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Longitudinal Follow Up of Impedance Drift in Deep Brain Stimulation Cases

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Longitudinal Follow Up of Impedance Drift in Deep Brain Stimulation Cases
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Wong J, Gunduz A, Shute J, Eisinger R, Cernera S, Ho KWD, et al. Longitudinal Follow-up of Impedance Drift in Deep Brain Stimulation Cases. Tremor and Other Hyperkinetic Movements. 2018 Mar 26;7.
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Wong, Joshua
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Tremor and Other Hyperkinetic Movements
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Background: Impedance is an integral property of neuromodulation devices that determines the current delivered to brain tissue. Long-term variability in therapeutic impedance following deep brain stimulation (DBS) has not been extensively investigated across different brain targets. The aim was to evaluate DBS impedance drift and variability over an extended postoperative period across common DBS targets. Methods: Retrospective data from 1,764 electrode leads were included and drawn from 866 DBS patients enrolled in the University of Florida Institutional Review Board-approved INFORM database and analyzed up to 84 months post implantation. An exploratory analysis was conducted to identify trends in impedances using a Mann–Kendall test of trend. Results: There were 866 patients and 1,764 leads available for analysis. The majority of subjects had Parkinson’s disease (60.7%). The mean age at implantation was 58.7 years old and the mean follow-up time was 36.8 months. There were significant fluctuations in the mean impedance of all electrodes analyzed that largely stabilized by 6 months except for the subthalamic nucleus (STN) target, in which fluctuations persisted throughout the duration of follow-up with a continued downward trend (p , 0.001). Discussion: The drift in impedance observed primarily within the first 6 months is in keeping with prior studies and is likely due to surgical micro-lesioning effects and brain parenchyma remodeling at the electrode–tissue interface, typically at values approximating 1,000 V. The differences in impedance trends over time in the various DBS targets may be due to underlying differences in structure and tissue composition.
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Collected for University of Florida's Institutional Repository by the UFIR Self-Submittal tool. Submitted by Joshua Wong.

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Articles LongitudinalFollow-upofImpedanceDriftinDeepBrainStimulationCases JoshuaWong 1 ,AysegulGunduz 1,2 ,JonathanShute 1,2 ,RobertEisinger 1,2 ,StephanieCernera 1,2 ,KwoWeiDavidHo 1 DanielMartinez-Ramirez 1 ,LeonardoAlmeida 1 ,ChristinaA.Wilson 1 ,MichaelS.Okun 1 &ChristopherW.Hess 1* 1 CenterforMovementDisordersandNeurorestoration,DepartmentofNeurology,UniversityofFloridaCollegeofMedicineandMcKnightBrainInstitu te, Gainesville,FL,USA, 2 J.CraytonPruittFamilyDepartmentofBiomedicalEngineering,UniversityofFloridaGainesville,FL,USA Abstract Background: Impedanceisanintegralpropertyofneuromodulationdevicesthatdeterminesthecurrentdeliveredtobraintissue.Long-termvariabilityin