Auditory brainstem development of naked mole-rats (Heterocephalus glaber).

Life underground often leads to animals having specialized auditory systems to accommodate the constraints of acoustic transmission in tunnels. Despite living underground, naked mole-rats use a highly vocal communication system, implying that they rely on central auditory processing. However, little is known about these animals' central auditory system, and whether it follows a similar developmental time course as other rodents. Naked mole-rats show slowed development in the hippocampus suggesting they have altered brain development compared to other rodents. Here, we measured morphological characteristics and voltage-gated potassium channel Kv3.3 expression and protein levels at different key developmental time points (postnatal days 9, 14, 21 and adulthood) to determine whether the auditory brainstem (lateral superior olive and medial nucleus of the trapezoid body) develops similarly to two common auditory rodent model species: gerbils and mice. Additionally, we measured the hearing onset of naked mole-rats using auditory brainstem response recordings at the same developmental timepoints. In contrast with other work in naked mole-rats showing that they are highly divergent in many aspects of their physiology, we show that naked mole-rats have a similar hearing onset, between postnatal day (P) 9 and P14, to many other rodents. On the other hand, we show some developmental differences, such as a unique morphology and Kv3.3 protein levels in the brainstem.

Robustness of neuronal tuning to binaural sound localization cues against age-related loss of inhibitory synaptic inputs.

Sound localization relies on minute differences in the timing and intensity of sound arriving at both ears. Neurons of the lateral superior olive (LSO) in the brainstem process these interaural disparities by precisely detecting excitatory and inhibitory synaptic inputs. Aging generally induces selective loss of inhibitory synaptic transmission along the entire auditory pathways, including the reduction of inhibitory afferents to LSO. Electrophysiological recordings in animals, however, reported only minor functional changes in aged LSO. The perplexing discrepancy between anatomical and physiological observations suggests a role for activity-dependent plasticity that would help neurons retain their binaural tuning function despite loss of inhibitory inputs. To explore this hypothesis, we use a computational model of LSO to investigate mechanisms underlying the observed functional robustness against age-related loss of inhibitory inputs. The LSO model is an integrate-and-fire type enhanced with a small amount of low-voltage activated potassium conductance and driven with (in)homogeneous Poissonian inputs. Without synaptic input loss, model spike rates varied smoothly with interaural time and level differences, replicating empirical tuning properties of LSO. By reducing the number of inhibitory afferents to mimic age-related loss of inhibition, overall spike rates increased, which negatively impacted binaural tuning performance, measured as modulation depth and neuronal discriminability. To simulate a recovery process compensating for the loss of inhibitory fibers, the strength of remaining inhibitory inputs was increased. By this modification, effects of inhibition loss on binaural tuning were considerably weakened, leading to an improvement of functional performance. These neuron-level observations were further confirmed by population modeling, in which binaural tuning properties of multiple LSO neurons were varied according to empirical measurements. These results demonstrate the plausibility that homeostatic plasticity could effectively counteract known age-dependent loss of inhibitory fibers in LSO and suggest that behavioral degradation of sound localization might originate from changes occurring more centrally.

The acoustical effect of the neck frill of the frill-necked lizard (Chlamydosaurus kingii).

Animals localise sound by making use of acoustical cues resulting from space and frequency dependent filtering of sound by the head and body. Sound arrives at each ear at different times, with different intensities, and with varying spectral content, all of which are affected by the animal's head and the relative sound source position. Location cues in mammals benefit from structures (pinnae) that modify these cues and provide information that helps resolve the cone of confusion and provide cues to sound source elevation. Animals without pinnae must rely on other mechanisms to solve localisation problems. Most non-mammals lack pinna-like structures, but some possess other anatomical features that could influence hearing. One such animal is the frill-necked lizard (Chlamydosaurus kingii). The species' elaborate neck frill has been speculated to act as an aid to hearing, but no acoustical measurements have been reported. In this study, we characterise the frill's influence on the acoustical information available to the animal. Results suggest that the change in binaural cues is not sufficiently large to impact localisation behavior within the species' likely audiometric range; however, the frill does increase gain for sounds directly in front of the animal similar to a directional microphone.

