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:

Perinatal stroke: mapping and modulating developmental plasticity

Nature Reviews Neurology volume 17, pages 415–432 (2021)Cite this article

Subjects

Abstract

Most cases of hemiparetic cerebral palsy are caused by perinatal stroke, resulting in lifelong disability for millions of people. However, our understanding of how the motor system develops following such early unilateral brain injury is increasing. Tools such as neuroimaging and brain stimulation are generating informed maps of the unique motor networks that emerge following perinatal stroke. As a focal injury of defined timing in an otherwise healthy brain, perinatal stroke represents an ideal human model of developmental plasticity. Here, we provide an introduction to perinatal stroke epidemiology and outcomes, before reviewing models of developmental plasticity after perinatal stroke. We then examine existing therapeutic approaches, including constraint, bimanual and other occupational therapies, and their potential synergy with non-invasive neurostimulation. We end by discussing the promise of exciting new therapies, including novel neurostimulation, brain–computer interfaces and robotics, all focused on improving outcomes after perinatal stroke.

Key points

  • As a focal, unilateral brain injury near the beginning of life, perinatal stroke is an ideal model of human developmental plasticity.

  • The motor system is often damaged in perinatal stroke, resulting in hemiparetic or unilateral cerebral palsy and dramatic alterations in how the motor system develops.

  • Advanced neuroimaging and brain mapping techniques can define these alterations in development, which often include control of the hemiparetic limbs by the non-lesioned (ipsilateral) hemisphere.

  • The design and administration of manual therapies for hemiparetic cerebral palsy are increasingly informed by clinical trials in which pre-interventional and post-interventional imaging and motor mapping are used to help define mechanisms of interventional plasticity.

  • Non-invasive neuromodulation can safely enhance motor learning in children and emerging clinical trial data suggest synergistic effects with therapy-induced endogenous plasticity.

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

Fig. 1: Perinatal stroke classification.
Fig. 2: Neurodevelopment after perinatal stroke.
Fig. 3: Models of developmental neuroplasticity after perinatal stroke.
Fig. 4: Using tractography to study developmental plasticity after perinatal stroke.
Fig. 5: Structural imaging of developmental plasticity after perinatal stroke.
Fig. 6: Functional imaging of developmental plasticity after perinatal stroke.
Fig. 7: TMS motor maps and corticospinal pathways.
Fig. 8: Manual therapies for hemiparetic cerebral palsy.

Similar content being viewed by others

References

  1. Kirton, A. & deVeber, G. Life after perinatal stroke. Stroke 44, 3265–3271 (2013). A review of perinatal stroke diseases with a particular focus on outcomes that affect children and families.

    PubMed  Google Scholar 

  2. Bemister, T. B., Brooks, B. L., Dyck, R. H. & Kirton, A. Predictors of caregiver depression and family functioning after perinatal stroke. BMC Pediatr. 15, 75 (2015).

    PubMed  PubMed Central  Google Scholar 

  3. Shepherd, E. et al. Neonatal interventions for preventing cerebral palsy: an overview of Cochrane systematic reviews. Cochrane Database Syst. Rev. 6, CD012409 (2018).

    PubMed  Google Scholar 

  4. Raju, T. N. K., Nelson, K. B., Ferriero, D., Lynch, J. K. & NICHD-NINDS Perinatal Stroke Workshop Participants. Ischemic perinatal stroke: summary of a workshop sponsored by the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke. Pediatrics 120, 609–616 (2007).

    PubMed  Google Scholar 

  5. Dunbar, M. & Kirton, A. Perinatal stroke: mechanisms, management, and outcomes of early cerebrovascular brain injury. Lancet Child Adolesc. Health 2, 666–676 (2018). A review that summarizes each perinatal stroke disease and examines the epidemiology, pathophysiology, acute management, outcomes (including the effect on parents and families) and emerging therapies to mitigate these lifelong morbidities.

    PubMed  Google Scholar 

  6. Cole, L. et al. Clinical characteristics, risk factors, and outcomes associated with neonatal hemorrhagic stroke: a population-based case-control study. JAMA Pediatr. 171, 230–238 (2017).

    PubMed  Google Scholar 

  7. Kirton, A., Deveber, G., Pontigon, A.-M., Macgregor, D. & Shroff, M. Presumed perinatal ischemic stroke: vascular classification predicts outcomes. Ann. Neurol. 63, 436–443 (2008).

    PubMed  Google Scholar 

  8. Lee, J. et al. Maternal and infant characteristics associated with perinatal arterial stroke in the infant. J. Am. Med. Assoc. 293, 723–729 (2005).

    CAS  Google Scholar 

  9. Kirton, A., Shroff, M., Pontigon, A.-M. & deVeber, G. Risk factors and presentations of periventricular venous infarction vs arterial presumed perinatal ischemic stroke. Arch. Neurol. 67, 842–848 (2010).

    PubMed  Google Scholar 

  10. Lee, J. et al. Predictors of outcome in perinatal arterial stroke: a population-based study. Ann. Neurol. 58, 303–308 (2005).

    PubMed  Google Scholar 

  11. Wu, Y. W., Lynch, J. K. & Nelson, K. B. Perinatal arterial stroke: understanding mechanisms and outcomes. Semin. Neurol. 25, 424–434 (2005).

    PubMed  Google Scholar 

  12. Fluss, J., Dinomais, M. & Chabrier, S. Perinatal stroke syndromes: similarities and diversities in aetiology, outcome and management. Eur. J. Paediatr. Neurol. 23, 368–383 (2019).

    PubMed  Google Scholar 

  13. Hilderley, A. J., Metzler, M. J. & Kirton, A. Noninvasive neuromodulation to promote motor skill gains after perinatal stroke. Stroke 50, 233–239 (2019).

    PubMed  Google Scholar 

  14. Dunbar, M. et al. Population based birth prevalence of disease-specific perinatal stroke. Pediatrics 146, e2020013201 (2020). Summarizes the birth prevalence of all subtypes of perinatal stroke by using a population-based cohort.

    PubMed  Google Scholar 

  15. Golomb, M. R. et al. Neonatal arterial ischemic stroke and cerebral sinovenous thrombosis are more commonly diagnosed in boys. J. Child Neurol. 19, 493–497 (2004).

    PubMed  Google Scholar 

  16. Kirton, A. et al. Symptomatic neonatal arterial ischemic stroke: the International Pediatric Stroke Study. Pediatrics 128, e1402–e1410 (2011).

    PubMed  Google Scholar 

  17. Estan, J. & Hope, P. Unilateral neonatal cerebral infarction in full term infants. Arch. Dis. Child. Fetal Neonatal Ed. 76, F88–F93 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Harteman, J. C. et al. Risk factors for perinatal arterial ischaemic stroke in full-term infants: a case-control study. Arch. Dis. Child. Fetal Neonatal Ed. 97, F411–F416 (2012).

    PubMed  Google Scholar 

  19. Chabrier, S. et al. Obstetrical and neonatal characteristics vary with birthweight in a cohort of 100 term newborns with symptomatic arterial ischemic stroke. Eur. J. Paediatr. Neurol. 14, 206–213 (2010).

    PubMed  Google Scholar 

  20. Martinez-Biarge, M. et al. Risk factors for neonatal arterial ischemic stroke: the importance of the intrapartum period. J. Pediatr. 173, 62–68.e1 (2016).

    PubMed  Google Scholar 

  21. Darmency-Stamboul, V. et al. Antenatal factors associated with perinatal arterial ischemic stroke. Stroke 43, 2307–2312 (2012).

    PubMed  Google Scholar 

  22. Elbers, J., Viero, S., MacGregor, D., deVeber, G. & Moore, A. M. Placental pathology in neonatal stroke. Pediatrics 127, e722–e729 (2011).

    PubMed  Google Scholar 

  23. Roy, B. et al. The role of the placenta in perinatal stroke: a systematic review. J. Child Neurol. 35, 773–783 (2020).

    PubMed  Google Scholar 

  24. Ferriero, D. M. et al. Management of stroke in neonates and children: a scientific statement from the American Heart Association/American Stroke Association. Stroke 50, e51–e96 (2019).

    PubMed  Google Scholar 

  25. Moharir, M. D. et al. Anticoagulants in pediatric cerebral sinovenous thrombosis: a safety and outcome study. Ann. Neurol. 67, 590–599 (2010).

    CAS  PubMed  Google Scholar 

  26. Bemister, T. B., Brooks, B. L., Dyck, R. H. & Kirton, A. Parent and family impact of raising a child with perinatal stroke. BMC Pediatr. 14, 182 (2014).

    PubMed  PubMed Central  Google Scholar 

  27. Dunbar, M. & Kirton, A. Perinatal stroke. Semin. Pediatr. Neurol. 32, 100767 (2019).

    PubMed  Google Scholar 

  28. Arner, M., Eliasson, A. C., Nicklasson, S., Sommerstein, K. & Hagglund, G. Hand function in cerebral palsy. Report of 367 children in a population-based longitudinal health care program. J. Hand Surg. Am. 33, 1337–1347 (2008).

    PubMed  Google Scholar 

  29. Kirton, A., Domi, T., Shroff, M. & Kouzmitcheva, E. Acute descending corticospinal tract diffusion changes predict motor outcome and reorganization patterns in children with arterial ischemic stroke. Neurology 68, S48 (2007).

    Google Scholar 

  30. van der Aa, N. E. et al. Neonatal neuroimaging predicts recruitment of contralesional corticospinal tracts following perinatal brain injury. Dev. Med. Child Neurol. 55, 707–712 (2013).

    PubMed  Google Scholar 

  31. Krumlinde-Sundholm, L. et al. Development of the Hand Assessment for Infants: evidence of internal scale validity. Dev. Med. Child Neurol. 59, 1276–1283 (2017).

    PubMed  Google Scholar 

  32. Holmström, L. et al. Efficacy of the Small Step Program in a randomized controlled trial for infants under 12 months old at risk of cerebral palsy (CP) and other neurological disorders. J. Clin. Med. 8, 1016 (2019).

