a new approach to characterize postural deficits in
TRANSCRIPT
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Preprint:Pleasenotethatthisarticlehasnotcompletedpeerreview.
Anewapproachtocharacterizeposturaldeficitsinchemotherapy-inducedperipheralneuropathyandtoanalyzeposturaladaptionsafteranexerciseinterventionCURRENTSTATUS:ACCEPTED
SarahKneisMedicalCenter,UniversityofFreiburg
[email protected]:https://orcid.org/0000-0001-8350-8309
AnjaWehrleMedicalCenter,UniversityofFreiburg
DanielaDalinMedicalCenter,UniversityofFreiburg
IsabellaKatharinaWiesmeierMedicalCenter,UniversityofFreiburg
JohannLambeckMedicalCenter,UniversityofFreiburg
AlbertGollhoferUniversityofFreiburg
HartmutBertzMedicalCenter,UniversityofFreiburg
ChristophMaurerMedicalCenter,UniversityofFreiburg
DOI:10.21203/rs.2.16028/v1
SUBJECTAREASNeurosurgery
KEYWORDS
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AbstractBackgroundPosturalinstabilitypresentsacommonanddisablingconsequenceofchemotherapy-
inducedperipheralneuropathy(CIPN).However,knowledgeaboutposturalbehaviorofCIPNpatients
issparse.Withthispilotstudy,weusedanewapproachtoi)characterizeposturalimpairmentsas
comparedtohealthysubjects,ii)allocatepossibleabnormalitiestoasetofparametersdescribing
sensorimotorfunction,andiii)evaluatetheeffectsofabalance-basedexerciseintervention.
MethodsWeanalyzedspontaneousandexternallyperturbedposturalcontrolineightCIPNpatients
beforeandafterabalance-basedexerciseinterventionbyusingamodificationofanestablished
posturalcontrolmodel.Thesefindingswerecomparedto15matchedhealthysubjects.
ResultsSpontaneousswayamplitudeandvelocitywerelargerinCIPNpatientscomparedtohealthy
subjects.CIPNpatients’reactionstoexternalperturbationsweresmallercomparedtohealthy
subjects,indicatingthatpatientsfavorvestibularoverproprioceptivesensoryinformation.The
balance-basedexerciseinterventionup-weightedproprioceptiveinformationinpatients.
ConclusionsCIPNpatients’majorposturaldeficitmayrelatetounderuseofproprioceptiveinformation
thatresultsinalessaccurateposturecontrolasspontaneousswayresultsindicate.Thebalance-
basedexerciseinterventionisabletopartiallycorrectforthisabnormality.Ourstudycontributestoa
betterunderstandingofposturalimpairmentsinCIPNpatientsandsuggestsaneffectivetreatment
strategy.
1.IntroductionChemotherapy-inducedperipheralneuropathy(CIPN)isacommonandclinicallyrelevantside-effect
ofcancertreatment(1–3).CIPNcancausetreatmentdelaysanddosereductions,interferingwith
generaloutcomeorcompromisingsurvival(3–6).ConsequencesofCIPNcanleadtoexcessive
healthcarecostsandresourceuse(7).SymptomsofCIPNprimarilyincludeparaesthesia,dysesthesia,
numbnessandpainwithasymmetric,distal,length-dependent"gloveandstocking"distribution(3,8)
andlimitpatients’everydaylifeconsiderably.Additionally,CIPNpatientsoftensufferfrompostural
instability(9–17),contributingtoalowerqualityoflife(5,18),ahigherriskofmortality(19–22)and
increasedhealthcarecosts(23,24).
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QuantitativereportsaboutCIPNpatients’posturalinstabilityarecurrentlyrising:CIPNhasbeen
associatedwithreducedgaitabilities(13,14)andchangesincenterofpressure(COP)displacements
(10,12,25).However,underlyingmechanismsaresparselydescribed(10,25):Wampleretal.(10)
assumedthatbesidessomatosensoryimpairmentsalsodiminishedvestibularfunctioncauses
increasedposturalswayinCIPNpatients.Furthermore,inanearlierstudywefoundchangesin
elicitabilityandsensitivityofspinalreflexcircuitryassociatedwithposturalinstabilityinCIPNpatients
(25).Morecomprehensiveknowledgeaboutneuropathy-inducedposturalinstabilityhasbeenderived
frompatientsdiagnosedwithdiabetes:Bonnetetal.(26)deducedlargerCOPdisplacements,which
weremorepronouncedwithvisualdisturbance.Diabeticneuropathypatientsseemtodelaypostural
reactions(27),shiftfromankletohipstrategy(26,28,29),andseemtousevestibularratherthan
proprioceptivecues(30).However,proprioceptionmaybeessentialforstabilityinbothquietstance
andduringunexpectedposturalperturbations(26,31–33),sinceitprovidesinformationaboutlower
limborientationwithrespecttothesupportbase(34,35).Theyreportaclearincreaseinpostural
swaywhenproprioceptivecuesaredeficient(10,26,32).Ourfirstaimhereistocharacterizethe
posturaldeficitsinCIPNandtoextractthesensorimotorabnormalitiesusingawell-establishedmodel
ofposturalcontrol(36–38).
