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SummaryOctopus cells are remarkable projection neurons of the mammalian cochlear nucleus, with extremely fast membranes and wide frequency tuning. They are considered prime examples of coincidence detectors but are poorly characterized in vivo. We discover that octopus cells are selective to frequency sweep direction, a feature that is absent in their auditory nerve inputs. In vivo intracellular recordings reveal that direction selectivity does not derive from cross-channel coincidence detection but hinges on the amplitudes and activation sequence of auditory nerve inputs tuned to clusters of “hotspot” frequencies. A simple biophysical model of octopus cell excited with real nerve spike trains recreates direction selectivity through interaction of intrinsic membrane conductances with activation sequence of clustered inputs. We conclude that octopus cells are sequence detectors, sensitive to temporal patterns across cochlear frequency channels. The detection of sequences rather than coincidences is a much simpler but powerful operation to extract temporal information.

Many mammals, including humans, are exquisitely sensitive to tiny time differences between sounds at the two ears. These interaural time differences are an important source of information for sound detection, for sound localization in space, and for environmental awareness. Two brainstem circuits are involved in the initial temporal comparisons between the ears, centered on the medial and lateral superior olive. Cells in these nuclei, as well as their afferents, display a large number of striking physiological and anatomical specializations to enable submillisecond sensitivity. As such, they provide an important model system to study temporal processing in the central nervous system. We review the progress that has been made in characterizing these primary binaural circuits as well as the variety of mechanisms that have been proposed to underlie their function.

Locomotion generates adventitious sounds which enable detection and localization of predators and prey. Such sounds contain brisk changes or transients in amplitude. We investigated the hypothesis that ill-understood temporal specializations in binaural circuits subserve lateralization of such sound transients, based on different time of arrival at the ears (interaural time differences, ITDs). We find that Lateral Superior Olive (LSO) neurons show exquisite ITD-sensitivity, reflecting extreme precision and reliability of excitatory and inhibitory postsynaptic potentials, in contrast to Medial Superior Olive neurons, traditionally viewed as the ultimate ITD-detectors. In vivo, inhibition blocks LSO excitation over an extremely short window, which, in vitro, required synaptically evoked inhibition. Light and electron microscopy revealed inhibitory synapses on the axon initial segment as the structural basis of this observation. These results reveal a neural vetoing mechanism with extreme temporal and spatial precision and establish the LSO as the primary nucleus for binaural processing of sound transients. ispartof: ELIFE vol:10 ispartof: location:England status: published

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

The flat-envelope harmonic complexes devised by Schroeder (1970) contain a linear frequency sweep whose direction and speed depend on phase curvature C. Physiological studies have focused on responses at a given characteristic frequency (CF), which show only a subtle dependence on the sign and magnitude of C. The question arises whether CNS neurons are sensitive to the temporal pattern across nerve fibers differing in CF. Octopus cells in the cochlear nucleus receive convergent excitatory input from nerve fibers spanning a wide range of CFs and are thought to be monaural coincidence detectors. We studied their spike output and membrane responses to Schroeder complexes in anesthetized gerbils. Octopus cells were indeed tuned to a wide frequency range but showed discrete frequency “hotspots” of differing strength. Most cells showed marked sensitivity to C, with some neurons preferring upward and others downward frequency sweeps, which was broadly stable across SPL and fundamental frequency. The sensitivity to C arises not from coincidence detection, but from a sensitivity to the temporal sequence of activation of inputs tuned to different frequencies. We conclude that marked sensitivity to Schroeder phase exists at the first CNS processing stage and is based on temporal sequence detection across frequency channels.

Harmonic templates are a critical component of spectral pitch theories. Shamma and Klein (2000) hypothesize that such templates can arise from neural coincidence patterns in response to stochastic stimuli without pitch.The key feature of their computational model is a higher number of coincidences between neurons with harmonically related characteristic frequencies (CFs). We tested the hypothesis with physiological data and a computational model. We recorded neural responses in chinchilla to various periodic and non-periodic stimuli, both from the auditory nerve and the trapezoid body. We then examined counts of spike coincidences across fibers. The key prediction of a higher number of coincidences between pairs of fibers with harmonically related CFs than for other pairs was observed for responses to narrowband signals (tones at CF), but not to broadband noise. We then tested a model similar to that of Shamma and Klein. Only with cochlear filters sharper than plausible even in humans, followed by additional spectral sharpening through lateral inhibition and extreme temporal sharpening, do we obtain harmonic templates similar to their model. Although our results do not speak to the existence of harmonic templates per se, we conclude that the specific mechanism of this hypothesis has little physiological plausibility.

