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  • NoTremor Deliverable D6.2 .2 -PU- Grant Agreement No. 610391

    December, 31, 2016 -1- UNITN

    SEVENTHFRAMEWORKPROGRAMMEINFORMATIONANDCOMMUNICATIONTECHNOLOGIES

    Project:NoTremorVirtual,PhysiologicalandComputationalNeuromuscularModelsforthePredictiveTreatmentofParkinsonsdisease

    (NoTremor,GrantAgreementNo.610391)

    Deliverablenumberandtitle:

    D6.2.2NoTremorframeworkevaluation(finalversion)

    Leadbeneficiary: UNITN

    WP.no,titleandactivitytype

    WP6Applicationscenariosdevelopment,validationandevaluation

    ContributingTask(s) T6.1Correlationofobjectiveandclinicalscalesandmonitoringofacohortevolution

    T6.2Simulationofestablishedmedication

    T6.3Assessmentandevaluation

    Disseminationlevel PUPublic

    Deliverydate December2016

    Status

  • NoTremor Deliverable D6.2 .2 -PU- Grant Agreement No. 610391

    December, 31, 2016 -2- UNITN

    AuthorsList

    Editor:UniversitdegliStudidiTrento(UNITN)

    Name/Surname Beneficiary Name(ShortName)

    Contactemail

    MauroDaLio UNITN mauro.dalio@unitn.it

    MariolinoDeCecco UNITN mariolino.dececco@unitn.it

    PaoloBosetti UNITN paolo.bosetti@unitn.it

    DanieleBortoluzzi UNITN daniele.bortoluzzi@unitn.it

    KonstantinosMoustakas UPAT moustakas@ece.upatras.gr

    TasosDimas UPAT dimas@ece.upatras.gr

    GiannisLakoumentas UPAT lakoumentas@ece.upatras.gr

    DimitarStanev UPAT stanev@ece.upatras.gr

    OtiliaKocsis UPAT okocsis@ece.upatras.gr

    ElisavetXroni UPAT echroni@upatras.gr

    VeltistaDimitra UPAT dveltsista@yahoo.gr

    DimitriosTzovaras CERTH tzovaras@iti.gr

    KonstantinosVotis CERTH kvotis@iti.gr

    PanagiotisMoschonas CERTH moschona@iti.gr

    AlexBlenkinsop USFD a.blenkinsop@sheffield.ac.uk

    SebJames USFD seb.james@sheffield.ac.uk

    PeterBrown UOX peter.brown@ndcn.ox.ac.uk

    ChrystalinaAntoniades UOX chrystalina.antoniades@ndcn.ox.ac.uk

    MicheleHu UOX michele.hu@ndnc.ox.ac.uk

    JillGallagher PUK jgallagher@parkinsons.org.uk

  • NoTremor Deliverable D6.2 .2 -PU- Grant Agreement No. 610391

    December, 31, 2016 -3- UNITN

    ExecutiveSummary