Normative Study of the Binaural Interaction Component of the Human Auditory Brainstem Response as a Function of Interaural Time Differences.

OBJECTIVES: The binaural interaction component (BIC) of the auditory brainstem response (ABR) is obtained by subtracting the sum of the monaural right and left ear ABRs from the binaurally evoked ABR. The result is a small but prominent negative peak (herein called "DN1"), indicating a smaller binaural than summed ABR, which occurs around the latency of wave V or its roll-off slope. The BIC has been proposed to have diagnostic value as a biomarker of binaural processing abilities; however, there have been conflicting reports regarding the reliability of BIC measures in human subjects. The objectives of the current study were to: (1) examine prevalence of BIC across a large group of normal-hearing young adults; (2) determine effects of interaural time differences (ITDs) on BIC; and (3) examine any relationship between BIC and behavioral ITD discrimination acuity. DESIGN: Subjects were 40 normal-hearing adults (20 males and 20 females), aged 21 to 48 years, with no history of otologic or neurologic disorders. Midline ABRs were recorded from electrodes at high forehead (Fz) referenced to the nape of the neck (near the seventh cervical vertebra), with Fpz (low forehead) as the ground. ABRs were also recorded with a conventional earlobe reference for comparison to midline results. Stimuli were 90 dB peSPL biphasic clicks. For BIC measurements, stimuli were presented in a block as interleaved right monaural, left monaural, and binaural stimuli with 2000+ presentations per condition. Four measurements were averaged for a total of 8000+ stimuli per analyzed waveform. BIC was measured for ITD = 0 (simultaneous bilateral) and for ITDs of ±500 and ±750 µs. Subjects separately performed a lateralization task, using the same stimuli, to determine ITD discrimination thresholds. RESULTS: An identifiable BIC DN1 was obtained in 39 of 40 subjects at ITD = 0 µs in at least one of two measurement sessions, but was seen in lesser numbers of subjects in a single session or as ITD increased. BIC was most often seen when a subject was relaxed or sleeping, and less often when they fidgeted or reported neck tension, suggesting myogenic activity as a possible factor in disrupting BIC measurements. Mean BIC latencies systematically increased with increasing ITD, and mean BIC amplitudes tended to decrease. However, across subjects, there was no significant relationship between the amplitude or latency of the BIC and behavioral ITD thresholds. CONCLUSIONS: Consistent with previous studies, measurement of the BIC was time consuming and a BIC was sometimes difficult to obtain in awake normal-hearing subjects. The BIC will thus continue to be of limited clinical utility unless stimulus parameters and measurement techniques can be identified that produce a more robust response. Nonetheless, modulation of BIC characteristics by ITD supports the concept that the ABR BIC indexes aspects of binaural brainstem processing and thus may prove useful in selected research applications, e.g. in the examination of populations expected to have aberrant binaural signal processing ability.

Effects of interaural decoherence on sensitivity to interaural level differences across frequency.

The interaural level difference (ILD) is a robust indicator of sound source azimuth, and human ILD sensitivity persists under conditions that degrade normally-dominant interaural time difference (ITD) cues. Nonetheless, ILD sensitivity varies somewhat with both stimulus frequency and interaural correlation (coherence). To further investigate the combined binaural perceptual influence of these variables, the present study assessed ILD sensitivity at frequencies 250-4000 Hz using stimuli of varied interaural correlation. In the first of two experiments, ILD discrimination thresholds were modestly elevated, and subjective lateralization slightly reduced, for both half-correlated and uncorrelated narrowband noise tokens relative to correlated tokens. Different from thresholds in the correlated condition, which were worst at 1000 Hz [Grantham, D.W. (1984). J. Acoust. Soc. Am. 75, 1191-1194], thresholds in the decorrelated conditions were independent of frequency. However, intrinsic envelope fluctuations in narrowband stimuli caused moment-to-moment variation of the nominal ILD, complicating interpretation of measured thresholds. Thus, a second experiment employed low-fluctuation noise tokens, revealing a clear effect of interaural decoherence per se that was strongly frequency-dependent, decreasing in magnitude from low to high frequencies. Measurements are consistent with known integration times in ILD-sensitive neurons and also suggest persistent influences of covert ITD cues in putative "ILD" tasks.

