The derived-band envelope following response and its sensitivity to sensorineural hearing deficits.

The envelope following response (EFR) has been proposed as a non-invasive marker of synaptopathy in animal models. However, its amplitude is affected by the spread of basilar-membrane excitation and other coexisting sensorineural hearing deficits. This study aims to (i) improve frequency specificity of the EFR by introducing a derived-band EFR (DBEFR) technique and (ii) investigate the effect of lifetime noise exposure, age and outer-hair-cell (OHC) damage on DBEFR magnitudes. Additionally, we adopt a modelling approach to validate the frequency-specificity of the DBEFR and test how different aspects of sensorineural hearing loss affect peripheral generators. The combined analysis of simulations and experimental data proposes that the DBEFRs extracted from the [2-6]-kHz frequency band is a sensitive and frequency-specific measure of synaptopathy in humans. Individual variability in DBEFR magnitudes among listeners with normal audiograms was explained by their self-reported amount of experienced lifetime noise-exposure and corresponded to amplitude variability predicted by synaptopathy. Older listeners consistently had reduced DBEFR magnitudes in comparison to young normal-hearing listeners, in correspondence to how age-induced synaptopathy affects EFRs and compromises temporal envelope encoding. To a lesser degree, OHC damage was also seen to affect the DBEFR magnitude, hence the DBEFR metric should ideally be combined with a sensitive marker of OHC damage to offer a differential diagnosis of synaptopathy in listeners with impaired audiograms.

Measuring temporal response properties of auditory nerve fibers in cochlear implant recipients.

Auditory nerve fibers' (ANFs) refractoriness and facilitation can be quantified in electrically evoked compound action potentials (ECAPs) recorded via neural response telemetry (NRT). Although facilitation has been observed in animals and human cochlear implant (CI) recipients, no study has modeled this in human CI users until now. In this study, recovery and facilitation effects at different masker and probe levels for three test electrodes (E6, E12 and E18) in 11 CI subjects were recorded. The ECAP recovery and facilitation were modeled by exponential functions and the same function used for +10 CL masker offset condition can be applied to all other masker offsets measurements. Goodness of fit was evaluated for the exponential functions. A significant effect of probe level was observed on a recovery time constant which highlights the importance of recording the recovery function at the maximum acceptable stimulus level. Facilitation time constant and amplitude showed no dependency on the probe level. However, facilitation was stronger for masker level at or around the threshold of the ECAP (T-ECAP). There was a positive correlation between facilitation magnitude and amplitude growth function (AGF) slope, which indicates that CI subjects with better peripheral neural survival have stronger facilitation.

Middle Latency Responses to Optimized Chirps in Adult Cochlear Implant Users.

BACKGROUND: Cochlear implant (CI) outcomes can be assessed using objective measures that reflect the integrity of the auditory pathway. One such measure is the middle latency response (MLR), which can provide valuable information for clinicians. PURPOSE: Traditional stimuli for evoking MLRs, that is, clicks or tone bursts, do not stimulate all parts of the cochlea simultaneously, whereas chirp stimuli compensate for the cochlear neural delay and, therefore, produce more synchronous responses from the different neural elements of the cochlea. The purpose of the present study was to determine whether chirp stimuli can elicit reliable MLRs in CI users and whether those responses correlate with clinical outcomes and with deprivation-related factors. RESEARCH DESIGN: We presented 2,000 free-field optimized chirp stimuli to CI and control participants while their electroencephalography (EEG) was being recorded. STUDY SAMPLE: Twenty-four adult CI users and 24 matched normal-hearing (NH) individuals (age range from 18 to 63 years) participated in this study. DATA COLLECTIONS AND ANALYSIS: The EEG was recorded from 64 active electrodes placed on the scalp. EEG signals were processed using EEGLAB and ERPLAB toolboxes. We characterized the latencies and amplitudes of the different MLR components in both groups. RESULTS: Chirp stimuli reliably evoked qualitatively similar MLRs across all NH and CI participants with a couple of differences observed between the NH and CI group. Among the different MLR components, the Na latency was significantly shorter for the CI group. A significant amplitude difference was also found between groups for the Pa-Nb complex, with higher amplitudes observed in the NH group. Finally, there were no significant correlations between MLR latencies (or amplitudes) and clinical outcomes or deprivation-related measures. CONCLUSIONS: Free-field-presented optimized chirp stimuli were shown to evoke measurable and reliable MLRs in CI users. In this experiment, the MLR morphology in CI users was similar to those observed in NH participants. Even though we did not replicate here a significant relationship between MLR and speech perception measures, we were able to successfully collect acoustically evoked MLRs, which could constitute an important supplemental measure to the standard behavioral tests presently being used in postoperative clinical evaluation settings.

