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Accurate and objective assessment of higher order auditory processing is challenging and mainly relies on evaluations that require a subjects' active participation in tests such as frequency discrimination or speech perception in noise. This study investigates the value of cortical auditory evoked potentials (CAEPs) evoked in response to auditory change stimuli, known as acoustic change complexes (ACCs), as an objective measurement of auditory performance in hearing impairment. Secondary objectives were to assess the effect of hearing loss and non-professional musical experience on the ACC, and compare the ACC to the 'conventional' CAEP evoked in response to stimulus onset. In 24 normal-hearing subjects, consisting of 12 musicians and 12 non-musicians, and 13 age-matched hearing-impaired subjects ACCs were recorded in response to 12% frequency increases at four base frequencies (0.5, 1, 2 and 4 kHz). ACC amplitudes and latencies were compared to frequency discrimination thresholds at each base frequency, and to speech perception in noise. Frequency discrimination and speech perception in noise were significantly better for larger ACC N1-P2 amplitudes and shorter N1 latencies, whereas both frequency discrimination and speech perception did not correlate with onset CAEP amplitude or latency. Multiple regression analysis for prediction of speech perception in noise revealed that the strongest model was obtained by averaging over three frequencies (1, 2 and 4 kHz) with two significant predictors: hearing loss (R 2  = 0.52) and ACC latency (R 2  = 0.35). Thus, explaining 87% of the variance, this model indicates that subjects with longer ACC latencies have worse speech perception in noise than subjects with comparable hearing thresholds and shorter ACC latencies. If hearing loss was removed from this model, the combination of ACC amplitude and latency over those three frequencies explained 74% of the total variance in speech perception in noise. There were no differences in frequency discrimination, speech perception, CAEP, or ACC between recreational musicians and non-musicians. We conclude that the objective ACC N1 latency is a good predictor of speech perception in noise. When confirmed in validation studies with larger numbers of subjects, it can aid clinicians in their evaluation of auditory performance and higher order processing, in particular when behavioral testing is unreliable., (Copyright © 2022. Published by Elsevier B.V.)

