Integrating Molecular, Cellular, and Systems Approaches to Repairing the Brain After Stroke

  • Max O. Krucoff
  • Stephen C. Harward
  • Shervin Rahimpour
  • Keith Dombrowski
  • Erik F. Hauck
  • Shivanand P. Lad
  • Dennis A. Turner
Chapter
Part of the Springer Series in Translational Stroke Research book series (SSTSR)

Abstract

A stroke implies a sudden and spontaneous onset of neurological symptoms due to a vascular insult. Despite the brain’s inherent capacity for plasticity and spontaneous improvement, strokes still leave many patients with devastating deficits that can permanently affect independence and quality of life. This chapter focuses on ways to help restore the functionality of the central nervous system (CNS) after this type of injury. Understanding how neurons interact on both individual (i.e. cellular and molecular) and population (i.e. synapses and circuits) levels is crucial to developing successful restorative strategies, as is appreciating how these interactions change over the injury-recovery timeline. The CNS has several characteristics that make its restitution exceptionally difficult; beyond even its incredible intricacy, its parenchymal cells, or neurons, do not regenerate well after injury, and this damaged neuronal substrate embodies a consciousness system that must be engaged in its own recovery. In fact, there is now data suggesting that conscious intention, often invoked through goal-oriented rehabilitation, plays a crucial role in facilitating functional plasticity and long-range axonal sprouting. To capitalize on this principle, neural interfaces and electrical stimulation strategies are being integrated into rehabilitation paradigms to provide critically-timed feedback that can reinvigorate injured circuits. Combining these approaches with interventions at the cellular and molecular level (e.g. immunological or genetic modulations aimed at promoting neuronal outgrowth, or stem cells that can replace damaged parenchyma) has the chance to improve neurological recovery to back toward baseline levels. Ultimately, because cells of the CNS do not regrow on their own, and because regrowth and synapse formation does not necessarily ensure restoration of function, harmonious application of synergistic approaches at both the micro- and macroscopic levels will be needed to establish long-lasting functional plasticity and meaningful recovery.

Keywords

Neural repair Neural regeneration Stroke Neurorehabilitation Brain-machine interface Brain-computer interface Neural interface Axonal regeneration Neural restoration 

Abbreviations

AMPA

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

AP

Action potential

BCI

Brain-computer interface

BCM

Bienenstock–Cooper–Munro

BMI

Brain-machine interface

BSDS

Brain state dependent stimulation

cAMP

Cyclic adenosine monophosphate

CIMT

Constraint-induced movement therapy

CNS

Central nervous system

CNTF

Ciliary neurotrophic factor

CPP

Cerebral perfusion pressure

CSPG

Chondroitin sulfate proteoglycans

DBS

Deep brain stimulation

DOC

Disorder of consciousness

DRG

Dorsal root ganglion

FDA

Federal Drug Administration

FES

Functional electrical stimulation

GABA

Gamma-aminobutyric acid

GAP43

Growth associated protein 43

GDF10

Growth and differentiation factor 10

ICA

Internal carotid artery

ICP

Intracranial pressure

IFG-1

Insulin-like growth factor 1

LTD

Long-term depression

LTP

Long-term potentiation

M1

Primary motor cortex

MAG

Myelin-associated

MAI

Myelin-associated inhibitory molecule

MCA

Middle cerebral artery

mTOR

Mechanistic target of rapamycin

NgR

Nogo receptor

NMDA

N-Methyl-d-aspartate

NSAID

Non-steroidal anti-inflammatory drug

OMgp

Oligodendrocyte-myelin glycoprotein

OPN

Osteopontin

PAS

Paired associative stimulation

PMC

Premotor cortices

PTEN

Phosphatase and tensin homolog

RGC

Retinal ganglion cell

rTMS

Repetitive transcranial magnetic stimulation

SCI

Spinal cord injury

SGZ

Subgranular zone

STDP

Spike-timing dependent plasticity

SVZ

Subventricular zone

TGF-β

Transforming growth factor beta

TGFβR

Transforming growth factor beta receptor

TMS

Transcranial magnetic stimulation

Notes

Conflict of Interest

The authors declare they have no conflict of interest.

