Pathologic mechanoelectric transduction of outer hair cells as the cause of recruitment

It is believed that the sound-induced travelling wave in the mammalian cochlea is enhanced and sharpened by a positive feedback mechanism. This causes the passive linear basilar membrane growth function to become non-linear. The present paper shows that nonlinear basilar membrane vibration is due to the nonlinear growth function of the receptor potential of outer hair cells, which can be described by a 2nd-order Boltzmann function. Since intensity coding in the inner ear depends on an interaction of nonlinear basilar membrane motion and nerve fibers with three different types of synaptic threshold and growth function, the process is directly dependent on an intact mechanoelectrical transduction of outer hair cells. According to the proposed model, a loss in efficiency of outer hair cell mechanoelectrical transduction must lead to both a reduction in gain (i.e., hearing loss) and a linearizing of the response. As a result, once above threshold, the changes of stereociliary displacement, basilar membrane displacement and neural firing rate per unit change of sound intensity must be larger than for the healthy cochlea with its compressive nonlinearity.     

A model for the responses of low-frequency auditory-nerve fibers in cat

A computational model was developed for the responses of low-frequency auditory-nerve (AN) fibers in cat. The goal was to produce realistic temporal response properties and average discharge rates in response to simple and complex stimuli. Temporal and average-rate properties of AN responses change as a function of sound-pressure level due to nonlinearities in the auditory periphery. The input stage of the AN model is a narrow-band filter that simulates the mechanical tuning of the basilar membrane. The parameters of this filter vary continuously as a function of stimulus level via a feedback mechanism, simulating the compressive nonlinearity associated with the mechanics of the basilar membrane. A memoryless, saturating nonlinearity and two low-pass filters simulate transduction and membrane properties of the inner hair cell (IHC). A diffusion model for the IHC-AN synapse introduces adaptation. Finally, a nonhomogeneous Poisson process, modified by absolute and relative refractoriness, provides the output discharge times. Responses to several different stimuli are presented. These responses illustrate nonlinear temporal response properties that cannot be achieved with linear models for AN fibers.     

Linearized Stability and Accuracy for Step-by-Step Solutions of Certain Nonlinear Systems

In this work, stability and accuracy of the Newmark method for nonlinear systems are obtained from a linearized analysis. This analysis reveals that an unconditionally stable integration method for linear elastic systems is unconditionally stable for nonlinear systems and a conditionally stable integration method for linear elastic systems remains conditionally stable for nonlinear systems except that its upper stability limit might vary with the step degree of nonlinearity and step degree of convergence. A sufficient condition to have a stable computation for nonlinear systems in a whole step-by-step integration procedure is also developed in this study. Furthermore, it is also found that numerical accuracy in the solution of nonlinear systems is closely related to the step degree of nonlinearity and step degree of convergence although its characteristics are similar to those of the preceding works for linear elastic systems. Since these results are obtained from a linearized analysis, they can be applicable to the nonlinear systems that satisfied the simplifications for the analysis but may not be applicable to general nonlinear systems.     

Low doses of ethanol reduce evidence for nonlinear structure in brain activity

Recent theories of the effects of ethanol on the brain have focused on its direct actions on neuronal membrane proteins. However, neuromolecular mechanisms whereby ethanol produces its CNS effects in low doses typically used by social drinkers (e.g., 2-3 drinks, 10-25 mM, 0.05-0.125 gm/dl) remain less well understood. We propose the hypothesis that ethanol may act by introducing a level of randomness or "noise" in brain electrical activity. We investigated the hypothesis by applying a battery of tests originally developed for nonlinear time series analysis and chaos theory to EEG data collected from 32 men who had participated in an ethanol/placebo challenge protocol. Because nonlinearity is a prerequisite for chaos and because we can detect nonlinearity more reliably than chaos, we concentrated on a series of measures that quantitated different aspects of nonlinearity. For each of these measures the method of surrogate data was used to assess the significance of evidence for nonlinear structure. Significant nonlinear structure was found in the EEG as evidenced by the measures of time asymmetry, determinism, and redundancy. In addition, the evidence for nonlinear structure in the placebo condition was found to be significantly greater than that for ethanol. Nonlinear measures, but not spectral measures, were found to correlate with a subject's overall feeling of intoxication. These findings are consistent with the notion that ethanol may act by introducing a level of randomness in neuronal processing as assessed by EEG nonlinear structure.     

