Assessment of cochlear toxicity in response to chronic 3,3'-iminodipropionitrile in mice reveals early and reversible functional loss that precedes overt histopathology.

The peripheral auditory and vestibular systems rely on sensorineural structures that are vulnerable to ototoxic agents that cause hearing loss and/or equilibrium deficits. Although attention has focused on hair cell loss as the primary pathology underlying ototoxicity, evidence from the peripheral vestibular system indicates that hair cell loss during chronic exposure is preceded by synaptic uncoupling from the neurons and is potentially reversible. To determine if synaptic pathology also occurs in the peripheral auditory system, we examined the extent, time course, and reversibility of functional and morphological alterations in cochleae from mice exposed to 3,3'-iminodipropionitrile (IDPN) in drinking water for 2, 4 or 6 weeks. Functionally, IDPN exposure caused progressive high- to low-frequency hearing loss assessed by measurement of auditory brainstem response wave I absolute thresholds and amplitudes. The extent of hearing loss scaled with the magnitude of vestibular dysfunction assessed behaviorally. Morphologically, IDPN exposure caused progressive loss of outer hair cells (OHCs) and synapses between the inner hair cells (IHCs) and primary auditory neurons. In contrast, IHCs were spared from ototoxic damage. Importantly, hearing loss consistent with cochlear synaptopathy preceded loss of OHCs and synapses and, moreover, recovered if IDPN exposure was stopped before morphological pathology occurred. Our observations suggest that synaptic uncoupling, perhaps as an early phase of cochlear synaptopathy, also occurs in the peripheral auditory system in response to IDPN exposure. These findings identify novel mechanisms that contribute to the earliest stages of hearing loss in response to ototoxic agents and possibly other forms of acquired hearing loss.

A retrospective cohort study of adverse event assessment during anesthesia-related procedures for cochlear implant candidacy assessment and cochlear implantation in infants and toddlers.

BACKGROUND: Cochlear implantation in children with sensorineural hearing loss is preferably performed at youngest age because early auditory input is essential to prevent neural plasticity decline. In contrast, the rate of anesthetic adverse events is increased during infancy. Therefore, to provide recommendations regarding an optimal pediatric implantation age, these possible anesthetic risks in infants need to be taken into account. AIMS: This study aimed at assessing the relation between the age at cochlear implant surgery and anesthetic and surgical adverse events. Secondary aims were to evaluate anesthetic and surgical adverse events in relation to (a) the number of preoperative anesthesia-related procedures for cochlear implant candidacy assessment and (b) the anesthetic maintenance agent (total intravenous anesthesia versus inhalation anesthesia) during implantation. METHODS: We executed a retrospective cohort study to evaluate cochlear implantation performed in infants and toddlers between January 2008 and July 2015 in a tertiary pediatric center. We compared anesthetic and surgical adverse events between age-at-implantation (0-12 and 12-24 months of age) groups. Furthermore, we assessed whether anesthetic adverse events occurred during preoperative anesthesia-related procedures for cochlear implant candidacy assessment. RESULTS: Forty-six cochlear implantations were performed in 43 patients requiring 42 preoperative anesthesia-related procedures. Nineteen cochlear implantations (41.3%) were performed during infancy. During implantation, the maintenance agent was either sevoflurane (n = 22) or propofol (n = 24). None of the patients encountered major anesthetic adverse events, whereas minor adverse events occurred during 34 cochlear implantations. Those attributed to surgery occurred following six implantations. Neither the age at implantation nor the anesthetic maintenance agent was significantly related to the occurrence of both types of adverse events. CONCLUSIONS: Adverse events occur independent of the age at implantation, the number of anesthetic preoperative procedures, and the type of anesthetic maintenance agent in patients who received a cochlear implant before 24 months of age.

Effectiveness of Bone Conduction Stimulation Applied Directly to the Otic Capsule Measured at Promontory: Assessment in Cadavers.

INTRODUCTION: The aims of this study included: (a) to develop a method of direct acoustic bone conduction (BC) stimulation applied directly to the otic capsule, (b) to investigate the effect of different stimulation sites on the promontory displacement amplitude, and (c) to find the best stimulation site (among 2 located directly on the otic capsule and 1 standard site approved for clinical use) that provides the greatest transmission of vibratory energy. METHODS: Measurements were performed on 9 cadaveric whole human heads. A commercial scanning laser Doppler vibrometer was used. The promontory displacement was recorded in response to BC stimulation delivered by an implant at 3 sites: BC1 on the squamous part of the temporal bone, BC2 on the ampulla of the lateral semicircular canal, and BC3 between the semicircular canals. The displacement of the promontory was analyzed in detail. RESULTS: The results show that BC1 caused an overall smaller promontory displacement than both sites BC2 and 3. BC3 stimulation is more efficient than that at BC2. CONCLUSIONS: BC is an effective method of acoustic stimulus delivery into the inner ear, with the effectiveness increasing when approaching closer to the cochlea. Placing the implant directly on the labyrinth and thus applying vibrations directly to the otic capsule is possible and very effective as proved in this study. The results are encouraging and represent the potential of new stimulation sites that could be introduced in the field of BC hearing rehabilitation as the possible future locations for implantable BC hearing devices.

