动物生理学原理-耳鸣和听觉过敏的神经生物学机制

Advancesinneurobiologyoftinnitusandhyreracusis耳鸣和听觉过敏的神经生物学研究进展杨明建2014 12 16 研究背景 Hearingimpairmentisaconsiderablediseaseburden Ithasbeenestimatedthatadult onsethearingimpairmentisthethirdleadingcauseofdisability WHO 2008 Forty twopreviousreportspublishedbetween1973and2010in29countrieshaverevealedincreasedhearinglosswithage Developingcountriesreporthigherratesofmoderateandmoderately severehearingimpairmentduetohigherratesofpre andpostnatalchildhoodinfectionssuchasrubella 风疹 measles 麻疹 andmeningit 脑膜炎 andfromtheuseofototoxicdrugs 耳毒性药物 Stevensetal 2013 However inindustrializedcountries noise inducedhearingloss NIHL 噪声性听力损失 isacommoncauseofhearingimpairments Luetal 2005 withaprevalencethatissecondtopresbycusis 老年性耳聋 Stanburyetal 2008 Hyperacusiandtinnitusarepotentiallydevastatingconditionsthatarestillincurable Epidemiology 流行病学 oftinnitus Tinnitusisadisorderofperceptionofphantomsoundthatisalsoknownasringingintheearorhead Tinnitusaffects10 20 ofthegeneralpopulation Galazyuketal 2012 Shargorodskyetal 2010 AccordingtotheAmericanTinnitusAssociation anestimated50millionpeopleintheUnitedStateshavechronictinnitus persistingforlongerthansixmonths Shargorodskyetal 2010 For12millionindividuals itissevereenoughtointerferewithdailyactivities Tinnituscanoccurinchildren ShetyeandKennedy 2010 andprevalenceincreaseswithage Adamsetal 1999 AhmadandSeidman 2004 peakingbetween60and69yearsofage Shargorodskyetal 2010 Morecommoninmenthaninwomen morelikelyinformersmokers andinadultswithhypertension hearingimpairment loudnoiseexposure orgeneralizedanxietydisorder 广泛性焦虑障碍 Shargorodskyetal 2010 Hearinglossandstress emotionalaswellaspsychosocial areimportantriskfactorsfortinnitus Hebertetal 2012 Jastreboff 2007 Langguthetal 2009 althoughtinnituscanoccurindependentlyfrombroadincreaseofhearingthresholds Gevenetal 2011 Langersetal 2012 Lockwoodetal 2002 耳鸣的分类 耳鸣有间歇性 也有持续性 有单一频率窄带噪音或白噪音等多种表现 耳鸣一般可分为中枢性及周围性两大类 周围性耳鸣根据是否被别人听见分为主观性耳鸣和客观性耳鸣 前者多见 后者少见 耳鸣又可根据其特征分为持续性耳鸣与节律性耳鸣 持续性耳鸣可有单一频率或多频率声调的混合 多为主观性耳鸣 节律性耳鸣多与血管跳动一致 偶尔与呼吸一致 耳鸣的频率较低 如为肌肉收缩引起 则耳鸣的频率较高 节律性耳鸣 多为客观性耳鸣 Epidemiology 流行病学 ofhyperacusis Hyperacusisisadisorderofloudnessperception 响度感知紊乱 inwhichsoundintensitiesthatareconsideredcomfortablebymostpeopleareperceivedunbearablyloud Baguley 2003 Inhyperacusis soundsarenotsimplyabitloud buttrulyunbearable 难以忍受 Hyperacusiscanoccurwithoutalossofhearingthresholds Guetal 2010 Statisticsonhyperacusisarescarce andalthoughitisoftencoincidentwithtinnitus limitedevidencehassupportedtheco occurrenceofthetwoconditions Anderssonetal 2002 Guetal 2010 NelsonandChen 2004 Withanapproximateprevalenceofabout10 15 ofthepopulation Gillesetal 2012 theprevalenceofhyperacusisiscomparabletotinnitus Shargorodskyetal 2010 Fortinnitusandhyperacusis hearingloss however isamajorriskfactor Astheincidenceofhearinglosswillincreasewiththeagingofthepopulation alsotheincidenceoftinnitusandhyperacusismayincrease Aretinnitusandhyperacusisintheearorthebrain 越来越多的证据表明耳鸣和听觉过敏形成的机制中外周听觉器官损伤只是起因 