Mesoscale simulations predict the role of synergistic cerebellar plasticity during classical eyeblink conditioning.

According to the motor learning theory by Albus and Ito, synaptic depression at the parallel fibre to Purkinje cells synapse (pf-PC) is the main substrate responsible for learning sensorimotor contingencies under climbing fibre control. However, recent experimental evidence challenges this relatively monopolistic view of cerebellar learning. Bidirectional plasticity appears crucial for learning, in which different microzones can undergo opposite changes of synaptic strength (e.g. downbound microzones-more likely depression, upbound microzones-more likely potentiation), and multiple forms of plasticity have been identified, distributed over different cerebellar circuit synapses. Here, we have simulated classical eyeblink conditioning (CEBC) using an advanced spiking cerebellar model embedding downbound and upbound modules that are subject to multiple plasticity rules. Simulations indicate that synaptic plasticity regulates the cascade of precise spiking patterns spreading throughout the cerebellar cortex and cerebellar nuclei. CEBC was supported by plasticity at the pf-PC synapses as well as at the synapses of the molecular layer interneurons (MLIs), but only the combined switch-off of both sites of plasticity compromised learning significantly. By differentially engaging climbing fibre information and related forms of synaptic plasticity, both microzones contributed to generate a well-timed conditioned response, but it was the downbound module that played the major role in this process. The outcomes of our simulations closely align with the behavioural and electrophysiological phenotypes of mutant mice suffering from cell-specific mutations that affect processing of their PC and/or MLI synapses. Our data highlight that a synergy of bidirectional plasticity rules distributed across the cerebellum can facilitate finetuning of adaptive associative behaviours at a high spatiotemporal resolution.

A multi-layer mean-field model of the cerebellum embedding microstructure and population-specific dynamics.

Mean-field (MF) models are computational formalism used to summarize in a few statistical parameters the salient biophysical properties of an inter-wired neuronal network. Their formalism normally incorporates different types of neurons and synapses along with their topological organization. MFs are crucial to efficiently implement the computational modules of large-scale models of brain function, maintaining the specificity of local cortical microcircuits. While MFs have been generated for the isocortex, they are still missing for other parts of the brain. Here we have designed and simulated a multi-layer MF of the cerebellar microcircuit (including Granule Cells, Golgi Cells, Molecular Layer Interneurons, and Purkinje Cells) and validated it against experimental data and the corresponding spiking neural network (SNN) microcircuit model. The cerebellar MF was built using a system of equations, where properties of neuronal populations and topological parameters are embedded in inter-dependent transfer functions. The model time constant was optimised using local field potentials recorded experimentally from acute mouse cerebellar slices as a template. The MF reproduced the average dynamics of different neuronal populations in response to various input patterns and predicted the modulation of the Purkinje Cells firing depending on cortical plasticity, which drives learning in associative tasks, and the level of feedforward inhibition. The cerebellar MF provides a computationally efficient tool for future investigations of the causal relationship between microscopic neuronal properties and ensemble brain activity in virtual brain models addressing both physiological and pathological conditions.

Dual STDP processes at Purkinje cells contribute to distinct improvements in accuracy and speed of saccadic eye movements.

Saccadic eye-movements play a crucial role in visuo-motor control by allowing rapid foveation onto new targets. However, the neural processes governing saccades adaptation are not fully understood. Saccades, due to the short-time of execution (20-100 ms) and the absence of sensory information for online feedback control, must be controlled in a ballistic manner. Incomplete measurements of the movement trajectory, such as the visual endpoint error, are supposedly used to form internal predictions about the movement kinematics resulting in predictive control. In order to characterize the synaptic and neural circuit mechanisms underlying predictive saccadic control, we have reconstructed the saccadic system in a digital controller embedding a spiking neural network of the cerebellum with spike timing-dependent plasticity (STDP) rules driving parallel fiber-Purkinje cell long-term potentiation and depression (LTP and LTD). This model implements a control policy based on a dual plasticity mechanism, resulting in the identification of the roles of LTP and LTD in regulating the overall quality of saccade kinematics: it turns out that LTD increases the accuracy by decreasing visual error and LTP increases the peak speed. The control policy also required cerebellar PCs to be divided into two subpopulations, characterized by burst or pause responses. To our knowledge, this is the first model that explains in mechanistic terms the visual error and peak speed regulation of ballistic eye movements in forward mode exploiting spike-timing to regulate firing in different populations of the neuronal network. This elementary model of saccades could be extended and applied to other more complex cases in which single jerks are concatenated to compose articulated and coordinated movements.

