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Introduction: Investigating the recovery function and refractory properties of auditory nerve is essential for us to understand the physiology at neural level, not many tools are available to carry out research in humans. Electrically Evoked Compound Action Potential (ECAP) helps us to record the action potential and also provides us with an option of varying the Interpulse Interval (IPI), hence there is a need to carry out research in Cochlear Implant (CI) users with the help of ECAP. Aim: To investigate the refractory property of the neurons and the response characteristics at different cochlear regions. Materials and Methods: Fifty CI users from age 3-10 years with a minimum hearing experience of three months underwent ECAP measures at various IPI. The data were further statistically analysed using SPSS software version 20.0, descriptive and inferential statistics were carried out using ANOVA. Results: It was found that a high ECAP threshold (648 cu) could be found at the basal region of cochlea when compared to medial (658 cu) and apical region (785 cu) at 300 µs and similar higher thresholds at different IPI, thus attributing to the fact that with increase in population of nerve fibres, a better threshold could be achieved. Another finding revealed that with very low IPI, the ECAP thresholds were elevated, with neural recruitment being a contributing factor. Conclusion: There was a difference in neural population amongst individuals, even with better auditory performance. ECAP is one of the objective tool to measure neural function and outcomes in CI individuals. [ABSTRACT FROM AUTHOR]

Bioelectronic medicine uses electrical stimulation of the nervous system to improve health outcomes throughout the body primarily by regulating immune responses. This concept, however, has yet to be applied systematically to the auditory system. There is growing interest in how cochlear damage and associated neuroinflammation may contribute to hearing loss. In conjunction with recent findings, we propose here a new perspective, which could be applied alongside advancing technologies, to use auditory nerve (AN) stimulation to modulate immune responses in hearing health disorders and following surgeries for auditory implants. In this article we will: (1) review the mechanisms of inflammation in the auditory system in relation to various forms of hearing loss, (2) explore nerve stimulation to reduce inflammation throughout the body and how similar neural-immune circuits likely exist in the auditory system (3) summarize current methods for stimulating the auditory system, particularly the AN, and (4) propose future directions to use bioelectronic medicine to ameliorate harmful immune responses in the inner ear and auditory brainstem to treat refractory conditions. We will illustrate how current knowledge from bioelectronic medicine can be applied to AN stimulation to resolve inflammation associated with implantation and disease. Further, we suggest the necessary steps to get discoveries in this emerging field from bench to bedside. Our vision is a future for AN stimulation that includes additional protocols as well as advances in devices to target and engage neural-immune circuitry for therapeutic benefits., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Seicol, Guo, Garrity and Xie.)

This paper summarizes recent efforts in implementing a model of the ear's inner hair cell and auditory nerve on a neuromorphic hardware platform, the SpiNNaker machine. This exploits the massive parallelism of the target architecture to obtain real-time modeling of a biologically realistic number of human auditory nerve fibres. We show how this model can be integrated with additional modules that simulate previous stages of the early auditory pathway running on the same hardware architecture, thus producing a full-scale spiking auditory nerve output from a single sound stimulus. The results of the SpiNNaker implementation are shown to be comparable with a MATLAB version of the same model algorithms, while removing the inherent performance limitations associated with an increase in auditory model scale that are seen in the conventional computer simulations. Finally, we outline the potential for using this system as part of a full-scale, real-time digital model of the complete human auditory pathway on the SpiNNaker platform. [ABSTRACT FROM AUTHOR]

Frequency analysis of sound by the cochlea is the most fundamental property of the auditory system. Despite its importance, the resolution of this frequency analysis in humans remains controversial. The controversy persists because the methods used to estimate tuning in humans are indirect and have not all been independently validated in other species. Some data suggest that human cochlear tuning is considerably sharper than that of laboratory animals, while others suggest little or no difference between species. We show here in a single species (ferret) that behavioral estimates of tuning bandwidths obtained using perceptual masking methods, and objective estimates obtained using otoacoustic emissions, both also employed in humans, agree closely with direct physiological measurements from single auditory-nerve fibers. Combined with human behavioral data, this outcome indicates that the frequency analysis performed by the human cochlea is of significantly higher resolution than found in common laboratory animals. This finding raises important questions about the evolutionary origins of human cochlear tuning, its role in the emergence of speech communication, and the mechanisms underlying our ability to separate and process natural sounds in complex acoustic environments. [ABSTRACT FROM AUTHOR]

