Acoustic Hearing After Murine Cochlear Implantation: Effects of Trauma and Implant Type.

OBJECTIVES: To model the contribution of implant material and insertion trauma on loss of acoustic hearing after cochlear implantation in an appropriate animal model. METHODS: Sixty-five C57Bl/6J mice underwent unilateral implantation with implant grade materials: 2 implant grade silicones and a third uncoated platinum wire. A sham surgery group was included as a control. Serial auditory brainstem response (ABR) thresholds and distortion product otoacoustic emissions (DPOAEs) were used to discern effects on hearing over 22 weeks. Histologic measurements of damage to the organ of Corti and spiral ganglion were correlated with degree of hearing loss and material type. RESULTS: Organ of Corti damage correlated with rate of hearing loss soon after implantation (0-2 weeks) but not subsequently (2-22 weeks). Organ of Corti damage did not depend on implant type and was present even in sham surgery subjects when hearing was severely damaged. Spiral ganglia appeared unaffected. There was no evidence of an inflammatory or toxic effect of the materials beyond the site of implant insertion. CONCLUSIONS: Hearing loss and cochlear damage appear to be related to insertion trauma, with minimal effect on delayed hearing loss caused by different materials. In the C57Bl/6J mouse model, the sensory epithelium appears to be the location of damage after cochlear implantation.

Mouse cochleostomy: a minimally invasive dorsal approach for modeling cochlear implantation.

OBJECTIVES/HYPOTHESIS: The murine model has been used extensively to model and study human deafness. Technical difficulty in the surgical approach due to the small size of the tympanic bulla and a robust stapedial artery has limited its application for studies of cochlear implantation and electrical stimulation. We describe a minimally traumatic, stapedial artery-sparing approach to the round window that may be used to access the mouse cochlea for acute or chronic studies of implantation and stimulation. STUDY DESIGN: Animal model. METHODS: Fifteen C57BL6J mice were used to validate this approach. Auditory brainstem response threshold and distortion product otoacoustic emissions were obtained preoperatively and 2 weeks postoperatively to determine hearing preservation results. RESULTS: The approach provided excellent exposure for round-window implantation. Substantial hearing was preserved in all animals with a mean postimplantation auditory brainstem response threshold increase of 27.8 dB. Otoacoustic emissions were lost in subjects with the largest threshold shifts. CONCLUSIONS: Residual hearing after cochlear implantation is a determinant of success both with standard cochlear implant electrodes and with electrodes designed to optimize hearing preservation. Here, we have preserved usable hearing after implantation of C57BL6J mice, an endogenous model of human presbycusia. The murine model may become a powerful tool to assay the effects of cochlear intervention in different genetic backgrounds.

Neural masking by sub-threshold electric stimuli: animal and computer model results.

Electric stimuli can prosthetically excite auditory nerve fibers to partially restore sensory function to individuals impaired by profound or severe hearing loss. While basic response properties of electrically stimulated auditory nerve fibers (ANF) are known, responses to complex, time-changing stimuli used clinically are inadequately understood. We report that forward-masker pulse trains can enhance and reduce ANF responsiveness to subsequent stimuli and the novel observation that sub-threshold (nonspike-evoking) electric trains can reduce responsiveness to subsequent pulse-train stimuli. The effect is observed in the responses of cat ANFs and shown by a computational biophysical ANF model that simulates rate adaptation through integration of external potassium cation (K) channels. Both low-threshold (i.e., Klt) and high-threshold (Kht) channels were simulated at each node of Ranvier. Model versions without Klt channels did not produce the sub-threshold effect. These results suggest that some such accumulation mechanism, along with Klt channels, may underlie sub-threshold masking observed in cat ANF responses. As multichannel auditory prostheses typically present sub-threshold stimuli to various ANF subsets, there is clear relevance of these findings to clinical situations.

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 (F(0) 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 F(0) 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 F(0) 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 F(0) measures were sensitive to adaptation-related changes over different spike-rate ranges, there is value in assessing both measures.

Auditory nerve fiber responses to combined acoustic and electric stimulation.

