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1.  Resolution of interaural time differences in the avian sound localization circuit—a modeling study 
Interaural time differences (ITDs) are a main cue for sound localization and sound segregation. A dominant model to study ITD detection is the sound localization circuitry in the avian auditory brainstem. Neurons in nucleus laminaris (NL) receive auditory information from both ears via the avian cochlear nucleus magnocellularis (NM) and compare the relative timing of these inputs. Timing of these inputs is crucial, as ITDs in the microsecond range must be discriminated and encoded. We modeled ITD sensitivity of single NL neurons based on previously published data and determined the minimum resolvable ITD for neurons in NL. The minimum resolvable ITD is too large to allow for discrimination by single NL neurons of naturally occurring ITDs for very low frequencies. For high frequency NL neurons (>1 kHz) our calculated ITD resolutions fall well within the natural range of ITDs and approach values of below 10 μs. We show that different parts of the ITD tuning function offer different resolution in ITD coding, suggesting that information derived from both parts may be used for downstream processing. A place code may be used for sound location at frequencies above 500 Hz, but our data suggest the slope of the ITD tuning curve ought to be used for ITD discrimination by single NL neurons at the lowest frequencies. Our results provide an important measure of the necessary temporal window of binaural inputs for future studies on the mechanisms and development of neuronal computation of temporally precise information in this important system. In particular, our data establish the temporal precision needed for conduction time regulation along NM axons.
doi:10.3389/fncom.2014.00099
PMCID: PMC4143899  PMID: 25206329
sound localization; interaural time differences; avian brainstem; nucleus laminaris; ITD resolution
2.  Asymmetric Excitatory Synaptic Dynamics Underlie Interaural Time Difference Processing in the Auditory System 
PLoS Biology  2010;8(6):e1000406.
In order to localize sounds in the environment, the auditory system detects and encodes differences in signals between each ear. The exquisite sensitivity of auditory brain stem neurons to the differences in rise time of the excitation signals from the two ears allows for neuronal encoding of microsecond interaural time differences.
Low-frequency sound localization depends on the neural computation of interaural time differences (ITD) and relies on neurons in the auditory brain stem that integrate synaptic inputs delivered by the ipsi- and contralateral auditory pathways that start at the two ears. The first auditory neurons that respond selectively to ITD are found in the medial superior olivary nucleus (MSO). We identified a new mechanism for ITD coding using a brain slice preparation that preserves the binaural inputs to the MSO. There was an internal latency difference for the two excitatory pathways that would, if left uncompensated, position the ITD response function too far outside the physiological range to be useful for estimating ITD. We demonstrate, and support using a biophysically based computational model, that a bilateral asymmetry in excitatory post-synaptic potential (EPSP) slopes provides a robust compensatory delay mechanism due to differential activation of low threshold potassium conductance on these inputs and permits MSO neurons to encode physiological ITDs. We suggest, more generally, that the dependence of spike probability on rate of depolarization, as in these auditory neurons, provides a mechanism for temporal order discrimination between EPSPs.
Author Summary
Animals can locate the source of a sound by detecting microsecond differences in the arrival time of sound at the two ears. Neurons encoding these interaural time differences (ITDs) receive an excitatory synaptic input from each ear. They can perform a microsecond computation with excitatory synapses that have millisecond time scale because they are extremely sensitive to the input's “rise time,” the time taken to reach the peak of the synaptic input. Current theories assume that the biophysical properties of the two inputs are identical. We challenge this assumption by showing that the rise times of excitatory synaptic potentials driven by the ipsilateral ear are faster than those driven by the contralateral ear. Further, we present a computational model demonstrating that this disparity in rise times, together with the neurons' sensitivity to excitation's rise time, can endow ITD-encoding with microsecond resolution in the biologically relevant range. Our analysis also resolves a timing mismatch. The difference between contralateral and ipsilateral latencies is substantially larger than the relevant ITD range. We show how the rise time disparity compensates for this mismatch. Generalizing, we suggest that phasic-firing neurons—those that respond to rapidly, but not to slowly, changing stimuli—are selective to the temporal ordering of brief inputs. In a coincidence-detection computation the neuron will respond more robustly when a faster input leads a slower one, even if the inputs are brief and have similar amplitudes.
doi:10.1371/journal.pbio.1000406
PMCID: PMC2893945  PMID: 20613857
3.  Responses of Auditory Nerve and Anteroventral Cochlear Nucleus Fibers to Broadband and Narrowband Noise: Implications for the Sensitivity to Interaural Delays 
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.
