Review ArticlePhysical Exercise as a Diagnostic Rehabilitationand Preventive Tool Influence on Neuroplasticity andMotor Recovery after Stroke

Caroline Pin-Barre12 and Jeacuterocircme Laurin1

1Aix Marseille Universite CNRS ISM UMR 7287 13288 Marseille France2Universite de Nice Sophia-Antipolis et Universite de Sud Toulon-Var LAMHESS UPRES EA 630906204 Nice France

Correspondence should be addressed to Jerome Laurin jeromelaurinuniv-amufr

Received 30 January 2015 Revised 3 June 2015 Accepted 18 June 2015

Academic Editor Brandon A Miller

Copyright copy 2015 C Pin-Barre and J Laurin This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Stroke remains a leading cause of adult motor disabilities in the world and accounts for the greatest number of hospitalizations forneurological disease Stroke treatmentstherapies need to promote neuroplasticity to improve motor function Physical exerciseis considered as a major candidate for ultimately promoting neural plasticity and could be used for different purposes inhuman and animal experiments First acute exercise could be used as a diagnostic tool to understand new neural mechanismsunderlying stroke physiopathology Indeed better knowledge of stroke mechanisms that affect movements is crucial for enhancingtreatmentrehabilitation effectiveness Secondly it is well established that physical exercise training is advised as an effectiverehabilitation tool Indeed it reduces inflammatory processes and apoptotic marker expression promotes brain angiogenesisand expression of some growth factors and improves the activation of affected muscles during exercise Nevertheless exercisetraining might also aggravate sensorimotor deficits and brain injury depending on the chosen exercise parameters For the last fewyears physical training has been combined with pharmacological treatments to accentuate andor accelerate beneficial neural andmotor effects Finally physical exercise might also be considered as a major nonpharmacological preventive strategy that providesneuroprotective effects reducing adverse effects of brain ischemia Therefore prestroke regular physical activity may also decreasethe motor outcome severity of stroke

1 Introduction

Despite progress in functional rehabilitation stroke patientsfrequently present chronic motor disabilities [1] Thereforeit seems crucial that both scientists and therapists con-tinue to investigate stroke physiopathology and improvethe effectiveness of physical training programs on motorrecovery In recent years physical exercise was used in strokeexperiments for 3 main purposes namely the detection ofphysical dysfunctions the improvement of motor activityand the prevention of severe damage Such contributionsmight ultimately improve both physical independence andquality of life while reducing cardiovascular complicationsand recurrent stroke [2 3]

First acute fatiguing exercise is used in preclinical exper-iments as a diagnostic tool to detect sensorimotor dysfunc-tions andor reveal treatment effectiveness that cannot beobserved in resting condition Indeed alteration of motorunit activation in both affected and unaffected sides orchanges of the motor reflex regulation were highlightedduringafter acute exercise [4 5] Moreover a higher corti-cospinal tract activity was found only after acute treadmillexercise in trained patients contrary to untrained patients[6]

Then added to its beneficial effects on cardiorespiratoryfitness and muscular endurance chronic physical activityis effective as a rehabilitation tool for improving functionalrecovery and promoting neural plasticity [3 7] Indeed it

Hindawi Publishing CorporationNeural PlasticityVolume 2015 Article ID 608581 12 pageshttpdxdoiorg1011552015608581

2 Neural Plasticity

was recently found that physical training promoted cerebralangiogenesis vasomotor reactivity and neurotrophic factorrelease but also reduced apoptosis processes excitotoxicityand inflammation into the peri-infarct site and could improvethe regulation of motor unit activation [8ndash12]

Nevertheless physical training seems to remain insuffi-cient to completely restore neural and motor functions Arecent approach for stroke therapy is to combine physicaltraining with pharmacological treatments known to accen-tuate andor accelerate neuroplasticity In the present reviewwe discuss the influence of physical training with or withoutadditional pharmacological treatment on neuroplasticity andmotor recovery after stroke

Although regular exercise reduces the risk of developingstroke [13] it may occur for physically active individuals [1415] However endogenous neuroprotective effects induced byprestroke physical activitymay exhibit beneficial influence onrecovery by reducing both brain damage and motor outcomeseverity [16ndash19]

Thepresent review is designed to discuss themultiple usesof physical exercise to improve neural and motor recoveryfollowing cerebral ischemiastroke from both animal andhuman studies We suggested that exercise-induced neuralplasticity is crucial to better understanding motor outcomesafter stroke and improving rehabilitation program effective-ness

2 Acute Exercise-Induced NeuralAdjustments after Stroke

Animal and human studies reported that acute exercise couldreveal changes in muscle activation regulation after cere-bral ischemia More precisely the electromyographic (EMG)activity was lower in affected hindlimb muscles during asingle bout of treadmill exercise compared to unaffectedmuscles reflecting a strong decrease of the motoneuronalrecruitment from spinal andor supraspinal motor pathways[4 20] A reduced corticospinal excitability to the pareticquadriceps was also observed by showing strong decrease ofthe motor evoked potential (MEP) amplitude during a run-ning exercise [4] In addition cortical activation increased inthe unaffected side while it decreased in the affected side afterankle dorsiflexion movements that suggested compensatoryneural mechanisms [21ndash26]

Spinal motor reflex plasticity also seems to contributeto motor disorders after stroke but the underlying neuralmechanisms remain poorly understood [36 37] A recentstudy has demonstrated that the motor reflex regulation (Hreflex) was acutely altered following an exhaustive isometricexercise on affected triceps brachii in MCAO rats whereasrestingH reflex did not differ between injured andnoninjuredanimals [5] It was postulated that such findings might bepartially due to an alteration of motor reflex regulation bymuscle afferents that remained activated after intense exercise(groups III and IV muscle afferents)

Fatigue process alterations could also be observed duringdynamic exercise after cerebral ischemia by using EMGrecording When fatigue progresses there is a shift to lowermotor unit frequencies Median power frequency (MPF)

which is the sum of product of the EMG power spectrumand the frequency divided by the total sum of the powerspectrum is frequently used for the assessment of musclefatigue in surface EMG signals [38] Therefore a decreasein MPF serves as an index of fatigue [39] After cerebralischemia the observed MPF drop at the unaffected hindlimbreflected a higher muscle fatigue compared to the affectedone (no MPF decrement) A lesser fatigue-related decreasein median frequency was also observed in humans at theparetic side compared to the nonparetic side during bothvoluntary contractions and locomotor activity [20 40] Thisaccelerated fatigue process of the unaffected hindlimb wasusually explained by its higher weight bearing that com-pensated for the affected side Nevertheless reduction ofwork without MPF decrease of affected muscle was reportedduring repeated eccentric-concentric actions suggesting thatperipheral fatigue through excitation-contraction couplingdisruption might contribute to exercise intolerance andneuromuscular disorders of stroke patients [41]

It was also found that acute exercise-induced neuraladjustments could reveal the effectiveness of a given treat-ment Indeed Forrester and colleagues have first comparedtrained and untrained stroke patients on the observed neuralresponse to a single bout of treadmill exercise [6] Theyfound that the MEP amplitude increased in trained patientsafter this exercise contrary to untrained individuals inwhich MEP amplitude remained unchanged Such trainingcorticospinal adaptation was not observed in the preexerciseMEP amplitudes but only after exercise and provided insightinto the effectiveness of 6-month treadmill training [6]

3 Effects of Poststroke Physical Training onNeuroplasticity and Motor Recovery

The effects of chronic physical training in stroke patientshave received more attention in scientific literature thanthe ones of acute exercise Indeed physical rehabilitationremains the first-line intervention strategy to attenuatechronic impairments of sensorimotor function by promotingbrain organization and reducing infarct volume during thefirst weeks after stroke [42 43] Given that the infarct size wasnot always correlated with motor recovery it was suggestedthat other adaptive mechanisms might take part [44 45]Numerous recent studies indicated that early treadmill train-ing promotes neuroplasticity by acting on brain vasomotoractivity and angiogenesis neurotrophic factor and apoptosismarker expressions brain inflammatory processes bloodbrain barrier (BBB) integrity and muscle activation control(Figure 1) [46ndash48]

Cerebral blood flow in the ischemic region is affectedfollowing human stroke and cerebral ischemia in mice dueto impaired cerebral vasomotor reactivity [8 49] Thereforerestoring an adequate cerebral vasomotor reserve capacityis crucial to supplying required nutriments and O

2 as

well as reducing infarct volume and functional deficits [5051] Preclinical and clinical studies bring strong evidenceon endurance training effectiveness to promote vasomo-tor reactivity (endothelium-dependent vasorelaxation) andangiogenesis in the ischemic penumbra which contribute to

Neural Plasticity 3

speed

Physical exercise

infarct volume

BBB permeability

muscle fatigue

adaptive neuroplasticity and brain activity during movement

angiogenesis cerebral vasomotor reactivity mitochondrial biogenesis

EMG burst duration (paretic side)

balance and motor coordination body weight support and walking

limb placement test score

cholinergic system regulation

Figure 1 Beneficial structural and functional plasticity induced byphysical exercise in stroke individuals

limiting brain damage and motor deficits [9 50] Indeedtreadmill training increased the most commonly stud-ied angiogenic growth factor expression namely vascularendothelial growth factor (VEGF) and its regulatory proteincaveolin-1 that might contribute to explaining the increaseof new vessel growth and vascular density [52ndash56] Thetraining effect on angiogenesis was reinforced by evidenceshowing that 2 weeks of treadmill training increased theangiopoietin expression another angiogenic growth factorthat has a key role in new vessel formation [54] Otherfindings revealed that the area of platelet-endothelial celladhesion molecule- (PECAM-1-) immunopositive cells (pro-tein involved in angiogenesis and integrin activation) wassignificantly increased around the infarct after 28 days oftreadmill training [46] Daily treadmill training induced anincrease of GFAP expression (proteins playing a role invascular cerebral plasticity) suggesting that area of neovas-cularization was higher in exercised animals [47] More-over voluntary running training upregulated by 3- to 4-fold aortic endothelial nitric oxide synthase (eNOS) mRNAexpression and it remained elevated 10 days after training[8 9] Such findings concur with the fact that beneficialeffect of running was completely abolished in animals lackingeNOS expression and in mice treated with a NOS inhibitoror an antiangiogenic compound such as endostatin [9]Moreover training program increased endothelial progenitorcells (EPC) in bone marrow that are known to stronglyinfluence eNOS expression It is noteworthy to add thatonly 3 days of aerobic exercise reduced brain microvascularendothelial cell apoptosis related to the increase of shearstress that was followed by modest improvement of cerebralblood flow [51]

Physical training can also upregulate the expressionof some neurotrophic factors such as brain-derived neu-rotrophic factor (BDNF) nerve growth factor (NGF) andinsulin-like growth factor (IGF-1)

BDNF is one of the most active neurotrophins thatbinds to the tyrosine kinase receptor (trkB) Overall thisassociation triggers several molecular pathways that promoteneural proliferation and survival and synaptic and axonalplasticity by enhancing synapse formation dendritic growthand remodeling [57] Furthermore BDNF seems also to acton motor function because blocking BDNF mRNA expres-sion by injecting antagonist reduced skilled motor abilities[58]

The neuroprotective effect of endogenous and exogenousBDNF is well established after brain infarction [12 59ndash62]Basal endogenous BDNFtrkB expression increased withinboth hemispheres following moderate cerebral ischemia(including the penumbra) during the first 2 weeks butmotor recovery remains widely insufficient [63ndash65] There-fore treatments that enhance BDNFtrkB production seemrelevant to improve motor recovery (even if infarct size isnot modified) [11 66] It was found that delayed intravenousBDNF administration (20 120583gday) for 5 days improved long-term functional outcomes such as running and sensorimotorrecovery after ischemia [11 66 67]

Interestingly endurance training stimulated endogenousBDNFtkrB expression and may play a neuroplastic rolefollowing cerebral ischemia or intracerebral hemorrhage inrat and mice [58 63 68ndash72] This enhanced BDNFtkrBwas observed in both hemispheres but especially in thenonlesional hemisphere compared to healthy animals underthe same program (that might represent a compensatorymechanism) [53 69] Despite the fact that there is no directevidence the training-related BDNF expression is oftenassociated with motor recovery improvement [58 63 70] Itwas demonstrated that 7 consecutive training days could besufficient to increase BDNF expression and improve motorrecovery [72ndash74] Although endurance exercise upregulatesBDNF expression in striatum and cortex functional outcomeimprovement might be more related to hippocampal BDNFexpression [70 72] Indeed voluntary wheel exercise isknown to induce substantial motor recovery associated withthe highest hippocampal BDNF level [70] Another study alsofound a positive correlation betweenmotor function recoveryrate and hippocampal BDNF expression after treadmill train-ing following cerebral infarction [72]

Finally the number of NGF-immunopositive cells pro-moting cell growth and neuronal activity was particularlyincreased over a widespread region around the infarct zonein trained rats [46] NGF expression which may be theresult of heightened neuronal activity during exercise couldcontribute to reducing brain damage around 4 weeks afterischemic stroke

Physical training could reduce ischemic brain damageand motor deficits by other mechanisms such as reductionof acute inflammatory reactions and neuronal apoptosis [75]Indeed it was demonstrated that the neurotrophic factormidkine (MK) which could delay the process of neuronaldeath during the early phase after cerebral infarction washigher expressed in the cells of the peri-infarct region afterphysical training program [46]

Cerebral ischemia-induced cell death is commonlyattributed to necrosis and apoptosis but it was recently found

4 Neural Plasticity

that inappropriate autophagy might also lead to cell death[76] However physical training mitigated autophagosomesaccumulation and attenuated apoptosis in the peri-infarctregion while improving the modified neurological severityscore scale Physical training could also upregulate IGF-1expression which is known to attenuate autophagy and alsoto promote neurogenesis [75]

In addition several studies reported that neuronal deathin both the striatum and the cerebral cortex caused a degen-eration of nigral dopaminergic neurons that are known tocontribute to regulating motor activity [77] However tread-mill training promoted axon regeneration of newborn stri-atonigral and corticonigral projection neurons in ischemicbrain while improving motor function It was thus suggestedthat exercise could enhance restoration of functional neuralcircuitry within the basal ganglia The cerebellum plays animportant role in the motor coordination learning andequilibrium and also seems to be involved in motor deficitsfollowing cerebral injury Therefore it is not surprising thattreadmill training promoted both synaptogenesis and neu-rite outgrowth via 25-kDa synaptosomal-associated proteinexpression in the cerebellum Likewise such training alsoincreased glial fibrillary acidic protein in the cerebellumwhich plays a role in axonal growth and improved motorcoordination as observed with the rotarod test (longer timeto fall from the rotating rod) [47]

Disruption of the BBB increasing thus its permeabil-ity is one of the major contributors to the pathogene-sis of cerebral ischemia Such event was observed whenmatrix metalloproteinase-9 (MMP-9) is strongly upregulatedthat impairs the extracellular matrix of the BBB [78 79]However physical training attenuated BBB disruption asrevealed by a decrease of MMP-9 expression and a par-allel increase expression of MMP-9 inhibitor the tissueinhibitor of metalloproteinase-1 (TIMP-1) Interestingly suchmechanisms might contribute to decreasing the observedneurological deficits infarct volume and brain edema [80]

These neuroplasticity processes require energy frommitochondria However cerebral ischemia induces damageof the cerebral mitochondria biogenesis contributing to theextent of neuronal ischemic injury [81] Nevertheless 7-day endurance training increased mitochondrial biogenesisafter cerebral ischemia by enhancing both the amount ofmitochondrial DNA and the expression of numerous mito-chondrial biogenesis factors such as the mitochondrial tran-scription factor proliferator activated receptor coactivator-1(PGC-1) nuclear respiratory factor 1 (NRF-1) protein andmitochondrial transcription factor A (TFAM) [82] It wassuggested that these events are involved in decreasing infarctvolume and the improvement of neurological score

Very few studies using rat model of cerebral ischemiaenable better understanding of the treadmill training out-comes on muscle activation regulation Cerebral ischemiais believed to affect synaptic activity including the choliner-gic system which leads to decreasing both neuromuscularjunction and cholinergic brain synaptic transmission It wasshown that aerobic treadmill training (20minday during 21days) improved cholinergic system regulationhomeostasisby decreasing acetylcholinesterase activity (ie hydrolyzing

the acetylcholine) and by enhancing choline acetyltransferaseactivity (ie synthesis of acetylcholine) [53] It was thussuggested that such adaption might allow better motorlimb function as indicated by improvement of the limbplacement test score Moreover 10 days of treadmill trainingimproved balance functional outcome (behavioral score)and motor coordination Indeed the asymmetry of muscleactivation pattern between affected and unaffected hindlimbswas restored because the EMG burst duration was increasedat the affected side [83] Muscle fatigue observed duringlocomotion was reduced as indicated by the increase of MPFat the unaffected side (see Section 2) [4]

A previous human study indicated that effective gaittraining on treadmill with body weight support improvingwalking speed and endurance was characterized by anincrease of brain activity in the bilateral primary sensori-motor cortices the cingulate motor areas the caudate nucleibilaterally and the thalamus of the affected hemisphereduring paretic foot movement [84] In addition treadmillexercise (improving cardiovascular fitness by 18) activatessubcortical neural networks during single knee movementsof the lower extremity as observed by fMRI Indeed physicaltraining changed brain activation during paretic limb move-ment showing 72 and 18 increased activation in posteriorcerebellar lobe andmidbrain respectively [85] After 10weeksof training the improvement in sensorimotor functionassessed with the Fugl-Meyer Index seemed strongly relatedto the improvement in aerobic capacity [86]

It is noteworthy that some neural mechanisms afterphysical exercise remain to be investigated such as diaschisisIndeed functional deficitsmay also be associatedwith distanteffects after subcortical lesions resulting from deafferentationto a region not directly involved in the stroke Moreoverit was found that several rehabilitation exercises inducingblood flow and metabolic changes in the contralesionalhemisphere might act on diaschisis Given that alleviation ofdiaschisis could contribute to motor recovery [87] it seemsimportant that further studies will determine how enduranceexercises may influence diaschisis after cerebral ischemia

4 Influence of Exercise Parameters onNeuroplasticity and Functional Outcomes

Depending on the chosen exercise parameters (volumeintensity session frequency and timing of exercise initiation)neuroplasticity can be either adaptive or maladaptive torecovery and thus may affect the training effectiveness aftercerebral ischemia [46 87ndash91] Strong evidence suggested atime-limited period of enhanced neuroplasticity [89 92ndash94]Animal studies underlined that the limb function was lessimproved when training started before 24 h after ischemiacompared with a start during the 5 first days [89] Moreoverearly intense training might induce larger cortical infarctvolume and thalamic atrophy when the program starts before24 h [95] Exercise detrimental effects were also observedon neuroplasticity when animals performed treadmill exer-cise shortly after trauma [96] The lesional aggravationmight be related to localized and prolonged hyperthermiaIndeed physical exercise known to induce hyperthermia

Neural Plasticity 5

could accentuate the cerebral ischemia-induced release ofglutamate and catecholamines that lead to neural excito-toxicity [95 97] However it seems important to add thatother processes than hyperthermia might be involved in thesensorimotor deficit aggravations and need to be exploredFurthermore early running training downregulated proteinsinvolved in neuroplasticity such as MAPK CAMKII PKCsynapsin I orCREB expression [98] anddecreased the level ofproinflammatory cytokines known to be related to neuropro-tection [99 100] Finally Yagita et al (2006) had shown thattwo weeks of running exercise reduced the number of new-born neurons in ischemic rats and thus limited neurogenesisin the hippocampus [101] The author suggested that runningwas too stressful and enhanced the corticosterone levelknown to decrease neurogenesis Likewise an immediateoveruse of the lesioned forelimb could also increase tissue lossaround the lesion and aggravated sensorimotor deficits on alonger term [102ndash104] One explanation could be related toanatomical damage resulting from the reduction of dendriticgrowth in the ischemic hemisphere [104]

In addition an augmented volume of exercise or increaseof inpatient therapy duration for stroke did not indicatesuperior effects on functional recovery and activities of dailyliving [105 106] Interestingly when healthy active men weresubjected to a strong increase of volume training physicalperformance was also not improved [107] It thus seems thatvolume is not the main exercise parameter that should beinvestigated for improving aerobic program

Greater improvements were observed with higher exer-cise intensities after stroke and neurodegenerative disease butalso for healthy individuals [92 108ndash110] However the effectof intensity on neuroplasticity remains unclear because it ispoorly investigated in stroke patients or in ischemic animalmodels (ongoing study in our laboratory) It should also bepointed that one major methodological limitation is relatedto the exercise intensity determination Indeed trainingintensity was mainly based onmaximal oxygen consumptionor maximal exercise heart rate (or even intensity basedon empirical values) However these parameters were notappropriated because stroke patients never reached maximalcapabilities It was recently suggested that prescribing inten-sity should rather be based on submaximal parameters suchas ventilatory or lactic threshold that were more accurate indistinguishing moderate to intense exercise [111]

5 Beneficial Effect of Physical TrainingRehabilitation in Combination withPharmacological Treatments

Using multiple recovery processes (physical exercise andpharmacologic treatments) may be critical for enhancingfunctional outcomes in contrast to monotherapies targetingsingle mechanisms (Table 1)

Given that recent findings have established that anti-inflammation may be an important target for stroke treat-ment [112] some authors demonstrated that combinationof skilled reaching training with indomethacin or minocy-cline accentuated recovery [10] First beneficial effects of

such combination included an improvement of sensorimotorfunction as indicated by higher correct placements of theimpaired forelimb during a walking task Secondly thenumber of proliferating microglia was more reduced and thesurvival of newborn astrocytes in the peri-infarct zone wasincreased compared to rats that underwent training aloneAuthors suggested that the motor outcome improvementmight be partially explained by the observed changes ofneural response

In addition therapeutic drug such as S-nitrosogluta-thione (GSNO) exhibits similar neurovascular protectingeffects compared to physical training following traumaticbrain trauma and cerebral ischemia in rats [18 27] Adminis-tration of GSNO could reduce neuronal apoptotic cell deathexcitotoxicity and inflammation as well as protecting BBBintegrity GSNO could also stimulate the expression of VEGFand BDNF after traumatic brain injury Several authors havedemonstrated that combining rotating rod motor exercisewith GSNO administration accelerated and accentuated bothwalking and balance abilities compared to the effects inducedby each treatment applied separatelyMoreover the improvedmotor function was associated with a reduction of bothinfarct volume and neuronal cell death as well as an increaseof PECAM-1 and BDNF expression [28]

D-amphetamine acting primarily through norepineph-rine and dopamine mechanisms is a potent modulator ofneurological function and cortical excitation that facilitatedmotor skill abilities [113] It was demonstrated that a singleinjection of D-amphetamine on the first day of trainingfacilitates effectiveness of motor skill training compared withD-amphetamine treatment alone after a focal cortical infarctin squirrel monkeys [29] However administration of ahigh dose of D-amphetamine combined with rehabilitationtraining failed to promote fine motor recovery in a ratembolic stroke model Authors explained this result by thefact that the dose of D-amphetamine was too high therebylimiting animal engagement in the staircase test [114]

Other pharmacological agents could improve motorrecovery by focusing on different neural mechanisms Forexample Nogo-A protein a myelin-associated inhibitorappears to be partially responsible for inhibition of axonalgrowth in white matter Therefore suppressing this myelin-associated neurite outgrowth inhibitor by specific antagonistsof Nogo-A such as NEP 1-40 or NGR(310)Ecto-FC increasedneurite outgrowth and axonal regeneration after stroke [3031] Five-week motor training combined with NEP 1-40treatment accelerated motor recovery (skilled reach and footfault tests) from the first week after cerebral ischemia com-pared to treatments applied alone in which beneficial effectswere observed later (weeks 2 and 4) [30] Unfortunatelyneural plasticity mechanisms underlying this improvementremain unknown but these findings showed that this therapycombination could accelerate the recovery process followingcerebral ischemia

Neurons and glial cells in brain can synthesize proges-terone that exhibits neuroprotective effects after cerebralischemia [115ndash118] Rehabilitation could increase reorganiza-tion of cortical maps whereas the progesterone might reducethe infarct volume through its neuroprotective effect by

6 Neural Plasticity

Table 1 Influence of pharmacological agents associated with physical exercise on motor recovery after brain stroke

Drug agents Targets Results References

Indomethacin Minocycline Inflammatory processes

infarct volume (indomethacin only) sensorimotor performance

microglia astroglia

[10]

GSNOOxidative stress

Inflammatory processesExcitotoxicity

infarct volume apoptotic cell death neurological score motor recovery

and survival rate CBF synaptic plasticity and BBB

leakage TNF-120572 IL-1120573 and iNOS

[18 27 28]

D-Amphetamine Noradrenergic 1205721-receptor agonist motor recovery [29]

NEP 1-40 Nogo-A protein inhibitor early motor recovery axonal growth [30]

NgR(310)Ecto-Fc Nogo-NgR pathwayinhibitor

motor recovery axonal plasticity [31]

Progesterone ExcitotoxicityInflammatory processes

infarct volume forelimbs strength and motor recovery [32]

EGFlowast and EPOlowast Neuron proliferation migrationand differentiation accelerated fine motor recovery [33 34]

Chondroitinase ABC Chondroitin sulphate proteoglycans(CSPGs)

CSPGs synaptic plasticitymotor recovery

[35]

indicates an increase and a decrease respectively NEP 1-40 NOGO extracellular peptide EGF epidermal growth factor EPO erythropoietin GSNOS-nitrosoglutathione CBF cerebral blood flow BDNF brain developed neurotrophic factor trkB tropomyosin receptor kinase B BBB blood brain barrierlowastMolecules combination

targeting excitotoxicity Although this combination had noadditional effect in reducing infarct volume functional recov-ery effectiveness was promoted as shown by the increasedrotarod performance and forelimb grip strength at all timepoints within 7 days after ischemic stroke [32]

In addition some authors indicated that combination oftwo pharmacological treatments could improve functionalrecovery and neural plasticity compared to either treatmentalone For example association of epidermal growth fac-tor (EGF) and erythropoietin (EPO) treatments is moreeffective in promoting tissue regeneration and proliferationof neural precursor cells than monotherapy [33] Howeveran even greater improvement in skilled reaching ability inthe staircase test was observed when physical rehabilitationwas added to serial application of both EGF and EPO[34] Authors have also indicated that fine motor skillimprovement was observed 10 weeks after functional reha-bilitation alone whereas 4-week-long treatment combinationwas sufficient to improve sensorimotor function It meansthat functional recovery is also clearly accelerated with thiscombination

Another strategy consists of recreating a tissue environ-ment free from growth inhibiting molecules Chondroiti-nase ABC which degrades inhibitory chondroitin sulphateproteoglycans present in the extracellular matrix reducesthe neurite-inhibitory environment and facilitates axonalsprouting and sensorimotor recovery after spinal cord injury[119 120] and after cerebral ischemia [121 122]This treatmentwas applied at the ipsilesional cortex in rats in combinationwith functional rehabilitation Synaptic plasticity assessed by

measuring the expression of glutamate vesicular transporter(vGLUT1 and vGLUT2) and the GABA vesicular transporter(vGAT) and functional recovery were promoted by thesynergic effect of these treatments [35]

Given that some promising treatments developed inpreclinical studies failed to be effective in clinical studies[123 124] it seems crucial to assess the pharmacologicaleffectiveness in stroke patients before combining it withphysical exerciseTherefore we need to keep inmind that notall the effective combinations found in animal studies couldbe considered effective for human Nevertheless assessingboth treatments and exercise in rodentmodels seems relevantto found new therapeutic strategies to highlight the mosteffective and applicable strategies for human

6 Influence of Prestroke Physical Activity onMotor Dysfunction Severity

To avoid administration of several pharmacological sub-stances in individuals with high risks of stroke (may inducedeleterious interaction between drugs and complications dueto their side effects) physical activity might be a major alter-native preventive strategy for reducing the brain secondaryinjury when stroke occurs Several recent human and animalstudies have well demonstrated that preischemic physicalactivity may reduce initial stroke severity on functionalmotor outcomes edema and infarct volume by acting oninflammation vascular processes BDNF expression andmetabolic disorders [14 16 17 125 126]

Neural Plasticity 7

Ischemia-induced brain inflammation is believed toplay a pivotal role in the development of secondary braininjury by intensifying the inflammatory cell accumulationandmicrovascular impairments Indeed adhesionmoleculessuch as intercellular adhesion molecule 1 (ICAM-1) pro-mote leukocyte infiltration into injury site and leukocyteadhesion to microvascular endothelium Preischemic phys-ical training-induced neuroprotection was associated with adecrease in ICAM-1 mRNA expression and in the number ofICAM-1-positive vessels [17] Consequently leukocyte accu-mulation in damaged cortex and striatum vessels decreasedresulting in reduction of brain inflammation during reperfu-sion

Brain angiogenesis is another neuroprotective mecha-nism for reducing the detrimental motor effect of cere-bral ischemia Physical training prior to cerebral ischemiaincreased short- and long-term effects onmicrovascular den-sity and cerebral blood flow by promoting angiogenesis andincreasing cerebral vasomotor reactivity It was found thatpreischemic exercise improved vasorelaxation by enhancingVEGF levels into the ischemic region which is knownto activate eNOS and EPCs recruitment [8 19] Likewiseexercise decreased the endothelin-1 (a powerful vasocon-strictor agent) expression thereby reducing the impact ofvasoconstriction on cerebral blood flow [127]

Preischemic training could also attenuate brain dam-age by limiting metabolic disorders after cerebral ischemiaIndeed 51015840AMP-activated protein kinase (AMPK) phos-phofructokinase-1 (PFK) and hypoxia-induced factor-1120572(HIF-1120572) involved in glycolysis [18 128] were significantlyhigher in preischemic trained rats [129] Moreover theincrease of glucose transporters in neurons and endothelialcells of the BBB (GLUT3 and GLUT1 resp) results inan improved glucose oxidation immediately after cerebralischemia allowing a faster and more substantial increase inATP production

Moreover it was postulated that preischemic exercise(30min on a treadmill 5 daysweek for 3 weeks) decreasesBBB dysfunctions and thus reduces infarct volume andedema as confirmed by the MMP-9 expression decrement[130 131] Preischemic treadmill training-induced neuro-protection in ischemic rats increased endogenous BDNFexpression that leads to motor recovery improvement [1617 67 132] Interestingly the preischemic treadmill exer-cise improved the therapeutic effectiveness of postischemictreadmill training onmotor function compared with animalsperforming it only after cerebral ischemia [53]

Neuronal excitotoxicity induced by excessive glutamaterelease is a major deleterious event of the brain secondaryinjury [133 134] It was found that preischemic treadmilltraining could also reduce the expression of glutamate recep-tors mGluR5 and NR2B reflecting a decrease of glutamateeffect on surrounding cells [135ndash137] Moreover it was pos-tulated that the reduction of infarct volume induced by 12weeks of treadmill might be related to increase of NGFexpression and this receptor p75 known to promote neu-roprotection against excitotoxicity and free-radical damage[138]

Individuals who were physically active prior to strokehave been shown to exhibit less deleterious functional out-comes as indicated by higher Barthel Index scores as wellas Oxford Handicap Scale [14 15] Indeed it was recentlyrevealed that patients with high levels of prestroke physicalactivity were associated with milder stroke severity at admis-sion with faster early motor improvement and with a lowerfinal infarct volume [139] Interestingly it seems that simplywalking 1 hday during 5 days per week or doing a vigorousaerobic activity 1 hday twice a week is sufficient to inducepreventive effects However findings remain conflicting inhuman studies because no strong association between higherlevels of physical activity and better functional outcomes afterstroke was found in a large prospective cohort [126]

7 Conclusion

Although acute exercise appears to be useful for better under-standing neural andmotor recoverymechanisms few studieshave used this experimental model to investigate strokephysiopathology Neural adaptations remain thus unclearFurthermore physical training appears to be promising toimprove functional motor recovery by promoting neuro-plasticity at different cellular and molecular levels Thesebeneficial effects seem accelerated andor accentuated whenexercise is combined with an additional pharmacologicaltreatment Nevertheless optimal parameters of training andtreatment need to be investigated to maximizeaccelerateneuroplasticity and motor recovery and avoid undesirableeffects of exercise All these findings could help researchersand therapists to justify the effectiveness of their physicaltraining programs in order to increase the patient willingnessto regularly perform physical activity before and after stroke

Conflict of Interests

Each author of the present review declared no conflict ofinterests

Acknowledgment

The authors are grateful to Dr Vincent Pertici for commentson earlier version of this paper

References

[1] E Broussalis M Killer M McCoy A Harrer E Trinkaand J Kraus ldquoCurrent therapies in ischemic stroke Part ARecent developments in acute stroke treatment and in strokepreventionrdquoDrug Discovery Today vol 17 no 7-8 pp 296ndash3092012

[2] F M Ivey R F Macko A S Ryan and C E Hafer-MackoldquoCardiovascular health and fitness after strokerdquo Topics in StrokeRehabilitation vol 12 no 1 pp 1ndash16 2005

[3] D LMarsden A Dunn R Callister C R Levi andN J SprattldquoCharacteristics of exercise training interventions to improvecardiorespiratory fitness after stroke a systematic review withmeta-analysisrdquo Neurorehabilitation and Neural Repair vol 27no 9 pp 775ndash788 2013

8 Neural Plasticity

[4] L Li W Rong Z Ke X Hu S P Yip and K Y Tong ldquoMuscleactivation changes during body weight support treadmill train-ing after focal cortical ischemia a rat hindlimb modelrdquo Journalof Electromyography and Kinesiology vol 21 no 2 pp 318ndash3262011

[5] C Pin-Barre J Laurin M-S Felix et al ldquoAcute neuromuscularadaptation at the spinal level following middle cerebral arteryocclusion-reperfusion in the ratrdquoPLoSONE vol 9 no 2 ArticleID e89953 2014

[6] L W Forrester D F Hanley and R F Macko ldquoEffectsof treadmill exercise on transcranial magnetic stimulation-induced excitability to quadriceps after strokerdquo Archives ofPhysical Medicine and Rehabilitation vol 87 no 2 pp 229ndash2342006

[7] R FMacko FM Ivey LW Forrester et al ldquoTreadmill exerciserehabilitation improves ambulatory function and cardiovas-cular fitness in patients with chronic stroke a randomizedcontrolled trialrdquo Stroke vol 36 no 10 pp 2206ndash2211 2005

[8] M Endres K Gertz U Lindauer et al ldquoMechanisms of strokeprotection by physical activityrdquoAnnals of Neurology vol 54 no5 pp 582ndash590 2003

[9] K Gertz J Priller G Kronenberg et al ldquoPhysical activityimproves long-term stroke outcome via endothelial nitric oxidesynthase-dependent augmentation of neovascularization andcerebral blood flowrdquo Circulation Research vol 99 no 10 pp1132ndash1140 2006

[10] S Liebigt N Schlegel J Oberland O W Witte C Redeckerand S Keiner ldquoEffects of rehabilitative training and anti-inflammatory treatment on functional recovery and cellularreorganization following strokerdquo Experimental Neurology vol233 no 2 pp 776ndash782 2012

[11] W-R Schabitz T Steigleder C M Cooper-Kuhn et al ldquoIntra-venous brain-derived neurotrophic factor enhances poststrokesensorimotor recovery and stimulates neurogenesisrdquo Strokevol 38 no 7 pp 2165ndash2172 2007

[12] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[13] I-M Lee C H Hennekens K Berger J E Buring and J EManson ldquoExercise and risk of stroke inmale physiciansrdquo Strokevol 30 no 1 pp 1ndash6 1999

[14] D Deplanque I Masse C Lefebvre C Libersa D Leys andR Bordet ldquoPrior TIA lipid-lowering drug use and physicalactivity decrease ischemic stroke severityrdquo Neurology vol 67no 8 pp 1403ndash1410 2006

[15] N Stroud T M L Mazwi L D Case et al ldquoPrestroke physicalactivity and early functional status after strokerdquo Journal ofNeurology Neurosurgery and Psychiatry vol 80 no 9 pp 1019ndash1022 2009

[16] Y Ding J Li X Luan et al ldquoExercise pre-conditioningreduces brain damage in ischemic rats that may be associatedwith regional angiogenesis and cellular overexpression of neu-rotrophinrdquo Neuroscience vol 124 no 3 pp 583ndash591 2004

[17] Y-H Ding C N Young X Luan et al ldquoExercise precondi-tioning ameliorates inflammatory injury in ischemic rats duringreperfusionrdquoActaNeuropathologica vol 109 no 3 pp 237ndash2462005

[18] MKhan B Sekhon S Giri et al ldquoS-Nitrosoglutathione reducesinflammation and protects brain against focal cerebral ischemiain a rat model of experimental strokerdquo Journal of Cerebral BloodFlow and Metabolism vol 25 no 2 pp 177ndash192 2005

[19] W Schmidt M Endres F Dimeo and G J JungehulsingldquoTrain the vessel gain the brain physical activity and vesselfunction and the impact on stroke prevention and outcome incerebrovascular diseaserdquo Cerebrovascular Diseases vol 35 no4 pp 303ndash312 2013

[20] W R Frontera L Grimby and L Larsson ldquoFiring rate ofthe lower motoneuron and contractile properties of its musclefibers after upper motoneuron lesion in manrdquoMuscle amp Nervevol 20 no 8 pp 938ndash947 1997

[21] C M Cirstea C R Savage R J Nudo et al ldquoHandgrip-relatedactivation in the primary motor cortex relates to underlyingneuronal metabolism after strokerdquo Neurorehabilitation andNeural Repair vol 28 no 5 pp 433ndash442 2013

[22] C Enzinger H Johansen-Berg H Dawes et al ldquoFunctionalMRI correlates of lower limb function in stroke victims withgait impairmentrdquo Stroke vol 39 no 5 pp 1507ndash1513 2008

[23] A R Luft L Forrester R F Macko et al ldquoBrain activationof lower extremity movement in chronically impaired strokesurvivorsrdquo NeuroImage vol 26 no 1 pp 184ndash194 2005

[24] A R Luft S Waller L Forrester et al ldquoLesion locationalters brain activation in chronically impaired stroke survivorsrdquoNeuroImage vol 21 no 3 pp 924ndash935 2004

[25] N S Ward ldquoFunctional reorganization of the cerebral motorsystem after strokerdquo Current Opinion in Neurology vol 17 no6 pp 725ndash730 2004

[26] A C Zemke P J Heagerty C Lee and S C Cramer ldquoMotorcortex organization after stroke is related to side of stroke andlevel of recoveryrdquo Stroke vol 34 no 5 pp e23ndashe28 2003

[27] M Khan H Sakakima T S Dhammu et al ldquoS-nitrosoglutathione reduces oxidative injury and promotesmechanisms of neurorepair following traumatic brain injury inratsrdquo Journal of Neuroinflammation vol 8 article 78 2011

[28] H Sakakima M Khan T S Dhammu et al ldquoStimulationof functional recovery via the mechanisms of neurorepairby S-nitrosoglutathione and motor exercise in a rat modelof transient cerebral ischemia and reperfusionrdquo RestorativeNeurology and Neuroscience vol 30 no 5 pp 383ndash396 2012

[29] S Barbay E V Zoubina N Dancause et al ldquoA single injectionof D-amphetamine facilitates improvements in motor trainingfollowing a focal cortical infarct in squirrel monkeysrdquo Neurore-habilitation and Neural Repair vol 20 no 4 pp 455ndash458 2006

[30] P-C Fang S Barbay E J Plautz E Hoover S M Strittmatterand R J Nudo ldquoCombination of NEP 1-40 treatment andmotortraining enhances behavioral recovery after a focal corticalinfarct in ratsrdquo Stroke vol 41 no 3 pp 544ndash549 2010

[31] J-K Lee J-E Kim M Sivula and S M Strittmatter ldquoNogoreceptor antagonism promotes stroke recovery by enhancingaxonal plasticityrdquo The Journal of Neuroscience vol 24 no 27pp 6209ndash6217 2004

[32] J Wang X Feng Y Du L Wang and S Zhang ldquoCombinationtreatment with progesterone and rehabilitation training furtherpromotes behavioral recovery after acute ischemic stroke inmicerdquo Restorative Neurology and Neuroscience vol 31 no 4 pp487ndash499 2013

[33] B Kolb C Morshead C Gonzalez et al ldquoGrowth factor-stimulated generation of new cortical tissue and functionalrecovery after stroke damage to the motor cortex of ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 27 no 5pp 983ndash997 2007

[34] M S Jeffers A Hoyles C Morshead and D Corbett ldquoEpi-dermal growth factor and erythropoietin infusion accelerate

Neural Plasticity 9

functional recovery in combination with rehabilitationrdquo Strokevol 45 no 6 pp 1856ndash1858 2014

[35] L Gherardini M Gennaro and T Pizzorusso ldquoPerilesionaltreatment with chondroitinase ABC and motor training pro-mote functional recovery after stroke in ratsrdquo Cerebral Cortexvol 25 no 1 pp 202ndash212 2015

[36] D P Fuchs N Sanghvi J Wieser and S Schindler-IvensldquoPedaling alters the excitability and modulation of vastusmedialis H-reflexes after strokerdquo Clinical Neurophysiology vol122 no 10 pp 2036ndash2043 2011

[37] I-S Hwang C-F Lin L-C Tung and C-H Wang ldquoRespon-siveness of the H reflex to loading and posture in patientsfollowing strokerdquo Journal of Electromyography and Kinesiologyvol 14 no 6 pp 653ndash659 2004

[38] M A Oskoei and H Hu ldquoSupport vector machine-basedclassification scheme for myoelectric control applied to upperlimbrdquo IEEE Transactions on Biomedical Engineering vol 55 no8 pp 1956ndash1965 2008

[39] G L Soderberg and L M Knutson ldquoA guide for use andinterpretation of kinesiologic electromyographic datardquo PhysicalTherapy vol 80 no 5 pp 485ndash498 2000

[40] N A Riley and M Bilodeau ldquoChanges in upper limb jointtorque patterns and EMG signals with fatigue following astrokerdquoDisability andRehabilitation vol 24 no 18 pp 961ndash9692002

[41] U M Svantesson K S Sunnerhagen U S Carlsson and GGrimby ldquoDevelopment of fatigue during repeated eccentric-concentric muscle contractions of plantar flexors in patientswith strokerdquo Archives of Physical Medicine and Rehabilitationvol 80 no 10 pp 1247ndash1252 1999

[42] K N Arya S Pandian R Verma and R K Garg ldquoMovementtherapy induced neural reorganization and motor recovery instroke a reviewrdquo Journal of Bodywork andMovementTherapiesvol 15 no 4 pp 528ndash537 2011

[43] R J Nudo ldquoNeural bases of recovery after brain injuryrdquo Journalof Communication Disorders vol 44 no 5 pp 515ndash520 2011

[44] T Kawamata N E Alexis W D Dietrich and S P FinklesteinldquoIntracisternal basic fibroblast growth factor (bFGF) enhancesbehavioral recovery following focal cerebral infarction in theratrdquo Journal of Cerebral Blood Flow and Metabolism vol 16 no4 pp 542ndash547 1996

[45] T Yamaguchi M Suzuki and M Yamamoto ldquoYM796 anovel muscarinic agonist improves the impairment of learningbehavior in a rat model of chronic focal cerebral ischemiardquoBrain Research vol 669 no 1 pp 107ndash114 1995

[46] F Matsuda H Sakakima and Y Yoshida ldquoThe effects of earlyexercise on brain damage and recovery after focal cerebralinfarction in ratsrdquoActa Physiologica vol 201 no 2 pp 275ndash2872011

[47] K Mizutani S Sonoda N Hayashi et al ldquoAnalysis of proteinexpression profile in the cerebellum of cerebral infarction ratsafter treadmill trainingrdquo American Journal of Physical Medicineamp Rehabilitation vol 89 no 2 pp 107ndash114 2010

[48] P Zhang Y Zhang J Zhang et al ldquoEarly exercise protectsagainst cerebral ischemic injury through inhibiting neuronapoptosis in cortex in ratsrdquo International Journal of MolecularSciences vol 14 no 3 pp 6074ndash6089 2013

[49] L M Cupini M Diomedi F Placidi M Silvestrini and PGiacomini ldquoCerebrovascular reactivity and subcortical infarc-tionsrdquo Archives of Neurology vol 58 no 4 pp 577ndash581 2001

[50] F M Ivey A S Ryan C E Hafer-Macko and R F MacKoldquoImproved cerebral vasomotor reactivity after exercise trainingin hemiparetic stroke survivorsrdquo Stroke vol 42 no 7 pp 1994ndash2000 2011

[51] S Tian Y Zhang S Tian et al ldquoEarly exercise training improvesischemic outcome in rats by cerebral hemodynamicsrdquo BrainResearch vol 1533 pp 114ndash121 2013

[52] Y Gao Y Zhao J Pan et al ldquoTreadmill exercise promotesangiogenesis in the ischemic penumbra of rat brains throughcaveolin-1VEGF signaling pathwaysrdquo Brain Research vol 1585pp 83ndash90 2014

[53] G Kim and E Kim ldquoEffects of treadmill training on limbmotorfunction and acetylcholinesterase activity in rats with strokerdquoJournal of PhysicalTherapy Science vol 25 no 10 pp 1227ndash12302013

[54] Q Zheng D Zhu Y Bai Y Wu J Jia and Y Hu ldquoExerciseimproves recovery after ischemic brain injury by inducing theexpression of angiopoietin-1 and Tie-2 in ratsrdquo The TohokuJournal of Experimental Medicine vol 224 no 3 pp 221ndash2282011

[55] T M Hansen A J Moss and N P J Brindle ldquoVascularendothelial growth factor and angiopoietins in neurovascularregeneration and protection following strokerdquo Current Neu-rovascular Research vol 5 no 4 pp 236ndash245 2008

[56] D M Hermann and A Zechariah ldquoImplications of vascu-lar endothelial growth factor for postischemic neurovascularremodelingrdquo Journal of Cerebral Blood Flow and Metabolismvol 29 no 10 pp 1620ndash1643 2009

[57] C S Mang K L Campbell C J D Ross and L A Boyd ldquoPro-moting neuroplasticity for motor rehabilitation after strokeconsidering the effects of aerobic exercise and genetic variationon brain-derived neurotrophic factorrdquo PhysicalTherapy vol 93no 12 pp 1707ndash1716 2013

[58] M Ploughman VWindle C LMacLellan NWhite J J Doreand D Corbett ldquoBrain-derived neurotrophic factor contributesto recovery of skilled reaching after focal ischemia in ratsrdquoStroke vol 40 no 4 pp 1490ndash1495 2009

[59] I Kiprianova TM Freiman SDesiderato et al ldquoBrain-derivedneurotrophic factor prevents neuronal death and glial activa-tion after global ischemia in the ratrdquo Journal of NeuroscienceResearch vol 56 no 1 pp 21ndash27 1999

[60] R J Nudo E J Plautz and S B Frost ldquoRole of adaptiveplasticity in recovery of function after damage to motor cortexrdquoMuscle amp Nerve vol 24 no 8 pp 1000ndash1019 2001

[61] W-R Schabitz S Schwab M Spranger and W Hacke ldquoIntra-ventricular brain-derived neurotrophic factor reduces infarctsize after focal cerebral ischemia in ratsrdquo Journal of CerebralBlood Flow and Metabolism vol 17 no 5 pp 500ndash506 1997

[62] W-R Schabitz C Sommer W Zoder et al ldquoIntravenousbrain-derived neurotrophic factor reduces infarct size andcounterregulates Bax andBcl-2 expression after temporary focalcerebral ischemiardquo Stroke vol 31 no 9 pp 2212ndash2217 2000

[63] M-W Kim M-S Bang T-R Han et al ldquoExercise increasedBDNF and trkB in the contralateral hemisphere of the ischemicrat brainrdquo Brain Research vol 1052 no 1 pp 16ndash21 2005

[64] Z Kokaia Q Zhao M Kokaia et al ldquoRegulation of brain-derived neurotrophic factor gene expression after transientmiddle cerebral artery occlusion with and without brain dam-agerdquo Experimental Neurology vol 136 no 1 pp 73ndash88 1995

[65] L R Zhao B Mattsson and B B Johansson ldquoEnvironmentalinfluence on brain-derived neurotrophic factormessenger RNA

10 Neural Plasticity

expression after middle cerebral artery occlusion in sponta-neously hypertensive ratsrdquo Neuroscience vol 97 no 1 pp 177ndash184 2000

[66] H D Muller K M Hanumanthiah K Diederich S SchwabW-R Schabitz and C Sommer ldquoBrain-derived neurotrophicfactor but not forced armuse improves long-term outcome afterphotothrombotic stroke and transiently upregulates bindingdensities of excitatory glutamate receptors in the rat brainrdquoStroke vol 39 no 3 pp 1012ndash1021 2008

[67] W-R Schabitz C Berger R Kollmar et al ldquoEffect of brain-derived neurotrophic factor treatment and forced arm use onfunctional motor recovery after small cortical ischemiardquo Strokevol 35 no 4 pp 992ndash997 2004

[68] J Chen J Qin Q Su Z Liu and J Yang ldquoTreadmillrehabilitation treatment enhanced BDNF-TrkB but not NGF-TrkA signaling in a mouse intracerebral hemorrhage modelrdquoNeuroscience Letters vol 529 no 1 pp 28ndash32 2012

[69] J-Y Chung M-W Kim M-S Bang and M Kim ldquoIncreasedexpression of neurotrophin 4 following focal cerebral ischemiain adult rat brain with treadmill exerciserdquo PLoS ONE vol 8 no3 Article ID e52461 2013

[70] Z Ke S P Yip L Li X X Zheng W K Tam and K Y TongldquoThe effects of voluntary involuntary and forced exercises onmotor recovery in a stroke rat modelrdquo in Proceedings of theAnnual International Conference of the IEEE Engineering inMedicine and Biology Society (EMBC rsquo11) vol 2011 pp 8223ndash8226 Boston Mass USA August 2011

[71] P-C Shih Y-R Yang and R-Y Wang ldquoEffects of exerciseintensity on spatial memory performance and hippocampalsynaptic plasticity in transient brain ischemic ratsrdquo PLoS ONEvol 8 no 10 Article ID e78163 2013

[72] J Sun Z Ke S P Yip X-L Hu X-X Zheng and K-Y TongldquoGradually increased training intensity benefits rehabilitationoutcome after stroke by BDNF upregulation and stress sup-pressionrdquo BioMed Research International vol 2014 Article ID925762 8 pages 2014

[73] R Marin A Williams S Hale et al ldquoThe effect of voluntaryexercise exposure on histological and neurobehavioral out-comes after ischemic brain injury in the ratrdquo Physiology andBehavior vol 80 no 2-3 pp 167ndash175 2003

[74] S Vaynman Z Ying and F Gomez-Pinilla ldquoExercise inducesBDNF and synapsin I to specific hippocampal subfieldsrdquo Jour-nal of Neuroscience Research vol 76 no 3 pp 356ndash362 2004

[75] L Zhang X Hu J Luo et al ldquoPhysical exercise improves func-tional recovery through mitigation of autophagy attenuationof apoptosis and enhancement of neurogenesis after MCAO inratsrdquo BMC Neuroscience vol 14 article 46 2013

[76] J Puyal and P G H Clarke ldquoTargeting autophagy to preventneonatal stroke damagerdquoAutophagy vol 5 no 7 pp 1060ndash10612009

[77] Q-W Zhang X-X Deng X Sun J-X Xu and F-Y SunldquoExercise promotes axon regeneration of newborn striatonigraland corticonigral projection neurons in rats after ischemicstrokerdquo PLoS ONE vol 8 no 11 Article ID e80139 2013

[78] M Asahi K Asahi J-C Jung G J del ZoppoM E Fini and EH Lo ldquoRole for matrix metalloproteinase 9 after focal cerebralischemia effects of gene knockout and enzyme inhibition withBB-94rdquo Journal of Cerebral Blood Flow amp Metabolism vol 20no 12 pp 1681ndash1689 2000

[79] M Asahi X Wang T Mori et al ldquoEffects of matrixmetalloproteinase-9 gene knock-out on the proteolysis of

blood-brain barrier andwhitematter components after cerebralischemiardquoThe Journal of Neuroscience vol 21 no 19 pp 7724ndash7732 2001

[80] Y Zhang P Zhang X Shen et al ldquoEarly exercise protects theblood-brain barrier from ischemic brain injury via the regula-tion of MMP-9 and occludin in ratsrdquo International Journal ofMolecular Sciences vol 14 no 6 pp 11096ndash11112 2013

[81] I G Onyango J Lu M Rodova E Lezi A B Crafter and RH Swerdlow ldquoRegulation of neuron mitochondrial biogenesisand relevance to brain healthrdquo Biochimica et Biophysica ActamdashMolecular Basis of Disease vol 1802 no 1 pp 228ndash234 2010

[82] Q Zhang Y Wu P Zhang et al ldquoExercise induces mitochon-drial biogenesis after brain ischemia in ratsrdquo Neuroscience vol205 pp 10ndash17 2012

[83] L Li W Rong Z Ke X Hu and K-Y Tong ldquoThe effects oftraining intensities on motor recovery and gait symmetry in arat model of ischemiardquo Brain Injury vol 27 no 4 pp 408ndash4162013

[84] C Enzinger H Dawes H Johansen-Berg et al ldquoBrain activitychanges associated with treadmill training after strokerdquo Strokevol 40 no 7 pp 2460ndash2467 2009

[85] A R Luft R FMacKo LW Forrester et al ldquoTreadmill exerciseactivates subcortical neural networks and improves walkingafter stroke a randomized controlled trialrdquo Stroke vol 39 no12 pp 3341ndash3350 2008

[86] K Potempa M Lopez L T Braun J P Szidon L Fogg and TTincknell ldquoPhysiological outcomes of aerobic exercise trainingin hemiparetic stroke patientsrdquo Stroke vol 26 no 1 pp 101ndash1051995

[87] F Buma G Kwakkel and N Ramsey ldquoUnderstanding upperlimb recovery after strokerdquo Restorative Neurology and Neuro-science vol 31 no 6 pp 707ndash722 2013

[88] A E Baird A Benfield G Schlaug et al ldquoEnlargementof human cerebral ischemic lesion volumes measured bydiffusion-weighted magnetic resonance imagingrdquo Annals ofNeurology vol 41 no 5 pp 581ndash589 1997

[89] A Schmidt J Wellmann M Schilling et al ldquoMeta-analysis ofthe efficacy of different training strategies in animal models ofischemic strokerdquo Stroke vol 45 no 1 pp 239ndash247 2014

[90] R-Y Wang S-M Yu and Y-R Yang ldquoTreadmill trainingeffects in different age groups following middle cerebral arteryocclusion in ratsrdquo Gerontology vol 51 no 3 pp 161ndash165 2005

[91] P ZhangH YuN Zhou et al ldquoEarly exercise improves cerebralblood flow through increased angiogenesis in experimentalstroke rat modelrdquo Journal of NeuroEngineering and Rehabilita-tion vol 10 article 43 2013

[92] J Laurin andC Pin-Barre ldquoPhysiological adaptations followingendurance exercises after stroke focus on the plausible roleof high-intensity interval trainingrdquo International Journal ofPhysical Medicine amp Rehabilitation vol 2 no 3 pp 1ndash6 2014

[93] THMurphy andDCorbett ldquoPlasticity during stroke recoveryfrom synapse to behaviourrdquo Nature Reviews Neuroscience vol10 no 12 pp 861ndash872 2009

[94] M Svensson J Lexell and T Deierborg ldquoEffects of physicalexercise on neuroinflammation neuroplasticity neurodegener-ation and behavior what we can learn from animal models inclinical settingsrdquoNeurorehabilitation and Neural Repair vol 29no 6 pp 577ndash589 2015

[95] A Risedal J Zeng and B B Johansson ldquoEarly training mayexacerbate brain damage after focal brain ischemia in the ratrdquoJournal of Cerebral Blood Flow andMetabolism vol 19 no 9 pp997ndash1003 1999

Neural Plasticity 11

[96] C-S Piao B A Stoica J Wu et al ldquoLate exercise reducesneuroinflammation and cognitive dysfunction after traumaticbrain injuryrdquoNeurobiology of Disease vol 54 pp 252ndash263 2013

[97] J L Humm D A Kozlowski S T Bland D C James andT Schallert ldquoUse-dependent exaggeration of brain injury isglutamate involvedrdquo Experimental Neurology vol 157 no 2 pp349ndash358 1999

[98] G S Griesbach F Gomez-Pinilla and D A Hovda ldquoTheupregulation of plasticity-related proteins following TBI isdisrupted with acute voluntary exerciserdquo Brain Research vol1016 no 2 pp 154ndash162 2004

[99] J WMcAlees L T Smith R S Erbe D Jarjoura N M Ponzioand V M Sanders ldquoEpigenetic regulation of beta2-adrenergicreceptor expression in T

1198671 and T

1198672 cellsrdquo Brain Behavior and

Immunity vol 25 no 3 pp 408ndash415 2011[100] G Zhao S Zhou A Davie and Q Su ldquoEffects of moderate and

high intensity exercise on T1T2 balancerdquo Exercise ImmunologyReview vol 18 pp 98ndash114 2012

[101] Y Yagita K Kitagawa T Sasaki et al ldquoPostischemic exercisedecreases neurogenesis in the adult rat dentate gyrusrdquo Neuro-science Letters vol 409 no 1 pp 24ndash29 2006

[102] S T Bland T Schallert R Strong J Aronowski and J CGrottaldquoEarly exclusive use of the affected forelimb aftermoderate tran-sient focal ischemia in rats functional and anatomic outcomerdquoStroke vol 31 no 5 pp 1144ndash1152 2000

[103] S B DeBow J E McKenna B Kolb and F ColbourneldquoImmediate constraint-inducedmovement therapy causes localhyperthermia that exacerbates cerebral cortical injury in ratsrdquoCanadian Journal of Physiology and Pharmacology vol 82 no4 pp 231ndash237 2004

[104] D A Kozlowski D C James and T Schallert ldquoUse-dependentexaggeration of neuronal injury after unilateral sensorimotorcortex lesionsrdquo The Journal of Neuroscience vol 16 no 15 pp4776ndash4786 1996

[105] B Balaban F Tok F Yavuz E Yasar and R Alaca ldquoEarlyrehabilitation outcome in patients with middle cerebral arterystrokerdquo Neuroscience Letters vol 498 no 3 pp 204ndash207 2011

