On the Difficulty Predicting Word Recognition Performance After Cochlear Implantation.

HYPOTHESIS: Preimplantation word scores cannot reliably predict postimplantation outcomes. BACKGROUND: To date, there is no model based on preoperative data that can reliably predict the postoperative outcomes of cochlear implantation in the postlingually deafened adult patient. METHODS: In a group of 228 patients who received a cochlear implant between 2002 and 2021, we tested the predictive power of nine variables (age, etiology, sex, laterality of implantation, preimplantation thresholds and word scores, as well as the design, insertion approach, and angular insertion depth of the electrode array) on postimplantation outcomes. Results of multivariable linear regression analyses were then interpreted in light of data obtained from histopathological analyses of human temporal bones. RESULTS: Age and etiology were the only significant predictors of postimplantation outcomes. In agreement with many investigations, preimplantation word scores failed to significantly predict postimplantation outcomes. Analysis of temporal bone histopathology suggests that neuronal survival must fall below 40% before word scores in quiet begin to drop. Scores fall steeply with further neurodegeneration, such that only 20% survival can support acoustically driven word scores of 50%. Because almost all cochlear implant implantees have at least 20% of their spiral ganglion neurons (SGNs) surviving, it is expected that most cochlear implant users on average should improve to at least 50% word recognition score, as we observed, even if their preimplantation score was near zero as a result of widespread hair cell damage and the fact that ~50% of their SGNs have likely lost their peripheral axons. These "disconnected" SGNs would not contribute to acoustic hearing but likely remain electrically excitable. CONCLUSION: The relationship between preimplantation word scores and data describing the survival of SGNs in humans can explain why preimplantation word scores obtained in unaided conditions fail to predict postimplantation outcomes.

Large-scale annotated dataset for cochlear hair cell detection and classification.

Our sense of hearing is mediated by cochlear hair cells, of which there are two types organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains 5-15 thousand terminally differentiated hair cells, and their survival is essential for hearing as they do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. Machine learning can be used to automate the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, rat, guinea pig, pig, primate, and human cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 107,000 hair cells which have been identified and annotated as either inner or outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair-cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to give other hearing research groups the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.

Noise-induced synaptic loss and its post-exposure recovery in CBA/CaJ vs. C57BL/6J mice.

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

Ultrastructure of noise-induced cochlear synaptopathy.

Acoustic overexposure can eliminate synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs), even if hair-cell function recovers. This synaptopathy has been extensively studied by confocal microscopy, however, understanding the nature and sequence of damage requires ultrastructural analysis. Here, we used focused ion-beam scanning electron microscopy to mill, image, segment and reconstruct ANF terminals in mice, 1 day and 1 week after synaptopathic exposure (8-16 kHz, 98 dB SPL). At both survivals, ANF terminals were normal in number, but 62% and 53%, respectively, lacked normal synaptic specializations. Most non-synapsing fibers (57% and 48% at 1 day and 1 week) remained in contact with an IHC and contained healthy-looking organelles. ANFs showed a transient increase in mitochondrial content (51%) and efferent innervation (34%) at 1 day. Fibers maintaining synaptic connections showed hypertrophy of pre-synaptic ribbons at both 1 day and 1 week. Non-synaptic fibers were lower in mitochondrial content and typically on the modiolar side of the IHC, where ANFs with high-thresholds and low spontaneous rates are normally found. Even 1 week post-exposure, many ANF terminals remained in IHC contact despite loss of synaptic specializations, thus, regeneration efforts at early post-exposure times should concentrate on synaptogenesis rather than neurite extension.

Evidence of cochlear neural degeneration in normal-hearing subjects with tinnitus.

Tinnitus, reduced sound-level tolerance, and difficulties hearing in noisy environments are the most common complaints associated with sensorineural hearing loss in adult populations. This study aims to clarify if cochlear neural degeneration estimated in a large pool of participants with normal audiograms is associated with self-report of tinnitus using a test battery probing the different stages of the auditory processing from hair cell responses to the auditory reflexes of the brainstem. Self-report of chronic tinnitus was significantly associated with (1) reduced cochlear nerve responses, (2) weaker middle-ear muscle reflexes, (3) stronger medial olivocochlear efferent reflexes and (4) hyperactivity in the central auditory pathways. These results support the model of tinnitus generation whereby decreased neural activity from a damaged cochlea can elicit hyperactivity from decreased inhibition in the central nervous system.

