How To Understand The Effects Of Age Related Cochlear Pathology On Hearing

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1 J Am Acad Audiol 7 : (1996) Anatomic and Physiologic Aging : A Behavioral Neuroscience Perspective James F. Willott* Abstract Because hearing is accomplished by the brain (with neural input from the cochlea), presbyacusis can be ultimately accounted for by changes in brain activity that accompany aging. The anatomic and physiologic changes that accompany aging are of two basic types : the central effects of biological aging (CEBA) and the central effects of peripheral pathology (CEPP). Research using inbred mice and other animal models has provided insights into both CEPP and CEBA, and some implications of this research are reviewed, including the following. Age-related cochlear pathology results in changes in how frequency is "mapped" in the central auditory system (CAS), especially at higher anatomic levels, and this has potentially negative consequences for hearing. Aging and/or age-related hearing loss may impair neural inhibition in the CAS. CEPP may result in abnormalities in neural responses involved in binaural hearing and cause exaggerated "masking" of neural responses by noise. The extent of age-related anatomic change (CEBA and CEPP) varies among CAS subdivisions and accelerates during the terminal phase of life. Genes have been found to influence the time course and severity of presbyacusis as well as the role dietary restriction plays in ameliorating age-related hearing loss in mice. Key Words : Aging, binaural, biological aging, hearing loss, presbyacusis o optimize progress in research on aging and the auditory system, it is essential T that researchers in audiology and the neurosciences share their efforts. Audiologists provide many of the questions and issues addressed by auditory neuroscientists (anatomists, neurophysiologists, biophysicists, physiologic psychologists, molecular biologists, and others who study the biology of the auditory system). For their part, neuroscientists can provide some answers to these questions (leading to new or improved clinical approaches) and suggest new bases for hearing problems to be considered by audiologists. To further encourage this interaction, this article presents some ideas about presbyacusis that stem from anatomic and physiologic research on the aging auditory system. The research is viewed from a behavioral neuroscience perspective : an attempt to relate behavior (in this case, hearing) to underlying neural and other biological processes. I have 'Department of Psychology, Northern Illinois University, DeKalb, Illinois Reprint requests : James F Willott, Department of Psychology, Northern Illinois University, DeKalb, IL chosen topics with which I am especially familiar, having addressed them in my own research. Thus, the discussion draws heavily from work by my colleagues and myself. It is not meant to be a comprehensive review of the literature (see Willott, 1991 for such a review). BACKGROUND earing is made possible by the brain's ability to take the trains of electrical impulses H traversing the auditory nerve fibers and transform them into auditory sensations and perceptions. There can be no hearing without appropriate neural activity in the central auditory system (CAS) and, in this respect, all agerelated changes in hearing can be ultimately accounted for by changes in brain activity that accompany aging. Two major factors contribute to age-related changes in CAS activity : the central effects of biologic aging (CEBA) and the central effects of peripheral pathology (CEPP). As the brain ages, its many regions are, to a greater or lesser extent, afflicted by a loss of neurons, reduction in the number of synaptic contacts with other neurons (e.g., because of a loss of dendritic branches, the site of many synapses),

2 Journal of the American Academy of Audiology/ Volume 7, Number 3, June 1996 dysfunction of excitatory and inhibitory neurotransmitter systems, and numerous other degenerative changes (Duara et al, 1985 ; Willott, 1991). These are examples of CEBA, and they occur throughout the brain in both auditory and nonauditory regions. It is well known that the cochlea and spiral ganglion cells are prone to age-related degeneration (Schuknecht, 1974 ; Johnsson and Hawkins, 1979 ; Willott, 1991). Threshold elevations, sensorineural histopathology, and/or peripheral pathophysiology result in the loss or diminution of neural input to the CAS. Failure of certain sounds to engage the processes by which the peripheral auditory system transduces acoustic energy into auditory nerve action potentials obviously results in the inability to hear those sounds. However, more subtle central physiologic effects may occur also, as described below. Furthermore, because neurons are often significantly affected by removal or alteration of their normal synaptic input (Powell and Erulkar, 1962 ; Jean-Baptiste and Morest, 1975 ; Gulley et al, 1978 ; Morest, 1982; Morest and Bohne,1983), it is likely that the basic anatomic and physiologic properties of some central neurons are influenced in various ways by age-related peripheral pathology (much of the recent important research on age-related changes in the cochlea has used biochemical or molecular biological approaches, which are beyond the scope of this discussion and cannot be addressed here). Dealing with the clinical aspects