Validation of the acoustic change complex (ACC) prediction model to predict speech perception in noise in adult patients with hearing loss: a study protocol.

BACKGROUND: Speech perception tests are essential to measure the functional use of hearing and to determine the effectiveness of hearing aids and implantable auditory devices. However, these language-based tests require active participation and are influenced by linguistic and neurocognitive skills limiting their use in patients with insufficient language proficiency, cognitive impairment, or in children. We recently developed a non-attentive and objective speech perception prediction model: the Acoustic Change Complex (ACC) prediction model. The ACC prediction model uses electroencephalography to measure alterations in cortical auditory activity caused by frequency changes. The aim is to validate this model in a large-scale external validation study in adult patients with varying degrees of sensorineural hearing loss (SNHL) to confirm the high predictive value of the ACC model and to assess its test-retest reliability. METHODS: A total of 80 participants, aged 18-65 years, will be enrolled in the study. The categories of severity of hearing loss will be used as a blocking factor to establish an equal distribution of patients with various degrees of sensorineural hearing loss. During the first visit, pure tone audiometry, speech in noise tests, a phoneme discrimination test, and the first ACC measurement will be performed. During the second visit (after 1-4 weeks), the same ACC measurement will be performed to assess the test-retest reliability. The acoustic change stimuli for ACC measurements consist of a reference tone with a base frequency of 1000, 2000, or 4000 Hz with a duration of 3000 ms, gliding to a 300-ms target tone with a frequency that is 12% higher than the base frequency. The primary outcome measures are (1) the level of agreement between the predicted speech reception threshold (SRT) and the behavioral SRT, and (2) the level of agreement between the SRT calculated by the first ACC measurement and the SRT of the second ACC measurement. Level of agreement will be assessed with Bland-Altman plots. DISCUSSION: Previous studies by our group have shown the high predictive value of the ACC model. The successful validation of this model as an effective and reliable biomarker of speech perception will directly benefit the general population, as it will increase the accuracy of hearing evaluations and improve access to adequate hearing rehabilitation.

Spectral-temporal processing of naturalistic sounds in monkeys and humans.

Human speech and vocalizations in animals are rich in joint spectrotemporal (S-T) modulations, wherein acoustic changes in both frequency and time are functionally related. In principle, the primate auditory system could process these complex dynamic sounds based on either an inseparable representation of S-T features or, alternatively, a separable representation. The separability hypothesis implies an independent processing of spectral and temporal modulations. We collected comparative data on the S-T hearing sensitivity in humans and macaque monkeys to a wide range of broadband dynamic spectrotemporal ripple stimuli employing a yes-no signal-detection task. Ripples were systematically varied, as a function of density (spectral modulation frequency), velocity (temporal modulation frequency), or modulation depth, to cover a listener's full S-T modulation sensitivity, derived from a total of 87 psychometric ripple detection curves. Audiograms were measured to control for normal hearing. Determined were hearing thresholds, reaction time distributions, and S-T modulation transfer functions (MTFs), both at the ripple detection thresholds and at suprathreshold modulation depths. Our psychophysically derived MTFs are consistent with the hypothesis that both monkeys and humans employ analogous perceptual strategies: S-T acoustic information is primarily processed separable. Singular value decomposition (SVD), however, revealed a small, but consistent, inseparable spectral-temporal interaction. Finally, SVD analysis of the known visual spatiotemporal contrast sensitivity function (CSF) highlights that human vision is space-time inseparable to a much larger extent than is the case for S-T sensitivity in hearing. Thus, the specificity with which the primate brain encodes natural sounds appears to be less strict than is required to adequately deal with natural images.NEW & NOTEWORTHY We provide comparative data on primate audition of naturalistic sounds comprising hearing thresholds, reaction time distributions, and spectral-temporal modulation transfer functions. Our psychophysical experiments demonstrate that auditory information is primarily processed in a spectral-temporal-independent manner by both monkeys and humans. Singular value decomposition of known visual spatiotemporal contrast sensitivity, in comparison to our auditory spectral-temporal sensitivity, revealed a striking contrast in how the brain encodes natural sounds as opposed to natural images, as vision appears to be space-time inseparable.

The efficacy of a TrkB monoclonal antibody agonist in preserving the auditory nerve in deafened guinea pigs.

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.

Development of the Musi-CI Training, A Musical Listening Training for Cochlear Implant Users: A Participatory Action Research Approach.

