Experimental and Computational Study on Motor Control and Recovery After Stroke: Toward a Constructive Loop Between Experimental and Virtual Embodied Neuroscience

Being able to replicate real experiments with computational simulations is a unique opportunity to refine and validate models with experimental data and redesign the experiments based on simulations. However, since it is technically demanding to model all components of an experiment, traditional approaches to modeling reduce the experimental setups as much as possible. In this study, our goal is to replicate all the relevant features of an experiment on motor control and motor rehabilitation after stroke. To this aim, we propose an approach that allows continuous integration of new experimental data into a computational modeling framework. First, results show that we could reproduce experimental object displacement with high accuracy via the simulated embodiment in the virtual world by feeding a spinal cord model with experimental registration of the cortical activity. Second, by using computational models of multiple granularities, our preliminary results show the possibility of simulating several features of the brain after stroke, from the local alteration in neuronal activity to long-range connectivity remodeling. Finally, strategies are proposed to merge the two pipelines. We further suggest that additional models could be integrated into the framework thanks to the versatility of the proposed approach, thus allowing many researchers to achieve continuously improved experimental design.

[1]  Michael H. Dickinson,et al.  A modular display system for insect behavioral neuroscience , 2008, Journal of Neuroscience Methods.

[2]  B. Hawkins,et al.  A framework: , 2020, Harmful Interaction between the Living and the Dead in Greek Tragedy.

[3]  T. Murphy,et al.  Mesoscale Mapping of Mouse Cortex Reveals Frequency-Dependent Cycling between Distinct Macroscale Functional Modules , 2017, The Journal of Neuroscience.

[4]  Xiao-Jing Wang,et al.  A Recurrent Network Mechanism of Time Integration in Perceptual Decisions , 2006, The Journal of Neuroscience.

[5]  S. Carmichael,et al.  Molecular, cellular and functional events in axonal sprouting after stroke , 2017, Experimental Neurology.

[6]  U. Kamil,et al.  Functional imaging , 2001, 2001 Conference Proceedings of the 23rd Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[7]  T. Murphy,et al.  Extensive Turnover of Dendritic Spines and Vascular Remodeling in Cortical Tissues Recovering from Stroke , 2007, The Journal of Neuroscience.

[8]  Mikael Djurfeldt,et al.  Closed Loop Interactions between Spiking Neural Network and Robotic Simulators Based on MUSIC and ROS , 2016, Front. Neuroinform..

[9]  Andrew W. Kraft,et al.  Functional connectivity structure of cortical calcium dynamics in anesthetized and awake mice , 2017, PloS one.

[10]  Brenda C. Shields,et al.  Thy1-GCaMP6 Transgenic Mice for Neuronal Population Imaging In Vivo , 2014, PloS one.

[11]  Viktor K. Jirsa,et al.  Noise during Rest Enables the Exploration of the Brain's Dynamic Repertoire , 2008, PLoS Comput. Biol..

[12]  Niels Birbaumer,et al.  Movement related slow cortical potentials in severely paralyzed chronic stroke patients , 2015, Front. Hum. Neurosci..

[13]  Hui He,et al.  Integrated DNA and RNA extraction using magnetic beads from viral pathogens causing acute respiratory infections , 2017, Scientific Reports.

[14]  Marc-Oliver Gewaltig,et al.  NEST (NEural Simulation Tool) , 2007, Scholarpedia.

[15]  Heidi Johansen-Berg,et al.  Using diffusion imaging to study human connectional anatomy. , 2009, Annual review of neuroscience.

[16]  David P. Bashor,et al.  A large-scale model of some spinal reflex circuits , 1998, Biological Cybernetics.

[17]  Roger N. Lemon THE CIRCUITRY OF THE HUMAN SPINAL CORD: ITS ROLE IN MOTOR CONTROL AND MOVEMENT DISORDERS By Emmanuel Pierrot-Deseilligny and David Burke 2005 Cambridge: Cambridge University Press Price: £110.00 ISBN: 978-0-521-82581-8 , 2006 .

[18]  Rogério Rodrigues Lima Cisi,et al.  Simulation system of spinal cord motor nuclei and associated nerves and muscles, in a Web-based architecture , 2008, Journal of Computational Neuroscience.

[19]  Aneta Stefanovska,et al.  Alterations in the coupling functions between cortical and cardio-respiratory oscillations due to anaesthesia with propofol and sevoflurane , 2016, Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences.

[20]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[21]  Christoph Zrenner,et al.  Closed-Loop Neuroscience and Non-Invasive Brain Stimulation: A Tale of Two Loops , 2016, Front. Cell. Neurosci..

