Auditory Research publications

There are no Food and Drug Administration‐approved drugs for treating noise‐induced hearing loss (NIHL), reflecting the absence of clear specific therapeutic targets and effective delivery strategies. Noise trauma is demonstrated results in nicotinamide adenine dinucleotide (NAD+) downregulation and mitochondrial dysfunction in cochlear hair cells (HCs) and spiral ganglion neurons (SGNs) in mice, and NAD+ boosted by nicotinamide (NAM) supplementation maintains cochlear mitochondrial homeostasis and prevents neuroexcitatory toxic injury in vitro and ex vivo, also significantly ameliorated NIHL in vivo. To tackle the limited drug delivery efficiency due to sophisticated anatomical barriers and unique clearance pathway in ear, personalized NAM‐encapsulated porous gelatin methacryloyl (PGMA@NAM) are developed based on anatomy topography of murine temporal bone by micro‐computed tomography and reconstruction of round window (RW) niche, realizing hydrogel in situ implantation completely, NAM sustained‐release and long‐term auditory preservation in mice. This study strongly supports personalized PGMA@NAM as NIHL protection drug with effective inner ear delivery, providing new inspiration for drug‐based treatment of NIHL.

Background Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease. Recently, novel biological therapies, such as mesenchymal stem cells (MSCs) and their products, namely, exosomes, are showing promising therapeutic potential due to their low immunogenicity, few ethical concerns, and easy accessibility. Nevertheless, the precise mechanisms underlying the therapeutic effects of MSC-derived exosomes remain unclear. Results Exosomes derived from MSCs reduced hearing and hair cell loss caused by neomycin-induced damage in models in vivo and in vitro. In addition, MSC-derived exosomes modulated autophagy in hair cells to exert a protective effect. Mechanistically, exogenously administered exosomes were internalized by hair cells and subsequently upregulated endocytic gene expression and endosome formation, ultimately leading to autophagy activation. This increased autophagic activity promoted cell survival, decreased the mitochondrial oxidative stress level and the apoptosis rate in hair cells, and ameliorated neomycin-induced ototoxicity. Conclusions In summary, our findings reveal the otoprotective capacity of exogenous exosome-mediated autophagy activation in hair cells in an endocytosis-dependent manner, suggesting possibilities for deafness treatment.

Plasticity from auditory experience shapes the brain’s encoding and perception of sound. However, whether such long-term plasticity alters the trajectory of short-term plasticity during speech processing has yet to be investigated. Here, we explored the neural mechanisms and interplay between short- and long-term neuroplasticity for rapid auditory perceptual learning of concurrent speech sounds in young, normal-hearing musicians and nonmusicians. Participants learned to identify double-vowel mixtures during ~ 45 min training sessions recorded simultaneously with high-density electroencephalography (EEG). We analyzed frequency-following responses (FFRs) and event-related potentials (ERPs) to investigate neural correlates of learning at subcortical and cortical levels, respectively. Although both groups showed rapid perceptual learning, musicians showed faster behavioral decisions than nonmusicians overall. Learning-related changes were not apparent in brainstem FFRs. However, plasticity was highly evident in cortex, where ERPs revealed unique hemispheric asymmetries between groups suggestive of different neural strategies (musicians: right hemisphere bias; nonmusicians: left hemisphere). Source reconstruction and the early (150–200 ms) time course of these effects localized learning-induced cortical plasticity to auditory-sensory brain areas. Our findings reinforce the domain-general benefits of musicianship but reveal that successful speech sound learning is driven by a critical interplay between long- and short-term mechanisms of auditory plasticity, which first emerge at a cortical level.

