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Falten més estudis conductuals amb animals afectats de tinnitus i hiperacúsia
1. REVIEW ARTICLE
published: 17 September 2014
doi: 10.3389/fneur.2014.00179
Behavioral models of tinnitus and hyperacusis in animals
Sarah H. Hayes1*, Kelly E. Radziwon1, Daniel J. Stolzberg2 and Richard J. Salvi 1
1 Center for Hearing and Deafness, Department of Communicative Disorders and Sciences, University at Buffalo, The State University of NewYork, Buffalo, NY, USA
2 Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University ofWestern Ontario, London, ON, Canada
Edited by:
Arnaud Norena, Université de
Provence, France
Reviewed by:
Martin Pienkowski, Salus University,
USA
Alexander Galazyuk, Northest Ohio
Medical University, USA
*Correspondence:
Sarah H. Hayes, Department of
Communicative Disorders and
Sciences, Center for Hearing and
Deafness, University at Buffalo, The
State University of NewYork, 137
Cary Hall, 3435 Main Street, Buffalo,
NY 14214, USA
e-mail: shhayes@buffalo.edu
The phantom perception of tinnitus and reduced sound-level tolerance associated with
hyperacusis have a high comorbidity and can be debilitating conditions for which there
are no widely accepted treatments. One factor limiting the development of treatments for
tinnitus and hyperacusis is the lack of reliable animal behavioral models of these disorders.
Therefore, the purpose of this review is to highlight the current animal models of tinnitus
and hyperacusis, and to detail the advantages and disadvantages of each paradigm. To
date, this is the first review to include models of both tinnitus and hyperacusis.
Keywords: tinnitus, hyperacusis, lick suppression, operant conditioning, startle reflex, reaction time, behavior
INTRODUCTION
Subjective tinnitus refers to the perception of a sound in one or
both ears, or from inside the head, in the absence of an external
acoustic source (1, 2). The phantom sound of tinnitus is a serious
condition affecting 10–15% of the general population, with ~1%
of the population experiencing a debilitating form of chronic tin-nitus
that interferes with daily life (3). Hyperacusis, defined as a
hypersensitivity to moderate-intensity sounds (4–7), is a condi-tion
affecting ~6% of the general population and often co-occurs
with tinnitus (4). The prevalence of hyperacusis in the tinnitus
population has been estimated to be as high as 80% (8), suggest-ing
a common mechanism of dysfunction for these two perceptual
disorders.
At present, the neural basis of tinnitus and hyperacusis remains
elusive, and there are no widely accepted treatments or cures for
individuals suffering from these conditions. However, studies in
both humans and animals have led to a number of proposed
neurophysiological models thought to underlie these conditions
including tonotopic map reorganization, changes in spontaneous
activity, or altered neural synchrony along the auditory pathway
[for review, see Ref. (9)]. Rigorous testing of these hypotheses, as
well as screening for potential therapeutic treatments, requires a
reliable animal behavioral paradigm that not only identifies ani-mals
with tinnitus and/or hyperacusis but also allows for the use of
invasive techniques, such as electrophysiological recordings from
the brain and neuroanatomy, which are inappropriate for use in
human patients.
In order to identify and investigate potential underlying mech-anisms
of tinnitus and hyperacusis, a number of animal models
have been developed (10–15). Since an animal cannot directly
communicate its subjective experiences,behavioral paradigmsthat
extrapolate an animal’s perception based on changes in behavioral
performance have been devised to indicate whether an animal is
experiencing tinnitus and/or hyperacusis. Such paradigms have
utilized a number of behavioral training techniques including lick
or lever pressing suppression (10–14), two-choice operant con-ditioning
(16–18), and reflex modification (15). Ultimately, any
behavioral model of hyperacusis or tinnitus should closely mirror
what we know about these disorders in the human population.
When evaluating animal models of tinnitus and hyperacusis, a
number of important factors should be considered, including
whether the method, time-course, and variability of tinnitus or
hyperacusis induction, aswell as any measures of pitch or loudness,
are consistent with evidence from human tinnitus/hyperacusis
patients. Furthermore, behavioral paradigms should be resis-tant
to confounding influences, such as hearing loss, that often
accompany noise or drug-induced tinnitus/hyperacusis.
Thus, the goal of this review will be to evaluate current ani-mal
behavioral models of tinnitus and hyperacusis with a focus
on the most widely used and newest paradigms in the literature.
For each paradigm, a brief summary will be provided as well as a
discussion of the paradigm’s major advantages and disadvantages.
Important factors such as consistency with the human condition
and resilience to the secondary effects of drug or noise exposure
will also be discussed. Although previous reviews have thoroughly
evaluated many of the proposed animal models of tinnitus (19–
25), to our knowledge, this review will be the first to incorporate
evaluations of animal models of hyperacusis, as well as models of
tinnitus, which is necessary given the frequent co-occurrence of
these two disorders.
HUMAN STUDIES OF TINNITUS
In order to evaluate animal models of tinnitus, it is important
to have an understanding of the key characteristics of tinnitus in
the human population. Much of what we know about the fea-tures
of tinnitus comes from subjective descriptions by tinnitus
www.frontiersin.org September 2014 | Volume 5 | Article 179 | 1
2. Hayesetal. Animal modelsoftinnitusandhyperacusis
patients.Studiesinwhichtinnitusisinducedinindividualsfol-
lowingexposuretoloudsoundorototoxicagents,aswellasstudies
ofindividualswithlong-standingtinnitus,provideuswithinfor-
mationregardingtinnituspitch,intensity,timecourseforonset
followingexposure,andvariabilityofinduction.
Measurementsoftinnituspitcharecommonlyconductedusing
pitchmatchingtechniquesinwhichindividualsarepresentedwith
tonesofvaryingfrequencyandaskedtoselectthetonethatis
closestinpitchtotheirtinnitus[foramethodologicalreview,
seeRef.(26)]. Anumberofstudieshavedemonstratedalink
betweenthepitchoftinnitusandtheconfigurationofanindivid-
ual’shearingloss.Tinnituspitchmeasurementshavebeenmade
in individualsimmediatelyfollowingexposuretoloudsounds
(27–29) andinindividualswithlong-standingtinnitus(30–33).
