Neural correlates of tonal loudness, intensity discrimination, and duration discrimination.

A long-standing quest in audition concerns understanding relations between behavioral measures and neural representations of changes in sound intensity. Here, we examined relations between aspects of intensity perception and central neural responses within the inferior colliculus of unanesthetized rabbits (by averaging the population's spike count/level functions). We found parallels between the population's neural output and: (1) how loudness grows with intensity; (2) how loudness grows with duration; (3) how discrimination of intensity improves with increasing sound level; (4) findings that intensity discrimination does not depend on duration; and (5) findings that duration discrimination is a constant fraction of base duration.

Amplitude modulation transfer functions reveal opposing populations within both the inferior colliculus and medial geniculate body.

Based on single-unit recordings of modulation transfer functions (MTFs) in the inferior colliculus (IC) and the medial geniculate body (MGB) of the unanesthetized rabbit, we identified two opposing populations: band-enhanced (BE) and band-suppressed (BS) neurons. In response to amplitude-modulated (AM) sounds, firing rates of BE and BS neurons were enhanced and suppressed, respectively, relative to their responses to an unmodulated noise with a one-octave bandwidth. We also identified a third population, designated hybrid neurons, whose firing rates were enhanced by some modulation frequencies and suppressed by others. Our finding suggests that perception of AM may be based on the co-occurrence of enhancement and suppression of responses of the opposing populations of neurons. Because AM carries an important part of the content of speech, progress in understanding auditory processing of AM sounds should lead to progress in understanding speech perception. Each of the BE, BS, and hybrid types of MTFs comprised approximately one-third of the total sample. Modulation envelopes having short duty cycles of 20-50% and raised-sine envelopes accentuated the degree of enhancement and suppression and sharpened tuning of the MTFs. With sinusoidal envelopes, peak modulation frequencies were centered around 32-64 Hz among IC BE neurons, whereas the MGB peak frequencies skewed toward lower frequencies, with a median of 16 Hz. We also tested an auditory-brainstem model and found that a simple circuit containing fast excitatory synapses and slow inhibitory synapses was able to reproduce salient features of the BE- and BS-type MTFs of IC neurons.NEW & NOTEWORTHY Opposing populations of neurons have been identified in the mammalian auditory midbrain and thalamus. In response to amplitude-modulated sounds, responses of one population (band-enhanced) increased whereas responses of another (band-suppressed) decreased relative to their responses to an unmodulated sound. These opposing auditory populations are analogous to the ON and OFF populations of the visual system and may improve transfer of information carried by the temporal envelopes of complex sounds such as speech.

Speech Coding in the Midbrain: Effects of Sensorineural Hearing Loss.

In response to voiced speech sounds, auditory-nerve (AN) fibres phase-lock to harmonics near best frequency (BF) and to the fundamental frequency (F0) of voiced sounds. Due to nonlinearities in the healthy ear, phase-locking in each frequency channel is dominated either by a single harmonic, for channels tuned near formants, or by F0, for channels between formants. The alternating dominance of these factors sets up a robust pattern of F0-synchronized rate across best frequency (BF). This profile of a temporally coded measure is transformed into a mean rate profile in the midbrain (inferior colliculus, IC), where neurons are sensitive to low-frequency fluctuations. In the impaired ear, the F0-synchronized rate profile is affected by several factors: Reduced synchrony capture decreases the dominance of a single harmonic near BF on the response. Elevated thresholds also reduce the effect of rate saturation, resulting in increased F0-synchrony. Wider peripheral tuning results in a wider-band envelope with reduced F0 amplitude. In general, sensorineural hearing loss reduces the contrast in AN F0-synchronized rates across BF. Computational models for AN and IC neurons illustrate how hearing loss would affect the F0-synchronized rate profiles set up in response to voiced speech sounds.

Auditory distance coding in rabbit midbrain neurons and human perception: monaural amplitude modulation depth as a cue.