    PubMed Central  Google Scholar 

  33. Béjot, Y., Giroud, M., Moreau, T. & Benatru, I. Clinical spectrum of movement disorders after stroke in childhood and adulthood. Eur. Neurol. 68, 59–64 (2012).

    PubMed  Google Scholar 

  34. Gaillard, F. et al. Kinematic motion abnormalities and bimanual performance in children with unilateral cerebral palsy. Dev. Med. Child Neurol. 60, 839–845 (2018).

    PubMed  Google Scholar 

  35. Russo, R. N., Skuza, P. P., Sandelance, M. & Flett, P. Upper limb impairments, process skills, and outcome in children with unilateral cerebral palsy. Dev. Med. Child Neurol. 61, 1080–1086 (2019).

    PubMed  PubMed Central  Google Scholar 

  36. Lust, J. M., Spruijt, S., Wilson, P. H. & Steenbergen, B. Motor planning in children with cerebral palsy: a longitudinal perspective. J. Clin. Exp. Neuropsychol. 40, 559–566 (2018).

    PubMed  Google Scholar 

  37. Kuczynski, A. M., Kirton, A., Semrau, J. A. & Dukelow, S. P. Bilateral reaching deficits after unilateral perinatal ischemic stroke: a population-based case-control study. J. Neuroeng. Rehabil. 15, 77 (2018).

    PubMed  PubMed Central  Google Scholar 

  38. Rich, T. L., Menk, J. S., Rudser, K. D., Feyma, T. & Gillick, B. T. Less-affected hand function in children with hemiparetic unilateral cerebral palsy: a comparison study with typically developing peers. Neurorehabil. Neural Repair 31, 965–976 (2017).

    PubMed  PubMed Central  Google Scholar 

  39. World Health Organization. International Classification of Functioning, Disability and Health (ICF) (WHO, 2001).

  40. Lee, A. M. Using the ICF-CY to organise characteristics of children’s functioning. Disabil. Rehabil. 33, 605–616 (2011).

    PubMed  Google Scholar 

  41. Eyre, J. A. Corticospinal tract development and its plasticity after perinatal injury. Neurosci. Biobehav. Rev. 31, 1136–1149 (2007). A review presenting evidence that increased ipsilateral projections from the non-infarcted motor cortex arise from perturbation of ongoing developmental processes.

    CAS  PubMed  Google Scholar 

  42. Nordstrand, L., Eliasson, A.-C. & Holmefur, M. Longitudinal development of hand function in children with unilateral spastic cerebral palsy aged 18 months to 12 years. Dev. Med. Child Neurol. 58, 1042–1048 (2016).

    PubMed  Google Scholar 

  43. Hoare, B. J. et al. Constraint-induced movement therapy in children with unilateral cerebral palsy. Cochrane Database Syst. Rev. 4, CD004149 (2019).

    PubMed  Google Scholar 

  44. Martin, J. H., Friel, K. M., Salimi, I. & Chakrabarty, S. Activity- and use-dependent plasticity of the developing corticospinal system. Neurosci. Biobehav. Rev. 31, 1125–1135 (2007).

    PubMed  PubMed Central  Google Scholar 

  45. Wen, T.-C. et al. Plasticity in one hemisphere, control from two: adaptation in descending motor pathways after unilateral corticospinal injury in neonatal rats. Front. Neural Circuits 12, 28 (2018).

    PubMed  PubMed Central  Google Scholar 

  46. Martin, J. H., Kably, B. & Hacking, A. Activity-dependent development of cortical axon terminations in the spinal cord and brain stem. Exp. Brain Res. 125, 184–199 (1999).

    CAS  PubMed  Google Scholar 

  47. Eyre, J. A., Taylor, J. P., Villagra, F., Smith, M. & Miller, S. Evidence of activity-dependent withdrawal of corticospinal projections during human development. Neurology 57, 1543–1554 (2001).

    CAS  PubMed  Google Scholar 

  48. Staudt, M. Reorganization after pre- and perinatal brain lesions. J. Anat. 217, 469–474 (2010). Summarizes mechanisms of post-lesional reorganization in the developing human brain, with a special emphasis on the development of motor and somatosensory pathways in children with early brain lesions.

    PubMed  PubMed Central  Google Scholar 

  49. Farmer, S. F., Harrison, L. M., Ingram, D. A. & Stephens, J. A. Plasticity of central motor pathways in children with hemiplegic cerebral palsy. Neurology 41, 1505–1510 (1991).

    CAS  PubMed  Google Scholar 

  50. Carr, L. J., Harrison, L. M., Evans, A. L. & Stephens, J. A. Patterns of central motor reorganization in hemiplegic cerebral palsy. Brain 116, 1223–1247 (1993).

    PubMed  Google Scholar 

  51. Maegaki, Y. et al. Mechanisms of central motor reorganization in pediatric hemiplegic patients. Neuropediatrics 28, 168–174 (1997).

    CAS  PubMed  Google Scholar 

  52. Staudt, M. et al. Two types of ipsilateral reorganization in congenital hemiparesis: a TMS and fMRI study. Brain 125, 2222–2237 (2002).

    PubMed  Google Scholar 

  53. Zewdie, E., Damji, O., Ciechanski, P., Seeger, T. & Kirton, A. Contralesional corticomotor neurophysiology in hemiparetic children with perinatal stroke. Neurorehabil. Neural Repair 31, 261–271 (2017).

    PubMed  Google Scholar 

  54. Mayston, M. J., Harrison, L. M. & Stephens, J. A. A neurophysiological study of mirror movements in adults and children. Ann. Neurol. 45, 583–594 (1999).

    CAS  PubMed  Google Scholar 

  55. Riddell, M., Kuo, H.-C., Zewdie, E. & Kirton, A. Mirror movements in children with unilateral cerebral palsy due to perinatal stroke: clinical correlates of plasticity reorganization. Dev. Med. Child Neurol. 61, 943–949 (2019).

    PubMed  Google Scholar 

  56. Craig, B. T., Hilderley, A., Kirton, A. & Carlson, H. L. Imaging developmental and interventional plasticity following perinatal stroke. Can. J. Neurol. Sci. 48, 157–171 (2021).

    PubMed  Google Scholar 

  57. Nighoghossian, N. et al. Early diagnosis of hemorrhagic transformation: diffusion/perfusion-weighted MRI versus CT scan. Cerebrovasc. Dis. 11, 151–156 (2001).

    CAS  PubMed  Google Scholar 

  58. Kirton, A. & deVeber, G. Advances in perinatal ischemic stroke. Pediatr. Neurol. 40, 205–214 (2009).

    PubMed  Google Scholar 

  59. Mackay, M. T. et al. Pediatric ASPECTS predicts outcomes following acute symptomatic neonatal arterial stroke. Neurology 94, e1259–e1270 (2020).

    PubMed  Google Scholar 

  60. Wiedemann, A. et al. Impact of stroke volume on motor outcome in neonatal arterial ischemic stroke. Eur. J. Paediatr. Neurol. 25, 97–105 (2020).

    PubMed  Google Scholar 

  61. De Vries, L. S., Van der Grond, J., Van Haastert, I. C. & Groenendaal, F. Prediction of outcome in new-born infants with arterial ischaemic stroke using diffusion-weighted magnetic resonance imaging. Neuropediatrics 36, 12–20 (2005).

    PubMed  Google Scholar 

  62. Kirton, A. et al. Diffusion imaging of cerebral diaschisis in childhood arterial ischemic stroke. Int. J. Stroke 11, 1028–1035 (2016).

    PubMed  Google Scholar 

  63. Srivastava, R. et al. Diffusion imaging of cerebral diaschisis in neonatal arterial ischemic stroke. Pediatr. Neurol. 100, 49–54 (2019).

    PubMed  Google Scholar 

  64. Yoshida, S. et al. Quantitative diffusion tensor tractography of the motor and sensory tract in children with cerebral palsy. Dev. Med. Child Neurol. 52, 935–940 (2010).

    PubMed  Google Scholar 

  65. van der Aa, N. E. et al. Does diffusion tensor imaging-based tractography at 3 months of age contribute to the prediction of motor outcome after perinatal arterial ischemic stroke? Stroke 42, 3410–3414 (2011).

    PubMed  Google Scholar 

  66. Hodge, J., Goodyear, B., Carlson, H., Wei, X.-C. & Kirton, A. Segmental diffusion properties of the corticospinal tract and motor outcome in hemiparetic children with perinatal stroke. J. Child Neurol. 32, 550–559 (2017).

    PubMed  Google Scholar 

  67. Kuczynski, A. M. et al. Sensory tractography and robot-quantified proprioception in hemiparetic children with perinatal stroke. Hum. Brain Mapp. 38, 2424–2440 (2017).

    PubMed  PubMed Central  Google Scholar 

  68. Kuczynski, A. M. et al. Corticospinal tract diffusion properties and robotic visually guided reaching in children with hemiparetic cerebral palsy. Hum. Brain Mapp. 39, 1130–1144 (2018).

    PubMed  Google Scholar 

  69. Fornito, A., Zalesky, A. & Breakspear, M. The connectomics of brain disorders. Nat. Rev. Neurosci. 16, 159–172 (2015). A review highlighting how brain network topology shapes neural responses to damage.

    CAS  PubMed  Google Scholar 

  70. Craig, B. T. et al. Developmental neuroplasticity of the white matter connectome in children with perinatal stroke. Neurology 95, e2476–e2486 (2020).

    PubMed  PubMed Central  Google Scholar 

  71. Craig, B. T. et al. Crossed cerebellar atrophy in perinatal stroke. Stroke 50, 175–177 (2019).

    Google Scholar 

  72. Craig, B. T., Carlson, H. L. & Kirton, A. Thalamic diaschisis following perinatal stroke is associated with clinical disability. Neuroimage Clin. 21, 101660 (2019).

    PubMed  PubMed Central  Google Scholar 

  73. Shinde, K., Craig, B., Hassett, J., Kirton, A. & Carlson, H. Bilateral developmental alterations in cortical morphology in children with perinatal stroke [abstract]. Stroke 52, A54 (2021).

