Isolating auditory-nerve contributions to electrocochleography by high-pass filtering: A better biomarker for cochlear nerve degeneration?

In search of biomarkers for cochlear neural degeneration (CND) in electrocochleography from humans with normal thresholds, we high-pass and low-pass filtered the responses to separate contributions of auditory-nerve action potentials (N) from hair-cell summating potentials (SP). The new N measure is better correlated with performance on difficult word-recognition tasks used as a proxy for CND. Furthermore, the paradoxical correlation between larger SPs and worse word scores, observed with classic electrocochleographic analysis, disappears with the new metric.

Predicting neural deficits in sensorineural hearing loss from word recognition scores.

The current gold standard of clinical hearing assessment includes a pure-tone audiogram combined with a word recognition task. This retrospective study tests the hypothesis that deficits in word recognition that cannot be explained by loss in audibility or cognition may reflect underlying cochlear nerve degeneration (CND). We collected the audiological data of nearly 96,000 ears from patients with normal hearing, conductive hearing loss (CHL) and a variety of sensorineural etiologies including (1) age-related hearing loss (ARHL); (2) neuropathy related to vestibular schwannoma or neurofibromatosis of type 2; (3) Ménière's disease; (4) sudden sensorineural hearing loss (SSNHL), (5) exposure to ototoxic drugs (carboplatin and/or cisplatin, vancomycin or gentamicin) or (6) noise damage including those with a 4-kHz "noise notch" or reporting occupational or recreational noise exposure.

Estimated cochlear neural degeneration is associated with loudness hypersensitivity in individuals with normal audiograms.

In animal models, cochlear neural degeneration (CND) is associated with excess central gain and hyperacusis, but a compelling link between reduced cochlear neural inputs and heightened loudness perception in humans remains elusive. The present study examined whether greater estimated cochlear neural degeneration (eCND) in human participants with normal hearing thresholds is associated with heightened loudness perception and sound aversion. Results demonstrated that loudness perception was heightened in ears with greater eCND and in subjects who self-report loudness aversion via a hyperacusis questionnaire.

The summating potential in human electrocochleography: Gaussian models and Fourier analysis.

In recent electrocochleographic studies, the amplitude of the summating potential (SP) was an important predictor of performance on word-recognition in difficult listening environments among normal-hearing listeners; paradoxically the SP was largest in those with the worst scores. SP has traditionally been extracted by visual inspection, a technique prone to subjectivity and error. Here, we assess the utility of a fitting algorithm [Kamerer, Neely, and Rasetshwane (2020).

Preserving Wideband Tympanometry Information With Artifact Mitigation.

Objective: Absorbance measured using wideband tympanometry (WBT) has been shown to be sensitive to changes in middle and inner ear mechanics, with potential to diagnose various mechanical ear pathologies. However, artifacts in absorbance due to measurement noise can obscure information related to pathologies and increase intermeasurement variability. Published reports frequently present absorbance that has undergone smoothing to minimize artifact; however, smoothing changes the true absorbance and can destroy important narrow-band characteristics such as peaks and notches at different frequencies.

Envelope following responses predict speech-in-noise performance in normal-hearing listeners.

Permanent threshold elevation after noise exposure or aging is caused by loss of sensory cells; however, animal studies show that hair cell loss is often preceded by degeneration of the synapses between sensory cells and auditory nerve fibers. Silencing these neurons is likely to degrade auditory processing and may contribute to difficulties understanding speech in noisy backgrounds. Reduction of suprathreshold ABR amplitudes can be used to quantify synaptopathy in inbred mice.

Idiopathic Sudden Sensorineural Hearing Loss: Speech Intelligibility Deficits Following Threshold Recovery.

Objectives: This retrospective study tests the hypothesis that patients who have recovered from idiopathic sudden sensorineural hearing loss (SSNHL) show deficits in word recognition tasks that cannot be entirely explained by a loss in audibility.

Design: We reviewed the audiologic profile of 166 patients presenting with a unilateral SSNHL. Hearing loss severity, degree of threshold recovery, residual hearing loss, and word recognition performance were considered as outcome variables.

Electrophysiological markers of cochlear function correlate with hearing-in-noise performance among audiometrically normal subjects.