Neural Degeneration in Normal-Aging Human Cochleas: Machine-Learning Counts and 3D Mapping in Archival Sections.

Quantifying the survival patterns of spiral ganglion cells (SGCs), the cell bodies of auditory-nerve fibers, is critical to studies of sensorineural hearing loss, especially in human temporal bones. The classic method of manual counting is tedious, and, although stereology approaches can be faster, they can only be used to estimate total cell numbers per cochlea. Here, a machine-learning algorithm that automatically identifies, counts, and maps the SGCs in digitized images of semi-serial human temporal-bone sections not only speeds the analysis, with no loss of accuracy, but also allows 3D visualization of the SGCs and fine-grained mapping to cochlear frequency. Applying the algorithm to 62 normal-aging human ears shows significantly faster degeneration of SGCs in the basal than the apical half of the cochlea. Comparison to fiber counts in the same ears shows that the fraction of surviving SGCs lacking a peripheral axon steadily increases with age, reaching more than 50% in the apical cochlea and almost 66% in basal regions.

Predicting Atrophy of the Cochlear Stria Vascularis from the Shape of the Threshold Audiogram.

Several lines of evidence have suggested that steeply sloping audiometric losses are caused by hair cell degeneration, while flat audiometric losses are caused by strial atrophy, but this concept has never been rigorously tested in human specimens. Here, we systematically compare audiograms and cochlear histopathology in 160 human cases from the archival collection of celloidin-embedded temporal bones at the Massachusetts Eye and Ear. The dataset included 106 cases from a prior study of normal-aging ears, and an additional 54 cases selected by combing the database for flat audiograms. Audiogram shapes were classified algorithmically into five groups according to the relation between flatness (i.e., SD of hearing levels across all frequencies) and low-frequency pure-tone average (i.e., mean at 0.25, 0.5, and 1.0 kHz). Outer and inner hair cell losses, neural degeneration, and strial atrophy were all quantified as a function of cochlear location in each case. Results showed that strial atrophy was worse in the apical than the basal half of the cochlea and was worse in females than in males. The degree of strial atrophy was uncorrelated with audiogram flatness. Apical atrophy was correlated with low-frequency thresholds and basal atrophy with high-frequency thresholds, and the former correlation was higher. However, a multivariable regression with all histopathological measures as predictors and audiometric thresholds as the outcome showed that strial atrophy was a significant predictor of threshold shift only in the low-frequency region, and, even there, the contribution of outer hair cell damage was larger.SIGNIFICANCE STATEMENT Cochlear pathology can only be assessed postmortem; thus, human cochlear histopathology is critical to our understanding of the mechanisms of hearing loss. Dogma holds that relative damage to sensory cells, which transduce mechanical vibration into electrical signals, versus the stria vascularis, the cellular battery that powers transduction, can be inferred by the shape of the audiogram, that is, down-sloping (hair cell damage) versus flat (strial atrophy). Here we quantified hair cell and strial atrophy in 160 human specimens to show that it is the degree of low-frequency hearing loss, rather than the audiogram slope, that predicts strial atrophy. Results are critical to the design of clinical trials for hearing-loss therapeutics, as current drugs target only hair cell, not strial, regeneration.

Large-scale annotated dataset for cochlear hair cell detection and classification.

Our sense of hearing is mediated by cochlear hair cells, localized within the sensory epithelium called the organ of Corti. There are two types of hair cells in the cochlea, which are organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains a few thousands of hair cells, and their survival is essential for our perception of sound because they are terminally differentiated and do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. However, the sheer number of cells along the cochlea makes manual quantification impractical. Machine learning can be used to overcome this challenge by automating the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, human, pig and guinea pig cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 90'000 hair cells, all of which have been manually identified and annotated as one of two cell types: inner hair cells and outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to supply other groups within the hearing research community with the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.