[106] G Kwakkel R van Peppen R C Wagenaar et al ldquoEffects ofaugmented exercise therapy time after stroke a meta-analysisrdquoStroke vol 35 no 11 pp 2529ndash2539 2004

[107] D L Costill M G Flynn J P Kirwan et al ldquoEffects of repeateddays of intensified training on muscle glycogen and swimmingperformancerdquo Medicine amp Science in Sports amp Exercise vol 20no 3 pp 249ndash254 1988

[108] M A Hirsch and B G Farley ldquoExercise and neuroplasticityin persons living with Parkinsonrsquos diseaserdquo European Journal ofPhysical and Rehabilitation Medicine vol 45 no 2 pp 215ndash2292009

[109] M Katz-Leurer M Shochina E Carmeli and Y FriedlanderldquoThe influence of early aerobic training on the functional capac-ity in patients with cerebrovascular accident at the subacutestagerdquo Archives of Physical Medicine and Rehabilitation vol 84no 11 pp 1609ndash1614 2003

[110] J D Schaechter ldquoMotor rehabilitation and brain plasticity afterhemiparetic strokerdquo Progress in Neurobiology vol 73 no 1 pp61ndash72 2004

[111] P R Bosch S Holzapfel and T Traustadottir ldquoFeasibility ofmeasuring ventilatory threshold in adults with stroke-inducedhemiparesis implications for exercise prescriptionrdquo Archives ofPhysical Medicine and Rehabilitation 2015

[112] D P Stirling K Khodarahmi J Liu et al ldquoMinocyclinetreatment reduces delayed oligodendrocyte death attenuatesaxonal dieback and improves functional outcome after spinalcord injuryrdquoThe Journal of Neuroscience vol 24 no 9 pp 2182ndash2190 2004

[113] S Barbay and R J Nudo ldquoThe effects of amphetamine onrecovery of function in animal models of cerebral injury acritical appraisalrdquo NeuroRehabilitation vol 25 no 1 pp 5ndash172009

[114] R S Rasmussen K Overgaard E S Hildebrandt-Eriksen andG Boysen ldquoD-Amphetamine improves cognitive deficits andphysical therapy promotes fine motor rehabilitation in a ratembolic stroke modelrdquo Acta Neurologica Scandinavica vol 113no 3 pp 189ndash198 2006

[115] C L Gibson B Coomber and S P Murphy ldquoProgesterone isneuroprotective following cerebral ischaemia in reproductivelyageing female micerdquo Brain vol 134 no 7 pp 2125ndash2133 2011

[116] T Ishrat I Sayeed F Atif and D G Stein ldquoEffects ofprogesterone administration on infarct volume and functionaldeficits following permanent focal cerebral ischemia in ratsrdquoBrain Research vol 1257 pp 94ndash101 2009

[117] M Prencipe C Ferretti A R Casini M Santini F Giubileiand F Culasso ldquoStroke disability and dementia results of apopulation surveyrdquo Stroke vol 28 no 3 pp 531ndash536 1997

[118] I Sayeed B Wali and D G Stein ldquoProgesterone inhibitsischemic brain injury in a rat model of permanent middle cere-bral artery occlusionrdquo Restorative Neurology and Neurosciencevol 25 no 2 pp 151ndash159 2007

[119] H Lee R J McKeon and R V Bellamkonda ldquoSustaineddelivery of thermostabilized chABC enhances axonal sproutingand functional recovery after spinal cord injuryrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 8 pp 3340ndash3345 2010

[120] V J Tom R Kadakia L Santi and J D Houle ldquoAdministrationof chondroitinase ABC rostral or caudal to a spinal cord injurysite promotes anatomical but not functional plasticityrdquo Journalof Neurotrauma vol 26 no 12 pp 2323ndash2333 2009

[121] J J Hill K Jin X O Mao L Xie and D A GreenbergldquoIntracerebral chondroitinase ABC and heparan sulfate proteo-glycan glypican improve outcome from chronic stroke in ratsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 23 pp 9155ndash9160 2012

[122] S Soleman P K Yip D A Duricki and L D FMoon ldquoDelayedtreatment with chondroitinase ABC promotes sensorimotorrecovery and plasticity after stroke in aged ratsrdquo Brain vol 135no 4 pp 1210ndash1223 2012

[123] B E Skolnick A I Maas R K Narayan et al ldquoA clinical trialof progesterone for severe traumatic brain injuryrdquo The NewEngland Journal of Medicine vol 371 no 26 pp 2467ndash24762014

[124] DWWright SD Yeatts R Silbergleit et al ldquoVery early admin-istration of progesterone for acute traumatic brain injuryrdquo TheNew England Journal of Medicine vol 371 no 26 pp 2457ndash2466 2014

[125] L-H Krarup T Truelsen C Gluud et al ldquoPrestroke physicalactivity is associated with severity and long-term outcome fromfirst-ever strokerdquo Neurology vol 71 no 17 pp 1313ndash1318 2008

[126] P M Rist I-M Lee C S Kase J Michael Gaziano and TKurth ldquoPhysical activity and functional outcomes from cerebralvascular events in menrdquo Stroke vol 42 no 12 pp 3352ndash33562011

12 Neural Plasticity

[127] Q Zhang L Zhang X Yang Y Wan and J Jia ldquoThe effectsof exercise preconditioning on cerebral blood flow change andendothelin-1 expression after cerebral ischemia in ratsrdquo Journalof Stroke and Cerebrovascular Diseases vol 23 no 6 pp 1696ndash1702 2014

[128] M Bernaudin A-S Nedelec D Divoux E T MacKenzie EPetit and P Schumann-Bard ldquoNormobaric hypoxia inducestolerance to focal permanent cerebral ischemia in associationwith an increased expression of hypoxia-inducible factor-1 andits target genes erythropoietin and VEGF in the adult mousebrainrdquo Journal of Cerebral Blood Flow and Metabolism vol 22no 4 pp 393ndash403 2002

[129] D Dornbos III N Zwagerman M Guo et al ldquoPreischemicexercise reduces brain damage by ameliorating metabolic dis-order in ischemiareperfusion injuryrdquo Journal of NeuroscienceResearch vol 91 no 6 pp 818ndash827 2013

[130] Y-H Ding Y Ding J Li D A Bessert and J A RafolsldquoExercise pre-conditioning strengthens brain microvascularintegrity in a rat stroke modelrdquo Neurological Research vol 28no 2 pp 184ndash189 2006

[131] M Guo B Cox S Mahale et al ldquoPre-ischemic exercise reducesmatrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in strokerdquo Neuroscience vol 151 no2 pp 340ndash351 2008

[132] M Ploughman Z Attwood N White J J E Dore and DCorbett ldquoEndurance exercise facilitates relearning of forelimbmotor skill after focal ischemiardquo The European Journal ofNeuroscience vol 25 no 11 pp 3453ndash3460 2007

[133] L L Guyot F G Diaz M H OrsquoRegan S McLeod H Park andJW Phillis ldquoReal-timemeasurement of glutamate release fromthe ischemic penumbra of the rat cerebral cortex using a focalmiddle cerebral artery occlusion modelrdquo Neuroscience Lettersvol 299 no 1-2 pp 37ndash40 2001

[134] K Matsumoto R Graf G Rosner J Taguchi and W-D HeissldquoElevation of neuroactive substances in the cortex of cats duringprolonged focal ischemiardquo Journal of Cerebral Blood Flow andMetabolism vol 13 no 4 pp 586ndash594 1993

[135] J Jia Y-S Hu Y Wu et al ldquoPre-ischemic treadmill trainingaffects glutamate and gamma aminobutyric acid levels in thestriatal dialysate of a rat model of cerebral ischemiardquo LifeSciences vol 84 no 15-16 pp 505ndash511 2009

[136] F Zhang J Jia Y Wu Y Hu and Y Wang ldquoThe effect of tread-mill training pre-exercise on glutamate receptor expression inrats after cerebral ischemiardquo International Journal of MolecularSciences vol 11 no 7 pp 2658ndash2669 2010

[137] J Jia Y-S Hu Y Wu et al ldquoTreadmill pre-training suppressesthe release of glutamate resulting from cerebral ischemia inratsrdquo Experimental Brain Research vol 204 no 2 pp 173ndash1792010

[138] E T Ang P T H Wong S Moochhala and Y K NgldquoNeuroprotection associated with running is it a result ofincreased endogenous neurotrophic factorsrdquoNeuroscience vol118 no 2 pp 335ndash345 2003

[139] A C Ricciardi E Lopez-Cancio N Perez De La Ossa et alldquoPrestroke physical activity is associated with good functionaloutcome and arterial recanalization after stroke due to a largevessel occlusionrdquo Cerebrovascular Diseases vol 37 no 4 pp304ndash311 2014

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

2 Neural Plasticity

was recently found that physical training promoted cerebralangiogenesis vasomotor reactivity and neurotrophic factorrelease but also reduced apoptosis processes excitotoxicityand inflammation into the peri-infarct site and could improvethe regulation of motor unit activation [8ndash12]

Nevertheless physical training seems to remain insuffi-cient to completely restore neural and motor functions Arecent approach for stroke therapy is to combine physicaltraining with pharmacological treatments known to accen-tuate andor accelerate neuroplasticity In the present reviewwe discuss the influence of physical training with or withoutadditional pharmacological treatment on neuroplasticity andmotor recovery after stroke

Although regular exercise reduces the risk of developingstroke [13] it may occur for physically active individuals [1415] However endogenous neuroprotective effects induced byprestroke physical activitymay exhibit beneficial influence onrecovery by reducing both brain damage and motor outcomeseverity [16ndash19]

Thepresent review is designed to discuss themultiple usesof physical exercise to improve neural and motor recoveryfollowing cerebral ischemiastroke from both animal andhuman studies We suggested that exercise-induced neuralplasticity is crucial to better understanding motor outcomesafter stroke and improving rehabilitation program effective-ness

2 Acute Exercise-Induced NeuralAdjustments after Stroke

Animal and human studies reported that acute exercise couldreveal changes in muscle activation regulation after cere-bral ischemia More precisely the electromyographic (EMG)activity was lower in affected hindlimb muscles during asingle bout of treadmill exercise compared to unaffectedmuscles reflecting a strong decrease of the motoneuronalrecruitment from spinal andor supraspinal motor pathways[4 20] A reduced corticospinal excitability to the pareticquadriceps was also observed by showing strong decrease ofthe motor evoked potential (MEP) amplitude during a run-ning exercise [4] In addition cortical activation increased inthe unaffected side while it decreased in the affected side afterankle dorsiflexion movements that suggested compensatoryneural mechanisms [21ndash26]

Spinal motor reflex plasticity also seems to contributeto motor disorders after stroke but the underlying neuralmechanisms remain poorly understood [36 37] A recentstudy has demonstrated that the motor reflex regulation (Hreflex) was acutely altered following an exhaustive isometricexercise on affected triceps brachii in MCAO rats whereasrestingH reflex did not differ between injured andnoninjuredanimals [5] It was postulated that such findings might bepartially due to an alteration of motor reflex regulation bymuscle afferents that remained activated after intense exercise(groups III and IV muscle afferents)

Fatigue process alterations could also be observed duringdynamic exercise after cerebral ischemia by using EMGrecording When fatigue progresses there is a shift to lowermotor unit frequencies Median power frequency (MPF)

which is the sum of product of the EMG power spectrumand the frequency divided by the total sum of the powerspectrum is frequently used for the assessment of musclefatigue in surface EMG signals [38] Therefore a decreasein MPF serves as an index of fatigue [39] After cerebralischemia the observed MPF drop at the unaffected hindlimbreflected a higher muscle fatigue compared to the affectedone (no MPF decrement) A lesser fatigue-related decreasein median frequency was also observed in humans at theparetic side compared to the nonparetic side during bothvoluntary contractions and locomotor activity [20 40] Thisaccelerated fatigue process of the unaffected hindlimb wasusually explained by its higher weight bearing that com-pensated for the affected side Nevertheless reduction ofwork without MPF decrease of affected muscle was reportedduring repeated eccentric-concentric actions suggesting thatperipheral fatigue through excitation-contraction couplingdisruption might contribute to exercise intolerance andneuromuscular disorders of stroke patients [41]

It was also found that acute exercise-induced neuraladjustments could reveal the effectiveness of a given treat-ment Indeed Forrester and colleagues have first comparedtrained and untrained stroke patients on the observed neuralresponse to a single bout of treadmill exercise [6] Theyfound that the MEP amplitude increased in trained patientsafter this exercise contrary to untrained individuals inwhich MEP amplitude remained unchanged Such trainingcorticospinal adaptation was not observed in the preexerciseMEP amplitudes but only after exercise and provided insightinto the effectiveness of 6-month treadmill training [6]

3 Effects of Poststroke Physical Training onNeuroplasticity and Motor Recovery

The effects of chronic physical training in stroke patientshave received more attention in scientific literature thanthe ones of acute exercise Indeed physical rehabilitationremains the first-line intervention strategy to attenuatechronic impairments of sensorimotor function by promotingbrain organization and reducing infarct volume during thefirst weeks after stroke [42 43] Given that the infarct size wasnot always correlated with motor recovery it was suggestedthat other adaptive mechanisms might take part [44 45]Numerous recent studies indicated that early treadmill train-ing promotes neuroplasticity by acting on brain vasomotoractivity and angiogenesis neurotrophic factor and apoptosismarker expressions brain inflammatory processes bloodbrain barrier (BBB) integrity and muscle activation control(Figure 1) [46ndash48]

Cerebral blood flow in the ischemic region is affectedfollowing human stroke and cerebral ischemia in mice dueto impaired cerebral vasomotor reactivity [8 49] Thereforerestoring an adequate cerebral vasomotor reserve capacityis crucial to supplying required nutriments and O

2 as

well as reducing infarct volume and functional deficits [5051] Preclinical and clinical studies bring strong evidenceon endurance training effectiveness to promote vasomo-tor reactivity (endothelium-dependent vasorelaxation) andangiogenesis in the ischemic penumbra which contribute to

Neural Plasticity 3

speed

Physical exercise

infarct volume

BBB permeability

muscle fatigue

adaptive neuroplasticity and brain activity during movement

angiogenesis cerebral vasomotor reactivity mitochondrial biogenesis

EMG burst duration (paretic side)

balance and motor coordination body weight support and walking

limb placement test score

cholinergic system regulation

Figure 1 Beneficial structural and functional plasticity induced byphysical exercise in stroke individuals

limiting brain damage and motor deficits [9 50] Indeedtreadmill training increased the most commonly stud-ied angiogenic growth factor expression namely vascularendothelial growth factor (VEGF) and its regulatory proteincaveolin-1 that might contribute to explaining the increaseof new vessel growth and vascular density [52ndash56] Thetraining effect on angiogenesis was reinforced by evidenceshowing that 2 weeks of treadmill training increased theangiopoietin expression another angiogenic growth factorthat has a key role in new vessel formation [54] Otherfindings revealed that the area of platelet-endothelial celladhesion molecule- (PECAM-1-) immunopositive cells (pro-tein involved in angiogenesis and integrin activation) wassignificantly increased around the infarct after 28 days oftreadmill training [46] Daily treadmill training induced anincrease of GFAP expression (proteins playing a role invascular cerebral plasticity) suggesting that area of neovas-cularization was higher in exercised animals [47] More-over voluntary running training upregulated by 3- to 4-fold aortic endothelial nitric oxide synthase (eNOS) mRNAexpression and it remained elevated 10 days after training[8 9] Such findings concur with the fact that beneficialeffect of running was completely abolished in animals lackingeNOS expression and in mice treated with a NOS inhibitoror an antiangiogenic compound such as endostatin [9]Moreover training program increased endothelial progenitorcells (EPC) in bone marrow that are known to stronglyinfluence eNOS expression It is noteworthy to add thatonly 3 days of aerobic exercise reduced brain microvascularendothelial cell apoptosis related to the increase of shearstress that was followed by modest improvement of cerebralblood flow [51]

Physical training can also upregulate the expressionof some neurotrophic factors such as brain-derived neu-rotrophic factor (BDNF) nerve growth factor (NGF) andinsulin-like growth factor (IGF-1)

BDNF is one of the most active neurotrophins thatbinds to the tyrosine kinase receptor (trkB) Overall thisassociation triggers several molecular pathways that promoteneural proliferation and survival and synaptic and axonalplasticity by enhancing synapse formation dendritic growthand remodeling [57] Furthermore BDNF seems also to acton motor function because blocking BDNF mRNA expres-sion by injecting antagonist reduced skilled motor abilities[58]

The neuroprotective effect of endogenous and exogenousBDNF is well established after brain infarction [12 59ndash62]Basal endogenous BDNFtrkB expression increased withinboth hemispheres following moderate cerebral ischemia(including the penumbra) during the first 2 weeks butmotor recovery remains widely insufficient [63ndash65] There-fore treatments that enhance BDNFtrkB production seemrelevant to improve motor recovery (even if infarct size isnot modified) [11 66] It was found that delayed intravenousBDNF administration (20 120583gday) for 5 days improved long-term functional outcomes such as running and sensorimotorrecovery after ischemia [11 66 67]

Interestingly endurance training stimulated endogenousBDNFtkrB expression and may play a neuroplastic rolefollowing cerebral ischemia or intracerebral hemorrhage inrat and mice [58 63 68ndash72] This enhanced BDNFtkrBwas observed in both hemispheres but especially in thenonlesional hemisphere compared to healthy animals underthe same program (that might represent a compensatorymechanism) [53 69] Despite the fact that there is no directevidence the training-related BDNF expression is oftenassociated with motor recovery improvement [58 63 70] Itwas demonstrated that 7 consecutive training days could besufficient to increase BDNF expression and improve motorrecovery [72ndash74] Although endurance exercise upregulatesBDNF expression in striatum and cortex functional outcomeimprovement might be more related to hippocampal BDNFexpression [70 72] Indeed voluntary wheel exercise isknown to induce substantial motor recovery associated withthe highest hippocampal BDNF level [70] Another study alsofound a positive correlation betweenmotor function recoveryrate and hippocampal BDNF expression after treadmill train-ing following cerebral infarction [72]

Finally the number of NGF-immunopositive cells pro-moting cell growth and neuronal activity was particularlyincreased over a widespread region around the infarct zonein trained rats [46] NGF expression which may be theresult of heightened neuronal activity during exercise couldcontribute to reducing brain damage around 4 weeks afterischemic stroke

Physical training could reduce ischemic brain damageand motor deficits by other mechanisms such as reductionof acute inflammatory reactions and neuronal apoptosis [75]Indeed it was demonstrated that the neurotrophic factormidkine (MK) which could delay the process of neuronaldeath during the early phase after cerebral infarction washigher expressed in the cells of the peri-infarct region afterphysical training program [46]

Cerebral ischemia-induced cell death is commonlyattributed to necrosis and apoptosis but it was recently found

4 Neural Plasticity

that inappropriate autophagy might also lead to cell death[76] However physical training mitigated autophagosomesaccumulation and attenuated apoptosis in the peri-infarctregion while improving the modified neurological severityscore scale Physical training could also upregulate IGF-1expression which is known to attenuate autophagy and alsoto promote neurogenesis [75]

In addition several studies reported that neuronal deathin both the striatum and the cerebral cortex caused a degen-eration of nigral dopaminergic neurons that are known tocontribute to regulating motor activity [77] However tread-mill training promoted axon regeneration of newborn stri-atonigral and corticonigral projection neurons in ischemicbrain while improving motor function It was thus suggestedthat exercise could enhance restoration of functional neuralcircuitry within the basal ganglia The cerebellum plays animportant role in the motor coordination learning andequilibrium and also seems to be involved in motor deficitsfollowing cerebral injury Therefore it is not surprising thattreadmill training promoted both synaptogenesis and neu-rite outgrowth via 25-kDa synaptosomal-associated proteinexpression in the cerebellum Likewise such training alsoincreased glial fibrillary acidic protein in the cerebellumwhich plays a role in axonal growth and improved motorcoordination as observed with the rotarod test (longer timeto fall from the rotating rod) [47]

Disruption of the BBB increasing thus its permeabil-ity is one of the major contributors to the pathogene-sis of cerebral ischemia Such event was observed whenmatrix metalloproteinase-9 (MMP-9) is strongly upregulatedthat impairs the extracellular matrix of the BBB [78 79]However physical training attenuated BBB disruption asrevealed by a decrease of MMP-9 expression and a par-allel increase expression of MMP-9 inhibitor the tissueinhibitor of metalloproteinase-1 (TIMP-1) Interestingly suchmechanisms might contribute to decreasing the observedneurological deficits infarct volume and brain edema [80]

These neuroplasticity processes require energy frommitochondria However cerebral ischemia induces damageof the cerebral mitochondria biogenesis contributing to theextent of neuronal ischemic injury [81] Nevertheless 7-day endurance training increased mitochondrial biogenesisafter cerebral ischemia by enhancing both the amount ofmitochondrial DNA and the expression of numerous mito-chondrial biogenesis factors such as the mitochondrial tran-scription factor proliferator activated receptor coactivator-1(PGC-1) nuclear respiratory factor 1 (NRF-1) protein andmitochondrial transcription factor A (TFAM) [82] It wassuggested that these events are involved in decreasing infarctvolume and the improvement of neurological score

Very few studies using rat model of cerebral ischemiaenable better understanding of the treadmill training out-comes on muscle activation regulation Cerebral ischemiais believed to affect synaptic activity including the choliner-gic system which leads to decreasing both neuromuscularjunction and cholinergic brain synaptic transmission It wasshown that aerobic treadmill training (20minday during 21days) improved cholinergic system regulationhomeostasisby decreasing acetylcholinesterase activity (ie hydrolyzing

the acetylcholine) and by enhancing choline acetyltransferaseactivity (ie synthesis of acetylcholine) [53] It was thussuggested that such adaption might allow better motorlimb function as indicated by improvement of the limbplacement test score Moreover 10 days of treadmill trainingimproved balance functional outcome (behavioral score)and motor coordination Indeed the asymmetry of muscleactivation pattern between affected and unaffected hindlimbswas restored because the EMG burst duration was increasedat the affected side [83] Muscle fatigue observed duringlocomotion was reduced as indicated by the increase of MPFat the unaffected side (see Section 2) [4]

A previous human study indicated that effective gaittraining on treadmill with body weight support improvingwalking speed and endurance was characterized by anincrease of brain activity in the bilateral primary sensori-motor cortices the cingulate motor areas the caudate nucleibilaterally and the thalamus of the affected hemisphereduring paretic foot movement [84] In addition treadmillexercise (improving cardiovascular fitness by 18) activatessubcortical neural networks during single knee movementsof the lower extremity as observed by fMRI Indeed physicaltraining changed brain activation during paretic limb move-ment showing 72 and 18 increased activation in posteriorcerebellar lobe andmidbrain respectively [85] After 10weeksof training the improvement in sensorimotor functionassessed with the Fugl-Meyer Index seemed strongly relatedto the improvement in aerobic capacity [86]

It is noteworthy that some neural mechanisms afterphysical exercise remain to be investigated such as diaschisisIndeed functional deficitsmay also be associatedwith distanteffects after subcortical lesions resulting from deafferentationto a region not directly involved in the stroke Moreoverit was found that several rehabilitation exercises inducingblood flow and metabolic changes in the contralesionalhemisphere might act on diaschisis Given that alleviation ofdiaschisis could contribute to motor recovery [87] it seemsimportant that further studies will determine how enduranceexercises may influence diaschisis after cerebral ischemia

4 Influence of Exercise Parameters onNeuroplasticity and Functional Outcomes

Depending on the chosen exercise parameters (volumeintensity session frequency and timing of exercise initiation)neuroplasticity can be either adaptive or maladaptive torecovery and thus may affect the training effectiveness aftercerebral ischemia [46 87ndash91] Strong evidence suggested atime-limited period of enhanced neuroplasticity [89 92ndash94]Animal studies underlined that the limb function was lessimproved when training started before 24 h after ischemiacompared with a start during the 5 first days [89] Moreoverearly intense training might induce larger cortical infarctvolume and thalamic atrophy when the program starts before24 h [95] Exercise detrimental effects were also observedon neuroplasticity when animals performed treadmill exer-cise shortly after trauma [96] The lesional aggravationmight be related to localized and prolonged hyperthermiaIndeed physical exercise known to induce hyperthermia

Neural Plasticity 5

could accentuate the cerebral ischemia-induced release ofglutamate and catecholamines that lead to neural excito-toxicity [95 97] However it seems important to add thatother processes than hyperthermia might be involved in thesensorimotor deficit aggravations and need to be exploredFurthermore early running training downregulated proteinsinvolved in neuroplasticity such as MAPK CAMKII PKCsynapsin I orCREB expression [98] anddecreased the level ofproinflammatory cytokines known to be related to neuropro-tection [99 100] Finally Yagita et al (2006) had shown thattwo weeks of running exercise reduced the number of new-born neurons in ischemic rats and thus limited neurogenesisin the hippocampus [101] The author suggested that runningwas too stressful and enhanced the corticosterone levelknown to decrease neurogenesis Likewise an immediateoveruse of the lesioned forelimb could also increase tissue lossaround the lesion and aggravated sensorimotor deficits on alonger term [102ndash104] One explanation could be related toanatomical damage resulting from the reduction of dendriticgrowth in the ischemic hemisphere [104]

In addition an augmented volume of exercise or increaseof inpatient therapy duration for stroke did not indicatesuperior effects on functional recovery and activities of dailyliving [105 106] Interestingly when healthy active men weresubjected to a strong increase of volume training physicalperformance was also not improved [107] It thus seems thatvolume is not the main exercise parameter that should beinvestigated for improving aerobic program

Greater improvements were observed with higher exer-cise intensities after stroke and neurodegenerative disease butalso for healthy individuals [92 108ndash110] However the effectof intensity on neuroplasticity remains unclear because it ispoorly investigated in stroke patients or in ischemic animalmodels (ongoing study in our laboratory) It should also bepointed that one major methodological limitation is relatedto the exercise intensity determination Indeed trainingintensity was mainly based onmaximal oxygen consumptionor maximal exercise heart rate (or even intensity basedon empirical values) However these parameters were notappropriated because stroke patients never reached maximalcapabilities It was recently suggested that prescribing inten-sity should rather be based on submaximal parameters suchas ventilatory or lactic threshold that were more accurate indistinguishing moderate to intense exercise [111]

5 Beneficial Effect of Physical TrainingRehabilitation in Combination withPharmacological Treatments

Using multiple recovery processes (physical exercise andpharmacologic treatments) may be critical for enhancingfunctional outcomes in contrast to monotherapies targetingsingle mechanisms (Table 1)

Given that recent findings have established that anti-inflammation may be an important target for stroke treat-ment [112] some authors demonstrated that combinationof skilled reaching training with indomethacin or minocy-cline accentuated recovery [10] First beneficial effects of

such combination included an improvement of sensorimotorfunction as indicated by higher correct placements of theimpaired forelimb during a walking task Secondly thenumber of proliferating microglia was more reduced and thesurvival of newborn astrocytes in the peri-infarct zone wasincreased compared to rats that underwent training aloneAuthors suggested that the motor outcome improvementmight be partially explained by the observed changes ofneural response

In addition therapeutic drug such as S-nitrosogluta-thione (GSNO) exhibits similar neurovascular protectingeffects compared to physical training following traumaticbrain trauma and cerebral ischemia in rats [18 27] Adminis-tration of GSNO could reduce neuronal apoptotic cell deathexcitotoxicity and inflammation as well as protecting BBBintegrity GSNO could also stimulate the expression of VEGFand BDNF after traumatic brain injury Several authors havedemonstrated that combining rotating rod motor exercisewith GSNO administration accelerated and accentuated bothwalking and balance abilities compared to the effects inducedby each treatment applied separatelyMoreover the improvedmotor function was associated with a reduction of bothinfarct volume and neuronal cell death as well as an increaseof PECAM-1 and BDNF expression [28]

D-amphetamine acting primarily through norepineph-rine and dopamine mechanisms is a potent modulator ofneurological function and cortical excitation that facilitatedmotor skill abilities [113] It was demonstrated that a singleinjection of D-amphetamine on the first day of trainingfacilitates effectiveness of motor skill training compared withD-amphetamine treatment alone after a focal cortical infarctin squirrel monkeys [29] However administration of ahigh dose of D-amphetamine combined with rehabilitationtraining failed to promote fine motor recovery in a ratembolic stroke model Authors explained this result by thefact that the dose of D-amphetamine was too high therebylimiting animal engagement in the staircase test [114]

Other pharmacological agents could improve motorrecovery by focusing on different neural mechanisms Forexample Nogo-A protein a myelin-associated inhibitorappears to be partially responsible for inhibition of axonalgrowth in white matter Therefore suppressing this myelin-associated neurite outgrowth inhibitor by specific antagonistsof Nogo-A such as NEP 1-40 or NGR(310)Ecto-FC increasedneurite outgrowth and axonal regeneration after stroke [3031] Five-week motor training combined with NEP 1-40treatment accelerated motor recovery (skilled reach and footfault tests) from the first week after cerebral ischemia com-pared to treatments applied alone in which beneficial effectswere observed later (weeks 2 and 4) [30] Unfortunatelyneural plasticity mechanisms underlying this improvementremain unknown but these findings showed that this therapycombination could accelerate the recovery process followingcerebral ischemia

Neurons and glial cells in brain can synthesize proges-terone that exhibits neuroprotective effects after cerebralischemia [115ndash118] Rehabilitation could increase reorganiza-tion of cortical maps whereas the progesterone might reducethe infarct volume through its neuroprotective effect by

6 Neural Plasticity

Table 1 Influence of pharmacological agents associated with physical exercise on motor recovery after brain stroke

Drug agents Targets Results References

Indomethacin Minocycline Inflammatory processes

infarct volume (indomethacin only) sensorimotor performance

microglia astroglia

[10]

GSNOOxidative stress

Inflammatory processesExcitotoxicity

infarct volume apoptotic cell death neurological score motor recovery

and survival rate CBF synaptic plasticity and BBB

leakage TNF-120572 IL-1120573 and iNOS

[18 27 28]

D-Amphetamine Noradrenergic 1205721-receptor agonist motor recovery [29]

NEP 1-40 Nogo-A protein inhibitor early motor recovery axonal growth [30]

NgR(310)Ecto-Fc Nogo-NgR pathwayinhibitor

motor recovery axonal plasticity [31]

Progesterone ExcitotoxicityInflammatory processes

infarct volume forelimbs strength and motor recovery [32]

EGFlowast and EPOlowast Neuron proliferation migrationand differentiation accelerated fine motor recovery [33 34]

Chondroitinase ABC Chondroitin sulphate proteoglycans(CSPGs)

CSPGs synaptic plasticitymotor recovery

[35]

indicates an increase and a decrease respectively NEP 1-40 NOGO extracellular peptide EGF epidermal growth factor EPO erythropoietin GSNOS-nitrosoglutathione CBF cerebral blood flow BDNF brain developed neurotrophic factor trkB tropomyosin receptor kinase B BBB blood brain barrierlowastMolecules combination

targeting excitotoxicity Although this combination had noadditional effect in reducing infarct volume functional recov-ery effectiveness was promoted as shown by the increasedrotarod performance and forelimb grip strength at all timepoints within 7 days after ischemic stroke [32]

In addition some authors indicated that combination oftwo pharmacological treatments could improve functionalrecovery and neural plasticity compared to either treatmentalone For example association of epidermal growth fac-tor (EGF) and erythropoietin (EPO) treatments is moreeffective in promoting tissue regeneration and proliferationof neural precursor cells than monotherapy [33] Howeveran even greater improvement in skilled reaching ability inthe staircase test was observed when physical rehabilitationwas added to serial application of both EGF and EPO[34] Authors have also indicated that fine motor skillimprovement was observed 10 weeks after functional reha-bilitation alone whereas 4-week-long treatment combinationwas sufficient to improve sensorimotor function It meansthat functional recovery is also clearly accelerated with thiscombination

Another strategy consists of recreating a tissue environ-ment free from growth inhibiting molecules Chondroiti-nase ABC which degrades inhibitory chondroitin sulphateproteoglycans present in the extracellular matrix reducesthe neurite-inhibitory environment and facilitates axonalsprouting and sensorimotor recovery after spinal cord injury[119 120] and after cerebral ischemia [121 122]This treatmentwas applied at the ipsilesional cortex in rats in combinationwith functional rehabilitation Synaptic plasticity assessed by

measuring the expression of glutamate vesicular transporter(vGLUT1 and vGLUT2) and the GABA vesicular transporter(vGAT) and functional recovery were promoted by thesynergic effect of these treatments [35]

Given that some promising treatments developed inpreclinical studies failed to be effective in clinical studies[123 124] it seems crucial to assess the pharmacologicaleffectiveness in stroke patients before combining it withphysical exerciseTherefore we need to keep inmind that notall the effective combinations found in animal studies couldbe considered effective for human Nevertheless assessingboth treatments and exercise in rodentmodels seems relevantto found new therapeutic strategies to highlight the mosteffective and applicable strategies for human

6 Influence of Prestroke Physical Activity onMotor Dysfunction Severity

To avoid administration of several pharmacological sub-stances in individuals with high risks of stroke (may inducedeleterious interaction between drugs and complications dueto their side effects) physical activity might be a major alter-native preventive strategy for reducing the brain secondaryinjury when stroke occurs Several recent human and animalstudies have well demonstrated that preischemic physicalactivity may reduce initial stroke severity on functionalmotor outcomes edema and infarct volume by acting oninflammation vascular processes BDNF expression andmetabolic disorders [14 16 17 125 126]

Neural Plasticity 7

Ischemia-induced brain inflammation is believed toplay a pivotal role in the development of secondary braininjury by intensifying the inflammatory cell accumulationandmicrovascular impairments Indeed adhesionmoleculessuch as intercellular adhesion molecule 1 (ICAM-1) pro-mote leukocyte infiltration into injury site and leukocyteadhesion to microvascular endothelium Preischemic phys-ical training-induced neuroprotection was associated with adecrease in ICAM-1 mRNA expression and in the number ofICAM-1-positive vessels [17] Consequently leukocyte accu-mulation in damaged cortex and striatum vessels decreasedresulting in reduction of brain inflammation during reperfu-sion

Brain angiogenesis is another neuroprotective mecha-nism for reducing the detrimental motor effect of cere-bral ischemia Physical training prior to cerebral ischemiaincreased short- and long-term effects onmicrovascular den-sity and cerebral blood flow by promoting angiogenesis andincreasing cerebral vasomotor reactivity It was found thatpreischemic exercise improved vasorelaxation by enhancingVEGF levels into the ischemic region which is knownto activate eNOS and EPCs recruitment [8 19] Likewiseexercise decreased the endothelin-1 (a powerful vasocon-strictor agent) expression thereby reducing the impact ofvasoconstriction on cerebral blood flow [127]

Preischemic training could also attenuate brain dam-age by limiting metabolic disorders after cerebral ischemiaIndeed 51015840AMP-activated protein kinase (AMPK) phos-phofructokinase-1 (PFK) and hypoxia-induced factor-1120572(HIF-1120572) involved in glycolysis [18 128] were significantlyhigher in preischemic trained rats [129] Moreover theincrease of glucose transporters in neurons and endothelialcells of the BBB (GLUT3 and GLUT1 resp) results inan improved glucose oxidation immediately after cerebralischemia allowing a faster and more substantial increase inATP production

Moreover it was postulated that preischemic exercise(30min on a treadmill 5 daysweek for 3 weeks) decreasesBBB dysfunctions and thus reduces infarct volume andedema as confirmed by the MMP-9 expression decrement[130 131] Preischemic treadmill training-induced neuro-protection in ischemic rats increased endogenous BDNFexpression that leads to motor recovery improvement [1617 67 132] Interestingly the preischemic treadmill exer-cise improved the therapeutic effectiveness of postischemictreadmill training onmotor function compared with animalsperforming it only after cerebral ischemia [53]

Neuronal excitotoxicity induced by excessive glutamaterelease is a major deleterious event of the brain secondaryinjury [133 134] It was found that preischemic treadmilltraining could also reduce the expression of glutamate recep-tors mGluR5 and NR2B reflecting a decrease of glutamateeffect on surrounding cells [135ndash137] Moreover it was pos-tulated that the reduction of infarct volume induced by 12weeks of treadmill might be related to increase of NGFexpression and this receptor p75 known to promote neu-roprotection against excitotoxicity and free-radical damage[138]

Individuals who were physically active prior to strokehave been shown to exhibit less deleterious functional out-comes as indicated by higher Barthel Index scores as wellas Oxford Handicap Scale [14 15] Indeed it was recentlyrevealed that patients with high levels of prestroke physicalactivity were associated with milder stroke severity at admis-sion with faster early motor improvement and with a lowerfinal infarct volume [139] Interestingly it seems that simplywalking 1 hday during 5 days per week or doing a vigorousaerobic activity 1 hday twice a week is sufficient to inducepreventive effects However findings remain conflicting inhuman studies because no strong association between higherlevels of physical activity and better functional outcomes afterstroke was found in a large prospective cohort [126]

7 Conclusion

Although acute exercise appears to be useful for better under-standing neural andmotor recoverymechanisms few studieshave used this experimental model to investigate strokephysiopathology Neural adaptations remain thus unclearFurthermore physical training appears to be promising toimprove functional motor recovery by promoting neuro-plasticity at different cellular and molecular levels Thesebeneficial effects seem accelerated andor accentuated whenexercise is combined with an additional pharmacologicaltreatment Nevertheless optimal parameters of training andtreatment need to be investigated to maximizeaccelerateneuroplasticity and motor recovery and avoid undesirableeffects of exercise All these findings could help researchersand therapists to justify the effectiveness of their physicaltraining programs in order to increase the patient willingnessto regularly perform physical activity before and after stroke

Conflict of Interests

Each author of the present review declared no conflict ofinterests

Acknowledgment

The authors are grateful to Dr Vincent Pertici for commentson earlier version of this paper

References

[1] E Broussalis M Killer M McCoy A Harrer E Trinkaand J Kraus ldquoCurrent therapies in ischemic stroke Part ARecent developments in acute stroke treatment and in strokepreventionrdquoDrug Discovery Today vol 17 no 7-8 pp 296ndash3092012

[2] F M Ivey R F Macko A S Ryan and C E Hafer-MackoldquoCardiovascular health and fitness after strokerdquo Topics in StrokeRehabilitation vol 12 no 1 pp 1ndash16 2005

[3] D LMarsden A Dunn R Callister C R Levi andN J SprattldquoCharacteristics of exercise training interventions to improvecardiorespiratory fitness after stroke a systematic review withmeta-analysisrdquo Neurorehabilitation and Neural Repair vol 27no 9 pp 775ndash788 2013

8 Neural Plasticity

[4] L Li W Rong Z Ke X Hu S P Yip and K Y Tong ldquoMuscleactivation changes during body weight support treadmill train-ing after focal cortical ischemia a rat hindlimb modelrdquo Journalof Electromyography and Kinesiology vol 21 no 2 pp 318ndash3262011

[5] C Pin-Barre J Laurin M-S Felix et al ldquoAcute neuromuscularadaptation at the spinal level following middle cerebral arteryocclusion-reperfusion in the ratrdquoPLoSONE vol 9 no 2 ArticleID e89953 2014

[6] L W Forrester D F Hanley and R F Macko ldquoEffectsof treadmill exercise on transcranial magnetic stimulation-induced excitability to quadriceps after strokerdquo Archives ofPhysical Medicine and Rehabilitation vol 87 no 2 pp 229ndash2342006

[7] R FMacko FM Ivey LW Forrester et al ldquoTreadmill exerciserehabilitation improves ambulatory function and cardiovas-cular fitness in patients with chronic stroke a randomizedcontrolled trialrdquo Stroke vol 36 no 10 pp 2206ndash2211 2005

[8] M Endres K Gertz U Lindauer et al ldquoMechanisms of strokeprotection by physical activityrdquoAnnals of Neurology vol 54 no5 pp 582ndash590 2003

[9] K Gertz J Priller G Kronenberg et al ldquoPhysical activityimproves long-term stroke outcome via endothelial nitric oxidesynthase-dependent augmentation of neovascularization andcerebral blood flowrdquo Circulation Research vol 99 no 10 pp1132ndash1140 2006

[10] S Liebigt N Schlegel J Oberland O W Witte C Redeckerand S Keiner ldquoEffects of rehabilitative training and anti-inflammatory treatment on functional recovery and cellularreorganization following strokerdquo Experimental Neurology vol233 no 2 pp 776ndash782 2012

[11] W-R Schabitz T Steigleder C M Cooper-Kuhn et al ldquoIntra-venous brain-derived neurotrophic factor enhances poststrokesensorimotor recovery and stimulates neurogenesisrdquo Strokevol 38 no 7 pp 2165ndash2172 2007

[12] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[13] I-M Lee C H Hennekens K Berger J E Buring and J EManson ldquoExercise and risk of stroke inmale physiciansrdquo Strokevol 30 no 1 pp 1ndash6 1999

[14] D Deplanque I Masse C Lefebvre C Libersa D Leys andR Bordet ldquoPrior TIA lipid-lowering drug use and physicalactivity decrease ischemic stroke severityrdquo Neurology vol 67no 8 pp 1403ndash1410 2006

[15] N Stroud T M L Mazwi L D Case et al ldquoPrestroke physicalactivity and early functional status after strokerdquo Journal ofNeurology Neurosurgery and Psychiatry vol 80 no 9 pp 1019ndash1022 2009

[16] Y Ding J Li X Luan et al ldquoExercise pre-conditioningreduces brain damage in ischemic rats that may be associatedwith regional angiogenesis and cellular overexpression of neu-rotrophinrdquo Neuroscience vol 124 no 3 pp 583ndash591 2004

[17] Y-H Ding C N Young X Luan et al ldquoExercise precondi-tioning ameliorates inflammatory injury in ischemic rats duringreperfusionrdquoActaNeuropathologica vol 109 no 3 pp 237ndash2462005

[18] MKhan B Sekhon S Giri et al ldquoS-Nitrosoglutathione reducesinflammation and protects brain against focal cerebral ischemiain a rat model of experimental strokerdquo Journal of Cerebral BloodFlow and Metabolism vol 25 no 2 pp 177ndash192 2005

[19] W Schmidt M Endres F Dimeo and G J JungehulsingldquoTrain the vessel gain the brain physical activity and vesselfunction and the impact on stroke prevention and outcome incerebrovascular diseaserdquo Cerebrovascular Diseases vol 35 no4 pp 303ndash312 2013

[20] W R Frontera L Grimby and L Larsson ldquoFiring rate ofthe lower motoneuron and contractile properties of its musclefibers after upper motoneuron lesion in manrdquoMuscle amp Nervevol 20 no 8 pp 938ndash947 1997

[21] C M Cirstea C R Savage R J Nudo et al ldquoHandgrip-relatedactivation in the primary motor cortex relates to underlyingneuronal metabolism after strokerdquo Neurorehabilitation andNeural Repair vol 28 no 5 pp 433ndash442 2013

[22] C Enzinger H Johansen-Berg H Dawes et al ldquoFunctionalMRI correlates of lower limb function in stroke victims withgait impairmentrdquo Stroke vol 39 no 5 pp 1507ndash1513 2008

[23] A R Luft L Forrester R F Macko et al ldquoBrain activationof lower extremity movement in chronically impaired strokesurvivorsrdquo NeuroImage vol 26 no 1 pp 184ndash194 2005

[24] A R Luft S Waller L Forrester et al ldquoLesion locationalters brain activation in chronically impaired stroke survivorsrdquoNeuroImage vol 21 no 3 pp 924ndash935 2004

[25] N S Ward ldquoFunctional reorganization of the cerebral motorsystem after strokerdquo Current Opinion in Neurology vol 17 no6 pp 725ndash730 2004

[26] A C Zemke P J Heagerty C Lee and S C Cramer ldquoMotorcortex organization after stroke is related to side of stroke andlevel of recoveryrdquo Stroke vol 34 no 5 pp e23ndashe28 2003

[27] M Khan H Sakakima T S Dhammu et al ldquoS-nitrosoglutathione reduces oxidative injury and promotesmechanisms of neurorepair following traumatic brain injury inratsrdquo Journal of Neuroinflammation vol 8 article 78 2011

[28] H Sakakima M Khan T S Dhammu et al ldquoStimulationof functional recovery via the mechanisms of neurorepairby S-nitrosoglutathione and motor exercise in a rat modelof transient cerebral ischemia and reperfusionrdquo RestorativeNeurology and Neuroscience vol 30 no 5 pp 383ndash396 2012

[29] S Barbay E V Zoubina N Dancause et al ldquoA single injectionof D-amphetamine facilitates improvements in motor trainingfollowing a focal cortical infarct in squirrel monkeysrdquo Neurore-habilitation and Neural Repair vol 20 no 4 pp 455ndash458 2006

[30] P-C Fang S Barbay E J Plautz E Hoover S M Strittmatterand R J Nudo ldquoCombination of NEP 1-40 treatment andmotortraining enhances behavioral recovery after a focal corticalinfarct in ratsrdquo Stroke vol 41 no 3 pp 544ndash549 2010

[31] J-K Lee J-E Kim M Sivula and S M Strittmatter ldquoNogoreceptor antagonism promotes stroke recovery by enhancingaxonal plasticityrdquo The Journal of Neuroscience vol 24 no 27pp 6209ndash6217 2004

[32] J Wang X Feng Y Du L Wang and S Zhang ldquoCombinationtreatment with progesterone and rehabilitation training furtherpromotes behavioral recovery after acute ischemic stroke inmicerdquo Restorative Neurology and Neuroscience vol 31 no 4 pp487ndash499 2013

[33] B Kolb C Morshead C Gonzalez et al ldquoGrowth factor-stimulated generation of new cortical tissue and functionalrecovery after stroke damage to the motor cortex of ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 27 no 5pp 983ndash997 2007

[34] M S Jeffers A Hoyles C Morshead and D Corbett ldquoEpi-dermal growth factor and erythropoietin infusion accelerate

Neural Plasticity 9

functional recovery in combination with rehabilitationrdquo Strokevol 45 no 6 pp 1856ndash1858 2014

[35] L Gherardini M Gennaro and T Pizzorusso ldquoPerilesionaltreatment with chondroitinase ABC and motor training pro-mote functional recovery after stroke in ratsrdquo Cerebral Cortexvol 25 no 1 pp 202ndash212 2015

[36] D P Fuchs N Sanghvi J Wieser and S Schindler-IvensldquoPedaling alters the excitability and modulation of vastusmedialis H-reflexes after strokerdquo Clinical Neurophysiology vol122 no 10 pp 2036ndash2043 2011

[37] I-S Hwang C-F Lin L-C Tung and C-H Wang ldquoRespon-siveness of the H reflex to loading and posture in patientsfollowing strokerdquo Journal of Electromyography and Kinesiologyvol 14 no 6 pp 653ndash659 2004

[38] M A Oskoei and H Hu ldquoSupport vector machine-basedclassification scheme for myoelectric control applied to upperlimbrdquo IEEE Transactions on Biomedical Engineering vol 55 no8 pp 1956ndash1965 2008

[39] G L Soderberg and L M Knutson ldquoA guide for use andinterpretation of kinesiologic electromyographic datardquo PhysicalTherapy vol 80 no 5 pp 485ndash498 2000

[40] N A Riley and M Bilodeau ldquoChanges in upper limb jointtorque patterns and EMG signals with fatigue following astrokerdquoDisability andRehabilitation vol 24 no 18 pp 961ndash9692002

[41] U M Svantesson K S Sunnerhagen U S Carlsson and GGrimby ldquoDevelopment of fatigue during repeated eccentric-concentric muscle contractions of plantar flexors in patientswith strokerdquo Archives of Physical Medicine and Rehabilitationvol 80 no 10 pp 1247ndash1252 1999

[42] K N Arya S Pandian R Verma and R K Garg ldquoMovementtherapy induced neural reorganization and motor recovery instroke a reviewrdquo Journal of Bodywork andMovementTherapiesvol 15 no 4 pp 528ndash537 2011

[43] R J Nudo ldquoNeural bases of recovery after brain injuryrdquo Journalof Communication Disorders vol 44 no 5 pp 515ndash520 2011

[44] T Kawamata N E Alexis W D Dietrich and S P FinklesteinldquoIntracisternal basic fibroblast growth factor (bFGF) enhancesbehavioral recovery following focal cerebral infarction in theratrdquo Journal of Cerebral Blood Flow and Metabolism vol 16 no4 pp 542ndash547 1996

[45] T Yamaguchi M Suzuki and M Yamamoto ldquoYM796 anovel muscarinic agonist improves the impairment of learningbehavior in a rat model of chronic focal cerebral ischemiardquoBrain Research vol 669 no 1 pp 107ndash114 1995

[46] F Matsuda H Sakakima and Y Yoshida ldquoThe effects of earlyexercise on brain damage and recovery after focal cerebralinfarction in ratsrdquoActa Physiologica vol 201 no 2 pp 275ndash2872011

[47] K Mizutani S Sonoda N Hayashi et al ldquoAnalysis of proteinexpression profile in the cerebellum of cerebral infarction ratsafter treadmill trainingrdquo American Journal of Physical Medicineamp Rehabilitation vol 89 no 2 pp 107ndash114 2010

[48] P Zhang Y Zhang J Zhang et al ldquoEarly exercise protectsagainst cerebral ischemic injury through inhibiting neuronapoptosis in cortex in ratsrdquo International Journal of MolecularSciences vol 14 no 3 pp 6074ndash6089 2013

[49] L M Cupini M Diomedi F Placidi M Silvestrini and PGiacomini ldquoCerebrovascular reactivity and subcortical infarc-tionsrdquo Archives of Neurology vol 58 no 4 pp 577ndash581 2001

[50] F M Ivey A S Ryan C E Hafer-Macko and R F MacKoldquoImproved cerebral vasomotor reactivity after exercise trainingin hemiparetic stroke survivorsrdquo Stroke vol 42 no 7 pp 1994ndash2000 2011

[51] S Tian Y Zhang S Tian et al ldquoEarly exercise training improvesischemic outcome in rats by cerebral hemodynamicsrdquo BrainResearch vol 1533 pp 114ndash121 2013

[52] Y Gao Y Zhao J Pan et al ldquoTreadmill exercise promotesangiogenesis in the ischemic penumbra of rat brains throughcaveolin-1VEGF signaling pathwaysrdquo Brain Research vol 1585pp 83ndash90 2014

[53] G Kim and E Kim ldquoEffects of treadmill training on limbmotorfunction and acetylcholinesterase activity in rats with strokerdquoJournal of PhysicalTherapy Science vol 25 no 10 pp 1227ndash12302013

[54] Q Zheng D Zhu Y Bai Y Wu J Jia and Y Hu ldquoExerciseimproves recovery after ischemic brain injury by inducing theexpression of angiopoietin-1 and Tie-2 in ratsrdquo The TohokuJournal of Experimental Medicine vol 224 no 3 pp 221ndash2282011

[55] T M Hansen A J Moss and N P J Brindle ldquoVascularendothelial growth factor and angiopoietins in neurovascularregeneration and protection following strokerdquo Current Neu-rovascular Research vol 5 no 4 pp 236ndash245 2008

[56] D M Hermann and A Zechariah ldquoImplications of vascu-lar endothelial growth factor for postischemic neurovascularremodelingrdquo Journal of Cerebral Blood Flow and Metabolismvol 29 no 10 pp 1620ndash1643 2009

[57] C S Mang K L Campbell C J D Ross and L A Boyd ldquoPro-moting neuroplasticity for motor rehabilitation after strokeconsidering the effects of aerobic exercise and genetic variationon brain-derived neurotrophic factorrdquo PhysicalTherapy vol 93no 12 pp 1707ndash1716 2013

[58] M Ploughman VWindle C LMacLellan NWhite J J Doreand D Corbett ldquoBrain-derived neurotrophic factor contributesto recovery of skilled reaching after focal ischemia in ratsrdquoStroke vol 40 no 4 pp 1490ndash1495 2009

[59] I Kiprianova TM Freiman SDesiderato et al ldquoBrain-derivedneurotrophic factor prevents neuronal death and glial activa-tion after global ischemia in the ratrdquo Journal of NeuroscienceResearch vol 56 no 1 pp 21ndash27 1999

[60] R J Nudo E J Plautz and S B Frost ldquoRole of adaptiveplasticity in recovery of function after damage to motor cortexrdquoMuscle amp Nerve vol 24 no 8 pp 1000ndash1019 2001

[61] W-R Schabitz S Schwab M Spranger and W Hacke ldquoIntra-ventricular brain-derived neurotrophic factor reduces infarctsize after focal cerebral ischemia in ratsrdquo Journal of CerebralBlood Flow and Metabolism vol 17 no 5 pp 500ndash506 1997

[62] W-R Schabitz C Sommer W Zoder et al ldquoIntravenousbrain-derived neurotrophic factor reduces infarct size andcounterregulates Bax andBcl-2 expression after temporary focalcerebral ischemiardquo Stroke vol 31 no 9 pp 2212ndash2217 2000

[63] M-W Kim M-S Bang T-R Han et al ldquoExercise increasedBDNF and trkB in the contralateral hemisphere of the ischemicrat brainrdquo Brain Research vol 1052 no 1 pp 16ndash21 2005

[64] Z Kokaia Q Zhao M Kokaia et al ldquoRegulation of brain-derived neurotrophic factor gene expression after transientmiddle cerebral artery occlusion with and without brain dam-agerdquo Experimental Neurology vol 136 no 1 pp 73ndash88 1995

[65] L R Zhao B Mattsson and B B Johansson ldquoEnvironmentalinfluence on brain-derived neurotrophic factormessenger RNA

10 Neural Plasticity

expression after middle cerebral artery occlusion in sponta-neously hypertensive ratsrdquo Neuroscience vol 97 no 1 pp 177ndash184 2000

[66] H D Muller K M Hanumanthiah K Diederich S SchwabW-R Schabitz and C Sommer ldquoBrain-derived neurotrophicfactor but not forced armuse improves long-term outcome afterphotothrombotic stroke and transiently upregulates bindingdensities of excitatory glutamate receptors in the rat brainrdquoStroke vol 39 no 3 pp 1012ndash1021 2008

[67] W-R Schabitz C Berger R Kollmar et al ldquoEffect of brain-derived neurotrophic factor treatment and forced arm use onfunctional motor recovery after small cortical ischemiardquo Strokevol 35 no 4 pp 992ndash997 2004

[68] J Chen J Qin Q Su Z Liu and J Yang ldquoTreadmillrehabilitation treatment enhanced BDNF-TrkB but not NGF-TrkA signaling in a mouse intracerebral hemorrhage modelrdquoNeuroscience Letters vol 529 no 1 pp 28ndash32 2012

[69] J-Y Chung M-W Kim M-S Bang and M Kim ldquoIncreasedexpression of neurotrophin 4 following focal cerebral ischemiain adult rat brain with treadmill exerciserdquo PLoS ONE vol 8 no3 Article ID e52461 2013

[70] Z Ke S P Yip L Li X X Zheng W K Tam and K Y TongldquoThe effects of voluntary involuntary and forced exercises onmotor recovery in a stroke rat modelrdquo in Proceedings of theAnnual International Conference of the IEEE Engineering inMedicine and Biology Society (EMBC rsquo11) vol 2011 pp 8223ndash8226 Boston Mass USA August 2011

[71] P-C Shih Y-R Yang and R-Y Wang ldquoEffects of exerciseintensity on spatial memory performance and hippocampalsynaptic plasticity in transient brain ischemic ratsrdquo PLoS ONEvol 8 no 10 Article ID e78163 2013

[72] J Sun Z Ke S P Yip X-L Hu X-X Zheng and K-Y TongldquoGradually increased training intensity benefits rehabilitationoutcome after stroke by BDNF upregulation and stress sup-pressionrdquo BioMed Research International vol 2014 Article ID925762 8 pages 2014

[73] R Marin A Williams S Hale et al ldquoThe effect of voluntaryexercise exposure on histological and neurobehavioral out-comes after ischemic brain injury in the ratrdquo Physiology andBehavior vol 80 no 2-3 pp 167ndash175 2003

[74] S Vaynman Z Ying and F Gomez-Pinilla ldquoExercise inducesBDNF and synapsin I to specific hippocampal subfieldsrdquo Jour-nal of Neuroscience Research vol 76 no 3 pp 356ndash362 2004

[75] L Zhang X Hu J Luo et al ldquoPhysical exercise improves func-tional recovery through mitigation of autophagy attenuationof apoptosis and enhancement of neurogenesis after MCAO inratsrdquo BMC Neuroscience vol 14 article 46 2013

[76] J Puyal and P G H Clarke ldquoTargeting autophagy to preventneonatal stroke damagerdquoAutophagy vol 5 no 7 pp 1060ndash10612009

[77] Q-W Zhang X-X Deng X Sun J-X Xu and F-Y SunldquoExercise promotes axon regeneration of newborn striatonigraland corticonigral projection neurons in rats after ischemicstrokerdquo PLoS ONE vol 8 no 11 Article ID e80139 2013

[78] M Asahi K Asahi J-C Jung G J del ZoppoM E Fini and EH Lo ldquoRole for matrix metalloproteinase 9 after focal cerebralischemia effects of gene knockout and enzyme inhibition withBB-94rdquo Journal of Cerebral Blood Flow amp Metabolism vol 20no 12 pp 1681ndash1689 2000

[79] M Asahi X Wang T Mori et al ldquoEffects of matrixmetalloproteinase-9 gene knock-out on the proteolysis of

blood-brain barrier andwhitematter components after cerebralischemiardquoThe Journal of Neuroscience vol 21 no 19 pp 7724ndash7732 2001

[80] Y Zhang P Zhang X Shen et al ldquoEarly exercise protects theblood-brain barrier from ischemic brain injury via the regula-tion of MMP-9 and occludin in ratsrdquo International Journal ofMolecular Sciences vol 14 no 6 pp 11096ndash11112 2013

[81] I G Onyango J Lu M Rodova E Lezi A B Crafter and RH Swerdlow ldquoRegulation of neuron mitochondrial biogenesisand relevance to brain healthrdquo Biochimica et Biophysica ActamdashMolecular Basis of Disease vol 1802 no 1 pp 228ndash234 2010

[82] Q Zhang Y Wu P Zhang et al ldquoExercise induces mitochon-drial biogenesis after brain ischemia in ratsrdquo Neuroscience vol205 pp 10ndash17 2012

