Mechanisms of Active Process and Amplification in Cochlea

Choi, Chul-Hee

Review

Hearing sciences

Korean Journal of Audiology 2010;14(2):81-87.

Mechanisms of Active Process and Amplification in Cochlea

Department of Audiology Speech-Language Pathology, The Catholic University of Daegu College of Medical Sciences, Kyungsan, Korea

Mechanisms of Active Process and Amplification in Cochlea

Chul-Hee Choi^, PhD

Department of Audiology Speech-Language Pathology, The Catholic University of Daegu College of Medical Sciences, Kyungsan, Korea

Address for correspondence : Chul-Hee Choi, PhD, Department of Audiology and Speech-Language Pathology, The Catholic University of Daegu College of Medical Sciences, 5 Geumnak-ro, Hayang-eup, Kyungsan 712-702, Korea
Tel : +82-53-850-3185, Fax : +82-53-850-3383, E-mail : cchoi@cu.ac.kr

Introduction

   Of all the organs in the mammalian body, the cochlea is the most important organ of hearing. Hearing is critically affected by both the passive and active mechanical properties of the cochlea. In the passive mechanisms found in the dead cochlea, the reciprocal relationship between the mass and the stiffness of the cochlear partition varies systematically along the length of the cochlea, acting as a cascade of passive filters. This creates a tonotopic organization to the cochlea, in which high frequencies are best represented at the base and low frequencies are best represented at the apex. Measurements of basilar membrane stiffness in the human and gerbil cochlea demonstrate a relative change in stiffness of two or four orders of magnitude from the base to the apex.^1,^2,^3,^4,⁵⁾ In addition, other passive properties such as the tectorial membrane and supporting cells are probably also important to cochlear tuning.^6,⁷⁾ However, in the living cochlea, measurements of basilar membrane vibration suggest a compressive nonlinearity which provides positive feedback locally along the cochlear partition on a cycle-to-cycle basis resulting in high sensitivity, frequency selectivity, and wide dynamic range of hearing.^8,^9,¹⁰⁾ This concept is called an active process within the cochlea, which is used interchangeably with "cochlear amplifier". Hearing sensitivity in the normal cochlea is improved by about 40 dB by the active process.¹⁰⁾ Gold first proposed the idea that there is the presence of an cochlear amplifier to improve hearing sensitivity at low sound levels because using only passive responses to sound, the cochlea simply could not be as sensitive as it is.⁹⁾ The evidence of the cochlear amplifier was provided by the discovery of active hair-bundle motion, otoacoustic emissions, and somatic electromotility.^11,^12,^13,^14,^15,^16,^17,¹⁸⁾ It suggests that the cochlear amplifier is directly involved in the functions of outer hair cells (OHCs). Within the OHCs, it is believed that there are two transduction processes: mechanoelectrical (MET) and electro-mechanical transductions (EMT). While MET located within the stereocilia on the apex of the cells generates receptor potentials by opening the transducer channels in response to hair cell bundle deflection,^19,^20,²¹⁾ EMT placed in the OHC lateral wall triggers changes in the OHC length in response to the receptor potentials.^10,^11,¹⁸⁾ These length changes, called electromotility, were first observed in isolated OHC cells.¹⁸⁾ This is the biophysical characteristic that differentiates OHC from other known cell types.
A classical problem in hearing science is the finding that human patients with similar degrees and configurations of sensorineural hearing loss differ on temporal and frequency resolution, hearing sensitivity, loudness growth, sound localization, speech discrimination and other psychoacoustic tasks and vary in satisfaction with hearing aids. One reason for the lack of homogeneity is that hearing threshold measures provide only a rough estimate of the underlying cochlear pathology. With increasing knowledge of the cochlear transductions, a more specific evaluation of cochlear structures and transduction processes can be made. Therefore, this paper will review recent studies related with characterization and quantification of the cochlear transductions. Furthermore, this paper will provide a greater understanding of the pathophysiology associated with sensorineural hearing loss, a new classification scheme for sensorineural hearing loss based on cochlear pathophysiology, which leads to new treatment strategies such as improved signal processing algorithms for hearing aids, and with future developments in hair cell regeneration and genetic therapy, provides a specific site for targeting therapeutic agents.

