Publications using the PA5

Differences in ear of presentation and level do not prevent effective integration of concurrent speech cues such as formant frequencies. For example, presenting the higher formants of a consonant-vowel syllable in the opposite ear to the first formant protects them from upward spread of masking, allowing them to remain effective speech cues even after substantial attenuation. This study used three-formant (F1+F2+F3) analogues of natural sentences and extended the approach to include competitive conditions. Target formants were presented dichotically (F1+F3; F2), either alone or accompanied by an extraneous competitor for F2 (i.e., F1±F2C+F3; F2) that listeners must reject to optimize recognition. F2C was created by inverting the F2 frequency contour and using the F2 amplitude contour without attenuation. In experiment 1, F2C was always absent and intelligibility was unaffected until F2 attenuation exceeded 30 dB; F2 still provided useful information at 48-dB attenuation. In experiment 2, attenuating F2 by 24 dB caused considerable loss of intelligibility when F2C was present, but had no effect in its absence. Factors likely to contribute to this interaction include informational masking from F2C acting to swamp the acoustic-phonetic information carried by F2, and interaural inhibition from F2C acting to reduce the effective level of F2.

Pitch is a fundamental attribute of auditory perception. The interaction of concurrent pitches gives rise to a sensation that can be characterized by its degree of consonance or dissonance. In this work, we propose that human auditory cortex (AC) processes pitch and consonance through a common neural network mechanism operating at early cortical levels. First, we developed a new model of neural ensembles incorporating realistic neuronal and synaptic parameters to assess pitch processing mechanisms at early stages of AC. Next, we designed a magnetoencephalography (MEG) experiment to measure the neuromagnetic activity evoked by dyads with varying degrees of consonance or dissonance. MEG results show that dissonant dyads evoke a pitch onset response (POR) with a latency up to 36 ms longer than consonant dyads. Additionally, we used the model to predict the processing time of concurrent pitches; here, consonant pitch combinations were decoded faster than dissonant combinations, in line with the experimental observations. Specifically, we found a striking match between the predicted and the observed latency of the POR as elicited by the dyads. These novel results suggest that consonance processing starts early in human auditory cortex and may share the network mechanisms that are responsible for (single) pitch processing.

Hearing loss has been implicated as a risk factor for schizophrenia, but it is not known whether this association arises from common etiology, top-down influences (e.g., social isolation), bottom-up neurobiological mechanisms, or combinations of these factors. Patients with 22q11.2 Deletion Syndrome (22q11.2DS) have a 25-30% risk of developing schizophrenia, and also suffer frequent hearing loss. Here, we used the Df1 /+ mouse model of 22q11.2DS to investigate the relationship between hearing loss and susceptibility to schizophrenia-relevant brain and behavioral abnormalities. Df1 /+ mice have a multi-gene deletion analogous to the chromosomal microdeletion that causes human 22q11.2DS, and like human 22q11.2DS patients exhibit high rates of hearing loss arising primarily from susceptibility to middle ear inflammation. We found that hearing loss in Df1 /+ mice affected schizophrenia-relevant endophenotypes, including electrophysiological measures of central auditory gain and behavioral measures of auditory sensorimotor gating. Moreover, PV+ inhibitory interneurons, another marker for schizophrenia pathology, were significantly reduced in density in auditory cortex but not secondary motor cortex of Df1 /+ mice with hearing loss. These results reveal bottom-up neurobiological mechanisms through which peripheral hearing loss arising from the 22q11.2 deletion may promote the emergence of schizophrenia-relevant auditory brain and behavioral abnormalities, and also suggest a link between conductive hearing loss and reduced PV+ interneuron density in the auditory cortex. SIGNIFICANCE STATEMENT Hearing loss is a known risk factor for schizophrenia. Deletion of chromosomal locus 22q11.2 is associated with both schizophrenia and hearing loss in humans. In the Df1 /+ mouse model of human 22q11.2 Deletion Syndrome, we find that hearing loss shapes measures that are considered schizophrenia-relevant endophenotypes, such as central auditory gain and auditory sensorimotor gating. Moreover, we report a reduction in density of PV+ inhibitory interneurons in the auditory cortex, but not secondary motor cortex, of Df1 /+ mice with hearing loss. These results suggest mechanisms through which hearing loss associated with the 22q11.2 deletion may promote emergence of schizophrenia-relevant auditory brain and behavioral abnormalities and indicate that conductive hearing loss may influence PV+ interneuron density in the auditory cortex.

