Case reopened: A temporal basis for harmonic pitch templates in the early auditory system?a).

A fundamental assumption of rate-place models of pitch is the existence of harmonic templates in the central nervous system (CNS). Shamma and Klein [(2000). J. Acoust. Soc. Am. 107, 2631-2644] hypothesized that these templates have a temporal basis. Coincidences in the temporal fine-structure of neural spike trains, even in response to nonharmonic, stochastic stimuli, would be sufficient for the development of harmonic templates. The physiological plausibility of this hypothesis is tested. Responses to pure tones, low-pass noise, and broadband noise from auditory nerve fibers and brainstem "high-sync" neurons are studied. Responses to tones simulate the output of fibers with infinitely sharp filters: for these responses, harmonic structure in a coincidence matrix comparing pairs of spike trains is indeed found. However, harmonic template structure is not observed in coincidences across responses to broadband noise, which are obtained from nerve fibers or neurons with enhanced synchronization. Using a computer model based on that of Shamma and Klein, it is shown that harmonic templates only emerge when consecutive processing steps (cochlear filtering, lateral inhibition, and temporal enhancement) are implemented in extreme, physiologically implausible form. It is concluded that current physiological knowledge does not support the hypothesis of Shamma and Klein (2000).

Enhancement of phase-locking in rodents. II. An axonal recording study in chinchilla.

The trapezoid body (TB) contains axons of neurons residing in the anteroventral cochlear nucleus (AVCN) that provide excitatory and inhibitory inputs to the main monaural and binaural nuclei in the superior olivary complex (SOC). To understand the monaural and binaural response properties of neurons in the medial and lateral superior olive (MSO and LSO), it is important to characterize the temporal firing properties of these inputs. Because of its exceptional low-frequency hearing, the chinchilla (Chinchilla lanigera) is one of the widely used small animal models for studies of hearing. However, the characterization of the output of its ventral cochlear nucleus to the nuclei of the SOC is fragmentary. We obtained responses of TB axons to stimuli typically used in binaural studies and compared these responses to those of auditory nerve (AN) fibers, with a focus on temporal coding. We found enhancement of phase-locking and entrainment, i.e., the ability of a neuron to fire action potentials at a certain stimulus phase for nearly every stimulus period, in TB axons relative to AN fibers. Enhancement in phase-locking and entrainment are quantitatively more modest than in the cat but greater than in the gerbil. As in these species, these phenomena occur not only in low-frequency neurons stimulated at their characteristic frequency but also in neurons tuned to higher frequencies when stimulated with low-frequency tones, to which complex phase-locking behavior with multiple modes of firing per stimulus cycle is frequently observed.NEW & NOTEWORTHY The sensitivity of neurons to small time differences in sustained sounds to both ears is important for binaural hearing, and this sensitivity is critically dependent on phase-locking in the monaural pathways. Although studies in cat showed a marked improvement in phase-locking from the peripheral to the central auditory nervous system, the evidence in rodents is mixed. Here, we recorded from AN and TB of chinchilla and found temporal enhancement, though more limited than in cat.

Use of reverse noise to measure ongoing delay.

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 features and response. It is desirable to have such a measure within the analysis framework of coincidence counting. Single neuron responses were obtained, from 130 fibers in several tracts (auditory nerve, trapezoid body, lateral lemniscus), 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 were 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. Correlograms between forward- and reverse-noise responses show maxima at values consistent with latencies measured with other methods; the pattern of latencies with characteristic frequency, sound pressure level, and recording location was also consistent. At low characteristic frequencies, correlograms were well-predicted by reverse-correlation functions. We conclude that reverse noise provides an easy and reliable means to estimate latency of auditory nerve and brainstem neurons.

Matching 3D Facial Shape to Demographic Properties by Geometric Metric Learning: A Part-Based Approach.

Face recognition is a widely accepted biometric identifier, as the face contains a lot of information about the identity of a person. The goal of this study is to match the 3D face of an individual to a set of demographic properties (sex, age, BMI, and genomic background) that are extracted from unidentified genetic material. We introduce a triplet loss metric learner that compresses facial shape into a lower dimensional embedding while preserving information about the property of interest. The metric learner is trained for multiple facial segments to allow a global-to-local part-based analysis of the face. To learn directly from 3D mesh data, spiral convolutions are used along with a novel mesh-sampling scheme, which retains uniformly sampled points at different resolutions. The capacity of the model for establishing identity from facial shape against a list of probe demographics is evaluated by enrolling the embeddings for all properties into a support vector machine classifier or regressor and then combining them using a naive Bayes score fuser. Results obtained by a 10-fold cross-validation for biometric verification and identification show that part-based learning significantly improves the systems performance for both encoding with our geometric metric learner or with principal component analysis.

Mammalian octopus cells are direction selective to frequency sweeps by excitatory synaptic sequence detection.

Octopus 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 across-frequency coincidence detection but hinges on the amplitudes and activation sequence of auditory nerve inputs tuned to clusters of hot spot frequencies. A simple biophysical octopus cell model excited with real nerve spike trains recreates direction selectivity through interaction of intrinsic membrane conductances with the activation sequence of clustered excitatory 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.

