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1.  Response Characteristics in the Apex of the Gerbil Cochlea Studied Through Auditory Nerve Recordings 
In this study, we analyze the processing of low-frequency sounds in the cochlear apex through responses of auditory nerve fibers (ANFs) that innervate the apex. Single tones and irregularly spaced tone complexes were used to evoke ANF responses in Mongolian gerbil. The spike arrival times were analyzed in terms of phase locking, peripheral frequency selectivity, group delays, and the nonlinear effects of sound pressure level (SPL). Phase locking to single tones was similar to that in cat. Vector strength was maximal for stimulus frequencies around 500 Hz, decreased above 1 kHz, and became insignificant above 4 to 5 kHz. We used the responses to tone complexes to determine amplitude and phase curves of ANFs having a characteristic frequency (CF) below 5 kHz. With increasing CF, amplitude curves gradually changed from broadly tuned and asymmetric with a steep low-frequency flank to more sharply tuned and asymmetric with a steep high-frequency flank. Over the same CF range, phase curves gradually changed from a concave-upward shape to a concave-downward shape. Phase curves consisted of two or three approximately straight segments. Group delay was analyzed separately for these segments. Generally, the largest group delay was observed near CF. With increasing SPL, most amplitude curves broadened, sometimes accompanied by a downward shift of best frequency, and group delay changed along the entire range of stimulus frequencies. We observed considerable across-ANF variation in the effects of SPL on both amplitude and phase. Overall, our data suggest that mechanical responses in the apex of the cochlea are considerably nonlinear and that these nonlinearities are of a different character than those known from the base of the cochlea.
doi:10.1007/s10162-010-0255-y
PMCID: PMC3085685  PMID: 21213012
cochlear mechanics; cochlear apex; phase locking; Meriones unguiculatus
2.  Phase-Locked Responses to Tones of Chinchilla Auditory Nerve Fibers: Implications for Apical Cochlear Mechanics 
Responses to tones with frequency ≤ 5 kHz were recorded from auditory nerve fibers (ANFs) of anesthetized chinchillas. With increasing stimulus level, discharge rate–frequency functions shift toward higher and lower frequencies, respectively, for ANFs with characteristic frequencies (CFs) lower and higher than ∼0.9 kHz. With increasing frequency separation from CF, rate–level functions are less steep and/or saturate at lower rates than at CF, indicating a CF-specific nonlinearity. The strength of phase locking has lower high-frequency cutoffs for CFs >4 kHz than for CFs < 3 kHz. Phase–frequency functions of ANFs with CFs lower and higher than ∼0.9 kHz have inflections, respectively, at frequencies higher and lower than CF. For CFs >2 kHz, the inflections coincide with the tip-tail transitions of threshold tuning curves. ANF responses to CF tones exhibit cumulative phase lags of 1.5 periods for CFs 0.7–3 kHz and lesser amounts for lower CFs. With increases of stimulus level, responses increasingly lag (lead) lower-level responses at frequencies lower (higher) than CF, so that group delays are maximal at, or slightly above, CF. The CF-specific magnitude and phase nonlinearities of ANFs with CFs < 2.5 kHz span their entire response bandwidths. Several properties of ANFs undergo sharp transitions in the cochlear region with CFs 2–5 kHz. Overall, the responses of chinchilla ANFs resemble those in other mammalian species but contrast with available measurements of apical cochlear vibrations in chinchilla, implying that either the latter are flawed or that a nonlinear “second filter” is interposed between vibrations and ANF excitation.
doi:10.1007/s10162-009-0197-4
PMCID: PMC2862913  PMID: 19921334
basilar membrane; cochlear apex; phase–frequency functions; rate–frequency functions
3.  The Group Delay and Suppression Pattern of the Cochlear Microphonic Potential Recorded at the Round Window 
PLoS ONE  2012;7(3):e34356.
Background
It is commonly assumed that the cochlear microphonic potential (CM) recorded from the round window (RW) is generated at the cochlear base. Based on this assumption, the low-frequency RW CM has been measured for evaluating the integrity of mechanoelectrical transduction of outer hair cells at the cochlear base and for studying sound propagation inside the cochlea. However, the group delay and the origin of the low-frequency RW CM have not been demonstrated experimentally.
Methodology/Principal Findings
This study quantified the intra-cochlear group delay of the RW CM by measuring RW CM and vibrations at the stapes and basilar membrane in gerbils. At low sound levels, the RW CM showed a significant group delay and a nonlinear growth at frequencies below 2 kHz. However, at high sound levels or at frequencies above 2 kHz, the RW CM magnitude increased proportionally with sound pressure, and the CM phase in respect to the stapes showed no significant group delay. After the local application of tetrodotoxin the RW CM below 2 kHz became linear and showed a negligible group delay. In contrast to RW CM phase, the BM vibration measured at location ∼2.5 mm from the base showed high sensitivity, sharp tuning, and nonlinearity with a frequency-dependent group delay. At low or intermediate sound levels, low-frequency RW CMs were suppressed by an additional tone near the probe-tone frequency while, at high sound levels, they were partially suppressed only at high frequencies.
Conclusions/Significance
We conclude that the group delay of the RW CM provides no temporal information on the wave propagation inside the cochlea, and that significant group delay of low-frequency CMs results from the auditory nerve neurophonic potential. Suppression data demonstrate that the generation site of the low-frequency RW CM shifts from apex to base as the probe-tone level increases.
doi:10.1371/journal.pone.0034356
PMCID: PMC3314608  PMID: 22470560
4.  Wiener Kernels of Chinchilla Auditory-Nerve Fibers: Verification Using Responses to Tones, Clicks, and Noise and Comparison With Basilar-Membrane Vibrations 
Journal of neurophysiology  2005;93(6):3635-3648.
