Impact of quantum and neuromorphic computing on biomolecular simulations: Current status and perspectives.

New high-performance computing architectures are becoming operative, in addition to exascale computers. Quantum computers (QC) solve optimization problems with unprecedented efficiency and speed, while neuromorphic hardware (NMH) simulates neural network dynamics. Albeit, at the moment, both find no practical use in all atom biomolecular simulations, QC might be exploited in the not-too-far future to simulate systems for which electronic degrees of freedom play a key and intricate role for biological function, whereas NMH might accelerate molecular dynamics simulations with low energy consumption. Machine learning and artificial intelligence algorithms running on NMH and QC could assist in the analysis of data and speed up research. If these implementations are successful, modular supercomputing could further dramatically enhance the overall computing capacity by combining highly optimized software tools into workflows, linking these architectures to exascale computers.

Multiscale co-simulation design pattern for neuroscience applications.

Integration of information across heterogeneous sources creates added scientific value. Interoperability of data, tools and models is, however, difficult to accomplish across spatial and temporal scales. Here we introduce the toolbox Parallel Co-Simulation, which enables the interoperation of simulators operating at different scales. We provide a software science co-design pattern and illustrate its functioning along a neuroscience example, in which individual regions of interest are simulated on the cellular level allowing us to study detailed mechanisms, while the remaining network is efficiently simulated on the population level. A workflow is illustrated for the use case of The Virtual Brain and NEST, in which the CA1 region of the cellular-level hippocampus of the mouse is embedded into a full brain network involving micro and macro electrode recordings. This new tool allows integrating knowledge across scales in the same simulation framework and validating them against multiscale experiments, thereby largely widening the explanatory power of computational models.

Enhanced simulations of whole-brain dynamics using hybrid resting-state structural connectomes.

The human brain, composed of billions of neurons and synaptic connections, is an intricate network coordinating a sophisticated balance of excitatory and inhibitory activity between brain regions. The dynamical balance between excitation and inhibition is vital for adjusting neural input/output relationships in cortical networks and regulating the dynamic range of their responses to stimuli. To infer this balance using connectomics, we recently introduced a computational framework based on the Ising model, first developed to explain phase transitions in ferromagnets, and proposed a novel hybrid resting-state structural connectome (rsSC). Here, we show that a generative model based on the Kuramoto phase oscillator can be used to simulate static and dynamic functional connectomes (FC) with rsSC as the coupling weight coefficients, such that the simulated FC well aligns with the observed FC when compared to that simulated with traditional structural connectome. Simulations were performed using the open source framework The Virtual Brain on High Performance Computing infrastructure.

Enhanced simulations of whole-brain dynamics using hybrid resting-state structural connectomes.

The human brain, composed of billions of neurons and synaptic connections, is an intricate network coordinating a sophisticated balance of excitatory and inhibitory activities between brain regions. The dynamical balance between excitation and inhibition is vital for adjusting neural input/output relationships in cortical networks and regulating the dynamic range of their responses to stimuli. To infer this balance using connectomics, we recently introduced a computational framework based on the Ising model, which was first developed to explain phase transitions in ferromagnets, and proposed a novel hybrid resting-state structural connectome (rsSC). Here, we show that a generative model based on the Kuramoto phase oscillator can be used to simulate static and dynamic functional connectomes (FC) with rsSC as the coupling weight coefficients, such that the simulated FC aligns well with the observed FC when compared with that simulated traditional structural connectome.

Exploring Parameter and Hyper-Parameter Spaces of Neuroscience Models on High Performance Computers With Learning to Learn.

Neuroscience models commonly have a high number of degrees of freedom and only specific regions within the parameter space are able to produce dynamics of interest. This makes the development of tools and strategies to efficiently find these regions of high importance to advance brain research. Exploring the high dimensional parameter space using numerical simulations has been a frequently used technique in the last years in many areas of computational neuroscience. Today, high performance computing (HPC) can provide a powerful infrastructure to speed up explorations and increase our general understanding of the behavior of the model in reasonable times. Learning to learn (L2L) is a well-known concept in machine learning (ML) and a specific method for acquiring constraints to improve learning performance. This concept can be decomposed into a two loop optimization process where the target of optimization can consist of any program such as an artificial neural network, a spiking network, a single cell model, or a whole brain simulation. In this work, we present L2L as an easy to use and flexible framework to perform parameter and hyper-parameter space exploration of neuroscience models on HPC infrastructure. Learning to learn is an implementation of the L2L concept written in Python. This open-source software allows several instances of an optimization target to be executed with different parameters in an embarrassingly parallel fashion on HPC. L2L provides a set of built-in optimizer algorithms, which make adaptive and efficient exploration of parameter spaces possible. Different from other optimization toolboxes, L2L provides maximum flexibility for the way the optimization target can be executed. In this paper, we show a variety of examples of neuroscience models being optimized within the L2L framework to execute different types of tasks. The tasks used to illustrate the concept go from reproducing empirical data to learning how to solve a problem in a dynamic environment. We particularly focus on simulations with models ranging from the single cell to the whole brain and using a variety of simulation engines like NEST, Arbor, TVB, OpenAIGym, and NetLogo.