Concerningtreatment,knowledgeaboutthemanagementofCIPN-inducedposturalinstabilityisstill
sparse(39–41).Generally,itisincreasinglysuggestedtofocusonstrengthandespeciallybalance
exercisesinordertoimprovephysicalfunctioningofCIPNpatients(11),whatwecouldconfirmina
randomizedcontrolledtrialbyourselves(42).Untilrecently,thereareonlytwootherinterventional
studiesshowingthatbalanceexercisesimprovedCIPN-relatedposturalcontroldeficits(39,41).
However,evidencefromdiabetesresearchonneuropathyfurthersupportsthisassumption(43–45).
Balancetrainingingeneralhasproventoenhanceposturalstabilitybyinducingneuronaladaptations
andimprovingmuscularoutput(46,47).Hence,weaimedtoimplementabalance-basedexercise
interventionforCIPNpatients.
Insum,thepresentstudywasundertakentoi)specifytheposturalabnormalitiesassociatedwith
CIPNduringspontaneousandexternallyperturbedstance,ii)toidentifytheunderlyingsensorimotor
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malfunction,andiii)tomonitortheeffectofabalance-basedexerciseinterventioninapilotapproach.
2.Methods2.1.Patients
Thepresentpilotstudyprovidestwoapproaches:across-sectionalapproachtoidentifypostural-
controldifferencesbetweenCIPNpatientsandmatchedhealthycontrolsubjectsandaone-armed
longitudinalapproachtoevaluatetheeffectsofabalance-basedexerciseinterventiononCIPN-related
posturaldeficits.
Therefore,weexaminedeightcancerpatientswithdifferentcancerlocalizationsandtreatment
status,allreportingsevereneuropathysymptomsduetochemotherapy(CIPN).Thechemotherapies
appliedentailedtheneurotoxicagentsbortezomib,carboplatin,cisplatin,paclitaxal,docetaxaland
vincristine.Noneofthepatientshadanyneuropathysymptombeforetheapplicationofneurotoxic
agents.CIPNwasclinicallyandelectrophysiologicallyconfirmedinallpatients.Moreover,weassessed
patients’subjectiveCIPNsymptomsviatheneurotoxicitysubscale(NtxS)ofFACT&GOG(Functional
AssessmentofCancerTherapy/GynaecologyOncologyGroup)scoredfrom0–44(0=severe
symptoms;44=nosymptoms);Table1summarizesourpatients’clinicalinformation.
Weexcludedpatientswithotherpossiblesourcesofneuropathy(eghereditary,diabetes-oralcohol-
induced)andpatientssufferingfromadditionaldeficitsthatmightinteractwiththeirposturalcontrol
suchasarelevantreductionofmuscularstrengthorcertaincomorbidities(egosteolysis,severe
vertebraldegeneration,vestibulardeficits).Specifically,allpatientsunderwentdetailedvestibular
testingusingarotatingchair.Inaddition,patientsperformedanincrementalstresselectrocardiogram
onastationarybicycleintheInstituteforExercise-andOccupationalMedicine,MedicalCenter–
UniversityofFreiburginordertoexcludecardiovascularrisksduringexerciseandtodeterminethe
lactatethresholdforexercisecontrol.
Thecontrolgroupfortheposturalcontrolexperimentsconsistedof15healthysubjectsmatchedto
patients’age,weightandheight.Patientsunderwentassessmentsofposturecontroltwice(before
andafter12weeksofasupervisedexerciseintervention)whilehealthycontrolsubjectsunderwent
theassessmentonlyonce.
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Patients'recruitmentanddatacollectiontookplaceintheClinicofInternalMedicineIandposture
analysesandclinicalassessmentstookplaceintheDepartmentofNeurologyandClinical
Neurophysiology,MedicalCenter–UniversityofFreiburg.
ThestudywasapprovedbytheEthicsCommissionofUniversityofFreiburg.Allsubjectsprovided
writteninformedconsenttotheexperimentalprocedureinaccordancewiththeDeclarationof
Helsinki.
2.2.Intervention
Theone-on-onetrainingsessionstookplaceinthedivisionofSportsOncologyintheClinicofInternal
MedicineI,twiceperweekover12weeks.Theinterventionprotocolincludedacardiovascularwarm-
upofupto20minutesonastationarybicyclewithanintensityof75–80%ofmaximumheartrate,
followedbythebalance-basedexercisesfor30minutesandmuscularendurancetrainingforthemain
musclegroups.Themainfocuswasonthebalancepartofthetraining.Balancetrainingprescription
includedaprogressiveincreaseovertheinterventionperiodintheexerciseamount(threetoeight
exerciseswiththreerepetitionseachà20–30s)anddifficultybyreducingthesupportsurfaceand
visualinput,addingmotor/cognitivetasksandinducinginstabilitytostimulatethesensorimotor
systemadequately(46,48).Wedocumentedvitalparameters,trainingprogress,andreasonsfor
missedsessions.
2.3.Procedureanddataanalysis
Forevaluatingposturalcontrol,spontaneousswayandperturbedstanceweremeasuredwitha
custom-builtmotionplatform(49,50)undertwovisualconditions,witheyesopenandwitheyes
closed.Eachtriallastedoneminute.Theparticipantsweretoldtostanduprightontheplatformin
comfortableshoes.Stancewidthwaspredeterminedwithinamarkedarea.Forsafetyreasons,
participantshadtoholdtworopeshangingfromtheceilinginacrossed-armspositionsothatthey
couldnotperceiveasomatosensoryspatialorientationsignal(Figure1D).