[22]  Gustavo Deco,et al.  The dynamics of resting fluctuations in the brain: metastability and its dynamical cortical core , 2016, bioRxiv.

[23]  Stefan Mihalas,et al.  Synchronization dependent on spatial structures of a mesoscopic whole-brain network , 2019, PLoS Comput. Biol..

[24]  Joelle Zimmermann,et al.  Structural architecture supports functional organization in the human aging brain at a regionwise and network level , 2016, Human brain mapping.

[25]  Stefan Ulbrich,et al.  A Domain-Specific Language (DSL) for Integrating Neuronal Networks in Robot Control , 2015 .

[26]  G. Loeb,et al.  Mathematical models of proprioceptors. I. Control and transduction in the muscle spindle. , 2006, Journal of neurophysiology.

[27]  Sergio Martinoia,et al.  A simulated neuro-robotic environment for bi-directional closed-loop experiments , 2010, Paladyn J. Behav. Robotics.

[28]  Viktor K. Jirsa,et al.  Transmission time delays organize the brain network synchronization , 2019, Philosophical Transactions of the Royal Society A.

[29]  Olaf Sporns,et al.  Network structure of cerebral cortex shapes functional connectivity on multiple time scales , 2007, Proceedings of the National Academy of Sciences.

[30]  Vivek Prabhakaran,et al.  Role of the Contralesional vs. Ipsilesional Hemisphere in Stroke Recovery , 2017, Front. Hum. Neurosci..

[31]  Byron M. Yu,et al.  A high-performance brain–computer interface , 2006, Nature.

[32]  K. Svoboda,et al.  Imaging Calcium Concentration Dynamics in Small Neuronal Compartments , 2004, Science's STKE.

[33]  Andreas Daffertshofer,et al.  Generative Models of Cortical Oscillations: Neurobiological Implications of the Kuramoto Model , 2010, Front. Hum. Neurosci..

[34]  Karl Deisseroth,et al.  Optogenetic neuronal stimulation promotes functional recovery after stroke , 2014, Proceedings of the National Academy of Sciences.

[35]  O. Sporns,et al.  Key role of coupling, delay, and noise in resting brain fluctuations , 2009, Proceedings of the National Academy of Sciences.

[36]  Jürgen Kurths,et al.  Synchronization: Phase locking and frequency entrainment , 2001 .

[37]  Trygve B Leergaard,et al.  Spatial registration of serial microscopic brain images to three-dimensional reference atlases with the QuickNII tool , 2019, PloS one.

[38]  Ayman Habib,et al.  OpenSim: Simulating musculoskeletal dynamics and neuromuscular control to study human and animal movement , 2018, PLoS Comput. Biol..

[39]  Viktor K. Jirsa,et al.  Fast–Slow Bursters in the Unfolding of a High Codimension Singularity and the Ultra-slow Transitions of Classes , 2016, The Journal of Mathematical Neuroscience.

[40]  Gustavo Deco,et al.  Structure-Function Discrepancy: Inhomogeneity and Delays in Synchronized Neural Networks , 2014, PLoS Comput. Biol..

[41]  Pierre Yger,et al.  PyNN: A Common Interface for Neuronal Network Simulators , 2008, Front. Neuroinform..

[42]  J. Cowan,et al.  Excitatory and inhibitory interactions in localized populations of model neurons. , 1972, Biophysical journal.

[43]  Lin Tian,et al.  Functional imaging of hippocampal place cells at cellular resolution during virtual navigation , 2010, Nature Neuroscience.

[44]  Silvestro Micera,et al.  A Robotic System for Adaptive Training and Function Assessment of Forelimb Retraction in Mice , 2018, IEEE Transactions on Neural Systems and Rehabilitation Engineering.

[45]  Cecilia Laschi,et al.  Proprioceptive Feedback through a Neuromorphic Muscle Spindle Model , 2017, Front. Neurosci..

[46]  Carl D. Hacker,et al.  Decreased integration and information capacity in stroke measured by whole brain models of resting state activity , 2017, Brain : a journal of neurology.

[47]  George Krasadakis A Framework for , 2020, The Innovation Mode.

[48]  Alain Destexhe,et al.  Modeling mesoscopic cortical dynamics using a mean-field model of conductance-based networks of adaptive exponential integrate-and-fire neurons , 2017, bioRxiv.

[49]  Cori Bargmann,et al.  Microfluidics for in vivo imaging of neuronal and behavioral activity in Caenorhabditis elegans , 2007, Nature Methods.

