A developmental study of distortion product otoacoustic emission (2f1-f2) suppression in humans

Suppression of the 2f1-f2 distortion product otoacoustic emission (DPOAE) provides an effective paradigm for the study of functional cochlear maturation in humans. DPOAE iso-suppression tuning curves (STCs) represent some aspect of peripheral filtering, probably related to the boundaries of distortion generation. Studies conducted thus far suggest that the cochlear tuning assessed by this technique is adult-like in humans by term birth (Abdala et al., Hear. Res. 98 (1996) 38-53; Abdala and Sininger, Ear Hear. 17 (1996) 374-385). However, there have been no studies of cochlear tuning in premature human neonates. DPOAE STCs and suppression growth functions were measured from 14 normal-hearing adults, 33 term and 85 premature neonates to investigate the developmental time course of cochlear frequency resolution and non-linearity. Premature neonates showed non-adult-like DPOAE suppression at f2 of 1500 and 6000 Hz: (1) STCs were narrower in width (Q10) and steeper in slope on the low-frequency flank of the tuning curve; (2) suppressor tones lower in frequency than f2 produced atypically shallow growth of DPOAE suppression. The influence of immature conductive pathways cannot be entirely ruled out as a factor contributing to these results. However, findings may indicate that an immaturity exists in cochlear frequency resolution and non-linearity just prior to term birth. The bases of this immaturity are hypothesized to be outer hair cell in origin.     

Growth behavior of the 2 f1-f2 distortion product otoacoustic emission in tinnitus

High-resolution hearing threshold and 2 f1-f2 distortion product otoacoustic emission (DP) were measured with the same in-the-ear sound probe and same calibration at 51 frequencies between 500 and 8000 Hz in 39 sensorineural hearing loss ears associated with tinnitus. Using a primary tone setting L1 = 0.4L2 + 39 that accounts for the nonlinear interaction of the two primary tones at the DP generation site at f2, DPs were elicited in a wide range from L2 = 65 to 20 dB SPL. We failed to find a uniform DP behavior in the 39 tinnitus ears tested. Seventeen of them behaved like impaired ears without tinnitus. In these ears a linearized DP growth was observed where the DP level decreased and the slope of the DP I/O functions steepened with increasing hearing loss and as a result both the DP level and the DP slope strongly correlated with hearing threshold. The other population, 22 tinnitus ears, exhibited a poor or even inverse relationship between DP level and hearing threshold, i.e., displayed an increase of DP level with increasing hearing loss. Despite the severe hearing loss but due to the high level, DPs could be recorded well in the frequency range that corresponded to the appearance of the tinnitus. The DP slope, however, increased with increasing hearing loss and, therefore, did still correlate with hearing threshold revealing pathological alteration. The data suggest that the DP level alone is hardly capable of assessing hearing impairment in tinnitus ears and may even be misleading. Thus just the DP slope seems to be the only reliable indicator of cochlear malfunction around the tinnitus frequency. The observed nonuniform DP behavior suggests different cochlear impairments in tinnitus ears. In those ears where the DP level decreases and the slope of the I/O functions increases with hearing loss, cochlear sensitivity and tuning are supposed to be diminished. In those ears where the DP level increases with increasing hearing loss, a reinforced mechanical distortion is hypothetized to be generated by cochlear hyperactivity that can be the source of both the abnormally high DP level and the tinnitus.     

Frequency tuning and spontaneous activity in the auditory nerve and cochlear nucleus magnocellularis of the barn owl Tyto alba

Single-unit recordings were obtained from the brain stem of the barn owl at the level of entrance of the auditory nerve. Auditory nerve and nucleus magnocellularis units were distinguished by physiological criteria, with the use of the response latency to clicks, the spontaneous discharge rate, and the pattern of characteristic frequencies encountered along an electrode track. The response latency to click stimulation decreased in a logarithmic fashion with increasing characteristic frequency for both auditory nerve and nucleus magnocellularis units. The average difference between these populations was 0.4-0.55 ms. The average most sensitive thresholds were approximately 0 dB SPL and varied little between 0.5 and 9 kHz. Frequency-threshold curves showed the simple V shape that is typical for birds, with no indication of a low-frequency tail. Frequency selectivity increased in a gradual, power-law fashion with increasing characteristic frequency. There was no reflection of the unusual and greatly expanded mapping of higher frequencies on the basilar papilla of the owl. This observation is contrary to the equal-distance hypothesis that relates frequency selectivity to the spatial representation in the cochlea. On the basis of spontaneous rates and/or sensitivity there was no evidence for distinct subpopulations of auditory nerve fibers, such as the well-known type I afferent response classes in mammals. On the whole, barn owl auditory nerve physiology conformed entirely to the typical patterns seen in other bird species. The only exception was a remarkably small spread of thresholds at any one frequency, this being only 10-15 dB in individual owls. Average spontaneous rate was 72.2 spikes/s in the auditory nerve and 219.4 spikes/s for nucleus magnocellularis. This large difference, together with the known properties of endbulb-of-Held synapses, suggests a convergence of approximately 2-4 auditory nerve fibers onto one nucleus magnocellularis neuron. Some auditory nerve fibers as well as nucleus magnocellularis units showed a quasiperiodic spontaneous discharge with preferred intervals in the time-interval histogram. This phenomenon was observed at frequencies as high as 4.7 kHz.     

