Efficacy and Safety of Transcutaneous Electrical Acupoint Stimulation to Treat Muscle Spasticity

15 Pages·2015·0.58 MB·English

RESEARCHARTICLE
Efficacy and Safety of Transcutaneous
Electrical Acupoint Stimulation to Treat
Muscle Spasticity following Brain Injury:
A Double-Blinded, Multicenter, Randomized
Controlled Trial
WenliZhao1‡,ChaoWang2‡,ZhongzhengLi2,LeiChen3,JianboLi3,WeidongCui3,
ShashaDing2,QiangXi2,FanWang2,FeiJia2,ShuhuaXiao2,YiGuo2,YeZhao4*
1 DepartmentofNeurology,TianjinNankaiHospital,Tianjin,300100,China,2 DepartmentofAcupuncture
andMoxibustion,TianjinUniversityofTraditionalChineseMedicine,Tianjin,300193,China,3 Departmentof
AcupunctureandMoxibustion,TianjinNingheHospital,Tianjin,301500,China,4 DepartmentofClinical
Research,TianjinNankaiHospitalandTianjinAcademyofIntegrativeMedicine,Tianjin,300100,China
‡Theseauthorscontributedequallytothiswork.
* [email protected]
OPENACCESS
Citation:ZhaoW,WangC,LiZ,ChenL,LiJ,CuiW,
etal.(2015)EfficacyandSafetyofTranscutaneous Abstract
ElectricalAcupointStimulationtoTreatMuscle
SpasticityfollowingBrainInjury:ADouble-Blinded,
Multicenter,RandomizedControlledTrial.PLoSONE Objective
10(2):e0116976.doi:10.1371/journal.pone.0116976
Thisstudywasaimedatevaluatingtheclinicalefficacyandsafetyoftranscutaneouselectri-
AcademicEditor:MicheleSterling,Griffith calacupointstimulation(TEAS)totreatmusclespasticityafterbraininjury(ChineseClinical
University,AUSTRALIA
TrialRegistry:ChiCTR-TRC-11001310).
Received:August13,2014
Methods
Accepted:December7,2014
Published:February2,2015 Atotalof60patientswithmusclespasticityafterbraininjurywererandomizedtothefollow-
ing3groups:100,2,and0Hz(sham)TEAS.TheacupointsHegu(LI4)—Yuji(LU10)and
Copyright:©2015Zhaoetal.Thisisanopen
accessarticledistributedunderthetermsofthe Zusanli(ST36)—Chengshan(BL57)ontheinjuredsidewerestimulatedat0,2,or100Hz,
CreativeCommonsAttributionLicense,whichpermits 5timesperweekfor4weeks.Thepatientswerefollowedupfor1and2monthsafterthe
unrestricteduse,distribution,andreproductioninany
treatments.Theeffectsofthetreatmentsonmusclespasticityatthewrist,thumb,theother
medium,providedtheoriginalauthorandsourceare
4fingers,elbow,shoulder,knee,andanklewereevaluatedbytheModifiedAshworth
credited.
Scale,andtheeffectsondisabilitywereassessedbytheDisabilityAssessmentScale.The
DataAvailabilityStatement:Allrelevantdataare
walkingcapabilitywasevaluatedbytheHoldenfunctionalambulationclassificationscore.
withinthepaperanditsSupportingInformationfiles.
TheoverallperformancewasassessedbytheGlobalAssessmentScalescoreandtheim-
Funding:Author:ChaoWang.Thisworkwas
provedBarthelIndex.Thesafetyofthetreatmentsadministeredwasalsomonitored.
supportedbytheScienceFoundationonTraditional
ChineseMedicine(TCM)/IntegrativeMedicineofthe
TianjinAdministrationofTCM(grantno.11031).The Results
fundershadnoroleinstudydesign,datacollection
Thewristspasticitywassignificantlyreducedfrombaselineatweeks2,3,and4oftreat-
andanalysis,decisiontopublish,orpreparationof
themanuscript. mentandatthe1-and2-monthfollow-upvisitsinthe100Hzgroup(P<0.01).Compared
with2HzorshamTEAS,100HzTEASdecreasedwristspasticityatweeks2,3,and4of
CompetingInterests:Theauthorshavedeclared
thatnocompetinginterestsexist. treatmentand1monthaftertreatment(P<0.001).Theotherendpointswerenotaffected
PLOSONE|DOI:10.1371/journal.pone.0116976 February2,2015 1/15
TEASTreatsMuscleSpasticity
bythetreatments.Notreatment-emergentadverseeventswerereportedduringtreatments
andfollow-upvisits.