Dataanalysiswasconductedoff-linewithcustom-madesoftwareprogrammedinMATLAB®(The
MathWorksInc.,Natick,MA,USA).
Spontaneousswaywasmeasuredonthenon-movingplatform.Thecenterofpressure(COP)sway
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pathwasdetectedwithaforcetransducingplatform(Figure1E-G,Kistlerplatformtype9286,
Winterthur,Switzerland).FromtheCOPexcursionsovertimeinanterior-posterior(ap)andmedio-
lateral(ml)swaydirections,wecalculatedtherootmeansquare(RMS)aroundthemeanCOP
position.Afterdifferentiatingthetimeseries,wecalculatedmeanvelocity(MV).Inaddition,center
frequency(CF)wasextractedfromthepowerspectrum(51,52).
Perturbedstancewasmeasuredonthemovingplatformtodifferentiatesensorycontributionsin
reactiontoexternaldisturbances.Weanalyzedrotationaltiltsinthesagittalplanewiththetiltaxis
passingthroughtheparticipant’sanklejoints.Platformrotationsweredesignedaspseudorandom
stimuli(PRTS,pseudorandomternarysequence,seeFigure1C)(53).ThePRTSstimulushasawide
spectralbandwidthwiththevelocitywaveformhavingspectralandstatisticalproperties
approximatingawhitenoisestimulus(53).Assuch,thisstimulusappearedtobeunpredictabletothe
testsubject.Weappliedtwopeakangulardisplacements(stimulusamplitude:0.5°and1°peak-to-
peak)andanalyzedatelevenstimulusfrequencies(0.05,0.15,0.3,0.4,0.55,0.7,0.9,1.1,1.35,1.75
and2.2Hz).
Angularexcursionsofthelower(hip-to-ankle:hipmovement)andupper(shoulder-to-hip:shoulder
movement)bodysegmentsandtheplatforminspaceweremeasuredusinganoptoelectronicmotion-
measuringdevicewithmarkersattachedtoshoulderandhip(Optotrak3020,Waterloo,Canada).
Eachmarkerconsistedofthreelight-emittingdiodes(LED)fixedtoarigidtriangle.Thetriangleswere
fixedtotheparticipant’shipsandshouldersandtoarigidbarontheplatform(Figure1D).3-DLED
positionsofthetriangleswereusedtocalculatemarkerpositions(Figure1A,B).Optotrak®and
Kistler®outputsignalsaswellasthestimulussignalsweresampledat100Hzusingananalogue-
digitalconverter.WerecordedalldatawithsoftwareprogrammedinLabView®(National
Instruments,Austin,Texas,USA).
Toanalyseposturalreactionsinrelationtoplatformstimuli,transferfunctionsfromstimulus-response
datawerecalculatedviaadiscreteFouriertransform.Fouriercoefficientsofstimulusandresponse
timeseriesareusedtodetermineGAINandPHASEwithrespecttostimulusfrequencies.GAIN
representsthesizeoftheposturalreactionasafunctionofstimulussize(platformangle),while
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PHASEisrelatedtotherelativetimingbetweenposturalreactionandstimulus(54).
Furthermore,wecalculatedCOHERENCE,ameasureofreproducibilityoftheresponse.Whereasa
COHERENCEvalueofonereflectsperfectreproducibility,avalueofzeromeansnoreproducibilityat
all.
insertFigure1.
2.4.Parameteridentification
Transferfunctionsservedastheexperimentaldatabasisformodelsimulationsusingaspecific
versionofanestablishedposturalcontrolmodel(36,49,53,55–57)withactivetime-delayed
proportional,derivative,andintegralfeedbackaswellaspassivestiffnessanddampingtoextract
basicconstituentsofposturalcontrol.Thephysicalpartofthemodelisasingleinvertedpendulum
modelwithcorrectivetorqueappliedattheanklejoint.Themodelusedhereincludesanegative
feedbackloopthatrelatesbodyexcursiondetectedbyvisual,vestibular,andproprioceptivesensors
toacorrectivetorqueviaaneuralcontroller.Withthehelpofanautomatedoptimizationtool
(fmincon,MATLAB®,TheMathWorksInc.),whichminimizedthedifferencebetweenexperimentaland
simulatedGAINandPHASEcurves,weestimatedtheneuralcontroller’sparameterswithproportional
(Kp),derivative(Kd)andintegral(Ki)contributions(PDI-controller).Neuralcontrollergainsare,in
part,determinedbymassandheightofeachsubject’scenterofmass(COM).(53)Peterka,2002)
Becauseourcontrolgrouppresentedlowermassesandheightsthanpatients,wehadtocorrect
neuralcontrollergainsforthiseffect.Thatiswhyweprovidenumbersfor(Kp/mgh),(Kd/mgh),and
(Ki/mgh),where(mgh)representsthegravitationalpull(mass)x(gravitationalconstant)x(heightof
COM).Moreover,wederivedtimedelay(Td),proprioceptivesensoryweight(Wp),andbiomechanical
elasticity(Ppas)anddamping(Dpas)ofthemusclesandtendons.Wefittedmodelsimulationsto
experimentaltransferfunctionsunderdifferentstimulusamplitudesandvisualconditions.
