Robust modulation of arousal regulation, performance, and frontostriatal activity through central

22 Pages·2016·5.19 MB·English

JNeurophysiol116:2383–2404,2016.
FirstpublishedAugust31,2016;doi:10.1152/jn.01129.2015.
Robust modulation of arousal regulation, performance, and frontostriatal
activity through central thalamic deep brain stimulation in healthy
nonhuman primates
Jonathan L. Baker,1 Jae-Wook Ryou,1 Xuefeng F. Wei,2 Christopher R. Butson,3 Nicholas D. Schiff,1
and Keith P. Purpura1
1FeilFamilyBrainandMindResearchInstitute,WeillCornellMedicine,NewYork,NewYork;2CollegeofNewJersey,
DepartmentofBiomedicalEngineering,EwingTownship,NewJersey;and3UniversityofUtah,ScientificComputing&
Imaging(SCI)Institute,DepartmentofBioengineering,SaltLakeCity,Utah
Submitted21December2015;acceptedinfinalform8August2016
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BakerJL,RyouJW,WeiXF,ButsonCR,SchiffND,Purpura support cognition, and here we demonstrate that CT-DBS nlo
KP.Robustmodulationofarousalregulation,performance,andfron- robustly modulates cognition when stimulating a specific a
d
tostriatal activity through central thalamic deep brain stimulation in centralthalamictargetusinganovelmethod.Theseresults e
d
FheirasltthpyubnloinshheudmaAnugpurismta3t1e,s.2J01N6e;udroopi:h1y0s.i1o1l5121/j6n:.021318239–.22400145,.—20T1h6e. sauppiepsorfotronSgBoIinpgaticelnintsic.al studies to provide effective ther- from
centralthalamus(CT)isakeycomponentofthebrain-widenetwork h
underlying arousal regulation and sensory-motor integration during THE CENTRAL THALAMUS (CT) has long been considered an ttp
wakefulnessinthemammalianbrain.DysfunctionoftheCT,typically essential component of a larger arousal regulation network ://jn
aresultofseverebraininjury(SBI),leadstolong-lastingimpairments within the mammalian brain that maintains wakefulness and .p
in arousal regulation and subsequent deficits in cognition. Central h
organizes resources in the anterior forebrain to support cogni- y
thalamicdeepbrainstimulation(CT-DBS)isproposedasatherapyto s
tion and goal-directed behaviors (Mair et al. 2011; Schiff io
reestablish and maintain arousal regulation to improve cognition in lo
select SBI patients. However, a mechanistic understanding of CT- 2008). Humans with damage to the CT, as a result of severe gy
DBSandanoptimalmethodofimplementingthispromisingtherapy brain injuries (SBI) of varying etiologies (Adams et al. 2000; .o
amreateusnk(NnoHwPns.),HMeraecawcae dmeumlaotntas,trtahteatinloctwatoionh-esaplethcyificnoCnThu-DmBanS pimri-- CStausstsaigenteale.t1a9l.8199,8119;9L4i;ttVleaent aDl.er20W10e;rfMeatxawl.el2l0e0t0a,l.22000036);, byrg/
provesperformanceinvisuomotortasksandisassociatedwithphys- persistently suffer from a variety of long-lasting cognitive 1
0
iologicaleffectsconsistentwithenhancementofendogenousarousal. impairments,includingdeficitsinattention,episodicandwork- .2
2
Specifically, CT-DBS within the lateral wing of the central lateral ingmemory,information-processingspeed,arousalregulation, 0
nucleus and the surrounding medial dorsal thalamic tegmental tract and executive functions (such as planning, initiating, and .33
(DTTm)producesarapidandrobustmodulationofperformanceand directing actions, monitoring actions, problem solving, and .1
arousal, as measured by neuronal activity in the frontal cortex and o
inhibitory control), which significantly impact daily activities n
striatum. Notably, the most robust and reliable behavioral and phys- D
iologicalresponsesresultedwhenweimplementedanovelmethodof and their quality of life (Corrigan et al. 2014; Dikmen et al. e
c
CT-DBS that orients and shapes the electric field within the DTTm 2003; 2009; Levine et al. 2005; Ponsford 2013; Ziino and em
usingspatiallyseparatedDBSleads.Collectively,ourresultsdemon- Ponsford2006).Thesecognitivedeficitslackrobusttherapeu- b
e
strate that selective activation within the DTTm of the CT robustly ticoptions(FridmanandSchiff2014;Talskyetal.2010),and r 1
regulatesendogenousarousalandenhancescognitiveperformancein deep brain stimulation within the central thalamus (CT-DBS) 2
theintactNHP;thesefindingsprovideinsightsintothemechanismof hasbeenproposed(SchiffandPurpura2002;Schiff2012)asa , 2
0
CT-DBSandfurthersupportthedevelopmentofCT-DBSasatherapy therapeuticmethodforrestoringarousalregulationandfrontal- 1
6
for reestablishing arousal regulation to support cognition in SBI striatal-thalamic integration in SBI patients to facilitate and
patients.
support rehabilitation. It fact, it has been demonstrated that
central thalamus; deep brain stimulation; arousal regulation; intrala- CT-DBScaneffectivelyrestoremultiplebehavioralcapacities,
minarnuclei;severebraininjury includingfunctionalrecoveryofspeechandpartialrecoveryof
executivefunctionsinanSBIpatientwhohadremainedinthe
minimally conscious state for over six years (Schiff et al.
2007).
NEW & NOTEWORTHY Fewstudies,however,haveexaminedthebasicmechanisms
underlying CT-DBS, and a precise clinical target for DBS in
Severe brain injuries (SBI) annually encumber an esti-
the central thalamus is unknown (Schiff 2012). To date, the
mated 125,000 individuals in the US with life-long cogni-
rodentmodelhasprovidedthebestevidencesupportingtheuse
tive disabilities, and no effective therapies exist. Central
of CT-DBS for modulating arousal and global brain activity,
thalamic deep brain stimulation (CT-DBS) is proposed as
an effective therapy to reestablish arousal regulation to andstudiesconductedinintactrodentshavedemonstratedthat
modulationofinnateortrainedbehaviors(MairandHembrook
2008; Shirvalkar et al. 2006) and shifts in arousal (Gummad-
Address for reprint requests and other correspondence: J. L. Baker, Feil
avelli et al. 2015; Quinkert and Pfaff 2012) can be achieved
FamilyBrainandMindResearchInstitute,WeillCornellMedicine,LC809,
1300YorkAve.,NewYork,NY10065(e-mail:[email protected]). with CT-DBS. In addition, recent studies have demonstrated
www.jn.org 0022-3077/16Copyright©2016theAmericanPhysiologicalSociety 2383
2384 CENTRAL THALAMIC STIMULATION ROBUSTLY MODULATES PERFORMANCE
that CT-DBS increases arousal and motor activity following Inthisstudy,behavioralandphysiologicaldatawerecollectedover
repeated incidences of traumatic brain injury (TBI) in mice a 30-mo period in NHP1 and over an 18-mo period in NHP2.
