Auditory Neurophysiology publications

The systematic and topographic representation of frequency is a first principle of organization throughout the auditory system. The dorsal cochlear nucleus (DCN) receives direct tonotopic projections from the auditory nerve (AN) as well as secondary and descending projections from other sources. Among the recipients of AN input in the DCN are vertical cells (also called tuberculoventral cells), glycinergic interneurons thought to provide on‐ or near‐best‐frequency feed‐forward inhibition to principal cells in the DCN and various cells in the anteroventral cochlear nucleus (AVCN). Differing lines of physiological and anatomical evidence suggest that vertical cells and their projections are organized with respect to frequency, but this has not been conclusively demonstrated in the intact mammalian brain. To address this issue, we retrogradely labeled vertical cells via physiologically targeted injections in the AVCN of the CBA/J mouse. Results from multiple cases were merged with a normalized 3D template of the cochlear nucleus (Muniak et al. [ ] J. Comp. Neurol. 521:1510–1532) to demonstrate quantitatively that the arrangement of vertical cells is tonotopic and aligned to the innervation pattern of the AN. These results suggest that vertical cells are well positioned for providing immediate, frequency‐specific inhibition onto cells of the DCN and AVCN to facilitate spectral processing. J. Comp. Neurol. 522:937–949, 2014. © 2013 Wiley Periodicals, Inc.

Selective attention is the mechanism that allows focusing one's attention on a particular stimulus while filtering out a range of other stimuli, for instance, on a single conversation in a noisy room. Attending to one sound source rather than another changes activity in the human auditory cortex, but it is unclear whether attention to different acoustic features, such as voice pitch and speaker location, modulates subcortical activity. Studies using a dichotic listening paradigm indicated that auditory brainstem processing may be modulated by the direction of attention. We investigated whether endogenous selective attention to one of two speech signals affects amplitude and phase locking in auditory brainstem responses when the signals were either discriminable by frequency content alone, or by frequency content and spatial location. Frequency-following responses to the speech sounds were significantly modulated in both conditions. The modulation was specific to the task-relevant frequency band. The effect was stronger when both frequency and spatial information were available. Patterns of response were variable between participants, and were correlated with psychophysical discriminability of the stimuli, suggesting that the modulation was biologically relevant. Our results demonstrate that auditory brainstem responses are susceptible to efferent modulation related to behavioral goals. Furthermore they suggest that mechanisms of selective attention actively shape activity at early subcortical processing stages according to task relevance and based on frequency and spatial cues.

Cortical inhibitory circuits play important roles in shaping sensory processing. In auditory cortex, however, functional properties of genetically identified inhibitory neurons are poorly characterized. By two-photon imaging-guided recordings, we specifically targeted 2 major types of cortical inhibitory neuron, parvalbumin (PV) and somatostatin (SOM) expressing neurons, in superficial layers of mouse auditory cortex. We found that PV cells exhibited broader tonal receptive fields with lower intensity thresholds and stronger tone-evoked spike responses compared with SOM neurons. The latter exhibited similar frequency selectivity as excitatory neurons. The broader/weaker frequency tuning of PV neurons was attributed to a broader range of synaptic inputs and stronger subthreshold responses elicited, which resulted in a higher efficiency in the conversion of input to output. In addition, onsets of both the input and spike responses of SOM neurons were significantly delayed compared with PV and excitatory cells. Our results suggest that PV and SOM neurons engage in auditory cortical circuits in different manners: while PV neurons may provide broadly tuned feedforward inhibition for a rapid control of ascending inputs to excitatory neurons, the delayed and more selective inhibition from SOM neurons may provide a specific modulation of feedback inputs on their distal dendrites.

The function of ultrasonic vocalizations (USVs) produced by mice (Mus musculus) is a topic of broad interest to many researchers. These USVs differ widely in spectrotemporal characteristics, suggesting different categories of vocalizations, although this has never been behaviorally demonstrated. Although electrophysiological studies indicate that neurons can discriminate among vocalizations at the level of the auditory midbrain, perceptual acuity for vocalizations has yet to be determined. Here, we trained CBA/CaJ mice using operant conditioning to discriminate between different vocalizations and between a spectrotemporally modified vocalization and its original version. Mice were able to discriminate between vocalization types and between manipulated vocalizations, with performance negatively correlating with spectrotemporal similarity. That is, discrimination performance was higher for dissimilar vocalizations and much lower for similar vocalizations. The behavioral data match previous neurophysiological results in the inferior colliculus (IC), using the same stimuli. These findings suggest that the different vocalizations could carry different meanings for the mice. Furthermore, the finding that behavioral discrimination matched neural discrimination in the IC suggests that the IC plays an important role in the perceptual discrimination of vocalizations.