2.5.Statistics
StatisticalanalyseswereperformedusingMicrosoftExcel,JMP®andStatview(SASInstituteInc.,
Cary,NC,USA).Weappliedparametricmethodsaftertestingthenormaldistributionand
homogeneityofvarianceswiththeKolmogorov-Smirnovtest.Duetotheexpecteddependency
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betweenexperimentalconditionsandoutcomemeasures,statisticalsignificancewastestedbyan
analysisofvariance(ANOVA)forthecomparisonofhealthysubjectsandpatients.Visualcondition,
swaydirection,andbodysegment(hip,shoulder)werethewithin-subjects’factorsforspontaneous
sway.Forperturbedstance,weappliedvisualcondition,stimulusamplitude,stimulusfrequency,and
bodysegment(hip,shoulder)aswithin-subjects’factors.Fortheanalysisofthebalancebased
exerciseinterventioneffectonpatients,weusedamultivariateanalysisofvariance(MANOVA)witha
timeastherepeatedmeasurevariable,inaddition.Thelevelofstatisticalsignificancewassetat
p=0.05.
3.ResultsNoadverseeventswereobservedduringthestudyperiod.Theinterventioncomplianceintermsof
numberofsessionsperformedbythepatientswas70.1%,mainlyduetotheunderlyingdisease.
3.1.Spontaneoussway
ThepatientgroupbeforeinterventiondisplayedasignificantlylargerCOPRMSthancontrolsubjects
(Figures2A-BandTable2).Groupdesignationsignificantlyinteractedwithswaydirection,iethe
differencebetweencontrolsubjectsandCIPNpatientsislargerinapdirection.Moreover,group
designationsignificantlyinteractedwithvisualcondition,duetothelargeRMSinpatientswitheyes
closed.Afterintervention,thepatients’RMStendedtobesmaller(beforeintervention0.533cm;after
it0.501cm;F=2.98;p<0.088).
AswithRMS,thepre-interventionMVofthepatientgroupwassignificantlylargerthanincontrol
subjects(Figures2C-D,Table2).Thegroupdesignationsignificantlyinteractedwithvisualcondition
(seeTable2):MVvaluesdidnotdifferbetweengroupsintheeyes-opencondition,whereasthe
patients’MVwassignificantlylargerintheeyes-closedcondition.MVdidnotchangeafter
intervention.
CFdidnotdiffersignificantlybetweenpatientsandcontrolsubjects(Figures2E-F,Table2).
Furthermore,patientsdisplayednointerventioneffectsonCF.
[insertFigure2.]
3.2.Perturbedstance
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ThetransferfunctionbetweenplatformtiltandbodyangulardisplacementischaracterizedbyGAIN
andPHASEbehavior.
Thedisturbance-inducedbodysway,ieGAINwassignificantlysmallerinpatientsbeforeintervention
(1.57)comparedtocontrolsubjects(1.87;F=62.3;p<0.0001;Fig.3A)andincreasedafter
intervention(1.63;F=18.0;p<0.0001;Fig.3A,Fig.4A-D).Furthermore,groupdesignationinteracted
significantlywithstimulusfrequency(F=3.70;p<0.0001),duetoadistortionofthetransferfunction
(Fig.3A,Fig.4A-D).Moreover,controlsubjects'GAINislargerwithclosedeyesthanopeneyes
whereaspatients’GAINwasalmostsimilarindependentofthevisualcondition:groupdesignation
significantlyinteractedwithvisualcondition(eyesopen:controlsubjects1.58;patientsbefore
intervention1.46;afterintervention1.51;eyesclosed:controlsubjects2.15;patientsbefore
intervention1.67;afterintervention1.74;visualcondition:F=25.6;p<0.0001,Fig.3D,Fig.4A-D).
Thedifferencebetweenshoulderandhipswayasafunctionofplatformtiltswasgreaterincontrol
subjectsthaninpatients(Fig.3E,Fig.4A-D):withasignificantinteractionbetweengroupdesignation
andbodysegment(F=2.85;p=0.022).Groupdesignationandstimulusamplitudedidnotinteract
significantlyastheeffectofstimulusamplitude(non-linearity)onGAINdidnotdifferbetweengroups.
ThePHASElaginthepatients’groupbeforeinterventionwasslightlybutsignificantlylesspronounced
thaninthecontrolgroup(controlsubjects-118.3;patients-107.6,F=10.3;p<0.0001;Fig.3B).After
intervention,PHASEchangedsignificantlyandfellintherangeofthecontrolsubjects’values(-121.3;
F=15.4;p<0.0001;Fig.3B).Groupdesignationsignificantlyinteractedwithvisualcondition(F=4.45,
p=0.01,Fig.3F),bodysegment(F=13.1,p<0.0001,Fig.3G),andstimulusamplitude(F=9.89,
p<0.0001).Theinteractionwithvisualconditionisbasedonthefactthatpatientswithopeneyes
displayedaPHASEadvanceof20degreeswithrespecttocontrolsubjects,whereastherewasno
significantPHASEdifferencebetweenpatientsandcontrolsubjectswitheyesclosed.Theinteraction
withbodysegmentisbasedonthefactthatthedifferencebetweenshoulderandhipPHASEwas
largerincontrolsubjectsthaninpatients.Theinteractionwithstimulusamplitudeisbasedona
pronouncedphasedifferencewithsmallstimulusamplitudes.Groupdesignationandstimulus
frequencydidnotinteractsignificantly(F=0.41;p=0.99):thePHASEeffectsweredistributedequally
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acrossallfrequencies.
