Rehabilitation promotes the recovery of structural and functional features of healthy neuronal networks after stroke

Rehabilitation is the most effective treatment for promoting the recovery of motor deficits after stroke. One of the most challenging experimental goals is to unambiguously link brain rewiring to motor recovery prompted by rehabilitative therapy. Here, we investigated which aspects of cortical remodeling are induced by rehabilitation by combining optical imaging and manipulation tools in a mouse model of stroke. We revealed that the stabilization of peri-infarct synaptic contacts fostered by rehabilitation goes along with increased vascular density induced by angiogenesis. Furthermore, we showed the progressive formation of a new motor representation in the peri-infarct area where temporal and spatial features of cortical activation recovered towards pre-stroke condition. In the same animals we observed the reinforcement of inter-hemispheric connectivity after rehabilitation. The present work provides the first evidences that rehabilitation promotes the combined recovery of structural and functional features distinctive of healthy neuronal networks.

[1]  M. Raichle.  Cerebral blood flow and metabolism. , 1975, Ciba Foundation symposium.

[2]  HighWire Press.  The journal of neuroscience : the official journal of the Society for Neuroscience. , 1981 .

[3]  E. Mackenzie,et al.  Cerebral Blood Flow and Metabolism , 1993 .

[4]  S. Lipton,et al.  Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function , 1995, Neuron.

[5]  O. Steward,et al.  Injury-Induced Physiological Events that may Modulate Gene Expression in Neurons and Glia , 1997, Reviews in the neurosciences.

[6]  David J. Reinkensmeyer,et al.  Design of robot assistance for arm movement therapy following stroke , 2001, Adv. Robotics.

[7]  S. Carmichael,et al.  New Patterns of Intracortical Projections after Focal Cortical Stroke , 2001, Neurobiology of Disease.

[8]  T. Jones,et al.  Cortical electrical stimulation combined with rehabilitative training: Enhanced functional recovery and dendritic plasticity following focal cortical ischemia in rats , 2003, Neurological research.

[9]  Ann M. Stowe,et al.  Post-infarct cortical plasticity and behavioral recovery using concurrent cortical stimulation and rehabilitative training: A feasibility study in primates , 2003, Neurological research.

[10]  S. Strittmatter,et al.  Nogo Receptor Antagonism Promotes Stroke Recovery by Enhancing Axonal Plasticity , 2004, The Journal of Neuroscience.

[11]  S. Simpson.  Of Mice . . . , 2004, Science.

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

[13]  S. Carmichael.  Cellular and molecular mechanisms of neural repair after stroke: Making waves , 2006, Annals of neurology.

[14]  T. Jones,et al.  Contralesional neural plasticity and functional changes in the less-affected forelimb after large and small cortical infarcts in rats , 2006, Experimental Neurology.

[15]  C. Bütefisch.  Neurobiological bases of rehabilitation , 2006, Neurological Sciences.

[16]  L. Cohen,et al.  Functional imaging of intervention effects in stroke motor rehabilitation. , 2006, Archives of physical medicine and rehabilitation.

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

[18]  L. Maffei,et al.  Transient Synaptic Silencing of Developing Striate Cortex Has Persistent Effects on Visual Function and Plasticity , 2007, The Journal of Neuroscience.

[19]  S. Kirker,et al.  Combined transcranial direct current stimulation and robot-assisted arm training in subacute stroke patients: a pilot study. , 2007, Restorative neurology and neuroscience.

[20]  B. Roysam,et al.  Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. , 2008, Cell stem cell.

[21]  G. Opala,et al.  Perfusion computed tomography in prediction of functional outcome in patients with acute ischaemic stroke. , 2009, Nuclear medicine review. Central & Eastern Europe.

[22]  T. Murphy,et al.  In Vivo Voltage-Sensitive Dye Imaging in Adult Mice Reveals That Somatosensory Maps Lost to Stroke Are Replaced over Weeks by New Structural and Functional Circuits with Prolonged Modes of Activation within Both the Peri-Infarct Zone and Distant Sites , 2009, The Journal of Neuroscience.

[23]  T. Murphy,et al.  Automated light-based mapping of motor cortex by photoactivation of channelrhodopsin-2 transgenic mice , 2009, Nature Methods.

[24]  D. Kleinfeld,et al.  Correlations of Neuronal and Microvascular Densities in Murine Cortex Revealed by Direct Counting and Colocalization of Nuclei and Vessels , 2009, The Journal of Neuroscience.

[25]  T. Murphy,et al.  Longitudinal in vivo Imaging Reveals Balanced and Branch-Specific Remodeling of Mature Cortical Pyramidal Dendritic Arbors after Stroke , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[26]  W. Otte,et al.  Correspondence between Altered Functional and Structural Connectivity in the Contralesional Sensorimotor Cortex after Unilateral Stroke in Rats: A Combined Resting-State Functional MRI and Manganese-Enhanced MRI Study , 2010, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[27]  M. Corbetta,et al.  Resting interhemispheric functional magnetic resonance imaging connectivity predicts performance after stroke , 2009, Annals of neurology.

