Semin Neurol 2021; 41(02): 157-166
DOI: 10.1055/s-0041-1725140
Review Article

Principles of Neural Repair and Their Application to Stroke Recovery Trials

1   Center for Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts
4   VA RR&D Center for Neurorestoration and Neurotechnology, Rehabilitation R&D Service, Department of VA Medical Center, Providence, Rhode Island
,
Steven C. Cramer
2   Department of Neurology, University of California, Los Angeles, California
3   California Rehabilitation Institute, Los Angeles, California
› Author Affiliations

Abstract

Neural repair is the underlying therapeutic strategy for many treatments currently under investigation to improve recovery after stroke. Repair-based therapies are distinct from acute stroke strategies: instead of salvaging threatened brain tissue, the goal is to improve behavioral outcomes on the basis of experience-dependent brain plasticity. Furthermore, timing, concomitant behavioral experiences, modality specific outcome measures, and careful patient selection are fundamental concepts for stroke recovery trials that can be deduced from principles of neural repair. Here we discuss core principles of neural repair and their implications for stroke recovery trials, highlighting related issues from key studies in humans. Research suggests a future in which neural repair therapies are personalized based on measures of brain structure and function, genetics, and lifestyle factors.

Disclosures

D.J.L. reports no disclosures. S.C.C. serves as a consultant for Constant Therapeutics, Neurolutions, MicroTransponder, SanBio, Fujifilm Toyama Chemical Co., NeuExcell, Medtronics, and TRCare.




Publication History

Article published online:
04 March 2021

© 2021. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 
  • References

  • 1 Lin DJ, Finklestein SP, Cramer SC. New directions in treatments targeting stroke recovery. Stroke 2018; 49 (12) 3107-3114
  • 2 Wieloch T, Nikolich K. Mechanisms of neural plasticity following brain injury. Curr Opin Neurobiol 2006; 16 (03) 258-264
  • 3 Nudo RJ. Neural bases of recovery after brain injury. J Commun Disord 2011; 44 (05) 515-520
  • 4 Carmichael ST. Emergent properties of neural repair: elemental biology to therapeutic concepts. Ann Neurol 2016; 79 (06) 895-906
  • 5 Weiller C, Chollet F, Friston KJ, Wise RJ, Frackowiak RS. Functional reorganization of the brain in recovery from striatocapsular infarction in man. Ann Neurol 1992; 31 (05) 463-472
  • 6 Weiller C, Isensee C, Rijntjes M. et al. Recovery from Wernicke's aphasia: a positron emission tomographic study. Ann Neurol 1995; 37 (06) 723-732
  • 7 Cramer SC, Nelles G, Benson RR. et al. A functional MRI study of subjects recovered from hemiparetic stroke. Stroke 1997; 28 (12) 2518-2527
  • 8 Carter AR, Astafiev SV, Lang CE. et al. Resting interhemispheric functional magnetic resonance imaging connectivity predicts performance after stroke. Ann Neurol 2010; 67 (03) 365-375
  • 9 Grefkes C, Fink GR. Connectivity-based approaches in stroke and recovery of function. Lancet Neurol 2014; 13 (02) 206-216
  • 10 Schaechter JD, Moore CI, Connell BD, Rosen BR, Dijkhuizen RM. Structural and functional plasticity in the somatosensory cortex of chronic stroke patients. Brain 2006; 129 (Pt 10): 2722-2733
  • 11 Gauthier LV, Taub E, Mark VW, Barghi A, Uswatte G. Atrophy of spared gray matter tissue predicts poorer motor recovery and rehabilitation response in chronic stroke. Stroke 2012; 43 (02) 453-457