    Google Scholar 

  74. Li, D., Hodge, J., Wei, X. C. & Kirton, A. Reduced ipsilesional cortical volumes in fetal periventricular venous infarction. Stroke 43, 1404–1407 (2012).

    PubMed  Google Scholar 

  75. Al Harrach, M. et al. Alterations in cortical morphology after neonatal stroke: compensation in the contralesional hemisphere? Dev. Neurobiol. 79, 303–316 (2019).

    PubMed  Google Scholar 

  76. Heeger, D. J. & Ress, D. What does fMRI tell us about neuronal activity? Nat. Rev. Neurosci. 3, 142–151 (2002).

    CAS  PubMed  Google Scholar 

  77. Chu, D., Huttenlocher, P. R., Levin, D. N. & Towle, V. L. Reorganization of the hand somatosensory cortex following perinatal unilateral brain injury. Neuropediatrics 31, 63–69 (2000).

    CAS  PubMed  Google Scholar 

  78. Thickbroom, G. W., Byrnes, M. L., Archer, S. A., Nagarajan, L. & Mastaglia, F. L. Differences in sensory and motor cortical organization following brain injury early in life. Ann. Neurol. 49, 320–327 (2001).

    CAS  PubMed  Google Scholar 

  79. Wilke, M. et al. Somatosensory system in two types of motor reorganization in congenital hemiparesis: topography and function. Hum. Brain Mapp. 30, 776–788 (2009).

    PubMed  Google Scholar 

  80. Guzzetta, A. et al. Reorganisation of the somatosensory system after early brain damage. Clin. Neurophysiol. 118, 1110–1121 (2007).

    CAS  PubMed  Google Scholar 

  81. Arichi, T. et al. The effects of hemorrhagic parenchymal infarction on the establishment of sensori-motor structural and functional connectivity in early infancy. Neuroradiology 56, 985–994 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Weinstein, M. et al. Understanding the relationship between brain and upper limb function in children with unilateral motor impairments: a multimodal approach. Eur. J. Paediatr. Neurol. 22, 143–154 (2018).

    PubMed  Google Scholar 

  83. Cao, Y., Vikingstad, E. M., Huttenlocher, P. R., Towle, V. L. & Levin, D. N. Functional magnetic resonance studies of the reorganization of the human hand sensorimotor area after unilateral brain injury in the perinatal period. Proc. Natl Acad. Sci. USA 91, 9612–9616 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Vandermeeren, Y. et al. Functional reorganization of brain in children affected with congenital hemiplegia: fMRI study. Neuroimage 20, 289–301 (2003).

    PubMed  Google Scholar 

  85. Van de Winckel, A. et al. How does brain activation differ in children with unilateral cerebral palsy compared to typically developing children, during active and passive movements, and tactile stimulation? An fMRI study. Res. Dev. Disabil. 34, 183–197 (2013).

    PubMed  Google Scholar 

  86. Dinomais, M. et al. The effect of video-guidance on passive movement in patients with cerebral palsy: fMRI study. Res. Dev. Disabil. 34, 3487–3496 (2013).

    PubMed  Google Scholar 

  87. van der Hoorn, A., Potgieser, A. R. E., Brouwer, O. F. & de Jong, B. M. Compensatory cerebral motor control following presumed perinatal ischemic stroke. Eur. J. Paediatr. Neurol. 18, 793–795 (2014).

    PubMed  Google Scholar 

  88. Biswal, B., Yetkin, F. Z., Haughton, V. M. & Hyde, J. S. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn. Reson. Med. 34, 537–541 (1995). One of the first demonstrations of functional connectivity in the brain at rest.

    CAS  PubMed  Google Scholar 

  89. Ilves, N. et al. Resting-state functional connectivity and cognitive impairment in children with perinatal stroke. Neural Plast. 2016, 2306406 (2016).

    PubMed  PubMed Central  Google Scholar 

  90. Woodward, K. E. et al. Sensory-motor network functional connectivity in children with unilateral cerebral palsy secondary to perinatal stroke. Neuroimage Clin. 21, 101670 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Saunders, J., Carlson, H. L., Cortese, F., Goodyear, B. G. & Kirton, A. Imaging functional motor connectivity in hemiparetic children with perinatal stroke. Hum. Brain Mapp. 40, 1632–1642 (2019).

    PubMed  Google Scholar 

  92. Manning, K. Y. et al. Resting state and diffusion neuroimaging predictors of clinical improvements following constraint-induced movement therapy in children with hemiplegic cerebral palsy. J. Child Neurol. 30, 1507–1514 (2015).

    PubMed  Google Scholar 

  93. Rae, C. D. A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra. Neurochem. Res. 39, 1–36 (2014).

    CAS  PubMed  Google Scholar 

  94. Carlson, H. L., MacMaster, F. P., Harris, A. D. & Kirton, A. Spectroscopic biomarkers of motor cortex developmental plasticity in hemiparetic children after perinatal stroke. Hum. Brain Mapp. 38, 1574–1587 (2017).

    PubMed  Google Scholar 

  95. Rajapakse, T. & Kirton, A. Non-invasive brain stimulation in children: applications and future directions. Transl. Neurosci. 4, 217–233 (2013).

    Google Scholar 

  96. Bikson, M. et al. Safety of transcranial direct current stimulation: evidence based update 2016. Brain Stimulat. 9, 641–661 (2016). A review presenting evidence on the safety of transcranial direct current stimulation.

    Google Scholar 

  97. Zewdie, E. et al. Safety and tolerability of transcranial magnetic and direct current stimulation in children: prospective single center evidence from 3.5 million stimulations. Brain Stimulat. 13, 565–575 (2020). A study presenting evidence that non-invasive brain stimulation is safe and tolerable in children.

    CAS  Google Scholar 

  98. Barker, A. T., Jalinous, R. & Freeston, I. L. Non-invasive magnetic stimulation of human motor cortex. Lancet 1, 1106–1107 (1985).

    CAS  PubMed  Google Scholar 

  99. Bestmann, S. & Krakauer, J. W. The uses and interpretations of the motor-evoked potential for understanding behaviour. Exp. Brain Res. 233, 679–689 (2015).

    PubMed  Google Scholar 

  100. Staudt, M. Reorganization of the developing human brain after early lesions. Dev. Med. Child Neurol. 49, 564 (2007).

    PubMed  Google Scholar 

  101. Wittenberg, G. F. Motor mapping in cerebral palsy. Dev. Med. Child Neurol. 51, 134–139 (2009).

    PubMed  Google Scholar 

  102. Grab, J. G. et al. Robotic TMS mapping of motor cortex in the developing brain. J. Neurosci. Methods 309, 41–54 (2018).

    CAS  PubMed  Google Scholar 

  103. Wilson, S. A., Thickbroom, G. W. & Mastaglia, F. L. Transcranial magnetic stimulation mapping of the motor cortex in normal subjects: the representation of two intrinsic hand muscles. J. Neurol. Sci. 118, 134–144 (1993).

    CAS  PubMed  Google Scholar 

  104. Pascual-Leone, A. et al. Modulation of muscle responses evoked by transcranial magnetic stimulation during the acquisition of new fine motor skills. J. Neurophysiol. 74, 1037–1045 (1995).

    CAS  PubMed  Google Scholar 

  105. Garvey, M. A. & Gilbert, D. L. Transcranial magnetic stimulation in children. Eur. J. Paediatr. Neurol. 8, 7–19 (2004).

    PubMed  Google Scholar 

  106. Hamzei, F., Liepert, J., Dettmers, C., Weiller, C. & Rijntjes, M. Two different reorganization patterns after rehabilitative therapy: an exploratory study with fMRI and TMS. Neuroimage. 31, 710–720 (2006).

    PubMed  Google Scholar 

  107. Kirton, A. Can noninvasive brain stimulation measure and modulate developmental plasticity to improve function in stroke-induced cerebral palsy? Semin. Pediatr. Neurol. 20, 116–126 (2013).

    PubMed  Google Scholar 

  108. Friel, K. M., Gordon, A. M., Carmel, J. B., Kirton, A. & Gillick, B. T. in Pediatric Brain Stimulation: Mapping and Modulating the Developing Brain (eds Kirton, A. & Gilbert, D. L.). 131–149 (Elsevier, 2016).

  109. Gillick, B. T., Friel, K. M., Menk, J. & Rudser, K. in Pediatric Brain Stimulation: Mapping and Modulating the Developing Brain (eds Kirton, A. & Gilbert, D. L.) 209–236 (Elsevier, 2016).

  110. Staudt, M. in Pediatric Brain Stimulation: Mapping and Modulating the Developing Brain (eds. Kirton, A. & Gilbert, D. L.) 183–194 (Elsevier, 2016).

  111. Maegaki, Y. et al. Central motor reorganization in cerebral palsy patients with bilateral cerebral lesions. Pediatr. Res. 45, 559–567 (1999).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Mall, V. et al. Low level of intracortical inhibition in children shown by transcranial magnetic stimulation. Neuropediatrics 35, 120–125 (2004).

    CAS  PubMed  Google Scholar 

  114. Liepert, J. Transcranial magnetic stimulation in neurorehabilitation. Acta Neurochir. Suppl. 93, 71–74 (2005).

    CAS  PubMed  Google Scholar 

  115. 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).

    PubMed  Google Scholar 

  116. Ziemann, U. Sensory-motor integration in human motor cortex at the pre-motoneurone level: beyond the age of simple MEP measurements. J. Physiol. 534, 625 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Berweck, S. et al. Abnormal motor cortex excitability in congenital stroke. Pediatr. Res. 63, 84–88 (2008).

    PubMed  Google Scholar 

  118. Pal, P. K. et al. Effect of low-frequency repetitive transcranial magnetic stimulation on interhemispheric inhibition. J. Neurophysiol. 94, 1668–1675 (2005).

    PubMed  Google Scholar 

  119. Kirton, A., deVeber, G., Gunraj, C., Friefeld, S. & Chen, R. Cortical excitability and interhemispheric inhibition in subcortical pediatric stroke: chronic reorganization and effects of contralesional inhibitory rTMS. Brain Stimul. 1, 271 (2008).