Counts of spike coincidences provide a powerful means to compare responses to different stimuli or of different neurons, particularly regarding temporal factors. A drawback is that these methods do not provide an absolute measure of latency, i.e., the temporal interval between stimulus and response. It is desirable to obtain such a measurement within the same analysis framework of coincidence counting. Single neuron responses were obtained from several fiber tracts (nerve, trapezoid body, lateral lemniscus) in two species to a broadband noise and its polarity-inverted version. The spike trains in response to these stimuli are the “forward noise” responses. The same stimuli were also played time-reversed. The resulting spike trains are then again time-reversed: these are the “reverse noise” responses. The forward and reverse responses were then analyzed with the coincidence count methods we have introduced earlier. Latency measurements derived from correlograms between forward and reverse noise responses show maxima at twice the latency value measured with other methods, as expected. Correlograms were often asymmetric but, at low-characteristic frequencies, were well-predicted by crosscorrelation of the reverse-correlation function and its reverse. We conclude that reverse noise provides an easy and reliable means to estimate latency of auditory nerve and brainstem neurons.

Binaural hearing is alluring not only because of its acuity, but particularly because it is more than twice as tractable as monaural hearing. It provides fertile space for the interplay of anatomical, physiological, behavioral, and computational approaches, for which the Acoustical Society is a major platform. The binaural and by extension the auditory community is a particularly pleasant one to get bashed by and we are grateful for the recognition by our peers of our research, through this award. I will review some of our findings: those that have been most surprising, rewarding, or plain fun, and some of which even have relevance for the understanding of monaural hearing. Coincidences and delays have been major ingredients of our research and illustrate this weird but—despite much current negative press covfefe—marvellous group effort we call science, which we are privileged to be part of.

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

In vitro and in silico studies have suggested that octopus cells in the mammalian posterior ventral cochlear nucleus (PVCN) are monaural coincidence detectors that encode the temporal structure of complex sounds. In vivo studies on these neurons, however, are rare due to several technical difficulties. We used sharp high-impedance electrodes in anesthetized gerbils to study the responses of octopus cells to click trains. We find that, even though octopus cells only fire an onset spike to pure tones, they fire in sustained fashion to trains of transients. They entrain to click trains up to 400 Hz with vector strength almost equal to one and spike jitter at ∼100 microseconds. This temporal precision is unmatched by any other cell type in the auditory system. ispartof: ACTA ACUSTICA UNITED WITH ACUSTICA vol:104 issue:5 pages:852-855 ispartof: location:DENMARK, Snekkersten status: published

Pitch is a perceptual attribute enabling perception of melody. There is no consensus regarding the fundamental nature of pitch and its underlying neural code. A stimulus which has received much interest in psychophysical and computational studies is noise with a sharp spectral edge. High- or low-pass noise gives rise to a pitch near the edge frequency (“monaural edge pitch”, MEP). The simplicity of this stimulus, combined with its spectral and autocorrelation properties, make it an interesting stimulus to examine spectral versus temporal cues that could underly its pitch. We recorded responses of single auditory nerve fibers in chinchilla to MEP-stimuli varying in edge frequency. Temporal cues were examined with shuffled autocorrelogram (SAC) analysis. Correspondence between the population’s dominant interspike interval and reported pitch estimates was poor. A fuller analysis of the population interspike interval distribution, which incorporates not only the dominant but all intervals, results in good matches with behavioral results, but not for the entire range of edge frequencies that generates pitch. Finally, we also examined temporal structure over a slower time scale, intermediate between average firing rate and interspike intervals, by studying the SAC envelope. We found that, in response to a given MEP stimulus, this feature also systematically varies with edge frequency, across fibers with different characteristic frequency. Because neural mechanisms to extract envelope cues are well-established, and because this cue is not limited by coding of stimulus fine-structure, this newly identified slower temporal cue is a more plausible basis for pitch than cues based on fine-structure. Significance Statement A longstanding debate concerns the neural underpinnings of pitch, which is a label the brain computes for periodic sounds. Perceptual studies have not resolved whether pitch is based on spectral or temporal cues, or both. Because the neural processing requirements for temporal and place cues are very different, neurophysiological data can in principle resolve this debate. We studied responses of neurons in the auditory nerve to a simple aperiodic stimulus and examined candidate cues that may underly its unusual pitch. We find that fine temporal cues could potentially underly edge pitch, but only for a restricted range over which it is observed behaviorally. The data draw attention to a temporal cue at a slower time scale than is traditionally considered.

