Alternating Current Stimulation for Vision Restoration after Optic Nerve Damage

19 Pages·2016·1.74 MB·English

RESEARCHARTICLE
Alternating Current Stimulation for Vision
Restoration after Optic Nerve Damage: A
Randomized Clinical Trial
CarolinGall1☯*,SeinSchmidt2☯,MichaelP.Schittkowski3,AndreaAntal4,Géza
GergelyAmbrus4,WalterPaulus4,MoritzDannhauer5,RomualdaMichalik1,AlfMante2,
MichalBola1,AnkeLux6,SiegfriedKropf6,StephanA.Brandt2,BernhardA.Sabel1
1 InstituteofMedicalPsychology,MedicalFaculty,Otto-von-GuerickeUniversityMagdeburg,Magdeburg,
Germany,2 DepartmentofNeurology,Charité-UniversitätsmedizinBerlin,Berlin,Germany,3 Departmentof
a11111
Ophthalmology,UniversityMedicalCenter,Georg-AugustUniversityofGoettingen,Goettingen,Germany,
4 DepartmentofClinicalNeurophysiology,UniversityMedicalCenter,Georg-AugustUniversity,Goettingen,
Germany,5 CenterforIntegrativeBiomedicalComputingandtheScientificComputingandImagingInstitute,
UniversityofUtah,SaltLakeCity,Utah,UnitedStatesofAmerica,6 InstituteforBiometryandMedical
Informatics,Otto-von-GuerickeUniversityMagdeburg,Magdeburg,Germany
☯Theseauthorscontributedequallytothiswork.
*[email protected]
OPENACCESS
Citation:GallC,SchmidtS,SchittkowskiMP,Antal
A,AmbrusGG,PaulusW,etal.(2016)Alternating Abstract
CurrentStimulationforVisionRestorationafterOptic
NerveDamage:ARandomizedClinicalTrial.PLoS
ONE11(6):e0156134.doi:10.1371/journal. Background
pone.0156134
Visionlossafteropticneuropathyisconsideredirreversible.Here,repetitivetransorbital
Editor:MargaretMDeAngelis,UniversityofUtah,
alternatingcurrentstimulation(rtACS)wasappliedinpartiallyblindpatientswiththegoalof
UNITEDSTATES
activatingtheirresidualvision.
Received:November15,2015
Accepted:May10,2016 Methods
Published:June29,2016
Weconductedamulticenter,prospective,randomized,double-blind,sham-controlledtrial
Copyright:©2016Galletal.Thisisanopenaccess inanambulatorysettingwithdailyapplicationofrtACS(n=45)orsham-stimulation(n=37)
articledistributedunderthetermsoftheCreative
for50minforadurationof10weekdays.Avolunteersampleofpatientswithopticnerve
CommonsAttributionLicense,whichpermits
damage(meanage59.1yrs)wasrecruited.Theprimaryoutcomemeasureforefficacywas
unrestricteduse,distribution,andreproductioninany
medium,providedtheoriginalauthorandsourceare super-thresholdvisualfieldswith48hrsafterthelasttreatmentdayandat2-monthsfollow-
credited. up.Secondaryoutcomemeasureswerenear-thresholdvisualfields,reactiontime,visual
DataAvailabilityStatement:Dataareavailablefrom acuity,andresting-stateEEGstoassesschangesinbrainphysiology.
InstituteforBiometryandMedicalInformatics,Otto-
von-GuerickeUniversityMagdeburgforresearchers Results
whomeetthecriteriaforaccesstoconfidentialdata.
[email protected] ThertACS-treatedgrouphadameanimprovementinvisualfieldof24.0%whichwassignif-
icantlygreaterthanaftersham-stimulation(2.5%).Thisimprovementpersistedforatleast2
Funding:Thisstudywasfundedinpart,bythe
GermanFederalEducationandResearchMinistry, monthsintermsofbothwithin-andbetween-groupcomparisons.Secondaryanalyses
grantERA-netNeuron(BMBF01EW1210)toBAS revealedimprovementsofnear-thresholdvisualfieldsinthecentral5°andincreased
andCG,bytheUniversityofMagdeburg(LOM-grant
thresholdsinstaticperimetryafterrtACSandimprovedreactiontimes,butvisualacuitydid
toMB),bytheGermanResearchFoundation,Grant
notchangecomparedtoshams.VisualfieldimprovementinducedbyrtACSwasassociated
numberBR1691/8-1toSS,andbytheNational
InstituteofGeneralMedicalSciencesoftheNational withEEGpower-spectraandcoherencealterationsinvisualcorticalnetworkswhichare
PLOSONE|DOI:10.1371/journal.pone.0156134 June29,2016 1/19
AlternatingCurrentStimulationforVisionRestoration
InstitutesofHealth(USA)undergrantnumberP41 interpretedassignsofneuromodulation.Currentflowsimulationindicatescurrentinthe
GM103545-17toMD,andbyEBS(Germany).The frontalcortex,eye,andopticnerveandinthesubcorticalbutnotinthecorticalregions.