  • 12 Cramer SC, Moore CI, Finklestein SP, Rosen BR. A pilot study of somatotopic mapping after cortical infarct. Stroke 2000; 31 (03) 668-671
  • 13 Cramer SC, Crafton KR. Somatotopy and movement representation sites following cortical stroke. Exp Brain Res 2006; 168 (1-2): 25-32
  • 14 Rosen HJ, Petersen SE, Linenweber MR. et al. Neural correlates of recovery from aphasia after damage to left inferior frontal cortex. Neurology 2000; 55 (12) 1883-1894
  • 15 Finklestein S, Ren J. Growth factors as treatments for stroke. In: Cramer SC, Nudo RJ. eds. Brain Repair After Stroke. Cambridge, UK: Cambridge University Press; 2010: 259-266
  • 16 Schäbitz WR, Laage R, Vogt G. et al. AXIS: a trial of intravenous granulocyte colony-stimulating factor in acute ischemic stroke. Stroke 2010; 41 (11) 2545-2551
  • 17 England TJ, Abaei M, Auer DP. et al. Granulocyte-colony stimulating factor for mobilizing bone marrow stem cells in subacute stroke: the stem cell trial of recovery enhancement after stroke 2 randomized controlled trial. Stroke 2012; 43 (02) 405-411
  • 18 Ringelstein EB, Thijs V, Norrving B. et al; AXIS 2 Investigators. Granulocyte colony-stimulating factor in patients with acute ischemic stroke: results of the AX200 for Ischemic Stroke trial. Stroke 2013; 44 (10) 2681-2687
  • 19 Cramer SC, Fitzpatrick C, Warren M. et al. The beta-hCG+ erythropoietin in acute stroke (BETAS) study: a 3-center, single-dose, open-label, noncontrolled, phase IIa safety trial. Stroke 2010; 41 (05) 927-931
  • 20 Yip HK, Tsai TH, Lin HS. et al. Effect of erythropoietin on level of circulating endothelial progenitor cells and outcome in patients after acute ischemic stroke. Crit Care 2011; 15 (01) R40
  • 21 Cramer SC, Hill MD. REGENESIS-LED Investigators. Human choriogonadotropin and epoetin alfa in acute ischemic stroke patients (REGENESIS-LED trial). Int J Stroke 2014; 9 (03) 321-327
  • 22 Li S, Carmichael ST. Growth-associated gene and protein expression in the region of axonal sprouting in the aged brain after stroke. Neurobiol Dis 2006; 23 (02) 362-373
  • 23 Cheatwood JL, Emerick AJ, Schwab ME, Kartje GL. Nogo-A expression after focal ischemic stroke in the adult rat. Stroke 2008; 39 (07) 2091-2098
  • 24 See J, Dodakian L, Chou C. et al. A standardized approach to the Fugl-Meyer assessment and its implications for clinical trials. Neurorehabil Neural Repair 2013; 27 (08) 732-741
  • 25 Cramer SC, Enney LA, Russell CK, Simeoni M, Thompson TR. Proof-of-concept randomized trial of the monoclonal antibody GSK249320 versus placebo in stroke patients. Stroke 2017; 48 (03) 692-698
  • 26 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 (14) 1277-1286
  • 27 Savitz SI. Developing cellular therapies for stroke. Stroke 2015; 46 (07) 2026-2031
  • 28 Crisostomo EA, Duncan PW, Propst M, Dawson DV, Davis JN. Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients. Ann Neurol 1988; 23 (01) 94-97
  • 29 Walker-Batson D, Smith P, Curtis S, Unwin H, Greenlee R. Amphetamine paired with physical therapy accelerates motor recovery after stroke. Further evidence. Stroke 1995; 26 (12) 2254-2259
  • 30 Scheidtmann K, Fries W, Müller F, Koenig E. Effect of levodopa in combination with physiotherapy on functional motor recovery after stroke: a prospective, randomised, double-blind study. Lancet 2001; 358 (9284): 787-790
