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1、 Review TRENDS in Neurosciences Vol.27 No.11 November 2004 The neuroscience of tinnitus Jos J. Eggermont1 and Larry E. Roberts2 1Department of Physiology and Biophysics, and Department of Psychology, University of Calgary, Alberta, Canada, T2N 1N4 2Department of Psychology, McMaster University, Hami

2、lton, Ontario, Canada, L8S 4K1 Tinnitus is an auditory phantom sensation (ringing of the ears) experienced when no external sound is present. Most but not all cases are associated with hearing loss induced by noise exposure or aging. Neuroscience research has begun to reveal how tinnitus is generate

3、d by the brain when hearing loss occurs, and to suggest new avenues for management and prevention of tinni- tus following hearing injuries. Downregulation of intra- cortical inhibition induced by damage to the cochlea or to auditory projection pathways highlights neural processes that underlie the s

4、ensation of phantom sound. Many, if not most, people have experienced ringing in their ears when no external sound is present. Typically the sensation is associated with a reversible cause such as listening to loud music, fever, use of aspirin or quinine, or transient perturbations of the middle ear

5、 and subsides over a period of time ranging from a few seconds to a few days. However, in 515% of the general population, the tinnitus sensation is unremitting 1. Chronic tinnitus is more prevalent among seniors (12% after age 60) than in young adults (5% in the 2030 age group) but can occur at any

6、age. In 13% of the general population, the tinnitus sensation is sufficiently loud to affect the quality of life, involving sleep disturbance, work impairment and psy- chiatric distress 2. Most cases of chronic tinnitus are associated with hearing loss that is induced by noise exposure or accompanie

7、s the aging process. The preva- lence of tinnitus could be increasing as the senior population grows and as young people are increasingly exposed to industrial and recreational noise 3. Tinnitus is of interest to auditory neuroscientists because it represents a meeting ground for neuroscience and pr

8、oblems of human health. It is a significant medical, psychological and workplace challenge for millions of people. Although a variety of procedures can help tinnitus sufferers adapt to and modulate their tinnitus sensation, at present there are no treatments that reliably eliminate tinnitus itself.

9、Neuroscientists are, however, beginning to understand how tinnitus is generated when hearing loss occurs. Their findings suggest new approaches to the management and prevention of tinnitus and provide insight into the question of how the brain generates the sensation of sound. Is tinnitus in the ear

10、 or the brain? Tinnitus sensations associated with hearing loss are usually localized towards the affected ear(s). Does this Corresponding author: Jos J. Eggermont (eggermonucalgary.ca). Available online 9 September 2004 mean that tinnitus is generated in the ear? This con- tentious issue, which has

11、 great implications for which types of treatment should be developed, can only be resolved in animal models that are conditioned to signal the presence of tinnitus following application of ototoxic drugs 4,5 or excessive noise 6. There is limited support for the assumption that tinnitus is the resul

12、t of increased spontaneous activity in auditory nerve fibers: evidence is found after high-dose application of salicylate 7, but low doses do not increase spontaneous firing rates (SFR) 8,9, even though tinnitus can be demonstrated behaviorally for low doses 5. Other ototoxic drugs that cause tinnit

13、us, such as quinine 10 and aminoglycosides 11, show a consistent decrease in the SFR of auditory nerve fibers. A similar decrease is reported after noise-induced hearing loss 12. These results showing reduced SFR in auditory nerve fibers following noise exposure or ototoxicity point to a central cau

14、se of tinnitus, possibly related to changes in the balance of excitatory and inhibitory inputs conveyed to central auditory structures. Two qualifications here are that tinnitus can be prevented if NMDA receptor blockers are infused into the cochlea before salicylate application 13, and that prior a

15、dministration of NMDA receptor blockers can limit hearing loss resulting from noise trauma 14. It seems that by reducing the extent of the hearing loss, probably by preventing the neurotoxic effects of excessive glutamate release at cochlear NMDA recep- tors, the tinnitus is also prevented. These fi

16、ndings are consistent with the view that the origin of tinnitus lies in an imbalance of firing patterns across the tonotopic array of auditory nerve fibers 11, but not with the view that tinnitus reflects increased spontaneous activity generated there. Tinnitus sensations often persist even when inp

17、ut from the ear is removed by section of the auditory nerve 15. Currently, most evidence based on SFR measurements points to changes in the central auditory system following dysfunction of the cochlear receptors as the source of tinnitus (Figure 1). Diminished output from the affected region causes