doi:10.1007/s10162-011-0268-1
PMCID: PMC3123442  PMID: 21567250
coincidence detection; interaural time difference; discrimination; binaural; sound localization
4.  Responses of Auditory Nerve and Anteroventral Cochlear Nucleus Fibers to Broadband and Narrowband Noise: Implications for the Sensitivity to Interaural Delays 
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.
doi:10.1007/s10162-011-0268-1
PMCID: PMC3123442  PMID: 21567250
coincidence detection; interaural time difference; discrimination; binaural; sound localization
5.  Mechanisms for Adjusting Interaural Time Differences to Achieve Binaural Coincidence Detection 
Understanding binaural perception requires detailed analyses of the neural circuitry responsible for the computation of interaural time differences (ITDs). In the avian brainstem, this circuit consists of internal axonal delay lines innervating an array of coincidence detector neurons that encode external ITDs. Nucleus magnocellularis (NM) neurons project to the dorsal dendritic field of the ipsilateral nucleus laminaris (NL) and to the ventral field of the contralateral NL. Contralateral-projecting axons form a delay line system along a band of NL neurons. Binaural acoustic signals in the form of phase-locked action potentials from NM cells arrive at NL and establish a topographic map of sound source location along the azimuth. These pathways are assumed to represent a circuit similar to the Jeffress model of sound localization, establishing a place code along an isofrequency contour of NL. Three-dimensional measurements of axon lengths reveal major discrepancies with the current model; the temporal offset based on conduction length alone makes encoding of physiological ITDs impossible. However, axon diameter and distances between Nodes of Ranvier also influence signal propagation times along an axon. Our measurements of these parameters reveal that diameter and internode distance can compensate for the temporal offset inferred from axon lengths alone. Together with other recent studies these unexpected results should inspire new thinking on the cellular biology, evolution and plasticity of the circuitry underlying low frequency sound localization in both birds and mammals.
doi:10.1523/JNEUROSCI.3464-09.2010
PMCID: PMC2822993  PMID: 20053889
Sound; Localization; Auditory; Brainstem; Axon; Conduction; Velocity
6.  Bilateral matching of frequency tuning in neural cross-correlators of the owl 
Biological cybernetics  2009;100(6):521-531.
Sound localization requires comparison between the inputs to the left and right ears. One important aspect of this comparison is the differences in arrival time to each side, also called interaural time difference (ITD).A prevalent model of ITD detection, consisting of delay lines and coincidence-detector neurons, was proposed by Jeffress (J Comp Physiol Psychol 41:35–39, 1948). As an extension of the Jeffress model, the process of detecting and encoding ITD has been compared to an effective cross-correlation between the input signals to the two ears. Because the cochlea performs a spectrotemporal decomposition of the input signal, this cross-correlation takes place over narrow frequency bands. Since the cochlear tonotopy is arranged in series, sounds of different frequencies will trigger neural activity with different temporal delays. Thus, the matching of the frequency tuning of the left and right inputs to the cross-correlator units becomes a ‘timing’ issue. These properties of auditory transduction gave theoretical support to an alternative model of ITD-detection based on a bilateral mismatch in frequency tuning, called the ‘stereausis’ model. Here we first review the current literature on the owl’s nucleus laminaris, the equivalent to the medial superior olive of mammals, which is the site where ITD is detected. Subsequently, we use reverse correlation analysis and stimulation with uncorrelated sounds to extract the effective monaural inputs to the cross-correlator neurons. We show that when the left and right inputs to the cross-correlators are defined in this manner, the computation performed by coincidence-detector neurons satisfies conditions of cross-correlation theory. We also show that the spectra of left and right inputs are matched, which is consistent with predictions made by the classic model put forth by Jeffress.
doi:10.1007/s00422-009-0312-y
PMCID: PMC2719282  PMID: 19396457
Barn owl; Interaural time difference; Cross-correlation; Coincidence detection; Cochlear delays; Sound localization; Nucleus laminaris; Stereausis
7.  Neuronal specializations for the processing of interaural difference cues in the chick 
Sound information is encoded as a series of spikes of the auditory nerve fibers (ANFs), and then transmitted to the brainstem auditory nuclei. Features such as timing and level are extracted from ANFs activity and further processed as the interaural time difference (ITD) and the interaural level difference (ILD), respectively. These two interaural difference cues are used for sound source localization by behaving animals. Both cues depend on the head size of animals and are extremely small, requiring specialized neural properties in order to process these cues with precision. Moreover, the sound level and timing cues are not processed independently from one another. Neurons in the nucleus angularis (NA) are specialized for coding sound level information in birds and the ILD is processed in the posterior part of the dorsal lateral lemniscus nucleus (LLDp). Processing of ILD is affected by the phase difference of binaural sound. Temporal features of sound are encoded in the pathway starting in nucleus magnocellularis (NM), and ITD is processed in the nucleus laminaris (NL). In this pathway a variety of specializations are found in synapse morphology, neuronal excitability, distribution of ion channels and receptors along the tonotopic axis, which reduces spike timing fluctuation in the ANFs-NM synapse, and imparts precise and stable ITD processing to the NL. Moreover, the contrast of ITD processing in NL is enhanced over a wide range of sound level through the activity of GABAergic inhibitory systems from both the superior olivary nucleus (SON) and local inhibitory neurons that follow monosynaptic to NM activity.