Responses to tones, clicks, and noise were recorded from chinchilla auditory-nerve fibers (ANFs). The responses to noise were analyzed by computing the zeroth-, first-, and second-order Wiener kernels (h0, h1, and h2). The h1s correctly predicted the frequency tuning and phases of responses to tones of ANFs with low characteristic frequency (CF). The h2s correctly predicted the frequency tuning and phases of responses to tones of all ANFs, regardless of CF. Also regardless of CF, the kernels jointly predicted about 77% of the features of ANF responses to “frozen” samples of noise. Near-CF group delays of kernels and signal-front delays of responses to intense rarefaction clicks exceeded by 1 ms the corresponding basilar-membrane delays at both apical and basal sites of the chinchilla cochlea. This result, confirming that synaptic and neural processes amount to 1 ms regardless of CF, permitted drawing a map of basilar-membrane delay as a function of position for the entire length of the chinchilla cochlea, a first for amniotic species.
doi:10.1152/jn.00885.2004
PMCID: PMC1876724  PMID: 15659530
5.  Mechanics of the Mammalian Cochlea 
Physiological reviews  2001;81(3):1305-1352.
In mammals, environmental sounds stimulate the auditory receptor, the cochlea, via vibrations of the stapes, the innermost of the middle ear ossicles. These vibrations produce displacement waves that travel on the elongated and spirally wound basilar membrane (BM). As they travel, waves grow in amplitude, reaching a maximum and then dying out. The location of maximum BM motion is a function of stimulus frequency, with high-frequency waves being localized to the “base” of the cochlea (near the stapes) and low-frequency waves approaching the “apex” of the cochlea. Thus each cochlear site has a characteristic frequency (CF), to which it responds maximally. BM vibrations produce motion of hair cell stereocilia, which gates stereociliar transduction channels leading to the generation of hair cell receptor potentials and the excitation of afferent auditory nerve fibers. At the base of the cochlea, BM motion exhibits a CF-specific and level-dependent compressive nonlinearity such that responses to low-level, near-CF stimuli are sensitive and sharply frequency-tuned and responses to intense stimuli are insensitive and poorly tuned. The high sensitivity and sharp-frequency tuning, as well as compression and other nonlinearities (two-tone suppression and intermodulation distortion), are highly labile, indicating the presence in normal cochleae of a positive feedback from the organ of Corti, the “cochlear amplifier.” This mechanism involves forces generated by the outer hair cells and controlled, directly or indirectly, by their transduction currents. At the apex of the cochlea, nonlinearities appear to be less prominent than at the base, perhaps implying that the cochlear amplifier plays a lesser role in determining apical mechanical responses to sound. Whether at the base or the apex, the properties of BM vibration adequately account for most frequency-specific properties of the responses to sound of auditory nerve fibers.
PMCID: PMC3590856  PMID: 11427697
6.  Auditory brainstem responses predict auditory nerve fiber thresholds and frequency selectivity in hearing impaired chinchillas 
Hearing research  2011;280(1-2):236-244.
Non-invasive auditory brainstem responses (ABRs) are commonly used to assess cochlear pathology in both clinical and research environments. In the current study, we evaluated the relationship between ABR characteristics and more direct measures of cochlear function. We recorded ABRs and auditory nerve (AN) single-unit responses in seven chinchillas with noise induced hearing loss. ABRs were recorded for 1–8 kHz tone burst stimuli both before and several weeks after four hours of exposure to a 115 dB SPL, 50 Hz band of noise with a center frequency of 2 kHz. Shifts in ABR characteristics (threshold, wave I amplitude, and wave I latency) following hearing loss were compared to AN-fiber tuning curve properties (threshold and frequency selectivity) in the same animals. As expected, noise exposure generally resulted in an increase in ABR threshold and decrease in wave I amplitude at equal SPL. Wave I amplitude at equal sensation level (SL), however, was similar before and after noise exposure. In addition, noise exposure resulted in decreases in ABR wave I latency at equal SL and, to a lesser extent, at equal SPL. The shifts in ABR characteristics were significantly related to AN-fiber tuning curve properties in the same animal at the same frequency. Larger shifts in ABR thresholds and ABR wave I amplitude at equal SPL were associated with greater AN threshold elevation. Larger reductions in ABR wave I latency at equal SL, on the other hand, were associated with greater loss of AN frequency selectivity. This result is consistent with linear systems theory, which predicts shorter time delays for broader peripheral frequency tuning. Taken together with other studies, our results affirm that ABR thresholds and wave I amplitude provide useful estimates of cochlear sensitivity. Furthermore, comparisons of ABR wave I latency to normative data at the same SL may prove useful for detecting and characterizing loss of cochlear frequency selectivity.
doi:10.1016/j.heares.2011.06.002
PMCID: PMC3179834  PMID: 21699970
Auditory brainstem response (ABR); auditory nerve; auditory threshold; frequency selectivity; hearing loss
7.  A new auditory threshold estimation technique for low frequencies: Proof of concept 
Ear and hearing  2013;34(1):42-51.
Objectives
Presently available non-behavioral methods to estimate auditory thresholds perform less well at frequencies below 1 kHz than at 1 kHz and above. For many uses, such as providing accurate infant hearing aid amplification for low-frequency vowels, we need an accurate non-behavioral method to estimate low-frequency thresholds. Here we develop a novel technique to estimate low-frequency cochlear thresholds based on the use of a previously-reported waveform. We determine how well the method works by comparing the resulting thresholds to thresholds from onset-response compound action potentials (CAPs) and single auditory-nerve (AN) fibers in cats. A long-term goal is to translate this technique for use in humans.