18、reduced inhibition in central auditory structures 1618, leading to hyperexcitability of the central auditory system 19,20. This reduced inhibition has been indirectly demonstrated, after low-dose salicy- late application, by the increase in SFR of neurons in the central (ICc) and external (ICx) nucl

19、ei of the inferior colliculus (IC) 21,22 and in secondary auditory cortex (AII) 23. In primary auditory cortex (AI), a low dose of salicylate did not produce changes in SFR 24, whereas a high dose did 25. After cis-platin application, SFR was increased in the dorsal cochlear nucleus (DCN) of hamster

20、s 26. Quinine application increased SFR in AII 23 but not 0166-2236/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2004.08.010 Review TRENDS in Neurosciences Vol.27 No.11 November 2004 677 Amygdala Core cortex AI MGB Belt cortex AII in AI 27. Noise trauma increas

21、ed SFR in DCN 28 and AI 2931. Studies in DCN after noise trauma found increased spontaneous activity in fusiform cells 32 and potentially also in cartwheel cells 33. These findings (Table 1) point to an increase in SFR in cortical and subcortical auditory structures following noise trauma and exposu

22、re to ototoxic drugs. Whether increases in SFR relate directly to the sensation of tinnitus is, however, unclear. An interesting aspect is that, although tinnitus is often experienced immediately after noise exposure, increases in SFR took a few hours to materialize in AI Somato- sensory LN ICc SOC

23、ICx 31 and several days to appear in DCN 34. The temporal correlation of changes in SFR with the time course of tinnitus needs to be further investigated. Two other possible correlates of tinnitus that have been investigated using animal models of hearing loss are burst firing and neural synchrony.

24、Although burst firing increases after salicylate application in ICx 22, in cortical neurons the amount of bursting observed after salicylate or quinine application 24,27 or after noise trauma 29,30 does not change; transitory increases in AI after noise trauma DCN VCN Auditory return to baseline wit

25、hin a few hours 31. A second feature of spontaneous activity in AI, the synchronization of the firings of several neurons as measured by cross- correlation, is increased immediately after a noise trauma O H C O H C IHC nerve fibers for neurons in the affected frequency region 31, and also after quin

26、ine application 27. Synchrony in the affected Sound O H C frequency region also increases with time and relates to reorganization of the cortical tonotopic representation by noise trauma (as will be described later). Thus, evidence Lemniscal afferents Lemniscal feedback for a strong central componen

27、t in most cases of tinnitus is Extralemniscal afferents Olivocochlear feedback Extralemniscal feedback Cochlear amplifier TRENDS in Neurosciences mounting. Evidence from human brain imaging studies confirms involvement of central structures in tinnitus and points to changes accompanying tinnitus not

28、 only in the Figure 1. Schematic outline of the auditory system. This figure excludes binaural pathways and interhemispheric connections, but indicates parts where tinnitus- related studies have been conducted (yellow). Sound activates the outer hair cells (OHC) and inner hair cells (IHC) in the coc

29、hlea (bottom). The cochlea decomposes multi-frequency signals into a spatial output organized according to frequency; this is tonotopic mapping. The OHC act mainly as amplifiers of the mechanical movement of the basilar membrane, thereby sharpening the frequency resolution and enhancing sensitivity.

30、 Their working point and effectiveness are under control of the central auditory system (CAS), through olivocochlear bundle feedback (dark blue lines) from the superior olivary complex (SOC). The IHC are the mechanoelectric transducers (microphones) in the cochlea, whose neural output forms the audi

31、tory nerve. Auditory nerve fibers bifurcate to send collaterals into both the ventral cochlear nucleus (VCN) and dorsal cochlear nucleus (DCN); both structures show tonotopic maps. Such mappings are found throughout the CAS and the nerve fiber tracts that propagate this frequency-specific informatio

32、n by the lemniscal pathway (thick black lines). The DCN, in addition to auditory nerve input, is also innervated by fibers from various parts of the somatosensory system (cyan), so this structure is a multi-modal processing station that is probably heavily involved in tinnitus resulting from, for ex

33、ample, orofacial movements and gaze changes. For that reason, this structure is considered here to be part of the extralemniscal pathway (green). Other parts of the extralemniscal pathway are the lateral nucleus (LN) and external nucleus (ICx) of the inferior colliculus, parts of the medial genicula

34、te body (MGB) in the thalamus, and the secondary auditory cortex (AII), which are all characterized by sensitivity to somatosensory stimuli. The MGB and auditory cortical areas project to the amygdala (top left), which is associated with fear conditioning and emotional processing. The CAS is charact

