Auditory Research publications

Auditory cortex is essential for mammals, including rodents, to detect temporal "shape" cues in the sound envelope but it remains unclear how different cortical fields may contribute to this ability (Lomber and Malhotra, 2008; Threlkeld et al., 2008). Previously, we found that precise spiking patterns provide a potential neural code for temporal shape cues in the sound envelope in the primary auditory (A1), and ventral auditory field (VAF) and caudal suprarhinal auditory field (cSRAF) of the rat (Lee et al., 2016). Here, we extend these findings and characterize the time course of the temporally precise output of auditory cortical neurons in male rats. A pairwise sound discrimination index and a Naive Bayesian classifier are used to determine how these spiking patterns could provide brain signals for behavioral discrimination and classification of sounds. We find response durations and optimal time constants for discriminating sound envelope shape increase in rank order with: A1 < VAF < cSRAF. Accordingly, sustained spiking is more prominent and results in more robust sound discrimination in non-primary cortex versus A1. Spike-timing patterns classify 10 different sound envelope shape sequences and there is a twofold increase in maximal performance when pooling output across the neuron population indicating a robust distributed neural code in all three cortical fields. Together, these results support the idea that temporally precise spiking patterns from primary and non-primary auditory cortical fields provide the necessary signals for animals to discriminate and classify a large range of temporal shapes in the sound envelope.SIGNIFICANCE STATEMENT Functional hierarchies in the visual cortices support the concept that classification of visual objects requires successive cortical stages of processing including a progressive increase in classical receptive field size. The present study is significant as it supports the idea that a similar progression exists in auditory cortices in the time domain. We demonstrate for the first time that three cortices provide temporal spiking patterns for robust temporal envelope shape discrimination but only the ventral non-primary cortices do so on long time scales. This study raises the possibility that primary and non-primary cortices provide unique temporal spiking patterns and time scales for perception of sound envelope shape.

Neurons in sensory cortex are tuned to diverse features in natural scenes. But what determines which features neurons become selective to? Here we explore the idea that neuronal selectivity is optimized to represent features in the recent sensory past that best predict immediate future inputs. We tested this hypothesis using simple feedforward neural networks, which were trained to predict the next few moments of video or audio in clips of natural scenes. The networks developed receptive fields that closely matched those of real cortical neurons in different mammalian species, including the oriented spatial tuning of primary visual cortex, the frequency selectivity of primary auditory cortex and, most notably, their temporal tuning properties. Furthermore, the better a network predicted future inputs the more closely its receptive fields resembled those in the brain. This suggests that sensory processing is optimized to extract those features with the most capacity to predict future input.

Loudness dependence of auditory evoked potentials (LDAEP) is a widely used EEG-based biomarker for central serotonergic activity. Serotonin has been shown to be associated with different psychiatric disorders such as depression and schizophrenia. Despite its clinical significance, the underlying neurochemical mechanism of this promising marker is not fully understood, and further research is needed to improve its validity. Other neurotransmitters might have a significant impact on this measure. Thus, we assessed the inhibitory action through individual GABA/H20 concentrations and GABA/glutamate ratios by means of magnetic resonance spectroscopy at 3T in healthy subjects. The measurements were assessed in the primary auditory cortex to investigate the association with the LDAEP, whose generators are mainly in the primary auditory cortex. For the first time, this study examines the link between GABAergic neurotransmission and LDAEP, and the data preliminary show that GABA may not contribute to the generation of EEG-based LDAEP.

The brainstem’s lateral superior olive (LSO) is thought to be crucial for localizing high-frequency sounds by coding interaural sound level differences (ILD). Its neurons weigh contralateral inhibition against ipsilateral excitation, making their firing rate a function of the azimuthal position of a sound source. Since the very first in vivo recordings, LSO principal neurons have been reported to give sustained and temporally integrating ‘chopper’ responses to sustained sounds. Neurons with transient responses were observed but largely ignored and even considered a sign of pathology. Using the Mongolian gerbil as a model system, we have obtained the first in vivo patch clamp recordings from labeled LSO neurons and find that principal LSO neurons, the most numerous projection neurons of this nucleus, only respond at sound onset and show fast membrane features suggesting an importance for timing. These results provide a new framework to interpret previously puzzling features of this circuit.

