Auditory Research publications

Mitochondrial dysfunction causes poorly understood tissue-specific pathology stemming from primary defects in respiration, coupled with altered reactive oxygen species (ROS), metabolic signaling, and apoptosis. The A1555G mtDNA mutation that causes maternally inherited deafness disrupts mitochondrial ribosome function, in part, via increased methylation of the mitochondrial 12S rRNA by the methyltransferase mtTFB1. In patient-derived A1555G cells, we show that 12S rRNA hypermethylation causes ROS-dependent activation of AMP kinase and the proapoptotic nuclear transcription factor E2F1. This retrograde mitochondrial-stress relay is operative in vivo, as transgenic-mtTFB1 mice exhibit enhanced 12S rRNA methylation in multiple tissues, increased E2F1 and apoptosis in the stria vascularis and spiral ganglion neurons of the inner ear, and progressive E2F1-dependent hearing loss. This mouse mitochondrial disease model provides a robust platform for deciphering the complex tissue specificity of human mitochondrial-based disorders, as well as the precise pathogenic mechanism of maternally inherited deafness and its exacerbation by environmental factors.

Understanding speech in noisy environments is often taken for granted; however, this task is particularly challenging for people with cochlear hearing loss, even with hearing aids or cochlear implants. A significant limitation to improving auditory prostheses is our lack of understanding of the neural basis for robust speech perception in noise. Perceptual studies suggest the slowly varying component of the acoustic waveform (envelope, ENV) is sufficient for understanding speech in quiet, but the rapidly varying temporal fine structure (TFS) is important in noise. These perceptual findings have important implications for cochlear implants, which currently only provide ENV; however, neural correlates have been difficult to evaluate due to cochlear transformations between acoustic TFS and recovered neural ENV. Here, we demonstrate the relative contributions of neural ENV and TFS by quantitatively linking neural coding, predicted from a computational auditory nerve model, with perception of vocoded speech in noise measured from normal hearing human listeners. Regression models with ENV and TFS coding as independent variables predicted speech identification and phonetic feature reception at both positive and negative signal-to-noise ratios. We found that: (1) neural ENV coding was a primary contributor to speech perception, even in noise; and (2) neural TFS contributed in noise mainly in the presence of neural ENV, but rarely as the primary cue itself. These results suggest that neural TFS has less perceptual salience than previously thought due to cochlear signal processing transformations between TFS and ENV. Because these transformations differ between normal and impaired ears, these findings have important translational implications for auditory prostheses.

The ability to recognize spoken words interrupted by silence was investigated with young normal-hearing listeners and older listeners with and without hearing impairment. Target words from the revised SPIN test by Bilger et al. [J. Speech Hear. Res. 27(1), 32–48 (1984)] were presented in isolation and in the original sentence context using a range of interruption patterns in which portions of speech were replaced with silence. The number of auditory “glimpses” of speech and the glimpse proportion (total duration glimpsed/word duration) were varied using a subset of the SPIN target words that ranged in duration from 300 to 600 ms. The words were presented in isolation, in the context of low-predictability (LP) sentences, and in high-predictability (HP) sentences. The glimpse proportion was found to have a strong influence on word recognition, with relatively little influence of the number of glimpses, glimpse duration, or glimpse rate. Although older listeners tended to recognize fewer interrupted words, there was considerable overlap in recognition scores across listener groups in all conditions, and all groups were affected by interruption parameters and context in much the same way.

The reliability of distortion-product otoacoustic emission (DPOAE) measurements and their relation to loudness measurements was examined in 16 normal-hearing subjects and 58 subjects with hearing loss. The level of the distortion product (Ld) was compared across two sessions and resulted in correlations that exceeded 0.90. The reliability of DPOAEs was less when parameters from nonlinear fits to the input/output (I/O) functions were compared across visits. Next, the relationship between DPOAE I/O parameters and the slope of the low-level portion of the categorical loudness scaling (CLS) function (soft slope) was assessed. Correlations of 0.65, 0.74, and 0.81 at 1, 2, and 4 kHz were observed between CLS soft slope and combined DPOAE parameters. Behavioral threshold had correlations of 0.82, 0.83, and 0.88 at 1, 2, and 4 kHz with CLS soft slope. Combining DPOAEs and behavioral threshold provided little additional information. Lastly, a multivariate approach utilizing the entire DPOAE I/O function was used to predict the CLS rating for each input level (dB SPL). Standard error of the estimate when using this method ranged from 2.4 to 3.0 categorical units (CU), suggesting that DPOAE I/O functions can predict CLS measures within the CU step size used in this study (5).