Bayesian Integration in a Spiking Neural System for Sensorimotor Control.

The brain continuously estimates the state of body and environment, with specific regions that are thought to act as Bayesian estimator, optimally integrating noisy and delayed sensory feedback with sensory predictions generated by the cerebellum. In control theory, Bayesian estimators are usually implemented using high-level representations. In this work, we designed a new spike-based computational model of a Bayesian estimator. The state estimator receives spiking activity from two neural populations encoding the sensory feedback and the cerebellar prediction, and it continuously computes the spike variability within each population as a reliability index of the signal these populations encode. The state estimator output encodes the current state estimate. We simulated a reaching task at different stages of cerebellar learning. The activity of the sensory feedback neurons encoded a noisy version of the trajectory after actual movement, with an almost constant intrapopulation spiking variability. Conversely, the activity of the cerebellar output neurons depended on the phase of the learning process. Before learning, they fired at their baseline not encoding any relevant information, and the variability was set to be higher than that of the sensory feedback (more reliable, albeit delayed). When learning was complete, their activity encoded the trajectory before the actual execution, providing an accurate sensory prediction; in this case, the variability was set to be lower than that of the sensory feedback. The state estimator model optimally integrated the neural activities of the afferent populations, so that the output state estimate was primarily driven by sensory feedback in prelearning and by the cerebellar prediction in postlearning. It was able to deal even with more complex scenarios, for example, by shifting the dominant source during the movement execution if information availability suddenly changed. The proposed tool will be a critical block within integrated spiking, brain-inspired control systems for simulations of sensorimotor tasks.

Attention Analysis in Robotic-Assistive Therapy for Children With Autism.

Children with Autism Spectrum Disorder (ASD) show severe attention deficits, hindering their capacity to acquire new skills. The automatic assessment of their attention response would provide the therapists with an important biomarker to better quantify their behaviour and monitor their progress during therapy. This work aims to develop a quantitative model, to evaluate the attention response of children with ASD, during robotic-assistive therapeutic sessions. Previous attempts to quantify the attention response of autistic subjects during human-robot interaction tasks were limited to restrained child movements. Instead, we developed an accurate quantitative system to assess the attention of ASD children in unconstrained scenarios. Our approach combines gaze extraction (Gaze360 model) with the definition of angular Areas-of-Interest, to characterise periods of attention towards elements of interest in the therapy environment during the session. The methodology was tested with 12 ASD children, achieving a mean test accuracy of 79.5 %. Finally, the proposed attention index was consistent with the therapists' evaluation of patients, allowing a meaningful interpretation of the automatic evaluation. This encourages the future clinical use of the proposed system.

Cerebellum Involvement in Dystonia During Associative Motor Learning: Insights From a Data-Driven Spiking Network Model.

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures, or both. Although dystonia is traditionally associated with basal ganglia dysfunction, recent evidence has been pointing to a role of the cerebellum, a brain area involved in motor control and learning. Cerebellar abnormalities have been correlated with dystonia but their potential causative role remains elusive. Here, we simulated the cerebellar input-output relationship with high-resolution computational modeling. We used a data-driven cerebellar Spiking Neural Network and simulated a cerebellum-driven associative learning task, Eye-Blink Classical Conditioning (EBCC), which is characteristically altered in relation to cerebellar lesions in several pathologies. In control simulations, input stimuli entrained characteristic network dynamics and induced synaptic plasticity along task repetitions, causing a progressive spike suppression in Purkinje cells with consequent facilitation of deep cerebellar nuclei cells. These neuronal processes caused a progressive acquisition of eyelid Conditioned Responses (CRs). Then, we modified structural or functional local neural features in the network reproducing alterations reported in dystonic mice. Either reduced olivocerebellar input or aberrant Purkinje cell burst-firing resulted in abnormal learning curves imitating the dysfunctional EBCC motor responses (in terms of CR amount and timing) of dystonic mice. These behavioral deficits might be due to altered temporal processing of sensorimotor information and uncoordinated control of muscle contractions. Conversely, an imbalance of excitatory and inhibitory synaptic densities on Purkinje cells did not reflect into significant EBCC deficit. The present work suggests that only certain types of alterations, including reduced olivocerebellar input and aberrant PC burst-firing, are compatible with the EBCC changes observed in dystonia, indicating that some cerebellar lesions can have a causative role in the pathogenesis of symptoms.

