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Journal of the Association For Research... Oct 2023Loss of auditory nerve afferent synapses with cochlear hair cells, called cochlear synaptopathy, is a common pathology in humans caused by aging and noise overexposure....
PURPOSE
Loss of auditory nerve afferent synapses with cochlear hair cells, called cochlear synaptopathy, is a common pathology in humans caused by aging and noise overexposure. The perceptual consequences of synaptopathy in isolation from other cochlear pathologies are still unclear. Animal models provide an effective approach to resolve uncertainty regarding the physiological and perceptual consequences of auditory nerve loss, because neural lesions can be induced and readily quantified. The budgerigar, a parakeet species, has recently emerged as an animal model for synaptopathy studies based on its capacity for vocal learning and ability to behaviorally discriminate simple and complex sounds with acuity similar to humans. Kainic acid infusions in the budgerigar produce a profound reduction of compound auditory nerve responses, including wave I of the auditory brainstem response, without impacting physiological hair cell measures. These results suggest selective auditory nerve damage. However, histological correlates of neural injury from kainic acid are still lacking.
METHODS
We quantified the histological effects caused by intracochlear infusion of kainic acid (1 mM; 2.5 µL), and evaluated correlations between the histological and physiological assessments of auditory nerve status.
RESULTS
Kainic acid infusion in budgerigars produced pronounced loss of neural auditory nerve soma (60% on average) in the cochlear ganglion, and of peripheral axons, at time points 2 or more months following injury. The hair cell epithelium was unaffected by kainic acid. Neural loss was significantly correlated with reduction of compound auditory nerve responses and auditory brainstem response wave I.
CONCLUSION
Compound auditory nerve responses and wave I provide a useful index of cochlear synaptopathy in this animal model.
Topics: Humans; Animals; Melopsittacus; Kainic Acid; Acoustic Stimulation; Auditory Threshold; Cochlear Nerve; Cochlea; Hearing Loss, Noise-Induced; Evoked Potentials, Auditory, Brain Stem; Synapses
PubMed: 37798548
DOI: 10.1007/s10162-023-00910-5 -
The Journal of Neuroscience : the... Oct 2022Dysfunction of the peripheral auditory nerve (AN) contributes to dynamic changes throughout the central auditory system, resulting in abnormal auditory processing,...
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 produce a haploinsufficiency syndrome characterized by ASD, language, and cognitive deficits. A mouse model of this syndromic ASD (-Het) recapitulates many of the haploinsufficiency syndrome-linked behaviors, including communication deficits. We show here that -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 -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. This is the first report of peripheral auditory nerve (AN) impairment in a mouse model of human haploinsufficiency syndrome that has well-characterized ASD-related behaviors, including communication deficits, hyperactivity, repetitive behavior, and social deficits. We identify multiple underlying cellular, subcellular, and molecular abnormalities that may contribute to peripheral AN impairment. Our findings also highlight the important roles of immune cells (e.g., cochlear macrophages) and other non-neuronal elements (e.g., glial cells and cells in the stria vascularis) in auditory impairment in ASD. The methodological significance of the study is the establishment of a comprehensive approach for evaluating peripheral AN function and impact of peripheral AN deficits with minimal hearing loss.
Topics: Male; Female; Mice; Animals; Humans; Autistic Disorder; Autism Spectrum Disorder; MEF2 Transcription Factors; Cochlear Nerve; Disease Models, Animal
PubMed: 36180228
DOI: 10.1523/JNEUROSCI.0253-22.2022 -
Journal of Neurosurgery Feb 2023The goal of microsurgical resection of vestibular schwannoma (VS) is gross-total resection (GTR) to provide oncological cure. However, a popular strategy is to halt the...
