Hearing dysfunction heralds an increase in non-motor burden and a worse quality of life in Parkinson's disease: new insights from non-motor spectrum.

BACKGROUND: Sensorial non-motor symptoms (NMSs) in Parkinson's disease (PD) still lack appropriate investigation in clinical practice. This study aimed to assess if and to what extent auditory dysfunction is associated with other NMSs in PD and its impact on patient's quality of life (QoL). METHODS: We selected patients with idiopathic PD, without other concomitant neurological diseases, dementia, or diagnosis of any audiological/vestibular disease. Demographic and clinical data were collected. Patients underwent otoscopic examination, audiological testing with pure tone audiometry (PTA) and distortion product otoacoustic emissions (DPOAEs) and completed Non-Motor Symptoms Scale (NMSS) and Parkinson's Disease Questionnaires-39 (PDQ-39). ANCOVA and partial correlation analysis have been used for statistical analysis. RESULTS: 60 patients were enrolled and completed PTA and DPOAEs. 32 patients with hearing impairment (HI), assessed by PTA, (hearing threshold ≥ 25 dB) showed similar disease duration, motor impairment, and staging, compared to patients without HI, but higher scores both in NMSS and in PDQ-39, except for cardiovascular (CV), gastrointestinal (GI), urogenital (U) and sexual function (SF) of NMSS. In addition, DPOAEs showed a significant correlation with higher scores both in NMSS and PDQ-39, except for CV, SF, GI, U and perceptual problem subdomains of NMSS. CONCLUSION: This study demonstrated that PD patients with HI have a greater burden of NMS and lower related QoL and functioning. Our results highlight the importance to reconsider HI as a NMS, in parallel with the others. HI evaluation, even in asymptomatic patients, may reveal a wider pathology with a worse QoL.

NMR Untargeted and HPLC-MS/MS Targeted Metabolomic Approaches for Evaluating Styrene Exposure in the Urine of Shipyard Workers.

Due to its chemical properties, styrene is largely employed in the manufacturing of several products including rubber, polymers and resins, and it is particularly suitable for shipbuilding industry purposes. In this context, the main exposure to styrene occurs in occupational settings. Despite its widespread use, its long-term effects on human health at the occupational level are still unclear. The aim of this pilot study was to evaluate changes in styrene exposure biomarkers related to the metabolic and oxidative stress profiles in the urine of seventeen shipyard workers and seventeen non-exposed subjects. Urinary metabolites were assessed by means of NMR spectroscopy, including mandelic and phenylglyoxylic acids; four oxidative stress biomarkers, namely 8-oxo-7,8-dihydroguanine, 8-oxo-7,8-dihydroguanosine, and 8-oxo-7,8-dihydro-2'-deoxyguanosine and 3-nitrotyrosine, were evaluated via HPLC-MS/MS. The metabolic profiles of exposed workers showed both long- and short-term metabolic responses to styrene exposure compared to non-exposed subjects. From the comparison between non-exposed and before-shift workers, only 8-oxo-7,8-dihydroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine levels were significantly different (long term exposure response). At the same time, comparing the non-exposed group with after-shift workers, we observed lower levels of pseudouridine and 1-methylnicotinamide and higher glutamine levels in after-shift workers. The comparison between before-shift and after-shift workers showed that 8-oxo-7,8-dihydroguanine significantly increased after the shift, suggesting its involvement in the exposure to styrene (short-term exposure response). The obtained results, although preliminary, allow us to lay the basis for further human studies aimed at establishing a global understanding of styrene metabolism.

Fluid Focusing Contributes to the BM Vibration Amplification by Boosting the Pressure.

