Cochlear Nerve Aplasia with Detectable Olivocochlear Efferent Function: A Distinct Presentation of Auditory Neuropathy Spectrum Disorder.

BACKGROUND: Cochlear nerve aplasia (CNA) may present with features of auditory neuropathy spectrum disorder (ANSD), having detectable otoacoustic emissions (OAE) but profound hearing loss. We propose that some children with CNA have a distinct form of afferent ANSD in which efferent cochlear nerve function can be detected using contralateral suppression of OAE. METHODS: Children were prospectively enrolled with MRI and auditory brainstem response evidence of unilateral CNA, a normal contralateral ear, and detectable OAE bilaterally. Distortion product OAE (DPOAE) levels were recorded in real time with default primary tone settings: frequency (f)2 = 4.5 kHz and f2/f1 = 1.22 kHz, with level (L)1 = 65 dB SPL and L2 = 55 dB SPL. Recordings were made over 2 min with simultaneous application of an intermittent contralateral broadband noise (CBBN) stimulus at 60 dB SPL. RESULTS: Three girls, aged 4.5, 7, and 8 years, participated. Suppression of DPOAE of 0.15-1.3 dB was detected in all 3 ears with CNA in response to CBBN stimulation. No response was detected in the normal ears. CONCLUSIONS: Children with unilateral ANSD can have normal efferent cochlear nerve function despite MRI evidence of ipsilateral CNA. The importance of these findings for newborn hearing screening and cochlear implantation is discussed.

Changes to Neural Activation Patterns (c-fos Labeling) in Chinchilla Auditory Midbrain following Neonatal Exposure to an Enhanced Sound Environment.

Sensory brain regions show neuroplastic changes following deficits or experimental augmentation of peripheral input during a neonatal period. We have previously shown reorganization of cortical tonotopic maps after neonatal cochlear lesions or exposure to an enhanced acoustic environment. Such experiments probe the cortex and show reorganization, but it is unclear if such changes are intrinsically cortical or reflect projections from modified subcortical regions. Here, we ask whether an enhanced neonatal acoustic environment can induce midbrain (inferior colliculus (IC)) changes. Neonatal chinchillas were chronically exposed to a 70 dB SPL narrowband (2 ± 0.25 kHz) sound stimulus for 4 weeks. In line with previous studies, we hypothesized that such exposure would induce widening of the 2 kHz tonotopic map region in IC. To probe c-fos expression in IC (central nucleus), sound-exposed and nonexposed animals were stimulated with a 2 kHz stimulus for 90 minutes. In sound-exposed subjects, we find no change in the width of the 2 kHz tonotopic region; thus, our hypothesis is not supported. However, we observed a significant increase in the number of c-fos-labeled neurons over a broad region of best frequencies. These data suggest that neonatal sound exposure can modify midbrain regions and thus change the way neurons in IC respond to sound stimulation.

Midbrain Frequency Representation following Moderately Intense Neonatal Sound Exposure in a Precocious Animal Model (Chinchilla laniger).

Auditory brain areas undergo reorganization resulting from abnormal sensory input during early postnatal development. This is evident from studies at the cortical level but it remains unclear whether there is reorganization in the auditory midbrain in a species similar to the human, that is, with early hearing onset. We have explored midbrain plasticity in the chinchilla, a precocious species that matches the human in terms of hearing development. Neonatal chinchillas were chronically exposed to a 2 kHz narrowband sound at 70 dB SPL for 4 weeks. Tonotopic maps in inferior colliculus (central nucleus) were defined based on single neuron characteristic frequency. We hypothesized an overrepresentation of the 2 kHz region of the maps. However, we observed a significant decrease in the proportion of neurons dedicated to the 2 kHz octave band and also away from the exposure frequency at 8 kHz. In addition, we report a significant increase in low frequency representation (<1 kHz), again a change to tonotopic mapping distant to the 2 kHz region. Thus in a precocious species, tonotopic maps in auditory midbrain are altered following abnormal stimulation during development. However, these changes are more complex than the overrepresentation of exposure related frequency regions that are often reported.

On the biological plausibility of Wind Turbine Syndrome.

