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  • Magnetoelectric materials for miniature, wireless neural … · 1 Magnetoelectric materials for miniature, wireless neural stimulation at 2 therapeutic frequencies 3 4 Amanda Wickens1,2,
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Magnetoelectric materials for miniature, wireless neural stimulation at 1 therapeutic frequencies 2 3 Amanda Wickens 1,2 , Benjamin Avants 2 , Nishant Verma 3 , Eric Lewis 2 , Joshua C. Chen 3 , 4 Ariel K. Feldman 4,5 , Shayok Dutta 2 , Joshua Chu 2 , John O’Malley 6 , Michael Beierlein 6 , 5 Caleb Kemere 2,3 , Jacob T. Robinson 1,2,3,7 6 7 1 Applied Physics Program, Rice University, Houston, Texas, USA, 2 Department of Electrical and 8 Computer Engineering, Rice University, Houston, Texas, USA, 3 Department of Bioengineering, Rice 9 University, Houston, Texas, USA, 4 Department of Computer Science, Rice University, Houston, Texas, 10 USA, 5 Department of Cognitive Science, Rice University, Houston, Texas, USA, 6 Department of 11 Neurobiology and Anatomy, McGovern Medical School at UTHealth, Houston, Texas, USA, 12 7 Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA 13 14 A fundamental challenge for bioelectronics is to deliver power to miniature 15 devices inside the body. Wires are common failure points and limit device 16 placement. Wireless power by electromagnetic or ultrasound waves must 17 overcome absorption by the body and impedance mismatches between air, 18 bone, and tissue. Magnetic fields, on the other hand, suffer little absorption by 19 the body or differences in impedance at interfaces between air, bone, and 20 tissue. These advantages have led to magnetically-powered stimulators based 21 on induction or magnetothermal effects. However, fundamental limitations in 22 these power transfer technologies have prevented miniature magnetically- 23 powered stimulators from applications in many therapies and disease models 24 because they do not operate in clinical “high-frequency” ranges above 20 Hz. 25 Here we show that magnetoelectric materials – applied for the first time in 26 bioelectronics devices – enable miniature magnetically-powered neural 27 stimulators that operate at clinically relevant high-frequencies. As an 28 example, we show that ME neural stimulators can effectively treat the 29 symptoms of a Parkinson’s disease model in a freely behaving rodent. We also 30 show that ME-powered devices can be miniaturized to sizes smaller than a 31 grain of rice while maintaining effective stimulation voltages. These results 32 suggest that ME materials are an excellent candidate for wireless power 33 delivery that will enable miniature neural stimulators in both clinical and 34 research applications. 35 36 Wireless neural stimulators have the potential to provide less invasive, longer 37 lasting interfaces to brain regions and peripheral nerves compared to battery- 38 powered devices or wired stimulators. Indeed, wires are a common failure point for 39 bioelectronic devices. Percutaneous wires present a pathway for infection 1 and 40 implanted wires can also limit the ability of the stimulators to move with the tissue, 41 leading to a foreign body response or loss of contact with the target tissue 2,3 . 42 Additionally, chronic stress and strain on wires, particularly for devices in the 43 periphery, can lead to failure in the wire itself or its connection to the stimulator 4 . In 44 small animals like rats and mice, wires used to power neural stimulators can 45 interfere with natural behavior, particularly when studying social interaction 46 between multiple animals 5 . 47 not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which was this version posted November 5, 2018. ; https://doi.org/10.1101/461855 doi: bioRxiv preprint

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  • Magnetoelectricmaterialsforminiature,wirelessneuralstimulationat1therapeuticfrequencies23AmandaWickens1,2,BenjaminAvants2,NishantVerma3,EricLewis2,JoshuaC.Chen3,4ArielK.Feldman4,5,ShayokDutta2,JoshuaChu2,JohnO’Malley6,MichaelBeierlein6,5CalebKemere2,3,JacobT.Robinson1,2,3,7671AppliedPhysicsProgram,RiceUniversity,Houston,Texas,USA,2DepartmentofElectricaland8ComputerEngineering,RiceUniversity,Houston,Texas,USA,3DepartmentofBioengineering,Rice9University,Houston,Texas,USA,4DepartmentofComputerScience,RiceUniversity,Houston,Texas,10USA,5DepartmentofCognitiveScience,RiceUniversity,Houston,Texas,USA,6Departmentof11NeurobiologyandAnatomy,McGovernMedicalSchoolatUTHealth,Houston,Texas,USA,127DepartmentofNeuroscience,BaylorCollegeofMedicine,Houston,Texas,USA1314Afundamentalchallengeforbioelectronicsistodeliverpowertominiature15devicesinsidethebody.Wiresarecommonfailurepointsandlimitdevice16placement.Wirelesspowerbyelectromagneticorultrasoundwavesmust17overcomeabsorptionbythebodyandimpedancemismatchesbetweenair,18bone,andtissue.Magneticfields,ontheotherhand,sufferlittleabsorptionby19thebodyordifferencesinimpedanceatinterfacesbetweenair,bone,and20tissue.Theseadvantageshaveledtomagnetically-poweredstimulatorsbased21oninductionormagnetothermaleffects.However,fundamentallimitationsin22thesepowertransfertechnologieshavepreventedminiaturemagnetically-23poweredstimulatorsfromapplicationsinmanytherapiesanddiseasemodels24becausetheydonotoperateinclinical“high-frequency”rangesabove20Hz.25Hereweshowthatmagnetoelectricmaterials–appliedforthefirsttimein26bioelectronicsdevices–enableminiaturemagnetically-poweredneural27stimulatorsthatoperateatclinicallyrelevanthigh-frequencies.Asan28example,weshowthatMEneuralstimulatorscaneffectivelytreatthe29symptomsofaParkinson’sdiseasemodelinafreelybehavingrodent.Wealso30showthatME-powereddevicescanbeminiaturizedtosizessmallerthana31grainofricewhilemaintainingeffectivestimulationvoltages.Theseresults32suggestthatMEmaterialsareanexcellentcandidateforwirelesspower33deliverythatwillenableminiatureneuralstimulatorsinbothclinicaland34researchapplications.3536Wirelessneuralstimulatorshavethepotentialtoprovidelessinvasive,longer37lastinginterfacestobrainregionsandperipheralnervescomparedtobattery-38powereddevicesorwiredstimulators.Indeed,wiresareacommonfailurepointfor39bioelectronicdevices.Percutaneouswirespresentapathwayforinfection1and40implantedwirescanalsolimittheabilityofthestimulatorstomovewiththetissue,41leadingtoaforeignbodyresponseorlossofcontactwiththetargettissue2,3.42Additionally,chronicstressandstrainonwires,particularlyfordevicesinthe43periphery,canleadtofailureinthewireitselforitsconnectiontothestimulator4.In44smallanimalslikeratsandmice,wiresusedtopowerneuralstimulatorscan45interferewithnaturalbehavior,particularlywhenstudyingsocialinteraction46betweenmultipleanimals5.47

    not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which wasthis version posted November 5, 2018. ; https://doi.org/10.1101/461855doi: bioRxiv preprint