of CEBA and CEPP will require somewhat different strategies. Understanding CEBA and devising clinical interventions must take neurogerontologic approaches for studying the aging brain and apply them to those parts of the brain involved with hearing. For example, we need to know if certain CAS regions, nuclei, subnuclei, or types of neurons are more or less vulnerable to agerelated degeneration, if age-related changes in the functioning of particular neurotransmitter systems are altered in a way that could affect hearing, whether normal neuronal metabolism is maintained throughout the CAS in the elderly, and the extent to which central changes that interfere with certain cognitive processes affect hearing. With respect to CEPP, two general strategies can be used: intervening at the periphery or within the CAS. The first approach attempts to counteract the peripheral pathology causing CEPP Examples are the use of hearing aids to make the cochlea provide input to the CAS that is more normal, engaging prophylactic measures to reduce cochlear damage (e.g., controlling exposure to noise), or the use of cochlear prostheses to restore lost neural input to the CAS. To the extent that such measures work, CEPP is ameliorated because the quality of neural input to the brain is enhanced. The second approach is to counteract changes within the CAS that are caused by the existence of peripheral pathology. This tactic demands that we know what types of anatomic and physiologic changes are induced in the CAS by cochlear dysfunction. Unfortunately, the road to understanding CEBA and CEPP in humans presents two serious obstacles. First, whereas CEPP can occur without CEBA (e.g., in individuals exhibiting cochlear pathology during middle age), and CEBA can occur without CEPP (e.g., in elderly individuals who have been spared serious cochlear pathology), the majority of elderly listeners are afflicted by some degree of hearing loss (Willott,1991). Thus, CEBA and CEPP are likely to coexist and interact in most cases, making it difficult to separate the two phenomena. Second, most sophisticated research tools of neuroscience cannot be applied to human subjects for technical and ethical reasons. To circumvent these problems, animal models must be used in research on CEBA and CEPP For these reasons, most of the research to be reviewed here has used animal models. In reviewing the anatomic and physiologic research on the aging auditory system, implications for presbyacusis in humans will be proposed, even though the work has used nonhuman animal models. It is always the case that research findings from other species may not be fully generalizable to humans. Nevertheless, animal models show us what kinds of anatomic and physiologic phenomena can and do occur in mammalian auditory systems that are in many respects similar to our own. Indeed, when comparing, for example, mice and humans with regard to their physiologic responses to aging, ototoxic agents, drugs, etc., it is common to find close similarities rather than striking differences. In our research (which will constitute the bulk of this discussion), two inbred strains of mice have been used most often. C57BL/6J (C57) mice exhibit genetically determined age-related cochlear pathology during middle age (e.g., between 5 and 12 months of age), providing excellent models to study CEPP. CBA mice, which exhibit little age-related cochlear pathology, can be used to evaluate CEBA. Old C57 mice and/or CBA mice with induced cochlear damage provide means to evaluate CEPP and 142

3 Anatomy and Physiology/Willott CEBA in combination. Other researchers have tended to use animal models that are best suited to study CEBA because the animals chosen exhibit little age-related cochlear degeneration until late in life. AGE-RELATED CHANGES IN FREQUENCY REPRESENTATION IN THE CAS M any parts of the normal auditory system are tonotopically organized : neurons in a particular location respond to tones within a limited band of frequencies, and an orderly relationship exists between the effective frequencies and the location of neurons within that region of the auditory system. For example, neurons in the dorsal portion of the inferior colliculus (IC) respond to low frequencies; neurons at progressively more ventral locations respond to progressively higher frequencies. This tonotopic organization is one principle by which frequency is thought to be "represented" in the CAS (e.g., there are neural "maps" of frequency in various regions of the CAS). Tonotopic organization depends on the existence of anatomic connections from the cochlea to the appropriate tonotopic region. For example, high-frequency regions of the basal cochlea must connect via some anatomic pathway(s) to high-frequency tonotopic regions of the CAS. Young adult C57 mice exhibit sensorineural pathology in the basal region of the cochlea with concomitant threshold elevations for high-frequency sounds (Mikaelian, 1979 ; Henry and Chole, 1980 ; Willott, 1986 ; Shone et al, 1991 ; Li, 1992) - the pattern of hearing loss typical of people with presbyacusis (Willott, 1991). The result is the removal or attenuation of neural input to the tonotopically organized regions of the CAS that normally respond well to high-frequency sounds only (e.g., the more ventral regions of the IC). Several consequences of cochlear pathology on frequency representation in C57 mice have been found. Age-related