therapeuticimpedancefollowingdeepbrainstimulation(DBS)hasnotbeenextensivelyinvestigatedacrossdifferentbraintargets.Theaimwastoe valuateDBS impedancedriftandvariabilityoveranextendedpostoperativeperiodacrosscommonDBStargets. Methods: Retrospectivedatafrom1,764electrodeleadswereincludedanddrawnfrom866DBSpatientsenrolledintheUniversityofFloridaInstitutional ReviewBoard-approvedINFORMdatabaseandanalyzedupto84monthspostimplantation.Anexploratoryanalysiswasconductedtoidentifytrendsin impedancesusingaMann–Kendalltestoftrend. Results: Therewere866patientsand1,764leadsavailableforanalysis.ThemajorityofsubjectshadParkinson’sdisease(60.7%).Themeanageatimplantatio n was58.7yearsoldandthemeanfollow-uptimewas36.8months.Thereweresignificantfluctuationsinthemeanimpedanceofallelectrodesanalyzedth atlargely stabilizedby6monthsexceptforthesubthalamicnucleus(STN)target,inwhichfluctuationspersistedthroughoutthedurationoffollow-upwithac ontinued downwardtrend(p 0.001). Discussion: Thedriftinimpedanceobservedprimarilywithinthefirst6monthsisinkeepingwithpriorstudiesandislikelyduetosurgicalmicro-lesioningeffe cts andbrainparenchymaremodelingattheelectrode–tissueinterface,typicallyatvaluesapproximating1,000 V .Thedifferencesinimpedancetrendsovertimeinthe variousDBStargetsmaybeduetounderlyingdifferencesinstructureandtissuecomposition. Keywords: Deepbrainstimulation,impedance,Parkinson’sdisease,subthalamicnucleus,globuspallidusinternus Citation: WongJ,GunduzA,ShuteJ,EisingerR,CerneraS,HoKWD,etal.Longitudinalfollowupofimpedancedriftindeepbrainstimulationcases.Tremor OtherHyperkinetMov.2018;8.doi:10.7916/D8M62XTC *Towhomcorrespondenceshouldbeaddressed.E-mail:Christopher.Hess@neurology.ufl.edu Editor: ElanD.Louis,YaleUniversity,USA Received: January19,2018 Accepted: February22,2018 Published: Copyright:  2018Wongetal.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttribution–Noncommercial–NoDerivativesLicen se,whichpermits theusertocopy,distribute,andtransmittheworkprovidedthattheoriginalauthorsandsourcearecredited;thatnocommercialuseismadeofthewor k;andthattheworkisnotaltered ortransformed. Funding: None. FinancialDisclosures: None. ConflictofInterests: Theauthorsreportnoconflictofinterest. EthicsStatement: ThisstudywasperformedinaccordancewiththeethicalstandardsdetailedintheDeclarationofHelsinki.Theauthors’institutionalethicscommit teehasapproved thisstudyandallpatientshaveprovidedwritteninformedconsent. Introduction Deepbrainstimulation(DBS)isaninvasiveneuromodulatory therapythathasbeenutilizedforthetreatmentofselectedpatients withmovementandpsychiatricdisorders. 1 DBSiscurrentlyFoodand DrugAdministrationapprovedforuseinParkinson’sdisease(PD), dystonia,essentialtremor(ET),andobsessive–compulsivedisorder. 2–5 ItisunderinvestigationforseveralotherconditionsincludingTourette syndrome,depressionandobesity. 6–8 AlthoughthetherapeuticbenefitfromDBSiswellestablished,thebiologicalresponseandthe mechanismsofactionofDBS,aswellasitslong-termstability,remain unknown. 9,10 Recentstudiescontinuetofocusontheelectricalstability ofDBSdevicesandtheevaluationofdevice–tissueinteractionsacross multiplebraintargetsanddisorders. 11–13 Thesimplestmeasureofdevice–tissueinteractionisimpedance, whichistheresistancetoelectricalchargeflow. 14 WithrespecttoDBS, impedancedependsonelectrodecompositionandthetissue–electrode interface.Largedeviationsinimpedancecanreflectissuesindevice functionalitysuchasshortcircuits,migrationofcerebrospinalfluid, Freely available online Tremor and Other Hyperkinetic Movements htt p ://www.tremor j ournal.or g Columbia University Libraries 1 March26,2018