doi:10.3389/fncir.2014.00047
PMCID: PMC4023016  PMID: 24847212
brainstem auditory nucleus; interaural difference cues; SON; tonic inhibition; phasic inhibition
8.  Cross-Correlation in the Auditory Coincidence Detectors of Owls 
Interaural time difference (ITD) plays a central role in many auditory functions, most importantly in sound localization. The classic model for how ITD is computed was put forth by Jeffress (1948). One of the predictions of the Jeffress model is that the neurons that compute ITD should behave as cross-correlators. Whereas cross-correlation-like properties of the ITD-computing neurons have been reported, attempts to show that the shape of the ITD response function is determined by the spectral tuning of the neuron, a core prediction of cross-correlation, have been unsuccessful. Using reverse correlation analysis, we demonstrate in the barn owl that the relationship between the spectral tuning and the ITD response of the ITD-computing neurons is that predicted by cross-correlation. Moreover, we show that a model of coincidence detector responses derived from responses to binaurally uncorrelated noise is consistent with binaural interaction based on cross-correlation. These results are thus consistent with one of the key tenets of the Jeffress model. Our work sets forth both the methodology to answer whether cross-correlation describes coincidence detector responses and a demonstration that in the barn owl, the result is that expected by theory.
doi:10.1523/JNEUROSCI.1969-08.2008
PMCID: PMC2637928  PMID: 18685035
barn owl; interaural time difference; cross-correlation; coincidence detection; sound localization; nucleus laminaris
9.  Biophysical basis of the sound analog membrane potential that underlies coincidence detection in the barn owl 
Interaural time difference (ITD), or the difference in timing of a sound wave arriving at the two ears, is a fundamental cue for sound localization. A wide variety of animals have specialized neural circuits dedicated to the computation of ITDs. In the avian auditory brainstem, ITDs are encoded as the spike rates in the coincidence detector neurons of the nucleus laminaris (NL). NL neurons compare the binaural phase-locked inputs from the axons of ipsi- and contralateral nucleus magnocellularis (NM) neurons. Intracellular recordings from the barn owl's NL in vivo showed that tonal stimuli induce oscillations in the membrane potential. Since this oscillatory potential resembled the stimulus sound waveform, it was named the sound analog potential (Funabiki et al., 2011). Previous modeling studies suggested that a convergence of phase-locked spikes from NM leads to an oscillatory membrane potential in NL, but how presynaptic, synaptic, and postsynaptic factors affect the formation of the sound analog potential remains to be investigated. In the accompanying paper, we derive analytical relations between these parameters and the signal and noise components of the oscillation. In this paper, we focus on the effects of the number of presynaptic NM fibers, the mean firing rate of these fibers, their average degree of phase-locking, and the synaptic time scale. Theoretical analyses and numerical simulations show that, provided the total synaptic input is kept constant, changes in the number and spike rate of NM fibers alter the ITD-independent noise whereas the degree of phase-locking is linearly converted to the ITD-dependent signal component of the sound analog potential. The synaptic time constant affects the signal more prominently than the noise, making faster synaptic input more suitable for effective ITD computation.
doi:10.3389/fncom.2013.00102
PMCID: PMC3821004  PMID: 24265615
phase-locking; sound localization; auditory brainstem; periodic signals; oscillation; owl
10.  Glycinergic inhibition tunes coincidence detection in the auditory brainstem 
Nature Communications  2014;5:3790.
Neurons in the medial superior olive (MSO) detect microsecond differences in the arrival time of sounds between the ears (interaural time differences or ITDs), a crucial binaural cue for sound localization. Synaptic inhibition has been implicated in tuning ITD sensitivity, but the cellular mechanisms underlying its influence on coincidence detection are debated. Here we determine the impact of inhibition on coincidence detection in adult Mongolian gerbil MSO brain slices by testing precise temporal integration of measured synaptic responses using conductance-clamp. We find that inhibition dynamically shifts the peak timing of excitation, depending on its relative arrival time, which in turn modulates the timing of best coincidence detection. Inhibitory control of coincidence detection timing is consistent with the diversity of ITD functions observed in vivo and is robust under physiologically relevant conditions. Our results provide strong evidence that temporal interactions between excitation and inhibition on microsecond timescales are critical for binaural processing.