Audiological and electrophysiological assessment of professional orchestral musicians / Avaliação audiológica e eletrofisiológica em músicos profissionais de orquestra

ABSTRACT Purpose: to verify whether the frequent musical exposure can impair peripheral and central auditory pathway responses in professional orchestral musicians. Methods: 45 male individuals from 19 to 40 years old participated in the study. They were divided into two groups: one comprising 30 orchestral musicians who played strings or wind instruments, and another with 15 nonmusicians. The two groups were submitted to both conventional and high-frequency pure-tone audiometry, transient-evoked otoacoustic emissions, and frequency-following response. The results were subjected to descriptive and inferential statistical analysis, using the one-way ANOVA unmatched samples parametric test, with a 5% significance level. Results: no significant differences were observed between the hearing thresholds in both conventional and high-frequency audiometry and frequency-following response. However, there were statistically significant differences between transient-evoked otoacoustic emission responses, with lower responses to musicians in comparison to the nonmusician group. Conclusion: the results suggest that frequent musical exposure experienced by orchestral musicians can impair the cochlear hair cells' function. Therefore, audiological monitoring is important to detect subclinical impairments.

RESUMO Objetivo: verificar se a frequente exposição musical é capaz de prejudicar as respostas das vias auditivas periférica e central em músicos profissionais de orquestra. Métodos: participaram 45 indivíduos do sexo masculino, entre 19 e 40 anos, divididos em Grupo de músicos formado por 30 músicos de orquestra que tocavam instrumentos de corda ou de sopro, e Grupo de não músicos formado por 15 indivíduos. Ambos os grupos foram submetidos à audiometria tonal nas frequências convencionais e em altas frequências, Emissões Otoacústicas Transientes e Frequency Following Response. Os resultados foram submetidos à análise estatística descritiva e inferencial, por meio do teste ANOVA One-Way para amostras não pareadas, sendo o nível de significância de 5%. Resultados: não houve diferenças significantes entre os limiares auditivos, tanto nas frequências convencionais quanto nas altas frequências e no Frequency Following Response. No entanto, observou-se diferenças entre as respostas das Emissões Otoacústicas Transientes, sendo que os músicos apresentaram respostas diminuídas em relação ao grupo de não músicos. Conclusão: os resultados sugeriram que a frequente exposição musical que indivíduos que tocam em orquestra vivenciam é capaz de prejudicar a função das células ciliadas da cóclea. Sendo assim, o monitoramento audiológico é importante a fim de detectar alterações subclínicas.

Peri-operative electrically evoked auditory brainstem response assessment of facial nerve/cochlea interaction at cochlear implantation.

OBJECTIVES: Dehiscence between the cochlear otic capsule and the facial nerve canal is a rare and relatively newly described pathology. In cochlear implantation (CI), this dehiscence may lead to adverse electric facial nerve stimulation (FNS) already at low levels, rendering its use impossible. Here, we describe an assessment technique to foresee this complication. METHODS: Pre- and postoperative computed tomography (CT) scans and intraoperative electrically evoked auditory brainstem response (e-ABR) measurements were analyzed in two patients with cochlear-facial dehiscence (CFD). RESULTS: Because of the relatively low resolution, the confirmation of CFD with a clinical CT was difficult. The e-ABR displayed a large potential with 6 and 7.5 ms latency, respectively, which did not occur otherwise. DISCUSSION: Potential strategies to resolve and manage FNS are described. CONCLUSION: Prediction of FNS by assessing the distance between the labyrinthine portion of the facial nerve and the cochlea is difficult using conventional CT scans. A large evoked late myogenic potential at low stimulation levels during intraoperative e-ABR measurement may foresee FNS at CI activation.

The Use of Lexical Neighborhood Test (LNT) in the Assessment of Speech Recognition Performance of Cochlear Implantees with Normal and Malformed Cochlea.

