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Modulation of brain plasticity in stroke: a novel model for neurorehabilitation

Key Points

  • Noninvasive brain stimulation (NIBS) is a promising approach to enhance recovery after stroke, but its beneficial effect is limited and the technique is not yet ready for broad clinical use

  • We suggest that the disappointments in NIBS trials are related to over-reliance on the interhemispheric competition and vicariation models of recovery, which are oversimplified and do not apply to all patients with stroke

  • The concept of 'structural reserve' integrates the effects that interhemispheric inhibition and vicariation exert on the unlesioned residual network

  • We propose a unified 'bimodal balance–recovery model' that takes into account this individual residual network

  • The model could be used to tailor treatment for individual patients and increase the efficacy of NIBS in stroke rehabilitation

Abstract

Noninvasive brain stimulation (NIBS) techniques can be used to monitor and modulate the excitability of intracortical neuronal circuits. Long periods of cortical stimulation can produce lasting effects on brain function, paving the way for therapeutic applications of NIBS in chronic neurological disease. The potential of NIBS in stroke rehabilitation has been of particular interest, because stroke is the main cause of permanent disability in industrial nations, and treatment outcomes often fail to meet the expectations of patients. Despite promising reports from many clinical trials on NIBS for stroke recovery, the number of studies reporting a null effect remains a concern. One possible explanation is that the interhemispheric competition model—which posits that suppressing the excitability of the hemisphere not affected by stroke will enhance recovery by reducing interhemispheric inhibition of the stroke hemisphere, and forms the rationale for many studies—is oversimplified or even incorrect. Here, we critically review the proposed mechanisms of synaptic and functional reorganization after stroke, and suggest a bimodal balance–recovery model that links interhemispheric balancing and functional recovery to the structural reserve spared by the lesion. The proposed model could enable NIBS to be tailored to the needs of individual patients.

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Figure 1: TMS paired-pulse protocols.
Figure 2: Neurophysiological parameters in acute stroke predict prognosis.
Figure 3: The bimodal balance–recovery model.
Figure 4: Noninvasive neuromodulatory techniques.

References

  1. 1

    Kolominsky-Rabas, P. L., Weber, M., Gefeller, O., Neundoerfer, B. & Heuschmann, P. U. Epidemiology of ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke 32, 2735–2740 (2001).

    CAS  Article  Google Scholar 

  2. 2

    Roger, V. L. et al. Heart disease and stroke statistics. A report from the American Heart Association. Circulation 123, e18–e209 (2011).

    Article  Google Scholar 

  3. 3

    Veerbeek, J. M., Kwakkel, G., van Wegen, E. E., Ket, J. C. & Heymans, M. W. Early prediction of outcome of activities of daily living after stroke: a systematic review. Stroke 42, 1482–1488 (2011).

    Article  Google Scholar 

  4. 4

    Lansberg, M. G., Bluhmki, E. & Thijs, V. N. Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a meta-analysis. Stroke 40, 2438–2441 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    Maulden, S. A., Gassaway, J., Horn, S. D., Smout, R. J. & DeJong, G. Timing of initiation of rehabilitation after stroke. Arch. Phys. Med. Rehabil. 86, S34–S40 (2005).

    Article  Google Scholar 

  6. 6

    Dobkin, B. H. Clinical practice. Rehabilitation after stroke. N. Engl. J. Med. 352, 1677–1684 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Wagner, T. H. et al. An economic analysis of robot-assisted therapy for long-term upper-limb impairment after stroke. Stroke 42, 2630–2632 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Lo, A. C. et al. Robot-assisted therapy for long-term upper-limb impairment after stroke. N. Engl. J. Med. 362, 1772–1783 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Klamroth-Marganska, V. et al. Three-dimensional, task-specific robot therapy of the arm after stroke: a multicentre, parallel-group randomised trial. Lancet Neurol. 13, 159–166 (2014).

    Article  Google Scholar 

  10. 10

    Hao, Z., Wang, D., Zeng, Y. & Liu, M. Repetitive transcranial magnetic stimulation for improving function after stroke. Cochrane Database of Systematic Reviews, Issue 5. Art. No.: Cd008862. http://dx.doi.org/10.1002/14651858.CD008862.pub2.

  11. 11

    Elsner, B., Kugler, J., Pohl, M. & Mehrholz, J. Transcranial direct current stimulation (tDCS) for improving function and activities of daily living in patients after stroke. Cochrane Database of Systematic Reviews, Issue 11. Art. No.: Cd009645. http://dx.doi.org/10.1002/14651858.CD009645.pub2.

  12. 12

    Adeyemo, B. O., Simis, M., Macea, D. D. & Fregni, F. Systematic review of parameters of stimulation, clinical trial design characteristics, and motor outcomes in non-invasive brain stimulation in stroke. Front. Psychiatry 3, 88 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Hsu, W. Y., Cheng, C. H., Liao, K. K., Lee, I. H. & Lin, Y. Y. Effects of repetitive transcranial magnetic stimulation on motor functions in patients with stroke: a meta-analysis. Stroke 43, 1849–1857 (2012).

    Article  Google Scholar 

  14. 14

    Di Lazzaro, V. et al. I-wave origin and modulation. Brain Stimul. 5, 512–525 (2012).

