Auditory Research publications

Aging leads to degeneration of the peripheral and central auditory systems, hearing loss, and difficulty understanding sounds in noise. Aging is also associated with changes in susceptibility to or recovery from damaging noise exposures, although the effects of the interaction between acute noise exposure and age on the perception of sounds are not well studied. We tested these effects in the CBA/CaJ mouse model of age-related hearing loss using operant conditioning procedures before and after noise exposure and longitudinally measured changes in their sensitivity for detecting tones in quiet or noise backgrounds. Cochleae from a subset of the behaviorally tested mice were immunolabeled to examine organ of Corti damage relative to what is expected based on aging alone. Mice tested in both quiet and noise background conditions experienced worse behavioral sensitivity immediately after noise exposure, but mice exposed at older ages generally showed greater threshold shifts and reduced recovery over time. Surprisingly, day-to-day stability in thresholds was markedly higher for mice detecting signals in the presence of a noise masker compared with detection in quiet conditions. Cochlear analysis revealed decreases in the total number of outer hair cells (OHCs) and the number of ribbons per inner cell in high-frequency regions in aged, noise-exposed mice relative to aging alone. Our findings build on previous work showing interactions between age and noise exposure and add that background noise can increase the stability of behavioral hearing sensitivity after noise damage.

Surrounding context influences speech listening, resulting in dynamic shifts to category percepts. To examine its neural basis, event-related potentials (ERPs) were recorded during vowel identification with continua presented in random, forward, and backward orders to induce perceptual warping. Behaviorally, sequential order shifted individual listeners’ categorical boundary, versus random delivery, revealing perceptual warping (biasing) of the heard phonetic category dependent on recent stimulus history. ERPs revealed later (∼300 ms) activity localized to superior temporal and middle/inferior frontal gyri that predicted listeners’ hysteresis/enhanced contrast magnitudes. Findings demonstrate that interactions between frontotemporal brain regions govern top-down, stimulus history effects on speech categorization.

It is a well-demonstrated phenomenon that listeners can discriminate native phonetic contrasts better than nonnative ones. Recent neuroimaging studies have started to reveal the underlying neural mechanisms. By focusing on the mismatch negativity/response (MMN/R), a widely studied index of neural sensitivity to sound change, researchers have observed larger MMNs for native contrasts than for nonnative ones in EEG, but also a more focused and efficient neural activation pattern for native contrasts in MEG. However, direct relations between behavioral discrimination and MMN/R are rarely reported. In the current study, 15 native English speakers and 15 native Spanish speakers completed both a behavioral discrimination task and a separate MEG recording to measure MMR to a VOT-based speech contrast (i.e., pre-voiced vs. voiced stop consonant), which represents a phonetic contrast native to Spanish speakers but is nonnative to English speakers. At the group level, English speakers exhibited significantly lower behavioral sensitivity (d’) to the contrast but a more expansive MMR, replicating previous studies. Across individuals, a significant relation between behavioral sensitivity and the MMR was only observed in the Spanish group. Potential differences in the mechanisms underlying behavioral discrimination for the two groups are discussed.

Functional hair cell regeneration in the adult mammalian inner ear remains challenging. This study aimed to study the function of new hair cells induced by a DNA demethylating agent 5-azacytidine. Adult mice were deafened chemically, followed by injection of 5-azacytidine or vehicle into the inner ear. Functionality of regenerated hair cells was evaluated by expression of hair cell proteins, auditory brainstem response (ABR), and distortion-product otoacoustic emission (DPOAE) tests for 6 weeks. In the vehicle-treated group, no cells expressed the hair cell-specific protein myosin VIIa in the cochlea, whereas numerous myosin VIIa-expressing cells were found in the 5-azacytidine-treated cochlea, suggesting the regeneration of auditory hair cells. Moreover, regenerated hair cells were co-labeled with functional proteins espin and prestin. Expression of ribbon synapse proteins suggested synapse formation between new hair cells and neurons. In hearing tests, progressive improvements in ABR [5–30 dB sound pressure level (SPL)] and DPOAE (5–20 dB) thresholds were observed in 5-azacytidine-treated mice. In vehicle-treated mice, there were <5 dB threshold changes in hearing tests. This study demonstrated the ability of 5-azacytidine to promote the functional regeneration of auditory hair cells in a mature mouse model via DNA demethylation, which may provide insights into hearing regeneration using an epigenetic approach.