Persons with a prosthesis implanted in a cochlea with residual acoustic sensitivity can, in some cases, achieve better speech perception with "hybrid" stimulation than with either acoustic or electric stimulation presented alone. Such improvements may involve "across auditory-nerve fiber" processes within central nuclei of the auditory system and within-fiber interactions at the level of the auditory nerve. Our study explored acoustic-electric interactions within feline auditory nerve fibers (ANFs) so as to address two goals. First, we sought to better understand recent results that showed non-monotonic recovery of the electrically evoked compound action potential (ECAP) following acoustic masking (Nourski et al. 2007, Hear. Res. 232:87-103). We hypothesized that post-masking changes in ANF temporal properties and responsiveness (spike rate) accounted for the ECAP results. We also sought to describe, more broadly, the changes in ANF responses that result from prior acoustic stimulation. Five response properties-spike rate, latency, jitter, spike amplitude, and spontaneous activity-were examined. Post-masking reductions in spike rate, within-fiber jitter and across-fiber variance in latency were found, with the changes in temporal response properties limited to ANFs with high spontaneous rates. Thus, our results suggest how non-monotonic ECAP recovery occurs for ears with spontaneous activity, but cannot account for that pattern of recovery when there is no spontaneous activity, including the results from the presumably deafened ears used in the Nourski et al. (2007) study. Finally, during simultaneous (electric+acoustic) stimulation, the degree of electrically driven spike activity had a strong influence on spike rate, but did not affect spike jitter, which apparently was determined by the acoustic noise stimulus or spontaneous activity.

Effects of temporal properties on compound action potentials in response to amplitude-modulated electric pulse trains in guinea pigs.

The electrically evoked compound action potential (ECAP) of the auditory nerve in response to amplitude-modulated pulse trains varies over time, but the response amplitudes are not linearly proportional to the level of stimulus pulses. At least two mechanisms could contribute to the deviations of the ECAP response pattern from that of the stimulus envelope. The first mechanism is time-invariant or stationary that reflects the non-linear growth of response amplitude with changes in stimulus level that is evident in the response to single pulses. This can be considered a time-invariant or stationary effect. The second mechanism is time-variant or non-stationary and reflects neural refractoriness and adaptation. The purpose of this study was to characterize the auditory nerve responses to amplitude-modulated pulse trains and also to evaluate the extent to which the stationary and non-stationary effects may contribute to those responses. ECAP amplitudes were predicted from single-pulse growth functions of the auditory nerve to account for time-invariant effects. Linear regression was performed on the measured vs. predicted ECAP amplitudes to quantify the discrepancies between the two datasets, thereby separating the influence of non-linear growth from time-varying effects on ECAP amplitudes. The results demonstrated a bandpass function of the modulated response amplitudes, with a low-cutoff modulation frequency at 300Hz and a high-cutoff modulation frequency at 800Hz, depending on the carrier pulse rate. The relative contribution of the temporal effects on ECAP amplitudes is greatest at low stimulus levels and low modulation depths.

Changes across time in the temporal responses of auditory nerve fibers stimulated by electric pulse trains.

Most auditory prostheses use modulated electric pulse trains to excite the auditory nerve. There are, however, scant data regarding the effects of pulse trains on auditory nerve fiber (ANF) responses across the duration of such stimuli. We examined how temporal ANF properties changed with level and pulse rate across 300-ms pulse trains. Four measures were examined: (1) first-spike latency, (2) interspike interval (ISI), (3) vector strength (VS), and (4) Fano factor (FF, an index of the temporal variability of responsiveness). Data were obtained using 250-, 1,000-, and 5,000-pulse/s stimuli. First-spike latency decreased with increasing spike rate, with relatively small decrements observed for 5,000-pulse/s trains, presumably reflecting integration. ISIs to low-rate (250 pulse/s) trains were strongly locked to the stimuli, whereas ISIs evoked with 5,000-pulse/s trains were dominated by refractory and adaptation effects. Across time, VS decreased for low-rate trains but not for 5,000-pulse/s stimuli. At relatively high spike rates (>200 spike/s), VS values for 5,000-pulse/s trains were lower than those obtained with 250-pulse/s stimuli (even after accounting for the smaller periods of the 5,000-pulse/s stimuli), indicating a desynchronizing effect of high-rate stimuli. FF measures also indicated a desynchronizing effect of high-rate trains. Across a wide range of response rates, FF underwent relatively fast increases (i.e., within 100 ms) for 5,000-pulse/s stimuli. With a few exceptions, ISI, VS, and FF measures approached asymptotic values within the 300-ms duration of the low- and high-rate trains. These findings may have implications for designs of cochlear implant stimulus protocols, understanding electrically evoked compound action potentials, and interpretation of neural measures obtained at central nuclei, which depend on understanding the output of the auditory nerve.

Electrically evoked auditory steady-state responses in a guinea pig model: latency estimates and effects of stimulus parameters.

