James F. Willott

The aging auditory system: anatomic and physiologic changes and implications for rehabilitation

Over the last century, research in the area of age-related hearing loss has provided a vast amount of knowledge regarding age-related effects on the anatomy and physiology of the auditory system. As we enter the new millennium, researchers are beginning to shift their attention towards developing methods of modulating the effects of age-related hearing loss and the development of efficacious intervention strategies to meet all of an individuals hearing-related rehabilitative needs. The purpose of this review is to provide a framework for considering how the biological aspects of the aging auditory system interact with the most common current therapeutic intervention for age-related hearing loss—the use of amplification—and also how the biological aspects point to other potential intervention strategies.

Modulation of Presbycusis: Current Status and Future Directions

Literature and ideas are reviewed concerning the modulation of presbycusis – the influence of variables that can alter the severity and/or time course of presbycusis or counteract its negative aspects. Eleven topics are identified: variables related to biological aging; genetics; noise-induced hearing loss; moderately augmented acoustic environment; neural plasticity and the central auditory system; neural plasticity and hearing aids; socioeconomic and cultural barriers to hearing aid use; lifestyle (diet, exercise, etc.); medical variables; pharmaceutical interventions for presbycusis, and cognitive variables. It is concluded that the field of otogerontology will best be served by a comprehensive, integrative interaction among basic researchers and clinical scientists who will continue to learn how the auditory problems associated with presbycusis can be intentionally modulated in beneficial ways.

Age-related increases in calcium-binding protein immunoreactivity in the cochlear nucleus of hearing impaired C57BL/6J mice

Aging C57BL/6J (C57) mice (1-30 months old), were used to study calcium-binding protein immunoreactivity (parvalbumin, calbindin and calretinin) in the cochlear nucleus. A quantitative stereological method, the optical fractionator was used to determine the total number of neurons, and the total number of immunostained neurons in the posteroventral- and dorsal cochlear nuclei (PVCN and DCN). A statistically significant age-related decrease of the total number of neurons was found in the PVCN and DCN using Nissl staining. In the DCN, an age-related increase in the total number of parvalbumin-positive neurons was found, while no changes in the total number of calbindin or calretinin positive neurons were demonstrated. In the PVCN, the total number of parvalbumin, calbindin, or calretinin positive neurons remained stable with increasing age. The percentage of parvalbumin, calbindin, and calretinin positive neurons significantly increased in the DCN, and the percentage of parvalbumin and calbindin-positive neurons increased in the PVCN. These findings imply that there is a relative up-regulation of calcium-binding proteins in neurons that had not previously expressed these proteins. This plastic response in the profoundly hearing impaired C57 mouse may be a survival strategy for cochlear nucleus neurons.

Effects of prolonged exposure to an augmented acoustic environment on the auditory system of middle-aged C57BL/6J mice: Cochlear and central histology and sex differences

Genetic progressive sensorineural hearing loss in mice of the C57BL/6J (B6) inbred strain begins at high frequencies during young adulthood and is severe by 12 months (middle age). Nightly treatment with an augmented acoustic environment (AAE)—12‐hour periods of exposure to repetitive noise bursts of moderate intensity, begun at age 25 days—resulted in less severe hearing loss compared with control mice. Cochlear histopathological correlates of AAE treatment, assessed at 12–14 months of age, included lessened severity of progressive loss of outer hair cells in both sexes as well as small savings of spiral ganglion cells in females and inner hair cells in males. AAE effects on the number of surviving neurons (age 12–14 months) in the anterior ventral cochlear nucleus (AVCN) depended on sex. Compared with controls, the loss of AVCN neurons that typically accompanies the initial period of hearing loss (between 2 and 7 months of age) was not significantly affected by AAE treatment in females. In contrast, males treated with the AAE exhibited more severe loss of neurons in the dorsal and ventral extremes of the AVCN than male controls of the same age. AAE treatment begun at age 3–5 months resulted in significant but less severe loss of AVCN neurons in 1‐year‐old male mice. J. Comp. Neurol. 472:358–370, 2004.

Ameliorative Effects of Exposing DBA/2J Mice to an Augmented Acoustic Environment on Histological Changes in the Cochlea and Anteroventral Cochlear Nucleus

DBA/2J (D2) mice, which exhibit very early progressive sensorineural hearing loss, were treated nightly with an augmented acoustic environment (AAE) initiated before the onset of hearing, and consisting of repetitive bursts of a 70-dB sound pressure level (SPL), 4–25xa0kHz noise band. At 55 days of age, AAE-treated mice exhibited less elevation of auditory brainstem response thresholds, fewer missing hair cells, and greatly reduced loss of anteroventral cochlear nucleus (AVCN) volume and neuron number compared to untreated control mice. It was hypothesized that the central neuroprotective effect was associated with increased afferent input to AVCN neurons evoked by the AAE as well as a healthier cochlea.

Measurement of the auditory brainstem response (ABR) to study auditory sensitivity in mice.

The ABR is an electroencephalographic response measured with scalp electrodes. It provides a quick, easy, and reliable method for physiological assessment of auditory sensitivity in mice. A series of brief tone pips or clicks is presented to an anesthetized mouse at a high rate of speed; each click evokes waves of neural activity in the brainstem that are computer‐averaged so they are differentiated from non‐auditory background voltages. The intensity of the clicks is reduced in steps until an ABR can no longer be discerned, thereby defining the ABR threshold, which is closely related to the hearing threshold. Key procedural issues are: (1) accurate calibration of the acoustics (what sounds arrive at the mouses ear), (2) anesthetization of the mouse, (3) setting up the recording electrodes, (4) the protocol for presenting acoustic stimuli and obtaining thresholds, and (5) interpretation of ABR data.