An emerging environmental health issue relates to potential ill-effects of wind turbine noise. There have been numerous suggestions that the low-frequency acoustic components in wind turbine signals can cause symptoms associated with vestibular system disorders, namely vertigo, nausea, and nystagmus. This constellation of symptoms has been labeled as Wind Turbine Syndrome, and has been identified in case studies of individuals living close to wind farms. This review discusses whether it is biologically plausible for the turbine noise to stimulate the vestibular parts of the inner ear and, by extension, cause Wind Turbine Syndrome. We consider the sound levels that can activate the semicircular canals or otolith end organs in normal subjects, as well as in those with preexisting conditions known to lower vestibular threshold to sound stimulation.

Remodelling at the calyx of Held-MNTB synapse in mice developing with unilateral conductive hearing loss.

Structure and function of central synapses are profoundly influenced by experience during developmental sensitive periods. Sensory synapses, which are the indispensable interface for the developing brain to interact with its environment, are particularly plastic. In the auditory system, moderate forms of unilateral hearing loss during development are prevalent but the pre- and postsynaptic modifications that occur when hearing symmetry is perturbed are not well understood. We investigated this issue by performing experiments at the large calyx of Held synapse. Principal neurons of the medial nucleus of the trapezoid body (MNTB) are innervated by calyx of Held terminals that originate from the axons of globular bushy cells located in the contralateral ventral cochlear nucleus. We compared populations of synapses in the same animal that were either sound deprived (SD) or sound experienced (SE) after unilateral conductive hearing loss (CHL). Middle ear ossicles were removed 1 week prior to hearing onset (approx. postnatal day (P) 12) and morphological and electrophysiological approaches were applied to auditory brainstem slices taken from these mice at P17-19. Calyces in the SD and SE MNTB acquired their mature digitated morphology but these were structurally more complex than those in normal hearing mice. This was accompanied by bilateral decreases in initial EPSC amplitude and synaptic conductance despite the CHL being unilateral. During high-frequency stimulation, some SD synapses displayed short-term depression whereas others displayed short-term facilitation followed by slow depression similar to the heterogeneities observed in normal hearing mice. However SE synapses predominantly displayed short-term facilitation followed by slow depression which could be explained in part by the decrease in release probability. Furthermore, the excitability of principal cells in the SD MNTB had increased significantly. Despite these unilateral changes in short-term plasticity and excitability, heterogeneities in the spiking fidelity among the population of both SD and SE synapses showed similar continuums to those in normal hearing mice. Our study suggests that preservations in the heterogeneity in spiking fidelity via synaptic remodelling ensures symmetric functional stability which is probably important for retaining the capability to maximally code sound localization cues despite moderate asymmetries in hearing experience.

Separating the contributions of olivocochlear and middle ear muscle reflexes in modulation of distortion product otoacoustic emission levels.

OBJECTIVES: Mediated by the medial olivocochlear system (MOCS), distortion product otoacoustic emission (DPOAE) levels are reduced by presentation of contralateral acoustic stimuli. Such acoustic signals can also evoke a middle ear muscle reflex (MEMR) that also attenuates recorded DPOAE levels. Our aim is to clearly differentiate these two inhibitory mechanisms and to analyze each separately, perhaps allowing the development of novel tests of hearing function. METHODS: DPOAE were recorded in real time from chinchillas with normal auditory brainstem response thresholds and middle ear function. Amplitude reduction and its onset latency caused by contralateral presentation of intermittent narrow-band noise (NBN) were measured. Stapedius and tensor tympani muscle tendons were divided without disturbing the ossicular chain, and DPOAE testing was repeated. RESULTS: Peak reduction of (2f1 - f2) DPOAE levels occurred when the center frequency of contralateral NBN approximated the primary tone f2, indicating an f2-frequency-specific response. For a 4.5-kHz centered NBN, DPOAE (f2 = 4.4 kHz) inhibition was 0.1 dB (p < 0.001). This response remained present after tendon division, consistent with an MOCS origin. Low-frequency NBN (center frequency: 0.5 kHz) reduced otoacoustic emission levels (0.1 dB, p < 0.001) across a wide range of DPOAE frequencies. This low-frequency response was abolished by division of the middle ear muscle tendons, clearly indicating MEMR involvement. CONCLUSIONS: Following middle ear muscle tendon division, DPOAE inhibition by contralateral stimuli approximating the primary tone f2 persists, whereas responses evoked by lower contralateral frequencies are abolished. This distinguishes the different roles of the MOCS (f2 frequency specific) and MEMR (low frequency only) in contralateral modulation of DPOAE. This analysis helps clarify the pathways involved in an objective test that might have clinical benefit in the testing of neonates.