In praise of adventitious sounds.

Study of the characteristics, neural processing, and behavioral effects of communication sounds are an important focus of hearing research. The goal of this paper is to bring attention to another, rather neglected class of sounds that are omnipresent and that are arguably at least equally important for the daily survival of many species and have been in the evolution of the mammalian auditory system. All terrestrial mammals produce adventitious sounds when they locomote. The handful of studies that examined the characteristics of such sounds suggests that high-frequency transients are an important component. Acoustic propagation of such sounds is limited in distance, particularly for sources and receivers on a vegetated ground plane. It follows that the presence of such sounds is an indication of a nearby animal, and that detection and localization of high-frequency transients is vital for both prey and predator. It is suggested that consideration of adventitious sounds is important in grasping the importance of auditory morphological and physiological features. As an illustration, a hypothesis on the relationship of one binaural brainstem circuit to adventitious sounds is briefly discussed.

Intrinsic mechanical sensitivity of mammalian auditory neurons as a contributor to sound-driven neural activity.

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 mouse, and chinchilla, AN are 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. Combining neurotransmission and mechanical sensation to control spike patterns gives the mammalian AN a secondary receptor role, an emerging theme in primary neuronal functions.

Bloodstain impact pattern Area of Origin estimation using least-squares angles: A HemoVision validation study.

Bloodstain impact pattern Area of Origin (AO) estimation is an important but time-consuming process in criminal investigations. HemoVision is a software package that automates and accelerates this process. To date, however, no study has been published that evaluates HemoVision's accuracy. Moreover, HemoVision relies on an automated variant of the tangent method to estimate a pattern's AO, even though the use of front-view projections has been shown to provide biased AO estimates. Therefore, the goal of this paper is twofold. First, a novel AO estimation method is proposed, whereby AO estimation is formulated as a least-squares optimisation problem that operates in three dimensions directly, eliminating the need for front view projections. Second, ten impact patterns with known AO coordinates at both 50 cm and 100 cm with respect to the target wall are created and used to compare the proposed approach's accuracy and robustness to the manual tangent method, HemoSpat, and HemoVision's automated tangent method. Results show that for impacts at 100 cm or less to the target wall, the proposed approach achieves the lowest average error of 17.29 cm with the least uncertainty, and that it performs significantly better than the manual tangent and automated tangent methods at a 5% significance level. Moreover, it is shown to achieve errors of less than 30 cm at these distances with just nine stains, whereas the automated tangent method requires a minimum of 16 stains to achieve the same average error.

Temporal Correlates to Monaural Edge Pitch in the Distribution of Interspike Interval Statistics in the Auditory Nerve.

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-pass (HP) or low-pass (LP) 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 (AN) 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 (CF). 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.

Glycinergic axonal inhibition subserves acute spatial sensitivity to sudden increases in sound intensity.

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.

Neural Mechanisms of Binaural Processing in the Auditory Brainstem.

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.

Early Binaural Hearing: The Comparison of Temporal Differences at the Two Ears.

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.

The upper frequency limit for the use of phase locking to code temporal fine structure in humans: A compilation of viewpoints.

The relative importance of neural temporal and place coding in auditory perception is still a matter of much debate. The current article is a compilation of viewpoints from leading auditory psychophysicists and physiologists regarding the upper frequency limit for the use of neural phase locking to code temporal fine structure in humans. While phase locking is used for binaural processing up to about 1500 Hz, there is disagreement regarding the use of monaural phase-locking information at higher frequencies. Estimates of the general upper limit proposed by the contributors range from 1500 to 10000 Hz. The arguments depend on whether or not phase locking is needed to explain psychophysical discrimination performance at frequencies above 1500 Hz, and whether or not the phase-locked neural representation is sufficiently robust at these frequencies to provide useable information. The contributors suggest key experiments that may help to resolve this issue, and experimental findings that may cause them to change their minds. This issue is of crucial importance to our understanding of the neural basis of auditory perception in general, and of pitch perception in particular.

Neural binaural sensitivity at high sound speeds: Single cell responses in cat midbrain to fast-changing interaural time differences of broadband sounds.

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.

The Calyx of Held: A Hypothesis on the Need for Reliable Timing in an Intensity-Difference Encoder.

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.

High-resolution frequency tuning but not temporal coding in the human cochlea.

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.

Principal cells of the brainstem's interaural sound level detector are temporal differentiators rather than integrators.

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.

Temporal effects in interaural and sequential level difference perception.

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.

Signatures of Somatic Inhibition and Dendritic Excitation in Auditory Brainstem Field Potentials.

Extracellular voltage recordings (Ve ; field potentials) provide an accessible view of in vivo neural 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-evoked Ve can resemble, strikingly, Ve generated 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-like Ve patterns in sustained responses to monaural tones with frequencies >∼1000 Hz (Goldwyn et al., 2014). We have observed, however, that Ve patterns 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 of Ve responses 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 to Ve responses). 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 from Ve patterns we provide a new perspective on MSO physiology.SIGNIFICANCE STATEMENT Extracellular 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.

Enhancement of phase-locking in rodents. I. An axonal recording study in gerbil.

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.