Учебники / Auditory Trauma, Protection, and Repair Fay 2008

Wood JD, Muchinsky SJ, Filoteo AG, Penniston JT, Tempel BL (2004b) Low endolymph calcium concentrations in deafwaddler2J mice suggest that PMCA2 contributes to endolymph calcium maintenance. J Assoc Res Otolaryngol 5:99–110.

Xia A, Katori Y, Oshima T, Watanabe K, Kikuchi T, Ikeda K (2001) Expression of connexin 30 in the developing mouse cochlea. Brain Res 898:364–367.

Xia A, Kikuchi T, Hozawa K, Katori Y, Takasaka T (1999) Expression of connexin 26 and Na,K-ATPase in the developing mouse cochlear lateral wall: functional implications. Brain Res 846:106–111.

Xia AP, Ikeda K, Katori Y, Oshima T, Kikuchi T, Takasaka T (2000) Expression of connexin 31 in the developing mouse cochlea. NeuroReport 11:2449–2453.

Xia AP, Kikuchi T, Minowa O, Katori Y, Oshima T, Noda T, Ikeda K (2002) Late–onset hearing loss in a mouse model of DFN3 non-syndromic deafness: morphologic and immunohistochemical analyses. Hear Res 166:150–158.

Xie H, Bevan JA (1999) Oxidized low-density lipoprotein enhances myogenic tone in the rabbit posterior cerebral artery through the release of endothelin-1. Stroke 30: 2423–2429.

Yada T, Shimokawa H, Kajiya F (2006) Cardioprotective effect of hydroxyfasudil as a specific Rho-kinase inhibitor, on ischemia-reperfusion injury in canine coronary microvessels in vivo. Clin Hemorheol Microcirc 34:177–183.

Yamakawa K (1938) Über pathologische Veränderungen bei einem Menière-Kranken. J Otolaryngol Soc Jpn 44:181–182.

Yamashita H, Sekitani T, Bagger-Sjöbäck D (1992) Expression of carbonic anhydrase isoenzyme-like immunoreactivity in the limbus spiralis of the human fetal cochlea. Hear Res 64:118–122.

Yamauchi D, Raveendran NN, Pondugula SR, Kampalli SB, Sanneman JD, Harbidge DG, Marcus DC (2005) Vitamin D upregulates expression of ECaC1 mRNA in semicircular canal. Biochem Biophys Res Commun 331:1353–1357.

Yamoah EN, Lumpkin EA, Dumont RA, Smith PJ, Hudspeth AJ, Gillespie PG (1998) Plasma membrane Ca2+–ATPase extrudes Ca2+ from hair cell stereocilia. J Neurosci 18:610–624.

Yatomi Y (2006) Sphingosine 1–phosphate in vascular biology: possible therapeutic strategies to control vascular diseases. Curr Pharm Des 12:575–587.

Yoo TJ, Tomoda K, Hernandez AD (1984) Type II collagen-induced autoimmune inner ear lesions in guinea pigs. Ann Otol Rhinol Laryngol Suppl 113:3–5.

Zelante L, Gasparini P, Estivill X, Melchionda S, D’Agruma L, Govea N, Mila M, Monica MD, Lutfi J, Shohat M, Mansfield E, Delgrosso K, Rappaport E, Surrey S, Fortina P (1997) Connexin26 mutations associated with the most common form of nonsyndromic neurosensory autosomal recessive deafness (DFNB1) in Mediterraneans. Hum Mol Genet 6:1605–1609.

Zhang Y, Tang W, Ahmad S, Sipp JA, Chen P, Lin X (2005) Gap junction-mediated intercellular biochemical coupling in cochlear supporting cells is required for normal cochlear functions. Proc Natl Acad Sci USA 102:15201–15206.

Zhao HB (2005) Connexin26 is responsible for anionic molecule permeability in the cochlea for intercellular signalling and metabolic communications. Eur J Neurosci 21:1859–1868.

Zhao HB, Yu N, Fleming CR (2005) Gap junctional hemichannel-mediated ATP release and hearing controls in the inner ear. Proc Natl Acad Sci USA 102:18724–18729.

Zidanic M, Brownell WE (1990) Fine structure of the intracochlear potential field. I. The silent current. Biophys J 57:1253–1268.