Frequency discrimination ability varies within the normal hearing population, partially explained by factors such as musical training and age, and it deteriorates with hearing loss. Frequency discrimination, while essential for several auditory tasks, is not routinely measured in clinical setting. This study investigates cortical auditory evoked potentials in response to frequency changes, known as acoustic change complexes (ACCs), and explores their value as a clinically applicable objective measurement of frequency discrimination. In 12 normal-hearing and 13 age-matched hearing-impaired subjects, ACC thresholds were recorded at 4 base frequencies (0.5, 1, 2, 4 kHz) and compared to psychophysically assessed frequency discrimination thresholds. ACC thresholds had a moderate to strong correlation to psychophysical frequency discrimination thresholds. In addition, ACC thresholds increased with hearing loss and higher ACC thresholds were associated with poorer speech perception in noise. The ACC threshold in response to a frequency change therefore holds promise as an objective clinical measurement in hearing impairment, indicative of frequency discrimination ability and related to speech perception. However, recordings as conducted in the current study are relatively time consuming. The current clinical application would be most relevant in cases where behavioral testing is unreliable., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Several studies have shown that treatment with various neurotrophins protects spiral ganglion cells (SGCs) from degeneration in hair-cell deprived cochleas. In most of these studies the neurotrophins are delivered by means of intracochlear delivery methods. Recently, other application methods that might be more suited in cochlear implant patients have been developed. We have examined if round window membrane application of gelfoam infiltrated with a neurotrophin resulted in SGC survival in deafened guinea pigs. Two weeks after deafening, gelfoam cubes infiltrated with 6 μg of brain-derived neurotrophic factor (BDNF) were deposited onto the round window membrane of the right cochleas. Electric pulses were delivered through an electrode positioned within the round window niche to electrically evoke auditory brainstem responses (eABRs). Two or four weeks after deposition of the gelfoam all cochleas were histologically examined. We found that local BDNF treatment enhances the survival of SGCs in the basal cochlear turn after two and four weeks. The treatment had no effect on SGC size or shape. In animals treated with BDNF, eABR amplitudes were smaller than in normal-hearing control animals and similar to those in deafened controls. We conclude that BDNF delivered by means of local gelfoam application provides a protective effect, which is limited compared to intracochlear delivery methods., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Introduction: The results from different Cochrane studies justify considerable professional equipoise concerning different treatment options for tinnitus. In case of professional equipoise, Shared Decision Making (SDM) is an indispensable tool for guiding patients to the intervention that best fits their needs. To improve SDM we developed a method to assess the accuracy and utility of decisions made by tinnitus patients when freely choosing between different treatment options during their patient journey. The different treatment options were audiological care and psychosocial counseling. Methods: We developed a statistical model by combining Signal Detection Theory (SDT) with the Health Belief Model (HBM). HBM states that perceived severity of an illness is strongly related to sick-role behavior. As proxies for perceived severity, we selected hearing loss and Tinnitus Handicap Inventory (THI) score at baseline. Next, we used these proxies as predictors in linear regression models based on SDT to determine the likelihood ratio of true positive decisions (choosing a treatment option and experiencing an improvement of more than 7 points in THI-score) and false positive decisions (choosing a treatment option and experiencing an improvement of less than 7 points in THI-score) for audiological care and psychosocial counseling, respectively. Data was gathered in a prospective cohort of 145 adults referred for tinnitus care to an outpatient audiology clinic in the Netherlands. The participants were asked to decide freely on uptake of audiological care (provision of hearing aids with or without a sound generator) and uptake of psychosocial counseling. Logistic regression with Bayesian inference was used to determine the cumulative distribution functions and the probability density functions of true positive decisions and false positive decisions as function of hearing loss and baseline THI-score for both treatment options, respectively. With the cumulative distribution functions, we determined the accuracy of the decisions. With the probability density functions we calculated the likelihood ratios of true positive decisions versus false positive decisions as function of hearing loss and baseline THI-score. These likelihood ratio functions allow assessment of the utility of the decisions by relating a decision criterion to perceived benefits and costs. Results: Baseline THI-score drives decisions about psychosocial counseling and hearing loss drives decisions about audiological care. Decisions about psychosocial counseling are more accurate than decisions about audiological care. Both decisions have a low accuracy (0.255 for audiological care and − 0.429 for psychosocial counseling), however. For decisions about audiological care the unbiased decision criterion is 37 dB(HL), meaning that a lenient decision criterion (likelihood ratio < 1) is adopted by patients with a hearing loss below 37 dB and a strict criterion (likelihood ratio > 1) by patients with a hearing loss exceeding 37 dB. For psychosocial counseling uptake the decision criterion is always strict, regardless of baseline THI-score. The distributions of the populations, that do and do not experience a clinically important change in THI-score, have unequal variances for psychosocial counseling, while they have almost equal variances for audiological care. Discussion: Combining SDT and HBM can help assess accuracy and utility of patient decisions and thus may provide valuable information that can help to improve SDM by combining patient related outcome measures, decision drivers, and perceived benefits and costs of a treatment. [ABSTRACT FROM AUTHOR]

Introduction: The leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is a tissue resident stem cell marker, which it is expressed in supporting cells (SCs) in the organ of Corti in the mammalian inner ear. These LGR5+ SCs can be used as an endogenous source of progenitor cells for regeneration of hair cells (HCs) to treat hearing loss and deafness. We have recently reported that LGR5+ SCs survive 1 week after ototoxic trauma. Here, we evaluated Lgr5 expression in the adult cochlea and long-term survival of LGR5+ SCs following severe hearing loss. Methods: Lgr5GFP transgenic mice and wild type mice aged postnatal day 30 (P30) and P200 were used. P30 animals were deafened with a single dose of furosemide and kanamycin. Seven and 28 days after deafening, auditory brainstem responses (ABRs) were recorded. Cochleas were harvested to characterize mature HCs and LGR5+ SCs by immunofluorescence microscopy and quantitative reverse transcription PCR (q-RT-PCR). Results: There were no significant age-related changes in Lgr5 expression when comparing normal-hearing (NH) mice aged P200 with P30. Seven and 28 days after ototoxic trauma, there was severe outer HC loss and LGR5 was expressed in the third row of Deiters' cells and in inner pillar cells. Seven days after induction of ototoxic trauma there was an up-regulation of the mRNA expression of Lgr5 compared to the NH condition; 28 days after ototoxic trauma Lgr5 expression was similar to NH levels. Discussion: The presence of LGR5+ SCs in the adult mouse cochlea, which persists after severe HC loss, suggests potential regenerative capacity of endogenous cochlear progenitor cells in adulthood. To our knowledge, this is the first study showing not only long-term survival of LGR5+ SCs in the normal and ototoxically damaged cochlea, but also increased Lgr5 expression in the adult mouse cochlea after deafening, suggesting long-term availability of potential target cells for future regenerative therapies. [ABSTRACT FROM AUTHOR]