2f1-f2 distortion product otoacoustic emissions in White Leghorn chickens (Gallus domesticus): effects of frequency ratio and relative level

The effects of primary tone frequency ratio (f2/f1 ratio) and relative level (L2/L1) on the amplitude of the cubic difference tone (CDT: 2f1-f2) distortion product otoacoustic emissions (DPOAEs) were investigated in adult White Leghorn chickens (Gallus domesticus). In experiment 1, 9 f2/f1 ratios ranging from 1.05 to 1.8 were investigated. Measurements were obtained from both ears of 4 chickens at 7 f1 frequencies ranging from 0.8 to 4.0 kHz. The primary tones were equal in level, and varied from 20 to 80 dB SPL. The mean CDT amplitude increased with increasing primary tone level once the measurement noise floor was exceeded. The input/ output functions assumed one of two shapes: one in which there was a systematic increase in DPOAE amplitude with increasing primary tone level, and the other in which there was a plateau in the input/output function near 65-70 dB SPL. At the highest primary tone level (80 dB SPL), there was a decrease in the CDT amplitude with increasing f2/f1 ratio. At high primary tone levels, the f2/f1 ratio which produced the largest CDT was 1.05 or 1.1, while at lower primary tone levels the largest CDT occurred at f2/f1 ratios of 1.2-1.3. In experiment 2, L2 was held constant at 70 dB SPL, and L1 varied from 50 to 80 dB SPL. For f1 frequencies of 0.8 and 3.2 kHz, there was an increase in the CDT amplitude with increasing L1, followed by an asymptote at higher levels. In contrast, for 1.6 and 2.0 kHz f1 frequencies, the amplitude increased, plateaued and then increased again at higher levels. Informal measurements suggest that spontaneous otoacoustic emissions (SOAEs) are rarely seen in chickens. However, a reliable SOAE was observed in 1 chicken, which could be suppressed by external sounds and anoxia.     

Interpretation of distortion product otoacoustic emission measurements. II. Estimating tuning characteristics using three stimulus tones

The simple model introduced in Part I [J. Acoust. Soc. Am. 102, 413-429 (1997)] is used to simulate the response of the cochlea to three stimulus tones. The focus is on "emission suppression tuning curves" constructed using a third tone to suppress the cubic distortion tone emission (CDT, 2f1-f2) generated by two primary tones at frequencies f1 and f2 (intensities L1 and L2). A criterion decrease (here, 5 dB) of the CDT emission amplitude defines the 2f1-f2 emission suppression tuning curve. Applying traditional tuning curve measures to emission suppression tuning curves appears ineffective in determining the underlying cochlear amplifier characteristics. However, it is shown that there are three characteristics of emission suppression tuning curves which are particularly useful: (1) the "f2 threshold" which is the level of the third tone, L3, required for the criterion CDT amplitude decrease, under the condition that the third tone frequency, f3, is approximately equal to f2; (2) the "shoulder threshold" similarly defined for f3 < f2; and (3) the "tuning width," w40. The tuning width is defined to be the distance (in octaves) from the frequency f2 to the upper f3 frequency for which there is a criterion CDT decrease, in this case using the L3 level which is 40 dB above the f2 threshold. Model calculations appropriate to gerbils show that these measures are most accurately related to the underlying cochlear amplifier characteristics for parameters where the primary stimulus amplitudes satisfy L1/L2 > 20 dB and for which L1 is 25 dB or more below the sharp "notch" seen in the two tone input-output function. In this parameter region, the cochlear amplifier characteristics are related to measured quantities by the relationships wr approximately equal to w40 and Ga approximately equal to TE + w40gp. Here, Ga is the gain (dB) of the cochlear amplifier, defined as the total increase in cochlear response over the passive response, wr is the distance (octaves) over which the active cochlear response rises to a maximum, and gp is the passive increase (dB/octave) of the traveling wave along the basilar membrane. The measured quantities are TE, the difference (dB) between the shoulder threshold and the f2 threshold, and the tuning width, w40 (octaves), defined above. Model predictions are confirmed by measurements in adult gerbils.     