[28]  M. Viergever,et al.  Recovery of Sensorimotor Function after Experimental Stroke Correlates with Restoration of Resting-State Interhemispheric Functional Connectivity , 2010, The Journal of Neuroscience.

[29]  M. Chopp,et al.  Angiogenesis, neurogenesis and brain recovery of function following injury. , 2010, Current opinion in investigational drugs.

[30]  S. Barbay,et al.  Combination of NEP 1-40 Treatment and Motor Training Enhances Behavioral Recovery After a Focal Cortical Infarct in Rats , 2010, Stroke.

[31]  T. Murphy,et al.  In Vivo 2-Photon Imaging of Fine Structure in the Rodent Brain: Before, During, and After Stroke , 2010, Stroke.

[32]  I. Módy,et al.  Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. , 2010, Nature.

[33]  C. Portera-Cailliau,et al.  Local Hemodynamics Dictate Long-Term Dendritic Plasticity in Peri-Infarct Cortex , 2010, The Journal of Neuroscience.

[34]  Monica A. Perez,et al.  Mechanisms of Short-Term Training-Induced Reaching Improvement in Severely Hemiparetic Stroke Patients , 2011, Neurorehabilitation and neural repair.

[35]  R. Nudo,et al.  Shaping plasticity to enhance recovery after injury. , 2011, Progress in brain research.

[36]  A. Ergul,et al.  Angiogenesis: A Harmonized Target for Recovery After Stroke , 2012, Stroke.

[37]  M. Chopp,et al.  Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation , 2012, The Lancet Neurology.

[38]  N. Lehman,et al.  Axonal Outgrowth and Dendritic Plasticity in the Cortical Peri-Infarct Area After Experimental Stroke , 2012, Stroke.

[39]  J. Krakauer,et al.  Getting Neurorehabilitation Right , 2012, Neurorehabilitation and neural repair.

[40]  C. Portera-Cailliau,et al.  Chronic in vivo imaging shows no evidence of dendritic plasticity or functional remapping in the contralesional cortex after stroke. , 2013, Cerebral cortex.

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

[42]  T. Murphy,et al.  Displacement of Sensory Maps and Disorganization of Motor Cortex After Targeted Stroke in Mice , 2013, Stroke.

[43]  T. Murphy,et al.  Optogenetic Mapping after Stroke Reveals Network-Wide Scaling of Functional Connections and Heterogeneous Recovery of the Peri-Infarct , 2014, The Journal of Neuroscience.

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

[45]  José C. Rubio,et al.  Asynchronous therapy restores motor control by rewiring of the rat corticospinal tract after stroke , 2014, Science.

[46]  Abraham Z. Snyder,et al.  Optical imaging of disrupted functional connectivity following ischemic stroke in mice , 2014, NeuroImage.

[47]  C. Ayata,et al.  High-resolution in vivo optical imaging of stroke injury and repair , 2015, Brain Research.

[48]  L. Carey,et al.  A Randomized Controlled Trial of the Effect of Early Upper-Limb Training on Stroke Recovery and Brain Activation , 2015, Neurorehabilitation and neural repair.

[49]  S. Carmichael,et al.  Blood-brain barrier breakdown and neovascularization processes after stroke and traumatic brain injury. , 2015, Current opinion in neurology.

[50]  T. Jones,et al.  Motor System Reorganization After Stroke: Stimulating and Training Toward Perfection. , 2015, Physiology.

[51]  Mark D. Huffman,et al.  AHA Statistical Update Heart Disease and Stroke Statistics — 2012 Update A Report From the American Heart Association WRITING GROUP MEMBERS , 2010 .

[52]  Francesco S. Pavone,et al.  Optogenetics design of mechanistically-based stimulation patterns for cardiac defibrillation , 2016, Scientific Reports.

[53]  M. Tuszynski,et al.  Rehabilitation drives enhancement of neuronal structure in functionally relevant neuronal subsets , 2016, Proceedings of the National Academy of Sciences.

[54]  Ying Ma,et al.  Wide-field optical mapping of neural activity and brain haemodynamics: considerations and novel approaches , 2016, Philosophical Transactions of the Royal Society B: Biological Sciences.

[55]  Timothy H. Murphy,et al.  High-throughput automated home-cage mesoscopic functional imaging of mouse cortex , 2016, Nature Communications.

[56]  Mariel G Kozberg,et al.  Resting-state hemodynamics are spatiotemporally coupled to synchronized and symmetric neural activity in excitatory neurons , 2016, Proceedings of the National Academy of Sciences.

[57]  T. Komiyama,et al.  Transformation of Cortex-wide Emergent Properties during Motor Learning , 2017, Neuron.

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

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

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

[61]  Kevin C. Chan,et al.  Macroscale variation in resting-state neuronal activity and connectivity assessed by simultaneous calcium imaging, hemodynamic imaging and electrophysiology , 2018, NeuroImage.

[62]  A. L. Allegra Mascaro,et al.  Whole-Brain Vasculature Reconstruction at the Single Capillary Level , 2017, Scientific Reports.

[63]  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.