Effects of selective auditory-nerve damage on the behavioral audiogram and temporal integration in the budgerigar.

Auditory-nerve fibers are lost steadily with age and as a possible consequence of noise-induced glutamate excitotoxicity. Auditory-nerve loss in the absence of other cochlear pathologies is thought to be undetectable with a pure-tone audiogram while degrading real-world speech perception (hidden hearing loss). Perceptual deficits remain unclear, however, due in part to the limited behavioral capacity of existing rodent models to discriminate complex sounds. The budgerigar is an avian vocal learner with human-like behavioral sensitivity to many simple and complex sounds and the capacity to mimic speech. Previous studies in this species show that intracochlear kainic-acid infusion reduces wave 1 of the auditory brainstem response by 40-70%, consistent with substantial excitotoxic auditory-nerve damage. The present study used operant-conditioning procedures in trained budgerigars to quantify kainic-acid effects on tone detection across frequency (0.25-8 kHz; the audiogram) and as a function of duration (20-160 ms; temporal integration). Tone thresholds in control animals were lowest from 1 to 4 kHz and decreased with increasing duration as in previous studies of the budgerigar. Behavioral results in kainic-acid-exposed animals were as sensitive as in controls, suggesting preservation of the audiogram and temporal integration despite auditory-nerve loss associated with up to 70% wave 1 reduction. Distortion-product otoacoustic emissions were also preserved in kainic-acid exposed animals, consistent with normal hair-cell function. These results highlight considerable perceptual resistance of tone-detection performance with selective auditory-nerve loss. Future behavioral studies in budgerigars with auditory-nerve damage can use complex speech-like stimuli to help clarify aspects of auditory perception impacted by this common cochlear pathology.

Improved interaural timing of acoustic nerve stimulation affects sound localization in single-sided deaf cochlear implant users.

The main impairment associated with single-sided deafness (SSD) is the loss of binaural hearing. Currently, the most effective treatment to compensate for this deficit is to supply patients suffering from SSD with a cochlear implant (CI) in the deaf ear. With this approach binaural hearing abilities can be restored to a certain extent, which is expressed in an improvement in such patients with regard to sound source localization and speech comprehension in noise after receipt of a CI. However, binaural performance of these listeners does not reach the level of normal-hearing listeners. One of the reasons for this might be that the electrical stimulation via CI and the physiological stimulation via the intact ear are not synchronized: the CI transmits the information to the auditory nerve with different timing than does the intact inner ear. As a result, there is a timing mismatch of the information transfer between the left and the right side, which may account for the limited binaural performance. The effective mismatch in timing depends on the CI system because of different stimulation strategies implemented in devices from different manufacturers. For the particular CI device used in this study (MED-EL Mi1000/Mi1200) electrical stimulation led to faster activation of the auditory nerve than natural for a wide frequency range. In particular, electrical stimulation was about 1 to up to 2 ms ahead of time for frequencies above 1.5 kHz. Hence, it was hypothesized that information transfer between the left and the right ear can be tuned by delaying the CI signal. The goal of the present study was to investigate whether such a delay in the CI signal affects binaural performance of CI users with SSD. For this purpose, sound source localization and speech perception in noise were tested in a sample of 12 CI users with SSD (mean age 51 ±â€¯12 years). The tests were performed for four different delay times of the CI signal applied spontaneously (0.5, 1, 2 and 4 ms) and for the base line condition "no delay" in the CI signal (i.e. everyday use). It was found that delaying the signal had a significant impact on sound source localization. Speech perception in noise was affected, but less pronounced than was sound localization. Regarding sound source localization, a signal delay of 1 ms applied to this particular CI device produced the best performance in our patients. It is concluded that improving the synchronisation between the CI-transferred signal and the naturally transferred signal could increase binaural hearing performance in CI users with SSD.

Postoperative Electrocochleography from Hybrid Cochlear Implant users: An Alternative Analysis Procedure.

