动物生理学原理-耳鸣和听觉过敏的神经生物学机制.ppt

Advances in neurobiology of tinnitus and hyreracusis耳鸣和听觉过敏的神经生物学研究进展杨明建2014.12.16研究背景研究背景Hearing impairment is a considerable disease burden.It hasHearing impairment is a considerable disease burden.It hasbeen estimated that adult-onset hearing impairment is been estimated that adult-onset hearing impairment is the thirdthe thirdleading cause of disabilityleading cause of disability (WHO,2008).(WHO,2008).Forty-two previous reports published between 1973 and 2010 in Forty-two previous reports published between 1973 and 2010 in 29 countries have revealed increased hearing loss with age;29 countries have revealed increased hearing loss with age;Developing countriesDeveloping countries report higher rates of moderate and moderately-report higher rates of moderate and moderately-severe hearing impairment due to higher rates of pre-andsevere hearing impairment due to higher rates of pre-and postnatal childhood infections such as rubella(postnatal childhood infections such as rubella(风风疹）疹）疹）疹）,measles,measles（麻（麻（麻（麻疹）疹）疹）疹）and meningitand meningit（脑脑膜炎）膜炎）膜炎）膜炎）,and from the use of ototoxic drugs,and from the use of ototoxic drugs（耳毒性（耳毒性（耳毒性（耳毒性药药物）物）物）物）(Stevens et al.,2013).(Stevens et al.,2013).However,in However,in industrialized countriesindustrialized countries,noise-induced hearing loss noise-induced hearing loss (NIHL)(NIHL)（噪声性听力（噪声性听力（噪声性听力（噪声性听力损损失）失）失）失）is a common cause of hearing impairments (Lu et is a common cause of hearing impairments (Lu et al.,2005),with a prevalence that is second to presbycusisal.,2005),with a prevalence that is second to presbycusis（老年性耳（老年性耳（老年性耳（老年性耳 聋聋）(Stanbury et al.,2008).(Stanbury et al.,2008).HyperacusiHyperacusi and tinnitus are potentially devastating conditions that areand tinnitus are potentially devastating conditions that are still incurable.still incurable.Epidemiology（流行病学）（流行病学）of tinnitus Tinnitus is a disorder of perception of Tinnitus is a disorder of perception of phantom soundphantom sound that is also known as that is also known as ringing in the ear or head.ringing in the ear or head.Tinnitus affects Tinnitus affects 1020%of the general population1020%of the general population (Galazyuk et al.,2012;(Galazyuk et al.,2012;Shargorodsky et al.,2010);According to the American Tinnitus Association,an Shargorodsky et al.,2010);According to the American Tinnitus Association,an estimated estimated 50 million people50 million people in the United States have in the United States have chronic tinnituschronic tinnitus,persisting for longer than six months (Shargorodsky et al.,2010).For persisting for longer than six months (Shargorodsky et al.,2010).For 12 12 million individualsmillion individuals,it is severe enough to interfere with daily activities.Tinnitus ,it is severe enough to interfere with daily activities.Tinnitus can occur in childrencan occur in children (Shetye and Kennedy,2010)and prevalence (Shetye and Kennedy,2010)and prevalence increases increases with agewith age (Adams et al.,1999;Ahmad and Seidman,2004),peaking between (Adams et al.,1999;Ahmad and Seidman,2004),peaking between 60 and 69 years of age(Shargorodsky et al.,2010).More common in men than 60 and 69 years of age(Shargorodsky et al.,2010).More common in men than in women,more likely in former smokers,and in adults with hypertension,in women,more likely in former smokers,and in adults with hypertension,hearing impairment,loud noise exposure,or generalized anxiety disorder(hearing impairment,loud noise exposure,or generalized anxiety disorder(广泛性广泛性广泛性广泛性焦焦焦焦虑虑障碍）障碍）障碍）障碍）(Shargorodsky et al.,2010).