Role of attention in the generation and modulation of tinnitus

(1)

ContentslistsavailableatScienceDirect

Neuroscience

and

Biobehavioral

Reviews

j o u r n a l ho me p ag e :w w w . e l s e v i e r . c o m / l o c a t e / n e u b i o r e v

Review

Role

of

attention

in

the

generation

and

modulation

of

tinnitus

夽

Larry

E. Roberts

a,∗

_,

_Fatima

_T.

_Husain

b,c,d,1

_,

_Jos

_J.

_Eggermont

e,f,2

a_Department_of_Psychology,_{Neuroscience,}_and_Behaviour,_McMaster_University,₁₂₈₀_Main_Street_West,_Hamilton,_Ontario_L8S_4K1,_Canada b_Department_of_Speech_and_Hearing_Science,_University_of_Illinois_at_{Urbana-Champaign,}₉₀₁_South_Sixth_Street,_Champaign,_IL_61820,_USA c_The_Neuroscience_Program,_University_of_Illinois_at_{Urbana-Champaign,}_Champaign,_IL,_USA

d_The_Beckman_Institute_for_Advanced_Science_and_Technology,_University_of_Illinois_at_{Urbana-Champaign,}_Champaign,_IL,_USA e_Department_of_Physiology_and_{Pharmacology,}_Hotchkiss_Brain_Institute,_University_of_Calgary,_Calgary,_AB,_Canada f_Department_of_Psychology,_University_of_Calgary,₂₅₀₀_University_Drive_N.W.,_Calgary,_AB_T2N_1N4,_Canada

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received25April2013

Receivedinrevisedform24June2013 Accepted11July2013

Keywords:

Neuralmechanismsoftinnitus Auditoryattention Neuralplasticity Neuralsynchrony Cholingericneuromodulation Hyperacusis

a

b

s

t

r

a

c

t

Neuralmechanismsthatdetectchangesintheauditoryenvironmentappeartorelyonprocessesthat predictsensorystate.Hereweproposethatintinnitusthereisadisparitybetweenwhatthebrainpredicts itshouldbehearing(thispredictionbasedonaberrantneuralactivityoccurringincorticalfrequency regionsaffectedbyhearinglossandunderlyingthetinnituspercept)andtheacousticinformationthatis deliveredtothebrainbythedamagedcochlea.Thedisparitybetweenthepredictedanddeliveredinputs activatesasystemforauditoryattentionthatfacilitatesthroughsubcorticalneuromodulatorysystems neuroplasticchangesthatcontributetothegenerationoftinnitus.Wereviewbehavioralandfunctional brainimagingevidenceforpersistingauditoryattentionintinnitusandpresentaqualitativemodelfor howattentionoperatesinnormalhearingandmaybetriggeredintinnitusaccompaniedbyhearingloss. Theviewpointhasimplicationsfortheroleofcochlearpathologyintinnitus,forneuralplasticityand thecontributionofforebrainneuromodulatorysystemsintinnitus,andfortinnitusmanagementand treatment.

1. Introduction... 1755

2. Neuralmechanismsforattention... 1755

2.1. Top-downandbottom-upauditoryattention... 1755

2.2. Roleofbasalforebrainandtegmentalcholinergicsystems... 1756

3. Auditoryattentionandtinnitus... 1758

3.1. Neuralchangesintinnitus... 1758

3.2. Roleofauditoryattentionintinnitus... 1760

4. Evidenceofaroleforauditoryattentionintinnitus... 1762

4.1. Behavioralstudies... 1762

4.2. Electrophysiologicalevidence ... 1762

4.3. FMRIandPETimaging... 1765

4.4. Oscillatorybraindynamicsintinnitus... 1765

5. Summary,limitations,andlookingahead... 1767

5.1. Isaconceptofattentionneeded?... 1767

5.2. RoleoftheBFcholinergicandotherneuromodulatorysystems... 1768

5.3. Tinnitusandperipheralhearingfunction... 1769

5.4. Tinnitusmanagement... 1769

Acknowledgments... 1769

AppendixA. Supplementarydata... 1770

References... 1770

夽 _This_is_an_open-access_article_distributed_under_the_terms_of_the_Creative_Commons_{Attribution-NonCommercial-No}_Derivative_Works_License,_which_permits non-commercialuse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited.

∗_{Corresponding}_author._Tel.:₊₁₍₉₀₅₎₅₂₅_9140x24052;_fax:₊₁₍₉₀₅₎₅₂₉_6225.

E-mailaddresses:[email protected](L.E.Roberts),[email protected](F.T.Husain),[email protected](J.J.Eggermont). 1 _Tel.:₊₁₍₂₁₇₎₃₃₃_7561.

2 _Tel.:₊₁₍₄₀₃₎₂₂₀_5214.

(2)

1. Introduction

Individualsexperiencingapersistenttinnitus(chronicringing

of the ears) commonly report that their awareness of tinnitus

decreaseswhentheyfocusonactivitiesthatareabsorbinganddo

notrequireprocessingofsignalsintheauditorydomain.

Modula-tionoftinnitusawarenesscanﬂuctuaterapidly,suggestingeither

thattheneuralactivityunderlyingtinnitusisdynamicallyaltered

orthatitsaccesstoconsciousnessisgatedbybrainmechanisms

thataresensitivetocontextortaskdemands.Brainmechanisms

thatdirectthefocusofconsciousnessarecommonlydescribedas

thosethatperformtop-downattention-likefunctions.Incontrast,

studiesofneuralplasticityintheauditorycortex(Fritzetal.,2003;

Weinberger,2007)andothersensorysystems(Ramanathanetal.,

2009)indicatethatcholinergicneuromodulatorsdeployedtothe

cortexfromthebasalforebraingatesynapticplasticityfor

unex-pectedandbehaviorallyrelevantstimuli,performingabottom-up

attention-likefunction.Attentionhasbeencitedasafactor

con-tributingto thedevelopment and/ormodulation of tinnitusby

severalmodelsofthiscondition(Jastreboff,1995;Jastreboffand

Jastreboff,2006;Zenneretal.,2006;Searchﬁeldetal.,2012b)and

asapossiblefactorcontributingtotheﬁndingsofresearchstudies

(Guetal.,2010;Husainetal.,2011;Hoareetal.,2012).However,

themechanismsbywhichattentioniscalledandhowitsroleis

expressedintheneuralchangesunderlyingtinnitusremainatopic

ofdiscussion(Robertsetal.,2010).

Inthispaperwediscusshowattentionmaybeinvolvedinthe

generationoftinnitusanditsmodulationbytaskdemands.A

qual-itativemodelforaroleofattentionintinnitusispresentedand

recentevidenceisdiscussedinthelightofit.Akeyassumptionof

themodelisthatintinnitusthereisadisparitybetweenwhatthe

brainpredictsitshouldbehearing(thisexpectationinﬂuencedby

neuralactivityunderlyingthetinnituspercept)andtheacoustic

informationthatisdeliveredbytheeartothebrain,whencochlear

damageindexedbytheaudiogramormoresensitivemeasuresis

present.Thedisparitybetweenthepredictedandobtainedinputs

activatesmechanismsofauditoryattentionthatmaycontributeto

theestablishmentandpersistenceoftinnitusandtoitsmodulation

bycompetingtasks.

2. Neuralmechanismsforattention

Understanding how attention might beinvolved in tinnitus

isassistedbyaprovisionalunderstandingofhowattention

sys-temsareorganizedinthenormalhearingmammalianbrain.Brain

regionsthatshowdifferentialactivitybetweenaconditioninwhich

soundsareattendedto,andaconditioninwhichtheyarenot,can

bevariabledependingonthesoundattributetobedetected,the

prevailingmultisensorycontext,andthesigniﬁcanceofthesound

includingitspredictivevalueandthementalorbehavioral

oper-ationstobeperformed(Fritzetal.,2007).Thisvariabilityarises

inpartbecauseauditoryattentiondoesnot operatein isolation

ofbrainnetworksforotherfunctionsthatmaybeengagedbya

task,suchascomparingtaskstimulitothoseinmemory,

organiz-ingbehavioralresponses,andprocessingfeedbackfromthem.The

questionofhowbrainnetworksconcernedwithauditory

atten-tionrelatetonetworksthatperformsuchfunctionsortothose

thatunderlie consciousexecutivecontrolprocesses isthetopic

ofextensiveongoingresearch(PalvaandPalva,2012;Sadaghiani

etal.,2009;DehaeneandChangeux,2011).Alsodebatedarethe

neuraland synapticmechanismsbywhich theeffects of

atten-tionareachieved.Detaileddiscussionsofthesetopicsarefoundin

recentreviews(Fritzetal.,2007;PalvaandPalva,2012;Dehaene

andChangeux,2011)whichhaveprovidedabackdropforthe

dis-cussiontofollow.Itmaybethatoneshouldspeaknotofasingle

mechanismforattention,auditoryorotherwise,but ofmultiple

suchmechanismsdependingonthesensorymodalityandstimulus

attributestobeattendedtoandtheconditionsoftesting.

Alter-natively,top-downandbottom-upformsofattentionmayshare

neuralresourcessufﬁcienttospeakofasinglesystemforattention,

eventhoughitsexpressioninbrainnetworkactivitymaydepend

onthespeciﬁctaskstimulithatarepresentandthebehavioraland

cognitiveperformancerequirementsofthetaskprocedure.