Based on anatomical connectivity and basic response characteristics, primate auditory cortex is divided into a central core surrounded by belt and parabelt regions. The encoding of pitch, a prototypical element of sound identity, has been studied in primary auditory cortex (A1) but little is known about how it is encoded and represented beyond A1. The caudal auditory belt and parabelt cortical fields process spatial information but also contain information on non-spatial aspects of sounds. In this study, we examined neuronal responses in these areas to pitch-varied marmoset vocalizations, to derive the consequent representation of pitch in these regions and the potential underlying mechanisms, to compare to the encoding and representation of pitch of the same sounds in A1. With respect to response patterns to the vocalizations, neurons in caudal medial belt (CM) showed similar short-latency and short-duration response patterns to A1, but caudal lateral belt (CL) neurons at the same hierarchical level and caudal parabelt (CPB) neurons at a higher hierarchical level showed delayed or much delayed response onset and prolonged response durations. With respect to encoding of pitch, neurons in all cortical fields showed sensitivity to variations in the vocalization pitch either through modulation of spike-count or of first spike-latency. The utility of the encoding mechanism differed between fields: pitch sensitivity was reliably represented by spike-count variations in A1 and CM, while first spike-latency variation was better for encoding pitch in CL and CPB. In summary, our data show that (a) the traditionally-defined belt area CM is functionally very similar to A1 with respect to the representation and encoding of complex naturalistic sounds, (b) the CL belt area, at the same hierarchical level as CM, and the CPB area, at a higher hierarchical level, have very different response patterns and appear to use different pitch-encoding mechanisms, and (c) caudal auditory fields, proposed to be specialized for encoding spatial location, can also contain robust representations of sound identity.

It is well-known that outer hair cell (OHC) loss occurs in the cochlea of animal models of permanent hearing loss induced by intense noise exposure. Our earlier studies demonstrated the production of hydroxynonenal and peroxynitrite, as well as the disruption of gap junction-mediated intercellular communication (GJIC), in the cochlear spiral ligament prior to noise-induced sudden hearing loss. The goal of the present study was to evaluate the mechanism underlying cochlear OHC loss after sudden hearing loss induced by intense noise exposure. In organ of Corti explant cultures from mice, no significant OHC loss was observed after in vitro exposure to 4-hydroxynonenal (a product of lipid peroxidation), H2O2, SIN-1 (peroxynitrite generator), and carbenoxolone (a gap junction inhibitor). Interestingly, in vivo intracochlear carbenoxolone injection through the posterior semicircular canal caused marked OHC and hearing loss, as well as the disruption of gap junction-mediated intercellular communication in the cochlear spiral ligament. However, no significant OHC loss was observed in vivo in animals treated with 4-hydroxynonenal and SIN-1. Taken together, our data suggest that disruption of GJIC in the cochlear lateral wall structures is an important cause of cochlear OHC loss in models of hearing loss, including those induced by noise.

Evaluation of patients who are unable to provide behavioral responses on standard clinical measures is challenging due to the lack of standard objective (non-behavioral) clinical audiological measures that assess the outcome of an intervention (e.g., hearing aids). Brainstem responses to short consonant-vowel stimuli (speech-auditory brainstem responses [speech-ABRs]) have been proposed as a measure of subcortical encoding of speech, speech detection, and speech-in-noise performance in individuals with normal hearing. Here, we investigated the potential application of speech-ABRs as an objective clinical outcome measure of speech detection, speech-in-noise detection and recognition, and self-reported speech understanding in 98 adults with sensorineural hearing loss. We compared aided and unaided speech-ABRs, and speech-ABRs in quiet and in noise. In addition, we evaluated whether speech-ABR F0 encoding (obtained from the complex cross-correlation with the 40 ms [da] fundamental waveform) predicted aided behavioral speech recognition in noise or aided self-reported speech understanding. Results showed that (a) aided speech-ABRs had earlier peak latencies, larger peak amplitudes, and larger F0 encoding amplitudes compared to unaided speech-ABRs; (b) the addition of background noise resulted in later F0 encoding latencies but did not have an effect on peak latencies and amplitudes or on F0 encoding amplitudes; and (c) speech-ABRs were not a significant predictor of any of the behavioral or self-report measures. These results show that speech-ABR F0 encoding is not a good predictor of speech-in-noise recognition or self-reported speech understanding with hearing aids. However, our results suggest that speech-ABRs may have potential for clinical application as an objective measure of speech detection with hearing aids.