    https://doi.org/10.1101/461855

  • 48Oneoftheprimarychallengesforwirelessneuralstimulatorsistocreateefficient49miniaturedevices(<1cminlength)thatoperatereliablybeneathboneandtissue50asananimalorhumanpatientengagesinnormalactivity.Atlengthsoflessthan151cm,devicescouldbefullyimplantedintheperipheryandbelightenoughtoallow52forunrestrictedanimalbehavior;howeverfordevicesthissmall,powerdelivery53remainsachallenge.Efficientpowertransferwithpropagatingelectromagnetic54wavesrequiresantennaswithfeaturesizescomparabletotheelectromagnetic55wavelength.Thus,forsub-millimeterdevices,suchastheproposedRFpowered56“neurograins6,”effectivepower-transferfrequencieslieintheGHzrange,where57electromagneticradiationisabsorbedbythebody7.Absorptionofthisradio-58frequencyelectromagneticenergylimitstheamountofpowerthatcanbesafely59deliveredtoimplantsdeepinsidetissue7.Asaresult,researcherstypicallyturnto60magneticinductionorbatteriestopowerimplanteddevices;however,these61techniquesalsolimitthedegreeofminiaturization.Batteriesincreasethesizeofthe62deviceandaddconsiderableweight.Additionally,batteriesrequirereplacementor63charging,whichcanlimitthepotentialuses.Inductivelycoupledcoils,ontheother64hand,canbemadesmallerandlighterthanbatteries,however;thepowera65receivingcoilcangenerateisdirectlyrelatedtotheamountoffluxcapturedbythe66areaofthecoils.Thus,whenthereceivercoilsareminiaturized,theoutputpower67reducesandbecomesmoresensitivetoperturbationsinthedistanceorangle68betweenthetransmitterandreceiver8.Forexample,Freemanetal.demonstrated69thatsmallinductivecoilslessthan1mmindiametercanpowerstimulatorsforthe70sciaticnerveinanesthetizedrats9;however,initspresentform,thisdevicewould71havedifficultyprovidingstablestimulationinfreelymovinganimalsduetothe72reducedpowercouplingefficiencythataccompanieschangesintheangleand73distancebetweenthereceiverandtransmittercoils.7475Additionally,forneuralstimulatorstotreatanumberofneurologicaldisorderslike76Parkinson’sDisease(PD),obsessive-compulsivedisorder,andepilepsy,theymust77operatesafelyandeffectivelyinthehigh-frequency“therapeuticband”between10078and200Hz10–12.Thistypeofhigh-frequencyneuralstimulationischallenging79becausechargeontheelectrodemustbedissipatedbetweensuccessivestimulation80pulsestopreventelectrolysis,tissuedamage,andchangestothelocalpH13.Charge81dissipationathigh-frequenciesisaccomplishedbyusingabiphasicstimulus82waveformthatactivelyorpassivelychargesanddischargestheelectrodewitheach83cycle.Indeedallclinicallyapprovedelectricalneuralstimulationtherapiesinthis84therapeuticbandusevariousformsof“chargebalanced”biphasicstimulation85waveforms14.8687Recently,severalpromisingalternativestomagneticinductionandbatterieshave88enabledminiatureneuralstimulators;however,theseapproacheshaveyetto89demonstrateinvivooperationinthetherapeutichigh-frequencybandinfreely90movinganimals.Montgomeryetal.andHoetal.haveshownthatonecanusethe91mousebodyasanelectromagneticresonantcavitytoeffectivelytransferenergyto92sub-wavelengthscaledevicesimplantedinsidetheanimal15,16.Thisapproachis93

    not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which wasthis version posted November 5, 2018. ; https://doi.org/10.1101/461855doi: bioRxiv preprint

    https://doi.org/10.1101/461855

  • particularlyeffectivetodrivetinyLEDsforoptogeneticstimulation.However,94becausetheelectricalwaveformismonophasic,electricalstimulationhasbeen95limitedto<20Hz.Usingsuperparamagneticnanoparticlestoabsorbenergyfrom96high-frequency(500kHz)magneticfields17,onecanheatspecificregionsofthe97brain18,19infreelymovinganimals19.Thislocalheatcanstimulateneuralactivity98whenthetargetedbrainregionisgeneticallymodifiedtorespondtochangesin99temperature18,19.Howeverthisapproachrequirestransgenesis,whichadds100regulatorycomplexityandhasyettoshowhigh-frequencyoperationduethe101requirementforthetissuetocoolbetweenstimulationintervals.Ultrasound102providesapromisingandefficientmethodtopowerbioelectronicimplantsbecause103ultrasoundwavelengthsare105timessmallerthanelectromagneticwavesatthe104samefrequencyallowingsub-millimeter-sizeddevicestohavewavelength-scale105piezoelectricantennas20,21.However,implementationofthese“neuraldust”motes106canbechallenginginfreelymovinganimalsbecausetheimpedancemismatch107betweenair,bone,andtissuerequirescontactbetweensofttissueandthe108ultrasoundtransducerforefficientpowertransfer.Asaresult,therehasyettobea109demonstrationofultrasound-poweredneuralstimulatorsinfreelymoving110animals22.111112Hereweshowthatmagnetoelectric(ME)materialsenablethefirstmagnetically113poweredminiatureneuralstimulatorsthatoperateinthetherapeutichigh-114frequencyband.Similartoinductivecoils,thesematerialstransformamagnetic115fieldtoanelectricfield,butinsteadofusinganimplantedcoilweuseamaterialthat116generatesavoltageviamechanicalcouplingbetweenmagnetostrictiveand117piezoelectriclayersinathinfilm.Namely,themagneticfieldgeneratesstraininthe118magnetostrictivelayerasthemagneticdipolesalignwiththeappliedfield.That119strainexertsaforceonthepiezoelectriclayer,whichgeneratesavoltage(Fig.1).By120exploitingthistransductionmechanism,magnetoelectricsdonotsufferfromthe121sameminiaturizationconstraintsascoilsandcanbedrivenbyweakmagneticfields122ontheorderofafewmillitesla.Thesepropertieshaveledresearcherstopropose123magnetoelectricsasapromisingmaterialforbioelectronicimplants23–27.Herewe124demonstratethefirstproof-of-principlewirelessneuralstimulatorsbasedonME125materialsinafreelybehavingrodentmodelforParkinson’sDisease(PD),andthat126thesematerialscouldpowerminiaturedevicesdeepwithinthehumanbrain.127128FabricationandcharacterizationofMEstimulators129130Wefabricatedproof-of-principleMEstimulatorsbybondingarectangular131magnetostrictivelayer(Metglas)toaplatinumcoatedpiezoelectriclayer,132polyvinlydinefluoride(PVDF).Wethenencapsulatedthefilmsinaprotective133parylene-Clayer(8-10μmthick)(Fig.1a,seeMethods).WeusedPVDFlayers134between28and110μm,whichyieldedtotaldevicethicknessesbetween50-150135μm.Whenwemeasuredthevoltageacrossthefilm,wefoundadramaticvoltage136increasewhentheappliedmagneticfieldfrequency,matchesanacousticresonant137frequency(Fig.1b).Becausetheresonantfrequencyisproportionaltotheinverseof138thefilmlength,wecandesignmultiplefilmsandselectivelyactivatethemby139

    not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which wasthis version posted November 5, 2018. ; https://doi.org/10.1101/461855doi: bioRxiv preprint

    https://doi.org/10.1101/461855

  • changingthestimulusfrequency(Fig.S2b).Usingthisprinciple,wecanusedifferent140magneticfieldfrequenciestoactivateseparatedevicesthatmaybeindifferentareas141ofthebody,orcreatebiphasicstimulatorsbyinterleavedresonantstimulationof142twodifferentfilms,witheachfilmdrivingeitherthepositiveornegativephaseof143theneuralstimulus.144