[50]  A. Hodgkin,et al.  A quantitative description of membrane current and its application to conduction and excitation in nerve , 1990 .

[51]  Bard Ermentrout,et al.  Linearization of F-I Curves by Adaptation , 1998, Neural Computation.

[52]  Stefan R. Pulver,et al.  Ultra-sensitive fluorescent proteins for imaging neuronal activity , 2013, Nature.

[53]  Gustavo Deco,et al.  Cognitive performance in healthy older adults relates to spontaneous switching between states of functional connectivity during rest , 2017, Scientific Reports.

[54]  A. Destexhe,et al.  Enhanced Responsiveness and Low-Level Awareness in Stochastic Network States , 2017, Neuron.

[55]  Yoshihiko Nakamura,et al.  Modeling and Identification of a Realistic Spiking Neural Network and Musculoskeletal Model of the Human Arm, and an Application to the Stretch Reflex , 2016, IEEE Transactions on Neural Systems and Rehabilitation Engineering.

[56]  Andrew Howard,et al.  Design and use paradigms for Gazebo, an open-source multi-robot simulator , 2004, 2004 IEEE/RSJ International Conference on Intelligent Robots and Systems (IROS) (IEEE Cat. No.04CH37566).

[57]  G. Deco,et al.  Emerging concepts for the dynamical organization of resting-state activity in the brain , 2010, Nature Reviews Neuroscience.

[58]  Christophe Bernard,et al.  The Virtual Mouse Brain: A Computational Neuroinformatics Platform to Study Whole Mouse Brain Dynamics , 2017, eNeuro.

[59]  Gustavo Deco,et al.  Bottom up modeling of the connectome: Linking structure and function in the resting brain and their changes in aging , 2013, NeuroImage.

[60]  Tanuj Gulati,et al.  Low frequency cortical activity is a neuromodulatory target that tracks recovery after stroke , 2018, Nature Medicine.

[61]  A. L. Allegra Mascaro,et al.  Combined Rehabilitation Promotes the Recovery of Structural and Functional Features of Healthy Neuronal Networks after Stroke. , 2019, Cell reports.

[62]  Daniel A. Wagenaar,et al.  The Neurally Controlled Animat: Biological Brains Acting with Simulated Bodies , 2001, Auton. Robots.

[63]  Michael B. Reiser,et al.  Real neuroscience in virtual worlds , 2012, Current Opinion in Neurobiology.

[64]  Francesco Saverio Pavone,et al.  Large Scale Double-Path Illumination System with Split Field of View for the All-Optical Study of Inter-and Intra-Hemispheric Functional Connectivity on Mice , 2019, Methods and protocols.

[65]  G. B. Young,et al.  Continuous EEG monitoring in the intensive care unit. , 2017, Handbook of clinical neurology.

[66]  Ann M. Stowe,et al.  Extensive Cortical Rewiring after Brain Injury , 2005, The Journal of Neuroscience.

[67]  G. Loeb,et al.  Mathematical models of proprioceptors. II. Structure and function of the Golgi tendon organ. , 2006, Journal of neurophysiology.

[68]  W. Stacey,et al.  On the nature of seizure dynamics. , 2014, Brain : a journal of neurology.

[69]  Ludovico Silvestri,et al.  Towards a comprehensive understanding of brain machinery by correlative microscopy , 2015, Journal of biomedical optics.

[70]  Frans C. T. van der Helm,et al.  Analysis of reflex modulation with a biologically realistic neural network , 2007, Journal of Computational Neuroscience.

[71]  Andreas Spiegler,et al.  Selective Activation of Resting-State Networks following Focal Stimulation in a Connectome-Based Network Model of the Human Brain , 2016, eNeuro.

[72]  Steve M. Potter,et al.  Closed-loop neuroscience and neuroengineering , 2014, Front. Neural Circuits.

[73]  F. Varela,et al.  Measuring phase synchrony in brain signals , 1999, Human brain mapping.

[74]  A Stefanovska,et al.  Characterizing an ensemble of interacting oscillators: the mean-field variability index. , 2013, Physical review. E, Statistical, nonlinear, and soft matter physics.

[75]  Viktor K. Jirsa,et al.  The Virtual Brain: a simulator of primate brain network dynamics , 2013, Front. Neuroinform..

[76]  Jiwei He,et al.  Perturbation of Brain Oscillations after Ischemic Stroke: A Potential Biomarker for Post-Stroke Function and Therapy , 2015, International journal of molecular sciences.