fundershadnoroleinstudydesign,datacollection
andanalysis,decisiontopublish,orpreparationof
Conclusion
themanuscript.
rtACStreatmentisasafeandeffectivemeanstopartiallyrestorevisionafteropticnerve
CompetingInterests:Theauthorshavedeclared
thatnocompetinginterestsexist. damageprobablybymodulatingbrainplasticity.Thisclass1evidencesuggeststhatvisual
fieldscanbeimprovedinaclinicallymeaningfulway.
Abbreviations:ACS,alternatingcurrentstimulation;
CSF,conductivecerebrospinalfluid;HRP,high
resolutionperimetry;QoL,qualityoflife;tDCS, TrialRegistration
transcranialdirectcurrentstimulation;rtACS,
repetitivetransorbitalalternatingcurrentstimulation; ClinicalTrials.govNCT01280877
VF,visualfield.
Introduction
Opticneuropathyandglaucomaarefrequentcausesofchronicblindness[1].Afteraspontane-
ousrecoveryperiod,visualfield(VF)lossisconsideredirreversiblewhichcompromisesvision-
relatedqualityoflife(QoL)[2–4].Asystematicsearchforameanstoimprovesuchvisionloss
isurgentlyneeded.
Transcranialdirectcurrentstimulation(tDCS)andalternatingcurrentstimulation(ACS)
ofthebrainarenewmethodstomodifybrainexcitabilityandsynchronicityinhealthysubjects
andpatientswithbraininjuriesaffectingdifferentmodalitiessuchasthemotor[5],language
[6],orsomatosensorydomains[7].Inthevisualsystem,exploratoryevidenceindicatesthat
ACScanenhanceneuronalfunctionbothinnormalsubjects[8–9]andinpatientswithVFloss
whostillhavesomeresidualvision[10].Theproposedmechanismofactionisneuromodula-
tionofoscillatorybrainactivitytowardsamoresynchronizedEEGviaentrainmentofspecific
stimulationfrequencies[10–11],andthereorganizationofbrainfunctionalconnectivitynet-
works[12]isconsideredtobeanovelandpromisingavenueforvisualrehabilitation[13].
Inasmallsamplestudy,ACSwasdeliveredinfrequenciesrangingfromthetatohighbeta
viaelectrodesplacedneartheeyetore-activateresidualvisioninopticneuropathy[14].Here,
10dailyrtACSsessionsincreasedlightdetectionperformanceandimprovedpatient-reported
vision-relatedQoLwhichwasmoderatelycorrelatedwithVFgains[15].Theseimprovements
wereassociatedwithincreasedalpha-poweratoccipitalsitesinresting-EEGs[14,16]and
increasedneuronalsynchronizationoffunctionalconnectivitiesbetweentheoccipitaland
frontalregions[12].Yet,thelevelofclinicalevidenceisstillnotdefinitivebecausethetrials
includedonlysmallpatientsamples[12,14–16].Wehypothesizedthatefficacyandsafety
couldbedocumentedinalargersampleprospectivetrial.
Wenowreportthefirstconfirmatory,large-sample,doubleblind,randomized,multi-center
clinicaltrialtoestablishtheefficacyandsafetyofrtACSstimulationinpatientswithvision
impairmentscausedbyopticnervedamage.
Methods
Studydesign
ThetrialflowdiagramandstudydesignareshowninFig1Aand1B.Diagnosticevaluations
wereconductedatBASELINE,aftercompletionofthe10-daytreatment(POST),andaftera
2-monthtreatment-freeinterval(FOLLOW-UP).TheCONSORTchecklist(S1File)andstatis-
ticalanalysesprotocol(S2File)areincludedassupportinginformation.