Supporting-cell vs. hair-cell survival in the human cochlea: Implications for regenerative therapies.

Animal studies have shown that the supporting-cells surviving in the organ of Corti after cochlear insult can be transdifferentiated into hair cells as a treatment for sensorineural hearing loss. Clinical trials of small-molecule therapeutics have been undertaken, but little is known about how to predict the pattern and degree of supporting-cell survival based on audiogram, hearing loss etiology or any other metric obtainable pre-mortem. To address this, we systematically assessed supporting-cell and hair cell survival, as a function of cochlear location in 274 temporal bone cases from the archives at the Massachusetts Eye and Ear and compared the histopathology with the audiograms and hearing-loss etiologies. Results showed that supporting-cell survival was always significantly greater in the apical half than the basal half of the cochlea, that inner pillars were more robust than outer pillars or Deiters' cells, and that total replacement of all supporting cells with a flat epithelium was rare outside of the extreme basal 20% of the cochlea. Supporting cell survival in the basal half of the cochlea was better correlated with the slope of the audiogram than with the mean high-frequency threshold per se: i.e. survival was better with flatter audiograms than with steeply down-sloping audiograms. Cochlear regions with extensive hair cell loss and exceptional supporting cell survival were most common in cases with hearing loss due to ototoxic drugs. Such cases also tended to have less pathology in other functionally critical structures, i.e. spiral ganglion neurons and the stria vascularis.

Supporting-cell vs. hair-cell survival in the human cochlea: Implications for regenerative therapies.

Animal studies have shown that the supporting-cells surviving in the organ of Corti after cochlear insult can be transdifferentiated into hair cells as a treatment for sensorineural hearing loss. Clinical trials of small-molecule therapeutics have been undertaken, but little is known about how to predict the pattern and degree of supporting-cell survival based on audiogram, hearing loss etiology or any other metric obtainable pre-mortem. To address this, we systematically assessed supporting-cell and hair cell survival, as a function of cochlear location in 274 temporal bone cases from the archives at the Massachusetts Eye and Ear and compared the histopathology with the audiograms and hearing-loss etiologies. Results showed that supporting-cell survival was always significantly greater in the apical half than the basal half of the cochlea, that inner pillars were more robust than outer pillars or Deiters' cells, and that total replacement of all supporting cells with a flat epithelium was rare outside of the extreme basal 20% of the cochlea. Supporting cell survival in the basal half of the cochlea was better correlated with the slope of the audiogram than with the mean high-frequency threshold per se: i.e. survival was better with flatter audiograms than with steeply down-sloping audiograms. Cochlear regions with extensive hair cell loss and exceptional supporting cell survival were most common in cases with hearing loss due to ototoxic drugs. Such cases also tended to have less pathology in other functionally critical structures, i.e. spiral ganglion neurons and the stria vascularis. Highlights: Supporting cell survival was systematically assessed in 274 human cochleasSupporting cell survival was better with flat than with down-sloping audiogramsSupporting cell survival was most robust when hearing loss was from ototoxic drugsOtotoxic cases also showed less pathology in other critical cochlear structuresThe data can inform clinical trials for regeneration via supporting cell conversion.

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 (N1) from hair-cell summating potentials (SP). The new N1 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. Classic SP is simultaneous with and opposite in phase to an early neural contribution, and filtering separates the sources to eliminate this interference.

Predictors and impact of postoperative atrial fibrillation following thoracic surgery: a state-of-the-art review.

This review of 19 studies (39,783 patients) of atrial fibrillation after thoracic surgery addresses the pathophysiology, incidence, and consequences of atrial fibrillation in this population, as well as its prevention and management. Interestingly, atrial fibrillation was most often identified in patients not previously known to have the disease. Rhythm control with amiodarone was the most commonly used treatment and nearly all patients were discharged in sinus rhythm. Major predictors were age; male sex; history of atrial fibrillation; congestive heart failure; left atrial enlargement; elevated brain natriuretic peptide level; and the invasiveness of procedures. Overall, patients with atrial fibrillation stayed 3 days longer in hospital. We also discuss the importance of standardising research on this subject and provide recommendations that might mitigate the impact postoperative atrial fibrillation on hospital resources.