More than 29 million adults in the United States have been diagnosed with hearing loss. Interestingly, elevated homocysteine (Hcy) levels, known as hyperhomocysteinemia (HHcy), are also associated with impaired hearing. However, the associated mechanism remains obscure. The collagen receptor such as discoidin domain receptor 1 and matrix metalloproteinase (MMP) play a significant role in inner ear structure and function. We hypothesize that HHcy increases hearing thresholds by compromise in inner ear vasculature resulted from impaired Hcy metabolism, increased oxidative stress, collagen IVa and collagen Ia turnover. The treatment with folic acid (FA) protects elevated hearing thresholds and prevents reduction in vessel density by lowering abundant collagen deposition and oxidative stress in inner ear. To test this hypothesis we employed 8 weeks old male wild type (WT), cystathionine-beta-synthase heterozygote knockout (CBS+/-) mice, WT + FA (0.0057 μg/g/day, equivalent to a 400 μg/70 kg/day human dose in drinking water); and CBS(+/-) +FA. The mice were treated for four weeks. The hearing thresholds were determined by recording the auditory brainstem responses. Integrity of vessels was analyzed by perfusion of horseradish peroxidase (HRP) tracer. Endothelial permeability was assessed, which indicated restoration of HRP leakage by FA treatment. A total Hcy level was increased in stria vascularis (SV) and spiral ligament (SL) of CBS+/- mice which was lowered by FA. Interestingly, FA treatment lowered Col IVa Immunostaining by affecting its turnover. The levels of MMP-2, -9, methylenetetrahydrofolate reductase (MTHFR) and cystathione gamma lyase (CSE) were measured by Western blot analysis. The oxidative stress was high in SV and SL of CBS+/- compared to WT however the treatment with FA lowered oxidative stress in CBS+/- mice. These data suggested that hearing loss in CBS+/- mice was primarily due to leakage in inner ear circulation, also partly by induced collagen imbalance, increase in Hcy and oxidative stress in inner ear.

Purpose In perception studies, it is common to use vowel stimuli from standardized recordings or synthetic stimuli created using values from well-known published research. Although the use of standardized stimuli is convenient, unconsidered dialect and regional accent differences may introduce confounding effects. The goal of this study was to examine the effect of regional accent variation on vowel identification. Method The authors analyzed formant values of 8 monophthong vowels produced by 12 talkers from the region where the research took place and compared them with standardized vowels. Fifteen listeners with normal hearing identified synthesized vowels presented in varying levels of noise and at varying spectral distances from the local-dialect values. Results Acoustically, local vowels differed from standardized vowels, and distance varied across vowels. Perceptually, there was a robust effect of accent similarity such that identification was reduced for vowels at greater distances from local values. Conclusions Researchers and clinicians should take care in choosing stimuli for perception experiments. It is recommended that regionally validated vowels be used instead of relying on standardized vowels in vowel perception tasks.

Because of the availability of disease and genetic models, the mouse has become a valuable species for auditory neuroscience that will facilitate long-term goals of understanding neuronal mechanisms underlying the perception and processing of sounds. The goal of this study was to define the basic sound-evoked response properties of single neurons in the mouse dorsal cochlear nucleus (DCN). Neurons producing complex spikes were distinguished as cartwheel cells (CWCs), and other neurons were classified according to the response map scheme previously developed in DCN. Similar to observations in other rodent species, neurons of the mouse DCN exhibit relatively little sound-driven inhibition. As a result, type III was the most commonly observed response. Our findings are generally consistent with the model of DCN function that has been developed in the cat and the gerbil, suggesting that this in vivo mouse preparation will be a useful tool for future studies of auditory physiology.