Compression, gain, and nonlinear distortion in an active cochlear model with subpartitions

The propagation of inhomogeneous, weakly nonlinear waves is considered in a cochlear model having two degrees of freedom that represent the transverse motions of the tectorial and basilar membranes within the organ of Corti. It is assumed that nonlinearity arises from the saturation of outer hair cell active force generation. I use multiple scale asymptotics and treat nonlinearity as a correction to a linear hydroelastic wave. The resulting theory is used to explain experimentally observed features of the response of the cochlear partition to a pure tone, including: the amplification of the response in a healthy cochlea vs a dead one; the less than linear growth rate of the response to increasing sound pressure level; and the amount of distortion to be expected at high and low frequencies at basal and apical locations, respectively. I also show that the outer hair cell nonlinearity generates retrograde waves.     

Psychophysical measures of auditory nonlinearities as a function of frequency in individuals with normal hearing

In order to gain a better understanding of how auditory nonlinear phenomena vary as a function of location along the cochlea, several psychophysical measures of nonlinearity were examined as a function of signal frequency. Six normal-hearing individuals completed three experiments, each designed to measure one aspect of nonlinear behavior: (1) the effects of level on frequency selectivity in simultaneous masking, measured using notched-noise maskers at spectrum levels of 30 and 50 dB, (2) two-tone suppression, measured using forward maskers at the signal frequency (fs) and suppressor tones above fs, and (3) growth of masking, measured using forward maskers below fs at a signal/masker frequency ratio of 1.44. Four signal frequencies (375, 750, 1500, and 3000 Hz) were tested to sample the nonlinear behavior at different locations along the basilar membrane, in order to test the hypothesis that the apical (low-frequency) region of the cochlea behaves more linearly than the basal (high-frequency) region. In general, all three measures revealed a progressive increase in nonlinear behavior as signal frequency increased, with little or no nonlinearity at the lowest frequency, consistent with the hypothesis.     

Effect of sodium benzoate on cerebral and hepatic energy metabolites in spf mice with congenital hyperammonemia

The outer hair cell (OHC) is known to have the ability to change its length in response to voltage changes across its membrane. The apparent function of this OHC motility is to enhance the tuning of the basilar membrane. The model presented in this paper represents the displacement-to-voltage and voltage-to-displacement transducers of the OHC explicitly, each as low-pass filter functions. The model results show that this OHC representation is sufficient to provide a model of cochlear mechanics with mechanical tuning at the inner hair cell which is comparable to the threshold tuning curves observed in single auditory nerve fibers. The enhancement of tuning provided by OHC motility can be interpreted as the combined action of a cochlear amplifier and a second filter. This model demonstrates that realistic cochlear tuning does not require intrinsic resonance in any cochlear structure other than the basilar membrane.     

Psychoacoustic consequences of compression in the peripheral auditory system.

Input–output functions on the basilar membrane of the cochlea show a strong compressive nonlinearity at midrange levels for frequencies close to the characteristic frequency of a given place. This article shows how many different phenomena can be explained as consequences of this nonlinearity, including the "excess" masking produced when 2 nonsimultaneous maskers are combined, the nonlinear growth of forward masking with masker level, the influence of component phase on the effectiveness of complex forward maskers, changes in the ability to detect increments and decrements with level, temporal integration, and the influence of component phase and level on the perception of vowellike sounds. Cochlear hearing loss causes basilar-membrane responses to become more linear. This can account for loudness recruitment, linear additivity of nonsimultaneous masking, linear growth of forward masking, reduced temporal resolution for sounds with fluctuating envelopes, and reduced temporal integration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Vibration of reflective beads placed on the basilar membrane

Most investigators place reflective beads on the basilar membrane to measure its vibration with optical methods. It is therefore important to find out if the beads faithfully follow the motion of the structures on which they are placed. Vibration of the beads on the basilar membrane and basilar membrane adjacent to the beads are measured in the third turn of the guinea pig cochlea in a temporal bone preparation. It is shown that the beads do not follow the motion of the organ. The mechanism by which this departure may occur is investigated by modeling the motion of the beads on the Claudius' cells.     