Head-related transfer functions of the barn owl: measurement and neural responses

Sounds arriving at the eardrum are filtered by the external ear and associated structures in a frequency and direction specific manner. When convolved with the appropriate filters and presented to human listeners through headphones, broadband noises can be precisely localized to the corresponding position outside of the head (reviewed in Blauert, 1997). Such a 'virtual auditory space' can be a potentially powerful tool for neurophysiological and behavioral work in other species as well. We are developing a virtual auditory space for the barn owl, Tyto alba, a highly successful auditory predator that has become a well-established model for hearing research. We recorded catalogues of head-related transfer functions (HRTFs) from the frontal hemisphere of 12 barn owls and compared virtual and free sound fields acoustically and by their evoked neuronal responses. The inner ca. 1 cm of the ear canal was found to contribute little to the directionality of the HRTFs. HRTFs were recorded by inserting probetube microphones to within about 1 or 2 mm of the eardrum. We recorded HRTFs at frequencies between 2 and 11 kHz, which includes the frequencies most useful to the owl for sound localization (3-9 kHz; Konishi, 1973). Spectra of virtual sounds were within +/- 1 dB of amplitude and +/- 10 degrees of phase of the spectra of free field sounds measured near to the eardrum. The spatial pattern of responses obtained from neurons in the inferior colliculus were almost indistinguishable in response to virtual and to free field stimulation.     

Development of AMPA-selective glutamate receptors in the auditory brainstem of the barn owl

AMPA receptor specific antibodies were used to study the distribution and development of glutamate receptor subtypes (GluR1-4) in nucleus magnocellularis, angularis, laminaris, and the superior olive of the barn owl. Each nucleus in the adult barn owl expresses characteristic levels of AMPA receptor subtypes, and all are enriched in the subunits associated with rapid desensitization (GluR2 and 4). In the auditory hindbrain of the barn owl, the levels of expression of all AMPA receptors were very low at the time of hatching. In all nuclei, the level of GluR1 immunoreactivity was low to undetectable at all ages studied. In the cochlear nuclei, angularis and magnocellularis, levels of GluR2/3 and GluR4 immunoreactivity increased over the first 2 weeks after hatching, coinciding with the morphological maturation of auditory nerve terminals in NM. In the nucleus laminaris and in the superior olive, GluR2/3 and GluR4 immunoreactivity reached adult-like patterns by 3 weeks after hatching. Thus, adult-like patterns of immunoreactivity appeared at least 1 month before the end of the sensitive period in all nuclei studied.     

Effects of aging on the fine structure of the 2f1-f2 acoustic distortion product

The fine structures of 2f1-f2 acoustic distortion products (ADP) were measured in four groups of human subjects: (1) young with normal hearing, (2) aged with normal or near-normal hearing, (3) aged subjects with more severe hearing loss above 2000 Hz, and (4) young with hearing similar to those of the normal- or near-normal-hearing aged group. The purpose of this study was to investigate how ADP fine structure changes with age and hearing loss. Results show that the fine structure is observable whenever the ADP is measurable, and its sharpness, defined as the peak-to-peak frequency distance, is independent of age hearing loss, and longitudinal amplitude change. There is a large variance in ADP peak amplitudes in aged subjects with or without hearing loss as compared to young normal hearing subjects, the aged group generally having lower peak amplitudes than those of the young group. According to an ANOVA analysis with absolute threshold as covariate, the null hypothesis stating that there is no aging effect on the ADP peak responses cannot be ruled out, a conclusion similar to that made by Stover and Norton [J. Acoust. Soc. Am. 94, 2670-2681 (1993)]. On the other hand, threshold changes cannot explain all the differences in ADP amplitude. It is clear that the relationship between ADP amplitudes and behavioral thresholds can differ between young and aged populations. At primary levels of 50 dB SPL, almost normal ADP magnitudes are often found in aged subjects even when associated with a 35-dB hearing loss, whereas for young subjects ADPs typically were not measurable when associated with the pure-tone thresholds of 20 dB HL or higher. This dichotomy may be explained by the different etiologies of cochlear pathologies predominant in the two groups.     