  • 31 Ford GA, Bhakta BB, Cozens A. et al. Safety and efficacy of co-careldopa as an add-on therapy to occupational and physical therapy in patients after stroke (DARS): a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2019; 18 (06) 530-538
  • 32 Chollet F, Tardy J, Albucher JF. et al. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol 2011; 10 (02) 123-130
  • 33 Collaboration FT. FOCUS Trial Collaboration. Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial. Lancet 2019; 393 (10168): 265-274
  • 34 Joy MT, Ben Assayag E, Shabashov-Stone D. et al. CCR5 is a therapeutic target for recovery after stroke and traumatic brain injury. Cell 2019; 176 (05) 1143-1157.e13
  • 35 Hao Z, Wang D, Zeng Y, Liu M. Repetitive transcranial magnetic stimulation for improving function after stroke. Cochrane Database Syst Rev 2013; 5 (05) CD008862
  • 36 Shah PP, Szaflarski JP, Allendorfer J, Hamilton RH. Induction of neuroplasticity and recovery in post-stroke aphasia by non-invasive brain stimulation. Front Hum Neurosci 2013; 7: 888
  • 37 Harvey RL, Edwards D, Dunning K. et al; NICHE Trial Investigators. Randomized sham-controlled trial of navigated repetitive transcranial magnetic stimulation for motor recovery in stroke. Stroke 2018; 49 (09) 2138-2146
  • 38 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 2019; 33 (05) 847-864
  • 39 Jones TA, Schallert T. Overgrowth and pruning of dendrites in adult rats recovering from neocortical damage. Brain Res 1992; 581 (01) 156-160
  • 40 Stroemer RP, Kent TA, Hulsebosch CE. Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats. Stroke 1998; 29 (11) 2381-2393 , discussion 2393–2395
  • 41 Green AR, Hainsworth AH, Jackson DM. GABA potentiation: a logical pharmacological approach for the treatment of acute ischaemic stroke. Neuropharmacology 2000; 39 (09) 1483-1494
  • 42 Ovbiagele B, Kidwell CS, Starkman S, Saver JL. Neuroprotective agents for the treatment of acute ischemic stroke. Curr Neurol Neurosci Rep 2003; 3 (01) 9-20
  • 43 Kozlowski DA, Jones TA, Schallert T. Pruning of dendrites and restoration of function after brain damage: role of the NMDA receptor. Restor Neurol Neurosci 1994; 7 (02) 119-126
  • 44 Wahlgren NG, Martinsson L. New concepts for drug therapy after stroke. Can we enhance recovery?. Cerebrovasc Dis 1998; 8 (Suppl. 05) 33-38
  • 45 Barth T, Hoane M, Barbay S. et al. Effects of glutamate antagonists on the recovery and maintenance of behavioral function after brain injury. In: Goldstein L. ed. Restorative Neurology: Advances in Pharmacotherapy for Recovery After Stroke. Armonk, NY: Futura Publishing Co., Inc.; 1998
  • 46 Narasimhan P, Liu J, Song YS, Massengale JL, Chan PH. VEGF stimulates the ERK 1/2 signaling pathway and apoptosis in cerebral endothelial cells after ischemic conditions. Stroke 2009; 40 (04) 1467-1473
  • 47 Clarkson AN, Overman JJ, Zhong S, Mueller R, Lynch G, Carmichael ST. AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke. J Neurosci 2011; 31 (10) 3766-3775
  • 48 Zhao BQ, Tejima E, Lo EH. Neurovascular proteases in brain injury, hemorrhage and remodeling after stroke. Stroke 2007; 38 (2, Suppl): 748-752
  • 49 Allan SM, Rothwell NJ. Inflammation in central nervous system injury. Philos Trans R Soc Lond B Biol Sci 2003; 358 (1438): 1669-1677
  • 50 Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol 2006; 147 (Suppl. 01) S232-S240
