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1、Advances in neurobiology of tinnitus and hyreracusis耳鳴和聽覺過敏的神經(jīng)生物學研究進展楊明建2014.12.16研究背景研究背景Hearing impairment is a considerable disease burden.It hasbeen estimated that adult-onset hearing impairment is the thirdleading cause of disability (WHO,2008).Forty-two previous reports published between 1973

2、and 2010 in 29 countries have revealed increased hearing loss with age;Developing countries report higher rates of moderate and moderately-severe hearing impairment due to higher rates of pre-and postnatal childhood infections such as rubella(風疹）風疹）,measles（麻（麻疹）疹）and meningit（腦膜炎）（腦膜炎）,and from the

3、 use of ototoxic drugs（耳毒性藥物）（耳毒性藥物）(Stevens et al.,2013).However,in industrialized countries,noise-induced hearing loss (NIHL)（噪聲性聽力損失）（噪聲性聽力損失）is a common cause of hearing impairments (Lu et al.,2005),with a prevalence that is second to presbycusis（老年性耳（老年性耳 聾）聾）(Stanbury et al.,2008).Hyperacusi a

4、nd tinnitus are potentially devastating conditions that are still incurable.Epidemiology（流行病學）（流行病學）of tinnitusTinnitus is a disorder of perception of phantom sound that is also known as ringing in the ear or head.Tinnitus affects 1020%of the general population (Galazyuk et al.,2012;Shargorodsky et

5、al.,2010);According to the American Tinnitus Association,an estimated 50 million people in the United States have chronic tinnitus,persisting for longer than six months (Shargorodsky et al.,2010).For 12 million individuals,it is severe enough to interfere with daily activities.Tinnitus can occur in

6、children (Shetye and Kennedy,2010)and prevalence increases with age (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 in women,more likely in former smokers,and in adults with hypertension,hearing impairment,loud noise

7、 exposure,or generalized anxiety disorder(廣泛性廣泛性焦慮障礙）焦慮障礙）(Shargorodsky et al.,2010).Hearing loss and stress (emotional as well as psychosocial)are important risk factors for tinnitus (Hebert et al.,2012;Jastreboff,2007;Langguth et al.,2009),although tinnitus can occur independently from broad incre

8、ase of hearing thresholds (Geven et al.,2011;Langers et al.,2012;Lockwood et al.,2002).耳鳴的分類耳鳴的分類耳鳴有耳鳴有間歇性，也有持續(xù)性間歇性，也有持續(xù)性。有。有單一頻率窄帶噪單一頻率窄帶噪音或白噪音音或白噪音等多種表現(xiàn)。耳鳴一般可分為等多種表現(xiàn)。耳鳴一般可分為中樞性中樞性及周圍性兩大類及周圍性兩大類。周圍性耳鳴根據(jù)是否被別人聽。周圍性耳鳴根據(jù)是否被別人聽見分為見分為主觀性耳鳴和客觀性耳鳴主觀性耳鳴和客觀性耳鳴。前者多見，后。前者多見，后者少見。耳鳴又可根據(jù)其特征分為者少見。耳鳴又可根據(jù)其特征分為持續(xù)性耳鳴

9、與持續(xù)性耳鳴與節(jié)律性耳鳴節(jié)律性耳鳴。持續(xù)性耳鳴可有單一頻率或多頻率。持續(xù)性耳鳴可有單一頻率或多頻率聲調(diào)的混合，多為主觀性耳鳴。節(jié)律性耳鳴多與聲調(diào)的混合，多為主觀性耳鳴。節(jié)律性耳鳴多與血管跳動一致，偶爾與呼吸一致，耳鳴的頻率較血管跳動一致，偶爾與呼吸一致，耳鳴的頻率較低。如為肌肉收縮引起，則耳鳴的頻率較高。節(jié)低。如為肌肉收縮引起，則耳鳴的頻率較高。節(jié)律性耳鳴，多為客觀性耳鳴。律性耳鳴，多為客觀性耳鳴。Epidemiology（流行病學）（流行病學）of hyperacusisHyperacusis is a disorder of loudness perception（響度感知紊亂）（響度感知

