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Dichotic pitches are perceptual illusions created centrally through binaural interactions that offer an opportunity to test theories of pitch and binaural hearing. Here we show that binaural neurons in auditory midbrain encode the frequency of two salient types of dichotic pitches via specific features in the pattern of firing rates along the tonotopic axis. This is the first combined single-unit and modeling study of responses of auditory neurons to stimuli evoking a dichotic pitch.

Although pitch is closely related to temporal periodicity, stimuli with a degree of temporal irregularity can evoke a pitch sensation in human listeners. However, the neural mechanisms underlying pitch perception for irregular sounds are poorly understood. Here, we recorded responses of single units in the inferior colliculus (IC) of normal hearing (NH) rabbits to acoustic pulse trains with different amounts of random jitter in the inter-pulse intervals and compared with responses to electric pulse trains delivered through a cochlear implant (CI) in a different group of rabbits. In both NH and CI animals, many IC neurons demonstrated tuning of firing rate to the average pulse rate (APR) that was robust against temporal jitter, although jitter tended to increase the firing rates for APRs ≥ 1280 Hz. Strength and limiting frequency of spike synchronization to stimulus pulses were also comparable between periodic and irregular pulse trains, although there was a slight increase in synchronization at high APRs with CI stimulation. There were clear differences between CI and NH animals in both the range of APRs over which firing rate tuning was observed and the prevalence of synchronized responses. These results suggest that the pitches of regular and irregular pulse trains are coded differently by IC neurons depending on the APR, the degree of irregularity, and the mode of stimulation. In particular, the temporal pitch produced by periodic pulse trains lacking spectral cues may be based on a rate code rather than a temporal code at higher APRs.

Cochlear implant (CI) users with a prelingual onset of hearing loss show poor sensitivity to interaural time differences (ITDs), an important cue for sound localization and speech reception in noise. Similarly, neural ITD sensitivity in the inferior colliculus (IC) of neonatally-deafened animals is degraded compared with animals deafened as adults. Here, we show that chronic bilateral CI stimulation during development can partly reverse the effect of early-onset deafness on ITD sensitivity. The prevalence of ITD sensitive neurons was restored to the level of adult-deaf (AD) rabbits in the early-deaf rabbits of both sexes that received chronic stimulation and behavioral training with wearable bilateral sound processors during development. We also found a partial improvement in neural ITD sensitivity in the early-deaf and stimulated rabbits compared with unstimulated rabbits. In contrast, chronic CI stimulation did not improve temporal coding in early-deaf rabbits. The present study is the first report showing functional restoration of ITD sensitivity with CI stimulation in single neurons and highlights the importance of auditory experience during development on the maturation of binaural circuitry.SIGNIFICANCE STATEMENTAlthough cochlear implants (CI) are highly successful in providing speech reception in quiet for many profoundly deaf people, CI users still face difficulty in noisy everyday environment. This is partly because of their poor sensitivity to differences in the timing of sounds arriving at the two ears [interaural time differences (ITDs)], which help to identify where the sound is coming from. This problem is especially acute in those who lost hearing early in life. Here, we present the first report that sensitivity of auditory neurons to ITDs is restored by CI stimulation during development in an animal model of neonatal deafness. These findings highlight the importance of providing early binaural auditory experience with CIs in deaf children.

Reverberation is ubiquitous in everyday acoustic environments. It degrades both binaural cues and the envelope modulations of sounds and thus can impair speech perception. Still, both humans and animals can accurately perceive reverberant stimuli in most everyday settings. Previous neurophysiological and perceptual studies have suggested the existence of neural mechanisms that partially compensate for the effects of reverberation. However, these studies were limited by their use of either highly simplified stimuli or rudimentary reverberation simulations. To further characterize how reverberant stimuli are processed by the auditory system, we recorded single-unit (SU) and multiunit (MU) activity from the inferior colliculus (IC) of unanesthetized rabbits in response to natural speech utterances presented with no reverberation (“dry”) and in various degrees of simulated reverberation (direct-to-reverberant energy ratios (DRRs) ranging from 9.4 to –8.2 dB). Linear stimulus reconstruction techniques (Mesgarani et al., 2009) were used to quantify the amount of speech information available in the responses of neural ensembles. We found that high-quality spectrogram reconstructions could be obtained for dry speech and in moderate reverberation from ensembles of 25 units. However, spectrogram reconstruction quality deteriorated in severe reverberation for both MUs and SUs such that the neural degradation paralleled the degradation in the stimulus spectrogram. Furthermore, spectrograms reconstructed from responses to reverberant stimuli resembled spectrograms of reverberant speech better than spectrograms of dry speech. Overall, the results provide no evidence for a dereverberation mechanism in neural responses from the rabbit IC when studied with linear reconstruction techniques.