Design
An electrode near the cochlea records a combination of cochlear microphonic (CM) and neural responses. In response to low-frequency, near threshold-level tones, the CM is almost sinusoidal while the neural responses occur preferentially at one phase of the tone. If the tone is presented again but with its polarity reversed, the neural response keeps the same shape, but shifts ½ cycle in time. Averaging responses to tones presented separately at opposite polarities overlaps and interleaves the neural responses and yields a waveform in which the CM is cancelled and the neural response appears twice each tone cycle, i.e. the resulting neural response is mostly at twice the tone frequency. We call the resultant waveform “the auditory nerve overlapped waveform” (ANOW). ANOW level functions were measured in anesthetized cats from 10 to 80 dB SPL in 10 dB steps using tones between 0.3 and 1 kHz. As a response metric, we calculated the magnitude of the ANOW component at twice the tone frequency (ANOW2f). The ANOW threshold was the sound level where the interpolated ANOW2f crossed a statistical criterion that was higher than 95% of the noise floor distribution. ANOW thresholds were compared to onset-CAP thresholds from the same recordings and single-AN-fiber thresholds from the same animals.
Results
We obtained ANOW and onset-CAP level functions for 0.3 to 1 kHz tones, and single-AN-fiber responses from cats. Except at 1 kHz, typical ANOW thresholds were mostly 10-20 dB more sensitive than onset-CAP thresholds and 10-20 dB less sensitive than the most sensitive single-AN-fiber thresholds.
Conclusions
ANOW provides frequency-specific estimates of cochlear neural thresholds over a frequency range that is important for hearing but is not well accessed by non-behavioral, non-invasive methods. Our results suggest that, with further targeted development, the ANOW low-frequency threshold estimation technique can be useful both clinically in humans and in basic-science animal experiments.
doi:10.1097/AUD.0b013e31825f9bd3
PMCID: PMC3495092  PMID: 22874644
audiogram; auditory nerve neurophonic; compound action potential; neural synchrony; phase locking
8.  Development of wide-band middle ear transmission in the Mongolian gerbila) 
Stapes vibrations were measured in deeply anesthetized adult and neonatal (ages: 14 to 20 days) Mongolian gerbils. In adult gerbils, the velocity magnitude of stapes responses to tones was approximately constant over the entire frequency range of measurements, 1 to 40 kHz. Response phases referred to pressure near the tympanic membrane varied approximately linearly as a function of increasing stimulus frequency, with a slope corresponding to a group delay of 30 μs. In neonatal gerbils, the sensitivity of stapes responses to tones was lower than in adults, especially at mid-frequencies (e.g., by about 15 dB at 10–20 kHz in gerbils aged 14 days). The input impedance of the adult gerbil cochlea, calculated from stapes vibrations and published measurements of pressure in scala vestibuli near the oval window [E. Olson, J. Acoust. Soc. Am. 103, 3445–3463 (1998)], is principally dissipative at frequencies lower than 10 kHz.
Conclusions
(a) middle-ear vibrations in adult gerbils do not limit the input to the cochlea up to at least 40 kHz, i.e., within 0.5 oct of the high-frequency cutoff of the behavioral audiogram; and (b) the results in both adult and neonatal gerbils are inconsistent with the hypothesis that mass reactance controls high-frequency ossicular vibrations and support the idea that the middle ear functions as a transmission line.
doi:10.1121/1.1420382
PMCID: PMC1868569  PMID: 11831800
9.  Maintaining acoustic communication at a cocktail party: heterospecific masking noise improves signal detection through frequency separation 
The Journal of experimental biology  2013;216(0 24):4655-4665.
SUMMARY
We examined acoustic masking in a chirping katydid species of the Mecopoda elongata complex due to interference with a sympatric Mecopoda species where males produce continuous trills at high amplitudes. Frequency spectra of both calling songs range from 1 to 80 kHz; the chirper species has more energy in a narrow frequency band at 2 kHz and above 40 kHz. Behaviourally, chirper males successfully phase-locked their chirps to playbacks of conspecific chirps under masking conditions at signal-to-noise ratios (SNRs) of −8 dB. After the 2 kHz band in the chirp had been equalised to the level in the masking trill, the breakdown of phase-locked synchrony occurred at a SNR of +7 dB. The remarkable receiver performance is partially mirrored in the selective response of a first-order auditory interneuron (TN1) to conspecific chirps under these masking conditions. However, the selective response is only maintained for a stimulus including the 2 kHz component, although this frequency band has no influence on the unmasked TN1 response. Remarkably, the addition of masking noise at 65 dB sound pressure level (SPL) to threshold response levels of TN1 for pure tones of 2 kHz enhanced the sensitivity of the response by 10 dB. Thus, the spectral dissimilarity between masker and signal at a rather low frequency appears to be of crucial importance for the ability of the chirping species to communicate under strong masking by the trilling species. We discuss the possible properties underlying the cellular/synaptic mechanisms of the ‘novelty detector’.
doi:10.1242/jeb.089888
PMCID: PMC3971153  PMID: 24307713
selective encoding; insect; auditory interneuron; katydid; ambient noise; novelty detection
10.  Basilar membrane responses to two-tone and broadband stimuli 
SUMMARY
The responses to sound of mammalian cochlear neurons exhibit many nonlinearities, some of which (such as two-tone rate suppression and intermodulation distortion) are highly frequency specific, being strongly tuned to the characteristic frequency (cf) of the neuron. With the goal of establishing the cochlear origin of these auditory-nerve nonlinearities, mechanical responses to clicks and to pairs of tones were studied in relatively healthy chinchilla cochleae at a basal site of the basilar membrane with cf of 8–10 kHz. Responses were also obtained in cochleae in which hair cell receptor potentials were reduced by systemic furosemide injection. Vibrations were recorded using either the Mössbauer technique or laser Doppler-shift velocimetry. Responses to tone pairs contained intermodulation distortion products whose magnitudes as a function of stimulus frequency and intensity were comparable to those of distortion products in cochlear afferent responses. Responses to cf tones could be selectively suppressed by tones with frequency either higher or lower than cf; in most respects, mechanical two-tone suppression resembled rate suppression in cochlear afferents. Responses to clicks displayed a cf-specific compressive nonlinearity, similar to that present in responses to single tones, which could be profoundly and selectively reduced by furosemide. The present findings firmly support the hypothesis that all cf-specific nonlinearities present in the auditory nerve originate in analogous phenomena of basilar membrane vibration. However, because of their lability, it is almost certain that the mechanical nonlinearities themselves originate in outer hair cells.
doi:10.1098/rstb.1992.0063
PMCID: PMC3578387  PMID: 1354369
11.  Timing of cochlear responses inferred from frequency-threshold tuning curves of auditory-nerve fibers 
Hearing research  2010;272(1-2):178-186.