Cartwheel interneurons of the dorsal cochlear nucleus (DCN) potently suppress multisensory signals that converge with primary auditory afferent input, and thus regulate auditory processing. Noradrenergic fibers from locus coeruleus project to the DCN, and α2-adrenergic receptors inhibit spontaneous spike activity but simultaneously enhance synaptic strength in cartwheel cells, a dual effect leading to enhanced signal-to-noise for inhibition. However, the ionic mechanism of this striking modulation is unknown. We generated a glycinergic neuron-specific knockout of the Na + leak channel NALCN in mice and found that its presence was required for spontaneous firing in cartwheel cells. Activation of α2-adrenergic receptors inhibited both NALCN and spike generation, and this modulation was absent in the NALCN knockout. Moreover, α2-dependent enhancement of synaptic strength was also absent in the knockout. GABA B receptors mediated inhibition through NALCN as well, acting on the same population of channels as α2 receptors, suggesting close apposition of both receptor subtypes with NALCN. Thus, multiple neuromodulatory systems determine the impact of synaptic inhibition by suppressing the excitatory leak channel, NALCN.

Most people can conjure images and sounds that they experience in their minds. There are, however, marked individual differences. Some people report that they cannot generate imagined sensory experiences at all (aphantasics) and others report that they have unusually intense imagined experiences (hyper-phantasics). These individual differences have been linked to activity in sensory brain regions, driven by feedback. We would therefore expect imagined experiences to be associated with specific frequencies of oscillatory brain activity, as these can be a hallmark of neural interactions within and across regions of the brain. Replicating a number of other studies, relative to a Resting-State we find that the act of engaging in auditory or in visual imagery is linked to reductions in the power of oscillatory brain activity across a broad range of frequencies, with prominent peaks in the alpha band (8–12 Hz). This oscillatory activity, however, did not predict individual differences in the subjective intensity of imagined experiences. For audio imagery, these were rather predicted by reductions within the theta (6–9 Hz) and gamma (33–38 Hz) bands, and by increases in beta (15–17 Hz) band activity. For visual imagery these were predicted by reductions in lower (14–16 Hz) and upper (29–32 Hz) beta band activity, and by an increase in mid-beta band (24–26 Hz) activity. Our data suggest that there is sufficient ground truth in the subjective reports people use to describe the intensity of their imagined sensory experiences to allow these to be linked to the power of distinct rhythms of brain activity. In future, we hope to combine this approach with better measures of the subjective intensity of imagined sensory experiences to provide a clearer picture of individual differences in the subjective intensity of imagined experiences, and of why these eventuate.

Stimulus-specific adaptation (SSA), the reduction of neural activity to a common stimulus that does not generalize to other, rare stimuli, is an essential property of our brain. Although well characterized in adults, it is still unknown how it develops during adolescence and what neuronal circuits are involved. Using in vivo electrophysiology and optogenetics in the lemniscal pathway of the mouse auditory system, we observed SSA to be stable from postnatal day 20 (P20) in the inferior colliculus, to develop until P30 in the auditory thalamus and even later in the primary auditory cortex (A1). We found this maturation process to be experience-dependent in A1 but not in thalamus and to be related to alterations in deep but not input layers of A1. We also identified corticothalamic projections to be implicated in thalamic SSA development. Together, our results reveal different circuits underlying the sequential SSA maturation and provide a unique perspective to understand predictive coding and surprise across sensory systems.

