Population Of Auditory Nerve Fibers Research Articles

Computational modeling of the human compound action potential.

The auditory nerve (AN) compound action potential (CAP) is an important tool for assessing auditory disorders and monitoring the health of the auditory periphery during surgical procedures. The CAP has been mathematically conceptualized as the convolution of a unit response (UR) waveform with the firing rate of a population of AN fibers. Here, an approach for predicting experimentally recorded CAPs in humans is proposed, which involves the use of human-based computational models to simulate AN activity. CAPs elicited by clicks, chirps, and amplitude-modulated carriers were simulated and compared with empirically recorded CAPs from human subjects. In addition, narrowband CAPs derived from noise-masked clicks and tone bursts were simulated. Many morphological, temporal, and spectral aspects of human CAPs were captured by the simulations for all stimuli tested. These findings support the use of model simulations of the human CAP to refine existing human-based models of the auditory periphery, aid in the design and analysis of auditory experiments, and predict the effects of hearing loss, synaptopathy, and other auditory disorders on the human CAP.

A computational modelling framework for assessing information transmission with cochlear implants

Computational models are useful tools to investigate scientific questions that would be complicated to address using an experimental approach. In the context of cochlear-implants (CIs), being able to simulate the neural activity evoked by these devices could help in understanding their limitations to provide natural hearing. Here, we present a computational modelling framework to quantify the transmission of information from sound to spikes in the auditory nerve of a CI user. The framework includes a model to simulate the electrical current waveform sensed by each auditory nerve fiber (electrode-neuron interface), followed by a model to simulate the timing at which a nerve fiber spikes in response to a current waveform (auditory nerve fiber model). Information theory is then applied to determine the amount of information transmitted from a suitable reference signal (e.g., the acoustic stimulus) to a simulated population of auditory nerve fibers. As a use case example, the framework is applied to simulate published data on modulation detection by CI users obtained using direct stimulation via a single electrode. Current spread as well as the number of fibers were varied independently to illustrate the framework capabilities. Simulations reasonably matched experimental data and suggested that the encoded modulation information is proportional to the total neural response. They also suggested that amplitude modulation is well encoded in the auditory nerve for modulation rates up to 1000 Hz and that the variability in modulation sensitivity across CI users is partly because different CI users use different references for detecting modulation.

Modeling temporal information encoding by the population of fibers in the healthy and synaptopathic auditory nerve

We report a theoretical study aimed at investigating the impact of cochlear synapse loss (synaptopathy) on the encoding of the envelope (ENV) and temporal fine structure (TFS) of sounds by the population of auditory nerve fibers. A computational model was used to simulate auditory-nerve spike trains evoked by sinusoidally amplitude-modulated (AM) tones at 10 Hz with various carrier frequencies and levels. The model included 16 cochlear channels with characteristic frequencies (CFs) from 250 Hz to 8 kHz. Each channel was innervated by 3, 4 and 10 fibers with low (LSR), medium (MSR), and high spontaneous rates (HSR), respectively. For each channel, spike trains were collapsed into three separate ‘population’ post-stimulus time histograms (PSTHs), one per fiber type. Information theory was applied to reconstruct the stimulus waveform, ENV, and TFS from one or more PSTHs in a mathematically optimal way. The quality of the reconstruction was regarded as an estimate of the information present in the used PSTHs. Various synaptopathy scenarios were simulated by removing fibers of specific types and/or cochlear regions before stimulus reconstruction. We found that the TFS was predominantly encoded by HSR fibers at all stimulus carrier frequencies and levels. The encoding of the ENV was more complex. At lower levels, the ENV was predominantly encoded by HSR fibers with CFs near the stimulus carrier frequency. At higher levels, the ENV was equally well or better encoded by HSR fibers with CFs different from the AM carrier frequency as by LSR fibers with CFs at the carrier frequency. Altogether, findings suggest that a healthy population of HSR fibers (i.e., including fibers with CFs around and remote from the AM carrier frequency) might be sufficient to encode the ENV and TFS over a wide range of stimulus levels. Findings are discussed regarding their relevance for diagnosing synaptopathy using non-invasive ENV- and TFS-based measures.

Efficient population coding depends on stimulus convergence and source of noise.