Conclusions
TEASappearstobeasafeandeffectivetherapytorelievemusclespasticityafterbraininju-
ry,althoughlarge-scalestudiesarerequiredtofurtherverifythefindings.
TrialRegistration
ChineseClinicalTrialRegistryChiCTR-TRC-11001310http://www.chictr.org
INTRODUCTION
Spasticity—characterizedbyexaggeratedtendonjerksandclonus—isacommoncomplication
followingbrainorspinalcorddamages,andadverselyaffectsworkandqualityoflifeofpa-
tients[1–4].Theexactpathophysiologyofspasticityremainsunclear.Excessiveactivityofthe
alphamotorneuron(-MN)poolcausedbytheimbalancebetweeninhibitoryandexcitatoryef-
fectsisthoughttocontributetospasticityafterbraininjury[5].Brainandspinalcordinjuries
frequentlydamagethedorsalreticulospinaltract,whichmediatesinhibitoryeffectsand,thus,
consequentlyleadtotheexaggerationofexcitatoryinputsfromthemedialreticulospinaland
vestibulospinaltractsand,ultimately,spasticity[6].
Conventionaltherapiesforspasticityincludingphysicaltherapy,surgery,andpharmaco-
therapyoftenproduceunsatisfactoryoutcomes.Theoutcomesofsurgicalinterventionvary,
dependinguponthelocationandtheseverityofspasticity[7],whereastheeffectsofpharmaco-
logictreatmentsareoftenshorttermformanypatientsandseveresideeffectsoccursometimes
[8–10].Transcutaneouselectricalnervestimulation(TENS)hasalsobeenshowntoimprove
clinical,electrophysiological,andfunctionalvariablesinpatientswithspasticitywithasimilar
efficacyasbaclofen[11].SimilartoTENS,transcutaneouselectricalacupointstimulation
(TEAS)isalsoanelectricalstimulationmethodinwhichacupointsspecificallyassociatedwith
medicalconditionsarestimulated.
TEAShas,recently,beenemergingasapopulartherapeuticapproachandhasbeenwidely
testedinmanymedicalconditions,suchaspain,gastrointestinaldisorder,inflammation,can-
cer,andAlzheimer[12–17].Althoughcontroversialresultshavebeenreported,TEASappears
tobeincreasinglyusedinclinicalpracticenow[18–20].ThemechanismofactionofTEAS
mightbesimilartothatofelectricalacupuncture(EA),inwhichacupointsarestimulatedby
electricalimpulsesgiventhroughneedles.StudiesonpainmanagementusingEAinanimal
modelsandpatientssuggestthatEAblockspainbyactivatingabroadspectrumofbioactive
chemicalssuchasopioids,serotonin,andnorepinephrinetodesensitizeperipheralnociceptors
andreduceproinflammatorycytokinesperipherallyandinthespinalcord[20,21].
StudiesontherapeuticapplicationofTEASinthemanagementofspasticityaresparse,but
theresultsfromthosestudiesconsistentlyshowthebeneficialeffectsofTEASonpatientswith
spasticityfollowingspinalcordinjuryorstroke[22–26].Yanetal.conductedarandomized
controlledtrialtocomparetheeffectsofTEAS,placebostimulation,andstandardrehabilita-
tionaloneonmusclefunctionafteracutestrokeandfoundthatTEASsignificantlyincreased
theproportionofpatientswithimprovedmusclefunction[22].Wangetal.evaluatedtheeffi-
cacyof0,2,and100HzTEASonspasticityafterspinalcordinjuryandfound100HzTEASre-
lievedspasticitymoreefficientlyandeffectivelythan2HzTEASinpatients[23].Althoughthe
PLOSONE|DOI:10.1371/journal.pone.0116976 February2,2015 2/15
TEASTreatsMuscleSpasticity
resultsareconsistent,mostofthestudiesexceptthereportbyYanetal.arenotrandomized
controlledtrials,significantlycompromisingthequalityofthedata.Here,weconductedaran-
domizedcontrolledtrialtoevaluatetheclinicalefficacyandsafetyofTEASandcomparetheef-
ficacyofhighversuslowTEASfrequencyonpatientswithspasticityfollowingbraininjury.