A cochlear implant (CI) is a prosthesis that allows people with severe to profound hearing loss to understand speech in quiet settings. However, listening to music presents a challenge to most CI users; they often do not enjoy music or avoid it altogether. The Musi-CI training course was developed for CI users with the goal of reducing music aversion and improving music enjoyment. A consortium was established consisting of a professional musician with CI, CI rehabilitation professionals and researchers. Participatory action research (PAR) was applied to develop and evaluate the training experiences, collaborating with 37 CI users during three cycles of eight training sessions, each held over a period of 3 months. Input and feedback were collected after each training session using questionnaires, observations and focus group interviews. Almost all participants (86%) completed the training. After completing the training a large majority of participants reported increased music appreciation, increased social participation in musical settings and a positive impact on general auditory perception. The resulting Musi-CI training programme focuses on music listening skills, self-efficacy, and self-motivation. It consists of exercises intended to strengthen attention and working memory, to improve beat and rhythm perception (with online rhythm exercises) and exercises to distinguish timbre of instruments and emotion in music. A Melody Game was developed to improve pitch and melodic contour discrimination.

Long-term survival of LGR5 expressing supporting cells after severe ototoxic trauma in the adult mouse cochlea.

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.

Regeneration of Hair Cells from Endogenous Otic Progenitors in the Adult Mammalian Cochlea: Understanding Its Origins and Future Directions.

Sensorineural hearing loss is caused by damage to sensory hair cells and/or spiral ganglion neurons. In non-mammalian species, hair cell regeneration after damage is observed, even in adulthood. Although the neonatal mammalian cochlea carries regenerative potential, the adult cochlea cannot regenerate lost hair cells. The survival of supporting cells with regenerative potential after cochlear trauma in adults is promising for promoting hair cell regeneration through therapeutic approaches. Targeting these cells by manipulating key signaling pathways that control mammalian cochlear development and non-mammalian hair cell regeneration could lead to regeneration of hair cells in the mammalian cochlea. This review discusses the pathways involved in the development of the cochlea and the impact that trauma has on the regenerative capacity of the endogenous progenitor cells. Furthermore, it discusses the effects of manipulating key signaling pathways targeting supporting cells with progenitor potential to promote hair cell regeneration and translates these findings to the human situation. To improve hearing recovery after hearing loss in adults, we propose a combined approach targeting (1) the endogenous progenitor cells by manipulating signaling pathways (Wnt, Notch, Shh, FGF and BMP/TGFß signaling pathways), (2) by manipulating epigenetic control, and (3) by applying neurotrophic treatments to promote reinnervation.

Acute effects of cochleostomy and electrode-array insertion on compound action potentials in normal-hearing guinea pigs.

Introduction: Electrocochleography (ECochG) is increasingly used in cochlear implant (CI) surgery, in order to monitor the effect of insertion of the electrode array aiming to preserve residual hearing. However, obtained results are often difficult to interpret. Here we aim to relate changes in ECochG responses to acute trauma induced by different stages of cochlear implantation by performing ECochG at multiple time points during the procedure in normal-hearing guinea pigs. Materials and methods: Eleven normal-hearing guinea pigs received a gold-ball electrode that was fixed in the round-window niche. ECochG recordings were performed during the four steps of cochlear implantation using the gold-ball electrode: (1) Bullostomy to expose the round window, (2) hand-drilling of 0.5-0.6 mm cochleostomy in the basal turn near the round window, (3) insertion of a short flexible electrode array, and (4) withdrawal of electrode array. Acoustical stimuli were tones varying in frequency (0.25-16 kHz) and sound level. The ECochG signal was primarily analyzed in terms of threshold, amplitude, and latency of the compound action potential (CAP). Midmodiolar sections of the implanted cochleas were analyzed in terms of trauma to hair cells, modiolar wall, osseous spiral lamina (OSL) and lateral wall. Results: Animals were assigned to cochlear trauma categories: minimal (n = 3), moderate (n = 5), or severe (n = 3). After cochleostomy and array insertion, CAP threshold shifts increased with trauma severity. At each stage a threshold shift at high frequencies (4-16 kHz) was accompanied with a threshold shift at low frequencies (0.25-2 kHz) that was 10-20 dB smaller. Withdrawal of the array led to a further worsening of responses, which probably indicates that insertion and removal trauma affected the responses rather than the mere presence of the array. In two instances, CAP threshold shifts were considerably larger than threshold shifts of cochlear microphonics, which could be explained by neural damage due to OSL fracture. A change in amplitudes at high sound levels was strongly correlated with threshold shifts, which is relevant for clinical ECochG performed at one sound level. Conclusion: Basal trauma caused by cochleostomy and/or array insertion should be minimized in order to preserve the low-frequency residual hearing of CI recipients.

