Otitis media (OM) is the most common group of inflammatory diseases of the middle ear encountered in pediatric populations, many of which result from bacterial infection (Klein 1994). Up to 75% of children will experience one or more bouts before they reach 5 years of age, making it the most common cause for physician visits and antibiotic prescriptions in pediatric outpatients (Pennie 1998). These bouts can reoccur with a cumulative incidence of 42% by 2 years of age and 60% by age 3 years of age (Kaur et al. 2017). Several studies of patients presenting with a unilateral chronic OM (COM) showed that bone conduction (BC) thresholds were significantly poorer on the affected side, suggesting that a sensorineural component had developed as well (da Costa et al. 2009; Jesic et al. 2012; Joglekar et al. 2010; Kolo et al. 2012; Luntz et al. 2013; Redaelli de Zinis et al. 2005; Yehudai et al. 2015; Yoshida et al. 2014). Others have shown long-lasting deficits in spatial hearing as well as receptive language skills that persist after the middle ear pathology has resolved (for review, see Deggouj et al. 2012).
Sensorineural damage associated with cholesteatomas in addition to conductive hearing loss (CHL) is well documented (Rosito et al. 2016). Histopathologic studies of both human and animal temporal bones suggested that penetration of bacterial toxins and inflammatory mediators into the inner ear compartment via the round window membrane can be the cause of hair cell damage and related sensorineural loss (Paparella et al. 1984; Joglekar et al. 2010; Katano et al. 2005; MacArthur et al. 2013a,2013b). Sensorineural damage is further increased when a fistula of the inner ear has been created by the erosive properties of the cholesteatoma. The use of ototoxic topical aminoglycosides is an additional potential cause of damage, and a surgical intervention can also contribute to sensorineural loss as cholesteatomas necessitate removal. The finding that some pathologies with a conductive component can lead to sensorineural damage, however, cannot explain why patients with single-sided congenital ear malformation (and therefore presenting CHL) have poorer speech recognition scores in quiet and in noise on the malformed side, despite having similar BC thresholds in the normal and the affected ear (Priwin et al. 2007; Snik et al. 1994).
Animal studies on the effects of sound deprivation have shown long-lasting impact on brain and behavior. However, most studies disrupted the middle ear during the neonatal period (e.g., Smith et al. 1983; Tucci et al. 1985,1987) and most have evaluated its effects on the higher centers of the auditory pathways rather than in the cochlea (Clarkson et al. 2016; Dahmen & King 2007; Grande et al. 2014; Harrison & Negandhi 2012; Hutson et al. 2008; Kandler & Gillespie 2005; Wang et al. 2011; Zhuang et al. 2017). Recently, we showed in mice that a chronic (1-year duration) CHL from eardrum resection in the mature animal led to a reduction in cochlear efferent innervation and a loss of up to 30% of the afferent synapses between the cochlear nerve and the sensory cells (Liberman et al. 2015). This surprising finding revealed signs of plasticity of cochlear innervation in the fully developed ear. This type of subtotal cochlear synaptopathy will not elevate behavioral or electrophysiologic thresholds until it becomes extreme (Lobarinas et al. 2013; Woellner & Schuknecht 1955) because the most vulnerable cochlear neurons in other forms of cochlear synaptopathy tend to be those with high thresholds and low spontaneous rates (Furman et al. 2013; Schmiedt et al. 1996). However, it should degrade the signal-coding abilities of the auditory nerve and might impair performance on more complex tasks such as speech recognition.
The present study aims to determine whether patients with chronic reduction in sound transmission through the middle ear show increased difficulty with word recognition (WR) tasks as predicted by the synaptopathic effects of chronic CHL in animal models.
MATERIALS AND METHODS
We collected audiologic data from patients seen at the Massachusetts Eye & Ear Infirmary between 1993 and 2017 for otologic evaluation. To be included, patient must have presented with normal (≤25 dB HL) and symmetrical BC thresholds bilaterally (interaural difference ≤10 dB from 250 to 4 kHz) and a unilateral CHL at the first visit. A CHL was defined as ≥15 dB difference between the mean pure-tone average (PTA) for air conduction (AC) and BC thresholds (air-bone gap). The CHL was defined as chronic when the air-bone gap remained ≥15 dB between the first and the last visit. It was defined as acute when the air-bone gap was <15 dB at the second visit and remained so on follow-up appointments. Records spanning <2 years and patients with fewer than three hearing evaluations were excluded. Patients <10 years of age were not considered because hearing assessment differs in the pediatric setting. Further characteristics of patient’s profile including age, observation spans, and visit intervals are described in Figure 1. With the exception of 1 patient, who was excluded, none of the study population wore traditional or bone-anchored hearing aids. This research study was reviewed and approved by the Institutional Review Board of the Massachusetts Eye & Ear.
