, Volume 3, Issue 4, pp 420–427 | Cite as


  • Randolph J. NudoEmail author


Over the past 20 years, evidence has mounted regarding the capacity of the central nervous system to alter its structure and function throughout life. Injury to the central nervous system appears to be a particularly potent trigger for plastic mechanisms to be elicited. Following focal injury, widespread neurophysiological and neuroanatomical changes occur both in the peri-infarct region, as well as throughout the ipsi- and contralesional cortex, in a complex, time-dependent cascade. Since such post-injury plasticity can be both adaptive or maladaptive, current research is directed at understanding how plasticity may be modulated to develop more effective therapeutic interventions for neurological disorders, such as stroke. Behavioral training appears to be a significant contributor to adaptive plasticity after injury, providing a neuroscientific foundation for the development of physical therapeutic approaches. Adjuvant therapies, such as pharmacological agents and exogenous electrical stimulation, may provide a more receptive environment through which behavioral therapies may be imparted. This chapter reviews some of the recent results from animal models of injury and recovery that depict the complex time course of plasticity following cortical injury and implications for neurorehabilitation.

Key Words

plasticity learning stroke brain repair motor systems cortex 


  1. 1.
    Butefisch CM, Davis BC, Wise SP, Sawaki L, Kopylev L, Classen J, Cohen LG. Mechanisms of use-dependent plasticity in the human motor cortex. Proc Natl Acad Sci USA 2000;97: 3661–3665.PubMedCrossRefGoogle Scholar
  2. 2.
    Cheung SW, Nagarajan SS, Schreiner CE, Bedenbaugh PH, Wong A. Plasticity in primary auditory cortex of monkeys with altered vocal production. J Neurosci 2005;25: 2490–2503.PubMedCrossRefGoogle Scholar
  3. 3.
    Jones EG. Cortical and subcortical contributions to activity-dependent plasticity in primate somatosensory cortex. Annu Rev Neurosci 2000;23: 1–37.PubMedCrossRefGoogle Scholar
  4. 4.
    Kleim JA, Barbay S, Cooper NR, Hogg TM, Reidel CN, Remple MS, Nudo RJ. Motor learning-dependent synaptogenesis is localized to functionally reorganized motor cortex. Neurobiol Learn Mem 2002;77: 63–77.PubMedCrossRefGoogle Scholar
  5. 5.
    Meliza CD, Dan Y. Receptive-field modification in rat visual cortex induced by paired visual stimulation and single-cell spiking. Neuron 2006;49: 183–189.PubMedCrossRefGoogle Scholar
  6. 6.
    Stettler DD, Yamahachi H, Li W, Denk W, Gilbert CD. Axons and synaptic boutons are highly dynamic in adult visual cortex. Neuron 2006;49: 877–887.PubMedCrossRefGoogle Scholar
  7. 7.
    Diamond MC, Rosenzweig MR, Bennett EL, Lindner B, Lyon L. Effects of environmental enrichment and impoverishment on rat cerebral cortex. J Neurobiol 1972;3: 47–64.PubMedCrossRefGoogle Scholar
  8. 8.
    Mohammed AH, Zhu SW, Darmopil S, Hjerling-Leffler J, Ern-fors P, Winblad B, Diamond MC, Eriksson PS, Bogdanovic N. Environmental enrichment and the brain. Prog Brain Res 2002; 138: 109–133.PubMedCrossRefGoogle Scholar
  9. 9.
    Bennett EL, Diamond MC, Krech D, Rosenzweig MR. Chemical and anatomical plasticity of the brain. Science 1964;146: 610–619.PubMedCrossRefGoogle Scholar
  10. 10.
    Kempermann G, Kuhn HG, Gage FH. Experience-induced neuro-genesis in the senescent dentate gyrus. J Neurosci 1998;18: 3206–3212.PubMedGoogle Scholar
  11. 11.
    Rosenzweig MR, Bennett EL, Hebert M, Morimoto H. Social grouping cannot account for cerebral effects of enriched environments. Brain Res 1978;153: 563–576.PubMedCrossRefGoogle Scholar