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andopencircuits.Valueslessthan50 V likelyrepresentashortcircuit, andvaluesgreaterthan2,000 V usuallyrepresentabrokenlead.15Studiesmeasuringimpedanceinepilepticfocireportedaninitial periodofinstability,followedbyageneralconvergenceofimpedances acrosspatients.11However,withinthecontextofDBS,impedance studiesareusuallylimitedtowithin-subjectanalyses.16Investigating impedancedriftovertimeacrosssubjectsrequireslargesamplesizes duetothewiderangeoffactorsincludingthechoiceofanatomical target,clinicaldiagnosis,andstimulationsettings. Inthisstudy,wepresentthelong-term(upto7years)reviewof impedancemeasurementsthatweredrawnfromover800patients implantedwithDBSinthesubthalamicnucleus(STN),theglobus pallidusinternus(GPi),orthenucleusventralisintermedius(VIM). Wealsoexaminedimpedancemeasurementsfromafewless-common braintargetsandreportavailableinformationfromthesetargets. Wediscusspotentialsourcesfordeviationsinimpedancemeasurements,particularlybetweenDBStargets. Methods Studysubjects DatawereretrospectivelycollectedfollowingInstitutionalReview BoardapprovaltoaccesstheUniversityofFlorida(UF)INFORM (CenterforMovementDisorders&Neurorestoration)database. Patientdatafrom866patientswith1,764DBSleadswereextracted fromthedatabase.TheUFINFORMisalongitudinalclinical researchdatabase,whichprovidesinformationonpatientdemographics,andclinical,surgical,andfun ctionalcharacteristicsofpatients. Currently,thedatabasehasapproximately10,000patients,including allDBSpatientsimplantedattheUniversityofFlorida.Pertinent recordeddatareviewedincludedindicationforsurgery,stimulator model,implantationsite,implantationdate,lateralityofimplant, therapeuticimpedancemeasurement(measuredateachfollow-up visit),stimulationsettings(measuredateachfollow-upvisit),age,and gender.AllpatientsinthisstudyhadeitheraMedtronicSoletra, MedtronicInc.,Minneapolis,MN,USAorKinetraimplantablepulse generator(IPG)andusedaMedtronic3387lead.AllDBSsystemsin thisstudyutilizedconstantvoltagestimulationsettings. Followingimplantation,patientsattendedclinicalfollow-upvisitsfor DBSprogramming.Atrainedclinicalprogrammerassessedthetherapeuticeffectivenessofstimulationsettingsateachfollow-upvisituntila clinicallydefinedbesttherapeuticsettingwasachieved(frequency, voltage,pulsewidth,activeDBScontact(s),andleadlocation).The therapeuticimpedancewasmeasuredwithstimulationparameters thoughttoprovidethebestclinicalbenefitwithnosideeffects.Data werederivedfromeachprogrammingvisit,typicallymonthlyforthe first6monthsandthenonceortwiceayearthereafter,asdeterminedby individualizedpatientcare.Impedancevaluesinthisstudyrefertothe therapeuticimpedancemeasurementattheclinicallydefinedbestsetting fromtheactiveDBScontact.Thetherapeuticimpedancewasmeasured attheendofeachclinicvisitafterallprogrammingchangesweremade. Databaseprocessing Thedatabasewasparsedforpatientdemographics,implantation