耳鸣和听觉过敏的形成和维持更多的是听觉传导通路上各级中枢的作用 耳蜗损伤等造成的异常神经活动经中枢核团逐级传递并在边缘系统等非听觉系统的参与下最终在听皮层被感知为耳鸣 M Knipper P V Dijk I Nunes etal Advancesintheneurobiologyofhearingdisorders RecentdevelopmentsregardingthebasisoftinnitusandhyperacusisProgressinNeurobiology 111 2013 17 33J J Eggermont L E Roberts Theneuroscienceoftinnitus TRENDSinNeurosciences 27 2004 676 682 Fig 1 SchematicillustrationoftheadultorganofCorti ThenervefibersofIHCs 内毛细胞 sendinformationtothebrain whereasthenervesofOHCs 外毛细胞 mainlyreceiveinformationfromthebrain IHCsare therefore thetruesensorycellsofhearing OHCsarecharacterizedbytheirelectromotileproperties theyareresponsiblefortheamplificationoftheacousticsignal whichinturnactivatesIHCs TheIHCstransmitelectricalsignalsinafrequency specificmannertohigherauditorybrainareas 内耳柯蒂氏器 螺旋器 示意图 1 cochleardamage NIHL 噪声性听力损失 hasbeen inapreviousview typicallydefinedbyapermanentlossofhearingthresholds 听阈永久性损失 Normalthresholdsrelyontheproperfunctionofouterhaircells OHCs DallosandHarris 1978 Perinnerear thereareapproximately11 000OHCs whichare inthehumancochlea typicallyarrangedin3rows Fig 1 OHC OHCfunctionistononlinearlyamplifybasilarmembranevibrationinresponsetosoftsoundsneartheplaceofcharacteristicfrequencywithinthecochlea Ashmore 2008 OHCsarethereforecrucialforthehighsensitivityofthehearingorgan itsfrequencyselectivity andunderstandingspeechinnoise Ashmore 2008 Dallos 2008 Aftermildacousticoverexposure hearingfunctioncanrecoverwithin2 3weeks Milleretal 1963 Thiscorrespondstoatemporarythresholdshift 暂时性阈移 duetoreversibledamagetothemechanosensoryhairbundlesofhaircells Fig 1 stereocilia LibermanandDodds 1984a b Schneideretal 2002 Afterintenseorrepeatedacousticoverstimulation however hearingfunctionstabilizesatanelevatedvalue leadingtopermanentthresholdshift 永久性阈移 thatmostlyoccursduetodestructionofOHCs Spoendlin 1985 Inthedailyclinicalroutine permanenthearinglossistypicallydetectedthroughtheincreaseofhearingthresholdsastestedbytone audiometry 听力测定 Moredetailedclinicaldiagnostictestingmayalsoincludeauditorybrainstemresponse ABR 听性脑干反应 testingorrecordingdistortionproductotoacousticemissions DPOAEs 畸变产物耳声发射 ABRresponsesrepresentthesummedactivityofneuronsintheascendingauditorypathways ThespecificfunctionofintactOHCscanbemeasuredbyamplitudesofDPOAEs DPOAEsareacousticsignalsthatarisefromdistortionsintheOHCs mechanoelectricalresponsetotwocontinuoustones Thesedistortionproducts whichareatfrequenciesnotpresentintheinputstimulus aregeneratedbytheOHCs biologicalmotorsandcanbedetectedwithamicrophoneintheearcanal DPOAEsresponsesthusreflecttheelectromotilepropertiesofOHCs Fitzgeraldetal 1993 Huangetal 2005 WecanconcludethatlossofhearingthresholdsafternoiseexposureismostlylinkedtoOHCloss whichspecificallycanbemeasuredbyDPOAEs ThroughDPOAEandABRmeasurements incombination adifferentialdamageofOHCsandIHCscanbedetected Fig 2 Predictedsubcellularpositionsofhigh andlow SRfibersattheinnerhaircell IHC AfferentauditorynervefibersofIHCsareclassifiedaccordingtotheirspontaneousactionpotentialdischargerate