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
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.
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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).
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).
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).
Wade, D. T. & Hewer, R. L. Functional abilities after stroke: measurement, natural history and prognosis. J. Neurol. Neurosurg. Psychiatry 50, 177–182 (1987).
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).
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).
Langhorne, P., Coupar, F. & Pollock, A. Motor recovery after stroke: a systematic review. Lancet Neurol. 8, 741–754 (2009).
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).
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).
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).
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).
Prabhakaran, S. et al. Inter-individual variability in the capacity for motor recovery after ischemic stroke. Neurorehabil. Neural Repair 22, 64–71 (2008).
Zarahn, E. et al. Prediction of motor recovery using initial impairment and fMRI 48 h poststroke. Cereb. Cortex 21, 2712–2721 (2011).
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).
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).
Lazar, R. M. et al. Improvement in aphasia scores after stroke is well predicted by initial severity. Stroke 41, 1485–1488 (2010).
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).
Zeiler, S. R. & Krakauer, J. W. The interaction between training and plasticity in the poststroke brain. Curr. Opin. Neurol. 26, 609–616 (2013).
Biernaskie, J., Chernenko, G. & Corbett, D. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J. Neurosci. 24, 1245–1254 (2004).
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).
Murphy, T. H. & Corbett, D. Plasticity during stroke recovery: from synapse to behaviour. Nat. Rev. Neurosci. 10, 861–872 (2009).
Carmichael, S. T. Emergent properties of neural repair: elemental biology to therapeutic concepts. Ann. Neurol. 79, 895–906 (2016).
Cramer, S. C. & Chopp, M. Recovery recapitulates ontogeny. Trends Neurosci. 23, 265–271 (2000).
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).
Wieloch, T. & Nikolich, K. Mechanisms of neural plasticity following brain injury. Curr. Opin. Neurobiol. 16, 258–264 (2006).
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).
Jin, K. et al. Evidence for stroke-induced neurogenesis in the human brain. Proc. Natl Acad. Sci. USA 103, 13198–13202 (2006).
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).
Li, S. et al. An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke. Nat. Neurosci. 13, 1496–1504 (2010).
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).
Benowitz, L. I. & Carmichael, S. T. Promoting axonal rewiring to improve outcome after stroke. Neurobiol. Dis. 37, 259 (2010).
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).
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).
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).
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).
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).
Pendharkar, A. V. et al. Optogenetic modulation in stroke recovery. Neurosurg. Focus 40, E6 (2016).
Carmichael, S. T. Brain excitability in stroke: the yin and yang of stroke progression. Arch. Neurol. 69, 161–167 (2012).
Lai, T. W., Zhang, S. & Wang, Y. T. Excitotoxicity and stroke: identifying novel targets for neuroprotection. Prog. Neurobiol. 115, 157–188 (2014).
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).
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).
Chen, J. L. et al. Structural basis for the role of inhibition in facilitating adult brain plasticity. Nat. Neurosci. 14, 587–594 (2011).
Felling, R. J. & Song, H. Epigenetic mechanisms of neuroplasticity and the implications for stroke recovery. Exp. Neurol. 268, 37–45 (2015).
Alia, C. et al. Reducing GABAA-mediated inhibition improves forelimb motor function after focal cortical stroke in mice. Sci. Rep. 6, 37823 (2016).
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).
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).
Takatsuru, Y. et al. Neuronal circuit remodeling in the contralateral cortical hemisphere during functional recovery from cerebral infarction. J. Neurosci. 29, 10081–10086 (2009).
Que, M. et al. Changes in GABAA and GABAB receptor binding following cortical photothrombosis: a quantitative receptor autoradiographic study. Neuroscience 93, 1233–1240 (1999).
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).
Schäbitz, W.-R. et al. Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis. Stroke 38, 2165–2172 (2007).
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).
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).
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).
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).
Clarkson, A. N. Perisynaptic GABA receptors the overzealous protector. Adv. Pharmacol. Sci. 2012, 708428 (2012).
