Skip to main content

Translational Hurdles in Stroke Recovery Studies

Translational Stroke Research volume 7, pages 331–342 (2016)Cite this article

Abstract

Emerging understanding of brain plasticity has opened new avenues for the treatment of stroke. The promising preclinical evidence with neuroprotective drugs has not been confirmed in clinical trials, thus nowadays, researchers, pharmaceutical companies, and funding bodies hesitate to initiate these expensive trials with restorative therapies. Since many of the previous failures can be traced to low study quality, a number of guidelines such as STAIR and STEPS were introduced to rectify these shortcomings. However, these guidelines stem from the study design for neuroprotective drugs and one may question whether they are appropriate for restorative approaches, which rely heavily on behavioral testing. Most of the recovery studies conducted in stroke patients have been small-scale, proof-of-concept trials. Consequently, the overall effect sizes of pooled phase II trials have proved unreliable and unstable in most meta-analyses. Although the methodological quality of trials in humans is improving, most studies still suffer from methodological flaws and do not meet even the minimum of evidence-based standards for reporting randomized controlled trials. The power problem of most phase II trials is mostly attributable to a lack of proper stratification with robust prognostic factors at baseline as well as the incorrect assumption that all patients will exhibit the same proportional amount of spontaneous neurological recovery poststroke. In addition, most trials suffer from insufficient treatment contrasts between the experimental and control arm and the outcomes have not been sufficiently responsive to detect small but clinically relevant changes in neurological impairments and activities. This narrative review describes the main factors that bias recovery studies, both in experimental animals and stroke patients.

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

Access options

Buy single article

Instant access to the full article PDF.

£ 29.95

Price includes VAT (United Kingdom)
Tax calculation will be finalised during checkout.

References

  1. Langhorne P, Bernhardt J, Kwakkel G. Stroke rehabilitation. Lancet Lond Engl. 2011;377:1693–702. doi:10.1016/S0140-6736(11)60325-5.

    Article  Google Scholar 

  2. Olesen J, Gustavsson A, Svensson M, Wittchen H-U, Jönsson B, CDBE2010 study group, et al. The economic cost of brain disorders in Europe. Eur J Neurol Off J Eur Fed Neurol Soc. 2012;19:155–62. doi:10.1111/j.1468-1331.2011.03590.x.

    CAS  Google Scholar 

  3. O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59:467–77. doi:10.1002/ana.20741.

    PubMed  Article  CAS  Google Scholar 

  4. Savitz SI. A critical appraisal of the NXY-059 neuroprotection studies for acute stroke: a need for more rigorous testing of neuroprotective agents in animal models of stroke. Exp Neurol. 2007;205:20–5. doi:10.1016/j.expneurol.2007.03.003.

    CAS  PubMed  Article  Google Scholar 

  5. Hermann DM, Chopp M. Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation. Lancet Neurol. 2012;11:369–80. doi:10.1016/S1474-4422(12)70039-X.

    PubMed  PubMed Central  Article  Google Scholar 

  6. Detante O, Jaillard A, Moisan A, Barbieux M, Favre IM, Garambois K, et al. Biotherapies in stroke. Rev Neurol (Paris). 2014;170:779–98. doi:10.1016/j.neurol.2014.10.005.

    CAS  Article  Google Scholar 

  7. Stroke Therapy Academic Industry Roundtable (STAIR). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke J Cereb Circ. 1999;30:2752–8.

    Article  Google Scholar 

  8. Fisher M, Stroke Therapy Academic Industry Roundtable. Recommendations for advancing development of acute stroke therapies: Stroke Therapy Academic Industry Roundtable 3. Stroke J Cereb Circ. 2003;34:1539–46. doi:10.1161/01.STR.0000072983.64326.53.

    CAS  Article  Google Scholar 

  9. Stem Cell Therapies as an Emerging Paradigm in Stroke Participants. Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS): bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. Stroke J Cereb Circ. 2009;40:510–5. doi:10.1161/STROKEAHA.108.526863.

    Article  Google Scholar 

  10. Savitz SI, Chopp M, Deans R, Carmichael T, Phinney D, Wechsler L, et al. Stem Cell Therapy as an Emerging Paradigm for Stroke (STEPS) II. Stroke J Cereb Circ. 2011;42:825–9. doi:10.1161/STROKEAHA.110.601914.