indication,site,andlaterality.Implantationsiteswithfewerthan 10totalleadsdocumentedinthedatabasewereexcludedfromthis query.Oncethisinitialquerywascompleted,aseconditerationwas performedtoincorporatestimulationsettingsincludingthevoltage, frequency,pulsewidthandthetherapeuticimpedance.Groupstimulationsettingsweredeterminedbycalculatingthemeanandstandard deviationofthepatientsinthedataset.Timewasdefinedasthe numberofmonthssinceDBSimplantation.Asclinicalparameters dictatedpatientfollow-up,visitsweremorevariableandirregularwith increasingtimefromthedateofimplantation.Toaccommodatefor thisvariability,timerangesratherthandateswereusedtoencompass asmanypatientvisitsaspossibleandthismethodallowedforvarious issuesincludingschedulingconflicts,transportationissues,andother barrierstoscheduledclinicvisits. Weexaminedprogrammingsettingsacrosssubjectsforpatient demographics,anatomicaltargets,implantationlaterality,anddiagnoses.Valuesweredrawnfromthefirstvisitoccurringbetween18and 30monthspostimplantation(i.e.,24 ¡ 6months). Thetherapeuticimpedancemeasurementswerealsocompared againsttime.Timepointsforeachimpedancemeasurementwere calculatedbydeterminingthenumberofmonthsbetweenthedateof theclinicvisitandthedateofimplantation.Theimpedancesofthe threemostfrequentlyselectedtargetsites(GPi,STN,andVIM)were plottedagainsttimeuptoamaximumof84months’follow-up. Foreachmonthfrom0to84,themeanimpedanceandstandarderror ofthemeanwerecalculatedfromallrecordedvisitsforeachrespectivetargetsite.Acompositecalculationwasalsoperformedtodeterminethemeanimpedanceandstandarderrorofthemeanfromall electrodesforeachmonth.Impedancemeasurementsof‘‘NULL’’or zerowereexcludedfromthisanalysisastheyweredeemedtobe erroneousmeasurements(n 5 1178).Measurementsat2,000 V and 4,000 V wereexcludedastheylikelyrepresentedadeviceorrecording malfunctioncausingareadinggreaterthanthemaximumdevice threshold(n 5 376).Thesevalueswerechosenbasedonthetechnical specificationsdescribedintheMedtronicapplicationmanualforthe SoletraandKinetraIPGsthatlistedthemaximumdeviceimpedance as2,000and4,000 V respectively.Additionally,impedancemeasurementsover9,000 V wereexcluded(n 5 6)astheywereconsidered tobeeithererroneousorlikelyassociatedwithmechanicalfailure.15Impedancemeasurementsfromclinicvisitsthatprecededthesurgery datewerealsoexcludedastheywerethoughttobeerroneously recordedorrepresentedpatientswhounderwentDBSsurgeryatan outsidefacilityandwerereferredtoourclinicforevaluationofDBS failurewithsubsequentleadrevision(n 5 164).Atotalof8,322 timepointsremainedforanalysis.Afterthemeanimpedanceswere determined,aMann–Kendalltestoftrendwasperformedtoevaluate forevidenceofupwardordownwardtrendinimpedanceovertime. AWilcoxonsignedranktestwasalsoperformedonthemeanimpedancesofallelectrodesfrommonths0to12.BoththeMann–Kendall testandtheWilcoxonsignedranktestwerechosenaswedidnotWongJ,GunduzA,ShuteJ,etal. ImpedanceDriftinDBS Tremor and Other Hyperkinetic Movements http://www.tremorjournal.org Columbia University Libraries 2