Cerebellum involvement in dystonia: insights from a spiking neural network model during associative learning.

Dystonia is a neurological movement disorder characterized by twisting and repetitive movements or abnormal fixed postures. This complex brain disease has usually been associated with damages to the Basal Ganglia. However, recent studies point out the potential role of the cerebellum. Indeed, motor learning is impaired in dystonic patients, e.g. during eyeblink classical conditioning, a typical cerebellum-driven associative learning protocol, and rodents with local cerebellar damages exhibit dystonic movements. Alterations in the olivocerebellar circuit connectivity have been identified as a potential neural substrate of dystonia. Here, we investigated this hypothesis through simulations of eyeblink conditioning driven by a realistic spiking model of the cerebellum. The pathological model was generated by decreasing the signal transmission from the Inferior Olive to cerebellar cortex, as observed in animal experiments. The model was able to reproduce a reduced acquisition of eyeblink motor responses, with also an unproper timing. Indeed, this pathway is fundamental to drive cerebellar cortical plasticity, which is the basis of cerebellum-driven motor learning. Exploring different levels of damage, the model predicted the possible amount of underlying impairment associated with the misbehavior observed in patients. Simulations of other debated lesions reported in mouse models of dystonia will be run to investigate the cerebellar involvement in different types of dystonia. Indeed, the eyeblink conditioning phenotype could be used to discriminate between them, identifying specific deficits in the generation of motor responses. Future studies will also include simulations of pharmacological or deep brain stimulation treatments targeting the cerebellum, to predict their impact in improving symptoms.

Brain-Inspired Spiking Neural Network Controller for a Neurorobotic Whisker System.

It is common for animals to use self-generated movements to actively sense the surrounding environment. For instance, rodents rhythmically move their whiskers to explore the space close to their body. The mouse whisker system has become a standard model for studying active sensing and sensorimotor integration through feedback loops. In this work, we developed a bioinspired spiking neural network model of the sensorimotor peripheral whisker system, modeling trigeminal ganglion, trigeminal nuclei, facial nuclei, and central pattern generator neuronal populations. This network was embedded in a virtual mouse robot, exploiting the Human Brain Project's Neurorobotics Platform, a simulation platform offering a virtual environment to develop and test robots driven by brain-inspired controllers. Eventually, the peripheral whisker system was adequately connected to an adaptive cerebellar network controller. The whole system was able to drive active whisking with learning capability, matching neural correlates of behavior experimentally recorded in mice.

Development of an Interactive Total Body Robot Enhanced Imitation Therapy for ASD children.

Autism is a neurodevelopmental disorder in which the available therapies target the improvement of social skills, in order to ensure a high quality of life for the child. The use of Social Assistive Robots offers new therapeutic possibilities in which robots can act as therapy enhancers. IOGIOCO project emerges in this framework: it aims at the development of a Robot- Assisted Therapy protocol for the treatment of Autism Spectrum Disorder, through gesture training. The definition of these gestures and their recognition by the robot are parameters that directly affect the engagement of the children. However, the design of a protocol becomes harder in a highly unconstrained environment. Therefore, the current work aims at expanding the gesture set and improving the gesture recognition algorithm available in the IOGIOCO platform. More specifically, total body gestures have been added to the available upper limbs movements, and a custom Activity Detection method has been developed, which allows the identification of the time window in which a gesture is performed. The insertion of this method on a recognition algorithm based on a ResNet, a particular kind of Convolutional Neural Network, improved its F1-score from 57% obtained with the previously-available version, in a dataset of ASD children, to 76%, demonstrating the effectiveness of the Activity Detection method. Furthermore, the expansion of the interaction possibilities to total body movements was positively evaluated by the clinical staff, increasing the engagement of patients and the set of possible trained skills. Therefore, the results of the current work are encouraging. To reinforce the conclusions drawn, the proposed algorithm should be tested in real time on several autistic children within a complete Randomized Clinical Trial, also to study the effectiveness of this type of treatment. From the technical point of view, further improvements of the developed methodology should tackle the remained issues, such as further increasing the recognition capability, especially in the transitions from sitting to standing, that proved to be a hard task for the developed method.