    Article  Google Scholar 

  11. Lapchak PA, Zhang JH, Noble-Haeusslein LJ. RIGOR guidelines: escalating STAIR and STEPS for effective translational research. Transl Stroke Res. 2013;4:279–85. doi:10.1007/s12975-012-0209-2.

    PubMed  Article  Google Scholar 

  12. Levin MF, Kleim JA, Wolf SL. What do motor “recovery” and “compensation” mean in patients following stroke? Neurorehabil Neural Repair. 2009;23:313–9. doi:10.1177/1545968308328727.

    CAS  PubMed  Article  Google Scholar 

  13. Murphy TH, Corbett D. Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci. 2009;10:861–72. doi:10.1038/nrn2735.

    CAS  PubMed  Article  Google Scholar 

  14. Buma F, Kwakkel G, Ramsey N. Understanding upper limb recovery after stroke. Restor Neurol Neurosci. 2013;31:707–22. doi:10.3233/RNN-130332.

    PubMed  Google Scholar 

  15. Jolkkonen J, Puurunen K, Rantakömi S, Härkönen A, Haapalinna A, Sivenius J. Behavioral effects of the alpha(2)-adrenoceptor antagonist, atipamezole, after focal cerebral ischemia in rats. Eur J Pharmacol. 2000;400:211–9.

    CAS  PubMed  Article  Google Scholar 

  16. Puurunen K, Jolkkonen J, Sirviö J, Haapalinna A, Sivenius J. An alpha(2)-adrenergic antagonist, atipamezole, facilitates behavioral recovery after focal cerebral ischemia in rats. Neuropharmacology. 2001;40:597–606.

    CAS  PubMed  Article  Google Scholar 

  17. Biernaskie J, Chernenko G, Corbett D. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J Neurosci Off J Soc Neurosci. 2004;24:1245–54. doi:10.1523/JNEUROSCI.3834-03.2004.

    CAS  Article  Google Scholar 

  18. Kwakkel G, Kollen B, Twisk J. Impact of time on improvement of outcome after stroke. Stroke J Cereb Circ. 2006;37:2348–53. doi:10.1161/01.STR.0000238594.91938.1e.

    Article  Google Scholar 

  19. Duncan PW, Goldstein LB, Matchar D, Divine GW, Feussner J. Measurement of motor recovery after stroke. Outcome assessment and sample size requirements. Stroke J Cereb Circ. 1992;23:1084–9.

    CAS  Article  Google Scholar 

  20. Duncan PW, Goldstein LB, Horner RD, Landsman PB, Samsa GP, Matchar DB. Similar motor recovery of upper and lower extremities after stroke. Stroke J Cereb Circ. 1994;25:1181–8.

    CAS  Article  Google Scholar 

  21. Kwakkel G, Wagenaar RC, Twisk JW, Lankhorst GJ, Koetsier JC. Intensity of leg and arm training after primary middle-cerebral-artery stroke: a randomised trial. Lancet Lond Engl. 1999;354:191–6. doi:10.1016/S0140-6736(98)09477-X.

    CAS  Article  Google Scholar 

  22. Byblow WD, Stinear CM, Barber PA, Petoe MA, Ackerley SJ. Proportional recovery after stroke depends on corticomotor integrity. Ann Neurol. 2015. doi:10.1002/ana.24472.

    PubMed  Google Scholar 

  23. van Kordelaar J, van Wegen EEH, Nijland RHM, Daffertshofer A, Kwakkel G. Understanding adaptive motor control of the paretic upper limb early poststroke: the EXPLICIT-stroke program. Neurorehabil Neural Repair. 2013;27:854–63. doi:10.1177/1545968313496327.

    PubMed  Article  Google Scholar 

  24. Nijboer TCW, Kollen BJ, Kwakkel G. Time course of visuospatial neglect early after stroke: a longitudinal cohort study. Cortex J Devoted Study Nerv Syst Behav. 2013;49:2021–7. doi:10.1016/j.cortex.2012.11.006.

    Article  Google Scholar 

  25. Winters C, van Wegen EEH, Daffertshofer A, Kwakkel G. Generalizability of the proportional recovery model for the upper extremity after an ischemic stroke. Neurorehabil Neural Repair. 2015;29:614–22. doi:10.1177/1545968314562115.