MATERIALSANDMETHOD
Theprotocolforthistrial,supportingCONSORTchecklist,andtheoriginaldataoftheclinical
trialareavailableassupportinginformation;seeS1Protocol,S1CONSORTChecklist,andS1
Table.
Trialdesign
Thisdouble-blinded,multicenter,randomizedcontrolledtrialwasconductedat6clinicalcen-
tersinthecityofTianjinanditssurroundingcountiesbetweenMarchandSeptember2011.
ThistrialwasconductedinaccordancewiththeprinciplesoftheDeclarationofHelsinki
(VersionEdinburgh2000)andapprovedbytheChineseEthicsCommitteeofRegisteringClin-
icalTrial.ThestudywasregisteredattheChineseClinicalTrialRegistry(http://www.chictr.
org/cn,UniqueIdentifier:ChiCTR-TRC-11001310).Thestudyprotocolwasapprovedbythe
InstitutionalEthicsCommitteeofTianjinUniversityofTraditionalChineseMedicine
(TJUTCM-EC20110001).Writteninformedconsentwasobtainedfromallpatients.TheCON-
SORTflowdiagramisdisplayedinFig.1.ThetrialdesignisillustratedinFig.2.
Figure1.TheCONSORTflowdiagram.
doi:10.1371/journal.pone.0116976.g001
PLOSONE|DOI:10.1371/journal.pone.0116976 February2,2015 3/15
TEASTreatsMuscleSpasticity
Figure2.Studydesign.
doi:10.1371/journal.pone.0116976.g002
Patients
Eligiblepatientswereadults18–85yearsofage(bothyearsinclusive)whodidnotreceivepre-
viousTENSorTEAStreatmentsandhad:experiencedatleast1episodeofbraininjurysuchas
cerebralhemorrhage,cerebralinfarction,orbraintrauma(confirmedbyexaminingpatients’
medicalrecordsandcomputedtomographyormagneticresonanceimagingofthebrain)at
least3monthsbeforestudyenrollment;increasedmuscletoneoftheflexorcarpiontheaffect-
edsidewithModifiedAshworthScale(MAS)score(cid:1)3;anddisabilityscore(cid:1)2accordingto
theDisabilityAssessmentScale(DAS).Patientswiththefollowingconditionswereexcluded
fromthestudy:severecontractureatthejointsofaffectedlimbs(inabilitytopassivelymove
thejointby>10°),previousAchillestendonlengtheningortransplantationsurgery,previous
nerveresectionsurgery,injectionofbotulinumtoxinintothetargetlimbwithin4monthsbe-
foreenrollment,localneuromuscularblockingtherapyororalantispasmodicmedicationwith-
in2weeksbeforeenrollment,severemuscleatrophyorinfectionintargetlimbs,pregnantor
planningtobecomepregnantduringthecourseofthestudy,orsevereconditionsinotheror-
ganssuchassevereliverandrenaldysfunctionorwearingacardiacpacemaker.
Randomization,allocation,andblinding
Acentralrandomizationschemewasusedtoassigneligiblepatientsto3groups—100,2,or0
HzTEAS(sham)—ina1:1:1ratioattheTianjinUniversityofTraditionalChineseMedicine.
Apermuted-blockrandomizationprocedurewasusedtogenerateanallocationsequence.The
blocksizeforrandomizationwas6.Sealedopaqueenvelopescontainingthepatientnumber
andtheallocatedtreatmentwereprepared.Theenvelopesweresequentiallynumbered.Several
levelsofblindingstrategywereimplementedtominimizepossiblebias.Thepersonnelwhore-
cruitedpatients,professionalassessorswhoevaluatedpatientperformance,andthestatistician
wereblindedtotreatmentallocation.Thepatientstoo,werecompletelyblindedtothetreat-
mentadministered.Attherecruitmentinterview,theparticipantswereinformedthatthey
weretoundergo1of3newtherapiesformusclespasticity.Thefollowingdetailedexplanations
ofthenewtherapieswerealsoprovidedtotheparticipants:“Duringtreatment,acupuncture
pointswillbestimulatedbymicro-currentsgeneratedbyaspecialelectricaldevice.Themagni-
tudeofthemicro-currentsissolowthatapersonmightexperienceonlymildelectriccurrent
sensationorfeelnothingatall.”Topreventanypossiblepsychologicalinterferenceonthere-
sults,thepatientswereallowedtowatchtheoperationoftheelectricalstimulatorandbelieved
PLOSONE|DOI:10.1371/journal.pone.0116976 February2,2015 4/15
TEASTreatsMuscleSpasticity
thattheyreceivedrealtreatments.IntheshamTEASgroup,theelectrodeswereplacedonthe
sameacupointsandtreatedforthesamedurationastheother2groups.Tofurtherensurethe
participantswereblindedfortreatmentsadministeredandtopreventanypossiblepsychologi-
calinterference,ateachtreatmentsession,atrainednursewhowasblindedtotreatmentalloca-
tionwaspresentandengagedaconversationwiththeparticipantstodistractandhelp
themrelax.