The pitch of harmonic complex tones (HCT) plays important roles in speech and music perception and in the perceptual organization of sound. Human listeners rely primarily on the spectral pattern of harmonics individually resolved by the frequency analysis in the cochlea to derive a pitch percept. Yet, evidence for a robust neural representation of resolved harmonics in animal models has been elusive, and some species appear to rely on temporal envelope cues rather than on resolved harmonics to discriminate pitch. We performed both behavioral experiments on pitch discrimination by rabbits and single-unit recordings from the auditory nerve (AN) and inferior colliculus (IC) using HCTs with equal-amplitude harmonics in which the fundamental frequency (F0) was varied over a wide range. We found that rabbits can discriminate the pitch of HCT using the spectral pattern of resolved harmonics for F0s within the range of conspecific vocalizations. Correspondingly, many IC neurons contribute to a rate-place code for the frequencies of resolved harmonics for F0s >500 Hz, and this code is more robust to variations in stimulus level than that found in the AN. A remaining challenge is to identify the neural mechanisms underlying enhanced rate-place coding in IC. [Work supported by NIH-NIDCD DC002258.]

The pitch of harmonic complex tones (HCTs) common in speech, music, and animal vocalizations plays a key role in the perceptual organization of sound. Unraveling the neural mechanisms of pitch perception requires animal models, but little is known about complex pitch perception by animals, and some species appear to use different pitch mechanisms than humans. Here, we tested rabbits’ ability to discriminate the fundamental frequency (F0) of HCTs with missing fundamentals, using a behavioral paradigm inspired by foraging behavior in which rabbits learned to harness a spatial gradient in F0 to find the location of a virtual target within a room for a food reward. Rabbits were initially trained to discriminate HCTs with F0s in the range 400–800 Hz and with harmonics covering a wide frequency range (800–16,000 Hz) and then tested with stimuli differing in spectral composition to test the role of harmonic resolvability (experiment 1) or in F0 range (experiment 2) or in both F0 and spectral content (experiment 3). Together, these experiments show that rabbits can discriminate HCTs over a wide F0 range (200–1,600 Hz) encompassing the range of conspecific vocalizations and can use either the spectral pattern of harmonics resolved by the cochlea for higher F0s or temporal envelope cues resulting from interaction between unresolved harmonics for lower F0s. The qualitative similarity of these results to human performance supports the use of rabbits as an animal model for studies of pitch mechanisms, providing species differences in cochlear frequency selectivity and F0 range of vocalizations are taken into account. NEW & NOTEWORTHY Understanding the neural mechanisms of pitch perception requires experiments in animal models, but little is known about pitch perception by animals. Here we show that rabbits, a popular animal in auditory neuroscience, can discriminate complex sounds differing in pitch using either spectral cues or temporal cues. The results suggest that the role of spectral cues in pitch perception by animals may have been underestimated by predominantly testing low frequencies in the range of human voice.

