Auditory Neurophysiology publications

Aging and noise over-exposure lead to complex mixtures of cochlear degradation that impair the structure and function of outer hair cells, inner hair cells (IHCs), and the cochlear nerve. However, IHC damage and cochlear synaptopathy (CS) remain pathologies “hidden” from the audiogram. This study aimed to identify and differentiate the physiological signatures of these two distinct pathologies using promising non-invasive assays: Envelope Following Responses (EFRs), Auditory Brainstem Response (ABRs), Wideband middle-ear reflexes (WB-MEMRs), and Distortion Product Otoacoustic Emissions (DPOAEs). We utilized chinchilla models of carboplatin-induced (CA) IHC damage (N = 4) and temporary threshold shift (TTS) noise-induced CS (N = 4) to compare the physiological signatures of each pathology. While both groups showed unchanged ABR thresholds two weeks after exposure, EFRs, ABR Wave V/I ratios, and MEMRs showed distinct effects of exposure. Despite non-elevated ABR-derived audiometric thresholds after exposure, both CA and TTS exposure resulted in severe in EFR “peakiness”, particularly for sharp, short-duty-cycle stimuli and significant elevations in ABR Wave V/I ratios. However, these findings were less-pronounced in the TTS-exposed animals. WB-MEMR amplitudes were decreased with elevated thresholds in both groups; this effect was more pronounced in the TTS group. Opposite trends in DPOAE amplitudes indicated that while both IHC damage and CS result in similar suprathreshold temporal coding deficits, effects on outer-hair-cell integrity and auditory efferent physiology may differ between the two pathologies. Future work and novel diagnostics should aim to distinguish these specific cochlear pathologies in clinical populations, or at the very least consider their overlap. Highlights A multi-metric diagnostic approach was used with chinchilla models of inner-hair-cell (IHC) damage and cochlear synaptopathy (CS). IHC damage and synaptopathy both cause suprathreshold deficits “hidden” from the audiogram. IHC damage results in more severe temporal envelope coding degradation than does synaptopathy. A combination of EFR “peakiness”, ABR Wave V/I ratio, and Wideband Middle Ear Muscle Reflex (WB-MEMR) appear to be useful measures for profiling IHC damage and CS.

The superior para-olivary nucleus (SPN or SPON) is a prominent nucleus in the superior olivary complex of the auditory brainstem. The cellular composition of the nucleus reportedly differs between species, but a prominent recurring feature is the unusual characteristic to not respond during a sound but at its offset. Blocking glycine has shown that sound-induced inhibition is the mechanism, but the time course of the responsible synaptic events has not been directly measured in vivo. We obtained intracellular recordings in the Mongolian gerbil (meriones unguiculatus) with patch electrodes containing biocytin, and retrieved 12 labeled neurons with large dendritic trees within and around the SPN region. We found that these neurons could be categorized into three classes that show consistency along multiple dimensions like ultrastructure, spontaneous activity, and responses to current injection and a variety of ipsi- and contralateral sounds. Fast cells fire at onset of depolarizing current, generate short-latency rebound spikes to sound or hyperpolarizing current, and show dense synaptic coverage. Slow cells show sparse synaptic coverage, sustained responses to depolarization, and inhibition with a slow time course to hyperpolarizing current or sound. Uninhibited cells form a third class which profoundly differ in their responses to sound, lacking rebound spiking. We propose that fast cells project to the inferior colliculus, and slow cells to the cochlear nucleus.

Sensory-motor interactions in the auditory system play an important role in vocal self-monitoring and control. These result from top-down corollary discharges, relaying predictions about vocal timing and acoustics. Recent evidence suggests such signals may be two distinct processes, one suppressing neural activity during vocalization and another enhancing sensitivity to sensory feedback, rather than a single mechanism. Single-neuron recordings have been unable to disambiguate due to overlap of motor signals with sensory inputs. Here, we sought to disentangle these processes in marmoset auditory cortex during production of multi-phrased ‘twitter’ vocalizations. Temporal responses revealed two timescales of vocal suppression: temporally-precise phasic suppression during phrases and sustained tonic suppression. Both components were present within individual neurons, however, phasic suppression presented broadly regardless of frequency tuning (gating), while tonic was selective for vocal frequencies and feedback (prediction). This suggests that auditory cortex is modulated by concurrent corollary discharges during vocalization, with different computational mechanisms.