Regional changes of brain structure during progression of idiopathic Parkinson's disease - A longitudinal study using deformation based morphometry.

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder with a broad spectrum of motor and non-motor symptoms. The neuropathological characteristics of idiopathic PD are the degeneration of dopaminergic neurons in the striatum, and the propagation of aggregates of misfolded α-synuclein in the brain following a specific pattern (Braak et al., 2006). The relationship of this pattern with motor and cognitive symptoms is still equivocal. Therefore, we investigated longitudinally the spatio-temporal patterns of atrophy propagation in PD, their inter-individual variability and associations with clinical symptoms. Magnetic resonance (MR) images of 37 PD patients and 27 controls were acquired at up to 15 time-points per subject, and over observation periods of up to 8.8 years (mean: 3.7 years). MR images were analyzed by Deformation-based Morphometry to measure region volumes and their longitudinal changes. Differences of these regional volume data between patients and controls and their associations with clinical symptoms were calculated. At baseline, group differences in the regional volumes were found mainly in areas of the sensory, motor and orbitofrontal cortices, areas in the frontal operculum, inferior frontal sulcus, hippocampus and entorhinal cortex, and in the substantia nigra, among others. The longitudinal analysis yielded more widespread and more pronounced group differences, with significantly accelerated volume decreases in PD patients in the occipital and temporal lobes, the inferior parietal lobule, as well as in the insula, putamen and nucleus basalis Meynert. The white matter was less affected than the gray matter. Worse clinical scores (MMSE, PDQ-39, UPDRS-III) were in particular associated with volume decreases of cortical areas, amygdala and basal forebrain nuclei, but not of the basal ganglia. The observed longitudinal patterns of accelerated volume decrease in PD patients largely coincide with the pattern of α-synuclein pathology in PD stages 3-5 as proposed by Braak and colleagues. Thus, longitudinal DBM appears to depict already in-vivo the progression of neuropathological changes.

Brain simulation as a cloud service: The Virtual Brain on EBRAINS.

The Virtual Brain (TVB) is now available as open-source services on the cloud research platform EBRAINS (ebrains.eu). It offers software for constructing, simulating and analysing brain network models including the TVB simulator; magnetic resonance imaging (MRI) processing pipelines to extract structural and functional brain networks; combined simulation of large-scale brain networks with small-scale spiking networks; automatic conversion of user-specified model equations into fast simulation code; simulation-ready brain models of patients and healthy volunteers; Bayesian parameter optimization in epilepsy patient models; data and software for mouse brain simulation; and extensive educational material. TVB cloud services facilitate reproducible online collaboration and discovery of data assets, models, and software embedded in scalable and secure workflows, a precondition for research on large cohort data sets, better generalizability, and clinical translation.

RateML: A Code Generation Tool for Brain Network Models.

Whole brain network models are now an established tool in scientific and clinical research, however their use in a larger workflow still adds significant informatics complexity. We propose a tool, RateML, that enables users to generate such models from a succinct declarative description, in which the mathematics of the model are described without specifying how their simulation should be implemented. RateML builds on NeuroML's Low Entropy Model Specification (LEMS), an XML based language for specifying models of dynamical systems, allowing descriptions of neural mass and discretized neural field models, as implemented by the Virtual Brain (TVB) simulator: the end user describes their model's mathematics once and generates and runs code for different languages, targeting both CPUs for fast single simulations and GPUs for parallel ensemble simulations. High performance parallel simulations are crucial for tuning many parameters of a model to empirical data such as functional magnetic resonance imaging (fMRI), with reasonable execution times on small or modest hardware resources. Specifically, while RateML can generate Python model code, it enables generation of Compute Unified Device Architecture C++ code for NVIDIA GPUs. When a CUDA implementation of a model is generated, a tailored model driver class is produced, enabling the user to tweak the driver by hand and perform the parameter sweep. The model and driver can be executed on any compute capable NVIDIA GPU with a high degree of parallelization, either locally or in a compute cluster environment. The results reported in this manuscript show that with the CUDA code generated by RateML, it is possible to explore thousands of parameter combinations with a single Graphics Processing Unit for different models, substantially reducing parameter exploration times and resource usage for the brain network models, in turn accelerating the research workflow itself. This provides a new tool to create efficient and broader parameter fitting workflows, support studies on larger cohorts, and derive more robust and statistically relevant conclusions about brain dynamics.