Sensory organs transmit information to downstream brain circuits using a neural code comprised of spikes from multiple neurons. According to the prominent efficient coding framework, the properties of sensory populations have evolved to encode maximum information about stimuli given biophysical constraints. How information coding depends on the way sensory signals from multiple channels converge downstream is still unknown, especially in the presence of noise which corrupts the signal at different points along the pathway. Here, we calculated the optimal information transfer of a population of nonlinear neurons under two scenarios. First, a lumped-coding channel where the information from different inputs converges to a single channel, thus reducing the number of neurons. Second, an independent-coding channel when different inputs contribute independent information without convergence. In each case, we investigated information loss when the sensory signal was corrupted by two sources of noise. We determined critical noise levels at which the optimal number of distinct thresholds of individual neurons in the population changes. Comparing our system to classical physical systems, these changes correspond to first- or second-order phase transitions for the lumped- or the independent-coding channel, respectively. We relate our theoretical predictions to coding in a population of auditory nerve fibers recorded experimentally, and find signatures of efficient coding. Our results yield important insights into the diverse coding strategies used by neural populations to optimally integrate sensory stimuli in the presence of distinct sources of noise.

Developing a device measuring the middle ear reflex in rat ears: A preliminary study

Purpose The middle ear muscle (MEM) reflex is the contraction of the stapedius and tensor tympani muscles in the middle ear cavity in response to loud sound, and relies on a healthy population of auditory nerve fibers. Thus, the MEM reflex can be used as a diagnostic test to quantify auditory nerve survival. This study aims to develop a device to measure the MEM reflex in an animal model, with a long-term goal to develop a biomarker for auditory nerve degeneration. Methods A source device was constructed using a hearing aid speaker attached to a long and thin tube to create high impedance. A probe consists of a microphone placed near the tip of the tube and the sound source. Sound pressure that reflects the MEM reflex was measured in the probe ear of anesthetized rats while an elicitor stimulus was presented in an opposite ear. Results The probe to measure the MEM reflex was verified having a constant volume velocity sensitive to changes in sound pressure. Increases in amplitude of sound pressure were apparent when the stimulation signal was presented in the stimulating ear and the amplitude was decreased to baseline when the signal was turned off. After sacrifice of the animal, the reflex was absent. Conclusions Results showed the feasibility of the probe with high source impedance to measure the MEM reflex in animal ears. Absent reflex after animal sacrifice indicates that the MEM reflex measured using this probe was not an artifact or biological noise. Keywords: Middle ear muscle reflex; Impedance; Rat

Pulse-rate discrimination deficit in cochlear implant users: is the upper limit of pitch peripheral or central?

Cochlear implant (CI) users do not reliably associate an increase in pulse rate above 300 pulses per second (pps) with an increase in pitch. The locus of this upper limit of pitch remains unknown. The present study tested the hypothesis that this deficit resides at least initially at the auditory nerve. The hypothesis was tested by comparing pulse rate discrimination in different neural excitation patterns, in which a large versus small population of auditory nerve fibers was activated. If poorer pulse rate discrimination was found under conditions where narrower spread of neural excitation (SOE) was anticipated where a relatively small neural population was activated, then it would support the hypothesis that the rate processing deficit found in CI users is related to peripheral neural degeneration. Nine listeners (12 ears) implanted with the Cochlear Americas Nucleus® devices participated in the study. Different SOE conditions were created by (1) selecting electrodes that showed narrow versus broad forward-masked psychophysical spatial tuning curves, and (2) by measuring these electrodes in monopolar (MP) and narrow bipolar (BP0) electrode configurations. Rate discrimination difference limen (DL) was measured at the selected electrodes in two electrode configurations at three base rates (200, 300 and 500 pps). Consistent with the prediction, group mean DL was better (1) at stimulation sites measured with broader tuning, and (2) in MP relative to BP stimulation. These effects were more salient at the more challenging base rates. There was a weak relationship between rate discrimination (above thresholds) and the effect of rate on detection thresholds. Finally, rate discrimination at rates above the known upper limit (i.e., 500 pps) was correlated with duration of deafness and highly predicted the subjects’ speech recognition performance in noise. These findings support that pulse rate discrimination depends, at least partially, on neural conditions at the auditory periphery and this peripheral limit predicts speech recognition outcomes with a CI.