Spatial hearing, and more specifically the ability to localize sounds in space, is one of the most studied and best understood aspects of hearing. Because there is no coding of acoustic space at the receptor organ, physiological sensitivity to spatial aspects of sounds first emerges in the central nervous system. Much progress has been made in the identification and characterization of the circuits in the auditory brainstem that create sensitivity to binaural and monaural cues toward acoustic space. We review the progress over the past third of a century, with a focus on the mammalian brainstem and on the anatomy and cellular physiology underlying the physiological tuning of monaural and binaural circuits to acoustic cues toward spatial hearing. In addition to examining the detailed mechanisms involved in the processing of the three main spatial cues, we also review the integration of these cues and their use toward behavior. © 2019 American Physiological Society. Compr Physiol 9:1503-1575, 2019.

Relative motion between the body and the outside world is a rich source of information. Neural selectivity to motion is well-established in several sensory systems, but is controversial in hearing. This study examines neural sensitivity to changes in the instantaneous interaural time difference of sounds at the two ears. Midbrain neurons track such changes up to extremely high speeds, show only a coarse dependence of firing rate on speed, and lack directional selectivity. These results argue against the presence of selectivity to auditory motion at the level of the midbrain, but reveal an acuity which enables coding of fast-fluctuating binaural cues in realistic sound environments. no ISSN ispartof: The Journal of the Acoustical Society of America Express Letters vol:145 issue:1 pages:EL45-EL51 ispartof: location:United States status: published

Frequency tuning and phase-locking are two fundamental properties generated in the cochlea, enabling but also limiting the coding of sounds by the auditory nerve (AN). In humans, these limits are unknown, but high resolution has been postulated for both properties. Electrophysiological recordings from the AN of normal-hearing volunteers indicate that human frequency tuning, but not phase-locking, exceeds the resolution observed in animal models., Author summary The coding of sounds by the cochlea depends on two primary properties: frequency selectivity, which refers to the ability to separate sounds into their different frequency components, and phase-locking, which refers to the neural coding of the temporal waveform of these components. These properties have been well characterized in animals using neurophysiological recordings from single neurons of the auditory nerve (AN), but this approach is not feasible in humans. As a result, there is considerable controversy as to how these two properties may differ between humans and the small animals typically used in neurophysiological studies. It has been proposed that humans excel both in frequency selectivity and in the range of frequencies over which they have phase-locking. We developed a technique to quantify these properties using mass potentials from the AN, recorded via the middle ear in human volunteers with normal hearing. We find that humans have unusually sharp frequency tuning but that the upper frequency limit of phase-locking is at best similar to—and more likely lower than—that of the nonhuman animals conventionally used in experiments.

The brainstem's lateral superior olive (LSO) is thought to be crucial for localizing high-frequency sounds by coding interaural sound level differences (ILD). Its neurons weigh contralateral inhibition against ipsilateral excitation, making their firing rate a function of the azimuthal position of a sound source. Since the very first in vivo recordings, LSO principal neurons have been reported to give sustained and temporally integrating 'chopper' responses to sustained sounds. Neurons with transient responses were observed but largely ignored and even considered a sign of pathology. Using the Mongolian gerbil as a model system, we have obtained the first in vivo patch clamp recordings from labeled LSO neurons and find that principal LSO neurons, the most numerous projection neurons of this nucleus, only respond at sound onset and show fast membrane features suggesting an importance for timing. These results provide a new framework to interpret previously puzzling features of this circuit. ispartof: ELIFE vol:7 ispartof: location:England status: published

The calyx of Held is the preeminent model for the study of synaptic function in the mammalian CNS. Despite much work on the synapse and associated circuit, its role in hearing remains enigmatic. We propose that the calyx is one of the key adaptations that enables an animal to lateralize transient sounds. The calyx is part of a binaural circuit that is biased toward high sound frequencies and is sensitive to intensity differences between the ears. This circuit also shows marked sensitivity to interaural time differences, but only for brief sound transients ("clicks"). In a natural environment, such transients are rare except as adventitious sounds generated by other animals moving at close range. We argue that the calyx, and associated temporal specializations, evolved to enable spatial localization of sound transients, through a neural code congruent with the circuit's sensitivity to interaural intensity differences, thereby conferring a key benefit to survival.