Followingacuteexposuretoloudsound,thepitchoftinnitus
was foundtooccurabovethefrequencyofthenoiseexposure,
eitherinthehigh-frequencyedgeofasharplylocalizedhearing
loss (27) orclosetotheregionofmaximumhearinglosspro-
ducedbythenoiseexposure(28, 29) (Figure1A). Similarly,in
individualswithlong-standinghearinglossandtinnitus,thetin-
nituspitchwasmatchedeithertothefrequenciesattheedgeof
the hearingloss(31), ortothefrequencyregionofmaximalhear-
ing loss(32) (Figure1B). Tinnituspitchmatchingmeasureshave
also beencompletedinindividualsexposedtosodiumsalicylate,a
drugknowntoreliablyinducetemporaryhearinglossandtinnitus
in humansandanimalswhentakenathighdoses[forreview,see
Ref.(34, 35)]. Althoughsomestudieshavematchedthepitchof
salicylate-inducedtinnitusandhearinglossacrossabroadrangeof
frequencies,salicylate-inducedtinnitusandhearinglossareboth
most commonlyreportedtooccuratthehighfrequencies(34). In
general,thepitchoftinnitusresultingfromacutenoiseexposureor
long-standinghearinglosscommonlyoccurswithintheregionof
hearinglossandabovethefrequencyofthenoiseexposureused
toinducehearingloss(36). However,measurementsoftinnitus
pitcharecomplicatedbyfindingsthattinnituspitchalsodepends
ontheetiologyofthetinnitus(37) andthattinnituspitchtends
tobelowerinfrequencyforindividualswithnormalaudiometric
profiles,i.e.,normalthresholdsat250–8000Hz(30).
FIGURE 1|Measurementsoftinnituspitchinhumansubjectswithacute
noise-induced tinnitusorlong-standingtinnitus. (A) Followingacutenoise
exposure,tinnituspitchhasbeenfoundtooccurabovethefrequencyofthe
noise exposureclosetotheregionofmaximalhearinglossgeneratedbythe
noise exposure[fromRef.(29) withpermission;NIST,noise-inducedshort
duration tinnitus;MTS,maximumthresholdshift]. (B) Similarly,tinnituspitch
has beenmatchedtofrequenciesintheregionofmaximumhearinglossfor
individuals withlong-standingtinnitus[fromRef.(32)].
FrontiersinNeurology | Neuro-otology September 2014|Volume5|Article179 | 2
3. Hayesetal. Animal modelsoftinnitusandhyperacusis
Loudnessmatchinghasalsobeenconductedonindividu-
als experiencingtinnitusfollowingexposuretoloudsoundsor
sodiumsalicylate,aswellasinindividualswithlong-standing
hearinglossandtinnitus.Themedianintensityoftinnitusresult-
ing fromacuteexposuretoloudnoisewasfoundtobe9dBSL,
whereasthetinnitusresultingfromsodiumsalicylatewasmatched
at 5–15dBSL(29, 34). Inindividualswithlong-standingtinnitus,
the intensityreportedbyindividualsrangesfrom7.1to18.9dBSL
(31). However,loudnessrecruitment,steeperthannormalloud-
ness growthfunctionsfoundinpatientswithhearingloss(5), can
contaminatetinnitus-loudnessmatchesbyunderestimatingthe
perceivedloudnessoftinnitus(26).
Additionalfactorstoconsiderregardingtinnitusinthehuman
populationarethetimecourseforonsetfollowingexposureto
noiseorsodiumsalicylateandthevariabilityofitsinduction.For
individualsexposedbrieflytoloudnoise,tinnitusonsetisreported
tooccurimmediatelyfollowingtheexposure(28, 29). Giventhe
shortdurationofnoiseexposureinsomeofthesestudies(5min),
tinnituswasreportedtolastfornearly15minfollowingtheexpo-
sure(29). However,followingexposuretoahighdoseofsodium
salicylate,tinnitusonsetoccursbetween1and3hpostexposure
and typicallydissipateswithin1–2daysfollowingtheexposure
(34). Despitethedifferencesintinnitusonsetforacutenoise
exposureandsalicylate,bothmethodsresultinvariabilityinthe
inductionoftinnitus.Followingacutenoiseorsalicylateexposure,
not allindividualsdeveloptinnitus(28, 29, 34). Interestingly,some
individualswithapreexistinghearinglossexposedtohighcon-
centrationsofsalicylatefailedtoexperiencetinnitus,suggestingan
individualvariabilityforsusceptibilitytosalicylate-inducedtinni-
tusinthispopulation(34). Thus,tinnituspitch,intensity,onset,
and variabilityinthehumanpopulationareimportantfactorsto
considerwhenevaluatinganimalmodelsoftinnitus.
ANIMAL MODELSOFTINNITUS
JASTREBOFF
Thefirstbehavioralmodeloftinnitusinanimalswasdeveloped
byJastreboffetal.(10). Inthis conditionedlick-suppressionpara-
digm, ratsweretrainedtolickforwaterduringperiodsinwhich
a steadybackgroundnoisewaspresent,andtosuppresstheirlick-
ing duringbriefperiodsofsilence(conditionedstimulus),which
werefollowedbyafoot-shock(unconditionedstimulus).Inthe
initialstudy,tinnituswasinducedusinganinjectionofsodium
salicylatefollowingtraining.Duringthetestingphase,thefoot-
shockwasturnedoffresultingintheeventualextinctionofthe
lick-suppressionbehavior.Therateofextinctionwasassessedover
multipletestdaysandwasusedasanindicatorforthepresence
oftinnitus;specifically,animalsgiventhetinnitusinducersalicy-
latebeganlickingduringthesilentintervalsearlierthananimals
givensalinepresumablybecausetheyheardtheirtinnitusduring
the quietintervals.Therapidextinctionofthelick-suppression
behaviorinthesalicylate-treatedratswasinterpretedasthepres-
enceoftinnitusbecauseanimalswithtinnitusdonotexperience
silenceandwereexpectedtobehaveasifasoundisbeingpresented.
A seriesofimportantcontrolswereperformedusingthispar-
adigmtoensurethattheobservedbehaviorwasrepresentative
oftinnitusandnotanotherconfoundingfactorassociatedwith
salicylateadministration.First,todemonstratethattheobserved
resultswereauditory-specific,alightstimuluswasusedinplace
ofthebackgroundsoundandanimalsweretrainedtosuppress
lickingwhenthelightwasturnedoff.Salicylateadministration
followingtrainingwiththelightstimulushadnoeffectonthe
behavior,indicatingthattheeffectsofsalicylateareauditory-
specific.Theeffectsofsalicylateonthirstandmotivationwere
also controlledbyadministeringsalicylateduringtrainingaswell
as duringtesting.Ratsgivensalicylateduringtrainingassociated
theirtinnitusperceivedduringthesilentintervalswiththefoot-
shockandsuppressedtheirlickingduringthesilent(tinnitus)
intervalsduringtesting.Salicylateadministrationdidnotresultin
a generaleffectondrinkingbehaviorsinceratsadministeredsali-
cylateduringtraining decreased theirlickingduringsilentintervals
whereasratsadministeredsalicylateaftertraining increased their
lickingduringsilentintervals.Furthermore,hearinglossasacon-
foundingfactorwasalsoinvestigatedbydecreasingtheintensity
ofthebackgroundsound,whichdidnotaffectthebehavior.