Head and Eye Movements Reveal Compensatory Strategies for Acute Binaural Deficits During Sound Localization.

The present study aimed to define use of head and eye movements during sound localization in children and adults to: (1) assess effects of stationary versus moving sound and (2) define effects of binaural cues degraded through acute monaural ear plugging. Thirty-three youth (MAge = 12.9 years) and seventeen adults (MAge = 24.6 years) with typical hearing were recruited and asked to localize white noise anywhere within a horizontal arc from -60° (left) to +60° (right) azimuth in two conditions (typical binaural and right ear plugged). In each trial, sound was presented at an initial stationary position (L1) and then while moving at ∼4°/s until reaching a second position (L2). Sound moved in five conditions (±40°, ±20°, or 0°). Participants adjusted a laser pointer to indicate L1 and L2 positions. Unrestricted head and eye movements were collected with gyroscopic sensors on the head and eye-tracking glasses, respectively. Results confirmed that accurate sound localization of both stationary and moving sound is disrupted by acute monaural ear plugging. Eye movements preceded head movements for sound localization in normal binaural listening and head movements were larger than eye movements during monaural plugging. Head movements favored the unplugged left ear when stationary sounds were presented in the right hemifield and during sound motion in both hemifields regardless of the movement direction. Disrupted binaural cues have greater effects on localization of moving than stationary sound. Head movements reveal preferential use of the better-hearing ear and relatively stable eye positions likely reflect normal vestibular-ocular reflexes.

Hearing loss caused by CMV infection is correlated with reduced endocochlear potentials caused by strial damage in murine models.

Congenital cytomegalovirus (CMV) infection is a significant cause of neonatal hearing loss. However, at the cochlear level, the anatomical lesions and pathophysiological mechanisms that underlie hearing loss are still not clearly understood. In murine models of CMV infection, we have observed early damage to the capillary networks in stria vascularis, as well as hearing loss manifested in ABR threshold elevations. Our experimental hypothesis is that strial damage causes a reduced endocochlear potential (EP) resulting in impaired haircell activation and consequent hearing loss. We have studied strial damage, EP, and ABR threshold elevations in two mouse models (BALB/c and C57BL6 strains) infected with murine CMV. Neonatal (P3) pups were inoculated with murine CMV (2µl of 200pfu) by intra cerebral injection. Control mice were saline injected. At 6 weeks, ABR thresholds to tonal stimuli at 8, 16 and 32 kHz were determined for each ear. At 8 weeks a sub-group of treated and control animals was prepared for study of cochlear capillary networks using scanning electron microscopy of corrosion cast specimens. In a second group, at 8 weeks, EP measurements from both cochleas were made. We report that in both mouse strains, CMV infection caused capillary loss in the stria vascularis, initially at the cochlear apex, and extending to lower cochlear turns in some subjects. After CMV infection, in both BALB/c and C57BL6 mice, reduced EPs and ABR threshold elevations were observed, and there was a within-animal correlation between loss of EP and ABR threshold elevations across the sound frequencies tested. These results suggest that CMV induced damage to stria vascularis results in EP reduction that is correlated with ABR threshold elevations. Extrapolating to the human condition, we suggest that strial damage and its physiological consequences may contribute to the initial hearing loss in congenital CMV infection. The early involvement of cochlear capillary damage may encourage a focus on therapeutic interventions that can prevent vascular damage, or subsequently promote vascular healing or angiogenesis.

Ultrasonic bone removal from the ossicular chain affects cochlear structure and function.