References

  1. 1.
    Kwakkel G, Kollen B, Lindeman E. Understanding the pattern of functional recovery after stroke: facts and theories. Restor Neurol Neurosci. 2004;22:281–99.PubMedGoogle Scholar
  2. 2.
    Christophe BR, Mehta SH, Garton ALA, Sisti J, Connolly ES. Current and future perspectives on the treatment of cerebral ischemia. Expert Opin Pharmacother. 2017;18:573–80.PubMedCrossRefGoogle Scholar
  3. 3.
    Członkowska A, Leśniak M. Pharmacotherapy in stroke rehabilitation. Expert Opin Pharmacother. 2009;10:1249–59.PubMedCrossRefGoogle Scholar
  4. 4.
    Winstein CJ, et al. AHA/ASA guideline guidelines for adult stroke rehabilitation and recovery. Stroke. 2016;47:e98–e169.PubMedCrossRefGoogle Scholar
  5. 5.
    Alia C, et al. Neuroplastic changes following brain ischemia and their contribution to stroke recovery: novel approaches in neurorehabilitation. Front Cell Neurosci. 2017;11:1–22.CrossRefGoogle Scholar
  6. 6.
    Hermann DM, Chopp M. Promoting neurological recovery in the post-acute stroke phase: Benefits and challenges. Eur Neurol. 2014;72:317–25.PubMedCrossRefGoogle Scholar
  7. 7.
    Corbett D, Nguemeni C, Gomez-Smith M. How can you mend a broken brain? Neurorestorative approaches to stroke recovery. Cerebrovasc Dis. 2014;38:233–9.PubMedCrossRefGoogle Scholar
  8. 8.
    Fishman HM, Bittner GD. Vesicle-mediated restoration of a plasmalemmal barrier in severed axons. News Physiol Sci. 2003;18:115–8.PubMedGoogle Scholar
  9. 9.
    Schlaepfer WW, Bunge RP. Effects of calcium ion concentration on the degeneration of amputated axons in tissue culture. J Cell Biol. 1973;59:456–70.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Hill CE, Beattie MS, Bresnahan JC. Degeneration and sprouting of identified descending supraspinal axons after contusive spinal cord injury in the rat. Exp Neurol. 2001;171:153–69.PubMedCrossRefGoogle Scholar
  11. 11.
    Li Y, Raisman G. Sprouts from cut corticospinal axons persist in the presence of astrocytic scarring in long-term lesions of the adult rat spinal cord. Exp Neurol. 1995;134:102–11.PubMedCrossRefGoogle Scholar
  12. 12.
    Shetty AK, Turner DA. Aging impairs axonal sprouting response of dentate granule cells following target loss and partial deafferentation. J Comp Neurol. 1999;414:238–54.PubMedCrossRefGoogle Scholar
  13. 13.
    Conforti L, Gilley J, Coleman MP. Wallerian degeneration: an emerging axon death pathway linking injury and disease. Nat Rev Neurosci. 2014;15:394–409.PubMedCrossRefGoogle Scholar
  14. 14.
    Benowitz LI, Yin Y. Combinatorial treatments for promoting axon regeneration in the CNS: strategies for overcoming inhibitory signals and activating neurons’ intrinsic growth state. Dev Neurobiol. 2007;67:1148–65.PubMedCrossRefGoogle Scholar
  15. 15.
    Bernstein DR, Stelzner DJ. Plasticity of the corticospinal tract following midthoracic spinal injury in the postnatal rat. J Comp Neurol. 1983;221:382–400.PubMedCrossRefGoogle Scholar
  16. 16.
    Bulinski JC, et al. Changes in dendritic structure and function following hippocampal lesions: Correlations with developmental events? Prog Neurobiol. 1998;55:641–50.PubMedCrossRefGoogle Scholar
  17. 17.
    Magavi SS, Leavitt BR, Macklis JD. Induction of neurogenesis in the neocortex of adult mice. Nature. 2000;405:951–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Shetty AK, Turner DA. Enhanced cell survival in fetal hippocampal suspension transplants grafted to adult rat hippocampus following kainate lesions: a three-dimensional graft reconstruction study. Neuroscience. 1995;67:561–82.PubMedCrossRefGoogle Scholar
  19. 19.
    Alvarez-Buylla A, Lim D. For the long run: maintaining germinal niches in the adult brain. Neuron. 2004;41:683–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Doetsch F, Caillé I, Lim DA, García-Verdugo JM, Alvarez-Buylla A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell. 1999;97:703–16.PubMedCrossRefGoogle Scholar
