Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Restoring brain function after stroke — bridging the gap between animals and humans

Nature Reviews Neurology volume 13, pages 244–255 (2017)Cite this article

Subjects

Key Points

  • Stroke is the leading cause of complex adult disability in the world, but currently we do not provide a sufficient dose of the right physical or behavioural interventions to drive recovery

  • Clear lesion-induced changes occur in brain structure and function early after stroke, which result in an environment with unique heightened plasticity that can support restoration of function, termed spontaneous biological recovery

  • Intense, high-dose behavioural training aimed at the reduction of impairment and the restoration of function should be (but currently is not) delivered in this critical time window

  • The basis of spontaneous biological recovery in humans is unclear, which yields uncertainty over how and when to augment or prolong this process with novel therapies — further characterization is required to enable realistic phase III trials

  • Human neuroimaging techniques combined with modelling approaches can provide the appropriate biomarkers with which to map out a mechanistic approach to understand who and when to treat

  • The use of structural imaging to quantify damage in a range of brain regions can help predict long-term outcomes and provide the basis for stratification in restorative trials

Abstract

Stroke is the leading cause of complex adult disability in the world. Recovery from stroke is often incomplete, which leaves many people dependent on others for their care. The improvement of long-term outcomes should, therefore, be a clinical and research priority. As a result of advances in our understanding of the biological mechanisms involved in recovery and repair after stroke, therapeutic opportunities to promote recovery through manipulation of poststroke plasticity have never been greater. This work has almost exclusively been carried out in preclinical animal models of stroke with little translation into human studies. The challenge ahead is to develop a mechanistic understanding of recovery from stroke in humans. Advances in neuroimaging techniques now enable us to reconcile behavioural accounts of recovery with molecular and cellular changes. Consequently, clinical trials can be designed in a stratified manner that takes into account when an intervention should be delivered and who is most likely to benefit. This approach is expected to lead to a substantial change in how restorative therapeutic strategies are delivered in patients after stroke.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Proportional motor recovery in the upper limb.
Figure 2: Poststroke plasticity and recovery.
Figure 3: Characterization of anatomical damage.

Similar content being viewed by others

References

  1. Feigin, V. L. et al. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet 383, 245–254 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Lackland, D. T. et al. Factors influencing the decline in stroke mortality: a statement from the American Heart Association/American Stroke Association. Stroke 45, 315–353 (2014).

    Article  PubMed  Google Scholar 

  3. Crichton, S. L., Bray, B. D., McKevitt, C., Rudd, A. G. & Wolfe, C. D. A. Patient outcomes up to 15 years after stroke: survival, disability, quality of life, cognition and mental health. J. Neurol. Neurosurg. Psychiatry 87, 1091–1098 (2016).

    Article  PubMed  Google Scholar 

  4. Wade, D. T. & Hewer, R. L. Functional abilities after stroke: measurement, natural history and prognosis. J. Neurol. Neurosurg. Psychiatry 50, 177–182 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Luengo-Fernandez, R., Leal, J. & Gray, A. UK research spend in 2008 and 2012: comparing stroke, cancer, coronary heart disease and dementia. BMJ Open 5, e006648 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Krakauer, J. W., Carmichael, S. T., Corbett, D. & Wittenberg, G. F. Getting neurorehabilitation right: what can be learned from animal models? Neurorehabil. Neural Repair 26, 923–931 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Langhorne, P., Coupar, F. & Pollock, A. Motor recovery after stroke: a systematic review. Lancet Neurol. 8, 741–754 (2009).

    Article  PubMed  Google Scholar 

  8. Lai, S.-M., Studenski, S., Duncan, P. W. & Perera, S. Persisting consequences of stroke measured by the Stroke Impact Scale. Stroke 33, 1840–1844 (2002).

    Article  PubMed  Google Scholar 

  9. Kwakkel, G., Kollen, B. J., van der Grond, J. & Prevo, A. J. H. Probability of regaining dexterity in the flaccid upper limb: impact of severity of paresis and time since onset in acute stroke. Stroke 34, 2181–2186 (2003).