Two hydrodynamic effects are introduced in the standard transmission-line formalism, the focusing of the pressure and fluid velocity fields near the basilar membrane and the viscous damping at the fluid-basilar membrane interface, which significantly affect the cochlear response in the short-wave region. In this region, in which the wavelength is shorter than the cochlear duct height, only a layer of fluid of order of the wavelength is effectively involved in the traveling wave. This has been interpreted [8] as a reduced fluid contribution to the system inertia in the peak region, which is a viewpoint common to the 3-D FEM solutions. In this paper we propose an alternative approach, from a slightly different physical viewpoint. Invoking the fluid flux conservation along the traveling wave propagation direction, we can derive a rigorous propagation equation for the pressure integrated along the vertical axis. Consequently, the relation between the average pressure and the local pressure [4] at the fluid-BM interface can be written. The local pressure is amplified by a factor dependent on the local wavenumber with respect to the average pressure, a phenomenon we refer to as "fluid focusing", which plays a relevant role in the BM total amplification gain. This interpretation of the hydrodynamic boost to the pressure provides a physical justification to the strategy [10] of fitting the BM admittance with a polynomial containing both a conjugated pole and a zero. In the short-wave region, the sharp gradients of the velocity field yield a second important effect, a damping force on the BM motion, proportional to the local wavenumber, which stabilizes active models and shifts the peak of the response towards the base, with respect to the resonant place. This way, the peaked BM response is not that of a proper resonance, corresponding to a sharp maximum of the admittance, but rather a focusing-driven growth toward the resonant place, which is "aborted" before reaching it by the sharply increasing viscous losses. The large values of the wavenumber that ensure strong focusing are ultimately fueled, against viscosity, by the nonlinear OHC mechanism, hence the otherwise puzzling observation of a wide nonlinear gain dynamics with almost level-independent admittance.

Maternal exposure to zinc oxide nanoparticles causes cochlear dysfunction in the offspring.

Introduction: Zinc oxide nanoparticles (ZnO NPs) have been engineered and are largely used in material science and industry. This large and increasing use justifies a careful study about the toxicity of this material for human subjects. The concerns regard also the reproductive toxicity and the fetotoxicity. Materials and methods: The effect of the exposure to ZnO NPs on the cochlear function was studied in a group of pregnant CD1 mice and in their offspring. This study is part of a larger toxicological study about the toxicity of ZnO NPs during pregnancy. Four groups were analyzed and compared, exposed and non-exposed dams and their offspring. The cochlear function was quantitatively assessed by means of Distortion Product Otoacoustic Emissions (DPOAEs). Results and discussion: A large statistically significant difference was found between the non-exposed dams offspring and the exposed dams offspring (p = 1.6 · 10-3), whose DPOAE levels were significantly lower than those of non-exposed dams offspring and comparable to those of the adults. The DPOAE levels of the exposed and non-exposed dams were very low and not significantly different. This occurrence is related to the fact that these mice encounter a rapid aging process. Conclusion: Our findings show that maternal exposure to ZnO NPs does not reflect in overt toxicity on fetal development nor impair offspring birth, however it may damage the nervous tissue of the inner ear in the offspring. Other studies should confirm this result and identify the mechanisms through which ZnO NPs may affect ear development.

Oxidative stress and inflammation cause auditory system damage via glial cell activation and dysregulated expression of gap junction proteins in an experimental model of styrene-induced oto/neurotoxicity.

BACKGROUND: Redox imbalance and inflammation have been proposed as the principal mechanisms of damage in the auditory system, resulting in functional alterations and hearing loss. Microglia and astrocytes play a crucial role in mediating oxidative/inflammatory injury in the central nervous system; however, the role of glial cells in the auditory damage is still elusive. OBJECTIVES: Here we investigated glial-mediated responses to toxic injury in peripheral and central structures of the auditory pathway, i.e., the cochlea and the auditory cortex (ACx), in rats exposed to styrene, a volatile compound with well-known oto/neurotoxic properties. METHODS: Male adult Wistar rats were treated with styrene (400 mg/kg daily for 3 weeks, 5/days a week). Electrophysiological, morphological, immunofluorescence and molecular analyses were performed in both the cochlea and the ACx to evaluate the mechanisms underlying styrene-induced oto/neurotoxicity in the auditory system. RESULTS: We showed that the oto/neurotoxic insult induced by styrene increases oxidative stress in both cochlea and ACx. This was associated with macrophages and glial cell activation, increased expression of inflammatory markers (i.e., pro-inflammatory cytokines and chemokine receptors) and alterations in connexin (Cxs) and pannexin (Panx) expression, likely responsible for dysregulation of the microglia/astrocyte network. Specifically, we found downregulation of Cx26 and Cx30 in the cochlea, and high level of Cx43 and Panx1 in the ACx. CONCLUSIONS: Collectively, our results provide novel evidence on the role of immune and glial cell activation in the oxidative/inflammatory damage induced by styrene in the auditory system at both peripheral and central levels, also involving alterations of gap junction networks. Our data suggest that targeting glial cells and connexin/pannexin expression might be useful to attenuate oxidative/inflammatory damage in the auditory system.