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).
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).
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).
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).
Fritsch, B. et al. Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning. Neuron 66, 198–204 (2010).
Bonaiuto, J. J. & Bestmann, S. Understanding the nonlinear physiological and behavioral effects of tDCS through computational neurostimulation. Prog. Brain Res. 222, 75–103 (2015).
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).
Prokic, E. J. et al. Cortical oscillatory dynamics and benzodiazepine-site modulation of tonic inhibition in fast spiking interneurons. Neuropharmacology 95, 192–205 (2015).
Hiu, T. et al. Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target. Brain 139, 468–480 (2016).
Cohen, L., Chaaban, B. & Habert, M.-O. Transient improvement of aphasia with zolpidem. N. Engl. J. Med. 350, 949–950 (2004).
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).
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).
Chollet, F. et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 10, 123–130 (2011).
Mead, G. E. et al. Selective serotonin reuptake inhibitors (SSRIs) for stroke recovery. Cochrane Database Syst. Rev. 11, CD009286 (2012).
Maya Vetencourt, J. F. et al. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 320, 385–388 (2008).
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).
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).
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).
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).
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).
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).
Ward, N. S. Getting lost in translation. Curr. Opin. Neurol. 21, 625–627 (2008).
Schulz, R. et al. Assessing the integrity of corticospinal pathways from primary and secondary cortical motor areas after stroke. Stroke 43, 2248–2251 (2012).
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).
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).
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).
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).
Ward, N. S. et al. Motor system activation after subcortical stroke depends on corticospinal system integrity. Brain 129, 809–819 (2006).
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).
Wang, L. et al. Dynamic functional reorganization of the motor execution network after stroke. Brain 133, 1224–1238 (2010).
Grefkes, C. et al. Cortical connectivity after subcortical stroke assessed with functional magnetic resonance imaging. Ann. Neurol. 63, 236–246 (2008).
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).
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).
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).
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).
Ward, N. S. Using oscillations to understand recovery after stroke. Brain 138, 2811–2813 (2015).
Bernhardt, J. et al. Moving rehabilitation research forward: developing consensus statements for rehabilitation and recovery research. Int. J. Stroke 11, 454–458 (2016).
Heiss, W.-D. et al. Permanent cortical damage detected by flumazenil positron emission tomography in acute stroke. Stroke 29, 454–461 (1998).
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).
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).
Paggiaro, A. et al. Magnetoencephalography in stroke recovery and rehabilitation. Front. Neurol. 7, 35 (2016).
Proudfoot, M., Woolrich, M. W., Nobre, A. C. & Turner, M. R. Magnetoencephalography. Pract. Neurol. 14, 336–343 (2014).
Murakami, S. & Okada, Y. Contributions of principal neocortical neurons to magnetoencephalography and electroencephalography signals. J. Physiol. 575, 925–936 (2006).
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).
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).
Hall, S. D. et al. The role of GABAergic modulation in motor function related neuronal network activity. Neuroimage 56, 1506–1510 (2011).
Muthukumaraswamy, S. D. et al. The effects of elevated endogenous GABA levels on movement-related network oscillations. Neuroimage 66, 36–41 (2013).
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).
Laaksonen, K. et al. Alterations in spontaneous brain oscillations during stroke recovery. PLoS ONE 8, e61146 (2013).
Laaksonen, K. et al. Effect of afferent input on motor cortex excitability during stroke recovery. Clin. Neurophysiol. 123, 2429–2436 (2012).
Roiha, K. et al. Reorganization of the primary somatosensory cortex during stroke recovery. Clin. Neurophysiol. 122, 339–345 (2011).
Reinkensmeyer, D. J. et al. Computational neurorehabilitation: modeling plasticity and learning to predict recovery. J. Neuroeng. Rehabil. 13, 42 (2016).
Moran, R. J. et al. Bayesian estimation of synaptic physiology from the spectral responses of neural masses. Neuroimage 42, 272–284 (2008).
