Radha Kalluri

Frequency selectivity in Old-World monkeys corroborates sharp cochlear tuning in humans

Frequency selectivity in the inner ear is fundamental to hearing and is traditionally thought to be similar across mammals. Although direct measurements are not possible in humans, estimates of frequency tuning based on noninvasive recordings of sound evoked from the cochlea (otoacoustic emissions) have suggested substantially sharper tuning in humans but remain controversial. We report measurements of frequency tuning in macaque monkeys, Old-World primates phylogenetically closer to humans than the laboratory animals often taken as models of human hearing (e.g., cats, guinea pigs, chinchillas). We find that measurements of tuning obtained directly from individual auditory-nerve fibers and indirectly using otoacoustic emissions both indicate that at characteristic frequencies above about 500 Hz, peripheral frequency selectivity in macaques is significantly sharper than in these common laboratory animals, matching that inferred for humans above 4–5 kHz. Compared with the macaque, the human otoacoustic estimates thus appear neither prohibitively sharp nor exceptional. Our results validate the use of otoacoustic emissions for noninvasive measurement of cochlear tuning and corroborate the finding of sharp tuning in humans. The results have important implications for understanding the mechanical and neural coding of sound in the human cochlea, and thus for developing strategies to compensate for the degradation of tuning in the hearing-impaired.

Comparing stimulus-frequency otoacoustic emissions measured by compression, suppression, and spectral smoothing

Stimulus-frequency otoacoustic emissions (SFOAEs) have been measured in several different ways, including (1) nonlinear compression, (2) two-tone suppression, and (3) spectral smoothing. Each of the three methods exploits a different cochlear phenomenon or signal-processing technique to extract the emission. The compression method makes use of the compressive growth of emission amplitude relative to the linear growth of the stimulus. The emission is defined as the complex difference between ear-canal pressure measured at one intensity and the rescaled pressure measured at a higher intensity for which the emission is presumed negligible. The suppression method defines the SFOAE as the complex difference between the ear-canal pressure measured with and without a suppressor tone at a nearby frequency. The suppressor tone is presumed to substantially reduce or eliminate the emission. The spectral smoothing method involves convolving the complex ear-canal pressure spectrum with a smoothing function. The analysis exploits the differing latencies of stimulus and emission and is equivalent to windowing in the corresponding latency domain. Although the three methods are generally assumed to yield identical emissions, no equivalence has ever been established. This paper compares human SFOAEs measured with the three methods using procedures that control for temporal drifts, contamination of the calibration by evoked emissions, and other potential confounds. At low stimulus intensities, SFOAEs measured using all three methods are nearly identical. At higher intensities, limitations of the procedures contribute to small differences, although the general spectral shape and phase of the three SFOAEs remain similar. The near equivalence of SFOAEs measured by compression, suppression, and spectral smoothing indicates that SFOAE characteristics are not mere artifacts of measurement methodology.

Measuring stimulus-frequency otoacoustic emissions using swept tones

Although stimulus-frequency otoacoustic emissions (SFOAEs) offer compelling advantages as noninvasive probes of cochlear function, they remain underutilized compared to other evoked emission types, such as distortion-products (DPOAEs), whose measurement methods are less complex and time-consuming. Motivated by similar advances in the measurement of DPOAEs, this paper develops and characterizes a more efficient SFOAE measurement paradigm based on swept tones. In contrast to standard SFOAE measurement methods, in which the emissions are measured in the sinusoidal steady-state using discrete tones of well defined frequency, the swept-tone method sweeps rapidly across frequency (typically at rates of 1 Hz/ms or greater) using a chirp-like stimulus. Measurements obtained using both swept- and discrete-tone methods in an interleaved suppression paradigm demonstrate that the two methods of measuring SFOAEs yield nearly equivalent results, the differences between them being comparable to the run-to-run variability encountered using either method alone. The match appears robust to variations in measurement parameters, such as sweep rate and direction. The near equivalence of the SFOAEs obtained using the two measurement methods enables the interpretation of swept-tone SFOAEs within existing theoretical frameworks. Furthermore, the data demonstrate that SFOAE phase-gradient delays-including their large and irregular fluctuations across frequency-reflect actual physical time delays at different frequencies, showing that the physical emission latency, not merely the phase gradient, is inherently irregular.

