Search

This study introduces and evaluates the PHAST+ model, part of a computational framework designed to simulate the behavior of auditory nerve fibers in response to the electrical stimulation from a cochlear implant. PHAST+ incorporates a highly efficient method for calculating accommodation and adaptation, making it particularly suited for simulations over extended stimulus durations. The proposed method uses a leaky integrator inspired by classic biophysical nerve models. Through evaluation against single-fiber animal data, our findings demonstrate the model's effectiveness across various stimuli, including short pulse trains with variable amplitudes and rates. Notably, the PHAST+ model performs better than its predecessor, PHAST (a phenomenological model by van Gendt et al.), particularly in simulations of prolonged neural responses. While PHAST+ is optimized primarily on spike rate decay, it shows good behavior on several other neural measures, such as vector strength and degree of adaptation. The future implications of this research are promising. PHAST+ drastically reduces the computational burden to allow the real-time simulation of neural behavior over extended periods, opening the door to future simulations of psychophysical experiments and multi-electrode stimuli for evaluating novel speech-coding strategies for cochlear implants. • A highly efficient new auditory nerve fiber model is presented that can replicate spike rate decay of various animal experiments accurately. • This new model allows for quick simulations of long pulse trains and multi-electrode pulse trains, for fibers of the entire cochlea. • Although not optimized for measures of synchronization and adaptation, the model still performs sufficiently on other metrics included in the animal studies. [ABSTRACT FROM AUTHOR]

• Systematic review and meta-analysis. • Age-related deficits in auditory nerve function are consistent across studies. • Evidence for noise-exposure-related deficits in auditory nerve function are weak. • Large-sample study finds age does not interact with noise exposure. • Longitudinal studies of auditory function and histology are needed in humans. Auditory nerve (AN) function has been hypothesized to deteriorate with age and noise exposure. Here, we perform a systematic review of published studies and find that the evidence for age-related deficits in AN function is largely consistent across the literature, but there are inconsistent findings among studies of noise exposure history. Further, evidence from animal studies suggests that the greatest deficits in AN response amplitudes are found in noise-exposed aged mice, but a test of the interaction between effects of age and noise exposure on AN function has not been conducted in humans. We report a study of our own examining differences in the response amplitude of the compound action potential N1 (CAP N1) between younger and older adults with and without a self-reported history of noise exposure in a large sample of human participants (63 younger adults 18–30 years of age, 103 older adults 50–86 years of age). CAP N1 response amplitudes were smaller in older than younger adults. Noise exposure history did not appear to predict CAP N1 response amplitudes, nor did the effect of noise exposure history interact with age. We then incorporated our results into two meta-analyses of published studies of age and noise exposure history effects on AN response amplitudes in neurotypical human samples. The meta-analyses found that age effects across studies are robust (r = -0.407), but noise exposure effects are weak (r = -0.152). We conclude that noise exposure effects may be highly variable depending on sample characteristics, study design, and statistical approach, and researchers should be cautious when interpreting results. The underlying pathology of age-related and noise-induced changes in AN function are difficult to determine in living humans, creating a need for longitudinal studies of changes in AN function across the lifespan and histological examination of the AN from temporal bones collected post-mortem. [ABSTRACT FROM AUTHOR]

• Recovery from noise-induced synaptopathy is more robust in C57Bl/6J than CBA/CaJ mice. • Most recovery is from reversible reduction in immunostaining for post-synaptic GluA2. • Immunostaining for ribbon markers is transiently increased by synaptopathic noise. • Synaptopathic noise causes transient neurite extension in C57Bl/6J not CBA/CaJ. • Interstrain differences may arise from noise-induced upregulation of neurotrophins. Acute noise-induced loss of synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs) has been documented in several strains of mice, but the extent of post-exposure recovery reportedly varies dramatically. If such inter-strain heterogeneity is real, it could be exploited to probe molecular pathways mediating neural remodeling in the adult cochlea. Here, we compared synaptopathy repair in CBA/CaJ vs. C57BL/6J, which are at opposite ends of the reported recovery spectrum. We evaluated C57BL/6J mice 0 h, 24 h, 2 wks or 8 wks after exposure for 2 h to octave-band noise (8–16 kHz) at either 90, 94 or 98 dB SPL, to compare with analogous post-exposure results in CBA/CaJ at 98 or 101 dB. We counted pre- and post-synaptic puncta in immunostained cochleas, using machine learning to classify paired (GluA2 and CtBP2) vs. orphan (CtBP2 only) puncta, and batch-processing to quantify immunostaining intensity. At 98 dB, both strains show ongoing loss of ribbons and synapses between 0 and 24 h, followed by partial recovery, however the extent and degree of these changes were greater in C57BL/6J. Much of the synaptic recovery is due to transient reduction in GluA2 intensity in synaptopathic regions. In contrast, CtBP2 intensity showed only transient increases (at 2 wks). Neurofilament staining revealed transient extension of ANF terminals in C57BL/6J, but not in CBA/CaJ, peaking at 24 h and reverting by 2 wks. Thus, although interstrain differences in synapse recovery are dominated by reversible changes in GluA2 receptor levels, the neurite extension seen in C57BL/6J suggests a qualitative difference in regenerative capacity. [ABSTRACT FROM AUTHOR]

• Single auditory nerve fibers can be studied across species to compare cochlear frequency tuning. • Threshold tuning curves suggest sharper frequency tuning in macaque monkeys compared to cat. • Responses to suprathreshold wideband tone complexes provide both gain and phase spectra. • Monkey gain functions show sharper tuning than cat for fibers in the basal half of the cochlea. • Phase spectra show larger group delays in high-frequency fibers from monkey than in cat. Data from non-human primates can help extend observations from non-primate species to humans. Here we report measurements on the auditory nerve of macaque monkeys in the context of a controversial topic important to human hearing. A range of techniques have been used to examine the claim, which is not generally accepted, that human frequency tuning is sharper than traditionally thought, and sharper than in commonly used animal models. Data from single auditory-nerve fibers occupy a pivotal position to examine this claim, but are not available for humans. A previous study reported sharper tuning in auditory-nerve fibers of macaque relative to the cat. A limitation of these and other single-fiber data is that frequency selectivity was measured with tonal threshold-tuning curves, which do not directly assess spectral filtering and whose shape is sharpened by cochlear nonlinearity. Our aim was to measure spectral filtering with wideband suprathreshold stimuli in the macaque auditory nerve. We obtained responses of single nerve fibers of anesthetized macaque monkeys and cats to a suprathreshold, wideband, multicomponent stimulus designed to allow characterization of spectral filtering at any cochlear locus. Quantitatively the differences between the two species are smaller than in previous studies, but consistent with these studies the filters obtained show a trend of sharper tuning in macaque, relative to the cat, for fibers in the basal half of the cochlea. We also examined differences in group delay measured on the phase data near the characteristic frequency versus in the low-frequency tail. The phase data are consistent with the interpretation of sharper frequency tuning in monkey in the basal half of the cochlea. We conclude that use of suprathreshold, wide-band stimuli supports the interpretation of sharper frequency selectivity in macaque nerve fibers relative to the cat, although the difference is less marked than apparent from the assessment with tonal threshold-based data. [ABSTRACT FROM AUTHOR]

