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This study uses a 3-D representation of the cochlear fluid to extend the results of a recent paper [Sisto, Belardinelli, and Moleti (2021b). J. Acoust. Soc. Am. 150, 4283–4296] in which two hydrodynamic effects, pressure focusing and viscous damping of the BM motion, both associated with the sharp increase in the wavenumber in the peak region, were analyzed for a 2-D fluid, coupled to a standard 1-D transmission-line WKB approach to cochlear modeling. The propagation equation is obtained from a 3-D fluid volume conservation equation, yielding the focusing effect, and the effect of viscosity is represented as a correction to the local 1-D admittance. In particular, pressure focusing amplifies the BM response without modifying the peak admittance, and viscous damping determines the position of the response peak counteracting focusing, as sharp gradients of the velocity field develop. The full 3-D WKB formalism is necessary to represent satisfactorily the behavior of the fluid velocity field near the BM-fluid interface, strictly related to viscous losses. As in finite element models, a thin layer of fluid is effectively attached to the BM due to viscosity, and the viscous force associated with the vertical gradient of the fluid vertical velocity acts on the BM through this layer.

In a previous study, we observed: (i) significant hearing function impairment, assessed with pure tone audiometry and distortion product otoacoustic emissions, in patients with Parkinson’s disease, compared with a matched control group, and (ii) lateralization of the hearing dysfunction, worse on the side affected by more pronounced Parkinson’s disease motor symptoms. This study investigates the association between the basal ganglia dopamine transporter availability and the hearing function in Parkinson’s disease patients, focusing also on the lateralization of both dysfunctions, with respect to that of the motor symptoms, and introducing a further distinction between patients with left-sided and right-sided predominant motor symptoms. Patients with right-handed Parkinson’s disease with a recent estimation of 123I-FP-CIT striatal uptake were audiologically tested with pure tone audiometry and distortion product otoacoustic emissions. Thirty-nine patients were included in the study. A statistically significant association was found, in the left-side predominant group only, between the distortion product otoacoustic emission levels and the contralateral dopamine transporter availability, and between the hearing threshold and the dopamine transporter availability difference between the ipsi- and the contralateral sides. The hearing impairment lateralization correlated to the motor symptom asymmetry was found significant only in the left-side predominant patients. The association between hearing function and basal ganglia dopamine transporter availability supports the hypothesis that the peripheral hearing function decline associated with dopamine depletion is involved in Parkinson’s disease development, with a significant difference between patients with left- and right-sided predominant motor symptoms. These findings also suggest that peripheral hearing function evaluation and its lateralization could be key elements for subtyping the disease.

This paper discusses the role of two-dimensional (2-D)/three-dimensional (3-D) cochlear fluid hydrodynamics in the generation of the large nonlinear dynamical range of the basilar membrane (BM) and pressure response, in the decoupling between cochlear gain and tuning, and in the dynamic stabilization of the high-gain BM response in the peak region. The large and closely correlated dependence on stimulus level of the BM velocity and fluid pressure gain [Dong, W., and Olson, E. S. (2013). Biophys. J. 105(4), 1067-1078] is consistent with a physiologically oriented schematization of the outer hair cell (OHC) mechanism if two hydrodynamic effects are accounted for: amplification of the differential pressure associated with a focusing phenomenon, and viscous damping at the BM-fluid interface. The predictions of the analytical 2-D Wentzel-Kramers-Brillouin (WKB) approach are compared to solutions of a 3-D finite element model, showing that these hydrodynamic phenomena yield stable high-gain response in the peak region and a smooth transition among models with different effectiveness of the active mechanism, mimicking the cochlear nonlinear response over a wide stimulus level range. This study explains how an effectively anti-damping nonlinear outer hair cells (OHC) force may yield large BM and pressure dynamical ranges along with an almost level-independent admittance.

Distortion product otoacoustic emission (DPOAE) levels plotted as a function of stimulus frequency ratio demonstrate a bandpass shape. This bandpass shape is narrower at higher frequencies compared to lower frequencies and thus has been thought to be related to cochlear mechanical tuning. However, the frequency- and level-dependence of these functions above 8 kHz is largely unknown. Furthermore, how tuning estimates from these functions are related to behavioral tuning is not fully understood. From experiment 1, we report DPOAE level ratio functions (LRF) from seven normal-hearing, young-adults for f(2) = 0.75-16 kHz and two stimulus levels of 62/52 and 52/37 dB FPL. We found that LRFs became narrower as a function of increasing frequency and decreasing level. Tuning estimates from these functions increased as expected from 1-8 kHz. In experiment 2, we compared tuning estimates from DPOAE LRF to behavioral tuning in 24 normal-hearing, young adults for 1 and 4 kHz and found that behavioral tuning generally predicted DPOAE LRF estimated tuning. Our findings suggest that DPOAE LRFs generally reflect the tuning profile consistent with basilar membrane, neural, and behavioral tuning. However, further investigations are warranted to fully determine the use of DPOAE LRF as a clinical measure of cochlear tuning.

Acoustic Diagnostics is an Italian Space Agency (ASI) biomedical experiment exploiting the diagnostic potential of otoacoustic emissions (OAEs) to monitor the astronauts’ hearing health on board the International Space Station (ISS). It is being performed (July 2019–April 2020) on the ISS, in the framework of the BEYOND mission, sponsored by European Space Agency (ESA). A dedicated instrument for measuring distortion product OAE (DPOAE) in a noisy environment was designed by University of Rome Tor Vergata and INAIL. Aerospace Logistics Technology Engineering Company (ALTEC) took care of the payload development, mechanical, thermal and electromagnetic tests, verification, and acceptance. Two astronauts were subjected, before leaving for their mission on the ISS, to the DPOAE test, along with a full set of audiological tests (Baseline Data Collection, BDC), especially designed at University of Roma La Sapienza and Campus Bio-Medico. An identical DPOAE apparatus was used five times on board the ISS to test the two astronauts. Finally, a post-flight BDC was performed, few days after return to Earth. Preliminary analysis demonstrated that the payload was able to record DPOAEs on board the ISS with very low instrumental noise level, despite the high noise level of the ISS environment. ASI, in the frame of its national mission of promoting and fostering the culture of space across the Country, provides access to the ISS as a laboratory in space. The utilization support services are provided, thanks to a contract, awarded by ASI, to ARGOTEC/Telespazio (UTISS Team).