OBJECTIVE: Shorter electrode arrays and soft surgical techniques allow for preservation of acoustic hearing in many cochlear implant (CI) users. Recently, we developed a method of using the Neural Response Telemetry (NRT) system built in Custom Sound EP clinical software to record acoustically evoked electrocochleography (ECoG) responses from an intracochlear electrode in Nucleus Hybrid CI users (Abbas et al., 2017). We recorded responses dominated by the hair cells (cochlear microphonic, CM/DIF) and the auditory nerve (auditory nerve neurophonic, ANN/SUM). Unfortunately, the recording procedure was time consuming, limiting potential clinical applications. This report describes a modified method to record the ECoG response more efficiently. We refer to this modified technique as the "short window" method, while our previous technique (Abbas et al., 2017) is referred as the "long window" method. In this report, our goal was to 1) evaluate the feasibility of the short window method to record the CM/DIF and ANN/SUM responses, 2) characterize the reliability and sensitivity of the measures recorded using the short window method, and 3) evaluate the relationship between the CM/DIF and ANN/SUM measures recorded using the modified method and audiometric thresholds. METHOD: Thirty-four postlingually deafened adult Hybrid CI users participated in this study. Acoustic tone bursts were presented at four frequencies (250, 500, 750, and 1000 Hz) at various stimulation levels via an insert earphone in both condensation and rarefaction polarities. Acoustically evoked ECoG responses were recorded from the most apical electrode in the intracochlear array. These two responses were subtracted to emphasize the CM/DIF responses and added to emphasize the ANN/SUM responses. Response thresholds were determined based on visual inspection of time waveforms, and trough-to-peak analysis technique was used to quantify response amplitudes. Within-subject comparison of responses measured using both short and long window methods were obtained from seven subjects. We also assessed the reliability and sensitivity of the short window method by comparing repeated measures from 19 subjects at different times. Correlations between CM/DIF and ANN/SUM measures using the short window recording method and audiometric thresholds were also assessed. RESULTS: Regardless of the recording method, CM/DIF responses were larger than ANN/SUM responses. Responses obtained using the short window method were positively correlated to those obtained using the conventional long window method. Subjects who had stable acoustic hearing at two different time points had similar ECoG responses at those points, confirming high test-retest reliability of the short window method. Subjects who lost hearing between two different time points showed increases in ECoG thresholds, suggesting that physiologic ECoG responses are sensitive to audiometric changes. Correlations between CM/DIF and ANN/SUM thresholds and audiometric thresholds at all tested frequencies were significant. CONCLUSION: This study compares two different recording methods. Intracochlear ECoG measures recorded using the short window technique were efficient, reliable, and repeatable. We were able to collect more frequency specific data with the short window method, and observed similar results between the long window and short window methods. Correlations between physiological thresholds and audiometric thresholds were similar to those reported previously using the long window method (Abbas et al., 2017). This is an important finding because it demonstrates that clinically-available software can be used to measure frequency-specific ECoG responses with enhanced efficiency, increasing the odds that this technique might move from the laboratory into clinical practice.

Assessing auditory nerve condition by tone decay in deaf subjects with a cochlear implant.

The condition of the auditory nerve is a factor determining hearing performance of cochlear implant (CI) recipients. Abnormal loudness adaptation is associated with poor auditory nerve survival. We examined which stimulus conditions are suitable for tone decay measurements to differentiate between CI recipients with respect to their speech perception. Tone decay was defined here as occurring when the percept disappears before the stimulus stops. We measured the duration of the percept of a 60-s pulse train. Current levels ranged from below threshold up to maximum acceptable loudness, pulse rates from 250 to 5000 pulses/s, and duty cycles (percentages of time the burst of pulses is on) from 10% to 100%. Ten adult CI recipients were included: seven with good and three with poor speech perception. Largest differences among the subjects were found at 5000 pulses/s and 100% duty cycle. The well performing subjects had a continuous percept of the 60-s stimulus within 3 dB above threshold. Two poorly performing subjects showed abnormal loudness adaptation, that is, no continuous percept even at levels greater than 6 dB above threshold. We conclude that abnormal loudness adaptation can be detected via an electric tone decay test using a high pulse rate and 100% duty cycle.

Intraoperative Auditory System Monitoring.