(Tabanskyetal.2014)andthereexistsafrequencydependence Experimentalsessionswereconductedinablockdesign,whereeach
animal was provided several 2-, 4-, and/or 6-mo breaks between
intherecruitmentoffrontostriatalpopulationsduringselective
blocks of experimental sessions to maintain their health and to
optogenetic activation of central lateral (CL) neurons (opto-
facilitatedatamanagementandanalysis.Theanimalswereeuthanized
CT-DBS) in the rat (Liu et al., 2015). While these rodent
to reconstruct all recording and stimulation sites once an adequate
studiesprovideimportantdataandinsight,thefuturedevelop- amountofbehavioralandphysiologicaldatawerecollected.Forthis
mentofahumanCT-DBStherapynecessitatesamoreprecise study, 218 experimental sessions in NHP1 and 68 in NHP2 were
characterization of CT-DBS in the larger brain of the intact analyzed.InNHP2,234DBSperiodswereexcludedbecausestimu-
NHP.NHPsareawell-establishedDBSresearchanimalmodel lationwasconductedwithinthefasciculusretroflexus(i.e.,habenula-
pedunculartract),arobustbundleoffibersthattraversethecenterof
that is closely linked phylogenetically with humans, share a
the Pf nucleus, a component of the caudal central thalamus (Jones
prominentexpansionoftheanteriorforebrain,anddemonstrate
2007;Sutherland1982),andresultsfromfasciculusretroflexusDBS
the capacity to work over extended periods of time while (fr-DBS)arenotthefocusinthisstudy.NumerousCT-DBSexperi-
performing complex goal-directed behaviors requiring sus- mentalsessionsinbothanimalswereexcludediftheanimals’starting
tained attention, working memory, speed, accuracy, and moti- performance was low ((cid:2)20%) or they refused to work for water D
o
vation,allaspectsofcognitionnotwellcharacterizedinrodent rewards.Thesesessionsarepresumedtoreflectdaysoflowmotiva- w
models. tion as a result of factors beyond the control of the investigators nlo
related to facility operations, group housing, and animal care. Addi- a
Therefore in this study, for the first time, behavioral and d
tionalexperimentalsessions,includingelectroanatomyandbehavioral e
physiologicaleffectsofCT-DBSweresystematicallyexplored d
intwohealthyNHPsusingcustom-designedCT-DBSsystems dfiaetlad,-swhaepreincgorlelevcietewdsdoufrtihnegDthBeSmcoonntoapcotslairn,bboiptholaanri,maanldsbmuutlatirpeonloart from
scaled for the NHP and employing large-scale recording de-
includedinthisstudy. h
vices to broadly sample neuronal activity from frontal and Behavioral experiments. Here we modeled “cognitive fatigue” ttp
strtariianteadl taorepaesrfoorfmthseevearnatlerviiosruofmoroetborraivni.gilTahneceatnaismksa,lssimwielraer ucosignngitisviemrpelseouvricgeilsainncethetaisnktsactthNatHpProbdyurceequsiirginnigficsuansttaidneemda“nmdesnotanl ://jn.p
to tasks used to study vigilance or sustained mental effort in effort”(Sarteretal.2006)overextendedperiodsoftime.Performance h
y
humans(DaviesandParasuraman1982;Kinomuraetal.1996; decrements in these tasks are identified as an increased rate of sio
Luce 1984; Posner 1978; Steinborn and Langner 2012), and incorrect and/or incomplete trial performance accompanied by a lo
when repeated over long time periods, produce significant slowing and increased variance of reaction times, and a greater gy
prevalenceofeyeclosure,drowsiness,andputative“sleep”episodes .o
danemd/aonrddsecorenmeantttesnotinonvaiglilraenscoeurtcaesks.s iPnehrfuomrmanasncaerevaattrriiabtuiotends neteaarl.th2e00la9t;teSrmhiatlhf oetfaelx.p2e0ri0m9e).ntMalosteivsasitoionns i(nFfligu.en1c,eBs apnedrfoCr;mSahnache byrg/
tofluctuationsinarousal,motivation,distraction,andboredom throughout the tasks; however, this aspect of performance was not 1
(Davies and Parasuraman 1982; Langner et al. 2010; Sarter et systematically investigated, as has been done in other NHP studies 0.2
al. 2006), which can naturally lead to “cognitive fatigue,” a (Bouret and Richmond 2015; Varazzani et al. 2015). Additional 20
sequelae persistently experienced by many SBI patients (Dik- experimental sessions were conducted where reward schedule was .3
3
menetal.2003;2009;Levineetal.2005;Ponsford2013;Ziino randomizedorsignificantlydecreasedand/orincreasedoverblocksof .1
and Ponsford 2006). trialstoassessmotivation;however,thesedataarenotincludedinthis o
n
We show here that CT-DBS in the intact NHP facilitates study.Wefoundthattheanimalscontinuedtomonitorrewardvalue D
prior to, during, and after CT-DBS (data not shown) throughout a e
behavioralperformanceandlinkthesechangestoendogenous c
day’s experimental session and would predictably shift performance e
arousal,asmeasuredinthepowerspectraoflocalfieldpoten- m
depending on reward size, as demonstrated in other NHP studies b
tial (LFP) activity recorded within frontal and striatal cell e
populationsoftheanteriorforebrain.Critically,wediscovered (BouretandRichmond2015;Varazzanietal.2015). r 1
Behavioralexperimentswereprogrammedandimplementedusing 2
thatamaximalbehavioralandphysiologicaleffectisachieved areal-timecomputercontrolsystem(TEMPO,ReflectiveComputing, , 2
whentheelectricfieldisshapedandelongatedwithinaspecific St. Louis, MO, running under DOS 6.0; Microsoft, Redmond, WA). 01
6
regionoftheCTthroughtheuseofadjacentpairsofDBSleads The video display monitor (SONY) was controlled by a VSG2/3
separated by several millimeters along the anterior-posterior graphic processor (Cambridge Research Systems, Kent, UK) with a
axis, here termed “field-shaping CT-DBS.” In this study, the refreshrateof100Hzandpositioned114cmfromthebridgeofthe
impactofCT-DBSonbehavioralperformanceandfrontostria- noseoftheheadfixedanimals.ControlsignalsbetweentheTEMPO
and VSG2/3 computers used standard DIO protocols. Eye position
tal activity as demonstrated in intact NHPs is aimed at trans-
was measured and tracked using horizontal and vertical analog volt-
lating these novel results into new therapeutic options for
age signals from an E5000 infrared video eye tracking system fitted
persons suffering from the chronic cognitive sequelae follow-
withatelephotolens(ASL,Bedford,MA).Theanimal’sgazeposition
ing SBI (Schiff 2012).
was calibrated each day prior to experiment sessions and then mod-
ified whenever necessary to ensure the accuracy of the calibration.
Horizontal and vertical eye position signals were recorded and pro-
METHODS cessed to determine the occurrence of saccades, their amplitude,
Studydesign.Allworkwasperformedinstrictaccordancewiththe velocity,direction,andthepositionsanddurationsoffixationperiods.
National Institutes of Health Guidelines for Use of Animals in Fixation during the task was considered to be broken if the eye
Research and under an approved protocol from the Weill Cornell position left a 2.5–3.5° window around the fixation targets. The eye
Medical College Institutional Animal Care and Use Committee trackerhasaresolutionof1.3°ofvisualangle.
(IACUC). A detailed description of the surgical techniques, behav- Theanimalsperformedamodificationofastandardvariabledelay
ioral control, and data-acquisition systems can be found elsewhere periodreactiontimetask“S1-S2,”or“phasicalerting”paradigmused
(Purpuraetal.2003;Schiffetal.2013). in humans and in prior NHP studies (Kinomura et al. 1996; Posner
JNeurophysiol•doi:10.1152/jn.01129.2015•www.jn.org
CENTRAL THALAMIC STIMULATION ROBUSTLY MODULATES PERFORMANCE 2385
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e
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fro
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h
ttp
Fig.1.Theanimal’stypicalbehavioralperformanceofthevigilancetaskduringexperimentalsessionswithoutcentralthalamicdeepbrainstimulation.When ://jn
motivatedtoworkforjuicerewards,bothanimalstypicallyperformeduntilsatiatedandthenceasedtowork.A:structureofthevigilancetask.Toperform .p
correctly,theanimalhadtomaintainstablefixation(2degreevisualangle)onthedisplayedtarget(red/blackdartboard)thatwouldundergocontrastreversal, h
y
at10Hz,duringstablefixation.Thecontrastreversalindicatedthestartofthevariabledelayperiodthatwouldlast1.5–4.5sandendedwhenthecolorofthe s
targetswitchedfromred/blacktogreen/black,“GO”cue,instructingtheanimaltotouchaninfraredswitchforjuicereward.B:nativebehavioralperformance iolo
ofnonhumanprimate1(NHP1)duringthevigilancetask.Theperformanceestimateisshownasasmoothlyvaryingblueline(Smithetal.2009),andreaction g
y
timesofcorrectlyperformedtrialsareplottedinblack.Theredlineindicatesthecumulativenumberofincorrecttrials.Periodsofslowrollingeyemovements, .o
eyeclosure,andapresumedincreaseindrowsinessco-occurredwithmarkedincreasesinthepoweroflow-frequencyoscillatoryactivity(4–8Hz)recordedin rg
frontal and midline ECoG electrodes (see METHODS) and are marked in green along the zero performance line. Mean delay period was 2.2 s and average b/
performanceinthissessionwas60%correct(660of1,100trials).Trialnumberandtotaltimeontaskareindicated.C:sameasinBbutforNHP2.Meandelay y
period was 4.2 s and average performance during this session was 61% correct (673/1,100 trials). Note the trending decrease in average performance and 10
increasedvarianceinreactiontimesfollowingtrial600inbothanimals,correspondingto(cid:4)43and68mintimeontask,respectively.Periodsofeyeclosureand .2
presumed increased drowsiness occurred frequently in the latter half of most experimental sessions. These trends are consistent with performance changes 20
observedinadditionalanimalsperformingtheidenticalvigilancetask(Shahetal.2009;Smithetal.2009)andinhumansperformingsimilartaskscontinuously .3
3
overextendperiodsoftime(Pausetal.1997). .1
o
1978;Schiffetal.2013;Shahetal.2009;Smithetal.2009).Briefly, theNHPwasonlyrewardediffixationwasheldatthetargetposition n D
the structure of this task is initiated by the appearance of a target (a for500ms.AtrialwasconsideredtobeincorrectiftheNHPbroke e
black/red checkerboard or dartboard 5 degree (cid:3) 5 degree of visual fixationorthesaccadetothetargetwasnotwithina2.5to3.5degree ce
m
angle)atoneof9locations(chosenatrandomoneachtrial)onaCRT windowwithin500msofthefixationspotoffset. b
e
monitorpositionedinfrontoftheanimal.Aftera1-speriodofstable Electrophysiological recording methods. Following successful be- r 1
fixationofthetarget,thetargetunderwentcontrastreversalat10Hz havioraltraining,thetwoadultmaleNHPs(Macacamulatta),NHP1(11 2
for a variable delay period until changing to a black/green checker- kg)andNHP2(10kg),wereimagedusingstandardhigh-resolutionMR , 2
0
board or dartboard (Fig. 1A). The transition to black/green from andCTseriestoconstructasurgicalplanfortargetingthecentralthalami 1
6
black/redwastheGOcue(Fig.1A)forcontactingtheinfraredtouch withDBSleadsandfrontalandstriatallocationswithmicroelectrodes.