Simulating electrical modulation detection thresholds using a biophysical model of the auditory nerve.

Modulation detection thresholds (MDTs) assess listeners' sensitivity to changes in the temporal envelope of a signal and have been shown to strongly correlate with speech perception in cochlear implant users. MDTs are simulated with a stochastic model of a population of auditory nerve fibers that has been verified to accurately simulate a number of physiologically important temporal response properties. The procedure to estimate detection thresholds has previously been applied to stimulus discrimination tasks. The population model simulates the MDT-stimulus intensity relationship measured in cochlear implant users. The model also recreates the shape of the modulation transfer function and the relationship between MDTs and carrier rate. Discrimination based on fluctuations in synchronous firing activity predicts better performance at low carrier rates, but quantitative measures of modulation coding predict better neural representation of high carrier rate stimuli. Manipulating the number of fibers and a temporal integration parameter, the width of a sliding temporal integration window, varies properties of the MDTs, such as cutoff frequency and peak threshold. These results demonstrate the importance of using a multi-diameter fiber population in modeling the MDTs and demonstrate a wider applicability of this model to simulating behavioral performance in cochlear implant listeners.

Insertion trauma and recovery of function after cochlear implantation: Evidence from objective functional measures

Partial loss and subsequent recovery of cochlear implant function in the first few weeks following cochlear implant surgery has been observed in previous studies using psychophysical detection thresholds. In the current study, we explored this putative manifestation of insertion trauma using objective functional measures: electrically-evoked compound action potential (ECAP) amplitude-growth functions (ECAP amplitude as a function of stimulus level). In guinea pigs implanted in a hearing ear with good post-implant hearing and good spiral ganglion neuron (SGN) survival, consistent patterns of ECAP functions were observed. The slopes of ECAP growth functions were moderately steep on the day of implant insertion, decreased to low levels over the first few days after implantation and then increased slowly over several weeks to reach a relatively stable level. In parallel, ECAP thresholds increased over time after implantation and then recovered, although more quickly, to a relatively stable low level as did thresholds for eliciting a facial twitch. Similar results were obtained in animals deafened but treated with an adenovirus with a neurotrophin gene insert that resulted in good SGN preservation. In contrast, in animals implanted in deaf ears that had relatively poor SGN survival, ECAP slopes reached low levels within a few days after implantation and remained low. These results are consistent with the idea that steep ECAP growth functions require a healthy population of auditory nerve fibers and that cochlear implant insertion trauma can temporarily impair the function of a healthy SGN population.This article is part of a Special Issue entitled <IEB Kyoto>.

Cellular signaling protective against noise-induced hearing loss – A role for novel intrinsic cochlear signaling involving corticotropin-releasing factor?

Hearing loss afflicts approximately 15% of the world's population, and crosses all socioeconomic boundaries. While great strides have been made in understanding the genetic components of syndromic and non-syndromic hearing loss, understanding of the mechanisms underlying noise-induced hearing loss (NIHL) have come much more slowly. NIHL is not simply a mechanism by which older individuals loose their hearing. Significantly, the incidence of NIHL is increasing, and is now involving ever younger populations. This may predict future increased occurrences of hearing loss. Current research has shown that even short-term exposures to loud sounds generating what was previously considered temporary hearing loss, actually produces an almost immediate and permanent loss of specific populations of auditory nerve fibers. Additionally, recurrent exposures to intense sound may hasten age-related hearing loss. While NIHL is a significant medical concern, to date, few compounds have delivered significant protection, arguing that new targets need to be identified. In this commentary, we will explore cellular signaling processes taking place in the cochlea believed to be involved in protection against hearing loss, and highlight new data suggestive of novel signaling not previously recognized as occurring in the cochlea, that is perhaps protective of hearing. This includes a recently described local hypothalamic–pituitary–adrenal axis (HPA)-like signaling system fully contained in the cochlea. This system may represent a local cellular stress–response system based on stress hormone release similar to the systemic HPA axis. Its discovery may hold hope for new drug therapies that can be delivered directly to the cochlea, circumventing systemic side effects.

Broadband onset inhibition can suppress spectral splatter in the auditory brainstem.