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assumetheimpedancemeasurestobenormallydistributed.Analpha levelwassetat0.05(i.e.,aconfidencelevelof95%).Allthestatistical analysesandcalculationswereperformedusingMathWorksMATLABR2015bandIBMSPSSStatistics24. Results Patientrecordsfrom866patientswith1,764leadswerecollectedfor analysis.Atotalof8,322leadmeasurementswereutilizedinthestudy aftertheexclusioncriteriawereapplied.Forty-fivepercentofpatients receivedunilateralDBS;allothers(n 5 389)receivedbilateralDBS. AsummaryofimplantationsitesandindicationsforDBSisshownin Table1.ThemajorityofthesubjectsincludedinthisstudyhadPD (60.7%).Themeanageatimplantationwas58.7years.Ofpatients, 35.6%werefemaleand54.5%ofleadswereplacedinthelefthemisphere.Themeanfollow-uptimewas36.8monthsandthemaximum follow-uptimewas143months.Avisualizationoftherelationship betweenthepatient’sprimarydiagnosisandimplantationsiteissummarizedinTable2.Acomprehensivebreakdownofindication,lead location,gender,averagestimulationsettings,andaverageimpedance isavailableinTable3. Impedancemeasurementswereanalyzedasafunctionoftimepost implantation.TheresultsareshowninFigure1.Thereweresignificantfluctuationsinthemeanimpedanceofallelectrodes,butthese changesstabilizedbythesixthmonthforallleadlocationsexceptfor theSTN,wherefluctuationspersistedthroughoutthedurationof follow-up.Forallrecordedelectrodes,Wilcoxonsignedranktestswere performedindividuallybetweentheimpedanceat12monthsand month0tomonth11.Wefoundthatthemeanatmonths0–5were significantlydifferentfromthemeanat12months(p 0.001).There wasnosignificantdifferenceinthemeanimpedancesfrommonth6–11 versusmonth12bytheWilcoxonsignedranktest.Thisfindingsuggestedthatimpedancetendedtofluctuatemostwithinthefirst 6months. Toinvestigateimpedancefluctuationsfurther,weassessedfortrends usingaMann–Kendalltestoftrendacrosselectrodesandseparatedby DBSbraintargets(Figure1B–D).AlthoughtheMann–Kendalltestis primarilyusedformonotonictrends,ithasbeenextensivelyusedinthe environmentalsciencesliteraturetoevaluatecyclictrendssuchasin annualrainfallandwaterqualitysurveillance.17–19Inthisscenario, theMann–Kendalltestevaluatestheglobaltrendbutisunableto interpretanysinglecycletrends.Withrespecttotheimpedancedata showninFigure1,wecananalyzethedegreeoftrendovertimebut areunabletocommentonmonth-to-monthchanges.Inthecomposite datasetofallelectrodes,therewasevidenceofsignificantdownward trendingfrommonths0to23(p 0.043)butdownwardtrending frommonths24to84wasnotsignificant(p 5 0.058).TheTaub coefficients(thedegreeoftrendingmeasuredbytheMann–Kendall test)were–0.612and–0.166respectively.IntheSTNtarget,therewas evidenceofsignificantdownwardtrendingincludingall84months offollow-up(p 5 1.00 6 10–13).TheTaubcoefficientwas–0.552. IntheGPitarget,therewasnostatisticalevidenceofupwardor downwardtrendingforall84months(p 5 0.195).TheKendallTaub correlationcoefficientwas–0.0958.IntheVIMtarget,therewas evidenceofdownwardtrendingfrommonths0to27(p 0.036); however,frommonths28to84therewasnoevidenceoftrending (p 5 0.079).TheTaubcoefficientswere–0.305and–0.159respectively. Discussion Ourstudyfoundthatimpedancedriftwasmostprominentwithin thefirst6monthsfollowingDBSimplantation.Followingthisinitial Table 1. PatientDemographicsandImplantationInformation CharacteristicsN(%)Gender,mean(SD) Male Female Notspecified 836(64.3) 463(35.6) 465 Age,mean(SD) 40 40–60 60 Notspecified 106(12.4) 254(29.6) 498(58.0) 906 Primarydiagnosis,mean(SD) Parkinson’sdisease Essentialtremor Primarydystonia Tremor(nototherwisespecified) Secondarydystonia