Effects of sex, gonadal hormones, and augmented acoustic environments on sensorineural hearing loss and the central auditory system: Insights from research on C57BL/6J mice

Mice of the C57BL/6J (B6) inbred strain exhibit genetic progressive sensorineural hearing loss and have been widely used as a model of adult-onset hearing loss and presbycusis. Males and females exhibit similar degrees of hearing loss until about 3 months of age, after which, the loss accelerates in females. This paper reviews research on how the B6 auditory system is affected by sex, gonadectomy (i.e., a reduction of gonadal hormone levels), and nightly exposure to moderately intense augmented acoustic environments (AAEs) - a low-frequency noise band (LAAE) or high-frequency band (HAAE). Several findings indicate a negative effect of ovarian hormones on the female B6 auditory system. Whereas the sex difference in high-frequency hearing loss was not significantly affected by gondadectomies, the female disadvantage in ABR thresholds at lower frequencies was erased by ovariectomy. Moreover, exposure to the LAAE or HAAE caused losses of hair cells that were more severe in intact females than in ovariectomized females or in males. Finally, intact females had more severe loss of neurons in the low-frequency region of the anterior ventral cochlear nucleus (AVCN) than other groups. In contrast, the presence of androgens had beneficial effects. Loss of hair cells and AVCN neurons after AAE exposure were more severe in orchidectomized males than in intact males. Ideas, hypotheses, and potential mechanisms concerning the findings are discussed.

EFFECTS OF EXPOSING C57BL/6J MICE TO HIGH- AND LOW-FREQUENCY AUGMENTED ACOUSTIC ENVIRONMENTS: AUDITORY BRAINSTEM RESPONSE THRESHOLDS, CYTOCOCHLEOGRAMS, ANTERIOR COCHLEAR NUCLEUS MORPHOLOGY AND THE ROLE OF GONADAL HORMONES

Gonadectomized and intact adult C57BL/6J (B6) mice of both sexes were exposed for 12h nightly to an augmented acoustic environment (AAE): repetitive bursts of a 70dB SPL noise band. The high-frequency AAE (HAAE) was a half-octave band centered at 20kHz; the low-frequency AAE (LAAE) was a 2-8kHz band. The effects of sex, gonadectomy, and AAE treatment on genetic progressive hearing loss (a trait of B6 mice) were evaluated by obtaining auditory brainstem response (ABR) thresholds at ages 3-, 6-, and 9-months. At 9-months of age, hair cell counts (cytocochleograms) were obtained, and morphometric measures of the anteroventral cochlear nucleus (AVCN) were obtained. LAAE treatment caused elevation in ABR thresholds (8-24kHz), with the highest thresholds occurring in intact females. LAAE treatment caused some loss of outer hair cells in the basal half of the cochlea (in addition to losses normally occurring in B6 mice), with intact females losing more cells than intact males. The loss of AVCN neurons and shrinkage of tissue volume that typically occur in 9-month-old B6 mice was lessened by LAAE treatment in intact (but not gonadectomized) male mice, whereas the degenerative changes were exacerbated in intact (but not gonadectomized) females. These LAAE effects were prominent in, but not restricted to, the tonotopic low-frequency (ventral) AVCN. HAAE treatment resulted in some loss of neurons in the high-frequency (dorsal) AVCN. In general, LAAE treatment plus male gonadal hormones (intact males) had an ameliorative effect whereas HAAE or LAAE treatment plus ovarian hormones (intact females) had a negative effect on age-related changes in the B6 auditory system.

Effects of exposing DBA/2J mice to a high-frequency augmented acoustic environment on the cochlea and anteroventral cochlear nucleus.

DBA/2J (D2) mice, which exhibit very early progressive sensorineural hearing loss, were treated for 12h nightly with an augmented acoustic environment (AAE) initiated before the onset of hearing. The AAE consisted of repetitive bursts of a 70 dB sound pressure level, half-octave noise band centered at 20 kHz (i.e. low frequencies were excluded). At 55 days of age, AAE-treated mice, compared to control mice, exhibited less elevation of auditory brainstem response thresholds for tone frequencies from 16 to 32 kHz and fewer missing outer hair cells in the high-frequency tonotopic region of the cochlea. The dorsal region of their anteroventral cochlear nucleus (most strongly stimulated by the AAE) was larger, had more surviving neurons, and larger neurons than those of untreated control mice. These and previous findings using an AAE band containing lower frequencies indicate that AAE treatment effects are frequency-related. The findings provide support for the hypothesis that the beneficial effects of AAE treatment on the cochlea are associated with increased physiological activity evoked by the AAE, and the central AAE effects result from increased AAE-evoked neural activity and a healthier cochlea providing the auditory input.

Interventions and Future Therapies: Lessons from Animal Models

The chapters in this book provide ample evidence that age-related hearing loss is caused by multiple factors combining genetic traits with a constant barrage of lifetime insults to the hearing organ. Such insults may include noise exposure in occupational settings or at leisure (from loud machinery to iPods or rock concerts), chemicals and solvents in the work place, life style (drinking, smoking), diseases (diabetes, infections), and even the adverse “ototoxic” effects of medications on the inner ear. It is not even necessary that the insults be severe enough to cause immediate damage. Kujawa and Liberman (2006) subjected adult mice to a noise level that did not induce any threshold shifts two weeks after exposure. However, as the animals aged, they showed a continuing primary neural degeneration and deterioration of neural responses. Age-related changes in the central auditory system add to the complexity of the problem. Determining the cause(s) of hearing difficulties in an aging patient is challenging to say the least, let alone the question of how to prevent or treat such hearing impairment.