Auditory Research publications

Background: Difficulty understanding in background noise is a common complaint of cochlear implant (CI) recipients. Programming options are available to improve speech recognition in noise for CI users including automatic dynamic range optimization (ADRO), autosensitivity control (ASC), and a two-stage adaptive beamforming algorithm (BEAM). However, the processing option that results in the best speech recognition in noise is unknown. In addition, laboratory measures of these processing options often show greater degrees of improvement than reported by participants in everyday listening situations. To address this issue, Compton-Conley and colleagues developed a test system to replicate a restaurant environment. The R-SPACE™ consists of eight loudspeakers positioned in a 360 degree arc and utilizes a recording made at a restaurant of background noise. Purpose: The present study measured speech recognition in the R-SPACE with four processing options: standard dual-port directional (STD), ADRO, ASC, and BEAM. Research Design: A repeated-measures, within-subject design was used to evaluate the four different processing options at two noise levels. Study Sample: Twenty-seven unilateral and three bilateral adult Nucleus Freedom CI recipients. Intervention: The participants’ everyday program (with no additional processing) was used as the STD program. ADRO, ASC, and BEAM were added individually to the STD program to create a total of four programs. Data Collection and Analysis: Participants repeated Hearing in Noise Test sentences presented at 0 degrees azimuth with R-SPACE restaurant noise at two noise levels, 60 and 70 dB SPL. The reception threshold for sentences (RTS) was obtained for each processing condition and noise level. Results: In 60 dB SPL noise, BEAM processing resulted in the best RTS, with a significant improvement over STD and ADRO processing. In 70 dB SPL noise, ASC and BEAM processing had significantly better mean RTSs compared to STD and ADRO processing. Comparison of noise levels showed that STD and BEAM processing resulted in significantly poorer RTSs in 70 dB SPL noise compared to the performance with these processing conditions in 60 dB SPL noise. Bilateral participants demonstrated a bilateral improvement compared to the better monaural condition for both noise levels and all processing conditions, except ASC in 60 dB SPL noise. Conclusions: The results of this study suggest that the use of processing options that utilize noise reduction, like those available in ASC and BEAM, improve a CI recipient's ability to understand speech in noise in listening situations similar to those experienced in the real world. The choice of the best processing option is dependent on the noise level, with BEAM best at moderate noise levels and ASC best at loud noise levels for unilateral CI recipients. Therefore, multiple noise programs or a combination of processing options may be necessary to provide CI users with the best performance in a variety of listening situations.

CBA/CaJ and CBA/J inbred mouse strains appear relatively resistant to age- and noise-related cochlear pathology, and constitute the predominant 'good hearing' control strains in mouse studies of hearing and deafness. These strains have often been treated as nearly equivalent in their hearing characteristics, and have even been mixed in some studies. Nevertheless, we recently showed that their trajectories with regard to age-associated cochlear pathology diverge after one year of age (Ohlemiller et al., 2010a). We also recently reported that they show quite different susceptibility to cochlear noise injury during the 'sensitive period' of heightened vulnerability to noise common to many models, CBA/J being far more vulnerable than CBA/CaJ (Fernandez et al., 2010 J. Assoc. Res. Otolaryngol. 11:235-244). Here we explore this relation in a side-by-side comparison of the effect of varying noise exposure duration in young (6 week) and older (6 month) CBA/J and CBA/CaJ mice, and in F1 hybrids formed from these. Both the extent of permanent noise-induced threshold shifts (NIPTS) and the probability of a defined NIPTS were determined as exposure to intense broadband noise (4-45 kHz, 110 dB SPL) increased by factors of two from 7 s to 4 h. At 6 months of age the two strains appeared very similar by both measures. At 6 weeks of age, however, both the extent and probability of NIPTS grew much more rapidly with noise duration in CBA/J than in CBA/CaJ. The 'threshold' exposure duration for NIPTS was <1.0 min in CBA/J versus >4.0 min in CBA/CaJ. F1 hybrid mice showed both NIPTS and hair cell loss similar to that in CBA/J. This suggests that dominant-acting alleles at unknown loci distinguish CBA/J from CBA/CaJ. These loci have novel effects on hearing phenotype, as they come into play only during the sensitive period, and may encode factors that demarcate this period. Since the cochlear cells whose fragility defines the early window appear to be hair cells, these loci may principally impact the mechanical or metabolic resiliency of hair cells or the organ of Corti.