Moran, R. J. et al. Dynamic causal models and physiological inference: a validation study using isoflurane anaesthesia in rodents. PLoS ONE 6, e22790 (2011).
Ward, N. S. Does neuroimaging help to deliver better recovery of movement after stroke? Curr. Opin. Neurol. 28, 323–329 (2015).
Chen, C.-C. et al. Nonlinear coupling in the human motor system. J. Neurosci. 30, 8393–8399 (2010).
Bhatt, M. B. et al. Computational modelling of movement-related beta-oscillatory dynamics in human motor cortex. Neuroimage 133, 224–232 (2016).
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).
Muthukumaraswamy, S. D. et al. Broadband cortical desynchronization underlies the human psychedelic state. J. Neurosci. 33, 15171–15183 (2013).
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).
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).
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).
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).
Lo, A. C. et al. Robot-assisted therapy for long-term upper-limb impairment after stroke. N. Engl. J. Med. 362, 1772–1783 (2010).
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).
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).
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).
Ward, N. S. et al. The Queen Square intensive upper limb rehabilitation programme. Int. J. Stroke. 11, S14 (2016).
Bhogal, S. K., Teasell, R. & Speechley, M. Intensity of aphasia therapy, impact on recovery. Stroke 34, 987–993 (2003).
Krakauer, J. W. & Marshall, R. S. The proportional recovery rule for stroke revisited. Ann. Neurol. 78, 845–847 (2015).
Lang, C. E. et al. Observation of amounts of movement practice provided during stroke rehabilitation. Arch. Phys. Med. Rehabil. 90, 1692–1698 (2009).
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).
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).
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).
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).
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).
Saur, D. et al. Early functional magnetic resonance imaging activations predict language outcome after stroke. Brain 133, 1252–1264 (2010).
Rehme, A. K. et al. Identifying neuroimaging markers of motor disability in acute stroke by machine learning techniques. Cereb. Cortex 25, 3046–3056 (2015).
Stinear, C. M. & Ward, N. S. How useful is imaging in predicting outcomes in stroke rehabilitation? Int. J. Stroke 8, 33–37 (2013).
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).
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).
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).
Seghier, M. L. et al. The PLORAS Database: a data repository for predicting language outcome and recovery after stroke. Neuroimage 124, 1208–1212 (2016).
Carter, A. R. et al. Upstream dysfunction of somatomotor functional connectivity after corticospinal damage in stroke. Neurorehabil. Neural Repair 26, 7–19 (2012).
Carter, A. R. et al. Resting interhemispheric functional magnetic resonance imaging connectivity predicts performance after stroke. Ann. Neurol. 67, 365–375 (2010).
Quinlan, E. B. et al. Neural function, injury, and stroke subtype predict treatment gains after stroke. Ann. Neurol. 77, 132–145 (2015).
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).
Dachir, S. et al. Inosine improves functional recovery after experimental traumatic brain injury. Brain Res. 1555, 78–88 (2014).
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).
Li, S. et al. GDF10 is a signal for axonal sprouting and functional recovery after stroke. Nat. Neurosci. 18, 1737–1745 (2015).
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).
Azad, T. D., Veeravagu, A. & Steinberg, G. K. Neurorestoration after stroke. Neurosurg. Focus 40, E2 (2016).
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).
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).
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).
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).
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).
Cramer, S. C. et al. Safety, pharmacokinetics, and pharmacodynamics of escalating repeat doses of GSK249320 in patients with stroke. Stroke 44, 1337–1342 (2013).
Pizzorusso, T. et al. Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298, 1248–1251 (2002).
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).
Anderson, M. A. et al. Astrocyte scar formation aids central nervous system axon regeneration. Nature 532, 195–200 (2016).
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).
Luria, A. Restoration of Function after Brain Injury (Pergammon Press, 1963).
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).
The author declares no competing financial interests.
Abnormality or loss of physiological or psychological body function or body structure
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.
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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
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