In the diverse mechanosensory systems that animals evolved, the waveform of stimuli can be encoded by phase-locking in spike trains of primary afferents. Coding of the fine-structure of sounds via phase-locking is thought to be critical for hearing. The upper frequency limit of phase-locking varies across species and is unknown in humans. We applied a method developed earlier, based on neural adaptation evoked by forward masking, to analyse mass potentials recorded on the cochlea and auditory nerve in the cat. The method allows us to separate neural phase-locking from receptor potentials. We find that the frequency limit of neural phase-locking obtained from mass potentials was very similar to that reported for individual auditory nerve fibers. The results suggest that this is a promising approach to examine neural phase-locking in humans with normal or impaired hearing or in other species for which direct recordings from primary afferents are not feasible. ispartof: Journal of Neuroscience vol:35 issue:5 pages:2255-2268 ispartof: location:United States status: published

Sound localization critically depends on detection of differences in arrival time of sounds at the two ears (acoustic delay). The fundamental mechanisms are debated, but all proposals include a process of coincidence detection and a separate source of internal delay which offsets the acoustic delay and determines neural tuning. We obtained in vivo patch clamp recordings of binaural neurons in the Mongolian gerbil, combined with pharmacological manipulations, to directly compare neuronal input to output and to separate excitation from inhibition. The results cannot be accounted for by existing models and reveal that coincidence detection is not an instantaneous process but is shaped by the interaction of intrinsic conductances with preceding synaptic activity. This interaction generates an internal delay as an intrinsic part of the process of coincidence detection. The multiplication and time-shifting stages thought to extract synchronous activity in many brain areas can thus be combined in a single operation.

Temporal effects in interaural level difference (ILD) perception are not well understood. While it is often assumed that ILD sensitivity is independent of the temporal stimulus properties, a reduction of ILD sensitivity for stimuli with a high modulation rate has been reported (known under the term binaural adaptation). Experiment 1 compared ILD thresholds and sequential-level-difference (SLD) thresholds using 300-ms bandpass-filtered pulse trains (centered at 4 kHz) with rates of 100, 400, and 800 pulses per second (pps). In contrast to the SLD thresholds, ILD thresholds were elevated at 800 pps, consistent with literature data that had previously been attributed to binaural adaptation. Experiment 2 showed better ILD sensitivity for pulse trains than for pure tones, suggesting that amplitude modulation enhances ILD sensitivity. The present ILD data and binaural adaptation data from the literature were predicted by a model combining well-established auditory periphery front-ends with an interaural comparison stage. The model also accounted for other published ILD data, including target ILD thresholds in diotic forward and backward fringes and ILD thresholds with different amounts of interaural correlation. Overall, a variety of temporal effects in ILD perception, including binaural adaptation, appear to be largely attributable to monaural peripheral auditory processing. ispartof: JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA vol:142 issue:5 pages:3267-3283 ispartof: location:United States status: published

The trapezoid body (TB) contains axons of neurons in the anteroventral cochlear nucleus projecting to monaural and binaural nuclei in the superior olivary complex (SOC). Characterization of these monaural inputs is important for the interpretation of response properties of SOC neurons. In particular, understanding of the sensitivity to interaural time differences (ITDs) in neurons of the medial and lateral superior olive requires knowledge of the temporal firing properties of the monaural excitatory and inhibitory inputs to these neurons. In recent years, studies of ITD sensitivity of SOC neurons have made increasing use of small animal models with good low-frequency hearing, particularly the gerbil. We presented stimuli as used in binaural studies to monaural neurons in the TB and studied their temporal coding. We found that general trends as have been described in the cat are present in gerbil, but with some important differences. Phase-locking to pure tones tends to be higher in TB axons and in neurons of the medial nucleus of the TB (MNTB) than in the auditory nerve for neurons with characteristic frequencies (CFs) below 1 kHz, but this enhancement is quantitatively more modest than in cat. Stronger enhancement is common when TB neurons are stimulated at low frequencies below CF. It is rare for TB neurons in gerbil to entrain to low-frequency stimuli, i.e., to discharge a well-timed spike on every stimulus cycle. Also, complex phase-locking behavior, with multiple modes of increased firing probability per stimulus cycle, is common in response to low frequencies below CF.NEW & NOTEWORTHY Phase-locking is an important property of neurons in the early auditory pathway: it is critical for the sensitivity to time differences between the two ears enabling spatial hearing. Studies in cat have shown an improvement in phase-locking from the peripheral to the central auditory nervous system. We recorded from axons in an output tract of the cochlear nucleus and show that a similar but more limited form of temporal enhancement is present in gerbil. ispartof: JOURNAL OF NEUROPHYSIOLOGY vol:118 issue:4 pages:2009-2023 ispartof: location:United States status: published