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.

Sensory deprivation during development induces lifelong changes to central nervous system function that are associated with perceptual impairments. However, the relationship between neural and behavioral deficits is uncertain due to a lack of simultaneous measurements during task performance. Therefore, we telemetrically recorded from auditory cortex neurons in gerbils reared with developmental conductive hearing loss as they performed an auditory task in which rapid fluctuations in amplitude are detected. These data were compared to a measure of auditory brainstem temporal processing from each animal. We found that developmental HL diminished behavioral performance, but did not alter brainstem temporal processing. However, the simultaneous assessment of neural and behavioral processing revealed that perceptual deficits were associated with a degraded cortical population code that could be explained by greater trial-to-trial response variability. Our findings suggest that the perceptual limitations that attend early hearing loss are best explained by an encoding deficit in auditory cortex.

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.

In speech, the highly flexible modulation of vocal pitch creates intonation patterns that speakers use to convey linguistic meaning. This human ability is unique among primates. Here, we used high-density cortical recordings directly from the human brain to determine the encoding of vocal pitch during natural speech. We found neural populations in bilateral dorsal laryngeal motor cortex (dLMC) that selectively encoded produced pitch but not non-laryngeal articulatory movements. This neural population controlled short pitch accents to express prosodic emphasis on a word in a sentence. Other larynx cortical representations controlling voicing and longer pitch phrase contours were found at separate sites. dLMC sites also encoded vocal pitch during a non-speech singing task. Finally, direct focal stimulation of dLMC evoked laryngeal movements and involuntary vocalization, confirming its causal role in feedforward control. Together, these results reveal the neural basis for the voluntary control of vocal pitch in human speech. VIDEO ABSTRACT.

Audible alarms are a ubiquitous feature of all high-paced, high-risk domains such as aviation and nuclear power where operators control complex systems. In such settings, a missed alarm can have disastrous consequences. It is conventional wisdom that for alarms to be heard, “louder is better,” so that alarm levels in operational environments routinely exceed ambient noise levels. Through a robust experimental paradigm in an anechoic environment to study human response to audible alerting stimuli in a cognitively demanding setting, akin to high-tempo and high-risk domains, clinician participants responded to patient crises while concurrently completing an auditory speech intelligibility and visual vigilance distracting task as the level of alarms were varied as a signal-to-noise ratio above and below hospital background noise. There was little difference in performance on the primary task when the alarm sound was −11 dB below background noise as compared with +4 dB above background noise—a typical real-world situation. Concurrent presentation of the secondary auditory speech intelligibility task significantly degraded performance. Operator performance can be maintained with alarms that are softer than background noise. These findings have widespread implications for the design and implementation of alarms across all high-consequence settings.

A vast array of motor skills can be maintained throughout life. Do these behaviors require stability of individual neuron tuning or can the output of a given circuit remain constant despite fluctuations in single cells? This question is difficult to address due to the variability inherent in most motor actions studied in the laboratory. A notable exception, however, is the courtship song of the adult zebra finch, which is a learned, highly precise motor act mediated by orderly dynamics within premotor neurons of the forebrain. By longitudinally tracking the activity of excitatory projection neurons during singing using two-photon calcium imaging, we find that both the number and the precise timing of song-related spiking events remain nearly identical over the span of several weeks to months. These findings demonstrate that learned, complex behaviors can be stabilized by maintaining precise and invariant tuning at the level of single neurons.