    Figure1|MEfilmsconvertalternatingmagneticfieldsintoavoltage.(a)DiagramofaMEdeviceonafreelymovingratforwirelessneuralstimulation.TheactiveMEelementconsistsofpiezoelectricPVDF(blue)andMetglas(gray)laminateencapsulatedbyParylene-C.Insetshowstheoperatingprinciplewherebythestrainproducedwhenmagnetizingthegraymagnetostrictivelayeristransferredtothebluepiezoelectriclayer,whichcreatesavoltageacrossthefilm.(b)ExampleofaresonantresponsecurveforaMEfilmshowingthatthemaximumvoltageisproducedwhenthemagneticfieldfrequencymatchesanacousticresonanceat171kHz.PhotographinsetshowsanexampleofanassembledMEstimulator.The“Stressprofile”insetshowsatopviewofthestressproducedinaMEfilmascalculatedbyafiniteelementsimulationonandoffresonance(COMSOL).(c)Devicetestingsetupwithapermanentmagnettoapplyabiasfieldandanelectromagneticcoiltoapplyanalternatingmagneticfield(scalebars:upper=1cm,lower=2mm)(d)Maximumstimulationduration(usinga400μs/phasepulserepeatedatincreasingfrequencies)foraMEdeviceinbiphasicandmonophasicoperation.Maximumstimulationtimeisdeterminedbytimeofelectrolysisonastereotrodeinsalineasevidencedbygasbubbles(errorbars+/-1standarddeviationforn=4trials).Dashedlinesindicatefrequenciesofelectricalstimulationusedinvariousclinicalapplications,showingthatbiphasicoperationisnecessaryformanyclinicallyrelevantapplications.Romannumeralsindicatestimulationfrequenciesdemonstratedbypreviouslypublishedminiaturemagneticstimulators(i:Magnetothermal,Chenet.al,2015,ii:Magnetothermal,Munshiet.al,2017,iii:Mid-FieldOptogenetics,Montgomeryet.al,2015,iv:RFInductiveCoupling,Freemanet.al,2017).

    not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which wasthis version posted November 5, 2018. ; https://doi.org/10.1101/461855doi: bioRxiv preprint

    https://doi.org/10.1101/461855

  • 145WecanfurtherenhancethevoltagegeneratedbytheMEfilmsbyapplyinga146constantbiasfieldwithapermanentmagnetoranelectromagnet(Fig.1c).Because147thestraininthemagnetostrictivematerialisasigmoidalfunctionofthemagnetic148fieldstrength,thechangeinvoltageproducedbythealternatingfieldislargest149whenthefieldoscillatesaboutthemidpointofthesigmoid(Fig.S1)28,29.Thus,we150useabiasfieldtooffsetthemagneticfieldnearthecenterofthesigmoidal151magnetostrictiveresponsecurve.Thisbiasfieldallowsustogeneratetherapeutic152voltagelevelswhileapplyingasmall(fewmT)alternatingmagneticfieldusingan153electromagneticcoilandcustomcontrolcircuitrythatspecifiesthefrequencyand154timingofthealternatingmagneticfield(Fig.S3).155156ToidentifytheoperationalfrequenciesforourMEstimulatorswetestedthemin157salineandfoundthatwithabiphasicstimulationwaveformwecouldapplyconstant158stimulationuptoatleast800Hzwithoutsignificanthydrolysis.Forthistestwe159operatedeitheronefilmformonophasicstimulationortwofilmsforbiphasic160stimulationattachedtoastereotrode(Microprobes)insaline(seeMethods).We161thenmeasuredthetimeatwhichwecouldseebubblesattheelectrodetipresulting162fromhydrolysis.Thishydrolysiseventindicatesconditionsthatwouldlesionthe163surroundingtissue.Wefoundthatwithamonophasicstimulationwaveform164stimulationfrequenciesabove50Hzproducedhydrolysiswhilebiphasiccharge-165balancedstimulationshowednohydrolysisuptothemaximumtestedfrequencyof166800Hz.Comparedtopreviouslydemonstratedminiaturemagneticneural167stimulators,thebiphasicMEdevicesshownherearethefirsttoaccessthehigh-168frequencybandsusedforclinicalapplicationslikethetreatmentofParkinson’s169diseaseandobsessive-compulsivedisorder(Fig1d).170171Anadditionalchallengeforanywirelesslypoweredneuralstimulatoristomaintain172awell-regulatedstimulationvoltage.Thischallengeisespeciallyprevalentas173devicesbecomesmall,whichoftenreducesthepowertransferefficiencyresultingin174agreatersensitivitytothealignmentbetweenthedeviceandpowertransmitter.ME175materialsoffertwomainadvantagesthatcanenablestableandeffectivestimulation176evenasdevicesbecomesmallandmovewithrespecttothedrivercoils:177178First,MEdevicesgeneratevoltageswellinexcessoftheeffectivestimulation179potential,allowingthemtobeeffectiveevenifthematerialsaremisalignedwiththe180drivercoils.Atresonance,wehavemeasuredMEvoltagesinexcessof30Vatafield181strengthofonly1mT(Fig.S2c,d).Becauseeffectivestimulationvoltagesareusually182between1-5V,wecancaptheappliedvoltagetothiseffectivestimulationrange183usinganLEDorZenerdiode.AslongasthevoltagegeneratedbytheMEfilmis184greaterthanorequaltothecappingvoltage,wewillapplyapproximatelythesame185stimulusvoltageregardlessoftheangleordistancebetweenthedrivercoilandthe186MEfilm.Foratypicalfilmwefoundthatwecouldreorientthefilmby+/-80187degreesandmaintainvoltagesinexcessof3V(Fig.S1h).Thislargeangular188toleranceisaidedbythelargemagneticpermeabilityoftheMetglaslayer,which189

    not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which wasthis version posted November 5, 2018. ; https://doi.org/10.1101/461855doi: bioRxiv preprint

    https://doi.org/10.1101/461855

  • helpstodirectthemagneticfieldlinesalongthelongaxisofthefilm,wheretheyare190mosteffectiveatcreatingamagnetostrictiveresponse.191192Second,thevoltagegeneratedbyapiezoelectricmaterialdependsonthethickness193ofthepiezoelectriclayerandnottheareaofthefilm30,allowingustofabricatesmall194magnetoelectricfilmsthatgenerateroughlythesamestimulationvoltageaslarger195devices.FigureS2showsthepeakvoltagegeneratedandqualityfactorforMEfilms196ofdifferentareas.Wefoundthat,fora52μmthickPVDFlayer,thevoltageremains197around10Vevenasthefilmlengthdecreases.Variationsof+/-40%inpeak198voltageandqualityfactorsarelikelyduetodefectsproducedduringfilm199fabrication,whichmaybereducedwithimprovedmanufacturing.Wealsoverified200thattheoutputvoltagedependsonlyonthepiezoelectricfilmthicknessby201measuringthepeakvoltagesfromMEdeviceswiththreedifferentthicknessesof202PVDF:28μm,52μm,and110μm.Asexpected,weseethatthepeakvoltage203increaseslinearlywiththePVDFthicknessandisindependentofthefilmlength.We204calculated(andexperimentallyconfirmed)thatthepowergeneratedbyaMEdevice205isproportionaltothefilmwidthforagiventhicknessandalength-to-widthratio>3206(seeFig.S2f).Despitethedecreaseinpowerasfilmsbecomesmaller,wecalculate207thatfilmslessthan1cmlongcangenerateupto4mW,whichismorethan208sufficientformanywirelessapplicationsincludingneuralstimulation31.209210MonophasicstimulationbyMEfilmsevokeactionpotentialsinvitro211212Usingfluorescencemicroscopytoimagevoltageinculturedcells,wefoundthat213monophasicstimulationfor50msat100HzbyMEfilmsreliablystimulatedaction214potentials(APs).Fortheseexperimentsweused“spiking”humanembryonickidney215(HEK)celllinesthatweremodifiedtoexpresssodiumandpotassiumchannels.216Thesecellshavespike-likeelectricalwaveformsthatarerectangularinshapeand217canlastforafewsecondsdependingontheconfluencyoftheculture32.To218determinetherelativetimingbetweenmagneticstimulationandactionpotential219generation,wetransfectedthesecellswithArcLight33-ageneticallyencodedvoltage220indicatorthatallowsustomeasureactionpotentialsusingfluorescencemicroscopy.221222