[83] L Li W Rong Z Ke X Hu and K-Y Tong ldquoThe effects oftraining intensities on motor recovery and gait symmetry in arat model of ischemiardquo Brain Injury vol 27 no 4 pp 408ndash4162013

[84] C Enzinger H Dawes H Johansen-Berg et al ldquoBrain activitychanges associated with treadmill training after strokerdquo Strokevol 40 no 7 pp 2460ndash2467 2009

[85] A R Luft R FMacKo LW Forrester et al ldquoTreadmill exerciseactivates subcortical neural networks and improves walkingafter stroke a randomized controlled trialrdquo Stroke vol 39 no12 pp 3341ndash3350 2008

[86] K Potempa M Lopez L T Braun J P Szidon L Fogg and TTincknell ldquoPhysiological outcomes of aerobic exercise trainingin hemiparetic stroke patientsrdquo Stroke vol 26 no 1 pp 101ndash1051995

[87] F Buma G Kwakkel and N Ramsey ldquoUnderstanding upperlimb recovery after strokerdquo Restorative Neurology and Neuro-science vol 31 no 6 pp 707ndash722 2013

[88] A E Baird A Benfield G Schlaug et al ldquoEnlargementof human cerebral ischemic lesion volumes measured bydiffusion-weighted magnetic resonance imagingrdquo Annals ofNeurology vol 41 no 5 pp 581ndash589 1997

[89] A Schmidt J Wellmann M Schilling et al ldquoMeta-analysis ofthe efficacy of different training strategies in animal models ofischemic strokerdquo Stroke vol 45 no 1 pp 239ndash247 2014

[90] R-Y Wang S-M Yu and Y-R Yang ldquoTreadmill trainingeffects in different age groups following middle cerebral arteryocclusion in ratsrdquo Gerontology vol 51 no 3 pp 161ndash165 2005

[91] P ZhangH YuN Zhou et al ldquoEarly exercise improves cerebralblood flow through increased angiogenesis in experimentalstroke rat modelrdquo Journal of NeuroEngineering and Rehabilita-tion vol 10 article 43 2013

[92] J Laurin andC Pin-Barre ldquoPhysiological adaptations followingendurance exercises after stroke focus on the plausible roleof high-intensity interval trainingrdquo International Journal ofPhysical Medicine amp Rehabilitation vol 2 no 3 pp 1ndash6 2014

[93] THMurphy andDCorbett ldquoPlasticity during stroke recoveryfrom synapse to behaviourrdquo Nature Reviews Neuroscience vol10 no 12 pp 861ndash872 2009

[94] M Svensson J Lexell and T Deierborg ldquoEffects of physicalexercise on neuroinflammation neuroplasticity neurodegener-ation and behavior what we can learn from animal models inclinical settingsrdquoNeurorehabilitation and Neural Repair vol 29no 6 pp 577ndash589 2015

[95] A Risedal J Zeng and B B Johansson ldquoEarly training mayexacerbate brain damage after focal brain ischemia in the ratrdquoJournal of Cerebral Blood Flow andMetabolism vol 19 no 9 pp997ndash1003 1999

Neural Plasticity 11

[96] C-S Piao B A Stoica J Wu et al ldquoLate exercise reducesneuroinflammation and cognitive dysfunction after traumaticbrain injuryrdquoNeurobiology of Disease vol 54 pp 252ndash263 2013

[97] J L Humm D A Kozlowski S T Bland D C James andT Schallert ldquoUse-dependent exaggeration of brain injury isglutamate involvedrdquo Experimental Neurology vol 157 no 2 pp349ndash358 1999

[98] G S Griesbach F Gomez-Pinilla and D A Hovda ldquoTheupregulation of plasticity-related proteins following TBI isdisrupted with acute voluntary exerciserdquo Brain Research vol1016 no 2 pp 154ndash162 2004

[99] J WMcAlees L T Smith R S Erbe D Jarjoura N M Ponzioand V M Sanders ldquoEpigenetic regulation of beta2-adrenergicreceptor expression in T

1198671 and T

1198672 cellsrdquo Brain Behavior and

Immunity vol 25 no 3 pp 408ndash415 2011[100] G Zhao S Zhou A Davie and Q Su ldquoEffects of moderate and

high intensity exercise on T1T2 balancerdquo Exercise ImmunologyReview vol 18 pp 98ndash114 2012

[101] Y Yagita K Kitagawa T Sasaki et al ldquoPostischemic exercisedecreases neurogenesis in the adult rat dentate gyrusrdquo Neuro-science Letters vol 409 no 1 pp 24ndash29 2006

[102] S T Bland T Schallert R Strong J Aronowski and J CGrottaldquoEarly exclusive use of the affected forelimb aftermoderate tran-sient focal ischemia in rats functional and anatomic outcomerdquoStroke vol 31 no 5 pp 1144ndash1152 2000

[103] S B DeBow J E McKenna B Kolb and F ColbourneldquoImmediate constraint-inducedmovement therapy causes localhyperthermia that exacerbates cerebral cortical injury in ratsrdquoCanadian Journal of Physiology and Pharmacology vol 82 no4 pp 231ndash237 2004

[104] D A Kozlowski D C James and T Schallert ldquoUse-dependentexaggeration of neuronal injury after unilateral sensorimotorcortex lesionsrdquo The Journal of Neuroscience vol 16 no 15 pp4776ndash4786 1996

[105] B Balaban F Tok F Yavuz E Yasar and R Alaca ldquoEarlyrehabilitation outcome in patients with middle cerebral arterystrokerdquo Neuroscience Letters vol 498 no 3 pp 204ndash207 2011

[106] G Kwakkel R van Peppen R C Wagenaar et al ldquoEffects ofaugmented exercise therapy time after stroke a meta-analysisrdquoStroke vol 35 no 11 pp 2529ndash2539 2004

[107] D L Costill M G Flynn J P Kirwan et al ldquoEffects of repeateddays of intensified training on muscle glycogen and swimmingperformancerdquo Medicine amp Science in Sports amp Exercise vol 20no 3 pp 249ndash254 1988

[108] M A Hirsch and B G Farley ldquoExercise and neuroplasticityin persons living with Parkinsonrsquos diseaserdquo European Journal ofPhysical and Rehabilitation Medicine vol 45 no 2 pp 215ndash2292009

[109] M Katz-Leurer M Shochina E Carmeli and Y FriedlanderldquoThe influence of early aerobic training on the functional capac-ity in patients with cerebrovascular accident at the subacutestagerdquo Archives of Physical Medicine and Rehabilitation vol 84no 11 pp 1609ndash1614 2003

[110] J D Schaechter ldquoMotor rehabilitation and brain plasticity afterhemiparetic strokerdquo Progress in Neurobiology vol 73 no 1 pp61ndash72 2004

[111] P R Bosch S Holzapfel and T Traustadottir ldquoFeasibility ofmeasuring ventilatory threshold in adults with stroke-inducedhemiparesis implications for exercise prescriptionrdquo Archives ofPhysical Medicine and Rehabilitation 2015

[112] D P Stirling K Khodarahmi J Liu et al ldquoMinocyclinetreatment reduces delayed oligodendrocyte death attenuatesaxonal dieback and improves functional outcome after spinalcord injuryrdquoThe Journal of Neuroscience vol 24 no 9 pp 2182ndash2190 2004

[113] S Barbay and R J Nudo ldquoThe effects of amphetamine onrecovery of function in animal models of cerebral injury acritical appraisalrdquo NeuroRehabilitation vol 25 no 1 pp 5ndash172009

[114] R S Rasmussen K Overgaard E S Hildebrandt-Eriksen andG Boysen ldquoD-Amphetamine improves cognitive deficits andphysical therapy promotes fine motor rehabilitation in a ratembolic stroke modelrdquo Acta Neurologica Scandinavica vol 113no 3 pp 189ndash198 2006

[115] C L Gibson B Coomber and S P Murphy ldquoProgesterone isneuroprotective following cerebral ischaemia in reproductivelyageing female micerdquo Brain vol 134 no 7 pp 2125ndash2133 2011

[116] T Ishrat I Sayeed F Atif and D G Stein ldquoEffects ofprogesterone administration on infarct volume and functionaldeficits following permanent focal cerebral ischemia in ratsrdquoBrain Research vol 1257 pp 94ndash101 2009

[117] M Prencipe C Ferretti A R Casini M Santini F Giubileiand F Culasso ldquoStroke disability and dementia results of apopulation surveyrdquo Stroke vol 28 no 3 pp 531ndash536 1997

[118] I Sayeed B Wali and D G Stein ldquoProgesterone inhibitsischemic brain injury in a rat model of permanent middle cere-bral artery occlusionrdquo Restorative Neurology and Neurosciencevol 25 no 2 pp 151ndash159 2007

[119] H Lee R J McKeon and R V Bellamkonda ldquoSustaineddelivery of thermostabilized chABC enhances axonal sproutingand functional recovery after spinal cord injuryrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 8 pp 3340ndash3345 2010

[120] V J Tom R Kadakia L Santi and J D Houle ldquoAdministrationof chondroitinase ABC rostral or caudal to a spinal cord injurysite promotes anatomical but not functional plasticityrdquo Journalof Neurotrauma vol 26 no 12 pp 2323ndash2333 2009

[121] J J Hill K Jin X O Mao L Xie and D A GreenbergldquoIntracerebral chondroitinase ABC and heparan sulfate proteo-glycan glypican improve outcome from chronic stroke in ratsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 23 pp 9155ndash9160 2012

[122] S Soleman P K Yip D A Duricki and L D FMoon ldquoDelayedtreatment with chondroitinase ABC promotes sensorimotorrecovery and plasticity after stroke in aged ratsrdquo Brain vol 135no 4 pp 1210ndash1223 2012

[123] B E Skolnick A I Maas R K Narayan et al ldquoA clinical trialof progesterone for severe traumatic brain injuryrdquo The NewEngland Journal of Medicine vol 371 no 26 pp 2467ndash24762014

[124] DWWright SD Yeatts R Silbergleit et al ldquoVery early admin-istration of progesterone for acute traumatic brain injuryrdquo TheNew England Journal of Medicine vol 371 no 26 pp 2457ndash2466 2014

[125] L-H Krarup T Truelsen C Gluud et al ldquoPrestroke physicalactivity is associated with severity and long-term outcome fromfirst-ever strokerdquo Neurology vol 71 no 17 pp 1313ndash1318 2008

[126] P M Rist I-M Lee C S Kase J Michael Gaziano and TKurth ldquoPhysical activity and functional outcomes from cerebralvascular events in menrdquo Stroke vol 42 no 12 pp 3352ndash33562011

12 Neural Plasticity

[127] Q Zhang L Zhang X Yang Y Wan and J Jia ldquoThe effectsof exercise preconditioning on cerebral blood flow change andendothelin-1 expression after cerebral ischemia in ratsrdquo Journalof Stroke and Cerebrovascular Diseases vol 23 no 6 pp 1696ndash1702 2014

[128] M Bernaudin A-S Nedelec D Divoux E T MacKenzie EPetit and P Schumann-Bard ldquoNormobaric hypoxia inducestolerance to focal permanent cerebral ischemia in associationwith an increased expression of hypoxia-inducible factor-1 andits target genes erythropoietin and VEGF in the adult mousebrainrdquo Journal of Cerebral Blood Flow and Metabolism vol 22no 4 pp 393ndash403 2002

[129] D Dornbos III N Zwagerman M Guo et al ldquoPreischemicexercise reduces brain damage by ameliorating metabolic dis-order in ischemiareperfusion injuryrdquo Journal of NeuroscienceResearch vol 91 no 6 pp 818ndash827 2013

[130] Y-H Ding Y Ding J Li D A Bessert and J A RafolsldquoExercise pre-conditioning strengthens brain microvascularintegrity in a rat stroke modelrdquo Neurological Research vol 28no 2 pp 184ndash189 2006

[131] M Guo B Cox S Mahale et al ldquoPre-ischemic exercise reducesmatrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in strokerdquo Neuroscience vol 151 no2 pp 340ndash351 2008

[132] M Ploughman Z Attwood N White J J E Dore and DCorbett ldquoEndurance exercise facilitates relearning of forelimbmotor skill after focal ischemiardquo The European Journal ofNeuroscience vol 25 no 11 pp 3453ndash3460 2007

[133] L L Guyot F G Diaz M H OrsquoRegan S McLeod H Park andJW Phillis ldquoReal-timemeasurement of glutamate release fromthe ischemic penumbra of the rat cerebral cortex using a focalmiddle cerebral artery occlusion modelrdquo Neuroscience Lettersvol 299 no 1-2 pp 37ndash40 2001

[134] K Matsumoto R Graf G Rosner J Taguchi and W-D HeissldquoElevation of neuroactive substances in the cortex of cats duringprolonged focal ischemiardquo Journal of Cerebral Blood Flow andMetabolism vol 13 no 4 pp 586ndash594 1993

[135] J Jia Y-S Hu Y Wu et al ldquoPre-ischemic treadmill trainingaffects glutamate and gamma aminobutyric acid levels in thestriatal dialysate of a rat model of cerebral ischemiardquo LifeSciences vol 84 no 15-16 pp 505ndash511 2009

[136] F Zhang J Jia Y Wu Y Hu and Y Wang ldquoThe effect of tread-mill training pre-exercise on glutamate receptor expression inrats after cerebral ischemiardquo International Journal of MolecularSciences vol 11 no 7 pp 2658ndash2669 2010

[137] J Jia Y-S Hu Y Wu et al ldquoTreadmill pre-training suppressesthe release of glutamate resulting from cerebral ischemia inratsrdquo Experimental Brain Research vol 204 no 2 pp 173ndash1792010

[138] E T Ang P T H Wong S Moochhala and Y K NgldquoNeuroprotection associated with running is it a result ofincreased endogenous neurotrophic factorsrdquoNeuroscience vol118 no 2 pp 335ndash345 2003

[139] A C Ricciardi E Lopez-Cancio N Perez De La Ossa et alldquoPrestroke physical activity is associated with good functionaloutcome and arterial recanalization after stroke due to a largevessel occlusionrdquo Cerebrovascular Diseases vol 37 no 4 pp304ndash311 2014

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Psychiatry Journal

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity 3

speed

Physical exercise

infarct volume

BBB permeability

muscle fatigue

adaptive neuroplasticity and brain activity during movement

angiogenesis cerebral vasomotor reactivity mitochondrial biogenesis

EMG burst duration (paretic side)

balance and motor coordination body weight support and walking

limb placement test score

cholinergic system regulation

Figure 1 Beneficial structural and functional plasticity induced byphysical exercise in stroke individuals

limiting brain damage and motor deficits [9 50] Indeedtreadmill training increased the most commonly stud-ied angiogenic growth factor expression namely vascularendothelial growth factor (VEGF) and its regulatory proteincaveolin-1 that might contribute to explaining the increaseof new vessel growth and vascular density [52ndash56] Thetraining effect on angiogenesis was reinforced by evidenceshowing that 2 weeks of treadmill training increased theangiopoietin expression another angiogenic growth factorthat has a key role in new vessel formation [54] Otherfindings revealed that the area of platelet-endothelial celladhesion molecule- (PECAM-1-) immunopositive cells (pro-tein involved in angiogenesis and integrin activation) wassignificantly increased around the infarct after 28 days oftreadmill training [46] Daily treadmill training induced anincrease of GFAP expression (proteins playing a role invascular cerebral plasticity) suggesting that area of neovas-cularization was higher in exercised animals [47] More-over voluntary running training upregulated by 3- to 4-fold aortic endothelial nitric oxide synthase (eNOS) mRNAexpression and it remained elevated 10 days after training[8 9] Such findings concur with the fact that beneficialeffect of running was completely abolished in animals lackingeNOS expression and in mice treated with a NOS inhibitoror an antiangiogenic compound such as endostatin [9]Moreover training program increased endothelial progenitorcells (EPC) in bone marrow that are known to stronglyinfluence eNOS expression It is noteworthy to add thatonly 3 days of aerobic exercise reduced brain microvascularendothelial cell apoptosis related to the increase of shearstress that was followed by modest improvement of cerebralblood flow [51]

Physical training can also upregulate the expressionof some neurotrophic factors such as brain-derived neu-rotrophic factor (BDNF) nerve growth factor (NGF) andinsulin-like growth factor (IGF-1)

BDNF is one of the most active neurotrophins thatbinds to the tyrosine kinase receptor (trkB) Overall thisassociation triggers several molecular pathways that promoteneural proliferation and survival and synaptic and axonalplasticity by enhancing synapse formation dendritic growthand remodeling [57] Furthermore BDNF seems also to acton motor function because blocking BDNF mRNA expres-sion by injecting antagonist reduced skilled motor abilities[58]

The neuroprotective effect of endogenous and exogenousBDNF is well established after brain infarction [12 59ndash62]Basal endogenous BDNFtrkB expression increased withinboth hemispheres following moderate cerebral ischemia(including the penumbra) during the first 2 weeks butmotor recovery remains widely insufficient [63ndash65] There-fore treatments that enhance BDNFtrkB production seemrelevant to improve motor recovery (even if infarct size isnot modified) [11 66] It was found that delayed intravenousBDNF administration (20 120583gday) for 5 days improved long-term functional outcomes such as running and sensorimotorrecovery after ischemia [11 66 67]

Interestingly endurance training stimulated endogenousBDNFtkrB expression and may play a neuroplastic rolefollowing cerebral ischemia or intracerebral hemorrhage inrat and mice [58 63 68ndash72] This enhanced BDNFtkrBwas observed in both hemispheres but especially in thenonlesional hemisphere compared to healthy animals underthe same program (that might represent a compensatorymechanism) [53 69] Despite the fact that there is no directevidence the training-related BDNF expression is oftenassociated with motor recovery improvement [58 63 70] Itwas demonstrated that 7 consecutive training days could besufficient to increase BDNF expression and improve motorrecovery [72ndash74] Although endurance exercise upregulatesBDNF expression in striatum and cortex functional outcomeimprovement might be more related to hippocampal BDNFexpression [70 72] Indeed voluntary wheel exercise isknown to induce substantial motor recovery associated withthe highest hippocampal BDNF level [70] Another study alsofound a positive correlation betweenmotor function recoveryrate and hippocampal BDNF expression after treadmill train-ing following cerebral infarction [72]

Finally the number of NGF-immunopositive cells pro-moting cell growth and neuronal activity was particularlyincreased over a widespread region around the infarct zonein trained rats [46] NGF expression which may be theresult of heightened neuronal activity during exercise couldcontribute to reducing brain damage around 4 weeks afterischemic stroke

Physical training could reduce ischemic brain damageand motor deficits by other mechanisms such as reductionof acute inflammatory reactions and neuronal apoptosis [75]Indeed it was demonstrated that the neurotrophic factormidkine (MK) which could delay the process of neuronaldeath during the early phase after cerebral infarction washigher expressed in the cells of the peri-infarct region afterphysical training program [46]

Cerebral ischemia-induced cell death is commonlyattributed to necrosis and apoptosis but it was recently found

4 Neural Plasticity

that inappropriate autophagy might also lead to cell death[76] However physical training mitigated autophagosomesaccumulation and attenuated apoptosis in the peri-infarctregion while improving the modified neurological severityscore scale Physical training could also upregulate IGF-1expression which is known to attenuate autophagy and alsoto promote neurogenesis [75]

In addition several studies reported that neuronal deathin both the striatum and the cerebral cortex caused a degen-eration of nigral dopaminergic neurons that are known tocontribute to regulating motor activity [77] However tread-mill training promoted axon regeneration of newborn stri-atonigral and corticonigral projection neurons in ischemicbrain while improving motor function It was thus suggestedthat exercise could enhance restoration of functional neuralcircuitry within the basal ganglia The cerebellum plays animportant role in the motor coordination learning andequilibrium and also seems to be involved in motor deficitsfollowing cerebral injury Therefore it is not surprising thattreadmill training promoted both synaptogenesis and neu-rite outgrowth via 25-kDa synaptosomal-associated proteinexpression in the cerebellum Likewise such training alsoincreased glial fibrillary acidic protein in the cerebellumwhich plays a role in axonal growth and improved motorcoordination as observed with the rotarod test (longer timeto fall from the rotating rod) [47]

Disruption of the BBB increasing thus its permeabil-ity is one of the major contributors to the pathogene-sis of cerebral ischemia Such event was observed whenmatrix metalloproteinase-9 (MMP-9) is strongly upregulatedthat impairs the extracellular matrix of the BBB [78 79]However physical training attenuated BBB disruption asrevealed by a decrease of MMP-9 expression and a par-allel increase expression of MMP-9 inhibitor the tissueinhibitor of metalloproteinase-1 (TIMP-1) Interestingly suchmechanisms might contribute to decreasing the observedneurological deficits infarct volume and brain edema [80]

These neuroplasticity processes require energy frommitochondria However cerebral ischemia induces damageof the cerebral mitochondria biogenesis contributing to theextent of neuronal ischemic injury [81] Nevertheless 7-day endurance training increased mitochondrial biogenesisafter cerebral ischemia by enhancing both the amount ofmitochondrial DNA and the expression of numerous mito-chondrial biogenesis factors such as the mitochondrial tran-scription factor proliferator activated receptor coactivator-1(PGC-1) nuclear respiratory factor 1 (NRF-1) protein andmitochondrial transcription factor A (TFAM) [82] It wassuggested that these events are involved in decreasing infarctvolume and the improvement of neurological score

Very few studies using rat model of cerebral ischemiaenable better understanding of the treadmill training out-comes on muscle activation regulation Cerebral ischemiais believed to affect synaptic activity including the choliner-gic system which leads to decreasing both neuromuscularjunction and cholinergic brain synaptic transmission It wasshown that aerobic treadmill training (20minday during 21days) improved cholinergic system regulationhomeostasisby decreasing acetylcholinesterase activity (ie hydrolyzing

the acetylcholine) and by enhancing choline acetyltransferaseactivity (ie synthesis of acetylcholine) [53] It was thussuggested that such adaption might allow better motorlimb function as indicated by improvement of the limbplacement test score Moreover 10 days of treadmill trainingimproved balance functional outcome (behavioral score)and motor coordination Indeed the asymmetry of muscleactivation pattern between affected and unaffected hindlimbswas restored because the EMG burst duration was increasedat the affected side [83] Muscle fatigue observed duringlocomotion was reduced as indicated by the increase of MPFat the unaffected side (see Section 2) [4]

A previous human study indicated that effective gaittraining on treadmill with body weight support improvingwalking speed and endurance was characterized by anincrease of brain activity in the bilateral primary sensori-motor cortices the cingulate motor areas the caudate nucleibilaterally and the thalamus of the affected hemisphereduring paretic foot movement [84] In addition treadmillexercise (improving cardiovascular fitness by 18) activatessubcortical neural networks during single knee movementsof the lower extremity as observed by fMRI Indeed physicaltraining changed brain activation during paretic limb move-ment showing 72 and 18 increased activation in posteriorcerebellar lobe andmidbrain respectively [85] After 10weeksof training the improvement in sensorimotor functionassessed with the Fugl-Meyer Index seemed strongly relatedto the improvement in aerobic capacity [86]

It is noteworthy that some neural mechanisms afterphysical exercise remain to be investigated such as diaschisisIndeed functional deficitsmay also be associatedwith distanteffects after subcortical lesions resulting from deafferentationto a region not directly involved in the stroke Moreoverit was found that several rehabilitation exercises inducingblood flow and metabolic changes in the contralesionalhemisphere might act on diaschisis Given that alleviation ofdiaschisis could contribute to motor recovery [87] it seemsimportant that further studies will determine how enduranceexercises may influence diaschisis after cerebral ischemia

4 Influence of Exercise Parameters onNeuroplasticity and Functional Outcomes

Depending on the chosen exercise parameters (volumeintensity session frequency and timing of exercise initiation)neuroplasticity can be either adaptive or maladaptive torecovery and thus may affect the training effectiveness aftercerebral ischemia [46 87ndash91] Strong evidence suggested atime-limited period of enhanced neuroplasticity [89 92ndash94]Animal studies underlined that the limb function was lessimproved when training started before 24 h after ischemiacompared with a start during the 5 first days [89] Moreoverearly intense training might induce larger cortical infarctvolume and thalamic atrophy when the program starts before24 h [95] Exercise detrimental effects were also observedon neuroplasticity when animals performed treadmill exer-cise shortly after trauma [96] The lesional aggravationmight be related to localized and prolonged hyperthermiaIndeed physical exercise known to induce hyperthermia

Neural Plasticity 5

could accentuate the cerebral ischemia-induced release ofglutamate and catecholamines that lead to neural excito-toxicity [95 97] However it seems important to add thatother processes than hyperthermia might be involved in thesensorimotor deficit aggravations and need to be exploredFurthermore early running training downregulated proteinsinvolved in neuroplasticity such as MAPK CAMKII PKCsynapsin I orCREB expression [98] anddecreased the level ofproinflammatory cytokines known to be related to neuropro-tection [99 100] Finally Yagita et al (2006) had shown thattwo weeks of running exercise reduced the number of new-born neurons in ischemic rats and thus limited neurogenesisin the hippocampus [101] The author suggested that runningwas too stressful and enhanced the corticosterone levelknown to decrease neurogenesis Likewise an immediateoveruse of the lesioned forelimb could also increase tissue lossaround the lesion and aggravated sensorimotor deficits on alonger term [102ndash104] One explanation could be related toanatomical damage resulting from the reduction of dendriticgrowth in the ischemic hemisphere [104]

In addition an augmented volume of exercise or increaseof inpatient therapy duration for stroke did not indicatesuperior effects on functional recovery and activities of dailyliving [105 106] Interestingly when healthy active men weresubjected to a strong increase of volume training physicalperformance was also not improved [107] It thus seems thatvolume is not the main exercise parameter that should beinvestigated for improving aerobic program

Greater improvements were observed with higher exer-cise intensities after stroke and neurodegenerative disease butalso for healthy individuals [92 108ndash110] However the effectof intensity on neuroplasticity remains unclear because it ispoorly investigated in stroke patients or in ischemic animalmodels (ongoing study in our laboratory) It should also bepointed that one major methodological limitation is relatedto the exercise intensity determination Indeed trainingintensity was mainly based onmaximal oxygen consumptionor maximal exercise heart rate (or even intensity basedon empirical values) However these parameters were notappropriated because stroke patients never reached maximalcapabilities It was recently suggested that prescribing inten-sity should rather be based on submaximal parameters suchas ventilatory or lactic threshold that were more accurate indistinguishing moderate to intense exercise [111]

5 Beneficial Effect of Physical TrainingRehabilitation in Combination withPharmacological Treatments

Using multiple recovery processes (physical exercise andpharmacologic treatments) may be critical for enhancingfunctional outcomes in contrast to monotherapies targetingsingle mechanisms (Table 1)

Given that recent findings have established that anti-inflammation may be an important target for stroke treat-ment [112] some authors demonstrated that combinationof skilled reaching training with indomethacin or minocy-cline accentuated recovery [10] First beneficial effects of

such combination included an improvement of sensorimotorfunction as indicated by higher correct placements of theimpaired forelimb during a walking task Secondly thenumber of proliferating microglia was more reduced and thesurvival of newborn astrocytes in the peri-infarct zone wasincreased compared to rats that underwent training aloneAuthors suggested that the motor outcome improvementmight be partially explained by the observed changes ofneural response

In addition therapeutic drug such as S-nitrosogluta-thione (GSNO) exhibits similar neurovascular protectingeffects compared to physical training following traumaticbrain trauma and cerebral ischemia in rats [18 27] Adminis-tration of GSNO could reduce neuronal apoptotic cell deathexcitotoxicity and inflammation as well as protecting BBBintegrity GSNO could also stimulate the expression of VEGFand BDNF after traumatic brain injury Several authors havedemonstrated that combining rotating rod motor exercisewith GSNO administration accelerated and accentuated bothwalking and balance abilities compared to the effects inducedby each treatment applied separatelyMoreover the improvedmotor function was associated with a reduction of bothinfarct volume and neuronal cell death as well as an increaseof PECAM-1 and BDNF expression [28]

D-amphetamine acting primarily through norepineph-rine and dopamine mechanisms is a potent modulator ofneurological function and cortical excitation that facilitatedmotor skill abilities [113] It was demonstrated that a singleinjection of D-amphetamine on the first day of trainingfacilitates effectiveness of motor skill training compared withD-amphetamine treatment alone after a focal cortical infarctin squirrel monkeys [29] However administration of ahigh dose of D-amphetamine combined with rehabilitationtraining failed to promote fine motor recovery in a ratembolic stroke model Authors explained this result by thefact that the dose of D-amphetamine was too high therebylimiting animal engagement in the staircase test [114]

Other pharmacological agents could improve motorrecovery by focusing on different neural mechanisms Forexample Nogo-A protein a myelin-associated inhibitorappears to be partially responsible for inhibition of axonalgrowth in white matter Therefore suppressing this myelin-associated neurite outgrowth inhibitor by specific antagonistsof Nogo-A such as NEP 1-40 or NGR(310)Ecto-FC increasedneurite outgrowth and axonal regeneration after stroke [3031] Five-week motor training combined with NEP 1-40treatment accelerated motor recovery (skilled reach and footfault tests) from the first week after cerebral ischemia com-pared to treatments applied alone in which beneficial effectswere observed later (weeks 2 and 4) [30] Unfortunatelyneural plasticity mechanisms underlying this improvementremain unknown but these findings showed that this therapycombination could accelerate the recovery process followingcerebral ischemia

Neurons and glial cells in brain can synthesize proges-terone that exhibits neuroprotective effects after cerebralischemia [115ndash118] Rehabilitation could increase reorganiza-tion of cortical maps whereas the progesterone might reducethe infarct volume through its neuroprotective effect by

6 Neural Plasticity

Table 1 Influence of pharmacological agents associated with physical exercise on motor recovery after brain stroke

Drug agents Targets Results References

Indomethacin Minocycline Inflammatory processes

infarct volume (indomethacin only) sensorimotor performance

microglia astroglia

[10]

GSNOOxidative stress

Inflammatory processesExcitotoxicity

infarct volume apoptotic cell death neurological score motor recovery

and survival rate CBF synaptic plasticity and BBB

leakage TNF-120572 IL-1120573 and iNOS

[18 27 28]

D-Amphetamine Noradrenergic 1205721-receptor agonist motor recovery [29]

NEP 1-40 Nogo-A protein inhibitor early motor recovery axonal growth [30]

NgR(310)Ecto-Fc Nogo-NgR pathwayinhibitor

motor recovery axonal plasticity [31]

Progesterone ExcitotoxicityInflammatory processes

infarct volume forelimbs strength and motor recovery [32]

EGFlowast and EPOlowast Neuron proliferation migrationand differentiation accelerated fine motor recovery [33 34]

Chondroitinase ABC Chondroitin sulphate proteoglycans(CSPGs)

CSPGs synaptic plasticitymotor recovery

[35]

indicates an increase and a decrease respectively NEP 1-40 NOGO extracellular peptide EGF epidermal growth factor EPO erythropoietin GSNOS-nitrosoglutathione CBF cerebral blood flow BDNF brain developed neurotrophic factor trkB tropomyosin receptor kinase B BBB blood brain barrierlowastMolecules combination

targeting excitotoxicity Although this combination had noadditional effect in reducing infarct volume functional recov-ery effectiveness was promoted as shown by the increasedrotarod performance and forelimb grip strength at all timepoints within 7 days after ischemic stroke [32]

In addition some authors indicated that combination oftwo pharmacological treatments could improve functionalrecovery and neural plasticity compared to either treatmentalone For example association of epidermal growth fac-tor (EGF) and erythropoietin (EPO) treatments is moreeffective in promoting tissue regeneration and proliferationof neural precursor cells than monotherapy [33] Howeveran even greater improvement in skilled reaching ability inthe staircase test was observed when physical rehabilitationwas added to serial application of both EGF and EPO[34] Authors have also indicated that fine motor skillimprovement was observed 10 weeks after functional reha-bilitation alone whereas 4-week-long treatment combinationwas sufficient to improve sensorimotor function It meansthat functional recovery is also clearly accelerated with thiscombination

Another strategy consists of recreating a tissue environ-ment free from growth inhibiting molecules Chondroiti-nase ABC which degrades inhibitory chondroitin sulphateproteoglycans present in the extracellular matrix reducesthe neurite-inhibitory environment and facilitates axonalsprouting and sensorimotor recovery after spinal cord injury[119 120] and after cerebral ischemia [121 122]This treatmentwas applied at the ipsilesional cortex in rats in combinationwith functional rehabilitation Synaptic plasticity assessed by

measuring the expression of glutamate vesicular transporter(vGLUT1 and vGLUT2) and the GABA vesicular transporter(vGAT) and functional recovery were promoted by thesynergic effect of these treatments [35]

Given that some promising treatments developed inpreclinical studies failed to be effective in clinical studies[123 124] it seems crucial to assess the pharmacologicaleffectiveness in stroke patients before combining it withphysical exerciseTherefore we need to keep inmind that notall the effective combinations found in animal studies couldbe considered effective for human Nevertheless assessingboth treatments and exercise in rodentmodels seems relevantto found new therapeutic strategies to highlight the mosteffective and applicable strategies for human

6 Influence of Prestroke Physical Activity onMotor Dysfunction Severity

To avoid administration of several pharmacological sub-stances in individuals with high risks of stroke (may inducedeleterious interaction between drugs and complications dueto their side effects) physical activity might be a major alter-native preventive strategy for reducing the brain secondaryinjury when stroke occurs Several recent human and animalstudies have well demonstrated that preischemic physicalactivity may reduce initial stroke severity on functionalmotor outcomes edema and infarct volume by acting oninflammation vascular processes BDNF expression andmetabolic disorders [14 16 17 125 126]

Neural Plasticity 7

Ischemia-induced brain inflammation is believed toplay a pivotal role in the development of secondary braininjury by intensifying the inflammatory cell accumulationandmicrovascular impairments Indeed adhesionmoleculessuch as intercellular adhesion molecule 1 (ICAM-1) pro-mote leukocyte infiltration into injury site and leukocyteadhesion to microvascular endothelium Preischemic phys-ical training-induced neuroprotection was associated with adecrease in ICAM-1 mRNA expression and in the number ofICAM-1-positive vessels [17] Consequently leukocyte accu-mulation in damaged cortex and striatum vessels decreasedresulting in reduction of brain inflammation during reperfu-sion

Brain angiogenesis is another neuroprotective mecha-nism for reducing the detrimental motor effect of cere-bral ischemia Physical training prior to cerebral ischemiaincreased short- and long-term effects onmicrovascular den-sity and cerebral blood flow by promoting angiogenesis andincreasing cerebral vasomotor reactivity It was found thatpreischemic exercise improved vasorelaxation by enhancingVEGF levels into the ischemic region which is knownto activate eNOS and EPCs recruitment [8 19] Likewiseexercise decreased the endothelin-1 (a powerful vasocon-strictor agent) expression thereby reducing the impact ofvasoconstriction on cerebral blood flow [127]

Preischemic training could also attenuate brain dam-age by limiting metabolic disorders after cerebral ischemiaIndeed 51015840AMP-activated protein kinase (AMPK) phos-phofructokinase-1 (PFK) and hypoxia-induced factor-1120572(HIF-1120572) involved in glycolysis [18 128] were significantlyhigher in preischemic trained rats [129] Moreover theincrease of glucose transporters in neurons and endothelialcells of the BBB (GLUT3 and GLUT1 resp) results inan improved glucose oxidation immediately after cerebralischemia allowing a faster and more substantial increase inATP production

Moreover it was postulated that preischemic exercise(30min on a treadmill 5 daysweek for 3 weeks) decreasesBBB dysfunctions and thus reduces infarct volume andedema as confirmed by the MMP-9 expression decrement[130 131] Preischemic treadmill training-induced neuro-protection in ischemic rats increased endogenous BDNFexpression that leads to motor recovery improvement [1617 67 132] Interestingly the preischemic treadmill exer-cise improved the therapeutic effectiveness of postischemictreadmill training onmotor function compared with animalsperforming it only after cerebral ischemia [53]

Neuronal excitotoxicity induced by excessive glutamaterelease is a major deleterious event of the brain secondaryinjury [133 134] It was found that preischemic treadmilltraining could also reduce the expression of glutamate recep-tors mGluR5 and NR2B reflecting a decrease of glutamateeffect on surrounding cells [135ndash137] Moreover it was pos-tulated that the reduction of infarct volume induced by 12weeks of treadmill might be related to increase of NGFexpression and this receptor p75 known to promote neu-roprotection against excitotoxicity and free-radical damage[138]

Individuals who were physically active prior to strokehave been shown to exhibit less deleterious functional out-comes as indicated by higher Barthel Index scores as wellas Oxford Handicap Scale [14 15] Indeed it was recentlyrevealed that patients with high levels of prestroke physicalactivity were associated with milder stroke severity at admis-sion with faster early motor improvement and with a lowerfinal infarct volume [139] Interestingly it seems that simplywalking 1 hday during 5 days per week or doing a vigorousaerobic activity 1 hday twice a week is sufficient to inducepreventive effects However findings remain conflicting inhuman studies because no strong association between higherlevels of physical activity and better functional outcomes afterstroke was found in a large prospective cohort [126]

7 Conclusion

Although acute exercise appears to be useful for better under-standing neural andmotor recoverymechanisms few studieshave used this experimental model to investigate strokephysiopathology Neural adaptations remain thus unclearFurthermore physical training appears to be promising toimprove functional motor recovery by promoting neuro-plasticity at different cellular and molecular levels Thesebeneficial effects seem accelerated andor accentuated whenexercise is combined with an additional pharmacologicaltreatment Nevertheless optimal parameters of training andtreatment need to be investigated to maximizeaccelerateneuroplasticity and motor recovery and avoid undesirableeffects of exercise All these findings could help researchersand therapists to justify the effectiveness of their physicaltraining programs in order to increase the patient willingnessto regularly perform physical activity before and after stroke

Conflict of Interests

Each author of the present review declared no conflict ofinterests

Acknowledgment

The authors are grateful to Dr Vincent Pertici for commentson earlier version of this paper

References

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[2] F M Ivey R F Macko A S Ryan and C E Hafer-MackoldquoCardiovascular health and fitness after strokerdquo Topics in StrokeRehabilitation vol 12 no 1 pp 1ndash16 2005

[3] D LMarsden A Dunn R Callister C R Levi andN J SprattldquoCharacteristics of exercise training interventions to improvecardiorespiratory fitness after stroke a systematic review withmeta-analysisrdquo Neurorehabilitation and Neural Repair vol 27no 9 pp 775ndash788 2013

8 Neural Plasticity

[4] L Li W Rong Z Ke X Hu S P Yip and K Y Tong ldquoMuscleactivation changes during body weight support treadmill train-ing after focal cortical ischemia a rat hindlimb modelrdquo Journalof Electromyography and Kinesiology vol 21 no 2 pp 318ndash3262011

[5] C Pin-Barre J Laurin M-S Felix et al ldquoAcute neuromuscularadaptation at the spinal level following middle cerebral arteryocclusion-reperfusion in the ratrdquoPLoSONE vol 9 no 2 ArticleID e89953 2014

[6] L W Forrester D F Hanley and R F Macko ldquoEffectsof treadmill exercise on transcranial magnetic stimulation-induced excitability to quadriceps after strokerdquo Archives ofPhysical Medicine and Rehabilitation vol 87 no 2 pp 229ndash2342006

[7] R FMacko FM Ivey LW Forrester et al ldquoTreadmill exerciserehabilitation improves ambulatory function and cardiovas-cular fitness in patients with chronic stroke a randomizedcontrolled trialrdquo Stroke vol 36 no 10 pp 2206ndash2211 2005

[8] M Endres K Gertz U Lindauer et al ldquoMechanisms of strokeprotection by physical activityrdquoAnnals of Neurology vol 54 no5 pp 582ndash590 2003

[9] K Gertz J Priller G Kronenberg et al ldquoPhysical activityimproves long-term stroke outcome via endothelial nitric oxidesynthase-dependent augmentation of neovascularization andcerebral blood flowrdquo Circulation Research vol 99 no 10 pp1132ndash1140 2006

[10] S Liebigt N Schlegel J Oberland O W Witte C Redeckerand S Keiner ldquoEffects of rehabilitative training and anti-inflammatory treatment on functional recovery and cellularreorganization following strokerdquo Experimental Neurology vol233 no 2 pp 776ndash782 2012

[11] W-R Schabitz T Steigleder C M Cooper-Kuhn et al ldquoIntra-venous brain-derived neurotrophic factor enhances poststrokesensorimotor recovery and stimulates neurogenesisrdquo Strokevol 38 no 7 pp 2165ndash2172 2007

[12] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[13] I-M Lee C H Hennekens K Berger J E Buring and J EManson ldquoExercise and risk of stroke inmale physiciansrdquo Strokevol 30 no 1 pp 1ndash6 1999

[14] D Deplanque I Masse C Lefebvre C Libersa D Leys andR Bordet ldquoPrior TIA lipid-lowering drug use and physicalactivity decrease ischemic stroke severityrdquo Neurology vol 67no 8 pp 1403ndash1410 2006

[15] N Stroud T M L Mazwi L D Case et al ldquoPrestroke physicalactivity and early functional status after strokerdquo Journal ofNeurology Neurosurgery and Psychiatry vol 80 no 9 pp 1019ndash1022 2009

[16] Y Ding J Li X Luan et al ldquoExercise pre-conditioningreduces brain damage in ischemic rats that may be associatedwith regional angiogenesis and cellular overexpression of neu-rotrophinrdquo Neuroscience vol 124 no 3 pp 583ndash591 2004

[17] Y-H Ding C N Young X Luan et al ldquoExercise precondi-tioning ameliorates inflammatory injury in ischemic rats duringreperfusionrdquoActaNeuropathologica vol 109 no 3 pp 237ndash2462005

[18] MKhan B Sekhon S Giri et al ldquoS-Nitrosoglutathione reducesinflammation and protects brain against focal cerebral ischemiain a rat model of experimental strokerdquo Journal of Cerebral BloodFlow and Metabolism vol 25 no 2 pp 177ndash192 2005

[19] W Schmidt M Endres F Dimeo and G J JungehulsingldquoTrain the vessel gain the brain physical activity and vesselfunction and the impact on stroke prevention and outcome incerebrovascular diseaserdquo Cerebrovascular Diseases vol 35 no4 pp 303ndash312 2013

[20] W R Frontera L Grimby and L Larsson ldquoFiring rate ofthe lower motoneuron and contractile properties of its musclefibers after upper motoneuron lesion in manrdquoMuscle amp Nervevol 20 no 8 pp 938ndash947 1997

[21] C M Cirstea C R Savage R J Nudo et al ldquoHandgrip-relatedactivation in the primary motor cortex relates to underlyingneuronal metabolism after strokerdquo Neurorehabilitation andNeural Repair vol 28 no 5 pp 433ndash442 2013

[22] C Enzinger H Johansen-Berg H Dawes et al ldquoFunctionalMRI correlates of lower limb function in stroke victims withgait impairmentrdquo Stroke vol 39 no 5 pp 1507ndash1513 2008

[23] A R Luft L Forrester R F Macko et al ldquoBrain activationof lower extremity movement in chronically impaired strokesurvivorsrdquo NeuroImage vol 26 no 1 pp 184ndash194 2005

[24] A R Luft S Waller L Forrester et al ldquoLesion locationalters brain activation in chronically impaired stroke survivorsrdquoNeuroImage vol 21 no 3 pp 924ndash935 2004

[25] N S Ward ldquoFunctional reorganization of the cerebral motorsystem after strokerdquo Current Opinion in Neurology vol 17 no6 pp 725ndash730 2004

[26] A C Zemke P J Heagerty C Lee and S C Cramer ldquoMotorcortex organization after stroke is related to side of stroke andlevel of recoveryrdquo Stroke vol 34 no 5 pp e23ndashe28 2003

[27] M Khan H Sakakima T S Dhammu et al ldquoS-nitrosoglutathione reduces oxidative injury and promotesmechanisms of neurorepair following traumatic brain injury inratsrdquo Journal of Neuroinflammation vol 8 article 78 2011

[28] H Sakakima M Khan T S Dhammu et al ldquoStimulationof functional recovery via the mechanisms of neurorepairby S-nitrosoglutathione and motor exercise in a rat modelof transient cerebral ischemia and reperfusionrdquo RestorativeNeurology and Neuroscience vol 30 no 5 pp 383ndash396 2012

[29] S Barbay E V Zoubina N Dancause et al ldquoA single injectionof D-amphetamine facilitates improvements in motor trainingfollowing a focal cortical infarct in squirrel monkeysrdquo Neurore-habilitation and Neural Repair vol 20 no 4 pp 455ndash458 2006

[30] P-C Fang S Barbay E J Plautz E Hoover S M Strittmatterand R J Nudo ldquoCombination of NEP 1-40 treatment andmotortraining enhances behavioral recovery after a focal corticalinfarct in ratsrdquo Stroke vol 41 no 3 pp 544ndash549 2010

[31] J-K Lee J-E Kim M Sivula and S M Strittmatter ldquoNogoreceptor antagonism promotes stroke recovery by enhancingaxonal plasticityrdquo The Journal of Neuroscience vol 24 no 27pp 6209ndash6217 2004

[32] J Wang X Feng Y Du L Wang and S Zhang ldquoCombinationtreatment with progesterone and rehabilitation training furtherpromotes behavioral recovery after acute ischemic stroke inmicerdquo Restorative Neurology and Neuroscience vol 31 no 4 pp487ndash499 2013

[33] B Kolb C Morshead C Gonzalez et al ldquoGrowth factor-stimulated generation of new cortical tissue and functionalrecovery after stroke damage to the motor cortex of ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 27 no 5pp 983ndash997 2007

[34] M S Jeffers A Hoyles C Morshead and D Corbett ldquoEpi-dermal growth factor and erythropoietin infusion accelerate

Neural Plasticity 9

functional recovery in combination with rehabilitationrdquo Strokevol 45 no 6 pp 1856ndash1858 2014

[35] L Gherardini M Gennaro and T Pizzorusso ldquoPerilesionaltreatment with chondroitinase ABC and motor training pro-mote functional recovery after stroke in ratsrdquo Cerebral Cortexvol 25 no 1 pp 202ndash212 2015

[36] D P Fuchs N Sanghvi J Wieser and S Schindler-IvensldquoPedaling alters the excitability and modulation of vastusmedialis H-reflexes after strokerdquo Clinical Neurophysiology vol122 no 10 pp 2036ndash2043 2011

[37] I-S Hwang C-F Lin L-C Tung and C-H Wang ldquoRespon-siveness of the H reflex to loading and posture in patientsfollowing strokerdquo Journal of Electromyography and Kinesiologyvol 14 no 6 pp 653ndash659 2004

[38] M A Oskoei and H Hu ldquoSupport vector machine-basedclassification scheme for myoelectric control applied to upperlimbrdquo IEEE Transactions on Biomedical Engineering vol 55 no8 pp 1956ndash1965 2008

[39] G L Soderberg and L M Knutson ldquoA guide for use andinterpretation of kinesiologic electromyographic datardquo PhysicalTherapy vol 80 no 5 pp 485ndash498 2000

[40] N A Riley and M Bilodeau ldquoChanges in upper limb jointtorque patterns and EMG signals with fatigue following astrokerdquoDisability andRehabilitation vol 24 no 18 pp 961ndash9692002

[41] U M Svantesson K S Sunnerhagen U S Carlsson and GGrimby ldquoDevelopment of fatigue during repeated eccentric-concentric muscle contractions of plantar flexors in patientswith strokerdquo Archives of Physical Medicine and Rehabilitationvol 80 no 10 pp 1247ndash1252 1999

[42] K N Arya S Pandian R Verma and R K Garg ldquoMovementtherapy induced neural reorganization and motor recovery instroke a reviewrdquo Journal of Bodywork andMovementTherapiesvol 15 no 4 pp 528ndash537 2011

[43] R J Nudo ldquoNeural bases of recovery after brain injuryrdquo Journalof Communication Disorders vol 44 no 5 pp 515ndash520 2011

[44] T Kawamata N E Alexis W D Dietrich and S P FinklesteinldquoIntracisternal basic fibroblast growth factor (bFGF) enhancesbehavioral recovery following focal cerebral infarction in theratrdquo Journal of Cerebral Blood Flow and Metabolism vol 16 no4 pp 542ndash547 1996

[45] T Yamaguchi M Suzuki and M Yamamoto ldquoYM796 anovel muscarinic agonist improves the impairment of learningbehavior in a rat model of chronic focal cerebral ischemiardquoBrain Research vol 669 no 1 pp 107ndash114 1995

[46] F Matsuda H Sakakima and Y Yoshida ldquoThe effects of earlyexercise on brain damage and recovery after focal cerebralinfarction in ratsrdquoActa Physiologica vol 201 no 2 pp 275ndash2872011

[47] K Mizutani S Sonoda N Hayashi et al ldquoAnalysis of proteinexpression profile in the cerebellum of cerebral infarction ratsafter treadmill trainingrdquo American Journal of Physical Medicineamp Rehabilitation vol 89 no 2 pp 107ndash114 2010

[48] P Zhang Y Zhang J Zhang et al ldquoEarly exercise protectsagainst cerebral ischemic injury through inhibiting neuronapoptosis in cortex in ratsrdquo International Journal of MolecularSciences vol 14 no 3 pp 6074ndash6089 2013

[49] L M Cupini M Diomedi F Placidi M Silvestrini and PGiacomini ldquoCerebrovascular reactivity and subcortical infarc-tionsrdquo Archives of Neurology vol 58 no 4 pp 577ndash581 2001

[50] F M Ivey A S Ryan C E Hafer-Macko and R F MacKoldquoImproved cerebral vasomotor reactivity after exercise trainingin hemiparetic stroke survivorsrdquo Stroke vol 42 no 7 pp 1994ndash2000 2011

[51] S Tian Y Zhang S Tian et al ldquoEarly exercise training improvesischemic outcome in rats by cerebral hemodynamicsrdquo BrainResearch vol 1533 pp 114ndash121 2013

[52] Y Gao Y Zhao J Pan et al ldquoTreadmill exercise promotesangiogenesis in the ischemic penumbra of rat brains throughcaveolin-1VEGF signaling pathwaysrdquo Brain Research vol 1585pp 83ndash90 2014

[53] G Kim and E Kim ldquoEffects of treadmill training on limbmotorfunction and acetylcholinesterase activity in rats with strokerdquoJournal of PhysicalTherapy Science vol 25 no 10 pp 1227ndash12302013

[54] Q Zheng D Zhu Y Bai Y Wu J Jia and Y Hu ldquoExerciseimproves recovery after ischemic brain injury by inducing theexpression of angiopoietin-1 and Tie-2 in ratsrdquo The TohokuJournal of Experimental Medicine vol 224 no 3 pp 221ndash2282011

[55] T M Hansen A J Moss and N P J Brindle ldquoVascularendothelial growth factor and angiopoietins in neurovascularregeneration and protection following strokerdquo Current Neu-rovascular Research vol 5 no 4 pp 236ndash245 2008

[56] D M Hermann and A Zechariah ldquoImplications of vascu-lar endothelial growth factor for postischemic neurovascularremodelingrdquo Journal of Cerebral Blood Flow and Metabolismvol 29 no 10 pp 1620ndash1643 2009

[57] C S Mang K L Campbell C J D Ross and L A Boyd ldquoPro-moting neuroplasticity for motor rehabilitation after strokeconsidering the effects of aerobic exercise and genetic variationon brain-derived neurotrophic factorrdquo PhysicalTherapy vol 93no 12 pp 1707ndash1716 2013

[58] M Ploughman VWindle C LMacLellan NWhite J J Doreand D Corbett ldquoBrain-derived neurotrophic factor contributesto recovery of skilled reaching after focal ischemia in ratsrdquoStroke vol 40 no 4 pp 1490ndash1495 2009

[59] I Kiprianova TM Freiman SDesiderato et al ldquoBrain-derivedneurotrophic factor prevents neuronal death and glial activa-tion after global ischemia in the ratrdquo Journal of NeuroscienceResearch vol 56 no 1 pp 21ndash27 1999

[60] R J Nudo E J Plautz and S B Frost ldquoRole of adaptiveplasticity in recovery of function after damage to motor cortexrdquoMuscle amp Nerve vol 24 no 8 pp 1000ndash1019 2001

[61] W-R Schabitz S Schwab M Spranger and W Hacke ldquoIntra-ventricular brain-derived neurotrophic factor reduces infarctsize after focal cerebral ischemia in ratsrdquo Journal of CerebralBlood Flow and Metabolism vol 17 no 5 pp 500ndash506 1997

[62] W-R Schabitz C Sommer W Zoder et al ldquoIntravenousbrain-derived neurotrophic factor reduces infarct size andcounterregulates Bax andBcl-2 expression after temporary focalcerebral ischemiardquo Stroke vol 31 no 9 pp 2212ndash2217 2000

[63] M-W Kim M-S Bang T-R Han et al ldquoExercise increasedBDNF and trkB in the contralateral hemisphere of the ischemicrat brainrdquo Brain Research vol 1052 no 1 pp 16ndash21 2005

[64] Z Kokaia Q Zhao M Kokaia et al ldquoRegulation of brain-derived neurotrophic factor gene expression after transientmiddle cerebral artery occlusion with and without brain dam-agerdquo Experimental Neurology vol 136 no 1 pp 73ndash88 1995

[65] L R Zhao B Mattsson and B B Johansson ldquoEnvironmentalinfluence on brain-derived neurotrophic factormessenger RNA

10 Neural Plasticity

expression after middle cerebral artery occlusion in sponta-neously hypertensive ratsrdquo Neuroscience vol 97 no 1 pp 177ndash184 2000

[66] H D Muller K M Hanumanthiah K Diederich S SchwabW-R Schabitz and C Sommer ldquoBrain-derived neurotrophicfactor but not forced armuse improves long-term outcome afterphotothrombotic stroke and transiently upregulates bindingdensities of excitatory glutamate receptors in the rat brainrdquoStroke vol 39 no 3 pp 1012ndash1021 2008

[67] W-R Schabitz C Berger R Kollmar et al ldquoEffect of brain-derived neurotrophic factor treatment and forced arm use onfunctional motor recovery after small cortical ischemiardquo Strokevol 35 no 4 pp 992ndash997 2004

[68] J Chen J Qin Q Su Z Liu and J Yang ldquoTreadmillrehabilitation treatment enhanced BDNF-TrkB but not NGF-TrkA signaling in a mouse intracerebral hemorrhage modelrdquoNeuroscience Letters vol 529 no 1 pp 28ndash32 2012

[69] J-Y Chung M-W Kim M-S Bang and M Kim ldquoIncreasedexpression of neurotrophin 4 following focal cerebral ischemiain adult rat brain with treadmill exerciserdquo PLoS ONE vol 8 no3 Article ID e52461 2013

[70] Z Ke S P Yip L Li X X Zheng W K Tam and K Y TongldquoThe effects of voluntary involuntary and forced exercises onmotor recovery in a stroke rat modelrdquo in Proceedings of theAnnual International Conference of the IEEE Engineering inMedicine and Biology Society (EMBC rsquo11) vol 2011 pp 8223ndash8226 Boston Mass USA August 2011

[71] P-C Shih Y-R Yang and R-Y Wang ldquoEffects of exerciseintensity on spatial memory performance and hippocampalsynaptic plasticity in transient brain ischemic ratsrdquo PLoS ONEvol 8 no 10 Article ID e78163 2013

[72] J Sun Z Ke S P Yip X-L Hu X-X Zheng and K-Y TongldquoGradually increased training intensity benefits rehabilitationoutcome after stroke by BDNF upregulation and stress sup-pressionrdquo BioMed Research International vol 2014 Article ID925762 8 pages 2014

[73] R Marin A Williams S Hale et al ldquoThe effect of voluntaryexercise exposure on histological and neurobehavioral out-comes after ischemic brain injury in the ratrdquo Physiology andBehavior vol 80 no 2-3 pp 167ndash175 2003

[74] S Vaynman Z Ying and F Gomez-Pinilla ldquoExercise inducesBDNF and synapsin I to specific hippocampal subfieldsrdquo Jour-nal of Neuroscience Research vol 76 no 3 pp 356ndash362 2004

[75] L Zhang X Hu J Luo et al ldquoPhysical exercise improves func-tional recovery through mitigation of autophagy attenuationof apoptosis and enhancement of neurogenesis after MCAO inratsrdquo BMC Neuroscience vol 14 article 46 2013

[76] J Puyal and P G H Clarke ldquoTargeting autophagy to preventneonatal stroke damagerdquoAutophagy vol 5 no 7 pp 1060ndash10612009

[77] Q-W Zhang X-X Deng X Sun J-X Xu and F-Y SunldquoExercise promotes axon regeneration of newborn striatonigraland corticonigral projection neurons in rats after ischemicstrokerdquo PLoS ONE vol 8 no 11 Article ID e80139 2013

[78] M Asahi K Asahi J-C Jung G J del ZoppoM E Fini and EH Lo ldquoRole for matrix metalloproteinase 9 after focal cerebralischemia effects of gene knockout and enzyme inhibition withBB-94rdquo Journal of Cerebral Blood Flow amp Metabolism vol 20no 12 pp 1681ndash1689 2000

[79] M Asahi X Wang T Mori et al ldquoEffects of matrixmetalloproteinase-9 gene knock-out on the proteolysis of

blood-brain barrier andwhitematter components after cerebralischemiardquoThe Journal of Neuroscience vol 21 no 19 pp 7724ndash7732 2001

[80] Y Zhang P Zhang X Shen et al ldquoEarly exercise protects theblood-brain barrier from ischemic brain injury via the regula-tion of MMP-9 and occludin in ratsrdquo International Journal ofMolecular Sciences vol 14 no 6 pp 11096ndash11112 2013

[81] I G Onyango J Lu M Rodova E Lezi A B Crafter and RH Swerdlow ldquoRegulation of neuron mitochondrial biogenesisand relevance to brain healthrdquo Biochimica et Biophysica ActamdashMolecular Basis of Disease vol 1802 no 1 pp 228ndash234 2010

[82] Q Zhang Y Wu P Zhang et al ldquoExercise induces mitochon-drial biogenesis after brain ischemia in ratsrdquo Neuroscience vol205 pp 10ndash17 2012

[83] L Li W Rong Z Ke X Hu and K-Y Tong ldquoThe effects oftraining intensities on motor recovery and gait symmetry in arat model of ischemiardquo Brain Injury vol 27 no 4 pp 408ndash4162013

