動物生理學原理-耳鳴和聽覺過敏的神經(jīng)生物學機制

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,Hearing impairment is a considerable disease burden. It hasbeen estimated that adult-onset hearing imp

2、airment is the thirdleading cause of disability (WHO, 2008). Forty-two previous reports published between 1973 and 2010 in 29 countries have revealed increased hearing loss with age

3、; 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）, me

4、asles（麻疹） and meningit（腦膜炎）, and from the use of ototoxic drugs （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） is a com

5、mon cause of hearing impairments ( Lu et al., 2005), with a prevalence that is second to presbycusis（老年性耳 聾） ( Stanbury et al., 2008).Hyperacusi and tinnitus are potentially devastating

6、conditions that are still incurable.,Epidemiology（流行病學） of tinnitus,Tinnitus is a disorder of perception of phantom sound that is also known as ringing in the ear or head. Tin

7、nitus affects 10–20% of the general population (Galazyuk et al., 2012; Shargorodsky et al., 2010); According to the American Tinnitus Association, an estimated 50 million people in the Un

8、ited 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.

9、Tinnitus can occur in 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 (

10、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 exposure, or generalized anx

11、iety disorder (廣泛性焦慮障礙） ( Shargorodsky et al., 2010).Hearing loss and stress (emotional as well as psychosocial) are important risk factors for tinnitus ( Hebert et al., 2012; Jas

12、treboff, 2007; Langguth et al., 2009), although tinnitus can occur independently from broad increase of hearing thresholds ( Geven et al., 2011; Langers et al., 2012; Lockwood et a

13、l., 2002).,耳鳴的分類,耳鳴有間歇性，也有持續(xù)性。有單一頻率窄帶噪音或白噪音等多種表現(xiàn)。耳鳴一般可分為中樞性及周圍性兩大類。周圍性耳鳴根據(jù)是否被別人聽見分為主觀性耳鳴和客觀性耳鳴。前者多見，后者少見。耳鳴又可根據(jù)其特征分為持續(xù)性耳鳴與節(jié)律性耳鳴。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)律性耳鳴，多為客觀性耳鳴。

14、,Epidemiology（流行病學） of hyperacusis,Hyperacusis is a disorder of loudness perception（響度感知紊亂）, in which sound intensities that are considered comfortable by most people are perceived unbearably

15、loud ( Baguley, 2003). In hyperacusis, sounds are not simply a bit loud, but truly unbearable（難以忍受）. Hyperacusis can occur without a loss of hearing thresholds ( Gu et al., 2010). Statist

16、ics on hyperacusis 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;

17、Gu et al., 2010; Nelson and Chen, 2004). With an approximate prevalence of about 10–15% of the population ( Gilles et al., 2012), the prevalence of hyperacusis is comparable to t

18、innitus (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 o

19、f the population, also the incidence of tinnitus and hyperacusis may increase.,Are tinnitus and hyperacusis 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外周聽覺器官損傷只是起因，耳鳴和聽覺過敏的形成和維持更多的是 聽覺傳導通路上各級中樞的作用。耳

20、蝸損傷等造成的異常神經(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)的參與下最終在聽皮層被感知為耳鳴。M. Knipper, P.V. Dijk， I. Nunes， et al. Advances in the neurobiology of hearing disorders: Recent developments regarding the basis of tinnitus a

21、nd hyperacusis Progress in Neurobiology, 111 (2013) 17–33J. J. Eggermont， L. E. Roberts. The neuroscience of tinnitus. TRENDS in Neurosciences, 27 (2004) 676-682.,Fig. 1. Schematic illustration of the adult or

22、gan 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

23、 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

24、 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 damage,NIHL（噪聲性聽力損失） has been, in a previous view, typically defin

25、ed by a permanent loss of hearing thresholds（聽閾永久性損失）. Normal thresholds rely on the proper function of outer hair cells (OHCs) (Dallos and Harris, 1978). Per inner ear, there are

26、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 response t

27、o 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 s

28、electivity, and understanding speech in noise (Ashmore, 2008; Dallos, 2008).After mild acoustic overexposure, hearing function can recover within 2–3 weeks ( Miller et al., 1963). This

29、 corresponds to a temporary threshold shift （暫時性閾移） due to reversible damage to the mechanosensory hair bundles of hair cells ( Fig. 1 , stereocilia) ( Liberman and Dodds, 19

30、84a,b; Schneider et al., 2002). After intense or repeated acoustic overstimulation, however, hearing function stabilizes at an elevated value, leading to permanent threshold s

31、hift （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 hear

32、ing thresholds as tested by tone-audiometry（聽力測定）. More detailed clinical diagnostic testing may also include auditory brainstem response (ABR) （聽性腦干反應） testing or recording distortion produ

33、ct otoacoustic emissions (DPOAEs)（畸變產(chǎn)物耳聲發(fā)射）.ABR responses represent the summed activity of neurons in the ascending auditory pathways.The specific function of intact OHCs can be mea