Long-Term Desynchronization by Coordinated Reset Stimulation in a Neural Network Model With Synaptic and Structural Plasticity.

Several brain disorders are characterized by abnormal neuronal synchronization. To specifically counteract abnormal neuronal synchrony and, hence, related symptoms, coordinated reset (CR) stimulation was computationally developed. In principle, successive epochs of synchronizing and desynchronizing stimulation may reversibly move neural networks with plastic synapses back and forth between stable regimes with synchronized and desynchronized firing. Computationally derived predictions have been verified in pre-clinical and clinical studies, paving the way for novel therapies. However, as yet, computational models were not able to reproduce the clinically observed increase of desynchronizing effects of regularly administered CR stimulation intermingled by long stimulation-free epochs. We show that this clinically important phenomenon can be computationally reproduced by taking into account structural plasticity (SP), a mechanism that deletes or generates synapses in order to homeostatically adapt the firing rates of neurons to a set point-like target firing rate in the course of days to months. If we assume that CR stimulation favorably reduces the target firing rate of SP, the desynchronizing effects of CR stimulation increase after long stimulation-free epochs, in accordance with clinically observed phenomena. Our study highlights the pivotal role of stimulation- and dosing-induced modulation of homeostatic set points in therapeutic processes.

On the influence of prior information evaluated by fully Bayesian criteria in a personalized whole-brain model of epilepsy spread.

Individualized anatomical information has been used as prior knowledge in Bayesian inference paradigms of whole-brain network models. However, the actual sensitivity to such personalized information in priors is still unknown. In this study, we introduce the use of fully Bayesian information criteria and leave-one-out cross-validation technique on the subject-specific information to assess different epileptogenicity hypotheses regarding the location of pathological brain areas based on a priori knowledge from dynamical system properties. The Bayesian Virtual Epileptic Patient (BVEP) model, which relies on the fusion of structural data of individuals, a generative model of epileptiform discharges, and a self-tuning Monte Carlo sampling algorithm, is used to infer the spatial map of epileptogenicity across different brain areas. Our results indicate that measuring the out-of-sample prediction accuracy of the BVEP model with informative priors enables reliable and efficient evaluation of potential hypotheses regarding the degree of epileptogenicity across different brain regions. In contrast, while using uninformative priors, the information criteria are unable to provide strong evidence about the epileptogenicity of brain areas. We also show that the fully Bayesian criteria correctly assess different hypotheses about both structural and functional components of whole-brain models that differ across individuals. The fully Bayesian information-theory based approach used in this study suggests a patient-specific strategy for epileptogenicity hypothesis testing in generative brain network models of epilepsy to improve surgical outcomes.

Inter-subject and inter-parcellation variability of resting-state whole-brain dynamical modeling.

Modern approaches to investigate complex brain dynamics suggest to represent the brain as a functional network of brain regions defined by a brain atlas, while edges represent the structural or functional connectivity among them. This approach is also utilized for mathematical modeling of the resting-state brain dynamics, where the applied brain parcellation plays an essential role in deriving the model network and governing the modeling results. There is however no consensus and empirical evidence on how a given brain atlas affects the model outcome, and the choice of parcellation is still rather arbitrary. Accordingly, we explore the impact of brain parcellation on inter-subject and inter-parcellation variability of model fitting to empirical data. Our objective is to provide a comprehensive empirical evidence of potential influences of parcellation choice on resting-state whole-brain dynamical modeling. We show that brain atlases strongly influence the quality of model validation and propose several variables calculated from empirical data to account for the observed variability. A few classes of such data variables can be distinguished depending on their inter-subject and inter-parcellation explanatory power.

ConGen-A Simulator-Agnostic Visual Language for Definition and Generation of Connectivity in Large and Multiscale Neural Networks.

An open challenge on the road to unraveling the brain's multilevel organization is establishing techniques to research connectivity and dynamics at different scales in time and space, as well as the links between them. This work focuses on the design of a framework that facilitates the generation of multiscale connectivity in large neural networks using a symbolic visual language capable of representing the model at different structural levels-ConGen. This symbolic language allows researchers to create and visually analyze the generated networks independently of the simulator to be used, since the visual model is translated into a simulator-independent language. The simplicity of the front end visual representation, together with the simulator independence provided by the back end translation, combine into a framework to enhance collaboration among scientists with expertise at different scales of abstraction and from different fields. On the basis of two use cases, we introduce the features and possibilities of our proposed visual language and associated workflow. We demonstrate that ConGen enables the creation, editing, and visualization of multiscale biological neural networks and provides a whole workflow to produce simulation scripts from the visual representation of the model.