    Article  PubMed  Google Scholar 

  10. Broeks, J. G., Lankhorst, G. J., Rumping, K. & Prevo, A. J. The long-term outcome of arm function after stroke: results of a follow-up study. Disabil. Rehabil. 21, 357–364 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Coupar, F., Pollock, A., Rowe, P., Weir, C. & Langhorne, P. Predictors of upper limb recovery after stroke: a systematic review and meta-analysis. Clin. Rehabil. 26, 291–313 (2012).

    Article  PubMed  Google Scholar 

  12. Prabhakaran, S. et al. Inter-individual variability in the capacity for motor recovery after ischemic stroke. Neurorehabil. Neural Repair 22, 64–71 (2008).

    Article  PubMed  Google Scholar 

  13. Zarahn, E. et al. Prediction of motor recovery using initial impairment and fMRI 48 h poststroke. Cereb. Cortex 21, 2712–2721 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Winters, C., van Wegen, E. E. H., Daffertshofer, A. & Kwakkel, G. Generalizability of the proportional recovery model for the upper extremity after an ischemic stroke. Neurorehabil. Neural Repair 29, 614–622 (2014).

    Article  PubMed  Google Scholar 

  15. Byblow, W. D., Stinear, C. M., Barber, P. A., Petoe, M. A. & Ackerley, S. J. Proportional recovery after stroke depends on corticomotor integrity. Ann. Neurol. 78, 848–859 (2015).

    Article  PubMed  Google Scholar 

  16. Lazar, R. M. et al. Improvement in aphasia scores after stroke is well predicted by initial severity. Stroke 41, 1485–1488 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Nijboer, T. C. W., Kollen, B. J. & Kwakkel, G. Time course of visuospatial neglect early after stroke: a longitudinal cohort study. Cortex 49, 2021–2027 (2013).

    Article  PubMed  Google Scholar 

  18. Zeiler, S. R. & Krakauer, J. W. The interaction between training and plasticity in the poststroke brain. Curr. Opin. Neurol. 26, 609–616 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Biernaskie, J., Chernenko, G. & Corbett, D. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J. Neurosci. 24, 1245–1254 (2004).

    Article  CAS  PubMed  Google Scholar 

  20. Zeiler, S. R. et al. Paradoxical motor recovery from a first stroke after induction of a second stroke: reopening a postischemic sensitive period. Neurorehabil. Neural Repair 30, 794–800 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Carmichael, S. T. Emergent properties of neural repair: elemental biology to therapeutic concepts. Ann. Neurol. 79, 895–906 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Cramer, S. C. & Chopp, M. Recovery recapitulates ontogeny. Trends Neurosci. 23, 265–271 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Wahl, A.-S. & Schwab, M. E. Finding an optimal rehabilitation paradigm after stroke: enhancing fiber growth and training of the brain at the right moment. Front. Hum. Neurosci. 8, 381 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Wieloch, T. & Nikolich, K. Mechanisms of neural plasticity following brain injury. Curr. Opin. Neurobiol. 16, 258–264 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Carmichael, S. T., Kathirvelu, B., Schweppe, C. A. & Nie, E. H. Molecular, cellular and functional events in axonal sprouting after stroke. Exp. Neurol. 287, 384–394 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jin, K. et al. Evidence for stroke-induced neurogenesis in the human brain. Proc. Natl Acad. Sci. USA 103, 13198–13202 (2006).

    Article  CAS  PubMed  Google Scholar 

  28. Sanin, V., Heeß, C., Kretzschmar, H. A. & Schüller, U. Recruitment of neural precursor cells from circumventricular organs of patients with cerebral ischaemia. Neuropathol. Appl. Neurobiol. 39, 510–518 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Li, S. et al. An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke. Nat. Neurosci. 13, 1496–1504 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li, S. & Carmichael, S. T. Growth-associated gene and protein expression in the region of axonal sprouting in the aged brain after stroke. Neurobiol. Dis. 23, 362–373 (2006).

    Article  CAS  PubMed  Google Scholar 

  31. Benowitz, L. I. & Carmichael, S. T. Promoting axonal rewiring to improve outcome after stroke. Neurobiol. Dis. 37, 259 (2010).