Coincidence detector neurons in the mammalian brainstem encode interaural time differences (ITDs) that are implicated in auditory processing. Myoga et al. study a previously developed neuronal model and find that inhibition is crucial for sound localization, but more dynamically than previously thought.
doi:10.1038/ncomms4790
PMCID: PMC4024823  PMID: 24804642
11.  Axonal branching patterns as sources of delay in the mammalian auditory brainstem: a reexamination 
In models of temporal processing, time delays incurred by axonal propagation of action potentials play a prominent role. A preeminent model of temporal processing in audition is the binaural model of Jeffress (1948), which has dominated theories regarding our acute sensitivity to interaural time differences (ITDs). In Jeffress’ model a binaural cell is maximally active when the ITD is compensated by an internal delay, which brings the inputs from left and right ears in coincidence, and which would arise from axonal branching patterns of monaural input fibers. By arranging these patterns in systematic and opposite ways for the ipsi- and contralateral inputs, a range of length differences, and thereby of internal delays, is created so that ITD is transformed into a spatial activation pattern along the binaural nucleus. We reanalyze single, labeled and physiologically characterized, axons of spherical bushy cells of the cat anteroventral cochlear nucleus (AVCN) which project to binaural coincidence detectors in the medial superior olive (MSO). The reconstructions largely confirm the observations of two previous reports, but several features are observed which are inconsistent with Jeffress’ model. We found that ipsilateral projections can also form a caudally-directed delay line pattern, which would counteract delays incurred by caudally-directed contralateral projections. Comparisons of estimated axonal delays with binaural physiological data indicate that the suggestive anatomical patterns cannot account for the frequency-dependent distribution of best delays in the cat. Surprisingly, the tonotopic distribution of the afferents endings indicate that low CFs are under- rather than overrepresented in the MSO.
doi:10.1523/JNEUROSCI.5175-10.2011
PMCID: PMC3157295  PMID: 21414923
12.  Detection of Interaural Time Differences in the Alligator 
The auditory systems of birds and mammals use timing information from each ear to detect interaural time difference (ITD). To determine whether the Jeffress-type algorithms that underlie sensitivity to ITD in birds are an evolutionarily stable strategy, we recorded from the auditory nuclei of crocodilians, who are the sister group to the birds. In alligators, precisely timed spikes in the first-order nucleus magnocellularis (NM) encode the timing of sounds, and NM neurons project to neurons in the nucleus laminaris (NL) that detect interaural time differences. In vivo recordings from NL neurons show that the arrival time of phase-locked spikes differs between the ipsilateral and contralateral inputs. When this disparity is nullified by their best ITD, the neurons respond maximally. Thus NL neurons act as coincidence detectors. A biologically detailed model of NL with alligator parameters discriminated ITDs up to 1 kHz. The range of best ITDs represented in NL was much larger than in birds, however, and extended from 0 to 1000 μs contralateral, with a median ITD of 450 μs. Thus, crocodilians and birds employ similar algorithms for ITD detection, although crocodilians have larger heads.
doi:10.1523/JNEUROSCI.6154-08.2009
PMCID: PMC3170862  PMID: 19553438
13.  The Neural Code for Auditory Space Depends on Sound Frequency and Head Size in an Optimal Manner 
PLoS ONE  2014;9(11):e108154.
A major cue to the location of a sound source is the interaural time difference (ITD)–the difference in sound arrival time at the two ears. The neural representation of this auditory cue is unresolved. The classic model of ITD coding, dominant for a half-century, posits that the distribution of best ITDs (the ITD evoking a neuron’s maximal response) is unimodal and largely within the range of ITDs permitted by head-size. This is often interpreted as a place code for source location. An alternative model, based on neurophysiology in small mammals, posits a bimodal distribution of best ITDs with exquisite sensitivity to ITDs generated by means of relative firing rates between the distributions. Recently, an optimal-coding model was proposed, unifying the disparate features of these two models under the framework of efficient coding by neural populations. The optimal-coding model predicts that distributions of best ITDs depend on head size and sound frequency: for high frequencies and large heads it resembles the classic model, for low frequencies and small head sizes it resembles the bimodal model. The optimal-coding model makes key, yet unobserved, predictions: for many species, including humans, both forms of neural representation are employed, depending on sound frequency. Furthermore, novel representations are predicted for intermediate frequencies. Here, we examine these predictions in neurophysiological data from five mammalian species: macaque, guinea pig, cat, gerbil and kangaroo rat. We present the first evidence supporting these untested predictions, and demonstrate that different representations appear to be employed at different sound frequencies in the same species.
