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This report explores the consequences of acoustic overexposures on hearing in noisy environments for two macaque monkeys trained to perform a reaction time detection task using a Go/No-Go lever release paradigm. Behavioral and non-invasive physiological assessments were obtained before and after narrowband noise exposure. Physiological measurements showed elevated auditory brainstem response (ABR) thresholds and absent distortion product otoacoustic emissions (DPOAEs) post-exposure relative to pre-exposure. Audiograms revealed frequency specific increases in tone detection thresholds, with the greatest increases at the exposure band frequency and higher. Masked detection was affected in a similar frequency specific manner: threshold shift rates (change of masked threshold per dB increase in noise level) were lower than pre-exposure values at frequencies higher than the exposure band. Detection thresholds in sinusoidally amplitude modulated (SAM) noise post-exposure showed no difference from those in unmodulated noise, whereas pre-exposure masked detection thresholds were lower in the presence of SAM noise compared to unmodulated noise. These frequency-dependent results were correlated with cochlear histopathological changes in monkeys that underwent similar noise exposure. These results reveal that behavioral and physiological effects of noise exposure in macaques are similar to those seen in humans and provide preliminary information on the relationship between noise exposure, cochlear pathology and perceptual changes in hearing within individual subjects.

In a previous study we observed that a 7-day post-trauma magnesium treatment significantly reduced auditory threshold shifts measured 7 days after gunshot noise exposure. However this improvement was only temporary, suggesting that it could be potentially beneficial to prolong this treatment. The aim of the present study was to evaluate the efficacy of a long-term (1 month) magnesium treatment after an impulse noise trauma, in comparison with either a 7-day magnesium treatment, an administration of methylprednisolone (conventional treatment), or a placebo (NaCl). Guinea pigs were exposed to impulse noise (three blank gunshots, 170 dB SPL peak). They received one of the four treatments, 1 h after the noise exposure. Auditory function was explored by recording the auditory brainstem response (ABR) and measuring the distortion product otoacoustic emissions (DPOAE) over a 3-month recovery period after the gunshot exposure. The functional hearing study was supplemented by a histological analysis. The results showed that a 1-month treatment with magnesium was the most effective treatment in terms of hair cell preservation. The DPOAE confirmed this effectiveness. Methylprednisolone accelerated recovery but its final efficacy remained moderate. It is probable that magnesium acts on the later metabolic processes that occur after noise exposure. Multiple mechanisms could be involved: calcium antagonism, anti-ischaemic effect or NMDA channel blockage. Regardless of the specific mechanism, a 1-month treatment with magnesium clearly attenuates NIHL, and presents the advantage of being safe for use in humans.

We have measured the effects of changing perilymphatic K+ by perfusing scala tympani in guinea pigs with salt solutions high or low in K+, while monitoring the distortion product otoacoustic emissions (DPOAEs) in the ear canal (a measure of mechanical vibration of the organ of Corti), the summating potential (SP) evoked by high-frequency tone-bursts (taken to be a measure of pre-synaptic electrical activity of the inner hair cells) and the compound action potential (CAP) of the auditory nerve (taken to be a measure of post-synaptic neural activity). We have attempted to investigate the osmotic effects of our perfusates by comparison with simple hyperosmotic sucrose perfusates and iso-osmotic versions of perfusates, and for the effects of changes in other ions (e.g. Na+ and Cl-) by keeping these constant in some perfusates while elevating K+. We have found that changing the K+ concentration over the range 0-30mM elevated the SP and CAP thresholds almost equally in normal animals, and not at all in animals devoid of outer hair cells (OHCs), showing that OHCs are sensitive to the perfusates we have used, but the inner hair cells (IHCs) and the type I afferent dendrites are not, presumably because IHCs are shielded from perilymph by supporting cells, and the membranes of the afferent dendrite membranes exposed directly to our perfusates are dominated by Cl(-) permeability, rather than by K+ permeability. This view is supported by experiments in which the perilymphatic Cl(-) concentration was reduced, producing a large elevation in CAP threshold, but a much smaller elevation of SP threshold, suggesting disruption of action potential initiation. The view that threshold elevations with changes in perilymphatic K+ are due almost solely to a disruption of OHC function and a consequent change in the mechanical sensitivity of the organ of Corti was supported by measurements of amplitude of the 2f1-f2 distortion product otoacoustic emission. During elevations in K+, DPOAEs followed a similar time-course to that for SP and CAP, although the changes were less for DPOAEs. The lack of a 1:1 relationship between DPOAEs and SP and CAP is probably because the iso-input DPOAE measure used is a more complex indicator of mechanical sensitivity than the iso-output measure used by others. Taken together, these results suggest that changes in K+ in pathological conditions probably produce a hearing loss by disrupting OHCs rather than IHCs or neurones, and that OHC disruption in our experiments was due to a mixture of osmotic, K+ and possibly Cl(-) effects.

Distortion product otoacoustic emissions (DPOAEs) were measured in the absence and presence of contralateral noise at five levels--below, equal to, and above the middle-ear muscle (MEM) reflex threshold. The resultant changes in DPOAE level and phase were dependent on stimulus frequency and noise level. Both low-level noise, believed to elicit the medial olivocochlear (MOC) reflex, and high-level noise, thought to activate both MOC and MEM reflexes, significantly decreased the DPOAE level. However, the shift from sole MOC effect to mixed MOC and MEM effects was not as dramatic as we thought. While low-level noise resulted in a minimum DPOAE phase change, high-level noise caused a substantial phase lead for 1 and 2kHz. With increasing frequency, phase lag became more notable. The present study suggests the following: (1) DPOAE contralateral suppression by low-level sound most likely does not involve the effect of the MEM reflex and signal crossover; and (2) combined analysis of DPOAE level and phase changes warrants further investigations to overcome the difficulty in separating the effects of MOC efferents and MEM contraction. The results also imply that OAE measurement has the potential for being used to investigate the effect of the MEM reflex on sound transmission.

Low-frequency tones were reported to modulate the amplitude of distortion product otoacoustic emissions (DPOAEs) indicating periodic changes of the operating point of the cochlear amplifier. The present study investigates potential differences between infrasound and low-frequency sounds in their ability to modulate human DPOAEs. DPOAEs were recorded in 12 normally hearing subjects in the presence of a biasing tone with f(B)=6Hz and a level L(B)=130dB SPL. Primary frequencies were fixed at f(1)=1.6 and f(2)=2.0kHz with fixed levels L(1)=51 and L(2)=30dB SPL. A new measure, the modulation index (MI), was devised to characterise the degree of DPOAE modulation. In subsequent measurements with biasing tones of f(B) = 12, 24 and 50Hz, L(B) was adjusted to maintain the MI as obtained individually at 6Hz. Modulation patterns lagged with increasing f(B). The necessary L(B) decreased by 12dB/octave with increasing f(B) and ran almost parallel to the published infrasound detection threshold. No signs of an abrupt change in transmission into the cochlea were found between infra- and low-frequency sounds. The results show clearly that infrasound enters the inner ear, and can alter cochlear processing.

The effect of perceived spatial separation, induced by the precedence effect, on release from noise or speech masking was investigated. Listeners were asked to orally repeat Chinese nonsense sentences, which were spoken by a female talker and presented by both the left (-45 degrees) and right (+45 degrees) loudspeakers, when maskers, which were either speech-spectrum noise sounds or Chinese nonsense sentences spoken by two other female talkers, were presented by the same two loudspeakers. Delays between identical sounds presented over the two loudspeakers were used to control the perceived locations of the target (right only) and masker (right, center, or left). The results show that perceived 45 degrees and 90 degrees separations of target speech from masking speech led to equivalently marked improvement in speech recognition, even though the degree of improvement was smaller than that reported in [J. Acoust. Soc. Am. 106 (1999) 3578 (using English nonsense speech)]. When the masker was noise, however, perceived separation only marginally improved speech recognition. These results indicate that release from informational masking, due to perceived target/masker spatial separation induced by the precedence effect, also occurs for tonal Chinese speech. Compared to the 45 degrees perceived within-hemifield separation, the 90 degrees perceived cross-hemifield separation does not produce further unmasking.

