Here we provide an overview of several brain stimulation technologieswithdifferentmodalitiesthatcanbeemployedfor oscillotherapeutics. In addition to the time-targeting nature of closed-loop configurations, brain stimulation technologiesoffer space-targeting.Combininglessaversivetime-andspace-targeting enablesoscillotherapeuticstoprovidetherapeuticoptionsdistinct from pharmacologicaltreatments, which are easierin terms of their application but have sustained and off target effects. We discussdeepbrainstimulation(DBS),transcranialelectrical stimu-lation(TES),transcranialmagneticstimulation(TMS),transcranial focusedultrasoundstimulation(tFUS),andoptogeneticstimulation forthespace-targeting.
5.1. Deepbrainstimulation
ThemainadvantagesofDBSforoscillotherapeuticsareits focal-ityandefficacy(Kringelbachetal.,2007).Stimulusleadsaredirectly inserted intothe brain.Electricalstimulation can belimited to thetargetstructureandthestimulationenergydirectlyactivates nearbyneuronsandaxonalfiberswithoutshuntingviatheskull.
However,oneofdrawbacksofDBSisitsinvasiveness.Thereare risksofinfectionandbleedingbecauseoftheelectrodeinsertion.
AlthoughDBSisbasicallyreversible,theinsertioncauses microle-sionalongtheelectrodetrackfromthesurfacetothetargetregion.
Thus,ifthetargetregionissuperficial,transcranialstimulationmay beconsidered.
DBSelectrodesarepreciselylocatedwithstereotaxicsurgery while stimuli aredeliveredto validateitseffects onsymptoms especiallyfor motordisorders.DBSstimulationcanbeprovided in a closed-loop responsive manner to achieve time-targeting (Bouthouretal.,2019).DBSstimulationsareusuallyprovidedas pulsetrainsandtheycanbedeliveredchronically,intermittently, orpreciselysynchronizedwithelectrophysiologicalorbehavioural signalsinaclosed-loopmanner.Thestimulusparametersinclude frequency, pulse width, pulseamplitude etc. These parameters havebeentitratedbyphysiciansempirically,buttheycanbeguided bypre-clinicalstudiesusingoptogenetics(Creedetal.,2015).The stimulationparameterscanbeupdatedonlineusingclosed-loop adaptivetechniques.Forexample,dynamicchangingofamplitude inresponsetobeta-bandpowerintheSTNforPD(Bouthouretal., 2019;Provenzaetal.,2019).DBShasalreadybeenusedfor PD, drug-resistantepilepsy,treatmentresistantdepression,anddrug addiction(Deuschletal.,2006;Liand Cook,2018).DBSforAD, schizophrenia,GAD,andPTSDareunderinvestigation(Binaand Langevin,2018;Kracketal.,2010).DBSactsrapidlyformovement disordersbutittakestimefordepressiontreatment.
5.2. Transcranialelectricalstimulationtechnologies
TESisanon-invasivebrainstimulationtechnique.Itisasafeand reversibleadjunctivetherapybecauseitsstimuluselectrodesare locatedoutsidetheskull.TEStechnologiesareclassifiedintoECT andnon-convulsivetherapy.AlthoughECTonthePFCisoneofthe effectivetherapiesfordepression(andisstillusedfor schizophre-niaindevelopingcountries),wefocushereonnon-convulsiveTES.
Thisisbecauseofitstherapeuticpotentialfortheon-demand con-trolofmanysymptomsofneurologicalandpsychiatricdisorders, combinedwithclosed-looptime-targetingnature.Thefocalityof TESisnotasgoodasDBSorTMSbecauseofitstranscranialnature.
However,itsdiffusemildmodulationoverthecortexmaybean advantageforintervention(e.g.desynchronization)of pathologi-caloscillationsinwidespreadcorticalregionsforexampleabsence seizures(Berényietal.,2012;KozákandBerényi,2017). Further-more,thefocalityofTEShasimprovedviarecentadvancesinthe technologieswediscussbelow.Traditionally,thestimulus inten-sityofnon-convulsiveTEShasbeenlimitedtoupto2mAandit hasbeenusedforneuromodulation.
However,werecentlyfoundthatthisamountofstimulus inten-sityisnotenoughtodirectlyinducelargeenoughelectricalfields (1mV/mm)that in turnreliably induceaction potentialin the intracranialspace,becauseoftheshunteffectoftheskullandskin (Liuetal.,2018).Thus,wehavedevelopedanewTEStechnology (Intersectional-ShortPulse(ISP)stimulation)bywhich electrical stimulationcanbetranscraniallyfocusedinanyintracranialspace, enablingmuchhigherelectricalcurrents(Vöröslakosetal.,2018).