SR High threshold low andmedium SRfibersarepresumablypreferentiallylocatedatthemodiolarsideoftheIHC wherelargerribbonsareassociatedwithsmallerpatchesofNMDA RandAMPA R Low threshold high SRfibersarepresumablypreferentiallylocatedatthepillarsideoftheIHC wheresmallerribbonsopposelargerAMPA Rpatches Alsocharacteristicofribbonsynapses 带状突触 CaV1 3channelsareclusterednearsynapticribbons andtherebystabilizethecontactwithafferentneurons 内耳毛细胞高自发放电率和低自发放电率纤维亚细胞位置 RegardingmorerecentfindingsonNIHL itismostimportanttorememberthatOHClosscanbeaccompaniedbyIHC Fig 1 IHC damage LibermanandDodds 1984a b TheIHCsaretheprimarysensoryhaircellsofthecochleathattransmitsoundinformationoveranintensityrangespanning12ordersofmagnitude 120dB and3ordersofmagnitudeoffrequency 20Hzto20kHz RoblesandRuggero 2001 ThispowerfulcapacityofIHCsynapsesisachievedthroughtheirnumerousspecializedafferentcontacts EachIHCisinnervatedby8 human orupto20 rodents GlowatzkiandFuchs 2002 unbranchedspiralganglionneurons 螺旋神经节神经元 whichrepresentabout90 95 ofallafferentfibers AF intheauditorynerve AN Fig 1 AN Figs 1and2 AFtypeI EachIHCcontainselectron densepresynapticsubcellularstructures 高电子密度突触前亚细胞结构 so calledribbons Figs 1and2 red thattether 100synapticvesicles GlowatzkiandFuchs 2002 Thisspecializedpresynapticmachinerytherebymaintainsalargereleasablepoolofneurotransmitter allowingafferentauditoryneuronstocodethetemporalcharacteristicsofsoundwithhighreliabilityandtemporalprecision Buranetal 2010 更可靠和精确编码声音的时相特征 The3500IHCs Figs 1and2 IHC inthecochleararelydiefromNIHL however Instead theinnervateddendritesoftheauditorynervefibersundergoneurodegeneration 神经退化 KujawaandLiberman 2009 Linetal 2011 ThisprocesshasbeenrevealedtobetightlycorrelatedwithanalterednumberoftransmitterreleasesitesinIHCnerveterminals Fig 2 blue Jaumannetal 2012 KujawaandLiberman 2009 Linetal 2011 Zuccottietal 2012 thelong standingdogmathatcochlearnervedegenerationisaconsequenceofIHCdeathafteracoustictraumawasonlyrecentlyoverturned asdegenerationcanoccurwhenIHCsarepresent Acompletesetoffunctional intactIHCribbonsynapses 带状突触 andtheirpropercontactstoauditoryfibersarecrucialelementstoachievethefulldynamicloudnessrange aswellashighprecisionoftemporalsoundinformation Fig 3 Comparisonofthebasolateralpolelengthofinnerhaircells IHCs fromratswithorwithouttinnitusinindicatedcochlearturns BothgroupsexhibitedreducedlengthofthebasolateralpoleofIHCsinhighfrequencycochlearturns Ruttigeretal 2013 2 Alteredcentralbrainresponsestocochleardamage ThefirstABRwave Fig 3B ABRwaveI representsthesummedactivityoftheauditorynerve whereaslaterABRwavesarisefromsynchronousneuralactivityintheauditorybrainstem MelcherandKiang 1996 Soundprocessingcanalsoactivatelimbicstructures 边缘系统 Fig 3A drawningreen Theamygdala 杏仁核 andthehippocampus 海马 twomajorregionsofthelimbicsystem receivedirectandindirectneuralinputfromthecentralauditorysystem Noise inducedstresscanactivatethebasolateralamygdala 底外侧杏仁核 throughthehypothalamic pituitary adrenalaxis 下丘脑 垂体 肾上腺轴 HPAaxis Fig 3A