Auditory Research publications

Age-related hearing loss (AHL) is a multifactorial disorder characterized by a decline in peripheral and central auditory function. Here, we examined synaptic transmission in DBA/2 mice, which carry the AHL8 gene, at the identifiable glutamatergic synapse in the medial nucleus of the trapezoid body (MNTB), a nucleus in the superior olivary complex critical for acoustic timing. Mice exhibited raised auditory brainstem thresholds by P14, soon after hearing onset. Excitatory postsynaptic currents were prolonged; however, postsynaptic excitability was normal. By P18, high-frequency hearing loss was evident. Coincident with the onset of hearing loss, MNTB principal neurons displayed changes in intrinsic firing properties. These results suggest that changes in transmission in the superior olivary complex are associated with early onset hearing loss.

Delivery of therapeutic compounds to the inner ear via absorption through the round window membrane (RWM) has advantages over direct intracochlear infusions; specifically, minimizing impact upon functional hearing measures. However, previous reports show that significant basal-to-apical concentration gradients occur, with the potential to impact treatment efficacy. Here we present a new approach to inner ear drug delivery with induced advection aiding distribution of compounds throughout the inner ear in the murine cochlea. Polyimide microtubing was placed near the RWM niche through a bullaostomy into the middle ear cavity allowing directed delivery of compounds to the RWM. We hypothesized that a posterior semicircular canalostomy would induce apical flow from the patent cochlear aqueduct to the canalostomy due to influx of cerebral spinal fluid. To test this hypothesis, young adult CBA/CaJ mice were divided into two groups: bullaostomy approach only (BA) and bullaostomy+canalostomy (B+C). Cochlear function was evaluated by distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) thresholds during and after middle ear infusion of salicylate in artificial perilymph (AP), applied near the RWM. The mice recovered for 1week, and were re-tested. The results demonstrate there was no significant impact on auditory function utilizing the RWM surgical procedure with or without the canalostomy, and DPOAE thresholds were elevated reversibly during the salicylate infusion. Comparing the threshold shifts for both methods, the B+C approach had more of a physiological effect than the BA approach, including at lower frequencies representing more apical cochlear locations. Unlike mouse cochleostomies, there was no deleterious auditory functional impact after 1week recovery from surgery. The B+C approach had more drug efficacy at lower frequencies, underscoring potential benefits for more precise control of delivery of inner ear therapeutic compounds.

We have developed a classifier capable of locating and identifying speech sounds using activity from rat auditory cortex with an accuracy equivalent to behavioral performance and without the need to specify the onset time of the speech sounds. This classifier can identify speech sounds from a large speech set within 40 ms of stimulus presentation. To compare the temporal limits of the classifier to behavior, we developed a novel task that requires rats to identify individual consonant sounds from a stream of distracter consonants. The classifier successfully predicted the ability of rats to accurately identify speech sounds for syllable presentation rates up to 10 syllables per second (up to 17.9 ± 1.5 bits/s), which is comparable to human performance. Our results demonstrate that the spatiotemporal patterns generated in primary auditory cortex can be used to quickly and accurately identify consonant sounds from a continuous speech stream without prior knowledge of the stimulus onset times. Improved understanding of the neural mechanisms that support robust speech processing in difficult listening conditions could improve the identification and treatment of a variety of speech-processing disorders.

Switching attention between different stimuli of interest based on particular task demands is important in many everyday settings. In audition in particular, switching attention between different speakers of interest that are talking concurrently is often necessary for effective communication. Recently, it has been shown by multiple studies that auditory selective attention suppresses the representation of unwanted streams in auditory cortical areas in favor of the target stream of interest. However, the neural processing that guides this selective attention process is not well understood. Here we investigated the cortical mechanisms involved in switching attention based on two different types of auditory features. By combining magneto- and electro-encephalography (M-EEG) with an anatomical MRI constraint, we examined the cortical dynamics involved in switching auditory attention based on either spatial or pitch features. We designed a paradigm where listeners were cued in the beginning of each trial to switch or maintain attention halfway through the presentation of concurrent target and masker streams. By allowing listeners time to switch during a gap in the continuous target and masker stimuli, we were able to isolate the mechanisms involved in endogenous, top-down attention switching. Our results show a double dissociation between the involvement of right temporoparietal junction (RTPJ) and the left inferior parietal supramarginal part (LIPSP) in tasks requiring listeners to switch attention based on space and pitch features, respectively, suggesting that switching attention based on these features involves at least partially separate processes or behavioral strategies.

