The spinal cord facilitates cerebellar upper limb motor learning and control; inputs from neuromusculoskeletal simulation.

Complex interactions between brain regions and the spinal cord (SC) govern body motion, which is ultimately driven by muscle activation. Motor planning or learning are mainly conducted at higher brain regions, whilst the SC acts as a brain-muscle gateway and as a motor control centre providing fast reflexes and muscle activity regulation. Thus, higher brain areas need to cope with the SC as an inherent and evolutionary older part of the body dynamics. Here, we address the question of how SC dynamics affects motor learning within the cerebellum; in particular, does the SC facilitate cerebellar motor learning or constitute a biological constraint? We provide an exploratory framework by integrating biologically plausible cerebellar and SC computational models in a musculoskeletal upper limb control loop. The cerebellar model, equipped with the main form of cerebellar plasticity, provides motor adaptation; whilst the SC model implements stretch reflex and reciprocal inhibition between antagonist muscles. The resulting spino-cerebellar model is tested performing a set of upper limb motor tasks, including external perturbation studies. A cerebellar model, lacking the implemented SC model and directly controlling the simulated muscles, was also tested in the same. The performances of the spino-cerebellar and cerebellar models were then compared, thus allowing directly addressing the SC influence on cerebellar motor adaptation and learning, and on handling external motor perturbations. Performance was assessed in both joint and muscle space, and compared with kinematic and EMG recordings from healthy participants. The differences in cerebellar synaptic adaptation between both models were also studied. We conclude that the SC facilitates cerebellar motor learning; when the SC circuits are in the loop, faster convergence in motor learning is achieved with simpler cerebellar synaptic weight distributions. The SC is also found to improve robustness against external perturbations, by better reproducing and modulating muscle cocontraction patterns.

Bidirectional recurrent learning of inverse dynamic models for robots with elastic joints: a real-time real-world implementation.

Collaborative robots, or cobots, are designed to work alongside humans and to alleviate their physical burdens, such as lifting heavy objects or performing tedious tasks. Ensuring the safety of human-robot interaction (HRI) is paramount for effective collaboration. To achieve this, it is essential to have a reliable dynamic model of the cobot that enables the implementation of torque control strategies. These strategies aim to achieve accurate motion while minimizing the amount of torque exerted by the robot. However, modeling the complex non-linear dynamics of cobots with elastic actuators poses a challenge for traditional analytical modeling techniques. Instead, cobot dynamic modeling needs to be learned through data-driven approaches, rather than analytical equation-driven modeling. In this study, we propose and evaluate three machine learning (ML) approaches based on bidirectional recurrent neural networks (BRNNs) for learning the inverse dynamic model of a cobot equipped with elastic actuators. We also provide our ML approaches with a representative training dataset of the cobot's joint positions, velocities, and corresponding torque values. The first ML approach uses a non-parametric configuration, while the other two implement semi-parametric configurations. All three ML approaches outperform the rigid-bodied dynamic model provided by the cobot's manufacturer in terms of torque precision while maintaining their generalization capabilities and real-time operation due to the optimized sample dataset size and network dimensions. Despite the similarity in torque estimation of these three configurations, the non-parametric configuration was specifically designed for worst-case scenarios where the robot dynamics are completely unknown. Finally, we validate the applicability of our ML approaches by integrating the worst-case non-parametric configuration as a controller within a feedforward loop. We verify the accuracy of the learned inverse dynamic model by comparing it to the actual cobot performance. Our non-parametric architecture outperforms the robot's default factory position controller in terms of accuracy.

A ring-like accretion structure in M87 connecting its black hole and jet.

The nearby radio galaxy M87 is a prime target for studying black hole accretion and jet formation1,2. Event Horizon Telescope observations of M87 in 2017, at a wavelength of 1.3 mm, revealed a ring-like structure, which was interpreted as gravitationally lensed emission around a central black hole3. Here we report images of M87 obtained in 2018, at a wavelength of 3.5 mm, showing that the compact radio core is spatially resolved. High-resolution imaging shows a ring-like structure of [Formula: see text] Schwarzschild radii in diameter, approximately 50% larger than that seen at 1.3 mm. The outer edge at 3.5 mm is also larger than that at 1.3 mm. This larger and thicker ring indicates a substantial contribution from the accretion flow with absorption effects, in addition to the gravitationally lensed ring-like emission. The images show that the edge-brightened jet connects to the accretion flow of the black hole. Close to the black hole, the emission profile of the jet-launching region is wider than the expected profile of a black-hole-driven jet, suggesting the possible presence of a wind associated with the accretion flow.

