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Noise-induced cochlear synaptopathy is characterized by irreversible loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) despite normal hearing thresholds. We analyzed hearing performance and cochlear structure in C57BL/6 N mice exposed to 100, 106, or 112 dB SPL broadband noise (8–16 kHz) for 2 h. Auditory brainstem responses (ABRs) were assessed before, directly after, and up to 28 days post-trauma. Finally, the number, size, and pairing of IHC presynaptic (CtBP2-positive) ribbons and postsynaptic AMPA receptor scaffold (Homer1-positive) clusters were analyzed along the cochlea. Four weeks after the 100 dB SPL trauma, a permanent threshold shift (PTS) was observed at 45 kHz, which after the higher traumata extended toward middle to low frequencies. Loss in ABR wave I amplitudes scaled with trauma strength indicating loss of functional IHC synaptic connections. Latencies of wave I mostly increased with trauma strength. No trauma-related OHC loss was found. The number of synaptic pairs was reduced in the midbasal and basal cochlear region in all trauma conditions, with ribbon loss amounting up to 46% of control. Ribbons surviving the trauma were paired, whereas 4–6 unpaired postsynapses/IHC were found in the medial, midbasal, and basal regions irrespective of trauma strength, contrasting findings in CBA/CaJ mice. Our data confirm the susceptibility of ribbon synapses and ABR wave I amplitudes to a noise trauma of 100 dB SPL or larger. Notably, peripheral dendrites bearing IHC postsynapses were less vulnerable than presynaptic ribbons in C57BL/6 N mice. [ABSTRACT FROM AUTHOR]

Endolymphatic hydrops, increased endolymphatic fluid within the cochlea, is the key pathologic finding in patients with Meniere's disease, a disease of episodic vertigo, fluctuating hearing loss, tinnitus, and aural fullness. Endolymphatic hydrops also can occur after noise trauma and its presence correlates with cochlear synaptopathy, a form of hearing loss caused by reduced numbers of synapses between hair cells and auditory nerve fibers. Here we tested whether there is a mechanistic link between these two phenomena by using multimodal imaging techniques to analyze the cochleae of transgenic mice exposed to blast and osmotic challenge. In vivo cochlear imaging after blast exposure revealed dynamic increases in endolymph that involved hair cell mechanoelectrical transduction channel block but not the synaptic release of glutamate at the hair cell–auditory nerve synapse. In contrast, ex vivo and in vivo auditory nerve imaging revealed that synaptopathy requires glutamate release from hair cells but not endolymphatic hydrops. Thus, although endolymphatic hydrops and cochlear synaptopathy are both observed after noise exposure, one does not cause the other. They are simply co-existent sequelae that derive from the traumatic stimulation of hair cell stereociliary bundles. Importantly, these data argue that Meniere's disease derives from hair cell transduction channel blockade. [ABSTRACT FROM AUTHOR]

Abstract Endolymphatic hydrops, increased endolymphatic fluid within the cochlea, is the key pathologic finding in patients with Meniere’s disease, a disease of episodic vertigo, fluctuating hearing loss, tinnitus, and aural fullness. Endolymphatic hydrops also can occur after noise trauma and its presence correlates with cochlear synaptopathy, a form of hearing loss caused by reduced numbers of synapses between hair cells and auditory nerve fibers. Here we tested whether there is a mechanistic link between these two phenomena by using multimodal imaging techniques to analyze the cochleae of transgenic mice exposed to blast and osmotic challenge. In vivo cochlear imaging after blast exposure revealed dynamic increases in endolymph that involved hair cell mechanoelectrical transduction channel block but not the synaptic release of glutamate at the hair cell–auditory nerve synapse. In contrast, ex vivo and in vivo auditory nerve imaging revealed that synaptopathy requires glutamate release from hair cells but not endolymphatic hydrops. Thus, although endolymphatic hydrops and cochlear synaptopathy are both observed after noise exposure, one does not cause the other. They are simply co-existent sequelae that derive from the traumatic stimulation of hair cell stereociliary bundles. Importantly, these data argue that Meniere’s disease derives from hair cell transduction channel blockade.

Spiral ganglion neurons (SGNs) transmit auditory information from cochlear hair cells to the brain. SGNs are thus not only important for normal hearing, but also for effective functioning of cochlear implants, which stimulate SGNs when hair cells are missing. SGNs slowly degenerate following aminoglycosideinduced hair cell loss, a process thought to involve an immune response. However, the specific immune response pathways involved remain unknown. We used RNAseq to gain a deeper understanding immune-related and other transcriptomic changes that occur in the rat spiral ganglion after kanamycininduced deafening. Among the immune and inflammatory genes that were selectively upregulated in deafened spiral ganglia, the complement cascade genes were prominent. We then assessed SGN survival, as well as immune cell numbers and activation, in the spiral ganglia of rats with a CRISPR-Cas9-mediated knockout of complement component 3 (C3). Similar to previous findings in our lab and other deafened rodent models, we observed an increase in macrophage number and increased expression of CD68, a marker of phagocytic activity and cell activation, in macrophages in the deafened ganglia. Moreover, we found an increase in MHCII expression on spiral ganglion macrophages and an increase in lymphocyte number in the deafened ganglia, suggestive of an adaptive immune response. However, C3 knockout did not affect SGN survival or increase in macrophage number/activation, implying that complement activation does not play a role in SGN death after deafening. Together, these data suggest that both innate and adaptive immune responses are activated in the deafened spiral ganglion, with the adaptive response directly contributing to cochlear neurodegeneration. [ABSTRACT FROM AUTHOR]

Introduction: Cochlear afferent synapses connecting inner hair cells to spiral ganglion neurons are susceptible to excitotoxic trauma on exposure to loud sound, resulting in a noise-induced cochlear synaptopathy (NICS). Here we assessed the ability of cyclic AMP-dependent protein kinase (PKA) signaling to promote cochlear synapse regeneration, inferred from its ability to promote axon regeneration in axotomized CNS neurons, another system refractory to regeneration. Methods: We mimicked NICS in vitro by applying a glutamate receptor agonist, kainic acid (KA) to organotypic cochlear explant cultures and experimentally manipulated cAMP signaling to determine whether PKA could promote synapse regeneration. We then delivered the cAMP phosphodiesterase inhibitor rolipram via implanted subcutaneous minipumps in noise-exposed CBA/CaJ mice to test the hypothesis that cAMP signaling could promote cochlear synapse regeneration in vivo. Results: We showed that the application of the cell membrane-permeable cAMP agonist 8-cpt-cAMP or the cAMP phosphodiesterase inhibitor rolipram promotes significant regeneration of synapses in vitro within twelve hours after their destruction by KA. This is independent of neurotrophin-3, which also promotes synapse regeneration. Moreover, of the two independent signaling effectors activated by cAMP - the cAMP Exchange Protein Activated by cAMP and the cAMP-dependent protein kinase - it is the latter that mediates synapse regeneration. Finally, we showed that systemic delivery of rolipram promotes synapse regeneration in vivo following NICS. Discussion: In vitro experiments show that cAMP signaling promotes synapse regeneration after excitotoxic destruction of cochlear synapses and does so via PKA signaling. The cAMP phosphodiesterase inhibitor rolipram promotes synapse regeneration in vivo in noise-exposed mice. Systemic administration of rolipram or similar compounds appears to provide a minimally invasive therapeutic approach to reversing synaptopathy post-noise. [ABSTRACT FROM AUTHOR]

Cochlear implants (CIs), a revolutionary breakthrough in auditory technology, have profoundly impacted the lives of individuals with severe hearing impairment. Surgically implanted behind the ear and within the delicate cochlea, these devices represent a direct pathway to restoring the sense of hearing. Implanting hope alongside innovation, their captivating history unfolds through pivotal dates and transformative milestones. From the first human implantation by Drs. William House and John Doyle in 1961 to FDA approval in 1984, each step in their evolution mirrors a triumph of human ingenuity. The 1990s witnessed significant miniaturization, enhancing accessibility, while the 21st century brought about improvements in speech processing and electrode technology. These strides have elevated CIs beyond functional devices to life-changing instruments, enriching both auditory experiences and communication skills. This entry delves into the captivating history of CIs, spotlighting key dates that paint a vivid picture of challenges overcome and remarkable progress achieved. It explores the people and moments that defined their development, ultimately shaping these implants into indispensable tools that continually redefine the landscape of hearing assistance.