100 P. Wangemann

Ziegler EA, Brieger J, Heinrich UR, Mann WJ (2004) Immunohistochemical localization of cyclooxygenase isoforms in the organ of Corti and the spiral ganglion cells of guinea pig cochlea. ORL J Otorhinolaryngol Relat Spec 66:297–301.

Zimmermann U, Kopschall I, Rohbock K, Bosman GJ, Zenner HP, Knipper M (2000) Molecular characterization of anion exchangers in the cochlea. Mol Cell Biochem 205:25–37.

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a significant source of morbidity in chronic tinnitus. Clinical studies that examine the effects of intervention to mitigate tinnitus must carefully address the dichotomous nature of the problem and apply appropriate instruments to measure relevant factors comprehensively.

Tinnitus demographics have been studied world-wide, with some disparity in the findings. Many of the disparities likely stem from the difficulty in surveying large groups of people, the reliance on anamnestic data, and the imprecise nature of language in accurately capturing the sensory features of tinnitus. Relatively few studies have quantified the sensory features of tinnitus using either psychoacoustic measurements or validated questionnaires or both. Demographic data relevant to tinnitus include age, gender, hearing loss, history of cardiovascular disease, head injury, and exposure to noise or ototoxins.

Tinnitus is estimated to affect 8% to 30% of adults worldwide. In a national study of hearing in the United Kingdom, 10% of adults reported experiencing tinnitus for longer than 5 min, unrelated to tinnitus of immediate onset after noise exposure. In this study, 5% of adults described their tinnitus as moderate or severely annoying, 1% as severely affecting their quality of life, and 0.5% as prohibiting a normal life (Evered and Lawrenson 1981). A recent Australian study of tinnitus in a large population-based sample of 2015 adults, ages 55 to 99 years, combined detailed tinnitus questionnaires with audiologic assessment (Sindhusake et al. 2003): 30% of the sample reported experiencing tinnitus. Tinnitus prevalence was not related to age or gender but related to audiometric thresholds, and the association between tinnitus and hearing loss was greater in subjects younger than age 65. Tinnitus prevalence in people with normal hearing was lower (26.6%) than in people with hearing loss (35.1%). Mildly annoying tinnitus was reported by 50% of those with tinnitus, while extremely annoying tinnitus was reported by 16% of sufferers. Similar results were reported in a survey of 674 70-year-olds in Sweden (Rosenhall and Karlsson 1991). A recent prospective population based study of hearing loss, in Beaver Dam, Wisconsin, examined 3753 adults 48 to 92 years of age. On enrollment, subjects were questioned about ‘significant tinnitus,’ with a reported prevalence of 8.2%. The 5-year incidence of tinnitus, among those not reporting tinnitus at enrollment, was 5.7% (Nondahl et al. 2002).

2.1 Types of Tinnitus

The most common type of tinnitus is idiopathic subjective tinnitus. Although this form of tinnitus can be descriptively characterized by its sensory–perceptual properties, it does not have acoustic properties, in that it cannot be measured or detected with sound pressure instruments. This stands in contrast to objective tinnitus, which does have acoustic properties that can be measured. Examples of objective tinnitus include somatosensory sounds such as vascular bruits, the muscle contractions of palatal myoclonus and tensor tympani spasm, and the pathologic airflow via a patulous eustachian tube. An uncommon source of

objective tinnitus is spontaneous otoacoustic emissions (SOAEs), related to an estimated to cause about 4% of bothersome tinnitus (Penner 1990).

Idiopathic subjective tinnitus is usually associated with auditory pathology and measurable deficits in auditory functioning. The two most common etiologies for chronic subjective tinnitus are noise-induced hearing loss and age-related hearing loss. Less common causes of tinnitus are specific pathologies including autoimmune disease, endolymphatic hydrops, ototoxin exposure, barotrauma, ischemia, infections, and neoplasms. All these etiologies imply pathology in the auditory system as the source of tinnitus.