(Shargorodsky et al.,2010).Hearing loss and stress (emotional as well as psychosocial)Hearing loss and stress (emotional as well as psychosocial)are are important risk factors for tinnitus (Hebert et al.,2012;Jastreboff,2007;important risk factors for tinnitus (Hebert et al.,2012;Jastreboff,2007;Langguth et al.,2009),although tinnitus Langguth et al.,2009),although tinnitus can occur independentlycan occur independently from broad from broad increase of hearing thresholds (Geven et al.,2011;Langers et al.,2012;increase of hearing thresholds (Geven et al.,2011;Langers et al.,2012;Lockwood et al.,2002).Lockwood et al.,2002).耳鸣的分类耳鸣的分类耳耳耳耳鸣鸣有有有有间间歇性，也有持歇性，也有持歇性，也有持歇性，也有持续续性性性性。有。有。有。有单单一一一一频频率窄率窄率窄率窄带带噪音或白噪音或白噪音或白噪音或白噪音噪音噪音噪音等多种表等多种表等多种表等多种表现现。耳。耳。耳。耳鸣鸣一般可分一般可分一般可分一般可分为为中枢性及周中枢性及周中枢性及周中枢性及周围围性两大性两大性两大性两大类类。周。周。周。周围围性耳性耳性耳性耳鸣鸣根据是否被根据是否被根据是否被根据是否被别别人听人听人听人听见见分分分分为为主主主主观观性耳性耳性耳性耳鸣鸣和和和和客客客客观观性耳性耳性耳性耳鸣鸣。前者多。前者多。前者多。前者多见见，后者少，后者少，后者少，后者少见见。耳。耳。耳。耳鸣鸣又可根据其特又可根据其特又可根据其特又可根据其特征分征分征分征分为为持持持持续续性耳性耳性耳性耳鸣鸣与与与与节节律性耳律性耳律性耳律性耳鸣鸣。持。持。持。持续续性耳性耳性耳性耳鸣鸣可有可有可有可有单单一一一一频频率或多率或多率或多率或多频频率声率声率声率声调调的混合，多的混合，多的混合，多的混合，多为为主主主主观观性耳性耳性耳性耳鸣鸣。节节律性耳律性耳律性耳律性耳鸣鸣多与血管跳多与血管跳多与血管跳多与血管跳动动一致，偶一致，偶一致，偶一致，偶尔尔与呼吸一致，耳与呼吸一致，耳与呼吸一致，耳与呼吸一致，耳鸣鸣的的的的频频率率率率较较低。如低。如低。如低。如为为肌肉收肌肉收肌肉收肌肉收缩缩引起，引起，引起，引起，则则耳耳耳耳鸣鸣的的的的频频率率率率较较高。高。高。高。节节律性耳律性耳律性耳律性耳鸣鸣，多，多，多，多为为客客客客观观性耳性耳性耳性耳鸣鸣。Epidemiology（流行病学）（流行病学）of hyperacusis Hyperacusis is Hyperacusis is a disorder of loudness perceptiona disorder of loudness perception（响度感知紊乱）（响度感知紊乱）（响度感知紊乱）（响度感知紊乱）,in which ,in which sound intensities that are considered comfortable by most people are sound intensities that are considered comfortable by most people are perceived unbearably loud (Baguley,2003).perceived unbearably loud (Baguley,2003).In hyperacusis,sounds are not simply a bit loud,but truly In hyperacusis,sounds are not simply a bit loud,but truly unbearableunbearable（难难以以以以忍受）忍受）忍受）忍受）.Hyperacusis can occur without a loss of hearing thresholds (Gu et Hyperacusis can occur without a loss of hearing thresholds (Gu et al.,2010).al.,2010).Statistics on hyperacusis are scarce,and although it is often Statistics on hyperacusis are scarce,and although it is often coincident with tinnitus,coincident with tinnitus,limited evidence has supported the co-occurrence of limited evidence has supported the co-occurrence of the two conditionsthe two conditions (Andersson et al.,2002;Gu et al.,2010;Nelson and (Andersson et al.,2002;Gu et al.,2010;Nelson and Chen,2004).Chen,2004).With an approximate prevalence of about With an approximate prevalence of about 1015%of the population1015%of the population (Gilles (Gilles et al.,2012),the prevalence of hyperacusis is comparable to tinnitus et al.,2012),the prevalence of hyperacusis is comparable to tinnitus (Shargorodsky et al.,2010).(Shargorodsky et al.,2010).For tinnitus and hyperacusis,For tinnitus and hyperacusis,hearing losshearing loss,however,is a major risk factor.,however,is a major risk factor.As the incidence of hearing loss will As the incidence of hearing loss will increase with the aging of the increase with the aging of the populationpopulation,also the incidence of tinnitus and hyperacusis may increase.,also the incidence of tinnitus and hyperacusis may increase.Are tinnitus and hyperacusis in the ear or the brain?越来越多的越来越多的越来越多的越来越多的证证据表明耳据表明耳据表明耳据表明耳鸣鸣和听和听和听和听觉过觉过敏形成的机制中敏形成的机制中敏形成的机制中敏形成的机制中外周听外周听外周听外周听觉觉器官器官器官器官损伤损伤只是起因只是起因只是起因只是起因，耳，耳，耳，耳鸣鸣和听和听和听和听觉过觉过敏的形成和敏的形成和敏的形成和敏的形成和维维持更多持更多持更多持更多的是的是的是的是 听听听听觉传导觉传导通路上各通路上各通路上各通路上各级级中枢的作用中枢的作用中枢的作用中枢的作用。耳耳耳耳蜗损伤蜗损伤等造成的等造成的等造成的等造成的异常神异常神异常神异常神经经活活活活动经动经中枢核中枢核中枢核中枢核团团逐逐逐逐级传递级传递并在并在并在并在边缘边缘系系系系统统等非听等非听等非听等非听觉觉系系系系统统的参与下最的参与下最的参与下最的参与下最终终在听皮在听皮在听皮在听皮层层被感知被感知被感知被感知为为耳耳耳耳鸣鸣。