    PubMed  Article  Google Scholar 

  26. Popa-Wagner A, Pirici D, Petcu EB, Mogoanta L, Buga A-M, Rosen CL, et al. Pathophysiology of the vascular wall and its relevance for cerebrovascular disorders in aged rodents. Curr Neurovasc Res. 2010;7:251–67.

    CAS  PubMed  Article  Google Scholar 

  27. Buga AM, Margaritescu C, Scholz CJ, Radu E, Zelenak C, Popa-Wagner A. Transcriptomics of post-stroke angiogenesis in the aged brain. Front Aging Neurosci. 2014;6:44. doi:10.3389/fnagi.2014.00044.

    PubMed  PubMed Central  Article  Google Scholar 

  28. Balseanu AT, Buga A-M, Catalin B, Wagner D-C, Boltze J, Zagrean A-M, et al. Multimodal approaches for regenerative stroke therapies: combination of granulocyte colony-stimulating factor with bone marrow mesenchymal stem cells is not superior to G-CSF alone. Front Aging Neurosci. 2014;6:130. doi:10.3389/fnagi.2014.00130.

    PubMed  PubMed Central  Article  Google Scholar 

  29. Buga A-M, Sascau M, Pisoschi C, Herndon JG, Kessler C, Popa-Wagner A. The genomic response of the ipsilateral and contralateral cortex to stroke in aged rats. J Cell Mol Med. 2008;12:2731–53. doi:10.1111/j.1582-4934.2008.00252.x.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Zhao S-S, Zhao Y, Xiao T, Zhao M, Jolkkonen J, Zhao C-S. Increased neurogenesis contributes to the promoted behavioral recovery by constraint-induced movement therapy after stroke in adult rats. CNS Neurosci Ther. 2013;19:194–6. doi:10.1111/cns.12058.

    PubMed  Article  Google Scholar 

  31. Sofroniew MV. Reactive astrocytes in neural repair and protection. Neurosci Rev J Bringing Neurobiol Neurol Psychiatry. 2005;11:400–7. doi:10.1177/1073858405278321.

    CAS  Google Scholar 

  32. Badan I, Buchhold B, Hamm A, Gratz M, Walker LC, Platt D, et al. Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2003;23:845–54. doi:10.1097/01.WCB.0000071883.63724.A7.

    CAS  Article  Google Scholar 

  33. Buga A-M, Di Napoli M, Popa-Wagner A. Preclinical models of stroke in aged animals with or without comorbidities: role of neuroinflammation. Biogerontology. 2013;14:651–62. doi:10.1007/s10522-013-9465-0.

    CAS  PubMed  Article  Google Scholar 

  34. Carmichael ST. Cellular and molecular mechanisms of neural repair after stroke: making waves. Ann Neurol. 2006;59:735–42. doi:10.1002/ana.20845.

    CAS  PubMed  Article  Google Scholar 

  35. Prabhakaran S, Zarahn E, Riley C, Speizer A, Chong JY, Lazar RM, et al. Inter-individual variability in the capacity for motor recovery after ischemic stroke. Neurorehabil Neural Repair. 2008;22:64–71. doi:10.1177/1545968307305302.

    PubMed  Article  Google Scholar 

  36. Zarahn E, Alon L, Ryan SL, Lazar RM, Vry M-S, Weiller C, et al. Prediction of motor recovery using initial impairment and fMRI 48 h poststroke. Cereb Cortex N Y N. 2011;1991(21):2712–21. doi:10.1093/cercor/bhr047.

    Article  Google Scholar 

  37. Lipsanen A, Jolkkonen J. Experimental approaches to study functional recovery following cerebral ischemia. Cell Mol Life Sci CMLS. 2011;68:3007–17. doi:10.1007/s00018-011-0733-3.

    CAS  PubMed  Article  Google Scholar 

  38. Denes A, Pradillo JM, Drake C, Buggey H, Rothwell NJ, Allan SM. Surgical manipulation compromises leukocyte mobilization responses and inflammation after experimental cerebral ischemia in mice. Front Neurosci. 2013;7:271. doi:10.3389/fnins.2013.00271.

    PubMed  Google Scholar 

  39. Sakai H, Sheng H, Yates RB, Ishida K, Pearlstein RD, Warner DS. Isoflurane provides long-term protection against focal cerebral ischemia in the rat. Anesthesiology. 2007;106:92–9. discussion 8–10.

