Restricted accessResearch articleFirst published online 2017-7
Enhancing the alignment of the preclinical and clinical stroke recovery research pipeline: Consensus-based core recommendations from the Stroke Recovery and Rehabilitation Roundtable translational working group
Stroke recovery research involves distinct biological and clinical targets compared to the study of acute stroke. Guidelines are proposed for the pre-clinical modeling of stroke recovery and for the alignment of pre-clinical studies to clinical trials in stroke recovery.
HayMThomasDWCraigheadJLEconomidesCRosenthalJ. Clinical development success rates for investigational drugs. Nat Biotechnol2014; 32: 40–51.
2.
MarchettiSSchellensJHM. The impact of FDA and EMEA guidelines on drug development in relation to Phase 0 trials. Br J Cancer2007; 97: 577–581.
3.
GladstoneDJBlackSEHakimAM. Heart and Stroke Foundation of Ontario Centre of Excellence in Stroke Recovery. Toward wisdom from failure: lessons from neuroprotective stroke trials and new therapeutic directions. Stroke2002; 33: 2123–2136.
4.
O’CollinsVEMacleodMRDonnanGAHorkyLLvan der WorpBHHowellsDW. 1,026 experimental treatments in acute stroke. Ann Neurol2006; 59: 467–477.
5.
KochanekPMBramlettHMDixonCE. Approach to modeling, therapy evaluation, drug selection, and biomarker assessments for a multicenter pre-clinical drug screening consortium for acute therapies in severe traumatic brain injury: operation brain trauma therapy. J Neurotrauma2016; 33: 513–522.
6.
CarmichaelST. Emergent properties of neural repair: elemental biology to therapeutic concepts. Ann Neurol2016; 79: 895–906.
7.
BiernaskieJChernenkoGCorbettD. Efficacy of rehabilitative experience declines with time after focal ischemic brain injury. J Neurosci2004; 24: 1245–1254.
8.
MurphyTHCorbettD. Plasticity during stroke recovery: from synapse to behaviour. Nat Rev Neurosci2009; 10: 861–872.
9.
WahlA-SSchwabME. Finding an optimal rehabilitation paradigm after stroke: enhancing fiber growth and training of the brain at the right moment. Front Hum Neurosci2014; 8: 381.
10.
BernhardtJBorschmannKBoydL. Moving rehabilitation research forward: developing consensus statements for rehabilitation and recovery research. Int J Stroke2016; 11: 454–458.
11.
FisherMFeuersteinGHowellsDW. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke2009; 40: 2244–2250.
12.
SavitzSIChoppMDeansR. Stem cell therapy as an emerging paradigm for stroke (STEPS) II. Stroke2011; 42: 825–829.
13.
CummingTBMarshallRSLazarRM. Stroke, cognitive deficits, and rehabilitation: still an incomplete picture. Int J Stroke2013; 8: 38–45.
14.
FluriFSchuhmannMKKleinschnitzC. Animal models of ischemic stroke and their application in clinical research. Drug Des Dev Ther2015; 9: 3445–3454.
15.
CaleoM. Rehabilitation and plasticity following stroke: insights from rodent models. Neuroscience2015; 311: 180–194.
16.
JolkkonenJJokivarsiKLaitinenTGröhnO. Subacute hemorrhage and resolution of edema in rose bengal stroke model in rats coincides with improved sensorimotor functions. Neurosci Lett2007; 428: 99–102.
17.
LaiSPanareseASpallettiC. Quantitative kinematic characterization of reaching impairments in mice after a stroke. Neurorehabil Neural Repair2015; 29: 382–392.
18.
ChoJKwonD-HKimRG. Remodeling of neuronal circuits after reach training in chronic capsular stroke. Neurorehabil Neural Repair2016; 30: 941–950.
19.
BouetVBoulouardMToutainJ. The adhesive removal test: a sensitive method to assess sensorimotor deficits in mice. Nat Protoc2009; 4: 1560–1564.
20.
BogousslavskyJVan MelleGRegliF. The Lausanne Stroke Registry: analysis of 1,000 consecutive patients with first stroke. Stroke1988; 19: 1083–1092.
21.
CorbettaMRamseyLCallejasA. Common behavioral clusters and subcortical anatomy in stroke. Neuron2015; 85: 927–941.
22.
El AmkiMClavierTPerzoNBernardRGuichetPOCastelH. Hypothalamic, thalamic and hippocampal lesions in the mouse MCAO model: potential involvement of deep cerebral arteries?J Neurosci Meth2015; 254: 80–85.
23.