Severe hearing loss or deafness is often caused by cochlear hair cell loss and can be mitigated by a cochlear implant (CI). CIs target the auditory nerve, consisting of spiral ganglion cells (SGCs), which degenerate gradually, following hair cell loss. In animal models, it has been established that treatment with the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) reduce SGC degeneration. In this study, we aimed to investigate whether treatment with both BDNF and NT-3 (Cocktail) is superior to treatment with each neurotrophin separately regarding cell preservation and neural responsiveness to electrical stimulation. To this end, deafened guinea pigs received neurotrophic treatment in their right ear via a gelatin sponge on the perforated round window membrane, followed by cochlear implantation 4 weeks later in the same ear for electrophysiological recordings to various stimulation paradigms. Normal-hearing and deafened untreated guinea pigs were included as positive and negative controls, respectively. Substantial SGC loss occurred in all deafened animals. Each of the neurotrophic treatments led to enhanced SGC survival mainly in the basal turn of the cochlea, gradually decreasing toward the apex. The Cocktail treatment resulted in the highest SGC survival in the treated ear, followed by BDNF, with the least protection of SGCs following NT-3 treatment. Survival of the SGC's peripheral processes (PPs) followed the same trend in response to the treatment. However, survival of SGCs and PPs in the contralateral untreated ears was also highest in the Cocktail group. Consequently, analysis of the ratio between the treated and untreated ears showed that the BDNF group, which showed low SGC survival in the untreated ear, had the highest relative SGC survival of the three neurotrophin-treated groups. Neurotrophic treatment had positive effects in part of the electrically evoked compound action-potential recording paradigms. These effects were only observed for the BDNF or Cocktail treatment. We conclude that treatment with either BDNF or a cocktail of BDNF and NT-3 is preferred to NT-3 alone. Furthermore, since the Cocktail treatment resulted in better electrophysiological responsiveness and overall higher SGC survival than BDNF alone, we are inclined to recommend the Cocktail treatment rather than BDNF alone. [ABSTRACT FROM AUTHOR]

After substantial loss of cochlear hair cells, exogenous neurotrophins prevent degeneration of the auditory nerve. Because cochlear implantation, the current therapy for profound sensorineural hearing loss, depends on a functional nerve, application of neurotrophins is being investigated. We addressed two questions important for fundamental insight into the effects of exogenous neurotrophins on a degenerating neural system, and for translation to the clinic. First, does temporary treatment with brain-derived neurotrophic factor (BDNF) prevent nerve degeneration on the long term? Second, how does a BDNF-treated nerve respond to electrical stimulation? Deafened guinea pigs received a cochlear implant, and their cochleas were infused with BDNF for 4 weeks. Up to 8 weeks after treatment, their cochleas were analyzed histologically. Electrically evoked compound action potentials (eCAPs) were recorded using stimulation paradigms that are informative of neural survival. Spiral ganglion cell (SGC) degeneration was prevented during BDNF treatment, resulting in 1.9 times more SGCs than in deafened untreated cochleas. Importantly, SGC survival was almost complete 8 weeks after treatment cessation, when 2.6 times more SGCs were observed. In four eCAP characteristics (three involving alteration of the interphase gap of the biphasic current pulse and one involving pulse trains), we found large and statistically significant differences between normal-hearing and deaf controls. Importantly, for BDNF-treated animals, these eCAP characteristics were near normal, suggesting healthy responsiveness of BDNF-treated SGCs. In conclusion, clinically practicable short-term neurotrophin treatment is sufficient for long-term survival of SGCs, and it can restore or preserve SGC function well beyond the treatment period. [ABSTRACT FROM AUTHOR]

We investigated whether treatment with brain-derived neurotrophic factor (BDNF), which is known to protect spiral ganglion cells (SGCs), could also protect hair cells (HCs) and supporting cells (SCs) in the organ of Corti of a guinea pig model of sensorineural hearing loss. Hearing loss was induced by administration of kanamycin/furosemide and two BDNF treatments were performed: (1) by gelatin sponge (BDNF-GS) with acute cochlear implantation (CI), and (2) through a mini-osmotic pump (BDNF-OP) with chronic CI. Outer HCs (OHCs), inner HCs (IHCs), Border, Phalangeal, Pillar, Deiters', and Hensen's cells were counted. The BDNF-GS cochleas had significantly fewer OHCs compared to the untreated ones, while the IHC and SC numbers did not differ between treated and untreated cochleas. The BDNF-OP group showed similar cell numbers to the untreated group. SGC packing density was not correlated with the total number of SCs for either BDNF group. Our data suggest that: (1) BDNF does not prevent cell death in the organ of Corti, and that the protection of SGCs could result from a direct targeting by BDNF; (2) BDNF might induce a different function/activity of the remaining cells in the organ of Corti (independently from cell number). [ABSTRACT FROM AUTHOR]