In vivo intracellular responses to auditory stimuli revealed that, in a particular population of cells of the ventral nucleus of the lateral lemniscus (VNLL) of rats, fast inhibition occurred before the first action potential. These experimental data were used to constrain a leaky integrate-and-fire (LIF) model of the neurons in this circuit. The post-synaptic potentials of the VNLL cell population were characterized using a method of triggered averaging. Analysis suggested that these inhibited VNLL cells produce action potentials in response to a particular magnitude of the rate of change of their membrane potential. The LIF model was modified to incorporate the VNLL cells’ distinctive action potential production mechanism. The model was used to explore the response of the population of VNLL cells to simple speech-like sounds. These sounds consisted of a simple tone modulated by a saw tooth with exponential decays, similar to glottal pulses that are the repeated impulses seen in vocalizations. It was found that the harmonic component of the sound was enhanced in the VNLL cell population when compared to a population of auditory nerve fibers. This was because the broadband onset noise, also termed spectral splatter, was suppressed by the fast onset inhibition. This mechanism has the potential to greatly improve the clarity of the representation of the harmonic content of certain kinds of natural sounds.

A point process framework for modeling electrical stimulation of the auditory nerve

Model-based studies of responses of auditory nerve fibers to electrical stimulation can provide insight into the functioning of cochlear implants. Ideally, these studies can identify limitations in sound processing strategies and lead to improved methods for providing sound information to cochlear implant users. To accomplish this, models must accurately describe spiking activity while avoiding excessive complexity that would preclude large-scale simulations of populations of auditory nerve fibers and obscure insight into the mechanisms that influence neural encoding of sound information. In this spirit, we develop a point process model of individual auditory nerve fibers that provides a compact and accurate description of neural responses to electric stimulation. Inspired by the framework of generalized linear models, the proposed model consists of a cascade of linear and nonlinear stages. We show how each of these stages can be associated with biophysical mechanisms and related to models of neuronal dynamics. Moreover, we derive a semianalytical procedure that uniquely determines each parameter in the model on the basis of fundamental statistics from recordings of single fiber responses to electric stimulation, including threshold, relative spread, jitter, and chronaxie. The model also accounts for refractory and summation effects that influence the responses of auditory nerve fibers to high pulse rate stimulation. Throughout, we compare model predictions to published physiological data of response to high and low pulse rate stimulation. We find that the model, although constructed to fit data from single and paired pulse experiments, can accurately predict responses to unmodulated and modulated pulse train stimuli. We close by performing an ideal observer analysis of simulated spike trains in response to sinusoidally amplitude modulated stimuli and find that carrier pulse rate does not affect modulation detection thresholds.

Sound Decoding from Auditory Nerve Activity

Event Abstract Back to Event Sound Decoding from Auditory Nerve Activity Marek Rudnicki1, 2*, Marcelo K. Zuffo2 and Werner Hemmert1 1 Technische Universität München, Electrical Engineering and Information Technology, Germany 2 University of São Paulo, Brazil In the inner ear sounds are converted to discrete action potentials and sent to the central nervous system. This transformation is non-linear and results in massive information loss. However, we still can hear and analyze sounds with high fidelity. This is because the crucial features of sounds are still present in the auditory nerve signals. Here we present a method which decodes sounds from a large population of simulated auditory nerve fibers (ANFs). We also use the procedure to reconstruct sounds from a model of an impaired cochlea. This way we are able to mimic how hearing impaired subjects perceive sounds. The problem of reconstructing stimuli from neural activity is usually only approached with relatively small numbers of spikes. Procedures usually rely on the optimization of a linear filter using the reverse correlation technique (Bialek et al. 1991). Our approach leverages responses of a large population of ANFs (close to the number present in the human ear) and non-linear reconstruction using an artificial neural network (ANN). We used the biophysical auditory periphery model from Zilany et al. (2009) which we adapted to replicate the human hearing range and thresholds. The particular ANN used was a multi-layer perceptron (MLP) with a single hidden layer. The input to the MLP was a 10 ms sliding window from multiple spike trains across 10 different characteristic frequencies. The output was a single value of the reconstructed signal. In this way we trained and tested the MLP with sounds below 2 kHz. Unfortunately, this approach did not work for frequencies above 2 kHz, because of the lacking phase information (phase locking) in spike trains. We therefore developed a two-stage algorithm to reconstruct high frequency signals. First, spike trains were converted to a spectrogram by MLPs. Second, the spectrogram was transformed to an acoustic signal using an iterative method (Decorsiere et al. 2011). In order to convert spike trains to a spectrogram we trained 51 MLPs. The input to each MLP was a sliding window of 5 ms from multiple spike trains and the output one of 51 frequency channels of a spectrogram. Characteristic frequencies of the input fibers corresponded to the frequency of the generated output channel. The system was trained with pure tones and a few seconds of speech samples. After training we were able to generate sound files from trains of a large population of nerve action potentials. The reconstructed speech was clearly understandable and well perceived. In addition, we reconstructed sounds from an impaired cochlear model and demonstrated how perception is degraded by outer hair cell loss. Our reconstruction is a valuable tool to evaluate how well speech is encoded in different models of the auditory system. We can also use it to illustrate acoustically the effects of hearing loss.