Objective: To evaluate the ototoxic effect of the exposure to different organic solvents and noise using distortion product otoacoustic emissions (DPOAEs).Design: The exposure to different solvents...

Uncertainties regarding the generation mechanism and source of human stimulus frequency otoacoustic emissions (SFOAEs), as well as the possible generation of artifacts, have previously restricted the use of SFOAEs in clinical settings for assessing cochlear function. Over the years, advanced time-frequency analysis of SFOAEs, using models of SFOAE delays as a function of frequency, have been implemented in an effort to isolate the long-latency (LL) component of SFOAEs—improving the signal-to-noise ratio and the artifact rejection as noteworthy byproducts. In order to test the hypothesis that behavioral measures and SFOAE LL component both reflect the activity of limited cochlear regions, the relationship between SFOAE LL component and behavioral measures was investigated. SFOAEs, behavioral thresholds and psychophysical tuning curves (PTCs) were measured for probe frequencies centered around 0.75, 1, 2, 4, 8, 10, 12.5 and 14 kHz. Stimulus levels for PTCs (10 dB SL) and SFOAEs (10, 20 and 30 dB SL) were referenced to behavioral thresholds at each frequency. Using the same in situ calibration technique using Thevenin-equivalent source parameters, behavioral thresholds and SFOAE-estimated thresholds from input-output functions of the SFOAE LL component were strongly correlated. Furthermore, there was a strong correlation between SFOAE-based and psychophysical tuning estimates.

The zero crossings of basilar-membrane (BM) responses to clicks are nearly independent of stimulus intensity. This work explores the constraints that this invariance imposes on one-dimensional nonlinear cochlear models with two degrees of freedom (2DoF). The locations of the poles and zeros of the BM admittance, calculated for a set of linear models in which the strength of the active force is progressively decreased, provides a playground for evaluating the behavior of a corresponding nonlinear model at increasing stimulus levels. Mathematical constraints on the model parameters are derived by requiring that the poles of the admittance move horizontally in the s-plane as the active force is varied. These constraints ensure approximate zero-crossing invariance over a wide stimulus level range in a nonlinear model in which the active force varies as a function of the local instantaneous BM displacement and velocity. Two different 2DoF models are explored, each capable of reproducing the main qualitative characteristics of the BM response to tones (i.e., the tall and broad activity pattern at low stimulus levels, the large gain dynamics, and the partial decoupling between gain and phase). In each model, the motions of the two masses are compared with response data from animal experiments.

The mammalian cochlea achieves its remarkable sensitivity, frequency selectivity, and dynamic range by spatially segregating the different frequency components of sound via nonlinear processes that remain only partially understood. As a consequence of the wave-based nature of cochlear processing, the different frequency components of complex sounds interact spatially and nonlinearly, mutually suppressing one another as they propagate. Because understanding nonlinear wave interactions and their effects on hearing appears to require mathematically complex or computationally intensive models, theories of hearing that do not deal specifically with cochlear mechanics have often neglected the spatial nature of suppression phenomena. Here we describe a simple framework consisting of a nonlinear traveling-wave model whose spatial response properties can be estimated from basilar-membrane (BM) transfer functions. Without invoking jazzy details of organ-of-Corti mechanics, the model accounts well for the peculiar frequency-dependence of suppression found in two-tone suppression experiments. In particular, our analysis shows that near the peak of the traveling wave, the amplitude of the BM response depends primarily on the nonlinear properties of the traveling wave in more basal (high-frequency) regions. The proposed framework provides perhaps the simplest representation of cochlear signal processing that accounts for the spatially distributed effects of nonlinear wave propagation. Shifting the perspective from local filters to non-local, spatially distributed processes not only elucidates the character of cochlear signal processing, but also has important consequences for interpreting psychophysical experiments.

The spatial extent of the cochlear region that actually contributes to the DPOAE signal measured in the ear canal may be evaluated experimentally using interference tones or computed numerically using nonlinear cochlear models. A nonlinear transmission-line cochlear model is used in this study to evaluate whether the recently reported nonlinear behavior of the reticular lamina (RL) over a wide basal region may be associated with generation of a significant distortion product otoacoustic emission (DPOAE) component. A two-degrees-of-freedom 1-D nonlinear model was used as discussed by Sisto et al. (2019), in which each local element consists of two coupled oscillators, roughly representing the basilar membrane (BM) and the RL. In this model, the RL shows a strongly nonlinear response over a wide region basal to the characteristic place, whereas the BM response is linear outside the narrow peak region. Such a model may be considered as that using the minimal number of degrees of freedom necessary to separately predict the motion of the BM and RL, while preserving important cochlear symmetries, such as the zero-crossing invariance of the impulse response. In the numerical simulations, the RL nonlinearity generates indeed a large intracochlear distortion product source, extended down to very basal cochlear regions. Nevertheless, due to the weak and indirect coupling between the RL motion and the differential fluid pressure in the basal part of the traveling wave path, no significant contribution from this mechanism is predicted by the model to the generation of the DPOAE signal that is eventually measured in the ear canal.

Background Although styrene is an established ototoxic agent at occupational exposure levels, the mechanisms of styrene toxicity in the auditory system are still unclear. Objectives The aim of this study was to identify the consequences of styrene chronic exposure in cochlear structures, looking for the mechanisms of ototoxicity of this organic compound and focusing on cell targets and oxidative stress/inflammatory processes. Methods Male adult Wistar rats were exposed to styrene (400 mg/kg by gavage for 5 days/week, 3 consecutive weeks). Hearing loss was evaluated by measuring auditory brainstem responses (ABR), morphological analysis were performed to evaluate hair cell and spiral ganglion neuron survival, as well as synaptic damage. Analysis of apoptotic (p53) and inflammatory (NF-κB, TNF-α, IL-1β and IL-10) mediators were performed by immunofluorescence analysis and western blot. Results Styrene ototoxic effects induced a hearing loss of about 35–40 dB. Immunofluorescence and western blotting analyses demonstrated that styrene administration induced redox imbalance and activated inflammatory processes, targeting sensory hair cell and neural dysfunction by a cross-talk between oxidative and inflammatory mediators. Discussion Major findings connect styrene ototoxicity to an interplay between redox imbalance and inflammation, leading to the intriguing assumption of a mixed sensory and neural styrene-induced ototoxicity. Thus, in a clinical perspective, data reported here have important implications for styrene risk assessment in humans.

