1

Preprint:Pleasenotethatthisarticlehasnotcompletedpeerreview.

Anewapproachtocharacterizeposturaldeficitsinchemotherapy-inducedperipheralneuropathyandtoanalyzeposturaladaptionsafteranexerciseinterventionCURRENTSTATUS:ACCEPTED

SarahKneisMedicalCenter,UniversityofFreiburg

sarah.kneis@uniklinik-freiburg.deCorrespondingAuthorORCiD: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

2

Posturalstability,chemotherapy-inducedperipheralneuropathy,motorcontrol,sensoryweighting,model

3

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).

4

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

5

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.

6

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

7

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

8

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

9

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

10

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

11

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

12

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

13

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

14

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

15

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.

8.References1.ArgyriouAA,KyritsisAP,MakatsorisT,KalofonosHP.Chemotherapy-inducedperipheralneuropathy

inadults:acomprehensiveupdateoftheliterature.CancerManagRes.2014;6:135–47.

2.HanY,SmithMT.Pathobiologyofcancerchemotherapy-inducedperipheralneuropathy(CIPN).

FrontPharmacol.2013Dec18;4:156.

3.HershmanDL,LacchettiC,DworkinRH,SmithEML,BleekerJ,CavalettiG,etal.Preventionand

ManagementofChemotherapy-InducedPeripheralNeuropathyinSurvivorsofAdultCancers:

AmericanSocietyofClinicalOncologyClinicalPracticeGuideline.JClinOncol.2014Jun

20;32(18):1941–67.

4.Gutiérrez-GutiérrezG,SerenoM,MirallesA,Casado-SáenzE,Gutiérrez-RivasE.Chemotherapy-

inducedperipheralneuropathy:clinicalfeatures,diagnosis,preventionandtreatmentstrategies.Clin

TranslOncolOffPublFedSpanOncolSocNatlCancerInstMex.2010Feb;12(2):81–91.

5.StubblefieldMD,BursteinHJ,BurtonAW,CustodioCM,DengGE,HoM,etal.NCCNtaskforce

report:managementofneuropathyincancer.JNatlComprCancerNetwJNCCN.2009Sep;7Suppl

5:S1–26;quizS27-28.

6.WindebankAJ,GrisoldW.Chemotherapy-inducedneuropathy.JPeripherNervSyst.2008;13(1):27–

46.

7.PikeCT,BirnbaumHG,MuehlenbeinCE,PohlGM,NataleRB.Healthcarecostsandworklossburden

ofpatientswithchemotherapy-associatedperipheralneuropathyinbreast,ovarian,headandneck,

andnonsmallcelllungcancer.ChemotherResPract.2012;2012:913848.

8.AsburyA,ThomasP.PeripheralNerveDisorders2.Butterworth-Heinemann;1995.336p.

9.TofthagenC,OvercashJ,KipK.Fallsinpersonswithchemotherapy-inducedperipheralneuropathy.

SupportCareCancer.2012;20(3):583–9.

10.WamplerMA,ToppKS,MiaskowskiC,BylNN,RugoHS,HamelK.QuantitativeandClinical

DescriptionofPosturalInstabilityinWomenWithBreastCancerTreatedWithTaxaneChemotherapy.

ArchPhysMedRehabil.2007Aug;88(8):1002–8.

18

11.Winters-StoneKM,HorakF,JacobsPG,TrubowitzP,DieckmannNF,StoylesS,etal.Falls,

Functioning,andDisabilityAmongWomenWithPersistentSymptomsofChemotherapy-Induced

PeripheralNeuropathy.JClinOncol.2017Aug10;35(23):2604–12.

12.HermanHK,MonfortSM,PanXJ,ChaudhariAMW,LustbergMB.Effectofchemotherapy-induced

peripheralneuropathyonposturalcontrolincancersurvivors.JClinOncol.2017Feb

10;35(5_suppl):128–128.

13.MarshallTF,ZippGP,BattagliaF,MossR,BryanS.Chemotherapy-induced-peripheralneuropathy,

gaitandfallriskinolderadultsfollowingcancertreatment.JCancerResPract.2017Dec1;4(4):134–

8.

14.MonfortSM,PanX,PatrickR,RamaswamyB,WesolowskiR,NaughtonMJ,etal.Gait,balance,and

patient-reportedoutcomesduringtaxane-basedchemotherapyinearly-stagebreastcancerpatients.

BreastCancerResTreat.2017Jul1;164(1):69–77.

15.GewandterJS,FanL,MagnusonA,MustianK,PepponeL,HecklerC,etal.Fallsandfunctional

impairmentsincancersurvivorswithchemotherapy-inducedperipheralneuropathy(CIPN):a

UniversityofRochesterCCOPstudy.SupportCareCancer.2013Jul;21(7):2059–66.