Hearing loss caused by noise exposure, ototoxic drugs, or aging results from the loss of sensory cells, as reflected in audiometric threshold elevation. Animal studies show that loss of hair cells can be preceded by loss of auditory-nerve peripheral synapses, which likely degrades auditory processing. While this condition, known as cochlear synaptopathy, can be diagnosed in mice by a reduction of suprathreshold cochlear neural responses, its diagnosis in humans remains challenging.

Middle Ear Muscle Reflex and Word Recognition in "Normal-Hearing" Adults: Evidence for Cochlear Synaptopathy?

Objectives: Permanent threshold elevation after noise exposure, ototoxic drugs, or aging is caused by loss of sensory cells; however, animal studies show that hair cell loss is often preceded by degeneration of synapses between sensory cells and auditory nerve fibers. The silencing of these neurons, especially those with high thresholds and low spontaneous rates, degrades auditory processing and may contribute to difficulties in understanding speech in noise. Although cochlear synaptopathy can be diagnosed in animals by measuring suprathreshold auditory brainstem responses, its diagnosis in humans remains a challenge.

Chronic Conductive Hearing Loss Is Associated With Speech Intelligibility Deficits in Patients With Normal Bone Conduction Thresholds.

Objectives: The main objective of this study is to determine whether chronic sound deprivation leads to poorer speech discrimination in humans.

Design: We reviewed the audiologic profile of 240 patients presenting normal and symmetrical bone conduction thresholds bilaterally, associated with either an acute or chronic unilateral conductive hearing loss of different etiologies.

Results: Patients with chronic conductive impairment and a moderate, to moderately severe, hearing loss had lower speech recognition scores on the side of the pathology when compared with the healthy side.

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

Cochlear synaptopathy, i.e. the loss of auditory-nerve connections with cochlear hair cells, is seen in aging, noise damage, and other types of acquired sensorineural hearing loss.

A Gain-of-Function Mutation in the α9 Nicotinic Acetylcholine Receptor Alters Medial Olivocochlear Efferent Short-Term Synaptic Plasticity.

Gain control of the auditory system operates at multiple levels. Cholinergic medial olivocochlear (MOC) fibers originate in the brainstem and make synaptic contacts at the base of the outer hair cells (OHCs), the final targets of several feedback loops from the periphery and higher-processing centers. Efferent activation inhibits OHC active amplification within the mammalian cochlea, through the activation of a calcium-permeable α9α10 ionotropic cholinergic nicotinic receptor (nAChR), functionally coupled to calcium activated SK2 potassium channels.

Toward a Differential Diagnosis of Hidden Hearing Loss in Humans.

Recent work suggests that hair cells are not the most vulnerable elements in the inner ear; rather, it is the synapses between hair cells and cochlear nerve terminals that degenerate first in the aging or noise-exposed ear. This primary neural degeneration does not affect hearing thresholds, but likely contributes to problems understanding speech in difficult listening environments, and may be important in the generation of tinnitus and/or hyperacusis. To look for signs of cochlear synaptopathy in humans, we recruited college students and divided them into low-risk and high-risk groups based on self-report of noise exposure and use of hearing protection.

Type II Cochlear Ganglion Neurons Do Not Drive the Olivocochlear Reflex: Re-Examination of the Cochlear Phenotype in Peripherin Knock-Out Mice.

The cochlear nerve includes a small population of unmyelinated sensory fibers connecting outer hair cells to the brain. The functional role of these type II afferent neurons is controversial, because neurophysiological data are sparse. A recent study (Froud et al.

Perinatal thiamine deficiency causes cochlear innervation abnormalities in mice.

Neonatal thiamine deficiency can cause auditory neuropathy in humans. To probe the underlying cochlear pathology, mice were maintained on a thiamine-free or low-thiamine diet during fetal development or early postnatal life. At postnatal ages from 18 days to 22 wks, cochlear function was tested and cochlear histopathology analyzed by plastic sections and cochlear epithelial whole-mounts immunostained for neuronal and synaptic markers.

Oncomodulin, an EF-Hand Ca2+ Buffer, Is Critical for Maintaining Cochlear Function in Mice.

