David M. Mills

Vulnerability and adaptation of distortion product otoacoustic emissions to endocochlear potential variation

The endocochlear potential (EP) was reversibly decreased in adult gerbils by the intraperitoneal injection of furosemide, while cochlear functioning was monitored by measurement of distortion production otoacoustic emissions (DPE) at a range of stimulus intensities. Stimulus frequencies for DPEs were f1 = 6.8 and f2 = 8 kHz (f2/f1 = 1.18). Emissions monitored in the ear canal and scala media were 2f1-f2, 3f1-2f2, 2f2-f1, and f2-f1. Typically, the EP decreased smoothly, reached a minimum one-half hour after injection, then recovered slowly over several hours. Emissions at 2f1-f2 and 3f1-2f2 at low stimulus levels were particularly vulnerable to the change in EP. These vulnerable emissions showed characteristic trajectories in which the amplitudes changed little with the initial EP decrease, then dropped sharply as the EP continued to decrease. However, the amplitudes then began to recover even before the EP reached minimum, and recovered completely while the EP remained subnormal. The trajectories of the other odd order emissions were similar, but lacked the abrupt decrease. The variation of the even order (f2-f1) component was completely different, but appeared related to the odd order trajectories in a complex fashion. During the initial decrease for the vulnerable components, the decrease in emission amplitude (in dB) was found to be proportional to the square of the change in EP (in mV). The recovery with a subnormal EP was interpreted as an adaptive effect with a time constant of about 15 min.

Effects of age on the distortion product otoacoustic emission growth functions.

Age-related hearing loss (presbycusis) is thought to result from age-related degeneration (aging) of the cochlea plus the cumulative effects of extrinsic damage (noise and other ototoxic agents) and intrinsic disorders (e.g. systemic diseases). Previous studies have implicated dysfunction of the hair cells (sensory presbycusis) as the principal mechanism of age-related hearing loss. However, recent evidence from quiet-reared gerbils suggests that cochlear aging results primarily from atrophy of the stria vascularis, which is associated with diminished endocochlear potential (EP), spiral ganglion atrophy, and a relatively flat audiometric loss, termed metabolic presbycusis. Because it is not currently possible to measure EP directly in the clinical setting, we wondered if cochlear metabolic dysfunction might be evidenced indirectly from existing clinical tests, specifically, the input-output (IO) growth function of the distortion product (DP) otoacoustic emissions in relation to behavioral hearing threshold levels (HTL). We anticipated finding discordance between the IO functions and HTL with either a greater decline with age in HTL than in IO functions if an age-related metabolic dysfunction of the cochlea was operant, or a greater loss of IO function than HTL if outer hair cell dysfunction was the dominant pathology. To address this supposition we analyzed existing auditory data from a large cohort of adults to determine the change with age in three aspects of the DP IO function: area under the curve, threshold, and slope. The analyses demonstrated a greater effect of age on HTL than on the DP IO measures. This effect supports the hypothesis that strial dysfunction is a substantive factor in cochlear aging. The etiology and mechanisms for this dysfunction are conjectural at present.

10-Year prospective study of noise exposure and hearing damage among construction workers

Objectives To characterise the effects of noise exposure, including intermittent and peaky exposure, on hearing damage as assessed by standard pure-tone thresholds and otoacoustic emissions, a longitudinal study was conducted on newly hired construction apprentices and controls over a 10-year period. Methods Among the 456 subjects recruited at baseline, 316 had at least two (mean 4.6) examinations and were included in this analysis. Annual examinations included hearing threshold levels (HTLs) for air conducted pure tones and distortion product otoacoustic emission (DPOAE) amplitudes. Task-based occupational noise exposure levels and recreational exposures were estimated. Linear mixed models were fit for HTLs and DPOAEs at 3, 4 and 6 kHz in relation to time since baseline and average noise level since baseline, while controlling for hearing level at baseline and other risk factors. Results Estimated LEQ noise exposures were 87±3.6 dBA among the construction workers. Linear mixed modelling demonstrated significant exposure-related elevations in HTL of about 2–3 dB over a projected 10-year period at 3, 4 or 6 kHz for a 10 dB increase in exposure. The DPOAE models (using L1=40) predicted about 1 dB decrease in emission amplitude over 10 years for a 10 dB increase in exposure. Conclusions The study provides evidence of noise-induced damage at an average exposure level around the 85 dBA level. The predicted change in HTLs was somewhat higher than would be predicted by standard hearing loss models, after accounting for hearing loss at baseline. Limited evidence for an enhanced effect of high peak component noise was observed, and DPOAEs, although similarly affected, showed no advantage over standard hearing threshold evaluation in detecting effects of noise on the ear and hearing.

