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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.  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
4.  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
5.  Variation in the Phase of Response to Low-Frequency Pure Tones in the Guinea Pig Auditory Nerve as Functions of Stimulus Level and Frequency 
The directionality of hair cell stimulation combined with the vibration of the basilar membrane causes the auditory nerve fiber action potentials, in response to low-frequency stimuli, to occur at a particular phase of the stimulus waveform. Because direct mechanical measurements at the cochlear apex are difficult, such phase locking has often been used to indirectly infer the basilar membrane motion. Here, we confirm and extend earlier data from mammals using sine wave stimulation over a wide range of sound levels (up to 90 dB sound pressure level). We recorded phase-locked responses to pure tones over a wide range of frequencies and sound levels of a large population of auditory nerve fibers in the anesthetized guinea pig. The results indicate that, for a constant frequency of stimulation, the phase lag decreases with increases in the characteristic frequency (CF) of the nerve fiber. The phase lag decreases up to a CF above the stimulation frequency, beyond which it decreases at a much slower rate. Such phase changes are consistent with known basal cochlear mechanics. Measurements from individual fibers showed smaller but systematic variations in phase with sound level, confirming previous reports. We found a “null” stimulation frequency at which little variation in phase occurred with sound level. This null frequency was often not at the CF. At stimulation frequencies below the null, there was a progressive lag with sound level and a progressive lead for stimulation frequencies above the null. This was maximally 0.2 cycles.
doi:10.1007/s10162-008-0151-x
PMCID: PMC2674197  PMID: 19093151
auditory nerve; phase response; basilar membrane; guinea pig
6.  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
7.  Auditory Nerve Excitation via a Non-traveling Wave Mode of Basilar Membrane Motion 
Basilar membrane (BM) motion and auditory nerve fiber (ANF) tuning are generally very similar, but the ANF had appeared to be unresponsive to a plateau mode of BM motion that occurs at frequencies above an ANF’s characteristic frequency (CF). We recorded ANF responses from the gerbil, concentrating on this supra-CF region. We observed a supra-CF plateau in ANF responses at high stimulus level, indicating that the plateau mode of BM motion can be excitatory.
doi:10.1007/s10162-011-0272-5
PMCID: PMC3173553  PMID: 21626227
cochlea; tuning curve; frequency threshold curve; characteristic frequency; hair cell
8.  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
9.  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
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.  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
12.  Acoustic over-exposure triggers burst firing in dorsal cochlear nucleus fusiform cells 
Hearing Research  2012;283(1-2):98-106.
Acoustic over-exposure (AOE) triggers deafness in animals and humans and provokes auditory nerve degeneration. Weeks after exposure there is an increase in the cellular excitability within the dorsal cochlear nucleus (DCN) and this is considered as a possible neural correlate of tinnitus. The origin of this DCN hyperactivity phenomenon is still unknown but it is associated with neurons lying within the fusiform cell layer. Here we investigated changes of excitability within identified fusiform cells following AOE. Wistar rats were exposed to a loud (110 dB SPL) single tone (14.8 kHz) for 4 h. Auditory brainstem response recordings performed 3–4 days after AOE showed that the hearing thresholds were significantly elevated by about 20–30 dB SPL for frequencies above 15 kHz. Control fusiform cells fired with a regular firing pattern as assessed by the coefficient of variation of the inter-spike interval distribution of 0.19 ± 0.11 (n = 5). Three to four days after AOE, 40% of fusiform cells exhibited irregular bursting discharge patterns (coefficient of variation of the inter-spike interval distribution of 1.8 ± 0.6, n = 5; p < 0.05). Additionally the maximal firing following step current injections was reduced in these cells (from 83 ± 11 Hz, n = 5 in unexposed condition to 43 ± 6 Hz, n = 5 after AOE) and this was accompanied by an increased firing gain (from 0.09 ± 0.01 Hz/pA, n = 5 in unexposed condition to 0.56 ± 0.25 Hz/pA, n = 5 after AOE). Current and voltage clamp recordings suggest that the presence of bursts in fusiform cells is related to a down regulation of high voltage activated potassium currents.
In conclusion we showed that AOE triggers deafness at early stages and this is correlated with profound changes in the firing pattern and frequency of the DCN major output fusiform cells. The changes here described could represent the initial network imbalance prior to the emergence of tinnitus.