  21. 21.
    Laywell ED, Rakic P, Kukekov VG, Holland EC, Steindler DA. Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc Natl Acad Sci U S A. 2000;97:13883–8.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Ohab JJ, Carmichael ST. Poststroke neurogenesis: emerging principles of migration and localization of immature neurons. Neuroscientist. 2008;14:369–80.PubMedCrossRefGoogle Scholar
  23. 23.
    Seri B, García-Verdugo JM, McEwen BS, Alvarez-Buylla A. Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci. 2001;21:7153–60.PubMedGoogle Scholar
  24. 24.
    Shetty A, Turner D. Fetal hippocampal cells grafted to kainate-lesioned CA3 region of adult hippocampus suppress aberrant supragranular sprouting of host mossy fibers. Exp Neurol. 1997;143:231–45.PubMedCrossRefGoogle Scholar
  25. 25.
    Thored P, et al. Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells. 2006;24:739–47.PubMedCrossRefGoogle Scholar
  26. 26.
    Macas J, Nern C, Plate KH, Momma S. Increased generation of neuronal progenitors after ischemic injury in the aged adult human forebrain. J Neurosci. 2006;26:13114–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Zhang RL, Zhang ZG, Zhang L, Chopp M. Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience. 2001;105:33–41.PubMedCrossRefGoogle Scholar
  28. 28.
    Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002;8:963–70.PubMedCrossRefGoogle Scholar
  29. 29.
    Carmichael ST, et al. Growth-associated gene expression after stroke: Evidence for a growth-promoting region in peri-infarct cortex. Exp Neurol. 2005;193:291–311.PubMedCrossRefGoogle Scholar
  30. 30.
    Grenningloh G, Soehrman S, Bondallaz P, Ruchti E, Cadas H. Role of the microtubule destabilizing proteins SCG10 and stathmin in neuronal growth. J Neurobiol. 2004;58:60–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Sun F, He Z. Neuronal intrinsic barriers for axon regeneration in the adult CNS. Curr Opin Neurobiol. 2010;20:510–8.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Tedeschi A. Tuning the orchestra: transcriptional pathways controlling axon regeneration. Front Mol Neurosci. 2011;4:60.PubMedGoogle Scholar
  33. 33.
    Park KK, et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science. 2008;322:963–6.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    de Lima S, et al. Full-length axon regeneration in the adult mouse optic nerve and partial recovery of simple visual behaviors. Proc Natl Acad Sci. 2012;109:9149–54.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Smith PD, et al. SOCS3 deletion promotes optic nerve regeneration in vivo. Neuron. 2009;64:617–23.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Xu B, Xie X. Neurotrophic factor control of satiety and body weight. Nat Rev Neurosci. 2016;17:282–92.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Chen D, Schneider G, Martinou J, Tonegawa S. Bcl-2 promotes regeneration of severed axons in mammalian CNS. Nature. 1997;385:434–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Goldberg JL, et al. Retinal ganglion cells do not extend axons by default. Neuron. 2002;33:689–702.PubMedCrossRefGoogle Scholar
  39. 39.
    Benowitz LI, Carmichael ST. Promoting axonal rewiring to improve outcome after stroke. Neurobiol Dis. 2010;37:259–66.PubMedCrossRefGoogle Scholar
  40. 40.
    Omura T, et al. Robust axonal regeneration occurs in the injured CAST/Ei mouse CNS. Neuron. 2015;86:1215–27.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    de Lima S, Habboub G, Benowitz LI. Combinatorial therapy stimulates long-distance regeneration, target reinnervation, and partial recovery of vision after optic nerve injury in mice. Int Rev Neurobiol. 2012;106:153–72.PubMedCrossRefGoogle Scholar