cochlear pathology results in changes in frequency representation in the CAS of C57 mice. After the high-frequency regions of the IC and auditory cortex have been relieved of their ability to respond to the absent high frequencies, they become increasingly responsive to lower frequencies (Willott, 1984, 1986 ; Willott et al, 1988c, 1993a) : lower frequency sounds now evoke vigorous responses in these neurons, whereas such stimuli are normally ineffective in high-frequency tonotopic regions. In addition, the "best frequency" (the frequency for which threshold is lowest) shifts downward for many neurons. Indeed, virtually the entire IC and auditory cortex of middle-aged C57 mice come to respond well to those middle and low frequencies that remain audible. Because this central change is induced by age-related peripheral pathology, it is an example of CEPP This sort of neural response change or plasticity - reorganization of central "maps" after partial deafferentation - appears to occur in other sensory and motor systems as well, and is probably a general reaction of the brain to the loss of sensory input (Kaas, 1991). Indeed, evidence of central plasticity in the somatosensory cortex has been obtained recently in human amputees (Yang et al, 1994). Given that C57 mice and many aging people exhibit similar progressive high-frequency hearing loss, it is certainly feasible that similar plasticity may occur in humans with presbyacusis. Behavioral work with C57 mice indicates that central plasticity has consequences for hearing. Willott et al (1994c) used the prepulse inhibition (PPI) paradigm to assess behavioral/perceptual correlates of the CAS plasticity in C57 mice. PPI is a robust behavioral phenomenon in which the prepulse, when presented 50 to 100 msec before a reflex-evoking stimulus, results in a reduction (inhibition) of the reflex amplitude (Hoffman and Ison, 1980). We used the degree of PPI as an indication of the behavioral saliency of tone prepulses (Sls) of 4, 8, 12, 16, and 24 khz presented 100 msec prior to a startle-evoking noise stimulus (S2). A decrease in startle amplitude when Sl and S2 were paired relative to control trials (S2 only) served as the measure of PPI. While C57 mice exhibited the expected diminution of PPI to 24 khz Sls between 1 and 12 months of age (because of basal cochlear pathology), the saliency of lower frequencies was significantly enhanced. In 5 month olds, enhancement was greatest for the middle-frequency Sls, khz. For example, the presence of a 70 db SPL prepulse at one of these frequencies reduced startle reflex amplitude by about 30 percent in 1 month olds. The same stimuli reduced startle amplitude by more than 50 percent in 5 month olds. This was the case even though absolute thresholds for 16- khz tones are slightly elevated in 5-month-old C57 mice. CBA mice with normal hearing exhibited no age-related changes in PPI. The findings suggest that, in C57 mice, central plasticity in response to high-frequency hearing loss alters the behavioral/perceptual effectiveness of sounds that remain audible.

4 Journal of the American Academy of Audiology/Volume 7, Number 3, June 1996 Plasticity of frequency representation in the CAS has potentially negative consequences for hearing. After the reorganization of frequency maps in hearing-impaired individuals, more central neurons respond to sounds that are still audible. This could provide a sort of central "amplification" of sounds that are heard, as suggested by the behavior work using PPI (Willott et al, 1994c). Whereas this could be a potential benefit, it is well known to audiologists that amplification of sounds is often deleterious to hearing in listeners with sensorineural hearing loss. Therefore, plasticity could have negative consequences. Another potential negative exists because, with disruption of normal tonotopic organization, the "rules" have been changed with regard to frequency coding. A basic central place coding theory of hearing implies that spectral components of sounds (at least higher frequencies) are coded according to the specific sets of tonotopically organized neurons that are responding : if neurons in high-frequency tonotopic regions are responding, the sound is perceived as containing high frequencies. After central reorganization, however, these same "high-frequency" neurons are responding when middle frequencies are present. Thus, there is the potential for the brain to make errors in frequency coding leading to altered perception. In summary, if frequency map plasticity were to occur in people with chronic high-frequency hearing loss (as is typical with aging), this could explain some of the perceptual problems that typify presbyacusis. The degree of plasticity differs at different levels of the CAS. As sensorineural pathology develops in the basal cochlea of aging C57 mice, the loss of high-frequency responses is, of course, shared by all CAS structures. Nevertheless, the degree of plasticity of frequency representation differs considerably in the ventral cochlear nucleus (VCN), IC, and auditory cortex (Willott et al, 1991, 1993a ; Willott, 1996). Plasticity is greatest in auditory cortex, followed by the IC, and then by the VCN. In auditory cortex and IC, "best frequencies" shift downward while assuming thresholds similar to those of neurons in lower frequency tonotopic regions (i.e., close to the audiometric thresholds for those