The present study aims to use the model-based test Lexical Neighborhood Test (LNT), to assess speech recognition performance in early and late implanted hearing impaired children with normal and malformed cochlea. The LNT was administered to 46 children with congenital (prelingual) bilateral severe-profound sensorineural hearing loss, using Nucleus 24 cochlear implant. The children were grouped into Group 1-(early implantees with normal cochlea-EI); n = 15, 31/2-61/2 years of age; mean age at implantation-3½ years. Group 2-(late implantees with normal cochlea-LI); n = 15, 6-12 years of age; mean age at implantation-5 years. Group 3-(early implantees with malformed cochlea-EIMC); n = 9; 4.9-10.6 years of age; mean age at implantation-3.10 years. Group 4-(late implantees with malformed cochlea-LIMC); n = 7; 7-12.6 years of age; mean age at implantation-6.3 years. The following were the malformations: dysplastic cochlea, common cavity, Mondini's, incomplete partition-1 and 2 (IP-1 and 2), enlarged IAC. The children were instructed to repeat the words on hearing them. Means of the word and phoneme scores were computed. The LNT can also be used to assess speech recognition performance of hearing impaired children with malformed cochlea. When both easy and hard lists of LNT are considered, although, late implantees (with or without normal cochlea), have achieved higher word scores than early implantees, the differences are not statistically significant. Using LNT for assessing speech recognition enables a quantitative as well as descriptive report of phonological processes used by the children.

Analytical and numerical modeling of the hearing system: Advances towards the assessment of hearing damage.

Hearing is an extremely complex phenomenon, involving a large number of interrelated variables that are difficult to measure in vivo. In order to investigate such process under simplified and well-controlled conditions, models of sound transmission have been developed through many decades of research. The value of modeling the hearing system is not only to explain the normal function of the hearing system and account for experimental and clinical observations, but to simulate a variety of pathological conditions that lead to hearing damage and hearing loss, as well as for development of auditory implants, effective ear protections and auditory hazard countermeasures. In this paper, we provide a review of the strategies used to model the auditory function of the external, middle, inner ear, and the micromechanics of the organ of Corti, along with some of the key results obtained from such modeling efforts. Recent analytical and numerical approaches have incorporated the nonlinear behavior of some parameters and structures into their models. Few models of the integrated hearing system exist; in particular, we describe the evolution of the Auditory Hazard Assessment Algorithm for Human (AHAAH) model, used for prediction of hearing damage due to high intensity sound pressure. Unlike the AHAAH model, 3D finite element models of the entire hearing system are not able yet to predict auditory risk and threshold shifts. It is expected that both AHAAH and FE models will evolve towards a more accurate assessment of threshold shifts and hearing loss under a variety of stimuli conditions and pathologies.

Assessment of organs-at-risk contouring practices in radiosurgery institutions around the world - The first initiative of the OAR Standardization Working Group.

BACKGROUND AND PURPOSE: This study was an initiative of the Organs-at-Risk Standardization Working Group for evaluating the current degree of variability in the clinical practice of contouring organs-at-risk (OAR) for radiosurgery planning. MATERIALS AND METHODS: Imaging datasets for typical lesions (cavernous sinus meningioma, vestibular schwannoma, pituitary adenoma) treated with Leksell Gamma Knife Perfexion were circulated to 12 centers. Observers were asked to contour the target and OARs as per their standard clinical practice. The analyzed parameters were the intersection (AV100), union volumes (AV100/N) and the 50% agreement volume (AV50). The ratio of AV100 and AV100/N (the Agreement Volume Index, AVI) was used as a measure of agreement level together with a generalized conformity index (CIgen) and a pairwise averaged conformity index (CIpairs). The maximum doses were also determined. RESULTS: Results showed a wide variability in terminology, choice of structures contoured and in the size and shape of the contoured structures. The highest variability was observed for the left and right optic tract for cavernous sinus meningioma where the AV100 was zero. The highest consistency was observed for the right optic nerve in the cavernous sinus case followed by the cochlea for the vestibular schwannoma case for which the AVI was still only 0.13 and 0.054, respectively. Corresponding results for the CIgen and CIpairs also showed the highest variability for the right optic tract and the highest consistency in contours for the right optic nerve, both in the cavernous sinus meningioma case. CONCLUSION: The results quantify the large variability in OAR contouring in clinical practice across Gamma Knife radiosurgery centers with respect to the choice of OARs to be contoured, nomenclature and size and shape of OARs. This motivates future effort to standardize practices to enable more effective collaboration.

Assessment of the expression and role of the α1-nAChR subunit in efferent cholinergic function during the development of the mammalian cochlea.