Electrophysiological Properties of Octopus Neurons of the Cat Cochlear Nucleus: an In Vitro Study

Electrophysiological studies from mice in vitro have suggested that octopus cells of the mammalian ventral cochlear nucleus (VCN) are anatomically and biophysically specialized for detecting the coincident firing of a population of auditory nerve fibers. Recordings from cats in vivo have shown that octopus cells fire rapidly and with exceptional temporal precision as they convey the timing of that coincidence to higher auditory centers. The current study addresses the question whether the biophysical properties of octopus cells that have until now been examined only in mice, are shared by octopus cells in cats. Whole-cell patch-clamp recordings confirm that octopus cells in brain slices from kittens share the anatomical and biophysical features of octopus cells in mice. As in mice, octopus cells in kittens have large cell bodies and thick dendrites that extend in one direction. Voltage changes produced by depolarizing and hyperpolarizing current injection were small and rapid. Input resistances and membrane time constants in octopus cells of 16-day-old kittens were 15.8 +/- 1.5 MOmega (n = 16) and 1.28 +/- 0.3 ms (n = 16), respectively. Octopus cells fired only a single action potential at the onset of a depolarizing current pulse; suprathreshold stimuli were greater than 1.8 nA. A tetrodotoxin (TTX)-sensitive sodium conductance (gNa) was responsible for the generation of the action potentials. Octopus cells displayed outward rectification that lasted for the duration of the depolarizing pulses. Hyperpolarizations produced by the injection of current exhibited a depolarizing sag of the membrane potential toward the resting value. A 4-aminopyridine (4-AP) and alpha-dendrotoxin (alpha-DTX)-sensitive, low-voltage-activated potassium conductance (gKL) and a ZD7288-sensitive, mixed-cation conductance (gh) were partially activated at rest, giving the octopus cells low input resistances and, as a consequence, brief time constants. In 7-day-old kittens, action potentials were taller and broader, input resistances higher, and both inward and outward rectification was weaker than in 16-day-old kittens. Also as in mice, stellate cells of the VCN fired trains of action potentials with constant interspike intervals when they were depolarized (n = 10) and bushy cells of the VCN fired only a single action potential at the onset of depolarizations (n = 6). In conclusion, the similarity of octopus cells in mice and kittens suggests that the anatomical and biophysical specializations that allow octopus cells to detect and convey synchronous firing among auditory nerve fibers are common to all mammals.

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.

Threshold and Beyond: Modeling The Intensity Dependence of Auditory Responses

In many studies of auditory-evoked responses to low-intensity sounds, the response amplitude appears to increase roughly linearly with the sound level in decibels (dB), corresponding to a logarithmic intensity dependence. But the auditory system is assumed to be linear in the low-intensity limit. The goal of this study was to resolve the seeming contradiction. Based on assumptions about the rate-intensity functions of single auditory-nerve fibers and the pattern of cochlear excitation caused by a tone, a model for the gross response of the population of auditory nerve fibers was developed. In accordance with signal detection theory, the model denies the existence of a threshold. This implies that regarding the detection of a significant stimulus-related effect, a reduction in sound intensity can always be compensated for by increasing the measurement time, at least in theory. The model suggests that the gross response is proportional to intensity when the latter is low (range I), and a linear function of sound level at higher intensities (range III). For intensities in between, it is concluded that noisy experimental data may provide seemingly irrefutable evidence of a linear dependence on sound pressure (range II). In view of the small response amplitudes that are to be expected for intensity range I, direct observation of the predicted proportionality with intensity will generally be a challenging task for an experimenter. Although the model was developed for the auditory nerve, the basic conclusions are probably valid for higher levels of the auditory system, too, and might help to improve models for loudness at threshold.

