Age-Related Changes in Auditory Sensation

C H A P T E R

2 Age-Related Changes in Auditory Sensation Auditory sensation reflects the result of exploring the environment with our ears. The threshold of auditory sensation is quantified by the audiogram, and dominantly reflects structural and functional changes in the auditory periphery, that is, cochlea and auditory nerve. The efferent system, descending from the cortex and affecting the cochlear hair cells and auditory nerve fibers, can influence hearing thresholds as well (evidence from animal research in Chapter 7).

2.1 LIFE-SPAN CHANGES IN HEARING ACUITY 2.1.1 Standard Audiometry Standard audiometry is generally limited to measuring thresholds at octave spaced frequencies from 250 Hz up to and including 8 kHz (Fig. 2.1) despite our ability to hear up to 20 kHz at a young age (Eggermont, 2017). Audiograms change dramatically with age. Sommers et al. (2011) studied 433 participants equally divided into seven decades (ages 20 89 years) and found that hearing loss for frequencies above 1 kHz tends to accelerate for the oldest participants. Changes in hearing loss with age, for example, at 4 and 8 kHz, show a nearly exponential increase as originally elucidated by Spoor (1967). Importantly, the trajectories for the frequencies (2, 4, and 8 kHz) making up the pure-tone average for high frequencies show declines starting before the age-related decrease in listening comprehension (Chapter 1). In contrast, the thresholds for the low frequencies (250, 500, and 1000 Hz) are relatively unchanged until after 65 years of age. The changes in the low frequencies might reflect pure aging effects, whereas the thresholds in the higher frequencies might also be affected by genetic and environmental factors (Chapter 6).

The Auditory Brain and Age-Related Hearing Impairment DOI: https://doi.org/10.1016/B978-0-12-815304-8.00002-5

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FIGURE 2.1 Mean hearing loss (dB HL) in the best ear for participants in each of seven age groups plotted as a function of test frequency. Source: From Sommers, M.S., Hale, S., Myerson, J., Rose, N., Tye-Murray, N., Spehar, B., 2011. Listening comprehension across the adult lifespan. Ear Hear. 32 (6), 775 781, with permission from Wolters Kluwer Health.

Investigating the changes in hearing loss in the older elderly, Hietanen et al. (2004) performed a prospective 10-year study in 219 people aged 80 years at baseline. The participants’ hearing was assessed at ages 80, 85, and 90 years, using pure-tone audiometry, speech audiometry, and self-report on hearing difficulties. Participants showed significant increases in hearing thresholds in both the longitudinal and cross-sectional assessments over the 10-year follow-up period. The increase of hearing loss in the high frequencies was modest, especially in men, in contrast that in the speech frequencies (0.5, 1, and 2 kHz) was considerable, as shown by Sommers et al. (2011) (Fig. 2.1) in their cross-sectional study for the increase in low frequencies from age 70 79 to age 80 89. In a retrospective study, Wattamwar et al. (2017) reviewed audiometric evaluations of 647 patients aged between 80 and 106 years, of whom 141 had multiple audiograms taken. They compared the degree of hearing loss across the following age groups: 80 84 years, 85 89 years, 90 94 years, and 95 years and older. At all frequencies, the mean changes in hearing threshold across all 647 patients were larger during the 10th decade of life than in the 9th decade and ranged from 5.4 11.9 dB. Correspondingly, the annual rate of low-frequency hearing loss was faster during the 10th decade by 3.8 dB per year at 0.25 and 0.5 kHz, and 3.2 dB per year at 1 kHz.

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Emphasizing the increasing variability of changes in hearing loss with age, Humes et al. (2010) presented hearing thresholds for groups of young (n 5 122; mean age 5 22.3 years), middle-aged (n 5 45; mean age 5 48.3 years), and older (n 5 172; mean age 5 70.4 years) adults (Fig. 2.2). As can be seen for the older age group, a considerable number

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FIGURE 2.2 Scatterplots of hearing threshold in dB SPL as a function of participant age for pure-tone frequencies of 500 (top), 1414 (middle), and 4000 (top) Hz and for young (circles), middle-aged (triangles), and older (squares) adults. SPL, Sound pressure level. Source: From Humes, L.E., Kewley-Port, D., Fogerty, D., Kinney, D., 2010. Measures of hearing threshold and temporal processing across the adult lifespan. Hear. Res. 264, 30 40, with permission from Elsevier.