Temporal differences between the two ears are critical for spatial hearing. They can be described along axes of interaural time difference (ITD) and interaural correlation, and their processing starts in the brainstem with the convergence of monaural pathways which are tuned in frequency and which carry temporal information. In previous studies, we examined the bandwidth (BW) of frequency tuning at two stages: the auditory nerve (AN) and inferior colliculus (IC), and showed that BW depends on characteristic frequency (CF) but that there is no difference in the mean BW of these two structures when measured in a binaural, temporal framework. This suggested that there is little frequency convergence in the ITD pathway between AN and IC and that frequency selectivity determined by the cochlear filter is preserved up to the IC. Unexpectedly, we found that AN and IC neurons can be similar in CF and BW, yet responses to changes in interaural correlation in the IC were different than expected from coincidence patterns ("pseudo-binaural" responses) in the AN. To better understand this, we here examine the responses of bushy cells, which provide monaural inputs to binaural neurons. Using broadband noise, we measured BW and correlation sensitivity in the cat trapezoid body (TB), which contains the axons of bushy cells. This allowed us to compare these two metrics at three stages in the ITD pathway. We found that BWs in the TB are similar to those in the AN and IC. However, TB neurons were found to be more sensitive to changes in stimulus correlation than AN or IC neurons. This is consistent with findings that show that TB fibers are more temporally precise than AN fibers, but is surprising because it suggests that the temporal information available monaurally is not fully exploited binaurally.

The auxiliary subunit α 2 δ3 modulates the expression and function of voltage-gated calcium channels. Here we show that α 2 δ3 mRNA is expressed in spiral ganglion neurons and auditory brainstem nuclei and that the protein is required for normal acoustic responses. Genetic deletion of α 2 δ3 led to impaired auditory processing, with reduced acoustic startle and distorted auditory brainstem responses. α 2 δ3 −/− mice learned to discriminate pure tones, but they failed to discriminate temporally structured amplitude-modulated tones. Light and electron microscopy analyses revealed reduced levels of presynaptic Ca 2+ channels and smaller auditory nerve fiber terminals contacting cochlear nucleus bushy cells. Juxtacellular in vivo recordings of sound-evoked activity in α 2 δ3 −/− mice demonstrated impaired transmission at these synapses. Together, our results identify a novel role for the α 2 δ3 auxiliary subunit in the structure and function of specific synapses in the mammalian auditory pathway and in auditory processing disorders.

Duration-tuned neurons (DTNs) in the mammalian inferior colliculus (IC) arise from a combination of excitatory and inhibitory synaptic inputs. Previous research has shown that the inhibition responsible for creating DTNs has a shorter latency than that of excitation and lasts longer than the stimulus duration. We used monotic and dichotic paired tone stimulation and recorded responses of DTNs from the IC of the bat to assess the relative contributions of each ear in forming duration-tuned circuits. The stimulus consisted of a short best duration (BD) excitatory tone and a longer duration nonexcitatory (NE) tone. In the monotic condition, when the BD and NE tones were presented to the contralateral ear and were sufficiently close in time, the NE tone always suppressed spikes evoked by the BD tone. In the dichotic condition, when the BD tone was presented to the contralateral ear and the NE tone to the ipsilateral ear, half of DTNs no longer showed spike suppression to the NE tone. Of those DTNs with suppression in both conditions, the latency of the inhibition was shorter and the duration of the inhibition was longer in the monotic condition. Therefore, in the monotic condition, DTNs received a contralaterally evoked inhibitory input that preceded the excitatory input to the same neuron. In the dichotic condition, DTNs received an ipsilaterally evoked inhibitory input that was weaker, longer in latency, and shorter in duration than the inputs from the contralateral ear. These findings indicate that the neural mechanisms that create DTNs in the IC are monaural.

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

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

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

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

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

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

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

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

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

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

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

The neural response to a sensory stimulus tends to be more strongly reduced when the stimulus is preceded by the same, rather than a different, stimulus. This stimulus-specific adaptation (SSA) is ubiquitous across the senses. In hearing, SSA has been suggested to play a role in change detection as indexed by the mismatch negativity. This study sought to test whether SSA, measured in human auditory cortex, is caused by neural fatigue (reduction in neural responsiveness) or by sharpening of neural tuning to the adapting stimulus. For that, we measured event-related cortical potentials to pairs of pure tones with varying frequency separation and stimulus onset asynchrony (SOA). This enabled us to examine the relationship between the degree of specificity of adaptation as a function of frequency separation and the rate of decay of adaptation with increasing SOA. Using simulations of tonotopic neuron populations, we demonstrate that the fatigue model predicts independence of adaptation specificity and decay rate, whereas the sharpening model predicts interdependence. The data showed independence and thus supported the fatigue model. In a second experiment, we measured adaptation specificity after multiple presentations of the adapting stimulus. The multiple adapters produced more adaptation overall, but the effect was more specific to the adapting frequency. Within the context of the fatigue model, the observed increase in adaptation specificity could be explained by assuming a 2.5-fold increase in neural frequency selectivity. We discuss possible bottom-up and top-down mechanisms of this effect.

Motion direction is a crucial cue for predicting future states in natural scenes. In the auditory system, the mechanisms that confer direction selectivity to neurons are not well understood. Neither is it known whether sound motion is encoded independently of stationary sound location. Here we investigated these questions in neurons of the owl's external nucleus of the inferior colliculus, where auditory space is represented in a map. Using a high-density speaker array, we show that the preferred direction and the degree of direction selectivity can be predicted by response adaptation to sounds moving over asymmetric spatial receptive fields. At the population level, we found that preference for sounds moving toward frontal space increased with eccentricity in spatial tuning. This distribution was consistent with larger receptive-field asymmetry in neurons tuned to more peripheral auditory space. A model of suppression based on spatiotemporal summation predicted the observations. Thus, response adaptation and receptive-field shape can explain direction selectivity to acoustic motion and an orderly distribution of preferred direction.