The influence of the crossed medial efferent system on cochlear mechanics of the mustached bat was tested by measuring delayed evoked otoacoustic emissions (DEOAEs), cochlear microphonics, distortion product otoacoustic emissions (DPOAEs) and stimulus frequency otoacoustic emissions. Contralaterally delivered sinusoids, broadband noise and bat echolocation calls were used for acoustic stimulation of the efferent system. With all four measures we found a level-dependent suppression under stimulation with both broadband noise and echolocation calls. In addition, the sharply tuned cochlear resonance of the mustached bat which is involved in processing echolocation signals at 61 kHz shifted upward in frequency by several 100 Hz. Presentation of sinusoids did not have any significant effect. DEOAEs and DPOAEs were in some cases enhanced during contralateral presentation of the bat calls at moderate intensities. The most important function of the efferent system in the mustached bat might be the control of the extraordinarily fine-tuned resonator of this species, which is close to instability as evident from the very pronounced evoked otoacoustic emissions which sometimes convert into spontaneous otoacoustic emissions of high level.

Recent studies have demonstrated that the detection of complex temporal envelopes relies – at least partially – on the perception of a distortion component generated by a peripheral (cochlear) and/or central (post-cochlear) non-linearity. In the present study, first- and second-order amplitude modulation (AM) detection thresholds were obtained in normally hearing (NH) and hearing-impaired (HI) listeners using a 2-kHz pure-tone carrier. In both groups of listeners, first-order AM detection thresholds were measured for AM rates fm ranging between 4 and 87 Hz, and second-order AM detection thresholds were measured for second-order AM rates fm ′ ranging between 4 and 23 Hz, using a fixed first-order ‘carrier’ AM rate fm of 64 Hz. When the sound pressure level was adjusted in order to yield equal detectability in both groups for the 64-Hz first-order carrier modulation, (i) first-order AM detection thresholds for the HI listeners were normal at fm =87 Hz, and better-than-normal at fm =4 and 16 Hz, and (ii) second-order AM detection thresholds were identical at all modulation rates in NH and HI listeners. Similar results were obtained when the audibility of the 2-kHz pure-tone carrier was equated for both groups, i.e. when listeners were tested at the same sensation level. These results demonstrate clearly that cochlear damage has no effect on the detection of complex temporal envelopes, and indicate that the distortion component must be generated by a more central non-linearity than cochlear compression, transduction, or short-term adaptation.

Distortion-product otoacoustic emission (DPOAE) suppression tuning curves (STCs) can be obtained in a variety of laboratory animals and humans by sweeping the frequencies and levels of a third tone (f(3)) around a set of f(1) and f(2) primaries. In small laboratory animals, it was previously observed that, when the suppressor tone (f(3)) is above f(2), substantial suppression and or enhancement (suppression/enhancement) could be obtained. In the present study, it was of interest to determine if similar suppression/enhancement phenomena could be observed in humans and to what extent this might influence the interpretation of STC results reported in the literature. To this end, STCs were measured for DPOAEs at 2f(1)-f(2) and 2f(2)-f(1) in human subjects at geometric-mean frequencies (GM) of 1, 2, 3, and 4 kHz, and primary-tone equilevels of 80/80 and 75/75 dB SPL and unequal levels of 65/55 dB SPL. Overall, STC parameters were found to be comparable to those reported in the literature. For the 2f(1)-f(2) DPOAE, STC tip frequencies tuned to the region of the primaries, and tip frequencies were slightly influenced by primary-tone level. STC tip thresholds were typically within 10 dB of the level of L(2), and Q(10dB) values ranged from 1.0 to 2.5, which was consistent with the higher-level primaries employed. The 2f(1)-f(2) DPOAE showed consistent regions of suppression that were approximately an octave above the GM for the 1-kHz, 65/55-dB SPL condition. The 2f(2)-f(1) DPOAE tuned to its characteristic place above f(2) and showed reliable enhancement above the STC tip region for the 1-kHz, 75/75-dB SPL primaries. Overall, the results clearly revealed that human ears also display suppression/enhancement phenomena when f(3) reaches frequencies considerably above f(2). If suppression/enhancement phenomena reflect secondary DPOAE sources, then these sources are present in the ear-canal signal from humans as well as small laboratory animals.

Distortion product otoacoustic emissions (DPOAEs) and auditory steady state evoked response potentials (ASSRs) can both be evoked by tone pairs with frequencies f 1 and f 2 . The DPOAE is maximal at 2 f 1 − f 2 and the ASSR is maximal at f 2 − f 1 . Since DPOAE magnitude depends on the ratio f 2 / f 1 , but ASSR amplitude depends on the beat frequency f 2 − f 1 , compromises are necessary when recording both responses concurrently. Tone pairs with f 2 of 900, 1800 and 3600 Hz were presented simultaneously at either 40 or 50 dB sound pressure level (SPL). The f 1 frequency of each pair was approximately 85 or 180 Hz lower than f 2 . Phase measurements were used to calculate apparent latencies at 40 dB SPL. For increasing f 2 , DPOAE latencies were 14.5, 9.7 and 6.3 ms for 85 Hz beats, and 11.5, 9.0 and 4.3 ms for 180 Hz beats. ASSR latencies were 22.0, 15.7 and 17.8 ms at 85 Hz, and 17.7, 11.3 and 9.6 ms at 180 Hz. From a model of the mechanical transmission in the cochlea, delays between the basilar membrane and the generator of the ASSR were estimated as 15.4, 12.2 and 15.3 ms at 85 Hz and 8.6, 7.6 and 8.0 ms at 180 Hz.

This study compares the effects of mutations in the gap junction protein connexin 26 (Cx26), on outer hair cells (OHCs), inner hair cells (IHCs) and auditory nerve/brainstem among carriers of these mutations. One hundred and twenty eight individuals, from a village with widespread consanguinity and congenital deafness, due to three Cx26 mutations, were selected among relatives of deaf persons, and divided into non-carriers, carriers of one mutation, homozygous to one mutation, or compound heterozygous carriers of two different mutations. Distortion product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABRs) and audiometric evaluation were compared in these genetic groups. Hearing loss among homozygotes and compound heterozygotes was comparable and ranged from mild to profound. Most ABRs from these groups showed no responses or partial responses (peaks III, V) with prolonged latencies, but some individuals had all peaks at normal latencies. DPOAEs were absent, except sporadic responses. Carriers of one mutation had significantly smaller DPOAEs compared to non-carriers, although normal pure tone audiograms and ABRs were found in these groups. In conclusion, based on DPOAEs, Cx26 mutations may impact OHC function among carriers of one or two Cx26 mutations. IHC/nerve impairment among homozygotes and compound heterozygotes is variable. OHCs may be more susceptible to Cx26 mutations compared to IHCs and the auditory nerve and brainstem pathway activated by them.

In distortion product otoacoustic emission (DPOAE) measurements the ear is stimulated with two pure tones f 1 and f 2. To maximize DPOAE levels and hence increase the sensitivity of DPOAE measurements, the separation of the two primary tone levels has been shown to play a crucial role. In contrast to conventionally used paradigms where the difference between the stimulus levels L 1 and L 2 is constant, Whitehead et al. [Whitehead, M.L. et al., 1995. J. Acoust. Soc. Am. 97, 2359–2377] found a variable level separation L 1− L 2, which is increasing with decreasing overall stimulus levels, to be optimal for evoking maximal DPOAE levels. This optimal level separation was quantified by Kummer et al. [Kummer, P. et al., 2000. Hear. Res. 146, 47–56] for humans. The aim of our study was to find out if such optimal level differences also exist in the gerbil Meriones unguiculatus in order to obtain an adequate animal model for determination of auditory sensitivity and its pathologies. The results clearly indicate that, as in humans, a variable level separation L 1− L 2 is optimal for generation of maximal DPOAE levels in the gerbil. This level separation strongly depends on the frequency relation between f 1 and f 2 and the deviation of the optimal level difference from L 1= L 2 increases with the frequency ratio f 2/ f 1.