Purpose The phase delay of stimulus frequency otoacoustic emissions (SFOAEs) has been proposed as a noninvasive, objective, and fast source for estimating cochlear mechanical tuning. However, the implementation of SFOAEs clinically has been thwarted by the gaps in understanding of the stability of SFOAE delay-based tuning estimates and their relationship to behavioral measures of tuning. Therefore, the goals of this study were (a) to investigate the relationship between delay-based tuning estimates from SFOAEs and simultaneously masked psychophysical tuning curves (PTCs) and (b) to assess the across- and within-session repeatability of tuning estimates from behavioral and OAE measures. Method Three sets of behavioral and OAE measurements were collected in 24 normal-hearing, young adults for two probe frequencies, 1 and 4 kHz. For each participant, delay-based tuning estimates were derived from the phase gradient of SFOAEs. SFOAE-based and behavioral estimates of tuning obtained using the fast-swept PTC paradigm were compared within and across sessions. Results In general, tuning estimates were sharper at 4 kHz compared to 1 kHz for both PTCs and SFOAEs. Statistical analyses revealed a significant correlation between SFOAE delay-based tuning and PTCs at 4 kHz, but not 1 kHz. Lastly, SFOAE delay-based tuning estimates showed better intra- and intersession repeatability compared to PTCs. Conclusions SFOAE phase-gradient delays reflect aspects of cochlear mechanical tuning, in that a frequency dependence similar to that of basilar membrane tuning was observed. Furthermore, the significant correlation with PTCs at 4 kHz and the high repeatability of SFOAE-based tuning measures offer promise of an objective, nonbehavioral assay of tuning in human ears.

In the last decade, animal studies highlighted the sensitivity of hearing function to lack of specific cochlear dopamine receptors, while several studies on humans reported association between hearing loss and Parkinson’s disease, partially recovered after levodopa administration in de novo patients. Taken together, these observations suggest investigating the possible use of cochlear function outcome variables, particularly, otoacoustic emissions, as sensitive biomarkers of Parkinson’s disease. Any lateralization of hearing dysfunction correlated with Parkinson’s disease lateralization would (i) further confirm their association and (ii) provide a disease-specific differential outcome variable. Differential indicators are particularly useful for diagnostic purposes, because their effectiveness is not limited by physiological inter-subject fluctuations of the outcome variable. Recent advances in the acquisition and analysis techniques of otoacoustic emissions suggest using them for evaluating differential cochlear damage in the two ears. In this study, we quantitatively evaluated hearing function in a population of subjects with Parkinson’s disease, to investigate the occurrence of hearing loss, and, particularly, whether hearing dysfunction shows lateralization correlated with motor symptoms. Pure tone audiometry and distortion product otoacoustic emissions were used as outcome variables in 80 patients (mean age 65 ± 9 years) and 41 controls (mean age 64 ± 10 years). An advanced customized acquisition and analysis system was developed and used for otoacoustic testing, which guarantees response stability independent of probe insertion depth, and has the sensitivity necessary to accurately assess the low levels of otoacoustic response typical of elderly subjects. To our knowledge, this is the first study introducing the distinction between ipsilateral and contralateral ear, with respect to the body side more affected by Parkinson’s disease motor symptoms. Significant asymmetry was found in the auditory function, as both otoacoustic responses and audiometric hearing levels were worse in the ipsilateral ear. Significantly worse hearing function was also observed in patients with Parkinson’s disease compared to controls, confirming previous studies. Several pathophysiological mechanisms may be hypothesized to explain asymmetric cochlear damage in Parkinson's disease, including the impairment of dopamine release and the involvement of extra-dopaminergic circuits, with the cholinergic pathway as a likely candidate. The observed asymmetry in the audiological response of patients with Parkinson’s disease suggests that lateralization of hearing dysfunction could represent a specific non-motor signature of the disease. The possible diagnostic use of cochlear dysfunction asymmetry as a specific biomarker of Parkinson’s disease deserves further investigation, needing a more precise quantitative assessment, which would require a larger sample size., Hearing function was evaluated in 80 subjects with Parkinson’s disease, by means of pure tone audiometry and distortion product otoacoustic emissions. Significant auditory asymmetry was found, as parameters were worse on the body side more affected by motor symptoms. Also, patients showed worse auditory function when compared to controls., Graphical Abstract Graphical Abstract

A two-degrees-of-freedom nonlinear cochlear model [Sisto, Shera, Altoè, and Moleti (2019). J. Acoust. Soc. Am. 146, 1685-1695] correctly predicts that the reticular lamina response is nonlinear over a wide basal region. Numerical simulations of suppression tuning curves agree with a recent experiment [Dewey, Applegate, and Oghalai (2019). J. Neurosci. 39, 1805-1816], supporting the idea that the strong susceptibility of the reticular lamina response to suppression by high-frequency tones does not imply that the total traveling wave energy builds-up in correspondingly basal regions. This happens because the reticular lamina is the lightest element of a coupled-oscillators system, only indirectly coupled to the differential pressure.

An experimental study has been performed on the effect of exposure to noise (N), vibration (V), and combined noise and vibration (NV), on the distortion product otoacoustic emission (DPOAE) level. The aim of the study is investigating the possible synergistic effect of noise and vibration, increasing the risk of damage to the hearing function due to noise only. Twelve normal-hearing volunteers were randomly exposed to hand arm vibration (HAV) only, noise only, and HAV and noise simultaneously. The exposure consisted of five consecutive sessions interspersed with quiet periods. DPOAEs were recorded during the quiet intervals following each exposure session, and during recovery, and compared to their baseline level, and among different test treatments. An ad hoc acquisition system developed in Labview was used to record high frequency-resolution DPOAE spectra in a suitably short time. Time-frequency filtering, based on the wavelet transform, was used to separate the DPOAE components coming from different generation mechanisms. The three test treatments, N, V, and NV, yielded significantly different results. The condition affecting most significantly all DPOAE component levels was the exposure to vibration only, causing a statistically significant increase of the signal level during all the exposure periods, with a decreasing trend during recovery. Also the exposure to noise only, N, caused a DPOAE level increase, statistically significant for the long latency (LL) DPOAE component. Only when exposure to noise was in combination with vibration, the zero-latency (ZL) component was clearly suppressed during the exposure. The results suggest a synergistic adverse effect of noise and vibration on the cochlear function. Relevance to industry The simultaneous exposure to noise and hand arm vibration is a very common industrial scenario. The risk that exposure to mild noise levels could interfere with the exposure to vibration, enhancing the adverse effect on the hearing function, should be considered to optimize prevention strategies at the workplace.

