High-Frequency Cochlear Amplifier Dysfunction: A Dominating Contribution to the Cognitive-Ear Link

Objective: The objective of this study was to investigate the role of the high-frequency cochlear dysfunction in the cognitive-ear link.Methods: Seventy-four presbycusis patients (PC group) and seventy-one age-, sex-, and education-level matched normal hearing controls (NH group) were recruited in this study. Participants underwent a battery of cognitive tests estimated by Montreal Cognitive Assessment (MoCA), Stroop Color-Word Interference Test (Stroop), Symbol Digit Modalities Test (SDMT), Auditory Verbal Learning Test (AVLT), and Trail-Making Test (TMT-A and B), as well as auditory tests including distortion product otoacoustic emission (DPOAE), pure tone (PT) thresholds, and speech reception thresholds (SRT). Data were analyzed using the factor analysis, partial correlation analysis, multiple linear regression models, and mediation models.Results: Distortion product otoacoustic emission detection amplitudes and PT thresholds performed worse gradually from low to high frequencies in both the NH and PC groups. High-frequency DPOAE (H-DPOAE) was significantly correlated with cognitive domains in the PC group (AVLT: r = 0.30, p = 0.04; SDMT: r = 0.36, p = 0.01; Stroop: r = –0.32, p = 0.03; TMT-A: r = –0.40, p = 0.005; TMT-B: r = –0.34, p = 0.02). Multiple linear regression models showed that H-DPOAE predicted cognitive impairment effectively for aspects of memory (R2 = 0.27, 95% CI, 0.03 to 1.55), attention (R2 = 0.32, 95% CI, –6.18 to –0.40), processing speed (R2 = 0.37, 95% CI, 0.20 to 1.64), and executive function (TMT-A: R2 = 0.34, 95% CI, –5.52 to 1.03; TMT-B: R2 = 0.29, 95% CI, –11.30 to –1.12). H-DPOAE directly affected cognition and fully mediated the relationship between pure tone average (PTA)/SRT and cognitive test scores, excluding MoCA.Conclusion: This study has demonstrated that the high-frequency cochlear amplifier dysfunction has a direct predictive effect on the cognitive decline and makes a large contribution to the cognitive-ear link.

Modelling the Generation of the Cochlear Microphonic

<p>The human ear is a remarkable sensory organ. A normal healthy human ear is able to process sounds covering a wide range of frequencies and intensities, while distinguishing between different components of complex sounds such as a musical chord. In the last four decades, knowledge about the cochlea and the mechanisms involved in its operation has greatly increased, but many details about these mechanisms remain unresolved and disputed. The cochlea has a vulnerable structure. Consequently, measuring and monitoring its mechanical and electrical activities even with contemporary devices is very difficult. Modelling can be used to fill gaps between those measurements that are feasible and actual cochlear function. Modelling techniques can also help to simplify complex cochlear operation to a tractable and comprehensible level while still reproducing certain behaviours of interest. Modelling therefore can play an essential role in developing a better understanding of the cochlea. The Cochlear Microphonic (CM) is an electrical signal generated inside the cochlea in response to sound. This electrical signal reflects mechanical activity in the cochlea and the excitation processes involved in its generation. However, the difficulty of obtaining this signal and the simplicity of other methods such as otoacoustic emissions have discouraged the use of the cochlear microphonic as a tool for studying cochlear functions. In this thesis, amodel of the cochlea is presented which integrates bothmechanical and electrical aspects, enabling the interaction between them to be investigated. The resulting model is then used to observe the effect of the cochlear amplifier on the CM. The results indicate that while the cochlear amplifier significantly amplifies the basilar membrane displacement, the effect on the CM is less significant. Both of these indications agree with previous physiological findings. A novel modelling approach is used to investigate the tuning discrepancy between basilar membrane and CMtuning curves. The results suggest that this discrepancy is primarily due to transversal phase cancellation in the outer hair cell rather than longitudinal phase cancellation along the basilar membrane. In addition, the results of the model suggest that spontaneous cochlear microphonic should exist in the cochlea. The existence of this spontaneous electrical signal has not yet been reported.</p>

Modelling the Generation of the Cochlear Microphonic

<p>The human ear is a remarkable sensory organ. A normal healthy human ear is able to process sounds covering a wide range of frequencies and intensities, while distinguishing between different components of complex sounds such as a musical chord. In the last four decades, knowledge about the cochlea and the mechanisms involved in its operation has greatly increased, but many details about these mechanisms remain unresolved and disputed. The cochlea has a vulnerable structure. Consequently, measuring and monitoring its mechanical and electrical activities even with contemporary devices is very difficult. Modelling can be used to fill gaps between those measurements that are feasible and actual cochlear function. Modelling techniques can also help to simplify complex cochlear operation to a tractable and comprehensible level while still reproducing certain behaviours of interest. Modelling therefore can play an essential role in developing a better understanding of the cochlea. The Cochlear Microphonic (CM) is an electrical signal generated inside the cochlea in response to sound. This electrical signal reflects mechanical activity in the cochlea and the excitation processes involved in its generation. However, the difficulty of obtaining this signal and the simplicity of other methods such as otoacoustic emissions have discouraged the use of the cochlear microphonic as a tool for studying cochlear functions. In this thesis, amodel of the cochlea is presented which integrates bothmechanical and electrical aspects, enabling the interaction between them to be investigated. The resulting model is then used to observe the effect of the cochlear amplifier on the CM. The results indicate that while the cochlear amplifier significantly amplifies the basilar membrane displacement, the effect on the CM is less significant. Both of these indications agree with previous physiological findings. A novel modelling approach is used to investigate the tuning discrepancy between basilar membrane and CMtuning curves. The results suggest that this discrepancy is primarily due to transversal phase cancellation in the outer hair cell rather than longitudinal phase cancellation along the basilar membrane. In addition, the results of the model suggest that spontaneous cochlear microphonic should exist in the cochlea. The existence of this spontaneous electrical signal has not yet been reported.</p>