    Article  PubMed  Google Scholar 

  32. Wahl, A. S. et al. Neuronal repair. Asynchronous therapy restores motor control by rewiring of the rat corticospinal tract after stroke. Science 344, 1250–1255 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Allred, R. P., Maldonado, M. A., Hsu, J. E. & Jones, T. A. Training the 'less-affected' forelimb after unilateral cortical infarcts interferes with functional recovery of the impaired forelimb in rats. Restor. Neurol. Neurosci. 23, 297–302 (2005).

    CAS  PubMed  Google Scholar 

  34. Kim, S. Y. et al. Experience with the 'good' limb induces aberrant synaptic plasticity in the perilesion cortex after stroke. J. Neurosci. 35, 8604–8610 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nih, L. R., Carmichael, S. T. & Segura, T. Hydrogels for brain repair after stroke: an emerging treatment option. Curr. Opin. Biotechnol. 40, 155–163 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Memanishvili, T. et al. Generation of cortical neurons from human induced-pluripotent stem cells by biodegradable polymeric microspheres loaded with priming factors. Biomed. Mater. 11, 025011 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Pendharkar, A. V. et al. Optogenetic modulation in stroke recovery. Neurosurg. Focus 40, E6 (2016).

    Article  PubMed  Google Scholar 

  38. Carmichael, S. T. Brain excitability in stroke: the yin and yang of stroke progression. Arch. Neurol. 69, 161–167 (2012).

    Article  PubMed  Google Scholar 

  39. Lai, T. W., Zhang, S. & Wang, Y. T. Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog. Neurobiol. 115, 157–188 (2014).

    Article  CAS  PubMed  Google Scholar 

  40. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bavelier, D., Levi, D. M., Li, R. W., Dan, Y. & Hensch, T. K. Removing brakes on adult brain plasticity: from molecular to behavioral interventions. J. Neurosci. 30, 14964–14971 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Chen, J. L. et al. Structural basis for the role of inhibition in facilitating adult brain plasticity. Nat. Neurosci. 14, 587–594 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Felling, R. J. & Song, H. Epigenetic mechanisms of neuroplasticity and the implications for stroke recovery. Exp. Neurol. 268, 37–45 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Alia, C. et al. Reducing GABAA-mediated inhibition improves forelimb motor function after focal cortical stroke in mice. Sci. Rep. 6, 37823 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Winship, I. R. & Murphy, T. H. In vivo calcium imaging reveals functional rewiring of single somatosensory neurons after stroke. J. Neurosci. 28, 6592–6606 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hagemann, G., Redecker, C., Neumann-Haefelin, T., Freund, H. J. & Witte, O. W. Increased long-term potentiation in the surround of experimentally induced focal cortical infarction. Ann. Neurol. 44, 255–258 (1998).

    Article  CAS  PubMed  Google Scholar 

  47. Takatsuru, Y. et al. Neuronal circuit remodeling in the contralateral cortical hemisphere during functional recovery from cerebral infarction. J. Neurosci. 29, 10081–10086 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Que, M. et al. Changes in GABAA and GABAB receptor binding following cortical photothrombosis: a quantitative receptor autoradiographic study. Neuroscience 93, 1233–1240 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. Clarkson, A. N. et al. AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke. J. Neurosci. 31, 3766–3775 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Schäbitz, W.-R. et al. Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis. Stroke 38, 2165–2172 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Neumann-Haefelin, T., Hagemann, G. & Witte, O. W. Cellular correlates of neuronal hyperexcitability in the vicinity of photochemically induced cortical infarcts in rats in vitro. Neurosci. Lett. 193, 101–104 (1995).

    Article  CAS  PubMed  Google Scholar 

  52. 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).

    Article  CAS  PubMed  Google Scholar 

  53. Zeiler, S. R. et al. Medial premotor cortex shows a reduction in inhibitory markers and mediates recovery in a mouse model of focal stroke. Stroke 44, 483–489 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Lake, E. M. R. et al. The effects of delayed reduction of tonic inhibition on ischemic lesion and sensorimotor function. J. Cereb. Blood Flow Metab. 35, 1601–1609 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Clarkson, A. N. Perisynaptic GABA receptors the overzealous protector. Adv. Pharmacol. Sci. 2012, 708428 (2012).

    PubMed  PubMed Central  Google Scholar 

  56. Sakuma, M., Hyakawa, N., Kato, H. & Araki, T. Time dependent changes of striatal interneurons after focal cerebral ischemia in rats. J. Neural Transm. (Vienna) 115, 413–422 (2008).