Background Behavior consists of the interaction between an organism and its environment, and is controlled by the brain. Brain activity varies at sub-second time scales, but behavioral measures are usually coarse (often consisting of only binary trial outcomes). Results To overcome this mismatch, we developed the Rat Interactive Foraging Facility (RIFF): a programmable interactive arena for freely moving rats with multiple feeding areas, multiple sound sources, high-resolution behavioral tracking, and simultaneous electrophysiological recordings. The paper provides detailed information about the construction of the RIFF and the software used to control it. To illustrate the flexibility of the RIFF, we describe two complex tasks implemented in the RIFF, a foraging task and a sound localization task. Rats quickly learned to obtain rewards in both tasks. Neurons in the auditory cortex as well as neurons in the auditory field in the posterior insula had sound-driven activity during behavior. Remarkably, neurons in both structures also showed sensitivity to non-auditory parameters such as location in the arena and head-to-body angle. Conclusions The RIFF provides insights into the cognitive capabilities and learning mechanisms of rats and opens the way to a better understanding of how brains control behavior. The ability to do so depends crucially on the combination of wireless electrophysiology and detailed behavioral documentation available in the RIFF.

Evoked neural responses to sensory stimuli have been extensively investigated in humans and animal models both to enhance our understanding of brain function and to aid in clinical diagnosis of neurological and neuropsychiatric conditions. Recording and imaging techniques such as electroencephalography (EEG), magnetoencephalography (MEG), local field potentials (LFPs), and calcium imaging provide complementary information about different aspects of brain activity at different spatial and temporal scales. Modeling and simulations provide a way to integrate these different types of information to clarify underlying neural mechanisms. In this study, we aimed to shed light on the neural dynamics underlying auditory evoked responses by fitting a rate-based model to LFPs recorded via multi-contact electrodes which simultaneously sampled neural activity across cortical laminae. Recordings included neural population responses to best-frequency (BF) and non-BF tones at four representative sites in primary auditory cortex (A1) of awake monkeys. The model considered major neural populations of excitatory, parvalbumin-expressing (PV), and somatostatin-expressing (SOM) neurons across layers 2/3, 4, and 5/6. Unknown parameters, including the connection strength between the populations, were fitted to the data. Our results revealed similar population dynamics, fitted model parameters, predicted equivalent current dipoles (ECD), tuning curves, and lateral inhibition profiles across recording sites and animals, in spite of quite different extracellular current distributions. We found that PV firing rates were higher in BF than in non-BF responses, mainly due to different strengths of tonotopic thalamic input, whereas SOM firing rates were higher in non-BF than in BF responses due to lateral inhibition. In conclusion, we demonstrate the feasibility of the model-fitting approach in identifying the contributions of cell-type specific population activity to stimulus-evoked LFPs across cortical laminae, providing a foundation for further investigations into the dynamics of neural circuits underlying cortical sensory processing.

The human brain networks responsible for selectively listening to a voice amid other talkers remain to be clarified. The present study aimed to investigate relationships between cortical activity and performance in a speech-in-speech task, before (Experiment I) and after training-induced improvements (Experiment II). In Experiment I, 74 participants performed a speech-in-speech task while their cortical activity was measured using a functional near infrared spectroscopy (fNIRS) device. One target talker and one masker talker were simultaneously presented at three different target-to-masker ratios (TMRs): adverse, intermediate and favorable. Behavioral results show that performance may increase monotonically with TMR in some participants and failed to decrease, or even improved, in the adverse-TMR condition for others. On the neural level, an extensive brain network including the frontal (left prefrontal cortex, right dorsolateral prefrontal cortex and bilateral inferior frontal gyri) and temporal (bilateral auditory cortex) regions was more solicited by the intermediate condition than the two others. Additionally, bilateral frontal gyri and left auditory cortex activities were found to be positively correlated with behavioral performance in the adverse-TMR condition. In Experiment II, 27 participants, whose performance was the poorest in the adverse-TMR condition of Experiment I, were trained to improve performance in that condition. Results show significant performance improvements along with decreased activity in bilateral inferior frontal gyri, the right dorsolateral prefrontal cortex, the left inferior parietal cortex and the right auditory cortex in the adverse-TMR condition after training. Arguably, lower neural activity reflects higher efficiency in processing masker inhibition after speech-in-speech training. As speech-in-noise tasks also imply frontal and temporal regions, we suggest that regardless of the type of masking (speech or noise) the complexity of the task will prompt the implication of a similar brain network. Furthermore, the initial significant cognitive recruitment will be reduced following a training leading to an economy of cognitive resources.