Electrical coupling regulated by GABAergic nucleo-olivary afferent fibres facilitates cerebellar sensory-motor adaptation.

The inferior olivary (IO) nucleus makes up the signal gateway for several organs to the cerebellar cortex. Located within the sensory-motor-cerebellum pathway, the IO axons, i.e., climbing fibres (CFs), massively synapse onto the cerebellar Purkinje cells (PCs) regulating motor learning whilst the olivary nucleus receives negative feedback through the GABAergic nucleo-olivary​ (NO) pathway. The NO pathway regulates the electrical coupling (EC) amongst the olivary cells thus facilitating synchrony and timing. However, the involvement of this EC regulation on cerebellar adaptive behaviour is still under debate. In our study we have used a spiking cerebellar model to assess the role of the NO pathway in regulating vestibulo-ocular-reflex (VOR) adaptation. The model incorporates spike-based synaptic plasticity at multiple cerebellar sites and an electrically-coupled olivary system. The olivary system plays a central role in regulating the CF spike-firing patterns that drive the PCs, whose axons ultimately shape the cerebellar output. Our results suggest that a systematic GABAergic NO deactivation decreases the spatio-temporal complexity of the IO firing patterns thereby worsening the temporal resolution of the olivary system. Conversely, properly coded IO spatio-temporal firing patterns, thanks to NO modulation, finely shape the balance between long-term depression and potentiation, which optimises VOR adaptation. Significantly, the NO connectivity pattern constrained to the same micro-zone helps maintain the spatio-temporal complexity of the IO firing patterns through time. Moreover, the temporal alignment between the latencies found in the NO fibres and the sensory-motor pathway delay appears to be crucial for facilitating the VOR. When we consider all the above points we believe that these results predict that the NO pathway is instrumental in modulating the olivary coupling and relevant to VOR adaptation.

Computational epidemiology study of homeostatic compensation during sensorimotor aging.

The vestibulo-ocular reflex (VOR) stabilizes vision during head motion. Age-related changes of vestibular neuroanatomical properties predict a linear decay of VOR function. Nonetheless, human epidemiological data show a stable VOR function across the life span. In this study, we model cerebellum-dependent VOR adaptation to relate structural and functional changes throughout aging. We consider three neurosynaptic factors that may codetermine VOR adaptation during aging: the electrical coupling of inferior olive neurons, the long-term spike timing-dependent plasticity at parallel fiber - Purkinje cell synapses and mossy fiber - medial vestibular nuclei synapses, and the intrinsic plasticity of Purkinje cell synapses Our cross-sectional aging analyses suggest that long-term plasticity acts as a global homeostatic mechanism that underpins the stable temporal profile of VOR function. The results also suggest that the intrinsic plasticity of Purkinje cell synapses operates as a local homeostatic mechanism that further sustains the VOR at older ages. Importantly, the computational epidemiology approach presented in this study allows discrepancies among human cross-sectional studies to be understood in terms of interindividual variability in older individuals. Finally, our longitudinal aging simulations show that the amount of residual fibers coding for the peak and trough of the VOR cycle constitutes a predictive hallmark of VOR trajectories over a lifetime.

A cerebellar-based solution to the nondeterministic time delay problem in robotic control.

The presence of computation and transmission-variable time delays within a robotic control loop is a major cause of instability, hindering safe human-robot interaction (HRI) under these circumstances. Classical control theory has been adapted to counteract the presence of such variable delays; however, the solutions provided to date cannot cope with HRI robotics inherent features. The highly nonlinear dynamics of HRI cobots (robots intended for human interaction in collaborative tasks), together with the growing use of flexible joints and elastic materials providing passive compliance, prevent traditional control solutions from being applied. Conversely, human motor control natively deals with low power actuators, nonlinear dynamics, and variable transmission time delays. The cerebellum, pivotal to human motor control, is able to predict motor commands by correlating current and past sensorimotor signals, and to ultimately compensate for the existing sensorimotor human delay (tens of milliseconds). This work aims at bridging those inherent features of cerebellar motor control and current robotic challenges­namely, compliant control in the presence of variable sensorimotor delays. We implement a cerebellar-like spiking neural network (SNN) controller that is adaptive, compliant, and robust to variable sensorimotor delays by replicating the cerebellar mechanisms that embrace the presence of biological delays and allow motor learning and adaptation.