Theconditionedlick-suppressionparadigmoffersanumber
ofadvantagesincludingitsrelativelyshorttrainingtimeandthe
observationthatitisnotaffectedbyconfoundingfactorsrelated
totinnitusinductionsuchashearinglossandnon-auditoryeffects
ofsalicylate.However,thislick-suppressionparadigmisnotuseful
forlong-termstudiesoftinnitusbecausethebehaviorextin-
guishes. Sincetheanimalsaretestedinextinctionoveraperiodof
severaldays,theynolongerremainunderstimuluscontrolwhen
the shockisturnedoff.Additionally,theparadigmrequirescom-
parisonofgroupsofanimals(tinnitusversuscontrol)andhas
not beenusedforassessingthepresenceoftinnitusinindividual
animals.
BAUER ANDBROZOSKI
Asmentionedabove,onelimitationoftheJastrebofflick-
suppressionparadigmwasitsinabilitytotestforlong-termtinni-
tusinrodents.Motivatedbytheneedtotestpharmaceuticalsfor
treatingtinnitus,BauerandBrozoskidevelopedanaversivecondi-
tioningbehavioralparadigmderivedfromtheJastreboffmodelin
ordertoprovidelong-termquantitativeandqualitativeassessment
oftinnitusperceptioninrats(11).
SimilartotheJastreboffmodel,BauerandBrozoskideveloped
a shock-avoidanceparadigminwhichratsweretrainedtodis-
criminatesound(whitenoiseortonesofvariousfrequenciesand
intensities)fromsilence(0dBSPL).Initially,therat’sbehaviorwas
shapedtofrequentlypressaleverwhileawhitenoiseoratonewas
presented.Thisbehaviorwasreinforcedbyavariableintervalof
reinforcementwithafoodpellet.Oneminutesilentperiodsinter-
ruptedthewhitenoiseandwerefollowedbyabrieffoot-shock
if theleverwaspressed.Thisprocedurequicklytrainedtheratto
avoidpressingtheleveronlyduringthesilentperiods.Following
initialtraining,thefoot-shockwasturnedoninfrequently,occur-
ringapproximatelyonceperweekperrat.Aleversuppression
ratio, R D B
.ACB/ , wasusedtoquantifywhetherornotthenumber
ofleverpressesduringthecurrent1minperiod, A, differedfrom
the immediatelyprecedingperiod, B. Avalueof R D0.0 indicated
completesuppressionofleverpressing(i.e.,ratsreportednosound
was present),whereasavalueof RD0.5 indicatednosuppression
ofleverpressingcomparedtothepreviouswhitenoisestimulus
(i.e., asoundwaspresent).
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4. Hayesetal. Animal modelsoftinnitusandhyperacusis
Behavioralperformanceonthistaskhasbeenobservedfollow-
ing chronicexposuretoeithersodiumsalicylateindrinkingwater
(11) oracuteunilateralnoisetrauma(38). Intheinitialstudyusing
sodiumsalicylate,blood-serumlevelsofsalicylateweresimilarto
those measuredinhumanswithsalicylate-inducedtinnitus.Rats
treatedwithsalicylatedemonstratednodifferenceinleverpress-
ing duringsilentintervalscomparedtocontrolanimals,butdid
demonstratehigher R values(moreleverpressing)totonestimuli,
withthemaximumincreasein R valueoccurringwiththe15-kHz
tonalstimulus.Thiswasinterpretedtorepresentthepresenceof
tinnitusinthesalicylate-treatedsubjects,asamaximalinterac-
tionwasexpectedtooccurattonalfrequenciesthatmostclosely
resembledthetinnitusfrequency.Theexplanationforthebehav-
ioralshifttotonalstimuliwasthatthesalicylate-treatedsubjects
heardthetonesdifferentlythancontrolsubjectsandperceivedthe
tonesasmorenoise-likeduetotheirtinnitus.Inotherwords,the
tinnitusperceptwasexpectedtointeractwiththeperceptionofthe
externallypresentedtonalstimulitoproducea“noisy”perceptif
the tonesweresimilartothetinnituspitch.Sincetheanimalswere
trainedtopressduringnoisestimuli,theanimalswereexpected
topressmoreoftenwhenthetesttonesinteractedwiththeirtin-
nitustocreatethisnoise-likepercept.Thetinnitus-likebehavior
was reversedintheexperimentalgroupsoonaftertreatmentwith
salicylatewasstopped.
Inasubsequentstudy(38), a1-or2-hunilateraltraumatizing
noiseexposurecenteredat16kHzwasusedtoinducetinnitusin
ratstrainedonthisbehavioralparadigm.Followingthe1-hnoise
exposure,themaximumshiftin R valueoccurredduringtest-
ing sessionswherethe20-kHztesttonestimuluswaspresented.
However,unlikethepreviousstudyinwhichsalicylate-induced
increases in R valuewereinterpretedastheevidenceoftinnitus,
unilateralnoiseexposureresultedinasignificant decrease in R
valuefortonalstimuliwhichwasinterpretedasthepresenceof
tinnitus.Thereductionin R valueinthenoise-exposedanimals
was reportedforupto17monthsfollowingnoiseexposure,i.e.,
persistenttinnitus.
Importantly,inthesamestudy,thepossibleconfoundingeffects
ofhearinglosswerecontrolledbyincludinganadditionalexperi-
mentalgroup,whichwerenotnoise-exposedbutwereoutfitted
withfoamearplugsfixedintheearcanalwithcyanoacrylate.
Thesuppressionratio, R, ofthisgroupwasunaffectedbythe
~40 dBconductivehearinglossduetotheearplug.Thisisstrong
evidencethatthebehavioralparadigmisrobusttoamoderate
unilateralconductivehearingloss;however,thisdoesnotexclude
the possibilitythatunilateralsensori-neuralhearingloss,andthe
subsequentloudnessrecruitment,maybeaconfoundingfactor.
Thereareafewnotablestrengthsofthisbehavioralparadigm
fortheassessmentoftinnitusinratsincludingtheabilitytotest
subjectsoverlongperiodsoftime,itsresiliencetounilateralcon-
ductivehearingloss,abilitytodeterminetinnituspitch,andthe
rigorthroughwhichtheparadigmhasbeentestedbyitscreators.
One limitationoftheparadigmisthattheresultsarepresented
as ameanofallanimalsperformingwithinagroup.Whilethis
approachmaybeeffectiveandappropriatefortestingtheviability
ofvariouspharmaceuticalsusinggroupstatistics,itislesseffective
in assessingtinnitusinanindividualsubject,andthetimecourseof
tinnitusonset.Anotherdisadvantageoftheparadigmisthatsince
onlyonetonefrequencyispresentedduringeachsession,many
testingsessionsarerequiredtodeterminethepitchoftinnitus.