Significance Syllables are important building blocks of speech. They occur at a rate between 4 and 8 Hz, corresponding to the theta frequency range of neural activity in the cerebral cortex. When listening to speech, the theta activity becomes aligned to the syllabic rhythm, presumably aiding in parsing a speech signal into distinct syllables. However, this neural activity cannot only be influenced by sound, but also by somatosensory information. Here, we show that the presentation of vibrotactile signals at the syllabic rate can enhance the comprehension of speech in background noise. We further provide evidence that this multisensory enhancement of speech comprehension reflects the multisensory integration of auditory and tactile information in the auditory cortex.

Mechanosensation – by which mechanical stimuli are converted into a neuronal signal – is the basis for the sensory systems of hearing, balance, and touch. Mechanosensation is unmatched in speed and its diverse range of sensitivities, reaching its highest temporal limits with the sense of hearing; however, hair cells (HCs) and the auditory nerve (AN) serve as obligatory bottlenecks for sounds to engage the brain. Like other sensory neurons, auditory neurons use the canonical pathway for neurotransmission and millisecond-duration action potentials (APs). How the auditory system utilizes the relatively slow transmission mechanisms to achieve ultrafast speed, and high audio-frequency hearing remains an enigma. Here, we address this paradox and report that the mouse, and chinchilla, AN are mechanically sensitive, and minute mechanical displacement profoundly affects its response properties. Sound-mimicking sinusoidal mechanical and electrical current stimuli affect phase-locked responses. In a phase-dependent manner, the two stimuli can also evoke suppressive responses. We propose that mechanical sensitivity interacts with synaptic responses to shape responses in the AN, including frequency tuning and temporal phase locking. Combining neurotransmission and mechanical sensation to control spike patterns gives the mammalian AN a secondary receptor role, an emerging theme in primary neuronal functions.

Locomotion generates adventitious sounds which enable detection and localization of predators and prey. Such sounds contain brisk changes or transients in amplitude. We investigated the hypothesis that ill-understood temporal specializations in binaural circuits subserve lateralization of such sound transients, based on different time of arrival at the ears (interaural time differences, ITDs). We find that Lateral Superior Olive (LSO) neurons show exquisite ITD-sensitivity, reflecting extreme precision and reliability of excitatory and inhibitory postsynaptic potentials, in contrast to Medial Superior Olive neurons, traditionally viewed as the ultimate ITD-detectors. In vivo, inhibition blocks LSO excitation over an extremely short window, which, in vitro, required synaptically evoked inhibition. Light and electron microscopy revealed inhibitory synapses on the axon initial segment as the structural basis of this observation. These results reveal a neural vetoing mechanism with extreme temporal and spatial precision and establish the LSO as the primary nucleus for binaural processing of sound transients.