COHERENCEasameasureforthereproducibilityoftheresponsewassmallerinpatientsbefore
intervention(0.43)comparedtocontrolsubjects(0.50;F=103;p<0.0001;Fig.3C).COHERENCEdid
notchangeafterintervention(0.45).However,COHERENCEsignificantlyvariedwithstimulus
amplitude,frequency,visualcondition,andbodysegment,similarlyinbothgroups.
[insertFigure3and4.]
Thefollowingresultsarederivedfromthemodel-basedparameteridentificationprocedure(Fig.5D),
andpresenttherelevantparameterdifferencesbetweenpatientsandcontrolsubjects.
Therewasnosignificanteffectfortheintegralpartoftheneuralcontroller(Ki),aswellasforthe
proportional(Kp)andderivativepart(Kd)oftheneuralcontroller.
ThesensoryweightingfactorWpdifferedsignificantlybetweenpatientsandcontrolsubjects(F=9.89,
p=0.0001;Fig.5B).Whereaspatientsrelywithanaveragefactorof0.53onproprioceptivecuesand
hence0.47onspatialcues,controlsubjectsrelywithafactorof0.67onproprioceptiveand0.33on
spatialcues.Afterintervention,therewasasmallbutsignificantchangetowardscontrolsubjects(Wp
0.56,F=9.13,p=0.006).Groupdesignationdidnotinteractwithvisualconditionorstimulus
amplitude.
Thetimedelaybetweenstimulusandresponse(Td)didnotdiffersignificantlybetweenpatientsand
controlsubjects(F=1.10;p=0.34;Fig.5C).However,wedidnoteatendencytowardslargertime
delaysinpatientsbeforeintervention(175ms)comparedtocontrolsubjects(167ms)andpatients
afterintervention(168ms).
Parametersrelatedtopassivemuscleandtendonbehavior(PpasandDpas)didnotdiffersignificantly
betweengroupsandwerenotaffectedbytheintervention.
[insertFigure5.]
4.DiscussionAsposturalinstabilityisamomentoussymptomofCIPN(9–16),thefirstaimofthisstudywasto
assessthespecificsetofposturalcontroldeficitsassociatedwithCIPNcomparedtohealthysubjects.
Furthermore,sinceCIPNtreatmentoptionsareverylimitedsofar(3)andhintsintherecentliterature
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indicatethatCIPNpatientsmightbenefitfromexercising(39,41,58),weevaluatedabalance-based
exerciseinterventionaimingtotreatpatients'functionalimpairmentsduetoCIPN.Whileformer
studiesmostlyinvestigatedspontaneousswaymeasures(displacement-,velocity-,andfrequency-
relatedmeasures),weaimedtodescribeCIPNpatients'sensorimotorbehaviorinmuchgreaterdetail
andtherefore,weadditionallygeneratedtransferfunctionsofpatients’behaviorasafunctionof
stanceperturbationwithpseudorandomstimulitoachieveourobjectives.
Concerningspontaneoussway,wefoundgreaterposturalswayinCIPNpatientssimilarlytoprevious
CIPNstudies(10,12,14,39).Additionally,ourfindingscorrespondtothatofothertypesofneuropathy.
Forexample,manyworkinggroups(59–63)reportincreasedRMSandMVinpatientswithdiabetic-
inducedneuropathy.Inourstudy,RMSandMVweresignificantlylargerinCIPNpatientsthanin
healthysubjects.Moreover,weobservedaspecificpreponderanceofdeficitsinanterior-posterior
direction(60)andamorepronouncedposturalswaywithclosedratherthanopeneyes(60,61).
Generally,closingtheireyescausessubjectstousevestibularandproprioceptivecuesforcontrolling
balance.Asproprioceptiveinformationareoftendeficientinneuropathypatients(26),itseems
reasonabletoassumethatpatientsmayprefervestibularoverproprioceptivecues.However,itiswell
knownthatthevestibularsignalcarriesalargeramountofnoisethantheproprioceptivesignal(64)
leadingtolessaccurateposturecontrol.Wespeculateatthispointthatthemainsourceforthelarger
RMSandMVisrelatedtoasensoryshifttowardsvestibularcues(seebelowsensoryweighting,and
Horaketal.(65)).Ifthatistrue,wemightbeabletorecoverthisfindingwhendissociating
proprioceptivefromvestibularframesoforientationusingplatformtilts.Whereasproprioceptivecues
maydragthebodyalongplatformmovements,quantifiedbyarelativelargerGAINastransfer
functionbetweenbodyexcursionsandplatformtilts,vestibularcueswouldstabilizethebodyin
space,quantifiedbyarelativesmallerGAIN.Infact,CIPNpatientspresentedsmallerGAINvalues
sincetheirreactiontoplatformtiltswerelesspronouncedthanthatofcontrolsubjects.Thus,they
mightratherusespacecoordinatesthanplatformmovementsforposturecontrol.Furthermore,GAIN
wassignificantlyaffectedbyvisualconditionandbodysegment.ThelargerGAINdifferencebetween
CIPNpatientsandcontrolsubjectsintheeyes-closedcomparedtotheeyes-openconditionsuggests
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thatunder-usageofproprioceptionisdominantwhentherearelessadditionalorientingcues.