Audiometric thresholds were obtained using a number of different audiometers including Grason-Stadler (GS-10, GS-16), Interacoustics AC-30, Virtual 320, and Interacoustics Equinox, running under the same Harvard Audiometer Operating System (AOS; Thornton et al. 1994). Pure-tone AC thresholds were measured at standard audiometric frequencies from 0.25 to 8 kHz, in octave steps using TDH39 headphones or ER-3A insert earphones. BC thresholds were acquired from 250 to 4000 Hz with a Radioear B-71 vibrator over the mastoid. The PTA was defined as the average threshold at 500, 1000, and 2000 Hz. Hearing loss configurations were divided into 3 groups: (1) upward sloping when mean AC thresholds at 250 and 500 Hz were 10 dB worse than mean thresholds at 4 and 8 kHz; (2) downward sloping for patients with mean AC thresholds at 250 and 500 Hz 10 dB better than mean thresholds at 4 and 8 kHz; and (3) flat for all other hearing loss profiles.
Speech recognition performance was assessed using a recorded Central Institute for the Deaf W-22 phonetically balanced test, consisting of 50 consonant-vowel nucleus-consonant word lists presented with a contralateral speech-shaped noise. The Articulation Index was used to predict the performance/intensity function for speech (Pavlovic et al. 1986; Wilde & Humes 1990) based on the audiogram, using a transfer function for Central Institute for the Deaf W-22 (ANSI 1997; Sherbecoe & Studebaker 1990). This procedure was automatically generated by the Harvard AOS software as described in Halpin et al. (1994). The level at which maximal intelligibility was predicted was chosen as presentation level. If this value, however, fell below 70 dB HL, presentation level remained at 70 dB HL. All WR scores were obtained from native speakers of English. The scores reported here are those at the time of the initial visit, for patients with acute CHL, and at the time of the final visit for patients with chronic conditions.
All statistical analyses were performed under the JMP statistical data analysis software (SAS Institute Inc., Cary, NC). The threshold for statistical significance was p = 0.05. Equivalent testing using the “two-one-sided t-tests” procedure was considered to examine whether interaural changes in threshold differed among groups. The nonparametric Steel-Dwass test was used to perform multiple group comparisons. A two-way analysis of variance (ANOVA) followed by a Mann-Whitney U test were performed to compare WR scores across groups. Finally, the relationship between AC and BC thresholds as a function of WR score was tested using a Spearman rank correlation coefficient method.
Out of 240 cases meeting our inclusion criteria, 169 cases were chronic conditions with one of three etiologies: 15 with atresia and/or a congenital middle ear malformation, 71 with COM, and 83 with cholesteatoma. An additional 71 cases were acute conditions: 20 with acute OM (AOM) and 51 with OM with effusion (OME). Figure 2 shows the mean AC and BC thresholds of each cohort on the side of the conductive impairment. Note that whatever small intergroup differences there are, the mean BC thresholds are slightly worse in the acute groups than in the chronic groups, especially at 4 kHz where the difference was statistically significant (ANOVA: F = 2.15; p = 0.04).
Whereas all patients presented with a mild to moderately severe CHL in one ear, in the contralateral ear, there was no significant air-bone gap, and PTAs for AC and BC thresholds were within normal limits (Fig. 3). Patients were separated into two PTA groups, as color coded in Figure 3: mild CHL when AC threshold was ≤40 dB HL and moderate to moderately severe CHL for AC thresholds were between 40 and 70 dB HL.
To quantify interaural differences in BC thresholds over the observation period (Fig. 1) and track signs of progressive hair cell damage on the CHL side, changes in BC thresholds as a function of time were calculated for each chronic condition group in each ear (Fig. 4). There were no statistically significant differences in the rate of threshold deterioration (dB/year) between the CHL ear and the contralateral ear in either PTA group, as examined with an equivalence testing approach using the two-one-sided t-tests procedure (congenital, p = 0.53; COM, p = 0.37; cholesteatoma, p = 0.59; Fig. 3).