Development of electrophysiological means to assess the medial olivocochlear (MOC) system in humans is important to further our understanding of the function of that system and for the refinement and validation of psychoacoustical and otoacoustic emission methods which are thought to probe the MOC. Based on measurements in anesthetized animals it has been hypothesized that the MOC-reflex (MOCR) can enhance the response to signals in noise, and several lines of evidence support such a role in humans. A difficulty in these studies is the isolation of efferent effects. Efferent activation can be triggered by acoustic stimulation of the contralateral or ipsilateral ear, but ipsilateral stimulation is thought to be more effective. However, ipsilateral stimulation complicates interpretation of effects since these sounds can affect the perception of other ipsilateral sounds by mechanisms not involving olivocochlear efferents. We assessed the ipsilaterally evoked MOCR in human using a transtympanic procedure to record mass-potentials from the cochlear promontory or the niche of the round window. Averaged compound action potential (CAP) responses to masked probe tones of 4 kHz with and without a precursor (designed to activate the MOCR but not the stapedius reflex) were extracted with a polarity alternating paradigm. The masker was either a simultaneous narrow band noise masker or a short (20-ms) tonal ON- or OFF-frequency forward masker. The subjects were screened for normal hearing (audiogram, tympanogram, threshold stapedius reflex) and psychoacoustically tested for the presence of a precursor effect. We observed a clear reduction of CAP amplitude by the precursor, for different masking conditions. Even without an MOCR, this is expected because the precursor will affect the response to subsequent stimuli via neural adaptation. To determine whether the precursor also activated the efferent system, we measured the CAP over a range of masker levels, with or without precursor, and for different types of masker. The results show CAP reduction consistent with the type of gain reduction caused by the MOCR. These results generally support psychoacoustical paradigms designed to probe the efferent system as indeed activating the MOCR system, but not all observations are consistent with this mechanism. ispartof: Frontiers in Neuroscience vol:11 issue:331 ispartof: location:Switzerland status: published

Development of electrophysiological means to assess the medial olivocochlear (MOC) system in humans is important to further our understanding of the function of that system and for the refinement and validation of psychoacoustical and otoacoustic emission methods which are thought to probe the MOC. Based on measurements in anesthetized animals it has been hypothesized that the MOC-reflex (MOCR) can enhance the response to signals in noise, and several lines of evidence support such a role in humans. A difficulty in these studies is the isolation of efferent effects. Efferent activation can be triggered by acoustic stimulation of the contralateral or ipsilateral ear, but ipsilateral stimulation is thought to be more effective. However, ipsilateral stimulation complicates interpretation of effects since these sounds can affect the perception of other ipsilateral sounds by mechanisms not involving olivocochlear efferents. We assessed the ipsilaterally evoked MOCR in human using a transtympanic procedure to record mass-potentials from the cochlear promontory or the niche of the round window. Averaged compound action potential (CAP) responses to masked probe tones of 4 kHz with and without a precursor (designed to activate the MOCR but not the stapedius reflex) were extracted with a polarity alternating paradigm. The masker was either a simultaneous narrow band noise masker or a short (20-ms) tonal ON- or OFF-frequency forward masker. The subjects were screened for normal hearing (audiogram, tympanogram, threshold stapedius reflex) and psychoacoustically tested for the presence of a precursor effect. We observed a clear reduction of CAP amplitude by the precursor, for different masking conditions. Even without an MOCR, this is expected because the precursor will affect the response to subsequent stimuli via neural adaptation. To determine whether the precursor also activated the efferent system, we measured the CAP over a range of masker levels, with or without precursor, and for different types of masker. The results show CAP reduction consistent with the type of gain reduction caused by the MOCR. These results generally support psychoacoustical paradigms designed to probe the efferent system as indeed activating the MOCR system, but not all observations are consistent with this mechanism.

Extracellular voltage recordings (Ve; field potentials) provide an accessible view ofin vivoneural activity, but proper interpretation of field potentials is a long-standing challenge. Computational modeling can aid in identifying neural generators of field potentials. In the auditory brainstem of cats, spatial patterns of sound-evokedVecan resemble, strikingly,Vegenerated by current dipoles. Previously, we developed a biophysically-based model of a binaural brainstem nucleus, the medial superior olive (MSO), that accounts qualitatively for observed dipole-likeVepatterns in sustained responses to monaural tones with frequencies >∼1000 Hz (Goldwyn et al., 2014). We have observed, however, thatVepatterns in cats of both sexes appear more monopole-like for lower-frequency tones. Here, we enhance our theory to accurately reproduce dipole and non-dipole features ofVeresponses to monaural tones with frequencies ranging from 600 to 1800 Hz. By applying our model to data, we estimate time courses of paired input currents to MSO neurons. We interpret these inputs as dendrite-targeting excitation and soma-targeting inhibition (the latter contributes non-dipole-like features toVeresponses). Aspects of inferred inputs are consistent with synaptic inputs to MSO neurons including the tendencies of inhibitory inputs to attenuate in response to high-frequency tones and to precede excitatory inputs. Importantly, our updated theory can be tested experimentally by blocking synaptic inputs. MSO neurons perform a critical role in sound localization and binaural hearing. By solving an inverse problem to uncover synaptic inputs fromVepatterns we provide a new perspective on MSO physiology.SIGNIFICANCE STATEMENTExtracellular voltages (field potentials) are a common measure of brain activity. Ideally, one could infer from these data the activity of neurons and synapses that generate field potentials, but this “inverse problem” is not easily solved. We study brainstem field potentials in the region of the medial superior olive (MSO); a critical center in the auditory pathway. These field potentials exhibit distinctive spatial and temporal patterns in response to pure tone sounds. We use mathematical modeling in combination with physiological and anatomical knowledge of MSO neurons to plausibly explain how dendrite-targeting excitation and soma-targeting inhibition generate these field potentials. Inferring putative synaptic currents from field potentials advances our ability to study neural processing of sound in the MSO.