Four frog species, Rana pipiens, Scaphiopus couchii, Xenopus laevis and Bombina orientalis, were examined for distortion product otoacoustic emissions (DPOAE). These species were chosen for their diverse otic morphologies. Rana has a well-developed caudal extension of the amphibian papilla within the inner ear; Scaphiopus, Xenopus and Bombina do not. Rana and Scaphiopus have a tympanic middle ear, Xenopus has a subcutaneous tympanic disk and Bombina has only an operculum. DPOAEs were present in Rana and Xenopus, with amplitudes up to 55 and 20 dB SPL, respectively. DPOAEs could be detected in neither Scaphiopus nor Bombina. These results show that (1) a well-developed caudal extension is not necessary for generation of DPOAEs, and (2) a tympanic middle ear is neither required nor sufficient to have DPOAEs.

The cellular antioxidant system appears to protect cochlear hair cells from oxidative stress due to noise and aging. The role of individual metabolic variables remains poorly understood, however. We examined the role of a number of metabolic factors on human cochlear function in noise-exposed individuals. In 58 factory workers we measured audiometry and distortion product otoacoustic emissions prior to a workshift. Simultaneously we measured levels of vitamin E, vitamin C, and polymorphism status for two metabolic genes related to glutathione S-transferase function (GSTM1 and GSTT1). Age and total noise exposure were predictive of hearing status. Vitamin E levels were negatively correlated with hearing function, and this effect was partly explained by an increase in vitamin E levels with age. No effect was found for vitamin C. Individuals possessing the GSTM1 gene had significantly better high frequency otoacoustic emissions compared to GSTM1 null individuals. The protective effect of GSTM1 was present even after adjusting for age, race, sex, and years of noise exposure. GSTT1 did not exhibit a similarly protective effect. While the cross-sectional nature of the study precludes drawing conclusions about causation, these data suggest that GSTM1, an antioxidant enzyme which is found in the mammalian cochlea, may play a protective role in humans against hair cell damage due to noise or aging.

The effects of electrical stimulation of the inferior colliculus (IC) on the activation of olivocochlear nerve fibers were investigated in guinea pigs in which the 2f1−f2 distortion product otoacoustic emissions (DPOAE) were recorded. Animals were anesthetized with ketamine (33 mg/kg) and xylazine (6.6 mg/kg). Bipolar electrical stimulation of the IC by a train of pulses with currents less than the threshold for evoking muscle twitches resulted in a small depression of the DPOAE amplitude by 0.1–2 dB. The maximal effect was observed when the stimulating electrodes were located in the rostro-medial or ventral parts of the IC. The suppression of electrically evoked DPOAE was similar to the DPOAE suppression produced by acoustical stimulation of the contralateral ear by a broad-band noise. Suppression of DPOAE amplitude in response to both acoustical and electrical stimulation was abolished 1–2 h after a single intramuscular injection of gentamicin (210–250 mg/kg). The results indicate that electrical stimulation of the IC can activate the efferent system and produce DPOAE changes by similar mechanisms as does acoustical stimulation of the contralateral ear.

The study was carried out to test whether or not cubic distortion otoacoustic emissions were more sensitive than auditory-evoked potentials for assessing styrene-induced hearing losses in the Long-Evans rat. For the purposes of comparison, changes in cubic distortion product otoacoustic emissions (DeltaDPOAE), evoked potential permanent threshold shifts (PTS) and outer hair cell losses were measured in a population of styrene-treated rats. Each rat was exposed to either 650 or 750 ppm of styrene for 4 weeks, 5 days per week, 6 h per day. Only the 750 ppm exposure caused significant hearing losses. For this concentration, DPOAEs appeared as sensitive to styrene as the audiometry performed with evoked potentials, but not more. A high coefficient of correlation [0.84< or =r< or =0.91] between DeltaDPOAE and PTS was obtained across the styrene-induced effects for frequencies ranging from 5 to 12 kHz. This experiment demonstrates that DPOAEs can be used to monitor the ototoxicity induced by styrene even though they cannot be considered as a more sensitive index of cochlear pathology than the evoked potentials, at least under our experimental conditions. Likewise evoked potentials, normal DPOAEs may not guarantee a normal cochlear status and therefore results of DPOAE measurements should be interpreted cautiously. The use of both techniques and the determination of the ratio DeltaDPOAE/PTS may be useful in determining the cause of hearing loss: mechanical or chemical process. Moreover, because of its non-invasive and objective characteristics, the use of DPOAEs could play a greater role in a prevention policy.

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.

Myasthenia gravis (MG) induces a reduction of transient evoked otoacoustic emissions (TEOAEs) and distortion product otoacoustic emissions (DPOAEs) that reverses partially after administration of an acetylcholinesterase (AChE) inhibitor. In normal subjects a contralateral acoustic stimulation (CAS) produces an amplitude reduction of TEOAEs and DPOAEs. This effect, called contralateral suppression (CS), is mediated by the efferent auditory system. Twenty subjects affected by MG underwent DPOAE recording with and without contralateral white noise in a drug-free baseline period ('basal') and 1 h ('post') after administration of a reversible AChE inhibitor. In 'basal' condition CAS did not induce significant DPOAE amplitude changes but a paradoxical slight increase was observed. After drug administration, CAS produced a significant decrease of DPOAE amplitudes for middle frequencies (f(2) between 1306 and 2600 Hz). In normal controls CAS caused a significant decrease (P

Noise and aminoglycosides initially attack cochlear outer hair cells (OHCs). Distortion product otoacoustic emissions (DPOAEs) are used for the early diagnosis of damage to OHCs. The effects of sub-damaging doses of amikacin, an aminoglycoside antibiotic agent, on noise-induced hearing loss (NIHL) were examined in guinea pigs. Animals were grouped by gender and exposed to broadband noise at 105 dB SPL for 12 h and/or injected i.m. with either amikacin (100 mg/kg/day) or saline for 10 days. Auditory brainstem response (ABR) thresholds, along with DPOAE amplitudes, were measured serially before and after noise exposure. DPOAE amplitudes decreased and ABR thresholds elevated immediately after noise exposure and then gradually recovered. At all frequencies, the emission amplitudes recovered completely to pre-exposure baseline values by 4 days after noise exposure. There was no effect of amikacin on either the ABR threshold or DPOAE amplitudes, in animals treated with amikacin only. However, amikacin significantly prolonged the effect of noise exposure on DPOAE amplitude but not on the noise-induced temporary threshold shift (TTS) of the ABR. In animals treated with a combination of noise and amikacin, significant changes in DPOAE amplitudes were still observed at 4 weeks after cessation of noise exposure. No gender difference in the responses to noise and/or amikacin could be demonstrated. The present findings indicate that even sub-damaging dosages of amikacin might impair recovery from NIHL in guinea pigs.

When the cochlea is stimulated by a sinusoidal current, the inner ear emits an acoustic signal at the stimulus frequency, termed the electrically evoked otoacoustic emission (EEOAE). Recent studies have found EEOAEs in birds lacking outer hair cells (OHCs), raising the possibility that other types of hair cells, including inner hair cells (IHCs), may generate EEOAEs. To determine the relative contribution of IHCs and OHCs to the generation of the EEOAE, we measured the amplitude of EEOAEs, distortion product otoacoustic emissions (DPOAEs), the cochlear microphonic (CM) and the compound action potential (CAP) in normal chinchillas and chinchillas with IHC lesions or IHC plus OHC lesions induced by carboplatin. Selective IHC loss had little or no effect on CM amplitude and caused a slight reduction in mean DPOAE amplitude. However, IHC loss resulted in a massive reduction in CAP amplitude. Importantly, selective IHC lesions did not reduce EEOAE amplitude, but instead, EEOAE amplitude increased at high frequencies. When both IHCs and OHCs were destroyed, the amplitude of the CM, DPOAE and EEOAE all decreased. The increase in EEOAE amplitude seen with IHC loss may be due to (1) loss of tonic efferent activity to the OHCs, (2) change in the mechanical properties of the cochlea or (3) elimination of EEOAEs produced by IHCs in phase opposition to those from OHCs.