  • 51 Ng KL, Gibson EM, Hubbard R. et al. Fluoxetine maintains a state of heightened responsiveness to motor training early after stroke in a mouse model. Stroke 2015; 46 (10) 2951-2960
  • 52 Biernaskie J, Chernenko G, Corbett D. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J Neurosci 2004; 24 (05) 1245-1254
  • 53 Hubel DH, Wiesel TN. The period of susceptibility to the physiological effects of unilateral eye closure in kittens. J Physiol 1970; 206 (02) 419-436
  • 54 LeVay S, Wiesel TN, Hubel DH. The development of ocular dominance columns in normal and visually deprived monkeys. J Comp Neurol 1980; 191 (01) 1-51
  • 55 Cramer SC, Chopp M. Recovery recapitulates ontogeny. Trends Neurosci 2000; 23 (06) 265-271
  • 56 Nahmani M, Turrigiano GG. Adult cortical plasticity following injury: Recapitulation of critical period mechanisms?. Neuroscience 2014; 283: 4-16
  • 57 Biernaskie J, Corbett D. Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury. J Neurosci 2001; 21 (14) 5272-5280
  • 58 Ren J, Kaplan PL, Charette MF, Speller H, Finklestein SP. Time window of intracisternal osteogenic protein-1 in enhancing functional recovery after stroke. Neuropharmacology 2000; 39 (05) 860-865
  • 59 Kolb B, Morshead C, Gonzalez C. et al. Growth factor-stimulated generation of new cortical tissue and functional recovery after stroke damage to the motor cortex of rats. J Cereb Blood Flow Metab 2007; 27 (05) 983-997
  • 60 Barbay S, Nudo RJ. The effects of amphetamine on recovery of function in animal models of cerebral injury: a critical appraisal. NeuroRehabilitation 2009; 25 (01) 5-17
  • 61 Barbay S, Plautz EJ, Friel KM. et al. Behavioral and neurophysiological effects of delayed training following a small ischemic infarct in primary motor cortex of squirrel monkeys. Exp Brain Res 2006; 169 (01) 106-116
  • 62 Hsu JE, Jones TA. Time-sensitive enhancement of motor learning with the less-affected forelimb after unilateral sensorimotor cortex lesions in rats. Eur J Neurosci 2005; 22 (08) 2069-2080
  • 63 Sugiyama Y, Higo N, Yoshino-Saito K. et al. Effects of early versus late rehabilitative training on manual dexterity after corticospinal tract lesion in macaque monkeys. J Neurophysiol 2013; 109 (12) 2853-2865
  • 64 Dromerick AW, Lang CE, Birkenmeier RL. et al. Very Early Constraint-Induced Movement during Stroke Rehabilitation (VECTORS): a single-center RCT. Neurology 2009; 73 (03) 195-201
  • 65 Lohse KR, Lang CE, Boyd LA. Is more better? Using metadata to explore dose-response relationships in stroke rehabilitation. Stroke 2014; 45 (07) 2053-2058
  • 66 AVERT Trial Collaboration Group. Efficacy and safety of very early mobilisation within 24 h of stroke onset (AVERT): a randomised controlled trial. Lancet 2015; 386 (9988): 46-55
  • 67 Feeney DM, Gonzalez A, Law WA. Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury. Science 1982; 217 (4562): 855-857
  • 68 García-Alías G, Barkhuysen S, Buckle M, Fawcett JW. Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nat Neurosci 2009; 12 (09) 1145-1151
  • 69 Fang PC, Barbay S, Plautz EJ, Hoover E, Strittmatter SM, Nudo RJ. Combination of NEP 1-40 treatment and motor training enhances behavioral recovery after a focal cortical infarct in rats. Stroke 2010; 41 (03) 544-549
  • 70 Starkey ML, Schwab ME. Anti-Nogo-A and training: can one plus one equal three?. Exp Neurol 2012; 235 (01) 53-61