2.1. Top-downandbottom-upauditoryattention

Notwithstandingthisquestion,thereisaconsensusthatseveral

brainstructuresareactiveinauditoryattentioninthenormal

hear-ingbrain,andthatauditoryattentioncanbecalledbybottom-upas

wellasbytop-downsignals.Effectsattributabletotop-down

audi-toryattentionarerevealedbytasksthatdirectthefocusofattentive

processingtoauditorysignalswhenbottom-upsensoryinputand

othertaskvariablesareheldconstant.Contrastscomparingbrain

activationsbetweenasilentbaselineconditionandaconditionin

whichsoundsarepresentedpassivelyhavefoundincreasedblood

oxygenleveldependent(BOLD)responsesinprimary(A1,

postero-medialHeschl’sgyrus)andnonprimary(A2,surroundingauditory

belt and parabeltcortex)auditory regions that reﬂect stimulus

drivenactivityoccurringintheseregions(Halletal.,2000;Johnson

andZatorre,2005;Petkovetal.,2004;Tzourioetal.,1997),although

thepossibility of somedegreeof attentionbeing drawnto the

soundscannotbeexcluded.Whenthesamesoundsareexplicitly

processedin attentiontofulﬁlla taskrequirement,brain

activ-ityincreasesfurtherintheseauditoryregions(Gradyetal.,1997;

Degermanetal.,2006;Paltoglouetal.,2009), althoughthe

pat-ternofauditoryactivationmaydependonthenatureofsounds

thatare attended.For example,attentiontosimple spoken

syl-lables (Jäncke et al., 1999)or amplitudemodulated puretones

(Ganderetal.,2010a,b)hasbeenreportedtoactivateA1andA2,

whereasattentiondirectedtomelodiesactivatedposteriorregions

ofthesuperiortemporalgyrus(STG)wheremorecomplexforms

of auditoryprocessing are believed to takeplace (Johnson and

Zatorre,2005,2006;Petkovetal.,2004).Supportingevidencefor

theviewthattheseactivationsserveanattentionalroleisfound

intheobservationthat baselineBOLDactivityintheseauditory

regionsiselevatedwhensubjectslisteninsilenceforan

impend-ingsound(Voisinetal.,2006)andwhensubjectsconsciouslydetect

atargetnoiseburstonadiscriminationtask(hits)comparedto

tri-alsonwhichthesamesoundisnotdetected(misses;Sadaghiani

etal.,2009).InthelatterstudytheanticipatoryBOLDincrement

waslargerfor hits than missessuggesting that neuronscoding

forthetargetsound hadbeensensitizedby attention,although

a contributionfrom behavioral response preparation cannot be

ruledout.Interestingly,inthelatterstudyneuralactivityintwo

non-auditorybrainnetworks,oneconsistingofbrainregions

func-tionallyconnectedinbaselinerestingstates(thefrontal/parietal

“defaultmode”network;Raichleetal.,2001;Raichle,2010)andthe

otherofnon-auditorybrainregionsfunctionallycoupledduringthe

maintenanceoftaskset(the“intrinsicalertnessnetwork”including

theanteriorcingulategyrusandanteriorinsula;Dosenbachetal.,

2006,2007),wasalsoelevatedpriortotargetdetection,while

activ-ityinathirdnetwork(thedorsalattentionsystem,consistingof

therightinfraparietalcortexandfrontaleyeﬁelds;Corbettaand

Shulman,2002)wassuppressed.Modulationoftheseadditional

networksmayreﬂectthediscriminativerequirementsofthe

detec-tiontaskandtheneedtolinkbehavioralresponseswithspeciﬁc

auditorysignals.Overalltheresultssupporttheviewthatdistinct

auditoryareas(A1andA2)areengagedbythespeciﬁcstimulus

con-tentofsoundswhentop-downauditoryattentioniscalled,butthat

otherbrainregionscanalsobemodulated.Thedorsalattention

(3)

attribute(Shomsteinand Yantis,2006; Wuetal.,2007),

under-scoringthatthespeciﬁcbrainregionsassociatedwithtop-down

auditoryattentioncanbetaskdependent.

Unliketop-downeffectsofattentionthataredirectedbytask

objectives,bottom-upeffectsofattentionaredrivenbystimulithat

occuroutsideofataskfocus.Suchstimuliareusuallymoderately

intenseorarenotpredictedbythecurrentcontext.Nonetheless,

althoughtheinitiatingevent(thetaskorstimulus)isdifferentin

thetwoattentiontypes,bottom-upstimuliappeartoengage(at

leastinearlyprocessing)thesamenetworksthatsupporttop-down

auditoryattention.Soundsthatdeviateinsomeattributefroma

repetitivestandardevokethemismatchnegativity(MMN),a

dif-ferencewave intheelectroencephalogram(EEG;deviantminus

standard)thatreachesitspeakoveralatencywindow100–250ms

afterthe occurrence of thedeviant sound. However,while the

MMNisalonglatencyresponse,devianceisexpressedatleastas

earlyastheNbauditorymiddlelatencyresponse(latency∼40ms),

whichis withintherange of earlycorticalprocessingand

sug-gests that a series of events underliesgeneration of the MMN

waveform(Grimmetal.,2011).Consistentwiththisview,fMRI

studiesoftheMMNandsourcemodelingoftheMMNEEG

wave-form(Schönwiesneretal.,2007)haveidentiﬁedgeneratorsforthis

responseinA1(Heschl’sgyrus)andinA2(superiortemporalgyrus

andplanumtemporale),aswellasinregionsofmid-ventrolateral

prefrontalcortex thathavebeenimplicated intop-down

atten-tional or executive control in primates (Petrides et al., 2002).

Alatencydifference of∼60ms betweenthetemporal and

pre-frontalresponsessuggeststhatchange-relatedactivityinfrontal

regionsmayrelyonafferentprojectionsfromthetemporallobes,

althoughreciprocalcommunication betweentheregions isalso

possible(Schönwiesneretal.,2007).Inadditiontothispathway

thereticularactivatingsystem(RAS)sendsprojectionsfromthe

brainstemtothesuperﬁcialneocorticallaminae(Eggermontand

Moore,2012)thatbypassthethalamusandmaymodulateearly

corticalresponsessuchastheNbwhendrivenbyarousal-worthy

(unpredicted)sounds.Activationofthecortexbyunpredicted

sig-nalsmayprovideaccesstohigherordermemoryrepresentations

thatmaybeneededtoassessnovelsensoryinputs.Thevariable

natureoftheserepresentationsmaycontributetothevariability

inthelatencyoftheMMNthatisseenacrossdifferenttasksand

stimulusprocedures(Grimmetal.,2011).

2.2. Roleofbasalforebrainandtegmentalcholinergicsystems

Theinvolvementofprefrontalregionsintop-downand

bottom-upattentionisworthyofnote,becausethisregionisreciprocally

innervatedbythebasalforebrain(BF)cholinergicsystemwhich

hasalsobeenimplicatedinattention-likefunctions(Sarteretal.,

2005).CholinergicefferentsoriginatingfromnucleiintheBF(see

Fig.1a,adaptedfromSarteretal.,2009)projecttoallregionsofthe

neocorticalmantleinacoarseregionaltopography(Mesulametal.,

1983;Jiménez-Capdevilleetal.,1997),includingprefrontal,

pari-etal,andallocorticalstructuresimplicatedinattentionalprocessing

aswellasthe“GlobalNeuronalWorkspace”proposedbyDehaene

andChangeux(2011)tobeactiveinconsciousprocessing.This

pro-jectionisbelievedtomakethetargetedpyramidalneuronsmore

sensitivetotheirafferent inputsby promotingthe

extrasynap-ticreleaseofacetylcholineonmuscarinicandnicotinicreceptors

(Metherate and Ashe, 1993; Metherate, 2011)or by acting on

heteroreceptorstoachievefunction-speciﬁceffects(Sarteretal.,

2009).AparallelGABAergicinnervationhasbeendescribed(Freund

andMeskenaite,1992)targetinginhibitorycorticalinterneurons

suggestingasynergisticeffectoncorticalprocessing.A

choliner-gicprojectionfromtheBFtothereticularnucleusofthethalamus

hasalsobeendescribed, whichaltersthalamicneuronresponse

patternsevokedbypreviouslytrainedsoundsandmayplayarole

inmodulatingthalamocorticaltransmissionbasedonthe

learn-inghistoryoftheanimal(Hallangeretal.,1987).Theoveralleffect

of activating the BF cholinergic system is to shift the balance

ofexcitationand inhibitionincorticalnetworks,facilitatingthe

processingofthalamocorticalrelativetolocalintracorticalinputs

totheneocorticalmantle(Sarteretal.,2005).TheBFcholinergic

systemisdrivenbottom-upbyauditoryandothersensoryinputs

viathalamicafferentsconveyedthroughtheamygdalaaswellas

bydopaminergic reward systemsin theventraltegmental area

(VTA);inreturn,theBFsystemreceivestop-downprojectionsfrom

prefrontalcortex(PFC)eitherdirectlyormediatedbythenucleus

accumbens(NAc:seeFig.1a).Thisdualinnervationbybottom-up

andtop-downinputsimplicatestheBFasakeystructureinboth

typesofattention.DistributedprojectionsfromtheBFtothe

neo-corticalmantlecouldenablehighlyspeciﬁcbrainactivationsdriven

bythespeciﬁccontentofenvironmentalstimuli,withouttheneed

forspecializedattentionsystemsfordifferentsensoryattributes.

Attentionalmodulationsarisingfromamechanismofthistype

wouldbeexpectedtodependonthelearninghistoryofthe

organ-ism.Passiveimmersion ina distinctivesound environment has

beenshowntoleadtosubstantialchangesincorticalmap

orga-nizationfortheexposurefrequenciesintheimmaturebrain(de

Villers-Sidanietal.,2007;Zhangetal.,2001)andmorerecently

inmatureanimalsaswell(Nore ˜naetal.,2006;Pienkowskiand

Eggermont,2009,2010,2011,2012;ZhouandMerzenich,2012).

Althoughtherulesofthisformofplasticityareonlypartly

estab-lished,evidencesuggeststhatpassiveexposure-inducedplasticity

indevelopingandadultanimalsmaysharecommonmechanisms

but differin theconstraintsapplied tothesemechanismsafter

theclosureofdevelopmentalsensitiveperiods(Pienkowskietal.,

2013).CholinergicprojectionsfromtheBFtotheneocortical

man-tlearealsodevelopmentallydependent,reachingmaturityinthe

ratbrainatatime correspondingapproximatelytoadolescence

inprimates(KissandPatel,1992).Whileitsroleinpassive

learn-ingisnotpresentlyknown,theBFcholinergicsystemisinvolved

ingatingneuralplasticityonactivelearningtasks,inwhichadult

animalsaretrainedtorespondtospeciﬁcauditorysignalstoobtain

reward(Weinberger,2004).Thespectrotemporalreceptiveﬁeldsof

auditoryneuronsarepreciselysculptedbysuchtrainingto

repre-sentthespeciﬁcsoundattributescontainedinthesignal(Dahmen

andKing,2007),includingbestfrequency(Recanzoneetal.,1993; Weinberger,2007),amplitudeandfrequencymodulations(Kilgard etal.,2001;Fritzetal.,2005),andtemporalpatterning(Kilgard and Merzenich, 1998, 2002). Changes occurred only when the

trainedsoundssignaledimportantgoalssuchasafoodpelletor

animpendingelectricshock,implicatingaroleforattention;

pre-sentationofthesamesoundswhiletheanimalperformedatask

requiringattentiontoadifferentsensorymodalitydidnotalter

corticalrepresentationsfortheauditorystimuli(Recanzoneetal.,

1993;BuonomanoandMerzenich,1998)althoughthereisevidence

thatperceptualperformancecanimprovewithoutsubstantialmap

changes(Brownetal.,2004).Followingauditorytrainingon

mul-tiplespectrotemporaltasksinferrets,thetuningpropertiesofA1

neuronsarerapidlymodulatedbychangesinthetaskcontext

sug-gestingacquiredtop-downattention-likeeffects(Fritzetal.,2007).