Simulation of ILD sensitive neurons in the inferior colliculus of the barn owl

The barn owl (Tyto alba) uses interaural level difference (ILD) as a cue for the localization of sound. The first site of binaural convergence in the pathway that processes ILD is the ventral lateral lemniscus pars posterior (VLVp). Neurons in VLVp receive excitatory input from the contralateral nucleus angularis, and inhibitory input from the contralateral VLVp. Within the lateral shell of the inferior colliculus are ILD sensitive neurons that show maximum spike rate at a specific ILD value, with response falling off sharply on each side. Adolphs has developed a model of such lateral shell neurons based on anatomic and physiological data. In his model, lateral shell neurons receive inhibitory input from VLVp on both sides, and this inhibition, applied against a constant excitatory input, produces the observed two-sided response curves. We simulated, in Matlab 4, Adolphs' model, and obtained supporting results. Our simulation suggests that VLVp provides a repository of simple ILD filters from which higher centers construct more complex filters, including the single-peaked curves observed by Adolphs. The VLVp filters are organized along the inhibitory gradient, with broad filters ventral, sharp filters dorsal.     

Suppression of human acoustic distortion product: dual origin of 2f1-f2

In order to explore the origin of acoustic distortion product (DP) in the ear canal, the effect of the level and the frequency of the suppressor tone on the level of the DP was investigated. The results broadly support previous studies in showing that, with increasing suppressor level, the DP level shows an initial relatively stable plateau or gradual decline, followed by a rapid decline. The shape of the human iso-suppression contours derived from these "suppression-rate" curves was found to depend upon the size of the iso-suppression criterion. Low-level suppressor tones close in frequency to 2f1-f2 were effective at suppressing the DP by up to 3 dB in subjects where the distortion frequency fell at a region of strong stimulus frequency re-emission. It is probable that contributions from the DP frequency region, as well as components from the primary frequency region, make up the ear canal measured DP. With a 6-dB iso-suppression criterion, suppressor tones in the primary frequency region suppress DP most effectively.     

Pharmacological specialization of learned auditory responses in the inferior colliculus of the barn owl

Neural tuning for interaural time difference (ITD) in the optic tectum of the owl is calibrated by experience-dependent plasticity occurring in the external nucleus of the inferior colliculus (ICX). When juvenile owls are subjected to a sustained lateral displacement of the visual field by wearing prismatic spectacles, the ITD tuning of ICX neurons becomes systematically altered; ICX neurons acquire novel auditory responses, termed "learned responses," to ITD values outside their normal, pre-existing tuning range. In this study, we compared the glutamatergic pharmacology of learned responses with that of normal responses expressed by the same ICX neurons. Measurements were made in the ICX using iontophoretic application of glutamate receptor antagonists. We found that in early stages of ITD tuning adjustment, soon after learned responses had been induced by experience-dependent processes, the NMDA receptor antagonist D, L-2-amino-5-phosphonopentanoic acid (AP-5) preferentially blocked the expression of learned responses of many ICX neurons compared with that of normal responses of the same neurons. In contrast, the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) blocked learned and normal responses equally. After long periods of prism experience, preferential blockade of learned responses by AP-5 was no longer observed. These results indicate that NMDA receptors play a preferential role in the expression of learned responses soon after these responses have been induced by experience-dependent processes, whereas later in development or with additional prism experience (we cannot distinguish which), the differential NMDA receptor-mediated component of these responses disappears. This pharmacological progression resembles the changes that occur during maturation of glutamatergic synaptic currents during early development.     

Neural coding of relational invariance in speech: Human language analogs to the barn owl.

The ability to form perceptual equivalence classes from variable input stimuli is common in both animals and humans. Neural circuitry that can disambiguate ambiguous stimuli to arrive at perceptual constancy has been documented in the barn owl's inferior colliculus where sound-source azimuth is signaled by interaural phase differences spanning the frequency spectrum of the sound wave. Extrapolating from the sound-localization system of the barn owl to human speech, 2 hypothetical models are offered to conceptualize the neural realization of relative invariance in (a) categorization of stop consonants /b, d, g/ across varying vowel contexts and (b) vowel identity across speakers. 2 computational algorithms employing real speech data were used to establish acoustic commonalities to form neural mappings representing phonemic equivalence classes in the form of functional arrays similar to those seen in the barn owl. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Early monaural occlusion alters the neural map of interaural level differences in the inferior colliculus of the barn owl