A Comparison of Intracochlear Pressures During Ipsilateral and Contralateral Stimulation With a Bone Conduction Implant.

OBJECTIVES: To compare contralateral to ipsilateral stimulation with percutaneous and transcutaneous bone conduction implants. BACKGROUND: Bone conduction implants (BCIs) effectively treat conductive and mixed hearing losses. In some cases, such as in single-sided deafness, the BCI is implanted contralateral to the remaining healthy ear in an attempt to restore some of the benefits provided by binaural hearing. While the benefit of contralateral stimulation has been shown in at least some patients, it is not clear what cues or mechanisms contribute to this function. Previous studies have investigated the motion of the ossicular chain, skull, and round window in response to bone vibration. Here, we extend those reports by reporting simultaneous measurements of cochlear promontory velocity and intracochlear pressures during bone conduction stimulation with two common BCI attachments, and directly compare ipsilateral to contralateral stimulation. METHODS: Fresh-frozen whole human heads were prepared bilaterally with mastoidectomies. Intracochlear pressure (PIC) in the scala vestibuli (PSV) and tympani (PST) was measured with fiber optic pressure probes concurrently with cochlear promontory velocity (VProm) via laser Doppler vibrometry during stimulation provided with a closed-field loudspeaker or a BCI. Stimuli were pure tones between 120 and 10,240 Hz, and response magnitudes and phases for PIC and VProm were measured for air and bone conducted sound presentation. RESULTS: Contralateral stimulation produced lower response magnitudes and longer delays than ipsilateral in all measures, particularly for high-frequency stimulation. Contralateral response magnitudes were lower than ipsilateral response magnitudes by up to 10 to 15 dB above ~2 kHz for a skin-penetrating abutment, which increased to 25 to 30 dB and extended to lower frequencies when applied with a transcutaneous (skin drive) attachment. CONCLUSIONS: Transcranial attenuation and delay suggest that ipsilateral stimulation will be dominant for frequencies over ~1 kHz, and that complex phase interactions will occur during bilateral or bimodal stimulation. These effects indicate a mechanism by which bilateral users could gain some bilateral advantage.

Across Species "Natural Ablation" Reveals the Brainstem Source of a Noninvasive Biomarker of Binaural Hearing.

The binaural interaction component (BIC) of the auditory brainstem response is a noninvasive electroencephalographic signature of neural processing of binaural sounds. Despite its potential as a clinical biomarker, the neural structures and mechanism that generate the BIC are not known. We explore here the hypothesis that the BIC emerges from excitatory-inhibitory interactions in auditory brainstem neurons. We measured the BIC in response to click stimuli while varying interaural time differences (ITDs) in subjects of either sex from five animal species. Species had head sizes spanning a 3.5-fold range and correspondingly large variations in the sizes of the auditory brainstem nuclei known to process binaural sounds [the medial superior olive (MSO) and the lateral superior olive (LSO)]. The BIC was reliably elicited in all species, including those that have small or inexistent MSOs. In addition, the range of ITDs where BIC was elicited was independent of animal species, suggesting that the BIC is not a reflection of the processing of ITDs per se. Finally, we provide a model of the amplitude and latency of the BIC peak, which is based on excitatory-inhibitory synaptic interactions, without assuming any specific arrangement of delay lines. Our results show that the BIC is preserved across species ranging from mice to humans. We argue that this is the result of generic excitatory-inhibitory synaptic interactions at the level of the LSO, and thus best seen as reflecting the integration of binaural inputs as opposed to their spatial properties.SIGNIFICANCE STATEMENT Noninvasive electrophysiological measures of sensory system activity are critical for the objective clinical diagnosis of human sensory processing deficits. The binaural component of sound-evoked auditory brainstem responses is one such measure of binaural auditory coding fidelity in the early stages of the auditory system. Yet, the precise neurons that lead to this evoked potential are not fully understood. This paper provides a comparative study of this potential in different mammals and shows that it is preserved across species, from mice to men, despite large variations in morphology and neuroanatomy. Our results confirm its relevance to the assessment of binaural hearing integrity in humans and demonstrates how it can be used to bridge the gap between rodent models and humans.