doi:10.1371/journal.pone.0108154
PMCID: PMC4220907  PMID: 25372405
14.  Dichotic sound localization properties of duration-tuned neurons in the inferior colliculus of the big brown bat 
Electrophysiological studies on duration-tuned neurons (DTNs) from the mammalian auditory midbrain have typically evoked spiking responses from these cells using monaural or free-field acoustic stimulation focused on the contralateral ear, with fewer studies devoted to examining the electrophysiological properties of duration tuning using binaural stimulation. Because the inferior colliculus (IC) receives convergent inputs from lower brainstem auditory nuclei that process sounds from each ear, many midbrain neurons have responses shaped by binaural interactions and are selective to binaural cues important for sound localization. In this study, we used dichotic stimulation to vary interaural level difference (ILD) and interaural time difference (ITD) acoustic cues and explore the binaural interactions and response properties of DTNs and non-DTNs from the IC of the big brown bat (Eptesicus fuscus). Our results reveal that both DTNs and non-DTNs can have responses selective to binaural stimulation, with a majority of IC neurons showing some type of ILD selectivity, fewer cells showing ITD selectivity, and a number of neurons showing both ILD and ITD selectivity. This study provides the first demonstration that the temporally selective responses of DTNs from the vertebrate auditory midbrain can be selective to binaural cues used for sound localization in addition to having spiking responses that are selective for stimulus frequency, amplitude, and duration.
doi:10.3389/fphys.2014.00215
PMCID: PMC4050336  PMID: 24959149
auditory neurophysiology; binaural hearing; dichotic stimulation; Eptesicus fuscus; sound localization
15.  Neural coding of ITD with bilateral cochlear implants: Effects of congenital deafness 
Human bilateral cochlear implant users do poorly on tasks involving interaural time differences (ITD), a cue which provides important benefits to the normal hearing, especially in challenging acoustic environments. Yet the precision of neural ITD coding in acutely-deafened, bilaterally-implanted cats is essentially normal (Smith and Delgutte, J. Neurosci. 27:6740–6750). One explanation for this discrepancy is that the extended periods of binaural deprivation typically experienced by cochlear implant users degrades neural ITD sensitivity, either by impeding normal maturation of the neural circuitry or by altering it later in life. To test this hypothesis, we recorded from single units in inferior colliculus (IC) of two groups of bilaterally-implanted, anesthetized cats that contrast maximally in binaural experience: acutely-deafened cats, which had normal binaural hearing until experimentation, and congenitally deaf white cats, which received no auditory inputs until the experiment. Rate responses of only half as many neurons showed significant ITD sensitivity to low-rate pulse trains in congenitally deaf cats compared to acutely deafened cats. For neurons that were ITD sensitive, ITD tuning was broader and best ITDs were more variable in congenitally deaf cats, leading to poorer ITD coding within the naturally-occurring range. A signal detection model constrained by the observed physiology supports the idea that the degraded neural ITD coding resulting from deprivation of binaural experience contributes to poor ITD discrimination by human implantees.
doi:10.1523/JNEUROSCI.3213-10.2010
PMCID: PMC3025489  PMID: 20962228
binaural hearing; electric stimulation; congenital deafness; cochlear implant; inferior colliculus; ITD
16.  Preservation of Spectrotemporal Tuning Between the Nucleus Laminaris and the Inferior Colliculus of the Barn Owl 
Journal of neurophysiology  2007;97(5):3544-3553.
Performing sound recognition is a task that requires an encoding of the time-varying spectral structure of the auditory stimulus. Similarly, computation of the interaural time difference (ITD) requires knowledge of the precise timing of the stimulus. Consistent with this, low-level nuclei of birds and mammals implicated in ITD processing encode the ongoing phase of a stimulus. However, the brain areas that follow the binaural convergence for the computation of ITD show a reduced capacity for phase locking. In addition, we have shown that in the barn owl there is a pooling of ITD-responsive neurons to improve the reliability of ITD coding. Here we demonstrate that despite two stages of convergence and an effective loss of phase information, the auditory system of the anesthetized barn owl displays a graceful transition to an envelope coding that preserves the spectrotemporal information throughout the ITD pathway to the neurons of the core of the central nucleus of the inferior colliculus.