    CAS  Article  Google Scholar 

  15. 15

    Attwell, D. & Laughlin, S. B. An energy budget for signaling in the grey matter of the brain. J. Cereb. Blood Flow Metab. 21, 1133–1145 (2001).

    CAS  Article  Google Scholar 

  16. 16

    Astrup, J., Siesjo, B. K. & Symon, L. Thresholds in cerebral ischemia: the ischemic penumbra. Stroke 12, 723–725 (1981).

    CAS  Article  Google Scholar 

  17. 17

    Symon, L. The relationship between CBF, evoked potentials and the clinical features in cerebral ischaemia. Acta Neurol. Scand. Suppl. 78, 175–190 (1980).

    CAS  Google Scholar 

  18. 18

    Krnjevic´, K. & Xu, Y. Mechanisms underlying anoxic hyperpolarization of hippocampal neurons. Can. J. Physiol. Pharmacol. 68, 1609–1613 (1990).

    Article  Google Scholar 

  19. 19

    Somjen, G. G. (Ed.) Ions in the Brain: Normal Function, Seizures, and Stroke: Normal Function, Seizures, and Stroke (Oxford University Press, 2004).

    Google Scholar 

  20. 20

    Gerard, R. The response of nerve to oxygen lack. Am. J. Physiol. 92, 498–541 (1930).

    CAS  Article  Google Scholar 

  21. 21

    Zhu, P. & Krnjevic´, K. Anoxia selectively depresses excitatory synaptic transmission in hippocampal slices. Neurosci. Lett. 166, 27–30 (1994).

    CAS  Article  Google Scholar 

  22. 22

    Khazipov, R., Bregestovski, P. & Ben-Ari, Y. Hippocampal inhibitory interneurons are functionally disconnected from excitatory inputs by anoxia. J. Neurophysiol. 70, 2251–2259 (1993).

    CAS  Article  Google Scholar 

  23. 23

    Murphy, T. H. & Corbett, D. Plasticity during stroke recovery: from synapse to behaviour. Nat. Rev. Neurosci. 10, 861–872 (2009).

    CAS  Article  Google Scholar 

  24. 24

    Clarkson, A. N., Huang, B. S., MacIsaac, S. E., Mody, I. & Carmichael, S. T. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature 468, 305–309 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Carmichael, S. T. Brain excitability in stroke: the yin and yang of stroke progression. Arch. Neurol. 69, 161 (2012).

    Article  Google Scholar 

  26. 26

    Buchkremer-Ratzmann, I., August, M., Hagemann, G. & Witte, O. W. Electrophysiological transcortical diaschisis after cortical photothrombosis in rat brain. Stroke 27, 1105–1111 (1996).

    CAS  Article  Google Scholar 

  27. 27

    Schiene, K. et al. Neuronal hyperexcitability and reduction of GABAA-receptor expression in the surround of cerebral photothrombosis. J. Cereb. Blood Flow Metab. 16, 906–914 (1996).

    CAS  Article  Google Scholar 

  28. 28

    Bruehl, C., Neumann-Haefelin, T. & Witte, O. Enhancement of whole cell calcium currents following transient MCAO. Brain Res. 884, 129–138 (2000).

    CAS  Article  Google Scholar 

  29. 29

    Bahn, M. M., Oser, A. B. & Cross, D. T. CT and MRI of stroke. J. Magn. Reson. Imaging 6, 833–845 (1996).

    CAS  Article  Google Scholar 

  30. 30

    Cicinelli, P., Traversa, R. & Rossini, P. Post-stroke reorganization of brain motor output to the hand: a 2–4 month follow-up with focal magnetic transcranial stimulation. Electroencephalogr. Clin. Neurophysiol. 105, 438–450 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Traversa, R., Cicinelli, P., Bassi, A., Rossini, P. M. & Bernardi, G. Mapping of motor cortical reorganization after stroke. A brain stimulation study with focal magnetic pulses. Stroke 28, 110–117 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32

    Traversa, R., Cicinelli, P., Pasqualetti, P., Filippi, M. & Rossini, P. M. Follow-up of interhemispheric differences of motor evoked potentials from the 'affected'and 'unaffected' hemispheres in human stroke. Brain Res. 803, 1–8 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33

    Traversa, R. et al. Neurophysiological follow-up of motor cortical output in stroke patients. Clin. Neurophysiol. 111, 1695–1703 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Catano, A., Houa, M., Caroyer, J., Ducarne, H. & Noel, P. Magnetic transcranial stimulation in acute stroke: early excitation threshold and functional prognosis. Electroencephalogr. Clin. Neurophysiol. 101, 233–239 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Heald, A., Bates, D., Cartlidge, N., French, J. & Miller, S. Longitudinal study of central motor conduction time following stroke. 2. Central motor conduction measured within 72 h after stroke as a predictor of functional outcome at 12 months. Brain 116, 1371–1385 (1993).