Hearing deficits impact on the communication with the external world and severely compromise perception of the surrounding. Deafness can be caused by particular mutations in the neuroplastin ( Nptn ) gene, which encodes a transmembrane recognition molecule of the immunoglobulin (Ig) superfamily and plasma membrane Calcium ATPase (PMCA) accessory subunit. This study investigates whether the complete absence of neuroplastin or the loss of neuroplastin in the adult after normal development lead to hearing impairment in mice analyzed by behavioral, electrophysiological, and in vivo imaging measurements. Auditory brainstem recordings from adult neuroplastin-deficient mice ( Nptn −/− ) show that these mice are deaf. With age, hair cells and spiral ganglion cells degenerate in Nptn −/− mice. Adult Nptn −/− mice fail to behaviorally respond to white noise and show reduced baseline blood flow in the auditory cortex (AC) as revealed by single-photon emission computed tomography (SPECT). In adult Nptn −/− mice, tone-evoked cortical activity was not detectable within the primary auditory field (A1) of the AC, although we observed non-persistent tone-like evoked activities in electrophysiological recordings of some young Nptn −/− mice. Conditional ablation of neuroplastin in Nptn lox/loxEmx1Cre mice reveals that behavioral responses to simple tones or white noise do not require neuroplastin expression by central glutamatergic neurons. Loss of neuroplastin from hair cells in adult Nptn Δlox/loxPrCreERT mice after normal development is correlated with increased hearing thresholds and only high prepulse intensities result in effective prepulse inhibition (PPI) of the startle response. Furthermore, we show that neuroplastin is required for the expression of PMCA 2 in outer hair cells. This suggests that altered Ca 2+ homeostasis underlies the observed hearing impairments and leads to hair cell degeneration. Our results underline the importance of neuroplastin for the development and the maintenance of the auditory system.

Multisensory integration of auditory and tactile information occurs already at the level of the cochlear nucleus. Rodents use their whiskers for tactile perception to guide them in their exploration of the world. As nocturnal animals with relatively poor vision, audiotactile interactions are of great importance for this species. Here, the influence of whisker deflections on sound-evoked spiking in the cochlear nucleus was investigated in vivo in anesthetized mice. Multichannel, silicon-probe electrophysiological recordings were obtained from both the dorsal and ventral cochlear nucleus. Whisker deflections evoked an increased spiking activity in fusiform cells of the dorsal cochlear nucleus and t-stellate cells in ventral cochlear nucleus, whereas bushy cells in the ventral cochlear nucleus showed a more variable response. The response to broadband noise stimulation increased in fusiform cells and primary-like bushy cells when the sound stimulation was preceded (~ 20 ms) by whisker stimulation. Multi-sensory integration of auditory and whisker input can thus occur already in this early brainstem nucleus, emphasizing the importance of early integration of auditory and somatosensory information.

The ability to recognize sounds in noise is a key part of hearing, and the mechanisms by which the brain identifies sounds in noise are of considerable interest to scientists, clinicians and engineers. Yet we know little about the necessity of regions such as auditory cortex for hearing in noise, or how cortical processing of sounds is adversely affected by noise. Here we used reversible cortical inactivation and extracellular electrophysiology in ferrets performing a vowel discrimination task to identify and understand the causal contribution of auditory cortex to hearing in noise. Cortical inactivation by cooling impaired task performance in noisy but not clean conditions, while responses of auditory cortical neurons were less informative about vowel identity in noise. Simulations mimicking cortical inactivation indicated that effects of inactivation were related to the loss of information about sounds represented across neural populations. The addition of noise to target sounds drove spiking activity in auditory cortex and recruitment of additional neural populations that were linked to degraded behavioral performance. To suppress noise-related activity, we used continuous exposure to background noise to adapt the auditory system and recover behavioral performance in both ferrets and humans. Inactivation by cooling revealed that the benefits of continuous exposure were not cortically dependent. Together our results highlight the importance of auditory cortex in sound discrimination in noise and the underlying mechanisms through which noise-related activity and adaptation shape hearing.

Although information theoretic approaches have been used extensively in the analysis of the neural code, they have yet to be used to describe how information is accumulated in time while sensory systems are categorizing dynamic sensory stimuli such as speech sounds or visual objects. Here, we present a novel method to estimate the cumulative information for stimuli or categories. We further define a time-varying categorical information index that, by comparing the information obtained for stimuli versus categories of these same stimuli, quantifies invariant neural representations. We use these methods to investigate the dynamic properties of avian cortical auditory neurons recorded in zebra finches that were listening to a large set of call stimuli sampled from the complete vocal repertoire of this species. We found that the time-varying rates carry 5 times more information than the mean firing rates even in the first 100 ms. We also found that cumulative information has slow time constants (100-600 ms) relative to the typical integration time of single neurons, reflecting the fact that the behaviorally informative features of auditory objects are time-varying sound patterns. When we correlated firing rates and information values, we found that average information correlates with average firing rate but that higher-rates found at the onset response yielded similar information values as the lower-rates found in the sustained response: the onset and sustained response of avian cortical auditory neurons provide similar levels of independent information about call identity and call-type. Finally, our information measures allowed us to rigorously define categorical neurons; these categorical neurons show a high degree of invariance for vocalizations within a call-type. Peak invariance is found around 150 ms after stimulus onset. Surprisingly, call-type invariant neurons were found in both primary and secondary avian auditory areas.