frequencies) ; VCN neurons exhibit elevation of thresholds with little if any plasticity of this type. Neurons in the dorsal cochlear nucleus (DCN) of middle-aged C57 mice tend to have lower thresholds than VCN neurons for low-to-middle frequencies (similar to what is found in the IC). The differential plasticity of VCN, DCN, IC, and auditory cortex has interesting implications because these CAS structures undoubtedly play different roles in various auditory perceptual capacities. The functions that depend on them should, likewise, be affected to different extents by neural plasticity. For example, auditory functions mediated primarily at subcortical levels (e.g., auditory reflexes) might be less plastic than those mediated cortically (e.g., certain perceptual processes). Certain aspects of auditory perception may be affected by neural plasticity, but the extent could depend on which CAS pathways are involved. AGE-RELATED CHANGES IN NEURAL INHIBITION IN THE CAS T he responses of neurons throughout the brain are shaped by the interplay between excitatory and inhibitory synapses. Many central auditory neurons may be either excited (made to generate impulses) or inhibited (prevented from generating impulses), depending on variations in stimulus parameters such as frequency, intensity, or spatial location. Because excitatory-inhibitory interactions are thought to play an important role in neural coding of sounds, age-related factors that alter this interplay could have serious consequences on hearing. Several lines of research have indicated that this may be the case. Age-related cochlear pathology may impair short-latency inhibitory circuit(s) in the cochlear nucleus. Psychophysical studies have shown that, when one brief auditory stimulus precedes another by a brief interval, perception of the second stimulus is diminished (Gardiner, 1968 ; Wickesberg and Oertel, 1990). For example, Harris et al (1963) showed that when two clicks were presented with an interval of about 2 to 5 msec, perception of the second click was suppressed. Because of the short time course of this inhibition, they suggested that circuits in the cochlear nucleus (CN) were involved. Oertel and colleagues have demonstrated the appropriate circuitry in the mouse CN : tuberculoventral cells are interneurons in the DCN that inhibit neurons projecting to other parts of the CAS from the VCN and DCN (Wu and Oertel, 1986 ; Wickesberg and Oertel, 1990 ; Zhang and Oertel, 1993, 1994). The tuberculoventral neurons are believed to be activated by branches of auditory nerve fibers and appear to use glycine as an inhibitory neurotransmitter. Preliminary findings from our laboratory have shown that glycinergic neurons in 144

5 Anatomy and Physiology/Willott the deep layer of DCN are lost in very old C57 mice with severe hearing loss (Willott et al, 1995), suggesting that these inhibitory neurons are vulnerable to cochlear pathology and/or aging. We are currently performing a series of behavioral experiments using a variant of the PPI procedure in which the interstimulus intervals (ISIs) between the S1 prepulse and the startle-evoking S2 are short, ranging from 1 to 10 msec. As shown in Figure 1, in 1 month olds, startle amplitude is greatly reduced by the prepulse, when the ISI is between 2 to 5 msec. This inhibitory process is diminished in 5-month-old C57 mice, however, suggesting impairment of this short-latency inhibitory circuit (note that PPI elicited with longer ISIs behaves differently, being enhanced in the older mice, as discussed earlier). Taken together, the immunocytochemical and behavioral findings suggest that the tuberculoventral inhibitory system may be impaired as a function of cochlear pathology, indicating another manifestation of CEPP Impairment of this system in human listeners could have serious perceptual consequences when sounds occur in rapid succession or in a reverberant environment. Diminution of neural inhibition in the auditory midbrain is a manifestation of both CEPP and CEBA. Whereas the findings just described are suggestive of diminution of glycinergic inhibition in the CN, compelling evidence has been obtained to indicate that inhibition in the IC is affected by aging and or hearing loss. In the IC of middle-aged C57 mice, increases in spontaneous neural activity (i.e., action potentials occurring in the absence of intended acoustic stimulation) are observed in electrophysiologic recordings from individual neurons (Willott et al, 1988c). Furthermore, fewer IC neurons are inhibited by high-intensity sounds (i.e., neurons in which an increase in stimulus intensity reduces the number of evoked discharges). Once again, because these changes are seen in middle-aged, hearing-impaired mice (but not in likeaged, well-hearing CBA mice), they are presumed to be an example of CEPP. Caspary and colleagues have provided strong evidence that inhibitory processes involving the neurotransmitter GABA become diminished in the IC of aging Fischer 344 rats (Caspary et al, 1990 ; Helfert et al, 1993 ; Milbrandt et al, 1994 ; Raza et al, 1994). Older rats were characterized by fewer IC neurons containing GABA (as shown by immunocytochemistry), decreased basal concentrations of GABA, decreased release of GABA by IC neurons, decreased activity of Startle Amplitude (% re : control trials) Interstimulus Interval (msec) --)K-- 1-month-olds -a 5-month-olds S1 : 12 khz, 70 db ; S2 : 12 khz in