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of ears have clinically normal thresholds at 0.5, 1.414, and 4 kHz. The choice of 1.414 kHz reflects the geometric mean between 0.5 and 4 kHz. It is also obvious that the maximum hearing loss increases with age and ranges from clinically normal, that is, # 20 dB sound pressure level (SPL) in the young adults regardless of frequency, to B60 dB SPL at 500 Hz and to B80 dB SPL for 4 kHz in the older age group. Consequently, the variability, that is, the range, of hearing loss increases very much with age, from about 20 dB SPL in young adults to more than 80 dB SPL at 4 kHz in the oldest participants.

2.1.2 Prevalence and Effects of Occupational Noise Exposure 2.1.2.1 Prevalence of Hearing Loss Gates et al. (1990) tested 1662 participants 60 90 years of age of the Framingham cohort, 1983 85. Pure-tone thresholds increased with age but the rate of change with age did not differ by gender, even though men had poorer threshold sensitivity. Maximum word recognition ability declined with age more rapidly in men than in women and was poorer in men than in women at all ages. Cruickshanks et al. (1998) measured the prevalence of hearing loss in adults aged 48 92 years, residing in Beaver Dam, Wisconsin. Of the 4541 eligible people, 3753 (82.6%) participated in the hearing study (1993 95). The average age of participants was 65.8 years, and 57.7% were women. The prevalence of hearing loss was 45.9%. The odds of hearing loss increased with age [odds ratio (OR) 5 1.88 for 5 years, 95% confidence interval (CI) 5 1.80 1.97] and were greater for men than women (OR 5 4.42, 95% CI 5 3.73 5.24). The excess of hearing loss in males remained statistically significant after adjusting for age, education, noise exposure, and occupation (OR 5 3.65). In a 1996 98 study of adults, Borchgrevink et al. (2005) collected audiometric data from 50,723 participants (age range 20 101 years) in 17 of 23 municipalities in Nord-Trondelag, Norway. The PTA0.5 4 kHz showed hearing impairment .25 dB in the worst ear in 32% of males and 23% of females. For a representative sample of 705 subjects from a rural population aged 31 50 years, Karlsmose et al. (2000) reported longitudinal changes in hearing sensitivity over a 5-year period in Jutland, Denmark. The median hearing deterioration was 2.5 dB at 3 4 kHz and 0 dB at 0.5 2 kHz. If hearing deterioration was defined as on average $ 10 dB/5 years at 3 4 kHz in at least one ear, deterioration was present in 23.5% of the sample. To estimate the overall prevalence of audiometric hearing loss in the United States, Lin et al. (2011) analyzed pure tone thresholds from people (n 5 7490) aged 12 years to well over 70 years from the 2001 through 2008 cycles of the National Health and Nutritional Examination

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Surveys (NHANES). A PTA0.5 4 kHz of $ 25 dB hearing level (HL) in both ears was taken as an indication of hearing loss. From this sample, the authors extrapolated that 12.7% of Americans 12 years and older in the period of 2001 08 had bilateral hearing loss, and this estimate increased to 20.3% when individuals with unilateral hearing loss were included. Overall, the prevalence of hearing loss increased with every age decade. The prevalence of hearing loss was lower in women than in men, and in black vs white individuals across nearly all age decades. In a large study of UK adults aged 40 69 years (n 5 164,770), Dawes et al. (2014) measured unaided speech reception thresholds using the Digit Triplet Test (Smits et al., 2004) in the better ear. They found that overall 10.7% of adults (95% CI 5 10.5% 10.9%) had a significant hearing impairment. This result is comparable to the findings of Ikeda et al. (2009) in a US population, but the impairment is less than in a US Hispanic/Latino population (Cruickshanks et al., 2015). Here, the prevalence of hearing impairment was higher among people 45 years and older, ranging from 29.35% to 41.20% among men (n 5 6301) and 17.89% to 32.11% among women (n 5 9415). Across these studies, the UK sample stands out with a much lower prevalence compared to the Scandinavian and US samples. Homans et al. (2017) conducted a large prospective cohort study of older adults between February 2011 and July 2015. Pure-tone air- and bone-conduction thresholds were measured for 4743 participants. Compared with previous studies (Gates et al., 1990; Cruickshanks et al., 1998), men had less hearing loss at the frequencies of 2 kHz and above. Hearing thresholds in women, however, were significantly higher at 4 and 8 kHz. Above the age of 65 years, the prevalence of hearing loss .35 dB HL was about 30%. The difference in hearing loss between men and women was significantly less than in earlier studies. 2.1.2.2 Effects of Occupational Noise Exposure Does previous noise exposure have an effect on age-related changes in hearing thresholds? Hederstierna and Rosenhall (2016) conducted a prospective, population-based, longitudinal study of individuals aged 70 75 years in Gothenburg, Sweden. Participants filled out a questionnaire on noise exposure. There were no significant differences in the rate of threshold increase, at any frequency, for those aged 70 75 years between the noise-exposed (n 5 62 men, 22 women) and the nonexposed groups (n 5 96 men, 158 women). For both men and women, the decline was most pronounced in the high frequencies, at 2 8 kHz, where it ranged from about 1.3 dB/year to more than 2 dB/year for men (mean values). For women the corresponding values ranged from 1.6 dB/year to almost 3 dB/year. Below 1 kHz the decline was about 0.5 dB/year for men and about 1 dB/year for women. Gates et al. (2000) also

