which govern how astrocytes support brain function.Table of contentsMain pointsThe Blue Brain Project digitally reconstructs a part of neocortical Neuro-Glia-Vascular organizationInterdependencies and topological methods allow dense in silico reconstruction from sparse experimental dataThe polarized role of protoplasmic astrocytes constrains their shapes and numbersTable of contents image

Between 1966 to 1969, Bernhard Grzimek (Frankfurt Zoological Society, FZS) introduced chimpanzees (Pan troglodytes) previously held in European institutions to Rubondo Island in Lake Victoria in Tanzania. Earlier publications report various numbers of released animals and that all founders originated from West Africa. We revise these assumptions through consultation of archived FZS records and genetic analyses of surviving descendants. Accordingly, 17 chimpanzees were transported to Africa in four waves, with male-female ratios of 3:8, 1:0, 1:0 and 2:2; one female died in transit. Thus, 16 chimpanzees were released in total. FZS and studbook records allocate a West African provenance to only 19% of the founders and a generic "Africa" origin to 56%. Still, studbook records render it unlikely that any of the founders were captive-born. In addition, our genetic analyses based on biological samples from the current descendants trace the geographical origin of their ancestors back to West Africa (P. t. verus) and Central Africa (P. t. troglodytes). Based on counts of individuals and night nests, we estimate that the population, since 1969, grew to around 35 individuals in 2014 (annual increase 3.3%). Thus, chimpanzees released onto a large forested island free from predators or hunting pressure, habitat destruction and conspecific competition can form a self-sustaining island population without human support.

Detailed conductance-based nonlinear neuron models consisting of thousands of synapses are key for understanding of the computational properties of single neurons and large neuronal networks, and for interpreting experimental results. Simulations of these models are computationally expensive, considerably curtailing their utility. Neuron_Reduce is a new analytical approach to reduce the morphological complexity and computational time of nonlinear neuron models. Synapses and active membrane channels are mapped to the reduced model preserving their transfer impedance to the soma; synapses with identical transfer impedance are merged into one NEURON process still retaining their individual activation times. Neuron_Reduce accelerates the simulations by 40–250 folds for a variety of cell types and realistic number (10,000–100,000) of synapses while closely replicating voltage dynamics and specific dendritic computations. The reduced neuron-models will enable realistic simulations of neural networks at unprecedented scale, including networks emerging from micro-connectomics efforts and biologically-inspired “deep networks”. Neuron_Reduce is publicly available and is straightforward to implement., Realistic simulations of neurons and neural networks are key for understanding neural computations. Here the authors describe Neuron_Reduce, an analytic approach to simplify neurons receiving thousands of synapses and accelerate their simulations by 40–250 folds, while preserving voltage dynamics and dendritic computations.

Background We present a software workflow capable of building large scale, highly detailed and realistic volumetric models of neocortical circuits from the morphological skeletons of their digitally reconstructed neurons. The limitations of the existing approaches for creating those models are explained, and then, a multi-stage pipeline is discussed to overcome those limitations. Starting from the neuronal morphologies, we create smooth piecewise watertight polygonal models that can be efficiently utilized to synthesize continuous and plausible volumetric models of the neurons with solid voxelization. The somata of the neurons are reconstructed on a physically-plausible basis relying on the physics engine in Blender. Results Our pipeline is applied to create 55 exemplar neurons representing the various morphological types that are reconstructed from the somatsensory cortex of a juvenile rat. The pipeline is then used to reconstruct a volumetric slice of a cortical circuit model that contains ∼210,000 neurons. The applicability of our pipeline to create highly realistic volumetric models of neocortical circuits is demonstrated with an in silico imaging experiment that simulates tissue visualization with brightfield microscopy. The results were evaluated with a group of domain experts to address their demands and also to extend the workflow based on their feedback. Conclusion A systematic workflow is presented to create large scale synthetic tissue models of the neocortical circuitry. This workflow is fundamental to enlarge the scale of in silico neuroscientific optical experiments from several tens of cubic micrometers to a few cubic millimeters. AMS Subject Classification Modelling and Simulation Electronic supplementary material The online version of this article (doi:10.1186/s12859-017-1788-4) contains supplementary material, which is available to authorized users.