Links between frequency tuning and timing were explored in the responses to sound of auditory-nerve fibers. Synthetic transfer functions were constructed by combining filter functions, derived via minimum-phase computations from average frequency-threshold tuning curves of chinchilla auditory-nerve fibers with high spontaneous activity (A. N. Temchin et al., J. Neurophysiol. 100: 2889–2898, 2008), and signal-front delays specified by the latencies of basilar-membrane and auditory-nerve fiber responses to intense clicks (A. N. Temchin et al., J. Neurophysiol. 93: 3635–3648, 2005). The transfer functions predict several features of the phase-frequency curves of cochlear responses to tones, including their shape transitions in the regions with characteristic frequencies of 1 kHz and 3–4 kHz (A. N. Temchin and M. A. Ruggero, JARO 11: 297–318, 2010). The transfer functions also predict the shapes of cochlear impulse responses, including the polarities of their frequency sweeps and their transition at characteristic frequencies around 1 kHz. Predictions are especially accurate for characteristic frequencies < 1 kHz.
doi:10.1016/j.heares.2010.10.002
PMCID: PMC3039049  PMID: 20951191
12.  Basilar Membrane Vibrations Near the Round Window of the Gerbil Cochlea 
Using a laser velocimeter, responses to tones were measured at a basilar membrane site located about 1.2 mm from the extreme basal end of the gerbil cochlea. In two exceptional cochleae in which function was only moderately disrupted by surgical preparations, basilar membrane responses had characteristic frequencies (CFs) of 34–37 kHz and exhibited a CF-specific compressive nonlinearity: Sensitivity near the CF decreased systematically and the response peaks shifted toward lower frequencies with increasing stimulus level. Response phases also changed with increases in stimulus level, exhibiting small relative lags and leads at frequencies just lower and higher than CF, respectively. Basilar membrane responses to low-level CF tones exceeded the magnitude of stapes vibrations by 54–56 dB. Response phases led stapes vibrations by about 90° at low stimulus frequencies; at higher frequencies, basilar membrane responses increasingly lagged stapes vibration, accumulating 1.5 periods of phase lag at CF. Postmortem, nonlinearities were abolished and responses peaked at ~0.5 octave below CF, with phases which lagged and led in vivo responses at frequencies lower and higher than CF, respectively. In conclusion, basilar membrane responses near the round window of the gerbil cochlea closely resemble those for other basal cochlear sites in gerbil and other species.
doi:10.1007/sl01620020023
PMCID: PMC1868570  PMID: 12382108
inner ear; auditory; basilar membrane; cochlear mechanics; compressive nonlinearity
13.  Brain-Derived Neurotrophic Factor Modulates Auditory Function in the Hearing Cochlea 
Neurotrophins prevent spiral ganglion neuron (SGN) degeneration in animal models of ototoxin-induced deafness and may be used in the future to improve the hearing of cochlear implant patients. It is increasingly common for patients with residual hearing to undergo cochlear implantation. However, the effect of neurotrophin treatment on acoustic hearing is not known. In this study, brain-derived neurotrophic factor (BDNF) was applied to the round window membrane of adult guinea pigs for 4 weeks using a cannula attached to a mini-osmotic pump. SGN survival was first assessed in ototoxically deafened guinea pigs to establish that the delivery method was effective. Increased survival of SGNs was observed in the basal and middle cochlear turns of deafened guinea pigs treated with BDNF, confirming that delivery to the cochlea was successful. The effects of BDNF treatment in animals with normal hearing were then assessed using distortion product otoacoustic emissions (DPOAEs), pure tone, and click-evoked auditory brainstem responses (ABRs). DPOAE assessment indicated a mild deficit of 5 dB SPL in treated and control groups at 1 and 4 weeks after cannula placement. In contrast, ABR evaluation showed that BDNF lowered thresholds at specific frequencies (8 and 16 kHz) after 1 and 4 weeks posttreatment when compared to the control cohort receiving Ringer’s solution. Longer treatment for 4 weeks not only widened the range of frequencies ameliorated from 2 to 32 kHz but also lowered the threshold by at least 28 dB SPL at frequencies ≥16 kHz. BDNF treatment for 4 weeks also increased the amplitude of the ABR response when compared to either the control cohort or prior to treatment. We show that BDNF applied to the round window reduces auditory thresholds and could potentially be used clinically to protect residual hearing following cochlear implantation.
doi:10.1007/s10162-011-0297-9
PMCID: PMC3254718  PMID: 22086147
neurotrophins; residual hearing; cochlear implant; guinea pig; auditory brainstem response; otoacoustic emissions
14.  Apoptotic Pattern of Cochlear Outer Hair Cells and Frequency-specific Hearing Threshold Shift in Noise-exposed BALB/c Mice 
Objectives
Apoptosis of outer hair cell (OHC) can be identified through nuclear staining by specific nuclear changes. The change of filamentous actin (F-actin) is also involved in early cell death process. The study was designed to investigate OHC death along the whole length of the organ of Corti.