Highlights
► Wistar rats were exposed to 15 kHz, 110 dB SPL (acoustic over exposure, AOE). ► AOE triggered hearing loss in rats for frequencies exceeding 15 kHz. ► AOE triggered bursts in dorsal cochlear nucleus fusiform cells. ► AOE reduced high voltage activated K+ currents in those cells.
doi:10.1016/j.heares.2011.10.008
PMCID: PMC3315001  PMID: 22085487
ABR, auditory brainstem response; ACSF, artificial cerebrospinal fluid; AP, action potential; AOE, acoustic over-exposure; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; CV, coefficient of variation; Cw, cartwheel cells; DCN, dorsal cochlear nucleus; DL-AP5, DL-2-amino-5-phosphonopentanoic acid; DNQX, 6,7-dinitroquinoxaline-2,3-dione; FCs, fusiform cells; ½ Fmax, half maximal frequency; HVA, high voltage activated; ISI, inter-spike intervals; Fmax, maximal frequency; N.S., non significant; SPL, sound pressure level; Vm, membrane potential
13.  Improved neural representation of vowels in electric stimulation using desynchronizing pulse trainsa) 
Current cochlear implant processors poorly represent sound waveforms in the temporal discharge patterns of auditory-nerve fibers (ANFs). A previous study [Litvak et al., J. Acoust. Soc. Am. 114, 2079–2098 (2003)] showed that the temporal representation of sinusoidal stimuli can be improved in a majority of ANFs by encoding the stimuli as small modulations of a sustained, high-rate (5 kpps), desynchronizing pulse train (DPT). Here, these findings are extended to more complex stimuli by recording ANF responses to pulse trains modulated by bandpass filtered vowels. Responses to vowel modulators depended strongly on the discharge pattern evoked by the unmodulated DPT. ANFs that gave sustained responses to the DPT had period histograms that resembled the modulator waveform for low (<5%) modulation depths. Spectra of period histograms contained peaks near the formant frequencies. In contrast, ANFs that gave a transient (<1 min) response to the DPT poorly represented the formant frequencies. A model incorporating a linear modulation filter, a noisy threshold, and neural refractoriness predicts the shapes of period histograms for both types of fibers. These results suggest that a DPT-enhanced strategy may achieve good representation of the stimulus fine structure in the temporal discharge patterns of ANFs for frequencies up to 1000 Hz. It remains to be seen whether these temporal discharge patterns can be utilized by cochlear implant subjects.
doi:10.1121/1.1612494
PMCID: PMC2275169  PMID: 14587608
14.  Basilar Membrane Responses to Tones and Tone Complexes: Nonlinear Effects of Stimulus Intensity 
The mammalian inner ear combines spectral analysis of sound with multiband dynamic compression. Cochlear mechanics has mainly been studied using single-tone and tone-pair stimulation. Most natural sounds, however, have wideband spectra. Because the cochlea is strongly nonlinear, wideband responses cannot be predicted by simply adding single-tone responses. We measured responses of the gerbil basilar membrane to single-tone and wideband stimuli and compared them, while focusing on nonlinear aspects of the response. In agreement with previous work, we found that frequency selectivity and its dependence on stimulus intensity were very similar between single-tone and wideband responses. The main difference was a constant shift in effective sound intensity, which was well predicted by a simple gain control scheme. We found expansive nonlinearities in low-frequency responses, which, with increasing frequency, gradually turned into the more familiar compressive nonlinearities. The overall power of distortion products was at least 13 dB below the overall power of the linear response, but in a limited band above the characteristic frequency, the power of distortion products often exceeded the linear response. Our results explain the partial success of a “quasilinear” description of wideband basilar membrane responses, but also indicate its limitations.