Background Redox imbalance and inflammation have been proposed as the principal mechanisms of damage in the auditory system, resulting in functional alterations and hearing loss. Microglia and astrocytes play a crucial role in mediating oxidative/inflammatory injury in the central nervous system; however, the role of glial cells in the auditory damage is still elusive. Objectives Here we investigated glial-mediated responses to toxic injury in peripheral and central structures of the auditory pathway, i.e., the cochlea and the auditory cortex (ACx), in rats exposed to styrene, a volatile compound with well-known oto/neurotoxic properties. Methods Male adult Wistar rats were treated with styrene (400 mg/kg daily for 3 weeks, 5/days a week). Electrophysiological, morphological, immunofluorescence and molecular analyses were performed in both the cochlea and the ACx to evaluate the mechanisms underlying styrene-induced oto/neurotoxicity in the auditory system. Results We showed that the oto/neurotoxic insult induced by styrene increases oxidative stress in both cochlea and ACx. This was associated with macrophages and glial cell activation, increased expression of inflammatory markers (i.e., pro-inflammatory cytokines and chemokine receptors) and alterations in connexin (Cxs) and pannexin (Panx) expression, likely responsible for dysregulation of the microglia/astrocyte network. Specifically, we found downregulation of Cx26 and Cx30 in the cochlea, and high level of Cx43 and Panx1 in the ACx. Conclusions Collectively, our results provide novel evidence on the role of immune and glial cell activation in the oxidative/inflammatory damage induced by styrene in the auditory system at both peripheral and central levels, also involving alterations of gap junction networks. Our data suggest that targeting glial cells and connexin/pannexin expression might be useful to attenuate oxidative/inflammatory damage in the auditory system.

Introduction The mechanisms underlying tinnitus perception are still under research. One of the proposed hypotheses involves an alteration in top-down processing of auditory activity. Low-frequency oscillations in the delta and theta bands have been recently described in brain and cochlear infrasonic signals during selective attention paradigms in normal hearing controls. Here, we propose that the top-down oscillatory activity observed in brain and cochlear signals during auditory and visual selective attention in normal subjects, is altered in tinnitus patients, reflecting an abnormal functioning of the corticofugal pathways that connect brain circuits with the cochlear receptor. Methods To test this hypothesis, we used a behavioral task that alternates between auditory and visual top-down attention while we simultaneously measured electroencephalogram (EEG) and distortion-product otoacoustic emissions (DPOAE) signals in 14 tinnitus and 14 control subjects. Results We found oscillatory activity in the delta and theta bands in cortical and cochlear channels in control and tinnitus patients. There were significant decreases in the DPOAE oscillatory amplitude during the visual attention period as compared to the auditory attention period in tinnitus and control groups. We did not find significant differences when using a between-subjects statistical approach comparing tinnitus and control groups. On the other hand, we found a significant cluster in the delta band in tinnitus when using within-group statistics to compare the difference between auditory and visual DPOAE oscillatory power. Conclusion These results confirm the presence of top-down infrasonic low-frequency cochlear oscillatory activity in the delta and theta bands in tinnitus patients, showing that the corticofugal suppression of cochlear oscillations during visual and auditory attention in tinnitus patients is preserved.

Non‐human primates (NHPs) are crucial models for studies of neuronal activity. Emerging photoacoustic imaging modalities offer excellent tools for studying NHP brains with high sensitivity and high spatial resolution. In this research, a photoacoustic microscopy (PAM) device was used to provide a label‐free quantitative characterization of cerebral hemodynamic changes due to peripheral mechanical stimulation. A 5 × 5 mm area within the somatosensory cortex region of an adult squirrel monkey was imaged. A deep, fully connected neural network was characterized and applied to the PAM images of the cortex to enhance the vessel structures after mechanical stimulation on the forelimb digits. The quality of the PAM images was improved significantly with a neural network while preserving the hemodynamic responses. The functional responses to the mechanical stimulation were characterized based on the improved PAM images. This study demonstrates capability of PAM combined with machine learning for functional imaging of the NHP brain.

Background Individuals with autism spectrum disorders (ASD) often exhibit altered sensory processing and deficits in language development. Prenatal exposure to valproic acid (VPA) increases the risk for ASD and impairs both receptive and expressive language. Like individuals with ASD, rodents prenatally exposed to VPA exhibit degraded auditory cortical processing and abnormal neural activity to sounds. Disrupted neuronal morphology has been documented in earlier processing areas of the auditory pathway in VPA-exposed rodents, but there are no studies documenting early auditory pathway physiology. Therefore, the objective of this study is to characterize inferior colliculus (IC) responses to different sounds in rats prenatally exposed to VPA compared to saline-exposed rats. Methods In vivo extracellular multiunit recordings from the inferior colliculus were collected in response to tones, speech sounds, and noise burst trains. Results Our results indicate that the overall response to speech sounds was degraded in VPA-exposed rats compared to saline-exposed controls, but responses to tones and noise burst trains were unaltered. Conclusions These results are consistent with observations in individuals with autism that neural responses to complex sounds, like speech, are often altered, and lays the foundation for future studies of potential therapeutics to improve auditory processing in the VPA rat model of ASD.