Three-dimensional quantification of fibrosis and ossification after cochlear implantation via virtual re-sectioning: Potential implications for residual hearing.

Hearing preservation may be achieved initially in the majority of patients after cochlear implantation, however, a significant proportion of these patients experience delayed hearing loss months or years later. A prior histological report in a case of delayed hearing loss suggested a potential cochlear mechanical origin of this hearing loss due to tissue fibrosis, and older case series highlight the frequent findings of post-implantation fibrosis and neoosteogenesis though without a focus on the impact on residual hearing. Here we present the largest series (N = 20) of 3-dimensionally reconstructed cochleae based on digitally scanned histologic sections from patients who were implanted during their lifetime. All patients were implanted with multichannel electrodes via a cochleostomy or an extended round window insertion. A quantified analysis of intracochlear tissue formation was carried out via virtual re-sectioning orthogonal to the cochlear spiral. Intracochlear tissue formation was present in every case. On average 33% (SD 14%) of the total cochlear volume was occupied by new tissue formation, consisting of 26% (SD 12%) fibrous and 7% (SD 6%) bony tissue. The round window was completely covered by fibro-osseous tissue in 85% of cases and was associated with an obstruction of the cochlear aqueduct in 100%. The basal part of the basilar membrane was at least partially abutted by the electrode or new tissue formation in every case, while the apical region, corresponding with a characteristic frequency of < 500 Hz, appeared normal in 89%. This quantitative analysis shows that after cochlear implantation via extended round window or cochleostomy, intracochlear fibrosis and neoossification are present in all cases at anatomical locations that could impact normal inner ear mechanics.

Cochlear Neurotrophin-3 overexpression at mid-life prevents age-related inner hair cell synaptopathy and slows age-related hearing loss.

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.

Dopaminergic and cholinergic innervation in the mouse cochlea after noise-induced or age-related synaptopathy.

Cochlear synaptopathy, the loss of or damage to connections between auditory-nerve fibers (ANFs) and inner hair cells (IHCs), is a prominent pathology in noise-induced and age-related hearing loss. Here, we investigated if degeneration of the olivocochlear (OC) efferent innervation is also a major aspect of the synaptopathic ear, by quantifying the volume and spatial organization of its cholinergic and dopaminergic components, using antibodies to vesicular acetylcholine transporter (VAT) and tyrosine hydroxylase (TH), respectively. CBA/CaJ male mice were examined 1 day to 8 months after a synaptopathic noise exposure, and compared to unexposed age-matched controls and unexposed aged mice at 24-28 months. In normal ears, cholinergic lateral (L)OC terminals were denser in the apical half of the cochlea and on the modiolar side of the inner hair cells (IHCs), where ANFs of low-spontaneous rate are typically found, while dopaminergic terminals were more common in the basal third of the cochlea and, re the IHC axes, were offset towards the habenula with respect to cholinergic terminals. The noise had only small and transient effects on the density of LOC innervation, its spatial organization around the IHC axes, or the extent to which TH and VAT signal were colocalized. The synaptopathic noise also had relatively small and transient effects on cholinergic innervation density in the outer hair cell (OHC) area, which normally peaks in the 16 kHz region and falls monotonically towards higher and lower frequencies. In contrast, in the aged ears, there was massive degeneration of OHC efferents, especially in the apical half of the cochlea, where there was also significant loss of OHCs. In the IHC area, there was significant loss of cholinergic terminals in both apical and basal regions and of dopaminergic innervation in the basal half. Furthermore, the cholinergic terminals in the aged ears spread from their normal clustering near the IHC basolateral pole, where the ANF synapses are found, to positions up and down the IHC somata and regions of the neuropil closer to the habenula. This apparent migration was most striking in the apex, where the hair cell pathology was greatest, and may be a harbinger of impending hair cell death.