However, as shown in Figure 5, WR scores were significantly poorer on the CHL side, when the PTA was >40 dB HL and when the condition was chronic, whether assessed by ANOVA (congenital: F = 4.70, p = 0.01; COM: F = 13.91, p < 0.001; cholesteatoma: F = 6.21, p < 0.001; AOM: F = 0.54, p > 0.05; OME: F = 6.86, p = 0.01) or by a post hoc Steel-Dwass test for multiple comparisons (congenital: AC ≤ 40, Z = 1.57, p > 0.05/AC > 40, Z = 3.03, p = 0.04; COM: AC ≤ 40, Z = 0.16, p > 0.05/AC > 40, Z = 3.64, p = 0.04; cholesteatoma: AC ≤ 40, Z = 1.31, p > 0.05/AC > 40, Z = 3.72, p = 0.04). Another statistical approach was to use a two-way ANOVA to show that duration (acute versus chronic) and degree of hearing loss had significant effects on the difference in WR scores between the affected and the unaffected ear (acute versus chronic: F = 49.7, p < 0.001; degree of hearing loss: F = 16.7, p < 0.001), with no interaction between diagnosis and degree (p = 0.48). Finally, post hoc analysis showed a statistically significant effect of the degree of hearing loss in chronic conditions (p < 0.001), but not in acute conditions (p = 0.68). Similarly, we found no statistically significant difference between chronic and acute conditions in patients with mild hearing loss (p = 0.99), while these differences became significant in patients with a moderate to moder
ately severe loss (p = 0.03). Finally, there was no statistically significant effect of sex in any of the chronic groups (Table 1).
The results suggest that both degree and duration of hearing loss are relevant to the decrement in WR score. This relationship is further supported by (1) the statistically significant correlations obtained between WR score and AC-PTA thresholds in chronic conditions, as shown in Figure 6D–E (congenital: ρ = −0.59, p = 0.02; COM-cholesteatoma: ρ = −0.24, p = 0.001) and (2) by the absence of correlation between BC-PTA thresholds and word scores (Fig. 6A–C) in the same group of patients (congenital: ρ = −0.12, p = 0.66; COM-cholesteatoma: ρ = 0.03, p = 0.81; AOM-OME: ρ = −0.24, p = 0.09). Thus, inner ear threshold sensitivity, as measured with BC, is not significantly associated with WR score in these patients. Note that a higher Spearman rank correlation coefficient was seen for the congenital group compared with groups that included patients who experienced repeated middle ear infections and/or cholesteatoma.
This study shows that patients with chronic conditions associated with at least a moderate unilateral CHL have poorer word recognition scores (WRS) on the affected side compared with the unaffected side, even if BC thresholds remain symmetrical and within normal limits bilaterally.
A number of methodologic limitations intrinsic to retrospective studies need to be acknowledged. First, as a result of our inclusion criteria, cohorts with acute CHL were significantly older than patients with chronic conditions (Fig. 1). Indeed, audiometric data were collected from patients with AOM who did not repeat the condition, excluding therefore younger patients who tend to repeat ear infections (Tos 1984; Williamson et al. 1994). Similarly, we excluded patients with poor BC thresholds (>25 dB HL). Given that BC thresholds decline with age, patients with COM and/or a cholesteatoma were relatively younger. Poorer WRS were observed in chronic CHL cohorts; thus, age is unlikely to be a significant factor detrimental to WRS in this study population.
A second limitation lies with how WR performance was assessed: speech material was delivered at a single presentation level, obtained from an estimate of the speech intelligibility index curve (see Methods). It is possible that the level at which maximum performance was predicted by this procedure was not optimal. However, this is unlikely, as the predicted presentation level would have to be off by >14 dB to produce WRS as poor as those observed in the chronic condition groups, as determined using the Harvard AOS software.
It is also possible that hearing loss configuration could alter speech perception performance by filtering out energy from the speech signal. While a majority of these chronic CHL produced “flat” audiograms as defined in Methods (74 out of 169), 41 patients presented with an upward-sloping and 54 presented with a downward-sloping configuration (Fig. 7). Although the speech material was not spectrally adjusted to compensate for audiometric losses, we found no evidence that hearing loss configuration had a significant impact on WR scores (ANOVA: congenital: F = 0.63, p = 0.48; COM: F = 0.53, p = 0.65; cholesteatoma: F = 2.47, p = 0.10).