Moreover,thefindingofrelativelysmallGAINsinCIPNpatients’lowercomparedtotheirupperbody
segmentpointtoaslightlydifferentintersegmentalstrategy(29).OurPHASEfindings,representing
therelativetimingbetweenposturalreactionandstimulusalsopointtoadifferentintersegmental
behaviorintermsofupperwithrespecttolowerbodyangulardisplacements(26,28,29).Weassume
thatpatientsproactivelyorientatethemselves,especiallytheirupperbody,moretowardsspace
coordinates.ThisalsoindicatesanespeciallylowuseofproprioceptionaccordingtoourGAINresults.
Moreover,wespeculatethatCIPNpatientsproactivelyassumeasafetystrategythatmayfollowan
enhancedmuscleco-contraction(25),leadingtosmallerbodyexcursions.However,greaterco-
contractionlimitsone’sabilitytopreciselycontrolposture(66,67).
Toaddressthetransfer-functionabnormalitiesinCIPNpatients,wefittedthesubjects’dataviaa
simplefeedbacksystem(36,56,64,68).Usingthemodel-basedparameterestimation,weidentified
andquantifiedtheCIPNpatients’diminisheduseofproprioceptivecues:Thesensory-weightingfactor
forproprioception(Wp)issignificantlysmallerinCIPNpatientsthanincontrolsubjects.However,
patientsdidnotpresentadifferenterrorcorrectiongain(KpandKd)ofthefeedbackloop.
Furthermore,parametersrelatedtopassivemuscleandtendonbehavior(passivestiffnessand
damping,KpasandBpas)didalsonotdifferbetweenCIPNpatientsandcontrolsubjects.Thisseems
tobeinlinewiththenotionthatdifferencesinposturalcontrolbetweenCIPNpatientsandhealthy
subjectsmainlyrelyonthedifferentuseofsensorycues.Moreover,thisfindingmightindicatethat
musclesandtendonswerenotaffectedsupportingCIPN'sprimarilysensorycharacteristic.
HowdoestheexerciseinterventioninfluenceCIPNpatients’behavior?Interestingly,weobservedthat
CIPNpatients’mainabnormality(down-weightedproprioception)wasmodifiedbyexercise
intervention.CIPNpatients’GAINandPHASEvaluesapproachedthoseofhealthysubjectsduetothe
proprioceptiveup-weightingmentionedabove.Interestingly,theeffectofup-weightingproprioception
istheonlysignificantmodel-basedparametermodificationafterintervention.WhywouldCIPN
patientsprofitfromup-weightingproprioceptionwhilesufferingfromasupposedproprioceptive
deficit?Ourclinicalassessmentsdidnotsufficetoconclusivelyspecifyneurallesionsoridentify
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CIPN'snervefibercontributionoccurringinourpatients.However,allpatientssufferedfromstrong
paresthesiaandreportedsignificantbalanceproblemsconfirmedbyourspontaneoussway
experiments.CIPNsensorysymptomsaredescribedtoreferto‘terminalarbordegeneration’andthe
preferentialdamageofmyelinatedprimaryafferentsensorynervefibers(2,69).Therefore,we
speculatethatpatients'peripheralinformationandsubsequentstimulusconductionarealtered,but
notcompletelydysfunctional.Thedown-weightingofproprioceptivecuescouldbeinterpretedasan
excessivecompensatorymechanism,whichletsCIPNpatientspre-interventionremaininasuboptimal
state.Theexerciseinterventionmaythuspartiallycorrectthisexcessandmaystimulatetheuseof
lessdamagedpathways.Asasideeffectofproprioceptiveup-weighting,theinterventionmaytrigger
down-weightingofvestibularcues,therebyreducingvestibularnoise.Asaconsequence,postural-
controlbehaviormightbemoreaccurateintermsoflessvariability.
Conclusively,wemaintainthatup-weightingproprioceptionandtherebydown-weightingvestibular
informationtowardsthebehaviorofhealthysubjectsrepresentsaclearbenefitforCIPNpatients.The
proprioceptivecueisconsideredtobemoreaccuratethanvestibularcuesforposturalstability(64).
Regardingtimedelay,patientsafterinterventiontendedtoimprovetheirreactiontimebetween
stimulusandresponse.WealsoidentifiedatendencyofspontaneousswayRMSvaluestobesmaller
afterintervention,beinginlinewithposturalswayfindingsafterbalancetraininginastudyof
Schwenketal.(39).Although,ourinterventioneffectsaresmall,weareconvincedthatCIPNpatients
benefitfromexercisingintermsofimprovedposturebehavoirthatsubstantiallycontributesto
patients'functionalstatus.Functionalperformanceisanacknowledgedprognosisfactorforcancer
survivor(70)whywestronglyproposetoverifyourinterventionresultsinagreaterrandomized
controlledtrial.Ourfindingsarelimitedbythesmallsamplesizeandthelackofpatientcontrol
group.Furthermore,expandingneurophysiologicalassessmentswouldprovideinsightsinadaptive
processesunexaminedinthisstudy.
5.ConclusionWebelievethatournewapproachcontributedtoadeeperunderstandingofCIPNpatients’postural
instability.Proprioceptivedown-weightingmightrepresentthemainposturaldeficitinCIPN.Our
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exerciseinterventiontargetedspecificallythisabnormalitypresumablybyprimarilycorrectingthe
overactivecompensation,whichledtoasignificantimprovementinposturalstability.Webelievethat
abalance-basedexerciseinterventionisapromisingstrategytomanagefunctionalimpairmentsdue
toCIPNandthatitshouldthereforeberoutinelyintegratedwithinthetreatmentregimensofpatients
receivingneurotoxicagents.