  42. 42.
    Krucoff MO, Rahimpour S, Slutzky MW, Edgerton VR, Turner DA. Enhancing nervous system recovery through neurobiologics, neural interface training, and neurorehabilitation. Front Neurosci. 2016;10Google Scholar
  43. 43.
    Alilain W, Horn KP, Hu H, Dick TE, Silver J. Functional regeneration of respiratory pathways after spinal cord injury. Nature. 2011;475:196–200.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Liu K, Tedeschi A, Park KK, He Z. Neuronal intrinsic mechanisms of axon regeneration. Annu Rev Neurosci. 2011;34:131–52.PubMedCrossRefGoogle Scholar
  45. 45.
    Dickendesher TL, et al. NgR1 and NgR3 are receptors for chondroitin sulfate proteoglycans. Nat Neurosci. 2012;15:703–12.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Lee J-K, Kim J-E, Sivula M, Strittmatter SM. Nogo receptor antagonism promotes stroke recovery by enhancing axonal plasticity. J Neurosci. 2004;24:6209–17.PubMedCrossRefGoogle Scholar
  47. 47.
    Freund P, et al. Nogo-A-specific antibody treatment enhances sprouting and functional recovery after cervical lesion in adult primates. Nat Med. 2006;12:790–2.PubMedCrossRefGoogle Scholar
  48. 48.
    Maier IC, et al. Differential effects of anti-Nogo-A antibody treatment and treadmill training in rats with incomplete spinal cord injury. Brain. 2009;132:1426–40.PubMedCrossRefGoogle Scholar
  49. 49.
    Wahl AS, et al. Asynchronous therapy restores motor control by rewiring of the rat corticospinal tract after stroke. Science. 2014;344:1250–5.PubMedCrossRefGoogle Scholar
  50. 50.
    Bei F, et al. Restoration of visual function by enhancing conduction in regenerated axons. Cell. 2016;164:219–32.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Li S, et al. GDF10 is a signal for axonal sprouting and functional recovery after stroke. Nat Neurosci. 2015;18:1737–45.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Stroemer RP, Kent TA, Hulsebosch CE. Neocortical neural sprouting, synaptogenesis, and behavioral recovery after neocortical infarction in rats. Stroke. 1995;26:2135–44.PubMedCrossRefGoogle Scholar
  53. 53.
    Schaechter JD, Moore CI, Connell BD, Rosen BR, Dijkhuizen RM. Structural and functional plasticity in the somatosensory cortex of chronic stroke patients. Brain. 2006;129:2722–33.PubMedCrossRefGoogle Scholar
  54. 54.
    Murphy TH, Corbett D. Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci. 2009;10:861–72.PubMedCrossRefGoogle Scholar
  55. 55.
    Zai L, et al. Inosine alters gene expression and axonal projections in neurons contralateral to a cortical infarct and improves skilled use of the impaired limb. J Neurosci. 2009;29:8187–97.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Zai L, et al. Inosine augments the effects of a Nogo receptor blocker and of environmental enrichment to restore skilled forelimb use after stroke. J Neurosci. 2011;31:5977–88.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Kim D, et al. Inosine enhances axon sprouting and motor recovery after spinal cord injury. PLoS One. 2013;8:15–21.CrossRefGoogle Scholar
  58. 58.
    Chen P, et al. Inosine induces axonal rewiring and behavioral outcome after stroke. PNAS. 2002;99:9031–6.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Dachir S, et al. Inosine improves functional recovery after experimental traumatic brain injury. Brain Res. 2014;1555:78–88.PubMedCrossRefGoogle Scholar
  60. 60.
    Baldwin KT, Carbajal KS, Segal BM, Giger RJ. Neuroinflammation triggered by β-glucan/dectin-1 signaling enables CNS axon regeneration. Proc Natl Acad Sci U S A. 2015;112:2581–6.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Benowitz LI, Popovich PG. Inflammation and axon regeneration. Curr Opin Neurol. 2011;24:577–83.PubMedCrossRefGoogle Scholar