Mechanisms underlying sound source distance localization are not well understood. Here we tested the hypothesis that a novel mechanism can create monaural distance sensitivity: a combination of auditory midbrain neurons' sensitivity to amplitude modulation (AM) depth and distance-dependent loss of AM in reverberation. We used virtual auditory space (VAS) methods for sounds at various distances in anechoic and reverberant environments. Stimulus level was constant across distance. With increasing modulation depth, some rabbit inferior colliculus neurons increased firing rates whereas others decreased. These neurons exhibited monotonic relationships between firing rates and distance for monaurally presented noise when two conditions were met: (1) the sound had AM, and (2) the environment was reverberant. The firing rates as a function of distance remained approximately constant without AM in either environment and, in an anechoic condition, even with AM. We corroborated this finding by reproducing the distance sensitivity using a neural model. We also conducted a human psychophysical study using similar methods. Normal-hearing listeners reported perceived distance in response to monaural 1 octave 4 kHz noise source sounds presented at distances of 35-200 cm. We found parallels between the rabbit neural and human responses. In both, sound distance could be discriminated only if the monaural sound in reverberation had AM. These observations support the hypothesis. When other cues are available (e.g., in binaural hearing), how much the auditory system actually uses the AM as a distance cue remains to be determined.

Near-field discrimination of sound source distance in the rabbit.

The acoustical cues and physiological processing mechanisms underlying the perception of the distance of sound sources are not well understood. To understand the relation between physiology and behavior, a first step is to use an animal model to study distance sensitivity. The goal of these experiments was to establish the capacity of the Dutch-belted rabbit to discriminate between sound sources at two distances. Trains of noise bursts were presented from speakers that were located either directly in front of the rabbit or at a 45 ° angle in azimuth. The reference speaker was positioned at distances of 20, 40, and 60 cm from the subject, and the more distant test speaker was systematically moved to determine the smallest difference in distance that could be reliably discriminated by the subject. Noise stimuli had one of three bandwidths: wideband (0.1-10 kHz), low-pass (0.1-3 kHz), or high-pass (3-10 kHz). The mean stimulus level was 60 dB sound pressure level (SPL) at the location of the rabbit's head, and the level was roved over a 12-dB range from trial to trial to reduce the availability of level cues. An operant one-interval two-alternative non-forced choice task was used, with a blocked two-down-one-up tracking procedure to determine the distance discriminability. Rabbits were consistently able to discriminate two distances when they were sufficiently separated. Sensitivity was better when the reference distance was 60 cm at either azimuth (distance ratio = 1.5) and was worse when the reference distance was 20 cm (distance ratio = 2.4 at 0 ° and 1.75 at 45 °).

Azimuth and envelope coding in the inferior colliculus of the unanesthetized rabbit: effect of reverberation and distance.

Recognition and localization of a sound are the major functions of the auditory system. In real situations, the listener and different degrees of reverberation transform the signal between the source and the ears. The present study was designed to provide these transformations and examine their influence on neural responses. Using the virtual auditory space (VAS) method to create anechoic and moderately and highly reverberant environments, we found the following: 1) In reverberation, azimuth tuning was somewhat degraded with distance whereas the direction of azimuth tuning remained unchanged. These features remained unchanged in the anechoic condition. 2) In reverberation, azimuth tuning and envelope synchrony were degraded most for neurons with low best frequencies and least for neurons with high best frequencies. 3) More neurons showed envelope synchrony to binaural than to monaural stimulation in both anechoic and reverberant environments. 4) The percentage of envelope-coding neurons and their synchrony decreased in reverberation with distance, whereas it remained constant in the anechoic condition. 5) At far distances, for both binaural and monaural stimulation, the neural gain in reverberation could be as high as 30 dB and as much as 10 dB higher than those in the anechoic condition. 6) The majority of neurons were able to code both envelope and azimuth in all of the environments. This study provides a foundation for understanding the neural coding of azimuth and envelope synchrony at different distances in reverberant and anechoic environments. This is necessary to understand how the auditory system processes "where" and "what" information in real environments.

Conditional knockout of tumor overexpressed gene in mouse neurons affects RNA granule assembly, granule translation, LTP and short term habituation.