Definition: Cochlear implants (CIs), a revolutionary breakthrough in auditory technology, have profoundly impacted the lives of individuals with severe hearing impairment. Surgically implanted behind the ear and within the delicate cochlea, these devices represent a direct pathway to restoring the sense of hearing. Implanting hope alongside innovation, their captivating history unfolds through pivotal dates and transformative milestones. From the first human implantation by Drs. William House and John Doyle in 1961 to FDA approval in 1984, each step in their evolution mirrors a triumph of human ingenuity. The 1990s witnessed significant miniaturization, enhancing accessibility, while the 21st century brought about improvements in speech processing and electrode technology. These strides have elevated CIs beyond functional devices to life-changing instruments, enriching both auditory experiences and communication skills. This entry delves into the captivating history of CIs, spotlighting key dates that paint a vivid picture of challenges overcome and remarkable progress achieved. It explores the people and moments that defined their development, ultimately shaping these implants into indispensable tools that continually redefine the landscape of hearing assistance. [ABSTRACT FROM AUTHOR]

In mammalian hearing, type-I afferent auditory nerve fibers comprise the basis of the afferent auditory pathway. They are connected to inner hair cells of the cochlea via specialized ribbon synapses. Auditory nerve fibers of different physiological types differ subtly in their synaptic location and morphology. Low-spontaneous-rate auditory nerve fibers typically connect on the modiolar side of the inner hair cell, while high-spontaneous-rate fibers are typically found on the pillar side. In aging and noise-damaged ears, this fine-tuned balance between auditory nerve fiber populations can be disrupted and the functional consequences are currently unclear. Here, using immunofluorescent labeling of presynaptic ribbons and postsynaptic glutamate receptor patches, we investigated changes in synaptic morphology at three different tonotopic locations along the cochlea of aging gerbils compared to those of young adults. Quiet-aged gerbils showed about 20% loss of afferent ribbon synapses. While the loss was random at apical, low-frequency cochlear locations, at the basal, high-frequency location it almost exclusively affected the modiolar-located synapses. The subtle differences in volumes of pre- and postsynaptic elements located on the inner hair cell's modiolar versus pillar side were unaffected by age. This is consistent with known physiology and suggests a predominant, age-related loss in the low-spontaneous-rate auditory nerve population in the cochlear base, but not the apex. [ABSTRACT FROM AUTHOR]

Purpose: Frequency selectivity is a fundamental property of the peripheral auditory system; however, the invasiveness of auditory nerve (AN) experiments limits its study in the human ear. Compound action potentials (CAPs) associated with forward masking have been suggested as an alternative to assess cochlear frequency selectivity. Previous methods relied on an empirical comparison of AN and CAP tuning curves in animal models, arguably not taking full advantage of the information contained in forward-masked CAP waveforms. Methods: To improve the estimation of cochlear frequency selectivity based on the CAP, we introduce a convolution model to fit forward-masked CAP waveforms. The model generates masking patterns that, when convolved with a unitary response, can predict the masking of the CAP waveform induced by Gaussian noise maskers. Model parameters, including those characterizing frequency selectivity, are fine-tuned by minimizing waveform prediction errors across numerous masking conditions, yielding robust estimates. Results: The method was applied to click-evoked CAPs at the round window of anesthetized chinchillas using notched-noise maskers with various notch widths and attenuations. The estimated quality factor Q10 as a function of center frequency is shown to closely match the average quality factor obtained from AN fiber tuning curves, without the need for an empirical correction factor. Conclusion: This study establishes a moderately invasive method for estimating cochlear frequency selectivity with potential applicability to other animal species or humans. Beyond the estimation of frequency selectivity, the proposed model proved to be remarkably accurate in fitting forward-masked CAP responses and could be extended to study more complex aspects of cochlear signal processing (e.g., compressive nonlinearities). [ABSTRACT FROM AUTHOR]

Spiral ganglion neurons (SGNs) transmit auditory information from cochlear hair cells to the brain. SGNs are thus not only important for normal hearing, but also for effective functioning of cochlear implants, which stimulate SGNs when hair cells are missing. SGNs slowly degenerate following aminoglycoside-induced hair cell loss, a process thought to involve an immune response. However, the specific immune response pathways involved remain unknown. We used RNAseq to gain a deeper understanding immune-related and other transcriptomic changes that occur in the rat spiral ganglion after kanamycin-induced deafening. Among the immune and inflammatory genes that were selectively upregulated in deafened spiral ganglia, the complement cascade genes were prominent. We then assessed SGN survival, as well as immune cell numbers and activation, in the spiral ganglia of rats with a CRISPR-Cas9-mediated knockout of complement component 3 (C3). Similar to previous findings in our lab and other deafened rodent models, we observed an increase in macrophage number and increased expression of CD68, a marker of phagocytic activity and cell activation, in macrophages in the deafened ganglia. Moreover, we found an increase in MHCII expression on spiral ganglion macrophages and an increase in lymphocyte number in the deafened ganglia, suggestive of an adaptive immune response. However, C3 knockout did not affect SGN survival or increase in macrophage number/activation, implying that complement activation does not play a role in SGN death after deafening. Together, these data suggest that both innate and adaptive immune responses are activated in the deafened spiral ganglion, with the adaptive response directly contributing to cochlear neurodegeneration.

IntroductionCochlear afferent synapses connecting inner hair cells to spiral ganglion neurons are susceptible to excitotoxic trauma on exposure to loud sound, resulting in a noise-induced cochlear synaptopathy (NICS). Here we assessed the ability of cyclic AMP-dependent protein kinase (PKA) signaling to promote cochlear synapse regeneration, inferred from its ability to promote axon regeneration in axotomized CNS neurons, another system refractory to regeneration.MethodsWe mimicked NICS in vitro by applying a glutamate receptor agonist, kainic acid (KA) to organotypic cochlear explant cultures and experimentally manipulated cAMP signaling to determine whether PKA could promote synapse regeneration. We then delivered the cAMP phosphodiesterase inhibitor rolipram via implanted subcutaneous minipumps in noise-exposed CBA/CaJ mice to test the hypothesis that cAMP signaling could promote cochlear synapse regeneration in vivo.ResultsWe showed that the application of the cell membrane-permeable cAMP agonist 8-cpt-cAMP or the cAMP phosphodiesterase inhibitor rolipram promotes significant regeneration of synapses in vitro within twelve hours after their destruction by KA. This is independent of neurotrophin-3, which also promotes synapse regeneration. Moreover, of the two independent signaling effectors activated by cAMP – the cAMP Exchange Protein Activated by cAMP and the cAMP-dependent protein kinase – it is the latter that mediates synapse regeneration. Finally, we showed that systemic delivery of rolipram promotes synapse regeneration in vivo following NICS.DiscussionIn vitro experiments show that cAMP signaling promotes synapse regeneration after excitotoxic destruction of cochlear synapses and does so via PKA signaling. The cAMP phosphodiesterase inhibitor rolipram promotes synapse regeneration in vivo in noise-exposed mice. Systemic administration of rolipram or similar compounds appears to provide a minimally invasive therapeutic approach to reversing synaptopathy post-noise.

Introduction: The trans-tympanic electrically evoked auditory brainstem response measurement in local anesthesia (= LA-TT-EABR) has been shown as a useful tool in doubtful CI candidacy to objectively evaluate the excitability of the auditory pathway up to the brainstem. Previous studies in this matter were of relatively low subjects number. To update the knowledge of the reliability of LA-TTEABR, we re-evaluated the latest results from a bigger subjects dataset from our clinic and follow up regarding hearing sensation post-operatively. Methods: LA-TT-EABR was performed, as described in previous publications, with a trans-tympanic golf-club electrode in the round window niche for pre-operative stimulation in local anesthesia and with an evoked potential device for EABR recording. Hearing sensations were monitored in the implanted CI subjects. Results: 39 of 40 planned subjects were included in this study. In 22 subjects, a positive LA-TT-EABR was recorded. In 11 subjects, the response was insecure. In 6 subjects, no response was recorded. One subject was excluded because of pain during the paracentesis. Among them, 19 were implanted with a CI, and 18 had hearing sensations with a hearing prosthesis post-operative. The sensitivity and specificity of LA-TTEABR in estimating the excitability of the auditory nerve preoperatively are both 100%. Conclusion: LA-TT-EABR was shown as a reliable pre-operative test to objectively evaluate the auditory brainstem response. In addition to LA-TT-EABR, an analysis of the auditory cortex using LA-TT-EALR may provide correlation and confirmation of LA-TT-EABR results and additional information about cortical reorganization after long deafness.