    CAS  PubMed  Article  Google Scholar 

  40. Tétrault S, Chever O, Sik A, Amzica F. Opening of the blood-brain barrier during isoflurane anaesthesia. Eur J Neurosci. 2008;28:1330–41. doi:10.1111/j.1460-9568.2008.06443.x.

    PubMed  Article  Google Scholar 

  41. Longa EZ, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke J Cereb Circ. 1989;20:84–91.

    CAS  Article  Google Scholar 

  42. Zhao Q, Memezawa H, Smith ML, Siesjö BK. Hyperthermia complicates middle cerebral artery occlusion induced by an intraluminal filament. Brain Res. 1994;649:253–9.

    CAS  PubMed  Article  Google Scholar 

  43. Dittmar M, Spruss T, Schuierer G, Horn M. External carotid artery territory ischemia impairs outcome in the endovascular filament model of middle cerebral artery occlusion in rats. Stroke J Cereb Circ. 2003;34:2252–7. doi:10.1161/01.STR.0000083625.54851.9A.

    Article  Google Scholar 

  44. Hossmann K-A. The two pathophysiologies of focal brain ischemia: implications for translational stroke research. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2012;32:1310–6. doi:10.1038/jcbfm.2011.186.

    Article  Google Scholar 

  45. van Groen T, Puurunen K, Mäki H-M, Sivenius J, Jolkkonen J. Transformation of diffuse beta-amyloid precursor protein and beta-amyloid deposits to plaques in the thalamus after transient occlusion of the middle cerebral artery in rats. Stroke J Cereb Circ. 2005;36:1551–6. doi:10.1161/01.STR.0000169933.88903.cf.

    Article  CAS  Google Scholar 

  46. Mäkinen S, van Groen T, Clarke J, Thornell A, Corbett D, Hiltunen M, et al. Coaccumulation of calcium and beta-amyloid in the thalamus after transient middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2008;28:263–8. doi:10.1038/sj.jcbfm.9600529.

    Article  CAS  Google Scholar 

  47. Mitkari B, Kerkelä E, Nystedt J, Korhonen M, Jolkkonen J. Unexpected complication in a rat stroke model: exacerbation of secondary pathology in the thalamus by subacute intraarterial administration of human bone marrow-derived mesenchymal stem cells. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2015;35:363–6. doi:10.1038/jcbfm.2014.235.

    CAS  Article  Google Scholar 

  48. Aho L, Jolkkonen J, Alafuzoff I. Beta-amyloid aggregation in human brains with cerebrovascular lesions. Stroke J Cereb Circ. 2006;37:2940–5. doi:10.1161/01.STR.0000248777.44128.93.

    CAS  Article  Google Scholar 

  49. Lipsanen A, Kalesnykas G, Pro-Sistiaga P, Hiltunen M, Vanninen R, Bernaudin M, et al. Lack of secondary pathology in the thalamus after focal cerebral ischemia in nonhuman primates. Exp Neurol. 2013;248:224–7. doi:10.1016/j.expneurol.2013.06.016.

    PubMed  Article  Google Scholar 

  50. Chen ST, Hsu CY, Hogan EL, Maricq H, Balentine JD. A model of focal ischemic stroke in the rat: reproducible extensive cortical infarction. Stroke J Cereb Circ. 1986;17:738–43.

    CAS  Article  Google Scholar 

  51. Sharkey J, Butcher SP. Characterisation of an experimental model of stroke produced by intracerebral microinjection of endothelin-1 adjacent to the rat middle cerebral artery. J Neurosci Methods. 1995;60:125–31.

    CAS  PubMed  Article  Google Scholar 

  52. Windle V, Szymanska A, Granter-Button S, White C, Buist R, Peeling J, et al. An analysis of four different methods of producing focal cerebral ischemia with endothelin-1 in the rat. Exp Neurol. 2006;201:324–34. doi:10.1016/j.expneurol.2006.04.012.

    CAS  PubMed  Article  Google Scholar 

  53. Watson BD, Dietrich WD, Busto R, Wachtel MS, Ginsberg MD. Induction of reproducible brain infarction by photochemically initiated thrombosis. Ann Neurol. 1985;17:497–504. doi:10.1002/ana.410170513.

    CAS  PubMed  Article  Google Scholar 

  54. Jolkkonen J, Jokivarsi K, Laitinen T, Gröhn O. Subacute hemorrhage and resolution of edema in Rose Bengal stroke model in rats coincides with improved sensorimotor functions. Neurosci Lett. 2007;428:99–102. doi:10.1016/j.neulet.2007.09.043.

