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.

Patient-Led Research to Develop a Training Programme for Restoring Musical Joy in Cochlear Implant Recipients: A Reflexive Process Evaluation.

BACKGROUND: The role of patients in healthcare research is slowly evolving, although patient roles in the research process are limited. This paper reports on a patient-led research project aiming to develop a musical hearing training programme for patients with a cochlear implant (CI): the Musi-CI programme. A CI is an inner ear prosthesis that allows people with severe hearing loss to hear. However, while speech can be understood, CI users cannot fully enjoy music or feel aversion to it. The Musi-CI programme aims to reduce this music aversion to ultimately improve music enjoyment and social participation. The development of the Musi-CI programme was supported by a consortium of professionals in CI rehabilitation and research. The aim of this paper is to describe and evaluate the Musi-CI programme development process and its impact on professional CI rehabilitation and research. METHODS: Programme development was described using a 3-layered process model of action research, distinguishing the CI user process, the healthcare professional process and the research process. To evaluate perceptions on the programme development process, consortium partners provided written comments and participated in a reflexive evaluation session that was video-recorded. Reflexive evaluation aims for collective learning and strengthening collaboration among participants. Written comments and video data were analysed using template analysis. RESULTS: The involvement of an expert by experience was perceived as challenging but rewarding for all consortium partners, opening up new perspectives on CI-rehabilitation practice and research. Data analysis revealed two themes on the programme development process, professional space and acknowledgement, and two themes on the outcomes on CI rehabilitation and research: critical reflection and paradigm shift. CONCLUSION: Experts by experience represent a different knowledge domain that may contribute to change in rehabilitation and research. PATIENT OR PUBLIC CONTRIBUTION: The development of the programme was initiated by a professional musician and CI user who organized the funding, had a leading role throughout the research process, including the write-up of the results, and co-authored this paper.

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.

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.

Assessing auditory nerve condition by tone decay in deaf subjects with a cochlear implant.

The condition of the auditory nerve is a factor determining hearing performance of cochlear implant (CI) recipients. Abnormal loudness adaptation is associated with poor auditory nerve survival. We examined which stimulus conditions are suitable for tone decay measurements to differentiate between CI recipients with respect to their speech perception. Tone decay was defined here as occurring when the percept disappears before the stimulus stops. We measured the duration of the percept of a 60-s pulse train. Current levels ranged from below threshold up to maximum acceptable loudness, pulse rates from 250 to 5000 pulses/s, and duty cycles (percentages of time the burst of pulses is on) from 10% to 100%. Ten adult CI recipients were included: seven with good and three with poor speech perception. Largest differences among the subjects were found at 5000 pulses/s and 100% duty cycle. The well performing subjects had a continuous percept of the 60-s stimulus within 3 dB above threshold. Two poorly performing subjects showed abnormal loudness adaptation, that is, no continuous percept even at levels greater than 6 dB above threshold. We conclude that abnormal loudness adaptation can be detected via an electric tone decay test using a high pulse rate and 100% duty cycle.

Temporary Neurotrophin Treatment Prevents Deafness-Induced Auditory Nerve Degeneration and Preserves Function.

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. Significance statement: Successful restoration of hearing in deaf subjects by means of a cochlear implant requires a healthy spiral ganglion cell population. Deafness-induced degeneration of these cells can be averted with neurotrophic factors. In the present study in deafened guinea pigs, we investigated the long-term effects of temporary (i.e., clinically practicable) treatment with brain-derived neurotrophic factor (BDNF). We show that, after treatment cessation, the neuroprotective effect remains for at least 8 weeks. Moreover, for the first time, it is shown that the electrical responsiveness of BDNF-treated spiral ganglion cells is preserved during this period as well. These findings demonstrate that treatment of the auditory nerve with neurotrophic factors may be relevant for cochlear implant users.

Assessing the Firing Properties of the Electrically Stimulated Auditory Nerve Using a Convolution Model.

The electrically evoked compound action potential (eCAP) is a routinely performed measure of the auditory nerve in cochlear implant users. Using a convolution model of the eCAP, additional information about the neural firing properties can be obtained, which may provide relevant information about the health of the auditory nerve. In this study, guinea pigs with various degrees of nerve degeneration were used to directly relate firing properties to nerve histology. The same convolution model was applied on human eCAPs to examine similarities and ultimately to examine its clinical applicability. For most eCAPs, the estimated nerve firing probability was bimodal and could be parameterised by two Gaussian distributions with an average latency difference of 0.4 ms. The ratio of the scaling factors of the late and early component increased with neural degeneration in the guinea pig. This ratio decreased with stimulation intensity in humans. The latency of the early component decreased with neural degeneration in the guinea pig. Indirectly, this was observed in humans as well, assuming that the cochlear base exhibits more neural degeneration than the apex. Differences between guinea pigs and humans were observed, among other parameters, in the width of the early component: very robust in guinea pig, and dependent on stimulation intensity and cochlear region in humans. We conclude that the deconvolution of the eCAP is a valuable addition to existing analyses, in particular as it reveals two separate firing components in the auditory nerve.