Between-ear sound frequency disparity modulates a brain stem biomarker of binaural hearing.

The auditory brain stem response (ABR) is an evoked potential that indexes a cascade of neural events elicited by sound. In the present study we evaluated the influence of sound frequency on a derived component of the ABR known as the binaural interaction component (BIC). Specifically, we evaluated the effect of acoustic interaural (between-ear) frequency mismatch on BIC amplitude. Goals were to 1) increase basic understanding of sound features that influence this long-studied auditory potential and 2) gain insight about the persistence of the BIC with interaural electrode mismatch in human users of bilateral cochlear implants, presently a limitation on the prospective utility of the BIC in audiological settings. Data were collected in an animal model that is audiometrically similar to humans, the chinchilla (Chinchilla lanigera; 6 females). Frequency disparities and amplitudes of acoustic stimuli were varied over broad ranges, and associated variation of BIC amplitude was quantified. Subsequently, responses were simulated with the use of established models of the brain stem pathway thought to underlie the BIC. Collectively, the data demonstrate that at high sound intensities (≥85 dB SPL), the acoustically elicited BIC persisted with interaurally disparate stimulation (click frequencies ≥1.5 octaves apart). However, sharper tuning emerged at moderate sound intensities (65 dB SPL), with the largest BIC occurring for stimulus frequencies within ~0.8 octaves, equivalent to ±1 mm in cochlear place. Such responses were consistent with simulated responses of the presumed brain stem generator of the BIC, the lateral superior olive. The data suggest that leveraging focused electrical stimulation strategies could improve BIC-based bilateral cochlear implant fitting outcomes.NEW & NOTEWORTHY Traditional hearing tests evaluate each ear independently. Diagnosis and treatment of binaural hearing dysfunction remains a basic challenge for hearing clinicians. We demonstrate in an animal model that the prospective utility of a noninvasive electrophysiological signature of binaural function, the binaural interaction component (BIC), depends strongly on the intensity of auditory stimulation. Data suggest that more informative BIC measurements could be obtained with clinical protocols leveraging stimuli restricted in effective bandwidth.

Air- and Bone-Conducted Sources of Feedback With an Active Middle Ear Implant.

OBJECTIVES: Active middle ear implants (AMEI) have been used to treat hearing loss in patients for whom conventional hearing aids are unsuccessful for varied biologic or personal reasons. Several studies have discussed feedback as a potential complication of AMEI usage, though the feedback pathway is not well understood. While reverse propagation of an acoustic signal through the ossicular chain and tympanic membrane constitutes an air-conducted source of feedback, the implanted nature of the device microphone near the mastoid cortex suggests that bone conduction pathways may potentially be another significant factor. This study examines the relative contributions of potential sources of feedback during stimulation with an AMEI. DESIGN: Four fresh-frozen, hemi-sectioned, human cadaver specimens were prepared with a mastoid antrostomy and atticotomy to visualize the posterior incus body. A Carina active middle ear implant actuator (Cochlear Ltd., Boulder, CO) was coupled to the incus by two means: (1) a stereotactic arm mounted independently of the specimen and (2) a fixation bracket anchored directly to the mastoid cortical bone. The actuator was driven with pure-tone frequencies in 1/4 octave steps from 500 to 6000 Hz. Acoustic sound intensity in the ear canal was measured with a probe tube microphone (Bruel & Kjær, Nærum, Denmark). Bone-conducted vibration was quantified with a single-axis laser Doppler vibrometer (Polytec Inc., Irvine, CA) from both a piece of reflective tape placed on the skin overlying the mastoid and a bone-anchored titanium screw and pedestal (Cochlear Ltd., Centennial, CO) implanted in the cortical mastoid bone. RESULTS: Microphone measurements revealed ear-canal pressures of 60-89 dB SPL, peaking in the frequency range below 2 kHz. Peak LDV measurements were greatest on the mastoid bone (0.32-0.79 mm/s with mounting bracket and 0.21-0.36 mm/s with the stereotactic suspension); peak measurements on the skin ranged from 0.05 to 0.15 mm/s with the bracket and 0.03 to 0.13 mm/s with stereotactic suspension. CONCLUSION: AMEI produce both air- and bone-conducted signals of adequate strength to be detected by the implanted device microphone, potentially resulting in reamplification. Understanding the relative contribution of these sources may play an important role in the development of targeted mitigation algorithms, as well as surgical techniques emphasizing acoustic isolation.