    Google Scholar 

  120. Eng, D., Zewdie, E., Ciechanski, P., Damji, O. & Kirton, A. Interhemispheric motor interactions in hemiparetic children with perinatal stroke: clinical correlates and effects of neuromodulation therapy. Clin. Neurophysiol. 129, 397–405 (2018).

    PubMed  Google Scholar 

  121. Choudhary, A. et al. Efficacy of modified constraint induced movement therapy in improving upper limb function in children with hemiplegic cerebral palsy: a randomized controlled trial. Brain Dev. 35, 870–876 (2013).

    PubMed  Google Scholar 

  122. Eliasson, A. C., Krumlinde-sundholm, L., Shaw, K. & Wang, C. Effects of constraint-induced movement therapy in young children with hemiplegic cerebral palsy: an adapted model. Dev. Med. Child Neurol. 47, 266–275 (2005).

    PubMed  Google Scholar 

  123. Taub, E., Ramey, S. L., DeLuca, S. & Echols, K. Efficacy of constraint-induced movement therapy for children with cerebral palsy with asymmetric motor impairment. Pediatrics 113, 305–312 (2004).

    PubMed  Google Scholar 

  124. Novak, I. & Honan, I. Effectiveness of paediatric occupational therapy for children with disabilities: a systematic review. Aust. Occup. Ther. J. 66, 258–273 (2019).

    PubMed  PubMed Central  Google Scholar 

  125. Sakzewski, L., Ziviani, J. & Boyd, R. N. Efficacy of upper limb therapies for unilateral cerebral palsy: a meta-analysis. Pediatrics 133, e175–e204 (2014).

    PubMed  Google Scholar 

  126. Gordon, A. M. et al. Bimanual training and constraint-induced movement therapy in children with hemiplegic cerebral palsy: a randomized trial. Neurorehabil. Neural Repair 25, 692–702 (2011).

    PubMed  Google Scholar 

  127. Hoare, B. & Greaves, S. Unimanual versus bimanual therapy in children with unilateral cerebral palsy: same, same, but different. J. Pediatr. Rehabil. Med. 10, 47–59 (2017).

    PubMed  Google Scholar 

  128. Sakzewski, L. et al. Randomized trial of constraint-induced movement therapy and bimanual training on activity outcomes for children with congenital hemiplegia. Dev. Med. Child Neurol. 53, 313–320 (2011).

    PubMed  Google Scholar 

  129. Sakzewski, L. et al. Randomized comparison trial of density and context of upper limb intensive group versus individualized occupational therapy for children with unilateral cerebral palsy. Dev. Med. Child Neurol. 57, 539–547 (2015).

    PubMed  Google Scholar 

  130. Tervahauta, M. H., Girolami, G. L. & Øberg, G. K. Efficacy of constraint-induced movement therapy compared with bimanual intensive training in children with unilateral cerebral palsy: a systematic review. Clin. Rehabil. 31, 1445–1456 (2017).

    CAS  PubMed  Google Scholar 

  131. Deppe, W. et al. Modified constraint-induced movement therapy versus intensive bimanual training for children with hemiplegia – a randomized controlled trial. Clin. Rehabil. 27, 909–920 (2013).

    PubMed  Google Scholar 

  132. Facchin, P. et al. Multisite trial comparing the efficacy of constraint-induced movement therapy with that of bimanual intensive training in children with hemiplegic cerebral palsy: postintervention results. Am. J. Phys. Med. Rehabil. 90, 539–553 (2011).

    PubMed  Google Scholar 

  133. Charles, J. & Gordon, A. M. Development of hand-arm bimanual intensive training (HABIT) for improving bimanual coordination in children with hemiplegic cerebral palsy. Dev. Med. Child Neurol. 48, 931–936 (2006).

    PubMed  Google Scholar 

  134. Brauers, L., Geijen, M. M. E., Speth, L. A. W. M. & Rameckers, E. A. A. Does intensive upper limb treatment modality Hybrid Constrained Induced Movement Therapy (H-CIMT) improve grip and pinch strength or fatigability of the affected hand? J. Pediatr. Rehabil. Med. 10, 11–17 (2017).

    CAS  PubMed  Google Scholar 

  135. Lee, G. K., Pascual, M. & Rethlefsen, S. A. A hybrid model of modified constraint induced movement therapy to improve upper extremity performance in children with unilateral upper extremity paresis: retrospective case series. Br. J. Occup. Ther. 84, 271–277 (2021).

    Google Scholar 

  136. Garzon, L. C., Switzer, L., Musselman, K. E. & Fehlings, D. The use of functional electrical stimulation to improve upper limb function in children with hemiplegic cerebral palsy: a feasibility study. J. Rehabil. Assist. Technol. Eng. 5, 2055668318768402 (2018).

    PubMed  PubMed Central  Google Scholar 

  137. Kapadia, N. M. et al. Functional electrical stimulation therapy for recovery of reaching and grasping in severe chronic pediatric stroke patients. J. Child Neurol. 29, 493–499 (2014).

    PubMed  Google Scholar 

  138. Xu, K., Wang, L., Mai, J. & He, L. Efficacy of constraint-induced movement therapy and electrical stimulation on hand function of children with hemiplegic cerebral palsy: a controlled clinical trial. Disabil. Rehabil. 34, 337–346 (2012).

    PubMed  Google Scholar 

  139. Pieber, K. et al. Functional electrical stimulation combined with botulinum toxin type A to improve hand function in children with spastic hemiparesis – a pilot study. Wien. Klin. Wochenschr. 123, 100–105 (2011).

    CAS  PubMed  Google Scholar 

  140. Ozer, K., Chesher, S. P. & Scheker, L. R. Neuromuscular electrical stimulation and dynamic bracing for the management of upper-extremity spasticity in children with cerebral palsy. Dev. Med. Child Neurol. 48, 559–563 (2006).

    PubMed  Google Scholar 

  141. Scheker, L. R., Chesher, S. P. & Ramirez, S. Neuromuscular electrical stimulation and dynamic bracing as a treatment for upper-extremity spasticity in children with cerebral palsy. J. Hand Surg. Br. 24, 226–232 (1999).

    CAS  PubMed  Google Scholar 

  142. Musselman, K. E., Manns, P., Dawe, J., Delgado, R. & Yang, J. F. The feasibility of functional electrical stimulation to improve upper extremity function in a two-year-old child with perinatal stroke: a case report. Phys. Occup. Ther. Pediatr. 38, 97–112 (2018).

    PubMed  Google Scholar 

  143. Wright, P. A. & Granat, M. H. Therapeutic effects of functional electrical stimulation of the upper limb of eight children with cerebral palsy. Dev. Med. Child Neurol. 42, 724–727 (2000).

    CAS  PubMed  Google Scholar 

  144. Yıldızgören, M. T., Nakipoğlu Yüzer, G. F., Ekiz, T. & Özgirgin, N. Effects of neuromuscular electrical stimulation on the wrist and finger flexor spasticity and hand functions in cerebral palsy. Pediatr. Neurol. 51, 360–364 (2014).

    PubMed  Google Scholar 

  145. Postans, N. et al. The combined effect of dynamic splinting and neuromuscular electrical stimulation in reducing wrist and elbow contractures in six children with cerebral palsy. Prosthet. Orthot. Int. 34, 10–19 (2010).

    PubMed  Google Scholar 

  146. Rodríguez-Reyes, G., Alessi-Montero, A., Díaz-Martínez, L., Miranda-Duarte, A. & Pérez-Sanpablo, A. I. Botulinum toxin, physical and occupational therapy, and neuromuscular electrical stimulation to treat spastic upper limb of children with cerebral palsy: a pilot study. Artif. Organs 34, 230–234 (2010).

    PubMed  Google Scholar 

  147. Metzler, M. J., Cole, L. & Kirton, A. A case of neuromuscular electrical stimulation for childhood stroke hyperkinesis: a brief report. Dev. Neurorehabil. 23, 407–411 (2020).

    PubMed  Google Scholar 

  148. Deconinck, F. J. A. et al. Reflections on mirror therapy: a systematic review of the effect of mirror visual feedback on the brain. Neurorehabil. Neural Repair 29, 349–361 (2015).

    PubMed  Google Scholar 

  149. Small, S. L., Buccino, G. & Solodkin, A. Brain repair after stroke – a novel neurological model. Nat. Rev. Neurol. 9, 698–707 (2013).

    PubMed  PubMed Central  Google Scholar 

  150. Buccino, G. Action observation treatment: a novel tool in neurorehabilitation. Phil. Trans. R. Soc. B 369, 20130185 (2014).

    PubMed  PubMed Central  Google Scholar 

  151. Buccino, G. et al. Improving upper limb motor functions through action observation treatment: a pilot study in children with cerebral palsy. Dev. Med. Child Neurol. 54, 822–828 (2012).

    PubMed  Google Scholar 

  152. Buccino, G. et al. Action observation treatment improves upper limb motor functions in children with cerebral palsy: a combined clinical and brain imaging study. Neural Plast. 2018, 4843985 (2018).

    PubMed  PubMed Central  Google Scholar 

  153. Kirkpatrick, E., Pearse, J., James, P. & Basu, A. Effect of parent-delivered action observation therapy on upper limb function in unilateral cerebral palsy: a randomized controlled trial. Dev. Med. Child Neurol. 58, 1049–1056 (2016).

    PubMed  Google Scholar 

  154. Quadrelli, E. et al. Electrophysiological correlates of action observation treatment in children with cerebral palsy: a pilot study. Dev. Neurobiol. 79, 934–948 (2019).

    PubMed  Google Scholar 

  155. Simon-Martinez, C. et al. Randomized controlled trial combining constraint-induced movement therapy and action-observation training in unilateral cerebral palsy: clinical effects and influencing factors of treatment response. Ther. Adv. Neurol. Disord. 13, 1756286419898065 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Bruchez, R. et al. Mirror therapy in children with hemiparesis: a randomized observer-blinded trial. Dev. Med. Child Neurol. 58, 970–978 (2016).