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. Word recognition was scored using CID W-22 monosyllabic word lists. The Articulation Index was used to predict the speech intelligibility curve using a transfer function for CID W-22. The level at which maximal intelligibility was predicted was used as presentation level (70 dB HL minimum). Word scores decreased dramatically with age and thresholds in all groups with SNHL etiologies, but relatively little in the conductive hearing loss group. Discrepancies between measured and predicted word scores were largest in patients with neuropathy, Ménière's disease and SSNHL, intermediate in the noise-damage and ototoxic drug groups, and smallest in the ARHL group. In the CHL group, the measured and predicted word scores were very similar. Since word-score predictions assume that audiometric losses can be compensated by increasing stimulus level, their accuracy in predicting word score for CHL patients is unsurprising. The lack of a strong age effect on word scores in CHL shows that cognitive decline is not a major factor in this test. Amongst the possible contributions to word score discrepancies, CND is a prime candidate: it should worsen intelligibility without affecting thresholds and has been documented in human temporal bones with SNHL. Comparing the audiological trends observed here with the existing histopathological literature supports the notion that word score discrepancies may be a useful CND metric.

Age-related stereocilia pathology in the human cochlea.

Age-related hearing loss in humans is characterized by progressive loss of threshold sensitivity, especially at high frequencies. A multivariable regression of histopathological metrics from normal-aging human cochleae (Wu et al., 2020) showed that hair cell loss better predicts the audiometric shifts than either neural loss or strial atrophy, however considerable variability in age-related threshold elevation remained unexplained. Here, we develop and apply an algorithm to quantify stereocilia pathology in high-power confocal images of inner and outer hair cells in normal aging human cochleae, aged 21 - 71 yrs. Microdissected epithelial wholemounts of the cochleae were immunostained for myosin VIIa and espin to show cuticular plates and stereocilia, respectively, and each cochlea was imaged at 10 log-spaced locations along the cochlear spiral. An approach based on Fourier transforms was used to quantify the regularity of each stereocilia bundle, and the outcome was compared to a parallel analysis by a human observer. Results show a significant age-related decline in stereocilia regularity and increase in stereocilia loss and fusion. Stereocilia pathology was especially severe on the outer hair cells and in the basal half of the cochlea, and may represent a key contributor to age-related threshold elevations. For the one case with an associated pre-mortem audiogram, the threshold shifts are better predicted from the pattern of stereocilia damage than from the pattern of hair cell loss alone.

Noise Masking in Cochlear Synaptopathy: Auditory Brainstem Response vs. Auditory Nerve Response in Mouse.

After acoustic overexposure, many auditory-nerve fiber (ANF) synapses permanently retract from surviving cochlear hair cells. This synaptopathy is hard to diagnose, since it does not elevate audiometric thresholds until almost no synapses remain, nevertheless it may degrade discrimination of complex stimuli especially in noisy environments. Here, we study an assay based on masking the auditory brainstem responses (ABRs) to a moderate-level probe tone with continuous noise of varied sound levels, and we investigate the underlying ANF responses at the single-fiber level. Synaptopathy was induced by overexposure to octave-band noise, resulting in a permanent synaptic loss of ~50%, without permanent threshold elevation except at the highest frequencies. The normal progressive delay of ABR peaks with increasing masker level is diminished in synaptopathic ears; however, the single-fiber analysis suggests that this normal latency shift does not arise because contributing ANFs shift from low-threshold fibers (with high spontaneous rates) to high-threshold fibers (with low spontaneous rates). Rather, it may arise because of a shift in the cochlear region dominating the response. Surprisingly, the dynamic range of masking, i.e. the difference between the lowest masker level that attenuates the ABR to a fixed-level probe and the lowest masker level that eliminates the ABR, is enhanced in the synaptopathic ears. This ABR behavior mirrors the single-fiber data showing a paradoxical enhancement of onset-response synchrony and resistance to masking in responses of ANFs in the synaptopathic regions. An assay based on the dynamic range of masking could be useful in diagnosing synaptic damage in human populations.

Human vestibular schwannoma reduces density of auditory nerve fibers in the osseous spiral lamina.