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    Manganotti, P. et al. Motor disinhibition in affected and unaffected hemisphere in the early period of recovery after stroke. Clin. Neurophysiol. 113, 936–943 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    Thickbroom, G. W., Byrnes, M. L., Archer, S. A. & Mastaglia, F. L. Motor outcome after subcortical stroke: MEPs correlate with hand strength but not dexterity. Clin. Neurophysiol. 113, 2025–2029 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    Turton, A., Wroe, S., Trepte, N., Fraser, C. & Lemon, R. Contralateral and ipsilateral EMG responses to transcranial magnetic stimulation during recovery of arm and hand function after stroke. Electroencephalogr. Clin. Neurophysiol. 101, 316–328 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    Catano, A., Houa, M. & Noël, P. Magnetic transcranial stimulation: dissociation of excitatory and inhibitory mechanisms in acute strokes. Electroencephalogr. Clin. Neurophysiol. 105, 29–36 (1997).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40

    Palliyath, S. Role of central conduction time and motor evoked response amplitude in predicting stroke outcome. Electromyogr. Clin. Neurophys. 40, 315–320 (2000).

    CAS  Google Scholar 

  41. 41

    Rapisarda, G., Bastings, E., de Noordhout, A. M., Pennisi, G. & Delwaide, P. Can motor recovery in stroke patients be predicted by early transcranial magnetic stimulation? Stroke 27, 2191–2196 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Hendricks, H. T., Zwarts, M. J., Plat, E. F. & van Limbeek, J. Systematic review for the early prediction of motor and functional outcome after stroke by using motor-evoked potentials. Arch. Phys. Med. Rehabil. 83, 1303–1308 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    Byrnes, M. L., Thickbroom, G. W., Phillips, B. A. & Mastaglia, F. L. Long-term changes in motor cortical organisation after recovery from subcortical stroke. Brain Res. 889, 278–287 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Pennisi, G. et al. Transcranial magnetic stimulation after pure motor stroke. Clin. Neurophysiol. 113, 1536–1543 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    Pennisi, G. et al. Absence of response to early transcranial magnetic stimulation in ischemic stroke patients: prognostic value for hand motor recovery. Stroke 30, 2666–2670 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    Delvaux, V. et al. Post-stroke reorganization of hand motor area: a 1-year prospective follow-up with focal transcranial magnetic stimulation. Clin. Neurophysiol. 114, 1217–1225 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    Stinear, C. M., Barber, P. A., Petoe, M., Anwar, S. & Byblow, W. D. The PREP algorithm predicts potential for upper limb recovery after stroke. Brain 135, 2527–2535 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    Liepert, J., Storch, P., Fritsch, A. & Weiller, C. Motor cortex disinhibition in acute stroke. Clin. Neurophysiol. 111, 671–676 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    Cicinelli, P. et al. Interhemispheric asymmetries of motor cortex excitability in the postacute stroke stage: a paired-pulse transcranial magnetic stimulation study. Stroke 34, 2653–2658 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Swayne, O. B., Rothwell, J. C., Ward, N. S. & Greenwood, R. J. Stages of motor output reorganization after hemispheric stroke suggested by longitudinal studies of cortical physiology. Cereb. Cortex 18, 1909–1922 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    Bütefisch, C. M., Netz, J., Wessling, M., Seitz, R. J. & Hömberg, V. Remote changes in cortical excitability after stroke. Brain 126, 470–481 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Di Lazzaro, V. et al. The level of cortical afferent inhibition in acute stroke correlates with long-term functional recovery in humans. Stroke 43, 250–252 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  53. 53

    Foltys, H. et al. Motor representation in patients rapidly recovering after stroke: a functional magnetic resonance imaging and transcranial magnetic stimulation study. Clin. Neurophysiol. 114, 2404–2415 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    Shimizu, T. et al. Motor cortical disinhibition in the unaffected hemisphere after unilateral cortical stroke. Brain 125, 1896–1907 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Fridman, E. A. et al. Reorganization of the human ipsilesional premotor cortex after stroke. Brain 127, 747–758 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  56. 56

    Liepert, J., Hamzei, F. & Weiller, C. Motor cortex disinhibition of the unaffected hemisphere after acute stroke. Muscle Nerve 23, 1761–1763 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Murase, N., Duque, J., Mazzocchio, R. & Cohen, L. G. Influence of interhemispheric interactions on motor function in chronic stroke. Ann. Neurol. 55, 400–409 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    Jacobs, K. M. & Donoghue, J. P. Reshaping the cortical motor map by unmasking latent intracortical connections. Science 251, 944–947 (1991).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59

    Pineiro, R., Pendlebury, S., Johansen-Berg, H. & Matthews, P. Functional MRI detects posterior shifts in primary sensorimotor cortex activation after stroke: evidence of local adaptive reorganization? Stroke 32, 1134–1139 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Rossini, P. et al. Hand motor cortical area reorganization in stroke: a study with fMRI, MEG and TCS maps. Neuroreport 9, 2141–2146 (1998).

    CAS  Article  Google Scholar 

  61. 61

    Calautti, C., Leroy, F., Guincestre, J.-Y. & Baron, J.-C. Displacement of primary sensorimotor cortex activation after subcortical stroke: a longitudinal PET study with clinical correlation. Neuroimage 19, 1650–1654 (2003).

    Article  Google Scholar 

  62. 62

    Seitz, R. J. et al. Role of the premotor cortex in recovery from middle cerebral artery infarction. Arch. Neurol. 55, 1081–1088 (1998).

    CAS  Article  Google Scholar 

  63. 63

    Chollet, F. et al. The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography. Ann. Neurol. 29, 63–71 (1991).

    CAS  Article  Google Scholar 

  64. 64

    Weiller, C., Chollet, F., Friston, K. J., Wise, R. J. & Frackowiak, R. S. Functional reorganization of the brain in recovery from striatocapsular infarction in man. Ann. Neurol. 31, 463–472 (1992).