Mechano-Electrical Transduction

   Hair cells are the places where MET occurs in the cochlea. MET is a nonlinear process in which cochlear partition motion (mechanical stimulus) made by acoustic signals is transformed into hair-cell receptor potentials (electrical signals) through deflection of hair cell stereocilia opening or closing ion channels located within or in the vicinity of the stereocilia.^22,^23,²⁴⁾ Deflection of hair bundle into the tallest stereocilia opens transduction channels increasing the apical conductance of hair cells (hair cell receptor potentials) and allowing K⁺ and Ca²⁺ ions to the cell. This results in depolarization. In neonatal mice, the mean maximal transducer conductance in OHCs is 5.5nS and the number of transducer channel is 120 pS while the OHC bundle required about 150 nm of tip displacement to activate 90% of the maximum transducer conductance.²⁵⁾ Deflection in the opposite direction closes transduction channels decreasing the apical conductance of hair cell (hair cell receptor potentials) and outflowing K⁺ and Ca²⁺ out of the cell, which leads to hyperpolarization.²⁶⁾
   A nonlinear function describing MET has been described by several mathematical functions such as a second-order Boltzmann function relating transducer conductance to hair bundle displacement as follows

                           Α
   ƒ_Tr(x) = ―――――――――――――――――――
               1+e⁽^bx-c⁾[1+e⁽^dx-e⁾] ^,

where ƒ_Tr(x) is the hair-cell receptor current, x is the stereocilial displacement, A is the maximal conductance, constants b and d are related to the slope of ƒ_Tr or the sensitivity of the transduction, and c and e are constants related to the resting position of the stereocilia,^27,²⁸⁾ a hyperbolic-tangent function relating hair-cell receptor potential to angular stereocilia displacement,²⁹⁾ and a first-order Boltzmann function relating hair cell bundle's deflection to the probability of channel opening as follows

1
P = ――――――――――――――
1+e^-z⁽^x-x0^)/^KT^,

where P is the probability of channel opening, Z is the gating sensitivity of the transduction process, X is the hair bundle's deflection from its resting potential X₀, K is the Boltzmann constant and T is temperature.^30,³¹⁾ These mathematical functions are derived from physical arguments to calculate the energy amount required for ion channels mechanics and are relating hair-cell receptor potential to stereocilia displacement from isolated hair cells.
Historically, MET in isolated OHC has been considered as a source of active process or cochlear amplifier. Since the early 1980s, many researchers of cochlear models had used feedback motor, negative damping, active feedback, and reverse transduction to describe the term of cochlear amplifier in MET. In a cochlear model, Weiss³²⁾ first suggested that electrical potential changes of the OHC membrane would result in the movement of hair cell bundles setting up a feedback mechanism which could amplify the stimulus. In another cochlear model, Kim³³⁾ postulated a bidirectional transduction mechanism: forward and reverse transductions. The forward transduction refers to a process in which a mechanical signal applied to the hair bundle is transduced into electrophysiological signals while the reverse transduction indicates an electrophysiological signal applied to the hair cell is converted into generation of mechanical forces and related displacement. Later, several research groups have showed that the hair bundles are the main source of active process with in vitro preparations. The evidences of the active movement of the hair bundle were provided in various animals such as turtle,^21,³⁴⁾ frog,²⁴⁾ and lizards.¹²⁾ Active hair-cell bundle movements observed in these non-mammalian species ranged between 5 and 80 nm.²¹⁾ With in vitro cochlear preparations of gerbils, cochlear amplification depends on calcium current through the MET channels of OHCs and inner hair cells.³⁵⁾ In addition, hair bundles of OHCs in rat produce force of a magnitude on the order of 500 pN and of submillisecond timescale linked to adaptation of the MET channels.³⁶⁾ However, another study shows that hair bundle movements with peak responses of up to 830 nm in gerbils are not based on MET channels but originated in somatic motility of the OHCs.³⁷⁾ Therefore, in mammals, the active mechanism driving the hair-cell bundle displacement is not fully understood. In addition, there is no direct evidence to support the active process in the hair-cell bundle in mammals.^12,³⁸⁾