Analytic treatment of the compound action potential: Estimating the summed post-stimulus time histogram and unit response

The convolution of an equation representing a summed post-stimulus time histogram computed across auditory nerve fibers [P(t)] with an equation representing a single-unit wave form [U(t)], resulted in an analytic expression for the compound action potential (CAP). The solution was fit to CAPs recorded to low and high frequency stimuli at various signal levels. The correlation between the CAP and the analytic expression was generally greater than 0.90. At high levels the width of P(t) was broader for low frequency stimuli than for high frequency signals, but delays were comparable. This indicates that at high signal levels there is an overlap in the population of auditory nerve fibers contributing to the CAP for both low and high frequency stimuli but low frequencies include contributions from more apical regions. At low signal levels the width of P(t) decreased for most frequencies and delays increased. The frequency of oscillation of U(t) was largest for high frequency stimuli and decreased for low frequency stimuli. The decay of U(t) was largest at 8 kHz and smallest at 1 kHz. These results indicate that the hair cell or neural mechanisms involved in the generation of action potentials may differ along the cochlear partition.

Response of the auditory nerve to sinusoidal electrical stimulation: effects of high-rate pulse trains

Electrical stimulation of the auditory nerve produces highly synchronized responses. As a consequence, electrical stimulation may result in a narrow dynamic range of hearing and poor temporal representation of an input signal. The electrically evoked compound action potential (ECAP) is an electrophysiologic response used for neural assessment in individuals with auditory prostheses. Because the ECAP arises from the activity of a population of auditory nerve fibers, within- and across-fiber synchrony should be evident in the responses. Due to its clinical relevance and reflection of neural response properties, the ECAP is used in the present study to examine changes in neural synchrony. Empirical and modeled single-fiber data indicate that stimulation with electrical pulses of a sufficiently high rate may induce stochastic neural response behaviors. This study investigated the effects of adding high-rate conditioning pulses (5000 pps) on the ECAP in response to 100 Hz electrical sinusoids. The results showed that high-rate conditioning pulses increased response amplitudes at low sinusoidal levels and decreased the amplitudes at high sinusoidal levels, indicating a decrease in the slope of the ECAP growth functions to sinusoidal stimuli. The results are consistent with a hypothesis that high-rate conditioning pulses increase single-fiber relative spread (RS) in response to sinusoidal stimuli, and the effect is highly dependent on the level of the high-rate conditioning pulses.

Auditory response to intracochlear electric stimuli following furosemide treatment

The influence of functional hair cells on electrical stimulation of the auditory nerve is an important issue as individuals with significant residual hearing are now cochlear implant candidates. Previous work has shown that chemical deafening during the course of acute experiments changes the auditory nerve’s responses to electrical stimulation [Third Quarterly Progress Report, NIH contract N01-DC-9-2106 (2000), Final Report, NIH Contract N01-DC-9-2106 (2002)]. This study extended that work by investigating the changes and subsequent recovery following furosemide injections which reversibly impair hair-cell function [Hear. Res. (1980) 79–89; Hear. Res. 14 (1984) 305–314, J. Physiol. 347 (1984) 685–696; Hear. Res. 71 (1993) 202–207]. Acoustic sensitivity of guinea pig subjects was repeatedly monitored with the click-evoked compound action potential. Responses to single biphasic electric pulses and biphasic electric pulse trains delivered by a monopolar intracochlear electrode were also repeatedly assessed using the electrically evoked compound action potential (ECAP). Our measures demonstrated a clear relationship between the state of hair-cell function and ECAP responses, as changes in the latter coincided with the loss or recovery of acoustic sensitivity. ECAP growth functions demonstrated increased slope and increased maximum (saturation) amplitude. Both trends were reversible and followed approximately the time course of post-furosemide hearing recovery. Additional changes were observed using electric pulse-train stimulation: (1) the magnitude of ECAP amplitude alternation (observed in response to successive stimulus pulses) increased, (2) the degree of ECAP adaptation (measured 80–100 ms after pulse-train onset) increased, and (3) the degree of refractoriness (measured by the ratio of ECAP amplitudes to the second and first pulses) tended to increase. All these trends are consistent with the hypothesis that functional hair cells desynchronize the population of auditory nerve fibers, thereby changing the electrically evoked responses. Viable hair cells may therefore provide positive effects on auditory response to electric stimuli delivered to implant patients with residual hearing, as they may enhance the random activity of the stimulated nerve.