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Fig1.Consortflowchartandstudydesign.(A)Patientflowforcasesincludedintheprimaryoutcome
measureanalysis.Of98eligiblepatients,45weretreatedwithrtACSand37withsham-stimulation.Five
subjectsleftthestudybetweeninitialscreeningandBASELINEfordifferentreasonsandanotherfive
subjectswereexcludedduetoviolationofaninclusioncriterion(unacceptablefluctuationsbetweeninitial
screeningandBASELINE).Duringthetreatmentphasethreesubjectsdroppedoutbecauseofmedical
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conditionsthatwereunrelatedtostudyparticipation.Threetreatedcasesoflegallyblindsubjectswere
excludedfromsubsequentanalysesduetoviolationofinclusioncriterion(noresidualvision).(B)Study
designwithdiagnosticandtreatmentvisits.RandomizationwasdoneafterBASELINEassessment.Stability
ofVFdefectswasascertainedbycomparingVFsatBASELINEwiththoseobtainedduringthescreeningvisit
2weeksearlier.Uponcompletionofthe10-daytreatment,allinitialdiagnostictestswererepeated(POST).
TheFOLLOW-UPdiagnosticassessmentwasconductedafteratherapy-freeintervalofatleast2months.
doi:10.1371/journal.pone.0156134.g001
Thestudydesignwasprospectiveanddoubleblind;neitherthepatientsnorthediagnostic
examinerswereawaretowhichtreatmentarmthepatientbelonged.Forallocationconceal-
ment,patientsofthesham-groupreceivedminimaldosestimulation.Theinvestigatoradmin-
isteringthetreatmentwasawareofthegroupidentitybutwasinstructednottorevealtothe
patientswhichtreatmenttheyreceived.Patientswereinformedtowhichgrouptheybelonged
onlyaftertheFOLLOW-UPtests,andallsham-stimulationpatientswereofferedrtACS.
Informedwrittenconsentwasobtainedpriortorandomization.Studyparticipantsreceiveda
compensationforstudyparticipation.Theethicscommitteesoftheparticipatingstudycenters
inMagdeburg,Berlin,andGoettingenapprovedthestudy,andastatisticalanalysisplanwas
filedwiththeleadethicscommittee.ThestudywasconductedaccordingtotheDeclarationof
HelsinkiandregisteredatClinicalTrials.gov(NCT01280877).ThetrialwasregisteredinJanu-
ary2011uponreceivingapprovalfromtheleadingethicscommitteeinDecember2010.The
daterangeforpatientrecruitmentandfollow-upwasfromDecember2010untilFebruary
2012.Theauthorsconfirmthatallongoingandrelatedtrialsforthisinterventionare
registered.
Studysampledescription
Patientswhosufferedvisualfieldlosscausedbyglaucoma(n=33)orAION(n=32)wereran-
domized.Thefollowingetiologiesofopticatrophywerealsoincluded:post-acuteinflamma-
tion(n=12),opticnervecompression(n=5,ofwhich4weretumor-inducedand1
intracranialhemorrhage),congenitalorunknownetiologyofopticatrophy(n=5),andLeber's
hereditaryopticneuropathy(n=3).Eightpatientshadtwoconcomitantdiagnosesofoptic
nerveatrophy.Thesamplesizesateachstudycenterwereasfollows:CharitéBerlin(n=33),
Otto-von-GuerickeUniversityMagdeburg(n=31),andDepartmentofOphthalmology,
Georg-AugustUniversityofGoettingen/EyeClinicKassel(n=18).Table1summarizesthe
demographicsandlesionvariables.WithrespecttoBASELINEvariables,resultsdidnotsignifi-
cantlydifferbetweenthertACS-andthesham-group(Table2).
Samplesizeandrandomization
ThesamplesizecalculationwasbasedonresultsoftwoearlierpilotstudiesattheInstituteof
MedicalPsychology(UniversityofMagdeburg)consideringsimilarpatientsandequivalent
stimulationschemes,i.e.,rtACS-andsham-groupsasinthepresenttrial.Inthefirsttriala
meanpercentageincrease(±standarddeviation)of65.61±104.35wasobservedinthertACS-
group(n=19)and16.93±31.22inthesham-group(n=14).Thecorrespondingresultsofthe
subsequenttrialwere30.68±41.97inthestimulationgroup(n=12)and9.57±12.05(n=13)
fortheshamgroup.Usingthesemeansandstandarddeviationsinasamplesizecalculation
(α=0.05,two-sided,power1–β=0.80)foratwo-samplet-test(Satterthwaiteversion)with
nQueryAdvisor7.0resultedin41patientspergroupforthefirsttrialand36patientsper
groupforthesecondtrial.Therefore,weadoptedaconservativeapproachofconsideringupto
10percentdrop-outandplannedtorecruit45patientspergroup.Patientswereassignedto
eitherthertACS-orthesham-groupby“RandomizationInTreatmentArms”software(RITA,
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Table1. Patients’demographicsandlesioncharacteristics.