In neurons, specific RNAs are assembled into granules, which are translated in dendrites, however the functional consequences of granule assembly are not known. Tumor overexpressed gene (TOG) is a granule-associated protein containing multiple binding sites for heterogeneous nuclear ribonucleoprotein (hnRNP) A2, another granule component that recognizes cis-acting sequences called hnRNP A2 response elements (A2REs) present in several granule RNAs. Translation in granules is sporadic, which is believed to reflect monosomal translation, with occasional bursts, which are believed to reflect polysomal translation. In this study, TOG expression was conditionally knocked out (TOG cKO) in mouse hippocampal neurons using cre/lox technology. In TOG cKO cultured neurons granule assembly and bursty translation of activity-regulated cytoskeletal associated (ARC) mRNA, an A2RE RNA, are disrupted. In TOG cKO brain slices synaptic sensitivity and long term potentiation (LTP) are reduced. TOG cKO mice exhibit hyperactivity, perseveration and impaired short term habituation. These results suggest that in hippocampal neurons TOG is required for granule assembly, granule translation and synaptic plasticity, and affects behavior.

Approaches to the study of neural coding of sound source location and sound envelope in real environments.

The major functions of the auditory system are recognition (what is the sound) and localization (where is the sound). Although each of these has received considerable attention, rarely are they studied in combination. Furthermore, the stimuli used in the bulk of studies did not represent sound location in real environments and ignored the effects of reverberation. Another ignored dimension is the distance of a sound source. Finally, there is a scarcity of studies conducted in unanesthetized animals. We illustrate a set of efficient methods that overcome these shortcomings. We use the virtual auditory space method (VAS) to efficiently present sounds at different azimuths, different distances and in different environments. Additionally, this method allows for efficient switching between binaural and monaural stimulation and alteration of acoustic cues singly or in combination to elucidate neural mechanisms underlying localization and recognition. Such procedures cannot be performed with real sound field stimulation. Our research is designed to address the following questions: Are IC neurons specialized to process what and where auditory information? How does reverberation and distance of the sound source affect this processing? How do IC neurons represent sound source distance? Are neural mechanisms underlying envelope processing binaural or monaural?

Amplitude modulation detection by human listeners in reverberant sound fields: Carrier bandwidth effects and binaural versus monaural comparison.

Previous work [Zahorik et al., POMA, 12, 050005 (2011)] has reported that for a broadband noise carrier signal in a simulated reverberant sound field, human sensitivity to amplitude modulation (AM) is higher than would be predicted based on the broadband acoustical modulation transfer function (MTF) of the listening environment. Interpretation of this result was complicated by the fact that acoustical MTFs of rooms are often quite different for different carrier frequency regions, and listeners may have selectively responded to advantageous carrier frequency regions where the effective acoustic modulation loss due to the room was less than indicated by a broadband acoustic MTF analysis. Here, AM sensitivity testing and acoustic MTF analyses were expanded to include narrowband noise carriers (1-octave and 1/3-octave bands centered at 4 kHz), as well as monaural and binaural listening conditions. Narrowband results were found to be consistent with broadband results: In a reverberant sound field, human AM sensitivity is higher than indicated by the acoustical MTFs. The effect was greatest for modulation frequencies above 32 Hz and was present whether the stimulation was monaural or binaural. These results are suggestive of mechanisms that functionally enhance modulation in reverberant listening.

Spatial tuning to sound-source azimuth in the inferior colliculus of unanesthetized rabbit.