Oxidative stress in occupational exposure to styrene vapors and dangerous chemicals in the shipbuilding industry.

Introduction: In the shipbuilding industry, workers are exposed to a variety of dangerous chemicals, styrene being one of them. The International Agency for Research on Cancer classified styrene as a chemical belonging to group 2A, which means it is probably carcinogenic to humans. This study aimed at evaluating the oxidative stress effects due to occupational exposure to styrene and other chemicals. Materials and methods: Styrene urinary metabolites, such as mandelic acid and phenylglyoxylic acid, and the urinary biomarkers of oxidative stress, i.e., oxidation products of DNA and RNA and of proteins, were measured in a group of 17 workers and compared to the concentrations found in a group of 17 healthy volunteers who had not been exposed to chemicals. Results and discussion: Statistically significant differences were found for 8-oxo-7,8-dihydroguanine (8-oxoGua) and 8-oxo-7,8-dihydro-2'-deoxiguanosine (8-oxodGuo) concentrations that are higher in workers than in the control group. The workers performing the tasks of painting are the most exposed to styrene and show higher concentrations of 8-oxo-7,8-dihydroguanosine (8-oxoGuo). Workers performing the tasks of wood refining and welding are less exposed to styrene but have higher concentrations of 8-oxoGua and 8-oxodGuo. Conclusion: The exposure scenario in shipbuilding is a complex one, in which different xenobiotics are simultaneously present. The oxidative stress effect biomarkers, obtained from the oxidation product of RNA and DNA, are promising, sensitive, but not specific.

Enhanced suppression of otoacoustic emissions by contralateral stimulation in Parkinson's disease.

Dopamine depletion affects several aspects of hearing function. Previous work [Wu, Yi, Manca, Javaid, Lauer, and Glowatzki, eLife 9, e52419 (2020)] demonstrated the role of dopamine in reducing the firing rates of inner ear cells, which is thought to decrease synaptic excitotoxicity. Thus, a lack of dopamine could indirectly increase acoustic stimulation of medial olivocochlear efferents. To investigate that, here we studied contralateral suppression of distortion product otoacoustic emissions in a population of Parkinsonian patients, compared to an age-matched control group, both audiometrically tested. To rule out activation of the acoustic reflex, middle ear impedance was monitored during testing. The results show significantly stronger contralateral suppression in the patient group.

Association between hearing sensitivity and dopamine transporter availability in Parkinson's disease.

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.

Crucial 3-D viscous hydrodynamic contributions to the theoretical modeling of the cochlear response.

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.

Contribution of Genetic Polymorphisms in Human Health.

Human health is influenced by various factors; these include genetic inheritance, behavioral lifestyle, socioeconomic and environmental conditions, and public access to care and therapies in case of illness, with the support of the national health system. All these factors represent the starting point for the prevention and promotion of a healthy lifestyle. However, it is not yet clear to what extent these factors may actually affect the health of an entire population. The exposures to environmental and occupational factors are several, most of which might be poorly known, contributing to influencing individual health. Personal habits, including diet, smoking, alcohol, and drug consumption, together with unhealthy behaviors, may inevitably lead people to the development of chronic diseases, contributing to increasing aging and decreasing life expectancy. In this article, we highlight the role of susceptibility biomarkers, i.e., the genetic polymorphisms of individuals of different ethnicities, with particular attention to the risk factors in the response to specific exposures of Europeans. Moreover, we discuss the role of precision medicine which is representing a new way of treating and preventing diseases, taking into account the genetic variability of the individual with each own clinical history and lifestyle.

MicroRNA expression is associated with auditory dysfunction in workers exposed to ototoxic solvents and noise.

This study is part of a project on early hearing dysfunction induced by combined exposure to volatile organic compounds (VOCs) and noise in occupational settings. In a previous study, 56 microRNAs were found differentially expressed in exposed workers compared to controls. Here, we analyze the statistical association of microRNA expression with audiometric hearing level (HL) and distortion product otoacoustic emission (DPOAE) level in that subset of differentially expressed microRNAs. The highest negative correlations were found; for HL, with miR-195-5p and miR-122-5p, and, for DPOAEs, with miR-92b-5p and miR-206. The homozygous (mut) and heterozygous (het) variants of the gene hOGG1 were found disadvantaged with respect to the wild-type (wt), as regards the risk of hearing impairment due to exposure to VOCs. An unsupervised artificial neural network (auto contractive map) was also used to detect and show, using graph analysis, the hidden connections between the explored variables. These findings may contribute to the formulation of mechanistic hypotheses about hearing damage due to co-exposure to noise and ototoxic solvents.