The place of the posterolateral superior temporal (PLST) gyrus within the hierarchical organization of the human auditory cortex is unknown. Understanding how PLST processes spectral information is imperative for its functional characterization. Pure-tone stimuli were presented to subjects undergoing invasive monitoring for refractory epilepsy. Recordings were made using high-density subdural grid electrodes. Pure tones elicited robust high gamma event-related band power responses along a portion of PLST adjacent to the transverse temporal sulcus (TTS). Responses were frequency selective, though typically broadly tuned. In several subjects, mirror-image response patterns around a low-frequency center were observed, but typically, more complex and distributed patterns were seen. Frequency selectivity was greatest early in the response. Classification analysis using a sparse logistic regression algorithm yielded above-chance accuracy in all subjects. Classifier performance typically peaked at 100-150 ms after stimulus onset, was comparable for the left and right hemisphere cases, and was stable across stimulus intensities. Results demonstrate that representations of spectral information within PLST are temporally dynamic and contain sufficient information for accurate discrimination of tone frequencies. PLST adjacent to the TTS appears to be an early stage in the hierarchy of cortical auditory processing. Pure-tone response patterns may aid auditory field identification.

In auditory research, hearing function of mouse mutants is assessed in vivo by evoked potential recording. Evaluation of the response parameters should be performed with reference to the evoked responses recorded from wild-type mice. This study reports normative data calculated on auditory brainstem responses (ABRs) obtained from 20 wild-type C57 BL/6J mice at a postnatal age between 21 and 45 days. Acoustic stimuli consisted tone bursts at 8, 14, 20, 26, 32 kHz, and clicks. Each stimulus was delivered in free field at stimulation intensity starting from a maximum of 100 dB peak equivalent SPL (dB peSPL) at decreasing steps of 10 dB with a repetition rate of 13/sec. Evoked responses were recorded by needle electrodes inserted subcutaneously. At high intensity stimulation, five response waveforms, each consisting of a positive peak and a subsequent negative valley, were identified within 7 msec, and were labelled with sequential capital Roman numerals from I to V. Peak IV was the most robust and stable at low intensities for both tone burst and click stimuli, and was therefore utilized to estimate hearing thresholds. Both latencies and amplitudes of ABR peaks showed good reproducibility with acceptable standard deviations. Mean wave IV thresholds measured across all animals ranged from a maximum of 23 dB peSPL for clicks to a minimum of 7 dB peSPL for 20 kHz-tone burst stimuli. Statistical analysis of the distribution of latencies and amplitudes of peaks from I to V performed for each stimulus type yielded a normative data set which was utilised to obtain the most consistent fitting-curve model. This could serve as a reference for further studies on murine models of hearing loss.

Short-term tinnitus develops shortly after the administration of a high dose of salicylate. Since salicylate selectively potentiates N-methyl- D-aspartate (NMDA) currents in spiral ganglion neurons, it may play a vital role in tinnitus by amplifying NMDA-mediated neurotransmission. The aim of this study was to determine whether systemic treatment with a NMDA channel blocker, memantine, could prevent salicylate-induced tinnitus in animals. Additional experiments were performed to evaluate the effect of memantine on the auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to test for changes in hearing function. Thirty-six rats were divided into 3 groups and treated daily for four consecutive days. One group (n = 12) was injected with salicylate (300 mg/kg/d, IP), the second (n = 12) was treated with memantine (5 mg/kg/d, IP) and the third group (n = 12) was injected with salicylate and memantine. All rats were tested for tinnitus and hearing loss at 2, 24, 48 and 72 h after the first drug administration and 24 h post treatment; tinnituslike behaviour was assessed with gap prepulse inhibition of acoustic startle (GPIAS), and hearing function was measured with DPOAE, ABR and noise burst prepulse inhibition of acoustic startle (NBPIAS). Rats in the salicylate group showed impaired GPIAS indicative of transient tinnitus-like behaviour near 16 kHz that recovered 24 h after the last salicylate treatment. Memantine did not cause a significant change in GPIAS. Combined injection of salicylate and memantine significantly attenuated GPIAS tinnitus-like behaviour at 48 hours after the first injection. None of the treatments induced permanent threshold shifts in the ABR and DPOAE, which recovered completely within one day post treatment. Animals treated with salicylate plus memantine showed results comparable to animals treated with salicylate alone, confirming that there is no effect of memantine on DPOAE which reflects OHC function. The present study confirms the role of cochlear NMDA receptors in the induction of salicylate-induced tinnitus.