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.

Code Generation in Computational Neuroscience: A Review of Tools and Techniques.

Advances in experimental techniques and computational power allowing researchers to gather anatomical and electrophysiological data at unprecedented levels of detail have fostered the development of increasingly complex models in computational neuroscience. Large-scale, biophysically detailed cell models pose a particular set of computational challenges, and this has led to the development of a number of domain-specific simulators. At the other level of detail, the ever growing variety of point neuron models increases the implementation barrier even for those based on the relatively simple integrate-and-fire neuron model. Independently of the model complexity, all modeling methods crucially depend on an efficient and accurate transformation of mathematical model descriptions into efficiently executable code. Neuroscientists usually publish model descriptions in terms of the mathematical equations underlying them. However, actually simulating them requires they be translated into code. This can cause problems because errors may be introduced if this process is carried out by hand, and code written by neuroscientists may not be very computationally efficient. Furthermore, the translated code might be generated for different hardware platforms, operating system variants or even written in different languages and thus cannot easily be combined or even compared. Two main approaches to addressing this issues have been followed. The first is to limit users to a fixed set of optimized models, which limits flexibility. The second is to allow model definitions in a high level interpreted language, although this may limit performance. Recently, a third approach has become increasingly popular: using code generation to automatically translate high level descriptions into efficient low level code to combine the best of previous approaches. This approach also greatly enriches efforts to standardize simulator-independent model description languages. In the past few years, a number of code generation pipelines have been developed in the computational neuroscience community, which differ considerably in aim, scope and functionality. This article provides an overview of existing pipelines currently used within the community and contrasts their capabilities and the technologies and concepts behind them.

Toward Rigorous Parameterization of Underconstrained Neural Network Models Through Interactive Visualization and Steering of Connectivity Generation.

Simulation models in many scientific fields can have non-unique solutions or unique solutions which can be difficult to find. Moreover, in evolving systems, unique final state solutions can be reached by multiple different trajectories. Neuroscience is no exception. Often, neural network models are subject to parameter fitting to obtain desirable output comparable to experimental data. Parameter fitting without sufficient constraints and a systematic exploration of the possible solution space can lead to conclusions valid only around local minima or around non-minima. To address this issue, we have developed an interactive tool for visualizing and steering parameters in neural network simulation models. In this work, we focus particularly on connectivity generation, since finding suitable connectivity configurations for neural network models constitutes a complex parameter search scenario. The development of the tool has been guided by several use cases-the tool allows researchers to steer the parameters of the connectivity generation during the simulation, thus quickly growing networks composed of multiple populations with a targeted mean activity. The flexibility of the software allows scientists to explore other connectivity and neuron variables apart from the ones presented as use cases. With this tool, we enable an interactive exploration of parameter spaces and a better understanding of neural network models and grapple with the crucial problem of non-unique network solutions and trajectories. In addition, we observe a reduction in turn around times for the assessment of these models, due to interactive visualization while the simulation is computed.

Automatic Generation of Connectivity for Large-Scale Neuronal Network Models through Structural Plasticity.

With the emergence of new high performance computation technology in the last decade, the simulation of large scale neural networks which are able to reproduce the behavior and structure of the brain has finally become an achievable target of neuroscience. Due to the number of synaptic connections between neurons and the complexity of biological networks, most contemporary models have manually defined or static connectivity. However, it is expected that modeling the dynamic generation and deletion of the links among neurons, locally and between different regions of the brain, is crucial to unravel important mechanisms associated with learning, memory and healing. Moreover, for many neural circuits that could potentially be modeled, activity data is more readily and reliably available than connectivity data. Thus, a framework that enables networks to wire themselves on the basis of specified activity targets can be of great value in specifying network models where connectivity data is incomplete or has large error margins. To address these issues, in the present work we present an implementation of a model of structural plasticity in the neural network simulator NEST. In this model, synapses consist of two parts, a pre- and a post-synaptic element. Synapses are created and deleted during the execution of the simulation following local homeostatic rules until a mean level of electrical activity is reached in the network. We assess the scalability of the implementation in order to evaluate its potential usage in the self generation of connectivity of large scale networks. We show and discuss the results of simulations on simple two population networks and more complex models of the cortical microcircuit involving 8 populations and 4 layers using the new framework.