However, it is important to note that an estimated 10% of chronic subjective tinnitus occurs in the absence of identifiable auditory pathology on routine clinical testing (Barnea et al. 1990; Borchgrevink et al. 2001). Conversely, an estimated 20% of people with profound hearing loss do not experience tinnitus (Levine 1999). Further, the incidence of tinnitus in population studies of noise-induced hearing loss (NIHL) ranges between 40% and 80% (Man and Naggan 1981; Axelsson and Sandh 1985). These observations suggest that the pathology that results in tinnitus is perhaps unique from the pathology of hearing loss.

Tinnitus is often described as tonal, buzzing, hissing, or noise-like. Although many of the sensory features and the affective reactions to tinnitus are not unique to or determined by tinnitus etiology, some qualitative aspects are nevertheless associated with particular etiologies. Tinnitus associated with endolymphatic hydrops is described as roaring or machine-like; tinnitus related to presbycusis or a high-frequency hearing loss is said to resemble crickets or cicadas on a summer night; tinnitus associated with acoustic trauma characterized by a focal notched hearing loss between 4 and 6 kHz, is typically tonal (perhaps the classic “ringing in the ears”). Despite years of inquiry, it is not known if, or how, the qualitative features of tinnitus are related to either the patterns of peripheral auditory pathology or possible compensatory changes in central auditory function induced by the peripheral pathology.

Clinical observations have identified several unique forms of tinnitus (see Cacace 2003 for review). These include typewriter tinnitus, somatic tinnitus, and cutaneous and gaze-evoked tinnitus. These less common forms of tinnitus have distinct features that may derive from pathological processes that are not shared by the more typical forms of subjective tinnitus. Nevertheless, these uncommon tinnitus types have been instructive in advancing understanding of how a phantom sound is generated.

A unique “somatic” form of tinnitus has been observed in individuals with the ability to modulate the loudness, laterality, or tonality of their tinnitus, using either head-and-neck maneuvers or stimulation of head and neck areas. This type of tinnitus was first noted in a small group of patients who underwent surgery for treatment of large vestibular schwannomas. Postoperatively, these patients noted the ability to modulate their chronic tinnitus by exaggerated eye movements, so-called gaze-evoked tinnitus. Subsequently, a more general form of somatosensory modulation has been described (Sanchez et al. 2002; Abel and

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Levine 2004). In 65% to 80% of people with mild tinnitus, the loudness and pitch of the perception can be modified by forceful isometric contractions of head and neck muscles. Fifty-eight percent of study subjects without preexisting tinnitus could induce tinnitus by strong contractions of muscles in the jaw, head, or neck (Levine et al. 2003).

Animal research has established that a variety of multimodal and somatic inputs are integrated into the auditory pathway, (Itoh et al. 1987; Ryugo et al. 2003; Shore et al. 2003; Shore 2005; Shore and Zhou 2006). The parallels between the observed neuroanatomical projections and the clinical observations in humans are intriguing and may lead to important developments in understanding how tinnitus develops and is modulated. For example, it is possible that reduction of normal afferent input to brain stem auditory nuclei, such as following acoustic trauma or in presbycusis, results in inappropriate up-regulation of somatosensory inputs to the auditory system. In the normal auditory brain stem, somatic inputs may modulate auditory processing so that the hearing system is informed of relevant somatic events such as head position or movementgenerated sound. After partial deafferentation, normally modulatory somatic inputs could partially replace lost auditory input and thus become part of the auditory stream, and be heard as “sound.”

3. Animal Models

Advances in understanding the pathology of tinnitus were highly constrained for many years because tinnitus research was limited to studying the disorder in humans. In the clinical setting, it is very difficult to distinguish factors relevant to tinnitus from factors relevant to the typical coexisting hearing loss. Although recent advances in diagnostic audiometric testing and functional imaging have expanded capabilities for studying tinnitus in people, these methods still do not match the analytic power provided by reliable and valid animal models.

There are several critical features that determine the utility, reliability, and validity of an animal model of tinnitus. First, the metric representing tinnitus should be a measurement of tinnitus perception, that is, the animal’s response to what it hears, as opposed to systemic measures presumed to reflect tinnitus. Before the development of behavioral animal models of tinnitus, surrogate measures presumed to represent tinnitus were the primary measures available. Examples of surrogate measures include the neural ensemble of spontaneous activity, bursting activity, and synchronized activity (Eggermont 1990). The problem with using these associative measures is that there is no evidence that these measures are reflecting the phenomenon of tinnitus rather than hearing loss or other phenomena resulting from the experimental manipulation. A useful animal model of tinnitus relies on a measure that cannot be easily interpreted as reflecting auditory dysfunction other than that of hearing a sound of endogenous origin. To maximize utility, a model should lend itself to repeated measurement.