Early Noise-Induced Hearing Loss Accelerates Presbycusis Altering Aging Processes in the Cochlea.

Several studies identified hearing loss as a risk factor for aging-related processes, including neurodegenerative diseases, as dementia and age-related hearing loss (ARHL). Although the association between hearing impairment in midlife and ARHL has been widely documented by epidemiological and experimental studies, the molecular mechanisms underlying this association are not fully understood. In this study, we used an established animal model of ARHL (C57BL/6 mice) to evaluate if early noise-induced hearing loss (NIHL) could affect the onset or progression of age-related cochlear dysfunction. We found that hearing loss can exacerbate ARHL, damaging sensory-neural cochlear epithelium and causing synaptopathy. Moreover, we studied common pathological markers shared between hearing loss and ARHL, demonstrating that noise exposure can worsen/accelerate redox status imbalance [increase of reactive oxygen species (ROS) production, lipid peroxidation, and dysregulation of endogenous antioxidant response] and vascular dysfunction [increased expression of hypoxia-inducible factor-1alpha (HIF-1α) and vascular endothelial growth factor C (VEGFC)] in the cochlea. Unveiling the molecular mechanisms underlying the link between hearing loss and aging processes could be valuable to identify effective therapeutic strategies to limit the effect of environmental risk factors on age-related diseases.

Hearing Aids Performance in Hypobaric Environments.

OBJECTIVE: High altitudes imply exposure to a decreased ambient air pressure. Such a situation may also alter the performance of acoustic transducers using vibrating diaphragms due to air rarefaction. This study aimed at analyzing the performance at high altitude of hearing aids (HAs) where mechano-electric and electro-mechanic transducers are used. METHODS: A hypobaric chamber was used to perform two separated experimental sessions. In the first one two commercial models of HAs were exposed to a simulated altitude of 25,000 ft (7620 m) and to a subsequent rapid decompression profile, with a rapid climb (< 3 s) from 8000 (2438 m) to 25,000 ft. The second session separately analyzed the performance of microphone and receiver at an altitude of 9000 and 15,000 ft (2743 and 4572 m). Before and after the first session, the HAs were tested with an electronic ear while a dedicated recording system was used in the second session. RESULTS: No HA damage or dysfunction was detected during the first session. In the second one, the microphone showed a mild decrease of its output, while the receiver exhibited a much higher reduction of its output. CONCLUSION: Our findings highlight the safe use of HAs even under extreme environmental pressure changes. For altitudes exceeding 10,000 ft (3048 m), a recalibration of the HAs output via a dedicated program may be suggested. Lucertini M, Sanjust F, Manca R, Cerini L, Lucertini L, Sisto R. Hearing aids performance in hypobaric environments. Aerosp Med Hum Perform. 2021; 92(9):738743.

The Elusive Cochlear Filter: Wave Origin of Cochlear Cross-Frequency Masking.

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.

Oxidative Stress Biomarkers in Urine of Metal Carpentry Workers Can Be Diagnostic for Occupational Exposure to Low Level of Welding Fumes from Associated Metals.

Urinary concentrations of 16 different exposure biomarkers to metals were determined at the beginning and at the end of a working shift on a group of workers in the metal carpentry industry. Five different oxidative stress biomarkers were also measured, such as the oxidation products of RNA and DNA metabolized and excreted in the urine. The results of workers exposed to metals were compared to those of a control group. The metal concentrations found in these workers were well below the occupational exposure limit values and exceeded the mean concentrations of the same metals in the urine of the control group by a factor of four at maximum. Barium (Ba), mercury (Hg), lead (Pb) and strontium (Sr) were correlated with the RNA oxidative stress biomarker, 8-oxo-7, 8-dihydroguanosine (8-oxoGuo), which was found able to discriminate exposed workers from controls with a high level of specificity and sensitivity. The power of this early diagnostic technique was assessed by means of the ROC curve. Ba, rubidium (Rb), Sr, tellurium (Te), and vanadium (V) were correlated with the level of the protein oxidation biomarker 3-Nitrotyrosine (3-NO2Tyr), and Ba, beryllium (Be), copper (Cu), and Rb with 5-methylcytidine (5-MeCyt), an epigenetic marker of RNA damage. These effect biomarkers can help in identifying those workers that can be defined as "occupationally exposed" even at low exposure levels, and they can provide information about the impact that such doses have on their health.