    Article  CAS  Google Scholar 

  57. Kharlamov, E. A., Downey, K. L., Jukkola, P. I., Grayson, D. R. & Kelly, K. M. Expression of GABA A receptor alpha1 subunit mRNA and protein in rat neocortex following photothrombotic infarction. Brain Res. 1210, 29–38 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. 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  PubMed  Google Scholar 

  59. Kang, N., Summers, J. J. & Cauraugh, J. H. Transcranial direct current stimulation facilitates motor learning post-stroke: a systematic review and meta-analysis. J. Neurol. Neurosurg. Psychiatry 87, 2345–355 (2016).

    Article  Google Scholar 

  60. Fritsch, B. et al. Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning. Neuron 66, 198–204 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Bonaiuto, J. J. & Bestmann, S. Understanding the nonlinear physiological and behavioral effects of tDCS through computational neurostimulation. Prog. Brain Res. 222, 75–103 (2015).

    Article  PubMed  Google Scholar 

  62. de Berker, A. O., Bikson, M & Bestmann, S. Predicting the behavioral impact of transcranial direct current stimulation: issues and limitations. Front. Hum. Neurosci. 7, 613 (2008).

    Google Scholar 

  63. Prokic, E. J. et al. Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons. Neuropharmacology 95, 192–205 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Hiu, T. et al. Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target. Brain 139, 468–480 (2016).

    Article  PubMed  Google Scholar 

  65. Cohen, L., Chaaban, B. & Habert, M.-O. Transient improvement of aphasia with zolpidem. N. Engl. J. Med. 350, 949–950 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Hall, S. D. et al. GABAA alpha-1 subunit mediated desynchronization of elevated low frequency oscillations alleviates specific dysfunction in stroke — a case report. Clin. Neurophysiol. 121, 549–555 (2010).

    Article  CAS  PubMed  Google Scholar 

  67. Phillips, J. P., Devier, D. J. & Feeney, D. M. Rehabilitation pharmacology: bridging laboratory work to clinical application. J. Head Trauma Rehabil. 18, 342–356 (2003).

    Article  PubMed  Google Scholar 

  68. Chollet, F. et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 10, 123–130 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Mead, G. E. et al. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Cochrane Database Syst. Rev. 11, CD009286 (2012).

    PubMed  Google Scholar 

  70. Maya Vetencourt, J. F. et al. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 320, 385–388 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Ng, K. L. et al. Fluoxetine maintains a state of heightened responsiveness to motor training early after stroke in a mouse model. Stroke 46, 2951–2960 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Puig, M. V., Watakabe, A., Ushimaru, M., Yamamori, T. & Kawaguchi, Y. Serotonin modulates fast-spiking interneuron and synchronous activity in the rat prefrontal cortex through 5-HT1A and 5-HT2A receptors. J. Neurosci. 30, 2211–2222 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Méndez, P., Pazienti, A., Szabó, G. & Bacci, A. Direct alteration of a specific inhibitory circuit of the hippocampus by antidepressants. J. Neurosci. 32, 16616–16628 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Komlósi, G. et al. Fluoxetine (prozac) and serotonin act on excitatory synaptic transmission to suppress single layer 2/3 pyramidal neuron-triggered cell assemblies in the human prefrontal cortex. J. Neurosci. 32, 16369–16378 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Clarke, J., Langdon, K. D. & Corbett, D. Early poststroke experience differentially alters periinfarct layer II and III cortex. J. Cereb. Blood Flow Metab. 34, 630–637 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Cumberland Consensus Working Group et al. The future of restorative neurosciences in stroke: driving the translational research pipeline from basic science to rehabilitation of people after stroke. Neurorehabil. Neural Repair 23, 97–107 (2009).

  77. Ward, N. S. Getting lost in translation. Curr. Opin. Neurol. 21, 625–627 (2008).

    Article  PubMed  Google Scholar 

  78. Schulz, R. et al. Assessing the integrity of corticospinal pathways from primary and secondary cortical motor areas after stroke. Stroke 43, 2248–2251 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Schulz, R. et al. White matter integrity of premotor-motor connections is associated with motor output in chronic stroke patients. Neuroimage Clin. 7, 82–86 (2015).