Cochlear synaptopathy, i.e. the loss of auditory-nerve connections with cochlear hair cells, is seen in aging, noise damage, and other types of acquired sensorineural hearing loss. Because the subset of auditory-nerve fibers with high thresholds and low spontaneous rates (SRs) is disproportionately affected, audiometric thresholds are relatively insensitive to this primary neural degeneration. Although suprathreshold amplitudes of wave I of the auditory brainstem response (ABR) are attenuated in synaptopathic mice, there is not yet a robust diagnostic in humans. The middle-ear muscle reflex (MEMR) might be a sensitive metric (Valero et al., 2016), because low-SR fibers may be important drivers of the MEMR (Liberman and Kiang, 1984; Kobler et al., 1992). Here, to test the hypothesis that narrowband reflex elicitors can identify synaptopathic cochlear regions, we measured reflex growth functions in unanesthetized mice with varying degrees of noise-induced synaptopathy and in unexposed controls. To separate effects of the MEMR from those of the medial olivocochlear reflex, the other sound-evoked cochlear feedback loop, we used a mutant mouse strain with deletion of the acetylcholine receptor required for olivocochlear function. We demonstrate that the MEMR is normal when activated from non-synaptopathic cochlear regions, is greatly weakened in synaptopathic regions, and is a more sensitive indicator of moderate synaptopathy than the suprathreshold amplitude of ABR wave I.

Ultrasound (US) can noninvasively activate intact brain circuits, making it a promising neuromodulation technique. However, little is known about the underlying mechanism. Here, we apply transcranial US and perform brain mapping studies in guinea pigs using extracellular electrophysiology. We find that US elicits extensive activation across cortical and subcortical brain regions. However, transection of the auditory nerves or removal of cochlear fluids eliminates the US-induced activity, revealing an indirect auditory mechanism for US neural activation. Our findings indicate that US activates the ascending auditory system through a cochlear pathway, which can activate other non-auditory regions through cross-modal projections. This cochlear pathway mechanism challenges the idea that US can directly activate neurons in the intact brain, suggesting that future US stimulation studies will need to control for this effect to reach reliable conclusions.

When speaking, we dynamically coordinate movements of our jaw, tongue, lips, and larynx. To investigate the neural mechanisms underlying articulation, we used direct cortical recordings from human sensorimotor cortex while participants spoke natural sentences that included sounds spanning the entire English phonetic inventory. We used deep neural networks to infer speakers' articulator movements from produced speech acoustics. Individual electrodes encoded a diversity of articulatory kinematic trajectories (AKTs), each revealing coordinated articulator movements toward specific vocal tract shapes. AKTs captured a wide range of movement types, yet they could be differentiated by the place of vocal tract constriction. Additionally, AKTs manifested out-and-back trajectories with harmonic oscillator dynamics. While AKTs were functionally stereotyped across different sentences, context-dependent encoding of preceding and following movements during production of the same phoneme demonstrated the cortical representation of coarticulation. Articulatory movements encoded in sensorimotor cortex give rise to the complex kinematics underlying continuous speech production. VIDEO ABSTRACT.

Music and language are two intricately linked communication modalities in humans. A deficit in music pitch processing as manifested in the condition of congenital amusia has been related to difficulties in lexical tone processing for both tone and non-tonal languages. However, it is still unclear whether amusia also affects the perception of vowel phonemes in quiet and in noise. In this study, we examined vowel-plus-tone identification in quiet and noise conditions among Mandarin-speaking amusics with and without speech tone difficulties (tone agnosics and pure amusics, respectively), and IQ- and age-matched controls. Overall, pure amusics showed vowel and tone identification comparable to the controls in both quiet and noise conditions. Compared to pure amusics and controls, tone agnosics showed deficits in tone perception in both quiet and noise conditions. More importantly, their vowel perception was lower than pure amusics and controls in noise conditions, e.g., at a signal-to-noise ratio of -4 dB, although they showed normal-like performance in quiet and at a signal-to-noise ratio of -8 dB. These results suggest that when amusia affected speech tone processing (e.g., tone agnosics), it could also compromise vowel processing in noise. However, amusia alone does not affect tone or vowel perception in Mandarin Chinese either in quiet or in noise. Overall, the current study highlights the necessity of taking heterogeneity within the amusic group into account when considering the related speech deficits in this group.