switch located within the primate chair (Crist Instrument, Hager- Severalrecordingchambers(GrayMatterResearch,Bozeman,MT)and
stown, MD). The variable delay period was randomly drawn from a aheadfixationpost(CristInstruments,MD)werethenimplantedusing
normaldistributionwithmeanof2,500msandSDof250ms.Atrial standard sterile surgical technique under deep isoflurane anesthesia (as
wasconsideredtobeincorrectiftheNHPbrokefixationpriortothe describedindetailinPurpuraetal.2003).Ahigh-density32-microelec-
GOcueortouchedtheIRswitchbeforeorwithin250msaftertheGO trodemicrodrive(ModelSC32,GrayMatterResearch,Bozeman,MT)
cue (early touch) or failed to respond within 800 ms after the green waspositionedovertherightfrontalcortexofbothanimalstochronically
target(latetouch). record broadband signals from frontal eye fields (FEF), dorsal lateral
In addition to the vigilance task, NHP1 was trained to perform a prefrontal(DLPF),dorsalpremotor(PMd)anddorsalcaudateandputa-
memoryguidedsaccadetask(HikosakaandWurtz1983).Briefly,the men. Each microelectrode (Alpha Omega LTD, Nazareth, Israel) was
animal was required to fixate a central green fixation square for 500 attached to a lead-screw and shuttle and had a maximum linear travel
ms and a white square (“target”) would briefly appear (80 ms) depthof(cid:4)20mm.The(cid:4)6(cid:3)6electrodegridspanned7.5mmwithan
randomlyin1of8positionslocatedintheperiphery,eachequidistant interelectrodespacingof1.5mm.Toisolateunitactivity,thepositionof
fromthecentralfixationsquare.Theanimalwasrequiredtomaintain eachmicroelectrodewasadjustedpriortoeachrecordingsessionwitha
fixation for a variable delay period randomly drawn from a normal customscrewdriver(1rotation(cid:4)125(cid:2)m)andpreciserecordingdepths
distributionwithmeanof2,500msandSDof250ms,untilthecentral werecataloguedandadjustedrelativetothecorticalsurfacefollowingthe
fixationspotextinguished.Theanimalthenhadtomakeasaccadeto histology.Graytowhitematterboundariesduringtheexperimentswere
therememberedlocationofthetarget.Ifthesaccadewasperformed judgedbasedonrecordingdepth,lackofunitactivity,andhigh-imped-
correctly, the target reappeared 300 ms after the end of saccade and ance characteristics of white matter and were used to exclude LFP
JNeurophysiol•doi:10.1152/jn.01129.2015•www.jn.org
2386 CENTRAL THALAMIC STIMULATION ROBUSTLY MODULATES PERFORMANCE
recordingsfrommicroelectrodespresumedtobeoutsideofgraymatter. Based on the successful demonstration of behavioral facilitation
In NHP1 3,295 independent microelectrode recording sites and 206 in utilizing bilateral monopolar and bipolar CT-DBS in a single SBI
NHP2wereincludedinthisstudy.ThelowernumbercollectedinNHP2 subject (Schiff et al. 2007), we conducted a cathode review of all
resulted from a mechanical disruption of the microdrive requiring its intra-lead mono- and bipolar configurations to thoroughly evaluate
earlyremovalandcessationofmicroelectroderecordingsfromthefrontal behavior and physiological effects in both animals. The cathode
cortex.Inadditiontothemicrodrives,custom10-channelECoGarrays review consisted of an incremental ramp of current with 0.25-mA
werechronicallyimplantedtorecordfromtheanimal’scerebralcortices. steps,startingfrom0.25mAandendingat3.0mA,usingastimula-
The ECoG arrays consisted of radiotranslucent 4 mm Ag-AgCl elec- tion frequency of 150 Hz. Behavioral responses, including eye,
trodes(BioPacSystems,Goleta,CA)bondedto2(cid:3)6mmtitaniumbone pinnae,andbodymovements,vocalizations,andgeneralizedchanges
screws(SalvinDentalSpecialties,Charlotte,NC)thatpenetratedtheskull in normal activity in the form of hyperkinetic movements, abrupt
andtouchedtheduralsurface. shifts in posture, or localized touching suggestive of paresthesias,
All neurophysiological signals were recorded with the RZ2 data- were noted. Consistent behavioral responses during these reviews
acquisition system (Tucker Davis Technologies, Alachua, FL) at a were noted and the current level for each termed “threshold.” The
maximum rate of (cid:4)25 kHz. Task-relevant signals, horizontal and monopolarconfigurationsusedthetitaniumbonescrewsandtitanium
vertical eye signals (High speed stationary Optics, ASL, Bedford, bone plate located within the diploë of the occipital calvarium for
MA) were synchronized and recorded with the RZ2 system. For all current return. The standard intra-lead bipolar configurations placed
DBS experimental sessions, high-resolution video (Panasonic HDC- anode(s) and cathode(s) contacts on the same DBS lead. We sus- D
o
HS900K, 1080 p at 30 fps) of the animals performing the tasks was pended use of monopolar CT-DBS during the experimental sessions w
synchronizedwiththedata-acquisitionsystemandstimulator. due to a combination of electrical artifact issues and nonspecific nlo
Central thalamic deep brain stimulation rationale and methods. motor, visuomotor, and somatosensory effects produced in the first a
d
We chronically implanted multiple DBS leads scaled for the NHP animal that consistently interrupted task performance at lower than e
d
(MEelddetrroneitc,alM. i2n0n0e5a)p,olbisa,seMdNo)n, ihnutomathneDthBaSlamleiadosf (twMoodNelHP33s8t7o, alenatdicsipwaatesdthceunrrepnutrsleuveedlsm.SortaensdyasrtdembiaptoiclaalrlyCTan-DdBdSurwinigththoinsepororctwesos from
systematically stimulate multiple CT targets using various standard we discovered that inter-lead bipolar CT-DBS [where anode(s) and h
andnovelconfigurationsofDBS.Intralaminarthalamicneuronsofthe cathode(s) are placed separately on the contacts of the two spatially ttp
C(JTonseesn2d0d0i7f;fuMseacpcrhoijeacntdionBsentotivlaorggleioe1x9p8a6n)seasnodfecxohritbeixtuannidqusetrifiartuinmg sDeBpaSr)a,tewdasDmBoSreleeaffdesc]t,ivheerine ftaecrimlietadtinfigelbde-hshaavpioinraglpCeTrf-oDrBmSan(cfesCanTd- ://jn.p
properties (Glen and Steriade 1982; Steriade et al. 1993) that shift frontostriatalactivityinbothanimals.Here,fsCT-DBSisproducedby h
y
markedly during periods of arousal. Cellular groups of the CT that anyconfigurationthatassignstheanode(s)andcathode(s)toseparate s
io
represent promising DBS targets for restoring arousal regulation in DBS leads displaced by several millimeters within the central lo
SBIhumans(Schiff2008)includetherostralcentrallateral(CL),the thalamus. gy
paracentral (PC) nuclei, and the caudal centromedian-parafascicular Customdeepbrainrecordingandstimulation(DBRS)deviceswith .o
cthormoupglehxt(hCeMov-Perfl)y,iwnghicsohmaaretoaslelnascocreyssainbdleptaoriDetBalScloeratdicepse.neMtroadtiuolnas- a(01.735-pmosmitioOnDra)diinatlogrtihdewtheareladmeiv.eEloapcehdDtoBgSuildeeadmhualtsipsliexDpBlaStinleuamds/ byrg/
tions in the firing rates of these neuronal populations are linked to iridium annular contacts (impedances 1.0–10 k(cid:5)), each 0.5 mm in 1
0
cognitivefunctionandgradewithtaskperformanceinNHPs(Matsu- height, with an intra-lead spacing of 0.5 mm and insulated by .2
motoetal.2001;Minamimotoetal.2009;Schiffetal.2013;Schlag polyurethane(NuMED,Hopkins,NY).Amaximumcurrentdensityof 20
and Schlag-Rey 1984; Schlag-Rey and Schlag 1984; Wyder et al. 2.6mA/mm2andmaximumchargedensityof20.4(cid:2)C·cm(cid:6)2·phase(cid:6)1 .3
3
2003,2004).Thesesameregionsexhibitgradedactivationinhumans was delivered during 3.0-mA stimulation during this study. The .1
performingsimilarvisualattentiontasks(Kinomuraetal.1996;Paus surface of each contact was coated with BT DOT (Biotectix, Ann o
n
et al. 1997; Portas et al. 1998), hence their proposed role in arousal Arbor,MI)priortoimplantationtoreduceandstabilizetheimpedance D
regulation (Schiff and Purpura, 2002; Schiff 2008) and as potential levelsofeachcontact.Impedancelevelsweremeasuredonaweekly e
c
DBStargetsinselectSBIpatients(Schiff2012). basis with a metal electrode impedance tester model IMP-1 (Bak e
m
DBS is known to produce a mixture of effects in neural tissue Electronics,Sanford,FL)usinga1-kHzsignal.Contactswithimped- b
(McIntyreetal.2004;MontgomeryandGale2008;Viteketal.2008). ances above 10 k(cid:5) were not used to limit waveform distortions er 1
Therefore we used a DBS waveform that mirrors the output of the delivered to the tissue. Waveforms were passed through a custom- 2
Medtronicclinicalsystem(asdescribedinButsonetal.2011),which built current-sensing circuit and visualized on a digital oscilloscope , 2
0
isdesignedtosafelyandoptimallystimulatelargemyelinatedaxons (TBS1000,Tektronix,Beaverton,OR)toconfirmthepresenceand/or 1
6
(Merrill et al. 2005; Nowak and Bullier 1998). The DBS pulse absenceofwaveformdistortions.FromthedistalcontactoftheDBS
consistedofan80-(cid:2)ssquarecathodalpulsefollowedbyanisoelectric lead,individualcontactswerenumbered0to5.Thefreeendsofthe
period of 60 (cid:2)s and ended with a 400-(cid:2)s square anodal pulse to DBS contacts were connected to a low profile 6-pin Nano Circular
balancethetotalchargeinjected.Eachpulselastedatotalof540(cid:2)s. Connector (Omnetics Connector Minneapolis, MN) and rigidly se-
During the experimental sessions stimulation was delivered in stan- curedwithintheDBRSsystem.