Thus acoustictraumacandamagethecochleaandaffectthebasolateralamygdalaandthehippocampus Krausetal 2010 Fig 4 Centralauditorycircuitsandauditorybrainstemresponses Besidscentralauditorycircuits Thereareauditory limbicinteractions drawningreen Thebasolateralamygdala BLA 底外侧杏仁核 receivesdirectneuralinputsfromtheauditorythalamus MGB greenandthe AC TheBLA inturn contactsthehippocampuswhichhasdirectcontactwiththeAC TheBLAalsoprojectstotheIC therebygeneratinganamygdalar auditoryfeedbackloop 杏仁核听觉反馈环路 TheBLAalsoactivates e g duetonoise inducedstress thehypothalamic pituitary adrenalaxis HPAaxis 下丘脑 垂体 肾上腺轴 therebyinfluencingthelevelofbloodcortisol皮质醇 human orcorticosterone皮质酮 rodents aswellasthecochlea greendashedlines ThenormalABRconsistsoffiveprominentwavesthatoccurduringthefirst10msafterpresentationofatransientsound Thecentralauditorysystemcompensatesfordiminishedinputbyupregulatingitsresponsivenessincentralcircuitries Salvietal 2000 Centralcompensationthatfollowsreducedauditorynerveactivitymayoccurfirstattheleveloftheauditorybrainstem fromwherealteredactivitypatternsthenspreadtoascendingauditorynuclei Manzooretal 2013 MuldersandRobertson 2013 Inhumans Guetal 2012 andanimals Singeretal 2013 auditorynerveandbrainstemfunctioninresponsetosound assessedbyABRs havebeenusedtoanalyzecompensatingcentralactivityfollowingcochleardamage 3 Researchontinnitusorhyperacusisinanimals Inbothhumansandanimals determiningthepresenceoftinnitusandhyperacusisisachallenge Humanscan ofcourse indicatethepresenceoftinnitus butitisnotpossibletoconfirmthiswithanobjectivemeasurement Animalsareunabletoreportthepresenceoftinnitus andhencebehavioralmodelshavebeendevelopedforthispurpose Interestinginthiscontextisthatonlyrecently inamousemodel ithasbeenobservedthatthecentralbrainrespondsintwodifferentwaystoauditorydeprivationandIHCribbonloss dependingonthepresenceorabsenceofbrain derivedneurotrophicfactor 脑源性神经营养因子 BDNF thatstabilizesordestabilizesIHC auditorynervecontacts Zuccottietal 2012 First itcanrespondwithanincreaseinresponsegain synapticstrength maintainingthestableneuronalcircuit andsecond itcanrespondwithafailuretoappropriatelyadaptthecentralresponsegain whichmaycausetinnitusorhyperacusis 3 1耳鸣的动物模型 目前用于研究耳鸣的动物模型主要有两类 一类是强声暴露 intensesoundexposure 引起的耳鸣 另一类是耳毒性药物 如水杨酸盐 奎宁等 引起的耳鸣 两者皆从病因学角度模拟人类耳鸣发生条件 Jastrebof 1994 等用行为学方法验证了注射水杨酸或强声暴露的大鼠能够产生耳鸣的感觉 从而为用注射水杨酸或强声暴露的方法造成动物耳鸣模型进行进一步研究的途径提供了实验依据 Thesemodelsdependonananimal slearnedorreflex likebehaviorinthepresenceoftinnitus Variousanimalmodelshavebeendevelopedtodetecttinnituswhichincludeeitheraconditionedbehavioralresponsetosilence BauerandBrozoski 2001 HeffnerandKoay 2005 JastreboffandBrennan 1994 Jastreboffetal 1988 Middletonetal 2011 orthefailureofapre pulsegaptosuppressasound pulse evokedstartlereflex Bergeretal 2013 Dehmeletal 2012a Engineeretal 2011 Krausetal 2010 Lobarinasetal 2013 Middletonetal 2011 Nowotnyetal 2011 Turneretal 2006 TurnerandParrish 2008 Gapsinnoisebandsservesaspre pulsestosuppressasoundpulse evokedstartlereflex