Electrically evoked compound action potentials (eCAPs) are measurements of the auditory nerve's response to electrical stimulation. ECAP amplitudes during pulse trains can exhibit temporal alternations. The magnitude of this alternation tends to diminish over time during the stimulus. How this pattern relates to the temporal behavior of nerve fibers is not known. We hypothesized that the stochasticity, refractoriness, adaptation of the threshold and spike-times influence pulse-train eCAP responses. Thirty thousand auditory nerve fibers were modeled in a three-dimensional cochlear model incorporating pulse-shape effects, pulse-history effects, and stochasticity in the individual neural responses. ECAPs in response to pulse trains of different rates and amplitudes were modeled for fibers with different stochastic properties (by variation of the relative spread) and different temporal properties (by variation of the refractory periods, adaptation and latency). The model predicts alternation of peak amplitudes similar to available human data. In addition, the peak alternation was affected by changing the refractoriness, adaptation, and relative spread of auditory nerve fibers. As these parameters are related to factors such as the duration of deafness and neural survival, this study suggests that the eCAP pattern in response to pulse trains could be used to assess the underlying temporal and stochastic behavior of the auditory nerve. As these properties affect the nerve's response to pulse trains, they are of uttermost importance to sound perception with cochlear implants. • Responses of thirty thousand auditory nerve fibers were modeled in a three-dimensional cochlear model. • The cochlear and auditory nerve model incorporates pulse-shape, temporal, and stochastic effects. • Electrically evoked compound action potentials (eCAPs) responses to pulse trains were predicted. • The typical temporal alternation pattern is related to stochastic, refractory and adaptive behavior. • The eCAP pattern in response to pulse trains can be used to assess the state of the nerve. [ABSTRACT FROM AUTHOR]

Abstract Strial dysfunction is commonly observed as a key consequence of aging in the cochlea. A large body of animal research, especially in the quiet-aged Mongolian gerbil, shows specific histopathological changes in the cochlear stria vascularis and the putatively corresponding effects on endocochlear potential and auditory nerve responses. However, recent work suggests that synaptopathy, or the loss of inner hair cell-auditory nerve fiber synapses, also presents as a consequence of aging. It is now believed that the loss of synapses is the earliest age-related degenerative event. The present review aims to integrate classic and novel research on age-related pathologies of the inner ear. First, we summarize current knowledge on age-related strial dysfunction and synaptopathy. We describe how these cochlear pathologies fit into the categories for presbyacusis, as first defined by Schuknecht in the '70s. Further, we discuss how strial dysfunction and synaptopathy affect sound coding by the auditory nerve and how they can be experimentally induced to study their specific contributions to age-related hearing deficits. As such, we aim to give an overview of the current literature on age-related cochlear pathologies and hope to inspire further research on the role of cochlear aging in age-related hearing deficits. Highlights • Strial dysfunction is a well-known degenerative manifestation of aging in the cochlea. • Loss of IHC-auditory nerve fiber synapses was recently recognized as an important age-related degenerative phenomenon. • Synapse loss is probably the earliest manifestation of Schuknecht's neural presbyacusis. • The relative contributions of synapse loss and strial dysfunction to changes in auditory-nerve coding are discussed. • The gerbil is an excellent model for addressing questions about functional consequences of the aging cochlea. [ABSTRACT FROM AUTHOR]

Abstract Investigations of cochlear synaptopathy in living humans rely on proxy measures of auditory nerve function. Numerous procedures have been developed, typically based on the auditory brainstem response (ABR), envelope-following response (EFR), or middle-ear-muscle reflex (MEMR). Validation is challenging, due to the absence of a gold-standard measure in humans. Some metrics correlate with synaptic survival in animal models, but translation between species is not straightforward; measurements in humans are likely to reflect greater error and greater variability from non-synaptopathic sources. The present study assessed the reliability of seven measures, as well as testing for correlations between them. Thirty-one young women with normal audiograms underwent repeated measurements of ABR wave I amplitude, ABR wave I growth, ABR wave V latency shift in noise, EFR amplitude, EFR growth with stimulus modulation depth, MEMR threshold, and an MEMR across-frequency difference measure. Intraclass correlation coefficients for ABR wave I amplitude, EFR amplitude, and MEMR threshold ranged from 0.85 to 0.93, suggesting that such tests can yield highly reliable results, given careful measurement techniques. The ABR and EFR difference measures exhibited only poor-to-moderate reliability. No significant correlations, nor any consistent trends, were observed between the various measures, providing no indication that these metrics reflect the same underlying physiological processes. Findings suggest that many proxy measures of cochlear synaptopathy should be regarded with caution, at least when employed in young adults with normal audiograms. Highlights • Given careful measurement techniques, ABR and EFR amplitudes can be highly reliable. • The same is true of MEMR thresholds and MEMR across-frequency threshold difference. • Differential ABR and EFR measures exhibit only poor-to-moderate reliability. • Correlations between measures are not evident in young people with normal audiograms. • Proxy measures of synaptopathy in this population should be regarded with caution. [ABSTRACT FROM AUTHOR]

Abstract 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. Highlights • Intracochlear kainic-acid (KA) infusions were performed in the budgerigar. • KA reduced ABR wave I by 40–70% without impacting DPOAEs. • Tone perception was studied using operant-conditioning procedures. • Behavioral tone detection was unaffected as a function of frequency and duration. • The audiogram and temporal integration appear resistant to AN loss. [ABSTRACT FROM AUTHOR]

Computer models of the individual components of the peripheral auditory system – the outer, middle, and inner ears and the auditory nerve – have been developed in the past, with varying level of detail, breadth, and faithfulness of the underlying parameters. Building on previous work, we advance the modeling of the ear by presenting a complete, physiologically justified, bottom-up computer model based on up-to-date experimental data that integrates all of these parts together seamlessly. The detailed bottom-up design of the present model allows for the investigation of partial hearing mechanisms and their defects, including genetic, molecular, and microscopic factors. Also, thanks to the completeness of the model, one can study microscopic effects in the context of their implications on hearing as a whole, enabling the correlation with neural recordings and non-invasive psychoacoustic methods. Such a model is instrumental for advancing quantitative understanding of the mechanism of hearing, for investigating various forms of hearing impairment, as well as for devising next generation hearing aids and cochlear implants. • A globally coupled model of cochlear currents with tonotopically specialized hair cells is developed. • We employ a nonlinear 2D description of cochlear mechanics; the amplifier is driven by explicitly computed OHC potentials. • We present a detailed synapse morphology with Ca channel stochastic openings, currents, and diffusion. • The mechanism of hearing is described in detail allowing for modeling of effects of perturbations. • The model serves as a diagnostic tool correlating measurements with various sources of hearing loss. [ABSTRACT FROM AUTHOR]

Reductions in sound-evoked activity in the auditory nerve due to hearing loss have been shown to cause pathological changes in central auditory structures. Hearing loss due strictly to the aging process are less well documented. In this study of CBA/CaH mice, we provide evidence for age-related pathology in the endbulb of Held, a large axosomatic ending arising from myelinated auditory nerve fibers. Endbulbs are known to be involved in the processing of temporal cues used for sound localization and speech comprehension. Hearing thresholds as measured by auditory brainstem response (ABR) thresholds remained stable up to one year, whereas suprathreshold amplitudes of early ABR waves decreased by up to 50% in older mice, similar to that reported for age-related cochlear synaptopathy (Sergeyenko et al., 2013). The reduction of ABR response magnitude with age correlated closely in time with the gradual atrophy of endbulbs of Held, and is consistent with the hypothesis that endbulb integrity is dependent upon normal levels of spike activity in the auditory nerve. These results indicate that central auditory pathologies emerge as consequence of so-called “hidden” hearing loss and suggest that such brain changes require consideration when devising therapeutic interventions. [ABSTRACT FROM AUTHOR]