    Article  PubMed  Google Scholar 

  80. Ward, N. S., Brown, M. M., Thompson, A. J. & Frackowiak, R. S. J. Longitudinal changes in cerebral response to proprioceptive input in individual patients after stroke: an FMRI study. Neurorehabil. Neural Repair 20, 398–405 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Ward, N. S., Brown, M. M., Thompson, A. J. & Frackowiak, R. S. J. Neural correlates of motor recovery after stroke: a longitudinal fMRI study. Brain 126, 2476–2496 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ward, N. S., Brown, M. M., Thompson, A. J. & Frackowiak, R. S. J. Neural correlates of outcome after stroke: a cross-sectional fMRI study. Brain 126, 1430–1448 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ward, N. S. et al. Motor system activation after subcortical stroke depends on corticospinal system integrity. Brain 129, 809–819 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Ward, N. S., Brown, M. M., Thompson, A. J. & Frackowiak, R. S. J. The influence of time after stroke on brain activations during a motor task. Ann. Neurol. 55, 829–834 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Wang, L. et al. Dynamic functional reorganization of the motor execution network after stroke. Brain 133, 1224–1238 (2010).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  87. Dijkhuizen, R. M., Zaharchuk, G. & Otte, W. M. Assessment and modulation of resting-state neural networks after stroke. Curr. Opin. Neurol. 27, 637–643 (2014).

    Article  PubMed  Google Scholar 

  88. Swayne, O. B. C., 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 

  89. Blicher, J. U. et al. GABA levels are decreased after stroke and GABA changes during rehabilitation correlate with motor improvement. Neurorehabil. Neural Repair 29, 278–286 (2015).

    Article  PubMed  Google Scholar 

  90. Kim, Y. K., Yang, E. J., Cho, K., Lim, J. Y. & Paik, N.-J. Functional recovery after ischemic stroke is associated with reduced GABAergic inhibition in the cerebral cortex: a GABA PET study. Neurorehabil. Neural Repair 28, 576–583 (2014).

    Article  PubMed  Google Scholar 

  91. Ward, N. S. Using oscillations to understand recovery after stroke. Brain 138, 2811–2813 (2015).

    Article  PubMed  Google Scholar 

  92. Bernhardt, J. et al. Moving rehabilitation research forward: developing consensus statements for rehabilitation and recovery research. Int. J. Stroke 11, 454–458 (2016).

    Article  PubMed  Google Scholar 

  93. Heiss, W.-D. et al. Permanent cortical damage detected by flumazenil positron emission tomography in acute stroke. Stroke 29, 454–461 (1998).

    Article  CAS  PubMed  Google Scholar 

  94. Baron, J.-C., Yamauchi, H., Fujioka, M. & Endres, M. Selective neuronal loss in ischemic stroke and cerebrovascular disease. J. Cereb. Blood Flow Metab. 34, 2–18 (2014).

    Article  PubMed  Google Scholar 

  95. Rabiller, G., He, J.-W., Nishijima, Y., Wong, A. & Liu, J. Perturbation of brain oscillations after ischemic stroke: a potential biomarker for post-stroke function and therapy. Int. J. Mol. Sci. 16, 25605–25640 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Paggiaro, A. et al. Magnetoencephalography in stroke recovery and rehabilitation. Front. Neurol. 7, 35 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Proudfoot, M., Woolrich, M. W., Nobre, A. C. & Turner, M. R. Magnetoencephalography. Pract. Neurol. 14, 336–343 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Murakami, S. & Okada, Y. Contributions of principal neocortical neurons to magnetoencephalography and electroencephalography signals. J. Physiol. 575, 925–936 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yamawaki, N., Stanford, I. M., Hall, S. D. & Woodhall, G. L. Pharmacologically induced and stimulus evoked rhythmic neuronal oscillatory activity in the primary motor cortex in vitro. Neuroscience 151, 386–395 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Nutt, D. et al. Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: a study in healthy volunteers. Neuropharmacology 88, 155–163 (2015).

    Article  CAS  PubMed  Google Scholar 

  101. Hall, S. D. et al. The role of GABAergic modulation in motor function related neuronal network activity. Neuroimage 56, 1506–1510 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Muthukumaraswamy, S. D. et al. The effects of elevated endogenous GABA levels on movement-related network oscillations. Neuroimage 66, 36–41 (2013).