Methods
BALB/c hybrid mice were used in this study. The noise group was exposed to white noise of 120 dB SPL for 3 hr per day for 3 consecutive days. The tone burst auditory brainstem response (ABR) test was conducted and cochleas from each group were obtained for the immunostaining of FITC phalloidin for F-actin and propidium iodide (PI) for nuclei.
Results
ABR threshold of the noise group significantly increased after noise exposure (P<0.001). No threshold shift was found in the control group. Threshold shift of the noise group constantly increased from 4 to 16 kHz, but threshold shifts at 16 kHz and 32 kHz were similar. Patterns of OHC staining were subclassified as FITC+PI- cells, FITC+ PI+ cells, FITC-PI+ cells and missing cells. Proportion of normal live OHCs (FITC+PI-) rapidly decreased from the apex to the base. In the basal turn, FITC-PI+ cells and vacancy OHC (missing cells) were observed easily. Apoptotic and missing cells were most abundant at 60% of the whole length of the Corti organ.
Conclusion
We could subclassify morphologic changes in OHC death after noise exposure. Quantitative changes in OHCs along the whole Corti organ showed a plateau pattern similar to that of a frequency-specific threshold shift.
doi:10.3342/ceo.2008.1.2.80
PMCID: PMC2671795  PMID: 19434277
Noise-induced hearing loss; Apoptosis; Auditory brainstem evoked potential; Cell death
15.  How are Inner Hair Cells Stimulated? Evidence for multiple mechanical drives 
Hearing research  2012;292(1-2):35-50.
Recent studies indicate that the gap over outer hair cells (OHCs) between the reticular lamina (RL) and the tectorial membrane (TM) varies cyclically during low-frequency sounds. Variation in the RL-TM gap produces radial fluid flow in the gap that can drive inner hair cell (IHC) stereocilia. Analysis of RL-TM gap changes reveals three IHC drives in addition to classic SHEAR. For upward basilar-membrane (BM) motion, IHC stereocilia are deflected in the excitatory direction by SHEAR and OHC-MOTILITY, but in the inhibitory direction by TM-PUSH and CILIA-SLANT. Upward BM motion causes OHC somatic contraction which tilts the RL, compresses the RL-TM gap over IHCs and expands the RL-TM gap over OHCs, thereby producing an outward (away from the IHCs) radial fluid flow which is the OHC-MOTILITY drive. For upward BM motion, the force that moves the TM upward also compresses the RL-TM gap over OHCs causing inward radial flow past IHCs which is the TM-PUSH drive. Motions that produce large tilting of OHC stereocilia squeeze the supra-OHC RL-TM gap and caused inward radial flow past IHCs which is the CILIA-SLANT drive. Combinations of these drives explain: (1) the reversal at high sound levels of auditory nerve (AN) initial peak (ANIP) responses to clicks, and medial olivocochlear (MOC) inhibition of ANIP responses below, but not above, the ANIP reversal, (2) dips and phase reversals in AN responses to tones in cats and chinchillas, (3) hypersensitivity and phase reversals in tuning-curve tails after OHC ablation, and (4) MOC inhibition of tail-frequency AN responses. The OHC-MOTILITY drive provides another mechanism, in addition to BM motion amplification, that uses active processes to enhance the output of the cochlea. The ability of these IHC drives to explain previously anomalous data provides strong, although indirect, evidence that these drives are significant and presents a new view of how the cochlea works at frequencies below 3 kHz.
doi:10.1016/j.heares.2012.08.005
PMCID: PMC3549570  PMID: 22959529
cochlear mechanics; cochlear micromechanics; cochlear amplifier; BM motion amplifier; IHC drive amplifier
16.  Phase Locking of Auditory-Nerve Fibers to the Envelopes of High-Frequency Sounds: Implications for Sound Localization 
Journal of neurophysiology  2006;96(5):2327-2341.
Although listeners are sensitive to interaural time differences (ITDs) in the envelope of high-frequency sounds, both ITD discrimination performance and the extent of lateralization are poorer for high-frequency sinusoidally amplitude-modulated (SAM) tones than for low-frequency pure tones. Psychophysical studies have shown that ITD discrimination at high frequencies can be improved by using novel transposed-tone stimuli, formed by modulating a high-frequency carrier by a half-wave–rectified sinusoid. Transposed tones are designed to produce the same temporal discharge patterns in high-characteristic frequency (CF) neurons as occur in low-CF neurons for pure-tone stimuli. To directly test this hypothesis, we compared responses of auditory-nerve fibers in anesthetized cats to pure tones, SAM tones, and transposed tones. Phase locking was characterized using both the synchronization index and autocorrelograms. With both measures, phase locking was better for transposed tones than for SAM tones, consistent with the rationale for using transposed tones. However, phase locking to transposed tones and that to pure tones were comparable only when all three conditions were met: stimulus levels near thresholds, low modulation frequencies (<250 Hz), and low spontaneous discharge rates. In particular, phase locking to both SAM tones and transposed tones substantially degraded with increasing stimulus level, while remaining more stable for pure tones. These results suggest caution in assuming a close similarity between temporal patterns of peripheral activity produced by transposed tones and pure tones in both psychophysical studies and neurophysiological studies of central neurons.
doi:10.1152/jn.00326.2006
PMCID: PMC2013745  PMID: 16807349
17.  Traveling waves on the organ of Corti of the chinchilla cochlea: spatial trajectories of inner hair cell depolarization inferred from responses of auditory-nerve fibers 
Spatial magnitude and phase profiles for inner hair cell depolarization throughout the chinchilla cochlea were inferred from responses of auditory-nerve fibers to threshold- and moderate-level tones and tone complexes. Firing-rate profiles for frequencies ≤ 2 kHz are bimodal, with the major peak at the characteristic place and a secondary peak at 3–5 mm from the extreme base. Response-phase trajectories are synchronous with peak outward stapes displacement at the extreme cochlear base and accumulate 1.5-period lags at the characteristic places. High-frequency phase trajectories are very similar to the trajectories of basilar-membrane peak velocity toward scala tympani. Low-frequency phase trajectories undergo a polarity flip in a region, 6.5–9 mm from the cochlear base, where traveling-wave phase velocity attains a local minimum and a local maximum and where the onset latencies of near-threshold impulse responses computed from responses to near-threshold white noise exhibit a local minimum. That region is the same where frequency-threshold tuning curves of auditory-nerve fibers undergo a shape transition. Since depolarization of inner hair cells presumably indicates the mechanical stimulus to their stereocilia, the present results suggest that distinct low-frequency forward waves of organ of Corti vibration are launched simultaneously at the extreme base of the cochlea and at the 6.5–9 mm transition region, from where antiphasic reflections arise.