    PubMed  Google Scholar 

  157. Kara, O. K. et al. Combined effects of mirror therapy and exercises on the upper extremities in children with unilateral cerebral palsy: a randomized controlled trial. Dev. Neurorehabil. 23, 253–264 (2020).

    PubMed  Google Scholar 

  158. Bishop, L., Gordon, A. M. & Kim, H. Hand robotic therapy in children with hemiparesis: a pilot study. Am. J. Phys. Med. Rehabil. 96, 1–7 (2017).

    PubMed  Google Scholar 

  159. Gerber, C. N., Kunz, B. & van Hedel, H. J. A. Preparing a neuropediatric upper limb exergame rehabilitation system for home-use: a feasibility study. J. Neuroeng. Rehabil. 13, 33 (2016).

    PubMed  PubMed Central  Google Scholar 

  160. Kolb, B., Mychasiuk, R., Williams, P. & Gibb, R. Brain plasticity and recovery from early cortical injury. Dev. Med. Child Neurol. 53, 4–8 (2011).

    PubMed  Google Scholar 

  161. Dusing, S. C. et al. Supporting play exploration and early developmental intervention versus usual care to enhance development outcomes during the transition from the neonatal intensive care unit to home: a pilot randomized controlled trial. BMC Pediatr. 18, 46 (2018).

    PubMed  PubMed Central  Google Scholar 

  162. Friel, K. M., Williams, P. T. J. A., Serradj, N., Chakrabarty, S. & Martin, J. H. Activity-based therapies for repair of the corticospinal system injured during development. Front. Neurol. 5, 229 (2014).

    PubMed  PubMed Central  Google Scholar 

  163. Basu, A. P. Early intervention after perinatal stroke: opportunities and challenges. Dev. Med. Child Neurol. 56, 516–521 (2014).

    PubMed  PubMed Central  Google Scholar 

  164. Finch-Edmondson, M., Morgan, C., Hunt, R. W. & Novak, I. Emergent prophylactic, reparative and restorative brain interventions for infants born preterm with cerebral palsy. Front. Physiol. 10, 15 (2019).

    PubMed  PubMed Central  Google Scholar 

  165. Ryll, U. C. et al. Early prediction of unilateral cerebral palsy in infants with asymmetric perinatal brain injury – model development and internal validation. Eur. J. Paediatr. Neurol. 23, 621–628 (2019).

    PubMed  Google Scholar 

  166. Basu, A. P. et al. Feasibility trial of an early therapy in perinatal stroke (eTIPS). BMC Neurol. 18, 102 (2018).

    PubMed  PubMed Central  Google Scholar 

  167. Eliasson, A.-C. et al. The effectiveness of Baby-CIMT in infants younger than 12 months with clinical signs of unilateral-cerebral palsy; an explorative study with randomized design. Res. Dev. Disabil. 72, 191–201 (2017).

    PubMed  Google Scholar 

  168. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04698395 (2021).

  169. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04330859 (2021).

  170. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04642872 (2020).

  171. US National Library of Medicine. CilinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03518736 (2020).

  172. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03910075 (2021).

  173. Dunst, C. J. & Dempsey, I. Family–professional partnerships and parenting competence, confidence, and enjoyment. Int. J. Disabil. Dev. Educ. 54, 305–318 (2007).

    Google Scholar 

  174. Vroland-Nordstrand, K., Eliasson, A.-C., Jacobsson, H., Johansson, U. & Krumlinde-Sundholm, L. Can children identify and achieve goals for intervention? A randomized trial comparing two goal-setting approaches. Dev. Med. Child Neurol. 58, 589–596 (2016).

    PubMed  Google Scholar 

  175. Bandura, A. & Locke, E. A. Negative self-efficacy and goal effects revisited. J. Appl. Psychol. 88, 87–99 (2003).

    PubMed  Google Scholar 

  176. Majnemer, A., Shevell, M., Law, M., Poulin, C. & Rosenbaum, P. Level of motivation in mastering challenging tasks in children with cerebral palsy. Dev. Med. Child Neurol. 52, 1120–1126 (2010).

    PubMed  Google Scholar 

  177. Vroland-Nordstrand, K., Eliasson, A.-C., Krumlinde-Sundholm, L. & Johansson, U. Parents’ experiences of conducting a goal-directed intervention based on children’s self-identified goals, a qualitative study. Scand. J. Occup. Ther. 25, 243–251 (2018).

    PubMed  Google Scholar 

  178. Sakzewski, L., Boyd, R. & Ziviani, J. Clinimetric properties of participation measures for 5- to 13-year-old children with cerebral palsy: a systematic review. Dev. Med. Child Neurol. 49, 232–240 (2007).

    PubMed  Google Scholar 

  179. Metzler, M. J. et al. Goals of children with unilateral cerebral palsy in a brain stimulation arm rehabilitation trial. Dev. Med. Child Neurol. 63, 584–591 (2021).

    PubMed  Google Scholar 

  180. Beani, E. et al. Actigraph assessment for measuring upper limb activity in unilateral cerebral palsy. J. Neuroeng. Rehabil. 16, 30 (2019).

    PubMed  PubMed Central  Google Scholar 

  181. Braito, I. et al. Assessment of upper limb use in children with typical development and neurodevelopmental disorders by inertial sensors: a systematic review. J. Neuroeng. Rehabil. 15, 94 (2018).

    PubMed  PubMed Central  Google Scholar 

  182. Coker-Bolt, P. et al. Exploring the feasibility and use of accelerometers before, during, and after a camp-based CIMT program for children with cerebral palsy. J. Pediatr. Rehabil. Med. 10, 27–36 (2017).

    PubMed  Google Scholar 

  183. Kirton, A. et al. Brain stimulation and constraint for perinatal stroke hemiparesis: the PLASTIC CHAMPS trial. Neurology 86, 1659–1667 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Kirton, A. et al. Transcranial direct current stimulation for children with perinatal stroke and hemiparesis. Neurology 88, 259–267 (2017).

    PubMed  Google Scholar 

  185. Sakzewski, L., Provan, K., Ziviani, J. & Boyd, R. N. Comparison of dosage of intensive upper limb therapy for children with unilateral cerebral palsy: how big should the therapy pill be? Res. Dev. Disabil. 37, 9–16 (2015).

    PubMed  Google Scholar 

  186. Charles, J. R. & Gordon, A. M. A repeated course of constraint-induced movement therapy results in further improvement. Dev. Med. Child Neurol. 49, 770–773 (2007).

    PubMed  Google Scholar 

  187. DeLuca, S. C., Ramey, S. L., Trucks, M. R. & Wallace, D. A. Multiple treatments of pediatric constraint-induced movement therapy (pCIMT): a clinical cohort study. Am. J. Occup. Ther. 69, 6906180010 (2015).

    Google Scholar 

  188. Gordon, A. M. To constrain or not to constrain, and other stories of intensive upper extremity training for children with unilateral cerebral palsy. Dev. Med. Child Neurol. 53, 56–61 (2011).

    PubMed  Google Scholar 

  189. Christman, E., McAllister, K., Claar, K., Kaufman, S. & Page, S. J. Occupational therapists’ opinions of two pediatric constraint-induced movement therapy protocols. Am. J. Occup. Ther. 69, 6906180020 (2015).

    Google Scholar 

  190. Sakzewski, L., Ziviani, J. & Boyd, R. N. Translating evidence to increase quality and dose of upper limb therapy for children with unilateral cerebral palsy: a pilot study. Phys. Occup. Ther. Pediatr. 36, 305–329 (2016).

    PubMed  Google Scholar 

  191. Chen, H. et al. Improvement of upper extremity motor control and function after home-based constraint induced therapy in children with unilateral cerebral palsy: immediate and long-term effects. Arch. Phys. Med. Rehabil. 95, 1423–1432 (2014).

    PubMed  Google Scholar 

  192. Psychouli, P. & Kennedy, C. R. Modified constraint-induced movement therapy as a home-based intervention for children with cerebral palsy. Pediatr. Phys. Ther. 28, 154–160 (2016).

    PubMed  Google Scholar 

  193. Brandão, M. B. et al. Does dosage matter? A pilot study of hand-arm bimanual intensive training (HABIT) dose and dosing schedule in children with unilateral cerebral palsy. Phys. Occup. Ther. Pediatr. 38, 227–242 (2018).

    PubMed  Google Scholar 

  194. Sakzewski, L., Ziviani, J. & Boyd, R. N. Best responders after intensive upper-limb training for children with unilateral cerebral palsy. Arch. Phys. Med. Rehabil. 92, 578–584 (2011).

    PubMed  Google Scholar 

  195. Islam, M. et al. Is outcome of constraint-induced movement therapy in unilateral cerebral palsy dependent on corticomotor projection pattern and brain lesion characteristics? Dev. Med. Child Neurol. 56, 252–258 (2014).

    PubMed  Google Scholar 

  196. Kuhnke, N. et al. Do patients with congenital hemiparesis and ipsilateral corticospinal projections respond differently to constraint-induced movement therapy? Dev. Med. Child Neurol. 50, 898–903 (2008).

    CAS  PubMed  Google Scholar 

  197. Schertz, M. et al. Imaging predictors of improvement from a motor learning-based intervention for children with unilateral cerebral palsy. Neurorehabil. Neural Repair 30, 647–660 (2016).

    PubMed  Google Scholar 

  198. Smorenburg, A. R. P. et al. Does corticospinal tract connectivity influence the response to intensive bimanual therapy in children with unilateral cerebral palsy? Neurorehabil. Neural Repair 31, 250–260 (2016).

    PubMed  PubMed Central  Google Scholar 

  199. Silva, L. M., Silva, K. M. S., Lira-Bandeira, W. G., Costa-Ribeiro, A. C. & Araújo-Neto, S. A. Localizing the primary motor cortex of the hand by the 10-5 and 10-20 systems for neurostimulation: an MRI study. Clin. EEG Neurosci. https://doi.org/10.1177/1550059420934590 (2020).

    Article  PubMed  Google Scholar 

  200. Rich, T. L. et al. Determining electrode placement for transcranial direct current stimulation: a comparison of EEG- versus TMS-guided methods. Clin. EEG Neurosci. 48, 367–375 (2017).