It is worth noting as well that a great majority of the chronic-CHL cohort had cholesteatoma or COM, both of which can cause inner ear damage, as documented in many investigations. Histopathologic studies point at the cochlear basal turn as a target for middle ear infections (Cook et al. 1999; Cureoglu et al. 2004; Paparella et al. 1972), and children with a history of OM have poorer extended high-frequency thresholds compared with controls (Hunter et al. 1996; Margolis et al. 2000). The byproducts of bacterial infections and inflammatory mediators can alter gene expression in the inner ear (Ghaheri et al. 2007; MacArthur et al. 2013a), including those for ion channels and transporters in the stria vascularis and spiral ligament (MacArthur et al. 2013b). Such alterations could result in sensorineural hearing loss. However, here, we excluded patients with elevated BC thresholds (>25 dB HL) to minimize the contributions of hair cell damage, strial damage, or other non-neural cells in the cochlear duct to any observed degradation in speech-recognition performance on the affected side. It is possible that inflammatory byproducts of infection reach the inner ear and cause damage that is not captured by BC thresholds. Nevertheless, the WR score obtained in all group of patients with chronic etiologies and moderate to moderately severe hearing losses were significantly lower than that predicted from the speech intelligibility curve (>98%), and no significant correlation was observed between BC thresholds and WR score (Fig. 6A–C). Thus, even if there is damage to the most basal regions of the cochlea, it should not affect speech recognition scores to the extent observed here, when words are presented at comfortable levels to patients with bilaterally normal BC thresholds. In addition, as shown in Figure 2, acute cohorts (with the worse WR scores) actually had slightly poorer BC thresholds at 4 kHz compared with chronic cohorts. Therefore, a different mechanism likely underlies the decrement in WR score.
Evidence for a noninflammatory etiology is provided by patients with congenital malformations (e.g., atretic canal). These patients showed the strongest correlation between AC thresholds and WR score (Fig. 6). This result is consistent with the idea that a reduced acoustic drive to the inner ear is the root cause of the impairment in speech-recognition performance. Such CHL is a common form of auditory deprivation that has long-lasting deleterious effects on hearing when occurring during critical periods of development (for review, see Whitton & Polley 2011). Unilateral CHLs also alter interaural time and level differences of acoustic signals arriving at the two ears (Hall & Derlacki 1988; Thornton et al. 2012), and therefore affect spatial hearing, particularly in the horizontal plane. The resulting degraded afferent signals when carried to brain areas during critical periods of development will impact the formation of neural circuits that mediate perception, as evidenced at the cellular level by significantly reduced cell-body diameter and dendritic arborization in regions of the cochlear nucleus and superior olivary complex (Webster & Webster 1977,1979; Conlee et al. 1984,1986). CHL has also been found to disrupt temporal response properties of auditory cortical neurons in animal studies (e.g., Polley et al. 2013; Teichert & Bolz 2017) and, more recently, in increased neural response amplitudes in humans with a chronic unilateral CHL (Parry et al. 2019). Furthermore, several studies report that sound deprivation can alter the normal development of the central auditory system even after hearing thresholds return to normal by disrupting binaural integration, by impoverishing hearing in noise (Knudsen et al. 1984,Popescu & Polley 2010; Gay et al. 2014) and by disrupting normal binaural balance between the representation of sounds delivered to each ear (Clopton & Silverman 1977; Silverman & Clopton 1977,Moore & Irvine 1981; Popescu & Polley 2010). However, normal-hearing thresholds do not guarantee an absence of peripheral damage, and none of these studies looking at central effects of sound deprivation provided evidence of peripheral integrity at the neuronal level. Therefore, a peripheral involvement in the persistent perceptual impairments associated with chronic CHL in any of these prior studies cannot be ruled out.
In prior animal work, our group showed that prolonged unilateral CHL, due to resection of the eardrum, caused up to 30% loss of synapses between cochlear nerve fibers and their peripheral targets, the inner hair cells (Liberman et al. 2015). This type of cochlear synaptopathy could cause hearing impairments, especially in noisy environments (Liberman 2017) because the most vulnerable cochlear neurons to both noise and aging are those with high thresholds and low spontaneous rates (Furman et al. 2013; Schmiedt et al. 1996). These high-threshold fibers are key contributors to the coding of transient stimuli in noisy environments (Costalupes et al. 1984) despite the fact that their loss remained undetected because neural degeneration per se does not elevate behavioral or electrophysiologic thresholds until it becomes extreme (Lobarinas et al. 2013; Woellner & Schuknecht 1955). Because WR score in this study was obtained in quiet, the impairment experienced by these patients may be underestimated.