Octave effect in auditory attention.

After hearing a tone, the human auditory system becomes more sensitive to similar tones than to other tones. Current auditory models explain this phenomenon by a simple bandpass attention filter. Here, we demonstrate that auditory attention involves multiple pass-bands around octave-related frequencies above and below the cued tone. Intriguingly, this "octave effect" not only occurs for physically presented tones, but even persists for the missing fundamental in complex tones, and for imagined tones. Our results suggest neural interactions combining octave-related frequencies, likely located in nonprimary cortical regions. We speculate that this connectivity scheme evolved from exposure to natural vibrations containing octave-related spectral peaks, e.g., as produced by vocal cords.

Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans.

Animal studies have evidenced protection of the auditory nerve by exogenous neurotrophic factors. In order to assess clinical applicability of neurotrophic treatment of the auditory nerve, the safety and efficacy of neurotrophic therapies in various human disorders were systematically reviewed. Outcomes of our literature search included disorder, neurotrophic factor, administration route, therapeutic outcome, and adverse event. From 2103 articles retrieved, 20 randomized controlled trials including 3974 patients were selected. Amyotrophic lateral sclerosis (53%) was the most frequently reported indication for neurotrophic therapy followed by diabetic polyneuropathy (28%). Ciliary neurotrophic factor (50%), nerve growth factor (24%) and insulin-like growth factor (21%) were most often used. Injection site reaction was a frequently occurring adverse event (61%) followed by asthenia (24%) and gastrointestinal disturbances (20%). Eighteen out of 20 trials deemed neurotrophic therapy to be safe, and six out of 17 studies concluded the neurotrophic therapy to be effective. Positive outcomes were generally small or contradicted by other studies. Most non-neurodegenerative diseases treated by targeted deliveries of neurotrophic factors were considered safe and effective. Hence, since local delivery to the cochlea is feasible, translation from animal studies to human trials in treating auditory nerve degeneration seems promising.

Task-related preparatory modulations multiply with acoustic processing in monkey auditory cortex.

We characterised task-related top-down signals in monkey auditory cortex cells by comparing single-unit activity during passive sound exposure with neuronal activity during a predictable and unpredictable reaction-time task for a variety of spectral-temporally modulated broadband sounds. Although animals were not trained to attend to particular spectral or temporal sound modulations, their reaction times demonstrated clear acoustic spectral-temporal sensitivity for unpredictable modulation onsets. Interestingly, this sensitivity was absent for predictable trials with fast manual responses, but re-emerged for the slower reactions in these trials. Our analysis of neural activity patterns revealed a task-related dynamic modulation of auditory cortex neurons that was locked to the animal's reaction time, but invariant to the spectral and temporal acoustic modulations. This finding suggests dissociation between acoustic and behavioral signals at the single-unit level. We further demonstrated that single-unit activity during task execution can be described by a multiplicative gain modulation of acoustic-evoked activity and a task-related top-down signal, rather than by linear summation of these signals.

Does vestibular end-organ function recover after gentamicin-induced trauma in Guinea pigs?

Until 1993 it was commonly accepted that regeneration of vestibular hair cells was not possible in mammals. Two histological studies then showed structural evidence for spontaneous regeneration of vestibular hair cells after gentamicin treatment. There is less evidence for functional recovery going along with this regenerative process; in other words, do regenerated hair cells function adequately? This study aims to address this question, and in general evaluates whether spontaneous functional recovery may occur, in the short or long term, in mammals after ototoxic insult. Guinea pigs were treated with gentamicin for 10 consecutive days at a daily dose of 125 mg/kg body weight. Survival times varied from 1 day to 16 weeks. Vestibular short-latency evoked potentials (VsEPs) to linear acceleration pulses were recorded longitudinally to assess otolith function. After the final functional measurements we performed immunofluorescence histology for hair cell counts. Auditory brainstem responses (ABRs) to click stimuli were recorded to assess cochlear function. As intended, gentamicin treatment resulted in significant loss of utricular hair cells and accompanying declines in VsEPs. Hair cell counts 8 or 16 weeks after treatment did not significantly differ from counts after shorter survival periods. Maximal functional loss was achieved 1-4 weeks after treatment. After this period, only 2 animals showed recovery of VsEP amplitude - all other animals did not reveal signs of regeneration or recovery. In contrast, after initial ABR threshold shifts there was a small but significant recovery. We conclude that spontaneous recovery of otolith function, in contrast to cochlear function, is very limited in guinea pigs. These results support the concept of intratympanic gentamicin treatment where gentamicin is used for chemoablation of the vestibular sensory epithelia.