On Robot Compliance: A Cerebellar Control Approach.

The work presented here is a novel biological approach for the compliant control of a robotic arm in real time (RT). We integrate a spiking cerebellar network at the core of a feedback control loop performing torque-driven control. The spiking cerebellar controller provides torque commands allowing for accurate and coordinated arm movements. To compute these output motor commands, the spiking cerebellar controller receives the robot's sensorial signals, the robot's goal behavior, and an instructive signal. These input signals are translated into a set of evolving spiking patterns representing univocally a specific system state at every point of time. Spike-timing-dependent plasticity (STDP) is then supported, allowing for building adaptive control. The spiking cerebellar controller continuously adapts the torque commands provided to the robot from experience as STDP is deployed. Adaptive torque commands, in turn, help the spiking cerebellar controller to cope with built-in elastic elements within the robot's actuators mimicking human muscles (inherently elastic). We propose a natural integration of a bioinspired control scheme, based on the cerebellum, with a compliant robot. We prove that our compliant approach outperforms the accuracy of the default factory-installed position control in a set of tasks used for addressing cerebellar motor behavior: controlling six degrees of freedom (DoF) in smooth movements, fast ballistic movements, and unstructured scenario compliant movements.

Optimization of Efficient Neuron Models With Realistic Firing Dynamics. The Case of the Cerebellar Granule Cell.

Biologically relevant large-scale computational models currently represent one of the main methods in neuroscience for studying information processing primitives of brain areas. However, biologically realistic neuron models tend to be computationally heavy and thus prevent these models from being part of brain-area models including thousands or even millions of neurons. The cerebellar input layer represents a canonical example of large scale networks. In particular, the cerebellar granule cells, the most numerous cells in the whole mammalian brain, have been proposed as playing a pivotal role in the creation of somato-sensorial information representations. Enhanced burst frequency (spiking resonance) in the granule cells has been proposed as facilitating the input signal transmission at the theta-frequency band (4-12 Hz), but the functional role of this cell feature in the operation of the granular layer remains largely unclear. This study aims to develop a methodological pipeline for creating neuron models that maintain biological realism and computational efficiency whilst capturing essential aspects of single-neuron processing. Therefore, we selected a light computational neuron model template (the adaptive-exponential integrate-and-fire model), whose parameters were progressively refined using an automatic parameter tuning with evolutionary algorithms (EAs). The resulting point-neuron models are suitable for reproducing the main firing properties of a realistic granule cell from electrophysiological measurements, including the spiking resonance at the theta-frequency band, repetitive firing according to a specified intensity-frequency (I-F) curve and delayed firing under current-pulse stimulation. Interestingly, the proposed model also reproduced some other emergent properties (namely, silent at rest, rheobase and negligible adaptation under depolarizing currents) even though these properties were not set in the EA as a target in the fitness function (FF), proving that these features are compatible even in computationally simple models. The proposed methodology represents a valuable tool for adjusting AdEx models according to a FF defined in the spiking regime and based on biological data. These models are appropriate for future research of the functional implication of bursting resonance at the theta band in large-scale granular layer network models.

A Basal Ganglia Computational Model to Explain the Paradoxical Sensorial Improvement in the Presence of Huntington's Disease.

The basal ganglia (BG) represent a critical center of the nervous system for sensorial discrimination. Although it is known that Huntington's disease (HD) affects this brain area, it still remains unclear how HD patients achieve paradoxical improvement in sensorial discrimination tasks. This paper presents a computational model of the BG including the main nuclei and the typical firing properties of their neurons. The BG model has been embedded within an auditory signal detection task. We have emulated the effect that the altered levels of dopamine and the degree of HD affectation have in information processing at different layers of the BG, and how these aspects shape transient and steady states differently throughout the selection task. By extracting the independent components of the BG activity at different populations, it is evidenced that early and medium stages of HD affectation may enhance transient activity in the striatum and the substantia nigra pars reticulata. These results represent a possible explanation for the paradoxical improvement that HD patients present in discrimination task performance. Thus, this paper provides a novel understanding on how the fast dynamics of the BG network at different layers interact and enable transient states to emerge throughout the successive neuron populations.