rtACS-group Sham-group p
Samplesize,n 45 37
Age(years),mean±standarderrormean(SEM) 57.8±14.2 60.7±11.6 0.563
Male,(%) 71.1 40.5 0.005
Lesionage, 6–12months(%) 13.9 7.4 0.206
righteye 1–2years(%) 8.3 0.0
>2years(%) 77.8 92.6
Lesionage, 6–12months(%) 8.3 14.8 0.468
lefteye 1–2years(%) 16.7 7.4
>2years(%) 75.0 77.8
singlediagnosis 88.9 89.2 0.965
dualdiagnosis 11.1 10.8
Binocularlesionsn(%)1 60.0 46.0 0.442
Monocularlesions,oneeyeintact(%) 31.1 45.9
Monocularlesions,oneeyeblind(%) 8.9 8.1
1Incaseswithbinocularvisionlossbotheyeswereaveragedforsubsequentanalyses.P-valuesarereportedforWilcoxon-Mann-WhitneyUtests,two-
sidedandPearson-Chi-Squaretests,two-sided.
doi:10.1371/journal.pone.0156134.t001
StatSol,Lübeck)withstratifiedblockrandomizationconsideringthestudycenterandtheVF
defectdepthatBASELINEaspotentialprognosticfactors.Highvs.lowdefectdepthwas
definedasstimulusdetectionratesbelowvs.above30%insidetheVFdefect.
Randomizationresultedincomparableaveragebaselinesituationanddemographicsinthe
rtACS-andsham-group.Onlythepercentageofmalesvs.femaleswasunequallydistributed
butthiswasindependentofstudyresults.
Inclusionandexclusioncriteria
Thefollowingcriteriawereestablishedprospectively.Inclusioncriteriaincluded:(i)stableVF
defectwithresidualvisionasdetectedbysuper-thresholdperimetrytesting(HRP,cut-off1.5%
inatleastoneeye);(ii)lesionage>6months;(iii)patientage>18yrs;(iv)compliancewith
theexperimenters’instructionsduringdiagnostictesting;and(v)sufficientfixationability.
Exclusioncriteriaincluded:electricorelectronicimplants(suchascardiacpacemaker);any
metalartifactsintheheadortruncusarea(withtheexceptionofdentalimplants);epilepsyand
photo-sensibility;acuteauto-immunediseases;psychiatricdiagnoses;diabeticretinopathyor
otherdocumentedretinalimpairments;highbloodpressure(>160/100mmHg);acutecon-
junctivitis;retinitispigmentosa;pathologicalnystagmus;anunstableorhighlevelofintraocu-
larpressure(>27mmHg);andpresenceofanun-operatedtumororcancerrecurrence
anywhereinthebody.
Statisticalanalysesandstudyendpoints
Primarydataanalysiswasconductedindependentlybythebiometrydepartmentoftwoofthe
coauthors(A.L.,S.K.)andincludedsamplesizecalculation,statisticalanalysisplan,initializa-
tionofrandomizationanddatasourceverification.Primaryandsecondaryendpointswere
definedprospectively.
VFmappingwasconductedusingacampimetric,high-resolution,super-thresholdvisual
detectiontest(HRP)[17],amethodthatrevealsareasofresidualvisioninthecentralVFwith
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Table2. VisualfieldcharacteristicsatBASELINEaccordingtotreatmentarms.