The basolateral membrane of the mammalian inner hair cell (IHC) expresses large voltage and Ca 2+ gated outward K + currents. To quantify how the voltage-dependent activation of the K + channels affects the functionality of the auditory nerve innervating the IHC, this study adopts a model of mechanical-to-neural transduction in which the basolateral K + conductances of the IHC can be made voltage-dependent or not. The model shows that the voltage-dependent activation of the K + channels (i) enhances the phase-locking properties of the auditory fiber (AF) responses; (ii) enables the auditory nerve to encode a large dynamic range of sound levels; (iii) enables the AF responses to synchronize precisely with the envelope of amplitude modulated stimuli; and (iv), is responsible for the steep offset responses of the AFs. These results suggest that the basolateral K + channels play a major role in determining the well-known response properties of the AFs and challenge the classical view that describes the IHC membrane as an electrical low-pass filter. In contrast to previous models of the IHC-AF complex, this study ascribes many of the AF response properties to fairly basic mechanisms in the IHC membrane rather than to complex mechanisms in the synapse. [ABSTRACT FROM AUTHOR]

The initial neural encoding of acoustic information occurs by means of spikes in primary auditory afferents. Each mammalian primary auditory afferent (type-I auditory-nerve fiber; ANF) is associated with only one ribbon synapse in one receptor cell (inner hair cell; IHC). The properties of ANF spike trains therefore provide an indirect view of the operation of individual IHC synapses. We showed previously that a point process model of presynaptic vesicle pool depletion and deterministic exponential replenishment, combined with short postsynaptic neural refractoriness, accounts for the interspike interval (ISI) distributions, serial ISI correlations, and spike-count statistics of a population of cat-ANF spontaneous spike trains. Here, we demonstrate that this previous synapse model produces unrealistic properties when spike rates are high and show that this problem can be resolved if the replenishment of each release site is stochastic and independent. We assume that the depletion probability varies between synapses to produce differences in spontaneous rate and that the other model parameters are constant across synapses. We find that this model fits best with only four release sites per IHC synapse, a mean replenishment time of 17 ms, and absolute and mean relative refractory periods of 0.6 ms each. This model accounts for ANF spontaneous spike timing better than two influential, comprehensive models of the auditory periphery. It also reproduces ISI distributions from spontaneous and steady-state driven activity from other studies and other mammalian species. Adding fractal noise to the rate of depletion of each release site can yield long-range correlations as typically observed in long spike trains. We also examine two model variants having more complex vesicle cycles, but neither variant yields a markedly improved fit or a different estimate of the number of release sites. In addition, we examine a model variant having both short and long relative refractory components and find that it cannot account for all aspects of the data. These model results will be beneficial for understanding ribbon synapses and ANF responses to acoustic stimulation. [ABSTRACT FROM AUTHOR]

Recent cochlear mechanical measurements show that active processes increase the motion response of the reticular lamina (RL) at frequencies more than an octave below the local characteristic frequency (CF) for CFs above 5 kHz. A possible correlate is that in high-CF (>5 kHz) auditory-nerve (AN) fibers, responses to frequencies 1-3 octaves below CF (“tail” frequencies) can be inhibited by medial olivocochlear (MOC) efferents. These results indicate that active processes enhance the sensitivity of tail-frequency RL and AN responses. Perhaps related is that some apical low-CF AN fibers have tuning-curve (TC) “side-lobe” response areas at frequencies above and below the TC-tip that are MOC inhibited. We hypothesized that the tail and side-lobe responses are enhanced by the same active mechanisms as CF cochlear amplification. If responses to CF, tail-frequency, and TC-side-lobe tones are all enhanced by prestin motility controlled by outer-hair-cell (OHC) transmembrane voltage, then they should depend on OHC stereocilia position in the same way. To test this, we cyclically changed the OHC-stereocilia mechano-electric-transduction (MET) operating point with low-frequency “bias” tones (BTs) and increased the BT level until the BT caused quasi-static OHC MET saturation that reduced or “suppressed” the gain of OHC active processes. While measuring cat AN-fiber responses, 50 Hz BT level series, 70–120 dB SPL, were run alone and with CF tones, or 2.5 kHz tail-frequency tones, or side-lobe tones. BT-tone-alone responses were used to exclude BT sound levels that produced AN responses that might obscure BT suppression. Data were analyzed to show the BT phase that suppressed the tone responses at the lowest sound level. We found that AN responses to CF, tail-frequency, and side-lobe tones were suppressed at the same BT phase in almost all cases. The data are consistent with the enhancement of responses to CF, tail-frequency, and side-lobe tones all being due to the same OHC-stereocilia MET-dependent active process. Thus, OHC active processes enhance AN responses at frequencies outside of the cochlear-amplified TC-tip region in both high- and low-frequency cochlear regions. The data are consistent with the AN response enhancements being due to enhanced RL motion that drives IHC-stereocilia deflection by traditional RL-TM shear and/or by changing the RL-TM gap. Since tail-frequency basilar membrane (BM) motion is not actively enhanced, the tail-frequency IHC drive is from a vibrational mode little present on the BM, not a “second filter” of BM motion. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Common causes of hearing loss in humans - exposure to loud noise or ototoxic drugs and aging - often damage sensory hair cells, reflected as elevated thresholds on the clinical audiogram. Recent studies in animal models suggest, however, that well before this overt hearing loss can be seen, a more insidious, but likely more common, process is taking place that permanently interrupts synaptic communication between sensory inner hair cells and subsets of cochlear nerve fibers. The silencing of affected neurons alters auditory information processing, whether accompanied by threshold elevations or not, and is a likely contributor to a variety of perceptual abnormalities, including speech-in-noise difficulties, tinnitus and hyperacusis. Work described here will review structural and functional manifestations of this cochlear synaptopathy and will consider possible mechanisms underlying its appearance and progression in ears with and without traditional ‘hearing loss’ arising from several common causes in humans. [ABSTRACT FROM AUTHOR]

Damage to and loss of the organ of Corti leads to secondary degeneration of the spiral ganglion cell (SGC) somata of the auditory nerve. Extensively examined in animal models, this degeneration process of SGC somata following deafening is well known. However, degeneration of auditory nerve axons, which conduct auditory information towards the brainstem, and its relation to SGC soma degeneration are largely unknown. The consequences of degeneration of the axons are relevant for cochlear implantation, which is applied to a deafened system but depends on the condition of the auditory nerve. We investigated the time sequence of degeneration of myelinated type I axons in deafened guinea pigs. Auditory nerves in six normal-hearing and twelve deafened animals, two, six and fourteen weeks (for each group four) after deafening were histologically analyzed. We developed a semi-automated method for axon counting, which allowed for a relatively large sample size (20% of the total cross-sectional area of the auditory nerve). We observed a substantial loss of auditory nerve area (29%), reduction in axon number (59%) and decrease in axoplasm area (41%) fourteen weeks after deafening compared to normal-hearing controls. The correlation between axonal degeneration and that of the SGC somata in the same cochleas was high, although axonal structures appeared to persist longer than the somata, suggesting a slower degeneration process. In the first two weeks after induction of deafness, the axonal cross-sectional area decreased but the axon number did not. In conclusion, the data strongly suggest that each surviving SGC possesses an axon. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• An auditory nerve fiber model can be accurately approximated with deep learning. • A deep learning model can speed up simulations by five orders of magnitude. • Charge-balanced stimuli can be randomly generated via hyperplane projection. • Energy optimal stimulus waveforms have a Gaussian-like shape. • Gaussian-like stimuli can be up to 45% more energy efficient than square stimuli. Performing simulations with a realistic biophysical auditory nerve fiber model can be very time-consuming, due to the complex nature of the calculations involved. Here, a surrogate (approximate) model of such an auditory nerve fiber model was developed using machine learning methods, to perform simulations more efficiently. Several machine learning models were compared, of which a Convolutional Neural Network showed the best performance. In fact, the Convolutional Neural Network was able to emulate the behavior of the auditory nerve fiber model with extremely high similarity (R 2 > 0.99), tested under a wide range of experimental conditions, whilst reducing the simulation time by five orders of magnitude. In addition, a method for randomly generating charge-balanced waveforms using hyperplane projection is introduced. In the second part of this paper, the Convolutional Neural Network surrogate model was used by an Evolutionary Algorithm to optimize the shape of the stimulus waveform in terms of energy efficiency. The resulting waveforms resemble a positive Gaussian-like peak, preceded by an elongated negative phase. When comparing the energy of the waveforms generated by the Evolutionary Algorithm with the commonly used square wave, energy decreases of 8%–45% were observed for different pulse durations. These results were validated with the original auditory nerve fiber model, which demonstrates that the proposed surrogate model can be used as its accurate and efficient replacement. [ABSTRACT FROM AUTHOR]