An integrative methodology based on protein-protein interaction networks for identification and functional annotation of disease-relevant genes applied to channelopathies.

BACKGROUND: Biologically data-driven networks have become powerful analytical tools that handle massive, heterogeneous datasets generated from biomedical fields. Protein-protein interaction networks can identify the most relevant structures directly tied to biological functions. Functional enrichments can then be performed based on these structural aspects of gene relationships for the study of channelopathies. Channelopathies refer to a complex group of disorders resulting from dysfunctional ion channels with distinct polygenic manifestations. This study presents a semi-automatic workflow using protein-protein interaction networks that can identify the most relevant genes and their biological processes and pathways in channelopathies to better understand their etiopathogenesis. In addition, the clinical manifestations that are strongly associated with these genes are also identified as the most characteristic in this complex group of diseases. RESULTS: In particular, a set of nine representative disease-related genes was detected, these being the most significant genes in relation to their roles in channelopathies. In this way we attested the implication of some voltage-gated sodium (SCN1A, SCN2A, SCN4A, SCN4B, SCN5A, SCN9A) and potassium (KCNQ2, KCNH2) channels in cardiovascular diseases, epilepsies, febrile seizures, headache disorders, neuromuscular, neurodegenerative diseases or neurobehavioral manifestations. We also revealed the role of Ankyrin-G (ANK3) in the neurodegenerative and neurobehavioral disorders as well as the implication of these genes in other systems, such as the immunological or endocrine systems. CONCLUSIONS: This research provides a systems biology approach to extract information from interaction networks of gene expression. We show how large-scale computational integration of heterogeneous datasets, PPI network analyses, functional databases and published literature may support the detection and assessment of possible potential therapeutic targets in the disease. Applying our workflow makes it feasible to spot the most relevant genes and unknown relationships in channelopathies and shows its potential as a first-step approach to identify both genes and functional interactions in clinical-knowledge scenarios of target diseases. METHODS: An initial gene pool is previously defined by searching general databases under a specific semantic framework. From the resulting interaction network, a subset of genes are identified as the most relevant through the workflow that includes centrality measures and other filtering and enrichment databases.

VOR Adaptation on a Humanoid iCub Robot Using a Spiking Cerebellar Model.

We embed a spiking cerebellar model within an adaptive real-time (RT) control loop that is able to operate a real robotic body (iCub) when performing different vestibulo-ocular reflex (VOR) tasks. The spiking neural network computation, including event- and time-driven neural dynamics, neural activity, and spike-timing dependent plasticity (STDP) mechanisms, leads to a nondeterministic computation time caused by the neural activity volleys encountered during cerebellar simulation. This nondeterministic computation time motivates the integration of an RT supervisor module that is able to ensure a well-orchestrated neural computation time and robot operation. Actually, our neurorobotic experimental setup (VOR) benefits from the biological sensory motor delay between the cerebellum and the body to buffer the computational overloads as well as providing flexibility in adjusting the neural computation time and RT operation. The RT supervisor module provides for incremental countermeasures that dynamically slow down or speed up the cerebellar simulation by either halting the simulation or disabling certain neural computation features (i.e., STDP mechanisms, spike propagation, and neural updates) to cope with the RT constraints imposed by the real robot operation. This neurorobotic experimental setup is applied to different horizontal and vertical VOR adaptive tasks that are widely used by the neuroscientific community to address cerebellar functioning. We aim to elucidate the manner in which the combination of the cerebellar neural substrate and the distributed plasticity shapes the cerebellar neural activity to mediate motor adaptation. This paper underlies the need for a two-stage learning process to facilitate VOR acquisition.

Spike burst-pause dynamics of Purkinje cells regulate sensorimotor adaptation.