Additionally,usingthisparadigm,tinnitus-likebehaviordoesnot
appearuntilweeksfollowingexposuretounilateralnoisetrauma,
a resultatoddswiththehumanliteratureinwhichtinnitusonset
typicallyoccursimmediatelyfollowingexposuretointensenoise
(27–29). Furthermore,thereislittleevidenceinthehumanlit-
eratureindicatingthattinnitusinterfereswiththeperceptionof
externaltonesassuggestedbytheauthors.Indeed,externalsounds
~5–15 dBabovethresholdsmaybequiteeffectiveinsuppressing
tinnitus(26).
HEFFNER
InanattempttoimproveupontheJastrebofflick-suppression
paradigm,HeffnerandHarrington(12) trainedhamstersina con-
ditionedsuppression/avoidanceprocedure todrinkinthepresence
ofabroad-bandnoiseorvarioustones,andtostopdrinkingin
the absenceofthesesounds(silence)toavoidashock.Although
the lick-suppressionmethodsweresimilar,twocrucialdifferences
existbetweentheJastreboffandHeffnerparadigms.Forone,the
animals intheHeffnerconditionedsuppressionparadigmunder-
wentextensivetraininginthehopesoftestingindividualanimals
fortinnitus.Jastreboff,ontheotherhand,tooklesstimetotrain
eachanimalbutcouldonlyassessgroupsofanimalsfortinni-
tus.Anotherkeydifferencebetweenthetwoparadigmsisthat
the shockwasavoidableintheHeffnerconditionedsuppression
paradigmwhereastheelectricshockwasunavoidableintheJas-
treboffparadigm.Despitethesedifferences,thehypothesisfor
bothproceduresremainedthesame.Namely,whentheshock
was turnedoffduringtesting,animalswithnoise-induced(12) or
salicylate-induced(10) tinnituswerehypothesizedtoextinguish
fasterthananimalswithouttinnitus,becauseanimalswithtinni-
tusnolongerexperiencesilence,andtherefore,shouldnotknow
whentosuppresstheirlicking.
Althoughtinnituscouldbeassessedinindividualanimals,the
majordrawbackoftheHeffnerconditionedsuppressionpara-
digmwasthatasignificantoverlapinperformanceexistedbetween
the controlandnoise-exposedanimals(25). Moreover,sincethis
paradigmusedextinctionasitsbehavioralmeasureoftinnitus,
this paradigmcannotbeusedtodetectchronictinnitus(21). For
these reasons,Heffnerandcolleaguesdevelopedanothertinnitus
paradigmusinga two-choicesoundlocalizationprocedure.
Duringthesoundlocalizationprocedure,animalsweretrained
tolateralizesoundsbyrespondingtotherightsideofatestboxfor
sounds comingfromaspeakerontherightsideandtorespondto
the leftsideofatestboxforsoundscomingfromtheleftside(16,
39). Animalsweregivenwaterrewardforcorrectresponsesand
wereshockedforincorrectresponses.Importantly,silenttrials,or
probes,wereinterspersedon~24%oftrials,whichwereneither
reinforcednorpunishedbuttheanimalswereforcedtochoosea
side.Thesidepreferenceduringsilenttrialswasdeterminedfor
eachanimalpriortonoiseexposure.
Tinnituswasinducedbysound-exposingtheearoppositeeach
animal’ssidepreferenceduringsilenttrials(16). Forinstance,an
animal witharight-sidebiasforsilenttrialsduringtrainingwould
begivenaleftearsoundexposure.Accordingly,animalswithtinni-
tusshouldswitchtheirsidepreferenceduringsilenttrialsfromthe
FrontiersinNeurology | Neuro-otology September 2014|Volume5|Article179 | 4
5. Hayesetal. Animal modelsoftinnitusandhyperacusis
sidepreferredpriortonoiseexposure(therightsideintheabove
example)totheopposite,noise-exposedside(theleftsideinthe
aboveexample)becausetheanimalsnowhearaphantomsound
onthatexposedside.Inaccordancewiththeirhypothesis,the
researchersfoundthathamsters(16) andrats(39) willshifttheir
sidepreferenceonsilenttrialstothenoise-exposed,previously
non-preferredear,suggestingthattheyperceiveaphantomsound
in thatear.Asanimportantcontrolcondition,simplyplugging
oneearandproducingaconductivehearinglossdoesnotresultin
a shiftinbehavioronsilenttrials.However,thekeyassumptionof
this paradigmisthatexposingoneeartoloudsoundwillalways
inducetinnituslateralizedtothatearandneverproducebilat-
eraltinnitusortinnitusintheoppositeear.Therefore,amajor
drawbackofthisparadigmisthatitcannotbeusedtotestdrug-
inducedtinnitusorbinauralnoiseexposuresthatwouldlikely
inducebilateraltinnitus.
Yet,theadvantageofusingatwo-choiceparadigmtodetect
tinnitusisthatanimalswithtinnitusmakea qualitatively different
responsethananimalswithouttinnitus,whereasanimalswithtin-
nitusinlick-suppressionparadigmslickmoreorlessthananimals
withouttinnitus,resultingin quantitative differencesbetweenthe
twogroupsthatmaybetheresultofotherfactors,suchashearing
loss, thataccompanydrugornoise-inducedtinnitus(12). Inother
words,animalsperceivingtinnitusinatwo-choiceparadigmgo
toadifferentside,orpressadifferentlever,thananimalswith-
outtinnitus,whereasanimalsperceivingtinnitusinsuppression
paradigmslickmoreorlessthananimalswithouttinnitusbut
stillperformthesamelickingbehaviorinbothcases.Sincetin-
nitusanimalsintwo-choicetasksmakeaqualitativelydifferent
responsethannon-tinnitusanimals,thebehaviorintwo-choice
experimentsismoreresistanttochangesinmotivation,stress,
hearingloss,orhyperacusisthatfrequentlyco-occurwithdrugor
noise-inducedtinnitus(12, 17).
RÜTTIGER
Rüttigerandcolleagueshavedevelopedawater-reinforcedcondi-
tionedavoidanceparadigmforratswiththegoaloflimitingthe
needforlongperiodsofwaterdeprivationaswellasunavoid-
ableshock(13). Animalsaretrainedtoshuttlebetweentwowater
spoutsduringthepresentationofa70-dBSPLwhitenoiseback-
groundsoundinordertoreceivearewardof3%sugarwater.