rtACS-group Sham-group p
High-resolutionperimetry
DetectionaccuracywholeVF(%) 44.59[25.18;63.82] 53.48[37.34;75.70] 0.142
DetectionaccuracydefectiveVFsectors(%)1 17.92[12.06;31.03] 23.31[14.37;38.94] 0.228
Detectionaccuracywithin5°VF(%) 56.25[34.38;75.35] 62.50[45.83;76.74] 0.459
Fixationaccuracy(%) 91.70[83.46;97.26] 94.25[84.40;97.51] 0.586
Falsepositivereactions(%) 2.18[0.85;4.00] 1.30[0.49;3.57] 0.155
ReactiontimewholeVF(ms) 525[461;575] 509[463;569] 0.394
ReactiontimeHRPdefectiveVFsectors(ms) 554[510;581] 544[485;575] 0.261
Reactiontimewithin5°VF(ms) 484[432;565] 480[429;519] 0.554
Standardautomatedperimetry
Fovealthreshold,staticperimetry(dB) 21.25[15.50;27.00] 25.00[19.00;28.50] 0.113
Meanthreshold,staticperimetry(wholeVF,dB) 8.78[5.91;15.74] 11.95[6.7;15.97] 0.320
Fixationaccuracy,staticperimetry(%) 93.81[69.25;100] 94.87[86.13;100] 0.259
Meaneccentricity,kineticperimetry(degree) 46.82[34.29;55.40] 48.13[28.09;56.38] 0.899
MeanVFsize,kineticperimetry(squaredegree) 7280[4461;9743] 7907[3131;10053] 0.817
Visualacuity(logMAR)2
Uncorrectednearvision(n=77) 0.75[0.45;1.10] 0.80[0.60;1.10] 0.267
Uncorrectedfarvision(n=69) 0.50[0.29;0.92] 0.44[0.22;0.70] 0.708
Resultsaregivenasmediansandinterquartileranges.Thegroupsdidnotdiffersignificantlyinanyofthe
BASELINEmeasures(Wilcoxon-Mann-WhitneyUtests,two-sided).
1Tobalancethegroupsforrandomizationwithrespecttodefectdepth,theBASELINEVFdefectwas
classifiedashavingahighorlowdefectdepthwithathresholdof30%detectionaccuracyinthedefective
VF.Basedonthisclassification,55patients(67.1%)belongedtothehighand27(32.9%)tothelowdefect
depthgroup.Between-groupdifferencesoftheBASELINEdiagnosticvalueswerenotstatistically
significantinanymeasure(Wilcoxon-Mann-WhitneyUtest,two-sided).
2Visualacuitywascalculatedforallpatientswithbettervisualacuitythancountingfingers(logMAR=3).
Therefore,fivesubjectshadtobeexcludedfromtherecordingofnearvisionand13subjectsfromfar
visionacuity.
doi:10.1371/journal.pone.0156134.t002
lowerinter-test-variabilitythanstandardstaticperimetryduetotargetluminanceabove
threshold.Inadarkenedroom,thepatientwasviewinga17"monitorfromachin-head-restat
adistanceof42cm.Whitetargetstimuliwerepresentedatrandominagridof25x19stimulus
locationsandthetaskwastohitthespacebar.Theprocedureincludedafixationcontrolusing
isoluminantcolorchangesofthefixationpoint.Eyeswithintactvisionorcompleteblindness
werenotconsidered.Theprimaryendpointwas“percentchangeoverBASELINE”intheHRP
detectionrate.
SecondaryendpointsofHRPwerepercentagechangeofthestimulusdetectionrateinthe
defectiveVF(excludingintactareas),thecentral5°-VF,andaveragereactiontimeintotalHRP
VF.Furthersecondaryendpointswerestaticandkineticperimetryresults(fovealandmean
thresholdof30°-VFs,meaneccentricity/VFsize),bestcorrectednearandfarvisualacuity
(Landolt),andpatient-reportedoutcome,i.e.,anintervention-relatedquestionnairewitha
structuredresponseformatandavision-relatedQoLquestionnaire(NEI-VFQ-39)[18]toeval-
uatesubjectiveimprovementsof“visualfielddefectandrelatedimpairments”(15items)and
“generalhealthandmentaldistress”(fouritems)atPOSTandFOLLOW-UP.Concerning
staticperimetryfovealthresholdandmeanthresholdof30°-VFswereobtained.Afast
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thresholdstrategywasusedtodeterminethresholdvaluesat66positionswithinthe30°visual
field.Targetstimuli(size:III/4mm2,white,luminance:318cd/m2/0db,duration:0.2sec)were
presentedonabackgroundwithconstantluminanceof10cd/m2.Meanthresholdreferstothe
averagedBvaluesof66testpositions.InkineticperimetrytheVFborderwasdeterminedfor
24meridians(spacedby15°)inrandomizedorderataconstantluminancethresholdofIII/4e
(0dB)andavelocityof2°persec.Meaneccentricityreferstotheaverageof24meridians.