Despite decades of research devoted to the study of inferior colliculus (IC) neurons' tuning to sound-source azimuth, there remain many unanswered questions because no previous study has examined azimuth tuning over a full range of 360° azimuths at a wide range of stimulus levels in an unanesthetized preparation. Furthermore, a comparison of azimuth tuning to binaural and contralateral ear stimulation over ranges of full azimuths and widely varying stimulus levels has not previously been reported. To fill this void, we have conducted a study of azimuth tuning in the IC of the unanesthetized rabbit over a 300° range of azimuths at stimulus levels of 10-50 dB above neural threshold to both binaural and contralateral ear stimulation using virtual auditory space stimuli. This study provides systematic evidence for neural coding of azimuth. We found the following: 1) level-tolerant azimuth tuning was observed in the top 35% regarding vector strength and in the top 15% regarding vector angle of IC neurons; 2) preserved azimuth tuning to binaural stimulation at high stimulus levels was created as a consequence of binaural facilitation in the contralateral sound field and binaural suppression in the ipsilateral sound field; 3) the direction of azimuth tuning to binaural stimulation was primarily in the contralateral sound field, and its center shifted laterally toward -90° with increasing stimulus level; 4) at 10 dB, azimuth tuning to binaural and contralateral stimulation was similar, indicating that it was mediated by monaural mechanisms; and 5) at higher stimulus levels, azimuth tuning to contralateral ear stimulation was severely degraded. These findings form a foundation for understanding neural mechanisms of localizing sound-source azimuth.

Amplitude modulation detection by human listeners in sound fields.

The temporal modulation transfer function (TMTF) approach allows techniques from linear systems analysis to be used to predict how the auditory system will respond to arbitrary patterns of amplitude modulation (AM). Although this approach forms the basis for a standard method of predicting speech intelligibility based on estimates of the acoustical modulation transfer function (MTF) between source and receiver, human sensitivity to AM as characterized by the TMTF has not been extensively studied under realistic listening conditions, such as in reverberant sound fields. Here, TMTFs (octave bands from 2 - 512 Hz) were obtained in 3 listening conditions simulated using virtual auditory space techniques: diotic, anechoic sound field, reverberant room sound field. TMTFs were then related to acoustical MTFs estimated using two different methods in each of the listening conditions. Both diotic and anechoic data were found to be in good agreement with classic results, but AM thresholds in the reverberant room were lower than predictions based on acoustical MTFs. This result suggests that simple linear systems techniques may not be appropriate for predicting TMTFs from acoustical MTFs in reverberant sound fields, and may be suggestive of mechanisms that functionally enhance modulation during reverberant listening.

Acoustic cues for sound source distance and azimuth in rabbits, a racquetball and a rigid spherical model.

There are numerous studies measuring the transfer functions representing signal transformation between a source and each ear canal, i.e., the head-related transfer functions (HRTFs), for various species. However, only a handful of these address the effects of sound source distance on HRTFs. This is the first study of HRTFs in the rabbit where the emphasis is on the effects of sound source distance and azimuth on HRTFs. With the rabbit placed in an anechoic chamber, we made acoustic measurements with miniature microphones placed deep in each ear canal to a sound source at different positions (10-160 cm distance, ±150° azimuth). The sound was a logarithmically swept broadband chirp. For comparisons, we also obtained the HRTFs from a racquetball and a computational model for a rigid sphere. We found that (1) the spectral shape of the HRTF in each ear changed with sound source location; (2) interaural level difference (ILD) increased with decreasing distance and with increasing frequency. Furthermore, ILDs can be substantial even at low frequencies when distance is close; and (3) interaural time difference (ITD) decreased with decreasing distance and generally increased with decreasing frequency. The observations in the rabbit were reproduced, in general, by those in the racquetball, albeit greater in magnitude in the rabbit. In the sphere model, the results were partly similar and partly different than those in the racquetball and the rabbit. These findings refute the common notions that ILD is negligible at low frequencies and that ITD is constant across frequency. These misconceptions became evident when distance-dependent changes were examined.

Acoustic recordings in human ear canals to sounds at different locations.

The head and pinna shape the sound reaching the tympanum. We explored this signal transformation in humans and a mini basketball for different sound locations in an anechoic chamber. For humans, we embedded microphones in ear molds that were custom fitted to the subject's ear canal. For the ball, the microphones were flush with the surface at +/- 90 degrees azimuths on the equator. Sounds were generated with a custom point source. In the ball, the signal level was nearly flat across frequency, with no gains. In contrast, in the ears, signal level changed in a complex way across frequency, with considerable gains. For frequencies < 2 kHz, the interaural level difference (ILD) increased with decreasing distance similarly in the human ears and ball. For frequencies > 4 kHz, ILDs in the human ears were larger and more complex than those in the ball such that the human ILDs were nonmonotonic with distance whereas the ball ILDs were monotonic with distance.