6.Abbreviationsapanterior-posterior
CFcenterfrequency
CIPNchemotherapy-inducedperipheralneuropathy
COPcenterofpressure
Dpaspassivedamping
Kdderivativecontributionoftheneuralcontroller
Kiintegralcontributionoftheneuralcontroller
Kpproportionalcontributionoftheneuralcontroller
NtxSneurotoxicitysubscaleofFACT&GOG
mlmedio-lateral
MVmeanvelocity
Ppaspassivestiffness
RMSrootmeanssquare
Tdtimedelay
Wpproprioceptivesensoryweight
7.Declarations7.1.Ethicsapprovalandconsenttoparticipate
ThisstudywasapprovedbytheEthicsCommitteeoftheUniversityofFreiburg(478/11).All
proceduresperformedinstudiesinvolvinghumanparticipantswereinaccordancewiththeethical
standardsoftheinstitutionaland/ornationalresearchcommitteeandwiththe1964Helsinki
declarationanditslateramendmentsorcomparableethicalstandards.Writteninformedconsentwas
16
obtainedfromallindividualparticipantsincludedinthestudy.
7.2.Consentforpublication
Notapplicabl
7.3.Availabilityofdataandmaterial
Thedatasetsupportingtheconclusionsofthisarticleisincludedwithinthisarticle.Thedatathat
supportthefindingsofthisstudyareavailablefromthecorrespondingauthoruponreasonable
request.
7.4.Competinginterests
Theauthorsdeclarethattheresearchwasconductedintheabsenceofanycommercialorfinancial
relationshipsthatcouldbeconstruedasapotentialconflictofinterest.
7.5.Funding
SK,AWandCMcontributedtotheconceptionofthework,todataacquisition,analysisand
interpretation,wrotethefirstdraftandrevisedit.IW,DD,andJLcontributedtodataacquisitionand
analysisandrevisedtheworkcritically.AGandHBcontributedtothedesignoftheworkandrevised
itcritically.Allauthorsapprovedthefinalversionofthisarticleandagreetobeaccountableforall
aspectsoftheworkinensuringthatquestionsrelatedtotheaccuracyorintegrityofanypartofthe
workareappropriatelyinvestigatedandresolved.
7.6.Authors'contributions
SK,AWandCMcontributedtotheconceptionofthework,todataacquisition,analysisand
interpretation,wrotethefirstdraftandrevisedit.IW,DD,andJLcontributedtodataacquisitionand
analysisandrevisedtheworkcritically.AGandHBcontributedtothedesignoftheworkandrevised
itcritically.Allauthorsapprovedthefinalversionofthisarticleandagreetobeaccountableforall
aspectsoftheworkinensuringthatquestionsrelatedtotheaccuracyorintegrityofanypartofthe
workareappropriatelyinvestigatedandresolved.
7.7.Acknowledgements
Weacknowledgethecooperationandtrainingimplementationofsports-andphysiotherapistsofthe
SportsOncologyofDepartmentofMedicineI,MedicalCenter–UniversityofFreiburgandwethank
17
thepatientsandcontrolindividualsfortheircollaboration.
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TablesTable1Subjects'characteristic
24
Pat Sex Height(cm)
Weight(kg)
Age(years)
Diagnosis Status MonthssinceED(n)
Cyclesofneurotoxicdrugs(n)
1 m 182 125 55 B-NHL PR 185 14
2 m 182 80 67 MM SD 58 34
3 f 161 86 60 MM Relapse 82 7
4 f 162 60 68 Breastcancer SD 66 19
5 m 180 80 64 MM SD 8 4
6 m 167 92 63 Breastcancer SD 195 25
7 m 176 64 67 Rectalcancer PD 118 79
8 m 188 107 42 Germcellcancer CR 66 4mean±SD
m:f6:2
174.8±10.1
86.8±21.5
60.8±8.7
97.3±64.8
23.3±24.9
hCon mean±SD
m:f9:6
17.0±9.1
78.0±6.3
59.6±10.0
Pat,CIPNpatients;SD,standarddeviation;hCon,healthycontrolsubjects;m,male;f,female;B-NHL,
B-NonHodgkinLymphoma;MM,multiplemyeloma;PR,partialremission;SD,stabledisease;PD,
progressivedisease;CR,completeremission;NCV,nerveconductionvelocity(normalvalues:
≥41m/s);APA,actionpotentialamplitude(normalvalues:≥6µV);ATR,Achillestendonreflex;PRT,
Patellatendonreflex;"-",noreflex;"(-)",reducedreflex;"+",normalreflex;NtxS,neurotoxicity
subscaleofFACT/GOG(FunctionalAssessmentofCancerTherapy/GynaecologyOncologyGroup)
scoredfrom0(severesymptoms)–44(nosymptoms)
Table2Spontaneousswaymeasures(RMS,MV,CF)withgroupeffects,andinteractionsbetween
groupsandvisualconditions/swaydirections.