Introduction: Over the last years, in doubt of cochlear implant (CI) candidacy, assessment of excitability of the auditory nerve is performed with pre-operative tests. These tests are the pre-operative (pre-op.) performed electrical auditory brainstem (EABR) and the late response (EALR) recorded with trans-tympanic promontory stimulation in local anesthesia. But in some cases after such preoperative tests there is still doubt about the excitability of the auditory pathway. The most reliable EABR is recorded with using stimulation via the CI. However, before CI implantation,, an intra-cochlear test electrode could be used in order to achieve similar EABR results. Methods: In doubtful cases of patients who underwent pre-op. EABR, we performed EABR by a test electrode, part of the auditory nerve test system. This measurement was used to confirm the pre-operative results just before CI implantation. Additionally, EABR using CI stimulation was performed intra-operatively right after the CI implantation to confirm EABR using the test stimulation electrode results. Results: Six subjects were included in this study. They were tested by pre-op. EABR (n=6), pre-op. EALR (n=5), intra-op. EABR using test electrode (n=6), intraop. EABR via CI (n=6), and post-op. EABR (n=2), and postop. EALR (n=2). In two cases, intra-operative EABR showed a positive, i.e. clearly measureable, response whereas there was a doubtful response in pre-op. EABR. Intra-op. EABRs (test electrode and CI stimulation) showed the same results in all cases. Waveforms of EABR using test electrode look similar to EABR using CI stimulation but with more defined peaks compare to the pre-op. EABR. In one case with all-over positive EABR, pre-op. EALR, and post-operative EALR were matching. Conclusion: Intra-op. EABR using test electrode was easy to record and it shows similar results to EABR using CI stimulation. Intra-op. EABR using test electrode may help in confirming the results of not clear preop. EABR with a minimal increase in recording time.

The case report highlights the importance of the rehabilitative approach and the role of audiology in managing patients with Ramsay Hunt Syndrome (RHS). RHS is a rare condition characterized by neuropathies involving multiple cranial nerves. Out of three neurological variants noted in the literature, RHS type II is characterized by hearing loss, tinnitus, and vertigo. The current case report is of a 37-year-old female diagnosed with RHS type II who reported with the complaints of right-sided headache and chronic otalgia. The progression of the disease caused hearing loss and tinnitus on the right side. Subsequently, the patient also developed signs of imbalance, which were not reported till 2 weeks after the onset of other symptoms. Three audiological evaluations were done during the initial visit, treatment phase, and post-treatment. It also helped identify the need for vestibular rehabilitation therapy and medical treatment. A comprehensive team approach and timely intervention aided in the prevention of the long-lasting effects of RHS in this patient. Awareness about the roles of professionals in assessment and management can help significantly improve the quality of life of individuals, especially in syndromes and multiple disabilities. [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.

Sensorineural hearing loss is associated with dysfunction of cochlear cells. Although immune cells play a critical role in maintaining the inner ear microenvironment, the precise immune-related molecular mechanisms underlying the pathophysiology of hearing loss remain unclear. The complement cascade contributes to the regulation of immune cell activity. Additionally, activation of the complement cascade can lead to the cellular opsonization of cells and pathogens, resulting in their engulfment and elimination by phagocytes. Complement factor B (fB) is an essential activator protein in the alternative complement pathway, and variations in the fB gene are associated with age-related macular degeneration. Here we show that mice of both sexes deficient in fB functional alleles (fB-/-) demonstrate progressive hearing impairment. Transcriptomic analysis of auditory nerves from adult mice detected 706 genes that were significantly differentially expressed between fB-/- and wild-type control animals, including genes related to the extracellular matrix and neural development processes. Additionally, a subset of differentially expressed genes was related to myelin function and neural crest development. Histological and immunohistochemical investigations revealed pathological alterations in auditory nerve myelin sheathes of fB-/- mice. Pathological alterations were also seen in the stria vascularis of the cochlear lateral wall in these mice. Our results implicate fB as an integral regulator of myelin maintenance and stria vascularis integrity, underscoring the importance of understanding the involvement of immune signaling pathways in sensorineural hearing loss. [ABSTRACT FROM AUTHOR]

Cochlear synaptopathy is the loss of synapses between the inner hair cells and the auditory nerve despite survival of sensory hair cells. The findings of extensive cochlear synaptopathy in animals after moderate noise exposures challenged the long-held view that hair cells are the cochlear elements most sensitive to insults that lead to hearing loss. However, cochlear synaptopathy has been difficult to identify in humans. We applied novel algorithms to determine hair cell and neural contributions to electrocochleographic (ECochG) recordings from the round window of animal and human subjects. Gerbils with normal hearing provided training and test sets for a deep learning algorithm to detect the presence of neural responses to low frequency sounds, and an analytic model was used to quantify the proportion of neural and hair cell contributions to the ECochG response. The capacity to detect cochlear synaptopathy was validated in normal hearing and noise-exposed animals by using neurotoxins to reduce or eliminate the neural contributions. When the analytical methods were applied to human surgical subjects with access to the round window, the neural contribution resembled the partial cochlear synaptopathy present after neurotoxin application in animals. This result demonstrates the presence of viable hair cells not connected to auditory nerve fibers in human subjects with substantial hearing loss and indicates that efforts to regenerate nerve fibers may find a ready cochlear substrate for innervation and resumption of function. [ABSTRACT FROM AUTHOR]

Improved technology in vestibular neuroma resection and facial nerve protection has become more sophisticated, and the protection of hearing during vestibular schwannoma resection is crucial. Currently, brainstem auditory evoked potential (BAEP), cochlear electrography, and cochlear nerve compound action potential (CNAP) are frequently used. The CNAP waveform is stable; however, the recording electrode can easily affect the procedure and cannot map the auditory nerve. The purpose of the study was to explore a simple method to record the CNAP and map the auditory nerve. In this study, CNAP was recorded using a facial nerve bipolar stimulator to localize and protect the auditory nerve. The BAEP click stimulation mode was used. A bipolar stimulator was used as the recording electrode to record CNAP and locate anatomical displacement of the auditory nerve. The CNAP of 40 patients was monitored. Pure tone audiometry, speech discrimination score, and auditory evoked potential (BAEP) evaluations were performed on all patients before and after surgery. Of the 40 patients, 30 patients obtained CNAP during surgery, and the rate of CNAP obtained was significantly higher than that of BAEP. The sensitivity and specificity of decrease in CNAP in predicting significant hearing loss were 88.9% and 66.7%, respectively. The sensitivity and specificity of the disappearance of CNAP in predicting significant hearing loss were 52.9% and 92.3%, respectively. The bipolar facial nerve stimulator can locate and protect the auditory nerve by recording a stable potential. The CNAP obtained rate was significantly higher than that of BAEP. The disappearance of BAEP during acoustic neuroma monitoring can be used as a standard alert for the surgeon, and decrease in CNAP is an alert for the operator. [ABSTRACT FROM AUTHOR]

Optogenetic control of neural activity enables innovative approaches to improve functional restoration of diseased sensory and motor systems. For clinical translation to succeed, optogenetic stimulation needs to closely match the coding properties of the targeted neuronal population and employ optimally operating emitters. This requires the customization of channelrhodopsins, emitters and coding strategies. Here, we provide a framework to parametrize optogenetic neural control and apply it to the auditory pathway that requires high temporal fidelity of stimulation. We used a viral gene transfer of ultrafast targeting-optimized Chronos into spiral ganglion neurons (SGNs) of the cochlea of mice. We characterized the light-evoked response by in vivo recordings from individual SGNs and neurons of the anteroventral cochlear nucleus (AVCN) that detect coincident SGN inputs. Our recordings from single SGNs demonstrated that their spike probability can be graded by adjusting the duration of light pulses at constant intensity, which optimally serves efficient laser diode operation. We identified an effective pulse width of 1.6 ms to maximize encoding in SGNs at the maximal light intensity employed here (∼35 mW). Alternatively, SGNs were activated at lower energy thresholds using short light pulses (

