Enduring Poststroke Motor Functional Improvements by a Well–Timed Combination of Motor Rehabilitative Training and Cortical Stimulation in Rats

Background. In animal stroke models, peri-infarct cortical stimulation (CS) combined with rehabilitative reach training (RT) enhances motor functional outcome and cortical reorganization, compared with RT alone. It was unknown whether the effects of CS + RT (a) persist long after treatment, (b) can be enhanced by forcing greater use of the paretic limb, and (C) vary with treatment onset time. Objective. To test the endurance, time sensitivity, and the potential for augmentation by forced forelimb use of CS + RT treatment effects following ischemic stroke. Methods. Adult rats that were proficient in skilled reaching received unilateral ischemic motor cortical lesions. RT was delivered for 3 weeks alone or concurrently with 100-Hz cathodal epidural CS, delivered at 50% of movement thresholds. In study 1, this treatment was initiated at 14 days postinfarct, with some subgroups receiving an overlapping period of continuous constraint of the nonparetic forelimb to force use of the paretic limb. The function of the paretic limb was assessed weekly for 9 to 10 months posttreatment. In study 2, rats underwent CS, RT, and the combination during the chronic postinfarct period. Results. Early onset CS + RT resulted in greater functional improvements than RT alone. The CS-related gains persisted for 9 to 10 months posttreatment and were not significantly influenced by forced use of the paretic limb. When treatment onset was delayed until 3 months post-infarct, RT alone improved function, but CS + RT was no more effective than RT alone. Conclusion. CS can enhance the persistence, as well as the magnitude of RT-driven functional improvements, but its effectiveness in doing so may vary with time postinfarct.

[1]  T. Schallert,et al.  Use-dependent exacerbation of brain damage occurs during an early post-lesion vulnerable period , 1998, Brain Research.

[2]  L. Cohen,et al.  Modulation of motor learning and memory formation by non-invasive cortical stimulation of the primary motor cortex , 2011, Neuropsychological rehabilitation.

[3]  Randolph J. Nudo,et al.  Behavioral and neurophysiological effects of delayed training following a small ischemic infarct in primary motor cortex of squirrel monkeys , 2006, Experimental Brain Research.

[4]  J. Kleim,et al.  Cortical Synaptogenesis and Motor Map Reorganization Occur during Late, But Not Early, Phase of Motor Skill Learning , 2004, The Journal of Neuroscience.

[5]  K. Fuxe,et al.  Endothelin‐1 induced lesions of the frontoparietal cortex of the rat. A possible model of focal cortical ischemia , 1997, Neuroreport.

[6]  T. Schallert,et al.  CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury , 2000, Neuropharmacology.

[7]  D. Mozaffarian,et al.  Heart disease and stroke statistics--2011 update: a report from the American Heart Association. , 2011, Circulation.

[8]  J. Krakauer,et al.  Consensus: "Can tDCS and TMS enhance motor learning and memory formation?" , 2008, Brain stimulation.

[9]  N. Sogabe,et al.  in rats , 2014 .

[10]  J. Kleim,et al.  Distributed Versus Focal Cortical Stimulation to Enhance Motor Function and Motor Map Plasticity in a Rodent Model of Ischemia , 2011, Neurorehabilitation and neural repair.

[11]  Theresa A. Jones,et al.  Skill learning induced plasticity of motor cortical representations is time and age-dependent , 2012, Neurobiology of Learning and Memory.

[12]  Jeff Biernaskie,et al.  Enriched Rehabilitative Training Promotes Improved Forelimb Motor Function and Enhanced Dendritic Growth after Focal Ischemic Injury , 2001, The Journal of Neuroscience.

[13]  B. J. Anderson,et al.  Plasticity of gray matter volume: the cellular and synaptic plasticity that underlies volumetric change. , 2011, Developmental psychobiology.

[14]  T. Jones,et al.  Unilateral ischemic sensorimotor cortical damage in female rats: forelimb behavioral effects and dendritic structural plasticity in the contralateral homotopic cortex , 2004, Experimental Neurology.

[15]  D. Corbett,et al.  Efficacy of Rehabilitative Experience Declines with Time after Focal Ischemic Brain Injury , 2004, The Journal of Neuroscience.