SharkeyJRitchieIMKellyPAT. Perivascular microapplication of endothelin-1: a new model of focal cerebral ischaemia in the rat. J Cereb Blood Flow Metab1993; 13: 865–871.
24.
WindleVSzymanskaAGranter-ButtonS. An analysis of four different methods of producing focal cerebral ischemia with endothelin-1 in the rat. Exp Neurol2006; 201: 324–334.
25.
SozmenEGHinmanJDCarmichaelST. Models that matter: white matter stroke models. Neurotherapeutics2012; 9: 349–358.
26.
RouillerEMMoretVLiangF. Comparison of the connectional properties of the two forelimb areas of the rat sensorimotor cortex: support for the presence of a premotor or supplementary motor cortical area. Somatosens Mot Res1993; 10: 269–289.
27.
AlstermarkBOgawaJIsaT. Lack of monosynaptic corticomotoneuronal EPSPs in rats: disynaptic EPSPs mediated via reticulospinal neurons and polysynaptic EPSPs via segmental interneurons. J Neurophysiol2004; 91: 1832–1839.
28.
YangH-WLemonRN. An electron microscopic examination of the corticospinal projection to the cervical spinal cord in the rat: lack of evidence for cortico-motoneuronal synapses. Exp Brain Res2003; 149: 458–469.
29.
CookDJTevesLTymianskiM. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain - with comments. Nature2012; 483: 213–217.
30.
MergenthalerPMeiselA. Do stroke models model stroke?Dis Model Mech2012; 5: 718–725.
31.
WhishawIQPellisSM. The structure of skilled forelimb reaching in the rat: a proximally driven movement with a single distal rotatory component. Behav Brain Res1990; 41: 49–59.
32.
MontoyaCPCampbell-HopeLJPembertonKDDunnettSB. The “staircase test” a measure of independent forelimb reaching and grasping abilities in rats. J Neurosci Meth1993; 36: 219–228.
33.
AllredRPJonesTA. Experience – a double edged sword for restorative neural plasticity after brain damage. Future Neurol2008; 3: 189–198.
34.
MaclellanCLLangdonKDBotsfordAButtSCorbettD. A model of persistent learned nonuse following focal ischemia in rats. Neurorehabil Neural Repair2013; 27: 900–907.
35.
JonesTASchallertT. Use-dependent growth of pyramidal neurons after neocortical damage. J Neurosci1994; 14: 2140–2152.
36.
BiernaskieJCorbettD. Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury. J Neurosci2001; 21: 5272–5280.
37.
MetzGAWhishawIQ. Cortical and subcortical lesions impair skilled walking in the ladder rung walking test: a new task to evaluate fore-and hindlimb stepping, placing and coordination. J Neurosci Meth2002; 115: 169–179.
38.
ZörnerBSchwabME. Anti-Nogo on the go: from animal models to a clinical trial. Ann N Y Acad Sci2010; 1198: E22–E34.
39.
KerrALChefferKACurtisMCRodriguezA. Long-term deficits of the paretic limb follow post-stroke compensatory limb use in C57BL/6 mice. Behav Brain Res2016; 303: 103–108.
40.
ClarksonANOvermanJJZhongSMuellerRLynchGCarmichaelST. AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke. J Neurosci2011; 31: 3766–3775.
41.
TennantKAJonesTA. Sensorimotor behavioral effects of endothelin-1 induced small cortical infarcts in C57BL/6 mice. J Neurosci Meth2009; 181: 18–26.
42.
KwakkelGKollenBJVan der GrondJVPrevoAJH. Probability of regaining dexterity in the flaccid upper limb: impact of severity of paresis and time since onset in acute stroke. Stroke2003; 34: 2181–2186.
43.
TeasellRRiceDRichardsonM. The next revolution in stroke care. Expert Rev Neurother2014; 14: 1307–1314.
44.
LevinMFKleimJAWolfSL. What do motor “recovery” and “compensation” mean in patients following stroke?Neurorehabil Neural Repair2009; 23: 313–319.
45.
LambercyOSchubring-GieseMVigaruBGassertRLuftARHospJA. Sub-processes of motor learning revealed by a robotic manipulandum for rodents. Behav Brain Res2015; 278: 569–576.
46.
DancauseNNudoRJ. Shaping plasticity to enhance recovery after injury. Prog Brain Res2011; 192: 273–295.
47.
StroemerRPKentTAHulseboschCE. Neocortical neural sprouting, synaptogenesis, and behavioral recovery after neocortical infarction in rats. Stroke1995; 26: 2135–2144.
48.