The aim of the article was to compare the conditions of silent and contralateral noise on the temporal processing parameters. A total of 40 participants (20 males and 20 females) were enrolled in the study with a mean age of 21.7 years, participants with normal hearing thresholds and no history of middle ear pathology were enrolled for the study. The temporal processing tests such as duration discrimination test, gap detection test, and temporal modulation transfer function tests were carried out in these 40 individuals in the two conditions of silent and contralateral noise using MATLAB. Statistical analysis was carried out using the SPSS version 25.0 were descriptive and inferential statistics were carried out. Data was normally distributed on the Shapiro–Wilk's test of normality due to which a paired t test was carried out to establish the nature of significance between the silent and contralateral noise condition. Results reveal the presence of significant difference (p < 0.01) between the groups for all the parameters of temporal resolution with contralateral noise condition performing better than silent condition for the parameters. There is a positive effect of the efferent auditory pathway on the temporal resolution parameters thus implying that speech perception in noise is improved in the presence of background noise for normal hearing individuals due to this effect. [ABSTRACT FROM AUTHOR]

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Sensorineural hearing loss is associated with dysfunction of cochlear cells. Although immune cells play a critical role in maintaining the inner ear microenvironment, the precise immune-related molecular mechanisms underlying the pathophysiology of hearing loss remain unclear. The complement cascade contributes to the regulation of immune cell activity. Additionally, activation of the complement cascade can lead to the cellular opsonization of cells and pathogens, resulting in their engulfment and elimination by phagocytes. Complement factor B (fB) is an essential activator protein in the alternative complement pathway, and variations in the fB gene are associated with age-related macular degeneration. Here we show that mice of both sexes deficient in fB functional alleles (fB−/−) demonstrate progressive hearing impairment. Transcriptomic analysis of auditory nerves from adult mice detected 706 genes that were significantly differentially expressed between fB−/− and wild-type control animals, including genes related to the extracellular matrix and neural development processes. Additionally, a subset of differentially expressed genes was related to myelin function and neural crest development. Histological and immunohistochemical investigations revealed pathological alterations in auditory nerve myelin sheathes of fB−/− mice. Pathological alterations were also seen in the stria vascularis of the cochlear lateral wall in these mice. Our results implicate fB as an integral regulator of myelin maintenance and stria vascularis integrity, underscoring the importance of understanding the involvement of immune signaling pathways in sensorineural hearing loss.

Cochlear synaptopathy is the loss of synapses between the inner hair cells and the auditory nerve despite survival of sensory hair cells. The findings of extensive cochlear synaptopathy in animals after moderate noise exposures challenged the long-held view that hair cells are the cochlear elements most sensitive to insults that lead to hearing loss. However, cochlear synaptopathy has been difficult to identify in humans. We applied novel algorithms to determine hair cell and neural contributions to electrocochleographic (ECochG) recordings from the round window of animal and human subjects. Gerbils with normal hearing provided training and test sets for a deep learning algorithm to detect the presence of neural responses to low frequency sounds, and an analytic model was used to quantify the proportion of neural and hair cell contributions to the ECochG response. The capacity to detect cochlear synaptopathy was validated in normal hearing and noise-exposed animals by using neurotoxins to reduce or eliminate the neural contributions. When the analytical methods were applied to human surgical subjects with access to the round window, the neural contribution resembled the partial cochlear synaptopathy present after neurotoxin application in animals. This result demonstrates the presence of viable hair cells not connected to auditory nerve fibers in human subjects with substantial hearing loss and indicates that efforts to regenerate nerve fibers may find a ready cochlear substrate for innervation and resumption of function.

Introduction: In the past years, some groups established methods to use promontory stimulation and subjective responses as a tool for preoperative stimulation of the cochlea before cochlear implant (CI) surgery by a temporary transtympanic needle placed on the middle ear. Our research group tested CI candidates when the presence of the auditory nerve could not be confirmed by other pre-operative tests and analyzed objective results of electrical auditory brainstem response recorded with trans-tympanic promontory stimulation in local anesthesia (LA-TT-EABR) with a “golfclub” electrode placed on the round window niche (Polterauer et al. 2018). However, EABR recording suffers from an electrical artifact from the stimulation and focuses on the excitability of the solely auditory nerve. We hypothesize that late evoked potential response (EALR) can be used for the assessment of the auditory pathway up to the cortical area with less electrical artifact interference. Methods: The trans-tympanic electrically evoked auditory late response in local anesthesia (LA-TT-EALR) was added to our protocol right after the LA-TT-EABR in a unique recording session. In this study, we investigated the feasibility of LA-TT-EALR using MED-EL hardware and software. These two pre-operative trans-tympanic measurements, LATT- EABR and LA-TT-EALR, were compared. Results: In a total n=18 tested subjects, it could be possible to record LA-TT-EABR in 10 and LA-TT-EALR in 13. In contrast to the fact that acoustically evoked auditory late responses are often hard to detect, and an electrical artifact heavily affects LA-TT-EABR, we did not experience these problems on LA-TT-EALR recordings. The matching between two measurements was present in 67% of the cases. Conclusion: LA-TT-EALR may be a complement to the existing state-of-the-art LA-TT-EABR for pre-operative assessment before cochlear implantation offering information about auditory pathways in the auditory brainstem and cortex with a small increase of recording time. The equivalency of these two methods is encouraging.

Optogenetic control of neural activity enables innovative approaches to improve functional restoration of diseased sensory and motor systems. For clinical translation to succeed, optogenetic stimulation needs to closely match the coding properties of the targeted neuronal population and employ optimally operating emitters. This requires the customization of channelrhodopsins, emitters and coding strategies. Here, we provide a framework to parametrize optogenetic neural control and apply it to the auditory pathway that requires high temporal fidelity of stimulation. We used a viral gene transfer of ultrafast targeting-optimized Chronos into spiral ganglion neurons (SGNs) of the cochlea of mice. We characterized the light-evoked response by in vivo recordings from individual SGNs and neurons of the anteroventral cochlear nucleus (AVCN) that detect coincident SGN inputs. Our recordings from single SGNs demonstrated that their spike probability can be graded by adjusting the duration of light pulses at constant intensity, which optimally serves efficient laser diode operation. We identified an effective pulse width of 1.6 ms to maximize encoding in SGNs at the maximal light intensity employed here (∼35 mW). Alternatively, SGNs were activated at lower energy thresholds using short light pulses (<1 ms). An upper boundary of optical stimulation rates was identified at 316 Hz, inducing a robust spike rate adaptation that required a few tens of milliseconds to recover. We developed a semi-stochastic stimulation paradigm to rapidly (within minutes) estimate the input/output function from light to SGN firing and approximate the time constant of neuronal integration in the AVCN. By that, our data pave the way to design the sound coding strategies of future optical cochlear implants. • We demonstrate that spike probability of the spiral ganglion neurons (SGN) and anteroventral cochlear nucleus neurons can be gradually "dialed" by adjusting the width of light pulses like what can be achieved with acoustic clicks of different sound pressure levels. Varying duration rather than light intensity is an important objective as laser diodes operate most efficiently with large driver currents and short pulses. • Under our experimental condition (light intensity ∼35 mW), we identified an optimal pulse width of 1.6 ms for maximizing information coding in SGNs. • The lowest energy requirement to activate SGNs was achieved using short light pulses (<1 ms). • We identified a spike failure induced during high rate optical stimulation (>300 Hz) that likely was due to depolarization block and required a few tens of milliseconds to recover. This is another important constraint that future optogenetic coding strategies need to consider. • Our data reveal that the timing of optogenetically evoked SGN spikes varied little across iterations for a given neuron but substantially within an SGN population, reminiscent of what is observed acoustically. This insight indicates that optogenetic cochlear implants will likely overcome the problem of overly synchronized activity in the auditory nerve faced by current state of the art electrical cochlear implants. • We established a new framework to rapidly determine the input/output function from light to firing of the spiral ganglion neurons using a semi-stochastic stimulus. This stimulus allowed us to approximate the time constant of neuronal integration in the neurons of the anteroventral cochlear nucleus, which recode the firing transmitted from the spiral ganglion neurons. [ABSTRACT FROM AUTHOR]