As discussed earlier, a number of studies have documented changes in central auditory nuclei as a result of a chronic conductive impairment. Of particular interest are the changes in the superior olivary complex in animal models of neonatal CHL, where a significant abnormalities have been observed in rats (Myers et al. 2012), gerbils (Tucci et al. 2001), and guinea pigs (Potashner et al. 1997). For example, levels of oxidative enzymes, thought to reflect overall electrical activity (Wong-Riley et al. 1981), changed significantly within the lateral superior olive of adult gerbils as a result of unilateral malleus removal or cochlear ablation (Tucci et al. 2002). Given the importance of the lateral superior olive as the origin of olivocochlear feedback to the cochlea, these central changes may also lead to changes at the periphery. Our prior animal study of CHL also showed a reduction in the density of cochlear efferent fibers originating in the lateral superior olive and projecting to the dendrites of cochlear nerve fibers in the inner hair cell area (Liberman et al. 2015). The further observation that cochlear de-efferentation, per se, by surgical interruption of the fiber bundle, also leads to cochlear synaptopathy (Liberman et al. 2014), suggests that the cochlear neurodegeneration associated with CHL may be mediated by changes in the efferent feedback pathways to the inner ear. Together, these results from animal studies suggest that cochlear synaptopathy may be a contributing factor to the reduced WR scores observed in our cohort of human subjects with chronic CHL of a moderate to moderately severe degree.
This study also supports the idea that amplification should be considered in the management of unilateral CHL: if hearing cannot be medically improved, patients may benefit from either conventional amplification or from an osseointegrated device. In absence of amplification, our data suggest that speech recognition, particularly in adverse environments, may worsen on the side of the pathology, possibly also including deficits in sound localization. This speculation is further supported by a study of patients with bilateral symmetric CHL who received monaural versus binaural amplification: speech recognition in unaided ears was poorer than that in aided ears (Dieroff 1993). Lack of treatment for unilateral or asymmetric hearing loss can be based on the belief that the contralateral ear can compensate for the loss. Yet, children with asymmetric hearing loss have higher rates of academic, social, and behavioral difficulties (Lieu et al. 2012; Wie et al. 2010). Given that cochlear synaptopathy appears to be irreversible, peripheral deficits related to cochlear neural degeneration should be considered as well, when patients report lingering deficits in auditory processing after persistent middle ear issues are resolved.
The authors are grateful to William Goedicke and Dr. Barbara Herrmann for their technical help and logistic support.
American National Standards Institute, Method for the calculation of the speech intelligibility index. ANSI S3.79–1997. In Accredited Standards Committee S3, Bioacoustics. (1997). Melville, NY: Acoustical Society of America.
Clarkson C., Antunes F. M., Rubio M. E. Conductive hearing loss
has long-lasting structural and molecular effects on presynaptic and postsynaptic structures of auditory nerve synapses in the Cochlear nucleus. J Neurosci, (2016). 36, 10214–10227.
Clopton B. M., Silverman M. S. Plasticity of binaural interaction. II. Critical period and changes in midline response. J Neurophysiol, (1977). 40, 1275–1280.
Conlee J. W., Parks T. N., Romero C., et al. Auditory brainstem anomalies in albino cats: II. Neuronal atrophy in the superior olive. J Comp Neurol, (1984). 225, 141–148.
Conlee J. W., Parks T. N., Creel D. J. Reduced neuronal size and dendritic length in the medial superior olivary nucleus of albino rabbits. Brain Res, (1986). 363, 28–37.
Cook R. D., Postma D. S., Brinson G. M., et al. Cytotoxic changes in hair cells secondary to pneumococcal middle-ear infection. J Otolaryngol, (1999). 28, 325–331.
Costalupes J. A., Young E. D., Gibson D. J. Effects of continuous noise backgrounds on rate response of auditory nerve fibers in cat. J Neurophysiol, (1984). 51, 1326–1344.
Cureoglu S., Schachern P. A., Paparella M. M., et al. Cochlear changes in chronic otitis media
. Laryngoscope, (2004). 114, 622–626.
da Costa S. S., Rosito L. P., Dornelles C. Sensorineural hearing loss in patients with chronic otitis media
. Eur Arch Otorhinolaryngol, (2009). 266, 221–224.