doi:10.1523/JNEUROSCI.1138-12.2012
PMCID: PMC3436599  PMID: 22855802
18.  Enhancement and Distortion in the Temporal Representation of Sounds in the Ventral Cochlear Nucleus of Chinchillas and Cats 
PLoS ONE  2012;7(9):e44286.
A subset of neurons in the cochlear nucleus (CN) of the auditory brainstem has the ability to enhance the auditory nerve's temporal representation of stimulating sounds. These neurons reside in the ventral region of the CN (VCN) and are usually known as highly synchronized, or high-sync, neurons. Most published reports about the existence and properties of high-sync neurons are based on recordings performed on a VCN output tract—not the VCN itself—of cats. In other species, comprehensive studies detailing the properties of high-sync neurons, or even acknowledging their existence, are missing.
Examination of the responses of a population of VCN neurons in chinchillas revealed that a subset of those neurons have temporal properties similar to high-sync neurons in the cat. Phase locking and entrainment—the ability of a neuron to fire action potentials at a certain stimulus phase and at almost every stimulus period, respectively—have similar maximum values in cats and chinchillas. Ranges of characteristic frequencies for high-sync neurons in chinchillas and cats extend up to 600 and 1000 Hz, respectively. Enhancement of temporal processing relative to auditory nerve fibers (ANFs), which has been shown previously in cats using tonal and white-noise stimuli, is also demonstrated here in the responses of VCN neurons to synthetic and spoken vowel sounds.
Along with the large amount of phase locking displayed by some VCN neurons there occurs a deterioration in the spectral representation of the stimuli (tones or vowels). High-sync neurons exhibit a greater distortion in their responses to tones or vowels than do other types of VCN neurons and auditory nerve fibers.
Standard deviations of first-spike latency measured in responses of high-sync neurons are lower than similar values measured in ANFs' responses. This might indicate a role of high-sync neurons in other tasks beyond sound localization.
doi:10.1371/journal.pone.0044286
PMCID: PMC3445608  PMID: 23028514
19.  Ear-Canal Reflectance, Umbo Velocity and Tympanometry in Normal Hearing Adults 
Ear and hearing  2012;33(1):19-34.
Objective
This study compares measurements of ear-canal reflectance (ECR) to other objective measurements of middle-ear function including, audiometry, umbo velocity (VU), and tympanometry in a population of strictly defined normal hearing ears.
Design
Data were prospectively gathered from 58 ears of 29 normal hearing subjects, 16 female and 13 male, aged 22–64 years. Subjects met all of the following criteria to be considered as having normal hearing. (1) No history of significant middle-ear disease. (2) No history of otologic surgery. (3) Normal tympanic membrane (TM) on otoscopy. (4) Pure-tone audiometric thresholds of 20 dB HL or better for 0.25 – 8 kHz. (5) Air-bone gaps no greater than 15 dB at 0.25 kHz and 10 dB for 0.5 – 4 kHz. (6) Normal, type-A peaked tympanograms. (7) All subjects had two “normal” ears (as defined by these criteria). Measurements included pure-tone audiometry for 0.25 – 8 kHz, standard 226 Hz tympanometry, Ear canal reflectance(ECR) for 0.2 – 6 kHz at 60 dB SPL using the Mimosa Acoustics HearID system, and Umbo Velocity (VU ) for 0.3 – 6 kHz at 70–90 dB SPL using the HLV-1000 laser Doppler vibrometer (Polytec Inc).
Results
Mean power reflectance (|ECR|2) was near 1.0 at 0.2– 0.3 kHz, decreased to a broad minimum of 0.3 to 0.4 between 1 and 4 kHz, and then sharply increased to almost 0.8 by 6 kHz. The mean pressure reflectance phase angle (∠ECR) plotted on a linear frequency scale showed a group delay of approximately 0.1 ms for 0.2 – 6 kHz. Small significant differences were observed in |ECR|2 at the lowest frequencies between right and left ears, and between males and females at 4 kHz. |ECR|2 decreased with age, but reached significance only at 1 kHz. Our ECR measurements were generally similar to previous published reports. Highly significant negative correlations were found between |ECR|2 and VU for frequencies below 1 kHz. Significant correlations were also found between the tympanometrically determined peak total compliance and |ECR|2 and The results suggest that middle-ear compliance VU at frequencies below 1 kHz. contributes significantly to the measured power reflectance and umbo velocity at frequencies below 1 kHz, but not at higher frequencies.