16.BaoT,BasalC,SeluzickiC,LiSQ,SeidmanAD,MaoJJ.Long-termchemotherapy-induced

peripheralneuropathyamongbreastcancersurvivors:prevalence,riskfactors,andfallrisk.Breast

CancerResTreat.2016Sep;159(2):327–33.

17.KolbNA,SmithAG,SingletonJR,BeckSL,StoddardGJ,BrownS,etal.TheAssociationof

Chemotherapy-InducedPeripheralNeuropathySymptomsandtheRiskofFalling.JAMANeurol.2016

Jul1;73(7):860–6.

18.MolsF,BeijersT,VreugdenhilG,vandePoll-FranseL.Chemotherapy-inducedperipheral

neuropathyanditsassociationwithqualityoflife:asystematicreview.SupportCareCancer.2014

Aug;22(8):2261–9.

19.CesariM,KritchevskySB,NewmanAB,SimonsickEM,HarrisTB,PenninxBW,etal.Addedvalueof

physicalperformancemeasuresinpredictingadversehealth-relatedevents:resultsfromtheHealth,

AgingAndBodyCompositionStudy.JAmGeriatrSoc.2009;57(2):251–9.

19

20.CesariM,CerulloF,ZamboniV,PalmaRD,ScambiaG,BalducciL,etal.FunctionalStatusand

MortalityinOlderWomenWithGynecologicalCancer.JGerontolABiolSciMedSci.2013;68(9):1129–

33.

21.KlepinHD,GeigerAM,ToozeJA,NewmanAB,ColbertLH,BauerDC,etal.Physicalperformance

andsubsequentdisabilityandsurvivalinolderadultswithmalignancy:resultsfromthehealth,aging

andbodycompositionstudy.JAmGeriatrSoc.2010Jan;58(1):76–82.

22.OnderG,PenninxBWJH,FerrucciL,FriedLP,GuralnikJM,PahorM.Measuresofphysical

performanceandriskforprogressiveandcatastrophicdisability:resultsfromtheWomen’sHealth

andAgingStudy.JGerontolABiolSciMedSci.2005Jan;60(1):74–9.

23.AleknaV,StukasR,Tamulaitytė-MorozovienėI,ŠurkienėG,TamulaitienėM.Self-reported

consequencesandhealthcarecostsoffallsamongelderlywomen.MedKaunasLith.2015;51(1):57–

62.

24.AlexanderBH,RivaraFP,WolfME.Thecostandfrequencyofhospitalizationforfall-related

injuriesinolderadults.AmJPublicHealth.1992;82(7):1020–3.

25.KneisS,WehrleA,FreylerK,LehmannK,RudolphiB,HildenbrandB,etal.Balanceimpairments

andneuromuscularchangesinbreastcancerpatientswithchemotherapy-inducedperipheral

neuropathy.ClinNeurophysiol.2016Feb;127(2):1481–90.

26.BonnetC,CarelloC,TurveyMT.DiabetesandPosturalStability:ReviewandHypotheses.JMot

Behav.2009Mar;41:172–92.

27.DicksteinR,PeterkaRJ,HorakFB.Effectsoflightfingertiptouchonposturalresponsesinsubjects

withdiabeticneuropathy.JNeurolNeurosurgPsychiatry.2003Jan5;74(5):620–6.

28.DicksteinR,ShupertCL,HorakFB.Fingertiptouchimprovesposturalstabilityinpatientswith

peripheralneuropathy.GaitPosture.2001Dec;14(3):238–47.

29.SimmonsRW,RichardsonC,PozosR.Posturalstabilityofdiabeticpatientswithandwithout

cutaneoussensorydeficitinthefoot.DiabetesResClinPract.1997Jun;36(3):153–60.

30.HorakFB,HlavackaF.Somatosensorylossincreasesvestibulospinalsensitivity.JNeurophysiol.

2001Aug;86(2):575–85.

20

31.FitzpatrickR,McCloskeyDI.Proprioceptive,visualandvestibularthresholdsfortheperceptionof

swayduringstandinginhumans.JPhysiol.1994Jul1;478(Pt1):173–86.

32.NashnerLM,BlackFO,WallC.Adaptationtoalteredsupportandvisualconditionsduringstance:

patientswithvestibulardeficits.JNeurosci.1982May;2(5):536–44.

33.PeterkaRJ,BenolkenMS.Roleofsomatosensoryandvestibularcuesinattenuatingvisually

inducedhumanposturalsway.ExpBrainRes.1995;105(1):101–10.