Dahmen J. C., King A. J. Learning to hear: Plasticity of auditory cortical processing. Curr Opin Neurobiol, (2007). 17, 456–464.
Deggouj N., Castelein S., Grégoire A., et al. Functional consequences of chronic ENT inflammation on the development of hearing and communicative abilities. B-ENT, (2012). 8(Suppl 19), 105–115.
Dieroff H. G. Late-onset auditory inactivity (deprivation) in persons with bilateral essentially symmetric and conductive hearing impairment. J Am Acad Audiol, (1993). 4, 347–350.
Furman A. C., Kujawa S. G., Liberman M. C. Noise-induced cochlear neuropathy is selective for fibers with low spontaneous rates. J Neurophysiol, (2013). 110, 577–586.
Gay J. D., Voytenko S. V., Galazyuk A. V., et al. Developmental hearing loss impairs signal detection in noise: Putative central mechanisms. Front Syst Neurosci, (2014). 8, 162.
Ghaheri B. A., Kempton J. B., Pillers D. A., et al. Cochlear cytokine gene expression in murine chronic otitis media
. Otolaryngol Head Neck Surg, (2007). 137, 332–337.
Grande G., Negandhi J., Harrison R. V., et al. Remodelling at the calyx of Held-MNTB synapse in mice developing with unilateral conductive hearing loss
. J Physiol, (2014). 592, 1581–1600.
Hall J. W. III, Derlacki E. L. Binaural hearing after middle ear
surgery. Masking-level difference for interaural time and amplitude cues. Audiology, (1988). 27, 89–98.
Halpin C., Thornton A., Hasso M. Low-frequency sensorineural loss: Clinical evaluation and implications for hearing aid fitting. Ear Hear, (1994). 15, 71–81.
Harrison R. V., Negandhi J. Resting neural activity patterns in auditory brainstem and midbrain in conductive hearing loss
. Acta Otolaryngol, (2012). 132, 409–414.
Hunter L. L., Margolis R. H., Rykken J. R., et al. High frequency hearing loss associated with otitis media
. Ear Hear, (1996). 17, 1–11.
Hutson K. A., Durham D., Imig T., et al. Consequences of unilateral hearing loss: Cortical adjustment to unilateral deprivation. Hear Res, (2008). 237, 19–31.
Jesic S. D., Jotic A. D., Babic B. B. Predictors for sensorineural hearing loss in patients with tubotympanic otitis, cholesteatoma, and tympanic membrane retractions. Otol Neurotol, (2012). 33, 934–940.
Joglekar S., Morita N., Cureoglu S., et al. Cochlear pathology in human temporal bones with otitis media
. Acta Otolaryngol, (2010). 130, 472–476.
Kandler K., Gillespie D. C. Developmental refinement of inhibitory sound-localization circuits. Trends Neurosci, (2005). 28, 290–296.
Katano H., Iino Y., Murakami Y., et al. Temporal bone histopathology in a patient suspected of inner ear extension of otitis media
. Nihon Jibiinkoka Gakkai Kaiho, (2005). 108, 533–536.
Kaur R., Morris M., Pichichero M. E. Epidemiology of acute otitis media
in the postpneumococcal conjugate vaccine era. Pediatrics, (2017). 140, e20170181.
Klein J. O. Otitis media
. Clin Infect Dis, (1994). 19, 823–833.
Knudsen E. I., Esterly S. D., Knudsen P. F. Monaural occlusion alters sound localization during a sensitive period in the barn owl. J Neurosci, (1984). 4, 1001–1011.
Kolo E. S., Salisu A. D., Yaro A. M., et al. Sensorineural hearing loss in patients with chronic suppurative otitis media
. Indian J Otolaryngol Head Neck Surg, (2012). 64, 59–62.
Liberman M. C. Noise-induced and age-related hearing loss: New perspectives and potential therapies. F1000Res, (2017). 6, 927.
Liberman M. C., Liberman L. D., Maison S. F. Efferent feedback slows cochlear aging. J Neurosci, (2014). 34, 4599–4607.
Liberman M. C., Liberman L. D., Maison S. F. Chronic conductive hearing loss
leads to cochlear degeneration. PLoS One, (2015). 10, e0142341.