Representation of Multidimensional Stimuli: Quantifying the Most Informative Stimulus Dimension from Neural Responses.

A common way to assess the function of sensory neurons is to measure the number of spikes produced by individual neurons while systematically varying a given dimension of the stimulus. Such measured tuning curves can then be used to quantify the accuracy of the neural representation of the stimulus dimension under study, which can in turn be related to behavioral performance. However, tuning curves often change shape when other dimensions of the stimulus are varied, reflecting the simultaneous sensitivity of neurons to multiple stimulus features. Here we illustrate how one-dimensional information analyses are misleading in this context, and propose a framework derived from Fisher information that allows the quantification of information carried by neurons in multidimensional stimulus spaces. We use this method to probe the representation of sound localization in auditory neurons of chinchillas and guinea pigs of both sexes, and show how heterogeneous tuning properties contribute to a representation of sound source position that is robust to changes in sound level.SIGNIFICANCE STATEMENT Sensory neurons' responses are typically modulated simultaneously by numerous stimulus properties, which can result in an overestimation of neural acuity with existing one-dimensional neural information transmission measures. To overcome this limitation, we develop new, compact expressions of Fisher information-derived measures that bound the robust encoding of separate stimulus dimensions in the context of multidimensional stimuli. We apply this method to the problem of the representation of sound source location in the face of changes in sound source level by neurons of the auditory midbrain.

Physiological models of the lateral superior olive.

In computational biology, modeling is a fundamental tool for formulating, analyzing and predicting complex phenomena. Most neuron models, however, are designed to reproduce certain small sets of empirical data. Hence their outcome is usually not compatible or comparable with other models or datasets, making it unclear how widely applicable such models are. In this study, we investigate these aspects of modeling, namely credibility and generalizability, with a specific focus on auditory neurons involved in the localization of sound sources. The primary cues for binaural sound localization are comprised of interaural time and level differences (ITD/ILD), which are the timing and intensity differences of the sound waves arriving at the two ears. The lateral superior olive (LSO) in the auditory brainstem is one of the locations where such acoustic information is first computed. An LSO neuron receives temporally structured excitatory and inhibitory synaptic inputs that are driven by ipsi- and contralateral sound stimuli, respectively, and changes its spike rate according to binaural acoustic differences. Here we examine seven contemporary models of LSO neurons with different levels of biophysical complexity, from predominantly functional ones ('shot-noise' models) to those with more detailed physiological components (variations of integrate-and-fire and Hodgkin-Huxley-type). These models, calibrated to reproduce known monaural and binaural characteristics of LSO, generate largely similar results to each other in simulating ITD and ILD coding. Our comparisons of physiological detail, computational efficiency, predictive performances, and further expandability of the models demonstrate (1) that the simplistic, functional LSO models are suitable for applications where low computational costs and mathematical transparency are needed, (2) that more complex models with detailed membrane potential dynamics are necessary for simulation studies where sub-neuronal nonlinear processes play important roles, and (3) that, for general purposes, intermediate models might be a reasonable compromise between simplicity and biological plausibility.

Slow Temporal Integration Enables Robust Neural Coding and Perception of a Cue to Sound Source Location.

