Translational Hurdles in Stroke Recovery Studies

Translational Stroke Research

Volumn 7, Issue 4, 2016, Pages 331-342

  Jolkkonen, Jukka ^a,b   Kwakkel, Gert ^c,d,e,f  

^a UNIVERSITY OF EASTERN FINLAND   (Finland)

^b KUOPIO UNIVERSITY HOSPITAL   (Finland)

^c VU UNIVERSITY MEDICAL CENTER   (Netherlands)

^d Reade   (Netherlands)

^e VU UNIVERSITY AMSTERDAM   (Netherlands)

^f NORTHWESTERN UNIVERSITY   (United States)

Author keywords

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

Indexed keywords

ARTICLE; BRAIN ISCHEMIA; CEREBROVASCULAR ACCIDENT; DISEASE MODEL; DOSE RESPONSE; EXPERIMENTAL STROKE; HUMAN; MOTOR CONTROL; NERVE CELL PLASTICITY; NEUROPROTECTION; NEUROREHABILITATION; NONHUMAN; OUTCOME ASSESSMENT; PRACTICE GUIDELINE; PRIORITY JOURNAL; RODENT MODEL; STROKE PATIENT; STUDY DESIGN; THERAPY EFFECT; TRANSLATIONAL RESEARCH; ANIMAL; CLINICAL TRIAL (TOPIC); CONVALESCENCE; DRUG EFFECTS; PHYSIOLOGY; STROKE; TREATMENT OUTCOME;

NEUROPROTECTIVE AGENT;

ANIMALS; CLINICAL TRIALS AS TOPIC; DISEASE MODELS, ANIMAL; HUMANS; NEUROPROTECTIVE AGENTS; RECOVERY OF FUNCTION; STROKE; TREATMENT OUTCOME;

EID: 84961774768     PISSN: 18684483     EISSN: 1868601X     Source Type: Journal    
DOI: 10.1007/s12975-016-0461-y     Document Type: Article

References (107)

1. Langhorne P, Bernhardt J, Kwakkel G. Stroke rehabilitation. Lancet Lond Engl. 2011;377:1693–702. doi:10.1016/S0140-6736(11)60325-5.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
13. Murphy TH, Corbett D. Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci. 2009;10:861–72. doi:10.1038/nrn2735.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.