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determined whether the presence of noise exposure influenced auditory aging by examining the 15-year change in audiometric thresholds in 203 men from the Framingham Heart Study (Massachusetts, USA) cohort. The mean age at their first hearing test was 64 years (range 58 80). Occupational and recreational noise exposure over the 15 years was assumed to be minimal due to the age of the subjects. They quantified the “severity” of a notch—considered to be a marker of noise exposure—in the 3 6 kHz region. A loss of 15 34 dB was deemed a small notch, and elevations of 35 dB or greater were deemed large notches. Absence of a notch was used to encode those ears with ,15 dB elevation in the 3 6 kHz region. They found less change over time in the notch frequencies and significantly greater change in the adjacent frequency of 2 kHz in the large notch group as compared to the no notch and small notch groups. Above the notch frequency range, thresholds at 8 kHz showed a significant, but smaller, change in the small notch group as compared to the no notch and large notch groups. These data suggest that noise-damaged ears, that is, those with a notch do not age at the same rate as the non-noise-damaged ears. The finding of increased loss at 2 kHz in the large notch group suggested to Gates et al. (2000) that the effects of noise damage continue long after the noise exposure has stopped. In a cross-sectional study, Ciorba et al. (2011) compared 460 people (age range 70 93; median age 5 75 years) with presbycusis, of which 367 were without and 93 with a history of noise exposure. PTA0.125 8 kHz thresholds for each ear were compared between groups, and between sexes and ages within groups. Occupational noise exposure was investigated by asking the patient about their former occupation, particularly regarding the age of first occupational noise exposure and the duration of exposure. Occupational noise exposure was defined as exposure for three or more years. The type of workplace comprised 52% factory workers, 43% laborers, 4% air force or army, and 1% printing industry. Ciorba et al. (2011) found only a slight threshold difference between exposed and nonexposed groups at 4 kHz. This difference was related only to the mean group age. Note again that cross-sectional studies may be confounded by cohort selection.

2.1.3 Extended High-Frequency Audiometry High-frequency hearing loss typically manifests itself around age 50 in standard audiometry (cf. Fig. 2.1) but becomes more obvious, even at younger ages, when frequencies above 8 kHz are included. Lee et al. (2005) demonstrated this in a longitudinal study by analyzing pure-tone thresholds for standard and extended high-frequency audiometry in 188 older adults. At the time of entry into the study, people’s ages ranged

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from 60 to 81 years, with a mean age of 68 years. The participants were tested between 2 and 21 times over a period of 3 11.5 years. Lee et al. (2005) found that, on average, hearing thresholds increased approximately 1 dB/year for subjects age 60 and over. Subjects with higher initial thresholds at low and mid frequencies tended to have a faster rate of threshold change at 0.25 2 kHz in the following years. Subjects with higher initial thresholds at mid and higher frequencies tended to have a slower rate of change at 6 8 kHz in the following years. Noise exposure history did not have a significant effect on the rate of threshold changes. Extended high-frequency thresholds at 9 18 kHz were measured every 2 3 years. As expected, hearing loss was larger in males than in females for frequencies between 2 and 12 kHz, but not # 1 kHz and .12 kHz. Langers et al. (2012) and Melcher et al. (2013) corroborated this in tinnitus patients with “clinically normal” hearing, that is, with thresholds # 20 dB HL for frequencies # 8 kHz, and matched with a nontinnitus control group. Both studies found that the hearing loss increased sharply up to 16 kHz. A life-span audiometric study that also covered the extended highfrequency range was carried out by Jilek et al. (2014). A sample of 411 otologically normal men and women 16 70 years of age was assessed for both ears using a high-frequency audiometer (Fig. 2.3). The study showed that considerable high-frequency ( . 10 kHz) hearing loss already starts in the 30 39-year age group and increases considerably in the next decade for both females and males.