MeanvisualfieldsizereferstotheareainsidetheVFborderinkineticperimetry,i.e.,thesum
of24triangles(XaxiseccentricitymultipliedbyYaxiseccentricity/2).
ThepercentchangeoverBASELINEwasdeterminedat48hrs(minimuminterval)after
thelaststimulationday(i.e.,the10thstimulationsession)(POST)andat2monthsFOL-
LOW-UP(FU)foreachendpointas100(cid:1)(POSTresp.FOLLOW-UP–BASELINE)/BASE-
LINE.HRPreactiontime(absolutedifferences),visualacuity(logarithmicvalues)and
questionnairedatawereshownasabsolutevalues.Forbinoculardefectsthevalueofboth
eyeswasaveraged.Sincetherewerenocentereffects(neitherasthemainfactornorasan
interactionwiththetreatmentarm),nordependenciesofBASELINEresultsfortheprimary
endpoint,theprimarydataanalysisandsecondarybetween-groupcomparisonswereper-
formedforthepre-definedhypothesiswithaone-sidedU-test(p-value<0.05).TheHodges-
Lehmanneffectestimatorand95%-confidenceintervals(CI)arereported.Within-group
comparisonswerecalculatedwithWilcoxonmatched-pairssignedrank-tests.Analyseswere
doneinMatlabR2011bandSPSS21.
EEGpowerspectraafterrtACS
Allsubjectswereseatedinadimlylitroomandinstructedtokeeptheireyesclosedduringthe
wholerecordingsession.Electroencephalography(EEG)wasrecordedfor2minbeforeand
aftereachstimulationsessionusing16electrodes(10–20system)withimpedances<10kΩ
witheyesclosed(atrest)inadarkenedroom.TheEEG-signalatoccipital(O1,O2)areasof
interest(AOIs)wasreferencedagainstthegrand-averageandpreprocessedwithASA™-soft-
ware(ANT,Enschede,Netherlands)includingabandpass-filter(0.5–40Hz,filter-slope24dB/
oct.),2secbins,andbaselinecorrection.Power-spectraatoccipitalsitesO1andO2were
assessedwithFastFourierTransformation(FFT)todeterminebandwidthspecificpower
(μV2)withautomaticartifact-rejection(min/maxallowedamplitude:±75.00μV),normalized
power-spectraandDC-correctionduringFFT-averaging.Restingstateeyes-closedEEGimme-
diatelybeforeandafteronedayoftreatmentwasanalyzedafterthefirstrtACSsession.The
EEGdatawereanalyzedin3steps.First,wedefined5spectralbands:delta,1–3Hz;theta,3–7
Hz;alpha(alphaI),7–14Hz;andbeta,14–30Hz.Between-groupcomparisonswereconducted
withindependentsamplesttest.TheeffectsofrtACSorsham-stimulationonEEGmeasures
wereanalyzedasΔEEG=EEGpost−EEGpre.Toassessfunctionalinteractionsbetweenbrain
regionscoherencewasanalyzedindicatingcouplingbetweentwosignalsasafunctionoffre-
quency[19].Coherencewascalculatedforeachpairofchannelsijanddefinedasfollows:
jS ðfÞj2
C ðfÞ¼ ij
ij S ðfÞS ðfÞ
ii jj
InthisequationSdenotesthespectrumofsignalsfromtwoEEGchannelsiandj,fora
givenfrequencybinf.
Changesinspectralpowerofoscillatorybrainactivityandstrengthoffunctionalconnectiv-
ityoverthevisualcortexafterthefirststimulationsessionwerethenrelatedtotheprimaryout-
comemeasure.ToassesstherelationshipbetweenEEGandprimaryoutcomemeasures,
Spearmancorrelationcoefficientwasused.
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Repetitivetransorbitalalternatingcurrentstimulation
AfterBASELINEassessmentspatientswerestimulatedwitheitherrtACSorsham-stimulation
on2×5weekdaysfor25minatday1to50minatday10witheyesclosed.Four10mmGrass
goldelectrodes(SAFELEAD™,Astro-Med,Inc,USA),2foreacheye,wereplacedontheskin
neartheorbitalcavity(“transorbital”),andbiphasicsquare-pulseswereappliedinbursts
(AlphaSYNCstimulator,EBSGermany).Thereturnelectrode(stainlesssteelplate,32x30
mm)waspositionedontherightarm.Stimulationcurrentstrengthwas125%ofphosphene
thresholdrecordedduring5Hzstimulation.rtACSwasconductedwithfrequenciesbetween
8–25Hz.Toconcealgroupidentity,sham-patientsreceivedonlyoneACSburstperminute
(“minimal”stimulation)tocreatephospheneexperiences.