Metabolic Presbycusis: Differential Changes in Auditory Brainstem and Otoacoustic Emission Responses with Chronic Furosemide Application in the Gerbil

Auditory characteristics of metabolic or strial presbycusis were investigated using an animal model in which young adult Mongolian gerbils (Merionesunguiculates) were implanted with an osmotic pump supplying furosemide continuously to the round window. This model causes chronic lowering of the endocochlear potential (EP) and results in auditory responses very similar to those seen in quiet-aged gerbils (Schmiedt et al., J. Neurosci. 22:9643–9650, 2002). Auditory function was examined up to one week post-implant by measurement of auditory brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs). Emission “threshold” was defined as the stimulus level required to reach a criterion emission amplitude. Comparing all responses on a “threshold-shift diagram,” where emission threshold increases were plotted versus ABR threshold increases, the following results were obtained: (1) On average, the increase of the emission threshold was about 55% of the increase in ABR threshold, with comparatively little scatter. (2) The main dysfunction in metabolic presbycusis appears to be a decrease in the gain of the cochlear amplifier, combined with an additional, smaller increase in neural threshold, both effects caused by a chronically low EP. (3) For ABR threshold increases over 20 dB, the points for the chronic low-EP condition were largely separate from those previously found for permanent acoustic damage. The threshold-shift diagram therefore provides a method for noninvasive differential diagnosis of two common hearing dysfunctions.

Wideband energy reflectance measurements of ossicular chain discontinuity and repair in human temporal bone.

Objective: Recent studies have suggested the potential of wideband energy reflectance (ER) for the assessment of middle ear disorders. The purpose of this study was to examine the use of wideband ER in the evaluation of an ossicular discontinuity and its repair in human cadaver temporal bones. Design: ER measurements at ambient pressure were made on five human cadaver ears in three conditions: (1) baseline with intact ossicular chain, (2) with the ossicular chain cut using an argon laser, and (3) with the ossicular chain repaired. Laser Doppler vibrometry measurements of stapes footplate velocity were also made in the three conditions to monitor the effect of the experimental manipulations on sound transfer through the middle ear. Results: Disarticulating the ossicular chain resulted in the appearance of a deep notch in ER in each specimen ranging in center frequency from 561 to 841 Hz. The average reduction in ER was 31% at a frequency of 630 Hz. Laser Doppler vibrometry measurements confirmed the effect of the disarticulation and then repair using ionomeric cement. The low-frequency notch in ER was eliminated following repair of the ossicular chain. There was a small decrease in average high-frequency ER for both the cut and repaired conditions. A simple series impedance model of the middle ear was used to model the change in ER based on changes in middle ear impedance. The primary finding of the modeling was that the low-frequency notch in ER in the disarticulated ear occurs at the resonance frequency at which the reactance goes through zero consistent with the data. Conclusions: A disarticulation of the ossicular chain in human cadaver ears produces a low-frequency notch in ER that recovers with repair of the disarticulation. These results suggest that ER has the potential for use in the diagnosis of ossicular discontinuity and to monitor the status of the repaired ossicular chain. More data are needed to compare ER results from patients undergoing surgery for ossicular discontinuity with those of patients with other ossicular disorders such as otosclerosis.

Development of distortion product emissions in the gerbil: “Filter” response and signal delay

Amplitude and phase responses of distortion product otoacoustic emissions as a function of stimulus frequency ratio were measured for frequencies between 2 and 48 kHz, in Mongolian gerbils (Meriones unguiculates) aged 15 to 30 days after birth. After baseline measurements, furosemide was administered to distinguish active from passive emissions. At all ages, structure in the form of multiple peaks was observed in the amplitude responses of specific odd-order emissions. This structure depended on the emission frequency, not the stimulus frequency ratio, and did not generally depend on the stimulus amplitude. Nor was it dependent on the functioning of the cochlear amplifier: At moderate stimulus levels, the observed emission distribution simply shifted to lower amplitudes when the cochlear amplifier was made temporarily dysfunctional by furosemide injection. The center frequencies and widths of the peaks in the amplitude response did not generally change with age, except that the relative amplitudes of the higher-frequency peaks were increased in younger animals. At 2 kHz, however, the distribution showed other evidence of maturation, with the frequency of maximum emission moving downward with age. The phase responses yielded estimates of the round trip signal (group or traveling wave) delay. At a given frequency, the active signal delay typically decreased substantially with increasing stimulus level. However, there was a rapid variation in delay as the stimulus level passed the normal active-passive crossover level. At stimulus levels measured relative to the active-passive crossover level, i.e., either 20 or 30 dB lower, the active signal delay decreased only slightly with age. Overall, both filter response and signal delay characteristics were found to be essentially mature near the onset of hearing.

Evaluation of cochlear hearing disorders: normative distortion product otoacoustic emission measurements.