Age and hearing-level matched tinnitus and control groups were presented with a 40 Hz AM sound using a carrier frequency of either 5 kHz (in the tinnitus frequency region of the tinnitus subjects) or 500 Hz (below this region). On attended blocks subjects pressed a button after each sound indicating whether a single 40 Hz AM pulse of variable increased amplitude (target, probability 0.67) had or had not occurred. On passive blocks subjects rested and ignored the sounds. The amplitude of the 40 Hz auditory steady-state response (ASSR) localizing to primary auditory cortex (A1) increased with attention in control groups probed at 500 Hz and 5 kHz and in the tinnitus group probed at 500 Hz, but not in the tinnitus group probed at 5 kHz (128 channel EEG). N1 amplitude (this response localizing to nonprimary cortex, A2) increased with attention at both sound frequencies in controls but at neither frequency in tinnitus. We suggest that tinnitus-related neural activity occurring in the 5 kHz but not the 500 Hz region of tonotopic A1 disrupted attentional modulation of the 5 kHz ASSR in tinnitus subjects, while tinnitus-related activity in A1 distributing nontonotopically in A2 impaired modulation of N1 at both sound frequencies.

One of the most efficient mechanisms to optimize signal-to-noise ratios is the Lombard effect - an involuntary rise in call amplitude due to ambient noise. It is often accompanied by changes in the spectro-temporal composition of calls. We examined the effects of broadband-filtered noise on the spectro-temporal composition of horseshoe bat echolocation calls, which consist of a constant-frequency component and an initial and terminal frequency-modulated portion. We find that the frequency-modulated components became larger for almost all noise conditions, whereas the bandwidth of the constant-frequency component increased only when broadband-filtered noise was centered on or above the calls' dominant or fundamental frequency. This indicates that ambient noise modifies the associated acoustic parameters of the Lombard-effect, such as spectro-temporal features, independently and could significantly affect the bat's ability to detect and locate targets. Our findings may be of significance in evaluating the impact of environmental noise on echolocation behavior in bats.

Previous studies have shown that sodium salicylate (SS) activates not only central auditory structures, but also nonauditory regions associated with emotion and memory. To identify electrophysiological changes in the nonauditory regions, we recorded sound-evoked local field potentials and multiunit discharges from the striatum, amygdala, hippocampus, and cingulate cortex after SS-treatment. The SS-treatment produced behavioral evidence of tinnitus and hyperacusis. Physiologically, the treatment significantly enhanced sound-evoked neural activity in the striatum, amygdala, and hippocampus, but not in the cingulate. The enhanced sound evoked response could be linked to the hyperacusis-like behavior. Further analysis showed that the enhancement of sound-evoked activity occurred predominantly at the midfrequencies, likely reflecting shifts of neurons towards the midfrequency range after SS-treatment as observed in our previous studies in the auditory cortex and amygdala. The increased number of midfrequency neurons would lead to a relative higher number of total spontaneous discharges in the midfrequency region, even though the mean discharge rate of each neuron may not increase. The tonotopical overactivity in the midfrequency region in quiet may potentially lead to tonal sensation of midfrequency (the tinnitus). The neural changes in the amygdala and hippocampus may also contribute to the negative effect that patients associate with their tinnitus.