Processing temporal modulations in binaural and monaural auditory stimuli by neurons in the inferior colliculus and auditory cortex.

Processing dynamic changes in the stimulus stream is a major task for sensory systems. In the auditory system, an increase in the temporal integration window between the inferior colliculus (IC) and auditory cortex is well known for monaural signals such as amplitude modulation, but a similar increase with binaural signals has not been demonstrated. To examine the limits of binaural temporal processing at these brain levels, we used the binaural beat stimulus, which causes a fluctuating interaural phase difference, while recording from neurons in the unanesthetized rabbit. We found that the cutoff frequency for neural synchronization to the binaural beat frequency (BBF) decreased between the IC and auditory cortex, and that this decrease was associated with an increase in the group delay. These features indicate that there is an increased temporal integration window in the cortex compared to the IC, complementing that seen with monaural signals. Comparable measurements of responses to amplitude modulation showed that the monaural and binaural temporal integration windows at the cortical level were quantitatively as well as qualitatively similar, suggesting that intrinsic membrane properties and afferent synapses to the cortical neurons govern the dynamic processing. The upper limits of synchronization to the BBF and the band-pass tuning characteristics of cortical neurons are a close match to human psychophysics.

Optimizing the stimuli to evoke the amplitude modulation following response (AMFR) in neonates.

OBJECTIVE: The goal was to identify stimulus features that enhance the detection of the amplitude modulation following response (AMFR) in neonates. The features explored were (1) envelope type, sinusoidal versus a half-wave rectified sinusoid (transposed); (2) best modulation frequency; and (3) spectral content, i.e., tone versus band-pass noise. DESIGN: Results are based on recordings from 149 babies (80 babies in the neonatal intensive care unit and 69 newborn infants). All had passed hearing screening based on the click-evoked ABR. Babies were not sedated. We used carrier frequencies of approximately 500, 1000, 2000, and 4000 Hz and modulation frequencies between approximately 25 and 98 Hz. For the noise stimuli, we used band-pass noise at center frequencies of 500, 1000, 2000, and 4000 Hz. All stimuli were presented through insert earphones delivered simultaneously to both ears, at intensities ranging from 20 to 70 dB SPL. Magnitude squared coherence, phase coherence, and spectral criteria were used to detect criterion AMFRs. We analyzed four measures: (1) percent of satisfied runs; (2) the amplitude of criterion AMFR; (3) time to detect a criterion AMFR; and (4) response strength (e.g., the value of the magnitude squared coherence when it reached criterion minus the critical value it had to exceed for that number of averages all divided by the critical value). RESULTS: (1) The AMFRs evoked by transposed tones were larger and detected faster than those to sinusoidal amplitude modulated tones. Consequently, remaining protocols all used the transposed envelopes. (2) The range of effective modulation frequencies was broad (41 to 88 Hz) across carrier frequencies. (3) The AMFRs evoked by transposed noise were faster and more efficient than those to transposed tones. CONCLUSIONS: In neonates, transposed tones are more effective than sinusoidal amplitude modulated tones in evoking the AMFR, modulation frequencies between 41 to 88 Hz are almost equally effective in evoking the AMFR, and band-pass noises are more effective in evoking the AMFR than tones. These three stimulus factors all add incrementally to the efficiency of evoking the AMFR. The short detection times indicate that the AMFR could be an effective tool for hearing screening.

Sensitivity to interaural time differences in the dorsal nucleus of the lateral lemniscus of the unanesthetized rabbit: comparison with other structures.

Interaural time differences, a cue for azimuthal sound location, are first encoded in the superior olivary complex (SOC), and this information is then conveyed to the dorsal nucleus of the lateral lemniscus (DNLL) and inferior colliculus (IC). The DNLL provides a strong inhibitory input to the IC and may serve to transform the coding of interaural time differences (ITDs) in the IC. Consistent with the projections from the SOC, the DNLL and IC had similar distributions of peak- and trough-type neurons, characteristic delays, and best ITDs. The ITD tuning widths of DNLL neurons were intermediate between those of the SOC and IC. Further sharpening is seen in the auditory thalamus, indicating that sharpening mechanisms are not restricted to the midbrain. The proportion of neurons that phase-locked to the tones delivered to each ear progressively decreased from the SOC to the auditory thalamus. The degree of phase-locking for a large majority of DNLL neurons was too weak to support their involvement in processing monaural inputs to generate a sensitivity to ITDs. The response rates of DNLL neurons were on average approximately 60% greater than in the IC or SOC, indicating that the inhibitory input provided to the IC by the DNLL is robust.