UNLABELLED: In mammals, localization of sound sources in azimuth depends on sensitivity to interaural differences in sound timing (ITD) and level (ILD). Paradoxically, while typical ILD-sensitive neurons of the auditory brainstem require millisecond synchrony of excitatory and inhibitory inputs for the encoding of ILDs, human and animal behavioral ILD sensitivity is robust to temporal stimulus degradations (e.g., interaural decorrelation due to reverberation), or, in humans, bilateral clinical device processing. Here we demonstrate that behavioral ILD sensitivity is only modestly degraded with even complete decorrelation of left- and right-ear signals, suggesting the existence of a highly integrative ILD-coding mechanism. Correspondingly, we find that a majority of auditory midbrain neurons in the central nucleus of the inferior colliculus (of chinchilla) effectively encode ILDs despite complete decorrelation of left- and right-ear signals. We show that such responses can be accounted for by relatively long windows of bilateral excitatory-inhibitory interaction, which we explicitly measure using trains of narrowband clicks. Neural and behavioral data are compared with the outputs of a simple model of ILD processing with a single free parameter, the duration of excitatory-inhibitory interaction. Behavioral, neural, and modeling data collectively suggest that ILD sensitivity depends on binaural integration of excitation and inhibition within a ≳3 ms temporal window, significantly longer than observed in lower brainstem neurons. This relatively slow integration potentiates a unique role for the ILD system in spatial hearing that may be of particular importance when informative ITD cues are unavailable. SIGNIFICANCE STATEMENT: In mammalian hearing, interaural differences in the timing (ITD) and level (ILD) of impinging sounds carry critical information about source location. However, natural sounds are often decorrelated between the ears by reverberation and background noise, degrading the fidelity of both ITD and ILD cues. Here we demonstrate that behavioral ILD sensitivity (in humans) and neural ILD sensitivity (in single neurons of the chinchilla auditory midbrain) remain robust under stimulus conditions that render ITD cues undetectable. This result can be explained by "slow" temporal integration arising from several-millisecond-long windows of excitatory-inhibitory interaction evident in midbrain, but not brainstem, neurons. Such integrative coding can account for the preservation of ILD sensitivity despite even extreme temporal degradations in ecological acoustic stimuli.

Roles for Coincidence Detection in Coding Amplitude-Modulated Sounds.

Many sensory neurons encode temporal information by detecting coincident arrivals of synaptic inputs. In the mammalian auditory brainstem, binaural neurons of the medial superior olive (MSO) are known to act as coincidence detectors, whereas in the lateral superior olive (LSO) roles of coincidence detection have remained unclear. LSO neurons receive excitatory and inhibitory inputs driven by ipsilateral and contralateral acoustic stimuli, respectively, and vary their output spike rates according to interaural level differences. In addition, LSO neurons are also sensitive to binaural phase differences of low-frequency tones and envelopes of amplitude-modulated (AM) sounds. Previous physiological recordings in vivo found considerable variations in monaural AM-tuning across neurons. To investigate the underlying mechanisms of the observed temporal tuning properties of LSO and their sources of variability, we used a simple coincidence counting model and examined how specific parameters of coincidence detection affect monaural and binaural AM coding. Spike rates and phase-locking of evoked excitatory and spontaneous inhibitory inputs had only minor effects on LSO output to monaural AM inputs. In contrast, the coincidence threshold of the model neuron affected both the overall spike rates and the half-peak positions of the AM-tuning curve, whereas the width of the coincidence window merely influenced the output spike rates. The duration of the refractory period affected only the low-frequency portion of the monaural AM-tuning curve. Unlike monaural AM coding, temporal factors, such as the coincidence window and the effective duration of inhibition, played a major role in determining the trough positions of simulated binaural phase-response curves. In addition, empirically-observed level-dependence of binaural phase-coding was reproduced in the framework of our minimalistic coincidence counting model. These modeling results suggest that coincidence detection of excitatory and inhibitory synaptic inputs is essential for LSO neurons to encode both monaural and binaural AM sounds.

Test-Retest Reliability of the Binaural Interaction Component of the Auditory Brainstem Response.