The ability to determine a sound’s location is critical in everyday life. However, sound source localization is severely compromised for patients with hearing loss who receive bilateral cochlear implants (BiCIs). Several patient factors relate to poorer performance in listeners with BiCIs, associated with auditory deprivation, experience, and age. Critically, characteristic errors are made by patients with BiCIs (e.g., medial responses at lateral target locations), and the relationship between patient factors and the type of errors made by patients has seldom been investigated across individuals. In the present study, several different types of analysis were used to understand localization errors and their relationship with patient-dependent factors (selected based on their robustness of prediction). Binaural hearing experience is required for developing accurate localization skills, auditory deprivation is associated with degradation of the auditory periphery, and aging leads to poorer temporal resolution. Therefore, it was hypothesized that earlier onsets of deafness would be associated with poorer localization acuity and longer periods without BiCI stimulation or older age would lead to greater amounts of variability in localization responses. A novel machine learning approach was introduced to characterize the types of errors made by listeners with BiCIs, making them simple to interpret and generalizable to everyday experience. Sound localization performance was measured in 48 listeners with BiCIs using pink noise trains presented in free-field. Our results suggest that older age at testing and earlier onset of deafness are associated with greater average error, particularly for sound sources near the center of the head, consistent with previous research. The machine learning analysis revealed that variability of localization responses tended to be greater for individuals with earlier compared to later onsets of deafness. These results suggest that early bilateral hearing is essential for best sound source localization outcomes in listeners with BiCIs.

Before hearing onset (postnatal day 12 in mice), inner hair cells (IHCs) spontaneously fire action potentials, thereby driving pre-sensory activity in the ascending auditory pathway. The rate of IHC action potential bursts is modulated by inner supporting cells (ISCs) of Kölliker’s organ through the activity of the Ca 2+ -activated Cl - -channel TMEM16A (ANO1). Here, we show that conditional deletion of Ano1 ( Tmem16a ) in mice disrupts Ca 2+ waves within Kölliker’s organ, reduces the burst-firing activity and the frequency selectivity of auditory brainstem neurons in the medial nucleus of the trapezoid body (MNTB), and also impairs the functional refinement of MNTB projections to the lateral superior olive. These results reveal the importance of the activity of Kölliker’s organ for the refinement of central auditory connectivity. In addition, our study suggests the involvement of TMEM16A in the propagation of Ca 2+ waves, which may also apply to other tissues expressing TMEM16A.

A previous investigation demonstrated differences between younger adult normal-hearing listeners and older adult hearing-impaired listeners in the perceived emotion of clear and conversational speech. Specifically, clear speech sounded angry more often than conversational speech for both groups, but the effect was smaller for the older listeners. These listener groups differed by two confounding factors, age (younger vs. older adults) and hearing status (normal vs. impaired). The objective of the present study was to evaluate the contributions of aging and hearing loss to the reduced perception of anger in older adults with hearing loss. We investigated perceived anger in clear and conversational speech in younger adults with and without a simulated age-related hearing loss, and in older adults with normal hearing. Younger adults with simulated hearing loss performed similarly to normal-hearing peers, while normal-hearing older adults performed similarly to hearing-impaired peers, suggesting that aging was the primary contributor to the decreased anger perception seen in previous work. These findings confirm reduced anger perception for older adults compared to younger adults, though the significant speaking style effect—regardless of age and hearing status—highlights the need to identify methods of producing clear speech that is emotionally neutral or positive.