Canavan disease is a leukodystrophy caused by mutations in the ASPA gene. This gene encodes the enzyme that converts N-acetylaspartate into acetate and aspartic acid. In Canavan disease spongiform encephalopathy of the brain causes progressive mental retardation, motor deficit and death. We have isolated a mouse with a novel ethylnitrosourea-induced mutation in Aspa. This mutant, named deaf14, carries a c.516T>A mutation that is predicted to cause a p.Y172X protein truncation. No full-length ASPA protein is produced in deaf14 brain and there is extensive spongy degeneration. Interestingly, we found that deaf14 mice have an attenuated startle in response to loud noise. The first auditory brainstem response peak has normal latency and amplitude but peaks II, III, IV and V have increased latency and decreased amplitude in deaf14 mice. Our work reveals a hitherto unappreciated pathology in a mouse model of Canavan disease, implying that auditory brainstem response testing could be used in diagnosis and to monitor the progression of this disease.

Human listeners, and other animals too, use interaural time differences (ITD) to localize sounds. If the sounds are pure tones, a simple frequency factor relates the ITD to the interaural phase difference (IPD), for which there are known iso-IPD boundaries, 90°, 180°… defining regions of spatial perception. In this article, iso-IPD boundaries for humans are translated into azimuths using a spherical head model (SHM), and the calculations are checked by free-field measurements. The translated boundaries provide quantitative tests of an ecological interpretation for the dramatic onset of ITD insensitivity at high frequencies. According to this interpretation, the insensitivity serves as a defense against misinformation and can be attributed to limits on binaural processing in the brainstem. Calculations show that the ecological explanation passes the tests only if the binaural brainstem properties evolved or developed consistent with heads that are 50% smaller than current adult heads. Measurements on more realistic head shapes relax that requirement only slightly. The problem posed by the discrepancy between the current head size and a smaller, ideal head size was apparently solved by the evolution or development of central processes that discount large IPDs in favor of interaural level differences. The latter become more important with increasing head size.

Frequency tagging of sensory inputs (presenting stimuli that fluctuate periodically at rates to which the cortex can phase lock) has been used to study attentional modulation of neural responses to inputs in different sensory modalities. For visual inputs, the visual steady-state response (VSSR) at the frequency modulating an attended object is enhanced, while the VSSR to a distracting object is suppressed. In contrast, the effect of attention on the auditory steady-state response (ASSR) is inconsistent across studies. However, most auditory studies analyzed results at the sensor level or used only a small number of equivalent current dipoles to fit cortical responses. In addition, most studies of auditory spatial attention used dichotic stimuli (independent signals at the ears) rather than more natural, binaural stimuli. Here, we asked whether these methodological choices help explain discrepant results. Listeners attended to one of two competing speech streams, one simulated from the left and one from the right, that were modulated at different frequencies. Using distributed source modeling of magnetoencephalography results, we estimate how spatially directed attention modulates the ASSR in neural regions across the whole brain. Attention enhances the ASSR power at the frequency of the attended stream in contralateral auditory cortex. The attended-stream modulation frequency also drives phase-locked responses in the left (but not right) precentral sulcus (lPCS), a region implicated in control of eye gaze and visual spatial attention. Importantly, this region shows no phase locking to the distracting stream. Results suggest that the lPCS in engaged in an attention-specific manner. Modeling results that take account of the geometry and phases of the cortical sources phase locked to the two streams (including hemispheric asymmetry of lPCS activity) help to explain why past ASSR studies of auditory spatial attention yield seemingly contradictory results.

The American bullfrog (Rana catesbeiana) has an amphibian papilla (AP) that senses airborne, low-frequency sound and generates distortion-product otoacoustic emissions (DPOAEs) similar to other vertebrate species. Although ranid frogs are typically found in noisy environments, the effects of noise on the AP have not been studied. First, we determined the noise levels that diminished DPOAE at 2f1-f2 using an f2 stimulus level at 80 dB SPL and that also produced morphological damage of the sensory epithelium. Second, we compared DPOAE (2f1-f2) responses with histopathologic changes occurring in bullfrogs after noise exposure. Consistent morphological damage such as fragmented hair cells and missing bundles as well as elimination of DPOAE responses were seen only after very high-level (>150 dB SPL) sound exposures. The morphological response of hair cells to noise differed along the mediolateral AP axis: medial hair cells were sensitive to noise and lateral hair cells were relatively insensitive to noise. Renewed or repaired hair cells were not observed until 9 days post exposure. Following noise exposure, DPOAE responses disappeared within 24 hours and then recovered to normal pre-exposure levels within 3 – 4 days. Our results suggest that DPOAEs in the bullfrog are sensitive to the initial period of hair cell damage. After noise-induce damage, the bullfrog AP has functional recovery mechanisms that do not depend on substantial hair cell regeneration or repair. Thus, the bullfrog auditory system might serve as an interesting model for investigations of ways to prevent noise damage.