Users of cochlear implant (CI) face challenges in everyday situations such as understanding conversations in noise, even with CIs in both ears. These challenges are related to difficulties with tasks that require fine temporal processing such as discrimination of pulse rates or interaural time differences (ITD), a major cue for sound localization. The degradation in temporal processing and ITD sensitivity are especially acute in those who lost hearing in early childhood. Here, we characterized temporal coding and ITD sensitivity of single neurons in a novel animal model of early-onset deafness. Rabbits were deafened as neonates and deprived of auditory stimulation until they reached adult age when single-unit recordings from the auditory midbrain were made chronically using an unanesthetized preparation. The results are compared to measurements from adult-deafened rabbits with normal auditory development to understand the effect of early-onset deafness on neural temporal coding and ITD sensitivity. Neurons in the inferior colliculus (IC) of early-deafened rabbits were less likely to show sustained, excitatory responses to pulse train stimulation and more likely to show suppressive responses compared to neurons in adult-deaf animals. Fewer neurons showed synchronized responses to pulse trains at any rate in the early-deaf group. In addition, fewer neurons showed significant ITD sensitivity in their overall firing rate in the early-deaf group compared to adult-deaf animals. Neural ITD discrimination thresholds in the early-deaf group were poorer than thresholds in adult-deaf group, especially at high pulse rates. The overall degradation in neural ITD sensitivity is consistent with the difficulties encountered by human CI users with early-onset hearing loss. These results lay the groundwork for investigating whether the degradations in temporal coding and ITD sensitivity observed in early-deaf animals can be reversed by appropriate CI stimulation during development.

Harmonic complex tones (HCTs) commonly occurring in speech and music evoke a strong pitch at their fundamental frequency (F0), especially when they contain harmonics individually resolved by the cochlea. When all frequency components of an HCT are shifted by the same amount, the pitch of the resulting inharmonic tone (IHCT) can also shift, although the envelope repetition rate is unchanged. A rate-place code, whereby resolved harmonics are represented by local maxima in firing rates along the tonotopic axis, has been characterized in the auditory nerve and primary auditory cortex, but little is known about intermediate processing stages. We recorded single-neuron responses to HCT and IHCT with varying F0 and sound level in the inferior colliculus (IC) of unanesthetized rabbits of both sexes. Many neurons showed peaks in firing rate when a low-numbered harmonic aligned with the neuron's characteristic frequency, demonstrating “rate-place” coding. The IC rate-place code was most prevalent for F0 > 800 Hz, was only moderately dependent on sound level over a 40 dB range, and was not sensitive to stimulus harmonicity. A spectral receptive-field model incorporating broadband inhibition better predicted the neural responses than a purely excitatory model, suggesting an enhancement of the rate-place representation by inhibition. Some IC neurons showed facilitation in response to HCT relative to pure tones, similar to cortical “harmonic template neurons” (Feng and Wang, 2017), but to a lesser degree. Our findings shed light on the transformation of rate-place coding of resolved harmonics along the auditory pathway.SIGNIFICANCE STATEMENTHarmonic complex tones are ubiquitous in speech and music and produce strong pitch percepts when they contain frequency components that are individually resolved by the cochlea. Here, we characterize a “rate-place” code for resolved harmonics in the auditory midbrain that is more robust across sound levels than the peripheral rate-place code and insensitive to the harmonic relationships among frequency components. We use a computational model to show that inhibition may play an important role in shaping the rate-place code. Our study fills a major gap in understanding the transformations in neural representations of resolved harmonics along the auditory pathway.

Bilateral cochlear implant (CI) users have poor perceptual sensitivity to interaural time differences (ITDs), which limits their ability to localize sounds and understand speech in noisy environments. This is especially true for high-rate (> 300 pps) periodic pulse trains, which are used as carriers in CI processors. Here, we investigate a novel stimulation strategy in which extra pulses are added to high-rate periodic pulse trains to introduce short inter-pulse intervals (SIPIs). We hypothesized that SIPIs can improve neural ITD sensitivity similarly to the effect observed by randomly jittering IPIs (Hancock et al., J. Neurophysiol. 108:714–28, 2012). To test this hypothesis, we measured ITD sensitivity of single units in the inferior colliculus (IC) of unanesthetized rabbits with bilateral CIs. Introducing SIPIs into high-rate pulse trains significantly increased firing rates for ~ 60 % of IC neurons, and the extra spikes tended to be synchronized to the SIPIs. The additional firings produced by SIPIs uncovered latent ITD sensitivity that was comparable to that observed with low-rate pulse trains. In some neurons, high spontaneous firing rates masked the ITD sensitivity introduced by SIPIs. ITD sensitivity in these neurons could be revealed by emphasizing stimulus-synchronized spikes with a coincidence detection analysis. Overall, these results with SIPIs are consistent with the effects observed previously with jittered pulse trains, with the added benefit of retaining control over the timing and number of SIPIs. A novel CI processing strategy could incorporate SIPIs by inserting them at selected times to high-rate pulse train carriers. Such a strategy could potentially improve ITD perception without degrading speech intelligibility and thereby improve outcomes for bilateral CI users.