Cochlear implant speech processors typically extract envelope information of speech signals for presentation to the auditory nerve as modulated trains of electric pulses. Recent studies showed the feasibility of recording, at the scalp, the electrically evoked auditory steady-state response using amplitude-modulated electric stimuli. Sinusoidally amplitude-modulated electric stimuli were used to elicit such responses from guinea pigs in order to characterize this response. Response latencies were derived to provide insight regarding neural generator sites. Two distinct sites, one cortical and another more peripheral, were indicated by latency estimates of 22 and 2 ms, respectively, with the former evoked by lower (13-49 Hz) and the latter by higher (55-320 Hz) modulation frequencies. Furthermore, response amplitudes declined with increasing carrier frequency, exhibited a compressive growth with increasing modulation depths, and were sensitive to modulation depths to as low as 5%.

Acoustic-electric interactions in the guinea pig auditory nerve: simultaneous and forward masking of the electrically evoked compound action potential.

The study investigated the time course of the effects of acoustic and electric stimulation on the electrically evoked compound action potential (ECAP). Adult guinea pigs were used in acute experimental sessions. Bursts of acoustic noise and high-rate (5000 pulses/s) electric pulse trains were used as maskers. Biphasic electric pulses were used as probes. ECAPs were recorded from the auditory nerve trunk. Simultaneous masking of the ECAP with acoustic noise featured an onset effect and a decrease in the amount of masking to a steady state. It was characterized by a two-component exponential function. The amount of masking increased with masker level and decreased with probe level. Post-stimulatory ECAP recovery often featured a non-monotonic time course, described by a three-component exponent. Electric maskers produced similar post-stimulatory effects in hearing and acutely deafened subjects. Acoustic stimulation affects the ECAP in a level- and time-dependent manner. Simultaneous masking follows a time course comparable to that of adaptation to an acoustic stimulus. Refractoriness, spontaneous activity, and adaptation are suggested to play a role in ECAP recovery. Post-stimulatory changes in synchrony, possibly due to recovery of spontaneous activity and an additional hair-cell independent mechanism, are hypothesized to contribute to the observed non-monotonicity of recovery.

Prosurvival and proapoptotic intracellular signaling in rat spiral ganglion neurons in vivo after the loss of hair cells.

Neurons depend on afferent input for survival. Rats were given daily kanamycin injections from P8 to P16 to destroy hair cells, the sole afferent input to spiral ganglion neurons (SGNs). Most SGNs die over an approximately 14-week period after deafferentation. During this period, the SGN population is heterogeneous. At any given time, some SGNs exhibit apoptotic markers--TUNEL and cytochrome c loss--whereas others appear nonapoptotic. We asked whether differences among SGNs in intracellular signaling relevant to apoptotic regulation could account for this heterogeneity. cAMP response element binding protein (CREB) phosphorylation, which reflects neurotrophic signaling, is reduced in many SGNs at P16, P23, and P32, when SGNs begin to die. In particular, nearly all apoptotic SGNs exhibit reduced phospho-CREB, implying that apoptosis is due to insufficient neurotrophic support. However, >32% of SGNs maintain high phospho-CREB levels, implying access to neurotrophic support. By P60, when approximately 50% of the SGNs have died, phospho-CREB levels in surviving neurons are not reduced, and SGN death is no longer correlated with reduced phospho-CREB. Activity in the proapoptotic Jun N-terminal kinase (JNK)-Jun signaling pathway is elevated in SGNs during the cell death period. This too is heterogeneous: <42% of the SGNs exhibited high phospho-Jun levels, but nearly all SGNs undergoing apoptosis exhibited elevated phospho-Jun. Thus, heterogeneity among SGNs in prosurvival and proapoptotic signaling is correlated with apoptosis. SGN death following deafferentation has an early phase in which apoptosis is correlated with reduced phospho-CREB and a later phase in which it is not. Proapoptotic JNK-Jun signaling is tightly correlated with SGN apoptosis.

Changes across time in spike rate and spike amplitude of auditory nerve fibers stimulated by electric pulse trains.

We undertook a systematic evaluation of spike rates and spike amplitudes of auditory nerve fiber (ANF) responses to trains of electric current pulses. Measures were obtained from acutely deafened cats to examine time-related changes free from the effects of hair-cell and synaptic adaptation. Such data relate to adaptation that likely occurs in ANFs of cochlear-implant users. A major goal was to determine and compare rate adaptation observed at different pulse rates (primarily 250, 1000, and 5000 pulse/s) and describe them using decaying exponential models similar to those used in acoustic studies. Rate-vs.-time functions were best described by two-exponent models and produced time constants similar to (although slightly greater than) the "rapid" and "short-term" components described in acoustic studies. There was little dependence of these time constants on onset spike rate, but pulse-rate effects were noted. Spike amplitude changes followed a time course different from that of rate adaptation consistent with a process related to ANF interspike intervals. The fact that two time constants governed rate adaptation in electrically stimulated and deafened fibers suggests that future computational models of adaptation should not only include hair cell and synapse components, but also components determined by fiber membrane characteristics.