State-of-the-art simulations of detailed neural models follow the Bulk Synchronous Parallel execution model. Execution is divided in equidistant communication intervals, equivalent to the shortest synaptic delay in the network. Neurons stepping is performed independently, with collective communication guiding synchronization and exchange of synaptic events. The interpolation step size is fixed and chosen based on some prior knowledge of the fastest possible dynamics in the system. However, simulations driven by stiff dynamics or a wide range of time scales - such as multiscale simulations of neural networks - struggle with fixed step interpolation methods, yielding excessive computation of intervals of quasi-constant activity, inaccurate interpolation of periods of high volatility solution, and being incapable of handling unknown or distinct time constants. A common alternative is the usage of adaptive stepping methods, however they have been deemed inefficient in parallel executions due to computational load imbalance at the synchronization barriers that characterize the BSP execution model. We introduce a distributed fully-asynchronous execution model that removes global synchronization, allowing for longer variable timestep interpolations. Asynchronicity is provided by active point-to-point communication notifying neurons' time advancement to synaptic connectivities. Time stepping is driven by scheduled neuron advancements based on synaptic delays across neurons, yielding an "exhaustive yet not speculative" adaptive-step execution. Execution benchmarks on 64 Cray XE6 compute nodes demonstrate a reduced number of interpolation steps, higher numerical accuracy and lower time to solution, compared to state-of-the-art methods. Efficiency is shown to be activity-dependent, with scaling of the algorithm demonstrated on a simulation of a laboratory experiment.

International audience; A key element of the European Union's Human Brain Project (HBP) and other large-scale brain research projects is the simulation of large-scale model networks of neurons. Here, we argue why such simulations will likely be indispensable for bridging the scales between the neuron and system levels in the brain, and why a set of brain simulators based on neuron models at different levels of biological detail should therefore be developed. To allow for systematic refinement of candidate network models by comparison with experiments, the simulations should be multimodal in the sense that they should predict not only action potentials, but also electric, magnetic, and optical signals measured at the population and system levels.

Simulations of electrical activity of networks of morphologically detailed neuron models allow for a better understanding of the brain. State-of-the-art simulations describe the dynamics of ionic currents and biochemical processes within branching topological representations of the neurons. Acceleration of such simulation is possible in the weak scaling limit by modeling neurons as indivisible computation units and increasing the computing power. Strong scaling and simulations close to biological time are difficult, yet required, for the study of synaptic plasticity and other use cases requiring simulation of neurons for long periods of time. Current methods rely on parallel Gaussian Elimination, computing triangulation and substitution of many branches simultaneously. Existing limitations are: (a) high heterogeneity of compute time per neuron leads to high computational load imbalance; and (b) difficulty in providing a computation model that fully utilizes the computing resources on distributed multi-core architectures with Single Instruction Multiple Data (SIMD) capabilities. To address these issues, we present a strategy that extracts flow-dependencies between parameters of the ODEs and the algebraic solver of individual neurons. Based on the resulting map of dependencies, we provide three techniques for memory, communication, and computation reorganization that yield a load-balanced distributed asynchronous execution. The new computation model distributes datasets and balances computational workload across a distributed memory space, exposing a tree-based parallelism of neuron topological structure, an embarrassingly parallel execution model of neuron subtrees, and a SIMD acceleration of subtree state updates. The capabilities of our methods are demonstrated on a prototype implementation developed on the core compute kernel of the NEURON scientific application, built on the HPX runtime system for the ParalleX execution model. Our implementation yields an asynchronous distributed and parallel simulation that accelerates single neuron to medium-sized neural networks. Benchmark results display better strong scaling properties, finer-grained parallelism, and lower time to solution compared to the state of the art, on a wide range of distributed multi-core compute architectures.