INTRODUCTION: Ultrasonic bone removal devices (UBD) are capable of cutting through bony tissue without injury to adjacent soft tissue. The feasibility and safety of using this technology for removal of bone from an intact ossicular chain (as might be required for otosclerosis or congenital fixation) was investigated in an animal model. METHODS: This was a prospective animal study conducted on seven anesthetised adult chinchillas. An UBD was used to remove bone from the malleus head in situ. Pre and post-operative distortion product otoacoustic emission (DPOAE) levels and auditory brainstem response (ABR) thresholds were recorded. Scanning electron microscopy (SEM) was used to assess cochlear haircell integrity. RESULTS: Precise removal of a small quantity of bone from the malleus head was achieved by a 30s application of UBD without disruption of the ossicular chain or tympanic membrane. DPOAEs became undetectable after the intervention with signal-to-noise ratios (SNR) < 5 dB SPL in all ears. Furthermore, ABR thresholds were elevated > 85 dB SPL in 13 ears. SEM showed significant disruption of structural integrity of the organ of Corti, specifically loss and damage of outer haircells. CONCLUSIONS: Although UBD can be used to reshape an ossicle without middle ear injury, prolonged contact with the ossicular chain can cause structural and functional injury to the cochlea. Extensive cochlea pathology was found, but we did not investigate for recovery from any temporary threshold shift. In the authors' opinion, further study should be undertaken before consideration is given to use of the device for release of ossicular fixation.

Synthetic Simulator for Surgical Training in Tracheostomy and Open Airway Surgery.

OBJECTIVE(S): To create and validate a synthetic simulator for teaching tracheostomy and laryngotracheal reconstruction (LTR) using anterior costal cartilage and thyroid ala cartilage grafts. METHODS: A late adolescent/adult neck and airway simulator was constructed based on CT scans from a cadaver and a live patient. Images were segmented to create three-dimensional printed molds from which anatomical parts were casted. To evaluate the simulator, expert otolaryngologists - head and neck surgeons performed tracheostomy and LTR using anterior costal cartilage and thyroid ala cartilage grafts on a live anesthetized porcine model (gold standard) followed by the synthetic simulator. They evaluated each model for face validity (realism and anatomical accuracy) and content validity (perceived effectiveness as a training tool) using a five-point Likert scale. For each expert, differences for each item on each simulator were compared using Wilcoxon Signed-Rank tests with Sidak correction. RESULTS: Nine expert faculty surgeons completed the study. Experts rated face and content validity of the synthetic simulator an overall median of 4 and 5, respectively. There was no difference in scores between the synthetic model and the live porcine model for any of the steps of any of the surgical procedures. CONCLUSION: The synthetic simulator created for this study has high face and content validity for tracheostomy and LTR with anterior costal cartilage and thyroid ala cartilage grafts and was not found to be different than the live porcine model for these procedures. LEVEL OF EVIDENCE: 5 Laryngoscope, 131:E2378-E2386, 2021.

Does riboflavin depletion cause auditory neuropathy spectrum disorder in at risk neonates?

We present a new hypothesis for the pathogenesis of auditory neuropathy spectrum disorder (ANSD) in at risk neonates involving depletion of riboflavin. The association between neonatal hyperbilirubinemia and ANSD is well recognized, yet causation has not been proven. The risk of ANSD does not correlate clearly with severity of hyperbilirubinemia and ASND only occurs in a small proportion of hyperbilirubinemic neonates. Additional, perhaps co-dependent, factors are therefore likely to be involved in pathogenesis. The metabolism of bilirubin consumes riboflavin and levels of riboflavin are depleted further by phototherapy. The neonate may also be deficient in riboflavin secondary to maternal deficiency, and reduced intake or impaired absorption. We propose that riboflavin depletion may be a significant contributor to development of ANSD in at risk neonates. The basis of this hypothesis is the recent recognition that impairment of riboflavin metabolism caused by genetic mutations (SLC52A2 or AIMF1) also causes ANSD.

Live porcine model for surgical training in tracheostomy and open-airway surgery.