Nonlinear Response of Fluid-Filled Membrane in Gravity Waves

This paper describes a time-domain model for the nonlinear response of fluid-filled membranes in gravity waves. A formulation based on the principle of virtual work provides an integral governing equation for membrane deformation that fully accounts for geometric nonlinearity, which is known to be important even for relatively small deformation. The incident wave amplitude and membrane deformation are considered to be small, to allow linearization of the hydrodynamic problems. The potential flows inside and outside the membrane are solved by two boundary element models, which are coupled to the finite element model of the membrane. An iterative scheme based on Newmark’s method integrates the resulting nonlinear equations of motion in time. The computed results for a bottom-mounted fluid-membrane system show favorable agreement with available experimental and numerical data. Membrane geometric nonlinearity increases the system stiffness due to strain-stiffening and gives rise to hysteresis response at some frequencies.     

The level dependence of response phase: observations from cochlear hair cells

Hair cell responses are recorded from third turn of the guinea pig cochlea in order to define the relationship between hair cell depolarization and position of the basilar membrane. Because the latter is determined locally, using the cochlear microphonic recorded in the organ of Corti (OC) fluid space, no corrections are required to compensate traveling wave and/or synaptic delays. At low levels, inner hair cells (IHC) depolarize near basilar membrane velocity to scala vestibuli reflecting the free standing nature of their stereocilia. At high levels, the time of depolarization changes rapidly from velocity to scala vestibuli to the scala tympani phase of the basilar membrane response. This change in response phase, recorded in the fundamental component of the IHC response, is associated with a decrease in response magnitude. The absence of this behavior in OC and outer hair cell responses implies that basilar membrane mechanics may not be responsible for these response patterns. Because these features are reminiscent of the magnitude notches and the large phase shifts observed in single unit responses at high stimulus levels, they provide the IHC correlates of these phenomena.     

Nonlinear preprocessing in short-range motion

The phenomenon of non-Fourier motion (visually perceived motion that cannot be explained simply on the basis of the autocorrelation structure of the visual stimulus) is well recognized, and is generally considered to be due to nonlinear preprocessing of the visual stimulus prior to a stage of standard motion analysis. We devised a sequence of novel visual stimuli in which the availability of a motion stimulus depends on the nature of the nonlinear preprocessing: an nth order stimulus Pn will generate a perception of motion if it is preprocessed by a nonlinearity of polynomial order n or greater, but not if preprocessed by a nonlinearity of polynomial order less than n. We found that unambiguous motion direction was perceived for P2, P3, and P4, but not for higher-order stimuli, and we measured the contrast thresholds for direction discrimination with superimposed noise. We found that an asymmetric compressive nonlinearity can, in a unified fashion, account for these results, while a purely quadratic nonlinearity or a rectification of the form T(p) = magnitude of p cannot. We compared velocity discrimination judgements for second-order non-Fourier stimuli (P2) with standard drifting gratings. Although velocity comparisons were veridical, uncertainties were greater for the non-Fourier stimuli. This could be reproduced by substituting a Fourier grating with superimposed noise for the non-Fourier grating. These findings are consistent with a single pathway which processes both Fourier and non-Fourier short-range motion, and are discussed in the context of other investigations which have been interpreted as demonstrating separate pathways.     

A tracer interaction method for nonlinear pharmacokinetics analysis: application to evaluation of nonlinear elimination

A drug tracer is most commonly applied to get information about the pharmacokinetics (PK) of a drug that is not confounded by an endogenously produced drug or an unknown drug input. An equally important use of tracers that has not been fully recognized is their use in the study of nonlinear PK behavior. In the present study a system analysis is applied to examine the interaction between drug molecules characteristic and intrinsic to any nonlinear process which enables the nonlinearity to be identified and modeled using a drug tracer. The proposed Tracer Interaction Methodology (TIM) forms a general developmental framework for novel methods for examining nonlinear phenomena. Such methods are potentially much more sensitive and accurate than previous methods not exploiting the tracer principle. The methodology proposed is demonstrated in a simulation study and with real data in a specific implementation aimed at determining the Michaelis-Menten (MM) parameters of nonlinear drug elimination while accounting for drug distribution effects. The simulation study establishes that the TIM-based, MM parameter evaluation produces substantially more accurate parameter estimates than a nontracer (NT) conventional method. In test simulations the accuracy of the TIM was in many cases an order of magnitude better than the NT method without evidence of bias. The TIM-based, MM parameter estimation methodology proposed is ideally suitable for dynamic, non-steady-state conditions. Thus, it offers greater applicability and avoids the many problems specific to steady state evaluations previously proposed. TIM is demonstrated in an evaluation of the nonlinear elimination behavior of erythropoietin, a process that likely takes place via receptor-based endocytosis. Due to its high sensitivity, accuracy, and intrinsic nonlinearity the TIM may be suitable for in-vivo studies of receptor binding of the many biotechnology produced peptide drugs and endogenous compounds displaying receptor-mediated elimination.     