Acoustic Diagnostics is an experiment dedicated to monitoring the hearing function of the astronauts on board the International Space Station (ISS). The Italian Space Agency (ASI) provides access to the ISS as a laboratory in space to the Italian research community, through agreements between ASI and NASA for its use and between ASI and the European Space Agency (ESA) for the "BEYOND" mission, and via the Italian participation to the ISS as a member state of ESA. The main aim of the "Acoustic Diagnostics" experiment on board the space station ISS is investigating possible dysfunction of the human auditory system related to long-term missions on board the station. Some astronauts reported indeed mild hearing damage after long-term permanence in orbit. Probable hazard sources might be noise and micro-gravity, which affects intracranial fluid pressure. Before and after the mission, the astronauts will be subjected to full audiological examination, including pure tone audiometry, ABR, tuning and time-resolution measurements, impedance measurements, and otoacoustic emission (OAE) tests, which are a particularly sensitive tool for the early detection of mild hearing loss. The OAE test employed will be the measurement of distortion product otoacoustic emissions (DPOAEs) monitored during the flight, as a function of their permanence, in at least three in-flight sessions. OAE-based measurements are objective, non-invasive, and fast tests. The particular technology used for this type of tests on board will allow measurements relatively unaffected by the high noise levels of the ISS environment, and special precautions will be used to limit the EMI disturbances. High reproducibility of the measurements is guaranteed thanks to the forward-pressure calibration using the Thevenin methodology and a substantial (10dB) SNR increase will be provided by a customized time-frequency filtering procedure based on the wavelet transform.

Otoacoustic emissions are a by-product of the active nonlinear amplification mechanism located in the cochlear outer hair cells, which provides high sensitivity and frequency resolution to human hearing. Being intrinsically sensitive to hearing loss at a cochlear level, they represent a promising non-invasive, fast, and objective diagnostic tool. On the other hand, the complexity of their linear and nonlinear generation mechanisms and other confounding physical phenomena (e.g., interference between different otoacoustic components, acoustical resonances in the ear canal, transmission of the middle ear) introduce a large inter-subject variability in their measured levels, which makes it difficult using them as a direct measure of the hearing threshold using commercially available devices. Nonlinear cochlear modeling has been successfully used to understand the complexity of the otoacoustic generation mechanisms, and to design new acquisition and analysis techniques that help disentangling the different components of the otoacoustic response, therefore improving the correlation between measured otoacoustic levels and audiometric thresholds. In particular, nonlinear cochlear modeling was able to effectively describe the complex (amplitude and phase) response of the basilar membrane, and the generation of otoacoustic emissions by two mechanisms, nonlinear distortion and linear reflection by cochlear roughness. Different phase-frequency relations are predicted for the otoacoustic components generated by the two mechanisms, so they can be effectively separated according to their different phase-gradient delay, using an innovative time-frequency domain filtering technique based on the wavelet transform. A brief introduction to these topics and some new theoretical and experimental results are presented and discussed in this study.

An objective technique based on the time-frequency analysis of otoacoustic emissions is proposed to get fast and stable estimates of cochlear tuning. Time-frequency analysis allows one to get stable measurements of the delay/frequency function, which is theoretically expected to be a function of cochlear tuning. Theoretical considerations and numerical solutions of a nonlinear cochlear model suggest that the average phase-gradient delay of the otoacoustic emission single-reflection components, weighted, for each frequency, by the amplitude of the corresponding wavelet coefficients, approximately scales as the square root of the cochlear quality factor. The application of the method to human stimulus-frequency and transient-evoked otoacoustic emissions shows that tuning decreases approximately by a factor of 2, as the stimulus level increases by 30 dB in a moderate stimulus level range. The results also show a steady increase of tuning with increasing frequency, by a factor of 2 between 1 and 5 kHz. This last result is model-dependent, because it relies on the assumption that cochlear scale-invariance breaking is only due to the frequency dependence of tuning. The application of the method to the reflection component of distortion product otoacoustic emissions, separated using time-frequency filtering, is complicated by the necessity of effectively canceling the distortion component.

Evaluating the correlation between otoacoustic emission levels, styrene exposure, and oxidative stress biomarkers concentration in styrene-exposed subjects, to investigate the role of oxidative stress in outer hair cell damage.Distortion product otoacoustic emissions were measured in the exposed workers and in a control group. Separation between the distortion and reflection otoacoustic components was performed by time-frequency-domain filtering. The urinary concentration of the DNA and RNA oxidation products, namely 8-oxo-7,8-dihydroguanine (oxoGua), 8-oxo-7,8-dihydro-2'-deoxyguanosine (oxodGuo), and 8-oxo-7,8-dihydroguanosine (oxoGuo), were evaluated.Nine subjects exposed to styrene in a fiberglass factory, eight control subjects. The two groups were statistically equivalent in mean age.Statistically significant differences were found in the distortion component levels between the exposed and the control group. High levels of the oxidative damage biomarkers were found in the workers exposed to high levels of styrene. Significant negative correlation was found between the otoacoustic emission distortion component levels and the concentration of the oxoGuo biomarker.Exposure-induced damage of the cochlear amplifier is shown in the mid-frequency range, confirming animal experiments, in which hair cells in the cochlear middle turn were damaged. Hearing damage is consistent with the outer hair cell apoptosis pathway associated with oxidative stress.