doi:10.1152/jn.01162.2006
PMCID: PMC2532515  PMID: 17314241
17.  Interaural timing difference circuits in the auditory brainstem of the emu (Dromaius novaehollandiae) 
In the auditory system, precise encoding of temporal information is critical for sound localization, a task with direct behavioral relevance. Interaural timing differences are computed using axonal delay lines and cellular coincidence detectors in nucleus laminaris (NL). We present morphological and physiological data on the timing circuits in the emu, Dromaius novaehollandiae, and compare these results with those from the barn owl (Tyto alba) and the domestic chick (Gallus gallus). Emu NL was composed of a compact monolayer of bitufted neurons whose two thick primary dendrites were oriented dorsoventrally. They showed a gradient in dendritic length along the presumed tonotopic axis. The NL and nucleus magnocellularis (NM) neurons were strongly immunoreactive for parvalbumin, a calcium-binding protein. Antibodies against synaptic vesicle protein 2 and glutamic acid decarboxlyase revealed that excitatory synapses terminated heavily on the dendritic tufts, while inhibitory terminals were distributed more uniformly. Physiological recordings from brainstem slices demonstrated contralateral delay lines from NM to NL. During whole-cell patch-clamp recordings, NM and NL neurons fired single spikes and were doubly-rectifying. NL and NM neurons had input resistances of 30.0 ± 19.9 MΩ and 49.0 ± 25.6 MΩ, respectively, and membrane time constants of 12.8 ± 3.8 ms and 3.9 ± 0.2 ms. These results provide further support for the Jeffress model for sound localization in birds. The emu timing circuits showed the ancestral (plesiomorphic) pattern in their anatomy and physiology, while differences in dendritic structure compared to chick and owl may indicate specialization for encoding ITDs at low best frequencies.
doi:10.1002/cne.20862
PMCID: PMC2948976  PMID: 16435285
avian; nucleus laminaris; nucleus magnocellularis; dendrite; coincidence detection; sound localization
18.  Maps of interaural time difference in the chicken’s brainstem nucleus laminaris 
Biological cybernetics  2008;98(6):541-559.
Animals, including humans, use interaural time differences (ITDs) that arise from different sound path lengths to the two ears as a cue of horizontal sound source location. The nature of the neural code for ITD is still controversial. Current models differentiate between two population codes: either a map-like rate-place code of ITD along an array of neurons, consistent with a large body of data in the barn owl, or a population rate code, consistent with data from small mammals. Recently, it was proposed that these different codes reflect optimal coding strategies that depend on head size and sound frequency. The chicken makes an excellent test case of this proposal because its physical pre-requisites are similar to small mammals, yet it shares a more recent common ancestry with the owl. We show here that, like in the barn owl, the brainstem nucleus laminaris in mature chickens displayed the major features of a place code of ITD. ITD was topographically represented in the maximal responses of neurons along each isofrequency band, covering approximately the contralateral acoustic hemisphere. Furthermore, the represented ITD range appeared to change with frequency, consistent with a pressure gradient receiver mechanism in the avian middle ear. At very low frequencies, below400 Hz, maximal neural responses were symmetrically distributed around zero ITD and it remained unclear whether there was a topographic representation. These findings do not agree with the above predictions for optimal coding and thus revive the discussion as to what determines the neural coding strategies for ITDs.
doi:10.1007/s00422-008-0220-6
PMCID: PMC3170859  PMID: 18491165
Auditory; Hearing; Sound localization; Sensory
19.  Mutation in the Kv3.3 Voltage-Gated Potassium Channel Causing Spinocerebellar Ataxia 13 Disrupts Sound-Localization Mechanisms 
PLoS ONE  2013;8(10):e76749.
Normal sound localization requires precise comparisons of sound timing and pressure levels between the two ears. The primary localization cues are interaural time differences, ITD, and interaural level differences, ILD. Voltage-gated potassium channels, including Kv3.3, are highly expressed in the auditory brainstem and are thought to underlie the exquisite temporal precision and rapid spike rates that characterize brainstem binaural pathways. An autosomal dominant mutation in the gene encoding Kv3.3 has been demonstrated in a large Filipino kindred manifesting as spinocerebellar ataxia type 13 (SCA13). This kindred provides a rare opportunity to test in vivo the importance of a specific channel subunit for human hearing. Here, we demonstrate psychophysically that individuals with the mutant allele exhibit profound deficits in both ITD and ILD sensitivity, despite showing no obvious impairment in pure-tone sensitivity with either ear. Surprisingly, several individuals exhibited the auditory deficits even though they were pre-symptomatic for SCA13. We would expect that impairments of binaural processing as great as those observed in this family would result in prominent deficits in localization of sound sources and in loss of the "spatial release from masking" that aids in understanding speech in the presence of competing sounds.