  62. 62.
    Kurimoto T, et al. Neutrophils express oncomodulin and promote optic nerve regeneration. J Neurosci. 2013;33:14816–24.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Yin Y, et al. Macrophage-derived factors stimulate optic nerve regeneration. J Neurosci. 2003;23:2284–93.PubMedGoogle Scholar
  64. 64.
    Yin Y, et al. Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells. Nat Neurosci. 2006;9:843–52.PubMedCrossRefGoogle Scholar
  65. 65.
    Yin Y, et al. Oncomodulin links inflammation to optic nerve regeneration. Proc Natl Acad Sci U S A. 2009;106:19587–92.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Benowitz L, Yin Y. Rewiring the injured CNS: lessons from the optic nerve. Exp Neurol. 2008;209:389–98.PubMedCrossRefGoogle Scholar
  67. 67.
    Napieralski JA, Butler AK, Chesselet MF. Anatomical and functional evidence for lesion-specific sprouting of corticostriatal input in the adult rat. J Comp Neurol. 1996;373:484–97.PubMedCrossRefGoogle Scholar
  68. 68.
    Nudo RJ. Recovery after brain injury: mechanisms and principles. Front Hum Neurosci. 2013;7:887.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Langhorne P, Bernhardt J, Kwakkel G. Stroke rehabilitation. Lancet. 2011;377:1693–702.PubMedCrossRefGoogle Scholar
  70. 70.
    Teasell RW, Murie Fernandez M, McIntyre A, Mehta S. Rethinking the continuum of stroke rehabilitation. Arch Phys Med Rehabil. 2014;95:595–6.PubMedCrossRefGoogle Scholar
  71. 71.
    DeFina PA, et al. Improving outcomes of severe disorders of consciousness. Restor Neurol Neurosci. 2010;28:769–80.PubMedGoogle Scholar
  72. 72.
    Breceda EY, Dromerick AW. Motor rehabilitation in stroke and traumatic brain injury: stimulating and intense. Curr Opin Neurol. 2013;26:595–601.PubMedCrossRefGoogle Scholar
  73. 73.
    Krieger DW. Therapeutic drug approach to stimulate clinical recovery after brain injury. Front Neurol Neurosci. 2013;32:76–87.PubMedCrossRefGoogle Scholar
  74. 74.
    Dobkin BH. Behavioral, temporal, and spatial targets for cellular transplants as adjuncts to rehabilitation for stroke. Stroke. 2007;38:832–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Cote DJ, et al. Ethical clinical translation of stem cell interventions for neurologic disease. Neurology. 2017;88(3):322–8.  https://doi.org/10.1212/WNL.0000000000003506.PubMedCrossRefGoogle Scholar
  76. 76.
    Smith EJ, et al. Implantation site and lesion topology determine efficacy of a human neural stem cell line in a rat model of chronic stroke. Stem Cells. 2012;30:785–96.PubMedCrossRefGoogle Scholar
  77. 77.
    Wang Q, et al. Effect of stem cell-based therapy for ischemic stroke treatment: a meta-analysis. Clin Neurol Neurosurg. 2016;146:1–11.PubMedCrossRefGoogle Scholar
  78. 78.
    Moniche F, et al. Intra-arterial bone marrow mononuclear cells (BM-MNCs) transplantation in acute ischemic stroke (IBIS trial): protocol of a phase II, randomized, dose-finding, controlled multicenter trial. Int J Stroke. 2015;10:1149–52.PubMedCrossRefGoogle Scholar
  79. 79.
    Steinberg GK, et al. Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: a phase 1/2a study. Stroke. 2016;47:1817–24.PubMedCrossRefGoogle Scholar
  80. 80.
    Tornero D, et al. Synaptic inputs from stroke-injured brain to grafted human stem cell-derived neurons activated by sensory stimuli. Brain. 2017;140:692–706.PubMedGoogle Scholar
  81. 81.
    DeFina P, et al. The new neuroscience frontier: promoting neuroplasticity and brain repair in traumatic brain injury. Clin Neuropsychol. 2009;23:1391–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Demirtas-Tatlidede A, Vahabzadeh-Hagh AM, Bernabeu M, Tormos JM, Pascual-Leone A. Noninvasive brain stimulation in traumatic brain injury. J Head Trauma Rehabil. 2012;27:274–92.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Nahmani M, Turrigiano GG. Adult cortical plasticity following injury: recapitulation of critical period mechanisms? Neuroscience. 2014;283:4–16.PubMedCrossRefGoogle Scholar