Sensory hypersensitivity, especially in the auditory system, is a common symptom in Fragile X syndrome (FXS), the most common monogenic form of intellectual disability. However, linking phenotypes across genetic background strains of mouse models has been a challenge and could underly some of the issues with translatability of drug studies to the human condition. This study is the first to characterize the auditory brain stem response (ABR), a minimally invasive physiological readout of early auditory processing that is also used in humans, in a commonly used mouse background strain model of FXS, C57BL/6J. We measured morphological features of pinna and head and used ABR to measure the hearing range, and monaural and binaural auditory responses in hemizygous males, homozygous females, and heterozygous females compared with those in wild-type mice. Consistent with previous study, we showed no difference in morphological parameters across genotypes or sexes. There was no significant difference in hearing range between the sexes or genotypes, however there was a trend towards high frequency hearing loss in male FXS mice. In contrast, female mice with homozygous FXS had a decreased amplitude of wave IV of the monaural ABR, while there was no difference in males for amplitudes and no change in latency of ABR waveforms across sexes and genotypes. Finally, males with FXS had an increased latency of the binaural interaction component (BIC) at 0 interaural timing difference compared with that in wild-type males. These findings further clarify auditory brain stem processing in FXS by adding more information across genetic background strains allowing for a better understanding of shared phenotypes.

Congenital cytomegalovirus (cCMV) infection is the leading infectious cause of neurodevelopmental disorders. However, the neuropathogenesis remains largely elusive due to a lack of informative animal models. In this study, we developed a congenital murine CMV (cMCMV) infection mouse model with high survival rate and long survival period that allowed long-term follow-up study of neurodevelopmental disorders. This model involves in utero intracranial injection and mimics many reported clinical manifestations of cCMV infection in infants, including growth restriction, hearing loss, and impaired cognitive and learning-memory abilities. We observed that abnormalities in MRI/CT neuroimaging were consistent with brain hemorrhage and loss of brain parenchyma, which was confirmed by pathological analysis. Neuropathological findings included ventriculomegaly and cortical atrophy associated with impaired proliferation and migration of neural progenitor cells in the developing brain at both embryonic and postnatal stages. Robust inflammatory responses during infection were shown by elevated inflammatory cytokine levels, leukocyte infiltration, and activation of microglia and astrocytes in the brain. Pathological analyses and CT neuroimaging revealed brain calcifications induced by cMCMV infection and cell death via pyroptosis. Furthermore, antiviral treatment with ganciclovir significantly improved neurological functions and mitigated brain damage as shown by CT neuroimaging. These results demonstrate that this model is suitable for investigation of mechanisms of infection-induced brain damage and long-term studies of neurodevelopmental disorders, including the development of interventions to limit CNS damage associated with cCMV infection.

We tested whether sensitivity to acoustic spectrotemporal modulations can be observed from reaction times for normal-hearing and impaired-hearing conditions. In a manual reaction-time task, normal-hearing listeners had to detect the onset of a ripple (with density between 0–8 cycles/octave and a fixed modulation depth of 50%), that moved up or down the log-frequency axis at constant velocity (between 0–64 Hz), in an otherwise-unmodulated broadband white-noise. Spectral and temporal modulations elicited band-pass filtered sensitivity characteristics, with fastest detection rates around 1 cycle/oct and 32 Hz for normal-hearing conditions. These results closely resemble data from other studies that typically used the modulation-depth threshold as a sensitivity criterion. To simulate hearing-impairment, stimuli were processed with a 6-channel cochlear-implant vocoder, and a hearing-aid simulation that introduced separate spectral smearing and low-pass filtering. Reaction times were always much slower compared to normal hearing, especially for the highest spectral densities. Binaural performance was predicted well by the benchmark race model of binaural independence, which models statistical facilitation of independent monaural channels. For the impaired-hearing simulations this implied a “best-of-both-worlds” principle in which the listeners relied on the hearing-aid ear to detect spectral modulations, and on the cochlear-implant ear for temporal-modulation detection. Although singular-value decomposition indicated that the joint spectrotemporal sensitivity matrix could be largely reconstructed from independent temporal and spectral sensitivity functions, in line with time-spectrum separability, a substantial inseparable spectral-temporal interaction was present in all hearing conditions. These results suggest that the reaction-time task yields a valid and effective objective measure of acoustic spectrotemporal-modulation sensitivity.