Thesechangesarecoherentwithneuralresponsesrecorded

simul-taneouslyfromregions ofPFCcortexthatarehomologouswith

prefrontalregionsimplicatedintop-downattentioninprimates

(Fritzetal.,2010).Whilethespeciﬁcmechanismsunderlyingthese

observationsarenotfullyknown,controloftheneuralresponses

bytaskcuesestablishedbytheirlearninghistoriesislikelytohave

actedthroughtheBFcholinergicsystem(Weinberger,2007).

Con-sistentwiththis hypothesis,plasticchangesthatareinducedin

corticalforelimbrepresentationsbyskilledforelimbtraininginrats

werepreventedwhentheBFcholinergicprojectionwasablatedby

(4)

Fig.1. Cholinergicneuromodulatorysystems.(a)Thebasalforebraincholinergicsystem(shownfortherat,adaptedfromSarteretal.,2009,withpermission).Cholinergic neuronsoriginatefromthenucleusbasalisofMeynert,thesubstantiainnominataandtheverticalandhorizontalnucleiofthediagonalbandofBroca(collectivelytermed theBF)andinnervateallcorticalareasandlayers.Theprefrontalcortex(PFC)istheonlycorticalregion,inrodentsandprimates,thatisknowntoprojectbacktothe BFbothdirectlyandindirectlythroughthenucleusaccumbens(NAc).Thisorganizationprovidesanavenuefortop-downcontroloftheBFbythePFC.TheBF,PFCand NAcarefurtherinnervatedbydopaminergicneuronsfromtheventraltegmentalarea(VTA,dashedlines),whiledopaminergicneuronsareinturncontactedbyPFC projectionsallowinginteractionsbetweenattentionandreward/arousalpathways.NotshownareprojectionstotheBFfromthalamicsensorynucleiviatheamygdala, returnprojectionstothalamicandsubcorticalstructures,orparallelGABAergicprojectionsfromtheBFtargetinginhibitorycorticalinterneurons(FreundandMeskenaite, 1992).(b)Pontomesencephaliccholinergicsystem.Subcorticalcholinergicprojectionsfromthepontomesencephalictegmentum(PMT,shadedpink)andsuperiorolivary complex(SOC,shadedblue)tothecochlearnucleus(CN)areshown.ArrowsindicateprojectionsfromtheSOCandtwonucleiofthePMT,thepedunculopontinetegmental nucleus(PPT)andthelaterodorsaltegmentalnucleus(LDT),totheCN.AlsodepictedareascendingprojectionsfromthePMTtothethalamusandcortex,andreturnprojections fromlayerVpyramidalcellsinauditorycortextothePMTwhichprovideapathwayfortop-downinﬂuences.(AdaptedfromMellottetal.,2011,withpermission;SCP: superiorcerebellarpeduncle;IC:inferiorcolliculus.)(Forinterpretationofthereferencestocolorinthisﬁgurelegend,thereaderisreferredtothewebversionofthearticle).

deafferentationinthesameanimals(facialmotornerve

transec-tion)wasnotaffectedbythisprocedure(Ramanathanetal.,2009).

CholinergicprojectionstotheneocorticalmantlefromtheBF

thusappeartoperformanattention-likefunction,gatingneural

plasticityin accordance with thesigniﬁcance of environmental

soundsand othertaskstimuli.Asecondcholinergicpathwayin

subcorticalstructureshasbeenidentiﬁedinthepedunculopontine

(PPT)andlaterodorsal(LDT)nucleiofthemidbraintegmentum,

referred tocollectively as the pontomesencephalic tegmentum

(PMT;MottsandSchoﬁeld,2010;seeFig.1b,adaptedfromMellott

etal.,2011).AlthoughthePMTisconsideredtoformpartofan

ascendingarousalsystemthatmodulatestheﬂowofinformation

throughthethalamus invariousstagesofthesleep–wakecycle

(Edeline,2003;Hennevinetal.,2007),itsfunctionaland

anatom-icalconnectivityalsosuggestarole ingatingsensorystimuliin

thealertanimal(SchoﬁeldandMotts,2009).Inadditionto

send-ingcholinergicprojectionstoseveralauditorysubcorticalnuclei

includingthemedialgeniculatebody,inferiorcolliculus,and

dor-salcochlearnucleus(MottsandSchoﬁeld,2010),thePMTreceives

direct projections from layer V pyramidal neurons in primary

auditorycortex,whichcouldexertatop-downinﬂuenceon

neu-ral processing in subcortical auditory structures (Schoﬁeld and

Motts,2009).Electricalstimulationofcholinergicinputstothe

dor-salcochlear nucleusinvitromodulatesthesignofspike-timing

dependent plasticity (STDP) in this structure, converting

Heb-bianlong-termpotentiationtoanti-Hebbiandepressioninparallel

ﬁber-fusiformcellsynapsesthroughretrogradeendocannabinoid

signaling(ZhaoandTzounopoulos, 2011).Ithasbeensuggested

thatanti-Hebbiandepressionofthesesynapsesformsanegative

imageofongoingauditorynerveactivityoccurringintheparallel

ﬁbersystem(ZhaoandTzounopoulos,2011).Becauseparallelﬁbers

conveysomatosensoryinformation fromtheregionof thehead

andneckincludingthevocaltractandpinnae(KanoldandYoung,

2001), this mechanism couldperform a ﬁltering, attention-like

function,bysuppressingauditoryresponsestoone’sown

vocali-zationsrelativetothosethatarisefromexternal soundsources.

InputsfromthetegmentalandBFcholinergicsystemsconverge

atthelevelofthethalamus(Hallangeretal.,1987)wherejointly

theymayinﬂuencethetransmission ofinformation tothe

cor-texduringattentiveprocessingandlearning.Afurthersubcortical

cholinergicprojectionfromthesuperiorolivarycomplex(SOC)to

thecochlearnucleus(CN)isthoughttoplayaroleingatinginput

fromtheearviaolivocochlearefferents(Mellottetal.,2011;see

Fig.1b).Olivocochlearefferentsfromthelateralsuperiorolive(LSO)

releasedopamineontoinnerhaircells,regulatingtheirsensitivity

andprotectingagainstglutamateexcitotoxicityinthepresenceof

loudsounds(Lendvaietal.,2011).Aftercochleardamageinduced

(5)

dorsal(DCN)cochlearnucleusisupregulatedforupto2months

(thelongestdurationstudied),suggestingaroleforthispathway

inadaptationsthatoccurinhearingloss(Jinetal.,2006;Kaltenbach

andZhang,2007;Meidingeretal.,2006).

GiventheroleoftheBFandpontomesencephaliccholinergic

systemsingatingsensorystimuliandinmodulatingneural

plastic-ity,itisplausibletoaskwhetherauditoryattentionactingthrough

thesesystemsmaybeinvolvedintheneuralchangesthat

under-lietinnitus.Ifauditoryattentionisinvolved,howistheattention

systeminvolvingthesestructuressignaled,andhowmightit

con-tributetothegenerationand/ormaintenanceoftinnitus?Inthe

nextsectionweaddressthesequestions,startingwithanaccount

oftheneuralchangesassociatedwithtinnitusandtheirrelation

tohearingloss.Inlatersectionstheroleofotherneuromodulatory

systemsisalsoconsidered.

3. Auditoryattentionandtinnitus

Mostcasesoftinnitusareassociatedwithhearinglossexpressed

eitherintheaudiogramorputativelydetectedbymoresensitive

measures.Whensubjectsareaskedtorateseveralsound

frequen-ciesforsimilaritytotheirtinnitus,similarityjudgmentstypically

commenceneartheedgeofnormalhearingintheaudiogramand

increaseinproportionwiththedepthofhearingloss,yieldinga

tinnitusspectrumthatspansthehearinglossregion(Nore ˜naetal.,

2002;Robertsetal.,2006;Seredaetal.,2011;Zhouetal.,2011).

Itisalsoknownthatband-passmaskingsoundsthat producea

post-maskingsuppressionoftinnitus(residualinhibition,RI)doso

optimallyinproportiontotheextenttowhichtheircenter

frequen-cies(CFs)areinthesamefrequencyregion(Robertsetal.,2008).

Theseresultssuggestthataberrantneuralchanges takingplace

inthehearinglossregionsofcentralauditorystructuresunderlie

tinnitus,anddisruptingthesechangessuppressesit(seeFig.2a).

Researchinanimalmodelsofhearinglosshasbeguntoidentify

someoftheneuralchangesinvolved.