Objective: The overall objective was to begin the investigation, in humans, of distortion product otoacoustic emission measurements, which are intended to be part of a diagnostic protocol being developed. This protocol, designed to distinguish among different cochlear hearing disorders, has been tested to date only through lesion studies in the gerbil (Mills, Ear and Hearing, 27, 508–525, 2006). To be applied successfully to human subjects, it was required that parameters and procedures for emission measurements be found, which resulted in sufficiently small intersubject variability in normal subjects, among other requirements. To attain these objectives, measurements of particular otoacoustic emission responses were made in a reference group of young adults having excellent hearing. Design: Twenty young adults (age 18 to 24 yr; 40 ears) comprised the subject group, with equal numbers of men and women. Inclusion criteria included hearing thresholds of 10 dB HL or better in both ears at all frequencies (0.5, 1, 2, 3, 4, 6, and 8 kHz), plus a tympanometric peak response located within ±30 daPa of ambient pressure in both ears. The otoacoustic emission stimulus consisted of two tones (frequencies f1 and f2) varied in level using 5-dB steps with the lower-frequency stimulus level always 10 dB greater than that of the higher-frequency stimulus. The emission isoresponse threshold was defined to be the stimulus level required to obtain an emission amplitude of −10 dB SPL. Another potential measure was defined to be the emission amplitude at the highest stimulus levels routinely tested. Mean emission amplitudes and thresholds were determined for f2 frequencies equal to audiometric frequencies from 1 to 8 kHz, using two different stimulus frequency ratios, f2/f1 = 1.21 and 1.28. Results: One result of the study was the derivation of reference standards for the emission threshold level, similar to the HL scale for pure-tone thresholds. For use in diagnosis, the optimal measure was found to be the otoacoustic emission threshold for the stimulus frequency ratio f2/f1 = 1.21 and for f2 frequencies from 1 to 6 kHz. The f2 frequency of 8 kHz seemed less useful because the emission had a relatively high mean threshold. For frequencies 1 to 6 kHz, the variances were adequately small: 95% of the emission thresholds fell within ±13 dB of the mean at each frequency, a variability only slightly larger than that for the gerbil. Finally, even within the 10-dB HL limit, responses showed a slight trend for increased emission thresholds with increased auditory threshold. Only at 8 kHz was the amount of covariance important, however, with the relationship between emission and auditory thresholds strongest for men. Conclusions: Emission reference standards can be developed by testing a group of young adults with excellent hearing. The diagnostic procedure previously proposed on the basis of gerbil lesion studies may be adapted with relatively little modification for use in human subjects. However, validity of the test and specific numerical results for human subjects remain to be firmly established for the purpose of distinguishing among different cochlear disorders.

Development of active and passive processes in gerbil cochlea

Distortion product otoacoustic emissions were monitored in neonatal gerbils during furosemide intoxication, to examine the ontogeny of different mechanisms underlying cochlear responses to acoustic stimuli. Results indicate: (1) Above 2 kHz, active processes were functional at adult levels at all ages. (2) In the youngest animals (14 days) the maximum frequency seen for the active response was 16 kHz, while in adults it was 40 kHz. This limitation on the active frequency response is believed to be due to the underlying passive cochlear mechanical response, and is consistent with the known place code shift. (3) The length of the active amplification zone at the extreme base decreased from 1.2 mm at 15–19 days to 0.6 mm at maturity. (4) At midfrequencies, there was an increase in net active gain from 15 to 19 days, then a subsequent decrease to reach a uniform 25‐dB gain across frequency by maturity. Overall, these results are consistent with an increase in the rate of gain (dB/mm) from 15 to 19 days as the...

A 10-year prospective study of noise and hearing in construction workers

Objectives To quantitatively evaluate the effect of noise exposure on hearing, an inception cohort of construction workers were monitored over a 10 year period. Methods Construction apprentices and student controls (n=316) were enrolled in 1999 and assessed for hearing approximately annually through 2009. At each of 2896 time points, hearing was measured using pure-tone audiometry, and health, work history, non-occupational exposures and other information was collected via survey. 1310 full shift noise measurements were used to estimate task-based individual average Leq noise exposures. Changes in measurement techniques necessitated analyses within two phases, as well as over the whole study period. Results In unadjusted analyses, adverse changes over time and in relation to exposure were observed in hearing thresholds at 3 and 4 kHz. At 6 kHz there was an apparent improvement in hearing. Changes in thresholds within each phase were consistent with the overall trend. The effect at 4 kHz demonstrated a loss of 0.81 (+0.11) dB per year among construction workers, compared to 0.34 (+0.09) dB among controls. Linear mixed models were developed to estimate the change in hearing in relation to exposure, while controlling for ear within subject, and relevant covariates, and demonstrate similar effects. Conclusions Hearing thresholds at noise-sensitive frequencies increased with exposure over a 10 year study period, consistent with the predicted loss for an 85 dBA exposure. However, challenges of monitoring construction workers over this extended period of time make the magnitude of the effect uncertain.