    CAS  PubMed  Article  Google Scholar 

  55. Ahmad AS, Satriotomo I, Fazal J, Nadeau SE, Doré S. Considerations for the optimization of induced white matter injury preclinical models. Front Neurol. 2015;6:172. doi:10.3389/fneur.2015.00172.

    PubMed  PubMed Central  Article  Google Scholar 

  56. Zhao C-S, Puurunen K, Schallert T, Sivenius J, Jolkkonen J. Behavioral and histological effects of chronic antipsychotic and antidepressant drug treatment in aged rats with focal ischemic brain injury. Behav Brain Res. 2005;158:211–20. doi:10.1016/j.bbr.2004.09.001.

    CAS  PubMed  Article  Google Scholar 

  57. Popa-Wagner A, Buga A-M, Doeppner TR, Hermann DM. Stem cell therapies in preclinical models of stroke associated with aging. Front Cell Neurosci. 2014;8:347. doi:10.3389/fncel.2014.00347.

    PubMed  PubMed Central  Article  Google Scholar 

  58. Mitkari B, Nitzsche F, Kerkelä E, Kuptsova K, Huttunen J, Nystedt J, et al. Human bone marrow mesenchymal stem/stromal cells produce efficient localization in the brain and enhanced angiogenesis after intra-arterial delivery in rats with cerebral ischemia, but this is not translated to behavioral recovery. Behav Brain Res. 2014;259:50–9. doi:10.1016/j.bbr.2013.10.030.

    PubMed  Article  Google Scholar 

  59. Hicks AU, Lappalainen RS, Narkilahti S, Suuronen R, Corbett D, Sivenius J, et al. Transplantation of human embryonic stem cell-derived neural precursor cells and enriched environment after cortical stroke in rats: cell survival and functional recovery. Eur J Neurosci. 2009;29:562–74. doi:10.1111/j.1460-9568.2008.06599.x.

    PubMed  Article  Google Scholar 

  60. Chen J, Ye X, Yan T, Zhang C, Yang X-P, Cui X, et al. Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats. Stroke J Cereb Circ. 2011;42:3551–8. doi:10.1161/STROKEAHA.111.627174.

    Article  Google Scholar 

  61. Dirnagl U, Hakim A, Macleod M, Fisher M, Howells D, Alan SM, et al. A concerted appeal for international cooperation in preclinical stroke research. Stroke J Cereb Circ. 2013;44:1754–60. doi:10.1161/STROKEAHA.113.000734.

    Article  Google Scholar 

  62. Diamandis T, Borlongan CV. One, two, three steps toward cell therapy for stroke. Stroke J Cereb Circ. 2015;46:588–91. doi:10.1161/STROKEAHA.114.007105.

    Article  Google Scholar 

  63. Feeney DM, Gonzalez A, Law WA. Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury. Science. 1982;217:855–7.

    CAS  PubMed  Article  Google Scholar 

  64. Mering S, Jolkkonen J. Proper housing conditions in experimental stroke studies-special emphasis on environmental enrichment. Front Neurosci. 2015;9:106. doi:10.3389/fnins.2015.00106.

    PubMed  PubMed Central  Article  Google Scholar 

  65. Savitz SI, Cramer SC, Wechsler L, STEPS 3 Consortium. Stem cells as an emerging paradigm in stroke 3: enhancing the development of clinical trials. Stroke J Cereb Circ. 2014;45:634–9. doi:10.1161/STROKEAHA.113.003379.

    Article  Google Scholar 

  66. Veerbeek JM, van Wegen E, van Peppen R, van der Wees PJ, Hendriks E, Rietberg M, et al. What is the evidence for physical therapy poststroke? A systematic review and meta-analysis. PLoS One. 2014;9:e87987. doi:10.1371/journal.pone.0087987.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. Mehrholz J, Hädrich A, Platz T, Kugler J, Pohl M. Electromechanical and robot-assisted arm training for improving generic activities of daily living, arm function, and arm muscle strength after stroke. Cochrane Database Syst Rev. 2012;6:CD006876. doi:10.1002/14651858.CD006876.pub3.