[77]  Karl J. Friston,et al.  The Dynamic Brain: From Spiking Neurons to Neural Masses and Cortical Fields , 2008, PLoS Comput. Biol..

[78]  Ferdinando A. Mussa-Ivaldi,et al.  Connecting Brains to Robots: An Artificial Body for Studying the Computational Properties of Neural Tissues , 2000, Artificial Life.

[79]  Rüdiger Dillmann,et al.  Connecting Artificial Brains to Robots in a Comprehensive Simulation Framework: The Neurorobotics Platform , 2017, Front. Neurorobot..

[80]  Viktor K. Jirsa,et al.  Phase-lags in large scale brain synchronization: Methodological considerations and in-silico analysis , 2018, PLoS Comput. Biol..

[81]  E. Izhikevich Phase models with explicit time delays , 1998 .

[82]  R. N. Lemon,et al.  An electron microscopic examination of the corticospinal projection to the cervical spinal cord in the rat: lack of evidence for cortico-motoneuronal synapses , 2003, Experimental Brain Research.

[83]  P MALABIA,et al.  [Dynamic brain]. , 1956, Medicina espanola.

[84]  Stefan Mihalas,et al.  Synchronization dependent on spatial structures of a mesoscopic whole-brain network , 2018, bioRxiv.

[85]  Silvestro Micera,et al.  Boosting generalized recovery by combined optogenetic stimulation and training after stroke , 2020, bioRxiv.

[86]  Sergio Martinoia,et al.  Modular Neuronal Assemblies Embodied in a Closed-Loop Environment: Toward Future Integration of Brains and Machines , 2012, Front. Neural Circuits.

[87]  G. Palù,et al.  The Mouse Brain , 2008, Neurobiology of Disease.

[88]  Diane Lipscombe,et al.  Neuronal L-Type Calcium Channels Open Quickly and Are Inhibited Slowly , 2005, The Journal of Neuroscience.

[89]  Gemma Lancaster,et al.  Surrogate data for hypothesis testing of physical systems , 2018, Physics Reports.

[90]  Wulfram Gerstner,et al.  Adaptive exponential integrate-and-fire model as an effective description of neuronal activity. , 2005, Journal of neurophysiology.

[91]  S. Micera,et al.  A Robotic System for Quantitative Assessment and Poststroke Training of Forelimb Retraction in Mice , 2014, Neurorehabilitation and neural repair.

[92]  Maurizio Corbetta,et al.  On the low dimensionality of behavioral deficits and alterations of brain network connectivity after focal injury , 2018, Cortex.

[93]  Stefan J. Kiebel,et al.  Inferring Neuronal Dynamics from Calcium Imaging Data Using Biophysical Models and Bayesian Inference , 2016, PLoS Comput. Biol..

[94]  Haley R Pipkins,et al.  Polyamine transporter potABCD is required for virulence of encapsulated but not nonencapsulated Streptococcus pneumoniae , 2017, PloS one.

[95]  S. Micera,et al.  Mechanisms Underlying the Neuromodulation of Spinal Circuits for Correcting Gait and Balance Deficits after Spinal Cord Injury , 2016, Neuron.

[96]  Jürgen Kurths,et al.  Synchronization - A Universal Concept in Nonlinear Sciences , 2001, Cambridge Nonlinear Science Series.

[97]  Marcello Massimini,et al.  Shaping the Default Activity Pattern of the Cortical Network , 2017, Neuron.

[98]  Mark P. Richardson,et al.  Dynamics on Networks: The Role of Local Dynamics and Global Networks on the Emergence of Hypersynchronous Neural Activity , 2014, PLoS Comput. Biol..

[99]  Maurizio Corbetta,et al.  Resting-State Temporal Synchronization Networks Emerge from Connectivity Topology and Heterogeneity , 2015, PLoS Comput. Biol..

[100]  Alain Destexhe,et al.  Self-sustained Asynchronous Irregular States and Up–down States in Thalamic, Cortical and Thalamocortical Networks of Nonlinear Integrate-and-fire Neurons , 2022 .

[101]  Viktor K. Jirsa,et al.  A Low Dimensional Description of Globally Coupled Heterogeneous Neural Networks of Excitatory and Inhibitory Neurons , 2008, PLoS Comput. Biol..

[102]  Allan R. Jones,et al.  A mesoscale connectome of the mouse brain , 2014, Nature.

[103]  Viktor K. Jirsa,et al.  Mathematical framework for large-scale brain network modeling in The Virtual Brain , 2015, NeuroImage.