doi:10.1007/s10162-012-0345-0
PMCID: PMC3505585  PMID: 22935903
cochlear mechanics; laser interferometry; quasilinear filtering; automatic gain control
15.  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
16.  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/s101620020023
PMCID: PMC1868570  PMID: 12382108
17.  Medial-olivocochlear-efferent inhibition of the first peak of auditory-nerve responses: Evidence for a new motion within the cochlea 
Despite the insights obtained from click responses, the effects of medial-olivocochlear (MOC) efferents on click responses from single-auditory-nerve (AN) fibers have not been reported. We recorded responses of cat single AN fibers to randomized click level series with and without electrical stimulation of MOC efferents. MOC stimulation inhibited (1) the whole response at low sound levels, (2) the decaying part of the response at all sound levels, and (3) the first peak of the response at moderate to high sound levels. The first two effects were expected from previous reports using tones and are consistent with a MOC-induced reduction of cochlear amplification. The inhibition of the AN first peak, which was strongest in the apex and middle of the cochlea, was unexpected because the first peak of the classic basilar-membrane (BM) traveling wave receives little or no amplification. In the cochlear base, the click data were ambiguous, but tone data showed particularly short group delays in the tail-frequency region that is strongly inhibited by MOC efferents. Overall, the data support the hypothesis that there is a motion that bends inner-hair-cell stereocilia and can be inhibited by MOC efferents, a motion that is present through most, or all, of the cochlea and for which there is no counterpart in the classic BM traveling wave.
doi:10.1121/1.2017899
PMCID: PMC1810352  PMID: 16266164
18.  Stimulus Phase Locking of Cortical Oscillation for Auditory Stream Segregation in Rats 
PLoS ONE  2013;8(12):e83544.
The phase of cortical oscillations contains rich information and is valuable for encoding sound stimuli. Here we hypothesized that oscillatory phase modulation, instead of amplitude modulation, is a neural correlate of auditory streaming. Our behavioral evaluation provided compelling evidences for the first time that rats are able to organize auditory stream. Local field potentials (LFPs) were investigated in the cortical layer IV or deeper in the primary auditory cortex of anesthetized rats. In response to ABA- sequences with different inter-tone intervals and frequency differences, neurometric functions were characterized with phase locking as well as the band-specific amplitude evoked by test tones. Our results demonstrated that under large frequency differences and short inter-tone intervals, the neurometric function based on stimulus phase locking in higher frequency bands, particularly the gamma band, could better describe van Noorden’s perceptual boundary than the LFP amplitude. Furthermore, the gamma-band neurometric function showed a build-up-like effect within around 3 seconds from sequence onset. These findings suggest that phase locking and amplitude have different roles in neural computation, and support our hypothesis that temporal modulation of cortical oscillations should be considered to be neurophysiological mechanisms of auditory streaming, in addition to forward suppression, tonotopic separation, and multi-second adaptation.
doi:10.1371/journal.pone.0083544
PMCID: PMC3869811  PMID: 24376715
19.  Computational Diversity in the Cochlear Nucleus Angularis of the Barn Owl 
Journal of Neurophysiology  2002;89(4):2313-2329.
The cochlear nucleus angularis (NA) is widely assumed to form the starting point of a brain stem pathway for processing sound intensity in birds. Details of its function are unclear, however, and its evolutionary origin and relationship to the mammalian cochlear-nucleus complex are obscure. We have carried out extracellular single-unit recordings in the NA of ketamine-anesthetized barn owls. The aim was to re-evaluate the extent of heterogeneity in NA physiology because recent studies of cellular morphology had established several distinct types. Extensive characterization, using tuning curves, phase locking, peristimulus time histograms and rate-level functions for pure tones and noise, revealed five major response types. The most common one was a primary-like pattern that was distinguished from auditory-nerve fibers by showing lower vector strengths of phase locking and/or lower spontaneous rates. Two types of chopper responses were found (chopper-transient and a rare chopper-sustained), as well as onset units. Finally, we routinely encountered a complex response type with a pronounced inhibitory component, similar to the mammalian typeIV. Evidence is presented that this range of response types is representative for birds and that earlier conflicting reports may be due to methodological differences. All five response types defined were similar to well-known types in the mammalian cochlear nucleus. This suggests convergent evolution of neurons specialized for encoding different behaviorally relevant features of the auditory stimulus. It remains to be investigated whether the different response types correlate with morphological types and whether they establish different processing streams in the auditory brain stem of birds.