    PubMed  Google Scholar 

  68. Mehrholz J, Elsner B, Werner C, Kugler J, Pohl M. Electromechanical-assisted training for walking after stroke. Cochrane Database Syst Rev. 2013;7:CD006185. doi:10.1002/14651858.CD006185.pub3.

    PubMed  Google Scholar 

  69. Kwakkel G, Veerbeek JM, van Wegen EEH, Wolf SL. Constraint-induced movement therapy after stroke. Lancet Neurol. 2015;14:224–34. doi:10.1016/S1474-4422(14)70160-7.

    PubMed  PubMed Central  Article  Google Scholar 

  70. Kwakkel G, Winters C, van Wegen E, Nijland R, van Kuijk A, Visser-Meily J, et al. Effects of unilateral upper limb training in two distinct prognostic groups early after stroke. The EXPLICIT-stroke randomized clinical trial. Neurorehab Neural Repair. in press (n.d.).

  71. Janowski M, Walczak P, Date I. Intravenous route of cell delivery for treatment of neurological disorders: a meta-analysis of preclinical results. Stem Cells Dev. 2010;19:5–16. doi:10.1089/scd.2009.0271.

    CAS  PubMed  Article  Google Scholar 

  72. Schmidt A, Wellmann J, Schilling M, Strecker J-K, Sommer C, Schäbitz W-R, et al. Meta-analysis of the efficacy of different training strategies in animal models of ischemic stroke. Stroke J Cereb Circ. 2014;45:239–47. doi:10.1161/STROKEAHA.113.002048.

    Article  Google Scholar 

  73. Veerbeek JM, Kwakkel G, van Wegen EEH, Ket JCF, Heymans MW. Early prediction of outcome of activities of daily living after stroke: a systematic review. Stroke J Cereb Circ. 2011;42:1482–8. doi:10.1161/STROKEAHA.110.604090.

    Article  Google Scholar 

  74. Lohse KR, Lang CE, Boyd LA. Is more better? Using metadata to explore dose-response relationships in stroke rehabilitation. Stroke J Cereb Circ. 2014;45:2053–8. doi:10.1161/STROKEAHA.114.004695.

    Article  Google Scholar 

  75. Kwakkel G, Kollen BJ, Krebs HI. Effects of robot-assisted therapy on upper limb recovery after stroke: a systematic review. Neurorehabil Neural Repair. 2008;22:111–21. doi:10.1177/1545968307305457.

    PubMed  Article  Google Scholar 

  76. Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke J Cereb Circ. 1986;17:472–6.

    CAS  Article  Google Scholar 

  77. Rogers DC, Campbell CA, Stretton JL, Mackay KB. Correlation between motor impairment and infarct volume after permanent and transient middle cerebral artery occlusion in the rat. Stroke J Cereb Circ. 1997;28:2060–5. discussion 2066.

    CAS  Article  Google Scholar 

  78. De Ryck M, Van Reempts J, Borgers M, Wauquier A, Janssen PA. Photochemical stroke model: flunarizine prevents sensorimotor deficits after neocortical infarcts in rats. Stroke J Cereb Circ. 1989;20:1383–90.

    Article  Google Scholar 

  79. Woodlee MT, Asseo-García AM, Zhao X, Liu S-J, Jones TA, Schallert T. Testing forelimb placing “across the midline” reveals distinct, lesion-dependent patterns of recovery in rats. Exp Neurol. 2005;191:310–7. doi:10.1016/j.expneurol.2004.09.005.

    PubMed  Article  Google Scholar 

  80. Hamm RJ, Pike BR, O’Dell DM, Lyeth BG, Jenkins LW. The rotarod test: an evaluation of its effectiveness in assessing motor deficits following traumatic brain injury. J Neurotrauma. 1994;11:187–96.

    CAS  PubMed  Article  Google Scholar 

  81. Montoya CP, Campbell-Hope LJ, Pemberton KD, Dunnett SB. The “staircase test”: a measure of independent forelimb reaching and grasping abilities in rats. J Neurosci Methods. 1991;36:219–28.

    CAS  PubMed  Article  Google Scholar 

  82. Whishaw IQ, Alaverdashvili M, Kolb B. The problem of relating plasticity and skilled reaching after motor cortex stroke in the rat. Behav Brain Res. 2008;192:124–36. doi:10.1016/j.bbr.2007.12.026.