[104]  G. Edelman,et al.  Large-scale model of mammalian thalamocortical systems , 2008, Proceedings of the National Academy of Sciences.

[105]  Michelle Y. Cheng,et al.  Optogenetic modulation in stroke recovery. , 2016, Neurosurgical focus.

[106]  A. Hodgkin,et al.  A quantitative description of membrane current and its application to conduction and excitation in nerve , 1952, The Journal of physiology.

[107]  Murray Shanahan,et al.  Effects of lesions on synchrony and metastability in cortical networks , 2015, NeuroImage.

[108]  Hauke R. Heekeren,et al.  Linking neuronal variability to perceptual decision making via neuroimaging , 2011 .

[109]  D. Winter,et al.  Models of recruitment and rate coding organization in motor-unit pools. , 1993, Journal of neurophysiology.

[110]  J. Fetcho,et al.  In Vivo Imaging of Zebrafish Reveals Differences in the Spinal Networks for Escape and Swimming Movements , 2001, The Journal of Neuroscience.

[111]  G. Deco,et al.  Ongoing Cortical Activity at Rest: Criticality, Multistability, and Ghost Attractors , 2012, The Journal of Neuroscience.

[112]  Viktor Jirsa,et al.  Individual structural features constrain the mouse functional connectome , 2019, Proceedings of the National Academy of Sciences.

[113]  Maurizio Corbetta,et al.  Linking Entropy at Rest with the Underlying Structural Connectivity in the Healthy and Lesioned Brain , 2018, Cerebral cortex.

[114]  Silvestro Micera,et al.  Boosting generalized recovery by combined optogenetic stimulation and training after stroke , 2020, bioRxiv.

[115]  Anthony R. McIntosh,et al.  The Virtual Brain: Modeling Biological Correlates of Recovery after Chronic Stroke , 2015, Front. Neurol..

[116]  Andreas Spiegler,et al.  Heterogeneity of time delays determines synchronization of coupled oscillators. , 2016, Physical review. E.

[117]  Joachim Gross,et al.  Perilesional pathological oscillatory activity in the magnetoencephalogram of patients with cortical brain lesions , 2004, Neuroscience Letters.

[118]  Anthony R. McIntosh,et al.  Functional Mechanisms of Recovery after Chronic Stroke: Modeling with the Virtual Brain123 , 2016, eNeuro.

[119]  Stefan Ulbrich,et al.  A Framework for Coupled Simulations of Robots and Spiking Neuronal Networks , 2016, J. Intell. Robotic Syst..

[120]  Morten L. Kringelbach,et al.  Modeling the outcome of structural disconnection on resting-state functional connectivity , 2012, NeuroImage.

[121]  Matthew Millard,et al.  Flexing computational muscle: modeling and simulation of musculotendon dynamics. , 2013, Journal of biomechanical engineering.

[122]  David A. Abbink,et al.  A rigorous model of reflex function indicates that position and force feedback are flexibly tuned to position and force tasks , 2009, Experimental Brain Research.

[123]  Gustavo Deco,et al.  Role of local network oscillations in resting-state functional connectivity , 2011, NeuroImage.

[124]  Christine Grienberger,et al.  Imaging Calcium in Neurons , 2012, Neuron.

[125]  R. Traub Simulation of intrinsic bursting in CA3 hippocampal neurons , 1982, Neuroscience.

[126]  Robert W. Batterman,et al.  Minimal Model Explanations , 2014, Philosophy of Science.

[127]  M. Chesselet,et al.  Synchronous Neuronal Activity Is a Signal for Axonal Sprouting after Cortical Lesions in the Adult , 2002, The Journal of Neuroscience.

[128]  James G. King,et al.  Reconstruction and Simulation of Neocortical Microcircuitry , 2015, Cell.

[129]  R. Nudo Recovery after brain injury: mechanisms and principles , 2013, Front. Hum. Neurosci..

[130]  A. Stefanovska,et al.  Kuramoto model with time-varying parameters. , 2011, Physical review. E, Statistical, nonlinear, and soft matter physics.

[131]  L. Lenchik Functional imaging , 2007, Annals of Biomedical Engineering.

[132]  Karl J. Friston,et al.  Degeneracy and cognitive anatomy , 2002, Trends in Cognitive Sciences.

[133]  Dipanjan Roy,et al.  Phase description of spiking neuron networks with global electric and synaptic coupling. , 2011, Physical review. E, Statistical, nonlinear, and soft matter physics.

[134]  S. Micera,et al.  Combining robotic training and inactivation of the healthy hemisphere restores pre-stroke motor patterns in mice , 2017, eLife.