On the other hand, the Boltzmann function and other nonlinear transducer functions in vivo can be estimated by the cochlear microphonic (CM). The CM is an extracellular electric potential produced primarily by the spatial summation of outer hair cell receptor currents appearing as an alternating current (AC) voltage.^39,⁴⁰⁾ Recorded in the round window in animals, the CM is mainly dominated by outer hair-cell currents from the cell at the base of the cochlea.⁴¹⁾ In 1930, Wever and Bray first demonstrated the presence of the CM and called CM because the cochlear electric responses can be amplified and reproduced like the AC voltage from a microphone.⁴²⁾ Then, Tasaki et al.⁴³⁾ provide clear evidence as to the site of production of the cochlear microphonic. Furthermore, the CM could be elicited by different stimuli such as pure tones and Gaussian noise.^44,^45,^46,^47,^48,⁴⁹⁾ Recently, a cochlear transducer function could be obtained from the CM using a low-frequency bias tone.^28,⁵⁰⁾ The low frequency bias tone has been used to displace the Organ of Corti position toward either scala vestibule or scala tympani due to a pressure differential across the cochlear partition.^39,⁴⁰⁾ A cochlear transducer function obtained from low frequency modulated CM was essentially proportional to the first derivative of the cochlear transducer function.²⁸⁾
Another method to derive a cochlear transducer function is to use the summating potential (SP), a dc component in the electrical response of the cochlea.⁵⁰⁾ A cochlear transducer function obtained from the SP was proportional to the second derivative of the cochlear transducer function. The cochlear transducer functions obtained from the CM and the SP are significantly different in its dynamic range, the optimal gain, and the symmetry. The cochlear transducer function derived from the CM had larger dynamic range, greater gain at the inflection point, and was more symmetrical than that obtained from the SP. The above differences in the transducer properties are consistent with the measurements from the in vivo intracellular ac and dc receptor potentials recorded from the OHCs and the IHCs.^51,^52,⁵³⁾ Usually, OHCs produce the largest ac receptor potentials than dc components whereas IHCs produce larger dc electrical response with smaller dynamic range. At the base of the cochlea, a dc response in IHC is preponderant while OHCs do not generate a depolarizing dc response as IHCs except at the highest levels. In addition, the IHC receptor potentials are more asymmetrical than the OHC receptor potentials.⁵⁴⁾ Therefore, the major differences between the cochlear transducer functions obtained from the CM and the SP may result from different sources of OHCs and IHCs. Comparing the cochlear transducer function of the CM from that of the SP,^28,⁵⁰⁾ the SP is more helpful than the CM in evaluating cochlear function under certain pathologic conditions because the SP is less sensitive to vector summating than the CM. In addition, the SP and CM may have different sources.
There are several ototoxic drugs to affect on MET channels. Dihydrostreptomycin (DHSM, an antibiotic drug) and cisplatin (an anticancer drug) block the MET channels in a dose- and voltage-dependent manner.⁵⁵⁾ Salicylate (an anti-inflammatory component of asprin and a common drug fluently used in the clinic), 4-aminopyridine (a blocker of potassium channels), and furosemide (a loop diuretic) block MET channels measured in CM.^56,⁵⁷⁾ The aminoglycoside antibiotic neomycin sulphate, the ionophore A23187 and the lectin Concanavalin A modulate the stereocilia bundle stiffness⁵⁸⁾ while aminoglycoside antibiotics blocks the MET channels of hair cells in the bullfrog's sacculus.⁵⁹⁾ On the other hand, TRPA1 channels (a member of branch A of the transient receptor potential family of cation channels) mediate MET in hair cells in mammalian animals and these channels are blocked by gentamicin, gadolinium, amiloride, and ruthenium red.⁶⁰⁾