    CAS  Article  Google Scholar 

  65. 65

    Weiller, C., Ramsay, S., Wise, R., Friston, K. & Frackowiak, R. Individual patterns of functional reorganization in the human cerebral cortex after capsular infarction. Ann. Neurol. 33, 181–189 (1993).

    CAS  Article  Google Scholar 

  66. 66

    Johansen-Berg, H. et al. The role of ipsilateral premotor cortex in hand movement after stroke. Proc. Natl Acad. Sci. 99, 14518–14523 (2002).

    CAS  Article  Google Scholar 

  67. 67

    Lotze, M. et al. The role of multiple contralesional motor areas for complex hand movements after internal capsular lesion. J. Neurosci. 26, 6096–6102 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Jang, S. H. A review of the ipsilateral motor pathway as a recovery mechanism in patients with stroke. NeuroRehabilitation 24, 315–320 (2009).

    Google Scholar 

  69. 69

    Ago, T. et al. Deterioration of pre-existing hemiparesis brought about by subsequent ipsilateral lacunar infarction. J. Neurol. Neurosurg. Psychiatry 74, 1152–1153 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Song, Y.-M., Lee, J.-Y., Park, J.-M., Yoon, B.-W. & Roh, J.-K. Ipsilateral hemiparesis caused by a corona radiata infarct after a previous stroke on the opposite side. Arch. Neurol. 62, 809–811 (2005).

    Article  Google Scholar 

  71. 71

    Yamamoto, S., Takasawa, M., Kajiyama, K., Baron, J.-C. & Yamaguchi, T. Deterioration of hemiparesis after recurrent stroke in the unaffected hemisphere: three further cases with possible interpretation. Cerebrovasc. Dis. 23, 35–39 (2006).

    Article  Google Scholar 

  72. 72

    Biernaskie, J., Szymanska, A., Windle, V. & Corbett, D. Bi-hemispheric contribution to functional motor recovery of the affected forelimb following focal ischemic brain injury in rats. Eur. J. Neurosci. 21, 989–999 (2005).

    Article  Google Scholar 

  73. 73

    Lemon, R. N. Descending pathways in motor control. Annu. Rev. Neurosci. 31, 195–218 (2008).

    CAS  Article  Google Scholar 

  74. 74

    Boudrias, M.-H., McPherson, R. L., Frost, S. B. & Cheney, P. D. Output properties and organization of the forelimb representation of motor areas on the lateral aspect of the hemisphere in rhesus macaques. Cerebr. Cortex 20, 169–186 (2010).

    Article  Google Scholar 

  75. 75

    Baker, S. N. The primate reticulospinal tract, hand function and functional recovery. J. Physiol. 589, 5603–5612 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    Eisner-Janowicz, I. et al. Early and late changes in the distal forelimb representation of the supplementary motor area after injury to frontal motor areas in the squirrel monkey. J. Neurophysiol. 100, 1498–1512 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    Brus-Ramer, M., Carmel, J. B., Chakrabarty, S. & Martin, J. H. Electrical stimulation of spared corticospinal axons augments connections with ipsilateral spinal motor circuits after injury. J. Neurosci. 27, 13793–13801 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78

    Verstynen, T., Diedrichsen, J., Albert, N., Aparicio, P. & Ivry, R. B. Ipsilateral motor cortex activity during unimanual hand movements relates to task complexity. J. Neurophysiol. 93, 1209–1222 (2005).

    Article  Google Scholar 

  79. 79

    Hummel, F., Kirsammer, R. & Gerloff, C. Ipsilateral cortical activation during finger sequences of increasing complexity: representation of movement difficulty or memory load? Clin. Neurophys. 114, 605–613 (2003).

    Article  Google Scholar 

  80. 80

    Rose, D. & Winstein, C. The co-ordination of bimanual rapid aiming movements following stroke. Clin. Rehabil. 19, 452–462 (2005).

    CAS  Article  Google Scholar 

  81. 81

    Lewis, G. N. & Byblow, W. D. Bimanual coordination dynamics in poststroke hemiparetics. J. Mot. Behav. 36, 174–188 (2004).

    Article  Google Scholar 

  82. 82

    Grefkes, C. et al. Cortical connectivity after subcortical stroke assessed with functional magnetic resonance imaging. Ann. Neurol. 63, 236–246 (2008).

    Article  Google Scholar 

  83. 83

    Finger, S. In Handbook of Clinical Neurology Vol. 95 Ch. 51 (eds Aminoff, J. A. et al.) 833–841 (Elsevier, 2009).

    Google Scholar 

  84. 84

    Duque, J. et al. Transcallosal inhibition in chronic subcortical stroke. Neuroimage 28, 940–946 (2005).

    Article  Google Scholar 

  85. 85

    Werhahn, K. J., Mortensen, J., Van Boven, R. W., Zeuner, K. E. & Cohen, L. G. Enhanced tactile spatial acuity and cortical processing during acute hand deafferentation. Nat. Neurosci. 5, 936–938 (2002).

    CAS  Article  Google Scholar 

  86. 86

    Floel, A. et al. Influence of somatosensory input on motor function in patients with chronic stroke. Ann. Neurol. 56, 206–212 (2004).