    Article  CAS  PubMed  Google Scholar 

  103. Espenhahn, S., de Berker, A. O., van Wijk, B. C. M., Rossiter, H. E. & Ward, N. S. Movement-related beta oscillations show high intra-individual reliability. Neuroimage 147, 175–185 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Laaksonen, K. et al. Alterations in spontaneous brain oscillations during stroke recovery. PLoS ONE 8, e61146 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Laaksonen, K. et al. Effect of afferent input on motor cortex excitability during stroke recovery. Clin. Neurophysiol. 123, 2429–2436 (2012).

    Article  PubMed  Google Scholar 

  106. Roiha, K. et al. Reorganization of the primary somatosensory cortex during stroke recovery. Clin. Neurophysiol. 122, 339–345 (2011).

    Article  PubMed  Google Scholar 

  107. Reinkensmeyer, D. J. et al. Computational neurorehabilitation: modeling plasticity and learning to predict recovery. J. Neuroeng. Rehabil. 13, 42 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Moran, R. J. et al. Bayesian estimation of synaptic physiology from the spectral responses of neural masses. Neuroimage 42, 272–284 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Moran, R. J. et al. Dynamic causal models and physiological inference: a validation study using isoflurane anaesthesia in rodents. PLoS ONE 6, e22790 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ward, N. S. Does neuroimaging help to deliver better recovery of movement after stroke? Curr. Opin. Neurol. 28, 323–329 (2015).

    Article  CAS  PubMed  Google Scholar 

  111. Chen, C.-C. et al. Nonlinear coupling in the human motor system. J. Neurosci. 30, 8393–8399 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Bhatt, M. B. et al. Computational modelling of movement-related beta-oscillatory dynamics in human motor cortex. Neuroimage 133, 224–232 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Weiler, N., Wood, L., Yu, J., Solla, S. A. & Shepherd, G. M. G. Top-down laminar organization of the excitatory network in motor cortex. Nat. Neurosci. 11, 360–366 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Muthukumaraswamy, S. D. et al. Broadband cortical desynchronization underlies the human psychedelic state. J. Neurosci. 33, 15171–15183 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Winstein, C. J. et al. Effect of a task-oriented rehabilitation program on upper extremity recovery following motor stroke: the ICARE randomized clinical trial. JAMA 315, 571–581 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Kwakkel, G. et al. Effects of unilateral upper limb training in two distinct prognostic groups early after stroke: the EXPLICIT-Stroke randomized clinical trial. Neurorehabil. Neural Repair 30, 804–816 (2016).

    Article  Google Scholar 

  117. Harris, J. E., Eng, J. J., Miller, W. C. & Dawson, A. S. A self-administered Graded Repetitive Arm Supplementary Program (GRASP) improves arm function during inpatient stroke rehabilitation: a multi-site randomized controlled trial. Stroke 40, 2123–2128 (2009).

    Article  PubMed  Google Scholar 

  118. Han, C., Wang, Q., Meng, P. & Qi, M. Effects of intensity of arm training on hemiplegic upper extremity motor recovery in stroke patients: a randomized controlled trial. Clin. Rehabil. 27, 75–81 (2013).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Lang, C. E. et al. Dose-response of task-specific upper limb training in people at least 6 months post stroke: a phase II, single-blind, randomized, controlled trial. Ann. Neurol. 80, 342–354 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  121. 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  PubMed  Google Scholar 

  122. McCabe, J., Monkiewicz, M., Holcomb, J., Pundik, S. & Daly, J. J. Comparison of robotics, functional electrical stimulation, and motor learning methods for treatment of persistent upper extremity dysfunction after stroke: a randomized controlled trial. Arch. Phys. Med. Rehabil. 96, 981–990 (2015).

    Article  PubMed  Google Scholar 

  123. Ward, N. S. et al. The Queen Square intensive upper limb rehabilitation programme. Int. J. Stroke. 11, S14 (2016).

    Google Scholar 

  124. Bhogal, S. K., Teasell, R. & Speechley, M. Intensity of aphasia therapy, impact on recovery. Stroke 34, 987–993 (2003).