Obsessivecompulsivedisorder Tourettesyndrome Other Notspecified 789(60.7) 192(14.8) 143(11.0) 80(6.2) 36(2.8) 13(1.0) 9(0.7) 37(2.8) 465 Implantationsite,mean(SD) Subthalamicnucleus Globuspallidusinternus Ventralisintermediusofthalamus Ventralisoralisposterior/anteriorofthalamus Anteriorlimbofinternalcapsule Centromediannucleusofthalamus Notspecified 688(45.1) 444(29.1) 332(21.8) 39(2.6) 13(0.9) 10(0.7) 238 Implantationlaterality,mean(SD) Left Right 962(54.5) 802(45.5) Totalnumberofleads1,764Abbreviation:SD,StandardDeviation. Thenumberofimplantedleadswithinvarioustargetsand fordifferentdisordersandthesummarystatisticsofthe patientpopulationfromwhich theseresultswerederivedare shown.Inthesupplementarymethodsisamorecomplete summaryofthedatasetwithadditionalinformation.ImpedanceDriftinDBS WongJ,GunduzA,ShuteJ,etal. Tremor and Other Hyperkinetic Movements htt p ://www.tremor j ournal.or g Columbia University Libraries 3

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Table 2. PatientDiagnosesandTargets DiagnosisSTNGPiVIMVoa/VopALICCMPrimarydiagnosis,N Parkinson’sdisease40322323300 Essentialtremor52168400 Primarydystonia191087000 Tremor(nototherwisespecified)40312700 Secondarydystonia10192100 Obsessivecompulsivedisorder0000120 Tourettesyndrome022004 Other8184100 Notspecified2397295316Abbreviations:ALIC,AnteriorLimbofInternalCapsule;CM,CentromedianNucleusoftheThalamus;GPi,GlobusPallidusInternus;STN, SubthalamicNucleus;VIM,VentralisIntermediusofThalamus;Voa/Vop,VentralisOralisPosterior/AnteriorofThalamus. ThetableshowsasummaryofthevariousDBSimplantationtargetsiteswithrespecttotheprimarypatientdiagnosis. Table 3. SummaryStatistics CharacteristicsN(%)Voltage(V)Frequency(Hz)PulseWidth(ms)Impedance(Ohms)Gender,mean(SD) Male Female 206(68.9) 93(31.1) 2.7(0.6) 2.7(0.7) 147.9(31.3) 140.1(40.2) 112.3(60.1) 126.4(81.0) 948.9(315.1) 960.7(312.4) Age,mean(SD) 40 40–60 60 36(12.0) 101(33.8) 162(54.2) 2.9(0.6) 2.6(0.7) 2.7(0.7) 126.0(46.3) 144.0(33.3) 151.0(30.3) 186.9(113.0) 114.7(61.2) 102.2(44.8) 1003.5(433.4) 975.2(305.1) 927.1(286.4) Primarydiagnosis,mean(SD) Parkinson’sdisease Essentialtremor Primarydystonia 183(61.2) 48(16.0) 36(12.0) 2.7(0.6) 2.7(0.7) 2.8(0.8) 148.6(28.4) 155.5(23.6) 117.5(50.6) 94.7(23.5) 103.3(31.6) 215.6(115.4) 955.2(320.6) 931.8(287.7) 994.8(251.1) Implantationsite,mean(SD) Globuspallidusinternus Subthalamicnucleus Ventralisintermediusofthalamus Ventralisoralisposterior/anterior Anteriorlimbofinternalcapsule 86(28.8) 141(47.2) 59(19.7) 8(2.7) 4(1.3) 2.8(0.7) 2.6(0.6) 2.7(0.7) 2.7(0.6) 2.9(0.6) 136.2(43.6) 146.9(28.9) 156.5(25.1) 169.4(21.9) 116.3(37.5) 156.5(106.3) 95.4(23.3) 105.9(39.2) 112.5(13.9) 172.5(56.8) 1004.3(296.4) 932.9(311.5) 952.1(300.7) 941.8(523.9) 515.3(132.8) Implantationlaterality,mean(SD) Left Right 188(62.9) 111(37.1) 2.7(0.6) 2.7(0.7) 147.9(33.1) 141.7(36.3) 113.9(60.5) 121.3(77.9) 945.0(286.3) 965.3(356.6)Abbreviation:SD,StandardDeviation. Thetableshowsacomprehensivebreakdownofaveragestimulationsettingsandimpedanceseenatapproximately24monthspostimplantation groupedbygender,age,indicationandleadlocation.WongJ,GunduzA,ShuteJ,etal. ImpedanceDriftinDBS Tremor and Other Hyperkinetic Movements http://www.tremorjournal.org Columbia University Libraries 4