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.

Stable bottom-up processing during dynamic top-down modulations in monkey auditory cortex.

It is unclear whether top-down processing in the auditory cortex (AC) interferes with its bottom-up analysis of sound. Recent studies indicated non-acoustic modulations of AC responses, and that attention changes a neuron's spectrotemporal tuning. As a result, the AC would seem ill-suited to represent a stable acoustic environment, which is deemed crucial for auditory perception. To assess whether top-down signals influence acoustic tuning in tasks without directed attention, we compared monkey single-unit AC responses to dynamic spectrotemporal sounds under different behavioral conditions. Recordings were mostly made from neurons located in primary fields (primary AC and area R of the AC) that were well tuned to pure tones, with short onset latencies. We demonstrated that responses in the AC were substantially modulated during an auditory detection task and that these modulations were systematically related to top-down processes. Importantly, despite these significant modulations, the spectrotemporal receptive fields of all neurons remained remarkably stable. Our results suggest multiplexed encoding of bottom-up acoustic and top-down task-related signals at single AC neurons. This mechanism preserves a stable representation of the acoustic environment despite strong non-acoustic modulations.

Bilateral low-frequency repetitive transcranial magnetic stimulation of the auditory cortex in tinnitus patients is not effective: a randomised controlled trial.

BACKGROUND: Although some therapies may be beneficial for some patients in reducing tinnitus, there is no curative therapy. Repetitive transcranial magnetic stimulation (rTMS) has been applied as a treatment for chronic tinnitus, but the effect remains controversial. MATERIAL AND METHODS: Fifty patients were treated with rTMS or placebo. Treatment consisted of 2,000 TMS pulses on each auditory cortex, at a rate of 1 Hz and an intensity of 110% of the individual motor threshold, on 5 consecutive days. rTMS and placebo effects were evaluated directly after treatment, after 1 week, and after 1, 3 and 6 months. Primary outcome was the Tinnitus Questionnaire (TQ). Secondary outcomes were the Tinnitus Handicap Inventory (THI) and a visual analogue scale. RESULTS: At none of the follow-up evaluation moments a significant difference between rTMS and placebo was observed with respect to changes in TQ or THI scores relative to pretreatment scores. Multilevel modelling (MLM) analyses did not show a global treatment effect either. Patients with a higher degree of burden showed slightly greater improvement after rTMS (only significant on the THI with MLM analyses). CONCLUSION: Bilateral low-frequency rTMS of the auditory cortex was not effective in treating tinnitus.

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.

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.

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.

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.

Combined administration of kanamycin and furosemide does not result in loss of vestibular function in Guinea pigs.

Aminoglycoside antibiotics are known to damage the vestibular and auditory sensory epithelia. Although loop diuretics enhance the cochleotoxic effect of aminoglycosides, it is not known whether concomitant administration of an aminoglycoside and a loop diuretic affects the vestibular system. The aim of our study was to investigate the effect of co-administration of kanamycin and furosemide upon the otolith organs and to compare it to the known vestibulotoxic effect of gentamicin. Five guinea pigs were injected with a single dose of both kanamycin (400 mg/kg, s.c.) and furosemide (100 mg/kg, i.v.), 5 animals received gentamicin (100 mg/kg, i.p.) for 10 days, and 5 untreated animals served as controls. After 7 days, vestibular function was assessed by measuring vestibular short-latency evoked potentials (VsEPs) to linear acceleration stimuli and cochlear function by auditory brainstem responses (ABRs) to clicks. Hair cell densities were determined in phalloidin-stained whole mounts of the utricles and saccules, and in midmodiolar sections of resin-embedded cochleae. Co-administration of kanamycin and furosemide had no significant effect on VsEPs and hair cell densities in the utricles and saccules were not reduced. ABR thresholds were increased to a great extent (by ∼60 dB), and histologically a severe loss of cochlear hair cells was observed. The effect of gentamicin, both on vestibular and cochlear function, was just the opposite. VsEP thresholds to horizontal stimulation were elevated and suprathreshold amplitudes showed a decrease, whereas cochlear function was not reduced. With this protocol, we have a tool to selectively induce cochlear or vestibular damage, which may be of interest to researchers and clinicians alike.