Electro-Mechanical Transduction and Electromotility

EMT is a nonlinear process in which the length and form of isolated OHCs modulates in response to the changes of OHC receptor potentials in mammals, called the electromotility.¹⁸⁾ When the increased OHC receptor shortens the isolated OHCs (thick) and moves up the basilar membrane (BM) while the decreased OHC receptor elongates (thin) the cell and moves down the BM. This phenomenon is unique to only mammals. In mammals, the presence of cochlear amplifier is necessary for high hearing sensitivity, narrow frequency selectivity (tuning), and wide dynamic range of hearing.
The anatomy of the OHC is critical to the EMT. Electromotility occurs at frequencies up to 100 kHz and does not require ATP or calcium. The cell is also unique for vertebrate cells in being a hydrostat with a pressurized fluid core and a mechanically reinforced lateral wall that maintains its cylindrical shape. The lateral wall has three sublaminate structures such as a plasma membrane, a cytoskeleton, and a membranous organelle called the subsurface cisternae. The plasma membrane is a phospholipid bilayer that holds many particles between the inner and outer leaflets, recently demonstrated to include prestin^61,⁶²⁾ while the cytoskeleton includes parallel actin filaments crosslinked with spectrin, associated with Protein 4.1.^63,⁶⁴⁾ Pillars of unknown composition tether the actin filaments to the plasma membrane while the subsurface cisternae are an intracellular organelle, similar to endoplasmic reticulum or Golgi apparatus, that lines the inside of the cytoskeleton.^64,⁶⁵⁾
Electromotility resides within the lateral wall of the OHC and prestin is central to this process.^66,⁶⁷⁾ Prestin forms motor complexes with other proteins and lipids of the lateral wall. Each motor complex within the plasma membrane senses the transmembrane potential and individually generates force by changing its surface area.^68,^69,^70,^71,^72,⁷³⁾ The forces generated by each of the individual motors are coupled together through the lateral wall plasma membrane and cytoskeleton in order to achieve a net change in cell length. Because the OHC is fixed apically to the reticular lamina and basally to the cup of a Deiter's cell, electromotile shape changes can modify the vibration of the cochlear partition.^65,⁷⁴⁾ Intracellular anions (Ca²⁺ and Cl^-) can modulate prestin function and may function as the voltage sensor.^75,⁷⁶⁾ Changing the intracellular anion content inhibits electromotility and decreases the longitudinal stiffness of OHC.⁷⁷⁾ Prestin is required for electromotility of the outer hair cell and for the cochlear amplifier in normal hearing.⁷⁸⁾
The OHC electromotility in vivo can be estimated by measuring the movement (vibration) of the BM. Historically, the movement of the BM was first measured by von Bekesy in human and animal cadavers.⁷⁹⁾ When an external sound impinges on the eardrum, the stapes starts to vibrate and the vibration results in a travelling wave of displacement on the BM. The BM vibration starts at the cochlear base and propagates toward the apex. The amplitude of the vibration gradually grows toward the apex, reaches its maximum at the best frequency, and beyond the point, dies out quickly. High frequency sounds generate its maximal vibration at the base while low-frequency sounds produce its peak at the apex. The speed of the BM vibration decreases slowly toward the apex. However, in the living cochlea, the location of the cochlear amplifier was investigated with a laser-diode interferometer to measure in vivo the distribution along the BM of nonlinear vibrations to 15 kHz tones.⁸⁰⁾ The site of the cochlear amplifier for the 15 kHz region in guinea pig is restricted to a 1.25 mm length of BM extending both apical and basal to the 15 kHz point. For low-level tones, the peak of BM vibration was observed at the best frequency and the gain of BM decreased progressively with increasing stimulus level at the best frequency from 1,000-fold at 15 dB SPL to 10-fold at 100 dB SPL. In another study, the gain of BM in chinchilla increased to 10,000-fold at low levels.⁸¹⁾ There is a shift in the location of the maximum with increasing stimulus level toward the base extending over a 2-3 mm region around the location of the best frequency for cochlear amplification.⁸¹⁾ With a scanning laser interferometer, the BM vibration measured in the basal turn of the gerbil cochlea showed the peak at 2,500 μm from the base indicating a longitudinal extent of 0.6 mm.⁸²⁾ The peak response extends more toward the base than toward the apex with the increasing intensity. The velocity magnitude of the BM showed a nonlinear compression that the velocity magnitude of 10 μm/s at 10 dB SPL increased to 1,500 μm/s at 90 dB SPL.^11,⁸²⁾ In this study, the location of the cochlear amplifier is centered at the best frequency and extends over 1.0 mm. The growth of the nonlinear compression was greater at the apical part of the best frequency than the basal part. The electrically evoked intracochlear stimulus can result in conventional traveling wave within the cochlea as well as otoacoustic emissions providing direct support for a mechanism of cochlear sensitivity and tuning involving high-frequency OHC electromotility.⁸³⁾
The mechanism behind OHC electromotility is thought to be the origin of spontaneous otoacoustic emissions which are low-level, tonal signals measured in the external ear canal in the absence of any known stimulus. The generation of the spontaneous otoacoustic emissions is due to the ability of OHC to change its length requiring the mechanical flexibility, the structural integrity of the organ of Corti requiring considerable compressive rigidity along its major axis, and a unique hydraulic skeleton providing compressive stength.⁸³⁾ Furthermore, with several ototoxic reagents, OHC electomotility can provide enough force requiring for both low and high intensity distortion product otoacoustic emissions (DPOAE) and transient evoked otoacoustic emissions.^65,⁸⁴⁾ Otoacoustic emissions have been increasingly used for diagnosing cochlear pathophysiology and as a research tool for studying auditory physiology and pathophysiology because they provide noninvasive information of the cochlear status.^85,^86,⁸⁷⁾ The electrically evoked otoacoustic emissions have been used to assess in vivo the contribution of OHC electromotility to otoacoustic emissions.^88,⁸⁹⁾ Recently, a new method to derive a cochlear transducer function from low-frequency modulated DPOAE was introduced.^90,^91,⁹²⁾ The cubic difference tone (CDT, 2f1-f2) produced from the odd-order terms of a power series is proportional to the third derivative of the cochlear transducer function when the primary levels are sufficiently small⁹⁰⁾ while the quadratic difference tone (QDT, f1-f2) is proportional to the absolute value of the second derivative of the cochlear transducer function within one period of the bias tone and the QDT originates from the compression that coexists with the active hysteresis in cochlear transduction.⁹¹⁾ These studies indicate that the low-frequency modulated DPOAE can be used to estimate the cochlear transducer function originating from the OHC electromotility. However, a recent study showed an interesting result that OHC somatic motility may not require for the production of high level DPOAEs in a prestin knockout mutant mouse.⁹³⁾
There are ototoxic drugs to affect on OHC electromotility. Salicylate and aspirin reduces the magnitude of electromotility measured in otoacoustic emissions in guinea pig.^94,⁹⁵⁾ Specific sulfhydryl reagents such as p-chloromercuriphenylsulfonic acid (pCMPS) and p-hydroxymercuriphenylsulfonic acid (pHMPS) inhibit progressively the cubic difference tone from high to low frequency regions.⁸⁴⁾ Quinine (a well known ototoxic drug) affects in vivo electromotility of OHCs at low concentration and changes the cochlear amplifier via an effect on EMT.⁹⁶⁾ Chlorpromazine changes the OHC membrane voltage without affecting its magnitude and inhibits cochlear function measured in DPOAE and compound action potential in guinea pig.^97,⁹⁸⁾ In addition, changing the turgor pressure of OHCs through osmotic challenge can modulate their ability to produce electromotile forces.⁹⁹⁾