The frequency extent over which fine structure is coded in the auditory nerve has been physiologically characterized in laboratory animals but is unknown in humans. Knowledge of the upper frequency limit in humans would inform the debate regarding the role of fine structure in human hearing. Of the presently available techniques, only the recording of mass neural potentials offers the promise to provide a physiological estimate of neural phase locking in humans. A challenge is to disambiguate neural phase locking from the receptor potentials. We studied mass potentials recorded on the cochlea and auditory nerve of cat and used several experimental manipulations to isolate the neural contribution to these potentials. We find a surprisingly large neural contribution in the signal recorded on the cochlear round window, and this contribution is in many aspects similar to the potential measured on the auditory nerve. The results suggest that recording of mass potentials through the middle ear is a promising approach to examine neural phase locking in humans. ispartof: Jaro-Journal Of The Association For Research In Otolaryngology vol:15 issue:5 pages:767-787 ispartof: location:United States status: published

Interaural time differences (ITDs) are a major cue for localizing low-frequency (We circumvented these difficulties by recording from the axons of MSO neurons in the lateral lemniscus (LL) of the chinchilla, a species with pronounced low-frequency sensitivity. Employing sharp glass electrodes we successfully recorded from neurons with ITD sensitivity: the location, response properties, latency, and spike shape were consistent with an MSO axonal origin. The main difficulty encountered was mechanical stability. We obtained responses to binaural beats and dichotic noise bursts to characterize the best delay versus characteristic frequency distribution, and compared the data to recordings we obtained in the inferior colliculus (IC). In contrast to most reports in other rodents, many best delays were close to zero ITD, both in MSO and IC, with a majority of the neurons recorded in the LL firing maximally within the presumed ethological ITD range.

The lateral nucleus of the trapezoid body (LNTB) is a prominent nucleus in the superior olivary complex in mammals including humans. Its physiology in vivo is poorly understood due to a paucity of recordings. It is thought to provide a glycinergic projection to the medial superior olive (MSO) with an important role in binaural processing and sound localization. We combined in vivo patch clamp recordings with labeling of individual neurons in the Mongolian gerbil. Labeling of the recorded neurons allowed us to relate physiological properties to anatomy at the light and electron microscopic level. We identified a population of quite dorsally located neurons with surprisingly large dendritic trees on which most of the synaptic input impinges. In most neurons, one or more of these dendrites run through and are then medial to the MSO. These neurons were often binaural and could even show sensitivity to interaural time differences (ITDs) of stimulus fine structure or envelope. Moreover, a subpopulation showed enhanced phase-locking to tones delivered in the tuning curve tail. We propose that these neurons constitute the gerbil main LNTB (mLNTB). In contrast, a smaller sample of neurons was identified that was located more ventrally and that we designate to be in posteroventral LNTB (pvLNTB). These cells receive large somatic excitatory terminals from globular bushy cells. We also identified previously undescribed synaptic inputs from the lateral superior olive. pvLNTB neurons are usually monaural, display a primary-like-with-notch response to ipsilateral short tones at CF and can phase-lock to low frequency tones. We conclude that mLNTB contains a population of neurons with extended dendritic trees where most of the synaptic input is found, that can show enhanced phase-locking and sensitivity to ITD. pvLNTB cells, presumed to provide glycinergic input to the MSO, get large somatic globular bushy synaptic inputs and are typically monaural with short tone responses similar to their primary input from the cochlear nucleus. ispartof: Frontiers in Neural Circuits vol:10 issue:AUG ispartof: location:Switzerland status: published

Spectral resolution is fundamental to audition. Auditory-nerve-fiber responses provide a window onto cochlear tuning. Typically, resolution is quantified using threshold tuning curves. Superficially, these suggest dramatic and systematic filter broadening with increasing intensity, a view often invoked to explain psychoacoustic phenomena. We recorded auditory-nerve-fiber spike times from normal-hearing chinchillas in response to 0.01-20 kHz wideband noise. We gathered data over a wide intensity range from each fiber. Linear filter estimates were obtained at each level by reverse correlation. We characterized their magnitude and phase response. We considered responses from 175 fibers (CF range: [0.1, 3.0] kHz; all SR groups), with noise level varying over a 40 to 100-dB range. 10-dB bandwidth varied minimally with sound level over a 40 to 50-dB range. Some fibers demonstrated phase pivoting with level; however, most did not follow this simple scheme. Common teaching is “auditory filters broaden with level,...