OBJECTIVE
The goal of microsurgical resection of vestibular schwannoma (VS) is gross-total resection (GTR) to provide oncological cure. However, a popular strategy is to halt the resection if the surgical team feels the risk of cranial nerve injury is imminent, achieving a maximally safe subtotal resection (STR) instead. The tumor remnant can then be treated with stereotactic radiosurgery (SRS) once the patient has recovered from the immediate postoperative period, or it can be followed with serial imaging and treated with SRS in a delayed fashion if residual tumor growth is seen. In this study, the authors evaluated the efficacy of this multimodality approach, particularly the influence of timing and dose of SRS on radiological tumor control, need for salvage treatment, and cranial nerve function.
METHODS
VS patients treated with initial microsurgery and subsequent radiosurgery were retrospectively included from two tertiary treatment centers and dichotomized depending on whether SRS was given upfront (defined as before 12 months) or later. Radiological tumor control was defined as less than 20% tumor volume expansion and oncological tumor control as an absence of salvage treatment. Facial and cochlear nerve functions were assessed after surgery, at the time of SRS, and at last follow-up. Finally, a systematic literature review was conducted according to PRISMA guidelines.
RESULTS
A total of 110 VS patients underwent SRS following microsurgical resection, with a mean preradiosurgical tumor volume of 2.2 cm3 (SD 2.5 cm3) and mean post-SRS follow-up time of 5.8 years (SD 4.1 years). The overall radiological tumor control and oncological tumor control were 77.3% and 90.9%, respectively. Thirty-five patients (31.8%) received upfront SRS, while 75 patients (68.2%) were observed for a minimum of 12 months prior to SRS. The timing of SRS did not influence the radiological tumor control (p = 0.869), the oncological tumor control (p = 0.560), or facial nerve (p = 0.413) or cochlear nerve (p = 0.954) function. An escalated marginal dose (> 12 Gy) was associated with greater tumor shrinkage (p = 0.020) and superior radiological tumor control (p = 0.020), but it did not influence the risk of salvage treatment (p = 0.904) or facial (p = 0.351) or cochlear (p = 0.601) nerve deterioration.
CONCLUSIONS
Delayed SRS after close observation of residuals following STR is a safe alternative to upfront SRS regarding tumor control and cranial nerve preservation in selected patients.
Topics: Humans; Neuroma, Acoustic; Radiosurgery; Retrospective Studies; Treatment Outcome; Microsurgery; Follow-Up Studies
PubMed: 35907189
DOI: 10.3171/2022.5.JNS22249 -
International Journal of Molecular... Mar 2021Growth hormone (GH) plays an important role in auditory development during the embryonic stage. Exogenous agents such as sound, noise, drugs or trauma, can induce the... (Review)
Review
Growth hormone (GH) plays an important role in auditory development during the embryonic stage. Exogenous agents such as sound, noise, drugs or trauma, can induce the release of this hormone to perform a protective function and stimulate other mediators that protect the auditory pathway. In addition, GH deficiency conditions hearing loss or central auditory processing disorders. There are promising animal studies that reflect a possible regenerative role when exogenous GH is used in hearing impairments, demonstrated in in vivo and in vitro studies, and also, even a few studies show beneficial effects in humans presented and substantiated in the main text, although they should not exaggerate the main conclusions.
Topics: Animals; Auditory Cortex; Auditory Pathways; Cochlea; Cochlear Nerve; Gene Expression Regulation; Growth Hormone; Hearing Loss, Functional; Hearing Loss, Sensorineural; Hippocampus; Humans; Insulin-Like Growth Factor I; Nerve Regeneration; Noise
PubMed: 33799503
DOI: 10.3390/ijms22062829 -
World Neurosurgery Jul 2023Improved technology in vestibular neuroma resection and facial nerve protection has become more sophisticated, and the protection of hearing during vestibular schwannoma...
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
Topics: Humans; Neuroma, Acoustic; Action Potentials; Facial Nerve; Cochlear Nerve; Evoked Potentials, Auditory, Brain Stem; Deafness
PubMed: 37030482
DOI: 10.1016/j.wneu.2023.03.146 -
International Journal of Molecular... Feb 2024In 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...
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.
