Auditory Research publications

Cannabinoids have been suggested as a therapeutic target for a variety of brain disorders. Despite the presence of their receptors throughout the auditory system, little is known about how cannabinoids affect auditory function. We sought to determine whether administration of arachidonyl-2'-chloroethylamide (ACEA), a highly-selective CB1 agonist, could attenuate a variety of auditory effects caused by prior administration of salicylate, and potentially treat tinnitus. We recorded cortical resting-state activity, auditory-evoked cortical activity and auditory brainstem responses (ABRs), from chronically-implanted awake guinea pigs, before and after salicylate + ACEA. Salicylate-induced reductions in click-evoked ABR amplitudes were smaller in the presence of ACEA, suggesting that the ototoxic effects of salicylate were less severe. ACEA also abolished salicylate-induced changes in cortical alpha band (6-10 Hz) oscillatory activity. However, salicylate-induced increases in cortical evoked activity (suggestive of the presence of hyperacusis) were still present with salicylate + ACEA. ACEA administered alone did not induce significant changes in either ABR amplitudes or oscillatory activity, but did increase cortical evoked potentials. Furthermore, in two separate groups of non-implanted animals, we found no evidence that ACEA could reverse behavioural identification of salicylate- or noise-induced tinnitus. Together, these data suggest that while ACEA may be potentially otoprotective, selective CB1 agonists are not effective in diminishing the presence of tinnitus or hyperacusis.

Spike sorting is an essential first step in most analyses of extracellular in vivo electrophysiological recordings. Here we show that spike-sorting success depends critically on characteristics of coordinated population activity that can differ between anesthetic states. In tetrode recordings from mouse auditory cortex, spike sorting was significantly less successful under ketamine/medetomidine (ket/med) than urethane anesthesia. Surprisingly, this difficulty with sorting under ket/med anesthesia did not appear to result from either greater millisecond-scale burstiness of neural activity or increased coordination of activity among neighboring neurons. Rather, the key factor affecting sorting success appeared to be the amount of coordinated population activity at long time intervals and across large cortical distances. We propose that spike-sorting success is directly dependent on overall coordination of activity, and is most disrupted by large-scale fluctuations in cortical population activity. Reliability of single-unit recording may therefore differ not only between urethane-anesthetized and ket/med-anesthetized states as demonstrated here, but also between synchronized and desynchronized states, asleep and awake states, or inattentive and attentive states in unanesthetized animals.

The mechanisms underlying multi-sensory interactions are still poorly understood despite considerable progress made since the first neurophysiological recordings of multi-sensory neurons. While the majority of single-cell neurophysiology has been performed in anesthetized or passive-awake laboratory animals, the vast majority of behavioral data stems from studies with human subjects. Interpretation of neurophysiological data implicitly assumes that laboratory animals exhibit perceptual phenomena comparable or identical to those observed in human subjects. To explicitly test this underlying assumption, we here characterized how two rhesus macaques and four humans detect changes in intensity of auditory, visual, and audio-visual stimuli. These intensity changes consisted of a gradual envelope modulation for the sound, and a luminance step for the LED. Subjects had to detect any perceived intensity change as fast as possible. By comparing the monkeys' results with those obtained from the human subjects we found that (1) unimodal reaction times differed across modality, acoustic modulation frequency, and species, (2) the largest facilitation of reaction times with the audio-visual stimuli was observed when stimulus onset asynchronies were such that the unimodal reactions would occur at the same time (response, rather than physical synchrony), and (3) the largest audio-visual reaction-time facilitation was observed when unimodal auditory stimuli were difficult to detect, i.e., at slow unimodal reaction times. We conclude that despite marked unimodal heterogeneity, similar multisensory rules applied to both species. Single-cell neurophysiology in the rhesus macaque may therefore yield valuable insights into the mechanisms governing audio-visual integration that may be informative of the processes taking place in the human brain.