The Molecular Basis of Outer Hair Cell Electromotility is Defined by Prestin’s Conformational Cycle

The voltage-dependent motor protein Prestin (SLC26A5) is responsible for the electromotive behavior of outer hair cells (OHCs) and underlies the cochlear amplifier 1. Knock out or impairment of Prestin causes severe hearing loss 2-5. Despite Prestin’s key physiological role in hearing, the mechanism by which mammalian Prestin senses voltage and transduces it into cellular-scale movements (electromotility) is poorly understood. Here, we determined the structure of dolphin Prestin in six distinct states using single particle cryo-electron microscopy. Our structural and functional data suggest that Prestin adopts a unique and complex set of states, tunable by the identity of bound anions (Cl- or SO4=). Salicylate, a drug that can cause reversible hearing loss, competes for the anion-binding site of Prestin, inhibits its function by immobilizing locking in a novel conformation. This suggests that the anion together with its coordinating fixed charges act as a dynamic voltage sensor. Analysis of all anion-dependent conformations reveals how structural rearrangements in the voltage sensor are coupled to conformational transitions at the protein-membrane interface, suggesting a novel mechanism of area expansion. Visualization of Prestin’s electromotility cycle distinguishes Prestin from closely related SLC26 anion transporters, highlighting the basis for evolutionary specialization of the mammalian cochlear amplifier at high resolution.

A role for tectorial membrane mechanics in activating the cochlear amplifier

The mechanical and electrical responses of the mammalian cochlea to acoustic stimuli are nonlinear and highly tuned in frequency. This is due to the electromechanical properties of cochlear outer hair cells (OHCs). At each location along the cochlear spiral, the OHCs mediate an active process in which the sensory tissue motion is enhanced at frequencies close to the most sensitive frequency (called the characteristic frequency, CF). Previous experimental results showed an approximate 0.3 cycle phase shift in the OHC-generated extracellular voltage relative the basilar membrane displacement, which was initiated at a frequency approximately one-half octave lower than the CF. Findings in the present paper reinforce that result. This shift is significant because it brings the phase of the OHC-derived electromotile force near to that of the basilar membrane velocity at frequencies above the shift, thereby enabling the transfer of electrical to mechanical power at the basilar membrane. In order to seek a candidate physical mechanism for this phenomenon, we used a comprehensive electromechanical mathematical model of the cochlear response to sound. The model predicts the phase shift in the extracellular voltage referenced to the basilar membrane at a frequency approximately one-half octave below CF, in accordance with the experimental data. In the model, this feature arises from a minimum in the radial impedance of the tectorial membrane and its limbal attachment. These experimental and theoretical results are consistent with the hypothesis that a tectorial membrane resonance introduces the correct phasing between mechanical and electrical responses for power generation, effectively turning on the cochlear amplifier.

A role for tectorial membrane mechanics in activating the cochlear amplifier

ABSTRACTThe mechanical and electrical responses of the mammalian cochlea to acoustic stimuli are nonlinear and highly tuned in frequency. This is due to the electromechanical properties of cochlear outer hair cells (OHCs). At each location along the cochlear spiral, the OHCs mediate an active process in which the sensory tissue motion is enhanced at frequencies close to the most sensitive frequency (called the characteristic frequency CF). Previous experimental results showing an approximate 0.3 cycle phase shift in the OHC-generated extracellular voltage relative the basilar membrane displacement that is initiated at a frequency approximately one-half octave lower than the CF are repeated in the present paper with similar findings. This shift is significant because it brings the phase of the OHC-derived electromotile force near to that of the basilar membrane velocity at frequencies above the shift, thereby enabling the transfer of electrical to mechanical power at the basilar membrane. In order to seek a candidate physical mechanism for this phenomenon, we used a comprehensive electromechanical mathematical model of the cochlear response to sound. The model predicts the phase shift in the extracellular voltage referenced to the basilar membrane at a frequency approximately one-half octave below CF, in accordance with the experimental data. In the model, this feature arises from a minimum in the radial impedance of the tectorial membrane and its limbal attachment. These experimental and theoretical results are consistent with the hypothesis that a tectorial membrane resonance introduces the correct phasing between mechanical and electrical responses for power generation, effectively turning on the cochlear amplifier.SIGNIFICANCEThe mechanical and electrical responses of the mammalian cochlea are nonlinear exhibiting up to a thousand-fold difference in gain depending on the frequency and level of sound stimulus. Cochlear outer hair cells (OHC) are broadband electro-mechanical energy converters that mediate this nonlinear active process. However, the mechanism by which the OHC electromotile force acquires the appropriate phase to power this nonlinearity remains unknown. By analyzing new and existing experimental data and using a mathematical model, we address this open issue. We present evidence which suggests that a relatively simple feature, the frequency dependence of the radial impedance of the tectorial membrane, provides requisite mechanics to turn on the frequency-specific nonlinear process essential for healthy hearing.