We used low-frequency “bias” tones (BT's) to explore whether click and tone responses are affected in the same way by cochlear active processes. In nonlinear systems the responses to clicks are not always simply related to the responses to tones. Cochlear amplifier gain depends on the incremental slope of the outer-hair-cell (OHC) stereocilia mechano-electric transduction (MET) function. BTs transiently change the operating-point of OHC MET channels and can suppress cochlear-amplifier gain by pushing OHC METs into low-slope saturation regions. BT effects on single auditory-nerve (AN) fibers have been studied on tone responses but not on click responses. We recorded from AN fibers in anesthetized cats and compared tone and click responses using 50 Hz BTs at 70–120 dB SPL to manipulate OHC stereocilia position. BTs can also excite and thereby obscure the BT suppression. We measured AN-fiber response synchrony to BTs alone so that we could exclude suppression measurements when the BT synchrony might obscure the suppression. BT suppression of low-level tone and click responses followed the traditional pattern of twice-a-BT-cycle suppression with more suppression at one phase than the other. The major suppression phases of most fibers were tightly grouped with little difference between click and tone suppressions, which is consistent with low-level click and tone responses being amplified in the same way. The data are also consistent with the operating point of the OHC MET function varying smoothly from symmetric in the base to offset in the apex, and, in contrast, with the IHC MET function being offset throughout the cochlea. As previously reported, bias-tones presented alone excited AN fibers at one or more phases, a phenomena termed “peak splitting” with most BT excitation phases ∼¼ cycle before or after the major suppression phase. We explain peak splitting as being due to distortion in multiple fluid drives to inner-hair-cell stereocilia. [ABSTRACT FROM AUTHOR]

Cochlear implants (CIs) rehabilitate hearing impairment through direct electrical stimulation of the auditory nerve. New stimulation strategies can be evaluated using computational models. In this study, a computationally efficient model that accurately predicts auditory nerve responses to CI pulse train input was developed. A three-dimensional volume conduction and active nerve model developed at Leiden University Medical Center was extended with stochasticity, adaptation, and accommodation. This complete model includes spatial and temporal characteristics of both the cochlea and the auditory nerve. The model was validated by comparison with experimentally measured single fiber action potential responses to pulse trains published in the literature. The effects of pulse rate and pulse amplitude on spiking patterns were investigated. The modeled neural responses to CI stimulation were very similar to the single fiber action potential measurements in animal experiments. The model's responses to pulse train stimulation with respect to spatial location were also investigated. Adaptation was stronger at the borders of the stimulated area than in the center. By combining spatial details with long-term temporal components and a broad implementation of stochasticity a comprehensive model was developed that was validated for long duration electric stimulation of a wide range of pulse rates and amplitudes. The model can be used to evaluate auditory nerve responses to cochlear implant sound coding strategies. [ABSTRACT FROM AUTHOR]

Auditory nerve fibers in the adult ear are divided into functional subgroups according to spontaneous rate (SR) and threshold sensitivity. The high-threshold, low-SR fibers are morphologically and spatially distinct from the low-threshold high-SR fibers at their synaptic contacts with inner hair cells. This distinction between SR groups in the adult ear is visible in confocal microscopy as complementary size gradients of presynaptic ribbons and post-synaptic glutamate receptor patches across the modiolar-pillar and habenular-cuticular axes in the inner hair cell area. The aim of the present study was to track the post-natal development of this morphological gradient, in mouse, to determine the earliest age at which this important aspect of cochlear organization is fully mature. Here we show, using morphometric analysis of the organ of Corti immunostained for pre- and post-synaptic markers of efferent and afferent innervation, that this SR-based morphological gradient is not fully established until postnatal day 28, well after other features, such as synaptic counts and efferent innervation density in both the inner and outer hair cell areas, appear fully mature. [ABSTRACT FROM AUTHOR]

Cochlear implants (CIs) provide acoustic information to implanted patients by electrically stimulating nearby auditory nerve fibers (ANFs) which then transmit the information to higher-level neural structures for further processing and interpretation. Computational models that simulate ANF responses to CI stimuli enable the exploration of the mechanisms underlying CI performance beyond the capacity of in vivo experimentation alone. However, all ANF models developed to date utilize to some extent anatomical/morphometric data, biophysical properties and/or physiological data measured in non-human animal models. This review compares response properties of the electrically stimulated auditory nerve (AN) in human listeners and different mammalian models. Properties of AN responses to single pulse stimulation, paired-pulse stimulation, and pulse-train stimulation are presented. While some AN response properties are similar between human listeners and animal models (e.g., increased AN sensitivity to single pulse stimuli with long interphase gaps), there are some significant differences. For example, the AN of most animal models is typically more sensitive to cathodic stimulation while the AN of human listeners is generally more sensitive to anodic stimulation. Additionally, there are substantial differences in the speed of recovery from neural adaptation between animal models and human listeners. Therefore, results from animal models cannot be simply translated to human listeners. Recognizing the differences in responses of the AN to electrical stimulation between humans and other mammals is an important step for creating ANF models that are more applicable to various human CI patient populations. [ABSTRACT FROM AUTHOR]

• Distorted tonotopy (DT) is primary factor in degraded speech-in-noise coding w/ NIHL • DT has differential effects on temporal coding depending on stimulus bandwidth • DT increases across-fiber correlation and thus reduces information capacity to brain • DT varies across etiologies and may contribute to individual differences Listeners with sensorineural hearing loss (SNHL) have substantial perceptual deficits, especially in noisy environments. Unfortunately, speech-intelligibility models have limited success in predicting the performance of listeners with hearing loss. A better understanding of the various suprathreshold factors that contribute to neural-coding degradations of speech in noisy conditions will facilitate better modeling and clinical outcomes. Here, we highlight the importance of one physiological factor that has received minimal attention to date, termed distorted tonotopy, which refers to a disruption in the mapping between acoustic frequency and cochlear place that is a hallmark of normal hearing. More so than commonly assumed factors (e.g., threshold elevation, reduced frequency selectivity, diminished temporal coding), distorted tonotopy severely degrades the neural representations of speech (particularly in noise) in single- and across-fiber responses in the auditory nerve following noise-induced hearing loss. Key results include: 1) effects of distorted tonotopy depend on stimulus spectral bandwidth and timbre, 2) distorted tonotopy increases across-fiber correlation and thus reduces information capacity to the brain, and 3) its effects vary across etiologies, which may contribute to individual differences. These results motivate the development and testing of noninvasive measures that can assess the severity of distorted tonotopy in human listeners. The development of such noninvasive measures of distorted tonotopy would advance precision-audiological approaches to improving diagnostics and rehabilitation for listeners with SNHL. [ABSTRACT FROM AUTHOR]