OBJECTIVES/HYPOTHESIS: To evaluate the validity of a live porcine model for surgical training in tracheostomy and open-airway surgery. STUDY DESIGN: Prospective observational study. METHODS: Eleven expert otolaryngologists-head and neck surgeons rated a live porcine model's realism/anatomical accuracy (face validity) and perceived effectiveness as a training tool (content validity) for tracheostomy and laryngotracheoplasty using anterior costal cartilage and thyroid ala cartilage grafts using a 53-item post-trial questionnaire with a five-point Likert scale. RESULTS: Experts rated the face validity of the live porcine model a median (interquartile range [IQR]) of 4/5 (4-5) and the content validity a median (IQR) of 5/5 (4-5) for each surgical procedure. Overall, 91% strongly agreed or agreed that the simulator would increase trainee competency for tracheostomy and laryngotracheoplasty using costal cartilage graft, and 82% strongly agreed or agreed that it would increase trainee competency for laryngotracheoplasty using thyroid ala cartilage graft. CONCLUSIONS: The live porcine model has high face and content validity as a training tool for tracheostomy and laryngotracheoplasty using costal cartilage and thyroid ala cartilage grafts. This training model can help surgical trainees practice these complex, low-frequency procedures. LEVEL OF EVIDENCE: NA Laryngoscope, 130: 2063-2068, 2020.

Measurement of cerebral blood volume in mouse brain regions using micro-computed tomography.

Micro-computed tomography (micro-CT) is an X-ray imaging technique that can produce detailed 3D images of cerebral vasculature. This paper describes the development of a novel method for using micro-CT to measure cerebral blood volume (CBV) in the mouse brain. As an application of the methodology, we test the hypotheses that differences in CBV exist over anatomical brain regions and that high energy demanding primary sensory regions of the cortex have locally elevated CBV, which may reflect a vascular specialization. CBV was measured as the percentage of tissue space occupied by a radio-opaque silicon rubber that fills the vasculature. To ensure accuracy of the CBV measurements, several innovative refinements were made to standard micro-CT specimen preparation and analysis procedures. Key features of the described method are vascular perfusion under controlled pressure, registration of the micro-CT images to an MRI anatomical brain atlas and re-scaling of micro-CT intensities to CBV units with selectable exclusion of major vessels. Histological validation of the vascular perfusion showed that the average percentage of vessels filled was 93+/-3%. Comparison of thirteen brain regions in nine mice revealed significant differences in CBV between regions (p<0.0001) while cortical maps showed that primary visual and auditory areas have higher CBV than primary somatosensory areas.

Early Enzyme Replacement Therapy Improves Hearing and Immune Defects in Adenosine Deaminase Deficient-Mice.

Background: Inherited defects in adenosine deaminase (ADA) cause severe immune deficiency, which can be corrected by ADA enzyme replacement therapy (ERT). Additionally, ADA-deficient patients suffer from hearing impairment. We hypothesized that ADA-deficient (-/-) mice also exhibit hearing abnormalities and that ERT from an early age will improve the hearing and immune defects in these mice. Methods: Auditory brainstem evoked responses, organ weights, thymocytes numbers, and subpopulations, lymphocytes in peripheral blood as well as T lymphocytes in spleen were analyzed in ADA-/- and ADA-proficient littermate post-partum (pp). The cochlea was visualized by scanning electron microscopy (SEM). The effects of polyethylene glycol conjugated ADA (PEG-ADA) ERT or 40% oxygen initiated at 7 days pp on the hearing and immune abnormalities were assessed. Results: Markedly abnormal hearing thresholds responses were found in ADA-/- mice at low and medium tone frequencies. SEM demonstrated extensive damage to the cochlear hair cells of ADA-/- mice, which were splayed, short or missing, correlating with the hearing deficits. The hearing defects were not reversed when hypoxia in ADA-/- mice was corrected. Progressive immune abnormalities were detected in ADA-/- mice from 4 days pp, initially affecting the thymus followed by peripheral lymphocytes and T cells in the spleen. ERT initiated at 7 days pp significantly improved the hearing of ADA-/- mice as well as the number of thymocytes and T lymphocytes, although not all normalized. Conclusions: ADA deficiency is associated with hearing deficits and damage to cochlear hair cells. Early initiation of ERT improves the hearing and immune abnormalities.

Effects of stimulus manipulation on electrophysiological responses in pediatric cochlear implant users. Part I: duration effects.