34、sured 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

35、 at frequencies not present in the input stimulus, are generated by the OHCs’ biological motors and can be detected with a microphone in the ear canal. DPOAEs responses thus reflec

36、t 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 linked to OHC

37、 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 subc

38、ellular positions of high- and low-SR fibers at the inner haircell (IHC).,Afferent auditory nerve fibers of IHCs are classified accordingto their spontaneous action p

39、otential 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

40、 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 p

41、atches. 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,Re

42、garding 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 a

43、re the primary sensory hair cells of the cochlea that transmit sound information over an intensity range spanning 12 orders of magnitude (120 dB) and 3 orders of magnitude of

44、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

45、 innervated by 8 (human) or up to 20 (rodents) ( Glowatzki and Fuchs, 2002) unbranched spiral ganglion neurons（螺旋神經(jīng)節(jié)神經(jīng)元）, which represent about 90–95% of all afferent fibers (AF

46、) 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構）, so-called ribbons ( Figs

47、. 1 and 2, red) that tether > 100 synaptic vesicles ( Glowatzki and Fuchs, 2002). This specialized presynaptic machinery thereby maintains a large releasable pool of neurotransmitter,

48、 allowing afferent auditory neurons to code the temporal characteristics of sound with high reliability and temporal precision ( Buran et al., 2010)（更可靠和精確編碼聲音的時相特征）.,The 3500 IHCs ( Figs.

49、 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） ( Kujawa and Liberman, 20

50、09; Lin et al., 2011). This process has been revealed to be tightly correlated with an altered number of transmitter release sites in IHC nerve terminals ( Fig. 2, blue) ( Jaumann et

51、 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 acoust

52、ic trauma was only recently overturned, as degeneration can occur when IHCs are present.A complete set of functional, intact IHC ribbon synapses（帶狀突觸） and their proper contacts to audi

53、tory 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 lengt

54、h of inner hair cells (IHCs) from rats with or without tinnitus in indicated cochlear turns.,Both groups exhibited reduced length of the basolateral pole of IHCs in high frequenc

55、y cochlear turns ( Ruttiger et al., 2013),2. Altered central brain responses to cochlear damage,The first ABR wave ( Fig. 3B, ABR wave I) represents the summed activity of the au

56、ditory nerve, whereas later ABR waves arise from synchronous neural activity in the auditory brainstem ( Melcher and Kiang, 1996).Sound processing can also activate limbic structure

57、s（邊緣系統(tǒng)） ( Fig. 3A, drawn in green). The amygdala（杏仁核） and the hippocampus（海馬）, two major regions of the limbic system, receive direct and indirect neuralinput from the central aud

58、itory system.Noise-induced stress can activate the basolateral amygdala )( （底外側杏仁核) through the hypothalamic-pituitary-adrenal axis )(下丘腦-垂體-腎上腺軸） (HPA axis) （Fig. 3A). Thus, acoustic trauma

59、can damage the cochlea and affect the basolateral amygdala and the hippocampus. ( Kraus et al., 2010).,Fig. 4. Central auditory circuits and auditory brainstem responses.,Besids cent

60、ral auditory circuits, There are auditory-limbic interactions (drawn in green). The basolateral amygdala (BLA)( 底外側杏仁核) receives directneural inputs from the auditory thalamus (MGB, green and

61、 the (AC). The BLA, in turn, contacts the hippocampus which has direct contact with the AC. The BLA also projects to the IC , thereby generating an amygdalar-auditory feedback lo

62、op(杏仁核聽覺反饋環(huán)路）. The BLA also activates (e.g. due to noise-induced stress) the hypothalamic-pituitary-adrenal axis (HPA axis)(下丘腦-垂體-腎上腺軸）, thereby influencing the level of blood cortisol 皮

63、質(zhì)醇 (human) or corticosterone 皮質(zhì)酮 (rodents), as well as the cochlea (greendashed lines).,The normal ABR consists of five prominent waves that occur during the first 10 ms after pre

64、sentation of a transient sound.,The central auditory system compensates for diminished input by upregulating its responsiveness in central circuitries ( Salvi et al., 2000). Central com

65、pensation that follows reduced auditory nerve activity may occur first at the level of the auditory brainstem, from where altered activity patterns then spread to ascending audito

66、ry nuclei ( Manzoor et al., 2013; Mulders and Robertson, 2013). In humans ( Gu et al., 2012) and animals (Singeret al., 2013), auditory nerve and brainstem function in respons

67、e to sound, assessed by ABRs, have been used to analyze compensating central activity following cochlear damage.,3. Research on tinnitus or hyperacusis in animals,In both humans and ani

68、mals, determining the presence of tinnitus and hyperacusis is a challenge. Humans can, of course, indicate the presence of tinnitus, but it is not possible to confirm this with