• Across-frequency fluctuation profiles predict speech intelligibility in noise • Model predicts effects of level and different noise types, incl. masking release • Model predicts effects of individual hearing loss • Plausible effects of inner- and outer-hair-cell impairment This study presents a major update and full evaluation of a speech intelligibility (SI) prediction model previously introduced by Scheidiger, Carney, Dau, and Zaar [(2018), Acta Acust. United Ac. 104 , 914-917]. The model predicts SI in speech-in-noise conditions via comparison of the noisy speech and the noise-alone reference. The two signals are processed through a physiologically inspired nonlinear model of the auditory periphery, for a range of characteristic frequencies (CFs), followed by a modulation analysis in the range of the fundamental frequency of speech. The decision metric of the model is the mean of a series of short-term, across-CF correlations between population responses to noisy speech and noise alone, with a sensitivity-limitation process imposed. The decision metric is assumed to be inversely related to SI and is converted to a percent-correct score using a single data-based fitting function. The model performance was evaluated in conditions of stationary, fluctuating, and speech-like interferers using sentence-based speech-reception thresholds (SRTs) previously obtained in 5 normal-hearing (NH) and 13 hearing-impaired (HI) listeners. For the NH listener group, the model accurately predicted SRTs across the different acoustic conditions (apart from a slight overestimation of the masking release observed for fluctuating maskers), as well as plausible effects in response to changes in presentation level. For HI listeners, the model was adjusted to account for the individual audiograms using standard assumptions concerning the amount of HI attributed to inner-hair-cell (IHC) and outer-hair-cell (OHC) impairment. HI model results accounted remarkably well for elevated individual SRTs and reduced masking release. Furthermore, plausible predictions of worsened SI were obtained when the relative contribution of IHC impairment to HI was increased. Overall, the present model provides a useful tool to accurately predict speech-in-noise outcomes in NH and HI listeners, and may yield important insights into auditory processes that are crucial for speech understanding. [ABSTRACT FROM AUTHOR]

• Experimental models of blast vs noise demonstrate similar patterns of cochlear damage. • Variations in experimental methodology in blast studies make data synthesis challenging. • Endolymphatic hydrops is an indicator of subsequent cochlear synaptic loss. • Central auditory system injury is mediated by both cochlear damage and brain trauma. • More mechanistic studies are needed to develop effective treatments. The auditory system is particularly vulnerable to blast injury due to the ear's role as a highly sensitive pressure transducer. Over the past several decades, studies have used a variety of animal models and experimental procedures to recreate blast-induced acoustic trauma. Given the developing nature of this field and our incomplete understanding of molecular mechanisms underlying blast-related auditory disturbances, an updated discussion about these studies is warranted. Here, we comprehensively review well-established blast-related auditory pathology including tympanic membrane perforation and hair cell loss. In addition, we discuss important mechanistic studies that aim to bridge gaps in our current understanding of the molecular and microstructural events underlying blast-induced cochlear, auditory nerve, brainstem, and central auditory system damage. Key findings from the recent literature include the association between endolymphatic hydrops and cochlear synaptic loss, blast-induced neuroinflammatory markers in the peripheral and central auditory system, and therapeutic approaches targeting biochemical markers of blast injury. We conclude that blast is an extreme form of noise exposure. Blast waves produce cochlear damage that appears similar to, but more extreme than, the standard noise exposure protocols used in auditory research. However, experimental variations in studies of blast-induced acoustic trauma make it challenging to compare and interpret data across studies. [ABSTRACT FROM AUTHOR]

Abstract: Auditory neuropathy is a hearing disorder characterized by normal function of outer hair cells, evidenced by intact cochlear microphonic (CM) potentials and otoacoustic emissions (OAEs), with absent or severely dys-synchronized auditory brainstem responses (ABRs). To determine if selective lesions of inner hair cells (IHCs) and auditory nerve fibers (ANFs) can account for these primary clinical features of auditory neuropathy, we measured physiological responses from chinchillas with large lesions of ANFs (about 85%) and IHCs (45% loss in the apical half of the cochlea; 73% in the basal half). Distortion product OAEs and CM potentials were significantly enhanced, whereas summating potentials and compound action potentials (CAPs) were significantly reduced. CAP threshold was elevated by 7.5dB, but response synchrony was well preserved down to threshold levels of stimulation. Similarly, ABR threshold was elevated by 5.6dB, but all waves were present and well synchronized down to threshold levels in all animals. Thus, large lesions of IHCs and ANFs reduced response amplitudes but did not abolish or severely dys-synchronize CAPs or ABRs. Pathologies other than or in addition to ANF and IHC loss are likely to account for the evoked potential dys-synchrony that is a clinical hallmark of auditory neuropathy in humans. [Copyright &y& Elsevier]

• Frequency-following responses (FFRs) to tones and sweeps are reduced in older normal-hearing adults. • FFR reductions observed across lower and higher carrier frequencies (200 – 1200 Hz). • FFR reductions consistent with auditory nerve model simulations of age-dependent fiber loss. Healthy aging may be associated with neural degeneration in the cochlea even before clinical hearing loss emerges. Reduction in frequency-following responses (FFRs) to tonal carriers in older clinically normal-hearing listeners has previously been reported, and has been argued to reflect an age-dependent decline in temporal processing in the central auditory system. Alternatively, age-dependent loss of auditory nerve fibers (ANFs) may have little effect on audiometric sensitivity and yet compromise the precision of neural phase-locking relying on joint activity across populations of fibers. This peripheral loss may, in turn, contribute to reduced neural synchrony in the brainstem as reflected in the FFR. Here, we combined human electrophysiology and auditory nerve (AN) modeling to investigate whether age-related changes in the FFR would be consistent with peripheral neural degeneration. FFRs elicited by pure tones and frequency sweeps at carrier frequencies between 200 and 1200 Hz were obtained in older (ages 48–76) and younger (ages 20–30) listeners, both groups having clinically normal audiometric thresholds up to 6 kHz. The same stimuli were presented to a computational model of the AN in which age-related loss of hair cells or ANFs was modelled using human histopathological data. In the older human listeners, the measured FFRs to both sweeps and pure tones were found to be reduced across the carrier frequencies examined. These FFR reductions were consistent with model simulations of age-related ANF loss. In model simulations, the phase-locked response produced by the population of remaining fibers decreased proportionally with increasing loss of the ANFs. Basal-turn loss of inner hair cells also reduced synchronous activity at lower frequencies, albeit to a lesser degree. Model simulations of age-related threshold elevation further indicated that outer hair cell dysfunction had no negative effect on phase-locked AN responses. These results are consistent with a peripheral source of the FFR reductions observed in older normal-hearing listeners, and indicate that FFRs at lower carrier frequencies may potentially be a sensitive marker of peripheral neural degeneration. [ABSTRACT FROM AUTHOR]