Model simulations unveil the structure-function-dynamics relationship of the cerebellar cortical microcircuit.

The cerebellar network is renowned for its regular architecture that has inspired foundational computational theories. However, the relationship between circuit structure, function and dynamics remains elusive. To tackle the issue, we developed an advanced computational modeling framework that allows us to reconstruct and simulate the structure and function of the mouse cerebellar cortex using morphologically realistic multi-compartmental neuron models. The cerebellar connectome is generated through appropriate connection rules, unifying a collection of scattered experimental data into a coherent construct and providing a new model-based ground-truth about circuit organization. Naturalistic background and sensory-burst stimulation are used for functional validation against recordings in vivo, monitoring the impact of cellular mechanisms on signal propagation, inhibitory control, and long-term synaptic plasticity. Our simulations show how mossy fibers entrain the local neuronal microcircuit, boosting the formation of columns of activity travelling from the granular to the molecular layer providing a new resource for the investigation of local microcircuit computation and of the neural correlates of behavior.

A realistic morpho-anatomical connection strategy for modelling full-scale point-neuron microcircuits.

The modeling of extended microcircuits is emerging as an effective tool to simulate the neurophysiological correlates of brain activity and to investigate brain dysfunctions. However, for specific networks, a realistic modeling approach based on the combination of available physiological, morphological and anatomical data is still an open issue. One of the main problems in the generation of realistic networks lies in the strategy adopted to build network connectivity. Here we propose a method to implement a neuronal network at single cell resolution by using the geometrical probability volumes associated with pre- and postsynaptic neurites. This allows us to build a network with plausible connectivity properties without the explicit use of computationally intensive touch detection algorithms using full 3D neuron reconstructions. The method has been benchmarked for the mouse hippocampus CA1 area, and the results show that this approach is able to generate full-scale brain networks at single cell resolution that are in good agreement with experimental findings. This geometric reconstruction of axonal and dendritic occupancy, by effectively reflecting morphological and anatomical constraints, could be integrated into structured simulators generating entire circuits of different brain areas facilitating the simulation of different brain regions with realistic models.

Sharing Worlds: Design of a Real-Time Attention Classifier for Robotic Therapy of ASD Children.

Joint attention is the capacity of sharing attention between two agents and an aspect of the environment, through the use of different cues, namely gaze. This capacity is of paramount importance for social skills. People with Autism Spectrum Disorder (ASD) present certain deficits in joint attention. Therefore, there is an increasing interest in finding therapies to improve this skill. Some of these therapies include robots since they are known to be attractive to people with autism due to their motivation ability and predictability when compared with humans. In this line, we have designed a real-time attention classifier for a triadic robotic therapy, using Gaze360 and geometrical considerations of the scene. We were able to classify the gaze of the therapist and the one of the child during the whole session, even in a highly unconstrained scenario with a single camera, achieving a mean accuracy of 59%. This classifier can be used for the measurement of joint attention, an important metric for the development of adaptive robotic therapies, where increasing levels of difficulty and engagement are provided dependent on the ASD children, who are characterised by high heterogeneity. Future work will pass by the calculation of this metric and integration on a robotic platform for ASD therapy to understand the impact of these robotic therapies in improving ASD symptoms, specifically on how ASD children share their attention with other people present in the rehabilitation scenarios.

Design of a Robotic Coach for Motor, Social and Cognitive Skills Training Toward Applications With ASD Children.