When measured as a function of primary frequency ratio r = f(2)/f(1), using a constant f(2), distortion product otoacoustic emission (DPOAE) response demonstrates a bandpass shape, previously interpreted as the evidence for a cochlear “second filter.” In this study, an alternate, interference-based explanation, previously advanced in variants, is forwarded on the basis of experimental data along with numerical and analytical solutions of nonlinear and linear cochlear models. The decrease of the DPOAE response with increasing and decreasing ratios is explained by a diminishing “overlap” generation region and the onset of negative interference among wavelets of different phase, respectively. In this paper, the additional quantitative hypothesis is made that negative interference becomes the dominant effect when the spatial width of the generation (overlap) region exceeds half a wavelength of the DPOAE wavelets. Therefore, r is predicted to be optimal when this condition is matched. Additionally, the minimum on the low-ratio side of the DPOAE curve is predicted to occur as the overlap region width equals one wavelength. As the width of the overlap region depends on both tuning and ratio, while wavelength depends on tuning only, an experimental method for estimating tuning from either the width of the pass band or the optimal ratio of the DPOAE vs. ratio curve has been theoretically formulated and evaluated using numerical simulations. A linear model without the possibility of nonlinear suppression is shown to reasonably approximate data from human subjects at low ratios reinforcing the relevance of the proposed negative interference effect. The different dependence of the distortion and reflection DPOAE components on r as well as the nonmonotonic behavior of the distortion component observed at very low ratios are also in agreement with this interpretation.

Hearing loss is an injury that can develop over time, and people may not even be aware of it until it becomes a severe disability. Ototoxicants are substances that may damage the inner ear by either affecting the structures in the ear itself or by affecting the nervous system. We have examined the possibility that ototoxicants may present a health hazard in association with environmental exposures, adding to existing knowledge of their proven hazards under medical therapeutic conditions or occupational activities. In addition to the already described human environmental ototoxicants, mainly organochlorines such as polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethylene (DDE), hexachlorocyclohexane (HCH) and hexachlorobenzene (HCB), we have examined the ubiquitous chemical stressors phthalates, bisphenol A/S/F/, PFCs, flame retardants (FRs) and cadmium for potential ototoxic properties, both as single substances or as chemical mixtures. Our literature review confirmed that these chemicals may disturb thyroid hormones homeostasis, activate aryl hydrocarbon receptor (AhR), and induce oxidative stress, which in turn may initiate a chain of events resulting in impairment of cochlea and hearing loss. With regard to auditory plasticity, diagnostics of a mixture of effects of ototoxicants, potential interactions of chemical and physical agents with effects on hearing, parallel deterioration of hearing due to chemical exposures and ageing, metabolic diseases or obesity, even using specific methods as brainstem auditory evoked potentials (BAEP) or otoacoustic emissions (OAEs) registration, may be difficult, and establishment of concentration-response relationships problematic. This paper suggests the establishment of a class of environmental oxotoxicants next to the established classes of occupational and drug ototoxicants. This will help to properly manage risks associated with human exposure to chemical stressors with ototoxic properties and adequate regulatory measures.

Introduction Evidence for synergistic interaction between noise and styrene in inducing cochlear damage can be found in the literature. At present a mechanistic explanation of such an interaction is not available, although animal studies are shedding light on the phenomenon. At the aim of clarifying the effect of simultaneous exposure to noise (mild level) and styrene on the cochlear functionality, distortion product otoacoustic emissions (DPOAEs) were used as biomarkers of the cochlear status. In this work, the correlation between the DPOAE level and blood concentration of oxidative stress biomarkers is studied in a sample of subjects professionally exposed to styrene. This study is aimed at investigating the role of the oxidative stress in the inner ear damage in workers exposed to styrene. Methods Nine subjects exposed to styrene in a fibreglass factory and eight control subjects were enrolled in this study. The mean age was the same in the exposed and control groups. The airborne concentration of styrene was evaluated by means of ambiental and personal samplers. The end shift urinary concentration of the phenylglyoxylic (PGA) and mandelic acid (MA) was also evaluated. Distortion product otoacoustic emissions were measured in the exposed workers and in a control group. The DPOAE component generated by a nonlinear mechanism, characterised by zero latency, and the long-latency component, generated by a linear reflection mechanism, were separately analysed, using a time-frequency domain wavelet filter for component unmixing. The urinary concentration of the DNA and RNA oxidation products, namely 8-oxo-7,8-dihydroguanine (oxoGua), 8-oxo-7,8-dihydro-20-deoxyguanosine (oxodGuo), and 8-oxo-7,8-dihydroguanosine (oxoGuo), were evaluated and correlated to the DPOAE level. Results A statistically significant negative correlation was found between the DPOAE level and the PGA and MA urinary concentration. A dose response relation was proposed correlating the styrene concentration, the exposure duration and the DPOAE level, used as outcome variables. High levels of the oxidative damage biomarkers were found in the workers exposed to high levels of styrene. Significant negative correlation was found between the otoacoustic emission distortion component levels and the concentration of the oxoGuo biomarker. Conclusions This experiment confirms that the styrene exposure is responsible for cochlear dysfunctionality. A quantitative relation between the styrene exposure and the reduction of cochlear functionality, expressed in terms of DPOAE amplitude, can be found. Exposure-induced damage of the cochlear amplifier is shown in the mid-frequency range, confirming the results of animal experiments, in which hair cells in the middle turn of the cochlea were damaged. Hearing damage is consistent with the outer hair cell apoptosis pathway associated with oxidative stress.

The DPOAE response consists of the linear superposition of two components, a nonlinear distortion component generated in the overlap region, and a reflection component generated by roughness in the DP resonant region. Due to approximate scaling symmetry, the DPOAE distortion component has approximately constant phase. As the reflection component may be considered as a SFOAE generated by the forward DP traveling wave, it has rapidly rotating phase, relative to that of its source, which is also equal to the phase of the DPOAE distortion component. This different phase behavior permits effective separation of the DPOAE components (unmixing), using time-domain or time-frequency domain filtering. Departures from scaling symmetry imply fluctuations around zero delay of the distortion component, which may seriously jeopardize the accuracy of these filtering techniques. The differential phase-gradient delay of the reflection component obeys causality requirements, i.e., the delay is positive only, and the fine-structure oscillations of amplitude and phase are correlated to each other, as happens for TEOAEs and SFOAEs relative to their stimulus phase. Performing the inverse Fourier (or wavelet) transform of a modified DPOAE complex spectrum, in which a constant phase function is substituted for the measured one, the time (or time-frequency) distribution shows a peak at (exactly) zero delay and long-latency specular symmetric components, with a modified (positive and negative) delay, which is that relative to that of the distortion component in the original response. Component separation, applied to this symmetrized distribution, becomes insensitive to systematic errors associated with violation of the scaling symmetry in specific frequency ranges.