Hair cell (HC) activity in the mammalian cochlea is modulated by cholinergic efferent inputs from the brainstem. These inhibitory inputs are mediated by calcium-permeable nicotinic acetylcholine receptors (nAChRs) containing α9- and α10-subunits and by subsequent activation of calcium-dependent potassium channels. Intriguingly, mRNAs of α1- and γ-nAChRs, subunits of the "muscle-type" nAChR have also been found in developing HCs (Cai T, Jen HI, Kang H, Klisch TJ, Zoghbi HY, Groves AK. J Neurosci 35: 5870-5883, 2015; Scheffer D, Sage C, Plazas PV, Huang M, Wedemeyer C, Zhang DS, Chen ZY, Elgoyhen AB, Corey DP, Pingault V. J Neurochem 103: 2651-2664, 2007; Sinkkonen ST, Chai R, Jan TA, Hartman BH, Laske RD, Gahlen F, Sinkkonen W, Cheng AG, Oshima K, Heller S. Sci Rep 1: 26, 2011) prompting proposals that another type of nAChR is present and may be critical during early synaptic development. Mouse genetics, histochemistry, pharmacology, and whole cell recording approaches were combined to test the role of α1-nAChR subunit in HC efferent synapse formation and cholinergic function. The onset of α1-mRNA expression in mouse HCs was found to coincide with the onset of the ACh response and efferent synaptic function. However, in mouse inner hair cells (IHCs) no response to the muscle-type nAChR agonists (±)-anatoxin A, (±)-epibatidine, (-)-nicotine, or 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) was detected, arguing against the presence of an independent functional α1-containing muscle-type nAChR in IHCs. In α1-deficient mice, no obvious change of IHC efferent innervation was detected at embryonic day 18, contrary to the hyperinnervation observed at the neuromuscular junction. Additionally, ACh response and efferent synaptic activity were detectable in α1-deficient IHCs, suggesting that α1 is not necessary for assembly and membrane targeting of nAChRs or for efferent synapse formation in IHCs.

Safety assessment of trans-tympanic photobiomodulation.

We evaluated functional and morphological changes after trans-tympanic laser application using several different powers of photobiomodulation (PBM). The left (L) ears of 17 rats were irradiated for 30 min daily over 14 days using a power density of 909.1 (group A, 5040 J), 1136.4 (group B, 6300 J), and 1363.6 (group C, 7560 J) mW/cm(2). The right (N) ears served as controls. The safety of PBM was determined by endoscopic findings, auditory brainstem response (ABR) thresholds, and histological images of hair cells using confocal microscopy, and light microscopic images of the external auditory canal (EAC) and tympanic membrane (TM). Endoscopic findings revealed severe inflammation in the TM of C group; no other group showed damage in the TM. No significant difference in ABR threshold was found in the PBM-treated groups (excluding the group with TM damage). Confocal microscopy showed no histological difference between the AL and AN, or BL and BN groups. However, light microscopy showed more prominent edema, inflammation, and vascular congestion in the TM of BL ears. This study found a dose-response relationship between laser power parameters and TM changes. These results will be useful for defining future allowance criteria for trans-tympanic laser therapies.

Assessment of the limits of neural phase-locking using mass potentials.

In the diverse mechanosensory systems that animals evolved, the waveform of stimuli can be encoded by phase locking in spike trains of primary afferents. Coding of the fine structure of sounds via phase locking is thought to be critical for hearing. The upper frequency limit of phase locking varies across species and is unknown in humans. We applied a method developed previously, which is based on neural adaptation evoked by forward masking, to analyze mass potentials recorded on the cochlea and auditory nerve in the cat. The method allows us to separate neural phase locking from receptor potentials. We find that the frequency limit of neural phase locking obtained from mass potentials was very similar to that reported for individual auditory nerve fibers. The results suggest that this is a promising approach to examine neural phase locking in humans with normal or impaired hearing or in other species for which direct recordings from primary afferents are not feasible.

Imaging assessment of profound sensorineural deafness with inner ear anatomical abnormalities.

OBJECTIVE: To explore the value of a combined computed tomography (CT) and magnetic resonance imaging (MRI) in evaluating profound sensorineural deafness patients before cochlear implant (CI) surgery. METHODS: A retrospective analysis of 1012 cases of profound sensorineural deafness that received CI was performed. RESULTS: A total of 96 cases were diagnosed with inner ear abnormalities including large vestibular aqueduct syndrome (LVAS, n = 61), Michel deformity (n = 3), cochlear incomplete partition I (n = 2), cochlear incomplete partition II (n = 6), cochlear hypoplasia with vestibular malformation (n = 3), cochlear ossification (n = 3), bilateral internal auditory canal obstruction (n = 5) and internal auditory canal stenosis (n = 2). CONCLUSION: High resolution CT (HRCT) can display bony structures while MRI can image the membranous labyrinth in preoperative evaluation for cochlear implantation. The combination of these two modalities provides reliable anatomical information regarding the bony and membranous labyrinths, as well as the auditory nerve.