dard monopolar, bipolar, and novel multipolar, field-shaping config- In NHP1, two DBS leads were implanted into the right thalamus
urations, at various frequencies (20, 40, 150, 175, 200, and 225 Hz) withaninterleadseparationof2.4mm.InNHP2,twoDBSleadswere
and amplitudes (0.25–3.0 mA) under current control, to maintain implantedintotherightthalamuswithaninterleadseparationof1.8
pulseshapeovertime-varyingimpedancesforeachcontact(Lempka mmandtwoDBSleadswereimplantedintotheleftthalamuswithan
etal.2010).Inthisstudy,periodicDBSwasusedtoactivate(Garcia interlead separation of 2.7 mm. In NHP1 DBS lead locations and
etal.2003,2005;Hashimotoetal.2003)CTcellularpopulationsand interleadspacingweresettooptimizetargetingofthe“wing”ofthe
the DTTm (Edlow et al. 2012), which is composed of thalamic central lateral (CL) nucleus (Glen and Steriade 1982), principal CT
efferents and en passant fibers within the internal medullary lamina fibers,andenpassantfibers(Jones2007;ScheibelandScheibel1967)
thatencasetheCTnuclei(Jones2007;MacchiandBentivoglio1986). oftheDTTmbasedonpostoperativereconstructionoffiducialguide-
Our goal was to artificially enhance the afferent drive into various tubemarkersrelativetothemodeledCTnuclei(Paxinosetal.1999).
anteriorforebraintargets(Jones2007;MacchiandBentivoglio1986; We estimated a spatial uncertainty of (cid:4)1 mm or less in electrode
MinamimotoandKimura2002;Steriade2000),thereby“activating” positions based on the MR image resolution and histological confir-
theanteriorforebrain(Steriadeetal.1991;Steriade2000)torobustly mation of the DBS lead locations. Based on preliminary behavioral
modulatebehavioralperformance. andphysiologicalresultsobtainedinNHP1,DBSleadsinNHP2were
JNeurophysiol•doi:10.1152/jn.01129.2015•www.jn.org
CENTRAL THALAMIC STIMULATION ROBUSTLY MODULATES PERFORMANCE 2387
positionedtotargetthecaudalCM-PfcomponentoftheCTandmore stimulation pulses were calculated in NEURON 7.1 (Hines and
medialportionsofmedialdorsalis(MD).Modelreconstructionofthe Carnevale1997).
DBSleadsandindividualcontactlocationsrelativetotheCTtargets Histology. Histology staining was performed by FD Neurotech-
arenotedbelowinModelingandRESULTS,respectively.Conformation nologies(Columbia,MD).Followingstandardtranscardialperfusion,
of lead locations was determined through standard Myelin and nissl formaldehyde-fixed(4%)tissueblockscontainingthetractsofthe
histology(FDNeurotechnologies,Colombia,MD),lightmicroscopy DBS leads were dehydrated through graded ethanol and xylenes,
andcomparisonwithneuroanatomicalatlasesoftheNHP(Paxinoset andthenembeddedinparaffin.Serialsections(10(cid:2)minthickness)
al.1999,https://scalablebrainatlas.incf.org). were cut through the whole tissue block with a rotary microtome.
A four-channel Multi Channel Systems (MCS) stimulator The 1st section of every group of 4 (or 10) sections following the
(STG4004-3.2mA)withacomplianceof120Vwasconnectedtothe discovery of the DBS lead tract was mounted on 25 (cid:3) 75 mm
DBS leads to deliver stimulation. Each of the four channels of the Superfrost Plus microscope slides. All sections were stained with
MCSstimulatorisopticallyisolatedtoensurereliablecurrentdelivery FD Luxol fast blue solution and counterstained with FD cresyl
whenmultiplechannelsareusedsimultaneously.TimingoftheMCS violet solution to mark myelinated fibers and cell bodies, respec-
stimulatorwascontrolledwithTTLpulsesgeneratedbytheTDTRZ2 tively. Sections were cleared in xylene and then coverslipped in
system and synchronized with the behavioral control computer. All Permount(FisherScientific,FairLawn,NJ).Slidescontainingthe
DBSpulsetimesandvoltagewaveformswerecollectedwithaTDT DBS lead tracts were digitized with a microscope using a 2X
RP2.1EnhancedReal-TimeProcessorwithasamplingrateof(cid:4)100 objectiveandcomparedwithastandardhistologyatlasoftheNHP D
o
kHzinordertovisualizeandidentifywaveformdistortions. (Paxinos et al. 1999, http://scalablebrainatlas.incf.org) to identify w
Modeling DBS activation in the central thalamus. Computational thalamicnucleiandmajorfibertracts.Corticalandstriatalrecord- nlo
modelswereusedtopredicttheeffectsofDBSineachNHP.These ingsiteswereidentifiedfromNissl-stainedsections,andelectrode a
d
predictions have been validated in prior human and NHP studies recording depths were adjusted based on the histology. e
d
(dBetuatislosncaent able. 2fo0u0n7d; Miniopcreinvoiovuicseptuball.ic2a0ti0o9n)s, (aBndutsmonetheotdaol.lo2g0i1c1a;l rewBaerhdas,vitohrealandiamtaalsapnearlfyosrism.aWncheewnamsotytipviactaeldlythoigwhoartkthfeorstlairqtuoidf from
ButsonandMcIntyre2008).Briefly,pre-andpostoperativeCTand eachexperimentalsessionandthengraduallydiminishedastotaltime h
MR imaging enabled surgical planning and model reconstruction ontaskincreased(Fig.1,BandC;Schiffetal.2013;Shahetal.2009; ttp
rmeoladteivleotfotCheT-tDarBgeStecdocnesnistrtsalothfalfaomuricmnuacinlei.coTmhepocnoemnptsu:ta1ti)onaanl Sremlaittihveettaol.t2h0e0G9)O.Ccourereoctclcyuprreirnfgormbeetdwetreinals2i5n0claundded8r0e0acmtiosnintimthees ://jn.p
animal-specific 3D anatomical model of major thalamic nuclei vigilance task and between 150 and 500 ms in the memory-guided h
y
constructed from the Paxinos atlas (Paxinos et al. 1999; https:// saccade task. Incorrect trials are categorized as “incomplete” trials s
io
scalablebrainatlas.incf.org)thatwasregisteredtoeachNHP’spre- (brokenfixation,earlyandlatetouchoftheIRswitch)and“incorrect” lo
and postoperative CT and MR imaging data; 2) a finite element trials (failure to acquire the target, failure to respond after the GO gy
modelofthesix-contactDBSleadsandelectricfieldsgeneratedin cue).Thesecondtypeof“incorrect”trialoccurredrarely.Anestimate .o
ataplh5y.7si-o(cid:2)lmogiccaabllme emdoiudmel(nBeuutrsoonnsedtisatlr.i2b0u0te7d);a3r)oumnudlttihceomlepaadrst;maennd- ocofrrbeechta(v“i1o”ra)lanpderfionrcmorarneccet (w“0a”s)ctroimalpsuutseidngfraomstattheesptiamceemseordieeslinogf byrg/
4) probabilistic fiber orientations of neurons based on a diffusion approach (Smith et al. 2009). This smooth estimate of performance 1
0
tensor (DTI) brain template for rhesus macaques (Adluru et al. ratewasusedtovisualizeperformanceasafunctionoftrialnumber .2
2012).Themodelservedtwomainpurposes:1)toprovidestereo- inrelationtotheCT-DBSONandOFFperiods(Fig.2andFig.3,A 20
taxiccoordinatesoftheCTnucleartargetstoaccuratelyguidethe andC). .3
3
placementofmultipleDBSleads;and2)tovisualizethepredicted TheoddsratiowasusedtoquantifytheeffectsizeofDBSrelative .1
axon activation during DBS under the various stimulation param- tobaselineperformancebycalculatingtheratiooftheoddsofgetting o
n
eters conducted in this study. a correct trial during CT-DBS ON periods to the odds of getting a D
A 3-T Siemens MAGNETROM TRIO was used to collect high- correct trial during CT-DBS OFF periods. Odds ratios for all DBS e
c
resolutionMRimages(0.5-mm3voxel)withenhancedcontrast(Ab- periodswerecomputedandsubjectedtoa95%confidencebasedon e
m
lavar,LantheusMedicalImaging,NorthBellerica,MA),andaGen- the standard error and the total number of trials in both the ON and b
e
eral Electric Medical Systems Discovery LS Model was used to OFFperiods.Aminimumof20trialspriortotheonsetand20trials r 1
collect CT images with a voxel depth of 1.25 mm. Analyze 9.0 during DBS were required for a DBS period to be included in this 2
software (Mayo Clinic, Rochester, MN) was used to outline the study.Reactiontimedistributionsofcorrectlyperformedtrialsduring , 2
0
individual thalamic nuclei across atlas slices, and SCIRun 4.5 soft- ONandOFFDBSperiodswerecomparedusingarank-sumtestwith 1
ware(ScientificComputing&ImagingInstitute,UniversityofUtah, a significance of P (cid:2) 0.05. The coefficient of variation (CV), the 6
Salt Lake City, UT) was used to coregister the 3D thalamic nuclei standard deviation divided by the mean reaction times, was used to
withallMRandCTimagingusingapreviouslypublishedalgorithm quantifythevarianceofreactiontimeswithinasetperiod.