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period,changesinimpedanceweremoresubtlebutoveralltrended downwardwithtimeinalltargetsexceptintheGPi.Thestability oftheGPianddownwardtrendofothertargetswereconsistent withobservationsfrompreviouslyperformedsmallerstudies.12,14,20,21Thesechangesinimpedancehavebeenattributedtocerebraledema andinflammationsecondarytosurgicalmicro-lesioningeffectsand duetoforeignbodyresponsesasthebrainparenchymaremodelsto accommodatetheelectrode–tissueinterface;however,thisexplanation remainsunconfirmedinthehumanbrain.12,13,15,22Inthisstudy,the therapeuticimpedancefromallimplantationsitesequalizedtoward Figure 2. ConstantVoltagevs.ConstantCurrent. Thecharacteristicsofaconstant-voltagedevicecanbeseeninA–CandconstantcurrentdeviceinD–F. Theblueboxhighlightsakeyfeatureofconstant-currentdevices:regardlessofphysiologicimpedance,theamountofcurrentstimulationdelivere dtothetarget tissuewillalwaysbethesame. Figure 1. AverageImpedanceofDeepBrainStimulationElectrodeLeadsVersusTime. Thesolidcenterbluelinerepresentstheaverageimpedanceof allelectrodemeasurementsofthespecifiedtargetsite:(A)foralltargets,(B)forsubthalamicnucleus,(C)forglobuspallidusinternus,and(D)f orventralisintermedius ofthalamusat1-monthintervalsfrom0to84months.Theshadedregionaboveandbelowthelinerepresentstwostandarderrorsofthemean.Asteriskwit hbar indicatesp 0.001differencefromaverageimpedanceatmonth12.ImpedanceDriftinDBS WongJ,GunduzA,ShuteJ,etal. Tremor and Other Hyperkinetic Movements htt p ://www.tremor j ournal.or g Columbia University Libraries 5

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therangeofapproximately1000 V ,presumablyastheelectrode–tissue interfacestabilized.Downwardtrendsinimpedanceweakenedwith continuedfollow-upovertime,supportingtheideaofstabilization oftheelectrode–tissueinterface.Onelimitationofthisretrospective analysisisthesignificantdecreaseinclinicvisitsafter60monthsof follow-up.Assuch,thevariabilityofimpedanceinalltargetsafter 60monthsismuchhigherthanpriorto60months.Thisislikelydueto thedecreaseinsamplesizeratherthanchangestotheelectrode–tissue interface. WhileimpedanceintheGPItargetwasrelativelystablethroughout thedurationoffollow-up,impedanceintheSTNcontinuedtotrend downwardthroughouttheentire84monthsofclinicalfollow-up. OnemaincomponentofimpedancevariabilityinDBSisthedegree oftissueencapsulationasaforeignbodyreactiontotheDBSelectrodeandtheconductivityofthatencapsulation.15Itisthoughtthat electricalstimulationcanmodifythetissuearchitectureofthe immediatevicinity,causinganincreaseinconductivityanddecrease inimpedance.Thelong-termfindingsofthisstudymaysuggestthat theencapsulationresponseintheSTNisnotentirelyidenticaltothat oftheGPi.Thismayalsoberelatedtotheunderlyingstructural differencesbetweenthetworegionsaswellasduetothechemical compositionofthetissueandneurotransmittersthatprimarilyconstituteaffectedneuralstructures.23Researchershaveproposedthat differencesinthegraytowhitematterratioandcorresponding distributionofperi-electrodeCSFcouldplayaroleintheconductance oftheoverallsystem.8Itisalsothoughtthatthesefactorsmaybetied totheunderlyingencapsulationresponse,althoughnostudieshave definitivelydescribedthisrelationshipyet. Impedanceattheelectrode–tissueinterfaceisanimportantfactor