Conclusion

Generally, sensorineural hearing loss may result from many different causes such as noise exposure, ototoxicity, prebycusis, and chemical exposure. The common location of damage for all of sensorineural hearing loss is the OHC within the inner ear. The OHC is the most important organ of the cochlea because it is directly involved in the cochlea amplifier which consists of mechano-electrical and electro-mechanical transduction. Many molecular and cellular studies have shown that OHC produces forces requiring for cochlear amplifier through two different mechanisms of hair bundle displacement and OHC electromotility. The MET is located within the stereocilia on the apex of the OHC in the non-mammalian cochlea whereas the EMT originates in the lateral wall of the cell in the mammalian cochlea. However, although many intensive studies have demonstrated the existence of the cochlear amplifier for several decades, the fundamental mechanisms behind the cochlear amplification still remains unanswered and many experimental data of the cochlear amplification are not consistent.
In spite of experimental and theoretical limitation to prove the active mechanisms in the cochlea, a clear and thorough understanding of the MET and the EMT provides a new classification scheme that can differentiate a sensorineural hearing loss associated with the MET from that related to the EMT and hearing loss associated with cochlear transduction from other hearing losses. In addition, diagnosis based on cochlear pathophysiology provides a clinically useful method to quantify the amount of the cochlear transduction and locate the sites of the cochlear transduction which lead to a new treatment and protection interventions such as improved algorithms for hearing aids, better hair cell regeneration and genetic techniques for therapy, and drug treatment.