Lieu J. E., Tye-Murray N., Fu Q. Longitudinal study of children with unilateral hearing loss. Laryngoscope, (2012). 122, 2088–2095.
Lobarinas E., Salvi R., Ding D. Insensitivity of the audiogram to carboplatin induced inner hair cell loss in chinchillas. Hear Res, (2013). 302, 113–120.
Luntz M., Yehudai N., Haifler M., et al. Risk factors for sensorineural hearing loss in chronic otitis media
. Acta Otolaryngol, (2013). 133, 1173–1180.
MacArthur C. J., Hausman F., Kempton J. B., et al. Otitis media
impacts hundreds of mouse middle and inner ear genes. PLoS One, (2013a). 8, e75213.
MacArthur C. J., Hausman F., Kempton J. B., et al. Inner ear tissue remodeling and ion homeostasis gene alteration in murine chronic otitis media
. Otol Neurotol, (2013b). 34, 338–346.
Margolis R. H., Saly G. L., Hunter L. L. High-frequency hearing loss and wideband middle ear
impedance in children with otitis media
histories. Ear Hear, (2000). 21, 206–211.
Moore D. R., Irvine D. R. Plasticity of binaural interaction in the cat inferior colliculus. Brain Res, (1981). 208, 198–202.
Myers A. K., Ray J., Kulesza R. J. Jr. Neonatal conductive hearing loss
disrupts the development of the Cat-315 epitope on perineuronal nets in the rat superior olivary complex. Brain Res, (2012). 1465, 34–47.
Paparella M. M., Morizono T., Le C. T., et al. Sensorineural hearing loss in otitis media
. Ann Otol Rhinol Laryngol, (1984). 93(6 Pt 1), 623–629.
Paparella M. M., Oda M., Hiraide F., et al. Pathology of sensorineural hearing loss in otitis media
. Ann Otol Rhinol Laryngol, (1972). 81, 632–647.
Parry L. V., Maslin M. R. D., Schaette R., et al. Increased auditory cortex neural response amplitude in adults with chronic unilateral conductive hearing impairment. Hear Res, (2019). 372, 10–16.
Pavlovic C. V., Studebaker G. A., Sherbecoe R. L. An articulation index based procedure for predicting the speech recognition performance of hearing-impaired individuals. J Acoust Soc Am, (1986). 80, 50–57.
Pennie R. A. Prospective study of antibiotic prescribing for children. Can Fam Physician, (1998). 44, 1850–1856.
Polley D. B., Thompson J. H., Guo W. Brief hearing loss disrupts binaural integration during two early critical periods of auditory cortex development. Nat Commun, (2013). 4, 2547.
Popescu M. V., Polley D. B. Monaural deprivation disrupts development of binaural selectivity in auditory midbrain and cortex. Neuron, (2010). 65, 718–731.
Potashner S. J., Suneja S. K., Benson C. G. Regulation of D-aspartate release and uptake in adult brain stem auditory nuclei after unilateral middle ear
ossicle removal and cochlear ablation. Exp Neurol, (1997). 148, 222–235.
Priwin C., Jönsson R., Magnusson L., et al. Audiological evaluation and self-assessed hearing problems in subjects with single-sided congenital external ear malformations and associated conductive hearing loss
. Int J Audiol, (2007). 46, 162–171.
Redaelli de Zinis L. O., Campovecchi C., Parrinello G., et al. Predisposing factors for inner ear hearing loss association with chronic otitis media
. Int J Audiol, (2005). 44, 593–598.
Rosito L. S., Netto L. S., Teixeira A. R., et al. Sensorineural hearing loss in cholesteatoma. Otol Neurotol, (2016). 37, 214–217.
Schmiedt R. A., Mills J. H., Boettcher F. A. Age-related loss of activity of auditory-nerve fibers. J Neurophysiol, (1996). 76, 2799–2803.
Sherbecoe R. L., Studebaker G. A. Regression equations for the transfer functions of ANSI S3.5-1969. J Acoust Soc Am, (1990). 88, 2482–2483.
Silverman M. S., Clopton B. M. Plasticity of binaural interaction. I. Effect of early auditory deprivation. J Neurophysiol, (1977). 40, 1266–1274.
Smith Z. D., Gray L., Rubel E. W. Afferent influences on brainstem auditory nuclei of the chicken: n. laminaris dendritic length following monaural conductive hearing loss
. J Comp Neurol, (1983). 220, 199–205.