The medial olivocochlear reflex (MOCR) has been implicated in several auditory processes. The putative role of the MOCR in improving speech perception in noise is particularly relevant for children who complain of listening difficulties (LiD). The hypothesis that the MOCR may be impaired in individuals with LiD or auditory processing disorder has led to several investigations but without consensus. In two related studies, we compared the MOCR functioning of children with LiD and typically developing (TD) children in the same age range (7–17 years). In Study 1, we investigated ipsilateral, contralateral, and bilateral MOCR using forward-masked click-evoked otoacoustic emissions (CEOAEs; n = 17 TD, 17 LiD). In Study 2, we employed three OAE types: CEOAEs ( n = 16 TD, 21 LiD), stimulus frequency OAEs ( n = 21 TD, 30 LiD), and distortion product OAEs ( n = 17 TD, 22 LiD) in a contralateral noise paradigm. Results from both studies suggest that the MOCR functioning is not significantly different between the two groups. Some likely reasons for differences in findings among published studies could stem from the lack of strict data quality measures (e.g., high signal-to-noise ratio, control for the middle ear muscle reflex) that were enforced in the present study. The inherent variability of the MOCR, the subpar reliability of current MOCR methods, and the heterogeneity in auditory processing deficits that underlie auditory processing disorder make detecting clinically relevant differences in MOCR function impractical using current methods.

Psychophysical methods similar to those employed with bats were used to examine jittered echo-delay resolution in bottlenose dolphins (Tursiops truncatus). Two dolphins were trained to produce echolocation clicks and report a change from electronic echoes with a fixed delay of ~ 12.6 ms (~ 9.4 m simulated range) to echoes with delays that alternated (jittered) between successive emitted signals. Jitter delays varied from 0 to 50 µs. Jittered echo-delay thresholds were between 1 and 2 µs-the lowest achievable (non-zero) values with the hardware configuration. Error functions matched the click autocorrelation function near zero jitter delay, and were well within the envelope of the autocorrelation function; however, measured jitter delay thresholds were larger than predictions for a coherent or semicoherent receiver at comparable signal-to-noise ratios. When one of the two alternating jittered echoes was inverted in polarity, both dolphins reliably discriminated echoes at all jittered echo delays, including 0 µs (i.e., only jittering in polarity, not delay). Finally, both dolphins used unusual patterns of click emissions, where groups of echolocation clicks were interspersed with silent gaps. Further tests with sub-microsecond jitter values and various echo signal-to-noise ratios would be necessary for proper direct comparison with jitter detection values obtained for bats.

Stream segregation for a test sequence comprising high-frequency (H) and low-frequency (L) pure tones, presented in a galloping rhythm, is much greater when preceded by a constant-frequency induction sequence matching one subset than by an inducer configured like the test sequence; this difference persists for several seconds. It has been proposed that constant-frequency inducers promote stream segregation by capturing the matching subset of test-sequence tones into an on-going, pre-established stream. This explanation was evaluated using 2-s induction sequences followed by longer test sequences (12–20 s). Listeners reported the number of streams heard throughout the test sequence. Experiment 1 used LHL– sequences and one or other subset of inducer tones was attenuated (0–24 dB in 6-dB steps, and ∞). Greater attenuation usually caused a progressive increase in segregation, towards that following the constant-frequency inducer. Experiment 2 used HLH– sequences and the L inducer tones were raised or lowered in frequency relative to their test-sequence counterparts (ΔfI = 0, 0.5, 1.0, or 1.5 × ΔfT). Either change greatly increased segregation. These results are concordant with the notion of attention switching to new sounds but contradict the stream-capture hypothesis, unless a “proto-object” corresponding to the continuing subset is assumed to form during the induction sequence.