OBJECTIVES: The binaural interaction component (BIC) is the residual auditory brainstem response (ABR) obtained after subtracting the sum of monaurally evoked from binaurally evoked ABRs. The DN1 peak-the first negative peak of the BIC-has been postulated to have diagnostic value as a biomarker for binaural hearing abilities. Indeed, not only do DN1 amplitudes depend systematically upon binaural cues to location (interaural time and level differences), but they are also predictive of central hearing deficits in humans. A prominent issue in using BIC measures as a diagnostic biomarker is that DN1 amplitudes not only exhibit considerable variability across subjects, but also within subjects across different measurement sessions. DESIGN: In this study, the authors investigate the DN1 amplitude measurement reliability by conducting repeated measurements on different days in eight adult guinea pigs. RESULTS: Despite consistent ABR thresholds, ABR and DN1 amplitudes varied between and within subjects across recording sessions. However, the study analysis reveals that DN1 amplitudes varied proportionally with parent monaural ABR amplitudes, suggesting that common experimental factors likely account for the variability in both waveforms. Despite this variability, the authors show that the shape of the dependence between DN1 amplitude and interaural time difference is preserved. The authors then provide a BIC normalization strategy using monaural ABR amplitude that reduces the variability of DN1 peak measurements. Finally, the authors evaluate this normalization strategy in the context of detecting changes of the DN1 amplitude-to-interaural time difference relationship. CONCLUSIONS: The study results indicate that the BIC measurement variability can be reduced by a factor of two by performing a simple and objective normalization operation. The authors discuss the potential for this normalized BIC measure as a biomarker for binaural hearing.

The Physiological Basis and Clinical Use of the Binaural Interaction Component of the Auditory Brainstem Response.

The auditory brainstem response (ABR) is a sound-evoked noninvasively measured electrical potential representing the sum of neuronal activity in the auditory brainstem and midbrain. ABR peak amplitudes and latencies are widely used in human and animal auditory research and for clinical screening. The binaural interaction component (BIC) of the ABR stands for the difference between the sum of the monaural ABRs and the ABR obtained with binaural stimulation. The BIC comprises a series of distinct waves, the largest of which (DN1) has been used for evaluating binaural hearing in both normal hearing and hearing-impaired listeners. Based on data from animal and human studies, the authors discuss the possible anatomical and physiological bases of the BIC (DN1 in particular). The effects of electrode placement and stimulus characteristics on the binaurally evoked ABR are evaluated. The authors review how interaural time and intensity differences affect the BIC and, analyzing these dependencies, draw conclusion about the mechanism underlying the generation of the BIC. Finally, the utility of the BIC for clinical diagnoses are summarized.

Sound frequency-invariant neural coding of a frequency-dependent cue to sound source location.

The century-old duplex theory of sound localization posits that low- and high-frequency sounds are localized with two different acoustical cues, interaural time and level differences (ITDs and ILDs), respectively. While behavioral studies in humans and behavioral and neurophysiological studies in a variety of animal models have largely supported the duplex theory, behavioral sensitivity to ILD is curiously invariant across the audible spectrum. Here we demonstrate that auditory midbrain neurons in the chinchilla (Chinchilla lanigera) also encode ILDs in a frequency-invariant manner, efficiently representing the full range of acoustical ILDs experienced as a joint function of sound source frequency, azimuth, and distance. We further show, using Fisher information, that nominal "low-frequency" and "high-frequency" ILD-sensitive neural populations can discriminate ILD with similar acuity, yielding neural ILD discrimination thresholds for near-midline sources comparable to behavioral discrimination thresholds estimated for chinchillas. These findings thus suggest a revision to the duplex theory and reinforce ecological and efficiency principles that hold that neural systems have evolved to encode the spectrum of biologically relevant sensory signals to which they are naturally exposed.

Amplitude and phase equalization of stimuli for click evoked auditory brainstem responses.

Although auditory brainstem responses (ABRs), the sound-evoked brain activity in response to transient sounds, are routinely measured in humans and animals there are often differences in ABR waveform morphology across studies. One possible reason may be the method of stimulus calibration. To explore this hypothesis, click-evoked ABRs were measured from seven ears in four Mongolian gerbils (Meriones unguiculatus) using three common spectrum calibration strategies: Minimum phase filter, linear phase filter, and no filter. The results show significantly higher ABR amplitude and signal-to-noise ratio, and better waveform resolution with the minimum phase filtered click than with the other strategies.

Biophysics of directional hearing in the American alligator (Alligator mississippiensis).