A new electrophysiological system for intraoperative, continuous, near-real time monitoring of cochlear nerve function through acoustic stimulation in the ear canal and recording of the evoked dorsal cochlear nucleus potentials (DNAPs) by a specially designed DNAP electrode placed directly on the brainstem is described. The system is denominated "(cerebellopontine angle) CPA Master" and is designed for hearing preservation surgery in the cerebello-pontine angle, through the retro-sigmoid or the retro-labyrinthine approach. As an additional novelty within the field, the system allows intraoperative mapping and thus precise localization of the cochlear nerve in its entire trajectory from the brainstem to the fundus of the internal auditory canal, which is a major advance in relation to atraumatic dissection of the nerve. The system can be used for surgery of all types of CPA tumors, for example, vestibular schwannomas, meningiomas and epidermoid cysts, but also for vestibular nerve section and vascular decompression. The system also allows evaluation of the electrical functionality of an anatomically intact cochlear nerve in translabyrinthine surgery, thus predicting the benefit of optional cochlear implantation.

Supra-threshold auditory brainstem response amplitudes in humans: Test-retest reliability, electrode montage and noise exposure.

The auditory brainstem response (ABR) is a sub-cortical evoked potential in which a series of well-defined waves occur in the first 10 ms after the onset of an auditory stimulus. Wave V of the ABR, particularly wave V latency, has been shown to be remarkably stable over time in individual listeners. However, little attention has been paid to the reliability of wave I, which reflects auditory nerve activity. This ABR component has attracted interest recently, as wave I amplitude has been identified as a possible non-invasive measure of noise-induced cochlear synaptopathy. The current study aimed to determine whether ABR wave I amplitude has sufficient test-retest reliability to detect impaired auditory nerve function in an otherwise normal-hearing listener. Thirty normal-hearing females were tested, divided equally into low- and high-noise exposure groups. The stimulus was an 80 dB nHL click. ABR recordings were made from the ipsilateral mastoid and from the ear canal (using a tiptrode). Although there was some variability between listeners, wave I amplitude had high test-retest reliability, with an intraclass correlation coefficient (ICC) comparable to that for wave V amplitude. There were slight gains in reliability for wave I amplitude when recording from the ear canal (ICC of 0.88) compared to the mastoid (ICC of 0.85). The summating potential (SP) and ratio of SP to wave I were also quantified and found to be much less reliable than measures of wave I and V amplitude. Finally, we found no significant differences in the amplitude of any wave components between low- and high-noise exposure groups. We conclude that, if the other sources of between-subject variability can be controlled, wave I amplitude is sufficiently reliable to accurately characterize individual differences in auditory nerve function.

Effects of cochlear synaptopathy on middle-ear muscle reflexes in unanesthetized mice.

Cochlear synaptopathy, i.e. the loss of auditory-nerve connections with cochlear hair cells, is seen in aging, noise damage, and other types of acquired sensorineural hearing loss. Because the subset of auditory-nerve fibers with high thresholds and low spontaneous rates (SRs) is disproportionately affected, audiometric thresholds are relatively insensitive to this primary neural degeneration. Although suprathreshold amplitudes of wave I of the auditory brainstem response (ABR) are attenuated in synaptopathic mice, there is not yet a robust diagnostic in humans. The middle-ear muscle reflex (MEMR) might be a sensitive metric (Valero et al., 2016), because low-SR fibers may be important drivers of the MEMR (Liberman and Kiang, 1984; Kobler et al., 1992). Here, to test the hypothesis that narrowband reflex elicitors can identify synaptopathic cochlear regions, we measured reflex growth functions in unanesthetized mice with varying degrees of noise-induced synaptopathy and in unexposed controls. To separate effects of the MEMR from those of the medial olivocochlear reflex, the other sound-evoked cochlear feedback loop, we used a mutant mouse strain with deletion of the acetylcholine receptor required for olivocochlear function. We demonstrate that the MEMR is normal when activated from non-synaptopathic cochlear regions, is greatly weakened in synaptopathic regions, and is a more sensitive indicator of moderate synaptopathy than the suprathreshold amplitude of ABR wave I.

What can stimulus polarity and interphase gap tell us about auditory nerve function in cochlear-implant recipients?