Wearableorimplantabledevicesforclosed-loop,focusedTES inter-ventionwillbeavailableinthefuturebecauseTESdevicecanbe implementedinsmallerdevicesthanTMSandtFUStechnologies (seeSection6).
5.2.1. Highdefinitiontranscranialdirectcurrentstimulation tDCSisusedforinducingplasticchangesbyintroducing sub-threshold membrane potentials in the neurons in thecerebral cortex.ClassicaltDCSemploystwolargeelectrodes(25–35cm2) forthestimulation.tDCSinducessubthresholddepolarizationof corticalneuronsbelowtheanodalelectrode,andhyperpolarization belowthecathodalelectrode.RepeatedtDCSconductedonceaday forfiveormoreconsecutivedays,caninducelong-lastingeffectson motorperformance,depressedmood,andotherfunctionsforone monthormoreafterstimulation(Buchetal.,2017;Looetal.,2012).
EffortshavebeenmadetoincreasethefocalityoftDCSbyreducing thesizeoftherelativelylargestimuluselectrodeplacedoverthe targetarea,byincreasingthesizeofthereturnelectrode,and/or byplacingthereturnelectrodeatanotherlocationotherthanthe scalp(forexample,theneck,shoulder,andarms,orknee).
Alternatively,anelectrodeconfigurationhasbeendevelopedto optimizestimulationfocalityonthebasisofthemodellingof elec-tricalfieldstrength.Theso-calledhighdefinitiontDCS(HD-tDCS) isoneoftheseapproaches(Nitscheetal.,2015).Relativelysmall electrodesareplacedinthevicinityofthestimulationelectrode forthisapproach(Dattaetal.,2009).Sincethedistancebetween therespectiveelectrodesisrelativelyshort,shuntingisenhanced relativetothemoreconventionalelectrodearrangements. There-fore,current densityhastobe relativelyhightoobtainsimilar effectsaslargeelectrodepads.StudieshaverevealedthatHD-tDCS treatmenthasalleviatedsymptomsofepilepsyandpainperception (Castillo-Saavedraetal.,2016;Meironetal.,2019).
5.2.2. Highdefinitiontranscranialalternatingcurrentstimulation Transcranialalternatingcurrentstimulation(tACS)isrelatively a newly developed stimulation technique that non-invasively modulatescorticalexcitability andactivity.While tDCSinduces neuroplasticity viathe constant polarizationof neuronal mem-branepotentialswiththeapplicationofatonicsubthresholddirect current,tACSisthoughttoaffectneuronalmembranepotentialsby oscillatoryelectricalstimulationwithaspecificfrequency(Nitsche etal.,2015).ThestimulationusedfortACSand itsdurationare quitesimilartotDCS.tACSatanormalstimulusfrequency(1–100 Hz)doesnotinduceanyplasticitybutitinteractswiththeintrinsic oscillatoryactivitiesinthebrain(Antaletal.,2008).However,tACS
atamuchhigherfrequency(140tolowkHzrange)mayinduce neuroplasticexcitabilityalterations(Antaletal.,2017).
Recently, a new tACS configuration has emerged, the so-calledhigh-definition(HD-tACS).Stimulusfocalityisdramatically increased in HD-tACS via having one stimulating electrode on thetargetstructuresurroundedbyseveralanti-phasereturning electrodes.Severalcorticalregionscanbeindependently stimu-latedwithdistinctoscillatorystimuluswaveformsbyusingthis stimulationtechnology.Reinharthasartificiallysynchronizedand desynchronizedthehumanmedialfrontalcortexandthelateral PFCintheta-bandfrequency,andsuccessfullymodulated execu-tivefunctionsusingHD-tACSstimulation(Reinhart,2017).Reinhart andNguyen alsofoundthattheforcedcouplingofthePFCand thetemporalcortexinthetafrequencyimprovedworkingmemory taskperformanceinagedadults(60–76yearsofage)(Reinhartand Nguyen,2019).HD-tACScanbedeliveredinaclosed-loopmanner.