  • 71 Hovda DA, Fenney DM. Amphetamine with experience promotes recovery of locomotor function after unilateral frontal cortex injury in the cat. Brain Res 1984; 298 (02) 358-361
  • 72 Adkins DL, Hsu JE, Jones TA. Motor cortical stimulation promotes synaptic plasticity and behavioral improvements following sensorimotor cortex lesions. Exp Neurol 2008; 212 (01) 14-28
  • 73 Adkins DL, Boychuk J, Remple MS, Kleim JA. Motor training induces experience-specific patterns of plasticity across motor cortex and spinal cord. J Appl Physiol (1985) 2006; 101 (06) 1776-1782
  • 74 Adkins-Muir DL, Jones TA. Cortical electrical stimulation combined with rehabilitative training: enhanced functional recovery and dendritic plasticity following focal cortical ischemia in rats. Neurol Res 2003; 25 (08) 780-788
  • 75 Boychuk JA, Schwerin SC, Thomas N. et al. Enhanced motor recovery after stroke with combined cortical stimulation and rehabilitative training is dependent on infarct location. Neurorehabil Neural Repair 2016; 30 (02) 173-181
  • 76 Jeffers MS, Hoyles A, Morshead C, Corbett D. Epidermal growth factor and erythropoietin infusion accelerate functional recovery in combination with rehabilitation. Stroke 2014; 45 (06) 1856-1858
  • 77 Jeffers MS, Corbett D. Synergistic effects of enriched environment and task-specific reach training on poststroke recovery of motor function. Stroke 2018; 49 (06) 1496-1503
  • 78 Papadopoulos CM, Tsai SY, Guillen V, Ortega J, Kartje GL, Wolf WA. Motor recovery and axonal plasticity with short-term amphetamine after stroke. Stroke 2009; 40 (01) 294-302
  • 79 Beltran EJ, Papadopoulos CM, Tsai SY, Kartje GL, Wolf WA. Long-term motor improvement after stroke is enhanced by short-term treatment with the alpha-2 antagonist, atipamezole. Brain Res 2010; 1346: 174-182
  • 80 Mattsson B, Sørensen JC, Zimmer J, Johansson BB. Neural grafting to experimental neocortical infarcts improves behavioral outcome and reduces thalamic atrophy in rats housed in enriched but not in standard environments. Stroke 1997; 28 (06) 1225-1231 , discussion 1231–1232
  • 81 Puurunen K, Jolkkonen J, Sirviö J, Haapalinna A, Sivenius J. Selegiline combined with enriched-environment housing attenuates spatial learning deficits following focal cerebral ischemia in rats. Exp Neurol 2001; 167 (02) 348-355
  • 82 Hicks AU, Hewlett K, Windle V. et al. Enriched environment enhances transplanted subventricular zone stem cell migration and functional recovery after stroke. Neuroscience 2007; 146 (01) 31-40
  • 83 Mering S, Jolkkonen J. Proper housing conditions in experimental stroke studies-special emphasis on environmental enrichment. Front Neurosci 2015; 9: 106
  • 84 Zai L, Ferrari C, Subbaiah S. et al. Inosine alters gene expression and axonal projections in neurons contralateral to a cortical infarct and improves skilled use of the impaired limb. J Neurosci 2009; 29 (25) 8187-8197
  • 85 Duncan PW, Sullivan KJ, Behrman AL. et al; LEAPS Investigative Team. Body-weight-supported treadmill rehabilitation after stroke. N Engl J Med 2011; 364 (21) 2026-2036
  • 86 Cramer SC, Dobkin BH, Noser EA, Rodriguez RW, Enney LA. Randomized, placebo-controlled, double-blind study of ropinirole in chronic stroke. Stroke 2009; 40 (09) 3034-3038
  • 87 Cramer SC. Repairing the human brain after stroke. II. Restorative therapies. Ann Neurol 2008; 63 (05) 549-560