Conclusions
This study has established a database of objective measurements of middle ear function (ear-canal reflectance, umbo velocity, tympanometry) in a population of strictly defined normal hearing ears. The data will promote our understanding of normal middle ear function, and will serve as a control for comparison to similar measurements made in pathological ears.
doi:10.1097/AUD.0b013e31822ccb76
PMCID: PMC3223546  PMID: 21857517
20.  Age-Related Hearing Loss in C57BL/6J Mice has both Frequency-Specific and Non-Frequency-Specific Components that Produce a Hyperacusis-Like Exaggeration of the Acoustic Startle Reflex 
Auditory brainstem-evoked response (ABR) thresholds were obtained in a longitudinal study of C57BL/6J mice between 10 and 53 weeks old, with repeated testing every 2 weeks. On alternate weeks, acoustic startle reflex (ASR) amplitudes were measured, elicited by tone pips with stimulus frequencies of 3, 6, 12, and 24 kHz, and intensities from subthreshold up to 110 dB sound pressure level. The increase in ABR thresholds for 3 and 6 kHz test stimuli followed a linear time course with increasing age from 10 to 53 weeks, with a slope of about 0.7 dB/week, and for 48 kHz a second linear time course, but beginning at 10 weeks with a slope of about 2.3 dB/week. ABR thresholds for 12, 24, and 32 kHz increased after one linear segment with a 0.7 dB slope, then after a variable delay related to the test frequency, shifted to a second segment having slopes of 3–5 dB/week. Hearing loss initially reduced the ASR for all eliciting stimuli, but at about 6 months of age, the response elicited by intense 3 and 6 kHz stimuli began to increase to reach values about three times above normal, and previously subthreshold stimuli came to elicit vigorous responses seen at first only for the intense stimuli. This hyperacusis-like effect appeared in all mice but was especially pronounced in mice with more serious hearing loss. These ABR data, together with a review of histopathological data in the C57BL/6 literature, suggest that the non-frequency-specific slow time course of hearing loss results from pathology in the lateral wall of the cochlea, whereas the stimulus-specific hearing loss with a rapid time course results from hair cell loss. Delayed exaggeration of the ASR with hearing loss reveals a deficit in centrifugal inhibitory control over the afferent reflex pathways after central neural reorganization, suggesting that this mouse may provide a useful model of age-related tinnitus and associated hyperacusis.
doi:10.1007/s10162-007-0098-3
PMCID: PMC2538342  PMID: 17952509
aging; hearing loss; startle; plasticity; mixed strial/sensory presbycusis; tinnitus/hyperacusis
21.  Basilar-membrane responses to tones at the base of the chinchilla cochlea 
Basilar-membrane responses to single tones were measured, using laser velocimetry, at a site of the chinchilla cochlea located 3.5 mm from its basal end. Responses to low-level (<10–20 dB SPL) characteristic-frequency (CF) tones (9–10 kHz) grow linearly with stimulus intensity and exhibit gains of 66–76 dB relative to stapes motion. At higher levels, CF responses grow monotonically at compressive rates, with input–output slopes as low as 0.2 dB/dB in the intensity range 40–80 dB. Compressive growth, which is significantly correlated with response sensitivity, is evident even at stimulus levels higher than 100 dB. Responses become rapidly linear as stimulus frequency departs from CF. As a result, at stimulus levels >80 dB the largest responses are elicited by tones with frequency about 0.4–0.5 octave below CF. For stimulus frequencies well above CF, responses stop decreasing with increasing frequency: A plateau is reached. The compressive growth of responses to tones with frequency near CF is accompanied by intensity-dependent phase shifts. Death abolishes all nonlinearities, reduces sensitivity at CF by as much as 60–81 dB, and causes a relative phase lead at CF.
PMCID: PMC3578390  PMID: 9104018
22.  Influence of Calibration Method on DPOAE Measurements: II. Threshold Prediction 
Ear and hearing  2010;31(4):546-554.
Objective
Distortion-product otoacoustic emission (DPOAE) stimulus calibrations are typically performed in sound pressure level (SPL) prior to DPOAE measurements. These calibrations may yield unpredictable DPOAE response levels, presumably due to the presence of standing waves in the ear canal. Forward pressure level (FPL) has been proposed as an alternative method for stimulus calibration because it avoids complications due to standing waves. DPOAE thresholds following four FPL calibrations and one SPL calibration were compared to behavioral thresholds to determine which calibration results in data that yield the highest correlations between the two threshold estimates.
Design
Fifty-two subjects with normal hearing and 103 subjects with hearing loss participated, with ages ranging from 11 to 75 years. These were the same individuals whose data were used to address the influence of calibration method on test performance in an accompanying paper (Burke et al., 2010). DPOAE input/output (I/O) functions were obtained at f2 frequencies of 2, 3, 4, 6, and 8 kHz with the primary frequency ratio fixed at f2/f1≈1.22. L1 was set according to the equation L1=0.4L2+39 (Kummer et al. 1998, 2000) with L2 levels ranging from −20 to 70 dB SPL and FPL in 5-dB steps. I/O functions were obtained at each frequency for each of five stimulus calibrations: SPL, daily FPL at room temperature, daily FPL at body temperature, reference FPL at room temperature, and reference FPL at body temperature. DPOAE thresholds were estimated using two methods. In the first, DPOAE threshold was taken as the lowest L2 for which DPOAE level is 3 dB or greater above the noise floor (SNR ≥ 3 dB). In a second method, a linear regression method first described by Boege & Janssen (2002) and later adapted by Gorga et al. (2003), all DPOAE levels in each I/O function are converted to linear pressure and extrapolated to 0 μPa, where the L2 is taken as threshold. Correlations of DPOAE thresholds with behavioral thresholds were obtained for each frequency, calibration method, and threshold-prediction method.
Results
Correlations were greatest for frequencies of 3–6 kHz and lowest for 8 kHz, consistent with the previous frequency effects reported by Gorga et al. (2003). Calibration method made little difference in correlations between DPOAE and behavioral thresholds at any frequency. A small difference was noted in correlations for the two threshold-prediction methods, with the linear regression method yielding slightly higher correlations at all frequencies.