3.1. Neuralchangesintinnitus

Oneoftheneuralchangesconsequentonhearinglossis

tono-topicmapreorganization,in which neuronsinthehearingloss

regionofprimaryauditorycortex(A1)begintoexpressthetuning

preferencesoftheirunaffectedneighborstherebyaugmentingthe

representation of neighboring frequencies in the cortical place

map (Rajan and Irvine, 1998a; Eggermont and Komiya, 2000;

Fig.2b).Map reorganizationinA1, whichhasbeenobservedin

humantinnitussuffererswithhearingloss(Wienbruchetal.,2006),

suggeststhatpre-existinginputs onlateralconnections to

neu-ronsinthehearinglossregionnowhaveastrongerinﬂuenceon

theseneuronsthandosurvivinginputsfromthalamocortical

path-ways(EggermontandRoberts,2004;Fig.1c).Otherhearingloss

inducedchanges includeshifts inthebalance ofexcitation and

inhibitioninauditorycorticalnetworks(SchollandWehr,2008),

increased spontaneous activity of neurons in central auditory

structures(Kaltenbachetal.,2004;Nore ˜naandEggermont,2003;

Dehmeletal.,2012),increasedburstﬁringinsomeofthese

struc-tures(Nore ˜naand Eggermont,2003; Finlaysonand Kaltenbach,

2009),andincreasedsynchronousactivityamongcorticalneurons

affectedbyhearingloss(Nore ˜naandEggermont,2003).Changesin

centralgaininauditorypathways,inwhichtheinput/output

func-tionsofauditoryneuronsaffectedbyhearinglossareampliﬁedto

compensatefordiminishedinputfromthecochlea(Nore ˜na,2011;

Schaetteand McAlpine,2011; Chrostowskietal.,2011;Dehmel

etal.,2012),maycontributetothesechangesandtohyperacusis

(increasedsensitivitytosounds)thatoftenaccompaniestinnitus

andmaybeanearlymarkerforthecondition.Althoughthespeciﬁc

contributionofthesevariousneuralchangestotinnituspercepts

isnotfullyunderstood,enhancedneuralsynchronyinthe

audi-torycortexisalikelyproximalneuralcorrelateoftinnitus,because

itislargelyconﬁnedtothehearinglossfrequencies(Nore ˜naand

Eggermont, 2003) which is the frequency range where human

subjectsalsolocalizetheirtinnituspercepts(Nore ˜naetal.,2002;

Robertsetal.,2008).Computationalfactorsalsopointtoarolefor

synchrony,sincephaselockedoutputfromanetworkofneuronsis

morelikelytodepolarizeapostsynaptictargetthanistemporally

incoherentinputtothesameneurons(Nieburetal.,2002;Singer,

1999;StevensandZador,1998).

Formsofneuralplasticityarebelievedtocontributetothese

neuralchangesfollowinghearingimpairment.Cochleardamage

inananimalmodelofhearinglossisfollowedwithin2weeksby

anupregulationofsomatosensoryinputstoauditoryneuronsin

theDCN,oneoftheearlyprocessing stagesinsubcortical

audi-torypathways(Zengetal.,2009,2012).Thischangeisbelieved

toreﬂectaformofplasticitycalledhomeostaticplasticity,which

actstopreservetheglobalﬁringratesofdeafferentedneuronsin

corticaland subcorticalstructures withina prescribeddynamic

range(Turrigianoand Nelson,2004;PozoandGoda,2010).

Evi-denceforhomeostaticplasticityoperatingintinnitusisfoundin

recentreportsofdifferencesbetweenindividualswithand

with-outtinnitusin componentsoftheauditorybrainstemresponse

(ABR),whenhearingthresholdsarenormalinbothgroups.

Com-paredtocontrolswithnormalhearingWaveIoftheABR(latency

∼2ms,reﬂectingoutputfromthecochlea)isreducedintinnitus

suffererswithnormalaudiograms,implyingundetecteddamage

tothecochleasuchasthatattributabletolossofhighthreshold

ribbonsynapsesoninnerhaircells(IHCs)followingnoiseexposure

(KujawaandLiberman,2009)orcochleardeadregionsmissedby

conventionalaudiometry(Weiszetal.,2006).However,ABRwave

V(latency∼6ms,originatingfromgeneratorsintheauditory

mid-brain)iseithernotreduced(SchaetteandMcAlpine,2011)oreven

augmented(Guetal.,2012),suggestingcompensatorychangesin

theinterveningcentralauditorystructures.Atthecorticallevel

anundesirableconsequenceofhomeostaticplasticitymaybean

increaseinthespontaneousanddrivenactivityofauditory

neu-ronsfollowinghearingimpairment(Nore ˜na,2011;Schaetteand

McAlpine,2011;Chrostowski etal.,2011), setting thestagefor

thedevelopmentoftinnitusandabnormalsoundleveltolerance

orhyperacusiswhich isexperienced bymanytinnitussufferers

(Nore ˜na,2011;Guetal.,2010;Hébertetal.,2013).

Increasedneuralsynchrony,whichmayplayacrucialroleinthe

generationoftinnituspercepts,isafurtherneuralcorrelateof

tinni-tusthatmayresultfromneuroplasticmechanisms(Eggermontand

Roberts,2004;Weiszetal.,2007a,b).Followinghearinglossand

diminishedintracorticalinhibition,corticalneuronsintheregions

affectedbyhearinglossbegintodischargeinphaselocked

pat-terns(SekiandEggermont,2003;Nore ˜naandEggermont,2003)

likely mediatedby theirlateralconnectionsor byother shared

inputssuchasrhythmiclocalﬁeldpotentialsarisingfromrecurrent

corticothalamicactivitydisinhibitedbyhearingloss(Llinasetal.,

2005).Subsequentlysuchcorticalnetworkactivitymaybeforged

intolargerfunctionalassembliesbyspike-timingdependent

plas-ticity(STDP)inthecorticalhearinglossregion(cf.YaoandDan,

2001),givingrisetotinnitussounds.Changesinspontaneous

activ-ity(occurringeitherintrinsicallyintheauditorycortexorconveyed

fromsubcorticalauditorystructures)inducedbycochleardamage

couldprovideasubstratefor thedevelopmentofsuchnetwork

activity.Ifthisprocesscontinuesunabatedoveraperiodoftime,

chronicfunctionalchangesmayresultinatinnitusthatis

depend-entwhollyoncentral mechanismsand resistanttotherapeutic

intervention(Nore ˜naandFarley,2013).Althoughitisnotknown

whether STDP or someother neuroplastic process is involved,

(6)

Fig.2.Psychoacousticpropertiesandcorticalmapreorganizationintinnitus.(a)Thegroup-averagedaudiogram,tinnitusspectrum,andRIfunctionfor47participantswith chronicbilateraltinnitusareshown.Toobtainthetinnitusspectrum,participantsratedeachof11soundsdifferingincenterfrequencyforsimilaritytotheirtinnitus(a likenessrating>40indicatedasoundbeginningtoresembletinnitus).TheRIfunctionshowsthesuppressionoftinnitusreportedaftercessationofband-limitednoisesounds differingincenterfrequency(−5equaled“tinnitusgone;”0,nochange;+5,tinnitusworse).TheRIfunctionisplottednegativeuptoshowitssimilaritytothetinnitus spectrum.WN,whitenoise(fromRobertsetal.,2008,withpermission).(b)Inthenormalhearingcat(diamonds),thecharacteristicfrequencytuningofneuronsatlow soundintensityshowsanorderlygradientfromlowtohighfrequenciesacrossthesurfaceofA1(tonotopy).Incatsexposedtonoisetrauma(+),neuronsinthehearingloss region(above8kHzinthisexample)respondedpreferentiallytosoundfrequenciesattheedgeofnormalhearing(fromEggermontandKomiya,2000,withpermission). (c)Modelformapreorganizationinprimaryauditorycortex.Thedashedlinesrepresentdiminishedthalamocorticalinputtocorticalcellsinthehearinglossregion.Afew inhibitoryfeedforwardconnectionsareindicated(oneislabeledi)thatsuppressthesamecellsreceivingthalamicinputsafteronesynapticdelay.Feedbackinhibitionis indicatedbyoneexample(ii).Hearinglossreducesexcitationandfeedforwardinhibitionarisingfromthalamocorticalpathways,suchthattheaffectedneuronsbeginto respondpreferentiallytoinputsfromtheirunaffectedneighborsviahorizontalconnectionsinthetonotopicmap.Theoutputoftheaffectedneuronsremainsintactandis heardintermsoftheiroriginalcochleotopictuningasthetinnituspercept.

(7)

describedinsubcorticalauditorynucleifollowingcochlear

dam-ageinducedbynoisetrauma.Intheinferiorcolliculus(IC)ofguinea

pigsincreasedspontaneousactivityinducedbycochleardamageis

reducedbystimulatingolivocochlearefferentsorbycochlear

abla-tionuptoabout6weeksafternoisetrauma,demonstratingthat

initsearlystageIChyperactivityisatleastpartiallydependenton

continuedafferentinputfromtheear(Muldersetal.,2010).

How-ever,afterabout8weekscochlearablationnolongerhadanyeffect

onIChyperactivity,indicatingatransitiontomechanisms

intrin-sictotheICorinauditoryregionsprojectingtothisstructurehad

occurredoverthis timewindow(Mulders andRobertson,2011;

Robertsonetal.,2013).

3.2. Roleofauditoryattentionintinnitus

Givenitsroleinmodulatingthesensitivityofcorticalneurons

totheirafferentinputsanditsconsequencesforneuralplasticity,a

mechanismforauditoryattention(particularlyoneinvolvingthe

basalforebraincholinergicsystem)couldbeexpectedtoplay a

roleinforgingneuralnetworkactivitiesthatunderlietinnitus

per-cepts.Zenneretal.(2006)similarlyproposedaroleforattention

inestablishingtheneuralchangesunderlyingtinnitus,although

aspeciﬁcmechanism forattentionand thecircumstances

lead-ingtoitsengagementwerenotdescribed.InFig.3wedescribe

aqualitativemodelofhowattentionandtinnitusmightbelinked.