Obesity is a chronic condition, affecting central and peripheral nervous system. Studies on cranial nerve conduction in obesity are scarce and unclear; therefore, we planned this study. The aim of this study was to evaluate optic and auditory nerve conductions in obesity. It was a case-control study, with inclusion of 40 young males (20 obese and 20 controls) in age group of 18–30 years. We recorded pattern reversal visual evoked potential (PRVEP) and brainstem auditory evoked potential (BAEP). The PRVEP P100 latency and BAEP absolute and interpeak latencies were analyzed. In obese individuals, BAEP absolute latencies of wave V were significantly prolonged in both the ears and wave I in left ear. In addition, significant prolongation of interpeak latency III–V was observed in both the ears and I–V latency, in right ear among obese cases. A positive correlation was seen between body mass index and interpeak latency I–V. In PRVEP recordings, P100 latency did not show any significant difference in both the groups. Therefore, we can conclude that obesity does not affect optic nerve conduction, but auditory nerve conduction is affected. BAEP I–V interpeak latency may be an indicator of subclinical auditory conduction defects in young obese males. [ABSTRACT FROM AUTHOR]

Objective: To investigate the electrophysiology of the cochlear summating potential (SP) in patients with Meniere's disease (MD). Although long considered a purely hair cell potential, recent studies show a neural contribution to the SP. Patients with MD have an enhanced SP compared to those without the disease. Consequently, this study was to determine if the enhancement of the SP was in whole or part due to neural dysfunction. Design: Study participants included 41 adults with MD and 53 subjects with auditory neuropathy spectrum disorder (ANSD), undergoing surgery where the round window was accessible. ANSD is a condition with known neural dysfunction, and thus represents a control group for the study. The ANSD subjects and 17 of the MD subjects were undergoing cochlear implantation (CI) surgery; the remaining MD subjects were undergoing either endolymphatic sac decompression or labyrinthectomy to alleviate the symptoms of MD. Electrocochleography was recorded from the round window using high intensity (90 dB nHL) tone bursts. The SP and compound action potential (CAP) were measured to high frequencies (> = 2 kHz) and the SP, cochlear microphonic (CM) and auditory nerve neurophonic (ANN) to low frequencies. Linear mixed models were used to assess differences between MD and ANSD subjects. Results: Across frequencies, the MD subjects had smaller alternating current (AC) response than the ANSD subjects (F = 31.61,534, p < 0.001), but the SP magnitudes were larger (F = 94.31,534, p < 0.001). For frequencies less than 4 kHz the SP magnitude in the MD group was significantly correlated with the magnitude of the CM (p's < 0.001) but not in the ANSD group (p's > 0.05). Finally, the relative proportions of both ANN and CAP were greater in MD compared to ANSD subjects. The shapes of the waveforms in the MD subjects showed the presence of multiple components contributing to the SP, including outer and inner hair cells and neural activity. Conclusion: The results support the view that the increased negative polarity SP in MD subjects is due to a change in the operating point of hair cells rather than a loss of neural contribution. The steady-state SP to tones in human subjects is a mixture of different sources with different polarities. [ABSTRACT FROM AUTHOR]

Neural coding of the slow amplitude fluctuations of sound (i.e., temporal envelope) is thought to be essential for speech understanding; however, such coding by the human auditory nerve is poorly understood. Here, neural coding of the temporal envelope by the human auditory nerve is inferred from measurements of the compound action potential in response to an amplitude modulated carrier (CAPENV) for modulation frequencies ranging from 20 to 1000 Hz. The envelope following response (EFR) was measured simultaneously with CAPENV from active electrodes placed on the high forehead and tympanic membrane, respectively. Results support the hypothesis that phase locking to higher modulation frequencies (> 80 Hz) will be stronger for CAPENV, compared to EFR, consistent with the upper-frequency limits of phase locking for auditory nerve fibers compared to auditory brainstem/cortex neurons. Future work is needed to determine the extent to which (1) CAPENV is a useful tool for studying how temporal processing of the auditory nerve is affected by aging, hearing loss, and noise-induced cochlear synaptopathy and (2) CAPENV reveals the relationship between auditory nerve temporal processing and perception of the temporal envelope. [ABSTRACT FROM AUTHOR]

In the avian auditory brain stem, acoustic timing and intensity cues are processed in separate, parallel pathways via the two divisions of the cochlear nucleus, nucleus angularis (NA) and nucleus magnocellularis (NM). Differences in excitatory and inhibitory synaptic properties, such as release probability and short-term plasticity, contribute to differential processing of the auditory nerve inputs. We investigated the distribution of synaptotagmin, a putative calcium sensor for exocytosis, via immunohistochemistry and double immunofluorescence in the embryonic and hatchling chick brain stem (Gallus gallus). We found that the two major isoforms, synaptotagmin 1 (Syt1) and synaptotagmin 2 (Syt2), showed differential expression. In the NM, anti-Syt2 label was strong and resembled the endbulb terminals of the auditory nerve inputs, while anti-Syt1 label was weaker and more punctate. In NA, both isoforms were intensely expressed throughout the neuropil. A third isoform, synaptotagmin 7 (Syt7), was largely absent from the cochlear nuclei. In nucleus laminaris (NL, the target nucleus of NM), anti-Syt2 and anti-Syt7 strongly labeled the dendritic lamina. These patterns were established by embryonic day 18 and persisted to postnatal day 7. Double-labeling immunofluorescence showed that Syt1 and Syt2 were associated with vesicular glutamate transporter 2 (VGluT2), but not vesicular GABA transporter (VGAT), suggesting that these Syt isoforms were localized to excitatory, but not inhibitory, terminals. These results suggest that Syt2 is the major calcium binding protein underlying excitatory neurotransmission in the timing pathway comprising NM and NL, while Syt2 and Syt1 regulate excitatory transmission in the parallel intensity pathway via cochlear nucleus NA. [ABSTRACT FROM AUTHOR]

The electrically evoked compound action potential (eCAP) is a direct measure of the responsiveness of the auditory nerve to electrical stimulation from a cochlear implant (CI). CIs offer a unique opportunity to study the auditory nerve's electrophysiological behavior in individual human subjects over time. In order to understand exactly how the eCAP relates to the condition of the auditory nerve, it is crucial to compare changes in the eCAP over time in a controlled model of deafness-induced auditory nerve degeneration. In the present study, 10 normal-hearing young adult guinea pigs were implanted and deafened 4 weeks later, so that the effect of deafening could be monitored within-subject over time. Following implantation, but before deafening, most examined eCAP characteristics significantly changed, suggesting increasing excitation efficacy (e.g., higher maximum amplitude, lower threshold, shorter latency). Conversely, inter-phase gap (IPG) effects on these measures – within-subject difference measures that have been shown to correlate well with auditory nerve survival – did not vary for most eCAP characteristics. After deafening, we observed an initial increase in excitability (steeper slope of the eCAP amplitude growth function (AGF), lower threshold, shorter latency and peak width) which typically returned to normal-hearing levels within a week, after which a slower process, probably reflecting spiral ganglion cell loss, took place over the remaining 6 weeks (e.g., decrease in maximum amplitude, AGF slope, peak area, and IPG effect for AGF slope; increase in IPG effect for latency). Our results suggest that gradual changes in peak width and latency reflect the rate of neural degeneration, while peak area, maximum amplitude, and AGF slope reflect neural population size, which may be valuable for clinical diagnostics. [ABSTRACT FROM AUTHOR]

Dysfunction of the peripheral auditory nerve (AN) contributes to dynamic changes throughout the central auditory system, resulting in abnormal auditory processing, including hypersensitivity. Altered sound sensitivity is frequently observed in autism spectrum disorder (ASD), suggesting that AN deficits and changes in auditory information processing may contribute to ASD-associated symptoms, including social communication deficits and hyperacusis. The MEF2C transcription factor is associated with risk for several neurodevelopmental disorders, and mutations or deletions of MEF2C produce a haploinsufficiency syndrome characterized by ASD, language, and cognitive deficits. A mouse model of this syndromic ASD (Mef2c-Het) recapitulates many of the MEF2C haploinsufficiency syndrome-linked behaviors, including communication deficits. We show here that Mef2c-Het mice of both sexes exhibit functional impairment of the peripheral AN and a modest reduction in hearing sensitivity. We find that MEF2C is expressed during development in multiple AN and cochlear cell types; and in Mef2c-Het mice, we observe multiple cellular and molecular alterations associated with the AN, including abnormal myelination, neuronal degeneration, neuronal mitochondria dysfunction, and increased macrophage activation and cochlear inflammation. These results reveal the importance of MEF2C function in inner ear development and function and the engagement of immune cells and other non-neuronal cells, which suggests that microglia/macrophages and other non-neuronal cells might contribute, directly or indirectly, to AN dysfunction and ASD-related phenotypes. Finally, our study establishes a comprehensive approach for characterizing AN function at the physiological, cellular, and molecular levels in mice, which can be applied to animal models with a wide range of human auditory processing impairments. [ABSTRACT FROM AUTHOR]