Two mouse models, the Coch(G88E/G88E) or "knock-in" and the Coch(-/-) or "knock-out" (Coch null), have been developed to study the human late-onset, progressive, sensorineural hearing loss and vestibular dysfunction known as DFNA9. This disorder results from missense and in-frame deletion mutations in COCH (coagulation factor C homology), encoding cochlin, the most abundantly detected protein in the inner ear. We have performed hearing and vestibular analyses by auditory brainstem response (ABR) and vestibular evoked potential (VsEP) testing of the Coch(-/-) and Coch(G88E/G88E) mouse models. Both Coch(-/-) and Coch(G88E/G88E) mice show substantially elevated ABRs at 21 months of age, but only at the highest frequency tested for the former and all frequencies for the latter. At 21 months, 9 of 11 Coch(-/-) mice and 4 of 8 Coch(G88E/G88E) mice have absent ABRs. Interestingly Coch(-/+) mice do not show hearing deficits, in contrast to Coch(G88E/+), which demonstrate elevated ABR thresholds similar to homozyotes. These results corroborate the DFNA9 autosomal dominant mode of inheritance, in addition to the observation that haploinsufficiency of Coch does not result in impaired hearing. Vestibular evoked potential (VsEP) thresholds were analyzed using a two factor ANOVA (Age X Genotype). Elevated VsEP thresholds are detected in Coch(-/-) mice at 13 and 21 months, the two ages tested, and as early as seven months in the Coch(G88E/G88E) mice. These results indicate that in both mouse models, vestibular function is compromised before cochlear function. Analysis and comparison of hearing and vestibular function in these two DFNA9 mouse models, where deficits occur at such an advanced age, provide insight into the pathology of DFNA9 and age-related hearing loss and vestibular dysfunction as well as an opportunity to investigate potential interventional therapies.

Conductive hearing loss (CHL) is known to produce hearing deficits, including deficits in sound localization ability. The differences in sound intensities and timing experienced between the two tympanic membranes are important cues to sound localization (ILD and ITD, respectively). Although much is known about the effect of CHL on hearing levels, little investigation has been conducted into the actual impact of CHL on sound location cues. This study investigated effects of CHL induced by earplugs on cochlear microphonic (CM) amplitude and timing and their corresponding effect on the ILD and ITD location cues. Acoustic and CM measurements were made in 5 chinchillas before and after earplug insertion, and again after earplug removal using pure tones (500 Hz to 24 kHz). ILDs in the unoccluded condition demonstrated position and frequency dependence where peak far-lateral ILDs approached 30 dB for high frequencies. Unoccluded ear ITD cues demonstrated positional and frequency dependence with increased ITD cue for both decreasing frequency (±420 μs at 500 Hz, ±310 μs for 1-4 kHz) and increasingly lateral sound source locations. Occlusion of the ear canal with foam plugs resulted in a mild, frequency-dependent conductive hearing loss of 10-38 dB (mean 31 ± 3.9 dB) leading to a concomitant frequency dependent increase in ILDs at all source locations. The effective ITDs increased in a frequency dependent manner with ear occlusion as a direct result of the acoustic properties of the plugging material, the latter confirmed via acoustical measurements using a model ear canal with varying volumes of acoustic foam. Upon ear plugging with acoustic foam, a mild CHL is induced. Furthermore, the CHL induced by acoustic foam results in substantial changes in the magnitudes of both the ITD and ILD cues to sound location.

Combinations of aminoglycosides and loop diuretics have been known to have a synergistic effect in ototoxic injury. Because murine hair cells are relatively resistant to ototoxicity compared to those of other mammals, investigators have turned to combination therapies to create ototoxic lesions in the mouse inner ear. In this paper, we perform a systematic comparison of hearing thresholds, hair cell damage and monocyte migration into the mouse cochlea after kanamycin versus combined kanamycin/furosemide and explore the pathophysiology of enhanced hair cell loss in aminoglycoside ototoxicity in the presence of loop diuretic. Combined kanamycin-furosemide resulted in elevation of threshold not only in the high frequencies, but across all frequencies with more extensive loss of outer hair cells when compared to kanamycin alone. The stria vascularis was severely atrophied and stellate cells in the spiral limbus were missing in kanamycin-furosemide exposed mice while these changes were not observed in mice receiving kanamycin alone. Monocytes and macrophages were recruited in large numbers to the spiral ligament and spiral ganglion in these mice. Combination therapy resulted in a greater number of macrophages in total, and many more macrophages were present further apically when compared to mice given kanamycin alone. Combined kanamycin-furosemide provides an effective method of addressing the relative resistance to ototoxicity that is observed in most mouse strains. As the mouse becomes increasingly more common in studies of hearing loss, and combination therapies gain popularity, recognition of the overall effects of combined aminoglycoside-loop diuretic therapy will be critical to interpretation of the interventions that follow.