  • 88 Johansson BB. Brain plasticity and stroke rehabilitation. The Willis lecture. Stroke 2000; 31 (01) 223-230
  • 89 Freburger JK, Holmes GM, Ku LJ, Cutchin MP, Heatwole-Shank K, Edwards LJ. Disparities in postacute rehabilitation care for stroke: an analysis of the state inpatient databases. Arch Phys Med Rehabil 2011; 92 (08) 1220-1229
  • 90 Cramer SC, Koroshetz WJ, Finklestein SP. The case for modality-specific outcome measures in clinical trials of stroke recovery-promoting agents. Stroke 2007; 38 (04) 1393-1395
  • 91 Goodman AD, Brown TR, Edwards KR. et al; MSF204 Investigators. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol 2010; 68 (04) 494-502
  • 92 Hier DB, Mondlock J, Caplan LR. Recovery of behavioral abnormalities after right hemisphere stroke. Neurology 1983; 33 (03) 345-350
  • 93 Marshall JW, Cross AJ, Jackson DM, Green AR, Baker HF, Ridley RM. Clomethiazole protects against hemineglect in a primate model of stroke. Brain Res Bull 2000; 52 (01) 21-29
  • 94 Markgraf CG, Green EJ, Hurwitz BE. et al. Sensorimotor and cognitive consequences of middle cerebral artery occlusion in rats. Brain Res 1992; 575 (02) 238-246
  • 95 Stinear CM, Barber PA, Smale PR, Coxon JP, Fleming MK, Byblow WD. Functional potential in chronic stroke patients depends on corticospinal tract integrity. Brain 2007; 130 (Pt 1): 170-180
  • 96 Riley JD, Le V, Der-Yeghiaian L. et al. Anatomy of stroke injury predicts gains from therapy. Stroke 2011; 42 (02) 421-426
  • 97 Marchina S, Zhu LL, Norton A, Zipse L, Wan CY, Schlaug G. Impairment of speech production predicted by lesion load of the left arcuate fasciculus. Stroke 2011; 42 (08) 2251-2256
  • 98 Lai SM, Duncan PW, Keighley J, Johnson D. Depressive symptoms and independence in BADL and IADL. J Rehabil Res Dev 2002; 39 (05) 589-596
  • 99 Gillen R, Tennen H, McKee TE, Gernert-Dott P, Affleck G. Depressive symptoms and history of depression predict rehabilitation efficiency in stroke patients. Arch Phys Med Rehabil 2001; 82 (12) 1645-1649
  • 100 Cramer SC, Parrish TB, Levy RM. et al. Predicting functional gains in a stroke trial. Stroke 2007; 38 (07) 2108-2114
  • 101 Wu J, Srinivasan R, Burke Quinlan E, Solodkin A, Small SL, Cramer SC. Utility of EEG measures of brain function in patients with acute stroke. J Neurophysiol 2016; 115 (05) 2399-2405
  • 102 Wang LE, Fink GR, Diekhoff S, Rehme AK, Eickhoff SB, Grefkes C. Noradrenergic enhancement improves motor network connectivity in stroke patients. Ann Neurol 2011; 69 (02) 375-388
  • 103 Siegel JS, Ramsey LE, Snyder AZ. et al. Disruptions of network connectivity predict impairment in multiple behavioral domains after stroke. Proc Natl Acad Sci U S A 2016; 113 (30) E4367-E4376
  • 104 Kato M, Serretti A. Review and meta-analysis of antidepressant pharmacogenetic findings in major depressive disorder. Mol Psychiatry 2010; 15 (05) 473-500
  • 105 Kohen R, Cain KC, Buzaitis A. et al. Response to psychosocial treatment in poststroke depression is associated with serotonin transporter polymorphisms. Stroke 2011; 42 (07) 2068-2070
  • 106 Pearson-Fuhrhop KM, Minton B, Acevedo D, Shahbaba B, Cramer SC. Genetic variation in the human brain dopamine system influences motor learning and its modulation by L-Dopa. PLoS One 2013; 8 (04) e61197
  • 107 MacDonald HJ, Stinear CM, Ren A. et al. Dopamine gene profiling to predict impulse control and effects of dopamine agonist ropinirole. J Cogn Neurosci 2016; 28 (07) 909-919