Discrepancies between electrophysiological and behavioral thresholds in cochlear implant users might be due to differences in stimuli such as the duration and rate of the electrical pulse train. In the present study, we asked: Is there an effect of stimulus duration on electrophysiological responses of the auditory brainstem, thalamo-cortex, and behavioral thresholds? In 5 pediatric cochlear implant users, behavioral thresholds in response to electrical pulse trains at 500 pulses per second (pps) were significantly lower for 40ms than 2ms duration pulse trains. Clear electrically evoked auditory brainstem responses (EABR) and electrically evoked middle latency responses (EMLR) were generated by single electrical pulses and 2, 6, and 10ms pulse trains (500pps) in 5 children. There was a linear decrease in the inter-wave latency between the eV of the EABR and the Na of the EMLR as duration increased. No significant effect of duration was found on eV latency relative to the last pulse in the train or Na latency relative to the onset of the stimuli. Behavioral threshold data is consistent with temporal integration of auditory activity. Electrophysiological data indicates that: (a) recognizable EABR and EMLR waveforms can be recorded in response to electrical pulse trains of up to 10ms; and (b) pulse train stimuli have unique effects on the auditory brainstem compared to thalamo-cortical areas.

Effects of stimulus manipulation on electrophysiological responses of pediatric cochlear implant users. Part II: rate effects.

Electrophysiological thresholds do not accurately predict behavioral thresholds in pediatric cochlear implant users possibly due to differences in rate and duration of pulse presentation. We asked: (1) Is there an effect of rate of stimulus presentation on the electrophysiological responses of the auditory brainstem and thalamo-cortex? and (2) can the relationship between electrophysiological and behavioral thresholds be improved by using the same rate of pulse presentation? Behavioral and electrophysiological (EABR and EMLR) responses were elicited for 14 children to single electrical pulses and pulse trains of 2ms ranging in rate from 500 to 3600 pulses per second (pps). Low rate (500pps) pulse trains resulted in an increase in EABR wave eIII amplitude and a decrease in wave eV amplitude. Further rate increases resulted in smaller EABR wave amplitudes. EMLR amplitudes were unaffected by increases in rate as were EABR and EMLR latencies. Behavioral thresholds decreased with increasing rate, however, there was no associated reduction in electrophysiological thresholds. Correlation between behavioral and electrophysiological thresholds did not improve by using the same rate of electrical pulse stimulation. Results suggest: (1) Higher rates of electrical pulse presentation increase the potential for neural adaptation in the auditory brainstem and (2) using the same rate of electrical pulse presentation does not improve the ability of EABR and EMLR thresholds to predict behavioral thresholds.

Noise-induced hearing loss in children: A 'less than silent' environmental danger.

A review of the problems of noise-induced hearing loss in children, especially related to recreational music and the use of personal entertainment devices. The pathophysiology of noise-induced hearing loss and its associated problems (eg, tinnitus) are discussed. The evidence for an increase in noise-induced hearing loss in children and young people is reviewed. Some practical advice (for clinicians, caregivers and children) on hearing loss prevention is provided.

Cytomegalovirus (CMV) Infection Causes Degeneration of Cochlear Vasculature and Hearing Loss in a Mouse Model.

Cytomegalovirus (CMV) infection is one of the most common causes of congenital hearing loss in children. We have used a murine model of CMV infection to reveal functional and structural cochlear pathogenesis. The cerebral cortex of Balb/c mice (Mus musculus) was inoculated with 2000 pfu (plaque forming units) of murine CMV on postnatal day 3. At 6 weeks of age, cochlear function was monitored using auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measures. Histological assessment of cochlear vasculature using a corrosion cast technique was made at 8 weeks. Vascular casts of mCMV-damaged cochleas, and those of untreated control animals, were examined using scanning electron microscopy. We find very large variations in the degree of vascular damage in animals given identical viral injections (2000 pfu). The primary lesion caused by CMV infection is to the stria vascularis and to the adjacent spiral limbus capillary network. Capillary beds of the spiral ligament are generally less affected. The initial vascular damage is found in the mid-apical turn and appears to progress to more basal cochlear regions. After viral migration to the inner ear, the stria vascularis is the primary affected structure. We suggest that initial auditory threshold losses may relate to the poor development or maintenance of the endocochlear potential caused by strial dysfunction. Our increased understanding of the pathogenesis of CMV-related hearing loss is important for defining methods for early detection and treatment.