Duringsilentperiods,however,theanimalsreceiveamildfoot-
shockiftheyaccessthewaterspouts.Theanimalsaretrained
overaperiodofweeksuntiltheirresponsestothewaterspouts
duringsilentperiodsaresufficientlysuppressedcomparedto
the responsesduringwhitenoisebackgroundsoundpresenta-
tion.Importantly,avariablereinforcementrateisintroduced
duringthefinalstagesoftraininginordertoreduceextinc-
tionoftheresponses,giventhatboththereward(sugarwater)
and foot-shockareturnedoffduringthetestingphase.Ani-
mals withtinnitusareexpectedtoincreasetheirresponsesat
the waterspoutsduringsilentperiodsindicatingthattheyare
experiencingaphantomsound.Thisparadigmhasbeenused
todeterminethepresenceofbothsalicylateandnoise-induced
tinnitus(13, 40). Ithasalsobeenusedtodeterminetheinten-
sityoftinnitusbycomparingtheresponserateofratstreated
withsalicylatetothatofanimalsinwhichthebackground
sound waspresentedatvaryingintensities,andwasestimated
tobe~30dBSPL.
Thisparadigmhasanumberofadvantages.Asmentionedpre-
viously,itdoesnotrequirelong-termdeprivationofwateror
presentationofanunavoidablefoot-shock.Itcanbeusedtotest
individualanimalsfortinnitusbyinjectingsaline,asacontrol,or
salicylateinthesameanimalsondifferentdaysandcomparing
behavioralperformance.However,althoughtrainedanimalsare
reportedtogo6–8monthswithouttrainingandstillperformthe
task tocriterion,itcannotbeusedtotestanimalsrepeatedlyfortin-
nitusoverlongdurationsduetoextinctionoftheresponsewhen
reward/punishmentisturnedoffduringtestingandwhenper-
sistenttinnitusispresentfollowingnoiseexposure.Furthermore,
althoughtheparadigmhasbeenusedtodeterminetheintensity
oftinnitus,ithasnotbeenusedtodeterminethefrequencyof
tinnitus.
LOBARINAS
Lobarinasandcolleaguesintroducedaschedule-inducedpolydip-
sia avoidanceconditioning(SIP-AC)paradigmtoassessratsfor
salicylate-inducedtinnitus(14). Thisparadigmdifferedfromthe
previouslymentionedlick-suppressionparadigmsintwoways.
Forone,theanimalswerenotwaterrestricted,butwerefood
restrictedandtrainedtolickawaterspoutwhilewaitingfora
foodpellettodropintoatrough.IntheSIP-ACparadigm,ani-
malswouldreceiveonefoodpelletperminuteandwouldconsume
water,eventhoughtheywerenotwaterdeprived,whilewaiting
foranotherpellettodrop.Thisbehaviorisreferredtoaspolydip-
sia becausetheanimalsdrankthewatereventhoughtheywere
not waterdeprived(14). Second,unliketheotherlick-suppression
paradigmswheretheanimalsweretrainedtostoplickinginthe
absenceofsound(quiet),animalsintheSIP-ACparadigmwere
trainedtostoplickinginthepresenceofsounds.Inotherwords,
animals couldlickforwaterinquietbutwereshockedforlicking
duringsoundtrials.Therefore,ifanimalsexperiencetinnitusin
the SIP-ACparadigm,theyshouldceaselickingduringquiettrials
becausetheynowhearasound.Thebenefitofthisprocedureis
that theshockneverhastobeturnedoffbecauseananimalwith
tinnitusshouldnotlickduringsoundorquiettrials,andtherefore,
wouldnotgetincorrectlyshocked.Sincetheshockisneverturned
off,extinctionisnotaproblemwiththisparadigm;therefore,it
can potentiallybeusedtomeasurechronictinnitus.
However,likeallofthepreviouslick-suppressionparadigms,
SIP-ACisnotrobusttochangesinmotivationorhearingloss
that accompanysalicylateand/ornoise-inducedtinnitus(23). For
instance,ananimalgivenalargedoseofsalicylatemightbecome
sickandlessmotivatedtodrinkoverallregardlessofwhetherit
has tinnitusornot.Similarly,ananimalwithasubstantialdrugor
noise-inducedhearinglossmightmistakenlylickduringasound
trial,perceivingitasaquiettrial,andreceiveashock.Sincethe
animal isnotwaterdeprived,theanimalmightstoplickingalto-
gethertoavoidtheshock.Therefore,ananimalwithhearingloss
couldconceivablytestpositivefortinnitus(23).
SEDERHOLM ANDSWEDBERG
Recently,SederholmandSwedberg(17) trainedratsina two-choice
operantconditioningprocedure toidentifyratswithsalicylateand
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6. Hayesetal. Animal modelsoftinnitusandhyperacusis
noise-inducedtinnitus.Forthisprocedure,eachratwastrained
topressa“tone”leverwhenitheardatoneandtopressa“0Hz”
(silence)leverwhennosoundwaspresented.Correctresponses
wererewardedwithfoodandincorrectresponsesresultedinareset
ofthefixedratiorequirement(20additionalleverpresses)onthe
appropriatelever.Aftertheanimalsweretrainedtocriterion,the
animals weretestedfollowingsalicylateadministrationorintense
noiseexposureinaquietchamberwheretheirleverpressestothe
“tone”leverwerecounted(17). Animalswithtinnitusshouldhave
a greaternumberof“tone”leverpressesthan“0Hz”leverpresses
duringtestingeventhoughnosoundispresented.
Thebenefitsofthisprocedurearethatnoshockisrequiredto
traintheanimals;and,giventhatthisisatwo-choiceparadigm,itis
moreresistanttoconfoundingfactorsintinnitusinduction,such
as hearingloss,hyperacusis,motorimpairment,andlossofmoti-
vation,sincetheanimalsmakeaqualitativelydifferentresponse
whentheyexperiencetinnitus(12, 17). However,thisprocedure
requiresextensivetraining(2–3months)andtheauthorscould
onlytraintheiranimalstocriterionusinghighstimuluslevels
(55–65 dBSL)thatarelikelymuchhigherthantheperceivedtin-
nitusintensity.Furthermore,sincetheratswerealwaysreinforced
forrespondingduringtesting,itisnotclearhowlongtheanimals
remainunderstimuluscontrol.Forinstance,afterseveraltesting
sessions,itispossiblethattheanimalswouldrandomlypresseither
leversincebothleversresultinfoodreward,makingthispara-
digmproblematicforstudiesofchronictinnitus(17). Inaddition,
leverpressingduringtestingappearshighlyvariableacrossanimals
making tinnitusassessmentdifficult(Figures2A,B). However,
despitethesecriticisms,thisisanewtinnitusparadigmthat,with
moretesting,mightproveusefulinfuturetinnitusstudies.
STOLZBERG
A centralgoaloftinnitusresearchistoidentifyaputativeneuro-
physiologicalcorrelateoftinnitusperception.Majoradvanceshave
beenmadetowardthisobjectiveinelectrophysiologicalstudiesin
humantinnituspatients(41). Whilemanyreportsexistonneu-
rophysiologicalchangesfollowinginductionoftinnitusinanimal
models,onlyasmallsubsethavedonesowithbehavioralconfirma-
tionoftinnitusinalertanimalswithouttheinfluenceofanesthesia
[e.g.,Ref.(42)]. Inanattempttoovercomethisissue,Stolzberg
and colleaguesdevelopedanovelappetitive two-alternativeforced
choice assay,whichisbettersuitedtoinvestigatepossibleneuro-
physiologicalcorrelatesoftinnitusinananimalmodelbyallowing
neuralactivitytoberecordedwhiletheanimalisactivelyexhibiting
tinnitus-likebehavior(18).