2.2 CHANGES IN AUDIOGRAM PHENOTYPES Presbycusis, that is, age-related hearing loss, has been initially characterized in humans as metabolic and sensory phenotypes (Schuknecht, 1964), based on patterns of audiometric thresholds that were established in animal models (Ohlemiller, 2004; Chapter 7). The metabolic phenotype results from deterioration of the stria vascularis causing a reduced endocochlear potential (normally 5 180 mV) that decreases cochlear amplification (Fig. 2.4). The result is a mild, flat hearing loss at lower frequencies coupled with a gradually sloping hearing loss at higher frequencies. The sensory phenotype results from excessive noise or ototoxic drug exposure, which cause damage to sensory and nonsensory cells and loss of the outer hair cell (OHC)-based cochlear amplifier, and produce a 50 70 dB threshold shift at higher frequencies (Vaden et al., 2017). The neural phenotype, characterized by damage to the spiral ganglion, might result from damage to inner hair cell (IHC) synapses with subsequent neural degeneration.

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FIGURE 2.3 Average pure-tone audiograms in dB HL in (A) men and (B) women grouped by their age in decades (the parameter is age group in years). The extended highfrequency range is zoomed for clarity. Source: Reprinted from Jilek, M., Suta, D., Syka, J., 2014. Reference hearing thresholds in an extended frequency range as a function of age. J. Acoust. Soc. Am. 136 (4), 1821 1830, with permission from the acoustical Society of America.

Demeester et al. (2009) described the prevalence of specific audiogram configurations in a healthy, otologically screened population between 55 and 65 years old. The audiograms of 1147 subjects (549 males and 598 females) were classified according to the configuration of hearing loss. In this population, “flat” audiograms were most dominant (37%) followed by “high-frequency gently sloping” audiograms (35%), and both are indicative of the metabolic phenotype. The sensory

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Scala vestibuli 0 mV Scala Media +80 mV IHC Spiral ganglion

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FIGURE 2.4 Transection through the cochlea, with indication of some structures and voltages.

phenotype showing “high-frequency steeply sloping” audiograms occurred in 27%. Other audiogram configurations were very rare (together less than 1%). Allen and Eddins (2010) showed audiogram changes for ages up to 90 years. Hearing loss in males was somewhat larger than in females starting at about age 60 70 years, but then became nearly the same again for the age 90 group. Principal component (PC) analysis revealed that two PCs accounted for 74% of the variance among the 30 measures of hearing that were employed. These two components represented the overall degree (PC1) and configuration of hearing loss (flat vs sloping; PC2) and the phenotypes formed a continuum in PC1 PC2 space. A heuristic partitioning of this continuum produced classes of presbycusis that varied in their degree of sloping or flat hearing loss, suggesting that the previously reported subtypes of presbycusis arise from the categorical segregation of a continuous and heterogeneous distribution. Further, most phenotypes lie intermediate to the extremes of either flat or sloping loss, indicating that if audiometric configuration does predict presbycusis etiology, then a mixed origin is the most prevalent. Dubno et al. then carried out in-depth studies on audiogram phenotypes (Dubno et al., 2013; Vaden et al., 2017). Both studies were based on a classification of patterns of hearing loss associated with cochlear pathology in animal models to define schematic boundaries of human audiograms (Chapter 7). Pathologies included evidence for metabolic

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(25%), sensory (23%), and a mixed metabolic/sensory (41%) phenotype; an older normal phenotype (11%) without threshold elevation was also defined. These percentages are comparable to those in the study of Demeester et al. (2009). Dubno et al. (2013) showed mean thresholds for the four different phenotypes (Fig. 2.5). In agreement with Allen and Eddins (2010) the mixed metabolic and sensorineural phenotype was the most common. The same group, Vaden et al. (2017) expanded on the cross-sectional study of Dubno et al. (2013) by examining audiograms collected longitudinally from 343 adults aged 50 93 years (n 5 686 ears) to test the hypothesis that the prevalence of metabolic phenotypes increases with age, in contrast with the sensory phenotype. They found that: “Although hearing loss increased systematically with increasing age, audiometric phenotypes remained stable for the majority of ears (61.5%) over an average of 5.5 years.” Audiograms were collected for the changing audiometric phenotypes over an average period of 8.2 years, and the majority of those ears transitioned to a metabolic or metabolic/sensory phenotype.

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FIGURE 2.5 Mean thresholds ( 6 1 standard error) of 338 exemplars in four audiometric phenotypes. Source: From Dubno, J.R., Eckert, M.A., Lee, F.-S., Matthews, L.J., Schmiedt, R. A., 2013. Classifying human audiometric phenotypes of age-related hearing loss from animal models. J. Assoc. Res. Otolaryngol. 14, 687 701, with permission from Springer Nature.