Modeling studies suggest that differences in neural responses between polarities might reflect underlying neural health. Specifically, large differences in electrically evoked compound action potential (eCAP) amplitudes and amplitude-growth-function (AGF) slopes between polarities might reflect poorer peripheral neural health, whereas more similar eCAP responses between polarities might reflect better neural health. The interphase gap (IPG) has also been shown to relate to neural survival in animal studies. Specifically, healthy neurons exhibit larger eCAP amplitudes, lower thresholds, and steeper AGF slopes for increasing IPGs. In ears with poorer neural survival, these changes in neural responses are generally less apparent with increasing IPG. The primary goal of this study was to examine the combined effects of stimulus polarity and IPG within and across subjects to determine whether both measures represent similar underlying mechanisms related to neural health. With the exception of one measure in one group of subjects, results showed that polarity and IPG effects were generally not correlated in a systematic or predictable way. This suggests that these two effects might represent somewhat different aspects of neural health, such as differences in site of excitation versus integrative membrane characteristics, for example. Overall, the results from this study suggest that the underlying mechanisms that contribute to polarity and IPG effects in human CI recipients might be difficult to determine from animal models that do not exhibit the same anatomy, variance in etiology, electrode placement, and duration of deafness as humans.

The Middle Ear Muscle Reflex in Rat: Developing a Biomarker of Auditory Nerve Degeneration.

OBJECTIVES: The long-term goal of this research is to determine whether the middle ear muscle reflex can be used to predict the number of healthy auditory nerve fibers in hearing-impaired ears. In this study, we develop a high-impedance source and an animal model of the middle ear muscle reflex and explore the influence of signal frequency and level on parameters of the reflex to determine an optimal signal to examine auditory nerve fiber survival. DESIGN: A high-impedance source was developed using a hearing aid receiver attached to a 0.06 diameter 10.5-cm length tube. The impedance probe consisted of a microphone probe placed near the tip of a tube coupled to a sound source. The probe was calibrated by inserting it into a syringe of known volumes and impedances. The reflex in the anesthetized rat was measured with elicitor stimuli ranging from 3 to 16 kHz presented at levels ranging from 35 to 100 dB SPL to one ear while the reflex was measured in the opposite ear containing the probe and probe stimulus. RESULTS: The amplitude of the reflex increased with elicitor level and was largest at 3 kHz. The lowest threshold was approximately 54 dB SPL for the 3-kHz stimulus. The rate of decay of the reflex was greatest at 16 kHz followed by 10 and 3 kHz. The rate of decay did not change significantly with elicitor signal level for 3 and 16 kHz, but decreased as the level of the 10-kHz elicitor increased. A negative feedback model accounts for the reflex decay by having the strength of feedback dependent on auditory nerve input. The rise time of the reflex varied with frequency and changed with level for the 10- and 16-kHz signals but not significantly for the 3-kHz signal. The latency of the reflex increased with a decrease in elicitor level, and the change in latency with level was largest for the 10-kHz stimulus. CONCLUSIONS: Because the amplitude of the reflex in rat was largest with an elicitor signal at 3 kHz, had the lowest threshold, and yielded the least amount of decay, this may be the ideal frequency to estimate auditory nerve survival in hearing-impaired ears.

A new approach for the determination of ECAP thresholds.

BACKGROUND: Electrically evoked compound action potentials (ECAPs) of the auditory nerve are routinely recorded for testing the cochlear implant integrity and its functional connection to the auditory system. The response thresholds derived from ECAP recordings are widely used as a helpful guide in the fitting of the dynamic range of electric stimulation, although they may not always predict the behavioral thresholds of individuals well. Conventionally, this threshold is based on the identification of a minimum N peak and maximum P peak and linear extrapolation of the resulting amplitude growth function (AGF). As an alternative, a new procedure involving numeric signal processing and requiring less user intervention is presented here. Data acquisition: In 12 adults implanted with MED-EL FLEX28 electrodes, two series of ECAPs were recorded immediately after implantation: (i) a full profile involving all 12 channels across the whole stimulus range in steps of 200 current units and (ii) a high resolution section (20 records in the immediate neighborhood of the threshold) of the AGF in one selected channel. Data treatment: It was observed that N and P wave latencies do not depend on stimulus intensity. Fixed time windows were hence defined for stimulus plus noise and noise alone regions. In these windows, the variance of the compound signal representing response and noise is extracted, whereas the noise variance is extracted from the tail of the curve following this time window. The base line is corrected by fitting an exponential function to reduce stimulus or amplifier artifacts. The response threshold is then derived from the response to noise ratio which should exceed the limit of 6 dB. RESULTS: The ECAP thresholds obtained from the new procedure coincide well with those determined by the conventional linear extrapolation of the AGF and they correlate to a greater degree with psychometric thresholds than the existing approach. CONCLUSIONS: The new ECAP algorithm looks promising and may reduce the need for user intervention in determining thresholds.