[84] C Enzinger H Dawes H Johansen-Berg et al ldquoBrain activitychanges associated with treadmill training after strokerdquo Strokevol 40 no 7 pp 2460ndash2467 2009

[85] A R Luft R FMacKo LW Forrester et al ldquoTreadmill exerciseactivates subcortical neural networks and improves walkingafter stroke a randomized controlled trialrdquo Stroke vol 39 no12 pp 3341ndash3350 2008

[86] K Potempa M Lopez L T Braun J P Szidon L Fogg and TTincknell ldquoPhysiological outcomes of aerobic exercise trainingin hemiparetic stroke patientsrdquo Stroke vol 26 no 1 pp 101ndash1051995

[87] F Buma G Kwakkel and N Ramsey ldquoUnderstanding upperlimb recovery after strokerdquo Restorative Neurology and Neuro-science vol 31 no 6 pp 707ndash722 2013

[88] A E Baird A Benfield G Schlaug et al ldquoEnlargementof human cerebral ischemic lesion volumes measured bydiffusion-weighted magnetic resonance imagingrdquo Annals ofNeurology vol 41 no 5 pp 581ndash589 1997

[89] A Schmidt J Wellmann M Schilling et al ldquoMeta-analysis ofthe efficacy of different training strategies in animal models ofischemic strokerdquo Stroke vol 45 no 1 pp 239ndash247 2014

[90] R-Y Wang S-M Yu and Y-R Yang ldquoTreadmill trainingeffects in different age groups following middle cerebral arteryocclusion in ratsrdquo Gerontology vol 51 no 3 pp 161ndash165 2005

[91] P ZhangH YuN Zhou et al ldquoEarly exercise improves cerebralblood flow through increased angiogenesis in experimentalstroke rat modelrdquo Journal of NeuroEngineering and Rehabilita-tion vol 10 article 43 2013

[92] J Laurin andC Pin-Barre ldquoPhysiological adaptations followingendurance exercises after stroke focus on the plausible roleof high-intensity interval trainingrdquo International Journal ofPhysical Medicine amp Rehabilitation vol 2 no 3 pp 1ndash6 2014

[93] THMurphy andDCorbett ldquoPlasticity during stroke recoveryfrom synapse to behaviourrdquo Nature Reviews Neuroscience vol10 no 12 pp 861ndash872 2009

[94] M Svensson J Lexell and T Deierborg ldquoEffects of physicalexercise on neuroinflammation neuroplasticity neurodegener-ation and behavior what we can learn from animal models inclinical settingsrdquoNeurorehabilitation and Neural Repair vol 29no 6 pp 577ndash589 2015

[95] A Risedal J Zeng and B B Johansson ldquoEarly training mayexacerbate brain damage after focal brain ischemia in the ratrdquoJournal of Cerebral Blood Flow andMetabolism vol 19 no 9 pp997ndash1003 1999

Neural Plasticity 11

[96] C-S Piao B A Stoica J Wu et al ldquoLate exercise reducesneuroinflammation and cognitive dysfunction after traumaticbrain injuryrdquoNeurobiology of Disease vol 54 pp 252ndash263 2013

[97] J L Humm D A Kozlowski S T Bland D C James andT Schallert ldquoUse-dependent exaggeration of brain injury isglutamate involvedrdquo Experimental Neurology vol 157 no 2 pp349ndash358 1999

[98] G S Griesbach F Gomez-Pinilla and D A Hovda ldquoTheupregulation of plasticity-related proteins following TBI isdisrupted with acute voluntary exerciserdquo Brain Research vol1016 no 2 pp 154ndash162 2004

[99] J WMcAlees L T Smith R S Erbe D Jarjoura N M Ponzioand V M Sanders ldquoEpigenetic regulation of beta2-adrenergicreceptor expression in T

1198671 and T

1198672 cellsrdquo Brain Behavior and

Immunity vol 25 no 3 pp 408ndash415 2011[100] G Zhao S Zhou A Davie and Q Su ldquoEffects of moderate and

high intensity exercise on T1T2 balancerdquo Exercise ImmunologyReview vol 18 pp 98ndash114 2012

[101] Y Yagita K Kitagawa T Sasaki et al ldquoPostischemic exercisedecreases neurogenesis in the adult rat dentate gyrusrdquo Neuro-science Letters vol 409 no 1 pp 24ndash29 2006

[102] S T Bland T Schallert R Strong J Aronowski and J CGrottaldquoEarly exclusive use of the affected forelimb aftermoderate tran-sient focal ischemia in rats functional and anatomic outcomerdquoStroke vol 31 no 5 pp 1144ndash1152 2000

[103] S B DeBow J E McKenna B Kolb and F ColbourneldquoImmediate constraint-inducedmovement therapy causes localhyperthermia that exacerbates cerebral cortical injury in ratsrdquoCanadian Journal of Physiology and Pharmacology vol 82 no4 pp 231ndash237 2004

[104] D A Kozlowski D C James and T Schallert ldquoUse-dependentexaggeration of neuronal injury after unilateral sensorimotorcortex lesionsrdquo The Journal of Neuroscience vol 16 no 15 pp4776ndash4786 1996

[105] B Balaban F Tok F Yavuz E Yasar and R Alaca ldquoEarlyrehabilitation outcome in patients with middle cerebral arterystrokerdquo Neuroscience Letters vol 498 no 3 pp 204ndash207 2011

[106] G Kwakkel R van Peppen R C Wagenaar et al ldquoEffects ofaugmented exercise therapy time after stroke a meta-analysisrdquoStroke vol 35 no 11 pp 2529ndash2539 2004

[107] D L Costill M G Flynn J P Kirwan et al ldquoEffects of repeateddays of intensified training on muscle glycogen and swimmingperformancerdquo Medicine amp Science in Sports amp Exercise vol 20no 3 pp 249ndash254 1988

[108] M A Hirsch and B G Farley ldquoExercise and neuroplasticityin persons living with Parkinsonrsquos diseaserdquo European Journal ofPhysical and Rehabilitation Medicine vol 45 no 2 pp 215ndash2292009

[109] M Katz-Leurer M Shochina E Carmeli and Y FriedlanderldquoThe influence of early aerobic training on the functional capac-ity in patients with cerebrovascular accident at the subacutestagerdquo Archives of Physical Medicine and Rehabilitation vol 84no 11 pp 1609ndash1614 2003

[110] J D Schaechter ldquoMotor rehabilitation and brain plasticity afterhemiparetic strokerdquo Progress in Neurobiology vol 73 no 1 pp61ndash72 2004

[111] P R Bosch S Holzapfel and T Traustadottir ldquoFeasibility ofmeasuring ventilatory threshold in adults with stroke-inducedhemiparesis implications for exercise prescriptionrdquo Archives ofPhysical Medicine and Rehabilitation 2015

[112] D P Stirling K Khodarahmi J Liu et al ldquoMinocyclinetreatment reduces delayed oligodendrocyte death attenuatesaxonal dieback and improves functional outcome after spinalcord injuryrdquoThe Journal of Neuroscience vol 24 no 9 pp 2182ndash2190 2004

[113] S Barbay and R J Nudo ldquoThe effects of amphetamine onrecovery of function in animal models of cerebral injury acritical appraisalrdquo NeuroRehabilitation vol 25 no 1 pp 5ndash172009

[114] R S Rasmussen K Overgaard E S Hildebrandt-Eriksen andG Boysen ldquoD-Amphetamine improves cognitive deficits andphysical therapy promotes fine motor rehabilitation in a ratembolic stroke modelrdquo Acta Neurologica Scandinavica vol 113no 3 pp 189ndash198 2006

[115] C L Gibson B Coomber and S P Murphy ldquoProgesterone isneuroprotective following cerebral ischaemia in reproductivelyageing female micerdquo Brain vol 134 no 7 pp 2125ndash2133 2011

[116] T Ishrat I Sayeed F Atif and D G Stein ldquoEffects ofprogesterone administration on infarct volume and functionaldeficits following permanent focal cerebral ischemia in ratsrdquoBrain Research vol 1257 pp 94ndash101 2009

[117] M Prencipe C Ferretti A R Casini M Santini F Giubileiand F Culasso ldquoStroke disability and dementia results of apopulation surveyrdquo Stroke vol 28 no 3 pp 531ndash536 1997

[118] I Sayeed B Wali and D G Stein ldquoProgesterone inhibitsischemic brain injury in a rat model of permanent middle cere-bral artery occlusionrdquo Restorative Neurology and Neurosciencevol 25 no 2 pp 151ndash159 2007

[119] H Lee R J McKeon and R V Bellamkonda ldquoSustaineddelivery of thermostabilized chABC enhances axonal sproutingand functional recovery after spinal cord injuryrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 8 pp 3340ndash3345 2010

[120] V J Tom R Kadakia L Santi and J D Houle ldquoAdministrationof chondroitinase ABC rostral or caudal to a spinal cord injurysite promotes anatomical but not functional plasticityrdquo Journalof Neurotrauma vol 26 no 12 pp 2323ndash2333 2009

[121] J J Hill K Jin X O Mao L Xie and D A GreenbergldquoIntracerebral chondroitinase ABC and heparan sulfate proteo-glycan glypican improve outcome from chronic stroke in ratsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 23 pp 9155ndash9160 2012

[122] S Soleman P K Yip D A Duricki and L D FMoon ldquoDelayedtreatment with chondroitinase ABC promotes sensorimotorrecovery and plasticity after stroke in aged ratsrdquo Brain vol 135no 4 pp 1210ndash1223 2012

[123] B E Skolnick A I Maas R K Narayan et al ldquoA clinical trialof progesterone for severe traumatic brain injuryrdquo The NewEngland Journal of Medicine vol 371 no 26 pp 2467ndash24762014

[124] DWWright SD Yeatts R Silbergleit et al ldquoVery early admin-istration of progesterone for acute traumatic brain injuryrdquo TheNew England Journal of Medicine vol 371 no 26 pp 2457ndash2466 2014

[125] L-H Krarup T Truelsen C Gluud et al ldquoPrestroke physicalactivity is associated with severity and long-term outcome fromfirst-ever strokerdquo Neurology vol 71 no 17 pp 1313ndash1318 2008

[126] P M Rist I-M Lee C S Kase J Michael Gaziano and TKurth ldquoPhysical activity and functional outcomes from cerebralvascular events in menrdquo Stroke vol 42 no 12 pp 3352ndash33562011

12 Neural Plasticity

[127] Q Zhang L Zhang X Yang Y Wan and J Jia ldquoThe effectsof exercise preconditioning on cerebral blood flow change andendothelin-1 expression after cerebral ischemia in ratsrdquo Journalof Stroke and Cerebrovascular Diseases vol 23 no 6 pp 1696ndash1702 2014

[128] M Bernaudin A-S Nedelec D Divoux E T MacKenzie EPetit and P Schumann-Bard ldquoNormobaric hypoxia inducestolerance to focal permanent cerebral ischemia in associationwith an increased expression of hypoxia-inducible factor-1 andits target genes erythropoietin and VEGF in the adult mousebrainrdquo Journal of Cerebral Blood Flow and Metabolism vol 22no 4 pp 393ndash403 2002

[129] D Dornbos III N Zwagerman M Guo et al ldquoPreischemicexercise reduces brain damage by ameliorating metabolic dis-order in ischemiareperfusion injuryrdquo Journal of NeuroscienceResearch vol 91 no 6 pp 818ndash827 2013

[130] Y-H Ding Y Ding J Li D A Bessert and J A RafolsldquoExercise pre-conditioning strengthens brain microvascularintegrity in a rat stroke modelrdquo Neurological Research vol 28no 2 pp 184ndash189 2006

[131] M Guo B Cox S Mahale et al ldquoPre-ischemic exercise reducesmatrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in strokerdquo Neuroscience vol 151 no2 pp 340ndash351 2008

[132] M Ploughman Z Attwood N White J J E Dore and DCorbett ldquoEndurance exercise facilitates relearning of forelimbmotor skill after focal ischemiardquo The European Journal ofNeuroscience vol 25 no 11 pp 3453ndash3460 2007

[133] L L Guyot F G Diaz M H OrsquoRegan S McLeod H Park andJW Phillis ldquoReal-timemeasurement of glutamate release fromthe ischemic penumbra of the rat cerebral cortex using a focalmiddle cerebral artery occlusion modelrdquo Neuroscience Lettersvol 299 no 1-2 pp 37ndash40 2001

[134] K Matsumoto R Graf G Rosner J Taguchi and W-D HeissldquoElevation of neuroactive substances in the cortex of cats duringprolonged focal ischemiardquo Journal of Cerebral Blood Flow andMetabolism vol 13 no 4 pp 586ndash594 1993

[135] J Jia Y-S Hu Y Wu et al ldquoPre-ischemic treadmill trainingaffects glutamate and gamma aminobutyric acid levels in thestriatal dialysate of a rat model of cerebral ischemiardquo LifeSciences vol 84 no 15-16 pp 505ndash511 2009

[136] F Zhang J Jia Y Wu Y Hu and Y Wang ldquoThe effect of tread-mill training pre-exercise on glutamate receptor expression inrats after cerebral ischemiardquo International Journal of MolecularSciences vol 11 no 7 pp 2658ndash2669 2010

[137] J Jia Y-S Hu Y Wu et al ldquoTreadmill pre-training suppressesthe release of glutamate resulting from cerebral ischemia inratsrdquo Experimental Brain Research vol 204 no 2 pp 173ndash1792010

[138] E T Ang P T H Wong S Moochhala and Y K NgldquoNeuroprotection associated with running is it a result ofincreased endogenous neurotrophic factorsrdquoNeuroscience vol118 no 2 pp 335ndash345 2003

[139] A C Ricciardi E Lopez-Cancio N Perez De La Ossa et alldquoPrestroke physical activity is associated with good functionaloutcome and arterial recanalization after stroke due to a largevessel occlusionrdquo Cerebrovascular Diseases vol 37 no 4 pp304ndash311 2014

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Psychiatry Journal

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

4 Neural Plasticity

that inappropriate autophagy might also lead to cell death[76] However physical training mitigated autophagosomesaccumulation and attenuated apoptosis in the peri-infarctregion while improving the modified neurological severityscore scale Physical training could also upregulate IGF-1expression which is known to attenuate autophagy and alsoto promote neurogenesis [75]

In addition several studies reported that neuronal deathin both the striatum and the cerebral cortex caused a degen-eration of nigral dopaminergic neurons that are known tocontribute to regulating motor activity [77] However tread-mill training promoted axon regeneration of newborn stri-atonigral and corticonigral projection neurons in ischemicbrain while improving motor function It was thus suggestedthat exercise could enhance restoration of functional neuralcircuitry within the basal ganglia The cerebellum plays animportant role in the motor coordination learning andequilibrium and also seems to be involved in motor deficitsfollowing cerebral injury Therefore it is not surprising thattreadmill training promoted both synaptogenesis and neu-rite outgrowth via 25-kDa synaptosomal-associated proteinexpression in the cerebellum Likewise such training alsoincreased glial fibrillary acidic protein in the cerebellumwhich plays a role in axonal growth and improved motorcoordination as observed with the rotarod test (longer timeto fall from the rotating rod) [47]

Disruption of the BBB increasing thus its permeabil-ity is one of the major contributors to the pathogene-sis of cerebral ischemia Such event was observed whenmatrix metalloproteinase-9 (MMP-9) is strongly upregulatedthat impairs the extracellular matrix of the BBB [78 79]However physical training attenuated BBB disruption asrevealed by a decrease of MMP-9 expression and a par-allel increase expression of MMP-9 inhibitor the tissueinhibitor of metalloproteinase-1 (TIMP-1) Interestingly suchmechanisms might contribute to decreasing the observedneurological deficits infarct volume and brain edema [80]

These neuroplasticity processes require energy frommitochondria However cerebral ischemia induces damageof the cerebral mitochondria biogenesis contributing to theextent of neuronal ischemic injury [81] Nevertheless 7-day endurance training increased mitochondrial biogenesisafter cerebral ischemia by enhancing both the amount ofmitochondrial DNA and the expression of numerous mito-chondrial biogenesis factors such as the mitochondrial tran-scription factor proliferator activated receptor coactivator-1(PGC-1) nuclear respiratory factor 1 (NRF-1) protein andmitochondrial transcription factor A (TFAM) [82] It wassuggested that these events are involved in decreasing infarctvolume and the improvement of neurological score

Very few studies using rat model of cerebral ischemiaenable better understanding of the treadmill training out-comes on muscle activation regulation Cerebral ischemiais believed to affect synaptic activity including the choliner-gic system which leads to decreasing both neuromuscularjunction and cholinergic brain synaptic transmission It wasshown that aerobic treadmill training (20minday during 21days) improved cholinergic system regulationhomeostasisby decreasing acetylcholinesterase activity (ie hydrolyzing

the acetylcholine) and by enhancing choline acetyltransferaseactivity (ie synthesis of acetylcholine) [53] It was thussuggested that such adaption might allow better motorlimb function as indicated by improvement of the limbplacement test score Moreover 10 days of treadmill trainingimproved balance functional outcome (behavioral score)and motor coordination Indeed the asymmetry of muscleactivation pattern between affected and unaffected hindlimbswas restored because the EMG burst duration was increasedat the affected side [83] Muscle fatigue observed duringlocomotion was reduced as indicated by the increase of MPFat the unaffected side (see Section 2) [4]

A previous human study indicated that effective gaittraining on treadmill with body weight support improvingwalking speed and endurance was characterized by anincrease of brain activity in the bilateral primary sensori-motor cortices the cingulate motor areas the caudate nucleibilaterally and the thalamus of the affected hemisphereduring paretic foot movement [84] In addition treadmillexercise (improving cardiovascular fitness by 18) activatessubcortical neural networks during single knee movementsof the lower extremity as observed by fMRI Indeed physicaltraining changed brain activation during paretic limb move-ment showing 72 and 18 increased activation in posteriorcerebellar lobe andmidbrain respectively [85] After 10weeksof training the improvement in sensorimotor functionassessed with the Fugl-Meyer Index seemed strongly relatedto the improvement in aerobic capacity [86]

It is noteworthy that some neural mechanisms afterphysical exercise remain to be investigated such as diaschisisIndeed functional deficitsmay also be associatedwith distanteffects after subcortical lesions resulting from deafferentationto a region not directly involved in the stroke Moreoverit was found that several rehabilitation exercises inducingblood flow and metabolic changes in the contralesionalhemisphere might act on diaschisis Given that alleviation ofdiaschisis could contribute to motor recovery [87] it seemsimportant that further studies will determine how enduranceexercises may influence diaschisis after cerebral ischemia

4 Influence of Exercise Parameters onNeuroplasticity and Functional Outcomes

Depending on the chosen exercise parameters (volumeintensity session frequency and timing of exercise initiation)neuroplasticity can be either adaptive or maladaptive torecovery and thus may affect the training effectiveness aftercerebral ischemia [46 87ndash91] Strong evidence suggested atime-limited period of enhanced neuroplasticity [89 92ndash94]Animal studies underlined that the limb function was lessimproved when training started before 24 h after ischemiacompared with a start during the 5 first days [89] Moreoverearly intense training might induce larger cortical infarctvolume and thalamic atrophy when the program starts before24 h [95] Exercise detrimental effects were also observedon neuroplasticity when animals performed treadmill exer-cise shortly after trauma [96] The lesional aggravationmight be related to localized and prolonged hyperthermiaIndeed physical exercise known to induce hyperthermia

Neural Plasticity 5

could accentuate the cerebral ischemia-induced release ofglutamate and catecholamines that lead to neural excito-toxicity [95 97] However it seems important to add thatother processes than hyperthermia might be involved in thesensorimotor deficit aggravations and need to be exploredFurthermore early running training downregulated proteinsinvolved in neuroplasticity such as MAPK CAMKII PKCsynapsin I orCREB expression [98] anddecreased the level ofproinflammatory cytokines known to be related to neuropro-tection [99 100] Finally Yagita et al (2006) had shown thattwo weeks of running exercise reduced the number of new-born neurons in ischemic rats and thus limited neurogenesisin the hippocampus [101] The author suggested that runningwas too stressful and enhanced the corticosterone levelknown to decrease neurogenesis Likewise an immediateoveruse of the lesioned forelimb could also increase tissue lossaround the lesion and aggravated sensorimotor deficits on alonger term [102ndash104] One explanation could be related toanatomical damage resulting from the reduction of dendriticgrowth in the ischemic hemisphere [104]

In addition an augmented volume of exercise or increaseof inpatient therapy duration for stroke did not indicatesuperior effects on functional recovery and activities of dailyliving [105 106] Interestingly when healthy active men weresubjected to a strong increase of volume training physicalperformance was also not improved [107] It thus seems thatvolume is not the main exercise parameter that should beinvestigated for improving aerobic program

Greater improvements were observed with higher exer-cise intensities after stroke and neurodegenerative disease butalso for healthy individuals [92 108ndash110] However the effectof intensity on neuroplasticity remains unclear because it ispoorly investigated in stroke patients or in ischemic animalmodels (ongoing study in our laboratory) It should also bepointed that one major methodological limitation is relatedto the exercise intensity determination Indeed trainingintensity was mainly based onmaximal oxygen consumptionor maximal exercise heart rate (or even intensity basedon empirical values) However these parameters were notappropriated because stroke patients never reached maximalcapabilities It was recently suggested that prescribing inten-sity should rather be based on submaximal parameters suchas ventilatory or lactic threshold that were more accurate indistinguishing moderate to intense exercise [111]

5 Beneficial Effect of Physical TrainingRehabilitation in Combination withPharmacological Treatments

Using multiple recovery processes (physical exercise andpharmacologic treatments) may be critical for enhancingfunctional outcomes in contrast to monotherapies targetingsingle mechanisms (Table 1)

Given that recent findings have established that anti-inflammation may be an important target for stroke treat-ment [112] some authors demonstrated that combinationof skilled reaching training with indomethacin or minocy-cline accentuated recovery [10] First beneficial effects of

such combination included an improvement of sensorimotorfunction as indicated by higher correct placements of theimpaired forelimb during a walking task Secondly thenumber of proliferating microglia was more reduced and thesurvival of newborn astrocytes in the peri-infarct zone wasincreased compared to rats that underwent training aloneAuthors suggested that the motor outcome improvementmight be partially explained by the observed changes ofneural response

In addition therapeutic drug such as S-nitrosogluta-thione (GSNO) exhibits similar neurovascular protectingeffects compared to physical training following traumaticbrain trauma and cerebral ischemia in rats [18 27] Adminis-tration of GSNO could reduce neuronal apoptotic cell deathexcitotoxicity and inflammation as well as protecting BBBintegrity GSNO could also stimulate the expression of VEGFand BDNF after traumatic brain injury Several authors havedemonstrated that combining rotating rod motor exercisewith GSNO administration accelerated and accentuated bothwalking and balance abilities compared to the effects inducedby each treatment applied separatelyMoreover the improvedmotor function was associated with a reduction of bothinfarct volume and neuronal cell death as well as an increaseof PECAM-1 and BDNF expression [28]

D-amphetamine acting primarily through norepineph-rine and dopamine mechanisms is a potent modulator ofneurological function and cortical excitation that facilitatedmotor skill abilities [113] It was demonstrated that a singleinjection of D-amphetamine on the first day of trainingfacilitates effectiveness of motor skill training compared withD-amphetamine treatment alone after a focal cortical infarctin squirrel monkeys [29] However administration of ahigh dose of D-amphetamine combined with rehabilitationtraining failed to promote fine motor recovery in a ratembolic stroke model Authors explained this result by thefact that the dose of D-amphetamine was too high therebylimiting animal engagement in the staircase test [114]

Other pharmacological agents could improve motorrecovery by focusing on different neural mechanisms Forexample Nogo-A protein a myelin-associated inhibitorappears to be partially responsible for inhibition of axonalgrowth in white matter Therefore suppressing this myelin-associated neurite outgrowth inhibitor by specific antagonistsof Nogo-A such as NEP 1-40 or NGR(310)Ecto-FC increasedneurite outgrowth and axonal regeneration after stroke [3031] Five-week motor training combined with NEP 1-40treatment accelerated motor recovery (skilled reach and footfault tests) from the first week after cerebral ischemia com-pared to treatments applied alone in which beneficial effectswere observed later (weeks 2 and 4) [30] Unfortunatelyneural plasticity mechanisms underlying this improvementremain unknown but these findings showed that this therapycombination could accelerate the recovery process followingcerebral ischemia

Neurons and glial cells in brain can synthesize proges-terone that exhibits neuroprotective effects after cerebralischemia [115ndash118] Rehabilitation could increase reorganiza-tion of cortical maps whereas the progesterone might reducethe infarct volume through its neuroprotective effect by

6 Neural Plasticity

Table 1 Influence of pharmacological agents associated with physical exercise on motor recovery after brain stroke

Drug agents Targets Results References

Indomethacin Minocycline Inflammatory processes

infarct volume (indomethacin only) sensorimotor performance

microglia astroglia

[10]

GSNOOxidative stress

Inflammatory processesExcitotoxicity

infarct volume apoptotic cell death neurological score motor recovery

and survival rate CBF synaptic plasticity and BBB

leakage TNF-120572 IL-1120573 and iNOS

[18 27 28]

D-Amphetamine Noradrenergic 1205721-receptor agonist motor recovery [29]

NEP 1-40 Nogo-A protein inhibitor early motor recovery axonal growth [30]

NgR(310)Ecto-Fc Nogo-NgR pathwayinhibitor

motor recovery axonal plasticity [31]

Progesterone ExcitotoxicityInflammatory processes

infarct volume forelimbs strength and motor recovery [32]

EGFlowast and EPOlowast Neuron proliferation migrationand differentiation accelerated fine motor recovery [33 34]

Chondroitinase ABC Chondroitin sulphate proteoglycans(CSPGs)

CSPGs synaptic plasticitymotor recovery

[35]

indicates an increase and a decrease respectively NEP 1-40 NOGO extracellular peptide EGF epidermal growth factor EPO erythropoietin GSNOS-nitrosoglutathione CBF cerebral blood flow BDNF brain developed neurotrophic factor trkB tropomyosin receptor kinase B BBB blood brain barrierlowastMolecules combination

targeting excitotoxicity Although this combination had noadditional effect in reducing infarct volume functional recov-ery effectiveness was promoted as shown by the increasedrotarod performance and forelimb grip strength at all timepoints within 7 days after ischemic stroke [32]

In addition some authors indicated that combination oftwo pharmacological treatments could improve functionalrecovery and neural plasticity compared to either treatmentalone For example association of epidermal growth fac-tor (EGF) and erythropoietin (EPO) treatments is moreeffective in promoting tissue regeneration and proliferationof neural precursor cells than monotherapy [33] Howeveran even greater improvement in skilled reaching ability inthe staircase test was observed when physical rehabilitationwas added to serial application of both EGF and EPO[34] Authors have also indicated that fine motor skillimprovement was observed 10 weeks after functional reha-bilitation alone whereas 4-week-long treatment combinationwas sufficient to improve sensorimotor function It meansthat functional recovery is also clearly accelerated with thiscombination

Another strategy consists of recreating a tissue environ-ment free from growth inhibiting molecules Chondroiti-nase ABC which degrades inhibitory chondroitin sulphateproteoglycans present in the extracellular matrix reducesthe neurite-inhibitory environment and facilitates axonalsprouting and sensorimotor recovery after spinal cord injury[119 120] and after cerebral ischemia [121 122]This treatmentwas applied at the ipsilesional cortex in rats in combinationwith functional rehabilitation Synaptic plasticity assessed by

measuring the expression of glutamate vesicular transporter(vGLUT1 and vGLUT2) and the GABA vesicular transporter(vGAT) and functional recovery were promoted by thesynergic effect of these treatments [35]

Given that some promising treatments developed inpreclinical studies failed to be effective in clinical studies[123 124] it seems crucial to assess the pharmacologicaleffectiveness in stroke patients before combining it withphysical exerciseTherefore we need to keep inmind that notall the effective combinations found in animal studies couldbe considered effective for human Nevertheless assessingboth treatments and exercise in rodentmodels seems relevantto found new therapeutic strategies to highlight the mosteffective and applicable strategies for human

6 Influence of Prestroke Physical Activity onMotor Dysfunction Severity

To avoid administration of several pharmacological sub-stances in individuals with high risks of stroke (may inducedeleterious interaction between drugs and complications dueto their side effects) physical activity might be a major alter-native preventive strategy for reducing the brain secondaryinjury when stroke occurs Several recent human and animalstudies have well demonstrated that preischemic physicalactivity may reduce initial stroke severity on functionalmotor outcomes edema and infarct volume by acting oninflammation vascular processes BDNF expression andmetabolic disorders [14 16 17 125 126]

Neural Plasticity 7

Ischemia-induced brain inflammation is believed toplay a pivotal role in the development of secondary braininjury by intensifying the inflammatory cell accumulationandmicrovascular impairments Indeed adhesionmoleculessuch as intercellular adhesion molecule 1 (ICAM-1) pro-mote leukocyte infiltration into injury site and leukocyteadhesion to microvascular endothelium Preischemic phys-ical training-induced neuroprotection was associated with adecrease in ICAM-1 mRNA expression and in the number ofICAM-1-positive vessels [17] Consequently leukocyte accu-mulation in damaged cortex and striatum vessels decreasedresulting in reduction of brain inflammation during reperfu-sion

Brain angiogenesis is another neuroprotective mecha-nism for reducing the detrimental motor effect of cere-bral ischemia Physical training prior to cerebral ischemiaincreased short- and long-term effects onmicrovascular den-sity and cerebral blood flow by promoting angiogenesis andincreasing cerebral vasomotor reactivity It was found thatpreischemic exercise improved vasorelaxation by enhancingVEGF levels into the ischemic region which is knownto activate eNOS and EPCs recruitment [8 19] Likewiseexercise decreased the endothelin-1 (a powerful vasocon-strictor agent) expression thereby reducing the impact ofvasoconstriction on cerebral blood flow [127]

Preischemic training could also attenuate brain dam-age by limiting metabolic disorders after cerebral ischemiaIndeed 51015840AMP-activated protein kinase (AMPK) phos-phofructokinase-1 (PFK) and hypoxia-induced factor-1120572(HIF-1120572) involved in glycolysis [18 128] were significantlyhigher in preischemic trained rats [129] Moreover theincrease of glucose transporters in neurons and endothelialcells of the BBB (GLUT3 and GLUT1 resp) results inan improved glucose oxidation immediately after cerebralischemia allowing a faster and more substantial increase inATP production

Moreover it was postulated that preischemic exercise(30min on a treadmill 5 daysweek for 3 weeks) decreasesBBB dysfunctions and thus reduces infarct volume andedema as confirmed by the MMP-9 expression decrement[130 131] Preischemic treadmill training-induced neuro-protection in ischemic rats increased endogenous BDNFexpression that leads to motor recovery improvement [1617 67 132] Interestingly the preischemic treadmill exer-cise improved the therapeutic effectiveness of postischemictreadmill training onmotor function compared with animalsperforming it only after cerebral ischemia [53]

Neuronal excitotoxicity induced by excessive glutamaterelease is a major deleterious event of the brain secondaryinjury [133 134] It was found that preischemic treadmilltraining could also reduce the expression of glutamate recep-tors mGluR5 and NR2B reflecting a decrease of glutamateeffect on surrounding cells [135ndash137] Moreover it was pos-tulated that the reduction of infarct volume induced by 12weeks of treadmill might be related to increase of NGFexpression and this receptor p75 known to promote neu-roprotection against excitotoxicity and free-radical damage[138]

Individuals who were physically active prior to strokehave been shown to exhibit less deleterious functional out-comes as indicated by higher Barthel Index scores as wellas Oxford Handicap Scale [14 15] Indeed it was recentlyrevealed that patients with high levels of prestroke physicalactivity were associated with milder stroke severity at admis-sion with faster early motor improvement and with a lowerfinal infarct volume [139] Interestingly it seems that simplywalking 1 hday during 5 days per week or doing a vigorousaerobic activity 1 hday twice a week is sufficient to inducepreventive effects However findings remain conflicting inhuman studies because no strong association between higherlevels of physical activity and better functional outcomes afterstroke was found in a large prospective cohort [126]

7 Conclusion

Although acute exercise appears to be useful for better under-standing neural andmotor recoverymechanisms few studieshave used this experimental model to investigate strokephysiopathology Neural adaptations remain thus unclearFurthermore physical training appears to be promising toimprove functional motor recovery by promoting neuro-plasticity at different cellular and molecular levels Thesebeneficial effects seem accelerated andor accentuated whenexercise is combined with an additional pharmacologicaltreatment Nevertheless optimal parameters of training andtreatment need to be investigated to maximizeaccelerateneuroplasticity and motor recovery and avoid undesirableeffects of exercise All these findings could help researchersand therapists to justify the effectiveness of their physicaltraining programs in order to increase the patient willingnessto regularly perform physical activity before and after stroke

Conflict of Interests

Each author of the present review declared no conflict ofinterests

Acknowledgment

The authors are grateful to Dr Vincent Pertici for commentson earlier version of this paper

References

[1] E Broussalis M Killer M McCoy A Harrer E Trinkaand J Kraus ldquoCurrent therapies in ischemic stroke Part ARecent developments in acute stroke treatment and in strokepreventionrdquoDrug Discovery Today vol 17 no 7-8 pp 296ndash3092012

[2] F M Ivey R F Macko A S Ryan and C E Hafer-MackoldquoCardiovascular health and fitness after strokerdquo Topics in StrokeRehabilitation vol 12 no 1 pp 1ndash16 2005

[3] D LMarsden A Dunn R Callister C R Levi andN J SprattldquoCharacteristics of exercise training interventions to improvecardiorespiratory fitness after stroke a systematic review withmeta-analysisrdquo Neurorehabilitation and Neural Repair vol 27no 9 pp 775ndash788 2013

8 Neural Plasticity

[4] L Li W Rong Z Ke X Hu S P Yip and K Y Tong ldquoMuscleactivation changes during body weight support treadmill train-ing after focal cortical ischemia a rat hindlimb modelrdquo Journalof Electromyography and Kinesiology vol 21 no 2 pp 318ndash3262011

[5] C Pin-Barre J Laurin M-S Felix et al ldquoAcute neuromuscularadaptation at the spinal level following middle cerebral arteryocclusion-reperfusion in the ratrdquoPLoSONE vol 9 no 2 ArticleID e89953 2014

[6] L W Forrester D F Hanley and R F Macko ldquoEffectsof treadmill exercise on transcranial magnetic stimulation-induced excitability to quadriceps after strokerdquo Archives ofPhysical Medicine and Rehabilitation vol 87 no 2 pp 229ndash2342006

[7] R FMacko FM Ivey LW Forrester et al ldquoTreadmill exerciserehabilitation improves ambulatory function and cardiovas-cular fitness in patients with chronic stroke a randomizedcontrolled trialrdquo Stroke vol 36 no 10 pp 2206ndash2211 2005

[8] M Endres K Gertz U Lindauer et al ldquoMechanisms of strokeprotection by physical activityrdquoAnnals of Neurology vol 54 no5 pp 582ndash590 2003

[9] K Gertz J Priller G Kronenberg et al ldquoPhysical activityimproves long-term stroke outcome via endothelial nitric oxidesynthase-dependent augmentation of neovascularization andcerebral blood flowrdquo Circulation Research vol 99 no 10 pp1132ndash1140 2006

[10] S Liebigt N Schlegel J Oberland O W Witte C Redeckerand S Keiner ldquoEffects of rehabilitative training and anti-inflammatory treatment on functional recovery and cellularreorganization following strokerdquo Experimental Neurology vol233 no 2 pp 776ndash782 2012

[11] W-R Schabitz T Steigleder C M Cooper-Kuhn et al ldquoIntra-venous brain-derived neurotrophic factor enhances poststrokesensorimotor recovery and stimulates neurogenesisrdquo Strokevol 38 no 7 pp 2165ndash2172 2007

[12] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[13] I-M Lee C H Hennekens K Berger J E Buring and J EManson ldquoExercise and risk of stroke inmale physiciansrdquo Strokevol 30 no 1 pp 1ndash6 1999

[14] D Deplanque I Masse C Lefebvre C Libersa D Leys andR Bordet ldquoPrior TIA lipid-lowering drug use and physicalactivity decrease ischemic stroke severityrdquo Neurology vol 67no 8 pp 1403ndash1410 2006

[15] N Stroud T M L Mazwi L D Case et al ldquoPrestroke physicalactivity and early functional status after strokerdquo Journal ofNeurology Neurosurgery and Psychiatry vol 80 no 9 pp 1019ndash1022 2009

[16] Y Ding J Li X Luan et al ldquoExercise pre-conditioningreduces brain damage in ischemic rats that may be associatedwith regional angiogenesis and cellular overexpression of neu-rotrophinrdquo Neuroscience vol 124 no 3 pp 583ndash591 2004

[17] Y-H Ding C N Young X Luan et al ldquoExercise precondi-tioning ameliorates inflammatory injury in ischemic rats duringreperfusionrdquoActaNeuropathologica vol 109 no 3 pp 237ndash2462005

[18] MKhan B Sekhon S Giri et al ldquoS-Nitrosoglutathione reducesinflammation and protects brain against focal cerebral ischemiain a rat model of experimental strokerdquo Journal of Cerebral BloodFlow and Metabolism vol 25 no 2 pp 177ndash192 2005

[19] W Schmidt M Endres F Dimeo and G J JungehulsingldquoTrain the vessel gain the brain physical activity and vesselfunction and the impact on stroke prevention and outcome incerebrovascular diseaserdquo Cerebrovascular Diseases vol 35 no4 pp 303ndash312 2013

[20] W R Frontera L Grimby and L Larsson ldquoFiring rate ofthe lower motoneuron and contractile properties of its musclefibers after upper motoneuron lesion in manrdquoMuscle amp Nervevol 20 no 8 pp 938ndash947 1997

[21] C M Cirstea C R Savage R J Nudo et al ldquoHandgrip-relatedactivation in the primary motor cortex relates to underlyingneuronal metabolism after strokerdquo Neurorehabilitation andNeural Repair vol 28 no 5 pp 433ndash442 2013

[22] C Enzinger H Johansen-Berg H Dawes et al ldquoFunctionalMRI correlates of lower limb function in stroke victims withgait impairmentrdquo Stroke vol 39 no 5 pp 1507ndash1513 2008

[23] A R Luft L Forrester R F Macko et al ldquoBrain activationof lower extremity movement in chronically impaired strokesurvivorsrdquo NeuroImage vol 26 no 1 pp 184ndash194 2005

[24] A R Luft S Waller L Forrester et al ldquoLesion locationalters brain activation in chronically impaired stroke survivorsrdquoNeuroImage vol 21 no 3 pp 924ndash935 2004

[25] N S Ward ldquoFunctional reorganization of the cerebral motorsystem after strokerdquo Current Opinion in Neurology vol 17 no6 pp 725ndash730 2004

[26] A C Zemke P J Heagerty C Lee and S C Cramer ldquoMotorcortex organization after stroke is related to side of stroke andlevel of recoveryrdquo Stroke vol 34 no 5 pp e23ndashe28 2003

[27] M Khan H Sakakima T S Dhammu et al ldquoS-nitrosoglutathione reduces oxidative injury and promotesmechanisms of neurorepair following traumatic brain injury inratsrdquo Journal of Neuroinflammation vol 8 article 78 2011

[28] H Sakakima M Khan T S Dhammu et al ldquoStimulationof functional recovery via the mechanisms of neurorepairby S-nitrosoglutathione and motor exercise in a rat modelof transient cerebral ischemia and reperfusionrdquo RestorativeNeurology and Neuroscience vol 30 no 5 pp 383ndash396 2012

[29] S Barbay E V Zoubina N Dancause et al ldquoA single injectionof D-amphetamine facilitates improvements in motor trainingfollowing a focal cortical infarct in squirrel monkeysrdquo Neurore-habilitation and Neural Repair vol 20 no 4 pp 455ndash458 2006

[30] P-C Fang S Barbay E J Plautz E Hoover S M Strittmatterand R J Nudo ldquoCombination of NEP 1-40 treatment andmotortraining enhances behavioral recovery after a focal corticalinfarct in ratsrdquo Stroke vol 41 no 3 pp 544ndash549 2010

[31] J-K Lee J-E Kim M Sivula and S M Strittmatter ldquoNogoreceptor antagonism promotes stroke recovery by enhancingaxonal plasticityrdquo The Journal of Neuroscience vol 24 no 27pp 6209ndash6217 2004

[32] J Wang X Feng Y Du L Wang and S Zhang ldquoCombinationtreatment with progesterone and rehabilitation training furtherpromotes behavioral recovery after acute ischemic stroke inmicerdquo Restorative Neurology and Neuroscience vol 31 no 4 pp487ndash499 2013

[33] B Kolb C Morshead C Gonzalez et al ldquoGrowth factor-stimulated generation of new cortical tissue and functionalrecovery after stroke damage to the motor cortex of ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 27 no 5pp 983ndash997 2007

[34] M S Jeffers A Hoyles C Morshead and D Corbett ldquoEpi-dermal growth factor and erythropoietin infusion accelerate

Neural Plasticity 9

functional recovery in combination with rehabilitationrdquo Strokevol 45 no 6 pp 1856ndash1858 2014

[35] L Gherardini M Gennaro and T Pizzorusso ldquoPerilesionaltreatment with chondroitinase ABC and motor training pro-mote functional recovery after stroke in ratsrdquo Cerebral Cortexvol 25 no 1 pp 202ndash212 2015

[36] D P Fuchs N Sanghvi J Wieser and S Schindler-IvensldquoPedaling alters the excitability and modulation of vastusmedialis H-reflexes after strokerdquo Clinical Neurophysiology vol122 no 10 pp 2036ndash2043 2011

[37] I-S Hwang C-F Lin L-C Tung and C-H Wang ldquoRespon-siveness of the H reflex to loading and posture in patientsfollowing strokerdquo Journal of Electromyography and Kinesiologyvol 14 no 6 pp 653ndash659 2004

[38] M A Oskoei and H Hu ldquoSupport vector machine-basedclassification scheme for myoelectric control applied to upperlimbrdquo IEEE Transactions on Biomedical Engineering vol 55 no8 pp 1956ndash1965 2008

[39] G L Soderberg and L M Knutson ldquoA guide for use andinterpretation of kinesiologic electromyographic datardquo PhysicalTherapy vol 80 no 5 pp 485ndash498 2000

[40] N A Riley and M Bilodeau ldquoChanges in upper limb jointtorque patterns and EMG signals with fatigue following astrokerdquoDisability andRehabilitation vol 24 no 18 pp 961ndash9692002

[41] U M Svantesson K S Sunnerhagen U S Carlsson and GGrimby ldquoDevelopment of fatigue during repeated eccentric-concentric muscle contractions of plantar flexors in patientswith strokerdquo Archives of Physical Medicine and Rehabilitationvol 80 no 10 pp 1247ndash1252 1999

[42] K N Arya S Pandian R Verma and R K Garg ldquoMovementtherapy induced neural reorganization and motor recovery instroke a reviewrdquo Journal of Bodywork andMovementTherapiesvol 15 no 4 pp 528ndash537 2011

[43] R J Nudo ldquoNeural bases of recovery after brain injuryrdquo Journalof Communication Disorders vol 44 no 5 pp 515ndash520 2011

[44] T Kawamata N E Alexis W D Dietrich and S P FinklesteinldquoIntracisternal basic fibroblast growth factor (bFGF) enhancesbehavioral recovery following focal cerebral infarction in theratrdquo Journal of Cerebral Blood Flow and Metabolism vol 16 no4 pp 542ndash547 1996

[45] T Yamaguchi M Suzuki and M Yamamoto ldquoYM796 anovel muscarinic agonist improves the impairment of learningbehavior in a rat model of chronic focal cerebral ischemiardquoBrain Research vol 669 no 1 pp 107ndash114 1995

[46] F Matsuda H Sakakima and Y Yoshida ldquoThe effects of earlyexercise on brain damage and recovery after focal cerebralinfarction in ratsrdquoActa Physiologica vol 201 no 2 pp 275ndash2872011

[47] K Mizutani S Sonoda N Hayashi et al ldquoAnalysis of proteinexpression profile in the cerebellum of cerebral infarction ratsafter treadmill trainingrdquo American Journal of Physical Medicineamp Rehabilitation vol 89 no 2 pp 107ndash114 2010

[48] P Zhang Y Zhang J Zhang et al ldquoEarly exercise protectsagainst cerebral ischemic injury through inhibiting neuronapoptosis in cortex in ratsrdquo International Journal of MolecularSciences vol 14 no 3 pp 6074ndash6089 2013

[49] L M Cupini M Diomedi F Placidi M Silvestrini and PGiacomini ldquoCerebrovascular reactivity and subcortical infarc-tionsrdquo Archives of Neurology vol 58 no 4 pp 577ndash581 2001

[50] F M Ivey A S Ryan C E Hafer-Macko and R F MacKoldquoImproved cerebral vasomotor reactivity after exercise trainingin hemiparetic stroke survivorsrdquo Stroke vol 42 no 7 pp 1994ndash2000 2011

[51] S Tian Y Zhang S Tian et al ldquoEarly exercise training improvesischemic outcome in rats by cerebral hemodynamicsrdquo BrainResearch vol 1533 pp 114ndash121 2013

[52] Y Gao Y Zhao J Pan et al ldquoTreadmill exercise promotesangiogenesis in the ischemic penumbra of rat brains throughcaveolin-1VEGF signaling pathwaysrdquo Brain Research vol 1585pp 83ndash90 2014

[53] G Kim and E Kim ldquoEffects of treadmill training on limbmotorfunction and acetylcholinesterase activity in rats with strokerdquoJournal of PhysicalTherapy Science vol 25 no 10 pp 1227ndash12302013

[54] Q Zheng D Zhu Y Bai Y Wu J Jia and Y Hu ldquoExerciseimproves recovery after ischemic brain injury by inducing theexpression of angiopoietin-1 and Tie-2 in ratsrdquo The TohokuJournal of Experimental Medicine vol 224 no 3 pp 221ndash2282011

[55] T M Hansen A J Moss and N P J Brindle ldquoVascularendothelial growth factor and angiopoietins in neurovascularregeneration and protection following strokerdquo Current Neu-rovascular Research vol 5 no 4 pp 236ndash245 2008

[56] D M Hermann and A Zechariah ldquoImplications of vascu-lar endothelial growth factor for postischemic neurovascularremodelingrdquo Journal of Cerebral Blood Flow and Metabolismvol 29 no 10 pp 1620ndash1643 2009

[57] C S Mang K L Campbell C J D Ross and L A Boyd ldquoPro-moting neuroplasticity for motor rehabilitation after strokeconsidering the effects of aerobic exercise and genetic variationon brain-derived neurotrophic factorrdquo PhysicalTherapy vol 93no 12 pp 1707ndash1716 2013

[58] M Ploughman VWindle C LMacLellan NWhite J J Doreand D Corbett ldquoBrain-derived neurotrophic factor contributesto recovery of skilled reaching after focal ischemia in ratsrdquoStroke vol 40 no 4 pp 1490ndash1495 2009

[59] I Kiprianova TM Freiman SDesiderato et al ldquoBrain-derivedneurotrophic factor prevents neuronal death and glial activa-tion after global ischemia in the ratrdquo Journal of NeuroscienceResearch vol 56 no 1 pp 21ndash27 1999

[60] R J Nudo E J Plautz and S B Frost ldquoRole of adaptiveplasticity in recovery of function after damage to motor cortexrdquoMuscle amp Nerve vol 24 no 8 pp 1000ndash1019 2001

[61] W-R Schabitz S Schwab M Spranger and W Hacke ldquoIntra-ventricular brain-derived neurotrophic factor reduces infarctsize after focal cerebral ischemia in ratsrdquo Journal of CerebralBlood Flow and Metabolism vol 17 no 5 pp 500ndash506 1997

[62] W-R Schabitz C Sommer W Zoder et al ldquoIntravenousbrain-derived neurotrophic factor reduces infarct size andcounterregulates Bax andBcl-2 expression after temporary focalcerebral ischemiardquo Stroke vol 31 no 9 pp 2212ndash2217 2000

[63] M-W Kim M-S Bang T-R Han et al ldquoExercise increasedBDNF and trkB in the contralateral hemisphere of the ischemicrat brainrdquo Brain Research vol 1052 no 1 pp 16ndash21 2005

[64] Z Kokaia Q Zhao M Kokaia et al ldquoRegulation of brain-derived neurotrophic factor gene expression after transientmiddle cerebral artery occlusion with and without brain dam-agerdquo Experimental Neurology vol 136 no 1 pp 73ndash88 1995

[65] L R Zhao B Mattsson and B B Johansson ldquoEnvironmentalinfluence on brain-derived neurotrophic factormessenger RNA

10 Neural Plasticity

expression after middle cerebral artery occlusion in sponta-neously hypertensive ratsrdquo Neuroscience vol 97 no 1 pp 177ndash184 2000

[66] H D Muller K M Hanumanthiah K Diederich S SchwabW-R Schabitz and C Sommer ldquoBrain-derived neurotrophicfactor but not forced armuse improves long-term outcome afterphotothrombotic stroke and transiently upregulates bindingdensities of excitatory glutamate receptors in the rat brainrdquoStroke vol 39 no 3 pp 1012ndash1021 2008

[67] W-R Schabitz C Berger R Kollmar et al ldquoEffect of brain-derived neurotrophic factor treatment and forced arm use onfunctional motor recovery after small cortical ischemiardquo Strokevol 35 no 4 pp 992ndash997 2004

[68] J Chen J Qin Q Su Z Liu and J Yang ldquoTreadmillrehabilitation treatment enhanced BDNF-TrkB but not NGF-TrkA signaling in a mouse intracerebral hemorrhage modelrdquoNeuroscience Letters vol 529 no 1 pp 28ndash32 2012

[69] J-Y Chung M-W Kim M-S Bang and M Kim ldquoIncreasedexpression of neurotrophin 4 following focal cerebral ischemiain adult rat brain with treadmill exerciserdquo PLoS ONE vol 8 no3 Article ID e52461 2013

[70] Z Ke S P Yip L Li X X Zheng W K Tam and K Y TongldquoThe effects of voluntary involuntary and forced exercises onmotor recovery in a stroke rat modelrdquo in Proceedings of theAnnual International Conference of the IEEE Engineering inMedicine and Biology Society (EMBC rsquo11) vol 2011 pp 8223ndash8226 Boston Mass USA August 2011

[71] P-C Shih Y-R Yang and R-Y Wang ldquoEffects of exerciseintensity on spatial memory performance and hippocampalsynaptic plasticity in transient brain ischemic ratsrdquo PLoS ONEvol 8 no 10 Article ID e78163 2013

[72] J Sun Z Ke S P Yip X-L Hu X-X Zheng and K-Y TongldquoGradually increased training intensity benefits rehabilitationoutcome after stroke by BDNF upregulation and stress sup-pressionrdquo BioMed Research International vol 2014 Article ID925762 8 pages 2014

[73] R Marin A Williams S Hale et al ldquoThe effect of voluntaryexercise exposure on histological and neurobehavioral out-comes after ischemic brain injury in the ratrdquo Physiology andBehavior vol 80 no 2-3 pp 167ndash175 2003

[74] S Vaynman Z Ying and F Gomez-Pinilla ldquoExercise inducesBDNF and synapsin I to specific hippocampal subfieldsrdquo Jour-nal of Neuroscience Research vol 76 no 3 pp 356ndash362 2004

[75] L Zhang X Hu J Luo et al ldquoPhysical exercise improves func-tional recovery through mitigation of autophagy attenuationof apoptosis and enhancement of neurogenesis after MCAO inratsrdquo BMC Neuroscience vol 14 article 46 2013

[76] J Puyal and P G H Clarke ldquoTargeting autophagy to preventneonatal stroke damagerdquoAutophagy vol 5 no 7 pp 1060ndash10612009

[77] Q-W Zhang X-X Deng X Sun J-X Xu and F-Y SunldquoExercise promotes axon regeneration of newborn striatonigraland corticonigral projection neurons in rats after ischemicstrokerdquo PLoS ONE vol 8 no 11 Article ID e80139 2013

[78] M Asahi K Asahi J-C Jung G J del ZoppoM E Fini and EH Lo ldquoRole for matrix metalloproteinase 9 after focal cerebralischemia effects of gene knockout and enzyme inhibition withBB-94rdquo Journal of Cerebral Blood Flow amp Metabolism vol 20no 12 pp 1681ndash1689 2000

[79] M Asahi X Wang T Mori et al ldquoEffects of matrixmetalloproteinase-9 gene knock-out on the proteolysis of

blood-brain barrier andwhitematter components after cerebralischemiardquoThe Journal of Neuroscience vol 21 no 19 pp 7724ndash7732 2001

[80] Y Zhang P Zhang X Shen et al ldquoEarly exercise protects theblood-brain barrier from ischemic brain injury via the regula-tion of MMP-9 and occludin in ratsrdquo International Journal ofMolecular Sciences vol 14 no 6 pp 11096ndash11112 2013

[81] I G Onyango J Lu M Rodova E Lezi A B Crafter and RH Swerdlow ldquoRegulation of neuron mitochondrial biogenesisand relevance to brain healthrdquo Biochimica et Biophysica ActamdashMolecular Basis of Disease vol 1802 no 1 pp 228ndash234 2010

[82] Q Zhang Y Wu P Zhang et al ldquoExercise induces mitochon-drial biogenesis after brain ischemia in ratsrdquo Neuroscience vol205 pp 10ndash17 2012

[83] L Li W Rong Z Ke X Hu and K-Y Tong ldquoThe effects oftraining intensities on motor recovery and gait symmetry in arat model of ischemiardquo Brain Injury vol 27 no 4 pp 408ndash4162013

[84] C Enzinger H Dawes H Johansen-Berg et al ldquoBrain activitychanges associated with treadmill training after strokerdquo Strokevol 40 no 7 pp 2460ndash2467 2009

[85] A R Luft R FMacKo LW Forrester et al ldquoTreadmill exerciseactivates subcortical neural networks and improves walkingafter stroke a randomized controlled trialrdquo Stroke vol 39 no12 pp 3341ndash3350 2008

[86] K Potempa M Lopez L T Braun J P Szidon L Fogg and TTincknell ldquoPhysiological outcomes of aerobic exercise trainingin hemiparetic stroke patientsrdquo Stroke vol 26 no 1 pp 101ndash1051995

[87] F Buma G Kwakkel and N Ramsey ldquoUnderstanding upperlimb recovery after strokerdquo Restorative Neurology and Neuro-science vol 31 no 6 pp 707ndash722 2013

[88] A E Baird A Benfield G Schlaug et al ldquoEnlargementof human cerebral ischemic lesion volumes measured bydiffusion-weighted magnetic resonance imagingrdquo Annals ofNeurology vol 41 no 5 pp 581ndash589 1997

[89] A Schmidt J Wellmann M Schilling et al ldquoMeta-analysis ofthe efficacy of different training strategies in animal models ofischemic strokerdquo Stroke vol 45 no 1 pp 239ndash247 2014

[90] R-Y Wang S-M Yu and Y-R Yang ldquoTreadmill trainingeffects in different age groups following middle cerebral arteryocclusion in ratsrdquo Gerontology vol 51 no 3 pp 161ndash165 2005

[91] P ZhangH YuN Zhou et al ldquoEarly exercise improves cerebralblood flow through increased angiogenesis in experimentalstroke rat modelrdquo Journal of NeuroEngineering and Rehabilita-tion vol 10 article 43 2013

[92] J Laurin andC Pin-Barre ldquoPhysiological adaptations followingendurance exercises after stroke focus on the plausible roleof high-intensity interval trainingrdquo International Journal ofPhysical Medicine amp Rehabilitation vol 2 no 3 pp 1ndash6 2014

[93] THMurphy andDCorbett ldquoPlasticity during stroke recoveryfrom synapse to behaviourrdquo Nature Reviews Neuroscience vol10 no 12 pp 861ndash872 2009

[94] M Svensson J Lexell and T Deierborg ldquoEffects of physicalexercise on neuroinflammation neuroplasticity neurodegener-ation and behavior what we can learn from animal models inclinical settingsrdquoNeurorehabilitation and Neural Repair vol 29no 6 pp 577ndash589 2015

[95] A Risedal J Zeng and B B Johansson ldquoEarly training mayexacerbate brain damage after focal brain ischemia in the ratrdquoJournal of Cerebral Blood Flow andMetabolism vol 19 no 9 pp997ndash1003 1999

Neural Plasticity 11

[96] C-S Piao B A Stoica J Wu et al ldquoLate exercise reducesneuroinflammation and cognitive dysfunction after traumaticbrain injuryrdquoNeurobiology of Disease vol 54 pp 252ndash263 2013

[97] J L Humm D A Kozlowski S T Bland D C James andT Schallert ldquoUse-dependent exaggeration of brain injury isglutamate involvedrdquo Experimental Neurology vol 157 no 2 pp349ndash358 1999

[98] G S Griesbach F Gomez-Pinilla and D A Hovda ldquoTheupregulation of plasticity-related proteins following TBI isdisrupted with acute voluntary exerciserdquo Brain Research vol1016 no 2 pp 154ndash162 2004

[99] J WMcAlees L T Smith R S Erbe D Jarjoura N M Ponzioand V M Sanders ldquoEpigenetic regulation of beta2-adrenergicreceptor expression in T

1198671 and T

1198672 cellsrdquo Brain Behavior and

Immunity vol 25 no 3 pp 408ndash415 2011[100] G Zhao S Zhou A Davie and Q Su ldquoEffects of moderate and

high intensity exercise on T1T2 balancerdquo Exercise ImmunologyReview vol 18 pp 98ndash114 2012

[101] Y Yagita K Kitagawa T Sasaki et al ldquoPostischemic exercisedecreases neurogenesis in the adult rat dentate gyrusrdquo Neuro-science Letters vol 409 no 1 pp 24ndash29 2006

[102] S T Bland T Schallert R Strong J Aronowski and J CGrottaldquoEarly exclusive use of the affected forelimb aftermoderate tran-sient focal ischemia in rats functional and anatomic outcomerdquoStroke vol 31 no 5 pp 1144ndash1152 2000

[103] S B DeBow J E McKenna B Kolb and F ColbourneldquoImmediate constraint-inducedmovement therapy causes localhyperthermia that exacerbates cerebral cortical injury in ratsrdquoCanadian Journal of Physiology and Pharmacology vol 82 no4 pp 231ndash237 2004