    PubMed  Article  Google Scholar 

  83. Moon S-K, Alaverdashvili M, Cross AR, Whishaw IQ. Both compensation and recovery of skilled reaching following small photothrombotic stroke to motor cortex in the rat. Exp Neurol. 2009;218:145–53. doi:10.1016/j.expneurol.2009.04.021.

    PubMed  Article  Google Scholar 

  84. Metz GA, Antonow-Schlorke I, Witte OW. Motor improvements after focal cortical ischemia in adult rats are mediated by compensatory mechanisms. Behav Brain Res. 2005;162:71–82. doi:10.1016/j.bbr.2005.03.002.

    PubMed  Article  Google Scholar 

  85. Boltze J, Lukomska B, Jolkkonen J, MEMS–IRBI consortium. Mesenchymal stromal cells in stroke: improvement of motor recovery or functional compensation? J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab. 2014;34:1420–1. doi:10.1038/jcbfm.2014.94.

    Article  Google Scholar 

  86. Hicks A, Schallert T, Jolkkonen J. Cell-based therapies and functional outcome in experimental stroke. Cell Stem Cell. 2009;5:139–40. doi:10.1016/j.stem.2009.07.009.

    CAS  PubMed  Article  Google Scholar 

  87. Kwakkel G, Kollen B, Lindeman E. Understanding the pattern of functional recovery after stroke: facts and theories. Restor Neurol Neurosci. 2004;22:281–99.

    PubMed  Google Scholar 

  88. van Kordelaar J, van Wegen E, Kwakkel G. Impact of time on quality of motor control of the paretic upper limb after stroke. Arch Phys Med Rehabil. 2014;95:338–44. doi:10.1016/j.apmr.2013.10.006.

    PubMed  Article  Google Scholar 

  89. Kitago T, Liang J, Huang VS, Hayes S, Simon P, Tenteromano L, et al. Improvement after constraint-induced movement therapy: recovery of normal motor control or task-specific compensation? Neurorehabil Neural Repair. 2013;27:99–109. doi:10.1177/1545968312452631.

    PubMed  Article  Google Scholar 

  90. Kitago T, Goldsmith J, Harran M, Kane L, Berard J, Huang S, et al. Robotic therapy for chronic stroke: general recovery of impairment or improved task-specific skill? J Neurophysiol. 2015;114:1885–94. doi:10.1152/jn.00336.2015.

    PubMed  Article  Google Scholar 

  91. Hirst JA, Howick J, Aronson JK, Roberts N, Perera R, Koshiaris C, et al. The need for randomization in animal trials: an overview of systematic reviews. PLoS One. 2014;9:e98856. doi:10.1371/journal.pone.0098856.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  92. Vu Q, Xie K, Eckert M, Zhao W, Cramer SC. Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke. Neurology. 2014;82:1277–86. doi:10.1212/WNL.0000000000000278.

    PubMed  PubMed Central  Article  Google Scholar 

  93. Chollet F, Tardy J, Albucher J-F, Thalamas C, Berard E, Lamy C, et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol. 2011;10:123–30. doi:10.1016/S1474-4422(10)70314-8.

    CAS  PubMed  Article  Google Scholar 

  94. Di Pino G, Pellegrino G, Assenza G, Capone F, Ferreri F, Formica D, et al. Modulation of brain plasticity in stroke: a novel model for neurorehabilitation. Nat Rev Neurol. 2014;10:597–608. doi:10.1038/nrneurol.2014.162.

    PubMed  Article  Google Scholar 

  95. Sun X, Zhou Z, Liu T, Zhao M, Zhao S, Xiao T, et al. Fluoxetine enhances neurogenesis in aged rats with cortical infarcts, but this is not reflected in a behavioral recovery. J Mol Neurosci MN. 2015. doi:10.1007/s12031-015-0662-y.

    Google Scholar 

  96. Jolkkonen J, Puurunen K, Rantakömi S, Sirviö J, Haapalinna A, Sivenius J. Effects-of fluoxetine on sensorimotor and spatial learning deficits following focal cerebral ischemia in rats. Restor Neurol Neurosci. 2000;17:211–6.

    CAS  PubMed  Google Scholar 

  97. Windle V, Corbett D. Fluoxetine and recovery of motor function after focal ischemia in rats. Brain Res. 2005;1044:25–32. doi:10.1016/j.brainres.2005.02.060.