  12. 12.
    Jenkins WM, Merzenich MM, Ochs MT, Allard T, Guic-Robles E. Functional reorganization of primary somatosensory cortex in adult owl monkeys after behaviorally controlled tactile stimulation. J Neurophysiol 1990;63: 82–104.PubMedGoogle Scholar
  13. 13.
    Clark SA, Allard T, Jenkins WM, Merzenich MM. Receptive fields in the body-surface map in adult cortex defined by temporally correlated inputs. Nature 1988;332: 444–445.PubMedCrossRefGoogle Scholar
  14. 14.
    Buonomano DV, Merzenich MM. Associative synaptic plasticity in hippocampal cal neurons is not sensitive to unpaired presynaptic activity. J Neurophysiol 1996;76: 631–636.PubMedGoogle Scholar
  15. 15.
    Sanes JN, Donoghue JP, Thangaraj V, Edelman RR, Warach S. Shared neural substrates controlling hand movements in human motor cortex. Science 1995;268: 1775–1777.PubMedCrossRefGoogle Scholar
  16. 16.
    Park MC, Belhaj-Saif A, Cheney PD. Properties of primary motor cortex output to forelimb muscles in rhesus macaques. J Neurophysiol 2004;92: 2968–2984.PubMedCrossRefGoogle Scholar
  17. 17.
    Huntley GW, Jones EG. Relationship of intrinsic connections to forelimb movement representations in monkey motor cortex: A correlative anatomic and physiological study. J Neurophysiol 1991;66: 390–413.PubMedGoogle Scholar
  18. 18.
    Stoney SD, Jr., Thompson WD, Asanuma H. Excitation of pyramidal tract cells by intracortical microstimulation: Effective extent of stimulating current. J Neurophysiol 1968;31: 659–669.PubMedGoogle Scholar
  19. 19.
    Nudo RJ, Milliken GW, Jenkins WM, Merzenich MM. Use-dependent alterations of movement representations in primary motor cortex of adult squirrel monkeys. J Neurosci 1996; 16: 785–807.PubMedGoogle Scholar
  20. 20.
    Withers GS, Greenough WT. Reach training selectively alters dendritic branching in subpopulations of layer ii–iii pyramids in rat motor-somatosensory forelimb cortex. Neuropsychologia 1989;27: 61–69.PubMedCrossRefGoogle Scholar
  21. 21.
    Plautz EJ, Milliken GW, Nudo RJ. Effects of repetitive motor training on movement representations in adult squirrel monkeys: Role of use versus learning. Neurobiol Learn Mem 2000;74: 27–55.PubMedCrossRefGoogle Scholar
  22. 22.
    Remple MS, Bruneau RM, VandenBerg PM, Goertzen C, Kleim JA. Sensitivity of cortical movement representations to motor experience: Evidence that skill learning but not strength training induces cortical reorganization. Behav Brain Res 2001;123: 133–141.PubMedCrossRefGoogle Scholar
  23. 23.
    Glees P, Cole J. Recovery of skilled motor functions after small repeated lesions in motor cortex in macaque. J Neurophysiol 1950; 13: 137–148.Google Scholar
  24. 24.
    Jenkins WM, Merzenich MMM. Reorganization of neocortical representations after brain injury: A neurophysiological model of the bases of recovery from Stroke. Prog Brain Res 1987;71: 249–266.PubMedCrossRefGoogle Scholar
  25. 25.
    Nudo RJ, Milliken GW. Reorganization of movement representations in primary motor cortex following focal ischemic infarcts in adult squirrel monkeys. J Neurophysiol 1996;75: 2144–2149.PubMedGoogle Scholar
  26. 26.
    Nudo RJ, Wise BM, SiFuentes F, Milliken GW. Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 1996;272: 1791–1794.PubMedCrossRefGoogle Scholar
  27. 27.
    Stroemer RP, Kent TA, Hulsebosch CE. Neocortical neural sprouting, synaptogenesis, and behavioral recovery after neocortical infarction in rats. Stroke 1995;26: 2135–2144.PubMedCrossRefGoogle Scholar
  28. 28.
    Carmichael ST. Plasticity of cortical projections after Stroke. Neuroscientist 2003;9: 64–75.PubMedCrossRefGoogle Scholar