Speech-recognition tests are widely used in both clinical and research audiology. The purpose of this study was the development of a novel speech-recognition test that combines concepts of different speech-recognition tests to reduce training effects and allows for a large set of speech material. The new test consists of four different words per trial in a meaningful construct with a fixed structure, the so-called phrases. Various free databases were used to select the words and to determine their frequency. Highly frequent nouns were grouped into thematic categories and combined with related adjectives and infinitives. After discarding inappropriate and unnatural combinations, and eliminating duplications of (sub-)phrases, a total number of 772 phrases remained. Subsequently, the phrases were synthesized using a text-to-speech system. The synthesis significantly reduces the effort compared to recordings with a real speaker. After excluding outliers, measured speech-recognition scores for the phrases with 31 normal-hearing participants at fixed signal-to-noise ratios (SNR) revealed speech-recognition thresholds (SRT) for each phrase varying up to 4 dB. The median SRT was −9.1 dB SNR and thus comparable to existing sentence tests. The psychometric function's slope of 15 percentage points per dB is also comparable and enables efficient use in audiology. Summarizing, the principle of creating speech material in a modular system has many potential applications.

The hearing abilities of mammals are impacted by factors such as social cues, habitat, and physical characteristics. Despite being used commonly to study social behaviors, hearing of the monogamous prairie vole (Microtus ochrogaster) has never been characterized. In this study, anatomical features are measured and auditory brainstem responses (ABRs) are used to measure auditory capabilities of prairie voles, characterizing monaural and binaural hearing and hearing range. Sexually naive male and female voles were measured to characterize differences due to sex. It was found that prairie voles show a hearing range with greatest sensitivity between 8 and 32 kHz, binaural hearing across interaural time difference ranges appropriate for their head sizes. No differences are shown between the sexes in binaural hearing or hearing range (except at 1 kHz), however, female voles have increased amplitude of peripheral ABR waves I and II and longer latency of waves III and IV compared to males. The results confirm that prairie voles have a broad hearing range, binaural hearing consistent with rodents of similar size, and differences in amplitudes and thresholds of monaural physiological measures between the sexes. These data further highlight the necessity to understand sex-specific differences in neural processing that may underly variability in responses between sexes.

Introduction The voice and hearing can be affected to different degrees by aging, which can cause communication difficulties for elderly people. Vocal production requires effective temporal auditory processing at central levels within the nervous system, which can be compromised by the aging process. Objective To analyze the correlation between voice and temporal auditory processing in older adults. Materials and Methods A total of 40 elderly people aged 60 years or older were subdivided into 2 groups according to the presence or absence of vocal symptoms measured by the Voice Symptom Scale. All of the participants were submitted to auditory temporal tests, vocal self-assessment, and acoustic and perceptual auditory analyses of voice. Results Most of the subjects assessed had decreased voice intensity and normal variability in terms of vocal quality. The performance was normal in the Pitch Pattern Sequence test and altered in the Random Gap Detection test. In the Masking Period Pattern test, the detection thresholds for the target signal were increased in the presence of masking in different temporal target signal positions. Only pitch differed between the two groups. There were differences between the genders regarding frequency, shimmer, the overall severity of the alteration, and roughness. There was a correlation regarding temporal resolution ability and the overall severity of the alteration and roughness of the voice. Conclusion There is a central auditory impairment in temporal resolution which is correlated with vocal alterations in the elderly.