Introduction: Exposure to gamma-aminobutyric acid-mimetics and N-methyl-D-aspartate-receptor antagonists during pregnancy may lead to hearing loss and long-term behavioral abnormalities in the offspring. The purpose of this study was to explore the association between prenatal exposure to sevoflurane (SEV) anesthesia and hearing impairment in mice. Materials and methods: On gestational day 15, pregnant Kunming mice were exposed for 2 hours to 2.5% SEV plus 100% oxygen (anesthesia group) or 100% oxygen alone (control group). Results: During auditory brainstem response testing on P30, offspring of the anesthesia group mice exhibited higher hearing thresholds at 8, 16, 24, and 32 kHz; longer peak latency of wave II at all four frequencies; and longer interpeak latencies from waves II to V at 16, 24, and 32 kHz, compared to the control offspring. Caspase-3, iNOS, and COX-2 activation occurred in the fetal cochlea of the anesthesia group. Mitochondrial swelling was observed in the anesthesia group offspring at P1 and P15. Conclusion: Our results suggest that SEV exposure during pregnancy may cause detrimental effects on the developing auditory system.

Introduction It is known that an interruption of acoustic input in early life will result in abnormal development of the auditory system. Here, we further show that this negative impact actually spans beyond the auditory system to the hippocampus, a system critical for spatial memory. Methods We induced a temporary conductive hearing loss (TCHL) in P14 rats by perforating the eardrum and allowing it to heal. The Morris water maze and Y‐maze tests were deployed to evaluate spatial memory of the rats. Electrophysiological recordings and anatomical analysis were made to evaluate functional and structural changes in the hippocampus following TCHL. Results The rats with the TCHL had nearly normal hearing at P42, but had a decreased performance with the Morris water maze and Y‐maze tests compared with the control group. A functional deficit in the hippocampus of the rats with the TCHL was found as revealed by the depressed long‐term potentiation and the reduced NMDA receptor‐mediated postsynaptic current. A structural deficit in the hippocampus of those animals was also found as revealed the abnormal expression of the NMDA receptors, the decreased number of dendritic spines, the reduced postsynaptic density and the reduced level of neurogenesis. Conclusions Our study demonstrates that even temporary auditory sensory deprivation in early life of rats results in abnormal development of the hippocampus and consequently impairs spatial memory in adulthood.

It is well known that auditory experience during early development shapes response properties of auditory cortex (AC) neurons, influencing, for example, tonotopical arrangement, response thresholds and strength, or frequency selectivity. Here, we show that rearing rat pups in a complex acoustically enriched environment leads to an increased reliability of responses of AC neurons, affecting both the rate and the temporal codes. For a repetitive stimulus, the neurons exhibit a lower spike count variance, indicating a more stable rate coding. At the level of individual spikes, the discharge patterns of individual neurons show a higher degree of similarity across stimulus repetitions. Furthermore, the neurons follow more precisely the temporal course of the stimulus, as manifested by improved phase-locking to temporally modulated sounds. The changes are persistent and present up to adulthood. The results document that besides basic alterations of receptive fields presented in our previous study, the acoustic environment during the critical period of postnatal development also leads to a decreased stochasticity and a higher reproducibility of neuronal spiking patterns.