  29. 29.
    Schiene K, Bruehl C, Zilles K, Qu M, Hagemann G, Kraemer M, Witte OW. Neuronal hyperexcitability and reduction of gabaa-receptor expression in the surround of cerebral photothrombosis. J Cereb Blood Flow Metab 1996;16: 906–914.PubMedCrossRefGoogle Scholar
  30. 30.
    Carmichael ST. Cellular and molecular mechanisms of neural repair after stroke: Making waves. Ann Neurol 2006;59: 735–742.PubMedCrossRefGoogle Scholar
  31. 31.
    Kleim JA, Jones TA, Schallert T. Motor enrichment and the induction of plasticity before or after brain injury. Neurochem Res 2003;28: 1757–1769.PubMedCrossRefGoogle Scholar
  32. 32.
    Jones TA, Schallert T. Overgrowth and pruning of dendrites in adult rats recovering from neocortical damage. Brain Res 1992; 581: 156–160.PubMedCrossRefGoogle Scholar
  33. 33.
    Dum RP, Strick PL. Frontal lobe inputs to the digit representations of the motor areas on the lateral surface of the hemisphere. J Neurosci 2005;25: 1375–1386.PubMedCrossRefGoogle Scholar
  34. 34.
    Dancause N, Barbay S, Frost SB, Plautz EJ, Chen D, Zoubina EV, Stowe AM, Nudo RJ. Extensive cortical rewiring after brain injury. J Neurosci 2005;25: 10167–10179.PubMedCrossRefGoogle Scholar
  35. 35.
    Frost SB, Barbay S, Friel KM, Plautz EJ, Nudo RJ. Reorganization of remote cortical regions after ischemic brain injury: A potential substrate for stroke recovery. J Neurophysiol 2003;89: 3205–3214.PubMedCrossRefGoogle Scholar
  36. 36.
    Dancause N, Barbay S, Frost SB, Plautz EJ, Stowe AM, Friel KM, Nudo RJ. Ipsilateral connections of the ventral premotor cortex in a new world primate. J Comp Neurol 2006;495: 374–390.PubMedCrossRefGoogle Scholar
  37. 37.
    Friel KM, Barbay S, Frost SB, Plautz EJ, Hutchinson DM, Stowe AM, Dancause N, Zoubina EV, Quaney BM, Nudo RJ. Dissociation of sensorimotor deficits after rostral versus caudal lesions in the primary motor cortex hand representation. J Neurophysiol 2005;94: 1312–1324.PubMedCrossRefGoogle Scholar
  38. 38.
    Taub E, Uswatte G, King DK, Morris D, Crago JE, Chatterjee A. A placebo-controlled trial of constraint-induced movement therapy for upper extremity after stroke. Stroke 2006;37: 1045–1049.PubMedCrossRefGoogle Scholar
  39. 39.
    Sunderland A, Tuke A. Neuroplasticity, learning and recovery after stroke: A critical evaluation of constraint-induced therapy. Neuropsychol Rehabil 2005;15: 81–96.PubMedCrossRefGoogle Scholar
  40. 40.
    Jones TA, Schallert T. Use-dependent growth of pyramidal neurons after neocortical damage. J Neurosci 1994;14: 2140–2152.PubMedGoogle Scholar
  41. 41.
    Bury SD, Adkins DL, Ishida JT, Kotzer CM, Eichhorn AC, Jones TA. Denervation facilitates neuronal growth in the motor cortex of rats in the presence of behavioral demand. Neurosci Lett 2000; 287: 85–88.PubMedCrossRefGoogle Scholar
  42. 42.
    Adkins DL, Bury SD, Jones TA. Laminar-dependent dendritic spine alterations in the motor cortex of adult rats following callosal transection and forced forelimb use. Neurobiol Learn Mem 2002; 78: 35–52.PubMedCrossRefGoogle Scholar
  43. 43.
    Jones TA, Chu CJ, Grande LA, Gregory AD. Motor skills training enhances lesion-induced structural plasticity in the motor cortex of adult rats. J Neurosci 1999;19: 10153–10163.PubMedGoogle Scholar
  44. 44.
    Biemaskie J, Corbett D. Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury. J Neurosci 2001;21: 5272–5280.Google Scholar
  45. 45.
    Kozlowski DA, James DC, Schallert T. Use-dependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J Neurosci 1996;16: 4776–4786.PubMedGoogle Scholar
  46. 46.