    not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which wasthis version posted November 5, 2018. ; https://doi.org/10.1101/461855doi: bioRxiv preprint

    https://doi.org/10.1101/461855

  • Toimagefluorescencewhileweappliedmagneticfields,wedevelopedan223experimentalsetupthatallowsustoplacecellsandMEfilmsbeneathanobjective224lensatthecenterofa10cmlongsolenoidwitha3cmgapinthecenter.This225configurationallowedustoplaceMEfilms,cells,andtheobjectivelensatthecenter226oftheappliedmagneticfield(Fig.2a).Twoslightlylargercoilsplacedoneitherside227ofthegapprovidetheconstantbiasfield.228229WethenapproximatedanimplantedMEstimulatorusingtwoexperimental230configurations:1)growingcellsdirectlyontheMEfilm(Fig.S4)and2)layinga231coverslipwithadherentcellsontopoftheMEfilm(Fig.2).Toculturecellsdirectly232ontheMEfilm,wecoatedthetopparylenelayerwithpoly-l-lysine.Thehealthy233proliferationofHEKsontheMEdeviceindicatesthatthisencapsulationapproach234preventstheMEmaterialsfromlimitingcellgrowth(Fig.S4b).However,inatypical235usecase,thetargetcellsmaynotadheretotheMEstimulator,sowealsotestedthe236responseofcellslaidontopoftheMEmaterials.Inthisconfigurationwefirstgrew237thecellsoncoverslipsfor3-5daysbeforeinvertingthecoverslipsandlayingthem238ontheMEfortesting(Fig.2,seeMethods).239

    Figure2|MonophasicMEstimulatorsactivatecellsinvitro(a)Schematicoftheexperimentalsetup(b)MicroscopeimageofholesstampedintotheMEfilmandfiniteelementsimulationoftheelectricfieldshowsthattheholesproducefringingelectricfieldsthatoverlaptheculturecells(c)VoltageacrosstheMEfilmwhenthemagneticfieldisonresonanceand(d)offresonance.Insetsshowazoominofthehighfrequencycarrierwaveform.(e-g)FluorescencefromspikingHEKstransfectedwithArcLightshowactionpotentialsaretriggeredbytheMEfilmdrivenatresonance(e),butnotwhenthefilmisdrivenoffresonance(f).FluorescencefromHEKcellstransfectedwithGFPshownoresponsewhentheMEfilmisdrivenonresonanceconfirmingthatthemeasuredArcLightresponseistheresultofachangeintransmembranepotentialandnotanartifactofthemagneticfieldoracousticresonanceoftheMEfilm.

    not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which wasthis version posted November 5, 2018. ; https://doi.org/10.1101/461855doi: bioRxiv preprint

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  • 240Tocreatefringingelectricfieldsthatinteractwiththeculturedcells,westamped241holesintheMEfilm(Fig.2b).Thefilmswereotherwisefabricatedasdescribed242above(Fig.1,Methods).InexperimentsusingMEfilmsandPtelectrodeswefound243thathigh-frequencybiphasicstimulationattheMEresonancefrequency(typically24420-150kHz)wasnoteffectivetostimulateAPsinculturedHEKs,aspredictedbythe245low-passfilteringpropertiesofthecellmembrane9.Tocreateaneffective246monophasicstimuluswaveform,weusedaSchottkydiodetorectifythevoltageto247createentirelypositiveornegativevoltagewaveformsdependingonthediode248direction.Thisrectifiedwaveformhasaslowlyvaryingmonophasicenvelopeinthe249

  • Thetransistorsblockcurrentsgeneratedbyonefilmfrompropagatingthroughthe286circuitryattachedtotheotherfilm,ensuringthatonlyonehalfofthecircuitisactive287atatime.ByswitchingthemagneticfieldfrequencybetweenthetwoMEresonance288frequencies,wecanalternatepositiveandnegativephasestimulationtocreatea289biphasicneuralstimulator(Fig.3b-d).Inthiscasetheresidualchargeof-2.3nC,290whichdischargesin500Hzwithoutaccumulatingcharge.292293WefoundthatourbiphasicMEstimulatoriscapableofrepeatableneural294stimulationusingneocorticalbrainslicesderivedfrommicethatexpressthe295geneticallyencodedcalciumindicatorGCaMP3inGABAergicneurons.Toimage296neuralactivityfollowingMEstimulationweinsertedastereotrodeattached297biphasicMEstimulatordescribedabovewhileweimagedGCaMPactivityusing298fluorescencemicroscopy(Fig.3e-g,Methods).Wechoseneuralstimulation299parameterssimilartothosecommonlyusedfordeepbrainstimulation34:100300biphasicpulsesat200Hzwitheachphaselasting175μs.Whenthemagneticfield301wasonweobservedacorrespondingincreaseinfluorescenceinn=23recordingsin302neocorticallayer5consistentwithactivity-mediatedcalciumincreases303(SupplementaryVideo2).Followingbathapplicationoftetrodotoxin(TTX,500304nM)fluorescenceincreaseswerecompletelyblockedinn=9recordingsconfirming305thatMEstimulationreliablyevokedsodium-channeldependentactionpotentialsin306nearbyneurons.307 308

    not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which wasthis version posted November 5, 2018. ; https://doi.org/10.1101/461855doi: bioRxiv preprint

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  • 309 310

    Figure3|BiphasicMEstimulatorsactivateneuronsinexvivobrainslices(a)SchematicofexperimentalsetupwithtwoMEfilmsforbiphasicstimulation(b)Measuredvoltagewaveformproducedbyourmagneticfieldgenerator.Whencoupledtothemagneticcoils,thiswaveformproducesmagneticfieldsthatalternatebetweentheresonantfrequenciesofthetwoMEfilms(c)Measuredvoltageacrossthestereotrodeshowstheexpectedbiphasicpulseshape(d)Calculatedcurrentbasedonmeasuringthevoltageacrossourloadresistor(VR)showsnearlyperfectchargebalancingwithonly2.3nCaccumulatingontheelectrodeperpulsetrain.(e)Brightfieldimageofstereotrodeinmousecortex(scalebar=1mm)withinsetofGCaMPsignalaveragedovera600μmx600μmregionaroundstereotrodetip.Arrowindicatingafluorescingcellbodynearthestereotrode(f)AverageGCaMPsignalwhenresonantmagneticfieldisappliedbefore(f)andafter(g)addingTTXshowsneuralactivityisinducedbytheMEstimulator.Thingreentracesrepresentseparateexperimentsfromtwodifferentbrainslices,andthickblacktracesrepresentthemeanofallexperiments.