Binaural interactions of electrically and acoustically evoked responses recorded from the inferior colliculus of guinea pigs.

Binaural interactions within the inferior colliculus (IC) elicited by electric and acoustic stimuli were investigated in this study. Using a guinea pig model, binaural acoustic stimuli were presented with different time delays, as were combinations of binaural electric and acoustic stimuli. Averaged evoked potentials were measured using electrodes inserted into the central nucleus of the IC to obtain the binaural interaction component (BIC), computed by subtracting the sum of the two monaural responses from the binaural response. The BICs to acoustic-acoustic stimulation and electric-acoustic stimulation were found to be similar. The BIC amplitude increased with stimulus intensity, but the shapes of the delay functions were similar across the levels tested. The gross-potential data are thus consistent with the thesis that the central auditory system processes binaural electric and acoustic stimuli in a similar manner. These results suggest that the binaural auditory system can process combinations of electric and acoustic stimulation presented across ears and that evoked gross potentials may be used to measure such interaction.

Selective cochlear degeneration in mice lacking the F-box protein, Fbx2, a glycoprotein-specific ubiquitin ligase subunit.

Little is known about the role of protein quality control in the inner ear. We now report selective cochlear degeneration in mice deficient in Fbx2, a ubiquitin ligase F-box protein with specificity for high-mannose glycoproteins (Yoshida et al., 2002). Originally described as a brain-enriched protein (Erhardt et al., 1998), Fbx2 is also highly expressed in the organ of Corti, in which it has been called organ of Corti protein 1 (Thalmann et al., 1997). Mice with targeted deletion of Fbxo2 develop age-related hearing loss beginning at 2 months. Cellular degeneration begins in the epithelial support cells of the organ of Corti and is accompanied by changes in cellular membrane integrity and early increases in connexin 26, a cochlear gap junction protein previously shown to interact with Fbx2 (Henzl et al., 2004). Progressive degeneration includes hair cells and the spiral ganglion, but the brain itself is spared despite widespread CNS expression of Fbx2. Cochlear Fbx2 binds Skp1, the common binding partner for F-box proteins, and is an unusually abundant inner ear protein. Whereas cochlear Skp1 levels fall in parallel with the loss of Fbx2, other components of the canonical SCF (Skp1, Cullin1, F-box, Rbx1) ubiquitin ligase complex remain unchanged and show little if any complex formation with Fbx2/Skp1, suggesting that cochlear Fbx2 and Skp1 form a novel, heterodimeric complex. Our findings demonstrate that components of protein quality control are essential for inner ear homeostasis and implicate Fbx2 and Skp1 as potential genetic modifiers in age-related hearing loss.

Electrically evoked auditory steady-state responses in Guinea pigs.

Most cochlear implant systems available today provide the user with information about the envelope of the speech signal. The goal of this study was to explore the feasibility of recording electrically evoked auditory steady-state response (ESSR) and in particular to evaluate the degree to which the response recorded using electrical stimulation could be separated from stimulus artifact. Sinusoidally amplitude-modulated electrical stimuli with alternating polarities were used to elicit the response in adult guinea pigs. Separation of the stimulus artifact from evoked neural responses was achieved by summing alternating polarity responses or by using spectral analysis techniques. The recorded response exhibited physiological response properties including a pattern of nonlinear growth and their abolishment following euthanasia or administration of tetrodotoxin. These findings demonstrate that the ESSR is a response generated by the auditory system and can be separated from electrical stimulus artifact. As it is evoked by a stimulus that shares important features of cochlear implant stimulation, this evoked potential may be useful in either clinical or basic research efforts.

Electrical excitation of the acoustically sensitive auditory nerve: single-fiber responses to electric pulse trains.