A 70-year-old woman complaining of shortness of breath despite decreased pericardial effusion

In order to investigate the characters of inner ear vessels using the microvascular corrosion casting technique and scanning electron microscope the three-dimensional spatial picture of the vessels in cochlear basilar membrane, utriculus, sacculus and three ampullae of guinea pig were observed. It was found that arteriole coils were present in the modiolus ampullae, utriculus and sacculus. The length of arterioles was therefore prolonged and could keep the blood supply in inner ear stable. The possibility of blood coagulation in these segments increased because the blood flow became slower here. Another character was that the capillary networks appeared denser in stria vascularis and central part of the crista, whereas the vessel meshes in basilar membrane of cochlea and in planum semiculatum of ampullae were looser. These findings suggested that the metabolism in stria vascularis and central part of the crista would be more prosperous than that in the basilar membrane and planum semiculatum of ampullae.     

Suppression and the upward spread of masking

The purpose of this study is to clarify the role of suppression in the growth of masking when a signal is well above the masker in frequency (upward spread of masking). Classical psychophysical models assume that masking is primarily due to the spread of masker excitation, and that the nonlinear upward spread of masking reflects a differential growth in excitation between the masker and the signal at the signal frequency. In contrast, recent physiological studies have indicated that upward spread of masking in the auditory nerve is due to the increasing effect of suppression with increasing masker level. This study compares thresholds for signals between 2.4 and 5.6 kHz in simultaneous and nonsimultaneous masking for conditions in which the masker is either at or well below the signal frequency. Maximum differences between simultaneous and nonsimultaneous masking were small (< 6 dB) for the on-frequency conditions but larger for the off-frequency conditions (15-32 dB). The results suggest that suppression plays a major role in determining thresholds at high masker levels, when the masker is well below the signal in frequency. This is consistent with the conclusions of physiological studies. However, for signal levels higher than about 40 dB SPL, the growth of masking for signals above the masker frequency is nonlinear even in the nonsimultaneous-masking conditions, where suppression is not expected. This is consistent with an explanation based on the compressive response of the basilar membrane, and confirms that suppression is not necessary for nonlinear upward spread of masking.     

Nonlinear Identification of Lumped-Mass Buildings Using Empirical Mode Decomposition and Incomplete Measurement

Most structures exhibit some degrees of nonlinearity such as hysteretic behavior especially under damage. It is necessary to develop applicable methods that can be used to characterize these nonlinear behaviors in structures. In this paper, one such method based on the empirical mode decomposition (EMD) technique is proposed for identifying and quantifying nonlinearity in damaged structures using incomplete measurement. The method expresses nonlinear restoring forces in semireduced-order models in which a modal coordinate approach is used for the linear part while a physical coordinate representation is retained for the nonlinear part. The method allows the identification of parameters from nonlinear models through linear least-squares. It has been shown that the intrinsic mode functions (IMFs) obtained from the EMD of a response measured from a nonlinear structure are numerically close to its nonlinear modal responses. Hence, these IMFs can be used as modal coordinates as well as provide estimates for responses at unmeasured locations if the mode shapes of the structure are known. Two procedures are developed for identifying nonlinear damage in the form of nonhysteresis and hysteresis in a structure. A numerical study on a seven-story shear-beam building model with cubic stiffness and hysteretic nonlinearity and an experimental study on a three-story building model with frictional magnetoreological dampers are performed to illustrate the proposed method. Results show that the method can quite accurately identify the presence as well as the severity of different types of nonlinearity in the structure.     