5.2.3. Temporalinterferencestimulation
Temporalinterference(TI)stimulationisanewlydevelopedTES techniquethatenablesdeepbrainstimulationwithoutelectrode insertion(Grossmanetal.,2017).TIstimulationutilizesthe tem-poralinterferencebetweentwoelectricalfieldswithalternating vectorialdirectionsinsimilarbutslightlydifferent,over-kiloHertz frequencies.Forexample,Grossmanandothersapplied2kHz(f1) and2.01kHz(f2)alternatingcurrentstimulationsontheheadsof mice.Dependingonthealignment oftheelectrodes,the super-positionofthetwoelectricfieldsinsidethebrainresultedinan electricalfieldattheaveragefrequencyoff1andf2,whose enve-lopewasmodulatedatthefrequencyofdeltaf(10Hz).The10Hz modulatedenvelopeentrainedtheactionpotentialsoftheneurons insidethebrain,whereastheveryhighfrequencyoscillating(>2 kHz)electricalfieldsdidnotcauseanychangesinthemembrane potentialsofcorticalneuronsbecauseofintrinsiclow-pass filter-ingpropertiesoftheneuronalmembrane.Theyalsoshowedthat TIstimulationcouldtranscraniallyinducecFos(immediateearly gene)expressioninthehippocampalneuronsofmice,butnotin neuronsintheoverlayingcortex.
The TI stimulation is an innovative technique, but only its proofofconcepthasbeenestablishedsofar,especiallybecause itdoesnotaddressthebottleneckofintensitydependent periph-eralside-effectsestablishingitsefficacywithnon-humanprimates orhealthyhumanvolunteersisrequiredbeforepossibleclinical application.Thespatialresolutionandmaximaldepthforeffective stimulationwillbedependentonthenumberand alignmentof electrodesonthescalp.Oneissuecouldbethepossibleoff-target effectsofveryhighfrequencyelectricalfieldsoverlargebrainareas.
StrongkHz-frequencyelectricalfieldscanblockthepropagation ofcompound action potentialinperipheralnerves(Kilgoreand Bhadra,2014).Intheirexperiments,the2kHzelectricalstimulation withhundredsmicroampereorderdidnotinduceanyacute physi-ologicaleffectsonthebrain.Furtherexperimentswillbenecessary fordetermining theupper limitof theelectrical field toensure thatanyconduction blockonaxonsinthebrainisnotinduced.
Chaiebandothershavereportedthatveryhighfrequency electri-calfields(1–5kHz)couldinduceneuralplasticitysimilartothat whichcanbeevokedbyanodaldirectcurrentstimulation(Chaieb etal.,2011).Thelong-termeffectsofkHzstimulationofTIshould bestudiedinfuture.TemporalresolutionofTIsimulationhasa limitationbecausetheintroductionofkHzelectricalfieldsinshort ramp-uptimesinducesthetransientnon-spatiallyfocused activa-tionofneurons,whereasslowramp-updoesnot.Becauseofthis limitation,closed-loopTIwithtimeprecision(e.g.phase-targeting stimulation)isnotfeasible.Therefore,TIstimulationseems prefer-abletoapplications forinducing plasticityin non-corticaldeep brainregions.
5.2.4. Intersectionalshortpulsestimulation
WehaverecentlydevelopedanewTEStechnology,bywhich stimulusinducedelectricalfieldscanbefocusedinanyregionofthe brain(Vöröslakosetal.,2018).Thespatially-targetedTEShasbeen achievedbyspatiotemporallyrotatingIntersectionalShortPulse (ISP)stimulation(2.5–10sduration,5–50spause,depending onthenumberofelectrodepairs)(Fig.3A).Thismethodexploits theintegrationtimeconstantoftheneuronalmembrane(5–20ms), amechanismthatcantemporallyintegratemultipleconsecutive electricalgradientswithsimilarvectordirections(Fig.3A).Because ofthis,ISPstimulationcouldtranscraniallyfocusastrongenough electricalfieldonatargetbrainregiontodirectlyinduceorinhibit actionpotentials(>1mV/mm)withoutplacingtoomuchcurrent densitiesonthescalp(i.e.itislesspainful).SpikesofHPCneurons couldsuccessfullybemodulatedinahemispherespecificmanner withISPstimulation.Furthermore,the1HzISPstimulation phase-andhemisphere-specificallymodulatedamplitudeofalpha-band activitiesofEEGinhealthyvolunteers.
ThemajoradvantagesofISPstimulationare: (1)Focality.ISP stimulation can focus on a small brain region. This focus can befurtherimprovedby placinganumber ofelectrode pairs on thescalp;(2)Time-resolution.Itcanbeeasilyimplementedwith a closed-loop configuration with millisecond precision. Phase-targetedclosed-loopstimulationispossible;(3)Intensity.Currents ashighasten-sixteenmAcanbeused(anorderofmagnitudelarger thanconventionalTES)becausethecurrentdensityoneach elec-trodeissimilartothatofconventionalTES;(4)Bilateralstimulation.