    PubMed  PubMed Central  Google Scholar 

  201. Friel, K. M. et al. Skilled bimanual training drives motor cortex plasticity in children with unilateral cerebral palsy. Neurorehabil. Neural Repair 30, 834–844 (2016).

    PubMed  PubMed Central  Google Scholar 

  202. Polanía, R., Paulus, W. & Nitsche, M. A. Modulating cortico-striatal and thalamo-cortical functional connectivity with transcranial direct current stimulation. Hum. Brain Mapp. 33, 2499–2508 (2012).

    PubMed  Google Scholar 

  203. Dukelow, S. & Kirton, A. Enhancing stroke recovery across the life span with noninvasive neurostimulation. J. Clin. Neurophysiol. 37, 150–163 (2020).

    PubMed  Google Scholar 

  204. Pollock, A. et al. Interventions for improving upper limb function after stroke. Cochrane Database Syst. Rev. 11, CD010820 (2014).

    Google Scholar 

  205. Moura, R. C. F. et al. Effects of a single session of transcranial direct current stimulation on upper limb movements in children with cerebral palsy: a randomized, sham-controlled study. Dev. Neurorehabil. 20, 368–375 (2017).

    PubMed  Google Scholar 

  206. Gillick, B. T. et al. Safety and feasibility of transcranial direct current stimulation in pediatric hemiparesis: randomized controlled preliminary study. Phys. Ther. 95, 337–349 (2015).

    PubMed  Google Scholar 

  207. 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).

    PubMed  Google Scholar 

  208. Lefaucheur, J.-P. et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin. Neurophysiol. 125, 2150–2206 (2014).

    PubMed  Google Scholar 

  209. Ridding, M. C. & Ziemann, U. Determinants of the induction of cortical plasticity by non-invasive brain stimulation in healthy subjects. J. Physiol. 588, 2291–2304 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Zewdie, E. & Kirton, A. in Pediatric Brain Stimulation: Mapping and Modulating the Developing Brain (eds Kirton, A. & Gilbert, D. L.) 3–22 (Elsevier, 2016).

  211. Xiang, H., Sun, J., Tang, X., Zeng, K. & Wu, X. The effect and optimal parameters of repetitive transcranial magnetic stimulation on motor recovery in stroke patients: a systematic review and meta-analysis of randomized controlled trials. Clin. Rehabil. 33, 847–864 (2019).

    PubMed  Google Scholar 

  212. Wang, Q., Zhang, D., Zhao, Y.-Y., Hai, H. & Ma, Y.-W. Effects of high-frequency repetitive transcranial magnetic stimulation over the contralesional motor cortex on motor recovery in severe hemiplegic stroke: a randomized clinical trial. Brain Stimul. 13, 979–986 (2020).

    PubMed  Google Scholar 

  213. Graef, P., Dadalt, M. L. R., Rodrigués, D. A. M. D. S., Stein, C. & Pagnussat, A. D. S. Transcranial magnetic stimulation combined with upper-limb training for improving function after stroke: a systematic review and meta-analysis. J. Neurol. Sci. 369, 149–158 (2016).

    PubMed  Google Scholar 

  214. Zhang, L. et al. Low-frequency repetitive transcranial magnetic stimulation for stroke-induced upper limb motor deficit: a meta-analysis. Neural Plast. 2017, 2758097 (2017).

    PubMed  PubMed Central  Google Scholar 

  215. Zhang, L. et al. Short- and long-term effects of repetitive transcranial magnetic stimulation on upper limb motor function after stroke: a systematic review and meta-analysis. Clin. Rehabil. 31, 1137–1153 (2017).

    PubMed  Google Scholar 

  216. Sung, W. H. et al. Efficacy of coupling inhibitory and facilitatory repetitive transcranial magnetic stimulation to enhance motor recovery in hemiplegic stroke patients. Stroke 44, 1375–1382 (2013).

    PubMed  Google Scholar 

  217. Gillick, B. T. et al. Safety of primed repetitive transcranial magnetic stimulation and modified constraint-induced movement therapy in a randomized controlled trial in pediatric hemiparesis. Arch. Phys. Med. Rehabil. 96, S104–S113 (2015).

    PubMed  Google Scholar 

  218. Hordacre, B. & Goldsworthy, M. R. Commentary: cooperation not competition: bihemispheric tDCS and fMRI show role for ipsilateral hemisphere in motor learning. Front. Hum. Neurosci. 12, 97 (2018).

    PubMed  PubMed Central  Google Scholar 

  219. Valle, A. C. et al. Low and high frequency repetitive transcranial magnetic stimulation for the treatment of spasticity. Dev. Med. Child Neurol. 49, 534–538 (2007).

    PubMed  Google Scholar 

  220. Batsikadze, G., Moliadze, V., Paulus, W., Kuo, M.-F. & Nitsche, M. A. Partially non-linear stimulation intensity-dependent effects of direct current stimulation on motor cortex excitability in humans. J. Physiol. 591, 1987–2000 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Lang, N., Nitsche, M. A., Paulus, W., Rothwell, J. C. & Lemon, R. N. Effects of transcranial direct current stimulation over the human motor cortex on corticospinal and transcallosal excitability. Exp. Brain Res. 156, 439–443 (2004).

    CAS  PubMed  Google Scholar 

  222. Nitsche, M. A. & Paulus, W. Excitability changes induced in the human motor cortex by weak transcranial direct current stimulation. J. Physiol. 527, 633–639 (2000). A study that found early evidence demonstrating in the intact human the possibility of a non-invasive modulation of motor cortex excitability by the application of weak direct current through the scalp.

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Nitsche, M. A. & Paulus, W. Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology 57, 1899–1901 (2001).

    CAS  PubMed  Google Scholar 

  224. Bastani, A. & Jaberzadeh, S. Differential modulation of corticospinal excitability by different current densities of anodal transcranial direct current stimulation. PLoS ONE 8, e72254 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Reis, J. et al. Noninvasive cortical stimulation enhances motor skill acquisition over multiple days through an effect on consolidation. Proc. Natl Acad. Sci. USA 106, 1590–1595 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Boggio, P. S. et al. Enhancement of non-dominant hand motor function by anodal transcranial direct current stimulation. Neurosci. Lett. 404, 232–236 (2006).

    CAS  PubMed  Google Scholar 

  227. Vines, B. W., Nair, D. G. & Schlaug, G. Contralateral and ipsilateral motor effects after transcranial direct current stimulation. Neuroreport 17, 671–674 (2006).

    PubMed  Google Scholar 

  228. Stagg, C. J. et al. Polarity and timing-dependent effects of transcranial direct current stimulation in explicit motor learning. Neuropsychologia 49, 800–804 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Hummel, F. et al. Effects of non-invasive cortical stimulation on skilled motor function in chronic stroke. Brain 128, 490–499 (2005).

    PubMed  Google Scholar 

  230. Hummel, F. & Cohen, L. G. Improvement of motor function with noninvasive cortical stimulation in a patient with chronic stroke. Neurorehabil. Neural Repair 19, 14–19 (2005).

    PubMed  Google Scholar 

  231. Fregni, S. et al. Transcranial direct current stimulation of the unaffected hemisphere in stroke patients. Neuroreport 16, 1551–1555 (2005).

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  233. Tedesco Triccas, L. et al. Multiple sessions of transcranial direct current stimulation and upper extremity rehabilitation in stroke: a review and meta-analysis. Clin. Neurophysiol. 127, 946–955 (2016).

    CAS  PubMed  Google Scholar 

  234. Elsner, B., Kwakkel, G., Kugler, J. & Mehrholz, J. Transcranial direct current stimulation (tDCS) for improving capacity in activities and arm function after stroke: a network meta-analysis of randomised controlled trials. J. Neuroeng. Rehabil. 14, 95 (2017).

    PubMed  PubMed Central  Google Scholar 

  235. Ciechanski, P., Carlson, H. L., Yu, S. S. & Kirton, A. Modeling transcranial direct-current stimulation-induced electric fields in children and adults. Front. Hum. Neurosci. 12, 268 (2018).

    PubMed  PubMed Central  Google Scholar 

  236. Moliadze, V. et al. Stimulation intensities of transcranial direct current stimulation have to be adjusted in children and adolescents. Clin. Neurophysiol. 126, 1392–1399 (2015).

    PubMed  Google Scholar 

  237. Cole, L. et al. Effects of high-definition and conventional transcranial direct-current stimulation on motor learning in children. Front. Neurosci. 12, 787 (2018).

    PubMed  PubMed Central  Google Scholar 

  238. Ciechanski, P. & Kirton, A. Transcranial direct-current stimulation can enhance motor learning in children. Cereb. Cortex 27, 2758–2767 (2017).

    PubMed  Google Scholar 

  239. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03216837 (2019).

  240. Young, S. J., Bertucco, M. & Sanger, T. D. Cathodal transcranial direct current stimulation in children with dystonia: a sham-controlled study. J. Child Neurol. 29, 232–239 (2014).

    PubMed  Google Scholar 

  241. Grecco, L. A. C. et al. Effect of a single session of transcranial direct-current stimulation on balance and spatiotemporal gait variables in children with cerebral palsy: a randomized sham-controlled study. Braz. J. Phys. Ther. 18, 419–427 (2014).

    PubMed  PubMed Central  Google Scholar 

  242. Lazzari, R. D. et al. Effect of a single session of transcranial direct-current stimulation combined with virtual reality training on the balance of children with cerebral palsy: a randomized, controlled, double-blind trial. J. Phys. Ther. Sci. 27, 763–768 (2015).

    PubMed  PubMed Central  Google Scholar 

  243. Grecco, L. A. C. et al. Effects of anodal transcranial direct current stimulation combined with virtual reality for improving gait in children with spastic diparetic cerebral palsy: a pilot, randomized, controlled, double-blind, clinical trial. Clin. Rehabil. 29, 1212–1223 (2015).

    Google Scholar 

  244. Duarte, N. et al. Effect of transcranial direct-current stimulation combined with treadmill training on balance and functional performance in children with cerebral palsy: a double-blind randomized controlled trial. PLoS ONE 9, e105777 (2014).