Stolzbergandcolleaguestrainedratstoaccessaleftfeeder
portinthepresenceofasteady,unmodulatednarrow-bandnoise
(NBN; 1/8thoctaveband-passnoisewithafrequencycenter
selectedrandomlyacrosstrials),andtoaccessarightfeederport
in thepresenceofasinusoidallyamplitudemodulatednoise(AM;
broad-bandnoisewithamplitudemodulated100%at5Hz)or
silence(Quiet)(Figure3B). Oneofthethreeacousticcondi-
tions(NBN,AM,Quiet)wascontinuouslypresentinthetesting
chamberatthestartofeachtrial.Ratsinitiatedatrialbynose-
pokingintoacenterport(Figure3A) andmaintainedthisposition
forarandomizedperiodof4–8suntilalightcuedthem(“go
cue”)torespondtoafeederportbasedontheacousticcondi-
tion.Correctresponseswerereinforcedwithafoodpelletand
incorrectresponsesresultedina“time-out”inwhichtheratwas
unabletoinitiateanewtrial.Duringtraining,thereinforcement
ratewasreducedfrom100to70%inordertominimizeextinc-
tionofthelearnedbehavior,andthepercentageoftrialtypeswas
dividedevenlybetweenthetwofeeders(NBNat50%;AMat30%;
Quietat20%).
On testingdays,inwhichratsreceivedeitheraninjectionof
saline orahighdoseofsalicylatetoinducetinnitus,Quiettrials
wereneitherreinforcednorpunished.Tinnitus-likebehaviorwas
indicatedbytheratshiftingitsresponseduringQuiettrialsfrom
the rightfeederassociatedwithAMandQuietduringtraining,to
the leftfeederassociatedwiththesteadyNBN(Figure3C). Follow-
ing treatmentwithsalicylate,ratsincorrectlyidentifiedtheQuiet
conditionasaNBNsignificantlymorethanbaselineorsaline,
indicatingthepresenceofasteadyNBN-likephantomsound
(i.e., tinnitus)duringQuiettrials(Figure3D). Importantly,this
FIGURE 2|Ratstrainedinatwo-choiceoperantconditioningparadigm
topressa“tone”leverwhentoneswerepresentedora“0Hz”(silence)
leverduringperiodsinwhichnosoundwaspresentedinordertoreceive
a foodreward. Changesintoneleverpressingduringsilentintervalswere
observedfollowingexposuretosalicylate (A) or unilateralacoustictrauma
(B). Thinlinesrepresentindividualanimaldatawhileboldlinesdepictgroup
data.Anincreaseintoneleverpressingduringsilencewasusedtoindicate
the presenceoftinnitusfollowingexposure[fromRef.(17), withpermission].
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7. Hayesetal. Animal modelsoftinnitusandhyperacusis
FIGURE 3|IllustrationofbehavioraltinnitusassayreportedinRef.
(18). (A) One ofthethreeconditions(AM,NBN,Quiet)ispresent.Therat
self-initiates atrialbynose-pokinginthecenterport. (B) Afteravariable
delay,alightcuestherattorespondtoafeedertroughlocatedtotheleftor
right ofthecenterport.TheNBNconditionispairedwiththeleftfeeder
trough. AMandQuietconditionsarepairedwiththerightfeedertrough.
(C) Followinginductionoftinnitus,ifarathearsasteadyphantomsoundit
should respondtotheleftfeederduringtheQuietconditionwhilestill
correctlyidentifyingAMandNBNconditions. (D) Comparison of
performanceofrats(nD7; eachcircle–squarepairrepresentsonerat)
betweensalineandsalicylatetreatments.FollowingsalinetreatmentAM
and QuietconditionswereinfrequentlymisidentifiedasNBN,whereas
NBN wasidentifiedcorrectly.FollowingsalicylatetreatmentQuiet
conditions weresignificantlymorelikelytobemisidentifiedasNBN,
indicating thatsalicylateinducedaphantomsoundperception(nsDnot
significant, p <0.001)[fromRef.(18), withpermission].
changeinbehaviorduringQuiettrialswasonlyobservedfollowing
injectionofsalicylateandnotfollowinginjectionwithsaline.Fur-
thermore,theratsstillcorrectlyidentifiedAMandNBNstimuli
suggestingthattheywerenotperformingrandomly(Figure3D).
Thisnoveltinnitusbehavioralassayhassomedistinctadvan-
tagesoverothertinnitusparadigms,includingtheabilitytoiden-
tifytinnitus-likebehaviorinindividualanimalsandthespecific
designforsimultaneousacquisitionofelectrophysiologicaldata.
Duringthe4–8speriodinwhichtheanimalsholdtheirheadin
the centerporttoinitiateatrial,neuralactivityfromchronically
implantedelectrodescanberecordedwithminimalartifactwhen
the animalislargelyimmobilewithitsheadinafixedpositionin
the soundfield.Inaddition,thisparadigmisveryrobusttothesec-
ondaryeffectsofsalicylate-inducedtinnitus,suchashearingloss,
hyperacusis,andhyper-reactivity,becausetheratsstillmaintain
correctperformanceonAMandNBNstimulisoitisclearthatthe
animals areunderstimuluscontrol.Furthermore,asintheother
two-choiceparadigms(16, 17), animalswithtinnitusmakea qual-itatively
differentresponsethananimalswithouttinnitus,unlike
in thesuppressionparadigmswhereitisdifficulttodifferenti-
atetinnitusfromhearingloss,stress,orotherfactorsassociated
withdrugornoiseexposure(12). However,itisuncertainifthe
paradigminitspresentformisappropriateforassessingchronic
tinnitus.Additionally,thisparadigmdoesnotprovideinformation
regardingtinnituspitchorloudness.