A fundamental task of the ascending auditory system is to produce representations that facilitate the recognition of complex sounds. This is particularly challenging in the context of acoustic variability, such as that between different talkers producing the same phoneme. These representations are transformed as information is propagated throughout the ascending auditory system from the inner ear to the auditory cortex (AI). Investigating these transformations and their role in speech recognition is key to understanding hearing impairment and the development of future clinical interventions. Here, we obtained neural responses to an extensive set of natural vowel-consonant-vowel phoneme sequences, each produced by multiple talkers, in three stages of the auditory processing pathway. Auditory nerve (AN) representations were simulated using a model of the peripheral auditory system and extracellular neuronal activity was recorded in the inferior colliculus (IC) and primary auditory cortex (AI) of anaesthetized guinea pigs. A classifier was developed to examine the efficacy of these representations for recognizing the speech sounds. Individual neurons convey progressively less information from AN to AI. Nonetheless, at the population level, representations are sufficiently rich to facilitate recognition of consonants with a high degree of accuracy at all stages indicating a progression from a dense, redundant representation to a sparse, distributed one. We examined the timescale of the neural code for consonant recognition and found that optimal timescales increase throughout the ascending auditory system from a few milliseconds in the periphery to several tens of milliseconds in the cortex. Despite these longer timescales, we found little evidence to suggest that representations up to the level of AI become increasingly invariant to across-talker differences. Instead, our results support the idea that the role of the subcortical auditory system is one of dimensionality expansion, which could provide a basis for flexible classification of arbitrary speech sounds. [ABSTRACT FROM AUTHOR]

Electrical stimulation of the auditory nerve with a penetrating intraneural (IN) electrode in acutely deafened cats produces much more restricted spread of excitation than is obtained in that preparation with a conventional cochlear implant (CI) as reported by Middlebrooks and Snyder (J Assoc Res Otolaryngol 8:258-279, 2007). That suggests that a future auditory prosthesis employing IN stimulation might offer human patients greater frequency selectivity than is available with a present-day CI. Nevertheless, it is a concern that the electrical field produced by an IN electrode might be too restricted to produce adequate stimulation of the partially depopulated auditory nerve of a deaf patient. We evaluated this by testing responses to IN and CI stimulation in adult-deafened cats. Activation of the auditory pathway was monitored by recording from the central nucleus of the inferior colliculus (ICC). Cats deaf for 153-277 days exhibited a ~ 30 % loss of auditory nerve fibers compared to cats deaf for < 18 h. Contrary to our concern, measures of thresholds and dynamic ranges showed no significant deafness-related impairment of excitation by IN or CN stimulation. Surprisingly, however, temporal acuity decreased dramatically in these adult-deafened cats, as demonstrated by a marked decrease in the maximum rate of electrical cochlear stimulation to which ICC neurons synchronized to IN or CI stimulation. For instance, half of ICC neurons synchronized to IN stimulation up to 203 pulses per second (pps) in acute deafness, whereas that number dropped to 79 pps for chronic deafness. Such a loss of temporal acuity might contribute to the poor sensitivity to temporal fine structure that has been reported in human CI users. Seemingly, the degraded temporal acuity that we observed in cats was even worse than the fine-structure sensitivity of human CI users, suggesting that most patients experience some improvement of temporal acuity resulting from restoration of patterned auditory nerve stimulation by a CI. [ABSTRACT FROM AUTHOR]

Aging listeners, even in the absence of overt hearing loss measured as changes in hearing thresholds, often experience impairments processing temporally complex sounds such as speech in noise. Recent evidence has shown that normal aging is accompanied by a progressive loss of synapses between inner hair cells and auditory nerve fibers. The role of this cochlear synaptopathy in degraded temporal processing with age is not yet understood. Here, we used population envelope following responses, along with other hair celland neural-based measures from an age-graded series of male and female CBA/CaJ mice to study changes in encoding stimulus envelopes. By comparing responses obtained before and after the application of the neurotoxin ouabain to the inner ear, we demonstrate that we can study changes in temporal processing on either side of the cochlear synapse. Results show that deficits in neural coding with age emerge at the earliest neural stages of auditory processing and are correlated with the degree of cochlear synaptopathy. These changes are seen before losses in neural thresholds and particularly affect the suprathreshold processing of sound. Responses obtained from more central sources show smaller differences with age, suggesting compensatory gain. These results show that progressive cochlear synaptopathy is accompanied by deficits in temporal coding at the earliest neural generators and contribute to the suprathreshold sound processing deficits observed with age. [ABSTRACT FROM AUTHOR]