Choice of treatment evaluated after trial periods with bone conduction devices and contralateral routing of sound systems in patients with single-sided deafness.

Objectives: Patients with single-sided deafness (SSD) may experience difficulties with speech perception in noise, sound localization, have tinnitus and experience a reduced quality of life (QoL). contralateral routing of sound hearing aids (CROS) or bone conduction devices (BCD) may partly improve subjective speech communication and QoL in SSD patients. A trial period with these devices can help in making a well-informed choice of treatment. Our aim was to evaluate factors influencing the choice of treatment made after a BCD and CROS trial period in adult SSD patients. Methods: Patients were randomized in the: "first BCD, then CROS" or "first CROS, then BCD" trial period group. After the BCD on headband and CROS were tested for 6 weeks each, patients choose for BCD, CROS or no treatment. Primary outcome was the distribution of choice of treatment. Secondary outcomes included the association between the choice of treatment and patient characteristics, reasons for treatment acceptance or rejection, device usage during the trial periods, and disease-specific QoL outcomes. Results: Of 91 patients randomized, 84 completed both trial periods and made their choice of treatment: 25 (30%) BCD, 34 (40%) CROS, and 25 (30%) no treatment. No characteristics were found to be related to choice of treatment. Top three reasons for acceptance or rejection were: device (dis)comfort, sound quality and (dis)advantage of subjective hearing. Average daily device use during the trial periods was higher for CROS than for BCD. Choice of treatment was significantly related with both duration of device usage and greater improvement of QoL after the corresponding trial period. Conclusion: The majority of SSD patients preferred BCD or CROS over no treatment. Evaluating device usage, discussing treatment (dis)advantages and disease-specific QoL outcomes after trial periods are to be considered during patient counseling and could facilitate whether to choose one of these treatments. Level of evidence: 1B.

mTOR Signaling in BDNF-Treated Guinea Pigs after Ototoxic Deafening.

The mammalian target of rapamycin (mTOR) signaling plays a critical role in cell homeostasis, growth and survival. Here, we investigated the localization of the main mTOR signaling proteins in the organ of Corti of normal-hearing and deafened guinea pigs, as well as their possible modulation by exogenously administered brain-derived neurotrophic factor (BDNF) in deafened guinea pigs. Animals were ototoxically deafened by systemic administration of kanamycin and furosemide, and one week later, the right cochleas were treated with gelatin sponge soaked in rhBDNF, while the left cochleas were used as negative controls. Twenty-four hours after treatment, animals were euthanized, and the cochleas were processed for subsequent analysis. Through immunofluorescence, we demonstrated the localization of AKT, pAKT, mTOR, pmTOR and PTEN proteins throughout the cochlea of guinea pigs for the first time, with a higher expression in supporting cells. Moreover, an increase in mTOR immunostaining was observed in BDNF-treated cochleas by means of fluorescence intensity compared to the other groups. Conversely, Western blot analysis showed no significant differences in the protein levels between groups, probably due to dilution of proteins in the neighboring tissues of the organ of Corti. Altogether, our data indicate that mTOR signaling proteins are expressed by the organ of Corti (with a major role for supporting cells) and that the modulation of mTOR may be a protective mechanism triggered by BDNF in the degenerating organ of Corti.

Combined brain-derived neurotrophic factor and neurotrophin-3 treatment is preferred over either one separately in the preservation of the auditory nerve in deafened guinea pigs.

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.

The effect of the surgical approach and cochlear implant electrode on the structural integrity of the cochlea in human temporal bones.