The aim of this study was to examine the hypothesis that organochlorine pesticides (OCPs), hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), and 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (p,p'-DDT) and its metabolite 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene (p,p'- DDE) are ototoxic to humans. A multivariate general linear model was designed, in which the statistical relation between blood serum concentrations of HCB, β-HCH, p,p'-DDT, or p,p'-DDE at different ages (at birth, 6, 16, and 45 months) and the distortion product otoacoustic emissions (DPOAEs) was treated as multivariate outcome variables. Polychlorinated biphenyl (PCB) congeners and OCPs were strongly correlated in serum of children from our cohort. To ascertain that the association between DPOAEs at a given frequency and concentration of a pesticide is not influenced by PCBs or other OCP also present in serum, we calculated benchmark concentrations (BMCs) relating DPOAEs to a serum pesticide alone and in presence of confounding PCB-153 or other OCPs. We found that BMCs relating DPOAEs to serum pesticides are not affected by confounders. DPOAE amplitudes were associated with serum OCPs at all investigated time intervals, however, in a positive way with prenatal exposure and in a negative way with all postnatal exposures. We observed tonotopicity in the association of pesticides with amplitude of DPOAEs as its strength was frequency dependent. We conclude that exposure to OCPs in infancy at environmental concentrations may be associated with hearing deficits.

Distortion product otoacoustic emissions (DPOAEs) have been accurately measured with an intensimetric technique, involving simultaneous measure of pressure and velocity in the ear canal, which allows one to correctly calibrate both the input stimuli and the otoacoustic emission (OAE) level. Suitable combinations of standard intensimetric quantities, active intensity and power density [Stanzial, Shiffrer, and Sacchi, J. Acoust. Soc. Am. 131, 269–280 (2012)], are used to equalize the stimuli transmitted to the middle ear, and to estimate the DPOAE level emitted by the eardrum. The DPOAE intensimetric spectra are consistent with those recorded with a high-quality conventional otoacoustic probe with state-of-the-art calibration of both stimulus and OAE response [Charaziak and Shera, J. Acoust. Soc. Am. 141, 515–525 (2017)], demonstrating the applicability of the intensimetric method to OAE measurements.

Long-delay components showing a symmetrical pattern with positive and negative delays can be observed in the time-frequency representation (or in the inverse Fourier transform) of distortion product otoacoustic emissions. Positive-only phase-gradient delays are predicted by place-fixed backscattering mechanisms, such as coherent reflection due to roughness, whereas the nonlinear distortion wave-fixed mechanism should generate an almost null-delay component. The symmetrical delay pattern arises whenever spectral amplitude fluctuations are not fully correlated to phase fluctuations. An interpretation of this phenomenon is proposed, involving place-fixed modulation of the spectral strength of the wave–fixed nonlinear generator. Experimental data are shown in which these negative-delay sources are particularly strong, and further amplified by contralateral stimulation, suggesting that this effect could be dynamically enhanced. Analytical solutions of a linear 1-d transmission line model, in which cubic nonlinearity and roughness were added as small perturbations, have been used to test this hypothesis.

Stimulus-frequency, transient-evoked, and distortion product otoacoustic emissions (OAEs) have been measured in eight normal-hearing human ears over a wide stimulus level range, with high spectral resolution. The single-reflection component of the response was isolated using time-frequency filtering, and its average delay was measured as a function of frequency and stimulus level. The apical-basal transition was studied by fitting the average delay of the filtered single-reflection OAEs, expressed in number of cycles, to a three-slope power-law function with two knot frequencies. The results show that the scale-invariant prediction of constant dimensionless delay approximately holds only over a narrow intermediate frequency range (1-2.5 kHz). Below 1 kHz, and, to some extent, above 2.5 kHz, the dimensionless delay increases with frequency, at all stimulus levels. Comparison with the numerical simulations of a delayed-stiffness active cochlear model show that the increase of tuning with frequency reported by behavioral experiments only partly explains this result. The low-frequency scaling symmetry breaking associated with the deviation of the Greenwood tonotopic map from a pure exponential function is also insufficient to explain the steep low-frequency increase of the OAE delay. Other sources of symmetry breaking, not included in the model, could therefore play a role.

The ototoxic effect of the exposure to styrene is evaluated, also in the presence of simultaneous exposure to noise, using otoacoustic emissions as biomarkers of mild cochlear damage. Transient-evoked and distortion product otoacoustic emissions were recorded and analyzed in a sample of workers (15 subjects) exposed to styrene and noise in a fiberglass manufacturing facility and in a control group of 13 non-exposed subjects. Individual exposure monitoring of the airborne styrene concentrations was performed, as well as biological monitoring, based on the urinary concentration of two styrene metabolites, the Mandelic and Phenylglyoxylic acids. Noise exposure was evaluated using wearable phonometers, and hearing loss with pure tone audiometry. Due to their different job tasks, one group of workers was exposed to high noise and low styrene levels, another group to higher styrene levels, close to the limit of 20 ppm, and to low noise levels. A significant negative correlation was found between the otoacoustic emission levels and the concentration of the styrene urinary metabolites. Otoacoustic emissions, and particularly distortion products, were able to discriminate the exposed workers from the controls, providing also a rough estimate of the slope of the dose-response relation between otoacoustic levels and styrene exposure.

Background: Epidemiological studies have demonstrated the ototoxic effects of exposure to polychlorinated biphenyls (PCBs). In a previous study, this effect was attributed to the PCB postnatal seru...