A bstract Sound localization and identification are challenging in acoustically rich environments. The relation between these two processes is still poorly understood. As natural sound-sources rarely occur exactly simultaneously, we wondered whether the auditory system could identify (“what”) and localize (“where”) two spatially separated sounds with synchronous onsets. While listeners typically report hearing a single source at an average location, one study found that both sounds may be accurately localized if listeners are explicitly being told two sources exist. We here tested whether simultaneous source identification (one vs. two) and localization is possible, by letting listeners choose to make either one or two head-orienting saccades to the perceived location(s). Results show that listeners could identify two sounds only when presented on different sides of the head, and that identification accuracy increased with their spatial separation. Notably, listeners were unable to accurately localize either sound, irrespective of whether one or two sounds were identified. Instead, the first (or only) response always landed near the average location, while second responses were unrelated to the targets. We conclude that localization of synchronous sounds in the absence of prior information is impossible. We discuss that the putative cortical ‘what’ pathway may not transmit relevant information to the ‘where’ pathway. We examine how a broadband interaural correlation cue could help to correctly identify the presence of two sounds without being able to localize them. We propose that the persistent averaging behavior reveals that the ‘where’ system intrinsically assumes that synchronous sounds originate from a single source. S ignificance S tatement It is poorly understood whether identification (‘what’) of sounds and their localization (‘where’) are inter-related, or independent neural processes. We measured sound-localization responses towards synchronous sounds to examine potential coupling of these processes. We varied the spatial configurations of two sounds and found that although identification improved considerably with larger spatial separation, their localization was unaffected: responses were always directed towards the average location. This shows absence of mutual coupling of information between the ‘what’ and ‘where’ streams in the auditory system. We also show how broadband interaural correlation could explain the improved identification results, without affecting localization performance, and explain how the persistent spatial averaging could be understood from strong internal priors regarding sound synchronicity.

Significance: Quantitative measurements of cerebral hemodynamic changes due to functional activation are widely accomplished with commercial continuous wave (CW-NIRS) instruments despite the availability of the more rigorous multi-distance frequency domain (FD-NIRS) approach. A direct comparison of the two approaches to functional near-infrared spectroscopy can help in the interpretation of optical data and guide implementations of diffuse optical instruments for measuring functional activation. Aim: We explore the differences between CW-NIRS and multi-distance FD-NIRS by comparing measurements of functional activation in the human auditory cortex. Approach: Functional activation of the human auditory cortex was measured using a commercial frequency domain near-infrared spectroscopy instrument for 70 dB sound pressure level broadband noise and pure tone (1000 Hz) stimuli. Changes in tissue oxygenation were calculated using the modified Beer–Lambert law (CW-NIRS approach) and the photon diffusion equation (FD-NIRS approach). Results: Changes in oxygenated hemoglobin measured with the multi-distance FD-NIRS approach were about twice as large as those measured with the CW-NIRS approach. A finite-element simulation of the functional activation problem was performed to demonstrate that tissue oxygenation changes measured with the CW-NIRS approach is more accurate than that with multi-distance FD-NIRS. Conclusions: Multi-distance FD-NIRS approaches tend to overestimate functional activation effects, in part due to partial volume effects.

Many hearing difficulties can be explained as a loss of audibility, a problem easily detected and treated using standard audiological procedures. Yet, hearing can be much poorer (or more impaired) than audibility predicts because of deficits in the suprathreshold mechanisms that encode the rapidly changing, spectral, temporal, and binaural aspects of the sound. The ability to evaluate these mechanisms requires well-defined stimuli and strict adherence to rigorous psychometric principles. This project reports on the comparison between a laboratory-based and a mobile system’s results for psychoacoustic assessment in adult listeners with normal hearing. A description of both systems employed is provided. Psychoacoustic tests include frequency discrimination, amplitude modulation detection, binaural encoding, and temporal gap detection. Results reported by the mobile system were not significantly different from those collected with the laboratory-based system for most of the tests and were consistent with those reported in the literature. The mobile system has the potential to be a feasible option for the assessment of suprathreshold auditory encoding abilities.