    Article  Google Scholar 

  87. 87

    Ward, N. S. & Cohen, L. G. Mechanisms underlying recovery of motor function after stroke. Arch. Neurol. 61, 1844–1848 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    Stinear, C. M. et al. Functional potential in chronic stroke patients depends on corticospinal tract integrity. Brain 130, 170–180 (2007).

    Article  Google Scholar 

  89. 89

    Lindenberg, R. et al. Structural integrity of corticospinal motor fibers predicts motor impairment in chronic stroke. Neurology 74, 280–287 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Bradnam, L. V., Stinear, C. M., Barber, P. A. & Byblow, W. D. Contralesional hemisphere control of the proximal paretic upper limb following stroke. Cerebr. Cortex 22, 2662–2671 (2012).

    Article  Google Scholar 

  91. 91

    Werhahn, K. J., Conforto, A. B., Kadom, N., Hallett, M. & Cohen, L. G. Contribution of the ipsilateral motor cortex to recovery after chronic stroke. Ann. Neurol. 54, 464–472 (2003).

    Article  Google Scholar 

  92. 92

    Seghier, M. L. Laterality index in functional MRI: methodological issues. Magn. Res. Imaging 26, 594–601 (2008).

    Article  Google Scholar 

  93. 93

    Johansen-Berg, H. Functional imaging of stroke recovery: what have we learnt and where do we go from here? Int. J. Stroke 2, 7–16 (2007).

    Article  Google Scholar 

  94. 94

    Johansen-Berg, H., Scholz, J. & Stagg, C. J. Relevance of structural brain connectivity to learning and recovery from stroke. Front. Syst. Neurosci. 4, 146 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  95. 95

    Bestmann, S. et al. The role of contralesional dorsal premotor cortex after stroke as studied with concurrent TMS–fMRI. J. Neurosci. 30, 11926–11937 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  96. 96

    Mochizuki, H., Huang, Y.-Z. & Rothwell, J. C. Interhemispheric interaction between human dorsal premotor and contralateral primary motor cortex. J. Physiol. 561, 331–338 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97

    Koch, G. et al. Time course of functional connectivity between dorsal premotor and contralateral motor cortex during movement selection. J. Neurosci. 26, 7452–7459 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98

    Lomarev, M., Kim, D., Richardson, S. P., Voller, B. & Hallett, M. Safety study of high-frequency transcranial magnetic stimulation in patients with chronic stroke. Clin. Neurophysiol. 118, 2072–2075 (2007).

    CAS  Article  Google Scholar 

  99. 99

    Magee, J. C. & Johnston, D. A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons. Science 275, 209–213 (1997).

    CAS  Article  Google Scholar 

  100. 100

    Bi, G. & Poo, M. Synaptic modification by correlated activity: Hebb's postulate revisited. Annu. Rev. Neurosci. 24, 139–166 (2001).

    CAS  Article  Google Scholar 

  101. 101

    Bi, G. Q. & Poo, M. M. Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type. J. Neurosci. 18, 10464–10472 (1998).

    CAS  Article  Google Scholar 

  102. 102

    Hoogendam, J. M., Ramakers, G. M. & Di Lazzaro, V. Physiology of repetitive transcranial magnetic stimulation of the human brain. Brain Stimul. 3, 95–118 (2010).

    Article  Google Scholar 

  103. 103

    Huang, Y.-Z., Rothwell, J. C., Chen, R.-S., Lu, C.-S. & Chuang, W.-L. The theoretical model of theta burst form of repetitive transcranial magnetic stimulation. Clin. Neurophysiol. 122, 1011–1018 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  104. 104

    Wolters, A. et al. A temporally asymmetric Hebbian rule governing plasticity in the human motor cortex. J. Neurophysiol. 89, 2339–2345 (2003).

    Article  Google Scholar 

  105. 105

    Stefan, K., Kunesch, E., Cohen, L. G., Benecke, R. & Classen, J. Induction of plasticity in the human motor cortex by paired associative stimulation. Brain 123, 572–584 (2000).

    Article  Google Scholar 

  106. 106

    Conforto, A. B. et al. Transcranial magnetic stimulation in mild to severe hemiparesis early after stroke: a proof of principle and novel approach to improve motor function. J. Neurol. 259, 1399–1405 (2012).

    Article  Google Scholar 

  107. 107

    Talelli, P. et al. Theta burst stimulation in the rehabilitation of the upper limb: a semirandomized, placebo-controlled trial in chronic stroke patients. Neurorehabil. Neural Repair 26, 976–987 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    Lindenberg, R., Zhu, L. L. & Schlaug, G. Combined central and peripheral stimulation to facilitate motor recovery after stroke: the effect of number of sessions on outcome. Neurorehabil. Neural Repair 26, 479–483 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  109. 109

    Avenanti, A., Coccia, M., Ladavas, E., Provinciali, L. & Ceravolo, M. Low-frequency rTMS promotes use-dependent motor plasticity in chronic stroke: a randomized trial. Neurology 78, 256–264 (2012).

    CAS  Article  Google Scholar 

  110. 110

    Kakuda, W. et al. A multi-center study on low-frequency rTMS combined with intensive occupational therapy for upper limb hemiparesis in post-stroke patients. J. Neuroeng. Rehabil. 9, 4 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Chang, W. H. et al. rTMS with motor training modulates cortico-basal ganglia-thalamocortical circuits in stroke patients. Restor. Neurol. Neurosci. 30, 179–189 (2012).