Conclusions
Little difference in threshold correlations was observed among the five calibration methods used to calibrate the stimuli prior to DPOAE measurements. These results were not anticipated given the known effects of standing waves on ear-canal estimates of SPL at the plane of the probe (Siegel, 1994; Siegel and Hirohata, 1994; Siegel, 2007; Driesbach and Siegel, 2001; Neely and Gorga, 1998; Scheperle et al., 2008). In addition, there was no effect of temperature (body vs. room) or timing (daily vs. reference) for FPL calibrations. It may be important to note that differences between SPL and FPL calibrations should not be seen if a standing wave does not occur at the plane of the probe at or near the frequency being tested. The frequencies 2–8 kHz were chosen because it was expected that effects from standing waves would occur between these frequencies due to the typical lengths of ear canals for the age group tested. Because measurements were taken at only five discrete frequencies in the interval, it is possible that standing waves were present but did not affect the specific test frequencies. In total, these results suggest that SPL calibrations may be adequate when attempting to predict pure-tone thresholds from DPOAEs, despite the fact that they are known to be susceptible to errors associated with standing waves.
doi:10.1097/AUD.0b013e3181d86b59
PMCID: PMC2896427  PMID: 20458245
23.  Interaural Phase and Level Difference Sensitivity in Low-Frequency Neurons in the Lateral Superior Olive 
The lateral superior olive (LSO) is believed to encode differences in sound level at the two ears, a cue for azimuthal sound location. Most high-frequency-sensitive LSO neurons are binaural, receiving inputs from both ears. An inhibitory input from the contralateral ear, via the medial nucleus of the trapezoid body (MNTB), and excitatory input from the ipsilateral ear enable level differences to be encoded. However, the classical descriptions of low-frequency-sensitive neurons report primarily monaural cells with no contralateral inhibition. Anatomical and physiological evidence, however, shows that low-frequency LSO neurons receive low-frequency inhibitory input from ipsilateral MNTB, which in turn receives excitatory input from the contralateral cochlear nucleus and low-frequency excitatory input from the ipsilateral cochlear nucleus. Therefore, these neurons would be expected to be binaural with contralateral inhibition. Here, we re-examined binaural interaction in low-frequency (less than ~3 kHz) LSO neurons and phase locking in the MNTB. Phase locking to low-frequency tones in MNTB and ipsilaterally driven LSO neurons with frequency sensitivities < 1.2 kHz was enhanced relative to the auditory nerve. Moreover, most low-frequency LSO neurons exhibited contralateral inhibition: ipsilaterally driven responses were suppressed by raising the level of the contralateral stimulus; most neurons were sensitive to interaural time delays in pure tone and noise stimuli such that inhibition was nearly maximal when the stimuli were presented to the ears in-phase. The data demonstrate that low-frequency LSO neurons of cat are not monaural and can exhibit contralateral inhibition like their high-frequency counterparts.
doi:10.1523/JNEUROSCI.1609-05.2005
PMCID: PMC1449742  PMID: 16291937
lateral superior olive; medial nucleus of the trapezoid body; interaural time delay; interaural level difference; sound localization; phase locking
24.  Maturation and Aging of the Human Cochlea: A View through the DPOAE Looking Glass 
Cochlear function changes throughout the human lifespan. Distortion product otoacoustic emissions (DPOAEs) were recorded in 156 ears to examine these changes and speculate as to their mechanistic underpinnings. DPOAEs were analyzed within the context of current OAE generation theory, which recognizes distinct emission mechanisms. Seven age groups including premature newborns through senescent adults were tested with a swept-tone DPOAE protocol to examine magnitude and phase features of both the mixed DPOAE and individual distortion and reflection components. Results indicate (1) 6–8-month-old infants have the most robust DPOAE and component levels for frequencies >1.5 kHz; (2) older adults show a substantial reduction in DPOAE and distortion-component levels combined with a smaller drop in reflection-component levels; (3) all age groups manifest a violation of distortion phase invariance at frequencies below 1.5 kHz consistent with a secular break in cochlear scaling; the apical phase delay is markedly longer in newborns; and (4) phase slope of reflection emissions is most shallow in the older adults. Combined findings suggest that basilar membrane motion in the apical half of the cochlea is immature at birth and that the cochlea of senescent adults shows reduced nonlinearity and relatively shallow reflection-component phase slope, which can be interpreted to suggest degraded tuning.
doi:10.1007/s10162-012-0319-2
PMCID: PMC3346898  PMID: 22476702
otoacoustic emissions; distortion; reflection; aging; maturation; tuning; cochlear scaling
25.  A Resonance Approach to Cochlear Mechanics 
PLoS ONE  2012;7(11):e47918.
Background
How does the cochlea analyse sound into its component frequencies? In the 1850s Helmholtz thought it occurred by resonance, whereas a century later Békésy's work indicated a travelling wave. The latter answer seemed to settle the question, but with the discovery in 1978 that the cochlea emits sound, the mechanics of the cochlea was back on the drawing board. Recent studies have raised questions about whether the travelling wave, as currently understood, is adequate to explain observations.
Approach
Applying basic resonance principles, this paper revisits the question. A graded bank of harmonic oscillators with cochlear-like frequencies and quality factors is simultaneously excited, and it is found that resonance gives rise to similar frequency responses, group delays, and travelling wave velocities as observed by experiment. The overall effect of the group delay gradient is to produce a decelerating wave of peak displacement moving from base to apex at characteristic travelling wave speeds. The extensive literature on chains of coupled oscillators is considered, and the occurrence of travelling waves, pseudowaves, phase plateaus, and forced resonance in such systems is noted.
Conclusion and significance
This alternative approach to cochlear mechanics shows that a travelling wave can simply arise as an apparently moving amplitude peak which passes along a bank of resonators without carrying energy. This highlights the possible role of the fast pressure wave and indicates how phase delays and group delays of a set of driven harmonic oscillators can generate an apparent travelling wave. It is possible to view the cochlea as a chain of globally forced coupled oscillators, and this model incorporates fundamental aspects of both the resonance and travelling wave theories.
doi:10.1371/journal.pone.0047918
PMCID: PMC3493581  PMID: 23144835

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