    PubMed Central  Google Scholar 

  245. Young, S. J., Bertucco, M., Sheehan-Stross, R. & Sanger, T. D. Cathodal transcranial direct current stimulation in children with dystonia: a pilot open-label trial. J. Child Neurol. 28, 1238–1244 (2013).

    PubMed  Google Scholar 

  246. Sterling, C. et al. Structural neuroplastic change after constraint-induced movement therapy in children with cerebral palsy. Pediatrics 131, e1664–e1669 (2013).

    PubMed  Google Scholar 

  247. Zatorre, R. J., Fields, R. D. & Johansen-Berg, H. Plasticity in gray and white: neuroimaging changes in brain structure during learning. Nat. Neurosci. 15, 528–536 (2012). A review presenting neuroimaging findings of structural plasticity and a discussion of cellular and molecular level changes that could underlie observed imaging effects.

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Fields, R. D. Neuroscience. Change in the brain’s white matter. Science 330, 768–769 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Fields, R. D. A new mechanism of nervous system plasticity: activity-dependent myelination. Nat. Rev. Neurosci. 16, 756–767 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. Kwon, J.-Y. et al. Changes in diffusion tensor tractographic findings associated with constraint-induced movement therapy in young children with cerebral palsy. Clin. Neurophysiol. 125, 2397–2403 (2014).

    PubMed  Google Scholar 

  251. Kim, J. H., Kwon, Y. M. & Son, S. M. Motor function outcomes of pediatric patients with hemiplegic cerebral palsy after rehabilitation treatment: a diffusion tensor imaging study. Neural Regen. Res. 10, 624–630 (2015).

    PubMed  PubMed Central  Google Scholar 

  252. Rickards, T. et al. Diffusion tensor imaging study of the response to constraint-induced movement therapy of children with hemiparetic cerebral palsy and adults with chronic stroke. Arch. Phys. Med. Rehabil. 95, 506–514.e1 (2014).

    PubMed  Google Scholar 

  253. Golomb, M. R. et al. In-home virtual reality videogame telerehabilitation in adolescents with hemiplegic cerebral palsy. Arch. Phys. Med. Rehabil. 91, 1–8.e1 (2010).

    PubMed  Google Scholar 

  254. Juenger, H. et al. Cortical neuromodulation by constraint-induced movement therapy in congenital hemiparesis: an FMRI study. Neuropediatrics 38, 130–136 (2007).

    CAS  PubMed  Google Scholar 

  255. Sutcliffe, T. L., Logan, W. J. & Fehlings, D. L. Pediatric constraint-induced movement therapy is associated with increased contralateral cortical activity on functional magnetic resonance imaging. J. Child Neurol. 24, 1230–1235 (2009).

    PubMed  Google Scholar 

  256. Sutcliffe, T. L., Gaetz, W. C., Logan, W. J., Cheyne, D. O. & Fehlings, D. L. Cortical reorganization after modified constraint-induced movement therapy in pediatric hemiplegic cerebral palsy. J. Child Neurol. 22, 1281–1287 (2007).

    PubMed  Google Scholar 

  257. Walther, M. et al. Motor cortex plasticity in ischemic perinatal stroke: a transcranial magnetic stimulation and functional MRI study. Pediatr. Neurol. 41, 171–178 (2009).

    PubMed  Google Scholar 

  258. You, S. H. et al. Cortical reorganization induced by virtual reality therapy in a child with hemiparetic cerebral palsy. Dev. Med. Child Neurol. 47, 628–635 (2005).

    PubMed  Google Scholar 

  259. Bleyenheuft, Y. et al. Capturing neuroplastic changes after bimanual intensive rehabilitation in children with unilateral spastic cerebral palsy: a combined DTI, TMS and fMRI pilot study. Res. Dev. Disabil. 43–44, 136–149 (2015).

    PubMed  PubMed Central  Google Scholar 

  260. Cope, S. M. et al. Upper limb function and brain reorganization after constraint-induced movement therapy in children with hemiplegia. Dev. Neurorehabil. 13, 19–30 (2010).

    PubMed  Google Scholar 

  261. Juenger, H. et al. Two types of exercise-induced neuroplasticity in congenital hemiparesis: a transcranial magnetic stimulation, functional MRI, and magnetoencephalography study. Dev. Med. Child Neurol. 55, 941–951 (2013).

    PubMed  Google Scholar 

  262. Weinstein, M. et al. Brain plasticity following intensive bimanual therapy in children with hemiparesis: preliminary evidence. Neural Plast. 2015, 798481 (2015).

    PubMed  PubMed Central  Google Scholar 

  263. Manning, K. Y. et al. Neuroplastic sensorimotor resting state network reorganization in children with hemiplegic cerebral palsy treated with constraint-induced movement therapy. J. Child Neurol. 31, 220–226 (2016).

    PubMed  Google Scholar 

  264. Reid, L. B. et al. Measuring neuroplasticity associated with cerebral palsy rehabilitation: an MRI based power analysis. Int. J. Dev. Neurosci. 58, 17–25 (2017).

    PubMed  Google Scholar 

  265. Carlson, H. L., Ciechanski, P., Harris, A. D., MacMaster, F. P. & Kirton, A. Changes in spectroscopic biomarkers after transcranial direct current stimulation in children with perinatal stroke. Brain Stimul. 11, 94–103 (2017).

    PubMed  Google Scholar 

  266. Auvichayapat, P. et al. Transient changes in brain metabolites after transcranial direct current stimulation in spastic cerebral palsy: a pilot study. Front. Neurol. 8, 366 (2017).

    PubMed  PubMed Central  Google Scholar 

  267. Stagg, C. J. & Johansen-Berg, H. Studying the effects of transcranial direct-current stimulation in stroke recovery using magnetic resonance imaging. Front. Hum. Neurosci. 7, 857 (2013).

    PubMed  PubMed Central  Google Scholar 

  268. Zaghi, S., Acar, M., Hultgren, B., Boggio, P. S. & Fregni, F. Noninvasive brain stimulation with low-intensity electrical currents: putative mechanisms of action for direct and alternating current stimulation. Neuroscientist 16, 285–307 (2010).

    PubMed  Google Scholar 

  269. Lee, W. et al. Image-guided transcranial focused ultrasound stimulates human primary somatosensory cortex. Sci. Rep. 5, 8743 (2015).

    PubMed  PubMed Central  Google Scholar 

  270. Oliviero, A. et al. Transcranial static magnetic field stimulation of the human motor cortex. J. Physiol. 589, 4949–4958 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  271. Hollis, A. et al. Transcranial static magnetic field stimulation of the motor cortex in children. Front. Neurosci. 14, 464 (2020).

    PubMed  PubMed Central  Google Scholar 

  272. Biasiucci, A. et al. Brain-actuated functional electrical stimulation elicits lasting arm motor recovery after stroke. Nat. Commun. 9, 2421 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  273. Zhang, J., Jadavji, Z., Zewdie, E. & Kirton, A. Evaluating if children can use simple brain computer interfaces. Front. Hum. Neurosci. 13, 24 (2019).

    PubMed  PubMed Central  Google Scholar 

  274. Chen, W.-L. et al. Functional near-infrared spectroscopy and its clinical application in the field of neuroscience: advances and future directions. Front. Neurosci. 14, 724 (2020).

    PubMed  PubMed Central  Google Scholar 

  275. Démas, J. et al. Mu rhythm: state of the art with special focus on cerebral palsy. Ann. Phys. Rehabil. Med. 63, 439–446 (2019).

    PubMed  Google Scholar 

  276. Wagenaar, N. et al. Brain activity and cerebral oxygenation after perinatal arterial ischemic stroke are associated with neurodevelopment. Stroke 50, 2668–2676 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  277. Nevalainen, P. et al. Bedside neurophysiological tests can identify neonates with stroke leading to cerebral palsy. Clin. Neurophysiol. 130, 759–766 (2019).

    PubMed  Google Scholar 

  278. Kuczynski, A. M., Dukelow, S. P., Semrau, J. A. & Kirton, A. Robotic quantification of position sense in children with perinatal stroke. Neurorehabil. Neural Repair 30, 762–772 (2016).

    PubMed  Google Scholar 

  279. Kuczynski, A. M., Semrau, J. A., Kirton, A. & Dukelow, S. P. Kinesthetic deficits after perinatal stroke: robotic measurement in hemiparetic children. J. Neuroeng. Rehabil. 14, 13 (2017).

    PubMed  PubMed Central  Google Scholar 

  280. Wagenaar, N. et al. Promoting neuroregeneration after perinatal arterial ischemic stroke: neurotrophic factors and mesenchymal stem cells. Pediatr. Res. 83, 372–384 (2018).

    CAS  PubMed  Google Scholar 

  281. Benders, M. J. et al. Feasibility and safety of erythropoietin for neuroprotection after perinatal arterial ischemic stroke. J. Pediatr. 164, 481–486.e1–2 (2014).

    CAS  PubMed  Google Scholar 

  282. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03171818 (2020).

  283. McAdams, R. M. & Berube, M. W. Emerging therapies and management for neonatal encephalopathy–controversies and current approaches. J. Perinatol. 41, 661–674 (2021).

    PubMed  Google Scholar 

  284. EFFECTS Trial Collaboration. Safety and efficacy of fluoxetine on functional recovery after acute stroke (EFFECTS): a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 19, 661–669 (2020).

    Google Scholar 

  285. Bemister, T. B., Brooks, B. L. & Kirton, A. Development, reliability, and validity of the Alberta Perinatal Stroke Project Parental Outcome Measure. Pediatr. Neurol. 51, 43–52 (2014).

    PubMed  Google Scholar 

  286. Murias, K. et al. Spatial orientation and navigation in children with perinatal stroke. Dev. Neuropsychol. 42, 160–171 (2017).

    PubMed  Google Scholar 

  287. Thareja, T., Ballantyne, A. O. & Trauner, D. A. Spatial analysis after perinatal stroke: patterns of neglect and exploration in extra-personal space. Brain Cogn. 79, 107–116 (2012).