    not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which wasthis version posted November 5, 2018. ; https://doi.org/10.1101/461855doi: bioRxiv preprint

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  • MENeuralStimulationinFreelyMovingRatsShowsBehavioralEfficacy311312AmajoradvantageofourMEstimulatorsisthefactthatremoteactivationenables313experimentswithfreelybehavinganimals.Asaproof-of-principleweadaptedour314biphasicstimulatorfordeepbrainstimulation(DBS)infreelymovingrats(Fig.4).315TotestMEstimulatorefficacy,weusedapreviouslyreportedprotocoltotestDBSin316hemi-parkinsonianrats36.Intheseexperimentsratsareinjectedwith6-OHDAinthe317leftmedialforebrainbundle(MFB)tocreateaunilaterallesionofthesubstantia318nigraparscompacta(SNc).Theanimalsarethenplacedina30cmdiametercircular319enclosure.Followingadoseofmethamphetamine,thehemi-parkinsonianratshave320beenshowntorotateipsilateraltotheinjection(e.g.leftforinjectionintotheleft321MFB).Duringtheserotations,theratprimarilymovesusingitscontralateral(right)322forepaw,rarelyplacingtheipsilateral(left)forepawontotheground.Whena323biphasicstimulusisappliedat200Hzinthesub-thalamicnucleus(STN)usinga324tetheredelectrodearraystimulator,ratstypicallystopturningtotheleftandexhibit325morenormalbehaviorsuchasmovingwithbothforepaws,maintainingasteady326orientation,orturningtothecontralateralside34.327328Tocreateawireless,biphasicMEstimulatorforfreelymovinganimalsweaddeda329smallpermanentmagnettotheMEstimulatortogenerateabiasfield,andwrapped330thebehavioralchamberwith18AWGcopperwiretocreateasolenoid(Fig.4a,S5).331Byintegratingthesmallpermanentmagnet(<0.25g)intotheMEstimulator,we332couldensurethatthebiasfieldwasconstantlyalignedwithMEfilmsastheanimal333movedwithintheenclosure.Wecouldalsoensurethatthepositiveandnegative334stimulihadequalamplitudesbyindependentlyadjustingthedistancebetweeneach335filmandthepermanentmagnet.ThisMEstimulatorwasthenconnectedtoa336commercialelectrodearray(Microprobes)implantedintheSTN(Fig4b,see337Methods).Weensuredthatthestimulationvoltageandcurrentwerewithinthesafe338andtherapeuticrangebymeasuringtheoutputoftheMEstimulatorconnectedto339anequivalentcircuitmodelofthebrain(Fig.4c,seemethods).Specifically,we340observedpeakvoltagesofapproximately+/-1.5Vandpeakcurrentsof341approximately+/-100μAfor400usatapproximatelya50%dutycycle(200μsof342overallcurrentperphase),whichiswithintheeffectivestimulationrangereported343forconventionalwiredstimulators36.Whenwetunethemagneticfieldfrequencyoff344resonanceweobservealmostnogeneratedvoltageorcurrent(Fig.4c).345

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  • 346WethentestedthewirelessversionofourbiphasicMEstimulatormountedtothe347headofafreelybehavingratandfoundthatMEstimulationshowedefficacy348comparabletopreviouslyreportedwiredDBSstimulators(Fig.4).Withamagnetic349fieldappliedatresonance,wefoundthatone-minuteperiodsof200Hzbiphasic350pulsesresultedinasignificantdecreaseintheanimal’srotationrate(Fig.4dgreen351intervals).Thisdecreasedrotationwasnotobservedwhenthemagneticstimulus352frequencywastunedoffresonance(Fig.4dblueintervals).Plotsofthehead353

    Figure4|EffectiveDBSinafreelymovingratusingawirelessMEstimulator(a)Experimentalsetupshowingratinacircularenclosurewrappedwithmagnetwire.InsetshowsabiphasicMEstimulatoronaonecentcoin(b)SchematicofthebiphasicMEstimulatorattachedtotheelectrodearraythatisimplantedintotheSTN(c)MeasuredvoltagegeneratedbytheMEdeviceandthecurrentappliedtothebrainonresonance(green)andoffresonance(blue).Approximately100μAbiphasicstimulationisappliedonlywhenthenthemagneticfieldfrequencymatchestheresonancecondition.(d)Angularvelocityofthehemi-Parkinsonianratovera40minuteDBStrialwithintervalsofresonantandnon-resonantstimulationshowsthatrotationsarereducedonlywhenthestimulatorisactivatedbyaresonantmagneticfield(e)Typicaltrajectoriesshowthelocationoftheanimal’sheadovertwo30-secondintervalsdenotedinc(scalebar=5cm)(f)Averageangularvelocityoftheratduringthe30secondsbeforestimulationandthefirst30secondsofstimulationforeachintervalduringthe40-minexperimentshowsaclearreductioninangularvelocityonlywhentheMEfilmisactivatedonresonance(***P=4x10-7,n.s.=notsignificantP=0.70,pairedt-test)

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  • trajectoriesshowthatthepathologicalrotationsobservedduringoff-resonant354magneticfieldstimulationarenotpresentwhentheMEstimulatorisactiveduring355resonantmagneticfieldstimulation(Fig.4e,Methods).Whenaveragedoverall356trials,averagerotationrateduringthefirsthalfofstimulationfelltoastatistically357significant1.6rotationsperminute(rpm),comparedto9.3rpmintheabsenceof358stimulation,or9.4rpmduringoff-resonantstimulation(pairedt-test,Fig.4f).We359furtherdemonstratedtherepeatabilityofthisstimulatorbyrepeatingthis360stimulationprotocolonasecondratandfoundsimilarresults(FigS5b).361362Withaweightof0.67g,theMEstimulatorsdescribedherearethefirstreported363miniature,magnetic,highfrequencystimulator.Furthermore,bychangingthe364frequencyandtimingoftheexternaldrivecoils,wecangenerateavarietyof365stimulationpatternsthroughoutthetherapeuticwindowof100-200Hzwith366applicationstootherdiseasemodels.Additionally,calculationsofthemagneticfield367strengthssuggestthatwecanreconfigurethedrivecoilsforanumberofbehavioral368experimentsbyplacingcoilsbeneaththefloorofananimalenclosure.Finite369elementsimulationsandmeasurementsshowthatevenatdistance4-5cmabovea370drivecoil,MEfilmsgeneratesufficientvoltageforstimulation(Fig.S6).This371distancecouldbefurtherimprovedbyoptimizingthegeometryofthecoilsor372increasingthepowerofthemagneticfield.373374Demonstrationofmultichanneldeepbrainstimulationinskullphantomusing375rice-sizedMEfilms376377Inadditiontosupportingexperimentsinfreelymovingrodents,MEmaterialscould378enableminiaturizedwirelessstimulatorsthatoperatedeepinthebrainoflarge379animalsorhumanpatientsandareindividuallyactivatedwithanexternal380electromagnet.Toourknowledge,thisisthefirsttechnologythatenables381independentexternalwirelesscontrolofmultipleminiaturestimulatorsdeep382beneathahumanskullphantom.Figure5ashowsthepredicteddepththatvarious383miniatureantennascouldbesafelyimplantedundertheskullandgenerate1mWof384power,whichisintheapproximatemaximumpowerrequiredforhigh-frequency385continuousneuralstimulation31.Asmentionedabove,radio-frequency(RF)386poweredantennasthatoperateatfrequenciesabove~1MHzhavelimitationsinthe387amountofpowerthatcansafelybedeliveredtoanimplanteddevicewithout388causingpotentiallyharmfultissueheating.Simulationsshowthatwhenoperating389withthesafepowerlimits,RF-antennasmustbeplacedonthesurfaceofthebrain390orinveryshallowregionstoharvest1mWofpower.“Mid-field”techniques37,391improvetheRFcouplingefficiencyenablingdeepoperation,butbecausethis392approachoperatesatafixedfrequencytherehaveyettobedemonstrationsof393individuallyaddressablemotesorbiphasicstimulation.Othertechniquesfor394wirelesspowerdeliverydiscussedpreviously,suchmagneticinduction,alsocannot395achievedeepmultichannelstimulation.Forexample,evenusingahigheroperating396frequencyof1MHzaninductivecoilwiththesameorientationandcross-sectional397areaastheMEfilmsshownherewouldrequireaminimumof500turnsofwireto398generate2Vusingthesame0.5mTfieldusedhere(assumingatypicalQ-factorof399