(Viola and Wells 1997). Following the initial implantation surgery Electrophysiological data analysis. Broadband activity (0.1–10
leadcontactlocationswereestimatedthroughisosurfaceprocessingof kHz) was collected from custom high-impedance (0.5–1.5 M(cid:5)) mi-
postoperativeCTimages. croelectrodes (Alpha Omega, Nazareth, Israel) positioned within a
A finite element model (COMSOL 3.5) was created to estimate the 32-microelectrode microdrive (SC32, Gray Matter Research, Boze-
electricfieldproducedduringDBS.Thismodelaccountedfortheencap- man, MT). The power spectra of the LFP signals were calculated
sulationlayeraroundtheelectrodeandinvivoimpedancemeasurements using the multitaper method (Mitra and Bokil 2008; Mitra and
(Butsonetal.2007).Extracellularpotentialswereappliedtomulticom- Pesaran 1999; Thomson 2002) implemented in the Chronux tool-
partment cable models of myelinated axons (McIntyre et al. 2002) box (http://chronux.org) to control the bias and variance in the
distributedaroundtheDBSleads,andthediffusiontensortemplateof spectralestimatesofneurophysiologicalsignalsusingthemtspec-
theNHP(Adluruetal.2012)wasusedtoselectaxondirectionsand trumc.m function. The log-transformed power spectra were sub-
locations that met stimulation criterion set during the behavioral jected to a bias-corrected two-group test to adjust for the unequal
experiments. Axon activation maps were generated as point clouds sample sizes that often arise when comparing across treatment
presentingthenodesofactionpotentialinitiationthatmetstimulation conditions (Bokil et al. 2007). At each frequency, the difference
thresholdcriterion.Thesamecharge-balancedasymmetricalbiphasic between the power spectra for the ON vs. OFF DBS periods was
squarepulsesusedduringtheexperimentswereappliedinthemodel, divided by an estimate of the variance in the two-group sample
and the time-dependent transmembrane potentials induced by the (Bokil et al. 2007). In addition, the P values of the resulting
JNeurophysiol•doi:10.1152/jn.01129.2015•www.jn.org
2388 CENTRAL THALAMIC STIMULATION ROBUSTLY MODULATES PERFORMANCE
Z-scores across the power spectra were subjected to a false- analysis described above was conducted on the recorded signals
discovery rate (FDR, P (cid:2) 0.05) test to correct for multiple containing the known sinusoidal test signals (10–50 Hz). In conclu-
comparisons arising from the multiple frequencies in the spectra sion we determined that all electric stimulation artifacts generated
(BenjaminiandHochberg1995).Z-scoresthatpassedscreeningof contributed0dBchangeinallsinusoidaltestsignals(10–50Hz),for
the two-group and FDR tests (two_group_test_spectrum.m) were all DBS lead configurations, stimulation parameters, and intermicro-
used to construct a distribution at each frequency of significant electrode-DBSleadseparationdistances.Afterconductingthesestan-
power differences in the LFPs between DBS ON and OFF condi- dardindustryprotocols,weareconfidentthatthemeasuredchangesin
tions. Z-score means and confidence intervals were computed by the frontostriatal LFP power spectra during all CT-DBS configura-
standard methods. tionsconductedinthisstudyareneurogenicinorigin.
ECoGsignalswererecordedfromacustomarrayof10electrodes
distributed over frontal, temporal, parietal, and occipital cortices. In
this study, a bipolar montage of two midline ECoG electrodes, RESULTS
roughly corresponding to human Fz and Cz, was used to monitor Two adult NHPs (Macaca mulatta) were implanted with
activity throughout each experimental session in both animals. The custom recording and DBS devices (see METHODS) and
power spectra of the Fz-Cz ECoG signal were calculated using the trained to perform several visually guided motor reaction
samemultitaperroutinesasdescribedabove.Asignificantincreasein
time tasks with variable delay periods for water rewards
the power spectra within the low-frequency band (4–12 Hz) was D
(Fig. 1A). In the absence of CT-DBS (Fig. 1, B and C) o
consistentlycorrelatedwitheye-closureandputative“sleep”episodes w
duringtheOFFDBSperiods. batehthaveiostraarltpoefrfaonrmeaxnpceeriomfebnotathl saensismioanlsawndastthyepnicgarlalyduhailglhy nlo
Electrical stimulation artifacts in neurophysiological signals. a
Stimulationartifactsweregeneratedinallneurophysiologicalsignals decreased over time, as observed in other NHPs performing de
d
cwoelrleecutesdedd.uTrihneghCigTh-D-frBeSquwehnecnysntaimtuurelatoifonthaemDpBlitSudpeuslsoefa0f.f5e–c3te.0dmthAe iadl.en2t0ic0a9l)t.asPkesrf(oSrcmhaifnfceetadle.c2r0em13e;nStshaihnceltuadle.d20a0n9;inScmreiathseedt from
majority of microelectrode recordings and precluded the analysis of rateofincorrectand/orincompletetrials,increasedvariance h
unitactivityduringDBSinthisstudy.Duringmonopolarstimulation, of reaction times, and a greater prevalence of eye closures ttp
thhaelf-psraetaumraptiloifine;rth(PeZre2f-o3r2e,wTeucdkiedrnDoatvaisnaTleyczhentohleosgeieds)atwa.asHcolwoseevetro, athnrdoupguhtatpiovwee“rdrflouwcstuinaetisosn”sanindm“sildeleipn”eeFpzi-sCozdeEsC(aosGasresecsosredd- ://jn.p
duringstandardandfield-shapingmultipolarCT-DBStheartifactwas h
well below the saturation point of the preamplifier that included a ings; see METHODS) near the latter half of the experimental ys
sessions (Fig. 1, B and C). This transition in behavioral io
4th-order low-pass (24 dB per octave) at 7.5 kHz anti-aliasing filter lo
for each channel and therefore did not impact the LFP through performance is consistent with a shift from a state of high gy
saturation or aliasing artifacts. All microelectrode broadband signals arousal and motivation at the start of the session to a state, .o
wkHerze.ArecdoigrditeadlBatu(cid:4)tte2r5wkoHrthz,fialntedrt(hfieltfiElCt.omG,4stihgnoarldsewr,e3redBrecpoerrdoecdtaavte1) adsrotwimsieneosns,taanskdlionwcremasoetisv,aotifognr,evaitgeirlasnactiee,tayn,dbovrigedoorm(S,aartnedr byrg/
was used in custom Matlab software (Mathworks, Natick, MA) to et al. 2006). Humans show similar changes in behavioral 1
0
removethestimulationartifactswithoutdistortingthepowerspectrum state when conducting similar long, sequential multitrial .2
of the LFP signals (0.1 to 50 Hz). We tested this assumption by tasks (Paus et al. 1997). 20
randomlyandperiodicallyintroducingaseriesofstimulationartifacts .3
In the two non-DBS sessions shown in Fig. 1, B and C, the 3
waveforms with varying amplitudes to actual non-DBS microelec- animals’ performance begins to decline following trial 600, cor- .1
trode broadband signals and then subjecting them to the above o
respondingto43-to68-mintimeontask.Putativesleepepisodes n
analysis.Thehigh-frequencycomponentsoftheaddedDBSartifacts D
had 0 dB impact on the power spectrum of the LFP signals (0.1 to (indicatedwithgreenmarkingsalongthezeroperformanceline) e
c
50Hz). are seen in both animals. Following trial 600, the CV of the e
m
In addition to the digital signal processing methods described reactiontimesincreasesslightlyfrom0.15to0.17inNHP1,and b
e
above,wefollowedstandardindustryprotocolstotestourrecording inNHP2reactiontimeCVincreasesmarkedlyfrom0.1to0.15, r 1
electronics (TDT RZ2-DAQ) during high-amplitude and high-fre- while average reaction times do not significantly change (rank 2
quencyDBSandforcharacterizingandremovingstimulationartifacts sum, P (cid:7) 0.05). The animals typically remained on task for 80 , 2
0
from biological signals (Stanslaski et al. 2012; and personal corre- and120minuntilsatiated,atwhichpointtheyrefusedtoworkfor 1
6
spondencewithDr.TimothyDenisonatMedtronic,Minnesota,MN).