quiet Figure 1 Preliminary data on modification of startle amplitude by prepulses in C57 mice. A tone prepulse stimulus (S1 : 12 khz, 70 db SPL, 1-msec duration) was presented before a startle-eliciting stimulus (S2 : 12 khz, 100 db SPL, 10-msec duration) at interstimulus intervals (ISIs) of 1 to 20 msec. Startle amplitude for these trials is presented relative to control (S2-only) amplitudes as an indication of whether the prepulse causes augmentation or inhibition of the startle. In young mice (solid line), Sls presented 1 msec before S2 had no significant effect on startle amplitude, but with ISIs of 2 to 5 msec, substantial inhibition occurred. By comparison, 5-month-old C57 mice with high-frequency hearing loss (dashed line) exhibit augmentation of startle amplitude with ISIs of 1 and 2 msec and diminished inhibition with ISIs of 3 to 5 msec. Because the inhibition of S2 by Sl is manifested at ISIs of 2 to 5 msec, inhibitory circuits activated by Sl are presumably in or near the cochlear nucleus. Each curve represents a mean of six mice. The data were obtained in collaboration with Ms. Charlene Brownfield in the Department of Psychology, Northern Illinois University. glutamic acid decarboxylase (an enzyme involved in making GABA), changes in GABA receptors at synapses, and a decrease in the number of presynaptic terminals using GABA (summarized in Caspary et al, 1995). Although Fischer 344 rats exhibit some age-related hearing loss, it is not severe (Willott, 1991), suggesting at least a partial role of CEBA. Old CBA mice also exhibit an increase in spontaneous neural activity (Willott et al, 1988b), again suggesting CEBA. Inhibitory processes appear to play important roles in the IC, with probable implications

6 Journal of the American Academy of Audiology/Volume 7, Number 3, June 1996 for auditory functions such as sound localization and discrimination of signals in noise (McFadden and Willott, 1994a, b; Caspary et al, 1995). Furthermore, an increase in the level of spontaneous neural activity could decrease the neural "signal-to-noise ratio" in the CAS. That is, evoked responses would be superimposed on a higherthan-normal level of background neural activity (a type of central "neural noise"). A diminution in inhibition (and/or increase in neural excitability) in the CAS with aging could explain some perceptual problems faced by elderly listeners such as tinnitus and poor hearing in noisy conditions. EFFECTS OF AGE-RELATED HEARING LOSS ON BINAURAL NEURAL PROCESSES M any hearing-impaired individuals, particularly the elderly, exhibit spatial localization deficits and other hearing problems that suggest alteration of binaural interactions (Willott, 1991). We studied C57 mice in an effort to find clues about central factors that might underlie these problems. Abnormality of neural responses involved in binaural hearing is a manifestation of CEPP. In an electrophysiologic study of neurons in the IC, McFadden and Willott (1994a) found that response properties thought to code the azimuthal location of sounds were abnormal in middle-aged C57 mice. In young C57 mice (as in mammals in general), when a sound is at an azimuth angle contralateral to the IC recording site, it tends to evoke excitation of IC neurons, but as it moves to the ipsilateral side, responses of IC neurons tend to be inhibited by the sound. In IC neurons of middle-aged C57 mice, this situation was often abnormal (e.g., the ipsilaterally evoked inhibition was weaker) and more likely to be reversed (i.e., ipsilateral sounds evoked excitatory responses). These findings suggest that age-related cochlear pathology can result in central changes in excitatory-inhibitory binaural responses of IC neurons. McFadden and Willott (1994a) hypothesized that the abnormalities in binaural responses were, at least in part, caused by reduced inhibitory processes in IC neurons, discussed earlier. For example, responses to ipsilateral stimuli (which normally evoked the now-impaired inhibitory responses) would be affected differently from responses evoked by contralateral stimuli (which evoke excitatory responses), altering binaural interactions. The McFadden and Willott (1994a) study suggests that such deficits might result from changes in binaural excitatory-inhibitory interactions in the auditory brain stem (and perhaps elsewhere) secondary to peripheral impairment. Age-related cochlear pathology is associated with exaggerated "masking" of neural responses by noise. In a companion study, McFadden and Willott (1994b) evaluated the effects of hearing loss on the responses of IC neurons to a signal (tone) in a fixed position when a continuous broadband masker was presented from different azimuth angles. For both young and middle-aged C57 mice, the presence of noise raised thresholds for tones at the three noise locations employed (azimuth angles of-90, 0, and +90 ). Separating the signal (fixed at -90 ) and masker sources improved masked tone thresholds (reduced masking) of young but not middleaged mice. It was concluded that the improvement in thresholds in young mice as signal and masker were separated depended (at least in part) on binaural interactions. Thus, disruption of binaural interactions as a function of hearing loss in the older mice (McFadden and Willott, 1994a) appeared to have contributed to the reduction in release from masking as signal and masker were spatially separated. A number of