Snik F. M., Teunissen B., Cremers W. R. Speech recognition in patients after successful surgery for unilateral congenital ear anomalies. Laryngoscope, (1994). 104(8 Pt 1), 1029–1034.
Teichert M., Bolz J. Data on the effect of conductive hearing loss
on auditory and visual cortex activity revealed by intrinsic signal imaging. Data Brief, (2017). 14, 659–664.
Thornton A., Halpin C., Han Y., et al. The Harvard Audiometer Operating System [Software]. (1994). Palo Alto, CA: Applitech Inc.
Thornton J. L., Chevallier K. M., Koka K., et al. The conductive hearing loss
due to an experimentally induced middle ear
effusion alters the interaural level and time difference cues to sound location. J Assoc Res Otolaryngol, (2012). 13, 641–654.
Tos M. Epidemiology and natural history of secretory otitis. Am J Otol, (1984). 5, 459–462.
Tucci D., Cant N. B., Durham D. Conductive hearing loss
results in changes in cytochrome oxidase activity in gerbil central auditory system. J Assoc Res Otolaryngol, (2002). 3, 89–106.
Tucci D. L., Born D. E., Rubel E. W. Changes in spontaneous activity and CNS morphology associated with conductive and sensorineural hearing loss in chickens. Ann Otol Rhinol Laryngol, (1987). 96(3 Pt 1), 343–350.
Tucci D. L., Cant N. B., Durham D. Effects of conductive hearing loss
on gerbil central auditory system activity in silence. Hear Res, (2001). 155, 124–132.
Tucci D. L., Rubel E. W. Afferent influences on brain stem auditory nuclei of the chicken: Effects of conductive and sensorineural hearing loss on n. magnocellularis. J Comp Neurol, (1985). 238, 371–381.
Wang H., Yin G., Rogers K., et al. Monaural conductive hearing loss
alters the expression of the GluA3 AMPA and glycine receptor α1 subunits in bushy and fusiform cells of the cochlear nucleus. Neuroscience, (2011). 199, 438–451.
Webster D. B., Webster M. Neonatal sound deprivation
affects brain stem auditory nuclei. Arch Otolaryngol, (1977). 103, 392–396.
Webster D. B., Webster M. Effects of neonatal conductive hearing loss
on brain stem auditory nuclei. Ann Otol Rhinol Laryngol, (1979). 88(5 Pt 1), 684–688.
Whitton J. P., Polley D. B. Evaluating the perceptual and pathophysiological consequences of auditory deprivation in early postnatal life: A comparison of basic and clinical studies. J Assoc Res Otolaryngol, (2011). 12, 535–547.
Wie O. B., Pripp A. H., Tvete O. Unilateral deafness in adults: Effects on communication and social interaction. Ann Otol Rhinol Laryngol, (2010). 119, 772–781.
Wilde G., Humes L. E. Application of the articulation index to the speech recognition of normal and impaired listeners wearing hearing protection. J Acoust Soc Am, (1990). 87, 1192–1199.
Williamson I. G., Dunleavey J., Bain J., et al. The natural history of otitis media
with effusion–a three-year study of the incidence and prevalence of abnormal tympanograms in four South West Hampshire infant and first schools. J Laryngol Otol, (1994). 108, 930–934.
Woellner R. C., Schuknecht H. F. Hearing loss from lesions of the cochlear nerve: An experimental and clinical study. Trans Am Acad Ophthalmol Otolaryngol, (1955). 59, 147–149.
Wong-Riley M. T., Walsh S. M., Leake-Jones P. A., et al. Maintenance of neuronal activity by electrical stimulation of unilaterally deafened cats demonstrable with cytochrome oxidase technique. Ann Otol Rhinol Laryngol Suppl, (1981). 90(2 Pt 3), 30–32.
Yehudai N., Most T., Luntz M. Risk factors for sensorineural hearing loss in pediatric chronic otitis media
. Int J Pediatr Otorhinolaryngol, (2015). 79, 26–30.
Yoshida H., Miyamoto I., Takahashi H. Relationship between CT findings and sensorineural hearing loss in chronic otitis media
. Auris Nasus Larynx, (2014). 41, 259–263.
Zhuang X., Sun W., Xu-Friedman M. A. Changes in properties of auditory nerve synapses following conductive hearing loss
. J Neurosci, (2017). 37, 323–332.