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  • 10).Thus,devicesbasedonmagneticinductorscannotbeminiaturizedwithout400sacrificingavailablepowerasdescribedpreviously9.401402Asaproof-of-conceptdemonstrationweshowthattworice-sizedMEfilmscanbe403individuallyaddressedatthecenterofahumanskullphantomusinganexternal404electromagnet.Thesetwo-filmswithlengthsof8mmand10mmhaveacoustic405resonantfrequenciesof180and200kHz,whicharedeterminedbythefilmlength.406WhenthesefilmsareattachedtoanorangeLED,theiroutputvoltageiscappedat407approximately1.8V,whichhelpstoregulatethestimulationvoltageandallowsus408tovisualizefilmactivation.MEfilmsofthissizearesmallerthancurrentDBSleads409andcouldpotentiallybeimplantedintodeepbrainareasasshowninFig5c.410Additionally,themagneticstimulationcoilissmallenoughtobeincorporatedintoa411stylishhatorvisorthatcouldbeworncomfortablybyapatient.Whenweplaced412

    Figure5|MiniaturizedMultichannelStimulationinHumanSkullPhantom(a)ComparisonofeffectivedepthbeneathahumanskullphantomforMEdevicescomparedtootherminiaturewirelessstimulators.Depthlimitisbasedonsafetylimitstogenerate1mW.(i:Parket.al,ProcNatAcSci,2016,ii:Yazdandoostet.al,AsiaPacMicrowConf,2009,iii:Yazdandoostet.al,Proc37EuropMicrowConf,2007,iv:Agrawalet.al,NatBiomedEng,2017)(b)PhotosofMEfilmsnexttoagrainofriceandthecorrespondingvoltageasafunctionofmagneticfieldfrequency(fieldstrength1mT,scalebars2mm)(c)SchematicofshowingpotentialapplicationoffullyimplantedMEfilmswiththemagneticfieldgeneratedbyanexternalcoilthatcanbeincorporatedintoahatorvisor(d)Frontviewand(e)topviewofskullphantomwiththetopremovedtoviewLEDs(filmlocationsindicatedbyarrows,scalebar1cm)(f)PhotoofLEDsattachedtoMEfilmswiththemagneticfieldsatappliedat180kHzand(g)200kHz.SelectiveilluminationoftheLEDscorrespondingtheresonantfrequenciesofthefilmsdemonstratessuccessfulmultichannelactivationofindividualfilms(scalebars1cm).Magneticfieldstrengthwasmeasuredtobe0.5mTatthelocationoftheMEfilms.

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  • thetwoMEfilmsatthecenterofaskullphantomwefoundthatwecould413individuallyilluminatetheLEDsoneachfilmwhenweappliedamagneticfieldat414theresonantfrequencyoftheselectedfilm(Fig5d-g).Forthisexperimentweuseda415400Wpowersupply,whichproducedafieldofapproximately0.5mTatthecenter416oftheskullphantom.Thetopoftheskullphantomwasremovedforvisualization,417buthadnoaffectonourabilitytodrivetheLEDindicators.Thenumberof418stimulationchannelscouldbeincreasedwiththeadditionofMEfilmswithdifferent419resonantfrequencies.420421Outlook422423Toourknowledge,thisisthefirstdemonstrationofaminiature,magneticneural424stimulatorthat1)operatesinthetherapeuticband(100-200Hz)infreelymoving425animalsand2)enablesindividuallyaddressableminiaturestimulatorsdeepwithin426ahumanskullphantom;however,theadvantagesofMEmaterialsextendbeyond427theseproof-of-principledemonstrations.428429MEstimulatorssuchastheonedescribedintheinvivoratexperimentcouldhave430animmediateimpactonthestudyofDBStherapiesusingrodentdiseasemodels.431BecausetheMEstimulatoriscompatiblewithcommercialimplantedelectrodes,and432themagneticstimulatorscanbeadaptedtoanumberofstandardbehavioral433experimentsoranimalenclosures,ourMEstimulatorscouldreadilyreplacethe434wiredDBSstimulatorscurrentlyinuse.Asaresult,newexperimentscanbe435developedtoprobetheeffectsofchronicandcontinuousDBSorDBSinsocial436contextswherewiredDBSstimulatorswouldbeimpracticable.437438Additionally,MEmaterialshavethepotentialtoenableminiatureneuralstimulators439thatcanbeimplanteddeepinthebrainoflargeanimalsorhumansandaddressed440externallywithasmallelectromagnet.Asshownhere,rice-sizedfilmscanbe441selectivelyactivatedbasedonuniqueresonantfrequencies.Additional442miniaturizationisnotexpectedtoreducethevoltageproducedbythesefilmssince443thevoltagedependsonthethicknessofthepiezoelectricfieldandnotthefilm444length(Fig.S2c),suggestingthatevensmallerfilmscouldserveaseffective445stimulators.446447WealsoforeseeapplicationsforMEmaterialsasawirelesspowertechnologyfor448morecompleximplantablebioelectronicdevices.Forexample,thedemonstrated449abilityofMEfilmstopowerLEDsimpliesthatMEmaterialscouldpower450implantableoptogeneticstimulators,orsmallintegratedcircuitsforphysiological451monitoring.452453Torealizethesefullyimplantablebioelectronicdevices,workisneededtoimprove454MEmaterialsandfabricationprocessestoreliablyproducehigh-qualityminiature455MEfilms,andencapsulatethemforchronicuse.Forwearabletechnologies,itisalso456necessarytofurtherminiaturizemagneticfieldgeneratorssothattheycanbe457

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  • batterypoweredandcomfortablyworn.Theseadvancesmustalsobeaccompanied458byinvivotestingtoshowsafetyandefficiencyforchronicuse.459460Overall,MEmaterialshavethepotentialtofillakeyneedforwirelesspower461deliverytominiaturebiphasicneuralstimulatorsandotherbioelectronicdevices462wherethemajorchallengeistransferringenergyoverdistancesofseveral463centimeterswithoutheatingthetissueorsufferinglossatinterfacesbetweentissue,464bone,andair.465466References467