34.CornaS,TarantolaJ,NardoneA,GiordanoA,SchieppatiM.Standingonacontinuouslymoving

platform:isbodyinertiacounteractedorexploited?ExpBrainRes.1999Feb;124(3):331–41.

35.SchieppatiM,GiordanoA,NardoneA.Variabilityinadynamicposturaltaskattestsample

flexibilityinbalancecontrolmechanisms.ExpBrainRes.2002May;144(2):200–10.

36.EngelhartD,PasmaJH,SchoutenAC,MeskersCGM,MaierAB,MergnerT,etal.Impairedstanding

balanceinelderly:anewengineeringmethodhelpstounravelcausesandeffects.JAmMedDir

Assoc.2014Mar;15(3):227.e1-6.

37.PasmaJH,EngelhartD,MaierAB,SchoutenAC,vanderKooijH,MeskersCGM.Changesinsensory

reweightingofproprioceptiveinformationduringstandingbalancewithageanddisease.J

Neurophysiol.2015Dec;114(6):3220–33.

38.WiesmeierIK,DalinD,MaurerC.ElderlyUseProprioceptionRatherthanVisualandVestibular

CuesforPosturalMotorControl.FrontAgingNeurosci.2015;7:97.

39.SchwenkM,GrewalGS,HollowayD,MuchnaA,GarlandL,NajafiB.InteractiveSensor-Based

BalanceTraininginOlderCancerPatientswithChemotherapy-InducedPeripheralNeuropathy:A

RandomizedControlledTrial.Gerontology.2016;62(5):553–63.

40.StreckmannF,ZopfEM,LehmannHC,MayK,RizzaJ,ZimmerP,etal.ExerciseIntervention

StudiesinPatientswithPeripheralNeuropathy:ASystematicReview.SportsMed.2014Jun14;44(9).

41.ZimmerP,TrebingS,Timmers-TrebingU,SchenkA,PaustR,BlochW,etal.Eight-week,

multimodalexercisecounteractsaprogressofchemotherapy-inducedperipheralneuropathyand

improvesbalanceandstrengthinmetastasizedcolorectalcancerpatients:arandomizedcontrolled

trial.SupportCareCancer.2017Sep30;26(2):615–24.

21

42.KneisS,WehrleA,MüllerJ,MaurerC,IhorstG,GollhoferA,etal.It’snevertoolate-balanceand

endurancetrainingimprovesfunctionalperformance,qualityoflife,andalleviatesneuropathic

symptomsincancersurvivorssufferingfromchemotherapy-inducedperipheralneuropathy:resultsof

arandomizedcontrolledtrial.BMCCancer.2019May2;19(1):414.

43.AlletL,ArmandS,deBieRA,GolayA,MonninD,AminianK,etal.Thegaitandbalanceofpatients

withdiabetescanbeimproved:arandomisedcontrolledtrial.Diabetologia.2010Mar;53(3):458–66.

44.LeeK,LeeS,SongC.Whole-bodyvibrationtrainingimprovesbalance,musclestrengthand

glycosylatedhemoglobininelderlypatientswithdiabeticneuropathy.TohokuJExpMed.

2013;231(4):305–14.

45.SongCH,PetrofskyJS,LeeSW,LeeKJ,YimJE.Effectsofanexerciseprogramonbalanceand

trunkproprioceptioninolderadultswithdiabeticneuropathies.DiabetesTechnolTher.2011

Aug;13(8):803–11.

46.TaubeW,GruberM,GollhoferA.Spinalandsupraspinaladaptationsassociatedwithbalance

trainingandtheirfunctionalrelevance.ActaPhysiolOxf.2008Jun;193(2):101–16.

47.ZechA,HübscherM,VogtL,BanzerW,HänselF,PfeiferK.Balancetrainingforneuromuscular

controlandperformanceenhancement:asystematicreview.JAthlTrain.2010Aug;45(4):392–403.

48.GranacherU,MuehlbauerT,TaubeW,GollhoferA,GruberM.SensorimotorTraining.In:Strength

andconditioning:biologicalprinciplesandpracticalapplications.SanFrancisco:Wiley-Blackwell;

2011.p.399.

49.CnyrimC,MergnerT,MaurerC.Potentialrolesofforcecuesinhumanstancecontrol.ExpBrain

Res.2009Feb14;194(3):419–33.

50.MaurerC,MergnerT,PeterkaRJ.Multisensorycontrolofhumanuprightstance.ExpBrainRes.

2006May;171(2):231–50.