Auditory cortex is required for sound localisation, but how neural firing in auditory cortex underlies our perception of sound sources in space remains unclear. Specifically, whether neurons in auditory cortex represent spatial cues or an integrated representation of auditory space across cues is not known. Here, we measured the spatial receptive fields of neurons in primary auditory cortex (A1) while ferrets performed a relative localisation task. Manipulating the availability of binaural and spectral localisation cues had little impact on ferrets’ performance, or on neural spatial tuning. A subpopulation of neurons encoded spatial position consistently across localisation cue type. Furthermore, neural firing pattern decoders outperformed two-channel model decoders using population activity. Together, these observations suggest that A1 encodes the location of sound sources, as opposed to spatial cue values.

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.

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.

Vocal communication is a sensory-motor process requiring auditory self-monitoring to correct errors and to ensure accurate vocal production. When presented with altered speech feedback, humans rapidly change their speech to compensate. Although previous evidence has demonstrated suppression of auditory cortex during both speech and animal vocalization, the specific role of auditory cortex in such feedback-dependent control is unknown. Here we show the relationship between neural activity in the auditory cortex and feedback-dependent vocal control in marmoset monkeys. We demonstrate that marmosets, like humans, exhibit feedback control of vocal acoustics. We further show that feedback-sensitive activity of auditory cortex neurons predict such compensatory vocal changes. Finally, we demonstrate that electrical microstimulation of auditory cortex rapidly evokes similar changes in vocal production. These results are evidence for a causal role of auditory cortex in vocal self-monitoring and feedback-dependent control, and have implications for understanding human speech motor control.

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.

A key function of the brain is to provide a stable representation of an object's location in the world. In hearing, sound azimuth and elevation are encoded by neurons throughout the auditory system, and auditory cortex is necessary for sound localization. However, the coordinate frame in which neurons represent sound space remains undefined: classical spatial receptive fields in head-fixed subjects can be explained either by sensitivity to sound source location relative to the head (egocentric) or relative to the world (allocentric encoding). This coordinate frame ambiguity can be resolved by studying freely moving subjects; here we recorded spatial receptive fields in the auditory cortex of freely moving ferrets. We found that most spatially tuned neurons represented sound source location relative to the head across changes in head position and direction. In addition, we also recorded a small number of neurons in which sound location was represented in a world-centered coordinate frame. We used measurements of spatial tuning across changes in head position and direction to explore the influence of sound source distance and speed of head movement on auditory cortical activity and spatial tuning. Modulation depth of spatial tuning increased with distance for egocentric but not allocentric units, whereas, for both populations, modulation was stronger at faster movement speeds. Our findings suggest that early auditory cortex primarily represents sound source location relative to ourselves but that a minority of cells can represent sound location in the world independent of our own position.

Perceptual constancy requires neural representations that are selective for object identity, but also tolerant for identity-preserving transformations. How such representations arise in the brain and contribute to perception remains unclear. Here we studied tolerant representations of sound identity in the auditory system by recording multi-unit activity in tonotopic auditory cortex of ferrets discriminating the identity of vowels which co-varied across orthogonal stimulus dimensions (fundamental frequency, sound level, location and voicing). We found that neural decoding of vowel identity was most successful across the same orthogonal dimensions over which animals generalized their behavior. We also decoded orthogonal sound features and behavioral variables including choice and accuracy to show a behaviorally-relevant, multivariate and multiplexed representation of sound, with each variable represented over a distinct time-course. Finally, information content and timing of sound feature encoding was modulated by task-engagement and training, suggesting that tolerant representations during perceptual constancy are attentionally and experience-dependent.