  84. 84.
    Villamar MF, Santos Portilla A, Fregni F, Zafonte R. Noninvasive brain stimulation to modulate neuroplasticity in traumatic brain injury. Neuromodulation. 2012;15:326–37.PubMedCrossRefGoogle Scholar
  85. 85.
    Dancause N, Nudo R. Shaping plasticity to enhance recovery after injury. Prog Brain Res. 2011;192:273–95.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Dancause N. Extensive cortical rewiring after brain injury. J Neurosci. 2005;25:10167–79.PubMedCrossRefGoogle Scholar
  87. 87.
    Kantak SS, Stinear JW, Buch ER, Cohen LG. Rewiring the brain: potential role of the premotor cortex in motor control, learning, and recovery of function following brain injury. Neurorehabil Neural Repair. 2012;26:282–92.PubMedCrossRefGoogle Scholar
  88. 88.
    Carmichael ST, Chesselet M-F. Synchronous neuronal activity is a signal for axonal sprouting after cortical lesions in the adult. J Neurosci. 2002;22:6062–70.PubMedGoogle Scholar
  89. 89.
    Favre I, et al. Upper limb recovery after stroke is associated with ipsilesional primary motor cortical activity: a meta-analysis. Stroke. 2014;45:1077–83.PubMedCrossRefGoogle Scholar
  90. 90.
    Kuner R. Central mechanisms of pathological pain. Nat Med. 2010;16:1258–66.PubMedCrossRefGoogle Scholar
  91. 91.
    Thickbroom GW, Mastaglia FL. Plasticity in neurological disorders and challenges for noninvasive brain stimulation (NBS). J Neuroeng Rehabil. 2009;6:4.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Flor H, et al. Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature. 1995;375:482–4.PubMedCrossRefGoogle Scholar
  93. 93.
    Teyler TJ, Morgan SL, Russell RN, Woodside BL. Synaptic plasticity and secondary epileptogenesis. Int Rev Neurobiol. 2001;45:253–67.PubMedCrossRefGoogle Scholar
  94. 94.
    Hasan A, et al. Dysfunctional long-term potentiation-like plasticity in schizophrenia revealed by transcranial direct current stimulation. Behav Brain Res. 2011;224:15–22.PubMedCrossRefGoogle Scholar
  95. 95.
    Quartarone A, Rizzo V, Morgante F. Clinical features of dystonia: a pathophysiological revisitation. Curr Opin Neurol. 2008;21:484–90.PubMedCrossRefGoogle Scholar
  96. 96.
    Dimitrijević MR, Nathan PW. Studies of spasticity in man. I Some features of spasticity. Brain. 1967;90:1–30.PubMedCrossRefGoogle Scholar
  97. 97.
    Taub E, Uswatte G, Elbert T. New treatments in neurorehabilitation founded on basic research. Nat Rev Neurosci. 2002;3:228–36.PubMedCrossRefGoogle Scholar
  98. 98.
    Taub E, Morris DM. Constraint-induced movement therapy to enhance recovery after stroke. Curr Atheroscler Rep. 2001;3:279–86.PubMedCrossRefGoogle Scholar
  99. 99.
    Allred RP, Maldonado MA, Hsu And JE, Jones TA. Training the less-affected forelimb after unilateral cortical infarcts interferes with functional recovery of the impaired forelimb in rats. Restor Neurol Neurosci. 2005;23:297–302.PubMedGoogle Scholar
  100. 100.
    Allred RP, Jones TA. Maladaptive effects of learning with the less-affected forelimb after focal cortical infarcts in rats. Exp Neurol. 2008;210:172–81.PubMedCrossRefGoogle Scholar
  101. 101.
    Kozlowski DA, James DC, Schallert T. Use-dependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions. J Neurosci. 1996;16:4776–86.PubMedGoogle Scholar
  102. 102.
    Wolf SL, et al. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: the EXCITE randomized clinical trial. JAMA. 2006;296:2095–104.PubMedCrossRefGoogle Scholar
  103. 103.