Cochlear implants (CI) restore hearing of severely hearing-impaired patients. Although this auditory prosthesis is widely considered to be very successful, structural cochlear trauma during cochlear implantation is an important problem, reductions of which could help to improve hearing outcomes and to broaden selection criteria. The surgical approach in cochlear implantation, i.e. round window (RW) or cochleostomy (CO), and type of electrode-array, perimodiolar (PM) or lateral wall (LW), are variables that might influence the probability of severe trauma. We investigated the effect of these two variables on scalar translocation (STL), a specific type of severe trauma. Thirty-two fresh frozen human cadaveric ears were evenly distributed over four groups receiving either RW or CO approach, and either LW or PM array. Conventional radiological multiplanar reconstruction (MPR) was compared with a reconstruction method that uncoils the spiral shape of the cochlea (UCR). Histological analysis showed that RW with PM array had STL rate of 87% (7/8), CO approach with LW array 75% (6/8), RW approach with LW array 50% (4/8) and CO approach with PM array 29% (2/7). STL assessment using UCR showed a higher inter-observer and histological agreement (91 and 94% respectively), than that using MPR (69 and 74% respectively). In particular, LW array positions were difficult to assess with MPR. In conclusion, the interaction between surgical approach and type of array should be preoperatively considered in cochlear implant surgery. UCR technique is advised for radiological assessment of CI positions, and in general it might be useful for pathologies involving the inner ear or other complex shaped bony tubular structures.

Changes in the Electrically Evoked Compound Action Potential over time After Implantation and Subsequent Deafening in Guinea Pigs.

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

The Acoustic Change Complex Compared to Hearing Performance in Unilaterally and Bilaterally Deaf Cochlear Implant Users.

OBJECTIVES: Clinical measures evaluating hearing performance in cochlear implant (CI) users depend on attention and linguistic skills, which limits the evaluation of auditory perception in some patients. The acoustic change complex (ACC), a cortical auditory evoked potential to a sound change, might yield useful objective measures to assess hearing performance and could provide insight in cortical auditory processing. The aim of this study is to examine the ACC in response to frequency changes as an objective measure for hearing performance in CI users. DESIGN: Thirteen bilaterally deaf and six single-sided deaf subjects were included, all having used a unilateral CI for at least 1 year. Speech perception was tested with a consonant-vowel-consonant test (+10 dB signal-to-noise ratio) and a digits-in-noise test. Frequency discrimination thresholds were measured at two reference frequencies, using a 3-interval, 2-alternative forced-choice, adaptive staircase procedure. The two reference frequencies were selected using each participant's frequency allocation table and were centered in the frequency band of an electrode that included 500 or 2000 Hz, corresponding to the apical electrode or the middle electrode, respectively. The ACC was evoked with pure tones of the same two reference frequencies with varying frequency increases: within the frequency band of the middle or the apical electrode (+0.25 electrode step), and steps to the center frequency of the first (+1), second (+2), and third (+3) adjacent electrodes. RESULTS: Reproducible ACCs were recorded in 17 out of 19 subjects. Most successful recordings were obtained with the largest frequency change (+3 electrode step). Larger frequency changes resulted in shorter N1 latencies and larger N1-P2 amplitudes. In both unilaterally and bilaterally deaf subjects, the N1 latency and N1-P2 amplitude of the CI ears correlated to speech perception as well as frequency discrimination, that is, short latencies and large amplitudes were indicative of better speech perception and better frequency discrimination. No significant differences in ACC latencies or amplitudes were found between the CI ears of the unilaterally and bilaterally deaf subjects, but the CI ears of the unilaterally deaf subjects showed substantially longer latencies and smaller amplitudes than their contralateral normal-hearing ears. CONCLUSIONS: The ACC latency and amplitude evoked by tone frequency changes correlate well to frequency discrimination and speech perception capabilities of CI users. For patients unable to reliably perform behavioral tasks, the ACC could be of added value in assessing hearing performance.

Cortical potentials evoked by tone frequency changes can predict speech perception in noise.

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 (R2 = 0.52) and ACC latency (R2 = 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.

Evaluating cochlear insertion trauma and hearing preservation after cochlear implantation (CIPRES): a study protocol for a randomized single-blind controlled trial.