doi:10.1371/journal.pone.0076749
PMCID: PMC3792041  PMID: 24116147
20.  Neural and Behavioral Sensitivity to Interaural Time Differences Using Amplitude Modulated Tones with Mismatched Carrier Frequencies 
Bilateral cochlear implantation is intended to provide the advantages of binaural hearing, including sound localization and better speech recognition in noise. In most modern implants, temporal information is carried by the envelope of pulsatile stimulation, and thresholds to interaural time differences (ITDs) are generally high compared to those obtained in normal hearing observers. One factor thought to influence ITD sensitivity is the overlap of neural populations stimulated on each side. The present study investigated the effects of acoustically stimulating bilaterally mismatched neural populations in two related paradigms: rabbit neural recordings and human psychophysical testing. The neural coding of interaural envelope timing information was measured in recordings from neurons in the inferior colliculus of the unanesthetized rabbit. Binaural beat stimuli with a 1-Hz difference in modulation frequency were presented at the best modulation frequency and intensity as the carrier frequencies at each ear were varied. Some neurons encoded envelope ITDs with carrier frequency mismatches as great as several octaves. The synchronization strength was typically nonmonotonically related to intensity. Psychophysical data showed that human listeners could also make use of binaural envelope cues for carrier mismatches of up to 2–3 octaves. Thus, the physiological and psychophysical data were broadly consistent, and suggest that bilateral cochlear implants should provide information sufficient to detect envelope ITDs even in the face of bilateral mismatch in the neural populations responding to stimulation. However, the strongly nonmonotonic synchronization to envelope ITDs suggests that the limited dynamic range with electrical stimulation may be an important consideration for ITD encoding.
doi:10.1007/s10162-007-0088-5
PMCID: PMC2538436  PMID: 17657543
sound localization; binaural; inferior colliculus; psychophysics
21.  Adaptation in Sound Localization Processing Induced by Interaural Time Difference in Amplitude Envelope at High Frequencies 
PLoS ONE  2012;7(7):e41328.
Background
When a second sound follows a long first sound, its location appears to be perceived away from the first one (the localization/lateralization aftereffect). This aftereffect has often been considered to reflect an efficient neural coding of sound locations in the auditory system. To understand determinants of the localization aftereffect, the current study examined whether it is induced by an interaural temporal difference (ITD) in the amplitude envelope of high frequency transposed tones (over 2 kHz), which is known to function as a sound localization cue.
Methodology/Principal Findings
In Experiment 1, participants were required to adjust the position of a pointer to the perceived location of test stimuli before and after adaptation. Test and adapter stimuli were amplitude modulated (AM) sounds presented at high frequencies and their positional differences were manipulated solely by the envelope ITD. Results showed that the adapter's ITD systematically affected the perceived position of test sounds to the directions expected from the localization/lateralization aftereffect when the adapter was presented at ±600 µs ITD; a corresponding significant effect was not observed for a 0 µs ITD adapter. In Experiment 2, the observed adapter effect was confirmed using a forced-choice task. It was also found that adaptation to the AM sounds at high frequencies did not significantly change the perceived position of pure-tone test stimuli in the low frequency region (128 and 256 Hz).
Conclusions/Significance
The findings in the current study indicate that ITD in the envelope at high frequencies induces the localization aftereffect. This suggests that ITD in the high frequency region is involved in adaptive plasticity of auditory localization processing.
doi:10.1371/journal.pone.0041328
PMCID: PMC3407190  PMID: 22848464
22.  Congenital and Prolonged Adult-Onset Deafness Cause Distinct Degradations in Neural ITD Coding with Bilateral Cochlear Implants 
Bilateral cochlear implant (CI) users perform poorly on tasks involving interaural time differences (ITD), which are critical for sound localization and speech reception in noise by normal-hearing listeners. ITD perception with bilateral CI is influenced by age at onset of deafness and duration of deafness. We previously showed that ITD coding in the auditory midbrain is degraded in congenitally deaf white cats (DWC) compared to acutely deafened cats (ADC) with normal auditory development (Hancock et al., J. Neurosci, 30:14068). To determine the relative importance of early onset of deafness and prolonged duration of deafness for abnormal ITD coding in DWC, we recorded from single units in the inferior colliculus of cats deafened as adults 6 months prior to experimentation (long-term deafened cats, LTDC) and compared neural ITD coding between the three deafness models. The incidence of ITD-sensitive neurons was similar in both groups with normal auditory development (LTDC and ADC), but significantly diminished in DWC. In contrast, both groups that experienced prolonged deafness (LTDC and DWC) had broad distributions of best ITDs around the midline, unlike the more focused distributions biased toward contralateral-leading ITDs present in both ADC and normal-hearing animals. The lack of contralateral bias in LTDC and DWC results in reduced sensitivity to changes in ITD within the natural range. The finding that early onset of deafness more severely degrades neural ITD coding than prolonged duration of deafness argues for the importance of fitting deaf children with sound processors that provide reliable ITD cues at an early age.