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2.3 STRUCTURAL CHANGES IN THE HUMAN COCHLEA WITH AGE Biological aging is characterized by progressive degradation of acute sensations (Gadkaree et al., 2016), of which age-related hearing loss is least noticeable to the outside world, yet probably the most handicapping of all. In this study a total of 276 participants (mean age 5 70 years, range 26 93) underwent vision, proprioception, vestibular, and hearing threshold tests. The sensitivity of all four systems declined with age. After adjustment for age, there were no remaining significant associations between the changes in the function of the sensory systems. These findings suggest that beyond the common mechanism of aging, other nonshared etiologic mechanisms may contribute to the decline in each sensory system. Presbycusis has a heterogeneous origin. Intrinsic (genetic) factors as well as extrinsic factors play a role in age-related degradation of hearing. The extrinsic factors, noise exposure, trauma, infections, and ototoxic drugs are well known for their potential to impair hearing (Gilad and Glorig, 1979a,b). Local vascular insufficiency in the inner ear is likely a significant factor in presbycusis of the metabolic type (Gilad and Glorig, 1979a,b; Nelson and Hinojosa, 2006; Kurata et al., 2016). Ohlemiller (2004) recalled that according to the Schuknecht scheme (Schuknecht, 1964), three major cochlear structures or cell types—spiral ganglion cells (SGCs), hair cells, and stria vascularis—can degenerate independently (Fig. 2.4), and exert independent influences on hearing ability. While each of these three components exhibits age-related changes in most people (Willott, 1991; Dubno et al., 2013), environmental or genetic influences (Chapter 6) may accelerate changes in only one of these, so that the audiogram (or speech perception) reflects principally one influence. When multiple influences interact, their effects are typically assumed to be additive. Gates and Mills (2005) were in agreement with the observations and conclusions of Schuknecht and Gacek (1993) that age-related degeneration of the stria vascularis (the metabolic phenotype of Dubno et al., 2013) is the most prominent anatomical characteristic of age-related hearing loss. Additionally, the audiometric pattern resulting from strial degeneration in animals (Schulte and Schmiedt, 1992; Gratton and Schulte, 1995; Gratton et al., 1996, 1997) is also the most typical finding in cohort studies of elderly people. By contrast, the steeply sloping audiogram of people with confirmed noiseinduced hearing loss (Dubno et al., 2013) differs greatly from the strial pattern and coincides with Schuknecht’s sensory presbycusis pattern. Support for the strial type of damage with aging comes from Nelson and Hinojosa (2006), who selected human temporal bones from individuals with presbycusis that showed downward-sloping audiometric

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thresholds. Outer hair cell loss and ganglion cell loss were observed in all individuals with presbycusis. IHC loss was observed in 18 of the 21 individuals with presbycusis, and stria vascularis loss was observed in 10 of the 21 individuals and was associated with the severity of hearing loss. In a retrospective case-control study, Kurata et al. (2016) examined the autopsy reports of 1024 patients in the temporal bone collection at the University of Minnesota. Inclusion criteria at the time of death consisted of being 60 years or older with sensorineural hearing loss and progression of hearing loss with age (presbycusis group). They reported increased thickness of the vascular walls of the modiolar arteries and stria vascularis, increased strial atrophy, and decreased number of strial vessels, which may have led to decreased cochlear microcirculation. They suggested that circulation and perfusion deficiencies in the cochlea may be a factor in presbycusis. The cochlear and neural substrates of hearing loss and hearing impairment in general are quite variable. Felder and Schrott-Fischer (1995) studied nine temporal bones of people who died between 47 and 67 years of age. They reported that the correlate of high-frequency hearing loss was typically not the loss of hair cells (Fig. 2.6A) but a

FIGURE 2.6 (A) The percentage of surviving IHCs is not correlated with audiogram frequency. (B) For frequencies $ 4 kHz, the percentage of surviving myelinated neurites is positively correlated with the percentage of IHC. (C) For frequencies $ 4 kHz, the percentage of myelinated neurites is positively correlated with hearing threshold. IHC, Inner hair cells; MNF, Myelinated nerve fibers. Source: Based on data from Felder and Schrott-Fischer (1995).