    PubMed  PubMed Central  Google Scholar 

  288. Ballantyne, A. O. & Trauner, D. A. Facial recognition in children after perinatal stroke. Neuropsychiatry Neuropsychol. Behav. Neurol. 12, 82–87 (1999).

    CAS  PubMed  Google Scholar 

  289. Ballantyne, A. O., Spilkin, A. M., Hesselink, J. & Trauner, D. A. Plasticity in the developing brain: intellectual, language and academic functions in children with ischaemic perinatal stroke. Brain 131, 2975–2985 (2008).

    PubMed  PubMed Central  Google Scholar 

  290. Trauner, D. A., Eshagh, K., Ballantyne, A. O. & Bates, E. Early language development after peri-natal stroke. Brain Lang. 127, 399–403 (2013).

    PubMed  Google Scholar 

  291. Trauner, D. A., Ballantyne, A., Friedland, S. & Chase, C. Disorders of affective and linguistic prosody in children after early unilateral brain damage. Ann. Neurol. 39, 361–367 (1996).

    CAS  PubMed  Google Scholar 

  292. Thal, D. J. et al. Early lexical development in children with focal brain injury. Brain Lang. 40, 491–527 (1991).

    CAS  PubMed  Google Scholar 

  293. Ballantyne, A. O., Spilkin, A. M. & Trauner, D. A. Language outcome after perinatal stroke: does side matter? Child Neuropsychol. 13, 494–509 (2007).

    PubMed  Google Scholar 

  294. Westmacott, R., Barry, V., MacGregor, D. & deVeber, G. Intellectual function in preschool and school-aged children with a history of acute neonatal stroke [abstract P445]. Stroke 38, 581 (2007).

    Google Scholar 

  295. Westmacott, R., MacGregor, D., Askalan, R. & deVeber, G. Late emergence of cognitive deficits after unilateral neonatal stroke. Stroke 40, 2012–2019 (2009).

    PubMed  Google Scholar 

  296. Fuentes, A., Deotto, A., Desrocher, M., deVeber, G. & Westmacott, R. Determinants of cognitive outcomes of perinatal and childhood stroke: a review. Child Neuropsychol. 22, 1–38 (2016).

    PubMed  Google Scholar 

  297. Murias, K., Brooks, B., Kirton, A. & Iaria, G. A review of cognitive outcomes in children following perinatal stroke. Dev. Neuropsychol. 39, 131–157 (2014).

    PubMed  Google Scholar 

  298. van Buuren, L. M. et al. Cognitive outcome in childhood after unilateral perinatal brain injury. Dev. Med. Child Neurol. 55, 934–940 (2013).

    PubMed  Google Scholar 

  299. Bosenbark, D. D. et al. Clinical predictors of attention and executive functioning outcomes in children after perinatal arterial ischemic stroke. Pediatr. Neurol. 69, 79–86 (2017).

    PubMed  Google Scholar 

  300. Ricci, D. et al. Cognitive outcome at early school age in term-born children with perinatally acquired middle cerebral artery territory infarction. Stroke 39, 403–410 (2008).

    PubMed  Google Scholar 

  301. Guzzetta, A., Fiori, S., Scelfo, D., Conti, E. & Bancale, A. Reorganization of visual fields after periventricular haemorrhagic infarction: potentials and limitations. Dev. Med. Child Neurol. 55, 23–26 (2013).

    PubMed  Google Scholar 

  302. James, S., Ziviani, J., Ware, R. S. & Boyd, R. N. Relationships between activities of daily living, upper limb function, and visual perception in children and adolescents with unilateral cerebral palsy. Dev. Med. Child Neurol. 57, 852–857 (2015).

    PubMed  Google Scholar 

  303. Mercuri, E. et al. Neonatal cerebral infarction and visual function at school age. Arch. Dis. Child. Fetal Neonatal Ed. 88, F487–F491 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  304. Koenraads, Y. et al. Prediction of visual field defects in newborn infants with perinatal arterial ischemic stroke using early MRI and DTI-based tractography of the optic radiation. Eur. J. Paediatr. Neurol. 20, 309–318 (2016).

    PubMed  Google Scholar 

  305. Laugesaar, R. et al. Epilepsy after perinatal stroke with different vascular subtypes. Epilepsia Open 3, 193–202 (2018).

    PubMed  PubMed Central  Google Scholar 

  306. Rattani, A. et al. Incidence of epilepsy and associated risk factors in perinatal ischemic stroke survivors. Pediatr. Neurol. 90, 44–55 (2019).

    PubMed  Google Scholar 

  307. Wanigasinghe, J. et al. Epilepsy in hemiplegic cerebral palsy due to perinatal arterial ischaemic stroke. Dev. Med. Child Neurol. 52, 1021–1027 (2010).

    PubMed  Google Scholar 

  308. Mineyko, A. et al. Neuropsychological outcome in perinatal stroke associated with epileptiform discharges in sleep. Can. J. Neurol. Sci. 44, 358–365 (2017).

    PubMed  Google Scholar 

  309. Sherman, V. et al. Feeding and swallowing impairment in children with stroke and unilateral cerebral palsy: a systematic review. Dev. Med. Child Neurol. 61, 761–769 (2019).

    PubMed  Google Scholar 

  310. Wrightson, J. G., Zewdie, E., Kuo, H.-C., Millet, G. Y. & Kirton, A. Fatigue in children with perinatal stroke: clinical and neurophysiological associations. Dev. Med. Child Neurol. 62, 234–240 (2020).

    PubMed  Google Scholar 

  311. Horwood, L. et al. Behavioral difficulties, sleep problems, and nighttime pain in children with cerebral palsy. Res. Dev. Disabil. 95, 103500 (2019).

    PubMed  Google Scholar 

  312. Westbom, L., Rimstedt, A. & Nordmark, E. Assessments of pain in children and adolescents with cerebral palsy: a retrospective population-based registry study. Dev. Med. Child Neurol. 59, 858–863 (2017).

    PubMed  Google Scholar 

  313. Doralp, S. & Bartlett, D. J. The prevalence, distribution, and effect of pain among adolescents with cerebral palsy. Pediatr. Phys. Ther. 22, 26–33 (2010).

    PubMed  Google Scholar 

  314. Lõo, S. et al. Long-term neurodevelopmental outcome after perinatal arterial ischemic stroke and periventricular venous infarction. Eur. J. Paediatr. Neurol. 22, 1006–1015 (2018).

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Calgary Pediatric Stroke Program, Alberta Children’s Hospital, Calgary, AB, Canada

    Adam Kirton, Megan J. Metzler, Brandon T. Craig, Alicia Hilderley, Mary Dunbar, Adrianna Giuffre, James Wrightson, Ephrem Zewdie & Helen L. Carlson

  2. Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada

    Adam Kirton, Brandon T. Craig, Alicia Hilderley, Mary Dunbar, Adrianna Giuffre, James Wrightson, Ephrem Zewdie & Helen L. Carlson

  3. Alberta Children’s Hospital Research Institute (ACHRI), Calgary, AB, Canada

    Adam Kirton, Megan J. Metzler, Brandon T. Craig, Alicia Hilderley, Mary Dunbar, Adrianna Giuffre, James Wrightson, Ephrem Zewdie & Helen L. Carlson

  4. Department of Pediatrics, University of Calgary, Calgary, AB, Canada

    Adam Kirton, Megan J. Metzler, Brandon T. Craig, Alicia Hilderley, Mary Dunbar, Adrianna Giuffre, James Wrightson, Ephrem Zewdie & Helen L. Carlson

  5. Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada

    Adam Kirton, Megan J. Metzler & Mary Dunbar

  6. Department of Radiology, University of Calgary, Calgary, AB, Canada

    Adam Kirton

Authors
  1. Adam Kirton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Megan J. Metzler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brandon T. Craig
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alicia Hilderley
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mary Dunbar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Adrianna Giuffre
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. James Wrightson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ephrem Zewdie
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Helen L. Carlson
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Adam Kirton.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Neurology thanks S. Chabrier (who co-reviewed with M. Chevin), A. Guzetta, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Review criteria

A literature search was performed on 7 August 2020. The following MeSH and keyword terms were searched in combination for relevance to the stated aims of the review: “cerebral palsy”, “hemiplegia”, “infant”, “newborn”, “child”, “neuronal plasticity”, “stroke”, “stroke rehabilitation”, “porencephaly”, “transcranial magnetic stimulation”, “transcranial direct current stimulation”, “occupational therapy” and “clinical trial” (MeSH terms); and “perinatal stroke”, “neonatal stroke”, “unilateral cerebral palsy”, “congenital hemiplegia”, “constraint-induced movement therapy” and “bimanual therapy” (independent terms). Search results were screened for results relevant to the predefined aims of the Review and incorporated accordingly.

Related links

International Alliance for Pediatric Stroke: https://iapediatricstroke.org

International Pediatric Stroke Organization: https://internationalpediatricstroke.org

Glossary

Global efficiency

A graph theory metric that quantifies the extent to which a network’s organization results in shortest path lengths between any two nodes and is equivalent to the average inverse shortest path length in the network.

Betweenness centrality

A graph theory metric that quantifies how central a node is by assessing how many connections go through a particular node to connect to other nodes within a network.

Clustering coefficient

A graph theory metric that quantifies the tendency for a node’s direct neighbours to be connected to each other, highlighting the presence of hub, or popular, structures within a network.

Mirror neurons

Neurons that depolarize during execution of goal-directed movement as well as during observation of someone else performing the same or similar movement.

Synaptic competition model

A model of developmental neuroplasticity after early injury describing competition between contralateral and ipsilateral populations of neurons that suggests that resulting organization of complex networks (motor, somatosensory, language) is dependent upon experience-dependent plasticity in early life.

Laterality

A quantification of symmetry or asymmetry between hemispheres, indicating which hemisphere has higher values of the variable of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kirton, A., Metzler, M.J., Craig, B.T. et al. Perinatal stroke: mapping and modulating developmental plasticity. Nat Rev Neurol 17, 415–432 (2021). https://doi.org/10.1038/s41582-021-00503-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-021-00503-x

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