Brieﬂy,thismodelproposesthataprincipalroleoftheauditory

cortexistoconstructdynamicrepresentationsoftheacoustic

envi-ronmentthatintegratecurrentauditoryinputwiththeorganism’s

pasthistorywithsound.Theserepresentationsserveastemplates

forﬁlteringandpredictingsensorystateandinthemodelofFig.3

arereadoutasapatternofexcitationonabankofpyramidal

neu-ronsthatperformacomparatorfunction.Soundsthatarepresent

intheenvironmentgenerateapatternofinhibitionconveyedto

thesameneurons.Innormalauditoryperception(Fig.3a)the

pre-dictedrepresentationisbuiltoncurrentauditoryinputinteracting

withinformationcontainedinmemoryaboutthehistoryofsounds

theorganismhasheardand theircorrelatesinthecurrent

con-text.Ifthisrepresentationiscongruentwithafferentinputarriving

fromauditorypathways,thepatternsrepresentingpredictedand

obtainedinputscanceleachotherandneuralprocessingcontinues

uninterruptedinaccordancewiththehistoryoftheorganismin

itscurrentauditoryenvironment.However,shouldanunexpected

auditoryeventoccur,thepredictedandobtainedpatternsnolonger

matchandasignalisgenerated,callingauditoryattentionwhich

facilitatesbuildinganewandmoreaccuraterepresentationofthe

auditoryscene.Innormalhearingwherecochlearfunctionisintact,

thisprocessmayrequireoneortwohundredmillisecondsormore

forcompletion(Rossetal.,2002).Butinthecaseoftinnituswhere

cochlearpathologyispresumedtobepresent(illustratedinFig.3b),

theoutcomeisdifferent.Herethesoundrepresentationgenerated

bytheauditorycortexincorporatesaberrantsynchronousneural

activityoccurringin the hearinglossregion that ispart ofthe

organism’shistoryandhasbeenencodedinmemoryinauditory

associationareasor highercenters. Becausethis representation

is not congruentwith bottom-up input arriving from auditory

pathways, the mismatch of top-downand bottom-up

informa-tionresultsinapersistingdeploymentofauditoryattention.The

BFcholinergicsystemwhichprojectsdenselytotheneocortical

mantlemaybeakeyelementinthisattentionsystem,although

aroleforpontomesencephaliccholinergicorother

neuromodula-torscannotbeexcluded.CholinergicmodulationbytheBFsystem

wouldbeexpectedtoexertapowerfuleffectonsynaptic

plastic-ity,broadeningthetuningpropertiesofthetargetedneuronsand

fosteringtheformationofspike-timingdependentlinkagesamong

them(Sarteretal.,2009;Pawlaketal.,2010).Becausecholinergic

modulationaltersthebalanceofexcitationandinhibitiontoward

excitationincentralauditorystructures,itcouldalsoincreasethe

spontaneousﬁringratesofauditoryneuronsinthesestructures.An

exceptiontothisscenariomayoccurwhenthesoundfrequencies

containedintheauditoryenvironmentcorrespondmoreclosely

withthosepredictedbyhigherauditorycenters.Underthese

con-ditions(suchasduringmaskingyieldingresidualinhibition)the

Fig.3.Aqualitativemodelfortheroleattentionnormalhearingandintinnitus.ThemodelisadaptedfromthecanonicalneocorticalcircuitdescribedbyDouglasandMartin (1990)fromneuroanatomicaldata,inwhichexcitationisdeliveredpreferentiallytopyramidalneuronsinthesuperficialneocorticallayersandfeedforwardinhibition preferentiallytopyramidalneuronsinthedeeplayersafteronesynapticdelay.(a)Innormalhearingpredictedsoundsmaybereadoutasapatternofexcitation(black)ona bankofpyramidalneuronswhereeachneuronperformsacomparatorfunction.Thispredictionisdeterminedbyintegrationofarunningmemoryofinputsfromtheintact earandoutputfromauditoryassociationareasthatprovidefeedforwardinformationaboutacousticinputsthatareexpectedintheprevailingauditorycontext.Soundsthat arepresentintheenvironmentgenerateapatternofinhibition(red)thatisconveyedtothesamecomparatorneurons.Althoughherefeedforwardinhibitionisassigned thisrole(Creutzigetal.,2010),anyinhibitoryprocesscouldperformitprovidedthatitcontainssufficientspectrotemporalspecificitytorepresentthesoundenvironment. Innormalhearingthetwoinputsmatchandcanceleachother,providedthattheauditorysceneisreasonablystable,suchthatcurrentsoundrepresentationscontinueto guideintracorticalprocessingandbehaviorinaccordancewiththerecenthistoryoftheorganism.(b)Intinnitus,aberrantsynchronousactivityforgedbyneuralplasticity infrequencyregionsaffectedbyearloss(thispatternstoredinauditormemory)generatesapatternofexcitationoncomparatorcellsthatisnotcanceledbyinibition arisingfromdamagedauditorypathways(brokenlines,redinhibitory,blackexcitatory).Themismatchbetweenpredictedandexperiencedinputscallsauditoryattention whichisexpressedinprimaryandsecondaryauditoryregionsandprefronalcortexasthecortexattempts(unsuccessfully)toconstructamoreaccuraterepresentationof theacousticenvironment.Cholinergicneuromodulationmayreinforcepersistentabberentneuralsynchronyunderlyingthetinnituspercept(green>facilitatory).(MGBv– ventralmedialgeniculatebodyinthethalamus;BF–basalforebrain;VM–ventromedialprefrontalcortex)(Forinterpretationofthereferencestocolorinthisfigurelegend, thereaderisreferredtothewebversionofthearticle.).

(8)

predictedandobtainedspectralpatternsofauditoryinput

corre-spondmorecloselywitheachother,andtheexperienceoftinnitus

maysubsideonlytoreturnwhenthecongruentsoundfrequencies

arenolongerpresentintheacousticscene.

Itwillbenotedthattheviewpointdescribedhereproposesa

keyrolefortheauditorycortexinthegenerationandmaintenance

oftinnitus percepts(Eggermontand Roberts,2004;Eggermont,

2012).Auditorycortexormoregenerallythethalamocortical

sys-temislikelynecessaryforperceivingtinnitus;withoutitthereis

usuallynotaconsciousauditorypercept,andlikelynotthe

annoy-anceaspect.Furthermore,thethalamocorticalsystemdoesmore

thanjustrelayinformationfromthemidbraintocortical

associ-ationareas.Morethan90%ofneuralinputstoacorticalneuron

arefromothercorticalcells;evenintheinputlayersofauditory

cortexatmost10%oftheinputsareofthalamicorigin(Abeles,

1991).Itisthuslikelythatauditorycorticalneuronsworkmostly

ontheirintrinsiccorticalinputs.Theoutputoftheauditory

cor-textothethalamusfaroutweighstheinputthethalamusreceives

fromtheauditorymidbrain,atleastifitparallelsthevisualsystem

(VanHornetal.,2000),whichsuggeststhatcorticofugalfeedback

fromtheauditorycortexexertsacontrolfunctiononsubcortical

structures.Theseanatomicalfeaturessuggestacortexthatismore

ofa representationaland informationprocessing systemthan a

passive recipientof bottom-up acoustic input.It has a

“world-view”thatcanonlybechangedwheninputfromtheenvironment

violates itsexpectations,inaccordance withatrusted principle

adoptedbywell-knownrulesthatdescribeassociativelearningin

severalspeciesand contexts(RescorlaandWagner,1972;Esber

andHaselgrove,2011).Thissensitivitytochangeisalsoreﬂectedin

severalformsofevent-relatedpotentialsthataregeneratedby

vio-lationsofexpectation.Thepre-attentiveMMNdiscussedaboveis

onesuchpotential,butothersreﬂectingchangedetectionincortical

networksatdifferentlevelsofprocessingincludelonglatencyP300

odd-ballresponsesorlanguage-relateddeviantssignalingsemantic

(N400)andsyntactic(P600)violations(Friederici,2002)whichmay

requirelonglatencytop-downinputfromhighercorticalmemory

centersinordertoformpredictiverepresentations.

Inadditiontoitsrepresentationalcapacity,otherfeatures of

auditory corticalprocessing that may be important in tinnitus

pertain tohowitsdynamics arealtered bydeafferentation and

howneuralplasticityisexpressedthere.Althoughformsofneural

plasticityareexpressedatmultiplelevelsoftheauditory

projec-tionpathway(Zengetal.,2009;ZhaoandTzounopoulos,2011),

corticalauditoryreceptiveﬁeldsareknowntobehighlypliable

throughlearningandarerapidlymodulatedbytrainingcontexts

toreﬂectpreviouslearninghistories(Fritzetal.,2003;Polleyetal.,

2006).Asdiscussed above,long-term passiveexposureto

low-levelbackgroundsoundswithoutsignalvaluecanalsoalterthe

responsepropertiesofauditoryneuronsoverwideswathsof

cor-tical territorythatpersistatleastontheorder ofmonthsafter

exposure(PienkowskiandEggermont,2009).Inthelatter

experi-mentschangesincorticalactivitywereachievedthroughexposure

toexternalsounds,whereasintinnitusauditoryintracortical

activ-itymayhaveadifferentsource(deafferentation);nonethelessin

bothcasessustainedintrinsicactivityappearstoproduceneural

changesintheauditorycortexthatarepersistent,althoughthe

sourceofintrinsicactivityanditsperceptualconsequencesmaynot

bethesame.Becauseitfosterscommunicationacrosswideregions

oftheauditorycortex,possiblyenablingspike-timingdependent

neuroplastic changes affectingthis region,tonotopic map

reor-ganizationmaybeacontributingfactorinenablingmaladaptive

plasticityafterhearingloss.Mapreorganizationinadultanimals

occursintheauditorycortex(Rajanetal.,1993;RajanandIrvine,

1998a)andauditorythalamus(Kamkeetal.,2003)followingnoise

traumaormechanicaldamagetothecochlearhaircells,butnot

intheauditorymidbrain(Irvineetal.,2003)orcochlearnucleus

(RajanandIrvine,1998b).Homeostaticplasticityisafurther

estab-lished mechanism operating indeafferented auditorypathways

(Zengetal.,2009)thatmayincreasecentralgainandthe

sponta-neousanddrivenresponsesinauditoryneurons.Thismechanismis

aputativesourceofincreasedsensitivitytoexternalsounds

(hyper-acusis)observedintinnituspatients(Hébertetal.,2013).However,

asdiscussedearlier,increasedneuralsynchronyincorticothalamic

regionsaffectedbyhearinglossmaybeespeciallyimportantfor

theexperienceoftinnitus.Increasedneuralsynchronycoincides

withtonotopicmapchangesandtheregionofimpairmentin

ani-malmodelsofhearingloss(Nore ˜naandEggermont,2003),while

inhumanstinnitusspectraandresidualinhibitionfunctions

simi-larlytracktheregionofthresholdshift(Nore ˜naetal.,2002;Roberts

etal.,2008).