Topics: Animals; Gerbillinae; Cochlea; Synapses; Cochlear Nerve; Hair Cells, Auditory, Inner
PubMed: 38473985
DOI: 10.3390/ijms25052738 -
The Journal of Neuroscience : the... Sep 2020Multiple forms of homeostasis influence synaptic function under diverse activity conditions. Both presynaptic and postsynaptic forms of homeostasis are important, but...
Multiple forms of homeostasis influence synaptic function under diverse activity conditions. Both presynaptic and postsynaptic forms of homeostasis are important, but their relative impact on fidelity is unknown. To address this issue, we studied auditory nerve synapses onto bushy cells in the cochlear nucleus of mice of both sexes. These synapses undergo bidirectional presynaptic and postsynaptic homeostatic changes with increased and decreased acoustic stimulation. We found that both young and mature synapses exhibit similar activity-dependent changes in short-term depression. Experiments using chelators and imaging both indicated that presynaptic Ca influx decreased after noise exposure, and increased after ligating the ear canal. By contrast, Ca cooperativity was unaffected. Experiments using specific antagonists suggest that occlusion leads to changes in the Ca channel subtypes driving neurotransmitter release. Furthermore, dynamic-clamp experiments revealed that spike fidelity primarily depended on changes in presynaptic depression, with some contribution from changes in postsynaptic intrinsic properties. These experiments indicate that presynaptic Ca influx is homeostatically regulated to enhance synaptic fidelity. Homeostatic mechanisms in synapses maintain stable function in the face of different levels of activity. Both juvenile and mature auditory nerve synapses onto bushy cells modify short-term depression in different acoustic environments, which raises the question of what the underlying presynaptic mechanisms are and the relative importance of presynaptic and postsynaptic contributions to the faithful transfer of information. Changes in short-term depression under different acoustic conditions were a result of changes in presynaptic Ca influx. Spike fidelity was affected by both presynaptic and postsynaptic changes after ear occlusion and was only affected by presynaptic changes after noise-rearing. These findings are important for understanding regulation of auditory synapses under normal conditions and also in disorders following noise exposure or conductive hearing loss.
Topics: Animals; Auditory Perception; Calcium; Cochlear Nerve; Cochlear Nucleus; Female; Homeostasis; Male; Mice; Mice, Inbred CBA; Neuronal Plasticity; Noise; Presynaptic Terminals; Synaptic Potentials
PubMed: 32747441
DOI: 10.1523/JNEUROSCI.1175-19.2020 -
Hearing Research Jul 2022The refractory recovery function (RRF) measures the electrically evoked compound action potential (eCAP) in response to a second pulse (probe) after masking by a first...
BACKGROUND
The refractory recovery function (RRF) measures the electrically evoked compound action potential (eCAP) in response to a second pulse (probe) after masking by a first pulse (masker). This RRF is usually used to assess the refractory properties of the electrically stimulated auditory nerve (AN) by recording the eCAP amplitude as a function of the masker probe interval. Instead of assessing eCAP amplitudes only, recorded waveforms can also be described as a combination of a short-latency component (S-eCAP) and a long-latency component (L-eCAP). It has been suggested that these two components originate from two different AN fiber populations with differing refractory properties. The main objective of this study was to explore whether the refractory characteristics revealed by S-eCAP, L-eCAP, and the raw eCAP (R-eCAP) differ from each other. For clinical relevance, we compared these refractory properties between children and adults and examined whether they are related to cochlear implant (CI) outcomes.
DESIGN
In this retrospective study, the raw RRF (R-RRF) was obtained from 121 Hi-Focus Mid-Scala or 1 J cochlear implant (Advanced Bionics, Valencia, CA) recipients. Each R-eCAP of the R-RRF was split into an S-eCAP and an L-eCAP using deconvolution to produce two new RRFs: S-RRF and L-RRF. The refractory properties were characterized by fitting an exponential decay function with three parameters: the absolute refractory period (T); the saturation level (A); and the speed of recovery from nerve refractoriness (τ), i.e., a measure of the relative refractory period. We compared the parameters of the R-RRF (R, R, Rτ) with those obtained from the S-RRF (S, S, Sτ) and L-RRF (L, L, Lτ) and investigated whether these parameters differed between children and adults. In addition, we examined the associations between these parameters and speech perception in adults with CI. Linear mixed modeling was used for the analyses.