Thesameeffects(excitationorinhibition)canbeappliedonboth hemispheressimultaneouslybyaligning electrodes(unlike con-ventionalTES,which inducesopposinganodal-cathodaleffects).
Thisis becausedirectionofelectricalfieldsalongdendrite-axon axis on neurons determines whether the electrical fields acti-vateorinhibitthetargetneurons(Liuet al.,2018), andISPcan inducesymmetricallydirectedelectricalfieldsontheboth hemi-spheres(Fig.3B);(5)Versatility.Severaldistinctstimuluswaves canbeemployedindependentlyforexampletointroducedistinct stimulusphasedifferencetodifferentbrainregions(Fig.3B).ISP stimulationcanbecombinedwithtDCS,tACS,andevenTI stimu-lationinprinciple;and(6)Simplicity.TheISPstimulationdevice caneasily beminiaturized tobe implantableor wearable.This enablesthelong-termcontrolofneurologicalandpsychiatric dis-orders,evenfordomiciliarycare(Fig.4B).ISPstimulationcould enablenon-invasiveon-demandclosed-loopcontrolwith space-andtime-targetedbrainstimulationforneurologicaland psychi-atricdisorders.
5.3. Transcranialmagneticstimulation
TMS is non-invasive brain stimulation technique that has beenusedformodulatingsymptomsofdepression,schizophrenia, addictionetc.(Dianaetal.,2017;Farzanetal.,2012;Foxetal.,2012).
TMSemploystheprincipleofelectromagneticinduction,inwhicha changingmagneticfieldgivesrisetoacompanionelectricfieldthat induceselectriccurrentsinnearbyconductivestructures(Hamada andRothwell,2015).Alargepulseofcurrentintheexternal stimu-latingcoilgeneratesarapidlychangingmagneticfieldthatrisesto (andfallsfrom)1Tormorewithin1ms.Thedesignoftheexternal stimulatingcoilaffectsthedistributionoftheinducedfieldinthe brain;thespreadanddepthofconventionalfigure-8stimulating coilsare5cm2and1.0–3.5cm,respectively(Dengetal.,2013).The maintargetofTMSisthecortex,butH-coilanddoubleconecoils alsoenablethestimulationofdeeperstructures.
The main advantageof TMS is its hightiterstimulation. Its inductedcurrentsintheintracranialspacearestrongenoughto directlyevoketheaction potentialsof corticalneuronswithout resonance (stimulation of the motor cortex can evoke muscle
movements).rTMSofthePFCachievesbetterorcomparable effi-cacythanECTfordepressionandithaslesscognitivesideeffects.
Thetime-resolutionofTMSisgoodenoughtobecombinedwith closed-loopconfigurations. MajordrawbacksofTMSareitscost andsize.Duetothephysicalconstrainsofcoilsize,TMS instru-mentscannotbeimplantedorwearable.TMStreatmentscanonly practicallybepossibleinhospitals.
5.4. Transcranialfocusedultrasonicstimulation
Low-intensitytFUSisanemergingbrainstimulationtechnology thatmodulatesmammalianbrainactivity(Fomenkoetal.,2018).
Relativelylowintensity(<3W/cm2)andlowfrequency(0.25–0.5 MHz) ultrasound stimulation is used for human neuromodula-tionstudies.Stimulationparameters(e.g.sonicationduration)and intensitydeterminewhetherastimulushasexcitatoryorinhibitory effects.Themechanismsbywhichlow-intensityultrasonic stimu-lationmodulatesneuronalactivityhavebeenpoorlyunderstood.
Thermalandnon-thermalmechanismshavebeenproposed,but thermal mechanisms are negligible because low-intensity tFUS does not cause a significant rise in tissue temperature during sonication (<0.1 ◦C). Direct effects onneuronal membrane and ion channelshave been suggested asnon-thermal mechanisms (Plaksinetal.,2014).
ThemajoradvantageoftFUSisitsfocalityevenfordeepbrain structures(however,compensationofbonescatteringis challeng-ing).Humanandnon-humanprimatestudieshaveshownthatthe stimulusfocuscanbeassmallas2–5mmandtFUScanfocuson (forexample)thebasalgangliawithoutaffectingthecortex(Legon etal.,2014).Inaddition,tFUScanbedeliveredin aclosed-loop manner(Fig.4A).Miniaturizationofthetransducerandamplifier willberequiredforimplantableorwearabledevices.Implantable transcranialultrasonicdevicesformicehavebeenreported,but noneforhumansyet(Lietal.,2019).tFUScantransientlyopenthe bloodbrainbarrieranditcanbeusedforbothtime-and space-targeteddrugdeliveryfor thecentralnervoussystemfollowing intravenousadministrationofnanoparticle-ormicrobubble-caged drugs(Landhuis,2017).