additionalwaterrewards.DuringCT-DBSexperimentalsessions,
Briefly,thesameAlpha-Omegamicroelectrodes(0.5to1.5M(cid:5))used
timeontaskrangedfrom35to262minforNHP1and35to227
to record broadband (0.1–8,000 Hz) neural activity in the animals
min for NHP2. Shorter experimental sessions presumably re-
wereplacedintoa300mlphysiologicalsalinebathandpositioned20
flected days of lower motivation. In NHP1, 218 experimental
mmfromtheactivecontactsoftwospatiallyseparatedDBSleadsto
approximate the distance between the central thalamic stimulation sessions with CT-DBS were recorded during 137 days and in
locations and the frontal cortex and dorsal striatum of the animals. NHP2, 68 experimental sessions with CT-DBS were recorded
Testswereconductedusingmultipleseparationdistancesbetweenthe during57days(seeMETHODS).
microelectrodesandthetwoDBSleads,rangingfrom1to50mmand Behavioral performance is robustly modulated with central
2 to 4 mm, respectively. Electric stimulation through the DBS leads thalamic deep brain stimulation. Periodic high-frequency
was then introduced to the saline bath using the same standard and fsCT-DBS,whenconductedoverblocksofcontiguoustrials
field-shapingstimulationprotocolswith150-,175-,200-,and225-Hz
(shown as colored regions in Fig. 2A), modulates robustly
stimulationfrequenciesandamplitudesrangingfrom0.25to3.0mA.
the animal’s performance. In this example, only the first
Inaddition,sinusoidaltestsignals(10–50Hz)ofvariousamplitudes
1,600 of 2,500 trials are shown, even though robust modu-
were introduced into the saline bath using a separate copper wire
lation of performance was observed throughout the entire
connected to a function generator, and the signals were recorded
through the microelectrodes using the identical experimental setup, session.Behavioralperformanceisquantifiedusingtheodds
without the animal, to mimic the amplitude of the recorded LFP ratio. The log of this ratio is the log odds ratio (LOR), and
oscillations. The same broadband recording, filtering, and spectral positive LOR values correspond to a greater probability of
JNeurophysiol•doi:10.1152/jn.01129.2015•www.jn.org
CENTRAL THALAMIC STIMULATION ROBUSTLY MODULATES PERFORMANCE 2389
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Fig.2.Centralthalamicdeepbrainstimulationmarkedlyaffectstheanimal’sperformanceonthevigilancetask.A:theperformanceestimateofNHP1onrepeated .p
trialsofthevigilancetaskisshownasasmoothlyvaryingblackline.Performancewasestimatedfromcorrectandincorrecttrialcompletion(Smithetal.2009) h
y
and only the first 1,600 (154 min) of 2,500 (230 min) trials in this example session are shown. Periods of continuous fsCT-DBS are colored according to s
significantbehavioralfacilitation(green)andnonsignificantchangeinbehavioralperformance(gray)basedontheLORvalue(P(cid:2)0.05)foreachperiod.The iolo
sameanode-cathodeconfiguration,rightcaudalcathodecontact0,rostralanodecontact0,andstimulationamplitudeof1.75mAwasusedinallperiodsshown. g
y
Twosegmentsofcontiguoustrialslabeled“induction”and“control”representphasesofbehavioralchangethatoccurredduringtheONandOFFfsCT-DBS .o
paradigm.Notethegeneraldeclineinaverageperformanceduringthe“induction”phase,andthentheeventual“control”ofperformance,establishedaftertrial rg
700(73min).B:reactiontimes(RT)ofcorrecttrialsduringfsCT-DBSONperiodsarecoloredasinAandblackduringOFFperiods.C:theperformanceestimate b/
ofNHP2onrepeatedtrialsofthevigilancetask.Thesameanode-cathodeconfiguration,bilateralcaudalcathodecontact4,rostralanodecontact4wasused y
throughout; however, significant facilitation (green) of performance was observed when stimulation amplitudes ranged from 0.5 to 1.0 mA and consistent 10
behavioralsuppression(red)wasobservedwhenstimulationamplitudesrangedfrom1.5to3.0mA.Asimilardeclineinaverageperformanceisseenduringthe .2
“induction”phaseandwithalesserdegreeof“control”establishedaftertrial700(66min)totrial1600(147min).D:RTofcorrecttrialsduringfsCT-DBSON 20
periodsarecoloredasinCandblackduringOFFperiods. .3
3
theanimalperformingacorrecttrialduringtheDBSperiod. Time-dependent properties of fsCT-DBS behavioral .1
o
Significance of the LOR value (P (cid:2) 0.05) is based on the performance.ModulationofbehavioralperformancebyfsCT- n
D
number of trials in the DBS ON and OFF periods, which DBS displays several time-dependent properties. First, the e
c
were roughly equal in number (see METHODS). influence of fsCT-DBS on performance and reaction times e
m
In Fig. 2A each field-shaping CT-DBS (fsCT-DBS) period is develops over the experimental session. The initial periods of b
e
cwoiltohresidggnrifiaycaonrtlgyrepeonsittoivreeflpeecritotdhseisnigdnicifiatceadncbeyogfretheenL(POR(cid:2)v0a.l0u5e), ftisoCnT-tiDmBeSs pforirmOarNilyfsaCffTec-DtrBeaSctpioenriotidmse(s3,8w5hemres,m1e6d4iacnorreraecc-t r 12
andnonsignificant(P(cid:7)0.05)bygray.Duringtheinitial“induc- trials) are significantly shortened by 40 ms (rank sum, P (cid:2) , 20
tion” phase the majority of LOR values range from (cid:6)2.1 to 0.7 1
0.05)betweentrials200and600comparedwiththeinterleav- 6
(P (cid:7) 0.05) and are colored gray, except for the two periods
ing OFF periods (164 correct trials)(Fig. 2B). However, the
coloredgreen,correspondingtopositiveLORvalues(P(cid:2)0.05)
reductioninreactiontimesdidnotpersistandonce“control”is
that demonstrate a significant facilitation of performance during
established after trial 700 median reaction times are slightly
fsCT-DBS.Duringthe“control”phase,LORvaluesofthefsCT-
increasedandmorevariable(CVof0.16,comparedwithCVof
DBSperiodsareallpositiveandsignificant,rangingfrom3.8to
6.7(P(cid:2)0.05)indicatingrobustfacilitationofperformanceduring 0.07), yet significantly different (rank sum P (cid:2) 0.05) for ON
(400ms,72correcttrials)andOFF(415ms,554correcttrials)
fsCT-DBS.Operationallyinthisstudy,weusetheterms“induc-
fsCT-DBS periods during the remainder of the session.