REFERENCES

Gummer AW, Johnstone BM, Armstrong NJ. Direct measurements of basilar membrane stiffness in the guinea pig. J Acoust Soc Am 1981;70:1298-309.
Miller CE. Structural implications of basilar membrane compliance measurements. J Acoust Soc Am 1985;77:1465-74.
Naidu RC, Mountain DC. Measurements of the stiffness map challenge a basic tenet of cochlear theories. Hear Res 1998;124:124-31.
Olson ES, Mountain DC. In vivo measurement of basilar membrane stiffness. J Acoust Soc Am 1991;89:1262-75.
von Bekesy G. Experiments in hearing. New York, USA: McGrawHill;1960.
Naidu RC, Mountain DC. Measurements of the stiffness map challenge a basic tenet of cochlear theories. Hear Res 1998;124:124-31.
Olson ES, Mountain DC. Mapping the cochlear partition's stiffness to its cellular architecture. J Acoust Soc Am 1994;95:395-400.
Davis H. An active process in cochlear mechanics. Hear Res 1983;9: 79-90.
Gold T. Hearing II. The physical basis of the action of the cochlea. Proc R Soc Lond B 1948;135:492-8.
Chen GD. Prestin gene expression in the rat cochlea following intense noise exposure. Hear Res 2006;222:54-61.
Ren T, Gillespie PG. A mechanism for active hearing. Curr Opin Neurobiol 2007;17:498-503.
Manley GA. Evidence for an active process and a cochlear amplifier in nonmammals. J Neurophysiol 2001;86:541-9.
Fettiplace R. Active hair bundle movements in auditory hair cells. J Physiol 2006;576(Pt 1):29-36.
Fettiplace R, Hackney CM. The sensory and motor roles of auditory hair cells. Nat Rev Neurosci 2006;7:19-29.
Ricci AJ, Kachar B, Gale J, Van Netten SM. Mechano-electrical transduction: new insights into old ideas. J Membr Biol 2006;209:71-88.
Weiss TF. Bidirectional transduction in vertebrate hair cells: a mechanism for coupling mechanical and electrical processes. Hear Res 1982;7:353-60.
Kemp DT. Stimulated acoustic emissions from the human auditory system. J Acoust Soc Am 1978;64:1386-91.
Brownell WE, Bader CR, Bertrand D, de Ribaupierre Y. Evoked mechanical responses of isolated cochlear outer hair cells. Science 1985; 227:194-6.
Howard J, Hudspeth AJ. Mechanical relaxation of the hair bundle mediates adaptation in mechanoelectrical transduction by the bullfrog's saccular hair cell. Proc Nat Acad Sci U S A 1987;84:3064-8.
Hudspeth AJ. How the ear's works work. Nature 1989;341:397-404.
Crawford AC, Fettiplace R. The mechanical properties of ciliary bundles of turtle cochlear hair cells. J Physiol 1985;364:359-79.
Hudspeth AJ, Jacobs R. Stereocilia mediate transduction in vertebrate hair cells(auditory system/cilium/vestibular system). Proc Natl Acad Sci U S A 1979;76:1506-9.
Hudspeth AJ. Extracellular current flow and the site of transduction by vertebrate hair cells. J Neurosci 1982;2:1-10.
Howard J, Hudspeth AJ. Compliance of the hair bundle associated with gating of mechanoelectrical transduction channels in the bullfrog's saccular hair cell. Neuron 1988;1:189-99.
Géléoc GS, Lennan GW, Richardson GP, Kros CJ. A quantitative comparison of mechanoelectrical transduction in vestibular and auditory hair cells of neonatal mice. Proc Biol Sci 1997;264:611-21.
Mammano F, Ashmore JF. Differential expression of outer hair cell potassium current in the isolated cochlea of guinea-pig. J Physiol 1996; 496(Pt 3):639-46.
Crawford AC, Evans MG, Fettiplace R. Activation and adaptation of transducer currents in turtle hair cells. J Physiol 1989;419: 405-34.
Choi CH, Chertoff ME, Bian L, Lerner D. Constructing a cochlear transducer function from the summating potential using a low-frequency bias tone. J Acoust Soc Am 2004;116:2996-3007.
Weiss TF, Leong R. A model for signal transmission in an ear having hair cells with free-standing stereocilia. IV. Mechanoelectric transduction stage. Hear Res 1985;20:175-95.
Holton T, Hudspeth AJ. The transduction channel of hair cell from the bull-frog characterized by noise analysis. J Physiol 1986;375: 195-227.
Chertoff ME, Yi X, Lichtenhan JT. Influence of hearing sensitivity on mechano-electric transduction. J Acoust Soc Am 2003;114(6 Pt 1): 3251-63.
Weiss TF. Bidirectional transduction in vertebrate hair cells: a mechanism for coupling mechanical and electrical processes. Hear Res 1982;7:353-60.
Kim DO. Active and nonlinear cochlear biomechanics and the role of outer hair-cell subsystem in the mammalian auditory system. Hear Res 1986;22:105-14.
Ricci AJ, Crawford AC, Fettiplace R. Active hair bundle motion linked to fast transducer adaptation in auditory hair cells. J Neurosci 2000;20: 7131-42.
Chan DK, Hudspeth AJ. Ca2+ current-driven nonlinear amplification by mammalian cochlea in vitro. Nat Neurosci 2005;8:149-55.