KohmuraEYuguchiTYamadaKSakaguchiTHayakawaT. Recombinant basic fibroblast growth factor spares thalamic neurons from retrograde degeneration after ablation of the somatosensory cortex in rats. Restor Neurol Neurosci1994; 6: 309–16.
49.
ZhangY-HBeleguVZouY. Endoplasmic reticulum protein 29 protects axotomized neurons from apoptosis and promotes neuronal regeneration associated with erk signal. Mol Neurobiol2015; 52: 522–532.
50.
HungCLinC-HChangH. Astrocytic GAP43 induced by the TLR4/NF-κB/STAT3 axis attenuates astrogliosis-mediated microglial activation and neurotoxicity. J Neurosci2016; 36: 2027–2043.
51.
BachmannLCLindauNTFelderPSchwabME. Sprouting of brainstem-spinal tracts in response to unilateral motor cortex stroke in mice. J Neurosci2014; 34: 3378–3389.
52.
WahlASOmlorWRubioJC. Neuronal repair. Asynchronous therapy restores motor control by rewiring of the rat corticospinal tract after stroke. Science2014; 344: 1250–1255.
53.
CarterAShulmanGCorbettaM. Why use a connectivity-based approach to study stroke and recovery of function?Neuroimage2012; 62: 2271–2280.
54.
GrefkesCFinkG. Connectivity-based approaches in stroke and recovery of function. Lancet Neurol2014; 13: 206–216.
55.
Dacosta-AguayoRGrañaMSavioA. Prognostic value of changes in resting-state functional connectivity patterns in cognitive recovery after stroke: a 3T fMRI pilot study. Hum Brain Mapp2014; 35: 3819–3831.
56.
BrownCEAminoltejariKErbHWinshipIRMurphyTH. In vivo voltage-sensitive dye imaging in adult mice reveals that somatosensory maps lost to stroke are replaced over weeks by new structural and functional circuits with prolonged modes of activation within both the peri-infarct zone and distant sites. J Neurosci2009; 29: 1719–1734.
LiSNieEHYinY. GDF10 is a signal for axonal sprouting and functional recovery after stroke. Nat Neurosci2015; 18: 1737–1745.
59.
OvermanJJClarksonANWannerIB. A role for ephrin-A5 in axonal sprouting, recovery, and activity-dependent plasticity after stroke. Proc Natl Acad Sci U S A2012; 109: E2230–E2239.
60.
SilasiGMurphyTH. Stroke and the connectome: how connectivity guides therapeutic intervention. Neuron2014; 83: 1354–1368.
61.
StinearC. Prediction of recovery of motor function after stroke. Lancet Neurol2010; 9: 1228–1232.
62.
WardNS. Does neuroimaging help to deliver better recovery of movement after stroke?Curr Opin Neurol2015; 28: 323–329.
63.
van MeerMPAOtteWMvan der MarelK. Extent of bilateral neuronal network reorganization and functional recovery in relation to stroke severity. J Neurosci2012; 32: 4495–4507.
64.
van MeerMPAvan der MarelKvan der SprenkelJWBDijkhuizenRM. MRI of bilateral sensorimotor network activation in response to direct intracortical stimulation in rats after unilateral stroke. J Cereb Blood Flow Metab2011; 31: 1583–1587.
65.
CarmichaelST. Cellular and molecular mechanisms of neural repair after stroke: making waves. Ann Neurol2006; 59: 735–742.
StarkeyMLSchwabME. Anti-Nogo-A and training: can one plus one equal three?Exp Neurol2012; 235: 53–61.
68.
ZaiLFerrariCDiceC. Inosine augments the effects of a nogo receptor blocker and of environmental enrichment to restore skilled forelimb use after stroke. J Neurosci2011; 31: 5977–5988.
69.
CholletFTardyJAlbucherJF. Fluoxetine for motor recovery after acute ischaemic stroke (FLAME): a randomised placebo-controlled trial. Lancet Neurol2011; 10: 123–130.
70.
WardNSNewtonJMSwayneOB. Motor system activation after subcortical stroke depends on corticospinal system integrity. Brain2006; 129: 809–819.
71.
PloughmanMWindleVMacLellanCLWhiteNDoréJJCorbettD. Brain-derived neurotrophic factor contributes to recovery of skilled reaching after focal ischemia in rats. Stroke2009; 40: 1490–1495.
72.
LakeEMRChaudhuriJThomasonL. The effects of delayed reduction of tonic inhibition on ischemic lesion and sensorimotor function. J Cereb Blood Flow Metab2015; 35: 1601–1609.
73.
BarakSDuncanPW. Issues in selecting outcome measures to assess functional recovery after stroke. NeuroRx2006; 3: 505–524.