    Dromerick AW, et al. Very early constraint-induced movement during stroke rehabilitation (VECTORS): a single-center RCT. Neurology. 2009;73:195–201.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    McIntyre A, et al. Systematic review and meta-analysis of constraint-induced movement therapy in the hemiparetic upper extremity more than six months post stroke. Top Stroke Rehabil. 2012;19:499–513.PubMedCrossRefGoogle Scholar
  105. 105.
    Lang CE, Lohse KR, Birkenmeier RL. Dose and timing in neurorehabilitation: prescribing motor therapy after stroke. Curr Opin Neurol. 2015;28:549–55.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Clarkson AN, et al. AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke. J Neurosci. 2011;31:3766–75.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Levy RM, et al. Cortical stimulation for the rehabilitation of patients with hemiparetic stroke: a multicenter feasibility study of safety and efficacy. J Neurosurg. 2008;108:707–14.PubMedCrossRefGoogle Scholar
  108. 108.
    Levy RM, et al. Epidural electrical stimulation for stroke rehabilitation: results of the prospective, multicenter, randomized, single-blinded everest trial. Neurorehabil Neural Repair. 2016;30:107–19.PubMedCrossRefGoogle Scholar
  109. 109.
    Guggenmos DJ, et al. Restoration of function after brain damage using a neural prosthesis. Proc Natl Acad Sci U S A. 2013;110:21177–82.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Kleim JA, et al. Motor cortex stimulation enhances motor recovery and reduces peri-infarct dysfunction following ischemic insult. Neurol Res. 2003;25:789–93.PubMedCrossRefGoogle Scholar
  111. 111.
    Plautz EJ, et al. Post-infarct cortical plasticity and behavioral recovery using concurrent cortical stimulation and rehabilitative training: a feasibility study in primates. Neurol Res. 2003;25:801–10.PubMedCrossRefGoogle Scholar
  112. 112.
    Nudo RJ, Milliken GW. Reorganization of movement representations in primary motor cortex following focal ischemic infarcts in adult squirrel monkeys. J Neurophysiol. 1996;75:2144–9.PubMedGoogle Scholar
  113. 113.
    Shin S, Dixon E, Okonkwo D, Richardson M. Neurostimulation for traumatic brain injury. J Neurosurg. 2014;121:1219–31.PubMedCrossRefGoogle Scholar
  114. 114.
    Nudo RJ, Jenkins WM, Merzenich MM. Repetitive microstimulation alters the cortical representation of movements in adult rats. Somatosens Mot Res. 1990;7:463–83.PubMedCrossRefGoogle Scholar
  115. 115.
    Monfils M-H, VandenBerg PM, Kleim JA, Teskey GC. Long-term potentiation induces expanded movement representations and dendritic hypertrophy in layer V of rat sensorimotor neocortex. Cereb Cortex. 2004;14:586–93.PubMedCrossRefGoogle Scholar
  116. 116.
    Elsner B, Kugler J, Pohl M, Mehrholz J. Transcranial direct current stimulation (tDCS) for improving activities of daily living, and physical and cognitive functioning, in people after stroke. Cochrane Database Syst Rev. 2016;3:CD009645.  https://doi.org/10.1002/14651858.CD009645.pub3.PubMedGoogle Scholar
  117. 117.
    Edwardson MA, Lucas TH, Carey JR, Fetz EE. New modalities of brain stimulation for stroke rehabilitation. Exp Brain Res. 2013;224:335–58.PubMedCrossRefGoogle Scholar
  118. 118.
    Gharabaghi A, et al. Coupling brain-machine interfaces with cortical stimulation for brain-state dependent stimulation: enhancing motor cortex excitability for neurorehabilitation. Front Hum Neurosci. 2014;8:122.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Hebb DO. The organization of behavior: a neuropsychological theory. Hoboken, NJ: Wiley; 1949.Google Scholar
  120. 120.
    Cooper SJ. Donald O. Hebb’s synapse and learning rule: a history and commentary. Neurosci Biobehav Rev. 2005;28:851–74.PubMedCrossRefGoogle Scholar
  121. 121.