A durable model can assess the chronicity of tinnitus and the effect of interventions. Because susceptibility to tinnitus most likely varies in animals as it does in people, the model should quantify tinnitus in individuals, or at least discriminate the presence or absence of tinnitus in individuals. Finally, the model should detect tinnitus regardless of etiology and duration. That is, the ideal model should be capable of detecting new onset, acute tinnitus, as well as chronic tinnitus, and tinnitus resulting from a variety of interventions, including noise trauma and ototoxicity. Currently there is no single model possessing all of these attributes. Existing models have selective strengths and weaknesses. The choice of a particular animal model is dictated by the experimental objectives of the investigator. A summary of the models is presented in Table 4.1 and a detailed review of different models is presented in the Addendum at the end of this chapter.

4. Mechanisms of Tinnitus Generation and Persistence

The primary objective of current tinnitus research is to understand the physiological basis of the disorder. Theories of tinnitus have been proposed to explain both its sensory features and the reactive components, such as the affective response of distress. Some theories have focused on specific brain regions that may act as tinnitus generators, while others have taken a systems approach and viewed tinnitus within existing frameworks, such as pain (Moller 1997; Tonndorf 1987) or aging (Milbrandt et al. 2000). A caveat for all theories and models of tinnitus is that the underlying pathology may be unique for different types and etiologies of tinnitus. New onset tinnitus may involve anatomic pathways and mechanisms that are different from those involved in chronic tinnitus. The pathophysiology of tinnitus from ototoxins (e.g., salicylate, carboplatin, cisplatin), acoustic trauma, cochlear ablation, and aging, may be similar or significantly different. This section reviews existing theories of tinnitus within the organizational framework of anatomical focus. It should be kept in mind that many of the theories presented here have not been evaluated via experimental methods that differentiate between the related, but distinct phenomena of hearing loss and tinnitus.

4.1 Cochlear Damage as the Source of Tinnitus

The complex structure, organization, and physiology of the cochlea is arguably the best understood and most extensively studied region of the auditory system. Although significant knowledge gaps remain, theories linking cochlear damage to tinnitus represent the earliest attempts to explain and understand tinnitus.

Tonndorf (1981) was the first to hypothesize that dysfunctional stereocilia might be responsible for a variety of auditory pathologies, including tinnitus. Partial loss of stereocilia function would lead to a partial or complete decoupling

of the hair cells from the tectorial membrane. Tight coupling between hair cells and tectorial membrane results in an intrinsic physiologic noise level that is 6 dB below threshold. Tonndorf estimated that a loose coupling would increase the intrinsic noise at the hair cell synapse by 55 dB. Narrow bands of decoupled hair cells would result in tonal tinnitus; broader areas of involvement might correspond to other qualitative forms of tinnitus such as hissing or roaring (Tonndorf 1981).

Recognizing that there would be many instances of tinnitus in which stereocilia decoupling would be irrelevant, as in the case of cochlear degeneration with loss of hair cells, other hypotheses about peripheral causes of tinnitus have been developed. Selective loss of populations of hair cells and loss of efferent control are two possible mechanisms that might contribute to tinnitus. Kaltenbach has studied patterns of hair cell loss and stereocilia damage in hamsters after acoustic trauma (Kaltenbach et al. 1992). A common observation in these subjects, all of which showed changes in the tonotopic map of the dorsal cochlear nucleus (DCN; see section 4.3), is the absence of significant inner or outer hair cell loss. Subsequent work combining behavioral assessment using the extinction model of Heffner with detailed cochlear histology suggested that outer hair cell lesions may be more relevant to tinnitus (Kaltenbach and Heffner 1999), although there has been some disagreement over the interpretation of these results (Heffner and Koay 2005). Bauer et al. (2007) studied cochlear histology in rats that displayed behavioral evidence of tinnitus after acoustic trauma. Exposed subjects displayed minimal evidence of inner or outer hair cell loss or stereocilia damage. Interestingly, there was a significant loss of the large diameter primary afferent dendrites within the osseous spiral lamina throughout the cochleas of subjects with evidence of tinnitus. The selective loss of this population of fibers was not limited to the tonotopic region that corresponded to the frequency of the tonal tinnitus detected with the behavioral tests but was highly correlated with behavioral evidence of tinnitus (Bauer et al. 2007).