    Thisdeliverable(D6.2.2)isthefocalpointoftheproject.ItdealswiththeevaluationoftheNoTremor system,which is carriedwitha twofoldapproach:a)withavarietyoftechnicalvalidationassessmenttasksconcerningthesystemand itsbuildingmodules,andb)usingthesysteminselectedusecases.Thepatientsandcontrolcohortsfortheusecasesare4(section2.1):1)theOxfordDiscoverycohort,whichisasubsetoftheUKDiscoverystudywitharichsetofclinicalassessments;2)theOxfordSurgerycohort,whichisasmallcohortofsubjectswithsurgicalelectrode implantationandrecordingofLFP;3)theSantaChiaracohortwhich isalongitudinal study simulating theuseof theNoTremor system formonitoring;4) theThessalonikicohort,whichisarichcohortcombininginternalmodelparameterestimationwithobjectivemetrics.ThemainachievementoftheNoTremorsystem isthecombinationofamathematicalmodeloftheParkinsonianbasalgangliaandmotorsystemwithanewlydevelopedmotortest(thelinetest).Usingalgorithmsthatallowfittingthemodelontotherecordedexecutionsofthetestbyindividualpatients,thesystemallowsestimatingtheindividualpatientsconnectionstrengthsinthebasalganglia(sections2.2and2.3).TheParkinsonianbasalgangliaaredescribedby3parameters(Da,modellingtheeffectofdopamine,disandmpymodellingvariationsoftheconnectionstrengths inresponsetolossofdopamineandTmodellingtheadaptationofthemotorsystemtothenoisybasalgangliawhichhasthemeaningofintendedmovementtime).AssuchtheNoTremorsystemdescribesthePDasvariationsoftheabove4parameterscompared tohealthy subjects (3of the4parametersdescribingmodifications inthebasalgangliaandthe4thaconsequenceinthemotorplanningstage).Hencethediseaseisdescribedwithapoint{Da,dis,mpy,T}ina4dimensionalspace,ratherthanbeingdescribedwithasinglescalar,suchase.g.,UPDRSoranyotherscalarmetricsthatcanbederivedbytesting.Another fundamentaldifferencewithmetricsand indicatorsofvariouskinds thatareemerging in the literature, is that {Da,dis,mpy,T}mapsontovariationsofcouplingstrengths(theproductofthedensityandpotencyofsynapticinnervation)thatactuallyhappen in thebasalgangliaandmotor systemas thediseaseprogresses.Section2.2summarizes themathematicalmodelof theParinsonianbasalandmotor systemanddescribesthefinalparameterizationusedtomodelPD.Section2.3 illustratesthefinal(quitecomplex)strategy that isused forestimating theparametersof individualsubjects.One first finding of theNoTremor system is the discovery of two clusters in the 4dimensionalparameterspacethathavebeennamedthedisclusterandmpyclusters.Ofthetwo,thempyclusterlookstobeimplausibleforthedescriptionofPD(aspointedoutbyspectralanalysisandotherconsiderations). Ithasbeen found (section2.4)thatthiscluster iscorrelatedwith lesserprobabilityofPDandmightbeamarkerindicatingthatthesubjectmightnothaveclassicalPD,butratheramimickingdiseasesuchasProgressiveSupranuclearPalsyorMultipleSystemAtrophy.Thediscluster,instead,hasanelongatedshapethatiscompatiblewiththenotionofdiseaseevolution.