TURNER (GAPPRE-PULSEINHIBITION)
In2006,Turnerandcolleaguesintroducedanoveltinnitusbehav-
ioralparadigm,referredtoasgappre-pulseinhibitionofthe
acousticstartlereflex(GPIAS),whichutilizesananimal’smotoric
response(startlereflex)toasuddenloudsound(startlestimulus)
that isrecordedbyamotionsensitivetransducer(15). Presenta-
tionoftheacousticstartlestimulusevokesarobustacousticstartle
reflex(ASR);however,thisreflexcanbesuppressedbyinsertion
ofashortdurationsilentgapinacontinuousbackgroundsound
justpriortothestartle-elicitingstimulus(15, 43). Inmoststud-
ies, theratiobetweenthestartleamplitudeduringtrialsinwhich
the startlestimulusispresentedalone(no-gaptrials)andtrials
in whichagapispresentedpriortothestartle-elicitingstimulus
(gaptrials)iscalculatedastheGPIASratio.Thisratioisusedas
an indicatoroftheeffectivenessofthesilentgaptoinhibitthe
startlereflex.Forananimalwithtinnitus,itisexpectedthatifthe
backgroundsoundinwhichthegapisembeddedisqualitatively
similar totheanimal’stinnitus,thentinnituswill‘fillin’thegap
resultinginanimpairedabilityofthesilentgaptoinhibitthe
startlereflex.Bycomparingtheabilityofsilentgapsincontinu-
ous backgroundsoundsofvaryingfrequencyandbandwidthto
inhibitthestartlereflex,theparadigmhasbeenusedtodetermine
the pitchofananimal’stinnitus.Usingthisparadigm,tinnitushas
beenassessedfollowingexposuretosalicylateaswellasnoiseina
varietyofspeciesincludingrats,mice,guineapigs,andhamsters
(15, 44–47).
GPIAShasquicklybecomethemostwidelyusedtinnitus
behavioralparadigmbecauseitcarriesanumberofadvantages
overtheotherpreviouslyreportedtinnitusparadigms.Itrequires
no behavioraltraining,nofoodorwaterdeprivation,canassess
tinnituspitch,andallowsforhigh-throughputscreeningfortin-
nitus.Because,thereisnotraininginvolved,itcanalsobeused
tomonitoranimalsfortinnitusrepeatedlyoverlongdurations.
InTurner’soriginalpublication,groupdatawaspresentedsince
baselineGPIASmeasureswerenotcompletedpriortotinnitus
inductionviaunilateralnoiseexposure(15). However,bycol-
lectingbaselineandpost-tinnitusinductionGPIASmeasures,the
paradigmcanbeusedtoidentifyindividualanimalswithtinnitus
allowingforanimalstobeseparatedintotinnitus-positiveand
tinnitus-negativegroups(48, 49).
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8. Hayesetal. Animal modelsoftinnitusandhyperacusis
However,despitetheseadvantages,anumberofconcernshave
recentlybeenraisedregardingtheGPIASparadigmanditsuse
forscreeninganimalsfortinnitus.Oneconcernisthediscrepancy
in tinnituspitchreportedinanimalsusingtheGPIASparadigm
followinginductionoftinnitusviaexposuretohigh-frequency
noise.Somestudies,includingtheoriginalTurnerstudy,have
reportedthetinnituspitchtofallbelowthenoiseexposurefre-
quency(15, 50),whileothersreportthetinnituspitchtofallabove
the noiseexposurefrequency(44, 48, 51–53). Equallyinteresting
is thefindingthatimmediatelyfollowingnoiseexposure,tinnitus
has beenfoundtooccuracrossawiderangeoffrequenciesbut
thenbecomesspecifictoalimitedfrequencybandoverthefollow-
ing weeks(54). Incontrast,thetinnituspitchinhumansubjects
exposedtoloudsoundmostfrequentlyoccursatorabovethe
noiseexposurefrequency(28, 29).
Anotherissueistheeffectofhearinglossfollowingexposure
tonoiseorototoxicdrugsonthestartlereflexamplitudeused
toassesspre-pulseinhibition.Hearinglosscanpotentiallyaffect
the outcomeofGPIASscreeninginanumberways:byinterfering
withaudibilityofthebackgroundsoundinwhichthesilentgaps
areimbeddedorbyalteringtheamplitudeofthestartlereflexto
the startlestimulusalone(no-gapcondition).Previousstudiesin
bothrodents(55) andhumans(56) havedemonstratedthathear-
ing lossalone,inducedbysodiumsalicylateexposure,caninterfere
in detectionofgapsinlow-levelcontinuousnoise.Thisissuehas
beenaddressedintheGPIASparadigmbyusingintensitiesof
backgroundsounds(60dBSPL)showntoberesilienttotheeffects
ofhearingloss,andbycarryingoutnoise-burstpre-pulsedetection
measures.Duringnoise-burstdetectionmeasures,ashortdura-
tionnoise-burstofthesameintensityasthebackgroundsound
usedinGPIAStestingispresentedpriortothestartle-eliciting
stimulustoserveasthepre-pulsecue.Itisassumedthatifthe
noise-burstreliablyinhibitsthestartlereflex,thenaudibilityofthe
backgroundsoundinwhichthesilentgapsareembeddedduring
GPIAStestingshouldnotbeanissue.
Inadditiontothepotentialconfoundingeffectsofhearingloss
onaudibilityofthebackgroundsound,anotherissueisthatunilat-
eralnoiseexposurecanreducetheamplitudeofthestartlereflex
duringstartle-alone(no-gap)trials(2, 44, 47, 50). Inonestudy
using rats,unilateralnoiseexposureresultedina57%reduction
in thestartleamplitudeduringstartle-alonetrials(2), whilein
anotherstudyusingmice,unilateralnoiseexposureresultedin
a 52%reductionoftheacousticstartlereflexevenafterhearing
thresholdsrecoveredtopre-noiseexposurelevels(44). Alterations
in startlereactivityposeanumberofissues.First,asthedependent
measureintheGPIASparadigm,arobuststartlereflexisneededin
ordertoobserveitsinhibition.Ifanimalsfailtostartlefollowing
manipulationstoinducetinnitus,theywillneedtobeexcluded
fromfurtheranalysis,apracticereportedinsomepreviousstudies
using thisparadigm(2, 50). Exclusionofanimalsfromanalysisnot
onlyreducesthehigh-throughputnatureoftheparadigmbutmay
also resultintheexclusionofanimalsthatactuallyhavetinnitus,
butcannotbetestedduetotheabsenceofarobuststartlereflex.