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clear loss of nerve fibers in the spiral lamina, that is, the myelinated neurites (r2 5 0.385, my own calculation, Fig. 2.6C), along the entire length of the cochlea. The percentage of myelinated neurites was also positively correlated with the percentage of remaining IHCs (r2 5 0.23, my own calculations, Fig. 2.6B). The loss of these spiral ganglion fibers was age-related. Reductions in nerve fiber count up to 30% 40%, in comparison to normal-hearing middle-aged persons, were found in cochleas from persons older than 60 years. In two cases only 13% of the nerve fibers remained in some regions of the cochlea. The hair-cell reduction as compared with a group of normal-hearing middle-aged persons was approximately 80% of the OHCs, mainly in the apical parts of the cochlea, with only small differences in the number of IHCs. However in their sample of nine temporal bones a loss of hair cells or primary degeneration of nerve fibers alone could not fully explain the degree of high-frequency hearing loss. Based on this observed variability in hair cell counts, Gates and Mills (2005) stated that aging alone does not cause hair-cell loss. They emphasized that sensory presbycusis probably has little to do with age and much to do with accumulated environmental noise toxicity. It is also known that the pure-tone threshold audiogram is a poor indicator of (diffuse) neural loss since any pattern from normal to near-complete deafness can be found. Yang et al (2015) compared the cochlear mechanisms underlying drug-, noise-, and age-related hearing loss (see also Op de Beeck et al., 2011). They noted that the triad of age-related, noise-exposuregenerated, and drug-induced hearing loss displays similarities in some cellular responses of cochlear sensory cells such as a potential involvement of reactive oxygen species and apoptotic and necrotic cell death (cf. Fig. 6.2). However, they found more similarities between drug- and noise-induced hearing loss than between those two and age-related loss. One of the reasons might be that age-related hearing loss is influenced by genetics as well as a lifetime of environmental factors (Chapter 6) that render its mechanisms and manifestations highly variable.

2.4 OTOACOUSTIC EMISSIONS AND AUDITORY BRAINSTEM RESPONSES Objective assessment of the changes in the cochlea with age can be performed using mechanical responses from the outer hair cells, that is, otoacoustic emissions (OAEs), and patency of the auditory brainstem using auditory brainstem responses.

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2.4.1 Otoacoustic Emissions Kemp (1978) discovered that sound could evoke “echoes” from the ear. These echoes, called OAEs, result from the action of the cochlear amplifier located in the outer hair cells. Guinan et al. (2012) described their generation as follows (Fig. 2.7): “As a traveling wave moves apically [along the BM] it generates distortion due to cochlear nonlinearities (mostly from nonlinear characteristics of the OHC [mechanoelectrical transduction] channels, the same source that produces the nonlinear growth of BM motion), and encounters irregularities due to variations in cellular properties. As a result, some of this energy travels backwards in the cochlea and the middle ear to produce OAEs.”

2. Stereocilia deflection TM 3. Receptor current

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FIGURE 2.7 Steps in the cochlear amplification of BM motion for BM movement toward scala vestibuli. (1) The pressure difference across the cochlear partition causes the BM to move up. (2) The upward BM movement causes rotation of the organ of Corti about the foot of the IP, movement of the RL toward the modiolus (left), and shear of the RL relative to the TM that deflects stereocilia in the excitatory direction (green arrow). (3) This deflection of OHC stereocilia opens mechanoelectrical transduction channels, which increases the receptor current driven into the OHC (blue arrow) by the potential difference between the 1100 mV endocochlear potential and the 240 mV OHC resting potential. The receptor current flowing through the impedance of the hair cell’s basolateral surface depolarizes the cell. (4) OHC depolarization causes its contraction, which pulls the BM upward toward the RL, which amplifies BM motion when the pull on the BM is in the correct phase. The downward RL motion in the OHC region is opposite from the RL motion produced in steps 1 2, which effectively applies negative feedback on the RL motion that is the drive to the OHC. BM, Basilar membrane; IP, Inner pillar; RL, Reticular lamina; TM, Tectorial membrane; OHC, Outer hair cell. Source: From Guinan, Jr., J.J., Salt, A., Cheatham, M.A., 2012. Progress in cochlear physiology after Be´ke´sy. Hear. Res. 293, 12 20, with permission from Elsevier.