5.5. Optogenetics
Optogenetics is an innovative technology for the cell-type-specific manipulation of neuronal excitability with millisecond precision. Causal relationshipsbetween neuronal activities and naturalbehaviorshavebeenextensivelyexploredinneuroscience fields using optogenetics (Grosenick et al., 2015). The major advantages of optogenetics as a brain stimulation technique comewiththegeneticallycodednatureofitsactuators(opsins).
Thisgeneticnaturecombinedwithvariouspromotersand viral vector-mediatedgenetransductionenablescell-type-andneural pathway-specific,andeven activity-dependentopsinexpression in arbitrary brain regions (Kim et al., 2017). Opsin expression canbepharmacologicallycontrolledviatheCre-estrogen recep-tororTeton/offsystem.Themanipulationofneuronalexcitability canbebidirectionalwithfinetemporalresolution.Forexample, channelrhodopsin-2 andiC++ canrespectively beused forblue light-mediatedexcitationandinhibition withmillisecond preci-sion.
The pathophysiology of neurological and psychiatric disor-ders and possible intervention strategies for them have been explored using animal models with closed-loop optogenetics.
For example,Krook-Magnusonandothers showedthat seizure-triggered on-demand optogenetic inhibition of HPC pyramidal neuronssuppressesHPCelectrographicseizuresinmice (Krook-Magnusonetal.,2013).Carlsonandothersshowedthatcortical slowoscillation-timedgammafrequencyoptogeneticactivationof
Fig.3.IntersectionalShortPulsestimulation:afocusedtranscranialelectricalstimulationtechnology.
(A)PrincipleofIntersectionalShortPulse(ISP)stimulation.Multipleanodalandcathodalelectrodepairsarelocatedontheskullorscalp.Electricalstimulationwastemporally interleavedat5–25sandrotatedwithintheelectrodepairs.Theelectricalfieldgeneratedbythestimulationisfocusedtoanarbitraryregionofthebrain.(B)Expansionof ISPtechnologyformultiplefocusingpointswithtwodistinctstimuluswaveforms(greenandmagentaintheleft).Dependingonelectrodealignmentandstimuluspolarity, multiplebrainregionscanbestimulatedusingdistinctstimuluswaveformscausingthesameeffect(excitatoryorinhibitory)onbothhemispheres(right).Greenandmagenta arrowsindicatecurrentflowsfromanodetocathode.Blackarrowsindicatephasedifferences(temporalshifts)betweenthedistinctstimuluswaveforms.
Fig.4.Futuredirectionandengineeringchallenges.
(A)Pre-clinicalresearchanddevelopmentofclosed-loopinterventionsforneurologicalandpsychiatricdisordersinthenearfuture.Efficientalgorithmsshouldbedeveloped forreal-timedetectionofspecificpathologicaloscillationpatternswithlarge-scaledatastreams.Severalbrainstimulationmodalities(e.g.electrical,ultrasonic,andoptical) areinvestigatedforefficienttranscranialstimulation.(B)Thedevelopmentofwearabledevicesfortheclosed-loopinterventionofneurologicalandpsychiatricdisorders.
Thereal-timedecodingofspecificfeaturesofchronicsymptomsfromrestingstateEEG(rs-EEG)willbemuchmoredemandingoncomputation.Parallelizationofprocessing unitswillbenecessaryforfastercomputationandlowerpowerconsumption.Thedevicesneedtobeminiaturizedtobecomewearableorimplantable.
thePFCtothalamicpathwayalleviateddepression-likebehaviorin mice(Carlsonetal.,2017).Majordrawbacksofoptogeneticsasa brainstimulationtechniqueforhumansaregeneintroductionand
invasiveness.Virus-mediatedgenetransductionandtheinsertion ofopticalfibersintothebrainisnoteasilyjustifiedintermsofrisk versusbenefit.Magnetorradio-wavesensitivegeneticallycoded
actuatorsmayenablethetranscranialmanipulationofdefined neu-ralcircuitswithoutopticalfiberinsertions,butgenemanipulation isstillrequired.However,Optogeneticsisaverypowerfuland use-fultechniqueforbasicoscillopathyresearch.