Safety
Possiblesideeffectswereevaluatedbyasemi-structureddailyinterviewthatincludedqueries
onmildheadache,discomfort,andvertigoasexpectedminoradverseevents.Patientswerealso
askedattheendofeachdailystimulationsessionandatPOSTandFOLLOW-UPtoreport
anyadverseeffects,suchasuncommonoruncomfortablesensations.
Simulatingalternatingcurrentflow
ForassessingcurrentflowpropertiesofrtACS,asinglecomputersimulationwasperformedto
mimicstimulationusinganelectrodeplacedovertherighteyeandreturnelectrodeattheneck
regionofthesubject.Althoughfourelectrodeswereusedfortreatment,theywereonlyused
oneatatime.Therefore,thecurrentflowsimulationwasdoneonlywithoneelectrode,repre-
sentingallotherelectrodes.Afiniteelementmodelwasdevelopedusingmulti-modalimaging
data(MRI/CT)ofa40-yrs-oldmale.Isotropicconductivitieswereassignedtoheadtissues
suchasscalp,cerebrospinalfluid,grayandwhitematter(0.43,1.79,0.33,0.142;[20]),airpock-
ets(1e-6S/m),skull(0.01S/m[21–22],andeyetissue(0.6,1.05,0.4S/mforsclera,intraocular
andnervetissue[23].Onecircularelectrode(height/diameter:3/10mm,conductivity:1.5S/
m)wasplacedabovethesubject'srighteyebrowandareturnelectrodewasmodeledasthelast
axialsliceoftheneckregion(SCIRunsoftware,currentinjection:+/-0.5mA[21].Thesimula-
tionrepresentsaquasi-staticsolutionoftheMaxwellequationsandservesasanapproximation
forcurrentdensityestimationofonetimesampleduringrtACSwhenthecathodeandanode
reachesitsmaximalcurrentintensityvalue.
Results
Safety
Noneoftheparticipantsreporteddiscomfortduringthestimulation.Oneseriousadverse
eventwithsubsequenthospitalizationoccurred,butitwasunrelatedtortACS.Transientver-
tigowasreportedbytwortACS-subjectsinatotaloffivesessionsandonesham-subjectexperi-
encedpersistentvertigofor0.5hrsaftereachsession.Temporarydizzinesswasreportedonce
afterasinglertACS-session.Mildheadacheduringasinglestimulationsessionwasreported
oncebyanrtACS-subjectandoncebyasham-subject.Furtherreportsweremildheadaches
immediatelyafterastimulationsessionbyfourrtACS-andtwosham-subjectsandcutaneous
sensationsineightsham-and12rtACS-subjects.Backpainandstiffneckwerereportedby
onertACS-subjectonthefirstfourstimulationdays.Thissubjectdroppedoutofthestudy.
Concerningautonomicactivity,wedidnotobservemeaningfulchangesinducedbyrtACS
(pre-sessionrtACSvalues:systolicpressure131.54±1.94mmHG,diastolicpressure
82.81±1.72mmHg,heartrate72.82±1.02,post-sessionrtACSvalues:systolicpressure
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129.19±2.94mmHg,diastolicpressure82.20±1.24mmHg,heartrate70.69±0.99;means
andSEM).
Primaryoutcomemeasure
Concerningtheprimaryoutcome,percentchangeoverbaselineindetectionratesinVFtests,
rtACS-treatedpatientsshowedsignificantlygreaterimprovementsthansham-treatedpatients
(p=0.011,Mann-WhitneyU,Fig2A).DuetothehighernumberofrespondersinthertACS-
groupthemeanimprovementofVFsatPOSTwas24.0%detectionaccuracyafterrtACSvs
2.5%aftersham-treatment.Thecorrespondingeffectestimatorofthemediandifference
(BASELINEvs.POST)betweentreatmentarmswas5.0%,CI[0.6;10.0].WhilethertACS-
groupexhibitedsignificantimprovementsinBASELINEvs.POSTcomparisonsofmedians
(Hodges-Lehmann-estimator6.4%,CI[2.9;11.6],p<0.001(Wilcoxonsignedranktest,one-
sided),thesham-groupdidnot(1.1%,CI[-2.0;4.3]).Fig2BdepictsHRPvisualchartsoftwo
patientswiththegreatestimprovementsintheprimaryoutcomemeasureinbothgroups.Reli-
abilityparametersofHRPandeye-trackingdocumentedexcellentretinotopicreliabilityofthe
primaryoutcomemeasure,validatingthatimprovedvisualdetectioncouldnotbeexplainedby
alteredeyemovements(S2Fig).