doi:10.1152/jn.00635.2002
PMCID: PMC3259745  PMID: 12612008
20.  Changes in Auditory Nerve Responses Across the Duration of Sinusoidally Amplitude-Modulated Electric Pulse-Train Stimuli 
Response rates of auditory nerve fibers (ANFs) to electric pulse trains change over time, reflecting substantial spike-rate adaptation that depends on stimulus parameters. We hypothesize that adaptation affects the representation of amplitude-modulated pulse trains used by cochlear prostheses to transmit speech information to the auditory system. We recorded cat ANF responses to sinusoidally amplitude-modulated (SAM) trains with 5,000 pulse/s carriers. Stimuli delivered by a monopolar intracochlear electrode had fixed modulation frequency (100 Hz) and depth (10%). ANF responses were assessed by spike-rate measures, while representation of modulation was evaluated by vector strength (VS) and the fundamental component of the fast Fourier transform (F0 amplitude). These measures were assessed across the 400 ms duration of pulse-train stimuli, a duration relevant to speech stimuli. Different stimulus levels were explored and responses were categorized into four spike-rate groups to assess level effects across ANFs. The temporal pattern of rate adaptation to modulated trains was similar to that of unmodulated trains, but with less rate adaptation. VS to the modulator increased over time and tended to saturate at lower spike rates, while F0 amplitude typically decreased over time for low driven rates and increased for higher driven rates. VS at moderate and high spike rates and degree of F0 amplitude temporal changes at low and moderate spike rates were positively correlated with the degree of rate adaptation. Thus, high-rate carriers will modify the ANF representation of the modulator over time. As the VS and F0 measures were sensitive to adaptation-related changes over different spike-rate ranges, there is value in assessing both measures.
doi:10.1007/s10162-010-0225-4
PMCID: PMC2975883  PMID: 20632064
spike rate; adaptation; vector strength; FFT; F0 amplitude; cochlear implant
21.  Discrimination of Low-Frequency Tones Employs Temporal Fine Structure 
PLoS ONE  2012;7(9):e45579.
An auditory neuron can preserve the temporal fine structure of a low-frequency tone by phase-locking its response to the stimulus. Apart from sound localization, however, much about the role of this temporal information for signal processing in the brain remains unknown. Through psychoacoustic studies we provide direct evidence that humans employ temporal fine structure to discriminate between frequencies. To this end we construct tones that are based on a single frequency but in which, through the concatenation of wavelets, the phase changes randomly every few cycles. We then test the frequency discrimination of these phase-changing tones, of control tones without phase changes, and of short tones that consist of a single wavelet. For carrier frequencies below a few kilohertz we find that phase changes systematically worsen frequency discrimination. No such effect appears for higher carrier frequencies at which temporal information is not available in the central auditory system.
doi:10.1371/journal.pone.0045579
PMCID: PMC3446936  PMID: 23029113
22.  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
23.  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
24.  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
25.  Role of Mannitol in Reducing Postischemic Changes in Distortion-Product Otoacoustic Emissions (DPOAEs): A Rabbit Model 
The Laryngoscope  2003;113(9):1615-1622.
Objectives
The aim of this study was to observe the effects of mannitol, administered topically at the round window (RW), on cochlear blood flow (CBF) and distortion-product otoacoustic emission (DPOAE) after repeated episodes of cochlear ischemia.
Methods
Ten young rabbits were used for this study. Reversible ischemic episodes within the cochlea were induced by directly compressing the internal auditory artery (IAA). CBF was measured using a laser-Doppler (LD) probe positioned at the RW niche. DPOAEs were measured at 4, 8, and 12 kHz geometric mean frequency (GMF) using 60 dB sound pressure level (SPL) primary tone stimuli. In five test ears, mannitol was administered topically at the RW for 30 minutes before the IAA compressions. In five control ears, the IAA compressions were undertaken without application of RW medication. Each ear underwent three 5 minute IAA compressions with a 60 minute rest period between compressions.
Results
In the control animals, it was observed that a progressive reduction in DPOAE level followed each successive IAA compression at all three test frequencies. The reduction in DPOAE amplitudes was consistently greater at the higher test frequencies. In the test rabbits, the RW administration of mannitol resulted in significantly less reduction in DPOAE level measures after repeated IAA compressions. For example, 30 minutes after reperfusion at 12 kHz GMF, DPOAE levels in the control ears were reduced by 1.5, 6.0, and 16 dB, compared with 1.5, 4.0, and 6.0 dB in the mannitol test ears.
Conclusions
Mannitol appears to exert a protective effect on cochlear function after periods of ischemia. The RW appears to be an efficacious route for topical administration of mannitol into the inner ear.
PMCID: PMC1769330  PMID: 12972944
Otoacoustic emissions; mannitol; cochlear blood flow; cochlear damage

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