[16]  J. Kleim,et al.  Age-Dependent Reorganization of Peri-Infarct “Premotor” Cortex With Task-Specific Rehabilitative Training in Mice , 2015, Neurorehabilitation and neural repair.

[17]  D. Mozaffarian,et al.  Heart disease and stroke statistics--2012 update: a report from the American Heart Association. , 2012, Circulation.

[18]  Ian Q. Whishaw,et al.  Animal models of neurological deficits: how relevant is the rat? , 2002, Nature Reviews Neuroscience.

[19]  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.

[20]  Klaus Funke,et al.  Dose-Dependence of Changes in Cortical Protein Expression Induced with Repeated Transcranial Magnetic Theta-Burst Stimulation in the Rat , 2013, Brain Stimulation.

[21]  B. Rosen,et al.  Motor Recovery and Cortical Reorganization after Constraint-Induced Movement Therapy in Stroke Patients: A Preliminary Study , 2002, Neurorehabilitation and neural repair.

[22]  Theresa A. Jones,et al.  Experience-Dependent Structural Plasticity in Cortex Heterotopic to Focal Sensorimotor Cortical Damage , 2000, Experimental Neurology.

[23]  S. Pellis,et al.  Impairment of pronation, supination, and body co-ordination in reach-to-grasp tasks in human Parkinson's disease (PD) reveals homology to deficits in animal models , 2002, Behavioural Brain Research.

[24]  Edward Taub,et al.  Constraint-induced movement therapy for chronic stroke hemiparesis and other disabilities. , 2004, Restorative neurology and neuroscience.

[25]  T. Jones,et al.  Motor Skill Training, but not Voluntary Exercise, Improves Skilled Reaching After Unilateral Ischemic Lesions of the Sensorimotor Cortex in Rats , 2008, Neurorehabilitation and neural repair.

[26]  E. Taub,et al.  Atrophy of Spared Gray Matter Tissue Predicts Poorer Motor Recovery and Rehabilitation Response in Chronic Stroke , 2012, Stroke.

[27]  Jenni M. Karl,et al.  Thinning, movement, and volume loss of residual cortical tissue occurs after stroke in the adult rat as identified by histological and magnetic resonance imaging analysis , 2010, Neuroscience.

[28]  Ian Q. Whishaw,et al.  The impairments in reaching and the movements of compensation in rats with motor cortex lesions: an endpoint, videorecording, and movement notation analysis , 1991, Behavioural Brain Research.

[29]  J. Kleim,et al.  Motor cortex stimulation enhances motor recovery and reduces peri-infarct dysfunction following ischemic insult , 2003, Neurological research.

[30]  Theresa A. Jones,et al.  Epidural cortical stimulation enhances motor function after sensorimotor cortical infarcts in rats , 2006, Experimental Neurology.

[31]  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.

[32]  T. Jones,et al.  Training the "less-affected" forelimb after unilateral cortical infarcts interferes with functional recovery of the impaired forelimb in rats. , 2005, Restorative neurology and neuroscience.

[33]  Lynne V. Gauthier,et al.  Remodeling the Brain: Plastic Structural Brain Changes Produced by Different Motor Therapies After Stroke , 2008, Stroke.

[34]  T. Jones,et al.  Behavioral and neuroplastic effects of focal endothelin-1 induced sensorimotor cortex lesions , 2004, Neuroscience.

[35]  R. Schwarting,et al.  Behavioral and neurochemical asymmetries following unilateral trephination of the rat skull: Is this control operation always appropriate? , 1994, Physiology & Behavior.

[36]  P. Schellinger,et al.  Strengthening the link: the critical role of children in the stroke chain of recovery. , 2008, Stroke.

[37]  Theresa A. Jones,et al.  Motor cortical stimulation promotes synaptic plasticity and behavioral improvements following sensorimotor cortex lesions , 2008, Experimental Neurology.

[38]  T. Jones,et al.  Unilateral Sensorimotor Cortex Lesions in Adult Rats Facilitate Motor Skill Learning with the “Unaffected” Forelimb and Training-Induced Dendritic Structural Plasticity in the Motor Cortex , 2002, The Journal of Neuroscience.

[39]  Janine Reis,et al.  Modulation of motor performance and motor learning by transcranial direct current stimulation. , 2011, Current opinion in neurology.