  • 108 Diaz Heijtz R, Almeida R, Eliasson AC, Forssberg H. Genetic variation in the dopamine system influences intervention outcome in children with cerebral palsy. EBioMedicine 2018; 28: 162-167
  • 109 Fridriksson J, Elm J, Stark BC. et al. BDNF genotype and tDCS interaction in aphasia treatment. Brain Stimul 2018; 11 (06) 1276-1281
  • 110 Stinear CM, Barber PA, Petoe M, Anwar S, Byblow WD. The PREP algorithm predicts potential for upper limb recovery after stroke. Brain 2012; 135 (Pt 8): 2527-2535
  • 111 Burke Quinlan E, Dodakian L, See J. et al. Neural function, injury, and stroke subtype predict treatment gains after stroke. Ann Neurol 2015; 77 (01) 132-145
  • 112 Nouri S, Cramer SC. Anatomy and physiology predict response to motor cortex stimulation after stroke. Neurology 2011; 77 (11) 1076-1083
  • 113 Crinion JT, Leff AP. Using functional imaging to understand therapeutic effects in poststroke aphasia. Curr Opin Neurol 2015; 28 (04) 330-337
  • 114 Cramer SC, Wolf SL, Adams Jr HP. et al. Stroke recovery and rehabilitation research: issues, opportunities, and the National Institutes of Health StrokeNet. Stroke 2017; 48 (03) 813-819
  • 115 Cramer SC, Dodakian L, Le V. et al; National Institutes of Health StrokeNet Telerehab Investigators. Efficacy of home-based telerehabilitation vs in-clinic therapy for adults after stroke: a randomized clinical trial. JAMA Neurol 2019; 76 (09) 1079-1087
  • 116 Fridriksson J, Rorden C, Elm J, Sen S, George MS, Bonilha L. Transcranial direct current stimulation vs sham stimulation to treat aphasia after stroke: a randomized clinical trial. JAMA Neurol 2018; 75 (12) 1470-1476
  • 117 Patsopoulos NA. A pragmatic view on pragmatic trials. Dialogues Clin Neurosci 2011; 13 (02) 217-224
  • 118 Ford G, Farrin A, Hartley S. et al. The DARS (Dopamine Augmented Rehabilitation in Stroke) Trial. Presented at the 10th UK Stroke Forum Conference Liverpool; 2015
  • 119 Wolf SL, Winstein CJ, Miller JP. et al; EXCITE Investigators. Effect of constraint-induced movement therapy on upper extremity function 3 to 9 months after stroke: the EXCITE randomized clinical trial. JAMA 2006; 296 (17) 2095-2104
  • 120 Ward NS, Brander F, Kelly K. Intensive upper limb neurorehabilitation in chronic stroke: outcomes from the Queen Square programme. J Neurol Neurosurg Psychiatry 2019; 90 (05) 498-506
  • 121 Lo AC, Guarino PD, Richards LG. et al. Robot-assisted therapy for long-term upper-limb impairment after stroke. N Engl J Med 2010; 362 (19) 1772-1783
  • 122 Rodgers H, Bosomworth H, Krebs HI. et al. Robot assisted training for the upper limb after stroke (RATULS): a multicentre randomised controlled trial. Lancet 2019; 394 (10192): 51-62
  • 123 Kwakkel G, Winters C, van Wegen EE. et al; EXPLICIT-Stroke Consortium. Effects of unilateral upper limb training in two distinct prognostic groups early after stroke: the EXPLICIT-stroke randomized clinical trial. Neurorehabil Neural Repair 2016; 30 (09) 804-816
  • 124 Levy RM, Harvey RL, Kissela BM. et al. Epidural electrical stimulation for stroke rehabilitation: results of the prospective, multicenter, randomized, single-blinded EVEREST trial. Neurorehabil Neural Repair 2016; 30 (02) 107-119
  • 125 Brown JA, Lutsep HL, Weinand M, Cramer SC. Motor cortex stimulation for the enhancement of recovery from stroke: a prospective, multicenter safety study. Neurosurgery 2006; 58 (03) 464-473