In speech audiometry, the speech-recognition threshold (SRT) is usually established by adjusting the signal-to-noise ratio (SNR) until 50% of the words or sentences are repeated correctly. However, these conditions are rarely encountered in everyday situations. Therefore, for a group of 15 young participants with normal hearing and a group of 12 older participants with hearing impairment, speech-recognition scores were determined at SRT and at four higher SNRs using several stationary and fluctuating maskers. Participants’ verbal responses were recorded, and participants were asked to self-report their listening effort on a categorical scale (self-reported listening effort, SR-LE). The responses were analyzed using an Automatic Speech Recognizer (ASR) and compared to the results of a human examiner. An intraclass correlation coefficient of r = .993 for the agreement between their corresponding speech-recognition scores was observed. As expected, speech-recognition scores increased with increasing SNR and decreased with increasing SR-LE. However, differences between speech-recognition scores for fluctuating and stationary maskers were observed as a function of SNR, but not as a function of SR-LE. The verbal response time (VRT) and the response speech rate (RSR) of the listeners’ responses were measured using an ASR. The participants with hearing impairment showed significantly lower RSRs and higher VRTs compared to the participants with normal hearing. These differences may be attributed to differences in age, hearing, or both. With increasing SR-LE, VRT increased and RSR decreased. The results show the possibility of deriving a behavioral measure, VRT, measured directly from participants’ verbal responses during speech audiometry, as a proxy for SR-LE.

Older adults with normal hearing or with age-related hearing loss face challenges when listening to speech in noisy environments. To better serve individuals with communication difficulties, precision diagnostics are needed to characterize individuals’ auditory perceptual and cognitive abilities beyond pure tone thresholds. These abilities can be heterogenous across individuals within the same population. The goal of the present study is to consider the suprathreshold variability and develop characteristic profiles for older adults with normal hearing (ONH) and with hearing loss (OHL). Auditory perceptual and cognitive abilities were tested on ONH ( n = 20) and OHL ( n = 20) on an abbreviated test battery using portable automated rapid testing. Using cluster analyses, three main profiles were revealed for each group, showing differences in auditory perceptual and cognitive abilities despite similar audiometric thresholds. Analysis of variance showed that ONH profiles differed in spatial release from masking, speech-in-babble testing, cognition, tone-in-noise, and binaural temporal processing abilities. The OHL profiles differed in spatial release from masking, speech-in-babble testing, cognition, and tolerance to background noise performance. Correlation analyses showed significant relationships between auditory and cognitive abilities in both groups. This study showed that auditory perceptual and cognitive deficits can be present to varying degrees in the presence of audiometrically normal hearing and among listeners with similar degrees of hearing loss. The results of this study inform the need for taking individual differences into consideration and developing targeted intervention options beyond pure tone thresholds and speech testing.

Cochlear synaptopathy is a common pathology in humans associated with aging and potentially sound overexposure. Synaptopathy is widely expected to cause "hidden hearing loss," including difficulty perceiving speech in noise, but support for this hypothesis is controversial. Here in budgerigars (Melopsittacus undulatus), we evaluated the impact of long-term cochlear synaptopathy on behavioral discrimination of Gaussian noise (GN) and low-noise noise (LNN) signals processed to have a flatter envelope. Stimuli had center frequencies of 1-3kHz, 100-Hz bandwidth, and were presented at sensation levels (SLs) from 10 to 30dB. We reasoned that narrowband, low-SL stimuli of this type should minimize spread of excitation across auditory-nerve fibers, and hence might reveal synaptopathy-related defects if they exist. Cochlear synaptopathy was induced without hair-cell injury using kainic acid (KA). Behavioral threshold tracking experiments characterized the minimum stimulus duration above which animals could reliably discriminate between LNN and GN. Budgerigar thresholds for LNN-GN discrimination ranged from 40 to 60ms at 30dB SL, were similar across frequencies, and increased for lower SLs. Notably, animals with long-term 39-77% estimated synaptopathy performed similarly to controls, requiring on average a ∼7.5% shorter stimulus duration (-0.7±1.0dB; mean difference ±SE) for LNN-GN discrimination. Decision-variable correlation analyses of detailed behavioral response patterns showed that individual animals relied on envelope cues to discriminate LNN and GN, with lesser roles of FM and energy cues; no difference was found between KA-exposed and control groups. These results suggest that long-term cochlear synaptopathy does not impair discrimination of low-level signals with different envelope statistics.