Panx1 forms plasma membrane channels in brain and several other organs, including the inner ear. Biophysical properties, activation mechanisms and modulators of Panx1 channels have been characterized in detail, however the impact of Panx1 on auditory function is unclear due to conflicts in published results. To address this issue, hearing performance and cochlear function of the Panx1-/- mouse strain, the first with a reported global ablation of Panx1, were scrutinized. Male and female homozygous (Panx1-/-), hemizygous (Panx1+/-) and their wild type (WT) siblings (Panx1+/+) were used for this study. Successful ablation of Panx1 was confirmed by RT-PCR and Western immunoblotting in the cochlea and brain of Panx1-/- mice. Furthermore, a previously validated Panx1-selective antibody revealed strong immunoreactivity in WT but not in Panx1-/- cochleae. Hearing sensitivity, outer hair cell-based "cochlear amplifier" and cochlear nerve function, analyzed by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) recordings, were normal in Panx1+/- and Panx1-/- mice. In addition, we determined that global deletion of Panx1 impacts neither on connexin expression, nor on gap-junction coupling in the developing organ of Corti. Finally, spontaneous intercellular Ca2+ signal (ICS) activity in organotypic cochlear cultures, which is key to postnatal development of the organ of Corti and essential for hearing acquisition, was not affected by Panx1 ablation. Therefore, our results provide strong evidence that, in mice, Panx1 is dispensable for hearing acquisition and auditory function.

Short-term memory load can impair attentional control, but prior work shows that the extent of the effect ranges from being very general to very specific. One factor for the mixed results may be reliance on point estimates of memory load effects on attention. Here we used auditory attention gradients as an analog measure to map-out the impact of short-term memory load over space. Verbal or spatial information was maintained during an auditory spatial attention task and compared to no-load. Stimuli were presented from five virtual locations in the frontal azimuth plane, and subjects focused on the midline. Reaction times progressively increased for lateral stimuli, indicating an attention gradient. Spatial load further slowed responses at lateral locations, particularly in the left hemispace, but had little effect at midline. Verbal memory load had no (Experiment 1), or a minimal (Experiment 2) influence on reaction times. Spatial and verbal load increased switch costs between memory encoding and attention tasks relative to the no load condition. The findings show that short-term memory influences the distribution of auditory attention over space; and that the specific pattern depends on the type of information in short-term memory.

Approximately 15% of American adults report some degree of difficulty hearing in a noisy environment or have auditory filtering difficulties. There are objective clinical tests of auditory filtering, yet few tests exist for mouse models that do not rely on extensive training. We have used reflex modification audiometry (RMA) and developed exclusion criteria for the mouse model. This RMA based test makes use of the acoustic startle response (ASR) and the ability of prepulses to inhibit the ASR [i.e., prepulse inhibition (PPI)] to assess the mouse's ability to detect prepulse signals presented in quiet or embedded in masking noise. We have studied PPI behavior across four inbred mouse strains with normal cochlear function and developed pre-testing exclusion criteria and test/retest reliability measures. Moreover, because both the medial (MOC) and the lateral (LOC) olivocochlear efferent feedback systems have been proposed to improve auditory behavior performance, especially in noisy backgrounds, we have examined PPI abilities in mice (with their littermate controls) either lacking the MOC receptor subunit α9 nicotinic acetylcholine receptor [α9 nAChR (-/-)] or expressing an overactive receptor [Ld'T mutation in α9 nAChR KI], or lacking an LOC efferent neuropeptide, alpha calcitonin gene-related peptide [αCGRP (-/-)] only in the CNS. Because CGRP receptor formation has been shown to mature from juvenile to adult ages, we also studied if this maturation would be reflected in PPI behavioral responses in juvenile and adult (+/+) controls and in adult αCGRP (-/-) animals. We show that 50% PPI response thresholds (sound level with 50% correct responses) in quiet are decreased in the (-/-) α9 nAChR animals, and 50% PPI responses are increased for mice with an overactive receptor (α9 nAChR KI) and are increased in adult mice lacking αCGRP (-/-). However, in background noise, only mice lacking αCGRP exhibited increased 50% PPI response thresholds, as there were no significant differences between α9 nAChR adult mouse lines and their littermate controls. These findings suggest that MOC and LOC olivocochlear neurotransmission work in tandem to improve behavioral responses to sound. These experiments further pave the way for rapid behavioral hearing assessments in other mouse models.