    Article  PubMed  Google Scholar 

  125. Krakauer, J. W. & Marshall, R. S. The proportional recovery rule for stroke revisited. Ann. Neurol. 78, 845–847 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Lang, C. E. et al. Observation of amounts of movement practice provided during stroke rehabilitation. Arch. Phys. Med. Rehabil. 90, 1692–1698 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  127. Bernhardt, J., Dewey, H., Thrift, A. & Donnan, G. Inactive and alone: physical activity within the first 14 days of acute stroke unit care. Stroke 35, 1005–1009 (2004).

    Article  PubMed  Google Scholar 

  128. MacLellan, C. L. et al. A critical threshold of rehabilitation involving brain-derived neurotrophic factor is required for poststroke recovery. Neurorehabil. Neural Repair 25, 740–748 (2011).

    Article  PubMed  Google Scholar 

  129. Lohse, K. R., Lang, C. E. & Boyd, L. A. Is more better? Using metadata to explore dose-response relationships in stroke rehabilitation. Stroke 45, 2053–2058 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  130. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N. Engl. J. Med. 333, 1581–1587 (1995).

  131. Winters, C., Heymans, M. W., van Wegen, E. E. H. & Kwakkel, G. How to design clinical rehabilitation trials for the upper paretic limb early post stroke? Trials 17, 468 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Saur, D. et al. Early functional magnetic resonance imaging activations predict language outcome after stroke. Brain 133, 1252–1264 (2010).

    Article  PubMed  Google Scholar 

  133. Rehme, A. K. et al. Identifying neuroimaging markers of motor disability in acute stroke by machine learning techniques. Cereb. Cortex 25, 3046–3056 (2015).

    Article  CAS  PubMed  Google Scholar 

  134. Stinear, C. M. & Ward, N. S. How useful is imaging in predicting outcomes in stroke rehabilitation? Int. J. Stroke 8, 33–37 (2013).

    Article  PubMed  Google Scholar 

  135. Bigourdan, A. et al. Early fiber number ratio is a surrogate of corticospinal tract integrity and predicts motor recovery after stroke. Stroke 47, 1053–1059 (2016).

    Article  PubMed  Google Scholar 

  136. Park, C.-H., Kou, N. & Ward, N. S. The contribution of lesion location to upper limb deficit after stroke. J. Neurol. Neurosurg. Psychiatry 87, 1283–1286 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Rondina, J. M., Filippone, M., Girolami, M. & Ward, N. S. Decoding post-stroke motor function from structural brain imaging. Neuroimage Clin. 12, 372–380 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Seghier, M. L. et al. The PLORAS Database: a data repository for predicting language outcome and recovery after stroke. Neuroimage 124, 1208–1212 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Carter, A. R. et al. Upstream dysfunction of somatomotor functional connectivity after corticospinal damage in stroke. Neurorehabil. Neural Repair 26, 7–19 (2012).

    Article  PubMed  Google Scholar 

  140. Carter, A. R. et al. Resting interhemispheric functional magnetic resonance imaging connectivity predicts performance after stroke. Ann. Neurol. 67, 365–375 (2010).

    PubMed  PubMed Central  Google Scholar 

  141. Quinlan, E. B. et al. Neural function, injury, and stroke subtype predict treatment gains after stroke. Ann. Neurol. 77, 132–145 (2015).

    Article  Google Scholar 

  142. 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. 29, 8187–8197 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Dachir, S. et al. Inosine improves functional recovery after experimental traumatic brain injury. Brain Res. 1555, 78–88 (2014).

    Article  CAS  PubMed  Google Scholar 

  144. 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. 31, 5977–5988 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Li, S. et al. GDF10 is a signal for axonal sprouting and functional recovery after stroke. Nat. Neurosci. 18, 1737–1745 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Kalladka, D. & Muir, K. W. Where are we in clinical applications of stem cells in ischaemic stroke? Adv. Clin. Neurosci. Rehabil. 16, 9–12 (2016).

    Google Scholar 

  147. Azad, T. D., Veeravagu, A. & Steinberg, G. K. Neurorestoration after stroke. Neurosurg. Focus 40, E2 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Tornero, D. et al. Human induced pluripotent stem cell-derived cortical neurons integrate in stroke-injured cortex and improve functional recovery. Brain 136, 3561–3577 (2013).