• Auditory nerve peripheral processes, somata and axons were examined in deafness. • BDNF treatment significantly increased survival of all three neural elements. • BDNF-mediated preservation persisted up to eight weeks after treatment cessation. • Peripheral processes were less well preserved than their somata and axons. Treatment with neurotrophins prevents degeneration of spiral ganglion cells (SGCs) after severe hair cell loss. In a previous study we demonstrated a long-lasting effect with brain-derived neurotrophic factor (BDNF) after cessation of treatment. In that study the survival of the SGC cell bodies was examined. Here we address the question whether their peripheral processes and central processes (axons) were protected by this treatment as well in the cochleas of the aforementioned study. Guinea pigs were deafened by co-administration of kanamycin and furosemide. Two weeks after deafening the right cochleas were implanted with an intracochlear electrode array combined with a cannula connected to an osmotic pump filled with BDNF solution. Four weeks later the treatment was stopped by surgically removing the osmotic pump. At that point, or another four or eight weeks later, the animals were sacrificed for histological analysis. Control groups consisted of normal-hearing animals, and three groups of deafened animals: two-weeks-deaf untreated animals, and six- and fourteen-weeks-deaf sham-treated animals. Cochleas were processed for analysis of: (1) the myelinated portion of peripheral processes in the osseous spiral lamina, (2) the cell bodies in Rosenthal's canal, and (3) axons in the internal acoustic meatus. Packing densities and cross-sectional areas were determined using light microscopy. Up to eight weeks after treatment cessation the numbers of peripheral processes and axons were significantly higher than in untreated cochleas of control animals. Whereas the numbers of cell bodies and axons were similar to those at the start of treatment, the peripheral processes were significantly less well preserved. This smaller protective effect was found mainly in the apical turns. Strategies to prevent SGC degeneration after hair cell loss should consider the differential effects on the various neural elements. [ABSTRACT FROM AUTHOR]

In deaf subjects using a cochlear implant (CI) for hearing restoration, the auditory nerve is subject to degeneration, which may negatively impact CI effectiveness. This nerve degeneration can be reduced by neurotrophic treatment. Here, we compare the preservative effects of the naturally occurring tyrosine receptor kinase B (TrkB) agonist brain-derived neurotrophic factor (BDNF) and the small-molecule TrkB agonist 7,8,3′-trihydroxyflavone (THF) on the auditory nerve in deafened guinea pigs. THF may be more effective than BDNF throughout the cochlea because of better pharmacokinetic properties. The neurotrophic compounds were delivered by placement of a gelatin sponge on the perforated round window membrane. To complement the histology of spiral ganglion cells (SGCs), electrically evoked compound action potential (eCAP) recordings were performed four weeks after treatment initiation. We analyzed the eCAP inter-phase gap (IPG) effect and measures derived from pulse-train evoked eCAPs, both indicative of SGC healthiness. BDNF but not THF yielded a significantly higher survival of SGCs in the basal cochlear turn than untreated controls. Regarding IPG effect and pulse-train responses, the BDNF-treated animals exhibited more normal responses than both untreated and THF-treated animals. We have thus confirmed the protective effect of BDNF, but we have not confirmed previously reported protective effects of THF with our clinically applicable delivery method. [ABSTRACT FROM AUTHOR]

Severe damage to the organ of Corti leads to degeneration of the spiral ganglion cells (SGCs) which form the auditory nerve. This degeneration starts at the level of synaptic connection of the peripheral processes (PPs) of SGCs with the cochlear hair cells. It is generally thought that from this point SGC degeneration progresses in a retrograde fashion: PPs degenerate first, followed by the SGC soma with a delay of several weeks to many months. Evidence for this course of events, both in animals and in humans, is not unambiguous, while this knowledge is important since the presence or absence of the different neural elements may greatly influence the response to electrical stimulation with a cochlear implant (CI). We therefore aimed to provide a comprehensive account of the course of SGC degeneration in the guinea pig cochlea after ototoxic treatment. Histological analysis of eighteen healthy and thirty-three deafened cochleas showed that the degeneration of SGCs and their peripheral processes was simultaneous rather than sequential. As the site of excitation for electrical stimulation with a CI may depend on the course of degeneration of the various neural elements, this finding is relevant both for understanding the electrophysiological mechanisms behind cochlear implantation and for recent efforts to induce PP resprouting for improved electrode-neural interface. Since excitation of the PPs is often thought to result in (secondary) longer-latency activity, we tested the hypothesis that having relatively many PPs produces a larger N 2 peak in the electrically evoked compound action potential (eCAP); the present findings however do not support this theory. The course of the degeneration process may vary among species, and may depend on the cause of deafness, but the present findings at least indicate that gradual retrograde degeneration of the auditory nerve is not an elemental process following severe damage to the organ of Corti. • After ototoxic deafening spiral ganglion cells degenerate following hair cell loss. • Peripheral processes degenerate simultaneously with their cell bodies. • Ultrastructural analysis shows that all surviving fibers are well-myelinated. • There is no evidence of functional contribution of peripheral processes to the eCAP. [ABSTRACT FROM AUTHOR]