Cochlear inflammatory response to various environmental insults, including acoustic and ototoxic overexposures, has been increasingly become a topic of interest. As the immune response is associated with both pathology and protection, targeting specific components of the immune response is expected to dissect the relationships between cellular damage and inflammation-associated protection and repair in the cochlea. Duffy antigen receptor for chemokines (DARC) is a member of a group of atypical chemokine receptors, and essential for chemokine-regulated leukocyte/neutrophil trafficking during inflammation. Previous studies have reported that Darc deficiency alters chemokine bioavailability and leukocyte homeostasis, leading to significant anti-inflammatory effects in tissues following injury. In this study, we have used Darc knockout mice to determine the impact of a deficiency in this gene on cochlear development, as well as function in cochlea subjected to various stresses. We observed that DARC is not required for normal development of cochlear function, as evidenced by typical hearing sensitivity in juvenile Darc-KO mice, as compared to wild type (WT) C57BL/6 mice. However, Darc-KO mice exhibited improved hearing recovery after intense noise exposure when compared to wild-type. The auditory brainstem response (ABR) threshold shift between KO and WT mice was most obvious at 1-week post-noise exposure. At cochlear locations above the frequency range of the energy band of damaging noise, both hair cell survival and ribbon synapse density were improved in Darc deficient animals. In addition, the mRNA levels of some major inflammatory effectors, including Mcp-1 and Gdf15, were altered in Darc-KO mice compared to control mice at 1, 3 and 7 days post-noise exposure. These data collectively suggest that the normal Darc-dependent inflammatory response slows down the process of hearing recovery, and exacerbates cellular damage in the cochlea after noise exposure.

Neurons in the auditory cortex exhibit distinct frequency tuning to the onset and offset of sounds, but the cause and significance of ON and OFF receptive field (RF) organisation are not understood. Here we demonstrate that distinct ON and OFF frequency tuning is largely absent in immature mouse auditory cortex and is thus a consequence of cortical development. Simulations using a novel implementation of a standard Hebbian plasticity model show that the natural alternation of sound onset and offset is sufficient for the formation of non-overlapping adjacent ON and OFF RFs in cortical neurons. Our model predicts that ON/OFF RF arrangement contributes towards direction selectivity to frequency-modulated tone sweeps, which we confirm by neuronal recordings. These data reveal that a simple and universally accepted learning rule can explain the organisation of ON and OFF RFs and direction selectivity in the developing auditory cortex.

Auditory nerve fibers (ANFs) encode pure tones through two modes of coding, spike time and spike rate, depending on the tone frequency. In response to a low-frequency tone, ANF firing is phase locked to the sinusoidal waveform. Because time coding vanishes with an increase in the tone frequency, high-frequency tone coding relies on the spike rate of the ANFs. Adding a continuous broadband noise to a tone compresses the rate intensity function of ANFs and shifts its dynamic range toward higher intensities. Therefore, the ANFs with high-threshold/low-spontaneous rate (SR) are thought to contribute to behavioral tone detection in noise. However, this theory relies on the discharge rate of the ANFs. The direct comparison with the masking threshold through spike timing, irrespective of the spontaneous rate, has not so far been investigated. Taking advantage of a unique proxy to quantify the spike synchrony (i.e., the shuffle autocorrelogram), we show in female gerbils that high-SR ANFs are more adapted to encode low-frequency thresholds through temporal code, giving them a strong robustness in noise. By comparing behavioral thresholds measured using prepulse inhibition of the acoustical startle reflex with population thresholds calculated from ANFs pooled per octave band, we show that threshold-based spike timing provides a better estimate of behavioral thresholds in the low-frequency range, whereas the high-frequency behavioral thresholds rely on the spiking rate, particularly in noise. This emphasizes the complementarity of temporal and rate modes to code tone-in-noise thresholds over a large range of frequencies.SIGNIFICANCE STATEMENT There is a general agreement that high-threshold/low-spontaneous rate (SR) auditory nerve fibers (ANFs) are of prime importance for tone detection in noise. However, this theory is based on the discharge rate of the fibers. Comparing the behavioral thresholds and single ANF thresholds shows that this is only true in the high-frequency range of tone stimulations. In the low-frequency range of tones (up to 2.7 kHz in the gerbil), the most sensitive ANFs (high-SR fibers) carry neural information through a spike-timing mode, even for noise in which tones do not induce a noticeable increment in the spike rate. This emphasizes the interplay between spike-time and spike-rate modes in the auditory nerve to encode tone-in-noise threshold over a large range of tone frequencies.