Age‐related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive pathology often has psychological and medical comorbidities, including social isolation, depression, and cognitive decline. Despite ARHL's enormous societal and economic impact, no therapies to prevent or slow its progression exist. Loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs), a.k.a. IHC synaptopathy, is an early event in cochlear aging, preceding neuronal and hair cell loss. To determine if age‐related IHC synaptopathy can be prevented, and if this impacts the time‐course of ARHL, we tested the effects of cochlear overexpression of neurotrophin‐3 (Ntf3) starting at middle age. We chose Ntf3 because this neurotrophin regulates the formation of IHC‐SGN synapses in the neonatal period. We now show that triggering Ntf3 overexpression by IHC supporting cells starting in middle age rapidly increases the amplitude of sound‐evoked neural potentials compared with age‐matched controls, indicating that Ntf3 produces a positive effect on cochlear function when the pathology is minimal. Furthermore, near the end of their lifespan, Ntf3‐overexpressing mice have milder ARHL, with larger sound‐evoked potentials along the ascending auditory pathway and reduced IHC synaptopathy compared with age‐matched controls. Our results also provide evidence that an age‐related decrease in cochlear Ntf3 expression contributes to ARHL and that Ntf3 supplementation could serve as a therapeutic for this prevalent disorder. Furthermore, these findings suggest that factors that regulate synaptogenesis during development could prevent age‐related synaptopathy in the brain, a process involved in several central nervous system degenerative disorders. [ABSTRACT FROM AUTHOR]

ObjectiveTo investigate the electrophysiology of the cochlear summating potential (SP) in patients with Meniere’s disease (MD). Although long considered a purely hair cell potential, recent studies show a neural contribution to the SP. Patients with MD have an enhanced SP compared to those without the disease. Consequently, this study was to determine if the enhancement of the SP was in whole or part due to neural dysfunction.DesignStudy participants included 41 adults with MD and 53 subjects with auditory neuropathy spectrum disorder (ANSD), undergoing surgery where the round window was accessible. ANSD is a condition with known neural dysfunction, and thus represents a control group for the study. The ANSD subjects and 17 of the MD subjects were undergoing cochlear implantation (CI) surgery; the remaining MD subjects were undergoing either endolymphatic sac decompression or labyrinthectomy to alleviate the symptoms of MD. Electrocochleography was recorded from the round window using high intensity (90 dB nHL) tone bursts. The SP and compound action potential (CAP) were measured to high frequencies (> = 2 kHz) and the SP, cochlear microphonic (CM) and auditory nerve neurophonic (ANN) to low frequencies. Linear mixed models were used to assess differences between MD and ANSD subjects.ResultsAcross frequencies, the MD subjects had smaller alternating current (AC) response than the ANSD subjects (F = 31.61,534, p < 0.001), but the SP magnitudes were larger (F = 94.31,534, p < 0.001). For frequencies less than 4 kHz the SP magnitude in the MD group was significantly correlated with the magnitude of the CM (p’s < 0.001) but not in the ANSD group (p’s > 0.05). Finally, the relative proportions of both ANN and CAP were greater in MD compared to ANSD subjects. The shapes of the waveforms in the MD subjects showed the presence of multiple components contributing to the SP, including outer and inner hair cells and neural activity.ConclusionThe results support the view that the increased negative polarity SP in MD subjects is due to a change in the operating point of hair cells rather than a loss of neural contribution. The steady-state SP to tones in human subjects is a mixture of different sources with different polarities.

Deficits in auditory nerve (AN) function for older adults reduce afferent input to the cortex. The extent to which the cortex in older adults adapts to this loss of afferent input and the mechanisms underlying this adaptation are not well understood. We took a neural systems approach measuring AN and cortical evoked responses within 50 older and 27 younger human adults (59 female) to estimate central gain or increased cortical activity despite reduced AN activity. Relative to younger adults, older adults’ AN response amplitudes were smaller, but cortical responses were not. We used the relationship between AN and cortical response amplitudes in younger adults to predict cortical response amplitudes for older adults from their AN responses. Central gain in older adults was thus defined as the difference between their observed cortical responses and those predicted from the parameter estimates of younger adults. In older adults, decreased afferent input contributed to lower cortical GABA levels, greater central gain, and poorer speech recognition in noise (SIN). These effects on SIN occur in addition to, and independent from, effects attributed to elevated hearing thresholds. Our results are consistent with animal models of central gain and suggest that reduced AN afferent input in some older adults may result in changes in cortical encoding and inhibitory neurotransmission, which contribute to reduced SIN. An advancement in our understanding of the changes that occur throughout the auditory system in response to the gradual loss of input with increasing age may provide potential therapeutic targets for intervention. [ABSTRACT FROM AUTHOR]

Exposure to nontraumatic noise in vivo drives long-lasting changes in auditory nerve synapses, which may influence hearing, but the induction mechanisms are not known. We mimicked activity in acute slices of the cochlear nucleus from mice of both sexes by treating them with high potassium, after which voltage-clamp recordings from bushy cells indicated that auditory nerve synapses had reduced EPSC amplitude, quantal size, and vesicle release probability (Pr). The effects of high potassium were prevented by blockers of nitric oxide (NO) synthase and protein kinase A. Treatment with the NO donor, PAPA-NONOate, also decreased Pr, suggesting NO plays a central role in inducing synaptic changes. To identify the source of NO, we activated auditory nerve fibers specifically using optogenetics. Strobing for 2 h led to decreased EPSC amplitude and Pr, which was prevented by antagonists against ionotropic glutamate receptors and NO synthase. This suggests that the activation of AMPA and NMDA receptors in postsynaptic targets of auditory nerve fibers drives release of NO, which acts retrogradely to cause long-term changes in synaptic function in auditory nerve synapses. This may provide insight into preventing or treating disorders caused by noise exposure. [ABSTRACT FROM AUTHOR]

Schroeder‐phase harmonic tone complexes have been used in physiological and psychophysical studies in several species to gain insight into cochlear function. Each pitch period of the Schroeder stimulus contains a linear frequency sweep; the duty cycle, sweep velocity, and direction are controlled by parameters of the phase spectrum. Here, responses to a range of Schroeder‐phase harmonic tone complexes were studied both behaviorally and in neural recordings from the auditory nerve and inferior colliculus of Mongolian gerbils. Gerbils were able to discriminate Schroeder‐phase harmonic tone complexes based on sweep direction, duty cycle, and/or velocity for fundamental frequencies up to 200 Hz. Temporal representation in neural responses based on the van Rossum spike‐distance metric, with time constants of either 1 ms or related to the stimulus' period, was compared with average discharge rates. Neural responses and behavioral performance were both expressed in terms of sensitivity, d', to allow direct comparisons. Our results suggest that in the auditory nerve, stimulus fine structure is represented by spike timing, whereas envelope is represented by rate. In the inferior colliculus, both temporal fine structure and envelope appear to be represented best by rate. However, correlations between neural d' values and behavioral sensitivity for sweep direction were strongest for both temporal metrics, for both auditory nerve and inferior colliculus. Furthermore, the high sensitivity observed in the inferior colliculus neural rate‐based discrimination suggests that these neurons integrate across multiple inputs arising from the auditory periphery. [ABSTRACT FROM AUTHOR]

• Auditory response amplitude and synchrony were measured from mice and humans. • Older mice and humans exhibit central gain in response amplitudes. • Synchrony decreases with age in both the auditory nerve and midbrain responses. • Age-related central gain occurs without an improvement in inter-trial synchrony. Aging is associated with auditory nerve (AN) functional deficits and decreased inhibition in the central auditory system, amplifying central responses in a process referred to here as central gain. Although central gain increases response amplitudes, central gain may not restore disrupted response timing. In this translational study, we measured responses putatively generated by the AN and auditory midbrain in younger and older mice and humans. We hypothesized that older mice and humans exhibit increased central gain without an improvement in inter-trial synchrony in the midbrain. Our data demonstrated greater age-related deficits in AN response amplitudes than auditory midbrain response amplitudes, as shown by significant interactions between inferred neural generator and age group, indicating increased central gain in auditory midbrain. However, synchrony decreases with age in both the AN and midbrain responses. These results reveal age-related increases in central gain without concomitant improvements in synchrony, consistent with those predictions based on decreases in inhibition. Persistent decreases in synchrony may contribute to auditory processing deficits in older mice and humans. [Display omitted] [ABSTRACT FROM AUTHOR]