Kennedy HJ, Crawford AC, Fettiplate R. Force generation by mammalian hair bundles supports a role in cochlear amplification. Nature 2005;433:880-3.
Jia S, He DZ. Motility-associated hair-bundle motion in mammalian outer hair cells. Nat Neurosci 2005;8:1028-34.
Yates GK, Kirk DL. Cochlear electrically evoked emissions modulated by mechanical transduction channels. J Neurosci 1998;18:1996-2003.
Nieder P, Nieder I. Some effects of tonal interactions as seen in the cochlear microphonic. J Acoust Soc Am 1968;43:1092-106.
Nieder P, Nieder I. Determination of microphonic generator transfer characteristic from modulation data. J Acoust Soc Am 1971;49:478-92.
Dallos P, Billone MC, Durant JD, Raynor WS. Cochlear inner and outer hair cells: functional differences. Science 1972;177:356-8.
Wever EG, Bray CW. Action currents in the auditory nerve in response to acoustical stimulation. Proc Natl Acad Sci U S A 1930;16: 344-50.
Tasaki I, Davis H, Eldredge DH. Exploration of cochlear potentials in guinea pig with a microelectrode. J Acoust Soc Am 1954;26:765-73.
Dallos P. Response characteristics of mammalian cochlear hair cells. J Neurosci 1985;5:1591-608.
Patuzzi RB. A model of the generation of the cochlear microphonic with nonlinear hair cell transduction and nonlinear basilar membrane mechanics. Hear Res 1987;30:73-82.
Patuzzi RB, Yates GK, Johnstone BM. Outer hair cell current and sensorineural hearing loss. Hear Res 1989;42:47-72.
Chertoff ME, Steele T, Ator GA, Bian L. Characterizing cochlear mechano-electric transduction using a nonlinear systems identification procedure. J Acoust Soc Am 1996;100:3741-53.
Chertoff ME, Steele TC, Bian L. Characterizing cochlear mechanoelectric transduction in ears damaged with pure tones. J Acoust Soc Am 1997;102:441-50.
Choi CH, Chertoff ME, Yi X. Characterizing cochlear mechano-electric transduction with a nonlinear system identification technique: the influence of the middle ear. J Acoust Soc Am 2002;112:2898-909.
Choi CH, Bian L, Chertoff ME. Deriving a cochlear transducer function from low frequency modulated cochlear microphonic. Korean J Communication Disorders 2010;15:232-50.
Dallos P. Neurobiology of cochlear inner and outer hair cells: intracellular recordings. Hear Res 1986;22:185-98.
Cody AR, Russell IJ. The response of hair cell in the basal turn of the guinea-pig cochlea to tones. J Physiol 1987;383:551-69.
Russell IJ, Sellick PM. Intracellular studies of hair cell in the mammalian cochlea. J Physiol 1978;284:261-90.
Cody AR, Russell IJ. Outer hair cells in the mammalian cochlea and noise-induced hearing loss. Nature 1985;315:662-5.
Kimitsuki T, Nakagawa T, Hisashi K, Komune S, Uemura T. The effects of ototoxic drugs on mechano-electric transduction channels in chick cochlear hair cells. Eur Arch Otorhinolaryngol 1994;251 Suppl 1:S53-6.
Bian L, Chertoff ME. Differentiation of cochlear pathophysiology in ears damged by salicylate or pure tone using a nonlinear systems identification technique. J Acoust Soc Am 1998;104:2261-71.
Bian L, Chertoff ME. Distinguishing cochlear pathophysiology in 4-aminopyridine and furosemide treate ears using a nonlinear systems identification technique. J Acoust Soc Am 2001;109:671-85.
Kossl M, Richardson GP, Russell IJ. Stereocilia bundle stiffenss: effects of neomycin sulphate, A23187 and concanavalin A. Hear Res 1990;44:217-29.
Kroese AB, Das A, Hudspth AJ. Blockage of the transduction channels of hair cells in the bullfrog's sacculus by aminoglycoside antibiotics. Hear Res 1989;37:203-17.
Nagata K, Duggan A, Kumar G, Garcia-Anoveros J. Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing. J Neurosci 2005;25:4052-61.
Forge A. Structural features of the lateral walls in mammalian cochlear outer hair cell. Cell Tissue Res 1991;265:473-83.
Zheng J, Shen W, He DZ, Long KB, Madison LD, Dallos P. Prestin is the motor protein of cochlear outer hair cells. Nature 2000;405: 149-55.
Holley MC, Ashmore JF. A cytoskeletal spring in cochlear outer hair cells. Nature 1988;335:635-37.
Flock A, Flock B, Ulfendahl M. Mechanisms of movement in outer hair cells and a possible structural basis. Arch Otorhinolaryngol 1986; 243:83-90.
Oghalai JS. The cochlear amplifier: augmentation of the tuning wave within the inner ear. Curr Opin Otolaryngol Head Neck Surg 2004; 12:431-8.
Dallos P, Evans BN, Hallworth R. Nature of the motor element in electrokinetic shape changes of cochlar outer hair cells. Nature 1991; 350:155-7.
Huang G, Santos-Sacchi J. Motility voltage sensor of the outer hair cell resides within the lateral plasma membrane. Proc Natl Acad Sci U S A 1994;91:12268-72.