    PubMed  PubMed Central  Google Scholar 

  112. 112

    Seniów, J. et al. Transcranial magnetic stimulation combined with physiotherapy in rehabilitation of poststroke hemiparesis: a randomized, double-blind, placebo-controlled study. Neurorehabil. Neural Repair 26, 1072–1079 (2012).

    Article  Google Scholar 

  113. 113

    Cazzoli, D. et al. Theta burst stimulation reduces disability during the activities of daily living in spatial neglect. Brain 135, 3426–3439 (2012).

    Article  Google Scholar 

  114. 114

    Ameli, M. et al. Differential effects of high-frequency repetitive transcranial magnetic stimulation over ipsilesional primary motor cortex in cortical and subcortical middle cerebral artery stroke. Ann. Neurol. 66, 298–309 (2009).

    Article  Google Scholar 

  115. 115

    Boggio, P. S. et al. Hand function improvement with low-frequency repetitive transcranial magnetic stimulation of the unaffected hemisphere in a severe case of stroke. Am. J. Phys. Med. Rehabil. 85, 927–930 (2006).

    Article  Google Scholar 

  116. 116

    Koch, G. et al. Theta-burst stimulation of the left hemisphere accelerates recovery of hemispatial neglect. Neurology 78, 24–30 (2012).

    CAS  Article  Google Scholar 

  117. 117

    Di Lazzaro, V. et al. Modulation of motor cortex neuronal networks by rTMS: comparison of local and remote effects of six different protocols of stimulation. J. Neurophysiol. 105, 2150–2156 (2011).

    CAS  Article  Google Scholar 

  118. 118

    Datta, A., Truong, D., Minhas, P., Parra, L. C. & Bikson, M. Inter-individual variation during transcranial direct current stimulation and normalization of dose using MRI-derived computational models. Front. Psychiatry 3, 91 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  119. 119

    Maeda, F., Keenan, J. P., Tormos, J. M., Topka, H. & Pascual-Leone, A. Interindividual variability of the modulatory effects of repetitive transcranial magnetic stimulation on cortical excitability. Exp. Brain Res. 133, 425–430 (2000).

    CAS  Article  Google Scholar 

  120. 120

    Hamada, M., Murase, N., Hasan, A., Balaratnam, M. & Rothwell, J. C. The role of interneuron networks in driving human motor cortical plasticity. Cereb. Cortex 23, 1593–1605 (2013).

    Article  Google Scholar 

  121. 121

    Cheeran, B. et al. A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS. J. Physiol. 586, 5717–5725 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    Nitsche, M. A., Müller-Dahlhaus, F., Paulus, W. & Ziemann, U. The pharmacology of neuroplasticity induced by non-invasive brain stimulation: building models for the clinical use of CNS active drugs. J. Physiol. 590, 4641–4662 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. 123

    Wu, D. et al. Effects on decreasing upper-limb poststroke muscle tone using transcranial direct current stimulation: a randomized sham-controlled study. Arch. Phys. Med. Rehabil. 94, 1–8 (2013).

    Article  Google Scholar 

  124. 124

    Khedr, E. M., Etraby, A. E., Hemeda, M., Nasef, A. M. & Razek, A. A. Long-term effect of repetitive transcranial magnetic stimulation on motor function recovery after acute ischemic stroke. Acta Neurol. Scand. 121, 30–37 (2010).

    CAS  Article  Google Scholar 

  125. 125

    Hesse, S. et al. Combined transcranial direct current stimulation and robot-assisted arm training in subacute stroke patients: an exploratory, randomized multicenter trial. Neurorehabil. Neural Repair 25, 838–846 (2011).

    Article  Google Scholar 

  126. 126

    Bolognini, N. et al. Neurophysiological and behavioral effects of tDCS combined with constraint-induced movement therapy in poststroke patients. Neurorehabil. Neural Repair 25, 819–829 (2011).

    Article  Google Scholar 

  127. 127

    Hummel, F. C. & Cohen, L. G. Non-invasive brain stimulation: a new strategy to improve neurorehabilitation after stroke? Lancet Neurol. 5, 708–712 (2006).

    Article  Google Scholar 

  128. 128

    Khedr, E. M., Ahmed, M. A., Fathy, N. & Rothwell, J. C. Therapeutic trial of repetitive transcranial magnetic stimulation after acute ischemic stroke. Neurology 65, 466–468 (2005).

    Article  Google Scholar 

  129. 129

    Nair, D. G., Renga, V., Lindenberg, R., Zhu, L. & Schlaug, G. Optimizing recovery potential through simultaneous occupational therapy and non-invasive brain-stimulation using tDCS. Restor. Neurol. Neurosci. 29, 411–420 (2011).

    PubMed  PubMed Central  Google Scholar 

  130. 130

    Grefkes, C. & Fink, G. R. Disruption of motor network connectivity post-stroke and its noninvasive neuromodulation. Curr. Opin. Neurol. 25, 670–675 (2012).

    Article  Google Scholar 

  131. 131

    Schlaug, G., Renga, V. & Nair, D. Transcranial direct current stimulation in stroke recovery. Arch. Neurol. 65, 1571–1576 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    Hummel, F. C. et al. Controversy: noninvasive and invasive cortical stimulation show efficacy in treating stroke patients. Brain Stim. 1, 370–382 (2008).