studies have shown that people with presbyacusis are less able to benefit from spatial separation between speech and noise sources (e.g., Warren et al, 1978 ; Duquesnoy, 1983 ; Gelfand et al, 1988 ; Bronkhorst and Plomp, 1989). The data obtained from C57 mice raise the possibility that alterations in central binaural processing mechanisms (that may occur as a result of peripheral hearing loss) may play a role in these deficits. Once again, the findings on C57 mice suggest another aspect of CEPP that might have consequences for humans with agerelated hearing loss. ANATOMIC RESEARCH ON AGING C57 AND CBA MICE W e have performed a series of anatomic studies on the auditory system of aging C57 and CBA mice. The following findings have implications for presbyacusis. Anatomic indications of CEPP vary among CAS subdivisions. To understand the anatomic aspects of CEPP, it must be recalled that fibers of the auditory nerve send branches to innervate the three major subdivisions of the CN : the anteroventral CN (AVCN), the posteroventral CN 146

7 Anatomy and Physiology/Willott (PVCN), and the DCN. In the DCN, most of the terminals of auditory nerve branches synapse in the deeper parts (especially layer 111), with few fibers terminating in the more superficial portions of DCN (Morest and Bohne, 1983 ; Moore, 1986). Neurons in these regions would be directly affected by diminution of synaptic input due to age-related cochlear dysfunction. As cochlear pathology develops in middleaged C57 mice, a loss of neurons is observed in the AVON, the octopus cell area (OCA) of the PVCN, and layer III of the DICK The size of neurons and neuropil volume of these CN subdivisions also decrease during this period, suggesting neural pathology (Willott et al, 1987 ; 1992 ; Briner and Willott, 1989 ; Willott and Bross, 1990). In contrast, DCN layers I and II, which receive relatively little direct primary fiber input, and the IC do not show these types of anatomic changes through the median lifespan age of 2 years, despite chronic, profound hearing loss. The variations in CEPP between AVON, PVCN, and DCN layer III versus IC and elsewhere have implications for hearing because, as mentioned earlier, each CAS region contributes to different neural circuits supporting different auditory functions. Differential severity of central changes might, likewise, have complex effects on various auditory functions. Noise-induced cochlear damage may have little additive effect on many age-related anatomic changes in the CAS. Willott et al (1994b) evaluated central anatomic features in aging CBA mice in which severe cochlear pathology had been induced during adulthood by noise exposure. These were compared with age-related changes in nonexposed (control) CBA mice. The study suggested that CEPP and CEBA were not additive. Anatomic changes (CEBA) occurred in the old control CBA mice, but these changes were not more severe than those seen in the mice with severe noise-induced hearing loss for long periods of their adult life (CEBA + CEPP). Apparently, at least some age-related central changes need not be exacerbated by additional cochlear pathology induced earlier in adulthood. The terminal phase of life is accompanied by acceleration of central anatomic changes. The last few months of life in both CBA and C57 mice are marked by increased central anatomic degenerative changes in some CAS regions (Willott and Bross, 1990 ; Willott et al, 1992). For example, in CBA mice, no loss of volume of the CN or IC occurs between the ages of 2 and 11 months (indeed, volume continues to increase during this period of adulthood). As shown in Figure 2, there is also little or no loss of CN or IC volume between 11 and 24 months of age (the approximate median life span for these mice). Beyond the median life span, however, significant volume reduction is observed in the AVON, OCA, and in DCN layers I and III. On the other hand, the volume of the IC and DCN layer II does not change significantly. These findings suggest that, in certain regions of the CAS, CEBA may become pronounced in very old individuals, presenting different clinical challenges when dealing with very old listeners. Some anatomic features of the CAS appear unchanged in the face of aging and chronic cochlear pathology. Despite the manifestations of CEPP in C57 mice discussed earlier, anatomic changes are often not apparent. Excluding the terminal phase, minimal age-related changes are observed in parts of the CAS with respect to the number of surviving neurons (Willott et al, 1987, 1992, 1994a, b ; Willott and Bross, 1990), many ultrastructural characteristics of neurons (Briner and Willott, 1989), levels of metabolic activity (Willott et al, 1988a), and integrity of 120 Percent change in volume re : 11-mo-olds mos 24 mos 29+ mos Age --&- AVCN -l- OCA --*- DCN 1-0- DCN II -49- DCN III -~ IC Figure 2 A summary of volumetric changes in cochlear nucleus and inferior colliculus of aging CBA mice. In each structure shown, no significant decrease in volume occurred between middle age (11 months) and the median life span age (24 months). During the terminal phase of life (24 to 29 months and older), a sharp loss of volume was observed in the AVCN, OCA, DCN layer II, and DCN layer III (solid lines). Volume changes were not observed in DCN layer II and IC (dashed lines). The data are derived from Willott and Bross (1990) and Willott et al (1992, 1993b, 1994a).