doi:10.1007/s10162-013-0380-5
PMCID: PMC3642270  PMID: 23462803
binaural hearing; congenital deafness; inferior colliculus; cochlear implants; ITD
23.  Responses to Interaural Time Delay in Human Cortex 
Journal of Neurophysiology  2008;100(5):2712-2718.
Humans use differences in the timing of sounds at the two ears to determine the location of a sound source. Various models have been posited for the neural representation of these interaural time differences (ITDs). These models make opposing predictions about the lateralization of ITD processing in the human brain. The weighted-image model predicts that sounds leading in time at one ear activate maximally the opposite brain hemisphere for all values of ITD. In contrast, the π-limit model assumes that ITDs beyond half the period of the stimulus center frequency are not explicitly encoded in the brain and that such “long” ITDs activate maximally the side of the brain to which the sound is heard. A previous neuroimaging study revealed activity in the human inferior colliculus consistent with the π-limit. Here we show that cortical responses to sounds with ITDs within the π-limit are in line with the predictions of both models. However, contrary to the immediate predictions of both models, neural activation is bilateral for “long” ITDs, despite these being perceived as clearly lateralized. Furthermore, processing of long ITDs leads to higher activation in cortex than processing of short ITDs. These data show that coding of ITD in cortex is fundamentally different from coding of ITD in the brain stem. We discuss these results in the context of the two models.
doi:10.1152/jn.90210.2008
PMCID: PMC2585401  PMID: 18799604
24.  Optical Imaging of Interaural Time Difference Representation in Rat Auditory Cortex 
We used in vivo voltage-sensitive dye optical imaging to examine the cortical representation of interaural time difference (ITD), which is believed to be involved in sound source localization. We found that acoustic stimuli with dissimilar ITD activate various localized domains in the auditory cortex. The main loci of the activation pattern shift up to 1 mm during the first 40 ms of the response period. We suppose that some of the neurons in each pool are sensitive to the definite ITD and involved in the transduction of information about sound source localization, based on the ITD. This assumption gives a reasonable fit to the Jeffress model in which the neural network calculates the ITD to define the direction of the sound source. Such calculation forms the basis for the cortex's ability to detect the azimuth of the sound source.
doi:10.3389/neuro.16.002.2009
PMCID: PMC2654020  PMID: 19277218
auditory cortex; interaural time difference; optical imaging; voltage-sensitive dye
25.  Sensitivity to Interaural Time Differences in the Inferior Colliculus with Bilateral Cochlear Implants 
Bilateral cochlear implantation attempts to increase performance over a monaural prosthesis by harnessing the binaural processing of the auditory system. Although many bilaterally implanted human subjects discriminate interaural time differences (ITDs), a major cue for sound localization and signal detection in noise, their performance is typically poorer than that of normal-hearing listeners. We developed an animal model of bilateral cochlear implantation to study neural ITD sensitivity for trains of electric current pulses delivered via bilaterally implanted intracochlear electrodes. We found that a majority of single units in the inferior colliculus of acutely deafened, anesthetized cats are sensitive to ITD and that electric ITD tuning is as sharp as found for acoustic stimulation with broadband noise in normal-hearing animals. However, the sharpness and shape of ITD tuning often depended strongly on stimulus intensity; some neurons had dynamic ranges of ITD sensitivity as low as 1 dB. We also found that neural ITD sensitivity was best at pulse rates below 100 Hz and decreased with increasing pulse rate. This rate limitation parallels behavioral ITD discrimination in bilaterally implanted individuals. The sharp neural ITD sensitivity found with electric stimulation at the appropriate intensity is encouraging for the prospect of restoring the functional benefits of binaural hearing in bilaterally implanted human subjects and suggests that neural plasticity resulting from previous deafness and deprivation of binaural experience may play a role in the poor ITD discrimination with current bilateral implants.
doi:10.1523/JNEUROSCI.0052-07.2007
PMCID: PMC2041852  PMID: 17581961
binaural hearing; electric stimulation; neural prosthesis; cochlear implant; inferior colliculus; ITD

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