51.MaurerC,PeterkaRJ.Anewinterpretationofspontaneousswaymeasuresbasedonasimple

modelofhumanposturalcontrol.JNeurophysiol.2005Jan;93(1):189–200.

52.PrietoTE,MyklebustJB,HoffmannRG,LovettEG,MyklebustBM.Measuresofposturalsteadiness:

differencesbetweenhealthyyoungandelderlyadults.IEEETransBiomedEng.1996Sep;43(9):956–

22

66.

53.PeterkaRJ.Sensorimotorintegrationinhumanposturalcontrol.JNeurophysiol.2002

Sep;88(3):1097–118.

54.WiesmeierIK,DalinD,WehrleA,GranacherU,MuehlbauerT,DietterleJ,etal.BalanceTraining

EnhancesVestibularFunctionandReducesOveractiveProprioceptiveFeedbackinElderly.FrontAging

Neurosci.2017;9:273.

55.KooijHvander,JacobsR,KoopmanB,HelmFvander.Anadaptivemodelofsensoryintegration

inadynamicenvironmentappliedtohumanstancecontrol.BiolCybern.2001Jan1;84(2):103–15.

56.MergnerT,MaurerC,PeterkaRJ.Sensorycontributionstothecontrolofstance:aposturecontrol

model.AdvExpMedBiol.2002;508:147–52.

57.WelchTDJ,TingLH.AFeedbackModelExplainstheDifferentialScalingofHumanPostural

ResponsestoPerturbationAccelerationandVelocity.JNeurophysiol.2009Jun;101(6):3294–309.

58.StreckmannF,KneisS,LeifertJA,BaumannFT,KleberM,IhorstG,etal.Exerciseprogram

improvestherapy-relatedside-effectsandqualityoflifeinlymphomapatientsundergoingtherapy.

AnnOncol.2014Jan2;25(2):493–9.

59.BoucherP,TeasdaleN,CourtemancheR,BardC,FleuryM.Posturalstabilityindiabetic

polyneuropathy.DiabetesCare.1995May;18(5):638–45.

60.CorriveauH,PrinceF,HébertR,RaîcheM,TessierD,MaheuxP,etal.EvaluationofPostural

StabilityinElderlywithDiabeticNeuropathy.DiabetesCare.2000Jan8;23(8):1187–91.

61.DiNardoW,GhirlandaG,CerconeS,PitoccoD,SoponaraC,CosenzaA,etal.Theuseofdynamic

posturographytodetectneurosensorialdisorderinIDDMwithoutclinicalneuropathy.JDiabetes

Complications.1999Apr;13(2):79–85.

62.SimoneauGG,UlbrechtJS,DerrJA,BeckerMB,CavanaghPR.Posturalinstabilityinpatientswith

diabeticsensoryneuropathy.DiabetesCare.1994Dec;17(12):1411–21.

63.UccioliL,GiacominiPG,MonticoneG,MagriniA,DurolaL,BrunoE,etal.Bodyswayindiabetic

neuropathy.DiabetesCare.1995Mar;18(3):339–44.

64.vanderKooijH,PeterkaRJ.Non-linearstimulus-responsebehaviorofthehumanstancecontrol

23

systemispredictedbyoptimizationofasystemwithsensoryandmotornoise.JComputNeurosci.

2011Jun;30(3):759–78.

65.HorakFB,DicksteinR,PeterkaRJ.Diabeticneuropathyandsurfacesway-referencingdisrupt

somatosensoryinformationforposturalstabilityinstance.SomatosensMotRes.2002Jan

1;19(4):316–26.

66.TuckerMG,KavanaghJJ,BarrettRS,MorrisonS.Age-relateddifferencesinposturalreactiontime

andcoordinationduringvoluntaryswaymovements.HumMovSci.2008Oct;27(5):728–37.

67.AllumJHJ,CarpenterMG,HoneggerF,AdkinAL,BloemBR.Age-dependentvariationsinthe

directionalsensitivityofbalancecorrectionsandcompensatoryarmmovementsinman.JPhysiol.

2002Jul15;542(Pt2):643–63.

68.MergnerT,MaurerC,PeterkaRJ.Amultisensoryposturecontrolmodelofhumanuprightstance.

ProgBrainRes.2003;142:189–201.

69.CataJP,WengHR,LeeBN,ReubenJM,DoughertyPM.Clinicalandexperimentalfindingsin

humansandanimalswithchemotherapy-inducedperipheralneuropathy.MinervaAnestesiol.2006

Mar;72(3):151–69.

70.BrownJC,HarhayMO,HarhayMN.Physicalfunctionasaprognosticbiomarkeramongcancer

survivors.BrJCancer.2015;112(1):194–8.

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.

27

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.