  • NoTremor Deliverable D6.2 .2 -PU- Grant Agreement No. 610391

    December, 31, 2016 -4- UNITN

    Inparticular,acrosssectionoftheparameterspaceintheDadisplaneshowsthatdis(themost importantvariationofconnectionstrengths) is related toDa inwhat lookslikeacausalrelationship:whenDadecreasesdisincreasesasexpectedifithastobeacompensatoryreactionofthebraintolossofdopamine(sections2.4,section2.6.1andanimationrelatedtoFig.13).Thecorrelationbetweenclinicalscalesandthemodelparameters{Da,dis,mpy,T}hasbeencarriedoutinsection2.4(correspondingtotaskT6.1).Severalregressionmodels(linear, but also nonlinearmodels such as Neural Network, Gaussian processes andRandomForestpredictors)havebeen tested. In theend, thesimple linear regressionhas been selected (and is reported in this deliverable).We have found a regressionmodelbetweenthe4parameters{Da,dis,mpy,T}andtheUPDRS3totalscorethatissignificant for all the 4 parameters (section 2.4, Fig.12; and similar to Kinetigraphbenchmarkexceptthelatterrequiresamuchlongerobservationtime).Thismeans that every point in the 4dimensional parameter spacemaps onto onepredictedvalueoftheUPDRSscore.Thefactthatthismappingismeaningfulimplies:a)thattheoverallmodelmeasurementfittingparameterestimationchainoutputdoeshavesomeusefulinformationcontent.Inotherwords,thattheestimatedparameters,albeitaffectedbyvariousformsofnoise,stillhaveasignificantamountofsignal(considerationsaboutthelevelofnoiseintheestimatedparameterscanbefoundinsection2.3.5,whilesection2.6clearlyshowsthatusingmoretestsforcomputingtheaveragetrajectorythebasicforparameterestimationsignificantlyimprovestheaccuracyoftheestimatedparameters).b)thattheestimatedparameterscanbeusedtopredictanequivalentUPDRSscore.Incombinationwithremotemonitoringtoolssuchasdescribedinsection2.6,thisgivesNoTremor the ability to bettermonitor the evolution of the disease, also revealingshort term fluctuationsand longer terms trends (thatcouldbeused, forexample, topreciselyassessthesubjectsresponsetodifferentmedications).Moreover,asshownin section 2.6, evolution of the disease tends to activate compensatorymechanisms(suchase.g.,reductionofDainducesincreaseofdis).Hence,atthemacroscopiclevel,thesameUPDRSscoreoccursfordifferentpointsinthediseasespace,whichhowevercanbediscriminatedbytheNoTremorsystem,allowinginprinciplemoreresolutionintrackingchangesthathavenotyettoaffecttheUPDRSscore.ThisattributemayproveparticularlyimportantinthecharacterisationofearlyandpresymptomaticPD,whereinternalcompensationcaneffectivelymaskclinicaldeficitoritsprogressionforseveralyears.Tobeabletotrackthehiddenchangesrelatedtothediseaseprocesswouldbeofmajorimportanceinthedevelopmentandtestingofdiseasemodifyingtreatments.Alinearregressionmodelbasedonbehaviouralparametersderivedfromthesamelinetest(PeakSpeed,StandardDeviationofPeakSpeedandStandarddeviationofTimeofPeakSpeed)wasalsofoundtobeabletopredicttheUPDRSscore,butnotabletobettertheperformanceofthepredictionmodelbasedonthemathematicalmodelparameters.Fromthisweconcludethatthemathematicalmodelwashighlyefficient incapturing the ability of performance in the line task to predict totalUPDRS, and couldachievethisusingabiologicallyinformedsetofhiddenparameters.

  • NoTremor Deliverable D6.2 .2 -PU- Grant Agreement No. 610391

    December, 31, 2016 -5- UNITN

    Monitoringofthediseaseevolution,basedonthediscoverycohort(section2.4.1)didnotshowsignificantvariationswhencohort1andcohort2whereconsidered intheirentirety.However,asignificantvariationinDawasobservedwhenthecomparisonwasrestrictedtothesubjectsthatcarriedoutboththebaselineandfollowuptest(hencecomparingexactlythesamecohort18monthsapart).Concerning the Levodopa use case (section 2.4.2) no significant variationswere observedinthe9subjectsoftheDiscoverycohortbutsignificantvariationswereobservedforDaanddisparametersbetweenONandOFFstateforthesurgicalcohort.Thismayberelatedtothefactthatthesecondcohortismoreadvanced(hencepotentiallybiggerdifferencebetweenONandOFF states)and that the Levodopachallenge for theDiscoverycohortwascarriedoutwithalesssevereprotocol(attenuatedlevodopachallenge,seeD2.3).Furtherusecasesaredescribedindescribedinsection2.5(correlationofforceandlinetestwithmanyobjectiveandclinical indicators)and insection2.6 (useofthesystemforlongitudinalmonitoring,includingtheassessmentofseveralinterestingbehaviouralparametersovertime,suchas,errorrates,peakspeed,distractorandfatigueeffects).Technicalvalidationactivitiesaredescribedinsection3.Inparticularsection3.1studiesthequestionwhether3modelparameters (Da,disandmpy)are reallynecessary forthe basal gangliamodelling. Amodelwithout thempy parameter has been studiedshowingthatwithonlyDaanddis,themodelwouldfailtocorrelatewithUPDRSscore.Technical assessment of the line test and of the Lumpedmodelwas carried out inD6.2.1(section3)andnotrepeatedhere.Previoustechnicalvalidationtasks(completedinD6.2.1)fortheLumpedModelandfortheLineTaskc