Astheacupuncturistshadtoadministertreatment,itwasimpossibletocompletelyblind
themtopatients’informationsuchassymptoms.However,theacupuncturistswereforbidden
tospeaktopatientsduringtreatments.Inthecasethatapatientexpressedconcernsorcom-
plainsregardingtreatments,thepatientspoketothenurseandthenurseforwardedtheinfor-
mationtotheacupuncturists,whowouldadjustthetreatments.AftersettinguptheTEAS
instrumentandensuringtheinstrumentworkedproperly,theacupuncturistsleftthetreatment
room.Theunblindingwasconductedin2steps.Thefirstdataunblindingwasperformedafter
thetrialwascompletedandthedatabasewaslocked.Thestatisticianwasexposedtothedata
organizedaccordingtotreatmentgroups,representedasA,B,andC.Theannotationofeach
letterwasnotrevealedtothestatistician.Theseconddataunblindingwasperformedafterdata
analyseswerecompleted.Alltheinformationonpatientsandtreatmentallocationwerethen
disclosedtoinvestigatorsparticipatinginthetrial.
Interventions
Allpatientswereallowedtocontinuetheirroutinerehabilitationtraininganddietaryregimen
duringthestudy.Alleligiblepatientswerealsoallowedtomaintaintheirexistingmedication
regimenaslongasitdidnotviolatetheinclusioncriteria.However,theywererequiredtore-
corddetailsoftheirmedicationregimenthroughoutthestudy.Atotalof2electricalcircuits
werestimulatedamongacupointsusingaTEASinstrument—theacupointnerveelectrical
stimulator(HANS-100A,NanjingGensunmedicaltechnologycompany,Nanjing,China).The
locationoftheacupointsisillustratedinFig.3.Onepairofroundpercutaneouselectrodes
(diameter,24mm)wasplacedontheacupointsHegu(LI4)–Yuji(LU10)ontheaffectedsideto
induceanelectriccircuit.Theotherelectriccircuitwasstimulatedbyplacinganotherpairof
electrodesontheacupointsZusanli(ST36)–Chengshan(BL57)onthesameside.These2pairs
ofelectrodeswereconnectedtotheacupointnervestimulator.Theacupointswerestimulated
at100or2Hzfor0.2ms.Frequencieswerechosenbasedonthereportsdescribingthethera-
peuticapplicationandmolecularmechanismofTEASinspasticity[23,27–29].Totreatpa-
tientsreceiving100or2HzTEAS,theacupuncturistsgraduallyincreasedtheintensityofthe
Figure3.LocationoftheacupointsHegu(L14)–Yuji(LU10)andZusanli(ST36)–Chengshan(BL57).
doi:10.1371/journal.pone.0116976.g003
PLOSONE|DOI:10.1371/journal.pone.0116976 February2,2015 5/15
TEASTreatsMuscleSpasticity
electricalstimulationtothelevel(usuallybetween20and40mA)thatrhythmiccontractionof
musclesonhandsorlegswasvisible.Patientsusuallydidnotexperienceanypainordiscomfort
atsuchalevelofintensity.Theaverageintensityoftheelectricalstimulationusedinthisstudy
wasapproximately30mA.Eachtreatmentsessionlasted30minutes,andthepatientsreceived
5treatmentsessions(1treatmentsessionperday)everyweekfor4weeks.IntheshamTEAS
group,theelectrodeswereplacedonthesameacupointsandtreatedforthesamedurationas
theother2groups;however,theintensityofelectricstimulationwas0mA.Allpatientswereal-
lowedtowatchtheoperationoftheelectricalstimulatorandtoviewtheentireproceduredur-
ingtreatmentsessions,andbelievedtheyreceivedrealtreatments.