The head-related transfer function (HRTF) describes the direction-dependent acoustic filtering by the head that occurs between a source signal in free-field space and the signal at the tympanic membrane. HRTFs contain information on sound source location via interaural differences of their magnitude or phase spectra and via the shapes of their magnitude spectra. The present study characterized HRTFs for source locations in the front horizontal plane for nine rabbits, which are a species commonly used in studies of the central auditory system. HRTF magnitude spectra shared several features across individuals, including a broad spectral peak at 2.6kHz that increased gain by 12 to 23dB depending on source azimuth; and a notch at 7.6kHz and peak at 9.8kHz visible for most azimuths. Overall, frequencies above 4kHz were amplified for sources ipsilateral to the ear and progressively attenuated for frontal and contralateral azimuths. The slope of the magnitude spectrum between 3 and 5kHz was found to be an unambiguous monaural cue for source azimuths ipsilateral to the ear. Average interaural level difference (ILD) between 5 and 16kHz varied monotonically with azimuth over ±31dB despite a relatively small head size. Interaural time differences (ITDs) at 0.5kHz and 1.5kHz also varied monotonically with azimuth over ±358 μs and ±260 μs, respectively. Remeasurement of HRTFs after pinna removal revealed that the large pinnae of rabbits were responsible for all spectral peaks and notches in magnitude spectra and were the main contribution to high-frequency ILDs (5-16kHz), whereas the rest of the head was the main contribution to ITDs and low-frequency ILDs (0.2-1.5kHz). Lastly, inter-individual differences in magnitude spectra were found to be small enough that deviations of individual HRTFs from an average HRTF were comparable in size to measurement error. Therefore, the average HRTF may be acceptable for use in neural or behavioral studies of rabbits implementing virtual acoustic space when measurement of individualized HRTFs is not possible.

A better understanding of the neural mechanisms of speech processing can have a major impact in the development of strategies for language learning and in addressing disorders that affect speech comprehension. Technical limitations in research with human subjects hinder a comprehensive exploration of these processes, making animal models essential for advancing the characterization of how neural circuits make speech perception possible. Here, we investigated the mouse as a model organism for studying speech processing and explored whether distinct regions of the mouse auditory cortex are sensitive to specific acoustic features of speech. We found that mice can learn to categorize frequency-shifted human speech sounds based on differences in formant transitions (FT) and voice onset time (VOT). Moreover, neurons across various auditory cortical regions were selective to these speech features, with a higher proportion of speech-selective neurons in the dorso-posterior region. Last, many of these neurons displayed mixed-selectivity for both features, an attribute that was most common in dorsal regions of the auditory cortex. Our results demonstrate that the mouse serves as a valuable model for studying the detailed mechanisms of speech feature encoding and neural plasticity during speech-sound learning.

We provide comparative data on primate audition of naturalistic sounds comprising hearing thresholds, reaction time distributions, and spectral-temporal modulation transfer functions. Our psychophysical experiments demonstrate that auditory information is primarily processed in a spectral-temporal-independent manner by both monkeys and humans. Singular value decomposition of known visual spatiotemporal contrast sensitivity, in comparison to our auditory spectral-temporal sensitivity, revealed a striking contrast in how the brain encodes natural sounds as opposed to natural images, as vision appears to be space-time inseparable.