Primary sensory cortices are traditionally regarded as stimulus analysers. However, studies of associative learning‐induced plasticity in the primary auditory cortex (A1) indicate involvement in learning, memory and other cognitive processes. For example, the area of representation of a tone becomes larger for stronger auditory memories and the magnitude of area gain is proportional to the degree that a tone becomes behaviorally important. Here, we used extinction to investigate whether ‘behavioral importance’ specifically reflects a sound’s ability to predict reinforcement (reward or punishment) vs. to predict any significant change in the meaning of a sound. If the former, then extinction should reverse area gains as the signal no longer predicts reinforcement. Rats ( n = 11) were trained to bar‐press to a signal tone (5.0 kHz) for water‐rewards, to induce signal‐specific area gains in A1. After subsequent withdrawal of reward, A1 was mapped to determine representational areas. Signal‐specific area gains, estimated from a previously established brain–behavior quantitative function, were reversed, supporting the ‘reinforcement prediction’ hypothesis. Area loss was specific to the signal tone vs. test tones, further indicating that withdrawal of reinforcement, rather than unreinforced tone presentation per se , was responsible for area loss. Importantly, the amount of area loss was correlated with the amount of extinction ( r = 0.82, P < 0.01). These findings show that primary sensory cortical representation can encode behavioral importance as a signal’s value to predict reinforcement, and that the number of cells tuned to a stimulus can dictate its ability to command behavior.

The dorsal cochlear nucleus (DCN) is the first neural site of bimodal auditory-somatosensory integration. Previous studies have shown that stimulation of somatosensory pathways results in immediate suppression or enhancement of subsequent acoustically evoked discharges. In the unimpaired auditory system suppression predominates. However, damage to the auditory input pathway leads to enhancement of excitatory somatosensory inputs to the cochlear nucleus, changing their effects on DCN neurons (Shore et al., 2008; Zeng et al., 2009). Given the well described connection between the somatosensory system and tinnitus in patients we sought to determine whether plastic changes in long-lasting bimodal somatosensory-auditory processing accompany tinnitus. Here we demonstrate for the first time in vivo long-term effects of somatosensory inputs on acoustically evoked discharges of DCN neurons in guinea pigs. The effects of trigeminal nucleus stimulation are compared between normal-hearing animals and animals overexposed with narrow band noise and behaviorally tested for tinnitus. The noise exposure resulted in a temporary threshold shift in auditory brainstem responses but a persistent increase in spontaneous and sound-evoked DCN unit firing rates and increased steepness of rate-level functions. Rate increases were especially prominent in buildup units. The long-term somatosensory enhancement of sound-evoked responses was strengthened while suppressive effects diminished in noise-exposed animals, especially those that developed tinnitus. Damage to the auditory nerve is postulated to trigger compensatory long-term synaptic plasticity of somatosensory inputs that might be an important underlying mechanism for tinnitus generation.

The coordinate response measure (CRM) corpus has gained broad acceptance as a research tool for investigating speech intelligibility in background competition and has been widely used in studies of informational masking. The purpose of this study is to establish the psychometric characteristics of CRM target-word identification in various backgrounds with the goal of being able to determine when it is appropriate or not to use adaptive threshold procedures with the CRM corpus. Target-word identification performance based on adaptive tracking mapped directly onto the monotonic psychometric functions obtained for two-talker, four-talker, and cafeteria noise interferers.

To the extent that sensorineural systems are efficient, redundancy should be extracted to optimize transmission of information, but perceptual evidence for this has been limited. Stilp and colleagues recently reported efficient coding of robust correlation (r = .97) among complex acoustic attributes (attack/decay, spectral shape) in novel sounds. Discrimination of sounds orthogonal to the correlation was initially inferior but later comparable to that of sounds obeying the correlation. These effects were attenuated for less-correlated stimuli (r = .54) for reasons that are unclear. Here, statistical properties of correlation among acoustic attributes essential for perceptual organization are investigated. Overall, simple strength of the principal correlation is inadequate to predict listener performance. Initial superiority of discrimination for statistically consistent sound pairs was relatively insensitive to decreased physical acoustic/psychoacoustic range of evidence supporting the correlation, and to more frequent presentations of the same orthogonal test pairs. However, increased range supporting an orthogonal dimension has substantial effects upon perceptual organization. Connectionist simulations and Eigenvalues from closed-form calculations of principal components analysis (PCA) reveal that perceptual organization is near-optimally weighted to shared versus unshared covariance in experienced sound distributions. Implications of reduced perceptual dimensionality for speech perception and plausible neural substrates are discussed.