Increasing attention is being given to the role of neurotransmitters and other signaling substances in the damage induced by intense sound to the cochlea. Adenosine triphosphate (ATP) is one example of a putative neurotransmitter that may alter cochlear mechanics during sound exposure. The purpose of the present study was to test the hypothesis that endogenous extracellular ATP has a role in the generation of the changes in cochlear mechanics induced by moderate intense sound exposure. Guinea pigs were exposed to either: (1) a perilymphatic administration of pyridoxal-phosphate-6-azophenyl-2′,4′-disulphonic acid (PPADS, 1 mM), an ATP antagonist; (2) a moderately intense sound (6 kHz tone, 95 dB SPL, 15 min); or (3) a combination of the PPADS and the sound. The effects on the cubic distortion product otoacoustic emissions (DPOAEs; 2f1−f2) were monitored using three sets of equal level primaries (f1=9.25 kHz, f2=10.8 kHz, 2f1−f2=7.7 kHz; f1=7.2 kHz, f2=8.4 kHz, 2f1−f2=6 kHz; f1=5.55 kHz, f2=6.5 kHz, 2f1−f2=4.6 kHz). PPADS alone had no effect on the cubic DPOAEs monitored. The intense sound alone suppressed all three cubic DPOAEs. The combination of PPADS with the intense sound induced a suppression of the cubic DPOAEs that was equal to or greater than induced by the intense sound alone at f2=10.8 kHz but was equal to or less than induced by the intense sound at f2=8.4 and 6.5 kHz. After washing the PPADS out of the cochlea with artificial perilymph, all three cubic DPOAEs were suppressed less in the PPADS with intense sound treatment group than in the intense sound alone group. The PPADS appeared to provide protection from the intense sound. Results are consistent with the hypothesis that extracellular ATP is involved in the changes in cochlear mechanics induced by moderately intense sound exposure.

Changes in cubic distortion product otoacoustic emissions (DeltaDPOAEs), evoked potential threshold shifts (TSs) and outer hair cell (OHC) losses were measured in a population of 95 noise-exposed chinchillas. Each animal was exposed to one of 23 different noises in an asymptotic threshold shift (ATS) producing paradigm or an interrupted noise paradigm which typically produced a toughening effect. Noises were narrow band (400 Hz) impacts with center frequencies of 0.5, 1.0, 2.0, 4.0 or 8.0 kHz presented 1 impact/s at peak SPLs of 109, 115, 121 or 127 dB. The duration of the exposures was 24 h/day for 5 days (ATS paradigm) or 6 h/day for 20 days (toughening paradigm). Based on a linear regression analysis of individual subject and group mean data, correlations among the following dependent variables were made: DeltaDPOAEs, ATS, toughening or TS recovery (TS(r)), permanent threshold shift (PTS) and OHC loss. Correlations among these metrics were generally highest for DPOAE primary frequency levels, L(1)=L(2)=70 dB. Correlation between DeltaDPOAE and TS(r) was typically low, while a considerably higher correlation was found between DeltaDPOAE and ATS. Correlations among the permanent measures of noise-induced effects, i.e. for DeltaDPOAE/PTS and DeltaDPOAE/OHC loss were typically poor when there was only a small or a moderate noise-induced effect (PTS

The inferior colliculus (IC) has been shown anatomically to make direct descending connections with medial olivocochlear (MOC) neurones in the auditory brainstem. The MOC neurones project to the outer hair cells in the cochlea and inhibit cochlear neural output. This study investigated the effect of IC stimulation on cochlear output in both guinea pigs and rats in order to determine the functional significance of the IC-to-olivocochlear system projection. Stimulation of the central nucleus and the external cortex of the IC in paralysed guinea pigs, both contra- and ipsilaterally to the test cochlea, resulted in a small increase of the cochlear microphonic amplitude and a small decrease of the compound action potential (CAP) amplitude, the latter equivalent to a 3–6 dB change in acoustic input. Effects on the CAP were maximal in the frequency range 6–10 kHz. These effects were consistent with partial activation of the MOC system. In unparalysed rats, stimulation of the inferior colliculus evoked a large, prolonged suppression ranging from 5–12 dB in the amplitude of distortion product otoacoustic emissions (2f1−f2; DPOAE), as reported previously by Scates et al. (1999). However, this suppression was decreased to only 0–3 dB when the animals were paralysed, suggesting that the larger suppression in the unparalysed state was the consequence of either a general masking effect caused by animal movement, or activation of middle ear muscles by the inferior colliculus stimulation. The results indicate a small but significant excitatory effect of the inferior colliculus on the medial olivocochlear system under conditions of anaesthesia and paralysis.

Distortion product otoacoustic emissions (DPOAEs), a sensitive detector of outer hair cell (OHC) function, cochlear microphonics (CM), and hair cell loss have been monitored in 12 awake guinea pigs before and after 2 h exposure to specific, played-back industrial noise (105 dB SPL maximal intensity). All animals had stable DPOAE levels before noise exposure. In the first hours after noise exposure DPOAE levels were reduced significantly. In about 70% a partial recovery of the DPOAEs was found within 4 months after noise exposure. In 16% of the investigated ears no recovery of DPOAEs was observed. However, in a few ears increased DPOAEs were observed after noise exposure. Exposure to industrial noise caused both morphological changes in the middle turns of the cochlea and electrophysiological changes in the middle frequency range. A close correlation existed between reduced DPOAE levels, loss in CM potentials, and area of damaged or lost OHCs, but not with the numbers of damaged or lost OHCs in the cochlea. It can be concluded that continuous industrial noise causes a damage to OHCs which differs form the damage caused by impulse noise.

The effects of eliminating the olivocochlear bundle (OCB) on cochlear electromechanical properties were examined by measuring cochlear microphonics (CM) and distortion product otoacoustic emissions (DPOAEs) in chronically de-efferented chinchillas. The OCB fibers to the right ears were successfully sectioned in six out of 15 adult chinchillas via a posterior paraflocular fossa approach. At the end of the experiment, these ears were histologically verified as being deprived of both lateral and medial OCB fibers. The opposite (left) ears from the animals served as controls. Following de-efferentation, changes of the inter-modulation distortion components (2f(1)-f(2), f(2)-f(1), 3f(1)-2f(2), 3f(2)-2f(1)) varied, depending on the frequencies and levels of the stimuli. DPOAE amplitudes to low-level stimuli were within the 95% confidence intervals around mean DPOAE amplitudes of the control ears at all the frequencies (1-8 kHz). At high stimulus levels, DPOAE amplitudes increased by 5-20 dB at 1 and 2 kHz while remaining in the normal range at 4 and 8 kHz. In contrast, the CM input/output functions to stimuli from 1 to 8 kHz were significantly reduced by approximately 40-50% at all input levels. The results suggest that the OCB may play a role in modulating electrical properties of the outer hair cells and in reducing the magnitude of cochlear distortion to high-level stimuli.

The purpose of this study was to investigate the changes in auditory function associated with aging in rhesus monkeys ( Macaca mulatta ) as a model for age-related changes in humans. One advantage of using monkeys from the Wisconsin Regional Primate Research Center was that lifestyle factors such as diet and excessive noise exposure were controlled. Twenty younger (mean: 10 years, 9 months, S.D.=±6 months) and 20 older (mean: 25 years, 11 months, S.D.=±11 months) monkeys were used in this study. Cochlear function in these monkeys was measured with distortion product otoacoustic emissions (DPOAEs); neural function was measured with auditory brainstem responses (ABRs) and middle latency responses (MLRs). Older monkeys had (1) significantly smaller DPOAEs, (2) significantly smaller ABR peak amplitudes, and (3) significantly longer ABR peak latencies compared to younger monkeys. Overall, these results suggest that older monkeys have decreased cochlear and neural function to the level of the brainstem as compared to younger monkeys. The decrease in DPOAE level and the increase in age accounted for approximately 70% of the increase in peak IV latency.