Cochlear implants are medical devices that provide hearing to nearly one million people around the world. Outcomes are impressive with most recipients learning to understand speech through this new way of hearing. Music perception and speech reception in noise, however, are notably poor. These aspects of hearing critically depend on sensitivity to pitch, whether the musical pitch of an instrument or the vocal pitch of speech. The present article examines cues for pitch perception in the auditory nerve based on computational models. Modeled neural synchrony for pure and complex tones is examined for three different electric stimulation strategies including Continuous Interleaved Sampling (CIS), High-Fidelity CIS (HDCIS), and Peak-Derived Timing (PDT). Computational modeling of current spread and neuronal response are used to predict neural activity to electric and acoustic stimulation. It is shown that CIS does not provide neural synchrony to the frequency of pure tones nor to the fundamental component of complex tones. The newer HDCIS and PDT strategies restore synchrony to both the frequency of pure tones and to the fundamental component of complex tones. Current spread reduces spatial specificity of excitation as well as the temporal fidelity of neural synchrony, but modeled neural excitation restores precision of these cues. Overall, modeled neural excitation to electric stimulation that incorporates temporal fine structure (e.g., HDCIS and PDT) indicates neural synchrony comparable to that provided by acoustic stimulation. Discussion considers the importance of stimulation rate and long-term rehabilitation to provide temporal cues for pitch perception. [ABSTRACT FROM AUTHOR]

Several physiological mechanisms act on the response of the auditory nerve (AN) during acoustic stimulation, resulting in an adjustment in auditory gain. These mechanisms include—but are not limited to—firing rate adaptation, dynamic range adaptation, the middle ear muscle reflex, and the medial olivocochlear reflex. A potential role of these mechanisms is to improve the neural signal-to-noise ratio (SNR) at the output of the AN in real time. This study tested the hypothesis that neural SNRs, inferred from non-invasive assessment of the human AN, improve over the duration of acoustic stimulation. Cochlear potentials were measured in response to a series of six high-level clicks embedded in a series of six lower-level broadband noise bursts. This paradigm elicited a compound action potential (CAP) in response to each click and to the onset of each noise burst. The ratio of CAP amplitudes elicited by each click and noise burst pair (i.e., neural SNR) was tracked over the six click/noise bursts. The main finding was a rapid (< 24 ms) increase in neural SNR from the first to the second click/noise burst, consistent with a real-time adjustment in the response of the auditory periphery toward improving the SNR of the signal transmitted to the brainstem. Analysis of cochlear microphonic and ear canal sound pressure recordings, as well as the time course for this improvement in neural SNR, supports the conclusion that firing rate adaptation is likely the primary mechanism responsible for improving neural SNR, while dynamic range adaptation, the middle ear muscle reflex, and the medial olivocochlear reflex played a secondary role on the effects observed in this study. Real-time improvements in neural SNR are significant because they may be essential for robust encoding of speech and other relevant stimuli in the presence of background noise. [ABSTRACT FROM AUTHOR]

Noise induced synaptopathy (NIS) and hidden hearing loss (NIHHL) have been hot topic in hearing research since a massive synaptic loss was identified in CBA mice after a brief noise exposure that did not cause permanent threshold shift (PTS) in 2009. Based upon the amount of synaptic loss and the bias of it to synapses with a group of auditory nerve fibers (ANFs) with low spontaneous rate (LSR), coding-in-noise deficit (CIND) has been speculated as the major difficult of hearing in subjects with NIS and NIHHL. This speculation is based upon the idea that the coding of sound at high level against background noise relies mainly on the LSR ANFs. However, the translation from animal data to humans for NIS remains to be justified due to the difference in noise exposure between laboratory animals and human subjects in real life, the lack of morphological data and reliable functional methods to quantify or estimate the loss of the afferent synapses by noise. Moreover, there is no clear, robust data revealing the CIND even in animals with the synaptic loss but no PTS. In humans, both positive and negative reports are available. The difficulty in verifying CINDs has led a re-examination of the hypothesis that CIND is the major deficit associated with NIS and NIHHL, and the theoretical basis of this idea on the role of LSR ANFs. This review summarized the current status of research in NIS and NIHHL, with focus on the translational difficulty from animal data to human clinicals, the technical difficulties in quantifying NIS in humans, and the problems with the SR theory on signal coding. Temporal fluctuation profile model was discussed as a potential alternative for signal coding at high sound level against background noise, in association with the mechanisms of efferent control on the cochlea gain. [ABSTRACT FROM AUTHOR]

A biophysically inspired signal processing model of the human cochlea is deployed to simulate the effects of specific noise‐induced inner hair cell (IHC) and outer hair cell (OHC) lesions on hearing thresholds, cochlear compression, and the spectral and temporal features of the auditory nerve (AN) coding. The model predictions were evaluated by comparison with corresponding data from animal studies as well as human clinical observations. The hearing thresholds were simulated for specific OHC and IHC damages and the cochlear nonlinearity was assessed at 0.5 and 4 kHz. The tuning curves were estimated at 1 kHz and the contributions of the OHC and IHC pathologies to the tuning curve were distinguished by the model. Furthermore, the phase locking of AN spikes were simulated in quiet and in presence of noise. The model predicts that the phase locking drastically deteriorates in noise indicating the disturbing effect of background noise on the temporal coding in case of hearing impairment. Moreover, the paper presents an example wherein the model is inversely configured for diagnostic purposes using a machine learning optimization technique (Nelder–Mead method). Accordingly, the model finds a specific pattern of OHC lesions that gives the audiometric hearing loss measured in a group of noise‐induced hearing impaired humans. [ABSTRACT FROM AUTHOR]

Auditory function declines with age, as evidenced by communication difficulties in challenging listening environments for older adults. Declining auditory function may arise, in part, from an age-related loss and/or inactivity of low-spontaneous-rate (SR) auditory nerve (AN) fibers, a subgroup of neurons important for suprathreshold processing. Compared to high-SR fibers, low-SR fibers take longer to recover from prior stimulation. Taking advantage of this difference, the forward-masked recovery function paradigm estimates the relative proportions of low- and high-SR fibers in the AN by quantifying the time needed for AN responses to recover from prior stimulation (ΔTrecovery). Due to the slower recovery of low-SR fibers, ANs that need more time to fully recover (longer ΔTrecovery) are estimated to have a larger proportion of low-SR fibers than ANs that need less time (shorter ΔTrecovery). To test the hypothesis that low-SR fiber activity is reduced in older humans, the current study assessed recovery functions in 32 older and 16 younger adults using the compound action potential. Results show that ΔTrecovery is shorter for older adults than for younger adults, consistent with a theorized age-related loss and/or inactivity of low-SR fibers. ΔTrecovery did not differ between individuals with and without a prior history of noise exposure as assessed by self-report. This study is the first to successfully assess forward-masked recovery functions in both younger and older adults and provides important insights into the structural and functional changes occurring in the AN with increasing age. [ABSTRACT FROM AUTHOR]

Cochlear implants are medical devices that provide hearing to nearly one million people around the world. Outcomes are impressive with most recipients learning to understand speech through this new way of hearing. Music perception and speech reception in noise, however, are notably poor. These aspects of hearing critically depend on sensitivity to pitch, whether the musical pitch of an instrument or the vocal pitch of speech. The present article examines cues for pitch perception in the auditory nerve based on computational models. Modeled neural synchrony for pure and complex tones is examined for three different electric stimulation strategies including Continuous Interleaved Sampling (CIS), High-Fidelity CIS (HDCIS), and Peak-Derived Timing (PDT). Computational modeling of current spread and neuronal response are used to predict neural activity to electric and acoustic stimulation. It is shown that CIS does not provide neural synchrony to the frequency of pure tones nor to the fundamental component of complex tones. The newer HDCIS and PDT strategies restore synchrony to both the frequency of pure tones and to the fundamental component of complex tones. Current spread reduces spatial specificity of excitation as well as the temporal fidelity of neural synchrony, but modeled neural excitation restores precision of these cues. Overall, modeled neural excitation to electric stimulation that incorporates temporal fine structure (e.g., HDCIS and PDT) indicates neural synchrony comparable to that provided by acoustic stimulation. Discussion considers the importance of stimulation rate and long-term rehabilitation to provide temporal cues for pitch perception.