Cerebellar Purkinje cells mediate accurate eye movement coordination. However, it remains unclear how oculomotor adaptation depends on the interplay between the characteristic Purkinje cell response patterns, namely tonic, bursting, and spike pauses. Here, a spiking cerebellar model assesses the role of Purkinje cell firing patterns in vestibular ocular reflex (VOR) adaptation. The model captures the cerebellar microcircuit properties and it incorporates spike-based synaptic plasticity at multiple cerebellar sites. A detailed Purkinje cell model reproduces the three spike-firing patterns that are shown to regulate the cerebellar output. Our results suggest that pauses following Purkinje complex spikes (bursts) encode transient disinhibition of target medial vestibular nuclei, critically gating the vestibular signals conveyed by mossy fibres. This gating mechanism accounts for early and coarse VOR acquisition, prior to the late reflex consolidation. In addition, properly timed and sized Purkinje cell bursts allow the ratio between long-term depression and potentiation (LTD/LTP) to be finely shaped at mossy fibre-medial vestibular nuclei synapses, which optimises VOR consolidation. Tonic Purkinje cell firing maintains the consolidated VOR through time. Importantly, pauses are crucial to facilitate VOR phase-reversal learning, by reshaping previously learnt synaptic weight distributions. Altogether, these results predict that Purkinje spike burst-pause dynamics are instrumental to VOR learning and reversal adaptation.

Corrigendum: Event- and Time-Driven Techniques Using Parallel CPU-GPU Co-processing for Spiking Neural Networks.

[This corrects the article on p. 7 in vol. 11, PMID: 28223930.].

A Metric for Evaluating Neural Input Representation in Supervised Learning Networks.

Supervised learning has long been attributed to several feed-forward neural circuits within the brain, with particular attention being paid to the cerebellar granular layer. The focus of this study is to evaluate the input activity representation of these feed-forward neural networks. The activity of cerebellar granule cells is conveyed by parallel fibers and translated into Purkinje cell activity, which constitutes the sole output of the cerebellar cortex. The learning process at this parallel-fiber-to-Purkinje-cell connection makes each Purkinje cell sensitive to a set of specific cerebellar states, which are roughly determined by the granule-cell activity during a certain time window. A Purkinje cell becomes sensitive to each neural input state and, consequently, the network operates as a function able to generate a desired output for each provided input by means of supervised learning. However, not all sets of Purkinje cell responses can be assigned to any set of input states due to the network's own limitations (inherent to the network neurobiological substrate), that is, not all input-output mapping can be learned. A key limiting factor is the representation of the input states through granule-cell activity. The quality of this representation (e.g., in terms of heterogeneity) will determine the capacity of the network to learn a varied set of outputs. Assessing the quality of this representation is interesting when developing and studying models of these networks to identify those neuron or network characteristics that enhance this representation. In this study we present an algorithm for evaluating quantitatively the level of compatibility/interference amongst a set of given cerebellar states according to their representation (granule-cell activation patterns) without the need for actually conducting simulations and network training. The algorithm input consists of a real-number matrix that codifies the activity level of every considered granule-cell in each state. The capability of this representation to generate a varied set of outputs is evaluated geometrically, thus resulting in a real number that assesses the goodness of the representation.

Event- and Time-Driven Techniques Using Parallel CPU-GPU Co-processing for Spiking Neural Networks.

Modeling and simulating the neural structures which make up our central neural system is instrumental for deciphering the computational neural cues beneath. Higher levels of biological plausibility usually impose higher levels of complexity in mathematical modeling, from neural to behavioral levels. This paper focuses on overcoming the simulation problems (accuracy and performance) derived from using higher levels of mathematical complexity at a neural level. This study proposes different techniques for simulating neural models that hold incremental levels of mathematical complexity: leaky integrate-and-fire (LIF), adaptive exponential integrate-and-fire (AdEx), and Hodgkin-Huxley (HH) neural models (ranged from low to high neural complexity). The studied techniques are classified into two main families depending on how the neural-model dynamic evaluation is computed: the event-driven or the time-driven families. Whilst event-driven techniques pre-compile and store the neural dynamics within look-up tables, time-driven techniques compute the neural dynamics iteratively during the simulation time. We propose two modifications for the event-driven family: a look-up table recombination to better cope with the incremental neural complexity together with a better handling of the synchronous input activity. Regarding the time-driven family, we propose a modification in computing the neural dynamics: the bi-fixed-step integration method. This method automatically adjusts the simulation step size to better cope with the stiffness of the neural model dynamics running in CPU platforms. One version of this method is also implemented for hybrid CPU-GPU platforms. Finally, we analyze how the performance and accuracy of these modifications evolve with increasing levels of neural complexity. We also demonstrate how the proposed modifications which constitute the main contribution of this study systematically outperform the traditional event- and time-driven techniques under increasing levels of neural complexity.