Occupational Exposure in Industrial Painters: Sensitive and Noninvasive Biomarkers to Evaluate Early Cytotoxicity, Genotoxicity and Oxidative Stress.

This study aimed to identify sensitive and noninvasive biomarkers of early cyto-genotoxic, oxidative and inflammatory effects for exposure to volatile organic compounds (VOCs) in shipyard painters. On 17 (11 spray and 6 roller) painters (previously characterized for VOCs exposure to toluene, xylenes, ethylbenzene, ethyl acetate) and on 18 controls, we performed buccal micronucleus cytome (BMCyt) assay; Fpg-comet assay on lymphocytes; detection of urinary 8-oxoGua (8-oxo-7,8-dihydroguanine), 8-oxodGuo (8-oxo-7,8-dihydro-2'-deoxyguanosine) and 8-oxoGuo (8-oxo-7,8-dihydroguanosine), and cytokines release on serum. We found induction of cyto-genotoxicity by BMCyt assay and inflammatory effects (IL-6 and TNFα) in roller painters exposed to lower VOC concentrations than spray painters. In contrast, in both worker groups, we found direct and oxidative DNA damage by comet assay (with slightly higher oxidative DNA damage in roller) and significant increase of 8-oxoGuo and decrease of 8-oxodGuo and 8-oxoGua in respect to controls. The cyto-genotoxicity observed only on buccal cells of roller painters could be related to the task's specificity and the different used protective equipment. Although limited by the small number of subjects, the study shows the usefulness of all the used biomarkers in the risk assessment of painters workers exposed to complex mixtures.

Cochlear tuning estimates from level ratio functions of distortion product otoacoustic emissions.

Objective: 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.Design: 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 behavioural tuning is not fully understood.Study Sample: From experiment 1, we report DPOAE level ratio functions (LRF) from seven normal-hearing, young-adults for f2 = 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.Results: Tuning estimates from these functions increased as expected from 1-8 kHz. In experiment 2, we compared tuning estimates from DPOAE LRF to behavioural tuning in 24 normal-hearing, young adults for 1 and 4 kHz and found that behavioural tuning generally predicted DPOAE LRF estimated tuning.Conclusions: Our findings suggest that DPOAE LRFs generally reflect the tuning profile consistent with basilar membrane, neural, and behavioural tuning. However, further investigations are warranted to fully determine the use of DPOAE LRF as a clinical measure of cochlear tuning.

Low-passed outer hair cell response and apical-basal transition in a nonlinear transmission-line cochlear model.

The low-pass characteristic of the outer hair cell (OHC) voltage response to mechanical stimulation could be considered a serious problem for cochlear models aiming at explaining high-frequency active amplification by introducing instantaneous nonlinear terms because active gain would dramatically decrease at high frequency. Evidence from experimental studies by Nam and Fettiplace [(2012). PloS One 7, e50572] suggests that the local cutoff frequency significantly increases approaching the cochlear base, somehow mitigating this problem. In this study, low-pass filtering of an internal force term, derived from a physiologically plausible OHC schematization by Lu, Zhak, Dallos, and Sarpeshkar [(2006). Hear. Res. 214, 45-67] is included in a simple one-dimensional (1-D) two-degrees-of-freedom transmission-line model by Sisto, Shera, Altoè, and Moleti [(2019). J. Acoust. Soc. Am. 146, 1685-1695] The frequency dependence of the low-pass filter phase-shift naturally yields a transition from sharp tuning and wide dynamical gain range in the basal cochlea to low tuning and poor dynamical range in the apical region. On the other hand, the frequency-dependent attenuation of low-pass filtering makes it more difficult to obtain the high gain (40-50 dB) of the basal basilar membrane response that is experimentally measured in mammals at low stimulus levels. Pressure focusing in the short-wave resonant region, which is not accounted for in this 1-D model, may help in acquiring the additional gain necessary to match the experimental data.

Fluid focusing and viscosity allow high gain and stability of the cochlear response.

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.