assumingthatongoingtinnitusmasksthegapandresultsinimpairedgapdetection However thestartlereflexismediatedbysubcorticalareasonly Therefore itisunclearwhethertheconditionsthatleadtoanabnormalstartleresponsealsocorrespondtoabnormalactivityintheauditorycortex Egger mont 2013 However astudydirectlycomparingtheoutcomeofthestartlereflexmethodandaconditionedresponsemethodhasshownsimilarresults Turneretal 2006 J J Eggermont L E Roberts Theneuroscienceoftinnitus TRENDSinNeurosciences 27 2004 676 682 3 2听觉过敏的动物模型 研究较少 WeiSun AnchunDeng AditiJayaram etal Noiseexposureenhancesauditorycortexresponsesrelatedtohyperacusisbehavior BrainResearch 1485 2012 108 116 Experimentalprocedures Animals Twenty fiveadultmaleSpragueDawleySDrats 3 6monthsold 300 500g Hyperacusisbehavioralassessment Theacousticstartleamplitudehasbeenusedtoevaluatehyperacusisbehavior Isonetal 2007 Sunetal 2009 Theacousticstartleresponseforthehyperacusistestwasevokedbyanarrowbandnoiseburst 50msduration centeredat8or16kHzwith1000Hzbandwidthfrom60to110dBSPL 10dBstep Noiseexposureandhearingevaluation Ratswereexposedtoanarrowbandnoisecenteredat12kHz 1kHzbandwidth at120dBSPLfor1hourinasoundproofroom Theauditorybrainstemresponse ABR wasrecordedinanesthetizedratsbeforeandafternoiseexposuretomonitortheirhearingthreshold Electrodeimplantationforthechronicrecording EightratswereimplantedwithlowimpedancecustomizedelectrodesmadeofTefloncoatedtungstenwire 0 3mmdiameter A MSystems W A intheICandtheACforthefieldpotentialrecordings Acousticstimuliandrecordings Tone bursts 50msduration 1msrise falltime wereusedtoelicitresponses soundintensitywasvariedfrom10to90dBSPL 10dBstep Fig 5 Theresponseoftheinferiorcolliculus IC beforeandafternoiseexposureat A 4kHz B 8kHz C 16kHzand D 24kHz TheICresponseshowedasignificantreduction1hourafterthenoiseexposureatlowintensityat16and24kHz butnotat4and8kHz Results Fig 6 Acousticevokedauditorycortex AC responseshowedasignificantincreaseafternoiseexposureat C 16kHzand D 24kHzshowedasignificantdifference two wayANOVA p 0 05 whereastherewasnosignificantchangeat A 4and B 8kHz Fig7 Theaverageamplitudeofacousticevokedauditorycortex AC responseat100dBSPLbeforeandafternoiseexposure TheamplitudeoftheACat4 8 16and24kHz A D showedanobviousincrease1hourafternoiseexposureandrecoveredin2days Fig 8 Noiseexposureincreasesthespikefiring rateoftheauditorycortex AC neurons A AtypicalACneuralresponsebeforenoiseexposure B TheACspikefiringrateshowedasignificantincrease1hourafterthenoiseexposure C Themeanspikefiringrate intensityfunctionoftheACneuronsmeasuredbeforeandafterthenoiseexposure NoiseexposuresignificantlyincreasedtheACspikefiringrate1hourafternoiseexposure two wayANOVA p 0 0001 D ThemeanspikefiringrateoftheACat90dBSPLrecoveredin1 3daysafterthenoiseexposure Fig 9 A Theauditorybrainstemresponse ABR showed 40dBthresholdshift1hourafternoiseexposure 120dBSPLat12kHz 1hour at16and24kHz Thethresholdshiftsgraduallyrecoveredinaweek TheABRthresholdsinindividualratsat8kHzand16kHzbeforeandafternoiseexposurewereshowninBandC