Connecting Artificial Brains to Robots in a Comprehensive Simulation Framework: The Neurorobotics Platform.

Combined efforts in the fields of neuroscience, computer science, and biology allowed to design biologically realistic models of the brain based on spiking neural networks. For a proper validation of these models, an embodiment in a dynamic and rich sensory environment, where the model is exposed to a realistic sensory-motor task, is needed. Due to the complexity of these brain models that, at the current stage, cannot deal with real-time constraints, it is not possible to embed them into a real-world task. Rather, the embodiment has to be simulated as well. While adequate tools exist to simulate either complex neural networks or robots and their environments, there is so far no tool that allows to easily establish a communication between brain and body models. The Neurorobotics Platform is a new web-based environment that aims to fill this gap by offering scientists and technology developers a software infrastructure allowing them to connect brain models to detailed simulations of robot bodies and environments and to use the resulting neurorobotic systems for in silico experimentation. In order to simplify the workflow and reduce the level of the required programming skills, the platform provides editors for the specification of experimental sequences and conditions, environments, robots, and brain-body connectors. In addition to that, a variety of existing robots and environments are provided. This work presents the architecture of the first release of the Neurorobotics Platform developed in subproject 10 "Neurorobotics" of the Human Brain Project (HBP). At the current state, the Neurorobotics Platform allows researchers to design and run basic experiments in neurorobotics using simulated robots and simulated environments linked to simplified versions of brain models. We illustrate the capabilities of the platform with three example experiments: a Braitenberg task implemented on a mobile robot, a sensory-motor learning task based on a robotic controller, and a visual tracking embedding a retina model on the iCub humanoid robot. These use-cases allow to assess the applicability of the Neurorobotics Platform for robotic tasks as well as in neuroscientific experiments.

Modeling the Cerebellar Microcircuit: New Strategies for a Long-Standing Issue.

The cerebellar microcircuit has been the work bench for theoretical and computational modeling since the beginning of neuroscientific research. The regular neural architecture of the cerebellum inspired different solutions to the long-standing issue of how its circuitry could control motor learning and coordination. Originally, the cerebellar network was modeled using a statistical-topological approach that was later extended by considering the geometrical organization of local microcircuits. However, with the advancement in anatomical and physiological investigations, new discoveries have revealed an unexpected richness of connections, neuronal dynamics and plasticity, calling for a change in modeling strategies, so as to include the multitude of elementary aspects of the network into an integrated and easily updatable computational framework. Recently, biophysically accurate "realistic" models using a bottom-up strategy accounted for both detailed connectivity and neuronal non-linear membrane dynamics. In this perspective review, we will consider the state of the art and discuss how these initial efforts could be further improved. Moreover, we will consider how embodied neurorobotic models including spiking cerebellar networks could help explaining the role and interplay of distributed forms of plasticity. We envisage that realistic modeling, combined with closed-loop simulations, will help to capture the essence of cerebellar computations and could eventually be applied to neurological diseases and neurorobotic control systems.

A Computational Framework for Realistic Retina Modeling.

Computational simulations of the retina have led to valuable insights about the biophysics of its neuronal activity and processing principles. A great number of retina models have been proposed to reproduce the behavioral diversity of the different visual processing pathways. While many of these models share common computational stages, previous efforts have been more focused on fitting specific retina functions rather than generalizing them beyond a particular model. Here, we define a set of computational retinal microcircuits that can be used as basic building blocks for the modeling of different retina mechanisms. To validate the hypothesis that similar processing structures may be repeatedly found in different retina functions, we implemented a series of retina models simply by combining these computational retinal microcircuits. Accuracy of the retina models for capturing neural behavior was assessed by fitting published electrophysiological recordings that characterize some of the best-known phenomena observed in the retina: adaptation to the mean light intensity and temporal contrast, and differential motion sensitivity. The retinal microcircuits are part of a new software platform for efficient computational retina modeling from single-cell to large-scale levels. It includes an interface with spiking neural networks that allows simulation of the spiking response of ganglion cells and integration with models of higher visual areas.