Common envelope-based stimulation strategies for cochlear implants (CIs) use relatively high carrier rates in order to properly encode the speech envelope. For such rates, CI listeners show poor sensitivity to interaural time differences (ITDs), which are important for horizontal-plane sound localization and spatial unmasking of speech. Based on the findings from previous studies, we predicted that ITD sensitivity can be enhanced by including pulses with short interpulse intervals (SIPIs), to a 1000-pulses-per-second (pps) reference pulse train. We measured the sensitivity of eight bilateral CI listeners to ITD while systematically varying both the rate at which SIPIs are introduced (“SIPI rate”) and the time interval between the two pulses forming a SIPI (“SIPI fraction”). Results showed largely enhanced ITD sensitivity relative to the reference condition, with the size of the improvement increasing with decreasing SIPI rate and decreasing SIPI fraction. For the lowest SIPI fraction, insertion of extra pulses brought ITD sensitivity to the level measured for low-rate pulse trains with rates matching the SIPI rates. The results appear promising for the goal of enhancing ITD sensitivity with envelope-based CI strategies by inserting SIPI pulses at strategic times in speech stimuli.

Introduction Le GRAINS, groupe de réflexion sur les AINS, est composé d’experts pluridisciplinaire hospitalier et de ville qui regroupe plusieurs médecins spécialistes. Il s’est constitué en vue de réfléchir sur le bon usage des anti-inflammatoires non-stéroïdiens (AINS) dans le contexte de la pandémie de COVID-19, et est soutenu par GlaxoSmithKline Santé Grand Public. Les travaux effectués par le GRAINS ont été publiés dans une revue de littérature exhaustive. L’objectif du GRAINS est d’avoir une discussion ouverte sur l’utilisation des AINS dans la gestion de la douleur dans le contexte de la COVID-19 et des infections en général, considérant les progrès réalisés dans la production de connaissances et les preuves de la littérature scientifique. Matériels et méthodes Ce groupe pluridisciplinaire d’experts constitué de rhumatologues, infectiologues, pédiatre, médecin généraliste, pharmacologue et pharmaciens, a pointé l’inquiétude et le manque d’informations énoncés par les patients à leur pharmacien. Les experts du GRAINS se sont réunis au travers de différentes assemblées et se sont accordés sur la nécessité de mettre à disposition des professionnels de santé une information synthétique de la littérature scientifique et des outils pour vulgariser cette information pour le grand public. La revue de littérature réalisée par les experts du GRAINS porte sur plus de 40 études internationales récentes concernant l’utilisation des AINS dans un contexte de la COVID-19. Résultats Le recours aux anti-inflammatoires non stéroïdiens (AINS) en général, et à l’ibuprofène en particulier, n’expose pas à un risque accru de la Covid-19 ni à des formes grave de cette infection. Discussion Encourager la discussion sur le bon usage des AINS en automédication. Les experts pointent l’inquiétude et le manque d’information énoncés par les patients à leur pharmacien. Par leur action ils souhaitent alerter sur les risques liés au surdosage d’alternatives aux AINS en particulier dans le traitement de la fièvre et de la douleur. Ils encouragent à ne pas se priver davantage de l’arsenal thérapeutique des AINS et militent pour une utilisation raisonnée de ces traitements. Conclusion Il n’existe actuellement aucune preuve scientifique établissant un lien entre l’ibuprofène et l’aggravation de l’infection due au SARS-CoV-2.