Abstract: Research in animal models has demonstrated that electrical stimulation from a cochlear implant (CI) may help prevent degeneration of the cochlear spiral ganglion (SG) neurons after deafness. In cats deafened early in life, effective stimulation of the auditory nerve with complex signals for several months preserves a greater density of SG neurons in the stimulated cochleae as compared to the contralateral deafened ear. However, SG survival is still far from normal even with early intervention with an implant. Thus, pharmacologic agents and neurotrophic factors that might be used in combination with an implant are of great interest. Exogenous administration of GM1 ganglioside significantly reduces SG degeneration in deafened animals studied at 7–8 weeks of age, but after several months of stimulation, GM1-treated animals show only modestly better preservation of SG density compared to age-matched non-treated animals. A significant factor influencing neurotrophic effects in animal models is insertion trauma, which results in significant regional SG degeneration. Thus, an important goal is to further improve human CI electrode designs and insertion techniques to minimize trauma. Another important issue for studies of neurotrophic effects in the developing auditory system is the potential role of critical periods. Studies examining animals deafened at 30 days of age (rather than at birth) have explored whether a brief initial period of normal auditory experience affects the vulnerability of the SG or cochlear nucleus (CN) to auditory deprivation. Interestingly, SG survival in animals deafened at 30-days was not significantly different from age-matched neonatally deafened animals, but significant differences were observed in the central auditory system. CN volume was significantly closer to normal in the animals deafened at 30 days as compared to neonatally deafened animals. However, no difference was observed between the stimulated and contralateral CN volumes in either deafened group. Measurements of AVCN spherical cell somata showed that after later onset of deafness in the 30-day deafened group, mean cell size was significantly closer to normal than in the neonatally deafened group. Further, electrical stimulation elicited a significant increase in spherical cell size in the CN ipsilateral to the implant as compared to the contralateral CN in both deafened groups. Neuronal tracer studies have examined the primary afferent projections from the SG to the CN in neonatally deafened cats. CN projections exhibit a clear cochleotopic organization despite severe auditory deprivation from birth. However, when normalized for the smaller CN size after deafness, projections were 30–50% broader than normal. After unilateral electrical stimulation there was no difference between projections from the stimulated and non-stimulated ears. These findings suggest that early normal auditory experience may be essential for the normal development (or subsequent maintenance) of the topographic precision of SG-to-CN projections. After early deafness, the CN volume is markedly smaller than normal, and the spatial precision of SG projections that underlie frequency resolution in the central auditory system is reduced. Electrical stimulation over several months did not reduce or exacerbate these degenerative changes. If similar principles pertain in the human auditory system, then findings in animal models suggest that the basic cochleotopic organization of neural projections in the central auditory system is probably intact even in congenitally deaf individuals. However, the reduced spatial resolution of the primary afferent projections in our studies suggests that there may be inherent limitations for CI stimulation in congenitally deaf subjects. Spatial (spectral) selectivity of stimulation delivered on adjacent CI channels may be poorer due to the greater overlap of SG central axons representing nearby frequencies. Such CI users may be more dependent upon temporal features of electrical stimuli, and it may be advantageous to enhance the salience of such cues, for example, by removing some electrodes from the processor “map” to reduce channel interaction. [Copyright &y& Elsevier]

Abstract: We have demonstrated recently in an animal model that stimulation with a penetrating auditory nerve electrode array is a feasible means of activating the ascending auditory pathway for auditory prosthesis. Compared to a conventional intrascalar cochlear implant, intraneural stimulation provides access to fibers serving a broader frequency range, activation of more tonotopically restricted fiber populations, lower thresholds, and reduced interference between simultaneously stimulated channels. The spread of excitation by a single intraneural electrode is broader than that by an acoustic tone but narrower than that by a cochlear-implant electrode. In the present study, we compare in an animal model two sites of intraneural stimulation: the modiolar trunk of the nerve accessed using a transcochlear approach and the intracranial portion of the nerve accessed using a posterior fossa approach. The two stimulation sites offer very similar thresholds, spread of activation, and dynamic ranges. The intracranial site differed in that there was greater between-animal variation in tonotopic patterns. We discuss the implications of these results for possible improvements in hearing prosthesis for human subjects. [Copyright &y& Elsevier]

Abstract: Noise vocoded speech tokens produce temporal patterns in the ensemble response of the auditory nerve similar to those of their naturally produced counterparts [Loebach, J.L., Wickesberg, R.E., 2006. The representation of noise vocoded speech in the auditory nerve of the chinchilla: Physiological correlates for the perception of spectrally reduced speech. Hear. Res. 213 (1–2), 130–144]. Moreover, the degree of pattern similarity increased as more noise bands were used to synthesize the vocoded stimuli, suggesting a relationship between the patterns that these stimuli evoke in the auditory nerve and their recognition by human subjects. In order to make a direct comparison between the psychoacoustic and physiological domains, the present study obtained the perceptual identification scores for these stimuli. A set of 120 stimuli containing the 16 tokens of interest was presented to 30 young normal hearing subjects, who identified the tokens in a closed set task. Overall, the perceptual identification of the tokens increased in accuracy with the addition of noise bands. The neural pattern similarity was quantified using dynamic time warping, and correlated with the perceptual identification scores for the target stimuli of interest. A significant linear relationship between the pattern similarity and perceptual identification scores was found, such that as neural pattern similarity increased, the accuracy of stimulus identification also increased. These findings suggest a possible physiological substrate for the recognition of noise vocoded consonants. [Copyright &y& Elsevier]

Abstract: Cochlear damage can change the spontaneous firing rates of neurons in the dorsal cochlear nucleus (DCN). Increased spontaneous firing rates (hyperactivity) after acoustic trauma have been observed in the DCN of rodents such as hamsters, chinchillas and rats. This hyperactivity has been interpreted as a neural correlate of tinnitus. In cats, however, the spontaneous firing rates of DCN neurons were not significantly elevated after acoustic trauma. Species-specific spontaneous firing rates after cochlear damage might be attributable to differences in the response types of DCN neurons: In gerbils, type III response characteristics are predominant, whereas in cats type IV responses are more frequent. To address the question of how the development of hyperactivity after cochlear damage depends on the response type of DCN neurons, we use a computational model of the basic circuit of the DCN. By changing the strength of two types of inhibition, we can reproduce salient features of the responses of DCN neurons. Simulated cochlear damage, which decreases the activity of auditory nerve fibers, is assumed to activate homeostatic plasticity in projection neurons (PNs) of the DCN. We find that the resulting spontaneous firing rates depend on the response type of DCN PNs: PNs with type III and type IV-T response characteristics may become hyperactive, whereas type IV PNs do not develop increased spontaneous firing rates after acoustic trauma. This theoretical framework for the mechanisms and circumstances of the development of hyperactivity in central auditory neurons might also provide new insights into the development of tinnitus. [Copyright &y& Elsevier]

Abstract: Detecting sounds in quiet is the simplest task performed by the auditory system, but the neural mechanisms underlying perceptual detection thresholds for sounds in quiet are still not understood. Heil and Neubauer [Heil, P., Neubauer, H., 2003. A unifying basis of auditory thresholds based on temporal summation. Proc. Natl. Acad. Sci. USA 100, 6151–6156] have provided evidence for a simple probabilistic model according to which the stimulus, at any point in time, has a certain probability of exceeding threshold and being detected. Consequently, as stimulus duration increases, the cumulative probability of detection events increases, performance improves, and threshold amplitude decreases. The origin of these processes was traced to the first synapse in the auditory system, between the inner hair cell and the afferent auditory-nerve fiber (ANF). Here we provide further support for this probabilistic “continuous-look” model. It is derived from analyses of the distributions of the latencies of the first spikes of cat ANFs with very low spontaneous discharge rates to tones of different amplitudes. The first spikes in these fibers can be considered detection events. We show that, as predicted, the distributions can be explained by the joint probability of the occurrence of three independent sub-events, where the probability of each of those occurring is proportional to the low-pass filtered stimulus amplitude. The “temporal integration” functions of individual ANFs, derived from their first-spike latencies, are remarkably similar in shape to “temporal integration” functions, which relate threshold sound pressure level at the perceptual level to stimulus duration. This further supports a close link between the mechanisms determining the timing of the first (and other) evoked spikes at the level of the auditory nerve and detection thresholds at the perceptual level. The possible origin and some functional consequences of the expansive power-law non-linearity are discussed. [Copyright &y& Elsevier]