The primary data are the impulse responses that were recorded in an echoic environment, using a set of twelve loudspeakers and a microphone. They were used as a part of an acoustic calibration process of large environments, as presented by Kazakov and Nelken (DOI: 10.1016/j.jneumeth.2018.08.025; Kazakov and Nelken, 2018). The impulse responses can be also used to localize the microphone in 3D (multi-lateration). The required audio files and the MATLAB code allows a complete reproduction of the experiment.

Many aspects of stress-induced physiological and psychological effects have been characterized in people and animals. However, stress effects on the auditory system are less explored and their mechanisms are not well-understood, in spite of its relevance for a variety of diseases, including tinnitus. To expedite further research of stress-induced changes in the auditory system, here we compare the reactions to stress among Wistar and Lewis rats. The animals were stressed for 24 h, and subsequently we tested the functionality of the outer hair cells (OHCs) using distortion product otoacoustic emissions (DPOAEs) and auditory neurons using evoked auditory brainstem responses (ABR). Lastly, using Western blot, we analyzed the levels of plasticity-related proteins in the inferior colliculus, confirming that the inferior colliculus is involved in the adaptive changes that occur in the auditory system upon stress exposure. Surprisingly, the two strains reacted to stress quite differently: Lewis rats displayed a lowering of their auditory threshold, whereas it was increased in Wistar rats. These functional differences were seen in OHCs of the apical region (low frequencies) and in the auditory neurons (across several frequencies) from day 1 until 2 weeks after the experimental stress ended. Wistar and Lewis rats may thus provide models for auditory threshold increase and decrease, respectively, which can both be observed in different patients in response to stress.

Frequency tuning and phase-locking are two fundamental properties generated in the cochlea, enabling but also limiting the coding of sounds by the auditory nerve (AN). In humans, these limits are unknown, but high resolution has been postulated for both properties. Electrophysiological recordings from the AN of normal-hearing volunteers indicate that human frequency tuning, but not phase-locking, exceeds the resolution observed in animal models.

To function as a mechanism in premating isolation, the divergent and species-specific calling songs of acoustic insects must be reliably processed by the afferent auditory pathway of receivers. Here, we analysed the responses of interneurons in a katydid species that uses long-lasting acoustic trills and compared these with previously reported data for homologous interneurons of a sympatric species that uses short chirps as acoustic signals. Some interneurons of the trilling species respond exclusively to the heterospecific chirp due to selective, low-frequency tuning and "novelty detection". These properties have been considered as evolutionary adaptations in the sensory system of the chirper, which allow it to detect signals effectively during the simultaneous calling of the sympatric sibling species. We propose that these two mechanisms, shared by the interneurons of both species, did not evolve in the chirper to guarantee its ability to detect the chirp under masking conditions. Instead we suggest that chirpers evolved an additional, 2-kHz component in their song and exploited pre-existing neuronal properties for detecting their song under masking noise. The failure of some interneurons to respond to the conspecific song in trillers does not prevent intraspecific communication, as other interneurons respond to the trill.

Plasticity of thalamocortical (TC) synapses is robust during early development and becomes limited in the adult brain. We previously reported that a short duration of deafening strengthens TC synapses in the primary visual cortex (V1) of adult mice. Here, we demonstrate that deafening restores NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) of TC synapses onto principal neurons in V1 layer 4 (L4), which is accompanied by an increase in NMDAR function. In contrast, deafening did not recover long-term depression (LTD) at TC synapses. Potentiation of TC synapses by deafening is absent in parvalbumin-positive (PV+) interneurons, resulting in an increase in feedforward excitation to inhibition (E/I) ratio. Furthermore, we found that a brief duration of deafening adult mice recovers rapid ocular dominance plasticity (ODP) mainly by accelerating potentiation of the open-eye responses. Our results suggest that cross-modal sensory deprivation promotes adult cortical plasticity by specifically recovering TC-LTP and increasing the E/I ratio.