Abnormal levels of acoustic activity can result in hearing problems such as tinnitus and language processing disorders, but the underlying cellular and synaptic changes triggered by abnormal activity are not well understood. To address this issue, we studied the time course of activity-dependent changes that occur at auditory nerve synapses in mice of both sexes after noise exposure and conductive hearing loss. We found that EPSC amplitude and synaptic depression decreased within 2 d of noise exposure through a decrease in the probability of vesicle release (Pr). This was followed by a gradual increase in EPSC amplitude through a larger pool of releasable vesicles (N). Occlusion of the ear canal led to a rapid decrease in EPSC amplitude through a decrease in N, which was followed by an increase in EPSC amplitude and synaptic depression through an increase in Pr. After returning to normal sound levels, synaptic depression recovered to control levels within 1-2 d. However, repeated exposure to noise for as little as 8 h/d caused synaptic changes after 7 d, suggesting recovery did not fully offset changes. Thus, there appear to be three activity-dependent mechanisms in auditory nerve synapses--bidirectional changes in Pr in 1-2 d, slower bidirectional changes in N through synaptic growth or retraction, and rapid downregulation of N with low activity. The dynamic changes indicate that multiple mechanisms are present to fine-tune synaptic fidelity across different acoustic conditions in a simple relay. [ABSTRACT FROM AUTHOR]

Objective: To describe a case of idiopathic bilateral cochlear nerve atrophy acquired in adulthood. Patient: A 75-year-old male with acquired bilateral cochlear nerve atrophy. Intervention(s): Unilateral cochlear implantation. Main Outcome and Results: Description of a patient with acquired bilateral cochlear nerve atrophy diagnosed at the age of 75. The patient had normal hearing and no communication deficits until the age of 66. At this point, the patient demonstrated a slight asymmetric hearing loss, which progressed to severe sensorineural hearing loss. Due to the resulting communication deficit, cochlear device implantation candidacy was pursued. Pre-operative magnetic resonance imaging (MRI) showed severe atrophy versus absence of the cochlear nerves bilaterally. After careful counseling regarding the expected communication outcomes given the MRI findings, the patient underwent left-sided cochlear implantation. The patient gained sound awareness, but no additional communication benefit compared to pre-operative baseline abilities. Conclusion: Cochlear nerve deficiency is a known finding in certain cases of congenital and acquired hearing loss, but no cases of idiopathic adult-onset bilateral nerve atrophy have been reported. Without MR imaging, the clinically significant finding would not have been identified. Thus, MRI is advantageous when compared with other imaging modalities in patients with progressive sensorineural hearing loss and enables improved patient counseling regarding expected auditory and communication outcomes. [ABSTRACT FROM AUTHOR]

Listeners with sensorineural hearing loss (SNHL) struggle to understand speech, especially in noise, despite audibility compensation. These real-world suprathreshold deficits are hypothesized to arise from degraded frequency tuning and reduced temporal-coding precision; however, peripheral neurophysiological studies testing these hypotheses have been largely limited to in-quiet artificial vowels. Here, we measured single auditory-nerve-fiber responses to a connected speech sentence in noise from anesthetized male chinchillas with normal hearing (NH) or noise-induced hearing loss (NIHL). Our results demonstrated that temporal precision was not degraded following acoustic trauma, and furthermore that sharpness of cochlear frequency tuning was not the major factor affecting impaired peripheral coding of connected speech in noise. Rather, the loss of cochlear tonotopy, a hallmark of NH, contributed the most to both consonant-coding and vowel-coding degradations. Because distorted tonotopy varies in degree across etiologies (e.g., noise exposure, age), these results have important implications for understanding and treating individual differences in speech perception for people suffering from SNHL. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study is to develop a biophysical model of human spiral ganglion neurons (SGNs) that includes voltage-gated hyperpolarization-activated cation (HCN) channels and low-threshold potassium voltage-gated, delayed-rectifier low-threshold potassium (KLT) channels, providing for a more complete simulation of spike-rate adaptation, a feature of most spiking neurons in which spiking activity is reduced in response to sustained stimulation. Methods: Our model incorporates features of spike-rate adaptation reported from in vivo studies, whilst also displaying similar behaviour to existing models of human SGNs, including the dependence of electrically evoked thresholds on the polarity of electrical pulses. Results: Hypothesizing that the mode of stimulation-intracellular or extracellular-predicts features of spike-rate adaptation similar to in vivo studies, including the influence of stimulus intensity and pulse-rate, we find that the mode of stimulation alters features of spike-rate adaptation. In particular, the reduction in spiking over time with sustained input was generally greater for extracellular, compared to intracellular, stimulation, when simulating a multi-compartment SGN with human morphological features. In contrast, time-constants of spike-rate adaption reported for in vivo data did not fit our predicted responses, highlighting the need for a more complete physiological understanding of the factors contributing to spike-rate adaptation in electrically stimulated human SGNs. Conclusion: Our model extends previous computational models of SGNs with human morphology with ionic channels accounting for features of spike-rate adaptation. Significance: The significance of this work resides in the ability to improve the modeling of cochlear implant (CI) stimulation and its effects on neural responses. This will help develop novel, and perhaps personalised, stimulation strategies to reduce variability in CI user outcomes. [ABSTRACT FROM AUTHOR]

Age-related hearing loss, or presbyacusis, is a prominent chronic degenerative disorder that affects many older people. Based on presbyacusis pathology, the degeneration occurs in both sensory and non-sensory cells, along with changes in the cochlear microenvironment. The progression of age-related neurodegenerative diseases is associated with an altered microenvironment that reflects chronic inflammatory signaling. Under these conditions, resident and recruited immune cells, such as microglia/macrophages, have aberrant activity that contributes to chronic neuroinflammation and neural cell degeneration. Recently, researchers identified and characterized macrophages in human cochleae (including those from older donors). Along with the age-related changes in cochlear macrophages in animal models, these studies revealed that macrophages, an underappreciated group of immune cells, may play a critical role in maintaining the functional integrity of the cochlea. Although several studies deciphered the molecular mechanisms that regulate microglia/macrophage dysfunction in multiple neurodegenerative diseases, limited studies have assessed the mechanisms underlying macrophage dysfunction in aged cochleae. In this review, we highlight the age-related changes in cochlear macrophage activities in mouse and human temporal bones. We focus on how complement dysregulation and the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 inflammasome could affect macrophage activity in the aged peripheral auditory system. By understanding the molecular mechanisms that underlie these regulatory systems, we may uncover therapeutic strategies to treat presbyacusis and other forms of sensorineural hearing loss. [ABSTRACT FROM AUTHOR]

Previous physiological and psychophysical studies have explored whether feedback to the cochlea from the efferent system influences forward masking. The present work proposes that the limited growth-of-masking (GOM) observed in auditory nerve (AN) fibers may have been misunderstood; namely, that this limitation may be due to the influence of anesthesia on the efferent system. Building on the premise that the unanesthetized AN may exhibit GOM similar to more central nuclei, the present computational modeling study demonstrates that feedback from the medial olivocochlear (MOC) efferents may contribute to GOM observed physiologically in onset-type neurons in both the cochlear nucleus and inferior colliculus (IC). Additionally, the computational model of MOC efferents used here generates a decrease in masking with longer masker-signal delays similar to that observed in IC physiology and in psychophysical studies. An advantage of this explanation over alternative physiological explanations (e.g., that forward masking requires inhibition from the superior paraolivary nucleus) is that this theory can explain forward masking observed in the brainstem, early in the ascending pathway. For explaining psychoacoustic results, one strength of this model is that it can account for the lack of elevation in thresholds observed when masker level is randomly varied from interval-to-interval, a result that is difficult to explain using the conventional temporal window model of psychophysical forward masking. Future directions for evaluating the efferent mechanism as a contributing mechanism for psychoacoustic results are discussed., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Maxwell et al.)