Cisplatin chemotherapy causes permanent hearing loss in 40–80% of treated patients. It is unclear whether the cochlea has unique sensitivity to cisplatin or is exposed to higher levels of the drug. Here we use inductively coupled plasma mass spectrometry (ICP-MS) to examine cisplatin pharmacokinetics in the cochleae of mice and humans. In most organs cisplatin is detected within one hour after injection, and is eliminated over the following days to weeks. In contrast, the cochlea retains cisplatin for months to years after treatment in both mice and humans. Using laser ablation coupled to ICP-MS, we map cisplatin distribution within the human cochlea. Cisplatin accumulation is consistently high in the stria vascularis, the region of the cochlea that maintains the ionic composition of endolymph. Our results demonstrate long-term retention of cisplatin in the human cochlea, and they point to the stria vascularis as an important therapeutic target for preventing cisplatin ototoxicity.

The hippocampus is known as a neuronal structure involved in learning, memory and spatial navigation using multi-sensory cues. However, the basic features of its response to acoustic stimuli without any behavioral tasks (conditioning) remains poorly studied. Here, we investigated the CA3 response to auditory stimuli using in vivo loose-patch recordings in awake and anesthetized C57 mice. Different acoustic stimuli in addition to broadband noise such as click, FM sound and pure tone were applied to test the response of CA3 in awake animals. It was found that the wakefulness of the animal is important for the recorded neurons to respond. The CA3 neurons showed a stronger response to broadband noise rather than the other type of stimuli which suggested that auditory information arrived at CA3 via broadband pathways. Finally, we investigated the excitatory and inhibitory inputs to CA3 neurons by using in vivo whole-cell voltage-clamp techniques with the membrane potential holding at -70 and 0 mV, respectively. In awake animals, the excitatory and inhibitory inputs CA3 neurons receive induced by noise are balanced by showing stable intervals and proportional changes of their latencies and peak amplitudes as a function of the stimulation intensities.

Today, the standard method to predict output levels of active middle ear implants (AMEIs) before clinical data are available is stapes vibration measurement in human cadaveric ears, according to ASTM standard F2504-05. Although this procedure is well established, the validity of the predicted output levels has never been demonstrated clinically. Furthermore, this procedure requires a mobile and visually accessible stapes and an AMEI stimulating the ossicular chain. Thus, an alternative method is needed to quantify the output level of AMEIs in all other stimulation modes, e.g. reverse stimulation of the round window. Intracochlear pressure difference (ICPD) is a good candidate for such a method as it correlates with evoked potentials in animals and it is measurable in cadaveric ears. To validate this method we correlated AMEI output levels calculated from ICPD and from stapes vibration in cadaveric ears with outputs levels determined from clinical data. Output levels calculated from ICPD were similar to output levels calculated from stapes vibration and almost identical to clinical data. Our results demonstrate that both ICPD and stapes vibration can be used as a measure to predict AMEI clinical output levels in cadaveric ears and that ICPD as reference provided even more accurate results.

Learning to recognize a stimulus category requires experience with its many natural variations. However, the mechanisms that allow a category's sensorineural representation to be updated after experiencing new exemplars are not well understood, particularly at the molecular level. Here we investigate how a natural vocal category induces expression in the auditory system of a key synaptic plasticity effector immediate early gene, Arc/Arg3.1 , which is required for memory consolidation. We use the ultrasonic communication system between mouse pups and adult females to study whether prior familiarity with pup vocalizations alters how Arc is engaged in the core auditory cortex after playback of novel exemplars from the pup vocal category. A computerized, 3D surface-assisted cellular compartmental analysis, validated against manual cell counts, demonstrates significant changes in the recruitment of neurons expressing Arc in pup-experienced animals (mothers and virgin females “cocaring” for pups) compared with pup-inexperienced animals (pup-naïve virgins), especially when listening to more familiar, natural calls compared to less familiar but similarly recognized tonal model calls. Our data support the hypothesis that the kinetics of Arc induction to refine cortical representations of sensory categories is sensitive to the familiarity of the sensory experience.