ThemodelofFig.3isintendedtoillustratehowpredicted

audi-toryeventsmightbeevaluatedatthelevel ofprimaryauditory

cortex.Althoughinputfromauditorypathwaystothecortexis

presumedtobeimpairedin tinnitus,leadingtoprediction

fail-ure,theoutputofcorticalneuronsrepresentingthetinnitussound

remainsintact,suchthatthepredictedpatternofauditoryactivity

maybeconveyedcorticofugallytosubcorticalstructuresaswell

ascorticopetallytohigherassociationareas,enablingthe

predic-tiontobeassessedat multiplelevelsoftheauditoryprojection

pathway.Predictionhasbeenproposedbyseveralauthorsasan

operatingprincipleintheauditorysystem(seeWinkleretal.,2009

andBendixenetal.,2012forreviews)andinotherdomains(Schultz andDickinson,2000).InthemodelofWinkleretal.(2009),whichis

concernedwithauditorysceneanalysis,attentionisconsideredto

beafactormodulatingthedetectionofpredictionfailure(detection

ofdeviance)andpromotingthestimulusdrivenbindingofsensory

attributestoformnewauditoryobjectsindynamicauditory

envi-ronments.Likethecurrentmodeloftheroleofattentionintinnitus,

Winkleretal.(2009)suggestthatpredictionfailure(thedetection

ofdeviancefrompredictedrepresentations)issignaledbyEEG

mis-matchresponses.Biologicalimplementationsofdeviancedetection

have beenstudied mostintensively in visualand sensorimotor

systemswherearepresentationoftheexpectedconsequencesof

theorganism’sactions(corollarydischargeorefferencecopy)is

usedtodetecterrorsandguidecorrectioninprimateocularand

motor behavior (Wurtz et al.,2011; Webb,2004; Guillery and

Sherman,2011;Rauschecker,2011;Shadmehretal.,2010)orto

cancel sensory signals that are generated by self-movement in

thecaptureof preybyelectricﬁsh(Harvey-Girardetal.,2010).

Computationsperformedbytheparallelﬁber-fusiformnetworkin

thedorsalcochlearnucleuscitedearlier(ZhaoandTzounopoulos,

2011)maybeanotherexampleofcontext-dependent,predictive

ﬁlteringperformedbycentralauditorystructures.Thewiderange

oflatenciescharacterizingdifferentformsofmismatchresponse

isconsistentwithpredictiveﬁlteringconductedatdifferent

lev-elsofneuralprocessing(Bendixenetal.,2012)includinga role

fortop-downinputsfrommemorystructuresinformingpredicted

neuralrepresentations(Winkleretal.,2009).Althoughthespeciﬁc

mechanismsunderlyingtheseresponsesareonlypartiallyknown,

Bendixenet al. (2009)found that theevoked potentialelicited

byomissionofafullypredictedtone(butnottheevoked

poten-tialelicitedbyanunpredictedomittedtone)wasidenticaltothat

evokedbythetoneitselfuptothetimeofprocessinginthe

audi-torycortex(∼50ms,theP1evokedpotential)butnotthereafter.

Thissuggeststhatearlycorticalorsubcorticalprocessinghad

gen-eratedaprediction(neuralrepresentation)oftheinputthatwas

expected,andthatsubsequentprocessinginhighercortical

cen-ters(Schönwiesneretal.,2007)wasevokedwhenpredictionfailure occurred.

AﬁnalaspectofthemodelofFig.3concernsthenatureofthe

attentionsystemthatisactivatedwhenpredictionfailureoccurs.

(9)

tegmentalcholinergicprojections)maybeakeycomponentofthis

system.However,theBF cholinergicsystemreceivestop-down

inputfromthePFCandinturnprojectstoallprimaryand

sec-ondarycorticalsensory regionsfacilitating neuralprocessing in

theseregions.Inprincipletop-downinputstotheBFsystemcould

reﬂecttheoutcomeofprocessinginothersensorydomains,sothat

involvementof thissystemis notuniquetoauditoryattention.

BecausetheBFsystemisknowntoplayacrucial rolein

learn-ingand memory(Sarteret al.,2005; Ramanathan etal., 2009),

itsengagementbyperceptualdisparitiesinothersensory

modal-ities may account for the close relationship betweenattention

andlearningseeninawiderangeoftasks(BifernoandDawson,

1977;Roberts etal., 1984).Othermodulatory systems arealso

knowntobesensitivetoexpectancyviolationsandmaysupport

attention-likefunctions(atopicwediscussfurtherinSection5.2).

Summarizingdataforeffectsofexpectancyfailureinmodulatory

systems,YuandDayan(2005)proposedamodelinwhich

cholin-ergicandnoradrenergicneuromodulatorsactintandemtodirect

top-downattentionandlearningunderconditionsofstimulusand

taskuncertainty.

4. Evidenceofaroleforauditoryattentionintinnitus

Theseconsiderationsbasedontheneuralchangesthatareseen

intinnitusandmechanismsforneuralplasticitygivereasonto

con-sideraroleforanauditoryattentionnetworkin thegeneration

andmaintenanceoftinnitus.Whatdoestheevidencesuggest?At

present,itmustbeacknowledgedthatdeﬁnitivestudiesonthe

questionarelacking.However,severallinesof evidencecanbe

interpretedtosuggestaroleforattentioninthedevelopmentand

maintenanceoftinnitus,whicharereviewedhere.

4.1. Behavioralstudies

Thattinnitusisitselfapersistentaudibleperceptcouldbetaken

asprimafacieevidenceforaninvolvementofauditoryattention

mechanisms.Althoughfewsystematicstudieshaveaddressedthe

question,theirﬁndingsaddweighttothehypothesis.IfanS1

stim-ulusconsistingofastandardsoundandaninfrequentdeviantis

presentedtooneear,witheachS1signalingthesubjecttocorrectly

categorizeanS2stimuluspresentedtotheotherear,performance

oftheS2taskisimpairedfollowingthedeviantS1comparedto

thestandardS1(Schröger,1996).Thishasbeentakentosuggest

thatthedeviantS1drawsor“captures”attentionawayfromtheS2

ear.Cunyetal.(2004)foundthatinpatientswithunilateral

tinn-itusattentionalcapturewasreducedwhentheS1andS2stimuli

werepresentedinthenontinnitusandtinnitusearrespectively,

ratherthaninthereversearrangement.Theysuggestedthat

audi-toryattentionwasautomaticallydirectedtothetinnitusear,such

thatadeviantS1stimuluscouldnotdrawattentionawayfromit.

Cunyetal.(2004)repeatedthisprocedurewithnormalhearing

subjectswhodidnotexperiencetinnitus,butatinnitus-like

exter-nalsoundwasplayedinoneear.PerformanceoftheS2taskdid

notdifferbetweenthetwoears,suggestingthatitisnotthe

pres-enceofasoundinoneearthatmodulatesattentionalcapturebut

whetherthesoundisanauditoryphantom.ThemodelofFig.3b

couldbetakentosuggest thatthedisparitybetweenatinnitus

soundandinputfromthedamagedeararousedattentiontothe

affectedearinunilateraltinnitus.Evidenceforear-speciﬁc

audi-toryattentionhasbeenreportedbyMülleretal.(2009)innormal

hearingsubjects,althoughundertheconditionsoftheirtest

mod-ulationofbrainactivitybytheearofattentionreachedsigniﬁcance

onlyinthelefthemisphereandonlyforasoundAMat20Hz.

Inanotherstudyrelevanttotheattentionhypothesis,Knobel

and Sanchez (2008) placed 66 normal hearing volunteers in a

silentsoundboothwheretheyperformedthreetasksinamixed

consecutiveorder,consistingoftheTowerofHanoitaskrequiring

problemsolvingandworkingmemory,asimplevisualtaskasking

subjects whether they noticed changes in illumination, and a

simpleauditorytaskaskingsubjectswhethertheyheardsounds

inenvironment.Unknowntothesubjects,thevisual(room

illu-mination)andauditory(silence)conditionsremainedconstanton

alltasks.Whenprobedaftereachtask,auditoryperceptionswere

reportedby68.2%of thesubjectsaftertheauditorytask, 45.5%

ofsubjectsafterthevisualtask,and 19.7%of subjectsafterthe

TowerofHanoi,butreportsofvisualperceptionswereinfrequent

overall(<16%ofsubjects)indicatingthatthesubjectswere

mak-ingdiscriminatedjudgments. Theseﬁndingssuggest eitherthat

phantomauditorysoundsarefacilitatedwhenthetaskcalls

atten-tiontoauditorysignals,orthat tasksthatrequirenon-auditory

cognitiveresourcesaremostsuppressiveofphantomsoundsthat

areotherwiseperceivedinasilentenvironment.Complementary

evidence from studies of tinnitus sufferers indicates that

per-sistent, attention-demanding tinnitus interferes with complex

informationprocessing.Individualswithchronictinnitusperform

morepoorlyoncognitivetasksthatrequireselectiveattentionand

workingmemorythandoindividualswithouttinnitus,evenwhen

theeffectsofhearinglevel,anxiety,anddepressionareregressed

out(Stevensetal.,2007;Rossiteretal.,2006).Theresultssuggest

thattinnitus-relatedneuralactivitypossiblysupportedby

audi-toryattentionremainsaﬁercecompetitorforaccesstotheglobal

workspacesupportingsuchtasks.

4.2. Electrophysiologicalevidence

Followinga differentapproach, Roberts and Bosnyak(2010)

askedsubjectswithtinnitusandageandhearing-levelmatched

controlstoadjusttheintensityofa5kHz40-Hzamplitude

mod-ulated(AM)sound(intheregionoftinnitusandhearingloss)and

asimilarlyAMmodulated500Hzsound(intherangeofnormal

hearingandbelowthetinnitusfrequencyrange)tomatchthe

loud-nessofa1kHzsoundpresentedat65dBSL(thissoundalsobelow

tinnitusfrequenciesandintherangeofnormalhearing).Theaim

ofthis procedurewasthatthe500Hz and5kHz soundsshould

beequal inperceivedloudnessfor allsubjectsregardlessofthe

differentcarrierfrequencies,thepresenceofthresholdshifts,and

possiblehyperacusisconsequentonalteredgainchanges.The

tinn-itusandcontrolsubjectswerethenprobed(inseparategroups)

withthe500and5kHz40-HzAMsounds(atrainof120.5sprobes

presentedat0.4Hz,eachtrainseparatedby60sofsilence)under

conditionsinwhichthetinnitussubjectswouldhaveheardtheir

tinnitus.TwoEEGresponses,onelocalizingtoprimary auditory

cortexandtheothertosecondaryauditoryregions(thestimulus

driven40-Hzsteady-stateresponseorASSR,andtheN1transient

response,respectively),weremeasured.Bothoftheseresponses

havebeenshownin previousresearchtobehighlysensitiveto

auditoryattentioninnormalhearingsubjects(seeGanderetal.,

2010a,b,forreviews).