Discharge properties of identified cochlear nucleus neurons and auditory nerve fibers in response to repetitive electrical stimulation of the auditory nerve.

Using the in vitro isolated whole brain preparation of the guinea pig maintained at 29 degrees C, we intracellularly recorded and stained cochlear nucleus (CN) neurons and auditory nerve (AN) fibers. Discharge properties of CN cells and AN axons were tested in response to 50-ms trains of electrical pulses delivered to the AN at rates ranging from 100 to 1000 pulses per second (pps). At low stimulation rates (200-300 pps), the discharges of AN fibers and a large proportion of principal cells (bushy, octopus, stellate) in the ventral cochlear nucleus (VCN) followed with high probability each pulse in the train, resulting in synchronization of discharges within large populations of AN fibers and CN cells. In contrast, at high stimulation rates (500 pps and higher), AN fibers and many VCN cells exhibited "primary-like", "onset" and some other discharge patterns resembling those produced by natural sound stimuli. Unlike cells in the VCN, principal cells (pyramidal, giant) of the dorsal CN did not follow the stimulating pulses even at low rates. Instead, they often showed "pauser" and "build-up" patterns of activity, characteristic for these cells in conditions of normal hearing. We hypothesize that, at low stimulation rates, the response behavior of AN fibers and VCN cells is different from the patterns of neuronal activity related to normal auditory processing, whereas high stimulation rates produce more physiologically meaningful discharge patterns. The observed differences in discharge properties of AN fibers and CN cells at different stimulation rates can contribute to significant advantages of high- versus low-rate electrical stimulation of the AN used for coding sounds in modern cochlear implants.

Potassium currents in octopus cells of the mammalian cochlear nucleus.

Octopus cells in the posteroventral cochlear nucleus (PVCN) of mammals are biophysically specialized to detect coincident firing in the population of auditory nerve fibers that provide their synaptic input and to convey its occurrence with temporal precision. The precision in the timing of action potentials depends on the low input resistance (approximately 6 MOmega) of octopus cells at the resting potential that makes voltage changes rapid (tau approximately 200 micros). It is the activation of voltage-dependent conductances that endows octopus cells with low input resistances and prevents repetitive firing in response to depolarization. These conductances have been examined under whole cell voltage clamp. The present study reveals the properties of two conductances that mediate currents whose reversal at or near the equilibrium potential for K(+) over a wide range of extracellular K(+) concentrations identifies them as K(+) currents. One rapidly inactivating conductance, g(KL), had a threshold of activation at -70 mV, rose steeply as a function of depolarization with half-maximal activation at -45 +/- 6 mV (mean +/- SD), and was fully activated at 0 mV. The low-threshold K(+) current (I(KL)) was largely blocked by alpha-dendrotoxin (alpha-DTX) and partially blocked by DTX-K and tityustoxin, indicating that this current was mediated through potassium channels of the Kv1 (also known as shaker or KCNA) family. The maximum low-threshold K(+) conductance (g(KL)) was large, 514 +/- 135 nS. Blocking I(KL) with alpha-DTX revealed a second K(+) current with a higher threshold (I(KH)) that was largely blocked by 20 mM tetraethylammonium (TEA). The more slowly inactivating conductance, g(KH), had a threshold for activation at -40 mV, reached half-maximal activation at -16 +/- 5 mV, and was fully activated at +30 mV. The maximum high-threshold conductance, g(KH), was on average 116 +/- 27 nS. The present experiments show that it is not the biophysical and pharmacological properties but the magnitude of the K(+) conductances that make octopus cells unusual. At the resting potential, -62 mV, g(KL) contributes approximately 42 nS to the resting conductance and mediates a resting K(+) current of 1 nA. The resting outward K(+) current is balanced by an inward current through the hyperpolarization-activated conductance, g(h), that has been described previously.