BACKGROUND: In order to preserve residual hearing in patients with sensorineural hearing loss (SNHL) who receive a cochlear implant (CI), insertion trauma to the delicate structures of the cochlea needs to be minimized. The surgical approach comprises the conventional mastoidectomy-posterior tympanotomy (MPT) to arrive at the middle ear, followed by either a cochleostomy (CO) or the round window (RW) approach. Both techniques have their benefits and disadvantages. Another important aspect in structure preservation is the design of the electrode array. Two different designs are used: a "straight" lateral wall lying electrode array (LW) or a "pre-curved" perimodiolar lying electrode array (PM). Interestingly, until now, the best surgical approach and design of the implant is uncertain. Our hypothesis is that there is a difference in hearing preservation outcomes between the four possible treatment options. METHODS: We designed a monocenter, multi-arm, randomized controlled trial to compare insertion trauma between four groups of patients, with each group having a unique combination of an electrode array type (LW or PM) and surgical approach (RW or CO). In total, 48 patients will be randomized into one of these four intervention groups. Our primary objective is the comparison of postoperative hearing preservation between these four groups. Secondly, we aim to assess structure preservation (i.e., scalar translocation, with basilar membrane disruption or tip fold-over of array) for each group. Thirdly, we will compare objective outcomes of hearing and structure preservation by way of electrocochleography (ECochG). DISCUSSION: Cochlear implantation by way of a cochleostomy or round window approach, using different electrode array types, is the standard medical care for patients with severe to profound bilateral sensorineural hearing loss, as it is a relatively simple and low-risk procedure that greatly benefits patients. However, loss of residual hearing remains a problem. This trial is the first randomized controlled trial that evaluates the effect of cochlear insertion trauma of several CI treatment options on hearing preservation. TRIAL REGISTRATION: Netherlands Trial Register (NTR) NL8586 . Registered on 4 May 2020. Retrospectively registered; 3/48 participants were included before registration.

LGR5-Positive Supporting Cells Survive Ototoxic Trauma in the Adult Mouse Cochlea.

Sensorineural hearing loss is mainly caused by irreversible damage to sensory hair cells (HCs). A subgroup of supporting cells (SCs) in the cochlea express leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), a marker for tissue-resident stem cells. LGR5+ SCs could be used as an endogenous source of stem cells for regeneration of HCs to treat hearing loss. Here, we report long-term presence of LGR5+ SCs in the mature adult cochlea and survival of LGR5+ SCs after severe ototoxic trauma characterized by partial loss of inner HCs and complete loss of outer HCs. Surviving LGR5+ SCs (confirmed by GFP expression) were located in the third row of Deiters' cells. We observed a change in the intracellular localization of GFP, from the nucleus in normal-hearing to cytoplasm and membrane in deafened mice. These data suggests that the adult mammalian cochlea possesses properties essential for regeneration even after severe ototoxic trauma.

Cortical potentials evoked by tone frequency changes compared to frequency discrimination and speech perception: Thresholds in normal-hearing and hearing-impaired subjects.

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.

Scalar Translocation Comparison Between Lateral Wall and Perimodiolar Cochlear Implant Arrays - A Meta-Analysis.

OBJECTIVES/HYPOTHESIS: Two types of electrode arrays for cochlear implants (CIs) are distinguished: lateral wall and perimodiolar. Scalar translocation of the array can lead to intracochlear trauma by penetrating from the scala tympani into the scala vestibuli or scala media, potentially negatively affecting hearing performance of CI users. This systematic review compares the lateral wall and perimodiolar arrays with respect to scalar translocation. STUDY DESIGN: Systematic review. METHODS: PubMed, Embase, and Cochrane databases were reviewed for studies published within the last 11 years. No other limitations were set. All studies with original data that evaluated the occurrence of scalar translocation or tip fold-over (TF) with postoperative computed tomography (CT) following primary cochlear implantation in bilateral sensorineuronal hearing loss patients were considered to be eligible. Data were extracted independently by two reviewers. RESULTS: We included 33 studies, of which none were randomized controlled trials. Meta-analysis of five cohort studies comparing scalar translocation between lateral wall and perimodiolar arrays showed that lateral wall arrays have significantly lower translocation rates (7% vs. 43%; pooled odds ratio = 0.12). Translocation was negatively associated with speech perception scores (weighted mean 41% vs. 55%). Tip fold-over of the array was more frequent with perimodiolar arrays (X2  = 6.8, P < .01). CONCLUSIONS: Scalar translocation and tip fold-overs occurred more frequently with perimodiolar arrays than with lateral wall arrays. In addition, translocation of the array negatively affects hearing with the cochlear implant. Therefore, if one aims to minimize clinically relevant intracochlear trauma, lateral wall arrays would be the preferred option for cochlear implantation. Laryngoscope, 131:1358-1368, 2021.

No Protective Effects of Hair Cells or Supporting Cells in Ototoxically Deafened Guinea Pigs upon Administration of BDNF.

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).

BDNF-mediated preservation of spiral ganglion cell peripheral processes and axons in comparison to that of their cell bodies.

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.