Background: Cochlear nerve aplasia (CNA) may present with features of auditory neuropathy spectrum disorder (ANSD), having detectable otoacoustic emissions (OAE) but profound hearing loss. We propose that some children with CNA have a distinct form of afferent ANSD in which efferent cochlear nerve function can be detected using contralateral suppression of OAE.Methods: Children were prospectively enrolled with MRI and auditory brainstem response evidence of unilateral CNA, a normal contralateral ear, and detectable OAE bilaterally. Distortion product OAE (DPOAE) levels were recorded in real time with default primary tone settings: frequency (f)2 = 4.5 kHz and f2/f1 = 1.22 kHz, with level (L)1 = 65 dB SPL and L2 = 55 dB SPL. Recordings were made over 2 min with simultaneous application of an intermittent contralateral broadband noise (CBBN) stimulus at 60 dB SPL.Results: Three girls, aged 4.5, 7, and 8 years, participated. Suppression of DPOAE of 0.15-1.3 dB was detected in all 3 ears with CNA in response to CBBN stimulation. No response was detected in the normal ears.Conclusions: Children with unilateral ANSD can have normal efferent cochlear nerve function despite MRI evidence of ipsilateral CNA. The importance of these findings for newborn hearing screening and cochlear implantation is discussed. [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]

Auditory nerve fibers (ANFs) encode pure tones through two modes of coding, spike time and spike rate, depending on the tone frequency. In response to a low-frequency tone, ANF firing is phase locked to the sinusoidal waveform. Because time coding vanishes with an increase in the tone frequency, high-frequency tone coding relies on the spike rate of the ANFs. Adding a continuous broadband noise to a tone compresses the rate intensity function of ANFs and shifts its dynamic range toward higher intensities. Therefore, the ANFs with high-threshold/low-spontaneous rate (SR) are thought to contribute to behavioral tone detection in noise. However, this theory relies on the discharge rate of the ANFs. The direct comparison with the masking threshold through spike timing, irrespective of the spontaneous rate, has not so far been investigated. Taking advantage of a unique proxy to quantify the spike synchrony (i.e., the shuffle autocorrelogram), we show in female gerbils that high-SR ANFs are more adapted to encode low-frequency thresholds through temporal code, giving them a strong robustness in noise. By comparing behavioral thresholds measured using prepulse inhibition of the acoustical startle reflex with population thresholds calculated from ANFs pooled per octave band, we show that threshold-based spike timing provides a better estimate of behavioral thresholds in the low-frequency range, whereas the high-frequency behavioral thresholds rely on the spiking rate, particularly in noise. This emphasizes the complementarity of temporal and rate modes to code tone-in-noise thresholds over a large range of frequencies. [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]

Background: Antenatal corticosteroids (ACS) improve preterm neonatal outcomes. However, uncertainty remains regarding the safety of ACS exposure for the developing fetus, particularly its neurosensory development. Objectives: We investigated the effect of single and multiple ACS exposures on auditory nerve development in an ovine model of pregnancy. Methods: Ewes with a single fetus (gestational age [GA] 100 days) received an intramuscular injection of 150 mg medroxyprogesterone-acetate, followed by intramuscular (i) betamethasone (0.5 mg/kg) on days 104, 111, and 118 GA; (ii) betamethasone on day 104 and saline on days 111 and 118 GA; or (iii) saline on days 104, 111, and 118 GA, with delivery on day 125 GA. Transmission electron microscope images of lamb auditory nerve preparations were digitally analyzed to determine auditory nerve morphology and myelination. Results: Relative to the control, mean auditory nerve myelin area was significantly increased in the multiple-treatment group (p < 0.001), but not in the single-treatment group. Increased myelin thickness was significantly changed only in a subgroup analysis for those axons with myelin thickness greater than the median value (p < 0.001). Morphological assessments showed that the increased myelin area was due to an increased likelihood of decompacted areas (p = 0.005; OR = 2.14, 95% CI 1.26–3.63; 31.6 vs. 18.2% in controls) and irregular myelin deposition (p = 0.001; OR = 5.91, 95% CI 2.16–16.19; 49.0 vs. 16.8% in controls) in the myelin sheath. Conclusions: In preterm sheep, ACS exposure increased auditory nerve myelin area, potentially due to disruption of normal myelin deposition. [ABSTRACT FROM AUTHOR]

Declines in auditory nerve (AN) function contribute to suprathreshold auditory processing and communication deficits in individuals with normal hearing, hearing loss, hyperacusis, and tinnitus. Procedures to characterize AN loss or dysfunction in humans are limited. We report several novel complementary metrics using the compound action potential (CAP), a direct measure of summated AN activity. Together, these metrics may be used to characterize AN function noninvasively in humans. We examined how these metrics change with stimulus intensity and interpreted these changes within a framework of known physiological properties of the basilar membrane and AN. Our results reveal how neural synchrony and the recruitment of AN fibers with longer first-spike latencies likely contribute to the CAP, affect auditory processing, and differ with noise exposure history in younger adults with normal pure-tone thresholds. Moving forward, this new battery of metrics provides a crucial step toward new diagnostics of AN function in humans. [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]