[104] D A Kozlowski D C James and T Schallert ldquoUse-dependentexaggeration of neuronal injury after unilateral sensorimotorcortex lesionsrdquo The Journal of Neuroscience vol 16 no 15 pp4776ndash4786 1996

[105] B Balaban F Tok F Yavuz E Yasar and R Alaca ldquoEarlyrehabilitation outcome in patients with middle cerebral arterystrokerdquo Neuroscience Letters vol 498 no 3 pp 204ndash207 2011

[106] G Kwakkel R van Peppen R C Wagenaar et al ldquoEffects ofaugmented exercise therapy time after stroke a meta-analysisrdquoStroke vol 35 no 11 pp 2529ndash2539 2004

[107] D L Costill M G Flynn J P Kirwan et al ldquoEffects of repeateddays of intensified training on muscle glycogen and swimmingperformancerdquo Medicine amp Science in Sports amp Exercise vol 20no 3 pp 249ndash254 1988

[108] M A Hirsch and B G Farley ldquoExercise and neuroplasticityin persons living with Parkinsonrsquos diseaserdquo European Journal ofPhysical and Rehabilitation Medicine vol 45 no 2 pp 215ndash2292009

[109] M Katz-Leurer M Shochina E Carmeli and Y FriedlanderldquoThe influence of early aerobic training on the functional capac-ity in patients with cerebrovascular accident at the subacutestagerdquo Archives of Physical Medicine and Rehabilitation vol 84no 11 pp 1609ndash1614 2003

[110] J D Schaechter ldquoMotor rehabilitation and brain plasticity afterhemiparetic strokerdquo Progress in Neurobiology vol 73 no 1 pp61ndash72 2004

[111] P R Bosch S Holzapfel and T Traustadottir ldquoFeasibility ofmeasuring ventilatory threshold in adults with stroke-inducedhemiparesis implications for exercise prescriptionrdquo Archives ofPhysical Medicine and Rehabilitation 2015

[112] D P Stirling K Khodarahmi J Liu et al ldquoMinocyclinetreatment reduces delayed oligodendrocyte death attenuatesaxonal dieback and improves functional outcome after spinalcord injuryrdquoThe Journal of Neuroscience vol 24 no 9 pp 2182ndash2190 2004

[113] S Barbay and R J Nudo ldquoThe effects of amphetamine onrecovery of function in animal models of cerebral injury acritical appraisalrdquo NeuroRehabilitation vol 25 no 1 pp 5ndash172009

[114] R S Rasmussen K Overgaard E S Hildebrandt-Eriksen andG Boysen ldquoD-Amphetamine improves cognitive deficits andphysical therapy promotes fine motor rehabilitation in a ratembolic stroke modelrdquo Acta Neurologica Scandinavica vol 113no 3 pp 189ndash198 2006

[115] C L Gibson B Coomber and S P Murphy ldquoProgesterone isneuroprotective following cerebral ischaemia in reproductivelyageing female micerdquo Brain vol 134 no 7 pp 2125ndash2133 2011

[116] T Ishrat I Sayeed F Atif and D G Stein ldquoEffects ofprogesterone administration on infarct volume and functionaldeficits following permanent focal cerebral ischemia in ratsrdquoBrain Research vol 1257 pp 94ndash101 2009

[117] M Prencipe C Ferretti A R Casini M Santini F Giubileiand F Culasso ldquoStroke disability and dementia results of apopulation surveyrdquo Stroke vol 28 no 3 pp 531ndash536 1997

[118] I Sayeed B Wali and D G Stein ldquoProgesterone inhibitsischemic brain injury in a rat model of permanent middle cere-bral artery occlusionrdquo Restorative Neurology and Neurosciencevol 25 no 2 pp 151ndash159 2007

[119] H Lee R J McKeon and R V Bellamkonda ldquoSustaineddelivery of thermostabilized chABC enhances axonal sproutingand functional recovery after spinal cord injuryrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 8 pp 3340ndash3345 2010

[120] V J Tom R Kadakia L Santi and J D Houle ldquoAdministrationof chondroitinase ABC rostral or caudal to a spinal cord injurysite promotes anatomical but not functional plasticityrdquo Journalof Neurotrauma vol 26 no 12 pp 2323ndash2333 2009

[121] J J Hill K Jin X O Mao L Xie and D A GreenbergldquoIntracerebral chondroitinase ABC and heparan sulfate proteo-glycan glypican improve outcome from chronic stroke in ratsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 23 pp 9155ndash9160 2012

[122] S Soleman P K Yip D A Duricki and L D FMoon ldquoDelayedtreatment with chondroitinase ABC promotes sensorimotorrecovery and plasticity after stroke in aged ratsrdquo Brain vol 135no 4 pp 1210ndash1223 2012

[123] B E Skolnick A I Maas R K Narayan et al ldquoA clinical trialof progesterone for severe traumatic brain injuryrdquo The NewEngland Journal of Medicine vol 371 no 26 pp 2467ndash24762014

[124] DWWright SD Yeatts R Silbergleit et al ldquoVery early admin-istration of progesterone for acute traumatic brain injuryrdquo TheNew England Journal of Medicine vol 371 no 26 pp 2457ndash2466 2014

[125] L-H Krarup T Truelsen C Gluud et al ldquoPrestroke physicalactivity is associated with severity and long-term outcome fromfirst-ever strokerdquo Neurology vol 71 no 17 pp 1313ndash1318 2008

[126] P M Rist I-M Lee C S Kase J Michael Gaziano and TKurth ldquoPhysical activity and functional outcomes from cerebralvascular events in menrdquo Stroke vol 42 no 12 pp 3352ndash33562011

12 Neural Plasticity

[127] Q Zhang L Zhang X Yang Y Wan and J Jia ldquoThe effectsof exercise preconditioning on cerebral blood flow change andendothelin-1 expression after cerebral ischemia in ratsrdquo Journalof Stroke and Cerebrovascular Diseases vol 23 no 6 pp 1696ndash1702 2014

[128] M Bernaudin A-S Nedelec D Divoux E T MacKenzie EPetit and P Schumann-Bard ldquoNormobaric hypoxia inducestolerance to focal permanent cerebral ischemia in associationwith an increased expression of hypoxia-inducible factor-1 andits target genes erythropoietin and VEGF in the adult mousebrainrdquo Journal of Cerebral Blood Flow and Metabolism vol 22no 4 pp 393ndash403 2002

[129] D Dornbos III N Zwagerman M Guo et al ldquoPreischemicexercise reduces brain damage by ameliorating metabolic dis-order in ischemiareperfusion injuryrdquo Journal of NeuroscienceResearch vol 91 no 6 pp 818ndash827 2013

[130] Y-H Ding Y Ding J Li D A Bessert and J A RafolsldquoExercise pre-conditioning strengthens brain microvascularintegrity in a rat stroke modelrdquo Neurological Research vol 28no 2 pp 184ndash189 2006

[131] M Guo B Cox S Mahale et al ldquoPre-ischemic exercise reducesmatrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in strokerdquo Neuroscience vol 151 no2 pp 340ndash351 2008

[132] M Ploughman Z Attwood N White J J E Dore and DCorbett ldquoEndurance exercise facilitates relearning of forelimbmotor skill after focal ischemiardquo The European Journal ofNeuroscience vol 25 no 11 pp 3453ndash3460 2007

[133] L L Guyot F G Diaz M H OrsquoRegan S McLeod H Park andJW Phillis ldquoReal-timemeasurement of glutamate release fromthe ischemic penumbra of the rat cerebral cortex using a focalmiddle cerebral artery occlusion modelrdquo Neuroscience Lettersvol 299 no 1-2 pp 37ndash40 2001

[134] K Matsumoto R Graf G Rosner J Taguchi and W-D HeissldquoElevation of neuroactive substances in the cortex of cats duringprolonged focal ischemiardquo Journal of Cerebral Blood Flow andMetabolism vol 13 no 4 pp 586ndash594 1993

[135] J Jia Y-S Hu Y Wu et al ldquoPre-ischemic treadmill trainingaffects glutamate and gamma aminobutyric acid levels in thestriatal dialysate of a rat model of cerebral ischemiardquo LifeSciences vol 84 no 15-16 pp 505ndash511 2009

[136] F Zhang J Jia Y Wu Y Hu and Y Wang ldquoThe effect of tread-mill training pre-exercise on glutamate receptor expression inrats after cerebral ischemiardquo International Journal of MolecularSciences vol 11 no 7 pp 2658ndash2669 2010

[137] J Jia Y-S Hu Y Wu et al ldquoTreadmill pre-training suppressesthe release of glutamate resulting from cerebral ischemia inratsrdquo Experimental Brain Research vol 204 no 2 pp 173ndash1792010

[138] E T Ang P T H Wong S Moochhala and Y K NgldquoNeuroprotection associated with running is it a result ofincreased endogenous neurotrophic factorsrdquoNeuroscience vol118 no 2 pp 335ndash345 2003

[139] A C Ricciardi E Lopez-Cancio N Perez De La Ossa et alldquoPrestroke physical activity is associated with good functionaloutcome and arterial recanalization after stroke due to a largevessel occlusionrdquo Cerebrovascular Diseases vol 37 no 4 pp304ndash311 2014

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Psychiatry Journal

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity 5

could accentuate the cerebral ischemia-induced release ofglutamate and catecholamines that lead to neural excito-toxicity [95 97] However it seems important to add thatother processes than hyperthermia might be involved in thesensorimotor deficit aggravations and need to be exploredFurthermore early running training downregulated proteinsinvolved in neuroplasticity such as MAPK CAMKII PKCsynapsin I orCREB expression [98] anddecreased the level ofproinflammatory cytokines known to be related to neuropro-tection [99 100] Finally Yagita et al (2006) had shown thattwo weeks of running exercise reduced the number of new-born neurons in ischemic rats and thus limited neurogenesisin the hippocampus [101] The author suggested that runningwas too stressful and enhanced the corticosterone levelknown to decrease neurogenesis Likewise an immediateoveruse of the lesioned forelimb could also increase tissue lossaround the lesion and aggravated sensorimotor deficits on alonger term [102ndash104] One explanation could be related toanatomical damage resulting from the reduction of dendriticgrowth in the ischemic hemisphere [104]

In addition an augmented volume of exercise or increaseof inpatient therapy duration for stroke did not indicatesuperior effects on functional recovery and activities of dailyliving [105 106] Interestingly when healthy active men weresubjected to a strong increase of volume training physicalperformance was also not improved [107] It thus seems thatvolume is not the main exercise parameter that should beinvestigated for improving aerobic program

Greater improvements were observed with higher exer-cise intensities after stroke and neurodegenerative disease butalso for healthy individuals [92 108ndash110] However the effectof intensity on neuroplasticity remains unclear because it ispoorly investigated in stroke patients or in ischemic animalmodels (ongoing study in our laboratory) It should also bepointed that one major methodological limitation is relatedto the exercise intensity determination Indeed trainingintensity was mainly based onmaximal oxygen consumptionor maximal exercise heart rate (or even intensity basedon empirical values) However these parameters were notappropriated because stroke patients never reached maximalcapabilities It was recently suggested that prescribing inten-sity should rather be based on submaximal parameters suchas ventilatory or lactic threshold that were more accurate indistinguishing moderate to intense exercise [111]

5 Beneficial Effect of Physical TrainingRehabilitation in Combination withPharmacological Treatments

Using multiple recovery processes (physical exercise andpharmacologic treatments) may be critical for enhancingfunctional outcomes in contrast to monotherapies targetingsingle mechanisms (Table 1)

Given that recent findings have established that anti-inflammation may be an important target for stroke treat-ment [112] some authors demonstrated that combinationof skilled reaching training with indomethacin or minocy-cline accentuated recovery [10] First beneficial effects of

such combination included an improvement of sensorimotorfunction as indicated by higher correct placements of theimpaired forelimb during a walking task Secondly thenumber of proliferating microglia was more reduced and thesurvival of newborn astrocytes in the peri-infarct zone wasincreased compared to rats that underwent training aloneAuthors suggested that the motor outcome improvementmight be partially explained by the observed changes ofneural response

In addition therapeutic drug such as S-nitrosogluta-thione (GSNO) exhibits similar neurovascular protectingeffects compared to physical training following traumaticbrain trauma and cerebral ischemia in rats [18 27] Adminis-tration of GSNO could reduce neuronal apoptotic cell deathexcitotoxicity and inflammation as well as protecting BBBintegrity GSNO could also stimulate the expression of VEGFand BDNF after traumatic brain injury Several authors havedemonstrated that combining rotating rod motor exercisewith GSNO administration accelerated and accentuated bothwalking and balance abilities compared to the effects inducedby each treatment applied separatelyMoreover the improvedmotor function was associated with a reduction of bothinfarct volume and neuronal cell death as well as an increaseof PECAM-1 and BDNF expression [28]

D-amphetamine acting primarily through norepineph-rine and dopamine mechanisms is a potent modulator ofneurological function and cortical excitation that facilitatedmotor skill abilities [113] It was demonstrated that a singleinjection of D-amphetamine on the first day of trainingfacilitates effectiveness of motor skill training compared withD-amphetamine treatment alone after a focal cortical infarctin squirrel monkeys [29] However administration of ahigh dose of D-amphetamine combined with rehabilitationtraining failed to promote fine motor recovery in a ratembolic stroke model Authors explained this result by thefact that the dose of D-amphetamine was too high therebylimiting animal engagement in the staircase test [114]

Other pharmacological agents could improve motorrecovery by focusing on different neural mechanisms Forexample Nogo-A protein a myelin-associated inhibitorappears to be partially responsible for inhibition of axonalgrowth in white matter Therefore suppressing this myelin-associated neurite outgrowth inhibitor by specific antagonistsof Nogo-A such as NEP 1-40 or NGR(310)Ecto-FC increasedneurite outgrowth and axonal regeneration after stroke [3031] Five-week motor training combined with NEP 1-40treatment accelerated motor recovery (skilled reach and footfault tests) from the first week after cerebral ischemia com-pared to treatments applied alone in which beneficial effectswere observed later (weeks 2 and 4) [30] Unfortunatelyneural plasticity mechanisms underlying this improvementremain unknown but these findings showed that this therapycombination could accelerate the recovery process followingcerebral ischemia

Neurons and glial cells in brain can synthesize proges-terone that exhibits neuroprotective effects after cerebralischemia [115ndash118] Rehabilitation could increase reorganiza-tion of cortical maps whereas the progesterone might reducethe infarct volume through its neuroprotective effect by

6 Neural Plasticity

Table 1 Influence of pharmacological agents associated with physical exercise on motor recovery after brain stroke

Drug agents Targets Results References

Indomethacin Minocycline Inflammatory processes

infarct volume (indomethacin only) sensorimotor performance

microglia astroglia

[10]

GSNOOxidative stress

Inflammatory processesExcitotoxicity

infarct volume apoptotic cell death neurological score motor recovery

and survival rate CBF synaptic plasticity and BBB

leakage TNF-120572 IL-1120573 and iNOS

[18 27 28]

D-Amphetamine Noradrenergic 1205721-receptor agonist motor recovery [29]

NEP 1-40 Nogo-A protein inhibitor early motor recovery axonal growth [30]

NgR(310)Ecto-Fc Nogo-NgR pathwayinhibitor

motor recovery axonal plasticity [31]

Progesterone ExcitotoxicityInflammatory processes

infarct volume forelimbs strength and motor recovery [32]

EGFlowast and EPOlowast Neuron proliferation migrationand differentiation accelerated fine motor recovery [33 34]

Chondroitinase ABC Chondroitin sulphate proteoglycans(CSPGs)

CSPGs synaptic plasticitymotor recovery

[35]

indicates an increase and a decrease respectively NEP 1-40 NOGO extracellular peptide EGF epidermal growth factor EPO erythropoietin GSNOS-nitrosoglutathione CBF cerebral blood flow BDNF brain developed neurotrophic factor trkB tropomyosin receptor kinase B BBB blood brain barrierlowastMolecules combination

targeting excitotoxicity Although this combination had noadditional effect in reducing infarct volume functional recov-ery effectiveness was promoted as shown by the increasedrotarod performance and forelimb grip strength at all timepoints within 7 days after ischemic stroke [32]

In addition some authors indicated that combination oftwo pharmacological treatments could improve functionalrecovery and neural plasticity compared to either treatmentalone For example association of epidermal growth fac-tor (EGF) and erythropoietin (EPO) treatments is moreeffective in promoting tissue regeneration and proliferationof neural precursor cells than monotherapy [33] Howeveran even greater improvement in skilled reaching ability inthe staircase test was observed when physical rehabilitationwas added to serial application of both EGF and EPO[34] Authors have also indicated that fine motor skillimprovement was observed 10 weeks after functional reha-bilitation alone whereas 4-week-long treatment combinationwas sufficient to improve sensorimotor function It meansthat functional recovery is also clearly accelerated with thiscombination

Another strategy consists of recreating a tissue environ-ment free from growth inhibiting molecules Chondroiti-nase ABC which degrades inhibitory chondroitin sulphateproteoglycans present in the extracellular matrix reducesthe neurite-inhibitory environment and facilitates axonalsprouting and sensorimotor recovery after spinal cord injury[119 120] and after cerebral ischemia [121 122]This treatmentwas applied at the ipsilesional cortex in rats in combinationwith functional rehabilitation Synaptic plasticity assessed by

measuring the expression of glutamate vesicular transporter(vGLUT1 and vGLUT2) and the GABA vesicular transporter(vGAT) and functional recovery were promoted by thesynergic effect of these treatments [35]

Given that some promising treatments developed inpreclinical studies failed to be effective in clinical studies[123 124] it seems crucial to assess the pharmacologicaleffectiveness in stroke patients before combining it withphysical exerciseTherefore we need to keep inmind that notall the effective combinations found in animal studies couldbe considered effective for human Nevertheless assessingboth treatments and exercise in rodentmodels seems relevantto found new therapeutic strategies to highlight the mosteffective and applicable strategies for human

6 Influence of Prestroke Physical Activity onMotor Dysfunction Severity

To avoid administration of several pharmacological sub-stances in individuals with high risks of stroke (may inducedeleterious interaction between drugs and complications dueto their side effects) physical activity might be a major alter-native preventive strategy for reducing the brain secondaryinjury when stroke occurs Several recent human and animalstudies have well demonstrated that preischemic physicalactivity may reduce initial stroke severity on functionalmotor outcomes edema and infarct volume by acting oninflammation vascular processes BDNF expression andmetabolic disorders [14 16 17 125 126]

Neural Plasticity 7

Ischemia-induced brain inflammation is believed toplay a pivotal role in the development of secondary braininjury by intensifying the inflammatory cell accumulationandmicrovascular impairments Indeed adhesionmoleculessuch as intercellular adhesion molecule 1 (ICAM-1) pro-mote leukocyte infiltration into injury site and leukocyteadhesion to microvascular endothelium Preischemic phys-ical training-induced neuroprotection was associated with adecrease in ICAM-1 mRNA expression and in the number ofICAM-1-positive vessels [17] Consequently leukocyte accu-mulation in damaged cortex and striatum vessels decreasedresulting in reduction of brain inflammation during reperfu-sion

Brain angiogenesis is another neuroprotective mecha-nism for reducing the detrimental motor effect of cere-bral ischemia Physical training prior to cerebral ischemiaincreased short- and long-term effects onmicrovascular den-sity and cerebral blood flow by promoting angiogenesis andincreasing cerebral vasomotor reactivity It was found thatpreischemic exercise improved vasorelaxation by enhancingVEGF levels into the ischemic region which is knownto activate eNOS and EPCs recruitment [8 19] Likewiseexercise decreased the endothelin-1 (a powerful vasocon-strictor agent) expression thereby reducing the impact ofvasoconstriction on cerebral blood flow [127]

Preischemic training could also attenuate brain dam-age by limiting metabolic disorders after cerebral ischemiaIndeed 51015840AMP-activated protein kinase (AMPK) phos-phofructokinase-1 (PFK) and hypoxia-induced factor-1120572(HIF-1120572) involved in glycolysis [18 128] were significantlyhigher in preischemic trained rats [129] Moreover theincrease of glucose transporters in neurons and endothelialcells of the BBB (GLUT3 and GLUT1 resp) results inan improved glucose oxidation immediately after cerebralischemia allowing a faster and more substantial increase inATP production

Moreover it was postulated that preischemic exercise(30min on a treadmill 5 daysweek for 3 weeks) decreasesBBB dysfunctions and thus reduces infarct volume andedema as confirmed by the MMP-9 expression decrement[130 131] Preischemic treadmill training-induced neuro-protection in ischemic rats increased endogenous BDNFexpression that leads to motor recovery improvement [1617 67 132] Interestingly the preischemic treadmill exer-cise improved the therapeutic effectiveness of postischemictreadmill training onmotor function compared with animalsperforming it only after cerebral ischemia [53]

Neuronal excitotoxicity induced by excessive glutamaterelease is a major deleterious event of the brain secondaryinjury [133 134] It was found that preischemic treadmilltraining could also reduce the expression of glutamate recep-tors mGluR5 and NR2B reflecting a decrease of glutamateeffect on surrounding cells [135ndash137] Moreover it was pos-tulated that the reduction of infarct volume induced by 12weeks of treadmill might be related to increase of NGFexpression and this receptor p75 known to promote neu-roprotection against excitotoxicity and free-radical damage[138]

Individuals who were physically active prior to strokehave been shown to exhibit less deleterious functional out-comes as indicated by higher Barthel Index scores as wellas Oxford Handicap Scale [14 15] Indeed it was recentlyrevealed that patients with high levels of prestroke physicalactivity were associated with milder stroke severity at admis-sion with faster early motor improvement and with a lowerfinal infarct volume [139] Interestingly it seems that simplywalking 1 hday during 5 days per week or doing a vigorousaerobic activity 1 hday twice a week is sufficient to inducepreventive effects However findings remain conflicting inhuman studies because no strong association between higherlevels of physical activity and better functional outcomes afterstroke was found in a large prospective cohort [126]

7 Conclusion

Although acute exercise appears to be useful for better under-standing neural andmotor recoverymechanisms few studieshave used this experimental model to investigate strokephysiopathology Neural adaptations remain thus unclearFurthermore physical training appears to be promising toimprove functional motor recovery by promoting neuro-plasticity at different cellular and molecular levels Thesebeneficial effects seem accelerated andor accentuated whenexercise is combined with an additional pharmacologicaltreatment Nevertheless optimal parameters of training andtreatment need to be investigated to maximizeaccelerateneuroplasticity and motor recovery and avoid undesirableeffects of exercise All these findings could help researchersand therapists to justify the effectiveness of their physicaltraining programs in order to increase the patient willingnessto regularly perform physical activity before and after stroke

Conflict of Interests

Each author of the present review declared no conflict ofinterests

Acknowledgment

The authors are grateful to Dr Vincent Pertici for commentson earlier version of this paper

References

[1] E Broussalis M Killer M McCoy A Harrer E Trinkaand J Kraus ldquoCurrent therapies in ischemic stroke Part ARecent developments in acute stroke treatment and in strokepreventionrdquoDrug Discovery Today vol 17 no 7-8 pp 296ndash3092012

[2] F M Ivey R F Macko A S Ryan and C E Hafer-MackoldquoCardiovascular health and fitness after strokerdquo Topics in StrokeRehabilitation vol 12 no 1 pp 1ndash16 2005

[3] D LMarsden A Dunn R Callister C R Levi andN J SprattldquoCharacteristics of exercise training interventions to improvecardiorespiratory fitness after stroke a systematic review withmeta-analysisrdquo Neurorehabilitation and Neural Repair vol 27no 9 pp 775ndash788 2013

8 Neural Plasticity

[4] L Li W Rong Z Ke X Hu S P Yip and K Y Tong ldquoMuscleactivation changes during body weight support treadmill train-ing after focal cortical ischemia a rat hindlimb modelrdquo Journalof Electromyography and Kinesiology vol 21 no 2 pp 318ndash3262011

[5] C Pin-Barre J Laurin M-S Felix et al ldquoAcute neuromuscularadaptation at the spinal level following middle cerebral arteryocclusion-reperfusion in the ratrdquoPLoSONE vol 9 no 2 ArticleID e89953 2014

[6] L W Forrester D F Hanley and R F Macko ldquoEffectsof treadmill exercise on transcranial magnetic stimulation-induced excitability to quadriceps after strokerdquo Archives ofPhysical Medicine and Rehabilitation vol 87 no 2 pp 229ndash2342006

[7] R FMacko FM Ivey LW Forrester et al ldquoTreadmill exerciserehabilitation improves ambulatory function and cardiovas-cular fitness in patients with chronic stroke a randomizedcontrolled trialrdquo Stroke vol 36 no 10 pp 2206ndash2211 2005

[8] M Endres K Gertz U Lindauer et al ldquoMechanisms of strokeprotection by physical activityrdquoAnnals of Neurology vol 54 no5 pp 582ndash590 2003

[9] K Gertz J Priller G Kronenberg et al ldquoPhysical activityimproves long-term stroke outcome via endothelial nitric oxidesynthase-dependent augmentation of neovascularization andcerebral blood flowrdquo Circulation Research vol 99 no 10 pp1132ndash1140 2006

[10] S Liebigt N Schlegel J Oberland O W Witte C Redeckerand S Keiner ldquoEffects of rehabilitative training and anti-inflammatory treatment on functional recovery and cellularreorganization following strokerdquo Experimental Neurology vol233 no 2 pp 776ndash782 2012

[11] W-R Schabitz T Steigleder C M Cooper-Kuhn et al ldquoIntra-venous brain-derived neurotrophic factor enhances poststrokesensorimotor recovery and stimulates neurogenesisrdquo Strokevol 38 no 7 pp 2165ndash2172 2007

[12] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[13] I-M Lee C H Hennekens K Berger J E Buring and J EManson ldquoExercise and risk of stroke inmale physiciansrdquo Strokevol 30 no 1 pp 1ndash6 1999

[14] D Deplanque I Masse C Lefebvre C Libersa D Leys andR Bordet ldquoPrior TIA lipid-lowering drug use and physicalactivity decrease ischemic stroke severityrdquo Neurology vol 67no 8 pp 1403ndash1410 2006

[15] N Stroud T M L Mazwi L D Case et al ldquoPrestroke physicalactivity and early functional status after strokerdquo Journal ofNeurology Neurosurgery and Psychiatry vol 80 no 9 pp 1019ndash1022 2009

[16] Y Ding J Li X Luan et al ldquoExercise pre-conditioningreduces brain damage in ischemic rats that may be associatedwith regional angiogenesis and cellular overexpression of neu-rotrophinrdquo Neuroscience vol 124 no 3 pp 583ndash591 2004

[17] Y-H Ding C N Young X Luan et al ldquoExercise precondi-tioning ameliorates inflammatory injury in ischemic rats duringreperfusionrdquoActaNeuropathologica vol 109 no 3 pp 237ndash2462005

[18] MKhan B Sekhon S Giri et al ldquoS-Nitrosoglutathione reducesinflammation and protects brain against focal cerebral ischemiain a rat model of experimental strokerdquo Journal of Cerebral BloodFlow and Metabolism vol 25 no 2 pp 177ndash192 2005

[19] W Schmidt M Endres F Dimeo and G J JungehulsingldquoTrain the vessel gain the brain physical activity and vesselfunction and the impact on stroke prevention and outcome incerebrovascular diseaserdquo Cerebrovascular Diseases vol 35 no4 pp 303ndash312 2013

[20] W R Frontera L Grimby and L Larsson ldquoFiring rate ofthe lower motoneuron and contractile properties of its musclefibers after upper motoneuron lesion in manrdquoMuscle amp Nervevol 20 no 8 pp 938ndash947 1997

[21] C M Cirstea C R Savage R J Nudo et al ldquoHandgrip-relatedactivation in the primary motor cortex relates to underlyingneuronal metabolism after strokerdquo Neurorehabilitation andNeural Repair vol 28 no 5 pp 433ndash442 2013

[22] C Enzinger H Johansen-Berg H Dawes et al ldquoFunctionalMRI correlates of lower limb function in stroke victims withgait impairmentrdquo Stroke vol 39 no 5 pp 1507ndash1513 2008

[23] A R Luft L Forrester R F Macko et al ldquoBrain activationof lower extremity movement in chronically impaired strokesurvivorsrdquo NeuroImage vol 26 no 1 pp 184ndash194 2005

[24] A R Luft S Waller L Forrester et al ldquoLesion locationalters brain activation in chronically impaired stroke survivorsrdquoNeuroImage vol 21 no 3 pp 924ndash935 2004

[25] N S Ward ldquoFunctional reorganization of the cerebral motorsystem after strokerdquo Current Opinion in Neurology vol 17 no6 pp 725ndash730 2004

[26] A C Zemke P J Heagerty C Lee and S C Cramer ldquoMotorcortex organization after stroke is related to side of stroke andlevel of recoveryrdquo Stroke vol 34 no 5 pp e23ndashe28 2003

[27] M Khan H Sakakima T S Dhammu et al ldquoS-nitrosoglutathione reduces oxidative injury and promotesmechanisms of neurorepair following traumatic brain injury inratsrdquo Journal of Neuroinflammation vol 8 article 78 2011

[28] H Sakakima M Khan T S Dhammu et al ldquoStimulationof functional recovery via the mechanisms of neurorepairby S-nitrosoglutathione and motor exercise in a rat modelof transient cerebral ischemia and reperfusionrdquo RestorativeNeurology and Neuroscience vol 30 no 5 pp 383ndash396 2012

[29] S Barbay E V Zoubina N Dancause et al ldquoA single injectionof D-amphetamine facilitates improvements in motor trainingfollowing a focal cortical infarct in squirrel monkeysrdquo Neurore-habilitation and Neural Repair vol 20 no 4 pp 455ndash458 2006

[30] P-C Fang S Barbay E J Plautz E Hoover S M Strittmatterand R J Nudo ldquoCombination of NEP 1-40 treatment andmotortraining enhances behavioral recovery after a focal corticalinfarct in ratsrdquo Stroke vol 41 no 3 pp 544ndash549 2010

[31] J-K Lee J-E Kim M Sivula and S M Strittmatter ldquoNogoreceptor antagonism promotes stroke recovery by enhancingaxonal plasticityrdquo The Journal of Neuroscience vol 24 no 27pp 6209ndash6217 2004

[32] J Wang X Feng Y Du L Wang and S Zhang ldquoCombinationtreatment with progesterone and rehabilitation training furtherpromotes behavioral recovery after acute ischemic stroke inmicerdquo Restorative Neurology and Neuroscience vol 31 no 4 pp487ndash499 2013

[33] B Kolb C Morshead C Gonzalez et al ldquoGrowth factor-stimulated generation of new cortical tissue and functionalrecovery after stroke damage to the motor cortex of ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 27 no 5pp 983ndash997 2007

[34] M S Jeffers A Hoyles C Morshead and D Corbett ldquoEpi-dermal growth factor and erythropoietin infusion accelerate

Neural Plasticity 9

functional recovery in combination with rehabilitationrdquo Strokevol 45 no 6 pp 1856ndash1858 2014

[35] L Gherardini M Gennaro and T Pizzorusso ldquoPerilesionaltreatment with chondroitinase ABC and motor training pro-mote functional recovery after stroke in ratsrdquo Cerebral Cortexvol 25 no 1 pp 202ndash212 2015

[36] D P Fuchs N Sanghvi J Wieser and S Schindler-IvensldquoPedaling alters the excitability and modulation of vastusmedialis H-reflexes after strokerdquo Clinical Neurophysiology vol122 no 10 pp 2036ndash2043 2011

[37] I-S Hwang C-F Lin L-C Tung and C-H Wang ldquoRespon-siveness of the H reflex to loading and posture in patientsfollowing strokerdquo Journal of Electromyography and Kinesiologyvol 14 no 6 pp 653ndash659 2004

[38] M A Oskoei and H Hu ldquoSupport vector machine-basedclassification scheme for myoelectric control applied to upperlimbrdquo IEEE Transactions on Biomedical Engineering vol 55 no8 pp 1956ndash1965 2008

[39] G L Soderberg and L M Knutson ldquoA guide for use andinterpretation of kinesiologic electromyographic datardquo PhysicalTherapy vol 80 no 5 pp 485ndash498 2000

[40] N A Riley and M Bilodeau ldquoChanges in upper limb jointtorque patterns and EMG signals with fatigue following astrokerdquoDisability andRehabilitation vol 24 no 18 pp 961ndash9692002

[41] U M Svantesson K S Sunnerhagen U S Carlsson and GGrimby ldquoDevelopment of fatigue during repeated eccentric-concentric muscle contractions of plantar flexors in patientswith strokerdquo Archives of Physical Medicine and Rehabilitationvol 80 no 10 pp 1247ndash1252 1999

[42] K N Arya S Pandian R Verma and R K Garg ldquoMovementtherapy induced neural reorganization and motor recovery instroke a reviewrdquo Journal of Bodywork andMovementTherapiesvol 15 no 4 pp 528ndash537 2011

[43] R J Nudo ldquoNeural bases of recovery after brain injuryrdquo Journalof Communication Disorders vol 44 no 5 pp 515ndash520 2011

[44] T Kawamata N E Alexis W D Dietrich and S P FinklesteinldquoIntracisternal basic fibroblast growth factor (bFGF) enhancesbehavioral recovery following focal cerebral infarction in theratrdquo Journal of Cerebral Blood Flow and Metabolism vol 16 no4 pp 542ndash547 1996

[45] T Yamaguchi M Suzuki and M Yamamoto ldquoYM796 anovel muscarinic agonist improves the impairment of learningbehavior in a rat model of chronic focal cerebral ischemiardquoBrain Research vol 669 no 1 pp 107ndash114 1995

[46] F Matsuda H Sakakima and Y Yoshida ldquoThe effects of earlyexercise on brain damage and recovery after focal cerebralinfarction in ratsrdquoActa Physiologica vol 201 no 2 pp 275ndash2872011

[47] K Mizutani S Sonoda N Hayashi et al ldquoAnalysis of proteinexpression profile in the cerebellum of cerebral infarction ratsafter treadmill trainingrdquo American Journal of Physical Medicineamp Rehabilitation vol 89 no 2 pp 107ndash114 2010

[48] P Zhang Y Zhang J Zhang et al ldquoEarly exercise protectsagainst cerebral ischemic injury through inhibiting neuronapoptosis in cortex in ratsrdquo International Journal of MolecularSciences vol 14 no 3 pp 6074ndash6089 2013

[49] L M Cupini M Diomedi F Placidi M Silvestrini and PGiacomini ldquoCerebrovascular reactivity and subcortical infarc-tionsrdquo Archives of Neurology vol 58 no 4 pp 577ndash581 2001

[50] F M Ivey A S Ryan C E Hafer-Macko and R F MacKoldquoImproved cerebral vasomotor reactivity after exercise trainingin hemiparetic stroke survivorsrdquo Stroke vol 42 no 7 pp 1994ndash2000 2011

[51] S Tian Y Zhang S Tian et al ldquoEarly exercise training improvesischemic outcome in rats by cerebral hemodynamicsrdquo BrainResearch vol 1533 pp 114ndash121 2013

[52] Y Gao Y Zhao J Pan et al ldquoTreadmill exercise promotesangiogenesis in the ischemic penumbra of rat brains throughcaveolin-1VEGF signaling pathwaysrdquo Brain Research vol 1585pp 83ndash90 2014

[53] G Kim and E Kim ldquoEffects of treadmill training on limbmotorfunction and acetylcholinesterase activity in rats with strokerdquoJournal of PhysicalTherapy Science vol 25 no 10 pp 1227ndash12302013

[54] Q Zheng D Zhu Y Bai Y Wu J Jia and Y Hu ldquoExerciseimproves recovery after ischemic brain injury by inducing theexpression of angiopoietin-1 and Tie-2 in ratsrdquo The TohokuJournal of Experimental Medicine vol 224 no 3 pp 221ndash2282011

[55] T M Hansen A J Moss and N P J Brindle ldquoVascularendothelial growth factor and angiopoietins in neurovascularregeneration and protection following strokerdquo Current Neu-rovascular Research vol 5 no 4 pp 236ndash245 2008

[56] D M Hermann and A Zechariah ldquoImplications of vascu-lar endothelial growth factor for postischemic neurovascularremodelingrdquo Journal of Cerebral Blood Flow and Metabolismvol 29 no 10 pp 1620ndash1643 2009

[57] C S Mang K L Campbell C J D Ross and L A Boyd ldquoPro-moting neuroplasticity for motor rehabilitation after strokeconsidering the effects of aerobic exercise and genetic variationon brain-derived neurotrophic factorrdquo PhysicalTherapy vol 93no 12 pp 1707ndash1716 2013

[58] M Ploughman VWindle C LMacLellan NWhite J J Doreand D Corbett ldquoBrain-derived neurotrophic factor contributesto recovery of skilled reaching after focal ischemia in ratsrdquoStroke vol 40 no 4 pp 1490ndash1495 2009

[59] I Kiprianova TM Freiman SDesiderato et al ldquoBrain-derivedneurotrophic factor prevents neuronal death and glial activa-tion after global ischemia in the ratrdquo Journal of NeuroscienceResearch vol 56 no 1 pp 21ndash27 1999

[60] R J Nudo E J Plautz and S B Frost ldquoRole of adaptiveplasticity in recovery of function after damage to motor cortexrdquoMuscle amp Nerve vol 24 no 8 pp 1000ndash1019 2001

[61] W-R Schabitz S Schwab M Spranger and W Hacke ldquoIntra-ventricular brain-derived neurotrophic factor reduces infarctsize after focal cerebral ischemia in ratsrdquo Journal of CerebralBlood Flow and Metabolism vol 17 no 5 pp 500ndash506 1997

[62] W-R Schabitz C Sommer W Zoder et al ldquoIntravenousbrain-derived neurotrophic factor reduces infarct size andcounterregulates Bax andBcl-2 expression after temporary focalcerebral ischemiardquo Stroke vol 31 no 9 pp 2212ndash2217 2000

[63] M-W Kim M-S Bang T-R Han et al ldquoExercise increasedBDNF and trkB in the contralateral hemisphere of the ischemicrat brainrdquo Brain Research vol 1052 no 1 pp 16ndash21 2005

[64] Z Kokaia Q Zhao M Kokaia et al ldquoRegulation of brain-derived neurotrophic factor gene expression after transientmiddle cerebral artery occlusion with and without brain dam-agerdquo Experimental Neurology vol 136 no 1 pp 73ndash88 1995

[65] L R Zhao B Mattsson and B B Johansson ldquoEnvironmentalinfluence on brain-derived neurotrophic factormessenger RNA

10 Neural Plasticity

expression after middle cerebral artery occlusion in sponta-neously hypertensive ratsrdquo Neuroscience vol 97 no 1 pp 177ndash184 2000

[66] H D Muller K M Hanumanthiah K Diederich S SchwabW-R Schabitz and C Sommer ldquoBrain-derived neurotrophicfactor but not forced armuse improves long-term outcome afterphotothrombotic stroke and transiently upregulates bindingdensities of excitatory glutamate receptors in the rat brainrdquoStroke vol 39 no 3 pp 1012ndash1021 2008

[67] W-R Schabitz C Berger R Kollmar et al ldquoEffect of brain-derived neurotrophic factor treatment and forced arm use onfunctional motor recovery after small cortical ischemiardquo Strokevol 35 no 4 pp 992ndash997 2004

[68] J Chen J Qin Q Su Z Liu and J Yang ldquoTreadmillrehabilitation treatment enhanced BDNF-TrkB but not NGF-TrkA signaling in a mouse intracerebral hemorrhage modelrdquoNeuroscience Letters vol 529 no 1 pp 28ndash32 2012

[69] J-Y Chung M-W Kim M-S Bang and M Kim ldquoIncreasedexpression of neurotrophin 4 following focal cerebral ischemiain adult rat brain with treadmill exerciserdquo PLoS ONE vol 8 no3 Article ID e52461 2013

[70] Z Ke S P Yip L Li X X Zheng W K Tam and K Y TongldquoThe effects of voluntary involuntary and forced exercises onmotor recovery in a stroke rat modelrdquo in Proceedings of theAnnual International Conference of the IEEE Engineering inMedicine and Biology Society (EMBC rsquo11) vol 2011 pp 8223ndash8226 Boston Mass USA August 2011

[71] P-C Shih Y-R Yang and R-Y Wang ldquoEffects of exerciseintensity on spatial memory performance and hippocampalsynaptic plasticity in transient brain ischemic ratsrdquo PLoS ONEvol 8 no 10 Article ID e78163 2013

[72] J Sun Z Ke S P Yip X-L Hu X-X Zheng and K-Y TongldquoGradually increased training intensity benefits rehabilitationoutcome after stroke by BDNF upregulation and stress sup-pressionrdquo BioMed Research International vol 2014 Article ID925762 8 pages 2014

[73] R Marin A Williams S Hale et al ldquoThe effect of voluntaryexercise exposure on histological and neurobehavioral out-comes after ischemic brain injury in the ratrdquo Physiology andBehavior vol 80 no 2-3 pp 167ndash175 2003

[74] S Vaynman Z Ying and F Gomez-Pinilla ldquoExercise inducesBDNF and synapsin I to specific hippocampal subfieldsrdquo Jour-nal of Neuroscience Research vol 76 no 3 pp 356ndash362 2004

[75] L Zhang X Hu J Luo et al ldquoPhysical exercise improves func-tional recovery through mitigation of autophagy attenuationof apoptosis and enhancement of neurogenesis after MCAO inratsrdquo BMC Neuroscience vol 14 article 46 2013

[76] J Puyal and P G H Clarke ldquoTargeting autophagy to preventneonatal stroke damagerdquoAutophagy vol 5 no 7 pp 1060ndash10612009

[77] Q-W Zhang X-X Deng X Sun J-X Xu and F-Y SunldquoExercise promotes axon regeneration of newborn striatonigraland corticonigral projection neurons in rats after ischemicstrokerdquo PLoS ONE vol 8 no 11 Article ID e80139 2013

[78] M Asahi K Asahi J-C Jung G J del ZoppoM E Fini and EH Lo ldquoRole for matrix metalloproteinase 9 after focal cerebralischemia effects of gene knockout and enzyme inhibition withBB-94rdquo Journal of Cerebral Blood Flow amp Metabolism vol 20no 12 pp 1681ndash1689 2000

[79] M Asahi X Wang T Mori et al ldquoEffects of matrixmetalloproteinase-9 gene knock-out on the proteolysis of

blood-brain barrier andwhitematter components after cerebralischemiardquoThe Journal of Neuroscience vol 21 no 19 pp 7724ndash7732 2001

[80] Y Zhang P Zhang X Shen et al ldquoEarly exercise protects theblood-brain barrier from ischemic brain injury via the regula-tion of MMP-9 and occludin in ratsrdquo International Journal ofMolecular Sciences vol 14 no 6 pp 11096ndash11112 2013

[81] I G Onyango J Lu M Rodova E Lezi A B Crafter and RH Swerdlow ldquoRegulation of neuron mitochondrial biogenesisand relevance to brain healthrdquo Biochimica et Biophysica ActamdashMolecular Basis of Disease vol 1802 no 1 pp 228ndash234 2010

[82] Q Zhang Y Wu P Zhang et al ldquoExercise induces mitochon-drial biogenesis after brain ischemia in ratsrdquo Neuroscience vol205 pp 10ndash17 2012

[83] L Li W Rong Z Ke X Hu and K-Y Tong ldquoThe effects oftraining intensities on motor recovery and gait symmetry in arat model of ischemiardquo Brain Injury vol 27 no 4 pp 408ndash4162013

[84] C Enzinger H Dawes H Johansen-Berg et al ldquoBrain activitychanges associated with treadmill training after strokerdquo Strokevol 40 no 7 pp 2460ndash2467 2009

[85] A R Luft R FMacKo LW Forrester et al ldquoTreadmill exerciseactivates subcortical neural networks and improves walkingafter stroke a randomized controlled trialrdquo Stroke vol 39 no12 pp 3341ndash3350 2008

[86] K Potempa M Lopez L T Braun J P Szidon L Fogg and TTincknell ldquoPhysiological outcomes of aerobic exercise trainingin hemiparetic stroke patientsrdquo Stroke vol 26 no 1 pp 101ndash1051995

[87] F Buma G Kwakkel and N Ramsey ldquoUnderstanding upperlimb recovery after strokerdquo Restorative Neurology and Neuro-science vol 31 no 6 pp 707ndash722 2013

[88] A E Baird A Benfield G Schlaug et al ldquoEnlargementof human cerebral ischemic lesion volumes measured bydiffusion-weighted magnetic resonance imagingrdquo Annals ofNeurology vol 41 no 5 pp 581ndash589 1997

[89] A Schmidt J Wellmann M Schilling et al ldquoMeta-analysis ofthe efficacy of different training strategies in animal models ofischemic strokerdquo Stroke vol 45 no 1 pp 239ndash247 2014

[90] R-Y Wang S-M Yu and Y-R Yang ldquoTreadmill trainingeffects in different age groups following middle cerebral arteryocclusion in ratsrdquo Gerontology vol 51 no 3 pp 161ndash165 2005

[91] P ZhangH YuN Zhou et al ldquoEarly exercise improves cerebralblood flow through increased angiogenesis in experimentalstroke rat modelrdquo Journal of NeuroEngineering and Rehabilita-tion vol 10 article 43 2013

[92] J Laurin andC Pin-Barre ldquoPhysiological adaptations followingendurance exercises after stroke focus on the plausible roleof high-intensity interval trainingrdquo International Journal ofPhysical Medicine amp Rehabilitation vol 2 no 3 pp 1ndash6 2014

[93] THMurphy andDCorbett ldquoPlasticity during stroke recoveryfrom synapse to behaviourrdquo Nature Reviews Neuroscience vol10 no 12 pp 861ndash872 2009

[94] M Svensson J Lexell and T Deierborg ldquoEffects of physicalexercise on neuroinflammation neuroplasticity neurodegener-ation and behavior what we can learn from animal models inclinical settingsrdquoNeurorehabilitation and Neural Repair vol 29no 6 pp 577ndash589 2015

[95] A Risedal J Zeng and B B Johansson ldquoEarly training mayexacerbate brain damage after focal brain ischemia in the ratrdquoJournal of Cerebral Blood Flow andMetabolism vol 19 no 9 pp997ndash1003 1999

Neural Plasticity 11

[96] C-S Piao B A Stoica J Wu et al ldquoLate exercise reducesneuroinflammation and cognitive dysfunction after traumaticbrain injuryrdquoNeurobiology of Disease vol 54 pp 252ndash263 2013

[97] J L Humm D A Kozlowski S T Bland D C James andT Schallert ldquoUse-dependent exaggeration of brain injury isglutamate involvedrdquo Experimental Neurology vol 157 no 2 pp349ndash358 1999

[98] G S Griesbach F Gomez-Pinilla and D A Hovda ldquoTheupregulation of plasticity-related proteins following TBI isdisrupted with acute voluntary exerciserdquo Brain Research vol1016 no 2 pp 154ndash162 2004

[99] J WMcAlees L T Smith R S Erbe D Jarjoura N M Ponzioand V M Sanders ldquoEpigenetic regulation of beta2-adrenergicreceptor expression in T

1198671 and T

1198672 cellsrdquo Brain Behavior and

Immunity vol 25 no 3 pp 408ndash415 2011[100] G Zhao S Zhou A Davie and Q Su ldquoEffects of moderate and

high intensity exercise on T1T2 balancerdquo Exercise ImmunologyReview vol 18 pp 98ndash114 2012

[101] Y Yagita K Kitagawa T Sasaki et al ldquoPostischemic exercisedecreases neurogenesis in the adult rat dentate gyrusrdquo Neuro-science Letters vol 409 no 1 pp 24ndash29 2006

[102] S T Bland T Schallert R Strong J Aronowski and J CGrottaldquoEarly exclusive use of the affected forelimb aftermoderate tran-sient focal ischemia in rats functional and anatomic outcomerdquoStroke vol 31 no 5 pp 1144ndash1152 2000

[103] S B DeBow J E McKenna B Kolb and F ColbourneldquoImmediate constraint-inducedmovement therapy causes localhyperthermia that exacerbates cerebral cortical injury in ratsrdquoCanadian Journal of Physiology and Pharmacology vol 82 no4 pp 231ndash237 2004

[104] D A Kozlowski D C James and T Schallert ldquoUse-dependentexaggeration of neuronal injury after unilateral sensorimotorcortex lesionsrdquo The Journal of Neuroscience vol 16 no 15 pp4776ndash4786 1996

[105] B Balaban F Tok F Yavuz E Yasar and R Alaca ldquoEarlyrehabilitation outcome in patients with middle cerebral arterystrokerdquo Neuroscience Letters vol 498 no 3 pp 204ndash207 2011

[106] G Kwakkel R van Peppen R C Wagenaar et al ldquoEffects ofaugmented exercise therapy time after stroke a meta-analysisrdquoStroke vol 35 no 11 pp 2529ndash2539 2004

[107] D L Costill M G Flynn J P Kirwan et al ldquoEffects of repeateddays of intensified training on muscle glycogen and swimmingperformancerdquo Medicine amp Science in Sports amp Exercise vol 20no 3 pp 249ndash254 1988

[108] M A Hirsch and B G Farley ldquoExercise and neuroplasticityin persons living with Parkinsonrsquos diseaserdquo European Journal ofPhysical and Rehabilitation Medicine vol 45 no 2 pp 215ndash2292009

[109] M Katz-Leurer M Shochina E Carmeli and Y FriedlanderldquoThe influence of early aerobic training on the functional capac-ity in patients with cerebrovascular accident at the subacutestagerdquo Archives of Physical Medicine and Rehabilitation vol 84no 11 pp 1609ndash1614 2003

[110] J D Schaechter ldquoMotor rehabilitation and brain plasticity afterhemiparetic strokerdquo Progress in Neurobiology vol 73 no 1 pp61ndash72 2004

[111] P R Bosch S Holzapfel and T Traustadottir ldquoFeasibility ofmeasuring ventilatory threshold in adults with stroke-inducedhemiparesis implications for exercise prescriptionrdquo Archives ofPhysical Medicine and Rehabilitation 2015

[112] D P Stirling K Khodarahmi J Liu et al ldquoMinocyclinetreatment reduces delayed oligodendrocyte death attenuatesaxonal dieback and improves functional outcome after spinalcord injuryrdquoThe Journal of Neuroscience vol 24 no 9 pp 2182ndash2190 2004

[113] S Barbay and R J Nudo ldquoThe effects of amphetamine onrecovery of function in animal models of cerebral injury acritical appraisalrdquo NeuroRehabilitation vol 25 no 1 pp 5ndash172009

[114] R S Rasmussen K Overgaard E S Hildebrandt-Eriksen andG Boysen ldquoD-Amphetamine improves cognitive deficits andphysical therapy promotes fine motor rehabilitation in a ratembolic stroke modelrdquo Acta Neurologica Scandinavica vol 113no 3 pp 189ndash198 2006

[115] C L Gibson B Coomber and S P Murphy ldquoProgesterone isneuroprotective following cerebral ischaemia in reproductivelyageing female micerdquo Brain vol 134 no 7 pp 2125ndash2133 2011

[116] T Ishrat I Sayeed F Atif and D G Stein ldquoEffects ofprogesterone administration on infarct volume and functionaldeficits following permanent focal cerebral ischemia in ratsrdquoBrain Research vol 1257 pp 94ndash101 2009

[117] M Prencipe C Ferretti A R Casini M Santini F Giubileiand F Culasso ldquoStroke disability and dementia results of apopulation surveyrdquo Stroke vol 28 no 3 pp 531ndash536 1997

[118] I Sayeed B Wali and D G Stein ldquoProgesterone inhibitsischemic brain injury in a rat model of permanent middle cere-bral artery occlusionrdquo Restorative Neurology and Neurosciencevol 25 no 2 pp 151ndash159 2007

[119] H Lee R J McKeon and R V Bellamkonda ldquoSustaineddelivery of thermostabilized chABC enhances axonal sproutingand functional recovery after spinal cord injuryrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 8 pp 3340ndash3345 2010

[120] V J Tom R Kadakia L Santi and J D Houle ldquoAdministrationof chondroitinase ABC rostral or caudal to a spinal cord injurysite promotes anatomical but not functional plasticityrdquo Journalof Neurotrauma vol 26 no 12 pp 2323ndash2333 2009

[121] J J Hill K Jin X O Mao L Xie and D A GreenbergldquoIntracerebral chondroitinase ABC and heparan sulfate proteo-glycan glypican improve outcome from chronic stroke in ratsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 23 pp 9155ndash9160 2012

[122] S Soleman P K Yip D A Duricki and L D FMoon ldquoDelayedtreatment with chondroitinase ABC promotes sensorimotorrecovery and plasticity after stroke in aged ratsrdquo Brain vol 135no 4 pp 1210ndash1223 2012

[123] B E Skolnick A I Maas R K Narayan et al ldquoA clinical trialof progesterone for severe traumatic brain injuryrdquo The NewEngland Journal of Medicine vol 371 no 26 pp 2467ndash24762014

[124] DWWright SD Yeatts R Silbergleit et al ldquoVery early admin-istration of progesterone for acute traumatic brain injuryrdquo TheNew England Journal of Medicine vol 371 no 26 pp 2457ndash2466 2014

[125] L-H Krarup T Truelsen C Gluud et al ldquoPrestroke physicalactivity is associated with severity and long-term outcome fromfirst-ever strokerdquo Neurology vol 71 no 17 pp 1313ndash1318 2008

[126] P M Rist I-M Lee C S Kase J Michael Gaziano and TKurth ldquoPhysical activity and functional outcomes from cerebralvascular events in menrdquo Stroke vol 42 no 12 pp 3352ndash33562011

12 Neural Plasticity

[127] Q Zhang L Zhang X Yang Y Wan and J Jia ldquoThe effectsof exercise preconditioning on cerebral blood flow change andendothelin-1 expression after cerebral ischemia in ratsrdquo Journalof Stroke and Cerebrovascular Diseases vol 23 no 6 pp 1696ndash1702 2014

[128] M Bernaudin A-S Nedelec D Divoux E T MacKenzie EPetit and P Schumann-Bard ldquoNormobaric hypoxia inducestolerance to focal permanent cerebral ischemia in associationwith an increased expression of hypoxia-inducible factor-1 andits target genes erythropoietin and VEGF in the adult mousebrainrdquo Journal of Cerebral Blood Flow and Metabolism vol 22no 4 pp 393ndash403 2002

[129] D Dornbos III N Zwagerman M Guo et al ldquoPreischemicexercise reduces brain damage by ameliorating metabolic dis-order in ischemiareperfusion injuryrdquo Journal of NeuroscienceResearch vol 91 no 6 pp 818ndash827 2013

[130] Y-H Ding Y Ding J Li D A Bessert and J A RafolsldquoExercise pre-conditioning strengthens brain microvascularintegrity in a rat stroke modelrdquo Neurological Research vol 28no 2 pp 184ndash189 2006

[131] M Guo B Cox S Mahale et al ldquoPre-ischemic exercise reducesmatrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in strokerdquo Neuroscience vol 151 no2 pp 340ndash351 2008

[132] M Ploughman Z Attwood N White J J E Dore and DCorbett ldquoEndurance exercise facilitates relearning of forelimbmotor skill after focal ischemiardquo The European Journal ofNeuroscience vol 25 no 11 pp 3453ndash3460 2007

[133] L L Guyot F G Diaz M H OrsquoRegan S McLeod H Park andJW Phillis ldquoReal-timemeasurement of glutamate release fromthe ischemic penumbra of the rat cerebral cortex using a focalmiddle cerebral artery occlusion modelrdquo Neuroscience Lettersvol 299 no 1-2 pp 37ndash40 2001

[134] K Matsumoto R Graf G Rosner J Taguchi and W-D HeissldquoElevation of neuroactive substances in the cortex of cats duringprolonged focal ischemiardquo Journal of Cerebral Blood Flow andMetabolism vol 13 no 4 pp 586ndash594 1993

[135] J Jia Y-S Hu Y Wu et al ldquoPre-ischemic treadmill trainingaffects glutamate and gamma aminobutyric acid levels in thestriatal dialysate of a rat model of cerebral ischemiardquo LifeSciences vol 84 no 15-16 pp 505ndash511 2009

[136] F Zhang J Jia Y Wu Y Hu and Y Wang ldquoThe effect of tread-mill training pre-exercise on glutamate receptor expression inrats after cerebral ischemiardquo International Journal of MolecularSciences vol 11 no 7 pp 2658ndash2669 2010

[137] J Jia Y-S Hu Y Wu et al ldquoTreadmill pre-training suppressesthe release of glutamate resulting from cerebral ischemia inratsrdquo Experimental Brain Research vol 204 no 2 pp 173ndash1792010

[138] E T Ang P T H Wong S Moochhala and Y K NgldquoNeuroprotection associated with running is it a result ofincreased endogenous neurotrophic factorsrdquoNeuroscience vol118 no 2 pp 335ndash345 2003

[139] A C Ricciardi E Lopez-Cancio N Perez De La Ossa et alldquoPrestroke physical activity is associated with good functionaloutcome and arterial recanalization after stroke due to a largevessel occlusionrdquo Cerebrovascular Diseases vol 37 no 4 pp304ndash311 2014

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Psychiatry Journal

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

6 Neural Plasticity

Table 1 Influence of pharmacological agents associated with physical exercise on motor recovery after brain stroke

Drug agents Targets Results References

Indomethacin Minocycline Inflammatory processes

infarct volume (indomethacin only) sensorimotor performance

microglia astroglia

[10]

GSNOOxidative stress

Inflammatory processesExcitotoxicity

infarct volume apoptotic cell death neurological score motor recovery

and survival rate CBF synaptic plasticity and BBB

leakage TNF-120572 IL-1120573 and iNOS

[18 27 28]

D-Amphetamine Noradrenergic 1205721-receptor agonist motor recovery [29]

NEP 1-40 Nogo-A protein inhibitor early motor recovery axonal growth [30]

NgR(310)Ecto-Fc Nogo-NgR pathwayinhibitor

motor recovery axonal plasticity [31]

Progesterone ExcitotoxicityInflammatory processes

infarct volume forelimbs strength and motor recovery [32]

EGFlowast and EPOlowast Neuron proliferation migrationand differentiation accelerated fine motor recovery [33 34]