    CAS  PubMed  Article  Google Scholar 

  98. Janssen H, Speare S, Spratt NJ, Sena ES, Ada L, Hannan AJ, et al. Exploring the efficacy of constraint in animal models of stroke: meta-analysis and systematic review of the current evidence. Neurorehabil Neural Repair. 2013;27:3–12. doi:10.1177/1545968312449696.

    PubMed  Article  Google Scholar 

  99. van Asseldonk EHF, Buurke JH, Bloem BR, Renzenbrink GJ, Nene AV, van der Helm FCT, et al. Disentangling the contribution of the paretic and non-paretic ankle to balance control in stroke patients. Exp Neurol. 2006;201:441–51. doi:10.1016/j.expneurol.2006.04.036.

    PubMed  Article  Google Scholar 

  100. Buurke JH, Nene AV, Kwakkel G, Erren-Wolters V, Ijzerman MJ, Hermens HJ. Recovery of gait after stroke: what changes? Neurorehabil Neural Repair. 2008;22:676–83. doi:10.1177/1545968308317972.

    PubMed  Article  Google Scholar 

  101. Kwakkel G, Wagenaar RC. Effect of duration of upper- and lower-extremity rehabilitation sessions and walking speed on recovery of interlimb coordination in hemiplegic gait. Phys Ther. 2002;82:432–48.

    PubMed  Google Scholar 

  102. Krakauer JW, Carmichael ST, Corbett D, Wittenberg GF. Getting neurorehabilitation right: what can be learned from animal models? Neurorehabil Neural Repair. 2012;26:923–31. doi:10.1177/1545968312440745.

    PubMed  PubMed Central  Article  Google Scholar 

  103. Lo AC, Guarino PD, Richards LG, Haselkorn JK, Wittenberg GF, Federman DG, et al. Robot-assisted therapy for long-term upper-limb impairment after stroke. N Engl J Med. 2010;362:1772–83. doi:10.1056/NEJMoa0911341.

    CAS  PubMed  Article  Google Scholar 

  104. Wolf SL, Thompson PA, Winstein CJ, Miller JP, Blanton SR, Nichols-Larsen DS, et al. The EXCITE stroke trial: comparing early and delayed constraint-induced movement therapy. Stroke J Cereb Circ. 2010;41:2309–15. doi:10.1161/STROKEAHA.110.588723.

    Article  Google Scholar 

  105. van de Port IGL, Wevers LEG, Lindeman E, Kwakkel G. Effects of circuit training as alternative to usual physiotherapy after stroke: randomised controlled trial. BMJ. 2012;344:e2672.

    PubMed  PubMed Central  Article  Google Scholar 

  106. Winstein CJ, Wolf SL, Dromerick AW, Lane CJ, Nelsen MA, Lewthwaite R, et al. Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE): a randomized controlled trial protocol. BMC Neurol. 2013;13:5. doi:10.1186/1471-2377-13-5.

    PubMed  PubMed Central  Article  Google Scholar 

  107. Duncan PW, Sullivan KJ, Behrman AL, Azen SP, Wu SS, Nadeau SE, et al. Body-weight-supported treadmill rehabilitation after stroke. N Engl J Med. 2011;364:2026–36. doi:10.1056/NEJMoa1010790.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Conflicts of Interest

The authors declare that they have no competing interests.

Author information

Affiliations

  1. Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland

    Jukka Jolkkonen

  2. Neurocenter, Neurology, University Hospital of Kuopio, Kuopio, Finland

    Jukka Jolkkonen

  3. Department of Rehabilitation Medicine, VU University Medical Center, MOVE Research Institute Amsterdam, Amsterdam, The Netherlands

    Gert Kwakkel

  4. Neurorehabilitation, Amsterdam Rehabilitation Research Center, Reade, Amsterdam, The Netherlands

    Gert Kwakkel

  5. Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands

    Gert Kwakkel

  6. Department of Physical Therapy and Human Movement Sciences, Northwestern University, Evanston, IL, USA

    Gert Kwakkel

Authors
  1. Jukka Jolkkonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gert Kwakkel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jukka Jolkkonen.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Jolkkonen, J., Kwakkel, G. Translational Hurdles in Stroke Recovery Studies. Transl. Stroke Res. 7, 331–342 (2016). https://doi.org/10.1007/s12975-016-0461-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-016-0461-y

Keywords

  • Functional recovery
  • Neuroprotection
  • Plasticity
  • Restorative therapies
  • Stroke
  • Translational research