35、erized by strong reciprocal connections between various structures, and the descending parts consist of interconnected feedback loops that allow the cortex to modulate activity of the entire subcortical CAS. There are strong direct feedback connections between primary auditory cortex (AI) and DCN, a

36、s well as from auditory cortical areas via the central nucleus of the inferior colliculus (ICc). Thus, changes in cortical activity as a result of a loss of inhibition could change the subcortical activity in the ICc and DCN (directly) and even in the cochlea (indirectly via the olivocochlear bundle

37、). Changes in the DCN, in turn, will directly affect the processing of lemniscal activity at the level of the VCN and the ICc. Thus, there could be a synergy between changes occurring in the cortex and those in the brainstem. inferior colliculus 35 and auditory cortex 36,37 but also in limbic struct

38、ures associated with emotion 37. These structures are modulated by activation of auditory nuclei that are also innervated by non-auditory inputs (e.g. the trigeminal nerve 38), and can become activated as a consequence of removal of acoustic tumors or head and neck injury 39,40. Multimodal inputs co

39、uld be at work in cases where tinnitus is modulated by gaze or jaw- clenching or where hearing loss is absent 41. Animal studies also suggest that metabolism after salicylate administration decreases in IC but increases in the auditory thalamus (medial geniculate body) and auditory cortex, as well a

40、s in the amygdala 42,43. Cortical reorganization in tinnitus The animal research reviewed here investigated the response properties of neurons following hearing injuries or application of ototoxic drugs, and points to changes in the balance of excitation and inhibition at multiple levels of the proj

41、ection pathway 5. It is reasonable to assume that expression of these effects in the cortex contributes in some way to the perception of tinnitus. One change that has been well documented is alteration of tonotopic maps in AI following cochlear damage induced by noise trauma. In the intact cortex (F

42、igure 2ai), there is an orderly tonotopic representation of spectral frequency across the auditory cortex in a caudal-to-rostral direction, which 678 Review TRENDS in Neurosciences Vol.27 No.11 November 2004 Table 1. Effects of drugs and trauma on spontaneous auditory activity and tinnitusa,b Salic

43、ylate low dose Salicylate high dose Quinine Cis-platin Noise trauma Refs Spontaneous activity Rate Rate Rate Synch. Rate Rate Synch. Auditory nerve fibers z Y NS Y Y NS 713 Dorsal cochlear nucleus NS NS NS NS NS 26,28,3234 Inferior colliculus NS NS NS NS NS NS 21,22 Primary auditory cortex z z NS 24

44、,25,27,2931,44 Secondary auditory cortex NS NS NS NS NS 23 Tinnitus Behavioral tinnitus Yes Yes Yes Yes Yes 5,53,55 aRate and synchrony (synch.) of spontaneous activity in parts of the auditory system can be affected by drugs and noise trauma. indicates a significant increase, Y indicates significan

45、t decrease and z indicates no change. Yes indicates that tinnitus has been signaled behaviorally after administration of the drug or trauma. bAbbreviation: NS, not studied. reflects place coding of sound frequency by the basilar membrane of the cochlea. After noise trauma, tonotopic organization in

46、the cortex is changed such that cortical neurons with characteristic frequencies (CFs) in the frequency region of the hearing loss no longer respond according to their place in the tonotopic map but reflect instead the frequency tuning of their less affected neighbors (Figure 2a,ii) 29,44. Neurons w

47、ith CFs in the (a) (i) Normal tonotopic map in cortex (ii) Reorganized map after hearing loss 245 PES AES 1 mm 1 mm 2.5 5 10 15 20 25 35 2.5 5 10 15 Frequency (kHz) Frequency (kHz) (b) Increasing firing rate Reorganized area (ii) Horizontal fibers (i) 1 2 3 4 5 6 7 8 9 10 11 12 13 Reduced input from

48、 periphery Frequency Normal frequency gradient TRENDS in Neurosciences Figure 2. Normal and reorganized tonotopic maps in primary auditory cortex (AI). (a) The characteristic frequency at each recording site is color-coded and overlaid on a photograph of the cortical surface for a control cat (i) an

49、d a cat with a noise induced hearing loss (ii). The hearing loss was limited to frequencies O10 kHz and amounted to 3 dB at 12 kHz, 12 dB at 16 kHz, 22 dB at 24 kHz and 23 dB at 32 kHz. (244 and 245 are cat identification numbers.) (b) The effect of restricted high-frequency hearing loss on the input to pyramidal cells (numbered 1