    Article  PubMed  Google Scholar 

  149. Steinberg, G. K. et al. Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: a phase 1/2a study. Stroke 47, 1817–1824 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Kalladka, D. et al. Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study. Lancet 388, 787–796 (2016).

    Article  PubMed  Google Scholar 

  151. Lindau, N. T. et al. Rewiring of the corticospinal tract in the adult rat after unilateral stroke and anti-Nogo-A therapy. Brain 137, 739–756 (2014).

    Article  PubMed  Google Scholar 

  152. Meininger, V. et al. Safety, pharmacokinetic, and functional effects of the nogo-a monoclonal antibody in amyotrophic lateral sclerosis: a randomized, first-in-human clinical trial. PLoS ONE 9, e97803 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Cramer, S. C. et al. Safety, pharmacokinetics, and pharmacodynamics of escalating repeat doses of GSK249320 in patients with stroke. Stroke 44, 1337–1342 (2013).

    Article  CAS  PubMed  Google Scholar 

  154. Pizzorusso, T. et al. Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298, 1248–1251 (2002).

    Article  CAS  PubMed  Google Scholar 

  155. Gherardini, L., Gennaro, M. & Pizzorusso, T. Perilesional treatment with chondroitinase ABC and motor training promote functional recovery after stroke in rats. Cereb. Cortex 25, 202–212 (2015).

    Article  PubMed  Google Scholar 

  156. Anderson, M. A. et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195–200 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Overman, J. J. et al. A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke. Proc. Natl Acad. Sci. USA 109, E2230–E2239 (2012).

    Article  CAS  PubMed  Google Scholar 

  158. Luria, A. Restoration of Function after Brain Injury (Pergammon Press, 1963).

    Google Scholar 

  159. Luria, A., Naydin, V., Tsvetkova, L. & Vinarskaya, E. in Handbook of Clinical Neurology Vol. 3 (eds Vinken, P. J. & Bruyn, G.W.) 368–433 (North Holland Publishing Company, 1963).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Sobell Department of Motor Neuroscience, UCL Institute of Neurology, University College London, 33 Queen Square, London, WC1N 3BG, UK

    Nick S. Ward

  2. The National Hospital for Neurology and Neurosurgery, Queen Square, WC1N 3BG, London, UK

    Nick S. Ward

  3. UCLPartners Centre for Neurorehabilitation, UCL Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, UK

    Nick S. Ward

Authors
  1. Nick S. Ward
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nick S. Ward.

Ethics declarations

Competing interests

The author declares no competing financial interests.

PowerPoint slides

Glossary

Impairment

Abnormality or loss of physiological or psychological body function or body structure

Biomarkers

Indicators of disease state that can be used clinically as a measure of underlying molecular or cellular processes that might be difficult to measure directly in humans, and can be used to predict recovery or treatment response.

Proportional recovery rule

The amount of function regained after stroke is a proportion of the initial deficit. For example, by 3 months, patients will regain ∼ 70% of the upper limb motor function that had been lost on day 3 after stroke.

Hemispatial neglect

Reduced awareness of stimuli on one side of space, even though sensory loss might be absent.

Spontaneous biological recovery

Recovery occurring in the first few weeks and months after stroke, attributable to increased poststroke plasticity mechanisms; recovery is rapid, occurs at the level of impairment and generalizes beyond the tasks that are used in poststroke training, compared with improvements seen in the chronic phase of stroke.

Neuronal oscillations

Rhythmic fluctuations in activity generated by neural tissue in the CNS either spontaneously or in response to stimuli; entrained oscillations in multiple neurons and neural networks are thought to form a critical interface between cellular activity and large-scale functions in the CNS.

Cortical microcircuits

Patterns of connections between specific excitatory and inhibitory neurons in the cortex.

Computational neurorehabilitation

A newly emerging field aimed at mathematical modelling of plasticity and learning to understand and improve recovery of individuals with neurological impairment.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ward, N. Restoring brain function after stroke — bridging the gap between animals and humans. Nat Rev Neurol 13, 244–255 (2017). https://doi.org/10.1038/nrneurol.2017.34

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2017.34

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing