Otherwise unexplained, idiopathic listening difficulty (LiD) often is termed auditory processing disorder (APD) in children who have symptoms of difficulty hearing and understanding speech, and abnormal results on more complex auditory tests, despite having normal pure-tone hearing sensitivity (Jerger & Musiek 2000; Musiek et al. 2017). While there is an assumption that peripheral hearing status is “normal” in children presenting with LiD or APD, peripheral auditory function has rarely been assessed beyond pure-tone thresholds and single frequency tympanometry. LiD that impacts communication and academic performance is prevalent in young children, with at least 10% of primary school-aged children reported to have LiD, in association with speech-language and/or reading problems (Sharma et al. 2009). Based on the prevalence of normal hearing thresholds in referrals to audiologists for complaints of listening difficulty, the prevalence of LiD is estimated at 0.5 to 1% of the general population (Hind et al. 2011; Halliday et al. 2017). Thus, LiD is a clinically important childhood disorder, is associated with other common developmental disabilities, and urgently requires improved understanding of the underlying auditory deficits to devise appropriate treatment strategies.
Theoretically, “hearing” necessarily involves both “bottom-up” (ear to brain) and “top-down” (cortical to subcortical) pathways through simultaneous and sequential processing (Moore & Hunter 2013). Two general, mechanistic hypotheses for LiD with normal audiometry have been proposed since the 1970s. Sensory processing difficulties (bottom-up), involving the central auditory nervous system, were proposed in relation to animal and human lesion studies (Snow et al. 1977). Various proponents of this theory have advocated assessment with low-redundancy speech tests (using added noise, filtering, rapid speech, etc.) to stress the highly redundant central auditory pathways to reveal deficits (Keith 1995,2000; Cameron et al. 2014). Alternatively, LiD was proposed to be a problem of higher-level cognition or attention (top-down), especially in children with language disorders (Rees 1973; Moore et al. 2010). Individuals could have involvement of one or both mechanisms, and each may suggest different management needs, for example, remote microphone communication devices versus language and cognitive-behavioral training.
Pure-tone audiometry is, by definition, normal in children with LiD, yet few studies have performed detailed assessments of the peripheral auditory system. There are multiple complex aspects of middle and inner ear function that could affect LiD. Decreased sensitivity in the extended high frequencies (EHFs; >8 kHz), although not currently an exclusion criterion for LiD could result from pathology in the basal cochlea, as has been reported in association with chronic childhood otitis media with effusion (OME) and treated with pressure equalization (PE) tubes (Hunter et al. 1996; Laitila et al. 1997; Margolis et al. 2000; Gravel et al. 2006). These studies have found that frequencies above 4 kHz and up to as high as 20 kHz have poorer thresholds that persist after recovery of middle ear function, including tympanometry, high-frequency middle ear reflectance and bone conduction. The difference in thresholds increases with greater frequency, suggesting basal cochlear involvement. Because OME is a common childhood condition, poorer EHF hearing could be a basis for poorer speech perception, especially in noise, for children with histories of recurrent or chronic OME. Other possibilities that could selectively affect EHF include cochlear pathology caused by a genetic mutation (Rance et al. 2012; Moser et al. 2013; Wynne et al. 2013), noise trauma (Gopal et al. 2013; Sulaiman et al. 2013), ototoxicity (Stavroulaki et al. 1999), heavy metal exposure (Shargorodsky et al. 2011), viral infection (Foulon et al. 2012; Karltorp et al. 2012), or cochlear neuropathy (Bharadwaj et al. 2014). The EHF is usually not included in audiologic testing, so these conditions could be undetected despite complaints of hearing difficulties.
Better hearing thresholds in the region from 6 to 12.5 kHz (Besser et al. 2015; Levy et al. 2015) have been associated with better reception of speech in background noise. The converse could also be important in that threshold impairment in higher frequency regions could negatively impact speech perception (Motlagh Zadeh et al. 2019). In a study of frequency selectivity, temporal masking, and temporal fine structure, speech recognition was not related to audibility once high-frequency sensitivity differences across subjects (5–8 kHz) were removed statistically (Summers et al. 2013). Thus, high-frequency hearing loss appeared to be associated with distortions in lower-frequency processing.
Known sequelae of conductive loss include impaired spatial processing (Cameron et al. 2014) and binaural interaction (Hall et al. 1995; Hogan et al. 1996). Cochlear pathology may affect the endocochlear potential (Li & Steyger 2009), outer hair cells (Marler et al. 2010), inner hair cells (Stone et al. 2008), and spiral ganglion neurons (Sone et al. 1998), subsequently impairing processing within the central auditory nervous system. Any of these auditory system conditions could underpin symptoms of LiD, for example, impaired temporal processing, increased auditory filter width, or enhanced masking may lead to poor speech perception. In addition, efferent influences that in turn affect outer hair cell (OHC) function may be altered by auditory experience, for example, pathological midline pontine function (Bajo et al. 2010; Irving et al. 2011) or altered forebrain lateralization (Markevych et al. 2011).
As part of a much broader longitudinal study entitled “sensitive indicators of childhood listening difficulties” (SICLID), we tested the hypothesis that subtle, undetected peripheral hearing impairment occurs in children with LiD. Our approach was to compare highly sensitive peripheral auditory tests in age- and gender-matched groups of children with and without an underlying LiD, based on caregiver-report using the Evaluation of Children’s Listening and Processing Skills (ECLiPS) validated questionnaire (Barry et al. 2015) independent of a required diagnosis of APD. This design avoids the conundrum that there is no accepted consensus or gold standard diagnosis of APD (Wilson & Arnott 2013) and fulfills the requirement that the presenting auditory complaints are tightly linked to the condition, while outcome measures are independent of the inclusion criteria. This design further ensures that children with validated LiD comprise the experimental group, but makes no assumptions concerning the etiology of their difficulties, similar to other studies that emphasize clinical presentation of LiD (Cameron & Dillon 2007a, b, 2008; Dhamani et al. 2013). Previous research on LiD has been based mainly on either clinical speech-based tests (Sharma et al. 2009; Musiek et al. 2011) or a selection of psychoacoustic tests (Moore 2011). Here, we justified test selection by focusing on defined levels of peripheral processing (middle ear, cochlea, auditory nerve, brainstem, efferent pathways) and proven test sensitivity.
MATERIALS AND METHODS
The study was approved by the Cincinnati Children’s Hospital (CCH) Institutional Review Board (IRB). The broader SICLID study, encompassing many aspects of LiD, is longitudinal, occurring in “Waves” with repeated assessment every two years for enrolled children. This report concerns Wave 1, in a total of 114 children who completed the full audiologic test battery. The sample was divided into two groups. Children identified with LiD aged 6 to 14 years old at enrollment and typically developing (TD) children. The TD group was aged 6 to 14 years were age- and gender-matched by proportional sampling. The LiD participants were recruited initially from a medical record review study of over 1100 children assessed for APD at CCH (Moore et al. 2018). We initially attempted to enroll only children who met clinical criteria for APD (two or more SD below on two or more age-appropriate tests used for diagnosing APD). However, few children met these criteria for APD diagnosis, although some had received an audiology diagnosis of “APD weakness,” documented in the audiologist’s report. While including these children in the study, we defined the score on a standardized and validated parent questionnaire tool, the ECLiPS (see below), to assign children into each group in lieu of an APD diagnosis.
Some children with LiD and all TD children were recruited from flyers that were posted in relevant CCH clinics (Audiology, Pediatrics, Speech-Language Pathology) and emailed to all CCH employees and families interested in research. We maximized efforts to recruit children with APD diagnoses, including sending advertisements to audiology clinics within 300 miles, offering families travel costs for visits. Other IRB-approved social and community listings in the local and regional areas were distributed to broaden the sample. Interested caregivers completed eligibility screening for their children, consisting of a detailed medical and educational background questionnaire, and a questionnaire about the child’s history of noise exposure. The TD group completed a identical clinical and research testing as the LiD group and was required to have no significant LiDs, hearing loss, or major developmental diagnoses. Children reported to have major neurologic or cognitive dysfunction were excluded on the screening questionnaires. Parental permission and child assent using IRB-approved forms were obtained before any assessments. Pure-tone hearing sensitivity was required to be normal from 0.25 to 8 kHz at all frequencies (≤20 dB HL) for both groups at the time of the assessments. Of the 60 participants with LiD and normal hearing, 39 had been evaluated with a central auditory processing evaluation by the CCH audiology clinic, but only 16 (27% of the LiD participants) had received a positive diagnosis of APD. The remainder of the LiD group were recruited based on their ECLiPS scores.
To ascertain the presence of LiD, validated and normalized caregiver reports of listening skills were completed by parents using the ECLiPS questionnaire, following a referral from the audiology clinic, or by the parent that a child had auditory processing problems (Barry et al. 2015; Roebuck & Barry 2018). The ECLiPS profiles the participant’s listening and communication difficulties. The ECLiPS has 38 simple statements (items) describing behaviors commonly observed in children. Caregivers are asked to rate how much they agree with each statement on a five-point Likert scale ranging from strongly disagree to strongly agree. The ratings are averaged to derive scores, scaled by age, on five subscales (speech and auditory processing, environmental and auditory sensitivity, language/literacy/laterality, memory and attention, and pragmatic and social skills) each containing 6 to 9 distinct items. A standardized total composite score can also be calculated; this total score forms the basis of data analysis in this study. In general, total standardized ECLiPS scores of ≥7 defined the TD group, and scores <7 (less than all TD children) defined the LiD group. However, there were four children with LiD who had a previous audiologic diagnosis of APD, that scored 7 (×3) or 9 (×1) on the ECLiPS. Because they had a diagnosis of APD, they were assigned to the APD group. The summary ECLiPS scores are shown in Table 1.
TABLE 1. -
Study Sample Characteristics for All Participants, Subdivided for the TD and the LiD Groups
All participants’ parents completed a comprehensive background questionnaire regarding the educational level of both parents, ethnicity, race, child and family history of hearing or listening problems, child histories of otitis media, PE tube surgeries, noise exposures, head injuries, prematurity, vision problems, diagnoses related to auditory, speech, language, psychology, educational and cognitive/development, therapy provided in each of these areas, and medications taken presently and in the past. Histories of PE tube surgery, diagnoses, and therapy reports were verified by an independent medical record review. The history of PE tubes reported by parents agreed with the medical record in 94.7% of cases.
Several additional tests were completed in the SICLID study, including auditory processing, speech perception, cognition, brainstem and cortical evoked responses, and structural and functional MRI that are beyond the scope of this analysis, and will be reported in subsequent articles.
Otoscopy was completed and if necessary, cerumen was removed before audiometry. All audiometric tests were completed in a double-walled soundproof booth (Industrial Acoustics Company, North Aurora, IL) that meets standards for acceptable room noise for audiometric rooms [ANSI/ASA 1999 (R2018)]. Standard and EHF (10–16 kHz) thresholds were measured using the manual Hughson–Westlake method for the range of 0.25 to 8 kHz at octave intervals and at four additional frequencies (10, 12.5, 14, and 16 kHz) using the Equinox audiometer (Interacoustics Inc., Middlefart, Denmark) with Sennheiser 300 HDA circumaural earphones (Old Lyme, CT). If any air conduction thresholds were greater than 20 dB HL, bone conduction was tested between 0.5 and 4 kHz using appropriate narrowband masking in the contralateral ear (Radioear Inc. B-71 bone vibrator, New Eagle, PA).
Middle Ear Measures
Wideband tympanometry (acoustic absorbance and group delay) was measured using click stimuli and analysis from 0.25 to 8 kHz over an ear canal pressure of +200 to −400 daPa using a custom recording system (Keefe et al. 2015) coupled to an AT235 immittance system (Interacoustics Inc., Middlefart, Denmark) to control air pressure. The wideband tympanometry technique is more sensitive and specific than standard clinical testing to many conductive disorders including OME, because it measures the full range of frequencies important for speech perception (Hunter et al. 2013). This technique has also been used to interpret high-frequency hearing thresholds (Margolis et al. 2000) and cochlear measures with respect to possible middle ear effects (Carpenter et al. 2012).
Middle Ear Muscle Reflexes
To assess the auditory afferent and efferent loop, middle ear muscle reflexes (MEMRs) were measured using a wideband absorbance technique. The wideband MEMR technique provides lower thresholds due to the more sensitive absorbance measurement across a range of frequencies activated by the middle ear muscle, it incorporates signal averaging to reduce contamination by noise, and it is automated for detection of the reflex based on both changes in absorbance and cross correlation of repeated stimuli (Feeney et al. 2017; Hunter et al. 2017b). Thus, the subjective bias that may be problematic in visual judgment of typical admittance-based MEMR procedures and lack of signal averaging to decrease noise contamination is improved. Details regarding the measurement and analysis procedures may be found in Keefe et al. (2017). Briefly, broad band noise (BBN) and pure-tone stimuli (0.5, 1, and 2 kHz) were presented both ipsilaterally and contralaterally while absorbance changes were monitored using a click stimulus to measure absorbance changes in the ear with a microphone. Ear canal air pressure was adjusted to the peak tympanometric pressure obtained during wideband tympanometry. To record responses, probe clicks were averaged across four stimuli, varying in 5-dB steps from 60 to 120 dB peSPL calibrated in a 2-cc coupler and in the real ear. Contralateral and ipsilateral MEMR testing used response averaging, artifact rejection and signal processing techniques to measure threshold, onset latency, and amplitude growth.
Activity in the cochlear partition was assessed using two different types of otoacoustic emissions. Distortion Product Otoacoustic Emissions (DPOAE; 1/3 octaves from 2 to 10 kHz) were measured with paired tones (f2 and f1) presented at 65- and 55-dB SPL, with an f2/f1 frequency ratio of 1.22 using an Interacoustics Titan system (Interacoustics Inc., Middlefart, Denmark). The DPOAE signal and noise level were measured at DPOAE frequency of 2f1–f2 in descending order at 10 f2 frequencies (10, 9.0, 8.2, 7.5, 6.2, 5.1, 3.8, 3.2, 2.6, and 2.1 kHz). The signal-to-noise ratio (SNR) was calculated by subtracting the DPOAE noise level from the DPOAE level at each f2 test frequency.
Chirp transient-evoked otoacoustic emissions (TEOAEs) were measured using an experimental system that employed positive swept (low to high frequencies) chirp stimuli, coupled with double-evoked methods to allow broader-frequency recording from 1 up to 14.7 kHz than is possible using commercial TEOAE systems (Keefe et al. 2019). The double-evoked method removes stimulus artifact, allowing recording at higher frequencies, and the chirp stimuli reduce distortion at higher intensity levels because the stimulus is extended in duration compared with click stimuli. Two chirp stimuli were used; the first covered the standard frequency range (0.5–8 kHz, 78 dB peSPL) and the second covered extended high frequencies (8–14.7 kHz, at 76 and 82 dB peSPL to test a lower and higher intensity), referenced to a click. Both stimuli were delivered at a sweep frequency rate of 188 Hz/ms. The maximum level was limited to 9 dB below the stimulus level that resulted in any system distortion measured in a long, reflection-free cylindrical tube (Keefe et al. 2019). TEOAE responses were measured using an Etymotic ER10B+ microphone, a pair of ER2 sound sources and a sound card at the 44-kHz sample rate (Card Deluxe), controlled by a custom program written in MATLAB.
Recordings were analyzed during each session for artifacts and noise, and repeated if necessary, during the same session after taking care to obtain the best probe insertion and quietest condition possible. Data were exported for each individual ear and condition, then were analyzed visually for recording errors and artifacts. If the test had been repeated, the cleanest recordings (lowest noise and artifact) were selected for further analysis employing SAS statistical software, version 9.3 (SAS Institute, Cary, NC). A two-sided significance level was set at p <0.05.
Results were analyzed first with descriptive statistics to summarize sample demographics and outcome measurements. The interval variables were summarized by central tendency and dispersion, and categorical variables were described by frequencies and percentages. Two-sample t-tests, Chi-Square, and Fisher Exact tests were performed to compare the demographics between the children with LiD and TD. Boxplots were created to study the distribution of the outcomes. Outcome variables were analyzed first in univariate, then multivariate mixed models that included Group (TD or LiD), age at EHF testing, sex, race, PE tube history, and EHF hearing loss as independent factors. The Pearson correlation coefficient was calculated to explore the relationship among the outcomes. A repeated measure analysis of variance using frequency as the repeated measure was conducted to study outcome differences between the LiD and TD group controlling for the above factors. Significant factors from the univariate analysis and between group demographics were included in the final multiple adjusted model, including significant interaction effects. The best variance-covariance structure was chosen by model fitting comparisons. The Tukey–Kramer multiple adjustment was applied for pairwise comparisons among the levels of the significant factors. In addition to the group analysis, the entire sample (LiD and TD) was also analyzed using multiple regression including the ECLiPS score as a continuous variable, race, maternal education level, and history of tubes. Covariates that were marginally significant were retained in the final model, while the ECLiPS score was retained in all regression analyses, as it was the primary question of interest.
As shown in Table 1, this report includes 114 children with a mean age of 9.9 years (SD = 1.99), ranging from 6.5 to 14.6 years. There were 60 children with LiD and 54 TD children, with equivalent ages for the two groups. Boys comprised the majority in both groups and the sex proportion was not significantly different in the LiD compared to TD group. The majority race was white in both groups, although significantly more so in the TD group, with more African American children in the LiD group. There was no group difference in Hispanic (Latino) ethnicity. There was not a significant group difference in the reported history of ear infections, or in treatment with PE tubes, reported in 28% of the LiD group and 22% of the TD group. In the LiD group, five children had two or more surgeries for PE tubes, while in the TD group, three had two or more PE tube surgeries.
Tone thresholds of individuals across audiometric frequencies were significantly (p < 0.05) correlated with each other (r = 0.22–0.76) except for the frequency pairs of 0.25 kHz versus 10 through 16 kHz (r = 0.13, p = 0.1832) and 2 versus 8 kHz (r = 0.15, p = 0.1232). Generally, the closer the frequencies were, the stronger the intercorrelation coefficient. After controlling for significant factors in the statistical model, the least square means of the audiometric thresholds at EHFs were significantly higher than at lower frequencies. For this reason and due to significant intercorrelation, the four EHFs (10, 12.5, 14, and 16) were averaged for further analysis. No significant proportional difference (p = 0.6816) was found between left and right ears in terms of EHF hearing level of >20 dB HL (X2 = 0.1683), thus the right and left ears were averaged for each child for further analysis.
Mean thresholds for standard and EHF audiometry for the TD compared with the LiD group are shown in Fig. 1A, including 95% confidence intervals. No significant difference was found in the overall hearing thresholds for group in the unadjusted or adjusted model (see Table 2). However, the interaction with frequency (group*frequency) was significant (p = 0.0322) in the adjusted model, as the average hearing thresholds were not parallel for the two groups (Fig. 1A). The interaction factor showed that the lowest frequencies (0.25–1 kHz) were actually a bit better in the LiD group, and then reversed to be worse at 8 to 16 kHz compared with the TD group. There was a highly significant effect of PE tube history as shown in Fig. 1B (p < 0.0001), with poorer hearing thresholds (0.5–16 kHz) for children with a history of PE tubes (across both groups), and the difference increased with frequency (Fig. 1B). The overall results of multivariate repeated measure analysis of variance models are provided in Table 2. In addition to the group analysis, a multivariate regression analysis was performed using the ECLiPS score as a continuous variable, along with audiogram test frequency, race, maternal education, and history of PE tubes. The ECLiPS score, race, and maternal education were not significantly related to EHF hearing thresholds; the regression analysis confirmed that the only significant predictive factor for audiometric thresholds was history of PE tubes (Table 3, p < 0.0001).
TABLE 2. -
Summary of Multivariate Analyses, With p
Values and F-test (DF) From the Adjusted Repeated Measures Analysis (N = 114)
||Age at EHF
||Hx of Tubes
| Standard and EHF
F (DF = 111)
| Ambient Pressure
F (DF = 97)
| Peak pressure
F (DF = 97)
| Group delay
F (DF = 96)
F (DF = 97)
F (DF = 97)
| Signal level
F (DF = 107)
F (DF = 107)
| SNR (1–8 kHz)
F (DF = 95)
| SNR (8–14.25 kHz)
F (DF = 95)
Only the factors that were included in the final models are shown. Note: Sex and race were insignificant for all univariate analyses, so were not included in the multivariate models. Variables not in the final model do not include F. p-values <0.05 are italicized.
DF indicates degrees of freedom; DPOAE, distortion product otoacoustic emission; EHF, extended high frequency; MEMR, middle ear muscle reflex; SNR, signal-to-noise ratio; TEOAE, transient-evoked otoacoustic emissions.
TABLE 3. -
Results of Regression Analysis for Both Groups Combined for Univariate and Multivariate Adjusted Models
||Univariate Regression p Values
||Multivariate Adjusted p Values
|Frequency, ECLiPS scaled score, race, history of tubes, maternal education level
||Frequency, ECLiPS scaled score, history of tubes
|Averaged EHF hearing thresholds; 10–16 kHz
||N.A., 0.2034, 0.8980, <0.0001, 0.8376
||N.A., 0.1448, <0.0001
|Wideband acoustic reflexes, contralateral; BBN, 1, 2, 4 kHz
||<0.0001, 0.3189, 0.5914, 0.0126, 0.0980
||<0.0001, 0.5109, 0.015
|DPOAE levels; 2–10 kHz
||<0.0001, 0.2897, 0.5684, 0.0006, 0.6532
||<0.0001, 0.2831, 0.0005
|TEOAE SNR; 0.7–8 kHz
||<0.0001, 0.0858, 0.7604, <0.0001, 0.5750
||<0.0001, 0.0480, <0.0001
|TEOAE SNR; 8–14.2 kHz
||<0.0001, 0.3470, 0.1302, 0.0835, 0.3674
||<0.0001, 0.8844, 0.1064
DPOAE indicates distortion product otoacoustic emission; EHF, extended high frequency; MEMR, middle ear muscle reflex; N.A., not applicable; SNR, signal-to-noise ratio; TEOAE, transient-evoked otoacoustic emissions.
Wideband acoustic absorbance
Wideband acoustic absorbance (Fig. 2) was analyzed at ambient pressure (equivalent room air pressure, Fig. 2A) and at tympanometric peak pressure (TPP) to equilibrate for any pressure differences due to Eustachian tube function. The correlation coefficients indicated significant correlations among most ambient absorbance frequencies, and the closer the frequencies were, the stronger the correlation.
In multivariate analyses, there were no significant differences in wideband acoustic absorbance at ambient pressure (p = 0.2208), or at TPP (p = 0.4211) for the TD compared with the LiD group. There was a significant interaction between group and frequency for ambient wideband absorbance (p = 0.0193) due to slightly higher absorbance at 1.5 kHz and slightly lower absorbance at 4 kHz for the LiD group. Age was not significantly associated with ambient absorbance measurements in the adjusted analyses, but there was a significant age by frequency interaction (p < 0.0001).
A history of PE tubes was not significant for ambient absorbance (p = 0.8129) or at TPP (p = 0.8912, Fig. 2B) in multivariate analyses, although in univariate analyses, there was higher absorbance for the ears with PE tube histories in the 1.5 to 2 kHz range. There were also no significant effects of age, sex, race, or the presence of EHF hearing loss on wideband absorbance at ambient pressure or at TPP in the multivariate models (see Table 2 for p values).
Wideband Acoustic Group delay
Group delay is a measure of the phase angles of the acoustic absorbance across various frequencies and reveals the influence of middle ear mechanics on transmission of the stimulus through the middle ear. Increased group delay in sound transmission occurs in ears that have more flaccidity, while shorter group delay occurs due to greater stiffness in the middle ear. As shown in Fig. 3A, there was no significant difference between LiD and TD groups for group delay at ambient pressure. The main effect of frequency was highly significant (p < 0.0001), and the within subject test indicated that the interaction of frequency and group was also highly significant (p < 0.0001). This interaction was due to a few frequencies that were higher in the TD group, indicating more stiffness at those frequencies. A history of tubes was significantly associated with group delay measurements in both unadjusted and adjusted analyses (Fig. 3B; p = 0.0026), as was the presence of EHF hearing loss (p = 0.0002). The correlation coefficients indicated significant correlations among the group delay measurements, and the closer the frequencies were, the stronger the correlation. Age was not significantly associated with group delay measurements in the adjusted analysis, but there was an interaction between age and frequency (p = 0.001).
There was no significance difference between TD and LiD groups as shown in Fig. 4A for the ipsilateral condition and Fig. 4B for the contralateral condition. The main effect of frequency was significant for both the ipsilateral and contralateral conditions (p <0.0001) among the BBN and pure-tone stimuli, but there was no significant interaction of frequency and group.
As shown in Fig. 4B, significantly higher contralateral MEMR thresholds were found for ears with EHF hearing loss for BBN, 1 and 2 kHz stimuli both ipsilaterally (p = 0.0152) and contralaterally (p = 0.0051). No significant difference was found between LiD and TD groups for wideband MEMR thresholds for BBN, 0.5, 1, or 2 kHz for ipsilateral or contralateral presentation modes. In the regression analysis, the ECLiPS score was not a significant predictor of MEMR function (p = 0.5109); only history of PE tubes (p = 0.015) and test frequency (BBN, 0.5, 1, and 2 kHz) remained in the final predictive model (Table 3).
Distortion Product Otoacoustic Emissions
There was no significant TD-LiD group difference for the DPOAE level in the multivariate analyses (p = 0.1482), consistent with the lack of audiometric threshold differences (Fig. 5A). However, for both groups combined, children with PE tube histories had significantly lower (poorer) DPOAE levels at most frequencies from 2 to 10 kHz (p = 0.0217), as shown in Fig. 5C. The signal-to-noise ratio (SNR) was lower for the LiD group (Fig. 5B; p = 0.0366) and in ears with PE tube history at most frequencies from 3.8 to 10 kHz (Fig. 5D; p = 0.0010). The DPOAE level and SNR were lower at 3 to 6 kHz in ears with EHF hearing loss (Fig. 5E, F). These effects are generally consistent with the higher-frequency hearing threshold data, and with a cochlear etiology for the EHF hearing loss. In the regression analysis for the DPOAE signal level, the ECLiPS score was not a significant predictor (p = 0.2831). Only history of PE tubes (p < 0.0001) and DPOAE frequency (f2; p < 0.0001) remained in the final predictive model (Table 3).
Transient-evoked Otoacoustic Emissions
TEOAE SNR for LiD compared with TD cases was not significantly different (p = 0.1492; Fig. 6). Chirp-evoked TEOAE SNR was significantly lower in ears with PE tube history (p = 0.0116; Fig 6A) as well as for cases with EHF hearing loss (p < 0.0001; Fig. 6B). Thus, chirp-evoked TEOAEs at standard and EHF were consistent with the DPOAE and EHF threshold effects found in ears with a history of PE tubes. In the regression analysis for TEOAE SNR, the ECLiPS score and demographic factors were not significant from 0.7 to 8 kHz (p = 0.0858) and from 8 to 14.2 kHz (p = 0.3470). Only a history of PE tubes (p < 0.0001, 0.0835 for <8 and ≥ 8 kHz, respectively) and TEOAE frequency (p < 0.0001) were significant in the final predictive model (Table 3).
To further examine relationships between OAE results and hearing sensitivity, multivariate canonical correlation analysis was used to test the overall relationships between the two sets of variables. Corresponding variable pairs were chosen at the closest frequencies for DPOAE F2 frequencies versus audiometric frequencies, and for TEOAE frequencies versus audiometric frequencies. Wilk’s lambda indicated that there was a significant relationship between TEOAE SNR and hearing thresholds (Wilks’ Lambda = 0.36, F [64, 594.8] = 1.78, p = 0.0003). TEOAE and hearing thresholds were negatively associated according to the correlations between the hearing thresholds and their canonical variables. The first canonical correlation coefficient was 0.62 (adjusted = 0.56) with an eigenvalue of 0.63. The shared variance between TEOAE and hearing thresholds was 38.7%. Wilk’s lambda indicated that there was also a significant relationship between DPOAE SNR and hearing thresholds [Wilk’s Lambda = 0.72, F [16, 648.3] = 4.60, p < 0.0001). DPOAE SNR and hearing thresholds were negatively associated according to the correlations between DPOAE SNR and their canonical variables. The first two canonical correlation coefficients were 0.45 and 0.28 (adjusted = 0.54 and 0.08) with eigenvalues of 0.26 and 0.08. The total shared variance between DPOAE SNR and hearing thresholds was 28.2% (20.5 + 7.7%).
The main aim of the current study was to determine if evidence for previously undetected peripheral hearing impairment occurs in children with defined LiD, and to explore other factors (PE tube history, sex, race, and maternal education) that may relate to their listening difficulties. The literature on peripheral hearing mechanisms in children with LiD is scant, and mostly consists of anecdotal or individual case reports. There is clearly an effect of even mild peripheral hearing loss in early childhood on speech-in-noise hearing and various aspects of cognition (Moore et al. 2019), including speech and language development (Tomblin et al. 2015), selective attention (Holmes et al. 2017), social use of language (Meinzen-Derr et al. 2014), and literacy (Harris et al. 2017). However, a specific linkage to LiD (also known as APD) and peripheral hearing has been difficult to ascertain because, by definition, APD pertains to normal audiologic results. The major finding of this study is that across a range of highly sensitive peripheral auditory tests, there was no difference between TD and LiD groups. It is important to point out that children with mild or greater pure-tone hearing thresholds were excluded in both groups, although that condition was infrequent (about 5%) among children referred to the study with APD or listening problems. Because LiD is clearly the hallmark of peripheral hearing loss, only after excluding hearing loss, as routinely excluded in current APD definitions (standard pure-tone audiometric thresholds), could we conclude that other subtle peripheral auditory dysfunction does not explain their listening problems.
We identified EHF hearing loss in a subgroup of children in both the LiD and TD groups which was specific to histories of PE tubes. About 32% of the children with listening difficulties and 20% of the TD group had elevated EHF hearing thresholds. However, this was not a significant difference in the proportion with EHF thresholds greater than 20 dB HL. As has been shown previously in multiple studies (Hunter et al. 1996; Laitila et al. 1997; Margolis et al. 2000; Gravel et al. 2006), EHF HL is associated with OME and PE tube histories in prospective studies of children. EHF HL in OME is related to the number of PE tubes and the severity of OME (Hunter et al. 1996). Animal studies of experimentally induced OME have shown that the mechanism for EHF hearing loss is round window transmission of bacterial endotoxins with basilar cochlear damage (Morizono et al. 1980; Paparella et al. 1984; Schachern et al. 2008). Inner ear morphology shows pathologic changes in the stria vascularis, suggesting it is a target of otitis media-induced damage, which may lead to sensorineural hearing loss (Tsuprun et al. 2008).
Hearing acuity above 8 kHz has been reported to be related to some aspects of challenging speech perception in competing spatial conditions in adults (Besser et al. 2015), but less information has been available regarding speech perception in children with EHF hearing loss. The unique aspect of the current study is the focus on children with LiD, rather than a history of OME, yet our primary finding was that children who had OME severe enough to be treated with PE tubes were the ones with poorer EHF hearing. The EHF hearing loss was also associated with OAE results, that is, poorer EHF hearing that increased with higher frequencies for cases with PE tube histories, consistent with the previous studies cited above, for example, outer hair cell effects due to the audiometric threshold configuration in the basal region of the cochlea.
We studied wideband absorbance as a measure of energy transfer into and through the middle ear across a range of frequencies. Increased absorbance corresponds to increased middle ear transmission and occurs in conditions such as ossicular erosion, where impedance is reduced, while decreased absorbance occurs in middle ear disorders such as OME that increase impedance of the middle ear. The LiD group did not have significantly different wideband absorbance compared with the TD group, indicating similar middle ear function across frequencies. However, PE tube history was again implicated, and was associated with increased wideband acoustic absorbance. The frequency region of increased absorbance in the PE tube group was not consistent with EHF hearing loss in ears with PE tube histories, because the frequency region and direction of the effect (increased absorbance with poorer hearing thresholds) were opposite to that expected. These absorbance effects were thus mechanical and restricted to the lower frequency region, in contrast to the EHF and OAE effects that are higher in frequency. Similarly, increased group delay in the lower frequencies was found for ears with a history of PE tubes. Consistent with the effect on wideband absorbance, increased group delay in the low-frequency range indicates increased eardrum flaccidity, a result of PE tube surgery (Hunter et al. 2017a). Thus, our interpretation is that increased absorbance and group delay are consistent with previous myringotomy to place PE tubes, resulting in increased flaccidity of the TM.
Otoacoustic emissions, both transient and distortion products, are affected when active OME is present at the time of measurement (Yeo et al. 2002). OAEs are recognized as a highly reliable method of screening and monitoring hearing changes associated with conductive loss due to OME (Ho et al. 2002; Hunter et al. 2017a). However, no previous reports were found that linked high-frequency OAE differences to LiD, or to histories of PE tubes and OME. In this study, the LiD group did not have lower DPOAE levels or SNRs compared with the TD group, consistent with their behavioral hearing thresholds and indicating that pure-tone hearing sensitivity was not related to parent complaints of LiD. However, for ears with a history of PE tubes and for those with EHF hearing loss, DPOAE levels and SNR were lower, with a significant relationship between TEOAE levels and hearing thresholds at similar frequencies. Thus, a novel finding in this study is that OAEs appear to be a sensitive measure of the impact upon cochlear function in children with poorer EHF hearing. Thus, the inclusion of OAE assessment is warranted to supplement pure-tone audiometry due to the brief and noninvasive nature of this test.
Chirp TEOAEs provide information about the reflection component of OAE generation, while DPOAEs are generated by primarily the distortion component, thus we included both emission types. The use of HF TEOAEs (>4 kHz), a first in any study for children with LiD, provides a physiological assessment of OHC function in the basal region of the basilar membrane, which is of relevance to the EHF hearing loss found in a subset of children in both groups. Suppression experiments in human ears provide evidence that TEOAEs are mainly generated near the tonotopic region of the stimulus (Zettner & Folsom 2003; Keefe et al. 2008), making them attractive for detection of OHC damage in the frequency region of both the stimulus and response. Chirp and click TEOAEs have similar properties across stimulus conditions for stimuli with the same energy spectrum, but click stimuli used to measure TEOAEs can generate system distortion at higher levels due to peak clipping by the sound source. The use of chirp stimuli to measure TEOAEs has the advantage of spreading the stimulus energy out over time so as to reduce the peak levels that generate distortion (Neumann et al. 1994). In this study, we found significant decreases in chirp TEOAE SNR at frequencies ≥8 kHz that were present in cases with PE tube history and with EHF hearing loss, and a significant relationship between TEOAE levels and hearing thresholds at similar frequencies. Interestingly, the effect was specific to EHF regions, strengthening the evidence that these effects were due to cochlear damage, rather than middle ear dysfunction.
MEMR threshold elevation for BBN and pure-tone stimuli was found specifically in the contralateral condition in ears that had PE tube histories and with poorer EHF hearing. This finding implicates efferent activation in the children who had a history of OME treated with tubes. This implies a central (brainstem) rather than a peripheral afferent mechanism; otherwise, ipsilateral effects would be expected. Ipsilateral MEMR should be at least as sensitive as contralateral measurement because lower thresholds are found with ipsilateral measurement. In other words, the ipsilateral measurement is less affected by stimulus output limitations. These MEMR results are consistent with a previous prospective study showing that frequent OME history in children was associated with elevated MEMR threshold for contralateral acoustic reflexes (Gravel et al. 2006). Thomas et al. (1985) reported that one-third of children with delays in language, learning disabilities, or suspected APD showed abnormal MEMR thresholds in both the ipsilateral and contralateral condition, and there was a slight positive correlation with delayed psychomotor development, but no control group was compared. Allen and Allan (2014) reported no significant difference in MEMR thresholds between a group of children diagnosed with APD compared with a group that passed APD tests, although both groups had absent MEMR reflexes in about 20% of cases. The Allen and Allan study did not include a normal control group, but a later study by the same group (Saxena et al. 2015) investigated acoustic reflex growth functions in “suspected APD” and control groups, and found shallower growth of the reflex in children suspected with APD. The present study utilized a more sensitive and reliable wideband absorbance measure to detect MEMR thresholds for both pure-tone and broadband noise stimuli, as well as a typically developing control group, yet our results did not show differences in children with LiD compared with controls. A bias that can occur in MEMR measures is a subjective interpretation of reflex presence. A strength of the technique used in the current study is the automatic detection algorithm that includes correlation and amplitude rules that objectify the presence of the acoustic reflex, quantify growth characteristics, and score threshold.
Overall, the results of this study in a carefully controlled sample of children with validated LiD compared with an age- and sex-matched typically developing control group showed no significant differences in peripheral function using highly sensitive measures, including EHF hearing thresholds, DPOAEs, chirp TEOAEs, wideband tympanometry, and wideband MEMR thresholds. In subgroups examining risk factors, EHF hearing thresholds were found to be highly associated with PE tube history. Furthermore, middle ear acoustic absorbance, DPOAE, TEOAE, and contralateral MEMR threshold differences were all significantly associated with PE tube histories and with EHF hearing. However, these findings did not appear to explain LiD, because these effects were also present in TD children with tube histories. To further explore factors related to LiD, we carried out additional analysis using the ECLiPS score as a continuous variable across both groups and added maternal education level as a demographic factor along with the factors found to be significant in the group analysis. The regression analysis was consistent with the group analysis, and again showed that PE tube history, not severity of the ECLiPS score, was the primary predictive factor across all the peripheral function tests.
Although we did not uncover peripheral hearing deficits that were specifically associated with LiD, we recommend that peripheral dysfunction be assessed in any child presenting with listening problems to determine whether potentially remediable peripheral hearing problems may be present. The inclusion of pure-tone thresholds above 8 kHz, OAE and acoustic reflex measures are quick and inexpensive measures that can ensure that hearing issues are fully investigated in such cases. Recurrent OME and tubes are a frequent occurrence in children, especially those with listening problems. A major result of this study is that these tests are sensitive to those histories. Although peripheral hearing problems may not be the primary cause of LiD, diagnostic audiologists are in the best position to uncover auditory system deficits and to provide appropriate remediation to lessen any additional impact to a child’s learning challenges.
Thanks to Douglas Keefe for providing the wideband immittance software and consultation in this study. We also thank our participating families and UC as well as Summer Undergraduate Research Foundation (SURF) scholars.
Allen P., Allan C. (Auditory processing disorders: relationship to cognitive processes and underlying auditory neural integrity. Int J Pediatr Otorhinolaryngol, 2014). 78, 198–208
ANSI/ASA. (Maximum permissible ambient noise levels for audiometric test rooms.In: American National Standards Institute1999 (R2018)). S3.1-1999Washington, DCAcoustical Society of America
Bajo V. M., Nodal F. R., Moore D. R., King A. J. (The descending corticocollicular pathway mediates learning-induced auditory plasticity. Nature Neurosci, 2010). 13, 253–260
Barry J. G., Tomlin D., Moore D. R., Dillon H. (Use of questionnaire-based measures in the assessment of listening difficulties in school-aged children. Ear Hear, 2015). 36, e300–e313
Besser J., Festen J. M., Goverts S. T., Kramer S. E., Pichora-Fuller M. K. (Speech-in-speech listening on the LiSN-S test by older adults with good audiograms depends on cognition and hearing acuity at high frequencies. Ear Hear, 2015). 36, 24–41
Bharadwaj H. M., Verhulst S., Shaheen L., Liberman M. C., Shinn-Cunningham B. G. (Cochlear neuropathy and the coding of supra-threshold sound. Front Syst Neurosci, 2014). 8, 26
Cacace A. T., McFarland D. J. (Factors influencing tests of auditory processing: A perspective on current issues and relevant concerns. J Am Acad Audiol, 2013). 24, 572–589
Cameron S., Dillon H. (Development of the listening in spatialized noise-sentences test (LISN-S). Ear Hear, 2007a). 28, 196–211
Cameron S., Dillon H. (The listening in spatialized noise-sentences test (LISN-S): test-retest reliability study. Int J Audiol, 2007b). 46, 145–153