The current study used a rat model to investigate the underlying mechanisms of blast-induced tinnitus, hearing loss, and associated traumatic brain injury (TBI). Seven rats were used to evaluate behavioral evidence of tinnitus and hearing loss, and TBI using magnetic resonance imaging following a single 10-msec blast at 14 psi or 194 dB sound pressure level (SPL). The results demonstrated that the blast exposure induced early onset of tinnitus and central hearing impairment at a broad frequency range. The induced tinnitus and central hearing impairment tended to shift towards high frequencies over time. Hearing threshold measured with auditory brainstem responses also showed an immediate elevation followed by recovery on day 14, coinciding with behaviorally-measured results. Diffusion tensor magnetic resonance imaging results demonstrated significant damage and compensatory plastic changes to certain auditory brain regions, with the majority of changes occurring in the inferior colliculus and medial geniculate body. No significant microstructural changes found in the corpus callosum indicates that the currently adopted blast exposure mainly exerts effects through the auditory pathways rather than through direct impact onto the brain parenchyma. The results showed that this animal model is appropriate for investigation of the mechanisms underlying blast-induced tinnitus, hearing loss, and related TBI. Continued investigation along these lines will help identify pathology with injury/recovery patterns, aiding development of effective treatment strategies.

Atonal homolog1 (Atoh1) is a bHLH transcription factor essential for inner ear hair cell differentiation. Targeted expression of Atoh1 at various stages in development can result in hair cell differentiation in the ear. However, the level and duration of Atoh1 expression required for proper hair cell differentiation and maintenance remain unknown. We generated an Atoh1 conditional knockout (CKO) mouse line using Tg(Atoh1-cre), in which the cre expression is driven by an Atoh1 enhancer element that is regulated by Atoh1 protein to "self-terminate" its expression. The mutant mice show transient, limited expression of Atoh1 in all hair cells in the ear. In the organ of Corti, reduction and delayed deletion of Atoh1 result in progressive loss of almost all the inner hair cells and the majority of the outer hair cells within three weeks after birth. The remaining cells express hair cell marker Myo7a and attract nerve fibers, but do not differentiate normal stereocilia bundles. Some Myo7a-positive cells persist in the cochlea into adult stages in the position of outer hair cells, flanked by a single row of pillar cells and two to three rows of disorganized Deiters cells. Gene expression analyses of Atoh1, Barhl1 and Pou4f3, genes required for survival and maturation of hair cells, reveal earlier and higher expression levels in the inner compared to the outer hair cells. Our data show that Atoh1 is crucial for hair cell mechanotransduction development, viability, and maintenance and also suggest that Atoh1 expression level and duration may play a role in inner vs. outer hair cell development. These genetically engineered Atoh1 CKO mice provide a novel model for establishing critical conditions needed to regenerate viable and functional hair cells with Atoh1 therapy.

The lake sturgeon, Acipenser fulvescens, belongs to one of the few extant nonteleost ray-finned fishes and diverged from the main vertebrate lineage about 250 million years ago. The aim of this study was to use this species to explore the peripheral neural coding strategies for sound direction and compare these results to modern bony fishes (teleosts). Extracellular recordings were made from afferent neurons innervating the saccule and lagena of the inner ear while the fish was stimulated using a shaker system. Afferents were highly directional and strongly phase locked to the stimulus. Directional response profiles resembled cosine functions, and directional preferences occurred at a wide range of stimulus intensities (spanning at least 60 dB re 1 nm displacement). Seventy-six percent of afferents were directionally selective for stimuli in the vertical plane near 90° (up down) and did not respond to horizontal stimulation. Sixty-two percent of afferents responsive to horizontal stimulation had their best axis in azimuths near 0° (front back). These findings suggest that in the lake sturgeon, in contrast to teleosts, the saccule and lagena may convey more limited information about the direction of a sound source, raising the possibility that this species uses a different mechanism for localizing sound. For azimuth, a mechanism could involve the utricle or perhaps the computation of arrival time differences. For elevation, behavioral strategies such as directing the head to maximize input to the area of best sensitivity may be used. Alternatively, the lake sturgeon may have a more limited ability for sound source localization compared with teleosts.