[40]  F. Colbourne,et al.  Constraint-Induced Movement Therapy and Rehabilitation Exercises Lessen Motor Deficits and Volume of Brain Injury After Striatal Hemorrhagic Stroke in Rats , 2003, Stroke.

[41]  M. Gorassini,et al.  Reduced functional recovery by delaying motor training after spinal cord injury. , 2005, Journal of neurophysiology.

[42]  Robert Teasell,et al.  Systematic Review and Meta-Analysis of Constraint-Induced Movement Therapy in the Hemiparetic Upper Extremity More Than Six Months Post Stroke , 2012, Topics in stroke rehabilitation.

[43]  T. Schallert,et al.  Use-Dependent Exaggeration of Neuronal Injury after Unilateral Sensorimotor Cortex Lesions , 1996, The Journal of Neuroscience.

[44]  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.

[45]  B. Johansson,et al.  Paw‐Reaching, Sensorimotor, and Rotational Behavior After Brain Infarction in Rats , 1993, Stroke.

[46]  Ian Q Whishaw,et al.  Evidence for bilateral control of skilled movements: ipsilateral skilled forelimb reaching deficits and functional recovery in rats follow motor cortex and lateral frontal cortex lesions , 2004, The European journal of neuroscience.

[47]  L. Cohen,et al.  Noninvasive brain stimulation in neurorehabilitation. , 2013, Handbook of clinical neurology.

[48]  J. P. Miller,et al.  Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: the EXCITE randomized clinical trial. , 2006, JAMA.

[49]  L. Cormack,et al.  Breeder and batch-dependent variability in the acquisition and performance of a motor skill in adult Long–Evans rats , 2011, Behavioural Brain Research.

[50]  Paul A Thompson,et al.  Retention of upper limb function in stroke survivors who have received constraint-induced movement therapy: the EXCITE randomised trial , 2008, The Lancet Neurology.

[51]  Yannan Fang,et al.  Effects of transcranial direct current stimulation on hemichannel pannexin-1 and neural plasticity in rat model of cerebral infarction , 2012, Neuroscience.

[52]  H. J. G. GUNDERSEN,et al.  Some new, simple and efficient stereological methods and their use in pathological research and diagnosis , 1988, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[53]  T. Jones,et al.  Long-Lasting Functional Disabilities in Middle-Aged Rats with Small Cerebral Infarcts , 2003, The Journal of Neuroscience.

[54]  N. Young,et al.  Cortical stimulation improves skilled forelimb use following a focal ischemic infarct in the rat , 2003, Neurological research.

[55]  F. Barone,et al.  Pharmacologic Interventions for Stroke: Looking Beyond the Thrombolysis Time Window Into the Penumbra With Biomarkers, Not a Stopwatch , 2009, Stroke.

[56]  I. Whishaw,et al.  Compensation aids skilled reaching in aging and in recovery from forelimb motor cortex stroke in the rat , 2010, Neuroscience.

[57]  T. Jones,et al.  d-Amphetamine enhances skilled reaching after ischemic cortical lesions in rats , 2005, Neuroscience Letters.

[58]  Heidi M. Schambra,et al.  Direct Current Stimulation Promotes BDNF-Dependent Synaptic Plasticity: Potential Implications for Motor Learning , 2010, Neuron.

[59]  T. Jones,et al.  Abnormalities in skilled reaching movements are improved by peripheral anesthetization of the less-affected forelimb after sensorimotor cortical infarcts in rats , 2007, Behavioural Brain Research.

[60]  J. Krakauer,et al.  Consensus: Can transcranial direct current stimulation and transcranial magnetic stimulation enhance motor learning and memory formation? , 2008, Brain Stimulation.

[61]  Mark Hallett,et al.  Constraint-Induced Therapy in Stroke: Magnetic-Stimulation Motor Maps and Cerebral Activation , 2003, Neurorehabilitation and neural repair.

[62]  Walter Paulus,et al.  Induction of Late LTP-Like Plasticity in the Human Motor Cortex by Repeated Non-Invasive Brain Stimulation , 2013, Brain Stimulation.

[63]  T. Jones,et al.  Laminar-Dependent Dendritic Spine Alterations in the Motor Cortex of Adult Rats Following Callosal Transection and Forced Forelimb Use , 2002, Neurobiology of Learning and Memory.