Second,alterationsinbaselinestartlemagnitude(i.e.,no-gap
trials)canpotentiallyconfoundtheinterpretationofpre-pulse
inhibitionmeasuresforbothrodentsandhumansubjects(2,
57). GiventhatGPIASiscalculatedasaratiobetweenthestartle
amplitudeinno-gapversusgaptrials,achangeineitherparame-
tercanresultinachangeintheGPIASratio.Traditionally,itwas
assumedthatachangeintheGPIASratioindicativeoftinnituswas
the resultofan increase in thestartleamplitudeduringgaptrialsif
animals failedtodetectthesilentgapduetotinnitus“filling-in”the
gap(Figures4A,B; ScenarioA).However,achangeintheGPAIS
ratioindicativeoftinnituscanalsooccuriftheno-gap-startle
FIGURE 4|Effectsofalterationsinstartlemagnitudeongappre-pulse
inhibition oftheacousticstartlereflex(GPIAS)interpretation. (A,B) A
changeinstartleamplitudeforeithergaptrials(ScenarioA,gap-startle
amplitudeincreases)orno-gaptrials(ScenarioB,no-gap-startleamplitude
decreases) canresultinchangesintheGPIAS-Startleratioindicativeof
tinnitus. (C) A decreaseinno-gaptrialstartleamplitude,similartothe
schematicofScenarioB,followingtemporaryunilateralconductivehearing
loss viaanearplughasbeenshowntoresultinafalse-positivescreening
fortinnitusinratsusingtheGPIASparadigm.Thefalse-positivescreening
fortinnituscouldbeeliminatedbyreplacingtheacousticstartlestimulus
with amulti-modalairpuffstartlestimuluswhichwasmoreresilienttothe
effectsofunilateralhearinglossonstartlereflexamplitude(fromRef.(2),
with permission;*indicatessignificantdifferencebetweenstartle
amplitudesingapversusno-gaptrials; † indicates significantdifferences
betweenstartleratiovaluesbetweenbaselineandpostearplugmeasures;
n.s. indicatesnosignificantdifference).
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9. Hayesetal. Animal modelsoftinnitusandhyperacusis
amplitude decreases, similartowhatisseenfollowingunilateral
noiseexposure(Figures4A,B; ScenarioB).Moreover,unilateral
conductivehearinglossviaanearplughasbeenshowntoresult
in afalse-positivescreeningfortinnitusinratsasaresultofa
reductioninstartlemagnitudeduringno-gaptrials(Figure4C)
(2). Importantly,thefalse-positivescreeningfortinnituscouldbe
eliminatedbyreplacingtheacousticstimuluswithamulti-modal
airpuffstimulus(acousticandsomatosensorystimulation),which
was moreresilienttotheeffectsofhearingloss(Figure4C). Any
changesintheno-gap-startlemagnitudepost-tinnitusinduction
needtobeaccountedforwhenusingtheGPIASratioasanindi-
catorfortinnitusinordertoensurethatGPIASratiochangesare
trulyreflectiveofimpaireddetectionofsilentgaps,andnotsimply
duetohearingloss(2). Closeinspectionofrawstartleampli-
tudesbeforeandaftertinnitusinduction,aswellascontrolling
formethodologicalissuessuchasstimulusparametersandanimal
handlingisstronglyrecommendedwhenusingandinterpreting
behavioralmeasuresusingtheGPIASparadigm(58).
InadditiontothepotentialeffectsofhearinglossonGPIAS
measures,anotherissueiswhetherthehypothesisthattinnitus
“fillsinthegap”isaccurate.Recentstudiesinbothhumans(59,
60) androdents(61, 62) haveaddressedthisissue.InoneGPIAS
study,humanpatientswithhigh-frequencytinnituswerefoundto
haveimpairedgapdetectionforgapspresentedinbothlowand
high-frequencybackgroundstimulicomparedtocontrolsubjects
(60) (Figure5A). Sincethesepatientswithhigh-frequencyhear-
ing lossalsohadhigh-frequencytinnitus,GPIASshouldonlybe
impairedathighfrequencies,notatlowfrequencies.Becausetheir
tinnituspatientswerefoundtohavesignificantlylessinhibition
ofthestartleresponseirrespectiveoffrequency,theauthorssug-
gestthattheimpairedgapdetectionmaybereflectiveofamore
generalcorticalprocessingdisorderratherthantinnitus“fillingin
the gaps.”
Inanotherstudy,gapdetectionabilitywasassessedinhuman
tinnituspatientsbyaskingwhethertheycouldperceive50msgaps
in 15dBSLbackgroundsoundspresentedeitherattheirtinni-
tuspitch,oroneoctaveaboveandbelowtheirtinnituspitch(59)
(Figure5B). Bothcontrolandtinnitussubjectshadnodifficulty
detectingthesilentgapsirrespectiveofbackgroundfrequency(i.e.,
tinnitusdidnot“fillin”thesilentgapsatfrequenciesabove,below,
oratthetinnituspitch).Itisimportanttonote,however,that
a directcomparisoningapdetectioncannotbemadebetween
the tinnitusandno-tinnitussubjectsinthisstudybecausethe
twogroupsweretestedwithdifferentbackgroundstimuli(con-
trolsubjectsdidnothavetinnitusandthereforecouldnothave
backgroundstimulimatchedtotheirtinnituspitch).Instead,by
comparingwithinthegroupoftinnitussubjectsacrossfrequency,
the datademonstratedthattinnitusdidnot“fillin”orinterfere
withdetectionofsilentgapsinbackgroundsoundsatthetinni-
tusfrequencyoratfrequenciesoneoctaveaboveandbelowthe
matchedtinnitusfrequency(Figure5B, comparegraybarsfor
eachfrequency).Inasimilarstudy,Boyenetal.(63) recentlyfound
that humantinnituspatientshadsimilargapdetectionthresholds
comparedtoamatchednon-tinnituscontrolgroupevenwhenthe
testfrequencymatchedthepatient’stinnitusfrequency(63).
Inadditiontohumanstudies,anumberofanimalstudies
havealsoinvestigatedthe“tinnitusfillingthegap”hypothesis.
FIGURE 5|Recentstudiesaddressingthe“tinnitusgapfilling”
hypothesis. (A) Gap pre-pulseinhibitionoftheacousticstartlereflex
measures inhumantinnitusandcontrolsubjects.Tinnitussubjects
demonstrate impairedgapdetection(lowerinhibition)forbothlowand
high-frequency backgroundsoundscomparedtocontrolsubjects[fromRef.
(60), withpermission]. (B) Subjectivegapdetectionabilityassessedin
human tinnitusandcontrolsubjects.Bothcontrolandtinnitussubjectshad
no difficultydetecting50msgapspresentedinnoiseat15dBSPL.
Narrow-bandnoiseswerepresented1octaveabove,beloworatthe
matchedtinnituspitchfortinnitussubjectsandat1.2,8,and12kHzfor
control subjectswithouttinnitus[datafromRef.(59)]. (C) Gap detection
assessed inratstrainedonago/no-gooperantgapdetectiontaskto
identify silentgapsembeddedincontinuousbroad-bandnoise(BBN)and
10–20or15–17kHznarrow-bandnoise(NBN)presentedat60dBSPL.
Salicylate hadnosignificanteffectongapdetection,asgapduration
thresholds remainedbelow6ms[datafromRef.(62)].
HickoxandLiberman(61) demonstratedthatgapdetection
deficitsinnoise-exposedrodentstestedwiththeGPIASpar-
adigmaredependentontheintervalbetweenthesilentgap
and thestartle-elicitingstimulus(43). Noise-exposedanimals
demonstratedGPIASdeficitsonlywhenthesilentgapwasplaced
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