Unlabelled: Oncomodulin (Ocm), a member of the parvalbumin family of calcium binding proteins, is expressed predominantly by cochlear outer hair cells in subcellular regions associated with either mechanoelectric transduction or electromotility. Targeted deletion of Ocm caused progressive cochlear dysfunction. Although sound-evoked responses are normal at 1 month, by 4 months, mutants show only minimal distortion product otoacoustic emissions and 70-80 dB threshold shifts in auditory brainstem responses.

Chronic Conductive Hearing Loss Leads to Cochlear Degeneration.

Synapses between cochlear nerve terminals and hair cells are the most vulnerable elements in the inner ear in both noise-induced and age-related hearing loss, and this neuropathy is exacerbated in the absence of efferent feedback from the olivocochlear bundle. If age-related loss is dominated by a lifetime of exposure to environmental sounds, reduction of acoustic drive to the inner ear might improve cochlear preservation throughout life. To test this, we removed the tympanic membrane unilaterally in one group of young adult mice, removed the olivocochlear bundle in another group and compared their cochlear function and innervation to age-matched controls one year later.

Olivocochlear innervation maintains the normal modiolar-pillar and habenular-cuticular gradients in cochlear synaptic morphology.

Morphological studies of inner hair cell (IHC) synapses with cochlear nerve terminals have suggested that high- and low-threshold fibers differ in the sizes of their pre- and postsynaptic elements as well as the position of their synapses around the hair cell circumference. Here, using high-power confocal microscopy, we measured sizes and spatial positions of presynaptic ribbons, postsynaptic glutamate receptor (GluR) patches, and olivocochlear efferent terminals at eight locations along the cochlear spiral in normal and surgically de-efferented mice. Results confirm a prior report suggesting a modiolar > pillar gradient in ribbon size and a complementary pillar > modiolar gradient in GluR-patch size.

Efferent feedback slows cochlear aging.

The inner ear receives two types of efferent feedback from the brainstem: one pathway provides gain control on outer hair cells' contribution to cochlear amplification, and the other modulates the excitability of the cochlear nerve. Although efferent feedback can protect hair cells from acoustic injury and thereby minimize noise-induced permanent threshold shifts, most prior studies focused on high-intensity exposures (>100 dB SPL). Here, we show that efferents are essential for long-term maintenance of cochlear function in mice aged 1 year post-de-efferentation without purposeful acoustic overexposure.

Efferent feedback minimizes cochlear neuropathy from moderate noise exposure.

Although protective effects of the cochlea's efferent feedback pathways have been well documented, prior work has focused on hair cell damage and cochlear threshold elevation and, correspondingly, on the high sound pressure levels (>100 dB SPL) necessary to produce them. Here we explore the noise-induced loss of cochlear neurons that occurs with lower-intensity exposures and in the absence of permanent threshold shifts. Using confocal microscopy to count synapses between hair cells and cochlear nerve fibers, and using measurement of auditory brainstem responses and otoacoustic emissions to assess cochlear presynaptic and postsynaptic function, we compare the damage from a weeklong exposure to moderate-level noise (84 dB SPL) in mice with varying degrees of cochlear de-efferentation induced by surgical lesion to the olivocochlear pathway.

Olivocochlear suppression of outer hair cells in vivo: evidence for combined action of BK and SK2 channels throughout the cochlea.

Cholinergic inhibition of cochlear hair cells via olivocochlear (OC)-efferent feedback is mediated by Ca(2+) entry through α9-/α10-nicotinic receptors, but the nature of the K(+) channels activated by this Ca(2+) entry has been debated (Yoshida N, Hequembourg SJ, Atencio CA, Rosowski JJ, Liberman MC. J Neurophysiol 85: 84-88, 2001). A recent in vitro study (Wersinger E, McLean WJ, Fuchs PA, Pyott SJ.

Contralateral-noise effects on cochlear responses in anesthetized mice are dominated by feedback from an unknown pathway.

Suppression of ipsilateral distortion product otoacoustic emissions (DPOAEs) by contralateral noise is used in humans and animals to assay the strength of sound-evoked negative feedback from the medial olivocochlear (MOC) efferent pathway. However, depending on species and anesthesia, contributions of other feedback systems to the middle or inner ear can cloud the interpretation. Here, contributions of MOC and middle-ear muscle reflexes, as well as autonomic feedback, to contra-noise suppression in anesthetized mice are dissected by selectively eliminating each pathway by surgical transection, pharmacological blockade, or targeted gene deletion.