Thehearinglossrecoveredinmostoftherats except 5developedapermanenthearingloss Fig 10 Acousticstartleresponseaffectedbynoiseexposure A Theaveragestartleamplitudeshowednosignificantdifferenceat8kHzbeforeandafternoiseexposure B Asignificantincreaseofthestartleamplitudewasrecordedat16kHz1hourafterthenoiseexposure n 7 two wayANOVA p 0 05 C D Therelativestartleamplitudeat100dBSPL theaveragestartleamplitudebeforenoiseexposureusedasthereference 100 at8and16kHzbeforeandafternoiseexposure Therelativestartleamplitudeshowedatransientincrease 100 200 rightafternoiseexposureandrecoveredin1 3days DISCUSSION Inthisstudywefoundthatthecorticalneuronsshowedenhancedresponsesrightafternoiseexposure suggestinganimmediateeffect 即时效应 oncorticalneuralresponsebynoiseexposure Astheexaggeratedacousticstartleresponseshappenedrightafternoiseexposure itispossiblethattheimpairmentsofthecentralnervoussystemcontributetothebehavioralreactiontosound Sinceoverreaction startle cry pain tosuddenloudsoundisacommonphenomenoninhumanwithlowsoundtolerance hyperacusis Gothelfetal 2006 Jansenetal 2009 wethinktheincreasedacousticstartleresponsemaybeindicativeofhyperacusisbehavior Isonetal 2007 Sunetal 2009 DISCUSSION Hyperacusisisoftenreportedinpatientswithtinnitus Eighty sixpercentofthepatientswhosechiefcomplaintishyperacusisalsoreportedtinnitus Anarietal 1999 Itispossiblethatthesetwoabnormalsoundperceptionsmaybecausedbythesamemechanisminsomepatients Ourrecentstudiesshowedthathighdosesofsalicylate 水杨酸盐 areliableinduceroftinnitus canalsocauseasignificantenhancementofsoundevokedcorticalresponseandacousticstartleresponse Sunetal 2009 Yangetal 2007 Itsuggeststhatthecorticalhyperexcitabilitymayplayanimportantroleinhyperacusisaswellasintinnitus 4 Iscentralcompensatingresponsegainlinkedtohyperacusisortinnitus Recently afirstindicationwasbroughtthatelevatedsubcorticalcentralgain previouslylinkedtotinnitus Lantingetal 2008 Melcheretal 2009 mayinfactberelatedtohyperacusis ratherthantinnitus Thus fMRIstudiesthatanalyzedmidbrainactivationinsubjectswithpreferentialhyperacusisorpreferentialtinnitusobservedsound inducedelevatedactivityonlyinsubjectswithhyperacusis Guetal 2010 reviewedin Eggermont 2012a b Elevatedmaximumdischargeratesandsteeperrate levelfunctionobservedafterauditorytraumahavebeensuggestedtooriginatefromdisinhibition Caietal 2009 Inconclusion novelfindingssuggestthatanover adaptivecompensatingcentralgainthatspreadsfromthebrainstemtowardascendingpathwaysmaybeassociatedwithhyperacusis butnotwithtinnitus 5 Whencentralcompensatingresponsegainfails thelinktotinnitusorhyperacusis Afailuretoincreasecentralresponseactivityintinnituswouldexplainwhynoelevatedsound inducedmidbrainactivityhasbeenobservedinpatientswithtinnitususingfMRIstudies Guetal 2010 andwhyanincreaseintinnitusloudnesshasbeenassociatedwithadecreaseinMGBactivity VanGendtetal 2012 Forhyperacusisandtinnituswethushypothesizecompensatingandnon compensatingcentralchanges respectively Itisimportanttonotethatthechangesmayoccurwithinthesamei