In a previous study, we demonstrated that word recognition performance was reduced when the low-frequency components of speech (0-1.2 kHz) were distorted by temporal jittering, but not when they were distorted by spectral smearing (Pichora-Fuller et al., 2007). Temporal jittering distorts the fine structure of the speech signal with negligible alteration of either its long-term spectral or amplitude envelope characteristics. Spectral smearing simulates the effects of broadened auditory filters that occur with cochlear hearing loss (Baer and Moore, 1993). In the present study, the high-frequency components of speech (1.2-7 kHz) were distorted with jittering and smearing. Word recognition in noise for both distortion conditions was poorer than in the intact condition. However, unlike our previous study, no significant difference was found in word recognition performance in the two distorted conditions. Whereas temporal distortion seems to have a deleterious effect that cannot be attributed to spectral distortion when only the lower frequencies are distorted, when the higher frequencies are distorted both temporal and spectral distortion reduce speech intelligibility.

Hearing sensitivity and the generation of acoustic-distortion products at 2f1-f2 were examined systematically in behaviorally trained rabbits, before, during, and following regular exposure to a 95-dB SPL octave band of noise, centered at 1 kHz. During the exposure period, the octave-band noise was interrupted once every 24 h in order to monitor the progressive loss in auditory function using tests of behavioral threshold and distortion-product otoacoustic emissions (DPOAEs). When low-frequency DPOAEs from 1-4 kHz diminished to noise-floor levels, i.e., when their amplitudes were reduced by about 20-30 dB, the exposure was terminated. Subsequent recovery of behavioral thresholds and DPOAE amplitudes and detection 'thresholds' was evaluated at regular intervals over a 3-week post-exposure period. Following the recovery period, the rabbits again received the identical exposure/recovery treatment until a permanent 10 dB or greater loss in DPOAE amplitudes was achieved for any point of measurement between 2-10 kHz. The primary result was that the number of days of overstimulation required for rabbits to reach the criterion loss in DPOAE amplitudes increased for each successive exposure session. In addition, DPOAEs accurately tracked the frequency pattern described by the behavioral threshold shifts during both the development and recovery stages of exposure.

As previously reported [Popelar, J., Groh, D., Pelanova, J., Canlon, B., Syka, J., 2006. Age-related changes in cochlear and brainstem auditory functions in Fischer 344 rats. Neurobiol. Aging 27, 490-500; Buckiova, D., Popelar, J., Syka, J., 2007. Aging cochleas in the F344 rat: morphological and functional changes. Exp. Gerontol. 42, 629-638; Bielefeld, E.C., Coling, D., Chen, G.D., Li, M.N., Tanaka, C., Hu, B.H., Henderson, D., 2008. Age-related hearing loss in the Fischer 344/NHsd rat substrain. Hear. Res. 241, 26-33], aged Fischer 344 (F344) rats with severe hearing loss retain many outer hair cells (OHCs) especially in the middle turn of the cochlea. The current study confirmed the previous findings showing that aged OHCs were present, but dysfunctional. Distortion product otoacoustic emissions (DPOAE), which are believed to reflect in vivo OHC motility, were absent in the aged rats while the majority of OHCs (>80%) were present and morphologically intact. There was no detectable injury of OHC stereocilia as assessed by actin-staining and examination under the light microscope. Cochlear microphonics (CM) at 12kHz, recorded from the middle turn, only showed a slight age-related reduction, indicating a normal mechanoelectrical transduction apparatus in the remaining OHCs in the cochlear regions with 10-20% OHC loss. Activities of succinate dehydrogenase (SDH), an enzyme shared by the citric acid cycle and the mitochondrial electron transport chain (METC), were also at normal levels in aged OHCs. Importantly, aged OHCs showed reduced levels of prestin immunolabeling compared to young controls. Together with our previous finding showing that the stria vascularis and endocochlear potential were essentially normal in aged F344 rats [Bielefeld, E.C., Coling, D., Chen, G.D., Li, M.N., Tanaka, C., Hu, B.H., Henderson, D., 2008. Age-related hearing loss in the Fischer 344/NHsd rat substrain. Hear. Res. 241, 26-33], the results suggest that disruption of prestin is the major cause of DPOAE loss and loss of cochlear sensitivity.

The aim of this study was to investigate whether distortion product otoacoustic emissions (DPOAEs) are a suitable means for detecting small changes in cochlear amplifier functionality due to occupational noise exposure of one workday and whether efferent reflex strength of the medial olivocochlear bundle is able to predict the ear's susceptibility to noise. High-resolution (Deltaf(2)= 47 Hz) DPOAEs were recorded between 3.5 and 4.5 kHz at close-to-threshold primary tone levels. For comparison, pure-tone audiometry was conducted. Efferent reflex strength was measured by means of DPOAEs at a specific frequency with and without contralateral acoustic stimulation. A statistically significant change was found for pure-tone thresholds (DeltaL(ht)=+1.6+/-3.0 dB, n=155) and DPOAE levels (DeltaL(dp)=-1.0+/-2.4 dB, n=646; L(2)=20 dB SPL) in factory workers but not in office workers (DeltaL(ht)=-1.3+/-3.3 dB, n=80; DeltaL(dp)=0.0+/-1.6 dB, n=336) (control group). However, the influence of systematic biases due to, e.g. ear probe calibration or measurement sequence effects, has to be considered. Moreover, there was no significant correlation between efferent reflex strength and shifts in pure-tone thresholds or shifts in DPOAE levels. Thus, the applied measures of efferent reflex strength do not seem to be suitable for predicting temporary changes in hearing capability.

When listening to two tones at frequency f1 and f2 (f2f1), one can hear pitches not only at f1 and f2 but also at distortion frequencies f2-f1, (n+1)f1-nf2, and (n+1)f2-nf1 (n=1,2,3...). Such two-tone distortion products (DPs) also can be measured in the ear canal using a sensitive microphone. These ear-generated sounds are called otoacoustic emissions (OAEs). In spite of the common applications of OAEs, the mechanisms by which these emissions travel out of the cochlea remain unclear. In a recent study, the basilar membrane (BM) vibration at 2f1-f2 was measured as a function of the longitudinal location, using a scanning laser interferometer. The data indicated a forward traveling wave and no measurable backward wave. However, this study had a relatively high noise floor and high stimulus intensity. In the current study, the noise floor of the BM measurement was significantly decreased by using reflective beads on the BM, and the vibration was measured at relatively low intensities at more than one longitudinal location. The results show that the DP phase at a basal location leads the phase at an apical location. The data indicate that the emission travels along the BM from base to apex as a forward traveling wave, and no backward traveling wave was detected under the current experimental conditions.

Noise-induced hearing loss may result from excessive release of glutamate, nitrogen oxide and reactive oxygen species. The effects of these factors on the inner ear may potentially be prevented or reduced by erythropoietin (EPO), as indicated by previously demonstrated neuro-protective effects of EPO upon damage to the central nervous system and the retina. This paper reports three separate trials, conducted to investigate the hypothesis that noise-induced hearing loss is prevented or reduced by erythropoietin. The trials employed three different modes of drug application, different administration time windows and different rodent species. In trial 1, guinea pigs were exposed to 110dB SPL, 4-20kHz wide band noise (WBN) for 8h. EPO was administered to the round window membrane 24h after noise exposure, either sustained by pump for a week or by single dose middle ear instillation. In trial 2, rats were exposed to 105dB SPL, 4-20kHz WBN for 8h. EPO was administered by single dose middle ear instillation 1 or 14h after noise exposure. In trial 3, rats were exposed to 105dB SPL, 4-20kHz WBN for 8 or 3x8h. EPO was injected intraperitoneally 1h before noise exposure. Oto-acoustic emissions and auditory brainstem responses (at 16kHz) were recorded before and after noise exposure in all trials. The noise exposure induced a hearing loss in all animals. In trial 1, no recovery and no improvement of hearing occurred in any treatment group. In trial 2 and 3, a partial hearing recovery was seen. However, the hearing loss of the EPO treated animals was significantly worse than controls in trial 2. In trial 3, the hearing of the EPO treated animals exposed for 3x8h was significantly worse than controls. Thus, surprisingly, the results from 2 of the 3 present trials indicate that erythropoietin may in fact augment noise-induced hearing loss. This is contradictory to the beneficial effect of EPO reported by the vast majority of studies on stressed neural tissues. EPO administration may alter the blood flow dynamics of the cochlear vascular bed during or after noise exposure, by a potential induction of vasoconstriction. This may be the cause of the surprising findings.