The precedence effect is a prerequisite for faithful sound localization in a complex auditory environment, and is a physiological phenomenon in which the auditory system selectively suppresses the directional information from echoes. Here we investigated how neurons in the inferior colliculus respond to the paired sounds that produce precedence-effect illusions, and whether their firing behavior can be modulated through inhibition with gamma-aminobutyric acid (GABA). We recorded extracellularly from 36 neurons in rat inferior colliculus under three conditions: no injection, injection with saline, and injection with gamma-aminobutyric acid. The paired sounds that produced precedence effects were two identical 4-ms noise bursts, which were delivered contralaterally or ipsilaterally to the recording site. The normalized neural responses were measured as a function of different inter-stimulus delays and half-maximal interstimulus delays were acquired. Neuronal responses to the lagging sounds were weak when the inter-stimulus delay was short, but increased gradually as the delay was lengthened. Saline injection produced no changes in neural responses, but after local gamma-aminobutyric acid application, responses to the lagging stimulus were suppressed. Application of gamma-aminobutyric acid affected the normalized response to lagging sounds, independently of whether they or the paired sounds were contralateral or ipsilateral to the recording site. These observations suggest that local inhibition by gamma-aminobutyric acid in the rat inferior colliculus shapes the neural responses to lagging sounds, and modulates the precedence effect.

Aging is often accompanied by hearing loss, which impacts how sounds are processed and represented along the ascending auditory pathways and within the auditory cortices. Here, we assess the impact of mild binaural hearing loss on the older adults' ability to both process complex sounds embedded in noise and to segregate a mistuned harmonic in an otherwise periodic stimulus. We measured auditory evoked fields (AEFs) using magnetoencephalography while participants were presented with complex tones that had either all harmonics in tune or had the third harmonic mistuned by 4 or 16% of its original value. The tones (75 dB sound pressure level, SPL) were presented without, with low (45 dBA SPL), or with moderate (65 dBA SPL) Gaussian noise. For each participant, we modeled the AEFs with a pair of dipoles in the superior temporal plane. We then examined the effects of hearing loss and noise on the amplitude and latency of the resulting source waveforms. In the present study, results revealed that similar noise-induced increases in N1m were present in older adults with and without hearing loss. Our results also showed that the P1m amplitude was larger in the hearing impaired than in the normal-hearing adults. In addition, the object-related negativity (ORN) elicited by the mistuned harmonic was larger in hearing impaired listeners. The enhanced P1m and ORN amplitude in the hearing impaired older adults suggests that hearing loss increased neural excitability in auditory cortices, which could be related to deficits in inhibitory control.

Noise-induced hearing loss (NIHL) is a major public health issue worldwide. Uncovering the early molecular events associated with NIHL would reveal mechanisms leading to the hearing loss. Our aim is to investigate the immediate molecular responses after different levels of noise exposure and identify the common and distinct pathways that mediate NIHL. Previous work showed mice exposed to 116 decibels sound pressure level (dB SPL) broadband noise for 1 h had greater threshold shifts than the mice exposed to 110 dB SPL broadband noise, hence we used these two noise levels in this study. Groups of 4-8-week-old CBA/CaJ mice were exposed to no noise (control) or to broadband noise for 1 h, followed by transcriptome analysis of total cochlear RNA isolated immediately after noise exposure. Previously identified and novel genes were found in all data sets. Following exposure to noise at 116 dB SPL, the earliest responses included up-regulation of 243 genes and down-regulation of 61 genes, while a similar exposure at 110 dB SPL up-regulated 155 genes and down-regulated 221 genes. Bioinformatics analysis indicated that mitogen-activated protein kinase (MAPK) signaling was the major pathway in both levels of noise exposure. Nevertheless, both qualitative and quantitative differences were noticed in some MAPK signaling genes, after exposure to different noise levels. Cacna1b , Cacna1g , and Pla2g6 , related to calcium signaling were down-regulated after 110 dB SPL exposure, while the fold increase in the expression of Fos was relatively lower than what was observed after 116 dB SPL exposure. These subtle variations provide insight on the factors that may contribute to the differences in NIHL despite the activation of a common pathway.