Assessments
Patientswererequiredtocompletethequestionnairesweeklyafterthefifthtreatmenteveryweek
andatthefollow-upvisits1and2monthsafterthetreatment.Theseverityofmusclespasticity
anddisability,walkingcapability,andoverallperformanceofdailyactivityofpatientswereas-
sessedbyaprofessionallytrainedassessoratenrollment,afterthefifthtreatmenteveryweek,and
ateachfollow-upvisit.MASwasusedtoassessmuscletone(0representsnoincreaseinmuscle
tone;4representsthehighestincreaseinmuscletonewithrigidityinflexionorextension)[30].
DisabilitywasassessedbyDASonascaleof0–3,with0indicatingnormaland3indicatingse-
veredisability[31].WalkingcapabilitywasevaluatedbytheHoldenfunctionalambulationclas-
sificationscoreonascaleof1–5,withhigherscoresindicatingbetterwalkingcapability[32],
whereasoverallperformancewasassessedbytheGlobalAssessmentScale(GAS)scoreatarange
of1–100withhigherscoressuggestingabetteroverallleveloffunctioningandcarryingouractiv-
itiesofdailyliving[33]andtheimprovedBarthelIndex(BI)scoreintherangeof1–100with
higherscoresindicatingabetterperformanceinactivitiesofdailyliving[34,35].Wealsocom-
paredthepercentageofpatientsversusthepercentageofcaregiversexpectingpost-treatmentim-
provementindailyactivitiesthatwereadverselyinfluencedbydisability.
Endpoints
TheprimaryendpointsincludedtheMASscoreofthewrist,thumb,andtheother4fingers.
ThesecondaryendpointsweretheMASscoreoftheelbow,shoulder,knee,andankle,theDAS
scoreofdisability,Holdenfunctionalambulationclassificationscore,GASscore,andimproved
BIscores.Adverseeventwasdefinedasanoccurrenceofanyofthefollowingevents:bleeding,
hematoma,syncope,severepain,andlocalinfection.Adverseeventsweremonitoredduring
thestudyanddocumentedduringtreatmentandatfollow-upvisits.
Samplesizecalculationandstatisticalanalysis
Basedonourpreviousstudy,todetectasignificantdifferenceatthelevelof0.05betweenthe
groupswith90%powerattheassumptionofadrop-outrateof15%anda1-tailedα=0.05,20
patients(total60patients)wererequiredforeachtreatmentgroup[23].Datawerepresentedas
mean±standarddeviation(SD).Countvariableswithnormaldistributionwereanalyzedby
one-wayorrepeated-measuresANOVAtoexaminedifferencesandbyPearson’schi-squaretest
todeterminecorrelation.Countvariableswithpartialdistributionwereanalyzedusingarank-
sumorSpearmanrankcorrelationtest.Forbaselinegeneralclinicalcharacteristics,one-way
ANOVAwasperformedoncontinuousvariablesincludingage,spasticityduration,height,
weight,andbloodpressure,whereasPearson’schi-squaretestwasusedoncountvariablesin-
cludinggender,braininjurytype,andcomorbiddisease.One-wayANOVAwasalsoperformed
onthebaselineprimary(MASscoreofthewrist,thumb,andtheother4fingers)andsecondary
endpoints(DASscore,Holdenfunctionalambulationclassificationscore,GASscore,and
PLOSONE|DOI:10.1371/journal.pone.0116976 February2,2015 6/15
TEASTreatsMuscleSpasticity
improvedBIscores).ThecorrelationsamongbaselineendpointswereanalyzedbyPearson’schi-
squaretest.Toassesstreatmentefficacy,dataoftheprimaryandsecondaryendpointswereex-
aminedbyMauchly’ssphericitytestfirst,andthenrepeated-measuresANOVAwasperformed
toanalyzethedata.Allstatisticalanalyseswereconductedontheintention-to-treat(ITT)popu-
lation.Theprimaryendpointsfromper-protocol(PP)datasetswerealsoanalyzedusingthe
samestatisticalanalyses.TheITTsetincludedalltheenrolledpatients(n=60);thePPsetinclud-
edpatientsintheITTsetwhodidnotdeviatefromtheprotocol.Intotal,9patients(15%)
droppedoutofthestudy,including8notreceivingtreatmentand1diedfromaninfectiouscom-
plicationunrelatedtotreatments.Thus,thePPsetincluded51patients.P<0.05(2-sided)was
consideredstatisticallysignificant.AllanalyseswereperformedusingtheSPSS18.0software.