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    585

    586

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  • Methods587588GeneralStatisticalMethods589ErrorbarsinFigureS2fgdenote+/-onestandarddeviationforn=~50datapoints.590WefurthermoreperformedaTukey’sHonestSignificantDifferencetestonthedata591inFigureS2g,whichindicatedthatthevoltageproducedateachdifferentPVDF592thicknessissignificantlydifferent.Pairedt-testswereusedfortherotationtestsin593figure4e.594595FilmFabrication596TofabricateMEfilms,weusedMetglasSA1alloy(MetglasInc)forthe597magnetostrictivelayerandpolyvinylidenefluoride“PVDF”(precisionacoustics)for598thepiezoelectriclayer.ThePVDFfilmsusedfortheseexperimentswerepre-599stretchedandpoledbythemanufacturer.Thetwolayerswerebondedtogether600usinganepoxycapableoftransferringthemechanicalstressbetweenthetwolayers601(Hardmandoublebubbleredepoxy).Priortobondingthetwolayerstogether,we602sputteredathinlayerofplatinum(

  • 633Tomaintainsimplicity,efficiency,andlowcostthecoilsweredrivenwithfullH-634Bridgestyleswitchingcircuits.Thedriversaredesignedtodeliverhighcurrentsto635thedrivecoilsintheformofbi-phasicpulsetrains.Thisreducesthecostand636complexityofthedriveritself,aswellasthepowersupplyandcontrolcircuitry637whencomparedtoarbitraryfunctiongenerators.Thedesignalsohaspotentialfor638improvedoperationalefficiencythroughimpedancematchingwiththedrivecoils.639Furthermore,itisalsopossibletoregulatepowerdeliveredtothedrivecoilsonthe640flybyadjustingthedutycycleofthecurrentpulses,allowingpowerbeingdelivered641totheMEfilmtobeeasilycontrolleddigitallywhilemaintainingtheresonant642carrierfrequency.Theoutputcarrierandpulsefrequenciesofthemagneticfieldare643generatedusingaTeensyLCboardandcustomArduinocodetogeneratethespecific644pulsetimingstodelivercontrolledMEstimulation(Fig.S3c,d).645646Thesecoilsanddriverscanbecombinedindifferentwaystogeneratethe647appropriatefieldforagivenexperiment.Forexample,thesetupusedtogenerate648thealternatingfieldintheinvivorotationexperimentsconsistedoffoursetsofcoils649eachwithfiveturnspoweredbyonedriverwithallfourdriverssyncedtothesame650outputsignal.InthiswaywecangeneratesufficientpowertogenerateamT-scale651magneticfieldsoverthewholebehavioralarea(Fig.S5a).652653CellCulture654Forexperimentsperformedoncoverslips,HEKcellsexpressingsodiumchannel655Na1.3andpotassiumchannelK2.1weregrownon12mmpoly-l-lysinecoated656coverslipstoapproximately30%confluency.Thecellswerethentransfectedwith657thegeneticallyencodedvoltageindicatorArcLightusingLipofectamine(Invitrogen)658followingmanufacturer’srecommendations.Twotothreedaysaftertransfection659thecoverslipswereinvertedontoMEfilmsfortesting.PreparationofGFPcontrols660followedthesameprocedurewiththeexceptionofreplacingtheArcLightvector661(AddGene)withaGFPexpressionvector(AddGene).Forexperimentsperformed662withcellsgrownonthefilms,HEKcellstransfectedwithArcLightwereplacedonto663parylenecoatedpoly-l-lysinetreatedfilms.Thefilmswereplacedincellularmedia664overnightandtestedthefollowingday.665666ArcLightandGFPwereexcitedat460nmwithanLEDlightsource.Fluorescence667imageswerecollectedat33fpsusingaCCDcamera.Imageswereanalyzedusing668Matlabtoquantifyfluorescencechangesinindividualcells.Invitrotestingwas669performedinextracellularbuffer(ECB,inmM:NaCl119,KCl5,Hepes10,CaCl22,670MgCl21;pH7.2;320mOsm)671672FigureS4bwasobtainedbygrowingunmodifiedHEKcellsonafilmsubmergedin673cellularmediaforfivedays.ThecellswerethenstainedwithHoechstandCalcein-674AMtolabelthenucleusandmembranerespectivelyinlivingcells.Thecellswere675thenfixedandimagedusingaconfocalmicroscope.676677678

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  • MouseBrainSliceProcedures679Weused40dayoldGAD2-GCaMP3mice,generatedbycrossingGAD2-Cre(JAX#68010802)withflox-GCaMP3(JAX#14538)animals.Preparationofbrainslices681followedproceduresdescribedbyTingetal.45andwascarriedoutinaccordance682withNationalInstitutesofHealthguidelinesandapprovedbytheUTHealthanimal683welfarecommittee.MiceweredeeplyanesthetizedwithIsofluraneandperfused684withicecoldNMDG-basedsolutionconsistingof(inmM):92NMDG,2.5KCl,1.25685NaH2PO4,10MgSO4,0.5CaCl2,30NaHCO3,20glucose,20HEPES,2thiouera,5Na-686Ascorbate,3Na-pyruvate,saturatedwith95%O2and5%CO2.,atarateof~6687ml/min.Coronalbrainslices(300µm)werecutusingavibratome(LeicaVT1200S),688incubatedfor15minat35°CinNMDGsolution,andthentransferredtoachamber689heldatroomtemperaturecontaining(inmM):92NaCl,2.5KCl,1.25NaH2PO4,2690MgSO4,2CaCl2,30NaHCO3,25glucose,20HEPES,2thiouera,5Na-Ascorbate,3Na-691pyruvate,saturatedwith95%O2and5%CO2.Forexperiments,sliceswereplaced692intoarecordingchamberperfusedwithACSFcontaining(inmM):126NaCl,2.5KCl,6931.25NaH2PO4,2MgCl2,2CaCl2,26NaHCO3,10glucose),heldat32-34°Cusingan694inlineheater.NBQX(10µM)wasincludedinthebathsolutiontoblockAMPA695receptor-mediatedsynaptictransmission.Thestereotrodewasplacedinlayer5of696somatosensory(barrel)cortex.697698GCaMP3wasexcitedat460nmwithanLEDlightsource.Fluorescenceimageswere699collectedat9.8fpsusingaCCDcameraattachedtoanOlympusBX51WImicroscope.700ImageswereanalyzedusingMatlabtoquantifyfluorescencechangesin600x600701μmregionsaroundthestereotrodetips.702703704ImplantDesignandRatSurgicalProcedures705706TwomaleLong-Evansrats(n≈1,400g)wereanesthetizedwithisofluranegas.Five707percentisofluranewasusedtoinduceanesthesiaandtwopercentwasusedto708maintainanestheticdepth.Buprenorphine(0.04mg/kg)wasadministered30709minutespriortoearbarsforanalgesia.5-7skullscrewswereplacedtoanchorthe710electrodearray.SkullscrewswereboundtoskullwithMetabonddentalacrylic.A711craniotomywasmadetoaccommodatethemicroelectrodearrayandexposean712injectionsiteforneurotoxin.A30gaugeneedlebentatthetipcutandpulledaway713theduramatercoveringofthebrain.Desipramine(DMI)reconstitutedinsalineata714concentrationof15mg/mLwasinjectedIPtoprotectnoradrenergnicneurons.The715doseofDMIwasapproximately15mg/kgandinjectedapproximately30minutes716priortoadministrationofneurotoxin.Toinduceahemiparkinsonianlesion,8ugof7176-hydroxydopamine(OHDA)at2ug/uLinsalinewasinjectedat0.2uL/minintothe718midforebrainbundle(MFB-1.2ML,-4AP,and-8.1DV).STNstimulationwas719deliveredviaa2x2platinumiridiummicroelectrodearray(Microprobes)with600x720600μmspacingof75μmelectrodes.Eachelectrodehadanominal10kOhm721impedance.Theelectrodearraywasloweredto-2.6ML,-3.6AP,andapproximately722-8.2DVfrombregma.Thearraywasfixedtotheskullwithdentalacrylic.All723

    not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which wasthis version posted November 5, 2018. ; https://doi.org/10.1101/461855doi: bioRxiv preprint