The study aim was to identify the timing of sensitive windows for ototoxicity related to perinatal exposure to PCBs. A total of 351 and 214 children from a birth cohort in eastern Slovakia underwent otoacoustic testing at 45 and 72 months, respectively, and distortion product otoacoustic emissions (DPOAEs) at 11 frequencies were recorded. Cord and child 6-, 16-, 45-, and 72- month blood samples were analyzed for PCB 153 concentration. The PCB 153 concentration-time profiles were approximated with a system model to calculate area under the PCB*time curves (AUCs) for specific time intervals (3 and 6 months for 45 and 72 months data, respectively). DPOAE amplitudes were correlated (Spearman) with cord serum PCB and AUCs, markers of prenatal and postnatal exposure, respectively. Two exposure critical windows were identified in infants, the first related to prenatal and early postnatal and the second to postnatal exposure to PCBs. Our data have shown tonotopicity, sexual dimorphism, and asymmetry in ototoxicity of PCBs.

The generation of stimulus-frequency otoacoustic emission (SFOAE) residuals in humans is analyzed both theoretically and experimentally to investigate the relation between the frequency difference between the probe and the suppressor tone and the localization of the residual source. Experimental measurements of the SFOAE residual were performed using suppressors of increasing frequency to separate the otoacoustic response from the probe stimulus. From the response to the probe alone, the SFOAE response was also estimated, using spectral smoothing, and compared with the residuals obtained for different frequency suppressors. A nonlinear delayed-stiffness active cochlear model was used to compute the spatial distribution of the residual sources according to a recent model of the local reflectivity from roughness, as a function of the suppressor frequency. The simulations clarified the role of high-frequency suppressors, showing that in humans, with increasing suppressor frequency, the generation region of the residual is only slightly basally shifted with respect to the case of a near-frequency suppressor, near the basal edge of the peak of the resonant basilar membrane response. As a consequence, the hierarchy among different-delay components correspondingly changes, gradually favoring short-delay components, with increasing suppressor frequency. Good agreement between the experimental and theoretical dependence of the level of otoacoustic components of different delay on the frequency shift between probe and suppressor confirms the validity of this interpretation.

In this study, a systematic analysis of the dependence on stimulus level and primary frequency ratio r of the different components of human distortion product otoacoustic emissions has been performed, to check the validity of theoretical models of their generation, as regards the localization of the sources and the relative weight of distortion and reflection generation mechanisms. 2f1 - f2 and 2f2 - f1 distortion product otoacoustic emissions of 12 normal hearing ears from six human subjects have been measured at four different levels, in the range [35, 65] dB sound pressure level, at eight different ratios, in the range [1.1, 1.45]. Time-frequency filtering was used to separate distortion and reflection components. Numerical simulations have also been performed using an active nonlinear cochlear model. Both in the experiment and in the simulations, the behavior of the 2f1 - f2 distortion and reflection components was in agreement with previous measurements and with the predictions of the two-source model. The 2f2 - f1 response showed a rotating-phase component only, whose behavior was in general agreement with that predicted for a component generated and reflected within a region basal to the characteristic place of frequency 2f2 - f1, although alternative interpretations, which are also discussed, cannot be ruled out.

Epidemiological studies have documented adverse associations between exposure to polychlorinated biphenyls (PCBs) and otological outcomes. Previously, we documented decreased distortion product otoacoustic emission (DPOAE) levels in children exposed to PCBs, up to the age of 45 months, amongst a cohort of children in eastern Slovakia. The objective of the present study is to evaluate cochlear dysfunction at 72 months of age in 214 children from this same cohort and to compare the otoacoustic test sensitivity to that of pure tone audiometry (PTA). The association between DPOAE, PTA, and PCBs was estimated by means of multivariate ANOVA (MANOVA) and linear regression models. ROC curves were computed to estimate the DPOAE-test power in children. The DPOAE level at 72 months was related to PCB-153 serum levels. The DPOAE Input/Output function test at mid-frequency (2kHz) has shown instead nonmonotonic dependence on PCB exposure, for the left ears of children, over the whole growth curve. No significant association was found between PTA hearing levels and PCB-153 concentration. High diagnostic power of the DPOAE-test was found in children, similar to that found by the same authors in adults. In conclusions the DPOAE-PCB correlation obtained at 72 months is similar to that at 45 months suggesting a permanent and stable ototoxic effect of the PCB exposure. The lack of statistical significance of the PCB-PTA correlation suggests that DPOAEs are sensitive biomarkers of cochlear damage.

This study focuses on the theoretical prediction and experimental evaluation of the latency of transient-evoked otoacoustic emissions. Response components with different delay have been identified in several studies. The main generator of the transient response is assumed to be coherent reflection from cochlear roughness near the resonant place. Additional components of different latency can be generated by different mechanisms. Experimental data are re-analyzed in this study to evaluate the dependence of the latency on stimulus level, for each component of the response, showing that previous estimates of the otoacoustic emission latency were affected by systematic errors. The latency of the emission from each generator changes very little with stimulus level, whereas their different growth rate causes sharp changes of the single-valued latency, estimated as the time of the absolute maximum of the bandpass filtered response. Results of passive linear models, in which gain and bandwidth of the cochlear amplifier are strictly related, are incompatible with the observations. Although active linear models including delayed stiffness terms do predict much slower dependence of latency on the stimulus level, a suitable nonlinear model should be designed, capable of decoupling more effectively the dependence on stimulus level of amplitude and phase of the otoacoustic response.

This study explores the phenomenology of distortion products in nonlinear cochlear models, predicting their amplitude and phase along the basilar membrane. The existence of a backward-traveling wave at the distortion-product frequency, which has been recently questioned by experiments measuring the phase of basilar-membrane vibration, is discussed. The effect of different modeling choices is analyzed, including feed-forward asymmetry, micromechanical roughness, and breaking of scaling symmetry. The experimentally observed negative slope of basilar-membrane phase is predicted by numerical simulations of nonlinear cochlear models under a wide range of parameters and modeling choices. In active models, positive phase slopes are predicted by the quasi-linear analytical computations and by the fully nonlinear numerical simulations only if the distortion-product sources are localized apical to the observation point and if the stapes reflectivity is unrealistically small. The results of this study predict a negative phase slope whenever the source is distributed over a reasonably wide cochlear region and/or a reasonably high stapes reflectivity is assumed. Therefore, the above-mentioned experiments do not contradict "classical" models of cochlear mechanics and of distortion-product generation.