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Normal human ears generally exhibit spontaneous OAEs (SOAEs). SOAEs arise from multiple reflections of forward and backward traveling waves that are powered by cochlear amplification (Fig. 2.7) likely via OHC-stereocilia resonance (Shera, 2003). OAEs can be measured with a sensitive microphone in the ear canal, and provide a noninvasive measure of cochlear amplification. There are two main types of OAEs in clinical use. Transient-evoked OAEs (TEOAEs) are evoked using a click stimulus. The evoked response from a click covers the frequency range up to around 4 kHz. Distortion product oto-acoustic emissions (DPOAEs) are evoked by simultaneously presenting a pair of primary tones f1 and f2 (f1 , f2) and with a frequency ratio f2/f1 , 1.4. The spectrum of the sound in the ear canal, in addition to the frequencies of the stimulus tones, contains harmonic and intermodulation distortion products at frequencies that are simple arithmetical combinations of those of the two tones. The most commonly used DPOAE is at the frequency 2f1 f2 (Siegel, 2008). Bonfils et al. (1988) investigated age-related changes of click-evoked OAEs in 151 ears from subjects whose age varied between 2 and 88 years. TEOAEs were present in 100% of the tested subjects until the age of 60 years, whereas after this age the incidence fell to 35%. TEOAE threshold did not vary until the age of 40 years but increased linearly after this age. Castor et al. (1994) found that age influences both TEOAEs and DPOAEs. However, the alterations found in TEOAEs and DPOAEs seem to be essentially due to the hearing loss. Gates et al. (2008) tested 241 volunteer members of a dementia surveillance cohort aged 71 96 years. They found that the mean DPOAE thresholds at 1, 2, and 3 kHz (DPOAE1,2,3kHz) increased 0.34 dB/year (95% CI 5 0.07 0.60), whereas the PTA1,2,3kHz increased by 0.5 dB/year (95% CI 5 0.32 0.81). More recently, Uchida et al. (2008) evaluated 331 subjects (136 men and 195 women) of a population-based sample of 2259 adults aged 40 82 years, who took part in the Longitudinal Study of Aging in Japan. Threshold levels from 250 to 8000 Hz did not exceed 15 dB HL. The mean age was 48.3 years (range, 41 72 years) in men and 49.6 years (range, 41 80 years) in women. There was a significant negative effect of age on DPOAE levels in men, but it was more extensive in women. Here, DPOAEs deteriorated with age independently of hearing sensitivity. Ueberfuhr et al. (2016) used DPOAEs to assess outer hair cell integrity in human ears with age-related hearing loss. The results suggested OHC loss as a contributing cause of age-related hearing, regardless of audiogram configuration. Summarizing, OAE tracks the patency of the OHCs, but since SGC loss is largely determining hearing loss, there is typically no correlation between OAE thresholds or strengths and audiometric hearing loss.

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2.4.2 Auditory Brainstem Responses Auditory brainstem responses (ABR) latencies reflect two aspects of brainstem changes, loss of input from the cochlea and changes in brainstem conduction velocity. Hearing loss is reflected in increased latencies for all ABR waves, whereas decreased brainstem conduction velocity results in increased interpeak latencies, predominantly measured as the I V latency difference. Which aspects does aging affect? Rowe (1978) had studied ABRs in 25 young (mean age 5 25.1 years) and 25 older (mean age 5 61.7 years) adults. They found that wave peak latencies increased with age, but that interpeak latencies were not affected by age. Jerger and Hall (1980) examined amplitude and latency of the ABR as functions of chronological age in 319 participants. They found that age had a slight effect on both latency (increase by 0.2 ms) and amplitude of wave V. Rosenhall et al. (1985) recorded ABRs in 268 healthy individuals ranging in age from 5 to 75 years, 153 females and 115 males. Their pure-tone thresholds were 20 dB HL or better at frequencies of 125 2000 Hz and 35 dB or better at frequencies of 4000 8000 Hz. They found that the latencies of waves I, III, and V increased by 0.1 0.2 ms with increasing age, but that the I V interpeak latency was the same in all age groups. More recently, Konrad-Martin et al. (2012) performed a cross-sectional study in 131 veteran participants, aged 26 71 years, to identify and quantify the effects of aging on the auditory brainstem response. Aging substantially diminished all ABR peak amplitudes, largely independent of any threshold differences within the participants. Age-related amplitude decrements for waves I and III were largest at a low (11/s) click rate. Aging also increased ABR peak latencies, with significant shifts limited to early waves. The I V interpeak latency did not change with age. For both younger and older subjects, increasing click presentation rate significantly decreased amplitudes of early peaks and prolonged latencies of later peaks, resulting in increased interpeak latencies. Advanced age did not enhance the effects of rate. These studies all suggest a largely age effect of the hearing loss causing absolute latency increase, and not brainstem abnormalities as reflected in interpeak latencies.

2.5 EFFECTS OF THE EFFERENT SYSTEM ON THE AUDITORY PERIPHERY Two groups of efferent nerve fibers innervate the cochlea: those projecting underneath the IHCs and synapsing with the spiral ganglion neuron dendrites, and those innervating directly with the OHCs (Fig. 2.8). These efferent fibers originate from two different areas in the

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Midline

MOCB

LOCB

Crossed

MOCB

LOCB

Uncrossed

OHC

IHC

FIGURE 2.8 Origin and distribution of efferent fibers of the right and left OCB in the superior olivary complex, to the right cochlea. Line thickness (cat data) indicates, but not to scale, the proportion of crossed and uncrossed fibers projecting from each MOCB and LOCB to IHCs and OHCs of the right cochlea. Only the crossed fibers from the left OCB and uncrossed fibers from the right OCB are shown. OCB, olivocochlear bundle; MOCB, medial olivocochlear bundle; LOCB, lateral olivocochlear bundle; IHCs, Inner hair cells; OHCs, Outer hair cells. Source: Based on Yasin et al. (2014).