Modeled auditory nerve responses to amplitude modulated cochlear implant stimulation.

Cochlear implants encode speech information by stimulating the auditory nerve with amplitude-modulated pulse trains. A computer model of the auditory nerve's response to electrical stimulation can be used to evaluate different approaches to improving CI patients' perception. In this paper a computationally efficient stochastic and adaptive auditory nerve model was used to investigate full nerve responses to amplitude-modulated electrical pulse trains. The model was validated for nerve responses to AM pulse trains via comparison with animal data. The influence of different parameters, such as adaptation and stochasticity, on long-term adaptation and modulation-following behavior was investigated. Responses to pulse trains with different pulse amplitudes, amplitude modulation frequencies, and modulation depths were modeled. Rate responses as well as period histograms, Vector Strength and the fundamental frequency were characterized in different time bins. The response alterations, including frequency following behavior, observed over the stimulus duration were similar to those seen in animal experiments. The tested model can be used to predict complete nerve responses to arbitrary input, and thus to different sound coding strategies.

Effect of stimulus level on the temporal response properties of the auditory nerve in cochlear implants.

Electrically evoked compound action potentials (ECAPs) have been used to examine temporal response patterns of the auditory nerve in cochlear implant (CI) recipients. ECAP responses to individual pulses in a pulse train vary across stimulation rates for individual CI users. For very slow rates, auditory neurons have ample time to discharge, recover, and respond to each pulse in the train. As the pulse rate increases, an alternating ECAP-amplitude pattern occurs. As the stimulation rate increases further, the alternating pattern eventually ceases and the overall ECAP amplitudes are diminished, yielding a relatively stochastic state that presumably reflects a combination of adaptation, desynchronization, and facilitation across fibers. Because CIs operate over a range of current levels in everyday use, it is important to understand auditory-nerve responses to pulse trains over a range of levels. The effect of stimulus level on ECAP temporal response patterns in human CI users has not been well studied. The first goal of this study was to examine the effect of stimulus level on various aspects of ECAP temporal responses to pulse-train stimuli. Because higher stimulus levels yield more synchronous responses and faster recovery, it was hypothesized that: (1) the maximum alternation would occur at slower rates for lower levels and faster rates at higher levels, (2) the alternation depth at its maximum would be smaller for lower levels, (3) the rate that produces a stochastic state ('stochastic rate') would decrease with level, (4) adaptation would be greater for lower levels as a result of slower recovery, and (5) refractory-recovery time constants would be longer (slower) for lower levels, consistent with earlier studies. The second goal of this study was to examine how refractory-recovery time constants relate specifically to maximum alternation and stochastic rate. Data were collected for 12 ears in 10 CI recipients. ECAPs were recorded in response to each of 13 pulses in an equal-amplitude pulse train ranging in rate from 900-3500 pps for three levels (low, medium, high). The results generally supported hypotheses 1-4; there were no significant effects of level on the refractory-recovery time constants (hypothesis 5). When data were pooled across level, there was a significant negative correlation between alternation depth and refractory recovery time. Understanding the effects of stimulus level on auditory-nerve responses may provide further insight into improving the use of objective measures for potentially optimizing speech-processing strategies.

Using Neural Response Telemetry to Monitor Physiological Responses to Acoustic Stimulation in Hybrid Cochlear Implant Users.