10、紊亂）,in which sound intensities that are considered comfortable by most people are perceived unbearably loud (Baguley,2003).In hyperacusis,sounds are not simply a bit loud,but truly unbearable（難以忍受）（難以忍受）.Hyperacusis can occur without a loss of hearing thresholds (Gu et al.,2010).Statistics on hypera

11、cusis are scarce,and although it is often coincident with tinnitus,limited evidence has supported the co-occurrence of the two conditions (Andersson et al.,2002;Gu et al.,2010;Nelson and Chen,2004).With an approximate prevalence of about 1015%of the population (Gilles et al.,2012),the prevalence of

12、hyperacusis is comparable to tinnitus (Shargorodsky et al.,2010).For tinnitus and hyperacusis,hearing loss,however,is a major risk factor.As the incidence of hearing loss will increase with the aging of the population,also the incidence of tinnitus and hyperacusis may increase.Are tinnitus and hyper

13、acusis in the ear or the brain?越來越多的證據(jù)表明耳鳴和聽覺過敏形成的機制中越來越多的證據(jù)表明耳鳴和聽覺過敏形成的機制中外周聽覺器官損傷只是起因外周聽覺器官損傷只是起因，耳鳴和聽覺過敏的形，耳鳴和聽覺過敏的形成和維持更多的是成和維持更多的是 聽覺傳導(dǎo)通路上各級中樞的作聽覺傳導(dǎo)通路上各級中樞的作用用。耳蝸損傷耳蝸損傷等造成的異常神經(jīng)活動經(jīng)中樞核團逐等造成的異常神經(jīng)活動經(jīng)中樞核團逐級傳遞并在邊緣系統(tǒng)等非聽覺系統(tǒng)的參與下最終在級傳遞并在邊緣系統(tǒng)等非聽覺系統(tǒng)的參與下最終在聽皮層被感知為耳鳴。聽皮層被感知為耳鳴。M.Knipper,P.V.Dijk，I.Nunes，et a

14、l.Advances in the neurobiology of hearing disorders:Recent developments regarding the basis of tinnitus and hyperacusis Progress in Neurobiology,111 (2013)1733J.J.Eggermont，L.E.Roberts.The neuroscience of tinnitus.TRENDS in Neurosciences,27(2004)676-682.Fig.1.Schematic illustration of the adult orga

15、n of Corti.The nerve fibers of IHCs(內(nèi)毛細胞）send information to the brain,whereas the nerves of OHCs（外毛細胞）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

16、 the acoustic signal,which in turn activates IHCs.The IHCs transmit electrical signals in a frequency-specific manner to higher auditory brain areas.內(nèi)耳柯蒂氏器（螺旋器）示意圖1.cochlear damageNIHL（噪聲性聽力損失）（噪聲性聽力損失）has been,in a previous view,typically defined by a permanent loss of hearing thresholds（聽閾永久性損失）（聽

17、閾永久性損失）.Normal thresholds rely on the proper function of outer hair cells (OHCs)(Dallos and Harris,1978).Per inner ear,there are approximately 11,000 OHCs,which are,in the human cochlea,typically arranged in 3 rows (Fig.1,OHC).OHC function is to nonlinearly amplify basilar membrane vibration in resp

18、onse to soft sounds near the place of characteristic frequency within the cochlea (Ashmore,2008).OHCs are therefore crucial for the high sensitivity of the hearing organ,its frequency selectivity,and understanding speech in noise (Ashmore,2008;Dallos,2008).After mild acoustic overexposure,hearing fu

19、nction can recover within 23 weeks (Miller et al.,1963).This corresponds to a temporary threshold shift（暫時性閾移）（暫時性閾移）due to reversible damage to the mechanosensory hair bundles of hair cells (Fig.1,stereocilia)(Liberman and Dodds,1984a,b;Schneider et al.,2002).After intense or repeated acoustic over

20、stimulation,however,hearing function stabilizes at an elevated value,leading to permanent threshold shift（永久性閾移）（永久性閾移）that mostly occurs due to destruction of OHCs(Spoendlin,1985).In the daily clinical routine,permanent hearing loss is typically detected through the increase of hearing thresholds a