Big science initiatives are trying to reconstruct and model the brain by attempting to simulate brain tissue at larger scales and with increasingly more biological detail than previously thought possible. The exponential growth of parallel computer performance has been supporting these developments, and at the same time maintainers of neuroscientific simulation code have strived to optimally and efficiently exploit new hardware features. Current state of the art software for the simulation of biological networks has so far been developed using performance engineering practices, but a thorough analysis and modeling of the computational and performance characteristics, especially in the case of morphologically detailed neuron simulations, is lacking. Other computational sciences have successfully used analytic performance engineering and modeling methods to gain insight on the computational properties of simulation kernels, aid developers in performance optimizations and eventually drive co-design efforts, but to our knowledge a model-based performance analysis of neuron simulations has not yet been conducted. We present a detailed study of the shared-memory performance of morphologically detailed neuron simulations based on the Execution-Cache-Memory (ECM) performance model. We demonstrate that this model can deliver accurate predictions of the runtime of almost all the kernels that constitute the neuron models under investigation. The gained insight is used to identify the main governing mechanisms underlying performance bottlenecks in the simulation. The implications of this analysis on the optimization of neural simulation software and eventually co-design of future hardware architectures are discussed. In this sense, our work represents a valuable conceptual and quantitative contribution to understanding the performance properties of biological networks simulations., 18 pages, 6 figures, 15 tables

The NEURON simulator has been developed over the past three decades and is widely used by neuroscientists to model the electrical activity of neuronal networks. Large network simulation projects using NEURON have supercomputer allocations that individually measure in the millions of core hours. Supercomputer centers are transitioning to next generation architectures and the work accomplished per core hour for these simulations could be improved by an order of magnitude if NEURON was able to better utilize those new hardware capabilities. In order to adapt NEURON to evolving computer architectures, the compute engine of the NEURON simulator has been extracted and has been optimized as a library called CoreNEURON. This paper presents the design, implementation and optimizations of CoreNEURON. We describe how CoreNEURON can be used as a library with NEURON and then compare performance of different network models on multiple architectures including IBM BlueGene/Q, Intel Skylake, Intel MIC and NVIDIA GPU. We show how CoreNEURON can simulate existing NEURON network models with 4-7x less memory usage and 2-7x less execution time while maintaining binary result compatibility with NEURON., Comment: Corresponding author: Felix Sch\"urman

Obtaining a catalog of cell types is a fundamental building block for understanding the brain. The ideal classification of cell-types is based on the profile of molecules expressed by a cell, in particular, the profile of genes expressed. One strategy is, therefore, to obtain as many single-cell transcriptomes as possible and isolate clusters of neurons with similar gene expression profiles. In this study, we explored an alternative strategy. We explored whether cell-types can be algorithmically derived by combining protein tissue stains with transcript expression profiles. We developed an algorithm that aims to distribute cell-types in the different layers of somatosensory cortex of the developing rat constrained by the tissue- and cellular level data. We found that the spatial distribution of major inhibitory cell types can be approximated using the available data. The result is a depth-wise atlas of inhibitory cell-types of the rat somatosensory cortex. In principle, any data that constrains what can occur in a particular part of the brain can also strongly constrain the derivation of cell-types. This draft inhibitory cell-type mapping is therefore dynamic and can iteratively converge towards the ground truth as further data is integrated.

One will not understand the brain without an integrated exploration of structure and function, these attributes being two sides of the same coin: together they form the currency of biological computation. Accordingly, biologically realistic models require the re-creation of the architecture of the cellular components in which biochemical reactions are contained. We describe here a process of reconstructing a functional oligocellular assembly that is responsible for energy supply management in the brain and creating a computational model of the associated biochemical and biophysical processes. The reactions that underwrite thought are both constrained by and take advantage of brain morphologies pertaining to neurons, astrocytes and the blood vessels that deliver oxygen, glucose and other nutrients. Each component of this neuro-glio-vasculature ensemble (NGV) carries-out delegated tasks, as the dynamics of this system provide for each cell-type its own energy requirements while including mechanisms that allow cooperative energy transfers. Our process for recreating the ultrastructure of cellular components and modeling the reactions that describe energy flow uses an amalgam of state-of the-art techniques, including digital reconstructions of electron micrographs, advanced data analysis tools, computational simulations and in silico visualization software. While we demonstrate this process with the NGV, it is equally well adapted to any cellular system for integrating multimodal cellular data in a coherent framework.