Ashmore JF. Mammalian hearing and the cellular mechanisms of the cochlear amplifier. In: Corey DP, Roper SD, editors. Sensory Transduction, 1^st ed. New York: Rockefeller University Press;1992. p.396-412.
Santos-Sacchi J. Reversible inhibition of voltage-dependent outer hair cell motility and capacitance. J Neurosci 1991;11:3096-110.
Iwasa KH, Chadwick RS. Elasticity and active force generation of cochlear outer hair cells. J Acoust Soc Am 1992;92:3169-73.
Iwasa KH. A membrane motor model for the fast motility of the outer hair cell. J Acoust Soc Am 1994;96:2216-24.
Gale JE, Ashmore JF. Charge displacement induced by rapid stretch in the basolateral membrane of the guinea-pig outer hair cell. Proc Biol Sci 1994;255:243-9.
Kakehata S, Santos-Sacchi J. Membrane tension directly shifts voltage dependence of outer hair cell motility and associated gating charge. Biophys J 1995;68:2190-7.
Mammano F, Ashmore JF. Reverse transduction measured in the isolated cochlea by laser Michelson interferometry. Nature 1993;365: 838-41.
Oliver D, He DZ, Klöcker N, Ludwig J, Schulte U, Waldegger S, et al. Intracellular anions as the voltage sensor of prestin, the outer hair cell motor protein. Science 2001;292:2340-3.
Rybalchenko V, Santos-Sacchi J. Cl- flux through a non-selective, stretch-sensitive conductance influences the outer hair cell motor of the guinea-pig. J Physiol 2003;547(Pt 3):873-91.
He DZ. Voltage-dependent somatic stiffness of cochlear outer hair cells. Abstracts of the 26th Meeting of the Association for Research in Otolaryngology 2003;26:208.
Liberman MC, Gao J, He DZ, Wu X, Jia S, Zuo J. Prestin is required for electromotility of the outer hair cell and for the cochlear amplifier. Nature 2002;419:300-4.
von Békésy G. Experiments in Hearing. New York, USA: McGrawHill;1960.
Russell IJ, Nilsen KE. The location of the cochlear amplifier: spatial representation of a single tone on the guinea pig basilar membrane. Proc Natl Acad Sci U S A 1997;94:2660-4.
Rhode WS, Recio A. Study of mechanical motions in the basal region of the chinchilla cochlea. J Acoust Soc Am 2000;107:3317-32.
Ren T. Longitudinal pattern of basilar membrane vibration in the sensitive cochlea. Proc Natl Acad Sci U S A 2002;99:17101-6.
Brownell WE. Outer hair cell electromotility and otoacoustic emissions. Ear Hear 1990;11:82-92.
Frolenkov GI, Belyantseva IA, Kurc M, Mastroianni MA, Kachar B. Cochlear outer hair cell can provide force for both low and high intensity distortion product otoacoustic emissions. Hear Res 1998;126: 67-74.
Kemp DT. Stimulated acoustic emissions from within the human auditory system. J Acoust Soc Am 1978;64:1386-91.
Kemp DT. Otoacoustic emissions, traveling wave and cochlear mechanisms. Hear Res 1986;22:95-104.
Probst R, Lonsbury-Martin BL, Martin GK. A review of otoacosutic emissions. J Acoust Soc Am 1991;89:2027-67.
Ren T, Nuttall AL. Extracochlear electrically evoked otoacoustic emissions: a model for in vivo assessment of outer hair cell electromotility. Hear Res 1995;92:178-83.
Nuttall AL, Ren T. Electromotile hearing: evidence from basilar membrane motion and otoacoustic emissions. Hear Res 1995;92:170-7.
Bian L, Chertoff ME, Miller E. Deriving a cochlear transducer function from low-frequency modulation of distortion product otoacoustic emissions. J Acoust Soc Am 2002;112:198-210.
Bian L. Cochlear compression: effects of low-frequency biasing on quadratic distortion product otoacoustic emissions. J Acoust Soc Am 2004;116:3559-71.
Bian L. Spectral fine-structures of low-frequency modulated distortion product otoacoustic emissions. J Acoust Soc Am 2006;119:3872-85.
Liberman MC, Zuo J, Guinan JJ Jr. Otoacoustic emissions without somatic motility: can stereocilia mechanics drive the mammalian cochlea? J Acoust Soc Am 2004;116:1649-55.
Shehata WE, Brownell WE, Dieler R. Effects of salicylate on shape, electromotility and membrane characteristics of isolated outer hair cells from guinea pig cochlea. Acta Otolayngol 1991;111:707-18.
Ueda H, Yamamoto Y, Yanagita N. Effect of aspirin on transiently evoked otoacoustic emissions in guinea pigs. ORL J Otorhinolaryngol Relat Spec 1996;58:61-7.
Zheng J, Ren T, Parthasarathi A, Nuttall AL. Quinine-induced alterations of electrically evoked otoacoustic emissions and cochlear potentials in guinea pigs. Hear Res 2001;154:124-34.
Lue AJ, Zhao HB, Brownell WE. Chlorpromazine alters outer hair cell electromotility. Otolaryngol Head Neck Surg 2001;125:71-6.
Oghalai JS. Chlorpromazine inhibits cochlear function in guinea pig. Hear Res 2004;198:59-68.
Choi CH, Oghalai JS. Perilymph osmolality modulates cochlear function. Laryngoscope 2008;118:1621-9.