Despite decades of microelectrode recordings, fundamental questions remain about how auditory cortex represents sound-source location. Here, we used in vivo 2-photon calcium imaging to measure the sensitivity of layer II/III neurons in mouse primary auditory cortex (A1) to interaural level differences (ILDs), the principal spatial cue in this species. Although most ILD-sensitive neurons preferred ILDs favoring the contralateral ear, neurons with either midline or ipsilateral preferences were also present. An opponent-channel decoder accurately classified ILDs using the difference in responses between populations of neurons that preferred contralateral-ear-greater and ipsilateral-ear-greater stimuli. We also examined the spatial organization of binaural tuning properties across the imaged neurons with unprecedented resolution. Neurons driven exclusively by contralateral ear stimuli or by binaural stimulation occasionally formed local clusters, but their binaural categories and ILD preferences were not spatially organized on a more global scale. In contrast, the sound frequency preferences of most neurons within local cortical regions fell within a restricted frequency range, and a tonotopic gradient was observed across the cortical surface of individual mice. These results indicate that the representation of ILDs in mouse A1 is comparable to that of most other mammalian species, and appears to lack systematic or consistent spatial order.

The ability to spontaneously feel a beat in music is a phenomenon widely believed to be unique to humans. Though beat perception involves the coordinated engagement of sensory, motor and cognitive processes in humans, the contribution of low-level auditory processing to the activation of these networks in a beat-specific manner is poorly understood. Here, we present evidence from a rodent model that midbrain preprocessing of sounds may already be shaping where the beat is ultimately felt. For the tested set of musical rhythms, on-beat sounds on average evoked higher firing rates than off-beat sounds, and this difference was a defining feature of the set of beat interpretations most commonly perceived by human listeners over others. Basic firing rate adaptation provided a sufficient explanation for these results. Our findings suggest that midbrain adaptation, by encoding the temporal context of sounds, creates points of neural emphasis that may influence the perceptual emergence of a beat.

Significance Sensory experience, even at prenatal periods, can shape brain connectivity. Thus, the emergence of sensory responses is a key step in cortical development. Sensory cortical responses are thought to emerge in cortical layer 4, which is the adult target of thalamic projections. However, in developing animals, thalamic fibers do not target layer 4 but instead target subplate neurons in the white matter. We show that subplate neurons respond to sounds before layer 4 is activated by thalamic axons. Moreover, early local field potential (LFP) responses demonstrate nascent topographic organization. Together we find that sound-evoked cortical activity and topographic organization emerge in a different layer than thought. Since subplate circuits are disrupted in autism spectrum disorder (ASD) models, disrupted emergence of sensory activity could be utilized for diagnosis and intervention.

The mechanism whereby anesthetics cause loss of consciousness (LOC) is poorly understood. Current theories suggest that impaired representation of information in cortico-thalamic networks contributes to LOC under anesthesia. We sought to determine whether such changes are present in auditory cortex using information theoretic analysis of multiunit responses in rats. We tested the effects of three agents with different molecular targets: isoflurane, which acts at multiple pre- and postsynaptic loci, propofol, which acts primarily on GABA A receptors, and dexmedetomidine, an α 2 adrenergic agonist. We reasoned that changes in the representation of sensory stimuli causative for LOC would be present regardless of the molecular target of the anesthetic. All three agents caused LOC, as assayed by the loss of righting reflex (LORR). We presented acoustic stimuli that varied across a wide range of temporal and spectral dynamics under control, sub-hypnotic (i.e. dose too low to cause LORR), just-hypnotic (a dose just sufficient to cause LORR) and recovery conditions. Changes in mutual information (MI) between the stimulus and spike responses under anesthesia diverged in two ways from predictions of a model in which stimulus representation is impaired upon LOC. First, the sign of changes in MI was agent-specific: MI increased under dexmedetomidine, while it decreased under isoflurane and propofol. Second, there was no consistent change in MI when transitioning from sub-hyptnotic to just-hypnotic doses: for none of the agents did MI decrease at the higher dose, and in some cases MI actually increased relative to the sub-hypnotic dose. Changes in MI under anesthesia were strongly correlated with changes in precision and reliability of spike timing, consistent with the importance of temporal stimulus features in driving auditory cortical activity. These data indicate that primary sensory cortex is not the locus for changes in information representation causative for LOC under anesthesia.