tion”and“control”tohighlightthetransitiontoanextendedblock
of trials where ON and OFF periods of fsCT-DBS were more Second, the distinct behavioral profiles of “induction” and
positively correlated with correct performance of the task. Of “control” phases observed in NHP1 (Fig. 2B) occurred in 153
note,bothanimalsdidperformduringthe“control”phasewithout of187experimentalsessionswhenfsCT-DBSwasused;how-
fsCT-DBS;thereforeperformancewasnotexclusivelycontingent ever, the duration of the “induction” phase varied across
on fsCT-DBS, as seen in both animals (Fig. 2). Here “control” experimental sessions. In some the shift from “induction” to
representsaperiodduringanexperimentalsessionwhereresump- “control”wasrapid,occurringwithinthefirstorsecondfsCT-
tion of reliable performance from a low or near zero baseline is DBS period ((cid:4)20 min time on task), and for others, the shift
observedinasequenceofblockedtrialsandquantifiedusingthe occurredlater,afterseveralfsCT-DBSperiods,(1–12periods,
LOR. median 2), as seen in Fig. 2B after the 8th fsCT-DBS period
JNeurophysiol•doi:10.1152/jn.01129.2015•www.jn.org
2390 CENTRAL THALAMIC STIMULATION ROBUSTLY MODULATES PERFORMANCE
(first period that is colored green). Importantly, the “control” electric field was generated within the CT using field-shaping
phase observed in NHP1 was never achieved with standard CT-DBSwithinasubsetofDBScontacts.However,adirectly
CT-DBS configurations even though performance could be comparable degree of behavioral control was not achieved in
facilitated (see Fig. 4C). Here, we postulate that the “control” NHP2 and never demonstrated the robust and consistent be-
phase represents a state of performance recovery, whereby havioralresponsetofsCT-DBS,asseenregularlyacrossthe30
fsCT-DBSisabletoboostperformancebacktolevelsachieved mo in NHP1.
earlierintheexperimentalsession.Ofnote,NHP1didresume Behavioral facilitation with fsCT-DBS is restricted to a
performance during the “control” phase without fsCT-DBS range of stimulation amplitudes. Behavioral performance in
whenenoughtimehadelapsedbetweenperiodsofstimulation, bothanimalswasdependentonfsCT-DBSamplitude.InNHP1
as seen around trials 1140 and 1415 (Fig. 2B), demonstrating (Fig. 3A), current levels between 1.0 and 2.5 mA, following
thattheanimalwasstillabletomobilizeitsownresourcesand trial 450, consistently facilitate performance (green periods,
resume performance. Spontaneous resumption of performance positiveLORvalues,P(cid:2)0.05),whilecurrentlevelsbelowor
while in the “control” phase and during OFF fsCT-DBS peri- abovethisrangehavenoeffectonperformance(grayperiods,
ods was observed in all 21 experimental sessions when time Fig. 3A). In NHP2, current levels from 0.25 to 1.25 mA have
between fsCT-DBS ON periods was purposefully extended. either no effect or facilitate performance (Fig. 3C), while
D
Comparable time-dependent effects in behavioral perfor- currents above 1.25 mA consistently suppress performance o
mancewereobservedinNHP2whenasimilarhigh-frequency (red colored periods, negative LOR, P (cid:2) 0.05). wn
fsCT-DBS protocol was used (example session shown in Fig. The relationship between the amplitude of fsCT-DBS stim- lo
a
2D). Here current levels between 0.5 and 1.0 mA either ulation and performance is illustrated by the red curve in Fig. de
d
fbaechialivtaioterdal(pgererfeonrmpearnicoed,s)wohrilehasdtimnouleaftfieocnt a(gmrpaylitpuedreisodasb)oovne 4v,alauefist(oFfiga.24n,dA- oarndderDp)o.lTynhoemfiitaldetomtohnestdriasttersibauntioinnvoefrtLedO-UR fro
m
1.0 mA, colored in red, consistently suppressed performance relationship (Mair et al. 2011; Yerkes and Dodson 1908) h
(Fig. 2D). During the “induction” phase in Fig. 2D, LOR betweenstimulationamplitudeandfacilitationofperformance ttp
values of fsCT-DBS periods are positive but not significant, in both animals. However, this relationship is restricted to ://jn
rangingfrom0.1to0.6(P(cid:7)0.05),whenamplitudesare0.5to amplitudes between 0.25 and 1.25 mA in NHP2 because .p
1.0mAandsignificantlynegative,rangingfrom(cid:6)1.7to(cid:6)5.1 stimulation amplitudes 1.5 mA and above consistently sup- hy
s
(P(cid:2)0.05),whenamplitudesabove1.0mAwereused.During pressed performance. However, this inverted U relationship is io
lo
the “control” phase, stimulation amplitudes between 0.75 and less clear during standard CT-DBS configurations (Fig. 4, B g
y
1.0mAconsistentlyfacilitatedperformance(greenperiods)or andE).Overallbothfield-shapingandstandardconfigurations .o
had no effect (gray periods), while stimulation amplitudes of CT-DBS resulted in both facilitation and suppression of rg
above1.0mA(redperiods)continuedtosuppressperformance performance. b/
y
(Fig. 2D). Overall, the shift from “induction” and “control” The average behavioral change in terms of percentage of 1
0
phases observed in NHP1 were not consistently observed in correct trials, shown for each subset of LOR values as a .2
2
NHP2; however, a resemblance of these “phase” transitions, function of trial number relative to DBS onset illustrates the 0
.3
whereincreasedperformancecorrelatedwithfsCT-DBSinthe overall behavioral effect of CT-DBS (Fig. 4, C and F). Each 3
latter half of the experimental session, was observed in 20 of profile is normalized to pre-DBS baseline performance levels .1
o
46 experimental sessions, occurring on average in the 5th or fordirectcomparisonacrossCT-DBSperiods.Thedarkgreen n
D
6th fsCT-DBS period (range 1 to 12 fsCT-DBS periods), profile, corresponding to fsCT-DBS periods with significantly e
corresponding to (cid:4)50 min time on task. positive LOR values (Fig. 4A) demonstrates a rapid enhance- ce
m
ThemarkedshiftinreactiontimesobservedinNHP1during ment in performance that peaks at the fourth trial post DBS b
the“induction”periodoffsCT-DBS(Fig.2B)wasnotconsis- onset (elapsed time of (cid:4)20 s) and then gradually declines er 1
tentlyobservedinNHP2(Fig.2D).However,reactiontimesin across the 20 trials shown (Fig. 4C). Of note, the decline in 2
NHP2 were influenced by fsCT-DBS, where median reaction performance following the peak, on average, did not fall to , 2
0
times between the start and trial 700 in Fig. 2D exhibit a zeroduringthefsCT-DBSperiodsusedinthisstudy.Standard 1
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gradual increase, from 345 ms to 370 ms, with current levels CT-DBS configurations also resulted in periods of significant
above 1.0 mA during the “induction” phase, consistent with behavioral facilitation; however, the behavioral profile shown
expected increases in reaction times in the later portions of inlightblue(Fig.4C)isnotasrobust,bothintermsofthepeak
experimentalsessions;however,thevarianceinreactiontimes andthedurationofthesustainedperformanceduringCT-DBS.
actuallydecreases,fromaCVof0.18to0.1.Oncebehavioral Ofnote,theaveragebehavioralprofilegeneratedbythefsCT-
“control”wasestablishedaftertrial700,allreactiontimesare DBS parameter sets that produced nonsignificant LOR values
significantly slower (median 480 ms, rank sum P (cid:2) 0.05) but (showninblack)exhibitsaninitialdipinthefirsttrialfollowed
not significantly different between subsequent ON and OFF by a modest increase, a profile not present in the standard
fsCT-DBS periods (Fig. 2D). CT-DBS configurations (Fig. 4C).
During the “induction” phase, behavioral performance was InNHP2,asimilardistributionofLORvalues(Fig.4,Dand
variablyinfluencedbyfsCT-DBS,exceptforreactiontimesin E) and corresponding average behavioral change (Fig. 4F) is
NHP1 (Fig. 2B). However, as time on task increased fsCT- observed, although the robust behavioral facilitation observed
DBS ultimately resulted in an unexpected “control” of behav- inNHP1duringfsCT-DBS(darkgreenprofileinFig.4C)was
ioral performance that was tightly correlated with subsequent not replicated in NHP2 (dark green profile in Fig. 4F). Both
fsCT-DBS ON periods in both animals (Fig. 2, A and C). fsCT-DBS and standard CT-DBS significantly facilitated be-
“Control”ofbehavioralperformanceinbothanimalswasonly havioralperformance(lightblueanddarkgreenprofilesinFig.
achieved with fsCT-DBS and only when a rostral to caudal 4F), to levels comparable to standard CT-DBS in NHP1 (Fig.