We have previously shown that adenosine amine congener (ADAC), a selective A 1 adenosine receptor agonist, can ameliorate noise- and cisplatin-induced cochlear injury. Here we demonstrate the dose-dependent rescue effects of ADAC on noise-induced cochlear injury in a rat model and establish the time window for treatment. Methods . ADAC (25–300 μ g/kg) was administered intraperitoneally to Wistar rats (8–10 weeks old) at intervals (6–72 hours) after exposure to traumatic noise (8–16 kHz, 110 dB sound pressure level, 2 hours). Hearing sensitivity was assessed using auditory brainstem responses (ABR) before and 12 days after noise exposure. Pharmacokinetic studies investigated ADAC concentrations in plasma after systemic (intravenous) administration. Results . ADAC was most effective in the first 24 hours after noise exposure at doses > 50 μ g/kg, providing up to 21 dB protection (averaged across 8–28 kHz). Pharmacokinetic studies demonstrated a short (5 min) half-life of ADAC in plasma after intravenous administration without detection of degradation products. Conclusion . Our data show that ADAC mitigates noise-induced hearing loss in a dose- and time-dependent manner, but further studies are required to establish its translation as a clinical otological treatment.

Chronic tinnitus is a debilitating condition and often accompanied by anxiety, depression, and sleep disturbance. It has been suggested that sleep disturbance, such as insomnia, may be a risk factor/predictor for tinnitus-related distress and the two conditions may share common neurobiological mechanisms. This study investigated whether acute stress-induced sleep disturbance could increase the susceptibility to acoustic trauma-induced tinnitus in rats. The animals were exposed to unilateral acoustic trauma 24 h before sleep disturbance being induced using the cage exchange method. Tinnitus perception was assessed behaviourally using a conditioned lick suppression paradigm 3 weeks after the acoustic trauma. Changes in the orexin system in the hypothalamus, which plays an important role in maintaining long-lasting arousal, were also examined using immunohistochemistry. Cage exchange resulted in a significant reduction in the number of sleep episodes and acoustic trauma-induced tinnitus with acoustic features similar to a 32 kHz tone at 100 dB. However, sleep disturbance did not exacerbate the perception of tinnitus in rats. Neither tinnitus alone nor tinnitus plus sleep disturbance altered the number of orexin-expressing neurons. The results suggest that acute sleep disturbance does not cause long-term changes in the number of orexin neurons and does not change the perception of tinnitus induced by acoustic trauma in rats.

Glass micropipettes are widely used to record neural activity from single neurons or clusters of neurons extracellularly in live animals. However, to date, there has been no comprehensive study of noise in extracellular recordings with glass micropipettes. The purpose of this work was to assess various noise sources that affect extracellular recordings and to create model systems in which novel micropipette neural amplifier designs can be tested. An equivalent circuit of the glass micropipette and the noise model of this circuit, which accurately describe the various noise sources involved in extracellular recordings, have been developed. Measurement schemes using dead brain tissue as well as extracellular recordings from neurons in the inferior colliculus, an auditory brain nucleus of an anesthetized gerbil, were used to characterize noise performance and amplification efficacy of the proposed micropipette neural amplifier. According to our model, the major noise sources which influence the signal to noise ratio are the intrinsic noise of the neural amplifier and the thermal noise from distributed pipette resistance. These two types of noise were calculated and measured and were shown to be the dominating sources of background noise for in vivo experiments.