superior olivary complex in the brainstem and run through the vestibular nerve towards the cochlea. The terms lateral and medial efferent systems are often used to designate the efferent fibers that project below the IHC and those of the OHCs, respectively. The lateral efferents, which represent about 50% 65% of the olivocochlear bundle (OCB) fibers, are unmyelinated and project dominantly towards SGC neurites in the ipsilateral cochlea. The medial efferents are myelinated and reach the OHCs via the crossed and uncrossed components of the OCB. The crossed component predominates the medial efferent innervation (Guinan, 2006). Collet et al. (1990) were the first to demonstrate the possibility that contralateral auditory stimulation along the medial efferent system pathways may alter active cochlear micromechanics and hence affect evoked OAEs in humans. They showed that low-intensity ( . 30 dB SPL) contralateral white noise reduced the OAE amplitude. Their findings suggested a way for functional exploration of the medial olivocochlear efferent system (Chapter 7). Micheyl and Collet (1996) investigated the involvement of auditory efferents in hearing-in-noise in

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humans, OCB functioning and detection-in-noise abilities were compared in 30 subjects. OCB function was assessed in terms of contralateral attenuation of TEOAEs: that is, the reduction in TEOAE amplitude elicited by a 30-dB SL contralateral broadband noise. They found significant correlations between the contralateral attenuation of TEOAEs and (1) the detection threshold of the 2-kHz signal and (2) the contralaterally induced shift in the 1- and 2-kHz thresholds. Furthermore, the correlation between contralaterally induced reduction of TEOAE amplitude and contralaterally induced threshold shift was observed only in the group of subjects who had first performed the detection task in the presence of contralateral stimulation. This suggests involvement of auditory cortex as later demonstrated by Perrot et al. (2006), who showed that corticofugal modulation of peripheral auditory activity exists in humans. In 10 epileptic patients, electrical stimulation of the contralateral auditory cortex led to a significant decrease in TEOAE amplitude, whereas no change occurred under stimulation of nonauditory contralateral areas. These findings provide evidence of a cortico-olivocochlear pathway, originating in the auditory cortex and modulating contralateral active cochlear micromechanisms via the medial olivocochlear efferent system, in humans. Quaranta et al. (2001) recorded TEOAEs without and with contralateral acoustical stimulation in 52 adults ranging from 20 to 78 years in age; they all had hearing levels from 0.5 to 4 kHz being better than 25 dB HL, normal tympanograms, and stapedial reflexes. The participants were divided into five age groups: 20 34 years (n 5 12), 35 44 years (n 5 11), 45 54 years (n 5 8), 55 64 years (n 5 10), and one aged 71 years. TEOAEs were always present in the first two groups, but they were absent in two ears from the 45 54 group and in one ear from the 55 64 group and the 71-year-old. Mean TEOAE amplitude decreased with age, but the differences between the five groups were not significant. Contralateral white noise suppressed emission amplitude, but the amount of suppression was not significantly different between the five groups. No effect of age on the amplitude of the efferent suppression was found. Keppler et al. (2010) investigated OAEs in 71 ears (range 20 79 years), 47 of which had normal hearing thresholds, and 24 ears had a high-frequency hearing loss caused by presbycusis. They found that TEOAEs, DPOAEs, and efferent suppression were more strongly correlated with age, than with pure-tone thresholds. They also concluded that the deterioration of OAEs and efferent suppression with advancing age is caused mainly by pure age effects, and additionally by the reduction in hearing thresholds. Konomi et al. (2014) assessed contralateral DPOAE suppression in 95 ears from 51 subjects (age range 2 52 years). They observed an age-related reduction in DPOAE amplitudes. Both the detectability and the degree of contralateral DPOAE

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suppression were decreased in older age groups, but there was no significant change in suppression time-constants. In addition to reduced emissions (OHC suppression) the increased latency of efferent suppression may reflect deterioration in auditory brainstem function. It is fair to conclude that efferent activity has no or very little effect of audiometric thresholds.

2.6 SUMMARY Sensation refers to the process of sensing our environment through touch, taste, sight, sound, and smell. Changes in hearing thresholds with age, are underlying presbycusis and the various forms are reflected in audiogram phenotypes for purely sensory, that is, high-frequency hearing loss. Purely metabolic forms show flat hearing losses and mixed sensory-metabolic forms do occur as well. A sizeable proportion of elderly have normal audiograms. The rate of threshold change with age appears to be independent of acquired hearing loss due to occupational noise. Objective indicators of outer hair cell damage, the OAEs, are reduced in amplitude regardless of the form of the audiogram, and appear to be more sensitive indicators of cochlear damage than the audiogram.

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