Monaural occlusion during early life causes adaptive changes in the tuning of units in the owl's optic tectum to interaural level differences (ILD) that tend to align the auditory with the visual map of space. We investigated whether these changes could be due to experience-dependent plasticity occurring in the auditory pathway prior to the optic tectum. Units were recorded in the external nucleus of the inferior colliculus (ICx), which is a major source of auditory input to the optic tectum. The tuning of ICx units to ILD was measured in normal barn owls and in barn owls raised with one ear occluded. ILD tuning at each recording site was measured with dichotic noise bursts, presented at a constant average binaural level, 20 dB above threshold. The best ILD at each site was defined as the midpoint of the range of ILD values which elicited more than 50% of the maximum response. A physiological map of ILD was found in the ICx of normal owls: best ILDs changed systematically from right-ear-greater to left-ear-greater as the electrode progressed from dorsal to ventral. Best ILDs ranged from 13 dB right-ear-greater to 15 dB left-ear-greater and progressed at an average rate of 12 dB/mm. The representations of ILD were similar on both sides of the brain. In the ICx of owls raised with one ear occluded, the map of ILD was shifted in the adaptive direction: ILD tuning was shifted towards values favoring the non-occluded ear (the direction that would restore a normal space map). The average magnitude of the shift was on the order of 8-10 dB in each of 4 owls. In one owl, the mean shift in ILD tuning was almost identical on both sides of the brain. In another owl, the mean shift was much larger on the side ipsilateral to the occlusion than on the contralateral side. In both cases, the mean shifts measured in each ICx were comparable to the mean shifts measured in the optic tectum on the same sides of the brain. Thus, the adjustments in ILD tuning that have been observed in the optic tectum in response to monaural occlusion are almost entirely due to adaptive mechanisms that operate at or before the level of the ICx.     

Phenotypic patterns of distortion product otoacoustic emission in inbred and F1 hybrid hearing mouse strains

Distortion product otoacoustic emissions (DPOE) were obtained from five different hearing mouse groups: CBA/J, MOLF/Rk, ct (homozygous normal mice of the curly-tail stock), and the F1 hybrid offspring of the matings CBA/J x dn/dn and MOLF/Rk x dn/dn (dn/dn mice are the curly-tail stock with recessive deafness). The DPOE patterns of the CBA/J and ct strains were similar to each other and different from that of the MOLF/Rk. The two sets of F1 hybrid mice, (CBA/J x dn/dn)F1 and (MOLF/Rk x dn/dn)F1, were found to have significantly larger DPOE amplitudes than their hearing parent strains, MOLF/Rk and CBA/J, respectively. In addition, the DPOE amplitudes were greater for the offspring of the MOLF/Rk x dn/dn cross than for those of the CBA/J x dn/dn cross, even though they were lower for MOLF/Rk than for CBA/J. The distinct features of DPOE patterns among these five groups suggest that DPOE testing can be used for auditory phenotyping.     

Temperature dependency of the frequency and level of a spontaneous otoacoustic emission during fever

Using a method of heterodyne mixing with display of beats on a chart recorder, measurements were made of the frequency and level of a spontaneous otoacoustic emission in a human subject on 17 occasions during a period of 13 consecutive days. Temperature measurement was obtained with a thermometer measuring infra-red radiation from the ear-drum, indicative of body core temperature. In the latter half of this period there was variation of body set point temperature due to fever, and it was found that there was clear evidence of inverse relationship between temperature and both the frequency and level of the emission. The occurrence of fever was due to simple urinary tract infection and was considered to be without ototoxic implication; there was no associated worsening of pure tone threshold nor change in measurements of middle ear function.     

Enhancement of the transient-evoked otoacoustic emission produced by the addition of a pure tone in the guinea pig

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase implicated in cell-matrix interaction and integrin signaling. It is well established that Tyr-397 is the FAK autophosphorylation site and Tyr-407, -576/577, -861, and -925 are the sites on murine FAK that are mediated by Src family kinases. To study how FAK is regulated by tyrosine phosphatase(s), cells overexpressing chicken FAK are treated with sodium vanadate. Both the phosphotyrosine content and the enzymatic activity of FAK are increased in response to vanadate. Interestingly, sustained FAK Tyr-576/577 and -863 phosphorylations are detected in vanadate-treated FAK overexpressors and are dependent on FAK autophosphorylation. Further analysis of sodium vanadate-treated FAK overexpressors reveals that the enhanced FAK kinase activity parallels its elevated Tyr-576/577 phosphorylation. Thus, we conclude that Src-mediated FAK phosphorylation is regulated by a tyrosine phosphatase(s) and may be of physioligical significance.