• A TrkB antibody agonist, M3, shown to be neuroprotective in vitro , was tested in vivo • M3 treatment yielded enhanced spiral ganglion cell survival in deafened guinea pigs • Functional measures of the auditory nerve did not improve upon M3 treatment • M3-mediated preservation of the auditory nerve was overall inferior to that with BDNF The auditory nerve typically degenerates following loss of cochlear hair cells or synapses. In the case of hair cell loss neural degeneration hinders restoration of hearing through a cochlear implant, and in the case of synaptopathy suprathreshold hearing is affected, potentially degrading speech perception in noise. It has been established that neurotrophins such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) can mitigate auditory nerve degeneration. Several potential BDNF mimetics have also been investigated for neurotrophic effects in the cochlea. A recent in vitro study showed favorable effects of M3, a TrkB monoclonal antibody agonist, when compared with BDNF. In the present study we set out to examine the effect of M3 on auditory nerve preservation in vivo. Thirty-one guinea pigs were bilaterally deafened, and unilaterally treated with a single 3-µl dose of 7 mg/ml, 0.7 mg/ml M3 or vehicle-only by means of a small gelatin sponge two weeks later. During the experiment and analyses the experimenters were blinded to the three treatment groups. Four weeks after treatment, we assessed the treatment effect (1) histologically, by quantifying survival of SGCs and their peripheral processes (PPs); and (2) electrophysiologically, with two different paradigms of electrically evoked compound action potential (eCAP) recordings shown to be indicative of neural health: single-pulse stimulation with varying inter-phase gap (IPG), and pulse-train stimulation with varying inter-pulse interval. We observed a consistent and significant preservative effect of M3 on SGC survival in the lower basal turn (approximately 40% more survival than in the untreated contralateral cochlea), but also in the upper middle and lower apical turn of the cochlea. This effect was similar for the two treatment groups. Survival of PPs showed a trend similar to that of the SGCs, but was only significantly higher for the highest dose of M3. The protective effect of M3 on SGCs was not reflected in any of the eCAP measures: no statistically significant differences were observed between groups in IPG effect nor between the M3 treatment groups and the control group using the pulse-train stimulation paradigm. In short, while a clear effect of M3 was observed on SGC survival, this was not clearly translated into functional preservation. [ABSTRACT FROM AUTHOR]

Damage to and loss of the organ of Corti leads to secondary degeneration of the spiral ganglion cell (SGC) somata of the auditory nerve. Extensively examined in animal models, this degeneration process of SGC somata following deafening is well known. However, degeneration of auditory nerve axons, which conduct auditory information towards the brainstem, and its relation to SGC soma degeneration are largely unknown. The consequences of degeneration of the axons are relevant for cochlear implantation, which is applied to a deafened system but depends on the condition of the auditory nerve. We investigated the time sequence of degeneration of myelinated type I axons in deafened guinea pigs. Auditory nerves in six normal-hearing and twelve deafened animals, two, six and fourteen weeks (for each group four) after deafening were histologically analyzed. We developed a semi-automated method for axon counting, which allowed for a relatively large sample size (20% of the total cross-sectional area of the auditory nerve). We observed a substantial loss of auditory nerve area (29%), reduction in axon number (59%) and decrease in axoplasm area (41%) fourteen weeks after deafening compared to normal-hearing controls. The correlation between axonal degeneration and that of the SGC somata in the same cochleas was high, although axonal structures appeared to persist longer than the somata, suggesting a slower degeneration process. In the first two weeks after induction of deafness, the axonal cross-sectional area decreased but the axon number did not. In conclusion, the data strongly suggest that each surviving SGC possesses an axon. [ABSTRACT FROM AUTHOR]