21、s tested by tone-audiometry（聽力測定）（聽力測定）.More detailed clinical diagnostic testing may also include auditory brainstem response (ABR)（聽性腦干反應(yīng)）（聽性腦干反應(yīng)）testing or recording distortion product otoacoustic emissions (DPOAEs)（畸變產(chǎn)物耳聲發(fā)射）（畸變產(chǎn)物耳聲發(fā)射）.ABR responses represent the summed activity of neurons in the

22、 ascending auditory pathways.The specific function of intact OHCs can be measured by amplitudes of DPOAEs.DPOAEs are acoustic signals that arise from distortions in the OHCs mechanoelectrical response to two continuous tones.These distortion products,which are at frequencies not present in the input

23、 stimulus,are generated by the OHCs biological motors and can be detected with a microphone in the ear canal.DPOAEs responses thus reflect the electromotile properties of OHCs (Fitzgerald et al.,1993;Huang et al.,2005).We can conclude that loss of hearing thresholds after noise exposure is mostly li

24、nked to OHC loss,which specifically can be measured by DPOAEs.Through DPOAE and ABR measurements,in combination,a differential damage of 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 ar

25、e 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

26、 presumably preferentially located at the pillar side of the IHC,where smaller ribbons oppose larger AMPA-R patches.Also characteristic of ribbon synapses(帶狀突觸）,CaV1.3 channels are clustered near synaptic ribbons,and thereby stabilize the contact with afferent neurons.內(nèi)耳毛細胞高自發(fā)放電率和低自發(fā)放電率纖維亞細胞位置Regard

27、ing more recent findings on NIHL,it is most important to remember that OHC loss can be accompanied by IHC (Fig.1,IHC)damage (Liberman and Dodds,1984a,b).The IHCs are the primary sensory hair cells of the cochlea that transmit sound information over an intensity range spanning 12 orders of magnitude

28、(120 dB)and 3 orders of magnitude of frequency (20 Hz to 20 kHz)(Robles and Ruggero,2001).This powerful capacity of IHC synapses is achieved through their numerous specialized afferent contacts.Each IHC is innervated by 8 (human)or up to 20 (rodents)(Glowatzki and Fuchs,2002)unbranched spiral gangli

29、on neurons（螺旋神經(jīng)節(jié)神經(jīng)元）（螺旋神經(jīng)節(jié)神經(jīng)元）,which represent about 9095%of all afferent fibers (AF)in the auditory nerve (AN)(Fig.1,AN;Figs.1 and 2,AF type I).Each IHC contains electron-dense presynaptic subcellular structures（高電子密度突觸前亞細胞結(jié)構(gòu)）（高電子密度突觸前亞細胞結(jié)構(gòu)）,so-called ribbons (Figs.1 and 2,red)that tether 100 synap

30、tic vesicles (Glowatzki and Fuchs,2002).This specialized presynaptic machinery thereby maintains a large releasable pool of neurotransmitter,allowing afferent auditory neurons to code the temporal characteristics of sound with high reliability and temporal precision (Buran et al.,2010)（更可靠和精（更可靠和精確編

31、碼聲音的時相特征）確編碼聲音的時相特征）.The 3500 IHCs (Figs.1 and 2,IHC)in the cochlea rarely die from NIHL,however.Instead,the innervated dendrites of the auditory nerve fibers undergo neurodegeneration（神經(jīng)退化）（神經(jīng)退化）(Kujawa and Liberman,2009;Lin et al.,2011).This process has been revealed to be tightly correlated with

32、an altered number of transmitter release sites in IHC nerve terminals (Fig.2,blue)(Jaumann et al.,2012;Kujawa and Liberman,2009;Lin et al.,2011;Zuccottiet al.,2012).the long-standing dogma that cochlear nerve degeneration is a consequence of IHC death after acoustic trauma was only recently overturn

33、ed,as degeneration can occur when IHCs are present.A complete set of functional,intact IHC ribbon synapses（帶狀突觸）（帶狀突觸）and their proper contacts to auditory fibers are crucial elements to achieve the full dynamic loudness range,as well as high precision of temporal sound information.Fig.3.Comparison of the basolateral pole length of inner hair cells (IHCs)from rats with or without tinnitus in indic