8 Journal of the American Academy of Audiology/Volume 7, Number 3, June 1996 axonal projections (Willott et al, 1985). In old CBA mice, physiologic response properties of many IC neurons remain normal (Willott et al, 1988b). Apparently, the CAS can retain healthy neurons and normal patterns of connections despite aging and/or chronic hearing loss. These findings suggest that large-scale degenerative changes need not occur in the aging CAS and provide an optimistic scenario with respect to the use of auditory prostheses and other interventions in the elderly. GENETIC FACTORS IN AGE-RELATED ANATOMIC AND PHYSIOLOGIC CHANGES IN THE AUDITORY SYSTEM hile it has been assumed that at least W some forms of presbyacusis have a genetic basis (Schuknecht, 1974 ; Willott, 1991), we know very little about this topic. Research has been stymied by the "contamination" of genetic influences on hearing by other factors that accrue over an older person's lifetime ; it is difficult to identify appropriate individuals and families for genetic research on presbyacusis. Fortunately, the study of mice may provide a means to gain insight into the genetic basis of presbyacusis, and several interesting findings have emerged. Genes may influence the time course and severity of presbyacusis. Every survey that has evaluated human hearing as a function of age has shown that mean thresholds in the population begin to show elevations (particularly at high frequencies) by middle age and earlier (Willott, 1991). Implicit in these observations is the conclusion that, for many people, presbyacusis is not an affliction that suddenly emerges at an advanced age (although this can certainly occur). The factors that initiate progressive age-related hearing loss in young or middle-aged adults are not understood but may involve the actions of genes. Work by Henry (1982, 1983) and Erway et al (1993) indicates that, in mice, specific genes can trigger the degenerative process at particular periods in the life span, ranging from young adulthood to late middle age. The prospect of someday identifying genes that place individuals at risk may provide a means for managing the course of presbyacusis before it occurs. Dietary restriction alters the course of agerelated hearing loss in some mouse genotypes but not in others. A large body of gerontologic literature has shown that calorically restricted diets can extend longevity and slow certain age-related physiologic declines (e.g., Weindruch et al, 1986 ; Harrison and Archer, 1987 ; Bronson and Lipman, 1991). To see if age-related changes in the auditory system would also be affected by caloric restriction, the author, in collaboration with L. C. Erway, J. R. Archer, and D. E. Harrison, evaluated the effects of a calorically restricted diet on age-related hearing loss in a number of inbred and F1 hybrid mouse strains (Willott, in press). Mice were maintained from a young age on either a high-energy or low-energy (calorically restricted) diet. In most of the 15 strains studied, little or no evidence was found to indicate that diet affected age-related hearing loss (determined at 16 and 23 months of age using the auditory brainstem response [ABR]) or the degree of cochlear pathology at the time of death. Several strains exhibited increased longevity with the restricted diet, and cochlear pathology appeared to continue to progress at a rate predictable according to the linear regression curve derived from the shorter-lived high-energy mice. In four strains, however, evidence was obtained to indicate that the restricted diet ameliorated age-related hearing loss as indicated by ABR thresholds and/or cochlear pathology. One of these strains was the C57, which exhibited both a slowing of hearing loss (lower click-evoked thresholds at 23 months) and less severe pathology at the time of death (cf. Park et al, 1990). Thus, dietary restriction reduced age-related changes in some strains but not in others, a conclusion also reached by Henry and colleagues, who measured ABR thresholds in several other strains (Henry, 1986 ; Sweet et al, 1988). The findings suggest that dietary restriction (and/or the physiologic mechanisms it engages) has the potential to slow or mitigate the progression of peripheral pathology with aging, presumably affecting CEPP. However, these effects appear to be tied to genotype, suggesting that ultimate application of some sort of longterm approach to humans may have to deal with substantial individual differences. With respect to the effects of dietary restriction on the CAS, sufficient data were available to make conclusions on one strain only, WB/ReJ (WB). Figure 3 presents data from WB mice showing the number of neurons in the AVON, measured in postmortem tissue from mice that died of natural causes ("old age"). In WB mice, dietary restriction (low-energy diet) resulted in prolongation of life. However, there is no evidence that dietary restriction lessened the loss ofavcn neurons. The mean number of neurons in the diet-restricted group (4585) is significantly smaller than that of the high-energy group 148