thatcaninfluencethecurrentdeliveredbyDBS.IntraditionalconstantvoltageDBSdevices,itmaybeparticularlyimportantsince electrodeimpedancedirectlycorrelatestotheamountofelectrical currentdeliveredtothebraintissue(Ohm’slaw: V 5 IR).Inconstant currentdevices,theimpedanceplaysalesserrolesincetheoutput voltageisregulatedtomaintainaspecifiedcurrentindependentofthe localimpedance.Theelectrophysiologicdifferencesbetweenthesetwo typesofdevicesaredemonstratedwithhypotheticaldatainFigure2. Thoughsomedegreeofimpedancedriftisanexpectedphenomenon thatcliniciansshouldbeawareof,theoverallstabilityofimpedance demonstratedinthislargedatabasecohortstudymayexplainwhy clinicianshavenotobserveddramaticdifferencesinoutcomesbetween constantcurrentandconstantvoltage.24Todate,therehavebeen nolargestudiesthathavedirectlycomparedconstantcurrentDBS devicesagainstconstantvoltagedevices.Smallerstudieshaverevealed constantcurrentdevicestobesimilarinsafetyandefficacywhen comparedtoconstantvoltagedevices.25,26Additionally,therehave beensubtledifferencesdocumentedinimpedanceamongthevarious brainimplantationsitesandthismayberelatedtoinherenttissue propertiesandcomposition.Futurestudiesshouldinvestigatepotential correlationsbetweenage,stimulationsettings,therapeuticimpedance, diseasestates,andclinicaloutcomesandthesestudiesshouldprovidea morestructuredfollow-up. Conclusions Thelargedatabasecohortassessedinourstudyprovidedaunique opportunitytoevaluatetheimpedancesofempiricallydetermined stimulationsettingsforalargenumberofbraintargetsandregions. Impedancedriftoccursprimarilyinthefirst6monthspostDBS implantation,anddownwardtrends(whenpresent)weakenovertime. Fluctuationsinimpedancearemostprominentanddownwardtrends mostpersistentintheSTNtarget,whichmaybeduetodifferencesin structureandtissuecompositionwhencomparedwithGPIDBS. Theseresultssuggestthatconstantcurrentdevicescouldbemore effectiveinmaintainingimpedancestability.Furtherinvestigationsof therelationshipbetweenimpedanceandotherDBSparameterscould possiblystreamlinetheprocessofinitialDBSprogrammingafter implantationandmayaidintheoptimizationofDBSprogramming settings. Acknowledgments WethanktheParkinson’sFoundationfortheirsupportthroughthe centerofexcellenceprogramandwethankthesupportoftheUF INFORMdatabase. References1. PerlmutterJS,MinkJW.Deepbrainstimulation. AnnuRevNeurosci 2006; 29:229–257.doi:10.1146/annurev.neuro.29.051605.112824 2. WeaverFM,FollettK,SternM,HurK,HarrisC,MarksWJ,etal. Bilateraldeepbrainstimulationvsbestmedicaltherapyforpatientswith advancedParkinsondisease:arandomizedcontrolledtrial. JAMA 2009;301: 63–73.doi:10.1001/jama.2008.929 3. VidailhetM,VercueilL,HouetoJL,KrystkowiakP,LagrangeC,YelnikJ, etal.Bilateral,pallidal,deep-brainstimulationinprimarygeneraliseddystonia: aprospective3yearfollow-upstudy. LancetNeurol 2007;6:223–229.doi:10.1016/ S1474-4422(07)70035-2 4. KumarR,LozanoAM,SimeE,LangAE.Long-termfollow-upof thalamicdeepbrainstimulationforessentialandparkinsoniantremor. Neurology 2003;61:1601–1604.doi:10.1212/01.WNL.0000096012.07360.1C 5. GreenbergBD,MaloneDA,FriehsGM,RezaiAR,KubuCS, MalloyPF,etal.Three-yearoutcomesindeepbrainstimulationforhighly resistantobsessive-compulsivedisorder. Neuropsychopharmacology 2006;31:2384– 2393.doi:10.1038/sj.npp.1301165 6. 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