Interaural differences in stimulus intensity and timing are major cues for sound localization. In mammals, these cues are first processed in the lateral and medial superior olive by interaction of excitatory and inhibitory synaptic inputs from ipsi- and contralateral cochlear nucleus neurons. To preserve sound localization acuity following changes in the acoustic environment, the processing of these binaural cues needs neuronal adaptation. Recent studies have shown that binaural sensitivity adapts to stimulation history within milliseconds, but the actual extent of binaural adaptation is unknown. In the current study, we investigated long-term effects on binaural sensitivity using extracellular in vivo recordings from single neurons in the dorsal nucleus of the lateral lemniscus that inherit their binaural properties directly from the lateral and medial superior olives. In contrast to most previous studies, we used a noninvasive approach to influence this processing. Adult gerbils were exposed for 2 weeks to moderate noise with no stable binaural cue. We found monaural response properties to be unaffected by this measure. However, neuronal sensitivity to binaural cues was reversibly altered for a few days. Computational models of sensitivity to interaural time and level differences suggest that upregulation of inhibition in the superior olivary complex can explain the electrophysiological data.

Multiple parallel auditory pathways ascend from the cochlear nucleus. It is generally accepted that the origin of these pathways are distinct groups of neurons differing in their anatomical and physiological properties. In extracellular in vivo recordings these neurons are typically classified on the basis of their peri-stimulus time histogram. In the present study we reconsider the question of classification of neurons in the anteroventral cochlear nucleus (AVCN) by taking a wider range of response properties into account. The study aims at a better understanding of the AVCN's functional organization and its significance as the source of different ascending auditory pathways. The analyses were based on 223 neurons recorded in the AVCN of the Mongolian gerbil. The range of analysed parameters encompassed spontaneous activity, frequency coding, sound level coding, as well as temporal coding. In order to categorize the unit sample without any presumptions as to the relevance of certain response parameters, hierarchical cluster analysis and additional principal component analysis were employed which both allow a classification on the basis of a multitude of parameters simultaneously. Even with the presently considered wider range of parameters, high number of neurons and more advanced analytical methods, no clear boundaries emerged which would separate the neurons based on their physiology. At the current resolution of the analysis, we therefore conclude that the AVCN units more likely constitute a multi-dimensional continuum with different physiological characteristics manifested at different poles. However, more complex stimuli could be useful to uncover physiological differences in future studies.

Pharmacological studies suggest that dopamine release from lateral olivocochlear efferent neurons suppresses spontaneous and sound-evoked activity in cochlear nerve fibers and helps control noise-induced excitotoxicity; however, the literature on cochlear expression and localization of dopamine receptors is contradictory. To better characterize cochlear dopaminergic signaling, we studied receptor localization using immunohistochemistry or reverse transcriptase PCR and assessed histopathology, cochlear responses and olivocochlear function in mice with targeted deletion of each of the five receptor subtypes. In normal ears, D1, D2, and D5 receptors were detected in microdissected immature (postnatal days 10–13) spiral ganglion cells and outer hair cells but not inner hair cells. D4 was detected in spiral ganglion cells only. In whole cochlea samples from adults, transcripts for D1, D2, D4, and D5 were present, whereas D3 mRNA was never detected. D1 and D2 immunolabeling was localized to cochlear nerve fibers, near the first nodes of Ranvier (D2) and in the inner spiral bundle region (D1 and D2) where presynaptic olivocochlear terminals are found. No other receptor labeling was consistent. Cochlear function was normal in D3, D4, and D5 knock-outs. D1 and D2 knock-outs showed slight, but significant enhancement and suppression, respectively, of cochlear responses, both in the neural output [auditory brainstem response (ABR) wave 1] and in outer hair cell function [distortion product otoacoustic emissions (DPOAEs)]. Vulnerability to acoustic injury was significantly increased in D2, D4 and D5 lines: D1 could not be tested, and no differences were seen in D3 mutants, consistent with a lack of receptor expression. The increased vulnerability in D2 knock-outs was seen in DPOAEs, suggesting a role for dopamine in the outer hair cell area. In D4 and D5 knock-outs, the increased noise vulnerability was seen only in ABRs, consistent with a role for dopaminergic signaling in minimizing neural damage.