The basic nature of pitch is much debated. A robust code for pitch exists in the auditory nerve in the form of an across-fiber pooled interspike interval (ISI) distribution, which resembles the stimulus autocorrelation. An unsolved question is how this representation can be “read out” by the brain. A new view is proposed in which a known brain-stem property plays a key role in the coding of periodicity, which I refer to as “entracking”, a contraction of “entrained phase-locking”. It is proposed that a scalar rather than vector code of periodicity exists by virtue of coincidence detectors that code the dominant ISI directly into spike rate through entracking. Perfect entracking means that a neuron fires one spike per stimulus-waveform repetition period, so that firing rate equals the repetition frequency. Key properties are invariance with SPL and generalization across stimuli. The main limitation in this code is the upper limit of firing (~ 500 Hz). It is proposed that entracking provides a periodicity tag which is superimposed on a tonotopic analysis: at low SPLs and fundamental frequencies > 500 Hz, a spectral or place mechanism codes for pitch. With increasing SPL the place code degrades but entracking improves and first occurs in neurons with low thresholds for the spectral components present. The prediction is that populations of entracking neurons, extended across characteristic frequency, form plateaus (“buttes”) of firing rate tied to periodicity.

The lateral superior olive (LSO) in the auditory brainstem generates sensitivity to interaural level differences (ILD), an important cue for sound localization, by comparing excitatory (E) input from the ipsilateral ear with inhibitory (I) input from the contralateral ear. Large axosomatic synapses (e.g., calyx of Held) point to the importance of precise temporal processing, but that is not easily reconciled with ILD detection. We propose that the IE interaction allows detection of interaural time differences (ITD) of acoustic transients, to which humans are exquisitely sensitive. We obtained in vivo whole cell recordings of LSO and MSO neurons in the gerbil, while presenting monaural and binaural clicks. We found that ITD functions to clicks in the LSO are surprisingly steep, in contrast to MSO neurons, which are considered the main ITD detectors. Intracellular LSO recordings show EPSPs generated by the ipsilateral click and IPSPs by the contralateral click, where IPSPs often arrive earlier. Binaural spi...

The quality of temporal coding of sound waveforms in the monaural afferents that converge on binaural neurons in the brainstem limits the sensitivity to temporal differences at the two ears. The anteroventral cochlear nucleus (AVCN) houses the cells that project to the binaural nuclei, which are known to have enhanced temporal coding of low-frequency sounds relative to auditory nerve (AN) fibers. We applied a coincidence analysis within the framework of detection theory to investigate the extent to which AVCN processing affects interaural time delay (ITD) sensitivity. Using monaural spike trains to a 1-s broadband or narrowband noise token, we emulated the binaural task of ITD discrimination and calculated just noticeable differences (jnds). The ITD jnds derived from AVCN neurons were lower than those derived from AN fibers, showing that the enhanced temporal coding in the AVCN improves binaural sensitivity to ITDs. AVCN processing also increased the dynamic range of ITD sensitivity and changed the shape of the frequency dependence of ITD sensitivity. Bandwidth dependence of ITD jnds from AN as well as AVCN fibers agreed with psychophysical data. These findings demonstrate that monaural preprocessing in the AVCN improves the temporal code in a way that is beneficial for binaural processing and may be crucial in achieving the exquisite sensitivity to ITDs observed in binaural pathways.

Phase-locking is a remarkable neural property of various mechanoreceptor-based sensory systems, and the neural coding of cochlear vibrations is the primary model system to study this phenomenon. Transduction and synaptic transmission by cochlear inner hair cells enables but also limits temporal coding in the auditory nerve. I will review phase-locking to sound fine-structure in the auditory nerve of various species, including humans, assessed with different types of sound stimuli and using different metrics. The upper-frequency limit of phase-locking in cell populations in the central nervous system is lower than that in the auditory nerve, and at the same time, the nature of the temporal code is transformed in these neurons: phase-locking is enhanced in that it is more consistent and has decreased jitter, and it has profound effects on the average discharge rate of various populations of neurons, both monaurally and binaurally. Similar phenomena (changing upper limits, enhancement, and rate effects) are observed in the temporal coding of envelopes and click trains. While it is increasingly clear that many cell groups in the auditory brainstem have specialized mechanisms towards temporal coding, the relationship of the resulting response properties to perception remains unclear.