The present study establishes the Mongolian gerbil ( Meriones unguiculatus ) as a model for investigating the perception of human speech sounds. We report data on the discrimination of logatomes (CVCs 1 - consonant-vowel-consonant combinations with outer consonants /b/, /d/, /s/ and /t/ and central vowels /a/, /a:/, /ε/, /e:/, /I/, /i:/, /ɔ/, /o:/, /℧/ and /u:/, VCVs 2 - vowel-consonant-vowel combinations with outer vowels /a/, /I/ and /℧/ and central consonants /b/, /d/, /f/, /g/, /k/, /l/, /m/, /n/, /p/, /s/, /t/ and /v/) by young gerbils. Four young gerbils were trained to perform an oddball target detection paradigm in which they were required to discriminate a deviant CVC or VCV in a sequence of CVC or VCV standards, respectively. The experiments were performed with an ICRA-1 noise masker with speech-like spectral properties, and logatomes of multiple speakers were presented at various signal-to-noise ratios. Response latencies were measured to generate perceptual maps employing multidimensional scaling, which visualize the gerbils’ internal representations of the sounds. The dimensions of the perceptual maps were correlated to multiple phonetic features of the speech sounds for evaluating which features of vowels and consonants are most important for the discrimination. The perceptual representation of vowels and consonants in gerbils was similar to that of humans, although gerbils needed higher signal-to-noise ratios for the discrimination of speech sounds than humans. The gerbils’ discrimination of vowels depended on differences in the frequencies of the first and second formant determined by tongue height and position. Consonants were discriminated based on differences in combinations of their articulatory features. The similarities in the perception of logatomes by gerbils and humans renders the gerbil a suitable model for human speech sound discrimination. Highlights Perceptual maps of vowels and consonants in Mongolian gerbils are derived Gerbils perceive vowels and consonants in the same way as humans Gerbils discriminate vowels based on frequency differences of the formants Gerbils discriminate consonants based on differences in articulatory features

Humans are sensitive to interaural time differences (ITDs) conveyed by slow modulations on high-frequency carrier signals. Sensitivity appears to be affected by temporal envelope sharpness, but it is unclear if there is a limit to which sharpness affects sensitivity. Pulse trains were varied in relative bandwidth (re: critical bandwidths) and center frequency. ITD sensitivity increased with increasing bandwidth. There was no effect of center frequency when relative bandwidths were analyzed, suggesting that the temporal envelope sharpness (concomitantly absolute bandwidth in Hz) did not affect performance. Rather, sensitivity was most easily explained by recruitment of additional auditory channels.

Spiral ganglion neurons (SGNs) can be injured by a wide variety of insults. However, there still is a lack of degeneration models to specifically damage the SGNs without disturbing other types of cells in the inner ear. This study aims to generate an SGN-specific damage model using the Cre-LoxP transgenic mouse strains. The Cre-inducible diphtheria toxin receptor ( iDTR +/+ ) knock-in mouse strain was crossed with a mouse strain with Cre activity specific to neurons ( Nefl CreER/CreER ). Expression of the Cre-recombinase activity was evaluated using the reporter mouse strain Ai9 at pre-hearing, hearing onset, and post-hearing stages. Accordingly, heterozygous Nefl CreER/ + ;iDTR +/– mice were treated with tamoxifen on postnatal days 1–5 (P1–5), followed by diphtheria toxin (DT) or vehicle injection on P7, P14, and P21 to evaluate the SGN loss. Robust tamoxifen-induced Cre-mediated Ai9 tdTomato fluorescence was observed in the SGN area of heterozygous Nefl CreER/ + ;Ai9 +/– mice treated with tamoxifen, whereas vehicle-treated heterozygote mice did not show tdTomato fluorescence. Compared to vehicle-treated Nefl CreER/ + ;iDTR +/– mice, DT-treated Nefl CreER/ + ;iDTR +/– mice showed significant auditory brainstem response (ABR) threshold shifts and SGN cell loss. Hair cell count and functional study did not show significant changes. These results demonstrate that the Nefl CreER/CreER mouse strain exhibits inducible SGN-specific Cre activity in the inner ear, which may serve as a valuable SGN damage model for regeneration research of the inner ear.