Temporal bone imaging in GJB2 deafness.

OBJECTIVE: To describe temporal bone findings on computed tomography (CT) imaging in GJB2-related hearing loss (HL). We asked whether evaluation of the temporal bone is required in individuals with biallelic GJB2 mutations. STUDY DESIGN: Randomized, blinded, controlled, prospective measurement. METHODS: Blood from 264 pediatric cochlear implant users was analyzed for mutations in the GJB2 gene. Thirty-six aspects of the temporal bone on CT imaging were evaluated in 53 individuals (106 ears) with biallelic disease causing GJB2 mutations. A subset of patients was age matched and compared with normally hearing individuals. Subjects with biallelic GJB2 mutations were tested for mutations in the SLC26A4 gene to rule out Pendred syndrome as a confounding cause of large vestibular aqueduct syndrome. RESULTS: Approximately 53% of ears of subjects (72% of subjects) with biallelic GJB2 mutations had at least one temporal bone anomaly. The most common findings were 1) dilated endolymphatic fossa (28%); 2) hypoplastic modiolus (25%); 3) large vestibular aqueduct (8%); 4) hypoplastic horizontal semicircular canal (8%); 5) hypoplastic cochlea (4%). Compared with normally hearing individuals, the GJB2 group had hypoplasia of the cochlear nerve canal, lateral semicircular canal vestibule, internal auditory canal (t tests, P < .001), and were 11 times more likely to have a hypoplastic modiolus. Dilated endolymphatic fossae were 1.4 times more common in the GJB2 group, and large vestibular aqueducts were 3 times more common in the GJB2 group, as compared with normally hearing controls. CONCLUSIONS: Temporal bone anomalies are common in GJB2-related HL, and imaging of the temporal bone should be included in routine evaluation of these individuals.

Auditory responses in cochlear implant users with and without GJB2 deafness.

OBJECTIVE/HYPOTHESIS: It is reasonable to suppose that the pattern of sensorineural damage along the length of the cochlea depends on the etiology of a hearing loss (HL). In GJB2-related deafness, we hypothesize that gap junction deficits are uniformly distributed and will result in similar damage along the length of the cochlea as compared with non-GJB2 subjects. We assessed this by measuring patterns of neural activity and hearing from apical versus basal cochlear implant electrode regions. STUDY DESIGN: This was a prospective, blind, controlled study. METHODS: Blood from 301 pediatric cochlear implant users was analyzed for mutations in GJB2 by direct sequencing. After exclusion of patients with monoallelic GJB2 mutations, associated syndromes, or risk factors for HL that were not congenital, 39 children with biallelic GJB2 mutations and 58 without GJB2 mutations were evaluated. Hearing was measured before implantation at frequencies ranging from 250 Hz to 8 kHz. After implantation, neural activity at the apical and basal ends of the implanted array was measured using electrically evoked compound action potentials of the auditory nerve (ECAPs) and evoked stapedius reflexes (ESRs). RESULTS: GJB2 and non-GJB2 groups were not significantly different with respect to sex, age at implantation, duration of auditory deprivation, hearing aid use, duration of aided hearing, ear implanted, implant model, or depth of insertion (P>.05). Children with GJB2-related HL had greater similarities between low- and high-frequency residual hearing and between neural activity electrically evoked at apical and basal regions of the cochlea as compared with children with non-GJB2-related HL who demonstrated larger deficits in basal regions. CONCLUSION: Results suggest more consistent spiral ganglion survival along the length of the cochlea in GJB2-related HL as compared with non-GJB2-related HL, which appears to involve a decreasing gradient of spiral ganglion survival from the apex to the base of the cochlea. Our findings support our premise that in GJB2-related HL, dysfunction of gap junctions likely occurs to a similar degree in the apical and basal regions of the cochlea. This knowledge might be used to customize implantable devices for patients with HL in the future.