Chondroitinase ABC Chondroitin sulphate proteoglycans(CSPGs)

CSPGs synaptic plasticitymotor recovery

[35]

indicates an increase and a decrease respectively NEP 1-40 NOGO extracellular peptide EGF epidermal growth factor EPO erythropoietin GSNOS-nitrosoglutathione CBF cerebral blood flow BDNF brain developed neurotrophic factor trkB tropomyosin receptor kinase B BBB blood brain barrierlowastMolecules combination

targeting excitotoxicity Although this combination had noadditional effect in reducing infarct volume functional recov-ery effectiveness was promoted as shown by the increasedrotarod performance and forelimb grip strength at all timepoints within 7 days after ischemic stroke [32]

In addition some authors indicated that combination oftwo pharmacological treatments could improve functionalrecovery and neural plasticity compared to either treatmentalone For example association of epidermal growth fac-tor (EGF) and erythropoietin (EPO) treatments is moreeffective in promoting tissue regeneration and proliferationof neural precursor cells than monotherapy [33] Howeveran even greater improvement in skilled reaching ability inthe staircase test was observed when physical rehabilitationwas added to serial application of both EGF and EPO[34] Authors have also indicated that fine motor skillimprovement was observed 10 weeks after functional reha-bilitation alone whereas 4-week-long treatment combinationwas sufficient to improve sensorimotor function It meansthat functional recovery is also clearly accelerated with thiscombination

Another strategy consists of recreating a tissue environ-ment free from growth inhibiting molecules Chondroiti-nase ABC which degrades inhibitory chondroitin sulphateproteoglycans present in the extracellular matrix reducesthe neurite-inhibitory environment and facilitates axonalsprouting and sensorimotor recovery after spinal cord injury[119 120] and after cerebral ischemia [121 122]This treatmentwas applied at the ipsilesional cortex in rats in combinationwith functional rehabilitation Synaptic plasticity assessed by

measuring the expression of glutamate vesicular transporter(vGLUT1 and vGLUT2) and the GABA vesicular transporter(vGAT) and functional recovery were promoted by thesynergic effect of these treatments [35]

Given that some promising treatments developed inpreclinical studies failed to be effective in clinical studies[123 124] it seems crucial to assess the pharmacologicaleffectiveness in stroke patients before combining it withphysical exerciseTherefore we need to keep inmind that notall the effective combinations found in animal studies couldbe considered effective for human Nevertheless assessingboth treatments and exercise in rodentmodels seems relevantto found new therapeutic strategies to highlight the mosteffective and applicable strategies for human

6 Influence of Prestroke Physical Activity onMotor Dysfunction Severity

To avoid administration of several pharmacological sub-stances in individuals with high risks of stroke (may inducedeleterious interaction between drugs and complications dueto their side effects) physical activity might be a major alter-native preventive strategy for reducing the brain secondaryinjury when stroke occurs Several recent human and animalstudies have well demonstrated that preischemic physicalactivity may reduce initial stroke severity on functionalmotor outcomes edema and infarct volume by acting oninflammation vascular processes BDNF expression andmetabolic disorders [14 16 17 125 126]

Neural Plasticity 7

Ischemia-induced brain inflammation is believed toplay a pivotal role in the development of secondary braininjury by intensifying the inflammatory cell accumulationandmicrovascular impairments Indeed adhesionmoleculessuch as intercellular adhesion molecule 1 (ICAM-1) pro-mote leukocyte infiltration into injury site and leukocyteadhesion to microvascular endothelium Preischemic phys-ical training-induced neuroprotection was associated with adecrease in ICAM-1 mRNA expression and in the number ofICAM-1-positive vessels [17] Consequently leukocyte accu-mulation in damaged cortex and striatum vessels decreasedresulting in reduction of brain inflammation during reperfu-sion

Brain angiogenesis is another neuroprotective mecha-nism for reducing the detrimental motor effect of cere-bral ischemia Physical training prior to cerebral ischemiaincreased short- and long-term effects onmicrovascular den-sity and cerebral blood flow by promoting angiogenesis andincreasing cerebral vasomotor reactivity It was found thatpreischemic exercise improved vasorelaxation by enhancingVEGF levels into the ischemic region which is knownto activate eNOS and EPCs recruitment [8 19] Likewiseexercise decreased the endothelin-1 (a powerful vasocon-strictor agent) expression thereby reducing the impact ofvasoconstriction on cerebral blood flow [127]

Preischemic training could also attenuate brain dam-age by limiting metabolic disorders after cerebral ischemiaIndeed 51015840AMP-activated protein kinase (AMPK) phos-phofructokinase-1 (PFK) and hypoxia-induced factor-1120572(HIF-1120572) involved in glycolysis [18 128] were significantlyhigher in preischemic trained rats [129] Moreover theincrease of glucose transporters in neurons and endothelialcells of the BBB (GLUT3 and GLUT1 resp) results inan improved glucose oxidation immediately after cerebralischemia allowing a faster and more substantial increase inATP production

Moreover it was postulated that preischemic exercise(30min on a treadmill 5 daysweek for 3 weeks) decreasesBBB dysfunctions and thus reduces infarct volume andedema as confirmed by the MMP-9 expression decrement[130 131] Preischemic treadmill training-induced neuro-protection in ischemic rats increased endogenous BDNFexpression that leads to motor recovery improvement [1617 67 132] Interestingly the preischemic treadmill exer-cise improved the therapeutic effectiveness of postischemictreadmill training onmotor function compared with animalsperforming it only after cerebral ischemia [53]

Neuronal excitotoxicity induced by excessive glutamaterelease is a major deleterious event of the brain secondaryinjury [133 134] It was found that preischemic treadmilltraining could also reduce the expression of glutamate recep-tors mGluR5 and NR2B reflecting a decrease of glutamateeffect on surrounding cells [135ndash137] Moreover it was pos-tulated that the reduction of infarct volume induced by 12weeks of treadmill might be related to increase of NGFexpression and this receptor p75 known to promote neu-roprotection against excitotoxicity and free-radical damage[138]

Individuals who were physically active prior to strokehave been shown to exhibit less deleterious functional out-comes as indicated by higher Barthel Index scores as wellas Oxford Handicap Scale [14 15] Indeed it was recentlyrevealed that patients with high levels of prestroke physicalactivity were associated with milder stroke severity at admis-sion with faster early motor improvement and with a lowerfinal infarct volume [139] Interestingly it seems that simplywalking 1 hday during 5 days per week or doing a vigorousaerobic activity 1 hday twice a week is sufficient to inducepreventive effects However findings remain conflicting inhuman studies because no strong association between higherlevels of physical activity and better functional outcomes afterstroke was found in a large prospective cohort [126]

7 Conclusion

Although acute exercise appears to be useful for better under-standing neural andmotor recoverymechanisms few studieshave used this experimental model to investigate strokephysiopathology Neural adaptations remain thus unclearFurthermore physical training appears to be promising toimprove functional motor recovery by promoting neuro-plasticity at different cellular and molecular levels Thesebeneficial effects seem accelerated andor accentuated whenexercise is combined with an additional pharmacologicaltreatment Nevertheless optimal parameters of training andtreatment need to be investigated to maximizeaccelerateneuroplasticity and motor recovery and avoid undesirableeffects of exercise All these findings could help researchersand therapists to justify the effectiveness of their physicaltraining programs in order to increase the patient willingnessto regularly perform physical activity before and after stroke

Conflict of Interests

Each author of the present review declared no conflict ofinterests

Acknowledgment

The authors are grateful to Dr Vincent Pertici for commentson earlier version of this paper

References

[1] E Broussalis M Killer M McCoy A Harrer E Trinkaand J Kraus ldquoCurrent therapies in ischemic stroke Part ARecent developments in acute stroke treatment and in strokepreventionrdquoDrug Discovery Today vol 17 no 7-8 pp 296ndash3092012

[2] F M Ivey R F Macko A S Ryan and C E Hafer-MackoldquoCardiovascular health and fitness after strokerdquo Topics in StrokeRehabilitation vol 12 no 1 pp 1ndash16 2005

[3] D LMarsden A Dunn R Callister C R Levi andN J SprattldquoCharacteristics of exercise training interventions to improvecardiorespiratory fitness after stroke a systematic review withmeta-analysisrdquo Neurorehabilitation and Neural Repair vol 27no 9 pp 775ndash788 2013

8 Neural Plasticity

[4] L Li W Rong Z Ke X Hu S P Yip and K Y Tong ldquoMuscleactivation changes during body weight support treadmill train-ing after focal cortical ischemia a rat hindlimb modelrdquo Journalof Electromyography and Kinesiology vol 21 no 2 pp 318ndash3262011

[5] C Pin-Barre J Laurin M-S Felix et al ldquoAcute neuromuscularadaptation at the spinal level following middle cerebral arteryocclusion-reperfusion in the ratrdquoPLoSONE vol 9 no 2 ArticleID e89953 2014

[6] L W Forrester D F Hanley and R F Macko ldquoEffectsof treadmill exercise on transcranial magnetic stimulation-induced excitability to quadriceps after strokerdquo Archives ofPhysical Medicine and Rehabilitation vol 87 no 2 pp 229ndash2342006

[7] R FMacko FM Ivey LW Forrester et al ldquoTreadmill exerciserehabilitation improves ambulatory function and cardiovas-cular fitness in patients with chronic stroke a randomizedcontrolled trialrdquo Stroke vol 36 no 10 pp 2206ndash2211 2005

[8] M Endres K Gertz U Lindauer et al ldquoMechanisms of strokeprotection by physical activityrdquoAnnals of Neurology vol 54 no5 pp 582ndash590 2003

[9] K Gertz J Priller G Kronenberg et al ldquoPhysical activityimproves long-term stroke outcome via endothelial nitric oxidesynthase-dependent augmentation of neovascularization andcerebral blood flowrdquo Circulation Research vol 99 no 10 pp1132ndash1140 2006

[10] S Liebigt N Schlegel J Oberland O W Witte C Redeckerand S Keiner ldquoEffects of rehabilitative training and anti-inflammatory treatment on functional recovery and cellularreorganization following strokerdquo Experimental Neurology vol233 no 2 pp 776ndash782 2012

[11] W-R Schabitz T Steigleder C M Cooper-Kuhn et al ldquoIntra-venous brain-derived neurotrophic factor enhances poststrokesensorimotor recovery and stimulates neurogenesisrdquo Strokevol 38 no 7 pp 2165ndash2172 2007

[12] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[13] I-M Lee C H Hennekens K Berger J E Buring and J EManson ldquoExercise and risk of stroke inmale physiciansrdquo Strokevol 30 no 1 pp 1ndash6 1999

[14] D Deplanque I Masse C Lefebvre C Libersa D Leys andR Bordet ldquoPrior TIA lipid-lowering drug use and physicalactivity decrease ischemic stroke severityrdquo Neurology vol 67no 8 pp 1403ndash1410 2006

[15] N Stroud T M L Mazwi L D Case et al ldquoPrestroke physicalactivity and early functional status after strokerdquo Journal ofNeurology Neurosurgery and Psychiatry vol 80 no 9 pp 1019ndash1022 2009

[16] Y Ding J Li X Luan et al ldquoExercise pre-conditioningreduces brain damage in ischemic rats that may be associatedwith regional angiogenesis and cellular overexpression of neu-rotrophinrdquo Neuroscience vol 124 no 3 pp 583ndash591 2004

[17] Y-H Ding C N Young X Luan et al ldquoExercise precondi-tioning ameliorates inflammatory injury in ischemic rats duringreperfusionrdquoActaNeuropathologica vol 109 no 3 pp 237ndash2462005

[18] MKhan B Sekhon S Giri et al ldquoS-Nitrosoglutathione reducesinflammation and protects brain against focal cerebral ischemiain a rat model of experimental strokerdquo Journal of Cerebral BloodFlow and Metabolism vol 25 no 2 pp 177ndash192 2005

[19] W Schmidt M Endres F Dimeo and G J JungehulsingldquoTrain the vessel gain the brain physical activity and vesselfunction and the impact on stroke prevention and outcome incerebrovascular diseaserdquo Cerebrovascular Diseases vol 35 no4 pp 303ndash312 2013

[20] W R Frontera L Grimby and L Larsson ldquoFiring rate ofthe lower motoneuron and contractile properties of its musclefibers after upper motoneuron lesion in manrdquoMuscle amp Nervevol 20 no 8 pp 938ndash947 1997

[21] C M Cirstea C R Savage R J Nudo et al ldquoHandgrip-relatedactivation in the primary motor cortex relates to underlyingneuronal metabolism after strokerdquo Neurorehabilitation andNeural Repair vol 28 no 5 pp 433ndash442 2013

[22] C Enzinger H Johansen-Berg H Dawes et al ldquoFunctionalMRI correlates of lower limb function in stroke victims withgait impairmentrdquo Stroke vol 39 no 5 pp 1507ndash1513 2008

[23] A R Luft L Forrester R F Macko et al ldquoBrain activationof lower extremity movement in chronically impaired strokesurvivorsrdquo NeuroImage vol 26 no 1 pp 184ndash194 2005

[24] A R Luft S Waller L Forrester et al ldquoLesion locationalters brain activation in chronically impaired stroke survivorsrdquoNeuroImage vol 21 no 3 pp 924ndash935 2004

[25] N S Ward ldquoFunctional reorganization of the cerebral motorsystem after strokerdquo Current Opinion in Neurology vol 17 no6 pp 725ndash730 2004

[26] A C Zemke P J Heagerty C Lee and S C Cramer ldquoMotorcortex organization after stroke is related to side of stroke andlevel of recoveryrdquo Stroke vol 34 no 5 pp e23ndashe28 2003

[27] M Khan H Sakakima T S Dhammu et al ldquoS-nitrosoglutathione reduces oxidative injury and promotesmechanisms of neurorepair following traumatic brain injury inratsrdquo Journal of Neuroinflammation vol 8 article 78 2011

[28] H Sakakima M Khan T S Dhammu et al ldquoStimulationof functional recovery via the mechanisms of neurorepairby S-nitrosoglutathione and motor exercise in a rat modelof transient cerebral ischemia and reperfusionrdquo RestorativeNeurology and Neuroscience vol 30 no 5 pp 383ndash396 2012

[29] S Barbay E V Zoubina N Dancause et al ldquoA single injectionof D-amphetamine facilitates improvements in motor trainingfollowing a focal cortical infarct in squirrel monkeysrdquo Neurore-habilitation and Neural Repair vol 20 no 4 pp 455ndash458 2006

[30] P-C Fang S Barbay E J Plautz E Hoover S M Strittmatterand R J Nudo ldquoCombination of NEP 1-40 treatment andmotortraining enhances behavioral recovery after a focal corticalinfarct in ratsrdquo Stroke vol 41 no 3 pp 544ndash549 2010

[31] J-K Lee J-E Kim M Sivula and S M Strittmatter ldquoNogoreceptor antagonism promotes stroke recovery by enhancingaxonal plasticityrdquo The Journal of Neuroscience vol 24 no 27pp 6209ndash6217 2004

[32] J Wang X Feng Y Du L Wang and S Zhang ldquoCombinationtreatment with progesterone and rehabilitation training furtherpromotes behavioral recovery after acute ischemic stroke inmicerdquo Restorative Neurology and Neuroscience vol 31 no 4 pp487ndash499 2013

[33] B Kolb C Morshead C Gonzalez et al ldquoGrowth factor-stimulated generation of new cortical tissue and functionalrecovery after stroke damage to the motor cortex of ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 27 no 5pp 983ndash997 2007

[34] M S Jeffers A Hoyles C Morshead and D Corbett ldquoEpi-dermal growth factor and erythropoietin infusion accelerate

Neural Plasticity 9

functional recovery in combination with rehabilitationrdquo Strokevol 45 no 6 pp 1856ndash1858 2014

[35] L Gherardini M Gennaro and T Pizzorusso ldquoPerilesionaltreatment with chondroitinase ABC and motor training pro-mote functional recovery after stroke in ratsrdquo Cerebral Cortexvol 25 no 1 pp 202ndash212 2015

[36] D P Fuchs N Sanghvi J Wieser and S Schindler-IvensldquoPedaling alters the excitability and modulation of vastusmedialis H-reflexes after strokerdquo Clinical Neurophysiology vol122 no 10 pp 2036ndash2043 2011

[37] I-S Hwang C-F Lin L-C Tung and C-H Wang ldquoRespon-siveness of the H reflex to loading and posture in patientsfollowing strokerdquo Journal of Electromyography and Kinesiologyvol 14 no 6 pp 653ndash659 2004

[38] M A Oskoei and H Hu ldquoSupport vector machine-basedclassification scheme for myoelectric control applied to upperlimbrdquo IEEE Transactions on Biomedical Engineering vol 55 no8 pp 1956ndash1965 2008

[39] G L Soderberg and L M Knutson ldquoA guide for use andinterpretation of kinesiologic electromyographic datardquo PhysicalTherapy vol 80 no 5 pp 485ndash498 2000

[40] N A Riley and M Bilodeau ldquoChanges in upper limb jointtorque patterns and EMG signals with fatigue following astrokerdquoDisability andRehabilitation vol 24 no 18 pp 961ndash9692002

[41] U M Svantesson K S Sunnerhagen U S Carlsson and GGrimby ldquoDevelopment of fatigue during repeated eccentric-concentric muscle contractions of plantar flexors in patientswith strokerdquo Archives of Physical Medicine and Rehabilitationvol 80 no 10 pp 1247ndash1252 1999

[42] K N Arya S Pandian R Verma and R K Garg ldquoMovementtherapy induced neural reorganization and motor recovery instroke a reviewrdquo Journal of Bodywork andMovementTherapiesvol 15 no 4 pp 528ndash537 2011

[43] R J Nudo ldquoNeural bases of recovery after brain injuryrdquo Journalof Communication Disorders vol 44 no 5 pp 515ndash520 2011

[44] T Kawamata N E Alexis W D Dietrich and S P FinklesteinldquoIntracisternal basic fibroblast growth factor (bFGF) enhancesbehavioral recovery following focal cerebral infarction in theratrdquo Journal of Cerebral Blood Flow and Metabolism vol 16 no4 pp 542ndash547 1996

[45] T Yamaguchi M Suzuki and M Yamamoto ldquoYM796 anovel muscarinic agonist improves the impairment of learningbehavior in a rat model of chronic focal cerebral ischemiardquoBrain Research vol 669 no 1 pp 107ndash114 1995

[46] F Matsuda H Sakakima and Y Yoshida ldquoThe effects of earlyexercise on brain damage and recovery after focal cerebralinfarction in ratsrdquoActa Physiologica vol 201 no 2 pp 275ndash2872011

[47] K Mizutani S Sonoda N Hayashi et al ldquoAnalysis of proteinexpression profile in the cerebellum of cerebral infarction ratsafter treadmill trainingrdquo American Journal of Physical Medicineamp Rehabilitation vol 89 no 2 pp 107ndash114 2010

[48] P Zhang Y Zhang J Zhang et al ldquoEarly exercise protectsagainst cerebral ischemic injury through inhibiting neuronapoptosis in cortex in ratsrdquo International Journal of MolecularSciences vol 14 no 3 pp 6074ndash6089 2013

[49] L M Cupini M Diomedi F Placidi M Silvestrini and PGiacomini ldquoCerebrovascular reactivity and subcortical infarc-tionsrdquo Archives of Neurology vol 58 no 4 pp 577ndash581 2001

[50] F M Ivey A S Ryan C E Hafer-Macko and R F MacKoldquoImproved cerebral vasomotor reactivity after exercise trainingin hemiparetic stroke survivorsrdquo Stroke vol 42 no 7 pp 1994ndash2000 2011

[51] S Tian Y Zhang S Tian et al ldquoEarly exercise training improvesischemic outcome in rats by cerebral hemodynamicsrdquo BrainResearch vol 1533 pp 114ndash121 2013

[52] Y Gao Y Zhao J Pan et al ldquoTreadmill exercise promotesangiogenesis in the ischemic penumbra of rat brains throughcaveolin-1VEGF signaling pathwaysrdquo Brain Research vol 1585pp 83ndash90 2014

[53] G Kim and E Kim ldquoEffects of treadmill training on limbmotorfunction and acetylcholinesterase activity in rats with strokerdquoJournal of PhysicalTherapy Science vol 25 no 10 pp 1227ndash12302013

[54] Q Zheng D Zhu Y Bai Y Wu J Jia and Y Hu ldquoExerciseimproves recovery after ischemic brain injury by inducing theexpression of angiopoietin-1 and Tie-2 in ratsrdquo The TohokuJournal of Experimental Medicine vol 224 no 3 pp 221ndash2282011

[55] T M Hansen A J Moss and N P J Brindle ldquoVascularendothelial growth factor and angiopoietins in neurovascularregeneration and protection following strokerdquo Current Neu-rovascular Research vol 5 no 4 pp 236ndash245 2008

[56] D M Hermann and A Zechariah ldquoImplications of vascu-lar endothelial growth factor for postischemic neurovascularremodelingrdquo Journal of Cerebral Blood Flow and Metabolismvol 29 no 10 pp 1620ndash1643 2009

[57] C S Mang K L Campbell C J D Ross and L A Boyd ldquoPro-moting neuroplasticity for motor rehabilitation after strokeconsidering the effects of aerobic exercise and genetic variationon brain-derived neurotrophic factorrdquo PhysicalTherapy vol 93no 12 pp 1707ndash1716 2013

[58] M Ploughman VWindle C LMacLellan NWhite J J Doreand D Corbett ldquoBrain-derived neurotrophic factor contributesto recovery of skilled reaching after focal ischemia in ratsrdquoStroke vol 40 no 4 pp 1490ndash1495 2009

[59] I Kiprianova TM Freiman SDesiderato et al ldquoBrain-derivedneurotrophic factor prevents neuronal death and glial activa-tion after global ischemia in the ratrdquo Journal of NeuroscienceResearch vol 56 no 1 pp 21ndash27 1999

[60] R J Nudo E J Plautz and S B Frost ldquoRole of adaptiveplasticity in recovery of function after damage to motor cortexrdquoMuscle amp Nerve vol 24 no 8 pp 1000ndash1019 2001

[61] W-R Schabitz S Schwab M Spranger and W Hacke ldquoIntra-ventricular brain-derived neurotrophic factor reduces infarctsize after focal cerebral ischemia in ratsrdquo Journal of CerebralBlood Flow and Metabolism vol 17 no 5 pp 500ndash506 1997

[62] W-R Schabitz C Sommer W Zoder et al ldquoIntravenousbrain-derived neurotrophic factor reduces infarct size andcounterregulates Bax andBcl-2 expression after temporary focalcerebral ischemiardquo Stroke vol 31 no 9 pp 2212ndash2217 2000

[63] M-W Kim M-S Bang T-R Han et al ldquoExercise increasedBDNF and trkB in the contralateral hemisphere of the ischemicrat brainrdquo Brain Research vol 1052 no 1 pp 16ndash21 2005

[64] Z Kokaia Q Zhao M Kokaia et al ldquoRegulation of brain-derived neurotrophic factor gene expression after transientmiddle cerebral artery occlusion with and without brain dam-agerdquo Experimental Neurology vol 136 no 1 pp 73ndash88 1995

[65] L R Zhao B Mattsson and B B Johansson ldquoEnvironmentalinfluence on brain-derived neurotrophic factormessenger RNA

10 Neural Plasticity

expression after middle cerebral artery occlusion in sponta-neously hypertensive ratsrdquo Neuroscience vol 97 no 1 pp 177ndash184 2000

[66] H D Muller K M Hanumanthiah K Diederich S SchwabW-R Schabitz and C Sommer ldquoBrain-derived neurotrophicfactor but not forced armuse improves long-term outcome afterphotothrombotic stroke and transiently upregulates bindingdensities of excitatory glutamate receptors in the rat brainrdquoStroke vol 39 no 3 pp 1012ndash1021 2008

[67] W-R Schabitz C Berger R Kollmar et al ldquoEffect of brain-derived neurotrophic factor treatment and forced arm use onfunctional motor recovery after small cortical ischemiardquo Strokevol 35 no 4 pp 992ndash997 2004

[68] J Chen J Qin Q Su Z Liu and J Yang ldquoTreadmillrehabilitation treatment enhanced BDNF-TrkB but not NGF-TrkA signaling in a mouse intracerebral hemorrhage modelrdquoNeuroscience Letters vol 529 no 1 pp 28ndash32 2012

[69] J-Y Chung M-W Kim M-S Bang and M Kim ldquoIncreasedexpression of neurotrophin 4 following focal cerebral ischemiain adult rat brain with treadmill exerciserdquo PLoS ONE vol 8 no3 Article ID e52461 2013

[70] Z Ke S P Yip L Li X X Zheng W K Tam and K Y TongldquoThe effects of voluntary involuntary and forced exercises onmotor recovery in a stroke rat modelrdquo in Proceedings of theAnnual International Conference of the IEEE Engineering inMedicine and Biology Society (EMBC rsquo11) vol 2011 pp 8223ndash8226 Boston Mass USA August 2011

[71] P-C Shih Y-R Yang and R-Y Wang ldquoEffects of exerciseintensity on spatial memory performance and hippocampalsynaptic plasticity in transient brain ischemic ratsrdquo PLoS ONEvol 8 no 10 Article ID e78163 2013

[72] J Sun Z Ke S P Yip X-L Hu X-X Zheng and K-Y TongldquoGradually increased training intensity benefits rehabilitationoutcome after stroke by BDNF upregulation and stress sup-pressionrdquo BioMed Research International vol 2014 Article ID925762 8 pages 2014

[73] R Marin A Williams S Hale et al ldquoThe effect of voluntaryexercise exposure on histological and neurobehavioral out-comes after ischemic brain injury in the ratrdquo Physiology andBehavior vol 80 no 2-3 pp 167ndash175 2003

[74] S Vaynman Z Ying and F Gomez-Pinilla ldquoExercise inducesBDNF and synapsin I to specific hippocampal subfieldsrdquo Jour-nal of Neuroscience Research vol 76 no 3 pp 356ndash362 2004

[75] L Zhang X Hu J Luo et al ldquoPhysical exercise improves func-tional recovery through mitigation of autophagy attenuationof apoptosis and enhancement of neurogenesis after MCAO inratsrdquo BMC Neuroscience vol 14 article 46 2013

[76] J Puyal and P G H Clarke ldquoTargeting autophagy to preventneonatal stroke damagerdquoAutophagy vol 5 no 7 pp 1060ndash10612009

[77] Q-W Zhang X-X Deng X Sun J-X Xu and F-Y SunldquoExercise promotes axon regeneration of newborn striatonigraland corticonigral projection neurons in rats after ischemicstrokerdquo PLoS ONE vol 8 no 11 Article ID e80139 2013

[78] M Asahi K Asahi J-C Jung G J del ZoppoM E Fini and EH Lo ldquoRole for matrix metalloproteinase 9 after focal cerebralischemia effects of gene knockout and enzyme inhibition withBB-94rdquo Journal of Cerebral Blood Flow amp Metabolism vol 20no 12 pp 1681ndash1689 2000

[79] M Asahi X Wang T Mori et al ldquoEffects of matrixmetalloproteinase-9 gene knock-out on the proteolysis of

blood-brain barrier andwhitematter components after cerebralischemiardquoThe Journal of Neuroscience vol 21 no 19 pp 7724ndash7732 2001

[80] Y Zhang P Zhang X Shen et al ldquoEarly exercise protects theblood-brain barrier from ischemic brain injury via the regula-tion of MMP-9 and occludin in ratsrdquo International Journal ofMolecular Sciences vol 14 no 6 pp 11096ndash11112 2013

[81] I G Onyango J Lu M Rodova E Lezi A B Crafter and RH Swerdlow ldquoRegulation of neuron mitochondrial biogenesisand relevance to brain healthrdquo Biochimica et Biophysica ActamdashMolecular Basis of Disease vol 1802 no 1 pp 228ndash234 2010

[82] Q Zhang Y Wu P Zhang et al ldquoExercise induces mitochon-drial biogenesis after brain ischemia in ratsrdquo Neuroscience vol205 pp 10ndash17 2012

[83] L Li W Rong Z Ke X Hu and K-Y Tong ldquoThe effects oftraining intensities on motor recovery and gait symmetry in arat model of ischemiardquo Brain Injury vol 27 no 4 pp 408ndash4162013

[84] C Enzinger H Dawes H Johansen-Berg et al ldquoBrain activitychanges associated with treadmill training after strokerdquo Strokevol 40 no 7 pp 2460ndash2467 2009

[85] A R Luft R FMacKo LW Forrester et al ldquoTreadmill exerciseactivates subcortical neural networks and improves walkingafter stroke a randomized controlled trialrdquo Stroke vol 39 no12 pp 3341ndash3350 2008

[86] K Potempa M Lopez L T Braun J P Szidon L Fogg and TTincknell ldquoPhysiological outcomes of aerobic exercise trainingin hemiparetic stroke patientsrdquo Stroke vol 26 no 1 pp 101ndash1051995

[87] F Buma G Kwakkel and N Ramsey ldquoUnderstanding upperlimb recovery after strokerdquo Restorative Neurology and Neuro-science vol 31 no 6 pp 707ndash722 2013

[88] A E Baird A Benfield G Schlaug et al ldquoEnlargementof human cerebral ischemic lesion volumes measured bydiffusion-weighted magnetic resonance imagingrdquo Annals ofNeurology vol 41 no 5 pp 581ndash589 1997

[89] A Schmidt J Wellmann M Schilling et al ldquoMeta-analysis ofthe efficacy of different training strategies in animal models ofischemic strokerdquo Stroke vol 45 no 1 pp 239ndash247 2014

[90] R-Y Wang S-M Yu and Y-R Yang ldquoTreadmill trainingeffects in different age groups following middle cerebral arteryocclusion in ratsrdquo Gerontology vol 51 no 3 pp 161ndash165 2005

[91] P ZhangH YuN Zhou et al ldquoEarly exercise improves cerebralblood flow through increased angiogenesis in experimentalstroke rat modelrdquo Journal of NeuroEngineering and Rehabilita-tion vol 10 article 43 2013

[92] J Laurin andC Pin-Barre ldquoPhysiological adaptations followingendurance exercises after stroke focus on the plausible roleof high-intensity interval trainingrdquo International Journal ofPhysical Medicine amp Rehabilitation vol 2 no 3 pp 1ndash6 2014

[93] THMurphy andDCorbett ldquoPlasticity during stroke recoveryfrom synapse to behaviourrdquo Nature Reviews Neuroscience vol10 no 12 pp 861ndash872 2009

[94] M Svensson J Lexell and T Deierborg ldquoEffects of physicalexercise on neuroinflammation neuroplasticity neurodegener-ation and behavior what we can learn from animal models inclinical settingsrdquoNeurorehabilitation and Neural Repair vol 29no 6 pp 577ndash589 2015

[95] A Risedal J Zeng and B B Johansson ldquoEarly training mayexacerbate brain damage after focal brain ischemia in the ratrdquoJournal of Cerebral Blood Flow andMetabolism vol 19 no 9 pp997ndash1003 1999

Neural Plasticity 11

[96] C-S Piao B A Stoica J Wu et al ldquoLate exercise reducesneuroinflammation and cognitive dysfunction after traumaticbrain injuryrdquoNeurobiology of Disease vol 54 pp 252ndash263 2013

[97] J L Humm D A Kozlowski S T Bland D C James andT Schallert ldquoUse-dependent exaggeration of brain injury isglutamate involvedrdquo Experimental Neurology vol 157 no 2 pp349ndash358 1999

[98] G S Griesbach F Gomez-Pinilla and D A Hovda ldquoTheupregulation of plasticity-related proteins following TBI isdisrupted with acute voluntary exerciserdquo Brain Research vol1016 no 2 pp 154ndash162 2004

[99] J WMcAlees L T Smith R S Erbe D Jarjoura N M Ponzioand V M Sanders ldquoEpigenetic regulation of beta2-adrenergicreceptor expression in T

1198671 and T

1198672 cellsrdquo Brain Behavior and

Immunity vol 25 no 3 pp 408ndash415 2011[100] G Zhao S Zhou A Davie and Q Su ldquoEffects of moderate and

high intensity exercise on T1T2 balancerdquo Exercise ImmunologyReview vol 18 pp 98ndash114 2012

[101] Y Yagita K Kitagawa T Sasaki et al ldquoPostischemic exercisedecreases neurogenesis in the adult rat dentate gyrusrdquo Neuro-science Letters vol 409 no 1 pp 24ndash29 2006

[102] S T Bland T Schallert R Strong J Aronowski and J CGrottaldquoEarly exclusive use of the affected forelimb aftermoderate tran-sient focal ischemia in rats functional and anatomic outcomerdquoStroke vol 31 no 5 pp 1144ndash1152 2000

[103] S B DeBow J E McKenna B Kolb and F ColbourneldquoImmediate constraint-inducedmovement therapy causes localhyperthermia that exacerbates cerebral cortical injury in ratsrdquoCanadian Journal of Physiology and Pharmacology vol 82 no4 pp 231ndash237 2004

[104] D A Kozlowski D C James and T Schallert ldquoUse-dependentexaggeration of neuronal injury after unilateral sensorimotorcortex lesionsrdquo The Journal of Neuroscience vol 16 no 15 pp4776ndash4786 1996

[105] B Balaban F Tok F Yavuz E Yasar and R Alaca ldquoEarlyrehabilitation outcome in patients with middle cerebral arterystrokerdquo Neuroscience Letters vol 498 no 3 pp 204ndash207 2011

[106] G Kwakkel R van Peppen R C Wagenaar et al ldquoEffects ofaugmented exercise therapy time after stroke a meta-analysisrdquoStroke vol 35 no 11 pp 2529ndash2539 2004

[107] D L Costill M G Flynn J P Kirwan et al ldquoEffects of repeateddays of intensified training on muscle glycogen and swimmingperformancerdquo Medicine amp Science in Sports amp Exercise vol 20no 3 pp 249ndash254 1988

[108] M A Hirsch and B G Farley ldquoExercise and neuroplasticityin persons living with Parkinsonrsquos diseaserdquo European Journal ofPhysical and Rehabilitation Medicine vol 45 no 2 pp 215ndash2292009

[109] M Katz-Leurer M Shochina E Carmeli and Y FriedlanderldquoThe influence of early aerobic training on the functional capac-ity in patients with cerebrovascular accident at the subacutestagerdquo Archives of Physical Medicine and Rehabilitation vol 84no 11 pp 1609ndash1614 2003

[110] J D Schaechter ldquoMotor rehabilitation and brain plasticity afterhemiparetic strokerdquo Progress in Neurobiology vol 73 no 1 pp61ndash72 2004

[111] P R Bosch S Holzapfel and T Traustadottir ldquoFeasibility ofmeasuring ventilatory threshold in adults with stroke-inducedhemiparesis implications for exercise prescriptionrdquo Archives ofPhysical Medicine and Rehabilitation 2015

[112] D P Stirling K Khodarahmi J Liu et al ldquoMinocyclinetreatment reduces delayed oligodendrocyte death attenuatesaxonal dieback and improves functional outcome after spinalcord injuryrdquoThe Journal of Neuroscience vol 24 no 9 pp 2182ndash2190 2004

[113] S Barbay and R J Nudo ldquoThe effects of amphetamine onrecovery of function in animal models of cerebral injury acritical appraisalrdquo NeuroRehabilitation vol 25 no 1 pp 5ndash172009

[114] R S Rasmussen K Overgaard E S Hildebrandt-Eriksen andG Boysen ldquoD-Amphetamine improves cognitive deficits andphysical therapy promotes fine motor rehabilitation in a ratembolic stroke modelrdquo Acta Neurologica Scandinavica vol 113no 3 pp 189ndash198 2006

[115] C L Gibson B Coomber and S P Murphy ldquoProgesterone isneuroprotective following cerebral ischaemia in reproductivelyageing female micerdquo Brain vol 134 no 7 pp 2125ndash2133 2011

[116] T Ishrat I Sayeed F Atif and D G Stein ldquoEffects ofprogesterone administration on infarct volume and functionaldeficits following permanent focal cerebral ischemia in ratsrdquoBrain Research vol 1257 pp 94ndash101 2009

[117] M Prencipe C Ferretti A R Casini M Santini F Giubileiand F Culasso ldquoStroke disability and dementia results of apopulation surveyrdquo Stroke vol 28 no 3 pp 531ndash536 1997

[118] I Sayeed B Wali and D G Stein ldquoProgesterone inhibitsischemic brain injury in a rat model of permanent middle cere-bral artery occlusionrdquo Restorative Neurology and Neurosciencevol 25 no 2 pp 151ndash159 2007

[119] H Lee R J McKeon and R V Bellamkonda ldquoSustaineddelivery of thermostabilized chABC enhances axonal sproutingand functional recovery after spinal cord injuryrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 8 pp 3340ndash3345 2010

[120] V J Tom R Kadakia L Santi and J D Houle ldquoAdministrationof chondroitinase ABC rostral or caudal to a spinal cord injurysite promotes anatomical but not functional plasticityrdquo Journalof Neurotrauma vol 26 no 12 pp 2323ndash2333 2009

[121] J J Hill K Jin X O Mao L Xie and D A GreenbergldquoIntracerebral chondroitinase ABC and heparan sulfate proteo-glycan glypican improve outcome from chronic stroke in ratsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 23 pp 9155ndash9160 2012

[122] S Soleman P K Yip D A Duricki and L D FMoon ldquoDelayedtreatment with chondroitinase ABC promotes sensorimotorrecovery and plasticity after stroke in aged ratsrdquo Brain vol 135no 4 pp 1210ndash1223 2012

[123] B E Skolnick A I Maas R K Narayan et al ldquoA clinical trialof progesterone for severe traumatic brain injuryrdquo The NewEngland Journal of Medicine vol 371 no 26 pp 2467ndash24762014

[124] DWWright SD Yeatts R Silbergleit et al ldquoVery early admin-istration of progesterone for acute traumatic brain injuryrdquo TheNew England Journal of Medicine vol 371 no 26 pp 2457ndash2466 2014

[125] L-H Krarup T Truelsen C Gluud et al ldquoPrestroke physicalactivity is associated with severity and long-term outcome fromfirst-ever strokerdquo Neurology vol 71 no 17 pp 1313ndash1318 2008

[126] P M Rist I-M Lee C S Kase J Michael Gaziano and TKurth ldquoPhysical activity and functional outcomes from cerebralvascular events in menrdquo Stroke vol 42 no 12 pp 3352ndash33562011

12 Neural Plasticity

[127] Q Zhang L Zhang X Yang Y Wan and J Jia ldquoThe effectsof exercise preconditioning on cerebral blood flow change andendothelin-1 expression after cerebral ischemia in ratsrdquo Journalof Stroke and Cerebrovascular Diseases vol 23 no 6 pp 1696ndash1702 2014

[128] M Bernaudin A-S Nedelec D Divoux E T MacKenzie EPetit and P Schumann-Bard ldquoNormobaric hypoxia inducestolerance to focal permanent cerebral ischemia in associationwith an increased expression of hypoxia-inducible factor-1 andits target genes erythropoietin and VEGF in the adult mousebrainrdquo Journal of Cerebral Blood Flow and Metabolism vol 22no 4 pp 393ndash403 2002

[129] D Dornbos III N Zwagerman M Guo et al ldquoPreischemicexercise reduces brain damage by ameliorating metabolic dis-order in ischemiareperfusion injuryrdquo Journal of NeuroscienceResearch vol 91 no 6 pp 818ndash827 2013

[130] Y-H Ding Y Ding J Li D A Bessert and J A RafolsldquoExercise pre-conditioning strengthens brain microvascularintegrity in a rat stroke modelrdquo Neurological Research vol 28no 2 pp 184ndash189 2006

[131] M Guo B Cox S Mahale et al ldquoPre-ischemic exercise reducesmatrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in strokerdquo Neuroscience vol 151 no2 pp 340ndash351 2008

[132] M Ploughman Z Attwood N White J J E Dore and DCorbett ldquoEndurance exercise facilitates relearning of forelimbmotor skill after focal ischemiardquo The European Journal ofNeuroscience vol 25 no 11 pp 3453ndash3460 2007

[133] L L Guyot F G Diaz M H OrsquoRegan S McLeod H Park andJW Phillis ldquoReal-timemeasurement of glutamate release fromthe ischemic penumbra of the rat cerebral cortex using a focalmiddle cerebral artery occlusion modelrdquo Neuroscience Lettersvol 299 no 1-2 pp 37ndash40 2001

[134] K Matsumoto R Graf G Rosner J Taguchi and W-D HeissldquoElevation of neuroactive substances in the cortex of cats duringprolonged focal ischemiardquo Journal of Cerebral Blood Flow andMetabolism vol 13 no 4 pp 586ndash594 1993

[135] J Jia Y-S Hu Y Wu et al ldquoPre-ischemic treadmill trainingaffects glutamate and gamma aminobutyric acid levels in thestriatal dialysate of a rat model of cerebral ischemiardquo LifeSciences vol 84 no 15-16 pp 505ndash511 2009

[136] F Zhang J Jia Y Wu Y Hu and Y Wang ldquoThe effect of tread-mill training pre-exercise on glutamate receptor expression inrats after cerebral ischemiardquo International Journal of MolecularSciences vol 11 no 7 pp 2658ndash2669 2010

[137] J Jia Y-S Hu Y Wu et al ldquoTreadmill pre-training suppressesthe release of glutamate resulting from cerebral ischemia inratsrdquo Experimental Brain Research vol 204 no 2 pp 173ndash1792010

[138] E T Ang P T H Wong S Moochhala and Y K NgldquoNeuroprotection associated with running is it a result ofincreased endogenous neurotrophic factorsrdquoNeuroscience vol118 no 2 pp 335ndash345 2003

[139] A C Ricciardi E Lopez-Cancio N Perez De La Ossa et alldquoPrestroke physical activity is associated with good functionaloutcome and arterial recanalization after stroke due to a largevessel occlusionrdquo Cerebrovascular Diseases vol 37 no 4 pp304ndash311 2014

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Psychiatry Journal

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity 7

Ischemia-induced brain inflammation is believed toplay a pivotal role in the development of secondary braininjury by intensifying the inflammatory cell accumulationandmicrovascular impairments Indeed adhesionmoleculessuch as intercellular adhesion molecule 1 (ICAM-1) pro-mote leukocyte infiltration into injury site and leukocyteadhesion to microvascular endothelium Preischemic phys-ical training-induced neuroprotection was associated with adecrease in ICAM-1 mRNA expression and in the number ofICAM-1-positive vessels [17] Consequently leukocyte accu-mulation in damaged cortex and striatum vessels decreasedresulting in reduction of brain inflammation during reperfu-sion

Brain angiogenesis is another neuroprotective mecha-nism for reducing the detrimental motor effect of cere-bral ischemia Physical training prior to cerebral ischemiaincreased short- and long-term effects onmicrovascular den-sity and cerebral blood flow by promoting angiogenesis andincreasing cerebral vasomotor reactivity It was found thatpreischemic exercise improved vasorelaxation by enhancingVEGF levels into the ischemic region which is knownto activate eNOS and EPCs recruitment [8 19] Likewiseexercise decreased the endothelin-1 (a powerful vasocon-strictor agent) expression thereby reducing the impact ofvasoconstriction on cerebral blood flow [127]

Preischemic training could also attenuate brain dam-age by limiting metabolic disorders after cerebral ischemiaIndeed 51015840AMP-activated protein kinase (AMPK) phos-phofructokinase-1 (PFK) and hypoxia-induced factor-1120572(HIF-1120572) involved in glycolysis [18 128] were significantlyhigher in preischemic trained rats [129] Moreover theincrease of glucose transporters in neurons and endothelialcells of the BBB (GLUT3 and GLUT1 resp) results inan improved glucose oxidation immediately after cerebralischemia allowing a faster and more substantial increase inATP production

Moreover it was postulated that preischemic exercise(30min on a treadmill 5 daysweek for 3 weeks) decreasesBBB dysfunctions and thus reduces infarct volume andedema as confirmed by the MMP-9 expression decrement[130 131] Preischemic treadmill training-induced neuro-protection in ischemic rats increased endogenous BDNFexpression that leads to motor recovery improvement [1617 67 132] Interestingly the preischemic treadmill exer-cise improved the therapeutic effectiveness of postischemictreadmill training onmotor function compared with animalsperforming it only after cerebral ischemia [53]

Neuronal excitotoxicity induced by excessive glutamaterelease is a major deleterious event of the brain secondaryinjury [133 134] It was found that preischemic treadmilltraining could also reduce the expression of glutamate recep-tors mGluR5 and NR2B reflecting a decrease of glutamateeffect on surrounding cells [135ndash137] Moreover it was pos-tulated that the reduction of infarct volume induced by 12weeks of treadmill might be related to increase of NGFexpression and this receptor p75 known to promote neu-roprotection against excitotoxicity and free-radical damage[138]

Individuals who were physically active prior to strokehave been shown to exhibit less deleterious functional out-comes as indicated by higher Barthel Index scores as wellas Oxford Handicap Scale [14 15] Indeed it was recentlyrevealed that patients with high levels of prestroke physicalactivity were associated with milder stroke severity at admis-sion with faster early motor improvement and with a lowerfinal infarct volume [139] Interestingly it seems that simplywalking 1 hday during 5 days per week or doing a vigorousaerobic activity 1 hday twice a week is sufficient to inducepreventive effects However findings remain conflicting inhuman studies because no strong association between higherlevels of physical activity and better functional outcomes afterstroke was found in a large prospective cohort [126]

7 Conclusion

Although acute exercise appears to be useful for better under-standing neural andmotor recoverymechanisms few studieshave used this experimental model to investigate strokephysiopathology Neural adaptations remain thus unclearFurthermore physical training appears to be promising toimprove functional motor recovery by promoting neuro-plasticity at different cellular and molecular levels Thesebeneficial effects seem accelerated andor accentuated whenexercise is combined with an additional pharmacologicaltreatment Nevertheless optimal parameters of training andtreatment need to be investigated to maximizeaccelerateneuroplasticity and motor recovery and avoid undesirableeffects of exercise All these findings could help researchersand therapists to justify the effectiveness of their physicaltraining programs in order to increase the patient willingnessto regularly perform physical activity before and after stroke

Conflict of Interests

Each author of the present review declared no conflict ofinterests

Acknowledgment

The authors are grateful to Dr Vincent Pertici for commentson earlier version of this paper

References

[1] E Broussalis M Killer M McCoy A Harrer E Trinkaand J Kraus ldquoCurrent therapies in ischemic stroke Part ARecent developments in acute stroke treatment and in strokepreventionrdquoDrug Discovery Today vol 17 no 7-8 pp 296ndash3092012

[2] F M Ivey R F Macko A S Ryan and C E Hafer-MackoldquoCardiovascular health and fitness after strokerdquo Topics in StrokeRehabilitation vol 12 no 1 pp 1ndash16 2005

[3] D LMarsden A Dunn R Callister C R Levi andN J SprattldquoCharacteristics of exercise training interventions to improvecardiorespiratory fitness after stroke a systematic review withmeta-analysisrdquo Neurorehabilitation and Neural Repair vol 27no 9 pp 775ndash788 2013

8 Neural Plasticity

[4] L Li W Rong Z Ke X Hu S P Yip and K Y Tong ldquoMuscleactivation changes during body weight support treadmill train-ing after focal cortical ischemia a rat hindlimb modelrdquo Journalof Electromyography and Kinesiology vol 21 no 2 pp 318ndash3262011

[5] C Pin-Barre J Laurin M-S Felix et al ldquoAcute neuromuscularadaptation at the spinal level following middle cerebral arteryocclusion-reperfusion in the ratrdquoPLoSONE vol 9 no 2 ArticleID e89953 2014

[6] L W Forrester D F Hanley and R F Macko ldquoEffectsof treadmill exercise on transcranial magnetic stimulation-induced excitability to quadriceps after strokerdquo Archives ofPhysical Medicine and Rehabilitation vol 87 no 2 pp 229ndash2342006

[7] R FMacko FM Ivey LW Forrester et al ldquoTreadmill exerciserehabilitation improves ambulatory function and cardiovas-cular fitness in patients with chronic stroke a randomizedcontrolled trialrdquo Stroke vol 36 no 10 pp 2206ndash2211 2005

[8] M Endres K Gertz U Lindauer et al ldquoMechanisms of strokeprotection by physical activityrdquoAnnals of Neurology vol 54 no5 pp 582ndash590 2003

[9] K Gertz J Priller G Kronenberg et al ldquoPhysical activityimproves long-term stroke outcome via endothelial nitric oxidesynthase-dependent augmentation of neovascularization andcerebral blood flowrdquo Circulation Research vol 99 no 10 pp1132ndash1140 2006

[10] S Liebigt N Schlegel J Oberland O W Witte C Redeckerand S Keiner ldquoEffects of rehabilitative training and anti-inflammatory treatment on functional recovery and cellularreorganization following strokerdquo Experimental Neurology vol233 no 2 pp 776ndash782 2012

[11] W-R Schabitz T Steigleder C M Cooper-Kuhn et al ldquoIntra-venous brain-derived neurotrophic factor enhances poststrokesensorimotor recovery and stimulates neurogenesisrdquo Strokevol 38 no 7 pp 2165ndash2172 2007

[12] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[13] I-M Lee C H Hennekens K Berger J E Buring and J EManson ldquoExercise and risk of stroke inmale physiciansrdquo Strokevol 30 no 1 pp 1ndash6 1999

[14] D Deplanque I Masse C Lefebvre C Libersa D Leys andR Bordet ldquoPrior TIA lipid-lowering drug use and physicalactivity decrease ischemic stroke severityrdquo Neurology vol 67no 8 pp 1403ndash1410 2006

[15] N Stroud T M L Mazwi L D Case et al ldquoPrestroke physicalactivity and early functional status after strokerdquo Journal ofNeurology Neurosurgery and Psychiatry vol 80 no 9 pp 1019ndash1022 2009

[16] Y Ding J Li X Luan et al ldquoExercise pre-conditioningreduces brain damage in ischemic rats that may be associatedwith regional angiogenesis and cellular overexpression of neu-rotrophinrdquo Neuroscience vol 124 no 3 pp 583ndash591 2004

[17] Y-H Ding C N Young X Luan et al ldquoExercise precondi-tioning ameliorates inflammatory injury in ischemic rats duringreperfusionrdquoActaNeuropathologica vol 109 no 3 pp 237ndash2462005

[18] MKhan B Sekhon S Giri et al ldquoS-Nitrosoglutathione reducesinflammation and protects brain against focal cerebral ischemiain a rat model of experimental strokerdquo Journal of Cerebral BloodFlow and Metabolism vol 25 no 2 pp 177ndash192 2005

[19] W Schmidt M Endres F Dimeo and G J JungehulsingldquoTrain the vessel gain the brain physical activity and vesselfunction and the impact on stroke prevention and outcome incerebrovascular diseaserdquo Cerebrovascular Diseases vol 35 no4 pp 303ndash312 2013

[20] W R Frontera L Grimby and L Larsson ldquoFiring rate ofthe lower motoneuron and contractile properties of its musclefibers after upper motoneuron lesion in manrdquoMuscle amp Nervevol 20 no 8 pp 938ndash947 1997

[21] C M Cirstea C R Savage R J Nudo et al ldquoHandgrip-relatedactivation in the primary motor cortex relates to underlyingneuronal metabolism after strokerdquo Neurorehabilitation andNeural Repair vol 28 no 5 pp 433ndash442 2013

[22] C Enzinger H Johansen-Berg H Dawes et al ldquoFunctionalMRI correlates of lower limb function in stroke victims withgait impairmentrdquo Stroke vol 39 no 5 pp 1507ndash1513 2008

[23] A R Luft L Forrester R F Macko et al ldquoBrain activationof lower extremity movement in chronically impaired strokesurvivorsrdquo NeuroImage vol 26 no 1 pp 184ndash194 2005

[24] A R Luft S Waller L Forrester et al ldquoLesion locationalters brain activation in chronically impaired stroke survivorsrdquoNeuroImage vol 21 no 3 pp 924ndash935 2004

[25] N S Ward ldquoFunctional reorganization of the cerebral motorsystem after strokerdquo Current Opinion in Neurology vol 17 no6 pp 725ndash730 2004

[26] A C Zemke P J Heagerty C Lee and S C Cramer ldquoMotorcortex organization after stroke is related to side of stroke andlevel of recoveryrdquo Stroke vol 34 no 5 pp e23ndashe28 2003

[27] M Khan H Sakakima T S Dhammu et al ldquoS-nitrosoglutathione reduces oxidative injury and promotesmechanisms of neurorepair following traumatic brain injury inratsrdquo Journal of Neuroinflammation vol 8 article 78 2011

[28] H Sakakima M Khan T S Dhammu et al ldquoStimulationof functional recovery via the mechanisms of neurorepairby S-nitrosoglutathione and motor exercise in a rat modelof transient cerebral ischemia and reperfusionrdquo RestorativeNeurology and Neuroscience vol 30 no 5 pp 383ndash396 2012

[29] S Barbay E V Zoubina N Dancause et al ldquoA single injectionof D-amphetamine facilitates improvements in motor trainingfollowing a focal cortical infarct in squirrel monkeysrdquo Neurore-habilitation and Neural Repair vol 20 no 4 pp 455ndash458 2006

[30] P-C Fang S Barbay E J Plautz E Hoover S M Strittmatterand R J Nudo ldquoCombination of NEP 1-40 treatment andmotortraining enhances behavioral recovery after a focal corticalinfarct in ratsrdquo Stroke vol 41 no 3 pp 544ndash549 2010

[31] J-K Lee J-E Kim M Sivula and S M Strittmatter ldquoNogoreceptor antagonism promotes stroke recovery by enhancingaxonal plasticityrdquo The Journal of Neuroscience vol 24 no 27pp 6209ndash6217 2004

[32] J Wang X Feng Y Du L Wang and S Zhang ldquoCombinationtreatment with progesterone and rehabilitation training furtherpromotes behavioral recovery after acute ischemic stroke inmicerdquo Restorative Neurology and Neuroscience vol 31 no 4 pp487ndash499 2013

[33] B Kolb C Morshead C Gonzalez et al ldquoGrowth factor-stimulated generation of new cortical tissue and functionalrecovery after stroke damage to the motor cortex of ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 27 no 5pp 983ndash997 2007

[34] M S Jeffers A Hoyles C Morshead and D Corbett ldquoEpi-dermal growth factor and erythropoietin infusion accelerate

Neural Plasticity 9

functional recovery in combination with rehabilitationrdquo Strokevol 45 no 6 pp 1856ndash1858 2014

[35] L Gherardini M Gennaro and T Pizzorusso ldquoPerilesionaltreatment with chondroitinase ABC and motor training pro-mote functional recovery after stroke in ratsrdquo Cerebral Cortexvol 25 no 1 pp 202ndash212 2015

[36] D P Fuchs N Sanghvi J Wieser and S Schindler-IvensldquoPedaling alters the excitability and modulation of vastusmedialis H-reflexes after strokerdquo Clinical Neurophysiology vol122 no 10 pp 2036ndash2043 2011

[37] I-S Hwang C-F Lin L-C Tung and C-H Wang ldquoRespon-siveness of the H reflex to loading and posture in patientsfollowing strokerdquo Journal of Electromyography and Kinesiologyvol 14 no 6 pp 653ndash659 2004

[38] M A Oskoei and H Hu ldquoSupport vector machine-basedclassification scheme for myoelectric control applied to upperlimbrdquo IEEE Transactions on Biomedical Engineering vol 55 no8 pp 1956ndash1965 2008

[39] G L Soderberg and L M Knutson ldquoA guide for use andinterpretation of kinesiologic electromyographic datardquo PhysicalTherapy vol 80 no 5 pp 485ndash498 2000

[40] N A Riley and M Bilodeau ldquoChanges in upper limb jointtorque patterns and EMG signals with fatigue following astrokerdquoDisability andRehabilitation vol 24 no 18 pp 961ndash9692002

[41] U M Svantesson K S Sunnerhagen U S Carlsson and GGrimby ldquoDevelopment of fatigue during repeated eccentric-concentric muscle contractions of plantar flexors in patientswith strokerdquo Archives of Physical Medicine and Rehabilitationvol 80 no 10 pp 1247ndash1252 1999

[42] K N Arya S Pandian R Verma and R K Garg ldquoMovementtherapy induced neural reorganization and motor recovery instroke a reviewrdquo Journal of Bodywork andMovementTherapiesvol 15 no 4 pp 528ndash537 2011

[43] R J Nudo ldquoNeural bases of recovery after brain injuryrdquo Journalof Communication Disorders vol 44 no 5 pp 515ndash520 2011

[44] T Kawamata N E Alexis W D Dietrich and S P FinklesteinldquoIntracisternal basic fibroblast growth factor (bFGF) enhancesbehavioral recovery following focal cerebral infarction in theratrdquo Journal of Cerebral Blood Flow and Metabolism vol 16 no4 pp 542ndash547 1996

[45] T Yamaguchi M Suzuki and M Yamamoto ldquoYM796 anovel muscarinic agonist improves the impairment of learningbehavior in a rat model of chronic focal cerebral ischemiardquoBrain Research vol 669 no 1 pp 107ndash114 1995

[46] F Matsuda H Sakakima and Y Yoshida ldquoThe effects of earlyexercise on brain damage and recovery after focal cerebralinfarction in ratsrdquoActa Physiologica vol 201 no 2 pp 275ndash2872011

[47] K Mizutani S Sonoda N Hayashi et al ldquoAnalysis of proteinexpression profile in the cerebellum of cerebral infarction ratsafter treadmill trainingrdquo American Journal of Physical Medicineamp Rehabilitation vol 89 no 2 pp 107ndash114 2010

[48] P Zhang Y Zhang J Zhang et al ldquoEarly exercise protectsagainst cerebral ischemic injury through inhibiting neuronapoptosis in cortex in ratsrdquo International Journal of MolecularSciences vol 14 no 3 pp 6074ndash6089 2013

[49] L M Cupini M Diomedi F Placidi M Silvestrini and PGiacomini ldquoCerebrovascular reactivity and subcortical infarc-tionsrdquo Archives of Neurology vol 58 no 4 pp 577ndash581 2001

[50] F M Ivey A S Ryan C E Hafer-Macko and R F MacKoldquoImproved cerebral vasomotor reactivity after exercise trainingin hemiparetic stroke survivorsrdquo Stroke vol 42 no 7 pp 1994ndash2000 2011