Socially assistive robots may help the treatment of autism spectrum disorder(ASD), through games using dyadic interactions to train social skills. Existing systems are mainly based on simplified protocols which qualitatively evaluate subject performance. We propose a robotic coaching platform for training social, motor and cognitive capabilities, with two main contributions: (i) using triadic interactions(adult, robot and child), with robotic mirroring, and (ii) providing quantitative performance indicators. The key system features were accurately designed, including type of protocols, feedback systems and evaluation metrics, contemplating the requirements for applications with ASD children. We implemented two protocols, Robot-Master and Adult-Master, where children performed different gestures guided by the robot or the adult respectively, eventually receiving feedback about movement execution. In both, the robot mirrors the subject during the movement. To assess system functionalities, with a homogeneous group of subjects, tests were carried out with 28 healthy subjects; one preliminary acquisition was done with an ASD child. Data analysis was customized to design protocol-specific parameters for movement characterization. Our tests show that robotic mirroring execution depends on the complexity and standardization of movements, as well as on the robot technical features. The feedback system evaluated movement phases and successfully estimated the completion of the exercises. Future work includes improving platform flexibility and adaptability, and clinical trials with ASD children to test the impact of the robotic coach on reducing symptoms. We trust that the proposed quantitative performance indicators extend the current state-of-the-art towards clinical usage of robotic-based coaching systems.

Response Dynamics in an Olivocerebellar Spiking Neural Network With Non-linear Neuron Properties.

Sensorimotor signals are integrated and processed by the cerebellar circuit to predict accurate control of actions. In order to investigate how single neuron dynamics and geometrical modular connectivity affect cerebellar processing, we have built an olivocerebellar Spiking Neural Network (SNN) based on a novel simplification algorithm for single point models (Extended Generalized Leaky Integrate and Fire, EGLIF) capturing essential non-linear neuronal dynamics (e.g., pacemaking, bursting, adaptation, oscillation and resonance). EGLIF models specifically tuned for each neuron type were embedded into an olivocerebellar scaffold reproducing realistic spatial organization and physiological convergence and divergence ratios of connections. In order to emulate the circuit involved in an eye blink response to two associated stimuli, we modeled two adjacent olivocerebellar microcomplexes with a common mossy fiber input but different climbing fiber inputs (either on or off). EGLIF-SNN model simulations revealed the emergence of fundamental response properties in Purkinje cells (burst-pause) and deep nuclei cells (pause-burst) similar to those reported in vivo. The expression of these properties depended on the specific activation of climbing fibers in the microcomplexes and did not emerge with scaffold models using simplified point neurons. This result supports the importance of embedding SNNs with realistic neuronal dynamics and appropriate connectivity and anticipates the scale-up of EGLIF-SNN and the embedding of plasticity rules required to investigate cerebellar functioning at multiple scales.

Corrigendum: Complex Electroresponsive Dynamics in Olivocerebellar Neurons Represented With Extended-Generalized Leaky Integrate and Fire Models.

[This corrects the article DOI: 10.3389/fncom.2019.00035.].

Complex Electroresponsive Dynamics in Olivocerebellar Neurons Represented With Extended-Generalized Leaky Integrate and Fire Models.

The neurons of the olivocerebellar circuit exhibit complex electroresponsive dynamics, which are thought to play a fundamental role for network entraining, plasticity induction, signal processing, and noise filtering. In order to reproduce these properties in single-point neuron models, we have optimized the Extended-Generalized Leaky Integrate and Fire (E-GLIF) neuron through a multi-objective gradient-based algorithm targeting the desired input-output relationships. In this way, E-GLIF was tuned toward the unique input-output properties of Golgi cells, granule cells, Purkinje cells, molecular layer interneurons, deep cerebellar nuclei cells, and inferior olivary cells. E-GLIF proved able to simulate the complex cell-specific electroresponsive dynamics of the main olivocerebellar neurons including pacemaking, adaptation, bursting, post-inhibitory rebound excitation, subthreshold oscillations, resonance, and phase reset. The integration of these E-GLIF point-neuron models into olivocerebellar Spiking Neural Networks will allow to evaluate the impact of complex electroresponsive dynamics at the higher scales, up to motor behavior, in closed-loop simulations of sensorimotor tasks.

Corrigendum: Complex Dynamics in Simplified Neuronal Models: Reproducing Golgi Cell Electroresponsiveness.

[This corrects the article DOI: 10.3389/fninf.2018.00088.].

Design and validation of two embodied mirroring setups for interactive games with autistic children using the NAO humanoid robot.