Cameron S., Dillon H. (The listening in spatialized noise-sentences test (LISN-S): Comparison to the prototype LISN and results from children with either a suspected (central) auditory processing disorder or a confirmed language disorder. J Am Acad Audiol, 2008). 19, 377–391
Cameron S., Dillon H., Glyde H., et al. (Prevalence and remediation of spatial processing disorder (SPD) in indigenous children in regional Australia. Int J Audiol, 2014). 53, 326–335
Carpenter M. S., Cacace A. T., Mahoney M. J. (Missing links in some curious auditory phenomena: A tale from the middle ear. J Am Acad Audiol, 2012). 23, 106–114
Dhamani I., Leung J., Carlile S., Sharma M. (Switch attention to listen. Sci Rep, 2013). 3, 1297
Feeney M. P., Keefe D. H., Hunter L. L., Fitzpatrick D. F., Garinis A. C., Putterman D. B., McMillan G. P. (Normative wideband reflectance
, equivalent admittance at the tympanic membrane, and acoustic stapedius reflex threshold in adults. Ear Hear, 2017). 38, e142–e160
Foulon I., Naessens A., Faron G., Foulon W., Jansen A. C., Gordts F. (Hearing thresholds in children with a congenital CMV infection: A prospective study. Int J Pediatr Otorhinolaryngol, 2012). 76, 712–717
Gopal K. V., Chesky K., Beschoner E. A., Nelson P. D., Stewart B. J. (Auditory risk assessment of college music students in jazz band-based instructional activity. Noise Health, 2013). 15, 246–252
Gravel J. S., Roberts J. E., Roush J., Grose J., Besing J., Burchinal M., Neebe E., Wallace I. F., Zeisel S. (Early otitis media with effusion, hearing loss, and auditory processes at school age. Ear Hear, 2006). 27, 353–368
Hall J. W. III, Grose J. H., Pillsbury H. C. (Long-term effects of chronic otitis media on binaural hearing in children. Arch Otolaryngol Head Neck Surg, 1995). 121, 847–852
Halliday L. F., Tuomainen O., Rosen S. (Auditory processing deficits are sometimes necessary and sometimes sufficient for language difficulties in children: Evidence from mild to moderate sensorineural hearing loss. Cognition, 2017). 166, 139–151
Harris M., Terlektsi E., Kyle F. E. (Literacy outcomes for primary school children who are deaf and hard of hearing: A cohort comparison study. J Speech Lang Hear Res, 2017). 60, 701–711
Hind S. E., Haines-Bazrafshan R., Benton C. L., Brassington W., Towle B., Moore D. R. (Prevalence of clinical referrals having hearing thresholds within normal limits. Int J Audiol, 2011). 50, 708–716
Ho V., Daly K. A., Hunter L. L., Davey C. (Otoacoustic emissions and tympanometry screening among 0-5 year olds. Laryngoscope, 2002). 112, 513–519
Hogan S. C., Meyer S. E., Moore D. R. (Binaural unmasking returns to normal in teenagers who had otitis media in infancy. Audiol Neurootol, 1996). 1, 104–111
Holmes E., Kitterick P. T., Summerfield A. Q. (Peripheral hearing loss reduces the ability of children to direct selective attention during multi-talker listening. Hear Res, 2017). 350, 160–172
Hunter L. L., Keefe D. H., Feeney M. P., Brown D. K., Meinzen-Derr J., Elsayed A. M., Amann J. M., Manickam V., Fitzpatrick D., Shott S. R. (Wideband acoustic immittance in children with Down syndrome: prediction of middle-ear dysfunction, conductive hearing loss and patent PE tubes. Int J Audiol, 2017a). 56, 622–634
Hunter L. L., Keefe D. H., Feeney M. P., Fitzpatrick D. F. (Pressurized wideband acoustic stapedial reflex thresholds: Normal development and relationships to auditory function in infants. J Assoc Res Otolaryngol, 2017b). 18, 49–63
Hunter L. L., Margolis R. H., Rykken J. R., Le C. T., Daly K. A., Giebink G. S. (High frequency hearing loss associated with otitis media. Ear Hear, 1996). 17, 1–11
Hunter L. L., Prieve B. A., Kei J., Sanford A. J. (Pediatric applications of wideband acoustic immittance measures. Ear Hear, 2013). 34(Suppl 1), 36S–42S
Irving S., Moore D. R., Liberman M. C., Sumner C. J. (Olivocochlear efferent control in sound localization and experience-dependent learning. J Neurosci, 2011). 31, 2493–2501
Jerger J. (On the diagnosis of auditory processing disorder (APD). J Am Acad Audiol, 2009). 20, 1p preceding 161
Jerger J., Musiek F. (Report of the consensus conference on the diagnosis of auditory processing disorders in school-aged children. J Am Acad Audiol, 2000). 11, 467–474
Karltorp E., Hellström S., Lewensohn-Fuchs I., Carlsson-Hansen E., Carlsson P. I., Engman M. L. (Congenital cytomegalovirus infection - a common cause of hearing loss of unknown aetiology. Acta Paediatr, 2012). 101, e357–e362
Keefe D. H., Ellison J. C., Fitzpatrick D. F., Gorga M. P. (Two-tone suppression of stimulus frequency otoacoustic emissions. J Acoust Soc Am, 2008). 123, 1479–1494
Keefe D. H., Feeney M. P., Hunter L. L., Fitzpatrick D. F. (Aural acoustic stapedius-muscle reflex threshold procedures to test human infants and adults. J Assoc Res Otolaryngol, 2017). 18, 65–88
Keefe D. H., Feeney M. P., Hunter L. L., Fitzpatrick D. F., Blankenship C. M., Garinis A. C., Putterman D. B., Wroblewski M. (High frequency transient-evoked otoacoustic emission measurements using chirp and click stimuli. Hear Res, 2019). 371, 117–139
Keefe D. H., Hunter L. L., Feeney M. P., Fitzpatrick D. F. (Procedures for ambient-pressure and tympanometric tests of aural acoustic reflectance and admittance in human infants and adults. J Acoust Soc Am, 2015). 138, 3625–3653
Keith R. W. (Development and standardization of SCAN-A: test of auditory processing disorders in adolescents and adults. J Am Acad Audiol, 1995). 6, 286–292
Keith R. W. (Development and standardization of SCAN-C test for auditory processing disorders in children. J Am Acad Audiol, 2000). 11, 438–445
Laitila P., Karma P., Sipilä M., Manninen M., Rakho T. (Extended high frequency hearing and history of acute otitis media in 14-year-old children in Finland. Acta Otolaryngol Suppl, 1997). 529, 27–29
Levy S. C., Freed D. J., Nilsson M., Moore B. C., Puria S. (Extended high-frequency bandwidth improves speech reception in the presence of spatially separated masking speech. Ear Hear, 2015). 36, e214–e224
Li H., Steyger P. S. (Synergistic ototoxicity due to noise exposure and aminoglycoside antibiotics. Noise Health, 2009). 11, 26–32
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
Markevych V., Asbjørnsen A. E., Lind O., Plante E., Cone B. (Dichotic listening and otoacoustic emissions: Shared variance between cochlear function and dichotic listening performance in adults with normal hearing. Brain Cogn, 2011). 76, 332–339
Marler J. A., Sitcovsky J. L., Mervis C. B., Kistler D. J., Wightman F. L. (Auditory function and hearing loss in children and adults with Williams syndrome: Cochlear impairment in individuals with otherwise normal hearing. Am J Med Genet C Semin Med Genet, 2010). 154C, 249–265
Meinzen-Derr J., Wiley S., Grether S., Phillips J., Choo D., Hibner J., Barnard H. (Functional communication of children who are deaf or hard-of-hearing. J Dev Behav Pediatr, 2014). 35, 197–206
Moore D. R. (The diagnosis and management of auditory processing disorder. Lang Speech Hear Serv Sch, 2011). 42, 303–308
Moore D. R. (Editorial: auditory processing disorder. Ear Hear, 2018). 39, 617–620
Moore D. R., Ferguson M. A., Edmondson-Jones A. M., Ratib S., Riley A. (Nature of auditory processing disorder in children. Pediatrics, 2010). 126, e382–e390
Moore D. R., Hunter L. L. (Auditory processing disorder (APD) in children: a marker of neurodevelopmental syndrome. Hearing, Balance and Communication, 2013). 11, 160–167
Moore D. R., Sieswerda S. L., Grainger M. M., Bowling A., Smith N., Perdew A., Eichert S., Alston S., Hilbert L. W., Summers L., Lin L., Hunter L. L. (Referral and diagnosis of developmental auditory processing disorder in a large, United States hospital-based audiology service. J Am Acad Audiol, 2018). 29, 364–377
Moore D. R., Zobay O., Ferguson M. A. (Minimal and mild hearing loss in children: association with auditory perception, cognition, and communication problems. Ear Hear2019).