A function of the auditory system is to accurately determine the location of a sound source. The main cues for sound location are interaural time (ITD) and level (ILD) differences. Humans use both ITD and ILD to determine the azimuth. Thus far, the conception of sound localization in barn owls was that their facial ruff and asymmetrical ears generate a two-dimensional grid of ITD for azimuth and ILD for elevation. We show that barn owls also use ILD for azimuthal sound localization when ITDs are ambiguous. For high-frequency narrowband sounds, midbrain neurons can signal multiple locations, leading to the perception of an auditory illusion called a phantom source. Owls respond to such an illusory percept by orienting toward it instead of the true source. Acoustical measurements close to the eardrum reveal a small ILD component that changes with azimuth, suggesting that ITD and ILD information could be combined to eliminate the illusion. Our behavioral data confirm that perception was robust against ambiguities if ITD and ILD information was combined. Electrophysiological recordings of ILD sensitivity in the owl’s midbrain support the behavioral findings indicating that rival brain hemispheres drive the decision to orient to either true or phantom sources. Thus, the basis for disambiguation, and reliable detection of sound source azimuth, relies on similar cues across species as similar response to combinations of ILD and narrowband ITD has been observed in humans.

Objective: Compared to basic-feature hearing aids, premium-feature hearing aids have more advanced technologies and sophisticated features. The objective of this study was to explore the difference between premium-feature and basic-feature hearing aids in horizontal sound localization in both laboratory and daily life environments. We hypothesized that premium-feature hearing aids would yield better localization performance than basic-feature hearing aids. Design: Exemplars of premium-feature and basic-feature hearing aids from two major manufacturers were evaluated. Forty-five older adults (mean age 70.3 years) with essentially symmetrical mild to moderate sensorineural hearing loss were bilaterally fitted with each of the four pairs of hearing aids. Each pair of hearing aids was worn during a 4-week field trial and then evaluated using laboratory localization tests and a standardized questionnaire. Laboratory localization tests were conducted in a sound-treated room with a 360°, 24-loudspeaker array. Test stimuli were high frequency and low frequency filtered short sentences. The localization test in quiet was designed to assess the accuracy of front/back localization, while the localization test in noise was designed to assess the accuracy of locating sound sources throughout a 360° azimuth in the horizontal plane. Results: Laboratory data showed that unaided localization was not significantly different from aided localization when all hearing aids were combined. Questionnaire data showed that aided localization was significantly better than unaided localization in everyday situations. Regarding the difference between premium-feature and basic-feature hearing aids, laboratory data showed that, overall, the premium-feature hearing aids yielded more accurate localization than the basic-feature hearing aids when high-frequency stimuli were used, and the listening environment was quiet. Otherwise, the premium-feature and basic-feature hearing aids yielded essentially the same performance in other laboratory tests and in daily life. The findings were consistent for both manufacturers. Conclusions: Laboratory tests for two of six major manufacturers showed that premium-feature hearing aids yielded better localization performance than basic-feature hearing aids in one out of four laboratory conditions. There was no difference between the two feature levels in self-reported everyday localization. Effectiveness research with different hearing aid technologies is necessary, and more research with other manufacturers’ products is needed. Furthermore, these results confirm previous observations that research findings in laboratory conditions might not translate to everyday life.

In forest clearings of the Malaysian rainforest, chirping and trilling Mecopoda species often live in sympatry. We investigated whether a phenomenon known as stochastic resonance (SR) improved the ability of individuals to detect a low-frequent signal component typical of chirps when members of the heterospecific trilling species were simultaneously active. This phenomenon may explain the fact that the chirping species upholds entrainment to the conspecific song in the presence of the trill. Therefore, we evaluated the response probability of an ascending auditory neuron (TN-1) in individuals of the chirping Mecopoda species to triple-pulsed 2, 8 and 20 kHz signals that were broadcast 1 dB below the hearing threshold while increasing the intensity of either white noise or a typical triller song. Our results demonstrate the existence of SR over a rather broad range of signal-to-noise ratios (SNRs) of input signals when periodic 2 kHz and 20 kHz signals were presented at the same time as white noise. Using the chirp-specific 2 kHz signal as a stimulus, the maximum TN-1 response probability frequently exceeded the 50% threshold if the trill was broadcast simultaneously. Playback of an 8 kHz signal, a common frequency band component of the trill, yielded a similar result. Nevertheless, using the trill as a masker, the signal-related TN-1 spiking probability was rather variable. The variability on an individual level resulted from correlations between the phase relationship of the signal and syllables of the trill. For the first time, these results demonstrate the existence of SR in acoustically-communicating insects and suggest that the calling song of heterospecifics may facilitate the detection of a subthreshold signal component in certain situations. The results of the simulation of sound propagation in a computer model suggest a wide range of sender-receiver distances in which the triller can help to improve the detection of subthreshold signals in the chirping species.