There are three main cues to sound location: the interaural differences in time (ITD) and level (ILD) as well as the monaural spectral shape cues. These cues are generated by the spatial- and frequency-dependent filtering of propagating sound waves by the head and external ears. Although the chinchilla has been used for decades to study the anatomy, physiology, and psychophysics of audition, including binaural and spatial hearing, little is actually known about the sound pressure transformations by the head and pinnae and the resulting sound localization cues available to them. Here, we measured the directional transfer functions (DTFs), the directional components of the head-related transfer functions, for 9 adult chinchillas. The resulting localization cues were computed from the DTFs. In the frontal hemisphere, spectral notch cues were present for frequencies from ∼6-18 kHz. In general, the frequency corresponding to the notch increased with increases in source elevation as well as in azimuth towards the ipsilateral ear. The ILDs demonstrated a strong correlation with source azimuth and frequency. The maximum ILDs were <10 dB for frequencies <5 kHz, and ranged from 10-30 dB for the frequencies >5 kHz. The maximum ITDs were dependent on frequency, yielding 236 μs at 4 kHz and 336 μs at 250 Hz. Removal of the pinnae eliminated the spectral notch cues, reduced the acoustic gain and the ILDs, altered the acoustic axis, and reduced the ITDs.

Objective: This study aimed to provide guidelines to optimize perception of soft speech and speech in noise for Advanced Bionics cochlear implant (CI) users. Design: Three programs differing in T-levels were created for ten subjects. Using the T-level setting that provided the lowest FM-tone, sound-field threshold levels for each subject, three additional programs were created with input dynamic range (IDR) settings of 50, 65 and 80 dB. Study sample: Subjects were postlinguistically deaf adults implanted with either the Clarion CII or 90K CI devices. Results: Sound-field threshold levels were lowest with T-levels set higher than 10% of M-levels and with the two widest IDRs. Group data revealed significantly higher scores for CNC words presented at a soft level with an IDR of 80 dB and 65 dB compared to 50 dB. Although no significant group differences were seen between the three IDRs for sentences in noise, significant individual differences were present. Conclusions: Setting Ts higher than the manufacturer's recommendation of 10% of M-levels and providing IDR options can improve overall speech perception; however, for some users, higher Ts and wider IDRs may not be appropriate. Based on the results of the study, clinical programming recommendations are provided.

Cells of the inner ear face constant metabolic and structural stress. Exposure to intense sound or certain drugs destroys cochlea hair cells, which in mammals do not regenerate. Thus, an endogenous stress response system may exist within the cochlea to protect it from everyday stressors. We recently described the existence of corticotropin-releasing factor (CRF) in the mouse cochlea. The CRF receptor type 1 (CRFR1) is considered the primary and canonical target of CRF signaling, and systemically it plays an essential role in coordinating the body-wide stress response via activation of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we describe an essential role for CRFR1 in auditory system development and function, and offer the first description of a complete HPA equivalent signaling system resident within the cochlea. To reveal the role of CRFR1 activation in the cochlea, we have used mice carrying a null ablation of the CRFR1 gene. CRFR1 −/− mice exhibited elevated auditory thresholds at all frequencies tested, indicating reduced sensitivity. Furthermore, our results suggest that CRFR1 has a developmental role affecting inner hair cell morphology and afferent and efferent synapse distribution. Given the role of HPA signaling in maintaining local homeostasis in other tissues, the presence of a cochlear HPA signaling system suggests important roles for CRFR1 activity in setting cochlear sensitivity, perhaps both neural and non-neural mechanisms. These data highlight the complex pleiotropic mechanisms modulated by CRFR1 signaling in the cochlea.