Nearly all studies on auditory-nerve responses to electric stimuli have been conducted using chemically deafened animals so as to more realistically model the implanted human ear that has typically been profoundly deaf. However, clinical criteria for implantation have recently been relaxed. Ears with "residual" acoustic sensitivity are now being implanted, calling for the systematic evaluation of auditory-nerve responses to electric stimuli as well as combined electric and acoustic stimuli in acoustically sensitive ears. This article presents a systematic investigation of single-fiber responses to electric stimuli in acoustically sensitive ears. Responses to 250 pulse/s electric pulse trains were collected from 18 cats. Properties such as threshold, dynamic range, and jitter were found to differ from those of deaf ears. Other types of fiber activity observed in acoustically sensitive ears (i.e., spontaneous activity and electrophonic responses) were found to alter the temporal coding of electric stimuli. The electrophonic response, which was shown to greatly change the information encoded by spike intervals, also exhibited fast adaptation relative to that observed in the "direct" response to electric stimuli. More complex responses, such as "buildup" (increased responsiveness to successive pulses) and "bursting" (alternating periods of responsiveness and unresponsiveness) were observed. Our findings suggest that bursting is a response unique to sustained electric stimulation in ears with functional hair cells.

Effects of acoustic noise on the auditory nerve compound action potentials evoked by electric pulse trains.

This study investigated the effects of acoustic noise on the auditory nerve compound action potentials in response to electric pulse trains. Subjects were adult guinea pigs, implanted with a minimally invasive electrode to preserve acoustic sensitivity. Electrically evoked compound action potentials (ECAP) were recorded from the auditory nerve trunk in response to electric pulse trains both during and after the presentation of acoustic white noise. Simultaneously presented acoustic noise produced a decrease in ECAP amplitude. The effect of the acoustic masker on the electric probe was greatest at the onset of the acoustic stimulus and it was followed by a partial recovery of the ECAP amplitude. Following cessation of the acoustic noise, ECAP amplitude recovered over a period of approximately 100-200 ms. The effects of the acoustic noise were more prominent at lower electric pulse rates (interpulse intervals of 3 ms and higher). At higher pulse rates, the ECAP adaptation to the electric pulse train alone was larger and the acoustic noise, when presented, produced little additional effect. The observed effects of noise on ECAP were the greatest at high electric stimulus levels and, for a particular electric stimulus level, at high acoustic noise levels.

Feasibility of using silicon-substrate recording electrodes within the auditory nerve.

The use of penetrating, silicon-substrate (i.e., "thin-film") probes within a cross-section of a sensory nerve offers the possibility of assessing the pattern and extent of fiber excitation within the nerve. We used acute cat preparations to assess the feasibility of this technique for recordings within the auditory nerve trunk. Four probe configurations fabricated by the University of Michigan Center for Neural Communication Technology were evaluated using acoustic and electric stimuli. Our main concerns were the nature of the recorded potentials and the degree of spatial selectivity provided by these probes. We also made some basic assessments of electrode-tissue compatibility. The recorded potentials were characterized as field potentials with varying degrees of spatial selectivity. In some cases, responses to pure tones demonstrated good spatial selectivity, with unique responses recorded by different electrode sites. When electrode sites were positioned at different longitudinal positions along the nerve trunk, responses with latencies characteristic of each site were recorded. These results indicate that thin-film electrodes are capable of providing spatially specific response information from sensory nerves. However, in the case of feline auditory nerves, place-specific responses were inconsistently observed, making it difficult to use this technique to obtain detailed cochleotopic maps of neural excitation. More productive results may be possible from other peripheral nerves with less complex spatial arrangements of fibers.

Intracochlear and extracochlear ECAPs suggest antidromic action potentials.

With experimental animals, the electrically evoked compound action potential (ECAP) can be recorded from multiple sites (e.g., round window, intracranial and intracochlear sites). However, human ECAPs are typically recorded from intracochlear electrodes of the implanted array. To bridge this difference, we obtained ECAPs from cats using both intracochlear and nerve-trunk recording sites. We also sought to determine how recording the site influences the acquired evoked potential and how those differences may provide insight into basic excitation properties. In the main experiment, ECAPs were recorded from four acutely deafened cats after implanting a Nucleus-style banded electrode array. Potentials were recorded from an electrode positioned on the nerve trunk and an intracochlear electrode. We manipulated stimulus level, electrode configuration (monopolar vs bipolar) and stimulus polarity, variables that influence the site of excitation. Intracochlear ECAPs were found to be an order of magnitude greater than those obtained with the nerve-trunk electrode. Also, compared with the nerve-trunk potentials, the intracochlear ECAPs more closely resembled those obtained from humans in that latencies were shorter and the waveform morphology was typically biphasic (a negative peak followed by a positive peak). With anodic monophasic stimuli, the ECAP had a unique positive-to-negative morphology which we attributed to antidromic action potentials resulting from a relatively central site of excitation. We also collected intracochlear ECAPs from twenty Nucleus 24 implant users. Compared with the feline ECAPs, the human potentials had smaller amplitudes and longer latencies. It is not clear what underlies these differences, although several factors are considered.

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.