[51] S Tian Y Zhang S Tian et al ldquoEarly exercise training improvesischemic outcome in rats by cerebral hemodynamicsrdquo BrainResearch vol 1533 pp 114ndash121 2013

[52] Y Gao Y Zhao J Pan et al ldquoTreadmill exercise promotesangiogenesis in the ischemic penumbra of rat brains throughcaveolin-1VEGF signaling pathwaysrdquo Brain Research vol 1585pp 83ndash90 2014

[53] G Kim and E Kim ldquoEffects of treadmill training on limbmotorfunction and acetylcholinesterase activity in rats with strokerdquoJournal of PhysicalTherapy Science vol 25 no 10 pp 1227ndash12302013

[54] Q Zheng D Zhu Y Bai Y Wu J Jia and Y Hu ldquoExerciseimproves recovery after ischemic brain injury by inducing theexpression of angiopoietin-1 and Tie-2 in ratsrdquo The TohokuJournal of Experimental Medicine vol 224 no 3 pp 221ndash2282011

[55] T M Hansen A J Moss and N P J Brindle ldquoVascularendothelial growth factor and angiopoietins in neurovascularregeneration and protection following strokerdquo Current Neu-rovascular Research vol 5 no 4 pp 236ndash245 2008

[56] D M Hermann and A Zechariah ldquoImplications of vascu-lar endothelial growth factor for postischemic neurovascularremodelingrdquo Journal of Cerebral Blood Flow and Metabolismvol 29 no 10 pp 1620ndash1643 2009

[57] C S Mang K L Campbell C J D Ross and L A Boyd ldquoPro-moting neuroplasticity for motor rehabilitation after strokeconsidering the effects of aerobic exercise and genetic variationon brain-derived neurotrophic factorrdquo PhysicalTherapy vol 93no 12 pp 1707ndash1716 2013

[58] M Ploughman VWindle C LMacLellan NWhite J J Doreand D Corbett ldquoBrain-derived neurotrophic factor contributesto recovery of skilled reaching after focal ischemia in ratsrdquoStroke vol 40 no 4 pp 1490ndash1495 2009

[59] I Kiprianova TM Freiman SDesiderato et al ldquoBrain-derivedneurotrophic factor prevents neuronal death and glial activa-tion after global ischemia in the ratrdquo Journal of NeuroscienceResearch vol 56 no 1 pp 21ndash27 1999

[60] R J Nudo E J Plautz and S B Frost ldquoRole of adaptiveplasticity in recovery of function after damage to motor cortexrdquoMuscle amp Nerve vol 24 no 8 pp 1000ndash1019 2001

[61] W-R Schabitz S Schwab M Spranger and W Hacke ldquoIntra-ventricular brain-derived neurotrophic factor reduces infarctsize after focal cerebral ischemia in ratsrdquo Journal of CerebralBlood Flow and Metabolism vol 17 no 5 pp 500ndash506 1997

[62] W-R Schabitz C Sommer W Zoder et al ldquoIntravenousbrain-derived neurotrophic factor reduces infarct size andcounterregulates Bax andBcl-2 expression after temporary focalcerebral ischemiardquo Stroke vol 31 no 9 pp 2212ndash2217 2000

[63] M-W Kim M-S Bang T-R Han et al ldquoExercise increasedBDNF and trkB in the contralateral hemisphere of the ischemicrat brainrdquo Brain Research vol 1052 no 1 pp 16ndash21 2005

[64] Z Kokaia Q Zhao M Kokaia et al ldquoRegulation of brain-derived neurotrophic factor gene expression after transientmiddle cerebral artery occlusion with and without brain dam-agerdquo Experimental Neurology vol 136 no 1 pp 73ndash88 1995

[65] L R Zhao B Mattsson and B B Johansson ldquoEnvironmentalinfluence on brain-derived neurotrophic factormessenger RNA

10 Neural Plasticity

expression after middle cerebral artery occlusion in sponta-neously hypertensive ratsrdquo Neuroscience vol 97 no 1 pp 177ndash184 2000

[66] H D Muller K M Hanumanthiah K Diederich S SchwabW-R Schabitz and C Sommer ldquoBrain-derived neurotrophicfactor but not forced armuse improves long-term outcome afterphotothrombotic stroke and transiently upregulates bindingdensities of excitatory glutamate receptors in the rat brainrdquoStroke vol 39 no 3 pp 1012ndash1021 2008

[67] W-R Schabitz C Berger R Kollmar et al ldquoEffect of brain-derived neurotrophic factor treatment and forced arm use onfunctional motor recovery after small cortical ischemiardquo Strokevol 35 no 4 pp 992ndash997 2004

[68] J Chen J Qin Q Su Z Liu and J Yang ldquoTreadmillrehabilitation treatment enhanced BDNF-TrkB but not NGF-TrkA signaling in a mouse intracerebral hemorrhage modelrdquoNeuroscience Letters vol 529 no 1 pp 28ndash32 2012

[69] J-Y Chung M-W Kim M-S Bang and M Kim ldquoIncreasedexpression of neurotrophin 4 following focal cerebral ischemiain adult rat brain with treadmill exerciserdquo PLoS ONE vol 8 no3 Article ID e52461 2013

[70] Z Ke S P Yip L Li X X Zheng W K Tam and K Y TongldquoThe effects of voluntary involuntary and forced exercises onmotor recovery in a stroke rat modelrdquo in Proceedings of theAnnual International Conference of the IEEE Engineering inMedicine and Biology Society (EMBC rsquo11) vol 2011 pp 8223ndash8226 Boston Mass USA August 2011

[71] P-C Shih Y-R Yang and R-Y Wang ldquoEffects of exerciseintensity on spatial memory performance and hippocampalsynaptic plasticity in transient brain ischemic ratsrdquo PLoS ONEvol 8 no 10 Article ID e78163 2013

[72] J Sun Z Ke S P Yip X-L Hu X-X Zheng and K-Y TongldquoGradually increased training intensity benefits rehabilitationoutcome after stroke by BDNF upregulation and stress sup-pressionrdquo BioMed Research International vol 2014 Article ID925762 8 pages 2014

[73] R Marin A Williams S Hale et al ldquoThe effect of voluntaryexercise exposure on histological and neurobehavioral out-comes after ischemic brain injury in the ratrdquo Physiology andBehavior vol 80 no 2-3 pp 167ndash175 2003

[74] S Vaynman Z Ying and F Gomez-Pinilla ldquoExercise inducesBDNF and synapsin I to specific hippocampal subfieldsrdquo Jour-nal of Neuroscience Research vol 76 no 3 pp 356ndash362 2004

[75] L Zhang X Hu J Luo et al ldquoPhysical exercise improves func-tional recovery through mitigation of autophagy attenuationof apoptosis and enhancement of neurogenesis after MCAO inratsrdquo BMC Neuroscience vol 14 article 46 2013

[76] J Puyal and P G H Clarke ldquoTargeting autophagy to preventneonatal stroke damagerdquoAutophagy vol 5 no 7 pp 1060ndash10612009

[77] Q-W Zhang X-X Deng X Sun J-X Xu and F-Y SunldquoExercise promotes axon regeneration of newborn striatonigraland corticonigral projection neurons in rats after ischemicstrokerdquo PLoS ONE vol 8 no 11 Article ID e80139 2013

[78] M Asahi K Asahi J-C Jung G J del ZoppoM E Fini and EH Lo ldquoRole for matrix metalloproteinase 9 after focal cerebralischemia effects of gene knockout and enzyme inhibition withBB-94rdquo Journal of Cerebral Blood Flow amp Metabolism vol 20no 12 pp 1681ndash1689 2000

[79] M Asahi X Wang T Mori et al ldquoEffects of matrixmetalloproteinase-9 gene knock-out on the proteolysis of

blood-brain barrier andwhitematter components after cerebralischemiardquoThe Journal of Neuroscience vol 21 no 19 pp 7724ndash7732 2001

[80] Y Zhang P Zhang X Shen et al ldquoEarly exercise protects theblood-brain barrier from ischemic brain injury via the regula-tion of MMP-9 and occludin in ratsrdquo International Journal ofMolecular Sciences vol 14 no 6 pp 11096ndash11112 2013

[81] I G Onyango J Lu M Rodova E Lezi A B Crafter and RH Swerdlow ldquoRegulation of neuron mitochondrial biogenesisand relevance to brain healthrdquo Biochimica et Biophysica ActamdashMolecular Basis of Disease vol 1802 no 1 pp 228ndash234 2010

[82] Q Zhang Y Wu P Zhang et al ldquoExercise induces mitochon-drial biogenesis after brain ischemia in ratsrdquo Neuroscience vol205 pp 10ndash17 2012

[83] L Li W Rong Z Ke X Hu and K-Y Tong ldquoThe effects oftraining intensities on motor recovery and gait symmetry in arat model of ischemiardquo Brain Injury vol 27 no 4 pp 408ndash4162013

[84] C Enzinger H Dawes H Johansen-Berg et al ldquoBrain activitychanges associated with treadmill training after strokerdquo Strokevol 40 no 7 pp 2460ndash2467 2009

[85] A R Luft R FMacKo LW Forrester et al ldquoTreadmill exerciseactivates subcortical neural networks and improves walkingafter stroke a randomized controlled trialrdquo Stroke vol 39 no12 pp 3341ndash3350 2008

[86] K Potempa M Lopez L T Braun J P Szidon L Fogg and TTincknell ldquoPhysiological outcomes of aerobic exercise trainingin hemiparetic stroke patientsrdquo Stroke vol 26 no 1 pp 101ndash1051995

[87] F Buma G Kwakkel and N Ramsey ldquoUnderstanding upperlimb recovery after strokerdquo Restorative Neurology and Neuro-science vol 31 no 6 pp 707ndash722 2013

[88] A E Baird A Benfield G Schlaug et al ldquoEnlargementof human cerebral ischemic lesion volumes measured bydiffusion-weighted magnetic resonance imagingrdquo Annals ofNeurology vol 41 no 5 pp 581ndash589 1997

[89] A Schmidt J Wellmann M Schilling et al ldquoMeta-analysis ofthe efficacy of different training strategies in animal models ofischemic strokerdquo Stroke vol 45 no 1 pp 239ndash247 2014

[90] R-Y Wang S-M Yu and Y-R Yang ldquoTreadmill trainingeffects in different age groups following middle cerebral arteryocclusion in ratsrdquo Gerontology vol 51 no 3 pp 161ndash165 2005

[91] P ZhangH YuN Zhou et al ldquoEarly exercise improves cerebralblood flow through increased angiogenesis in experimentalstroke rat modelrdquo Journal of NeuroEngineering and Rehabilita-tion vol 10 article 43 2013

[92] J Laurin andC Pin-Barre ldquoPhysiological adaptations followingendurance exercises after stroke focus on the plausible roleof high-intensity interval trainingrdquo International Journal ofPhysical Medicine amp Rehabilitation vol 2 no 3 pp 1ndash6 2014

[93] THMurphy andDCorbett ldquoPlasticity during stroke recoveryfrom synapse to behaviourrdquo Nature Reviews Neuroscience vol10 no 12 pp 861ndash872 2009

[94] M Svensson J Lexell and T Deierborg ldquoEffects of physicalexercise on neuroinflammation neuroplasticity neurodegener-ation and behavior what we can learn from animal models inclinical settingsrdquoNeurorehabilitation and Neural Repair vol 29no 6 pp 577ndash589 2015

[95] A Risedal J Zeng and B B Johansson ldquoEarly training mayexacerbate brain damage after focal brain ischemia in the ratrdquoJournal of Cerebral Blood Flow andMetabolism vol 19 no 9 pp997ndash1003 1999

Neural Plasticity 11

[96] C-S Piao B A Stoica J Wu et al ldquoLate exercise reducesneuroinflammation and cognitive dysfunction after traumaticbrain injuryrdquoNeurobiology of Disease vol 54 pp 252ndash263 2013

[97] J L Humm D A Kozlowski S T Bland D C James andT Schallert ldquoUse-dependent exaggeration of brain injury isglutamate involvedrdquo Experimental Neurology vol 157 no 2 pp349ndash358 1999

[98] G S Griesbach F Gomez-Pinilla and D A Hovda ldquoTheupregulation of plasticity-related proteins following TBI isdisrupted with acute voluntary exerciserdquo Brain Research vol1016 no 2 pp 154ndash162 2004

[99] J WMcAlees L T Smith R S Erbe D Jarjoura N M Ponzioand V M Sanders ldquoEpigenetic regulation of beta2-adrenergicreceptor expression in T

1198671 and T

1198672 cellsrdquo Brain Behavior and

Immunity vol 25 no 3 pp 408ndash415 2011[100] G Zhao S Zhou A Davie and Q Su ldquoEffects of moderate and

high intensity exercise on T1T2 balancerdquo Exercise ImmunologyReview vol 18 pp 98ndash114 2012

[101] Y Yagita K Kitagawa T Sasaki et al ldquoPostischemic exercisedecreases neurogenesis in the adult rat dentate gyrusrdquo Neuro-science Letters vol 409 no 1 pp 24ndash29 2006

[102] S T Bland T Schallert R Strong J Aronowski and J CGrottaldquoEarly exclusive use of the affected forelimb aftermoderate tran-sient focal ischemia in rats functional and anatomic outcomerdquoStroke vol 31 no 5 pp 1144ndash1152 2000

[103] S B DeBow J E McKenna B Kolb and F ColbourneldquoImmediate constraint-inducedmovement therapy causes localhyperthermia that exacerbates cerebral cortical injury in ratsrdquoCanadian Journal of Physiology and Pharmacology vol 82 no4 pp 231ndash237 2004

[104] D A Kozlowski D C James and T Schallert ldquoUse-dependentexaggeration of neuronal injury after unilateral sensorimotorcortex lesionsrdquo The Journal of Neuroscience vol 16 no 15 pp4776ndash4786 1996

[105] B Balaban F Tok F Yavuz E Yasar and R Alaca ldquoEarlyrehabilitation outcome in patients with middle cerebral arterystrokerdquo Neuroscience Letters vol 498 no 3 pp 204ndash207 2011

[106] G Kwakkel R van Peppen R C Wagenaar et al ldquoEffects ofaugmented exercise therapy time after stroke a meta-analysisrdquoStroke vol 35 no 11 pp 2529ndash2539 2004

[107] D L Costill M G Flynn J P Kirwan et al ldquoEffects of repeateddays of intensified training on muscle glycogen and swimmingperformancerdquo Medicine amp Science in Sports amp Exercise vol 20no 3 pp 249ndash254 1988

[108] M A Hirsch and B G Farley ldquoExercise and neuroplasticityin persons living with Parkinsonrsquos diseaserdquo European Journal ofPhysical and Rehabilitation Medicine vol 45 no 2 pp 215ndash2292009

[109] M Katz-Leurer M Shochina E Carmeli and Y FriedlanderldquoThe influence of early aerobic training on the functional capac-ity in patients with cerebrovascular accident at the subacutestagerdquo Archives of Physical Medicine and Rehabilitation vol 84no 11 pp 1609ndash1614 2003

[110] J D Schaechter ldquoMotor rehabilitation and brain plasticity afterhemiparetic strokerdquo Progress in Neurobiology vol 73 no 1 pp61ndash72 2004

[111] P R Bosch S Holzapfel and T Traustadottir ldquoFeasibility ofmeasuring ventilatory threshold in adults with stroke-inducedhemiparesis implications for exercise prescriptionrdquo Archives ofPhysical Medicine and Rehabilitation 2015

[112] D P Stirling K Khodarahmi J Liu et al ldquoMinocyclinetreatment reduces delayed oligodendrocyte death attenuatesaxonal dieback and improves functional outcome after spinalcord injuryrdquoThe Journal of Neuroscience vol 24 no 9 pp 2182ndash2190 2004

[113] S Barbay and R J Nudo ldquoThe effects of amphetamine onrecovery of function in animal models of cerebral injury acritical appraisalrdquo NeuroRehabilitation vol 25 no 1 pp 5ndash172009

[114] R S Rasmussen K Overgaard E S Hildebrandt-Eriksen andG Boysen ldquoD-Amphetamine improves cognitive deficits andphysical therapy promotes fine motor rehabilitation in a ratembolic stroke modelrdquo Acta Neurologica Scandinavica vol 113no 3 pp 189ndash198 2006

[115] C L Gibson B Coomber and S P Murphy ldquoProgesterone isneuroprotective following cerebral ischaemia in reproductivelyageing female micerdquo Brain vol 134 no 7 pp 2125ndash2133 2011

[116] T Ishrat I Sayeed F Atif and D G Stein ldquoEffects ofprogesterone administration on infarct volume and functionaldeficits following permanent focal cerebral ischemia in ratsrdquoBrain Research vol 1257 pp 94ndash101 2009

[117] M Prencipe C Ferretti A R Casini M Santini F Giubileiand F Culasso ldquoStroke disability and dementia results of apopulation surveyrdquo Stroke vol 28 no 3 pp 531ndash536 1997

[118] I Sayeed B Wali and D G Stein ldquoProgesterone inhibitsischemic brain injury in a rat model of permanent middle cere-bral artery occlusionrdquo Restorative Neurology and Neurosciencevol 25 no 2 pp 151ndash159 2007

[119] H Lee R J McKeon and R V Bellamkonda ldquoSustaineddelivery of thermostabilized chABC enhances axonal sproutingand functional recovery after spinal cord injuryrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 8 pp 3340ndash3345 2010

[120] V J Tom R Kadakia L Santi and J D Houle ldquoAdministrationof chondroitinase ABC rostral or caudal to a spinal cord injurysite promotes anatomical but not functional plasticityrdquo Journalof Neurotrauma vol 26 no 12 pp 2323ndash2333 2009

[121] J J Hill K Jin X O Mao L Xie and D A GreenbergldquoIntracerebral chondroitinase ABC and heparan sulfate proteo-glycan glypican improve outcome from chronic stroke in ratsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 23 pp 9155ndash9160 2012

[122] S Soleman P K Yip D A Duricki and L D FMoon ldquoDelayedtreatment with chondroitinase ABC promotes sensorimotorrecovery and plasticity after stroke in aged ratsrdquo Brain vol 135no 4 pp 1210ndash1223 2012

[123] B E Skolnick A I Maas R K Narayan et al ldquoA clinical trialof progesterone for severe traumatic brain injuryrdquo The NewEngland Journal of Medicine vol 371 no 26 pp 2467ndash24762014

[124] DWWright SD Yeatts R Silbergleit et al ldquoVery early admin-istration of progesterone for acute traumatic brain injuryrdquo TheNew England Journal of Medicine vol 371 no 26 pp 2457ndash2466 2014

[125] L-H Krarup T Truelsen C Gluud et al ldquoPrestroke physicalactivity is associated with severity and long-term outcome fromfirst-ever strokerdquo Neurology vol 71 no 17 pp 1313ndash1318 2008

[126] P M Rist I-M Lee C S Kase J Michael Gaziano and TKurth ldquoPhysical activity and functional outcomes from cerebralvascular events in menrdquo Stroke vol 42 no 12 pp 3352ndash33562011

12 Neural Plasticity

[127] Q Zhang L Zhang X Yang Y Wan and J Jia ldquoThe effectsof exercise preconditioning on cerebral blood flow change andendothelin-1 expression after cerebral ischemia in ratsrdquo Journalof Stroke and Cerebrovascular Diseases vol 23 no 6 pp 1696ndash1702 2014

[128] M Bernaudin A-S Nedelec D Divoux E T MacKenzie EPetit and P Schumann-Bard ldquoNormobaric hypoxia inducestolerance to focal permanent cerebral ischemia in associationwith an increased expression of hypoxia-inducible factor-1 andits target genes erythropoietin and VEGF in the adult mousebrainrdquo Journal of Cerebral Blood Flow and Metabolism vol 22no 4 pp 393ndash403 2002

[129] D Dornbos III N Zwagerman M Guo et al ldquoPreischemicexercise reduces brain damage by ameliorating metabolic dis-order in ischemiareperfusion injuryrdquo Journal of NeuroscienceResearch vol 91 no 6 pp 818ndash827 2013

[130] Y-H Ding Y Ding J Li D A Bessert and J A RafolsldquoExercise pre-conditioning strengthens brain microvascularintegrity in a rat stroke modelrdquo Neurological Research vol 28no 2 pp 184ndash189 2006

[131] M Guo B Cox S Mahale et al ldquoPre-ischemic exercise reducesmatrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in strokerdquo Neuroscience vol 151 no2 pp 340ndash351 2008

[132] M Ploughman Z Attwood N White J J E Dore and DCorbett ldquoEndurance exercise facilitates relearning of forelimbmotor skill after focal ischemiardquo The European Journal ofNeuroscience vol 25 no 11 pp 3453ndash3460 2007

[133] L L Guyot F G Diaz M H OrsquoRegan S McLeod H Park andJW Phillis ldquoReal-timemeasurement of glutamate release fromthe ischemic penumbra of the rat cerebral cortex using a focalmiddle cerebral artery occlusion modelrdquo Neuroscience Lettersvol 299 no 1-2 pp 37ndash40 2001

[134] K Matsumoto R Graf G Rosner J Taguchi and W-D HeissldquoElevation of neuroactive substances in the cortex of cats duringprolonged focal ischemiardquo Journal of Cerebral Blood Flow andMetabolism vol 13 no 4 pp 586ndash594 1993

[135] J Jia Y-S Hu Y Wu et al ldquoPre-ischemic treadmill trainingaffects glutamate and gamma aminobutyric acid levels in thestriatal dialysate of a rat model of cerebral ischemiardquo LifeSciences vol 84 no 15-16 pp 505ndash511 2009

[136] F Zhang J Jia Y Wu Y Hu and Y Wang ldquoThe effect of tread-mill training pre-exercise on glutamate receptor expression inrats after cerebral ischemiardquo International Journal of MolecularSciences vol 11 no 7 pp 2658ndash2669 2010

[137] J Jia Y-S Hu Y Wu et al ldquoTreadmill pre-training suppressesthe release of glutamate resulting from cerebral ischemia inratsrdquo Experimental Brain Research vol 204 no 2 pp 173ndash1792010

[138] E T Ang P T H Wong S Moochhala and Y K NgldquoNeuroprotection associated with running is it a result ofincreased endogenous neurotrophic factorsrdquoNeuroscience vol118 no 2 pp 335ndash345 2003

[139] A C Ricciardi E Lopez-Cancio N Perez De La Ossa et alldquoPrestroke physical activity is associated with good functionaloutcome and arterial recanalization after stroke due to a largevessel occlusionrdquo Cerebrovascular Diseases vol 37 no 4 pp304ndash311 2014

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Psychiatry Journal

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

8 Neural Plasticity

[4] L Li W Rong Z Ke X Hu S P Yip and K Y Tong ldquoMuscleactivation changes during body weight support treadmill train-ing after focal cortical ischemia a rat hindlimb modelrdquo Journalof Electromyography and Kinesiology vol 21 no 2 pp 318ndash3262011

[5] C Pin-Barre J Laurin M-S Felix et al ldquoAcute neuromuscularadaptation at the spinal level following middle cerebral arteryocclusion-reperfusion in the ratrdquoPLoSONE vol 9 no 2 ArticleID e89953 2014

[6] L W Forrester D F Hanley and R F Macko ldquoEffectsof treadmill exercise on transcranial magnetic stimulation-induced excitability to quadriceps after strokerdquo Archives ofPhysical Medicine and Rehabilitation vol 87 no 2 pp 229ndash2342006

[7] R FMacko FM Ivey LW Forrester et al ldquoTreadmill exerciserehabilitation improves ambulatory function and cardiovas-cular fitness in patients with chronic stroke a randomizedcontrolled trialrdquo Stroke vol 36 no 10 pp 2206ndash2211 2005

[8] M Endres K Gertz U Lindauer et al ldquoMechanisms of strokeprotection by physical activityrdquoAnnals of Neurology vol 54 no5 pp 582ndash590 2003

[9] K Gertz J Priller G Kronenberg et al ldquoPhysical activityimproves long-term stroke outcome via endothelial nitric oxidesynthase-dependent augmentation of neovascularization andcerebral blood flowrdquo Circulation Research vol 99 no 10 pp1132ndash1140 2006

[10] S Liebigt N Schlegel J Oberland O W Witte C Redeckerand S Keiner ldquoEffects of rehabilitative training and anti-inflammatory treatment on functional recovery and cellularreorganization following strokerdquo Experimental Neurology vol233 no 2 pp 776ndash782 2012

[11] W-R Schabitz T Steigleder C M Cooper-Kuhn et al ldquoIntra-venous brain-derived neurotrophic factor enhances poststrokesensorimotor recovery and stimulates neurogenesisrdquo Strokevol 38 no 7 pp 2165ndash2172 2007

[12] DWuandWMPardridge ldquoNeuroprotectionwith noninvasiveneurotrophin delivery to the brainrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 96 no1 pp 254ndash259 1999

[13] I-M Lee C H Hennekens K Berger J E Buring and J EManson ldquoExercise and risk of stroke inmale physiciansrdquo Strokevol 30 no 1 pp 1ndash6 1999

[14] D Deplanque I Masse C Lefebvre C Libersa D Leys andR Bordet ldquoPrior TIA lipid-lowering drug use and physicalactivity decrease ischemic stroke severityrdquo Neurology vol 67no 8 pp 1403ndash1410 2006

[15] N Stroud T M L Mazwi L D Case et al ldquoPrestroke physicalactivity and early functional status after strokerdquo Journal ofNeurology Neurosurgery and Psychiatry vol 80 no 9 pp 1019ndash1022 2009

[16] Y Ding J Li X Luan et al ldquoExercise pre-conditioningreduces brain damage in ischemic rats that may be associatedwith regional angiogenesis and cellular overexpression of neu-rotrophinrdquo Neuroscience vol 124 no 3 pp 583ndash591 2004

[17] Y-H Ding C N Young X Luan et al ldquoExercise precondi-tioning ameliorates inflammatory injury in ischemic rats duringreperfusionrdquoActaNeuropathologica vol 109 no 3 pp 237ndash2462005

[18] MKhan B Sekhon S Giri et al ldquoS-Nitrosoglutathione reducesinflammation and protects brain against focal cerebral ischemiain a rat model of experimental strokerdquo Journal of Cerebral BloodFlow and Metabolism vol 25 no 2 pp 177ndash192 2005

[19] W Schmidt M Endres F Dimeo and G J JungehulsingldquoTrain the vessel gain the brain physical activity and vesselfunction and the impact on stroke prevention and outcome incerebrovascular diseaserdquo Cerebrovascular Diseases vol 35 no4 pp 303ndash312 2013

[20] W R Frontera L Grimby and L Larsson ldquoFiring rate ofthe lower motoneuron and contractile properties of its musclefibers after upper motoneuron lesion in manrdquoMuscle amp Nervevol 20 no 8 pp 938ndash947 1997

[21] C M Cirstea C R Savage R J Nudo et al ldquoHandgrip-relatedactivation in the primary motor cortex relates to underlyingneuronal metabolism after strokerdquo Neurorehabilitation andNeural Repair vol 28 no 5 pp 433ndash442 2013

[22] C Enzinger H Johansen-Berg H Dawes et al ldquoFunctionalMRI correlates of lower limb function in stroke victims withgait impairmentrdquo Stroke vol 39 no 5 pp 1507ndash1513 2008

[23] A R Luft L Forrester R F Macko et al ldquoBrain activationof lower extremity movement in chronically impaired strokesurvivorsrdquo NeuroImage vol 26 no 1 pp 184ndash194 2005

[24] A R Luft S Waller L Forrester et al ldquoLesion locationalters brain activation in chronically impaired stroke survivorsrdquoNeuroImage vol 21 no 3 pp 924ndash935 2004

[25] N S Ward ldquoFunctional reorganization of the cerebral motorsystem after strokerdquo Current Opinion in Neurology vol 17 no6 pp 725ndash730 2004

[26] A C Zemke P J Heagerty C Lee and S C Cramer ldquoMotorcortex organization after stroke is related to side of stroke andlevel of recoveryrdquo Stroke vol 34 no 5 pp e23ndashe28 2003

[27] M Khan H Sakakima T S Dhammu et al ldquoS-nitrosoglutathione reduces oxidative injury and promotesmechanisms of neurorepair following traumatic brain injury inratsrdquo Journal of Neuroinflammation vol 8 article 78 2011

[28] H Sakakima M Khan T S Dhammu et al ldquoStimulationof functional recovery via the mechanisms of neurorepairby S-nitrosoglutathione and motor exercise in a rat modelof transient cerebral ischemia and reperfusionrdquo RestorativeNeurology and Neuroscience vol 30 no 5 pp 383ndash396 2012

[29] S Barbay E V Zoubina N Dancause et al ldquoA single injectionof D-amphetamine facilitates improvements in motor trainingfollowing a focal cortical infarct in squirrel monkeysrdquo Neurore-habilitation and Neural Repair vol 20 no 4 pp 455ndash458 2006

[30] P-C Fang S Barbay E J Plautz E Hoover S M Strittmatterand R J Nudo ldquoCombination of NEP 1-40 treatment andmotortraining enhances behavioral recovery after a focal corticalinfarct in ratsrdquo Stroke vol 41 no 3 pp 544ndash549 2010

[31] J-K Lee J-E Kim M Sivula and S M Strittmatter ldquoNogoreceptor antagonism promotes stroke recovery by enhancingaxonal plasticityrdquo The Journal of Neuroscience vol 24 no 27pp 6209ndash6217 2004

[32] J Wang X Feng Y Du L Wang and S Zhang ldquoCombinationtreatment with progesterone and rehabilitation training furtherpromotes behavioral recovery after acute ischemic stroke inmicerdquo Restorative Neurology and Neuroscience vol 31 no 4 pp487ndash499 2013

[33] B Kolb C Morshead C Gonzalez et al ldquoGrowth factor-stimulated generation of new cortical tissue and functionalrecovery after stroke damage to the motor cortex of ratsrdquoJournal of Cerebral Blood Flow and Metabolism vol 27 no 5pp 983ndash997 2007

[34] M S Jeffers A Hoyles C Morshead and D Corbett ldquoEpi-dermal growth factor and erythropoietin infusion accelerate

Neural Plasticity 9

functional recovery in combination with rehabilitationrdquo Strokevol 45 no 6 pp 1856ndash1858 2014

[35] L Gherardini M Gennaro and T Pizzorusso ldquoPerilesionaltreatment with chondroitinase ABC and motor training pro-mote functional recovery after stroke in ratsrdquo Cerebral Cortexvol 25 no 1 pp 202ndash212 2015

[36] D P Fuchs N Sanghvi J Wieser and S Schindler-IvensldquoPedaling alters the excitability and modulation of vastusmedialis H-reflexes after strokerdquo Clinical Neurophysiology vol122 no 10 pp 2036ndash2043 2011

[37] I-S Hwang C-F Lin L-C Tung and C-H Wang ldquoRespon-siveness of the H reflex to loading and posture in patientsfollowing strokerdquo Journal of Electromyography and Kinesiologyvol 14 no 6 pp 653ndash659 2004

[38] M A Oskoei and H Hu ldquoSupport vector machine-basedclassification scheme for myoelectric control applied to upperlimbrdquo IEEE Transactions on Biomedical Engineering vol 55 no8 pp 1956ndash1965 2008

[39] G L Soderberg and L M Knutson ldquoA guide for use andinterpretation of kinesiologic electromyographic datardquo PhysicalTherapy vol 80 no 5 pp 485ndash498 2000

[40] N A Riley and M Bilodeau ldquoChanges in upper limb jointtorque patterns and EMG signals with fatigue following astrokerdquoDisability andRehabilitation vol 24 no 18 pp 961ndash9692002

[41] U M Svantesson K S Sunnerhagen U S Carlsson and GGrimby ldquoDevelopment of fatigue during repeated eccentric-concentric muscle contractions of plantar flexors in patientswith strokerdquo Archives of Physical Medicine and Rehabilitationvol 80 no 10 pp 1247ndash1252 1999

[42] K N Arya S Pandian R Verma and R K Garg ldquoMovementtherapy induced neural reorganization and motor recovery instroke a reviewrdquo Journal of Bodywork andMovementTherapiesvol 15 no 4 pp 528ndash537 2011

[43] R J Nudo ldquoNeural bases of recovery after brain injuryrdquo Journalof Communication Disorders vol 44 no 5 pp 515ndash520 2011

[44] T Kawamata N E Alexis W D Dietrich and S P FinklesteinldquoIntracisternal basic fibroblast growth factor (bFGF) enhancesbehavioral recovery following focal cerebral infarction in theratrdquo Journal of Cerebral Blood Flow and Metabolism vol 16 no4 pp 542ndash547 1996

[45] T Yamaguchi M Suzuki and M Yamamoto ldquoYM796 anovel muscarinic agonist improves the impairment of learningbehavior in a rat model of chronic focal cerebral ischemiardquoBrain Research vol 669 no 1 pp 107ndash114 1995

[46] F Matsuda H Sakakima and Y Yoshida ldquoThe effects of earlyexercise on brain damage and recovery after focal cerebralinfarction in ratsrdquoActa Physiologica vol 201 no 2 pp 275ndash2872011

[47] K Mizutani S Sonoda N Hayashi et al ldquoAnalysis of proteinexpression profile in the cerebellum of cerebral infarction ratsafter treadmill trainingrdquo American Journal of Physical Medicineamp Rehabilitation vol 89 no 2 pp 107ndash114 2010

[48] P Zhang Y Zhang J Zhang et al ldquoEarly exercise protectsagainst cerebral ischemic injury through inhibiting neuronapoptosis in cortex in ratsrdquo International Journal of MolecularSciences vol 14 no 3 pp 6074ndash6089 2013

[49] L M Cupini M Diomedi F Placidi M Silvestrini and PGiacomini ldquoCerebrovascular reactivity and subcortical infarc-tionsrdquo Archives of Neurology vol 58 no 4 pp 577ndash581 2001

[50] F M Ivey A S Ryan C E Hafer-Macko and R F MacKoldquoImproved cerebral vasomotor reactivity after exercise trainingin hemiparetic stroke survivorsrdquo Stroke vol 42 no 7 pp 1994ndash2000 2011

[51] S Tian Y Zhang S Tian et al ldquoEarly exercise training improvesischemic outcome in rats by cerebral hemodynamicsrdquo BrainResearch vol 1533 pp 114ndash121 2013

[52] Y Gao Y Zhao J Pan et al ldquoTreadmill exercise promotesangiogenesis in the ischemic penumbra of rat brains throughcaveolin-1VEGF signaling pathwaysrdquo Brain Research vol 1585pp 83ndash90 2014

[53] G Kim and E Kim ldquoEffects of treadmill training on limbmotorfunction and acetylcholinesterase activity in rats with strokerdquoJournal of PhysicalTherapy Science vol 25 no 10 pp 1227ndash12302013

[54] Q Zheng D Zhu Y Bai Y Wu J Jia and Y Hu ldquoExerciseimproves recovery after ischemic brain injury by inducing theexpression of angiopoietin-1 and Tie-2 in ratsrdquo The TohokuJournal of Experimental Medicine vol 224 no 3 pp 221ndash2282011

[55] T M Hansen A J Moss and N P J Brindle ldquoVascularendothelial growth factor and angiopoietins in neurovascularregeneration and protection following strokerdquo Current Neu-rovascular Research vol 5 no 4 pp 236ndash245 2008

[56] D M Hermann and A Zechariah ldquoImplications of vascu-lar endothelial growth factor for postischemic neurovascularremodelingrdquo Journal of Cerebral Blood Flow and Metabolismvol 29 no 10 pp 1620ndash1643 2009

[57] C S Mang K L Campbell C J D Ross and L A Boyd ldquoPro-moting neuroplasticity for motor rehabilitation after strokeconsidering the effects of aerobic exercise and genetic variationon brain-derived neurotrophic factorrdquo PhysicalTherapy vol 93no 12 pp 1707ndash1716 2013

[58] M Ploughman VWindle C LMacLellan NWhite J J Doreand D Corbett ldquoBrain-derived neurotrophic factor contributesto recovery of skilled reaching after focal ischemia in ratsrdquoStroke vol 40 no 4 pp 1490ndash1495 2009

[59] I Kiprianova TM Freiman SDesiderato et al ldquoBrain-derivedneurotrophic factor prevents neuronal death and glial activa-tion after global ischemia in the ratrdquo Journal of NeuroscienceResearch vol 56 no 1 pp 21ndash27 1999

[60] R J Nudo E J Plautz and S B Frost ldquoRole of adaptiveplasticity in recovery of function after damage to motor cortexrdquoMuscle amp Nerve vol 24 no 8 pp 1000ndash1019 2001

[61] W-R Schabitz S Schwab M Spranger and W Hacke ldquoIntra-ventricular brain-derived neurotrophic factor reduces infarctsize after focal cerebral ischemia in ratsrdquo Journal of CerebralBlood Flow and Metabolism vol 17 no 5 pp 500ndash506 1997

[62] W-R Schabitz C Sommer W Zoder et al ldquoIntravenousbrain-derived neurotrophic factor reduces infarct size andcounterregulates Bax andBcl-2 expression after temporary focalcerebral ischemiardquo Stroke vol 31 no 9 pp 2212ndash2217 2000

[63] M-W Kim M-S Bang T-R Han et al ldquoExercise increasedBDNF and trkB in the contralateral hemisphere of the ischemicrat brainrdquo Brain Research vol 1052 no 1 pp 16ndash21 2005

[64] Z Kokaia Q Zhao M Kokaia et al ldquoRegulation of brain-derived neurotrophic factor gene expression after transientmiddle cerebral artery occlusion with and without brain dam-agerdquo Experimental Neurology vol 136 no 1 pp 73ndash88 1995

[65] L R Zhao B Mattsson and B B Johansson ldquoEnvironmentalinfluence on brain-derived neurotrophic factormessenger RNA

10 Neural Plasticity

expression after middle cerebral artery occlusion in sponta-neously hypertensive ratsrdquo Neuroscience vol 97 no 1 pp 177ndash184 2000

[66] H D Muller K M Hanumanthiah K Diederich S SchwabW-R Schabitz and C Sommer ldquoBrain-derived neurotrophicfactor but not forced armuse improves long-term outcome afterphotothrombotic stroke and transiently upregulates bindingdensities of excitatory glutamate receptors in the rat brainrdquoStroke vol 39 no 3 pp 1012ndash1021 2008

[67] W-R Schabitz C Berger R Kollmar et al ldquoEffect of brain-derived neurotrophic factor treatment and forced arm use onfunctional motor recovery after small cortical ischemiardquo Strokevol 35 no 4 pp 992ndash997 2004

[68] J Chen J Qin Q Su Z Liu and J Yang ldquoTreadmillrehabilitation treatment enhanced BDNF-TrkB but not NGF-TrkA signaling in a mouse intracerebral hemorrhage modelrdquoNeuroscience Letters vol 529 no 1 pp 28ndash32 2012

[69] J-Y Chung M-W Kim M-S Bang and M Kim ldquoIncreasedexpression of neurotrophin 4 following focal cerebral ischemiain adult rat brain with treadmill exerciserdquo PLoS ONE vol 8 no3 Article ID e52461 2013

[70] Z Ke S P Yip L Li X X Zheng W K Tam and K Y TongldquoThe effects of voluntary involuntary and forced exercises onmotor recovery in a stroke rat modelrdquo in Proceedings of theAnnual International Conference of the IEEE Engineering inMedicine and Biology Society (EMBC rsquo11) vol 2011 pp 8223ndash8226 Boston Mass USA August 2011

[71] P-C Shih Y-R Yang and R-Y Wang ldquoEffects of exerciseintensity on spatial memory performance and hippocampalsynaptic plasticity in transient brain ischemic ratsrdquo PLoS ONEvol 8 no 10 Article ID e78163 2013

[72] J Sun Z Ke S P Yip X-L Hu X-X Zheng and K-Y TongldquoGradually increased training intensity benefits rehabilitationoutcome after stroke by BDNF upregulation and stress sup-pressionrdquo BioMed Research International vol 2014 Article ID925762 8 pages 2014

[73] R Marin A Williams S Hale et al ldquoThe effect of voluntaryexercise exposure on histological and neurobehavioral out-comes after ischemic brain injury in the ratrdquo Physiology andBehavior vol 80 no 2-3 pp 167ndash175 2003

[74] S Vaynman Z Ying and F Gomez-Pinilla ldquoExercise inducesBDNF and synapsin I to specific hippocampal subfieldsrdquo Jour-nal of Neuroscience Research vol 76 no 3 pp 356ndash362 2004

[75] L Zhang X Hu J Luo et al ldquoPhysical exercise improves func-tional recovery through mitigation of autophagy attenuationof apoptosis and enhancement of neurogenesis after MCAO inratsrdquo BMC Neuroscience vol 14 article 46 2013

[76] J Puyal and P G H Clarke ldquoTargeting autophagy to preventneonatal stroke damagerdquoAutophagy vol 5 no 7 pp 1060ndash10612009

[77] Q-W Zhang X-X Deng X Sun J-X Xu and F-Y SunldquoExercise promotes axon regeneration of newborn striatonigraland corticonigral projection neurons in rats after ischemicstrokerdquo PLoS ONE vol 8 no 11 Article ID e80139 2013

[78] M Asahi K Asahi J-C Jung G J del ZoppoM E Fini and EH Lo ldquoRole for matrix metalloproteinase 9 after focal cerebralischemia effects of gene knockout and enzyme inhibition withBB-94rdquo Journal of Cerebral Blood Flow amp Metabolism vol 20no 12 pp 1681ndash1689 2000

[79] M Asahi X Wang T Mori et al ldquoEffects of matrixmetalloproteinase-9 gene knock-out on the proteolysis of

blood-brain barrier andwhitematter components after cerebralischemiardquoThe Journal of Neuroscience vol 21 no 19 pp 7724ndash7732 2001

[80] Y Zhang P Zhang X Shen et al ldquoEarly exercise protects theblood-brain barrier from ischemic brain injury via the regula-tion of MMP-9 and occludin in ratsrdquo International Journal ofMolecular Sciences vol 14 no 6 pp 11096ndash11112 2013

[81] I G Onyango J Lu M Rodova E Lezi A B Crafter and RH Swerdlow ldquoRegulation of neuron mitochondrial biogenesisand relevance to brain healthrdquo Biochimica et Biophysica ActamdashMolecular Basis of Disease vol 1802 no 1 pp 228ndash234 2010

[82] Q Zhang Y Wu P Zhang et al ldquoExercise induces mitochon-drial biogenesis after brain ischemia in ratsrdquo Neuroscience vol205 pp 10ndash17 2012

[83] L Li W Rong Z Ke X Hu and K-Y Tong ldquoThe effects oftraining intensities on motor recovery and gait symmetry in arat model of ischemiardquo Brain Injury vol 27 no 4 pp 408ndash4162013

[84] C Enzinger H Dawes H Johansen-Berg et al ldquoBrain activitychanges associated with treadmill training after strokerdquo Strokevol 40 no 7 pp 2460ndash2467 2009

[85] A R Luft R FMacKo LW Forrester et al ldquoTreadmill exerciseactivates subcortical neural networks and improves walkingafter stroke a randomized controlled trialrdquo Stroke vol 39 no12 pp 3341ndash3350 2008

[86] K Potempa M Lopez L T Braun J P Szidon L Fogg and TTincknell ldquoPhysiological outcomes of aerobic exercise trainingin hemiparetic stroke patientsrdquo Stroke vol 26 no 1 pp 101ndash1051995

[87] F Buma G Kwakkel and N Ramsey ldquoUnderstanding upperlimb recovery after strokerdquo Restorative Neurology and Neuro-science vol 31 no 6 pp 707ndash722 2013

[88] A E Baird A Benfield G Schlaug et al ldquoEnlargementof human cerebral ischemic lesion volumes measured bydiffusion-weighted magnetic resonance imagingrdquo Annals ofNeurology vol 41 no 5 pp 581ndash589 1997

[89] A Schmidt J Wellmann M Schilling et al ldquoMeta-analysis ofthe efficacy of different training strategies in animal models ofischemic strokerdquo Stroke vol 45 no 1 pp 239ndash247 2014

[90] R-Y Wang S-M Yu and Y-R Yang ldquoTreadmill trainingeffects in different age groups following middle cerebral arteryocclusion in ratsrdquo Gerontology vol 51 no 3 pp 161ndash165 2005

[91] P ZhangH YuN Zhou et al ldquoEarly exercise improves cerebralblood flow through increased angiogenesis in experimentalstroke rat modelrdquo Journal of NeuroEngineering and Rehabilita-tion vol 10 article 43 2013

[92] J Laurin andC Pin-Barre ldquoPhysiological adaptations followingendurance exercises after stroke focus on the plausible roleof high-intensity interval trainingrdquo International Journal ofPhysical Medicine amp Rehabilitation vol 2 no 3 pp 1ndash6 2014

[93] THMurphy andDCorbett ldquoPlasticity during stroke recoveryfrom synapse to behaviourrdquo Nature Reviews Neuroscience vol10 no 12 pp 861ndash872 2009

[94] M Svensson J Lexell and T Deierborg ldquoEffects of physicalexercise on neuroinflammation neuroplasticity neurodegener-ation and behavior what we can learn from animal models inclinical settingsrdquoNeurorehabilitation and Neural Repair vol 29no 6 pp 577ndash589 2015

[95] A Risedal J Zeng and B B Johansson ldquoEarly training mayexacerbate brain damage after focal brain ischemia in the ratrdquoJournal of Cerebral Blood Flow andMetabolism vol 19 no 9 pp997ndash1003 1999

Neural Plasticity 11

[96] C-S Piao B A Stoica J Wu et al ldquoLate exercise reducesneuroinflammation and cognitive dysfunction after traumaticbrain injuryrdquoNeurobiology of Disease vol 54 pp 252ndash263 2013

[97] J L Humm D A Kozlowski S T Bland D C James andT Schallert ldquoUse-dependent exaggeration of brain injury isglutamate involvedrdquo Experimental Neurology vol 157 no 2 pp349ndash358 1999

[98] G S Griesbach F Gomez-Pinilla and D A Hovda ldquoTheupregulation of plasticity-related proteins following TBI isdisrupted with acute voluntary exerciserdquo Brain Research vol1016 no 2 pp 154ndash162 2004

[99] J WMcAlees L T Smith R S Erbe D Jarjoura N M Ponzioand V M Sanders ldquoEpigenetic regulation of beta2-adrenergicreceptor expression in T

1198671 and T

1198672 cellsrdquo Brain Behavior and

Immunity vol 25 no 3 pp 408ndash415 2011[100] G Zhao S Zhou A Davie and Q Su ldquoEffects of moderate and

high intensity exercise on T1T2 balancerdquo Exercise ImmunologyReview vol 18 pp 98ndash114 2012

[101] Y Yagita K Kitagawa T Sasaki et al ldquoPostischemic exercisedecreases neurogenesis in the adult rat dentate gyrusrdquo Neuro-science Letters vol 409 no 1 pp 24ndash29 2006

[102] S T Bland T Schallert R Strong J Aronowski and J CGrottaldquoEarly exclusive use of the affected forelimb aftermoderate tran-sient focal ischemia in rats functional and anatomic outcomerdquoStroke vol 31 no 5 pp 1144ndash1152 2000

[103] S B DeBow J E McKenna B Kolb and F ColbourneldquoImmediate constraint-inducedmovement therapy causes localhyperthermia that exacerbates cerebral cortical injury in ratsrdquoCanadian Journal of Physiology and Pharmacology vol 82 no4 pp 231ndash237 2004

[104] D A Kozlowski D C James and T Schallert ldquoUse-dependentexaggeration of neuronal injury after unilateral sensorimotorcortex lesionsrdquo The Journal of Neuroscience vol 16 no 15 pp4776ndash4786 1996

[105] B Balaban F Tok F Yavuz E Yasar and R Alaca ldquoEarlyrehabilitation outcome in patients with middle cerebral arterystrokerdquo Neuroscience Letters vol 498 no 3 pp 204ndash207 2011

[106] G Kwakkel R van Peppen R C Wagenaar et al ldquoEffects ofaugmented exercise therapy time after stroke a meta-analysisrdquoStroke vol 35 no 11 pp 2529ndash2539 2004

[107] D L Costill M G Flynn J P Kirwan et al ldquoEffects of repeateddays of intensified training on muscle glycogen and swimmingperformancerdquo Medicine amp Science in Sports amp Exercise vol 20no 3 pp 249ndash254 1988

[108] M A Hirsch and B G Farley ldquoExercise and neuroplasticityin persons living with Parkinsonrsquos diseaserdquo European Journal ofPhysical and Rehabilitation Medicine vol 45 no 2 pp 215ndash2292009

[109] M Katz-Leurer M Shochina E Carmeli and Y FriedlanderldquoThe influence of early aerobic training on the functional capac-ity in patients with cerebrovascular accident at the subacutestagerdquo Archives of Physical Medicine and Rehabilitation vol 84no 11 pp 1609ndash1614 2003

[110] J D Schaechter ldquoMotor rehabilitation and brain plasticity afterhemiparetic strokerdquo Progress in Neurobiology vol 73 no 1 pp61ndash72 2004

[111] P R Bosch S Holzapfel and T Traustadottir ldquoFeasibility ofmeasuring ventilatory threshold in adults with stroke-inducedhemiparesis implications for exercise prescriptionrdquo Archives ofPhysical Medicine and Rehabilitation 2015

[112] D P Stirling K Khodarahmi J Liu et al ldquoMinocyclinetreatment reduces delayed oligodendrocyte death attenuatesaxonal dieback and improves functional outcome after spinalcord injuryrdquoThe Journal of Neuroscience vol 24 no 9 pp 2182ndash2190 2004

[113] S Barbay and R J Nudo ldquoThe effects of amphetamine onrecovery of function in animal models of cerebral injury acritical appraisalrdquo NeuroRehabilitation vol 25 no 1 pp 5ndash172009

[114] R S Rasmussen K Overgaard E S Hildebrandt-Eriksen andG Boysen ldquoD-Amphetamine improves cognitive deficits andphysical therapy promotes fine motor rehabilitation in a ratembolic stroke modelrdquo Acta Neurologica Scandinavica vol 113no 3 pp 189ndash198 2006

[115] C L Gibson B Coomber and S P Murphy ldquoProgesterone isneuroprotective following cerebral ischaemia in reproductivelyageing female micerdquo Brain vol 134 no 7 pp 2125ndash2133 2011

[116] T Ishrat I Sayeed F Atif and D G Stein ldquoEffects ofprogesterone administration on infarct volume and functionaldeficits following permanent focal cerebral ischemia in ratsrdquoBrain Research vol 1257 pp 94ndash101 2009

[117] M Prencipe C Ferretti A R Casini M Santini F Giubileiand F Culasso ldquoStroke disability and dementia results of apopulation surveyrdquo Stroke vol 28 no 3 pp 531ndash536 1997

[118] I Sayeed B Wali and D G Stein ldquoProgesterone inhibitsischemic brain injury in a rat model of permanent middle cere-bral artery occlusionrdquo Restorative Neurology and Neurosciencevol 25 no 2 pp 151ndash159 2007

[119] H Lee R J McKeon and R V Bellamkonda ldquoSustaineddelivery of thermostabilized chABC enhances axonal sproutingand functional recovery after spinal cord injuryrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 8 pp 3340ndash3345 2010

[120] V J Tom R Kadakia L Santi and J D Houle ldquoAdministrationof chondroitinase ABC rostral or caudal to a spinal cord injurysite promotes anatomical but not functional plasticityrdquo Journalof Neurotrauma vol 26 no 12 pp 2323ndash2333 2009

[121] J J Hill K Jin X O Mao L Xie and D A GreenbergldquoIntracerebral chondroitinase ABC and heparan sulfate proteo-glycan glypican improve outcome from chronic stroke in ratsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 23 pp 9155ndash9160 2012

[122] S Soleman P K Yip D A Duricki and L D FMoon ldquoDelayedtreatment with chondroitinase ABC promotes sensorimotorrecovery and plasticity after stroke in aged ratsrdquo Brain vol 135no 4 pp 1210ndash1223 2012

[123] B E Skolnick A I Maas R K Narayan et al ldquoA clinical trialof progesterone for severe traumatic brain injuryrdquo The NewEngland Journal of Medicine vol 371 no 26 pp 2467ndash24762014

[124] DWWright SD Yeatts R Silbergleit et al ldquoVery early admin-istration of progesterone for acute traumatic brain injuryrdquo TheNew England Journal of Medicine vol 371 no 26 pp 2457ndash2466 2014

[125] L-H Krarup T Truelsen C Gluud et al ldquoPrestroke physicalactivity is associated with severity and long-term outcome fromfirst-ever strokerdquo Neurology vol 71 no 17 pp 1313ndash1318 2008

[126] P M Rist I-M Lee C S Kase J Michael Gaziano and TKurth ldquoPhysical activity and functional outcomes from cerebralvascular events in menrdquo Stroke vol 42 no 12 pp 3352ndash33562011

12 Neural Plasticity

[127] Q Zhang L Zhang X Yang Y Wan and J Jia ldquoThe effectsof exercise preconditioning on cerebral blood flow change andendothelin-1 expression after cerebral ischemia in ratsrdquo Journalof Stroke and Cerebrovascular Diseases vol 23 no 6 pp 1696ndash1702 2014

[128] M Bernaudin A-S Nedelec D Divoux E T MacKenzie EPetit and P Schumann-Bard ldquoNormobaric hypoxia inducestolerance to focal permanent cerebral ischemia in associationwith an increased expression of hypoxia-inducible factor-1 andits target genes erythropoietin and VEGF in the adult mousebrainrdquo Journal of Cerebral Blood Flow and Metabolism vol 22no 4 pp 393ndash403 2002

[129] D Dornbos III N Zwagerman M Guo et al ldquoPreischemicexercise reduces brain damage by ameliorating metabolic dis-order in ischemiareperfusion injuryrdquo Journal of NeuroscienceResearch vol 91 no 6 pp 818ndash827 2013

[130] Y-H Ding Y Ding J Li D A Bessert and J A RafolsldquoExercise pre-conditioning strengthens brain microvascularintegrity in a rat stroke modelrdquo Neurological Research vol 28no 2 pp 184ndash189 2006

[131] M Guo B Cox S Mahale et al ldquoPre-ischemic exercise reducesmatrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in strokerdquo Neuroscience vol 151 no2 pp 340ndash351 2008

[132] M Ploughman Z Attwood N White J J E Dore and DCorbett ldquoEndurance exercise facilitates relearning of forelimbmotor skill after focal ischemiardquo The European Journal ofNeuroscience vol 25 no 11 pp 3453ndash3460 2007

[133] L L Guyot F G Diaz M H OrsquoRegan S McLeod H Park andJW Phillis ldquoReal-timemeasurement of glutamate release fromthe ischemic penumbra of the rat cerebral cortex using a focalmiddle cerebral artery occlusion modelrdquo Neuroscience Lettersvol 299 no 1-2 pp 37ndash40 2001

[134] K Matsumoto R Graf G Rosner J Taguchi and W-D HeissldquoElevation of neuroactive substances in the cortex of cats duringprolonged focal ischemiardquo Journal of Cerebral Blood Flow andMetabolism vol 13 no 4 pp 586ndash594 1993

[135] J Jia Y-S Hu Y Wu et al ldquoPre-ischemic treadmill trainingaffects glutamate and gamma aminobutyric acid levels in thestriatal dialysate of a rat model of cerebral ischemiardquo LifeSciences vol 84 no 15-16 pp 505ndash511 2009

[136] F Zhang J Jia Y Wu Y Hu and Y Wang ldquoThe effect of tread-mill training pre-exercise on glutamate receptor expression inrats after cerebral ischemiardquo International Journal of MolecularSciences vol 11 no 7 pp 2658ndash2669 2010

[137] J Jia Y-S Hu Y Wu et al ldquoTreadmill pre-training suppressesthe release of glutamate resulting from cerebral ischemia inratsrdquo Experimental Brain Research vol 204 no 2 pp 173ndash1792010

[138] E T Ang P T H Wong S Moochhala and Y K NgldquoNeuroprotection associated with running is it a result ofincreased endogenous neurotrophic factorsrdquoNeuroscience vol118 no 2 pp 335ndash345 2003

[139] A C Ricciardi E Lopez-Cancio N Perez De La Ossa et alldquoPrestroke physical activity is associated with good functionaloutcome and arterial recanalization after stroke due to a largevessel occlusionrdquo Cerebrovascular Diseases vol 37 no 4 pp304ndash311 2014

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Psychiatry Journal

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity 9

functional recovery in combination with rehabilitationrdquo Strokevol 45 no 6 pp 1856ndash1858 2014

[35] L Gherardini M Gennaro and T Pizzorusso ldquoPerilesionaltreatment with chondroitinase ABC and motor training pro-mote functional recovery after stroke in ratsrdquo Cerebral Cortexvol 25 no 1 pp 202ndash212 2015

[36] D P Fuchs N Sanghvi J Wieser and S Schindler-IvensldquoPedaling alters the excitability and modulation of vastusmedialis H-reflexes after strokerdquo Clinical Neurophysiology vol122 no 10 pp 2036ndash2043 2011

[37] I-S Hwang C-F Lin L-C Tung and C-H Wang ldquoRespon-siveness of the H reflex to loading and posture in patientsfollowing strokerdquo Journal of Electromyography and Kinesiologyvol 14 no 6 pp 653ndash659 2004

[38] M A Oskoei and H Hu ldquoSupport vector machine-basedclassification scheme for myoelectric control applied to upperlimbrdquo IEEE Transactions on Biomedical Engineering vol 55 no8 pp 1956ndash1965 2008

[39] G L Soderberg and L M Knutson ldquoA guide for use andinterpretation of kinesiologic electromyographic datardquo PhysicalTherapy vol 80 no 5 pp 485ndash498 2000

[40] N A Riley and M Bilodeau ldquoChanges in upper limb jointtorque patterns and EMG signals with fatigue following astrokerdquoDisability andRehabilitation vol 24 no 18 pp 961ndash9692002

[41] U M Svantesson K S Sunnerhagen U S Carlsson and GGrimby ldquoDevelopment of fatigue during repeated eccentric-concentric muscle contractions of plantar flexors in patientswith strokerdquo Archives of Physical Medicine and Rehabilitationvol 80 no 10 pp 1247ndash1252 1999

[42] K N Arya S Pandian R Verma and R K Garg ldquoMovementtherapy induced neural reorganization and motor recovery instroke a reviewrdquo Journal of Bodywork andMovementTherapiesvol 15 no 4 pp 528ndash537 2011