Theresultsofthestudydependedontheresponsemeasured

andonprobefrequency.N1amplitudewaselevatedinboth

tinn-itusgroupsatbothprobefrequencies(Fig.4,leftpanel,p<0.03),

consistentwitharousedauditoryattentionintinnitusexperienced

underbaselineconditions.ASSRamplitudewasalsoelevatedin

thetinnitusgroup,butonlyforthe500Hzprobe(p=0.003),

con-sistentwithanattentioneffectexpressedatthisfrequency(Fig.4,

rightpanel).At5kHzthegroupdifferencewasreversed,withASSR

amplitudelowerinthetinnitussubjectsthancontrols(p=0.044;

interactionoffrequencywithp=0.015;seesupplementary

infor-mation).ItwassuggestedthatincreasedASSRamplitudeat500Hz

mayhavereﬂectedabottom-upeffectofauditoryattentionin

tinni-tus,whichmaybefrequencynonspeciﬁc(thewholeauditorycortex

(10)

Fig.4.Electrophysiologicalresponsesintinnitus.Transient(N1,leftpanel)andsteady-state(ASSR,rightpanel)responsesareshownforindividualswithtinnitusandfor ageandhearing-levelmatchedcontrols.14–16subjectsweretestedineachoffourindependentgroups(tinnitusandcontrolsubjectsprobedateither500Hzor5kHz).The fourgroupswerematchedforageanddegreeofaudiometricthresholdshift.The5kHzprobewasinthetinnitusspectrumand500Hzbelowthetinnitusspectrumofthe tinnitussubjects.Probeintensitywasmatchedbyeachsubjecttoa1kHzsoundintherangeofnormalhearingtocontrolforvariationinloudnessperceptionrelatedtocarrier frequencyorhyperacusis.BecauseASSRandN1amplitudeareknowntodecreasewithcarrierfrequency(p<0.001inthisdataset),theresultsarealignedtoamplitudein thecontrolgroupsforeachfrequency.N1amplitude(leftpanel)waslargerinthetinnitusgroupsthaninthecontrolgroupsatbothprobefrequencies(p=0.023).Frequency dependencewasobservedforASSRamplitude(rightpanel).HereASSRamplitudewaslargerinthetinnitusgroupthaninthecontrolgroupwhere500Hzwasprobed (p=0.004),butsmallerintinnitussubjectsthancontrolsingroupswhere5000Hzwasprobed(p=0.045).Thegroupbyprobeinteractionwasalsosigniﬁcant(p=0.014). OnlyN1andASSRamplitudedistinguishedbetweenthetinnitusandcontrolgroups;P1,P2,andN2transientresponsesdidnot(resultsnotshown).

2010a,experiment2).ASSRamplitudeat5kHz,ontheotherhand,

mayhavebeenreducedinthetinnitusgroupbyneuralchanges

underlyingthetinnituspercept.Thepossibilitiesincludeabusyline

effect(neuronsforgedintosynchronousnetworksarenotavailable

forrecruitmentbytheAMenvelope),depressionof

thalamocorti-calsynapsesoncorticalneuronsbyuncorrelatedinputsfromthe

damagedear(RobertsandBosnyak,2010),orhyperpolarizationof

thalamicsourcesfollowingdeafferentation(Llinasetal.,2005).The

diminishedASSRresponseat5kHzinthetinnitusgroupis

con-sistentwith arecent fMRI studythat foundreduced functional

connectivitybetweenprimaryauditorycortexandthethalamusin

tinnituspatientscomparedtohearing-levelmatchedcontrols(van

Dijketal.,2013).However,thefrequencyproﬁleofthereduced

connectivitycouldnotbedeterminedfromtheprocedureused.

Persistingactivationofamechanismforauditoryattentionin

tinnitusmight beexpected toaffect theability of anattention

manipulationtomodulateASSRandN1responsesinindividuals

withtinnitus,comparedtoageandhearing-levelmatchcontrol

subjectswithouttinnitus.Robertsetal.(2012)trainedatinnitus

groupandagroupofageandhearing-levelmatchedcontrolsto

detectanauditorytargetembeddedina5kHz40-HzAMsound

(thissoundinthetinnitusfrequencyregionofthetinnitus

sub-jects). EEGwas measuredin theﬁrst, middle, and last session

ofatrainingseriesconsistingofsevensessionsdeliveredover2

weeks.Withineachsession,activeblocksrequiringauditory

atten-tionandbehavioralperformancealternatedwithpassiveblockson

whichsubjectswereinstructedtoignorethesoundsandrest.In

controlsubjectsN1andASSRamplitudeincreasedonactive

com-paredtopassiveblocksineachEEGsession(Fig.5,leftpanels),in

accordancewithpriorevidencerevealinganeffectspeciﬁcallyof

auditoryattentionontheseresponsesunderconditionsinwhich

behavioralresponserequirementswerecontrolled(Ganderetal.,

2010a).Neitherresponsechangedovertrainingsessionsinthe

con-trolsubjects,inagreementwithpreviousevidenceobtainedwith

thisprocedureshowingN1andASSRamplitudetoberesistantto

plasticchangeinnormalhearingindividuals(Bosnyaketal.,2004;

Ganderetal.,2010b).Theresultsinthetinnitusgroupwere

dif-ferent (Fig.5, rightpanels).Unlike the ﬁndings in controls, N1

amplitudedidnotdifferbetweenactiveandpassiveblocksinany

sessioninthetinnitusgroup,suggestingreducedmodulationby

attentionintinnitussubjects.ASSRamplitudedidnotmodulate

betweenactiveandpassiveblocksontheﬁrstdayoftraining,either,

inthetinnitusgroup.However,thisresponseincreasedonactive

blocks withcontinuedtraining in the tinnitusgroup,suchthat

overallamaineffectofactive/passiveblocks,andaninteractionof

blockswithsessions,wereobtainedinthisgroup.Itwassuggested

thatreducedinhibitionintheTFRofthetinnitussubjectsfostered

atraining-directed,neuroplasticexpansionofthe5kHz

represen-tationinthesesubjects,andthatattentionwhilenotmodulatedat

theoutsetoftrainingcametoexertadegreeofcontroloverthis

process.Anadditionalﬁndingwasthattheamplitudeofthelong

latencyN2transientresponse(latency326ms)andtheauditory

sustainedresponse(400–900ms)wasalsolargeronactivethanon

passiveblocksinthetinnitusgroup,andequallysoincontrol

sub-jects,suggestinganinﬂuenceofattentioninbothgroups.Although

thelonglatencyoftheseresponsesallowsthatbehavioralresponse

preparationcouldhavebeenacontributingfactor,thehypothesis

israisedthatreducedmodulationofN1responsesbetweenactive

andpassiveblocksintinnitussubjects,andreducedmodulation

ofASSRamplitudeearlyintraining,mayhavereﬂectedaberrant

neuralchangestakingplaceinthetinnitusfrequencyregionofthe

tinnitussubjects,ratherthanafrequencynonspeciﬁcdisturbance

ofauditoryattentioninthesesubjects.Weiszetal.(2004)found

abnormalMMNresponsesintinnituscomparedtocontrolsubjects

forsoundfrequenciesnearthetinnitusfrequencyregionbutnot

forsoundfrequencieswellbelowthisregion.

Thus,whiletheseelectrophysiologicalresultsraisethequestion

ofpossiblechangesin auditoryattentionintinnitus,itmust be

acknowledged that this literature doesnot speak with a clear

voiceonthetopic.TheresultsofFig.4arecongruentwiththoseof

Wienbruchetal.(2006)whofoundforbilateralcasesoftinnitus

largerASSRresponsesthanincontrolsforsoundfrequenciesbelow

2kHz,whichisbelowthetinnitusfrequencyregion.Inthatstudy

thegroupdifferencewasnotsigniﬁcantabovethisfrequency.It

mayfurtherbenotedthattheresultsofFig.4,wheresmallerASSR

responseswereevoked bya 5kHz 40-HzAMsoundin tinnitus

subjectscomparedtocontrolswhileN1amplitudewasincreased

intinnitus,arecongruentwiththoseofFig.5,whereN1amplitude

evokedbythesamesoundagaintendedtobelarger(p=0.077)

andASSRamplitudesmaller(p=0.22)intinnitusthanincontrols

onpassive blocks where attentionwas not required. However,

differentN1ﬁndingswerereportedbyDieschetal.(2012).These

investigators presented three carrier frequencies, each AM at

a different AM rate, either singly or in various combinations

totinnitus and control subjects,and observed nogroup

(11)

Fig.5. EffectsofauditorytrainingandattendedperformanceonN1andASSRresponsesintinnitus.Tinnitussubjects(n=11,rightpanels)andcontrols(n=11,leftpanels) weretrainedforsevensessionstodetectatarget(asingleamplitudeenhanced40-AMpulseofvariablemagnitude,ina5kHz40-HzAMstimulusof1sduration)present on2/3ofthetrialsineachsession.The5kHzcarrierfrequencywasintheTFRofthetinnitussubjects.Ineachsession(givenat2-dayintervals)activeblocks(blue)on whichsubjectsattendedtothetrainedsoundsandperformedthetaskwereinterleavedwithpassivetrials(red)onwhichsubjectsignoredthesoundsandrested.EEG(128 channels)wasmeasuredduringsessions1,4,and7.N1amplitude(toppanels)isreportedforelectrodeFzandtheASSR(bottompanels)asglobalfieldpower(thisresponse dipolar,peakingnearFzandOz).IncontrolsN1amplitude(p=0.03)andASSRamplitude(p=0.05)werelargerwhenthetrainingstimuluswasattendedthanwhenitwas not,withnosignificanteffectoftrainingsessionsoneitherresponse.InthetinnitusgroupN1amplitudedidnotdifferbetweenactiveandpassiveblocksinanysession anddidnotchangeoverthetrainingseries.ASSRamplitudedidnotdifferbetweenactiveandpassiveblocksonday1oftraininginthetinnitusgroup(congruentwith theirN1resultsonthisday),butthisresponseincreasedinamplitudeoverthetrainingsessionspreferentiallyonactiveblocks,yieldingasignificantoverallmaineffectof active/passiveblocks(p=0.033)andaninteractionofblockswithsessions(p=0.021).Itmayalsobenotedthatonpassiveblocks(red)whereattentionwasnotrequired,N1 amplitudetendedoveralltobelargerinthetinnitusgroupthanincontrols(p=0.077)andASSRsmallerintinnitusthancontrols(p=0.22;notethedifferentordinatesfor ASSRamplitude),inqualitativeagreementwithresultspresentedinFig.4forindependentgroupstestedwitha5kHz40-HzAMsound.Errorbarsare1SEofthedifference betweenactiveandpassiveblocks.(Forinterpretationofthereferencestocolorinthisfigurelegend,thereaderisreferredtothewebversionofthearticle.)