OBJECTIVE: This report describes the results of a series of experiments where we use the neural response telemetry (NRT) system of the Nucleus cochlear implant (CI) to measure the response of the peripheral auditory system to acoustic stimulation in Nucleus Hybrid CI users. The objectives of this study were to determine whether they could separate responses from hair cells and neurons and to evaluate the stability of these measures over time. DESIGN: Forty-four CI users participated. They all had residual acoustic hearing and used a Nucleus Hybrid S8, S12, or L24 CI or the standard lateral wall CI422 implant. The NRT system of the CI was used to trigger an acoustic stimulus (500-Hz tone burst or click), which was presented at a low stimulation rate (10, 15, or 50 per second) to the implanted ear via an insert earphone and to record the cochlear microphonic, the auditory nerve neurophonic and the compound action potential (CAP) from an apical intracochlear electrode. To record acoustically evoked responses, a longer time window than is available with the commercial NRT software is required. This limitation was circumvented by making multiple recordings for each stimulus using different time delays between the onset of stimulation and the onset of averaging. These recordings were then concatenated off-line. Matched recordings elicited using positive and negative polarity stimuli were added off-line to emphasize neural potentials (SUM) and subtracted off-line to emphasize potentials primarily generated by cochlear hair cells (DIF). These assumptions regarding the origin of the SUM and DIF components were tested by comparing the magnitude of these derived responses recorded using various stimulation rates. Magnitudes of the SUM and DIF components were compared with each other and with behavioral thresholds. RESULTS: SUM and DIF components were identified for most subjects, consistent with both hair cell and neural responses to acoustic stimulation. For a subset of the study participants, the DIF components grew as stimulus level was increased, but little or no SUM components were identified. Latency of the CAPs in response to click stimuli was long relative to reports in the literature of recordings obtained using extracochlear electrodes. This difference in response latency and general morphology of the CAPs recorded was likely due to differences across subjects in hearing loss configuration. The use of high stimulation rates tended to decrease SUM and CAP components more than DIF components. We suggest this effect reflects neural adaptation. In some individuals, repeated measures were made over intervals as long as 9 months. Changes over time in DIF, SUM, and CAP thresholds mirrored changes in audiometric threshold for the subjects who experienced loss of acoustic hearing in the implanted ear. CONCLUSIONS: The Nucleus NRT software can be used to record peripheral responses to acoustic stimulation at threshold and suprathreshold levels, providing a window into the status of the auditory hair cells and the primary afferent nerve fibers. These acoustically evoked responses are sensitive to changes in hearing status and consequently could be useful in characterizing the specific pathophysiology of the hearing loss experienced by this population of CI users.

The effect of progressive hearing loss on the morphology of endbulbs of Held and bushy cells.

Studies of congenital and early-onset deafness have demonstrated that an absence of peripheral sound-evoked activity in the auditory nerve causes pathological changes in central auditory structures. The aim of this study was to establish whether progressive acquired hearing loss could lead to similar brain changes that would degrade the precision of signal transmission. We used complementary physiologic hearing tests and microscopic techniques to study the combined effect of both magnitude and duration of hearing loss on one of the first auditory synapses in the brain, the endbulb of Held (EB), along with its bushy cell (BC) target in the anteroventral cochlear nucleus. We compared two hearing mouse strains (CBA/Ca and heterozygous shaker-2+/-) against a model of early-onset progressive hearing loss (DBA/2) and a model of congenital deafness (homozygous shaker-2-/-), examining each strain at 1, 3, and 6 months of age. Furthermore, we employed a frequency model of the mouse cochlear nucleus to constrain our analyses to regions most likely to exhibit graded changes in hearing function with time. No significant differences in the gross morphology of EB or BC structure were observed in 1-month-old animals, indicating uninterrupted development. However, in animals with hearing loss, both EBs and BCs exhibited a graded reduction in size that paralleled the hearing loss, with the most severe pathology seen in deaf 6-month-old shaker-2-/- mice. Ultrastructural pathologies associated with hearing loss were less dramatic: minor changes were observed in terminal size but mitochondrial fraction and postsynaptic densities remained relatively stable. These results indicate that acquired progressive hearing loss can have consequences on auditory brain structure, with prolonged loss leading to greater pathologies. Our findings suggest a role for early intervention with assistive devices in order to mitigate long-term pathology and loss of function.

Evidence that hidden hearing loss underlies amplitude modulation encoding deficits in individuals with and without tinnitus.