[43] R J Nudo ldquoNeural bases of recovery after brain injuryrdquo Journalof Communication Disorders vol 44 no 5 pp 515ndash520 2011

[44] T Kawamata N E Alexis W D Dietrich and S P FinklesteinldquoIntracisternal basic fibroblast growth factor (bFGF) enhancesbehavioral recovery following focal cerebral infarction in theratrdquo Journal of Cerebral Blood Flow and Metabolism vol 16 no4 pp 542ndash547 1996

[45] T Yamaguchi M Suzuki and M Yamamoto ldquoYM796 anovel muscarinic agonist improves the impairment of learningbehavior in a rat model of chronic focal cerebral ischemiardquoBrain Research vol 669 no 1 pp 107ndash114 1995

[46] F Matsuda H Sakakima and Y Yoshida ldquoThe effects of earlyexercise on brain damage and recovery after focal cerebralinfarction in ratsrdquoActa Physiologica vol 201 no 2 pp 275ndash2872011

[47] K Mizutani S Sonoda N Hayashi et al ldquoAnalysis of proteinexpression profile in the cerebellum of cerebral infarction ratsafter treadmill trainingrdquo American Journal of Physical Medicineamp Rehabilitation vol 89 no 2 pp 107ndash114 2010

[48] P Zhang Y Zhang J Zhang et al ldquoEarly exercise protectsagainst cerebral ischemic injury through inhibiting neuronapoptosis in cortex in ratsrdquo International Journal of MolecularSciences vol 14 no 3 pp 6074ndash6089 2013

[49] L M Cupini M Diomedi F Placidi M Silvestrini and PGiacomini ldquoCerebrovascular reactivity and subcortical infarc-tionsrdquo Archives of Neurology vol 58 no 4 pp 577ndash581 2001

[50] F M Ivey A S Ryan C E Hafer-Macko and R F MacKoldquoImproved cerebral vasomotor reactivity after exercise trainingin hemiparetic stroke survivorsrdquo Stroke vol 42 no 7 pp 1994ndash2000 2011

[51] S Tian Y Zhang S Tian et al ldquoEarly exercise training improvesischemic outcome in rats by cerebral hemodynamicsrdquo BrainResearch vol 1533 pp 114ndash121 2013

[52] Y Gao Y Zhao J Pan et al ldquoTreadmill exercise promotesangiogenesis in the ischemic penumbra of rat brains throughcaveolin-1VEGF signaling pathwaysrdquo Brain Research vol 1585pp 83ndash90 2014

[53] G Kim and E Kim ldquoEffects of treadmill training on limbmotorfunction and acetylcholinesterase activity in rats with strokerdquoJournal of PhysicalTherapy Science vol 25 no 10 pp 1227ndash12302013

[54] Q Zheng D Zhu Y Bai Y Wu J Jia and Y Hu ldquoExerciseimproves recovery after ischemic brain injury by inducing theexpression of angiopoietin-1 and Tie-2 in ratsrdquo The TohokuJournal of Experimental Medicine vol 224 no 3 pp 221ndash2282011

[55] T M Hansen A J Moss and N P J Brindle ldquoVascularendothelial growth factor and angiopoietins in neurovascularregeneration and protection following strokerdquo Current Neu-rovascular Research vol 5 no 4 pp 236ndash245 2008

[56] D M Hermann and A Zechariah ldquoImplications of vascu-lar endothelial growth factor for postischemic neurovascularremodelingrdquo Journal of Cerebral Blood Flow and Metabolismvol 29 no 10 pp 1620ndash1643 2009

[57] C S Mang K L Campbell C J D Ross and L A Boyd ldquoPro-moting neuroplasticity for motor rehabilitation after strokeconsidering the effects of aerobic exercise and genetic variationon brain-derived neurotrophic factorrdquo PhysicalTherapy vol 93no 12 pp 1707ndash1716 2013

[58] M Ploughman VWindle C LMacLellan NWhite J J Doreand D Corbett ldquoBrain-derived neurotrophic factor contributesto recovery of skilled reaching after focal ischemia in ratsrdquoStroke vol 40 no 4 pp 1490ndash1495 2009

[59] I Kiprianova TM Freiman SDesiderato et al ldquoBrain-derivedneurotrophic factor prevents neuronal death and glial activa-tion after global ischemia in the ratrdquo Journal of NeuroscienceResearch vol 56 no 1 pp 21ndash27 1999

[60] R J Nudo E J Plautz and S B Frost ldquoRole of adaptiveplasticity in recovery of function after damage to motor cortexrdquoMuscle amp Nerve vol 24 no 8 pp 1000ndash1019 2001

[61] W-R Schabitz S Schwab M Spranger and W Hacke ldquoIntra-ventricular brain-derived neurotrophic factor reduces infarctsize after focal cerebral ischemia in ratsrdquo Journal of CerebralBlood Flow and Metabolism vol 17 no 5 pp 500ndash506 1997

[62] W-R Schabitz C Sommer W Zoder et al ldquoIntravenousbrain-derived neurotrophic factor reduces infarct size andcounterregulates Bax andBcl-2 expression after temporary focalcerebral ischemiardquo Stroke vol 31 no 9 pp 2212ndash2217 2000

[63] M-W Kim M-S Bang T-R Han et al ldquoExercise increasedBDNF and trkB in the contralateral hemisphere of the ischemicrat brainrdquo Brain Research vol 1052 no 1 pp 16ndash21 2005

[64] Z Kokaia Q Zhao M Kokaia et al ldquoRegulation of brain-derived neurotrophic factor gene expression after transientmiddle cerebral artery occlusion with and without brain dam-agerdquo Experimental Neurology vol 136 no 1 pp 73ndash88 1995

[65] L R Zhao B Mattsson and B B Johansson ldquoEnvironmentalinfluence on brain-derived neurotrophic factormessenger RNA

10 Neural Plasticity

expression after middle cerebral artery occlusion in sponta-neously hypertensive ratsrdquo Neuroscience vol 97 no 1 pp 177ndash184 2000

[66] H D Muller K M Hanumanthiah K Diederich S SchwabW-R Schabitz and C Sommer ldquoBrain-derived neurotrophicfactor but not forced armuse improves long-term outcome afterphotothrombotic stroke and transiently upregulates bindingdensities of excitatory glutamate receptors in the rat brainrdquoStroke vol 39 no 3 pp 1012ndash1021 2008

[67] W-R Schabitz C Berger R Kollmar et al ldquoEffect of brain-derived neurotrophic factor treatment and forced arm use onfunctional motor recovery after small cortical ischemiardquo Strokevol 35 no 4 pp 992ndash997 2004

[68] J Chen J Qin Q Su Z Liu and J Yang ldquoTreadmillrehabilitation treatment enhanced BDNF-TrkB but not NGF-TrkA signaling in a mouse intracerebral hemorrhage modelrdquoNeuroscience Letters vol 529 no 1 pp 28ndash32 2012

[69] J-Y Chung M-W Kim M-S Bang and M Kim ldquoIncreasedexpression of neurotrophin 4 following focal cerebral ischemiain adult rat brain with treadmill exerciserdquo PLoS ONE vol 8 no3 Article ID e52461 2013

[70] Z Ke S P Yip L Li X X Zheng W K Tam and K Y TongldquoThe effects of voluntary involuntary and forced exercises onmotor recovery in a stroke rat modelrdquo in Proceedings of theAnnual International Conference of the IEEE Engineering inMedicine and Biology Society (EMBC rsquo11) vol 2011 pp 8223ndash8226 Boston Mass USA August 2011

[71] P-C Shih Y-R Yang and R-Y Wang ldquoEffects of exerciseintensity on spatial memory performance and hippocampalsynaptic plasticity in transient brain ischemic ratsrdquo PLoS ONEvol 8 no 10 Article ID e78163 2013

[72] J Sun Z Ke S P Yip X-L Hu X-X Zheng and K-Y TongldquoGradually increased training intensity benefits rehabilitationoutcome after stroke by BDNF upregulation and stress sup-pressionrdquo BioMed Research International vol 2014 Article ID925762 8 pages 2014

[73] R Marin A Williams S Hale et al ldquoThe effect of voluntaryexercise exposure on histological and neurobehavioral out-comes after ischemic brain injury in the ratrdquo Physiology andBehavior vol 80 no 2-3 pp 167ndash175 2003

[74] S Vaynman Z Ying and F Gomez-Pinilla ldquoExercise inducesBDNF and synapsin I to specific hippocampal subfieldsrdquo Jour-nal of Neuroscience Research vol 76 no 3 pp 356ndash362 2004

[75] L Zhang X Hu J Luo et al ldquoPhysical exercise improves func-tional recovery through mitigation of autophagy attenuationof apoptosis and enhancement of neurogenesis after MCAO inratsrdquo BMC Neuroscience vol 14 article 46 2013

[76] J Puyal and P G H Clarke ldquoTargeting autophagy to preventneonatal stroke damagerdquoAutophagy vol 5 no 7 pp 1060ndash10612009

[77] Q-W Zhang X-X Deng X Sun J-X Xu and F-Y SunldquoExercise promotes axon regeneration of newborn striatonigraland corticonigral projection neurons in rats after ischemicstrokerdquo PLoS ONE vol 8 no 11 Article ID e80139 2013

[78] M Asahi K Asahi J-C Jung G J del ZoppoM E Fini and EH Lo ldquoRole for matrix metalloproteinase 9 after focal cerebralischemia effects of gene knockout and enzyme inhibition withBB-94rdquo Journal of Cerebral Blood Flow amp Metabolism vol 20no 12 pp 1681ndash1689 2000

[79] M Asahi X Wang T Mori et al ldquoEffects of matrixmetalloproteinase-9 gene knock-out on the proteolysis of

blood-brain barrier andwhitematter components after cerebralischemiardquoThe Journal of Neuroscience vol 21 no 19 pp 7724ndash7732 2001

[80] Y Zhang P Zhang X Shen et al ldquoEarly exercise protects theblood-brain barrier from ischemic brain injury via the regula-tion of MMP-9 and occludin in ratsrdquo International Journal ofMolecular Sciences vol 14 no 6 pp 11096ndash11112 2013

[81] I G Onyango J Lu M Rodova E Lezi A B Crafter and RH Swerdlow ldquoRegulation of neuron mitochondrial biogenesisand relevance to brain healthrdquo Biochimica et Biophysica ActamdashMolecular Basis of Disease vol 1802 no 1 pp 228ndash234 2010

[82] Q Zhang Y Wu P Zhang et al ldquoExercise induces mitochon-drial biogenesis after brain ischemia in ratsrdquo Neuroscience vol205 pp 10ndash17 2012

[83] L Li W Rong Z Ke X Hu and K-Y Tong ldquoThe effects oftraining intensities on motor recovery and gait symmetry in arat model of ischemiardquo Brain Injury vol 27 no 4 pp 408ndash4162013

[84] C Enzinger H Dawes H Johansen-Berg et al ldquoBrain activitychanges associated with treadmill training after strokerdquo Strokevol 40 no 7 pp 2460ndash2467 2009

[85] A R Luft R FMacKo LW Forrester et al ldquoTreadmill exerciseactivates subcortical neural networks and improves walkingafter stroke a randomized controlled trialrdquo Stroke vol 39 no12 pp 3341ndash3350 2008

[86] K Potempa M Lopez L T Braun J P Szidon L Fogg and TTincknell ldquoPhysiological outcomes of aerobic exercise trainingin hemiparetic stroke patientsrdquo Stroke vol 26 no 1 pp 101ndash1051995

[87] F Buma G Kwakkel and N Ramsey ldquoUnderstanding upperlimb recovery after strokerdquo Restorative Neurology and Neuro-science vol 31 no 6 pp 707ndash722 2013

[88] A E Baird A Benfield G Schlaug et al ldquoEnlargementof human cerebral ischemic lesion volumes measured bydiffusion-weighted magnetic resonance imagingrdquo Annals ofNeurology vol 41 no 5 pp 581ndash589 1997

[89] A Schmidt J Wellmann M Schilling et al ldquoMeta-analysis ofthe efficacy of different training strategies in animal models ofischemic strokerdquo Stroke vol 45 no 1 pp 239ndash247 2014

[90] R-Y Wang S-M Yu and Y-R Yang ldquoTreadmill trainingeffects in different age groups following middle cerebral arteryocclusion in ratsrdquo Gerontology vol 51 no 3 pp 161ndash165 2005

[91] P ZhangH YuN Zhou et al ldquoEarly exercise improves cerebralblood flow through increased angiogenesis in experimentalstroke rat modelrdquo Journal of NeuroEngineering and Rehabilita-tion vol 10 article 43 2013

[92] J Laurin andC Pin-Barre ldquoPhysiological adaptations followingendurance exercises after stroke focus on the plausible roleof high-intensity interval trainingrdquo International Journal ofPhysical Medicine amp Rehabilitation vol 2 no 3 pp 1ndash6 2014

[93] THMurphy andDCorbett ldquoPlasticity during stroke recoveryfrom synapse to behaviourrdquo Nature Reviews Neuroscience vol10 no 12 pp 861ndash872 2009

[94] M Svensson J Lexell and T Deierborg ldquoEffects of physicalexercise on neuroinflammation neuroplasticity neurodegener-ation and behavior what we can learn from animal models inclinical settingsrdquoNeurorehabilitation and Neural Repair vol 29no 6 pp 577ndash589 2015

[95] A Risedal J Zeng and B B Johansson ldquoEarly training mayexacerbate brain damage after focal brain ischemia in the ratrdquoJournal of Cerebral Blood Flow andMetabolism vol 19 no 9 pp997ndash1003 1999

Neural Plasticity 11

[96] C-S Piao B A Stoica J Wu et al ldquoLate exercise reducesneuroinflammation and cognitive dysfunction after traumaticbrain injuryrdquoNeurobiology of Disease vol 54 pp 252ndash263 2013

[97] J L Humm D A Kozlowski S T Bland D C James andT Schallert ldquoUse-dependent exaggeration of brain injury isglutamate involvedrdquo Experimental Neurology vol 157 no 2 pp349ndash358 1999

[98] G S Griesbach F Gomez-Pinilla and D A Hovda ldquoTheupregulation of plasticity-related proteins following TBI isdisrupted with acute voluntary exerciserdquo Brain Research vol1016 no 2 pp 154ndash162 2004

[99] J WMcAlees L T Smith R S Erbe D Jarjoura N M Ponzioand V M Sanders ldquoEpigenetic regulation of beta2-adrenergicreceptor expression in T

1198671 and T

1198672 cellsrdquo Brain Behavior and

Immunity vol 25 no 3 pp 408ndash415 2011[100] G Zhao S Zhou A Davie and Q Su ldquoEffects of moderate and

high intensity exercise on T1T2 balancerdquo Exercise ImmunologyReview vol 18 pp 98ndash114 2012

[101] Y Yagita K Kitagawa T Sasaki et al ldquoPostischemic exercisedecreases neurogenesis in the adult rat dentate gyrusrdquo Neuro-science Letters vol 409 no 1 pp 24ndash29 2006

[102] S T Bland T Schallert R Strong J Aronowski and J CGrottaldquoEarly exclusive use of the affected forelimb aftermoderate tran-sient focal ischemia in rats functional and anatomic outcomerdquoStroke vol 31 no 5 pp 1144ndash1152 2000

[103] S B DeBow J E McKenna B Kolb and F ColbourneldquoImmediate constraint-inducedmovement therapy causes localhyperthermia that exacerbates cerebral cortical injury in ratsrdquoCanadian Journal of Physiology and Pharmacology vol 82 no4 pp 231ndash237 2004

[104] D A Kozlowski D C James and T Schallert ldquoUse-dependentexaggeration of neuronal injury after unilateral sensorimotorcortex lesionsrdquo The Journal of Neuroscience vol 16 no 15 pp4776ndash4786 1996

[105] B Balaban F Tok F Yavuz E Yasar and R Alaca ldquoEarlyrehabilitation outcome in patients with middle cerebral arterystrokerdquo Neuroscience Letters vol 498 no 3 pp 204ndash207 2011

[106] G Kwakkel R van Peppen R C Wagenaar et al ldquoEffects ofaugmented exercise therapy time after stroke a meta-analysisrdquoStroke vol 35 no 11 pp 2529ndash2539 2004

[107] D L Costill M G Flynn J P Kirwan et al ldquoEffects of repeateddays of intensified training on muscle glycogen and swimmingperformancerdquo Medicine amp Science in Sports amp Exercise vol 20no 3 pp 249ndash254 1988

[108] M A Hirsch and B G Farley ldquoExercise and neuroplasticityin persons living with Parkinsonrsquos diseaserdquo European Journal ofPhysical and Rehabilitation Medicine vol 45 no 2 pp 215ndash2292009

[109] M Katz-Leurer M Shochina E Carmeli and Y FriedlanderldquoThe influence of early aerobic training on the functional capac-ity in patients with cerebrovascular accident at the subacutestagerdquo Archives of Physical Medicine and Rehabilitation vol 84no 11 pp 1609ndash1614 2003

[110] J D Schaechter ldquoMotor rehabilitation and brain plasticity afterhemiparetic strokerdquo Progress in Neurobiology vol 73 no 1 pp61ndash72 2004

[111] P R Bosch S Holzapfel and T Traustadottir ldquoFeasibility ofmeasuring ventilatory threshold in adults with stroke-inducedhemiparesis implications for exercise prescriptionrdquo Archives ofPhysical Medicine and Rehabilitation 2015

[112] D P Stirling K Khodarahmi J Liu et al ldquoMinocyclinetreatment reduces delayed oligodendrocyte death attenuatesaxonal dieback and improves functional outcome after spinalcord injuryrdquoThe Journal of Neuroscience vol 24 no 9 pp 2182ndash2190 2004

[113] S Barbay and R J Nudo ldquoThe effects of amphetamine onrecovery of function in animal models of cerebral injury acritical appraisalrdquo NeuroRehabilitation vol 25 no 1 pp 5ndash172009

[114] R S Rasmussen K Overgaard E S Hildebrandt-Eriksen andG Boysen ldquoD-Amphetamine improves cognitive deficits andphysical therapy promotes fine motor rehabilitation in a ratembolic stroke modelrdquo Acta Neurologica Scandinavica vol 113no 3 pp 189ndash198 2006

[115] C L Gibson B Coomber and S P Murphy ldquoProgesterone isneuroprotective following cerebral ischaemia in reproductivelyageing female micerdquo Brain vol 134 no 7 pp 2125ndash2133 2011

[116] T Ishrat I Sayeed F Atif and D G Stein ldquoEffects ofprogesterone administration on infarct volume and functionaldeficits following permanent focal cerebral ischemia in ratsrdquoBrain Research vol 1257 pp 94ndash101 2009

[117] M Prencipe C Ferretti A R Casini M Santini F Giubileiand F Culasso ldquoStroke disability and dementia results of apopulation surveyrdquo Stroke vol 28 no 3 pp 531ndash536 1997

[118] I Sayeed B Wali and D G Stein ldquoProgesterone inhibitsischemic brain injury in a rat model of permanent middle cere-bral artery occlusionrdquo Restorative Neurology and Neurosciencevol 25 no 2 pp 151ndash159 2007

[119] H Lee R J McKeon and R V Bellamkonda ldquoSustaineddelivery of thermostabilized chABC enhances axonal sproutingand functional recovery after spinal cord injuryrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 8 pp 3340ndash3345 2010

[120] V J Tom R Kadakia L Santi and J D Houle ldquoAdministrationof chondroitinase ABC rostral or caudal to a spinal cord injurysite promotes anatomical but not functional plasticityrdquo Journalof Neurotrauma vol 26 no 12 pp 2323ndash2333 2009

[121] J J Hill K Jin X O Mao L Xie and D A GreenbergldquoIntracerebral chondroitinase ABC and heparan sulfate proteo-glycan glypican improve outcome from chronic stroke in ratsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 23 pp 9155ndash9160 2012

[122] S Soleman P K Yip D A Duricki and L D FMoon ldquoDelayedtreatment with chondroitinase ABC promotes sensorimotorrecovery and plasticity after stroke in aged ratsrdquo Brain vol 135no 4 pp 1210ndash1223 2012

[123] B E Skolnick A I Maas R K Narayan et al ldquoA clinical trialof progesterone for severe traumatic brain injuryrdquo The NewEngland Journal of Medicine vol 371 no 26 pp 2467ndash24762014

[124] DWWright SD Yeatts R Silbergleit et al ldquoVery early admin-istration of progesterone for acute traumatic brain injuryrdquo TheNew England Journal of Medicine vol 371 no 26 pp 2457ndash2466 2014

[125] L-H Krarup T Truelsen C Gluud et al ldquoPrestroke physicalactivity is associated with severity and long-term outcome fromfirst-ever strokerdquo Neurology vol 71 no 17 pp 1313ndash1318 2008

[126] P M Rist I-M Lee C S Kase J Michael Gaziano and TKurth ldquoPhysical activity and functional outcomes from cerebralvascular events in menrdquo Stroke vol 42 no 12 pp 3352ndash33562011

12 Neural Plasticity

[127] Q Zhang L Zhang X Yang Y Wan and J Jia ldquoThe effectsof exercise preconditioning on cerebral blood flow change andendothelin-1 expression after cerebral ischemia in ratsrdquo Journalof Stroke and Cerebrovascular Diseases vol 23 no 6 pp 1696ndash1702 2014

[128] M Bernaudin A-S Nedelec D Divoux E T MacKenzie EPetit and P Schumann-Bard ldquoNormobaric hypoxia inducestolerance to focal permanent cerebral ischemia in associationwith an increased expression of hypoxia-inducible factor-1 andits target genes erythropoietin and VEGF in the adult mousebrainrdquo Journal of Cerebral Blood Flow and Metabolism vol 22no 4 pp 393ndash403 2002

[129] D Dornbos III N Zwagerman M Guo et al ldquoPreischemicexercise reduces brain damage by ameliorating metabolic dis-order in ischemiareperfusion injuryrdquo Journal of NeuroscienceResearch vol 91 no 6 pp 818ndash827 2013

[130] Y-H Ding Y Ding J Li D A Bessert and J A RafolsldquoExercise pre-conditioning strengthens brain microvascularintegrity in a rat stroke modelrdquo Neurological Research vol 28no 2 pp 184ndash189 2006

[131] M Guo B Cox S Mahale et al ldquoPre-ischemic exercise reducesmatrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in strokerdquo Neuroscience vol 151 no2 pp 340ndash351 2008

[132] M Ploughman Z Attwood N White J J E Dore and DCorbett ldquoEndurance exercise facilitates relearning of forelimbmotor skill after focal ischemiardquo The European Journal ofNeuroscience vol 25 no 11 pp 3453ndash3460 2007

[133] L L Guyot F G Diaz M H OrsquoRegan S McLeod H Park andJW Phillis ldquoReal-timemeasurement of glutamate release fromthe ischemic penumbra of the rat cerebral cortex using a focalmiddle cerebral artery occlusion modelrdquo Neuroscience Lettersvol 299 no 1-2 pp 37ndash40 2001

[134] K Matsumoto R Graf G Rosner J Taguchi and W-D HeissldquoElevation of neuroactive substances in the cortex of cats duringprolonged focal ischemiardquo Journal of Cerebral Blood Flow andMetabolism vol 13 no 4 pp 586ndash594 1993

[135] J Jia Y-S Hu Y Wu et al ldquoPre-ischemic treadmill trainingaffects glutamate and gamma aminobutyric acid levels in thestriatal dialysate of a rat model of cerebral ischemiardquo LifeSciences vol 84 no 15-16 pp 505ndash511 2009

[136] F Zhang J Jia Y Wu Y Hu and Y Wang ldquoThe effect of tread-mill training pre-exercise on glutamate receptor expression inrats after cerebral ischemiardquo International Journal of MolecularSciences vol 11 no 7 pp 2658ndash2669 2010

[137] J Jia Y-S Hu Y Wu et al ldquoTreadmill pre-training suppressesthe release of glutamate resulting from cerebral ischemia inratsrdquo Experimental Brain Research vol 204 no 2 pp 173ndash1792010

[138] E T Ang P T H Wong S Moochhala and Y K NgldquoNeuroprotection associated with running is it a result ofincreased endogenous neurotrophic factorsrdquoNeuroscience vol118 no 2 pp 335ndash345 2003

[139] A C Ricciardi E Lopez-Cancio N Perez De La Ossa et alldquoPrestroke physical activity is associated with good functionaloutcome and arterial recanalization after stroke due to a largevessel occlusionrdquo Cerebrovascular Diseases vol 37 no 4 pp304ndash311 2014

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Psychiatry Journal

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

10 Neural Plasticity

expression after middle cerebral artery occlusion in sponta-neously hypertensive ratsrdquo Neuroscience vol 97 no 1 pp 177ndash184 2000

[66] H D Muller K M Hanumanthiah K Diederich S SchwabW-R Schabitz and C Sommer ldquoBrain-derived neurotrophicfactor but not forced armuse improves long-term outcome afterphotothrombotic stroke and transiently upregulates bindingdensities of excitatory glutamate receptors in the rat brainrdquoStroke vol 39 no 3 pp 1012ndash1021 2008

[67] W-R Schabitz C Berger R Kollmar et al ldquoEffect of brain-derived neurotrophic factor treatment and forced arm use onfunctional motor recovery after small cortical ischemiardquo Strokevol 35 no 4 pp 992ndash997 2004

[68] J Chen J Qin Q Su Z Liu and J Yang ldquoTreadmillrehabilitation treatment enhanced BDNF-TrkB but not NGF-TrkA signaling in a mouse intracerebral hemorrhage modelrdquoNeuroscience Letters vol 529 no 1 pp 28ndash32 2012

[69] J-Y Chung M-W Kim M-S Bang and M Kim ldquoIncreasedexpression of neurotrophin 4 following focal cerebral ischemiain adult rat brain with treadmill exerciserdquo PLoS ONE vol 8 no3 Article ID e52461 2013

[70] Z Ke S P Yip L Li X X Zheng W K Tam and K Y TongldquoThe effects of voluntary involuntary and forced exercises onmotor recovery in a stroke rat modelrdquo in Proceedings of theAnnual International Conference of the IEEE Engineering inMedicine and Biology Society (EMBC rsquo11) vol 2011 pp 8223ndash8226 Boston Mass USA August 2011

[71] P-C Shih Y-R Yang and R-Y Wang ldquoEffects of exerciseintensity on spatial memory performance and hippocampalsynaptic plasticity in transient brain ischemic ratsrdquo PLoS ONEvol 8 no 10 Article ID e78163 2013

[72] J Sun Z Ke S P Yip X-L Hu X-X Zheng and K-Y TongldquoGradually increased training intensity benefits rehabilitationoutcome after stroke by BDNF upregulation and stress sup-pressionrdquo BioMed Research International vol 2014 Article ID925762 8 pages 2014

[73] R Marin A Williams S Hale et al ldquoThe effect of voluntaryexercise exposure on histological and neurobehavioral out-comes after ischemic brain injury in the ratrdquo Physiology andBehavior vol 80 no 2-3 pp 167ndash175 2003

[74] S Vaynman Z Ying and F Gomez-Pinilla ldquoExercise inducesBDNF and synapsin I to specific hippocampal subfieldsrdquo Jour-nal of Neuroscience Research vol 76 no 3 pp 356ndash362 2004

[75] L Zhang X Hu J Luo et al ldquoPhysical exercise improves func-tional recovery through mitigation of autophagy attenuationof apoptosis and enhancement of neurogenesis after MCAO inratsrdquo BMC Neuroscience vol 14 article 46 2013

[76] J Puyal and P G H Clarke ldquoTargeting autophagy to preventneonatal stroke damagerdquoAutophagy vol 5 no 7 pp 1060ndash10612009

[77] Q-W Zhang X-X Deng X Sun J-X Xu and F-Y SunldquoExercise promotes axon regeneration of newborn striatonigraland corticonigral projection neurons in rats after ischemicstrokerdquo PLoS ONE vol 8 no 11 Article ID e80139 2013

[78] M Asahi K Asahi J-C Jung G J del ZoppoM E Fini and EH Lo ldquoRole for matrix metalloproteinase 9 after focal cerebralischemia effects of gene knockout and enzyme inhibition withBB-94rdquo Journal of Cerebral Blood Flow amp Metabolism vol 20no 12 pp 1681ndash1689 2000

[79] M Asahi X Wang T Mori et al ldquoEffects of matrixmetalloproteinase-9 gene knock-out on the proteolysis of

blood-brain barrier andwhitematter components after cerebralischemiardquoThe Journal of Neuroscience vol 21 no 19 pp 7724ndash7732 2001

[80] Y Zhang P Zhang X Shen et al ldquoEarly exercise protects theblood-brain barrier from ischemic brain injury via the regula-tion of MMP-9 and occludin in ratsrdquo International Journal ofMolecular Sciences vol 14 no 6 pp 11096ndash11112 2013

[81] I G Onyango J Lu M Rodova E Lezi A B Crafter and RH Swerdlow ldquoRegulation of neuron mitochondrial biogenesisand relevance to brain healthrdquo Biochimica et Biophysica ActamdashMolecular Basis of Disease vol 1802 no 1 pp 228ndash234 2010

[82] Q Zhang Y Wu P Zhang et al ldquoExercise induces mitochon-drial biogenesis after brain ischemia in ratsrdquo Neuroscience vol205 pp 10ndash17 2012

[83] L Li W Rong Z Ke X Hu and K-Y Tong ldquoThe effects oftraining intensities on motor recovery and gait symmetry in arat model of ischemiardquo Brain Injury vol 27 no 4 pp 408ndash4162013

[84] C Enzinger H Dawes H Johansen-Berg et al ldquoBrain activitychanges associated with treadmill training after strokerdquo Strokevol 40 no 7 pp 2460ndash2467 2009

[85] A R Luft R FMacKo LW Forrester et al ldquoTreadmill exerciseactivates subcortical neural networks and improves walkingafter stroke a randomized controlled trialrdquo Stroke vol 39 no12 pp 3341ndash3350 2008

[86] K Potempa M Lopez L T Braun J P Szidon L Fogg and TTincknell ldquoPhysiological outcomes of aerobic exercise trainingin hemiparetic stroke patientsrdquo Stroke vol 26 no 1 pp 101ndash1051995

[87] F Buma G Kwakkel and N Ramsey ldquoUnderstanding upperlimb recovery after strokerdquo Restorative Neurology and Neuro-science vol 31 no 6 pp 707ndash722 2013

[88] A E Baird A Benfield G Schlaug et al ldquoEnlargementof human cerebral ischemic lesion volumes measured bydiffusion-weighted magnetic resonance imagingrdquo Annals ofNeurology vol 41 no 5 pp 581ndash589 1997

[89] A Schmidt J Wellmann M Schilling et al ldquoMeta-analysis ofthe efficacy of different training strategies in animal models ofischemic strokerdquo Stroke vol 45 no 1 pp 239ndash247 2014

[90] R-Y Wang S-M Yu and Y-R Yang ldquoTreadmill trainingeffects in different age groups following middle cerebral arteryocclusion in ratsrdquo Gerontology vol 51 no 3 pp 161ndash165 2005

[91] P ZhangH YuN Zhou et al ldquoEarly exercise improves cerebralblood flow through increased angiogenesis in experimentalstroke rat modelrdquo Journal of NeuroEngineering and Rehabilita-tion vol 10 article 43 2013

[92] J Laurin andC Pin-Barre ldquoPhysiological adaptations followingendurance exercises after stroke focus on the plausible roleof high-intensity interval trainingrdquo International Journal ofPhysical Medicine amp Rehabilitation vol 2 no 3 pp 1ndash6 2014

[93] THMurphy andDCorbett ldquoPlasticity during stroke recoveryfrom synapse to behaviourrdquo Nature Reviews Neuroscience vol10 no 12 pp 861ndash872 2009

[94] M Svensson J Lexell and T Deierborg ldquoEffects of physicalexercise on neuroinflammation neuroplasticity neurodegener-ation and behavior what we can learn from animal models inclinical settingsrdquoNeurorehabilitation and Neural Repair vol 29no 6 pp 577ndash589 2015

[95] A Risedal J Zeng and B B Johansson ldquoEarly training mayexacerbate brain damage after focal brain ischemia in the ratrdquoJournal of Cerebral Blood Flow andMetabolism vol 19 no 9 pp997ndash1003 1999

Neural Plasticity 11

[96] C-S Piao B A Stoica J Wu et al ldquoLate exercise reducesneuroinflammation and cognitive dysfunction after traumaticbrain injuryrdquoNeurobiology of Disease vol 54 pp 252ndash263 2013

[97] J L Humm D A Kozlowski S T Bland D C James andT Schallert ldquoUse-dependent exaggeration of brain injury isglutamate involvedrdquo Experimental Neurology vol 157 no 2 pp349ndash358 1999

[98] G S Griesbach F Gomez-Pinilla and D A Hovda ldquoTheupregulation of plasticity-related proteins following TBI isdisrupted with acute voluntary exerciserdquo Brain Research vol1016 no 2 pp 154ndash162 2004

[99] J WMcAlees L T Smith R S Erbe D Jarjoura N M Ponzioand V M Sanders ldquoEpigenetic regulation of beta2-adrenergicreceptor expression in T

1198671 and T

1198672 cellsrdquo Brain Behavior and

Immunity vol 25 no 3 pp 408ndash415 2011[100] G Zhao S Zhou A Davie and Q Su ldquoEffects of moderate and

high intensity exercise on T1T2 balancerdquo Exercise ImmunologyReview vol 18 pp 98ndash114 2012

[101] Y Yagita K Kitagawa T Sasaki et al ldquoPostischemic exercisedecreases neurogenesis in the adult rat dentate gyrusrdquo Neuro-science Letters vol 409 no 1 pp 24ndash29 2006

[102] S T Bland T Schallert R Strong J Aronowski and J CGrottaldquoEarly exclusive use of the affected forelimb aftermoderate tran-sient focal ischemia in rats functional and anatomic outcomerdquoStroke vol 31 no 5 pp 1144ndash1152 2000

[103] S B DeBow J E McKenna B Kolb and F ColbourneldquoImmediate constraint-inducedmovement therapy causes localhyperthermia that exacerbates cerebral cortical injury in ratsrdquoCanadian Journal of Physiology and Pharmacology vol 82 no4 pp 231ndash237 2004

[104] D A Kozlowski D C James and T Schallert ldquoUse-dependentexaggeration of neuronal injury after unilateral sensorimotorcortex lesionsrdquo The Journal of Neuroscience vol 16 no 15 pp4776ndash4786 1996

[105] B Balaban F Tok F Yavuz E Yasar and R Alaca ldquoEarlyrehabilitation outcome in patients with middle cerebral arterystrokerdquo Neuroscience Letters vol 498 no 3 pp 204ndash207 2011

[106] G Kwakkel R van Peppen R C Wagenaar et al ldquoEffects ofaugmented exercise therapy time after stroke a meta-analysisrdquoStroke vol 35 no 11 pp 2529ndash2539 2004

[107] D L Costill M G Flynn J P Kirwan et al ldquoEffects of repeateddays of intensified training on muscle glycogen and swimmingperformancerdquo Medicine amp Science in Sports amp Exercise vol 20no 3 pp 249ndash254 1988

[108] M A Hirsch and B G Farley ldquoExercise and neuroplasticityin persons living with Parkinsonrsquos diseaserdquo European Journal ofPhysical and Rehabilitation Medicine vol 45 no 2 pp 215ndash2292009

[109] M Katz-Leurer M Shochina E Carmeli and Y FriedlanderldquoThe influence of early aerobic training on the functional capac-ity in patients with cerebrovascular accident at the subacutestagerdquo Archives of Physical Medicine and Rehabilitation vol 84no 11 pp 1609ndash1614 2003

[110] J D Schaechter ldquoMotor rehabilitation and brain plasticity afterhemiparetic strokerdquo Progress in Neurobiology vol 73 no 1 pp61ndash72 2004

[111] P R Bosch S Holzapfel and T Traustadottir ldquoFeasibility ofmeasuring ventilatory threshold in adults with stroke-inducedhemiparesis implications for exercise prescriptionrdquo Archives ofPhysical Medicine and Rehabilitation 2015

[112] D P Stirling K Khodarahmi J Liu et al ldquoMinocyclinetreatment reduces delayed oligodendrocyte death attenuatesaxonal dieback and improves functional outcome after spinalcord injuryrdquoThe Journal of Neuroscience vol 24 no 9 pp 2182ndash2190 2004

[113] S Barbay and R J Nudo ldquoThe effects of amphetamine onrecovery of function in animal models of cerebral injury acritical appraisalrdquo NeuroRehabilitation vol 25 no 1 pp 5ndash172009

[114] R S Rasmussen K Overgaard E S Hildebrandt-Eriksen andG Boysen ldquoD-Amphetamine improves cognitive deficits andphysical therapy promotes fine motor rehabilitation in a ratembolic stroke modelrdquo Acta Neurologica Scandinavica vol 113no 3 pp 189ndash198 2006

[115] C L Gibson B Coomber and S P Murphy ldquoProgesterone isneuroprotective following cerebral ischaemia in reproductivelyageing female micerdquo Brain vol 134 no 7 pp 2125ndash2133 2011

[116] T Ishrat I Sayeed F Atif and D G Stein ldquoEffects ofprogesterone administration on infarct volume and functionaldeficits following permanent focal cerebral ischemia in ratsrdquoBrain Research vol 1257 pp 94ndash101 2009

[117] M Prencipe C Ferretti A R Casini M Santini F Giubileiand F Culasso ldquoStroke disability and dementia results of apopulation surveyrdquo Stroke vol 28 no 3 pp 531ndash536 1997

[118] I Sayeed B Wali and D G Stein ldquoProgesterone inhibitsischemic brain injury in a rat model of permanent middle cere-bral artery occlusionrdquo Restorative Neurology and Neurosciencevol 25 no 2 pp 151ndash159 2007

[119] H Lee R J McKeon and R V Bellamkonda ldquoSustaineddelivery of thermostabilized chABC enhances axonal sproutingand functional recovery after spinal cord injuryrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 8 pp 3340ndash3345 2010

[120] V J Tom R Kadakia L Santi and J D Houle ldquoAdministrationof chondroitinase ABC rostral or caudal to a spinal cord injurysite promotes anatomical but not functional plasticityrdquo Journalof Neurotrauma vol 26 no 12 pp 2323ndash2333 2009

[121] J J Hill K Jin X O Mao L Xie and D A GreenbergldquoIntracerebral chondroitinase ABC and heparan sulfate proteo-glycan glypican improve outcome from chronic stroke in ratsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 23 pp 9155ndash9160 2012

[122] S Soleman P K Yip D A Duricki and L D FMoon ldquoDelayedtreatment with chondroitinase ABC promotes sensorimotorrecovery and plasticity after stroke in aged ratsrdquo Brain vol 135no 4 pp 1210ndash1223 2012

[123] B E Skolnick A I Maas R K Narayan et al ldquoA clinical trialof progesterone for severe traumatic brain injuryrdquo The NewEngland Journal of Medicine vol 371 no 26 pp 2467ndash24762014

[124] DWWright SD Yeatts R Silbergleit et al ldquoVery early admin-istration of progesterone for acute traumatic brain injuryrdquo TheNew England Journal of Medicine vol 371 no 26 pp 2457ndash2466 2014

[125] L-H Krarup T Truelsen C Gluud et al ldquoPrestroke physicalactivity is associated with severity and long-term outcome fromfirst-ever strokerdquo Neurology vol 71 no 17 pp 1313ndash1318 2008

[126] P M Rist I-M Lee C S Kase J Michael Gaziano and TKurth ldquoPhysical activity and functional outcomes from cerebralvascular events in menrdquo Stroke vol 42 no 12 pp 3352ndash33562011

12 Neural Plasticity

[127] Q Zhang L Zhang X Yang Y Wan and J Jia ldquoThe effectsof exercise preconditioning on cerebral blood flow change andendothelin-1 expression after cerebral ischemia in ratsrdquo Journalof Stroke and Cerebrovascular Diseases vol 23 no 6 pp 1696ndash1702 2014

[128] M Bernaudin A-S Nedelec D Divoux E T MacKenzie EPetit and P Schumann-Bard ldquoNormobaric hypoxia inducestolerance to focal permanent cerebral ischemia in associationwith an increased expression of hypoxia-inducible factor-1 andits target genes erythropoietin and VEGF in the adult mousebrainrdquo Journal of Cerebral Blood Flow and Metabolism vol 22no 4 pp 393ndash403 2002

[129] D Dornbos III N Zwagerman M Guo et al ldquoPreischemicexercise reduces brain damage by ameliorating metabolic dis-order in ischemiareperfusion injuryrdquo Journal of NeuroscienceResearch vol 91 no 6 pp 818ndash827 2013

[130] Y-H Ding Y Ding J Li D A Bessert and J A RafolsldquoExercise pre-conditioning strengthens brain microvascularintegrity in a rat stroke modelrdquo Neurological Research vol 28no 2 pp 184ndash189 2006

[131] M Guo B Cox S Mahale et al ldquoPre-ischemic exercise reducesmatrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in strokerdquo Neuroscience vol 151 no2 pp 340ndash351 2008

[132] M Ploughman Z Attwood N White J J E Dore and DCorbett ldquoEndurance exercise facilitates relearning of forelimbmotor skill after focal ischemiardquo The European Journal ofNeuroscience vol 25 no 11 pp 3453ndash3460 2007

[133] L L Guyot F G Diaz M H OrsquoRegan S McLeod H Park andJW Phillis ldquoReal-timemeasurement of glutamate release fromthe ischemic penumbra of the rat cerebral cortex using a focalmiddle cerebral artery occlusion modelrdquo Neuroscience Lettersvol 299 no 1-2 pp 37ndash40 2001

[134] K Matsumoto R Graf G Rosner J Taguchi and W-D HeissldquoElevation of neuroactive substances in the cortex of cats duringprolonged focal ischemiardquo Journal of Cerebral Blood Flow andMetabolism vol 13 no 4 pp 586ndash594 1993

[135] J Jia Y-S Hu Y Wu et al ldquoPre-ischemic treadmill trainingaffects glutamate and gamma aminobutyric acid levels in thestriatal dialysate of a rat model of cerebral ischemiardquo LifeSciences vol 84 no 15-16 pp 505ndash511 2009

[136] F Zhang J Jia Y Wu Y Hu and Y Wang ldquoThe effect of tread-mill training pre-exercise on glutamate receptor expression inrats after cerebral ischemiardquo International Journal of MolecularSciences vol 11 no 7 pp 2658ndash2669 2010

[137] J Jia Y-S Hu Y Wu et al ldquoTreadmill pre-training suppressesthe release of glutamate resulting from cerebral ischemia inratsrdquo Experimental Brain Research vol 204 no 2 pp 173ndash1792010

[138] E T Ang P T H Wong S Moochhala and Y K NgldquoNeuroprotection associated with running is it a result ofincreased endogenous neurotrophic factorsrdquoNeuroscience vol118 no 2 pp 335ndash345 2003

[139] A C Ricciardi E Lopez-Cancio N Perez De La Ossa et alldquoPrestroke physical activity is associated with good functionaloutcome and arterial recanalization after stroke due to a largevessel occlusionrdquo Cerebrovascular Diseases vol 37 no 4 pp304ndash311 2014

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Psychiatry Journal

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity 11

[96] C-S Piao B A Stoica J Wu et al ldquoLate exercise reducesneuroinflammation and cognitive dysfunction after traumaticbrain injuryrdquoNeurobiology of Disease vol 54 pp 252ndash263 2013

[97] J L Humm D A Kozlowski S T Bland D C James andT Schallert ldquoUse-dependent exaggeration of brain injury isglutamate involvedrdquo Experimental Neurology vol 157 no 2 pp349ndash358 1999

[98] G S Griesbach F Gomez-Pinilla and D A Hovda ldquoTheupregulation of plasticity-related proteins following TBI isdisrupted with acute voluntary exerciserdquo Brain Research vol1016 no 2 pp 154ndash162 2004

[99] J WMcAlees L T Smith R S Erbe D Jarjoura N M Ponzioand V M Sanders ldquoEpigenetic regulation of beta2-adrenergicreceptor expression in T

1198671 and T

1198672 cellsrdquo Brain Behavior and

Immunity vol 25 no 3 pp 408ndash415 2011[100] G Zhao S Zhou A Davie and Q Su ldquoEffects of moderate and

high intensity exercise on T1T2 balancerdquo Exercise ImmunologyReview vol 18 pp 98ndash114 2012

[101] Y Yagita K Kitagawa T Sasaki et al ldquoPostischemic exercisedecreases neurogenesis in the adult rat dentate gyrusrdquo Neuro-science Letters vol 409 no 1 pp 24ndash29 2006

[102] S T Bland T Schallert R Strong J Aronowski and J CGrottaldquoEarly exclusive use of the affected forelimb aftermoderate tran-sient focal ischemia in rats functional and anatomic outcomerdquoStroke vol 31 no 5 pp 1144ndash1152 2000

[103] S B DeBow J E McKenna B Kolb and F ColbourneldquoImmediate constraint-inducedmovement therapy causes localhyperthermia that exacerbates cerebral cortical injury in ratsrdquoCanadian Journal of Physiology and Pharmacology vol 82 no4 pp 231ndash237 2004

[104] D A Kozlowski D C James and T Schallert ldquoUse-dependentexaggeration of neuronal injury after unilateral sensorimotorcortex lesionsrdquo The Journal of Neuroscience vol 16 no 15 pp4776ndash4786 1996

[105] B Balaban F Tok F Yavuz E Yasar and R Alaca ldquoEarlyrehabilitation outcome in patients with middle cerebral arterystrokerdquo Neuroscience Letters vol 498 no 3 pp 204ndash207 2011

[106] G Kwakkel R van Peppen R C Wagenaar et al ldquoEffects ofaugmented exercise therapy time after stroke a meta-analysisrdquoStroke vol 35 no 11 pp 2529ndash2539 2004

[107] D L Costill M G Flynn J P Kirwan et al ldquoEffects of repeateddays of intensified training on muscle glycogen and swimmingperformancerdquo Medicine amp Science in Sports amp Exercise vol 20no 3 pp 249ndash254 1988

[108] M A Hirsch and B G Farley ldquoExercise and neuroplasticityin persons living with Parkinsonrsquos diseaserdquo European Journal ofPhysical and Rehabilitation Medicine vol 45 no 2 pp 215ndash2292009

[109] M Katz-Leurer M Shochina E Carmeli and Y FriedlanderldquoThe influence of early aerobic training on the functional capac-ity in patients with cerebrovascular accident at the subacutestagerdquo Archives of Physical Medicine and Rehabilitation vol 84no 11 pp 1609ndash1614 2003

[110] J D Schaechter ldquoMotor rehabilitation and brain plasticity afterhemiparetic strokerdquo Progress in Neurobiology vol 73 no 1 pp61ndash72 2004

[111] P R Bosch S Holzapfel and T Traustadottir ldquoFeasibility ofmeasuring ventilatory threshold in adults with stroke-inducedhemiparesis implications for exercise prescriptionrdquo Archives ofPhysical Medicine and Rehabilitation 2015

[112] D P Stirling K Khodarahmi J Liu et al ldquoMinocyclinetreatment reduces delayed oligodendrocyte death attenuatesaxonal dieback and improves functional outcome after spinalcord injuryrdquoThe Journal of Neuroscience vol 24 no 9 pp 2182ndash2190 2004

[113] S Barbay and R J Nudo ldquoThe effects of amphetamine onrecovery of function in animal models of cerebral injury acritical appraisalrdquo NeuroRehabilitation vol 25 no 1 pp 5ndash172009

[114] R S Rasmussen K Overgaard E S Hildebrandt-Eriksen andG Boysen ldquoD-Amphetamine improves cognitive deficits andphysical therapy promotes fine motor rehabilitation in a ratembolic stroke modelrdquo Acta Neurologica Scandinavica vol 113no 3 pp 189ndash198 2006

[115] C L Gibson B Coomber and S P Murphy ldquoProgesterone isneuroprotective following cerebral ischaemia in reproductivelyageing female micerdquo Brain vol 134 no 7 pp 2125ndash2133 2011

[116] T Ishrat I Sayeed F Atif and D G Stein ldquoEffects ofprogesterone administration on infarct volume and functionaldeficits following permanent focal cerebral ischemia in ratsrdquoBrain Research vol 1257 pp 94ndash101 2009

[117] M Prencipe C Ferretti A R Casini M Santini F Giubileiand F Culasso ldquoStroke disability and dementia results of apopulation surveyrdquo Stroke vol 28 no 3 pp 531ndash536 1997

[118] I Sayeed B Wali and D G Stein ldquoProgesterone inhibitsischemic brain injury in a rat model of permanent middle cere-bral artery occlusionrdquo Restorative Neurology and Neurosciencevol 25 no 2 pp 151ndash159 2007

[119] H Lee R J McKeon and R V Bellamkonda ldquoSustaineddelivery of thermostabilized chABC enhances axonal sproutingand functional recovery after spinal cord injuryrdquo Proceedings ofthe National Academy of Sciences of the United States of Americavol 107 no 8 pp 3340ndash3345 2010

[120] V J Tom R Kadakia L Santi and J D Houle ldquoAdministrationof chondroitinase ABC rostral or caudal to a spinal cord injurysite promotes anatomical but not functional plasticityrdquo Journalof Neurotrauma vol 26 no 12 pp 2323ndash2333 2009

[121] J J Hill K Jin X O Mao L Xie and D A GreenbergldquoIntracerebral chondroitinase ABC and heparan sulfate proteo-glycan glypican improve outcome from chronic stroke in ratsrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 109 no 23 pp 9155ndash9160 2012

[122] S Soleman P K Yip D A Duricki and L D FMoon ldquoDelayedtreatment with chondroitinase ABC promotes sensorimotorrecovery and plasticity after stroke in aged ratsrdquo Brain vol 135no 4 pp 1210ndash1223 2012

[123] B E Skolnick A I Maas R K Narayan et al ldquoA clinical trialof progesterone for severe traumatic brain injuryrdquo The NewEngland Journal of Medicine vol 371 no 26 pp 2467ndash24762014

[124] DWWright SD Yeatts R Silbergleit et al ldquoVery early admin-istration of progesterone for acute traumatic brain injuryrdquo TheNew England Journal of Medicine vol 371 no 26 pp 2457ndash2466 2014

[125] L-H Krarup T Truelsen C Gluud et al ldquoPrestroke physicalactivity is associated with severity and long-term outcome fromfirst-ever strokerdquo Neurology vol 71 no 17 pp 1313ndash1318 2008

[126] P M Rist I-M Lee C S Kase J Michael Gaziano and TKurth ldquoPhysical activity and functional outcomes from cerebralvascular events in menrdquo Stroke vol 42 no 12 pp 3352ndash33562011

12 Neural Plasticity

[127] Q Zhang L Zhang X Yang Y Wan and J Jia ldquoThe effectsof exercise preconditioning on cerebral blood flow change andendothelin-1 expression after cerebral ischemia in ratsrdquo Journalof Stroke and Cerebrovascular Diseases vol 23 no 6 pp 1696ndash1702 2014

[128] M Bernaudin A-S Nedelec D Divoux E T MacKenzie EPetit and P Schumann-Bard ldquoNormobaric hypoxia inducestolerance to focal permanent cerebral ischemia in associationwith an increased expression of hypoxia-inducible factor-1 andits target genes erythropoietin and VEGF in the adult mousebrainrdquo Journal of Cerebral Blood Flow and Metabolism vol 22no 4 pp 393ndash403 2002

[129] D Dornbos III N Zwagerman M Guo et al ldquoPreischemicexercise reduces brain damage by ameliorating metabolic dis-order in ischemiareperfusion injuryrdquo Journal of NeuroscienceResearch vol 91 no 6 pp 818ndash827 2013

[130] Y-H Ding Y Ding J Li D A Bessert and J A RafolsldquoExercise pre-conditioning strengthens brain microvascularintegrity in a rat stroke modelrdquo Neurological Research vol 28no 2 pp 184ndash189 2006

[131] M Guo B Cox S Mahale et al ldquoPre-ischemic exercise reducesmatrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in strokerdquo Neuroscience vol 151 no2 pp 340ndash351 2008

[132] M Ploughman Z Attwood N White J J E Dore and DCorbett ldquoEndurance exercise facilitates relearning of forelimbmotor skill after focal ischemiardquo The European Journal ofNeuroscience vol 25 no 11 pp 3453ndash3460 2007

[133] L L Guyot F G Diaz M H OrsquoRegan S McLeod H Park andJW Phillis ldquoReal-timemeasurement of glutamate release fromthe ischemic penumbra of the rat cerebral cortex using a focalmiddle cerebral artery occlusion modelrdquo Neuroscience Lettersvol 299 no 1-2 pp 37ndash40 2001

[134] K Matsumoto R Graf G Rosner J Taguchi and W-D HeissldquoElevation of neuroactive substances in the cortex of cats duringprolonged focal ischemiardquo Journal of Cerebral Blood Flow andMetabolism vol 13 no 4 pp 586ndash594 1993

[135] J Jia Y-S Hu Y Wu et al ldquoPre-ischemic treadmill trainingaffects glutamate and gamma aminobutyric acid levels in thestriatal dialysate of a rat model of cerebral ischemiardquo LifeSciences vol 84 no 15-16 pp 505ndash511 2009

[136] F Zhang J Jia Y Wu Y Hu and Y Wang ldquoThe effect of tread-mill training pre-exercise on glutamate receptor expression inrats after cerebral ischemiardquo International Journal of MolecularSciences vol 11 no 7 pp 2658ndash2669 2010

[137] J Jia Y-S Hu Y Wu et al ldquoTreadmill pre-training suppressesthe release of glutamate resulting from cerebral ischemia inratsrdquo Experimental Brain Research vol 204 no 2 pp 173ndash1792010

[138] E T Ang P T H Wong S Moochhala and Y K NgldquoNeuroprotection associated with running is it a result ofincreased endogenous neurotrophic factorsrdquoNeuroscience vol118 no 2 pp 335ndash345 2003

[139] A C Ricciardi E Lopez-Cancio N Perez De La Ossa et alldquoPrestroke physical activity is associated with good functionaloutcome and arterial recanalization after stroke due to a largevessel occlusionrdquo Cerebrovascular Diseases vol 37 no 4 pp304ndash311 2014

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Psychiatry Journal

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

12 Neural Plasticity

[127] Q Zhang L Zhang X Yang Y Wan and J Jia ldquoThe effectsof exercise preconditioning on cerebral blood flow change andendothelin-1 expression after cerebral ischemia in ratsrdquo Journalof Stroke and Cerebrovascular Diseases vol 23 no 6 pp 1696ndash1702 2014

[128] M Bernaudin A-S Nedelec D Divoux E T MacKenzie EPetit and P Schumann-Bard ldquoNormobaric hypoxia inducestolerance to focal permanent cerebral ischemia in associationwith an increased expression of hypoxia-inducible factor-1 andits target genes erythropoietin and VEGF in the adult mousebrainrdquo Journal of Cerebral Blood Flow and Metabolism vol 22no 4 pp 393ndash403 2002

[129] D Dornbos III N Zwagerman M Guo et al ldquoPreischemicexercise reduces brain damage by ameliorating metabolic dis-order in ischemiareperfusion injuryrdquo Journal of NeuroscienceResearch vol 91 no 6 pp 818ndash827 2013

[130] Y-H Ding Y Ding J Li D A Bessert and J A RafolsldquoExercise pre-conditioning strengthens brain microvascularintegrity in a rat stroke modelrdquo Neurological Research vol 28no 2 pp 184ndash189 2006

[131] M Guo B Cox S Mahale et al ldquoPre-ischemic exercise reducesmatrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in strokerdquo Neuroscience vol 151 no2 pp 340ndash351 2008

[132] M Ploughman Z Attwood N White J J E Dore and DCorbett ldquoEndurance exercise facilitates relearning of forelimbmotor skill after focal ischemiardquo The European Journal ofNeuroscience vol 25 no 11 pp 3453ndash3460 2007

[133] L L Guyot F G Diaz M H OrsquoRegan S McLeod H Park andJW Phillis ldquoReal-timemeasurement of glutamate release fromthe ischemic penumbra of the rat cerebral cortex using a focalmiddle cerebral artery occlusion modelrdquo Neuroscience Lettersvol 299 no 1-2 pp 37ndash40 2001

[134] K Matsumoto R Graf G Rosner J Taguchi and W-D HeissldquoElevation of neuroactive substances in the cortex of cats duringprolonged focal ischemiardquo Journal of Cerebral Blood Flow andMetabolism vol 13 no 4 pp 586ndash594 1993

[135] J Jia Y-S Hu Y Wu et al ldquoPre-ischemic treadmill trainingaffects glutamate and gamma aminobutyric acid levels in thestriatal dialysate of a rat model of cerebral ischemiardquo LifeSciences vol 84 no 15-16 pp 505ndash511 2009

[136] F Zhang J Jia Y Wu Y Hu and Y Wang ldquoThe effect of tread-mill training pre-exercise on glutamate receptor expression inrats after cerebral ischemiardquo International Journal of MolecularSciences vol 11 no 7 pp 2658ndash2669 2010

[137] J Jia Y-S Hu Y Wu et al ldquoTreadmill pre-training suppressesthe release of glutamate resulting from cerebral ischemia inratsrdquo Experimental Brain Research vol 204 no 2 pp 173ndash1792010

[138] E T Ang P T H Wong S Moochhala and Y K NgldquoNeuroprotection associated with running is it a result ofincreased endogenous neurotrophic factorsrdquoNeuroscience vol118 no 2 pp 335ndash345 2003

[139] A C Ricciardi E Lopez-Cancio N Perez De La Ossa et alldquoPrestroke physical activity is associated with good functionaloutcome and arterial recanalization after stroke due to a largevessel occlusionrdquo Cerebrovascular Diseases vol 37 no 4 pp304ndash311 2014

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Psychiatry Journal

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Submit your manuscripts athttpwwwhindawicom

Neurology Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Alzheimerrsquos DiseaseHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

International Journal of

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentSchizophrenia

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neural Plasticity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAutism

Sleep DisordersHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neuroscience Journal

Epilepsy Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Psychiatry Journal

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

Depression Research and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Brain ScienceInternational Journal of

StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Neurodegenerative Diseases

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Cardiovascular Psychiatry and NeurologyHindawi Publishing Corporationhttpwwwhindawicom Volume 2014