MM.Knipper,Knipper,P P.V V.Dijk Dijk，I I.Nunes Nunes，et al.et al.Advances in the Advances in the neurobiology of hearing disorders:Recentneurobiology of hearing disorders:Recent developments developments regarding the basis of tinnitus and hyperacusisregarding the basis of tinnitus and hyperacusis Progress in Progress in NeurobiologyNeurobiology,111 (2013)1733111 (2013)1733 J.J.EggermontJ.J.Eggermont，L.E.Roberts.L.E.Roberts.The neuroscience of tinnitusThe neuroscience of tinnitus.TRENDS in Neurosciences,27(2004)676-682.TRENDS in Neurosciences,27(2004)676-682.Fig.1.Schematic illustration of the adult organ of Corti.The nerve fibers of IHCs(内毛细胞）send information to the brain,whereas the nerves of OHCs（外毛细胞）mainly receive information from the brain.IHCs are,therefore,the true sensory cells of hearing.OHCs are characterized by their electromotile properties;they are responsible for the amplification of the acoustic signal,which in turn activates IHCs.The IHCs transmit electrical signals in a frequency-specific manner to higher auditory brain areas.内耳柯蒂氏器（螺旋器）示意图1.cochlear damage NIHLNIHL（噪声性听力（噪声性听力（噪声性听力（噪声性听力损损失）失）失）失）has been,in a previous view,typically defined by has been,in a previous view,typically defined by a a permanent loss of hearing thresholdspermanent loss of hearing thresholds（听（听（听（听阈阈永久性永久性永久性永久性损损失）失）失）失）.Normal thresholds rely on the proper function of outer hair cells (OHCs)Normal thresholds rely on the proper function of outer hair cells (OHCs)(Dallos and Harris,1978).(Dallos and Harris,1978).Per inner ear,there are approximately Per inner ear,there are approximately 11,000 11,000 OHCs,OHCs,which are,in the human cochlea,typically which are,in the human cochlea,typically arranged in 3 rowsarranged in 3 rows (Fig.1,(Fig.1,OHC).OHC function is to OHC).OHC function is to nonlinearly amplify basilar membrane vibrationnonlinearly amplify basilar membrane vibration in in response to soft sounds near the place of characteristic frequency within the response to soft sounds near the place of characteristic frequency within the cochlea (Ashmore,2008).cochlea (Ashmore,2008).OHCs are therefore OHCs are therefore crucial for the high sensitivity of the hearing organ,its crucial for the high sensitivity of the hearing organ,its frequency selectivity,and understanding speech in noisefrequency selectivity,and understanding speech in noise (Ashmore,2008;Dallos,(Ashmore,2008;Dallos,2008).2008).After After mild acoustic overexposuremild acoustic overexposure,hearing function can recover within 23 weeks ,hearing function can recover within 23 weeks (Miller et al.,1963).This corresponds to a(Miller et al.,1963).This corresponds to a temporary threshold shift temporary threshold shift（暂时暂时性性性性阈阈移）移）移）移）due to reversible damage to the due to reversible damage to the mechanosensory hair bundles of hair cells (Fig.1,stereocilia)mechanosensory hair bundles of hair cells (Fig.1,stereocilia)(Liberman and Dodds,1984a,b;Schneider et al.,2002).(Liberman and Dodds,1984a,b;Schneider et al.,2002).After After intense or repeated acoustic overstimulationintense or repeated acoustic overstimulation,however,hearing,however,hearing function stabilizes at an elevated value,leading to function stabilizes at an elevated value,leading to permanentpermanent threshold shift threshold shift（永久性（永久性（永久性（永久性阈阈移）移）移）移）that mostly occurs due to destruction of OHCs(that mostly occurs due to destruction of OHCs(Spoendlin,1985).Spoendlin,1985).In the daily clinical routine,permanent hearing loss is typically detected In the daily clinical routine,permanent hearing loss is typically detected through the increase of hearing thresholds as tested by through the increase of hearing thresholds as tested by tone-audiometrytone-audiometry（听（听（听（听力力力力测测定）定）定）定）.More detailed clinical diagnostic testing may also include .More detailed clinical diagnostic testing may also include auditory auditory brainstem response (ABR)brainstem response (ABR)（听性（听性（听性（听性脑脑干反干反干反干反应应）testing or recording testing or recording distortion distortion product otoacoustic emissions (DPOAEs)product otoacoustic emissions (DPOAEs)（畸（畸（畸（畸变产变产物耳声物耳声物耳声物耳声发发射）射）射）射）.ABR responses represent ABR responses represent the summed activity of neurons in the ascending the summed activity of neurons in the ascending auditory pathways.auditory pathways.The specific function of intact OHCs can be measured by amplitudes of The specific function of intact OHCs can be measured by amplitudes of DPOAEs.DPOAEs.DPOAEs are acoustic signals that arise from distortions in the DPOAEs are acoustic signals that arise from distortions in the OHCs mechanoelectrical response to two continuous tones.These distortion OHCs mechanoelectrical response to two continuous tones.These distortion products,which are at frequencies not present in the input stimulus,products,which are at frequencies not present in the input stimulus,are are generated by the OHCs biological motors and can be detected with a generated by the OHCs biological motors and can be detected with a microphone in the ear canalmicrophone in the ear canal.DPOAEs responses thus reflect the electromotile .DPOAEs responses thus reflect the electromotile properties of OHCs (Fitzgerald et al.,1993;Huang et al.,2005).properties of OHCs (Fitzgerald et al.,1993;Huang et al.,2005).We can conclude that loss of hearing thresholds after noise exposure is mostly We can conclude that loss of hearing thresholds after noise exposure is mostly linked to OHC loss,which specifically can be measured by DPOAEs.linked to OHC loss,which specifically can be measured by DPOAEs.Through Through DPOAE and ABR measurements,in combination,a differential damage of DPOAE and ABR measurements,in combination,a differential damage of OHCs and IHCs can be detected.OHCs and IHCs can be detected.Fig.2.Predicted subcellular positions of high-and low-SR fibers at the inner haircell (IHC).Afferent auditory nerve fibers of IHCs are classified accordingto their spontaneous action potential discharge rate (SR).High-threshold,low-and medium-SR fibers are presumably preferentially located at the modiolar side of the IHC,where larger ribbons are associated with smaller patches of NMDA-R and AMPA-R.Low-threshold,high-SR fibers are presumably preferentially located at the pillar side of the IHC,where smaller ribbons oppose larger AMPA-R patches.Also characteristic of ribbon synapses(带状突触）,CaV1.3 channels are clustered near synaptic ribbons,and thereby stabilize the contact with afferent neurons.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 Regarding more recent findings on NIHL,it is most important to Regarding more recent findings on NIHL,it is most important to remember that OHC loss can be accompanied by IHC (Fig.1,IHC)remember that OHC loss can be accompanied by IHC (Fig.1,IHC)damage (Liberman and Dodds,1984a,b).damage (Liberman and Dodds,1984a,b).The IHCs are the primary sensory hair cells of the cochlea thatThe IHCs are the primary sensory hair cells of the cochlea that transmit sound information over an intensity range spanning 12 orders of transmit sound information over an intensity range spanning 12 orders of magnitude (120 dB)and 3 orders of magnitude of frequency (20 Hz to magnitude (120 dB)and 3 orders of magnitude of frequency (20 Hz to 20 kHz)(Robles and Ruggero,2001).20 kHz)(Robles and Ruggero,2001).This powerful capacity of IHC synapses is achieved through their This powerful capacity of IHC synapses is achieved through their numerous specialized afferent contacts.numerous specialized afferent contacts.Each IHC is innervated by 8 Each IHC is innervated by 8 (human)or up to 20 (rodents)(Glowatzki and Fuchs,2002)(human)or up to 20 (rodents)(Glowatzki and Fuchs,2