RESULTS
Baselineclinicaldataaresimilaramongthetreatmentgroups
Ofthe123patientsscreened,60wererandomized,and51completedthestudy.Thepatient
flowchartisshowninFig.1.Themajorityofpatientsweremale;themeanageofthepatients
includedinthestudywas>60yearsinall3groups.Thebaselinecharacteristicsofthepatients
werecomparableacrossall3treatmentgroups(P>0.05;Table1).Additionally,thebaseline
musclespasticityatthewrist,thumb,theother4fingers,elbow,shoulder,knee,andankleeval-
uatedbytheMASscore,theseverityofdisabilityreflectedbyDASscore,walkingcapability
evaluatedbyHolderfunctionalambulationclassification,andoverallperformancereflectedby
theGASscoreandimprovedBIwerenotsignificantlydifferentamongthe3groups(P>0.05,
Table2).
Table1.Baselinecharacteristics.
Characteristic 100Hzgroup 2Hzgroup Shamgroup
Age(years) 62.00±9.20 63.50±9.29 62.45±8.44
Gender,n
Male 15 16 15
Female 5 4 5
Braininjurytype,n
Cerebralinfarction 15 15 17
Trauma 0 1 0
Hemorrhage 5 4 3
Comorbiddisease,n
Yes 14 9 11
No 6 11 9
Spasticityduration(years) 5.758±5.174 4.717±5.091 3.495±3.527
Height(cm) 171.70±7.47 170.85±6.35 169.75±7.33
Weight(kg) 69.33±8.35 66.40±8.46 66.15±8.94
Systolicpressure(mmHg) 136.35±12.487 138.50±8.599 135.25±12.298
Diastolicpressure(mmHg) 90.20±8.383 88.50±6.091 86.25±9.301
Dataarepresentedasmean±standarddeviationunlessotherwiseindicated.One-wayANOVAwas
performedoncontinuousvariablesincludingage,spasticityduration,height,weight,andbloodpressure;
theChi-squaretestwasusedoncountvariablesincludinggender,braininjurytype,andcomorbiddisease.
Allvariableswerenotsignificantlydifferentamongthe3groups(P>0.05).
doi:10.1371/journal.pone.0116976.t001
PLOSONE|DOI:10.1371/journal.pone.0116976 February2,2015 7/15
TEASTreatsMuscleSpasticity
Table2.BaselineMASscoreofthewrist,thumb,theother4fingers,elbow,shoulder,knee,and
ankle,DASscore,walkingcapability,andoverallperformance.
100Hzgroup 2Hzgroup Shamgroup
MASscore
Wrist 3.150±0.366 3.200±0.410 3.100±0.308
Thumb 2.400±0.868 2.550±0.742 2.450±0.686
Other4fingers 2.625±0.944 2.525±0.638 2.525±0.896
Elbow 2.900±0.837 2.575±0.950 2.450±0.985
Shoulder 1.725±1.019 1.525±0.819 1.725±0.678
Knee 2.200±0.938 2.175±0.766 1.800±0.571
Ankle 2.675±0.694 2.775±0.734 2.900±0.718
DASscore
Personalhygiene 2.800±0.410 2.850±0.366 2.750±0.550
Dressing 2.750±0.444 2.850±0.366 2.750±0.444
Posture 2.750±0.550 2.750±0.444 2.650±0.587
Painordiscomfort 1.350±1.040 1.300±0.657 1.450±0.759
Holderfunctionalambulationclassification 3.050±1.432 2.900±1.917 2.800±1.542
GASscore 56.65±15.83 55.00±16.16 53.40±11.27
ImprovedBarthelIndex 65.15±23.94 64.85±26.78 68.60±22.32
Dataarepresentedasmean±standarddeviation.MAS=ModifiedAshworthScale.DAS=Disability
AssessmentScale.GAS=GlobalAssessmentScale.One-wayANOVAwasperformedonthedata.Allthe
variableswerenotsignificantlydifferentamongthe3groups(P>0.05).
doi:10.1371/journal.pone.0116976.t002
Table3.Correlationofwristandhandfunctionwithactivitycapabilitybeforetreatment.