Hyperbilirubinemia (jaundice) is caused by raised levels of unconjugated bilirubin in the blood. When severe, susceptible brain regions including the cerebellum and auditory brainstem are damaged causing neurological sequelae such as ataxia, hearing loss and kernicterus. The mechanism(s) by which bilirubin exerts its toxic effect have not been completely understood to date. In this study we investigated the acute mechanisms by which bilirubin causes the neurotoxicity that contributes to hearing loss. We developed a novel mouse model that exhibits the neurological features seen in human Bilirubin-Induced Neurological Dysfunction (BIND) syndrome that we assessed with a behavioural score and auditory brainstem responses (ABR). Guided by initial experiments applying bilirubin to cultured cells in vitro, we performed whole genome gene expression measurements on mouse brain tissue (cerebellum and auditory brainstem) following bilirubin exposure to gain mechanistic insights into biochemical processes affected, and investigated further using immunoblotting. We then compared the gene changes induced by bilirubin to bacterial lipopolysaccharide (LPS), a well characterized inducer of neuroinflammation, to assess the degree of similarity between them. Finally, we examined the extent to which genetic perturbation of inflammation and both known and novel anti-inflammatory drugs could protect hearing from bilirubin-induced toxicity. The in vitro results indicated that bilirubin induces changes in gene expression consistent with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). These gene changes were similar to the gene expression signature of thapsigargin-a known ER stress inducer. It also induced gene expression changes associated with inflammation and NF-κB activation. The in vivo model showed behavioural impairment and a raised auditory threshold. Whole genome gene expression analysis confirmed inflammation as a key mechanism of bilirubin neurotoxicity in the auditory pathway and shared gene expression hallmarks induced by exposure to bacterial lipopolysaccharide (LPS) a well-characterized inducer of neuroinflammation. Interestingly, bilirubin caused more severe damage to the auditory system than LPS in this model, but consistent with our hypothesis of neuroinflammation being a primary part of bilirubin toxicity, the hearing loss was protected by perturbing the inflammatory response. This was carried out genetically using lipocalin-2 (LCN2)-null mice, which is an inflammatory cytokine highly upregulated in response to bilirubin. Finally, we tested known and novel anti-inflammatory compounds (interfering with NF-κB and TNFα signalling), and also demonstrated protection of the auditory system from bilirubin toxicity. We have developed a novel, reversible, model for jaundice that shows movement impairment and auditory loss consistent with human symptoms. We used this model to establish ER-stress and inflammation as major contributors to bilirubin toxicity. Because of the rapid and reversible onset of toxicity in this novel model it represents a system to screen therapeutic compounds. We have demonstrated this by targeting inflammation genetically and with anti-inflammatory small molecules that offered protection against bilirubin toxicity. This also suggests that anti-inflammatory drugs could be of therapeutic use in hyperbilirubinemia.

Cisplatin, a small platinum-containing molecule, is a widely used, highly effective anticancer drug. However, severe side effects have been found in cancer patients treated with cisplatin, including nephrotoxicity, neurotoxicity, and ototoxicity. These cisplatin-induced side effects can have a major impact on patient quality of life, including social development problems in pediatric patients that develop hearing loss. Previous studies have suggested that the major cause of cisplatin-induced ototoxicity is abnormal accumulation of reactive oxygen species (ROS) and oxidative stress. Alpha-lipoic acid (ALA), one of the most effective antioxidants, is known to be involved in the cellular antioxidant system and may have a protective effect on cisplatin-induced ototoxicity. However, the therapeutic effect of ALA on damaged hearing function and its detailed mechanism of action are not fully understood. This study focused on determining whether ALA has a potential as a protective and/or therapeutic agent for cisplatin-induced ototoxicity. Histological and physiological analyses were performed using cisplatin-treated mouse cochlea and HEI-OC1 culture cells in pre- and post-treatment with ALA in vitro and in vivo. We found that ALA contributes to protecting mitochondrial function by preventing ROS accumulation and inhibiting apoptotic cell death. Importantly, post-treatment with ALA consistently showed an almost equal restorative effect to pretreatment, in vitro and in vivo, supporting the possible use of ALA as a therapeutic agent for cisplatin-induced ototoxicity. This study is the first report on a strong therapeutic potential of ALA to rescue ototoxic hearing loss caused by cisplatin, and our data provide key evidence that ALA may act as a reducing agent for glutathione disulfide to increase glutathione levels on behalf of glutathione reductase. This result was consistent in both cultured cells and the mouse model, which improves the clinical value of ALA for therapy of cisplatin-induced ototoxicity.