Nonlinear Model for Lead–Rubber Bearings Including Axial-Load Effects

Existing models for isolation bearings neglect certain aspects of their response behavior. For instance, rubber bearings have been observed to decrease in stiffness with increasing axial load, and soften in the vertical direction at large lateral deformations. The yield strength of lead–rubber bearings has also been observed to vary with axial load, such that a lightly loaded bearing may not achieve its theoretical strength. Models that include these axial-load effects in lead–rubber bearings are developed by extending an existing linear two-spring model to include nonlinear behavior. The nonlinearity includes an empirical equation for the experimentally observed variation of yield strength. For numerical implementation, the bearing forces are found by solving the nonlinear equilibrium and kinematic equations using Newton’s method, and the instantaneous bearing stiffness matrix is formed from the differentials of these equations. The response behavior of the models is confirmed by comparison with experimental data.     

Nonlinear and asymmetric open channel characteristics of an ion-selective porin in planar membranes

The open channel characteristics of the bacterial porin Omp32 from Comamonas acidovorans were investigated by means of conductance measurements in planar lipid bilayers of the Montal-Mueller type. Particularly at low salt conditions (< or = 30 mM KCl) Omp32 exhibited some unusual asymmetric and nonlinear functional properties. Current-voltage relationship measurements showed that conductance depends on the orientation of porin molecules and is a nonlinear function of the applied membrane potential. Conductance also depends on the salt concentration in a manner not common to porins and the salt concentration modulates the nonlinearity of conductance-voltage relationships. Omp32 is strongly anion-selective. The nonlinear and asymmetric conductance of the open channel is a new observation in porins.     

Nonlinear Control Methodologies for Hysteresis in PZT Actuated On-Blade Elevons

While piezoelectric (PZT) actuators exhibit only mild nonlinear response at low voltage levels, it is well known that the response can be profoundly nonlinear at high field strengths. Moreover, the use of mechanical linkages and structural design to amplify the stroke of PZT-based actuation likewise induces sources of mechanical hysteresis (friction, backlash, etc.) that can couple with this material nonlinearity to yield a structural scale nonlinearity that is nonnegligible. These two sources of hysteresis, due to mechanism response and nonlinear material response, are not easily decoupled. In this paper, we investigate such a nonlinear response in a PZT actuated trailing edge flap attached to a scaled helicopter rotor blade. While the example studied in this paper is quite specific, the methodology derived is generally applicable. We extend the results of previous papers for the derivation of closed loop control for active material actuated devices. The goal is to derive a control methodology that accounts for the overall, total hysteresis due to material nonlinearities and mechanism response. In this technique, a compensator derived from an offline identification of a Krasnoselskii-Pokrovskii hysteresis operator is cascaded with the plant. We show that the methodology is well posed for the class of problems under consideration; we describe relevant closed loop stability and robustness conditions that can be associated with the prediction error in the identified hysteresis operator. We study the performance of our methodology in numerical examples and discuss relevant experimental results.     

Impairment of vasodilator function in basilar arteries from aged rats

BACKGROUND AND PURPOSE: Aging is associated with a reduction in cerebral perfusion. Impaired vasodilatation in large brain arteries could be implicated. This study sought age-related changes in vasodilator responses to norepinephrine in rat basilar artery and investigated which aspects of norepinephrine's action are responsible. To study the effect of aging per se, we used the rat, an animal with resistance to development of age-related pathologies. METHODS: Vascular responses were studied in basilar arteries from young (3 to 4 months old) and old (20 to 22 months old) normotensive Sprague-Dawley rats with wire myography. Endothelial structure was assessed with confocal microscopy. RESULTS: There was no age-related difference in blood pressure and in KCl or 5-hydroxytryptamine (5-HT) contractions. Relaxation to bradykinin or its absence predicted an intact or denuded endothelium, confirmed by confocal microscopy. Norepinephrine produced concentration-dependent relaxation that was significantly smaller in old rats, with or without endothelium. This response was significantly smaller in endothelium-denuded vessels, or after preincubation with NG-nitro-L-arginine methyl ester or propranolol, but not with rauwolscine. CONCLUSIONS: In old and young rats the vasodilator action of norepinephrine in basilar artery is dependent on beta-adrenoceptors and nitric oxide. The impaired vasodilatation to norepinephrine found in the basilar artery from old rats might be caused by (1) a reduction in nitric oxide production and/or release or (2) beta-adrenoceptor alteration at the endothelium and/or the vascular smooth muscle. This impairment of vasodilator function can be ascribed to the aging process per se and not to other age-related alterations, such as hypertension.