We investigated how physiologically observed forward suppression interacts with stimulus frequency in neuronal responses in the guinea pig auditory cortex. The temporal order and frequency proximity of sounds influence both their perception and neuronal responses. Psychophysically, preceding sounds (conditioners) can make successive sounds (probes) harder to hear. These effects are larger when the two sounds are spectrally similar. Physiological forward suppression is usually maximal for conditioner tones near to a unit's characteristic frequency (CF), the frequency to which a neuron is most sensitive. However, in most physiological studies, the frequency of the probe tone and CF are identical, so the role of unit CF and probe frequency cannot be distinguished. Here, we systemically varied the frequency of the probe tone, and found that the tuning of suppression was often more closely related to the frequency of the probe tone than to the unit's CF, i.e. suppressed tuning was specific to probe frequency. This relationship was maintained for all measured gaps between the conditioner and the probe tones. However, when the probe frequency and CF were similar, CF tended to determine suppressed tuning. In addition, the bandwidth of suppression was slightly wider for off-CF probes. Changes in tuning were also reflected in the firing rate in response to probe tones, which was maximally reduced when probe and conditioner tones were matched in frequency. These data are consistent with the idea that cortical neurons receive convergent inputs with a wide range of tuning properties that can adapt independently.

Animals can be induced to resist cochlear damage associated with acoustic trauma by exposure to a variety of “conditioning” stimuli, including restraint stress, moderate level sound, heat stress, hypoxia, and corticosteroids. Here we identify in mice a corticosteroid-responsive transcription factor, PLZF (promyelocytic leukemia zinc finger protein), which mediates conditioned protection of the cochlea from acoustic trauma. PLZF mRNA levels in the cochlea are increased following conditioning stimuli, including restraint stress, dexamethasone administration, and moderate-to-high level acoustic stimulation. Heterozygous mutant ( luxoid. Zbtb16 LU /J) mice deficient in PLZF have hearing and responses to acoustic trauma similar to their wild type littermates but are unable to generate conditioning-induced protection from acoustic trauma. PLZF immunoreactivity is present in the spiral ganglion, lateral wall of the cochlea, and organ of Corti, all targets for acoustic trauma. PLZF is also present in the brain and PLZF mRNA in brain is elevated following conditioning stimuli. The identification of a transcription factor that mediates conditioned protection from trauma provides a tool for understanding the protective action of corticosteroids, which are widely used in treating acute hearing loss, and has relevance to understanding the role of corticosteroids in trauma protection.

In this study, we analyze the processing of low-frequency sounds in the cochlear apex through responses of auditory nerve fibers (ANFs) that innervate the apex. Single tones and irregularly spaced tone complexes were used to evoke ANF responses in Mongolian gerbil. The spike arrival times were analyzed in terms of phase locking, peripheral frequency selectivity, group delays, and the nonlinear effects of sound pressure level (SPL). Phase locking to single tones was similar to that in cat. Vector strength was maximal for stimulus frequencies around 500 Hz, decreased above 1 kHz, and became insignificant above 4 to 5 kHz. We used the responses to tone complexes to determine amplitude and phase curves of ANFs having a characteristic frequency (CF) below 5 kHz. With increasing CF, amplitude curves gradually changed from broadly tuned and asymmetric with a steep low-frequency flank to more sharply tuned and asymmetric with a steep high-frequency flank. Over the same CF range, phase curves gradually changed from a concave-upward shape to a concave-downward shape. Phase curves consisted of two or three approximately straight segments. Group delay was analyzed separately for these segments. Generally, the largest group delay was observed near CF. With increasing SPL, most amplitude curves broadened, sometimes accompanied by a downward shift of best frequency, and group delay changed along the entire range of stimulus frequencies. We observed considerable across-ANF variation in the effects of SPL on both amplitude and phase. Overall, our data suggest that mechanical responses in the apex of the cochlea are considerably nonlinear and that these nonlinearities are of a different character than those known from the base of the cochlea.

Murine models are ideal for studying cochlear gene transfer, as many hearing loss-related mutations have been discovered and mapped within the mouse genome. However, because of the small size and delicate nature, the membranous labyrinth of the mouse is a challenging target for the delivery of viral vectors. To minimize injection trauma, we developed a procedure for the controlled release of adeno-associated viruses (AAVs) into the scala media of adult mice. This procedure poses minimal risk of injury to structures of the cochlea and middle ear, and allows for near-complete preservation of low and middle frequency hearing. In this study, transduction efficiency and cellular specificity of AAV vectors (serotypes 1, 2, 5, 6 and 8) were investigated in normal and drug-deafened ears. Using the cytomegalovirus promoter to drive gene expression, a variety of cell types were transduced successfully, including sensory hair cells and supporting cells, as well as cells in the auditory nerve and spiral ligament. Among all five serotypes, inner hair cells were the most effectively transduced cochlear cell type. All five serotypes of AAV vectors transduced cells of the auditory nerve, though serotype 8 was the most efficient vector for transduction. Our findings indicate that efficient AAV inoculation (via the scala media) can be performed in adult mouse ears, with hearing preservation a realistic goal. The procedure we describe may also have applications for intra-endolymphatic drug delivery in many mouse models of human deafness.