9 Anatomy and Physiology/Willott * High energy diet C Low energy diet Note : Regression line = Low energy group Figure 3 The number of AVCN neurons in WB/Re<7 mice maintained under high energy (HE) or low energy (LE, calorically restricted) diets. (5592). The smaller number ofavcn neurons in the restricted mice is presumably a function of their advanced age. The linear regression curve (Fig. 3) predicts that, had the diet-restricted mice died at earlier ages, the number of AVCN neurons would have been similar to that observed in high-energy mice. Whereas dietrelated factors that prolong life in WB mice do not appear to alter the neuronal attrition rate in AVCN, it is, of course, possible that different results would be obtained with other genotypes. F CONCLUSION rom the behavioral neuroscience perspective, it is counterproductive to conceptualize presbyacusis as "cochlear" or "central." Rather, all of the factors that interact to alter the anatomic and physiologic properties of the aging auditory system must be understood. To reiterate the theme that has run through most of this discussion, the anatomic and physiologic changes that accompany aging (CEBA) are typically accompanied by CEPP. Clinically significant cochlear pathology must affect how sounds are processed by the CAS, either because of central plasticity, changes in inhibition, or simply the removal or distortion of portions of the neural input from cochlea to brain. I shall conclude with two examples of how thinking about presbyacusis as an interaction of peripheral and central processes might suggest directions for clinical or basic research. First, significant loss of spiral ganglion cells is one of the most reliable concomitants of human aging (Schuknecht, 1974 ; Willott, 1991). Otte et al (1978) showed that audiograms and basic speech reception thresholds are often fairly normal despite substantial loss of spiral ganglion cells in elderly people, but we have no knowledge about how such losses would affect hearing under more challenging conditions (e.g., noise, poor-quality speech, etc.). A loss of ganglion cells would be expected to reduce the number of "information channels" from cochlea to CAS, perhaps with deleterious consequences for hearing under such conditions. It would seem advantageous to develop reliable, practical audiologic methods for assessing the condition of the spiral ganglion in living patients. Then, we could determine the consequences of a depleted spiral ganglion. If those consequences proved to be significant, spiral ganglion assessment might become an important clinical tool. Second, it is often written that there is little evidence for the "mechanical" or "cochlear conductive" presbyacusis proposed by Schuknecht (1974). This may be true if the search for evidence focuses on physical changes in the basilar membrane. However, basic auditory science has made it clear that the outer hair cells (OHCs) and their control by central efferent pathways affect cochlear mechanics in important ways. OHCs are commonly damaged in older people, suggesting that cochlear mechanics should be affected. It is also possible that efferent pathways may become functionally impaired with age (CEBA). Developing methods to evaluate efferent control of OHCs and the effects of aging on this process might have valuable clinical applications in the future. Acknowledgment. Preparation of this paper was supported by National Institute on Aging grant 1 R37 AG Unpublished data on the effects of diet on the histopathology of the mouse auditory system were supported by National Science Foundation grant BNS (to J. F. Willott and L. C. Erway) and National Institute on Aging grant R01 AG06232 (to D. E. Harrison). Lori Bross edited the manuscript. REFERENCES Briner WB, Willott JF. (1989). Ultrastructural features of neurons in the C57BL/6J mouse anteroventral cochlear nucleus : young mice versus old mice with chronic presbyacusis. Neurobiol Aging 10 :

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