GABA( A) synapses shape neuronal responses to sound intensity in the inferior colliculus.

Neurons in the inferior colliculus (IC) change their firing rates with sound pressure level. Some neurons maintain monotonic increases in firing rate over a wide range of sound intensities, whereas other neurons are monotonic over limited intensity ranges. We examined the conditions necessary for monotonicity in this nucleus in vitro in rat brain slices and in vivo in the unanesthetized rabbit. Our in vitro recordings indicate that concurrent activation of GABA(A) synapses with excitatory inputs facilitates monotonic increases in firing rate with increases in stimulus strength. In the absence of synaptic inhibition, excitatory input to IC neurons causes large depolarizations that result in firing block and nonmonotonicity. In vivo, although GABA(A) synapses decrease the firing rate in all IC neurons, they can have opposing effects on rate-level functions. GABAergic inputs activated by all sound intensities maintain monotonicity by keeping the postsynaptic potential below the level at which depolarization block occurs. When these inputs are blocked, firing block can occur and rate-level functions become nonmonotonic. High-threshold GABAergic inputs, in contrast, cause nonmonotonic responses by decreasing the firing rate at high intensities. Our results suggest that a dynamic regulation of the postsynaptic membrane potential by synaptic inhibition is necessary to allow neurons to respond monotonically to a wide range of sound intensities.

Transformations in processing interaural time differences between the superior olivary complex and inferior colliculus: beyond the Jeffress model.

Interaural time differences (ITDs) are used to localize sounds and improve signal detection in noise. Encoding ITDs in neurons depends on specialized mechanisms for comparing inputs from the two ears. Most studies have emphasized how the responses of ITD-sensitive neurons are consistent with the tenets of the Jeffress model. The Jeffress model uses neuronal coincidence detectors that compare inputs from both sides and delay lines so that different neurons achieve coincidence at different ITDs. Although Jeffress-type models are successful at predicting sensitivity to ITDs in humans, in many respects they are a limited representation of the responses seen in neurons. In the superior olivary complex (SOC), ITD-sensitive neurons are distributed across both the medial (MSO) and lateral (LSO) superior olives. Similar response types are found in neurons sensitive to ITDs in two signal types: low-frequency sounds and envelopes of high-frequency sounds. Excitatory-excitatory interactions in the MSO are associated with peak-type responses, and excitatory-inhibitory interactions in the LSO are associated with trough-type responses. There are also neurons with responses intermediate between peak- and trough-type. In the inferior colliculus (IC), the same basic types remain, presumably due to inputs arising from the MSO and LSO. Using recordings from the SOC and IC, we describe how the response types can be described within a continuum that extends to very large values of ITD, and compare the functional organization at the two levels.

Sources of the scalp-recorded amplitude-modulation following response.

The scalp-recorded amplitude-modulation following response (AMFR) is gaining recognition as an objective audiometric tool, but little is known about the neural sources that underlie this potential. We hypothesized, based on our human studies and single-unit recordings in animals, that the scalp-recorded AMFR reflects the interaction of multiple sources. We tested this hypothesis using an animal model, the unanesthetized rabbit. We compared AMFRs recorded from the surface of the brain at different locations and before and after the administration of agents likely to enhance or suppress neural generators. We also recorded AMFRs locally at several stations along the auditory neuraxis. We conclude that the surface-recorded AMFR is indeed a composite response from multiple brain generators. Although the response at any modulation frequency can reflect the activity of more than one generator, the AMFRs to low and high modulation frequencies appear to reflect a strong contribution from cortical and subcortical sources, respectively.