Secondaryoutcomemeasures
Table3summarizestheresultsofthetrial.Themedianbetween-groupdifferenceinpercentage
detectionratechangeinthedefectiveVFdidnotreachstatisticalsignificance,(8.2%CI
[-5.9%;22.5%,p=0.131)becausethisparametersignificantlyincreasedinbothgroups;by
41.3%(CI[31.5;54.3])inthertACS-and33.2%(CI[23.4;44.2])inthesham-group(both
p<0.001).ReactiontimechangesinHRPimprovedinthertACS-group(median)by8ms,(CI
[-16;0],p=0.023),withatrendinthesham-groupof4ms(CI[-15;2],p=0.069);thebetween-
groupdifferencewasnotsignificant(p=0.35).Othersecondaryoutcomemeasuresobtainedat
POSTdidnotrevealsignificantbetween-groupdifferences.Forexample,visualacuitydidnot
changesignificantly(Table3).
After10daysrtACS,themeanthresholdinstaticperimetry(medianchange9.3%;CI
[2.6;20.3],p=0.003)significantlyincreasedwhileaftersham-stimulationnosignificantchange
inthresholdinstaticperimetrywasnoted(medianchange1.9%;CI[-4.8%,8.8%]).Concerning
meanVFsizeobtainedinkineticperimetry,aclinicallynegligiblebutstillsignificantincrease
wasobservedinbothgroups(medianchangeafterrtACS4.3%[-0.3%,11.9%];p=0.036,and
aftersham-stimulation4.8%[-1.5%,16.1%],p=0.040).
Additionally,atBASELINE,POSTandFOLLOW-UP,patientscompletedaneuropsycho-
logicaltestbatterythatincludedanalertnessreactiontimetest,andatrail-makingpaper-pen-
cil-test.Performanceinthesetestsremainedlargelyunchangedinbothgroups.However,a
significantincreaseinreactiontimeinthealertnesstestwasobservedinthertACS-butnotin
thesham-group(S1Table).ImprovementsintheperformanceoftheTrailMakingTestwere
observedinbothgroups.
Outcomeassessmentat2-monthsFollow-Upandoutcomeprediction
ThedifferencesbetweenFOLLOW-UPandBASELINEaresomewhatsmallerthanthediffer-
encesbetweenPOSTandBASELINEwithapersistentsignificanteffectintheprimarymeasure
detectionaccuracyinHRPintermsofbothwithin-andbetween-groupcomparisons,indicat-
ingthestabilityofthegains(Fig2A).Interestingly,atFOLLOW-UPstaticperimetrythresh-
oldsincreasedbeyondPOST-levelsinthertACS-groupandreachedlevelssignificantlyhigher
thanatBASELINE(medianchange11.7%;CI[3.7;29.5];p=0.001)whichwasnotobservedin
PLOSONE|DOI:10.1371/journal.pone.0156134 June29,2016 9/19
AlternatingCurrentStimulationforVisionRestoration
Fig2.PerimetrymeasuresandEEG.(A)PrimaryandsecondaryanalysesofVFoutcomebetween-andwithin-groupsafter
rtACSandsham-stimulationbarchartsofprimary(firstuppergraph)andsecondaryparametersofVFdiagnosticsmeasured
usingHRPandstandard-automatedstaticandkineticperimetry.Resultsaregivenasmediansand95%-CI.Between-group
comparisonswereperformedaccordingtoapre-definedhypothesisusingaone-sidedU-test.Within-groupBASELINEvs.
POSTandBASELINEvs.FOLLOW-UPcomparisonswerecalculatedseparatelyforeachtreatmentarmusingWilcoxon
PLOSONE|DOI:10.1371/journal.pone.0156134 June29,2016 10/19