Physiological and anatomical studies have suggested that alligators have unique adaptations for spatial hearing. Sound localization cues are primarily generated by the filtering of sound waves by the head. Different vertebrate lineages have evolved external and/or internal anatomical adaptations to enhance these cues, such as pinnae and interaural canals. It has been hypothesized that in alligators, directionality may be enhanced via the acoustic coupling of middle ear cavities, resulting in a pressure difference receiver (PDR) mechanism. The experiments reported here support a role for a PDR mechanism in alligator sound localization by demonstrating that (1) acoustic space cues generated by the external morphology of the animal are not sufficient to generate location cues that match physiological sensitivity, (2) continuous pathways between the middle ears are present to provide an anatomical basis for coupling, (3) the auditory brainstem response shows some directionality, and (4) eardrum movement is directionally sensitive. Together, these data support the role of a PDR mechanism in crocodilians and further suggest this mechanism is a shared archosaur trait, most likely found also in the extinct dinosaurs.

The rapid decline in interaural-time-difference sensitivity for pure tones can be explained by peripheral filtering.

Purpose: The interaural time difference (ITD) is a primary horizontal-plane sound localization cue computed in the auditory brainstem. ITDs are accessible in the temporal fine structure of pure tones with a frequency of no higher than about 1400 Hz. Explaining how listeners' ITD sensitivity transitions from very best sensitivity near 700 Hz to impossible to detect within 1 octave currently lacks a fully compelling physiological explanation. Here, it was hypothesized that the rapid decline in ITD sensitivity is dictated not by a central neural limitation but by initial peripheral sound encoding, specifically, the low-frequency (apical) edge of the cochlear excitation pattern produced by a pure tone. Methods: ITD sensitivity was measured in 16 normal-hearing listeners as a joint function of frequency (900-1500 Hz) and level (10-50 dB sensation level). Results: Performance decreased with increasing frequency and decreasing sound level. The slope of performance decline was 90 dB/octave, consistent with the low-frequency slope of the cochlear excitation pattern. Conclusion: Fine-structure ITD sensitivity near 1400 Hz may be conveyed primarily by "off-frequency" activation of neurons tuned to lower frequencies near 700 Hz. Physiologically, this could be realized by having neurons sensitive to fine-structure ITD up to only about 700 Hz. A more extreme model would have only a single narrow channel near 700 Hz that conveys fine-structure ITDs. Such a model is a major simplification and departure from the classic formulation of the binaural display, which consists of a matrix of neurons tuned to a wide range of relevant frequencies and ITDs.

Computational model for synthesizing auditory brainstem responses to assess neuronal alterations in aging and autistic animal models.

The auditory brainstem response (ABR) is a widely used objective electrophysiology measure for non-invasively assessing auditory function and neural activities in the auditory brainstem, but its ability to reflect detailed neuronal processes is limited due to the averaging nature of the electroencephalogram recordings. This study addresses this limitation by developing a computational model of the auditory brainstem which is capable of synthesizing ABR traces based on a large, population scale neural extrapolation of a spiking neuronal network of auditory brainstem neural circuitry. The model was able to recapitulate alterations in ABR waveform morphology that have been shown to be present in two medical conditions: animal models of autism and aging. Moreover, in both of these conditions, these ABR alterations are caused by known distinct changes in auditory brainstem physiology, and the model could recapitulate these changes. In the autism model, the simulation revealed myelin deficits and hyperexcitability, which caused a decreased wave III amplitude and a prolonged wave III-V interval, consistent with experimentally recorded ABRs in Fmr1-KO mice. In the aging model, the model recapitulated ABRs recorded in aged gerbils and indicated a reduction in activity in the medial nucleus of the trapezoid body (MNTB), a finding validated by confocal imaging data. These results demonstrate not only the model's accuracy but also its capability of linking features of ABR morphologies to underlying neuronal properties and suggesting follow-up physiological experiments. Significance Statement: This study presents a novel computational model of the auditory brainstem, capable of synthesizing auditory brainstem response (ABR) traces by simulating large-scale neuronal activities. Addressing limitations of traditional ABR measurements, the model links ABR waveform features to underlying neuronal properties. Validated using empirical ABRs from animal models of autism and aging, the model accurately reproduced observed ABR alterations, revealing influences of myelin deficits and hyperexcitability in Fragile X syndrome, and degraded inhibitory activity in aging. These findings, supported by experimental data, demonstrate the model's potential for predicting changes in auditory brainstem physiology and guiding further physiological investigations, thus advancing our understanding of auditory neural processes.