    Article  Google Scholar 

  133. 133

    Plow, E. B., Carey, J. R., Nudo, R. J., & Pascual-Leone, A. Invasive cortical stimulation to promote recovery of function after stroke: a critical appraisal. Stroke 40, 1926–1931 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  134. 134

    Assenza, G. et al. Neuronal functionality assessed by magnetoencephalography is related to oxidative stress system in acute ischemic stroke. Neuroimage 44, 1267–1273 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  135. 135

    Sheorajpanday, R. V., Nagels, G., Weeren, A. J., van Putten, M. J. & De Deyn, P. P. Quantitative EEG in ischemic stroke: correlation with functional status after 6 months. Clin. Neurophysiol. 122, 874–883 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  136. 136

    Finnigan, S., Rose, S. E. & Chalk, J. B. Contralateral hemisphere delta EEG in acute stroke precedes worsening of symptoms and death. Clin. Neurophysiol. 119, 1690–1694 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. 137

    Tecchio, F. et al. Outcome prediction in acute monohemispheric stroke via magnetoencephalography. J. Neurol. 254, 296–305 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  138. 138

    Assenza, G., Zappasodi, F., Pasqualetti, P., Vernieri, F. & Tecchio, F. A contralesional EEG power increase mediated by interhemispheric disconnection provides negative prognosis in acute stroke. Restor. Neurol. Neurosci. 31, 177–188 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139

    Finnigan, S. & van Putten, M. J. EEG in ischaemic stroke: quantitative EEG can uniquely inform (sub-) acute prognoses and clinical management. Clin. Neurophysiol. 124, 10–9 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  140. 140

    Graziadio, S., Tomasevic, L., Assenza, G., Tecchio, F. & Eyre, J. The myth of the 'unaffected' side after unilateral stroke: is reorganisation of the non-infarcted corticospinal system to re-establish balance the price for recovery? Exp. Neurol. 238, 168–175 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    Ilmoniemi, R. J. et al. Neuronal responses to magnetic stimulation reveal cortical reactivity and connectivity. Neuroreport 8, 3537–3540 (1997).

    CAS  Article  Google Scholar 

  142. 142

    Ferreri, F. et al. Does an intraneural interface short-term implant for robotic hand control modulate sensorimotor cortical integration? An EEG–TMS co-registration study on a human amputee. Restor. Neurol. Neurosci. 32, 281–292 (2014).

    CAS  Google Scholar 

  143. 143

    Premoli, I. et al. TMS-EEG signatures of GABAergic neurotransmission in the human cortex. J. Neurosci. 34, 5603–5612 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Nikulin, V. V., Kicic, D., Kahkonen, S. & Ilmoniemi, R. J. Modulation of electroencephalographic responses to transcranial magnetic stimulation: evidence for changes in cortical excitability related to movement. Eur. J. Neurosci. 18, 1206–1212 (2003).

    Article  Google Scholar 

  145. 145

    Ferreri, F. et al. Human brain connectivity during single and paired pulse transcranial magnetic stimulation. Neuroimage 54, 90–102 (2011).

    Article  Google Scholar 

  146. 146

    Kujirai, T. et al. Corticocortical inhibition in human motor cortex. J. Physiol. 471, 501–519 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. 147

    Di Lazzaro, V. et al. Direct demonstration of the effect of lorazepam on the excitability of the human motor cortex. Clin. Neurophys. 111, 794–799 (2000).

    CAS  Article  Google Scholar 

  148. 148

    Calancie, B., Nordin, M., Wallin, U. & Hagbarth, K.-E. Motor-unit responses in human wrist flexor and extensor muscles to transcranial cortical stimuli. J. Neurophysiol. 58, 1168–1185 (1987).

    CAS  Article  Google Scholar 

  149. 149

    Valls-Solé, J., Pascual-Leone, A., Wassermann, E. M. & Hallett, M. Human motor evoked responses to paired transcranial magnetic stimuli. Electroencephalogr. Clin. Neurophysiol. 85, 355–364 (1992).

    Article  Google Scholar 

  150. 150

    Di Lazzaro, V. et al. Segregating two inhibitory circuits in human motor cortex at the level of GABAA receptor subtypes: a TMS study. Clin. Neurophys. 118, 2207–2214 (2007).

    CAS  Article  Google Scholar 

  151. 151

    Ziemann, U., Rothwell, J. C. & Ridding, M. C. Interaction between intracortical inhibition and facilitation in human motor cortex. J. Physiol. 496, 873–881 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. 152

    Di Lazzaro, V. et al. Origin of facilitation of motor-evoked potentials after paired magnetic stimulation: direct recording of epidural activity in conscious humans. J. Neurophysiol. 96, 1765–1771 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  153. 153

    Siebner, H. R. et al. Consensus paper: combining transcranial stimulation with neuroimaging. Brain Stimul. 2, 58–80 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  154. 154

    Ziemann, U. Transcranial magnetic stimulation at the interface with other techniques: a powerful tool for studying the human cortex. Neuroscientist 17, 368–381 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  155. 155

    Ilmoniemi, R. J. & Kicic, D. Methodology for combined TMS and EEG. Brain Topogr. 22, 233–248 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  156. 156

    Ziemann, U. et al. Consensus: motor cortex plasticity protocols. Brain Stim. 1, 164–182 (2008).