Hearing loss in patients with vestibular schwannoma (VS) is commonly attributed to mechanical compression of the auditory nerve, though recent studies suggest that this retrocochlear pathology may be augmented by cochlear damage. Although VS-associated loss of inner hair cells, outer hair cells, and spiral ganglion cells has been reported, it is unclear to what extent auditory-nerve peripheral axons are damaged in VS patients. Understanding the degree of damage VSs cause to auditory nerve fibers (ANFs) is important for accurately modeling clinical outcomes of cochlear implantation, which is a therapeutic option to rehabilitate hearing in VS-affected ears. A retrospective analysis of human temporal-bone histopathology was performed on archival specimens from the Massachusetts Eye and Ear collection. Seven patients met our inclusion criteria based on the presence of sporadic, unilateral, untreated VS. Tangential sections of five cochlear regions were stained with hematoxylin and eosin, and adjacent sections were stained to visualize myelinated ANFs and efferent fibers. Following confocal microscopy, peripheral axons of ANFs within the osseous spiral lamina were quantified manually, where feasible, and with a "pixel counting" method, applicable to all sections. ANF density was substantially reduced on the VS side compared to the unaffected contralateral side. In the upper basal turn, a significant difference between the VS side and unaffected contralateral side was found using both counting methods, corresponding to the region tuned to 2000 Hz. Even spiral ganglion cells (SGCs) contralateral to VS were affected by the tumor as the majority of contralateral SGC counts were below average for age. This observation provides histological insight into the clinical observation that unilateral vestibular schwannomas pose a long-term risk of progression of hearing loss in the contralateral ear as well. Our pixel counting method for ANF quantification in the osseous spiral lamina is applicable to other pathologies involving sensorineural hearing loss. Future research is needed to classify ANFs into morphological categories, accurately predict their electrical properties, and use this knowledge to inform optimal cochlear implant programming strategies.

Peristimulus Time Responses Predict Adaptation and Spontaneous Firing of Auditory-Nerve Fibers: From Rodents Data to Humans.

Sound-level coding in the auditory nerve is achieved through the progressive recruitment of auditory nerve fibers (ANFs) that differ in threshold of activation and in the stimulus level at which the spike rate saturates. To investigate the functional state of the ANFs, the electrophysiological tests routinely used in clinics only capture the first action potentials firing in synchrony at the onset of the acoustic stimulation. Assessment of other properties (e.g., spontaneous rate and adaptation time constants) requires single-fiber recordings directly from the nerve, which for ethical reasons is not allowed in humans. By combining neuronal activity measurements at the round window and signal-processing algorithms, we constructed a peristimulus time response (PSTR), with a waveform similar to the peristimulus time histograms (PSTHs) derived from single-fiber recordings in young adult female gerbils. Simultaneous recordings of round-window PSTR and single-fiber PSTH provided models to predict the adaptation kinetics and spontaneous rate of the ANFs tuned at the PSTR probe frequency. The predictive model derived from gerbils was then validated in female mice and finally applied to humans by recording PSTRs from the auditory nerve in normal-hearing patients who underwent cerebellopontine angle surgeries. A rapid adaptation time constant of ∼3 ms and a mean spontaneous rate of ∼22 spikes/s in the 4 kHz frequency range were found. This study offers a promising diagnostic tool to map the human auditory nerve, thus opening new avenues to better understanding auditory neuropathies, tinnitus, and hyperacusis.SIGNIFICANCE STATEMENT Neural adaptation in auditory nerve fibers corresponds to the reduction in the neuronal activity to prolonged or repeated sound stimulation. For obvious ethical reasons, single-fiber recordings from the auditory nerve are not feasible in humans, creating a critical gap in extending data obtained using animal models to humans. Using electrocochleography in rodents, we inferred adaptation kinetics and spontaneous discharge rates of the auditory nerve fibers in humans. Routinely used in basic and clinical laboratories, this tool will provide a better understanding of auditory disorders such as neuropathies, tinnitus, and hyperacusis, and will help to improve hearing-aid fittings.