ResultsfromRobertsetal.(2012).

steady-statewaveform.OnthisbasisDieschetal.(2012)concluded

thatattentionwasnotresponsibleforincreasesinASSRamplitude

reportedpreviouslyintinnitus.Overall,priorresearchcomparing

N1responsesbetweentinnitusandnormalhearingsubjectshave

produced an inconsistent picture with some studies reporting

increasesin N1 amplitude or N1 loudness growthfunctions in

tinnitussubjectscomparedtocontrolsfortonespresentednearthe

edgeofthetinnitusfrequencyregioncomparedtoother

frequen-cies(Dietrichetal.,2001;Nore ˜naetal.,1999;Hokeetal.,1989),

andotherstudiesreportingeitherdecreasesinthesevariablesat

frequenciesbeloworneartheedgeoftheputativetinnituspitch

(Kadneretal.,2002;Leeetal.,2007)ornochangesatallinN1

amplitudeintinnituscomparedtocontrols(Jacobsonetal.,1991;

JacobsonandMcCaslin, 2003;Diesch etal.,2012; Seredaetal.,

2013).Mostelectromagneticimagingstudiesoftinnitushavebeen

guidedbythehypothesisthatexpansionofthecortical

representa-tionforfrequenciesattheedgeofhearinglossshouldenhancebrain

responsesevokedbyedgefrequencysoundscomparedto

frequen-ciesbelowthehearinglossregion.However,therearenumerous

(12)

differentevokedbrainresponses,withsomechanges(forexample,

incentralgain)favoringaugmentedrespondingandotherchanges

(forexample, reduced connectivity) not, withdifferent degrees

offrequency dependence. Afurtherlimiting factoris thatmost

evokedpotentials,evenwhenthe3-Dlocationoftheirgeneratorsis

known,donotmapontodiscreteunderlyingneuralprocesses.

Cur-rentexperiencesuggeststhatconsiderableeffortmaybeneeded

toachievecorroboratingandmeaningfulresultsinthisliterature.

4.3. FMRIandPETimaging

MetabolicimagingbyPET orfMRIhasbeenusedtoidentify

brainregionsinwhichneuralactivityiselevatedorsuppressed

inindividuals withtinnituscompared tocontrolsubjects

with-outtinnitus(seeLantingetal.,2009andAdjamianetal.,2009for

reviews).AnadvantageofPETisthatintrinsicneuralactivationscan

beassessedintheabsenceofexternalsoundstimulation,whereas

themajority ofstudies employingfMRI have compared

sound-evoked activations to resting baselines between these groups.

Whilethereisvariabilityamongthestudieswithrespecttothe

speciﬁcbrainregionsthatdifferentiatetinnitusandcontrol

sub-jects,moststudiesconcurthatintrinsicorevokedneuralactivity

inprimaryauditorycortexandauditoryassociationareas(areas

thatareknowntobeattentionsensitive)isalsoelevatedin

tinni-tus(Lantingetal.,2009).Guetal.(2010)contrastedsound-evoked

brainactivitybetweenfourgroupsofindividuals,targetingspeciﬁc

regionsofinterestinauditorypathways.Allsubjectshadpuretone

thresholds<25dBHLto8kHz.Oneofthefourgroupsexperienced

tinnitusandabnormalsoundleveltolerance(thelattermeasured

bytwomethods),twogroupsexperiencedonebutnottheother

oftheseconditions,andafourthgroupdidnotexperienceeither

condition.Eachgroup wasprobedwithanidenticalbroadband

noisepresentedatthree soundlevelsin anfMRI scanner,using

asparsesampleprotocolthatmeasuredsound-evokedresponses

intheabsenceofscannernoise.Abnormalsoundleveltolerance

(hyperacusis)wasaccompaniedbyincreasedsound-evoked

activ-ity (BOLD responses) in the auditory midbrain, thalamus, and

medialandlateralHeschl’sgyrus(regionsofprimaryauditory

cor-tex),whereastinnituswasassociatedwithincreasedactivityonly

inregionsofprimaryauditorycortex.Itwassuggestedthat

hyper-acusisreﬂected changes in central gain in distributed auditory

structureswhereastinnitusmayreﬂectactivityintheauditorycore

regionsfacilitatedbypersistentauditoryattention.

InanotherrecentstudyLangersetal.(2012)compared

stimu-lusdrivenBOLDresponsesbetweenindividualswithtinnitusand

agematchedcontrols, withboth groupshavinghearing

thresh-oldsinthenormalrangeto8kHzandsomedegreeofhearingloss

abovethisfrequency.Puretonestimulivaryingbetween0.25and

8kHzwereused,whichpermittedfrequency-speciﬁcresponsesto

bespatiallyresolvedandmacroscopictonotopicorganizationin

medialandlateralHeschl’sgyrustobemappedto8kHz.

Macro-scopicmapstructuredidnotdifferbetweenthetwogroupsover

thesefrequencies,although thepossibilityofmore ﬁne-grained

mapdifferencescouldnotbeexcludedbythisanalysis.However,

sound-evokedBOLDresponsesweresigniﬁcantlylargerintinnitus

thancontrolsubjectsinleftlateralHeschl’sgyrus,wherevoxels

werepreferentiallytunedtosoundfrequenciesbelowabout1kHz.

Itmaybenoteworthythatthis resultissimilartogroup

differ-encesintheASSRreportedbyWienbruchetal.(2006)including

thehemispherictrend.Innormalhearingsubjectsmodulationof

the40-HzASSR(Rossetal.,2004)andofBOLDresponses(Jäncke

etal.,1999)byauditoryattentionhasbeenreportedtobelargerin

thelefthemispherethanintherighthemisphere,raisingthe

pos-sibilitythatlargerBOLDresponsesinthelefthemisphereobserved

byLangersetal.(2012)forlowfrequencysoundsintinnitusmay

havehadanattentionalorigin.

Althoughit cannotbe consideredanovelinsight (Jastreboff,

1995;Rauscheckeretal.,2010;DeRidderetal.,2011),one

impli-cationoftheviewpointdescribedhere,inwhichneuromodulatory

systemsactivatedbyattentiondistributewidelytocorticaland

subcorticaltargets,isthatbrainactivitydistinguishingindividuals

withand without tinnitusshould not beconﬁnedto the

audi-torycorticesbutshouldextendtonon-auditorybrainregionsas

well,dependingonthetaskprocedurethatisusedforscanning

andonwhethercorrelatedtinnitusattributessuchasemotionand

behaviorsofdistressarepresent.Thereisnowextensiveevidence

indicatingthatbrainactivityinnon-auditoryregionsisenhanced

in individuals with tinnitus compared to nontinnitus controls

(Lantingetal.,2009;Adjamianetal.,2009;Husainetal.,2011),

includingthemiddleandsuperiorfrontalgyri(Mirzetal.,1999,

2000),cingulategyrus(Mirzetal.,1999;Plewniaetal.,2007a),

amydgala(Mirzetal., 2000), theprecuneus(Mirzet al.,1999),

and theparietal cortices(Mirzet al.,1999).Elevatedactivityin

thehippocampalandparahippocampalgyrihasalsobeenreported

(Lockwoodetal.,1998;VannesteandDeRidder,2012),whichare

regionsimportantinmemorystorageandretrieval.Thesebrain

regionshavebeenidentiﬁedascomponentsoftheGlobalNeuronal

WorkspacedescribedbyDehaeneandChangeux(2011),whichis

engagedwhensubjectsarerequiredtoconsciouslyprocesstask

stimuliandmakediscriminatedbehavioralresponsestoachieve

taskgoals.

Morerecently,fMRIhasbeenusedtoexaminefunctional

net-work connectivity in individuals with tinnitus under baseline

conditions.Maudouxetal.(2012)examinedfunctional

connectiv-itypatternsamongauditoryandnon-auditoryregionsinpatients

withchronictinnitusandnormal hearingcontrols.Twodistinct

anticorrelatednetworkswereidentiﬁedincontrols,theﬁrst

net-workencompassingtheauditorycorticesandtheinsulaandthe

secondnetworkincludingthefrontoparietalandanteriorcingulate

cortices, brainstem,amygdala, basal ganglia/nucleusaccumbens

andparahippocampalregions.In tinnitusonlytheﬁrstnetwork

wasobserved,and whenconstrasted tocontrolsonly increased

functionalconnectivitybetweentheauditorycorticesinboth

hem-sipheres(A1and A2)and nowtheleftparahippocampal region

survived statisticalﬁltering.This increasein functional

connec-tivitybetweenauditoryandparahippocampalregionsintinnitus

isinaccordancewithVannesteetal.(2011a,b)whoreportedan

increaseinelectricalbrainactivityinthegammafrequencybandin

theparahippocampalareaandanincreaseinconnectivitybetween

parahippocampalregionsandauditorycorticesintinnituspatients

compared to control subjects.On theother hand,as discussed

above,vanDijketal.(2013)foundevidenceofreducedfunctional

connectivitybetweenthethalamusandtheauditorycortexin

tinn-ituscomparedtoacontrolgroupwithsimilaraudiometricproﬁles,

althoughanearlierstudybythisgroupfoundlargerstimulusdriven

BOLDresponsesforlowfrequencysoundsintheleftHeschl’sgyrus

oftinnituspatientscomparedtocontrolsubjects(Langersetal.,

2012).Overalltheseﬁndingssuggestthatatleasttwomechanisms,

onemodulatingattentionintheauditorycorticesandits

function-allycoupledregions,andtheotheraccountingforreducedstimulus

efﬁcacyin thetinnitusfrequency regionof A1, maybeneeded

toexplain current ﬁndings. Inbothersome tinnituscorrelations

depictingfunctional connectivity werepositive within auditory

corticalregionsbutnegativebetweenauditoryandvisualregions

comparedtonormalhearingcontrols,suggestingsuppressionof

communicationbetweenthelatterregionsbyauditoryattention

intinnitus(Burtonetal.,2012).

4.4. Oscillatorybraindynamicsintinnitus

Functional connectivity in baseline fMRI recordings depicts