    Humm JL, Kozlowski DA, Bland ST, James DC, Schallert T. Use-dependent exaggeration of brain injury: Is glutamate involved? Exp Neurol 1999;157: 349–358.PubMedCrossRefGoogle Scholar
  47. 47.
    Goldstein LB. Amphetamines and related drugs in motor recovery after Stroke. Phys Med Rehabil Clin N Am 2003;14: S125-S134.PubMedCrossRefGoogle Scholar
  48. 48.
    Feeney DM, Gonzalez A, Law WA. Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury. Science 1982;217: 855–857.PubMedCrossRefGoogle Scholar
  49. 49.
    Gladstone DJ, Danells CJ, Armesto A, McIlroy WE, Staines WR, Graham SJ, Herrmann N, Szalai JP, Black SE. Physiotherapy coupled with dextroamphetamine for rehabilitation after hemiparetic stroke: A randomized, double-blind, placebo-controlled trial. Stroke 2006;37: 179–185.PubMedCrossRefGoogle Scholar
  50. 50.
    Platz T, Kim IH, Engel U, Pinkowski C, Eickhof C, Kutzner M. Amphetamine fails to facilitate motor performance and to enhance motor recovery among stroke patients with mild arm paresis: Interim analysis and termination of a double blind, randomised, placebo-controlled trial. Restor Neurol Neurosci 2005;23: 271–280.PubMedGoogle Scholar
  51. 51.
    Barbay S, Zoubina EV, Dancause N, Frost SB, Eisner-Janowicz I, Stowe AM, Plautz EJ, Nudo RJ. A single injection of d-amphet-amine facilitates improvements in motor training following a focal cortical infarct in squirrel monkeys. Neurorehabil Neural Repair 2006. In press.Google Scholar
  52. 52.
    Adkins DL, Jones TA. D-amphetamine enhances skilled reaching after ischemic cortical lesions in rats. Neurosci Lett 2005; 380: 214–218.PubMedCrossRefGoogle Scholar
  53. 53.
    Gilmour G, Iversen SD, O’Neill MF, O’Neill MJ, Ward MA, Bannerman DM. Amphetamine promotes task-dependent recovery following focal cortical ischaemic lesions in the rat. Behav Brain Res 2005;165: 98–109.PubMedCrossRefGoogle Scholar
  54. 54.
    Brown JA, Lutsep HL, Weinand M, Cramer SC. Motor cortex stimulation for the enhancement of recovery from stroke: A prospective, multicenter safety study. Neurosurgery 2006;58: 464–473.PubMedCrossRefGoogle Scholar
  55. 55.
    Plautz EJ, Barbay S, Frost SB, Friel KM, Dancause N, Zoubina EV, Stowe AM, Quaney BM, Nudo RJ. Post-infarct cortical plasticity and behavioral recovery using concurrent cortical stimulation and rehabilitative training: A feasibility study in primates. Neurol Res 2003;25: 801–810.PubMedCrossRefGoogle Scholar
  56. 56.
    Adkins-Muir DL, Jones TA. Cortical electrical stimulation combined with rehabilitative training: Enhanced functional recovery and dendritic plasticity following focal cortical ischemia in rats. Neurol Res 2003;25: 780–788.PubMedCrossRefGoogle Scholar
  57. 57.
    Kleim JA, Bruneau R, VandenBerg P, MacDonald E, Mulrooney R, Pocock D. Motor cortex stimulation enhances motor recovery and reduces peri-infarct dysfunction following ischemic insult. Neurol Res 2003;25: 789–793.PubMedCrossRefGoogle Scholar
  58. 58.
    Carmichael ST, Archibeque I, Luke L, Nolan T, Momiy J, Li S. Growth-associated gene expression after stroke: Evidence for a growth-promoting region in peri-infarct cortex. Exp Neurol 2005; 193: 291–311.PubMedCrossRefGoogle Scholar
  59. 59.
    Jones TA, Bury SD, Adkins-Muir DL, Luke LM, Allied RP, Sakata JT. Importance of behavioral manipulations and measures in rat models of brain damage and brain repair. ILAR J 2003;44: 144–152.PubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2006

Authors and Affiliations

  1. 1.Landon Center on Aging and Department of Molecular and Integrative PhysiologyUniversity of Kansas Medical CenterKansas City

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