Analyzedparameters Pearsoncoefficient Pvalue(2sides)
Wrist(MASscore) Thumb(MASscore) 0.360 0.005**
Wrist(MASscore) Other4fingers(MASscore) 0.227 0.081
Thumb(MASscore) Other4fingers(MASscore) 0.403 0.001**
Thumb(MASscore) Personalhygiene(DASscore) 0.333 0.009**
Other4fingers(MASscore) Personalhygiene(DASscore) 0.357 0.005**
Other4fingers(MASscore) Posture(DASscore) 0.432 0.001**
Thumb(MASscore) Dressing(DASscore) 0.165 0.208
Other4fingers(MASscore) Dressing(DASscore) 0.211 0.106
Other4fingers(MASscore) GAS -0.240 0.065
Wrist(MASscore) ImprovedBarthelIndex -0.226 0.083
Other4fingers(MASscore) ImprovedBarthelIndex -0.312 0.015*
GAS ImprovedBarthelIndex 0.518 <0.0001**
Knee(MASscore) Holdenfunctionalambulationclassification -0.170 0.193
Ankle(MASscore) Holdenfunctionalambulationclassification -0.119 0.364
Knee(MASscore) ImprovedBarthelIndex -0.201 0.124
Ankle(MASscore) ImprovedBarthelIndex -0.055 0.676
DatawereanalyzedbyPearson’schi-squaretest.
*P0.05.
**P0.01.
MAS=ModifiedAshworthScale.DAS=DisabilityAssessmentScale.GAS=GlobalAssessmentScale.
doi:10.1371/journal.pone.0116976.t003
PLOSONE|DOI:10.1371/journal.pone.0116976 February2,2015 8/15
TEASTreatsMuscleSpasticity
Wethenanalyzedthepossibleassociationofmusclespasticityatthewristandfingerswith
thecapabilityofdailyactivitiesandthecorrelationofmusclespasticityatthekneeandankle
withwalkingcapabilityinourpatients.Theresultsshowsignificantcorrelationofmusclespas-
ticityatthewrist,thumb,andtheother4fingerswitheachotherandwiththecapabilitiesfor
personalhygieneandposture(P<0.01,Table3).Incontrast,theMASscoreofthekneeand
ankledidnotseemtobeassociatedwiththewalkingcapability.AsbothGASandimprovedBI
indicateoverallperformance,itisnotsurprisingthatthese2valueswerecloselyassociated
witheachother.Becauseimprovementinactivityforpersonalhygienewasthekeyexpectation
ofbothpatientsandcaregivers(S1Fig.)andwristandhandfunctionstronglycorrelatedwith
thisactivity,wefocusedontheimprovementofwristandhandspasticityinthisstudy.
Efficacy
TEASwith100Hzstimulationsignificantlyreduceswristspasticity.Comparedwithsham
treatment,100HzTEASsignificantlyreducedwristMASscoreatweeks2,3,and4ofthetreat-
ment,and1monthafterthetreatment,whereas2HzstimulationonlydecreasedwristMAS
Figure4.Efficacyof100Hz,2Hz,orshamTEAS.A.WristMASscorewassignificantlyreducedby100HzTEAScomparedwith2HzorshamTEAS.
Datawereanalyzedbyrepeated-measuresANOVA.The*representssignificantdifferencebetween100Hzandsham,P<0.05;#representssignificant
differencebetween100Hzand2Hz,P<0.05;&representssignificantdifferencebetween2Hzandsham.B.WristMASscoreinpatientstreatedwith100
HzTEASwassignificantlydecreasedfrombaselineduringtreatmentandatfollow-upvisits.Comparisonwithbaselinevalueswasanalyzedbyrepeated-
measuresANOVA.ThewristMASscoreswereusedforthestatisticalanalysis.Datawerepresentedasmean±standarderror.The*representssignificant
differencesbetweenpost-treatmentandthebaselinevalue,P<0.05.C.ThumbMASscorewasnotaffectedbytreatments.D.TheMASscoreoftheother4
fingerswasnotaffectedbytreatments.ResultsarefromtheanalysisonITTdataset.ANOVA=analysisofvariance.MAS=ModifiedAshworthScale.TEAS
=transcutaneouselectricalacupointstimulation.
doi:10.1371/journal.pone.0116976.g004
PLOSONE|DOI:10.1371/journal.pone.0116976 February2,2015 9/15
TEASTreatsMuscleSpasticity
Table4.MASscoreoftheelbow,shoulder,knee,andankle.