Morizono T., Paparella M. M., Juhn S. K. (Ototoxicity of propylene glycol in experimental animals. Am J Otolaryngol, 1980). 1, 393–399
Moser T., Predoehl F., Starr A. (Review of hair cell synapse defects in sensorineural hearing impairment. Otol Neurotol, 2013). 34, 995–1004
Motlagh Zadeh L., Silbert N. H., Sternasty K., Swanepoel D. W., Hunter L. L., Moore D. R. (Extended high frequency hearing enhances speech perception in noise. Proc National Acad Sci, 2019). 116, 23753–23759
Musiek F. E., Chermak G. D., Weihing J., Zappulla M., Nagle S. (Diagnostic accuracy of established central auditory processing test batteries in patients with documented brain lesions. J Am Acad Audiol, 2011). 22, 342–358
Musiek F. E., Shinn J., Chermak G. D., Bamiou D. E. (Perspectives on the pure-tone audiogram. J Am Acad Audiol, 2017). 28, 655–671
Neumann J., Uppenkamp S., Kollmeier B. (Chirp evoked otoacoustic emissions. Hear Res, 1994). 79, 17–25
Paparella M. M., Morizono T., Le C. T., Mancini F., Sipila P., Choo Y. B., Lidén G., Kim C. S. (Sensorineural hearing loss in otitis media. Ann Otol Rhinol Laryngol, 1984). 936 Pt 1623–629
Rance G., Ryan M. M., Bayliss K., Gill K., O”Sullivan C., Whitechurch M. (Auditory function in children with Charcot-Marie-Tooth disease. Brain, 2012). 135Pt 51412–1422
Rees N. S. (Auditory processing factors in language disorders: the view from Procrustes” bed. J Speech Hear Disord, 1973). 38, 304–315
Roebuck H., Barry J. G. (Parental perception of listening difficulties: an interaction between weaknesses in language processing and ability to sustain attention. Sci Rep, 2018). 8, 6985
Saxena U., Allan C., Allen P. (Crossed and uncrossed acoustic reflex growth functions in normal-hearing adults, typically developing children, and children with suspected auditory processing disorder. Int J Audiol, 2015). 54, 620–626
Schachern P., Tsuprun V., Cureoglu S., Ferrieri P., Briles D., Paparella M., Juhn S. (The round window membrane in otitis media: effect of pneumococcal proteins. Arch Otolaryngol Head Neck Surg, 2008). 134, 658–662
Shargorodsky J., Curhan S. G., Henderson E., Eavey R., Curhan G. C. (Heavy metals exposure and hearing loss in US adolescents. Arch Otolaryngol Head Neck Surg, 2011). 137, 1183–1189
Sharma M., Purdy S. C., Kelly A. S. (Comorbidity of auditory processing, language, and reading disorders. J Speech Lang Hear Res, 2009). 52, 706–722
Snow J. B. Jr, Rintelmann W. F., Miller J. M., Konkle D. F. (Central auditory imperception. Laryngoscope, 1977). 879 Pt 11450–1471
Sone M., Schachern P. A., Paparella M. M. (Loss of spiral ganglion cells as primary manifestation of aminoglycoside ototoxicity. Hear Res, 1998). 115, 217–223
Stavroulaki P., Apostolopoulos N., Dinopoulou D., Vossinakis I., Tsakanikos M., Douniadakis D. (Otoacoustic emissions–an approach for monitoring aminoglycoside induced ototoxicity in children. Int J Pediatr Otorhinolaryngol, 1999). 50, 177–184
Stone M. A., Moore B. C., Greenish H. (Discrimination of envelope statistics reveals evidence of sub-clinical hearing damage in a noise-exposed population with “normal” hearing thresholds. Int J Audiol, 2008). 47, 737–750
Sulaiman A. H., Seluakumaran K., Husain R. (Hearing risk associated with the usage of personal listening devices among urban high school students in Malaysia. Public Health, 2013). 127, 710–715
Summers V., Makashay M. J., Theodoroff S. M., Leek M. R. (Suprathreshold auditory processing and speech perception in noise: hearing-impaired and normal-hearing listeners. J Am Acad Audiol, 2013). 24, 274–292
Thomas W. G., McMurry G., Pillsbury H. C. (Acoustic reflex abnormalities in behaviorally disturbed and language delayed children. Laryngoscope, 1985). 957 Pt 1811–817
Tomblin J. B., Harrison M., Ambrose S. E., Walker E. A., Oleson J. J., Moeller M. P. (Language outcomes in young children with mild to severe hearing loss. Ear Hear, 2015). 36(Suppl 1), 76S–91S
Tsuprun V., Cureoglu S., Schachern P. A., Ferrieri P., Briles D. E., Paparella M. M., Juhn S. K. (Role of pneumococcal proteins in sensorineural hearing loss due to otitis media. Otol Neurotol, 2008). 29, 1056–1060
Vermiglio A. J. (On diagnostic accuracy in audiology: central site of lesion and central auditory processing disorder studies. J Am Acad Audiol, 2016). 27, 141–156
Wilson W. J., Arnott W. (Using different criteria to diagnose (central) auditory processing disorder: how big a difference does it make? J Speech Lang Hear Res, 2013). 56, 63–70
Wynne D. P., Zeng F. G., Bhatt S., Michalewski H. J., Dimitrijevic A., Starr A. (Loudness adaptation accompanying ribbon synapse and auditory nerve disorders. Brain, 2013). 136Pt 51626–1638
Yeo S. W., Park S. N., Park Y. S., Suh B. D. (Effect of middle-ear effusion on otoacoustic emissions. J Laryngol Otol, 2002). 116, 794–799
Zettner E. M., Folsom R. C. (Transient emission suppression tuning curve attributes in relation to psychoacoustic threshold. J Acoust Soc Am, 2003). 1134 Pt 12031–2041