Noise exposure is one of the most common causes of hearing loss and peripheral damage to the auditory system. A growing literature suggests that the auditory system can compensate for peripheral loss through increased central neural activity. The current study sought to investigate the link between noise exposure, increases in central gain, synaptic reorganization, and auditory function. All axons of the auditory nerve project to the cochlear nucleus, making it a requisite nucleus for sound detection. As the first synapse in the central auditory system, the cochlear nucleus is well positioned to respond plastically to loss of peripheral input. To investigate noise-induced compensation in the central auditory system, we measured auditory brainstem responses (ABRs) and auditory perception and collected tissue from mice exposed to broadband noise. Noise-exposed mice showed elevated ABR thresholds, reduced ABR wave 1 amplitudes, and spiral ganglion neuron loss. Despite peripheral damage, noise-exposed mice were hyperreactive to loud sounds and showed nearly normal behavioral sound detection thresholds. Ratios of late ABR peaks (2–4) relative to the first ABR peak indicated that brainstem pathways were hyperactive in noise-exposed mice, while anatomical analysis indicated there was an imbalance between expression of excitatory and inhibitory proteins in the ventral cochlear nucleus. The results of the current study suggest that a reorganization of excitation and inhibition in the ventral cochlear nucleus may drive hyperactivity in the central auditory system. This increase in central gain can compensate for peripheral loss to restore some aspects of auditory function.

Two synchronous sounds at different locations in the midsagittal plane induce a fused percept at a weighted-average position, with weights depending on relative sound intensities. In the horizontal plane, sound fusion (stereophony) disappears with a small onset asynchrony of 1–4 ms. The leading sound then fully determines the spatial percept (the precedence effect). Given that accurate localisation in the median plane requires an analysis of pinna-related spectral-shape cues, which takes ~25–30 ms of sound input to complete, we wondered at what time scale a precedence effect for elevation would manifest. Listeners localised the first of two sounds, with spatial disparities between 10–80 deg, and inter-stimulus delays between 0–320 ms. We demonstrate full fusion (averaging), and largest response variability, for onset asynchronies up to at least 40 ms for all spatial disparities. Weighted averaging persisted, and gradually decayed, for delays >160 ms, suggesting considerable backward masking. Moreover, response variability decreased with increasing delays. These results demonstrate that localisation undergoes substantial spatial blurring in the median plane by lagging sounds. Thus, the human auditory system, despite its high temporal resolution, is unable to spatially dissociate sounds in the midsagittal plane that co-occur within a time window of at least 160 ms.

Deviance sensitivity is the specific response to a surprising stimulus, one that violates expectations set by the past stimulation stream. In audition, deviance sensitivity is often conflated with stimulus-specific adaptation (SSA), the decrease in responses to a common stimulus that only partially generalizes to other, rare stimuli. SSA is usually measured using oddball sequences, where a common (standard) tone and a rare (deviant) tone are randomly intermixed. However, the larger responses to a tone when deviant does not necessarily represent deviance sensitivity. Deviance sensitivity is commonly tested using a control sequence in which many different tones serve as the standard, eliminating the expectations set by the standard ('deviant among many standards'). When the response to a tone when deviant (against a single standard) is larger than the responses to the same tone in the control sequence, it is concluded that true deviance sensitivity occurs. In primary auditory cortex of anesthetized rats, responses to deviants and to the same tones in the control condition are comparable in size. We recorded local field potentials and multiunit activity from the auditory cortex of awake, freely moving rats, implanted with 32-channel drivable microelectrode arrays and using telemetry. We observed highly significant SSA in the awake state. Moreover, the responses to a tone when deviant were significantly larger than the responses to the same tone in the control condition. These results establish the presence of true deviance sensitivity in primary auditory cortex in awake rats.