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  • experimentswereapprovedbytheInstitutionalAnimalCareandUseCommitteeof724RiceUniversity.725726Priortostimulatingeachratwiththemagnetoelectricstimulator,thestimulator727powerwasestimatedviaabenchtopapproximationoftherodentelectrode728impedance.ConstantcurrentstimulationoftherodentbrainwithanA-MSystems7294100stimulatorproducedcharacteristicvoltagewaveformsthatapproximateda730simplifiedparallelRCcircuit.A56kOhmresistor,and440pFcapacitorinparallel731closelyapproximatedtheimpedancecharacteristicsoftheratbrainacrossthe732stimulatingelectrodes.Usingthiscircuitmodel,weestimatedthefieldstrengthsand733pulsedurationsnecessarytoproducethedesiredstimulationeffectsandconfirm734thatthestimulationwaschargebalancedpriortorodentexperimentation.735736RotationTestExperiments737Priortoperformingtherotationteststheratwasbrieflyanesthetizedwith5%738isofluranegasandinjectedintraperitoneally(IP)withmethamphetamine(0.31ml7391.25mg/kg)andthewirelessbiphasicstimulatorwaspluggedintotheimplanted740electrodearray.Aftertheanesthesiahadwornoff(about5-10min)theratwas741placedinthecylindricalbehavioralchamber.Themagneticfieldwasappliedover742thewholebehavioralareatothefilmsonthedevice(FigS5a).743744Themagneticfieldwasappliedonresonanceandoffresonanceforoneminuteat745varioustimesduringthe40-minutetrial.Theresonantfrequencieswere73kHzand74677kHzandtheoffresonantfrequencieswere63kHzand87kHz.747748RodentTracking749Headpositionontherotationtaskwasgeneratedusingaslightlymodifiedversion750ofDeepLabCut46totrackears,snout,andimplant.Adatasettotaling286frames751fromboththeonandoffresonancerotationtaskswashandlabeledandtrainedfor752approximately140,000iterations.753754SkullPhantomDemonstration755Atthemagneticfieldfrequenciesusedforthisexperimentboneandtissueare756effectivelytransparent47,soweselectedalifesizedskullwiththesizeofanaverage757humanadultheadasaphantom(OrientInfinityLimited).Itwaswrappedwith18758AWGmagnetwireasshowninFig5.Thecoilconsistedoffourcoilsinparalleleach759wiredtoanindividualmagneticfielddriver.Alldriverswerewiredtothesame760inputfrequencysignalandpoweredfromthesamepowersupply.Thefilmswere761suspendedatthecenteroftheskullphantom.OrangeLEDs(Chanzon)withadiode762antiparallelwereattachedtothefilmsforwirelessverificationofthevoltage763generatedbythefilms.Forvisualizationpurposestheskulltopwasremovedto764betterphotographtheLED.765766767768769

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  • References77077145. Ting,J.T.,Daigle,T.L.,Chen,Q.&Feng,G.Acutebrainslicemethodsforadult772

    andaginganimals:applicationoftargetedpatchclampanalysisand773optogenetics.MethodsMol.Biol.1183,221–242(2014).774

    46. Mathis,A.etal.Markerlesstrackingofuser-definedfeatureswithdeep775learning.arXiv[cs.CV]1–14(2018).776

    47. Bottomley,P.A.&Andrew,E.R.RFmagneticfieldpenetration,phaseshiftand777powerdissipationinbiologicaltissue:ImplicationsforNMRimaging.Phys.778Med.Biol.23,630–643(1978). 779

    not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which wasthis version posted November 5, 2018. ; https://doi.org/10.1101/461855doi: bioRxiv preprint

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  • SupplementalFigure1|FilmoutputvoltageasafunctionofbiasfieldThepeakresonancevoltageissignificantlyincreasedbyamodestbiasfieldthatcanbeproducedbyapermanentmagnet.

    SupplementalFigure2|MEpropertiesasafunctionoffilmsize(a)Schematicofexperimentalsetupusedtogatherdata.TestingwasperformedforMEfilmswiththreedifferentPVDFthicknesses:28(blue),52(red),and110(yellow)μm(b)Resonantfrequencyasafunctionoffilmlength(c)Outputvoltageasafunctionoffilmlength(d)Outputvoltageasafunctionoffilmsurfacearea(e)Q-factorasafunctionoffilmlength(f)Maximumpoweroutputasafunctionoffilmwidthfor52umPVDFthickness(g)Peakresonantvoltageplottedvs.PVDFthicknessshowsthatthepeakMEvoltageincreaseswiththePVDFthickness.Errorbarsindicate+/-1standarddeviationforn≈50filmsforeachthickness.(h)MEvoltageasafunctionofanglebetweenthefilmandthecoil.Blueregionshowstherangeofoperatinganglesforwhichthevoltageisgreaterthantheexpectedstimulationvoltage

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  • not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which wasthis version posted November 5, 2018. ; https://doi.org/10.1101/461855doi: bioRxiv preprint

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  • not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which wasthis version posted November 5, 2018. ; https://doi.org/10.1101/461855doi: bioRxiv preprint

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  • SupplementalFigure3|MagneticFieldDriver(a)Schematicofthemajorcomponentsofthemagneticfielddriver.Dashedlinedenotescomponentsrenderedin(b).(c)Outputwaveformformonophasicstimulationandtheparametersthatcanbecontrolledbythedrivesoftware(d)Outputwaveformforbiphasicstimulation,andtheparametersthatcanbecontrolledbythedriversoftware.

    not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The copyright holder for this preprint (which wasthis version posted November 5, 2018. ; https://doi.org/10.1101/461855doi: bioRxiv preprint

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  • SupplementalFigure4|MEstimulationofcellsgrowndirectlyonMEfilm(a)Schematicofexperimentalsetup(b)Microscopeimageoffixedcellsadherenttotheregionaroundastampedhole(Hoechst/Calcein-AM,cellslabeledpriortofixing)(c)ArcLightfluorescenceofspikingHEKcellswhenmagneticfieldisonresonanceand(d)offresonance.

    SupplementalFigure5|MagneticFieldforDBSRotationExperiment(a)SchematicshowsthelocationandspacingofwiresandthenumberofdriversusedtogeneratethealternatingmagneticfieldoverlayingaCOMSOLsimulationofmagneticfieldstrengthinthechamber(b)ResultsfromrotationtestinRat2:Angularvelocityinthe30secondsbeforestimulationandthefirst30secondsofstimulationshowsaclearreductioninangularvelocityonlywhentheMEfilmisactivatedonresonance(***P=1.5x10-8,n.s.=notsignificantP=0.27,pairedt-test)

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  • SupplementalFigure6|MEdevicesoperateseveralcentimetersaboveasinglemagneticcoil(a)COMSOLsimulationofmagneticfieldaboveacircularcoiland(b)Measureddeviceoutputvoltageasafunctionofdistanceabovethecoil

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