A large proportion of age-related hearing loss is caused by loss or damage to outer hair cells in the organ of Corti. The organ of Corti is the mechanosensory transducing apparatus in the inner ear and is composed of inner hair cells, outer hair cells, and highly specialized supporting cells. The mechanisms that regulate differentiation of inner and outer hair cells are not known. Here we report that fibroblast growth factor 20 (FGF20) is required for differentiation of cells in the lateral cochlear compartment (outer hair and supporting cells) within the organ of Corti during a specific developmental time. In the absence of FGF20, mice are deaf and lateral compartment cells remain undifferentiated, postmitotic, and unresponsive to Notch-dependent lateral inhibition. These studies identify developmentally distinct medial (inner hair and supporting cells) and lateral compartments in the developing organ of Corti. The viability and hearing loss in Fgf20 knockout mice suggest that FGF20 may also be a deafness-associated gene in humans.

Rat ultrasonic vocalizations (USVs) are ethologically-essential social signals. Under natural conditions, 22kHz USVs and 50kHz USVs are emitted in association with negative and positive emotional states, respectively. Our first experiment examined freezing behavior elicited in naïve Sprague-Dawley rats by a 22kHz USV, a 50kHz USV, and frequency-matched tones. None of the stimuli elicited freezing, which is the most commonly-used index of fear. The second experiment examined single-unit responses to these stimuli in the amygdala (AM), which is well-known for its role in innate and acquired fear responses. Among 127 well-discriminated single units, 82% were auditory-responsive. Elicited firing patterns were classified using a multi-dimensional scheme that included transient (phasic) responses to the stimulus onsets and/or offsets as well as sustained (tonic) responses during the stimulus. Tonic responses, which are not ordinarily evaluated in AM, were 4.4-times more common than phasic responses. The 22kHz stimuli tended to elicit tonic increases in the firing rates, whereas the 50kHz stimuli more often elicited tonic decreases in firing rates. These opposing tonic responses correspond with the ethological valence of USVs in the two frequency bands. Thus, a relatively-small sample of single-unit responses in AM furnished a more sensitive index of emotional valence than freezing behavior. Latency analysis suggested that stimuli in the two frequency bands are processed through different pathways to AM. One possible interpretation is that phasic responses in AM reflect the detection of a stimulus change, whereas tonic responses indicate the valence of the detected stimulus.

Aminoglycosides, such as gentamycin, are well known ototoxic agents. Toxicity occurs via an activation process involving the formation of an iron-gentamycin complex with free radical production. Antioxidants like Q-ter (a soluble formulation of coenzyme Q(10), CoQ(10)), can limit or prevent cellular ototoxic damage. The present study was designed to investigate the possible protective effects of Q-ter on gentamycin ototoxicity in albino guinea pigs (250-300 g). Animals were divided into five experimental groups: I, a sham control group given an intra-peritoneal (I.P.) injection of 0.5 ml saline (SHAM); II, gentamycin group (GM), treated with an injection of gentamycin (100 mg/ kg); III, gentamycin + Q-ter group (GM+Q-ter), treated with gentamycin (same dose as group II) and an I.P. injection of coenzyme Q(10) terclatrate (Q-ter) at 100 mg/kg body weight; IV, injected with gentamycin (100 mg/kg) plus saline; V, treated with Q-ter alone (100 mg/ kg). All animals were treated for 14 consecutive days. Auditory function was evaluated by recording auditory brainstem responses (ABR) at 15 and 30 days from the beginning of treatment. Morphological changes were analyzed by rhodamine-phalloidine staining. Gentamycin-induced progressive high-frequency hearing loss of 45-55 dB SPL. Q-ter therapy slowed and attenuated the progression of hearing loss, yielding a threshold shift of 20 dB. The significant loss of outer hair cells (OHCs) in the cochlear medio-basal turn in gentamycin-treated animals was not observed in the cochleae of animals protected with Q-ter. This study supports the hypothesis that Q-ter interferes with gentamycin-induced free radical formation, and suggests that it may be useful in protecting OHC function from aminoglycoside ototoxicity, thus reducing hearing loss.