25
hControl PATpre PATpost F-value p-value RMS(cm) 0.46±0.1810.926 <0.000
10.56±0.27
visualcondition eyesopeneyesclosed
0.45±0.180.56±0.19
5.06 0.007 0.49±0.230.63±0.30
swaydirection anterior-posteriormedio-lateral
0.52±0.160.35±0.17
4.06 0.018 0.67±0.280.41±0.19
MV(cm/s) 0.35±0.147.80 0.0005 0.69±0.57
visualcondition eyesopeneyesclosed
0.32±0.130.39±0.14
8.00 0.0004 0.45±0.310.92±0.84
swaydirection anterior-posteriormedio-lateral
0.41±0.130.27±0.12
n.s. 0.82±0.780.51±0.44
CF(Hz) 0.37±0.11 n.s. 0.46±0.18
hControl=healthycontrolsubjects,PATpre=patientsbeforeintervention,PATpost=patientsafter
intervention,RMS=rootmeanssquare,MV=meanvelocity,CF=centerfrequency,n.s.=not
significant.
Figures
26
Figure1
ExperimentalsetupPerturbedstance:PosturalreactionsofAupperbodyandBlowerbody
on1°peak-to-peakplatformrotation(Cstimulus)over20secondswitheyesopenina
representativehealthycontrolsubject(hCon)andapatientbefore(pre)andafter(post)
intervention.Bodyreaction(A/B)followstheplatformmovement(C).Schemeofasubject
standingontheplatforminanuprightpositionD.Spontaneoussway:COPdisplacementof
onerepresentativesubjectofthecontrolsubjects'group(E,hCon)andthepatients'groupF
before(pre)andGafter(post)intervention.Patients'COPdisplacement(F/G)ismore
pronouncedthancontrolsubjects'(E),butreducedafterintervention(G).deg,degrees,sec,
seconds,ap,anterior-posterior,ml,medio-lateral,cm,centimeter.
28
Figure2
SpontaneousswayMeanandstandarddeviationofA/Brootmeansquare(RMS),C/Dmean
velocity(MV)andE/Fcenterfrequency(CF)ofCOPswayinanterior-posterior(ap)and
medio-lateral(ml)directioneachfortheeyes-openandeyes-closedconditioninhealthy
controlsubjects(hCon),patientsbefore(pre)andafter(post)intervention.Significant
differencesofRMSandMVbetweencontrolsubjectsandpatientsaremorepronouncedin
theapdirectionandtheeyes-closedcondition.NotethatthelargeerrorbarsinDare
specificallyrelatedtohighfrequencycontentofpatients’sway.
29
Figure3
TransferfunctionsMeanandstandarddeviationofAGain,BPhaseandCCoherence
behaviorasafunctionoffrequency(f)andD/EmeanGainandF/GmeanPhasebehaviorfor
lowerbody(LB)andupperbody(UB)andforeyes-open(eo)andeyes-closed(ec)condition
inhealthycontrolsubjects(hCon),patientsbefore(pre)andafter(post)intervention.
Differencesbetweenhealthysubjectsandpatientsaremorepronouncedfortheupperbody
andwithclosedeyes.Postintervention,patientsshiftedtheirGain,PhaseandCoherence
valuestowardstherangeofcontrolsubjects'values.
30
Figure4
GainfactorMeanandstandarddeviationofA/BupperbodyandC/DlowerbodyGAINFACTOR
behaviorofpatientsbefore(pre)andafter(post)interventionasafunctionoffrequency(f).
GAINFACTORrepresentspatients’GAINvaluesnormalizedtovaluesofhealthycontrol
subjects(hCon)intheeyes-openandeyes-closedcondition.Differencesbetweenhealthy
subjectsandpatientsaremorepronouncedforupperbodyandwitheyesclosed.After
interventionpatientsshiftedtheirGAINandPHASEvaluestowardstherangeofcontrol
subjects'values.
31
Figure5
ModelparametersMeanandstandarddeviationofAtheneuralcontrollerwiththe
proportional(Kp/mghin1/°),derivative(Kd/mghins/°)andintegral(Ki/mghin1/s*°)
contributioncorrectedforsubjects’massesandheights,ofBtheproprioceptivesensory
weight(Wpin°/°)andCthelumpedtimedelay(Tdinseconds)forhealthycontrolsubjects
(hCon),patientsbefore(pre)andafter(post)intervention,eachshownintheeyes-open(eo)
andeyes-closed(ec)conditionandforBWpin0.5and1degree(deg)platformrotation.D
32
showsthemodifiedpostural-controlmodelusedtoidentifyabnormalposturalcontrol
parametersinCIPNpatientsviaanoptimizationprocedurewheredifferencesbetween
experimentaldataandmodelsimulationswereminimized:Themodelconsistsofabody
representedbyaninvertedpendulumwiththemassconcentratedatthecenterofmass
(COM)ofthebodyandthesensorsandneuromuscularsystemsincludingaNeural
Controller.θ,bodyswayangle;h,heightoftheCOMabovetheanklejoints;θref,external
stimulus;Kp,proportionalgain(stiffnessfactor),Kd,derivativegain(dampingfactor),Ki,
integralgainoftheNeuralController;Ppas,passivestiffnessfactor;Dpas,passivedamping
factor;Wp,proprioceptivesensoryweight;Td,feedbacktimedelay;T,controltorque;J,
momentofinertiaofthebody;mgh,bodymass*gravitationalconstant*heightoftheCOM
fromtheanklejoint;s,Laplacetransformvariable.