Spatial hearing is crucial in real life but deteriorates in participants with severe sensorineural hearing loss or single-sided deafness. This ability can potentially be improved with a unilateral cochlear implant (CI). The present study investigated measures of sound localization in participants with single-sided deafness provided with a CI. Sound localization was measured separately at eight loudspeaker positions (4°, 30°, 60°, and 90°) on the CI side and on the normal-hearing side. Low- and high-frequency noise bursts were used in the tests to investigate possible differences in the processing of interaural time and level differences. Data were compared to normal-hearing adults aged between 20 and 83. In addition, the benefit of the CI in speech understanding in noise was compared to the localization ability. Fifteen out of 18 participants were able to localize signals on the CI side and on the normal-hearing side, although performance was highly variable across participants. Three participants always pointed to the normal-hearing side, irrespective of the location of the signal. The comparison with control data showed that participants had particular difficulties localizing sounds at frontal locations and on the CI side. In contrast to most previous results, participants were able to localize low-frequency signals, although they localized high-frequency signals more accurately. Speech understanding in noise was better with the CI compared to testing without CI, but only at a position where the CI also improved sound localization. Our data suggest that a CI can, to a large extent, restore localization in participants with single-sided deafness. Difficulties may remain at frontal locations and on the CI side. However, speech understanding in noise improves when wearing the CI. The treatment with a CI in these participants might provide real-world benefits, such as improved orientation in traffic and speech understanding in difficult listening situations.

Serotonin transporter (SERT) modulates the level of 5-HT and significantly affects the activity of serotonergic neurons in the central nervous system. The manipulation of SERT has lasting neurobiological and behavioral consequences, including developmental dysfunction, depression, and anxiety. Auditory disorders have been widely reported as the adverse events of these mental diseases. It is unclear how SERT impacts neuronal connections/interactions and what mechanism(s) may elicit the disruption of normal neural network functions in auditory cortex. In the present study, we report on the neuronal morphology and function of auditory cortex in SERT knockout (KO) mice. We show that the dendritic length of the fourth layer (L-IV) pyramidal neurons and the second-to-third layer (L-II/III) interneurons were reduced in the auditory cortex of the SERT KO mice. The number and density of dendritic spines of these neurons were significantly less than those of wild-type neurons. Also, the frequency-tonotopic organization of primary auditory cortex was disrupted in SERT KO mice. The auditory neurons of SERT KO mice exhibited border frequency tuning with high-intensity thresholds. These findings indicate that SERT plays a key role in development and functional maintenance of auditory cortical neurons. Auditory function should be examined when SERT is selected as a target in the treatment for psychiatric disorders.

It is generally assumed that listeners with normal audiograms have relatively symmetric hearing, and more specifically that diotic stimuli (having zero interaural differences) are heard as centered in the head. While measuring intracranial lateralization with a visual pointing task for tones and 50-Hz-wide narrowband noises from 300 to 700 Hz, examples of systematic and large (>50% from midline to the ear) lateralization biases were found. In a group of ten listeners, five showed consistent lateralization bias to the right or left side at all or a subset of frequencies. Asymmetries in hearing, not apparent in audiometric thresholds, may explain these lateralization biases.

The protective effect of the efferent system against acoustic trauma (AT) has been shown by several experimental approaches, including damage to one ear, sectioning of the olivocochlear bundle (OCB) in the floor of the IV ventricle, and knock-in mice overexpressing outer hair cell (OHC) cholinergic receptors, among others. Such effects have been related to changes in the regulation of the cholinergic efferent system and in cochlear amplification, which ultimately reverse upon protective hearing suppression. In addition to well-known circuits of the brainstem, the descending corticofugal pathway also regulates efferent neurons of the olivary complex. In this study, we applied our recently developed experimental paradigm of multiple sessions of electrical stimulation (ES) to activate the efferent system in combination with noise overstimulation. ABR thresholds increased 1 and 2 days after AT (8–16 kHz bandpass noise at 107 dB for 90 min) recovering at AT + 14 days. However, after multiple sessions of epidural anodal stimulation, no changes in thresholds were observed following AT. Although an inflammatory response was also observed 1 day after AT in both groups, the counts of reactive macrophages in both experimental conditions suggest decreased inflammation in the epidural stimulation group. Quantitative immunocytochemistry for choline acetyltransferase (ChAT) showed a significant decrease in the size and optical density of the efferent terminals 1 day after AT and a rebound at 14 days, suggesting depletion of the terminals followed by a long-term compensatory response. Such a synthesis recovery was significantly higher upon cortical stimulation. No significant correlation was found between ChAT optical density and size of the buttons in sham controls (SC) and ES/AT + 1day animals; however, significant negative correlations were shown in all other experimental conditions. Therefore, our comparative analysis suggests that cochleotopic cholinergic neurotransmission is also better preserved after multisession epidural stimulation.