Binaural cues occurring in natural environments are frequently time varying, either from the motion of a sound source or through interactions between the cues produced by multiple sources. Yet, a broad understanding of how the auditory system processes dynamic binaural cues is still lacking. In the current study, we directly compared neural responses in the inferior colliculus (IC) of unanesthetized rabbits to broadband noise with time-varying interaural time differences (ITD) with responses to noise with sinusoidal amplitude modulation (SAM) over a wide range of modulation frequencies. On the basis of prior research, we hypothesized that the IC, one of the first stages to exhibit tuning of firing rate to modulation frequency, might use a common mechanism to encode time-varying information in general. Instead, we found weaker temporal coding for dynamic ITD compared with amplitude modulation and stronger effects of adaptation for amplitude modulation. The differences in temporal coding of dynamic ITD compared with SAM at the single-neuron level could be a neural correlate of “binaural sluggishness,” the inability to perceive fluctuations in time-varying binaural cues at high modulation frequencies, for which a physiological explanation has so far remained elusive. At ITD-variation frequencies of 64 Hz and above, where a temporal code was less effective, noise with a dynamic ITD could still be distinguished from noise with a constant ITD through differences in average firing rate in many neurons, suggesting a frequency-dependent tradeoff between rate and temporal coding of time-varying binaural information. NEW & NOTEWORTHY Humans use time-varying binaural cues to parse auditory scenes comprising multiple sound sources and reverberation. However, the neural mechanisms for doing so are poorly understood. Our results demonstrate a potential neural correlate for the reduced detectability of fluctuations in time-varying binaural information at high speeds, as occurs in reverberation. The results also suggest that the neural mechanisms for processing time-varying binaural and monaural cues are largely distinct.

Harmonic complex tones (HCTs) found in speech, music, and animal vocalizations evoke strong pitch percepts at their fundamental frequencies. The strongest pitches are produced by HCTs that contain harmonics resolved by cochlear frequency analysis, but HCTs containing solely unresolved harmonics also evoke a weaker pitch at their envelope repetition rate (ERR). In the auditory periphery, neurons phase lock to the stimulus envelope, but this temporal representation of ERR degrades and gives way to rate codes along the ascending auditory pathway. To assess the role of the inferior colliculus (IC) in such transformations, we recorded IC neuron responses to HCT and sinusoidally modulated broadband noise (SAMN) with varying ERR from unanesthetized rabbits. Different interharmonic phase relationships of HCT were used to manipulate the temporal envelope without changing the power spectrum. Many IC neurons demonstrated band-pass rate tuning to ERR between 60 and 1,600 Hz for HCT and between 40 and 500 Hz for SAMN. The tuning was not related to the pure-tone best frequency of neurons but was dependent on the shape of the stimulus envelope, indicating a temporal rather than spectral origin. A phenomenological model suggests that the tuning may arise from peripheral temporal response patterns via synaptic inhibition. We also characterized temporal coding to ERR. Some IC neurons could phase lock to the stimulus envelope up to 900 Hz for either HCT or SAMN, but phase locking was weaker with SAMN. Together, the rate code and the temporal code represent a wide range of ERR, providing strong cues for the pitch of unresolved harmonics. NEW & NOTEWORTHY Envelope repetition rate (ERR) provides crucial cues for pitch perception of frequency components that are not individually resolved by the cochlea, but the neural representation of ERR for stimuli containing many harmonics is poorly characterized. Here we show that the pitch of stimuli with unresolved harmonics is represented by both a rate code and a temporal code for ERR in auditory midbrain neurons and propose possible underlying neural mechanisms with a computational model.

Harmonic complex tones (HCT) commonly occurring in speech and music evoke a strong pitch at their fundamental frequency (F0), especially when they contain harmonics individually resolved by the cochlea. When all frequency components of an HCT are shifted by the same amount, the pitch of the resulting inharmonic tone (IHCT) also shifts although the envelope repetition rate is unchanged. A rate-place code whereby resolved harmonics are represented by local maxima in firing rates along the tonotopic axis has been characterized in the auditory nerve and primary auditory cortex, but little is known about intermediate processing stages. We recorded single neuron responses to HCT and IHCT with varying F0 and sound level in the inferior colliculus (IC) of unanesthetized rabbits. Many neurons showed peaks in firing rates when a low-numbered harmonic aligned with the neuron’s characteristic frequency, demonstrating “rate-place” coding. The IC rate-place code was most prevalent for F0>800 Hz, was only moderately dependent on sound level over a 40 dB range, and was not sensitive to stimulus harmonicity. A spectral receptive-field model incorporating broadband inhibition better predicted the neural responses than a purely excitatory model, suggesting an enhancement of the rate-place representation by inhibition. Some IC neurons showed facilitation in response to HCT, similar to cortical “harmonic template neurons” (Feng and Wang 2017), but to a lesser degree. Our findings shed light on the transformation of rate-place coding of resolved harmonics along the auditory pathway, and suggest a gradual emergence of harmonic templates from low to high processing centers.Significance statementHarmonic complex tones are ubiquitous in speech and music and produce strong pitch percepts in human listeners when they contain frequency components that are individually resolved by the cochlea. Here, we characterize a “rate-place” code for resolved harmonics in the auditory midbrain that is more robust across sound levels than the peripheral rate-place code and insensitive to the harmonic relationships among frequency components. We use a computational model to show that inhibition may play an important role in shaping the rate-place code. We also show that midbrain auditory neurons can demonstrate similar properties as cortical harmonic template neurons. Our study fills a gap in understanding the transformation in neural representations of resolved harmonics along the auditory pathway.