Important progress in computational sciences has been made possible recently thanks to the increasing computing power of high performance systems. Following this trend, larger scientific studies, like brain tissue simulations, will continue to grow in the future. In addition to the challenges of conducting these experiments, we foresee an explosion of the amount of data generated and the consequent unfeasibility of analyzing and understanding the results with the current techniques.

Blue Brain has pushed high-performance visualization (HPV) to complement its HPC strategy since its inception in 2007. In 2011, this strategy has been accelerated to develop innovative visualization solutions through increased funding and strategic partnerships with other research institutions. We present the key elements of this HPV ecosystem, which integrates C++ visualization applications with novel collaborative display systems. We motivate how our strategy of transforming visualization engines into services enables a variety of use cases, not only for the integration with high-fidelity displays, but also to build service oriented architectures, to link into web applications and to provide remote services to Python applications., ISC 2017 Visualization at Scale workshop

In realistic neuronal modeling, once the ionic channel complement has been defined, the maximum ionic conductance (Gi-max) values need to be tuned in order to match the firing pattern revealed by electrophysiological recordings. Recently, selection/mutation genetic algorithms have been proposed to efficiently and automatically tune these parameters. Nonetheless, since similar firing patterns can be achieved through different combinations of Gi-max values, it is not clear how well these algorithms approximate the corresponding properties of real cells. Here we have evaluated the issue by exploiting a unique opportunity offered by the cerebellar granule cell (GrC), which is electrotonically compact and has therefore allowed the direct experimental measurement of ionic currents. Previous models were constructed using empirical tuning of Gi-max values to match the original data set. Here, by using repetitive discharge patterns as a template, the optimization procedure yielded models that closely approximated the experimental Gi-max values. These models, in addition to repetitive firing, captured additional features, including inward rectification, near-threshold oscillations, and resonance, which were not used as features. Thus, parameter optimization using genetic algorithms provided an efficient modeling strategy for reconstructing the biophysical properties of neurons and for the subsequent reconstruction of large-scale neuronal network models.

Throughout the nervous system, cells belonging to a certain electrical class (e-class)–sharing high similarity in firing response properties–may nevertheless have widely variable dendritic morphologies. To quantify the effect of this morphological variability on the firing of layer 5 thick-tufted pyramidal cells (TTCs), a detailed conductance-based model was constructed for a three-dimensional reconstructed exemplar TTC. The model exhibited spike initiation in the axon and reproduced the characteristic features of individual spikes, as well as of the firing properties at the soma, as recorded in a population of TTCs in young Wistar rats. When using these model parameters over the population of 28 three-dimensional reconstructed TTCs, both axonal and somatic ion channel densities had to be scaled linearly with the conductance load imposed on each of these compartments. Otherwise, the firing of model cells deviated, sometimes very significantly, from the experimental variability of the TTC e-class. The study provides experimentally testable predictions regarding the coregulation of axosomatic membrane ion channels density for cells with different dendritic conductance load, together with a simple and systematic method for generating reliable conductance-based models for the whole population of modeled neurons belonging to a particular e-class, with variable morphology as found experimentally.

Large multiscale neuronal network simulations are of increasing value as more big data are gathered about brain wiring and organization under the auspices of a current major research initiative, such as Brain Research through Advancing Innovative Neurotechnologies. The development of these models requires new simulation technologies. We describe here the current use of the NEURON simulator with message passing interface (MPI) for simulation in the domain of moderately large networks on commonly available high-performance computers (HPCs). We discuss the basic layout of such simulations, including the methods of simulation setup, the run-time spike-passing paradigm, and postsimulation data storage and data management approaches. Using the Neuroscience Gateway, a portal for computational neuroscience that provides access to large HPCs, we benchmark simulations of neuronal networks of different sizes (500–100,000 cells), and using different numbers of nodes (1–256). We compare three types of networks, composed of either Izhikevich integrate-and-fire neurons (I&F), single-compartment Hodgkin-Huxley (HH) cells, or a hybrid network with half of each. Results show simulation run time increased approximately linearly with network size and decreased almost linearly with the number of nodes. Networks with I&F neurons were faster than HH networks, although differences were small since all tested cells were point neurons with a single compartment.