DPOAE temporary level shift (TLS) at 2f(1)-f(2) and f(2)-f(1), ABR temporary threshold shift (TTS), and detailed histopathological findings were compared in three groups of chinchillas that were exposed for 24 h to an octave band of noise (OBN) centered at 4 kHz with a sound pressure level (SPL) of 80, 86 or 92 dB (n=3,4,6). DPOAE levels at 39 frequencies from f(1)=0.3 to 16 kHz (f(2)/f(1)=1.23; L(2) and L(1)=55, 65 and 75 dB, equal and differing by 10 dB) and ABR thresholds at 13 frequencies from 0.5 to 20 kHz were collected pre- and immediately post-exposure. The functional data were converted to pre- minus post-exposure shift and overlaid upon the cytocochleogram of cochlear damage using the frequency-place map for the chinchilla. The magnitude and frequency place of components in the 2f(1)-f(2) TLS patterns were determined and group averages for each OBN SPL and L(1), L(2) combination were calculated. The f(2)-f(1) TLS was also examined in ears with focal lesions equal to or greater than 0.4 mm. The 2f(1)-f(2) TLS (plotted at f(1)) and TTS aligned with the extent and location of damaged supporting cells. The TLS patterns over frequency had two features which were unexpected: (1) a peak at about a half octave above the center of the OBN with a valley just above and below it and (2) a peak (often showing enhancement) at the apical boundary of the supporting-cell damage. The magnitudes of the TLS and TTS generally increased with increasing SPL of the exposure. The peaks of the TLS and TTS, as well as the peaks and valleys of the TLS pattern moved apically as the SPL of the OBN was increased. However, there was little consistency in the pattern relations with differing L(1), L(2) combinations. In addition, neither the 2f(1)-f(2) nor f(2)-f(1) TLS for any L(1), L(2) combination reliably detected focal lesions (100% OHC loss) from 0.4 to 1.2 mm in size. Often, the TLS went in the opposite direction from what would be expected at focal lesions. Recovery from TLS and TTS was also examined in seven animals. Both TLS and TTS recovered partially or completely, the magnitude depending upon exposure SPL.

Distortion product otoacoustic emissions (DPOAE), permanent threshold shifts (PTS) and outer hair cell (OHC) losses were analyzed in a population of 187 noise-exposed chinchillas to determine the predictive accuracy (sensitivity and specificity) of the DPOAE for PTS and OHC loss. Auditory evoked potentials (AEP) recorded from the inferior colliculus of the brainstem were used to estimate hearing thresholds and surface preparation histology was used to determine sensory cell loss. The overlapping cumulative distributions and high variability in emission responses for both PTS and OHC loss made it difficult to predict AEP threshold and OHC loss from DPOAE level measurements alone. Using a strict criterion (i.e. emissions better than the 5th percentile of the preexposure DPOAE level, and PTSor = 5 dB or OHC lossor = 5%), it was found that the postexposure DPOAE level could be used with reasonable confidence to determine if the status of peripheral auditory system was either normal (i.e. PTSor = 5 dB) or abnormal (PTS30 dB or OHC loss40%). However, the high variability of individual DPOAE responses resulted in a broad region of 'uncertainty' (i.e. 5PTSor = 30 dB and 5%OHC lossor = 40%) making it difficult in the chinchilla model to use the postexposure DPOAE level with confidence to predict in individual subjects the amount of PTS or OHC loss. Our results also indicate that significant reductions in the amplitude of the DPOAE are related primarily to a systematic loss of OHCs, and that a postexposure DPOAE levelor = 10 dB SPL, obtained with a low frequency primary level of 65 dB SPL, represents a criterion value which can serve as an indication of significant OHC loss (or = 50%) or PTS (or = 35 dB) in noise-exposed chinchillas. Based on an exponential regression analysis of individual subjects, correlations were higher for PTS/DPOAE than for OHC loss/DPOAE.

Thapsigargin, a drug that inhibits sarco-endoplasmic reticulum Ca(2+) ATPases (SERCAs), was infused into the perilymph compartment of the guinea pig cochlea in increasing concentrations (0.1-10 microM) while sound evoked cochlear potentials were monitored. Thapsigargin significantly suppressed the compound action potential of the auditory nerve, cochlear microphonics, and increased N(1) latency at low (56 dB SPL) and high intensity (92 dB SPL) levels of sound, suppressed low intensity sound evoked summating potential (SP) and greatly increased the magnitude of the high intensity sound evoked SP. At 10 microM, the drug suppressed the cubic distortion product otoacoustic emissions (2f(1)-f(2)=8 kHz, f(2)=12 kHz) evoked by both high and low intensity primaries (45, 60, 70 dB SPL). Thapsigargin (10 microM; 30 min) increased the endocochlear potential slightly (5 mV). In chronic animals, thapsigargin (10 microM; 60 min) destroyed many outer hair cells and some inner hair cells, especially in the basal turns. These effects are consistent with the hypothesis that the inhibition of the SERCAs affects the function of the cochlear amplifier and outer hair cells to a greater degree than it affects other functions of the cochlea.

Delay times in the mammalian cochlea, whether from measurement of basilar membrane (BM) vibration or otoacoustic emissions (OAEs) have, to date, been largely based on phase-gradient estimates from steady-state responses. Here we report cochlear delays measured directly in the time domain from OAEs evoked by amplitude-modulated tone-burst (AMTB) stimuli. Measurement using OAEs provides a non-invasive estimate of cochlear delay but is confounded by the complexity of generation of such OAEs. At low to moderate stimulus levels, and provided that the stimulus frequency range does not include a region of the cochlea where there is a large change in effective reflectance, AMTB stimuli evoke an OAE with an envelope shape that is similar to the stimulus and allow a direct calculation of cochlear group delay. Such delays are commensurate with BM estimates of delay, estimates of cochlear delay inferred from neural recordings, and previous OAE measures of delay in the guinea pig. However, a nonlinear distortion mechanism, variation in effective reflectance, and intermodulation distortion products generated by the nonlinear interaction in the cochlea of the carrier and sidebands of the AMTB stimulus, may all contribute to OAEs arising with envelope shapes that are not a scaled representation of the stimulus, confounding the estimation of cochlear group delay.

A special stimulus paradigm needs to be applied when distortion product otoacoustic emission (DPOAE) input/output functions are used to investigate the loss of sensitivity and loss of compression of outer hair cell cochlear amplifiers during noise exposure, drug treatment, etc. This stimulus paradigm should be able to reflect cochlear non-linear compressive sound processing known from direct basilar membrane measurements. Such a paradigm has already been established for humans that accounts for the different compression of the primary tones at the DPOAE generation site at f2 with L1 = 0.4 L2 + 39 dB SPL ('scissor paradigm'). The purpose of the present study was to develop an equivalent parameter setting for guinea pigs. Ninety-six different L1 - L2 combinations were presented to 24 ears in 18 pigmented guinea pigs at seven f2 frequencies between 2 and 16 kHz. L2 ranged from 20 to 60 dB SPL, L1 from 20 to 65 dB SPL. An extreme value analysis was performed to achieve the maximum DPOAE level for L1 in relation to L2. Linear regression analysis yielded a scissor paradigm specific to guinea pigs (L1 = 0.46 L2 + 41 dB SPL) which is similar to that of humans.