Level dependence of distortion product otoacoustic emission phase is attributed to component mixing

Distortion product otoacoustic emissions (DPOAEs) measured in the ear canal represent the vector sum of components produced at two regions of the basilar membrane by distinct cochlear mechanisms. In this study, the effect of stimulus level on the 2f(1) - f(2) DPOAE phase was evaluated in 22 adult subjects across a three-octave range. Level effects were examined for the mixed DPOAE signal measured in the ear canal and after unmixing components to assess level effects individually on the distortion (generated at the f(1), f(2) overlap) and reflection (at f(dp)) sources. Results show that ear canal DPOAE phase slope becomes steeper with decreasing level; however, component analysis further explicates this result, indicating that interference between DPOAE components (rather than a shift in mechanics related to distortion generation) drives the level dependence of DPOAE phase measured in the ear canal. The relative contribution from the reflection source increased with decreasing level, producing more component interference and, at times, a reflection-dominated response at the lowest stimulus levels. These results have implications for the use of DPOAE phase to study cochlear mechanics and for the potential application of DPOAE phase for clinical purposes.

Stimulus-frequency otoacoustic emissions in human newborns

This study presents the first reported measurements of stimulus frequency emissions (SFOAEs) in 15 human newborns and compares their magnitudes and phase-gradient delays to those reported in adults. SFOAEs in newborns were measured at stimulus levels as low as 15 dB sound pressure level (SPL). Responses were compared between adults and newborns at stimulus levels where SFOAEs in both age groups demonstrated approximately linear growth (<40 dB SPL for newborns, <25 dB SPL for adults). Neonates had adult-like SFOAE delays when compared in this fashion, which compensates for newborn middle ear inefficiencies.

Towards a joint reflection-distortion otoacoustic emission profile: Results in normal and impaired ears

Otoacoustic emissions (OAEs) provide salient information about cochlear function and dysfunction. Two broad classes of emissions, linear reflection and nonlinear distortion, arise via distinct cochlear processes and hence, appear to provide independent information about cochlear health and hearing. Considered in combination, these two OAE types may characterize sensory hearing loss most effectively. In this study, the level-dependent growth of stimulus-frequency OAEs (a reflection-type emission) and distortion-product OAEs (a distortion-type emission) were measured in ten normal-hearing ears and eight ears with slight-to-moderate sensorineural hearing loss. Metrics of OAE strength and compression were derived from OAE input/output functions and then considered in a combined fashion. Results indicate that SFOAEs and DPOAEs differ significantly in their strength and compression features. When SFOAE and DPOAE metrics are displayed together on a two-dimensional plot, relatively well-defined data clusters describe their normative relationship. In hearing-impaired ears, this relationship is disrupted but not in a uniform way across ears; ears with similar audiograms showed differently altered joint-OAE profiles. Hearing loss sometimes affected only one OAE or one more than the other. Results suggest a joint-OAE profile is promising and warrants study in a large group of subjects with sensory hearing loss of varied etiologies.

Spatial Gradients in the Size of Inner Hair Cell Ribbons Emerge Before the Onset of Hearing in Rats

The size and locations of pre-synaptic ribbons and glutamate receptors within and around inner hair cells are correlated with auditory afferent response features such as the spontaneous discharge rate (SR), threshold, and dynamic range of sound intensity representation (the so-called SR-groups). To test if the development of these spatial gradients requires experience with sound intensity, we quantified the size and spatial distribution of synaptic ribbons from the inner hair cells of neonatal rats before and after the onset of hearing (from post-natal day (P) 3 to P33). To quantify ribbon size, we used high resolution fluorescence confocal microscopy and 3-D reconstructions of immunolabeled ribbons. The size, density, and spatial distribution of ribbons changed during development. At P3, ribbons were densely clustered near the basal/modiolar face of the hair cell where low SR-groups preferentially contact adult hair cells. By P12, the disparity in ribbon count was less striking and ribbons were equally likely to occupy both faces. At all ages before P12, ribbons were larger on the modiolar face than on the pillar face. These differences initially grew larger with age but collapsed around the onset of hearing. Between P12 and P33, the spatial gradients remained small and began to re-emerge around P33. Even by P12, we did not find spatial gradients in the size of the post-synaptic glutamate receptors as is found on afferent terminals contacting adult inner hair cells. These results suggest that spatial gradients in ribbon size develop in the absence of sensory experience.