Cochlear implant (CI) users with a pre-lingual onset of hearing loss show poor sensitivity to interaural time differences (ITD), an important cue for sound localization and speech reception in noise. Similarly, neural ITD sensitivity in the inferior colliculus (IC) of neonatally-deafened animals is degraded compared to animals deafened as adults. Here, we show that chronic bilateral CI stimulation during development can partly reverse the effect of early-onset deafness on ITD sensitivity. The prevalence of ITD sensitive neurons was restored to the level of adult-deaf rabbits in the early-deaf rabbits that received chronic stimulation with wearable bilateral sound processors during development. In contrast, chronic CI stimulation did not improve temporal coding in early-deaf rabbits. The present study is the first report showing functional restoration of ITD sensitivity with CI stimulation in single neurons and highlights the importance of auditory experience during development.

While motion is important for parsing a complex auditory scene into perceptual objects, how it is encoded in the auditory system is unclear. Perceptual studies suggest that the ability to identify the direction of motion is limited by the duration of the moving sound, yet we can detect changes in interaural differences at even shorter durations. To understand the source of these distinct temporal limits, we recorded from single units in the inferior colliculus (IC) of unanesthetized rabbits in response to noise stimuli containing a brief segment with linearly time-varying interaural time difference (“ITD sweep”) temporally embedded in interaurally uncorrelated noise. We also tested the ability of human listeners to either detect the ITD sweeps or identify the motion direction. Using a point-process model to separate the contributions of stimulus dependence and spiking history to single-neuron responses, we found that the neurons respond primarily by following the instantaneous ITD rather than exhibiting true direction selectivity. Furthermore, using an optimal classifier to decode the single-neuron responses, we found that neural threshold durations of ITD sweeps for both direction identification and detection overlapped with human threshold durations even though the average response of the neurons could track the instantaneous ITD beyond psychophysical limits. Our results suggest that the IC does not explicitly encode motion direction, but internal neural noise may limit the speed at which we can identify the direction of motion. NEW & NOTEWORTHY Recognizing motion and identifying an object’s trajectory are important for parsing a complex auditory scene, but how we do so is unclear. We show that neurons in the auditory midbrain do not exhibit direction selectivity as found in the visual system but instead follow the trajectory of the motion in their temporal firing patterns. Our results suggest that the inherent variability in neural firings may limit our ability to identify motion direction at short durations.

At lower levels of sensory processing, the representation of a stimulus feature in the response of a neural population can vary in complex ways across different stimulus intensities, potentially changing the amount of feature-relevant information in the response. How higher-level neural circuits could implement feature decoding computations that compensate for these intensity-dependent variations remains unclear. Here we focused on neurons in the inferior colliculus (IC) of unanesthetized rabbits, whose firing rates are sensitive to both the azimuthal position of a sound source and its sound level. We found that the azimuth tuning curves of an IC neuron at different sound levels tend to be linear transformations of each other. These transformations could either increase or decrease the mutual information between source azimuth and spike count with increasing level for individual neurons, yet population azimuthal information remained constant across the absolute sound levels tested (35, 50, and 65 dB SPL), as inferred from the performance of a maximum-likelihood neural population decoder. We harnessed evidence of level-dependent linear transformations to reduce the number of free parameters in the creation of an accurate cross-level population decoder of azimuth. Interestingly, this decoder predicts monotonic azimuth tuning curves, broadly sensitive to contralateral azimuths, in neurons at higher levels in the auditory pathway.