Abstract: Increasing numbers of cochlear implant subjects have some level of residual hearing at the time of implantation. The present study examined whether (i) hair cells that have survived one pathological insult (aminoglycoside deafening), can survive and function following long-term cochlear implantation and electrical stimulation (ES); and (ii) chronic ES in these cochleae results in greater trophic support of spiral ganglion neurons (SGNs) compared with cochleae devoid of hair cells. Eight cats, with either partial (n =4) or severe (n =4) sensorineural hearing loss, were bilaterally implanted with scala tympani electrode arrays 2 months after deafening, and received unilateral ES using charge balanced biphasic current pulses for periods of up to 235 days. Frequency-specific compound action potentials and click-evoked auditory brainstem responses (ABRs) were recorded periodically to monitor the residual acoustic hearing. Electrically evoked ABRs (EABRs) were recorded to confirm the stimulus levels were 3–6dB above the EABR threshold. On completion of the ES program the cochleae were examined histologically. Partially deafened animals showed no significant increase in acoustic thresholds over the implantation period. Moreover, chronic ES of an electrode array located in the base of the cochlea did not adversely affect hair cells in the middle or apical turns. There was evidence of a small but statistically significant rescue of SGNs in the middle and apical turns of stimulated cochleae in animals with partial hearing. Chronic ES did not, however, prevent a reduction in SGN density for the severely deaf cohort, although SGNs adjacent to the stimulating electrodes did exhibit a significant increase in soma area (p <0.01). In sum, chronic ES in partial hearing animals does not adversely affect functioning residual hair cells apical to the electrode array. Moreover, while there is an increase in the soma area of SGNs close to the stimulating electrodes in severely deaf cochleae, this trophic effect does not result in increased SGN survival. [Copyright &y& Elsevier]

Abstract: To determine the site of excitation on the spiral ganglion cell in response to electrical stimulation similar to that from a cochlear implant, single-fiber responses to electrical stimuli delivered by an electrode positioned in the scala tympani were compared to responses from stimuli delivered by an electrode placed in the internal auditory meatus. The response to intrameatal stimulation provided a control set of data with a known excitation site, the central axon of the spiral ganglion cell. For both intrameatal and scala tympani stimuli, the responses to single-pulse, summation, and refractory stimulus protocols were recorded. The data demonstrated that summation pulses, as opposed to single pulses, are likely to give the most insightful measures for determination of the site of excitation. Single-fiber summation data for both scala tympani and intrameatally stimulated fibers were analyzed with a clustering algorithm. Combining cluster analysis and additional numerical modeling data, it was hypothesized that the scala tympani responses corresponded to central excitation, peripheral excitation adjacent to the cell body, and peripheral excitation at a site distant from the cell body. Fibers stimulated by an intrameatal electrode demonstrated the greatest range of jitter measurements indicating that greater fiber independence may be achieved with intrameatal stimulation. [Copyright &y& Elsevier]

Abstract: This study investigated the neural representation of naturally produced and noise vocoded speech signals in the auditory nerve of the chinchilla. The syllables produced by male speakers were used to synthesize noise vocoded speech stimuli containing one, two, three and four bands of envelope modulated noise. The ensemble response of the auditory nerve, computed by pooling the PST histograms across many auditory nerve fibers, revealed temporal patterns in the responses to the natural tokens that uniquely identified the stop consonants. The responses to the 3- and 4-band noise vocoded tokens contained temporal patterns that were nearly identical to those observed for the natural tokens, while the responses to the 1- and 2-band tokens were significantly different (p <0.0001). The ALSR, ALIR and autocorrelation of the pooled PST histograms represented the detail of the frequency spectrum for a naturally produced vowel, while the driven rate was unreliable. Each of these spectral analyses failed to reveal significant information about the noise vocoded vowels. These results suggest that temporal patterns in the responses of the auditory nerve can provide the cues necessary for the recognition of noise vocoded stop consonants. [Copyright &y& Elsevier]

Abstract: Several physiological studies have linked experimentally induced tinnitus to increases in the spontaneous activity of auditory neurons. These results have led to the proposal of hyperactivity models of tinnitus in which elevated neural activity in the absence of auditory stimulation is perceived as phantom sound. Such models are appealing in their simplicity but remain controversial because a generalized elevation of spontaneous rates may not be observed after treatments that induce tinnitus in humans and experimental animals. Our study addressed these issues by characterizing the effects of common methods of tinnitus induction on spontaneous activity in the central nucleus of the inferior colliculus (ICC). The ICC is an interesting structure in tinnitus research because its diverse inputs include putative generator sites in the dorsal cochlear nucleus, as well as brainstem sources that appear to remain normal after tinnitus induction. Groups of CBA/J mice were subjected to one of three induction methods: bilateral or unilateral sound exposure, and acute salicylate intoxication. Relative to normal baselines, bilaterally exposed mice showed increases in the spontaneous rates of neurons with tuning near the exposure frequency. When the sample was separated into physiologically defined response classes, exposure effects were strongest among neurons with broad excitatory bandwidths. By contrast, salicylate decreased the spontaneous rates of low-frequency neurons with transient sound-evoked activity. Our results suggest that the disordered processes of hearing that give rise to tinnitus do not involve a pervasive elevation of spontaneous activity or a single mode of induction. [Copyright &y& Elsevier]

Abstract: Many kinds of information are carried in the acoustic signal that reaches auditory receptor cells in the cochlea. The analysis of this information is possible in large part because of the neuronal architecture of the auditory system. The mechanisms that establish the precise circuitry that underlies auditory processing have not yet been identified. The Eph receptor tyrosine kinases and their ligands are proteins that regulate axon guidance and have been shown to contribute to the establishment of topographic projections in several areas of the nervous system. Several studies have begun to investigate whether these proteins are involved in the formation of auditory system connections. Studies of gene expression show that Eph proteins are extensively expressed in structures of the inner ear as well as in neurons in the peripheral and central components of the auditory system. Functional studies have demonstrated that Eph signaling influences the assembly of auditory pathways. These studies suggest that Eph protein signaling has a significant role in the formation of auditory circuitry. [Copyright &y& Elsevier]

Abstract: With the advent of eCAP recording tools such as NRT and NRI for cochlear implants, neural monitoring has become widely used to ascertain the integrity of the neural/electrode interface as well as for assisting in the setting of program levels. The basic concepts of eCAP recordings are deduced from the acoustical equivalent of the electrocochleogram. There are, however, indications that under electrical stimulation some of these do not hold, like the unitary response concept (i.e., the principle that every fiber produces the same contribution to the eCAP). Computer modeling has proven to be a valuable tool for gaining insight into the functioning of electrical stimulation. In this study the extension of a three-dimensional human cochlea, incorporating back-measuring capabilities, is described. Using this new model, the contribution of single fiber action potentials (SFAPs) to the measured eCAP is investigated. The model predicts that contrary to common belief – the compound action potential as measured by the cochlear implant system does not necessarily reflect the propagated action potential along the auditory nerve. [Copyright &y& Elsevier]