A biophysical model examining the role of low-voltage-activated potassium currents in shaping the responses of vestibular ganglion neurons

The vestibular nerve is characterized by two broad groups of neurons that differ in the timing of their interspike intervals; some fire at highly regular intervals, whereas others fire at highly irregular intervals. Heterogeneity in ion channel properties has been proposed as shaping these firing patterns (Highstein SM, Politoff AL. Brain Res 150: 182-187, 1978; Smith CE, Goldberg JM. Biol Cybern 54: 41-51, 1986). Kalluri et al. (J Neurophysiol 104: 2034-2051, 2010) proposed that regularity is controlled by the density of low-voltage-activated potassium currents (IKL). To examine the impact of IKL on spike timing regularity, we implemented a single-compartment model with three conductances known to be present in the vestibular ganglion: transient sodium (gNa), low-voltage-activated potassium (gKL), and high-voltage-activated potassium (gKH). Consistent with in vitro observations, removing gKL depolarized resting potential, increased input resistance and membrane time constant, and converted current step-evoked firing patterns from transient (1 spike at current onset) to sustained (many spikes). Modeled neurons were driven with a time-varying synaptic conductance that captured the random arrival times and amplitudes of glutamate-driven synaptic events. In the presence of gKL, spiking occurred only in response to large events with fast onsets. Models without gKL exhibited greater integration by responding to the superposition of rapidly arriving events. Three synaptic conductance were modeled, each with different kinetics to represent a variety of different synaptic processes. In response to all three types of synaptic conductance, models containing gKL produced spike trains with irregular interspike intervals. Only models lacking gKL when driven by rapidly arriving small excitatory postsynaptic currents were capable of generating regular spiking.

Otoacoustic Estimates of Cochlear Tuning: Testing Predictions in Macaque

Otoacoustic estimates of cochlear frequency selectivity suggest substantially sharper tuning in humans. However, the logic and methodology underlying these estimates remain untested by direct measurements in primates. We report measurements of frequency tuning in macaque monkeys, Old-World primates phylogenetically closer to humans than the small laboratory animals often taken as models of human hearing (e.g., cats, guinea pigs, and chinchillas). We find that measurements of tuning obtained directly from individual nerve fibers and indirectly using otoacoustic emissions both indicate that peripheral frequency selectivity in macaques is significantly sharper than in small laboratory animals, matching that inferred for humans at high frequencies. Our results validate the use of otoacoustic emissions for noninvasive measurement of cochlear tuning and corroborate the finding of sharper tuning in humans.

Deviations from Scaling Symmetry in the Apical Half of the Human Cochlea.

Invariant distortion product otoacoustic emission (DPOAE) phase elucidates scaling symmetry in the cochlea. Below some low-frequency boundary, DPOAE phase slope steepens. The origin of this break in phase invariance is not clear. Stimulus frequency (SF)OAE delays computed from the slope of phase also manifest discontinuities at low frequencies, though the relationship between the breaking of cochlear scaling as defined by SFOAE and DPOAE metrics has not been examined. In this study, OAEs were recorded in normal-hearing human adults to probe cochlear scaling and its breaking and to examine the correspondence between two OAE metrics of scaling. Results indicate: (1) the apical break in DPOAE phase invariance cannot be explained by contributions from the reflection-source component; (2) DPOAE phase signals a break from scaling near 1.5 kHz and (3) DPOAE and SFOAE metrics of cochlear scaling produce phase discontinuities within approximately one-quarter octave of each other and show comparable rates of breaking, suggesting a common underlying origin.