Socially assistive robots have shown potential benefits in therapy of child and elderly patients with social and cognitive deficits. In particular, for autistic children, humanoid robots could enhance engagement and attention, thanks to their simplified toy-like appearance and the reduced set of possible movements and expressions. The recent focus on autism-related motor impairments has increased the interest on developing new robotic tools aimed at improving not only the social capabilities but also the motor skills of autistic children. To this purpose, we have designed two embodied mirroring setups using the NAO humanoid robot. Two different tracking systems were used and compared: Inertial Measurement Units and the Microsoft Kinect, a marker-less vision based system. Both platforms were able to mirror upper limb basic movements of two healthy subjects, an adult and a child. However, despite the lower accuracy, the Kinect-based setup was chosen as the best candidate for embodied mirroring in autism treatment, thanks to the lower intrusiveness and reduced setup time. A prototype of an interactive mirroring game was developed and successfully tested with the Kinect-based platform, paving the way to the development of a versatile and powerful tool for clinical use with autistic children.

Complex Dynamics in Simplified Neuronal Models: Reproducing Golgi Cell Electroresponsiveness.

Brain neurons exhibit complex electroresponsive properties - including intrinsic subthreshold oscillations and pacemaking, resonance and phase-reset - which are thought to play a critical role in controlling neural network dynamics. Although these properties emerge from detailed representations of molecular-level mechanisms in "realistic" models, they cannot usually be generated by simplified neuronal models (although these may show spike-frequency adaptation and bursting). We report here that this whole set of properties can be generated by the extended generalized leaky integrate-and-fire (E-GLIF) neuron model. E-GLIF derives from the GLIF model family and is therefore mono-compartmental, keeps the limited computational load typical of a linear low-dimensional system, admits analytical solutions and can be tuned through gradient-descent algorithms. Importantly, E-GLIF is designed to maintain a correspondence between model parameters and neuronal membrane mechanisms through a minimum set of equations. In order to test its potential, E-GLIF was used to model a specific neuron showing rich and complex electroresponsiveness, the cerebellar Golgi cell, and was validated against experimental electrophysiological data recorded from Golgi cells in acute cerebellar slices. During simulations, E-GLIF was activated by stimulus patterns, including current steps and synaptic inputs, identical to those used for the experiments. The results demonstrate that E-GLIF can reproduce the whole set of complex neuronal dynamics typical of these neurons - including intensity-frequency curves, spike-frequency adaptation, post-inhibitory rebound bursting, spontaneous subthreshold oscillations, resonance, and phase-reset - providing a new effective tool to investigate brain dynamics in large-scale simulations.

A Multiple-Plasticity Spiking Neural Network Embedded in a Closed-Loop Control System to Model Cerebellar Pathologies.

The cerebellum plays a crucial role in sensorimotor control and cerebellar disorders compromise adaptation and learning of motor responses. However, the link between alterations at network level and cerebellar dysfunction is still unclear. In principle, this understanding would benefit of the development of an artificial system embedding the salient neuronal and plastic properties of the cerebellum and operating in closed-loop. To this aim, we have exploited a realistic spiking computational model of the cerebellum to analyze the network correlates of cerebellar impairment. The model was modified to reproduce three different damages of the cerebellar cortex: (i) a loss of the main output neurons (Purkinje Cells), (ii) a lesion to the main cerebellar afferents (Mossy Fibers), and (iii) a damage to a major mechanism of synaptic plasticity (Long Term Depression). The modified network models were challenged with an Eye-Blink Classical Conditioning test, a standard learning paradigm used to evaluate cerebellar impairment, in which the outcome was compared to reference results obtained in human or animal experiments. In all cases, the model reproduced the partial and delayed conditioning typical of the pathologies, indicating that an intact cerebellar cortex functionality is required to accelerate learning by transferring acquired information to the cerebellar nuclei. Interestingly, depending on the type of lesion, the redistribution of synaptic plasticity and response timing varied greatly generating specific adaptation patterns. Thus, not only the present work extends the generalization capabilities of the cerebellar spiking model to pathological cases, but also predicts how changes at the neuronal level are distributed across the network, making it usable to infer cerebellar circuit alterations occurring in cerebellar pathologies.