RESULTS
We found that T was significantly longer than S and L, and S was significantly longer than L. R was significantly larger than S and L, and S was significantly larger than L. Also, Sτ was significantly longer in comparison to Rτ and Lτ, but no significant difference was found between Rτ and Lτ. Children presented a significantly larger S and L and a shorter R in comparison to adults. Shorter Sτ was significantly associated with better speech perception in adult CI recipients, but other parameters were not.
CONCLUSION
We demonstrated that the two components of the eCAP have different refractory properties and that these also differ from those of the R-eCAP. In comparison with the R-eCAP, the refractory properties derived from the S-eCAP and L-eCAP can reveal additional clinical implications in terms of the refractory difference between children and adults as well as speech performance after implantation. Thus, it is worthwhile considering the two components of the eCAP in the future when assessing the clinical value of the auditory refractory properties.
Topics: Action Potentials; Adult; Child; Cochlear Implantation; Cochlear Implants; Cochlear Nerve; Humans; Retrospective Studies
PubMed: 35617925
DOI: 10.1016/j.heares.2022.108522 -
European Archives of... Jun 2022In pediatric audiology, objective techniques for hearing threshold estimation in infants and children with profound or severe hearing loss play a key role. Auditory...
Comparison of ABR and ASSR using narrow-band-chirp-stimuli in children with cochlear malformation and/or cochlear nerve hypoplasia suffering from severe/profound hearing loss.
OBJECTIVES
In pediatric audiology, objective techniques for hearing threshold estimation in infants and children with profound or severe hearing loss play a key role. Auditory brainstem responses (ABR) and auditory steady-state responses (ASSR) are available for frequency-dependent hearing threshold estimations and both techniques show strong correlations but sometimes with considerable differences. The aim of the study was to compare hearing threshold estimations in children with and without cochlear and cochlear nerve malformations.
METHODS
Two groups with profound or severe hearing loss were retrospectively compared. In 20 ears (15 children) with malformation of the inner ear and/or cochlear nerve hypoplasia and a control group of 20 ears (11 children) without malformation, ABR were measured with the Interacoustics Eclipse EP25 ABR system (Denmark) with narrow-band CE-chirps at 500, 1000, 2000 and 4000 Hz and compared to ASSR at the same center frequencies under similar conditions.
RESULTS
ABR and ASSR correlated significantly in both groups (r = 0.413 in malformation group, r = 0.82 in control group). The malformation group showed a significantly lower percentage of "equal" hearing threshold estimations than the control group. In detail, patients with isolated cochlear malformation did not differ significantly from the control group, whereas patients with cochlear nerve hypoplasia showed significantly greater differences.
CONCLUSION
ABR and ASSR should be used jointly in the diagnostic approach in children with suspected profound or severe hearing loss. A great difference in hearing threshold estimation between these techniques could hint at the involvement of cochlear nerve or cochlear nerve hypoplasia itself.
Topics: Acoustic Stimulation; Auditory Threshold; Child; Cochlear Nerve; Evoked Potentials, Auditory, Brain Stem; Hearing Loss; Humans; Infant; Retrospective Studies
PubMed: 34318333
DOI: 10.1007/s00405-021-06990-4 -
Aging Cell Oct 2022Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive pathology often has psychological and medical comorbidities,...
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.
Topics: Animals; Cochlea; Evoked Potentials, Auditory, Brain Stem; Hair Cells, Auditory, Inner; Hearing Loss; Mice; Spiral Ganglion; Synapses
PubMed: 36088647
DOI: 10.1111/acel.13708