Ablation of the distal end of the short arm of chromosome 1 [1p36 deletion syndrome (1p36DS)] is one of the most commonly occurring terminal deletion syndromes in humans, occurring in ∼1 in 5000 newborns. Subjects with 1p36DS manifest a wide range of clinical features including growth delay, congenital heart defects, and craniofacial dysmorphism. In addition, individuals with 1p36DS often exhibit some form of neurological abnormality and are typically cognitively impaired. Although there is significant variability with regard to the extent of the deletion, several genes have been mapped to region 1p36 that are known to regulate neuronal function. One such gene— KCNAB2 —encodes the potassium channel auxiliary subunit Kvβ2, which has been previously shown to modulate voltage-gated potassium currents in heterologous expression systems. Here, we present experiments characterizing mice in which the ortholog of KCNAB2 was deleted. We find that deletion of Kcnab2 in mice leads to deficits in associative learning and memory. In addition, using whole-cell current-clamp, we find that deletion of Kcnab2 leads to a reduction in the slow afterhyperpolarization following a burst of action potentials and a concomitant increase in neuronal excitability in projection neurons in the lateral nucleus of the amygdala. Our results suggest that loss of Kvβ2 likely contributes to the cognitive and neurological impairments observed in 1p36DS patients.

A long debate in selective attention research is whether attention enhances sensory response or sharpens neural tuning by suppressing response to non-target input. In fact, both processes may occur as a function of load: an uncertain listener might use a broad attentional filter to enhance responses to all inputs (i.e., vigilance), yet employ sharpened tuning to focus on hard to discriminate targets. The present work used the greater signal gain, anatomical precision, and laterality separation of intracranial electrophysiological recordings (electrocorticograms) to investigate these competing effects. Data were recorded from acoustically-responsive cortex in the perisylvian region of a single hemisphere in five neurosurgery patients. Patients performed a dichotic listening task in which they alternately attended toward, away from, or completely ignored (silent reading) tones presented to designated ears at varying presentation rates. Comparisons between the grand-averaged event-related potential (ERP) waveforms show a striking change in the effect of selective auditory attention with attentional load. At slower presentation rates (low-load), ERPs were overall enhanced in response to both input channels and regardless of attended ear, including a significant enhancement of ipsilateral input. This result supports a broadly enhancing model of attention under low perceptual load conditions. At the fastest rate, however, only responses to attended inputs contralateral to grid location remained enhanced. This result supports an increasing suppression, or "sharpening," of neural responses to non-targets with increasing attentional load. These data provide support for an elastic model of attention in which attentional scope narrows with increasing load.

We explored age differences in auditory perception by measuring fMRI adaptation of brain activity to repetitions of sound identity (what) and location (where), using meaningful environmental sounds. In one condition, both sound identity and location were repeated allowing us to assess non-specific adaptation. In other conditions, only one feature was repeated (identity or location) to assess domain-specific adaptation. Both young and older adults showed comparable non-specific adaptation (identity and location) in bilateral temporal lobes, medial parietal cortex, and subcortical regions. However, older adults showed reduced domain-specific adaptation to location repetitions in a distributed set of regions, including frontal and parietal areas, and to identity repetition in anterior temporal cortex. We also re-analyzed data from a previously published 1-back fMRI study, in which participants responded to infrequent repetition of the identity or location of meaningful sounds. This analysis revealed age differences in domain-specific adaptation in a set of brain regions that overlapped substantially with those identified in the adaptation experiment. This converging evidence of reductions in the degree of auditory fMRI adaptation in older adults suggests that the processing of specific auditory "what" and "where" information is altered with age, which may influence cognitive functions that depend on this processing.

It is well established that auditory cortex is plastic on different time scales and that this plasticity is driven by the reinforcement that is used to motivate subjects to learn or to perform an auditory task. Motivated by these findings, we study in detail properties of neuronal firing in auditory cortex that is related to reward feedback. We recorded from the auditory cortex of two monkeys while they were performing an auditory categorization task. Monkeys listened to a sequence of tones and had to signal when the frequency of adjacent tones stepped in downward direction, irrespective of the tone frequency and step size. Correct identifications were rewarded with either a large or a small amount of water. The size of reward depended on the monkeys' performance in the previous trial: it was large after a correct trial and small after an incorrect trial. The rewards served to maintain task performance. During task performance we found three successive periods of neuronal firing in auditory cortex that reflected (1) the reward expectancy for each trial, (2) the reward-size received, and (3) the mismatch between the expected and delivered reward. These results, together with control experiments suggest that auditory cortex receives reward feedback that could be used to adapt auditory cortex to task requirements. Additionally, the results presented here extend previous observations of non-auditory roles of auditory cortex and shows that auditory cortex is even more cognitively influenced than lately recognized.