    Rebesco JM, Miller LE. Enhanced detection threshold for in vivo cortical stimulation produced by Hebbian conditioning. J Neural Eng. 2011;8:16011.CrossRefGoogle Scholar
  122. 122.
    Purves D, et al. Neuroscience. In: Neuroscience. Sunderland, MA: Sinauer Associates; 2008.Google Scholar
  123. 123.
    Bienenstock EL, Cooper LN, Munro PW. Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex. J Neurosci. 1982;2:32–48.PubMedGoogle Scholar
  124. 124.
    Cooper LN, Bear MF. The BCM theory of synapse modification at 30: interaction of theory with experiment. Nat Rev Neurosci. 2012;13:798–810.PubMedCrossRefGoogle Scholar
  125. 125.
    Stefan K, Kunesch E, Cohen LG, Benecke R, Classen J. Induction of plasticity in the human motor cortex by paired associative stimulation. Brain. 2000;123(Pt 3):572–84.PubMedCrossRefGoogle Scholar
  126. 126.
    Carson RG, Kennedy NC. Modulation of human corticospinal excitability by paired associative stimulation. Front Hum Neurosci. 2013;7:823.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Kobayashi M, Pascual-Leone A. Basic principles of magnetic stimulation. Lancet. 2003;2:145–56.PubMedCrossRefGoogle Scholar
  128. 128.
    Daly JJ, et al. A randomized controlled trial of functional neuromuscular stimulation in chronic stroke subjects. Stroke. 2006;37:172–8.PubMedCrossRefGoogle Scholar
  129. 129.
    Kafri M, Laufer Y. Therapeutic effects of functional electrical stimulation on gait in individuals post-stroke. Ann Biomed Eng. 2015;43:451–66.PubMedCrossRefGoogle Scholar
  130. 130.
    van den Brand R, et al. Restoring voluntary control of locomotion after paralyzing spinal cord injury. Science. 2012;336:1182–5.PubMedCrossRefGoogle Scholar
  131. 131.
    Mothe AJ, Tator CH. Advances in stem cell therapy for spinal cord injury. Thew J Clin Investig. 2012;122:3824–34.CrossRefGoogle Scholar
  132. 132.
    Warren Olanow C, et al. Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: a double-blind, randomized, controlled trial. Ann Neurol. 2015;78:248–57.PubMedCrossRefGoogle Scholar
  133. 133.
    Jarvis S, Schultz SR. Prospects for optogenetic augmentation of brain function. Front Syst Neurosci. 2015;9:157.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Furlanetti LL, et al. Continuous high-frequency stimulation of the subthalamic nucleus improves cell survival and functional recovery following dopaminergic cell transplantation in rodents. Neurorehabil Neural Repair. 2015;29:1001–12.PubMedCrossRefGoogle Scholar
  135. 135.
    Winstein CJ, et al. Effect of a task-oriented rehabilitation program on upper extremity recovery following motor stroke: the ICARE randomized clinical trial. JAMA. 2016;315:571–81.PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Brogaard B, Gatzia DE. What can neuroscience tell us about the hard problem of consciousness? Front Neurosci. 2016;10:1–4.CrossRefGoogle Scholar
  137. 137.
    Koch C, Massimini M, Boly M, Tononi G. Neural correlates of consciousness: progress and problems. Nat Rev Neurosci. 2016;17:307–21.PubMedCrossRefGoogle Scholar
  138. 138.
    Sandberg K, Frässle S, Pitts M. Future directions for identifying the neural correlates of consciousness. Nat Rev Neurosci. 2016.  https://doi.org/10.1038/nrn.2016.104.

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Max O. Krucoff
    • 1
  • Stephen C. Harward
    • 1
  • Shervin Rahimpour
    • 1
  • Keith Dombrowski
    • 2
  • Erik F. Hauck
    • 1
  • Shivanand P. Lad
    • 1
  • Dennis A. Turner
    • 1
    • 3
    • 4
  1. 1.Department of NeurosurgeryDuke University Medical CenterDurhamUSA
  2. 2.Department of NeurologyDuke University Medical CenterDurhamUSA
  3. 3.Department of NeurobiologyDuke UniversityDurhamUSA
  4. 4.Research and Surgery ServicesDurham Veterans Affairs Medical CenterDurhamUSA

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