The cryogenic resonant gravitational wave detectors NAUTILUS and EXPLORER, made of an aluminum alloy bar, can detect cosmic ray showers. At temperatures above 1 K, when the material is in the normal conducting state, the measured signals are in good agreement with the values expected based on the cosmic rays data and on the thermo-acoustic model. When NAUTILUS was operated at the temperature of 0.14 K, in superconductive state, large signals produced by cosmic ray interactions, more energetic than expected, were recorded. The NAUTILUS data in this case are in agreement with the measurements done by a dedicated experiment on a particle beam. The biggest recorded event was in EXPLORER and excited the first longitudinal mode to a vibrational energy of about 670 K, corresponding to about 360 TeV absorbed in the bar. Cosmic rays can be an important background in future acoustic detectors of improved sensitivity. At present, they represent a useful tool to verify the gravitational wave antenna performance., Comment: submitted to Astroparticle Physics

Experimental measurements of the latency of transient evoked otoacoustic emission and auditory brainstem responses are compared, to discriminate between different cochlear models for the backward acoustic propagation of otoacoustic emissions. In most transmission-line cochlear models otoacoustic emissions propagate towards the base as a slow transverse traveling wave, whereas other models assume fast backward propagation via longitudinal compression waves in the fluid. Recently, sensitive measurements of the basilar membrane motion have cast serious doubts on the existence of slow backward traveling waves associated with distortion product otoacoustic emissions [He et al., Hear. Res. 228, 112-122 (2007)]. On the other hand, recent analyses of "Allen-Fahey" experiments suggest instead that the slow mechanism transports most of the otoacoustic energy [Shera et al., J. Acoust. Soc. Am. 122, 1564-1575 (2007)]. The two models can also be discriminated by comparing accurate estimates of the otoacoustic emission latency and of the auditory brainstem response latency. In this study, this comparison is done using human data, partly original, and partly from the literature. The results are inconsistent with fast otoacoustic propagation, and suggest that slow traveling waves on the basilar membrane are indeed the main mechanism for the backward propagation of the otoacoustic energy.

Different time-frequency techniques may be used to investigate the relation between latency and frequency of transient-evoked otoacoustic emissions. In this work, the optimization of these techniques and the interpretation of the experimental result are discussed. Time-frequency analysis of click-evoked otoacoustic emissions of 42 normal-hearing young subjects has been performed, using both wavelet and matching pursuit algorithms. Wavelet techniques are very effective to provide fast and reliable evaluation of the average latency of large samples of subjects. A major advantage of the matching pursuit technique, as observed by Jedrzejczak et al. [J. Acoust. Soc. Am. 115, 2148-2158 (2004)], is to provide detailed information about the time evolution of the response of single ears at selected frequencies. A hybrid matching pursuit algorithm that includes Fourier spectral information was developed, capable of speeding-up computation times and of identifying "spurious" atoms, whose latency-frequency relation is apparently anomalous. These atoms could be associated with several known phenomena, either intrinsic, such as intermodulation distortion, spontaneous emissions and multiple internal reflections, or extrinsic, such as instrumental noise, linear ringing and the acquisition window onset. A correct interpretation of these phenomena is important to get accurate estimates of the otoacoustic emission latency.

In animal experiments, the strong dependence on stimulus level of the basilar membrane gain and tuning is not matched by a corresponding change in the phase slope in the resonant region. Linear models, in which the gain dependence on the stimulus level has to be schematized by explicitly changing the tuning parameters of the resonant model, do not easily match this feature of the experimental data. Nonlinear models predict a phase slope that is relatively decoupled from tuning. In addition, delayed-stiffness and feed-forward models also show a significant intrinsic decoupling between gain and tuning, which helps in matching the experimental data.

We have confirmed the ototoxic effect of polychlorinated biphenyls (PCBs) in human adolescents already observed in rats by measuring amplitudes of distortion product otoacoustic emissions (DPOAEs) ...

Objective To investigate the peripheral auditory pathway in Parkinson's disease (PD) by using objective, quantitative and non-invasive audiological techniques, transient-evoked (TEOAE) and distortion product (DPOAE) otoacoustic emissions, in order to detect subclinical alterations of cochlear functioning and possible changes after dopaminergic stimulation. Methods We enrolled 11 untreated de-novo PD patients and 11 age and sex-matched healthy controls. Subjects underwent a routine audiological evaluation and otoacoustic emission recordings. The patients were then slowly-titrated to a stable dose of 100 mg levodopa four times in a day. A post-treatment assessment was made in order to detect significant changes in audiological responses. Finally, possible associations between clinical data and hearing results were also evaluated. Results At pure-tone audiometry, higher auditory threshold levels were observed in PD when compared to the controls. Moreover, DPOAE responses in PD patients were found low at almost all tested frequencies, suggesting subclinical cochlear damage. Interestingly, after dopaminergic treatment, a significant increase in DPOAE responses was detected. Notably, DPOAE dysfunction correlated with clinical severity, whereas high hearing thresholds appeared positively related with more prolonged disease duration. Conclusions Our findings demonstrate that otoacoustic emission recording and pure-tone audiometry reveal levodopa-sensitive cochlear dysfunction and hearing loss in PD. A parallel improvement in subjective motor symptoms and DPOAE objective responses could help clinicians in monitoring therapeutic responses and dynamic changes during the course of the disease.

The experimental observation of long- and short-latency components in both stimulus-frequency and transient-evoked otoacoustic emissions admits a comprehensive explanation within the coherent reflection mechanism, in a linear active transmission-line cochlear model. A local complex reflectivity function associated with roughness was defined and analyzed by varying the tuning factor of the model, systematically showing, for each frequency, a multiple-peak spatial structure, compatible with the observed multiple-latency structure of otoacoustic emissions. Although this spatial pattern and the peak relative intensity changes with the chosen random roughness function, the multiple-peak structure is a reproducible feature of different “digital ears,” in good agreement with experimental data. If one computes the predicted transmission delays as a function of frequency and position for each source, one gets a good match to the latency-frequency patterns that are directly computed from synthesized otoacoustic spectra using time-frequency analysis. This result clarifies the role of the spatial distribution of the otoacoustic emission sources, further supporting the interpretation of different-latency otoacoustic components as due to reflection sources localized at different places along the basilar membrane.