Glutamate is the primary neurotransmitter at the synapse between inner hair cells and auditory nerve dendrites (Eybalin 1993). Glutamate excitotoxicity, altered spontaneous release of glutamate from damaged hair cells, or hair cells no longer appropriately regulated by efferent control, are possible mechanisms for tinnitus generation in the cochlea. Blockade of N-methyl- d-aspartate (NMDA)-induced, spontaneous activity of primary auditory fiber dendrites at the inner hair cell synapse has been demonstrated using the NMDA receptor antagonist 3,5-dimethyl-1-adamantamine hydrochloride (Oestreicher et al. 1998). In a conditioned avoidance task, behavioral evidence of salicylateinduced tinnitus in rats was blocked by various NMDA antagonists (Guitton et al. 2003, 2005). These results suggest that, at least for salicylate-induced tinnitus, cochlear NMDA receptors may serve as modulators of neural excitation that is perceived as tinnitus.

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4.2 Auditory Nerve as Site of Tinnitus Generation

Tonndorf (1987) and others (Kiang et al. 1976) have suggested that altered spontaneous activity within the auditory nerve may play a role in generating a tinnitus signal. Specifically, deviation from the normal random activity that is present within the nerve toward more synchronous spontaneous activity may be interpreted by higher auditory centers as cochlear stimulation. Indirect support for this hypothesis was found in the altered firing rate and firing pattern of single auditory nerve fibers in cat during salicylate infusion (Evans and Borerwe 1982). Additional support was provided by the finding that spectrally averaged spontaneous auditory nerve activity after acute salicylate infusion showed an increase near 200 Hz in acute cat preparations (Martin et al. 1993). Spectral averaging of the auditory nerve spontaneous activity [also referred to as ensemble spontaneous activity (ESA), ensemble background activity, and the spectrum of neural noise] is thought to reflect the summed spontaneous activity of the entire population of auditory nerve fibers. Altered ESA has been demonstrated in an awake guinea pig preparation under conditions of chronic salicylate exposure (Cazals et al. 1998). Similar to the findings in cat, a spectral peak in the ESA at 200 Hz was observed in guinea pigs after cochlear perfusion with the glutamate receptor antagonist 6-7-dinitroquinoxaline-2,3-dione (DNQX) and the purinergic receptor agonist adenosine 5 -O-(3-thiotriphosphate) (ATP S). Anecdotal observations from eighth nerve recordings in humans with tinnitus suggest that altered ESA of the auditory nerve may be relevant to the neural code for tinnitus, but little additional work in this area has been reported (Feldmeier and Lenarz 1996).

4.3 Cochlear Nucleus and Tinnitus

An intuitive and simple physiological explanation of tinnitus invokes elevated spontaneous neural activity in the auditory pathway. The elevated neural activity may occur at one or more levels of the auditory system, and may emerge as a consequence of peripheral damage or altered function elsewhere in the system. Studies from several laboratories have reported elevated spontaneous activity in the cochlear nucleus, primarily the DCN, after manipulations similar to those associated with permanent or reversible tinnitus in humans. A few of these studies have directly associated elevated DCN activity with evidence of tinnitus in the same animal subjects.

Kaltenbach and Afman (2000) have shown that noise exposure results in elevated multiunit spontaneous activity (MSA) in the DCN. Hamsters were exposed to unilateral acoustic trauma that resulted in well-defined hair cell lesions. MSA recorded from the surface of the DCN was obtained 30 to 58 days after exposure. Spectral response plots and spontaneous activity were recorded and mapped topographically, rather than tonotopically (threshold elevations above 7 kHz prevented tonotopic mapping). DCN MSA was significantly higher in exposed animals compared to unexposed control subjects. The maximum average rate occurred in a region of the DCN topographic map close to the