JNeurophysiol•doi:10.1152/jn.01129.2015•www.jn.org
CENTRAL THALAMIC STIMULATION ROBUSTLY MODULATES PERFORMANCE 2391
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Fig.3.Therelationshipbetweentheamplitudeofcentralthalamicdeepbrainstimulationandtheanimal’sperformanceonthevigilancetask.A:theperformance .p
estimateofNHP1onthevigilancetaskisshownasasmoothlyvaryingblackline(Smithetal.2009).Periodsofcontinuoushigh-frequencyfsCT-DBSarecolored hy
according to the significance of the LOR value (P (cid:2) 0.05) for each period: behavioral facilitation in green, behavioral suppression in red. and gray for no sio
significantchangeinperformance.Stimulationamplitudes,ranging0.75to3.0mA,arenotedaboveeachfsCT-DBSperiodalongwiththeLORvalue.Thesame lo
anode-cathode configuration, right caudal cathode contact 0, rostral anode contact 0 was used throughout. Note that once “control” of performance was g
y
establishedaftertrial500(57min),stimulationamplitudesbetween1.25and2.5robustlyfacilitatedperformancewhileamplitudesbelowandabovethisrange .o
hadlittleornoeffectonperformance.B:reactiontimesoccurringwithinfsCT-DBSONperiodsarecoloredasinAandblackduringOFFperiods.C:Same rg
asinA,butforNHP2.Inthissession,fsCT-DBSstimulationamplitudesof1.5mAandabovesignificantlysuppressedperformancewhileamplitudesbetween b/
0.25and1.25mAhadeithernoeffectormodestlyfacilitatedbehavioralperformance.Thesameanode-cathodeconfiguration,leftcaudalcathodecontact4, y 1
rostralanodecontact4wasusedthroughout.D:sameasinB,butforNHP2.Inbothanimalsstimulationamplitudemarkedlyinfluencedbehavioralperformance 0
where low and high amplitudes had either no effect or significantly suppressed performance (LOR, P (cid:2) 0.05) and where amplitudes in-between facilitated .2
2
performance,demonstratinganinverted-Urelationshipbetweenstimulationamplitudeandperformance(Mairetal.2008;YerkesandDodson1908). 0
.3
3
4C).Ofnote,fsCT-DBSandstandardCT-DBSdidresultinan and 5) of the caudal DBS leads and anodes placed on the .1
initialdipinperformanceduringnonsignificantperiods(black correspondingcontactsintherostralDBSleads;theeffects, on
and gray profiles in Fig. 4F). The critical finding here is that however, were not as robust as in NHP1. The polarity of D
e
behavioral facilitation in NHP2 only occurred when stimula- stimulation resulted in clear differences in behavioral per- ce
m
tion was restricted to a subset of contacts (3, 4, and 5) on the formance when all inter- and intra-lead CT-DBS configura-
b
two DBS leads indicating a narrow window of behavioral tions were explored in more detail in NHP1 (see Fig. 8). er 1
facilitation effects for this electrode configuration. We carried This novel method of CT-DBS orients the electric field 2
outcomputationalmodelingexperiments(seebelow)toexam- (Butson and McIntyre 2008; Chaturvedi et al. 2012) along , 2
0
ine the relationship of this isolated effect in NHP2 and the the anterior-posterior axis of the brain and across a larger 1
6
impactofCT-DBSusingthecontactsproducingrobustbehav- volume of tissue within the CT than is possible with stan-
ioral facilitation in NHP1 (0, 1, and 2) during fsCT-DBS. dard CT-DBS.
Behavioral facilitation is restricted to a specific polarity of Summary of the effects of field-shaping and standard CT-
fsCT-DBS. The high degree of “control” over behavior was DBS on behavioral performance. A large set of CT-DBS
contingent not only on the amplitude of fsCT-DBS (Figs. 3 parameter combinations in terms of frequency (20, 40, 150,
and 4), but also on the polarity of the electric field estab- 175,200,and225Hz),amplitude(0.25–3.0mA)andanode(s)
lished across the two DBS leads in both animals. In NHP1, and cathode(s) configurations were explored in both animals
tight coupling of behavioral performance to the ON and (Fig. 4). In this study, a total of 2,461 DBS periods are
OFFfsCT-DBSperiods(Figs.2B,3A,and4C)wasobserved analyzedfromNHP1,eachlastinganaverageof32(medianof
only when the polarity of the electric field was arranged in 26)trials,rangingfrom20to500trialsinlength,andinNHP2
arostraltocaudalorientationbyassigningatleastoneofthe 661 DBS periods are analyzed, each lasting an average of 32
anode(s) in the stimulation circuit to contacts 0, 1, and 2 on (median of 31) trials, ranging from 20 to 62 trials in length.
therostralleadandatleastoneofthecathode(s)tocontacts However, only a subset, 123 of 295 configurations in NHP1
0, 1, and 2 on the caudal lead. In NHP2 a similar relation- and 55 of 428 in NHP2, significantly affected behavioral
ship between the polarity of fsCT-DBS and behavioral performance,eitherresultinginfacilitation(positiveLOR,P(cid:2)
facilitation was observed (Figs. 2C and 4F) when cathodes 0.05) or suppression (negative LOR, P (cid:2) 0.05). In summary,
wereplacedonatleastoneoftheupperthreecontacts(3,4, fsCT-DBSresultedingreaterfacilitationofbehavioralperfor-
JNeurophysiol•doi:10.1152/jn.01129.2015•www.jn.org
2392 CENTRAL THALAMIC STIMULATION ROBUSTLY MODULATES PERFORMANCE
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Fig.4.Summaryofcentralthalamicdeepbrainstimulation’sinfluenceontheanimal’sbehavioralperformance.Here,theoddsratioistheprobabilityofthe .1
animalperformingacorrecttrialduringDBSdividedbytheprobabilityofperformingacorrecttrialpriortoDBSonset.Thelogofthisratioisthelogodds o
n
ratio(LOR).PositiveLORvaluescorrespondtoagreaterprobabilityoftheanimalperformingacorrecttrialduringDBS.A:boxplotsofLORvaluesforall D
periodsusingfield-shapingCT-DBS(fsCT-DBS)configurations(N(cid:8)2187)groupedbyamplitudeofstimulation(0.25to3.0mA)forNHP1,recordedacross e
c
195experimentalsessions.ThenumberoffsCT-DBSperiodsconductedforeachamplitudeisnoted.Theredlineillustratesthefitofa2ndorderpolynomial e
functiontoillustratetheinvertedUrelationshipbetweenperformanceandfsCT-DBSamplitude.B:sameasinA,butforallperiodsusingstandardCT-DBS m
configurations(N(cid:8)274)inNHP1,recordedacross72experimentalsessions.C:behavioralperformancecurvesforDBSperiodsinAandB,eachnormalized be
topre-DBSperformancelevels,including(cid:9)95%CI.DBSperiodswithsignificantpositiveLORvalues(P(cid:2)0.05)usingfsCT-DBSconfigurations(N(cid:8)947) r 1
areshownindarkgreenandinlightblueforstandardCT-DBSconfigurations(N(cid:8)36).DBSperiodswithnon-significantLORvalues(P(cid:7)0.05)during 2
fsCT-DBSconfigurations(N(cid:8)1091)areshowninblackandingrayforstandardCT-DBSconfigurations(N(cid:8)220).DBSperiodswithsignificantnegative , 2
0
LOR values (P (cid:2) 0.05) are not shown. The gray shaded region represents the DBS ON period. D: same as in A, but for NHP2, fsCT-DBS configurations 1
(N(cid:8)447)recordedacross46experimentalsessions.E:sameasinB,butforNHP2,standardCT-DBSconfigurations(N(cid:8)214)recordedacross21experimental 6
sessions.F:sameasinC,butforNHP2.
mance (947 in NHP1, 48 in NHP2) compared with standard with NHP2 (Fig. 5, A and E), a phenomenon that has been
CT-DBS (36 in NHP1, 22 in NHP2) (Fig. 4). reported in other NHP studies while recording from similar
LFP activity of frontostriatal recording sites during behavior. frontal(Dotsonetal.2014)andstriatal(Courtemancheetal.
As the animals performed the vigilance task, in the absence 2003) locations as the animals performed similar visuomo-
of CT-DBS, LFP activity recorded from frontal cortices in tor reaction time tasks. Enhancement of “beta-band” LFP
both animals and in striatal populations in NHP1 exhibited
activity is known to occur during periods of movement
graded and task related modulation of spectral power (Fig.
planning and preparation within both frontal (Brovelli et al.
5,A,B,E,andF).Asustainedincreaseofspectralpowerin
2004; Buschman and Miller 2007; Buschman et al. 2012;
the 13- to 25-Hz range, “beta-band,” and a corresponding
Dotsonetal.2014;Pesaranetal.2008;SanesandDonoghue
decrease of spectral power below 10 Hz during the delay
periodofcorrectlyperformedtrials(redcurve,Fig.5,Aand 1993; Verhoef et al. 2011; Witham et al. 2007; Zhang et al.
E)ispresentcomparedwiththepredelayperiodofInCorrect 2008) and striatal (Bartolo et al. 2014; Courtemanche et al.
trials (blue curve, Fig. 5, A and E). Of note, baseline and 2003) regions. Motor planning and preparation were two
peak activity within the “beta-band” range during both operations the NHPs had to organize to successfully com-
Correct and InCorrect trials is different in NHP1 compared plete trials in this study. On average, dynamics within LFPs
JNeurophysiol•doi:10.1152/jn.01129.2015•www.jn.org