In humans, distortion product otoacoustic emissions (DPOAEs) at frequencies lower than the f(2) stimulus frequency are a composite of two separate sources, these two sources involving two distinctly different mechanisms for their production: non-linear distortion and linear coherent reflection [Talmadge et al., J. Acoust. Soc. Am. 104 (1998) 1517-1543; Talmadge et al., J. Acoust. Soc. Am. 105 (1999) 275-292; Shera and Guinan, J. Acoust. Soc. Am. 105 (1999) 332-348; Kalluri and Shera, J. Acoust. Soc. Am. 109 (2001) 662-637]. In rodents, DPOAEs are larger, consistent with broader filters; however the evidence for two separate mechanisms of DPOAE production as seen in humans is limited. In this study, we report DPOAE amplitude and phase fine structure from the guinea pig with f(2)/f(1) held constant at 1.2 and f(2) swept over a range of frequencies. Inverse Fast Fourier Transform analysis and time-domain windowing were used to separate the two components. Both the 2f(1)-f(2) DPOAE and the 2f(2)-f(1) DPOAE were examined. It was found that, commensurate with human data, the guinea pig DPOAE is a composite of two components arising from different mechanisms. It would appear that the 2f(1)-f(2) emission measured in the ear canal is usually dominated by non-linear distortion, at least for a stimulus frequency ratio of 1.2. The 2f(2)-f(1) DPOAE exhibits amplitude fine structure that, for the animals examined, is predominantly due to the variation in amplitude of the place-fixed component. Cochlear delay times appear consistent with a linear coherent reflection mechanism from the distortion product place for both the 2f(1)-f(2) and 2f(2)-f(1) place-fixed components.

Ephrins and Eph receptors are a family of molecules that have been implicated in many developmental processes including neuronal network formation, guidance of cell migration, and axonal pathfinding. These molecules exhibit the ability to send bidirectional signals following ligand–receptor interactions resulting from cell–cell contacts. Gene-targeted knockout mice of B-class ephrins and Eph receptors have been shown to display phenotypic responses that correlate with anatomical defects. For example, disruption of the EphB2 receptor leads to defects of the vestibular system, including pathfinding abnormalities in efferent axons and reduced endolymph production. Such developmental distortions lead to deficiencies in ionic homeostasis and repetitive circling behaviors. The present study demonstrates that B-class ephrins and Eph receptors are expressed in cochlear tissues, suggesting that they may play some role in auditory function. To determine whether ephrins and Eph receptors have a functional role in the peripheral auditory system, distortion-product otoacoustic emission (DPOAE) levels, collected across a broad frequency range, were compared between groups of mice expressing different Eph receptor genotypes. In particular, EphB1 and EphB3 receptor knockout mice exhibited significantly diminished DPOAE levels as compared to wild-type littermates, indicating that these specific Eph receptors are necessary for normal cochlear function.

A detailed comparison of 2f(1)-f(2) distortion product otoacoustic emission (DPOAE) level shifts (LS) and auditory brainstem response (ABR) threshold shifts with noise-induced histopathology was conducted in chinchillas. DPOAE levels (i.e., L(1) and L(2)) at f(1) and f(2), respectively, ranged from 55-75 dB sound pressure level (SPL), with f(2)/f(1)=1.23, 6 points/octave, f(2)=0.41-20 kHz, and ABR thresholds at 0.5-20 kHz, 2 points/octave, were determined pre-exposure. The exposure was a 108 dB SPL octave band of noise centered at 4 kHz (1-1.75 h, n=6) or 80-86 dB SPL (24 h, n=5). DPOAE LSs (magnitude pre- minus post-exposure) and ABR threshold shifts (TS) were determined at 0 days and up to 28 days post-exposure. The cochleae were fixed, embedded in plastic and dissected into flat preparations. The length of the organ of Corti (OC) was measured; missing inner (IHC) and outer (OHC) hair cells counted; stereocilia damage rated; and regions of OC and nerve-fiber loss determined. Cytocochleograms were made showing functional loss and structural damage with the LS and TS overlaid. Some unexpected results were obtained. First, the best correlation of LS with histopathology required plotting the DPOAE data at f(1) with respect to the chinchilla-place map. The best correlation of TS was with IHC and nerve-fiber loss. Second, wide regions of up to 10% scattered OHC loss in the apical half of the OC showed little or no LS. Third, with the 108 dB SPL noise, there was 20-40 dB of recovery for DPOAEs at mid-high frequencies (3-10 kHz) in eight of 12 cochleae where there was 70-100% OHC loss in the basal half of the OC. The largest recovery at mid-high frequencies occurred in regions where the OC was entirely missing. Fourth, with the 80-86 dB SPL noise, there was no LS at small focal lesions (100% loss of OHCs over 0.4 mm) when the frequency place of either f(1) or f(2) was within the lesion but not both. There was no correlation of LS with OHC stereocilia loss, fusion or disarray. These results suggest that, after noise exposure, DPOAEs at mid-high frequencies can originate from or be augmented by generators located at someplace other than the frequency place of f(2), possibly the basal 20% of the OC when this region is intact. Also, noise-induced DPOAE LSs seemed to reflect differing mechanisms for temporary and permanent hearing loss.

A physiologically based nonlinear active cochlear model is presented. The model includes the three-dimensional viscous fluid effects, an orthotropic cochlear partition with dimensional and material property variation along its length, and a nonlinear active feed-forward mechanism of the organ of Corti. A hybrid asymptotic and numerical method combined with Fourier series expansions is used to provide a fast and efficient iterative procedure for modeling and simulation of the nonlinear responses in the active cochlea. The simulation results for the chinchilla cochlea compare very well with experimental measurements, capturing several nonlinear features observed in basilar membrane responses. These include compression of response with stimulus level, two-tone suppressions, and generation of harmonic distortion and distortion products.

The purpose of this study was to examine whether outer hair cells (OHCs), inner hair cells and the brainstem auditory pathway are impaired due to a mutation in a gap junction protein, connexin 26 (Cx26), 35delG. Fifty-six individuals, from a village with widespread consanguinity and profound, non-syndromic congenital deafness, due to 35delG mutation, were selected among relatives of deaf people. The individuals were either non-carriers (n=20), heterozygous (n=20) or homozygous (n=16) for the mutation. Distortion product oto-acoustic emissions (DPOAEs) and auditory brainstem evoked potentials (ABEPs) in mutation non-carriers, in heterozygotes (carriers) and in subjects homozygous for the mutation were compared in addition to audiometric evaluation. Most deaf homozygotes had no DPOAEs, except some sporadic responses at 1000, 8000 and 10000 Hz. This was also observed in audiometry which showed profound hearing loss in most cases. Two cases were unique: one had moderate to severe hearing loss and the other had severe to profound hearing loss. A significant difference was found between non-carriers and carriers of 35delG: non-carriers had larger DPOAE responses than heterozygotes at all frequencies. The prevalence of responses got lower with higher frequencies in both groups, but between 6000 and 10000 Hz 50-70% of the carriers had no DPOAE responses, compared to 30-60% of non-carriers. In both groups responses diminished with age, but no significant interaction was found between age and the genetic group. ABEPs among homozygotes were variable: in most homozygotes ABEPs were absent or partial (waves III, V) with prolonged latencies, but two subjects had ABEPs within normal limits, in one ear. ABEPs were normal with no differences between carriers and non-carriers. We suggest that OHC function is affected by the 35delG mutation in Cx26. In addition, the hearing of carriers of this mutation may be impaired at very high frequencies (8000-10000 Hz), which are not assessed in routine audiometry or ABEP testing.

The outer hair cell electromotile response is believed to underlie the sharp tuning and exquisite sensitivity of the mammalian inner ear, and contribute to the production of electrically evoked otoacoustic emissions (EEOAEs) and sound-evoked otoacoustic emissions (OAEs). Avian ears are also sharply tuned, extremely sensitive and generate spontaneous and sound-evoked OAEs, but avian hair cells do not exhibit somatic electromotility. However, stereocilia bundle movements have been observed in avian and amphibian hair cells suggesting that EEOAEs might arise from electrically evoked bundle movements. Here, we demonstrate for the first time that AC current applied to the round window of the chicken evokes EEOAE of up to 18 dB SPL. The EEOAE produces a bandpass response with maximum amplitude in the 1000-3000 Hz range; the response drops off rapidly above 4000 Hz and below 500 Hz. The impulse response to current pulses is characterized by a large peak sometimes followed by a damped oscillation with a frequency around 2000 Hz. EEOAEs decreased significantly after anoxia and paraformaldehyde damage of the cochlea. Kanamycin-induced hair cell loss also caused a significant reduction in EEOAE and distortion product OAE; these emissions showed only a small recovery at long recovery times, when most hair cells should have regenerated. These results suggest that the EEOAE has a biological origin in the cochlea, which could presumably involve electrically evoked stereocilia bundle movements.