We used suction electrodes to reliably record the activity of identified ascending auditory interneurons from the anterior surface of the brain in crickets. Electrodes were gently attached to the sheath covering the projection area of the ascending interneurons and the ringlike auditory neuropil in the protocerebrum. The specificity and selectivity of the recordings were determined by the precise electrode location, which could easily be changed without causing damage to the tissue. Different nonauditory fibers were recorded at other spots of the brain surface; stable recordings lasted for several hours. The same electrodes were used to deliver fluorescent tracers into the nervous system by means of electrophoresis. This allowed us to retrograde label the recorded auditory neurons and to reveal their cell body and dendritic structure in the first thoracic ganglion. By adjusting the amount of dye injected, we specifically stained the ringlike auditory neuropil in the brain, demonstrating the clusters of cell bodies contributing to it. Our data provide a proof that surface electrodes are a versatile tool to analyze neural processing in small brains of invertebrates. NEW & NOTEWORTHY We show that surface suction electrodes can be used to monitor the activity of auditory neurons in the cricket brain. They also allow delivering electrophoretically a fluorescent tracer to label the structure of the recorded neurons and the local neuropil to which the electrode was attached. This new extracellular recording and labeling technique is a versatile and useful method to explore neural processing in invertebrate sensory and motor systems.

Objectives: As people age, they experience reduced temporal processing abilities. This results in poorer ability to understand speech, particularly for degraded input signals. Cochlear implants (CIs) convey speech information via the temporal envelopes of a spectrally degraded input signal. Because there is an increasing number of older CI users, there is a need to understand how temporal processing changes with age. Therefore, the goal of this study was to quantify age-related reduction in temporal processing abilities when attempting to discriminate words based on temporal envelope information from spectrally degraded signals. Design: Younger normal-hearing (YNH) and older normal-hearing (ONH) participants were presented a continuum of speech tokens that varied in silence duration between phonemes (0 to 60 ms in 10-ms steps), and were asked to identify whether the stimulus was perceived more as the word “dish” or “ditch.” Stimuli were vocoded using tonal carriers. The number of channels (1, 2, 4, 8, 16, and unprocessed) and temporal envelope low-pass filter cutoff frequency (50 and 400 Hz) were systematically varied. Results: For the unprocessed conditions, the YNH participants perceived the word ditch for smaller silence durations than the ONH participants, indicating that aging affects temporal processing abilities. There was no difference in performance between the unprocessed and 16-channel, 400-Hz vocoded stimuli. Decreasing the number of spectral channels caused decreased ability to distinguish dish and ditch. Decreasing the envelope cutoff frequency also caused decreased ability to distinguish dish and ditch. The overall pattern of results revealed that reductions in spectral and temporal information had a relatively larger effect on the ONH participants compared with the YNH participants. Conclusions: Aging reduces the ability to utilize brief temporal cues in speech segments. Reducing spectral information—as occurs in a channel vocoder and in CI speech processing strategies—forces participants to use temporal envelope information; however, older participants are less capable of utilizing this information. These results suggest that providing as much spectral and temporal speech information as possible would benefit older CI users relatively more than younger CI users. In addition, the present findings help set expectations of clinical outcomes for speech understanding performance by adult CI users as a function of age.

To program a goal-directed response in the presence of multiple sounds, the audiomotor system should separate the sound sources. The authors examined whether the brain can segregate synchronous broadband sounds in the midsagittal plane, using amplitude modulations as an acoustic discrimination cue. To succeed in this task, the brain has to use pinna-induced spectral-shape cues and temporal envelope information. The authors tested spatial segregation performance in the midsagittal plane in two paradigms in which human listeners were required to localize, or distinguish, a target amplitude-modulated broadband sound when a non-modulated broadband distractor was played simultaneously at another location. The level difference between the amplitude-modulated and distractor stimuli was systematically varied, as well as the modulation frequency of the target sound. The authors found that participants were unable to segregate, or localize, the synchronous sounds. Instead, they invariably responded toward a level-weighted average of both sound locations, irrespective of the modulation frequency. An increased variance in the response distributions for double sounds of equal level was also observed, which cannot be accounted for by a segregation model, or by a probabilistic averaging model.