The accurate subdivision of spatially organized datasets is a complex problem in computer science but specifically important for load balancing in parallel environments. The problem is to (a) find a partitioning where each partition has the same number of elements and (b) the communication between partitions (duplicate members) is minimized. We present a novel parallel load-balancing framework — Sort Balance Split (SBS) — the first to our knowledge to perform accurate parallel partitioning of multidimensional data, while requiring a fixed number of communication steps independent of network size or input data distribution. When compared to the state of the art sampling and parallel partitioning methods adopted by HPC problems, it delivers better load balancing on a shorter time to solution. We analyse four partitioning schemes that SBS can be applied to, and evaluated our method on 4096 nodes of an IBM BlueGene/Q supercomputer partitioning up to 1 trillion elements, and exhibiting almost-linear scaling properties.

The European Dynamical Exascale Entry Platform (DEEP) is an example of a new type of heterogeneous supercomputing architecture that include both a standard multicore-based “Cluster” used to run less scalable parts of an application, and an Intel MIC-based “Booster” used to run highly scalable compute kernels. In this paper we describe how the compute engine of the widely used NEURON scientific application has been ported on both the DEEP and the Intel MIC platform. We discuss the design and implementation of the core simulator with an emphasis on the development workflow and implementation details that enable the efficient use of the new “Cluster-Booster” type of architectures. We describe optimizations of the data structures and algorithms tailored to the Intel Xeon Phi coprocessor which contributed to improve the overall performance of NEURON by a factor 5. Validation of our implementation has first been done on STAMPEDE supercomputer in order to emulate the DEEP architecture performance. Building on these results, we then explored opportunities offered by the DEEP platform to efficiently support complex scientific workflow.

Although the diversity of cortical interneuron electrical properties is well recognized, the number of distinct electrical types (e-types) is still a matter of debate. Recently, descriptions of interneuron variability were standardized by multiple laboratories on the basis of a subjective classification scheme as set out by the Petilla convention (Petilla Interneuron Nomenclature Group, PING). Here, we present a quantitative, statistical analysis of a database of nearly five hundred neurons manually annotated according to the PING nomenclature. For each cell, 38 features were extracted from responses to suprathreshold current stimuli and statistically analyzed to examine whether cortical interneurons subdivide into e-types. We showed that the partitioning into different e-types is indeed the major component of data variability. The analysis suggests refining the PING e-type classification to be hierarchical, whereby most variability is first captured within a coarse subpartition, and then subsequently divided into finer subpartitions. The coarse partition matches the well-known partitioning of interneurons into fast spiking and adapting cells. Finer subpartitions match the burst, continuous, and delayed subtypes. Additionally, our analysis enabled the ranking of features according to their ability to differentiate among e-types. We showed that our quantitative e-type assignment is more than 90% accurate and manages to catch several human errors.

Today's scientists are quickly moving from in vitro to in silico experimentation: they no longer analyze natural phenomena in a petri dish, but instead they build models and simulate them. Managing and analyzing the massive amounts of data involved in simulations is a major task. Yet, they lack the tools to efficiently work with data of this size. One problem many scientists share is the analysis of the massive spatial models they build. For several types of analysis they need to interactively follow the structures in the spatial model, e.g., the arterial tree, neuron fibers, etc., and issue range queries along the way. Each query takes long to execute, and the total time for executing a sequence of queries significantly delays data analysis. Prefetching the spatial data reduces the response time considerably, but known approaches do not prefetch with high accuracy. We develop SCOUT, a structure-aware method for prefetching data along interactive spatial query sequences. SCOUT uses an approximate graph model of the structures involved in past queries and attempts to identify what particular structure the user follows. Our experiments with neuro-science data show that SCOUT prefetches with an accuracy from 71% to 92%, which translates to a speedup of 4x-15x. SCOUT also improves the prefetching accuracy on datasets from other scientific domains, such as medicine and biology.