Damage to auditory nerve fibers that expresses with suprathreshold sounds but is hidden from the audiogram has been proposed to underlie deficits in temporal coding ability observed among individuals with otherwise normal hearing, and to be present in individuals experiencing chronic tinnitus with clinically normal audiograms. We tested whether these individuals may have hidden synaptic losses on auditory nerve fibers with low spontaneous rates of firing (low-SR fibers) that are important for coding suprathreshold sounds in noise while high-SR fibers determining threshold responses in quiet remain relatively unaffected. Tinnitus and control subjects were required to detect the presence of amplitude modulation (AM) in a 5 kHz, suprathreshold tone (a frequency in the tinnitus frequency region of the tinnitus subjects, whose audiometric thresholds were normal to 12 kHz). The AM tone was embedded within background noise intended to degrade the contribution of high-SR fibers, such that AM coding was preferentially reliant on low-SR fibers. We also recorded by electroencephalography the "envelope following response" (EFR, generated in the auditory midbrain) to a 5 kHz, 85 Hz AM tone presented in the same background noise, and also in quiet (both low-SR and high-SR fibers contributing to AM coding in the latter condition). Control subjects with EFRs that were comparatively resistant to the addition of background noise had better AM detection thresholds than controls whose EFRs were more affected by noise. Simulated auditory nerve responses to our stimulus conditions using a well-established peripheral model suggested that low-SR fibers were better preserved in the former cases. Tinnitus subjects had worse AM detection thresholds and reduced EFRs overall compared to controls. Simulated auditory nerve responses found that in addition to severe low-SR fiber loss, a degree of high-SR fiber loss that would not be expected to affect audiometric thresholds was needed to explain the results in tinnitus subjects. The results indicate that hidden hearing loss could be sufficient to account for impaired temporal coding in individuals with normal audiograms as well as for cases of tinnitus without audiometric hearing loss.

A physiologically-inspired model reproducing the speech intelligibility benefit in cochlear implant listeners with residual acoustic hearing.

This study introduces a speech intelligibility model for cochlear implant users with ipsilateral preserved acoustic hearing that aims at simulating the observed speech-in-noise intelligibility benefit when receiving simultaneous electric and acoustic stimulation (EA-benefit). The model simulates the auditory nerve spiking in response to electric and/or acoustic stimulation. The temporally and spatially integrated spiking patterns were used as the final internal representation of noisy speech. Speech reception thresholds (SRTs) in stationary noise were predicted for a sentence test using an automatic speech recognition framework. The model was employed to systematically investigate the effect of three physiologically relevant model factors on simulated SRTs: (1) the spatial spread of the electric field which co-varies with the number of electrically stimulated auditory nerves, (2) the "internal" noise simulating the deprivation of auditory system, and (3) the upper bound frequency limit of acoustic hearing. The model results show that the simulated SRTs increase monotonically with increasing spatial spread for fixed internal noise, and also increase with increasing the internal noise strength for a fixed spatial spread. The predicted EA-benefit does not follow such a systematic trend and depends on the specific combination of the model parameters. Beyond 300 Hz, the upper bound limit for preserved acoustic hearing is less influential on speech intelligibility of EA-listeners in stationary noise. The proposed model-predicted EA-benefits are within the range of EA-benefits shown by 18 out of 21 actual cochlear implant listeners with preserved acoustic hearing.

The potential use of low-frequency tones to locate regions of outer hair cell loss.

Current methods used to diagnose cochlear hearing loss are limited in their ability to determine the location and extent of anatomical damage to various cochlear structures. In previous experiments, we have used the electrical potential recorded at the round window -the cochlear response (CR) -to predict the location of damage to outer hair cells in the gerbil. In a follow-up experiment, we applied 10 mM ouabain to the round window niche to reduce neural activity in order to quantify the neural contribution to the CR. We concluded that a significant proportion of the CR to a 762 Hz tone originated from phase-locking activity of basal auditory nerve fibers, which could have contaminated our conclusions regarding outer hair cell health. However, at such high concentrations, ouabain may have also affected the responses from outer hair cells, exaggerating the effect we attributed to the auditory nerve. In this study, we lowered the concentration of ouabain to 1 mM and determined the physiologic effects on outer hair cells using distortion-product otoacoustic emissions. As well as quantifying the effects of 1 mM ouabain on the auditory nerve and outer hair cells, we attempted to reduce the neural contribution to the CR by using near-infrasonic stimulus frequencies of 45 and 85 Hz, and hypothesized that these low-frequency stimuli would generate a cumulative amplitude function (CAF) that could reflect damage to hair cells in the apex more accurately than the 762 stimuli. One hour after application of 1 mM ouabain, CR amplitudes significantly increased, but remained unchanged in the presence of high-pass filtered noise conditions, suggesting that basal auditory nerve fibers have a limited contribution to the CR at such low frequencies.