    Article  Google Scholar 

  157. 157

    Thickbroom, G. W. Transcranial magnetic stimulation and synaptic plasticity: experimental framework and human models. Exp. Brain Res. 180, 583–593 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  158. 158

    Huang, Y. Z., Edwards, M. J., Rounis, E., Bhatia, K. P. & Rothwell, J. C. Theta burst stimulation of the human motor cortex. Neuron 45, 201–206 (2005).

    CAS  Article  Google Scholar 

  159. 159

    Di Lazzaro, V. et al. Motor cortex plasticity predicts recovery in acute stroke. Cereb. Cortex 20, 1523–1528 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  160. 160

    Müller-Dahlhaus, F., Ziemann, U. & Classen, J. Plasticity resembling spike-timing dependent synaptic plasticity: the evidence in human cortex. Front. Synaptic Neurosci. 2, 34 (2010).

    PubMed  PubMed Central  Google Scholar 

  161. 161

    Stefan, K., Kunesch, E., Benecke, R., Cohen, L. G. & Classen, J. Mechanisms of enhancement of human motor cortex excitability induced by interventional paired associative stimulation. J. Physiol. 543, 699–708 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  162. 162

    Wolters, A. et al. Timing-dependent plasticity in human primary somatosensory cortex. J. Physiol. 565, 1039–1052 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  163. 163

    Heidegger, T., Krakow, K. & Ziemann, U. Effects of antiepileptic drugs on associative LTP-like plasticity in human motor cortex. Eur. J. Neurosci. 32, 1215–1222 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  164. 164

    Korchounov, A. & Ziemann, U. Neuromodulatory neurotransmitters influence LTP-like plasticity in human cortex: a pharmaco-TMS study. Neuropsychopharmacology 36, 1894–1902 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  165. 165

    Nitsche, M. A. et al. Transcranial direct current stimulation: state of the art 2008. Brain Stim. 1, 206–223 (2008).

    Article  Google Scholar 

  166. 166

    Ranieri, F. et al. Modulation of LTP at rat hippocampal CA3-CA1 synapses by direct current stimulation. J. Neurophysiol. 107, 1868–1880 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  167. 167

    Medeiros, L. F. et al. Neurobiological effects of transcranial direct current stimulation: a review. Front. Psychiatry 3, 110 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  168. 168

    Nitsche, M. A. et al. Modulating parameters of excitability during and after transcranial direct current stimulation of the human motor cortex. J. Physiol. 568, 291–303 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  169. 169

    Liebetanz, D., Nitsche, M. A., Tergau, F. & Paulus, W. Pharmacological approach to the mechanisms of transcranial DC-stimulation-induced after-effects of human motor cortex excitability. Brain 125, 2238–2247 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  170. 170

    Powell, J., Pandyan, A. D., Granat, M., Cameron, M. & Stott, D. J. Electrical stimulation of wrist extensors in poststroke hemiplegia. Stroke 30, 1384–1389 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  171. 171

    Conforto, A. B., Kaelin-Lang, A. & Cohen, L. G. Increase in hand muscle strength of stroke patients after somatosensory stimulation. Ann. Neurol. 51, 122–125 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  172. 172

    Ng, S. S. & Hui-Chan, C. W. Transcutaneous electrical nerve stimulation combined with task-related training improves lower limb functions in subjects with chronic stroke. Stroke 38, 2953–2959 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  173. 173

    Ada, L. & Foongchomcheay, A. Efficacy of electrical stimulation in preventing or reducing subluxation of the shoulder after stroke: a meta-analysis. Aust. J. Physiother. 48, 257–267 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  174. 174

    Price, C. I. & Pandyan, A. Electrical stimulation for preventing and treating post-stroke shoulder pain: a systematic Cochrane review. Clin. Rehabil. 15, 5–19 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  175. 175

    Sujith, O. Functional electrical stimulation in neurological disorders. Eur. J. Neurol. 15, 437–444 (2008).

    CAS  Article  Google Scholar 

  176. 176

    Wu, C. W.-H. & Kaas, J. H. The effects of long-standing limb loss on anatomical reorganization of the somatosensory afferents in the brainstem and spinal cord. Somatosens. Mot. Res. 19, 153–163 (2002).

    Article  Google Scholar 

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G.D.P. developed the model and wrote the article. G.P. searched the literature and wrote the section on the stimulation protocols and clinical trials. G.A. searched the literature and wrote the section on EEG and repetitive electric stimulation. F.C. searched the literature and participated in writing the section on predictors of recovery. F.F. searched the literature and wrote the section on TMS–EEG in the multimodal diagnostic approach. D.F. was involved in the computational development of the model. M.T. searched the literature and wrote the section on synaptic dysfunctions following stroke. F.R. provided substantial contributions to discussion of the content. U.Z., J.C.R. and V.D.L. guided the manuscript development and revised the manuscript.

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Correspondence to Vincenzo Di Lazzaro.

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Di Pino, G., Pellegrino, G., Assenza, G. et al. Modulation of brain plasticity in stroke: a novel model for neurorehabilitation. Nat Rev Neurol 10, 597–608 (2014). https://doi.org/10.1038/nrneurol.2014.162

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