The effects on hearing of simultaneous exposure to the ototoxic organic solvent ethyl benzene and broad-band noise were evaluated in rats. The effects of three ethyl benzene concentrations (0, 300 or 400 ppm) and three noise levels (95 or 105 dBlin SPL or background noise at 65 dBlin SPL) and all their combinations were investigated for a 5 day exposure at 8 h/day. Distortion product otoacoustic emissions and compound action potentials were affected after 105 dB noise alone, and after 105 dB noise in combination with ethyl benzene (300 and 400 ppm). However, the amount of loss for these combinations did not exceed the loss for 105 dB noise alone. Outer hair cell (OHC) loss after exposure to 300 ppm ethyl benzene was located in the third row of OHCs. At 400 ppm, the loss spread out to the second and first row of OHCs. Noise alone hardly affected the OHC counts except for a minor loss in the first row of OHCs after 105 dB SPL. Noise at 105 dB in combination with ethyl benzene at 300 and 400 ppm, however, showed OHC loss greater than the sum of the losses induced by noise and ethyl benzene alone. © 2001 Elsevier Science B.V. All rights reserved. Chemicals/CAS: Benzene Derivatives; ethylbenzene, 100-41-4

The noctuoid moth Empyreuma affinis has a simple tympanal organ with only two receptor cells attached to the eardrum. As in vertebrates, the growth of distortion-product otoacoustic emissions (DPOAE) with increasing stimulus level is characterized by two distinct components. An initial increase of DPOAE level for f 2 levels in the range of 30–65 dB SPL is followed by a second steep growth of the DPOAE at f 2 levels above 65 dB SPL. Both components increase at a slope of about 2 dB/dB and the difference between both components was used to assess a mechanical gain of the tympanal organ of 17 dB ( n =23). At around 65 dB SPL, a notch in the level function coincides with an abrupt phase change of up to 180°. The sensitive component induced by f 2 levels below 65 dB SPL is selectively affected by application of ethyl ether and disappears more quickly than the high-level component during ongoing deterioration of the moth preparation.

A number of studies have shown that the ear can be protected from sound over-exposure, either by activating the cochlear efferent system, or by sound ‘conditioning’ in which the role of the efferent system is less certain. To study more definitively the molecular basis of deliberately induced cochlear protection from excessive sounds, it is advantageous to determine, for an inbred mouse strain, a range of noise exposure parameters that effectively alter cochlear function. As an initial step towards this goal, young CBA/CaJ mice were exposed to a 105-dB SPL octave-band noise (OBN), centered at 10 kHz, for various lengths of time consisting of 10 min, or 0.5, 1, 3, or 6 h. Distortion product otoacoustic emissions (DPOAEs) at the 2f1−f2 frequency, in response to equilevel primary tones of low to moderate levels, were used to quantify the damaging effects of these sound over-exposures on cochlear function. In addition, staining for acetylcholinesterase (AChE) activity to assess for noise-induced changes in the pattern of efferent-nerve innervation to the cochlea was also performed in a subset of mice that were exposed to the longest-lasting 6-h OBN. The 10-min OBN resulted in only temporary reductions in DPOAE levels, which recovered to pre-exposure values within 5 days. Increasing the exposure to 0.5 h resulted in permanent DPOAE losses that, for low primary-tone levels, were still present at 31 days post-exposure. Additionally, the 1-h and longer exposures caused permanent reductions in DPOAEs for all test levels, which were measurable at 31 days following exposure. Light-microscopic observations restricted to the 11–18-kHz frequency region of the organ of Corti, for a subset of mice exposed to the 6-h OBN, uncovered a significant loss of outer hair cells (OHCs). However, despite the OHC loss in this region, the AChE activity associated with the related pattern of efferent innervation remained largely intact.

Epidemiological and experimental studies suggest that hypercholesterolemia promotes the development of sensorineural hearing loss; however, the underlying cellular pathomechanism remains obscure. In the present study, 20 healthy subjects and 20 patients with familial hypercholesterolemia were compared with respect to their hearing function. None of the 40 persons reported any history of hearing disorder. In accordance with this subjective impression, mean hearing thresholds were within the normal, age-dependent ranges in both groups. In contrast, the single-generator distortion product otoacoustic emissions (sgDPOAE) were reduced at and above 4 kHz. Input-output functions of DPOAE could be subdivided into three groups: (i) normal, with unity slope at low intensities and slope less than unity (0.24+/-0.07 dB/dB at higher intensities; (ii) pathologic, described by a single straight line; (iii) ill-defined, with data usually indistinguishable from the background noise level. The ill-defined DPOAE behavior was only found in patients with hypercholesterolemia; namely, for 25% of patients at f(2)=1.5 kHz and for 50% at f(2)=4 kHz. Patients belonging to the pathologic and ill-defined DPOAE groups had significantly (P0.05) higher total serum cholesterol and LDL-cholesterol levels compared with subjects from the normal DPOAE group. While hearing thresholds of patients with ill-defined growth functions were not statistically different from those of normal subjects, speech scores were significantly reduced in these cases. The data imply that nonlinear mechanical processes in the cochlea are compromised in hypercholesterolemic patients.

Effect of changes in stimulus levels of both lower (f(1)) and higher (f(2)) stimulus tones on phases of 2f(1)-f(2) component of the distortion product otoacoustic emission (DPOAE) was examined in five normal hearing adults. The f(2) was fixed at 4004 Hz in all of the measurements, and the stimulus frequency ratio (f(2)/f(1)) was varied from 1.15 to 1.3. Change of the level of lower stimulus tone (L(1)) and the level of higher stimulus tone (L(2)) showed different effects on the DPOAE phases. The phase lags increased with increasing L(1), when f(2)/f(1) was above 1.22, whereas the phase gains increased with increasing L(1), when f(2)/f(1) was below 1.22. On the other hand, the difference in L(2) minimally affected DPOAE phase at most f(1)s. The previous studies about basilar membrane vibration revealed that phase lags increase with increasing stimulus level, when the stimulus frequency is below the best frequency, while phase gains increase with increasing stimulus level, when the stimulus frequency is above the best frequency, and the effect of phase change in stimulus level diminished, when the stimulus frequency was far above the best frequency. Based on the comparison between the results of the present study and the previous findings of others concerning basilar membrane vibration, the DPOAE generation site is assumed to be located at apical of the peak of the f(2) traveling wave.

The effects of AC and DC current on spontaneous otoacoustic emissions (SOAEs) were studied in normal chinchillas and chinchillas with selective inner hair cell (IHC) loss. Electrical stimulation was delivered through an electrode on the round window or through an electrode in scala media. SOAE frequencies ranged from 4 to 11 kHz and amplitudes ranged from 13 to 51 dB SPL. AC simulation suppressed SOAE amplitude. The suppression contours had a narrowly tuned, low-threshold tip located above the frequency of the SOAE. AC suppression contours were similar to acoustic suppression contours except that the AC suppression contours lacked a high-threshold, low frequency tail. The lowest threshold of the AC suppression contour was 3.9 microA rms whereas the lowest acoustic suppression threshold was 19 dB SPL. AC stimulation, which induced an electrically evoked otoacoustic emission, interacted with the SOAE to generate distortion product otoacoustic emissions (DPOAEs) of up to 26 dB SPL at 2f(S)-f(AC) (f(S)=SOAE). DPOAE amplitude increased with AC current, but saturated at high levels. DC current steps affected both SOAE frequency and amplitude. Positive current at the round window decreased SOAE amplitude and frequency whereas negative current increased SOAE frequency, but had little effect on amplitude. The effects of AC and DC current on SOAEs in animals with IHC loss were similar to those in normal chinchillas.