Binaural signal detection in an NoS pi task relies on interaural disparities introduced by adding an antiphasic signal to diotic noise. What metric of interaural disparity best predicts performance? Some models use interaural correlation; others differentiate between dynamic interaural time differences (ITDs) and interaural level differences (ILDs) of the effective stimulus. To examine the relative contributions of ITDs and ILDs in binaural detection, we developed a novel signal processing technique that selectively degrades different aspects (potential cues) of binaural stimuli (e.g., only ITDs are scrambled). Degrading a particular cue will affect performance only if that cue is relevant to the binaural processing underlying detection. This selective scrambling technique was applied to the stimuli of a classic N0S pi task in which the listener had to detect an antiphasic 500-Hz signal in the presence of a diotic wideband noise masker. Data obtained from five listeners showed that (1) selective scrambling of ILDs had little effect on binaural detection, (2) selective scrambling of ITDs significantly degraded detection, and (3) combined scrambling of ILDs and ITDs had the same effect as exclusive scrambling of ITDs. Regarding the question which stimulus properties determine detection, we conclude that for this binaural task (1) dynamic ITDs dominate detection performance, (2) ILDs are largely irrelevant, and (3) interaural correlation of the stimulus is a poor predictor of detection. Two simple stimulus-based models that each reproduce all binaural aspects of the data quite well are described: (1) a single-parameter detection model using ITD variance as detection criterion and (2) a compressive transformation followed by a crosscorrelation analysis. The success of both of these contrasting models shows that our data alone cannot reveal the mechanisms underlying the dominance of ITD cues. The physiological implications of our findings are discussed.

The sharpness of cochlear frequency tuning in humans is debated. Evoked otoacoustic emissions and psychophysical measurements suggest sharper tuning in humans than in laboratory animals [15], but this is disputed based on comparisons of behavioral and electrophysiological measurements across species [14]. Here we used evoked mass potentials to electrophysiologically quantify tuning (Q10) in humans. We combined a notched noise forward masking paradigm [9] with the recording of trans tympanic compound action potentials (CAP) from masked probe tones in awake human and anesthetized monkey (Macaca mulatta). We compare our results to data obtained with the same paradigm in cat and chinchilla [16], and find that CAP-Q10values in human are ∼1.6x higher than in cat and chinchilla and ∼1.3x higher than in monkey. To estimate frequency tuning of single auditory nerve fibers (ANFs) in humans, we derive conversion functions from ANFs in cat, chinchilla, and monkey and apply these to the human CAP measurements. The dat...

Binaural neurons show remarkable sensitivity to temporal differences in the waveforms at the two ears. This ability obviously requires temporal coding of sound waveforms in the monaural afferents that converge on such binaural neurons. We introduce a new analysis to investigate how well responses of single monaural neurons support discrimination of decorrelations in waveforms. Spike trains from auditory nerve (AN) and anteroventral cochlear nucleus (AVCN) neurons of cats to many repetitions of a set of broadband and narrowband noise tokens were obtained. The normalized correlation between the noise tokens ranged from 0.99 to –1. A coincidence and signal detection analysis was used to perform a correlation discrimination task using the monaural spike trains. The correlation discrimination thresholds derived from AVCN neurons were lower than those derived from AN fibers and sometimes as low as human psychophysical just noticeable differences. Importantly, low detection thresholds required comparisons of spike trains at small internal delays. Bandwidth dependence of neural decorrelation thresholds agreed with psychophysical data when large internal delays contributed to the detection. We conclude that, in the context of correlation discrimination, coding by AVCN fibers is superior to that by AN fibers and that these discriminations require a distribution of internal or best delays in binaural processing that differs from the predictions from studies of discrimination in interaural time delays.

The human sensitivity to interaural temporal differences in the acoustic waveforms to the two ears shows remarkable acuity but is also very sluggish. Fast changes in binaural parameters are not detectable, and this inability contrasts sharply with the excellent temporal resolution of the monaural auditory system. We studied the response of binaural neurons in the inferior colliculus of the cat to sinusoidal changes in the interaural correlation of broadband noise. Responses to the same waveforms were also obtained from auditory nerve fibers and further analyzed with a coincidence analysis. Overall, the auditory nerve and inferior colliculus showed a similar ability to code changes in interaural correlation. This ability extended to modulation frequencies an order of magnitude higher than the highest frequencies detected binaurally in humans. We conclude that binaural sluggishness is not caused by a lack of temporal encoding of fast binaural changes at the level of the midbrain. We hypothesize that there is no neural substrate at the level of the midbrain or higher to read out this temporal code and that this constitutes a low-pass “sluggishness” filter.