Abstract: Ontogenesis of the human peripheral auditory pathway is relatively less explored. While the distal part of the auditory perception apparatus (i.e. the cochlea) received attention, studies on the neural element carrying information to the brainstem (i.e. the cochlear nerve) are scarce. In the present study, axonal differentiation, maturation and myelination of the distal end of the human cochlear nerve (CN) were assessed using light and electron microscopy. Seven human fetuses of 12, 15, 18, 20, 22, 28 and 38 weeks’ gestation (WG) were analyzed. Light microscopy revealed nerve fascicles as early as 12 WG, initially arranged loosely but later compacted by 18 WG. Myelinated fibers were clearly detected at 28 WG. Ultrastructurally, at 12 WG developing Schwann cells were present between the thin unmyelinated axons. At 15 WG, the fascicular arrangement was distinct with blood vessels in the perineurium. The maximum number of axons was found at 20 WG, which subsequently reduced to reach the adult level at 22 WG. The myelinated axons in the CN were first observed on the left side at 20 WG, following which the number and proportion of myelinated axons increased until term, incorporating both small and large axons. The right CN lagged behind in maturation. Axon size also increased with age. Thus, the maturation of the human CN commences during the mid-gestation period and produces exuberant axons that are eventually pruned at a time when axons start to myelinate. During this developmental period the human CN maintains maturational asymmetry, the functional consequences of which remain to be elucidated. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Ototoxicity of salicylate is accompanied by a temporary hearing loss and tinnitus and has therefore been used to study tinnitus in animal models. Salicylate induced elevated central auditory activity has been interpreted as a correlate of tinnitus. Whether this elevated activity in the central auditory system is due to an increased activity in the auditory nerve is still under discussion. To explore this issue, we recorded the activity of single auditory nerve fibres in anaesthetised gerbils following systemic injection of salicylic acid. Firstly, compound action potential (CAP) thresholds were determined at 5–0 min intervals. Fifteen to 30 min after 200 mg/kg salicylic acid, threshold loss developed in the high frequency range. At 2 h CAP threshold loss reached a plateau amounting to 15–20 dB above 16 kHz, 0–5 dB below 2 kHz. An almost immediate start of threshold loss was observed after 400 mg/kg salicylic acid. A plateau of threshold loss was reached after 1.5 h with values of 25 dB in the high, 5–10 dB in the low frequency range. Secondly, responses of single auditory nerve fibres were studied after administration of 200 mg/kg salicylic acid. Frequency tuning curves and rate intensity (RI) functions at characteristic frequency (CF) were measured. Two hours and more after application, single fibre thresholds were elevated by about 20 dB at all CFs. Sharpness of tuning was reduced. Mean spontaneous rate was significantly reduced at CFs below 5 kHz (mean: 44 vs 28 AP/s). At CFs above 5 kHz mean spontaneous rate remained unchanged. In RI functions no change in maximum discharge rate was observed. The altered response properties can be interpreted by the known effects of salicylate on the prestin mediated active process of the outer hair cells. The elevated activity in the central auditory system after salicylate intoxication thus cannot be caused by cochlear nerve hyperactivity. [Copyright &y& Elsevier]

Responses of auditory nerve fibers were obtained to harmonic complex tones in which single components could be mistuned. Human listeners hear the harmonic tones as single sounds, but the same tones with one component mistuned are heard as two separate sounds. Fourier analysis of the temporal discharge patterns indicated that auditory nerve fibers typically responded to one or two stimulus components near the fibers’ characteristic frequencies. At low stimulus levels, the discharge patterns could also exhibit low-frequency modulation that was produced by beating of two higher-frequency components. The same components were observed in the response spectra, whether those components were part of the original harmonic series or had been mistuned. The discharge patterns and response spectra were consistent with expectations based on previous studies of auditory nerve fibers with harmonic tones and other complex sounds. However, the discharge patterns differed dramatically from the discharge patterns elicited from inferior colliculus neurons by comparable stimuli [Sinex et al., Hear. Res. 168 (2002) 150–162]. [Copyright &y& Elsevier]

Carboplatin preferentially damages inner hair cells (IHC) and type I spiral ganglion neurons (SGNs) in the chinchilla; however, the temporal sequence of events leading to the destruction of these structures is poorly understood. To better understand the mechanisms leading up to the destruction of IHCs and type I SGNs, we measured the activity in single auditory nerve fibers for the first 8 h following carboplatin treatment and also monitored the development of histopathologies in SGNs and IHCs using a dose of carboplatin that killed approximately 50% of the IHCs. The spontaneous discharge rate (SDR) showed a slight increase around 3 h post carboplatin followed by a significant decline at 4–5 h. The saturation driven discharge rate (DDR) showed a significant increase 1–5 h post carboplatin. These physiological changes were associated with the formation of small vacuoles in type I afferent terminals and proximal nerve fibers 1–6 h post carboplatin; signs of IHC damage were first observed around 24–48 h. Thus, the neurotoxic effects of carboplatin occur approximately a day before the IHCs are damaged. The large fluctuations in SDR and DDR that occur several hours after carboplatin treatment are most likely due to the neurotoxic effects of carboplatin. [Copyright &y& Elsevier]

Gross electrical responses to tone bursts were measured in the guinea pig with electrodes located in scala tympani (ST) and scala vestibuli (SV) of the cochlea, on the central portion of the VIIIth nerve fibres in the internal auditory meatus, and on the surface of the cochlear nuclear complex (CN). Intracochlear perfusion of pharmacological blockers of neural and postsynaptic activity as well as aspiration of parts or all of the CN were used to dissect the origin of the many components of the gross responses. It was shown that single-ended recordings from either ST or SV or those derived from the sum of the ST and SV responses not only contain mixed responses from the auditory nerve fibres and cochlear hair cells, but are contaminated or modified by neural activity central to the internal auditory meatus, probably in various parts of the CN. Differential recordings between ST and SV were relatively uncontaminated by such activity. Recordings from central locations were largely uncontaminated by potentials from cochlear hair cells. These results suggest that a revised and extended system of nomenclature for the different components of the gross cochlear potentials is necessary, and interpretation of such potentials needs to take into account multiple central as well as peripheral generators. [Copyright &y& Elsevier]

The configuration of intracochlear electrodes used to electrically stimulate the auditory nerve influences the ensemble fiber response. For example, monopolar stimulation produces lower thresholds and greater spread of excitation than does bipolar stimulation. We used two approaches to investigate how the ensemble of auditory-nerve fibers responds to stimulation delivered by different electrode configurations. As the electrically evoked compound action potential (ECAP) reflects the ensemble response of the nerve, we used its morphology and changes with stimulus level to assess issues related to site-of-excitation and fiber recruitment. In our first approach, feline ECAPs were obtained using a nucleus-style banded electrode array. ECAP latency functions indicated that bipolar stimulation can initiate action potentials at more peripheral sites than does monopolar stimulation. We observed double-peaked ECAPs with bipolar and tripolar stimulation, suggesting excitation of both peripheral and central neural processes. Finally, we observed in some cases a tendency for monopolar stimulation to produce wider ECAP potentials, consistent with the notion that monopolar stimulation excites a broader spatial extent of the fiber population. In our second approach, we applied a simple model to published surveys of single-fiber responses to provide insight into the stochastic properties of the ensemble response. Our results suggest that broader recruitment of fiber activity produced by monopolar stimulation results in a population response with more probabilistic response characteristics and ensemble spike jitter. These observations and our ECAP results are consistent with reports of perceptual advantages attributed to monopolar or other less-focused modes of stimulation. [Copyright &y& Elsevier]

Recent physiological results from the auditory nerve suggest that specific response patterns for word-initial /d/ and /t/ are present across acoustic variations. In this study, single cell recordings from the auditory nerve of anesthetized chinchillas in response to the stop consonants /d/ and /t/ presented in a variety of acoustic contexts were analyzed. Consonants had variable word positions, vowel contexts, types of phonation, and speakers. The response patterns from individual auditory nerve fibers did not reliably differentiate the consonants /d/ and /t/. Global average peristimulus time histograms (GAPSTs) contained invariant patterns for all tokens of each word-final consonant, regardless of context. Ensemble responses to word-final consonants had similarities in their temporal patterns to those in GAPSTs for word-initial consonants. The similar representations in the ensemble auditory nerve response for consonants with different acoustic content suggest a possible substrate for perceptual normalization. Both invariant and variable elements of speech can be computed from the ensemble response of the auditory nerve. [Copyright &y& Elsevier]