MASElbow MASShoulder MASKnee MASAnkle
Baseline 100Hz 2.3±1.01 1.5±1.03 1.88±0.67 2.68±0.95
2Hz 2.6±0.84 1.8±0.62 2.0±0.72 2.8±0.52
Sham 3±0.84 1.725±0.85 2.35±0.81 2.875±0.6
Week1 100Hz 1.83±0.0.77 1.53±1.04 1.83±0.88 2.7±0.91
2Hz 2.53±0.97 1.75±0.53 2±0.69 2.8±0.68
Sham 2.75±0.7 1.825±0.73 2.35±0.86 2.9±0.55
Week2 100Hz 1.75±0.72 1.25±0.88 1.575±0.8 2.23±0.94
2Hz 2.55±0.87 1.68±0.65 1.88±0.70 2.73±0.6
Sham 2.6±0.74 1.78±0.83 2.15±0.86 2.88±0.6
Week3 100Hz 1.9±0.64 1.38±0.9 1.78±0.82 2.38±0.96
2Hz 2.35±0.84 1.55±0.63 1.85±0.71 2.65±0.65
Sham 2.33±0.8 1.6±0.85 2.08±0.78 2.85±0.59
Week4 100Hz 2±0.73 1.33±0.91 1.65±0.83 2.38±0.81
2Hz 2.25±0.7 1.7±0.7 1.73±0.5 2.53±0.7
Sham 2.4±0.79 1.7±0.85 2.05±0.65 2.7±0.57
Month1 100Hz 2±0.76 1.25±0.87 1.75±0.94 2.45±0.79
2Hz 2.35±0.78 1.7±0.5 1.8±0.66 2.7±0.7
Sham 2.48±0.77 1.68±0.73 2.13±0.69 2.78±0.57
Month2 100Hz 2.2±0.68 1.43±0.98 1.78±0.88 2.55±0.74
2Hz 2.35±0.83 1.53±0.55 1.73±0.47 2.7±0.55
Sham 2.6±0.66 1.83±0.75 2±0.71 2.78±0.57
Datawereanalyzedbyrepeated-measuresANOVA.MAS=ModifiedAshworthScale.
doi:10.1371/journal.pone.0116976.t004
scoresignificantlyatWeek4ofthetreatment(P<0.05;Fig.4A).Inaddition,TEAS100Hz
significantlyreducedwristMASscorefrombaselineatweeks2,3,and4oftreatmentandat
the1-and2-monthfollow-upvisits(P<0.05;Fig.4B).ThemaximalreductioninMASscore
atthewristfrombaseline(28.3%±4.54%)wasobservedatWeek3ofthe100Hztreatment
(Fig.4B).Theseresultssuggestthatwristspasticityfollowingbraininjurycanbesubstantially
attenuatedby100HzTEAS.Neither100Hznor2HztreatmentaffectedtheMASscoreofthe
thumb(Fig.4C)andtheother4fingers(Fig.4D).Theresultsfromrepeated-measures
ANOVAalsoshowthat,inadditiontotheintervention(P=0.012)andtime(P<0.001),the
interactionbetweentimeandinterventionalsosignificantlyaffectedwristMASscore
(P=0.003),indicatingthattherateofchangeintheMASscoreovertimeisdifferentforeach
treatmentgroup.TheMASscoreattheother4fingerswasonlysignificantlyaffectedbytime
(P<0.001).Time,intervention,orinteractionbetweentimeandinterventiondidnotaffect
thumbMASscoresignificantly.
Secondaryendpoints
Noneofthesecondaryendpoints,includingtheMASscorefortheelbow,shoulder,knee,and
ankle,DASscore,Holdenfunctionalambulationclassificationscore,GASscore,andtheim-
provedBIscorewerechangedwith100Hzor2Hztreatments(Tables4,5,6).Timeortheinter-
actionoftimeandinterventiondidnotaffectthesecondaryendpointssignificantly.
PLOSONE|DOI:10.1371/journal.pone.0116976 February2,2015 10/15