Recent work has demonstrated that sensitivity to interaural time differences (ITD) carried by high-rate cochlear implant pulse trains or analogous acoustic signals can be enhanced by imposing random temporal variation on the stimulus rate [see Goupell et al. (2009). J. Acoust. Soc. Am. 126, 2511–2521]. The present study characterized the effect of such “temporal jitter” on normal-hearing listeners’ weighting of ITD and interaural level differences (ILD) applied to brief trains of Gabor clicks (4 kHz center frequency) presented at nominal interclick intervals (ICI) of 1.25 and 2.5 ms. Lateral discrimination judgments were evaluated on the basis of the ITD or ILD carried by individual clicks in each train. Random perturbation of the ICI significantly reduced listeners’ weighting of onset cues for both ITD and ILD discrimination compared to corresponding isochronous conditions, consistent with enhanced sensitivity to post-onset binaural cues in jittered stimuli, although the reduction of onset weighting was not statistically significant at 1.25 ms ICI. An additional analysis suggested greater weighting of ITD or ILD presented following lengthened versus shortened ICI, although weights for such “gaps” and “squeezes” were comparable to other post-onset weights. Results are discussed in terms of binaural information available in jittered versus isochronous stimuli.

Many children with specific language impairment (SLI) have difficulty in perceiving stop consonant-vowel syllables (e.g., /ba/, /ga/, /da/) with rapid formant transitions, but perform normally when formant transitions are extended in time. This influential observation has helped lead to the development of the auditory temporal processing hypothesis, which posits that SLI is causally related to the processing of rapidly changing sounds in aberrantly expanded windows of temporal integration. We tested a potential physiological basis for this observation by examining whether syllables varying in their consonant place of articulation (POA) with prolonged formant transitions would evoke better differentiated patterns of activation along the tonotopic axis of A1 in awake monkeys when compared to syllables with short formant transitions, especially for more prolonged windows of temporal integration. Amplitudes of multi-unit activity evoked by /ba/, /ga/, and /da/ were ranked according to predictions based on responses to tones centered at the spectral maxima of frication at syllable onset. Population responses representing consonant POA were predicted by the tone responses. Predictions were stronger for syllables with prolonged formant transitions, especially for longer windows of temporal integration. Relevance of findings to normal perception and that occurring in SLI are discussed.

Background/aims: Thyroid hormones (THs) regulate many developmental processes, including the developmental onset of cochlear differentiation and function. TH action is mediated mostly by triiodothyronine (T3) bound to thyroid hormone nuclear receptors (TRs). At positive regulated genes and in the absence of THs, nuclear co-repressors are bound to TRs and decrease basal transcription rate. Ligand (T(3)) binding results in the dissociation of co-repressors and the recruitment of co-activators to the complex, which results in full transcriptional activation. Methods: We measured cochlear function in two knock-in mouse models: TRβ(E457A/E457A), with the TRβ co-activator binding surface (AF-2) disrupted to prevent co-activator binding; and TRβ(Δ337T/Δ337T), which is unable to bind T(3). Cochlear morphology and function were analyzed in 10-week-old normal and mutated mice. Cochlear function was determined by measuring auditory brainstem responses, cochlear tuning and compound action potential (CAP) thresholds. Results: All TRβ(Δ337T/Δ337T) and 85% of the TRβ(E457A/E457A) mice presented elevated CAP thresholds (P < 0.05 or less). Five percent of the TRβ(E457A/E457A) mice presented normal CAP thresholds with broadened cochlear tuning. TRβ(E457A/E457A) and TRβ(Δ337T/Δ337T) presented developmental defects that led to a decreased width (P < 0.01) and an increased thickness (P<0.01) of the tectorial membrane. In addition, TRβ(Δ337T/Δ337T) animals showed an increased tectorial membrane area (P<0.01). Conclusion: Both mutations were deleterious to tectorial membrane development and led to important alterations in cochlear morphology and loss of cochlear function.